JP2003055326A - Biaryl compound, method for producing the same and agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine having activities for increasing a low-density lipoprotein (LDL) receptor, and useful as an agent for reducing lipid in blood or the like. SOLUTION: The compound represented by the formula [wherein, A-ring and B-ring are each a 5- or 6-membered aromatic ring which may be substituted; R<1> and R<2> are each a hydrogen atom, a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted; X<1> , X<2> , X<3> and X<4> are each a bond or a divalent hydrocarbon group which may be substituted; Y is -NR<3> -CO-, -CO-NR<3> -, -NR<3> -SO2 -, -SO2 -NR<3> -, -NR<3> -CH2 - (R<3> is a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted) or the like; Z is -CO-NH-, -CS-NH, -CO- or -SO2 -; Ar is a cyclic hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted].

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel biaryl derivative having excellent properties as a medicine, a method for producing the same, and an agent containing the same.

[0002]

BACKGROUND OF THE INVENTION A number of epidemiological studies have revealed that hypercholesterolemia is a major risk factor for arteriosclerotic diseases such as myocardial infarction, angina, and cerebral infarction as well as hypertension and smoking. .. Therefore, proper control of blood cholesterol level is extremely important for the prevention or treatment of arteriosclerotic diseases including ischemic heart disease. Drugs that reduce blood cholesterol levels include cholestyramine (Cholestyramine) and cholestipol (Colestol).
ipol) and the like that trap bile acids and inhibit their absorption (US Pat. No. 4,027,092), melinamide (Melina)
mide) (disclosed in French Patent No. 1476569), which inhibits intestinal absorption of cholesterol by inhibiting acylcoenzyme A cholesterol acyltransferase (ACAT), and more recently, 3-hydroxy-3-methylglutaryl coenzyme A. Lovastatin (US Pat. No. 4,231,938), which inhibits (HMG-CoA) reductase, Simvastatin
(Disclosed in US Pat. No. 4,231,938), (disclosed in US Pat. No. 4,444,784), pravastatin (Pravasta
tin) (disclosed in U.S. Pat. No. 4,346,227) and other drugs that suppress cholesterol biosynthesis are drawing attention.

On the other hand, the liver low density lipoprotein (LDL) receptor plays a major role in cholesterol homeostasis. The circulating cholesterol in the form of LDL is
Cleared from plasma by a highly specific LDL receptor,
It is taken up intracellularly by receptor-mediated intracellular uptake. When taken up intracellularly, LDL particles are degraded in the lysosome, thereby liberating cholesterol and increasing the intracellular concentration of free cholesterol. Increased free cholesterol levels signal to hepatocytes to reduce the transcription rate of genes for key enzymes in the cholesterol biosynthetic pathway, resulting in decreased de novo cholesterol synthesis. In addition, LDL receptor mRNA and protein are down-regulated by increased cholesterol in cells, and increased LD
The liver's ability to remove L cholesterol from plasma is reduced. In addition, as a biphenyl compound, a special table 10-
In 510512, the formula

[Chemical 11] [In the formula, R ⁴ represents dialkylamino, phenyl which may have protected amino, etc., Y represents a bond, R ² represents lower alkyl, R ³ represents one or more suitable groups. Represents an optionally substituted aryl or the like,
n represents 0 or 1] or a salt thereof is useful as an ACAT inhibitor.

[0004]

Compounds that inhibit HMG-CoA reductase inhibit not only cholesterol biosynthesis but also biosynthesis of other components necessary for living body such as ubiquinone, dolichol and heme A. However, we do not provide a fully satisfactory drug, which may cause side effects due to them. However, a mechanism that independently upregulates LDL receptors is expected to significantly reduce plasma cholesterol levels by a layer, and agents that upregulate LDL receptors may become new blood lipid lowering agents. there is a possibility. Therefore, low density lipoprotein (LD
L) Development of a new type of drug such as a blood lipid lowering agent based on the receptor increasing action is desired.

[0005]

The present inventors have synthesized for the first time the following novel biaryl derivatives having the following specific substituents, which have excellent LDL receptor increasing activity and blood lipid lowering activity, We found it useful as a drug and completed this study.

That is, the present invention is (1) Formula (I)

[Chemical 12] [In the formula, each of the A ring and the B ring may be substituted.
Represents a 5- or 6-membered aromatic ring, R¹And R²Is that
Hydrogen atom, an optionally substituted hydrocarbon group or
A heterocyclic group which may be substituted, X¹, X², X³Oh
And X^FourEach may be a bond or may be substituted
Represents a divalent hydrocarbon group, Y is -NR³-CO-, -C
O-NR³-, -NR³-SO₂-, -SO₂-NR³-,
-NR³-CH ₂-, -CH₂-NR³-, -O-CO-N
R³-Or-NR³’-NR³-CO- (R³and
R³′ Is a hydrogen atom or carbon atom which may be substituted.
A hydrogen group or an optionally substituted heterocyclic group)
, Z is -CO-NH-, -CS-NH-, -CO-.
Or -SO₂Indicates-, and Ar may be substituted
A cyclic hydrocarbon group or an optionally substituted heterocyclic group
Show. However, the atom next to the atom of A ring that is bonded to B ring
Is unsubstituted. However, Y is -CO-NR³-, -S
O₂-NR³-Or-CH₂-NR³-Indicates X²Concludes
Show a hand, X³Represents a bond or methylene, and
When Z represents -CO-NH-, R¹-X¹-Y- is Zia
It is not a alkylamino group or a protected amino group. 〕so
A compound represented by the formula or a salt thereof [hereinafter referred to as compound (I)
May be done]; (2) R¹C which may be substituted_3-8Cycloalkyl
A compound according to the above (1), which is a group; (3) R¹Is an optionally substituted cyclohexyl group
A certain compound according to the above (1); (4) X¹Is a bond or C_1-6The above is an alkylene group
The compound described in (1); (5) X¹The compound according to (1) above, wherein is a bond; (6) Y is -NR³-CO-, -CO-NR³-Or-
NR³-CH₂-(R³Indicates the same meaning as described in (1) above
A compound according to (1) above, which is (7) X²Is a bond or C_1-6The above is an alkylene group
The compound described in (1); (8) X²The compound according to (1) above, wherein is a bond; (9) X³Is a bond or C_1-6The above is an alkylene group
The compound described in (1); (10) X³The compound according to (1) above, wherein is a methylene group.
object; (11) X^FourIs a bond or C_1-6Before being an alkylene group
A compound according to item (1); (12) X^FourThe compound according to (1) above, wherein is a methylene group.
object; (13) The compound described in (1) above, wherein Z is —CO—NH—.
Compound; (14) Z is -SO₂-The compound according to the above (1)
object; (15) R²An optionally substituted aromatic hydrocarbon group
Or an optionally substituted aromatic heterocyclic group described above
The compound described in (1); (16) Aromatic hydrocarbon group in which Ar may be substituted
Or an optionally substituted aromatic heterocyclic group described above
The compound described in (1); (17) Ring A is a benzene ring which may be substituted
The compound described in (1) above; (18) Ring B is an optionally substituted benzene ring
The compound described in (1) above; (19) Benzene in which A ring and B ring may be substituted
A compound described in (1) above, which is a ring; (20) 6-membered nitrogen-containing aroma in which ring A may be substituted
The compound according to (1) above, which is a group heterocycle; (21) 6-membered nitrogen-containing aroma in which ring B may be substituted
The compound according to (1) above, which is a group heterocycle; (22) 6-membered ring in which A ring and B ring may be substituted
The compound according to (1) above, which is a nitrogen-containing aromatic heterocycle; (23) The 6-membered nitrogen-containing aromatic heterocycle is a pyridine ring or
The above (20) to (22), which is a pyrimidine ring.
Compound; (24) Formula (I ')

[Chemical 13] [In the formula, each of the A ring and the B ring may be substituted.
Represents a 5- or 6-membered aromatic ring (provided that it is bonded to the B ring)
The atom next to the atom of ring A is unsubstituted. ), R ¹And
And R²Are hydrogen atoms and carbon atoms that may be substituted.
A hydrogen group or an optionally substituted heterocyclic group, X
^{1 '}Is a bond, X^{2 '}Is a bond or C_{1- 6}Arche
X group, X^{3 '}Is C_1-6Represents an alkylene group, X^Four'Is
Bond or C _1-6Represents an alkylene group, Y'is -NR³
-CO- (R³Is a hydrogen atom, optionally substituted carbonization
A hydrogen group or an optionally substituted heterocyclic group)
, Z is -CO-NH-, -CS-NH-, -CO-.
Or -SO₂Indicates-, and Ar may be substituted
A cyclic hydrocarbon group or an optionally substituted heterocyclic group
Shown] or a salt thereof [hereinafter, referred to as compound
(I ') may be referred to]; (25) Formula (I ″)

[Chemical 14] [In the formula, each of the A ring and the B ring may be substituted.
Represents a 5- or 6-membered aromatic ring (provided that it is bonded to the B ring)
The atom next to the atom of ring A is unsubstituted. ), R ¹And
And R²Are hydrogen atoms and carbon atoms that may be substituted.
A hydrogen group or an optionally substituted heterocyclic group, X
^{1 '}Is a bond, X^{2 '}Is a bond or C_{1- 6}Arche
X group, X^{3 '}Is C_1-6Represents an alkylene group, X^Four'Is
Bond or C _1-6Represents an alkylene group, and Y ″ is —CO
-NR³-(R³Is a hydrogen atom, optionally substituted carbonization
A hydrogen group or an optionally substituted heterocyclic group)
, Z is -CO-NH-, -CS-NH-, -CO-.
Or -SO₂Indicates-, and Ar may be substituted
A cyclic hydrocarbon group or an optionally substituted heterocyclic group
Compound] (where X is^{2 ''}Indicates a bond
Then X^{3 ''}Represents methylene, and Z represents -CO-NH-
When indicating¹-X^{1 '}-Y- is a protected amino group
Absent. ) Or a salt thereof (hereinafter referred to as compound (I ″))
Sometimes〕; (26) Formula (I ″ ″)

[Chemical 15] [In the formula, W represents CH or N, and R^{1 '''}Has been replaced
Represents a hydrocarbon group which may be present, R^{2 '''}Has been replaced
Represents a heterocyclic group, X^{1 '''}Is a bond or C _1-6A
Represents a alkylene group, X^{2 '''}Is a bond, X^{3 '}Is C
_1-6Represents an alkylene group, X^Four'''Is C_1-6Alkylene group
Show, Y^'''Represents -CO-NH-, Z^'''Is -SO₂
-Indicates Ar^'''Is an optionally substituted cyclic hydrocarbon
A compound represented by a basic group] or a salt thereof [hereinafter referred to as
Sometimes referred to as compound (I "')]; (27) 4-[(Cyclohexylamino) methyl] -4 '-[((3-
Pyridylmethyl) {[4- (trifluoromethyl) anilino] ca
Lubonyl} amino) methyl] -1,1'-biphenyl, 4-{[[([1,
1'-Biphenyl] -4-ylamino) carbonyl] (3-pyridyl
Methyl) amino] methyl} -4 '-[(cyclohexylamino) me
Tyl] -1,1'-biphenyl, N-({4 '-[(cyclohexylamido
No) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (2-pi
Lysyl) -4- (trifluoromethyl) benzenesulfonami
De, N-({4 '-[(cyclohexylamino) methyl] [1,1'-bi
Phenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4- (2
-Thienyl) benzamide, N-cyclohexyl-4 '-[((3-
Pyridylmethyl) {[4- (trifluoromethyl) anilino] ca
Rubonyl} amino) methyl] [1,1'-biphenyl] -4-carbo
Xamide, 4 '-{[[([1,1'-biphenyl] -4-ylamino) carb
Lubonyl] (3-pyridylmethyl) amino] methyl} -N-cyclo
Hexyl [1,1'-biphenyl] -4-carboxamide, N- (4'-
([([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridyl
Methyl) amino] methyl} [1,1'-biphenyl] -4-yl) shik
Rohexanecarboxamide, N- (4 '-{[([1,1'-biphenyl
Lu] -4-ylsulfonyl) (3-pyridylmethyl) amino] meth
Ru} [1,1'-biphenyl] -4-yl) -2- [2- (trifluorometh
(Cyl) phenyl] acetamide, N- [4 '-({(3-pyridylmeth
Tyl) [(3 ', 4', 5'-trimethoxy [1,1'-biphenyl] -4-i
Ru) sulfonyl] amino} methyl) [1,1′-biphenyl] -4-i
] -2- [2- (Trifluoromethyl) phenyl] acetami
4- (5-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-
Pyridylmethyl) amino] methyl} -2-pyridyl) -N-cyclo
(1) above, which is hexylbenzamide or a salt thereof
Listed compounds; (28) The prod of the compound or salt thereof described in (1) above.
Rag; (29) The compound according to (1) or a salt thereof, or
A pharmaceutical composition comprising the prodrug; (30) The above which is a low-density lipoprotein receptor increasing agent
(29) The composition described in; (31) The composition according to the above (29), which is a lipid lowering agent; (32) (1) hyperlipidemia, (2) arteriosclerosis, (3) high
Diabetic complications with lipemia or arteriosclerosis or
(4) Hypertensive complications associated with hyperlipidemia or arteriosclerosis
The composition according to (29) above, which is a prophylactic / therapeutic agent; (33) Formula (II)

[Chemical 16] [Each symbol in the formula has the same meaning as described in (1) above. Here, Y is preferably —NR ³ —CH ₂ — or —CH ₂ —.
NR ³ —, more preferably —NR ³ —CH ₂ —] or a salt thereof is subjected to a reaction with an isocyanate, a reaction with an isothiocyanate, an acylation reaction or a sulfonylation reaction. Characteristic Formula (I)

[Chemical 17] [Each symbol in the formula has the same meaning as described in (1) above. ] The manufacturing method of the compound or its salt represented by these; (34) Formula (III)

[Chemical 18] [Each symbol in the formula has the same meaning as described in (1) above. ] The compound or its salt represented by these is subjected to an acylation reaction, a sulfonylation reaction, or an alkylation reaction.

[Chemical 19] [In formula, Ya is -O-CO-NR < ³ >-, -CO-NR.
^3- , —SO ₂ —NR ³ — or —CH ₂ —NR ³ — (R ³ has the same meaning as described in (1) above), and other symbols have the same meaning as described in (1) above. Show. ] The manufacturing method of the compound or its salt represented by these; (35) Formula (IV)

[Chemical 20] [Each symbol in the formula has the same meaning as described in (1) above. Or a salt thereof] and the formula R ¹ -X ¹ -NH-R ³
Or ^{R 1 -X 1 -NR 3 '-NH} -R 3 [wherein each symbol is as defined above (1), wherein. ] The compound (Ib) characterized by reacting the compound represented by this or its salt.

[Chemical 21] [In the formula, Yb is -NR³-CO- or -NR³’-NR
³-CO- (R³And R ³'Has the same meaning as described in (1) above
Indicates. ), And other symbols are the same as described in (1) above.
Show significance. ] The manufacture of the compound or its salt represented by
Law; (36) An effective amount of the compound or salt thereof according to (1) above.
In a mammal, characterized in that
A method for increasing low density lipoprotein receptors; (37) An effective amount of the compound according to (1) or a salt thereof.
In a mammal, characterized in that
Lipid reduction method; (38) An effective amount of the compound or salt thereof according to (1) above.
In a mammal, characterized in that
(1) hyperlipidemia, (2) arteriosclerosis, (3) hyperlipidemia
Or diabetic complications with arteriosclerosis or (4) high
Prevention of hypertensive complications associated with lipemia or arteriosclerosis
Method of treatment; (39) For producing a low-density lipoprotein receptor-increasing drug
The use of the compound or the salt thereof described in (1) above; (40) A compound as described in (1) above for producing a lipid-lowering drug.
Use of compound or salt thereof; (41) (1) hyperlipidemia, (2) arteriosclerosis, (3) high
Diabetic complications with lipemia or arteriosclerosis or
(4) Hypertensive complications associated with hyperlipidemia or arteriosclerosis
The compound according to (1) above for producing a prophylactic / therapeutic drug for
Or use of a salt thereof;

The term "divalent hydrocarbon group" used in the present specification means, for example, an alkylene group having 1 to 15 carbon atoms (for example, methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, hepta). Methylene, octamethylene, etc .; preferably C _1-6 alkylene group, 2 to 16 alkenylene groups (eg vinylene, propenylene, 1-butenylene, 2-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene etc.) ; Preferably a C _2-6 alkenylene group), 2
To 16 alkynylene groups (for example, ethynylene, propynylene, 1-butynylene, 2-butynylene, 1-pentynylene, 2-pentynylene, 3-pentynylene, etc .; preferably C _2-6 alkynylene groups) and the like. It is a hydrocarbon group, a phenylene group, or a combination thereof. Examples of the substituent that the “divalent hydrocarbon group” may have include, for example, an optionally substituted alkyl group, an optionally substituted aralkyl group,
Optionally substituted aryl group, optionally substituted hydroxyl group (eg, optionally substituted hydrocarbon group, optionally substituted hydroxyl group, etc .; preferably, optionally substituted alkyl group) A hydroxyl group which may be substituted,
And the like, and an optionally substituted alkyl group is preferable. The "phenylene group" may have a substituent. Examples of the substituent of the “phenylene group” include a halogen atom (eg, fluorine, chlorine, bromine, iodine etc.), a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl etc.),
C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy etc.), C _1-4 alkylthio group (eg, methylthio, ethylthio, propylthio,
Isopropylthio, etc.), hydroxy group, carboxyl group, cyano group, nitro group, amino group, mono- or di-
C _1-4 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino etc.), formyl group, mercapto group, C _1-4 alkyl-carbonyl group (eg acetyl, propionyl, butyryl etc.), C _{1 -4} alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like), sulfo group (-SO ₃ H), C _1-4 alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like), 1 to 1 selected from a carbamoyl group and a mono- or di-C _1-4 alkyl-carbamoyl group (eg, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, etc.) Four are used.

The term "halogen atom" as used herein refers to, for example, fluorine, chlorine, bromine, iodine and the like. The term “hydrocarbon group” in the term “optionally substituted hydrocarbon group” used in the present specification means, for example, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an aralkyl group or an aryl group. The “cyclic hydrocarbon group” of the term “optionally substituted cyclic hydrocarbon group” used herein refers to, for example, a cycloalkyl group, a cycloalkenyl group, an aryl group and the like. Examples of the substituent that the “hydrocarbon group” may have include the “alkyl group”, “cycloalkyl group”, “alkenyl group”, “cycloalkenyl group”, “alkynyl group”, and “aralkyl” which will be described later. The same groups as the substituents which the “group” and the “aryl group” may have are used. Examples of the “alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl. A "linear or branched C _1-15 alkyl group" such as, and the like, preferably a C _1-6 alkyl group is used. Examples of the "cycloalkyl group", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. "C _{3- 8} cycloalkyl group" such as cyclooctyl, preferably C _5-7 cycloalkyl group is used.

The "alkyl group" and "cycloalkyl"
Examples of the substituent that the “group” may have include (i)
Toro group, (ii) hydroxy group, oxo group, (iii) cyano
Group, (iv) carbamoyl group, (v) mono- or di-C_1-4A
Rukyl-carbamoyl group (eg N-methylcarbamoyl
Yl, N-ethylcarbamoyl, N, N-dimethylcalcyl
Vamoyl, N, N-diethylcarbamoyl, etc.), (vi)
Carboxyl group, (vii) C_1-4Alkoxy-carbonyl group
(For example, methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, isopropoxycarbonyl
Etc.), (viii) sulfo group, (ix) halogen atom (for example, fluorine
Fluorine, chlorine, bromine, iodine, etc.), (x) halogenated
May be C_1-6An alkoxy group (eg, methoxy,
Ethoxy, propoxy, isopropoxy, etc.), halogen
C which may be converted to_5-7Cycloalkoxy group, halo
C which may be genated_5-7Cycloalkoxy-C_1-6
Alkoxy group, (xi) phenyl group, (xii) halogenated
Optionally a phenoxy group (eg o-, m- or
p-chlorophenoxy, o-, m- or p-bromophen
Phenoxy, etc.), phenoxy which may be halogenated
Sea C_1-4Alkyl group, (xiii) even if halogenated
Good C_1-6Alkyl group, optionally halogenated C
_1-6Alkylthio groups (eg methylthio, ethylthio
O, n-propylthio, isopropylthio, n-butyl
Thio, etc.), (xiv) mercapto group, thioxo group, (xv) ha
Optionally halogenated benzyl group, halogenated
Optionally benzyloxy group, halogenated
Good benzylthio group, (xvi) even if halogenated
Good phenylthio group, pyridylthio group, (xvii) C_1-6A
Rukylsulfinyl group (for example, methylsulfinyl,
Ethylsulfinyl), (xviii) C_1-6Alkylsul
Fonyl group (eg, methylsulfonyl, ethylsulfoni
, Etc.), (xix) amino group, aminosulfonyl group, (xx)
C_1-3Acylamino groups (eg acetylamino, pro
Pionylamino etc.), (xxi) mono- or di-C_1-4A
Ruky lamino group (eg, methylamino, ethylami
No, dimethylamino, diethylamino, etc.), (xxii) 4
To a 6-membered cyclic amino group (for example, 1-azetidinyl,
1-pyrrolidinyl, piperidino, morpholino, 1-pipe
(Radinyl etc.), (xxiii) C_1-3Acyl groups (for example,
Mil, acetyl, etc.), (xxiv) benzoyl group, (xxv) C
_1-4Alkyl or C_1-4Bonded through an alkoxy group
A 5- to 10-membered heterocyclic group (for example, 2- or 2-
Is 3-thienyl, 2- or 3-furyl, 3-, 4-
Or 5-pyrazolyl, 2-, 4- or 5-thiazoli
, 3-, 4- or 5-isothiazolyl, 2-, 4-
Or 5-oxazolyl, 1,2,3- or 1,2,
4-triazolyl, 1H- or 2H-tetrazolyl,
2-, 3- or 4-pyridyl, 2-, 4- or 5-
Pyrimidyl, 3- or 4-pyridazinyl, quinolyl,
Isoquinolyl indolyl) and (xxvi) C_1-4Al
Kill or C_1-4Even if they are bound via an alkoxy group
Good C_3-8Cycloalkyl groups (eg cyclohexyl
Methyl, cyclohexyl methoxy, etc.) are used
It The “alkyl group” is substituted at these substitutable positions with these
It may have 1 to 5 substituents.

Preferred as the “alkyl group”
Is, for example, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl,
Straight-chain or branched C such as ethyl and hexyl_1-6A
Examples of the alkyl group include the "C_1-6Alkyl group ”has
As the substituent which may be present, for example, a halogen atom, C
_1-4Alkoxy group, hydroxyl group, C_1-4Alkoxy-
Carbonyl group, carboxyl group, carbamoyl group, mono
-Or di-C_1-4Alkylcarbamoyl group, pyridyl
One to three thio groups and the like are used. The "Arkeni
Group, for example, vinyl, allyl, isopropenyl.
Le, 3-butenyl, 3-octenyl, 9-octadecen
Such as "C_2-18"Alkenyl group" and the like, preferably C
_2-6Alkenyl groups are used. The “cycloalkenyl
Examples of the “group” include cyclopropenyl and cyclobutenyl.
, Cyclopentenyl, cyclohexenyl, cyclohep
"C such as tenyl and cyclooctenyl_3-8Cycloarche
“Nyl group” and the like, preferably C_5-7Cycloalkenyl group
Used. The "alkenyl group" and "cycloalkenyl
Examples of the substituent that the “group” may have include the above-mentioned “alkyl group”.
The same substituents as the “kill group” may have are used.
To be Preferred examples of the "alkenyl group" include:
For example vinyl, allyl, 2-butenyl, 3-butenyl
Which C_2-6Examples thereof include an alkenyl group. The "C_2-6A
As the substituent which the “rukenyl group” may have,
For example, a substituent that the “alkyl group” may have and
Similar ones are used. As the "alkynyl group"
Is, for example, ethynyl, propynyl, 1-butynyl, 2
-Butynyl, 1-pentynyl, 2-pentynyl, 3-pe
"C _2-18Alkynyl group "and the like are preferable.
Is C_2-6An alkynyl group is used. The "alkynyl
Examples of the substituent which the “group” may have include the above-mentioned “alkyl group”.
And those similar to the substituents which the “group” may have are used.
Be done. Preferred examples of the "alkynyl group" include:
For example, ethynyl, propynyl, 1-butynyl, 2-butynyl.
C such as le_2-6Examples thereof include alkynyl group. The "C
_2-6An alkynyl group ”may have a substituent
Is, for example, a group which the above “alkyl group” may have.
The same as the substituent is used.

The "aralkyl group" is C_7-16Ara
For example, a benzyl group is used.
Le, phenethyl, 3-phenylpropyl, 4-phenyl
Phenyl-C such as butyl_1-6Alkyl group and
Ba (1-naphthyl) methyl, 2- (1-naphthyl) eth
And naphthyl-C such as 2- (2-naphthyl) ethyl_1-
6An alkyl group etc. are mentioned. The "aralkyl group" is
The substituent which may have is, for example, a halogen atom.
(Eg, fluorine, chlorine, bromine, iodine, etc.), halogen
C which may be converted to _1-4Alkyl groups (eg, methyl
, Ethyl, propyl, isopropyl, butyl, etc.),
C which may be halogenated_5-7Cycloalkyl group,
C_2-6Alkenyl groups (eg vinyl, allyl, 2-butene)
Tenyl, 3-butenyl, etc.), C_1-3Acyl group (eg
Formyl, acetyl, etc.), halogenated
Good C_1-4Alkoxy groups (eg methoxy, ethoxy)
Ci, propoxy, isopropoxy, etc.), nitro group,
Ano group, hydroxy group, hydroxy group-C_1-4Alkyl
Group, carboxyl group, C_1-4Alkoxy-carbonyl group
(For example, methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, isopropoxycarbonyl
Etc.), carbamoyl group, mono- or di-C_1-4Archi
Ru-carbamoyl group (for example, N-methylcarbamoyl group
L, N-ethylcarbamoyl, N, N-dimethylcarba
Moyl, N, N-diethylcarbamoyl, etc.), mono-
Or J-C_1-4Alkenyl-carbamoyl group (eg
, N-vinylcarbamoyl, etc.), and
Examples thereof include a substituent which the “alkyl group” may have.
And the “aralkyl group” has these positions at substitutable positions.
It may have 1 to 4 substituents. The "aryl
Examples of the “group” include phenyl, 1-naphthyl, 2-na
Futyl, biphenyl, phenanthryl, antryl
hryl) and other aromatic monocyclic, bicyclic or tricyclic C
_6-14An aryl group or the like is used. The "aryl group" is
Examples of the substituent which may have include the above-mentioned “aralkyl
In addition to the substituents that the "group" may have, oxo groups and the like are also used.
And the “aryl group” is substituted at these substitutable positions with these
Having 1 to 4 substituents, preferably 1 or 2 substituents
You may stay. Examples of the aryl group having an oxo group include
For example, benzoquinonyl, naphthoquinolyl, anthraquinoni.
And the like.

As used herein, the term “heterocyclic group” of the term “optionally substituted heterocyclic group” means, for example, an oxygen atom (ring atom) constituting a ring system,
Aromatic heterocyclic group containing at least one (preferably 1 to 4 and more preferably 1 to 2) heteroatoms 1 to 3 (preferably 1 to 2) selected from sulfur atom, nitrogen atom and the like. And saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups). Examples of the “aromatic heterocyclic group” include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,
2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,
3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,
3,4-thiadiazolyl, 1,2,3-triazolyl, 1,
5- or 6-membered aromatic monocyclic heterocyclic group such as 2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and, for example, benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, indolyl, Isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,
2-benzisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
Naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2- b ]. Pyridazinyl, pyrazolo [1,5- a ] pyridyl, imidazo [1,2- a ] pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,
8 such as 2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,2,4-triazolo [4,3- a ] pyridyl, 1,2,4-triazolo [4,3- b ] pyridazinyl To 12-membered fused aromatic heterocyclic group (preferably, a heterocyclic ring in which the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring or the above-mentioned 5- or 6-membered aromatic monocyclic group (A heterocycle in which two heterocycles of the same or different heterocycles are condensed, more preferably a heterocycle in which the above-mentioned 5- or 6-membered aromatic monocyclic heterocycle is condensed with a benzene ring)
Etc. Examples of the “non-aromatic heterocyclic group” include 3 to 8 members (preferably 5 to 6 members, such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. Member) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) or the like, or 1,2,3,4-tetrahydroquinolyl, 1,2,3,4
-Non-aromatic heterocyclic groups such as tetrahydroisoquinolyl, in which a part or all of the above-mentioned aromatic monocyclic heterocyclic groups or aromatic condensed heterocyclic groups are saturated with double bonds, and the like. The "heterocyclic group" in the "optionally substituted heterocyclic group" is preferably a 5- or 6-membered aromatic monocyclic heterocyclic group, and the "optionally substituted heterocyclic group". Examples of the substituent which the “heterocyclic group” in may have the same substituent as the substituent that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” may have. Can be mentioned.

In the above formula, ring A and ring B each represent an optionally substituted 5- or 6-membered aromatic ring (provided that the atom adjacent to the ring A atom bonded to ring B is unsubstituted). . Examples of the substituents which ring A and ring B may have include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine), a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl). , Butyl, etc.),
Hydroxy -C _1-4 alkyl group, C _1-4 alkoxy -C
_1-4 alkyl group, mono- or di-C _1-4 alkyl or C _5-7 cycloalkyl-amino group, C _1-4 alkoxy group (eg methoxy, ethoxy, propoxy, isopropoxy etc.), C _{1- 4} alkylthio groups (eg, methylthio, ethylthio, propylthio, isopropylthio, etc.), hydroxy groups, carboxyl groups, cyano groups, nitro groups, amino groups, mono- or di-C _1-4 alkylamino groups (eg, methylamino, Ethylamino, dimethylamino, diethylamino etc.), formyl group, mercapto group, C _1-4 alkyl-carbonyl group (eg acetyl, propionyl, butyryl etc.), C _1-4 alkoxy-carbonyl group (eg methoxycarbonyl, ethoxy) carbonyl, propoxycarbonyl), a sulfo group, C _1-4 alkylsulfonyl (E.g., methylsulfonyl and ethyl sulfonyl propylsulfonyl)
Carbamoyl group and mono- or di-C _1-4 alkyl or C _5-7 cycloalkyl-carbamoyl group (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, etc. ) And the like. 1 to 3 of these substituents may be substituted at substitutable positions on the A ring and the B ring. As ring A and ring B, ring B is preferably unsubstituted, especially ring A and ring B
The ring is preferably unsubstituted. "An optionally substituted 5- or 6-membered aromatic ring" represented by ring A and ring B
The “5- or 6-membered aromatic ring” in is, for example,
Examples thereof include a benzene ring and a 5- or 6-membered aromatic heterocycle. Here, as the 5- or 6-membered aromatic heterocycle,
For example, selected from nitrogen atom, sulfur atom and oxygen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, oxadiazole, thiadiazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine and triazine. 1 to 2 heteroatoms
Examples include 5- or 6-membered aromatic heterocycles containing 3 members, and among them, 6-membered nitrogen-containing aromatic heterocycles are preferable,
Especially, pyridine and pyrimidine are preferable. Preferred examples of ring A and ring B are a benzene ring in which ring A may be substituted; a benzene ring in which ring B may be substituted; a benzene ring in which ring A and ring B may be substituted; A 6-membered nitrogen-containing aromatic heterocycle in which A ring may be substituted (preferably, a pyridine ring which may be substituted or a pyrimidine ring which may be substituted); and B ring may be substituted. 6-membered nitrogen-containing aromatic heterocycle (preferably, optionally substituted pyridine ring or optionally substituted pyrimidine ring); 6-membered nitrogen-containing aromatic ring in which A ring and B ring may be substituted Group heterocycle (preferably a pyridine ring which may be substituted or a pyrimidine ring which may be substituted); and the like. Among them, a benzene ring in which A ring and B ring may be substituted. To be good Arbitrariness.

In the above formula, R ¹ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. Examples of the optionally substituted hydrocarbon group and the optionally substituted heterocyclic group represented by R ¹ include the above-mentioned “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic ring”. The same as "group" is used. As R ¹ , an optionally substituted C _3-8 cycloalkyl group is preferable, and an optionally substituted C _3-8 cycloalkyl group is preferable, and an optionally substituted cyclohexyl group is particularly preferable. Is preferred. In the above formula, R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. The optionally substituted hydrocarbon group and the optionally substituted heterocyclic group represented by R ² are the above-mentioned "optionally substituted hydrocarbon group" and "optionally substituted heterocycle". The same as "group" is used. As R ² ,
An optionally substituted aromatic hydrocarbon group, an optionally substituted aromatic heterocyclic group and the like are preferable, and above all, an optionally substituted phenyl group and an optionally substituted 5- or 6-membered group An aromatic heterocyclic group (preferably an optionally substituted pyridyl group) is preferable. In the above formula, R ³ and R ³ ′ each represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
Examples of the optionally substituted hydrocarbon group and the optionally substituted heterocyclic group represented by R ³ and R ³ 'include the above-mentioned "optionally substituted hydrocarbon group" and "substituted And the same as the "good heterocyclic group" is used. R ³ or R ³ ′ may combine with R ¹ to form a 5- to 10-membered cyclic amino group with the adjacent nitrogen atom of R ³ or R ³ ′. , For example, morpholino, piperidino, piperazin-1-yl, phthalimide and the like. The cyclic amino group may have an arbitrary substituent at a substitutable position, and such a substituent has a hydrocarbon group in the optionally substituted hydrocarbon group represented by R ^1. The same groups as the substituents that may be present (eg, hydroxy group-C
_1-4 alkyl group, carboxyl group, C _1-4 alkoxy-carbonyl group and the like). As R ³ and R ³ ′, a hydrogen atom, an optionally substituted alkyl group and the like are preferable, and among them, a hydrogen atom is preferable.

In the above formula, X ¹ represents a bond or an optionally substituted divalent hydrocarbon group. As the optionally substituted divalent hydrocarbon group represented by X ¹ , those similar to the above-mentioned "optionally substituted divalent hydrocarbon group" are used. As X ¹ , a bond or a C _1-6 alkylene group is preferable, and a bond is particularly preferable.
In the above formula, X ² represents a bond or a divalent hydrocarbon group which may be substituted. As the optionally substituted divalent hydrocarbon group represented by X ² , those similar to the above-mentioned "optionally substituted divalent hydrocarbon group" are used. As X ² , a bond or a C _1-6 alkylene group is preferable, and a bond is particularly preferable. In the above formula, X
³ represents a bond or an optionally substituted divalent hydrocarbon group. As the optionally substituted divalent hydrocarbon group represented by X ³ , those similar to the above-mentioned "optionally substituted divalent hydrocarbon group" are used. X ³ is preferably a bond or a C _1-6 alkylene group,
Of these, a methylene group is preferable. In the above formula, X ⁴ represents a bond or a divalent hydrocarbon group which may be substituted. As the optionally substituted divalent hydrocarbon group represented by X ⁴ , those similar to the above-mentioned “optionally substituted divalent hydrocarbon group” are used. As X ⁴ , a bond or a C _1-6 alkylene group is preferable, and among them, a methylene group is preferable. In the formula, Y is -NR ^{3
-CO -, - CO-NR 3} -, - NR 3 -SO 2 -, - S
^{_{O 2 -NR 3 -, - NR}} 3 -CH 2 -, - CH 2 -NR 3 -,
-O-CO-NR ³ or -NR ³ '-NR ³ -CO-
(R ³ and R ³ 'have the same meanings as described above). Y is —NR ³ —CO—, —NR ³ —CH ₂ — or —
CO-NR ³ - it is preferred. In the above formula, Z is -CO-N
H -, - CS-NH - , - CO- or -SO ₂ - shows a. The Z, -CO-NH- or -SO ₂ - are preferred. In the above formula, Ar represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group.
The "optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" represented by Ar are the above-mentioned "optionally substituted cyclic hydrocarbon group".
And those similar to the “optionally substituted heterocyclic group” are used. As Ar, an optionally substituted phenyl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group (preferably an optionally substituted pyridyl group) is preferable.

Among the compounds represented by the above formula (I), those represented by the formula (I ')

[Chemical formula 22] [In the formula, each of the A ring and the B ring may be substituted.
Represents a 5- or 6-membered aromatic ring (provided that it is bonded to the B ring)
The atom next to the atom of ring A is unsubstituted. ), R ¹And
And R²Are hydrogen atoms and carbon atoms that may be substituted.
A hydrogen group or an optionally substituted heterocyclic group, X
^{1 '}Is a bond, X^{2 '}Is a bond or C_{1- 6}Arche
X group, X^{3 '}Is C_1-6Represents an alkylene group, X^Four'Is
Bond or C _1-6Represents an alkylene group, Y'is -NR³
-CO- (R³Is a hydrogen atom, optionally substituted carbonization
A hydrogen group or an optionally substituted heterocyclic group)
, Z is -CO-NH-, -CS-NH-, -CO-.
Or -SO₂Indicates-, and Ar may be substituted
A cyclic hydrocarbon group or an optionally substituted heterocyclic group
Shown] or a salt thereof; formula (I ″)

[Chemical formula 23] [In the formula, each of the A ring and the B ring may be substituted.
Represents a 5- or 6-membered aromatic ring (provided that it is bonded to the B ring)
The atom next to the atom of ring A is unsubstituted. ), R ¹And
And R²Are hydrogen atoms and carbon atoms that may be substituted.
A hydrogen group or an optionally substituted heterocyclic group, X
^{1 '}Is a bond, X^{2 '}Is a bond or C_{1- 6}Arche
X group, X^{3 '}Is C_1-6Represents an alkylene group, X^Four'Is
Bond or C _1-6Represents an alkylene group, and Y ″ is —CO
-NR³-(R³Is a hydrogen atom, optionally substituted carbonization
A hydrogen group or an optionally substituted heterocyclic group)
, Z is -CO-NH-, -CS-NH-, -CO-.
Or -SO₂Indicates-, and Ar may be substituted
A cyclic hydrocarbon group or an optionally substituted heterocyclic group
Compound] (where X is^{2 ''}Indicates a bond
Then X^{3 ''}Represents methylene, and Z represents -CO-NH-
When indicating¹-X^{1 '}-Y- is a protected amino group
Absent. ) Or a salt thereof; formula (I ″ ″)

[Chemical formula 24] [In the formula, W represents CH or N, and R^{1 '''}Has been replaced
Represents a hydrocarbon group which may be present, R^{2 '''}Has been replaced
Represents a heterocyclic group, X^{1 '''}Is a bond or C _1-6A
Represents a alkylene group, X^{2 '''}Is a bond, X^{3 '}Is C
_1-6Represents an alkylene group, X^Four'''Is C_1-6Alkylene group
Show, Y^'''Represents -CO-NH-, Z^'''Is -SO₂
-Indicates Ar^'''Is an optionally substituted cyclic hydrocarbon
Or a salt thereof;
It is used well. A compound represented by the formula (I ″ ″)
By the way, R^{1 '''}Is an optionally substituted C_3-8
Cycloalkyl group, optionally substituted C_6-10Ally
Group is preferable, and cyclohexyl group and halogenated group are preferable.
May be C_1-6May be substituted with an alkyl group
A phenyl group and the like are more preferable. X^{1 '''}as,
A bond or a methylene group is preferable, and X is^{3 '}As
Is preferably a methylene group or the like, and X^Four'''As a meth
A len group and the like are preferable. R^{2 '''}Has been replaced as
Optionally substituted aromatic heterocyclic group and the like, which are substituted
And more preferably a pyridyl group, etc., Ar^'''When
Then, an optionally substituted aromatic hydrocarbon group, etc.
Halogen atom, optionally halogenated
C_1-6Alkyl group and optionally halogenated C
_1-6Substituted with 1 to 3 substituents selected from alkoxy groups
A phenyl group substituted with an optionally substituted phenyl group, etc.
Is more preferable.

The salt of the compound represented by the formula (I) of the present invention is preferably a pharmaceutically acceptable salt or a physiologically acceptable acid addition salt. As such salt,
For example, inorganic acids (eg hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.) or organic acids (eg acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid) , Benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc.) and the like are used. Further, when the compound (I) of the present invention has an acidic group such as carboxylic acid, the compound (I) may be, for example, an inorganic base (for example, alkali metal or alkaline earth metal such as sodium, potassium, calcium, magnesium). Or ammonia, etc.) or an organic base (eg, tri-C _1-3 alkylamine such as triethylamine etc.) may form a salt. As the raw material compound of the compound represented by the formula (I) of the present invention, the same salts as described above are used, but are not particularly limited as long as they do not interfere with the reaction. The prodrug of the compound represented by the formula (I) of the present invention or a salt thereof [hereinafter sometimes referred to as the compound (I)] is a compound (I) obtained by a reaction with an enzyme, gastric acid or the like under physiological conditions in the living body. ) A compound that converts to
A compound that undergoes reduction, hydrolysis, etc. to convert to compound (I), and a compound that undergoes hydrolysis, etc. due to gastric acid etc. to convert to compound (I). As a prodrug of compound (I), an amino group of compound (I) is acylated,
Alkylated and phosphorylated compound (for example, amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxy Carbonylation, tetrahydrofuranylation, pyrrolidylmethylation,
Pivaloyloxymethylated, tert-butylated compound, etc.), Compound (I) having a hydroxyl group acylated, alkylated, phosphorylated, and borated (for example, compound (I) having a hydroxyl group acetylated) , Palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds), or compounds in which the carboxyl group of compound (I) is esterified or amidated (eg, ,
The carboxyl group of the compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5- Methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds and the like) and the like. These compounds can be produced from compound (I) by a method known per se. In addition, the prodrug of compound (I) is a compound which is changed to compound (I) under physiological conditions, as described in Hirokawa Shoten, 1990, "Development of Pharmaceuticals", Volume 7, Molecular Design, pages 163 to 198. It may be.

The compound (I) may be a hydrate. Where an optically active form of compound (I) is required, it can be obtained, for example, using optically active starting materials or by resolution of the racemic forms of the compound using conventional methods. it can. In addition, the compound (I) may have an asymmetric carbon in the molecule, but the R coordination or S
When there are two stereoisomers of coordination, each of them or any of their mixtures are included in the present invention.

Preferred specific examples of the compound (I) of the present invention are shown below. 4-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4-{[[ ([1,1'-Biphenyl] -4-ylamino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl N-({4'-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4 -Yl} methyl) -N- (2-pyridyl) -4- (trifluoromethyl) benzenesulfonamide N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl } Methyl) -N- (3-pyridylmethyl) -4- (2-thienyl) benzamido N-cyclohexyl-4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino ) Methyl]
[1,1'-biphenyl] -4-carboxamide 4 '-{[[([1,1'-biphenyl] -4-ylamino) carbonyl]
(3-Pyridylmethyl) amino] methyl} -N-cyclohexyl
[1,1'-Biphenyl] -4-carboxamide N- (4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1' -Biphenyl] -4-yl) cyclohexanecarboxamide N- (4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl ] -4-yl) -2- [2- (trifluoromethyl) phenyl] acetamide, N- [4 '-({(3-pyridylmethyl) [(3', 4 ', 5'-trimethoxy
[1,1'-Biphenyl] -4-yl) sulfonyl] amino} methyl)
[1,1'-Biphenyl] -4-yl] -2- [2- (trifluoromethyl) phenyl] acetamide, 4- (5-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -2-pyridyl) -N-cyclohexylbenzamide and salts thereof. Further, as the salt, an acid addition salt is preferable, and among them, a hydrochloride or the like is preferably used.

The compound (I) of the present invention can be synthesized according to a reaction known per se, for example, by the following method. The compound (I) of the present invention can be synthesized, for example, by the following method. (A) method

[Chemical 25] [Each symbol in the formula has the same meaning as described above. ] (A-1) Method

[Chemical formula 26] [In the formula, Y ¹ is —NR ³ —CH ₂ — or —CH ₂ —NR ³
-, And other symbols have the same meanings as described above. ] (A-2) Method

[Chemical 27] [In the formula, Y ² is —NP ¹ —CH ₂ — or —CH ₂ —NP ¹
Represents —, Y ^{2 ′} is —NH—CH ₂ — or —CH ₂ —NH
- indicates, P ¹ is an amino-protecting group, and other symbols are as defined above. ] Isocyanate (A) of compound (II) in method (A)
The reaction with r-N = C = O) uses 1 to a large excess of isocyanate, preferably 1 to 3 equivalents. At this time, for example, as a base, an inorganic base (for example, potassium carbonate, sodium hydrogen carbonate, etc.), an organic base (for example, triethylamine, pyridine, dimethylamine, 1,8-
Diazabicyclo [5.4.0] -7-undecene etc.), alcoholates (eg sodium methylate, sodium ethylate, tert-butoxy potassium etc.), organometallic reagents (eg n-butyllithium etc.), hydroxylation You may use sodium, sodium amide, etc. The amount used is 1 to a large excess, preferably 1
Use 5 to 5 equivalents. The reaction temperature is 0 to 200.
C., preferably 20 to 100.degree. As the solvent to be used, hydrocarbons (for example, hexane, benzene, toluene, etc.), halogenated hydrocarbons (for example,
Methylene chloride, chloroform, dichloroethane, etc.),
Ethers (eg tetrahydrofuran, dioxane, diethyl ether etc.), esters (eg ethyl acetate, methyl acetate etc.), protic polar solvents (eg methanol, ethanol etc.), aprotic polar solvents (eg acetonitrile, N) , N-dimethylformamide, dimethyl sulfoxide, etc.).
The reaction time is generally 5 minutes to 24 hours, preferably 1 to 10 hours. Compound (II) in method (A)
The reaction with the isothiocyanate (Ar-N = C = S) can be carried out in the same manner as the reaction of the compound (II) with the isocyanate in the above method (A). (A)
The acylation reaction of compound (II) in the method can be synthesized by an ordinary amide formation reaction. That is, compound (II) and carboxylic acid (Ar-COOH) are synthesized using an amide-forming reagent, or alternatively, acid chloride and mixed acid anhydride synthesized from compound (II) and carboxylic acid (Ar-COOH). It can be synthesized by reacting a product or an active ester. Examples of the amide-forming reagent in the reaction of the above compound (II) and carboxylic acid include 1-ethoxy-1,2-dihydroquinoline, dicyclohexylcarbodiimide, 1
-Cyclohexyl-3- (2-morpholinoethyl) carbodiimide, meso-p-toluenesulfonate, N,
N'-carbonyldiimidazole, diethyl diphenyl phosphate, azide diphenyl phosphate, diethyl cyanophosphate 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and the like are used. The amide-forming reagent is used in the amount of 1 to 3 equivalents based on compound (II). At this time, for example, as a base, an inorganic base (for example, potassium carbonate, sodium hydrogen carbonate, etc.), an organic base (for example, triethylamine, pyridine, dimethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, etc. ), Alcoholates (eg, sodium methylate, sodium ethylate, potassium tert-butoxide, etc.), organometallic reagents (eg, n-butyllithium, etc.), sodium hydroxide, sodium amide, etc. in 1 to large excess, preferably 1 to 5 equivalents may be used. The reaction temperature is 0 to 200 ° C., preferably 0
To 100 ° C. As the solvent to be used, hydrocarbons (eg, hexane, benzene, toluene, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.) , Esters (eg ethyl acetate, methyl acetate etc.), protic polar solvents (eg methanol, ethanol etc.), aprotic polar solvents (eg acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide etc.). . The reaction time is usually 10
To 24 hours, preferably 1 to 10 hours.
The reaction between compound (II) and acid chloride is carried out by reacting compound (I)
1 to 3 equivalents of acid chloride are used with respect to I). At this time, for example, as a base, an inorganic base (for example, potassium carbonate, sodium hydrogen carbonate, etc.), an organic base (for example, triethylamine, pyridine, dimethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, etc. ), Alcoholates (eg, sodium methylate, sodium ethylate, potassium tert-butoxide, etc.), organometallic reagents (eg, n-butyllithium, etc.), sodium hydroxide, sodium amide, etc. in 1 to large excess, preferably 1 to 5 equivalents may be used. The reaction temperature is 0 to 200 ° C, preferably 0 to 60 ° C. As the solvent to be used, hydrocarbons (eg, hexane, benzene, toluene, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.) , Esters (eg ethyl acetate, methyl acetate etc.), protic polar solvents (eg methanol, ethanol etc.), aprotic polar solvents (eg acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide etc.), or these And a mixed solution of water and the solvent. The reaction time is usually 10 to 24
The time is preferably 1 to 10 hours. Compound (I
The reaction between I) and the mixed acid anhydride can be carried out in the same manner as the reaction between compound (II) and the acid chloride. The reaction of the compound (II) with the active ester is carried out by first converting the carboxylic acid into phenols such as 2,4,5-trichlorophenol, pentachlorophenol, pentafluorophenol, 2-nitrophenol and 4-nitrophenol, for example, , N-hydroxysuccinimide, 1-hydroxybenztriazole, N-hydroxypiperidine, N-hydroxy-5-norbornene-2,3-dicarbodiimide and other N-hydroxy compounds are reacted with an amide-forming reagent such as dicyclohexylcarbodiimide to be active. After synthesizing the ester, it is reacted with the compound (II). The reaction can be carried out in the same manner as the reaction of compound (II) with acid chloride, and can be carried out subsequent to the synthesis of active ester. Compound (I) in method (A)
In the sulfonylation reaction of I), 1 equivalent to 3 equivalents of sulfonyl chloride (Ar—SO ₂ —Cl) is used with respect to compound (IIa). At this time, for example, as a base, an inorganic base (for example, potassium carbonate, sodium hydrogen carbonate, etc.), an organic base (for example, triethylamine, pyridine, dimethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, etc. ), Alcoholates (eg, sodium methylate, sodium ethylate, potassium tert-butoxide, etc.), organometallic reagents (eg, n-butyllithium, etc.), sodium hydroxide, sodium amide, etc. in 1 to large excess, preferably 1 to 5 equivalents may be used. The reaction temperature is 0 to 200 ° C, preferably 0 to 60 ° C. As the solvent to be used, hydrocarbons (for example, hexane, benzene, toluene, etc.), halogenated hydrocarbons (for example,
Methylene chloride, chloroform, dichloroethane, etc.),
Ethers (eg, tetrahydrofuran, dioxane, diethyl ether etc.), esters (eg ethyl acetate, methyl acetate etc.), protic polar solvents (eg methanol, ethanol etc.), aprotic polar solvents (eg acetonitrile, N) , N-dimethylformamide, dimethylsulfoxide, etc.), or a mixed solution of these solvents and water. The reaction time is usually 10 to 24 hours, preferably 1 to 10 hours.
It's time. (A-1) method and (A-2) method,
It can be carried out in the same manner as the method (A). The reaction of the compound (II-ii) with isocyanate in the method (A-2), the reaction with isothiocyanate, the acylation reaction and the sulfonylation reaction include the reaction of the compound (II) with isocyanate and the reaction with isothiocyanate, It can be carried out in the same manner as the acylation reaction and the sulfonylation reaction. The subsequent deprotection reaction of P ¹ can be carried out by a method known per se.

Method (B)

[Chemical 28] [In the formula, E represents a leaving group such as halogen (eg, chlorine, bromine, iodine, etc.), methanesulfonyloxy, p-toluenesulfonyloxy, and the other symbols have the same meanings as described above. In the reductive alkylation reaction of compound (V) in the method (B), a Schiff base is formed by using a ketone or an aldehyde with respect to compound (V) in an amount of 1 equivalent to a large excess, preferably 1 equivalent to 5 equivalents. Is reduced using, for example, a metal hydride such as sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, lithium aluminum hydride in an amount of 1 equivalent to a large excess, preferably 1 equivalent to 3 equivalents. You can do it. At this time, for example, acetic acid as a reaction accelerator,
1 to a large excess of an acid such as hydrochloric acid, preferably 1 to 3
You may use an equivalent amount. The reaction temperature is 0 to 200 ° C, preferably 0 to 60 ° C. As the solvent to be used, a protic polar solvent (eg, methanol, ethanol, etc.), hydrocarbons (eg, hexane, benzene, toluene, etc.), halogenated hydrocarbons (eg,
Methylene chloride, chloroform, dichloroethane, etc.),
Ethers (eg, tetrahydrofuran, dioxane, diethyl ether etc.), esters (eg ethyl acetate, methyl acetate etc.), aprotic polar solvents (eg acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide etc.) and the like. To be The reaction time is generally 10 to 24 hours, preferably 1 to 10 hours. The reaction of the compound (V) in the method (B) with the compound represented by the formula R ¹ —X ¹ —CH ₂ —E or a salt thereof is carried out by reacting the compound (V) with R ¹ —X ₁ —CH _{2 —} −
E is used in 1 equivalent to a large excess, preferably 1 equivalent to 3 equivalents. At this time, for example, as the base, an inorganic base (eg, potassium carbonate, sodium hydrogencarbonate, etc.), an organic base (eg, triethylamine, pyridine, dimethylamine, 1,8-diazabicyclo [5.4.0] -7-)
Undecene etc.), alcoholates (eg sodium methylate, sodium ethylate, tert-butoxy potassium etc.), organometallic reagents (eg n-butyl lithium etc.), sodium hydroxide, sodium amide etc. in 1 to large excess, Preferably 1 to 5 equivalents may be used. The reaction temperature is 0 to 200 ° C, preferably 0 to 100 ° C. As the solvent to be used, a protic polar solvent (eg, methanol, ethanol, etc.), hydrocarbons (eg, hexane, benzene, toluene, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), Ethers (eg, tetrahydrofuran, dioxane, diethyl ether etc.), esters (eg ethyl acetate, methyl acetate etc.), aprotic polar solvents (eg acetonitrile, N, N-dimethylformamide, dimethylsulfoxide etc.), or these And a mixed solution of water and the solvent. The reaction time is usually 10 to 2
It is 4 hours, preferably 1 to 10 hours.

Method (C)

[Chemical 29] [In the formula, Y represents —O—CO—NR ³ —, —CO—NR ³ — or —SO ₂ —NR ³ —, and other symbols have the same meanings as described above. The acylation reaction or sulfonylation reaction of the compound (V) in the method (C) is carried out by the compound (II) in the method (A).
It can be carried out in the same manner as the acylation reaction or sulfonylation reaction of. In the oxycarbonylation reaction of the compound (V) in the method (C), for example, a carbonic anhydride or a halogenated carbonate is used in an amount of 1 equivalent to a large excess, preferably 1 equivalent to 3 equivalents, relative to the compound (V). At this time, for example, as the base, an inorganic base (for example, potassium carbonate, sodium hydrogen carbonate, etc.), an organic base (for example, triethylamine, pyridine, dimethylamine,
1,8-diazabicyclo [5.4.0] -7-undecene etc.), alcoholates (eg sodium methylate, sodium ethylate, tert-butoxy potassium etc.), organometallic reagents (eg n-butyllithium etc.) ), Sodium hydroxide, sodium amide, etc. may be used in 1 to large excess, preferably 1 to 5 equivalents. The reaction temperature is 0 to 200 ° C, preferably 0 to 100 ° C. As the solvent to be used, hydrocarbons
(Eg, hexane, benzene, toluene, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), esters (eg ethyl acetate, acetic acid, etc.) Methyl, etc.), an aprotic polar solvent (eg, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, etc.), or a mixed solution of these solvents and water. The reaction time is usually 10 to 24 hours,
It is preferably 1 to 10 hours.

Method (D)

[Chemical 30] Wherein, Y is -NR ³ -CO- or -NR ³ '-NR ³
Represents -CO-, and other symbols have the same meanings as described above. The compound of (D) Method and (IV) wherein R ¹ -X ¹ -NH
-R ³ or a compound represented by ^{R 1 -X 1 -NR 3 '-NH} -R 3 or condensation reaction with a salt thereof, reaction with an amide forming reagent of the compound (II) with a carboxylic acid, compound The reaction can be carried out under the same conditions as the reaction of (II) with acid chloride or mixed acid anhydride.

[0024]

[Chemical 31] [X ⁵ represents a bond or an optionally substituted divalent hydrocarbon group, and other symbols have the same meanings as described above. Compound (II) is a compound represented by (VI) (B)
It can be synthesized by a method similar to the reductive alkylation reaction of compound (V) in the method.

[0025]

[Chemical 32] [Each symbol in the formula has the same meaning as described above. The compound (II-ii) can be synthesized from the compound represented by (VI-ii) by the same method as the reductive alkylation reaction of the compound (V) in the method (B).

[0026]

[Chemical 33] [In the formula, E ² represents halogen (eg, chlorine, bromine, iodine, etc.), and other symbols have the same meanings as described above. ]

The compound (VI) can be synthesized from the compound (VII) using a Suzuki coupling reaction known per se.

[Chemical 34] Compound (VI-ii) can be synthesized from compound (VII-ii) using a Suzuki coupling reaction known per se.

Among the compounds (VII), Y is --NR ³ --C
The compound (VII-i) which is H ₂ — can be synthesized by, for example, the following methods (E), (F) and (G). (E) method

[Chemical 35] [The symbols in the formulas have the same meanings as described above. ] In (E) Method and (VIII) wherein R ¹ -X ¹ -NH-
The reaction with the compound represented by R ³ or a salt thereof is carried out by using (B)
The reaction can be carried out by the same method as the reaction of the compound (V) with the compound represented by the formula R ¹ -X ¹ -E or a salt thereof in the method. (F) method

[Chemical 36] [The symbols in the formulas have the same meanings as described above. ] The reaction of (IX) in the method (F) with the compound represented by the formula R ¹ -X ¹ -E or a salt thereof can be carried out by reacting the compound (V) in the method (B) with the formula R ¹ -X ¹ -E. It can be carried out by a method similar to the reaction with the represented compound or a salt thereof. (G) method

[Chemical 37] [The symbols in the formulas have the same meanings as described above. The reductive alkylation reaction of compound (IX) in method (G) can be carried out by the same method as the reductive alkylation reaction of compound (V) in method (B).

Of the compounds (VII-ii), Y ² is -N
The compound (VII-ii ′) which is P ¹ —CH ₂ — can be synthesized, for example, by the following methods (H), (I), and (J). (H) method

[Chemical 38] [The symbols in the formulas have the same meanings as described above. ] Wherein R ¹ -X ¹ in (H) compounds in Method (VIII) -
The reaction with the compound represented by NH ₂ or a salt thereof is
It can be carried out by the same method as the reaction of the compound (V) with the compound represented by the formula R ¹ -X ¹ -E or the salt thereof in the method (B). Subsequent protection of the amino group can be carried out by a method known per se. (I) method

[Chemical Formula 39] [The symbols in the formulas have the same meanings as described above. ] The reaction of the compound (X) in the method (I) with the compound represented by the formula R ¹ -X ¹ -E or a salt thereof can be carried out by reacting the compound (V) in the method (B) with the formula R ¹ -X ¹ -E. Can be carried out by a method similar to the reaction with the compound represented by or a salt thereof. Subsequent protection of the amino group can be carried out by a method known per se. (J) method

[Chemical 40] [The symbols in the formulas have the same meanings as described above. The reductive alkylation reaction of compound (X) in method (J) can be carried out by the same method as the reductive alkylation reaction of compound (V) in method (B). Subsequent protection of the amino group can be carried out by a method known per se.

[0030]

[Chemical 41] [In the formula, P ² represents a protecting group for an amino group, and other symbols have the same meanings as described above. The compound (V) in the method (B) can be synthesized by the same method as the synthesis of the compound (I) in the method (A) from the compound (XI).

[0031]

[Chemical 42] [The symbols in the formulas have the same meanings as described above. Compound (XI) can be synthesized by subjecting compound (XII) to a reductive alkylation reaction by a method similar to the reductive alkylation reaction of compound (V) in the method (B).

[0032]

[Chemical 43] [The symbols in the formulas have the same meanings as described above. The compound (XII) can be synthesized by using the Suzuki coupling reaction known per se for the compound (XIII).

[0033]

[Chemical 44] [The symbols in the formulas have the same meanings as described above. The amino group of compound (XIV) can be protected by a method known per se.

[0034]

[Chemical formula 45] [In the formula, R ⁴ represents a lower (C _1-6 ) alkyl group, and other symbols have the same meanings as described above. Compound (IV) can be synthesized from compound (XV) by a method similar to the synthesis of compound (I) in method (A). Subsequent hydrolysis of the ester can be carried out by treating the ester form with an acid or a base.
That is, the ester form is converted into an acid (eg, hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, iodine acid, etc.) or a base (eg,
Sodium hydroxide, potassium hydroxide, barium hydroxide,
Lithium hydroxide, etc.) in water or a lower alcohol (eg, methanol, ethanol, propanol, etc.) solution at 0 to 100 ° C., preferably 10 ° C. to 50 ° C.
At 0.5 to 50 hours, preferably 1 to 5 hours. The strength of the acid or base is preferably 1 to 10 N, preferably 2 to 5 N.

[0035]

[Chemical formula 46] [The symbols in the formulas have the same meanings as described above. Compound (XV) can be synthesized by a method similar to compound (XVI) in the reductive alkylation reaction of compound (V) in method (B).

[0036]

[Chemical 47] [The symbols in the formulas have the same meanings as described above. The compound (XVI) can be synthesized by using a Suzuki coupling reaction known per se for the compound (XVII).

[Chemical 48] [Each symbol in the formula has the same meaning as described above. The compound (VI) can be synthesized by oxidizing the compound represented by the formula (1) or a salt thereof [compound (1)]. For the oxidation reaction of compound (1) to an aldehyde, for example, 1 to 20 equivalents of an oxidant are used with respect to 1 equivalent of alcohol. Examples of the oxidizing agent include active manganese dioxide, pyridinium chlorochromate (PCC), pyridinium chromate (PDC), dimethyl sulfoxide-anhydride (acetic anhydride, trifluoroacetic anhydride, etc.), dimethyl sulfoxide-thionyl chloride, dimethyl. Examples thereof include sulfoxide-sulfuryl chloride, dimethylsulfoxide-oxalyl chloride, dimethylsulfoxide-chlorine, and dimethylsulfoxide-dicyclohexylcarbodiimide (DCC) in the presence of an acid (phosphoric acid, trifluoroacetic acid, dichloroacetic acid, etc.). The solvent used at this time can be appropriately selected depending on the kind of the oxidizing agent, for example, industrial compounds (e.g., tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (e.g., methylene chloride, chloroform, etc.), Ketones (eg, acetone, methyl ethyl ketone, etc.), aprotic polar solvents
(Eg, N, N-dimethylformamide, dimethylsulfoxide, etc.) and the like. The reaction time is 0.5 to 48 hours, preferably 1 to 24 hours. The reaction temperature is appropriately selected depending on the type of oxidant, and is from -80 ° C to +
It can be carried out at 100 ° C, preferably -70 ° C to + 30 ° C.

[Chemical 49] [Each symbol in the formula has the same meaning as described above. The compound (1) can be synthesized by reducing the compound represented by the formula (2) or a salt thereof. In the reduction reaction of compound (2), one reducing agent is added to compound (2).
Equivalent to large excess, preferably 2-10 equivalents are used.
As the reducing agent, lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride,
Examples thereof include metal hydrogen complex compounds such as sodium cyanoborohydride and diborane. The solvent used at this time can be appropriately selected depending on the type of reducing agent, for example, alcohols (eg, methanol, ethanol, etc.), ethers
(Eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide, etc.) and the like. The reaction time is 0.5 to 72 hours, preferably 1 to 24 hours. Reaction is -80 to +100
C., preferably at -80 to + 30.degree.

[Chemical 50] [In the formula, Y represents —NR ³ —CO—, and other symbols have the same meanings as described above. The reaction of the compound (3) with the compound represented by the formula R ¹ —X ¹ —NH—R ³ or a salt thereof is carried out by reacting the compound (I
V) can be synthesized by a method similar to the reaction of the compound represented by the formula R ¹ -X ¹ -NH-R ³ or a salt thereof.

[Chemical 51] [Each symbol in the formula has the same meaning as described above. The reaction of the compound (4) with the compound represented by the formula R ¹ —X ¹ —NH—R ³ or a salt thereof can be carried out by reacting the compound (I
V) can be synthesized by a method similar to the reaction of the compound represented by the formula R ¹ -X ¹ -NH-R ³ or a salt thereof.

[Chemical 52] [Each symbol in the formula has the same meaning as described above. The compound (3) can be synthesized by reacting the compound (5) with a boronic acid using Suzuki coupling known per se.

[Chemical 53] [Each symbol in the formula has the same meaning as described above. The compound (4) can be synthesized by hydrolyzing the compound (6) with 1 equivalent of a base. That is, the compound (4) is added in an amount of 0.5 to 1.5 equivalents, preferably 1 equivalent of a base (eg, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide) water or a lower alcohol (eg, methanol). , Ethanol, propanol) solution at 0 to 100 ° C., preferably 10 to 50 ° C. for 1 to 48 hours, preferably 1 to 12 hours.

[Chemical 54] [Each symbol in the formula has the same meaning as described above. The compound (XV) is obtained by halogenating the compound (7),
It can also be synthesized by reacting with an amine. That is, the halogenation reaction of the compound (7) is carried out in 1 to a large excess, preferably 1 to 10 equivalents of the halogenating agent such as N-halogenoimide (eg, N-bromosuccinimide, N-) with respect to the compound (7). Chlorosuccinimide, etc.), N-halogenolactam (eg, N
-Bromocaprolactam, etc.), N-halogenophthalimide (for example, N-bromophthalimide), 1,3-diflomo-5,5-dimethylhydantoin, etc. are used. The solvent used at this time is a halogenated hydrocarbon.
(Eg, carbon tetrachloride, methylene chloride, chloroform etc.), aromatic hydrocarbons (eg benzene etc.), esters (eg ethyl acetate, methyl acetate etc.) and the like. During the reaction, for example, 2,2-azobis (isobutyronitrile), perbenzoic acid or the like is added as a catalyst, or the reaction can be promoted by irradiation with light. The reaction time is 0.5 to 48 hours, preferably 1 to 12 hours. Reaction temperature is from -20 ℃ to +
It can be carried out at 200 ° C, preferably 0 ° C to + 100 ° C.

Compound (I) obtained by the above method
Can be isolated and purified by a conventional separation means such as recrystallization, distillation and chromatography. When the compound (I) thus obtained is obtained as a free form, it can be converted into a salt by a method known per se or a method analogous thereto (for example, neutralization etc.), and conversely when obtained as a salt. Can be converted into the free form or other salt by a method known per se or a method analogous thereto. Furthermore, when the compound (I) is an optically active substance, it can be separated into d-form and l-form by a usual optical resolution means.

The compound (I) of the present invention has excellent LDL receptor increasing activity and lipid lowering activity, and has low toxicity. Therefore, these compounds and salts thereof are used in mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, horses, sheep, monkeys, humans, etc.) such as prophylactic / therapeutic agents for arteriosclerosis, It can be safely used as a preventive and therapeutic drug for lipemia, a preventive and therapeutic drug for complications of diabetes, hypertension and renal disease. Compound (I) is
The bulk powder may be used, but it is usually a carrier for pharmaceutical preparations such as excipients (eg, calcium carbonate, kaolin, sodium hydrogen carbonate, lactose, starches, crystalline cellulose, talc, granulated sugar, porous substances, etc.), binders. (For example, dextrin, gums, alcoholized starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, etc.), disintegrant (for example, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, Partially pregelatinized starch, etc., lubricants (eg,
Magnesium stearate, calcium stearate,
Talc, starch, sodium benzoate, etc.), colorants (for example, tar pigments, caramel, iron sesquioxide, titanium oxide,
Riboflavins, etc.), corrigents (eg, sweeteners, flavors, etc.), stabilizers (eg, sodium sulfite, etc.), preservatives (eg, parabens, sorbic acid, etc.), etc. It is administered in the form prepared according to the method. The prophylactic / therapeutic agent of the present invention containing the above-mentioned preparation appropriately contains Compound (I) in an amount effective for treating and preventing a disease. The content of the compound (I) in the preparation of the present invention is usually 0.1 to 100% by weight based on the whole preparation. Further, the preparation used in the present invention may contain a pharmaceutical ingredient other than the compound (I) as an active ingredient, and these ingredients are not particularly limited as long as the object of the present invention is achieved, and they are appropriately suitable. It can be used in various mixing ratios. Specific examples of dosage forms include tablets (including sugar-coated tablets and film-coated tablets), pills, capsules, granules, fine granules, powders, syrups, emulsions, suspensions, injections, inhalants, An ointment or the like is used. These preparations are prepared according to a conventional method (for example, the method described in the Japanese Pharmacopoeia).

Specifically, the tablet production method is as follows: Compound (I) is mixed as it is with excipients, binders, disintegrants or other appropriate additives, and the mixture is evenly mixed.
After granulating by an appropriate method, a lubricant or the like is added and compression-molded, or the compound (I) is used as it is, or an excipient, a binder, a disintegrating agent or other appropriate additive is added and the mixture is evenly added. Alternatively, it can be produced by directly compression-molding a mixture of the above-mentioned ingredients, or by directly mixing the granules produced in advance, or by appropriately mixing them with an appropriate additive and then compression-molding them. In addition, this agent, if necessary, a coloring agent,
A flavoring agent or the like can be added. Furthermore, this agent can be coated with a suitable coating agent. The method for producing an injection is as follows: a fixed amount of Compound (I) is dissolved, suspended or emulsified in water for injection, physiological saline, Ringer's solution, etc. in the case of an aqueous solvent and usually vegetable oil, etc. in the case of a non-aqueous solvent. It can be prepared in a quantity or by sealing a fixed amount of the compound (I) in a container for injection. As the oral pharmaceutical carrier, substances commonly used in the pharmaceutical field such as starch, mannitol, crystalline cellulose, sodium carboxymethyl cellulose and the like can be used. As the carrier for injection, for example, distilled water, physiological saline, glucose solution, infusion solution and the like are used. In addition, additives generally used in preparations can be added as appropriate. The formulation of the present invention can also be used as a sustained release formulation. The sustained-release preparation of the present invention is, for example, dried in water (o / w method, w
/ O / w method, etc.), phase separation method, spray drying method or a method equivalent thereto, such as microcapsules (eg, microspheres / microcapsules, microparticles, etc.) as they are, or these microcapsules or spherical or acicular The pharmaceutical composition in the form of pellet, film, or cream can be formulated into various dosage forms as a raw material and administered. The dosage form includes, for example, parenteral agents (for example, intramuscular, subcutaneous, injection or implant into organs; transmucosal agents into nasal cavity, rectum, uterus, etc.), oral agents (for example, hard capsules, Soft capsules, granules, powders, suspensions, etc.) and the like. When the sustained-release preparation of the present invention is an injection, microcapsules are dispersed (for example, surfactants such as Tween 80 and HCO-60;
Carboxymethyl cellulose, sodium alginate,
Polysaccharides such as sodium hyaluronate; protamine sulfate,
Polyethylene glycol, etc.), preservatives (eg, methylparaben, propylparaben, etc.), tonicity agents (eg,
Sodium chloride, mannitol, sorbitol, glucose, etc.), local anesthetics (eg, xylocaine hydrochloride, chlorobutanol, etc.) and the like as an aqueous suspension, or vegetable oil (eg, sesame oil, corn oil, etc.) or phospholipids ( For example, a mixture of lecithin, etc., or a medium-chain fatty acid triglyceride (eg, Miglyol 812)
Etc.) to form a sustained-release injection as an oily suspension. When the sustained-release preparation of the present invention is a microcapsule, its average particle size is about 0.1 to about 300 μm, preferably about 1 to about 150 μm, more preferably about 2 to about 100 μm. Examples of aseptic preparations of microcapsules include, but are not limited to, a method of sterilizing all manufacturing steps, a method of sterilizing with gamma rays, and a method of adding a preservative.

The preparation of the present invention has low toxicity, is useful as a medicine, and has excellent LDL receptor increasing activity and lipid lowering activity. Therefore, the preparation of the present invention is useful as a prophylactic / therapeutic drug for diseases based on these pharmacological actions. That is, arteriosclerotic diseases, hyperlipidemia, hyperlipidemia or complications associated with arteriosclerosis (eg, diabetic complications associated with hyperlipidemia or arteriosclerosis, hyperlipidemia or arteriosclerosis Associated hypertension complications), diabetes, diabetic complications, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, obesity, renal disease, chronic renal failure, nephrotic syndrome, renal failure and renal dialysis complications, Treatment of myocardial infarction, angina, heart failure, arrhythmia, valvular heart disease, sequelae of myocardial infarction, stroke, cerebral infarction, transient cerebral ischemia, Alzheimer's disease, osteoporosis, peripheral vascular disease, thrombosis, pancreatic disorder, etc. Alternatively, it can be used for prevention. Among them, hyperlipidemia; arteriosclerosis; complications associated with hyperlipidemia or arteriosclerosis (eg, hyperlipidemia or diabetic complications associated with arteriosclerosis, hyperlipidemia or arteriosclerosis Associated with hypertension, etc.); The compound (I) and its salt have a cholesterol and triglyceride lowering action. Given their biological properties, hyperlipidemia, in particular hypertriglyceridemia, hyperlipoproteinemia and hypercholesterolemia and the atherosclerotic vascular lesions and their sequelae which arise therefrom, for example: It is particularly suitable for treatment and prevention of coronary artery disease, myocardial infarction, ischemic brain disease, cerebral ischemia, aneurysm, cerebral arteriosclerosis, peripheral arteriosclerosis, intermittent claudication, gangrene and the like.

In the treatment of these diseases, the compound (I) may be used alone for prevention and / or treatment, or may be used together with other lipid-lowering drug or cholesterol-lowering drug, in which case These compounds are preferably administered as an oral preparation, and if necessary, may be administered as a rectal preparation in the form of suppositories. In this case, components that can be combined include, for example, (1) fibrates (eg, clofibrate, bezafibrate, gemfibrozil, fenofibrate, etc.), nicotinic acid, its derivatives and analogs (eg, acipimox, probucol, etc.) , (2)
Bile acid-binding resins (eg, cholestyramine, colestipol, etc.), compounds that inhibit cholesterol absorption (eg, sitosterol, neomycin, etc.), (3) Compounds that inhibit cholesterol biosynthesis, eg, HMG-C
oA reductase inhibitors (lovastatin, simvastatin,
Pravastatin, cerivastatin, atorvastatin,
Fluvastatin, etc.), squalene synthase inhibitor, squalene epoxidase inhibitor (eg, NB-598 and its related compounds), oxidosqualene-lanosterol cyclase inhibitor (eg, decalin derivative,
(Azadecalin derivative, indane derivative, etc.), (4) drugs involved in cholesterol transfer, such as cholesteryl ester transfer protein (CETP) inhibitor, CETP vaccine, ACAT inhibitor, (5) antioxidants such as probucol, vitamin E, (6) Eicosapentaenoic acid and the like can be mentioned. Yet another possible combination component is MTP
(Microsome triglyceride transfer protein) inhibitors (eg, implitapide etc.) and the like can be mentioned. In addition, compound (I) is suitable for the prophylactic treatment of diseases associated with hyperchylomicronemia, eg acute pancreatitis. Regarding the mechanism of pancreatitis development, chylomicrons cause microembolism in pancreatic capillaries, or pancreatic lipase decomposes triglycerides to increase free fatty acids generated due to hyperchylomicronemia, which strongly stimulates the local area. It is also said to occur. Therefore, since the compound (I) of the present invention has a triglyceride lowering effect, it can be used alone or in combination with known therapeutic methods for the prophylactic treatment of pancreatitis. For the prophylactic treatment of the disease, compound (I) can be administered orally or topically, and they may be used alone or with known active compounds such as aprotinin,
It may be used in combination with gabexate methanesulfonate, nafamostat methanesulfonate, citicoline, ulinastatin and the like.

A further noteworthy application of compound (I) is secondary hyperlipidemia. These include hypertension, diabetes, insulin resistance (syndrome X), hypothyroidism, nephrotic syndrome, chronic renal failure, etc., which cause hyperlipidemia, but in many cases high It is said that lipemia exacerbates these diseases and forms a so-called vicious circle. In view of the hypolipidemic action, the compound (I) is also suitable for treating and preventing the progress of these diseases, in which the compound (I) is used alone or in combination with a known active compound, preferably by oral administration. Can be used. In combination with antihypertensive drugs,
For example, (1) diuretics (eg, furosemide, spironolactone, etc.), (2) sympathomimetics (eg, atenolol, etc.), (3) angiotensin II antagonists (eg, losartan, candesartan, etc.), (4) angiotensin. Examples thereof include I-converting enzyme inhibitors (eg, enalapril maleate, delapril hydrochloride, etc.), (5) calcium antagonists (eg, nifedipine, manidipine hydrochloride, etc.) and the like. When used in combination with a diabetes treatment drug, for example,
(1) Insulin preparation (eg, human insulin),
(2) Sulfonylurea agents (eg, glibenclamide, gliclazide, etc.), (3) α-glucosidase inhibitors (eg, voglibose, acarbose, etc.), (4)
Examples include insulin sensitivity enhancers (eg, pioglitazone, troglitazone, rosiglitazone, etc.), (5) aldose reductase inhibitors (eg, epalrestat, tolrestat, etc.), glycation inhibitors (eg, aminoguanidine, etc.) and the like. When used in combination with a therapeutic drug for hypothyroidism, dried thyroid, levothyroxine sodium, liothyronine sodium, etc. It may be used in combination, preferably orally.

Further possible uses of the compound (I) of the present invention include inhibition of thrombus formation. Hypertriglyceridemia promotes thrombus formation because blood triglyceride level is positively correlated with factor VII involved in blood coagulation, and intake of ω-3 fatty acids reduces triglyceride and suppresses coagulation. It is also thought to do. Moreover, since VLDL in hyperlipidemic patients strongly increased secretion of plasminogen activator inhibitor from vascular endothelial cells compared to normolipidemic patients, it is considered that triglyceride reduces fibrinolytic activity. Therefore, considering the triglyceride lowering action, the compound (I) is suitable for the prevention and treatment of thrombus formation. In that case, they may be used alone or with known therapeutic agents such as dipyridamole, dilazep hydrochloride, thrombolytic agents (eg, heparin sodium, urokinase, etc.), antiplatelet agents (eg, aspirin, sulfinpyrazone, ticlopidine hydrochloride, cilostazol, etc.).
It may be used preferably in combination with oral administration. A further notable indication of the compounds of formula (I) is osteoporosis associated with elevated blood cholesterol. Due to the excellent lipid-lowering action of the compound of formula (I), it can be used for the treatment / prevention of osteoporosis associated with the elevation of blood cholesterol. It can be administered together. Possible combinations in this case include, for example, sex hormones and related drugs (eg, estrogen preparations, ipriflavone (ostene), raloxifene, osaterone, tibolone, etc.),
Examples thereof include bone resorption inhibitors such as calcitonin, vitamin D preparations (eg, alfacalcidol, calcitriol, etc.), bisphosphonic acids (eg, etidronate, clodronate, etc.), fluorine compounds, and bone formation promoters such as PTH. Further notable applications of the compounds of formula (I) are the prevention and treatment of Alzheimer's disease. Elevated blood choleterol is known to be a risk factor for Alzheimer's disease. The compound represented by formula (I) or a salt thereof, or a prodrug thereof is
Due to its excellent lipid-lowering effect, it can be used for the prevention and treatment of Alzheimer's disease, in which case the compound represented by the formula (I) or a salt thereof may be administered alone or in combination with the agents exemplified below. it can. Possible combinations in this case include, for example, acetylcholinesterase inhibitors (e.g., Aricept, exerone, etc.), amyloid β production / secretion inhibitors (e.g., JT-52 and L
Γ or β secretase inhibitors such as Y-374973, or SIB-1848), amyloid β aggregation inhibitors (for example,
PTI-00703, BETABLOC (AN-1792, etc.), amyloid β vaccine and the like. When the compound of formula (I) is applied to each of the above diseases, it can be used in combination with various antibodies, various vaccine preparations, etc., and can also be applied as combination therapy in combination with various gene therapy methods. It is possible. Examples of antibodies and vaccine preparations include vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, antibodies against TNFα antibody and other cytokines, amyloid β vaccine preparations, and the like,
Antibodies or vaccine preparations against cytokines, renin-angiotensin enzymes and their products, antibodies or vaccine preparations against enzymes or proteins involved in blood lipid metabolism, antibodies or vaccine preparations against proteins involved in sugar metabolism or insulin resistance, etc. To be As gene therapy methods, for example, cytokines, renin-angiotensin enzymes and therapeutic products using genes related to their products, therapeutic methods using genes related to enzymes and proteins involved in blood lipid metabolism, Treatment methods using genes related to proteins involved in glucose metabolism and insulin resistance can be mentioned. Although the dose of the preparation of the present invention varies depending on the administration route, symptoms, age or weight of the patient, for example, it is orally administered to adult patients as a therapeutic agent for hyperlipidemia or therapeutic agent for arteriosclerosis. In that case, the amount of the compound (I) per day is 0.2 to 200 mg, preferably 0.2 to 50 mg, more preferably 1.5 to 3
It is desirable to administer 0 mg once to several times a day. The route of administration may be oral or parenteral. In addition, the dose of the sustained-release preparation of the present invention is determined by the route of administration, symptoms,
Although it varies depending not only on the patient's age or body weight, but also on the duration of release, etc., it is not particularly limited as long as the effective concentration of the compound (I) as the active ingredient is maintained in the body, and its administration The number of times can be appropriately selected depending on the situation such as once a day to 3 days or once a week to 3 months.

[0044]

The compound (I) of the present invention has excellent LDL.
Since it has a receptor increasing action and a lipid lowering action, pharmaceutical preparations containing these compounds can be safely and advantageously used as, for example, a prophylactic / therapeutic drug for arteriosclerotic diseases, a prophylactic / therapeutic drug for hyperlipidemia and the like.

[0045]

BEST MODE FOR CARRYING OUT THE INVENTION Experimental results showing the pharmacological effects of the compound (I) of the present invention will be described below. Test Example 1: LDL receptor gene transcription promoting action in HepG2 cells (reporter assay) [Test method] HepG2 cells purchased from ATCC (American Type Culture Collection) were used in RPMI1640 medium (10%
1.6 × 10 ⁴ cells / we in FCS-containing and phenol red-free)
ll (80 μl / well), and then seeded on a 96-well luminescence plate (Corning Costar). After culturing for 24 hours, pGL3 basic / LDLRP 0.3 μg / well, lipid (Superfecttr
ansfection reagent (QIAGEN)) 1 μl / well, RPMI1640 me
dium (without FCS, phenol red, antibiotics) 20 μl / we
ll mixed solution was added and reacted in a 37 ° C. carbon dioxide incubator to transiently introduce the reporter gene. Two
After a period of time, the culture supernatant was removed and RPMI1640 mediu containing 10% FCS was added.
m (phenol red-free) was replaced with 100 ml / well, and the test compound was added at the same time. After culturing for another 22 hours, PicaGene L
100 μl / well of T7.5 (Toyo Ink) was added and the luciferase activity was measured. In order to remove non-specific transcription promoters, instead of pGL3 basic / LDLRP, a reporter expressing the luciferase gene (pGL3-
A reporter assay was similarly performed using control (Promega). The results are shown in [Table 1] and [Table 2].

[0046]

[Table 1]

[0047]

[Table 2]

Test Example 2: LDL binding increasing action on HepG2 cells [Test method] Hep purchased from ATCC (American Type Culture Collection) by the method of JL Goldstein et al.
Transfer G2 cells to Eagle's minimum essential medium [MEM] (10%
6-well plate coated with collagen after being dispersed in FBS)
(Sumitomo Bakelite) was seeded and cultured for 4 days in a carbon dioxide incubator at 37 ° C. After washing the cells, MEM (10% F
25-hydroxycholeterol as a standard compound under BS)
(2.3 μM), each test compound was added at 5 μM, and then incubated in a carbon dioxide gas incubator for 20 hours. After washing with PBS, ¹²⁵ I-human LDL (4 μg / ml) in MEM (25
mM HEPBS, 1% BSA-FAF) was added. Furthermore, for non-specific binding ability (NSB), LDL (300 μg / ml) was added and binding was performed at 4 ° C. for 2 hours. It was dissociated with dextran sulfate to measure ¹²⁵ I, which was taken as the total binding capacity. The amount of protein was measured by lysing the cells with 0.5N NaOH and following the Lowry method. Specific binding capacity (LDL-Bi
For the nding value), the nonspecific binding ability was subtracted from the total binding ability, and the value corrected with the amount of protein was expressed as% of the control group. The results are shown in [Table 3].

[Table 3] From the results of [Table 1] to [Table 3], the compound (I) of the present invention
Has an excellent LDL receptor increasing action.
Therefore, the compound (I) of the present invention decreases LDL and VLDL in blood, and is therefore useful for cardiovascular diseases such as arteriosclerosis and hyperlipidemia.

[0049]

EXAMPLES The present invention will be further described in the following examples and reference examples, which are merely illustrative and are not intended to limit the present invention, and do not depart from the scope of the present invention. You may change with. ¹ H-NMR spectrum was measured by Varian Gemini 200 (200 MHz) using tetramethylsilane as an internal standard, and all δ values are shown in ppm. The numerical values shown for the mixed solvent are volume mixing ratios of the respective solvents unless otherwise specified. Unless otherwise specified,% means% by weight. In addition, the elution solvent in silica gel chromatography indicates a volume ratio unless otherwise specified. The room temperature (normal temperature) in the present specification refers to a temperature of about 20 ° C to about 30 ° C.

The symbols in the examples and reference examples have the following meanings. s: singlet, d: doublet,
t: triplet, q: quartet, br: wide range, J: coupling constant, dd: double doublet, m:
Multiplet, Hz: Hertz, CDCl _3: heavy chloroform,%: weight%.

Reference Example 1 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1 ′
-Biphenyl 1) N- (4-bromobenzyl) -N-cyclohexylamine 4-bromobenzyl bromide (24.0 g, 96.0 mmol) and cyclohexylamine (29 ml, 0.25 mol) in N, N-dimethylformamide (100 ml) was added to the solution. The mixture was stirred at room temperature for 2 hours. The reaction solution was mixed with water (3
It was diluted with 00 ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue
Purify with (chloroform: methanol = 20: 1-10: 1) and N-
(4-Bromobenzyl) -N-cyclohexylamine (24.5g, 9
5%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.00-2.00 (10H, m), 2.38-2.55 (1H,
m), 3.77 (2H, s), 7.20 (2H, d, J = 8.4Hz), 7.44 (2H, d, J = 8.
4Hz). 2) N- (4-bromobenzyl) -N-tert-butoxycarbonyl-
N-cyclohexylamine N- (4-bromobenzyl) -N-cyclohexylamine (24 g, 89.5 mmol) and ethyl acetate (300 m
l) and saturated aqueous sodium hydrogen carbonate (200 ml) were added with di-tert-butyl dicarbonate (23.4 g, 0.107 mol), and the mixture was stirred at room temperature for 5 hr. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate,
It was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: diethyl ether = 20: 1-5: 1) to give N- (4-bromobenzyl) -N-tert-butoxycarbonyl.
-N-Cyclohexylamine (32.8 g, 99%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.85 (19H, m), 3.90-4.20 (1H,
m), 4.30 (2H, s), 7.10 (2H, d, J = 8.2Hz), 7.41 (2H, d, J = 8.
2Hz). 3) 4 '-(N-tert-butoxycarbonyl-N-cyclohexyl)
Aminomethylbiphenyl-4-carbaldehyde N-4-bromobenzyl-N-tert-butoxycarbonyl-N-cyclohexylamine (11.0 g, 30 mmol), 4-formylbenzeneboronic acid (5.40 g, 36 mmol), tetrakistriphenyl Phosphine palladium (1.04 g, 0.9 mmol), sodium carbonate (6.36 g, 60 mmol), toluene (100 ml), water (100 ml)
The mixture was stirred at 70 ° C for 13 hours. Ethyl acetate in the reaction solution
(50 ml) was added for extraction, the extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue (hexane: diethyl ether)
= 10: 1-5: 1) to give 4 '-(N-tert-butoxycarbonyl-N-cyclohexyl) aminomethylbiphenyl-4-carbaldehyde (4.6g, 39%) as colorless crystals. . . Mp 113-114 ° C. as the elemental analysis C ₂₅ H ₃₁ NO _3, calc: C, 76.30; H, 7.94 ; N, 3.56 Found:. C, 76.33; H, 7.87; N, 3.58 1 H-NMR (CDCl ₃ ) δ: 0.90-1.84 (19H, m), 3.95-4.20 (1H,
m), 4.43 (2H, s), 7.35 (2H, d, J = 8.4Hz), 7.59 (2H, d, J = 8.
2Hz), 7.76 (2H, d, J = 8.4Hz), 7.80 (2H, d, J = 8.4Hz), 10.06
(1H, s, CHO). 4) 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,
1'-biphenyl 4 '-(N-tert-butoxycarbonyl-N-cyclohexyl) aminomethylbiphenyl-4-carbaldehyde (4.5g, 11.4mm
ol) and 3-aminomethylpyridine (1.40 ml, 13.7 mmol), acetic acid (1.57 ml, 14.9 mmol), sodium chloride (30 g) and methanol (50 ml) were stirred for 1 hour and then triacetoxy hydrogenated Elemental sodium (3.15 g, 14.9 mmol) was added in small portions. After stirring the reaction solution for 24 hours, saturated aqueous sodium hydrogen carbonate (300 m
It was diluted with l) and extracted with ethyl acetate (200, 100 ml). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Ethyl acetate = 1: 1-hexane: acetone: methanol = 15: 15:
Purified in 1), 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (3.73g, 67% ) Was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.95-1.85 (19H, m), 3.85 (3H, s), 3.9
0-4.20 (1H, m), 4.40 (2H, s), 7.22-7.36 (2H, m), 7.40 (2H,
d, J = 8.2Hz), 7.48-7.54 (5H, m), 7.68-7.80 (1H, m), 8.48
-8.57 (1H, m), 8.59 (1H, d, J = 1.8Hz).

Reference Example 2 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-(benzylaminomethyl) biphenyl 4'-(N-tert-butoxycarbonyl-N-cyclohexyl) aminomethylbiphenyl -4-carbaldehyde (4.2g, 10.7mm
ol) and benzylamine (1.28 ml, 11.7 mmol), acetic acid (0.73 m
l, 12.8mmol), sodium chloride (30g), methanol (70m
After stirring the mixed solution of l) for 1 hour, sodium triacetoxyborohydride (2.94 g, 13.9 mmol) was added little by little.
The reaction mixture was stirred for 12 hours, diluted with saturated aqueous sodium hydrogen carbonate (200 ml), and extracted with ethyl acetate (150 ml × 2). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate
= 3: 1-1: 1), 4- (N-tert-butoxycarbonyl-
N-Cyclohexylamino) methyl-4 ′-(benzylaminomethyl) biphenyl (3.2 g, 62%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.82 (19H, m), 3.84 (2H, s), 3.8
5 (2H, s), 3.90-4.20 (1H, m), 4.40 (2H, s), 7.25-7.50 (9
H, m), 7.50-7.65 (4H, m).

Reference Example 3 2-[(4 '-{[(3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl] -1H-isoindole-1,3 ( 2H)
-Dione 1) N- (4-bromobenzyl) methylphthalimide p-Bromobenzylbromide (15g, 60.0mmol) in N, N-dimethylformamide (100ml) was added to potassium phthalimide.
(13.3 g, 72.0 mmol) was added and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was diluted with water (500 ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to give N- (4-bromobenzyl) methylphthalimide (16.3 g, 86%). Melting point 123-124 ° C ¹ H-NMR (CDCl ₃ ) δ: 4.79 (2H, s), 7.31 (2H, d, J = 8.4Hz),
7.38-7.55 (2H, m), 7.65-7.80 (2H, m), 7.80-7.98 (2H, m). 2) 2-[(4'-formyl [1,1'-biphenyl] -4-yl) Methyl]
-1H-isoindole-1,3 (2H) -dione N- (4-bromobenzyl) methylphthalimide (6.32g, 20.0
mmol) and 4-formylbenzeneboronic acid (3.60 g, 24.0 mmo
l), tetrakistriphenylphosphine palladium (0.6
A mixture of 9 g, 0.60 mmol), sodium carbonate (4.24 g, 40.0 mmol), toluene (50 ml) and water (50 ml) was stirred at 70 ° C. for 20 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction mixture, and the mixture was extracted with dichloromethane (200,100 ml). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Silica gel column chromatography of the residue (chloroform: ethyl acetate = 5: 1)
Purified by 2-[(4'-formyl [1,1'-biphenyl] -4-yl) methyl] -1H-isoindole-1,3 (2H) -dione (5.15g,
75%) was obtained as crystals. As mp 176-177 ° C. Elemental analysis C ₂₂ H ₁₅ NO _3, calc: C, 77.41; H, 4.43 ; N, 4.10 Found:. C, 77.21; H, 4.27; N, 4.10 1 H-NMR ( CDCl ₃ ) δ: 4.91 (2H, s), 7.50-7.65 (4H, m), 7.65
-7.80 (4H, m), 7.80-8.00 (4H, m), 10.04 (1H, s). 3) 2-[(4 '-{[(3-pyridylmethyl) amino] methyl} [1,1'
-Biphenyl] -4-yl) methyl] -1H-isoindole-1,3
(2H) -dione 2-[(4'-formyl [1,1'-biphenyl] -4-yl) methyl] -1H
-Isoindole-1,3 (2H) -dione (4.5g, 13.2mmol) and 3-
Aminomethylpyridine (1.61ml, 15.8mmol), acetic acid (1.89m
l, 33.0 mmol), sodium chloride (25 g), methanol-chloroform (100 ml-100 ml) after stirring a mixed solution for 1 hour,
Sodium triacetoxyborohydride (3.63g, 17.1mm
ol) was added in small portions. The reaction mixture was stirred for 20 hours, diluted with saturated aqueous sodium hydrogen carbonate (150 ml), and extracted with ethyl acetate (200,100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 1: 1) and
-[(4 '-{[(3-Pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl] -1H-isoindole-1,3 (2H)-
Dione (2.95 g, 52%) was obtained as colorless crystals. Melting point 121-122 ° C ¹ H-NMR (CDCl ₃ ) δ: 4.84 (4H, s), 4.89 (2H, s), 7.20-7.34
(1H, m), 7.39 (2H, d, J = 8.0Hz), 7.46-7.63 (6H, m), 7.64
-7.80 (3H, m), 7.80-7.98 (2H, m), 8.50-8.56 (1H, m), 8.5
6- 8.63 (1H, m).

Reference Example 4 4- (2-thienyl) benzoic acid 1) Ethyl 4- (2-thienyl) benzoate p-Bromobenzoic acid ethyl ester (2.14 ml, 13.1 mmol) in water (60 ml) in water (60 ml) ), Sodium carbonate (2.78 g,
26.2 mmol), tetrakistriphenylphosphine palladium (0.76 g, 0.66 mmol), 2-thienylboronic acid (1.85 g,
14.4 mmol) were added in that order, and the mixture was stirred overnight at 80 ° C. under a nitrogen atmosphere. After the reaction was completed, it was diluted with ethyl acetate and washed with water and saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 40: 1-30: 1) to obtain ethyl 4- (2-thienyl) benzoate (0.60 g, 20%) as a colorless solid. Melting point 60-62 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.40 (3H, t, J = 7.0Hz) 4.39
(2H, q, J = 7.0Hz) 7.11 (1H, dd, J = 1.6, 4.8Hz,) 7.36
(1H, dd, J = 1.0, 4.8Hz) 7.41 (1H, dd, J = 1.0, 3.6H
z) 7.66 (2H, d, J = 8.4Hz) 8.06 (2H, d, J = 8.4Hz). 2) 4- (2-thienyl) benzoic acid 4- (2-thienyl) ethyl benzoate (0.60g, 2.58 mmol)
A 2N aqueous sodium hydroxide solution (3 ml, 6 mmol) was added dropwise to a tetrahydrofuran-methanol (1: 3, 12 ml) solution at room temperature, and the mixture was stirred at 50 ° C. for 2 hours. After completion of the reaction, the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give 4- (2-thienyl) benzoic acid (0.45 g, 80%) as colorless crystals. mp: 248-249 ℃ ¹ H-NMR (CDCl ₃ ) δ (ppm) 7.11 (1H, dd, H = 3.2, 4.6Hz)
7.38 (1H, d, J = 6.2Hz) 7.44 (1H, d, J = 3.4Hz) 7.71
(2H, d, J = 8.4Hz) 8.10 (2H, d, J = 8.0Hz).

Reference Example 5 4- (2-Furyl) benzoic acid 1) Ethyl 4- (2-furyl) benzoate p-iodo Ethyl benzoate (0.37 ml, 2.22 mmol) and tri-
Tetrakistriphenylphosphine palladium (0.13 g, 0.11 mmol) was added to a tetrahydrofuran solution (5 ml) of n-butyl (2-furyl) stannane (0.87 g, 2.44 mmol), and the mixture was refluxed for 20 hours under an argon atmosphere. The reaction was terminated with saturated aqueous sodium hydrogen carbonate, diluted with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 40: 1-30: 1). Ethyl 4- (2-furyl) benzoate (0.42g, 87%) was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.40 (3H, t, J = 7.4Hz) 4.38
(2H, q, J = 7.0Hz) 6.50 (1H, dd, J = 1.8. 3.2Hz) 6.78
(1H, d, J = 3.8Hz) 7.51 (1H, d, J = 1.8Hz) 7.72 (2H, d,
J = 8.4Hz) 8.05 (2H, d, J = 8.4Hz). 2) 4- (2-furyl) benzoic acid ethyl 4- (2-furyl) benzoate (0.42g, 1.94mmol) in tetrahydrofuran-methanol ( 1: 3, 8 ml) was added dropwise with 2N aqueous sodium hydroxide solution (2 ml, 4 mmol) at room temperature, and the mixture was stirred at 50 ° C. for 2 hours. After completion of the reaction, the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give 4- (2-furyl) benzoic acid (0.27 g, 69%) as colorless crystals. Melting point 235-236 ° C (decomposition) ¹ H-NMR (CDCl ₃ ) δ (ppm) 6.50-6.54 (1H, m) 6.80-6.81
(1H, m) 7.53-7.54 (1H, m) 7.69-7.75 (2H, m) 8.03-
8.09 (2H, m)

Reference Example 6 4- (N-tert-butoxycarbonyl-N-cycloheptylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1 ′
-Biphenyl 1) 4-Bromobenzylcycloheptylamine p-Bromobenzylamine (75 g, 300 mmol) in acetonitrile (500 ml) was added to cycloheptylamine (59 ml, 4
63 mmol) and triethylamine (63 ml, 452 mmol) were added at room temperature, and the mixture was stirred for 30 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1:
1, hexane: acetone = 1: 1). 4-Bromobenzylcycloheptylamine (63.44 g, 75%) was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.19 (1H, m) 1.36-1.88 (11
H, m) 2.26-2.66 (1H, m) 3.69 (2H, s) 7.15 (2H, d, J
= 8.4Hz) 7.40 (2H, d, J = 8.4Hz). 2) 4-Bromobenzyl (N-tert-butoxycarbonyl-N-cycloheptyl) amine 4-Bromobenzylcycloheptylamine (63.44g, 225m
(mol) in ethyl acetate (250 ml) and add saturated aqueous sodium hydrogen carbonate.
(250 ml) and di-tert-butyl dicarbonate (59 g, 270 mmol) were added in that order, and the mixture was stirred at room temperature for 1.5 hr. After the reaction was completed, it was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, saturated aqueous sodium hydrogen carbonate was added, N, N-dimethylaminopropylamine (5 ml) was added, and the mixture was stirred for 2 hr.
After diluting again with ethyl acetate, the organic layer was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 40: 1-30:
It was purified by 1-20: 1-5: 1). 4-Bromobenzyl (Nt
ert-Butoxycarbonyl-N-cycloheptyl) amine (8
7.66 g, quant.) Was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-1.8 (12H, m) 1.47 (9H,
s) 4.0-4.2 (1H, br) 4.27 (2H, s) 7.11 (2H, d, J = 7.
6Hz) 7.41 (2H, d, J = 8.4Hz). 3) 4 '-(N-tert-butoxycarbonyl-N-cycloheptylamino) methylbiphenyl-4-carbaldehyde 4-bromobenzyl (N-tert-butoxy) Carbonyl-N-cycloheptyl) amine (60 g, 157 mmol) to 4-formylbenzeneboronic acid (26 g, 173 mmol), tetrakistriphenylphosphine palladium (9.1 g, 7.85 mmol), sodium carbonate (33.3 g, 314 mmol), toluene ( 350ml), water (350
(ml) was stirred at 80 ° C for 21 hours. The reaction solution was diluted with ethyl acetate and washed with water. The extract was evaporated under reduced pressure after drying the organic layer with anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 40: 1-20: 1-5: 1) and 4 '-(N-tert-
Butoxycarbonyl-N-cycloheptylamino) methylbiphenyl-4-carbaldehyde (56.59 g, 93%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (12H, m) 1.35 (9H,
s) 4.0-4.2 (1H, br) 4.40 (2H, s) 7.35 (2H, d, J = 7.
8Hz) 7.59 (2H, d, J = 8.4Hz) 7.76 (2H, d, J = 8.4Hz)
7.95 (2H, d, J = 8.4Hz) 10.05 (1H, s). 4) 4- (N-tert-butoxycarbonyl-N-cycloheptylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl ] -1,
1'-biphenyl 4 '-(N-tert-butoxycarbonyl-N-cycloheptylamino) methylbiphenyl-4-carbaldehyde (55.59g,
146 mmol) in methanol (400 ml) in sodium chloride
(60 g) was added and 3-aminomethylpyridine (30 m
l, 296 mmol) and acetic acid (33 ml, 576 mmol) were added dropwise, and the mixture was stirred for 1 hour. Then, sodium triacetoxyborohydride (62 g, 296 mmol) was added little by little, and the mixture was stirred at room temperature for 1 hour. The reaction was terminated by adding saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1. : 1,
Hexane: acetone = 1: 1, hexane: acetone: methanol = 1: 1: 0.1) and purified by 4- (N-tert-butoxycarbonyl-N-cycloheptylamino) methyl-4 '-[(3-pyridyl Methyl) aminomethyl] -1,1'-biphenyl (70.71g, quant.)
Was obtained as colorless crystals. Melting point: 175-178 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (12H, m) 1.34 (9H,
s) 3.92 (2H, s) 3.94 (2H, s) 4.0-4.2 (1H, br) 4.36
(2H, s) 7.25-7.61 (9H, m) 8.10 (1H, d, J = 7.8Hz)
8.56 (1H, s) 8.58 (2H, s).

Reference Example 7 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(2-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl 4 '-(N-tert-butoxycarbonyl-N-cyclohexylamino) methylbiphenyl-4-carbaldehyde (1.55g, 3.9
4 mmol) in methanol (30 ml) in sodium chloride (5
g), acetic acid (0.56 ml, 9.9 mmol), 2-aminomethylpyridine
(0.61 ml, 5.9 mmol) were added in sequence. After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (1.25 g, 5.
9 mmol) was added little by little. After stirring at room temperature for 15.5 hours, saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
Purify with (hexane: acetone = 3: 2-1-1: 1: 2) and
-(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(2-pyridylmethyl) aminomethyl] -1,
1'-Biphenyl (1.31 g, 68%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (8H, m) 2.07 (2H,
s) 1.40 (9H, s) 3.89 (2H, s) 3.95 (2H, s) 4.0-4.2
(1H, br) 4.40 (2H, s) 7.16 (1H, dd, J = 6.0, 7.4Hz)
7.26-7.58 (10H, m) 7.65 (1H, dt, J = 1.8, 7.8Hz) 7.5
5-7.58 (1H, s)

Reference Example 8 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(4-pyridylmethyl) aminomethyl] -1,1 ′
-Biphenyl 4 '-(N-tert-butoxycarbonyl-N-cyclohexylamino) methylbiphenyl-4-carbaldehyde (1.55g, 3.9
4 mmol) in methanol (30 ml) in sodium chloride (5
g), acetic acid (0.56 ml, 9.9 mmol), 4-aminomethylpyridine
(0.61 ml, 5.9 mmol) were added in sequence. After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (1.25 g, 5.
9 mmol) was added little by little. After stirring at room temperature for 15.5 hours, saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
Purify with (hexane: acetone = 3: 2-1-1: 1: 2) and
-(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(2-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (1.31 g, 68%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (8H, m) 2.07 (2H,
s) 1.40 (9H, s) 3.89 (2H, s) 3.95 (2H, s) 4.0-4.2
(1H, br) 4.40 (2H, s) 7.16 (1H, dd, J = 6.0, 7.4Hz)
7.26-7.58 (10H, m) 7.65 (1H, dt, J = 1.8, 7.8Hz) 7.5
5-7.58 (1H, s)

Reference Example 9 N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -2
-Pyridineamine 4 '-(N-tert-butoxycarbonyl-N-cyclohexylamino) methylbiphenyl-4-carbaldehyde (1.55g, 3.94
Sodium chloride (10 ml) in methanol solution (30 ml)
g), acetic acid (2.3 ml, 39.4 mmol), 2-aminopyridine (1.85
g, 19.7 mmol) were added in sequence. After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (4.2g, 19.7mmo
l) was added little by little. After stirring at room temperature for 15 hours, saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
Silica gel column chromatography (hexane)
: N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl: purified with ethyl acetate = 1: 1, hexane: acetone = 1: 1) ] -4-yl} methyl) -2-pyridinamine (1.43g, 77%) was obtained as pale yellow crystals. Melting point: 100-103 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.10 (1H, br) 4.40 (2H, s) 4.55 (2H, d, J = 6.0Hz)
4.91 (1H, s) 6.39 (1H, d, J = 8.4Hz) 6.60 (1H, dd,
J = 5.0, 6.2Hz) 7.26-7.59 (9H, m) 8.12 (1H, dd, J = 1.
0, 5.2Hz).

Reference Example 10 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(2-methyl-3-pyridylmethyl) aminomethyl] -1,1'-biphenyl 2-methyl -3- (aminomethyl) pyridine dihydrochloride (2.28 g,
14.9 mmol) was dissolved in methanol (30 ml) and 4 '-(N-ter
t-butoxycarbonyl-N-cyclohexylamino) methylbiphenyl-4-carbaldehyde (2.93g, 7.44mmol),
Sodium chloride (10g), triethylamine (4.6ml, 33.
0 mmol) and acetic acid (3.8 ml, 66 mmol) were sequentially added at room temperature. After stirring at room temperature for 45 minutes, sodium triacetoxyborohydride (3.2 g, 14.88 mmol) was added little by little, and the mixture was stirred at room temperature overnight. The reaction was terminated by adding saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
5: 1-1: 1, hexane: acetone = 1: 1, hexane: acetone: methanol = 1: 1: 0.1) and purified with 4- (N-
tert-Butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(2-methyl-3-pyridylmethyl) aminomethyl]
-1,1'-Biphenyl (0.16 g, 4%) was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.38 (9H,
s) 2.55 (3H, s) 3.82 (2H, s) 3.89 (2H, s) 4.0-4.2
(1H, br) 4.40 (2H, s) 7.13 (1H, dd, J = J = 5.4,7.6Hz)
7.28 (2H, d, J = 9.2Hz) 7.41 (2H, d, J = 8.4Hz) 7.53
(2H, d, J = 8.4Hz) 7.58 (2H, d, J = 8.0Hz) 7.65-7.69
(1H, m) 8.40 (1H, dd, J = 1.8, 5.0Hz).

Reference Example 11 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(6-methyl-3-pyridylmethyl) aminomethyl] -1,1'-biphenyl 4'- (N-tert-butoxycarbonyl-N-cyclohexylamino) methylbiphenyl-4-carbaldehyde (1.87g, 4.75
mmol) in a methanol solution (30 ml) of 3- (aminomethyl)-
6-Methyl-pyridine dihydrochloride (1.03g, 5.22mmol), sodium chloride (10g), triethylamine (1.46ml, 10.5mm)
ol) and acetic acid (0.68 ml, 11.9 mmol) in that order at room temperature. After stirring at room temperature for 45 minutes, sodium triacetoxyborohydride (2.01 g, 9.5 mmol) was added little by little,
Stir overnight at room temperature. The reaction was terminated by adding saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
, Hexane: acetone = 1: 1, hexane: acetone: methanol = 1: 1: 0.1) and purified with 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4'-
[(6-Methyl-3-pyridylmethyl) aminomethyl] -1,1′-biphenyl (2.00 g, 85%) was obtained as a colorless solid. Melting point: 74-75 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 2.54 (3H, s) 3.79 (2H, s) 3.82 (2H, s) 4.0-4.2
(1H, br) 4.40 (2H, s) 7.12 (1H, d, J = 8.0Hz) 7.28 (2
H, d, J = 8.0Hz) 7.38 (2H, d, J = 8.0Hz) 7.40-7.58 (4
H, m) 7.61 (1H, d, J = 2.2Hz) 8.44 (1H, d, J = 2.0Hz).

Reference Example 12 4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4-anilinomethyl-1,1'-biphenyl 4'-(N-tert-butoxycarbonyl-N-cyclohexyl Amino) methylbiphenyl-4-carbaldehyde (1.46g, 3.7
1 mmol) in methanol (30 ml) in sodium chloride
(10 g), acetic acid (0.64 ml, 11.1 mmol), aniline (0.85 ml,
9.3 mmol) were added in sequence. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (2g, 9.3mmol) was added little by little. After stirring at room temperature for 18.5 hours, saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-7: 1) and 4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4-anilinomethyl-1, 1'-Biphenyl (1.48 g, 85%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.34 (2H, s) 4.39 (2H, s) 6.60
-6.75 (3H, m) 7.12-7.22 (2H, m) 7.28 (2H, d, J = 8.4H
z) 7.41 (2H, d, J = 8.4Hz) 7.49-7.58 (4H, m).

Reference Example 13 1) 4-{[N-tert-butoxycarbonyl-N-cyclohexyl)
Amino] methyl} -4 '-{[(4-methoxyanilino) methyl] -1,
1'-biphenyl 4 '-(N-tert-butoxycarbonyl-N-cyclohexylamino) methylbiphenyl-4-carbaldehyde (1.47g, 3.7
4 mmol) in methanol (30 ml) in sodium chloride
(5 g), acetic acid (0.64 ml, 11.22 mmol), p-anisidine (0.93
g, 7.48 mmol) were added in sequence. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (1.59g, 7.48mmol)
Was added little by little. After stirring at room temperature for 30 minutes, chloroform (20 ml) was added, and the mixture was stirred at room temperature for 4 days. Saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 5: 1), 4-{[N-tert-butoxycarbonyl-N-cyclohexyl] amino} methyl} -4 '-{[(4-methoxyanilino) methyl] -1,1' -Biphenyl (0.83g, 44%)
Was obtained as a red amorphous. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.38 (9H,
s) 3.74 (3H, s) 4.0-4.2 (1H, s) 4.32 (2H, s) 4.39
(2H, s) 6.62 (2H, d, J = 9.0Hz) 6.78 (2H, d, J = 9.2H
z) 7.28 (2H, d, J = 8.4Hz) 7.42 (2H. d, J = 8.4Hz) 7.5
1 (2H, d, J = 8.4Hz) 7.57 (2H, d, J = 8.6Hz).

Reference Example 14 4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4-n-butylaminomethyl-1,1'-biphenyl 4'-(N-tert-butoxycarbonyl -N-cyclohexylamino) methylbiphenyl-4-carbaldehyde (1.44g, 3.6
6 mmol) in methanol (30 ml) in sodium chloride
(10 g), acetic acid (0.46 ml, 8.04 mmol), n-butylamine (0.
73 ml, 7.32 mmol) were added in sequence. After stirring for 1 hour at room temperature,
Sodium triacetoxyborohydride (1.55g, 7.32m
mol) was added little by little. After stirring at room temperature for 18.5 hours, saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by recrystallization (ethanol-ether),
4 ′-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4-n-butylaminomethyl-1,1′-biphenyl (0.75 g, 45%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.87 (3H, t, J = 7.6Hz) 1.2-
1.9 (14H, m) 1.36 (9H, s) 2.75-2.83 (2H, m) 4.03 (2
H, s) 4.38 (2H, s) 7.24-7.28 (4H, m) 7.44 (2H, d,
J = 8.4Hz) 7.60 (2H, d, J = 8.8Hz) 7.66 (2H, d, J = 8.4H
z).

Reference Example 15 4 ′-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4-cyclohexylaminomethyl-1,1′-biphenyl 4 ′-(N-tert-butoxycarbonyl-N -Cyclohexylamino) methylbiphenyl-4-carbaldehyde (1.42g, 3.6
(0 mmol) in methanol (30 ml) in sodium chloride
(10 g), acetic acid (0.46 ml, 7.2 mmol) and cyclohexylamine (0.82 ml, 7.2 mmol) were sequentially added. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (1.53 g,
7.2 mmol) was added little by little. After stirring at room temperature for 18.5 hours, saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
Purified with (hexane: acetone = 1: 1, acetone), 4'-
[(N-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4-cyclohexylaminomethyl-1,1′-biphenyl (0.60 g, 35%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (18H, m) 1.39 (9H,
s) 1.9-2.0 (2H, m) 2.28 (1H, br) 2.53 (1H, br) 3.8
5 (2H, s) 4.0-4.2 (1H, br) 4.39 (2H, s) 7.28 (2H, s)
d, J = 7.6Hz) 7.39 (2H, d, J = 8.2Hz) 7.49-7.57 (4H,
m).

Reference Example 16 4-{[(N-tert-butoxycarbonyl-N-cyclohexyl) amino] methyl} -4 '-{[(cyclohexylmethyl) amino] methyl} -1,1'-biphenyl 4'- (N-tert-Butoxycarbonyl-N-cyclohexylamino) methylbiphenyl-4-carbaldehyde (1.49g, 3.7
9mmol) in methanol (30ml) in sodium chloride
(10 g), acetic acid (0.65 ml, 11.28 mmol) and aminomethylcyclohexane (0.99 ml, 7.6 mmol) were added in that order. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (1.
60 g, 7.60 mmol) was added little by little. After stirring at room temperature for 19 hours, saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 1: 1), and 4-{[(N-tert
-Butoxycarbonyl-N-cyclohexyl) amino] methyl} -4 '-{[(cyclohexylmethyl) amino] methyl} -1,1'
-Biphenyl (1.81g, 97%) was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.73 (21H, m) 1.39 (9H,
s) 2.48 (2H, d, J = 6.6Hz) 3.81 (2H, s) 4.0-4.2 (1
H, br) 4.40 (2H, s) 7.28 (2H, d, J = 8.0Hz) 7.37 (2
H, d, J = 8.0Hz) 7.51 (2H, d, J = 6.2Hz) 7.55 (2H, d,
(J = 6.2Hz)

Reference Example 17 4-{[(N-tert-butoxycarbonyl-N-cyclohexyl) amino] methyl} -4 ′-{[(2-thienylmethyl) amino] methyl}
-1,1'-Biphenyl 4 '-(N-tert-butoxycarbonyl-N-cyclohexylamino) methylbiphenyl-4-carbaldehyde (1.48g, 3.7
6 mmol) in methanol (30 ml) in sodium chloride
(10 g), acetic acid (0.65 ml, 11.28 mmol) and 2-aminomethylthiophene (0.78 ml, 7.52 mmol) were added in that order. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (1.
59 g, 7.52 mmol) was added little by little. After stirring at room temperature for 40 hours, saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 3: 1), 4-{[(N-tert
-Butoxycarbonyl-N-cyclohexyl) amino] methyl} -4 '-{[(2-thienylmethyl) amino] methyl} -1,1'-biphenyl (1.42 g, 77%) was obtained as colorless crystals. Melting point: 62-64 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.40 (9H,
s) 3.87 (2H, m) 4.02 (2H, m) 4.0-4.2 (2H, m) 4.40
(2H, s) 6.93-6.98 (2H, s) 7.21-7.30 (3H, m) 7.39 (2
H, d, J = 8.2Hz) 7.41-7.58 (4H, m).

Reference Example 18 4-{[N-tert-butoxycarbonyl-N-cyclohexyl) amino] methyl} -4 ′-{[(2-furylmethyl) amino] methyl}-
1,1'-biphenyl 4 '-(N-tert-butoxycarbonyl-N-cyclohexylamino) methylbiphenyl-4-carbaldehyde (1.04g, 2.6
4mmol) in methanol solution (20ml)
(5g), acetic acid (0.46ml, 7.92mmol), 2-furfurylamine
(0.47 ml, 5.28 mmol) were added in sequence. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (1.12 g,
5.28 mmol) was added little by little. After stirring at room temperature for 4 hours,
Saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 3: 1-2: 1) and 4-{[N-tert-butoxycarbonyl-N-cyclohexyl] amino} methyl}-
4 ′-{[(2-furylmethyl) amino] methyl} -1,1′-biphenyl (1.22 g, 97%) was obtained as colorless crystals. Melting point: 57-59 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 3.81 (2H, s) 3.82 (2H, m) 3.9-4.2 (2H, m) 4.40
(2H, s) 6.19 (1H, d, J = 3.2Hz) 6.31-6.34 (1H, m) 7.2
7 (2H, d, J = 9.2Hz) 7.36-7.40 (2H, m) 7.50-7.58 (5
H, m).

Reference Example 19 4-{[N-tert-butoxycarbonyl-N-cyclohexyl) amino] methyl} -4 ′-{[(2-phenylethyl) amino] methyl}
-1,1'-biphenyl 4 '-(N-tert-butoxycarbonyl-N-cyclohexylamino) methylbiphenyl-4-carbaldehyde (1.19g, 3.
02mmol) in methanol solution (30ml)
(5 g), acetic acid (0.52 ml, 9.06 mmol) and 2-phenylethylamine (0.76 ml, 6.04 mmol) were added in that order. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (1.28
g, 6.04 mmol) was added little by little. After stirring at room temperature for 3 hours, saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
Purified with (hexane: acetone = 2: 1-1: 1), 4-{[N-te
rt-Butoxycarbonyl-N-cyclohexyl] amino} methyl} -4 ′-{[(2-phenylethyl) amino] methyl} -1,1′-biphenyl (1.02 g, 68%) was obtained as colorless crystals. Melting point: 75-76 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.9-1.8 (10H, m) 1.38 (9H,
s) 2.80-2.98 (4H, m) 3.84 (2H, s) 4.04 (1H, br) 4.
40 (2H, s) 7.16-7.35 (9H, m) 7.49-7.56 (4H, m).

Reference Example 20 4-{[N-tert-butoxycarbonyl-N-cyclohexyl) amino] methyl} -4 ′-{[(2-naphthylamino] methyl) -1,1′-
Biphenyl 4 '-(N-tert-butoxycarbonyl-N-cyclohexylamino) methylbiphenyl-4-carbaldehyde (1.53g, 3.8
9mmol) in methanol (30ml) in sodium chloride
(5g), acetic acid (0.67ml, 11.67mmol), 2-naphthylamine
(1.11 g, 7.78 mmol) were added in sequence. After stirring for 1 hour at room temperature,
Sodium triacetoxyborohydride (1.65g, 7.78m
mol) was added little by little. After stirring at room temperature for 4 hours, saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
Silica gel column chromatography (hexane)
: Ethyl acetate = 7: 1-4: 1) and purified by 4-{[N-tert-butoxycarbonyl-N-cyclohexyl] amino} methyl}-
4 '-{[(2-naphthylamino) methyl] -1,1'-biphenyl (1.5
1 g, 75%) was obtained as pale yellow crystals. Melting point: 129-133 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.38 (9H,
s) 4.23 (1H, s) 4.39 (2H, s) 4.46 (2H, s) 6.84 (1
H, d, J = 2.2Hz) 6.92 (1H, dd, J = 2.6, 8.8Hz) 7.14-7.
38 (4H, m) 7.43-7.68 (9H, m).

Reference Example 21 4 '-[(N-tert-butoxycarbonyl) -N-cyclohexylaminomethyl] -N- (3-pyridylmethyl) -biphenyl-3-methylamine 1) 4'-[(N- tert-butoxycarbonyl) -N-cyclohexylaminomethyl] -1,1'-biphenyl-3-carbaldehyde 4-bromo-N-tert-butoxycarbonyl-N-cyclohexylbenzylamine (20.5g, 55.6 mmol) and 3- Formylbenzeneboronic acid (10 g, 66.7 mmol), tetrakistriphenylphosphine palladium (1.93 g, 1.67 mmol), sodium carbonate (11.8 g, 0.11 mol), toluene (150 ml), water (150 ml) under nitrogen atmosphere. The mixture was stirred at 70 ° C for 19 hours. Ethyl acetate
(100 ml) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give 4 '-[(N-tert-butoxycarbonyl) -N-cyclohexylaminomethyl] -1,1'-biphenyl-3. -Carbaldehyde (18g, 82%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.90 (19H, m), 3.60-4.25 (1H,
m), 4.42 (2H, s), 7.34 (2H, d, J = 8.0Hz), 7.50-7.70 (3
H, m), 7.80-7.95 (2H, m), 8.10-8.20 (1H, m), 10.09 (1H,
s, CHO). 2) 4 '-[(N-tert-butoxycarbonyl) -N-cyclohexylaminomethyl] -N- (3-pyridylmethyl) -biphenyl-3-
Methylamine 4 '-[(N-tert-butoxycarbonyl) -N-cyclohexylaminomethyl] -1,1'-biphenyl-3-carbaldehyde (10
g, 25.4 mmol) and 3-aminomethylpyridine (3.11 ml, 30.5
mmol), acetic acid (3.49 ml, 61.0 mmol), sodium chloride (30 g)
After stirring the mixture of methanol and methanol (200 ml) for 1 hour at room temperature, sodium triacetoxyborohydride (7.0 g, 33.0
mmol) was added in small portions. After stirring for 15 hours, the solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (200 ml) was added, and chloroform (100 ml x 3) was added.
It was extracted with. The extract is dried over anhydrous magnesium sulfate,
It was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane: acetone =
1: 1-hexane: acetone: methanol = 15: 15: 2) and purified to 4 '-[(N-tert-butoxycarbonyl) -N-cyclohexylaminomethyl] -N- (3-pyridylmethyl)- Biphenyl-3-
Methylamine (11.2g, 91%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.80 (19H, m), 3.86 (2H, s), 3.8
8 (2H, s), 3.90-4.20 (1H, m), 4.41 (2H, s), 7.20-7.37 (5
H, m), 7.40 (1H, t, J = 7.4Hz), 7.48-7.60 (3H, m), 7.70-7.
80 (1H, m), 8.51 (1H, dd, J = 7.2,2.0Hz), 8.60 (1H, d, J = 2.
0Hz).

Reference Example 22 3 '-[(N-tert-butoxycarbonyl) aminomethyl] -N- (3-
Pyridylmethyl) biphenyl-4-methylamine 1) N-tert-butoxycarbonyl-3-bromobenzylamine 3-bromobenzylamine hydrochloride (15 g, 67.4 mmol), saturated aqueous sodium hydrogen carbonate (200 ml) and ethyl acetate (200 ml) Ditert-butyl dicarbonate (14.7 g, 67.4 mmol) was added to the mixed solution of, and the mixture was stirred at room temperature for 2 hours. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give N.
-tert-Butoxycarbonyl-3-bromobenzylamine (1
9.0 g, 99%) was obtained as crystals. Melting point 45-46 ° C 2) 3 '-[(N-tert-butoxycarbonyl) aminomethyl] -1,
1'-biphenyl-4-carbaldehyde 3-bromo-N-tert-butoxycarbonylbenzylamine (1
5.8g, 55.6mmol) and 4-formylbenzeneboronic acid (10g,
66.7mmol), tetrakistriphenylphosphine palladium (1.92g, 1.66mmol), sodium carbonate (11.8g, 0.11mo
A mixture of l), toluene (150 ml) and water (150 ml) was stirred at 70 ° C. for 24 hours under a nitrogen atmosphere. Add ethyl acetate (100 ml),
After washing with saturated aqueous sodium hydrogen carbonate, drying over anhydrous magnesium sulfate,
It was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 3 '-[(N-
tert-Butoxycarbonyl) aminomethyl] -1,1′-biphenyl-4-carbaldehyde (11.0 g, 64%) was obtained as colorless crystals. Melting point 103-105 ° C Elemental analysis value C ₁₉ H ₂₁ NO ₃ Calculated value: C, 73.29; H, 6.80; N, 4.50 Measured value: C, 73.38; H, 6.65; N, 4.21. ¹ H-NMR ( _{CDCl 3) δ: 1.47 (9H} , s, Bu t), 4.40 (2H, d, J = 6.2H
z), 4.80-5.00 (1H, br, NH), 7.34 (1H, d, J = 7.2Hz), 7.45
(1H, t, J = 7.7Hz), 7.50-7.60 (2H, m), 7.74 (2H, d, J = 8.4
Hz), 7.95 (2H, d, J = 8.4Hz), 10.06 (1H, s, CHO). 3) 3 '-[(N-tert-butoxycarbonyl) aminomethyl] -N-
(3-Pyridylmethyl) biphenyl-4-methylamine 3 '-[(N-tert-butoxycarbonyl) aminomethyl] -1,1'-
Biphenyl-4-carbaldehyde (10 g, 32.1 mmol) and 3-aminomethylpyridine (3.92 ml, 38.5 mmol), acetic acid (4.23 ml,
A mixture of 73.9 mol), sodium chloride (30 g) and methanol (300 ml) was stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (8.85 g, 41.7 mmol) was added little by little.
After stirring for 15 hours, the solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (200 ml) was added, and the mixture was extracted with dichloromethane (100 ml × 3). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane: acetone = 1: 1-hexane: acetone: methanol = 5: 5: 1) to give 3 ′-[(N-tert. -Butoxycarbonyl) aminomethyl] -N- (3-pyridylmethyl) biphenyl-4-methylamine (9.99 g, 77%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s, Bu ^t ), 3.85 (2H, s), 4.38
(2H, d, J = 5.8Hz), 4.80-5.00 (1H, br, NH), 7.22-7.57 (7
H, m), 7.56 (2H, d, J = 8.0Hz), 7.73 (1H, d, J = 8.5Hz), 8.51
(1H, d, J = 4.4Hz), 8.59 (1H, brs).

Reference Example 23 3 '-[(N-tert-butoxycarbonyl) aminomethyl] -N- (3-
Pyridylmethyl) biphenyl-3-methylamine 1) 3 '-[(N-tert-butoxycarbonyl) aminomethyl] -1,
1'-biphenyl-3-carbaldehyde 3-bromo-N-tert-butoxycarbonylbenzylamine (2
3.8 g, 83.4 mmol) and 3-formyl-benzeneboronic acid (15 g,
0.10mol), tetrakistriphenylphosphine palladium (2.89g, 2.5mmol), sodium carbonate (17.7g, 0.167mo)
A mixed solution of l), toluene (200 ml) and water (200 ml) was stirred at 70 ° C. for 24 hours under a nitrogen atmosphere. Add ethyl acetate (100 ml),
After washing with saturated aqueous sodium hydrogen carbonate, drying over anhydrous magnesium sulfate,
It was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 3 '-[(N-
tert-Butoxycarbonyl) aminomethyl] -1,1′-biphenyl-3-carbaldehyde (25.3 g, 97%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s, Bu ^t ), 4.40 (2H, d, J = 6.0H
z), 4.80-5.05 (1H, m, NH), 7.20- 7.70 (5H, m), 7.80-8.00
(2H, m), 8.10 (1H, s), 10.09 (1H, s, CHO). 2) 3 '-[(N-tert-butoxycarbonyl) aminomethyl] -N-
(3-Pyridylmethyl) biphenyl-3-methylamine 3 '-[(N-tert-butoxycarbonyl) aminomethyl] -1,1'-
Biphenyl-3-carbaldehyde (20g, 64.2mmol) and 3-
Aminomethylpyridine (7.85ml, 77.1mmol), acetic acid (8.82m
l, 0.154mol), sodium chloride (40g) and methanol (300m
The mixture of l) was stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (17.7 g, 83.5 mmol) was added little by little. After stirring for 15 hours, the solvent was evaporated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution (200 m
l) was added and the mixture was extracted with dichloromethane (100 ml × 3). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Ethyl acetate = 1: 1-hexane: acetone = 1: 1-hexane: acetone: methanol = 4: 4: 1) and purified to 3 '-[(N-tert-butoxycarbonyl) aminomethyl] -N- (3-Pyridylmethyl) biphenyl-3-methylamine (20.8 g, 80%) was obtained as a colorless oil. _{^{1 H-NMR (CDCl 3)}} δ: 1.47 (9H, s, Bu t), 3.86 (2H, s), 3.88
(2H, s), 4.39 (2H, brd, J = 5.8Hz), 4.96 (1H, brs, NH), 7.2
0-7.60 (9H, m), 7.70-7.80 (1H, m), 8.52 (1H, dd, J = 4.8,1.
5Hz), 8.60 (1H, s).

Reference Example 24 4-tert-butoxycarbonylamino-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1′-biphenyl 1) p-bromo-N-tert-butoxycarbonylaniline p-bromo Aniline (10g, 58.1mmol) in ethyl acetate
(200 ml) in di-tert-butyl dicarbonate (12.68g, 58.1mmol)
Was added and the mixture was stirred at room temperature for 2 hours. Di-tert-butyl dicarbonate (6.0 g, 27.5 mmol) was added, triethylamine (9.7 ml, 69.7 mmol) was further added, the mixture was stirred at room temperature for 2 hours, and further refluxed for 25 hours. After disappearance of the raw materials, the mixture was diluted with ethyl acetate, and the organic layer was washed with 1M aqueous potassium hydrogen sulfate solution and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The precipitated crystals are recrystallized from cold hexane to give p-bromo-N-tert as colorless prisms.
-Butoxycarbonylaniline (9.57g, 61%) was obtained. Melting point: 103-107 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.50 (9H, s) 6.52 (1H,
s) 7.27 (2H, br) 7.36-7.40 (2H, br). 2) 4 '-(tert-butoxycarbonylamino) biphenyl-4-
Carboxaldehyde p-bromo-N-tert-butoxycarbonylaniline (2.72 g,
10 mmol) to 4-formylbenzeneboronic acid (1.8 g, 12 m
mol), tetrakistriphenylphosphine palladium
(0.58g, 0.5mmol), sodium carbonate (2.12g, 20mmol),
A mixture of toluene (40 ml) and water (40 ml) was stirred at 70 ° C for 21 hours. The reaction solution was diluted with ethyl acetate and washed with water. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Silica gel column chromatography of the residue
It was purified with (hexane: ethyl acetate = 5: 1) to obtain 4 ′-(tert-butoxycarbonylamino) biphenyl-4-carbaldehyde (2.48 g, 83%) as colorless crystals. Melting point: 142-145 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.54 (9H, s) 6.61 (1H, s)
7.48 (2H, d, J = 8.8Hz) 7.59 (2H, d, J = 8.8Hz) 7.72
(2H, d, J = 8.0Hz) 7.93 (2H, d, J = 8.4Hz) 10.03 (1H,
s). 3) 4-tert-butoxycarbonylamino-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl 4'-(tert-butoxycarbonylamino) biphenyl-4-carbaldehyde ( 1g, 3.36mmol) methanol (20ml)
Magnesium sulfate (3 g) was added to the solution, 3- (aminomethyl) pyridine (0.51 ml, 5.0 mmol) was added dropwise at room temperature, and the mixture was stirred for 1 hr. Then sodium borohydride (0.19g,
5.0 mmol) was added little by little, and the mixture was stirred at room temperature for 0.5 hour. The reaction was terminated by adding saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate,
Filtration, concentration under reduced pressure, and purification of the residue by silica gel column chromatography (hexane: acetone = 1: 1-2: 3-1: 4) to 4-tert-butoxycarbonylamino-4 '-[(3-pyridylmethyl). Aminomethyl] -1,1'-biphenyl (0.91g, 73
%) Was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.53 (9H, s) 3.84 (2H,
s) 3.86 (2H, s) 6.57 (1H, br) 7.26-7.80 (10H, m)
7.70 (1H, m) 8.52-8.58 (2H, m).

Reference Example 25 4 '-{[(3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid ethyl ester 1) 4'-formyl [1,1'-biphenyl] -4-carboxylic acid ethyl ester 4-bromobenzoic acid ethyl ester (6.37 g, 27.8 mmol)
4-Formylbenzeneboronic acid (5.0g, 33.3mmol), tetrakistriphenylphosphine palladium (0.96g, 0.83mm)
ol), sodium carbonate (5.89g, 55.6mmol), toluene (100m
A mixture of l) and water (100 ml) was stirred at 100 ° C. for 15 hours under a nitrogen atmosphere. The organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) and crystallized from cold hexane to give 4′-formyl [1,1′-biphenyl] -4-carboxylic acid ethyl ester ( 6.0 g, 85%) was obtained. Melting point 58-59 ° C. Elemental analysis value, calculated as C ₁₆ H ₁₄ O ₃ , calculated value: C, 75.57; H, 5.55 measured value: C, 75.78; H, 5.40. ¹ H-NMR (CDCl ₃ ) δ: 1.43 ( 3H, t, J = 7.0Hz), 4.20 (2H, q, J =
7.0Hz), 7.70 (2H, d, J = 8.4Hz), 7.79 (2H, d, J = 8.4Hz), 7.
99 (2H, d, J = 8.0Hz), 8.16 (2H, d, J = 8.0Hz), 10.08 (1H, s). 2) 4 '-{[(3-pyridylmethyl) amino] methyl} [1 , 1'-Biphenyl] -4-carboxylic acid ethyl ester 4'-formyl [1,1'-biphenyl] -4-carboxylic acid ethyl ester (10.17 g, 40 mmol) and 3-aminomethylpyridine (4.8
9 ml, 48 mmol), acetic acid (5.50 ml, 96 mmol), sodium chloride (4
A mixture of 0 g) and ethanol (100 ml) was stirred for 1 hour. Sodium triacetoxyborohydride (11.0 g, 52 mmol) was added little by little, and the mixture was stirred for 15 hours. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (150 ml) was added, and the mixture was extracted with chloroform (100 ml × 3). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Silica gel column chromatography of the residue
Purify with (hexane: ethyl acetate = 1: 1-hexane: acetone = 1: 1-hexane: acetone: ethanol = 10: 10: 1) to obtain 4'-
{[(3-Pyridylmethyl) amino] methyl} [1,1′-biphenyl] -4-carboxylic acid ethyl ester (6.44 g, 45%) was obtained as colorless crystals. Mp as 63-64 ° C. Elemental analysis _{C 22 H 22 N 2 O 2} · H 2 O, Calculated: C, 74.34; H, 6.81 ; N, 7.88 Found: C, 74.27; H, 6.44 ; N, 7.62 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.42 (3H, t, J = 7.1Hz), 3.86 (3H, s),
3.88 (3H, s), 4.40 (2H, q, J = 7.1Hz), 7.20-7.35 (1H, m),
7.44 (2H, d, J = 8.2Hz), 7.55-7.80 (5H, m), 8.07-8.20 (2H,
m), 8.53 (1H, brd, J = 4.4Hz), 8.60 (1H, brs).

Reference Example 26 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl]-
4-carboxylic acid 1) 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl)
Anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid ethyl ester 4 '-{[(3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid To a solution of acid ethyl ester (3.46 g, 10 mmol) in acetonitrile (50 ml), 4- (trifluoromethyl)
Phenylisocyanate (1.43 ml, 10 mmol) was added, and the mixture was stirred at room temperature for 1 hr. Water (100 ml) was added to the reaction solution, and the mixture was extracted with chloroform (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 4: 1-1: 1), and 4 ′-[((3-pyridylmethyl) {[4
-(Trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid ethyl ester
(4.85 g, 91%) was obtained as colorless crystals. Mp 184-185 As ℃ Elemental analysis _{C 30 H 26 F 3 N 3} O 3, Calcd: C, 67.53; H, 4.91 ; N, 7.88 Found:. C, 67.46; H, 4.82; N, 7.74 1 H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.2Hz), 4.41 (2H, q, J =
7.2Hz), 4.62 (2H, s), 4.72 (2H, s), 6.52 (1H, s), 7.25-
7.45 (5H, m), 7.50 (2H, d, J = 8.2Hz), 7.65 (2H, d, J = 8.2H
z), 7.67 (2H, d, J = 8.2Hz), 7.70-7.80 (1H, m), 8.13 (2
H, d, J = 8.2Hz), 8.57-8.65 (2H, m). 2) 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl)
Anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [ 1,1'-biphenyl]-
An aqueous solution (30 ml) of potassium carbonate (2.26 g, 16.3 mmol) was added to a solution of 4-carboxylic acid ethyl ester (4.36 g, 8.17 mmol) in tetrahydrofuran-methanol (50 ml-50 ml), and the mixture was heated under reflux for 15 hours. The reaction mixture was adjusted to pH 5-6 with 1N hydrochloric acid and extracted with ethyl acetate (200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crystals were added with water and collected by filtration to give 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4- Carboxylic acid (2.80 g, 68%) was obtained as crystals. This product was used as it was without further purification. ¹ H-NMR (d ₆ -DMSO) δ: 4.65 (2H, s), 4.71 (1H, s), 7.30-7.
47 (3H, m), 7.59 (2H, d, J = 8.4Hz), 7.66-7.90 (7H, m), 8.0
3 (2H, d, J = 8.4Hz), 8.45-8.55 (2H, m), 9.10 (1H, s).

Reference Example 27 4 '-{[[([1,1'-biphenyl] -4-ylamino) carbonyl]
(3-Pyridylmethyl) amino] methyl} [1,1'-biphenyl]-
4-Carboxylic acid 1) 4 '-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid Acid ethyl ester biphenyl-4-carboxylic acid (2.18 g, 11 mmol) in acetonitrile (50 ml), diphenylphosphoryl azide (2.60
ml, 12.1 mmol) and triethylamine (2.30 ml, 16.5 mmol)
Was added and the mixture was stirred for 15 minutes, and then heated under reflux for 1 hour. The reaction solution was cooled to room temperature and 4 '-{[(3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid ethyl ester
(3.46 g, 10 mmol) was added and the mixture was stirred for 30 minutes. Water as the reaction liquid
(150 ml) was added and the mixture was extracted with chloroform (150 ml × 2). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure.
The residue was subjected to silica gel column chromatography (chloroform: ethyl acetate = 2: 1, then chloroform: acetone =
2: 1) to give 4 '-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} [1,
1'-biphenyl] -4-carboxylic acid ethyl ester (4.548g,
84%) was obtained as colorless crystals. Melting point 195-197 ℃ Elemental analysis value C ₃₅ H ₃₁ N ₃ O ₃ Calculated value: C, 77.61; H, 5.77; N, 7.76 Measured value: C, 77.40; H, 5.60; N, 7.90. ¹ H- NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.0Hz), 4.41 (2H, q, J =
7.1Hz), 4.63 (2H, s), 4.73 (2H, s), 6.43 (1H, s), 7.20-
7.85 (16H, m), 8.13 (2H, d, J = 8.4Hz), 8.55-8.70 (2H, m). 2) 4 '-{[[([1,1'-biphenyl] -4-ylamino) Carbonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid 4 '-{[[([1,1'-biphenyl] -4-ylamino) carbonyl]
(3-Pyridylmethyl) amino] methyl} [1,1'-biphenyl]-
To a solution of 4-carboxylic acid ethyl ester (4.05 g, 7.48 mmol) in methanol-tetrahydrofuran (50 ml-50 ml) was added a solution of potassium carbonate (2.07 g, 15.0 mmol) in water (20 ml) to give 18
Heated to reflux for hours. The reaction solution was concentrated under reduced pressure, and 6N hydrochloric acid (7.4
After neutralizing with (8 ml), water was added to collect the precipitated crystals by filtration,
4 '-{[[([1,1'-biphenyl] -4-ylamino) carbonyl]
(3-Pyridylmethyl) amino] methyl} [1,1'-biphenyl]-
4-Carboxylic acid (3.25 g, 85%) was obtained as crystals. ¹ H-NMR (d ₆ -DMSO) δ: 4.65 (2H, s), 4.70 (2H, s), 7.20-7.
90 (16H, m), 8.03 (2H, d, J = 8.4Hz), 8.45-8.60 (2H, m), 8.
82 (1H, s).

Reference Example 28 4 '-{[{[([1,1'-biphenyl] -4-ylmethyl) amino] carbonyl} (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl]- 4-Carboxylic acid 1) 4 '-{[{[([1,1'-biphenyl] -4-ylmethyl) amino]
Carbonyl} (3-pyridylmethyl) amino] methyl} [1,1'-
Biphenyl] -4-carboxylic acid ethyl ester 4-biphenylacetic acid (2.76 g, 13 mmol) in acetonitrile (30
ml) solution, diphenylphosphoryl azide (3.55 ml, 16.5
mmol) and triethylamine (3.55 ml, 22.5 mmol)
After stirring for 15 minutes, the mixture was heated under reflux for 1 hour. The reaction solution was cooled to room temperature and 4 '-{[(3-pyridylmethyl) amino] methyl} [1,
1'-Biphenyl] -4-carboxylic acid ethyl ester (3.46g, 1
(0 mmol) was added and the mixture was stirred for 1 hour. Water (100 ml) was added to the reaction solution, and the mixture was extracted with chloroform (100 ml × 2). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 3: 1-1: 1) to give 4 '-{[{[[[1,1'-biphenyl] -4-ylmethyl) amino] carbonyl. } (3-Pyridylmethyl) amino] methyl} [1,1′-biphenyl] -4-carboxylic acid ethyl ester (4.19 g, 75%) was obtained as colorless crystals. Melting point 133-134 ℃ Elemental analysis value C ₃₆ H ₃₃ N ₃ O ₃ Calculated value: C, 77.81; H, 5.99; N, 7.56 Measured value: C, 77.66; H, 6.06; N, 7.59. ¹ H- NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.0Hz), 4.41 (2H, q, J =
7.0Hz), 4.51 (2H, s), 4.65 (2H, s), 4.79 (1H, t, J = 5.1H
z), 7.20-7.75 (13H, m), 8.10 (2H, d, J = 8.0Hz), 8.50-8.6
0 (2H, m). 2) 4 '-{[{[([1,1'-biphenyl] -4-ylmethyl) amino]
Carbonyl} (3-pyridylmethyl) amino] methyl} [1,1'-
Biphenyl] -4-carboxylic acid 4 '-{[{[([1,1'-biphenyl] -4-ylmethyl) amino] carbonyl} (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid ethyl ester (3.69g, 6.64mmo
An aqueous solution (20 ml) of potassium carbonate (2.75 g, 19.9 mmol) was added to a methanol-tetrahydrofuran (30 ml-30 ml) mixture of (l), and the mixture was heated under reflux for 24 hours. 6N hydrochloric acid (6.64m
(1, 39.8 mmol) was added to neutralize, and the mixture was concentrated under reduced pressure. The precipitated crystals were added with water, collected by filtration, washed with water and dried, and then 4 '-{[{[([1,1'
-Biphenyl] -4-ylmethyl) amino] carbonyl} (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (3.44 g, 98%) was obtained. Mp as 248-250 ° C. Elemental analysis _{C 34 H 29 N 3 O 3} · 1 / 4H 2 O, Calculated: C, 76.77; H, 5.59 ; N, 7.90 Found: C, 76.77; H, 5.56 ; N , 7.78. ¹ H-NMR (d ₆ -DMSO) δ: 4.36 (2H, d, J = 5.8Hz), 4.54 (2H, s),
4.56 (2H, s), 7.20-7.85 (14H, m), 8.02 (2H, d, J = 8.6Hz),
8.40-8.50 (2H, m).

Reference Example 29 4 '-{[[(4-phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid 1) 4'-{ [[(4-Phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid ethyl ester 4-phenoxybenzoic acid (3.21 g, 15 mmol) in acetonitrile ( 30 ml) solution, diphenylphosphoryl azide (3.55 ml,
16.5 mmol) and triethylamine (3.55 ml, 22.5 mmol) were added, the mixture was stirred for 15 minutes, and then heated under reflux for 1 hour. The reaction solution was cooled to room temperature, and 4 '-{[(3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid ethyl ester (3.
46 g, 10 mmol) was added and the mixture was stirred for 15 hours. Water (150 m
l) was added and extracted with chloroform (100 ml × 2). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 2: 1-1: 1) to give 4 '-{[[(4-phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl. } [1,1'-Biphenyl] -4-carboxylic acid ethyl ester
(4.42 g, 79%) was obtained as colorless crystals. Melting point 172-173 ° C Elemental analysis value C ₃₅ H ₃₁ N ₃ O ₄ Calculated value: C, 75.38; H, 5.60; N, 7.54 Found: C, 75.11; H, 5.59; N, 7.39. ¹ H- NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.0Hz), 4.40 (2H, q, J =
7.0Hz), 4.61 (2H, s), 4.71 (2H, s), 6.34 (1H, s), 6.90-
7.15 (5H, m), 7.15-7.50 (8H, m), 7.65 (4H, d, J = 8.2Hz),
7.70-7.80 (1H, m), 8.21 (2H, d, J = 8.2Hz), 8.55-8.65 (1H,
m). 2) 4 '-{[[(4-phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid 4'-{[[( 4-Phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid ethyl ester (4.0g, 7.17mmol) in methanol-tetrahydrofuran (30ml-30ml) And potassium carbonate (2.9
A solution of 7 g, 21.5 mmol) in water (20 ml) was added, and the mixture was heated under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, neutralized with 6N hydrochloric acid (7.17 ml), water was added, and the precipitated crystals were collected by filtration to give 4 '-{[[(4-phenoxyanilino) carbonyl] (3 -Pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (3.40 g, 88
%) Was obtained as crystals. mp199-202 ℃ Elemental analysis value C ₃₃ H ₂₇ N ₃ O ₄ Calculated value: C, 73.35; H, 5.26; N, 7.78 Measured value: C, 73.42; H, 5.46; N, 7.68 ¹ H-NMR (d ₆ -DMSO) δ: 4.62 (2H, s), 4.67 (2H, s), 6.94 (4
H, d, J = 7.0Hz), 7.00-7.15 (1H, m), 7.25-7.60 (5H, m), 8.
02 (2H, d, J = 7.0Hz), 8.40-8.55 (2H, m), 8.71 (1H, s).

Reference Example 30 4 '-[(2-pyridylamino) methyl] [1,1'-biphenyl] -4-
Carboxylic acid ethyl ester 4'-formyl [1,1'-biphenyl] -4-carboxylic acid ethyl ester (10.17 g, 40 mmol) and 2-aminopyridine (4.52 g, 48
mmol), acetic acid (5.50 ml, 96 mmol), sodium chloride (40 g) and ethanol (200 ml) were stirred for 1 hour. Sodium triacetoxyborohydride (11.0 g, 52 mmol) was added little by little, and the mixture was stirred for 15 hours. The solvent was distilled off under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added.
(150 ml) was added, and the mixture was extracted with chloroform (100 ml × 3).
The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 10: 1-5: 1) to give 4 '-[(2-
Pyridylamino) methyl] [1,1′-biphenyl] -4-carboxylic acid ethyl ester (2.74 g, 21%) was obtained as colorless crystals. As mp 157-158 ° C. Elemental analysis _{C 21 H 20 N 2 O 2} , Calcd: C, 75.88; H, 6.06 ; N, 8.43 Found:. C, 76.08; H, 5.84; N, 8.63 1 H- NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.6Hz), 4.40 (2H, q, J =
7.6Hz), 4.58 (2H, d, J = 5.8Hz), 4.85- 5.00 (1H, m), 6.40
(1H, d, J = 8.4Hz), 6.55-6.70 (1H, m), 7.46 (2H, d, J = 8.4H
z), 7.37-7.50 (1H, m), 7.55-7.75 (4H, m), 8.00-8.20 (3
H, m).

Reference Example 31 4 '-[(2-Pyridyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid 1) 4'-[ (2-Pyridyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1′-biphenyl] -4-carboxylic acid ethyl ester 4 ′-[(2-pyridylamino) methyl] [1, 1'-biphenyl] -4-
To a solution of carboxylic acid ethyl ester (2.0 g, 6.0 mmol) in N, N-dimethylformamide (30 ml) was added 4-trifluoromethylphenylisocyanate (0.86 ml, 6.0 mmol) to give 1
The mixture was stirred at 00 ° C for 24 hours (0.86 ml of 4-trifluoromethylphenyl isocyanate was added during the reaction). Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue
Purified with (hexane: ethyl acetate = 5: 1-4: 1) to give 4 '-[(2-pyridyl {[4- (trifluoromethyl) anilino] carbonyl}.
Amino) methyl] [1,1′-biphenyl] -4-carboxylic acid ethyl ester (2.58 g, 84%) was obtained as colorless crystals. Melting point 148-149 ° C Elemental analysis C ₂₉ H ₂₈ F ₃ N ₃ O ₃ Calculated: C, 67.05; H, 4.66; N, 8.09 Found: C, 67.03; H, 4.65; N, 8.01. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.0Hz), 4.39 (2H, q, J =
7.0Hz), 5.34 (2H, s), 6.97 (1H, d, J = 9.0Hz), 7.04 (1H, d
d, J = 7.2,5.0Hz), 7.39 (2H, d, J = 8.0Hz), 7.50-7.55 (8H,
m), 7.77 (2H, d, J = 8.2Hz), 8.10 (2H, d, J = 8.2Hz), 8.35-
8.45 (1H, m). 2) 4 '-[(2-Pyridyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid 4'- [(2-Pyridyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid ethyl ester (1.04g, 2.0mmol) in methanol-tetrahydrofuran (20ml -20 ml) solution into potassium carbonate (0.83
An aqueous solution (10 ml) of g, 6.0 mmol) was added and the mixture was heated under reflux for 5 hours. 1N Hydrochloric acid (12 ml) was added to the reaction solution, and the mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to give 4 '-[(2-pyridyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]. [1,1'-
Biphenyl] -4-carboxylic acid (0.92 g, 94%) was obtained as colorless crystals. Melting point 208-211 ° C (decomposition) Elemental analysis value C ₂₇ H ₂₀ F ₃ N ₃ O ₃ Calculated value: C, 65.98; H, 4.10; N, 8.55 Actual value: C, 65.95; H, 4.28; N, 8.49. ¹ H-NMR (d ₆ -DMSO) δ: 5.31 (2H, s), 7.10-7.30 (2H, m), 7.
43 (2H, d, J = 8.2Hz), 7.60-7.90 (6H, m), 8.00 (2H, d, J = 8.2
Hz), 8.45-8.55 (1H, m), 12.34 (1H, s).

Reference Example 32 4 '-{[(3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-acetic acid ethyl ester 1) 4'-formyl [1,1'-biphenyl]- 4-Acetic acid ethyl ester 4-bromophenylacetic acid ethyl ester (29.2g, 0.12mol)
And 4-formylbenzeneboronic acid (21.6g, 0.144mol), tetrakistriphenylphosphine palladium (4.16g, 3.6m
mol), sodium carbonate (25.4g, 0.24mol), toluene (200m
A mixture of l) and water (200 ml) was stirred under nitrogen at 90 ° C for 14 hours.
The toluene layer was separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-4: 1) to give 4'-formyl [1,1'-biphenyl] -4-acetic acid ethyl ester (25.2g, 78% ) Was obtained as crystals. Melting point 47-49 ° C Elemental analysis C ₁₇ H ₁₆ O ₃ Calculated: C, 76.10; H, 6.01 Found: C, 76.04; H, 5.81. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H , t, J = 7.1Hz), 3.68 (2H, s),
4.18 (2H, q, J = 7.1Hz), 7.40 (2H, d, J = 8.4Hz), 7.60 (2H,
d, J = 8.4Hz), 7.74 (2H, d, J = 8.4Hz), 7.94 (2H, d, J = 8.4H)
z), 10.05 (1H, s). 2) 4 '-{[(3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-acetic acid ethyl ester 4'-formyl [1,1' -Biphenyl] -4-acetic acid ethyl ester
(8.05g, 30mmol), 3-aminomethylpyridine (3.67ml, 36
mmol), acetic acid (4.12 ml, 72 mmol), sodium chloride (30 g) and ethanol (150 ml) were stirred for 1 hour, sodium triacetoxyborohydride (8.27 g, 39 mmol) was added little by little, and Stir for hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (100 ml) was added to the residue, and chloroform (100 ml x 3) was added.
It was extracted with. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane: ethyl acetate = 1: 1-hexane: acetone: methanol = 1: 1: 1) to give 4 ′-{[(3 -Pyridylmethyl) amino] methyl} [1,
1'-Biphenyl] -4-acetic acid ethyl ester (8.17 g, 76%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.2Hz), 3.66 (2H, s),
4.12 (4H, s), 4.18 (2H, q, J = 7.2Hz), 7.25-7.50 (6H, m),
7.50-7.65 (4H, m), 7.70-7.80 (1H, m), 8.50-8.60 (1H, m),
8.60 (1H, d, J = 1.8Hz).

Reference Example 33 {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl]-
4-yl} acetic acid 1) {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl} acetic acid Ethyl ester 4 '-{[(3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-acetic acid ethyl ester (4.0 g, 11.1 mmol) in toluene-acetonitrile (20 ml-20 ml) solution, 4-Trifluoromethylphenylisocyanate (1.59 ml, 11.1 mmol) was added and the mixture was stirred for 5 hours. The reaction mixture was diluted with ethyl acetate (150 ml), washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue
Purify with (chloroform: ethyl acetate = 4: 1-1: 1) to obtain (4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl} acetic acid ethyl ester (5.48g, 90%) colorless Obtained as crystals. Melting point 131-134 ° C Elemental analysis C ₃₁ H ₂₈ F ₃ N ₃ O ₃ Calculated value: C, 68.00; H, 5.15; N, 7.67 Found value: C, 68.02; H, 5.31; N, 7.56. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1Hz), 3.67 (2H, s),
4.18 (2H, q, J = 7.1Hz), 4.60 (2H, s), 4.73 (2H, s), 6.54 (1
H, s), 7.25-7.70 (13H, m), 7.70-7.82 (1H, m), 8.55-8.65
(2H, m). 2) {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl} Acetate {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl]-
4-Yyl} acetic acid ethyl ester (4.98 g, 9.09 mmol) in methanol-tetrahydrofuran (30 ml-20 ml) was added potassium carbonate (3.77 g, 27.3 mmol) in water (20 ml), and the mixture was heated under reflux for 3 hours. . The reaction solution was concentrated under reduced pressure and 6N hydrochloric acid (9.09 ml)
After neutralizing with, water (50 ml) was added, and the precipitated crystals were collected by filtration to give {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl. ] [1,1'-Biphenyl] -4-yl} acetic acid (4.29 g, 91%) was obtained as crystals. Melting point 216-217 ° C (decomposition) Elemental analysis value C ₂₉ H ₂₄ F ₃ N ₃ O ₃ Calculated value: C, 67.05; H, 4.66; N, 8.09 Found value: C, 66.82; H, 4.67; N, 7.92. ¹ H-NMR (d ₆ -DMSO) δ: 3.61 (2H, s), 4.64 (2H, s), 4.68 (2
H, s), 7.30-7.45 (5H, m), 7.55-7.80 (9H, m), 8.45-8.55
(2H, m), 9.08 (1H, s).

Reference Example 34 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl]-
4-carboxylic acid 1) 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl)
Phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid ethyl ester 4 '-{[(3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid Acid ethyl ester (2.6g, 7.50 mmol)
4-Trifluoromethylbenzenesulfonyl chloride (2.02 g, 8.26 mmol) and triethylamine (1.26 ml, 9.01 mmol) were added to a solution of the above in acetonitrile (30 ml), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: ethyl acetate = 3: 1).
-1: 1) to give 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,
1'-Biphenyl] -4-carboxylic acid ethyl ester (1.81g, 4
4%) was obtained as colorless crystals. Mp 135-136 As ℃ Elemental analysis _{C 29 H 29 F 3 N 2} O 4 S, Calcd: C, 62.81; H, 4.54 ; N, 5.05 Found: C, 62.94; H, 4.39 ; N, 4.93. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.0Hz), 4.40 (2H, q, J =
7.0Hz), 4.40 (2H, s), 7.14 (2H, d, J = 8.2Hz), 7.10-7.20
(1H, m), 7.47 (2H, d, J = 8.2Hz), 7.30-7.40 (1H, m), 7.58 (2
H, d, J = 8.8Hz), 7.80 (2H, d, J = 8.8Hz), 7.99 (2H, d, J = 8.2
Hz), 8.11 (2H, d, J = 8.8Hz), 8.30 (1H, s), 8.47 (2H, d, J =
4.6Hz). 2) 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl)
Phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [ 1,1'-biphenyl]-
To a solution of 4-carboxylic acid ethyl ester (6.08 g, 11.1 mmol) in methanol-tetrahydrofuran (50 ml-40 ml) was added a solution of potassium carbonate (4.62 g, 33.4 mmol) in water (30 ml), and the mixture was heated under reflux for 15 hours. The reaction mixture was neutralized with 6N hydrochloric acid (11.1 ml) and concentrated under reduced pressure. The precipitated crystals were added with water and collected by filtration to give 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl]- 4-Carboxylic acid (5.75 g, 98%) was obtained. Melting point 250-253 ° C Elemental analysis C ₂₇ H ₂₉ F ₃ N ₂ O ₄ S Calculated: C, 61.59; H, 4.02; N, 5.32 Found: C, 61.43; H, 4.21; N, 5.13. ¹ H-NMR (d ₆ -DMSO) δ: 4.45 (2H, s), 4.47 (2H, s), 7.15-7.
30 (1H, m), 7.25 (2H, d, J = 8.0Hz), 7.45-7.65 (3H, m), 7.7
2 (2H, d, J = 7.2Hz), 7.95-8.10 (4H, m), 8.13 (2H, d, J = 8.4H
z), 8.30 (1H, s), 8.30-8.40 (1H, m).

Reference Example 35 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid 1 ) 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid ethyl ester 4'-{ [(3-Pyridylmethyl) amino] methyl} [1,1′-biphenyl] -4-carboxylic acid ethyl ester (3.0 g, 8.66 mmol) in acetonitrile (100 ml) was added with 4-biphenylsulfonyl chloride (2.41 g, 9.53 mmol) and triethylamine (1.8
1 ml, 13.0 mmol) was added and the mixture was stirred at room temperature for 15 hours. Water (150 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml × 2).
The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1) to give 4'-
{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid ethyl ester (2.50 g, 51%) Obtained as colorless crystals. Melting point 126-127 ℃ Elemental analysis value C ₃₄ H ₃₀ N ₂ O ₄ S, calculated value: C, 72.57; H, 5.37; N, 4.98 Found value: C, 72.43; H, 5.63; N, 4.97. ¹ H -NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.2Hz), 4.22 (2H, q, J =
7.2Hz), 4.43 (4H, s), 7.19 (2H, d, J = 8.2Hz), 7.10-7.25
(1H, m), 7.40-7.70 (6H, m), 7.78 (2H, d, J = 8.2Hz), 7.97 (2
H, d, J = 8.4Hz), 8.11 (2H, d, J = 8.2Hz), 8.30-8.40 (1H, m),
8.40-8.55 (1H, m). 2) 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl]- 4-Carboxylic acid 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid ethyl ester ( 2.20 g, 3.91 mmol) in methanol-tetrahydrofuran (15 ml-15 ml) solution, potassium carbonate (1.
A solution of 08 g, 7.82 mmol) in water (10 ml) was added, and the mixture was heated under reflux for 15 hours. The reaction mixture was concentrated under reduced pressure, neutralized with 6N hydrochloric acid (2.60 ml), water was added, and the precipitated crystals were collected by filtration to give 4 '-{[([1,
1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl)
Amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (2.03
g, 97%) was obtained as crystals. Melting point 255-256 ° C Elemental analysis value Calculated as C ₃₂ H ₂₆ N ₃ O ₄ S: C, 71.89; H, 4.90; N, 5.24 Actual value: C, 71.72; H, 4.84; N, 5.24. ¹ H -NMR (d ₆ -DMSO) δ: 4.43 (4H, s), 7.19 (1H, dd, J = 7.6,4.
8Hz), 7.26 (2H, d, J = 8.0Hz), 7.40- 7.60 (6H, m), 7.65-
7.85 (4H, m), 7.85-8.10 (6H, m), 8.30-8.40 (2H, m).

Reference Example 36 4 '-[(2-pyridyl {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid 1) 4'-[ (2-Pyridyl {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4-carboxylic acid ethyl ester 4 ′-[(2-pyridylamino) methyl] [1, 1'-biphenyl] -4-
Carboxylic acid ethyl ester (1.67 g, 5.02 mmol), 4-trifluoromethylbenzenesulfonyl chloride (1.84 g, 7.54
mmol), triethylamine (3.50 ml, 25.1 mmol), 4-dimethylaminopyridine (0.92 g, 7.54 mmol) and toluene (30 ml)
The mixture was heated to reflux for 7 hours. Saturated sodium bicarbonate water (100
ml) and extracted with ethyl acetate (150 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 4 '-[(2-pyridyl {[4-
(Trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4-carboxylic acid ethyl ester
(1.65 g, 61%) was obtained as crystals. Mp 150-152 As ℃ Elemental analysis _{C 28 H 23 F 3 N 2} O 4 S, Calcd: C, 62.22; H, 4.29 ; N, 5.18 Found: C, 62.28; H, 4.40 ; N, 5.05. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.2Hz), 4.39 (2H, q, J =
7.2Hz), 5.04 (2H, s), 7.10-7.20 (1H, m), 7.39 (2H, d, J =
8.4Hz), 7.45-7.90 (10H, m), 8.07 (2H, d, J = 8.4Hz), 8.30-
8.40 (1H, m).

2) 4 '-[(2-pyridyl {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid 4'-[(2- Pyridyl {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid ethyl ester (1.45g, 2.68mmol) in methanol-tetrahydrofuran (20ml-20ml) , Potassium carbonate (1.
An aqueous solution of 11 g, 5.36 mmol) was added, and the mixture was heated under reflux for 24 hours.
The reaction mixture was concentrated under reduced pressure, adjusted to pH 5-6 with 6N hydrochloric acid, and then water (50 ml).
The precipitated crystals were collected by filtration, and 4 ′-[(2-pyridyl {[4-
(Trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4-carboxylic acid (1.23 g, 91%) was obtained as crystals. Melting point 220-221 ° C Elemental analysis value C ₂₆ H ₁₉ F ₃ N ₂ O ₄ S, calculated value: C, 60.93; H, 3.74; N, 5.47 Found value: C, 60.52; H, 3.43; N, 5.27. ¹ H-NMR (d ₆ -DMSO) δ: 2.51 (2H, s), 5.09 (2H, s), 7.20-7.
35 (1H, m), 7.35-7.55 (3H, m), 7.55-8.10 (12H, m), 8.30-
8.40 (1H, m).

Reference Example 37 {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl]-
4-yl} acetic acid 1) {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-yl} acetic acid Ethyl ester 4 '-{[(3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-acetic acid ethyl ester (4.0 g, 11.1 mmol) in acetonitrile (30 ml) was added with triethylamine (3.09 ml). , 22.2
mmol) and 4-trifluoromethylbenzenesulfonyl chloride (3.0 g, 12.2 mmol) were added and the mixture was stirred for 2 hours. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue
Purify with (hexane: ethyl acetate = 2: 1-1: 1) to obtain (4 '-[((3-
Pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4-yl} acetic acid ethyl ester (3.17 g, 50%) was obtained as colorless crystals. Mp 119-121 As ℃ Elemental analysis _{C 30 H 27 F 3 N 2} O 4 S, Calcd: C, 63.37; H, 4.79 ; N, 4.93 Found: C, 63.30; H, 4.84 ; N, 4.78. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1Hz), 3.66 (2H, s),
4.18 (2H, q, J = 7.1Hz), 4.39 (4H, s), 7.10 (2H, d, J = 8.0H
z), 7.10-7.20 (1H, m), 7.30-7.60 (7H, m), 7.80 (2H, d, J =
8.0Hz), 7.98 (2H, d, J = 8.0Hz), 8.30-8.40 (1H, m), 8.40
-8.55 (1H, m).

2) {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,
1'-biphenyl] -4-yl} acetic acid {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl]-
To a solution of 4-yl} acetic acid ethyl ester (2.92g, 5.14mmol) in methanol-tetrahydrofuran (20ml-20ml) was added potassium carbonate (1.42g, 10.3mmol) aqueous solution (15ml), and the mixture was heated under reflux for 4.5 hours. The reaction mixture was neutralized with 6N hydrochloric acid (3.42 ml, 20.6 mmol) and concentrated under reduced pressure. The precipitated crystals were added with water and collected by filtration to give {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl]. 4-yl} acetic acid (2.70 g, 97%) was obtained as colorless crystals. Mp 217-218 As ℃ Elemental analysis _{C 28 H 23 F 3 N 2} O 4 S, Calcd: C, 62.21; H, 4.29 ; N, 5.18 Found: C, 62.19; H, 4.22 ; N, 5.04. ¹ H-NMR (CDCl ₃ ) δ: 3.68 (2H, s), 4.43 (4H, s), 7.10-7.30
(3H, m), 7.34 (2H, d, J = 8.2Hz), 7.40-7.60 (5H, m), 7.95
(2H, d, J = 8.2Hz), 8.11 (2H, d, J = 8.2Hz), 8.20-8.40 (2H,
m).

Reference Example 38 4 '-({(3-pyridylmethyl) [4- (trifluoromethyl) benzoyl] amino} methyl) [1,1'-biphenyl] -4-carboxylic acid 1) 4'-( {(3-pyridylmethyl) [4- (trifluoromethyl)
Benzoyl] amino} methyl) [1,1'-biphenyl] -4-carboxylic acid ethyl ester 4 '-[(2-pyridylamino) methyl] [1,1'-biphenyl] -4-
To a mixed solution of carboxylic acid ethyl ester (3.46 g, 10 mmol), saturated aqueous sodium hydrogen carbonate (100 ml) and ethyl acetate (100 ml) was added 4-trifluoromethylbenzoyl chloride (1.63 ml, 11 mmol).
Stir for 1 hour. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate = 1: 1-1: 3)
Purified by 4 '-({(3-pyridylmethyl) [4- (trifluoromethyl) benzoyl] amino} methyl) [1,1'-biphenyl]-
4-Carboxylic acid ethyl ester (4.82 g, 93%) was obtained as colorless crystals.

Melting point 125-128 ° C. Elemental analysis value C ₃₀ H ₂₅ F ₃ N ₂ O ₃ .1.5H ₂ O, calculated value: C, 66.05; H, 5.17; N, 5.13 Found value: C, 65.80; H , 4.87; N, 4.96. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.1Hz), 4.41 (2H, q, J =
7.1Hz), 4.44 (2H, brs), 4.76 (2H, brs), 7.20-7.45 (4H,
m), 7.55-7.80 (8H, m), 8.14 (2H, d, J = 8.2Hz), 8.35-8.60
(1H, s), 8.59 (1H, m).

2) 4 '-({(3-pyridylmethyl) [4- (trifluoromethyl) benzoyl] amino} methyl) [1,1'-biphenyl] -4-carboxylic acid 4'-({(3 -Pyridylmethyl) [4- (trifluoromethyl) benzoyl] amino} methyl) [1,1'-biphenyl] -4-carboxylic acid ethyl ester (1.04g, 2.0mmol) in methanol (20ml)
An aqueous solution (20 ml) of potassium carbonate (0.55 g, 4.0 mmol) was added to the solution, and the mixture was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure and the concentration was adjusted to 1N hydrochloric acid.
(8 ml) was added for neutralization, and the precipitated crystals were collected by filtration and 4 '-({(3
-Pyridylmethyl) [4- (trifluoromethyl) benzoyl]
Amino} methyl) [1,1'-biphenyl] -4-carboxylic acid (0.98
g, 96%) was obtained as colorless crystals. Melting point 187-189 ° C Elemental analysis value C ₂₈ H ₂₁ F ₃ N ₂ O ₃ Calculated value: C, 66.14; H, 4.56; N, 5.51 Actual value: C, 66.22; H, 4.38; N, 5.36. ¹ H-NMR (d ₆ -DMSO) δ: 4.52 (2H, brs), 4.70 (2H, s), 7.25-
7.53 (4H, m), 7.65-7.90 (8H, m), 8.03 (2H, d, J = 7.6Hz),
8.30-8.60 (2H, m).

Reference Example 39 4 '-[N- [4- (trifluoromethoxy) phenylsulfonyl]
-N- (3-pyridylmethyl) aminomethyl] -1,1'-biphenyl
-4-carboxylic acid 1) ethyl 4 '-[N- [4- (trifluoromethoxy) phenylsulfonyl] -N- (3-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl-4-carboxylate ethyl 4 '-[N- (3-pyridylmethyl) aminomethyl] -1,1'-
Biphenyl-4-carboxylate (5.0 g, 14.4 mmol) and triethylamine (4.02 ml, 28.mmol) in acetonitrile (50
ml) solution, 4- (trifluoromethoxy) phenylsulfonyl chloride (2.4 ml, 17.3 mmol) was added and stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate (200 ml) was added to the reaction mixture, and the mixture was diluted with ethyl acetate (20 ml).
It was extracted with 0 ml). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1,1: 1),
Ethyl 4 '-[N- [4- (trifluoromethoxy) phenyl-sulfonyl] -N- (3-pyridylmethyl) aminomethyl] -1,1'-
Biphenyl-4-carboxylate (5.95 g, 72%) was obtained as colorless crystals.

Melting point 119-121 ° C. Elemental analysis value C ₂₉ H ₂₅ F ₃ N ₂ O ₅ S, calculated value: C, 61.04; H, 4.22; N, 4.91 Found value: C, 60.98; H, 4.52; N , 4.63. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.2Hz), 4.39 (2H, s),
4.44 (2H, s), 4.32 (2H, d, J = 7.2Hz), 7.14 (2H, d, J = 8.0H
z), 7.10-7.20 (1H, m), 7.37 (1H, d, J = 8.4Hz), 7.47 (2H,
d, J = 8.0Hz), 7.45-7.60 (1H, m), 7.59 (2H, d, J = 8.4Hz),
7.85-8.00 (2H, m), 8.10-8.20 (2H, m), 8.29 (1H, d, J = 2.6H
z), 8.40-8.65 (1H, m).

2) 4 '-[N- [4- (trifluoromethoxy) phenylsulfonyl] -N- (3-pyridylmethyl) aminomethyl]-
Ethyl 1,1'-biphenyl-4-carboxylate 4 '-[N- [4- (trifluoromethoxy) phenylsulfonyl] -N- (3-pyridylmethyl) aminomethyl] -1,1'-biphenyl-4 -Carboxylate (5.45 g, 9.55 mmol) in methanol-tetrahydrofuran (50 ml-30 ml) was dissolved in potassium carbonate (3.96 g, 28.7 mmol) in water (30 ml) under reflux for 6 hours. The reaction mixture was neutralized with 6N hydrochloric acid (9.55 ml) and concentrated under reduced pressure. The precipitated crystals were added with water and collected by filtration, and 4 '-[N-
[4- (trifluoromethoxy) phenylsulfonyl] -N- (3-
Pyridylmethyl) aminomethyl] -1,1′-biphenyl-4-carboxylic acid (4.89 g, 94%) was obtained. Melting point 233-234 ℃ Elemental analysis value C ₂₇ H ₂₁ F ₃ N ₂ O ₅ S, calculated value: C, 59.77; H, 3.90; N, 5.16 Found value: C, 59.33; H, 4.05; N, 5.19. ¹ H-NMR (d ₆ -DMSO) δ: 4.43 (2H, s), 4.45 (2H, s), 7.25 (2
H, d, J = 8.0Hz), 7.15-7.30 (1H, m), 7.45-7.70 (5H, m), 7.
71 (2H, d, J = 8.2Hz), 8.0 (1H, d, J = 8.4Hz), 8.05 (2H, d, J =
8.0Hz), 8.30-8.40 (1H, m), 8.36 (1H, d, J = 4.8Hz).

Reference Example 40 4-Aminotetrahydropyran hydrochloride 1) N-benzyl-N- (tetrahydropyran-4-yl) amine tetrahydropyran-4-one (4.5 g, 45 mmol), benzylamine (5.90 ml, 54.0) mmol), acetic acid (3.86 ml, 67.4 mmol),
Add 1 mixture of sodium chloride (30 g) and ethanol (100 ml).
After stirring for an hour, sodium cyanoborohydride (0.47 g,
A solution of 67.4 mmol) in ethanol (10 ml) was added dropwise. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and ethyl acetate (100 ml x
Extracted in 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 1: 1-hexane: acetone: ethanol = 3: 3: 1) to give N-benzyl-N-
(Tetrahydrofuran-4-yl) amine (2.06 g, 24%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.60 (2H, m), 1.80-2.00 (2H, m),
2.65-2.80 (1H, m), 3.39 (2H, td, J = 11.5,2.2Hz), 3.83 (2
H, s), 3.90-4.05 (2H, m), 7.20-7.40 (5H, m).

2) 4-Aminotetrahydropyran hydrochloride N-benzyl-N- (tetrahydropyran-4-yl) amine (2.
0g, 10.2mmol) in ethanol (20ml) in 10% palladium on carbon (1.0g) and 4N hydrogen chloride / ethyl acetate (2.56ml, 1
0.2 mmol) was added and catalytically reduced in a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The precipitated crystals were collected by filtration to give 4-aminotetrahydropyran hydrochloride (1.28g, 91%).
Got Melting point 204-210 ° C ¹ H-NMR (d ₆ -DMSO) δ: 1.40-1.70 (2H, m), 1.75-1.95 (2H,
m), 3.10-3.50 (3H, m), 3.70-4.00 (2H, m), 8.23 (3H, br, N
H ₃ ⁺ ).

Reference Example 41 4 '-[N- (4-phenoxyphenylsulfonyl) -N- (3-pyridylmethyl) aminomethyl] -1,1'-biphenyl-4-carboxylic acid 1) ethyl 4'-[ N- (4-phenoxyphenylsulfonyl) -N
-(3-Pyridylmethyl) aminomethyl] -biphenyl-4-carboxylate ethyl 4- [N- (3-pyridylmethyl) aminomethyl] -1,1'-
Biphenyl-4-carboxylate (7.21 g, 20 mmol) and triethylamine (5.58 ml, 40.0 mmol) in acetonitrile (5
4-phenoxyphenylsulfonyl chloride (6.45 g, 24.0 mmol) was added to the solution (0 ml), and the mixture was stirred for 3.5 hours. Saturated aqueous sodium hydrogen carbonate (150 ml) was added to the reaction mixture, and ethyl acetate (200 ml, 100 ml) was added.
It was extracted with. The extract is dried over anhydrous magnesium sulfate,
It was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 4: 1-2: 1),
Ethyl 4 '-[N- (4-phenoxyphenylsulfonyl) -N-
(3-Pyridylmethyl) aminomethyl] -1,1'-biphenyl-4-
The carboxylate (7.90 g, 68%) was obtained as colorless crystals.

Melting point 100-101 ° C. Elemental analysis value C ₃₄ H ₃₀ N ₂ O ₅ S, calculated value: C, 70.57; H, 5.23; N, 4.84 Found value: C, 70.54; H, 5.26; N, 4.67 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.42 (3H, t, J = 7.2Hz), 4.36 (4H, s),
4.41 (2H, q, J = 7.2Hz), 4.40 (2H, s), 7.00-7.30 (9H, m),
7.35-7.65 (6H, m), 7.75-7.90 (2H, m), 8.10-8.20 (2H, m),
8.27 (1H, d, J = 1.8Hz), 8.46 (1H, dd, J = 5.2,1.8Hz).

2) Ethyl 4 '-[N- (4-phenoxyphenylsulfonyl) -N- (3-pyridylmethyl) aminomethyl] -1,1'-biphenyl-4-carboxylate 4'-[N- ( 4-phenoxyphenylsulfonyl) -N- (3
-Pyridylmethyl) aminomethyl] -biphenyl-4-carboxylate (7.4g, 12.5mmol) in methanol-tetrahydrofuran (100ml-70ml) solution, potassium carbonate (5.18g, 62.
A solution of 4 mmol) in water (50 ml) was heated to reflux for 24 hours. Reaction solution 6
Normalized hydrochloric acid (12.5 ml) was added to neutralize, and the mixture was concentrated under reduced pressure. The precipitated crystals were added with water and collected by filtration to give 4 '-[N- (4-phenoxyphenylsulfonyl) -N- (3-pyridylmethyl) aminomethyl] -1,1'-biphenyl-4-carboxylic acid. (6.78 g, 96%) was obtained. Melting point 167-170 ℃ Elemental analysis value C ₃₂ H ₂₆ N ₂ O ₅ S Calculated value: C, 69.80; H, 4.76; N, 5.09 Measured value: C, 69.67; H, 4.70; N, 4.97. ¹ H -NMR (d ₆ -DMSO) δ: 4.38 (2H, s), 4.41 (2H, s), 7.10-7.
35 (8H, m), 7.40-7.55 (3H, m), 7.59 (2H, d, J = 8.0Hz), 7.7
4 (1H, d, J = 8.4Hz), 7.90 (2H, d, J = 8.4Hz), 8.01 (2H, d, J =
8.0Hz), 8.29 (1H, s), 9.36 (1H, d, J = 4.8Hz).

Example 1 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N'-(4-nitrophenyl) -N- (3 -Pyridylmethyl) urea dihydrochloride 1) tert-butyl cyclohexyl [(4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl}
[1,1'-Biphenyl] -4-yl) methyl] carbamate 4-{[(t
ert-butoxycarbonyl) (cyclohexyl) amino] methyl} -4 '-{[(3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (1.0 g, 2.06 mmol) in toluene (10 ml), Four-
Nitrophenyl isocyanate (0.34 g, 2.06 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Silica gel column chromatography (hexane: acetone = 1: 1)
Purified by tert-butyl cyclohexyl [(4 '-{[[(4-
Nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} [1,1′-biphenyl] -4-yl) methyl] carbamate (1.09 g, 81%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.85 (19H, m), 3.95-4.20 (1H,
m), 4.61 (2H, s), 4.76 (2H, s), 6.77 (1H, s), 7.25-7.50
(7H, m), 7.54 (2H, d, J = 8.0Hz), 7.66 (2H, d, J = 8.0Hz), 7.
75-7.85 (1H, m), 8.14 (2H, d, J = 8.4Hz), 8.58-8.67 (2H,
m). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N'-(4-nitrophenyl) -N-
(3-Pyridylmethyl) urea dihydrochloride tert-butyl cyclohexyl [(4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} [1,
1'-biphenyl] -4-yl) methyl] carbamate (0.91g,
Concentrated hydrochloric acid (10 ml) was added to a solution of 1.40 mmol) in ethanol (20 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether) to give N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl}.
Methyl) -N '-(4-nitrophenyl) -N- (3-pyridylmethyl)
Urea dihydrochloride (0.81 g, 92%) was obtained. Melting point 163-167 ° C Elemental analysis C ₃₃ H ₃₅ N ₃ O ₅・ 2HCl ・ 1 / 2H ₂ O Calculated: C, 62.75; H, 6.06; N, 11.09 Found: C, 62.34; H, 5.79 ^{; N, 11.07 1 H-NMR} (d 6 -DMSO) δ:. 0.85-1.90 (8H, m), 2.07-2.23 (2H,
m), 2.85-3.15 (1H, m), 4.10-4.30 (2H, m), 4.80 (2H, s),
4.83 (2H, s), 7.38 (2H, d, J = 8.0Hz), 7.61-7.80 (5H, m),
7.80-8.00 (4H, m), 8.17 (2H, d, J = 8.0Hz), 8.28-8.40 (1H,
m), 8.70-8.85 (2H, m), 9.12-9.32 (2H, m), 9.63 (1H, s).

Example 2 4-({benzyl [(4-nitroanilino) carbonyl] amino}
Methyl) -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl ・ hydrochloride 1) tert-butyl [4'-({benzyl [(4-nitroanilino) carbonyl] amino} methyl) [1, 1'-biphenyl] -4-yl] methyl (cyclohexyl) carbamate 4-{[(tert-butoxycarbonyl) (cyclohexyl) amino] methyl} -4 '-{[(benzyl) amino] methyl} -1,1' 4-Nitrophenyl isocyanate (0.33 g, 2.0 mmol) was added to a toluene (20 ml) solution of -biphenyl (0.97 g, 2.0 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution is directly used for silica gel column chromatography (hexane: ethyl acetate = 4: 1-2:
Purified by 2), tert-butyl [4 '-({benzyl [(4-nitroanilino) carbonyl] amino} methyl) [1,1'-biphenyl] -4-yl] methyl (cyclohexyl) carbamate (1.24
g, 95%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.85 (19H, m), 3.90-4.25 (1H,
m), 4.41 (2H, s), 4.67 (2H, s), 4.68 (2H, s), 6.72 (1H,
s), 7.25-7.50 (11H, m), 7.53 (2H, d, J = 8.2Hz), 7.63 (2H,
d, J = 8.2Hz), 8.12 (2H, d, J = 9.2Hz). 2) 4-({benzyl [(4-nitroanilino) carbonyl] amino} methyl) -4 '-[(cyclohexylamino) methyl] -1,1'-
Biphenyl hydrochloride tert-butyl [4 '-({benzyl [(4-nitroanilino) carbonyl] amino} methyl) [1,1'-biphenyl] -4-yl] methyl (cyclohexyl) carbamate (1.1g, 1.70mmol Concentrated hydrochloric acid (2 ml) was added to a toluene (50 ml) solution of) and stirred at room temperature for 4 hours. The reaction solution was distilled off under reduced pressure, and the precipitated crystals were collected by filtration, 4
-({Benzyl [(4-nitroanilino) carbonyl] amino} methyl) -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl.hydrochloride (0.88g, 89%) was obtained as crystals. Melting point 231-234 ° C Elemental analysis value C ₃₄ H ₃₆ N ₄ O ₃・ HCl Calculated value: C, 69.79; H, 6.37; N, 9.58 Found value: C, 69.69; H, 6.41; N, 9.55. ¹ H-NMR (CDCl ₃ ) δ: 1.05-1.70 (8H, m), 1.72-1.88 (2H, m),
2.08-2.23 (2H, m), 2.90-3.10 (1H, m), 4.15-4.27 (2H,
m), 4.67 (2H, s), 7.25-7.45 (7H, m), 7.62-7.80 (6H, m),
7.80-7.90 (2H, m), 9.08-9.25 (2H, br), 9.46 (1H, s).

Example 3 tert-Butyl (4 ′-{[[(4-nitroanilino) carbonyl] (3
-Pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-
1) 4-[(1,3-dioxo-1,3-dihydro-2H-isoindole)
-2-yl) methyl] -4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl 2-[(4'-{[(3- Pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl] -1H-isoindole-1,3 (2H)
4-dione (1.4 g, 3.23 mmol) in chloroform (20 ml) 4
-Nitrophenyl isocyanate (0.53 g, 3.23 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture is directly used for silica gel column chromatography (chloroform: ethyl acetate
= 1: 1-1: 2), and purified by'4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] -4 '-{[[( 4-Nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1′-biphenyl (1.91 g, 99%) was obtained as colorless crystals. Melting point 185-186 ° C. Elemental analysis value C ₃₅ H ₂₇ N ₅ O ₅ Calculated value: C, 70.34; H, 4.55; N, 11.72 Measured value: C, 69.94; H, 4.42; N, 11.67. ¹ H -NMR (CDCl ₃ ) δ: 4.60 (2H, s), 4.73 (2H, s), 4.90 (2H,
s), 6.77 (1H, s), 7.20-7.43 (6H, m), 7.58 (2H, s), 7.59
(2H, d, J = 8.6Hz), 7.65-7.80 (2H, m), 7.80-7.98 (2H, m),
8.12 (2H, d, J = 8.6Hz), 8.55-8.67 (2H, m). 2) tert-butyl (4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} [1,1'-Biphenyl] -4-yl) methylcarbamate 4-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-
(Yl) methyl] -4 '-{[[(4-nitroanilino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.8
37g, 1.4mmol) and hydrazine monohydrate (0.27ml, 5.6mmo
A mixture of l) and ethanol (20 ml) was refluxed for 3 hours. The solvent was distilled off under reduced pressure, and the residue was 2N sodium hydroxide aqueous solution.
(50 ml) was added and the mixture was extracted with dichloromethane (50 ml × 2).
The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Residue and ditert-butyl dicarbonate (0.46g, 2.1mm
ol), saturated aqueous sodium hydrogen carbonate (50 ml) and ethyl acetate (50 ml).
Stir for hours. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 2: 1-1: 1) to give tert-butyl (4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl) amino]. Methyl} [1,1'-biphenyl] -4-yl) methylcarbamate (0.63g, 79%) was obtained as an oil. _{^{1 H-NMR (CDCl 3)}} δ: 1.49 (9H, s, Bu t), 4.37 (2H, brd, J = 5.4
Hz), 4.61 (2H, s), 4.75 (2H, s), 4.82-5.00 (1H, m, NH),
6.75 (1H, s), 7.23-7.48 (7H, m), 7.56 (2H, d, J = 8.0Hz),
7.64 (2H, d, J = 8.0Hz), 7.72-7.83 (1H, m), 8.14 (2H, d, J =
9.2Hz), 8.57-8.67 (2H, m).

Example 4 4- (Aminomethyl) -4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride tert-butyl (4 '-{[[(4-nitroanilino) carbonyl] (3
-Pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-
To a solution of (yl) methyl carbamate (0.5 g, 0.88 mmol) in ethanol (10 ml) was added concentrated hydrochloric acid (8 ml), and the mixture was stirred at room temperature for 3 hours. The reaction solution was evaporated under reduced pressure, diethyl ether was added to the residue to give a powder, and 4- (aminomethyl) -4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl}-was obtained. 1,1'-biphenyl dihydrochloride (0.447g, 87%) was obtained as an amorphous powder. Elemental analysis value C ₂₇ H ₂₅ N ₅ O ₃・ 2HCl ・ 1 / 2Et ₂ O ・ H ₂ O calculated value: C, 58.36; H, 5.56; N, 12.08 Found value: C, 58.48; H, 5.59; N, 12.01. ¹ H-NMR (d ₆ -DMSO) δ: 4.06 (2H, brd, J = 6.0Hz), 4.84 (2H,
s), 4.87 (2H, s), 7.49 (1H, d, J = 8.4Hz), 7.52-8.02 (1H,
m), 8.14 (2H, d, J = 9.2Hz), 8.40 (1H, brd, J = 8.4Hz), 8.79
(1H, d, J = 5.4Hz), 8.84 (1H, s), 9.73 (1H, s).

Example 5 4-[(Cyclopentylamino) methyl] -4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl}
-1,1'-biphenyl dihydrochloride 4- (aminomethyl) -4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl di Hydrochloride (0.4 g, 0.74 mmol) and cyclopentanone (0.11
ml, 1.20mmol), triethylamine (0.26ml, 1.85mmo
l), acetic acid (0.13 ml, 2.31 mmol), sodium chloride (10 g),
A mixture of methanol (20 ml) was stirred for 1 hour. Sodium triacetoxyborohydride (0.26 g, 1.20 mmol) was added and stirred for 15 hours. Cyclopentanone (0.22ml, 2.40m
mol), acetic acid (0.13 ml, 2.31 mmol) and sodium triacetoxyborohydride (0.51 g, 2.40 mmol) were added, and the mixture was stirred for 15 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate (50 ml) and extracted with chloroform (50 ml × 3). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 25:
1--25: 2) to give 4-[(cyclopentylamino) methyl] -4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'- Biphenyl (0.37g, 75%)
Was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.32-2.10 (8H, m), 3.08-3.25 (1H, m),
3.83 (2H, s), 4.61 (2H, s), 4.74 (2H, s), 6.85 (1H, s),
7.30-7.50 (7H, m), 7.59 (2H, d, J = 8.4Hz), 7.62 (2H, d, J =
8.0Hz), 7.70-7.80 (1H, m), 8.08-8.20 (2H, m), 8.57-8.6
5 (2H, m). This oil 4-[(cyclopentylamino) methyl] -4 '-{[[(4-
Nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.37g) was added to ethanol (10m
l), dissolved in 4N hydrogen chloride / ethyl acetate (10 ml), and shaken. The solvent was evaporated under reduced pressure, diethyl ether was added to give a powder, and 4-[(cyclopentylamino) methyl]-
4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (0.41g,
96%) was obtained as an amorphous powder. Elemental analysis value C ₃₂ H ₃₃ N ₅ O ₃・ HCl ・ 1 / 2H ₂ O, calculated value: C, 62.24; H, 5.88; N, 11.34 Found value: C, 62.40; H, 6.15; N, 11.20. ¹ H-NMR (d ₆ -DMSO) δ: 1.40-2.12 (9H, m), 4.15 (2H, br),
4.82 (2H, s), 4.85 (2H, s), 7.39 (2H, d, J = 8.2Hz), 7.60-7.
80 (6H, m), 7.80-7.97 (3H, m), 8.17 (2H, d, J = 9.2Hz), 8.3
6 (1H, d, J = 9.2Hz), 8.477 (1H, d, J = 8.0Hz), 8.81 (1H, s),
9.37 (2H, br, NH ₂ ⁺ ), 9.66 (1H, s).

Example 6 4-{[(cyclohexylmethyl) amino] methyl} -4 '-{[[(4-
Nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-( {3-Pyridylmethyl) [(4-nitroanilino) carbonyl] amino} methyl) -1,1'-biphenyl 4- (aminomethyl) -4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl ) Amino] methyl} -1,1'-biphenyl dihydrochloride (0.6 g, 1.44 mmol) and cyclohexanecarbaldehyde (0.18 ml, 1.44 mmol), triethylamine (0.3
A mixed solution of 1 ml, 2.22 mmol), acetic acid (0.16 ml, 2.78 mmol), sodium chloride (10 g) and methanol (20 ml) was stirred for 1 hour. Sodium triacetoxyborohydride (0.35g, 1.
67 mmol) was added and the mixture was stirred for 5 hours. Saturated sodium bicarbonate water (5
The mixture was diluted with 0 ml) and ethyl acetate (50 ml), ditert-butyl dicarbonate (0.32 g, 1.44 mmol) was added, and the mixture was stirred for 1 hr. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Silica gel column chromatography of the residue
Purified with (hexane: acetone = 4: 1-2: 1), 4-[(N-tert-
Butoxycarbonyl-N-cyclohexylamino) methyl]-
4 '-({3-pyridylmethyl) [(4-nitroanilino) carbonyl] amino} methyl) -1,1'-biphenyl (0.62g, 84%)
Was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 0.80-1.80 (11H, m), 2.96 (1H, m), 2.9
6-3.17 (2H, br), 4.49 (2H, s), 4.61 (2H, s), 4.74 (2H, s),
6.78 (1H, s), 7.25-7.50 (7H, m), 7.55 (2H, d, J = 8.0Hz),
7.64 (2H, d, J = 8.0Hz), 7.72-7.80 (1H, m), 8.13 (2H, d, J =
9.0Hz), 8.58-8.65 (2H, m). 2) 4-{[(cyclohexylmethyl) amino] methyl} -4'-
{[[(4-Nitroanilino) carbonyl] (3-pyridylmethyl)
Amino] methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({3-pyridylmethyl) [(4-nitroanilino) Carbonyl] amino} methyl) -1,1'-biphenyl
(0.60 g, 0.90 mmol) in ethanol (20 ml) was added concentrated hydrochloric acid (15
ml) was added and stirred for 1 hour. The reaction solution was evaporated under reduced pressure, diethyl ether was added to give a powder, and 4-{[(cyclohexylmethyl) amino] methyl} -4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl) amino] Methyl} -1,1'-biphenyl dihydrochloride (0.55 g, 94%) was obtained as an amorphous powder. As Elemental analysis _{C 34 H 37 N 5 O 3} · 2HCl · 0.5H 2 O, Calculated: C, 63.25; H, 6.24 ; N, 10.85 Found:. C, 63.36; H, 6.43; N, 10.81 1 H-NMR (d ₆ -DMSO) δ: 0.80-1.35 (7H, m), 1.50-1.90 (4H,
m), 2.63-2.81 (2H, m), 4.08-4.25 (2H, m), 4.82 (2H, s),
4.85 (2H, s), 7.39 (2H, d, J = 8.0Hz), 7.60-7.80 (6H, m),
7.80-8.00 (3H, m), 8.17 (2H, d, J = 9.2Hz), 8.30-8.42 (1H,
m), 8.73-8.95 (2H, m), 9.20 (2H, br, NH ₂ ⁺ ), 9.65 (1H, s).

Example 7 4-{[(tert-butoxycarbonyl) amino] methyl} -4′-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 1) 4-[(1,3-dioxo-1,3-dihydro- 2H-isoindole
-2-yl) methyl] -4 '-{[(3-pyridylmethyl) [(4-trifluoromethylanilino) carbonyl] amino] methyl} -1,
1'-biphenyl 2-[(4 '-{[(3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl] -1H-isoindole-1,3 (2H)
4-Difluoromethylphenylisocyanate (1.7 ml, 11.9 mmol) was added to a solution of dione (4.62 g, 10.7 mmol) in acetonitrile-methylene chloride (30 ml-30 ml) at room temperature.
Stir for 1.5 hours. The reaction mixture was directly purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl]-. 4 '-{[(3-pyridylmethyl) [(4-
Trifluoromethylanilino) carbonyl] amino] methyl} -1,1′-biphenyl (6.73 g, 100%) was obtained as colorless crystals. Mp 94-96 ° C. Elemental analysis _{C 36 H 27 N 4 O 3} F 3 · H 2 O Calculated: C, 67.70; H, 4.58 ; N, 8.77 Found: C, 67.86; H, 4.62 ; N, 8.50. ¹ H-NMR (CDCl ₃ ) δ: 4.57 (2H, s) 4.70 (2H, s) 4.89
(2H, s) 6.65 (1H, s) 7.29-7.38 (5H, m) 7.45-7.59
(9H, m) 7.69-7.74 (3H, m) 7.80-7.87 (1H, m) 8.58 (2
H, m) 2) 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4-[(1,3-dioxo-1,3-dihydro-2H- Isoindole-2-
Iyl) methyl] -4 '-{[(3-pyridylmethyl) [(4-trifluoromethylanilino) carbonyl] amino] methyl} -1,1'-
Biphenyl (5.73g, 9.23mmol) and hydrazine monohydrate
(1.8 ml, 37.1 mmol), ethanol (130 ml) mixed solution
Refluxed for 1.5 hours. The solvent was evaporated under reduced pressure, a 2N aqueous sodium hydroxide solution (150 ml) was added to the residue, and the mixture was extracted with methylene chloride (100 ml × 3). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Residue and di-dicarbonate
rt-butyl (2.82g, 12.9mmol), saturated aqueous sodium hydrogen carbonate (100ml),
A mixture of ethyl acetate (100 ml) was stirred for 15.5 hours. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by recrystallization (ethyl acetate-hexane) to give 4-{[(tert-butoxycarbonyl) amino] methyl} -4 '.
-[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (3.7
5 g, 69%) was obtained as crystals. Melting point 149-153 ° C Elemental analysis C ₃₃ H ₃₃ N ₄ O ₃ F ₃ Calculated: C, 67.11; H, 5.63; N, 9.49 Found: C, 66.89; H, 5.67; N, 9.45. ¹ H -NMR (CDCl ₃ ) δ: 1.47 (9H, s) 4.35 (2H, d, J = 6.
0Hz) 4.59 (2H, s) 4.72 (2H, s) 4.90 (2H, s) 6.56 (1
H, s) 7.29-7.39 (7H, m) 7.47-7.63 (6H, m) 7.75 (1
H, d, J = 7.6Hz) 8.58-8.60 (2H, m)

Example 8 4- (Aminomethyl) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-biphenyl dihydrochloride 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (3.21
g, 5.43 mmol) in ethanol (30 ml) and concentrated hydrochloric acid (30 ml).
(ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was evaporated under reduced pressure, diethyl ether was added to the residue to give a powder,
4- (aminomethyl) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-biphenyl dihydrochloride (2.93g, 96%) was obtained as an amorphous powder. Elemental analysis value, calculated as C ₂₈ H ₂₅ N ₄ OF ₃・ 2HCl ・ H ₂ O: C, 57.84; H, 5.03; N, 9.69 Found value: C, 57.78; H, 5.17; N, 9.96. ¹ H -NMR (d ₆ -DMSO) δ: 4.05 (2H, d, J = 5.2Hz) 4.84
(4H, s) 7.38 (2H, d, J = 8.0Hz) 7.58-7.72 (10H, m)
7.83 (2H, d, J = 8.4Hz) 7.90-8.00 (1H, m) 8.40 (1H,
m) 8.58 (2H, s) 8.83 (2H, s) 9.45 (1H, s)

Example 9 4-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'- Biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} Amino) methyl] -1,
1'-biphenyl 4-[(tert-butoxycarbonylamino) methyl] -4 '-[((3-
Pyridylmethyl) amino) methyl] -1,1'-biphenyl (5.6
6 g, 11.65 mmol) in toluene (50 ml) in 4-trifluoromethylphenylisocyanate (1.66 ml, 11.65 mmo
l) was added and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution,
Purify directly by silica gel column chromatography (hexane: ethyl acetate = 1: 1-1: 2) to give 4-[(N-tert-
Butoxycarbonyl-N-cyclohexylamino) methyl]-
4 '-[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl
(7.74 g, 99%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₉ H ₄₃ F ₃ N ₄ O ₃・ 0.5H ₂ O: C, 68.70; H, 6.50; N, 8.22 Measured value: C, 68.67; H, 6.59; N, 8.35. ¹ H -NMR (CDCl ₃ ) δ: 1.05-1.76 (10H, m) 1.40 (9H, s)
4.0-4.2 (1H, m) 4.41 (2H, s) 4.59 (2H, s) 4.72 (2
H, s) 6.57 (1H, s) 7.26-7.38 (7H, m) 7.47-7.54 (4
H, m) 7.63 (2H, d, J = 8.0Hz) 7.73-7.77 (1H, m) 8.57
-8.60 (2H, m) 2) 4-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1, 1'-biphenyl dihydrochloride (Method A) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl ) Anilino] carbonyl} amino) methyl]-
1,1'-biphenyl (1.14g, 1.69mmol) in methanol (10
Concentrated hydrochloric acid (10 ml) was added dropwise to the (ml) solution. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue,
Powder, filter with a glass filter, wash well with diethyl ether, and then 4-[(cyclohexylamino) methyl]-
4 '-[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl
The dihydrochloride salt (1.02g, 93%) was obtained as an amorphous powder. Elemental analysis value Calculated as C ₃₄ H ₃₅ F ₃ N ₄ O ・ 2HCl ・ H ₂ O: C, 61.54: H, 5.92: N, 8.44 Actual value: C, 61.40: H, 5.92: N, 8.42. ¹ H -NMR (d ₆ -DMSO) δ: 1.09-1.76 (10H, m) 2.13-2.18
(2H, m) 2.96 (1H, br) 4.17 (2H, s) 4.85 (4H, s) 7.3
9 (2H, d, J = 8.4Hz) 7.58-7.71 (8H, m) 7.83 (2H, d,
J = 9.2Hz) 7.98-8.04 (1H, m) 8.49 (1H, d, J = 7.2Hz)
8.81-8.59 (2H, m) 9.44 (3H, br) (Method B) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[ 4- (Trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-biphenyl (7.7g, 11.44mmol) in ethanol (10
Concentrated hydrochloric acid (50 ml) was added dropwise to the solution (0 ml). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The solvent was distilled off under reduced pressure, and saturated aqueous sodium hydrogen carbonate (100
ml) was added and the mixture was extracted with methylene chloride (100 ml × 3). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: acetone = 1: 1-chloroform: methanol = 10: 1) to give 4-[(cyclohexylamino) methyl] -4 '-[((3
-Pyridylmethyl) {[4- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] -1,1'-biphenyl (5.8g, 85
%) Was obtained as crystals. Melting point 167-172 ℃ Elemental analysis value C ₃₄ H ₃₅ F ₃ N ₄ O ・ 3 / 2H ₂ O, calculated value: C, 68.10; H, 6.39; N, 9.34 Found value: C, 68.00; H, 6.02; N, 9.36. ¹ H-NMR (CDCl ₃ ) δ: 1.00-2.05 (19H, m), 2.45-2.65 (1H,
m), 3.87 (2H, s), 4.59 (2H, s), 4.73 (2H, s), 6.55 (1H,
s), 7.25-7.72 (12H, m), 7.72-7.80 (1H, m), 8.57-8.67 (2
H, m). 4-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (5.5 g) was dissolved in ethanol (100 ml), concentrated hydrochloric acid (2.0 ml) was added, and the mixture was shaken. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethanol-diethyl ether to give 4-[(cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) Anilino] carbonyl} amino) methyl] -1,1'-
Biphenyl dihydrochloride (6.10 g, 96%) was obtained. Melting point> 285 ° C (decomposition) Elemental analysis value C ₃₄ H ₃₅ F ₃ N ₄ O ・ 2HCl ・ 1 / 2H ₂ O, calculated value: C, 62.38; H, 5.85; N, 8.56 Found value: C, 62.67; H, 5.74; N, 8.75.

Example 10 4-[(Cyclopentylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'- Biphenyl dihydrochloride 1) 4-[(Cyclopentylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1' -Biphenyl 4-[(tert-butoxycarbonylamino) methyl] -4 '-[((3-
Pyridylmethyl) {[4- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] -1,1'-biphenyl (0.6g, 1m
(mol) dissolved in ethanol (10 ml) and concentrated hydrochloric acid (10 ml)
Was added dropwise, and the mixture was stirred at room temperature for 0.5 hour. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, the hydrochloride salt was dissolved in methanol (5 ml) and magnesium sulfate was added.
(2g), cyclopentanone (0.45ml, 5.1mmol), triethylamine (0.31ml, 2.2mmol), acetic acid (0.13ml, 2.3mmol)
Was added in that order, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.08 g, 5.1 mmol) was added little by little, and the mixture was stirred at room temperature for 16 hours. further,
Cyclopentanone (0.18ml, 2.04mmol), acetic acid (0.06ml,
1 mmol), sodium triacetoxyborohydride (432
(mg, 2 mmol) was added, and the mixture was stirred at room temperature for 8 hours. further,
Cyclopentanone (0.18ml, 2.04mmol), acetic acid (0.06ml, 1
mmol), sodium triacetoxyborohydride (432m
g, 2 mmol) was added and the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium hydrogen carbonate (30 ml) was added to terminate the reaction, and ethyl acetate (30 m
lx 3) and the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 30: 1
-10: 1) and purified by 4-[(cyclopentylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1, 1'-Biphenyl (0.32 g, 56%) was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ: 1.54-1.93 (8H, m) 2.76 (1H, m)
3.13-3.20 (1H, m) 3.83 (2H, s) 4.57 (2H, s) 4.69 (2
H, s) 6.74 (1H, br) 7.26-7.61 (12H, m) 7.70-7.75
(1H, m) 8.55-8.56 (2H, m) 2) 4-[(Cyclopentylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino ) Methyl] -1,1'-biphenyl dihydrochloride 4-[(cyclopentylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) Methyl] -1,1'-biphenyl (0.32g, 0.54mmo
Concentrated hydrochloric acid (5 ml) was added dropwise to a solution of l) in methanol (5 ml).
After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4-[(cyclopentylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- ( Trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-biphenyl dihydrochloride (0.38 g, 100%) was obtained as an amorphous powder. Elemental analysis value Calculated as C ₃₃ H ₃₃ N ₄ OF ₃・ 2HCl ・ H ₂ O: C, 61.02; H, 5.74; N, 8.63 Measured value: C, 61.19; H, 5.98; N, 8.70. ¹ H- NMR (d ₆ -DMSO) δ: 1.51-1.97 (8H, m) 3.42 (1H,
m) 4.14 (2H, s) 4.83, 4.85 (4H, each s) 7.38 (2H,
d, J = 8.4Hz) 7.41-7.70 (8H, m) 7.82 (2H, d, J = 8.4H
z) 7.96-8.03 (1H, m) 8.45 (1H, d, J = 8.4Hz) 8.79-8.
84 (2H, m) 9.42 (1H, s) 9.53 (2H, br)

Example 11 4-[(Cycloheptylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1' -Biphenyl dihydrochloride 1) 4-[(N-Cycloheptyl-N-tert-butoxycarbonylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] Carbonyl} amino) methyl] -1,
1'-biphenyl 4-[(tert-butoxycarbonylamino) methyl] -4 '-[((3-
Pyridylmethyl) {[4- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] -1,1'-biphenyl (1.3g, 2.
Dissolve 2 mmol) in ethanol (20 ml) and add concentrated hydrochloric acid (20 m
l) was added dropwise, the mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure. Diethyl ether was added to the residue to form a powder, which was collected by filtration with a glass filter and washed well with diethyl ether to obtain a pale yellow amorphous powder. Then, the hydrochloride salt (0.67 g,
1.2 mmol) was dissolved in methanol (10 ml), magnesium sulfate (1 g), cycloheptanone (0.7 ml, 6 mmol), triethylamine (0.41 ml, 3 mmol), acetic acid (0.34 ml, 6 mmo
l) were added in that order, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.26 g, 6 mmol) was added little by little, and the mixture was stirred at room temperature for 16 hours. In addition, cycloheptanone (0.7ml, 6mmol), acetic acid (0.34ml, 6mmo
l), sodium triacetoxyborohydride (1.26g, 6
mmol) was sequentially added, and the mixture was stirred at room temperature for 6 hours. Saturated sodium bicarbonate water
(30 ml) and ethyl acetate (30 ml) were added, followed by dicarbonate di-te.
rt-Butyl (1.3 g, 6.0 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 3: 1), and 4-[(N-
Cycloheptyl-N-tert-butoxycarbonylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl ( 0.38 g, 45%) was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ: 1.22-1.65 (12H, m) 1.47 (9H, s)
4.0-4.2 (1H, m) 4.38 (2H, s) 4.59 (2H, s) 4.72 (2
H, s) 6.57 (1H, s) 7.26-7.65 (11H, m) 7.63 (2H, d,
J = 8.0Hz) 7.73-7.77 (1H, m) 8.57-8.60 (2H, m) 2) 4-[(cycloheptylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- ( Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 4-[(N-cycloheptyl-N-tert-butoxycarbonylamino) methyl] -4 '-[((3 -Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-
Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of biphenyl (0.38 g, 0.54 mmol) in methanol (10 ml). After stirring at room temperature for 30 minutes,
It was concentrated under reduced pressure. Diethyl ether was added to the residue to form a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4-[(cycloheptylamino) methyl] -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride (0.28g, 78%) was obtained as an amorphous powder. It was Elemental analysis value Calculated as C ₃₅ H ₃₇ N ₄ OF ₃・ 2HCl ・ 1.5H ₂ O: C, 61.22; H, 6.17; N, 8.16 Found value: C, 61.46; H, 6.23; N, 8.29. ¹ H -NMR (d ₆ -DMSO) δ: 1.30-1.73 (10H, m) 2.13-2.17
(2H, m) 3.13 (1H, m) 4.16 (2H, s) 4.03 (2H, s) 4.8
5 (2H, s) 7.38 (2H, d, J = 8.0Hz) 7.58-7.70 (8H, m)
7.82 (2H, d, J = 8.4Hz) 7.96 (1H, dd, J = 6.0, 8.2Hz)
8.42 (1H, d, J = 7.6Hz) 8.78-8.82 (2H, m) 9.33 (2H,
br) 9.41 (1H, s)

Example 12 4-[(Cyclooctylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1' -Biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclooctylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] Carbonyl} amino) methyl] -1,
1'-biphenyl 4-[(tert-butoxycarbonylamino) methyl] -4 '-[((3
-Pyridylmethyl) {[4- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] -1,1'-biphenyl (0.83g,
1.4 mmol) was dissolved in methanol (10 ml) and concentrated hydrochloric acid (1
(0 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, the hydrochloride salt was dissolved in methanol (10 ml) and treated with sodium chloride.
(3 g), cyclooctanone (1.8 ml, 14 mmol), triethylamine (0.49 ml, 3.5 mmol) and acetic acid (0.8 ml, 14 mmol) were added in that order, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.48 g, 7.0 mmol) was added little by little, and the mixture was stirred at room temperature for 24 hours. After the reaction,
After adding saturated aqueous sodium hydrogen carbonate (25 ml) and ethyl acetate (20 ml),
Di-tert-butyl dicarbonate (1.5 g, 6.9 mmol) was added, and the mixture was stirred at room temperature for 1 hr. After the reaction was completed, ethyl acetate (30 ml x
The aqueous layer was extracted with 3), the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: acetone = 3: 1−2: 2).
1--1: 1) and 4-[(N-tert-butoxycarbonyl-
N-cyclooctylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl}
Amino) methyl] -1,1'-biphenyl (0.34g, 37%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.36-2.0 (14H, m) 1.50 (9H, s)
4.1-4.3 (1H, br) 4.39 (2H, s) 4.58 (2H, s) 4.71 (2
H, s) 6.93 (1H, s) 7.27-7.63 (9H, m) 7.75 (1H, d,
J = 8.2Hz) 8.56 (2H, s) 2) 4-[(cyclooctylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) Methyl] -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclooctylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (tri Fluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-
Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of biphenyl (0.42 g, 0.599 mmol) in methanol (10 ml). After stirring at room temperature for 30 minutes,
It was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4-[(cyclooctylamino) methyl] -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride (0.35g, 87%) was obtained as an amorphous powder. It was Elemental analysis value, calculated as C ₃₆ H ₃₉ N ₄ OF ₃・ 2HCl ・ 0.5H ₂ O: C, 63.34; H, 6.20; N, 8.21 Found: C, 63.41; H, 6.32; N, 8.17. ¹ H-NMR (d ₆ -DMSO) δ: 1.2-1.8 (12H, m) 2.0-2.2 (2
H, m) 3.19 (1H, br) 4.17 (2H, s) 4.86 (4H, s) 7.39
(2H, d, J = 8.4Hz) 7.41-7.71 (9H, m) 7.84 (2H, d, J =
8.4Hz) 7.97-8.04 (1H, m) 9.47 (1H, d, J = 8.4Hz) 8.8
1 (1H, d, J = 5.6Hz) 8.85 (1H, s) 9.37 (2H, br) 9.48
(1H, s)

Example 13 4-[(Cyclohexylmethylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1' -Biphenyl dihydrochloride 1) 4-[(N-cyclohexylmethyl-N-tert-butoxycarbonylamino) methyl] -4 '-[((3-pyridylmethyl) {[4-
(Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4-[(tert-butoxycarbonylamino) methyl] -4 '-[((3-
Pyridylmethyl) {[4- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] -1,1'-biphenyl (0.51g,
0.87 mmol) is dissolved in ethanol (10 ml) and concentrated hydrochloric acid is added.
(10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, this hydrochloride was dissolved in methanol (5 ml) and magnesium sulfate (2 g), cyclohexylcarbaldehyde (0.53 m
l, 4.38mmol), triethylamine (0.27ml, 1.9mmol),
Acetic acid (0.11 ml, 1.9 mmol) was added in that order, and the mixture was stirred at room temperature for 1 hr. Then, sodium triacetoxyborohydride (1.08g, 5.1mmol) was added little by little, and then at room temperature for 17.5
Stir for hours. Saturated aqueous sodium hydrogen carbonate (30 ml) was added to terminate the reaction, the mixture was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform:
Methanol = 30: 1 to 10: 1) and purified by 4-[(N-cyclohexylmethyl-N-tert-butoxycarbonylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- ( Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-
Biphenyl (0.15g, 25%) was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ: 0.88-1.79 (10H, m) 2.30 (1H, b
r) 2.50 (2H, d, J = 6.6Hz) 3.83 (2H, s) 4.58 (2H, s)
4.70 (2H, s) 6.69 (1H, s) 7.26-7.63 (12H, m) 7.70-
7.76 (1H, m) 8.55-8.58 (2H, m) 2) 4-[(cyclohexylmethylamino) methyl] -4 '-[((3-
Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 4-[(N-cyclohexylmethyl-N-tert-butoxycarbonylamino) methyl] -4 '-[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-biphenyl (0.15g, 0.25mmol) in methanol (5m
l) Concentrated hydrochloric acid (5 ml) was added dropwise to the solution. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue,
Powderize, filter with a glass filter, wash well with diethyl ether, and then wash with 4-[(cyclohexylmethylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl. } Amino) methyl] -1,1′-biphenyl dihydrochloride (0.11 g, 68%) was obtained as an amorphous powder. Elemental analysis value Calculated as C ₃₄ H ₃₅ N ₄ OF ₃・ 2HCl ・ H ₂ O: C, 61.54; H, 5.92; N, 8.44 Actual value: C, 61.51; H, 6.11; N, 8.18 ¹ H- NMR (d ₆ -DMSO) δ: 0.88-1.23 (5H, m) 1.64-1.80
(6H, m) 2.72 (2H, br) 4.14 (2H, s) 4.81, 4.84 (4H,
each s) 7.38 (2H, d, J = 8.0Hz) 7.58-7.82 (10H, m)
7.95 (1H, dd, J = 5.8, 8.0Hz) 8.41 (1H, d, J = 5.8Hz)
8.77-8.81 (2H, m) 9.31 (2H, br) 9.37 (1H, s)

Example 14 4-[(isopropylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl}
Amino) methyl] -1,1'-biphenyl dihydrochloride 1) 4-[(N-isopropyl-N-tert-butoxycarbonylamino) methyl] -4 '-[((3-pyridylmethyl) {[4 -(Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1 '
-Biphenyl 4- (aminomethyl) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-biphenyl dihydrochloride (0.6g, 1.1mmol) was dissolved in methanol (10ml), magnesium sulfate (1g), acetone (0.39ml, 5.3mmol), triethylamine (0.37m)
(1, 2.7 mmol) and acetic acid (0.3 ml, 5.3 mmol) were added in that order, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.12 g, 5.3 mmol) was added little by little, and the mixture was stirred at room temperature for 16 hours. In addition, acetone (0.39m
(l, 5.3 mmol), acetic acid (0.3 ml, 5.3 mmol) and sodium triacetoxyborohydride (1.12 g, 5.3 mmol) were sequentially added, and the mixture was stirred at room temperature for 6 hours. After adding saturated aqueous sodium hydrogen carbonate (30 ml) and ethyl acetate (30 ml), di-tert-butyl dicarbonate (1.16
g, 5.3 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Acetone = 3: 1), 4-[(N-isopropyl-N-te
rt-Butoxycarbonylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.36g, 52% ) Was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ: 1.11 (3H, s) 1.14 (3H, s) 1.42
(9H, s) 4.0-4.2 (1H, m) 4.39 (2H, s) 4.59 (2H, s)
4.72 (2H, s) 6.62 (1H, s) 7.26-7.55 (11H, m) 7.63
(2H, d, J = 8.0Hz) 7.75 (1H, d, J = 7.8Hz) 8.56-8.59
(2H, m) 2) 4-[(isopropylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1' -Biphenyl dihydrochloride 4-[(N-isopropyl-N-tert-butoxycarbonylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino ) Methyl] -1,1'-
Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of biphenyl (0.35 g, 0.54 mmol) in methanol (10 ml). After stirring at room temperature for 30 minutes,
It was concentrated under reduced pressure. Diethyl ether was added to the residue to form a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4-[(isopropylamino) methyl] -4 '-[((3
-Pyridylmethyl) {[4- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] -1,1′-biphenyl dihydrochloride (0.26 g, 78%) was obtained as an amorphous powder. Elemental analysis _{C 31 H 31 N 4O F 3} · 2HCl · 0.5H 2 O Calculated: C, 60.59; H, 5.58 ; N, 9.12 Found:. C, 60.28; H, 5.71; N, 9.05 1 H -NMR (d ₆ -DMSO) δ: 1.31, 1.34 (6H, each s) 3.24-
3.30 (1H, m) 4.16 (2H, s) 4.85, 4.86 (4H, each s)
7.39 (2H, d, J = 8.2Hz) 7.41-7.71 (8H, m) 7.83 (2H,
d, J = 8.4Hz) 7.98-8.05 (1H, m) 8.48 (1H, d, J = 8.0H
z) 8.81-8.86 (2H, m) 9.40-9.45 (3H, br)

Example 15 4-[(nonylamino) methyl] -4 '-[((3-pyridylmethyl)
{[4- (Trifluoromethyl) anilino] carbonyl} amino] methyl] -1,1'-biphenyl dihydrochloride 1) 4-[(N-nonyl-N-tert-butoxycarbonylamino) methyl] -4 '-[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4-[(tert-butoxycarbonylamino) methyl] -4'- [((3-
Pyridylmethyl) {[4- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] -1,1'-biphenyl (0.6g,
1.0 mmol) was dissolved in ethanol (10 ml) and concentrated hydrochloric acid (1
(0 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, this hydrochloride was dissolved in methanol (10 ml), magnesium sulfate (1 g), n-nonyl aldehyde (0.21 ml, 1.2 mmol), triethylamine (0.31 ml, 2.2 mmol), acetic acid (0.14 ml, 2.
(5 mmol) in that order, and stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (0.32g, 1.5mmo
l) was added little by little, and the mixture was stirred at room temperature for 4 hours. In addition, n-nonyl aldehyde (0.1 ml, 0.6 mmol), acetic acid (0.0
7ml, 1.2mmol), sodium triacetoxyborohydride
(0.17 g, 0.8 mmol) were sequentially added, and the mixture was stirred at room temperature for 16 hours. After adding saturated aqueous sodium hydrogen carbonate (10 ml) and ethyl acetate (10 ml), di-tert-butyl dicarbonate (0.65 g, 3.0 mmol) was added,
The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: acetone = 4: 1 to
3: 1) and 4-[(N-nonyl-N-tert-butoxycarbonylamino) methyl] -4 '-[((3-pyridylmethyl) {[4-
(Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1′-biphenyl (0.11 g, 18%) was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 6.6Hz) 1.25 (9H,
s) 1.1-1.60 (14H, m) 3.18 (2H, s) 4.46 (2H, s) 4.5
9 (2H, s) 4.71 (2H, s) 6.71 (1H, s) 7.26-7.63 (13
H, m) 7.74 (1H, d, J = 8.0Hz) 2) 4-[(nonylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} Amino) methyl] -1,1'-biphenyl dihydrochloride 4-[(N-nonyl-N-tert-butoxycarbonylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- ( Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1′-biphenyl (0.11 g, 0.67 mmol) in methanol (10 ml). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to form a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4-[(nonylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (tri Fluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride (0.06
g, 60%) was obtained as an amorphous powder. Elemental analysis value Calculated as C ₃₇ H ₄₃ N ₄ OF ₃・ 2HCl ・ H ₂ O: C, 62.79; H, 6.69; N, 7.92 Actual value: C, 63.12; H, 6.79; N, 7.69. ¹ H- NMR (d ₆ -DMSO) δ: 0.82-0.85 (3H, m) 1.25 (14H,
s) 2.86 (2H, s) 4.14 (2H, s) 4.78 (2H, s) 4.81 (2
H, s) 7.38 (2H, d, J = 8.0Hz) 7.40-7.91 (11H, m) 8.3
1 (1H, d, J = 8.4Hz) 8.73-8.76 (2H, m) 9.2-9.24 (3H,
br)

Example 16 4-{[bis (3-phenylpropyl) amino] methyl} -4 '-[((3
-Pyridylmethyl) {[4- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 1) 4-{[bis (3-phenylpropyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4-{[(t
ert-Butoxycarbonyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.91g, 1.54 mmo
l) was dissolved in methanol (10 ml), concentrated hydrochloric acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure and azeotroped with toluene to obtain a pale yellow amorphous powder. Subsequently, this hydrochloride was dissolved in methanol (10 ml) and sodium chloride (3 g), 3-phenethyl aldehyde was added.
(1.0ml, 7.7mmol), triethylamine (0.54ml, 3.85mm
ol) and acetic acid (0.44 ml, 7.7 mmol) were added in that order, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.6 g, 7.7 mmol) was added little by little, and the mixture was allowed to stand at room temperature for 7 minutes.
Stir for hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate (30 ml) was added, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Acetone = 5: 2 − 2: 1 − 1: 1) and purified with 4-{[bis (3-
Phenylpropyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl}
Amino) methyl] -1,1′-biphenyl (0.51 g, 46%) was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.72-1.87 (4H, m) 2.48-
2.65 (8H, m) 4.59 (2H, s) 4.72 (2H, s) 6.62 (1H, s)
7.11-7.55 (21H, m) 7.64 (2H, d, J = 8.4Hz) 7.75 (1
H, d, J = 8.2Hz) 8.56-8.58 (2H, m) 2) 4-{[bis (3-phenylpropyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 4-{[bis (3-phenylpropyl) amino] methyl } -4 '-[((3
-Pyridylmethyl) {[4- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] -1,1'-biphenyl (0.50g,
Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of 0.70 mmol) in methanol (10 ml). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to form a powder, which was collected by filtration with a glass filter and washed well with diethyl ether to give 4-{[bis
(3-Phenylpropyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride (0.45g,
82%) was obtained as an amorphous powder. As Elemental analysis _{C 46 H 45 N 4 OF 3} · 2HCl · 2 / 3H 2 O, Calculated: C, 68.06; H, 6.00 ; N, 6.90 Found: C, 68.40; H, 6.11 ; N, 6.50. ¹ H-NMR (d ₆ -DMSO) δ: 2.0-2.2 (4H, m) 2.50-2.72 (4
H, m) 2.99 (4H, m) 4.32 (2H, s) 4.86 (4H, s) 7.06-
7.43 (17H, m) 7.58-7.70 (5H, m) 7.85 (2H, d, J = 8.8H
z) 8.01 (1H, dd, J = 5.8, 8.0Hz) 8.49 (1H, d, J = 8.0H
z) 8.83 (1H, d, J = 5.8Hz) 8.86 (1H, s) 9.46 (1H, s)

Example 17 4-[(benzylamino) methyl] -4 '-[((3-pyridylmethyl)
{[4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4- (aminomethyl) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl ) Anilino] carbonyl} amino) methyl]-
Sodium chloride (2.5g), benzaldehyde (0.11ml, 1.08mmol), triethylamine (0.2ml) in 1,1'-biphenyl dihydrochloride (470mg, 0.834mmol) in methanol (5ml).
4 ml, 1.72 mmol) and acetic acid (0.06 ml, 1.05 mmol) were added in that order. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (248 mg, 1.17 mmol) was added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate was added, the mixture was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to give 4-[(benzylamino) methyl]-.
4 '-[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (2
33 mg, 54%) was obtained as a colorless transparent solid. Melting point 127-129 ℃ Elemental analysis value Calculated as C ₃₅ H ₃₁ F ₃ N ₄ O ・ 0.5H ₂ O: C, 71.29; H, 5.47; N, 9.50 Found: C, 71.55; H, 5.45; N, 9.61. ¹ H-NMR (CDCl ₃ ) δ: 3.84, 3.86 (4H, each s) 4.59 (2
H, s) 4.72 (2H, s) 6.58 (1H, s) 7.27-7.65 (19H, m)
7.73-7.77 (1H, m) 8.56-8.59 (2H, m)

Example 18 4-{[(4-Fluorobenzyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]- 1,1'-biphenyl dihydrochloride 1) 4-{[N-tert-butoxycarbonyl-N- (4-fluorobenzyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[4 -
(Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.96
g, 1.65 mmol) was dissolved in methanol (10 ml), concentrated hydrochloric acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, the hydrochloride was dissolved in methanol (10 ml) and sodium chloride (3 g), p-fluorobenzaldehyde (0.52 ml, 4.9 ml) was added.
mmol), triethylamine (0.57 ml, 4.1 mmol), acetic acid
(0.56 ml, 9.8 mmol) were added in that order, and the mixture was stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride
(1.04 g, 4.9 mmol) was added little by little, and the mixture was stirred at room temperature for 16 hours. Furthermore, p-fluorobenzaldehyde (0.26 ml,
4.4 mmol), acetic acid (0.28 ml, 4.9 mmol), and sodium triacetoxyborohydride (0.5 g, 2.4 mmol) were added in that order, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, saturated sodium bicarbonate water (3
0 ml) and ethyl acetate (30 ml) were added, followed by di-tert dicarbonate.
-Butyl (1.8 g, 8.25 mmol) was added, and the mixture was stirred at room temperature for 1 hr. After completion of the reaction, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 5: 2-1: 1) and 4-{[N-tert-butoxycarbonyl-N- (4-fluorobenzyl) amino] methyl} -4'- [((3-pyridylmethyl) {[4-
(Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1′-biphenyl (0.72 g, 63%) was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s) 4.38 (4H, s) 4.60
(2H, s) 4.72 (2H, s) 6.58 (1H, s) 6.98 (2H, d, J =
8.4Hz) 7.18-7.38 (9H, m) 7.47-7.60 (6H, m) 7.75 (1
H, d, J = 8.0Hz) 8.56-8.59 (2H, m) 2) 4-{[(4-fluorobenzyl) amino] methyl} -4 '-[((3-
Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 4-{[N-tert-butoxycarbonyl-N- (4-fluorobenzyl) Amino] methyl} -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-biphenyl (0.71g, 1.0mmol) in methanol (10m
l) Concentrated hydrochloric acid (10 ml) was added dropwise to the solution. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4-{[(4-fluorobenzyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-
Biphenyl dihydrochloride (0.63 g, 92%) was obtained as an amorphous powder. Elemental analysis value Calculated as C ₃₅ H ₃₀ F ₄ N ₄ O ・ 2HCl ・ H ₂ O: C, 60.96; H, 4.97; N, 8.12 Found: C, 61.20; H, 4.81; N, 8.37. ¹ H -NMR (d ₆ -DMSO) δ: 4.16 (4H, s) 4.86 (4H, s) 7.2
1-7.37 (5H, m) 7.49-7.72 (10H, m) 7.84 (2H, d, J =
8.8Hz) 8.02 (1H, dd, J = 5.8, 8.0Hz) 8.49 (1H, d, J =
8.0Hz) 8.82 (1H, d, J = 5.6Hz) 8.86 (1H, s) 9.50 (1
H, s) 10.03 (2H, s)

Example 19 4-{[(3-pyridylmethyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]- 1,1'-biphenyl trihydrochloride 1) 4-{[N-tert-butoxycarbonyl-N- (3-pyridylmethyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[4 -(Trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-biphenyl 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.82
g, 1.38 mmol) was dissolved in methanol (10 ml), concentrated hydrochloric acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, the hydrochloride was dissolved in methanol (10 ml) and sodium chloride (3 g), 3-pyridinecarbaldehyde (0.65 ml, 6.9 ml) was added.
mmol), triethylamine (0.48ml, 3.5mmol), acetic acid
(0.39 ml, 6.9 mmol) were added in that order, and the mixture was stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride
(1.17g, 5.54mmol) was added little by little and then at room temperature for 24.5g.
Stir for hours. After the reaction was completed, saturated aqueous sodium hydrogen carbonate (20 ml) and ethyl acetate (20 ml) were added, and then di-tert-butyl dicarbonate (1.
5 g, 6.9 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 3: 2-1-1: 2: 3) to give 4-
{[N-tert-Butoxycarbonyl-N- (3-pyridylmethyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1 '
-Biphenyl (0.70 g, 74%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H, s) 4.42 (4H, s) 4.60
(2H, s) 4.71 (2H, s) 6.76 (1H, s) 7.23-7.64 (14H, s)
m) 7.74 (2H, d, J = 8.2Hz) 8.45-8.57 (4H, m). 2) 4-{[(3-pyridylmethyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl trihydrochloride 4-{[N-tert-butoxycarbonyl-N- (3-pyridylmethyl)
Amino] methyl} -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,
1'-biphenyl (0.69g, 1.01mmol) in methanol (10m
l) Concentrated hydrochloric acid (10 ml) was added dropwise to the solution. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether to give 4-{[(3-pyridylmethyl) amino].
Methyl} -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl trihydrochloride (0.68g, 97%) Obtained as an amorphous powder. Elemental analysis _{C 34 H 30 F 3 N 5} O · 3HCl · H 2 O Calculated: C, 57.59; H, 4.98 ; N, 9.88 Found:. C, 57.89; H, 5.25; N, 10.12 1 H -NMR (d ₆ -DMSO) δ: 4.28 (2H, s) 4.47 (2H, s) 4.
87 (4H, s) 7.39 (2H, d, J = 8.0Hz) 7.59-7.71 (9H, m)
7.85 (2H, d, J = 8.0Hz) 8.00-8.14 (2H, m) 8.51 (1H,
d, J = 8.0Hz) 8.82-8.96 (4H, m) 9.19 (1H, s) 9.52
(1H, s) 10.49 (2H, br)

Example 20 4-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -4 '-({[4- (trifluoromethyl) benzyl] amino } Methyl) -1,1'-biphenyl
Dihydrochloride 1) 4-[((3-pyridylmethyl) {[4- (trifluoromethyl)
Anilino] carbonyl} amino) methyl] -4 '-({N-tert-butoxycarbonyl-N- [4- (trifluoromethyl) benzyl] amino} methyl) -1,1'-biphenyl 4-{[((tert -Butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.82
g, 1.38 mmol) was dissolved in methanol (10 ml), concentrated hydrochloric acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, this hydrochloride was dissolved in methanol (10 ml) and sodium chloride (3 g), 4-trifluoromethylbenzaldehyde was added.
(1.1ml, 8.28mmol), triethylamine (0.58ml, 4.17m
mol) and acetic acid (0.48ml, 8.28mmol) in that order, and add 1 at room temperature.
Stir for hours. Then, sodium triacetoxyborohydride (1.47 g, 6.9 mmol) was added little by little, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, saturated aqueous sodium hydrogen carbonate (25 ml)
And ethyl acetate (20 ml) were added, di-tert-butyl dicarbonate (1.5 g, 6.9 mmol) was added, and the mixture was stirred at room temperature for 1 hr.
After completion of the reaction, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1), and 4-[((3-
Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -4 '-({N-tert-butoxycarbonyl-N- [4- (trifluoromethyl) benzyl] amino} methyl)- 1,1'-Biphenyl (0.72 g, 69%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s) 4.46 (4H, s) 4.60
(2H, s) 6.64 (1H, s) 7.26-7.64 (13H, m) 7.75 (1H,
d, J = 7.2H, 8.59 (2H, s) 2) 4-[((3-pyridylmethyl) {[4- (trifluoromethyl)
Anilino] carbonyl} amino) methyl] -4 '-({[4- (trifluoromethyl) benzyl] amino} methyl) -1,1'-biphenyl dihydrochloride 4-[((3-pyridylmethyl) { [4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] -4 '-({N-tert-butoxycarbonyl-N- [4- (trifluoromethyl) benzyl] amino} methyl) -1,1' -Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of biphenyl (0.71 g, 0.948 mmol) in methanol (10 ml). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl. ] -4 '-({[4- (Trifluoromethyl) benzyl] amino} methyl) -1,1'-biphenyl dihydrochloride (0.66
g, 96%) was obtained as an amorphous powder. Elemental analysis _{C 36 H 30 N 4 OF 6} · 2HCl · H 2 O Calculated: C, 59.92; H, 4.47 ; N, 7.76 Found:. C, 59.70; H, 4.73; N, 7.57 1 H- NMR (d ₆ -DMSO) δ: 4.30 (4H, s) 4.87 (4H, s) 7.4
0 (2H, d, J = 7.2Hz) 7.64-7.97 (16H, m) 8.58 (1H, d,
J = 8.0Hz) 8.8 (2H, m) 9.46 (1H, s) 10.17 (2H, br)

Example 21 4-{[(4-methoxybenzyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]- 1,1'-biphenyl dihydrochloride 1) 4-{[N-tert-butoxycarbonyl-N- (4-methoxybenzyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[4 -(Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.84
g, 1.42 mmol) was dissolved in methanol (10 ml), concentrated hydrochloric acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, the hydrochloride was dissolved in methanol (10 ml), sodium chloride (3 g), 4-anisaldehyde (0.84 ml, 7.1 mmol),
Triethylamine (0.5ml, 3.55mmol), acetic acid (0.41ml,
7.1 mmol) in that order, and stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (1.5g, 7.
(1 mmol) was added little by little, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, saturated aqueous sodium hydrogen carbonate (25 ml) and ethyl acetate (20 ml) were added.
ml), followed by di-tert-butyl dicarbonate (1.5g, 6.9mmo
l) was added and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 5: 2-2: 1-1: 1) to give 4-{[N-tert-butoxycarbonyl-N- (4-methoxybenzyl) amino] methyl. } -4 '-[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.45g, 45%) as colorless amorphous powder Got as. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.51 (9H, s) 3.80 (3H,
s) 4.36 (4H, s) 4.56 (2H, d, J = 11.4Hz) 4.73 (2H,
d, J = 4.8Hz) 6.62 (1H, s) 6.86 (2H, d, J = 8.0Hz) 7.71
-7.64 (11H, m) 7.73-7.77 (1H, m) 7.82 (2H, d, J = 8.
2Hz) 8.21 (1H, d, J = 5.8Hz) 8.26 (1H, s) 8.56-8.59
(2H, m) 2) 4-{[(4-methoxybenzyl) amino] methyl} -4 '-[((3-
Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 4-{[N-tert-butoxycarbonyl-N- (4-methoxybenzyl) Amino] methyl} -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-biphenyl (0.43g, 0.60mmol) in methanol (10
Concentrated hydrochloric acid (10 ml) was added dropwise to the (ml) solution. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4-{[(4-methoxybenzyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-
Biphenyl dihydrochloride (0.34 g, 83%) was obtained as an amorphous powder. As Elemental analysis _{C 36 H 33 N 4 O 2} F 3 · 2HCl · 1.5H 2 O, Calculated: C, 60.85; H, 5.39 ; N, 7.88 Found: C, 60.70; H, 5.37 ; N, 7.87 _{^{. 1 H-NMR (d 6}} -DMSO) δ: 3.77 (3H, s) 4.09 (4H, s)
4.75 (2H, d, J = 9.6Hz) 4.85 (2H, s) 6.97 (2H, d, J =
8.8Hz) 7.39 (2H, d, J = 8.4Hz) 8.69 (1H, s) 8.80-8.8
5 (2H, m) 9.47 (1H, s) 9.87 (3H, s)

Example 22 4-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'- Biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} Amino) methyl] -1,
1'-biphenyl 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.9
1 g, 1.54 mmol) was dissolved in methanol (10 ml), concentrated hydrochloric acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure and azeotroped with toluene to obtain a pale yellow amorphous powder. Subsequently, the hydrochloride was added to methanol (10 m
Sodium chloride (3g), cyclohexanone (1.6ml, 15.4mmol), triethylamine (0.54ml, 3.
9 mmol) and acetic acid (0.88 ml, 15.4 mmol) were sequentially added, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.6 g, 7.7 mmol) was added little by little, and the mixture was stirred at room temperature for 15 hours. After the reaction was completed, saturated aqueous sodium hydrogen carbonate (30 ml)
And ethyl acetate (30 ml) were added, di-tert-butyl dicarbonate (1.5 g, 7.7 mmol) was added, and the mixture was stirred at room temperature for 1 hr.
After the reaction was completed, the aqueous layer was extracted with ethyl acetate (30 ml x 3),
The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
Purify with (hexane: acetone = 3: 1-5: 3), and then use 4-[(N-
tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.75 g, 72%) was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.80 (19H, m) 4.0-4.2 (1H,
br) 4.41 (2H, m) 7.73 (1H, d, J = 7.2Hz) 8.12 (1H, d,
J = 8.8Hz) 8.56-8.59 (2H, m) 2) 4-[(cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino ) Methyl] -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[2- (tri Fluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-
Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of biphenyl (0.74 g, 1.1 mmol) in methanol (10 ml). After stirring at room temperature for 30 minutes,
It was concentrated under reduced pressure. Diethyl ether is added to the residue to make a powder, which is collected by filtration with a glass filter and diethyl ether.
Wash well with 4-[(cyclohexylamino) methyl] -4'-
[((3-Pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride (0.65g, 92%) was obtained as an amorphous powder. It was Elemental analysis value, calculated as C ₃₄ H ₃₅ N ₄ OF ₃・ 2HCl ・ 0.5H ₂ O: C, 62.38; H, 5.85; N, 8.56 Found: C, 62.18; H, 6.08; N, 8.71. ¹ H-NMR (d ₆ -DMSO) δ: 1.0-1.81 (8H, m) 2.0-2.2 (2
H, m) 2.97 (1H, br) 4.17 (2H, s) 4.77 (4H, s) 7.41
(2H, d, J = 8.2Hz) 7.47-7.53 (2H, m) 7.64-7.72 (9H,
m) 8.03 (1H, dd, J = 5.8, 8.0Hz) 8.45 (1H, d, J = 8.
2Hz) 8.60 (1H, s) 8.83 (1H, d, J = 5.6Hz) 9.44 (2H,
br)

Example 23 4-{[bis (cyclohexylmethyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 1) 4-{[bis (cyclohexylmethyl) amino] methyl }-Four'
-[((3-Pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4-{[(tert-butoxycarbonyl) amino] methyl} -4 ' -
[((3-Pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (1.1
6 g, 1.96 mmol) was dissolved in methanol (10 ml), concentrated hydrochloric acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure and azeotroped with toluene to obtain a pale yellow amorphous powder. Subsequently, the hydrochloride was added to methanol (10 m
l), add sodium chloride (3g), cyclohexanecarboxaldehyde (1.2ml, 9.8mmol), triethylamine (0.7ml, 4.9mmol), acetic acid (0.56ml, 9.8mmol) in that order and stir at room temperature for 1 hour. did. Then, sodium triacetoxyborohydride (1.04 g, 4.9 mmol) was added little by little, and the mixture was stirred at room temperature for 3 hours. Further, cyclohexanecarboxaldehyde (1.2 ml, 9.8 mmol), acetic acid (0.56 ml, 9.8 mmol), and sodium triacetoxyborohydride (1.04 g, 4.9 mmol) were added. After the disappearance of raw materials,
Add saturated aqueous sodium hydrogen carbonate (30 ml) and add ethyl acetate (30 ml x 3).
The aqueous layer was extracted with, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue (hexane: acetone = 5: 2-1: 1)
Purified with 4-{[bis (cyclohexylmethyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1 '-Biphenyl (1.08g, 81%) was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.6-1.0 (4H, m) 1.13-1.2
9 (4H, m) 1.43-1.79 (14H, m) 2.13 (4H, d, J = 7.0Hz)
3.50 (2H, s) 4.61 (2H, s) 4.70 (2H, s) 6.79 (1H,
s) 7.09-7.17 (1H, m) 7.25-7.64 (11H, m) 7.73 (1H,
d, J = 8.0Hz) 8.13 (1H, d, J = 8.8Hz) 8.55-8.59 (2H, m) 2) 4-{[bis (cyclohexylmethyl) amino] methyl} -4 '
-[((3-Pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl.2
Hydrochloride 4-{[bis (cyclohexylmethyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (1.07
g, 1.58 mmol) in methanol (10 ml) in concentrated hydrochloric acid (10 ml)
Was dripped. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether.
{[Bis (cyclohexylmethyl) amino] methyl} -4 '-[((3
-Pyridylmethyl) {[2- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride
(1.14 g, 95%) was obtained as an amorphous powder. Elemental analysis value C ₄₂ H ₄₉ N ₄ OF ₃・ 2HCl ・ H ₂ O, calculated value: C, 65.19; H, 6.90; N, 7.24 Found value: C, 65.45; H, 6.95; N, 7.27. ¹ H -NMR (d ₆ -DMSO) δ: 0.80-1.10 (8H, m) 0.50-2.0 (1
2H, m) 2.88 (4H, s) 4.39 (2H, s) 4.78 (4H, s) 7.41
-7.54 (5H, m) 7.64-7.78 (8H, m) 8.05 (1H, dd, J = 5.
8, 8.0Hz) 8.46 (1H, d, J = 8.0Hz) 8.61 (1H, s) 8.80
(1H, s) 8.84 (1H, d, J = 5.6Hz) 10.06 (1H, br)

Example 24 4-{[(cyclohexylmethyl) amino] methyl} -4 '-[((3-
Pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 1) 4-{[N-tert-butoxycarbonyl-N-cyclohexylmethylamino] Methyl} -4 '-[((3-pyridylmethyl) {[2-
(Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.7
5 g, 1.27 mmol) was dissolved in methanol (10 ml), concentrated hydrochloric acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure and azeotroped with toluene to obtain a pale yellow amorphous powder. Subsequently, the hydrochloride was added to methanol (10 m
Sodium chloride (3g), cyclohexanecarboxaldehyde (0.46ml, 3.81mmol), triethylamine (0.44ml, 3.18mmol), acetic acid (0.22ml, 3.81mmo)
l) were added in that order, and the mixture was stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (0.8g, 3.81mmol)
After adding little by little, the mixture was stirred at room temperature for 15 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate (30 ml) and ethyl acetate (30 ml) were added, di-tert-butyl dicarbonate (1.5 g, 7.7 mmol) was added, and the mixture was stirred at room temperature for 1 hr. After completion of the reaction, ethyl acetate
The aqueous layer was extracted with (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: acetone =
3: 1-2: 1), 4-{[N-tert-butoxycarbonyl-N-cyclohexylmethylamino] methyl} -4 '-[((3-pyridylmethyl) {[2- (trifluoro Methyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.56g, 64%)
Was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.94 (1H, m) 1.1-1.70 (1
0H, m) 3.06 (2H, br) 4.48 (2H, br) 4.61 (2H, s) 4.
70 (2H, s) 6.80 (1H, s) 7.09-7.17 (1H, m) 7.27-7.3
7 (3H, m) 7.48-7.62 (4H, m) 7.70-7.74 (1H, m) 8.12
(1H, d, J = 8.4Hz) 8.55-8.58 (2H, m). 2) 4-{[(cyclohexylmethyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 4-{[N-tert-butoxycarbonyl-N-cyclohexyl Methylamino] methyl} -4 '-[((3-pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-biphenyl (0.53g, 0.74mmol) in methanol (10
Concentrated hydrochloric acid (10 ml) was added dropwise to the (ml) solution. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue,
Powder, filter with a glass filter, wash well with diethyl ether, and then wash with 4-{[(cyclohexylmethyl) amino]
Methyl} -4 '-[((3-pyridylmethyl) {[2- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride (0.43g, 88%) Obtained as an amorphous powder. As Elemental analysis _{C 35 H 37 N 4 OF 3} · 2HCl · 0.5H 2 O, Calculated: C, 62.87; H, 6.03 ; N, 8.38 Found:. C, 62.60; H, 6.30; N, 8.40 1 H-NMR (d ₆ -DMSO) δ: 0.89-1.23 (6H, m) 1.64-1.82
(5H, m) 2.73 (2H, s) 4.16 (2H, s) 4.77 (4H, s) 7.4
0-7.77 (9H, m) 7.98-8.05 (1H, m) 8.42 (1H, d, J = 7.4
Hz) 8.59 (1H, s) 8.78 (1H, s) 8.82 (1H, d, J = 5.6H
z) 9.37 (2H, s)

Example 25 4-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[3- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'- Biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[3- (trifluoromethyl) anilino] carbonyl} Amino) methyl] methyl] -1,1'-biphenyl 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[3- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.70
g, 1.15 mmol) in methanol (10 ml) and add concentrated hydrochloric acid.
(10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. continue,
This hydrochloride salt was dissolved in methanol (10 ml), sodium chloride (3 g), cyclohexanone (1.2 ml, 11.5 mmol), triethylamine (0.5 ml, 3.45 mmol), acetic acid (0.7 ml, 11.5 mmol).
mmol) in that order and stirred at room temperature for 1.5 hours. afterwards,
Sodium triacetoxyborohydride (1.3g, 5.75mm
ol) was added little by little, and then the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium hydrogen carbonate (30 ml) and ethyl acetate (30 ml) were added, di-tert-butyl dicarbonate (1.8 g, 8.25 mmol) was added, and the mixture was stirred at room temperature for 1 hr. After the reaction was completed, ethyl acetate (30ml x 3)
The aqueous layer was extracted with, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue (hexane: acetone = 3: 2-2: 1)
Purified by 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[3-
(Trifluoromethyl) anilino] carbonyl} amino) methyl] methyl] -1,1′-biphenyl (0.54 g, 68%) was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.70 (10H, m) 1.39 (9H, s)
4.0-4.2 (1H, br) 4.41 (2H, s) 4.59 (2H, s) 4.71 (2
H, s) 6.66 (1H, s) 7.24-7.64 (13H, m) 7.77 (1H, d,
J = 8.0Hz) 8.56-8.58 (2H, m). 2) 4-[(cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[3- (trifluoromethyl) anilino] carbonyl} Amino) methyl] methyl] -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[3 -(Trifluoromethyl) anilino] carbonyl} amino) methyl] methyl]
-1,1'-Biphenyl (0.67g, 1.10mmol) in methanol (10
Concentrated hydrochloric acid (10 ml) was added dropwise to the (ml) solution. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue,
Powder, filter with a glass filter, wash well with diethyl ether, and then 4-[(cyclohexylamino) methyl]-
4 '-[((3-Pyridylmethyl) {[3- (trifluoromethyl) anilino] carbonyl} amino) methyl] methyl] -1,1'-biphenyl dihydrochloride (0.46g, 72%) Obtained as a crystalline powder. Elemental analysis value Calculated as C ₂₉ H ₃₃ F ₃ N ₄ O ・ 2HCl ・ H ₂ O: C, 57.90; H, 6.20; N, 9.31 Found: C, 58.18; H, 6.06; N, 9.49 ¹ H -NMR (d ₆ -DMSO) δ: 1.36-1.71 (10H, m) 2.0-2.16
(2H, m) 3.07 (1H, br) 4.09 (2H, s) 4.83 (4H, s)
7.32 (2H, d, J = 8.0Hz) 7.58 (4H, d, J = 8.2Hz) 7.80
(2H, d, J = 8.4Hz) 8.01 (1H, dd, J = 5.8, 8.0Hz) 8.45
(1H, d, J = 8.4Hz) 8.77 (1H, s) 8.79-8.82 (1H, m) 9.
34 (2H, s) 9.45 (1H, s)

Example 26 4-{[[([1,1'-biphenyl] -2-ylamino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl dihydrochloride 1) 4-{[[[[1,1'-biphenyl] -2-ylamino ) Carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,
1'-biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (0.63g, 1.30mmol) in acetonitrile (10
2-biphenylisocyanate (0.25 ml, 1.43
mmol) was added and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane: acetone = 2: 1-3: 2) and 4-{[[([1,1, '-
Biphenyl] -2-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl
-N-cyclohexylamino) methyl] -1,1'-biphenyl
(0.87 g, 98%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.41 (9H,
s) 4.0-4.2 (1H, br) 4.32 (2H, s) 4.42 (2H, s) 4.52
(2H, s) 6.57 (1H, s) 7.06-7.59 (18H, m) 8.24 (1H, s)
d, J = 8.4Hz) 8.41 (1H, s) 8.52 (1H, d, J = 3.2Hz) 2) 4-{[[([1,1'-biphenyl] -2-ylamino) carbonyl] (3- Pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl dihydrochloride 4-{[[[[1,1'-biphenyl] -2-ylamino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-
Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of biphenyl (0.84 g, 1.23 mmol) in ethanol (10 ml). After stirring at room temperature for 30 minutes,
It was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether to give 4-{[[([1,1'-biphenyl] -2-ylamino).
Carbonyl] (3-pyridylmethyl) amino] methyl} -4'-
[(Cyclohexylamino) methyl] -1,1'-biphenyl dihydrochloride (0.75g, 93%) was obtained as an amorphous powder. Elemental analysis calculated as C ₃₉ H ₄₀ N ₄ O ・ 2HCl ・ 0.5H ₂ O: C, 70.68; H, 6.54; N, 8.45 Found: C, 70.67; H, 6.74; N, 8.43. ¹ H- NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 2.0-2.2 (2H,
m) 2.95 (1H, br) 4.17 (2H, s) 4.57 (2H, s) 4.60 (2
H, s) 7.17 (2H, d, J = 8.4Hz) 7.26-7.45 (9H, m) 7.60
(2H, d, J = 8.0Hz) 7.72 (4H, s) 7.92 (1H, dd, J = 5.6,
8.2Hz) 8.10 (1H, d, J = 7.6Hz) 8.34 (1H, s) 8.66 (1
H, s) 8.78 (1H, d, J = 3.4Hz) 9.50 (2H, br)

Example 27 4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl dihydrochloride 1) 4-[(1,1'-biphenyl) -4-ylamino] carbonyl] (3
-Pyridylmethyl) amino] methyl} -4 '-[(tert-butoxycarbonylamino) methyl] -1,1'-biphenyl 4- (tert-butoxycarbonylamino) methyl-4'-[(3-pyridylmethyl) Aminomethyl] -1,1'-biphenyl (0.61g,
To a solution of 1.51 mmol) in dichloromethane (20 ml) was added 4-biphenylisocyanate (0.32 ml, 1.66 mmol) at room temperature.
It was stirred for 30 minutes. After concentrating the reaction solution, silica gel column chromatography (hexane: acetone = 5: 2)
to [3: 2) to refine 4-[(1,1'-biphenyl) -4-ylamino] carbonyl] (3-pyridylmethyl) amino] methyl}-
4 '-[(tert-Butoxycarbonylamino) methyl] -1,1'-biphenyl (0.84g, 93%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.47 (9H, s) 4.35 (2H,
d, J = 6.0Hz) 4.59 (2H, s) 4.71 (2H, s) 4.92 (1H, s)
6.50 (1H, s) 7.25-7.62 (14H, m) 7.30-7.77 (1H, m)
8.54-8.59 (2H, m). 2) 4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} -4'- [(N- tert-
Butoxycarbonyl-N-cyclohexylamino) methyl]-
1,1'-biphenyl 4-[(tert-biphenyl) -4-ylamino] carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(tert-butoxycarbonylamino) methyl] -1,1' -Biphenyl (0.83g, 1.39mm
ol) in methanol (10 ml) and concentrated hydrochloric acid (10 ml)
Was added dropwise, and the mixture was stirred at room temperature for 0.5 hour. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, the hydrochloride salt was dissolved in methanol (10 ml) and the sodium chloride (3 ml
g), cyclohexanone (1.4ml, 13.9mmol), triethylamine (0.58ml, 4.17mmol), acetic acid (1.2ml, 13.9mmol)
Was added in that order, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.5 g, 7.0 mmol) was added little by little, and the mixture was stirred at room temperature for 12.5 hours. After adding saturated aqueous sodium hydrogen carbonate (25 ml) and ethyl acetate (20 ml), dicarbonate dicarbonate was added.
-tert-Butyl (1.5 g, 6.9 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr. After completion of the reaction, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 2: 1), and 4-
{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-
Pyridylmethyl) amino] methyl} -4 ′-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1′-biphenyl (0.79 g, 83%) was obtained as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.76 (10H, m) 1.39 (9H, s)
4.0-4.2 (1H, br) 4.41 (2H, s) 4.58 (2H, s) 4.70 (2
H, s) 6.69 (1H, s) 7.26-7.63 (18H, m) 7.74 (1H, d,
J = 7.6Hz) 8.53-8.56 (2H, m). 3) 4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 ' -[(Cyclohexylamino) methyl] -1,1'-biphenyl dihydrochloride 4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-
Biphenyl (0.55g, 0.808mmol) in methanol (10ml)
Concentrated hydrochloric acid (10 ml) was added dropwise to the solution. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue,
Powder, filter with a glass filter, wash well with diethyl ether, and then 4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 ' -
[(Cyclohexylamino) methyl] -1,1′-biphenyl dihydrochloride (0.57 g, 100%) was obtained as an amorphous powder. Elemental analysis calculated as C ₃₉ H ₄₀ N ₄ O ・ 2HCl ・ H ₂ O: C, 69.74; H, 6.60; N, 8.34 Found: C, 70.02; H, 6.67; N, 8.40 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 1.0-1.8 (8H, m) 2.12-
2.18 (2H, m) 2.96 (1H, br) 4.17 (2H, s) 4.85 (4H,
s) 7.30-7.71 (18H, m) 8.01 (1H, dd, J = 5.4, 8.0Hz)
8.48 (1H, d, J = 8.0Hz) 8.81 (1H, s) 8.84 (1H, s) 9.
10 (1H, s) 9.42 (2H, br)

Example 28 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl di Hydrochloride 1) 4-[(tert-butoxycarbonylamino) methyl] -4'-
[((4-Phenoxyanilino) carbonyl) (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl 4- (tert-butoxycarbonylamino) methyl-4 '-[(3-pyridylmethyl) amino Methyl] -1,1'-biphenyl (0.54g,
4-Phenoxyphenylisocyanate (0.27 ml, 1.47 mmol) was added to a dichloromethane (20 ml) solution of 1.34 mmol) and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture, it is purified directly by silica gel column chromatography (hexane: acetone = 5: 2 to 1: 1) and 4-[(tert-butoxycarbonylamino) methyl] -4 '-[((4-phenoxy Anilino) carbonyl) (3-pyridylmethyl) amino] methyl} -1,
1'-Biphenyl (0.75g, 91%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.47 (9H, s) 4.35 (2H,
d, J = 5.8Hz) 4.57 (2H, s) 4.69 (2H, s) 4.94 (1H, s)
6.45 (1H, s) 6.90-7.08 (6H, m) 7.20-7.37 (8H, m)
7.52-7.61 (4H, m) 7.24 (1H, d, J = 7.8Hz) 8.57 (2H,
br). 2) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl}- 1,1'-biphenyl 4-[(tert-butoxycarbonylamino) methyl] -4 '-[((4-
Phenoxyanilino) carbonyl) (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.74g, 1.22mmol) was dissolved in methanol (10ml), concentrated hydrochloric acid (10ml) was added dropwise, and the mixture was stirred at room temperature. Stir for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Then, this hydrochloride was dissolved in methanol (10 ml), sodium chloride (3 g), cyclohexanone (1.3 ml, 12.2 mmol), triethylamine
(0.51 ml, 3.66 mmol) and acetic acid (0.7 ml, 12.2 mmol) were sequentially added, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.3 g, 6.1 mmol) was added little by little, and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate water (25 ml)
And ethyl acetate (20 ml) were added, di-tert-butyl dicarbonate (1.3 g, 6.1 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr. After completion of the reaction, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 7: 2-2: 1-2: 3), 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{ [[(4-Phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.56g, 67%) was obtained as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.80 (10H, m) 1.40 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.57 (2H, s) 4.70
(2H, s) 6.42 (1H, s) 6.88-7.09 (6H, m) 7.14-7.35
(8H, m) 7.52 (2H, d, J = 8.6Hz) 7.61 (2H, d, J = 7.6H
z) 7.75 (1H, dt, J = 1.8, 7.8Hz) 8.54-8.57 (2H, m). 3) 4-[(cyclohexylamino) methyl] -4 '-{[(4-phenoxyanilino) carbonyl ] (3-Pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4- Phenoxyanilino) carbonyl]
(3-Pyridylmethyl) amino] methyl} -1,1'-biphenyl
Concentrated hydrochloric acid in a solution of (0.55g, 0.79mmol) in methanol (10ml).
(10 ml) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to form a powder, which was collected by filtration with a glass filter and washed well with diethyl ether to give 4-[(cyclohexylamino) methyl] -4 '-{[[(4-phenoxyanilino) carbonyl] ( 3-Pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (0.48g, 87%)
Was obtained as an amorphous powder. Elemental analysis value Calculated as C ₃₉ H ₄₀ N ₄ O ₂・ 2HCl ・ H ₂ O: C, 67.23; H, 6.51; N, 8.04 Found: C, 67.55; H, 6.72; N, 7.91 ¹ H- NMR (d ₆ -DMSO) δ: 1.1-1.80 (8H, m) 2.1-2.2 (2H,
m) 2.96 (1H, s) 4.17 (2H, s) 4.81 (4H, s) 6.93-7.1
9 (5H, m) 7.31-7.41 (5H, m) 7.56 (2H, d, J = 8.6Hz)
7.67-7.71 (5H, m) 8.02 (1H, dd, J = 5.8, 8.0Hz) 8.48
(1H, d, H = 8.2Hz) 8.81-8.83 (2H, m) 9.01 (1H, s)
9.40 (2H, s)

Example 29 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl di Hydrochloride 1) 4-[(tert-butoxycarbonylamino) methyl] -4'-
[((4-Methoxyanilino) carbonyl) (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl 4- (tert-butoxycarbonylamino) methyl-4 '-[(3-pyridylmethyl) amino Methyl] -1,1'-biphenyl (0.64g,
4-Methoxyphenylisocyanate (0.23 ml, 1.66 mmol) was added to a dichloromethane (15 ml) solution of 1.59 mmol) and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture, it is purified directly by silica gel column chromatography (hexane: acetone = 5: 2 to 1: 1) and 4-[(tert-butoxycarbonylamino) methyl] -4 '-[((4-methoxy Anilino) carbonyl) (3-pyridylmethyl) amino] methyl} -1,1′-biphenyl (0.83 g, 94%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.46 (9H, s) 3.73 (3H,
s) 4.33 (2H, d, J = 5.8Hz) 4.54 (2H, s) 4.64 (2H, s)
5.07 (1H, br) 6.56 (1H, s) 6.77 (2H, d, J = 9.2Hz)
7.15 (2H, d, J = 9.2Hz) 7.23-7.36 (2H, m) 7.52-7.58
(3H, m) 7.6-7.73 (1H, m) 8.51 (2H, dd, J = 1.8, 4.8H
z). 2) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl}- 1,1'-biphenyl 4-[(tert-butoxycarbonylamino) methyl] -4 '-[((4-
(Methoxyanilino) carbonyl) (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.82g, 1.48mmol) was dissolved in methanol (10ml) and concentrated hydrochloric acid (10ml) was added dropwise at room temperature. Stir for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Then, this hydrochloride was dissolved in methanol (10 ml), sodium chloride (3 g), cyclohexanone (1.5 ml, 14.8 mmol), triethylamine
(0.62 ml, 4.44 mmol) and acetic acid (0.85 ml, 14.8 mmol) were added in that order, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.6 g, 7.60 mmol) was added little by little, and the mixture was stirred at room temperature for 1 hr. Saturated sodium bicarbonate water (25m
l) and ethyl acetate (20 ml) were added, followed by di-tert-dicarbonate.
Butyl (1.6 g, 7.6 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr. After completion of the reaction, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 3: 1-2: 1), and 4-
[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.
55 g, 59%) was obtained as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.80 (10H, m) 1.40 (9H, s)
3.75 (3H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.56 (2
H, s) 4.69 (2H, s) 6.29 (1H, s) 6.79 (2H, d, J = 9.2
Hz) 7.14 (2H, d, J = 9.2Hz) 7.28-7.35 (5H, m) 7.52
(2H, d, J = 8.0Hz) 7.61 (2H, d, J = 8.2Hz) 7.72-7.77 (1
H, m) 8.54 (1H, d, J = 1.8Hz) 8.56 (1H, d, J = 1.4Hz). 3) 4-[(cyclohexylamino) methyl] -4 '-{[[(4-methoxyani Rino) carbonyl] (3-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.
54 g, 0.85 mmol) in methanol (10 ml) was added with concentrated hydrochloric acid (10 ml).
ml) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure.
Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether.
[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl}
-1,1'-Biphenyl dihydrochloride (0.37g, 72%) was obtained as an amorphous powder. Elemental analysis _{C 34 H 38 N 4 O 2} · 2HCl · 1.5H 2 O · 2 / 3Et 2 O Calculated: C, 65.86; H, 6.99 ; N, 8.70 Found: C, 65.97; H, 7.37 ; ^{. N, 9.07 1 H-NMR} (d 6 -DMSO) δ: 1.0-1.80 (8H, m) 2.0-2.2 (2
H, m) 2.96 (1H, br) 3.70 (3H, s) 4.16 (2H, s) 4.79
(4H, s) 6.84 (2H, d, J = 9.2Hz) 7.36-7.43 (4H, m) 7.
65-7.71 (6H, m) 8.01 (1H, dd, J = 6.0, 7.8Hz) 8.47
(1H, d, J = 8.0Hz) 8.81 (3H, s) 9.43 (2H, br)

Example 30 4-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethoxy) anilino] carbonyl} amino) methyl] -1,1'- Biphenyl dihydrochloride 1) 4-[(tert-butoxycarbonylamino) methyl] -4'-
[((3-Pyridylmethyl) {[4-trifluoromethoxy] anilino} carbonyl) amino] methyl] -1,1'-biphenyl 4- (tert-butoxycarbonylamino) methyl-4 '-[(3-pyridyl Methyl) aminomethyl] -1,1'-biphenyl (0.53g,
1.31 mmol) in dichloromethane (20 ml) in 4-trifluoromethoxyphenylisocyanate (0.22 ml, 1.44
mmol) was added and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture, the reaction mixture is directly purified by silica gel column chromatography (hexane: acetone = 5: 2 to 3: 2) and 4-[(ter
t-Butoxycarbonylamino) methyl] -4 '-[((3-pyridylmethyl) {[4-trifluoromethoxy] anilino} carbonyl) amino] methyl] -1,1'-biphenyl (0.76g, 96%)
Was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.47 (9H, s) 4.35 (2H,
d, J = 6.0Hz) 4.57 (2H, s) 4.69 (2H, s) 4.96 (1H, s)
6.59 (1H, s) 7.09 (2H, d, J = 8.4Hz) 7.28 (3H, d,
J = 7.0Hz) 7.36 (3H, d, J = 7.2Hz) 7.54 (2H, d, J = 8.4H
z) 7.59 (2H, d, J = 8.4Hz) 7.73 (2H, d, J = 7.6Hz) 8.5
6 (2H, br). 2) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethoxy) anilino] Carbonyl} amino) methyl]-
1,1'-biphenyl 4-[(tert-butoxycarbonylamino) methyl] -4 '-[((3-
Pyridylmethyl) {[trifluoromethoxy] anilino} carbonyl) amino] methyl] -1,1'-biphenyl (0.74g, 1.
22 mmol) was dissolved in methanol (10 ml) and concentrated hydrochloric acid (10 m
l) was added dropwise, and the mixture was stirred at room temperature for 0.5 hour. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, the hydrochloride was dissolved in methanol (10 ml), sodium chloride (3 g), cyclohexanone (1.3 ml, 12.2 mmol), triethylamine (0.51 ml, 3.66 mmol), acetic acid (0.7 ml, 12.2 mmo).
l) were added in that order, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.3 g, 6.1 mmol) was added little by little, and the mixture was stirred at room temperature for 12.5 hours. After adding saturated aqueous sodium hydrogen carbonate (25 ml) and ethyl acetate (20 ml), di-tert-butyl dicarbonate (1.3 g, 6.1 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr. After the reaction was completed, the aqueous layer was extracted with ethyl acetate (30 ml x 3), and the organic layer was dried over anhydrous magnesium sulfate,
It was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 3: 1-5: 3), and 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3- Pyridylmethyl) {[4- (trifluoromethoxy) anilino] carbonyl} amino) methyl]-
1,1'-Biphenyl (0.79g, 64%) was obtained as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-2.0 (10H, m) 1.41 (9H, s)
4.0-4.2 (1H, br) 4.41 (2H, s) 4.57 (2H, s) 4.70 (2
H, s) 6.49 (1H, s) 7.09 (2H, d, J = 8.4Hz) 7.23-7.34
(7H, m) 7.52 (2H, d, J = 8.4Hz) 7.62 (2H, d, J = 8.6H
z) 7.72 (1H, m) 8.58 (2H, s). 3) 4-[(cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethoxy) anilino] carbonyl } Amino) methyl] -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (Trifluoromethoxy) anilino] carbonyl} amino) methyl] -1,1 '
-Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of biphenyl (0.53 g, 0.77 mmol) in methanol (10 ml). After stirring at room temperature for 30 minutes,
It was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4-[(cyclohexylamino) methyl] -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethoxy) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride (0.48g, 94%) was obtained as an amorphous powder. It was Elemental analysis value Calculated as C ₃₄ H ₃₅ F ₃ N ₄ O ₂・ 2HCl ・ H ₂ O: C, 60.09; H, 5.78; N, 8.24 Actual value: C, 60.01; H, 5.74; N, 8.03. ¹ H-NMR (d ₆ -DMSO) δ: 1.10-1.80 (8H, m) 2.1-2.2 (2
H, m) 2.96 (1H, s) 4.17 (2H, s) 4.83 (4H, s) 7.26
(2H, d, J = 8.4Hz) 7.39 (2H, d, J = 8.2Hz) 7.57-7.81
(8H, m) 7.96-8.0 (1H, m) 8.45 (1H, d, J = 8.4Hz) 8.8
0-8.83 (2H, m) 9.26 (1H, s) 9.44 (2H, s)

Example 31 4-{[{[3,5-bis (trifluoromethyl) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1, 1'-biphenyl dihydrochloride 1) 4-{[{[3,5-bis (trifluoromethyl) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(tert-
Butoxycarbonylamino) methyl] -1,1'-biphenyl 4- (tert-butoxycarbonylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.52g,
1.29 mmol) in dichloromethane (20 ml) in 3,5-bis
(Trifluoromethyl) phenyl isocyanate (0.25m
(1, 60 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution, silica gel column chromatography as it is.
Purify with (hexane: acetone = 5: 2 to 3: 2) to 4-
{[{[3,5-bis (trifluoromethyl) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(tert-butoxycarbonylamino) methyl] -1,1'-biphenyl ( 0.81
g, 95%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.45 (9H, s) 4.31 (2H,
d, J = 5.8Hz) 4.59 (2H, s) 4.67 (2H, s) 5.02 (1H, s)
7.26-7.33 (5H, m) 7.48-7.58 (4H, m) 7.70 (1H, d,
J = 7.6Hz) 7.83 (2H, s) 8.52-8.55 (2H, m). 2) 4-{[{[3,5-bis (trifluoromethyl) anilino] carbonyl} (3-pyridylmethyl) amino] Methyl} -4 '-[(N-ter
t-Butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-biphenyl 4-{[{[3,5-bis (trifluoromethyl) anilino] carbonyl} (3-pyridylmethyl) amino] methyl}- 4 '-[(tert-butoxycarbonylamino) methyl] -1,1'-biphenyl (0.
80 g, 1.21 mmol) was dissolved in methanol (10 ml), concentrated hydrochloric acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, the hydrochloride was dissolved in methanol (10 ml) and sodium chloride (3 g), cyclohexanone (1.3 ml, 12.2 mm
ol), triethylamine (0.51 ml, 3.66 mmol), acetic acid (0.
(7 ml, 12.2 mmol) were added in that order, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.3 g,
(6.1 mmol) was added little by little, and the mixture was stirred at room temperature for 2 hours. After adding saturated aqueous sodium hydrogen carbonate (25 ml) and ethyl acetate (20 ml), di-tert-butyl dicarbonate (1.3 g, 6.1 mmol) was added,
Stir at room temperature for 1.5 hours. After the reaction was completed, ethyl acetate (30
The aqueous layer was extracted with (ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: acetone = 7: 2).
−2: 1) and purified by 4-{[{[3,5-bis (trifluoromethyl) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 ′-[(N-tert-butoxy Carbonyl-N-cyclohexylamino) methyl] -1,1'-biphenyl (0.56g, 62%) was obtained as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.70 (10H, m) 1.38 (9H, s)
4.0-4.2 (1H, br) 4.40 (2H, s) 4.59 (2H, s) 4.70 (2
H, s) 7.06 (1H, s) 7.24-7.34 (11H, m) 7.49-7.52 (3
H, m) 7.62 (2H, d, J = 8.0Hz) 7.73 (1H, d, J = 8.0Hz)
8.54-8.58 (2H, m). 3) 4-{[{[3,5-bis (trifluoromethyl) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) Methyl] -1,1'-biphenyl dihydrochloride 4-{[{[3,5-bis (trifluoromethyl) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(N -tert-
Butoxycarbonyl-N-cyclohexylamino) methyl]-
1,1'-biphenyl (0.55g, 0.74mmol) in methanol (10
Concentrated hydrochloric acid (10 ml) was added dropwise to the (ml) solution. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue,
Powder, filter with a glass filter, wash well with diethyl ether, and then wash with 4-{[{[3,5-bis (trifluoromethyl)
Anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl dihydrochloride (0.48g, 91%) was obtained as an amorphous powder. It was Elemental analysis value Calculated as C ₃₅ H ₃₄ N ₄ OF ₆・ 2HCl ・ 1 / 3H ₂ O ・ 1 / 3Et ₂ O: C, 58.63; H, 5.42; N, 7.53 Found: C, 58.20; H, 5.60 ; N, 7.60. ¹ H-NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 2.0-2.2 (2H,
m) 2.97 (1H, s) 4.17 (2H, s) 4.87 (4H, s) 7.41 (2
H, d, J = 8.0Hz) 7.46-7.71 (5H, m) 8.00 (1H, dd, J =
5.4-8.0Hz) 8.42 (2H, s) 8.49 (1H, d, J = 8.4Hz) 8.81
(1H, d, J = 5.8Hz) 8.88 (1H, s) 9.38 (2H, s) 9.85 (1
H, s)

Example 32 4-[(Cyclohexylamino) methyl] -4 '-{[[(2-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl di Hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(2-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1 , 1'-Biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (0.58g, 1.19mmol) in acetonitrile (10
2-methoxyphenylisocyanate (0.18m
(1, 1.3 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution, the residue is subjected to silica gel column chromatography.
Purify with (hexane: acetone = 5: 2) to prepare 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4'-
{[[(2-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.72g, 95%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.40 (9H,
s) 3.59 (3H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.62
(2H, s) 4.71 (2H, s) 6.73-6.75 (1H, m) 6.92-6.97
(2H, m) 7.14 (1H, s) 7.26-7.39 (5H, m) 7.52 (2H, m
d, J = 8.4Hz) 7.60 (2H, d, J = 8.2Hz) 7.75 (1H, d, J = 8.
0Hz) 2) 4-[(Cyclohexylamino) methyl] -4 '-{[[(2-methoxyanilino) carbonyl] (3-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(2-methoxyanilino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.7
1 g, 1.11 mmol) in ethanol (10 ml) in concentrated hydrochloric acid (10 m
l) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether.
[(Cyclohexylamino) methyl] -4 '-{[[(2-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl}
-1,1'-Biphenyl dihydrochloride (0.60 g, 89%) was obtained as an amorphous powder. Elemental analysis calculated as C ₃₄ H ₃₈ N ₄ O ₂・ 2HCl ・ H ₂ O: C, 65.27; H, 6.77; N, 8.96 Found: C, 65.43; H, 6.83; N, 8.84. ¹ H- NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 2.0-2.2 (2H,
m) 2.95 (1H, br) 3.69 (3H, s) 4.16 (2H, s) 4.77 (2
H, s) 4.86 (2H, s) 6.84-7.02 (3H, m) 7.45 (2H, d,
J = 8.2Hz) 7.66-7.77 (9H, m) 8.01-8.08 (1H, m) 8.52
(1H, d, J = 8.0Hz) 8.83 (1H, s) 8.86 (1H, s) 9.49 (2
H, br)

Example 33 4-[(Cyclohexylamino) methyl] -4 '-{[[(3-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl di Hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(3-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1 , 1'-Biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (0.60g, 1.24mmol) in acetonitrile (10m
l) In solution, 3-methoxyphenylisocyanate (0.18 ml,
1.3 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (hexane: acetone = 2: 1-1: 1) to give 4-[(N-tert-
Butoxycarbonyl-N-cyclohexylamino) methyl]-
4 ′-{[[(3-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1′-biphenyl (0.75 g, 95%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (10H, m) 1.39 (9H, s)
3.77 (3H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.56 (2
H, s) 4.70 (2H, s) 6.42 (1H, s) 6.55-6.60 (1H, m)
6.67-6.72 (1H, m) 7.04-7.16 (3H, m) 7.29-7.35 (4H,
m) 7.52 (2H, d, J = 8.0Hz) 7.61 (2H, d, J = 8.2Hz) 7.7
4 (1H, d, J = 7.6Hz) 8.55 (1H, s) 8.57 (1H, d, J = 1.6H
z) 2) 4-[(cyclohexylamino) methyl] -4 '-{[[(3-methoxyanilino) carbonyl] (3-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(3-methoxyanilino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.7
4 g, 1.17 mmol) in ethanol (10 ml) in concentrated hydrochloric acid (10 m
l) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether.
[(Cyclohexylamino) methyl] -4 '-{[[(3-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl}
-1,1'-biphenyl dihydrochloride (0.68g, 96%) was obtained as an amorphous powder. Elemental analysis calculated as C ₃₄ H ₃₈ N ₄ O ₂・ 2HCl ・ 1.5H ₂ O: C, 64.35; H, 6.83; N, 8.83 Found: C, 64.13; H, 7.09; N, 8.61. ¹ H -NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 2.0-2.2 (2H,
m) 2.95 (1H, br) 3.70 (3H, s) 4.17 (2H, s) 4.79 (4
H, s) 6.52-6.58 (1H, m) 7.13-7.16 (2H, m) 7.24 (1
H, s) 7.37 (2H, d, J = 7.6Hz) 7.66-7.71 (7H, m) 8.00
(1H, dd, J = 6.0,8.2) 8.45 (1H, d, J = 8.0Hz) 8.80 (1
H, s) 8.83 (1H, s) 8.91 (1H, s) 9.41 (2H, br)

Example 34 4-[(Cyclohexylamino) methyl] -4 '-{[[(2,5-dimethoxyanilino) carbonyl] (3-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(2,5-dimethoxyanilino) carbonyl ] (3-Pyridylmethyl) amino] methyl} -1,1'-biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1 , 1 '
-Biphenyl (0.57g, 1.17mmol) in acetonitrile (10m
l) 3-methoxyphenylisocyanate (0.23 ml,
1.29 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture, the residue was purified by silica gel column chromatography (hexane: acetone = 5: 2-2: 1-3: 2) to give 4-[(N
-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(2,5-dimethoxyanilino) carbonyl] (3-
Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.7
4g, 95%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (10H, m) 1.40 (9H, s)
3.54 (3H, s) 3.79 (3H, s) 4.0-4.2 (1H, br) 4.41 (2
H, s) 4.61 (2H, s) 4.71 (2H, s) 7.46 (1H, dd, J = 2.
8, 8.6Hz) 6.67 (1H, d, J = 8.8Hz) 7.26-7.38 (5H, m)
7.56 (2H, d, J = 8.4Hz) 7.60 (2H, d, J = 8.4Hz) 7.74
(1H, d, J = 7.6Hz) 7.93 (1H, d, J = 2.8Hz) 8.55-8.60 (2
H, m) 2) 4-[(Cyclohexylamino) methyl] -4 '-{[[(2,5-dimethoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl・ Dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(2,5-dimethoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} Concentrated hydrochloric acid in an ethanol (10 ml) solution of -1,1'-biphenyl (0.73g, 1.1mmol).
(10 ml) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4-[(cyclohexylamino) methyl] -4 '-{[[(2,5-dimethoxyanilino) carbonyl ] (3-Pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (0.58g, 83%)
Was obtained as an amorphous powder. Elemental analysis _{C 35 H 40 N 4 O 3} · 2HCl · H 2 O Calculated: C, 64.12; H, 6.76 ; N, 8.55 Found:. C, 64.36; H, 6.88; N, 8.51 1 H- NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 2.0-2.2 (2H,
m) 2.95 (1H, br) 3.62 (3H, s) 3.66 (3H, s) 4.16 (2
H, s) 4.78 (2H, s) 4.89 (2H, s) 6.52 (1H, dd, J = 5.
6, 8.2Hz) 8.54 (1H, d, J = 8.4Hz) 8.85 (1H, d, J = 5.6
Hz) 8.89 (1H, s) 9.53 (2H, br)

Example 35 N ′-(4-butoxyphenyl) -N-({4 ′-[(cyclohexylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) -N- (3 -
Pyridylmethyl) urea dihydrochloride 1) N '-(4-butoxyphenyl) -N-({4'-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-
Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) urea 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl]- 1,1 '
-Biphenyl (0.64g, 1.32mmol) in acetonitrile (10m
l) 4-butoxyphenyl isocyanate (0.26 ml,
1.45 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane: acetone = 5: 2-2: 1) and N '-(4-butoxyphenyl) -N-({4'-[(N- tert-butoxycarbonyl-N
-Cyclohexylamino) methyl] [1,1'-biphenyl] -4-
Ill} methyl) -N- (3-pyridylmethyl) urea (0.86g, 96
%) As a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, d, J = 7.4Hz) 1.0-1.8
(14H, m) 1.40 (9H, s) 3.90 (2H, t, J = 6.2Hz) 4.0-4.2
(1H, br) 4.41 (2H, s) 4.56 (2H, s) 4.69 (2H, s)
6.24 (1H, s) 6.79 (2H, d, J = 9.2Hz) 7.13 (2H, d, J =
9.2Hz) 7.26-7.35 (5H, m) 7.52 (2H, d, J = 8.0Hz) 7.61
(2H, d, J = 8.0Hz) 7.75 (1H, d, J = 8.0Hz) 8.55 (1H,
s) 8.57 (1H, s) 2) N '-(4-butoxyphenyl) -N-({4'-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)- N-
(3-Pyridylmethyl) urea dihydrochloride N '-(4-butoxyphenyl) -N-({4'-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'- Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) urea
Concentrated hydrochloric acid in a solution of (0.85g, 1.26mmol) in ethanol (10ml).
(10 ml) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4-[(cyclohexylamino) methyl] -4 '-{[[(2,5-dimethoxyanilino) carbonyl ] (3-Pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (0.69g, 84%)
Was obtained as an amorphous powder. Elemental analysis _{C 37 H 44 N 4 O 2} · 2HCl · 0.5H 2 O Calculated: C, 67.47; H, 7.19 ; N, 8.51 Found:. C, 67.36; H, 7.36; N, 8.39 1 H -NMR (d ₆ -DMSO) δ: 0.95 (3H, t, J = 7.2Hz) 1.0-1.
8 (8H, m) 2.0-2.2 (2H, m) 2.95 (1H, br) 3.90 (2H,
t, J = 6.6Hz) 4.16 (2H, s) 4.78 (4H, s) 6.82 (2H, d,
J = 5.0Hz) 7.36-7.42 (5H, m) 7.61-7.81 (6H, m) 8.00
(1H, dd, J = 6.0,8.2Hz) 8.43 (1H, d, J = 8.4Hz) 8.81
(3H, s) 9.50 (2H, s)

Example 36 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-ethoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl di Hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-ethoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1 , 1'-Biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (0.62g, 1.28mmol) in acetonitrile (10m
l) 4-ethoxyphenyl isocyanate (0.21 ml,
1.41 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture, the residue was purified by silica gel column chromatography (hexane: acetone = 5: 2-2: 1-1: 1) to give 4-
[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-ethoxyanilino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.
(83 g, 99%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.25 (3H,
t, J = 7.4Hz) 1.40 (9H, s) 3.97 (2H, d, J = 9.0Hz) 4.41
(2H, s) 4.55 (2H, s) 4.68 (2H, s) 6.35 (1H, s) 6.
78 (2H, d, J = 8.8Hz) 7.14 (2H, d, J = 8.8Hz) 7.26-7.3
4 (5H, m) 7.52 (2H, d, J = 8.0Hz) 7.60 (2H, d, J = 8.4H
z) 7.73 (1H, d, J = 7.6Hz). 2) 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-ethoxyanilino) carbonyl] (3-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-ethoxyanilino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.
17 g, 0.25 mmol) in ethanol (10 ml) in concentrated hydrochloric acid (10
ml) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure.
Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether.
[(Cyclohexylamino) methyl] -4 '-{[[(4-ethoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl}
-1,1'-Biphenyl dihydrochloride (0.66g, 84%) was obtained as an amorphous powder. Elemental analysis value Calculated as C ₃₅ H ₄₀ N ₄ O ₂・ 2HCl ・ H ₂ O: C, 65.72; H, 6.93; N, 8.76 Found: C, 65.94; H, 7.03; N, 8.68 ¹ H- NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 1.16 (3H,
t, J = 7.0Hz) 2.0-2.2 (2H, m) 2.83 (1H, br) 3.82 (2
H, q, J = 6.8Hz) 4.04 (2H, s) 4.64 (4H, s) 6.68 (2H,
d, J = 8.8Hz) 7.27-7.28 (4H, m) 7.48-7.67 (6H, m)
7.84 (1H, dd, J = 5.4, 7.6Hz) 8.29 (1H, d, J = 8.0Hz)
8.67 (3H, d, J = 4.0Hz) 9.32 (2H, br)

Example 37 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-isopropoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl Dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-isopropoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-Biphenyl 4-isopropoxybenzoic acid (0.41 g, 2.28 mmol) in acetonitrile (15 ml) was added to triethylamine (0.48 ml,
3.42mmol) and diphenylphosphoric acid azide (0.54ml, 2.51mmo
l) was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, return to room temperature, 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.77g, 1.59mmol) Was added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane: acetone = 2: 1) to give 4-
[(N-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-isopropoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (1.02 g, 97%) was obtained as a colorless amorphous powder. ¹ H-
NMR (CDCl ₃ ) δ: 1.0-1.8 (10H, m) 1.27 (3H, s) 1.3
0 (3H, s) 1.38 (9H, s) 4.0-4.2 (1H, br) 4.39 (2H, s)
s) 4.56 (2H, s) 4.5-4.7 (1H, m) 4.69 (2H, s) 6.27
(1H, s) 6.79 (2H, d, J = 9.2Hz) 7.13 (2H, d, J = 9.2H
z) 7.26-7.35 (5H, m) 7.52 (2H, d, J = 8.0Hz) 7.61 (2
H, d, J = 8.4Hz) 7.72-7.78 (1H, m). 2) 4-[(cyclohexylamino) methyl] -4 '-{[[(4-isopropoxyanilino) carbonyl] (3-pyridyl Methyl) amino] methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-isopropoxyanilino) Carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.89g, 1.35mmol) in ethanol solution (5ml)
Normal hydrogen chloride-ethyl acetate (10 ml) was added dropwise at room temperature to 1
Stir for hours. After the solvent was concentrated under reduced pressure, a solid was precipitated from the residue with ethanol-diethyl ether, collected by filtration, and dried under reduced pressure. 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-isopropoxyanilino) carbonyl] (3-
Pyridylmethyl) amino] methyl} -1,1′-biphenyl dihydrochloride (0.77 g, 90%) was obtained as a colorless solid. Melting point 146-157 ℃ Elemental analysis value Calculated as C ₃₆ H ₄₂ N ₄ O ₂・ 2HCl ・ 1.5H ₂ O: C, 66.61; H, 7.06; N, 8.63 Found: C, 66.49; H, 7.10; N , 8.34. ¹ H-NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 1.21 (3H, s)
1.24 (3H, s) 2.0-2.2 (2H, m) 2.96 (1H, br) 4.16 (2
H, s) 4.4-4.6 (1H, m) 4.77 (4H, s) 6.81 (2H, d, J =
8.8Hz) 7.38 (4H, d, J = 8.8Hz) 7.66-7.71 (6H, m) 7.9
6 (1H, dd, J = 5.4, 7.6Hz) 8.40 (1H, d, J = 8.0Hz) 8.7
8 (3H, s) 9.42 (2H, s)

Example 38 4-[(Cyclohexylamino) methyl] -4 '-{[[(3,5-dimethoxyanilino) carbonyl] (3-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(3,5-dimethoxyanilino) carbonyl ] (3-Pyridylmethyl) amino] methyl} -1,1'-biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1 , 1 '
-Biphenyl (0.62g, 1.28mmol) in acetonitrile (10m
l) 3,5-dimethoxyphenylisocyanate (0.2
5 g, 1.41 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution, the residue is subjected to silica gel column chromatography.
Purify with (hexane: acetone = 5: 2-3: 2-1: 1) to prepare 4-[(N
-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(3,5-dimethoxyanilino) carbonyl] (3-
Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.8
7 g, 100%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (10H, m) 1.40 (9H, s)
3.74 (6H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.55 (2
H, s) 4.70 (2H, s) 6.15 (1H, t, J = 2.2Hz) 6.42 (1H,
s) 6.51 (2H, d, J = 2.2Hz) 7.26-7.34 (5H, m) 7.52 (2
H, d, J = 8.0Hz) 7.61 (2H, d, J = 8.0Hz) 7.13 (1H, d,
J = 8.0Hz) 8.54 (1H, d, J = 1.4Hz) 8.57 (1H, d, J = 1.6H
z). 2) 4-[(Cyclohexylamino) methyl] -4 '-{[[(3,5-dimethoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl. Dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(3,5-dimethoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl}- Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of 1,1′-biphenyl (0.86 g, 1.29 mmol) in ethanol (10 ml). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder,
Filtered with a glass filter, washed well with diethyl ether, and then 4-[(cyclohexylamino) methyl] -4 '-{[[(3,5-dimethoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl}- 1,1'-Biphenyl dihydrochloride (0.68 g, 83%) was obtained as an amorphous powder. Elemental analysis value Calculated as C ₃₅ H ₄₀ N ₄ O ₃ .2HCl.H ₂ O: C, 64.12; H, 6.76; N, 8.55 Found: C, 64.09; H, 6.86; N, 8.61. ¹ H -NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 2.0-2.2 (2H,
m) 2.96 (1H, br) 3.38 (6H, s) 3.87 (2H, s) 4.48 (2
H, s) 4.50 (2H, s) 5.83 (1H, t, J = 2.2Hz) 6.57 (2H,
d, J = 2.6Hz) 7.07 (2H, d, J = 8.0Hz) 7.36-7.40 (6H,
m) 7.66 (1H, dd, J = 5.8, 8.0Hz) 8.10 (1H, d, J = 8.2H
z) 8.48 (1H, s) 8.50 (1H, s) 8.56 (1H, s) 9.10 (2
H, br)

Example 39 4-[(Cyclohexylamino) methyl] -4 '-{[[(3,4,5-trimethoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1 '-Biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4'-{[[(3,4,5-trimethoxyanilino)
Carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-
Biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (0.51g, 1.05mmol) in acetonitrile (10m
l) 3,4,5-trimethoxyphenyl isocyanate in solution
(0.24 g, 1.15 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture, the residue was purified by silica gel column chromatography (hexane: acetone = 5: 2-1: 1) to give 4-
[(N-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(3,4,5-trimethoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1, 1'-Biphenyl (0.70g, 96%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (10H, m) 1.38 (9H, s)
3.78, 3.79 (each s, 9H) 4.0-4.2 (1H, br) 4.41 (2H,
s) 4.57 (2H, s) 4.70 (2H, s) 6.35 (1H, s) 6.55 (2
H, s) 7.28-7.35 (4H, m) 7.52 (2H, d, J = 8.2Hz) 7.62
(2H, d, J = 8.4Hz) 7.70-7.75 (1H, m) 8.55 (1H, d, J
= 1.8Hz) 8.57 (1H, d, J = 1.8Hz) 2) 4-[(cyclohexylamino) methyl] -4 '-{[[(3,4,5-
Trimethoxyanilino) carbonyl] (3-pyridylmethyl)
Amino] methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(3,4,5-trimethoxyani Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of (lino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1′-biphenyl (0.70 g, 1.01 mmol) in ethanol (10 ml). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to form a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4-[(cyclohexylamino) methyl] -4 '-{[[(3,
4,5-Trimethoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (0.57
g, 84%) was obtained as an amorphous powder. Elemental analysis value, calculated as C ₃₆ H ₄₂ N ₄ O ₄ .2HCl.H ₂ O: C, 63.06; H, 6.76; N, 8.17 Found value: C, 63.08; H, 6.94; N, 8.16. ¹ H -NMR (d ₆ -DMSO) δ: 1.0-1.8 (18H, m) 2.0-2.2 (2
H, m) 2.96 (1H, br) 3.59 (3H, s) 3.70 (3H, s) 4.16
(2H, s) 4.81 (4H, s) 7.03 (2H, s) 7.38 (2H, d, J =
8.6Hz) 7.67-7.71 (7H, m) 8.03 (1H, dd, J = 6.0, 8.2H
z) 8.48 (1H, d, J = 8.2Hz) 8.82 (1H, s) 8.84 (1H, s)
8.89 (1H, s) 9.46 (2H, br)

Example 40 4-{[[(4-chloroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl dihydrochloride 1) 4-{[{[4-chloroanilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(tert-butoxycarbonylamino) methyl] -1,1'-biphenyl 4- (tert- Butoxycarbonylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.74g,
To a solution of 1.83 mmol) in dichloromethane (10 ml) was added 4-chlorophenylisocyanate (0.26 ml, 2.01 mmol), and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture, silica gel column chromatography (hexane: acetone)
= 5: 2 to 1: 1) to refine 4-{[{[4-chloroanilino]
Carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(t
ert-Butoxycarbonylamino) methyl] -1,1′-biphenyl (0.95 g, 93%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.47 (9H, s) 4.34 (2H,
d, J = 5.8Hz) 4.56 (2H, s) 4.68 (2H, s) 4.93 (1H, s)
6.46 (1H, s) 7.20 (4H, s) 7.27-7.52 (5H, m) 7.54
(2H, d, J = 8.6Hz) 7.59 (2H, d, J = 8.4Hz) 7.73 (1H, d
t, J = 1.6, 7.8Hz) 8.54-8.57 (2H, m). 2) 4-{[[(4-chloroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(N- tert-butoxycarbonyl
-N-Cyclohexylamino) methyl] -1,1'-biphenyl 4-{[{[4-chloroanilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(tert-butoxycarbonylamino) methyl ] -1,1'-Biphenyl (0.94g, 1.69mmol) is dissolved in methanol (10ml), concentrated hydrochloric acid (10ml) is added dropwise,
The mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Then, this hydrochloride was dissolved in methanol (10 ml), sodium chloride (3 g), cyclohexanone (1.76 ml, 16.9 mmol), triethylamine
(0.71 ml, 5.1 mmol) and acetic acid (0.97 ml, 16.9 mmol) were added in that order, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.79 g, 8.45 mmol) was added little by little, and the mixture was stirred at room temperature for 0.5 hr. Saturated sodium bicarbonate water (25m
l) and ethyl acetate (20 ml) were added, followed by di-tert-dicarbonate.
Butyl (1.84 g, 8.45 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 3: 1-2: 1), and 4-
{[[(4-chloroanilino) carbonyl] (3-pyridylmethyl)
Amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-biphenyl (0.55g,
59%) was obtained as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.80 (10H, m) 1.39 (9H,
s) 3.75 (3H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.56
(2H, s) 4.70 (2H, s) 6.46 (1H, s) 7.20 (4H, s) 7.30
-7.34 (5H, m) 7.52 (2H, d, J = 8.0Hz) 7.62 (2H, d, J
= 8.2Hz) 7.74 (1H, d, J = 8.0Hz) 8.55-8.57 (2H, m). 3) 4-{[[(4-chloroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(Cyclohexylamino) methyl] -1,1'-biphenyl dihydrochloride 4-{[[(4-chloroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4'-[(N- tert-butoxycarbonyl-N
-Cyclohexylamino) methyl] -1,1'-biphenyl (0.77
g, 1.2 mmol) in methanol (10 ml) in concentrated hydrochloric acid (10 ml)
Was dripped. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether.
{[[(4-chloroanilino) carbonyl] (3-pyridylmethyl)
Amino] methyl} -4 '-[(cyclohexylamino) methyl]-
1,1'-biphenyl dihydrochloride (0.64g, 88%) was obtained as an amorphous powder. Elemental analysis value C ₃₃ H ₃₅ N ₄ OCl ・ 2HCl ・ 3 / 4H ₂ O calculated value: C, 63.36; H, 6.20; N, 8.96 Found value: C, 63.33; H, 6.36; N, 8.74. ¹ H-NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 2.0-2.2 (2H,
m) 7.58 (2H, d, J = 8.8Hz) 7.60-7.69 (6H, m) 7.96-
8.03 (1H, m) 8.45 (1H, d, J = 8.0Hz) 8.78-8.81 (2H,
m) 9.07 (1H, s) 9.25 (2H, br)

Example 41 4-[(Cyclohexylamino) methyl] -4 '-{[{[4- (cyclopentyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'- Biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (cyclopentyloxy) anilino] carbonyl} (3-pyridylmethyl) Amino] methyl} -1,
1'-biphenyl 4-cyclopentyloxybenzoic acid (0.32g, 1.55mmol)
Acetonitrile solution (10 ml) was added to triethylamine (0.33
ml, 2.31 mmol) and diphenylphosphoric acid azide (0.37 ml,
1.70 mmol) was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.53g, 1.1mmol) Was added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:
4-[(N-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (cyclopentyl Roxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl}-
1,1'-Biphenyl (0.71g, 100%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-2.0 (18H, m) 1.40 (9H, s)
4.0-4.2 (1H, br) 4.41 (2H, s) 4.55 (2H, s) 4.67 (2
H, s) 6.35 (1H, s) 6.76 (2H, d, J = 9.2Hz) 7.12 (2H,
d, J = 8.8Hz) 7.25-7.34 (5H, m) 7.52 (2H, d, J = 8.6H
z) 7.60 (2H, d, J = 8.0Hz) 7.71-7.75 (1H, m) 8.53 (1
H, s) 8.55 (1H, s). 2) 4-[(cyclohexylamino) methyl] -4 '-{[{[4- (cyclopentyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl } -1,1'-Biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (cyclopentyloxy) anilino]
Carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-
Biphenyl (0.61g, 0.92mmol) in ethanol (5ml)
To this was added 4N hydrogen chloride-ethyl acetate (10 ml) dropwise, and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure to give an amorphous powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-[(cyclohexylamino) methyl] -4'-
{[{[4- (cyclopentyloxy) anilino] carbonyl} (3-
Pyridylmethyl) amino] methyl} -1,1′-biphenyl dihydrochloride (0.48 g, 82%) was obtained as a colorless amorphous powder. As Elemental analysis _{C 38 H 44 N 4 O 2} · 2HCl · 0.5H 2 O, Calculated: C, 68.05; H, 7.06 ; N, 8.35 Found:. C, 67.70; H, 7.19; N, 8.11 1 H-NMR (d ₆ -DMSO) δ: 1.0-1.8 (16H, m) 2.0-2.2 (2H,
m) 2.96 (1H, br) 4.16 (2H, s) 4.76 (5H, s) 6.79 (2
H, d, J = 9.0Hz) 7.36 (4H, d, J = 9.0Hz) 7.76-7.90 (5
H, m) 7.95 (1H, dd, J = 5.4, 8.0Hz) 8.39 (1H, d, J =
8.0Hz) 8.74-8.79 (3H, m) 9.38 (2H, s)

Example 42 4-[(Cyclohexylamino) methyl] -4 '-{[{[4- (cyclohexyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl Dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (cyclohexyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] Methyl} -1,
1'-biphenyl 4-cyclohexyloxybenzoic acid (0.69g, 3.13mmol)
Triethylamine (0.66) was added to acetonitrile solution (15 ml).
ml, 4.73 mmol) and diphenylphosphoric acid azide (0.75 ml,
3.48 mmol) was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, return to room temperature, 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (1.08g, 1.64mmol) Was added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:
Ethyl acetate = 1: 1-hexane: acetone = 3: 2)
4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (cyclohexyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,
1'-Biphenyl (1.45g, 92%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-2.0 (20H, m) 1.40 (9H, s)
4.0-4.2 (1H, br) 4.41 (2H, s) 4.55 (2H, s) 4.69 (2
H, s) 6.28 (1H, s) 6.80 (2H, d, J = 9.2Hz) 7.12 (2H,
d, J = 8.8Hz) 7.28-7.34 (5H, m) 7.52 (2H, d, J = 8.0H
z) 7.60 (2H, d, J = 8.2Hz) 7.72-7.77 (1H, m) 8.54-8.5
7 (2H, m). 2) 4-[(Cyclohexylamino) methyl] -4 '-{[{[4- (cyclohexyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1 '-Biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4'-{[{[4- (cyclohexyloxy) anilino]
Carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-
Biphenyl (1.25g, 1.78mmol) in ethanol (10m
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise to l),
Stirred at room temperature for 1 hour. After concentrating the solvent under reduced pressure, ethanol
-A solid was precipitated with diethyl ether and dried under reduced pressure. 4-[(Cyclohexylamino) methyl] -4 '-{[{[4- (cyclohexyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (1.16
g, 97%) was obtained as a colorless solid. Melting point 101-102 ° C Elemental analysis C ₃₉ H ₄₆ N ₄ O ₂・ 2HCl ・ H ₂ O Calculated: C, 67.52; H, 7.26; N, 8.08 Found: C, 67.4
9; H, 7.39; N, 7.79. ¹ H-NMR (d ₆ -DMSO) δ: 1.0-2.0 (18H, m) 2.0-2.2 (2
H, m) 2.95 (1H, br) 4.16 (3H, s) 4.77 (4H, s) 6.82
(2H, d, J = 8.8Hz) 7.37 (4H, d, J = 8.8Hz) 7.65-7.71
(5H, m) 7.96 (1H, dd, J = 5.6, 7.8Hz) 8.40 (1H, d, J
= 8.0Hz) 8.78 (3H, s) 9.47 (2H, s)

Example 43 4-{[{[4- (cycloheptyloxy) anilino] carbonyl} (3
-Pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl dihydrochloride 1) 4-{[{[4- (cycloheptyloxy) anilino] carbonyl} (3-Pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,
A solution of 1'-biphenyl 4-cycloheptyloxybenzoic acid (0.39g, 1.57mmol) in acetonitrile (10ml) was added with triethylamine (0.33m).
l, 2.36 mmol) and diphenylphosphoric acid azide (0.38 ml, 1.7
(3 mmol) was added at room temperature, and the mixture was heated under reflux for 1 hr. afterwards,
After returning to room temperature, 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.54g, 1.12mmol) was added. ,
Stir for 10 minutes at room temperature. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane: acetone = 3: 2) to give 4-
{[{[4- (cycloheptyloxy) anilino] carbonyl} (3-
Pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-biphenyl (0.75g, 94%) was obtained as a colorless amorphous powder. . ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (20H, m) 1.8-2.0 (2H,
m) 1.39 (9H, s) 4.0-4.2 (1H, br) 4.25-4.35 (1H, m)
4.41 (2H, s) 4.55 (2H, s) 4.68 (2H, s) 6.29 (1H,
s) 6.76 (2H, d, J = 9.2Hz) 7.12 (2H, d, J = 8.8Hz) 7.2
6-7.34 (5H, m) 7.52 (2H, d, J = 8.4Hz) 7.60 (2H, d,
J = 8.4Hz) 7.75 (1H, d, J = 8.0Hz) 8.54 (1H, s) 8.56
(1H, s). 2) 4-{[{[4- (cycloheptyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1, 1'-biphenyl dihydrochloride 4-{[{[4- (cycloheptyloxy) anilino] carbonyl} (3
-Pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-
Biphenyl (0.47g, 0.67mmol) in ethanol (5m
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise to l),
Stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to give an amorphous powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-{[{[4- (Cycloheptyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4'-
[(Cyclohexylamino) methyl] -1,1′-biphenyl dihydrochloride (0.37 g, 82%) was obtained as a colorless amorphous powder. As Elemental analysis _{C 40 H 47 N 3 O 2} · 2HCl · H 2 O, Calculated: C, 69.35; H, 7.42 ; N, 6.07 Found:. C, 69.71; H, 7.57; N, 6.07 1 H -NMR (d ₆ -DMSO) δ: 1.0-2.0 (20H, m) 2.0-2.2 (2
H, m) 2.96 (1H, br) 4.17 (2H, s) 4.51-4.59 (1H, m)
4.71 (2H, s) 4.74 (2H, s) 6.94 (2H, d, J = 8.8Hz)
7.32 (2H, d, J = 8.0Hz) 7.48 (2H, d, J = 8.4Hz) 7.67
(1H, d, J = 8.4Hz) 7.72 (6H, s) 7.91-7.98 (1H, m) 8.
39 (1H, br) 8.77 (1H, s) 8.80 (1H, s) 9.46 (2H, s)

Example 44 4-{[{[4- (benzyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl. Dihydrochloride 1) 4-{[{[4- (benzyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-Biphenyl 4-benzyloxybenzoic acid (0.59 g, 2.58 mmol) in acetonitrile (10 ml) was added to triethylamine (0.54 ml, 3.
87mmol) and diphenylphosphoric acid azide (0.62ml, 2.84mmo
l) was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, return to room temperature, 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.89g, 1.84mmol) Was added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane: acetone = 3: 2) to give 4-{[{[4
-(Benzyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N
-Cyclohexylamino) methyl] -1,1'-biphenyl (1.1
7 g, 90%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (10H, m) 1.39 (9H, s)
4.0-4.2 (1H, br) 4.41 (2H, s) 4.58 (2H, s) 4.64 (2
H, s) 5.07 (2H, s) 6.97 (2H, d, J = 8.8Hz) 7.24-7.61
(17H, m) 8.47 (1H, s) 8.55 (1H, dd, J = 1.8, 5.2H
z). 2) 4-{[{[4- (benzyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl ・ di Hydrochloride 4-{[{[4- (benzyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1, 1'-biphenyl (0.95g, 1.34mmol) in ethanol solution (5ml) 4
Normal hydrogen chloride-ethyl acetate (10 ml) was added dropwise at room temperature to 1
Stir for hours. After the solvent was concentrated under reduced pressure, a solid was precipitated with ethanol-diethyl ether and dried under reduced pressure. Four-
{[{[4- (benzyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino)
Methyl] -1,1′-biphenyl dihydrochloride (0.95 g, 98%) was obtained as a colorless solid. Melting point 138-152 ° C Elemental analysis C ₄₀ H ₄₂ N ₄ O ₂・ 2HCl ・ H ₂ O Calculated: C, 68.46; H, 6.61; N, 7.98 Found: C, 68.44; H, 6.75; N, 7.67. ¹ H-NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 2.0-2.2 (2H,
m) 2.94 (1H, br) 4.77 (4H, s) 5.05 (2H, s) 6.92 (2
H, d, J = 8.8Hz) 7.31-7.41 (9H, m) 7.66-7.71 (6H, m)
7.92-7.99 (1H, m) 8.40 (1H, d, J = 8.4Hz) 8.80 (3H,
s) 9.44 (2H, s)

Example 45 4-[(Cyclohexylamino) methyl] -4 '-{[{[4- (neopentyloxy) anilino] carbonyl} (3-pyridylmethyl)
Amino] methyl} -1,1'-biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (neopentyloxy) Anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,
1'-Biphenyl 4-neopentyloxybenzoic acid (0.32g, 1.54mmol) in acetonitrile (10ml) was added to triethylamine (0.33m).
l, 2.31 mmol) and diphenylphosphoric acid azide (0.37 ml, 1.7
(0 mmol) was added at room temperature, and the mixture was heated under reflux for 1 hr. afterwards,
After returning to room temperature, 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.53g, 1.1mmol) was added. ,
Stir at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane: acetone = 3: 2) to give 4-[(N
-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (neopentyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl ( 0.66 g, 62%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.00 (9H, s) 1.2-1.8 (10H, m)
1.40 (9H, s) 3.53 (2H, s) 4.0-4.2 (1H, br) 4.41 (2
H, s) 4.55 (2H, s) 4.67 (2H, s) 6.36 (1H, s) 6.79
(2H, d, J = 8.8Hz) 7.14 (2H, d, J = 8.8Hz) 7.25-7.34
(5H, m) 7.52 (2H, d, J = 8.4Hz) 7.60 (2H, d, J = 8.0Hz)
7.73 (1H, d, J = 7.6Hz) 8.54 (1H, s) 8.55 (1H, s). 2) 4-[(cyclohexylamino) methyl] -4 '-{[{[4- (neopentyloxy)) Anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{ [4- (Neopentyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.51g, 0.74mmol) in ethanol (5ml)
To this was added 4N hydrogen chloride-ethyl acetate (10 ml) dropwise, and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure to give an amorphous powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-[(cyclohexylamino) methyl] -4'-
{[{[4- (Neopentyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (0.41g, 84%) as colorless amorphous powder Obtained. Elemental analysis value Calculated as C ₃₈ H ₄₆ N ₄ O ₂・ 2HCl ・ H ₂ O: C, 66.95; H, 7.39; N, 8.22 Found: C, 66.98; H, 7.65; N, 8.08 ¹ H- NMR (d ₆ -DMSO) δ: 0.98 (9H, s) 1.0-1.8 (8H, m)
2.0-2.2 (2H, m) 2.96 (1H, br) 3.56 (2H, s) 4.16 (2
H, s) 4.75 (4H, s) 6.83 (2H, d, J = 9.2Hz) 7.38 (4H,
d, J = 7.4Hz) 7.66-7.70 (5H, m) 7.94 (1H, dd, J = 5.
8, 8.0Hz) 8.37 (1H, d, J = 8.0Hz) 8.74 (1H, s) 8.78
(2H, s) 9.38 (2H, s)

Example 46 4-[(Cyclohexylamino) methyl] -4 '-{[{[4- (dimethylamino) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl -Trihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (dimethylamino) anilino]
Carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-
Biphenyl 4-dimethylaminobenzoic acid (0.30 g, 1.44 mmol) in acetonitrile solution (10 ml) was added to triethylamine (0.23 ml, 1.6
5mmol) and diphenylphosphoric acid azide (0.47ml, 2.10mmol)
Was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl]-
Add 1,1'-biphenyl (0.50g, 1.03mmol) and add 1 at room temperature.
Stir for 0 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
1: 1 to hexane: acetone = 3: 2 to 5: 4)
4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (dimethylamino) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1 '-Biphenyl (0.56g, 84%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (10H, m) 1.40 (9H, s)
2.87 (6H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.55 (2
H, s) 4.67 (2H, s) 6.27 (1H, s) 6.65 (2H, d, J = 9.2H
z) 7.10 (2H, d, J = 9.2Hz) 7.25-7.35 (5H, m) 7.52 (2
H, d, J = 8.0Hz) 7.60 (2H, d, J = 8.4Hz) 7.72-7.77 (1H,
m) 8.53 (1H, d, J = 1.6Hz) 8.55 (1H, d, J = 1.4Hz). 2) 4-[(cyclohexylamino) methyl] -4 '-{[{[4- (dimethylamino) Anilino] carbonyl} (3-pyridylmethyl)
Amino] methyl} -1,1'-biphenyl trihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (dimethylamino) anilino] carbonyl } (3-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.42g, 0.65mmol) in ethanol solution (5ml)
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure to give an amorphous powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-[(cyclohexylamino) methyl] -4'-
{[{[4- (Dimethylamino) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl trihydrochloride
(0.35 g, 82%) was obtained as a colorless amorphous powder. Elemental analysis _{C 35 H 41 N 5 O 2} · 3HCl · 1.5H 2 O Calculated: C, 61.45; H, 6.92 ; N, 10.24 Found:. C, 61.65; H, 7.26; N, 9.99 1 H -NMR (CD ₃ OD) δ: 1.2-1.6 (4H, m) 1.6-1.8 (1H, m)
1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.15 (1H, s) 3.27
(6H, s) 4.27 (2H, s) 4.88 (4H, s) 7.42 (2H, d, J =
8.4Hz) 7.62-7.76 (10H, m) 8.02 (1H, dd, J = 5.8Hz)
8.56 (1H, d, J = 8.2Hz) 8.74 (1H, d, J = 5.4Hz)

Example 47 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-cyclohexylanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl di Hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-cyclohexylanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1 1,1'-biphenyl 4-cyclohexylbenzoic acid (0.30 g, 1.44 mmol) in acetonitrile solution (10 ml) was added to triethylamine (0.23 ml, 1.6
5mmol) and diphenylphosphoric acid azide (0.47ml, 2.10mmol)
Was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl]-
Add 1,1'-biphenyl (0.50g, 1.03mmol) and add 1 at room temperature.
Stir for 0 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
Purify with 1: 1 hexane: acetone = 3: 2) to prepare 4-[(Nt
ert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-cyclohexylanilino) carbonyl] (3-
Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.7
4g, quant.) Was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-2.0 (20H, m) 1.40 (9H, s)
2.42 (1H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.55 (2
H, s) 4.68 (2H, s) 6.44 (1H, s) 7.06-7.19 (4H, m)
7.25-7.34 (5H, m) 7.52 (2H, d, J = 8.4Hz) 7.59 (2H,
d, J = 8.4Hz) 7.73 (1H, d, J = 8.0Hz) 8.53 (1H, d, J = 1.
8Hz) 8.55 (1H, d, J = 1.4Hz). 2) 4-[(cyclohexylamino) methyl] -4 '-{[[(4-cyclohexylanilino) carbonyl] (3-pyridylmethyl) amino] methyl } -1,1'-Biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-cyclohexylanilino) carbonyl] (3-pyridyl Methyl) amino] methyl} -1,1'-biphenyl (0.57g, 0.83mmol) in ethanol solution (5ml)
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure to give an amorphous powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-[(cyclohexylamino) methyl] -4'-
{[[(4-Cyclohexylanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride
(0.50 g, 92%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₉ H ₄₆ N ₄ O ・ 2HCl ・ H ₂ O: C, 69.11; H, 7.44; N, 8.27 Found: C, 69.01; H, 7.58; N, 8.15. ¹ H-NMR (CD ₃ OD) δ: 1.2-1.6 (10H, m) 1.6-2.0 (8H,
m) 2.2-2.3 (2H, m) 2.45 (1H, br) 3.14 (1H, br) 4.2
6 (2H, s) 4.83 (2H, s) 4.87 (2H, s) 7.12 (2H, d, J
= 8.4Hz) 7.30 (2H, d, J = 5.8, 8.0Hz) 7.42 (2H, d, J =
8.4Hz) 7.58-7.74 (6H, m) 8.01 (1H, dd, J = 5.8, 8.0H
z) 8.54 (1H, d, J = 8.0Hz) 8.72 (1H, d, J = 5.6Hz) 8.75
(1H, s)

Example 48 4-{[[(4-tert-butylanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl di Hydrochloride 1) 4-{[[(4-tert-Butylanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1 Triethylamine (0.32ml, 2.25) was added to an acetonitrile solution (10ml) of 1,1'-biphenyl 4-tert-butylbenzoic acid (0.27g, 1.50mmol).
mmol) and diphenylphosphoric acid azide (0.36 ml, 1.65 mmol)
Was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl]-
Add 1,1'-biphenyl (0.53g, 1.09mmol) and add 1 at room temperature.
Stir for 0 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1:
Purified with 1-hexane: acetone = 3: 2) to give 4-{[[(4-tert-
Butylanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-biphenyl (0.60g, 84
%) Was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (10H, m) 1.26 (9H, s)
1.39 (9H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.56 (2
H, s) 4.69 (2H, s) 6.40 (1H, s) 7.15-7.34 (9H, m)
7.52 (2H, d, J = 8.4Hz) 7.60 (2H, d, J = 8.2Hz) 7.71-
7.76 (1H, m) 8.54 (1H, s) 8.56 (1H, s). 2) 4-{[[(4-tert-butylanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[ (Cyclohexylamino) methyl] -1,1'-biphenyl dihydrochloride 4-{[[(4-tert-butylanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(N-tert -Butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-biphenyl
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of (0.45 g, 0.68 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to give an amorphous powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-{[[(4-tert-Butylanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl dihydrochloride (0.35g, (81%)
Was obtained as a colorless amorphous powder. Elemental analysis _{C 37 H 44 N 4 O ·} 2HCl · H 2 O Calculated: C, 68.19; H, 7.42 ; N, 8.60 Found:. C, 68.46; H, 7.59; N, 8.56 1 H-NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 1.24 (9H, s)
2.0-2.2 (2H, m) 2.96 (1H, br) 4.16 (2H, s) 4.78 (4
H, s) 7.26 (2H, d, J = 8.8Hz) 7.37 (2H, d, J = 8.4Hz)
7.43 (2H, d, J = 8.8Hz) 7.66-7.71 (5H, m) 7.95 (1H,
dd, J = 6.0, 8.2Hz) 8.39 (1H, d, J = 8.0Hz) 8.77 (1H,
s) 8.79 (1H, s) 8.85 (1H, s) 9.41 (2H, s)

Example 49 4-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (2-thienyl) anilino] carbonyl} amino)
Methyl] -1,1'-biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- ( 2-thienyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4- (2-thienyl) benzoic acid (0.22g, 1.0mmol) in acetonitrile solution (10ml) in triethylamine (0.21ml, 1.5
mmol) and diphenylphosphoric acid azide (0.24 ml, 1.1 mmol)
Was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl]-
Add 1,1'-biphenyl (0.49g, 1.0mmol) and add 10
Stir for minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
1: 1 Hexane: Acetone = 3: 2) and purified with 4-[(N-te
rt-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (2-thienyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.49
g, 70%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (10H, m) 1.38 (9H, s)
4.0-4.2 (1H, br) 4.40 (2H, s) 4.58 (2H, s) 4.71 (2
H, s) 6.47 (1H, s) 7.04 (1H, t, J = 4.0Hz) 7.20-7.36
(9H, m) 7.47-7.55 (4H, m) 7.62 (2H, d, J = 8.0Hz)
7.74-7.78 (1H, m) 8.55 (1H, d, J = 1.8Hz) 8.59 (1H,
d, J = 1.4Hz). 2) 4-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (2-thienyl) anilino] carbonyl} amino) methyl] -1 , 1'-Biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (2-thienyl)
Anilino] carbonyl} amino) methyl] -1,1'-biphenyl
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of (0.39 g, 0.56 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to give an amorphous powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (2-thienyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride ( 0.32g, 85%)
Was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₇ H ₃₈ N ₄ OS ・ 2HCl ・ H ₂ O: C, 65.57; H, 6.25; N, 8.27 Actual value: C, 65.56; H, 6.39; N, 8.16. ¹ H-NMR (CD ₃ OD) δ (ppm) 1.2-1.6 (5H, m) 1.6-1.8 (1
H, m) 1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.14 (1H, b
r) 4.26 (2H, s) 4.84 (2H, s) 4.88 (2H, s) 7.03-7.0
7 (1H, m) 7.28-7.33 (2H, m) 7.41-7.49 (4H, m) 7.54
-7.74 (8H, m) 8.00 (1H, dd, J = 5.8, 8.4Hz) 8.54 (1H,
d, J = 8.0Hz) 8.72 (1H, d, J = 5.4Hz) 8.77 (1H, s).

Example 50 4-[(Cyclohexylamino) methyl] -4 '-{[{[4- (2-furyl) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'- Biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (2-furyl) anilino] carbonyl} (3-pyridylmethyl) Amino] methyl} -1,1'-biphenyl 4- (2-furyl) benzoic acid (0.22g, 1.09mmol) in acetonitrile solution (10ml) with triethylamine (0.23ml, 1.64)
mmol) and diphenylphosphoric acid azide (0.26 ml, 1.21 mmol)
Was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl]-
Add 1,1'-biphenyl (0.53g, 1.1mmol) and add 10
Stir for minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1:
1-hexane: acetone = 3: 2) for purification, 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4'-
{[{[4- (2-Furyl) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.51g, 68%)
Was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.2-1.8 (10H, m) 1.39 (9H, s)
4.0-4.2 (1H, br) 4.41 (2H, s) 4.58 (2H, s) 4.71 (2
H, s) 6.43 (1H, dd, J = 1.8, 3.2Hz) 6.51-6.54 (2H,
m) 7.26-7.35 (7H, m) 7.41 (1H, d, J = 1.8Hz) 7.50-7.
64 (6H, m) 7.73-7.77 (1H, m) 8.55 (1H, d, J = 1.4Hz)
8.57 (1H, s). 2) 4-[(Cyclohexylamino) methyl] -4 '-{[{[4- (2-furyl) anilino] carbonyl} (3-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (2-furyl) anilino] carbonyl}
(3-Pyridylmethyl) amino] methyl} -1,1'-biphenyl
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of (0.35 g, 0.51 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to give an amorphous powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-[(cyclohexylamino) methyl] -4 '-{[{[4- (2-
Furyl) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (0.28g, 85%)
Was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₉ H ₃₈ N ₄ O ₂・ 2HCl ・ H ₂ O: C, 67.16; H, 6.40; N, 8.47 Found: C, 67.18; H, 6.80; N, 8.29. ¹ H- NMR (CD ₃ OD) δ: 1.2-1.6 (5H, m) 1.6-1.8 (1H, m)
1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.14 (1H, br) 4.2
6 (2H, s) 4.84 (2H, s) 4.88 (2H, s) 6.47-6.49 (1H,
m) 6.66 (1H, d, J = 3.8Hz) 7.41-7.51 (5H, m) 7.57-
7.74 (8H, m) 7.97-8.04 (1H, m) 8.53 (1H, d, J = 8.8H
z) 8.73 (1H, d, J = 5.6Hz) 8.77 (1H, s)

Example 51 4-[(Cyclohexylamino) methyl] -4 '-{[{[4- (phenoxymethyl) anilino] carbonyl} (3-pyridylmethyl)
Amino] methyl} -1,1'-biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (phenoxymethyl) anilino ] Carbonyl} (3-pyridylmethyl) amino] methyl} -1,
1'-biphenyl 4-phenoxymethylbenzoic acid (0.24g, 1.05mmol) in acetonitrile (10ml) was added to triethylamine (0.22m).
l, 1.58mmol) and diphenylphosphoric acid azide (0.25ml, 1.
(15 mmol) was added at room temperature, and the mixture was heated under reflux for 1 hr. afterwards,
After returning to room temperature, 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.51g, 1.05mmol) was added. ,
Stir for 10 minutes at room temperature. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane: acetone = 3: 2) to give 4-[(N-
tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (phenoxymethyl) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.44g , 59%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.2-1.8 (10H, m) 1.39 (9H, s)
4.0-4.2 (1H, br) 4.41 (2H, s) 4.57 (2H, s) 4.69 (2
H, s) 4.98 (2H, s) 6.53 (1H, s) 6.89-6.96 (3H, m)
7.22-7.34 (11H, m) 7.52 (2H, d, J = 8.2Hz) 7.61 (2H,
d, J = 8.0Hz) 7.72-7.76 (1H, m) 8.55 (1H, d, J = 1.4H
z) 8.56 (1H, d, J = 1.8Hz). 2) 4-[(cyclohexylamino) methyl] -4 '-{[{[4- (phenoxymethyl) anilino] carbonyl} (3-pyridylmethyl) amino ] Methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (phenoxymethyl) anilino] carbonyl} (3-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.26g, 0.37mmol) in ethanol (5ml)
To this was added 4N hydrogen chloride-ethyl acetate (10 ml) dropwise, and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure to give an amorphous powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-[(cyclohexylamino) methyl] -4'-
Obtained {[{[4- (phenoxymethyl) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (0.24g, 96%) as a colorless amorphous powder It was Elemental analysis value Calculated as C ₄₀ H ₄₂ N ₄ O ₂・ 2HCl ・ 2.5H ₂ O: C, 65.93; H, 6.78; N, 7.69 Found: C, 66.10; H, 6.69; N, 7.70. ¹ H -NMR (CD ₃ OD) δ: 1.2-1.6 (5H, m) 1.6-1.8 (1H, m)
1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.14 (1H, br) 4.2
6 (2H, s) 4.84 (2H, s) 4.89 (4H, s) 6.75 (2H, d, J
= 8.8Hz) 7.11-7.19 (1H, m) 7.24-7.46 (8H, m) 7.59
(2H, d, J = 8.4Hz) 7.66 (2H, d, J = 8.4Hz) 7.72 (2H, d,
J = 8.4Hz) 8.02 (1H, dd, J = 5.8, 8.0Hz) 8.56 (1H, d,
J = 8.2Hz) 8.73 (1H, d, J = 5.6Hz) 8.78 (1H, s)

Example 52 4-{[[(4-benzylanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl di Hydrochloride 1) 4-{[[(4-benzylanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1 Triethylamine (0.27ml, 1.9mmo) was added to acetonitrile solution (10ml) of 1,1'-biphenyl-4- (benzyl) benzoic acid (0.27g, 1.27mmol).
l) and diphenylphosphoric acid azide (0.3 ml, 1.4 mmol) were added at room temperature, and the mixture was heated under reflux for 1 hr. Then return to room temperature,
4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (0.50 g, 1.03 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
, Hexane: acetone = 3: 2), and purified with 4-{[[(4-benzylanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl- N-Cyclohexylamino) methyl] -1,1'-biphenyl (0.37g, 52
%) Was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (10H, m) 1.39 (9H, s)
3.90 (2H, s) 4.0-4.2 (1H, br) 4.40 (2H, s) 4.55 (2
H, s) 4.68 (2H, s) 6.42 (1H, s) 7.04-7.33 (14H, m)
7.51 (2H, d, J = 8.2Hz) 7.60 (2H, d, J = 8.0Hz) 7.73
(1H, dd, J = 1.8,7.6Hz) 8.53 (1H, s) 8.55 (1H, s). 2) 4-{[[(4-benzylanilino) carbonyl] (3-pyridylmethyl) amino] methyl } -4 '-[(Cyclohexylamino) methyl] -1,1'-biphenyl dihydrochloride 4-{[[(4-benzylanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4' -[(N-tert-butoxycarbonyl
-N-cyclohexylamino) methyl] -1,1'-biphenyl
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of (0.27 g, 0.39 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to give an amorphous powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-{[[(4-benzylanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino)
Methyl] -1,1′-biphenyl dihydrochloride (0.23 g, 89%) was obtained as a colorless amorphous powder. ¹ H-NMR (CD ₃ OD) δ: 1.2-1.6 (5H, m) 1.6-1.8 (1H, m)
1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.14 (1H, br) 3.9
1 (2H.s) 4.26 (2H, s) 4.81 (2H, s) 4.85 (2H, s)
7.10-7.33 (9H, m) 7.41 (2H, d, J = 8.4Hz) 7.59 (2H,
d, J = 8.4Hz) 7.64 (2H, d, J = 8.4Hz) 7.72 (2H, d, J = 8.
4Hz) 8.00 (1H, dd, J = 5.6, 8.2Hz) 8.53 (1H, d, J = 8.4
Hz) 8.70-8.75 (2H, m)

Example 53 4-{[(cyclohexylmethyl) amino] methyl} -4 '-{[[(4-
Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride 1) 4-{[(N-tert-butoxycarbonyl-N-cyclohexylmethyl) amino] methyl} -4 '-{[[(4-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl 4-{[(N-tert-butoxycarbonyl) amino] methyl}- Four'-
{[[(4-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.88g, 1.59mmo
l) dissolved in methanol (15 ml) and concentrated hydrochloric acid (15 ml)
Was added dropwise, and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, this hydrochloride was dissolved in methanol (5 ml) and anhydrous magnesium sulfate (2 g), cyclohexanecarboxaldehyde (0.29 m
l, 2.40mmol), triethylamine (0.55 ml, 3.94mmo
l) and acetic acid (1.1 ml, 19.2 mmol) were added in that order, and the mixture was stirred at room temperature for 1 hr. Then sodium borohydride (0.12g,
(3.20 mmol) was added little by little, and the mixture was stirred at room temperature for 30 minutes. After adding saturated aqueous sodium hydrogen carbonate (30 ml) and ethyl acetate (30 ml), the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: acetone = 1: 1), 4-{[(N-tert-butoxycarbonyl-N-cyclohexylmethyl) amino] methyl} -4'-
{[[(4-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.39g, 38%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 0.95 (1H, br) 1.15-1.72 (10H,
m) 1.49 (9H, s) 3.04 (2H, br) 3.76 (3H, s) 4.49 (2
H, brs) 4.56 (2H, s) 4.69 (2H, s) 6.29 (1H, s) 6.80
(2H, d, J = 8.8Hz) 7.15 (2H, d, J = 9.0Hz) 7.26-7.35
(5H, m) 7.54 (2H, d, J = 8.2Hz) 7.60 (2H, d, J = 8.0H
z) 7.74 (1H, d, J = 8.0Hz) 8.54 (1H, d, J = 1.4Hz) 8.56
(1H, d, J = 1.8Hz). 2) 4-{[(cyclohexylmethyl) amino] methyl} -4'-
{[[(4-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride 4-{[(N-tert-butoxycarbonyl-N-cyclohexylmethyl) Amino] methyl} -4 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.38g, 0.59mmol) in methanol (10ml) Concentrated hydrochloric acid (10 ml) was added dropwise to. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether to give 4-{[(cyclohexylmethyl) amino] methyl}-.
4 '-{[[(4-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (0.24
g, 65%) was obtained as an amorphous powder. Elemental analysis value Calculated as C ₃₅ H ₄₀ N ₄ O ₂・ 2HCl ・ H ₂ O: C, 65.72; H, 6.93; N, 8.76 Actual value: C, 65.79; H, 6.90; N, 8.86. ¹ H- NMR (d ₆ -DMSO) δ: 0.8-1.3 (6H, m) 1.63-1.82 (5
H, m) 2.71 (2H, br) 3.70 (3H, s) 4.15 (2H, s) 4.78
(4H, s) 6.84 (2H, d, J = 9.2Hz) 7.36-7.38 (3H, m) 7.
62-7.70 (3H, m) 8.00 (1H, dd, J = 5.8, 8.0Hz) 8.40
(1H, s) 8.45 (1H, d, J = 8.0Hz) 8.80-8.82 (2H, m)

Example 54 4-[(Cycloheptylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl Dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl 4-{[(N-tert-butoxycarbonyl) amino] methyl} -4'-
{[[(4-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (1.06g, 1.92mmo
l) dissolved in methanol (15 ml) and concentrated hydrochloric acid (15 ml)
Was added dropwise, and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, this hydrochloride was dissolved in methanol (5 ml) and anhydrous magnesium sulfate (2 g), cycloheptanone (2.4 ml, 19.2 mmol), triethylamine (0.7 ml, 5.0 mmol), acetic acid (1.1 ml, 19.2 m).
mol), and the mixture was stirred at room temperature for 1 hour. After that, sodium triacetoxyborohydride (2.03g, 9.6mmo
l) was added little by little and then stirred at room temperature for 16 hours. After adding saturated aqueous sodium hydrogen carbonate (30 ml) and ethyl acetate (30 ml), the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 3: 2-1: 1), 4-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] -4 '-{[(( 4-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1′-biphenyl (0.7 g, 56%) was obtained as a colorless transparent oil. ¹ H-NMR (CDCl ₃ ) δ: 1.29-1.77 (12H, m) 1.47 (9H,
s) 3.75 (3H, s) 4.0-4.2 (1H, brm) 4.38 (2H, brs)
4.56 (2H, s) 4.68 (2H, s) 6.31 (1H, s) 6.79 (2H, s)
d, J = 8.8Hz) 7.15 (2H, d, J = 8.8Hz) 7.26-7.35 (5H,
m) 7.53 (2H, d, J = 8.0Hz) 7.61 (2H, d, J = 8.0Hz) 7.7
4 (1H, d, J = 8.0Hz) 8.54-8.57 (2H, m). 2) 4-[(Cycloheptylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3 -Pyridylmethyl) amino]
Methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.
7 g, 1.08 mmol) in methanol (10 ml) in concentrated hydrochloric acid (10 m
l) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether.
[(Cycloheptylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl}
-1,1'-Biphenyl dihydrochloride (0.56g, 83%) was obtained as an amorphous powder. Elemental analysis value Calculated as C ₃₅ H ₄₀ N ₄ O ₂・ 2HCl ・ H ₂ O: C, 65.72; H, 6.93; N, 8.76 Actual value: C, 65.55; H, 6.85; N, 8.88. ¹ H- NMR (d ₆ -DMSO) δ (ppm): 1.3-1.73 (10H, m) 2.13
(2H, m) 3.16 (1H, m) 3.70 (3H, s) 4.16 (2H, s) 4.7
7 (4H, s) 6.84 (2H, d, J = 9.2Hz) 7.36-7.43 (3H, m)
7.61-7.71 (3H, m) 7.99 (1H, dd, J = 6.0, 7.8Hz) 8.43
(1H, d, J = 8.2Hz) 8.79 (2H, m) 9.34 (2H, brs)

Example 55 4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -4 '-[(cycloheptylamino) methyl] -1,1'-biphenyl dihydrochloride 1) 4-{[[([1,1'-biphenyl] -4- Ilamino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] -1,
Triethylamine (0.42ml, 3.0mmol) in acetonitrile solution (10ml) of 1'-biphenyl 4-phenylbenzoic acid (0.40g, 2.0mmol)
And diphenylphosphoric acid azide (0.48 ml, 2.2 mmol) were added at room temperature, and the mixture was heated under reflux for 1 hr. Then return to room temperature, 4-
(N-tert-butoxycarbonyl-N-cycloheptylamino)
Methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.40g, 1.43mmol) was added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1,
After purification with hexane: acetone = 3: 2), the insoluble matter was filtered through Celite and washed with a mixed solution of hexane-ethyl acetate = 1: 1. 4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(N-ter
t-Butoxycarbonyl-N-cycloheptylamino) methyl] -1,1′-biphenyl (0.87 g, 88%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (12H, m) 1.39 (9H, s)
4.0-4.2 (1H, br) 4.38 (2H, s) 4.59 (2H, s) 4.71 (2
H, s) 6.56 (1H, s) 7.26-7.55 (16H, m) 7.62 (2H, d,
J = 8.0Hz) 7.73-7.78 (1H, m) 8.55 (1H, d, J = 1.4Hz)
8.58 (1H, s). 2) 4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(cycloheptylamino) Methyl] -1,1'-biphenyl dihydrochloride 4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] -1,1'-
Biphenyl (0.68g, 0.98mmol) in ethanol (5m
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise to l),
Stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to give an amorphous powder, which was collected by filtration, washed with diethyl ether and dried under reduced pressure to give 4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl. ] (3-Pyridylmethyl) amino] methyl} -4'-
[(Cycloheptylamino) methyl] -1,1′-biphenyl dihydrochloride (0.60 g, 92%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₄₀ H ₄₂ N ₄ O ₁・ 2HCl ・ H ₂ O: C, 70.06; H, 6.76; N, 8.17 Measured value: C, 70.19; H, 6.94; N, 8.07. ¹ H- NMR (d ₆ -DMSO) δ: 1.2-1.8 (10H, m) 2.0-2.2 (2
H, m) 3.13 (1H, br) 4.16 (2H, s) 4.81 (2H, s) 4.83
(2H, d, J = 8.8Hz) 7.27-7.47 (5H, m) 7.55-7.71 (11H,
m) 7.96 (1H, dd, J = 5.4, 8.0Hz) 8.41 (1H, d, J = 8.0
Hz) 8.78 (1H, s) 8.81 (1H, s) 9.07 (1H, s) 9.34 (2
H, s).

Example 56 4-[(Cycloheptylamino) methyl] -4 '-{[[(4-phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl. Dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] -4 '-{[[(4-phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-Biphenyl 4-phenoxybenzoic acid (0.49g, 2.29mmol) in acetonitrile (10ml) was added to triethylamine (0.48ml, 3.44).
mmol) and diphenylphosphoric acid azide (0.55 ml, 2.55 mmol)
Was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 4- (N-tert-butoxycarbonyl-N-cycloheptylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl]-
Add 1,1'-biphenyl (0.67g, 1.64mmol) and add 1 at room temperature.
Stir for 0 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1:
4-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] -4 'after purification with 1-hexane: acetone = 3: 2)
-{[[(4-Phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.91g, 78%)
Was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.2-2.0 (12H, m) 1.39 (9H, s)
4.0-4.2 (1H, br) 4.39 (2H, s) 4.57 (2H, s) 4.69 (2
H, s) 6.49 (1H, s) 6.90-7.08 (4H, m) 7.20-7.35 (10
H, m) 7.57 (2H, d, J = 8.4Hz) 7.61 (2H, d, J = 8.0Hz)
7.71-7.77 (1H, m) 8.54 (1H, d, J = 1.4Hz) 8.56 (1H,
d, J = 1.4Hz). 2) 4-[(Cycloheptylamino) methyl] -4 '-{[[(4-phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1 '-Biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] -4'-{[[(4-phenoxyanilino) carbonyl]
(3-Pyridylmethyl) amino] methyl} -1,1'-biphenyl
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of (0.73 g, 1.03 mmol), and the mixture was stirred at room temperature for 1 hour. After the solvent was concentrated under reduced pressure, a solid was precipitated with ethanol-diethyl ether and dried under reduced pressure. 4-[(Cycloheptylamino) methyl] -4 '-{[[(4-phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,
1'-Biphenyl dihydrochloride (0.63g, 90%) was obtained as a colorless solid. Melting point 157-166 ℃ Elemental analysis value Calculated as C ₄₀ H ₄₂ N ₄ O ₂・ 2HCl ・ H ₂ O: C, 68.46; H, 6.61; N, 7.98 Found: C, 68.31; H, 6.56; N, 7.80. ¹ H-NMR (d ₆ -DMSO) δ: 1.2-1.8 (10H, m) 2.0-2.2 (2H,
m) 3.12 (1H, br) 4.16 (2H, s) 4.80 (4H, s) 6.91-6.
97 (4H, m) 7.97 (1H, dd, J = 5.8, 8.0Hz) 8.42 (1H, d,
J = 8.0Hz) 8.79 (1H, s) 8.81 (1H, s) 9.03 (1H, s)
9.39 (2H, br)

Example 57 4-[(Cycloheptylamino) methyl] -4 '-{[{[4- (neopentyloxy) anilino] carbonyl} (3-pyridylmethyl)
Amino] methyl} -1,1'-biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] -4 '-{[{[4- (neopentyloxy ) Anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,
1'-biphenyl 4-neopentyloxybenzoic acid (0.37 g, 1.78 mmol) in acetonitrile (10 ml) was added to triethylamine (0.38 g).
ml, 2.72mmol) and diphenylphosphoric acid azide (0.42ml,
1.96 mmol) was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 4- (N-tert-butoxycarbonyl-N-cycloheptylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1′-biphenyl (0.63 g, 1.27 mmol ) Was added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:
Ethyl acetate = 1: 1-hexane: acetone = 5: 2),
[(N-tert-Butoxycarbonyl-N-cycloheptylamino) methyl] -4 '-{[{[4- (neopentyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1 '-Biphenyl (0.31 g, 35%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.00 (9H, s) 1.2-1.8 (12H, m)
3.53 (2H, s) 4.0-4.2 (1H, br) 4.39 (2H, s) 4.56 (2
H, s) 4.69 (2H, s) 6.27 (1H, s) 6.79 (2H, d, J = 8.8H
z) 7.13 (2H, d, J = 8.8Hz) 7.29-7.35 (4H, m) 7.53 (2
H, d, J = 8.2Hz) 7.61 (2H, d, J = 8.4Hz) 7.75 (1H, d,
J = 8.2Hz) 8.54-8.57 (2H, m). 2) 4-[(Cycloheptylamino) methyl] -4 '-{[{[4- (neopentyloxy) anilino] carbonyl} (3-pyridylmethyl ) Amino] methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] -4 '-{[{[4- (neopentyloxy) Anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.30g, 0.43mmol) in ethanol (5ml)
To this was added 4N hydrogen chloride-ethyl acetate (10 ml) dropwise, and the mixture was stirred at room temperature for 1 hr. The non-crystalline powder produced by concentrating the solvent under reduced pressure was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-[(Cycloheptylamino) methyl] -4 '-{[{[4-
(Neopentyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride
(0.27 g, 93%) was obtained as a colorless amorphous powder. ¹ H-NMR (CD ₃ OD) δ: 1.02 (9H, s) 1.4-2.0 (10H, m)
2.1-2.3 (2H, m) 3.2-3.4 (1H, br) 3.58 (2H, s) 4.26
(2H, s) 4.82 (2H, s) 4.84 (2H, s) 6.85 (2H, d, J =
7.4Hz) 7.25 (2H, d, J = 9.2Hz) 7.43 (2H, d, J = 8.0Hz)
7.59 (2H, d, J = 8.0Hz) 7.66 (2H, d, J = 8.0Hz) 7.73
(2H, d, J = 8.2Hz) 8.01 (1H, dd, J = 5.8,8.0Hz) 8.54
(1H, d, J = 8.0Hz) 8.72 (1H, s) 8.75 (1H, s)

Example 58 4-[(Cyclohexylamino) methyl] -4 '-{[[(1-naphthylamino) carbonyl] (3-pyridylmethyl) amino] methyl}
-1,1'-Biphenyl dihydrochloride 1) 4-[(tert-Butoxycarbonylamino) methyl] -4'-
[((1-naphthylamino) carbonyl) (3-pyridylmethyl)
Amino] methyl} -1,1'-biphenyl 4- (tert-butoxycarbonylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.72g,
To a solution of 1.78 mmol) in dichloromethane (15 ml) was added 1-naphthylisocyanate (0.28 ml, 1.95 mmol) at room temperature.
It was stirred for 30 minutes. After concentrating the reaction solution, silica gel column chromatography (hexane: acetone = 5: 2)
to 1: 1) and purified by 4-[(tert-butoxycarbonylamino) methyl] -4 '-[((1-naphthylamino) carbonyl) (3-
Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.
88 g, 86%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.48 (9H, s) 4.37 (2H,
d, J = 6.0Hz) 4.69 (2H, s) 4.83 (2H, s) 4.8-5.0 (2H,
s) 6.72 (1H, s) 6.91 (1H, d, J = 8.8Hz) 7.13-7.86
(16H, m) 8.60 (1H, d, J = 3.4Hz) 8.66 (1H, s). 2) 4-[(N-tert-butoxycarbonyl-cyclohexylamino) methyl] -4 '-{[[(1 -Naphtylamino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl 4-[(tert-butoxycarbonylamino) methyl] -4 '-[((1-
Naphthylamino) carbonyl) (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.87g, 1.52mmol) was dissolved in methanol (10ml), concentrated hydrochloric acid (10ml) was added dropwise, and the solution was added at room temperature to 0.5. Stir for hours. The reaction solution is concentrated under reduced pressure,
A pale yellow amorphous powder was obtained. Subsequently, the hydrochloride was dissolved in methanol (10 ml) and sodium chloride (3 g),
Cyclohexanone (1.6 ml, 15.2 mmol), triethylamine (0.64 ml, 4.56 mmol) and acetic acid (0.87 ml, 15.2 mmol) were added in that order, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.61 g, 7.60 mmol) was added little by little, and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate water
(25 ml) and ethyl acetate (20 ml) were added, followed by dicarbonate di-te.
rt-Butyl (1.7 g, 7.79 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr. After completion of the reaction, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 3: 1-2: 1), and 4-
[(N-tert-butoxycarbonyl-cyclohexylamino)
Methyl] -4 '-{[[(1-naphthylamino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.72g,
72%) was obtained as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.80 (10H, m) 1.40 (9H, s)
4.0-4.2 (1H, br) 4.42 (2H, s) 4.69 (2H, s) 4.83 (2
H, s) 6.74 (1H, s) 6.91 (1H, d, J = 8.8Hz) 7.12-7.86
(16H, m) 8.60 (1H, dd, J = 1.4, 4.8Hz) 8.66 (1H, d,
J = 2.2Hz). 3) 4-[(Cyclohexylamino) methyl] -4 '-{[[(1-naphthylamino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl. Dihydrochloride 4-[(N-tert-butoxycarbonyl-cyclohexylamino) methyl] -4 '-{[[(1-naphthylamino) carbonyl] (3-
Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.71
g, 1.08 mmol) in methanol (10 ml) and concentrated hydrochloric acid (10 m
l) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether.
[(Cyclohexylamino) methyl] -4 '-{[[(1-naphthylamino) carbonyl] (3-pyridylmethyl) amino] methyl}-
1,1'-Biphenyl dihydrochloride (0.62g, 91%) was obtained as an amorphous powder. Elemental analysis value Calculated as C ₃₇ H ₃₆ N ₄ O ・ 2HCl ・ 0.5H ₂ O ・ 0.5Et ₂ O: C, 69.53; H, 6.88; N, 8.32 Found: C, 69.55; H, 7.12; N, 8.60. ¹ H-NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 2.0-2.2 (2H,
m) 2.98 (1H, s) 4.18 (2H, s) 4.88 (2H, s) 4.90 (2
H, s) 7.42-7.51 (5H, m) 7.69-7.78 (10H, m) 7.89-7.
93 (1H, m) 8.06 (1H, dd, J = 5.4, 7.6Hz) 8.54 (1H,
d, J = 8.4Hz) 8.84 (1H, d, J = 6.0Hz) 8.88 (1H, s) 8.9
5 (1H, s) 9.43 (2H, br)

Example 59 N-[(4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl] cyclohesane Carboxamide hydrochloride 4- (aminomethyl) -4 '-{[[(4-nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (0.4g, 0.74 Cyclohexanecarbonyl chloride (0.12 ml, 0.89 mmol) was added to a mixture of ethyl acetate (30 ml), saturated aqueous sodium hydrogen carbonate (30 ml), and the mixture was stirred for 1 hour. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate,
It was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 2: 1-1: 1) to give N-
[(4 '-{[[(4-Nitroanilino) carbonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl] cyclohesanecarboxamide (0.39g, 91%) Was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.15-2.00 (11H, m), 4.46 (2H, d, J = 5.8
Hz), 4.62 (2H, s), 4.73 (2H, s), 5.80-5.95 (1H, m, NH),
7.02 (1H, s), 7.25-7.70 (11H, m), 7.70-7.82 (1H, m), 8.1
1 (2H, d, J = 9.2Hz), 8.55-8.65 (2H, m). This oil N-[(4 '-{[[(4-nitroanilino) carbonyl] (3-
Pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-
(Iyl) methyl] cyclohesancarboxamide (0.39 g) was dissolved in ethanol (10 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was shaken. The solvent was evaporated under reduced pressure, diethyl ether was added to give a powder, and N-[(4 '-{[[(4-nitroanilino) carbonyl]]
(3-Pyridylmethyl) amino] methyl} [1,1'-biphenyl]-
4-yl) methyl] cyclohesancarboxamide hydrochloride (0.
39 g, 93%) was obtained as an amorphous powder. Elemental analysis value C ₃₄ H ₃₅ N ₅ O ₄・ HCl ・ 1 / 2H ₂ O, calculated value: C, 65.53; H, 5.98; N, 11.24 Found value: C, 65.43; H, 6.19; N, 10.93. ¹ H-NMR (d ₆ -DMSO) δ: 0.90-1.85 (10H, m), 2.08-2.28 (1H,
m), 4.28 (2H, d, J = 5.8Hz), 4.80 (2H, s), 4.83 (2H, s), 7.
30 (2H, d, J = 8.6Hz), 7.36 (2H, d, J = 8.6Hz), 7.53-7.70 (4
H, m), 7.95 (1H, dd, J = 8.0,5.8Hz), 8.18 (2H, d, J = 9.6Hz),
8.23-8.35 (1H, m), 8.40 (1H, d, J = 8.0Hz), 7.83-8.85 (2H,
m), 9.61 (1H, s).

Example 60 N-({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl } Methyl) benzamido 4- (aminomethyl) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]-
Benzoyl chloride (0.16ml, 1.07m) was added to a solution of 1,1'-biphenyl dihydrochloride (500mg, 0.89mmol) in acetonitrile (3ml).
mol) and triethylamine (0.62ml, 4.45mmol) in that order
It was added at 0 ° C. Allow the reaction mixture to warm to room temperature and
It was stirred for a day. It was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (30 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol =
40: 1). N-({4 '-[((3-pyridylmethyl) {[4-
(Trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl} methyl) benzamide
(428 mg, 90%) was obtained as a colorless solid. Mp 152-153 ° C. Elemental analysis _{C 35 H 29 N 4 O 2} F 3 · H 2 O Calculated: C, 68.62; H, 5.10 ; N, 9.15 Found: C, 68.63; H, 4.98 ; N, 9.08. ¹ H-NMR (CDCl ₃ ) δ: 4.59 (2H, s) 4.69 (2H, s) 4.72
(2H, s) 6.40-6.50 (1H, br) 6.55 (1H, s) 7.32-7.64
(17H, m) 7.79-7.84 (2H, m) 8.60 (2H, m).

Example 61 N-({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl } Methyl) cyclohexanecarboxamide 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4- (tert-butoxycarbonylamino) methyl-4 '-[(3 -Pyridylmethyl) aminomethyl] -1,1'-biphenyl (4.23g, 1
0.5 mmol) in acetonitrile (50 ml) in 4-trifluoromethylphenylisocyanate (1.7 ml, 11.8 mmol)
Was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and purified by recrystallization (hexane-ethyl acetate) to give 4-{[(tert-butoxycarbonyl) amino] methyl} -4 '-[((3-pyridylmethyl) {[4- (tri Fluoromethyl) anilino] carbonyl} amino) methyl] -1,1′-biphenyl (5.85 g, 94%) was obtained as colorless crystals. Melting point 149-153 ° C Elemental analysis C ₃₃ H ₃₃ N ₄ O ₃ F ₃ Calculated: C, 67.11; H, 5.63; N, 9.49 Found: C, 66.89; H, 5.67; N, 9.45. ¹ H -NMR (CDCl ₃ ) δ: 1.47 (9H, s) 4.35 (2H, d, J = 6.0
Hz) 4.59 (2H, s) 4.72 (2H, s) 4.90 (2H, s) 6.56 (1
H, s) 7.29-7.39 (7H, m) 7.47-7.63 (6H, m) 7.75 (1
H, d, J = 7.6Hz) 8.58-8.60 (2H, m) 2) N-({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl ] [1,1'-Biphenyl] -4-yl} methyl) cyclohexanecarboxamide 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.6
g, 1.02 mmol) in methanol (10 ml) and add concentrated hydrochloric acid.
(10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. continue,
Triethylamine (0.72 ml, 5.1 mmol) and 4-cyclohexylcarbonyl chloride (0.16 ml, 0.74 mmol) were added to a suspension of this hydrochloride in acetonitrile (50 ml), and the mixture was stirred at room temperature for 3 hours. After adding saturated aqueous sodium hydrogen carbonate, the mixture was extracted with ethyl acetate (50 ml x 3). The extract was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Recrystallize the residue (hexane /
It was purified with ethyl acetate). N-({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl} methyl) cyclohexanecarboxamide ( 0.43 g, 70%) was obtained as colorless crystals. Melting point 190-193 ℃ Elemental analysis value C ₃₅ H ₃₅ F ₃ N ₄ O ₂・ 1/4 Calculated as AcOEt: C, 69.44; H, 5.99; N, 9.00 Found: C, 69.53; H, 5.95; N, 9.29. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.22-1.91 (10H, m) 2.11-2.
23 (1H, m) 4.45 (2H, d, J = 5.8Hz) 4.64 (2H, s) 4.66
(2H, s) 6.66 (1H, br) 7.27-7.71 (12H, m) 8.14 (1
H, s) 8.53-8.55 (2H, m).

Example 62 N-({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl } Methyl) -4- (trifluoromethyl) benzenesulfonamide 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.72
g, 1.22 mmol) in methanol (10 ml) and add concentrated hydrochloric acid.
(10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. continue,
Triethylamine (0.85 ml, 6.1 mmol) and 4-trifluoromethylbenzenesulfonyl chloride (0.36 g, 1.48 mmol) were added to a suspension of this hydrochloride in acetonitrile (10 ml), and the mixture was stirred at room temperature for 1 hour. After adding saturated aqueous sodium hydrogen carbonate, the mixture was extracted with ethyl acetate (50 ml x 3). The extract was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Recrystallize the residue
Purified with (hexane / ethyl acetate). N-({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (Trifluoromethyl) benzenesulfonamide
(0.76 g, 78%) was obtained as colorless crystals. Melting point: 196-198 ° C Elemental analysis C ₃₅ H ₂₈ N ₄ O ₃ SF ₆・ H ₂ O Calculated: C, 58.65; H, 4.22; N, 7.82 Found: C, 58.87; H, 4.21; N , 7.78. ¹ H-NMR (CDCl ₃ ) δ: 4.16 (2H, d, J = 5.8Hz) 4.64, 4.6
6 (4H, each s) 7.26-7.80 (17H, m) 7.95 (2H, d, J =
8.0Hz) 8.10 (1H, s) 8.53-8.54 (2H, m).

Example 63 N-({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl } Methyl) -4- (trifluoromethyl) benzamide 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.72
g, 1.22 mmol) in methanol (10 ml) and add concentrated hydrochloric acid.
(10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. continue,
Triethylamine (0.85 ml, 6.1 mmol) and 4-trifluoromethylbenzoyl chloride (0.22 ml, 1.48 mmol) were added to a suspension of this hydrochloride in acetonitrile (10 ml),
The mixture was stirred at room temperature for 1 hour. After adding saturated aqueous sodium hydrogen carbonate, the mixture was extracted with ethyl acetate (50 ml x 3). The extract was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was chromatographed on silica gel (hexane: acetone = 3: 2-1:
Purified in 1), N-({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,
1′-Biphenyl] -4-yl} methyl) -4- (trifluoromethyl) benzamide (0.77 g, 95%) was obtained as colorless crystals. Melting point 180-187 ℃ Elemental analysis value Calculated as C ₃₆ H ₂₈ F ₆ N ₄ O ₂ .0.5H ₂ O: C, 64.38; H, 4.35; N, 8.34 Found: C, 64.34; H, 4.08; N , 8.40. ¹ H-NMR (CDCl ₃ ) δ: 4.58 (2H, s) 4.67, 4.69 (4H,
each s) 6.69 (2H, s) 7.26-7.75 (16H, m) 7.91 (2H,
d, J = 8.0Hz) 8.55-8.57 (2H, m).

Example 64 4-Nitro-N-({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'
-Biphenyl] -4-yl} methyl) benzamide 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.7g,
1.19 mmol) in methanol (10 ml) and concentrated hydrochloric acid
(10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, triethylamine (0.83 ml, 5.95 mmol) and 4-nitrobenzoyl chloride (0.33 g, 1.79 mmol) were added to a suspension of this hydrochloride in acetonitrile (10 ml), and the mixture was stirred at room temperature for 1 hour. After adding saturated sodium bicarbonate water, ethyl acetate (50 ml x
Extracted in 3). After drying over anhydrous magnesium sulfate, it was filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 4: 3-1: 1), 4-nitro-N-({4 '-[((3-pyridylmethyl) {[4- (trifluoro Methyl) anilino] carbonyl} amino) methyl]
[1,1'-Biphenyl] -4-yl} methyl) benzamide (0.67
g, 88%) was obtained as colorless crystals. Mp 180-182 ° C. Elemental analysis _{C 35 H 28 F 3 N 5} O 4 Calculated: C, 65.72; H, 4.41 ; N, 10.95 Found:. C, 65.41; H, 4.51; N, 10.76 1 H -NMR (CDCl ₃ ) δ (ppm): 4.62 (2H, s) 4.65 (2H,
s) 4.67 (2H, s) 7.25-7.71 (14H, m) 8.01 (1H, s) 8.
18 (2H, d, J = 9.2Hz) 8.24 (2H, d, J = 9.2Hz) 8.39-8.4
3 (1H, m) 8.52-8.54 (2H, m)

Example 65 4-Fluoro-N-({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,
1'-biphenyl] -4-yl} methyl) benzamide 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.7g,
1.19 mmol) in methanol (10 ml) and concentrated hydrochloric acid
(10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, triethylamine (0.83 ml, 5.95 mmol) and 4-fluorobenzoyl chloride (0.28 ml, 1.79 mmol) were added to a suspension of this hydrochloride in acetonitrile (10 ml), and the mixture was stirred at room temperature for 1 hour. After adding saturated aqueous sodium hydrogen carbonate, ethyl acetate (50 ml
x 3). After drying over anhydrous magnesium sulfate, it was filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 4: 3-1: 1), and 4-fluoro-N-({4 '-[((3-pyridylmethyl) {[4- (trifluoro Methyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl} methyl) benzamide
(0.61 g, 84%) was obtained as colorless crystals. Melting point 177-180 ° C Elemental analysis C ₃₅ H ₂₈ N ₄ O ₂ F ₄ 1/4 Calculated as EtOAc: C, 68.12; H, 4.65; N, 9.08 Found: C, 68.26; H, 4.80; N, 8.96. ¹ H-NMR (CDCl ₃ ) δ: 4.58 (2H, s) 4.66 (2H, s) 4.69
(2H, s) 6.56 (1H, s) 6.70 (1H, s) 7.05-7.61 (14H,
m) 7.71-7.84 (4H, m) 8.55 (2H, s)

Example 66 4-Methoxy-N-({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,
1'-biphenyl] -4-yl} methyl) benzamide 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.7g,
1.19 mmol) in methanol (10 ml) and concentrated hydrochloric acid
(10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, triethylamine (1.7 ml, 11.9 mmol) and 4-methoxybenzoyl chloride (0.41 ml, 2.38 mmol) were added to a suspension of this hydrochloride in acetonitrile (10 ml), and the mixture was stirred at room temperature for 1 hour. After adding saturated sodium bicarbonate water, ethyl acetate (50 ml x
Extracted in 3). After drying over anhydrous magnesium sulfate, it was filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 4: 3-1: 1), and 4-methoxy-N-({4 '-[((3-pyridylmethyl) {[4- (trifluoro Methyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl} methyl) benzamide
(0.68 g, 91%) was obtained as colorless crystals. Melting point 175-179 ° C Elemental analysis C ₃₆ H ₃₁ F ₃ N ₄ O ₃ 1 / 3H ₂ O Calculated: C, 68.56; H, 5.06; N, 8.88 Found: C, 68.70; H, 5.20; N, 8.65. ¹ H-NMR (CDCl ₃ ) δ: 3.83 (3H, s) 4.58 (2H, s) 4.6
4 (2H, d, J = 6.0Hz) 4.69 (2H, s) 6.53 (1H, s) 6.82
(1H, s) 6.90 (2H, d, J = 9.2Hz) 7.26-7.74 (16H, m)
7.71-7.78 (3H, m) 8.56 (1H, br)

Example 67 4-Methyl-N-({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'
-Biphenyl] -4-yl} methyl) benzamide 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.7g,
1.19 mmol) in methanol (10 ml) and concentrated hydrochloric acid
(10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, triethylamine (1.7 ml, 11.9 mmol) and 4-methylbenzoyl chloride (0.32 ml, 2.38 mmol) were added to a suspension of this hydrochloride in acetonitrile (10 ml), and the mixture was stirred at room temperature for 1.5 hours. After adding saturated sodium bicarbonate water, ethyl acetate (50 ml x
Extracted in 3). After drying over anhydrous magnesium sulfate, it was filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 4: 3-1: 1), and 4-methyl-N-({4 '-[((3-pyridylmethyl) {[4- (trifluoro Methyl) anilino] carbonyl} amino) methyl]
[1,1'-Biphenyl] -4-yl} methyl) benzamide (0.63
g, 87%) was obtained as colorless crystals. Melting point: 168-171 ° C Elemental analysis C ₃₆ H ₃₁ F ₃ N ₄ O ₂ 1 / 3H ₂ O Calculated: C, 70.35; H, 5.19; N, 9.12 Found: C, 70.43; H, 5.36 ; N, 8.99. ¹ H-NMR (CDCl ₃ ) δ: 2.39 (3H, s) 4.59 (2H, s) 4.6
8 (2H, d, J = 6.0Hz) 4.71 (2H, s) 6.45 (1H, s) 6.61
(1H, s) 7.26-7.76 (15H, m) 8.58 (1H, m)

Example 68 4-Cyano-N-({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'
-Biphenyl] -4-yl} methyl) benzamide 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.72
g, 1.22 mmol) was dissolved in methanol (10 ml), concentrated hydrochloric acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, this hydrochloride was suspended in acetonitrile, p-cyanobenzoic acid (270 mg, 1.84 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (351 mg, 1.83 m)
mol), 1-hydroxybenzotriazole monohydrate (28
1mg, 1.83mmol), triethylamine (0.43ml, 3.1mmol)
Was added at room temperature and stirred for 3.5 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and water. The organic layer was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purified with acetone = 1: 1). Colorless crystals were obtained. This was purified by recrystallization (hexane / ethyl acetate), and 4-cyano-N-
({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl)
Anilino] carbonyl} amino) methyl] [1,1′-biphenyl] -4-yl} methyl) benzamide (0.66 g, 89%) was obtained as colorless crystals. Melting point 191-194 ° C Elemental analysis C ₃₆ H ₂₈ F ₃ N ₅ O ₂・ 1 / 4H ₂ O Calculated: C, 69.28; H, 4.60; N, 11.22 Found: C, 69.46; H, 4.71; ^{. N, 11.09 1 H-NMR} (CDCl 3) δ (ppm): 4.60 (2H, s) 4.68 (2H,
s) 4.71 (2H, s) 6.56 (1H, s) 7.29-7.63 (13H, m) 7.
74 (2H, d, J = 8.4Hz) 7.71-7.80 (1H, m) 7.90 (2H, d,
J = 8.4Hz) 8.58 (2H, d, J = 4.6Hz)

Example 69 N-({4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl } Methyl) hexanamide 4-{[(tert-butoxycarbonyl) amino] methyl} -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.7
g, 1.19 mmol) in methanol (10 ml) and add concentrated hydrochloric acid.
(10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. continue,
To a suspension of this hydrochloride in acetonitrile (10 ml) was added triethylamine (1.7 ml, 11.9 mmol), hexanoyl chloride.
(0.33 ml, 2.38 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After adding saturated aqueous sodium hydrogen carbonate, the mixture was extracted with ethyl acetate (50 ml x 3). After drying over anhydrous magnesium sulfate, it was filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 3: 2-1: 1), and N-((4 '
-[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-
Ill} methyl) hexanamide (0.45 g, 65%) was obtained as colorless crystals. Melting point 165-168 ℃ Elemental analysis value Calculated as C ₃₄ H ₃₅ F ₃ N ₄ O ₂ : C, 69.37; H, 5.99; N, 9.52 Found value: C, 69.13; H, 5.87; N, 9.48. ¹ H -NMR (CDCl ₃ ) δ: 0.89 (3H, br) 1.2-1.4 (6H, m)
2.23 (2H, t, J = 9.6Hz) 4.49 (2H, d, J = 5.4Hz) 4.59
(2H, s) 4.71 (2H, s) 5.78 (1H, brd) 6.60 (1H, s)
7.36-7.62 (9H, m) 7.73-7.76 (1H, m) 8.59 (2H, s)

Example 70 4-[(benzyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -4 ′-[(cyclohexylamino) methyl] -1,1′-biphenyl.hydrochloride 1 ) 4-[(N-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[(benzyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4'-benzylaminomethyl-1,1'-biphenyl
(0.7 g, 1.44 mmol) in toluene (10 ml), 4-trifluoromethylphenylisocyanate (0.21 ml, 1.44 mmol)
Was added and stirred at room temperature for 30 minutes. The reaction mixture is directly used for silica gel column chromatography (hexane: ethyl acetate).
= 5: 1), 4-[(N-tert-butoxycarbonyl-N-
Cyclohexylamino) methyl] -4 '-[(benzyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.96g, 99%) was obtained as a colorless oil. . ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.88 (19H, m), 3.90-4.20 (1H,
m), 4.41 (2H, s), 4.65 (2H, s), 4.67 (2H, s), 6.52 (1H,
s), 7.20-7.70 (17H, m). 2) 4-[(benzyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -4 '-[(cyclohexylamino)
Methyl] -1,1'-biphenyl hydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[(benzyl {[4- (trifluoromethyl) anilino] carbonyl} Amino) methyl] -1,1'-biphenyl
(0.81g, 1.21mmol) 4N hydrogen chloride / ethyl acetate (15ml)
And was stirred at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure, the precipitated crystals were added with diethyl ether and collected by filtration to give 4-
[(Benzyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl ・ hydrochloride (0.69g, 94%) was obtained. It was Melting point> 240 ° C (decomposition). Elemental analysis value C ₃₅ H ₃₆ F ₃ N ₃ O ・ HCl Calculated value: C, 69.13; H, 6.13; N, 6.91 Found value: C, 68.81; H, 5.90; N , 6.75. ¹ H-NMR (d ₆ -DMSO) δ: 1.10-1.90 (8H, m), 2.10-2.25 (2H,
m), 2.90-3.10 (1H, m), 4.20 (2H, brs), 4.63 (4H, s), 7.
20-7.45 (7H, m), 7.55-7.80 (10H, m), 8.99 (2H, brs, N
H ₂ ⁺ ), 9.09 (1H, s, NH).

Example 71 4-({benzyl [(4-methoxyanilino) carbonyl] amino} methyl) -4 '-[(cyclohexylamino) methyl] -1,1'-
Biphenyl hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-(benzyl {[4- (methoxyanilino)
Carbonyl] amino} methyl) -1,1'-biphenyl 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4'-benzylaminomethyl-1,1'-biphenyl
To a solution of (0.7 g, 1.44 mmol) in toluene (10 ml), 4-methoxyphenyl isocyanate (0.19 ml, 1.44 mmol) was added,
Stir for 30 minutes at room temperature. The reaction solution was directly purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-(benzyl {[4 -(Methoxyanilino) carbonyl] amino} methyl) -1,1'-biphenyl (0.9
1 g, 99%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.85 (19H, m), 3.75 (3H, s), 3.9
0-4.20 (1H, m), 4.41 (2H, s), 4.63 (2H, s), 6.23 (1H, s),
6.79 (2H, d, J = 8.8Hz), 7.13 (2H, d, J = 8.8Hz), 7.25-7.48
(9H, m), 7.48-7.67 (4H, m). 2) 4-({benzyl [(4-methoxyanilino) carbonyl] amino} methyl) -4 '-[(cyclohexylamino) methyl] -1,
1'-Biphenyl hydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-(benzyl {[4- (methoxyanilino) carbonyl] amino} methyl) -1,1 '-Biphenyl (0.76g, 1.20
mmol) was dissolved in 4N hydrogen chloride / ethyl acetate (15 ml), and the mixture was stirred at room temperature for 1 hr. The reaction solution was evaporated under reduced pressure, the precipitated crystals were added with diethyl ether and collected by filtration to give 4-({benzyl
[(4-Methoxyanilino) carbonyl] amino} methyl) -4'-
[(Cyclohexylamino) methyl] -1,1′-biphenyl hydrochloride (0.63 g, 92%) was obtained. Melting point 196-198 ° C. Elemental analysis value, calculated as C ₃₅ H ₃₉ N ₃ O ₂ .HCl: C, 73.73; H, 7.07; N, 7.37 Found: C, 73.73; H, 7.18; N, 7.27. ¹ H-NMR (d ₆ -DMSO) δ: 1.10-1.90 (8H, m), 2.00-2.25 (2H,
m), 2.90-3.10 (1H, m), 3.71 (3H, s), 4.19 (2H, brs), 4.5
8 (4H, s), 6.83 (2H, d, J = 9.2Hz), 7.20-7.50 (8H, m), 7.60-
7.80 (7H, m), 8.52 (1H, s, NH), 9.09 (2H, brs, NH ₂ ⁺ ).

Example 72 4-[(Cyclohexylamino) methyl] -4 '-[((2-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'- Biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((2-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} Amino) methyl] -1,
1'-biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(2-pyridylmethyl) aminomethyl] -1,1'
To a solution of -biphenyl (0.40g, 0.824mmol) in acetonitrile (10ml) was added p-methoxyphenylisocyanate (0.13ml, 0.91mmol) at room temperature. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: acetone = 3: 1), and 4-[(Nt
ert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((2-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.52 g, 94%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.40 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.48 (2H, s) 4.69
(2H, s) 6.95 (1H, d, J = 7.4Hz) 7.26-7.66 (14H, m)
8.62-8.73 (1H, m) 10.45 (1H, s) 2) 4-[(cyclohexylamino) methyl] -4 '-[((2-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} Amino) methyl] -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((2-pyridylmethyl) {[4- ( Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-
Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of biphenyl (0.51 g, 0.76 mmol) in ethanol (10 ml). After stirring at room temperature for 30 minutes,
It was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4-[(cyclohexylamino) methyl] -4'-
[((2-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride (0.44g, 90%) was obtained as an amorphous powder. It was Elemental analysis calculated as C ₃₄ H ₃₅ N ₄ OF ₃・ 2HCl ・ H ₂ O: C, 61.54; H, 5.92; N, 8.44 Found: C, 61.50; H, 5.91; N, 8.47 ¹ H- NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 4.17 (2H, s) 4.93 (2H, s) 4.
97 (2H, s) 7.41 (2H, d, J = 8.0Hz) 7.58-7.87 (13H,
m) 8.37-8.45 (1H, m) 8.79 (1H, d, J = 5.2Hz) 9.47 (2
H, br) 9.58 (1H, s)

Example 73 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-pyridylmethyl) amino] methyl} -1,1'-biphenyl di Hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-pyridylmethyl) amino] methyl} -1 , 1'-Biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(2-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (0.34g, 0.70mmol) in acetonitrile
(10 ml) at room temperature with p-methoxyphenylisocyanate
(0.11 ml, 0.77 mmol) was added. After stirring at room temperature for 30 minutes,
After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1), and 4-
[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.
44 g, 99%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.41 (9H,
s) 3.79 (3H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.48
(2H, s) 4.69 (2H, s) 6.87 (2H, d, J = 9.2Hz) 6.97 (1
H, d, J = 7.6Hz) 7.21-7.64 (12H, m) 8.58-8.62 (1H,
m) 9.42 (1H, s) 2) 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.
43 g, 0.677 mmol) in ethanol (10 ml) in concentrated hydrochloric acid (1
0 ml) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure.
Ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with ether, and then 4-[(cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2- Pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (0.32g, 78%) was obtained as an amorphous powder. Elemental analysis _{C 34 H 38 N 4 O 2} · 2HCl · H 2 O Calculated: C, 65.27; H, 6.77 ; N, 8.96 Found:. C, 65.24; H, 6.99; N, 8.79 1 H- NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 3.70 (3H, s) 4.16 (2H, s)
4.84 (2H, s) 4.87 (2H, s) 6.84 (4H, d, J = 9.2Hz) 7.
39 (2H, d, J = 8.8Hz) 7.61-7.72 (7H, m) 7.79 (2H, m)
8.33-8.40 (1H, m) 8.76 (1H, d, J = 4.8Hz) 8.91 (1H,
s) 9.39 (2H, s)

Example 74 4-[(Cyclohexylamino) methyl] -4 '-[((4-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'- Biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((4-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} Amino) methyl] -1,
1'-biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(4-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (0.40g, 0.82mmol) in acetonitrile
P-Trifluoromethylphenylisocyanate (0.13 ml, 0.91 mmol) was added to (10 ml) at room temperature. 30 at room temperature
After stirring for minutes, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: acetone = 5: 2),
4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((4-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1, 1'-
Biphenyl (0.26g, 47%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.62 (2H, s) 4.71
(2H, s) 6.57 (1H, s) 7.26-7.39 (8H, m) 7.48-7.55
(4H, m) 7.64 (2H, d, J = 8.0Hz) 8.61 (2H, d, J = 6.0H
z) 2) 4-[(Cyclohexylamino) methyl] -4 '-[((4-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl Dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((4-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-
Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of biphenyl (0.25 g, 0.37 mmol) in ethanol (10 ml). After stirring at room temperature for 30 minutes,
It was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4-[(cyclohexylamino) methyl] -4'-
[((4-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride (0.20g, 84%) was obtained as an amorphous powder. It was Elemental analysis calculated as C ₃₄ H ₃₅ N ₄ OF ₃・ 2HCl ・ H ₂ O: C, 61.54; H, 5.92; N, 8.44 Found: C, 61.72; H, 6.19; N, 8.23. ¹ H- NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.95 (1H, br) 4.16 (2H, s) 4.86 (2H, s) 4.
93 (2H, s) 7.40 (2H, d, J = 8.4Hz) 7.58-7.89 (13H,
m) 8.83 (2H, d, J = 6.6Hz) 9.42 (2H, br) 9.46 (1H,
s)

Example 75 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (4-pyridylmethyl) amino] methyl} -1,1'-biphenyl di Hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (4-pyridylmethyl) amino] methyl} -1 , 1'-Biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(4-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (0.61g, 1.26mmol) in acetonitrile
(10 ml) at room temperature with p-methoxyphenylisocyanate
(0.18 ml, 1.39 mmol) was added. After stirring at room temperature for 30 minutes,
After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane: acetone = 3: 1-5: 2-1: 1) and 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl]- 4 '-{[[(4-Methoxyanilino) carbonyl] (4-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.39g, 49%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.40 (9H,
s) 3.76 (3H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.59
(2H, s) 4.68 (2H, s) 6.24 (1H, s) 6.79 (2H, d, J =
8.8Hz) 7.17 (2H, d, J = 9.2Hz) 7.26-7.36 (10H, m) 7.
52 (2H, d, J = 8.6Hz) 7.61 (2H, d, J = 8.0Hz) 8.60 (2
H, d, J = 6.0Hz) 2) 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (4-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (4
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.
38 g, 0.60 mmol) in ethanol (10 ml) in concentrated hydrochloric acid (10
ml) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure.
Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether.
[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (4-pyridylmethyl) amino] methyl}
-1,1'-Biphenyl dihydrochloride (0.31g, 85%) was obtained as an amorphous powder. Elemental analysis value Calculated as C ₃₄ H ₃₈ N ₄ O ₂・ 2HCl ・ H ₂ O: C, 65.25; H, 6.77; N, 8.96 Measured value: C, 65.32; H, 7.14; N, 9.02 ¹ H- NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.95 (1H, br) 3.70 (3H, s) 4.16 (2H, s)
4.80 (2H, s) 4.89 (2H, s) 6.83 (2H, d, J = 9.2Hz) 7.
37-7.43 (4H, m) 7.66-7.71 (7H, m) 7.81 (2H, d, J =
6.2Hz) 8.83 (1H, s) 8.86 (2H, s) 9.49 (2H, s)

Example 76 4-{[[(4-chloroanilino) carbonyl] (4-pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl dihydrochloride 1) 4-{[[(4-chloroanilino) carbonyl] (4-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl
-N-cyclohexylamino) methyl] -1,1'-biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(4-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (0.83g, 1.7mmol) in acetonitrile
(10 ml) at room temperature with p-chlorophenyl isocyanate
(0.24 ml, 1.84 mmol) was added. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography.
Purify with (hexane: acetone = 3: 1-2: 1), 4-
{[[(4-chloroanilino) carbonyl] (4-pyridylmethyl)
Amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-biphenyl (0.59g,
54%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.59 (2H, s) 4.68
(2H, s) 6.47 (1H, s) 7.20-7.35 (10H, m) 7.52 (2H, s)
d, J = 8.0Hz) 7.62 (2H, d, J = 8.0Hz) 8.59 (2H, d, J =
6.2Hz) 2) 4-{[[(4-chloroanilino) carbonyl] (4-pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl dihydrochloride 4 -{[[(4-Chloroanilino) carbonyl] (4-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N
-Cyclohexylamino) methyl] -1,1'-biphenyl (0.58
g, 0.91 mmol) in ethanol (10 ml) and concentrated hydrochloric acid (10 m
l) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether.
{[[(4-chloroanilino) carbonyl] (4-pyridylmethyl)
Amino] methyl} -4 '-[(cyclohexylamino) methyl]-
1,1'-biphenyl dihydrochloride (0.48g, 86%) was obtained as an amorphous powder. Elemental analysis calculated as C ₃₃ H ₃₅ N ₄ OCl ・ 2HCl ・ 2 / 3H ₂ O ・ 1 / 3Et ₂ O: C, 63.56; H, 6.47; N, 8.64 Found: C, 63.27; H, 6.69; N, 8.90. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.70 (1H, s) 3.90 (2H, s) 4.57 (2H, s) 4.6
5 (2H, s) 7.01-7.15 (8H, m) 7.32-7.46 (5H, m) 7.62
(1H, d, J = 1.0Hz) 8.56 (1H, s) 8.60 (1H, s) 8.94 (1
H, s) 9.18 (2H, s)

Example 77 4-[(Cyclohexylamino) methyl] -4 '-[(2-pyridyl
{[4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[(2-Pyridyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl N-({4'-[(N-tert-butoxycarbonyl-N-cyclohexyl Amino) methyl] [1,1'-biphenyl] -4-yl} methyl) -2
-Pyridineamine (0.51g, 1.08mmol) in acetonitrile
-To a solution of methylene chloride (10 ml-10 ml) was added 4-trifluoromethylphenylisocyanate (0.17 ml, 1.19 mmol), and the mixture was stirred at room temperature for 30 minutes. Further, 4-trifluoromethylphenylisocyanate (0.17 ml, 1.19 mmol) and triethylamine (0.45 ml, 3.24 mmol) were added, and the mixture was refluxed overnight. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 2: 1) to give 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4. '-[(2-Pyridyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.20g, 28%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.37 (9H,
s) 3.8-4.2 (1H, br) 4.39 (2H, s) 5.31 (2H, s) 6.66
(2H, d, J = 8.4Hz) 6.95-7.05 (2H, m) 7.25-7.39 (6H,
m) 7.47-7.67 (4H, m) 7.75 (2H, d, J = 8.8Hz) 8.36-
8.40 (1H, m). 2) 4-[(Cyclohexylamino) methyl] -4 '-[(2-pyridyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'- Biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[(2-pyridyl {[4- (trifluoromethyl)
Anilino] carbonyl} amino) methyl] -1,1'-biphenyl
Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of (0.20 g, 0.304 mmol) in ethanol (10 ml). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder,
Filtered with a glass filter, washed well with diethyl ether, and then 4-[(cyclohexylamino) methyl] -4 '-[(2-pyridyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1, 1'-biphenyl dihydrochloride (0.16g, 83%)
Was obtained as an amorphous powder. Elemental analysis _{C 33 H 33 N 4 OF 3} · 2HCl · 0.5H 2 O Calculated: C, 61.88; H, 5.66 ; N, 8.75 Found:. C, 61.78; H, 5.81; N, 8.69 1 H -NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.94 (1H, br) 4.15 (2H, s) 5.31 (2H, s) 7.
10 (2H, d, J = 8.4Hz) 7.19 (1H, dd, J = 5.0, 6.8Hz) 7.
41 (2H, d, J = 8.2Hz) 7.57 (2H, d, J = 8.0Hz) 7.63-7.6
9 (6H, m) 7.83 (2H, d, J = 8.6Hz) 8.50 (1H, dd, J = 1.
8, 5.0Hz) 9.38 (2H, br) 12.18 (1H, s)

Example 78 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-pyridyl) amino] methyl} -1,
1'-biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-pyridyl) amino ] Methyl} -1,1'-biphenyl N-
({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -2-
Pyridineamine (0.58g, 1.23mmol) in acetonitrile-
4-Methoxyphenylisocyanate (0.18 ml, 1.39 mmol) and triethylamine (0.45 ml, 3.24 mmol) were added to a methylene chloride (10 ml-10 ml) solution, and the mixture was refluxed overnight. After concentrating the reaction solution, the residue is subjected to silica gel column chromatography.
Purify with (hexane: ethyl acetate = 5: 1-3: 1) to prepare 4-[(N
-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-pyridyl) amino] methyl} -1,1'-biphenyl (0.11g, 14 %)
Was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.38 (9H,
s) 3.78 (3H, s) 4.0-4.2 (1H, br) 4.39 (2H, s) 5.30
(2H, s) 6.84-6.97 (4H, m) 7.27 (2H, d, J = 8.0Hz)
7.34 (2H, d, J = 8.0Hz) 7.46-7.61 (8H, m) 8.32 (1H,
dd, J = 4.8Hz). 2) 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-pyridyl) amino] methyl}
-1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2
-Pyridyl) amino] methyl} -1,1'-biphenyl (0.11g,
0.177 mmol) in ethanol (10 ml) in concentrated hydrochloric acid (10 ml)
Was dripped. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to form a powder, which was collected by filtration with a glass filter and washed well with diethyl ether to give 4-[(cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] ( 2-Pyridyl) amino] methyl} -1,1'-biphenyl dihydrochloride (0.08g, 76%) was obtained as an amorphous powder. Elemental analysis _{C 33 H 36 N 4 O 2} · 2HCl · 1 / 4H 2 O Calculated: C, 66.27; H, 6.49 ; N, 9.37 Found:. C, 66.16; H, 6.76; N, 9.67 1 H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.97 (1H, br) 3.73 (3H, s) 4.09 (2H, s) 5.
29 (2H, s) 6.90 (2H, d, J = 8.8Hz) 7.09-7.21 (2H, m)
7.38 (2H, d, J = 8.0Hz) 7.50 (2H, d, J = 9.2Hz) 7.63-
7.68 (6H, m) 7.76-7.85 (1H, m) 8.44-8.46 (1H, m)
9.24 (2H, br) 11.92 (1H, s)

Example 79 4-{[[(4-chloroanilino) carbonyl] (2-pyridyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-
Biphenyl / hydrochloride 1) 4-{[[(4-chloroanilino) carbonyl] (2-pyridyl)
Amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-biphenyl N-({4'-[(N-tert-butoxycarbonyl-N-cyclohexyl Amino) methyl] [1,1'-biphenyl] -4-yl} methyl) -2
-Pyridineamine (0.51g, 1.08mmol) in toluene solution
Triethylamine (1.5 ml, 10.8 mmol) and p-chlorophenylisocyanate (0.34 g, 2.16 mmol) were added to (10 ml) at room temperature, and the mixture was heated under reflux for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-3: 1) and 4-{[[(4-chloroanilino) carbonyl] (2-pyridyl) amino] methyl} -4 '-[ (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,
1'-Biphenyl (0.63g, 93%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.37 (9H,
s) 4.0-4.2 (1H, br) 4.38 (2H, s) 5.30 (2H, s) 6.95
(1H, d, J = 8.8Hz) 6.99-7.02 (1H, .m) 7.25-7.36 (7
H, m) 7.47-7.66 (6H, m) 8.35 (1H, dd, J = 1.2, 4.8H
z). 2) 4-{[[(4-chloroanilino) carbonyl] (2-pyridyl)
Amino] methyl} -4 '-[(cyclohexylamino) methyl]-
1,1'-Biphenyl hydrochloride 4-{[[(4-chloroanilino) carbonyl] (2-pyridyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-Biphenyl (0.49g, 0.7
8 mmol) in ethanol solution (10 ml) with 4N hydrogen chloride
Ethyl acetate (10 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. After the solvent was concentrated under reduced pressure, a solid was precipitated from the residue with ethanol-diethyl ether, collected by filtration, and dried under reduced pressure.
4-{[[(4-chloroanilino) carbonyl] (2-pyridyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-
Biphenyl hydrochloride (0.40 g, 91%) was obtained as a colorless solid. Melting point: 136-146 ℃ Elemental analysis value Calculated as C ₃₂ H ₃₄ ClN ₂ O ・ HCl ・ 1.5H ₂ O: C, 65.30; H, 6.34; N, 9.52 Actual value: C, 65.12; H, 6.13; N , 9.20. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 4.16 (2H, s) 5.29 (2H, s) 7.
15 (1H, dd, J = 5.6, 7.4Hz) 7.22 (1H, d, J = 8.4Hz) 7.
35-7.41 (4H, m) 7.63-7.73 (8H, m) 7.77-7.86 (1H,
m) 8.47 (1H, dd, J = 1.4, 5.2Hz) 9.27 (2H, br)

Example 80 4-[(Cyclohexylamino) methyl] -4 '-[([(2-methyl-3
-Pyridyl) methyl] {[4- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[([(2-methyl-3 -Pyridyl) methyl]
{[4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(2-methyl- 3-Pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.16g, 0.32mmol) in acetonitrile (10ml) was added 4-trifluoromethylphenylisocyanate (0.051ml, 0.36mmol) at room temperature for 10
Stir for minutes. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: acetone = 5: 2).
− 1: 1) and purified with 4-[(N-tert-butoxycarbonyl-N-
Cyclohexylamino) methyl] -4 '-[([(2-methyl-3-pyridyl) methyl] {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.20g , 91
%) Was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 2.52 (3H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.60
(2H, s) 4.68 (2H, s) 6.63 (1H, s) 7.17 (1H, dd, J =
5.2, 7.8Hz) 7.26-7.40 (7H, m) 7.50-7.64 (6H, m) 8.
44-8.47 (1H, m). 2) 4-[(Cyclohexylamino) methyl] -4 '-[([(2-methyl-3-pyridyl) methyl] {[4- (trifluoromethyl) anilino] carbonyl } Amino) methyl] -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[([(2-methyl-3-pyridyl) Methyl] {[4-
Concentrated hydrochloric acid (5 ml) was added dropwise to an ethanol solution (5 ml) of (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1′-biphenyl (0.18 g, 0.26 mmol), and the mixture was stirred at room temperature for 1 hour. After the solvent was concentrated under reduced pressure, the resulting amorphous powder was collected by filtration, washed with diethyl ether, and dried under reduced pressure.
4-[(cyclohexylamino) methyl] -4 '-[([(2-methyl-3
-Pyridyl) methyl] {[4- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride
(0.11 g, 64%) was obtained as a colorless amorphous powder. Elemental analysis _{C 35 H 37 N 4 OF 3} · 2HCl · 1.5H 2 O Calculated: C, 61.22: H, 6.17 : N, 8.16 Found: C, 61.46: H, 6.41 :. N, 8.07 1 H -NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.74 (3H, s) 2.96 (1H, s) 4.17 (2H, s) 4.8
2 (4H, s) 7.42 (2H, d, J = 7.6Hz) 7.44-7.87 (10H, m)
8.21 (1H, d, J = 7.8Hz) 8.64 (1H, d, J = 5.0Hz) 9.38
(3H, br)

Example 81 4-[(Cyclohexylamino) methyl] -4 '-[([(6-methyl-3
-Pyridyl) methyl] {[4- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[([((6-methyl-3 -Pyridyl) methyl]
{[4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(2-methyl- 3-pyridylmethyl) aminomethyl] (0.52g, 1.04mmol) in toluene (10ml) 4-
Trifluoromethylphenyl isocyanate (0.17 ml,
(1.15 mmol) was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: acetone = 3: 1-2: 1) to give 4-
[(N-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[([(6-methyl-3-pyridyl) methyl] {[4-
(Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1′-biphenyl (0.75 g, 100%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 2.56 (3H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.57
(2H, s) 4.66 (2H, s) 6.64 (1H, s) 7.17 (1H, d, J = 8.
0Hz) 7.26-7.38 (6H, m) 7.46-7.54 (4H, m) 7.60-7.65
(3H, m) 8.43 (1H, d, J = 2.2Hz). 2) 4-[(cyclohexylamino) methyl] -4 '-[([(6-methyl-3-pyridyl) methyl] {[4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((( 6-methyl-3-pyridyl) methyl] {[4-
To a solution of (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.57g, 0.83mmol) in ethanol (4ml) was added 4N hydrogen chloride-ethyl acetate (6ml) dropwise at room temperature. Stir for 1 hour. After the solvent was concentrated under reduced pressure, the residue was precipitated with ethanol-diethyl ether to obtain a solid, which was collected by filtration and dried under reduced pressure. 4-[(cyclohexylamino) methyl] -4 '-[([((6-methyl -3-Pyridyl) methyl] {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride (0.52g, 95%)
Was obtained as a colorless solid. Mp: as 160-166 ° C. Elemental analysis _{C 35 H 37 N 4 OF 3} · 2HCl · 3 / 4H 2 O, Calculated: C, 62.45; H, 6.06 ; N, 8.32 Found: C, 62.71; H, 6.41; N, 8.27. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.71 (3H, s) 2.96 (1H, br) 4.17 (2H, s) 4.
78 (2H, s) 4.84 (2H, s) 7.38 (2H, d, J = 8.0Hz) 7.58-
7.86 (10H, m) 8.35 (1H, d, J = 8.4Hz) 8.67 (1H, s)
9.42 (3H, s)

Example 82 4-[(Cyclohexylamino) methyl] -4 '-({[(4-methoxyanilino) carbonyl] [(6-methyl-3-pyridyl) methyl]
Amino} methyl) -1,1'-biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({[(4-methoxyanilino) carbonyl ] [(6-Methyl-3-pyridyl) methyl] amino} methyl) -1,
1'-biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(2-methyl-3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.52g, 1.04 mmol) of toluene
(10 ml) solution with 4-methoxyphenylisocyanate (0.1
5 ml, 1.16 mmol) was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: acetone = 5: 2-3: 2).
4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({[(4-methoxyanilino) carbonyl]
[(6-Methyl-3-pyridyl) methyl] amino} methyl) -1,1'-
Biphenyl (0.68g, 100%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 2.55 (3H, s) 3.75 (3H, s) 4.0-4.2 (1H, br) 4.41
(2H, s) 4.54 (2H, s) 4.63 (2H, s) 6.33 (1H, s) 6.79
(2H, d, J = 9.2Hz) 7.15 (3H, d, J = 9.2Hz) 7.26-7.34
(4H, m) 7.52 (2H, d, J = 8.2Hz) 7.58-7.65 (3H, m) 8.
42 (1H, d, J = 2.2Hz). 2) 4-[(Cyclohexylamino) methyl] -4 '-({[(4-methoxyanilino) carbonyl] [(6-methyl-3-pyridyl) methyl ] Amino} methyl) -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({[(4-methoxyanilino) carbonyl]
[(6-Methyl-3-pyridyl) methyl] amino} methyl) -1,1'-
Biphenyl (0.54g, 0.83mmol) in ethanol (10m
Concentrated hydrochloric acid (10 ml) was added dropwise to l), and the mixture was stirred at room temperature for 30 minutes. After the solvent was concentrated under reduced pressure, a solid was precipitated from the residue with ethanol-diethyl ether, collected by filtration, and dried under reduced pressure. 4-[(cyclohexylamino) methyl] -4 '-({[(4-
Methoxyanilino) carbonyl] [(6-methyl-3-pyridyl)
Methyl] amino} methyl) -1,1'-biphenyl dihydrochloride (0.
46 g, 89%) was obtained as a colorless solid. Melting point: 160-168 ℃ Elemental analysis C ₃₅ H ₄₀ N ₄ O ₂・ 2HCl ・ 0.5H ₂ O ・ Et ₂ O Calculated: C, 66.56: H, 7.25: N, 8.39 Measured: C, 66.88: H, 7.47: N, 8.46. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.52 (3H, s) 2.96 (1H, br) 3.70 (3H, s) 4.
16 (2H, s) 4.72 (2H, s) 4.77 (2H, s) 6.83 (2H, d,
J = 8.8Hz) 7.35-7.44 (4H, m) 7.66-7.71 (6H, m) 7.84
(1H, d, J = 8.4Hz) 8.32 (1H, dd, J = 1.4, 8.0Hz) 8.62
(1H, d, J = 1.4Hz) 8.79 (1H, s) 9.42 (2H, s)

Example 83 4-[(Cyclohexylamino) methyl] -4 '-[({[4- (trifluoromethyl) anilino] carbonyl} anilino) methyl]-
1,1'-biphenyl ・ hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[({[4- (trifluoromethyl) anilino] carbonyl} anilino) Methyl] -1,1'-biphenyl 4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4-anilinomethyl-1,1'-biphenyl (0.4
Triethylamine (0.25 ml, 2.2 mmol) and 4-trifluoromethylphenylisocyanate (0.19 ml, 1.3 mmol) were added to a solution of 1 g, 0.87 mmol) in acetonitrile (5 ml), and the mixture was heated under reflux for 18 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-4: 1) and 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4. '-[({[4- (Trifluoromethyl) anilino] carbonyl} anilino) methyl] -1,1'-biphenyl (0.30g, 52%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 3.9-4.2 (1H, br) 4.40 (2H, s) 4.96 (2H, s) 6.36
(1H, s) 6.67 (1H, d, J = 8.4Hz) 7.17-7.54 (16H, m). 2) 4-[(cyclohexylamino) methyl] -4 '-[({[4- (trifluoromethyl ) Anilino] carbonyl} anilino) methyl] -1,1'-biphenyl ・ hydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[({[4- (trifluoro Methyl) Anilino]
Carbonyl} anilino) methyl] -1,1'-biphenyl (0.27g,
A solution of 0.41 mmol of 4N hydrogen chloride-ethyl acetate (10 ml) was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The pale yellow solid was collected with a glass filter, washed well with diethyl ether, and dried under reduced pressure to give 4-[(cyclohexylamino) methyl]-.
4 '-[({[4- (trifluoromethyl) anilino] carbonyl}
Anilino) methyl] -1,1'-biphenyl ・ hydrochloride (0.21g, 86
%) Was obtained as a pale yellow amorphous powder. Elemental analysis _{C 34 H 34 N 3 OF 3} · HCl · 1.5H 2 O Calculated: C, 65.75; H, 6.17 ; N, 6.77 Found:. C, 65.96; H, 5.91; N, 6.95 1 H -NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 4.16 (2H, s) 5.00 (2H, s) 6.
76 (1H, d, J = 8.4Hz) 7.24-7.43 (6H, m) 7.55-7.69 (9
H, m) 8.68 (1H, s) 9.27 (2H, br)

Example 84 4-[(Cyclohexylamino) methyl] -4 '-({[(4-methoxyanilino) carbonyl] anilino} methyl) -1,1'-biphenyl hydrochloride 1) 4- [ (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({[(4-methoxyanilino) carbonyl] anilino} methyl) -1,1'-biphenyl 4'-[(N-tert -Butoxycarbonyl-N-cyclohexylamino) methyl] -4-anilinomethyl-1,1'-biphenyl (0.6
To a solution of 2 g, 1.32 mmol) of N, N-dimethylformamide (5 ml) was added triethylamine (0.55 ml, 3.9 mmol), 4-methoxyphenylisocyanate (0.34 ml, 2.6 mmol) and the mixture was stirred at 80 ° C. overnight. The reaction solution was allowed to cool, diluted with ethyl acetate, and washed with 1N hydrochloric acid and water. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1-3: 1-5: 2) and purified by 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({[(4
-Methoxyanilino) carbonyl] anilino} methyl) -1,1 '
-Biphenyl (0.59g, 72%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 3.76 (3H, s) 4.0-4.2 (1H, br) 4.39 (2H, s) 4.95
(2H, s) 6.07 (1H, s) 6.79 (2H, d, J = 9.0Hz) 7.18-7.
46 (13H, m) 7.50 (2H, d, J = 8.4Hz). 2) 4-[(cyclohexylamino) methyl] -4 '-({[(4-methoxyanilino) carbonyl] anilino} methyl)- 1,1'-Biphenyl hydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({[(4-methoxyanilino) carbonyl] anilino} methyl) -1, 1'-biphenyl (0.58g, 0.94mmol)
4N hydrogen chloride-ethyl acetate (10 ml) solution at room temperature
After stirring for 30 minutes, the mixture was concentrated under reduced pressure. The resulting colorless amorphous powder was collected with a glass filter, washed well with diethyl ether, and dried under reduced pressure to give 4-[(cyclohexylamino) methyl] -4 '-({[(4-methoxyanilino) carbonyl] anilino. }
Methyl) -1,1′-biphenyl hydrochloride (0.46 g, 88%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₄ H ₃₇ N ₃ O ₂ F ₃・ HCl ・ 0.25H ₂ O: C, 72.84; H, 6.92; N, 7.50 Found: C, 72.87; H, 6.89; N, 7.44. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 3.69 (3H, s) 4.16 (2H, s) 4.
97 (2H, s) 6.81 (2H, d, J = 8.8Hz) 7.18-7.41 (5H, m)
7.62-7.69 (9H, m) 8.04 (1H, s) 9.28 (2H, s)

Example 85 4-[(Cyclohexylamino) methyl] -4 '-[(4-methoxy
{[4- (Trifluoromethyl) anilino] carbonyl} anilino) methyl] -1,1'-biphenyl ・ hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 ' -[(4-Methoxy {[4- (trifluoromethyl) anilino] carbonyl} anilino) methyl] -1,1'-biphenyl 4-{[N-tert-butoxycarbonyl-N-cyclohexyl] amino} methyl}- 4 '-([(4-methoxyanilino) methyl) -1,1'
4-Biphenyl (0.31g, 0.62mmol) in N, N-dimethylformamide (10ml) 4-trifluoromethylphenylisocyanate (0.18ml, 1.26mmol) triethylamine
(0.26 ml, 1.86 mmol) was added and the mixture was stirred at 50-60 ° C for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1). Purified with 4-[(N
-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[(4-methoxy {[4- (trifluoromethyl) anilino] carbonyl} anilino) methyl] -1,1'-biphenyl
(0.35 g, 82%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 3.82 (3H, s) 3.96 (1H, s) 4.40 (2H, s) 4.91 (2
H, s) 6.37 (1H, s) 6.67 (2H, d, J = 8.6Hz) 6.91 (2H,
d, J = 1.2Hz) 7.08 (2H, d, J = 8.8Hz) 7.25-7.56 (9H,
m) 7.78 (2H, d, J = 8.4Hz). 2) 4-[(cyclohexylamino) methyl] -4 '-[(4-methoxy {[4- (trifluoromethyl) anilino] carbonyl} anilino) methyl ] -1,1'-Biphenyl hydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[(4-methoxy {[4- (trifluoromethyl))
Anilino] carbonyl} anilino) methyl] -1,1'-biphenyl (11e) (0.35g, 0.51mmol) in ethanol (10ml)
Concentrated hydrochloric acid (5 ml) was added dropwise to the mixture, and the mixture was stirred at 60 ° C for 30 minutes. After the solvent was concentrated under reduced pressure, the residue was dissolved in ethanol and diethyl ether was added to precipitate crystals. This was collected by filtration and dried under reduced pressure. 4-[(Cyclohexylamino) methyl] -4 '-[(4-methoxy {[4- (trifluoromethyl) anilino] carbonyl} anilino) methyl] -1,1'-biphenyl ・ hydrochloride (0.16g, 50 %) Was obtained as a colorless solid. Mp: 212-219 ℃ (decomposition) Elemental analysis _{C 35 H 36 N 3 O 2} F 3 · HCl · 1 / 3H 2 O Calculated: C, 66.71; H, 6.02 ; N, 6.67 Found: C, 66.89; H, 5.93;. N , 6.55 1 H-NMR (d 6 -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.97 (1H, br) 3.74 (3H, s) 4.16 (2H, s) 4.
92 (2H, s) 6.94 (2H, d, J = 9.2Hz) 7.19 (2H, d, J = 8.8
Hz) 7.36 (2H, d, J = 8.0Hz) 7.54-7.74 (10H, m) 8.35
(1H, s) 9.18 (2H, br)

Example 86 4-[(cyclohexylamino) methyl] -4 '-({4-methoxy
[(4-Methoxyanilino) carbonyl] anilino} methyl)-
1,1'-biphenyl 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({4-methoxy [(4-methoxyanilino) carbonyl] anilino} methyl)- 1,1'-biphenyl 4-{[N-tert-butoxycarbonyl-N-cyclohexyl) amino] methyl} -4 '-{[(4-methoxyanilino] methyl} -1,1'
4-Methylphenylisocyanate (0.21ml, 1.62mmol) triethylamine (0.33ml, 2.) in a solution of -biphenyl (0.39g, 0.78mmol) in N, N-dimethylformamide (10ml).
38 mmol) was added and the mixture was stirred at 50-60 ° C for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 4-[(N-tert-
Butoxycarbonyl-N-cyclohexylamino) methyl]-
4 '-({4-Methoxy [(4-methoxyanilino) carbonyl] anilino} methyl) -1,1'-biphenyl (0.50g, 99%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 3.74 (3H, s) 3.79 (3H, s) 4.0-4.2 (1H, br) 4.39
(2H, s) 4.90 (2H, s) 6.08 (1H, s) 6.78 (2H, d, J =
9.0Hz) 6.88 (2H, d, J = 9.0Hz) 7.08 (2H, d, J = 8.8Hz)
7.17-7.34 (6H, m) 7.51 (4H, d, J = 8.0Hz). 2) 4-[(Cyclohexylamino) methyl] -4 '-({4-methoxy [(4-methoxyanilino) carbonyl] Anilino} methyl)
-1,1'-biphenyl 4-[(N-cyclohexyl-N-tert-butoxycarbonyl-amino) methyl] -4 '-({4-methoxy [(4-methoxyanilino)
Carbonyl] anilino} methyl) -1,1'-biphenyl (0.22
g, 0.34 mmol) in ethanol solution (10 ml) with concentrated hydrochloric acid (5 m
l) was added dropwise, and the mixture was stirred at 60 ° C for 30 minutes. After the solvent was concentrated under reduced pressure, the residue was dissolved in ethanol and diethyl ether was added to precipitate crystals. This was collected by filtration and dried under reduced pressure. 4-[(Cyclohexylamino) methyl] -4 '-({4-methoxy [(4-methoxyanilino) carbonyl] anilino} methyl) -1,1'-biphenyl (0.20g, 100%) as a colorless solid Obtained. Melting point: 193-199 ° C (decomposition) Elemental analysis value Calculated as C ₃₅ H ₃₉ N ₃ O ₃ .HCl ・ 1 / 2H ₂ O: C, 70.63; H, 6.94; N, 7.06 Found: C, 70.86; H, 6.81; N, 6.98. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.99 (1H, br) 3.69 (3H, s) 3.73 (3H, s) 4.
17 (2H, s) 4.88 (2H, s) 6.79 (2H, d, J = 8.8Hz) 6.92
(2H, d, J = 9.2Hz) 7.16 (2H, d, J = 9.2Hz) 7.31 (2H,
d, J = 8.6Hz) 7.35 (2H, d, J = 7.4Hz) 7.61-7.74 (6H, m)
9.14 (2H, br)

Example 87 4-[(Butyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -4 ′-[(cyclohexylamino) methyl] -1,1′-biphenyl.hydrochloride 1 ) 4-[(Butyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-biphenyl To a solution of 4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4-n-butylaminomethyl-1,1'-biphenyl (0.37g, 0.82mmol) in chloroform (10ml) was added triethylamine ( 0.71 ml, 5.1 mmol) and 4-trifluoromethylphenyl isocyanate (0.13 ml, 0.91 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 4-[(butyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -4. '-[(Nt
ert-Butoxycarbonyl-N-cyclohexylamino) methyl] -1,1′-biphenyl (0.44 g, 84%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.96 (3H, t, J = 7.2Hz) 1.2-
1.8 (14H, m) 3.43 (2H, t, J = 8.2Hz) 3.95-4.1 (1H, b
r) 4.41 (2H, s) 4.61 (2H, s) 6.48 (1H, s) 7.26-7.6
3 (12H, m). 2) 4-[(Butyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl Hydrochloride 4-[(Butyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -4 '-[(N-tert-butoxycarbonyl
-N-cyclohexylamino) methyl] -1,1'-biphenyl
(0.43g, 0.67mmol) was added to 4N hydrogen chloride-ethyl acetate (10
ml), stirred at room temperature for 30 minutes, and concentrated under reduced pressure. Collect the resulting colorless amorphous powder with a glass filter, wash well with diethyl ether, and dry under reduced pressure to dry 4-[(butyl ether).
{[4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] -4 '-[(cyclohexylamino) methyl] -1,1'-
Biphenyl hydrochloride (0.34 g, 88%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₂ H ₃₈ N ₃ OF ₃・ HCl ・ 0.5H ₂ O: C, 65.91; H, 6.91; N, 7.21 Found: C, 66.22; H, 6.89; N, 7.16. ¹ H -NMR (d ₆ -DMSO) δ (ppm) 0.87 (3H, t, J = 7.0Hz) 1.0
2-1.70 (10H, m) 1.7-1.90 (2H, m) 2.0-2.0 (2H, m)
2.97 (1H, br) 3.3-3.4 (2H, br) 4.17 (2H, s) 4.67
(2H, s) 7.37 (2H, d, J = 8.4Hz) 7.58 (2H, d, J = 8.8H
z) 7.66-7.78 (10H, m) 8.86 (1H, s) 9.29 (2H, br)

Example 88 4-({Butyl [(4-methoxyanilino) carbonyl] amino}
Methyl) -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl ・ hydrochloride 1) 4-({butyl [(4-methoxyanilino) carbonyl] amino} methyl) -4'-[( N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-biphenyl 4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4-n-butylaminomethyl-1 Triethylamine (0.17 ml, 1.22 mmol) and 4-methoxyphenyl isocyanate (0.12 ml, 0.88 mmol) were added to a chloroform (15 ml) solution of 1,1′-biphenyl (0.36 g, 0.80 mmol), and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3:
1-2 (1): 2-({Butyl [(4-methoxyanilino) carbonyl] amino} methyl) -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl]- 1,1'-Biphenyl (0.40 g, 83%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.95 (3H, t, J = 7.4Hz) 1.2-
1.8 (14H, m) 1.39 (9H, s) 3.39 (2H, t, J = 8.0Hz) 3.7
6 (3H, s) 4.0-4.2 (1H, brs) (1H, br) 4.41 (2H, s)
4.60 (2H, s) 6.17 (1H, s) 6.79 (2H, d, J = 9.0Hz) 7.
19 (2H, d, J = 9.2Hz) 7.28 (2H, d, J = 9.6Hz) 7.37 (2
H, d, J = 8.0Hz) 7.52 (2H, d, J = 8.0Hz) 7.59 (2H, d,
J = 8.6Hz). 2) 4-({Butyl [(4-methoxyanilino) carbonyl] amino} methyl) -4 '-[(cyclohexylamino) methyl] -1,1'-
Biphenyl hydrochloride 4-({butyl [(4-methoxyanilino) carbonyl] amino}
Methyl) -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-biphenyl (0.39g, 0.65mm
4N hydrogen chloride-ethyl acetate (10 ml) solution of ol) was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The resulting colorless amorphous powder was collected with a glass filter, washed well with diethyl ether, and dried under reduced pressure to give 4-({butyl [(4-methoxyanilino) carbonyl] amino} methyl) -4 '-[(cyclohexyl Amino) methyl] -1,1'-biphenyl ・ hydrochloride (0.29g, 83%)
Was obtained as a colorless amorphous powder. Elemental analysis calculated as C ₃₂ H ₄₂ N ₃ O ₂・ HCl ・ 3 / 4H ₂ O: C, 69.92; H, 7.98; N, 7.64 Found: C, 70.03; H, 7.89; N, 7.54. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 0.87 (3H, t, J = 7.0Hz) 1.0
5-1.60 (10H, m) 1.7-1.90 (2H, m) 2.0-2.0 (2H, m)
2.97 (1H, br) 3.3-3.4 (2H, br) 3.70 (3H, s) 4.16
(2H, s) 4.61 (2H, s) 6.82 (2H, d, J = 9.2Hz) 7.34-7.
39 (4H, m) 7.66-7.75 (6H, m) 8.27 (1H, s) 9.26 (2
H, br)

Example 89 4-[(Cyclohexylamino) methyl] -4 '-[(cyclohexyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl hydrochloride 1 ) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[(cyclohexyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-
Biphenyl 4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4-cyclohexylaminomethyl-1,1'-biphenyl (0.36g, 0.80mmol) in chloroform (10ml) solution with triethylamine (0.14 ml, 0.96mmol), 4-trifluoromethylphenylisocyanate (0.13ml, 0.96mm
ol) was added and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution,
Silica gel column chromatography (hexane)
: 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 'after purification with ethyl acetate = 5: 1-4: 1)
-[(Cyclohexyl {[4- (trifluoromethyl) anilino]]
Carbonyl} amino) methyl] -1,1'-biphenyl (0.26g,
33%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.90-1.8 (20H, m) 1.32 (9H,
s) 3.8-4.1 (2H, br) 4.32 (2H, s) 4.44 (2H, s) 6.3
1 (1H, s) 7.16-7.27 (4H, m) 7.32-7.36 (4H, m) 7.44
(2H, d, J = 8.0Hz) 7.54 (2H, d, J = 8.4Hz). 2) 4-[(cyclohexylamino) methyl] -4 '-[(cyclohexyl {[4- (trifluoromethyl) anilino ] Carbonyl}
Amino) methyl] -1,1'-biphenyl hydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[(cyclohexyl {[4- (trifluoromethyl) anilino] A solution of carbonyl} amino) methyl] -1,1′-biphenyl (0.25 g, 0.377 mmol) in 4N hydrogen chloride-ethyl acetate (10 ml) was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. Collect the resulting colorless amorphous powder with a glass filter, wash well with diethyl ether, and dry under reduced pressure.
[(Cyclohexylamino) methyl] -4 '-[(cyclohexyl
{[4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1′-biphenyl · hydrochloride (0.29 g, 83%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₄ H ₄₀ N ₃ OF ₃・ HCl ・ 0.5H ₂ O: C, 67.04; H, 6.95; N, 6.90 Measured value: C, 66.98; H, 6.88; N, 6.75. ¹ H -NMR (d ₆ -DMSO) δ: 1.0-1.8 (18H, m) 2.0-2.2 (2
H, m) 2.97 (1H, br) 4.16 (3H, s) 4.65 (2H, s) 7.35
(2H, d, J = 8.6Hz) 7.38-7.73 (9H, m) 8.82 (1H, s) 9.
24 (2H, s)

Example 90 4-[(Cyclohexylamino) methyl] -4 '-({cyclohexyl [(4-methoxyanilino) carbonyl] amino} methyl)-
1,1'-biphenyl ・ hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({cyclohexyl [(4-methoxyanilino) carbonyl] amino} methyl) -1,1'-biphenyl 4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4-cyclohexylaminomethyl-1,1'-biphenyl (0.23g, 0.48mmol) in chloroform (10ml) ) To the solution were added triethylamine (0.14 ml, 0.96 mmol) and 4-methoxyphenylisocyanate (0.13 ml, 0.96 mmol), and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-3: 1-2: 1) to give 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino). Methyl] -4'-
({Cyclohexyl [(4-methoxyanilino) carbonyl] amino} methyl) -1,1'-biphenyl (0.24g, 80%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (20H, m) 1.39 (9H,
s) 3.74 (3H, s) 4.0-4.2 (1H, br) 4.48 (3H, br) 4.5
2 (2H, s) 6.08 (1H, s) 6.75 (2H, d, J = 9.0Hz) 7.08
(2H, d, J = 9.0Hz) 7.30 (2H, d, J = 7.8Hz) 7.41 (2H,
d, J = 8.4Hz) 7.53 (2H, d, J = 8.4Hz). 2) 4-[(cyclohexylamino) methyl] -4 '-({cyclohexyl [(4-methoxyanilino) carbonyl] amino} methyl ) -1,1'-Biphenyl hydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({cyclohexyl [(4-methoxyanilino) carbonyl] amino} methyl) -1,1'-biphenyl (0.23
g, 0.367mmol) of 4N hydrogen chloride-ethyl acetate (10ml)
The solution was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The resulting colorless amorphous powder was collected with a glass filter, washed well with diethyl ether, and dried under reduced pressure to give 4-[(cyclohexylamino) methyl] -4 '-({cyclohexyl [(4-methoxyanilino) carbonyl]. Amino} methyl) -1,1'-biphenyl ・
The hydrochloride salt (0.17g, 82%) was obtained as a colorless amorphous powder. Elemental analysis _{C 34 H 43 N 3 O 2} · HCl · 0.5H 2 O Calculated: C, 71.49; H, 7.94 ; N, 7.36 Found:. C, 71.22; H, 7.84; N, 7.10 1 H -NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (18H, m) 2.0-2.2
(2H, m) 2.99 (1H, br) 3.69 (3H, s) 4.17 (3H, s) 4.5
9 (2H, s) 6.81 (2H, d, J = 8.8Hz) 7.29-7.38 (4H, m)
7.62-7.75 (6H, m) 6.18 (1H, s) 9.13 (2H, br)

Example 91 4-[(Cyclohexylamino) methyl] -4 '-[((cyclohexylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl. Hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((cyclohexylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]- 1,1'-biphenyl 4-{[(N-tert-butoxycarbonyl-N-cyclohexyl) amino] methyl} -4 '-{[(cyclohexylmethyl) amino] methyl} -1,1'-biphenyl (0.41g , 0.835mmol) in acetonitrile (10ml) was added 4-trifluoromethylphenylisocyanate (0.18ml, 1.26mmol) at room temperature.
It was stirred for 0 minutes. After concentrating the reaction solution, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1−
4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((cyclohexylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} after purification by 4: 1)
Amino) methyl] -1,1′-biphenyl (0.57 g, quant.) Was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (21H, m) 1.39 (9H, s)
3.28 (2H, d, J = 6.6Hz) 4.0-4.2 (1H, br) 4.41 (2H, s)
4.63 (2H, s) 6.54 (1H, s) 7.29 (2H, d, J = 8.2Hz)
7.35 (2H, d, J = 8.6Hz) 7.44 (2H, d, J = 8.0Hz) 7.52
(2H, d, J = 8.0Hz) 7.60 (2H, d, J = 8.4Hz). 2) 4-[(cyclohexylamino) methyl] -4 '-[((cyclohexylmethyl) {[4- (trifluoro Methyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl ・ hydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((cyclohexylmethyl) {[ 4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,
1'-biphenyl (0.44g, 0.649mmol) in ethyl acetate
4N Hydrogen chloride-ethyl acetate (5 ml) was added dropwise to (5 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure, ethanol was added to the residue, and diethyl ether was added to precipitate crystals. This was collected by filtration and dried under reduced pressure. Four-
[(Cyclohexylamino) methyl] -4 '-[((cyclohexylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl ・ hydrochloride (0.31g, 8
5%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₅ H ₄₂ F ₃ N ₃ O ・ HCl ・ 1 / 2H ₂ O: C, 67.46; H, 7.12; N, 6.74 Actual value: C, 67.29; H, 6.83; N, 6.76. ¹ H-NMR (d ₆ -DMSO) δ: 1.0-1.8 (19H, m) 2.0-2.2 (2
H, m) 2.97 (1H, br) 3.25 (2H, d, J = 6.2Hz) 4.17 (2
H, s) 4.68 (2H, s) 7.35 (2H, d, J = 8.0Hz) 7.58 (2H,
d, J = 8.4Hz) 7.66-7.76 (8H, m) 8.78 (1H, s) 9.28 (2
H, br)

Example 92 4-[(Cyclohexylamino) methyl] -4 '-({(cyclohexylmethyl) [(4-methoxyanilino) carbonyl] amino}
Methyl) -1,1'-biphenyl ・ hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({(cyclohexylmethyl) [(4-methoxyanilino) Carbonyl] amino} methyl) -1,1'-biphenyl 4-{[(N-tert-butoxycarbonyl-N-cyclohexyl) amino] methyl} -4 '-{[(cyclohexylmethyl) amino] methyl} -1, 4-Methoxyphenylisocyanate (0.17 ml, 1.31 mmol) was added to a solution of 1'-biphenyl (0.42 g, 0.856 mmol) in acetonitrile (10 ml), and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-3: 1) and 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({(Cyclohexylmethyl) [(4-
Methoxyanilino) carbonyl] amino} methyl) -1,1′-biphenyl (0.54 g, 99%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (21H, m) 1.39 (9H,
s) 3.23 (2H, d, J = 6.6Hz) 3.75 (3H, s) 4.0-4.2 (1H,
br) 4.40 (2H, s) 4.61 (2H, s) 6.24 (1H, s) 6.79 (2
H, d, J = 8.8Hz) 7.19 (H, d, J = 8.8Hz) 7.29 (2H, d, J
= 8.0Hz) 7.35 (2H, d, J = 8.0Hz) 7.59 (2H, d, J = 8.0H
z). 2) 4-[(Cyclohexylamino) methyl] -4 '-({(cyclohexylmethyl) [(4-methoxyanilino) carbonyl] amino} methyl) -1,1'-biphenyl hydrochloride 4- [(N-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({(cyclohexylmethyl) [(4-methoxyanilino) carbonyl] amino} methyl) -1,1'-biphenyl
4N hydrogen chloride-ethyl acetate (5 ml) was added dropwise to an ethyl acetate solution (5 ml) of (0.41 g, 0.64 mmol), and the mixture was stirred at room temperature for 3 hours.
Stir for 0 minutes. The solvent was concentrated under reduced pressure, ethanol was added to the residue, and diethyl ether was added to precipitate crystals. This is collected by filtration, dried under reduced pressure, and 4-[(cyclohexylamino) methyl] -4 '-({(cyclohexylmethyl) [(4-
Methoxyanilino) carbonyl] amino} methyl) -1,1'-biphenyl.hydrochloride (0.32g, 87%) was obtained as a pale yellow amorphous powder. Elemental analysis value Calculated as C ₃₅ H ₄₂ F ₃ N ₃ O ・ HCl ・ 1 / 2H ₂ O: C, 71.28; H, 8.12; N, 7.13 Found: C, 71.34; H, 8.18; N, 7.00. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 0.9-1.8 (19H, m) 2.0-2.2
(2H, m) 2.98 (1H, br) 3.20 (2H, br) 3.69 (3H, s) 4.
18 (2H, s) 4.62 (2H, s) 6.81 (2H, d, J = 8.8Hz) 7.35
(2H, d, J = 8.8Hz) 7.62-7.75 (6H, m) 8.23 (1H, s)
9.12 (2H, brs)

Example 93 4-[(Cyclohexylamino) methyl] -4 '-[((2-thienylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'- Biphenyl hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((2-thienylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino ) Methyl] -1,
1'-biphenyl 4-{[(N-tert-butoxycarbonyl-N-cyclohexyl) amino] methyl} -4 '-{[(2-thienylmethyl) amino] methyl}
4-Trifluoromethylphenylisocyanate (0.18 ml, 1.26 mmol) was added to a solution of -1,1'-biphenyl (0.51 g, 1.04 mmol) in acetonitrile (10 ml), and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1-2: 1).
Purified by 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((2-thienylmethyl) {[4-
(Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1′-biphenyl (0.70 g, 99%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (10H, m) 1.39 (9H, s)
4.0-4.2 (1H, br) 4.41 (2H, s) 4.66 (2H, s) 4.80 (2
H, s) 6.63 (1H, s) 6.98-7.04 (2H, m) 7.26-7.60 (11
H, m) 7.62 (2H, d, J = 8.2Hz). 2) 4-[(cyclohexylamino) methyl] -4 '-[((2-thienylmethyl) {[4- (trifluoromethyl) anilino] Carbonyl} amino) methyl] -1,1'-biphenyl ・ hydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((2-thienylmethyl) {[4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-
Biphenyl (0.56g, 0.826mmol) in ethyl acetate (5m
lN) was added dropwise with 4N hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 1 hour and 30 minutes. The solvent was concentrated under reduced pressure, ethanol was added to the residue, and diethyl ether was added to precipitate crystals. This was collected by filtration and dried under reduced pressure. Four-
[(Cyclohexylamino) methyl] -4 '-[((2-thienylmethyl) {[4- (trifluoromethyl) anilino] carbonyl}
Amino) methyl] -1,1'-biphenyl ・ hydrochloride (0.43g, 85%)
Was obtained as a pale yellow powder. Melting point 197-202 ° C Elemental analysis C ₃₃ H ₃₄ N ₃ OSF ₃・ HCl ・ 1 / 4H ₂ O Calculated: C, 64.07; H, 5.78; N, 6.79 Found: C, 64.11; H, 5.65; N, 6.88. ¹ H-NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 2.0-2.2 (2H,
m) 2.94 (1H, br) 4.14 (2H, s) 4.64 (2H, s) 4.74 (2
H, s) 6.95 (1H, dd, J = 3.4, 4.8Hz) 7.03 (1H, d, J = 2.
2Hz) 7.34 (2H, d, J = 8.0Hz) 7.42 (1H, dd, J = 1.6, 5.
4Hz) 7.55-7.75 (10H, m) 9.14 (3H, s)

Example 94 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-thienylmethyl) amino] methyl} -1,1'-biphenyl-hydrochloric acid Salt 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-thienylmethyl) amino] methyl} -1, 1'-biphenyl 4-{[(N-tert-butoxycarbonyl-N-cyclohexyl) amino] methyl} -4 '-{[(2-thienylmethyl) amino] methyl}
4-Methoxyphenylisocyanate was added to a solution of -1,1'-biphenyl (0.53g, 1.08mmol) in acetonitrile (10ml).
(0.17 ml, 1.31 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-3: 1) and 4
-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2
-Thienylmethyl) amino] methyl} -1,1'-biphenyl (0.
62 g, 90%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 3.75 (3H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.64
(2H, s) 4.77 (2H, s) 6.31 (1H, s) 6.79 (2H, d, J =
9.2Hz) 6.93-7.02 (2H, m) 7.15 (2H, d, J = 8.8Hz) 7.2
6-7.39 (5H, m) 7.53 (2H, d, J = 8.4Hz) 7.60 (2H, d,
J = 8.0Hz). 2) 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-thienylmethyl) amino]
Methyl} -1,1'-biphenyl ・ hydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2
-Thienylmethyl) amino] methyl} -1,1'-biphenyl (0.
To a solution of 49 g, 0.766 mmol) in ethyl acetate (5 ml) was added dropwise 4N hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure, ethanol was added to the residue, and diethyl ether was added to precipitate crystals.
This was collected by filtration and dried under reduced pressure. 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl]
(2-thienylmethyl) amino] methyl} -1,1'-biphenyl
The hydrochloride salt (0.45g, quant.) Was obtained as a pale yellow powder. Melting point 186-192 ° C Elemental analysis C ₃₃ H ₃₇ N ₃ O ₂ S Calculated as HCl ・ 1 / 2H ₂ O: C, 67.73; H, 6.72; N, 7.18 Found: C, 67.78; H, 6.80 ; N, 7.31. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.97 (1H, br) 3.70 (3H, s) 4.17 (2H, s) 4.
61 (2H, s) 4.71 (2H, s) 6.83 (2H, d, J = 9.0Hz) 6.96-
7.03 (2H, m) 7.30-7.46 (5H, m) 7.67-7.71 (6H, m)
8.59 (1H, s) 9.30 (2H, br)

Example 95 4-[(Cyclohexylamino) methyl] -4 '-[((2-furylmethyl) {[4- (trifluoromethyl) anilino] carbonyl}
Amino) methyl] -1,1'-biphenyl 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((2-furylmethyl) {[4- (trifluoro Methyl) anilino] carbonyl} amino) methyl] -1,1 '
-Biphenyl 4-{[N-tert-butoxycarbonyl-N-cyclohexyl] amino} methyl} -4 '-{[(2-furylmethyl) amino] methyl}-
1,1'-biphenyl (0.60g, 1.26mmol) in acetonitrile
4-Trifluoromethylphenylisocyanate (0.2 ml, 1.39 mmol) was added to the solution (10 ml), and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-3: 1) and 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((2-Furylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-Biphenyl (0.85g, 100%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.40 (9H,
s) 3.9-4.2 (1H, br) 4.41 (2H, s) 4.54 (2H, s) 4.65
(2H, s) 6.27 (1H, d, J = 2.6Hz) 6.36 (1H, dd, J = 2.0,
3.0Hz) 6.96 (1H, s) 7.29 (2H, d, J = 8.6Hz) 7.38 (2
H, d, J = 6.2Hz) 7.44-7.61 (13H, m). 2) 4-[(cyclohexylamino) methyl] -4 '-[((2-furylmethyl) {[4- (trifluoromethyl) Anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((2-furylmethyl) {[4- ( Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.34g, 0.51mmol) in methylene chloride (10
trimethylsilyltrifluoromethanesulfonate (0.23 ml, 1.27 mmol) was added dropwise to the solution (ml) under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate was added dropwise to terminate the reaction, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 15: 1), 4-[(cyclohexylamino) methyl] -4 '-[((2-furylmethyl) {[4- (trifluoromethyl)
Anilino] carbonyl} amino) methyl] -1,1'-biphenyl
(0.26g, 91%) was obtained as a colorless solid. Melting point: 109-113 ° C Elemental analysis C ₃₃ H ₃₄ N ₃ O ₂ F ₃・ H ₂ O Calculated: C, 68.38; H, 6.26; N, 7.25 Found: C, 68.36; H, 6.07; N , 7.18. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.4 (5H, m) 1.5-1.7 (1H, m)
1.7-1.8 (2H, m) 1.9-2.1 (2H, m) 2.24 (1H, br) 2.5
9 (1H, br) 3.89 (3H, s) 4.53 (2H, s) 4.65 (2H, s)
6.27 (1H, d, J = 3.2Hz) 6.36-6.39 (1H, m) 6.95 (1H, m
s) 7.35 (2H, d, J = 8.0Hz) 7.41-7.59 (13H, m)

Example 96 4-[(Cyclohexylamino) methyl] -4 '-({(2-furylmethyl) [(4-methoxyanilino) carbonyl] amino} methyl) -1,1'-biphenyl 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({(2-furylmethyl) [(4-methoxyanilino) carbonyl] amino} methyl) -1,1'- Biphenyl 4-{[N-tert-butoxycarbonyl-N-cyclohexyl] amino} methyl} -4 '-{[(2-furylmethyl) amino] methyl}-
1,1'-biphenyl (0.63g, 1.33mmol) in acetonitrile
(10 ml) solution with 4-methoxyphenylisocyanate (0.
17 ml, 1.46 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 2-3: 1) to give 4-
[(N-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({(2-furylmethyl) [(4-methoxyanilino) carbonyl] amino} methyl) -1,1'-biphenyl ( 0.81
g, 99%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (10H, m) 1.41 (9H, s)
3.78 (3H, s) 4.0-4.2 (1H, br) 4.30 (2H, s) 4.55 (2
H, s) 4.65 (2H, s) 6.28 (1H, d, J = 3.0Hz) 6.37 (1H,
dd, J = 1.8, 2.8Hz) 6.60 (1H, s) 6.83 (2H, d, J = 8.8H
z) 7.23 (2H, d, J = 8.6Hz) 7.28-7.43 (5H, m) 7.54 (2
H, d, J = 8.4Hz) 7.60 (2H, d, J = 8.0Hz). 2) 4-[(cyclohexylamino) methyl] -4 '-({(2-furylmethyl) [(4-methoxyanim Rino) carbonyl] amino} methyl) -1,1'-biphenyl 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({(2-furylmethyl) [(4-methoxy Anilino) carbonyl] amino} methyl) -1,1'-biphenyl (0.51
g, 0.82 mmol) in methylene chloride solution (10 ml) under ice-cooling trimethylsilyltrifluoromethanesulfonate (0.2
(2 ml, 1.27 mmol) was added dropwise, and the mixture was stirred at 0 ° C for 1 hr. Saturated aqueous sodium hydrogen carbonate was added dropwise to terminate the reaction, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue (chloroform: methanol = 20: 1-15: 1)
Purified with 4-[(cyclohexylamino) methyl] -4 '-({(2
-Furylmethyl) [(4-methoxyanilino) carbonyl] amino} methyl) -1,1'-biphenyl (0.42g, 98%) was obtained as a colorless solid. Melting point 131-135 ° C Elemental analysis C ₃₃ H ₃₇ N ₃ O ₃・ 3 / 4H ₂ O Calculated: C, 73.78; H, 7.22; N, 7.82 Found: C, 73.74; H, 6.98; N , 7.63. ¹ H-NMR (CDCl ₃ ) δ: 1.1-1.4 (5H, m) 1.5-1.8 (1H,
m) 1.9-2.0 (2H, m) 2.57 (1H, br) 2.74 (2H, br) 3.76
(3H, s) 3.87 (2H, s) 4.52 (2H, s) 4.63 (2H, s) 6.2
5 (1H, d, J = 3.0Hz) 6.35 (1H, dd, J = 1.8, 3.4Hz) 6.6
0 (1H, s) 6.81 (2H, d, J = 9.2Hz) 7.21 (2H, d, J = 9.2H
z) 7.34 (2H, d, J = 8.0Hz) 7.40-7.44 (3H, m) 7.53-7.
58 (4H, m)

Example 97 4-[(Cyclohexylamino) methyl] -4 '-[((2-phenylethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'- Biphenyl hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((2-phenylethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino ) Methyl] -1,
1'-biphenyl 4-{[N-tert-butoxycarbonyl-N-cyclohexyl) amino] methyl} -4 '-{[(2-phenylethyl) amino] methyl}
4-Trifluoromethylphenylisocyanate (0.12 ml, 0.84 mmol) was added to a solution of -1,1'-biphenyl (0.38 g, 0.76 mmol) in acetonitrile (10 ml), and the mixture was stirred at room temperature for 14 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[( (2-Phenylethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-Biphenyl (0.54g, 100%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 2.94 (2H, t, J = 7.0Hz) 3.66 (2H, t, J = 7.0Hz) 4.0
-4.2 (1H, br) 4.41 (2H, s) 4.58 (2H, s) 6.03 (1H,
s) 7.14 (2H, d, J = 8.8Hz) 7.26-7.46 (11H, m) 7.52
(2H, d, J = 8.0Hz) 7.61 (2H, d, J = 8.0Hz). 2) 4-[(cyclohexylamino) methyl] -4 '-[((2-phenylethyl) {[4- ( Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl hydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((2-phenyl Ethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-
Biphenyl (0.43g, 0.63mmol) in ethanol (4m
Concentrated hydrochloric acid (5 ml) was added dropwise to l) and the mixture was stirred at 60 ° C. for 30 minutes.
After the solvent was concentrated under reduced pressure, the residue was dissolved in ethanol,
Diethyl ether was added to precipitate crystals. This was collected by filtration and dried under reduced pressure. 4-[(Cyclohexylamino) methyl] -4 '-[((2-phenylethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl ・ hydrochloride (0.38 g, 97%) was obtained as a colorless solid. Mp: 255-263 ° C. (decomposition) Elemental analysis _{C 36 H 38 N 3 OF 3} · HCl Calculated: C, 69.50; H, 6.32 ; N, 6.75 Found: C, 69.24; H, 6.21 ; N, ^{. 6.56 1 H-NMR (d} 6 -DMSO) δ: 1.0-1.8 (8H, m) 2.0-2.2 (2H,
m) 2.8-2.90 (2H, m) 2.97 (1H, br) 3.56-3.65 (2H,
m) 4.17 (2H, s) 4.64 (2H, s) 7.18-7.29 (5H, m) 7.3
8 (2H, d, J = 8.0Hz) 7.56-7.75 (10H, m) 8.89 (1H, s)
9.19 (2H, br)

Example 98 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-phenylethyl) amino] methyl} -1,1'-biphenyl-hydrochloric acid Salt 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-phenylethyl) amino] methyl} -1, 1'-biphenyl 4-{[N-tert-butoxycarbonyl-N-cyclohexyl] amino} methyl} -4 '-{[(2-phenylethyl) amino] methyl}
4-Methoxyphenylisocyanate was added to a solution of -1,1'-biphenyl (0.51g, 1.02mmol) in acetonitrile (10ml).
(0.15 ml, 1.16 mmol) was added and the mixture was stirred at room temperature for 14 hours.
After concentrating the reaction mixture, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and 4-[(N
-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-phenylethyl) amino] methyl} -1,1'-biphenyl (0.65g,
98%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 2.93 (2H, t, J = 7.0Hz) 3.62 (2H, t, J = 6.8Hz) 3.7
5 (3H, s) 4.0-4.2 (1H, br) 4.40 (2H, s) 4.55 (2H, s)
s) 5.86 (1H, s) 6.75 (2H, d, J = 9.2Hz) 7.01 (2H, d,
J = 9.2Hz) 7.21-7.38 (9H, m) 7.52 (2H, d, J = 8.4Hz)
7.59 (2H, d, J = 8.0Hz). 2) 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-phenylethyl) amino]
Methyl} -1,1'-biphenyl ・ hydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2
-Phenylethyl) amino] methyl} -1,1'-biphenyl (0.
56 g, 0.86 mmol) in ethanol solution (10 ml) was added with concentrated hydrochloric acid (5
ml) was added dropwise, and the mixture was stirred at 60 ° C for 30 minutes. After the solvent was concentrated under reduced pressure, the residue was dissolved in ethanol and diethyl ether was added to precipitate crystals. This was collected by filtration and dried under reduced pressure. 4-[(cyclohexylamino) methyl] -4 '-{[((4-
Methoxyanilino) carbonyl] (2-phenylethyl) amino] methyl} -1,1'-biphenyl.hydrochloride (0.46g, 92%) was obtained as a colorless solid. Melting point:> 265 ° C Elemental analysis C ₃₆ H ₄₁ N ₃ O ₂・ HCl ・ Calculated as 1 / 3H ₂ O: C, 73.26; H, 7.29; N, 7.12 Found: C, 73.45; H, 7.18; N, 7.03. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.52-2.83 (2H, m) 2.87 (1H, br) 3.50-3.57
(2H, m) 3.70 (3H, s) 4.16 (2H, s) 4.59 (2H, s) 6.8
2 (2H, d, J = 9.2Hz) 7.15-7.38 (9H, m) 7.38 (2H, d,
J = 8.0Hz) 7.66-7.75 (6H, m) 8.33 (1H, s) 9.27 (2H,
br)

Example 99 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-naphthyl) amino] methyl} -1,
1'-biphenyl hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-naphthyl) amino] Methyl} -1,1'-biphenyl 4-{[N-tert-butoxycarbonyl-N-cyclohexyl] amino} methyl} -4 '-{[(2-naphthylamino) methyl] -1,1'-
Biphenyl (0.62g, 1.19mmol) in N, N-dimethylformamide (10ml) solution 4-methoxyphenylisocyanate (0.31ml, 2.38mmol), triethylamine (0.50ml,
(3.57 mmol) was added, and the mixture was stirred at 50-60 ° C for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1). Purified by 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4'-
{[[(4-Methoxyanilino) carbonyl] (2-naphthyl) amino] methyl} -1,1'-biphenyl (0.28g, 35%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (10H, m) 1.37 (9H, s)
3.75 (3H, s) 3.9-4.2 (1H, br) 4.39 (2H, s) 5.05 (2
H, s) 6.16 (1H, s) 6.78 (2H, d, J = 9.2Hz) 7.18-7.38
(7H, m) 7.48-7.58 (6H, m) 7.69 (1H, d, J = 1.8Hz)
7.77-7.91 (3H, m). 2) 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2-naphthyl) amino] methyl}
-1,1'-Biphenyl hydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (2
-Naphthyl) amino] methyl} -1,1'-biphenyl (0.39g,
0.82 mmol) in ethanol (10 ml) in concentrated hydrochloric acid (5 ml)
Was added dropwise, and the mixture was stirred at 50 ° C. for 1 hour. After the solvent was concentrated under reduced pressure, the resulting solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-[(cyclohexylamino) methyl] -4'-
{[[(4-Methoxyanilino) carbonyl] (2-naphthyl) amino] methyl} -1,1'-biphenyl.hydrochloride (0.15g, 88%) was obtained as a colorless solid. Melting point 190-195 ° C Elemental analysis C ₃₈ H ₃₉ N ₃ O ₂・ 2HCl ・ 1 / 4H ₂ O Calculated: C, 74.74; H, 6.68; N, 6.88 Found: C, 74.80; H, 6.75; N, 6.70. ¹ H-NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 2.0-2.2 (2H,
m) 2.97 (1H, br) 3.69 (3H, s) 4.16 (2H, s) 5.08 (2
H, s) 6.81 (2H, d, J = 8.8Hz) 7.33 (1H, d, J = 8.8Hz)
7.39-7.51 (6H, m) 7.83-7.92 (4H, m) 8.21 (1H, s)
9.10 (2H, br)

Example 100 4-[(Cyclohexylamino) methyl] -3 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'- Biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -3 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} Amino) methyl] -1,
1'-biphenyl 4-{[(tert-butoxycarbonyl) (cyclohexyl) amino] methyl} -3 '-{[(3-pyridylmethyl) amino] methyl}-
To a solution of 1,1'-biphenyl (1.0 g, 2.06 mmol) in toluene (10 ml) was added 4-trifluoromethylphenyl isocyanate (0.
29 ml, 2.06 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was directly purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-2: 3) to give 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -3'-.
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (1.34
g, 97%) was obtained as colorless crystals. Melting point 138-139 ℃ Elemental analysis value C ₃₉ H ₄₃ FN ₄ O ₃ Calculated value: C, 69.62; H, 6.44; N, 8.33 Found value: C, 69.64; H, 6.49; N, 8.36. ¹ H- NMR (CDCl ₃ ) δ: 0.90-1.90 (18H, m), 3.90-4.20 (1H,
m), 4.42 (2H, s), 4.62 (2H, s), 4.74 (2H, s), 6.58 (1H,
s), 7.20-7.70 (12H, m), 7.72-7.85 (1H, m), 8.58-8.70
(2H, m). 2) 4-[(Cyclohexylamino) methyl] -3 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1 '-Biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -3'-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} Amino) methyl] -1,1'-
Concentrated hydrochloric acid (15 ml) was added to a solution of biphenyl (1.1 g, 1.64 mmol) in ethanol (20 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, and the residue was triturated with ethanol-diethyl ether to give 4-[(cyclohexylamino) methyl] -3 '-[((3-
Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride
(1.05 g, 99%) was obtained as an amorphous powder. Elemental analysis value C ₃₄ H ₃₅ F ₃ N ₄ O ・ 2HCl ・ 1 / 4H ₂ O, calculated value: C, 62.82; H, 5.81; N, 8.62 Actual value: C, 62.90; H, 6.26; N, 8.33 _{^{. 1 H-NMR (d 6}} -DMSO) δ: 1.00-1.90 (6H, m), 2.08-2.25 (2H,
m), 2.38-2.65 (2H, m), 2.90- 3.10 (1H, m), 4.10-4.25 (2
H, m), 4.83 (2H, s), 4.86 (2H, s), 7.31 (1H, d, J = 7.2Hz),
7.46 (1H, t, J = 7.5Hz), 7.55-7.90 (10H, m), 7.90-8.00
(1H, m), 8.40 (1H, d, J = 7.6Hz), 8.78 (1H, d, J = 5.8Hz),
8.82 (1H, brs), 9.25-9.40 (2H, br, NH ₂ ⁺ ), 9.37 (1H, s).

Example 101 4-[(Cyclohexylamino) methyl] -3 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl di Hydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -3 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1 , 1'-Biphenyl 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -3 '-{[(3-pyridylmethyl) amino] methyl}-
4-methoxyphenylisocyanate (0.27 ml, 2.06 ml) was added to a solution of 1,1'-biphenyl (1.0 g, 2.06 mmol) in toluene (10 ml).
mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was directly purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-1: 2) to give 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -3 '-{. [[(4-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl (1.34g, 97%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.95-1.87 (19H, m), 3.76 (3H, s), 3.9
0-4.20 (1H, m), 4.42 (2H, s), 4.60 (2H, s), 4.71 (2H, s),
6.25 (1H, s), 6.81 (2H, d, J = 9.2Hz), 7.14 (2H, d, J = 9.2H
z), 7.20-7.70 (9H, m), 7.72-7.85 (1H, m), 8.55-8.65 (2
H, m). 2) 4-[(Cyclohexylamino) methyl] -3 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -3 '-{[[(4-methoxyanilino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (1.0
g, 1.58 mmol) in ethanol (20 ml) in concentrated hydrochloric acid (15 ml)
Was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, and the residue was triturated with ethanol-diethyl ether to give 4-
[(Cyclohexylamino) methyl] -3 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl}
-1,1'-Biphenyl dihydrochloride (0.95 g, 96%) was obtained as a colorless amorphous powder. Elemental analysis value C ₃₄ H ₃₈ N ₄ O ₂・ 2HCl ・ 1.1H ₂ O, calculated value: C, 65.09; H, 6.78; N, 8.93 Found value: C, 65.22; H, 7.13; N, 8.52. ¹ H-NMR (d ₆ -DMSO) δ: 1.00-1.90 (8H, m), 2.28-2.45 (2H,
m), 2.90-3.10 (1H, m), 3.71 (3H, s), 4.18 (2H, brs), 4.
78 (2H, s), 4.80 (2H, s), 6.83 (2H, d, J = 9.2Hz), 7.28-7.6
3 (9H, m), 7.95 (1H, dd, J = 7.8,5.8Hz), 8.39 (1H, d, J = 8.8
Hz), 8.75-8.90 (3H, m), 9.36 (2H, br, NH ₂ ⁺ ).

Example 102 3- (Aminomethyl) -4 ′-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-biphenyl dihydrochloride 1) 3- (tert-butoxycarbonylaminomethyl) -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 3- (tert-butoxycarbonylaminomethyl) -4 '-{[(3 -Pyridylmethyl) amino] methyl} -1,1'-biphenyl (4.95g,
4-Methoxyphenylisocyanate (1.59 ml, 12.3 mmol) was added to a solution of 12.3 mmol) in toluene (30 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was directly purified by silica gel column chromatography (hexane: acetone = 3: 1), and 3- (t
ert-Butoxycarbonylaminomethyl) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (5.65g, 83%) Was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s, Bu ^t ), 3.76 (3H, s), 4.39
(2H, d, J = 5.6Hz), 4.58 (2H, s), 4.70 (2H, s), 4.85-5.00
(1H, br, NH), 6.26 (1H, s), 6.77-6.90 (2H, m), 7.10-7.68
(11H, m), 7.70-7.82 (1H, m), 8.53-8.65 (2H, m). 2) 3- (aminomethyl) -4 '-[((3-pyridylmethyl) {[4- (tri Fluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 3- (tert-butoxycarbonylaminomethyl) -4 '-[((3-pyridylmethyl) {[4- (tri Fluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (5.80g, 9.82mm
Concentrated hydrochloric acid (20 ml) was added to a solution of ol) in ethanol (50 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, ethanol-diethyl ether was added to give a powder, and 3- (aminomethyl)-
4 '-[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl
The dihydrochloride salt (5.5 g, 98%) was obtained as a colorless amorphous powder. Elemental analysis value C ₂₈ H ₂₅ F ₃ N ₄ O ・ 2HCl ・ 1 / 2H ₂ O, calculated value: C, 58.75; H, 4.93; N, 9.79 Found value: C, 58.92; H, 5.19; N, 9.34 _{^{. 1 H-NMR (d 6}} -DMSO) δ: 4.00-4.20 (2H, m), 4.82 (2H, s), 4.
84 (2H, s), 7.39 (2H, d, J = 8.2Hz), 7.43-7.90 (10H, m),
7.95 (1H, dd, J = 8.2,5.8Hz), 8.40 (1H, d, J = 8.4Hz), 8.56
(3H, m, NH ₃ ⁺ ), 8.78-8.90 (2H, m).

Example 103 3-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'- Biphenyl dihydrochloride 1) 3-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} Amino) methyl] -1,
1'-biphenyl 3- (aminomethyl) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-biphenyl dihydrochloride (2.0 g, 3.80 mmol), cyclohexanone (3.92 ml, 38.0 mmol), 1,8-diazabicyclo [5.4.
0] Unde-7-cene (1.42 ml, 9.5 mmol), acetic acid (2.17 ml, 38.
After stirring a mixed solution of 0 mmol), sodium chloride (20 g) and methanol (30 ml) for 1 hour, sodium triacetoxyborohydride (4.02 g, 19.0 mmol) was added little by little. After stirring at room temperature for 5 hours, the solvent was distilled off under reduced pressure. Saturated aqueous sodium hydrogen carbonate (150 ml) was added to the residue, and the mixture was extracted with dichloromethane (100 ml × 2). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-3: 1) to give 3-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[( (3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1′-biphenyl (1.20 g, 47%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.80-1.90 (19H, m), 3.90-4.20 (1H,
m), 4.44 (2H, brs), 4.59 (2H, s), 4.73 (2H, s), 6.58 (1
H, s), 7.20-7.72 (12H, m), 7.72-7.80 (1H, m), 8.57-8.70
(2H, m). 2) 3-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1 '-Biphenyl dihydrochloride 3-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4'-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} Amino) methyl] -1,1 '
-Concentrated hydrochloric acid (5 ml) was added to a solution of biphenyl (1.0 g, 1.49 mmol) in ethanol (10 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, and the residue was triturated with ethanol-diethyl ether to give 3-[(cyclohexylamino) methyl] -4 '-[((3-
Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride
(0.90 g, 93%) was obtained as a colorless amorphous powder. Elemental analysis value C ₃₄ H ₃₅ F ₃ N ₄ O ・ 2HCl ・ 1 / 2H ₂ O Calculated value: C, 62.38; H, 5.85; N, 8.56 Measured value: C, 62.09; H, 6.05; N, 8.36 _{^{. 1 H-NMR (d 6}} -DMSO) δ: 1.00-1.90 (8H, m), 2.10-2.27 (2H,
m), 2.90-3.15 (1H, m), 4.20 (2H, brs), 4.80 (2H, s), 4.
83 (2H, s), 7.39 (2H, d, J = 8.2Hz), 7.45-7.87 (9H, m), 7.8
7-8.10 (2H, m), 8.38 (1H, d, J = 9.4Hz), 8.75-8.90 (2H, m),
9.30-9.50 (3H, m).

Example 104 3- (Aminomethyl) -4 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride 1 ) 3- (N-tert-butoxycarbonylaminomethyl) -4'-
{[[(4-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl 3- (N-tert-butoxycarbonylaminomethyl) -4 '-{[(3-
Pyridylmethyl) amino] methyl} -1,1'-biphenyl (4.9
4-Methoxyphenylisocyanate (1.59 ml, 12.3 mmol) was added to a toluene (30 ml) solution of 5 g, 12.3 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution is directly purified by silica gel column chromatography (hexane: acetone = 3: 1),
3- (N-tert-butoxycarbonylaminomethyl) -4 '-{[(4
-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (5.65 g, 83%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s, Bu ^t ), 3.76 (3H, s), 4.39
(2H, d, J = 5.6Hz), 4.58 (2H, s), 4.70 (2H, s), 4.85-5.00
(1H, br, NH), 6.26 (1H, s), 6.77-6.90 (2H, m), 7.10-7.68
(11H, m), 7.70-7.82 (1H, m), 8.53-8.65 (2H, m). 2) 3- (aminomethyl) -4 '-{[[(4-methoxyanilino) carbonyl] (3 -Pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride 3- (N-tert-butoxycarbonylaminomethyl) -4 '-{[[(4
-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (5.3g, 9.59mmol) in ethanol (30ml) was added concentrated hydrochloric acid (20ml) at room temperature for 2 hours. It was stirred. The reaction solution was evaporated under reduced pressure, ethanol-diethyl ether was added to give a powder, and 3- (aminomethyl) -4 '-{[[(4
-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (5.0 g, 98%) was obtained as a colorless amorphous powder. Elemental analysis value C ₂₈ H ₂₈ N ₄ O ₂・ 2HCl ・ 1 / 2H ₂ O, calculated value: C, 62.92; H, 5.85; N, 10.48 Found value: C, 62.96; H, 5.95; N, 10.24. ¹ H-NMR (d ₆ -DMSO) δ: 3.71 (3H, s), 4.00-4.20 (2H, m), 4.
75 (4H, s), 6.83 (1H, d, J = 9.2Hz), 7.15-7.75 (11H, m),
7.80-8.00 (2H, m), 8.50 (3H, m, NH ₃ ⁺ ), 8.70-8.85 (2H,
m).

Example 105 3-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl di Hydrochloride 1) 3-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1 , 1'-Biphenyl 3- (aminomethyl) -4 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (2.0 g, 3.81 mmol), cyclohexanone (1.9
7ml, 19.0mmol), 1,8-diazabicyclo [5.4.0] unde-7-
Sen (1.42 ml, 9.5 mmol), acetic acid (2.18 ml, 38.1 mmol), a mixture of sodium chloride (20 g) and methanol (50 ml) was stirred for 1 hour, and then sodium triacetoxyborohydride (2.42 ml) was added.
g, 11.4 mmol) was added in small portions. After stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure. Saturated aqueous sodium hydrogen carbonate (150 ml) and ethyl acetate (1
50 ml) and ditert-butyl dicarbonate (1.0 g, 4.57 mmol) were added to 1
Stir for 5 hours. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1-2:
Purified in 1), 3-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl } -1,
1'-Biphenyl (1.79 g, 74%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.90 (19H, m), 3.76 (3H, s), 3.9
0-4.20 (1H, m), 4.43 (2H, brs), 4.57 (2H, s), 4.70 (2H,
s), 6.25 (1H, s), 6.75-6.87 (2H, m), 7.10-7.50 (9H, m),
7.60 (2H, d, J = 8.4Hz), 7.70-7.82 (1H, m), 8.53-8.62 (2
H, m). 2) 3-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl dihydrochloride 3-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (1.5
3 g, 2.41 mmol) in ethanol (10 ml) in concentrated hydrochloric acid (15 ml)
Was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, and the residue was triturated with ethanol-diethyl ether to give 3-
[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl}
-1,1'-Biphenyl dihydrochloride (1.52 g, 96%) was obtained as a colorless amorphous powder. Elemental analysis value C ₃₄ H ₃₈ N ₄ O ₂・ 2HCl ・ 1 / 2Et ₂ O ・ 1 / 2H ₂ O Calculated value: C, 66.15; H, 7.09; N, 8.57 Actual value: C, 66.00; H, ^{. 7.37; N, 8.53 1 H} -NMR (d 6 -DMSO) δ: 1.00-1.90 (8H, m), 2.10-2.30 (2H,
m), 2.90-3.15 (1H, m), 3.71 (3H, s), 4.20 (2H, brs), 4.
75 (4H, s), 6.83 (2H, d, J = 8.4Hz), 8.70-8.85 (2H, m), 9.
38 (2H, br, NH ₂ ⁺ ).

Example 106 3- (aminomethyl) -3 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-biphenyl dihydrochloride 1) 3- (tert-butoxycarbonylaminomethyl) -3 '-[((3
-Pyridylmethyl) {[4- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] -1,1'-biphenyl 3- (tert-butoxycarbonylaminomethyl) -3 '-{[(3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (5.0g,
4-Trifluoromethylphenylisocyanate (1.77 ml, 1.24 mmol) was added to a toluene (30 ml) solution of 12.4 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution is directly used for silica gel column chromatography (hexane: ethyl acetate = 2: 1-1:
Purified in 1), 3- (tert-butoxycarbonylaminomethyl) -3 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1 '-Biphenyl (6.56 g, 90%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s, Bu ^t ), 4.37 (2H, d, J = 5.6H
z), 4.62 (2H, s), 4.72 (2H, s), 5.050-5.20 (1H, br, NH),
6.69 (1H, s), 7.20-7.60 (13H, m), 7.74 (1H, d, J = 7.6Hz),
8.52- 8.64 (2H, m). 2) 3- (aminomethyl) -3 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1 '-Biphenyl dihydrochloride 3- (tert-butoxycarbonylaminomethyl) -3'-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1 '-Biphenyl (6.35g, 10.8
Concentrated hydrochloric acid (20 ml) was added to an ethanol (50 ml) solution of (mmol) and stirred at room temperature for 2 hours. The reaction solution was distilled off under reduced pressure, and ethanol-
Diethyl ether was added to make powder, and 3- (aminomethyl) -3 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl -Dihydrochloride (5.90g, 90%) was obtained as a colorless amorphous powder. Elemental analysis value C ₂₈ H ₂₅ F ₃ N ₄ O ・ 2HCl ・ 1 / 2Et ₂ O ・ 1 / 2H ₂ O, calculated value: C, 59.12; H, 5.46; N, 9.35 Found value: C, 58.89; H , 5.44; N, 9.48. ¹ H-NMR (d ₆ -DMSO) δ: 4.05-4.20 (2H, m), 4.85 (4H, s), 7.
31 (1H, d, J = 5.4Hz), 7.40-7.70 (8H, m), 7.75-8.00 (4H,
m), 8.37 (1H, d, J = 8.2Hz), 8.45-8.70 (3H, m, NH ₃ ⁺ ), 8.75
(1H, d, J = 5.6Hz), 8.81 (1H, s).

Example 107 3-[(Cyclohexylamino) methyl] -3 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'- Biphenyl dihydrochloride 1) 3-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -3 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} Amino) methyl] -1,
1'-biphenyl 3- (aminomethyl) -3 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]-
1,1'-biphenyl dihydrochloride (2.0 g, 3.80 mmol), cyclohexanone (1.96 ml, 38.0 mmol), 1,8-diazabicyclo [5.
4.0] Unde-7-sen (1.42ml, 9.5mmol), acetic acid (2.17ml, 3
After stirring a mixed solution of 8.0 mmol), sodium chloride (20 g) and methanol (30 ml) for 1 hour, sodium triacetoxyborohydride (2.41 g, 11.4 mmol) was added little by little. 3 at room temperature
After stirring for an hour, saturated aqueous sodium hydrogen carbonate (100 ml) and ethyl acetate (100 ml) were added, and ditert-butyl dicarbonate (1.98 g, 9.10 mmol) was added.
Stir for 15 hours. The ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate
= 5: 1-3: 1) and purified by 3-[(N-tert-butoxycarbonyl-
N-cyclohexylamino) methyl] -3 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl}
Amino) methyl] -1,1′-biphenyl (0.49 g, 19%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.80-1.80 (19H, m), 3.90-4.20 (1H,
m), 4.43 (2H, brs), 4.63 (2H, s), 4.74 (2H, s), 6.56 (1H,
s), 7.20-7.70 (12H, m), 7.70-7.83 (1H, m), 8.57-8.63
(2H, m). 2) 3-[(Cyclohexylamino) methyl] -3 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1 '-Biphenyl dihydrochloride 3-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -3'-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} Amino) methyl] -1,1'-
Concentrated hydrochloric acid (5 ml) was added to a solution of biphenyl (0.39 g, 0.58 mmol) in ethanol (10 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure, and the residue was triturated with ethanol-diethyl ether to give 3-[(cyclohexylamino) methyl] -3'-.
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride (0.30g, 79%) was obtained as an amorphous powder. It was Elemental analysis value C ₃₄ H ₃₅ F ₃ N ₄ O ・ 2HCl ・ 1 / 2H ₂ O Calculated value: C, 62.38; H, 5.85; N, 8.56 Actual value: C, 62.49; H, 6.15; N, 8.36 _{^{. 1 H-NMR (d 6}} -DMSO) δ: 1.00-1.90 (8H, m), 2.10-2.30 (2H,
m), 2.90-3.15 (1H, m), 4.22 (2H, brs), 4.86 (4H, s), 7.
32 (1H, d, J = 7.2Hz), 7.40-7.70 (6H, m), 7.80 (2H, d, J = 8.4
Hz), 7.89 (1H, dd, J = 8.0,5.6Hz), 8.00 (1H, s), 8.35 (1
H, d, J = 7.8Hz), 8.75 (1H, d, J = 5.0Hz), 8.82 (1H, s), 9.
25-9.45 (3H, m).

Example 108 3- (aminomethyl) -3 ′-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1′-biphenyl dihydrochloride 1 ) 3- (N-tert-butoxycarbonylaminomethyl) -3'-
{[[(4-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl 3- (N-tert-butoxycarbonylaminomethyl) -3 '-{[(3-
Pyridylmethyl) amino] methyl} -1,1'-biphenyl (5.0
g, 12.4 mmol) in toluene (30 ml) to which 4-methoxyphenylisocyanate (1.85 ml, 12.4 mmol) was added and stirred at room temperature for 2
Stir for hours. The reaction solution is directly purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-1: 5), and 3- (N-tert-butoxycarbonylaminomethyl) -3′-
{[[(4-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (6.14 g, 90%) was obtained as a colorless oil. _{^{1 H-NMR (CDCl 3)}} δ: 1.46 (9H, s, Bu t), 3.76 (3H, s), 4.38
(1H, d, J = 5.8Hz), 4.60 (2H, s), 4.70 (2H, s), 5.00-5.20
(1H, br, NH), 6.29 (1H, s), 6.80 (2H, d, J = 9.0Hz), 7.14 (2
H, d, J = 9.0Hz), 7.20-7.60 (9H, m), 7.70-7.80 (1H, m),
8.53-8.65 (2H, m). 2) 3- (aminomethyl) -3 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl Dihydrochloride 3- (N-tert-butoxycarbonylaminomethyl) -3 '-{[[(4
-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (5.8g, 10.5mmol) in ethanol (50ml) was added concentrated hydrochloric acid (20ml) at room temperature for 2 hours. It was stirred. The reaction solution was evaporated under reduced pressure, and ethanol-diethyl ether was added to obtain 3- (aminomethyl) -3 ′-{[[(4-
Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1′-biphenyl dihydrochloride (5.74 g, 92%) was obtained as a colorless amorphous powder. ¹ H-NMR (d ₆ -DMSO) δ: 3.71 (3H, s), 4.00-4.20 (2H, m), 4.
80 (4H, s), 6.83 (2H, d, J = 9.2Hz), 7.31 (1H, d, J = 7.4Hz),
7.35-7.70 (9H, m), 7.86 (1H, s), 7.93 (1H, dd, J = 8.0,5.8H
z), 8.39 (1H, d, J = 7.8Hz), 8.50-8.70 (3H, m, NH ₃ ⁺ ), 8.73
-8.85 (2H, m).

Example 109 3-[(Cyclohexylamino) methyl] -3 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl di Hydrochloride 1) 3-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -3 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1 , 1'-Biphenyl 3- (aminomethyl) -3 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl dihydrochloride (2.0 g, 3.81mmol), cyclohexanone
(1.97ml, 19.0mmol), 1,8-diazabicyclo [5.4.0] unde
After stirring a mixture of -7-cene (1.42 ml, 9.5 mmol), acetic acid (2.18 ml, 38.1 mmol), sodium chloride (20 g) and methanol (50 ml) for 1 hour, sodium triacetoxyborohydride (2 .
42 g, 11.4 mmol) was added in small portions. After stirring at room temperature for 3 hours,
Saturated aqueous sodium hydrogen carbonate (100 ml) and ethyl acetate (100 ml) were added, ditert-butyl dicarbonate (2.00 g, 9.14 mmol) was added, and the mixture was stirred for 15 hr. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-2: 1) to give 3-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -3 '-{[ [(4-Methoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1′-biphenyl (1.38 g, 74%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.90 (19H, m), 3.76 (3H, s), 3.9
0-4.20 (1H, m), 4.43 (2H, brs), 4.60 (2H, s), 4.71 (2H,
s), 6.24 (1H, s), 6.80 (2H, d, J = 8.8Hz), 7.14 (2H, d, J = 8.
8Hz), 7.20-7.60 (9H, m), 7.72-7.82 (1H, m), 8.55-8.65
(2H, m). 2) 3-[(Cyclohexylamino) methyl] -3 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl dihydrochloride 3-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -3 '-{[[(4-methoxyanilino) carbonyl] (3
-Pyridylmethyl) amino] methyl} -1,1'-biphenyl (1.0
8 g, 1.70 mmol) in ethanol (20 ml) in concentrated hydrochloric acid (10 ml)
Was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure, and the residue was triturated with ethanol-diethyl ether to give 3-[(cyclohexylamino) methyl] -3 '-{[[(4-methoxyanilino) carbonyl] (3-pyridylmethyl). Amino] methyl} -1,
1'-biphenyl dihydrochloride (1.0 g, 97%) was obtained as a colorless amorphous powder. Elemental analysis value C ₃₄ H ₃₈ N ₄ O ₂・ 2HCl ・ 1 / 2Et ₂ O ・ 1 / 2H ₂ O, calculated value: C, 66.15; H, 7.09; N, 8.57 Found value: C, 66.25; H, ^{. 7.29; N, 8.55 1 H} -NMR (d 6 -DMSO) δ: 1.00-1.90 (8H, m), 2.10-2.30 (2H,
m), 2.90-3.15 (1H, m), 3.71 (3H, s), 4.15-4.30 (2H, m),
4.80 (2H, s), 6.83 (2H, d, J = 8.8Hz), 7.25-7.70 (9H, m),
7.90-8.00 (1H, m), 8.01 (1H, s), 8.39 (1H, d, J = 8.4Hz),
8.75-8.90 (3H, m), 9.35-9.55 (2H, m, NH ₂ ⁺ ).

Example 110 4-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbothioyl} amino) methyl] -1,1'- Biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbothioyl} Amino) methyl] -1,1'-biphenyl 4-[(tert-butoxycarbonyl) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbothioyl} amino) methyl ] -1,1'-Biphenyl (0.86g, 1.4
2 mmol) in methanol (10 ml) and concentrated hydrochloric acid (10 m
l) was added dropwise, and the mixture was stirred at room temperature for 0.5 hour. The reaction solution was concentrated under reduced pressure to obtain a pale yellow amorphous powder. Subsequently, the hydrochloride salt was dissolved in methanol (10 ml) and treated with sodium chloride.
(3g), cyclohexanone (1.5ml, 14.2mmol), triethylamine (0.6ml, 4.26mmol), acetic acid (0.82ml, 14.2mm)
ol) was added in that order, and the mixture was stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (1.5g, 7.1mmol)
Was added little by little, and the mixture was stirred at room temperature for 2 hours. After adding saturated aqueous sodium hydrogen carbonate (20 ml) and ethyl acetate (20 ml), dicarbonate dicarbonate was added.
-tert-Butyl (1.6 g, 7.1 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr. After the reaction was completed, the aqueous layer was extracted with ethyl acetate (30 ml x 3), and the organic layer was dried over anhydrous magnesium sulfate,
It was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 2: 1 to 1: 1) and 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3- Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbothioyl} amino) methyl] -1,1′-biphenyl (0.70 g, 72%) was obtained as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.0-1.80 (10H, m) 1.40
(9H, s) 4.0-4.2 (1H, br) 4.42 (2H, s) 4.91 (2H, s)
5.32 (2H, s) 7.31-7.67 (13H, m) 7.88 (1H, d, J = 5.8
Hz) 8.57-8.62 (2H, m). 2) 4-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbothioyl} amino) methyl ] -1,1'-Biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl ) Anilino] carbothioyl} amino) methyl] -1,
1'-biphenyl (0.65g, 0.94mmol) in methanol (10ml)
Concentrated hydrochloric acid (10 ml) was added dropwise to the solution. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue,
Powder, filter with a glass filter, wash well with diethyl ether, and then 4-[(cyclohexylamino) methyl]-
4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbothioyl} amino) methyl] -1,1'-biphenyl dihydrochloride (0.50g, 80%) is non-crystalline Obtained as a powder. Elemental analysis _{C 34 H 35 N 4 F 3} S · 2HCl · H 2 O Calculated: C, 60.08; H, 5.78 ; N, 8.24 Found:. C, 60.21; H, 5.95; N, 8.11 1 H -NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 2.0-2.2 (2
H, m) 2.96 (1H, br) 4.17 (2H, s) 5.30 (2H, s) 5.39
(2H, s) 7.41 (2H, d, J = 8.0Hz) 7.66-7.73 (10H, m)
7.99-8.06 (1H, m) 8.49 (1H, d, J = 8.4Hz) 8.82 (1H,
d, J = 4.8Hz) 8.87 (1H, s) 9.45 (2H, br) 10.26 (1H,
s)

Example 111 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbothioyl] (3-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbothioyl] ( 3-Pyridylmethyl) amino] methyl} -1,1'-biphenyl 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1 '
-Biphenyl (0.56g, 1.15mmol) in acetonitrile (10
4-methoxyphenylisothiocyanate (0.
18 ml, 1.27 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution, the residue is subjected to silica gel column chromatography.
Purify with (hexane: acetone = 2: 1-1: 1) and then use 4-[(N-
tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbothioyl] (3-
Pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.7
6 g, 100%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.0-1.8 (10H, m) 1.40 (9H, s)
3.77 (3H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.89 (2
H, s) 5.30 (2H, s) 6.79-6.87 (2H, m) 7.06-7.13 (2
H, m) 7.26-7.34 (6H, m) 7.52 (2H, d, J = 8.4Hz) 7.62
(2H, d, J = 8.0Hz) 7.88 (1H, dt, J = 1.6, 7.8Hz) 8.54
(1H, d, J = 1.4Hz) 8.56-8.58 (1H, m) 2) 4-[(cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbothioyl] (3-pyridylmethyl ) Amino] methyl} -1,1'-biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbothioyl] Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of (3-pyridylmethyl) amino] methyl} -1,1′-biphenyl (0.76 g, 1.15 mmol) in ethanol (10 ml). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder,
Filtered with a glass filter, washed well with diethyl ether, and then 4-[(cyclohexylamino) methyl] -4 '-{[[(4-methoxyanilino) carbothioyl] (3-pyridylmethyl) amino] methyl} -1, 1'-biphenyl dihydrochloride (0.64g, 89%)
Was obtained as an amorphous powder. Elemental analysis calculated as C ₃₄ H ₃₈ N ₄ OS ・ 2HCl ・ 1.5H ₂ O: C, 62.76; H, 6.66; N, 8.61 Found: C, 62.50; H, 6.36; N, 8.44. ¹ H- NMR (d ₆ -DMSO) δ: 1.0-1.8 (8H, m) 2.0-2.2 (2H,
m) 2.97 (1H, br) 3.74 (3H, s) 4.17 (2H, s) 5.19 (2
H, s) 5.32 (2H, s) 6.88 (2H, d, J = 8.8Hz) 7.17 (2H,
d, J = 8.8Hz) 7.39 (2H, d, J = 8.0Hz) 7.70-7.72 (6H,
m) 7.95-8.0 (1H, m) 8.41 (1H, d, J = 8.6Hz) 8.78 (1H,
s) 8.81 (1H, s) 9.42 (2H, br) 9.65 (1H, s)

Example 112 4- (Cyclohexylamino) -4 '-[((3-pyridylmethyl)
{[4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride 1) 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) -4 '-[ ((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4- (N-tert-butoxycarbonylamino) -4 '-[((3 -Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl (0.8g, 1.43mmol)
Was dissolved in methanol (10 ml), concentrated hydrochloric acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was concentrated under reduced pressure and azeotroped with toluene to obtain a colorless amorphous powder.
Subsequently, the hydrochloride was dissolved in methanol (10 ml),
Sodium chloride (3g), cyclohexanone (0.74ml, 7.1
5mmol), triethylamine (0.5ml, 3.6mmol), acetic acid
(0.8 ml, 7.15 mmol) were added in that order, and the mixture was stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride
(1.5 g, 7.15 mmol) was added little by little, and the mixture was stirred at room temperature for 17 hours. After disappearance of the raw materials, saturated aqueous sodium hydrogen carbonate (30 ml) was added, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 6), and 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) -4 '-[((3-pyridylmethyl) {[4 -(Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1′-biphenyl (0.58 g, 78%) was obtained as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.15-1.43 (4H, m) 1.65-
1.80 (4H, m) 2.0-2.2 (2H, m) 3.30 (1H, m) 4.54 (2
H, s) 4.72 (2H, s) 6.58 (1H, s) 6.65 (2H, d, J = 8.8
Hz) 7.26-7.58 (12H, m) 7.74 (1H, d, J = 8.0Hz) 8.56-
8.58 (2H, m). 2) 4- (Cyclohexylamino) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'- Biphenyl dihydrochloride 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]- Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of 1,1'-biphenyl (0.57 g, 1.02 mmol) in methanol (10 ml). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to form a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then 4- (cyclohexylamino) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl ) Anilino] carbonyl} amino) methyl] -1,1′-biphenyl dihydrochloride (0.61 g,
95%) was obtained as an amorphous powder. Elemental analysis value C ₃₃ H ₃₃ N ₄ OF ₃・ 2HCl ・ 0.5H ₂ O Calculated value: C, 61.88; H, 5.66; N, 8.75 Measured value: C, 62.13; H, 6.00; N, 8.79. ¹ H-NMR (d ₆ -DMSO) δ: 1.20-2.0 (10H, m) 3.40 (1H,
br) 4.83 (4H, s) 7.39 (2H, d, J = 8.2Hz) 7.58-7.84 (1
3H, m) 8.00 (1H, dd, J = 5.6, 8.2Hz) 8.47 (1H, d, J =
7.6Hz) 8.30-8.83 (2H, m) 9.40 (1H, s)

Example 113 4-Amino-4 ′-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1′-biphenyl dihydrochloride 1 ) 4- (N-tert-butoxycarbonylamino) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl 4- tert-Butoxycarbonylamino-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.9g, 2.4mmol)
4-Trifluoromethylphenylisocyanate (0.37 ml, 2.6 mmol) was added to a methylene chloride (15 ml) solution of and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated, the precipitated solid was purified by recrystallization to give 4- (N-tert-butoxycarbonylamino) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino]. Carbonyl} amino) methyl] -1,1′-biphenyl (1.38 g, 100%.) Was obtained as colorless crystals. Melting point 119-122 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s) 4.57 (2H, s) 4.71
(2H, s) 6.60 (2H, s) 7.26-7.61 (13H, m) 7.74 (1H,
d, J = 7.8Hz) 8.58 (2H, m). 2) 4-amino-4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1 , 1'-
Biphenyl dihydrochloride 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]- Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of 1,1'-biphenyl (0.49 g, 0.87 mmol) in methanol (10 ml). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to make a powder, which was collected by filtration with a glass filter and washed well with diethyl ether. 4-amino-4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] Carbonyl} amino) methyl] -1,1'-biphenyl dihydrochloride (0.40 g, 86%) was obtained as an amorphous powder. Elemental analysis value, calculated as C ₂₇ H ₂₃ F ₃ N ₄ O ・ 2HCl ・ 0.5H ₂ O: C, 58.07; H, 4.69; N, 10.03 Found: C, 58.34; H, 4.86; N, 10.14. ¹ H-NMR (d ₆ -DMSO) δ (ppm): 4.82 (4H, s) 7.36-7.81
(16H, m) 7.97-8.00 (1H, m) 8.43 (1H, d, J = 7.2Hz)
8.81 (2H, s) 9.38 (1H, s)

Example 114 4-[(Cyclohexylamino) methyl] -4 '-{[{[4- (cyclohexylmethoxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl Dihydrochloride 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (cyclohexylmethoxy) anilino] carbonyl} (3-pyridylmethyl) amino] Methyl}
-1,1'-Biphenyl 4-cyclohexylmethoxybenzoic acid (0.34g, 1.44mmol)
Triethylamine in 10 ml of acetonitrile
(0.31ml, 2.16mmol) and diphenylphosphoric acid azide (0.34m
1, 1.58 mmol) was added at room temperature, and the mixture was heated under reflux for 1 hour. Then, the temperature was returned to room temperature, and 4-[(N-cyclohexyl-N-tert-butoxycarbonyl) aminomethyl] -4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.50g, 1.03 mmol)
Was added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane: acetone = 3: 2).
Purified with 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (cyclohexylmethoxy) anilino] carbonyl} (3-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl (0.65g, 88%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-2.0 (21H, m) 1.39 (9H,
s) 3.68 (2H, d, J = 6.2Hz) 4.0-4.2 (1H, br) 4.41 (2
H, s) 4.55 (2H, s) 4.68 (2H, s) 6.29 (1H, s) 6.78
(2H, d, J = 9.2Hz) 7.12 (2H, d, J = 8.8Hz) 7.26-7.35
(5H, m) 7.52 (2H, d, J = 8.4Hz) 7.60 (2H, d, J = 8.4Hz)
7.74 (1H, dt, J = 1.8, 7.8Hz) 7.54 (1H, d, J = 1.6Hz)
8.6 (1H, d, J = 1.6Hz). 2) 4-[(Cyclohexylamino) methyl] -4 '-{[{[4- (cyclohexylmethoxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl } -1,1'-Biphenyl dihydrochloride 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (cyclohexylmethoxy) anilino] carbonyl} (3 -Pyridylmethyl) amino] methyl} -1,
1'-biphenyl (0.54g, 0.75mmol) in ethanol
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise to (5 ml), and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure and the resulting amorphous was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-[(cyclohexylamino) methyl] -4'-
{[{[4- (cyclohexylmethoxy) anilino] carbonyl}
(3-Pyridylmethyl) amino] methyl} -1,1'-biphenyl
The dihydrochloride salt (0.43g, 83%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₄₀ H ₄₈ N ₄ O ₂・ 2HCl ・ H ₂ O: C, 67.88; H, 7.41; N, 7.92 Actual value: C, 68.14; H, 7.66; N, 7.85. ¹ H- NMR (CD ₃ OD) δ (ppm) 1.0-1.9 (19H, m) 2.0-2.2 (2
H, m) 2.96 (1H, br) 3.71 (2H, d, J = 6.4Hz) 4.17 (2
H, s) 4.76 (4H, s) 6.82 (2H, d, J = 9.2Hz) 7.37 (4H,
d, J = 8.8Hz) 7.66-7.70 (6H, m) 7.95 (1H, dd, J = 5.4,
8.0Hz) 8.38 (1H, d, J = 8.0Hz) 8.74 (1H, s) 8.79 (2
H, s)

Example 115 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-isobutoxyanilino) carbonyl] (3-pyridylmethyl) amino]
Methyl} -1,1'-biphenyl 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-isobutoxyanilino) carbonyl] (3-pyridyl Methyl) amino] methyl} -1,1'-biphenyl 4-isobutoxybenzoic acid (0.28g, 1.44mmol) in acetonitrile suspension (10ml) in triethylamine (0.31ml, 2.
16mmol) and diphenylphosphoric acid azide (0.34ml, 1.58mmo
l) was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 4-[(N-cyclohexyl-N-tert-butoxycarbonyl) aminomethyl] -4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.50g, 1.03 mmol) was added and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, hexane: acetone = 3: 2).
[(N-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[[(4-isobutoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl (0.65 g, 88%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.97 (3H, s) 1.01 (3H, s)
1.2-1.8 (10H, m) 1.39 (9H, s) 1.95-2.05 (1H, m) 3.
65 (2H, d, J = 6.6Hz) 4.0-4.2 (1H, br) 4.41 (2H, s)
4.56 (2H, s) 4.69 (2H, s) 6.28 (1H, s) 6.79 (2H,
d, J = 8.8Hz) 7.13 (2H, d, J = 8.8Hz) 7.28-7.35 (5H,
m) 7.52 (2H, d, J = 8.0Hz) 7.61 (2H, d, J = 8.2Hz) 7.7
4 (1H, d, J = 7.8Hz) 8.54 (1H, d, J = 1.6Hz) 8.56 (1H,
d, J = 1.6Hz). 2) 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-isobutoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1,1 '-Biphenyl 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4'-{[[(4-isobutoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} -1 4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of 1,1′-biphenyl (0.49 g, 0.72 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and the resulting amorphous was collected by filtration, washed with ether, and dried under reduced pressure. 4-[(Cyclohexylamino) methyl] -4 '-{[[(4-isobutoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl}-
1,1'-Biphenyl (0.37g, 79%) was obtained as a colorless amorphous powder. Elemental analysis C ₃₇ H ₄₄ N ₄ O ₂・ 2HCl ・ 0.5H ₂ O ・ 0.5Et ₂ O Calculated: C, 67.24; H, 6.00; N, 9.80 Found: C, 67.50; H, 6.20; N , 9.53 ¹ H-NMR (CD ₃ OD) δ (ppm) 0.95 (3H, s) 0.98 (3H, s)
1.0-1.8 (8H, m) 1.9-2.1 (1H, m) 2.1-2.2 (2H, m) 2.9
7 (1H, br) 3.68 (2H, d, J = 6.4Hz) 4.17 (2H, s) 4.76
(4H, s) 6.82 (2H, d, J = 9.2Hz) 7.38 (4H, d, J = 9.2H)
z) 7.65-7.77 (6H, m) 7.95 (1H, dd, J = 6.0, 8.2Hz)
8.39 (1H, d, J = 8.4Hz) 8.75-8.79 (3H, m) 9.38 (2H, b
r)

Example 116 4-[(Cyclohexylamino) methyl] -4 '-{[{[4- (2-furylmethoxy) anilino] carbonyl} (3-pyridylmethyl)
Amino] methyl} -1,1'-biphenyl 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (2-furylmethoxy) anilino] carbonyl } (3-Pyridylmethyl) amino] methyl} -1,
1'-biphenyl 4- (2-furylmethoxy) benzoic acid (0.32g, 1.44mmol) in acetonitrile suspension (10ml) with triethylamine (0.
31ml, 2.16mmol) and diphenylphosphoric acid azide (0.34ml,
1.58 mmol) was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 4-[(N-cyclohexyl-N-tert-butoxycarbonyl) aminomethyl] -4 '-[(3-pyridylmethyl) was used.
Aminomethyl] -1,1'-biphenyl (0.50g, 1.03mmol) was added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure,
Silica gel column chromatography (hexane)
: Ethyl acetate = 1: 1-Hexane: Acetone = 3: 2-
1: 1) and purified by 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (2-furylmethoxy) anilino] carbonyl} (3-pyridyl Methyl) amino] methyl} -1,1'-biphenyl (0.56g, 78%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.56 (2H, s) 4.69
(2H, s) 4.94 (2H, s) 6.32-6.40 (3H, m) 6.87 (2H, s)
d, J = 8.8Hz) 7.16 (2H, d, J = 9.0Hz) 7.26-7.35 (5H,
m) 7.42 (1H, d, J = 1.2Hz) 7.52 (2H, d, J = 8.4Hz) 7.6
1 (2H, d, J = 8.0Hz) 7.74 (1H, d, J = 8.2Hz) 8.55 (1H,
s) 8.57 (1H, s). 2) 4-[(cyclohexylamino) methyl] -4 '-{[{[4- (2-furylmethoxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-{[{[4- (2-furylmethoxy) anilino] carbonyl} (3-pyridylmethyl ) Amino] methyl} -1,1'-biphenyl (0.22g, 0.32mmol) in dichloromethane (5
2,6-lutidine (0.23 ml, 1.97 mmol) was added to (ml), tert-butyldimethylsilyl trifluoromethanesulfonate (0.44 ml, 1.92 mmol) was added dropwise under ice cooling, and the mixture was stirred under ice cooling for 1 hour. Saturated aqueous sodium hydrogen carbonate was added dropwise to terminate the reaction, and the mixture was diluted with ethyl acetate. The organic layer was separated and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 ml) and tetra-n-butylammonium fluoride (1M in tetrahydrofuran) (0.96 ml, 0.96 mmol) under ice cooling.
Was added dropwise and stirred for 10 minutes. After diluting with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1-10: 1) to give 4-[(cyclohexylamino) methyl] -4 '-{[{[4- (2-furylmethoxy) anilino]. Carbonyl} (3-pyridylmethyl) amino] methyl} -1,1′-biphenyl (0.15 g, 78%) was obtained as colorless crystals. Mp 130-133 ° C. Elemental analysis _{C 38 H 40 N 4 O 3} · 0.5H 2 O Calculated: C, 74.85; H, 6.78 ; N, 9.19 Found: C, 75.06; H, 6.95 ; N, 9.21 _{^{. 1 H-NMR (CDCl 3}} ) δ (ppm) 1.0-1.4 (3H, m) 1.5-1.8 (3
H, m) 1.7-1.9 (2H, m) 2.0-2.2 (2H, br) 2.80 (1H,
s) 3.92 (2H, s) 4.50 (2H, s) 4.59 (2H, s) 4.93 (2H,
s) 6.34-6.40 (2H, m) 6.54 (1H, s) 6.86 (2H, d, J =
8.8Hz) 7.16 (2H, d, J = 8.8Hz) 7.22-7.31 (4H, m) 7.42
-7.46 (3H, m) 7.51-7.62 (4H, m) 7.71 (1H, d, J = 8.4
Hz) 8.45 (1H, s) 8.52 (1H, d, J = 3.6Hz)

Example 117 4-[(Cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (2-thienylmethoxy) anilino] carbonyl} amino) methyl] -1,1' -Biphenyl 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (2-thienylmethoxy) anilino] carbonyl} amino) Methyl] -1,
1'-Biphenyl 4- (2-thienylmethoxy) benzoic acid (0.35 g, 1.44 mmol) in acetonitrile (10 ml) in triethylamine (0.
31ml, 2.16mmol) and diphenylphosphoric acid azide (0.34ml,
1.58 mmol) was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[(3-pyridylmethyl) was used.
Aminomethyl] -1,1'-biphenyl (0.50g, 1.03mmol) was added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure,
Silica gel column chromatography (hexane)
: Ethyl acetate = 1: 1, Hexane: Acetone = 3: 2 −
1: 1), 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl)
{[4- (2-Thienylmethoxy) anilino] carbonyl} amino) methyl] -1,1′-biphenyl (0.57 g, 77%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.55 (2H, s) 4.68
(2H, s) 5.16 (2H, s) 6.34 (1H, s) 6.87 (2H, d, J =
8.8Hz) 6.97 (1H, dd, J = 3.2, 4.8Hz) 7.07 (1H, d, J =
3.0Hz) 7.15 (2H, d, J = 8.8Hz) 7.28-7.34 (6H, m) 7.52
(2H, d, J = 8.6Hz) 7.61 (2H, d, J = 8.0Hz) 7.74 (1H,
d, J = 8.0Hz) 8.56 (2H, s). 2) 4-[(cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (2-thienylmethoxy) anilino] carbonyl } Amino) methyl] -1,1'-biphenyl 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (2-thienyl Methoxy) anilino] carbonyl} amino) methyl] -1,1'-
Biphenyl (0.30g, 0.42mmol) in dichloromethane
2,6-lutidine (0.29 ml, 2.50 mmol) was added to (5 ml),
Tert-Butyldimethylsilyltrifluoromethanesulfonate (0.58 ml, 2.53 mmol) was added dropwise under ice cooling, and the mixture was stirred under ice cooling for 1 hour. Saturated aqueous sodium hydrogen carbonate was added dropwise to terminate the reaction, and the mixture was diluted with ethyl acetate. The organic layer was separated and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 ml), tetra-n-butylammonium fluoride (1M in tetrahydrofuran) (1.26 ml, 1.26 mmol) was added dropwise under ice cooling, and the mixture was stirred for 10 minutes. After diluting with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1-10: 1) and 4-[(cyclohexylamino) methyl] -4 '-[((3-pyridylmethyl) {[4- (2 -Thienylmethoxy) anilino] carbonyl} amino) methyl] -1,1'-
Biphenyl (0.19 g, 73%) was obtained as colorless crystals. Melting point 127-143 ℃ Elemental analysis C ₃₈ H ₄₀ F ₃ N ₄ O ₂ S ・ Calculated as 0.6H ₂ O: C, 72.72; H, 6.62; N, 8.93 Found: C, 72.48; H, 6.52; N, 8.89. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.4 (5H, m) 1.5-1.7 (1
H, m) 1.7-1.8 (2H, m) 1.8-2.0 (2H, m) 2.56 (1H, b
r) 3.86 (2H, s) 4.54 (2H, s) 4.66 (2H, s) 5.15 (2H,
s) 6.35 (1H, s) 6.86 (2H, d, J = 9.0Hz) 6.97 (1H, d
d, J = 3.2, 4.6Hz) 7.06-7.07 (1H, m) 7.15 (2H, d, J =
9.2Hz) 7.26-7.33 (4H, m) 7.43 (2H, d, J = 8.4Hz) 7.5
2-7.59 (4H, m) 7.73 (1H, d, J = 8.0Hz) 8.54-8.55 (2
H, m)

Example 118 4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (2
-Frylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl 1) 4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] ( 2-furylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'
Triphenylamine (0.93 ml, 6.64) was added to an acetonitrile suspension (30 ml) of -biphenyl p-phenylbenzoic acid (0.88 g, 4.43 mmol).
mmol) and diphenylphosphoric acid azide (1.05 ml, 4.87 mmol)
Was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 4-[(N-cyclohexyl-N-tert-butoxycarbonyl) aminomethyl] -4 '-{[3- (2-furylmethyl)] aminomethyl} -1,1'-biphenyl ( 1.5 g, 3.16 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-3: 1) to give 4-{[[[[[1,1 ' -Biphenyl] -4-ylamino) carbonyl] (2-furylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-biphenyl (1.97g , 92
%) Was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.56 (2H, s) 4.66
(2H, s) 6.28 (1H, d, J = 3.4Hz) 6.36 (1H, dd, J = 1.8,
3.4Hz) 6.82 (1H, s) 7.25-7.62 (18H, m). 2) 4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (2-furylmethyl) amino] methyl } -4 '-[(Cyclohexylamino) methyl] -1,1'-biphenyl 4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (2
-Furylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -1,1'-biphenyl (1.92g, 2.87mmol) in dichloromethane
Trimethylsilyl trifluoromethanesulfonate (0.78 ml, 4.31 mmol) was added dropwise to (20 ml) under ice cooling, and the mixture was stirred at 0 ° C for 1 hr. Saturated aqueous sodium hydrogen carbonate was added dropwise to terminate the reaction, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform, chloroform: methanol = 30: 1) and then purified by recrystallization (hexane-ethyl acetate) to give 4-{[[([1,1'-biphenyl] -4. -Ylamino) carbonyl] (2-furylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-
Biphenyl (1.23g, 75%) was obtained as a colorless solid. Mp 203-211 ° C. Elemental analysis _{C 38 H 39 N 3 O 2} · 0.5H 2 O Calculated: C, 78.86; H, 6.97 ; N, 7.26 Found: C, 78.82; H, 6.78 ; N, 7.47 _{^{. 1 H-NMR (CDCl 3}} ) δ (ppm) 1.0-1.4 (5H, m) 1.60 (2H,
m) 1.7-1.8 (2H, m) 1.8-2.0 (2H, m)
2.50 (1H, m) 3.86 (2H, s)
4.56 (2H, s) 4.67 (2H, s)
s) 6.28 (1H, d, J = 3.2Hz)
6.36 (1H, dd, J = 1.8, 3.4H
z) 6.79 (1H, s) 7.30-7.61
(18H, m)

Example 119 4-[(Cyclohexylamino) methyl] -4 '-({(2-furylmethyl) [(4-phenoxyanilino) carbonyl] amino} methyl) -1,1'-biphenyl 1) 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({(2-furylmethyl) [(4-phenoxyanilino) carbonyl] amino} methyl) -1,1'- Biphenyl p-phenoxybenzoic acid (0.95g, 4.42mmol) in acetonitrile (30ml) in triethylamine (0.93ml, 6.
64mmol) and diphenylphosphoric acid azide (1.05ml, 4.87mmo
l) was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 4-[(N-cyclohexyl-N-tert-butoxycarbonyl) aminomethyl] -4 '-{[3- (2-furylmethyl)] aminomethyl} -1,1'-biphenyl ( 1.5 g, 3.16 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-3: 1) to give 4-[(N-tert-butoxycarbonyl- N-cyclohexylamino) methyl] -4 '-({(2-furylmethyl) [(4-phenoxyanilino) carbonyl] amino} methyl) -1,1'-biphenyl (1.95g, 90%) Obtained as a crystalline powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.40 (2H, s) 4.53 (2H, s) 4.64
(2H, s) 6.25 (1H, d, J = 3.2Hz) 6.33 (1H, dd, J = 0.8,
1.8Hz) 6.80 (1H, s) 6.91-7.08 (5H, m) 7.23-7.41
(9H, m) 7.50-7.60 (4H, m). 2) 4-[(cyclohexylamino) methyl] -4 '-({(2-furylmethyl) [(4-phenoxyanilino) carbonyl] amino} methyl ) -1,1'-Biphenyl 4-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] -4 '-({(2-furylmethyl) [(4-phenoxyanilino) carbonyl] amino} Methyl) -1,1'-biphenyl (1.
To a dichloromethane solution (20 ml) of 92 g, 2.80 mmol) was added trimethylsilyltrifluoromethanesulfonate (0.76 ml, 4.2 mmol) dropwise under ice cooling, and the mixture was stirred at 0 ° C for 1 hour. Saturated aqueous sodium hydrogen carbonate was added dropwise to terminate the reaction, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform, chloroform: methanol = 30: 1) and then purified by recrystallization (hexane-ethyl acetate) to give 4-[(cyclohexylamino) methyl] -4'-.
({(2-Furylmethyl) [(4-phenoxyanilino) carbonyl] amino} methyl) -1,1′-biphenyl (1.25 g, 76%) was obtained as a colorless solid. Melting point 153-154 ° C Elemental analysis C ₃₈ H ₃₉ N ₃ O ₃ H ₂ O Calculated: C, 75.60; H, 6.84; N, 6.96 Found: C, 75.83; H, 6.58; N, 6.99. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.4 (5H, m) 1.63 (1H,
s) 1.7-1.8 (2H, m) 1.8-2.0 (2H, m) 2.52 (1H, m) 3.
85 (2H, s) 4.54 (2H, s) 4.65 (2H, s) 6.27 (1H, d,
J = 3.2Hz) 6.36 (1H, dd, J = 1.8, 2.8Hz) 6.69 (1H, s)
6.91-7.09 (5H, m) 7.24-7.43 (9H, m) 7.53-7.60 (4H,
m).

Example 120 N- [4 ′-(N-cyclohexyl) aminomethylbiphenyl-4-
Il] methyl-N- (3-pyridyl) methyl-4-trifluoromethylbenzamide dihydrochloride 1) N- [4 '-(N-tert-butoxycarbonyl-N-cyclohexyl) aminomethylbiphenyl-4-yl ] Methyl-N- (3-pyridyl) methyl-4-trifluoromethylbenzamide 4'-
(N-tert-butoxycarbonyl-N-cyclohexyl) aminomethyl-N- (3-pyridyl) methylbiphenyl-4-methylamine (0.90 g, 1.85 mmol) and ethyl acetate (30 ml) -saturated sodium bicarbonate water (3
(0 ml) to the mixed solution 4-trifluoromethylbenzoyl chloride
(0.33 ml, 2.22 mmol) was added and the mixture was stirred at room temperature for 3 hours. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 2), and N- [4 '
-(N-tert-Butoxycarbonyl-N-cyclohexyl) aminomethylbiphenyl-4-yl] methyl-N- (3-pyridyl) methyl-4-trifluoromethylbenzamide (0.96g, 79%)
Was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 0.80-1.85 (19H, m), 3.90-4.20 (1H,
m), 4.42 (4H, s), 4.75 (2H, s), 4.75 (2H, s), 7.15-7.45
(6H, m), 7.50-7.80 (8H, m), 8.35-8.65 (2H, m). 2) N- [4 '-(N-cyclohexyl) aminomethylbiphenyl
-4-yl] methyl-N- (3-pyridyl) methyl-4-trifluoromethylbenzamide dihydrochloride N- [4 '-(N-tert-butoxycarbonyl-N-cyclohexyl)
Aminomethylbiphenyl-4-yl] methyl-N- (3-pyridyl) methyl-4-trifluoromethylbenzamide (0.86g,
Concentrated hydrochloric acid (10 ml) was added to a solution of 1.31 mmol) in methanol (20 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether) to give N- [4 '-(N-cyclohexyl) aminomethylbiphenyl-4-yl] methyl-
N- (3-pyridyl) methyl-4-trifluoromethylbenzamide dihydrochloride (0.80 g, 94%) was obtained as crystals. Mp as 187-191 ° C. Elemental analysis _{C 34 H 34 F 3 N 3} O · 2HCl · H 2 O, Calculated: C, 62.96; H, 5.91 ; N, 6.48 Found: C, 63.20; H, 5.82 ; N, 6.42. ¹ H-NMR (d ₆ -DMSO) δ: 1.00-1.90 (8H, m), 2.07-2.28 (2H,
m), 2.90-3.10 (1H, m), 7.23-7.52 (2H, m), 4.18 (2H, br
s), 4.62 (2H, s), 4.65-4.85 (1H, m), 4.82 (2H, s), 7.23-
7.52 (2H, m), 7.60-8.00 (11H, m), 8.10-8.55 (1H, m), 8.6
0-8.95 (2H, m), 8.32 (2H, brs, NH ₂ ⁺ ).

Example 121 N-({4 ′-[(cyclohexylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) -4-methoxy-N- (3-pyridylmethyl) benzamide Dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-4-Methoxy-N- (3-pyridylmethyl) benzamide 4- (Nt
ert-Butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.61g, 1.26mmol) in acetonitrile (10ml)
To the mixture were added triethylamine (0.53 ml, 3.8 mmol) and p-methoxybenzoyl chloride (0.33 g, 1.93 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-hexane: acetone = 1: 1), and N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl ] [1,
1'-Biphenyl] -4-yl} methyl) -4-methoxy-N- (3-pyridylmethyl) benzamide (0.77g, 99%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 3.81 (3H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.59
(2H, s) 4.65 (2H, s) 6.90 (2H, d, J = 8.8Hz) 7.31 (4
H, m) 7.47-7.62 (6H, m) 8.47 (1H, s) 8.56 (1H, dd,
J = 1.4, 4.6Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-methoxy-N- (3-pyridyl Methyl) benzamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4
-Methoxy-N- (3-pyridylmethyl) benzamide (0.60g,
To a solution of 0.97 mmol) in ethyl acetate (3 ml) was added dropwise 4N hydrogen chloride-ethyl acetate (7 ml), and the mixture was stirred at room temperature for 30 minutes.
After the solvent was concentrated under reduced pressure, diethyl ether was added to give a powder, which was collected by filtration and dried under reduced pressure. N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl}
Methyl) -4-methoxy-N- (3-pyridylmethyl) benzamide dihydrochloride (0.31 g, 84%) was obtained as a colorless amorphous powder. Elemental analysis _{C 35 H 34 N 3 OF 3} · 2HCl · 0.5H 2 O Calculated: C, 67.88; H, 6.70 ; N, 6.98 Found:. C, 67.72; H, 6.80; N, 6.66 1 H -NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 3.78 (3H, s) 4.17 (2H, s) 4.
72 (2H, s) 4.76 (2H, s) 6.09 (1H, d, J = 8.2Hz) 7.00
(2H, d, J = 8.8Hz) 7.33 (2H, d, J = 7.4Hz) 7.53 (2H,
d, J = 8.0Hz) 7.66-7.72 (6H, m) 7.94-8.01 (1H, m) 8.
45 (1H, s) 8.80 (1H, s) 8.83 (1H, s) 9.45 (2H, s)

Example 122 N-({4 '-[(hexylamino) methyl] [1,1'-biphenyl] -4
-Yl} methyl) -N- (3-pyridylmethyl) [1,1'-biphenyl] -4-carboxamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N- Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (3-pyridylmethyl) [1,1'-biphenyl] -4-carboxamide 4-phenylbenzoic acid (0.24g, 1.26mmol) in acetonitrile suspension (10ml) in 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide hydrochloride (0.42g, 2.16mmol), 1-
Hydroxybenzotriazole monohydrate (0.33g, 2.16m
mol) was added and the solution was stirred for 10 minutes, then 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4'-
[(3-Pyridylmethyl) aminomethyl] -1,1'-biphenyl
(0.70 g, 1.44 mmol) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane: acetone = 3: 2), and N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl ] [1,1'-biphenyl]
-4-yl} methyl) -N- (3-pyridylmethyl) [1,1'-biphenyl] -4-carboxamide (0.49g, 61%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.54 (2H, s) 4.75
(2H, s) 7.29-7.66 (19H, m) 8.53 (1H, s) 8.57 (1H,
dd, J = 1.6, 4.8Hz). 2) N-({4 '-[(hexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [1,1'-Biphenyl] -4-carboxamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4- Ill} methyl) -N
-(3-Pyridylmethyl) [1,1'-biphenyl] -4-carboxamide (0.35g, 0.526mmol) in ethanol solution (5ml)
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure to give a powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure.
N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [1,1'-biphenyl] -4-carboxamide・ Dihydrochloride (0.32g, 95%)
Was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₉ H ₃₉ N ₃ O ・ 2HCl ・ H ₂ O: C, 71.33; H, 6.60; N, 6.40 Measured value: C, 71.71; H, 6.76; N, 6.37. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.98 (1H, br) 4.18 (2H, s) 4.72 (2H, s) 4.
78 (2H, s) 7.35-7.52 (11H, m) 7.67-7.79 (6H, m) 7.9
5 (1H, br) 8.48 (1H, br) 8.78 (1H, d, J = 5.2Hz) 8.8
5 (1H, s) 9.33 (2H, s)

Example 123 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-phenoxy-N- (3-pyridylmethyl) benzamide Dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
4-phenoxy-N- (3-pyridylmethyl) benzamide 4-phenoxybenzoic acid (0.26g, 1.21mmol) in acetonitrile suspension (10ml) in 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salt (0.42g, 2.16mmol), 1
-Hydroxybenzotriazole monohydrate (0.33g, 2.16
mmol) and stirred for 10 minutes as a solution, then 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4′-
[(3-Pyridylmethyl) aminomethyl] -1,1'-biphenyl
(0.70 g, 1.44 mmol) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane: acetone = 3: 2), and N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl ] [1,1'-biphenyl]
-4-yl} methyl) -4-phenoxy-N- (3-pyridylmethyl)
Benzamide (0.38g, 46%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.57 (2H, s) 4.66
(2H, s) 6.96-7.05 (4H, m) 7.11-7.18 (1H, m) 7.26-
7.39 (7H, m) 7.48-7.61 (7H, m) 8.48 (1H, s) 8.56
(1H, dd, J = 1.6, 4.8Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-phenoxy-N -(3-Pyridylmethyl) benzamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -Four
-Phenoxy-N- (3-pyridylmethyl) benzamide (0.25
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of g, 0.366 mmol) and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to give a powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. N-({4'-
[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-
Ilyl} methyl) -4-phenoxy-N- (3-pyridylmethyl) benzamide dihydrochloride (0.20 g, 83%) was obtained as a colorless amorphous powder. Elemental analysis calculated as C ₃₉ H ₃₉ N ₃ O ₂・ 2HCl ・ H ₂ O: C, 69.63; H, 6.44; N, 6.25 Found: C, 69.86; H, 6.69; N, 6.20. ¹ H- NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 4.17 (2H, s) 4.72 (2H, s) 4.
76 (2H, s) 7.01-7.09 (4H, m) 7.15-7.23 (1H, m) 7.3
4-7.46 (4H, m) 7.56-7.60 (1H, m) 7.65-7.71 (7H, m)
7.94 (1H, m) 8.42 (1H, br) 8.77 (1H, s) 8.80 (1H,
s) 9.44 (2H, s)

Example 124 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (cyclopentyloxy) -N- (3-
Pyridylmethyl) benzamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
4- (Cyclopentyloxy) -N- (3-pyridylmethyl) benzamide 4-cyclopentyloxybenzoic acid (0.35 g, 1.70 mmol)
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.22g, 1.13m) in acetonitrile suspension (10ml)
mol), 1-hydroxybenzotriazole monohydrate (0.18
g, 1.13 mmol) was added and the solution was stirred for 10 minutes, then 4- (N-
tert-Butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1′-biphenyl (0.73 g, 1.51 mmol) was added, and the mixture was stirred at room temperature for 13 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2), N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl ] -4-yl} methyl) -4- (cyclopentyloxy) -N- (3-pyridylmethyl) benzamide (0.56g, 55%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-2.0 (18H, m) 1.40 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.58 (2H, s) 4.64
(2H, s) 4.76 (1H, br) 6.86 (2H, d, J = 8.4Hz) 7.24-
7.33 (3H, m) 7.44-7.61 (6H, m) 8.47 (1H, s) 8.56
(1H, dd, J = 1.4, 4.6Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (cyclopentyl Roxy) -N- (3
-Pyridylmethyl) benzamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4
-(Cyclopentyloxy) -N- (3-pyridylmethyl) benzamide (0.37g, 0.55mmol) in ethanol solution (5ml)
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure to give a powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure.
N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (cyclopentyloxy) -N- (3-
Pyridylmethyl) benzamide dihydrochloride (0.33g, 93%)
Was obtained as a colorless amorphous powder. Elemental analysis _{C 38 H 43 N 3 O 2} · 2HCl · 0.5H 2 O Calculated: C, 69.61; H, 7.07 ; N, 6.41 Found:. C, 69.39; H, 6.95; N, 6.02 1 H -NMR (d ₆ -DMSO) δ (ppm) 1.0-2.0 (16H, m) 2.0-2.2
(2H, m) 2.95 (1H, br) 4.17 (2H, s) 4.71 (2H, s) 4.7
5 (2H, s) 4.8-4.9 (1H, br) 6.95 (2H, d, J = 8.6Hz)
7.40-7.60 (2H, m) 7.47-7.60 (2H, m) 7.66-7.72 (6H,
m) 7.9-8.0 (1H, m) 8.40 (1H, br) 8.78 (1H, s) 8.81
(1H, s) 9.45 (2H, br)

Example 125 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (cyclohexyloxy) -N- (3-
Pyridylmethyl) benzamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
4- (Cyclohexyloxy) -N- (3-pyridylmethyl) benzamide 4-Cyclohexyloxybenzoic acid (0.35g, 1.59mmol) in acetonitrile suspension (10ml) in 1-ethyl-3- (3-dimethylamino) Propyl) carbodiimide hydrochloride (0.42g, 2.19mmo
l), 1-hydroxybenzotriazole monohydrate (0.34 g,
2.19mmol) was added and the solution was stirred for 10 minutes, and then 4- (N-te
rt-Butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1′-biphenyl (0.70 g, 1.46 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane:
Acetone = 3: 2) and N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4 -(Cyclohexyloxy) -N- (3
-Pyridylmethyl) benzamide (0.73g, 73%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-2.0 (20H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.2-4.3 (1H, m) 4.41 (2H, s)
4.59 (2H, s) 4.64 (2H, s) 6.88 (2H, d, J = 8.4Hz) 7.
26-7.39 (5H, m) 7.44-7.61 (7H, m) 8.48 (1H, s) 8.5
6 (1H, dd, J = 1.8,4.8Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (cyclohex Siloxy) -N- (3
-Pyridylmethyl) benzamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4
-(Cyclohexyloxy) -N- (3-pyridylmethyl) benzamide (0.55g, 0.80mmol) in ethanol solution (5ml)
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. After the solvent was concentrated under reduced pressure, a solid was precipitated with ethanol-diethyl ether and dried under reduced pressure. N-
({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (cyclohexyloxy) -N- (3-pyridylmethyl) benzamide dihydrochloride (0.48 g, 91%) was obtained as a colorless solid. Melting point 216-221 ℃ Elemental analysis value Calculated as C ₃₉ H ₄₅ N ₃ O ₂・ 2HCl ・ 1.5H ₂ O: C, 68.11; H, 7.33; N, 6.11 Found: C, 68.20; H, 7.42; N , 5.87. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-2.0 (18H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 4.17 (2H, s) 4.38 (1H, br) 4.
71 (2H, s) 4.74 (2H, s) 6.98 (2H, d, J = 8.4Hz) 7.32
(2H, d, J = 8.0Hz) 7.48 (2H, d, J = 8.2Hz) 7.66-7.72
(6H, m) 7.90-7.97 (1H, m) 8.39 (1H, br) 8.77 (1H,
s) 8.80 (1H, s) 9.44 (2H, s)

Example 126 4- (Cycloheptyloxy) -N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3- Pyridylmethyl) benzamide dihydrochloride 1) 4- (Cycloheptyloxy) -N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzamide 4-cycloheptyloxybenzoic acid (0.49g, 1.97mmol)
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.48g, 2.50m) in acetonitrile suspension (10ml)
mol), 1-hydroxybenzotriazole monohydrate (0.38
g, 2.50 mmol) was added and the solution was stirred for 10 minutes, then 4- (N-
tert-Butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1′-biphenyl (0.80 g, 1.65 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, dilute with ethyl acetate and saturated aqueous sodium hydrogen carbonate,
After washing with saturated saline and drying over anhydrous magnesium sulfate,
It was filtered and concentrated under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate = 1: 1-hexane
: Acetone = 3: 2), 4- (cycloheptyloxy)-
N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N
-(3-Pyridylmethyl) benzamide (0.61 g, 52%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (20H, m) 1.39 (9H,
s) 1.9-2.1 (2H, m) 4.0-4.2 (1H, br) 4.38-4.48 (3H,
m) 4.59-4.70 (4H, br) 6.84 (2H, d, J = 8.8Hz) 7.26-
7.32 (5H, m) 7.44-7.61 (7H, m) 8.47 (1H, s) 8.55
(1H, dd, J = 1.8, 5.2Hz). 2) 4- (Cycloheptyloxy) -N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl } Methyl) -N-
(3-Pyridylmethyl) benzamide dihydrochloride 4- (cycloheptyloxy) -N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl ] -4-yl} methyl) -N- (3-pyridylmethyl) benzamide (0.47g, 0.67mmol) in ethanol solution (5ml), 4N hydrogen chloride-ethyl acetate (10ml) was added dropwise at room temperature for 1 hour. It was stirred. The solvent was concentrated under reduced pressure to give a powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4- (Cycloheptyloxy) -N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N-
(3-pyridylmethyl) benzamide dihydrochloride (0.37g,
82%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₄₀ H ₄₇ N ₃ O ₂・ 2HCl ・ H ₂ O: C, 69.35; H, 7.42; N, 6.07 Found: C, 69.71; H, 7.57; N, 6.07. ¹ H- NMR (d ₆ -DMSO) δ (ppm) 1.0-2.0 (20H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 4.17 (2H, s) 4.51-4.59 (1H,
m) 4.71 (2H, s) 4.74 (2H, s) 6.94 (2H, d, J = 8.8Hz)
7.32 (2H, d, J = 8.0Hz) 7.48 (2H, d, J = 8.4Hz) 7.67
(1H, d, J = 8.4Hz) 7.72 (6H, s) 7.91-7.98 (1H, m) 8.39
(1H, br) 8.77 (1H, s) 8.80 (1H, s) 9.46 (2H, s)

Example 127 4- (benzyloxy) -N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) Benzamide dihydrochloride 1) 4- (benzyloxy) -N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl ) -N- (3-Pyridylmethyl) benzamide 4-benzyloxybenzoic acid (0.30 g, 1.97 mmol) in acetonitrile suspension (10 ml) was added to 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.35 g, 1.83mmo
l), 1-hydroxybenzotriazole monohydrate (0.28 g,
1.83mmol) was added and stirred as a solution for 10 minutes, and then 4- (N-te
rt-Butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1′-biphenyl (0.57 g, 1.19 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane:
Acetone = 3: 2), 4- (benzyloxy) -N-((4'-
[(N-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzamide (0.50g, 61%) colorless Obtained as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.55 (2H, s) 4.68
(2H, s) 5.01 (2H, s) 6.33 (1H, s) 6.86 (2H, d, J =
9.2Hz) 7.14 (2H, d, J = 9.2Hz) 7.25-7.41 (9H, m) 7.5
2 (2H, d, J = 8.4Hz) 7.60 (2H, d, J = 8.0Hz) 7.71-7.76
(1H, m) 8.54-8.56 (2H, m). 2) 4- (benzyloxy) -N-((4 '-[(cyclohexylamino)
Methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzamide dihydrochloride 4- (benzyloxy) -N-({4 '-[(N-tert- Butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl]
-4-yl} methyl) -N- (3-pyridylmethyl) benzamide
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of (0.55 g, 0.50 mmol), and the mixture was stirred at room temperature for 1 hour. After the solvent was concentrated under reduced pressure, a solid was precipitated with ethanol-diethyl ether and dried under reduced pressure. 4- (benzyloxy) -N-({4 '-[(cyclohexylamino) methyl] [1,1'
-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzamide dihydrochloride (0.27g, 81%) was obtained as a colorless solid. Melting point 140-161 ° C Elemental analysis C ₄₀ H ₄₁ N ₃ O ₂・ 2HCl ・ 1.5H ₂ O Calculated: C, 69.06; H, 6.66; N, 6.04 Found: C, 69.35; H, 6.95; N ^{, 5.90. 1 H-NMR (} d 6 -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 4.17 (2H, s) 4.70 (2H, s) 4.
75 (2H, s) 8.14 (2H, s) 7.08 (2H, d, J = 8.8Hz) 7.30-
7.54 (9H, m) 7.65-7.71 (6H, m) 7.91-7.98 (1H, m)
8.41 (1H, br) 8.78 (1H, s) 8.80 (1H, s) 9.47 (2H,
s)

Example 128 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (neopentyloxy) -N- (3-pyridyl Methyl) benzamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
4- (Neopentyloxy) -N- (3-pyridylmethyl) benzamide 4-neopentyloxybenzoic acid (0.35 g, 1.68 mmol) in acetonitrile suspension (10 ml) in 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide hydrochloride (0.22g, 1.12mm
ol), 1-hydroxybenzotriazole monohydrate (0.18
g, 1.12 mmol) was added and the solution was stirred for 10 minutes, then 4- (N-
tert-Butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1′-biphenyl (0.73 g, 1.51 mmol) was added, and the mixture was stirred at room temperature for 13 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2), N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl ] -4-yl} methyl) -4- (neopentyloxy) -N- (3-pyridylmethyl) benzamide (0.50 g, 49%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.02 (9H, s) 1.20-1.80 (10
H, m) 1.40 (9H, s) 3.59 (2H, s) 4.0-4.2 (1H, br) 4.
41 (2H, s) 4.59 (2H, s) 4.65 (2H, s) 6.89 (2H, d,
J = 8.8Hz) 7.26-7.33 (6H, m) 7.45-7.61 (6H, m) 8.47
(1H, s) 8.56 (1H, dd, J = 1.8, 5.0Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (Neopentyloxy) -N- (3-
Pyridylmethyl) benzamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4
4- (neopentyloxy) -N- (3-pyridylmethyl) benzamide (0.41g, 0.61mmol) in ethanol solution (5ml) 4
Normal hydrogen chloride-ethyl acetate (10 ml) was added dropwise at room temperature to 1
Stir for hours. The solvent was concentrated under reduced pressure to give a powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. N-
({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (neopentyloxy) -N- (3-pyridylmethyl) benzamide dihydrochloride ( 0.34 g, 86%) was obtained as a colorless amorphous powder. Elemental analysis _{C 38 H 45 N 3 O 2} · 2HCl · 1.5H 2 O Calculated: C, 67.54; H, 7.46 ; N, 6.22 Found:. C, 67.40; H, 7.40; N, 5.94 1 H -NMR (d ₆ -DMSO) δ (ppm) 0.98 (9H, s) 1.0-1.8 (8H,
m) 2.0-2.2 (2H, m) 2.95 (1H, br) 3.65 (2H, s) 4.1
6 (2H, s) 4.71 (2H, s) 4.75 (2H, s) 6.99 (2H, d, J
= 8.4Hz) 7.32 (2H, d, J = 7.0Hz) 7.50 (2H, d, J = 7.8H
z) 7.65-7.72 (6H, m) 7.9-8.0 (1H, m) 8.42 (1H, br)
8.78 (1H, s) 8.81 (1H, s) 9.48 (2H, s)

Example 129 N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (dimethylamino) -N- (3-pyridylmethyl ) Benzamide trihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
4- (Dimethylamino) -N- (3-pyridylmethyl) benzamide 4-Dimethylaminobenzoic acid (0.58g, 1.2mmol) in acetonitrile suspension (10ml) in 1-ethyl-3- (3-dimethylamino) Propyl) carbodiimide hydrochloride (0.43g, 2.25mmo
l), 1-hydroxybenzotriazole monohydrate (0.34 g,
2.25mmol) was added and the solution was stirred for 10 minutes, and then 4- (N-te
rt-Butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1′-biphenyl (0.58 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane:
Purified with acetone = 3: 2 to 1: 1), N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,
1'-biphenyl] -4-yl} methyl) -4- (dimethylamino) -N
-(3-Pyridylmethyl) benzamide (0.29g, 31%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.40 (9H,
s) 2.98 (6H, s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.63
(2H, s) 4.66 (2H, s) 6.65 (2H, d, J = 8.8Hz) 7.26-7.
32 (5H, m) 7.45-7.68 (7H, m) 8.47 (1H, d, J = 1.8Hz)
8.55 (1H, dd, J = 1.4, 4.8Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (dimethyl Amino) -N- (3-pyridylmethyl) benzamide trihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4- Ill} methyl) -4
-(Dimethylamino) -N- (3-pyridylmethyl) benzamide
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of (0.21 g, 0.33 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to give a powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. N-
({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (dimethylamino) -N- (3-pyridylmethyl) benzamide trihydrochloride (0.18 g, 85%) was obtained as a colorless amorphous powder. Elemental analysis calculated as C ₃₅ H ₄₀ N ₄ O ・ 3HCl ・ 1.25H ₂ O: C, 63.25; H, 6.90; N, 8.43 Found: C, 63.52; H, 7.31; N, 8.27. ¹ H- NMR (CD ₃ OD) δ (ppm) 1.2-1.6 (5H, m) 1.6-1.8 (1
H, m) 1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.19 (1H, b
r) 3.25 (6H, s) 4.27 (2H, s) 4.79 (2H, s) 4.92 (2H,
s) 7.34 (2H, d, J = 8.0Hz) 7.59-7.80 (10H, m) 8.04
(1H, dd, J = 6.0, 8.4Hz) 8.58 (1H, d, J = 7.6Hz) 8.77
(1H, d, J = 5.8Hz) 8.82 (1H, s)

Example 130 4-Cyclohexyl-N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzamide Dihydrochloride 1) 4-Cyclohexyl-N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-Pyridylmethyl) benzamide 4-cyclohexylbenzoic acid (0.29 g, 1.4 mmol) in acetonitrile (10 ml) in 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.32g, 1.67mmo)
l), 1-hydroxybenzotriazole monohydrate (0.26 g,
1.70mmol) was added and stirred as a solution for 10 minutes, and then 4- (N-te
rt-Butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1′-biphenyl (0.54 g, 1.1 mmol) was added and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane:
Purified with acetone = 3: 2), 4-cyclohexyl-N-({4'-
[(N-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzamide (0.37g, 50%) colorless Obtained as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (20H, m) 1.39 (9H,
s) 2.50 (1H, br) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.5
0 (2H, s) 4.70 (2H, s) 7.21-7.33 (8H, m) 7.44 (2H, s)
d, J = 8.0Hz) 7.53 (2H, d, J = 8.0Hz) 7.59 (2H, d, J =
8.0Hz) 8.49 (1H, br) 8.56 (1H, d, J = 4.2Hz). 2) 4-cyclohexyl-N-({4 '-[(cyclohexylamino)
Methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzamide dihydrochloride 4-cyclohexyl-N-({4 '-[(N-tert-butoxycarbonyl -N-cyclohexylamino) methyl] [1,1'-biphenyl]
-4-yl} methyl) -N- (3-pyridylmethyl) benzamide
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of (0.27 g, 0.40 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to give a powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-Cyclohexyl-N-({4 '-[(cyclohexylamino) methyl]
[1,1′-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzamide dihydrochloride (0.19 g, 74%) was obtained as a colorless amorphous powder. Elemental analysis calculated as C ₃₉ H ₄₅ N ₃ O ・ 2HCl ・ H ₂ O: C, 70.68; H, 7.45; N, 6.34 Found: C, 70.80; H, 7.60; N, 6.27. ¹ H-NMR (CD ₃ OD) δ (ppm) 1.2-1.6 (10H, m) 1.6-2.0 (8
H, m) 2.0-2.1 (2H, m) 2.56 (1H, s) 3.15 (1H, s) 4.2
7 (2H, s) 4.80 (2H, s) 4.88 (2H, s) 7.33 (4H, d, J
= 8.2Hz) 7.51 (2H, d, J = 7.4Hz) 7.60-7.73 (6H, m) 8.
02 (1H, dd, J = 6.0, 8.2Hz) 8.55 (1H, br) 8.76 (1H,
d, J = 5.8Hz) 8.81 (1H, br)

Example 131 4-tert-butyl-N-({4 ′-[(cyclohexylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) Benzamide dihydrochloride 1) 4-tert-butyl-N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl]
4-yl-methyl) -N- (3-pyridylmethyl) benzamide 4-tert-butylbenzoic acid (0.26g, 1.24mmol) in acetonitrile suspension (10ml) in 1-ethyl-3- (3-dimethyl) Aminopropyl) carbodiimide hydrochloride (0.36g, 1.86mmol), 1
-Hydroxybenzotriazole monohydrate (0.29g, 1.86
mmol) and stirred for 10 minutes as a solution, then 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4′-
[(3-Pyridylmethyl) aminomethyl] -1,1'-biphenyl
(0.60 g, 1.42 mmol) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, hexane: acetone = 3: 2), and 4-tert-butyl-N-({4 '-[(N-tert-butoxycarbonyl- N-cyclohexylamino) methyl] [1,
1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl)
Benzamide (0.50g, 61%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.30 (9H,
s) 1.40 (9H, s) 4.0-4.2 (1H, br) 4.42 (2H, s) 4.52
(2H, s) 4.70 (2H, s) 7.26-7.61 (14H, m) 8.49 (1H,
br) 8.55 (1H, dd, J = 1.4, 4.8Hz). 2) 4-tert-butyl-N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl } Methyl) -N- (3-pyridylmethyl) benzamide dihydrochloride 4-tert-butyl-N-({4 '-[(N-tert-butoxycarbonyl-N
-Cyclohexylamino) methyl] [1,1'-biphenyl] -4-
Ill} methyl) -N- (3-pyridylmethyl) benzamide (0.37
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of g, 0.56 mmol) and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to give a powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-tert-Butyl-N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzamide dihydrochloride ( 0.35 g, 98%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₇ H ₄₃ N ₃ O ・ 2HCl ・ H ₂ O ・ 0.5Et ₂ O: C, 69.52; H, 7.78; N, 6.24 Found: C, 69.73; H, 7.92; N, 6.56 _{^{. 1 H-NMR (CD 3}} OD) δ (ppm) 1.2-1.6 (14H, m) 1.6-1.8 (1
H, m) 1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.14 (1H, br)
4.27 (2H, s) 4.88 (4H, s) 7.35 (2H, m) 7.53-7.74
(10H, m) 8.02 (1H, dd, J = 6.0, 8.0Hz) 8.55 (1H, br)
8.76 (1H, d J = 6.0Hz) 8.82 (1H, br)

Example 132 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4- (2- Thienyl) benzamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (3-Pyridylmethyl) -4- (2-thienyl) benzamide 4- (2-thienyl) benzoic acid (0.20 g, 0.92 mmol) in acetonitrile suspension (10 ml) in 1-ethyl-3- ( 3-Dimethylaminopropyl) carbodiimide hydrochloride (0.27g, 1.41mmo
l), 1-hydroxybenzotriazole monohydrate (0.22 g,
1.44mmol) was added and the solution was stirred for 10 minutes, then 4- (N-te
rt-Butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1′-biphenyl (0.45 g, 0.93 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, hexane:
Acetone = 3: 2), N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N -(3-Pyridylmethyl) -4- (2-
Thienyl) benzamide (0.55g, 84%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (8H, m) 1.38 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.53 (2H, s) 4.73
(2H, s) 7.07 (1H, dd, J = 1.8, 3.6Hz) 7.26-7.35 (7
H, m) 7.51-7.66 (9H, m) 8.52 (1H, br) 8.57 (1H, d
d, J = 1.8, 4.8Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4- (2-
Thienyl) benzamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N
-(3-Pyridylmethyl) -4- (2-thienyl) benzamide (0.
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of 41 g, 0.57 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent is concentrated under reduced pressure to give a powder, which is collected by filtration,
It was washed with diethyl ether and dried under reduced pressure. N-({4'-
[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-
Il} methyl) -N- (3-pyridylmethyl) -4- (2-thienyl) benzamide dihydrochloride (0.34 g, 87%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₇ H ₃₇ N ₃ OS ・ 2HCl ・ 1.4H ₂ O: C, 66.34; H, 6.29; N, 6.27 Found: C, 66.62; H, 6.74; N, 5.99. ¹ H- NMR (CD ₃ OD) δ (ppm) 1.2-1.6 (5H, m) 1.6-1.8 (1
H, m) 1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.15 (1H, b
r) 4.27 (2H, s) 4.83 (2H, s) 4.92 (2H, s) 7.11 (1H,
dd, J = 1.8, 8.0Hz) 7.35 (2H, d, J = 6.6Hz) 7.42-7.49
(2H, m) 7.59-7.77 (10H, m) 8.02 (1H, dd, J = 1.8,
8.0Hz) 8.56 (1H, br) 8.75 (1H, d, J = 5.8Hz) 8.82 (1
H, br)

Example 133 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (phenoxymethyl) -N- (3-pyridylmethyl ) Benzamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
4- (Phenoxymethyl) -N- (3-pyridylmethyl) benzamide 4-phenoxymethylbenzoic acid (0.24 g, 1.05 mmol) in acetonitrile suspension (10 ml) in 1-ethyl-3- (3-dimethylamino) Propyl) carbodiimide hydrochloride (0.31g, 1.62mmo
l), 1-hydroxybenzotriazole monohydrate (0.25 g,
1.62 mmol) was added and the solution was stirred for 10 minutes, and then 4- (N-te
rt-Butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1′-biphenyl (0.51 g, 1.05 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, hexane:
Acetone = 3: 2) and N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4 -(Phenoxymethyl) -N- (3-
Pyridylmethyl) benzamide (0.54g, 74%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-1.8 (8H, m) 1.40 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.48 (2H, s) 4.72
(2H, s) 5.08 (2H, s) 6.92-6.98 (3H, m) 7.22-7.33
(7H, m) 7.45-7.61 (9H, m) 8.55 (1H, d, J = 1.6Hz) 8.
57 (1H, d, J = 1.4Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (phenoxymethyl) -N- (3-
Pyridylmethyl) benzamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4
4- (phenoxymethyl) -N- (3-pyridylmethyl) benzamide (0.39g, 0.56mmol) in ethanol solution (5ml) 4
Normal hydrogen chloride-ethyl acetate (10 ml) was added dropwise at room temperature to 1
Stir for hours. The solvent was concentrated under reduced pressure to give a powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. N-
({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (phenoxymethyl) -N- (3-pyridylmethyl) benzamide dihydrochloride (0.34 g, 91%) was obtained as a colorless amorphous powder. Elemental analysis _{C 40 H 41 N 3 O 2} · 2HCl · H 2 O Calculated: C, 69.96; H, 6.61 ; N, 6.12 Found:. C, 69.68; H, 6.40; N, 6.04 1 H- NMR (CD ₃ OD) δ (ppm) 1.2-1.6 (5H, m) 1.6-1.8 (1
H, m) 1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.15 (1H, b
r) 4.27 (2H, s) 4.79 (2H, s) 4.89 (2H, s) 5.13 (2H,
m) 6.88-6.99 (3H, m) 7.20-7.33 (4H, m) 7.58-7.74
(11H, m) 7.99-8.06 (1H, m) 8.57 (1H, br) 8.75 (1H,
d, J = 6.0Hz) 8.83 (1H, br)

Example 134 4-Benzyl-N-({4 '-[(cyclohexylamino) methyl]
[1,1'-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzamide dihydrochloride 1) 4-benzyl-N-({4 '-[(N-tert-butoxycarbonyl -N
-Cyclohexylamino) methyl] [1,1'-biphenyl] -4-
1-ethyl-3- (3-dimethylaminopropyl) in a suspension of 4- (benzyl) benzoic acid (0.24g, 1.13mmol) in acetonitrile (10ml). Carbodiimide hydrochloride (0.33g, 1.70mmol), 1
-Hydroxybenzotriazole monohydrate (0.26g, 1.70
mmol) and stirred for 10 minutes as a solution, then 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4′-
[(3-Pyridylmethyl) aminomethyl] -1,1'-biphenyl
(0.55 g, 1.13 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Hexane: ethyl acetate = 1: 1, hexane: acetone
= 3: 2), 4-benzyl-N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-
Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzamide (0.65 g, 85%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (8H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.48 (2H, s) 4.70
(2H, s) 7.13-7.32 (13H, m) 7.44 (2H, d, J = 8.0Hz)
8.52 (2H, d, J = 8.0Hz) 7.58 (2H, d, J = 8.0Hz) 8.48
(1H, br) 8.55 (1H, dd, J = 1.8, 5.2Hz). 2) 4-benzyl-N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4- Iyl} methyl) -N- (3-pyridylmethyl) benzamide dihydrochloride 4-benzyl-N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1' -Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzamide (0.49
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of g, 0.72 mmol) and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to give a powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. 4-benzyl
-N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzamide dihydrochloride (0.45g, 96% ) Was obtained as a colorless amorphous powder. Elemental analysis calculated as C ₄₀ H ₄₁ N ₃ O ・ 2HCl ・ 0.5H ₂ O ・ 0.5Et ₂ O: C, 72.19; H, 7.07; N, 6.01 Found: C, 72.07; H, 7.27; N, 6.29. ¹ H-NMR (CD ₃ OD) δ (ppm) 1.2-1.6 (5H, m) 1.6-1.8 (1
H, m) 1.8-2.0 (2H, m) 2.2-2.3 (2H, m) 3.15 (1H, b
r) 4.00 (2H, s) 4.27 (2H, s) 4.78 (2H, s) 4.92 (2H,
s) 7.12-7.33 (9H, m) 7.49-7.72 (8H, m) 7.98-8.05
(1H, m) 8.55 (1H, br) 8.74 (1H, d, J = 6.0Hz) 8.81 (1
H, br)

Example 135 N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -1-benzofuran-2 -Carboxamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (3-pyridylmethyl) -1-benzofuran-2-carboxamide Benzofuran-2-carboxylic acid (0.23 g, 1.42 mmol) in acetonitrile (10 ml) in 1-ethyl-3- (3-dimethylamino) Propyl) carbodiimide hydrochloride (0.36g, 1.86mmo
l), 1-hydroxybenzotriazole monohydrate (0.29 g,
1.86mmol) was added and the solution was stirred for 10 minutes, and then 4- (N-te
rt-Butoxycarbonyl-N-cyclohexylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1′-biphenyl (0.60 g, 1.24 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate = 1: 1 to hexane:
Acetone = 3: 2), N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N -(3-Pyridylmethyl) -1-benzofuran-2-carboxamide (0.60g, 77%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-2.0 (10H, m) 1.41 (9H,
s) 4.0-4.2 (1H, br) 4.42 (2H, s) 4.82 (2H, s) 7.24
-7.67 (14H, m) 7.24 (1H, d, J = 7.2Hz) 8.56 (1H, s)
8.58 (1H, s). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -1- Benzofuran-2-carboxamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N
4- (3-pyridylmethyl) -1-benzofuran-2-carboxamide (0.44g, 0.56mmol) in ethanol solution (5ml) 4
Normal hydrogen chloride-ethyl acetate (10 ml) was added dropwise at room temperature to 1
Stir for hours. The solvent was concentrated under reduced pressure to give a powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure. N-
({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -1-benzofuran-2-carboxamide dihydrochloride (0.37 g, 88%) was obtained as a colorless amorphous powder. Elemental analysis _{C 35 H 35 N 3 O 2} · 2HCl · H 2 O Calculated: C, 67.74; H, 6.33 ; N, 6.77 Found:. C, 67.71; H, 6.79; N, 6.67 1 H- NMR (CD ₃ OD) δ (ppm) 1.2-1.6 (5H, m) 1.6-1.8 (1
H, m) 1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.15 (1H, b
r) 4.27 (2H, s) 4.86 (2H, s) 4.98-5.18 (2H, br) 7.
28-7.75 (13H, m) 8.05 (1H, dd, J = 5.8, 8.0Hz) 8.60
(1H, d, J = 8.4Hz) 8.77 (1H, d, J = 5.6Hz) 8.87 (1H.
s).

Example 136 N-[(4 '-{[(cyclohexylmethyl) amino] methyl} [1,1'
-Biphenyl] -4-yl) methyl] -N- (3-pyridylmethyl) -4
-(Trifluoromethyl) benzamide dihydrochloride 1) N-[(4 '-{[N-tert-butoxycarbonyl-N- (cyclohexylmethyl) amino] methyl} [1,1'-biphenyl] -4- Iyl) methyl] -N- (3-pyridylmethyl) -4- (trifluoromethyl) benzamide 4- (N-tert-butoxycarbonyl-N-cyclohexylmethylamino) methyl-4 '-[(3-pyridylmethyl) Aminomethyl] -1,1'-biphenyl (0.84g, 1.69mmol) in acetonitrile (10ml) was added to triethylamine (0.59ml, 4.23mm)
ol), p-trifluoromethylbenzoyl chloride (0.3
(8 ml, 2.54 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate = 1: 1, hexane: acetone = 2: 1)
Purified with N-[(4 '-{[N-tert-butoxycarbonyl-N- (cyclohexylmethyl) amino] methyl} [1,1'-biphenyl]
-4-yl) methyl] -N- (3-pyridylmethyl) -4- (trifluoromethyl) benzamide (0.99g, 87%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.8-1.0 (2H, m) 1.0-1.8 (18
H, m) 3.05-3.08 (2H, br) 4.43 (2H, s) 4.48 (2H, s)
4.75 (2H, s) 7.19-7.35 (5H, m) 7.52-7.70 (10H, m)
8.54-8.59 (1H, m). 2) N-[(4 '-{[(cyclohexylmethyl) amino] methyl}
[1,1'-Biphenyl] -4-yl) methyl] -N- (3-pyridylmethyl) -4- (trifluoromethyl) benzamide dihydrochloride N-[(4 '-{[N-tert- Butoxycarbonyl-N- (cyclohexylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl] -N- (3-pyridylmethyl) -4- (trifluoromethyl)
Benzamide (0.84g, 1.25mmol) in ethyl acetate (4
4N hydrogen chloride-ethyl acetate (8 ml) was added dropwise to
The mixture was stirred at room temperature for 30 minutes. After the solvent was concentrated under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give N-[(4 '
-{[(Cyclohexylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl] -N- (3-pyridylmethyl) -4- (trifluoromethyl) benzamide dihydrochloride (0.72 g, 90
%) Was obtained as a colorless solid. Melting point: 171-173 ° C Elemental analysis C ₃₅ H ₃₆ N ₃ OF ₃・ 2HCl ・ 0.25H ₂ O Calculated: C, 64.76; H, 5.98; N, 6.47 Found: C, 64.77; H, 5.90; ^{N, 6.54. 1 H-NMR} (d 6 -DMSO) δ (ppm) 0.8-1.4 (5H, m) 1.6-1.8
(6H, m) 2.71 (2H, s) 4.15 (2H, s) 4.63 (2H, s) 4.8
3 (2H, s) 7.30 (2H, d, J = 7.6Hz) 7.64-7.84 (10H, m)
7.95-8.02 (1H, m) 8.50 (1H, d, J = 6.8Hz) 8.81 (1H,
d, J = 5.0Hz) 8.90 (1H, s) 9.46 (2H, s)

Example 137 N-[(4 '-{[(cyclohexylmethyl) amino] methyl} [1,1'
-Biphenyl] -4-yl) methyl] -4-methoxy-N- (3-pyridylmethyl) benzamide dihydrochloride 1) N-[(4 '-{[N-tert-butoxycarbonyl-N- (cyclohexyl Methyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl] -4-methoxy-N- (3-pyridylmethyl) benzamide 4- (N-tert-butoxycarbonyl-N-cyclohexylmethylamino ) Methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.84g, 1.69mmol) in acetonitrile solution (10ml) in triethylamine (0.59ml, 4.23mm)
ol), p-methoxybenzoyl chloride (0.44g, 2.58mm
ol) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, hexane: acetone = 2: 1-1: 1), and N-[(4 '-{[N-tert-butoxycarbonyl-N- (Cyclohexylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl] -4-methoxy-N- (3-pyridylmethyl) benzamide (0.93g, 87%) as colorless amorphous powder Got as. ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.8-1.0 (2H, br) 1.0-1.8 (1
8H, m) 3.04-3.08 (2H, br) 3.81 (3H, s) 4.50 (2H, s)
4.59 (2H, s) 4.65 (2H, s) 6.90 (2H, d, J = 8.8Hz)
7.26-7.33 (4H, m) 7.47-7.61 (8H, m) 8.48 (1H, s)
8.56 (1H, dd, J = 1.8, 4.6Hz). 2) N-[(4 '-{[(cyclohexylmethyl) amino] methyl}
[1,1'-Biphenyl] -4-yl) methyl] -4-methoxy-N- (3-
Pyridylmethyl) benzamide dihydrochloride N-[(4 '-{[N-tert-butoxycarbonyl-N- (cyclohexylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl]- 4-methoxy-N- (3-pyridylmethyl) benzamide
4N hydrogen chloride-ethyl acetate (8 ml) was added dropwise to an ethyl acetate solution (4 ml) of (0.78 g, 1.23 mmol), and the mixture was stirred at room temperature for 30 minutes. After the solvent was concentrated under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give N-[(4 '-{[(cyclohexylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl). Methyl] -4-methoxy-N- (3-pyridylmethyl) benzamide dihydrochloride (0.71 g, 95%) was obtained as a colorless solid. Melting point: 186-195 ° C Elemental analysis C ₃₅ H ₃₉ N ₃ O ₂・ 2HCl ・ 0.25H ₂ O Calculated: C, 68.79; H, 6.84; N, 6.88 Found: C, 68.87; H, 6.77; N, 6.90. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 0.8-1.4 (5H, m) 1.6-1.9
(6H, m) 2.71 (2H, s) 3.78 (3H, s) 4.15 (2H, s) 4.7
0 (2H, s) 4.74 (2H, s) 7.00 (2H, s, J = 7.8Hz) 7.32
(2H, d, J = 7.0Hz) 7.52 (2H, d, J = 7.4Hz) 7.66-7.70
(6H, m) 7.9-8.0 (1H, m) 8.41 (1H, br) 8.77 (1H, s)
8.80 (1H, s) 9.40 (2H, br)

Example 138 N-({4 '-[(cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4- (tri Fluoromethyl) benzamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (3-pyridylmethyl) -4- (trifluoromethyl) benzamide 4- (N-tert-butoxycarbonyl-N-cycloheptylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl]- 1,1 '
-Biphenyl (0.84g, 1.69mmol) in acetonitrile
(10 ml) with triethylamine (0.47 ml, 3.38 mmol), p-
Trifluoromethylbenzoyl chloride (0.38ml, 2.
(54 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 20 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 1: 1, hexane: acetone = 1: 1), N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-biphenyl ] -4-yl} methyl) -N- (3-pyridylmethyl) -4- (trifluoromethyl) benzamide (0.97g, 86%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (12H, m) 1.36 (9H,
s) 4.0-4.2 (1H, br) 4.43 (4H, s) 4.75 (2H, s) 7.20
-7.35 (6H, m) 7.52-7.71 (8H, m) 8.54 (1H, s) 8.59
(1H, d, J = 3.4Hz). 2) N-({4 '-[(cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridyl Methyl) -4- (trifluoromethyl) benzamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-biphenyl] -4- Ill} methyl) -N
4- (3-pyridylmethyl) -4- (trifluoromethyl) benzamide (0.80 g, 1.20 mmol) in ethyl acetate (5 ml) was added to 4
Normal hydrogen chloride-ethyl acetate (5 ml) was added dropwise at room temperature.
Stir for hours. After the solvent was concentrated under reduced pressure, the resulting amorphous powder was collected by filtration and washed with diethyl ether. It was dried under reduced pressure. N-({4 '-[(cycloheptylamino) methyl] [1,1'
-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4
-(Trifluoromethyl) benzamide dihydrochloride (0.68g,
88%) was obtained as an amorphous powder. Elemental analysis _{C 35 H 36 N 3 OF 3} · 2HCl · 3 / 4H 2 O Calculated: C, 63.85: H, 6.05 : N, 6.38 Found: C, 63.93: H, 6.15 :. N, 6.33 1 H-NMR (d ₆ -DMSO) δ (ppm) 1.2-1.8 (10H, m) 2.0-2.2
(2H, m) 3.12 (1H, br) 4.16 (2H, s) 4.63 (2H, s) 4.8
4 (2H, s) 7.29 (2H, d, J = 7.6Hz) 7.64-7.84 (9H, m)
8.01 (1H, t, J = 6.6Hz) 8.54 (1H, d, J = 8.4Hz) 8.83
(1H, d, J = 5.2Hz) 8.92 (1H, s) 9.45 (2H, s)

Example 139 N-({4 '-[(cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-methoxy-N- (3-pyridylmethyl) benzamide Dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-4-methoxy-N- (3-pyridylmethyl) benzamide 4- (N-tert-butoxycarbonyl-N-cycloheptylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (0.82g, 1.65mmol) in acetonitrile
(10 ml) with triethylamine (0.58 ml, 4.13 mmol), p-
Methoxyphenylbenzoyl chloride (0.43ml, 2.8m
mol) was added under ice cooling, and the mixture was stirred at room temperature for 20 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 1: 1, hexane: acetone = 2: 1), N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-biphenyl ] -4-yl} methyl) -4-methoxy-N- (3-pyridylmethyl) benzamide
(0.93g, 89%) was obtained as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (12H, m) 1.35 (9H,
s) 3.81 (3H, s) 4.0-4.2 (1H, br) 4.38 (2H, s) 4.58
(2H, s) 4.65 (2H, s) 6.90 (2H, d, J = 8.8Hz) 7.27-7.
34 (4H, m) 7.48-7.62 (8H, m) 8.48 (1H, s) 8.57 (1
H, d, J = 4.8Hz). 2) N-({4 '-[(cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-methoxy-N- ( 3-Pyridylmethyl) benzamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)- Four
-Methoxy-N- (3-pyridylmethyl) benzamide (0.77g,
4N hydrogen chloride-ethyl acetate (5 ml) was added dropwise to an ethyl acetate solution (5 ml) of 1.22 mmol), and the mixture was stirred at room temperature for 30 minutes. After the solvent was concentrated under reduced pressure, the resulting amorphous powder was collected by filtration and washed with diethyl ether. It was dried under reduced pressure. N-
({4 '-[(Cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-methoxy-N- (3-pyridylmethyl)
Benzamide dihydrochloride (0.67 g, 91%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₄ H ₃₉ N ₃ O ₂・ 2HCl ・ H ₂ O: C, 67.30: H, 6.94: N, 6.73 Measured value: C, 67.66: H, 7.13: N, 6.49 ¹ H- NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (10H, m) 2.0-2.2
(2H, m) 3.13 (1H, br) 3.78 (3H, s) 4.16 (2H, s) 4.7
1 (2H, s) 4.75 (2H, s) 7.00 (2H, d, J = 8.8Hz) 7.31-
7.34 (2H, m) 7.50-7.54 (2H, m) 7.66-7.71 (6H, m)
7.93-8.00 (1H, m) 8.43 (1H, br) 8.79 (1H, s) 8.81
(1H, s) 9.38 (2H, br)

Example 140 N-({4 '-[(cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (neopentyloxy) -N- (3- Pyridylmethyl) benzamide 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-4- (Neopentyloxy) -N- (3-pyridylmethyl) benzamide 4-neopentyloxybenzoic acid (0.19 g, 0.91 mmol) in acetonitrile suspension (10 ml) in 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide hydrochloride (0.27g, 1.40mm
ol), 1-hydroxybenzotriazole monohydrate (0.21
g, 1.40 mmol) was added and the solution was stirred for 10 minutes, then 4- (N-
tert-Butoxycarbonyl-N-cycloheptylamino) methyl-4 ′-[(3-pyridylmethyl) aminomethyl] -1,1′-biphenyl (0.45 g, 0.91 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1-hexane:
Acetone = 5: 2), N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)- 4- (Neopentyloxy) -N- (3-
Pyridylmethyl) benzamide (0.11 g, 18%) was obtained as a colorless oil-permeable product. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.02 (9H, s) 1.2-1.8 (12H,
m) 1.37 (9H, s) 3.58 (2H, s) 4.0-4.2 (1H, br) 4.39
(2H, s) 4.59 (2H, s) 4.65 (2H, s) 6.89 (2H, d, J =
8.4Hz) 7.26-7.36 (5H, m) 7.46-7.62 (7H, m) 8.48 (1
H, s) 8.55 (1H, dd, J = 1.0, 4.4Hz). 2) N-({4 '-[(cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (Neopentyloxy) -N- (3-
Pyridylmethyl) benzamide N-((4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4
4- (neopentyloxy) -N- (3-pyridylmethyl) benzamide (0.11g, 0.16mmol) in ethanol solution (5ml) 4
Normal hydrogen chloride-ethyl acetate (10 ml) was added dropwise at room temperature to 1
Stir for hours. The solvent was concentrated under reduced pressure and the resulting powder was collected by filtration, washed with diethyl ether, and dried under reduced pressure. N-
({4 '-[(Cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (neopentyloxy) -N- (3-pyridylmethyl) benzamide (0.09g, 85%) was obtained as a colorless amorphous powder. Elemental analysis _{C 39 H 47 N 3 O 2} · 2HCl · 0.5H 2 O Calculated: C, 69.73; H, 7.50 ; N, 6.26 Found:. C, 69.44; H, 7.62; N, 6.56 1 H -NMR (CD ₃ OD) δ (ppm) 1.03 (9H, s) 1.4-2.0 (10H,
m) 2.1-2.3 (2H, m) 3.2-3.4 (1H, br) 3.66 (2H, s)
4.27 (2H, s) 4.84 (2H, s) 4.88 (2H, s) 7.00 (2H, s)
d, J = 8.8Hz) 7.2-7.4 (2H, m) 7.52-7.74 (8H, m) 8.02
(1H, dd, J = 5.4, 8.0Hz) 8.56 (1H, d, J = 7.2Hz) 8.74
-8.79 (2H, m)

Example 141 N-benzyl-N-({4 ′-[(cyclohexylamino) methyl]]
[1,1'-Biphenyl] -4-yl} methyl) -4- (trifluoromethyl) benzamide hydrochloride 1) N-benzyl-N-({4 '-[(N-tert-butoxycarbonyl-
N-Cyclohexylamino) methyl] [1,1'-biphenyl] -4-
Iyl} methyl) -4- (trifluoromethyl) benzamide 4-{[(tert-butoxycarbonyl) (cyclohexyl) amino] methyl} -4 '-{[(benzyl) amino] methyl} -1,1'-biphenyl (0.7 g, 1.44 mmol), ethyl acetate (30 ml), saturated aqueous sodium hydrogen carbonate
4-Trifluoromethylbenzoyl chloride (0.26 ml, 1.73 mmol) was added to the mixed solution of (30 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give N-benzyl-N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [ 1,1'-Biphenyl] -4-yl} methyl) -4- (trifluoromethyl) benzamide (0.92g, 9
7%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.85 (19H, m), 3.90-4.20 (1H,
m), 4.40 (4H, s), 4.76 (2H, s), 7.10- 7.50 (9H, m), 7.50
-7.75 (8H, m). 2) N-benzyl-N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (trifluoromethyl ) Benzamide hydrochloride N-benzyl-N-({4 '-[(N-tert-butoxycarbonyl-N-
Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (trifluoromethyl) benzamide (0.77
g, 1.17 mmol) was dissolved in 4N hydrogen chloride / ethyl acetate (15 ml), and the mixture was stirred at room temperature for 1 hr. The reaction solution was evaporated under reduced pressure, the precipitated crystals were added with diethyl ether and collected by filtration to give N-benzyl-N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4. -Yl} methyl) -4- (trifluoromethyl) benzamide hydrochloride (0.64 g, 92%) was obtained. Melting point 197-199 ° C. Elemental analysis value C ₃₅ H ₃₅ F ₃ N ₂ O ・ HCl Calculated value: C, 70.87; H, 6.12; N, 4.72 Found value: C, 70.76; H, 6.11; N, 4.85 _{^{. 1 H-NMR (d 6}} -DMSO) δ: 1.10-1.90 (8H, m), 2.10-2.35 (2H,
m), 2.90-3.10 (1H, m), 4.20 (2H, brs), 4.43 (2H, s), 4.
66 (4H, s), 7.15-7.50 (7H, m), 7.60-7.90 (10H, m), 9.10-
9.20 (2H, br, NH ₂ ⁺ ).

Example 142 N-benzyl-N-({4 '-[(cyclohexylamino) methyl]
[1,1'-Biphenyl] -4-yl} methyl) -4-methoxybenzamide ・ hydrochloride 1) N-benzyl-N-({4 '-[(N-tert-butoxycarbonyl-
N-Cyclohexylamino) methyl] [1,1'-biphenyl] -4-
Iyl} methyl) -4-methoxybenzamide 4-{[(tert-butoxycarbonyl) (cyclohexyl) amino] methyl} -4 '-{[(benzyl) amino] methyl} -1,1'-biphenyl (0.7g, 1.44 mmol), ethyl acetate (30 ml), saturated aqueous sodium hydrogen carbonate
(30 ml) to a mixture of 4-methoxybenzoyl chloride (0.3
0 g, 1.73 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-3: 1) to give N-benzyl-N.
-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4
-Methoxybenzamide (0.87g, 97%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.85 (19H, m), 3.81 (3H, s), 3.9
0-4.20 (1H, m), 4.41 (4H, s), 4.40- 4.80 (4H, m), 6.89 (2
H, d, J = 7.6Hz), 7.15-7.50 (8H, m), 7.50-7.70 (7H, m). 2) N-benzyl-N-((4 '-[(cyclohexylamino) methyl] [1 , 1'-Biphenyl] -4-yl} methyl) -4-methoxybenzamide hydrochloride N-benzyl-N-({4 '-[(N-tert-butoxycarbonyl-N-
Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-methoxybenzamide (0.72g, 1.16mmol)
Was dissolved in 4N hydrogen chloride / ethyl acetate (15 ml) and stirred at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure, the precipitated crystals were added with diethyl ether and collected by filtration, and N-benzyl-N-({4'-
[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-
Ill} methyl) -4-methoxybenzamide hydrochloride (0.57 g,
89%). Melting point 188-191 ° C. Elemental analysis value, calculated as C ₃₅ H ₃₈ N ₂ O ₂ .HCl: C, 75.72; H, 7.08; N, 5.05 Found: C, 75.55; H, 7.05; N, 4.98. ¹ H-NMR (d ₆ -DMSO) δ: 1.10-1.90 (8H, m), 2.10-2.25 (2H,
m), 2.90-3.10 (1H, m), 3.78 (3H, s), 4.20 (2H, brs), 4.5
6 (4H, s), 6.95-7.10 (1H, m), 7.20-7.55 (10H, m), 7.60-
7.80 (7H, m), 9.10-9.30 (2H, br, NH ₂ ⁺ ).

Example 143 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (2-pyridyl) -4- (trifluoromethyl) ) Benzamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (2-pyridyl) -4- (trifluoromethyl) benzamide N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4 -Yl} methyl) -2
-Pyridineamine (0.83g, 1.76mmol) in toluene
(10 ml) with triethylamine (0.59 ml, 4.23 mmol), 4-dimethylaminopyridine (43 mg, 0.35 mmol), p-trifluoromethylbenzoyl chloride (0.53 ml, 3.52 mmol)
Was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-4: 1) and N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1, 1′-Biphenyl] -4-yl} methyl) -N- (2-pyridyl) -4- (trifluoromethyl) benzamide (0.98 g, 87%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.36 (9H,
s) 4.0-4.2 (1H, br) 4.38 (2H, s) 5.36 (2H, s) 6.65
(1H, d, J = 8.0Hz) 7.02-7.09 (1H, m) 7.24-7.28 (2H,
m) 7.36-7.53 (11H, m) 8.44-8.47 (1H, m). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (2-pyridyl) -4- (trifluoromethyl) benzamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'- Biphenyl] -4-yl} methyl) -N
-(2-Pyridyl) -4- (trifluoromethyl) benzamide
To a solution of (0.84 g, 1.30 mmol) in ethyl acetate (4 ml) was added dropwise 4N hydrogen chloride-ethyl acetate (10 ml), and the mixture was stirred at room temperature for 1 hour. After the solvent was concentrated under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)-. N- (2-pyridyl) -4- (trifluoromethyl) benzamide dihydrochloride (0.75 g, 94%) was obtained as a colorless solid. Melting point: 125-131 ° C Elemental analysis C ₃₅ H ₃₉ N ₃ O ₂・ 2HCl ・ 0.25H ₂ O Calculated: C, 68.79: H, 6.84: N, 6.88 Found: C, 68.87: H, 6.77: N, 6.90. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.97 (1H, br) 4.17 (2H, s) 5.29 (2H, s) 7.
13-7.19 (2H, m) 7.46 (2H, d, J = 8.4Hz) 7.52 (2H, d,
J = 8.0Hz) 7.62-7.73 (9H, m) 8.32-8.35 (1H, m) 9.21
(2H, br)

Example 144 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-methoxy-N- (2-pyridyl) benzamide di Hydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-4-Methoxy-N- (2-pyridyl) benzamido N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl ) -2
-Pyridineamine (0.60g, 1.27mmol) in toluene
To (10 ml) was added triethylamine (0.36 ml, 2.6 mmol), p-methoxybenzoyl chloride (0.33 g, 1.91 mmol), 4-dimethylaminopyridine (16 mg, 0.13 mmol) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. . Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1), N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl ] -4-yl} methyl) -4-methoxy-N- (2-pyridyl) benzamide (0.69
g, 85%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 3.76 (3H, s) 4.0-4.2 (1H, br) 4.38 (2H, s) 5.37
(2H, s) 6.61 (1H, d, J = 8.0Hz) 6.71 (2H, d, J = 9.0H
z) 6.96-7.03 (1H, m) 7.25 (2H, d, J = 8.2Hz) 7.30-7.
50 (9H, m) 8.47 (1H, dd, J = 1.0, 4.6Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl ) -4-Methoxy-N- (2-pyridyl) benzamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl]- 4-yl} methyl) -4
-Methoxy-N- (2-pyridyl) benzamide (0.53g, 0.83mm
ol) in ethanol solution (10 ml) was added dropwise with concentrated hydrochloric acid (10 ml), and the mixture was stirred at room temperature for 30 minutes. After the solvent was concentrated under reduced pressure, diethyl ether was added to give a powder, which was collected by filtration and dried under reduced pressure. N-({4 '-[(cyclohexylamino) methyl] [1,
1′-Biphenyl] -4-yl} methyl) -4-methoxy-N- (2-pyridyl) benzamide dihydrochloride (0.44 g, 87%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₃ H ₃₅ N ₃ O ₂・ HCl ・ H ₂ O ・ EtOH: C, 69.35; H, 7.32; N, 6.93 Found: C, 69.25; H, 7.02; N, 6.82. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 3.72 (3H, s) 4.16 (2H, s) 5.
26 (2H, s) 6.82 (2H, d, J = 8.8Hz) 6.95 (1H, d, J = 8.0
Hz) 7.14 (1H, dd, J = 4.8, 8.0Hz) 7.27 (2H, d, J = 8.8
Hz) 7.45 (2H, d, J = 8.4Hz) 7.57-7.73 (7H, m) 8.40 (1
H, dd, J = 1.2, 4.8Hz) 9.31 (2H, s)

Example 145 N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (cyclohexylmethoxy) -N-
(3-Pyridylmethyl) benzamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl )
-4- (Cyclohexylmethoxy) -N- (3-pyridylmethyl) benzamide 4-cyclohexylmethoxybenzoic acid (0.32 g, 1.36 mmol)
1-Ethyl in N, N-dimethylformamide solution (10 ml)
-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
(0.36g, 1.88mmol) and 1-hydroxybenzotriazole monohydrate (0.29g, 1.88mmol) were added and stirred as a solution for 10 minutes. 4- (N-cyclohexyl-N-tert-butoxycarbonyl) aminomethyl -4 '-[(3-Pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.60g, 1.24mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1).
, Hexane: acetone = 3: 2) and N-({4 '-[(N-
tert-Butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (cyclohexylmethoxy) -N- (3-pyridylmethyl) benzamide
(0.62 g, 71%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-2.0 (21H, m) 1.39 (9H,
s) 3.75 (2H, d, J = 5.8Hz) 3.9-4.1 (1H, br) 4.41 (2
H, s) 4.58 (2H, s) 4.64 (2H, s) 6.88 (2H, d, J = 8.8H
z) 7.24-7.33 (6H, m) 7.47 (2H, d, J = 8.4Hz) 7.53 (2
H, d, J = 8.0Hz) 7.59 (2H, d, J = 8.0Hz) 8.47 (1H, s)
8.55 (1H, dd, J = 1.4, 4.8Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (cyclohexyl Methoxy)-
N- (3-pyridylmethyl) benzamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl )-Four
-(Cyclohexylmethoxy) -N- (3-pyridylmethyl) benzamide (0.48g, 0.68mmol) in ethanol (5ml)
To this was added 4N hydrogen chloride-ethyl acetate (10 ml) dropwise, and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure and the resulting powder was collected by filtration, washed with diethyl ether, and dried under reduced pressure.
N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (cyclohexylmethoxy) -N-
(3-Pyridylmethyl) benzamide dihydrochloride (0.46g, 100
%) As a colorless amorphous powder. Elemental analysis value C ₄₀ H ₄₇ N ₃ O ₂・ 2HCl ・ H ₂ O ・ 0.6Et ₂ O, calculated value: C, 69.08; H, 7.79; N, 5.70 Found value: C, 69.35; H, 8.14; N , 5.86. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (20H, m) 2.0-2.2
(2H, m) 2.95 (1H, br) 3.80 (2H, d, J = 6.2Hz) 4.18 (2
H, s) 4.71 (2H, s) 4.75 (2H, s) 6.98 (2H, d, J = 8.8
Hz) 7.32 (2H, d, J = 8.0Hz) 7.66-7.72 (6H, m) 7.91-
7.98 (1H, m) 8.41 (1H, br) 8.81 (2H, d, J = 1.4Hz)
9.41 (2H, br)

Example 146 N-({4 ′-[(cyclohexylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) -4-isobutoxy-N- (3-pyridylmethyl) benzamide Dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-4-Isobutoxy-N- (3-pyridylmethyl) benzamide 4-isobutoxybenzoic acid (0.27g, 1.39 mmol) in N, N-dimethylformamide (10 ml) in 1-ethyl-3- (3-dimethylaminopropyl) ) Carbodiimide hydrochloride (0.36g, 1.
88mmol), 1-hydroxybenzotriazole monohydrate
(0.29g, 1.88mmol) was added and stirred as a solution for 10 minutes, then 4
-[(N-Cyclohexyl-N-tert-butoxycarbonyl) aminomethyl] -4 '-[(3-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (0.60 g, 1.24 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, hexane: acetone = 3: 2), and N-({4 '-[(N-tert-
Butoxycarbonyl-N-cyclohexylamino) methyl]
[1,1'-Biphenyl] -4-yl} methyl) -4-isobutoxy-N-
(3-Pyridylmethyl) benzamide (0.64 g, 78%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.99 (3H, s) 1.11 (3H, s)
1.2-1.8 (10H, m) 1.39 (9H, s) 2.0-2.2 (1H, m) 3.72
(2H, d, J = 6.6Hz) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.5
8 (2H, s) 4.64 (2H, s) 6.89 (2H, d, J = 8.6Hz) 7.24-
7.33 (5H, m) 7.57 (2H, d, J = 8.8Hz) 7.53 (2H, d, J =
8.4Hz) 7.59 (2H, d, J = 8.2Hz) 7.4-7.8 (1H, m) 8.47
(1H, s) 8.55 (1H, dd, J = 1.6, 4.8Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-isobutoxy-N- (3-pyridylmethyl) benzamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl]- 4-yl} methyl) -4
-Isobutoxy-N- (3-pyridylmethyl) benzamide (0.
To a solution of 52 g (0.79 mmol) in ethanol (5 ml) was added dropwise 4N hydrogen chloride-ethyl acetate (10 ml) and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure and the resulting powder was collected by filtration, washed with diethyl ether, and dried under reduced pressure. N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl}
Methyl) -4-isobutoxy-N- (3-pyridylmethyl) benzamide dihydrochloride (0.44 g, 88%) was obtained as a colorless amorphous powder. Elemental analysis _{C 37 H 43 N 3 O 2} · 2HCl · H 2 O Calculated: C, 68.09; H, 7.26 ; N, 6.46 Found: C, 68.10; H, 7.62 ; N, 6.36 1 H-NMR (d ₆ -DMSO) δ (ppm) 0.95 (3H, s) 0.98 (3H, s)
1.0-1.8 (8H, m) 1.94-2.08 (1H, m) 2.14-2.19 (2H,
m) 2.95 (1H, br) 3.77 (2H, d, J = 6.6Hz) 4.17 (2H, s)
4.71 (2H, s) 4.75 (2H, s) 6.99 (2H, d, J = 8.4Hz)
7.32 (2H, d, J = 7.6Hz) 7.50 (2H, d, J = 8.8Hz) 7.66-
7.72 (6H, m) 7.93-8.00 (1H, m) 8.43 (1H, s) 8.79
(1H, s) 8.82 (1H, s) 9.48 (2H, br)

Example 147 N-({4 ′-[(cyclohexylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4- (trifluoro Methyl) benzenesulfonamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (3-pyridylmethyl) -4- (trifluoromethyl) benzenesulfonamide 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1 '
-Biphenyl (0.48g, 0.99mmol) in acetonitrile
(10 ml) with triethylamine (0.28 ml, 2.0 mmol), p-trifluoromethylbenzenesulfonyl chloride (0.29 ml).
g, 1.2 mmol) was added under ice cooling, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 3: 1-1: 1), N-({4 '-[(N-tert-
Butoxycarbonyl-N-cyclohexylamino) methyl]
[1,1'-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4- (trifluoromethyl) benzenesulfonamide
(0.51 g, 74%) was obtained as a pale yellow solid. Melting point: 147-148 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.40 (9H,
s) 4.0-4.2 (1H, br) 4.39 (6H, s) 7.06-7.18 (3H, m)
7.26-7.30 (2H, m) 7.41-7.53 (5H, m) 7.79 (2H, d,
J = 8.2Hz) 7.97 (2H, d, J = 8.0Hz) 8.31 (1H, s) 8.47-
8.49 (1H, m). 2) N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4- (Trifluoromethyl) benzenesulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N
-(3-Pyridylmethyl) -4- (trifluoromethyl) benzenesulfonamide (0.33g, 0.48mmol) in ethyl acetate
4N Hydrogen chloride-ethyl acetate (5 ml) was added dropwise to (5 ml), and the mixture was stirred at room temperature for 30 minutes. After the solvent was concentrated under reduced pressure, the resulting solid was collected by filtration and washed with diethyl ether. It was dried under reduced pressure. N-({4 '-[(cyclohexylamino) methyl]
[1,1'-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4- (trifluoromethyl) benzenesulfonamide
The dihydrochloride salt (0.31 g, 97%) was obtained as a pale yellow solid. Melting point: 230-240 ° C Elemental analysis C ₃₄ H ₃₆ N ₃ O ₂ SF ₃・ 2HCl ・ 1.5H ₂ O Calculated: C, 57.71: H, 5.84: N, 5.94 Found: C, 57.85: H, 5.86: N, 5.98. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 3.63 (2H, s) 4.17 (2H, s) 4.
50 (2H, s) 7.26 (2H, d, J = 8.4Hz) 7.49 (2H, d, J = 8.4
Hz) 7.61-7.71 (5H, m) 8.04 (2H, d, J = 8.0Hz) 8.09
(1H, s) 8.17 (2H, d, J = 8.0Hz) 8.52 (1H, d, J = 1.4Hz)
8.60 (1H, d, J = 4.4Hz) 9.28 (2H, br)

Example 148 N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-methoxy-N- (3-pyridylmethyl) benzenesulfone Amide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-4-Methoxy-N- (3-pyridylmethyl) benzenesulfonamide 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1 '
-Triphenylamine (0.26ml, 1.86mmol) in biphenyl (0.60g, 1.24mmol) in acetonitrile (10ml)
And p-methoxybenzenesulfonyl chloride (0.28g,
1.36 mmol) were added in sequence. After stirring at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then purified by silica gel column chromatography (hexane: acetone = 5: 2-2: 1). N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-methoxy-N- (3-pyridylmethyl ) Benzenesulfonamide (0.60 g, 74%) was obtained as an orange amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 3.89 (3H, s) 4.0-4.2 (1H, br) 4.32 (4H, s) 4.40
(2H, s) 7.01 (2H, d, J = 8.8Hz) 7.08-7.21 (3H, m)
7.26-7.30 (2H, m) 7.41-7.53 (5H, m) 7.81 (2H, d, J
= 8.8Hz) 8.25 (1H, s) 8.44 (1H, d, J = 3.6Hz) 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} Methyl) -4-methoxy-N- (3-pyridylmethyl) benzenesulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1' -Biphenyl] -4-yl} methyl) -4
Concentrated hydrochloric acid (10 ml) was added dropwise to a solution of -methoxy-N- (3-pyridylmethyl) benzenesulfonamide (0.59 g, 0.90 mmol) in methanol (10 ml). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue to form a powder, which was collected by filtration with a glass filter and washed well with diethyl ether, and then N-({4 '-[(cyclohexylamino) methyl] [1,
1'-biphenyl] -4-yl} methyl) -4-methoxy-N- (3-pyridylmethyl) benzenesulfonamide dihydrochloride (0.49g,
87%) was obtained as an amorphous powder. Elemental analysis value Calculated as C ₃₃ H ₃₇ N ₃ O ₃ S ・ 2HCl ・ 0.5H ₂ O: C, 62.16; H, 6.32; N, 6.59 Found: C, 62.10; H, 6.36; N, 6.58. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.95 (1H, br) 3.89 (3H, s) 4.15 (2H, s) 4.
42 (2H, s) 4.54 (2H, s) 7.19 (2H, d, J = 9.0Hz) 7.26
(2H, d, J = 8.4Hz) 7.48 (2H, d, J = 8.0Hz) 7.61-7.85
(5H, m) 7.91 (2H, d, J = 9.2Hz) 8.23 (1H, d, J = 8.2Hz)
8.57 (1H, s) 8.67 (1H, d, J = 4.8Hz) 9.51 (3H, br)

Example 149 4-Bromo-N-({4 '-[(cyclohexylamino) methyl] [1,
1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl)
Benzenesulfonamide dihydrochloride 1) 4-Bromo-N-({4 '-[(N-tert-butoxycarbonyl-N-
Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzenesulfonamide 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-Pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (4.0 g, 8.24 mmol) in acetonitrile
(50 ml) with triethylamine (2.4 ml, 17.2 mmol) and p-
Bromobenzenesulfonyl chloride (2.53g, 9.9mmo
l) was added at room temperature, and the mixture was stirred as it was overnight. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-bromo-N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl].
-4-yl} methyl) -N- (3-pyridylmethyl) benzenesulfonamide (4.48g, 77%) was obtained as a brown amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.35 (4H, s) 4.40 (2H, s) 7.09
(2H, d, J = 8.4Hz) 7.14-7.18 (1H, m) 7.28 (2H, d, J
= 8.4Hz) 7.42-7.54 (5H, m) 7.64-7.74 (4H, m) 8.27
(1H, d, J = 2.2Hz) 8.45 (1H, dd, J = 1.4, 4.8Hz). 2) 4-Bromo-N-({4 '-[(cyclohexylamino) methyl]
[1,1'-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzenesulfonamide dihydrochloride 4-bromo-N-({4 '-[(N-tert-butoxycarbonyl -N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl}
Methyl) -N- (3-pyridylmethyl) benzenesulfonamide
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of (0.36 g, 0.51 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure and the precipitated solid was collected by filtration,
It was washed with diethyl ether and dried under reduced pressure. 4-bromo
-N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) benzenesulfonamide dihydrochloride (0.33g, 96%) was obtained as a colorless solid. Melting point: 212-214 ° C Elemental analysis C ₃₂ H ₃₄ N ₃ O ₂ SBr ・ 2HCl ・ H ₂ O Calculated: C, 55.26: H, 5.51: N, 6.04 Found: C, 55.22: H, 5.67: N, 5.81. ¹ H-NMR (CD ₃ OD) δ (ppm) 1.2-1.6 (5H, m) 1.6-1.8 (1
H, m) 1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.13 (1H, b
r) 4.26 (2H, s) 4.50 (2H, s) 4.62 (2H, s) 7.30 (2H,
d, J = 8.6Hz) 7.47 (2H, d, J = 8.2Hz) 7.58 (2H, d, J =
8.4Hz) 7.66 (2H, d, J = 8.6Hz) 7.81-7.91 (5H, m) 8.37
(1H, d, J = 7.8Hz) 8.59 (1H, s) 8.62 (1H, s).

Example 150 N-({4 ′-[(cyclohexylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [1,1′- Biphenyl] -4-sulfonamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl )
-N- (3-pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) amino Methyl] -1,1 '
-Triphenylamine (0.22ml, 1.58mmol) was added to acetonitrile solution (10ml) of -biphenyl (0.50g, 1.03mmol).
p-Phenylbenzenesulfonyl chloride (0.29g, 1.1
(5 mmol) was added at room temperature, and the mixture was stirred as it was overnight. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N -(3-Pyridylmethyl) [1,1'-biphenyl] -4
-Sulfonamide (0.60g, 83%) was obtained as a brown amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.40 (9H,
s) 4.0-4.2 (1H, br) 4.39 (6H, s) 7.10-7.17 (3H, m)
7.25-7.29 (2H, m) 7.40-7.51 (6H, m) 7.53-7.65 (2
H, m) 7.74 (2H, d, J = 8.0Hz) 7.94 (2H, d, J = 8.6Hz)
8.29 (1H, d, J = 1.8Hz) 8.44 (1H, dd, J = 1.4, 4.8Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl]- 4-yl} methyl) -N- (3-pyridylmethyl) [1,1'-
Biphenyl] -4-sulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)- N
-(3-pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide (0.44g, 0.63mmol) in ethanol solution (5ml)
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure to give a powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure.
N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [1,1'-biphenyl] -4-sulfone The amide dihydrochloride salt (0.39 g, 92%) was obtained as a colorless solid. Melting point: 224-229 ° C Elemental analysis value Calculated as C ₃₈ H ₃₉ N ₃ O ₂ S ・ 2HCl ・ 0.5H ₂ O: C, 66.75; H, 6.19; N, 6.15 Actual value: C, 66.81; H, 6.23 ^{;. N, 6.09 1 H-} NMR (CD 3 OD) δ (ppm) 1.2-1.6 (5H, m) 1.6-1.8 (1
H, m) 1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.13 (1H, b
r) 4.26 (2H, s) 4.53 (2H, s) 4.65 (2H, s) 7.31-7.3
6 (2H, m) 7.45-7.75 (11H, m) 7.81-7.95 (3H, m) 8.0
2-8.08 (2H, m) 8.38-8.42 (1H, m) 8.60 (2H, s)

Example 151 N-({4 ′-[(cyclohexylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) -4-phenoxy-N- (3-pyridylmethyl) benzenesulfone Amide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-4-phenoxy-N- (3-pyridylmethyl) benzenesulfonamide 4-phenoxybenzenesulfonyl chloride (3.67 mmol)
In a flask containing, prepared separately, 4- (N-tert-butoxycarbonyl-N-cycloheptylamino) methyl-4 '-[(3-
Pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.49
g, 1 mmol) and a solution of triethylamine (1.4 ml, 10 mmol) in acetonitrile (10 ml) were added using a pipette, and the mixture was stirred at room temperature for 10 minutes. After the reaction was completed with saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
3: 1-2: 1-1: 1) and N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-
Biphenyl] -4-yl} methyl) -4-phenoxy-N- (3-pyridylmethyl) benzenesulfonamide (0.37 g, 52%) was obtained as a red amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.35 (4H, s) 4.40 (2H, s) 7.02
-7.15 (7H, m) 7.18 (1H, d, J = 2.6Hz) 7.28 (2H, d, J
= 8.8Hz) 7.36-7.56 (7H, m) 7.81 (2H, d, J = 11.8Hz)
8.26 (1H, d, J = 2.2Hz) 8.45 (1H, dd, J = 1.8, 4.6Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl]- 4-yl} methyl) -4-phenoxy-N- (3-pyridylmethyl) benzenesulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [ 1,1'-biphenyl] -4-yl} methyl) -4
-Phenoxy-N- (3-pyridylmethyl) benzenesulfonamide (0.25g, 0.37mmol) in ethanol solution (5ml)
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure to give a powder, which was collected by filtration, washed with diethyl ether, and dried under reduced pressure.
N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-phenoxy-N- (3-pyridylmethyl) benzenesulfonamide dihydrochloride ( (0.20g, 83%)
Was obtained as a pale red amorphous powder. Elemental analysis value Calculated as C ₃₉ H ₃₉ N ₃ O ₂・ 2HCl ・ H ₂ O: C, 69.63: H, 6.44: N, 6.25 Actual value: C, 69.86: H, 6.69: N, 6.20. ¹ H- NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 4.17 (2H, s) 4.72 (2H, s) 4.
76 (2H, s) 7.01-7.09 (4H, m) 7.15-7.23 (1H, m) 7.3
4-7.46 (4H, m) 7.56-7.60 (1H, m) 7.65-7.71 (7H, m)
7.94 (1H, m) 8.42 (1H, br) 8.77 (1H, s) 8.80 (1H,
s) 9.44 (2H, s)

Example 152 N-({4 ′-[(cyclohexylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) -4′-fluoro-N- (3-pyridylmethyl) [ 1,1'-Biphenyl] -4-sulfonamide dihydrochloride 1) N-({4 '-[(N-tertbutoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4 -Yl} methyl)
-4'-Fluoro-N- (3-pyridylmethyl) [1,1'-biphenyl]
-4-Sulfonamide 4-bromo-N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl}
Methyl) -N- (3-pyridylmethyl) benzenesulfonamide
Toluene solution (5 ml) of (0.70 g, 0.99 mmol) in water (5 m
l), sodium carbonate (0.21 g, 1.98 mmol), tetrakistriphenylphosphine palladium (0.060 g, 0.05 mmol),
p-Fluorophenylboronic acid (0.17 g, 1.19 mmol) was sequentially added, and the mixture was stirred overnight at 80 ° C. under a nitrogen atmosphere. After the reaction was completed, it was diluted with ethyl acetate and washed with water and saturated saline.
The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1-1: 1), and N-({4 '-[(N-ter
t-Butoxycarbonyl-N-cyclohexylamino) methyl]
[1,1'-Biphenyl] -4-yl} methyl) -4'-fluoro-N- (3-
Pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide
(0.71 g, 99%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.38 (9H,
s) 4.0-4.2 (1H, br) 4.39 (6H, m) 7.10-7.29 (8H, m)
7.41-7.47 (4H, m) 7.52-7.63 (3H, m) 7.69 (2H, d,
J = 8.8Hz) 7.93 (2H, d, J = 8.4Hz) 8.28 (1H, d, J = 1.8H
z) 8.45 (1H, d, J = 1.4, 5.8Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4' -Fluoro-N- (3-pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride N-({4 '-[(N-tertbutoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-Biphenyl] -4-yl} methyl) -4'-
Fluoro-N- (3-pyridylmethyl) [1,1'-biphenyl] -4-
Sulfonamide (0.61g, 0.85mmol) in ethanol
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise to (5 ml), and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure, and the precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure. N-({4 '-[(cyclohexylamino) methyl] [1,1'
-Biphenyl] -4-yl} methyl) -4'-fluoro-N- (3-pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride (0.52g, 88%) colorless Obtained as a solid. Melting point: 235-239 ℃ Elemental analysis value Calculated as C ₃₈ H ₃₈ N ₃ O ₂ SF ・ 2HCl ・ 0.5H ₂ O: C, 65.04: H, 5.89: N, 5.99 Found: C, 64.94: H, 5.81 : N, 5.92. ¹ H-NMR (CD ₃ OD) δ (ppm) 1.2-1.6 (5H, m) 1.6-1.8 (1
H, m) 1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.29 (1H, b
r) 4.26 (2H, s) 4.52 (2H, s) 4.64 (2H, s) 7.23 (2H, s)
d, J = 8.6Hz) 7.32 (2H, d, J = 8.4Hz) 7.46 (2H, d, J =
8.4Hz) 7.57 (2H, d, J = 8.0Hz) 7.64 (2H, d, J = 8.4Hz)
7.72-7.91 (5H, m) 8.04 (2H, d, J = 8.4Hz) 8.38 (1H,
d, J = 8.2Hz) 8.58 (1H, s) 8.61 (1H, s).

Example 153 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4'-(tri Fluoromethyl) [1,1'-biphenyl] -4-sulfonamide ・
Dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (3-pyridylmethyl) -4 '-(trifluoromethyl) [1,1'
-Biphenyl] -4-sulfonamide 4-bromo-N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl}
Methyl) -N- (3-pyridylmethyl) benzenesulfonamide
Toluene solution (5ml) of (0.50g, 0.71mmol) in water (5m
l), sodium carbonate (0.15 g, 1.42 mmol), tetrakistriphenylphosphine palladium (0.041 g, 0.04 mmol),
p-Trifluoromethylphenylboronic acid (0.17g, 0.85m
mol) were sequentially added, and the mixture was stirred at 80 ° C. for 15 hours under a nitrogen atmosphere. After the reaction was completed, it was diluted with ethyl acetate and washed with water and saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1-1: 1), and N-
({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N-
(3-Pyridylmethyl) -4 '-(trifluoromethyl) [1,1'-biphenyl] -4-sulfonamide (0.44g, 81%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.38 (9H,
s) 4.0-4.2 (1H, br) 4.40 (6H, m) 7.10-7.18 (8H, m)
7.28 (2H, d, J = 6.6Hz) 7.41-7.47 (4H, m) 7.54 (1H,
dt, J = 2.0, 7.8Hz) 7.69-7.77 (6H, m) 7.96 (2H, d,
J = 8.4Hz) 8.29 (1H, d, J = 2.2Hz) 8.45 (1H, dd, J = 1.
6, 4.8Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4'- (Trifluoromethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1' -Biphenyl] -4-yl} methyl) -N
-(3-Pyridylmethyl) -4 '-(trifluoromethyl) [1,1'-
Biphenyl] -4-sulfonamide (0.34g, 0.44mmol) in ethanol solution (5ml) 4N hydrogen chloride-ethyl acetate
(10 ml) was added dropwise and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and the precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure. N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4'-(trifluoromethyl) [1, 1'-Biphenyl] -4-sulfonamide dihydrochloride (0.29g, 88%) was obtained as a colorless solid. Melting point: 235-237 ° C Elemental analysis C ₃₉ H ₃₈ F ₃ N ₃ O ₂ S ・ 2HCl ・ 0.5H ₂ O Calculated: C, 62.31; H, 5.50; N, 5.59 Found: C, 62.42; H , 5.41; N, 5.35. ¹ H-NMR (CD ₃ OD) δ (ppm) 1.2-1.6 (5H, m) 1.6-1.8 (1
H, m) 1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.14 (1H, b
r) 4.26 (2H, s) 4.54 (2H, s) 4.66 (2H, s) 7.33 (2H,
d, J = 8.4Hz) 7.47 (2H, d, J = 8.6Hz) 7.56 (2H, d, J =
8.4Hz) 7.65 (2H, d, J = 8.8Hz) 7.80-8.01 (7H, m) 8.10
(2H, d, J = 8.6Hz) 8.38 (1H, d, J = 8.2Hz)

Example 154 N-({4 ′-[(cyclohexylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) -4- (2-furyl) -N- (3-pyridyl Methyl) benzenesulfonamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-4- (2-furyl) -N- (3-pyridylmethyl) benzenesulfonamide 4-bromo-N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1, 1'-biphenyl] -4-yl}
Methyl) -N- (3-pyridylmethyl) benzenesulfonamide
(0.86g, 1.22mmol) and tri-n-butyl (2-furyl) stannane (0.48g, 1.34mmol) in tetrahydrofuran (5m
l) to tetrakistriphenylphosphine palladium
(0.070g, 0.061mmol) was added and the mixture was added under argon atmosphere to 20
Reflux for hours. The reaction was terminated with saturated aqueous sodium hydrogen carbonate, diluted with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1).
-3: 1-3: 4). N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-
Biphenyl] -4-yl} methyl) -4- (2-furyl) -N- (3-pyridylmethyl) benzenesulfonamide (0.75g, 89%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.36 (4H, s) 4.39 (2H, m) 6.54
(1H, ddd, J = 0.8, 2.0, 3.4Hz) 6.84 (1H, d, J = 3.2H
z) 7.08-7.17 (3H, m) 7.25-7.26 (2H, m) 7.29-7.56
(10H, m) 7.80 (2H, d, J = 8.4Hz) 7.88 (2H, d, J = 8.8H
z) 8.26 (1H, d, J = 1.8Hz) 8.44 (1H, dd, J = 1.0, 4.6H
z). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (2-furyl) -N- (3-pyridylmethyl ) Benzenesulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4
4- (2-furyl) -N- (3-pyridylmethyl) benzenesulfonamide (0.58g, 0.84mmol) in ethanol solution (5ml)
Normal hydrogen chloride-ethyl acetate (10 ml) was added dropwise at room temperature to 1
Stir for hours. The solvent was concentrated under reduced pressure, and the precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure. N-
({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (2-furyl) -N- (3-pyridylmethyl) benzenesulfonamide dihydrochloride The salt (0.33g, 96%) was obtained as a colorless solid. Melting point: 235-237 ℃ Elemental analysis C ₃₆ H ₃₅ N ₃ O ₃ S ・ 2HCl ・ 0.5H ₂ O Calculated: C, 64.37; H, 5.70; N, 6.26 Found: C, 64.40; H, 5.84 ^{;. N, 6.22 1 H-} NMR (CD 3 OD) δ (ppm) 1.2-1.6 (5H, m) 1.6-1.8 (1
H, m) 1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.14 (1H, b
r) 4.26 (2H, s) 4.51 (2H, s) 4.63 (2H, s) 6.61 (1H,
dd, J = 1.8, 3.6Hz) 7.05 (1H, d, J = 3.4Hz) 7.32 (2H,
d, J = 8.2Hz) 7.46 (2H, d, J = 8.4Hz) 7.57 (2H, d, J =
8.4Hz) 7.64 (2H, d, J = 8.4Hz) 7.69 (1H, d, J = 1.0Hz)
7.84 (1H, dd, J = 5.4, 7.6Hz) 7.98 (4H, s) 8.39 (1H,
d, J = 8.0Hz) 8.59 (1H, s) 8.62 (1H, s)

Example 155 N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4- (2- Thienyl) benzenesulfonamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (3-pyridylmethyl) -4- (2-thienyl) benzenesulfonamide 4-bromo-N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1, 1'-biphenyl] -4-yl}
Methyl) -N- (3-pyridylmethyl) benzenesulfonamide
(0.70, 0.99mmol) and tri-n-butyl (2-thienyl) stannane (0.41g, 1.09mmol) in tetrahydrofuran (5m
l) to tetrakistriphenylphosphine palladium
(0.058 g) was added, and the mixture was refluxed for 20 hours under an argon atmosphere. The reaction was terminated with saturated aqueous sodium hydrogen carbonate, diluted with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate = 3: 1-2: 3)
Purified in. N-({4 '-[(N-tertbutoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4- ( 2-Thienyl) benzenesulfonamide (0.71 g, 99%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.37 (6H, s) 7.09-7.17 (4H, m)
7.26-7.29 (2H, m) 7.40-7.47 (6H, m) 7.51-7.55 (1
H, m) 7.75 (2H, d, J = 8.4Hz) 7.87 (2H, d, J = 8.8Hz)
8.28 (1H, d, J = 2.2Hz) 8.45 (1H, dd, J = 1.4, 4.8Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl]- 4-yl} methyl) -N- (3-pyridylmethyl) -4- (2-
Thienyl) benzenesulfonamide dihydrochloride N-({4 '-[(N-tertbutoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N-
To a solution of (3-pyridylmethyl) -4- (2-thienyl) benzenesulfonamide (0.59g, 0.83mmol) in ethanol (5ml) was added 4N hydrogen chloride-ethyl acetate (10ml) dropwise and the mixture was stirred at room temperature for 1 hour. did. The solvent was concentrated under reduced pressure, and the precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure.
N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4- (2-thienyl) benzenesulfonamide Dihydrochloride (0.47g, 83
%) Was obtained as a colorless solid. Melting point: 237-244 ° C Elemental analysis C ₃₆ H ₃₇ N ₃ O ₂ S ₂・ 2HCl ・ 0.5H ₂ O Calculated: C, 62.69: H, 5.85: N, 6.09 Found: C, 62.76: H, 5.91: N, 6.03. ¹ H-NMR (CD ₃ OD) δ (ppm) 1.2-1.6 (5H, m) 1.6-1.8 (1
H, m) 1.8-2.0 (2H, m) 2.1-2.3 (2H, m) 3.29 (1H, b
r) 4.26 (2H, s) 4.51 (2H, s) 4.63 (2H, s) 7.18 (1H,
dd, J = 3.6, 5.0Hz) 7.32 (2H, d, J = 8.0Hz) 7.46 (2H,
d, J = 8.0Hz) 7.54-7.65 (6H, m) 7.81-8.00 (5H, m)
8.40 (1H, d, J = 8.4Hz) 8.59-8.62 (2H, m)

Example 156 N-[(4 '-{[(cyclohexylmethyl) amino] methyl} [1,1'
-Biphenyl] -4-yl) methyl] -N- (3-pyridylmethyl) -4
-(Trifluoromethyl) benzenesulfonamide dihydrochloride 1) N-[(4 '-{[N-tert-butoxycarbonyl-N- (cyclohexylmethyl) amino] methyl} [1,1'-biphenyl]- 4-yl) methyl] -N- (3-pyridylmethyl) -4- (trifluoromethyl) benzenesulfonamide 4- (N-tert-butoxycarbonyl-N-cyclohexylmethylamino) methyl-4 '-[(3 -Pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.75g, 1.51mmol) in acetonitrile solution (10ml) with triethylamine (0.42ml, 3.02mm
ol) and p-trifluoromethylbenzenesulfonyl chloride (0.56 g, 2.27 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1), and N-
[(4 '-{[N-tert-butoxycarbonyl-N- (cyclohexylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl] -N- (3-pyridylmethyl) -4 -(Trifluoromethyl) benzenesulfonamide (0.72g, 68%) was obtained as a pale yellow amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.8-1.0 (2H, m) 1.0-1.8 (18
H, m) 3.03 (2H, br) 4.39 (4H, s) 4.47 (2H, d, J = 6.
2Hz) 7.08-7.18 (4H, m) 7.26-7.27 (1H, m) 7.40-7.53
(5H, m) 7.80 (2H, d, J = 8.2Hz) 8.00 (2H, d, J = 8.0H
z) 8.31 (1H, s) 8.47 (1H, d, J = 4.0Hz). 2) N-[(4 '-{[(cyclohexylmethyl) amino] methyl}
[1,1'-Biphenyl] -4-yl) methyl] -N- (3-pyridylmethyl) -4- (trifluoromethyl) benzenesulfonamide
Dihydrochloride N-[(4 '-{[N-tert-butoxycarbonyl-N- (cyclohexylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl] -N- (3- Pyridylmethyl) -4- (trifluoromethyl)
To a solution of benzenesulfonamide (0.57g, 0.81mmol) in ethyl acetate (3ml), 4N hydrogen chloride-ethyl acetate (7ml)
Was added dropwise, and the mixture was stirred at room temperature for 30 minutes. After concentration of the solvent under reduced pressure, the residual solid was collected by filtration with diethyl ether, washed well with diethyl ether, and dried to give N-[(4 '-{[(cyclohexylmethyl) amino] methyl} [1,1 '-Biphenyl]
-4-yl) methyl] -N- (3-pyridylmethyl) -4- (trifluoromethyl) benzenesulfonamide dihydrochloride (0.53g, 9
6%) was obtained as a colorless solid. Melting point: 210-214 ° C Elemental analysis C ₃₄ H ₃₆ N ₃ O ₂ SF ₃・ 2HCl Calculated: C, 60.00; H, 5.63; N, 6.17 Found: C, 59.75; H, 5.72; N, 6.06 _{^{. 1 H-NMR (d 6}} -DMSO) δ (ppm) 0.8-1.4 (5H, m) 1.6-1.9
(6H, m) 2.70 (2H, s) 4.14 (2H, s) 4.52 (2H, s) 4.6
5 (2H, s) 7.27 (2H, d, J = 8.0Hz) 7.63-7.80 (5H, m)
8.05 (2H, d, J = 8.4Hz) 8.19 (3H, d, J = 8.4Hz) 8.58
(1H, s) 8.65 (1H, d, J = 5.4Hz) 9.45 (2H, br)

Example 157 N-[(4 '-{[(cyclohexylmethyl) amino] methyl} [1,1'
-Biphenyl] -4-yl) methyl] -4-methoxy-N- (3-pyridylmethyl) benzenesulfonamide dihydrochloride 1) N-[(4 '-{[N-tert-butoxycarbonyl-N- (Cyclohexylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl] -4-methoxy-N- (3-pyridylmethyl) benzenesulfonamide 4- (N-tert-butoxycarbonyl-N -Cyclohexylmethylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.79g, 1.59mmol) in acetonitrile solution (10ml) with triethylamine (0.45ml, 3.18mm)
ol), p-methoxybenzenesulfonyl chloride (0.50
g, 2.40 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2-1-1: 1: 2), and N-
[(4 '-{[N-tert-Butoxycarbonyl-N- (cyclohexylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl] -4-methoxy-N- (3-pyridyl Methyl) benzenesulfonamide (0.72 g, 68%) was obtained as a pale yellow amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.8-1.0 (2H, br) 1.0-1.8 (1
8H, m) 1.36 (9H, s) 3.05 (2H, br) 3.89 (3H, s) 4.3
3 (4H, s) 4.49 (2H, br) 7.01 (2H, d, J = 8.8Hz) 7.09
-7.16 (3H, m) 7.26-7.29 (1H, br) 7.40-7.54 (5H, m)
7.82 (2H, d, J = 9.0Hz) 8.25 (1H, d, J = 1.4Hz) 8.44
(1H, dd, J = 1.8, 4.8Hz). 2) N-[(4 '-{[(cyclohexylmethyl) amino] methyl}
[1,1'-Biphenyl] -4-yl) methyl] -4-methoxy-N- (3-
Pyridylmethyl) benzenesulfonamide dihydrochloride N-[(4 '-{[N-tert-butoxycarbonyl-N- (cyclohexylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) methyl ] -4-Methoxy-N- (3-pyridylmethyl) benzenesulfonamide (0.58g, 0.87mmol) in ethyl acetate (3m
lN) was added dropwise with 4N hydrogen chloride-ethyl acetate (7 ml), and the mixture was stirred at room temperature for 30 minutes. After the solvent was concentrated under reduced pressure, the residual solid was collected by filtration with diethyl ether, washed well with diethyl ether, dried and N-[(4 '-{[(cyclohexylmethyl) amino] methyl} [1,1 '-Biphenyl] -4-yl) methyl]-
4-Methoxy-N- (3-pyridylmethyl) benzenesulfonamide dihydrochloride (0.52 g, 93%) was obtained as a colorless solid. Melting point: 173-175 ° C Elemental analysis C ₃₄ H ₃₉ N ₃ O ₃・ 2HCl ・ 0.5H ₂ O Calculated: C, 62.66; H, 6.50; N, 6.45 Found: C, 62.35; H, 6.52; ^{N, 6.32. 1 H-NMR} (d 6 -DMSO) δ (ppm) 0.8-1.4 (5H, m) 1.6-1.9
(6H, m) 2.71 (2H, s) 3.89 (3H, s) 4.14 (2H, s) 4.4
0 (2H, s) 4.50 (2H, s) 7.19 (2H, d, J = 8.8Hz) 7.26
(2H, d, J = 8.2Hz) 7.49 (2H, d, J = 8.2Hz) 7.65 (4H,
s) 7.73 (1H, dd, J = 5.8, 8.0Hz) 7.90 (2H, d, J = 8.4H
z) 8.10 (1H, d, J = 8.0Hz) 8.51 (1H, s) 8.62 (1H, d,
J = 5.0Hz) 9.30 (2H, s)

Example 158 N-({4 '-[(cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4- (tri Fluoromethyl) benzenesulfonamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl )
-N- (3-pyridylmethyl) -4- (trifluoromethyl) benzenesulfonamide 4- (N-tert-butoxycarbonyl-N-cycloheptylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl ] -1,1 '
-Biphenyl (0.60g, 1.2mmol) in acetonitrile
(10 ml) with triethylamine (0.51 ml, 3.6 mmol), p-trifluoromethylbenzenesulfonyl chloride (0.59 ml).
g, 2.4 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 17 hours.
Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate,
The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-1: 2), and N-({4 '-[(N
-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4- (trifluoromethyl) benzenesulfonamide ( 0.53 g, 63%) was obtained as a pale yellow solid. Melting point: 134-135 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-1.8 (12H, m) 1.35 (9H,
s) 4.0-4.2 (1H, br) 4.39 (6H, s) 7.09 (2H, d, J = 8.
2Hz) 7.16-7.19 (1H, m) 7.26-7.31 (2H, m) 7.41-7.48
(5H, m) 7.79 (2H, d, J = 8.4Hz) 7.97 (2H, d, J = 8.4H
z) 8.30 (1H, s) 8.47 (1H, d, J = 4.8Hz). 2) N-({4 '-[(cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} Methyl) -N- (3-pyridylmethyl) -4- (trifluoromethyl) benzenesulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-Biphenyl] -4-yl} methyl) -N
-(3-Pyridylmethyl) -4- (trifluoromethyl) benzenesulfonamide (0.34g, 0.48mmol) in ethyl acetate
4N Hydrogen chloride-ethyl acetate (5 ml) was added dropwise to (5 ml), and the mixture was stirred at room temperature for 30 minutes. After the solvent was concentrated under reduced pressure, the generated crystals were collected by filtration and washed with diethyl ether. It was dried under reduced pressure. N-({4 '-[(cycloheptylamino) methyl]
[1,1'-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4- (trifluoromethyl) benzenesulfonamide
The dihydrochloride salt (0.31 g, 95%) was obtained as a pale yellow solid. Mp: 225-233 ° C. Elemental analysis _{C 34 H 36 N 3 O 2} SF 3 · 2HCl Calculated: C, 60.00: H, 5.63 : N, 6.17 Found: C, 59.70: H, 5.77 : N, 6.29 _{^{. 1 H-NMR (d 6}} -DMSO) δ (ppm) 1.2-1.8 (10H, m) 2.0-2.2
(2H, m) 3.12 (1H, br) 4.16 (2H, s) 4.51 (2H, s) 4.6
3 (2H, s) 7.26 (2H, d, J = 8.0Hz) 7.48 (2H, d, J = 8.0
Hz) 7.61-7.77 (6H, m) 8.04 (2H, d, J = 8.4Hz) 8.06
(1H, s) 8.18 (2H, d, J = 8.0Hz) 8.56 (1H, s) 8.64 (1
H, d, J = 5.0Hz) 9.33 (2H, s)

Example 159 N-({4 '-[(Cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-methoxy-N- (3-pyridylmethyl) benzene Sulfonamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-4-Methoxy-N- (3-pyridylmethyl) benzenesulfonamide 4- (N-tert-butoxycarbonyl-N-cycloheptylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1, 1 '
-Biphenyl (0.61g, 1.23mmol) in acetonitrile
(10 ml) with triethylamine (0.52 ml, 3.69 mmol), p-
Methoxybenzenesulfonyl chloride (0.51ml, 2.46
mmol) was added under ice cooling, and the mixture was stirred at room temperature for 17 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-1: 2), and N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1 ,
1′-Biphenyl] -4-yl} methyl) -4-methoxy-N- (3-pyridylmethyl) benzenesulfonamide (0.57 g, 69%) was obtained as a pale yellow amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-1.8 (12H, m) 1.36 (9H,
s) 3.89 (3H, s) 4.0-4.2 (1H, br) 4.32 (4H, s) 4.37
(2H, br) 7.00 (2H, d, J = 9.0Hz) 7.08-7.17 (3H, m)
7.26-7.31 (2H, m) 7.41-7.54 (5H, m) 7.82 (2H, d, J
= 9.2Hz) 8.25 (1H, d, J = 1.8Hz) 8.45 (1H, dd, J = 1.8,
4.8Hz) 2) N-({4 '-[(Cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-methoxy-N- (3-pyridylmethyl) benzenesulfone Amide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4
To the ethyl acetate solution (5 ml) of -methoxy-N- (3-pyridylmethyl) benzenesulfonamide (0.49 g, 0.73 mmol) was added dropwise 4N hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 1 hour. After the solvent was concentrated under reduced pressure, the generated crystals were collected by filtration and washed with diethyl ether. It was dried under reduced pressure. N-
({4 '-[(Cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-methoxy-N- (3-pyridylmethyl)
Benzenesulfonamide dihydrochloride (0.43 g, 92%) was obtained as a pale yellow solid. Melting point: 174-182 ° C Elemental analysis C ₃₄ H ₃₉ N ₃ O ₃ S ・ Calculated as 2HCl: C, 63.54: H, 6.43: N, 6.54 Found: C, 63.38: H, 6.45: N, 6.67. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.2-1.8 (10H, m) 2.0-2.2
(2H, m) 3.12 (1H, s) 3.89 (3H, s) 4.15 (2H, s) 4.4
1 (2H, s) 4.52 (2H, s) 7.19 (2H, d, J = 9.2Hz) 7.26
(2H, d, J = 8.2Hz) 7.49 (2H, d, J = 8.0Hz) 7.61-7.81
(5H, m) 7.90 (2H, d, J = 8.8Hz) 8.18 (1H, d, J = 8.0Hz)
8.54 (1H, s) 8.64 (1H, d, J = 5.6Hz) 9.35 (2H, br)

Example 160 N-benzyl-N- [4- (4′-cyclohexylaminomethyl) biphenylmethyl] -4-trifluoromethylbenzenesulfonamide hydrochloride 1) N-benzyl-N- [4- [ 4 '-(N-tert-butoxycarbonyl-
N-cyclohexyl) aminomethyl] -1,1'-biphenylmethyl] -4-trifluoromethylbenzenesulfonamide 4-[(tert-butoxycarbonyl-N-cyclohexyl) amino] methyl-4'-benzylaminomethyl-1 , 1'-biphenyl
To a solution of (0.7 g, 1.44 mmol) in acetonitrile (10 ml) was added triethylamine (0.26 ml, 1.88 mmol) and 4-trifluoromethylbenzenesulfonyl chloride (0.39 g, 1.59 mmol), and the mixture was stirred at room temperature for 1 hour. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with aqueous potassium hydrogen sulfate solution and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1), and N-benzyl-N- [4- [4 '-(N-tert-butoxycarbonyl
-N-Cyclohexyl) aminomethyl] -4-trifluoromethylbenzenesulfonamide (0.93g, 93%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.85 (19H, m), 3.90-4.20 (1H,
m), 4.40 (6H, s), 7.00-7.18 (4H, m), 7.20-7.38 (5H, m),
7.40-7.58 (4H, m), 7.74 (2H, d, J = 8.8Hz), 7.92 (2H, d, J =
8.8Hz). 2) N-benzyl-N- [4- (4'-cyclohexylaminomethyl)
Biphenylmethyl] -4-trifluoromethylbenzenesulfonamide / hydrochloride N-benzyl-N- [4- [4 '-(N-tert-butoxycarbonyl-N-
Cyclohexyl) aminomethyl] -1,1'-biphenyl-methyl] -4-trifluoromethylbenzenesulfonamide (0.7
8 g, 1.13 mmol) of 4N hydrogen chloride / ethyl acetate (15 ml) was dissolved, and the mixture was stirred at room temperature for 30 minutes. Diethyl ether was added to the reaction solution, and the precipitated crystals were collected by filtration, and N-benzyl-N- [4-
(4'-Cyclohexylaminomethyl) biphenylmethyl] -4
-Trifluoromethylbenzenesulfonamide / hydrochloride
(0.65g, 92%) was obtained. Melting point 236-240 ° C. Elemental analysis value C ₃₄ H ₃₅ F ₃ N ₂ O ₂ S.HCl, calculated value: C, 64.90; H, 5.77; N, 4.45 Found value: C, 64.81; H, 5.73; N , 4.60. ¹ H-NMR (d ₆ -DMSO) δ: 1.05-1.90 (8H, m), 2.10-2.25 (2H,
m), 2.90-3.10 (1H, m), 4.18 (2H, brs), 4.42 (4H, s), 7.
10-7.30 (7H, m), 7.53 (2H, d, J = 7.0Hz), 7.67 (4H, s), 7.9
6 (2H, d, J = 8.0Hz), 8.09 (2H, d, J = 8.0Hz), 9.20 (2H, br,
NH ₂ ⁺ ).

Example 161 N-benzyl-N- [4- (4′-cyclohexylaminomethyl) biphenylmethyl] -4-methoxybenzenesulfonamide
Hydrochloride 1) N-benzyl-N- [4- [4 '-(N-tert-butoxycarbonyl-
N-Cyclohexyl) aminomethyl] -1,1'-biphenylmethyl] -4-methoxybenzenesulfonamide N-benzyl-4-[(N-tert-butoxycarbonyl-N-cyclohexyl) aminomethyl] -1,1 ' To a solution of -biphenyl-4-methylamine (0.7g, 1.44mmol) in acetonitrile (10ml) was added triethylamine (0.26ml, 1.88mmol) and 4-methoxybenzenesulfonyl chloride (0.33g, 1.59mmol) at room temperature. Stir for 1 hour. Water (100 ml) was added to the reaction solution, and ethyl acetate was added.
It was extracted with (100 ml). The extract was washed with an aqueous potassium hydrogen sulfate solution and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate,
It was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give N-benzyl-N- [4- [4 '-(N-tert-butoxycarbonyl-N-cyclohexyl) aminomethyl]. -1,1'-Biphenylmethyl] -4-methoxybenzenesulfonamide (0.80 g, 85%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.85 (19H, m), 3.88 (3H, s), 3.9
0-4.20 (1H, m), 4.34 (4H, s), 4.40 (2H, s), 6.93-7.05 (2
H, m), 7.05-7.18 (4H, m), 7.18-7.37 (5H, m), 7.40-7.55
(4H, m), 7.75-7.90 (2H, m). 2) N-benzyl-N- [4- (4'-cyclohexylaminomethyl)
Biphenylmethyl] -4-methoxybenzenesulfonamide / hydrochloride N-benzyl-N- [4- [4 '-(N-tert-butoxycarbonyl-N-
Cyclohexyl) aminomethyl] -1,1'-biphenylmethyl] -4-methoxybenzenesulfonamide (0.65g, 0.99mm
ol) was dissolved in 4N hydrogen chloride / ethyl acetate (15 ml), and the mixture was stirred at room temperature for 1 hr. Add diethyl ether to the reaction mixture,
The precipitated crystals were collected by filtration to obtain N-benzyl-N- [4- (4'-cyclohexylaminomethyl) biphenylmethyl] -4-methoxybenzenesulfonamide hydrochloride (0.53g, 90%). Melting point 224-228 ° C. Elemental analysis value C ₃₄ H ₃₈ N ₂ O ₃ S.HCl, calculated value: C, 69.07; H, 6.65; N, 4.74 Found value: C, 68.88; H, 6.53; N, 4.86 _{^{. 1 H-NMR (d 6}} -DMSO) δ: 1.10-1.90 (8H, m), 2.10-2.25 (2H,
m), 2.90-3.10 (1H, m), 3.87 (3H, s), 4.19 (2H, brs), 4.3
0 (4H, s), 7.05-7.35 (11H, m), 7.54 (2H, d, J = 7.8Hz), 7.6
0-7.80 (4H, m), 7.84 (2H, d, J = 9.0Hz), 9.08 (2H, br, N
H ₂ ⁺ ).

Example 162 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (2-pyridyl) -4- (trifluoromethyl) ) Benzenesulfonamide / hydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (2-pyridyl) -4- (trifluoromethyl) benzenesulfonamide N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -2
-Pyridineamine (0.22g, 0.47mmol) in toluene solution
(10 ml) with triethylamine (0.65 ml, 4.66 mmol), 4-dimethylaminopyridine (85 mg, 0.70 mmol) p-trifluoromethylbenzenesulfonyl chloride (0.17 g, 7.0 mm
ol) was added under ice cooling, and the mixture was heated under reflux overnight. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate was added, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
Purify with (hexane: ethyl acetate = 5: 1-4: 1) and N-
({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N-
(2-Pyridyl) -4- (trifluoromethyl) benzenesulfonamide (0.24g, 56%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.35 (9H,
s) 4.37 (4H, s) 5.01 (2H, s) 7.10-7.16 (1H, m) 7.2
3-7.32 (2H, m) 7.34 (2H, d, J = 8.0Hz) 7.43-7.62 (5
H, m) 7.62-7.81 (6H, m). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (2- Pyridyl) -4- (trifluoromethyl) benzenesulfonamide hydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4- Ill} methyl) -N
-(2-Pyridyl) -4- (trifluoromethyl) benzenesulfonamide (0.18g, 0.265mmol) in ethyl acetate (2ml)
To the mixture was added 4N hydrogen chloride-ethyl acetate (8 ml) dropwise, and the mixture was stirred at room temperature for 1 hour. After the solvent was concentrated under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give N-({4'-
[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-
Ill} methyl) -N- (2-pyridyl) -4- (trifluoromethyl)
Benzenesulfonamide hydrochloride (0.09 g, 52%) was obtained as a colorless solid. Mp 234-241 ° C. Elemental analysis _{C 32 H 32 N 3 O 2} SF 3 · HCl · 0.25H 2 O Calculated: C, 61.93; H, 5.44 ; N, 6.77 Found: C, 61.94; H, 5.71 ; N, 6.62. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.98 (1H, br) 4.16 (2H, s) 5.08 (2H, s) 7.
24-7.36 (1H, m) 7.36 (2H, d, J = 8.4Hz) 7.47 (1H, d,
J = 8.0Hz) 7.58-7.71 (6H, m) 7.84 (1H, dt, J = 1.8,
5.4Hz) 7.92-7.98 (4H, m) 8.31-8.34 (1H, m) 9.08 (2
H, br)

Example 163 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-methoxy-N- (2-pyridyl) benzenesulfonamide・ Hydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-4-Methoxy-N- (2-pyridyl) benzenesulfonamide N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl } Methyl) -2
-Pyridineamine (0.60g, 1.27mmol) in toluene
(10 ml) with triethylamine (3.1 ml, 2.18 mmol), p-methoxybenzenesulfonyl chloride (2.26 g, 10.9 mmo
l) and 4-dimethylaminopyridine (27 mg, 0.22 mmol) were added under ice cooling, and the mixture was heated under reflux for 15 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5:
1), N-({4 '-[(N-tert-butoxycarbonyl-N-
Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4-methoxy-N- (2-pyridyl) benzenesulfonamide (0.63g, 43%) was obtained as a red amorphous powder. It was ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 3.85 (3H, s) 4.0-4.2 (1H, br) 4.37 (2H, s) 5.00
(2H, s) 6.82-6.98 (3H, m) 7.03-7.09 (1H, m) 7.22-
7.76 (11H, m) 8.28 (1H, d, J = 4.8Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)- 4-Methoxy-N- (2-pyridyl) benzenesulfonamide / hydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4 -Yl} methyl) -4
-Methoxy-N- (2-pyridyl) benzenesulfonamide (0.
50 g, 0.74 mmol) in ethanol solution (10 ml) and concentrated hydrochloric acid (1
(0 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. After the solvent was concentrated under reduced pressure, a solid was precipitated from the residue with ethanol-diethyl ether, collected by filtration, and dried under reduced pressure. N-({4'-
[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-
Il} methyl) -4-methoxy-N- (2-pyridyl) benzenesulfonamide hydrochloride (0.37 g, 82%) was obtained as a colorless solid. Melting point: 180-194 ° C Elemental analysis C ₃₂ H ₃₆ N ₃ O ₃ S ・ HCl ・ 0.5H ₂ O Calculated: C, 65.46; H, 6.35; N, 7.16 Found: C, 65.70; H, 6.13 ; N, 7.14. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.99 (1H, br) 3.84 (3H, s) 4.17 (2H, s) 5.
05 (2H, s) 7.10 (2H, d, J = 8.8Hz) 7.21 (1H, dd, J =
4.8, 7.4Hz) 7.36 (2H, d, J = 8.2Hz) 7.50 (1H, d, J =
8.0Hz) 7.58-7.71 (8H, m) 7.81 (1H, m) 8.30 (1H, d,
J = 3.0Hz) 9.04 (2H, s)

Example 164 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N-[(6-methyl-3-pyridyl) methyl] -4- (trifluoromethyl) benzenesulfonamide
Dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N-[(6-Methyl-3-pyridyl) methyl] -4- (trifluoromethyl) benzenesulfonamide 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(2- Methyl-3-pyridylmethyl) aminomethyl] -1,1'-biphenyl (0.47g, 0.94mmol) in acetonitrile (10ml) was added to triethylamine (0.40ml, 2.86m).
mol) and 4-trifluoromethylbenzenesulfonyl chloride (0.35 g, 1.43 mmol) were added, and the mixture was stirred at room temperature for 1 hr. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: acetone = 5: 2-1: 1) to give N-({4 '-[(N-tert. -Butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl}
Methyl) -N-[(6-methyl-3-pyridyl) methyl] -4- (trifluoromethyl) benzenesulfonamide (0.61g, 92%)
Was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.38 (9H,
s) 2.49 (3H, s) 4.0-4.2 (1H, br) 4.35 (2H, s) 4.38
(4H, s) 7.01 (1H, d, J = 8.2Hz) 7.10 (2H, d, J = 8.4H
z) 7.26-7.31 (2H, m) 7.37-7.48 (6H, m) 7.78 (2H,
d, J = 8.0Hz) 7.86 (2H, d, J = 8.0Hz) 8.15 (1H, d, J = 2.
2Hz). 2) N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N-[(6-methyl-3-pyridyl) methyl]- 4- (Trifluoromethyl) benzenesulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} Methyl) -N
Concentrated hydrochloric acid (10 ml) was added dropwise to an ethanol solution (10 ml) of-[(6-methyl-3-pyridyl) methyl] -4- (trifluoromethyl) benzenesulfonamide (0.57g, 0.83mmol), and the mixture was stirred at room temperature for 1 hour. Stir for hours. After the solvent was concentrated under reduced pressure, a solid was precipitated from the residue with ethanol-diethyl ether, collected by filtration, and dried under reduced pressure. N-({4 '-[(cyclohexylamino)
Methyl] [1,1'-biphenyl] -4-yl} methyl) -N-[(6-methyl-3-pyridyl) methyl] -4- (trifluoromethyl) benzenesulfonamide dihydrochloride (0.42g , 93%) was obtained as a colorless solid. Melting point: 241-249 ° C Elemental analysis C ₃₄ H ₃₆ N ₃ O ₂ SF ₃・ 2HCl ・ 0.5H ₂ O Calculated: C, 59.21: H, 5.70: N, 6.09 Found: C, 58.92: H, 5.65: N, 6.02. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.55 (3H, s) 2.96 (1H, br) 4.17 (2H, s) 4.
50 (2H, s) 4.58 (2H, s) 7.26 (2H, d, J = 8.0Hz) 7.61
7.67 (5H, m) 8.02-8.06 (3H, m) 8.17 (2H, d, J = 8.0H
z) 8.40 (1H, s) 9.30 (2H, s)

Example 165 N-({4 ′-[(cyclohexylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) (phenyl) -N- (3-pyridylmethyl) methanesulfonamide Dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
(Phenyl) -N- (3-pyridylmethyl) methanesulfonamide 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (0.50g, 1.03mmol) in acetonitrile
Triethylamine (0.44 ml, 3.15 mmol) and benzylsulfonyl chloride (0.30 g, 1.55 mmol) were added to (10 ml) at room temperature, and the mixture was stirred for 30 minutes as it was. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine.
The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 -hexane: acetone = 3: 2), and N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl ] [1,1'-Biphenyl] -4-yl} methyl) (phenyl) -N- (3-pyridylmethyl) methanesulfonamide (0.43 g, 65%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-2.0 (10H, m) 1.40 (9H,
s) 4.10 (2H, s) 4.17 (2H, s) 4.25 (2H, s) 4.41 (2
H, s) 7.15-7.37 (10H, m) 7.47-7.62 (5H, m) 8.37 (1
H, s) 8.48 (1H, s). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) (phenyl) -N- (3 -Pyridylmethyl) methanesulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise to an ethanol solution (5 ml) of (phenyl) -N- (3-pyridylmethyl) methanesulfonamide (0.41 g, 0.64 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure and the precipitated powder was collected by filtration, washed with diethyl ether, and dried under reduced pressure. N-
({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) (phenyl) -N- (3-pyridylmethyl)
Methanesulfonamide dihydrochloride (0.31 g, 79%) was obtained as a colorless amorphous powder. Elemental analysis calculated as C ₃₃ H ₃₇ N ₃ O ₂ S ・ 2HCl ・ 0.5H ₂ O: C, 63.76; H, 6.49; N, 6.76 Found: C, 63.50; H, 6.82; N, 6.73. ¹ H-NMR (CD ₃ OD) δ (ppm) 1.1-1.8 (8H, m) 2.1-2.2 (2
H, m) 2.95 (1H, br) 4.16 (2H, s) 4.37 (2H, s) 4.52
(2H, s) 4.75 (2H, s) 7.27 (2H, d, J = 8.0Hz) 7.42-
7.49 (7H, m) 7.61-7.76 (5H, m) 8.14 (1H, d, J = 8.0H
z) 8.52 (1H, s) 8.61 (1H, d, J = 5.6Hz) 9.44 (2H, s)

Example 166 (4-Bromophenyl) -N-({4 '-[(cyclohexylamino)
Methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) methanesulfonamide dihydrochloride 1) (4-Bromophenyl) -N-({4 '-[ (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) methanesulfonamide 4- (N-tert-butoxy Carbonyl-N-cyclohexylamino) methyl-4 '-[(3-pyridylmethyl) aminomethyl] -1,1'
-Biphenyl (1.80g, 3.71mmol) in acetonitrile
(20 ml) with triethylamine (0.78 ml, 5.59 mmol) and p-
Bromobenzylsulfonyl chloride (1.10g, 4.08mmo
l) was added at room temperature and the mixture was stirred as it was for 30 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Hexane: Ethyl acetate = 1: 1-Hexane: Acetone = 1: 1)
Purified by (4-bromophenyl) -N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'
-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) methanesulfonamide (2.17g, 79%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.38 (9H,
s) 4.0-4.2 (1H, br) 4.12 (2H, s) 4.16 (2H, s) 4.21
(2H, s) 4.41 (2H, s) 7.01 (2H, d, J = 8.4Hz) 7.20-7.
32 (5H, m) 7.42-7.64 (7H, m) 8.44 (1H, s) 8.53 (1
H, d, J = 3.2Hz). 2) (4-Bromophenyl) -N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N -(3-Pyridylmethyl) methanesulfonamide dihydrochloride (4-bromophenyl) -N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'- Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) methanesulfonamide (0.40g, 0.54mmol) in ethanol (5m
l), 4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise,
Stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure and the precipitated powder was collected by filtration, washed with diethyl ether, and dried under reduced pressure. (4-Bromophenyl) -N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) methanesulfonamide di Hydrochloride (0.31g,
81%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₃ H ₃₈ BrN ₃ O ₂ S ・ 2HCl ・ H ₂ O: C, 55.70; H, 5.95; N, 5.91 Found: C, 55.59; H, 6.13; N, 5.75 ¹ H- NMR (CD ₃ OD) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2 (2
H, m) 2.95 (1H, br) 4.17 (2H, s) 4.40 (2H, s) 4.53
(2H, s) 4.75 (2H, s) 7.27 (2H, d, J = 8.0Hz) 7.42-
7.50 (4H, m) 7.63-7.75 (7H, m) 8.13 (1H, d, J = 8.6H
z) 8.61 (1H, d, J = 5.2Hz) 9.40 (2H, br).

Example 167 [1,1′-biphenyl] -4-yl-N-({4 ′-[(cyclohexylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) -N -(3-
Pyridylmethyl) methanesulfonamide dihydrochloride 1) [1,1'-biphenyl] -4-yl-N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1 , 1'-
Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) methanesulfonamide (4-bromophenyl) -N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl ] [1,1'-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) methanesulfonamide (0.53g, 0.72mmol) in toluene (5ml)
Water (5 ml), sodium carbonate (0.16 g, 1.44 mmol), tetrakistriphenylphosphine palladium (42 mg, 0.03
6 mmol) and phenylboronic acid (0.11 g, 0.86 mmol) were sequentially added, and the mixture was stirred overnight at 80 ° C. under a nitrogen atmosphere. After the reaction was completed, it was diluted with ethyl acetate and washed with water and saturated saline.
The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
Silica gel column chromatography (hexane)
: Ethyl acetate = 2: 1 -Hexane: Acetone = 3: 2) and purified by [1,1'-biphenyl] -4-yl-N-({4 '-[(N-tert-butoxycarbonyl-N -Cyclohexylamino) methyl] [1,1 '
-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) methanesulfonamide (0.47g, 89%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.40 (9H,
s) 4.0-4.2 (1H, br) 4.16 (2H, s) 4.23 (2H, s) 4.29
(2H, s) 4.41 (2H, s) 7.17-7.64 (19H, m) 8.41 (1H,
d, J = 2.0Hz) 8.50 (1H, dd, J = 1.8, 5.0Hz). 2) [1,1'-biphenyl] -4-yl-N-({4 '-[(cyclohexylamino) methyl] [1,1'-Biphenyl] -4-yl} methyl) -N
-(3-Pyridylmethyl) methanesulfonamide dihydrochloride [1,1'-biphenyl] -4-yl-N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) methanesulfonamide (0.36g, 0.46mmol) in ethanol solution (5ml) 4N hydrogen chloride-ethyl acetate (10ml) ) Was added dropwise, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure and the resulting powder was collected by filtration, washed with diethyl ether, and dried under reduced pressure. [1,1'-Biphenyl] -4-yl-N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl ) Methanesulfonamide dihydrochloride (0.35 g, 85%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₉ H ₄₁ N ₃ O ₂ S ・ 2HCl ・ 1.25H ₂ O: C, 65.86; H, 6.45; N, 5.91 Found value: C, 65.85; H, 6.58; N, 5.86. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.94 (1H, s) 3.15 (2H, s) 3.42 (2H, s) 4.5
5 (2H, s) 4.78 (2H, s) 7.27 (2H, d, J = 8.4Hz) 7.35
7.77 (16H, m) 8.13 (1H, d, J = 7.8Hz) 8.55 (1H, s)
8.60 (1H, d, J = 5.2Hz) 9.37 (2H, br)

Example 168 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [4'-(tri Fluoromethyl) [1,1'-biphenyl] -4-yl] methanesulfonamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1 , 1'-Biphenyl] -4-yl} methyl)
-N- (3-pyridylmethyl) [4 '-(trifluoromethyl) [1,1'
-Biphenyl] -4-yl] methanesulfonamide (4-bromophenyl) -N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl]- 4-yl} methyl) -N- (3-pyridylmethyl) methanesulfonamide (0.53g, 0.72mmol) in toluene (5ml)
Water (5 ml), sodium carbonate (0.16 g, 1.44 mmol), tetrakistriphenylphosphine palladium (42 mg, 0.04 mg).
36 mmol), p-trifluoromethylbenzeneboronic acid (0.1
7 g, 0.864 mmol) were added in that order, and the mixture was stirred overnight at 80 ° C. under a nitrogen atmosphere. After the reaction was completed, it was diluted with ethyl acetate and washed with water and saturated saline. After drying over anhydrous magnesium sulfate,
It was filtered and concentrated under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate = 2: 1-hexane
: Acetone = 3: 2) was performed to obtain a mixture of the raw material and the target substance. The reaction of this mixture was repeated again under exactly the same conditions, and silica gel column chromatography (hexane:
By purifying with ethyl acetate = 2: 1-hexane: acetone = 3: 2, N-({4 '-[(N-tert-butoxycarbonyl
-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4
-Yl} methyl) -N- (3-pyridylmethyl) [4 '-(trifluoromethyl) [1,1'-biphenyl] -4-yl] methanesulfonamide (0.39g, 72%) as colorless amorphous Obtained as a crystalline powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.40 (9H,
s) 4.0-4.2 (1H, br) 4.19 (2H, s) 4.25 (2H, s) 4.28
(2H, s) 4.41 (2H, s) 7.19-7.36 (7H, m) 7.48-7.69
(11H, m) 8.43 (1H, d, J = 2.2Hz) 8.52 (1H, dd, J = 1.
4, 4.8Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [4'- (Trifluoromethyl) [1,1'-biphenyl] -4-yl] methanesulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1 , 1'-Biphenyl] -4-yl} methyl) -N
-(3-Pyridylmethyl) [4 '-(trifluoromethyl) [1,1'-
Biphenyl] -4-yl] methanesulfonamide (0.36g, 0.
46 mmol) in ethanol solution (5 ml) with 4N hydrogen chloride
Ethyl acetate (10 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr.
The solvent was concentrated under reduced pressure and the resulting powder was collected by filtration, washed with diethyl ether, and dried under reduced pressure. N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (3-pyridylmethyl) [4 '-(trifluoromethyl) [1,1'
-Biphenyl] -4-yl] methanesulfonamide dihydrochloride
(0.29 g, 83%) was obtained as a colorless amorphous powder. Elemental analysis calculated as C ₄₀ H ₄₀ F ₃ N ₃ O ₂ S ・ 2HCl ・ H ₂ O: C, 62.01; H, 5.72; N, 5.42 Found: C, 61.97; H, 5.94; N, 5.29. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.93 (1H, s) 4.14 (2H, s) 4.44 (2H, s) 4.5
7 (2H, s) 4.81 (2H, s) 7.29 (2H, d, J = 8.4Hz) 7.48
(2H, d, J = 8.2Hz) 7.64-7.81 (7H, m) 7.81-7.86 (4H,
m) 7.96 (2H, d, J = 8.0Hz) 8.14 (1H, d, J = 8.0Hz) 8.5
5 (1H, s) 8.60 (1H, d, J = 5.0Hz) 9.40 (2H, br) 7.96
(2H, d, J = 8.0Hz) 8.14 (1H, d, J = 8.0Hz) 8.55 (1H,
s) 8.60 (1H, d, J = 5.0Hz) 9.40 (2H, br)

Example 169 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) [4- (2-furyl) phenyl] -N- (3 -Pyridylmethyl) methanesulfonamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl )
[4- (2-Furyl) phenyl] -N- (3-pyridylmethyl) methanesulfonamide (4-bromophenyl) -N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) Methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) methanesulfonamide (0.34g, 0.461mmol) and tri-n-butyl (2-
Tetrakistriphenylphosphine palladium (0.027 g) was added to a tetrahydrofuran solution (5 ml) of (furyl) stannane (0.20 g, 0.56 mmol), and the mixture was refluxed overnight under an argon atmosphere. The reaction was terminated with saturated aqueous sodium hydrogen carbonate, diluted with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1-
It was purified with hexane: acetone = 3: 2). N-({4 '-[(N-te
rt-Butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) [4- (2-furyl) phenyl] -N- (3-pyridylmethyl) methanesulfonamide
(0.22 g, 68%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.40 (9H,
s) 4.0-4.2 (1H, br) 4.41 (2H, s) 4.20 (2H, s) 4.26
(2H, s) 4.41 (2H, s) 6.48 (1H, dd, J = 1.8, 3.2Hz)
6.68 (1H, d, J = 3.4Hz) 7.14-7.32 (7H, m) 7.48-7.64
(8H, m) 8.41 (1H, s) 8.49 (1H, d, J = 42Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl } Methyl) [4- (2-furyl) phenyl] -N- (3-
Pyridylmethyl) methanesulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) [4
-(2-Furyl) phenyl] -N- (3-pyridylmethyl) methanesulfonamide (0.19g, 0.27mmol) in ethanol (5
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise to (ml) and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure and the resulting powder was collected by filtration, washed with diethyl ether, and dried under reduced pressure. N-({4 '-[(cyclohexylamino) methyl] [1,1'-
Biphenyl] -4-yl} methyl) [4- (2-furyl) phenyl] -N
-(3-Pyridylmethyl) methanesulfonamide dihydrochloride
(0.15 g, 82%) was obtained as a colorless amorphous powder. Elemental analysis calculated as C ₃₇ H ₃₉ N ₃ O ₃ S ・ 2HCl ・ 1.5H ₂ O: C, 62.97; H, 6.28; N, 5.95 Found: C, 62.73; H, 6.23; N, 5.73. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.96 (1H, s) 4.15 (2H, s) 4.39 (2H, s) 4.5
1 (2H, s) 4.75 (2H, s) 6.62 (1H, dd, J = 1.8, 3.2Hz)
7.02 (1H, d, J = 3.0Hz) 7.26 (2H, d, J = 8.0Hz) 7.46
(2H, d, J = 8.4Hz) 7.52 (2H, d, J = 8.4Hz) 7.59-7.79 (8
H, m) 8.12 (1H, d, J = 8.4Hz) 8.58 (1H, d, J = 5.0Hz)
9.32 (2H, br)

Example 170 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [4- (2- Thienyl) phenyl] methanesulfonamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl )
-N- (3-pyridylmethyl) [4- (2-thienyl) phenyl] methanesulfonamide (4-bromophenyl) -N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) Methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) methanesulfonamide (0.34g, 0.461mmol) and tri-n-butyl (2-thienyl) stannane (0.21 Tetrakistriphenylphosphine palladium (0.027 g, 0.023 mmol) was added to a tetrahydrofuran solution (5 ml) of g, 0.56 mmol), and the mixture was refluxed overnight under an argon atmosphere. Terminate the reaction with saturated aqueous sodium hydrogen carbonate,
After diluting with ethyl acetate, the extract was washed with saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-hexane: acetone = 2: 1). N-
({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N-
(3-Pyridylmethyl) [4- (2-thienyl) phenyl] methanesulfonamide (0.22g, 66%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.14 (2H, s) 4.22 (2H, s) 4.25
(2H, s) 4.41 (2H, s) 7.06-7.11 (1H, m) 7.15-7.35
(9H, m) 7.48-7.64 (7H, m) 8.42 (1H, s) 8.50 (1H,
d, J = 5.2Hz). 2) N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [4 -(2-
Thienyl) phenyl] methanesulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)- N
-(3-Pyridylmethyl) [4- (2-thienyl) phenyl] methanesulfonamide (0.21g, 0.29mmol) in ethanol
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise to (5 ml), and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure and the resulting powder was collected by filtration, washed with diethyl ether, and dried under reduced pressure. N-({4 '-[(cyclohexylamino) methyl] [1,1'-
Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [4-
(2-thienyl) phenyl] methanesulfonamide dihydrochloride
(0.15g, 74%) was obtained as a colorless amorphous powder. Elemental analysis value Calculated as C ₃₇ H ₃₉ N ₃ O ₂ S ₂・ 2HCl ・ H ₂ O: C,
62.35; H, 6.08; N, 5.90 Found: C, 61.99; H, 6.09; N, 5.67. ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2
(2H, m) 2.94 (1H, s) 4.15 (2H, s) 4.42 (2H, s) 4.5
6 (2H, s) 4.77 (2H, s) 7.15 (1H, t, J = 4.4Hz) 7.22
(2H, d, J = 8.0Hz) 7.29-7.78 (13H, m) 8.18 (1H, d, J
= 8.0Hz) 8.56 (1H, s) 8.62 (1H, d, J = 4.8Hz) 9.44 (2
H, br)

Example 171 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (2-furylmethyl) [1,1'- Biphenyl] -4-sulfonamide 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (2-furylmethyl) [1,1'-biphenyl] -4-sulfonamide 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(2-furylmethyl) amino Methyl] -1,1'-
Biphenyl (1.30g, 2.74mmol) in acetonitrile
(10 ml) with triethylamine (0.58 ml, 4.11 mmol) and p-
Phenylbenzenesulfonyl chloride (0.84g, 3.29m
mol) was added at room temperature, and the mixture was stirred as it was for 2 hours. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
Purify with (hexane: ethyl acetate = 5: 1-3: 1) and N-({4'-
[(N-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (2-furylmethyl) [1,1'-biphenyl] -4 -Sulfonamide (1.9
9 g, 100%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 4.0-4.2 (1
H, br) 4.40, 4.42 (6H, each s) 6.07 (1H, d, J = 2.8H
z) 6.20 (1H, dd, J = 1.8, 3.2Hz) 7.17-7.19 (1H, m)
7.25-7.71 (14H, m) 7.82-7.90 (3H, m). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N -(2-Furylmethyl) [1,1'-biphenyl] -4-sulfonamide N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl ] -4-yl} methyl) -N
To a solution of-(2-furylmethyl) [1,1'-biphenyl] -4-sulfonamide (1.95g, 2.74mmol) in dichloromethane (20ml) was added trimethylsilyltrifluoromethanesulfonate (0.75ml, 4.11mmol) under ice cooling. The mixture was added dropwise and stirred at 0 ° C for 1 hour. Saturated aqueous sodium hydrogen carbonate was added dropwise to terminate the reaction, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform, chloroform:
After performing methanol = 40: 1), it was purified by recrystallization (hexane-ethyl acetate), and N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} Methyl) -N- (2-furylmethyl) [1,1'-biphenyl] -4-sulfonamide (1.18g,
73%) was obtained as a colorless solid. Melting point: 254-260 ° C Elemental analysis C ₃₇ H ₃₈ N ₂ O ₃ S ・ Calculated as 1 / 4H ₂ O: C, 74.65; H, 6.52; N, 4.71 Found: C, 74.66; H, 6.42; N, 4.60 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.4 (4H, m) 1.6-2.0 (6
H, m) 2.54 (1H, br) 3.86 (2H, s) 4.40, 4.42 (4H, e
ach s) 6.06-6.08 (1H, m) 6.20 (1H, dd, J = 1.8,2.8H
z) 7.18 (1H, dd, J = 0.6, 2.4Hz) 7.34-7.70 (5H, m)
7.85 (2H, d, J = 8.8Hz).

Example 172 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (2-furylmethyl) -4-phenoxybenzenesulfone Amide 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (2-furylmethyl) -4-phenoxybenzenesulfonamide 4- (N-tert-butoxycarbonyl-N-cyclohexylamino) methyl-4 '-[(2-furylmethyl) aminomethyl] -1,1 '-
Biphenyl (1.30g, 2.74mmol) in acetonitrile
(10 ml) with triethylamine (1.16 ml, 8.22 mmol) and p-
Phenoxybenzene sulfonyl chloride (1.10g, 4.1
1 mmol) was added at room temperature, and the mixture was stirred as it was overnight. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
Purified with (hexane: ethyl acetate = 5: 1-3: 1), N-({4'-
[(N-tert-Butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (2-furylmethyl) -4-phenoxybenzenesulfonamide (1.
93 g, 99%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 3.9-4.1 (1H, br) 4.36, 4.38 (6H, each s) 6.07
(1H, dd, J = 0.8, 3.2Hz) 6.23 (1H, dd, J = 1.8, 3.2Hz)
6.96-7.08 (4H, m) 7.16-7.45 (8H, m) 7.50-7.71 (4
H, m) 7.74 (2H, d, J = 8.8Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (2-Furylmethyl) -4-phenoxybenzenesulfonamide N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl ) -N
Trimethylsilyl trifluoromethanesulfonate (0.73 ml, 3.99 mmol) was added dropwise to a dichloromethane solution (20 ml) of-(2-furylmethyl) -4-phenoxybenzenesulfonamide (1.88 g, 2.66 mmol) under ice cooling, and the mixture was stirred at 0 ° C. Stir for 1 hour. Saturated aqueous sodium hydrogen carbonate was added dropwise to terminate the reaction, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform, chloroform: methanol = 40: 1) and then purified by recrystallization (hexane-ethyl acetate) to give N-({4 '-[(cyclohexylamino) methyl] [1. , 1'-Biphenyl] -4-yl} methyl) -N- (2-furylmethyl) -4-phenoxybenzenesulfonamide (1.34g, 8
3%) was obtained as a colorless solid. Melting point: 96-97 ° C Elemental analysis C ₃₇ H ₃₈ N ₂ O ₄ S Calculated: C, 73.24; H, 6.31; N, 4.62 Found: C, 72.98; H, 6.41; N, 4.56 ¹ H- NMR (CDCl ₃ ) δ (ppm) 1.0-1.4 (5H, m) 1.4-1.8 (3
H, m) 1.8-2.0 (2H, m) 2.52 (1H, m) 3.86 (2H, s) 4.
37, 4.38 (4H, each s) 6.07 (1H, d, J = 2.8Hz) 6.23
(1H, dd, J = 1.8, 2.8Hz) 6.97-7.08 (4H, m) 7.18-7.26
(2H, m) 7.33-7.44 (6H, m) 7.56-7.71 (4H, m) 7.72-
7.78 (2H, m)

Example 173 4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -4 '-[(tert-butoxycarbonyl) amino] -1 , 1'-Biphenyl 4-{[(3-pyridylmethyl) amino] methyl} -4 '-[(tert-butoxycarbonyl) amino] -1,1'-biphenyl (4.0g, 10.
To a solution of 3 mmol) in acetonitrile (50 ml) was added 4-biphenylsulfonyl chloride (3.11 g, 12.3 mmol) and triethylamine (2.15 ml, 15.4 mmol), and the mixture was stirred at room temperature for 3 hours.
The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (100 ml) was added to the residue, and the mixture was extracted with chloroform (200,100 ml). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Silica gel chromatography of the residue (chloroform: ethyl acetate
= 2: 1), 4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -4 '-[(tert-
Butoxycarbonyl) amino] -1,1'-biphenyl (4.63g,
74%) was obtained as crystals. . Mp 203-206 ° C. as the elemental analysis _{C 36 H 35 N 3 O 4} S · 0.5H 2 O, Calculated: C, 70.96; H, 5.86 ; N, 6.90 Found: C, 70.86; H, 5.73 ; ^{. N, 6.98 1 H-NMR} (CDCl 3) δ: 1.49 (9H, s, Bu t), 4.40 (4H, s), 7.15-
7.30 (3H, m), 7.40-7.60 (10H, m), 7.76 (2H, d, J = 8.0Hz),
7.91 (2H, d, J = 8.0Hz), 7.99 (2H, d, J = 8.0Hz), 8.29 (1H, br
s), 8.35 (1H, d, J = 4.4Hz), 9.44 (1H, s).

Example 174 N- (4 ′-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1′-biphenyl] -4- 1) N-[(4'-amino [1,1'-biphenyl] -4-yl) methyl]-
N- (3-pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride 4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) Amino] methyl} -4 '-[(tert-butoxycarbonyl) amino] -1,1'-biphenyl (4.1g, 6.77mmol) in methanol (50ml) was added concentrated hydrochloric acid (30ml) at 30 ℃ at 70 ℃. Stir for minutes. The reaction solution was evaporated under reduced pressure, the precipitated crystals were added with methanol-diethyl ether and collected by filtration to give N-[(4'-amino [1,1'-biphenyl] -4-yl) methyl] -N- (3-Pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride
(3.80 g, 96%) was obtained. Melting point 204-207 ° C. Elemental analysis C ₃₁ H ₂₇ N ₃ O ₂ S ・ 2HCl ・ 0.5H ₂ O, calculated: C, 63.37; H, 5.15; N, 7.15 Found: C, 63.20; H, 5.23; N, 7.23. ¹ H-NMR (d ₆ -DMSO) δ: 4.48 (2H, s), 4.57 (2H, s), 7.20-7.4
0 (4H, m), 7.40-7.75 (7H, m), 7.75-7.83 (2H, m), 7.90-8.
15 (6H, m), 8.51 (1H, d, J = 5.0Hz). 2) N- (4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-
Pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-
Yl) cyclohexanecarboxamide N-[(4'-amino [1,1'-biphenyl] -4-yl) methyl] -N- (3
-Pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride (0.87g, 1.50mmol), chloroform (30ml), saturated aqueous sodium hydrogen carbonate (20ml) in cyclohexanecarbonyl chloride (0.24 (ml, 1.80 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The chloroform layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 2: 1) to give N- (4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3
-Pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-
(Il) cyclohexanecarboxamide (0.86 g, 93%) was obtained as crystals. . Mp 182-185 ° C. as the elemental analysis _{C 38 H 37 N 3 O 2} S, Calculated: C, 74.12; H, 6.06 ; N, 6.82 Found:. C, 73.85; H, 5.99; N, 6.92 1 H-NMR (CDCl ₃ ) δ: 1.20-2.40 (11H, m), 4.39 (2H, s), 7.11
(2H, d, J = 8.0Hz), 7.10-7.20 (1H, m), 7.35-7.70 (12H, m),
7.75 (2H, d, J = 8.0Hz), 7.94 (2H, d, J = 8.0Hz), 8.25-8.35
(1H, m), 8.40-8.50 (1H, m).

Example 175 N- (4 ′-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1′-biphenyl] -4- (Iyl) cycloheptanecarboxamide A mixture of cycloheptanecarboxylic acid (0.41 ml, 3.0 mmol), thionyl chloride (10 ml) and N, N-dimethylformamide (1 drop) was stirred at 60 ° C. for 1 hour and then distilled under reduced pressure. . Residue
N-[(4'-amino [1,1'-biphenyl] -4-yl) methyl] -N- (3
-Pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride (0.87g, 1.5mmol) in chloroform (20ml), saturated aqueous sodium hydrogen carbonate (20ml) Stir for 1 hour. The chloroform layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 3: 1) to give N- (4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3
-Pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-
Il) cycloheptanecarboxamide (0.80 g, 84%) was obtained as crystals. . Mp 187-188 ° C. Elemental analysis C ₃₉ H ₃₉ N ₃ O ₃ as S · 1 / 4H ₂ O, Calculated: C, 73.85; H, 6.28 ; N, 6.62 Found: C, 73.76; H, 6.19 ; N, 6.72 ¹ H-NMR (CDCl ₃ ) δ: 1.40-2.40 (12H, m), 2.30-2.50 (1H, m),
4.39 (4H, s), 7.05-7.25 (4H, m), 7.35-7.70 (12H, m), 7.
94 (2H, d, J = 8.0Hz), 8.30-8.40 (1H, m), 8.40-8.50 (1H,
m).

Example 176 N- (4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4- Yl) -2-Cyclohexylacetamide N-[(4'-amino [1,1'-biphenyl] -4-yl) methyl] -N- (3
-Pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride (0.87g, 1.50mmol) and cyclohexaneacetic acid (0.
28g, 1.95mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.28g, 1.95mmol), 1-hydroxybenzotriazole monohydrate (0.35g, 2.25mmol),
A mixture of triethylamine (0.87 ml, 3.75 mmol) and N, N-dimethylformamide (15 ml) was stirred at 60 ° C for 6 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction mixture, and ethyl acetate (100 ml) was added.
It was extracted with × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: acetone = 2: 1) to give N-
(4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl)
-2-Cyclohexylacetamide (0.43 g, 44%) was obtained as crystals. . Mp 164-167 ° C. Elemental analysis C ₃₉ H ₃₉ N ₃ O ₃ as S · H ₂ O, Calculated: C, 72.30; H, 6.38 ; N, 6.49 Found: C, 72.54; H, 6.19 ; N ^{, 6.53 1 H-NMR (CDCl} 3) δ:. 0.90-1.90 (11H, m), 2.24 (2H, d, J = 6.6H
z), 4.40 (4H, s), 7.05-7.25 (3H, m), 7.35-7.70 (12H, m),
7.76 (2H, d, J = 8.4Hz), 7.96 (2H, d, J = 8.4Hz), 8.31 (1H, b
rs), 8.40-8.50 (1H, m).

Example 177 N- (4 ′-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1′-biphenyl] -4- Yl) -2- [2- (trifluoromethyl) phenyl] acetamide 2- (trifluoromethyl) phenylacetic acid (0.46g, 2.25mmo
l) and thionyl chloride (10 ml), N, N-dimethylformamide (1
The mixture of (droplets) was stirred at 60 ° C. for 1 hour, and then evaporated under reduced pressure. The residue is N-[(4'-amino [1,1'-biphenyl] -4-yl)
Methyl] -N- (3-pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride (0.87g, 1.5mmol), chloroform (20ml), saturated sodium bicarbonate water (10ml) It was added to the mixture and stirred at room temperature for 1 hour. The chloroform layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (chloroform: ethyl acetate = 3:
Purified in 1), N- (4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4 -Yl) -2- [2- (trifluoromethyl) phenyl] acetamide (0.80 g, 84%) was obtained as crystals. . Mp 187-188 ° C. as the elemental analysis _{C 40 H 32 F 3 N 3} O 3 S, Calculated: C, 69.45; H, 4.66 ; N, 6.07 Found: C, 69.12; H, 4.58 ; N, 5.76 _{^{. 1 H-NMR (CDCl 3}} ) δ: 3.92 (2H, s), 4.39 (4H, s), 7.05-7.20
(3H, m), 7.12 (1H, br), 7.35-7.70 (11H, m), 7.70-7.80 (3
H, m), 7.93 (2H, d, J = 8.0Hz), 8.30 (1H, br), 8.44 (1H, d, J
= 4.4Hz).

Example 178 4-[(tert-butoxycarbonyl) amino] -4 '-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -1,1'-biphenyl 4 -{[(3-Pyridylmethyl) amino] methyl} -4 '-[(tert-butoxycarbonyl) amino] -1,1'-biphenyl (3.6g, 9.
4-Phenoxybenzenesulfonyl chloride (3.10 g, 11.6 mmol) and triethylamine (1.93 ml, 13.9 mmol) were added to a solution of 24 mmol) in acetonitrile (30 ml), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (chloroform: ethyl acetate =
3: 1) to give 4-[(tert-butoxycarbonyl) amino] -4 '-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -1,1' -Biphenyl (4.74g, 7
8%) was obtained as crystals. . Mp 120-122 ° C. Elemental analysis C ₃₆ H ₃₅ N ₃ O ₅ as S · 2H ₂ O, Calculated: C, 65.74; H, 5.97 ; N, 6.39 Found: C, 65.58; H, 5.41 ; N ^{, 6.25 1 H-NMR (CDCl} 3) δ:. 1.53 (9H, s, Bu t), 4.34 (4H, s), 6.56
(1H, s), 7.00-7.30 (8H, m), 7.35-7.60 (9H, m), 7.81 (2H,
d, J = 8.4Hz), 8.28 (1H, brs), 8.45 (1H, d, J = 4.8Hz).

Example 179 N- (4 '-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl)
Cyclohexanecarboxamide N-[(4'-amino [1,1'-biphenyl] -4-yl) methyl] -4-phenoxy-N- (3-pyridylmethyl) -benzenesulfonamide dihydrochloride (0.89g, 1.50 mmol) and chloroform (20 ml),
Cyclohexanecarbonyl chloride (0.24 ml, 1.80 mmol) was added to a mixed solution of saturated aqueous sodium hydrogen carbonate (10 ml), and the mixture was stirred at room temperature for 30 minutes. The chloroform layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 2: 1) to give N- (4 '-{[[(4-phenoxyphenyl) sulfonyl] (3
-Pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-
Il) cyclohexanecarboxamide (0.86 g, 91%) was obtained as crystals. Melting point 168-170 ° C. Elemental analysis C ₃₈ H ₃₇ N ₃ O ₂ S Calculated: C, 72.24; H, 5.90; N, 6.60 Found: C, 72.06; H, 5.79; N, 6.76. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.40 (11H, m), 4.35 (2H, s), 7.00
-7.35 (10H, m), 7.35-7.70 (8H, m), 7.81 (2H, d, J = 8.8Hz),
8.25-8.35 (1H, m), 8.40-8.50 (1H, m).

Example 180 N- (4 ′-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1′-biphenyl] -4-yl) cyclohexanecarboxamide 1) 4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(tert-butoxycarbonyl)
Amino] -1,1'-biphenyl 4-{[(3-pyridylmethyl) amino] methyl} -4 '-[(tert-butoxycarbonyl) amino] -1,1'-biphenyl (5.84g, 1
To a solution of 5.0 mmol) in acetonitrile (100 ml) was added 4-bromophenylsulfonyl chloride (4.60 g, 18 mmol) and triethylamine (3.14 ml, 225 mmol), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (150 ml) was added to the residue, and the mixture was extracted with ethyl acetate (300 ml). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel (chloroform: ethyl acetate =
3: 1-1: 1) and purified by 4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(tert-butoxycarbonyl) amino]- 1,1'-biphenyl (7.0g, 77
%) Was obtained as crystals. . Mp 182-185 ° C. as the elemental analysis _{C 30 H 30 BrN 3 O 4} S · 0.5H 2 O, Calculated: C, 58.35; H, 5.6 ; N, 6.80 Found: C, 58.10; H, 4.97 ; ^{. N, 6.69 1 H-NMR} (CDCl 3) δ: 1.54 (9H, s, Bu t), 4.35 (4H, s), 6.55 (1
H, brs, NH), 7.08 (2H, d, J = 8.4Hz), 7.15 (1H, dd, J = 7.4,5.
4Hz), 7.37-7.60 (7H, m), 7.60-7.80 (4H, m), 8.25-8.35
(1H, m), 8.47 (1H, dd, J = 4.8,1.8Hz). 2) N-[(4'-amino [1,1'-biphenyl] -4-yl) methyl] -4-
Bromo-N- (3-pyridylmethyl) benzenesulfonamide
Dihydrochloride 4-{[[(4-Bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(tert-butoxycarbonyl) amino] -1,1'-biphenyl (6.5g, 10.7 mmol) methanol
Concentrated hydrochloric acid (30 ml) was added to the (50 ml) solution, and the mixture was stirred at 60 ° C for 30 min. The reaction solution was evaporated under reduced pressure, and the precipitated crystals were methanol-
Diethyl ether was added and collected by filtration to obtain N-[(4'-amino [1,
1'-Biphenyl] -4-yl) methyl] -4-bromo-N- (3-pyridylmethyl) benzenesulfonamide dihydrochloride (6.20g, 9
7%). Melting point 156-160 ° C (decomposition). Elemental analysis value C ₂₅ H ₂₂ BrN ₃ O ₂ S ・ 2HCl ・ H ₂ O, calculated value: C, 50.86; H, 4.27; N, 7.12 Found value: C, 50.87; . H, 4.40; N, 7.12 1 H-NMR (d 6 -DMSO) δ: 4.45 (2H, s), 4.56 (2H, s), 7.25 (2H,
d, J = 8.4Hz), 7.40 (2H, d, J = 8.4Hz), 7.46 (2H, d, J = 8.4H)
z), 7.67 (2H, d, J = 8.4Hz), 7.60-7.80 (1H, m), 7.90 (4H,
s), 8.13 (1H, d, J = 8.4Hz), 8.53 (1H, brs), 8.65 (1H, d, J =
5Hz). 3) N- (4 '-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) cyclohexanecarboxamide N- [ (4'-Amino [1,1'-biphenyl] -4-yl) methyl] -4-bromo-N- (3-pyridylmethyl) benzene-sulfonamide
Cyclohexanecarbonyl was added to a mixture of dihydrochloride (5.0 g, 8.51 mmol), chloroform (50 ml) and saturated aqueous sodium hydrogen carbonate (30 ml).
Chloride (1.48 ml, 11.1 mmol) was added and the mixture was stirred at room temperature for 1 hour. The chloroform layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 2: 1-1: 1) to give N- (4 ′-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino]. Methyl} [1,1'-biphenyl] -4-yl)
Cyclohexanecarboxamide (4.52 g, 85%) was obtained as crystals. Melting point 233-234 ° C. Elemental analysis value C ₃₂ H ₃₂ BrN ₃ O ₃ S, calculated value: C, 62.13; H, 5.21; N, 6.79 Found value: C, 62.00; H, 5.12; N, 6.87. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.40 (11H, m), 4.35 (4H, s), 7.09
(2H, d, J = 8.0Hz), 7.14 (1H, dd, J = 7.0,4.4Hz), 7.23 (1H,
s), 7.40-7.80 (11H, m), 8.25-8.35 (1H, m), 8.40-8.50 (1
H, m).

Example 181 N- (4 '-{[{[4'-(hydroxymethyl) [1,1'-biphenyl] -4
-Yl] sulfonyl} (3-pyridylmethyl) amino] methyl}
[1,1'-Biphenyl] -4-yl) cyclohexanecarboxamide 1) N- (4 '-{[[(4'-formyl [1,1'-biphenyl] -4-yl)
Sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-
Biphenyl] -4-yl) cyclohexanecarboxamide N- (4 '-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) cyclohexane Carboxamide (0.5 g, 0.81 mmol) and 4-formylphenylboronic acid (0.145 g, 0.97 mmol), tetrakistriphenylphosphine palladium (28 mg, 0.024 mmol),
Sodium carbonate (0.17 g, 1.62 mmol), toluene (100 ml),
A mixture of water (20 ml) was heated under reflux for 3 hours under a nitrogen atmosphere. Ethyl acetate (50 ml) was added to remove insolubles, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 1: 1) to give N- (4 '-{[[(4'-
Formyl [1,1'-biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) cyclohexanecarboxamide (0.49g, 94%) crystallized Got as. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.40 (11H, m), 4.41 (4H, s), 7.1
2 (2H, d, J = 8.4Hz), 7.15-7.25 (1H, m), 7.41 (2H, d, J = 8.0
Hz), 7.44 (2H, d, J = 8.0Hz), 7.50-7.65 (4H, m), 7.78 (4H,
d, J = 8.4Hz), 7.95-8.10 (4H, m), 8.25-8.35 (1H, m), 8.4
0-8.50 (1H, m). 2) N- (4 '-{[{[4'-(hydroxymethyl) [1,1'-biphenyl] -4-yl] sulfonyl] (3-pyridylmethyl) amino ] Methyl} [1,1'-biphenyl] -4-yl) cyclohexanecarboxamide N- (4 '-{[[(4'-formyl [1,1'-biphenyl] -4-yl) sulfonyl] (3- Pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) cyclohexanecarboxamide (0.49
g, 0.76 mmol) methanol-tetrahydrofuran (20 ml-
Sodium borohydride (48 mg, 1.14 mmol) in a solution (20 ml)
Was added and stirred for 2 hours. Water (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel chromatography of the residue (chloroform: ethyl acetate
= 2: 1-1: 1 / chloroform: ethyl acetate = 2: 1),
N- (4 '-{[{[4'-(hydroxymethyl) [1,1'-biphenyl] -4
-Yl] sulfonyl} (3-pyridylmethyl) amino] methyl}
[1,1′-Biphenyl] -4-yl) cyclohexanecarboxamide (0.40 g, 79%) was obtained as crystals. Melting point 227-229 ° C. Elemental analysis value C ₃₉ H ₃₉ N ₃ O ₄ S ・ H ₂ O, calculated value: C, 70.56; H, 6.23; N, 6.33 Found value: C, 70.38; H, 6.00; N ^{, 6.36 1 H-NMR (CDCl} 3) δ:. 1.20-2.40 (11H, m), 4.38 (2H, s), 4.44
(2H, s), 4.79 (2H, s), 7.09 (2H, d, J = 8.4Hz), 7.17 (1H, d
d, J = 8.0,5.2Hz), 7.23 (1H, br), 7.30-7.65 (11H, m), 7.7
0 (2H, d, J = 8.4Hz), 7.88 (2H, d, J = 8.0Hz), 8.34 (1H, d, J =
2.2Hz), 8.40-8.50 (1H, m).

Example 182 N- (4 ′-{[{[3 ′-(hydroxymethyl) [1,1′-biphenyl] -4
-Yl] sulfonyl} (3-pyridylmethyl) amino] methyl}
[1,1'-Biphenyl] -4-yl) cyclohexanecarboxamide 1) N- (4 '-{[[(3'-formyl [1,1'-biphenyl] -4-yl)
Sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-
Biphenyl] -4-yl) cyclohexanecarboxamide N- (4 '-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) cyclohexane Carboxamide (1.0 g, 1.62 mmol) and 3-formylphenylboronic acid (0.29 g, 1.94 mmol), tetrakistriphenylphosphine palladium (56 mg, 0.048 mmol),
Sodium carbonate (0.34 g, 3.24 mmol), toluene (100 ml),
A mixture of water (20 ml) was heated under reflux for 2 hours under a nitrogen atmosphere. Ethyl acetate (50 ml) was added to remove insolubles, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 3: 1-1: 1), and N- (4'-
{[[(3'-Formyl [1,1'-biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) cyclohexanecarboxamide (0.89 g, 84
%) Was obtained as crystals. . Mp 122-125 ° C. Elemental analysis C ₃₉ H ₃₇ N ₃ O ₄ as S · 3 / 4H ₂ O, Calculated: C, 71.26; H, 5.90 ; N, 6.39 Found: C, 71.19; H, 5.84 ^{; N, 6.43 1 H-NMR} (CDCl 3) δ:. 1.20-2.40 (11H, m), 4.41 (4H, s), 7.0
5-7.30 (4H, m), 7.35-8.05 (14H, m), 7.99 (1H, s), 8.30-
8.40 (1H, m), 8.46 (1H, d, J = 4.8Hz), 10.12 (1H, s). 2) N- (4 '-{[{[3'-(hydroxymethyl) [1,1 ' -Biphenyl] -4-yl] sulfonyl} (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) cyclohexanecarboxamide N- (4 '-{[[(3'-formyl [ 1,1'-biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) cyclohexanecarboxamide (0.60g,
0.93 mmol) methanol-tetrahydrofuran (20 ml-10
(ml) solution, sodium borohydride (51 mg, 1.21 mmol) was added, and the mixture was stirred for 2 hours. Water (50 ml) was added to the reaction solution, and the mixture was extracted with chloroform (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 1: 1 / chloroform: ethyl acetate = 2: 1) to give N-
(4 '-{[{[3'-(hydroxymethyl) [1,1'-biphenyl] -4-
Ill] sulfonyl} (3-pyridylmethyl) amino] methyl}
[1,1′-Biphenyl] -4-yl) -cyclohexanecarboxamide (0.55 g, 90%) was obtained as crystals. . Mp 184-187 ° C. Elemental analysis C ₃₉ H ₃₉ N ₃ O ₄ as S · 1 / 2H ₂ O, Calculated: C, 71.54; H, 6.16 ; N, 6.42 Found: C, 71.25; H, 6.19 ^{; N, 6.41 1 H-NMR} (CDCl 3) δ:. 1.20-2.40 (11H, m), 4.39 (2H, s), 4.42
(2H, s), 4.79 (2H, brs), 7.10 (2H, d, J = 8.4Hz), 7.17 (1H, d
d, J = 7.0,4.8Hz), 7.23 (1H, brs), 7.30-7.65 (11H, m), 7.
73 (2H, d, J = 8.8Hz), 7.90 (2H, d, J = 8.8Hz), 8.30-8.40 (1
H, m), 8.40-8.50 (1H, m).

Example 183 N- (4 '-{[{[2'-(hydroxymethyl) [1,1'-biphenyl] -4
-Yl] sulfonyl} (3-pyridylmethyl) amino] methyl}
[1,1'-Biphenyl] -4-yl) cyclohexanecarboxamide 1) N- (4 '-{[[(2'-formyl [1,1'-biphenyl] -4-yl)
Sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-
Biphenyl] -4-yl) cyclohexanecarboxamide N- (4 '-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) cyclohexane Carboxamide (1.0 g, 1.62 mmol) and 2-formylphenylboronic acid (0.29 g, 1.94 mmol), tetrakistriphenylphosphine palladium (56 mg, 0.048 mmo
l), sodium carbonate (0.34g, 3.24mmol), toluene (100m
A mixture of l) and water (20 ml) was heated under reflux for 2 hours under a nitrogen atmosphere. After removing insoluble matter by adding ethyl acetate (50 ml),
The organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (chloroform: ethyl acetate = 1: 1 / chloroform: acetone =
2: 1) and N- (4 '-{[[(2'-formyl [1,1'-biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino]
Methyl} [1,1′-biphenyl] -4-yl) cyclohexanecarboxamide (0.91 g, 87%) was obtained as crystals. . Mp 196-198 ° C. as the elemental analysis _{C 39 H 37 N 3 O 4} S, Calcd: C, 72.76; H, 5.79 ; N, 6.53 Found:. C, 72.52; H, 5.97; N, 6.54 1 H-NMR (CDCl ₃ ) δ: 1.20-2.40 (11H, m), 4.44 (4H, s), 7.1
3 (2H, d, J = 8.4Hz), 7.10-7.30 (2H, m), 7.40-7.80 (12H,
m), 7.97 (2H, d, J = 8.4Hz), 8.00-8.15 (1H, m), 8.30-8.40
(1H, m), 8.40-8.55 (1H, m), 9.98 (1H, s). 2) N- (4 '-{[{[2'-(hydroxymethyl) [1,1'-biphenyl]- 4-yl] sulfonyl} (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) cyclohexanecarboxamide N- (4 '-{[[(2'-formyl [1,1' -Biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) cyclohexanecarboxamide (0.60 g,
0.93 mmol) methanol-tetrahydrofuran (20 ml-10 m
l) Sodium borohydride (51 mg, 1.21 mmol) was added to the solution, and the mixture was stirred for 2 hours. Water (50 ml) was added to the reaction solution, and the mixture was extracted with chloroform (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (hexane: acetone = 2: 1 /
1: 1) and N- (4 '-{[{[2'-(hydroxymethyl) [1,
1'-Biphenyl] -4-yl] sulfonyl} (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) cyclohexanecarboxamide (0.56 g, 93%) was obtained as crystals. . Mp 183-185 ° C. as the elemental analysis _{C 39 H 39 N 3 O 4} S, Calcd: C, 72.53; H, 6.09 ; N, 6.51 Found:. C, 72.39; H, 6.04; N, 6.57 1 H-NMR (CDCl ₃ ) δ: 1.20-2.40 (11H, m), 3.48 (1Hs,), 4.42
(2H, s), 4.46 (2H, s), 4.61 (2H, s), 7.10-7.35 (4H, m),
7.40-7.70 (13H, m), 7.75-7.80 (1H, m), 7.91 (2H, d, J = 8.8
Hz), 8.35-8.45 (1H, m).

Example 184 N- {4 ′-[((3-pyridylmethyl) {[4 ′-(trifluoromethyl) [1,1′-biphenyl] -4-yl] sulfonyl} amino) methyl] [ 1,1'-biphenyl] -4-yl} cyclohexanecarboxamide N- (4 '-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl]- 4-yl) cyclohexanecarboxamide (0.74g, 1.20mmol) and 4-trifluoromethylphenylboronic acid (0.27g, 1.44mmol),
Tetrakistriphenylphosphine palladium (41.6 mg,
A mixture of 0.036 mmol), sodium carbonate (0.25 g, 2.40 mmol), toluene (100 ml) and water (20 ml) was heated under reflux for 3 hours under a nitrogen atmosphere. Ethyl acetate (50 ml) was added to remove insolubles, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 3: 1/2: 1),
N- {4 '-[((3-pyridylmethyl) {[4'-(trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl} amino) methyl] [1,1'-biphenyl ] -4-yl} cyclohexanecarboxamide (0.70 g, 85%) was obtained as crystals. . Mp 214-215 ° C. as the elemental analysis _{C 39 H 36 F 3 N 3} O 3 S, Calculated: C, 68.50; H, 5.31 ; N, 6.15 Found: C, 68.33; H, 5.35 ; N, 6.20 _{^{. 1 H-NMR (CDCl 3}} ) δ:
1.20-2.40 (11H, m), 4.41 (4H, s), 7.05-7.30 (4H, m), 7.3
5-7.80 (13H, m), 7.97 (2H, d, J = 8.4Hz), 8.30-8.40 (1H,
m), 8.40-8.55 (1H, m).

Example 185 N- {4 ′-[((3-pyridylmethyl) {[2 ′-(trifluoromethyl) [1,1′-biphenyl] -4-yl] sulfonyl} amino) methyl] [ 1,1'-biphenyl] -4-yl} cyclohexanecarboxamide N- (4 '-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl]- 4-yl) cyclohexanecarboxamide (0.74 g, 1.20 mmol) and 4-trifluoromethylphenylboronic acid (0.27 g, 1.44 mmol),
Tetrakistriphenylphosphine palladium (41.6 mg,
A mixture of 0.036 mmol), sodium carbonate (0.25 g, 2.40 mmol), toluene (100 ml) and water (20 ml) was heated under reflux for 3 hours under a nitrogen atmosphere. Ethyl acetate (50 ml) was added to remove insolubles, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to give N- {4'-
[((3-pyridylmethyl) {[2 '-(trifluoromethyl) [1,1'
-Biphenyl] -4-yl] sulfonyl} amino) methyl] [1,1 '
-Biphenyl] -4-yl} cyclohexanecarboxamide
(0.71 g, 87%) was obtained as crystals. . Mp 168-170 ° C. as the elemental analysis _{C 39 H 36 F 3 N 3} O 3 S, Calculated: C, 68.50; H, 5.31 ; N, 6.15 Found: C, 68.58; H, 5.27 ; N, 6.26 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.20-2.40 (11H, m), 4.42 (4H, s), 7.0
7 (2H, d, J = 8.4Hz), 7.10-7.40 (3H, m), 7.40-7.70 (11H,
m), 7.85-7.90 (1H, m), 7.93 (2H, d, J = 8.4Hz), 8.30-8.40
(1H, m), 8.40-8.55 (1H, m).

Example 186 N-({4 ′-[(cyclopentylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4 ′-(tri Fluoromethyl) [1,1'-biphenyl] -4-sulfonamide ・
Dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclopentylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (3-pyridylmethyl) -4 '-(trifluoromethyl) [1,1'
-Biphenyl] -4-sulfonamide N-({4 '-[aminomethyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4'-(trifluoro (Methyl)
[1,1'-Biphenyl] -4-sulfonamide dihydrochloride (1.0 g,
1.63 mmol) in methanol (10 ml) in cyclopentanone (1.45 ml, 16.3 mmol), sodium chloride (3 g), triethylamine (0.48 ml, 3.42 mmol), acetic acid (1.87 ml, 32.6 m)
mol) were added in order, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.73g, 8.15mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, saturated aqueous sodium hydrogen carbonate (20 ml) and ethyl acetate (20 ml) were added to the reaction mixture, di-tert-butyl dicarbonate (0.72 g, 3.26 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
Stir for hours. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1-
3: 1-1: 1) and N-({4 '-[(N-tert-butoxycarbonyl-N-cyclopentylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4 '-(trifluoromethyl) [1,1'-biphenyl] -4-sulfonamide
(0.65 g, 55%) was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.41 (9H, s) 1.40-1.90 (8H,
m) 4.0-4.2 (1H, br) 4.40 (6H, s) 7.16-7.18 (3H,
m) 7.25 (2H, d, J = 8.6Hz) 7.42 (2H, d, J = 5.8Hz) 7.4
7 (2H, d, J = 6.4Hz) 7.54 (1H, dt, J = 2.0, 8.2Hz) 7.7
3-7.79 (6H, m) 7.96 (2H, d, J = 8.4Hz) 8.29 (1H, d,
J = 1.8Hz) 8.45 (1H, dd, J = 1.8, 4.8Hz). 2) N-({4 '-[(cyclopentylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-Pyridylmethyl) -4 '-(trifluoromethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride N-({4'-[(N-tert-butoxycarbonyl -N-Cyclopentylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N
-(3-Pyridylmethyl) -4 '-(trifluoromethyl) [1,1'-
Biphenyl] -4-sulfonamide (0.67 g, 0.89 mmol) in ethyl acetate solution (5 ml) was added with 4N hydrogen chloride-ethyl acetate (1
0 ml) was added dropwise and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure and then purified by recrystallization (ethanol-ether).
-({4 '-[(Cyclopentylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4'-(trifluoromethyl) [1,1 '-Biphenyl] -4-sulfonamide dihydrochloride (0.61 g, 94%) was obtained as a colorless solid. Melting point: 259-261 ° C Elemental analysis C ₃₈ H ₃₄ F ₃ N ₃ O ₂ S ・ 2HCl ・ 1.25H ₂ O Calculated: C, 61.36; H, 5.04; N, 5.61 Found: C, 61.26; H , 5.07; N, 5.19 ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.4-2.1 (8H, m) 3.43 (1H,
br) 4.13-4.15 (2H, m) 4.51 (2H, s) 4.61 (2H, s) 7.
29 (2H, d, J = 8.0Hz) 7.50 (2H, d, J = 8.4Hz) 7.65-7.7
5 (5H, m) 7.89 (2H, d, J = 8.4Hz) 8.00-8.14 (7H, m)
8.54 (1H, s) 8.62 (1H, d, J = 4.8Hz) 9.46 (2H, br)

Example 187 N-({4 ′-[(cycloheptylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4 ′-( Trifluoromethyl) [1,1'-biphenyl] -4-sulfonamide ・
Dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (3-pyridylmethyl) -4 '-(trifluoromethyl) [1,1'
-Biphenyl] -4-sulfonamide N-({4 '-[aminomethyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4'-(trifluoro (Methyl)
[1,1'-Biphenyl] -4-sulfonamide (1.03g, 1.67mmo
l) in methanol solution (15 ml) with cycloheptanone (0.9 ml).
9ml, 8.35mmol), sodium chloride (5g), triethylamine (0.51ml, 3.67mmol), acetic acid (0.96ml, 16.7mmol)
Were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Add sodium triacetoxyborohydride (1.77g, 8.35mmol) and add 3
Stir for 0 minutes at room temperature. Then, add saturated aqueous sodium hydrogen carbonate to the reaction mixture.
(30 ml) and ethyl acetate (30 ml) were added, followed by dicarbonate di-te.
rt-Butyl (1.82g, 8.35mmol) was added and the mixture was stirred at room temperature for 2 hours. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1-1: 1), and N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1 , 1'-Biphenyl] -4-yl}
Methyl) -N- (3-pyridylmethyl) -4 '-(trifluoromethyl) [1,1'-biphenyl] -4-sulfonamide (0.82g, 63%)
Was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-1.8 (21H, m) 4.0-4.2 (1
H, br) 4.40 (6H, s) 7.10-7.18 (3H, m) 7.28 (2H, d,
J = 8.8Hz) 7.41-7.57 (5H, m) 7.74-7.77 (6H, m) 7.96
(2H, d, J = 8.4Hz) 8.30 (1H, br) 8.46 (1H, d, J = 4.4)
2) N-({4 '-[(cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4'-(tri Fluoromethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cycloheptylamino) methyl] [1,1'- Biphenyl] -4-yl} methyl) -N
-(3-Pyridylmethyl) -4 '-(trifluoromethyl) [1,1'-
Biphenyl] -4-sulfonamide (0.79g, 1.01mmol) in ethyl acetate solution (5ml) with 4N hydrogen chloride-ethyl acetate
(10 ml) was added dropwise and the mixture was stirred at room temperature for 1 hour. After the solvent was concentrated under reduced pressure, it was purified by recrystallization (ethanol-ether) and N-({4 '-[(cycloheptylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N -(3-pyridylmethyl) -4'-
(Trifluoromethyl) [1,1′-biphenyl] -4-sulfonamide dihydrochloride (0.75 g, 98%) was obtained as a colorless solid. Melting point: 276-279 ° C Elemental analysis C ₄₀ H ₃₈ F ₃ N ₃ O ₂ S ・ 2HCl ・ 0.5H ₂ O Calculated: C, 62.90; H, 5.41; N, 5.50 Found: C, 62.58; H , 5.81; N, 5.13 ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.2-1.8 (10H, m) 2.0-2.2
(2H, m) 3.13 (1H, s) 4.17 (2H, s) 4.51 (2H, s) 4.6
2 (2H, s) 7.29 (2H, d, J = 8.4Hz) 7.49 (2H, d, J = 8.0H
z) 7.61-7.77 (5H, m) 7.89 (2H, d, J = 8.4Hz) 8.00-8.
17 (7H, m) 8.57 (1H, s) 8.64 (1H, d, J = 5.4Hz) 9.31
(2H, br)

Example 188 N-({4 '-[(cyclohexylmethylamino) methyl] [1,1'-
Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4 '
-(Trifluoromethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylmethylamino) methyl] [ 1,1'-biphenyl] -4-yl}
Methyl) -N- (3-pyridylmethyl) -4 '-(trifluoromethyl) [1,1'-biphenyl] -4-sulfonamide N-({4'-[aminomethyl] [1,1'- Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4 '-(trifluoromethyl)
[1,1'-Biphenyl] -4-sulfonamide (1.5g, 2.44mmol)
Cycloheptanone (0.36m
1, 2.97 mmol), sodium chloride (4 g), triethylamine (0.72 ml, 5.12 mmol) and acetic acid (0.34 ml, 5.86 mmol) were added in that order, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.04 g, 4.88 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, the reaction mixture was added with saturated aqueous sodium hydrogen carbonate (30
ml) and ethyl acetate (30 ml), and then add di-tert-dicarbonate.
Butyl (2.67 g, 12.2 mmol) was added and the mixture was stirred at room temperature for 2 hours. After separating the organic layer, after drying over anhydrous magnesium sulfate,
It was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-1: 1), and N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylmethylamino) methyl] [1 , 1'-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4 '-(trifluoromethyl) [1,1'-biphenyl] -4-sulfonamide (0.41g, 22
%) Was obtained as colorless crystals. Melting point: 152-153 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.8-1.0 (2H, m) 1.15-1.29
(3H, m) 1.44-1.69 (15H, m) 3.03-3.06 (2H, m) 4.41
(4H, s) 4.48 (2H, br) 7.13-7.17 (3H, m) 7.24-7.28
(2H, m) 7.40-7.57 (5H, m) 7.69-7.79 (6H, m) 7.96
(2H, d, J = 8.4Hz) 8.30 (1H, d, J = 1.8Hz) 8.45 (1H, d
d, J = 1.8, 4.6Hz). 2) N-({4 '-[(cyclohexylmethylamino) methyl] [1,
1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl)
-4 '-(Trifluoromethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride N-({4'-[(N-tert-butoxycarbonyl-N-cyclohexylmethylamino) methyl] [1,1'-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4 '-(trifluoromethyl)
[1,1'-Biphenyl] -4-sulfonamide (0.39g, 0.50mmo
4N Hydrogen chloride-ethyl acetate (10 ml) was added dropwise to a solution of l) in ethyl acetate (5 ml), and the mixture was stirred at room temperature for 1 hour. After concentrating the solvent under reduced pressure, the residue was purified by recrystallization (ethanol-ether), and N-({4 '-[(cyclohexylmethylamino) methyl]
[1,1'-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) -4 '-(trifluoromethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride (0.36 g, 95%) was obtained as a colorless solid. Melting point: 268-269 ° C Elemental analysis C ₄₀ H ₃₈ F ₃ N ₃ O ₂ S ・ 2HCl ・ 1.5H ₂ O Calculated: C, 61.46; H, 5.54; N, 5.38 Found: C, 61.79; H , 5.35; N, 5.00 ¹ H-NMR (d ₆ -DMSO) δ (ppm) 0.8-1.4 (5H, m) 1.6-1.8
(6H, m) 2.73 (2H, s) 4.15 (2H, s) 4.51 (2H, s) 4.6
0 (2H, s) 7.28 (2H, d, J = 8.2Hz) 7.50 (2H, d, J = 8.2H
z) 7.64-7.72 (5H, m) 7.89 (2H, d, J = 8.8Hz) 7.99-8.
11 (7H, m) 8.53 (1H, s) 8.61 (1H, d, J = 5.6Hz) 9.24
(2H, br).

Example 189 N-({4 ′-[(cyclohexylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [1,1′- Biphenyl] -3-sulfonamide dihydrochloride 1) 4-{[[(3-Bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl
-N-cyclohexylmethylamino) methyl] -1,1'-biphenyl 4-[(N-tert-butoxycarbonyl-N-cyclohexylmethylamino) methyl] -4 '-[(3-pyridylmethyl) aminomethyl]- Triethylamine (1.14ml, 8.16mm) in 1,1'-biphenyl (1.32g, 2.74mmol) in acetonitrile (10ml)
ol) and m-bromobenzenesulfonyl chloride (1.05g,
(4.08 mmol) was added at room temperature, and the mixture was stirred for 30 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Hexane: Ethyl acetate = 3: 1, Hexane: Acetone = 3: 2)
Purified with 4-{[[(3-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl-N-cyclohexylmethylamino) methyl] -1 , 1 '
-Biphenyl (1.54g, 80%) was obtained as a pale red amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.37 (6H, s) 7.11 (2H, d, J = 8.
4Hz) 7.13-7.20 (1H, dd, J = 4.8, 8.0Hz) 7.28 (2H, d,
J = 8.8Hz) 7.41-7.55 (6H, m) 7.71-7.81 (2H, m) 7.95
-7.96 (2H, m) 8.28 (1H, d, J = 2.0Hz) 8.47 (1H, dd,
J = 1.8, 4.8Hz). 2) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-N- (3-pyridylmethyl) [1,1'-biphenyl] -3-sulfonamide 4-{[[(3-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -4 '-[ (N-tert-butoxycarbonyl-N
-Cyclohexylmethylamino) methyl] -1,1'-biphenyl (1.52g, 2.16mmol) in toluene (10ml) was added to water (1
0 ml), sodium carbonate (0.46 g, 4.32 mmol), tetrakistriphenylphosphine palladium (0.13 g, 0.108 mmo)
l) and phenylboronic acid (0.32 g, 2.62 mmol) were sequentially added, and the mixture was stirred overnight at 80 ° C. under a nitrogen atmosphere. After the reaction was completed, it was diluted with ethyl acetate and washed with water and saturated saline.
The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, hexane: acetone = 3: 2), and N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl ] [1,1'-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [1,1'-biphenyl] -3-sulfonamide (1.39g, 92%) as colorless amorphous Obtained as a powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.39, 4.40 (6H, each s) 7.09-
7.16 (3H, m) 7.27 (2H, d, J = 7.8Hz) 7.36-7.65 (11H,
m) 7.81-7.88 (2H, m) 8.04-8.06 (1H, m) 8.28 (1H,
d, J = 1.8Hz). 3) N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [1 , 1'-
Biphenyl] -3-sulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)- N
4- (3-pyridylmethyl) [1,1'-biphenyl] -3-sulfonamide (1.35g, 1.92mmol) in ethyl acetate (5ml) was added to 4
Normal hydrogen chloride-ethyl acetate (10 ml) was added dropwise at room temperature to 1
Stir for hours. After concentrating the solvent under reduced pressure, the residue was purified by recrystallization (ethanol-ether) and N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-
Pyridylmethyl) [1,1'-biphenyl] -3-sulfonamide ・
The dihydrochloride (1.24g, 96%) was obtained as a colorless solid. Melting point: 305-306 ° C Elemental analysis C ₃₈ H ₃₇ N ₃ O ₂ S ・ 2HCl ・ H ₂ O Calculated: C, 66.08; H, 5.98; N, 6.08 Found: C, 66.27; H, 5.87; N, 5.91 ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (10H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 4.15-4.17 (2H, m) 4.52 (2H, m)
s) 4.63 (2H, s) 7.28 (2H, d, J = 8.0Hz) 7.41-7.82 (1
3H, m) 7.95-8.33 (4H, m) 8.56 (1H, s) 8.62 (1H, d,
J = 4.8Hz) 9.35 (2H, br)

Example 190 N-({4 ′-[(cyclohexylamino) methyl] [1,1′-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [1,1′- Biphenyl] -2-sulfonamide dihydrochloride 1) 4-{[[(2-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(N-tert-butoxycarbonyl
-N-cyclohexylmethylamino) methyl] -1,1'-biphenyl 4-[(N-tert-butoxycarbonyl-N-cyclohexylmethylamino) methyl] -4 '-[(3-pyridylmethyl) aminomethyl]- Triethylamine (0.87ml, 6.18mm) in 1,1'-biphenyl (1.01g, 2.06mmol) in acetonitrile (20ml)
ol) and o-bromobenzenesulfonyl chloride (0.79g,
(3.09 mmol) was added at room temperature, and the mixture was stirred for 30 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Hexane: Ethyl acetate = 2: 1-Hexane: Acetone = 2: 1
−3: 2) and purified by 4-{[[(2-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -4 ′-[(N-tert-butoxycarbonyl-N-cyclohexylmethylamino ) Methyl] -1,1'-biphenyl (0.67g, 47%) was obtained as a pale red amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.42 (4H, s) 4.47 (2H, s) 7.11
(2H, d, J = 8.4Hz) 7.21 (1H, ddd, J = 0.8, 4.8,7.8Hz)
7.29 (2H, d, J = 8.4Hz) 7.40-7.57 (7H, m) 7.78-7.83
(1H, m) 8.18-8.23 (1H, m) 8.26 (1H, d, J = 2.2Hz)
8.50 (1H, dd, J = 1.8, 4.8Hz). 2) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4- Ill} methyl)
-N- (3-pyridylmethyl) [1,1'-biphenyl] -2-sulfonamide 4-{[[(2-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -4 '-[ (N-tert-butoxycarbonyl-N
-Cyclohexylmethylamino) methyl] -1,1'-biphenyl (0.63g, 0.89mmol) in toluene solution (10ml) was added to water (1
0 ml), sodium carbonate (0.19 g, 1.79 mmol), tetrakistriphenylphosphine palladium (0.051 g, 0.045 mmo)
l) and phenylboronic acid (0.13 g, 1.07 mmol) were sequentially added, and the mixture was stirred under nitrogen atmosphere at 80 ° C. overnight. After the reaction was completed, it was diluted with ethyl acetate and washed with water and saturated saline.
The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, hexane: acetone = 3: 2), and N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl ] [1,1'-Biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [1,1'-biphenyl] -2-sulfonamide (0.60g, 96%) colorless and amorphous Obtained as a powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 1.39 (9H,
s) 4.0-4.2 (1H, br) 4.39, 4.40 (6H, each s) 7.09-
7.16 (3H, m) 7.27 (2H, d, J = 7.8Hz) 7.36-7.65 (11H,
m) 7.81-7.88 (2H, m) 8.04-8.06 (1H, m) 8.28 (1H,
d, J = 1.8Hz). 3) N-({4 '-[(Cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl) [1 , 1'-
Biphenyl] -2-sulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)- N
4- (3-pyridylmethyl) [1,1'-biphenyl] -2-sulfonamide (0.58g, 0.826mmol) in ethyl acetate solution (5ml)
Normal hydrogen chloride-ethyl acetate (10 ml) was added dropwise at room temperature to 1
Stir for hours. After concentrating the solvent under reduced pressure, the residue was purified by recrystallization (ethanol-ether) and N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-
Pyridylmethyl) [1,1'-biphenyl] -2-sulfonamide ・
The dihydrochloride salt (0.48g, 86%) was obtained as a colorless solid. mp: 242-243 ℃ Elemental analysis C ₃₈ H ₃₉ N ₃ O ₂ S ・ 2HCl ・ 0.75H ₂ O Calculated: C, 66.32; H, 6.22; N, 6.11 Found: C, 66.34; H, 6.22 ; N, 5.94 ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.8 (10H, m) 2.0-2.2
(2H, m) 2.96 (1H, br) 4.15-4.17 (2H, m) 4.52 (2H, m)
s) 4.63 (2H, s) 7.28 (2H, d, J = 8.0Hz) 7.41-7.82 (1
3H, m) 7.95-8.33 (4H, m) 8.56 (1H, s) 8.62 (1H, d,
J = 4.8Hz) 9.35 (2H, br)

Example 191 N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (neopentyloxy) -N- (3-pyridyl Methyl) benzenesulfonamide dihydrochloride 1) N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl)
-4- (Neopentyloxy) -N- (3-pyridylmethyl) benzenesulfonamide 4-[(N-cyclohexyl-N-tert-butoxycarbonyl) aminomethyl] -4 '-[(3-pyridylmethyl) amino Methyl] -1,
1'-Biphenyl (0.71g, 1.46mmol) in acetonitrile (10ml) was added with triethylamine (0.61ml, 4.38mmol).
p-Neopentyloxybenzenesulfonyl chloride (0.
(60 g, 2.33 mmol) was added at room temperature, and the mixture was stirred as it was overnight. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous magnesium sulfate,
It was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to hexane: acetone = 2: 1 to 3: 2), and N-({4 '-[(N-tert-butoxycarbonyl-N- Cyclohexylamino) methyl] [1,1'-
Biphenyl] -4-yl} methyl) -4- (neopentyloxy) -N-
(3-Pyridylmethyl) benzenesulfonamide (0.86g, 8
3%) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.06 (9H, s) 1.22-1.75 (10
H, m) 1.39 (9H, s) 3.67 (2H, s) 4.0-4.2 (1H, br) 4.
32 (4H, s) 4.40 (2H, s) 7.00 (2H, d, J = 8.8Hz) 7.09
-7.16 (3H, m) 7.27 (2H, d, J = 8.4Hz) 7.41-7.54 (5H,
m) 7.80 (2H, d, J = 8.8Hz) 8.25 (1H, d, J = 1.8Hz) 8.4
4 (1H, dd, J = 1.8, 4.8Hz). 2) N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4- (neo Pentoxy) -N- (3-
Pyridylmethyl) benzenesulfonamide dihydrochloride N-({4 '-[(N-tert-butoxycarbonyl-N-cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl} methyl) -4
-(Neopentyloxy) -N- (3-pyridylmethyl) benzenesulfonamide (0.85g, 1.20mmol) in ethyl acetate (5
4N hydrogen chloride-ethyl acetate (10 ml) was added dropwise to
Stirred at room temperature for 1 hour. After the solvent was concentrated under reduced pressure, the crystals were collected by filtration, washed with ether and dried. N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4-yl}
Methyl) -4- (neopentyloxy) -N- (3-pyridylmethyl)
Benzenesulfonamide dihydrochloride (0.71 g, 86%) was obtained as a colorless solid. Melting point: 257-260 ° C Elemental analysis C ₃₇ H ₄₃ N ₃ O ₃ S ・ 2HCl ・ H ₂ O Calculated: C, 63.42; H, 6.76; N, 6.00 Found: C, 63.61; H, 6.78; N, 5.86 ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.03 (9H, s) 1.13-1.76 (8
H, m) 2.11-2.17 (2H, m) 2.96 (1H, br) 3.76 (2H, s)
4.17 (2H, s) 4.39 (2H, s) 4.50 (2H, s) 7.18 (2H, s)
d, J = 9.2Hz) 7.26 (2H, d, J = 8.4Hz) 4.48 (2H, d, J =
8.4Hz) 7.61-7.86 (5H, m) 7.88 (2H, d, J = 8.8Hz) 8.13
(1H, d, J = 8.0Hz) 8.53 (1H, s) 8.63 (1H, d, J = 5.2H
z) 9.32 (2H, br)

Example 192 4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -4 '-{[(cyclohexyloxy)
Carbonyl] amino} -1,1'-biphenyl 4- [N- (4-biphenylsulfonyl) -N- (3-pyridylmethyl)
Aminomethyl] -1,1'-biphenyl-4-carboxylic acid (0.50g,
Triethylamine (0.20 ml, 1.40 mmol) and diphenylphosphoric acid azide (0.23 ml, 1.03 mmol) were added to a suspension of 0.935 mmol) in acetonitrile (10 ml) at room temperature, and the mixture was heated under reflux for 1 hr. Then cyclohexanol (0.20ml, 1.87mm
ol) was added and the mixture was heated under reflux for 1 hour. After completion of the reaction, the mixture was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate and saturated brine.
The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, hexane: acetone =).
3: 2) and purified by 4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -4 '-{[(cyclohexyloxy) carbonyl] amino } -1,1'-biphenyl
(0.32 g, 54%) was obtained as colorless crystals. Melting point: 200-201 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-2.0 (10H, m) 4.39 (4H,
s) 4.77-4.99 (1H, m) 6.63 (1H, s) 7.08-7.19 (3H,
m) 7.37-7.56 (10H, m) 7.62 (2H, dd, J = 1.4, 7.6Hz)
7.74 (2H, d, J = 8.8Hz) 7.94 (2H, d, J = 8.8Hz) 8.30
(1H, s) 8.44 (1H, s).

Example 193 N-cyclohexyl-4 ′-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl]
[1,1'-Biphenyl] -4-carboxamide 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl]-
4-carboxylic acid (0.5g, 0.99mmol) and cyclohexylamine
(0.14 ml, 1.19 mmol) N, N-dimethylformamide (10 ml)
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride (0.26g, 1.48mmol) and 1-hydroxybenzotriazole monohydrate (0.23g, 1.48mmol) were added to the solution and the mixture was stirred at room temperature for 4 hours. It was stirred. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 1-
1: 1), N-cyclohexyl-4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl}
Amino) methyl] [1,1'-biphenyl] -4-carboxamide
(0.52 g, 90%) was obtained as colorless crystals. Melting point 202-203 ℃ Elemental analysis value C ₃₄ H ₃₃ F ₃ N ₄ O ₂ Calculated value: C, 69.61; H, 5.67; N, 9.55 Actual value: C, 69.20; H, 5.75; N, 9.23. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.90 (8H, m), 1.95-2.15 (2H, m),
3.90-4.50 (1H, m), 4.62 (2H, s), 4.71 (2H, s), 6.04 (1H,
d, J = 8.4Hz), 6.80 (1H, s), 7.20-7.70 (11H, m), 7.70-7.9
0 (3H, m), 8.50-8.65 (2H, m).

Example 194 4- (1-Piperidylcarbonyl) -4 '-[((3-pyridylmethyl)
{[4- (Trifluoromethyl) anilino] carbonyl} amino] methyl] -1,1'-biphenyl 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) Methyl] [1,1'-biphenyl]-
4-carboxylic acid (0.5 g, 0.99 mmol) and piperidine (0.12 ml,
1.19 mmol) of N, N-dimethylformamide (10 ml) in 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide ・
Hydrochloride (0.26 g, 1.48 mmol) and 1-hydroxybenzotriazole monohydrate (0.23 g, 1.48 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Water (100 ml) was added to the reaction solution, and ethyl acetate (100 m
It was extracted in l). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1-1: 1) to give 4- (1-piperidylcarbonyl) -4 '-[((3-pyridylmethyl) {[4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1′-biphenyl (0.47 g, 83%) was obtained as colorless crystals. Melting point 122-125 ° C Elemental analysis C ₃₃ H ₃₁ F ₃ N ₄ O ₂ Calculated: C, 69.22; H, 5.46; N, 9.78 Found: C, 69.34; H, 5.45; N, 9.85. ¹ H-NMR (CDCl ₃ ) δ: 1.40-1.85 (6H, m), 3.3-3.55 (2H, m),
3.60-3.80 (2H, m), 4.60 (2H, s), 4.68 (2H, s), 7.02 (1H,
s), 7.20-7.70 (13H, m), 7.72 (1H, d, J = 8.0Hz), 8.50-8.7
5 (2H, m).

Example 195 N- (4-fluorobenzyl) -4 ′-[((3-pyridylmethyl) {[4-
(Trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-carboxamide 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino ) Methyl] [1,1'-biphenyl]-
4-carboxylic acid (0.5 g, 0.99 mmol) and 4-fluorobenzylamine (0.14 ml, 1.19 mmol) in N, N-dimethylformamide (1
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.26g, 1.48mmol) and 1-hydroxybenzotriazole monohydrate (0.23g, 1.48mmol) were added to the solution at room temperature. It was stirred for 4 hours. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: acetone).
= 2: 1-1: 1) and N- (4-fluorobenzyl) -4 '-[((3
-Pyridylmethyl) {[4- (trifluoromethyl) anilino]
Carbonyl} amino) methyl] [1,1′-biphenyl] -4-carboxamide (0.48 g, 79%) was obtained as colorless crystals. Melting point 191-193 ° C Elemental analysis C ₃₅ H ₂₈ F ₄ N ₄ O ₂ Calculated: C, 68.62; H, 4.61; N, 9.15 Found: C, 68.61; H, 4.53; N, 9.09. ¹ H-NMR (d ₆ -DMSO) δ: 4.48 (1H, s), 4.64 (2H, s), 4.69 (1
H, s), 7.02-7.22 (2H, m), 7.30-7.47 (3H, m), 7.58 (2H, d,
J = 8.8Hz), 7.65-7.80 (7H, m), 7.98 (2H, d, J = 8.4Hz), 8.4
5-8.53 (2H, m), 9.05-9.15 (2H, m).

Example 196 N- (4-methoxyphenyl) -4 ′-[((3-pyridylmethyl) {[4-
(Trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-carboxamide 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino ) Methyl] [1,1'-biphenyl]-
4-carboxylic acid (0.5g, 0.99mmol) and 4-methoxyaniline
(0.15g, 1.19mmol) N, N-dimethylformamide (10ml)
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride (0.26g, 1.48mmol) and 1-hydroxybenzotriazole monohydrate (0.23g, 1.48mmol) were added to the solution, and the mixture was stirred at room temperature for 2 hours. It was stirred. Water (100 ml) was added to the reaction solution, and the mixture was extracted with chloroform (400 ml). The extract was evaporated under reduced pressure, the crystals were collected by filtration, and N- (4-methoxyphenyl) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl}
Amino) methyl] [1,1'-biphenyl] -4-carboxamide
(0.47 g, 78%) was obtained as colorless crystals. Melting point 249-251 ℃ Elemental analysis value C ₃₅ H ₂₉ F ₃ N ₄ O ₃ Calculated value: C, 68.84; H, 4.79; N, 9.18 Found value: C, 68.59; H, 4.71; N, 8.99. ¹ H-NMR (d ₆ -DMSO) δ: 3.76 (3H, s), 4.66 (2H, s), 4.71 (2
H, s), 6.93 (2H, d, J = 8.8Hz), 7.33- 7.47 (3H, m), 7.60 (2
H, d, J = 8.4Hz), 7.65-7.90 (9H, m), 8.04 (2H, d, J = 8.0Hz),
8.45-8.55 (2H, m), 9.09 (1H, s), 10.16 (1H, s).

Example 197 4 ′-{[[([1,1′-biphenyl] -4-ylamino) carbonyl]
(3-Pyridylmethyl) amino] methyl} -N-cyclohexyl
[1,1'-biphenyl] -4-carboxamide 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (1.0g, 1.95mmol) and cyclohexylamine (0.27m
l, 2.35 mmol) in N, N-dimethylformamide (10 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.51 g, 2.92 mmol) and 1-hydroxybenzotriazole monohydrate. A Japanese product (0.45 g, 2.92 mmol) was added and the mixture was stirred for 5 hours. Water (100 ml) was added to the reaction solution, and ethyl acetate (100 m
It was extracted in l). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue (chloroform: ethyl acetate = 2: 1-1: 1)
Purified with 4 '-{[[([1,1'-biphenyl] -4-ylamino)
Carbonyl] (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1'-biphenyl] -4-carboxamide (0.75
g, 64%) was obtained as colorless crystals. Melting point 133-135 ° C Elemental analysis value C ₃₉ H ₃₈ N ₄ O ₂・ 0.3H ₂ O, measured value: C, 78.15; H, 6.33; N, 9.38. ¹ H-NMR (CDCl ₃ ) δ: 1.10- 1.90 (8H, m), 1.95-2.15 (2H, m),
3.90-4.15 (1H, m), 4.62 (2H, s), 4.72 (2H, s), 5.95-6.1
0 (1H, br, NH), 6.46 (1H, s), 7.20-7.90 (19H, m), 8.55-8.
65 (2H, m).

Example 198 4 '-{[{[([1,1'-biphenyl] -4-ylmethyl) amino] carbonyl} (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1' -Biphenyl] -4-carboxamide 4 '-{[{[([1,1'-biphenyl] -4-ylmethyl) amino] carbonyl} (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (0.79g, 1.50mmol) and cyclohexylamine (0.21ml, 1.80mmol) in N, N-dimethylformamide (10ml) solution, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salt (0.39g, 2.25mol) and 1-hydroxybenzotriazole monohydrate (0.35g, 2.25mmo
l) was added and the mixture was stirred for 3 hours. Add water (100 ml) to the reaction mixture,
It was extracted with chloroform (100 ml × 2). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1) to give 4 '-{[{[([1,1'-biphenyl] -4-ylmethyl) amino] carbonyl} (3- Pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1′-biphenyl] -4-carboxamide (0.86 g, 93%) was obtained as colorless crystals. Mp as 229-231 ° C. Elemental analysis _{C 40 H 40 N 4 O 2} · 1 / 2H 2 O, Calculated: C, 77.77; H, 6.69 ; N, 9.07 Found: C, 77.84; H, 6.64 ; N , 8.96. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.90 (8H, m), 2.00-2.15 (2H, m),
3.90-4.15 (1H, m), 4.49 (2H, d, J = 6.0Hz), 4.50 (2H, s),
4.65 (2H, s), 4.75-4.85 (1H, m), 5.98 (1H, brd, J = 7.4H
z), 7.20-7.75 (17H, m), 7.80 (2H, d, J = 8.4Hz), 8.50-8.
60 (2H, m).

Example 199 N-Cyclohexyl-4 ′-{[[(4-phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} [1,1′-biphenyl] -4-carboxamide 4′- {[[(4-Phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (0.79g, 1.5mmol) and cyclohexylamine (0.21ml,
1.8 mmol of N, N-dimethylformamide (15 ml) solution, 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.39g, 2.25mmol) and 1-hydroxybenzotriazole monohydrate (0.35g, 2.25mmol) were added and stirred for 3 hours. Water (100 ml) was added to the reaction solution, and ethyl acetate (100 ml x
Extracted in 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 2: 1) to give N-cyclohexyl-4 '-{[[(4-phenoxyanilino) carbonyl] (3-pyridylmethyl) amino] methyl. } [1,
1′-Biphenyl] -4-carboxamide (0.63 g, 67%) was obtained as colorless crystals. Melting point 125-127 ℃ Elemental analysis value C ₃₉ H ₃₇ N ₄ O ₃ H ₂ O Calculated value: C, 74.50; H, 6.41; N, 8.91 Found value: C, 74.20; H, 6.05; N, 8.77 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.10-1.90 (8H, m), 2.00-2.15 (2H, m),
3.90-4.15 (1H, m), 4.61 (2H, s), 4.71 (2H, s), 6.99 (1H,
brd, J = 7.2Hz), 6.36 (1H, s), 6.90-7.00 (4H, m), 7.06 (1
H, t, J = 6.9Hz), 7.20-7.45 (7H, m), 7.64 (4H, d, J = 8.4Hz),
7.70-7.85 (1H, m), 7.83 (2H, d, J = 8.4Hz), 8.55- 8.65 (2
H, m).

Example 200 N-Cyclohexyl-4 ′-[(2-pyridyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1′-biphenyl] -4-carboxamide 4′- [(2-Pyridyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid (0.55g, 1.12mmol) and cyclohexylamine (0.15m
l, 1.34 mmol) in N, N-dimethylformamide (10 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.29 g, 1.68 mmol) and 1-hydroxybenzotriazole monohydrate A Japanese product (0.26 g, 1.68 mmol) was added and stirred for 3 hours. The reaction mixture was diluted with water (100 ml) and ethyl acetate (100 ml).
It was extracted with. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1),
N-cyclohexyl-4 '-[(2-pyridyl {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-carboxamide (0.52g, 81%) colorless Obtained as crystals. Melting point 178-180 ° C Elemental analysis C ₃₃ H ₃₁ F ₃ N ₄ O ₂ Calculated: C, 69.22; H, 5.46; N, 9.78 Found: C, 69.19; H, 5.62; N, 9.63. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.90 (8H, m), 1.95-2.15 (2H, m),
3.90-4.15 (1H, m), 5.33 (2H, s), 5.99 (1H, d, J = 7.4Hz),
6.97 (2H, d, J = 8.4Hz), 7.03 (1H, dd, J = 6.6,4.8Hz), 7.38 (2
H, d, J = 8.4Hz), 7.50-7.90 (11H, m).

Example 201 N-cyclohexyl-2- {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl]- 4-yl} acetamide {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl]-
4-yl} acetic acid (0.52g, 1.0mmol) and cyclohexylamine
(0.14 ml, 1.2 mmol) of N, N-dimethylformamide (20 ml)
To the solution was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.26g, 1.5mmmol) and 1-hydroxybenzotriazole monohydrate (0.23g, 1.5mmol) to give 15
Stir for hours. Water (100 ml) was added to the reaction solution, and ethyl acetate was added.
It was extracted with (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: acetone = 2: 1-1:
Purified in 1), N-cyclohexyl-2- {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl} acetamide (0.53g, 88%) was obtained as colorless crystals. Melting point 202-204 ℃ Elemental analysis value C ₃₅ H ₃₅ F ₃ N ₄ O ₂ Calculated value: C, 69.98; H, 5.87; N, 9.33 Actual value: C, 69.79; H, 5.92; N, 9.24. ¹ H-NMR (CDCl ₃ ) δ: 0.95-1.80 (10H, m), 1.80-2.00 (2H,
m), 3.58 (2H, s), 3.65-3.95 (1H, m), 4.61 (2H, s), 4.73
(2H, s), 5.20-5.35 (1H, m), 6.57 (1H, s), 7.30-7.80 (14
H, m), 8.55-8.70 (2H, m).

Example 202 N- (4-methoxyphenyl) -2- {4 '-[((3-pyridylmethyl)
{[4- (Trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-yl} acetamide {4 '-[((3-pyridylmethyl) {[4- (trifluoro Methyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl]-
4-yl} acetic acid (0.52g, 1.0mmol) and p-anisidine (0.15g,
1.20 mmol) in N, N-dimethylformamide (10 ml) solution,
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloric acid (0.26 g, 1.50 mmol) 1-Hydroxybenzotriazole monohydrate (0.23 g, 1.50 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 ml) and washed with ethyl acetate (100 m
It was extracted in l). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from methanol-diethyl ether to give N- (4-methoxyphenyl) -2-
{4 '-[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] [1,1'-biphenyl]-
4-yl} acetamide (0.48 g, 77%) was obtained as colorless crystals. Mp 216-219 As ℃ Elemental analysis _{C 36 H 31 F 3 N 4} O 2, Calcd: C, 69.22; H, 5.00 ; N, 8.97 Found:. C, 68.95; H, 5.03; N, 8.84 1 H-NMR (d ₆ -DMSO) δ: 3.63 (2H, s), 3.71 (3H, s), 4.63 (2
H, s), 4.67 (2H, s), 6.85 (2H, d, J = 8.4Hz), 7.30-7.80 (1
7H, m), 8.40-8.55 (2H, m), 9.06 (1H, s).

Example 203 N-cyclohexyl-4 ′-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl]
[1,1'-Biphenyl] -4-carboxamidoethyl 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl]- An aqueous solution (50 ml) of potassium carbonate (0.49 g, 3.52 mmol) was added to methanol (50 ml) of 4-carboxylate (0.96 g, 1.76 mmol), and the mixture was refluxed for 1.5 hours. The reaction solution was dried under reduced pressure. Residue and cyclohexylamine (0.26ml, 2.29mmo
l), N, N-dimethylformamide (30 ml) in a mixed solution of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.45 g, 2.64 mmol) as 1-hydroxybenzotriazole monohydrate (0.40 g, 2.64 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Water (150 ml) was added to the reaction solution, and ethyl acetate (150 ml) was added.
ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1) to give N-cyclohexyl-4 '-[((3-pyridylmethyl) {[4
-(Trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxamide 0.24g, 22
%) As colorless crystals. Melting point 214-215 ° C Elemental analysis C ₃₃ H ₃₂ F ₃ N ₃ O ₃ S Calculated value: C, 65.22; H, 5.31; N, 6.91 Found value: C, 64.99; H, 5.23; N, 6.75. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.90 (8H, m), 1.98-2.17 (2H, m),
3.90-4.15 (1H, m), 4.40 (4H, s), 5.90 (1H, d, J = 5.6Hz),
7.10-7.22 (3H, m), 7.45 (2H, d, J = 8.4Hz), 7.58 (2H, d, J =
8.4Hz), 7.40-7.60 (1H, m), 7.75-7.90 (4H, m), 7.99 (2H,
d, J = 8.4Hz), 8.30 (1H, s), 8.43-8.52 (1H, m).

Example 204 N-Cycloheptyl-4 ′-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl]
[1,1'-Biphenyl] -4-carboxamide 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl]-
4-carboxylic acid (0.737 g, 1.4 mmol) and cycloheptylamine (0.21 ml, 1.68 mmol) in N, N-dimethylformamide (10
1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.36 g, 2.1 mmol) and 1-hydroxybenzotriazole monohydrate (0.32 g, 2.1 mmol) to the Stir for hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was extracted with chloroform (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 3: 1-1: 1), and N-cycloheptyl-4 ′-[((3-pyridylmethyl) {[4- (trifluoromethyl )
Phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4-carboxamide (0.83 g, 95%) was obtained as colorless crystals. Mp 218-219 As ℃ Elemental analysis _{C 34 H 34 F 3 N 3} O 3 S, Calculated: C, 65.68; H, 5.51 ; N, 6.76 Found: C, 65.65; H, 5.37 ; N, 6.62. ¹ H-NMR (CDCl ₃ ) δ: 1.45-2.20 (12H, m), 4.10-4.30 (1H,
m), 4.40 (2H, s), 6.07 (1H, d, J = 7.6Hz), 7.10-7.20 (3H,
m), 7.40-7.65 (5H, m), 7.78-7.90 (3H, m), 7.99 (2H, d, J
= 8.4Hz), 8.25-8.35 (1H, m), 8.40-8.55 (1H, m).

Example 205 N- (cyclohexylmethyl) -4 '-[((3-pyridylmethyl)
{[4- (Trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxamide 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl ] Sulfonyl} amino) methyl] [1,1'-biphenyl]-
4-Carboxylic acid (0.737 g, 1.4 mmol) and cyclohexylmethylamine (0.22 ml, 1.68 mmol) in N, N-dimethylformamide (10 ml) was added to 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. Salt (0.36g, 2.1mmol) and 1-hydroxybenzotriazole monohydrate (0.32g, 2.1mmol)
Was added and stirred for 3 hours. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 ml). The extract was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 3: 1-2: 1) and N- (cyclohexylmethyl) -4 '-[((3-pyridylmethyl) {[4- (tri Fluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1 '
-Biphenyl] -4-carboxamide (0.76 g, 87%) was obtained as colorless crystals. Melting point 210-212 ° C Calculated: C, 65.68; H, 5.51; N, 6.76 Found: C, 65.65; H, 5.59; N, 6.59. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.90 (11H, m), 3.34 (2H, t, J = 6.4
Hz), 4.41 (4H, s), 6.15-6.30 (1H, m), 7.10-7.20 (3H, m),
7.40-7.65 (5H, m), 7.65-7.90 (4H, m), 7.99 (2H, d, J = 8.
8Hz), 8.05-8.15 (1H, m), 8.40-8.55 (1H, m).

Example 206 N- (4-methoxybenzyl) -4 ′-[((3-pyridylmethyl) {[4-
(Trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4-carboxamide 4 ′-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino ) Methyl] [1,1'-biphenyl]-
4-Carboxylic acid (0.737g, 1.4mmol) and 4-methoxybenzylamine (0.22ml, 1.68mmol) in N, N-dimethylformamide (10ml) solution, 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydrochloride (0.36 g, 2.1 mmol) and 1-hydroxybenzotriazole monohydrate (0.32 g, 2.1 mmol) were added and stirred for 4 hours. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 2: 1) and N- (4-methoxybenzyl) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl ) Phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4-carboxamide (0.81 g, 90%) was obtained as colorless crystals. Mp 184-186 As ℃ Elemental analysis _{C 35 H 30 F 3 N 3} O 4 S, Calcd: C, 65.10; H, 4.68 ; N, 6.51 Found: C, 65.21; H, 4.53 ; N, 6.61. ¹ H-NMR (CDCl ₃ ) δ: 3.82 (3H, s), 4.40 (4H, s), 4.61 (2H,
d, J = 5.8Hz), 6.30-6.45 (1H, m), 6.90 (2H, d, J = 8.4Hz),
7.10-7.20 (3H, m), 7.31 (2H, d, J = 8.8Hz), 7.44 (2H, d, J =
8.4Hz), 7.45-7.60 (1H, m), 7.75-7.95 (4H, m), 7.98 (2H,
d, J = 8.0Hz), 8.25-8.35 (1H, m), 8.40-8.50 (1H, m).

Example 207 N- (2-pyridyl) -4 ′-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,
1'-biphenyl] -4-carboxamide 4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl]-
4-carboxylic acid (1.5g, 2.85mmol) and 2-aminopyridine
(0.32g, 3.42mmol) N, N-dimethylformamide (10ml)
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.73g, 4.27mmol) and 1-hydroxybenzotriazole monohydrate (0.66g, 4.27mmol) were added to the solution, and the mixture was stirred at room temperature for 2 hours. Stir for 2 hours and then 100 ° C. for 2 hours. Water (10
0 ml) was added, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate,
It was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 2: 1) to give N- (2-pyridyl) -4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl. ] Sulfonyl} amino) methyl] [1,1′-biphenyl] -4-carboxamide (0.33 g, 19%) was obtained as colorless crystals. Melting point 202-204 ℃ Elemental analysis value C ₃₂ H ₂₅ F ₃ N ₄ O ₃ S ・ 1 / 4H ₂ O, calculated value: C, 63.31; H, 4.23; N, 9.23 Found value: C, 63.11; H, 4.23; N, 8.92. ¹ H-NMR (CDCl ₃ ) δ: 4.41 (2H, s), 4.42 (2H, s), 7.05-7.20
(4H, m), 7.49 (2H, d, J = 8.4Hz), 7.45-7.60 (1H, m), 7.66
(2H, d, J = 8.4Hz), 7.70-7.85 (1H, m), 7.82 (2H, d, J = 8.4H
z), 7.95-8.10 (4H, m), 8.30-8.40 (2H, m), 8.42 (1H, d, J =
8.6Hz), 8.48 (1H, dd, J = 5.0,1.6Hz), 8.67 (1H, s).

Example 208 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1'-biphenyl] -4 -Carboxamide 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (0.80g, 1.5 mmol) and cyclohexylamine (0.21 m
l, 1.8 mmol) in N, N-dimethylformamide (10 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.39 g, 2.25 mmol) and 1-hydroxybenzotriazole monohydrate. A Japanese product (0.35 g, 2.25 mmol) was added and the mixture was stirred for 15 hours. Water (100 ml) was added to the reaction solution, and ethyl acetate (10 ml
It was extracted with 0 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 3: 1) to give 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino]. Methyl} -N-cyclohexyl [1,1'-biphenyl] -4-carboxamide (0.84g, 91%)
Was obtained as colorless crystals. Melting point 211-213 ° C Elemental analysis value C ₃₈ H ₃₇ N ₃ O ₃ S Calculated value: C, 74.12; H, 6.06; N, 6.82 Actual value: C, 74.61; H, 5.92; N, 6.86. ¹ H -NMR (CDCl ₃ ) δ: 1.10-1.90 (8H, m), 1.95-2.20 (2H, m),
3.90-4.15 (1H, m), 4.40 (2H, s), 4.41 (2H, s), 5.98 (1H,
d, J = 8.4Hz), 7.10-7.25 (3H, m), 7.40-7.70 (10H, m), 7.7
0-7.90 (4H, m), 7.95 (2H, d, J = 8.4Hz), 8.25-8.35 (1H,
m), 8.45 (1H, d, J = 4.0Hz).

Example 209 4 ′-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-cycloheptyl [1,1′-biphenyl]- 4-carboxamide 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (0.75g, 1.4 mmol) and cycloheptylamine (0.21 m
l, 1.68 mmol) in N, N-dimethylformamide (10 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.36 g, 2.1 mmol) and 1-hydroxybenzotriazole monohydrate A Japanese product (0.32 g, 2.1 mmol) was added and the mixture was stirred for 2 hours. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: ethyl acetate =
3: 1-2: 1) and 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-cycloheptyl [1 , 1'-Biphenyl] -4-carboxamide (0.77
g, 87%) was obtained as colorless crystals. Melting point 201-202 ℃ Elemental analysis value C ₃₉ H ₃₉ N ₃ O ₃ S Calculated value: C, 74.37; H, 6.24; N, 6.67 Actual value: C, 74.44; H, 6.22; N, 6.63. ¹ H -NMR (CDCl ₃ ) δ: 1.40-1.80 (10H, m), 1.95-2.20 (2H,
m), 4.10-4.30 (1H, m), 4.40 (2H, s), 6.08 (1H, brd, J = 8.8
Hz), 7.10-7.20 (3H, m), 7.40-7.70 (10H, m), 7.76 (2H, d,
J = 8.4Hz), 7.80 (2H, d, J = 8.4Hz), 7.95 (2H, d, J = 8.4Hz),
8.29 (1H, s), 8.40-8.50 (1H, m).

Example 210 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N- (cyclohexylmethyl)
[1,1'-biphenyl] -4-carboxamide 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (0.7g, 1.4mmol) and cyclohexylmethylamine
(0.20 ml, 1.57 mmol) N, N-dimethylformamide (10 ml)
To the solution was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.34g, 1.96mmol) and 1-hydroxybenzotriazole monohydrate (0.30g, 1.96mmol) to give 3
Stir for hours. Water (100 ml) was added to the reaction solution, and ethyl acetate was added.
It was extracted with (150 ml). The extract was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, passed through a small amount of silica gel, and evaporated under reduced pressure. Hexane-diethyl ether was added to the precipitated crystals, and the crystals were collected by filtration to give 4 '-{[([1,1'-biphenyl] -4-
(Ilsulfonyl) (3-pyridylmethyl) amino] methyl} -N-
(Cyclohexylmethyl) [1,1′-biphenyl] -4-carboxamide (0.79 g, 96%) was obtained as colorless crystals. Melting point 186-187 ℃ Elemental analysis value C ₃₉ H ₃₉ N ₃ O ₃ S Calculated value: C, 74.37; H, 6.24; N, 6.67 Actual value: C, 74.33; H, 6.17; N, 6.49. ¹ H -NMR (CDCl ₃ ) δ: 0.90-1.40 (6H, m), 1.50-1.90 (5H, m),
3.33 (2H, t, J = 6.6Hz), 4.40 (4H, s), 6.15-6.30 (1H, m),
7.10-7.20 (3H, m), 7.40-7.70 (10H, m), 7.70-7.90 (4H,
m), 7.95 (2H, d, J = 8.8Hz), 8.29 (1H, s), 8.44 (1H, d, J = 5.
2Hz).

Example 211 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N- [4- (trifluoromethoxy) phenyl] [ 1,1'-biphenyl] -4-carboxamide 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl]- 4-Carboxylic acid (0.75g, 1.4mmol) and 4-trifluoromethoxyaniline (0.23ml, 1.68mmol) in N, N-dimethylformamide
(10 ml) solution, 1-ethyl-3- (3-dimethylaminopropyl)
Carbodiimide hydrochloride (0.36 g, 2.1 mmol) and 1-hydroxybenzotriazole monohydrate (0.32 g, 2.1 mmol) were added and stirred for 15 hours. Water (100 ml) was added to the reaction solution, and the mixture was extracted with chloroform (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: ethyl acetate =
3 ') and purified by 4'-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N- [4- (trifluoromethoxy) Phenyl] [1,1'-biphenyl] -4-carboxamide (0.60 g, 61%) was obtained as colorless crystals. Mp 195-196 As ℃ Elemental analysis _{C 39 H 30 F 3 N 3} O 4 S, Calcd: C, 67.52; H, 4.36 ; N, 6.06 Found: C, 67.70; H, 4.26 ; N, 6.04. ¹ H-NMR (CDCl ₃ ) δ: 4.40 (4H, s), 4.42 (2H, s), 7.10-7.30
(4H, m), 7.40-7.80 (15H, m), 7.85-8.10 (5H, m), 8.27 (1
H, d, J = 1.6Hz), 8.45 (1H, dd, J = 4.8,1.6Hz).

Example 212 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N- [4- (trifluoromethyl)
Benzyl] [1,1'-biphenyl] -4-carboxamide 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'- Biphenyl] -4-carboxylic acid (0.75 g, 1.4 mmol) and 4-trifluoromethylbenzylamine (0.17 ml, 1.68 mmol) in N, N-dimethylformamide (15 ml) was added to 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide hydrochloride (0.36 g, 2.1 mmol) and 1-hydroxybenzotriazole monohydrate (0.32 g, 2.1 mmol) were added and stirred for 8 hours. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 3: 1) to give 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino]. Methyl} -N- [4- (trifluoromethyl) benzyl] [1,1′-biphenyl] -4-carboxamide (0.87 g, 90%) was obtained as colorless crystals. Mp 207-209 As ℃ Elemental analysis _{C 40 H 32 F 3 N 3} O 3 S, Calculated: C, 69.45; H, 4.66 ; N, 6.07 Found: C, 69.12; H, 4.57 ; N, 6.04. ¹ H-NMR (CDCl ₃ ) δ: 4.39 (2H, s), 4.41 (2H, s), 4.73 (2H,
d, J = 6.0Hz), 6.70 (1H, t, J = 6.0Hz), 7.10-7.25 (3H, m),
7.40-7.70 (14H, m), 7.76 (2H, d, J = 8.4Hz), 7.86 (2H, d, J =
8.4Hz), 7.94 (2H, d, J = 8.4Hz), 8.27 (1H, d, J = 2.0Hz), 8.
43 (1H, dd, J = 4.8,2.0Hz).

Example 213 4 ′-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N- [2- (trifluoromethyl)
Benzyl] [1,1'-biphenyl] -4-carboxamide 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'- Biphenyl] -4-carboxylic acid (0.75 g, 1.4 mmol) and 2-trifluoromethylbenzylamine (0.24 ml, 1.68 mmol) in N, N-dimethylformamide (20 ml) was added to 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide hydrochloride (0.36g, 2.1mmol) and 1-hydroxybenzotriazole monohydrate (0.32g, 2.1mmol)
Was added and stirred for 3 hours. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 3: 1) to give 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino]. Methyl} -N- [2- (trifluoromethyl) benzyl] [1,1′-biphenyl] -4-carboxamide (0.86 g, 89%) was obtained as colorless crystals. Melting point 160-161 ° C Calculated: C, 69.45; H, 4.66; N, 6.07 Found: C, 69.21; H, 4.61; N, 5.88. ¹ H-NMR (CDCl ₃ ) δ: 4.40 (2H, s) , 4.41 (2H, s), 4.86 (2H,
d, J = 6.2Hz), 6.55 (1H, t, J = 6.2Hz), 7.10-7.20 (3H, m),
7.35-7.90 (18H, m), 7.94 (2H, d, J = 8.4Hz), 8.29 (1H, s),
8.44 (1H, dd, J = 5.2Hz).

Example 214 N-Cyclohexyl-4 ′-[(2-pyridyl {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4-carboxamide 4′- [(2-Pyridyl {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid (0.40g, 0.79mmol) and cyclohexylamine (0.11m
l, 0.95 mmol) in N, N-dimethylformamide (10 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.20 g, 1.19 mmol) and 1-hydroxybenzotriazole monohydrate. A Japanese product (0.18 g, 1.19 mmol) was added and the mixture was stirred for 2 hours. Water (100 ml) was added to the reaction solution, and ethyl acetate (100 ml) was added.
ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 20: 1) to give N-cyclohexyl-4 '-[(2-pyridyl {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl. ] [1,
1′-Biphenyl] -4-carboxamide (0.43 g, 91%) was obtained as colorless crystals. Mp as 203-204 ° C. Elemental analysis _{C 32 H 30 F 3 N 3} O 3 S, Calculated: C, 64.74; H, 5.09 ; N, 7.08 Found: C, 64.67; H, 5.13 ; N, 6.93. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.90 (8H, m), 1.95-2.15 (2H, m),
3.90-4.10 (1H, m), 5.03 (2H, s), 5.97 (1H, brd, J = 8.4H
z), 7.10-7.20 (1H, m), 7.25-7.85 (14H, m), 8.30-8.40 (1
H, m).

Example 215 N-cyclohexyl-2- {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl]- 4-yl} acetamide {4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl]-
4-yl} acetic acid (0.757g, 1.5mmol) and cyclohexylamine (0.21ml, 1.80mmol) in N, N-dimethylformamide (15m
l) To the solution was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.39g, 2.25mmol) and 1-hydroxybenzotriazole monohydrate (0.35g, 2.25mmol) at room temperature. The mixture was stirred for 15 hours. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 2: 1-1: 1), and N-cyclohexyl-2- {4 '-[((3-
Pyridylmethyl) {[4- (trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4-yl} acetamide (0.80 g, 86%) was obtained as colorless crystals. Mp 215-218 As ℃ Elemental analysis _{C 34 H 34 F 3 N 3} O 3 S, Calculated: C, 65.69; H, 5.51 ; N, 6.76 Found: C, 65.62; H, 5.35 ; N, 6.77. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.75 (10H, m), 1.80-2.00 (2H,
m), 3.58 (2H, s), 3.60-3.90 (1H, m), 4.40 (4H, s), 5.20-
5.35 (1H, m), 7.05-7.60 (10H, m), 7.80 (2H, d, J = 8.4Hz),
7.98 (2H, d, J = 8.4Hz), 8.29 (1H, s), 8.47 (1H, d, J = 4.8H
z).

Example 216 N- (4-methoxyphenyl) -2- {4 '-[((3-pyridylmethyl)
{[4- (Trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-yl} acetamide {4 '-[((3-pyridylmethyl) {[4- (trifluoro Methyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl]-
4-yl} acetic acid (0.757g, 1.5mmol) and p-anisidine (0.22g,
1.80 mmol) in N, N-dimethylformamide (10 ml) solution, 1
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.39g, 2.25mmol) and 1-hydroxybenzotriazole monohydrate (0.35g, 2.25mmol) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with water (100 ml) and washed with ethyl acetate (10 ml).
It was extracted with 0 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 2: 1) and N- (4-methoxyphenyl) -2- {4 '-[((3-pyridylmethyl) {[4- ( Trifluoromethyl) phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4-yl} acetamide (0.81 g, 84%) was obtained as colorless crystals. Mp 162-163 As ℃ Elemental analysis _{C 35 H 30 F 3 N 3} O 4 S, Calcd: C, 65.10; H, 4.68 ; N, 6.51 Found: C, 65.00; H, 4.76 ; N, 6.35. ¹ H-NMR (CDCl ₃ ) δ: 3.76 (2H, s), 3.77 (3H, s), 4.40 (4H,
s), 6.83 (2H, d, J = 8.4Hz), 7.00- 7.20 (4H, m), 7.30-7.60
(9H, m), 7.80 (2H, d, J = 8.4Hz), 7.98 (2H, d, J = 8.4Hz), 8.
30 (1H, s), 8.47 (1H, d, J = 3.2Hz).

Example 217 N-Cyclohexyl-4 ′-({(3-pyridylmethyl) [4- (trifluoromethyl) benzoyl] amino} methyl) [1,1′-biphenyl] -4-carboxamide 4′- ({(3-Pyridylmethyl) [4- (trifluoromethyl) benzoyl] amino} methyl) [1,1'-biphenyl] -4-carboxylic acid (0.6 g, 1.22 mmol) and cyclohexylamine (0.17 ml,
1.47 mmol) in N, N-dimethylformamide (10 ml), 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide ・
Hydrochloride (0.32 g, 1.83 mmol) and 1-hydroxybenzotriazole monohydrate (0.28 g, 1.83 mmol) were added and stirred for 1 hour. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give N-cyclohexyl-4 '-({(3-pyridylmethyl) [4- (trifluoromethyl) benzoyl] amino} methyl. ) [1,1'-Biphenyl] -4-carboxamide (0.66 g, 94%) was obtained as colorless crystals. Melting point 175-176 ° C Elemental analysis C ₃₄ H ₃₂ F ₃ N ₃ O ₂ Calculated: C, 71.44; H, 5.64; N, 7.35 Found: C, 71.38; H, 5.56; N, 7.23. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.90 (8H, m), 2.00-2.20 (2H, m),
3.90-4.15 (1H, m), 4.45 (2H, s), 4.76 (2H, s), 5.95-6.1
0 (1H, m, NH), 7.20-7.40 (3H, m), 7.55-7.80 (9H, m), 7.85
(2H, d, J = 8.2Hz), 8.35-8.60 (1H, m), 8.59 (1H, d, J = 5.6H
z).

Example 218 4 ′-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1′-biphenyl] -4 -Carboxamide / hydrochloride 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1'-biphenyl] -4- To a solution of carboxamide (0.5 g, 0.81 mmol) in ethanol (50 ml) -tetrahydrofuran (50 ml) was added 4N hydrogen chloride / ethyl acetate (0.30 ml, 1.22 mmol), and the mixture was shaken. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration, 4'-
{[([1,1'-Biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1'-biphenyl] -4-carboxamide hydrochloride (0.51g, 95 %). Mp 200-202 As ℃ Elemental analysis _{C 38 H 37 N 3 O 3} S · HCl · 1 / 2H 2 O, Calculated: C, 69.02; H, 5.94 ; N, 6.35 Found: C, 68.95; H, 5.88; N, 6.18. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.95 (10H, m), 3.60-4.00 (2H,
m), 4.50 (2H, s), 4.57 (2H, s), 7.29 (2H, d, J = 8.4Hz), 7.
40-7.75 (8H, m), 7.75-7.85 (2H, m), 7.85-8.10 (6H, m),
8.26 (1H, d, J = 7.6Hz), 8.51 (1H, s), 8.55-8.65 (1H, m).

Example 219 N-Cyclohexyl-4 ′-[((3-pyridylmethyl) {[4- (trifluoromethoxy) phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4-carboxamide 4 '-[((3-pyridylmethyl) {[4- (trifluoromethoxy)
Phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid (0.81g, 1.5mmol) and cyclohexylamine (0.21ml, 1.80mmol) in N, N-dimethylformamide
(15 ml) solution, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.39 g, 2.25 mmol) and 1-hydroxybenzotriazole monohydrate (0.35 g, 2.25 mmo
l) was added and the mixture was stirred for 5 hours. Saturated sodium hydrogen carbonate solution (100 ml) in the reaction solution
Was added and extracted with chloroform (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 2: 1-1: 1), and N-cyclohexyl-4 '-[((3-pyridylmethyl) {[4- (trifluoromethoxy) Phenyl] sulfonyl} amino) methyl] [1,1'-
Biphenyl] -4-carboxamide (0.85 g, 91%) was obtained as colorless crystals. Melting point 215-216 ° C. Elemental analysis C ₃₃ H ₃₂ F ₃ N ₃ O ₄ S Calculated: C, 63.54; H, 5.17; N, 6.74 Found: C, 63.54; H, 5.09; N, 6.85 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.10-1.90 (8H, m), 1.98-2.15 (2H, m),
3.90-4.15 (1H, m), 4.38 (2H, s), 4.40 (2H, s), 5.99 (1H,
d, J = 9.0Hz), 7.10-7.20 (3H, m), 7.35-7.55 (5H, m), 7.58
(2H, d, J = 8.0Hz), 7.82 (2H, d, J = 8.6Hz), 7.91 (2H, d, J =
8.4Hz), 8.25-8.35 (1H, m), 8.40-8.50 (1H, m).

Example 220 N-Cycloheptyl-4 ′-[((3-pyridylmethyl) {[4- (trifluoromethoxy) phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4- Carboxamide 4 '-[((3-pyridylmethyl) {[4- (trifluoromethoxy)
Phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxylic acid (0.81g, 1.5mmol) and cycloheptylamine (0.23ml, 1.80mmol) in N, N-dimethylformamide (15ml) , 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.39 g, 2.25 mmol) and 1-
Hydroxybenzotriazole monohydrate (0.35g, 2.25m
mol) was added and the mixture was stirred for 5 hours. Saturated sodium bicarbonate water (100 m
l) was added and extracted with chloroform (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 2: 1-1: 1), and N-cycloheptyl-4 '-[((3-pyridylmethyl) {[4- (trifluoromethoxy ) Phenyl] sulfonyl} amino) methyl] [1,1'-
Biphenyl] -4-carboxamide (0.87 g, 91%) was obtained as colorless crystals. Melting point 212-214 ° C Elemental analysis value C ₃₄ H ₃₄ F ₃ N ₃ O ₄ S, calculated value: C, 64.04; H, 5.37; N, 6.59 Found value: C, 63.87; H, 5.03; N, 6.53. ¹ H-NMR (CDCl ₃ ) δ: 1.40-1.80 (10H, m), 1.95-2.15 (2H,
m), 4.10-4.30 (1H, m), 4.38 (2H, s), 4.40 (2H, s), 6.08
(1H, d, J = 8.0Hz), 7.10-7.20 (3H, m), 7.30-7.37 (5H, m),
7.58 (2H, d, J = 8.4Hz), 7.82 (2H, d, J = 8.0Hz), 7.90-8.00
(2H, m), 8.28-8.35 (1H, m).

Example 221 4 ′-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N- (2-pyridylmethyl) [1,1 ′ -
Biphenyl] -4-carboxamide 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid ( 0.80 g, 1.5 mmol) and 2-aminomethylpyridine (0.18
ml, 1.80 mol) in N, N-dimethylformamide (10 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.39 g, 2.25 mmol) and 1-hydroxybenzotriazole monohydrate. A Japanese product (0.35 g, 2.25 mmol) was added and the mixture was stirred for 4 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: acetone =
1: 1) to give 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N- (2-pyridylmethyl) [1 , 1'-Biphenyl] -4-carboxamide (0.9
0 g, 96%) was obtained as colorless crystals. Melting point 147-148 ℃ Elemental analysis As C ₃₈ H ₃₂ N ₄ O ₃ S ・ 1 / 2H ₂ O Calculated value: C, 72.02; H, 5.25; N, 8.84 Found value: C, 72.10; H, 5.11; N ^{, 8.76 1 H-NMR (CDCl} 3) δ:. 4.41 (4H, s), 4.80 (2H, s), 7.10-7.30
(5H, m), 7.30-7.80 (14H, m), 7.90-8.00 (4H, m), 8.25-8.
35 (1H, m), 8.40-8.50 (1H, m), 8.55-8.65 (1H, m).

Example 222 4 ′-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N- (2-pyridylmethyl) [1,1 ′ -
Biphenyl] -4-carboxamide hydrochloride 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N- (2-pyridylmethyl) [1 , 1'-
Biphenyl] -4-carboxamide (0.4g, 0.64mmol) in ethanol (5ml) solution 4N hydrogen chloride / ethyl acetate (0.48
ml, 1.92 mmol) was added and shaken and mixed. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue to give a powder, and 4 '
-{[([1,1'-Biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N- (2-pyridylmethyl) [1,1'-biphenyl] -4-carboxamide hydrochloride Salt (0.44g, 96%) was obtained as an amorphous powder. As Elemental Analysis _{C 38 H 32 N 4 O 3} S · HCl · H 2 O, Calculated: C, 63.77; H, 5.07 ; N, 7.83 Found:. C, 63.62; H, 5.51; N, 7.63 1 H -NMR (d ₆ -DMSO) δ: 4.52 (2H, s), 4.61 (2H, s), 4.80 (2H,
d, J = 5.2Hz), 7.30 (2H, d, J = 8.0Hz), 7.40-7.60 (5H, m),
7.65-7.90 (7H, m), 7.90-8.10 (6H, m), 8.10-8.25 (1H, m),
8.41 (1H, t, J = 7.8Hz), 8.57 (1H, s), 8.64 (1H, d, J = 5.6H
z), 8.78 (1H, d, J = 5.6Hz), 9.50-9.60 (1H, m).

Example 223 4 ′-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N- (3-pyridylmethyl) [1,1 ′ -
Biphenyl] -4-carboxamide 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid ( 0.80g, 1.5mmol) and 3-aminomethylpyridine (0.18m
l, 1.80 mol) in N, N-dimethylformamide (10 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.39 g, 2.25 mmol) and 1-hydroxybenzotriazole monohydrate. A Japanese product (0.35 g, 2.25 mmol) was added and the mixture was stirred for 5 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 1: 1) to give 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl. } -N- (3-
Pyridylmethyl) [1,1'-biphenyl] -4-carboxamide
(0.86 g, 90%) was obtained as colorless crystals. Melting point 162-163 ℃ Elemental analysis value C ₃₈ H ₃₂ N ₄ O ₃ S ・ 1 / 4H ₂ O, calculated value: C, 71.73; H, 5.94; N, 6.60 Found value: C, 71.79; H, 5.71; ^{. N, 6.55 1 H-NMR} (CDCl 3) δ: 4.40 (2H, s), 4.41 (2H, s), 4.90 (2H,
d, J = 5.6Hz), 6.55-6.70 (1H, m), 7.10-7.25 (3H, m), 7.25
-7.80 (14H, m), 7.86 (2H, d, J = 8.0Hz), 7.95 (2H, d, J = 8.4H
z), 8.25-8.35 (1H, m), 8.40-8.50 (1H, m), 8.55-8.60 (1
H, m), 8.60-8.70 (1H, m).

Example 224 4 ′-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N- (3-pyridylmethyl) [1,1 ′ -
Biphenyl] -4-carboxamide hydrochloride 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N- (3-pyridylmethyl) [1 , 1'-
Biphenyl] -4-carboxamide (0.4g, 0.64mmol) in methanol (5ml) solution 4N hydrogen chloride / ethyl acetate (1ml)
Was added and shaken. The solvent was evaporated under reduced pressure, diethyl ether was added to the residue to give a powder, and 4 ′-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N was obtained. -(3-Pyridylmethyl) [1,1'-biphenyl] -4-carboxamide hydrochloride (0.44 g, quant.) Was obtained as an amorphous powder. As Elemental analysis _{C 38 H 32 N 4 O 3} S · HCl · H 2 O, Calculated: C, 63.77; H, 5.07 ; N, 7.83 Found:. C, 63.94; H, 5.35; N, 7.55 1 H-NMR (d ₆ -DMSO) δ: 4.52 (2H, s), 4.62 (2H, s), 4.68 (2H,
d, J = 6.0Hz), 7.30 (2H, d, J = 8.0Hz), 7.40-7.65 (5H, m),
7.65-7.90 (5H, m), 7.90-8.20 (8H, m), 8.50-8.60 (2H, m),
8.60-8.70 (1H, m), 8.80-9.00 (1H, m), 9.45-9.60 (1H,
m).

Example 225 N-{[4 ′-(1-piperidinylcarbonyl) [1,1′-biphenyl]
-4-yl] methyl} -N- (3-pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) ( 3-Pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (0.80g, 1.5mmol) and piperidine (0.18ml, 1.80mo
l) in N, N-dimethylformamide (10 ml) solution, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.39 g, 2.25 mmol) and 1-hydroxybenzotriazole monohydrate ( 0.35 g, 2.25 mmol) was added and the mixture was stirred for 5 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was diluted with ethyl acetate (10 ml).
It was extracted with 0 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1) to give N-{[4 '-(1-piperidinylcarbonyl) [1,1'-
Biphenyl] -4-yl] methyl} -N- (3-pyridylmethyl) [1,
1′-Biphenyl] -4-sulfonamide (0.84 g, 93%) was obtained as colorless crystals. Melting point 166-168 ℃ Elemental analysis value C ₃₇ H ₃₅ N ₃ O ₃ S, calculated value: C, 73.85; H, 5.86; N, 6.98 Found value: C, 73.60; H, 5.82; N, 6.81. ¹ H -NMR (CDCl ₃ ) δ: 1.40-1.80 (6H, m), 3.30-3.60 (2H, m),
3.60-3.80 (2H, m), 4.41 (4H, s), 7.10-7.20 (3H, m), 7.4
0-7.70 (12H, m), 7.76 (2H, d, J = 8.4Hz), 7.95 (2H, d, J = 8.4
Hz), 8.25-8.35 (1H, m), 8.40-8.50 (1H, m).

Example 226 4 ′-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-tetrahydro-2H-pyran-4
-Yl [1,1'-biphenyl] -4-carboxamide 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'- Biphenyl] -4-carboxylic acid (1.07g, 2.0mmol) and 4-tetrahydropyran hydrochloride
(0.33g, 2.40mol) N, N-dimethylformamide (10ml)
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.52 g, 3.0 mmol) and 1-hydroxybenzotriazole monohydrate (0.46 g, 3.0 mmol) were added to the solution and stirred for 15 hours. did. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was extracted with chloroform (200 ml, 100 ml). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1-chloroform: acetone = 1: 1),
4 '-{[([1,1'-biphenyl] -4ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-tetrahydro-2H-pyran-4
-Yl [1,1'-biphenyl] -4-carboxamide (1.13g, 91
%) As colorless crystals. Melting point 246-247 ℃ Elemental analysis value C ₃₇ H ₃₅ N ₃ O ₄ S ・ H ₂ O, calculated value: C, 69.90; H, 5.87; N, 6.61 Found value: C, 69.59; H, 5.95; N, 6.53. ¹ H-NMR (d ₆ -DMSO) δ: 1.50-1.85 (4H, m), 3.30-3.50 (2H,
m), 3.80-3.95 (2H, m), 3.95-4.10 (1H, m), 4.43 (2H, s),
4.44 (2H, s), 7.15-7.25 (1H, m), 7.25 (2H, d, J = 8.4Hz),
7.45-7.60 (6H, m), 7.69 (2H, d, J = 8.4Hz), 7.77 (2H, d, J =
8.4Hz), 7.90-8.05 (6H, m), 8.30-8.40 (3H, m).

Example 227 4 ′-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N- (4-hydroxycyclohexyl) [1,1 ′ -Biphenyl] -4-carboxamide 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (0.80g, 1.5mmol) and trans-4-aminocyclohexanol (0.21g, 1.80mol) in N, N-dimethylformamide (1
0 ml) solution, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.39 g, 2.25 mmol) and 1-hydroxybenzotriazole monohydrate (0.35 g, 2.25 mmol).
Was added and stirred for 5 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was extracted with chloroform (200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 1: 1) to give 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl. } -N- (4-hydroxycyclohexyl) [1,1′-biphenyl] -4-carboxamide (0.83 g, 88%) was obtained as colorless crystals. Melting point 237-238 ℃ Elemental analysis value C ₃₈ H ₃₇ N ₃ O ₄ S ・ 1 / 4H ₂ O, calculated value: C, 71.73; H, 5.94; N, 6.60 Found value: C, 71.79; H, 5.71; ^{. N, 6.55 1 H-NMR} (d 6 -DMSO) δ: 1.15-1.55 (4H, m), 1.75-1.95 (4H,
m), 3.60-3.90 (1H, m), 4.43 (4H, s), 4.57 (1H, d, J = 4.8H
z), 7.15-7.25 (1H, m), 7.25 (2H, d, J = 8.0Hz), 7.40-7.60
(6H, m), 7.68 (2H, d, J = 8.0Hz), 7.77 (2H, d, J = 8.0Hz), 7.
85-8.00 (6H, m), 8.00 (2H, d, J = 8.0Hz), 8.15-8.30 (1H,
m), 8.30-8.40 (2H, m).

Example 228 N-{[4 '-(4-morpholinocarbonyl) [1,1'-biphenyl] -4
-Yl] methyl} -N- (3-pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3- Pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (0.80g, 1.5mmol) and morpholine (0.16ml, 1.80mol)
In N, N-dimethylformamide (10 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.39 g, 2.25 mmol) and 1-hydroxybenzotriazole monohydrate (0.35 g , 2.25 mmol) was added and stirred for 5 hours.
Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and ethyl acetate (100 m
It was extracted in l). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 2: 1-1: 2) to give N-{[4 '-(4-morpholinocarbonyl) [1,1'-biphenyl] -4-yl ] Methyl} -N- (3-pyridylmethyl) [1,1 '
-Biphenyl] -4-sulfonamide (0.75 g, 83%) was obtained as colorless crystals. Melting point 117-118 ° C Elemental analysis value C ₃₆ H ₃₃ N ₃ O ₄ S, calculated value: C, 71.60; H, 5.51; N, 6.96 Measured value: C, 71.59; H, 5.35; N, 6.93. ¹ H -NMR (CDCl ₃ ) δ: 3.40-3.90 (8H, m), 4.41 (4H, s), 7.10
-7.25 (3H, m), 7.35-7.70 (12H, m), 7.76 (2H, d, J = 8.4Hz),
7.95 (2H, d, J = 8.4Hz), 8.25-8.35 (1H, m), 8.40-8.50 (1
H, m).

Example 229 N-[(4 '-{[4- (2-hydroxyethyl) -1-piperidyl] carbonyl} [1,1'-biphenyl] -4-yl) methyl] -N- (3 -Pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1, 1'-Biphenyl] -4-carboxylic acid (0.80 g, 1.5 mmol) and piperidine-4-ethanol (0.23
3 g, 1.80 mol) in N, N-dimethylformamide (10 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.31 g, 1.80 mmol) and 1-hydroxybenzotriazole monohydrate. A Japanese product (0.28 g, 1.80 mmol) was added and the mixture was stirred for 6 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue (hexane: acetone = 1: 1-
Hexane: acetone: ethanol = 10: 10: 1) and N
-[(4 '-{[4- (2-hydroxyethyl) -1-piperidyl] carbonyl} [1,1'-biphenyl] -4-yl) methyl] -N- (3-pyridylmethyl) [1, 1'-biphenyl] -4-sulfonamide (0.73g,
75%) was obtained as colorless crystals. As mp 139-140 ° C. Elemental analysis _{C 39 H 39 N 3 O 4} S, Calcd: C, 72.53; H, 6.09 ; N, 6.51 Found:. C, 72.36; H, 6.33; N, 6.55 1 H -NMR (CDCl ₃ ) δ: 1.10-1.95 (9H, m), 2.60-3.20 (2H, m),
3.73 (2H, q, J = 4.8Hz), 3.70-4.00 (1H, m), 4.40 (4H, s),
4.60-4.80 (1H, m), 7.10-7.20 (3H, m), 7.40-7.70 (12H, m
m), 7.60 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.8Hz), 8.25-
8.35 (1H, m), 8.40-8.50 (1H, m).

Example 230 Ethyl 1-[(4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl]- 4-yl) carbonyl] -4-piperidinecarboxylate 4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (1.07g, 2.0mmol) and ethyl isonipecotinate
(0.33 ml, 2.40 mol) of N, N-dimethylformamide (10 m
l) solution, 1-ethyl-3- (3-dimethylaminopropyl)
Carbodiimide hydrochloride (0.52 g, 3.0 mmol) and 1-hydroxybenzotriazole monohydrate (0.46 g, 3.0 mmol) were added and stirred for 15 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 1: 1) to give ethyl 1-[(4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridyl Methyl) amino] methyl} [1,1′-biphenyl] -4-yl) carbonyl] -4-piperidinecarboxylate (1.28 g, 95%) was obtained as colorless crystals. Melting point 113-115 ° C Elemental analysis C ₄₀ H ₃₉ N ₃ O ₅ S Calculated value: C, 71.30; H, 5.83; N, 6.24 Actual value: C, 71.03; H, 5.62; N, 6.23. ¹ H -NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1Hz), 1.60-2.15 (4H,
m), 2.50-2.70 (1H, m), 2.95-3.20 (2H, m), 3.70-4.00 (1
H, m), 4.17 (2H, q, J = 7.1Hz), 4.41 (4H, s), 4.35-4.60 (1
H, m), 7.10-7.20 (3H, m), 7.35-7.70 (12H, m), 7.60 (2H,
d, J = 8.4Hz), 7.95 (2H, d, J = 8.4Hz), 8.25-8.35 (1H, m),
8.40-8.50 (1H, m).

Example 231 1-[(4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4 -Yl) carbonyl] -4-piperidinecarboxylate ethyl 1-[(4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1 '-Biphenyl] -4-yl) carbonyl] -4-piperidinecarboxylate (1.0g, 1.48mmol) methanol-tetrahydrofuran (1
5 ml, 5 ml) and add potassium carbonate solution (10 ml) to the solution.
Heated to reflux for hours. 1N hydrochloric acid (8.90ml, 8.9mm)
ol) was added for neutralization, and the solvent was concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with water, and then 1-[(4 '-{[([1,1'-biphenyl]-
4-ylsulfonyl) (3-pyridylmethyl) amino] methyl}
[1,1′-Biphenyl] -4-yl) carbonyl] -4-piperidinecarboxylic acid (0.92 g, 96%) was obtained. As mp 224-225 ° C. Elemental analysis _{C 38 H 35 N 3 O 5} S, Calcd: C, 70.68; H, 5.46 ; N, 6.51 Found:. C, 70.26; H, 5.73; N, 6.35 1 H -NMR (d ₆ -DMSO) δ: 1.40-2.00 (4H, m), 2.85-3.20 (2H,
m), 4.40 (4H, s), 4.20-4.50 (2H, m), 7.15-7.35 (3H, m),
7.40-7.60 (8H, m), 7.65 (2H, d, J = 8.4Hz), 7.77 (2H, d, J =
8.4Hz), 7.92 (2H, d, J = 8.4Hz), 8.00 (2H, d, J = 8.4Hz), 8.
25-8.40 (2H, m), 12.25-12.40 (1H, m).

Example 232 N-cyclohexyl-4 ′-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1′-biphenyl] -4-carboxamide 4 ′-{ [[(4-Phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (1.10 g, 2.0 mmol) and cyclohexylamine (0.28 ml,
2.40 mmol) in N, N-dimethylformamide (10 ml),
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.52 g, 3.0 mmol) and 1-hydroxybenzotriazole monohydrate (0.46 g, 4.0 mmol) were added and stirred for 3 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 2: 1) to give N-cyclohexyl-4 '-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino].
Methyl} [1,1'-biphenyl] -4-carboxamide (1.19g,
94%) was obtained as colorless crystals. Mp as 251-252 ° C. Elemental analysis _{C 38 H 37 N 3 O 4} S · 1 / 4H 2 O, Calculated: C, 71.73; H, 5.94 ; N, 6.60 Found: C, 71.61; H, 5.87 ; ^{. N, 6.49 1 H-NMR} (CDCl 3) δ: 1.10-1.90 (10H, m), 2.00-2.20 (2H,
m), 3.90-4.10 (1H, m), 4.35 (2H, s), 4.37 (2H, s), 6.02
(1H, d, J = 8.2Hz), 7.00-7.35 (8H, m), 7.35-7.55 (5H, m),
7.58 (2H, d, J = 8.4Hz), 7.83 (4H, d, J = 8.4Hz), 8.27 (1H,
d, J = 1.8Hz), 8.45 (1H, d, J = 4.8,1.4Hz).

Example 233 N-Cycloheptyl-4 ′-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1′-biphenyl] -4-carboxamide 4′- {[[(4-Phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (1.10 g, 2.0 mmol) and cycloheptylamine (0.31 ml,
2.40 mmol) in N, N-dimethylformamide (20 ml),
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.52 g, 3.0 mmol) and 1-hydroxybenzotriazole monohydrate (0.46 g, 4.0 mmol) were added and stirred for 3 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 2: 1) to give N-cycloheptyl-4 '-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl. } [1,1'-Biphenyl] -4-carboxamide (1.27
g, 98%) was obtained as colorless crystals. As mp 178-180 ° C. Elemental analysis _{C 39 H 39 N 3 O 4} S, Calcd: C, 72.53; H, 6.09 ; N, 6.51 Found:. C, 72.50; H, 5.91; N, 6.35 1 H -NMR (CDCl ₃ ) δ: 1.40-1.80 (8H, m), 2.00-2.25 (2H, m),
4.10-4.30 (1H, m), 4.35 (2H, s), 4.37 (2H, s), 6.08 (1H,
d, J = 8.0Hz), 7.00-7.30 (3H, m), 7.35-7.55 (6H, m), 7.58
(2H, d, J = 8.4Hz), 7.70-7.90 (3H, m), 8.20-8.30 (1H, m),
8.40-8.50 (1H, m).

Example 234 4 ′-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -N- [2- (trifluoromethyl) benzyl] [1,1′-biphenyl ] -4-Carboxamide 4 '-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (1.10 g, 2.0 mmol) 2- (Trifluoromethyl) benzylamine (0.34 ml, 2.40 mmol) in N, N-dimethylformamide (20 ml) was added with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.52 g, 3.0 mmol) and 1
-Hydroxybenzotriazole monohydrate (0.46g, 4.0
(mmol) and added and stirred for 3 hours. Saturated sodium bicarbonate water (100 m
l) was added, and the mixture was extracted with ethyl acetate (150 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 2: 1) to give 4 '-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino].
Methyl} -N- [2- (trifluoromethyl) benzyl] [1,1′-biphenyl] -4-carboxamide (1.36 g, 96%) was obtained as colorless crystals. Mp as 120-121 ° C. Elemental analysis _{C 40 H 32 F 3 N 3} O 4 S · 0.2H 2 O, Calculated: C, 67.54; H, 4.59 ; N, 5.91 Found: C, 67.35; H, 4.69 ; N, 5.92. ¹ H-NMR (CDCl ₃ ) δ: 4.35 (2H, s), 4.36 (2H, s), 4.86 (2H,
d, J = 6.2Hz), 6.50-6.70 (1H, m), 7.35-7.65 (9H, m), 7.68
(2H, d, J = 8.0Hz), 7.75-7.90 (4H, m), 8.25 (1H, d, J = 2.2H
z), 8.40-8.50 (1H, m).

Example 235 4-phenoxy-N-{[4 ′-(1-piperidylcarbonyl)] [1,
1'-biphenyl] -4-yl} methyl} -N- (3-pyridylmethyl)
Benzenesulfonamide 4 '-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylic acid (1.10 g, 2.0 mmol) and piperidine ( 0.24 ml, 2.40 mmol)
To an N, N-dimethylformamide (10 ml) solution, 1-ethyl-
3- (3-dimethylaminopropyl) carbodiimide hydrochloride
(0.52 g, 3.0 mmol) and 1-hydroxybenzotriazole
Monohydrate (0.46 g, 4.0 mmol) was added and the mixture was stirred for 5 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 2: 1) to give 4-phenoxy-N-{[4 '-(1-piperidylcarbonyl)] [1,1'-biphenyl] -4- Ilu} methyl} -N- (3-pyridylmethyl) benzenesulfonamide (1.12 g, 91%) was obtained as colorless crystals. Melting point 122-123 ℃ Elemental analysis value C ₃₇ H ₃₅ N ₃ O ₄ S ・ 0.7H ₂ O, calculated value: C, 70.50; H, 5.82; N, 6.67 Found value: C, 72.50; H, 5.67; N ^{, 6.40 1 H-NMR (CDCl} 3) δ:. 1.45-1.80 (6H, m), 3.30-3.60 (2H, m),
3.60-3.85 (2H, m), 4.36 (4H, s), 7.00-7.35 (7H, J = 4.8H
z, 1.8Hz).

Example 236 2- (4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4- Yl) -N-Cyclohexylacetamide (4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl )
Acetic acid (1.10g, 2.0mmol) and cyclohexylamine (0.28m
l, 2.4 mmol) in N, N-dimethylformamide (20 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.52 g, 3.0 mmol) and 1-hydroxybenzotriazole monohydrate. A Japanese product (0.46 g, 3.0 mmol) was added and the mixture was stirred for 5 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was extracted with chloroform (100 ml × 2). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: ethyl acetate =
3: 1-2: 1) and purified by 2- (4 '-{[([1,1'-biphenyl] -4-
(Ilsulfonyl) (3-pyridylmethyl) amino] methyl} [1,
1′-Biphenyl] -4-yl) -N-cyclohexylacetamide (1.15 g, 91%) was obtained as colorless crystals. Melting point 180-181 ℃ Elemental analysis value C ₃₉ H ₃₉ N ₃ O ₃ S Calculated value: C, 74.37; H, 6.24; N, 6.67 Actual value: C, 74.33; H, 6.05; N, 6.41. ¹ H -NMR (CDCl ₃ ) δ: 0.95-1.75 (8H, m), 1.75-1.95 (2H, m),
3.57 (2H, s), 3.60-3.90 (1H, m), 4.40 (2H, s), 4.41 (2H,
s), 5.20-5.40 (1H, m), 7.10-7.25 (3H, m), 7.30 (2H, d, J =
8.4Hz), 7.40-7.70 (10H, m), 7.70-7.80 (2H, m), 7.90-8.
00 (2H, m), 8.28 (1H, d, J = 1.6Hz), 8.45 (1H, dd, J = 4.4,1.6
Hz).

Example 237 N-({4 '-[2-oxo-2- (1-piperidyl) ethyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3- Pyridylmethyl) [1,1'-
Biphenyl] -4-sulfonamide (4 '-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl )
Acetic acid (1.10g, 2.0mmol) and piperidine (0.24ml, 2.40mmo
l) in N, N-dimethylformamide (10 ml) solution, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.52 g, 3.0 mmol) and 1-hydroxybenzotriazole monohydrate ( 0.46 g, 4.0 mmol) was added and the mixture was stirred for 6 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was diluted with ethyl acetate (10 ml).
It was extracted with 0 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: ethyl acetate = 2: 1-1:
Purified in 1), N-({4 '-[2-oxo-2- (1-pyridyl) ethyl] [1,1'-biphenyl] -4-yl} methyl) -N- (3-piperidyl Methyl) [1,1'-biphenyl] -4-sulfonamide (1.13g,
91%) was obtained as colorless crystals. Mp as 187-188 ° C. Elemental analysis _{C 38 H 37 N 3 O 3} S · 0.2H 2 O, Calculated: C, 73.69; H, 6.09 ; N, 6.78 Found: C, 73.63; H, 6.19 ; N , 6.73 ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.80 (6H, m), 3.41 (2H, t, J = 5.0H
z), 3.59 (2H, t, J = 5.0Hz), 3.76 (2H, s), 4.39 (4H, s), 7.
05-7.20 (3H, m), 7.30 (2H, d, J = 8.0Hz), 7.40-7.60 (8H,
m), 7.63 (2H, d, J = 8.0Hz), 7.75 (2H, d, J = 8.0Hz), 7.94 (2
H, d, J = 8.0Hz), 8.25-8.40 (1H, m), 8.44 (1H, d, J = 4.4Hz).

Example 238 N-cyclohexyl-4 ′-{[[(4′-fluoro [1,1′-biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1 '-Biphenyl] -4-carboxamidoethyl 4'-{[[(4'-fluoro [1,1'-biphenyl] -4-yl)
Sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-
Biphenyl] -4-carboxylate (0.64 g, 1.1 mmol)
Ethanol-tetrahydrofuran solution (2.4ml-2.4ml)
2N aqueous sodium hydroxide solution (1.2ml, 2.4mmol)
Was added at room temperature and stirred at 60 ° C. for 2 hours. After the reaction,
The organic solvent was evaporated, the aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. 4 '-{[[(4'-fluoro
[1,1'-Biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-benzoic acid
(0.52 g, 86%) was obtained as colorless crystals. This product was used for the next reaction as it was without purification. Melting point:> 300 ° C 4 '-{[[(4'-fluoro [1,1'-biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl]- 4-Benzoic acid (0.50 g, 0.90 mmol) in N, N-dimethylformamide suspension (10 ml) was added to 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.35 g, 1.8 mmo).
l), 1-hydroxybenzotriazole monohydrate (0.28 g,
1.8 mmol), cyclohexylamine (0.16 ml, 1.35 mmol)
Was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (chloroform) and N-cyclohexyl-4 '-{[[(4'-fluoro [1,1'-biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] methyl } [1,1′-Biphenyl] -4-carboxamide (0.44 g, 77%) was obtained as colorless crystals. Melting point: 229-230 ° C Elemental analysis C ₃₈ H ₃₆ N ₃ O ₃ SF ・ Calculated as 0.5H ₂ O: C, 71.00; H, 5.80; N, 6.54 Found: C, 71.08; H, 5.84; N ^{, 6.64. 1 H-NMR (} CDCl 3) δ (ppm) 1.2-1.8 (8H, m) 2.0-2.2 (2
H, m) 4.00 (1H, br) 4.39 (2H, s) 4.40 (2H, s) 7.10
-7.23 (5H, m) 7.44 (2H, d, J = 8.0Hz) 7.51-7.63 (5H,
m) 7.70 (2H, d, J = 8.4Hz) 7.80 (2H, d, J = 8.4Hz) 7.9
3 (2H, d, J = 8.4Hz) 8.27 (1H, d, J = 1.8Hz) 8.44 (1H,
(dd, J = 1.4, 4.8Hz)

Example 239 4 ′-{[[(4′-chloro [1,1′-biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1 '-Biphenyl] -4-carboxamidoethyl 4'-{[[(4'-chloro [1,1'-biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1 ' To a solution of -biphenyl] -4-carboxylate (1.03 g, 1.72 mmol) in ethanol-tetrahydrofuran (5 ml-5 ml) was added 2N aqueous sodium hydroxide solution (2 ml, 4 mmol) at room temperature, and the mixture was stirred at 60 ° C for 2 hours. . After completion of the reaction, the organic solvent was distilled off, the aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. 4 '-{[[(4'-chloro [1,1'-biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-benzoic acid ( 0.96 g, 98%) was obtained as colorless crystals. This product was used for the next reaction as it was without purification. (Melting point:> 300 ℃) 4 '-{[[(4'-chloro [1,1'-biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl ] -4-Benzoic acid (0.84g, 1.39 mmol) in N, N-dimethylformamide suspension (10 ml) was added to 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.54g, 2.78mm).
ol), 1-hydroxybenzotriazole monohydrate (0.43
g, 2.78mmol), cyclohexylamine (0.25ml, 2.12mm
ol) was added and the mixture was stirred at room temperature overnight. After the reaction was completed, it was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline,
The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by recrystallization (chloroform-hexane) and 4'-
{[[(4'-chloro [1,1'-biphenyl] -4-yl) sulfonyl]
(3-Pyridylmethyl) amino] methyl} -N-cyclohexyl
[1,1′-Biphenyl] -4-carboxamide (0.81 g, 88%) was obtained as colorless crystals. Melting point: 232-233 ° C Elemental analysis C ₃₈ H ₃₆ N ₃ O ₃ SCl ・ Calculated as 0.5H ₂ O: C, 69.23; H, 5.66; N, 6.37 Found: C, 69.52; H, 5.58; N , 6.38. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-1.8 (8H, m) 2.0-2.2 (2
H, m) 3.98-4.02 (1H, m) 4.39 (2H, s) 4.40 (2H, s)
6.04 (1H, d, J = 8.2Hz) 7.10-7.18 (3H, m) 7.41-7.57
(9H, m) 7.71 (2H, d, J = 8.4Hz) 7.80 (2H, d, J = 8.4H
z) 7.93 (2H, d, J = 8.8Hz) 8.27 (1H, d, J = 1.8Hz) 8.4
4 (1H, dd, J = 1.8, 5.0Hz)

Example 240 N-Cyclohexyl-4 ′-[((3-pyridylmethyl) {[4 ′-(trifluoromethyl) [1,1′-biphenyl] -4-yl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxamidoethyl 4 '-[((3-pyridylmethyl) {[4'-(trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl} amino ) Methyl] [1,1'-biphenyl] -4-carboxylate (1.30 g,
2.15mmol) in ethanol-tetrahydrofuran solution (10m
l-10 ml) with 2N aqueous sodium hydroxide solution (2.2 ml,
4.4 mmol) was added at room temperature, and the mixture was stirred at 50 ° C. for 2 hours. After completion of the reaction, the organic solvent was distilled off, the aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. 4 '-[((3-Pyridylmethyl) {[4'-(trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl} amino) methyl] [1,1'-biphenyl] benzoic acid (1.15 g, 93%) was obtained as colorless crystals. This product was used for the next reaction as it was without purification. Melting point: 321-323 ° C 4 '-[((3-pyridylmethyl) {[4'-(trifluoromethyl)
[1,1'-Biphenyl] -4-yl] sulfonyl} amino) methyl]
[1,1'-Biphenyl] benzoic acid (1.06g, 1.84mmol) in N, N-
1-Ethyl-3- (3-
Dimethylaminopropyl) carbodiimide hydrochloride (0.71
g, 3.68mmol), 1-hydroxybenzotriazole monohydrate (0.57g, 3.68mmol), cyclohexylamine (0.32m
l, 2.79 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate.
The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (from chloroform alone to chloroform: methanol = 30: 1) and then recrystallized (chloroform-hexane) to give N-cyclohexyl-4 '-[((3-pyridylmethyl) { [4 '-(Trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxamide (1.13g, 94%)
Was obtained as pale yellow crystals. Melting point: 228-230 ° C Elemental analysis C ₃₉ H ₃₆ N ₃ O ₃ F ₃ S ・ H ₂ O Calculated: C, 66.75; H, 5.46; N, 5.99 Found: C, 66.82; H, 5.34; N, 5.97. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.1-1.8 (8H, m) 2.0-2.2 (2
H, m) 4.00 (1H, br) 4.40, 4.41 (4H, each s) 6.02
(1H, d, J = 8.2Hz) 7.11-7.19 (3H, m) 7.44 (2H, d, J =
8.4Hz) 7.50-7.58 (3H, m) 7.69-7.83 (8H, m) 7.97 (2
H, d, J = 8.8Hz) 8.28 (1H, d, J = 1.8Hz) 8.45 (1H, dd,
(J = 12.4, 4.8Hz)

Example 241 N-Cyclohexyl-4 ′-[((3-pyridylmethyl) {[4- (2-furyl) phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4-carboxamide N-Cyclohexyl-4 '-{[(4-bromosulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxamide (1.04 g, 1.63 mmol) and tri-n-butyl (2-
To a solution of (furyl) stannane (0.70g, 1.96mmol) in N, N-dimethylformamide (5ml) was added tetrakis (triphenylphosphine) palladium (0.095g, 0.08mmol),
Refluxed overnight under an argon atmosphere. The reaction was terminated with saturated aqueous sodium hydrogen carbonate, diluted with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue (from chloroform only to chloroform: methanol = 30: 1)
Purified in. N-Cyclohexyl-4 '-[((3-pyridylmethyl) {[4- (2-furyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxamide (1.01g, quantitative ) Was obtained as colorless crystals. Melting point: 207-208 ℃ Elemental analysis value Calculated as C ₃₆ H ₃₅ N ₃ O ₄ S ・ 0.5H ₂ O: C, 70.33; H, 5.90; N, 6.84 Actual value: C, 70.24; H, 5.71; N , 6.85. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-1.8 (8H, m) 2.0-2.2 (2
H, m) 4.03 (1H, br) 4.38 (4H, s) 6.02 (1H, d, J = 8.
8Hz) 6.56 (1H, dd, J = 1.8, 3.2Hz) 6.83 (1H, dd, J =
2.0, 2.6Hz) 7.12-7.17 (3H, m) 7.42-7.59 (6H, m) 7.
79-7.91 (6H, m) 8.27 (1H, s) 8.44-8.46 (1H, m)

Example 242 N-cyclohexyl-4 ′-[((3-pyridylmethyl) {[4- (2-thienyl) phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4-carboxamide N-cyclohexyl-4 '-{[(4-bromosulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxamide (0.80 g, 1.26 mmol) and tri-n-butyl Tetrakis (triphenylphosphine) palladium (0.073 g, 0.06 mmol) was added to a solution of (2-thienyl) stannane (0.57 g, 1.51 mmol) in N, N-dimethylformamide (5 ml), and the mixture was refluxed overnight under an argon atmosphere. The reaction was terminated with saturated aqueous sodium hydrogen carbonate, diluted with ethyl acetate, and washed with saturated brine.
The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (from chloroform alone to chloroform: methanol = 30: 1) and then recrystallized (chloroform-hexane). N-
Cyclohexyl-4 '-[((3-pyridylmethyl) {[4- (2-thienyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxamide (0.65g, 83%) Obtained as colorless crystals. Mp: 220-221 ° C. Elemental analysis _{C 36 H 35 N 3 O 3} S 2 · 1.5H 2 O Calculated: C, 66.64; H, 5.90 ; N, 6.48 Found: C, 66.89; H, 5.66 ; N, 6.62. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-1.8 (8H, m) 2.0-2.2 (2
H, m) 4.00 (1H, br) 4.37 (4H, s) 6.01 (1H, d, J = 7.
8Hz) 7.11-7.17 (4H, m) 7.40-7.61 (7H, m) 7.38-7.89
(6H, m) 8.28 (1H, d, J = 1.8Hz) 8.44 (1H, dd, J = 2.
(0, 4.8Hz)

Example 243 N-Cyclohexyl-4 ′-[((3-pyridylmethyl) {[4- (2-pyridyl) phenyl] sulfonyl} amino) methyl] [1,1′-biphenyl] -4-carboxamide N-Cyclohexyl-4 '-{[(4-bromosulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxamide (0.81 g, 1.27 mmol) and tri-n-butyl To the solution of (2-pyridyl) stannane (0.57g, 1.51mmol) in N, N-dimethylformamide (10ml) was added tetrakis (triphenylphosphine) palladium (0.074g, 0.064mmol),
The mixture was stirred overnight at 70 ° C. under an argon atmosphere. The reaction was terminated with saturated aqueous sodium hydrogen carbonate, diluted with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(From chloroform only, chloroform: methanol =
Purified by 100: 1 to 60: 1 to 40: 1). N-Cyclohexyl-4 '-[((3-pyridylmethyl) {[4- (2-pyridyl) phenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4-carboxamide (0.09g, 11% ) Was obtained as colorless crystals. Melting point: 215-216 ℃ Elemental analysis value Calculated as C ₃₇ H ₃₆ N ₄ O ₃ S ・ 0.5H ₂ O: C, 71.01; H, 5.96; N, 8.95 Measured value: C, 70.68; H, 5.74; N , 8.78. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-1.8 (8H, m) 2.0-2.2 (2
H, m) 3.99 (1H, br) 4.37, 4.39 (4H, each s) 6.09
(1H, d, J = 8.6Hz) 7.09-7.16 (3H, m) 7.49-7.57 (3H,
m) 7.78-7.84 (4H, m) 7.97 (2H, d, J = 8.8Hz) 8.19 (2
H, d, J = 8.8Hz) 8.27 (1H, d, J = 2.2Hz) 8.43 (1H, dd,
J = 1.8, 4.8Hz) 8.73-8.77 (1H, m).

Example 244 4 ′-{[(benzylsulfonyl) (3-pyridylmethyl) amino]
Methyl} -N-cyclohexyl [1,1'-biphenyl] -4-carboxamide 4 '-{[(benzylsulfonyl) (3-pyridylmethyl) amino]
Methyl}-[1,1'-biphenyl] benzoic acid (0.50g, 1.06 mmo
l) of N, N-dimethylformamide solution (10 ml) in 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.61g, 3.18mmol), 1-hydroxybenzotriazole monohydrate (0.49g) , 3.18mmol) to prepare a solution 1
After stirring for 0 minutes, cyclohexylamine (0.24ml, 2.12mmo
l) was added and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) and 4 '
-{[(Benzylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1'-biphenyl] -4-carboxamide (0.41g, 70%) was obtained as a colorless solid. Melting point: 186-187 ° C Elemental analysis C ₃₃ H ₃₅ N ₃ O ₃ S ・ Calculated as 0.5H ₂ O: C, 70.43; H, 6.45; N, 7.47 Found: C, 70.73; H, 6.23; N ^{, 7.44. 1 H-NMR (} CDCl 3) δ (ppm) 1.10-1.8 (8H, m) 2.0-2.2 (2
H, m) 3.90-4.10 (1H, br) 4.11 (2H, s) 4.18 (2H, s)
4.27 (2H, s) 6.01 (1H, d, J = 8.0Hz) 7.15-7.38 (8H,
m) 7.49-7.62 (5H, m) 7.83 (2H, d, J = 8.0Hz) 8.36
(1H, d, J = 1.8Hz) 8.48 (1H, dd, J = 1.4, 4.8Hz).

Example 245 4 ′-{[(benzylsulfonyl) (3-pyridylmethyl) amino]
Methyl} -N-cycloheptyl [1,1'-biphenyl] -4-carboxamide 4 '-{[(benzylsulfonyl) (3-pyridylmethyl) amino]
Methyl}-[1,1'-biphenyl] benzoic acid (0.50g, 1.06 mmo
l) in N, N-dimethylformamide solution (10 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.61g, 3.18mmol), 1-hydroxybenzotriazole monohydrate (0.49g) , 3.18mmol) to prepare a solution 1
After stirring for 0 minutes, cyclohexylamine (0.27ml, 2.12mmo
l) was added and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) and 4 '
-{[(Benzylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-cycloheptyl [1,1'-biphenyl] -4-carboxamide (0.40g, 66%) was obtained as a colorless solid. Melting point: 176-177 ℃ Elemental analysis value Calculated as C ₃₄ H ₃₇ N ₃ O ₃ S ・ 0.5H ₂ O: C, 70.80; H, 6.64; N, 7.29 Actual value: C, 70.72; H, 6.78; N , 7.49. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.4-1.6 (10H, m) 2.0-2.2 (2
H, m) 4.11 (2H, s) 4.17 (2H, s) 4.27 (2H, s) 4.0-
4.2 (1H, br) 6.07 (1H, d, J = 8.2Hz) 7.15-7.38 (8H,
m) 7.49-7.62 (5H, m) 7.82 (2H, d, J = 8.2Hz) 8.36 (1
H, s) 8.48 (1H, d, J = 2.6Hz).

Example 246 N-Cyclohexyl-4 ′-[((3-pyridylmethyl) {[4- (1,3-
Thiazol-2-yl) phenyl] sulfonyl} amino) methyl]
[1,1'-Biphenyl] -4-carboxamide N-cyclohexyl-4 '-[((3-pyridylmethyl) {[4-bromophenyl] sulfonyl} amino) methyl] [1,1'-biphenyl] -4 -Carboxamide (0.70g, 1.10 mmol) and tri-n-
Butyl (1,3-thiazol-2-yl) stannane (0.83g, 2.2
0 mmol) of N, N-dimethylformamide solution (10 ml) in tetrakistriphenylphosphine palladium (0.13 g,
0.11 mmol) was added, and the mixture was refluxed overnight under a nitrogen atmosphere. The reaction was terminated with saturated aqueous sodium hydrogen carbonate, diluted with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform to chloroform: methanol = 30: 1) and then recrystallized (chloroform-hexane).
Purified in. N-cyclohexyl-4 '-[((3-pyridylmethyl) {[4- (1,3-thiazol-2-yl) phenyl] sulfonyl}
Amino) methyl] [1,1'-biphenyl] -4-carboxamide
(0.34 g, 44%) was obtained as a colorless amorphous powder. Melting point: 224-225 ℃ Elemental analysis value Calculated as C ₃₅ H ₃₄ N ₄ O ₃ S ・ H ₂ O: C, 66.54; H, 5.58; N, 8.87 Found: C, 66.82; H, 5.55; N, 8.82 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (10H, m) 2.0-2.2 (2
H, m) 4.00 (1H, br) 4.39 (4H, m) 6.01 (1H, d, J = 8.
2Hz) 7.13-7.17 (3H, m) 7.42-7.58 (6H, m) 7.80 (2H,
d, J = 8.4Hz) 7.92-7.98 (3H, m) 8.14 (2H, d, J = 8.8H
z) 8.28 (1H, d, J = 2.0Hz) 8.45 (1H, d, J = 3.8Hz)

Example 247 4 ′-{[([1,1′-biphenyl] -2-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1′-biphenyl] -4 -Carboxamide 1) ethyl 4 '-{[(2-bromobenzenesulfonyl) (3-pyridylmethyl) amino] methyl}-[1,1'-biphenyl] -4-carboxylate ethyl 4'-{[(3- Pyridylmethyl) amino] methyl}-[1,1 '
-Biphenyl] -4-carboxylate (0.77g, 2.22mmol)
Triethylamine (0.
62 ml, 4.44 mmol) and 2-bromobenzenesulfonyl chloride (0.85 g, 3.33 mmol) were added at room temperature, and the mixture was stirred for 30 minutes. After the reaction was completed, it was diluted with chloroform, saturated aqueous sodium hydrogen carbonate,
It was washed with saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, hexane: acetone = 3: 2), and ethyl 4 ′-{[(2-
(Bromobenzenesulfonyl) (3-pyridylmethyl) amino]
Methyl}-[1,1'-biphenyl] -4-carboxylate (0.65
g, 52%) was obtained as a pale red amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.41 (3H, t, J = 7.0Hz) 4.40
(2H, q, J = 7.0Hz) 4.45 (2H, s) 4.47 (2H, s) 7.15-7.2
6 (3H, m) 7.43-7.64 (7H, m) 7.79-7.84 (1H, m) 8.11
(2H, d, J = 8.4Hz) 8.18-8.26 (2H, m) 8.51 (1H, dd, J
= 1.2, 4.8Hz). 2) Ethyl 4 '-{[([1,1'-biphenyl] -2-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1'- Biphenyl] -4-carboxylate ethyl 4 '-{[(2-bromobenzenesulfonyl) (3-pyridylmethyl) amino] methyl}-[1,1'-biphenyl] -4-carboxylate (0.64 g, 1.13 mmol ) Toluene solution (10 ml)
Water (10 ml), sodium carbonate (0.24 g, 2.26 mmol), tetrakistriphenylphosphine palladium (0.066 g,
0.57 mmol) and phenylboronic acid (0.17 g, 1.36 mmol) were sequentially added, and the mixture was stirred overnight at 80 ° C. under a nitrogen atmosphere. After the reaction was completed, it was diluted with ethyl acetate and washed with water and saturated saline.
The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, hexane: acetone = 3: 2) and purified by ethyl 4 ′-{[([1,1′-biphenyl] -2-ylsulfonyl) ( 3-Pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1'-biphenyl] -4-carboxylate (0.58g, 91%)
Was obtained as a colorless amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.41 (3H, t, J = 7.0Hz) 3.76,
3.77 (4H, each s) 4.40 (2H, q, J = 7.2Hz) 6.98 (2H,
d, J = 8.2Hz) 7.11-7.19 (3H, m) 7.27-7.36 (5H, m)
7.45 (2H, d, J = 6.2Hz) 7.54-7.65 (4H, m) 8.04-8.12
(4H, m) 8.24 (1H, dd, J = 1.6, 8.0Hz) 8.44 (1H, dd, J
= 1.8, 4.8Hz). 3) 4 '-{[([1,1'-biphenyl] -2-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1'-
Biphenyl] -4-carboxamidoethyl 4 '-{[([1,1'-biphenyl] -2-ylsulfonyl) (3
-Pyridylmethyl) amino] methyl} -N-cyclohexyl [1,
1'-Biphenyl] -4-carboxylate (0.57 g, 1.01mmo
l) ethanol-tetrahydrofuran solution (5 ml-5 ml)
2N aqueous sodium hydroxide solution (1.5ml, 3.0mmol)
Was added at room temperature and stirred at 60 ° C. for 1 hour. After the reaction,
The organic solvent was evaporated, the aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. 4 '-{[([1,1'-biphenyl] -2-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1'-biphenyl] -4-carboxylic acid (0.54g , 100%) was obtained as colorless crystals. This product was used for the next reaction as it was without purification. 4 '-{[([1,1'-biphenyl] -2-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1'-biphenyl] -4-carboxylic acid (0.54g , 1.01 mmol) in N, N-dimethylformamide suspension (10 ml) in 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.39 g, 2.02
mmol), 1-hydroxybenzotriazole monohydrate (0.3
1g, 2.02mmol), cyclohexylamine (0.18ml, 1.52m
mol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1).
-Hexane: acetone = 3: 2) and purified, 4 '-{[([1,1'-biphenyl] -2-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1, 1'-Biphenyl] -4-carboxamide (0.42g, 68%) was obtained as a pale yellow amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2 (2
H, m) 3.75 (2H, s) 3.77 (2H, s) 3.90-4.10 (1H, m)
6.00 (1H, d, J = 8.0Hz) 6.97 (2H, d, J = 8.0Hz) 7.07-
7.19 (3H, m) 7.26-7.37 (5H, m) 7.42 (23H, d, J = 8.0
Hz) 7.50-7.69 (4H, m) 7.81 (2H, d, J = 8.4Hz) 8.04 (1
H, d, J = 2.2Hz) 8.27 (1H, dd, J = 1.6, 7.8Hz) 8.44 (1
(H, dd, J = 1.6, 4.8Hz)

Example 248 N-({4 '-[(2-cyclohexylhydrazino) carbonyl] [1,
1'-biphenyl] -4-yl} methyl) -N- (3-pyridylmethyl)
[1,1'-Biphenyl] -4-sulfonamide 4- [N- (4-biphenylsulfonyl) -N- (3-pyridylmethyl)
Aminomethyl] -1,1'-biphenyl-4-carboxylic acid (0.82g,
 1.53 mmol) in thionyl chloride (10 ml),
Add N, N-dimethylformamide (1 drop) and stir at 60 ° C for 1 hour.
It was stirred for a while. The reaction mixture was concentrated under reduced pressure, acetonitrile
Dissolved in triethylamine (0.93 ml, 9.18 mmol),
Chlohexylhydrazine hydrochloride (0.35g) was added, and the mixture was cooled to room temperature.
It was stirred for 2 hours. After diluting with ethyl acetate, water and saturated sodium bicarbonate
It was washed with water and saturated saline. Dry with anhydrous magnesium sulfate
After drying, it was filtered and concentrated under reduced pressure. Silica gel column residue
Chromatography (hexane: ethyl acetate = 1: 1, hex
Sun: acetone = 3: 2-1: Purify with N-({4 '-[(2-
Chlohexylhydrazino) carbonyl] [1,1'-biphenyl
Lu] -4-yl} methyl) -N- (3-pyridylmethyl) [1,1'-biff
Yellow] -4-Sulfonamide (0.09g, 9.3%)
Got as. Melting point: 214-215 ℃ ¹ H-NMR (CDCl₃) δ (ppm) 1.0-2.0 (10H, m) 2.90 (1H,
s) 4.39 (2H, s) 4.41 (2H, s) 7.10-7.18 (3H, m) 7.4
1-7.65 (11H, m) 7.73-7.83 (3H, m) 7.94 (2H, d, J = 8.
4Hz) 8.28-8.29 (1H, m) 8.43-8.46 (1H, m)

Reference Example 42 6- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -N
-Cyclohexylnicotinamide (1) 6-Bromo Nicotinic acid 2-Bromo-5-methylpyridine (10 g, 58.1 mmol) in water (200 ml) was added to Aliquat 336 (0.25 ml, 0.62 mmol) and 70-80 Heat to ℃ and potassium permanganate (25.5g,
161 mmol) was added portionwise over 3 hours. afterwards,
The mixture was stirred at 100 ° C for 1.5 hours. The solvent was distilled off under reduced pressure to about 50 ml, acidified with 48% hydrogen bromide aqueous solution, and left overnight in the refrigerator. The precipitated crystals were collected by filtration, washed with cold water and dried to give 6-bromonicotinic acid (6.42g, 55%) as colorless crystals. Melting point: 200-202 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 7.78 (1H, d, J = 8.0Hz) 8.15
(1H, dd, J = 2.6, 8.6Hz) 8.83 (1H, d, J = 2.2Hz). (2) 6-Bromo-N-cyclohexylnicotinamide 6-Bromonicotinic acid (5.0g, 24.8mmol) N 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (9.51 g, 49.6 mm) in N-dimethylformamide suspension (100 ml)
ol), 1-hydroxybenzotriazole monohydrate (7.60 g,
49.6mmol), cyclohexylamine (4.3ml, 37.2mmol)
Was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized (ethyl acetate-hexane) to give 6-bromo.
-N-Cyclohexylnicotinamide (4.20 g, 60%) was obtained as colorless crystals. Melting point: 180-181 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.15-1.52 (5H, m) 1.64-1.83
(3H, m) 1.99-2.05 (2H, m) 3.88-4.02 (1H, m) 6.18
(1H, d, J = 7.4Hz) 7.55 (1H, d, J = 8.2Hz) 7.92-7.98
(1H, m) 8.67-8.69 (1H, m) (3) 6- (4-formylphenyl) -N-cyclohexylnicotinamide 6-bromo-N-cyclohexylnicotinamide (3.11g, 11.
(0 mmol) in toluene-ethanol solution (50 ml-10 ml) with water.
(50 ml), sodium carbonate (2.34 g, 22 mmol), tetrakistriphenylphosphine palladium (0.64 g, 0.55 mmo)
l), p-formylbenzeneboronic acid (1.98g, 13.2mmol)
Were sequentially added, and the mixture was stirred overnight at 80 ° C. under a nitrogen atmosphere.
After the reaction was completed, it was diluted with ethyl acetate and washed with water and saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(From chloroform only, chloroform: methanol =
50: 1 to 30: 1 to 20: 1), and then recrystallize (chloroform-hexane) to purify 6- (4-formylphenyl) -N-
Cyclohexylnicotinamide (2.80 g, 83%) was obtained as pale yellow crystals. Melting point: 208-209 ℃ ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.19-1.55 (5H, m) 1.65-1.84
(3H, m) 2.03-2.09 (2H, m) 3.95-4.09 (1H, m) 6.14
(1H, d, J = 8.2Hz) 7.86 (1H, d, J = 9.0Hz) 7.99 (2H, d,
J = 8.4Hz) 8.01-8.23 (3H, m) 9.04-9.05 (1H, m) 10.0
9 (1H, s). (4) 6- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide 6- (4-formylphenyl) -N-cyclohexylnicotinamide ( 2.0 g, 6.50 mmol) in methanol solution (30 ml) 3-
(Aminomethyl) pyridine (1.0 ml, 9.75 mmol), sodium chloride (5 g) and acetic acid (1.12 ml, 19.5 mmol) were sequentially added at room temperature. After stirring at room temperature for 15 minutes, sodium triacetoxyborohydride (2.07 g, 9.75 mmol) was added little by little, and the mixture was stirred at room temperature for 2.5 hours. After adding saturated multi-layered water to make it basic, the aqueous phase was extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (from chloroform alone to chloroform: methanol = 30: 1
~ 10: 1) and then recrystallized (chloroform-hexane)
Purified with 6- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide (2.12g, 81%)
Was obtained as pale yellow crystals. Melting point: 153-154 ℃ ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-1.6 (5H, m) 1.6-1.8 (3
H, m) 2.0-2.2 (2H, m) 3.83 (2H, s) 3.88 (2H, s) 4.
01 (1H, br) 6.07 (1H, d, J = 7.6Hz) 7.24-7.30 (1H,
m) 7.46 (2H, d, J = 8.2Hz) 7.71 (1H, dt, J = 1.8, 7.6H
z) 7.78 (1H, dd, J = 1.0, 8.4Hz) 8.00 (2H, d, J = 8.0H
z) 8.15 (1H, dd, J = 2.6, 8.4Hz) 8.51 (1H, dd, J = 1.8,
4.8Hz) 8.58 (1H, d, J = 2.2Hz) 8.99-9.05 (1H, m).

Reference Example 43 N- [6- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -3-pyridyl] cyclohexanecarboxamide (1) N- (6-chloro-3-pyridyl) cyclohexane Carboxamide 5-amino-2-chloropyridine (5g, 38.9mmol) pyridine
(20 ml) solution with cyclohexane carbonyl chloride (5.72 m
(1, 42.8 mmol) was added dropwise and stirred for 30 minutes. Water (2
00 ml) was added and the mixture was extracted with an ethyl acetate layer (200 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. Silica gel chromatography of the residue
Purified with (chloroform: ethyl acetate = 10: 1), N- (6-chloro-3-pyridyl) cyclohexanecarboxamide (8.52
g, 92%) was obtained as crystals. . Mp 148-149 ° C. as the elemental analysis C ₁₂ H ₁₅ ClN ₂ O, Found:. C, 60.26; H, 6.27; N, 11.64 1 H-NMR (CHCl 3) δ: 1.20-2.10 (10H, m ), 2.15-2.40 (1H,
m), 7.29 (1H, brs), 7.90 (1H, s), 7.31 (1H, s), 8.20 (1H,
dd, J = 8.8,2.8Hz), 8.35 (1H, d, J = 8.8Hz). (2) N- [6- (4-formylphenyl) -3-pyridyl] cyclohexanecarboxamide N- (6-chloro- 3-Pyridyl) cyclohexanecarboxamide (7.0 g, 29.3 mmol) and 4-formylphenylboronic acid (5.2
8g, 35.2mmol), tetrakistriphenylphosphine palladium (1.02g, 0.88mmol), sodium carbonate (6.22g, 5
A mixed liquid of 8.6 mmol), toluene (300 ml) and water (150 ml) was heated under reflux for 48 hours under a nitrogen atmosphere. After removing insoluble matter by adding ethyl acetate (200 ml), the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (chloroform: ethyl acetate = 10:
Purification by 1-5: 1) gave N- [6- (4-formylphenyl) -3-pyridyl] cyclohexanecarboxamide (5.1 g, 56%) as crystals. Melting point 211-212 ° C. Elemental analysis value C ₁₉ H ₂₀ N ₂ O ₂ Calculated value: C, 74.00; H, 6.54; N, 9.08 Found value: C, 73.80; H, 6.50; N, 8.96. ¹ H -NMR (CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.20-2.40 (1H,
m), 7.32 (1H, s), 7.80 (2H, d, J = 8.4Hz), 7.97 (2H, d, J = 8.
4Hz), 8.15 (2H, d, J = 8.4Hz), 8.39 (1H, dd, J = 8.4,2.6Hz),
8.62 (1H, d, J = 2.6Hz), 10.07 (1H, s). (3) N- [6- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -3-pyridyl] cyclohexane Carboxamide N- [6- (4-formylphenyl) -3-pyridyl] cyclohexanecarboxamide (4.65g, 15.1mmol) and 3-aminomethylpyridine (1.84ml, 18.1mmol), acetic acid (2.07ml, 36.2mmo)
l), a mixture of NaCl (30 g) and ethanol (150 ml) was stirred for 1 hour, and then sodium triacetoxyborohydride (4.4
7 g, 21.1 mmol) was added little by little and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (150 ml) was added to the residue, and the mixture was extracted with chloroform (200 ml × 2). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Silica gel chromatography of the residue (chloroform: acetone = 1: 1, then hexane: acetone: methanol = 1: 1: 1)
And N- [6- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (4.3 g, 71%) was obtained as crystals. . Mp 139-141 ° C. as the elemental analysis C ₂₅ H ₂₈ N ₄ O, Calculated: C, 74.97; H, 7.05 ; N, 13.99 Found:. C, 74.89; H, 7.32; N, 13.97 1 H- NMR (CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.20-2.40 (1H,
m), 3.83 (2H, s), 3.86 (2H, s), 7.22-7.35 (1H, m), 7.40-
7.50 (3H, m), 7.71 (2H, d, J = 8.4Hz), 7.93 (2H, d, J = 8.4H
z), 8.32 (1H, dd, J = 8.8,2.6Hz), 8.52 (1H, dd, J = 5.2,1.6H
z), 8.55-8.65 (2H, m).

Reference Example 44 N- [6- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -3-pyridyl] -2- [2- (trifluoromethyl) phenyl]
Acetamide (1) N- (6-chloro-3-pyridyl) -2- [2- (trifluoromethyl) phenyl] acetamide 5-amino-2-chloropyridine (5.14g, 40.0mmol) in ethyl acetate (200ml) -To a mixture of saturated aqueous sodium hydrogen carbonate (100 ml), 2- [2- (trifluoromethyl) phenyl] acetyl chloride (2- [2-
(Trifluoromethyl) phenyl] acetic acid (12.2g, 60mmol)
And thionyl chloride (43.8 ml) were refluxed for 1 hour and then distilled off under reduced pressure to synthesize), and the mixture was stirred for 1 hour. The ethyl acetate layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 10: 1), and N- (6-chloro-3-pyridyl) -2- [2-
(Trifluoromethyl) phenyl] acetamide (9.67g, 7
7%) was obtained as crystals. . Mp 151-152 ° C. Elemental analysis C ₁₄ H ₁₀ ClN ₂ O as, Found:. C, 53.47; H, 3.18; N, 8.98 1 H-NMR (CHCl 3) δ: 3.93 (2H, s), 7.20 (1H, brs), 7.30 (1
H, s), 7.20-7.70 (3H, m), 7.74 (1H, d, J = 8.4Hz), 8.07 (1H,
dd, J = 8.4,3.0Hz), 8.28 (1H, d, J = 3.4Hz). (2) N- [6- (4-formylphenyl) -3-pyridyl] -2- [2-
(Trifluoromethyl) phenyl] acetamide N- (6-chloro-3-pyridyl) -2- [2- (trifluoromethyl)
Phenyl] acetamide (9.1 g, 28.9 mmol) and 4-formylphenylboronic acid (5.20 g, 33.7 mmol), tetrakistriphenylphosphine palladium (1.0 g, 0.87 mmol), sodium carbonate (6.13 g, 57.8 mmol), toluene ( 200 ml), water (10
The mixture (0 ml) was heated under reflux for 32 hours under a nitrogen atmosphere. After removing insoluble matter by adding ethyl acetate (200 ml), the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 10: 1-5: 1) to give N- [6- (4-formylphenyl) -3-pyridyl] -2- [2- (trifluoro Methyl) phenyl] acetamide (5.62 g, 51%) was obtained as crystals. . Mp 207-208 ° C. as the elemental analysis _{C 21 H 15 F 3 N 2} O 2, Calcd: C, 65.62; H, 3.93 ; N, 7.29 Found: C, 65.65; H, 3.78 ; N, 7.26. ¹ H-NMR (CDCl ₃ ) δ: 3.97 (3H, s), 7.26 (1H, s), 7.40-7.70
(3H, m), 7.70-7.90 (2H, m), 7.96 (2H, d, J = 8.4Hz), 8.13
(2H, d, J = 8.4Hz), 8.26 (1H, dd, J = 8.4,2.6Hz), 8.57 (1H,
d, J = 2.6Hz), 10.07 (1H, s). (3) N- [6- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -3-pyridyl] -2- [2 -(Trifluoromethyl) phenyl] acetamide N- [6- (4-formylphenyl) -3-pyridyl] -2- [2- (trifluoromethyl) phenyl] acetamide (5.30g, 13.8mmo
l) and 3-aminomethylpyridine (1.83 ml, 17.9 mmol), acetic acid (2.05 ml, 35.9 mmol), salt (30 g) and methanol (300 ml)
After stirring the mixture for 1 hour, sodium triacetoxyborohydride (4.9g, 19.3mmol) was added portionwise,
Stir for hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (200 ml) was added to the residue, and the mixture was extracted with chloroform (200 ml × 2). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: acetone = 1: 1, then chloroform: acetone: ethanol = 1: 1: 1) to give N- [6- (4-{[(3-pyridylmethyl) amino. ] Methyl} phenyl) -3-pyridyl] -2
-[2- (Trifluoromethyl) phenyl] acetamide (2.7
9 g, 42%) was obtained as crystals. . Mp 155-156 ° C. as the elemental analysis _{C 27 H 23 F 3 N 4} O, Calculated: C, 68.06; H, 4.87 ; N, 11.76 Found:. C, 67.60; H, 4.82; N, 11.56 1 H-NMR (CDCl ₃ ) δ: 3.83 (2H, s), 3.86 (2H, s), 3.95 (2H,
s), 7.20-7.40 (2H, m), 7.40-7.80 (8H, m), 7.91 (2H, d, J =
8.4Hz), 8.20 (1H, dd, J = 8.8,2.4Hz), 8.50-8.60 (2H, m),
8.55-8.65 (1H, m).

Reference Example 45 N- [5- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (1) N- (5-bromo-2-pyridyl) cyclohexane Carboxamide 2-amino-5-bromopyridine (15 g, 86.7 mmol), ethyl acetate (150 ml), saturated aqueous sodium hydrogen carbonate (100 ml) was added dropwise cyclohexanecarbonyl chloride (27.9 ml, 173 mmol) to a mixture, and 1
Stir for hours. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give N- (5-bromo-2-pyridyl) cyclohexanecarboxamide (12.2 g, 50%) as crystals. Melting point 142-144 ° C. Elemental analysis value, calculated as C ₁₂ H ₁₅ BrN ₂ O: C, 50.90; H, 5.34; N, 9.89 Found: C, 51.11; H, 5.29; N, 10.00. ¹ H- NMR (CHCl ₃ ) δ: 1.20-2.10 (10H, m), 2.10-2.40 (1H,
m), 7.81 (1H, dd, J = 8.8,2.0Hz), 7.90 (1H, s), 8.18 (1H,
d, J = 8.8Hz), 8.30 (1H, d, J = 2.0Hz). (2) N- [5- (4-formylphenyl) -2-pyridyl] cyclohexanecarboxamide N- (5-bromo-2- Pyridyl) cyclohexanecarboxamide (11.5g, 40.6mmol) and 2-formylphenylboronic acid
(7.31 g, 48.7 mmol), tetrakistriphenylphosphine palladium (1.41 g, 1.22 mmol), sodium carbonate (8.61
A mixture of g, 81.2 mmol), toluene (150 ml) and water (100 ml) was heated under reflux for 24 hours under a nitrogen atmosphere. Ethyl acetate (100m
l) was added to remove insolubles, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel chromatography of the residue (chloroform: ethyl acetate
= 10: 1) to give N- [5- (4-formylphenyl) -2-pyridyl] cyclohexanecarboxamide (9.7 g, 77%) as crystals. Melting point 152-153 ° C. Elemental analysis value, calculated as C ₁₉ H ₂₀ N ₂ O ₂ , calculated value: C, 74.00; H, 6.54; N, 9.08 Found value: C, 73.97; H, 6.57; N, 9.32. ¹ H -NMR (CDCl ₃ ) δ: 1.20-2.15 (10H, m), 2.20-2.40 (1H,
m), 7.74 (2H, d, J = 8.0Hz), 7.90-8.10 (4H, m), 8.36 (1H, d,
J = 8.4Hz), 8.55 (1H, d, J = 2.0Hz), 10.07 (1H, s). (3) N- [5- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-Pyridyl] cyclohexanecarboxamide N- [5- (4-formylphenyl) -2-pyridyl] cyclohexanecarboxamide (9.3g, 30.2mmol) and 3-aminomethylpyridine (3.69ml, 36.2mmol), acetic acid (5.87ml) , 10.3mmo
l), a mixture of sodium chloride (30 g) and ethanol (300 ml) was stirred for 1 hour and then sodium triacetoxyborohydride (8.9
5 g, 4.22 mmol) was added little by little and stirred for 15 hours.
The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (150 ml) was added to the residue, and the mixture was extracted with chloroform (200 ml). The extract was dried over magnesium sulfate and then evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 1: 1-chloroform: acetone = 1: 1-hexane: acetone: ethanol = 1: 1: 1) to give N- [5- (4- { [(3-Pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (6.12 g, 51%) was obtained as crystals. . Mp 122-123 ° C. as the elemental analysis C ₂₅ H ₂₈ N ₄ O, Calculated: C, 74.97; H, 7.05 ; N, 13.99 Found:. C, 74.85; H, 7.19; N, 14.09 1 H- NMR (CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.20-2.40 (1H,
m), 3.85 (2H, s), 3.87 (2H, s), 7.20-7.40 (1H, m), 7.44
(2H, d, J = 8.0Hz), 7.54 (2H, d, J = 8.0Hz), 7.65-7.80 (1H,
m), 7.91 (1H, dd, J = 8.4,2.2Hz), 8.01 (1H, s), 8.30 (1H,
d, J = 8.4Hz), 8.45-8.60 (2H, m), 8.60 (1H, s).

Reference Example 46 4- (5-{[(3-pyridylmethyl) amino] methyl} -2-pyridyl) -N-cyclohexylbenzamide (1) 5-hydroxymethyl-2-bromopyridine 6-bromonicotinic acid Borane-tetrahydrofuran complex (1M tetrahydrofuran) (20 ml, 20 mmol) was added dropwise to a tetrahydrofuran solution (30 ml) of (1.97 g, 9.75 mmol) using a dropping funnel. The temperature was raised to room temperature and the mixture was stirred for 2 hours. A 48% aqueous solution of hydrogen bromide was added dropwise under ice cooling to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. The aqueous layer was made basic with saturated multistory water and then extracted with ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered,
It was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 1) and purified with 5
-Hydroxymethyl-2-bromopyridine (0.93 g, 52%) was obtained as colorless crystals. Melting point: 47-49 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 2.89 (1H, br) 4.70 (2H, s)
7.46 (1H, d, J = 8.0Hz) 7.59 (1H, dd, J = 2.2, 8.0Hz)
8.29 (1H, dd, J = 0.8, 2.6Hz). (2) 4- (5-Hydroxymethyl-2-pyridyl) -N-cyclohexylbenzamide 5-hydroxymethyl-2-bromopyridine (4.13g, 22.5mmo
l) in acetonitrile (100 ml) with water (100 ml), sodium carbonate (4.77 g, 45 mmol), tetrakistriphenylphosphine palladium (1.30 g, 1.13 mmol), p-carboxybenzeneboronic acid (4.10 g, 24.7 mmol). The mixture was added in order, and the mixture was stirred at 90 ° C. under a nitrogen atmosphere overnight. After the reaction was completed, the insoluble matter was filtered off, and acetonitrile was distilled off under reduced pressure.
The aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration,
The crystals were washed with water and dried under reduced pressure to give carboxylic acid (4.29 g) as colorless crystals. This was directly used for the next reaction. This carboxylic acid (4.29 g, 19.1 mmol) in N, N-dimethylformamide suspension (100 ml) was added to 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (7.33 g, 38.2 mmol), 1
-Hydroxybenzotriazole monohydrate (5.85g, 38.2
mmol) and cyclohexylamine (3.28 ml, 28.7 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with chloroform-tetrahydrofuran (ca. 1: 1), washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: tetrahydrofuran =
1: 1) and then purified by recrystallization (tetrahydrofuran-hexane), 4- (5-hydroxymethyl-2-pyridyl) -N-
Cyclohexylbenzamide (3.20 g, 55%) was obtained as colorless crystals. Melting point: 221-223 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-1.8 (8H, m) 2.0-2.2 (2
H, m) 4.00 (1H, br) 4.79 (2H, s) 6.00 (1H, s) 7.74
-7.86 (4H, m) 8.04 (2H, d, J = 8.8Hz) 8.69 (1H, s). (3) 4- (5-formyl-2-pyridyl) -N-cyclohexylbenzamide 4- (5-hydroxy) Methyl-2-pyridyl) -N-cyclohexylbenzamide (3.20 g, 10.5 mmol) was added to dichloromethane (50
ml) and triethylamine (5.9 ml, 42 mmol)
Sulfur trioxide pyridine complex (6.70g, 42mmo
A solution of l) in dimethyl sulfoxide (50 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was diluted with chloroform and washed with water and saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (from chloroform alone to chloroform: methanol = 30: 1),
4- (5-Formyl-2-pyridyl) -N-cyclohexylbenzamide (2.88 g, 90%) was obtained as colorless crystals. Melting point: 224-225 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-1.8 (8H, m) 2.0-2.2 (2
H, m) 4.01 (1H, s) 6.08 (1H, d, J = 7.4Hz) 7.87-7.96
(3H, m) 8.15 (2H, d, J = 8.2Hz) 8.26 (1H, dd, J = 2.2,
8.0Hz) 9.14-9.15 (1H, m) 10.15 (1H, s). (4) 4- (5-{[(3-pyridylmethyl) amino] methyl} -2-pyridyl) -N-cyclohexylbenzamide 4- (5-formyl-2-pyridyl) -N-cyclohexylbenzamide (2.81 g, 9.25 mmol) in methanol (50 ml)
3- (Aminomethyl) pyridine (1.41 ml, 13.9 mmol), sodium chloride (5 g) and acetic acid (1.6 ml, 27.8 mmol) were sequentially added at room temperature. After stirring at room temperature for 15 minutes, sodium triacetoxyborohydride (2.94 g, 13.9 mmol) was added little by little, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was terminated with saturated multi-layered water, diluted with chloroform, the organic layer was separated, and then washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (from chloroform alone to chloroform: methanol = 30: 1) to give 4- (5-{[(3-pyridyl Methyl) amino] methyl} -2-pyridyl) -N-cyclohexylbenzamide (2.40 g, 66%) was obtained as colorless crystals. Melting point: 171-172 ℃ ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2 (2
H, m) 3.85 (2H, s) 3.87 (2H, s) 3.90-4.10 (1H, m)
6.13 (1H, d, J = 8.4Hz) 7.24-7.30 (1H, m) 7.68-7.87
(5H, m) 8.05 (2H, d, J = 8.2Hz) 8.52 (1H, d, J = 1.6,
4.8Hz) 8.59-8.66 (1H, m).

Reference Example 47 Ethyl 2-{[4-[(3-pyridylmethyl) amino] methyl] phenyl} pyrimidine-5-carboxylate (1) Ethyl 2-tolylpyrimidine-5-carboxylate a-formyl-b -Dimethylamino Aclaraldehyde (8.0g, 4
Triethylamine (9.71 ml, 69.6 mmol) and 4-methylbenzamidine hydrochloride (8.88 g, 52.0 mmol) were added to an ethanol solution (80 ml) of 6.0 mmol) at room temperature, and the mixture was heated under reflux for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with diluted hydrochloric acid, water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 10: 1) gave ethyl 2-tolylpyrimidine-5-carboxylate (6.63 g, 59%) as colorless crystals. Melting point: 116-117 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.43 (3H, t, J = 4.6Hz) 2.44
(3H, s) 4.45 (2H, q, J = 4.8Hz) 7.32 (2H, d, J = 5.8H
z) 8.39-8.42 (2H, m) 9.28-9.29 (2H, m).

(2) Ethyl 2-{[4-[(3-pyridylmethyl)
Amino] methyl] phenyl} pyrimidine-5-carboxylate ethyl 2-tolylpyrimidine-5-carboxylate (1.0 g,
4.12 mmol of carbon tetrachloride solution (20 ml) was added with 2,2'-azobisisobutyronitrile (34 mg, 0.05 mmol) and N-bromosuccinimide (0.78 g, 4.33 mmol) in that order and heated under reflux for 4 hours. . The insoluble material was filtered through Celite, and the residue was concentrated. A benzyl bromide form was obtained. This was used as it was in the next reaction. Chloroform-acetonitrile solution of benzyl bromide (4.13mmol) (50ml, 3: 2)
3- (aminomethyl) pyridine (1.3 ml, 12.39 mmol) was added to and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with chloroform and washed with saturated multistory water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-chloroform: methanol = 30: 1-20: 1), and ethyl 2 -{[Four-
[(3-Pyridylmethyl) amino] methyl] phenyl} pyrimidine-5-carboxylate (0.83 g, 58%) was obtained as colorless crystals. Melting point: 259-260 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.44 (3H, t, J = 7.0Hz) 3.84
(2H, s) 3.90 (2H, s) 4.45 (2H, q, J = 7.0Hz) 7.24-7.
31 (1H, m) 7.49 (2H, d, J = 8.4Hz) 7.72 (1H, dt, J =
2.2, 7.6Hz) 8.46-8.33 (3H, m) 8.58 (1H, d, J = 1.6H
z) 9.31 (2H, s).

Reference Example 48 N- [5- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-pyrimidyl] cyclohexanecarboxamide (1) N- (5-bromo-2-pyrimidyl) cyclohexane Carboxamide 5-Bromo-2-aminopyrimidine (15 g, 86.2 mmol) in pyridine (100 ml) was added with cyclohexanecarbonyl chloride.
(13.8 ml, 103.4 mmol) was added and the mixture was stirred at room temperature for 2 hours. Water (200 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (500,100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from hexane-diethyl ether to give N- (5-bromo-2-pyrimidyl) cyclohexanecarboxamide (22.0 g, 90%). Melting point 157-158 ° C. Elemental analysis value C ₁₁ H ₁₄ BrN ₃ O ・ 1 / 4H ₂ O, calculated value: C, 45.77; H, 5.06; N, 14.56 Found value: C, 45.87; H, 4.82; N , 14.93. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.50-2.70 (1H,
m), 8.07 (1H, brs), 8.63 (2H, brs). (2) N- [5- (4-formylphenyl) -2-pyrimidyl] cyclohexanecarboxamide N- (5-bromo-2-pyrimidyl) cyclohexane Carboxamide (11.4g, 40.0mmol), 4-formylbenzeneboronic acid
(7.20 g, 48.0 mmol), tetrakistriphenylphosphine palladium (1.39 g, 1.20 mmol), sodium carbonate (8.48
A mixture of g (80.00 mmol), toluene (200 ml) and water (100 ml) was heated under reflux for 15 hours under a nitrogen atmosphere. Ethyl acetate (100
(ml) was added to remove insolubles, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 5: 1 to 3: 1) to give N- [5- (4-formylphenyl)-
2-Pyrimidyl] cyclohexanecarboxamide (8.0g, 6
4%) was obtained as crystals. . Mp 184-185 ° C. as the elemental analysis _{C 18 H 19 N 3 O 2} , Calcd: C, 69.88; H, 6.19 ; N, 13.58 Found:. C, 69.63; H, 6.19; N, 13.48 1 H -NMR (CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.55-2.80 (1H,
m), 7.72 (1H, brs), 7.72 (2H, d, J = 8.0Hz), 8.02 (2H, d, J
= 8.0Hz), 8.20 (1H, s), 8.88 (2H, s), 10.09 (1H, s).
(3) N- [5- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-pyrimidyl] cyclohexanecarboxamide N- [5- (4-formylphenyl) -2-pyrimidyl] cyclohexanecarboxamide (7.0g, 22.6 mmol) and 3-aminomethylpyridine (2.76 ml, 27.2 mmol), acetic acid (5.18 ml, 90.5 mmo
l), a mixture of sodium chloride (30 g) and ethanol (300 ml) was stirred for 1 hour and then sodium triacetoxyborohydride (6.7
1 g, 31.7 mmol) was added little by little and stirred for 15 hours.
The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (250 ml) was added to the residue, and the mixture was extracted with chloroform (100 ml × 4). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel (hexane: acetone).
= 1: 1 to hexane: acetone: methanol = 1: 1: 1), N- [5- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-pyrimidyl] cyclohexane Carboxamide (6.
08g, 67%) was obtained as crystals. Melting point 132-133 ° C. Calculated as elemental analysis C ₂₄ H ₂₇ N ₅ O: C, 71.79; H, 6.78; N, 17.44 Found: C, 71.71; H, 6.70; N, 17.39. ¹ H- NMR (CDCl ₃ ) δ: 1.20-2.15 (10H, m), 2.50-2.75 (1H,
m), 3.85 (2H, s), 3.88 (2H, s), 7.20-7.35 (1H, m), 7.40-
7.60 (4H, m), 7.65-7.80 (1H, m), 8.07 (1H, brs), 8.50-9.
58 (1H, m), 8.58-8.65 (2H, m), 8.81 (1H, s).

Reference Example 49 6- (5-{[(3-pyridylmethyl) amino] methyl} pyridyl) -N
-Cyclohexylnicotinamide (1) 5,5'-Dimethyl-2,2'-bipyridyl 2-bromo-5-methylpyridine (20g, 116mmol) in N, N-dimethylformamide-isopropanol-water mixed solution
(14ml-19ml-5.2ml) with tetra-n-butylammonium bromide (18.7g, 58mmol), potassium carbonate (16.0g, 116mm
ol) was added, the atmosphere was replaced with nitrogen, and finally palladium acetate (1.30
g, 5.8 mmol) was added, and the mixture was stirred at 115 ° C. for 48 hours. After completion of the reaction, the insoluble matter was filtered through Celite, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (from chloroform alone to chloroform: methanol = 100: 1 to 40: 1).
5,5'-Dimethyl-2,2'-bipyridyl (9.14g, 86%) was obtained as pale yellow crystals. Melting point: 111-119 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 2.37 (6H, s) 7.60 (2H, d, J
= 5.6Hz) 8.23 (2H, d, J = 5.4Hz) 8.48-8.49 (2H, m). (2) Diethyl 2,2'-bipyridyl-5,5'-dicarboxylate 5,5'-dimethyl- 2,2'-Bipyridyl (8.0g, 43.4mmol) in water (600ml) was added to potassium permanganate (44g, 278m).
mol) at 80 ° C in small increments and then at 80-90 ° C for 6
Stir for hours. The precipitated manganese dioxide was filtered, the filtrate was acidified with 6N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. Dicarboxylic acid (7.97 g, 86%) was obtained as colorless crystals. This product was used for the next reaction as it was without purification. Concentrated sulfuric acid (23 ml) was slowly added dropwise to an ethanol suspension (200 ml) of dicarboxylic acid (7.97 g, 37.2 mmol), and the mixture was heated under reflux overnight. The insoluble material was filtered through Celite, and the reaction mixture was poured into ice water. The precipitated crystals were collected by filtration, dissolved in ethyl acetate, and washed with saturated multistory water and saturated brine.
The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude crystals were purified by recrystallization (ethanol), and diethyl 2,2'-bipyridyl-5,5'-dicarboxylate (5.77
g, 52%) was obtained as colorless crystals. Melting point: 151-152 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.44 (6H, t, J = 7.0Hz) 4.45
(4H, q, J = 7.4Hz) 8.43 (2H, dd, J = 2.2, 8.4Hz) 8.57
(2H, dd, J = 0.8, 8.2Hz) 9.29 (2H, dd, J = 0.8,2.2Hz). (3) 5 '-(ethoxycarbonyl) [2,2'-bipyridine] -5-carboxylate diethyl 2,2'-bipyridyl-5,5'-dicarboxylate
A suspension of (5.68g, 19.0mmol) in dichloromethane (200ml)
Solution of potassium hydroxide (1.07g, 19.0mml) in ethanol
(40 ml) was added, dichloromethane (100 ml) was further added, and the mixture was stirred at room temperature overnight. After distilling off the organic solvent under reduced pressure,
Water was added and acidified with 1N hydrochloric acid. The aqueous layer was extracted with chloroform and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude crystals were purified by recrystallization (ethanol) to obtain 5 '-(ethoxycarbonyl) [2,2'-bipyridine] -5-carboxylic acid (4.43g, 86%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.35 (3H, t, J = 4.8Hz) 4.37
(2H, q, J = 4.6Hz) 7.41-7.45 (2H, m) 8.52-8.56 (2H,
m) 9.19-9.18 (2H, m). (4) Ethyl 5 '-[(cyclohexylamino) carbonyl]
[2,2'-Bipyridine] -5-carboxylate 5 '-(ethoxycarbonyl) [2,2'-bipyridine] -5-carboxylic acid (4.42g, 16.3mmol) in N, N-dimethylformamide suspension (100 ml) in 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (6.25 g, 32.6 mmol), 1-hydroxybenzotriazole monohydrate (5.0 g, 32.6 mmol),
Cyclohexylamine (2.80 ml, 24.45 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with chloroform, washed with 1N hydrochloric acid, saturated multi-layered water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Ether was added to the residue, and the precipitated crystals were collected by filtration and washed with ether. Ethyl 5 '-[(cyclohexylamino) carbonyl] [2,2'-bipyridine] -5-carboxylate (3.35
g, 58%) was obtained as colorless crystals. Melting point: 176-177 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.19-1.82 (8H, m) 1.44 (3H,
t, J = 7.0Hz) 2.04-2.10 (2H, m) 4.00-4.04 (1H, m) 4.
45 (2H, q, J = 7.2Hz) 6.05 (1H, d, J = 7.2Hz) 7.20 (1
H, dd, J = 2.2, 8.2Hz) 8.39-8.45 (1H, m) 8.52-8.57
(2H, m) 9.04-9.05 (1H, m) 9.27-9.29 (1H, m). (5) 6-[(5-hydroxymethyl) pyridyl] -N-cyclohexylnicotinamide ethyl 5 '-[(cyclohexylamino ) Carbonyl] [2,2'-
Bipyridine] -5-carboxylate (3.20 g, 9.09 mmol)
Ethanol-tetrahydrofuran suspension (30ml-10ml)
2N aqueous sodium hydroxide solution (9 ml, 18 mmol) was added thereto at room temperature, and the mixture was stirred at 60 ° C. for 3 hours. After completion of the reaction, the organic solvent was distilled off, the aqueous layer was acidified with 6N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. Carboxylic acid (2.88g, 9
8%) was obtained as colorless crystals. This product was used for the next reaction as it was without purification. This carboxylic acid (2.88g, 8.89m
N-methylmorpholine (1.37 ml, 12.45 mmol) was added to a tetrahydrofuran suspension (80 ml) of (mol) and ethyl chlorocarbonate (1.02 ml, 10.67 mmol) was added dropwise under ice cooling, and the mixture was stirred under ice cooling for 2 hours. . Cool to about -20 ° C, add sodium borohydride (0.84g, 22.2mmol), and add methanol (4
0 ml) was slowly added dropwise. After completion of the reaction, the reaction mixture was quenched with 1N hydrochloric acid, and the aqueous layer was made basic with saturated multistory water.
It was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 4
0: 1 ~ 10: 1) purified 6-[(5-hydroxymethyl) pyridyl] -N-cyclohexylnicotinamide (1.50g, 54%)
Was obtained as colorless crystals. Melting point: 213-214 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.18-1.44 (5H, m) 1.65-1.69
(1H, m) 1.77-1.81 (2H, m) 2.00-2.04 (2H, m) 3.96-
4.00 (1H, m) 4.69-4.76 (1H, m) 4.73 (2H, s) 7.24 (1
H, d, J = 5.0Hz) 7.86 (1H, dd, J = 1.4, 5.4Hz) 8.23 (1
H, dd, J = 1.4, 5.4Hz) 8.39-8.43 (2H, m) 8.66 (1H,
d, J = 1.0Hz) 9.08-9.09 (1H, m). (6) 6- (5-{[(3-pyridylmethyl) amino] methyl} pyridyl) -N-cyclohexylnicotinamide 6-[(5- Hydroxymethyl) pyridyl] -N-cyclohexylnicotinamide (0.62g, 2.0mmol) in dichloromethane-dimethylsulfoxide solution (16ml-6ml) was added with triethylamine (1.12ml, 8.0mmol), then sulfur trioxide-pyridine complex (1.28g) , 8.0 mmol) in dimethyl sulfoxide
(10 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. Furthermore, triethylamine (0.56 ml, 4.0 mmol) and then sulfur trioxide-pyridine complex (0.64 g, 4.0 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was diluted with chloroform, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give an aldehyde derivative (0.99 g) as colorless crystals. This was not purified and used as it was in the next reaction. A suspension of this aldehyde (0.99 g, 2.0 mmol) in methanol (20 ml) was added with sodium chloride (5 g), 3-
(Aminomethyl) pyridine (0.33 ml, 3.0 mmol), acetic acid (0.
(35 ml, 6.0 mmol) was added, and the mixture was stirred at room temperature for 1 hr. Chloroform (20 ml) and sodium triacetoxyborohydride (2.94 g, 13.9 mmol) were added little by little, and the mixture was stirred at room temperature for 4
It was stirred for a day. The reaction was terminated by adding saturated multistory water, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (from chloroform alone,
Chloroform: methanol = 20: 1 to 10: 1) and
-(5-{[(3-pyridylmethyl) amino] methyl} pyridyl) -N-
Cyclohexylnicotinamide (0.42 g, 53%) was obtained as colorless crystals. Melting point: 172-173 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.18-1.55 (5H, m) 1.65-1.81
(3H, m) 2.04-2.09 (2H, m) 3.85 (2H, s) 3.90 (2H, m
s) 4.00-4.04 (1H, m) 6.10 (1H, d, J = 7.8Hz) 7.24-7.
31 (1H, m) 7.71 (1H, dt, J = 2.0, 8.2Hz) 7.84 (1H, d
d, J = 2.2, 8.4Hz) 8.17 (1H, dd, J = 2.2, 8.4Hz) 8.39-
8.54 (4H, m) 8.62 (1H, dd, J = 1.6, 12.6Hz) 9.01-9.0
3 (1H, m).

Reference Example 50 Methyl 4- (6-{[3-pyridylmethyl] amino} methyl) -3-pyridyl) benzoate (1) 2-formyl-5-bromopyridine 2,5-dibromopyridine (2.0 g, A solution of 8.44 mmol) in toluene (100 ml) was cooled to -78 ° C and n-butyllithium was added.
(6.4 ml, 10 mmol) was added dropwise and the mixture was stirred as it was for 2 hours, then N, N-dimethylformamide (0.85 ml, 11 mmol) was added dropwise and the mixture was stirred for 1 hour at -78 ° C. The reaction was terminated by adding saturated aqueous ammonium chloride solution, returning to room temperature, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 10:
1-), 2-formyl-5-bromopyridine (0.97g, 6
2%) was obtained as colorless crystals. Melting point: 92-93 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 7.85 (1H, dd, J = 0.4, 5.4Hz)
8.01-8.05 (1H, m) 8.85-8.86 (1H, m) 10.04 (1H,
s). (2) Methyl (6-formyl-3-pyridyl) benzoate 2-formyl-5-bromopyridine (3.0 g, 16.1 mmol) in acetonitrile (80 ml) in water (80 ml), sodium carbonate
(3.42 g, 32.2 mmol), tetrakistriphenylphosphine palladium (0.93 g, 0.81 mmol) and p-carboxybenzeneboronic acid (2.94 g, 17.7 mmol) were sequentially added, and the mixture was stirred at 90 ° C. for 13 hours under a nitrogen atmosphere. After the reaction was completed, the insoluble matter was filtered off, and acetonitrile was distilled off under reduced pressure. The aqueous layer was neutralized with 1N hydrochloric acid, the precipitated crystals were collected by filtration, washed with water,
After drying under reduced pressure, carboxylic acid (3.97 g) was obtained as colorless crystals. This was directly used for the next reaction. This carboxylic acid
(3.97 g, 16.1 mmol) N, N-dimethylformamide solution (50 ml) in potassium carbonate (3.34 g, 24.15 mmol),
Methyl iodide (1.21 ml, 19.32 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1),
Methyl (6-formyl-3-pyridyl) benzoate (1.04
g, 27%, 2 steps) were obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ (ppm) 3.97 (3H, s) 7.72 (2H, d, J
= 8.4Hz) 8.08-8.09 (2H, m) 8.19 (2H, d, J = 8.6Hz) 9.0
4-9.05 (1H, m) 10.64 (1H, s). (3) Methyl 4- (6-{[3-pyridylmethyl] amino} methyl)-
3-Pyridyl) benzoate Methyl (6-formyl-3-pyridyl) benzoate (1.04 g,
4.31 mmol) in methanol (20m) in sodium chloride (3g), 3- (aminomethyl) pyridine (0.66ml, 6.47mmo)
l) and acetic acid (0.74 ml, 12.93 mmol) were added, and the mixture was stirred at room temperature for 40 minutes, and sodium triacetoxyborohydride (1.37 ml) was added.
g, 6.47mmol) After stirring at room temperature for 2 hours, 3- (aminomethyl) pyridine (0.66ml, 6.47mmol) and acetic acid (0.74ml, 1
2.93 mmol), sodium triacetoxyborohydride (1.
37 g, 6.47 mmol) was added and the mixture was stirred at room temperature for 14 hours. The reaction was terminated by adding saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
Purify with (hexane: ethyl acetate = 1: 1 to hexane: acetone: methanol = 1: 1: 0.1) to give methyl 4
-(6-{[3-pyridylmethyl] amino} methyl) -3-pyridyl)
Benzoate (1.26 g, 88%) was obtained as pale yellow crystals. Melting point: 89-90 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 3.89 (3H, s) 3.95 (3H, s)
3.99 (2H, s) 7.24-7.30 (1H, m) 7.41 (1H, d, J = 8.2H
z) 7.65 (2H, d, J = 8.4Hz) 7.71-7.77 (1H, dt, J = 2.2,
7.8Hz) 7.88 (1H, dd, J = 2.2, 8.0Hz) 8.14 (2H, d, J
= 8.4Hz) 8.52 (1H, dd, J = 1.4, 4.8Hz) 8.60 (1H, d, J =
1.4Hz) 8.82 (1H, dd, J = 0.8, 2.6Hz).

Example 249 N-Cyclohexyl-4 ′-{[{[4- (neopentyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl}
[1,1'-Biphenyl] -4-carboxamide 1) ethyl 4 '-{[{[4- (neopentyloxy) anilino]
Carbonyl} (3-pyridylmethyl) amino] methyl} [1,1'-
Biphenyl] -4-carboxylate p-neopentyloxybenzoic acid (1.56 g, 6.0 mmol) in acetonitrile suspension (20 ml) was added to triethylamine (1.
26 ml, 9.0 mmol) and diphenylphosphoric acid azide (1.42 ml,
6.6 mmol) was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and ethyl 4 '-[(3-pyridyl) methylaminomethyl] -4-biphenylcarboxylate (1.50g, 4.3
(3 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated multistory water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography.
Purified with (chloroform: ethyl acetate = 1: 0-2: 1), ethyl 4 ′-{[{[4- (neopentyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} [ 1,1′-Biphenyl] -4-carboxylate (2.61 g, 100%) was obtained as colorless crystals. Melting point: 146-147 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.00 (9H, s) 1.41 (3H, t, J
= 6.8Hz) 3.53 (2H, s) 4.40 (2H, q, J = 7.2Hz) 4.58 (2
H, s) 4.68 (2H, s) 6.31 (1H, s) 6.80 (2H, d, J = 9.2H
z) 7.14 (2H, d, J = 8.8Hz) 7.26-7.35 (1H, m) 7.37 (2
H, d, J = 8.0Hz) 7.61-7.67 (4H, m) 7.74 (1H, dt, J = 1.
8, 8.0Hz) 8.12 (2H, d, J = 8.4Hz) 854-8.57 (2H, m). 2) N-cyclohexyl-4 '-{[{[4- (neopentyloxy)
Anilino] carbonyl} (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxamidoethyl 4 '-{[{[4- (neopentyloxy) anilino] carbonyl} (3- Pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylate (1.59 g, 2.88 mmol) in ethanol-tetrahydrofuran solution (10 ml-10 ml) 2
A specified aqueous sodium hydroxide solution (2.8 ml, 5.6 mmol) was added at room temperature, and the mixture was stirred at 60 ° C for 2 hr. After the reaction was completed, the organic solvent was distilled off, the aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. The carboxylic acid was obtained as colorless crystals. This product was used for the next reaction as it was without purification. This carboxylic acid suspension of N, N-dimethylformamide (1
1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.06 g, 5.5 mmol), 1-hydroxybenzotriazole monohydrate (0.85 g, 5.5 mmol), cyclohexylamine (0.48 ml, (4.13 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 3: 1-chloroform: methanol = 30: 1) and recrystallized (hexane).
-Ethyl acetate), N-cyclohexyl-4 '-{[{[4-
(Neopentyloxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} [1,1′-biphenyl] -4-carboxamide (1.28 g, 73% over 2 steps) was obtained as colorless crystals. Mp: 188-189 ° C. Elemental analysis C ₃₈ H ₄₄ N ₄ O ₃ Calculated: C, 75.47; H, 7.33 ; N, 9.26 Found: C, 75.23; H, 7.33 ; N, 9.07 1 H-NMR (CDCl ₃ ) δ (ppm) 1.00 (9H, s) 1.19-150 (5H,
m) 1.64-1.79 (3H, m) 2.02-2.06 (2H, m) 3.53 (2H,
s) 3.94-4.01 (1H, m) 4.58 (2H, s) 4.67 (2H, s) 6.0
6 (1H, d, J = 5.4Hz) 6.34 (1H, s) 6.80 (2H, d, J = 6.0
Hz) 7.15 (2H, d, J = 6.0Hz) 7.26-7.37 (3H, m) 7.59-7.
63 (4H, m) 7.74 (1H, d, J = 5.2Hz) 7.82 (2H, d, J = 5.4
Hz) 8.55 (2H, d, J = 1.8Hz).

Example 250 N-cyclohexyl-4 ′-{[{[4- (cyclohexylmethoxy)
Anilino] carbonyl} (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxamide 1) ethyl 4 '-{[{[4- (cyclohexylmethoxy) anilino] carbonyl} (3-pyridyl Methyl) amino] methyl} [1,
1'-Biphenyl] -4-carboxylate p- (cyclohexylmethoxy) benzoic acid (1.41 g, 6.0mmo
l) in acetonitrile suspension (20 ml) with triethylamine (1.26 ml, 9.0 mmol) and diphenylphosphoric azide (1.
(42 ml, 6.6 mmol) was added at room temperature, and the mixture was heated under reflux for 1 hr.
Then, the temperature was returned to room temperature, and ethyl 4 '-[(3-pyridyl) methylaminomethyl] -4-biphenylcarboxylate (1.50 g,
(4.33 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated multistory water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 0-2: 1), and ethyl 4 '-{[{[4- (Cyclohexylmethoxy) anilino] carbonyl} (3-pyridylmethyl) amino] methyl} [1,
1'-Biphenyl] -4-carboxylate (2.56 g, 100%) was obtained as colorless crystals. Melting point: 188-189 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.97-1.31 (5H, m) 1.41 (3H,
t, J = 7.0Hz) 1.70-1.87 (6H, m) 3.70 (2H, d, J = 6.2H
z) 4.40 (2H, q, J = 7.0Hz) 4.58 (2H, s) 4.68 (2H, s)
6.27 (1H, s) 6.79 (2H, d, J = 8.8Hz) 7.14 (2H, d, J
= 9.0Hz) 7.26-7.33 (1H, m) 7.37 (2H, d, J = 8.2Hz) 7.
62-7.67 (4H, m) 7.74 (1H, dt, J = 1.8, 8.0Hz) 8.12
(2H, d, J = 8.4Hz) 8.54-8.57 (2H, m). 2) N-cyclohexyl-4 '-{[{[4- (cyclohexylmethoxy) anilino] carbonyl} (3-pyridylmethyl) amino] Methyl} [1,1'-biphenyl] -4-carboxamidoethyl 4 '-{[{[4- (cyclohexylmethoxy) anilino]
Carbonyl} (3-pyridylmethyl) amino] methyl} [1,1'-
Biphenyl] -4-carboxylate (1.53 g, 2.65 mmol)
Ethanol-tetrahydrofuran solution (10ml-10ml)
2N aqueous sodium hydroxide solution (2.5ml, 5.0mmol)
Was added at room temperature and stirred at 60 ° C. for 2 hours. After the reaction,
The organic solvent was evaporated, the aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. The carboxylic acid was obtained as colorless crystals (1.30 g). This product was used for the next reaction as it was without purification. To this N, N-dimethylformamide suspension of carboxylic acid (15 ml) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.86 g, 4.5 mmo
l), 1-hydroxybenzotriazole monohydrate (0.69 g,
4.5 mmol), cyclohexylamine (0.39 ml, 3.38 mmol)
Was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform:
N-cyclohexyl-4 '-{[{[4- (cyclohexylmethoxy) anilino] carbonyl}} was purified by recrystallization (hexane-ethyl acetate) with ethyl acetate = 3: 1-chloroform: methanol = 30: 1). (3-Pyridylmethyl) amino] methyl} [1,
1'-Biphenyl] -4-carboxamide (0.77 g, 46%) was obtained as colorless crystals. Melting point: 196-197 ° C Elemental analysis value Calculated as C ₄₀ H ₄₆ N ₄ O ₃ : C, 76.19; H, 7.35; N, 8.88 Found: C, 75.97; H, 7.34; N, 8.71 ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.98-1.50 (10H, m) 1.67-1.8
5 (9H, m) 2.02-2.06 (2H, m) 3.69 (2H, d, J = 4.2Hz)
3.98-4.01 (1H, m) 4.58 (2H, s) 4.68 (2H, s) 6.04 (1
H, d, J = 5.4Hz) 6.30 (1H, s) 6.78 (2H, d, J = 5.8Hz)
7.15 (2H, d, J = 6.2Hz) 7.26-7.37 (3H, m) 7.59-7.64
(4H, m) 7.72-7.76 (1H, m) 7.82 (2H, d, J = 5.4Hz) 8.
56 (1H, s)

Example 251 N-Cyclohexyl-4 ′-[((3-pyridylmethyl) {[4- (2-thienylmethoxy) anilino] carbonyl} amino) methyl]
[1,1'-Biphenyl] -4-carboxamide 1) ethyl 4 '-[((3-pyridylmethyl) {[4- (2-thienylmethoxy) anilino] carbonyl} amino) methyl] [1,1'- Biphenyl] -4-carboxylate p- (2-thienylmethoxy) benzoic acid (0.76 g, 3.24 mmol)
Triethylamine in 10 ml of acetonitrile
(0.68 ml, 4.9 mmol) and diphenylphosphoric acid azide (0.77 m
(1, 3.6 mmol) was added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature and ethyl 4 '-[(3-pyridyl) methylaminomethyl] -4-biphenylcarboxylate (0.94g, 2.7m
mol) was added and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated multistory water and saturated saline.
The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 0- to 4: 1) to obtain ethyl 4 '-[((3- Pyridylmethyl) {[4- (2-thienylmethoxy)
Anilino] carbonyl} amino) methyl] [1,1′-biphenyl] -4-carboxylate (1.22 g, 78%) was obtained as colorless crystals. Melting point: 173-174 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.41 (3H, t, J = 4.8Hz) 4.40
(2H, q, J = 4.8Hz) 4.58 (2H, s) 4.68 (2H, s) 5.16 (2
H, s) 6.32 (1H, s) 6.88 (2H, d, J = 6.2Hz) 6.96-6.99
(1H, m) 7.06-7.08 (1H, m) 7.17 (2H, d, J = 5.8Hz)
7.28-7.32 (2H, m) 7.36 (2H, d, J = 5.6Hz) 7.61-7.67
(4H, m) 7.71-7.75 (1H, m) 8.12 (2H, d, J = 5.8Hz) 8.5
5-8.56 (2H, m). 2) N-cyclohexyl-4 '-[((3-pyridylmethyl) {[4- (2-
Thienylmethoxy) anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-carboxamidoethyl 4 '-[((3-pyridylmethyl) {[4- (2-thienylmethoxy) anilino] carbonyl} amino ) Methyl] [1,1'-biphenyl] -4-carboxylate (1.11 g, 1.92 mmol) in ethanol-tetrahydrofuran solution (10 ml-10 ml) 2
A specified aqueous sodium hydroxide solution (2 ml, 4.0 mmol) was added at room temperature, and the mixture was stirred at 60 ° C for 2 hr. After completion of the reaction, the organic solvent was distilled off, the aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water to give carboxylic acid as colorless crystals. This product was used for the next reaction as it was without purification. 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.74g, 3.84mmo) was added to a suspension of this carboxylic acid (1.92mmol) in N, N-dimethylformamide (20ml).
l), 1-hydroxybenzotriazole monohydrate (0.59 g,
3.84mmol), cyclohexylamine (0.33ml, 2.88mmo
l) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 1: 0- to 30: 1) and further recrystallized (hexane-ethyl acetate), and N-cyclohexyl-4 '-[((3-
Pyridylmethyl) {[4- (2-thienylmethoxy) anilino] carbonyl} amino) methyl] [1,1′-biphenyl] -4-carboxamide (0.98 g, 81%) was obtained as colorless crystals. Melting point: 150-151 ° C Elemental analysis C ₃₈ H ₃₈ N ₄ O ₃ S Calculated: C, 72.35; H, 6.07; N, 8.88 Found: C, 72.11; H, 6.03; N, 8.78 ¹ H- NMR (CDCl ₃ ) δ (ppm) 1.19-1.50 (5H, m) 1.69-1.78
(3H, m) 2.02-2.07 (2H, m) 3.98-4.01 (1H, m) 4.58
(2H, s) 4.68 (2H, s) 5.16 (2H, s) 6.02 (1H, d, J = 5.
4Hz) 6.32 (1H, s) 6.89 (2H, d, J = 6.0Hz) 6.98 (1H,
dd, J = 2.2, 3.4Hz) 7.07-7.08 (1H, m) 7.17 (2H, d, J
= 4.4Hz) 7.28-7.37 (4H, m) 7.60-7.64 (4H, m) 7.74
(1H, dt, J = 1.0, 5.0Hz) 7.82 (2H, d, J = 5.6Hz)

Example 252 N-cyclohexyl-4 ′-{[{[4- (neopentyloxy) phenyl] sulfonyl} (3-pyridylmethyl) amino] methyl}
[1,1'-biphenyl] -4-carboxamide 1) ethyl 4 '-{[{[4- (neopentyloxy) phenyl] sulfonyl} (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl ] -4-Carboxylate ethyl 4 '-[(3-pyridyl) methylaminomethyl] -4-biphenylcarboxylate (0.87g, 2.5mmol) in acetonitrile solution (15ml) in triethylamine (0.53ml, 3.8mm)
ol) and 4- (neopentyloxy) benzenesulfonyl chloride (0.58 g, 2.25 mmol) were added at room temperature, and the mixture was stirred for 30 minutes. After completion of the reaction, the mixture was diluted with chloroform and washed with saturated multistory water and saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform only, chloroform: ethyl acetate = 4: 1) and purified with ethyl 4 '-{[{[4
-(Neopentyloxy) phenyl] sulfonyl} (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxylate (1.09 g, 85%) was obtained as pale yellow crystals. Melting point: 131-132 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.06 (9H, s) 1.41 (3H, t, J
= 7.0Hz) 3.66 (2H, s) 4.32, 4.33 (4H, each s) 4.40
(2H, q, J = 7.2Hz) 7.01 (2H, d, J = 8.8Hz) 7.16 (2H, d,
J = 8.4Hz) 7.46 (2H, d, J = 8.4Hz) 7.49-7.55 (1H, m)
7.58 (2H, d, J = 8.8Hz) 7.80 (2H, d, J = 9.2Hz) 8.10
(2H, d, J = 8.4Hz) 8.25 (1H, d, J = 1.8Hz) 8.44 (1H, d
d, J = 1.4, 4.8Hz). 2) N-cyclohexyl-4 '-{[{[4- (neopentyloxy)
Phenyl] sulfonyl} (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxamidoethyl 4 '-{[{[4- (neopentyloxy) phenyl] sulfonyl} (3-pyridylmethyl ) Amino] methyl} [1,1'-biphenyl] -4-carboxylate (1.0 g, 1.76 mmol) in ethanol-tetrahydrofuran solution (10 ml-10 ml) with 2N aqueous sodium hydroxide solution (1.8 ml, 3.6 mmol) Was added at room temperature and stirred at 60 ° C. for 2 hours. After the reaction was completed, the organic solvent was distilled off, the aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. Colorless crystals of carboxylic acid (0.89
g, 1.64 mmol). This product was used for the next reaction as it was without purification. 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.63g, 3.28mmol), 1-hydroxy was added to an N, N-dimethylformamide suspension (10ml) of this carboxylic acid (to be 1.64mmol). Benzotriazole monohydrate (0.51 g, 3.28 mmol) and cyclohexylamine (0.28 ml, 2.46 mmol) were added, and the mixture was stirred at room temperature overnight.
After the reaction was completed, it was diluted with ethyl acetate, washed with saturated multistory water and saturated brine, dried over anhydrous magnesium sulfate, filtered,
It was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: ethyl acetate = 4: 1 and then chloroform: methanol = 30: 1) and recrystallized (chloroform-
Hexane), N-cyclohexyl-4 '-{[{[4- (neopentyloxy) phenyl] sulfonyl} (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxamide (0.72 g, 65% over 2 steps) was obtained as colorless crystals. Melting point: 208-209 ° C Elemental analysis C ₃₇ H ₄₃ N ₃ O ₄ S Calculated: C, 71.01; H, 6.93; N, 6.71 Found: C, 70.93; H, 6.93; N, 6.56 ¹ H- NMR (CDCl ₃ ) δ (ppm) 1.06 (9H, s) 1.19-1.30 (3H,
m) 1.38-1.51 (2H, m) 1.64-1.79 (3H, m) 2.02-2.06
(2H, m) 3.67 (2H, s) 3.95-4.01 (1H, m) 4.32,4.33
(4H, each s) 6.00 (1H, d, J = 5.6Hz) 7.02 (2H, d, J =
6.2Hz) 7.10-7.16 (3H, m) 7.43 (2H, d, J = 5.6Hz) 7.50
-7.53 (1H, m) 7.57 (2H, d, J = 5.4Hz) 7.79-7.82 (4H,
m) 8.24 (1H, s) 8.42-8.44 (1H, m)

Example 253 N-cyclohexyl-4 ′-{[{[4- (cyclohexylmethoxy)
Phenyl] sulfonyl} (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxamidoethyl 4 '-{[{[4- (cyclohexylmethoxy) phenyl]
Sulfonyl} (3-pyridylmethyl) amino] methyl} [1,1'-
Biphenyl] -4-carboxylate ethyl 4 '-[(3-pyridyl) methylaminomethyl] -4-biphenylcarboxylate (1.0 g, 2.89 mmol) in acetonitrile (15 ml) was added to triethylamine (0.61 ml, 3.9 m).
mol) and 4- (cyclohexylmethoxy) benzenesulfonyl chloride (0.99 g, 3.48 mmol) were added at room temperature and stirred for 1 hour. After completion of the reaction, the mixture was diluted with chloroform and washed with saturated multistory water and saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (from chloroform alone to chloroform: ethyl acetate = 4: 1) and purified with ethyl 4'-
{[{[4- (cyclohexylmethoxy) phenyl] sulfonyl}
(3-Pyridylmethyl) amino] methyl} [1,1'-biphenyl]-
4-Carboxylate (1.42 g, 82%) was obtained as pale yellow crystals. Melting point: 142-144 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.03-1.38 (5H, m) 1.41 (3H,
t, J = 6.8Hz) 1.68-1.90 (6H, m) 3.81 (2H, d, J = 6.0H
z) 4.33 (4H, s) 4.40 (2H, q, J = 7.4Hz) 6.99 (2H, d,
J = 8.8Hz) 7.10-7.17 (3H, m) 4.45 (2H, d, J = 8.0Hz)
7.49-7.55 (1H, m) 7.58 (2H, d, J = 8.6Hz) 7.80 (2H,
d, J = 8.8Hz) 8.10 (2H, d, J = 8.6Hz) 8.24 (1H, d, J = 1.
8Hz) 8.44 (1H, dd, J = 1.4, 4.6Hz). 2) N-cyclohexyl-4 '-{[{[4- (cyclohexylmethoxy) phenyl] sulfonyl} (3-pyridylmethyl) amino] methyl} [ 1,1'-biphenyl] -4-carboxamidoethyl 4 '-{[{[4- (cyclohexylmethoxy) phenyl]
Sulfonyl} (3-pyridylmethyl) amino] methyl} [1,1'-
Biphenyl] -4-carboxylate (1.09 g, 1.84 mmol)
Ethanol-tetrahydrofuran solution (10ml-10ml)
2N aqueous sodium hydroxide solution (1.9ml, 3.8mmol)
Was added at room temperature and stirred at 60 ° C. for 2 hours. After the reaction,
The organic solvent was evaporated, the aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. The carboxylic acid was obtained as colorless crystals (1.03 g, 1.81 mmol). This is not purified,
Used as such for the next reaction. This carboxylic acid (1.64mmol
And N) N-dimethylformamide suspension (10 ml)
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.70g, 3.62mmol), 1-hydroxybenzotriazole monohydrate (0.56g, 3.62mmol), cyclohexylamine (0.31ml, 2.71mmol) Was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1 then chloroform: methanol = 30: 1) and recrystallized (chloroform-hexane) to give N-cyclohexyl-4 '-{[{[4-
(Cyclohexylmethoxy) phenyl] sulfonyl} (3-pyridylmethyl) amino] methyl} [1,1′-biphenyl] -4-carboxamide (0.91 g, 76% over 2 steps) was obtained as colorless crystals. Melting point: 203-205 ° C Elemental analysis C ₃₉ H ₄₅ N ₃ O ₄ S Calculated: C, 71.86; H, 6.96; N, 6.45 Found: C, 71.44; H, 6.92; N, 6.27 ¹ H- NMR (CDCl ₃ ) δ (ppm) 1.05-1.50 (10H, m) 1.70-1.8
9 (9H, m) 2.03-2.08 (2H, m) 3.82 (2H, d, J = 4.2Hz)
3.95-4.05 (1H, m) 4.32, 4.33 (4H, each s) 6.00 (1
H, d, J = 5.4Hz) 6.99 (2H, d, J = 6.0Hz) 7.11-7.16 (3
H, m) 7.44 (2H, d, J = 5.4Hz) 7.49-7.58 (3H, m) 7.78-
7.82 (4H, m) 8.25 (1H, s) 8.43-8.44 (1H, m)

Example 254 4-{[({4 '-[(tert-butoxycarbonyl) amino] [1,1'-biphenyl] -4-yl} methyl) (3-pyridylmethyl) amino]
Sulfonyl} -3 ', 4', 5'-trimethoxy-1,1'-biphenyl 4-{[[(4-bromophenyl) sulfonyl]-(3-pyridylmethyl) amino] methyl} -4 '-[( tert-Butoxycarbonyl) amino] -1,1'-biphenyl (4.26g, 7.0mmol), 3,4,5-trimethoxybenzeneboronic acid (1.78g, 8.40mmol), tetrakistriphenylphosphine palladium (243g, 0.21 mmo
l), sodium carbonate (1.48g, 14.0mmol), toluene (100m
A mixture of l) and water (50 ml) was heated under reflux for 4 hours under a nitrogen atmosphere. Ethyl acetate (300 ml) was added and insoluble matter was removed with Celite, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 2) to give 4-
{[({4 '-[(tert-Butoxycarbonyl) amino]-[1,1'-biphenyl] -4-yl} methyl) (3-pyridylmethyl) amino]
Sulfonyl} -3 ', 4', 5'-trimethoxy-1,1'-biphenyl
(4.59 g, 93%) was obtained as crystals. Melting point 122-125 ° C (decomposition) .IRνmax ^KBr cm ^-1 : 1740,1709,1588,1345,1242,1161,1134,
822. As Elemental analysis _{C 39 H 41 N 3 O 7} S · 1 / 2H 2 O, Calculated: C, 66.46; H, 6.01 ; N, 5.96 Found: C, 66.52; H, 6.12 ; N, 5.61 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.53 (9H, s, Bu t), 3.92 (3H, s), 4.39
(6H, s), 6.55 (1H, s), 6.80 (2H, s), 7.11 (2H, d, J = 8.0H
z), 7.10-7.20 (1H, m), 7.35-7.50 (6H, m), 7.50-7.60 (1
H, m), 7.71 (2H, d, J = 8.0Hz), 7.92 (2H, d, J = 8.0Hz), 8.3
1 (1H, d, J = 1.4Hz), 8.46 (1H, dd, J = 4.8,1.8Hz).

Example 255 N- [4 '-({(3-pyridylmethyl) [(3', 4 ', 5'-trimethoxy
[1,1'-Biphenyl] -4-yl) sulfonyl] -amino} methyl) [1,1'-biphenyl] -4-yl] cyclohexanecarboxamide (1) N-[(4'-amino [1,1 '-Biphenyl] -4-yl) methyl] -3', 4 ', 5'-trimethoxy-N- (3-pyridylmethyl) [1,
1'-biphenyl] -4-sulfonamide dihydrochloride 4-{[({4 '-[(tert-butoxycarbonyl) amino] [1,1'-biphenyl] -4-yl} methyl) (3-pyridyl Methyl) amino]
Sulfonyl} -3 ', 4', 5'-trimethoxy-1,1'-biphenyl
To a solution of (4.0 g, 5.75 mmol) in ethanol (20 ml), concentrated hydrochloric acid (10 m
l) was added and the mixture was stirred at 50 ° C. for 30 minutes. The solvent was distilled off under reduced pressure,
Diethyl ether was added to the residue as a powder, and N-[(4 '
-Amino [1,1'-biphenyl] -4-yl) methyl] -3 ', 4', 5'-
Trimethoxy-N- (3-pyridylmethyl) [1,1'-biphenyl]
-4-Sulfonamide dihydrochloride (3.7 g, 98%) was obtained as an amorphous powder. IRνmax ^KBr cm ^-1 : 1590,1499,1343,1250,1159,1125,820. Elemental analysis value C ₃₄ H ₃ N ₃ O ₅ S ・ 2HCl, calculated value: C, 61.07; H, 5.28; N, 6.28 Found: C, 61.35; H, 5.47; N, 5.83. ¹ H-NMR (d ₆ -DMSO, 300 MHz) δ: 3.71 (3H, s), 3.88 (6H, s),
4.45 (2H, s), 4.55 (2H, s), 7.01 (2H, s), 7.10-7.40 (4H,
m), 7.43 (2H, d, J = 7.8Hz), 7.62 (2H, d, J = 7.8Hz), 7.60-7.
75 (1H, m), 7.97 (4H, s), 8.00-8.10 (1H, m), 8.49 (1H, s),
8.59 (1H, d, J = 5.7Hz). (2) N- [4 '-({(3-pyridylmethyl) [(3', 4 ', 5'-trimethoxy [1,1'-biphenyl]- 4-yl) sulfonyl] -amino}
Methyl) [1,1'-biphenyl] -4-yl] cyclohexanecarboxamide N-[(4'-amino [1,1'-biphenyl] -4-yl) methyl] -3 ',
4 ', 5'-Trimethoxy-N- (3-pyridylmethyl) [1,1'-biphenyl] -4-sulfonamide dihydrochloride (0.80g, 1.2mmol)
And chloroform (20 ml) and saturated aqueous sodium hydrogen carbonate (10 ml) in a mixed solution of cyclohexanecarbonyl chloride (0.19 ml, 1.44 mmol).
Was added and the mixture was stirred at room temperature for 30 minutes. The chloroform layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Silica gel chromatography of the residue (chloroform: ethyl acetate
= 1: 1), N- [4 '-({(3-pyridylmethyl) [(3',
Crystallized 4 ', 5'-trimethoxy [1,1'-biphenyl] -4-yl) sulfonyl] amino} methyl) [1,1'-biphenyl] -4-yl] cyclohexanecarboxamide (0.72g, 85%) Got as. Melting point 193-196 ° C. IRνmax ^KBr cm ^-1 : 3364,1684,1590,1514,1335,1157,1127,
903,826.Calculated for elemental analysis C ₄₁ H ₄₃ N ₃ O ₆ S: C, 69.76; H, 6.14; N, 5.95 Found: C, 69.50; H, 6.25; N, 5.78. ¹ H-NMR ( CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.10-2.40 (1H,
m), 3.92 (3H, s), 3.95 (6H, s), 4.39 (2H, s), 6.80 (2H,
s), 7.05-7.30 (4H, m), 7.35-7.75 (8H, m), 7.71 (2H, d, J =
8.8Hz), 7.92 (2H, d, J = 8.8Hz), 8.30-8.40 (1H, m), 8.40-
8.50 (1H, m).

Example 256 2,4-Difluoro-N- [4 ′-({(3-pyridylmethyl) [(3 ′, 4 ′,
5'-trimethoxy [1,1'-biphenyl] -4-yl) sulfonyl] amino} methyl) [1,1'-biphenyl] -4-yl] benzamido N- [4 '-({(3-pyridylmethyl ) [(3 ', 4', 5'-Trimethoxy
[1,1'-Biphenyl] -4-yl) sulfonyl] -amino} methyl) [1,1'-biphenyl] -4-yl] cyclohexanecarboxamide dihydrochloride (0.80g, 1.2mmol) and chloroform (20m
2,4-Difluorobenzoyl chloride (0.18 ml, 1.44 mmol) was added to a mixed solution of l) and saturated aqueous sodium hydrogen carbonate (10 ml), and the mixture was stirred at room temperature for 30 minutes. The chloroform layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 2: 1) to give 2,4
-Difluoro-N- [4 '-({(3-pyridylmethyl) [(3', 4 ', 5'-
Trimethoxy [1,1'-biphenyl] -4-yl) sulfonyl] amino} methyl) [1,1'-biphenyl] -4-yl] -benzamide
(0.72 g, 82%) was obtained as crystals. Melting point 167-169 ° C. IRν max ^KBr cm ^-1 : 1667,1595,1501,1339,1250,1157,1128,
As 822. Elemental analysis _{C 41 H 35 F 2 N 3} O 6 S, Found:. C, 66.82; H, 4.82; N, 5.59 1 H-NMR (CDCl 3) δ: 3.92 (3H, s), 3.95 (6H, s), 4.40 (2H,
s), 6.81 (2H, s), 6.90-7.05 (1H, m), 7.05-7.25 (5H, m),
7.44 (2H, d, J = 8.4Hz), 7.55 (2H, d, J = 8.4Hz), 7.71 (4H, d,
J = 8.4Hz), 7.93 (2H, d, J = 8.4Hz), 8.20-8.30 (1H, m), 8.3
1 (1H, m), 8.35-8.50 (2H, m).

Example 257 N- (4 ′-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,1′-biphenyl] -4-yl) -2-
[2- (trifluoromethyl) phenyl] acetamide 4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -4 '-[(tert-butoxycarbonyl) amino] -1, 1'-biphenyl (5.65g, 9.28mmol) ethanol
Concentrated hydrochloric acid (30 ml) was added to the (50 ml) solution, and the mixture was stirred at 60 ° C for 30 min. The reaction solution was dried under reduced pressure. 2- (trifluoromethyl)
A mixture of phenylacetic acid (2.84g, 13.9mmol), N, N-dimethylformamide (1 drop), and thionyl chloride (10ml) was refluxed for 1 hour and then distilled under reduced pressure to give 2- (trifluoromethyl).
Obtained phenylacetyl chloride. This acid chloride and the amino compound obtained above were mixed with chloroform (100 ml) and saturated aqueous sodium hydrogen carbonate (100 m
It was stirred in the mixture of l) for 2 hours. The chloroform layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 2: 1-1: 1), and N- (4 '-{[[(4-
Bromophenyl) sulfonyl] (3-pyridylmethyl) -amino] methyl} [1,1'-biphenyl] -4-yl) -2- [2- (trifluoromethyl) phenyl] acetamide (5.4g, 84%) Was obtained as a crystal. Melting point 152-153 ° C. IRνmax ^KBr cm ^-1 : 3333,1667,1537,1337,1316,1157,1113. Elemental analysis value C ₃₄ H ₂₇ BrF ₃ N ₃ O ₃ S, calculated value: C, 58.79; H , 3.92; N, 6.05 Example: C, 58.72; H, 3.66; N, 6.13. ¹ H-NMR (CDCl ₃ ) δ: 3.92 (2H, s), 4.34 (4H, s), 7.08 (2H,
d, J = 8.0Hz), 7.15 (1H, dd, J = 8.4,5.2Hz), 7.21 (1H, s),
7.39 (2H, d, J = 8.0Hz), 7.40-7.80 (13H, m), 8.25-8.35 (1
H, m), 8.40-8.50 (1H, m).

Example 258 N- (4 '-{[{[4'-(hydroxymethyl) [1,1'-biphenyl] -4
-Yl] sulfonyl} (3-pyridylmethyl) amino] methyl}
[1,1'-Biphenyl] -4-yl) -2- [2- (trifluoromethyl) phenyl] acetamide (1) N- (4 '-{[(4'-formyl [1,1'- Biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] methyl} [1,
1'-biphenyl] -4-yl) -2- [2- (trifluoromethyl) phenyl] acetamide N- (4 '-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl } [1,1'-Biphenyl] -4-yl) -2-
[2- (trifluoromethyl) phenyl] acetamide (1.39
g, 2.00 mmol) and 4-formylphenylboronic acid (0.36 g,
2.43 mmol), tetrakistriphenylphosphine palladium (69.3 mg, 0.06 mmol), sodium carbonate (0.42 g, 4.0 m
A mixture of (mol), toluene (50 ml) and water (30 ml) was heated under reflux for 3 hours under a nitrogen atmosphere. Ethyl acetate (100 ml) was added to remove insolubles, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 1: 1) to give N- (4 '-{[[(4'-formyl [1,1'-biphenyl] -4-yl) sulfonyl] sulfonyl]. (3-Pyridylmethyl) amino] methyl} [1,
1'-Biphenyl] -4-yl) -2- [2- (trifluoromethyl) phenyl] acetamide (1.25 g, 87%) was obtained as crystals. Melting point 178-180 ° C. IRν max ^KBr cm ^-1 : 1705,1605,1537,1499,1346,1319,1159,
1111.Calculated as elemental analysis C ₄₁ H ₃₂ F ₃ N ₃ O ₄ S: C, 68.42; H, 4.48; N, 5.84 Example: C, 68.30; H, 4.51; N, 5.94 ¹ H- NMR (CDCl ₃ ) δ: 3.93 (2H, s), 4.40 (4H, s), 7.12 (2H,
d, J = 8.0Hz), 7.10-7.25 (1H, m), 7.23 (1H, s), 7.30-7.65
(11H, m), 7.70-7.85 (4H, m), 7.90-8.10 (4H, m), 8.25-8.
35 (1H, m), 8.40-8.50 (1H, m), 10.10 (1H, s). (2) N- (4 '-{[{[4'-(hydroxymethyl) [1,1'-biphenyl ] -4-yl] sulfonyl} (3-pyridylmethyl) amino]
Methyl} [1,1'-biphenyl] -4-yl) -2- [2- (trifluoromethyl) phenyl] acetamido N- (4 '-{[(4'-formyl [1,1'-biphenyl ] -4-yl) Sulfonyl] (3-pyridylmethyl) amino] methyl}-[1,1'-biphenyl] -4-yl) -2- [2- (trifluoromethyl) phenyl]
Sodium borohydride (71 mg, 1.88 mmol) was added to a solution of acetamide (0.90 g, 1.25 mmol) in methanol-tetrahydrofuran (30 ml-50 ml), and the mixture was stirred for 1 hour. Water (100 ml) was added to the reaction solution, and the mixture was extracted with chloroform (100 ml × 2). After washing the extract with water and drying over anhydrous magnesium sulfate,
It was distilled off under reduced pressure. Silica gel chromatography of the residue
Purified with (chloroform: acetone = 2: 1), N- (4'-
{[{[4 '-(hydroxymethyl) [1,1'-biphenyl] -4-yl]
-Sulfonyl} (3-pyridylmethyl) amino] methyl} [1,1'-
Biphenyl] -4-yl) -2- [2- (trifluoromethyl) phenyl] acetamide (0.84 g, 93%) was obtained as crystals. Melting point 212-213 ° C. IRνmax ^KBr cm ^-1 : 3480,1690,1541,1319,1157,1117. Elemental analysis value C ₄₁ H ₃₄ F ₃ N ₃ O ₄ S, calculated value: C, 68.22; H, 4.75 ; N, 5.82 example:. C, 68.08; H, 4.73; N, 5.82 1 H-NMR (CHCl 3, 300MHz) δ: 3.95 (2H, s), 4.40 (2H, s), 4.
58 (2H, d, J = 5.4Hz), 5.30 (1H, d, J = 5.4Hz), 7.15-7.30 (3
H, m), 7.40-7.80 (16H, m), 7.91 (2H, d, J = 8.0Hz), 7.98 (2
H, d, = 8.0Hz), 8.29 (1H, brs), 8.30-8.40 (1H, m), 10.31
(1H, s).

Example 259 N- (4 '-{[{[2'-(hydroxymethyl) [1,1'-biphenyl] -4
-Yl] sulfonyl} (3-pyridylmethyl) -amino] methyl}
[1,1'-Biphenyl] -4-yl) -2- [2- (trifluoromethyl) phenyl] acetamide (1) N- (4 '-{[[(2'-formyl [1,1'- Biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] methyl}-[1,
1'-biphenyl] -4-yl) -2- [2- (trifluoromethyl) phenyl] acetamide N- (4 '-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl } [1,1'-Biphenyl] -4-yl) -2-
[2- (trifluoromethyl) phenyl] acetamide (1.39
g, 2.00 mmol) and 2-formylphenylboronic acid (0.36 g, 2.
43 mmol), tetrakistriphenylphosphine palladium (69.3 mg, 0.06 mmol), sodium carbonate (0.42 g, 4.0 mmo
A mixture of l), toluene (50 ml) and water (30 ml) was heated under reflux for 3 hours under a nitrogen atmosphere. Ethyl acetate (100 ml) was added to remove insolubles, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 1: 1) to give N- (4 '-{[[(2'-formyl [1,1'-biphenyl] -4-yl) sulfonyl] sulfonyl]. (3-Pyridylmethyl) amino] methyl} [1,
1′-Biphenyl] -4-yl) -2- [2- (trifluoromethyl) phenyl] acetamide (1.39 g, 95%) was obtained as crystals. Melting point 206-208 ° C. IRν max ^KBr cm ^-1 : 3320,1684,1595,1534,1339,1321,1155,
1111,1067,1040. Elemental analysis value C ₄₁ H ₃₂ F ₃ N ₃ O ₄ S ・ 3 / 4H ₂ O, calculated value: C, 67.16; H, 4.60; N, 5.73 Example: C, 67.07; H ^{, 4.43; N, 5.56 1 H} -NMR (CDCl 3) δ:. 3.93 (2H, s), 4.43 (4H, s), 7.12 (2H,
d, J = 8.0Hz), 7.10-7.25 (1H, m), 7.35-7.80 (17H, m), 7.9
6 (2H, d, J = 8.0Hz), 8.25-8.40 (1H, m), 8.46 (1H, d, J = 4.0H
(z), 9.97 (1H, s). (2) N- (4 '-{[{[2'-(hydroxymethyl) [1,1'-biphenyl] -4-yl] sulfonyl} (3-pyridylmethyl )-amino]
Methyl} [1,1'-biphenyl] -4-yl) -2- [2- (trifluoromethyl) phenyl] acetamido N- (4 '-{[(2'-formyl [1,1'-biphenyl ] -4-yl) Sulfonyl] (3-pyridylmethyl) amino] methyl}-[1,1'-biphenyl] -4-yl) -2- [2- (trifluoromethyl) phenyl]
Sodium borohydride (71 mg, 1.88 mmol) was added to a solution of acetamide 14 (0.90 g, 1.25 mmol) in methanol-tetrahydrofuran (20 ml-20 ml), and the mixture was stirred for 1 hour. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 ml).
The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: acetone = 2: 1) to give N- (4 '-{[{[2'-(hydroxymethyl) [1,1'-biphenyl] -4-yl]. Sulfonyl}
(3-Pyridylmethyl) amino] methyl} [1,1'-biphenyl]-
4-yl) -2- [2- (trifluoromethyl) phenyl] acetamide (0.84 g, 93%) was obtained as crystals. Melting point 149-150 ° C. IRν max ^KBr cm ^-1 : 3409,1682,1603,1541,1358,1339,1319,
1159,1119.Calculated as elemental analysis C ₄₁ H ₃₄ F ₃ N ₃ O ₄ S: C, 68.22; H, 4.75; N, 5.82 Example: C, 68.25; H, 4.91; N, 5.59. ¹ H-NMR (CHCl _3, 300MHz) δ: 3.53 (2H, s), 3.93 (2H, s), 4.
41 (2H, s), 4.45 (2H, s), 4.61 (2H, s), 7.15-7.35 (6H, m),
7.35-7.65 (14H, m), 7.73 (1H, d, J = 8.4Hz), 7.75-7.80 (1
H, m), 7.90 (2H, d, = 8.4Hz), 8.35-8.45 (1H, m).

Example 260 N- [4 '-({(3-pyridylmethyl) [(3', 4 ', 5'-trimethoxy
[1,1'-Biphenyl] -4-yl) sulfonyl] amino} methyl)
[1,1'-Biphenyl] -4-yl] -2- [2- (trifluoromethyl) phenyl] acetamide hydrochloride N- (4 '-{[[(4-bromophenyl) sulfonyl] (3-pyridyl Methyl) amino] methyl} [1,1'-biphenyl] -4-yl) -2-
[2- (trifluoromethyl) phenyl] acetamide (1.04
g, 1.50 mmol) and 3,4,5-trimethoxyphenylboronic acid
(0.38g, 1.80mmol), tetrakistriphenylphosphine palladium (52mg, 0.045mmol), sodium carbonate (0.32g
A mixture of g (3.0 mmol), toluene (100 ml) and water (30 ml) was heated under reflux for 2 hours under a nitrogen atmosphere. Ethyl acetate (100 ml) was added to remove insolubles, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: acetone = 2: 1) to give as an oil. This oily substance was converted into ethyl acetate (2
It was dissolved in 0 ml), 4N hydrogen chloride / ethyl acetate (2 ml) was added, and the mixture was shaken. The solvent was evaporated under reduced pressure, diethyl ether was added to give a powder, and N- [4 '-({(3-pyridylmethyl) [(3',
4 ', 5'-Trimethoxy [1,1'-biphenyl] -4-yl) sulfonyl] amino} methyl) [1,1'-biphenyl] -4-yl] -2- [2-
(Trifluoromethyl) phenyl] -acetamide hydrochloride
(1.04 g, 84%) was obtained as an amorphous powder. IRν max ^KBr cm ^-1 : 1688,1593,1532,1499,1343,1316,1159,
. 1125,1038 As Elemental analysis _{C 43 H 38 F 3 N 3} O 6 S HCl · 1 / 2H 2 O, ^{Calculated:. C, 62.43; H,} 4.87; N, 5.08 Found: C, 62.65; H ^{, 5.08; N, 5.16 1 H} -NMR (d 6 -DMSO) δ:. 3.73 (3H, s), 3.90 (6H, s), 4.46 (2
H, s), 4.57 (2H, s), 7.02 (2H, s), 7.23 (2H, d, J = 8.0Hz),
7.43 (2H, d, J = 8.0Hz), 7.50-7.80 (11H, m), 7.99 (2H, s),
8.60-8.70 (1H, m), 10.39 (1H, s).

Example 261 6- (4-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide 6- (4 -{[(3-Pyridylmethyl) amino] methyl} phenyl) -N
A solution of cyclohexylnicotinamide (0.81g, 2.02mmol) in dichloromethane (10ml) was added to triethylamine (0.56g).
5ml, 4.04mmol) and 4-biphenylsulfonyl chloride
(0.77 g, 3.03 mmol) was added at room temperature, and the mixture was stirred as it was overnight. The reaction was terminated with saturated multistory water, extracted with chloroform, and the organic layer was washed with saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (from chloroform alone,
Chloroform: methanol = 50: 1 to 20: 1), and then recrystallize (chloroform-hexane) to purify 6- (4-
{[([1,1'-Biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide (0.88 g, 71%) was obtained as colorless crystals. Melting point: 209-210 ℃ Elemental analysis value Calculated as C ₃₇ H ₃₆ N ₄ O ₃ S ・ 0.5H ₂ O: C, 71.01; H, 5.96; N, 8.98 Found: C, 71.00; H, 5.75; N , 8.90 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-1.8 (8H, m) 2.0-2.2 (2
H, m) 4.03 (1H, br) 4.38 (2H, s) 4.42 (2H, s) 6.06
(1H, d, J = 7.8Hz) 7.11-7.21 (3H, m) 7.41-7.55 (4H,
m) 7.61-7.65 (2H, dd, J = 1.4, 7.8Hz) 7.70-7.78 (3H,
m) 7.87 (2H, d, J = 8.4Hz) 7.94 (2H, d, J = 8.4Hz) 8.1
3 (1H, dd, J = 2.2, 8.4Hz) 8.28 (1H, s) 8.43-8.45 (1
H, m) 8.98 (1H, d, J = 2.2Hz)

Example 262 6- (4-{[[[[1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide hydrochloride 6- (4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide (0.40g, 0.67mmol) 4N Hydrogen chloride-ethyl acetate (5 ml) was added dropwise to a tetrahydrofuran solution (20 ml), and the mixture was stirred at room temperature for 5 minutes. The solvent was concentrated under reduced pressure and the resulting crystals were collected by filtration and recrystallized (ethanol-
Ether) and then 6- (4-{[[([1,1'-biphenyl] -4-
Ilamino) carbonyl] (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide hydrochloride (0.38 g, 85%) was obtained as a colorless solid. Melting point: 244-245 ℃ Elemental analysis value Calculated as C ₃₈ H ₃₇ N ₅ O ₂・ HCl ・ 2H ₂ O: C, 68.30; H, 6.34; N, 10.48 Found: C, 68.20; H, 6.35; N , 10.40 ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.5 (5H, m) 1.5-2.0
(5H, m) 3.78 (1H, s) 4.83 (2H, s) 7.27-7.34 (1H,
m) 7.39-7.47 (4H, m) 7.55-7.68 (6H, m) 8.01-8.17
(4H, m) 8.37 (1H, dd, J = 2.2, 8.0Hz) 8.49-8.58 (2H,
m) 8.82-8.87 (2H, m) 9.07-9.10 (2H, m).

Example 263 6- (4-{[[[[1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide p- Triethylamine (0.59ml, 4.2mmo) was added to a suspension of phenylbenzoic acid (0.56g, 2.8mmol) in acetonitrile (10ml).
l) and diphenylphosphoric acid azide (0.67 ml, 3.08 mmol) were added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 6- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide (0.80 g, 2.0 mmo
l) and dichloromethane (10 ml) were added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated multistory water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (from chloroform only, chloroform: methanol = 30: 1 to 20: 1).
After filtering the solid insoluble in chloroform through Celite,
Purified by recrystallization (chloroform-hexane), 6- (4-
{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-
Pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide (1.06 g, 89%) was obtained as colorless crystals. Melting point: 161-163 ° C Elemental analysis C ₃₈ H ₃₇ N ₅ O ₂・ Calculated as 0.5H ₂ O: C, 75.47; H, 6.33; N, 11.58 Found: C, 75.61; H, 6.53; N, 11.45 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.2-2.0 (8H, m) 2.0-2.2 (2
H, m) 4.03 (1H, br) 4.63 (2H, s) 4.70 (2H, s) 6.11
(1H, d, J = 8.0Hz) 6.55 (1H, s) 7.28-7.56 (12H, m)
7.77 (2H, d, J = 8.4Hz) 8.05 (2H, d, J = 8.4Hz) 8.15
(1H, dd, J = 2.2, 8.4Hz) 8.58 (1H, s) 9.00 (1H, d, J
= 1.8Hz)

Example 264 6- (4-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide dihydrochloride 6 -(4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide (0.38g, 0.616mmol) in ethanol-tetrahydrofuran 4N hydrogen chloride in solution (5ml-20ml)
Ethyl acetate (5 ml) was added dropwise, and the mixture was stirred at room temperature for 5 minutes. The solvent was concentrated under reduced pressure, and the resulting crystals were collected by filtration and purified by recrystallization (ethanol-ether) to give 6- (4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3- Pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide dihydrochloride (0.34 g, 80%) was obtained as a colorless solid. Melting point: 181-183 ° C Elemental analysis C ₃₇ H ₃₆ N ₄ O ₃ S ・ HCl ・ 2.5H ₂ O Calculated: C, 63.64; H, 6.06; N, 8.02 Found: C, 63.47; H, 5.73 ; N, 7.82 ¹ H-NMR (d ₆ -DMSO) δ (ppm) 1.0-1.5 (5H, m) 1.5-2.0
(5H, m) 3.80 (1H, br) 4.53 (2H, s) 7.34 (2H, d, J =
8.4Hz) 7.47-7.59 (3H, m) 7.76-7.86 (3H, m) 7.94-8.
07 (3H, m) 8.25-8.34 (2H, m) 8.51 (1H, d, J = 8.0Hz)
8.62 (1H, s) 8.67 (1H, d, J = 5.4Hz) 9.06 (1H, d, J
= 1.8Hz).

Example 265 6- (4-{[([1,1′-biphenyl] -2-ylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide 1) N- Cyclohexyl-4 '-{[(2-bromosulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxamide 6- (4-{[(3-pyridylmethyl) amino] Methyl} phenyl) -N
-Cyclohexylnicotinamide (0.41g, 1.02mmol)
Triethylamine (0.
29 ml, 2.04 mmol) and 2-bromobenzenesulfonyl chloride (0.39 g, 1.53 mmol) were added at room temperature, and the mixture was stirred for 30 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated multistory water and saturated saline. After drying over anhydrous magnesium sulfate,
It was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform only, chloroform: methanol = 30: 1), and N-cyclohexyl-4'-
{[(2-Bromosulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-carboxamide (0.31g, 49
%) Was obtained as a pale red amorphous powder. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2 (2
H, m) 3.90-4.10 (1H, br) 4.46 (4H, s) 6.01 (1H, d,
J = 8.4Hz) 7.17-7.26 (4H, m) 7.44-7.55 (3H, m) 7.75-
7.92 (2H, m) 7.94 (2H, d, J = 8.0Hz) 8.13-8.24 (3H,
m) 8.51 (1H, d, J = 4.4Hz) 9.00 (1H, d, J = 2.2Hz). 2) 6- (4-{[([1,1'-biphenyl] -2-ylsulfonyl) ( 3-
Pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide N-cyclohexyl-4 '-{[(2-bromosulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4 -Carboxamide (0.30g, 0.484mmol) in toluene solution (15ml)
Water (5 ml), sodium carbonate (0.11 g, 0.968 mmol), tetrakistriphenylphosphine palladium (0.028 g,
0.024 mmol) and phenylboronic acid (0.071 g, 0.58 mmol) were sequentially added, and the mixture was stirred with heating under reflux in a nitrogen atmosphere overnight. After the reaction was completed, it was diluted with ethyl acetate and washed with water and saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to hexane: acetone = 1: 1), and 6- (4-{[([1,1'-biphenyl] -2-ylsulfonyl) (3-Pyridylmethyl) amino] methyl} phenyl) -N-cyclohexylnicotinamide (0.16 g, 54%) was obtained as a pale red amorphous powder. Elemental analysis _{C 37 H 36 N 4 O 3} S · 0.5H 2 O Calculated: C, 71.01; H, 5.96 ; N, 8.95 Found: C, 70.85; H, 5.77 ; N, 8.58 1 H-NMR (CDCl ₃ ) δ (ppm) 1.2-1.8 (8H, m) 2.0-2.2 (2
H, m) 3.76 (4H, s) 4.0-4.2 (1H, br)
6.25 (1H, d, J = 6.6Hz) 6.9
9 (2H, d, J = 8.4 Hz) 7.07-
7.37 (5H, m) 7.40-7.73 (6
H, m) 7.85 (2H, d, J = 8.0H
z) 8.02 (1H, d, J = 1.8 Hz)
8.16 (1H, dd, J = 2.6, 8.4H
z) 8.26 (1H, dd, J = 1.6,
8.2 Hz) 8.43 (1H, dd, J = 1.
4, 4.8 Hz).

Example 266 N- [6- (4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-
Pyridylmethyl) amino] methyl} phenyl) -2-pyridyl]
Cyclohexanecarboxamide N- [6- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (0.8g,
2.0 mmol of N, N-dimethylformamide (10 ml) in 4
-Add biphenylsulfonyl chloride (0.66g, 2.6mmol) and triethylamine (0.42ml, 3.0mmol) at room temperature and
Stir for minutes. Water (100 ml) was added to the reaction mixture and ethyl acetate was added.
It was extracted with (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel chromatography of the residue (chloroform: ethyl acetate = 2: 1)
Purified by N- [6- (4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl)
-2-Pyridyl] cyclohexanecarboxamide (0.71g, 58
%) Was obtained as crystals. Melting point 190-191 ° C. IRν max ^KBr cm ^-1 : 3331,1669,1528,1507,1480,1337,1157. Calculated as C ₃₇ H ₃₆ N ₄ O ₃ C: 72.05; H, 5.88; N, 9.08 Found:. C, 71.71; H, 5.87; N, 8.97 1 H-NMR (CDCl 3) δ: 1.20-2.10 (10H, m), 2.20-2.40 (1H,
m), 4.38 (2H, s), 4.41 (2H, s), 7.10-7.20 (3H, m), 7.33
(1H, s), 7.40-7.60 (4H, m), 7.60-7.70 (3H, m), 7.70-7.9
0 (4H, m), 7.95 (2H, d, J = 8.4Hz), 8.25-8.40 (2H, m), 8.40
-8.50 (1H, m), 8.55-8.60 (1H, m).

Example 267 N- [6- (4-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -3-pyridyl] cyclohexanecarboxamide N- [6- ( 4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexane-carboxamide (0.8g,
2.0 mmol of N, N-dimethylformamide (10 ml) in 4
-Phenoxyphenylsulfonyl chloride (0.54g, 2.4mm
ol) and triethylamine (0.56 ml, 4.0 mmol) were added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 ml × 2). Wash the extract with water,
It was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 2: 1 to 1: 1) to give N- [6- (4-{[[4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl). Amino] methyl} phenyl) -3-pyridyl] cyclohexanecarboxamide (0.84g, 65%) was obtained as crystals. Melting point 191-193 ° C. IRνmax ^KBr cm ^-1 : 3374,1682,1584,1532,1487,1323,1238,
. 1154,1090,905 As Elemental analysis _{C 37 H 36 N 4 O 4} S · 1 / 2H 2 O, Calculated: C, 69.24; H, 5.81 ; N, 8.73 Found: C, 69.27; H, 5.72 ^{; N, 8.73 1 H-NMR} (CDCl 3) δ:. 1.20-2.10 (10H, m), 2.20-2.40 (1H,
m), 4.34 (2H, s), 4.36 (2H, s), 7.00-7.60 (12H, m), 7.66
(1H, d, J = 8.4Hz), 7.82 (4H, d, J = 8.8Hz), 8.20-8.40 (2H,
m), 8.40-8.50 (1H, m), 8.55-8.60 (1H, m).

Example 268 N- [6- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -3-pyridyl] cyclohexanecarboxamide N- [6- ( 4-{[(3-pyridylmethyl) amino] methyl} phenyl) -3-pyridyl] cyclohexanecarboxamide (2.0 g,
5.0 mmol) in N, N-dimethylformamide (20 ml) was added with 4-bromophenylsulfonyl chloride (1.40 g, 5.5 mmol) and triethylamine (1.39 ml, 10.0 mmol) at room temperature.
Stir for hours. Add water (150 ml) to the reaction mixture and add ethyl acetate.
It was extracted with (150 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (chloroform: ethyl acetate = 1: 1-
1: 2) and N- [6- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -3
-Pyridyl] cyclohexanecarboxamide (1.90g, 61%)
Was obtained as a crystal. Melting point 209-210 ° C. IRν max ^KBr cm ^-1 : 3339,1692,1667,1526,1507,1339,1161,
1088. As Elemental analysis _{C 31 H 31 BrN 4 O 3} S · 1 / 2H 2 O, Calculated: C, 59.23; H, 5.13 ; N, 8.91 Found: C, 58.96; H, 5.27 ; N, 8.79 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.20-2.15 (10H, m), 2.20-2.40 (1H,
m), 4.34 (2H, s), 4.37 (2H, s), 7.11 (2H, d, J = 8.0Hz), 7.
15-7.25 (1H, s), 7.32 (1H, s), 7.45-7.60 (1H, m), 7.60-
7.80 (5H, m), 7.82 (2H, d, J = 8.0Hz), 8.25-8.40 (2H, m),
8.40-8.55 (1H, m), 8.55-8.60 (1H, m).

Example 269 N- (6- {4-[((3-pyridylmethyl) {[4 '-(trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl} amino) methyl ] Phenyl} -3-pyridyl) cyclohexanecarboxamide N- [6- (4-{[([4-bromophenyl] -4-ylsulfonyl) (3-
Pyridylmethyl) amino] methyl} -phenyl) -3-pyridyl] cyclohexanecarboxamide (0.68 g, 1.1 mmol), 4
-(Trifluoromethyl) benzeneboronic acid (0.25g, 1.32m
mol), tetrakistriphenylphosphine palladium (3
8 mg, 0.033 mmol), sodium carbonate (0.23 g, 2.2 mmol),
Toluene (100 ml), water (50 ml) mixture under nitrogen atmosphere,
Heated to reflux for hours. Ethyl acetate (50 ml) was added and insoluble matter was removed with Celite, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 1: 1) to give N- (6- {4-[((3-pyridylmethyl) {[4 '-(trifluoromethyl) [1, 1'-biphenyl] -4-yl] sulfonyl}
Amino) methyl] phenyl} -3-pyridyl) cyclohexanecarboxamide (0.59g, 79%) was obtained as crystals. Melting point 218-222 ° C. IRν max ^KBr cm ^-1 : 1663,1530,1507,1480,1327,1159,1127,
As 1073. Elemental analysis _{C 38 H 35 F 3 N 4} O 3 S, Calculated: C, 66.65; H, 5.15 ; N, 8.18 Found:. C, 66.29; H, 5.11; N, 8.11 1 H- NMR (CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.20-2.40 (1H,
m), 4.40 (4H, s), 4.42 (2H, s), 7.14 (2H, d, J = 8.0Hz), 7.
10-7.25 (1H, m), 7.29 (1H, s), 7.50-7.62 (1H, m), 7.64 (1
H, d, J = 8.8Hz), 7.70-7.90 (8H, m), 7.97 (2H, d, J = 8.6Hz),
8.25-8.40 (2H, m), 8.40-8.50 (2H, m), 8.55 (1H, d, J = 2.6H
z)

Example 270 N- {6- [4-({(3-pyridylmethyl) [(3 ′, 4 ′, 5′-trimethoxy [1,1′-biphenyl] -4-yl) sulfonyl]- Amino} methyl) phenyl] -3-pyridyl} cyclohexanecarboxamide N- [6- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -3-pyridyl] cyclohexane Carboxamide (0.68 g, 1.10 mmol), 3,4,5-trimethoxybenzeneboronic acid (0.28 g, 1.32 mmol), tetrakistriphenylphosphine palladium (38 mg, 0.033
mmol), sodium carbonate (0.23 g, 2.2 mmol), toluene (50
A mixture of water (20 ml) and water (20 ml) was heated under reflux for 3 hours under a nitrogen atmosphere. Ethyl acetate (50 ml) was added and insoluble matter was removed with Celite, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: acetone = 1: 1) to give N- {6- [4-
({(3-pyridylmethyl) [(3 ', 4', 5'-trimethoxy [1,1'-
Biphenyl] -4-yl) sulfonyl] amino} methyl) phenyl] -3-pyridyl} cyclohexanecarboxamide (0.67 g,
86%) was obtained as crystals. Melting point 198-199 ° C. IRν max ^KBr cm ^-1 : 3343,1663,1591,1530,1508,1343,1159,
1130,1094,1009.Calculated as elemental analysis C ₄₀ H ₄₂ N ₄ O ₆ S: C, 67.97; H, 5.99; N, 7.93 Found: C, 67.52; H, 5.95; N, 7.85. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.20-2.40 (1H,
m), 3.92 (3H, s), 3.95 (6H, s), 4.38 (2H, s), 4.40 (2H,
s), 6.80 (2H, s), 7.14 (2H, d, J = 8.4Hz), 7.10-7.25 (1H,
m), 7.31 (1H, s), 7.50-7.60 (1H, m), 7.64 (2H, d, J = 8.6H
z), 7.71 (2H, d, J = 8.4Hz), 7.81 (2H, d, J = 8.4Hz), 8.25-
8.40 (2H, m), 8.56 (1H, d, J = 2.6Hz).

Example 271 N- [6- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -3-pyridyl] -2- [2-
(Trifluoromethyl) phenyl] acetamide N- [6- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -3-pyridyl] -2- [2- (trifluoro-methyl) phenyl] acetamide A solution of 20 (1.76 g, 3.69 mmol) in N, N-dimethylformamide (20 ml) was treated with 4-bromophenylsulfonyl chloride (1.04 g, 4.06 mmol) and triethylamine (1.03 g).
(ml, 7.39 mmol) was added and the mixture was stirred at room temperature for 1 hour. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 ml × 2).
The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 1: 1) to give N- [6- (4-
{[[(4-Bromophenyl) sulfonyl] (3-pyridylmethyl)
Amino] methyl} phenyl) -3-pyridyl] -2- [2- (trifluoromethyl) phenyl] acetamide (1.60 g, 62%) was obtained as crystals. Melting point 180-181 ° C. IRν max ^KBr cm ^-1 : 3322,1672,1574,1508,1339,1318,1159,
. 1127,772 As Elemental analysis _{C 33 H 26 BrF 3 N 4} O 3 S, Calculated: C, 56.98; H, 3.77 ; N, 8.06 Found:. C, 56.86; H, 3.69; N, 7.96 1 H-NMR (CDCl ₃ ) δ: 3.96 (2H, s), 4.33 (2H, s), 4.36 (2H,
s), 7.10 (2H, d, J = 8.6Hz), 7.10-7.20 (1H, m), 7.40-7.90
(13H, m), 8.15-8.25 (1H, m), 8.25-8.35 (1H, m), 8.40-8.
50 (1H, m), 8.51 (1H, d, J = 2.2Hz).

Example 272 N- [6- (4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-
Pyridylmethyl) amino] methyl} phenyl) -3-pyridyl]
-2- [2- (Trifluoromethyl) phenyl] acetamide N- [6- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -3-pyridyl] -2- [2- (trifluoro 4-Methyl) phenyl] acetamide (0.715 g, 1.5 mmol) in N, N-dimethylformamide (20 ml) was added to 4-biphenylsulfonyl chloride (0.49 g, 1.95 mmol) and triethylamine (0.42 ml, 3.0
mmol) was added and the mixture was stirred at room temperature for 1 hour. Water (100 m
l) was added and the mixture was extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 2: 1 to 1: 1), and N- [6- (4-
{[([1,1'-Biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl) -3-pyridyl] -2- [2-
(Trifluoromethyl) phenyl] acetamide (0.68g,
65%) was obtained as crystals. Melting point 199-200 ° C. IRνmax ^KBr cm ^-1 : 3330,1671,1510,1480,1337,1319,1155,
As 1113. Elemental analysis _{C 39 H 31 F 3 N 4} O 3 S, Calculated: C, 66.75; H, 4.60 ; N, 7.98 Found:. C, 66.44; H, 4.41; N, 7.99 1 H- NMR (CDCl ₃ ) δ: 3.95 (2H, s), 4.38 (2H, s), 4.40 (2H,
s), 7.13 (2H, d, J = 8.0Hz), 7.10-7.20 (1H, m), 7.40-7.70
(12H, m), 7.70-7.90 (4H, m), 7.94 (2H, d, J = 8.6Hz), 8.10
-8.23 (1H, m), 8.29 (1H, s), 8.40-8.50 (1H, m), 8.50-8.6
0 (1H, m).

Example 273 N- {6- [4-({(3-pyridylmethyl) [(3 ', 4', 5'-trimethoxy [1,1'-biphenyl] -4-yl) sulfonyl] amino] } Methyl) phenyl] -3-pyridyl} -2- [2- (trifluoromethyl)
Phenyl] acetamide dihydrochloride N- [6- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -3-pyridyl] -2- [2-
(Trifluoromethyl) phenyl] acetamide (1.04g,
1.5 mmol), 3,4,5-trimethoxybenzeneboronic acid (0.38
g, 1.80 mmol), tetrakistriphenylphosphine palladium (52 mg, 0.045 mmol), sodium carbonate (0.32 g, 3.0
A mixture of (mmol), toluene (100 ml) and water (50 ml) was heated under reflux for 2 hours under a nitrogen atmosphere. Ethyl acetate (50 ml) was added and insoluble matter was removed with Celite, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel chromatography of the residue (hexane: acetone = 1: 1)
After purification with, the resulting oil was dissolved in ethanol (5 ml), 4N hydrogen chloride / ethyl acetate (2 ml) was added, and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue to give a powder, and N- {6- [4-({(3-pyridylmethyl) [(3 ', 4', 5'-trimethoxy [1,1'-biphenyl] -4- Il) sulfonyl] amino} methyl) phenyl] -3-pyridyl} -2- [2- (trifluoromethyl) phenyl] acetamide dihydrochloride (1.14 g, 87%)
Was obtained as an amorphous powder. IR ν max ^KBr cm ^-1 : 1701,1561,1343,1316,1159,1125. Elemental analysis value C ₄₂ H ₃₇ F ₃ N ₄ O ₆ S ・ 2HCl ・ 1 / 2H ₂ O, calculated value: C, 58.33; H , 4.66; N, 6.48 Found: C, 58.62; H, 4.54; N, 6.34. ¹ H-NMR (d ₆ -DMSO) δ: 3.73 (3H, s), 3.90 (6H, s), 4.03 (2
H, s), 4.51 (2H, s), 4.62 (2H, s), 7.03 (1H, s), 7.32 (2H,
d, J = 8.0Hz), 7.40-8.10 (12H, m), 8.11 (2H, s), 8.26 (2H,
d, J = 8.0Hz), 8.60 (1H, s), 8.60-8.75 (1H, m), 8.93 (1H,
s), 10.98 (1H, brs).

Example 274 N- [5- (4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-
Pyridylmethyl) amino] methyl} phenyl) -2-pyridyl]
Cyclohexanecarboxamide N- [5- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexane-carboxamide (1.0 g,
2.50 mmol) of acetonitrile-N, N-dimethylformamide (20 ml-20 ml) in 4-biphenylsulfonyl chloride (0.76 g, 3.0 mmol) and triethylamine (0.7 ml, 5.0 mm
ol) was added and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure,
Water (100 ml) was added to the residue, and the mixture was extracted with ethyl acetate (200 ml). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 2: 1-1: 1), and N- [5- (4-
{[([1,1'-Biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (1.02g, 66%) was obtained as crystals. .. Mp 179-180 ℃ IRνmax ^KBr cm ^-1: 1698,1537,1337,1159,1096,841 as elemental analysis _{C 37 H 36 N 4 O 3} , Calcd: C, 72.05; H, 5.88 ; N, 9.08 example:. C, 72.06; H, 5.94; N, 9.05 1 H-NMR (CDCl 3) δ: 1.20-2.10 (10H, m), 2.15-2.40 (1H,
m), 4.39 (2H, s), 4.40 (2H, s), 7.10-7.20 (3H, m), 7.39
(2H, d, J = 8.0Hz), 7.40-7.60 (4H, m), 7.60-7.70 (2H, m),
7.76 (2H, d, J = 8.4Hz), 7.75-7.90 (1H, m), 7.90-8.00 (3H,
m), 8.25-8.35 (2H, m), 8.40-8.50 (2H, m).

Example 275 N- [5- (4-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide N- [5- ( 4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexane-carboxamide (1.0 g,
2.50 mmol) in acetonitrile-N, N-dimethylformamide (10 ml-10 ml) solution, 4-phenoxyphenylsulfonyl chloride (0.87 g, 3.25 mmol) and triethylamine (0.7 m
(1, 5.0 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, water (100 ml) was added to the residue, and ethyl acetate (20 ml) was added.
It was extracted with 0 ml). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 2: 1), and N- [5-
(4-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (0.94 g, 59%) was obtained as crystals. Melting point 155-156 ° C. IRν max ^KBr cm ^-1 : 1698,1586,1489,1337,1248,1155,1094,
1086. As Elemental analysis _{C 37 H 36 N 4 O 4} , calcd: C, 72.05; H, 5.88 ; N, 9.08 Example:. C, 72.06; H, 5.94; N, 9.05 1 H-NMR (CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.15-2.40 (1H,
m), 4.35 (2H, s), 4.36 (2H, s), 7.00-7.60 (13H, m), 7.8
0-8.00 (4H, m), 8.20-8.40 (2H, m), 8.40-8.50 (2H, m).

Example 276 N- [5- (4-{[[[[1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} phenyl) -2-
Pyridyl] cyclohexanecarboxamide 4-biphenylcarboxylic acid (0.99g, 5.0mmol) and triethylamine (1.05ml, 7.5mmol) in acetonitrile (30ml) was added diphenylphosphoryl azide (1.18ml, 5.5mmol) and stirred at room temperature for 40 minutes. After that, the mixture was heated to reflux for 1 hour. After cooling, N- [5- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (1.0 g, 2.50 mmol) and N, N-dimethylformamide (2
0 ml) was added and stirred for 1 hour. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (300 ml). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel (chloroform: ethyl acetate =
2: 1-1: 1) and N- [5- (4-{[[([1,1'-biphenyl]-
4-ylamino) carbonyl]-(3-pyridylmethyl) amino]
Methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (1.42 g, 95%) was obtained as crystals. Melting point 225-227 ℃. IRνmax ^KBr cm ^-1 : 3378,1698,1655,1591,1524,1507,1462,
1316,1219,837.Elemental analysis value C ₃₈ H ₃₇ N ₅ O ₂・ 1 / 4H ₂ O, calculated value: C, 76.04; H, 6.30; N, 11.67 Example: C, 76.04; H, 6.14; N, 11.57. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.20-2.40 (1H,
m), 4.62 (2H, s), 4.73 (2H, s), 6.43 (1H, s), 7.20-7.70
(14H, m), 7.70-7.85 (1H, m), 7.91 (1H, dd, J = 8.8,2.0H
z), 7.96 (1H, brs), 8.32 (1H, d, J = 8.4Hz), 8.45-8.55 (1
H, m), 8.55-8.70 (2H, m).

Example 277 N- [5- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide N- [5- ( 4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (2.6g,
4.49 mmol) in N, N-dimethylformamide (30 ml) solution
-Bromophenylsulfonyl chloride (2.16g, 8.44mmol)
And triethylamine (1.81 ml, 13.0 mmol) were added at room temperature.
Stir for 1 hour. Water (100 ml) was added to the reaction mixture and ethyl acetate was added.
It was extracted with (200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 2: 1) to give N- [5- (4-{[[(4-bromophenyl) sulfonyl] (3
-Pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (2.74 g, 68%) was obtained as crystals. Melting point 166-167 ° C. IRνmax ^KBr cm ^-1 : 3326,1686,1526,1514,1159,1084,903. Elemental analysis value C ₃₁ H ₃₁ BrN ₄ O ₃ S, calculated value: C, 60.09; H, 5.04 ; N, 9.04 example:. C, 60.20; H, 4.93; N, 9.00 1 H-NMR (CDCl 3) δ: 1.20-2.10 (10H, m), 2.20-2.40 (1H,
m), 4.36 (4H, s), 7.10-7.25 (3H, m), 7.40 (2H, d, J = 8.4H
z), 7.50-7.60 (1H, m), 7.60-7.80 (4H, m), 7.87 (1H, dd, J
= 8.8,6.2Hz), 7.95 (1H, s), 8.20-8.40 (2H, m), 8.40-8.
55 (2H, m).

Example 278 N- [5- (4-{[{[3 '-(hydroxymethyl) [1,1'-biphenyl]]
-4-yl] sulfonyl} (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide N- [5- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl ) Amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (1.24 g, 2.0 mmol), 3-formylbenzeneboronic acid (0.36 g, 2.4 mmol), tetrakistriphenylphosphine palladium (69.3 mg, 0.06 mmol), carbonic acid Sodium (0.42g, 4.0mmol), toluene (50ml), water (30m
The mixture of l) was heated under reflux for 12 hours under a nitrogen atmosphere. Ethyl acetate (100 ml) was added to remove insolubles, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 2: 1), and N-[5- (4-{[{[3'-
(Formyl) [1,1'-biphenyl] -4-yl] sulfonyl} (3-
Pyridylmethyl) amino] methyl} phenyl) -2-pyridyl]
Cyclohexanecarboxamide (1.10 g, 85%) was obtained as crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.15 (10H, m), 2.15-2.40 (1H,
m), 4.41 (4H, s), 7.10-7.25 (3H, m), 7.41 (2H, d, J = 8.0H
z), 7.55 (1H, d, J = 7.6Hz), 7.60-8.05 (9H, m), 8.15 (1H,
s), 8.25-8.40 (1H, m), 8.40-8.55 (2H, m), 10.12 (1H, s). N-[5- (4-{[{[3 '-(formyl) [1,1 '-Biphenyl] -4-yl] sulfonyl} (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (0.90
Sodium borohydride (110 mg, 2.80 mmol) was added to an ethanol (20 ml) solution of g, 1.4 mmol), and the mixture was stirred for 15 hours. Water (100 ml) was added to the reaction mixture, and ethyl acetate (100 ml x 2) was added.
It was extracted with. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (chloroform: ethyl acetate = 1: 1-chloroform:
After purification with acetone = 2: 1), N- [5- (4-{[{[3 '-(hydroxymethyl) [1,1'-biphenyl] -4-yl] sulfonyl} (3-pyridylmethyl ) Amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (0.42 g, 47%) was obtained as crystals. Melting point 122-124 ° C. IRνmax ^KBr cm ^-1 : 1698,1537,1337,1159,1096,1028,770. Calculated as C ₃₈ H ₃₈ N ₄ O ₄ S: C, 70.56; H, 5.92 N, 8.66 Example: C, 70.30; H, 5.97; N, 8.62. ¹ H-NMR (CHCl ₃ ) δ: 1.15-2.10 (10H, m), 2.15-2.40 (1H,
m), 4.40 (2H, s), 4.45 (2H, s), 7.10-7.25 (3H, m), 7.36
(2H, d, J = 8.0Hz), 7.40-7.70 (5H, m), 7.73 (2H, d, J = 8.4H
z), 7.80-8.00 (4H, m), 8.25-8.43 (3, m), 8.45-8.55 (1H,
m),

Example 279 N- [5- (4-{[[(4-bromoanilino) carbonyl] (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide N- [5- (4 -{[(3-Pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexane-carboxamide (1.23
g, 3.07 mmol) in N, N-dimethylformamide (20 ml) solution, 4-bromophenylisocyanate (0.73 g, 3.69 mmol)
Was added and the mixture was stirred at room temperature for 30 minutes. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: acetone = 2: 1-1: 1) to give N- [5- (4-{[[4-bromoanilino) carbonyl] (3-pyridylmethyl) amino]. Methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (1.
80 g, 91%) was obtained as crystals. Melting point 111-113 ° C. IRν max ^KBr cm ^-1 : 3326,1672,1651,1532,1495,1294,1236,
1204,814. Elemental analysis value C ₃₂ H ₃₂ BrN ₅ O ₂・ 1 / 2C ₆ H ₁₃ calculated value: C, 65.57; H, 6.05; N, 10.92 Example: C, 65.35; H, 6.45; N ^{, 10.72 1 H-NMR (CHCl} 3) δ:. 1.10-2.10 (10H, m), 2.20-2.40 (1H,
m), 4.59 (2H, s), 4.46 (2H, s), 6.37 (1H, s), 7.10-7.45
(7H, m), 7.58 (2H, d, J = 8.4Hz), 7.70-7.80 (1H, m), 7.90
(1H, dd, J = 8.8,2.6Hz), 7.97 (1H, s), 8.31 (1H, d, J = 8.4H
z), 8.48 (1H, d, H = 2.6Hz), 8.55-8.65 (2H, m).

Example 280 N- [5- (4-{[({[3 '-(hydroxymethyl) [1,1'-biphenyl] -4-yl] amino} carbonyl) (3-pyridylmethyl) amino ] Methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (1) N- [5- (4-{[({[3 '-(formyl) [1,1'-biphenyl]-
4-yl] amino} carbonyl) (3-pyridylmethyl) amino]
Methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide N- [5- (4-{[[(4-bromoanilino) carbonyl] (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (1.4 g, 2.34 mmol), 3-formylbenzeneboronic acid (0.42 g, 2.81 mmol), tetrakistriphenylphosphine palladium (81.1 mg, 0.07 mmol), sodium carbonate (0.50 g, 4.68 mmol), toluene (100 ml), water
The mixture of (30 ml) was heated under reflux for 15 hours under a nitrogen atmosphere.
Ethyl acetate (100 ml) was added to remove insolubles, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: acetone = 2: 1-3: 2) to give N- [5- (4-{[({[3'-
(Formyl) [1,1'-biphenyl] -4-yl] amino} carbonyl) (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (0.47g, 32%) was obtained as crystals. It was Melting point 185-187 ° C. IRν max ^KBr cm ^-1 : 1698,1674,1657,1595,1526,1462,1292,
1188.Calculated as elemental analysis value C ₃₉ H ₃₉ N ₅ O ₃ 1 / 2H ₂ O: C, 74.03; H, 6.05; N, 11.07 Example: C, 74.06; H, 6.04; N, 10.85. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.20-2.40 (1H,
m), 4.63 (2H, s), 4.73 (2H, s), 6.46 (1H, s), 7.25-7.50
(7H, m), 7.55 (2H, d, J = 8.4Hz), 7.60 (2H, d, J = 8.0Hz), 7.7
5-8.00 (4H, m), 8.05 (1H, s), 8.32 (1H, d, J = 8.8Hz), 8.45
-8.55 (1H, m), 10.07 (1H, s). (2) N- [5- (4-{[({[3 '-(hydroxymethyl) [1,1'-biphenyl] -4-yl] ] Amino} carbonyl) (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide N- [5- (4-{[({[3 '-(formyl) [1,1'-biphenyl ] -4-yl] amino} carbonyl) (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (0.45g, 0.72mmol) in ethanol-tetrahydrofuran
(10ml-5ml) solution in sodium borohydride (41mg, 1.08m
(mol) was added and stirred for 1 hour. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). Wash the extract with water,
The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: acetone = 3: 2-1: 1) and N- [5- (4-{[({[3 '-(hydroxymethyl) [1,1'- Biphenyl] -4-yl] amino} carbonyl)
(3-Pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (0.28 g, 62%) was obtained as crystals. Melting point 187-190 ° C. IRνmax ^KBr cm ^-1 : 1657,1593,1528,1462,1296,1032,799. Elemental analysis value C ₃₉ H ₃₉ N ₅ O ₃・ 1 / 4H ₂ O, calculated value: C, 74.32; H, 6.32; N, 11.11 example:. C, 74.18; H, 6.20; N, 10.98 1 H-NMR (CHCl 3) δ: 1.15-2.10 (10H, m), 2.20-2.40 (1H,
m), 4.61 (2H, s), 4.72 (2H, s), 4.75 (2H, s), 6.45 (1H,
s), 7.20-7.65 (13H, m), 7.77 (1H, d, J = 8.0Hz), 7.85-7.9
5 (1H, m), 7.96 (1H, s), 8.32 (1H, d, J = 8.8Hz), 8.40-8.50
(1H, m), 8.55-8.65 (2H, m),

Example 281 N- (5- {4-[((3-pyridylmethyl) {[4 '-(trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl} amino) methyl ] Phenyl} -2-pyridyl) cyclohexanecarboxamide N- [5- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (0.926 g, 1.5 mmol), 4-trifluoromethylbenzeneboronic acid (0.34 g, 1.8 mmol), tetrakistriphenylphosphine palladium (52 mg, 0.045
mmol), sodium carbonate (0.32 g, 3.0 mmol), toluene (50
A mixture of water (25 ml) and water (25 ml) was heated under reflux for 4 hours under a nitrogen atmosphere. Ethyl acetate (50 ml) was added and insoluble matter was removed with Celite, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 1: 1) to give N-
(5- {4-[((3-pyridylmethyl) {[4 '-(trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl} amino) methyl] phenyl} -2-pyridyl) Cyclohexanecarboxamide (0.86 g, 84%) was obtained as crystals. Melting point 196-199 ° C. IRνmax ^KBr cm ^-1 : 1698,1329,1161,1128,1071,824. Elemental analysis value C ₃₈ H ₃₅ F ₃ N ₄ O ₃ S, calculated value: C, 66.65; H, 5.15 ; N, 8.18 Found:. C, 66.56; H, 5.00; N, 8.29 1 H-NMR (CDCl 3) δ: 1.20-2.10 (10H, m), 2.20-2.40 (1H,
m), 4.41 (4H, s), 4.42 (2H, s), 7.10-7.25 (3H, m), 7.40
(2H, d, J = 8.0Hz), 7.50-7.60 (1H, m), 7.70-7.90 (6H, m),
7.90-8.05 (4H, m), 8.25-8.40 (2H, m), 8.40-8.55 (2H, m).

Example 282 N- [5- (4-{[[(4'-methoxy [1,1'-biphenyl] -4-yl) sulfonyl] (3-pyridylmethyl) amino] -methyl} phenyl) -2-Pyridyl] cyclohexanecarboxamide N- [5- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (0.926g, 1.5 mmol), 4-methoxybenzeneboronic acid (0.28 g, 1.8 mmol), tetrakistriphenylphosphine palladium (52 mg, 0.045 mmol), sodium carbonate (0.32 g, 3.0 mmol), toluene (50 ml), water (2
The mixture of (5 ml) was heated under reflux for 4 hours under a nitrogen atmosphere. Ethyl acetate (50 ml) was added to remove insoluble matter with Celite, the organic layer was separated, and dried over anhydrous magnesium sulfate,
It was distilled off under reduced pressure. Silica gel chromatography of the residue
Purified with (chloroform: ethyl acetate = 1: 1), N- [5- (4-
{[[(4'-Methoxy [1,1'-biphenyl] -4-yl) -sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexanecarboxamide (0.85g, 88%) Was obtained as a crystal. Melting point 197-200 ° C. IRν max ^KBr cm ^-1 : 1686,1595,1526,1346,1161,1096. Elemental analysis value C ₃₈ H ₃₈ N ₄ O ₄ S, calculated value: C, 70.56; H, 5.92; N , 8.66 Found: C, 70.35; H, 6.10; N, 8.72 ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.20-2.40 (1H,
m), 3.89 (3H, s), 4.38 (2H, s), 4.39 (2H, s), 7.03 (2H, d,
J = 8.8Hz), 7.10-7.20 (3H, m), 7.39 (2H, d, J = 8.0Hz), 7.50
-7.73 (3H, m), 7.72 (2H, d, J = 8.6Hz), 8.83 (1H, dd, J = 8.6,
2.4Hz), 7.90 (1H, s), 7.92 (2H, d, J = 8.6Hz), 8.25-8.35
(2H, m), 8.40-8.50 (2H, m).

Example 283 N- {5- [4-({(3-pyridylmethyl) [(3 ', 4', 5'-trimethoxy [1,1'-biphenyl] -4-yl) sulfonyl]- Amino} methyl) phenyl] -2-pyridyl} cyclohexanecarboxamide N- [5- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -2-pyridyl] cyclohexane Carboxamide (0.67 g, 1.5 mmol), 3,4,5-trimethoxybenzeneboronic acid (0.28 g, 1.30 mmol), tetrakistriphenylphosphine palladium (62 mg, 0.054 mm)
ol), sodium carbonate (0.23 g, 2.6 mmol), toluene (50 m
A mixture of l) and water (30 ml) was heated under reflux for 3 hours under a nitrogen atmosphere. Ethyl acetate (50 ml) was added and insoluble matter was removed with Celite, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: acetone = 1: 1) to give N- {5- [4-
({(3-pyridylmethyl) [(3 ', 4', 5'-trimethoxy [1,1'-
Biphenyl] -4-yl) sulfonyl] amino} methyl) phenyl] -2-pyridyl} cyclohexanecarboxamide (0.85 g,
88%) was obtained as crystals. Melting point 172-173 ° C. IRν max ^KBr cm ^-1 : 3316,1686,1588,1508,1339,1161,1127,
826.Calculated as elemental analysis C ₄₀ H ₄₂ N ₄ O ₆ S: C, 67.97; H, 5.99; N, 7.93 Found: C, 67.78; H, 5.98; N, 7.68 ¹ H-NMR ( CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.20-2.40 (1H,
m), 3.92 (3H, s), 3.95 (6H, s), 4.39 (2H, s), 4.40 (2H,
s), 6.81 (2H, s), 7.17 (2H, d, J = 8.4Hz), 7.10-7.25 (1H,
m), 7.40 (2H, d, J = 8.0Hz), 7.50-7.70 (2H, m), 7.73 (2H,
d, J = 8.4Hz), 7.84 (1H, dd, J = 8.6,2.4Hz), 7.90-8.00 (3H,
m), 8.25-8.40 (2H, m), 8.40-8.50 (2H, m).

Example 284 tert-butyl 5- (4-{[[(4-bromophenyl) sulfonyl]]
(3-Pyridylmethyl) amino] methyl} phenyl) -2-pyridylcarbamate tert-butyl 5- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-pyridylcarbamate (1.95 g, 5.0mmo
4-Bromophenylsulfonyl chloride (1.40 g, 5.49 mmol) and triethylamine (1.39 ml, 10.0 mmol) were added to a solution of l) in N, N-dimethylformamide (10 ml), and the mixture was stirred at room temperature for 1 hour. Water (100 ml) was added to the reaction solution, and ethyl acetate (100 m
It was extracted in l). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 1: 1) to give tert-butyl 5- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl}. Phenyl) -2-pyridyl carbamate (2.37 g, 78%) was obtained as crystals. Mp as 197-199 ° C. (decomposition) Elemental analysis _{C 29 H 29 B r N 4} O 4 S, Calcd:. C, 57.14; H, 4.80; N, 9.19 Found: C, 56.82; H, 4.55 ; ^{. N, 9.05 1 H-NMR} (CDCl 3) δ: 1.55 (9H, s, Bu t), 4.36 (4H, s), 7.05-
7.20 (3H, m), 7.40 (2H, d, J = 8.0Hz), 7.45-7.60 (1H, m),
7.65-7.80 (5H, m), 7.82 (1H, dd, J = 8.8,2.4Hz), 8.01 (1H,
d, J = 8.8Hz), 8.25-8.35 (1H, m), 8.40-8.50 (2H, m).

Example 285 4-{[(4- {6-[(tert-butoxycarbonyl) amino] -3-pyridyl} benzyl) (3-pyridylmethyl) amino] sulfonyl}
-3 ', 4', 5'-Trimethoxy-1,1'-biphenyl tert-butyl 5- (4-{[[(4-bromophenyl) sulfonyl]
(3-Pyridylmethyl) amino] methyl} phenyl) -2-pyridylcarbamate (2.15g, 3.53mmol) and 3,4,5-trimethoxyphenylboronic acid (0.90g, 4.23mmol), tetrakistriphenylphosphine palladium ( 0.12g, 0.11mmol),
Sodium carbonate (0.75 g, 7.05 mmol), toluene (100 ml),
A mixture of water (50 ml) was heated under reflux for 2 hours under a nitrogen atmosphere. Ethyl acetate (50 ml) was added to remove insolubles, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: acetone = 1: 1) to give 4-{[(4- {6-[(tert-butoxycarbonyl) amino] -3-pyridyl} benzyl) (3-pyridyl Methyl) amino] sulfonyl} -3 ′, 4 ′, 5′-trimethoxy-1,1′-biphenyl (2.40 g, 95%) was obtained as crystals. Melting point 194-195 ° C. Elemental analysis value C ₃₈ H ₄₀ N ₄ O ₇ S ・ H ₂ O, calculated value: C, 63.85; H, 5.92; N, 7.84 Found value: C, 63.55; H, 5.63; N ^{, 7.66 1 H-NMR (CDCl} 3) δ:. 1.55 (9H, s, Bu t), 3.92 (3H, s), 3.96 (6
H, s), 4.39 (4H, s), 6.81 (2H, s), 7.10-7.20 (3H, m), 7.3
9 (2H, d, J = 8.4Hz), 7.45-7.60 (2H, m), 7.72 (2H, d, J = 8.4H
z), 7.80 (1H, dd, J = 10.4,2.4Hz), 7.90-8.05 (3H, m), 8.2
8 (1H, br), 8.40-8.50 (2H, m).

Example 286 4- (5-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -2-pyridyl) -N-cyclohexylbenzamide 1) 4- (5-{[(3-Pyridylmethyl) amino] methyl} -2-pyridyl) -N-cyclohexylbenzamide 4- (5-formyl-2-pyridyl) -N-cyclohexylbenzamide (2.81 g, 9.25 mmol) In methanol solution (50 ml) of
-(Aminomethyl) pyridine (1.41 ml, 13.9 mmol), sodium chloride (5 g) and acetic acid (1.6 ml, 27.8 mmol) were sequentially added at room temperature. After stirring at room temperature for 15 minutes, sodium triacetoxyborohydride (2.94 g, 13.9 mmol) was added little by little, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was terminated with saturated multi-layered water, diluted with chloroform, the organic layer was separated, and then washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (from chloroform alone to chloroform: methanol = 30: 1).
-(5-{[(3-pyridylmethyl) amino] methyl} -2-pyridyl)
-N-Cyclohexylbenzamide (2.40 g, 66%) was obtained as colorless crystals. Melting point: 171-172 ℃ ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2 (2
H, m) 3.85 (2H, s) 3.87 (2H, s) 3.90-4.10 (1H, m)
6.13 (1H, d, J = 8.4Hz) 7.24-7.30 (1H, m) 7.68-7.87
(5H, m) 8.05 (2H, d, J = 8.2Hz) 8.52 (1H, d, J = 1.6,
4.8Hz) 8.59-8.66 (1H, m). 2) 4- (5-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-
Pyridylmethyl) amino] methyl} -2-pyridyl) -N-cyclohexylbenzamide 4- (5-{[(3-pyridylmethyl) amino] methyl} -2-pyridyl) -N-cyclohexylbenzamide (1.0g, 2.53mmol )
Triethylamine (0.71 ml, 5.06 mmol) and 4-biphenylsulfonyl chloride (0.96 g, 3.80 mmol) were added to acetonitrile-chloroform solution (10 ml-10 ml) at room temperature, and the mixture was stirred for 30 minutes. After completion of the reaction, the mixture was diluted with chloroform and washed with saturated multistory water and saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (from chloroform alone to chloroform: methanol = 30: 1) and then recrystallized (chloroform-hexane chloroform-hexane) to give 4- (5-{[([1,1, '-Biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -2-pyridyl) -N-cyclohexylbenzamide (1.0 g, 64%) was obtained as pale red crystals. Melting point: 206-207 ℃ Elemental analysis value Calculated as C ₃₇ H ₃₆ N ₄ O ₃ S ・ 0.5H ₂ O: C, 71.01; H, 5.96; N, 8.95 Found: C, 71.12; H, 5.88; N , 8.92 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2 (2
H, m) 4.00 (1H, br) 4.41 (4H, s) 6.05 (1H, d, J = 8.
0Hz) 7.12 (1H, dd, J = 4.8, 7.4Hz) 7.44-7.65 (8H, m)
7.76 (2H, d, J = 8.8Hz) 7.83 (2H, d, J = 8.4Hz) 7.92-
8.00 (4H, m) 8.33-8.36 (2H, m) 8.44 (1H, dd, J = 1.
6, 4.8Hz).

Example 287 4- (5-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} -2-pyridyl) -N-
Cyclohexylbenzamide p-Phenylbenzoic acid (0.66 g, 3.3 mmol) in acetonitrile (10 ml) was added to triethylamine (0.92 ml, 6.6 mmo).
l) and diphenylphosphoric acid azide (0.79 ml, 3.63 mmol) were added at room temperature, and the mixture was heated under reflux for 1 hr. Then, the temperature was returned to room temperature, and 4- (5-{[(3-pyridylmethyl) amino] methyl} -2-pyridyl) -N-cyclohexylbenzamide (0.87 g, 2.2 mmo
l) and chloroform (10 ml) were added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the insoluble matter was filtered through Celite, diluted with chloroform, and washed with saturated multistory water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (from chloroform alone to chloroform: methanol = 30:
After performing 1), the product was purified by recrystallization (chloroform-hexane chloroform-hexane), and then 4- (5-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl )
Amino] methyl} -2-pyridyl) -N-cyclohexylbenzamide (0.28g, 21%) was obtained as colorless crystals. Melting point: 173-174 ℃ Elemental analysis value Calculated as C ₃₈ H ₃₇ N ₅ O ₂・ 0.5H ₂ O: C, 75.47; H, 6.33; N, 11.58 Found: C, 75.87; H, 6.19; N, 11.51 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.0-1.8 (8H, m) 2.0-2.2 (2
H, m) 3.94 (1H, br) 4.69 (4H, s) 7.03 (1H, d, J = 8.
0Hz) 7.30-7.59 (8H, m) 7.70 (1H, d, J = 7.4Hz) 7.77
(2H, s) 7.92 (2H, d, J = 8.4Hz) 8.05 (2H, d, J = 8.4H
z) 8.31 (1H, s) 8.53-8.61 (3H, m).

Example 288 2- (4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexyl-5-pyrimidinecarboxamide 1 ) Ethyl 2- (4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl) pyrimidine-5-carboxylate ethyl 2-{[(3- Pyridylmethyl) amino] methylphenyl} pyrimidine-5-carboxylate (1.11g, 3.19mmol)
Solution of triethylamine (1.3 ml) in acetonitrile (30 ml).
4ml, 9.57mmol) and 4-biphenylsulfonyl chloride
(1.21 g, 4.79 mmol) was added at room temperature, and the mixture was stirred for 30 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated multistory water and saturated saline. After drying over anhydrous magnesium sulfate, filtration,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to hexane: acetone = 2: 1) and purified with ethyl 2- (4-{[([1,1'-biphenyl] -4-ylsulfonyl). ) (3-Pyridylmethyl) amino]
Methyl} phenyl) pyrimidine-5-carboxylate (1.44
g, 80%) was obtained as pale yellow crystals. Melting point: 176-177 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.44 (3H, t, J = 4.8Hz) 4.39-
4.49 (6H, m) 7.14 (1H, dd, J = 3.0, 5.2Hz) 7.21 (2H,
d, J = 5.6Hz) 7.42-7.56 (4H, m) 7.61-7.65 (2H, m) 7.
76 (2H, d, J = 5.6Hz) 7.94 (2H, d, J = 5.8Hz) 8.27 (1
H, d, J = 1.02Hz) 8.36 (2H, d, J = 5.8Hz) 8.44 (1H, dd,
J = 1.0, 3.0Hz) 9.26 (2H, s). 2) 2- (4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-
Pyridylmethyl) amino] methyl} phenyl) -N-cyclohexyl-5-pyrimidinecarboxamidoethyl 2- (4-{[([1,1'-biphenyl] -4-ylsulfonyl)
(3-pyridylmethyl) amino] methyl} phenyl) pyrimidine-5-carboxylate (1.34 g, 2.37 mmol) in ethanol-tetrahydrofuran solution (20 ml-20 ml) in 2N aqueous sodium hydroxide solution (2.5 ml, 5.0 mmol) Was added at room temperature and stirred at 60 ° C. for 2 hours. After the reaction was completed, the organic solvent was distilled off, the aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. Colorless crystals of carboxylic acid (1.17 g,
92%). This product was used for the next reaction as it was without purification. Of this carboxylic acid (1.17g, 2.18mmol)
1-Ethyl-3-in N, N-dimethylformamide suspension (20 ml)
(3-Dimethylaminopropyl) carbodiimide hydrochloride (0.
84g, 4.36mmol), 1-hydroxybenzotriazole monohydrate (0.67g, 4.36mmol), cyclohexylamine (0.50
ml, 4.36 mmol) was added and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(From chloroform only, chloroform: ethyl acetate = 2:
1- 1: 1) and purified by 2- (4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexyl-5 -Pyrimidine carboxamide
(1.14 g, 85%) was obtained as colorless crystals. Melting point: 243-245 ° C Elemental analysis C ₃₆ H ₃₅ N ₅ O ₃ S ・ Calculated as 1 / 4H ₂ O: C, 69.49; H, 5.75; N, 11.25 Found: C, 69.50; H, 5.68; N, 11.25 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.17-1.80 (8H, m) 2.02-2.09
(2H, m) 3.99-4.03 (1H, m) 4.38 (2H, s) 4.43 (2H,
s) 6.08 (1H, d, J = 7.6Hz) 7.44-7.55 (4H, m) 7.60-7.
65 (2H, m) 7.75 (2H, d, J = 8.4Hz) 7.94 (2H, d, J = 8.
4Hz) 8.27-8.35 (3H, m) 8.42-8.44 (1H, m) 9.10 (2H,
s).

Example 289 2- (4-{[(4-phenoxyphenylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexyl-5-
Pyrimidinecarboxamide 1) Ethyl 2- (4-{[(4-phenoxyphenylsulfonyl))
(3-Pyridylmethyl) amino] methyl} phenyl) pyrimidine-5-carboxylate ethyl 2-{[(3-pyridylmethyl) amino] methylphenyl} pyrimidine-5-carboxylate (1.08g, 3.10mmol)
Solution of triethylamine (1.3 ml) in acetonitrile (30 ml).
0 ml, 9.3 mmol) and 4-phenoxybenzenesulfonyl chloride (1.0 g, 3.72 mmol) were added at room temperature, and the mixture was stirred for 30 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated multistory water and saturated saline. After drying over anhydrous magnesium sulfate,
It was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to hexane: acetone = 2: 1) and purified by ethyl 2- (4-{[(4-phenoxyphenylsulfonyl) (3-pyridylmethyl) amino. ] Methyl} phenyl) pyrimidine-5-carboxylate
(1.29 g, 72%) was obtained as pale yellow crystals. Melting point: 161-163 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.44 (3H, t, J = 7.2Hz) 4.35
(2H, s) 4.39 (2H, s) 4.46 (2H, q, J = 7.0Hz) 7.05-7.
27 (7H, m) 7.39-7.47 (3H, m) 7.54 (1H, d, J = 7.6Hz)
7.82 (2H, d, J = 8.8Hz) 8.25 (1H, d, J = 1.8Hz) 8.38
(2H, d, J = 8.0Hz) 8.45 (1H, dd, J = 1.8, 4.6Hz) 9.30
(2H, s). 2) 2- (4-{[(4-phenoxyphenylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexyl-5-pyrimidinecarboxamidoethyl 2- (4- { ((4-phenoxyphenylsulfonyl) (3-
Pyridylmethyl) amino] methyl} phenyl) pyrimidine-
5-carboxylate (1.26 g, 2.17 mmol) ethanol-
To the tetrahydrofuran solution (30 ml-10 ml) was added 2N aqueous sodium hydroxide solution (2.5 ml, 5.0 mmol) at room temperature,
The mixture was stirred at 60 ° C for 2 hours. After the reaction was completed, the organic solvent was distilled off, the aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. Colorless crystals of carboxylic acid (1.10 g, 92
%). This product was used for the next reaction as it was without purification. N, N of this carboxylic acid (1.10g, 1.99mmol)
-Dimethylformamide suspension (20 ml) in 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide hydrochloride (0.77
g, 3.98 mmol), 1-hydroxybenzotriazole monohydrate (0.61 g, 3.98 mmol), cyclohexylamine (0.46 m
l, 3.98 mmol) was added and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(From chloroform only to chloroform: ethyl acetate = 1:
1), further purified by recrystallization (chloroform-hexane), 2- (4-{[(4-phenoxyphenylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexyl-5-pyrimidinecarboxamide (0.99 g, 78%) was obtained as colorless crystals. Melting point: 234-235 ° C Elemental analysis C ₃₆ H ₃₅ N ₅ O ₄ S Calculated: C, 68.23; H, 5.57; N, 11.05 Found: C, 67.94; H, 5.48; N, 11.12 ¹ H- NMR (CDCl ₃ ) δ (ppm) 1.21-1.81 (8H, m) 2.04-2.08
(2H, m) 4.00-4.03 (1H, m) 4.35 (2H, s) 4.39 (2H, m
s) 6.04 (1H, d, J = 5.2Hz) 7.05-7.26 (8H, m) 7.40-7.
45 (2H, m) 7.54 (1H, d, J = 1.2Hz) 7.82 (2H, d, J = 6.
0Hz) 8.25 (1H, d, J = 1.2Hz) 8.34 (2H, d, J = 5.4Hz)
8.44 (1H, dd, J = 8.0, 3.0Hz) 9.11 (2H, s).

Example 290 2- (4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexyl-5-pyrimidine Carboxamide 1) 2- (4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} phenyl) -N-
Cyclohexyl-5-pyridinecarboxamide p-phenylbenzoic acid (0.80 g, 4.02 mmol) in acetonitrile (20 ml) was added to triethylamine (0.85 ml, 6.0
mmol) and diphenylphosphoric acid azide (0.96 ml, 4.4 mmol)
Was added at room temperature, and the mixture was heated under reflux for 1 hr. After that, the temperature was returned to room temperature, and ethyl 2-{[(3-pyridylmethyl) amino] methylphenyl} pyrimidine-5-carboxylate (1.0 g, 2.87 mmol)
Was added and stirred at room temperature for 1 hour. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated multistory water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1 to hexane: acetone =).
2: 1) and further purified by recrystallization (hexane-ethyl acetate) to give 2- (4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] Methyl} phenyl) -N
-Cyclohexyl-5-pyridinecarboxamide (1.36g, 9
0%) was obtained as colorless crystals. Melting point: 189-190 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.44 (3H, t, J = 7.0Hz) 4.50
(2H, q, J = 7.4Hz) 4.65 (2H, s) 4.72 (2H, s) 6.43 (1
H, s) 7.26-7.56 (12H, m) 7.76 (1H, d, J = 7.6Hz) 8.5
4-8.59 (4H, m) 9.32 (2H, s). 2) 2- (4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl } Phenyl) -N-
Cyclohexyl-5-pyrimidinecarboxamide 2- (4-{[[[[1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl) amino] methyl} phenyl) -N-cyclohexyl-5-pyridine Carboxamide (1.30g, 2.39m
(mol) ethanol-tetrahydrofuran solution (10ml-40
2N sodium hydroxide solution (2.5ml, 5.0mm)
ol) was added at room temperature and stirred at 60 ° C. for 2 hours. After completion of the reaction, the organic solvent was distilled off, and the aqueous layer was neutralized with 1N hydrochloric acid,
The precipitated crystals were collected by filtration and washed with water. The carboxylic acid was obtained as colorless crystals (1.10 g, 89%). This product was used for the next reaction as it was without purification. This carboxylic acid (1.10
g, 2.13 mmol) of N, N-dimethylformamide suspension (20
1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.85 g, 4.44 mmol), 1-hydroxybenzotriazole monohydrate (0.68 g, 4.44 mmol), cyclohexylamine (0.51 ml, (4.44 mmol) was added and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the mixture was diluted with chloroform and washed with saturated multistory water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Ether was added to the residue, and the precipitated crystals were collected by filtration and washed with ether and water. The crude crystals were purified by recrystallization and purified by 2- (4-{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-pyridylmethyl)
Amino] methyl} phenyl) -N-cyclohexyl-5-pyrimidinecarboxamide (0.98 g, 77%) was obtained as colorless crystals. Melting point: 230-231 ° C Elemental analysis C ₃₇ H ₃₆ N ₆ O ₂ Calculated: C, 74.47; H, 6.08; N, 14.08 Found: C, 74.29; H, 5.98; N, 13.87 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.18-1.46 (5H, m) 1.69-1.81
(3H, m) 2.04-2.07 (2H, m) 3.99-4.02 (1H, br) 4.63
(2H, s) 4.70 (2H, s) 6.31 (1H, d, J = 5.6Hz) 6.56 (1
H, s) 7.26-7.54 (12H, m) 7.74 (1H, d, J = 5.2Hz) 8.4
9-8.57 (4H, m) 9.11 (2H, s).

Example 291 N- [5- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -2-pyrimidyl] cyclohexanecarboxamide N- [5- ( 4-{[(3-Pyridylmethyl) amino] methyl} phenyl) -2-pyrimidyl] cyclohexanecarboxamide (3.0
g, 7.47mmol) in N, N-dimethylformamide (30ml) solution to 4-bromophenylsulfonyl chloride (2.48g, 9.71mm
ol) and triethylamine (2.45 ml, 17.6 mmol) were added and the mixture was stirred at room temperature for 2 hours. Water (150 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (chloroform: ethyl acetate = 2: 1).
~ 1: 1) and N- [5- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl)
-2-Pyrimidyl] cyclohexanecarboxamide (2.74g,
68%) was obtained as crystals. Melting point 181-182 ℃. IRν max ^KBr cm ^-1 : 1678,1576,1437,1343,1275,1163,1090,
768.Calculated as elemental analysis C ₃₀ H ₃₀ BrN ₅ O ₃ S: C, 58.06; H, 4.87; N, 11.29 Found: C, 58.03; H, 4.81; N, 11.28. ¹ H-NMR ( CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.55-2.75 (1H,
m), 4.35 (2H, s), 4.37 (2H, s), 7.10-7.25 (3H, m), 7.38
(2H, d, J = 8.4Hz), 7.40-7.60 (1H, m), 7.60-7.80 (4H, m),
8.13 (1H, s), 8.20-8.30 (1H, m), 8.46 (1H, dd, J = 4.8,1.6H
z), 8.75 (2H, s).

Example 292 N- [5- (4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-
Pyridylmethyl) amino] methyl} phenyl) -2-pyrimidyl] cyclohexanecarboxamide N- [5- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-pyrimidyl] cyclohexane-carboxamide (0.8
g, 2.0 mmol) in N, N-dimethylformamide (20 ml) was added with 4-biphenylsulfonyl chloride (0.66 g, 2.6 mmol) and triethylamine (0.42 ml, 3.0 mmol) and stirred at room temperature for 1 hour. Water (100 ml) was added to the reaction solution, and ethyl acetate (10 ml
It was extracted with 0 ml × 2). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 2: 1) to give N
-[5- (4-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} phenyl) -2-pyrimidyl]
Cyclohexanecarboxamide (0.81 g, 66%) was obtained as crystals. Melting point 170-172 ° C. IRνmax ^KBr cm ^-1 : 1682,1593,1439,1333,1159,909. Elemental analysis value C ₃₆ H ₃₅ N ₅ O ₃ S, calculated value: C, 69.99; H, 5.71; N , 11.34 Example: C, 69.66; H, 5.63; N, 11.24. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.50-2.80 (1H,
m), 4.39 (2H, s), 4.41 (2H, s), 7.13 (1H, dd, J = 8.8,4.2H
z), 7.21 (2H, d, J = 8.2Hz), 7.37 (2H, d, J = 8.2Hz), 7.42-
7.60 (4H, m), 7.64 (2H, d, J = 8.2Hz), 7.77 (2H, d, J = 8.2H
z), 7.96 (2H, d, J = 8.2Hz), 8.13 (1H, s), 8.40-8.50 (1H,
m), 8.74 (2H, s).

Example 293 N- [5- (4-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -2-pyrimidyl]
Cyclohexanecarboxamide N- [5- (4-{[(3-pyridylmethyl) amino] methyl} phenyl) -2-pyrimidyl] cyclohexanecarboxamide (0.80
g, 2.0 mmol) in N, N-dimethylformamide (10 ml) was added to 4-phenoxyphenylsulfonyl chloride (0.70 g,
2.60 mmol) and triethylamine (0.42 ml, 3.0 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: acetone = 2: 1 to 1: 1) to give N- [5- (4-{[[(4-phenoxyphenyl) sulfonyl]].
-(3-Pyridylmethyl) amino] methyl} phenyl) -2-pyrimidyl] cyclohexanecarboxamide (0.85 g, 85%) was obtained as crystals. Melting point 107-109 ° C. IRν max ^KBr cm ^-1 : 1682,1582,1487,1437,1339,1246,1154. Elemental analysis value C ₃₆ H ₃₅ N ₄ O ₄ S, calculated value: C, 68.23; H, 5.57 N, 11.05 Found: C, 67.91; H, 5.58; N, 10.67. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.10 (10H, m), 2.50-2.75 (1H,
m), 4.34 (2H, s), 4.37 (2H, s), 7.00-7.30 (8H, m), 7.30
-7.60 (5H, m), 7.80-7.90 (2H, m), 8.11 (1H, s), 8.20-8.3
0 (1H, m), 8.45 (1H, dd, J = 4.8,2.0Hz), 8.75 (2H, s).

Example 294 N- (5- {4-[((3-pyridylmethyl) {[4 '-(trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl} amino) methyl ] Phenyl} -2-pyrimidyl) cyclohexanecarboxamide N- [5- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -2-pyrimidyl] cyclohexanecarboxamide (0.824 g, 1.4 mmol), 4-trifluoromethylphenylboronic acid (0.32 g, 1.68 mmol),
Tetrakistriphenylphosphine palladium (49 mg,
A mixture of 0.042 mmol), sodium carbonate (0.30 g, 2.8 mmol), toluene (50 ml) and water (30 ml) was heated under reflux for 10 hours under a nitrogen atmosphere. Ethyl acetate (50 ml) was added to remove insolubles, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: acetone = 2: 1 to 1: 1) to give N- (5-
{4-[((3-pyridylmethyl) {[4 '-(trifluoromethyl)
[1,1'-Biphenyl] -4-yl] sulfonyl} amino) methyl]
Phenyl} -2-pyrimidyl) cyclohexanecarboxamide (0.71 g, 74%) was obtained as crystals. Melting point 184-185 ° C. IRνmax ^KBr cm ^-1 : 1682,1507,1441,1327,1206,1161,1125,
As 1073. Elemental analysis _{C 37 H 34 F 3 N 5} O 3 S, Calculated: C, 64.80; H, 5.00 ; N, 19.21 Found:. C, 64.38; H, 4.94; N, 10.10 1 H- NMR (CDCl ₃ ) δ: 1.20-2.15 (10H, m), 2.50-2.70 (1H,
m), 4.40 (2H, s), 4.43 (2H, s), 7.10-7.20 (1H, m), 7.23
(2H, d, J = 8.4Hz), 7.38 (2H, d, J = 8.0Hz), 7.50-7.60 (1H,
m), 7.70-7.90 (6H, m), 7.99 (2H, d, J = 8.0Hz), 8.07 (1H,
s), 8.26 (1H, s), 8.40-8.50 (1H, m), 8.74 (2H, s).

Example 295 N- {5- [4-({(3-pyridylmethyl) [(3 ', 4', 5'-trimethoxy [1,1'-biphenyl] -4-yl) sulfonyl] amino] } Methyl) phenyl] -2-pyrimidyl} cyclohexanecarboxamide N- [5- (4-{[[(4-bromophenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} phenyl) -2-pyrimidyl] cyclohexanecarboxamide (0.824g, 1.4mmol), 3,4,5-
Trimethoxyphenylboronic acid (0.36 g, 1.68 mmol), tetrakistriphenylphosphine palladium (49 mg, 0.0
42 mmol), sodium carbonate (0.30 g, 2.8 mmol), toluene
A mixture of (50 ml) and water (30 ml) was heated under reflux for 10 hours under a nitrogen atmosphere. After removing insoluble matter by adding ethyl acetate (50 ml), the organic layer was separated and dried over anhydrous magnesium sulfate,
It was distilled off under reduced pressure. Silica gel chromatography of the residue
Purify with (hexane: acetone = 2: 1 to 1: 1) and use N- {5- [4-
({(3-pyridylmethyl)-[(3 ', 4', 5'-trimethoxy [1,1'-
Biphenyl] -4-yl) sulfonyl] amino} methyl) phenyl] -2-pyrimidyl} cyclohexanecarboxamide (0.51
g, 51%) was obtained as crystals. Melting point 200-202 ℃. IRνmax ^KBr cm ^-1 : 3331,1701,1590,1489,1437,1335,1159,
1128,907.Calculated as elemental analysis C ₃₉ H ₄₁ N ₅ O ₆ S: C, 66.18; H, 5.84; N, 9.89 Found: C, 66.17; H, 5.80; N, 9.83 ¹ H- NMR (CDCl ₃ ) δ: 1.20-2.15 (10H, m), 2.55-2.80 (1H,
m), 3.93 (3H, s), 3.96 (6H, s), 4.38 (2H, s), 4.41 (2H,
s), 6.81 (2H, s), 7.14 (1H, dd, J = 7.6,4.4Hz), 7.17 (2H,
d, J = 8.0Hz), 7.38 (2H, d, J = 8.0Hz), 7.50-7.60 (1H, m),
7.74 (2H, d, J = 8.4Hz), 7.95 (2H, d, J = 8.4Hz), 8.17 (1H,
s), 8.20-8.30 (1H, m), 8.40-8.50 (1H, m), 8.75 (2H, s).

Example 296 6- (5-{[([1,1′-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -2-pyridyl) -N-cyclohexylnicotinamide 6 -(5-{[(3-Pyridylmethyl) amino] methyl} -2-pyridyl) -N-cyclohexylnicotinamide (0.38g, 0.95mmo
l) acetonitrile-dichloromethane solution (10 ml-10 m
Triethylamine (0.40 ml, 2.85 mmol) and 4-biphenylsulfonyl chloride (0.36 g, 1.425 mmol) were added to l) at room temperature, and the mixture was stirred at 50 ° C. overnight. Further, triethylamine (0.40 ml, 2.85 mmol) and 4-biphenylsulfonyl chloride (0.36 g, 1.425 mmol) were added at room temperature, and the mixture was stirred for 1 hour. After completion of the reaction, saturated multistory water was added, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: ethyl acetate = 3: 1).
~ 1: 1, chloroform: methanol = 40: 1 ~ 30: 1) and purified by 6- (5-{[([1,1'-biphenyl] -4-ylsulfonyl)
(3-Pyridylmethyl) amino] methyl} -2-pyridyl) -N-cyclohexylnicotinamide (0.40 g, 67%) was obtained as pale yellow crystals. Melting point: 226-227 ℃ Elemental analysis value Calculated as C ₃₆ H ₃₅ N ₅ O ₃ S ・ 0.5H ₂ O: C, 69.49; H, 5.75; N, 11.25 Found value: C, 69.48; H, 5.71; N , 11.25 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.19-1.54 (5H, m) 1.63-1.81
(3H, m) 2.04-2.10 (2H, m) 4.00-4.03 (1H, m) 4.41
(2H, s) 4.43 (2H, s) 6.01 (1H, d, J = 7.6Hz) 7.14 (1
H, dd, J = 4.8, 7.8Hz) 7.44-7.64 (7H, m) 7.76 (2H,
d, J = 8.4Hz) 7.95 (2H, d, J = 8.6Hz) 8.14 (1H, dd, J =
2.2, 8.2Hz) 8.31-8.46 (5H, m) 8.98 (1H, d, J = 2.2H
z).

Example 297 4- (6-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -3-pyridyl) -N-cyclohexylbenzamide 1) Methyl 4- (6-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} -3-pyridyl) benzoate Methyl 4- (6-{[3-pyridyl Methyl] amino} methyl) -3-pyridyl) benzoate (0.63g, 1.89mmol) in acetonitrile solution (15ml) was added to triethylamine (0.79ml, 5.67mm).
ol), 4-biphenylsulfonyl chloride (0.72g, 2.84
mmol) was sequentially added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1 to hexane: acetone = 3: 2 to
Purified with 1: 1) and methyl 4- (6-{[([1,1'-biphenyl]
-4-ylsulfonyl) (3-pyridylmethyl) amino] methyl}
-3-Pyridyl) benzoate (0.91g, 88%) was obtained as pale yellow crystals. Melting point: 153-154 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 3.95 (3H, s) 4.54, 4.55 (4
H, each s) 7.12-7.16 (1H, m) 7.36 (1H, d, J = 5.6Hz)
7.43-7.74 (11H, m) 7.89 (2H, d, J = 5.8Hz) 8.10 (2
H, d, J = 5.8Hz) 8.40 (1H, d, J = 1.2Hz) 8.42 (1H, dd,
J = 4.2Hz) 8.57-8.58 (1H, m). 2) 4- (6-{[([1,1'-biphenyl] -4-ylsulfonyl) (3-
Pyridylmethyl) amino] methyl} -3-pyridyl) -N-cyclohexylbenzamidomethyl 4- (6-{[([1,1'-biphenyl] -4-ylsulfonyl)
(3-Pyridylmethyl) amino] methyl} -3-pyridyl) benzoate (0.78g, 1.41mmol) in methanol-tetrahydrofuran solution (5ml-20ml) with 2N aqueous sodium hydroxide solution (1.5ml, 3.0mmol) at room temperature Then, the mixture was stirred at 50 ° C. for 2 hours. After the reaction was completed, the organic solvent was distilled off, the aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. Carboxylic acid (0.70 g, 92%) was obtained as colorless crystals. This product was used for the next reaction as it was without purification.
To this suspension of carboxylic acid (0.70g, 1.30mmol) in N, N-dimethylformamide (10ml) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.50g, 2.60mmo).
l), 1-hydroxybenzotriazole monohydrate (0.40 g,
2.6mmol), cyclohexylamine (0.23ml, 1.95mmol)
Was added and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform: methanol = 30: 1) and then recrystallized (hexane-ethyl acetate) to give 4- (6-{[([1,1'-biphenyl] -4- Ilsulfonyl) (3-pyridylmethyl) amino] methyl} -3-pyridyl) -N-cyclohexylbenzamide (0.65 g, 81%) was obtained as colorless crystals. Melting point: 190-193 ℃ Elemental analysis value Calculated as C ₃₇ H ₃₆ N ₄ O ₃ S ・ 0.5H ₂ O: C, 71.01; H, 5.96; N, 8.95 Found: C, 71.04; H, 5.85; N , 8.87 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.20-1.52 (5H, m) 1.67-1.80
(3H, m) 2.04-2.07 (2H, m) 4.02 (1H, br) 4.54, 4.5
5 (4H, each s) 6.00 (1H, d, J = 5.8Hz) 7.13 (1H, dd,
J = 3.4, 5.2Hz) 7.40-7.53 (5H, m) 7.57-7.72 (6H, m)
7.81 (2H, d, J = 5.6Hz) 7.88 (2H, d, J = 5.8Hz) 8.40-
8.43 (2H, m) 8.55 (1H, d, J = 1.2Hz).

Example 298 N-Cyclohexyl-4- (6-{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -3-pyridyl) benzamide 1) Methyl 4- (6- {[[(4-phenoxyphenyl) sulfonyl]
(3-Pyridylmethyl) amino] methyl} -3-pyridyl) benzoate methyl 4- (6-{[3-pyridylmethyl] amino} methyl) -3-pyridyl) benzoate (0.56g, 1.68mmol) in acetonitrile ( 15ml) with triethylamine (0.71ml, 5.04mm
ol), 4-phenoxybenzenesulfonyl chloride (0.6
8 g, 2.52 mmol) were added in that order, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate,
The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1 to hexane: acetone = 1: 1.
1) and methyl 4- (6-{[[(4-phenoxyphenyl)
Sulfonyl] (3-pyridylmethyl) amino] methyl} -3-pyridyl) benzoate (0.84 g, 88%) was obtained as pale yellow crystals. Melting point: 117-118 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) 3.95 (3H, s) 4.49, 4.50 (4
H, each s) 7.00-7.08 (4H, m) 7.14 (1H, dd, J = 2.6,
4.6Hz) 7.35-7.43 (3H, m) 7.55-7.65 (3H, m) 7.71-7.
80 (3H, m) 8.11-8.15 (2H, m) 8.36 (1H, d, J = 1.0Hz)
8.42 (1H, dd, J = 1.2, 3.2Hz) 8.60-8.61 (1H, m). 2) N-cyclohexyl-4- (6-{[(4-phenoxyphenyl)
Sulfonyl] (3-pyridylmethyl) amino] methyl} -3-pyridyl) benzamidomethyl 4- (6-{[[(4-phenoxyphenyl) sulfonyl] (3
-Pyridylmethyl) amino] methyl} -3-pyridyl) benzoate (0.72g, 1.27mmol) in methanol-tetrahydrofuran solution (5ml-10ml) was added 2N sodium hydroxide solution (1.3ml, 2.6mmol) at room temperature. The mixture was stirred at 50 ° C for 2 hours. After the reaction was completed, the organic solvent was distilled off, the aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. Carboxylic acid (0.66 g, 94%) was obtained as colorless crystals.
This product was used for the next reaction as it was without purification. This carboxylic acid (0.66g, 1.20mmol) in N, N-dimethylformamide suspension (10ml) in 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.46g, 2.4mmol), 1-
Hydroxybenzotriazole monohydrate (0.37g, 2.4mm
ol) and cyclohexylamine (0.21 ml, 1.80 mmol) were added and the mixture was stirred at room temperature for 27 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform: methanol = 30: 1) and recrystallized (hexane-ethyl acetate), and N-cyclohexyl-4- (6-
{[[(4-phenoxyphenyl) sulfonyl] (3-pyridylmethyl) amino] methyl} -3-pyridyl) benzamide (0.63
g, 83%) was obtained as colorless crystals. Melting point: 182-183 ° C Elemental analysis C ₃₇ H ₃₆ N ₄ O ₄ S ・ Calculated as 0.5H ₂ O: C, 69.24; H, 5.81; N, 8.73 Found: C, 69.00; H, 5.66; N , 8.71 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.20-1.47 (5H, m) 1.65-1.80
(3H, m) 2.04-2.07 (2H, m) 4.01 (1H, br) 4.48 (2H, m)
s) 4.50 (2H, s) 6.02 (1H, d, J = 5.6Hz) 7.01-7.07
(4H, m) 7.12-7.16 (1H, m) 7.20-7.25 (1H, m) 7.26-
7.43 (3H, m) 7.56 (2H, d, J = 5.6Hz) 7.62 (1H, dt, J =
1.4, 5.4Hz) 7.78 (2H, d, J = 5.8Hz) 7.86 (2H, d, J = 6.
6Hz) 8.36 (1H, d, J = 1.4Hz) 8.42 (1H, dd, J = 1.0, 3.
2Hz) 8.58 (1H, d, J = 1.0Hz).

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/381 A61K 31/381 4C206 31/4402 31/4402 4H006 31/4406 31/4406 31/4409 31 / 4409 31/443 31/443 31/4436 31/4436 31/444 31/444 31/455 31/455 31/506 31/506 A61P 1/18 A61P 1/18 3/04 3/04 3/06 3 / 06 3/10 3/10 5/14 5/14 5/50 5/50 7/02 7/02 9/00 9/00 9/06 9/06 9/10 9/10 101 101 9/12 9 / 12 9/14 9/14 13/12 13/12 19/10 19/10 25/00 25/00 25/28 25/28 27/02 27/02 43/00 111 43/00 111 C07C 231/02 C07C 231/02 235/50 235/50 273/18 273/18 275/30 275/30 275/34 275/34 275/40 275/40 303/38 303/38 311/18 311/18 C07D 213/40 C07D 213/40 213/42 213/42 213/75 213/75 213/82 213/82 307/52 307/52 333/20 333/20 401/12 401/12 405/12 405/12 409/12 409 / 12 (72) Inventor Makoto Kobayashi 7-5-5 Kasugadai, Nishi-ku, Kobe-shi, Hyogo Prefecture F-reference (reference) 4C023 CA02 4C037 HA27 4C055 AA01 BA01 BA02 BA06 BA28 BA52 BA53 BB01 BB04 BB16 BB17 CA01 CA02 CA06 CA28 CA58 CB02 CB03 CB17 DA01 CB06 DA01 CB06 DA01 CB06 DA28 DB17 EA01 FA15 FA32 FA37 4C063 AA01 BB07 BB09 CC29 CC75 CC92 DD12 EE01 4C086 AA01 AA02 AA03 AA04 BC17 BC19 BC42 GA02 GA04 GA07 GA08 MA01 MA04 NA14 ZA02 ZA15 ZA16 ZA33 ZA36 ZA40 ZA44 ZA45 ZA54 ZA70 ZA81 ZA97 ZC02 ZC33 ZC35 4C206 AA04 GA07 GA28 HA30 JA13 KA01 MA01 MA04 MA12 MA13 NA14 ZA02 ZA15 ZA16 ZA33 ZA36 ZA40 ZA44 ZA45 ZA54 ZA70 ZA81 ZA97 ZC02 ZC33 ZC35 4H006 AA01 AA02 AA03 AB23 AB27 AC53 AC57 AC61

Claims (41)

[Claims] 1. A formula (I) [Chemical 1] [In the formula, each of the A ring and the B ring may be substituted.
Represents a 5- or 6-membered aromatic ring, R¹And R²Is that
Hydrogen atom, an optionally substituted hydrocarbon group or
A heterocyclic group which may be substituted, X¹, X², X³Oh
And X^FourEach may be a bond or may be substituted
Represents a divalent hydrocarbon group, Y is -NR³-CO-, -C
O-NR³-, -NR³-SO₂-, -SO₂-NR³-,
-NR³-CH ₂-, -CH₂-NR³-, -O-CO-N
R³-Or-NR³’-NR³-CO- (R³and
R³′ Is a hydrogen atom or carbon atom which may be substituted.
A hydrogen group or an optionally substituted heterocyclic group)
, Z is -CO-NH-, -CS-NH-, -CO-.
Or -SO₂Indicates-, and Ar may be substituted
A cyclic hydrocarbon group or an optionally substituted heterocyclic group
Show. However, the atom next to the atom of the A ring that is bonded to the B ring is
Unsubstituted; and Y is -CO-NR³-, -SO₂-N
R³-Or-CH₂-NR³-Is X²Is a bond, X³
Is a bond or methylene, and Z is -CO-NH-
When showing, R¹-X¹-Y- is a dialkylamino group and
Not a protected amino group. ] Or a compound represented by
Its salt. 2. The compound according to claim 1, wherein R ¹ is an optionally substituted C _3-8 cycloalkyl group. 3. The compound according to claim 1, wherein R ¹ is an optionally substituted cyclohexyl group. 4. The compound according to claim 1, wherein X ¹ is a bond or a C _1-6 alkylene group. 5. The compound according to claim 1, wherein X ¹ is a bond. 6. The compound according to claim 1, wherein Y is —NR ³ —CO—, —CO—NR ³ — or —NR ³ —CH ₂ — (R ³ has the same meaning as in claim 1). . 7. The compound according to claim 1, wherein X ² is a bond or a C _1-6 alkylene group. 8. The compound according to claim 1, wherein X ² is a bond. 9. The compound according to claim 1, wherein X ³ is a bond or a C _1-6 alkylene group. 10. The compound according to claim 1, wherein X ³ is a methylene group. 11. The compound according to claim 1, wherein X ⁴ is a bond or a C _1-6 alkylene group. 12. The compound according to claim 1, wherein X ⁴ is a methylene group. 13. The compound according to claim 1, wherein Z is —CO—NH—. 14. The compound according to claim 1, wherein Z is —SO ₂ —. 15. The compound according to claim 1, wherein R ² is an optionally substituted aromatic hydrocarbon group or an optionally substituted aromatic heterocyclic group. 16. The compound according to claim 1, wherein Ar is an optionally substituted aromatic hydrocarbon group or an optionally substituted aromatic heterocyclic group. 17. The compound according to claim 1, wherein ring A is a benzene ring which may be substituted. 18. The compound according to claim 1, wherein ring B is an optionally substituted benzene ring. 19. The compound according to claim 1, wherein ring A and ring B are optionally substituted benzene rings. 20. The compound according to claim 1, wherein ring A is an optionally substituted 6-membered nitrogen-containing aromatic heterocycle. 21. The compound according to claim 1, wherein ring B is an optionally substituted 6-membered nitrogen-containing aromatic heterocycle. 22. The compound according to claim 1, wherein ring A and ring B are optionally substituted 6-membered nitrogen-containing aromatic heterocycles. 23. The compound according to claim 20, wherein the 6-membered nitrogen-containing aromatic heterocycle is a pyridine ring or a pyrimidine ring. 24. Formula (I ') [Chemical 2] [In the formula, each of the A ring and the B ring may be substituted.
Represents a 5- or 6-membered aromatic ring (provided that it is bonded to the B ring)
The atom next to the atom of ring A is unsubstituted. ), R ¹And
And R²Are hydrogen atoms and carbon atoms that may be substituted.
A hydrogen group or an optionally substituted heterocyclic group, X
^{1 '}Is a bond, X^{2 '}Is a bond or C_{1- 6}Arche
X group, X^{3 '}Is C_1-6Represents an alkylene group, X^Four'Is
Bond or C _1-6Represents an alkylene group, Y'is -NR³
-CO- (R³Is a hydrogen atom, optionally substituted carbonization
A hydrogen group or an optionally substituted heterocyclic group)
, Z is -CO-NH-, -CS-NH-, -CO-.
Or -SO₂Indicates-, and Ar may be substituted
A cyclic hydrocarbon group or an optionally substituted heterocyclic group
[Shown] or a salt thereof. 25. Formula (I ″) [Chemical 3] [In the formula, each of the A ring and the B ring may be substituted.
Represents a 5- or 6-membered aromatic ring (provided that it is bonded to the B ring)
The atom next to the atom of ring A is unsubstituted. ), R ¹And
And R²Are hydrogen atoms and carbon atoms that may be substituted.
A hydrogen group or an optionally substituted heterocyclic group, X
^{1 '}Is a bond, X^{2 '}Is a bond or C_{1- 6}Arche
X group, X^{3 '}Is C_1-6Represents an alkylene group, X^Four'Is
Bond or C _1-6Represents an alkylene group, and Y ″ is —CO
-NR³-(R³Is a hydrogen atom, optionally substituted carbonization
A hydrogen group or an optionally substituted heterocyclic group)
, Z is -CO-NH-, -CS-NH-, -CO-.
Or -SO₂Indicates-, and Ar may be substituted
A cyclic hydrocarbon group or an optionally substituted heterocyclic group
Compound] (where X is^{2 ''}Is a bond, X
^{3 ''}Is methylene and Z is -CO-NH-.
Come, R¹-X^{1 '}-Y- is not a protected amino group. )
Or its salt. 26. Formula (I "") [Chemical 4] [In the formula, W represents CH or N, and R^{1 '''}Has been replaced
Represents a hydrocarbon group which may be present, R^{2 '''}Has been replaced
Represents a heterocyclic group, X^{1 '''}Is a bond or C _1-6A
Represents a alkylene group, X^{2 '''}Is a bond, X^{3 '}Is C
_1-6Represents an alkylene group, X^Four'''Is C_1-6Alkylene group
Show, Y^'''Represents -CO-NH-, Z^'''Is -SO₂
-Indicates Ar^'''Is an optionally substituted cyclic hydrocarbon
Or a salt thereof. 27. 4-[(Cyclohexylamino) methyl] -4'-
[((3-Pyridylmethyl) {[4- (trifluoromethyl) anilino] carbonyl} amino) methyl] -1,1'-biphenyl, 4-
{[[([1,1'-biphenyl] -4-ylamino) carbonyl] (3-
Pyridylmethyl) amino] methyl} -4 '-[(cyclohexylamino) methyl] -1,1'-biphenyl, N-({4'-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4 -Yl} methyl) -N- (2-pyridyl) -4- (trifluoromethyl) benzenesulfonamide, N-({4 '-[(cyclohexylamino) methyl] [1,1'-biphenyl] -4- Ill} methyl) -N- (3-pyridylmethyl) -4- (2-thienyl) benzamide, N-cyclohexyl-4 '-[((3-pyridylmethyl) {[4- (trifluoromethyl)
Anilino] carbonyl} amino) methyl] [1,1'-biphenyl] -4-carboxamide, 4 '-{[[[[1,1'-biphenyl] -4-
Ilamino) carbonyl] (3-pyridylmethyl) amino] methyl} -N-cyclohexyl [1,1'-biphenyl] -4-carboxamide, N- (4 '-{[([1,1'-biphenyl] -4 -Ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) cyclohexanecarboxamide, N- (4'-
{[([1,1'-biphenyl] -4-ylsulfonyl) (3-pyridylmethyl) amino] methyl} [1,1'-biphenyl] -4-yl) -2-
[2- (trifluoromethyl) phenyl] acetamide, N-
[4 '-({(3-pyridylmethyl) [(3', 4 ', 5'-trimethoxy [1,
1'-biphenyl] -4-yl) sulfonyl] amino} methyl) [1,
1'-biphenyl] -4-yl] -2- [2- (trifluoromethyl) phenyl] acetamide, 4- (5-{[([1,1'-biphenyl] -4-
(Ilsulfonyl) (3-pyridylmethyl) amino] methyl} -2-
The compound according to claim 1, which is pyridyl) -N-cyclohexylbenzamide or a salt thereof. 28. A prodrug of the compound according to claim 1 or a salt thereof. 29. A pharmaceutical composition comprising the compound according to claim 1, a salt thereof, or a prodrug thereof. 30. The composition according to claim 29 which is a low density lipoprotein receptor enhancer. 31. The composition according to claim 29, which is a lipid lowering agent. 32. (1) Hyperlipidemia, (2) Atherosclerosis,
30. The composition according to claim 29, which is (3) a diabetic complication associated with hyperlipidemia or arteriosclerosis, or (4) a prophylactic / therapeutic agent for hypertensive complication associated with hyperlipidemia or arteriosclerosis. 33. Formula (II): [Each symbol in the formula has the same meaning as in claim 1. ] A compound or a salt thereof represented by the reaction with an isocyanate,
A compound of formula (I), characterized in that it is subjected to a reaction with an isothiocyanate, an acylation reaction or a sulfonylation reaction [Each symbol in the formula has the same meaning as in claim 1. ] The manufacturing method of the compound or its salt represented by these. 34. Formula (III): [Each symbol in the formula has the same meaning as in claim 1. ] The compound represented by the formula or a salt thereof is subjected to an acylation reaction, a sulfonylation reaction or an alkylation reaction, and is represented by the formula (Ia): [In formula, Ya is -O-CO-NR < ³ >-, -CO-NR.
^3- , —SO ₂ —NR ³ — or —CH ₂ —NR ³ — (R ³ has the same meaning as in claim 1), and other symbols have the same meaning as in claim 1. ] The manufacturing method of the compound or its salt represented by these. 35. Formula (IV) [Chemical 9] [Each symbol in the formula has the same meaning as in claim 1. ]
Compound or salt thereof and formula R¹-X¹-NH-R³Well
Or R¹-X¹-NR³’-NH-R³[Each symbol in the formula is a contract
It has the same meaning as in claim 1. ] Or a compound represented by
Formula (Ib) characterized by reacting the salt [Chemical 10] [In the formula, Yb is -NR³-CO- or -NR³’-NR
³-CO- (R³And R ³'Has the same meaning as in claim 1.
Show. ), And other symbols have the same meaning as in claim 1.
Indicates. ] The manufacturing method of the compound or its salt represented by these. 36. A method for increasing low density lipoprotein receptor in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal. 37. A method for lowering lipids in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal. 38. An effective amount of the compound according to claim 1 or a salt thereof is administered to a mammal, (1) hyperlipidemia, (2) arteriosclerosis, (3) hypertension in the mammal. A method for preventing and / or treating diabetic complications associated with lipemia or arteriosclerosis or (4) hypertensive complications associated with hyperlipidemia or arteriosclerosis. 39. Use of the compound according to claim 1 or a salt thereof for the manufacture of a low density lipoprotein receptor-increasing drug. 40. Use of the compound according to claim 1 or a salt thereof for the manufacture of a lipid lowering drug. 41. (1) Hyperlipidemia, (2) Atherosclerosis,
The compound according to claim 1 for producing a prophylactic / therapeutic drug for (3) diabetic complications associated with hyperlipidemia or arteriosclerosis or (4) hypertensive complications associated with hyperlipidemia or arteriosclerosis Use of that salt.