JPH09194457A - Urea derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a urea derivative having an excellent acyl coenzyme, cholesterol acyltransferase-inhibiting activity and useful as an active ingredient for medicines used for preventing and/or treating hyperlipemia and atherosclerosis. SOLUTION: A compound of formula I [R1 -R3 are each independently H, hydroxyl, a 1-3C alkoxy, etc.; R4 is a 1-7C alkyl, a 3-7C cycloalkyl, etc.; R5 , R6 are each independently H, a 1-3C alkyl, etc.; Y is a 1-3C alkyl, a 6-10C aryl, etc.; (k) is an integer of 1-3; (l) is an integer of 2-4] or its salt, or their hydrates or solvates. N- 5-(1-imidazolyl)-2-methoxyphenyl}methyl-N-(1-pentyl)-N '-[2- 3-(4-phenyl-1-piperazdinyl)propoxy}-6-methylphenyl]urea is especially preferable as the component. The compound of formula I is obtained by converting an aniline derivative of formula II into a reactive intermediate of formula III (Z is a halogen, etc.,) and subsequently reacting the compound of formula III with an amine derivative of formula IV.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel urea derivative useful as an active ingredient of a drug used for the prevention and / or treatment of diseases such as hyperlipidemia and arteriosclerosis.

[0002]

2. Description of the Related Art Hyperlipidemia due to abnormal lipid metabolism is considered to be a cause of arteriosclerosis, and is also considered to be a risk factor for diseases such as ischemic heart disease and cerebral infarction. At present, blood cholesterol is mainly reduced as a drug treatment for hyperlipidemia and arteriosclerosis, but there is currently no drug that can be expected to prevent formation and regression of atherosclerotic lesions themselves . Recently, it has been revealed that acyl coenzyme cholesterol acyltransferase (ACAT) plays an important role in lipid metabolism, particularly cholesterol metabolism. A compound having an inhibitory activity of the enzyme ACAT lowers cholesterol in blood by inhibiting cholesterol absorption in the intestinal tract and suppressing production of very low density lipoprotein (VLDL) from the liver. Furthermore, in the arterial wall, since foaming of macrophages is inhibited and deposition of cholesterol ester is inhibited, formation of atherosclerotic lesions and regression can be expected.

[0003] Urea derivatives having ACAT inhibitory activity are disclosed in JP-A-5-9179 and JP-A-5-32666.
JP, JP-A-5-132463, JP-A-5-15-1
40102, JP-A-5-170727, JP-A-5-194475, JP-A-5-208948
JP-A-5-310678, JP-A-5-310678
39223, JP-A-5-923950, JP-A-6-172288, JP-A-6-247923
JP-A-6-263736, JP-A-6-3637
No. 40647, JP-A-7-2782, JP-A-7-33660, JP-A-5-508654, JP-A-6-50995, and JP-A-6-501
No. 252, etc.

[0004]

The present invention relates to the enzyme ACA
It is an object of the present invention to provide a compound which has a stronger inhibitory effect on T and can exert a blood cholesterol lowering effect and a macrophage foaming suppressing effect. Another object of the present invention is to include a compound having the above characteristics as an active ingredient, and prevent and / or treat hyperlipidemia,
Another object of the present invention is to provide a medicament useful for preventing and / or treating atherosclerosis. Still another object of the present invention is to provide a highly safe drug having the above characteristics.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted ingenious research to achieve the above-mentioned objects, and as a result, novel urea derivatives and salts thereof having extremely strong inhibitory activity against the macrophage enzyme ACAT. The present invention has been completed and the present invention has been completed.

That is, the present invention provides the following general formula (I):

Embedded image [In the general formula (I), R ₁ , R ₂ and R ₃ are each independently a hydrogen atom, a hydroxyl group, a C ₁ -C ₃ alkoxy group, Het- (CH ₂ ) _m- O- (Het Represents a heterocyclic residue having 1 to 2 nitrogen atoms and a total number of atoms of 5 to 6, and m represents an integer of 1 to 3), a C _{7 to} C ₉ aralkyloxy group, or a nitrogen atom. Represents a heterocyclic residue having 1 to 4 total atoms and having 5 to 6 atoms, and R ₁ and R ₂ together form —O— (CH ₂ ) _n —O— (n is 1 to 3). It represents an integer). R ₄ is a C ₁ -C ₇ alkyl group, a C ₃ -C ₇ cycloalkyl group, Ar- (CH
_{2) p} - (Ar represents an aryl group of C ₆ ~C _10, p represents represents) an integer of 1 to 3.. R ₅ and R ₆ each independently represent a hydrogen atom or a C ₁ -C ₃ alkyl group, but when R ₅ and R ₆ are taken together, — (CH ₂ ) _q —
(Q represents an integer of 3 to 5) may be represented. Y is C
_{It represents a 1 to} C ₃ alkyl group, a heterocyclic residue containing 1 to 4 nitrogen atoms and having a total of 5 to 6 atoms, or a C _{6 to} C ₁₀ aryl group. k represents an integer of 1 to 3, and l represents an integer of 2 to 4. ] The compound or its salt represented by these, or those hydrates or solvates are provided.

According to a preferred embodiment of the above invention, (1) R ₁ , R ₂ and R ₃ are each independently a hydrogen atom, a hydroxyl group, a C ₁ -C ₃ alkoxy group, He.
_{t- (CH 2) m -O- (} Het is a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group,
Pyrimidinyl group, pyridazinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group,
It represents a pyrazolidinyl group, a pyrazolinyl group, a piperidyl group, or a piperazinyl group, and m represents an integer of 1 to 3. ), Phenyl- (C ₁ -C ₃ ) alkoxy group, pyrrolyl group, imidazolyl group, pyrazolyl group, pyridyl group,
Pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group, triazolidinyl group, triazolyl group, triazinyl group, tetrazolyl group, or tetrazinyl group, or tetrazinyl group But when R ₁ and R ₂ come together-
_{O- (CH 2) n -O- (} n is an integer of 1-3.)
R ₄ may represent: C ₁ -C ₇ alkyl group, C ₃
Cycloalkyl group -C _7, or Ar- (CH _{2) p} -
(Ar represents a phenyl group, a tolyl group, or a naphthyl group, and p represents an integer of 1 to 3); R ₅ and R
Each ₆ independently represents a hydrogen atom or a C ₁ -C ₃ alkyl group, but when R ₅ and R ₆ are taken together,-(CH
₂ ) _q- (q represents an integer of 3 to 5); Y is a C _{1 to} C ₃ alkyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group,
Pyrimidinyl group, pyridazinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group,
Pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group, triazolidinyl group, triazolyl group,
Represents a triazinyl group, a tetrazolyl group, a tetrazinyl group, a phenyl group, a tolyl group, or a naphthyl group; k is 1 to
Represents an integer of 3 and 1 represents an integer of 2 to 4; or a hydrate or solvate thereof, characterized in that the above compound or salt thereof;

(2) R ₁ , R ₂ and R ₃ are each independently a hydrogen atom, a hydroxyl group, a C ₁ -C ₃ alkoxy group, Het- (CH ₂ ) _m -O- (Het is a pyridyl group. , M represents an integer of 1 to 3), phenyl-
Represents a (C ₁ -C ₃ ) alkoxy group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, or a triazolyl group.
₁ and R ₂ together form -O- (CH ₂ ) _n -O- (n
Represents an integer of 1 to 3. ) May be represented; R ₄ is C ₁
Alkyl group -C _7, cycloalkyl group C ₃ -C _7,
Or _{Ar- (CH 2) p - (} Ar represents a phenyl group,
p represents an integer of 1 to 3. R ₅ and R ₆ each independently represent a hydrogen atom or a C ₁ -C ₃ alkyl group, but when R ₅ and R ₆ are taken together, — (CH ₂ )
_q- (q represents an integer of 3 to 5) may be represented; Y
Represents a C _{1 to} C ₃ alkyl group, a pyridyl group, or a phenyl group; k represents an integer of 1 to 3 and l represents an integer of 2 to 4; Or a hydrate or solvate thereof;

(3) R ₁ , R ₂ and R ₃ are each independently a hydrogen atom, a C ₁ -C ₃ alkoxy group, Het-
(CH _{2) m} -O- (Het represents a 2-pyridyl, 3-pyridyl, or 4-pyridyl group, m represents 1.) Phenylmethyl group, 1-pyrrolyl group, 1
Represents an imidazolyl group, a 1-pyrazolyl group, or a 1-triazolyl group, wherein R ₁ and R ₂ together form -O-
(CH _{2) n} -O- _(n is 1.) May represent; R ₄ is an alkyl group of C ₁ -C _7, cyclopentyl, or _{Ar- (CH 2) p - (} Ar is phenyl Represents a group, p represents 1 or 3); R ₅ is C ₁ -C.
₃ represents an alkyl group, R ₆ represents a hydrogen atom, but R ₅
And R ₆ together _{- (CH 2) q - (} . Q is representative of the 4) may represent a; Y represents a 2-pyridyl group or a phenyl group; k represents 1 or 2, l Represents 3;
The above compound or salt thereof, or a hydrate or solvate thereof;

(4) At least 1 of R ₁ , R ₂ and R ₃
One is _{Het- (CH 2) m -O- (} Het represents a 2-pyridyl group or 3-pyridyl group, m represents 1.),
Represents a 1-imidazolyl group or 1-triazolyl group; R ₄ represents an n-propyl group, an n-pentyl group, a cyclopentyl group, or Ar- (CH ₂ ) _p- (Ar represents a phenyl group, p represents 1 or R ₅ represents a methyl group, R ₆ represents a hydrogen atom, and R ₅ and R ₆
There together _{- (CH 2) q - (} . Q is representative of the 4) may represent a; Y represents a phenyl group; k is 1 or 2
And 1 represents 3; or the above compound or a salt thereof, or a hydrate or solvate thereof; and (5) N- {5- (1-imidazolyl) -2- Methoxyphenyl} methyl-N- (1-pentyl) -N '-[2-
There is provided the above compound or a salt thereof, which is {3- (4-phenyl-1-piperazinyl) propoxy} -6-methylphenyl] urea, or a hydrate or solvate thereof.

According to another aspect of the present invention, a medicament comprising the above compound or a salt thereof, or a hydrate or solvate thereof; and the above compound or a salt thereof, or a hydrate thereof or There is provided a pharmaceutical composition comprising a solvate and a pharmaceutically acceptable carrier.
As a preferred embodiment of the above medicine, an antihyperlipidemic agent containing the above compound or salt thereof, or a hydrate or solvate thereof as an active ingredient; the above compound or salt thereof, or a hydrate or solvate thereof. Anti-arteriosclerotic agent containing a substance as an active ingredient; the above compound or a salt thereof,
Or a cholesterol lowering agent containing a hydrate or solvate thereof as an active ingredient; and a neutral fat lowering agent containing the above compound or a salt thereof, or a hydrate or solvate thereof as an active ingredient, respectively. To be done. Use of the above compound or a salt thereof, or a hydrate or solvate thereof for the production of each of these pharmaceutical compositions is also provided as one aspect of the present invention.

According to another aspect of the present invention, there is provided a method for preventing and / or treating hyperlipidemia, which is a substance selected from the group consisting of the above compounds and salts thereof, hydrates and solvates thereof. And a method for preventing and / or treating arteriosclerosis, which comprises the step of administering an effective amount of the above to a hyperlipidemic patient, which comprises the above compound and salts thereof, and hydrates and solvates thereof. A method comprising the step of administering an effective amount of a substance selected from the group to a patient with arteriosclerosis; a method for preventing and / or treating hypercholesterolemia, the compound and salts thereof, and hydrates and solvents thereof. A method comprising the step of administering an effective amount of a substance selected from the group consisting of Japanese products to a patient with hypercholesterolemia; and a method for preventing and / or treating high neutral steatosis, which comprises the compound and a salt thereof, and So How an effective amount of a substance comprising the step of administering to the patient a high triglyceride disease selected from the group consisting of hydrates and solvates of al is provided respectively.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (I), R ₁ , R ₂
Examples of the C ₁ -C ₃ alkoxy group for R ₃ and R ₃ include a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group. A methoxy group is particularly preferred. As the C _{7 to} C ₉ aralkyloxy group,
Examples thereof include a benzyloxy group, a phenethyloxy group and a phenylpropyloxy group, and preferably phenyl- (C
₁ -C ₃₎ alkoxy group, and more preferred are phenylmethyl group. Examples of the heterocyclic residue having 1 to 4 nitrogen atoms and having 5 to 6 total atoms include a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrrolidinyl group, a pyrrolinyl group and an imidazolidinyl group. Group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group, triazolidinyl group, triazolyl group, triazinyl group, tetrazolyl group, tetrazinyl group and the like. Of these, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, or a triazolyl group is preferable, more preferably a 1-pyrrolyl group, a 1-imidazolyl group, a 1-pyrazolyl group, or a 1-triazolyl group, and particularly preferably 1 -Imidazolyl group or 1-triazolyl group. Heterocyclic residue having 1 to 2 nitrogen atoms and having 5 to 6 total atoms, which is defined by "Het", has 1 to 2 nitrogen atoms among the above heterocyclic residues. Is mentioned. Of these, a pyridyl group is preferable, and a 2-pyridyl group or a 3-pyridyl group is particularly preferable.
It is a pyridyl group.

Examples of the C ₁ -C ₇ alkyl group for R ₄ include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group,
sec-butyl group, n-pentyl group, isopentyl group,
Examples thereof include sec-pentyl group, neopentyl group, n-hexyl group, isohexyl group, n-heptyl group, and the like, and particularly preferred is n-propyl group or n-pentyl group. Examples of the cycloalkyl group C ₃ -C _7, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and cycloheptyl group, and particularly preferred is cyclopentyl. C defined by Ar
Examples of the aryl group ₆ -C _10, phenyl group, a tolyl group, a naphthyl group, preferably a phenyl group.

[0015] The alkyl group of C ₁ -C ₃ in R ₅ and R _6, include those of the inner C ₁ -C ₃ alkyl group described above. Particularly preferred is a methyl group.
The alkyl group of C ₁ -C ₃ in the Y, are mentioned those of the inner C ₁ -C ₃ alkyl groups mentioned above, particularly preferred is a methyl group. Examples of the heterocyclic residue having 1 to 4 nitrogen atoms and having a total atom number of 5 to 6 include the same heterocyclic residues as described above, preferably a pyridyl group, more preferably 2-pyridyl. It is a base. C _{6 to} C ₁₀
Examples of the aryl group include the same aryl group as described above, and a phenyl group is preferable.

In the present invention, R ₁ and R ₂ may together represent -O- (CH ₂ ) _n -O- (n represents an integer of 1 to 3), in which case , N is more preferably 1. R ₄ is Ar- (CH ₂ ) _p- (A
r is as described above, and p represents an integer of 1 to 3. Is more preferably p represents 1 or 3. R ₅ and R ₆ together form-(CH ₂ ) _q
-(Q represents an integer of 3 to 5) may be represented, but in that case, it is more preferable that q represents 4. Further, k is more preferably 1 or 2, and l is 3
Is more preferable. Furthermore, in the present invention, at least one of R ₁ , R ₂ and R ₃ is Het-
(CH _{2) m} -O- (Het is 2-pyridyl or 3
Represents a pyridyl group, and m represents 1. ), A 1-imidazolyl group, or a 1-triazolyl group is a particularly preferred compound.

The preferred compound ranges in the present invention are as follows. (1) R ₁ , R ₂ and R ₃ are each independently a hydrogen atom, a hydroxyl group, a C ₁ -C ₃ alkoxy group,
_{Het- (CH 2) m -O- (} Het represents a pyridyl group, m is an integer of 1-3.), Phenyl - (C ₁ ~
C ₃ ) represents an alkoxy group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, or a triazolyl group, and R ₁ and R ₂
There together _{-O- (CH 2) n -O- (} n is 1-3
Represents an integer. ) May be represented; R ₄ is a C ₁ -C ₇ alkyl group, a C ₃ -C ₇ cycloalkyl group, or A
_{r- (CH 2) p - (} Ar represents phenyl group, p is 1
Represents an integer of 3; R ₅ and R ₆ each independently represent a hydrogen atom or a C ₁ -C ₃ alkyl group, but when R ₅ and R ₆ are taken together, — (CH ₂ ) _q —
(Q represents an integer of 3 to 5); Y represents C
Alkyl group of ₁ -C _3, represents a pyridyl group or a phenyl group,; k is an integer of 1 to 3, l is an integer of 2-4.

The range of more preferable compounds in the present invention is as follows. (2) R ₁ , R ₂ and R ₃ are each independently a hydrogen atom, a C ₁ -C ₃ alkoxy group, Het- (CH
₂ ) _m- O- (Het represents a 2-pyridyl group, a 3-pyridyl group, or a 4-pyridyl group, m represents 1), a phenylmethyloxy group, a 1-pyrrolyl group, a 1-imidazolyl group, It represents a 1-pyrazolyl group or a 1-triazolyl group, but R ₁ and R ₂ together form -O- (CH ₂ ) _n.
-O- (n represents 1) may be represented; R ₄ is C ₁
To C ₇ alkyl group, cyclopentyl group, or Ar-
_{(CH 2) p - (.} Ar represents a phenyl group, p is representative of a 1 or 3) represents a; R ₅ represents an alkyl group of C ₁ -C _3, but R ₆ represents a hydrogen atom, R ₅ and R ₆ together _{- (CH 2) q - (} . q is representative of the 4) may represent a; Y represents a 2-pyridyl group or a phenyl group; k
Represents 1 or 2 and l represents 3.

The ranges of particularly preferable compounds in the present invention are as follows. (3) At least one of R ₁ , R ₂ and R ₃ is He
_{t- (CH 2) m -O- (} Het represents a 2-pyridyl group or 3-pyridyl group, m represents 1.) represents a 1-imidazolyl group or a 1-triazolyl group,; R ₄ is n -Propyl group, n-pentyl group, cyclopentyl group,
Or _{Ar- (CH 2) p - (} Ar represents phenyl group, p is representative of 1 or 3.) Represents the; represents R ₅ is a methyl group, but R ₆ represents a hydrogen atom, R ₅ and R ₆ together - (CH _{2) q} - may also represent a (. q representing a 4); Y represents a phenyl group; represents a k is 1 or 2,
l represents 3. Specific examples thereof include (4) N- {5- (1-imidazolyl) -2-methoxyphenyl} methyl-N- (1-pentyl) -N '-[2
Examples thereof include-{3- (4-phenyl-1-piperazyl) propoxy} -6-methylphenyl] urea or a salt thereof, or a hydrate or solvate thereof.

The compounds of the present invention represented by the above formula (I) are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, It is also possible to form a salt with an organic acid such as fumaric acid, maleic acid, oxalic acid, citric acid, benzoic acid, toluenesulfonic acid and methanesulfonic acid. Further, the compound of the present invention or a salt thereof may form a hydrate, and thus methanol, ethanol, isopropanol, acetone,
In some cases, a solvate may be formed with a solvent such as ethyl acetate or methylene chloride, and all of these substances are included in the scope of the present invention.

Specific examples of the compound represented by formula (I) of the present invention are shown in Table 1 below. In the table, for the phenyl ring substituted by R ₁ , R ₂ and R ₃ in the compound (I), the kind of the substituent on the ring and the substitution position [1- (CH ₂ ) _k − is the 1-position. , And the structure is shown. Further, in the tables, Ph represents a phenyl group, benzyl represents a benzyl group _{(-CH 2 -C 6 H 5)} . R ₁ ,
2-OC for the phenyl ring substituted by R ₂ and R ₃
H ₂ O-3 means that a 2,3-methylenedioxy group is substituted on the phenyl group, and R ⁵ and R
About ⁶ - (CH _{2) 4} - shall be deemed to be replaced with, R ₅ and R ₆ together - (CH _{2) 4} - indicates that forms a. Furthermore, -O-CH ₂ -2-Py and imidazo
Notations such as lyl represent the following specific substituents.

Embedded image

[0022]

Embedded image

[Table 1] ─────────────────────────────────── R on the phenyl ring ₁ , R _Two , R _Three Position R _Four R _Five R ₆ Y kl 2-position 3-position 4-position 5-position ────────────────────────────────────- imidazolyl HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -imidazolyl HHH -CH (CH _Three ) _Two -CH _Three H -Ph 1 2 -imidazolyl HHH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 -imidazolyl HHH -CH _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 2 -imidazolyl HHH -C (CH _Three ) _Three -CH _Three H -Ph 1 2 -imidazolyl HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -imidazolyl HHH-(CH _Two ) _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 2 -imidazolyl HHH -CH _Two C (CH _Three ) _Three -CH _Three H -Ph 1 2 -imidazolyl HHH-(CH _Two ) _Five CH _Three -CH _Three H -Ph 1 2 -imidazolyl HHH-(CH _Two ) ₆ CH _Three -CH _Three H -Ph 1 2 H -imidazolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 H -imidazolyl HH -CH (CH _Three ) _Two -CH _Three H -Ph 1 2 H -imidazolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 H -imidazolyl HH -CH _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 2 H -imidazolyl HH -C (CH _Three ) _Three -CH _Three H -Ph 1 2 H -imidazolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 H -imidazolyl HH-(CH _Two ) _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 2 H -imidazolyl HH -CH _Two C (CH _Three ) _Three -CH _Three H -Ph 1 2 H -imidazolyl HH-(CH _Two ) _Five CH _Three -CH _Three H -Ph 1 2 H -imidazolyl HH-(CH _Two ) ₆ CH _Three -CH _Three H -Ph 1 2 HH -imidazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 HH -imidazolyl H -CH (CH _Three ) _Two -CH _Three H -Ph 1 2 HH -imidazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 HH -imidazolyl H -CH _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 2 HH -imidazolyl H -C (CH _Three ) _Three -CH _Three H -Ph 1 2 HH -imidazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 HH -imidazolyl H-(CH _Two ) _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 2 HH -imidazolyl H -CH _Two C (CH _Three ) _Three -CH _Three H -Ph 1 2 HH -imidazolyl H-(CH _Two ) _Five CH _Three -CH _Three H -Ph 1 2 HH -imidazolyl H-(CH _Two ) ₆ CH _Three -CH _Three H -Ph 1 2 -imidazolyl HH -OCH _Three -(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -imidazolyl HH -OCH _Three -(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 -imidazolyl HH -OCH _Three -(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl -CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl -CH _Two CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl -CH (CH _Three ) _Two -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl -CH _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl -C (CH _Three ) _Three -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl-(CH _Two ) _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl -CH _Two C (CH _Three ) _Three -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl-(CH _Two ) _Five CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl -benzyl -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H -CH _Three -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H -CH _Two CH _Three -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H -CH (CH _Three ) _Two -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H -CH _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H -C (CH _Three ) _Three -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H-(CH _Two ) _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H -CH _Two C (CH _Three ) _Three -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H-(CH _Two ) _Five CH _Three -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H -benzyl -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H-CH _Three -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H-CH _Two CH _Three -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H-CH (CH _Three ) _Two -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H-CH _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H -C (CH _Three ) _Three -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H-(CH _Two ) _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H-CH _Two C (CH _Three ) _Three -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H-(CH _Two ) _Five CH _Three -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H -benzyl -CH _Three H -Ph 1 2 -imidazolyl HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -imidazolyl HHH -CH (CH _Three ) _Two -CH _Three H -Ph 1 3 -imidazolyl HHH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 -imidazolyl HHH -CH _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 3 -imidazolyl HHH -C (CH _Three ) _Three -CH _Three H -Ph 1 3 -imidazolyl HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -imidazolyl HHH-(CH _Two ) _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 3 -imidazolyl HHH -CH _Two C (CH _Three ) _Three -CH _Three H -Ph 1 3 -imidazolyl HHH-(CH _Two ) _Five CH _Three -CH _Three H -Ph 1 3 -imidazolyl HHH-(CH _Two ) ₆ CH _Three -CH _Three H -Ph 1 3 H -imidazolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 H -imidazolyl HH -CH (CH _Three ) _Two -CH _Three H -Ph 1 3 H -imidazolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 H -imidazolyl HH -CH _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 3 H -imidazolyl HH -C (CH _Three ) _Three -CH _Three H -Ph 1 3 H -imidazolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 H -imidazolyl HH-(CH _Two ) _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 3 H -imidazolyl HH -CH _Two C (CH _Three ) _Three -CH _Three H -Ph 1 3 H -imidazolyl HH-(CH _Two ) _Five CH _Three -CH _Three H -Ph 1 3 H -imidazolyl HH-(CH _Two ) ₆ CH _Three -CH _Three H -Ph 1 3 HH -imidazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 HH -imidazolyl H -CH (CH _Three ) _Two -CH _Three H -Ph 1 3 HH -imidazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 13 HH -imidazolyl H -CH _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 3 HH -imidazolyl H -C (CH _Three ) _Three -CH _Three H -Ph 1 3 HH -imidazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 HH -imidazolyl H-(CH _Two ) _Two CH (CH _Three ) _Two -CH _Three H -Ph 13 HH -imidazolyl H -CH _Two C (CH _Three ) _Three -CH _Three H -Ph 1 3 HH -imidazolyl H-(CH _Two ) _Five CH _Three -CH _Three H -Ph 1 3 HH -imidazolyl H-(CH _Two ) ₆ CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H -CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H -CH _Two CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H -CH (CH _Three ) _Two -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H -CH _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H -C (CH _Three ) _Three -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H-(CH _Two ) _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H -CH _Two C (CH _Three ) _Three -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H-(CH _Two ) _Five CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H -benzyl -CH _Three H -Ph 1 3 -imidazolyl HH -OCH _Three -(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -imidazolyl HH -OCH _Three -(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 -imidazolyl HH -OCH _Three -(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl -CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl -CH _Two CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl -CH (CH _Three ) _Two -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl -CH _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl -C (CH _Three ) _Three -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl-(CH _Two ) _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl -CH _Two C (CH _Three ) _Three -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl-(CH _Two ) _Five CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl -benzyl -CH _Three H -Ph 1 3 H -imidazolyl -OCH _Three H-CH _Three -CH _Three H -Ph 1 3 H -imidazolyl -OCH _Three H-CH _Two CH _Three -CH _Three H -Ph 1 3 H -imidazolyl -OCH _Three H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 H -imidazolyl -OCH _Three H-CH (CH _Three ) _Two -CH _Three H -Ph 1 3 H -imidazolyl -OCH _Three H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 H -imidazolyl -OCH _Three H-CH _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 3 H -imidazolyl -OCH _Three H -C (CH _Three ) _Three -CH _Three H -Ph 1 3 H -imidazolyl -OCH _Three H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 H -imidazolyl -OCH _Three H-(CH _Two ) _Two CH (CH _Three ) _Two -CH _Three H -Ph 1 3 H -imidazolyl -OCH _Three H-CH _Two C (CH _Three ) _Three -CH _Three H -Ph 1 3 H -imidazolyl -OCH _Three H-(CH _Two ) _Five CH _Three -CH _Three H -Ph 1 3 H -imidazolyl -OCH _Three H -benzyl -CH _Three H -Ph 1 3 -imidazolyl HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -imidazolyl HHH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 -imidazolyl HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 H -imidazolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 H -imidazolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 H -imidazolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 HH -imidazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 HH -imidazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 HH -imidazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -imidazolyl HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -imidazolyl HHH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 -imidazolyl HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 H -imidazolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 H -imidazolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 H -imidazolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 HH -imidazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 HH -imidazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 HH -imidazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 H -OCH _Three -imidazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 H -OCH _Three -imidazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 H -OCH _Three -imidazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 H -OCH _Three -imidazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 H -OCH _Three -imidazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 H -OCH _Three -imidazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -imidazolyl HH -OCH _Three -(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -imidazolyl HH -OCH _Three -(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 -imidazolyl HH -OCH _Three -(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 -imidazolyl HH -OCH _Three -(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -imidazolyl HH -OCH _Three -(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 -imidazolyl HH -OCH _Three -(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -OCH _Three HH -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -OCH _Three HH -imidazolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 -OCH _Three HH -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 -OCH _Three HH -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -OCH _Three HH -imidazolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 -OCH _Three HH -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 H -imidazolyl -OCH _Three H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 H -imidazolyl -OCH _Three H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 H -imidazolyl -OCH _Three H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 H -imidazolyl -OCH _Three H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 H -imidazolyl -OCH _Three H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 H -imidazolyl -OCH _Three H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -imidazolyl HHH -cyclobutyl -CH _Three H -Ph 1 2 -imidazolyl HHH -cyclopentyl -CH _Three H -Ph 1 2 -imidazolyl HHH -cyclohexyl -CH _Three H -Ph 12 H -imidazolyl HH -cyclobutyl -CH _Three H -Ph 1 3 H -imidazolyl HH -cyclopentyl -CH _Three H -Ph 1 3 H -imidazolyl HH -cyclohexyl -CH _Three H -Ph 13 HH -imidazolyl H -cyclobutyl -CH _Three H -Ph 1 2 HH -imidazolyl H -cyclopentyl -CH _Three H -Ph 1 2 HH -imidazolyl H -cyclohexyl -CH _Three H -Ph 12 HH -imidazolyl H -cyclobutyl -CH _Three H -Ph 1 3 HH -imidazolyl H -cyclopentyl -CH _Three H -Ph 1 3 HH -imidazolyl H -cyclohexyl -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl -cyclobutyl -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl -cyclopentyl -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl -cyclohexyl -CH _Three H -Ph 1 2 -OCH _Three HH -imidazolyl -cyclobutyl -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl -cyclopentyl -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl -cyclohexyl -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -imidazolyl -cyclobutyl -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -imidazolyl -cyclopentyl -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -imidazolyl -cyclohexyl -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -imidazolyl -cyclobutyl -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -imidazolyl -cyclopentyl -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -imidazolyl -cyclohexyl -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -imidazolyl -cyclobutyl -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -imidazolyl -cyclopentyl -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -imidazolyl -cyclohexyl -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -imidazolyl -cyclobutyl -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -imidazolyl -cyclopentyl -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -imidazolyl -cyclohexyl -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H -cyclobutyl -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H -cyclopentyl -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H -cyclohexyl -CH _Three H -Ph 1 2 H -OCH _Three -imidazolyl H -cyclobutyl -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H -cyclopentyl -CH _Three H -Ph 1 3 H -OCH _Three -imidazolyl H -cyclohexyl -CH _Three H -Ph 1 3 -imidazolyl HHH -cyclobutyl -CH _Three H -Ph 2 2 -imidazolyl HHH -cyclopentyl -CH _Three H -Ph 2 2 -imidazolyl HHH -cyclohexyl -CH _Three H -Ph 2 2 H -imidazolyl HH -cyclobutyl -CH _Three H -Ph 2 3 H -imidazolyl HH -cyclopentyl -CH _Three H -Ph 2 3 H -imidazolyl HH -cyclohexyl -CH _Three H -Ph 2 3 HH -imidazolyl H -cyclobutyl -CH _Three H -Ph 2 2 HH -imidazolyl H -cyclopentyl -CH _Three H -Ph 2 2 HH -imidazolyl H -cyclohexyl -CH _Three H -Ph 2 2 HH -imidazolyl H -cyclobutyl -CH _Three H -Ph 2 3 HH -imidazolyl H -cyclopentyl -CH _Three H -Ph 2 3 HH -imidazolyl H -cyclohexyl -CH _Three H -Ph 2 3 H -imidazolyl -OCH _Three H -cyclobutyl -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H -cyclopentyl -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H -cyclohexyl -CH _Three H -Ph 1 2 H -imidazolyl -OCH _Three H -cyclobutyl -CH _Three H -Ph 1 3 H -imidazolyl -OCH _Three H -cyclopentyl -CH _Three H -Ph 1 3 H -imidazolyl -OCH _Three H -cyclohexyl -CH _Three H -Ph 1 3 -OCH _Three HH -imidazolyl -cyclobutyl -CH _Three H -Ph 2 2 -OCH _Three HH -imidazolyl -cyclopentyl -CH _Three H -Ph 2 2 -OCH _Three HH -imidazolyl -cyclohexyl -CH _Three H -Ph 2 2 -OCH _Three HH -imidazolyl -cyclobutyl -CH _Three H -Ph 2 3 -OCH _Three HH -imidazolyl -cyclopentyl -CH _Three H -Ph 2 3 -OCH _Three HH -imidazolyl -cyclohexyl -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -imidazolyl -cyclobutyl -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -imidazolyl -cyclopentyl -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -imidazolyl -cyclohexyl -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -imidazolyl -cyclobutyl -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -imidazolyl -cyclopentyl -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -imidazolyl -cyclohexyl -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -imidazolyl -cyclobutyl -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -imidazolyl -cyclopentyl -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -imidazolyl -cyclohexyl -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -imidazolyl -cyclobutyl -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -imidazolyl -cyclopentyl -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -imidazolyl -cyclohexyl -CH _Three H -Ph 2 3 H -OCH _Three -imidazolyl H -cyclobutyl -CH _Three H -Ph 2 2 H -OCH _Three -imidazolyl H -cyclopentyl -CH _Three H -Ph 2 2 H -OCH _Three -imidazolyl H -cyclohexyl -CH _Three H -Ph 2 2 H -OCH _Three -imidazolyl H -cyclobutyl -CH _Three H -Ph 2 3 H -OCH _Three -imidazolyl H -cyclopentyl -CH _Three H -Ph 2 3 H -OCH _Three -imidazolyl H -cyclohexyl -CH _Three H -Ph 2 3 H -imidazolyl -OCH _Three H -cyclobutyl -CH _Three H -Ph 2 2 H -imidazolyl -OCH _Three H -cyclopentyl -CH _Three H -Ph 2 2 H -imidazolyl -OCH _Three H -cyclohexyl -CH _Three H -Ph 2 2 H -imidazolyl -OCH _Three H -cyclobutyl -CH _Three H -Ph 2 3 H -imidazolyl -OCH _Three H -cyclopentyl -CH _Three H -Ph 2 3 H -imidazolyl -OCH _Three H -cyclohexyl -CH _Three H -Ph 2 3 -pyrazolyl HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -pyrazolyl HHH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 -pyrazolyl HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 H -pyrazolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 H -pyrazolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 H -pyrazolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 HH -pyrazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 HH -pyrazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 HH -pyrazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -pyrazolyl HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -pyrazolyl HHH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 -pyrazolyl HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 H -pyrazolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 H -pyrazolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 H -pyrazolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 HH -pyrazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 HH -pyrazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 HH -pyrazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -pyrazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 H -OCH _Three -pyrazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 H -OCH _Three -pyrazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 H -OCH _Three -pyrazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -pyrazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -pyrazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -pyrazolyl HH -OCH _Three -(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -pyrazolyl HH -OCH _Three -(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 -pyrazolyl HH -OCH _Three -(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -pyrazolyl HH -OCH _Three -(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -pyrazolyl HH -OCH _Three -(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 -pyrazolyl HH -OCH _Three -(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -pyrazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -pyrazolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -pyrazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -pyrazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -pyrazolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -pyrazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 H -pyrazolyl -OCH _Three H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 H -pyrazolyl -OCH _Three H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 H -pyrazolyl -OCH _Three H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 H -pyrazolyl -OCH _Three H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 H -pyrazolyl -OCH _Three H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 H -pyrazolyl -OCH _Three H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -pyrazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -pyrazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -pyrazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -pyrazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -pyrazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -pyrazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -pyrazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -pyrazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -pyrazolyl HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -pyrazolyl HHH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 -pyrazolyl HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 H -pyrazolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 H -pyrazolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 H -pyrazolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 HH -pyrazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 HH -pyrazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 HH -pyrazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 -pyrazolyl HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -pyrazolyl HHH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 -pyrazolyl HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 H -pyrazolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 H -pyrazolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 H -pyrazolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 HH -pyrazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 HH -pyrazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 HH -pyrazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 H -OCH _Three -pyrazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 H -OCH _Three -pyrazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 H -OCH _Three -pyrazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 H -OCH _Three -pyrazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 H -OCH _Three -pyrazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 H -OCH _Three -pyrazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -pyrazolyl HH -OCH _Three -(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -pyrazolyl HH -OCH _Three -(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 -pyrazolyl HH -OCH _Three -(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 -pyrazolyl HH -OCH _Three -(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -pyrazolyl HH -OCH _Three -(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 -pyrazolyl HH -OCH _Three -(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -pyrazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -pyrazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -pyrazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -pyrazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -pyrazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -pyrazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -pyrazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -pyrazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -OCH _Three HH -pyrazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -OCH _Three HH -pyrazolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 -OCH _Three HH -pyrazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 -OCH _Three HH -pyrazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -OCH _Three HH -pyrazolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 -OCH _Three HH -pyrazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 H -pyrazolyl -OCH _Three H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 H -pyrazolyl -OCH _Three H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 H -pyrazolyl -OCH _Three H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 H -pyrazolyl -OCH _Three H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 H -pyrazolyl -OCH _Three H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 H -pyrazolyl -OCH _Three H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -pyrazolyl HHH -cyclobutyl -CH _Three H -Ph 1 2 -pyrazolyl HHH -cyclopentyl -CH _Three H -Ph 1 2 -pyrazolyl HHH -cyclohexyl -CH _Three H -Ph 1 2 H -pyrazolyl HH -cyclobutyl -CH _Three H -Ph 1 2 H -pyrazolyl HH -cyclopentyl -CH _Three H -Ph 1 2 H -pyrazolyl HH -cyclohexyl -CH _Three H -Ph 1 2 HH -pyrazolyl H -cyclobutyl -CH _Three H -Ph 1 2 HH -pyrazolyl H -cyclopentyl -CH _Three H -Ph 1 2 HH -pyrazolyl H -cyclohexyl -CH _Three H -Ph 1 2 -pyrazolyl HHH -cyclobutyl -CH _Three H -Ph 1 3 -pyrazolyl HHH -cyclopentyl -CH _Three H -Ph 1 3 -pyrazolyl HHH -cyclohexyl -CH _Three H -Ph 1 3 H -pyrazolyl HH -cyclobutyl -CH _Three H -Ph 1 3 H -pyrazolyl HH -cyclopentyl -CH _Three H -Ph 1 3 H -pyrazolyl HH -cyclohexyl -CH _Three H -Ph 1 3 HH -pyrazolyl H -cyclobutyl -CH _Three H -Ph 1 3 HH -pyrazolyl H -cyclopentyl -CH _Three H -Ph 1 3 HH -pyrazolyl H -cyclohexyl -CH _Three H -Ph 1 3 H -OCH _Three -pyrazolyl H -cyclobutyl -CH _Three H -Ph 1 2 H -OCH _Three -pyrazolyl H -cyclopentyl -CH _Three H -Ph 1 2 H -OCH _Three -pyrazolyl H -cyclohexyl -CH _Three H -Ph 1 2 H -OCH _Three -pyrazolyl H -cyclobutyl -CH _Three H -Ph 1 3 H -OCH _Three -pyrazolyl H -cyclopentyl -CH _Three H -Ph 1 3 H -OCH _Three -pyrazolyl H -cyclohexyl -CH _Three H -Ph 1 3 -pyrazolyl HH -OCH _Three -cyclobutyl -CH _Three H -Ph 1 2 -pyrazolyl HH -OCH _Three -cyclopentyl -CH _Three H -Ph 1 2 -pyrazolyl HH -OCH _Three -cyclohexyl -CH _Three H -Ph 1 2 -pyrazolyl HH -OCH _Three -cyclobutyl -CH _Three H -Ph 1 3 -pyrazolyl HH -OCH _Three -cyclopentyl -CH _Three H -Ph 1 3 -pyrazolyl HH -OCH _Three -cyclohexyl -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -pyrazolyl -cyclobutyl -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -pyrazolyl -cyclopentyl -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -pyrazolyl -cyclohexyl -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -pyrazolyl -cyclobutyl -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -pyrazolyl -cyclopentyl -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -pyrazolyl -cyclohexyl -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -pyrazolyl -cyclobutyl -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -pyrazolyl -cyclopentyl -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -pyrazolyl -cyclohexyl -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -pyrazolyl -cyclobutyl -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -pyrazolyl -cyclopentyl -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -pyrazolyl -cyclohexyl -CH _Three H -Ph 1 3 -OCH _Three HH -pyrazolyl -cyclobutyl -CH _Three H -Ph 1 2 -OCH _Three HH -pyrazolyl -cyclopentyl -CH _Three H -Ph 1 2 -OCH _Three HH -pyrazolyl -cyclohexyl -CH _Three H -Ph 1 2 -OCH _Three HH -pyrazolyl -cyclobutyl -CH _Three H -Ph 1 3 -OCH _Three HH -pyrazolyl -cyclopentyl -CH _Three H -Ph 1 3 -OCH _Three HH -pyrazolyl -cyclohexyl -CH _Three H -Ph 1 3 H -pyrazolyl -OCH _Three H -cyclobutyl -CH _Three H -Ph 1 2 H -pyrazolyl -OCH _Three H -cyclopentyl -CH _Three H -Ph 1 2 H -pyrazolyl -OCH _Three H -cyclohexyl -CH _Three H -Ph 1 2 H -pyrazolyl -OCH _Three H -cyclobutyl -CH _Three H -Ph 1 3 H -pyrazolyl -OCH _Three H -cyclopentyl -CH _Three H -Ph 1 3 H -pyrazolyl -OCH _Three H -cyclohexyl -CH _Three H -Ph 1 3 -pyrazolyl HHH -cyclobutyl -CH _Three H -Ph 2 2 -pyrazolyl HHH -cyclopentyl -CH _Three H -Ph 2 2 -pyrazolyl HHH -cyclohexyl -CH _Three H -Ph 2 2 H -pyrazolyl HH -cyclobutyl -CH _Three H -Ph 2 2 H -pyrazolyl HH -cyclopentyl -CH _Three H -Ph 2 2 H -pyrazolyl HH -cyclohexyl -CH _Three H -Ph 2 2 HH -pyrazolyl H -cyclobutyl -CH _Three H -Ph 2 2 HH -pyrazolyl H -cyclopentyl -CH _Three H -Ph 2 2 HH -pyrazolyl H -cyclohexyl -CH _Three H -Ph 2 2 -pyrazolyl HHH -cyclobutyl -CH _Three H -Ph 2 3 -pyrazolyl HHH -cyclopentyl -CH _Three H -Ph 2 3 -pyrazolyl HHH -cyclohexyl -CH _Three H -Ph 2 3 H -pyrazolyl HH -cyclobutyl -CH _Three H -Ph 2 3 H -pyrazolyl HH -cyclopentyl -CH _Three H -Ph 2 3 H -pyrazolyl HH -cyclohexyl -CH _Three H -Ph 2 3 HH -pyrazolyl H -cyclobutyl -CH _Three H -Ph 2 3 HH -pyrazolyl H -cyclopentyl -CH _Three H -Ph 2 3 HH -pyrazolyl H -cyclohexyl -CH _Three H -Ph 2 3 H -OCH _Three -pyrazolyl H -cyclobutyl -CH _Three H -Ph 2 2 H -OCH _Three -pyrazolyl H -cyclopentyl -CH _Three H -Ph 2 2 H -OCH _Three -pyrazolyl H -cyclohexyl -CH _Three H -Ph 2 2 H -OCH _Three -pyrazolyl H -cyclobutyl -CH _Three H -Ph 2 3 H -OCH _Three -pyrazolyl H -cyclopentyl -CH _Three H -Ph 2 3 H -OCH _Three -pyrazolyl H -cyclohexyl -CH _Three H -Ph 2 3 -pyrazolyl HH -OCH _Three -cyclobutyl -CH _Three H -Ph 2 2 -pyrazolyl HH -OCH _Three -cyclopentyl -CH _Three H -Ph 2 2 -pyrazolyl HH -OCH _Three -cyclohexyl -CH _Three H -Ph 2 2 -pyrazolyl HH -OCH _Three -cyclobutyl -CH _Three H -Ph 2 3 -pyrazolyl HH -OCH _Three -cyclopentyl -CH _Three H -Ph 2 3 -pyrazolyl HH -OCH _Three -cyclohexyl -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -pyrazolyl -cyclobutyl -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -pyrazolyl -cyclopentyl -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -pyrazolyl -cyclohexyl -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -pyrazolyl -cyclobutyl -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -pyrazolyl -cyclopentyl -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -pyrazolyl -cyclohexyl -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -pyrazolyl -cyclobutyl -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -pyrazolyl -cyclopentyl -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -pyrazolyl -cyclohexyl -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -pyrazolyl -cyclobutyl -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -pyrazolyl -cyclopentyl -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -pyrazolyl -cyclohexyl -CH _Three H -Ph 2 3 -OCH _Three HH -pyrazolyl -cyclobutyl -CH _Three H -Ph 2 2 -OCH _Three HH -pyrazolyl -cyclopentyl -CH _Three H -Ph 2 2 -OCH _Three HH -pyrazolyl -cyclohexyl -CH _Three H -Ph 2 2 -OCH _Three HH -pyrazolyl -cyclobutyl -CH _Three H -Ph 2 3 -OCH _Three HH -pyrazolyl -cyclopentyl -CH _Three H -Ph 2 3 -OCH _Three HH -pyrazolyl -cyclohexyl -CH _Three H -Ph 2 3 H -pyrazolyl -OCH _Three H -cyclobutyl -CH _Three H -Ph 2 2 H -pyrazolyl -OCH _Three H -cyclopentyl -CH _Three H -Ph 2 2 H -pyrazolyl -OCH _Three H -cyclohexyl -CH _Three H -Ph 2 2 H -pyrazolyl -OCH _Three H -cyclobutyl -CH _Three H -Ph 2 3 H -pyrazolyl -OCH _Three H -cyclopentyl -CH _Three H -Ph 2 3 H -pyrazolyl -OCH _Three H -cyclohexyl -CH _Three H -Ph 2 3 -triazolyl HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -triazolyl HHH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 -triazolyl HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 H -triazolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 H -triazolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 H -triazolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 HH -triazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 HH -triazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 HH -triazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -triazolyl HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -triazolyl HHH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 -triazolyl HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 H -triazolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 H -triazolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 H -triazolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 HH -triazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 HH -triazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 HH -triazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -triazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 H -OCH _Three -triazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 H -OCH _Three -triazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 H -OCH _Three -triazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -triazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -triazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -triazolyl HH -OCH _Three -(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -triazolyl HH -OCH _Three -(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 -triazolyl HH -OCH _Three -(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -triazolyl HH -OCH _Three -(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -triazolyl HH -OCH _Three -(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 -triazolyl HH -OCH _Three -(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -triazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -triazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -triazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -triazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -triazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -triazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -triazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -triazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -triazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -triazolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -triazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -triazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -triazolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -triazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 H -triazolyl -OCH _Three H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 H -triazolyl -OCH _Three H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 H -triazolyl -OCH _Three H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 H -triazolyl -OCH _Three H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 H -triazolyl -OCH _Three H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 H -triazolyl -OCH _Three H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -triazolyl HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -triazolyl HHH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 -triazolyl HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 H -triazolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 H -triazolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 H -triazolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 HH -triazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 HH -triazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 HH -triazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 -triazolyl HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -triazolyl HHH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 -triazolyl HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 H -triazolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 H -triazolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 H -triazolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 HH -triazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 HH -triazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 HH -triazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 H -OCH _Three -triazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 H -OCH _Three -triazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 H -OCH _Three -triazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 H -OCH _Three -triazolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 H -OCH _Three -triazolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 H -OCH _Three -triazolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -triazolyl HH -OCH _Three -(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -triazolyl HH -OCH _Three -(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 -triazolyl HH -OCH _Three -(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 -triazolyl HH -OCH _Three -(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -triazolyl HH -OCH _Three -(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 -triazolyl HH -OCH _Three -(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -triazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -triazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -triazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -triazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -triazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -triazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -triazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -triazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -OCH _Three HH -triazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -OCH _Three HH -triazolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 -OCH _Three HH -triazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 -OCH _Three HH -triazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -OCH _Three HH -triazolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 -OCH _Three HH -triazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 H -triazolyl -OCH _Three H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 H -triazolyl -OCH _Three H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 H -triazolyl -OCH _Three H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 H -triazolyl -OCH _Three H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 H -triazolyl -OCH _Three H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 H -triazolyl -OCH _Three H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -triazolyl HHH -cyclobutyl -CH _Three H -Ph 1 2 -triazolyl HHH -cyclopentyl -CH _Three H -Ph 1 2 -triazolyl HHH -cyclohexyl -CH _Three H -Ph 1 2 H -triazolyl HH -cyclobutyl -CH _Three H -Ph 1 2 H -triazolyl HH -cyclopentyl -CH _Three H -Ph 1 2 H -triazolyl HH -cyclohexyl -CH _Three H -Ph 1 2 HH -triazolyl H -cyclobutyl -CH _Three H -Ph 1 2 HH -triazolyl H -cyclopentyl -CH _Three H -Ph 1 2 HH -triazolyl H -cyclohexyl -CH _Three H -Ph 1 2 -triazolyl HHH -cyclobutyl -CH _Three H -Ph 1 3 -triazolyl HHH -cyclopentyl -CH _Three H -Ph 1 3 -triazolyl HHH -cyclohexyl -CH _Three H -Ph 1 3 H -triazolyl HH -cyclobutyl -CH _Three H -Ph 1 3 H -triazolyl HH -cyclopentyl -CH _Three H -Ph 1 3 H -triazolyl HH -cyclohexyl -CH _Three H -Ph 1 3 HH -triazolyl H -cyclobutyl -CH _Three H -Ph 1 3 HH -triazolyl H -cyclopentyl -CH _Three H -Ph 1 3 HH -triazolyl H -cyclohexyl -CH _Three H -Ph 1 3 H -OCH _Three -triazolyl H -cyclobutyl -CH _Three H -Ph 1 2 H -OCH _Three -triazolyl H -cyclopentyl -CH _Three H -Ph 1 2 H -OCH _Three -triazolyl H -cyclohexyl -CH _Three H -Ph 1 2 H -OCH _Three -triazolyl H -cyclobutyl -CH _Three H -Ph 1 3 H -OCH _Three -triazolyl H -cyclopentyl -CH _Three H -Ph 1 3 H -OCH _Three -triazolyl H -cyclohexyl -CH _Three H -Ph 1 3 -triazolyl HH -OCH _Three -cyclobutyl -CH _Three H -Ph 1 2 -triazolyl HH -OCH _Three -cyclopentyl -CH _Three H -Ph 1 2 -triazolyl HH -OCH _Three -cyclohexyl -CH _Three H -Ph 1 2 -triazolyl HH -OCH _Three -cyclobutyl -CH _Three H -Ph 1 3 -triazolyl HH -OCH _Three -cyclopentyl -CH _Three H -Ph 1 3 -triazolyl HH -OCH _Three -cyclohexyl -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -triazolyl -cyclobutyl -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -triazolyl -cyclopentyl -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -triazolyl -cyclohexyl -CH _Three H -Ph 1 2 2-OCH _Two O-3 H -triazolyl -cyclobutyl -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -triazolyl -cyclopentyl -CH _Three H -Ph 1 3 2-OCH _Two O-3 H -triazolyl -cyclohexyl -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -triazolyl -cyclobutyl -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -triazolyl -cyclopentyl -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -triazolyl -cyclohexyl -CH _Three H -Ph 1 2 -OCH _Three -OCH _Three H -triazolyl -cyclobutyl -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -triazolyl -cyclopentyl -CH _Three H -Ph 1 3 -OCH _Three -OCH _Three H -triazolyl -cyclohexyl -CH _Three H -Ph 1 3 -OCH _Three HH -triazolyl -cyclobutyl -CH _Three H -Ph 1 2 -OCH _Three HH -triazolyl -cyclopentyl -CH _Three H -Ph 1 2 -OCH _Three HH -triazolyl -cyclohexyl -CH _Three H -Ph 1 2 -OCH _Three HH -triazolyl -cyclobutyl -CH _Three H -Ph 1 3 -OCH _Three HH -triazolyl -cyclopentyl -CH _Three H -Ph 1 3 -OCH _Three HH -triazolyl -cyclohexyl -CH _Three H -Ph 1 3 H -triazolyl -OCH _Three H -cyclobutyl -CH _Three H -Ph 1 2 H -triazolyl -OCH _Three H -cyclopentyl -CH _Three H -Ph 1 2 H -triazolyl -OCH _Three H -cyclohexyl -CH _Three H -Ph 1 2 H -triazolyl -OCH _Three H -cyclobutyl -CH _Three H -Ph 1 3 H -triazolyl -OCH _Three H -cyclopentyl -CH _Three H -Ph 1 3 H -triazolyl -OCH _Three H -cyclohexyl -CH _Three H -Ph 1 3 -triazolyl HHH -cyclobutyl -CH _Three H -Ph 2 3 -triazolyl HHH -cyclopentyl -CH _Three H -Ph 2 3 -triazolyl HHH -cyclohexyl -CH _Three H -Ph 2 3 H -triazolyl HH -cyclobutyl -CH _Three H -Ph 2 3 H -triazolyl HH -cyclopentyl -CH _Three H -Ph 2 3 H -triazolyl HH -cyclohexyl -CH _Three H -Ph 2 3 HH -triazolyl H -cyclobutyl -CH _Three H -Ph 2 3 HH -triazolyl H -cyclopentyl -CH _Three H -Ph 2 3 HH -triazolyl H -cyclohexyl -CH _Three H -Ph 2 3 -triazolyl HHH -cyclobutyl -CH _Three H -Ph 2 2 -triazolyl HHH -cyclopentyl -CH _Three H -Ph 2 2 -triazolyl HHH -cyclohexyl -CH _Three H -Ph 2 2 H -triazolyl HH -cyclobutyl -CH _Three H -Ph 2 2 H -triazolyl HH -cyclopentyl -CH _Three H -Ph 2 2 H -triazolyl HH -cyclohexyl -CH _Three H -Ph 2 2 HH -triazolyl H -cyclobutyl -CH _Three H -Ph 2 2 HH -triazolyl H -cyclopentyl -CH _Three H -Ph 2 2 HH -triazolyl H -cyclohexyl -CH _Three H -Ph 2 2 H -OCH _Three -triazolyl H -cyclobutyl -CH _Three H -Ph 2 2 H -OCH _Three -triazolyl H -cyclopentyl -CH _Three H -Ph 2 2 H -OCH _Three -triazolyl H -cyclohexyl -CH _Three H -Ph 2 2 H -OCH _Three -triazolyl H -cyclobutyl -CH _Three H -Ph 2 3 H -OCH _Three -triazolyl H -cyclopentyl -CH _Three H -Ph 2 3 H -OCH _Three -triazolyl H -cyclohexyl -CH _Three H -Ph 2 3 -triazolyl HH -OCH _Three -cyclobutyl -CH _Three H -Ph 2 2 -triazolyl HH -OCH _Three -cyclopentyl -CH _Three H -Ph 2 2 -triazolyl HH -OCH _Three -cyclohexyl -CH _Three H -Ph 2 2 -triazolyl HH -OCH _Three -cyclobutyl -CH _Three H -Ph 2 3 -triazolyl HH -OCH _Three -cyclopentyl -CH _Three H -Ph 2 3 -triazolyl HH -OCH _Three -cyclohexyl -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -triazolyl -cyclobutyl -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -triazolyl -cyclopentyl -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -triazolyl -cyclohexyl -CH _Three H -Ph 2 2 2-OCH _Two O-3 H -triazolyl -cyclobutyl -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -triazolyl -cyclopentyl -CH _Three H -Ph 2 3 2-OCH _Two O-3 H -triazolyl -cyclohexyl -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -triazolyl -cyclobutyl -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -triazolyl -cyclopentyl -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -triazolyl -cyclohexyl -CH _Three H -Ph 2 2 -OCH _Three -OCH _Three H -triazolyl -cyclobutyl -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -triazolyl -cyclopentyl -CH _Three H -Ph 2 3 -OCH _Three -OCH _Three H -triazolyl -cyclohexyl -CH _Three H -Ph 2 3 H -pyrolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 H -pyrolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 H -pyrolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 HH -pyrolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 HH -pyrolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 HH -pyrolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 H -pyrolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 H -pyrolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 H -pyrolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 HH -pyrolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 HH -pyrolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 HH -pyrolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -OCH _Three HH -pyrolyl -cyclobutyl -CH _Three H -Ph 1 2 -OCH _Three HH -pyrolyl -cyclopentyl -CH _Three H -Ph 1 2 -OCH _Three HH -pyrolyl -cyclohexyl -CH _Three H -Ph 1 2 -OCH _Three HH -pyrolyl -cyclobutyl -CH _Three H -Ph 1 3 -OCH _Three HH -pyrolyl -cyclopentyl -CH _Three H -Ph 1 3 -OCH _Three HH -pyrolyl -cyclohexyl -CH _Three H -Ph 1 3 -OCH _Three HH -pyrolyl -cyclobutyl -CH _Three H -Ph 2 2 -OCH _Three HH -pyrolyl -cyclopentyl -CH _Three H -Ph 2 2 -OCH _Three HH -pyrolyl -cyclohexyl -CH _Three H -Ph 2 2 -OCH _Three HH -pyrolyl -cyclobutyl -CH _Three H -Ph 2 3 -OCH _Three HH -pyrolyl -cyclopentyl -CH _Three H -Ph 2 3 -OCH _Three HH -pyrolyl -cyclohexyl -CH _Three H -Ph 2 3 H -pyrolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 H -pyrolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 H -pyrolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 HH -pyrolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 HH -pyrolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 HH -pyrolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 H -pyrolyl HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 H -pyrolyl HH-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 H -pyrolyl HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 HH -pyrolyl H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 HH -pyrolyl H-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 HH -pyrolyl H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -triazolyl -cyclobutyl -CH _Three H -Ph 2 2 -OCH _Three HH -triazolyl -cyclopentyl -CH _Three H -Ph 2 2 -OCH _Three HH -triazolyl -cyclohexyl -CH _Three H -Ph 2 2 -OCH _Three HH -triazolyl -cyclobutyl -CH _Three H -Ph 2 3 -OCH _Three HH -triazolyl -cyclopentyl -CH _Three H -Ph 2 3 -OCH _Three HH -triazolyl -cyclohexyl -CH _Three H -Ph 2 3 H -triazolyl -OCH _Three H -cyclobutyl -CH _Three H -Ph 2 2 H -triazolyl -OCH _Three H -cyclopentyl -CH _Three H -Ph 2 2 H -triazolyl -OCH _Three H -cyclohexyl -CH _Three H -Ph 2 2 H -triazolyl -OCH _Three H -cyclobutyl -CH _Three H -Ph 2 3 H -triazolyl -OCH _Three H -cyclopentyl -CH _Three H -Ph 2 3 H -triazolyl -OCH _Three H -cyclohexyl -CH _Three H -Ph 2 3 -OCH _Three HH -pyrolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -pyrolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -pyrolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -OCH _Three HH -pyrolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -pyrolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -pyrolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -OCH _Three HH -pyrolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -OCH _Three HH -pyrolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 2 -OCH _Three HH -pyrolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 -OCH _Three HH -pyrolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -OCH _Three HH -pyrolyl-(CH _Two ) _Three CH _Three -CH _Three H -Ph 2 3 -OCH _Three HH -pyrolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -O-CH _Two -2-Py HHH -CH _Three -CH _Three H -Ph 1 3 -O-CH _Two -2-Py HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -O-CH _Two -2-Py HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -O-CH _Two -2-Py HHH-(CH _Two ) ₆ CH _Three -CH _Three H -Ph 1 3 -O-CH _Two -2-Py HHH -benzyl -CH _Three H -Ph 1 3 -O-CH _Two -2-Py HHH-(CH _Two ) _Two -Ph -CH _Three H -Ph 1 3 -O-CH _Two -2-Py HHH-(CH _Two ) _Three -Ph -CH _Three H -Ph 1 3 -O-CH _Two -2-Py HHH -CH _Three -(CH _Two ) _Four --Ph 1 3 -O-CH _Two -2-Py HHH-(CH _Two ) _Two CH _Three -(CH _Two ) _Four --Ph 1 3 -O-CH _Two -2-Py HHH-(CH _Two ) _Four CH _Three -(CH _Two ) _Four --Ph 1 3 -O-CH _Two -2-Py HHH-(CH _Two ) ₆ CH _Three -(CH _Two ) _Four --Ph 1 3 -O-CH _Two -2-Py HHH -benzyl-(CH _Two ) _Four --Ph 1 3 -O-CH _Two -2-Py HHH-(CH _Two ) _Two -Ph-(CH _Two ) _Four --Ph 1 3 -O-CH _Two -2-Py HHH-(CH _Two ) _Three -Ph-(CH _Two ) _Four --Ph 1 3 -O-CH _Two -2-Py HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -O-CH _Two -2-Py HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -O-CH _Two -2-Py HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -O-CH _Two -2-Py HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 -O-CH _Two -2-Py HHH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -O-CH _Two -2-Py HHH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -O-CH _Two -3-Py HHH-(CH _Two ) _Two CH _Three -(CH _Two ) _Four --Ph 1 3 -O-CH _Two -4-Py HHH-(CH _Two ) _Two CH _Three -(CH _Two ) _Four --Ph 1 3 -O-benzyl HHH-(CH _Two ) ₆ CH _Three -(CH _Two ) _Four --Ph 1 3 -O-benzyl HHH-(CH _Two ) _Three -Ph-(CH _Two ) _Four --Ph 1 3 H -O-CH _Two -2-Py HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 H -O-CH _Two -2-Py HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 H -O-CH _Two -2-Py HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 H -O-CH _Two -2-Py HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 H -O-CH _Two -2-Py HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 H -O-CH _Two -2-Py HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 H -O-CH _Two -2-Py HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 H -O-CH _Two -2-Py HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 HH -O-CH _Two -2-Py H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 HH -O-CH _Two -2-Py H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 HH -O-CH _Two -2-Py H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 HH -O-CH _Two -2-Py H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 HH -O-CH _Two -2-Py H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 HH -O-CH _Two -2-Py H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 HH -O-CH _Two -2-Py H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 HH -O-CH _Two -2-Py H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -O-CH _Two -2-Py -OCH _Three HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -O-CH _Two -2-Py -OCH _Three HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -O-CH _Two -2-Py -OCH _Three HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -O-CH _Two -2-Py -OCH _Three HH-(CH _Two ) _Four CH _Three -(CH _Two ) _Four --Ph 1 3 -O-CH _Two -2-Py -OCH _Three HH-(CH _Two ) ₆ CH _Three -(CH _Two ) _Four --Ph 2 3 -O-CH _Two -2-Py H -OCH _Three H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -O-CH _Two -2-Py H -OCH _Three H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 H -O-CH _Two -2-Py -OCH _Three H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 H -O-CH _Two -2-Py -OCH _Three H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -O-CH _Two -2-Py H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -O-CH _Two -2-Py H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 H -OCH _Three -O-CH _Two -2-Py H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 H -OCH _Three -O-CH _Two -2-Py H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 H -OCH _Three -O-CH _Two -2-Py H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 H -OCH _Three -O-CH _Two -2-Py H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 H -OCH _Three -O-CH _Two -2-Py H-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 H -OCH _Three -O-CH _Two -2-Py H-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -O-CH _Two -2-Py HH -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -O-CH _Two -2-Py HH -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -O-CH _Two -2-Py HH -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 2 -O-CH _Two -2-Py HH -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 2 -O-CH _Two -2-Py HH -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 2 -O-CH _Two -2-Py HH -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 2 -O-CH _Two -2-Py HH -imidazolyl-(CH _Two ) _Two CH _Three -CH _Three H -Ph 2 3 -O-CH _Two -2-Py HH -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -OCH _Three HH -imidazolyl -CH _Two CH _Three -CH _Three H-CH _Three 1 3 -OCH _Three HH -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H-CH _Three 1 3 -OCH _Three HH -imidazolyl -CH _Two CH _Three -CH _Three H -2-Py 1 3 -OCH _Three HH -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -2-Py 1 3 -OCH _Three HH -imidazolyl -CH _Two CH _Three -CH _Three H -2-Py 2 3 -OCH _Three HH -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -2-Py 2 3 -OCH _Three HH -imidazolyl -CH _Two CH _Three -CH _Three H -pyrimidyl 1 3 -OCH _Three HH -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -pyrimidyl 1 3 -OCH _Three HH -imidazolyl -CH _Two CH _Three -CH _Three H -pyrimidyl 2 3 -OCH _Three HH -imidazolyl-(CH _Two ) _Four CH _Three -CH _Three H -pyrimidyl 2 3 -OH -OCH _Three HH-(CH _Two ) _Two CH _Three -CH _Three H -Ph 1 3 -OH -OCH _Three HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 1 3 -OH -OCH _Three HH-(CH _Two ) _Four CH _Three -CH _Three H -Ph 2 3 -OH -OCH _Three HH-(CH _Two ) _Four CH _Three -(CH _Two ) _Four --Ph 1 3 -OH -OCH _Three HH-(CH _Two ) ₆ CH _Three -(CH _Two ) _Four --Ph 2 3 ────────────────────────────────────

In the above compounds, R ₁ , R ₂ and R ₃ are each independently a hydrogen atom, a methoxy group, an imidazolyl group, a pyrazolyl group or a triazolyl group, and R ₄ is an n-propyl group, an isopropyl group, an n group. -Butyl group, isobutyl group, sec-butyl group, t-butyl group, n-pentyl group, isopentyl group, sec-pentyl group, t-pentyl group, neopentyl group, cyclopropyl group, cyclobutyl group or cyclopentyl group, A compound in which R ₅ is a methyl group, R ₆ is a hydrogen atom, Y is a phenyl group, k is 1 or 2, and 1 is 2 or 3 is preferable. Further, as the salt of the compound of the present invention, hydrogen chloride, sulfate, succinate, tartrate and methanesulfonate are preferable.

Next, a method for producing the compound of the present invention will be described. <Production method A>

Embedded image (Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , k, l
And Y are as defined in the above general formula (I), and Z represents a leaving group such as a halogen atom, an aryloxy group or an alkyloxy group. )

The compound (I) of the present invention is an aniline derivative (I
It is obtained by converting I) into a reactive intermediate (III) and then reacting it with an amine derivative (IV). Examples of the reactive intermediate (III) include aniline derivative (II)
Carbamoyl chloride (Z in the formula is a chlorine atom) obtained by reacting phosgene, trichloromethyl chloroformate, bis (trichloromethyl) carbonate, etc. with aniline derivative (II), aryl chloroformate, alkyl chloroformate, etc. Examples thereof include a carbamoylaryl ester or a carbamoylalkyl ester (Z in the formula is an aryloxy group or an alkyloxy group) thus obtained. As a reaction solvent for producing the reactive intermediate (III),
The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include benzene, toluene, hexane, heptane, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, methylene chloride, chloroform, 1,2-dichloroethane and the like. Also, organic amines not involved in the reaction, such as triethylamine, pyridine, 1,8-diazabicyclo [5.4.0. ] Undec-7-en (DB
U) or the like or an inorganic base such as sodium hydrogen carbonate, potassium carbonate or sodium carbonate may allow the reaction to proceed smoothly. The reaction temperature is from −15 ° C. to the boiling point of the solvent.

The compound (I) of the present invention can be obtained by reacting the reactive intermediate (III) with the amine derivative (IV) without isolation. Also in this reaction, organic amines not involved in the reaction, such as triethylamine, pyridine,
1,8-diazabicyclo [5.4.0. ] Undek-7
-The presence of ene (DBU) or the like, or an inorganic base such as sodium hydrogen carbonate, potassium carbonate, sodium carbonate or the like allows the reaction to proceed smoothly. The reaction temperature is from −15 ° C. to the boiling point of the solvent.

<Production Method B>: When R ₃ is a pyridylmethyloxy group

[Chemical 6] (In the formula, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , k, l and Y are as defined in the above general formula (I), and P
y represents a pyridyl group. )

The urea derivative (IB) obtained by the production method A
-1) (a compound of the general formula (I) in which R ₃ is a benzyloxy group) is subjected to hydrogenolysis in a solvent such as alcohol in the presence of a Pd-carbon catalyst to give a phenol derivative (I- The compound of the present invention (IB-3) can be obtained by reacting B-2) with chloromethylpyridine hydrochloride in the presence of a base. The reaction solvent when the compound of the present invention (IB-3) is produced from the phenol derivative (IB-2) is not particularly limited as long as it is a solvent that does not participate in the reaction, for example, benzene, toluene,
Hexane, heptane, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, methylene chloride, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and the like can be mentioned. Further, as a base, an organic amine which does not participate in the reaction, for example, triethylamine, pyridine, 1,8-diazabicyclo [5.4.0. ] Undec-7-ene (DBU) and the like, or inorganic bases such as sodium hydrogen carbonate, potassium carbonate and sodium carbonate.

The above amine derivative (IV) can be produced by the following method. <Production method C>

Embedded image (In the formula, R ₁ ′ and R ₂ ′ each independently represent a hydrogen atom or a C _{1 to} C ₃ alkoxy group, or R ₁ ′ and R 2
₂ ′ together form —O— (CH ₂ ) _n —O— (n is 1
Represents an integer of 3; ), V represents a phenyl group or a pyridyl group, and R ₄ is as defined in the above general formula (I). )

When V is a phenyl group, the hydroxybenzaldehyde derivative (VC) is reacted with benzyl chloride or benzyl bromide in the presence of a base, and when V is a pyridyl group, chloromethylpyridine hydrochloride. And the like to give a benzaldehyde derivative (VI-
C) is obtained. The reaction solvent in this case is not particularly limited as long as it does not participate in the reaction. For example, benzene, toluene, tetrahydrofuran, dioxane, chloroform, acetone, N, N-dimethylformamide,
Dimethyl sulfoxide, N-methylpyrrolidone and the like can be mentioned. Further, as a base, an organic amine which does not participate in the reaction, for example, triethylamine, pyridine, 1,8-diazabicyclo [5.4.0. ] Undec-7-ene (D
BU) and the like, or inorganic bases such as sodium hydrogen carbonate, potassium carbonate and sodium carbonate. The reaction temperature is from 10 ° C. to the boiling point of the solvent, and the reaction time is from 1 to 20 hours.

The benzaldehyde derivative (V
I-C) with R ₄ —NH ₂ (R ₄ is as defined in the above general formula (I)) in an alcohol solvent such as methyl alcohol, ethyl alcohol or isopropyl alcohol at a reaction temperature of −10 ° C. 1 to under the condition of solvent boiling point
Reacting for 24 hours to give an imine derivative (VII-C),
The amine derivative (IV-C) is obtained by reducing this with a reducing agent such as sodium borohydride without isolation. The reaction temperature is from −10 ° C. to the boiling point of the solvent, and the reaction time is from 1 to 10 hours.

<Production Method D>

Embedded image (In the formula, R ₁ ″ and R ₂ ″ are each independently a hydrogen atom,
Alkoxy groups _{C 1 ~C 3, Het- (CH} 2) m -
(Het and m are the same as defined above), or represents a C _{7 to} C ₉ aralkyloxy group, or R ₁ ″ and R ₂ ″ are combined to form —O— (CH ₂ ) _n —O— (n is Represents an integer of 1 to 3), R ₃ ′ represents a heterocyclic residue containing 1 to 4 nitrogen atoms and having a total number of 5 to 6, and R ₄ is the above general formula (I ) Is as defined in. )

R ₄ --NH ₂ was added to the bromobenzaldehyde derivative (V-D) in an alcohol solvent such as methyl alcohol, ethyl alcohol or isopropyl alcohol.
(R ₄ is as defined in the above general formula (I)) at a reaction temperature of −10 ° C. to a solvent boiling point for 1 to 2
The reaction was carried out for 4 hours to give an imine derivative (VII-D), which was not isolated but reduced with a reducing agent such as sodium borohydride to give a bromobenzylamine derivative (V
III-D) is obtained. The reaction temperature is from −10 ° C. to the boiling point of the solvent, and the reaction time is from 1 to 10 hours. Then, Y
oung S. Journal of by Lo, et al.
Medicinal Chemistry, 1992,
vol. 35, No. 26, 4790-4794, the method of coupling reaction of nitrogen-containing heterocyclic compound with copper catalyst as described in 26, 4790-4794 is used.
The amine derivative (IV-D) can be obtained by reacting -D) with a heterocyclic compound having 1 to 4 nitrogen atoms and having a total number of 5 to 6 atoms.

<Production Method E>

Embedded image (In the formula, R ₁ ′ and R ₂ ′ each independently represent a hydrogen atom or a C _{1 to} C ₃ alkoxy group, or R ₁ ′ and R 2
₂ ′ together form —O— (CH ₂ ) _n —O— (n is 1
Represents an integer of 3; ), V represents a phenyl group or a pyridyl group, K represents a chlorine atom, a bromine atom, or a methylthio group, L represents a chlorine atom, a bromine atom, or a methylsulfinyl group, and R ₄ represents It is as defined in the above general formula (I). )

The phenylacetic acid derivative (IX-E) can be easily synthesized from the benzaldehyde derivative (VI-C) obtained in the production method B by a general phenylacetic acid synthesis method. For example, New Experimental Chemistry Course 14 “Synthesis and Reaction of Organic Compounds (II)”, edited by The Chemical Society of Japan, Maruzen (1977), p.
It can be produced by introducing a dihalomethylene group by the Wittig reaction described in 971 and hydrolyzing the resulting compound (wherein K and L in the formula are chlorine atoms, or K and L are bromine atoms). ). Also, Chemistry Review, N
o. 19. New organic synthesis reaction, p. 75 (197
8), according to the method described in Organic Synthesis Society, 37, 903, (1979), a condensation reaction of methylthiomethylsulfoxide (FAMSO) is performed in the presence of benzyltrimethylammonium hydroxide (Triton B) (in the formula) (Wherein K is a methylthio group, L is a methylsulfinyl group), and then the obtained compound is acid-hydrolyzed.

The amide derivative (X-E) can be prepared by the general method, that is, phenylacetic acid derivative (IX-E) and R ₄ N.
H ₂ (R ₄ is as defined in the above general formula (I)) and dicyclohexylcarbodiimide (DC
It can be easily synthesized by using a condensing agent such as C) or by converting the phenylacetic acid derivative (IX-E) into an acid chloride or a mixed acid anhydride and reacting with R ₄ NH ₂ . The amine derivative (IV-E) can be obtained by reduction with sodium borohydride and a boron trifluoride ether complex in a tetrahydrofuran or dioxane solvent. These syntheses are described, for example, in H. C. Br
own and P.W. Journa by Heim, et al.
l of Organic Chemistry, 3
8, 912 (1973). The amine derivative (IV-E) can also be obtained by reduction with sodium borohydride and acetic acid in a tetrahydrofuran or dioxane solvent. These syntheses are described, for example, in N. Tetrahedr by Umino et al.
on. It can be carried out by the method described in Letter, 763 (1976).

<Production Method F>

Embedded image (In the formula, R ₁ ″ and R ₂ ″ are each independently a hydrogen atom,
Alkoxy groups _{C 1 ~C 3, Het- (CH} 2) m -
(Het and m are the same as defined above), or represents a C _{7 to} C ₉ aralkyloxy group, or R ₁ ″ and R ₂ ″ are combined to form —O— (CH ₂ ) _n —O— (n Represents an integer of 1 to 3), K represents a chlorine atom, a bromine atom or a methylthio group, L represents a chlorine atom, a bromine atom or a methylsulfinyl group, and R ₃ ′ represents a nitrogen atom. 1
Represents a heterocyclic residue having 5 to 6 total atoms containing
₄ is as defined in the above general formula (I). )

The amine derivative (IV-F) is prepared by converting the bromobenzaldehyde derivative (V-D) into a bromophenethylamine derivative (XV-F) according to the method of Production method E, and then producing the nitrogen-containing heterocyclic compound according to the method of Production method D. It can be obtained by carrying out a coupling reaction with. Alternatively, the bromobenzaldehyde derivative (V-D) is used as the bromoamide derivative (XIV-F) according to the method of Production method E, and the coupling reaction with the nitrogen-containing heterocyclic compound is performed according to the method of Production method D, and then the amide is produced. It can also be produced by reduction according to the method E.

<Production Method G>

Embedded image (In the formula, R ₁ ′ and R ₂ ′ are each independently a hydrogen atom,
Or represents a C ₁ -C ₃ alkoxy group, or R ₁ ′ and R
₂ ′ together form —O— (CH ₂ ) _n —O— (n is 1
Represents an integer of 3; ) May be represented, T is a hydrogen atom,
Alkyl C ₁ -C _6, or Ar- (CH ₂₎ p '
- (Ar represents an aryl group of C ₆ ~C _10, p 'is 0
Represents an integer of 2. ), R ₄ ′ is a C ₁ -C ₇ alkyl group, or Ar- (CH ₂ ) p- (Ar is C ₆ -C
Represents an aryl group of ₁₀ , and p represents an integer of 1 to 3. ), And V represents a phenyl group or a pyridyl group. )

The nitrostyrene derivative (XVII-G) is obtained by reacting the benzaldehyde derivative (VI-C) with nitromethane in the presence of ammonium acetate in a solvent such as toluene. This compound is reduced with LiAlH ₄ or the like in tetrahydrofuran or ether to give a phenethylamine derivative (XVIII-G). These syntheses are described, for example, in Macor JE,
Journal of Medicinal
Chemistry, 1992, vol. 35, no.
20, 3625-3632.
Then, the phenethylamine derivative was added to T-COCl or T-
Using COOH (T is as previously defined),
Prepared as an amide derivative (XIX-G) by a conventional method and then produced by the production method E.
The amine compound (IV-
G) can be obtained.

The above aniline derivative (II) can be produced by the following method. <Production method H>

Embedded image (In the formula, R ₅ , R ₆ , l and Y are each represented by the above general formula (I).
And M represents a chlorine atom or a bromine atom. )

Nitrophenol derivative (XX-H) and B
r (CH ₂ ) ₁ Cl, Br (CH ₂ ) ₁ Br, Cl (C
A nitrobenzene derivative (XXI-H) can be obtained by reacting with a compound represented by H ₂ ) ₁ Cl (1 is as defined above) in the presence of a base. The reaction solvent in this case is not particularly limited as long as it is a solvent that does not participate in the reaction, but for example, benzene, toluene, tetrahydrofuran, dioxane, chloroform, acetone, N,
N-dimethylformamide, dimethyl sulfoxide,
N-methylpyrrolidone etc. are mentioned. Further, as a base, an organic amine that does not participate in the reaction, for example, triethylamine, pyridine, 1,8-diazabicyclo [5.4.
0. ] Undec-7-ene (DBU) and the like, or inorganic bases such as sodium hydrogen carbonate, potassium carbonate and sodium carbonate. The reaction temperature is from 20 ° C. to the boiling point of the solvent, and the reaction time is from 1 to 20 hours. Then, the compound (XXII-H) is reacted with a piperazine derivative under the same reaction conditions as described above to obtain Pd in an alcohol solvent.
The aniline derivative (II-H) can be obtained by carrying out catalytic hydrogenation in the presence of a carbon catalyst or by carrying out a conventional reduction of a nitro group such as reduction with iron-acetic acid in an alcohol-water solvent.

The synthesis of these is based on Teiji Kimur.
a, Jour by Yasutake Takase et al.
nal of Medical Chemistr
y, 1993, vol. 11, No. 36, 1630-
1640 and TeijiKimura, Nobuhi
Journalof by sa Watanabe et al.
Medicinal Chemistry, 1993,
vol. 35, no. 26, 1641-1653. In the nitrophenol derivative (XX-H), R ₆ is a hydrogen atom and R ₅ is C
_The compound which is a _{1 to} C ₃ alkyl group can be easily obtained or produced by a known method (Bulletin).
of the Chemical Society o
fJapan, vol. 50 (1), 276-279
(1977)) Yes.

Among the nitrophenol derivatives (XX-H), the compound (XX-H-1) in which R ₅ and R ₆ are combined to form-(CH ₂ ) ₄ -is prepared by the following method.
Using 60% nitric acid in a solvent such as ether, -10 ° C ~
The phenol derivative (XXIII
-H) was nitrated with a reaction time of 0.5 hours to 5 hours and subjected to silica gel chromatography to obtain an isomer (XX-H-2).
Can be produced by separating and removing. <Production method I>

Embedded image

The compound of the present invention has a strong ACAT inhibitory activity, as will be shown in Examples below, and therefore, as a preventive and / or therapeutic drug for hyperlipidemia, and for preventing and / or treating atherosclerosis. It is also expected to be used as a therapeutic drug.

When the compound of the present invention is used as a prophylactic / therapeutic drug, it can be administered alone or in the form of a pharmaceutical composition prepared by being combined with a pharmaceutically acceptable carrier.
The composition of the pharmaceutical composition will be determined by the solubility of the compound, chemical characteristics, route of administration, dosage regimen, and the like. For example, a pharmaceutical composition in a dosage form such as granules, fine granules, powders, tablets, hard syrups, soft capsules, syrups, emulsions, suspensions, liposome encapsulations, or liquids is manufactured and administered orally. It may be used, or a pharmaceutical composition in the form of injections, infusions, rectal administrations (suppositories), transdermal absorptions, transmucosal absorptions, inhalants, ear drops, nasal drops, etc. It may be manufactured and administered parenterally.

Excipients used for producing solid preparations include, for example, lactose, sucrose, starch, talc,
Examples include cellulose, dextrin, kaolin, calcium carbonate and the like. Liquid preparations for oral administration, such as
Emulsions, syrups, suspensions, solutions and the like may contain commonly used inert diluents such as water or vegetable oils. These preparations may contain, in addition to an inert diluent, auxiliary agents such as lubricants, suspension auxiliary agents, sweetening agents, aromatic agents, coloring agents or preservatives. Liquid preparations may be prepared and included in capsules of an absorbable substance such as gelatin. Formulations for parenteral administration, that is, solvents or suspensions used for producing injections and the like include, for example, water, propylene glycol, polyethylene glycol,
Examples thereof include benzyl alcohol, oleic acid ester, and lecithin. Alternatively, the injection may be circulated in the form of a powder such as a lyophilized product, and may be dissolved and prepared by adding an appropriate solvent before use. Further, a pharmaceutical organic or inorganic solid or liquid carrier suitable for oral, enteral, parenteral or topical administration can be used together with the compound of the present invention. Preparation of the preparation may be performed by a conventional method.

The clinical dose is generally 1 to 1 in a daily dose of the compound of the present invention when orally administered to an adult.
It is 000 mg, preferably 10 to 600 mg, but it is preferable to appropriately increase or decrease according to conditions such as age of the patient, medical condition or symptom, presence or absence of simultaneous administration. The daily dose of the compound of the present invention may be administered once a day, or may be divided into two or three times a day at appropriate intervals, or may be intermittently administered with a drug holiday of one to several days. You may. When used as an injection, the daily weight of the compound of the present invention for an adult is, for example, 0.1 mg to 500 mg, preferably 0.5 mg to 100 mg.

[0049]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited by these Examples.

Reference Example-1 (Production Method C) Synthesis of N-heptyl- (2-benzyloxy-3-methoxyphenyl) methylamine 2-benzyloxy-3-methoxybenzaldehyde 1
30 g of ethyl alcohol in 0 g (41.3 mmol)
l, n-heptylamine 5.23 g (45.4 mmo)
1) was added, and the mixture was stirred with heating under reflux for 2 hours. Reaction liquid at 5 ℃
And cooled to 2.34 g (61.
9 mmol) was added, and the mixture was stirred at room temperature for 10 hours. 10 ml of water and a 6N aqueous hydrochloric acid solution were added to the reaction solution to decompose excess sodium borohydride, made alkaline with a 25% aqueous sodium hydroxide solution, and extracted with toluene. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and oily N-heptyl- (2-benzyloxy-3-methoxyphenyl) methylamine 13.
5 g were obtained. ¹ H NMR (CDCl ₃ ): δ = 0.86 (t, 3
H), 1.24 (m, 8H), 1.41 (t, 2H),
1.58 (bs, 1H), 2.49 (t, 2H), 3.
69 (s, 2H), 3.90 (s, 3H), 6.85
6.89 (m, 2H), 7.03 (t, 1H), 7.3
2 to 7.47 (m, 5H)

The following amine derivative (VI-C) was synthesized in the same manner as in Reference Example 1. N-heptyl- [2- (2-pyridylmethyloxy) phenyl] methylamine N- (3-phenylpropyl)-[2- (2-pyridylmethyloxy) phenyl] methylamine N- (3-phenylpropyl)- (2-Benzyloxy-3-methoxyphenyl) methylamine N-propyl- [2- (2-pyridylmethyloxy) phenyl] methylamine N-propyl- [2- (3-pyridylmethyloxy) phenyl] methylamine N -Propyl- [2- (4-pyridylmethyloxy) phenyl] methylamine N-methyl- [2- (2-pyridylmethyloxy) phenyl] methylamine N-pentyl- [2- (2-pyridylmethyloxy) phenyl ] Methylamine N-pentyl- [3- (2-pyridylmethyloxy) phenyl] methylamine - pentyl - [4- (2-pyridylmethyl) phenyl] methylamine N- pentyl - [2- (2-pyridylmethyloxy) -
3-Methoxyphenyl] methylamine N-pentyl- [2- (2-pyridylmethyloxy)-
4-Methoxyphenyl] methylamine N-pentyl- [3- (2-pyridylmethyloxy)-
4-Methoxyphenyl] methylamine N-pentyl- [4- (2-pyridylmethyloxy)-
3-Methoxyphenyl] methylamine N-cyclopentyl- (5-imidazolyl-2-methoxyphenyl) methylamine N-isobutyl- (5-imidazolyl-2-methoxyphenyl) methylamine N-isopropyl- (5-imidazolyl-2- Methoxyphenyl) methylamine Nt-butyl- (5-imidazolyl-2-methoxyphenyl) methylamine

Reference Example-2 (Production Method D) Synthesis of N-pentyl- (5-imidazolyl-2-methoxyphenyl) methylamine 5-bromo-2-methoxybenzaldehyde 30.0 g
(0.14 mol) in ethyl alcohol 150 ml, n
-Pentylamine (12.7 g, 0.146 mol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to 5 ° C., sodium borohydride (7.9 g, 0.209 mol) was added, and the mixture was stirred at room temperature for 8 hours. The reaction solution was added with 50 ml of water and a 6N aqueous hydrochloric acid solution to decompose excess sodium borohydride, made alkaline with a 25% aqueous sodium hydroxide solution, and extracted with toluene. The extract was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 38.0 g of oily N-pentyl- (5-bromo-2-methoxyphenyl) methylamine. ¹ H NMR (CDCl ₃ ): δ = 0.89 (t, 3
H), 1.30 (m, 4H), 1.48 (t, 2H),
1.61 (bs, 1H), 2.58 (t, 2H),
73 (s, 2H), 3.81 (s, 3H), 6.72
(D, 1H), 7.29 to 7.37 (m, 2H)

38.0 g (0.133 mo) of N-heptyl- (5-bromo-2-methoxyphenyl) methylamine
1) imidazole 11.8 g (0.173 mol)
Potassium carbonate (0.147 mol), cuprous chloride 1.4
g (0.014 mol), N-methylpyrrolidone 270
ml was added and the mixture was heated with stirring at 178 to 182 ° C. for 7 hours. After cooling the reaction solution, 200 ml of ethyl acetate was added, inorganic salts and the like were removed by filtration, and the solvent was distilled off. The residue was extracted with ethyl acetate, washed with 10% aqueous ammonia and subsequently with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue is subjected to silica gel chromatography (Wakogel C-30).
0: 360 g, eluent: methanol / ethyl acetate (1 /
10-1 / 3)) and oily N-pentyl-
21.3 g of (5-imidazolyl-2-methoxyphenyl) methylamine were obtained. ¹ H NMR (CDCl ₃ ): δ = 0.90 (t, 3
H), 1.32 (m, 4H), 1.53 (m, 2H),
1.77 (bs, 1H), 2.63 (t, 2H), 3.
82 (s, 2H), 3.89 (s, 3H), 6.92
(D, 1H), 7.18 to 7.33 (t, 4H), 7.
77 (s, 1H)

The following amine derivative (VI-D) was synthesized in the same manner as in Reference Example 2. N-pentyl- (2-imidazolylphenyl) methylamine N-pentyl- (3-imidazolylphenyl) methylamine N-pentyl- (4-imidazolylphenyl) methylamine N-pentyl- (2-imidazolyl-5-methoxyphenyl) Methylamine N-pentyl- (3-imidazolyl-4-methoxyphenyl) methylamine N-neopentyl- (5-imidazolyl-2-methoxyphenyl) methylamine N-benzyl- (5-imidazolyl-2-methoxyphenyl) methylamine N-propyl- (5-imidazolyl-2-methoxyphenyl) methylamine N-propyl- (5-imidazolyl-2,3-dimethoxyphenyl) methylamine N-pentyl- (5-imidazolyl-2,3-dimethoxyphenyl) Methylamine N-type Ropyl- (5-imidazolyl-2,3-methylenedioxyphenyl) methylamine N-pentyl- (5-imidazolyl-2,3-methylenedioxyphenyl) methylamine N-pentyl- [5-imidazolyl-2- ( 2-Pyridylmethyloxy) phenyl] methylamine N-pentyl- (5-pyrazolyl-2-methoxyphenyl) methylamine N-pentyl- (5-triazolyl-2-methoxyphenyl) methylamine N-pentyl- (5-pyrrolyl -2-Methoxyphenyl) methylamine

Reference Example-3 (Production Method F) Synthesis of N-pentyl-2- (5-imidazolyl-2,3-methylenedioxyphenyl) ethylamine 70.1 g (0.267mo) of triphenylphosphine
To a solution of 1) in 200 ml of methylene chloride, 44.3 g (0.134 mol) of carbon tetrabromide was added little by little under ice-cooling. Further, under ice-cooling, 27.65 g of 5-bromo-2,3-methylenedioxybenzaldehyde (0.121 mol)
A solution of l) in 100 ml of methylene chloride was added dropwise over 20 minutes. After stirring at room temperature for 2 hours, the reaction solution was washed with water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Ethyl acetate (200 ml) was added to the residue, heated to 60 ° C., and hexane (50 ml) was added. Cool to room temperature,
The precipitated triphenylphosphine oxide was separated by filtration, and the filtrate was concentrated. Similarly, triphenylphosphine oxide was filtered off from 100 ml of ethyl acetate and 100 ml of hexane, and the filtrate was concentrated. The residue was subjected to silica gel chromatography (Wakogel C-300: 200 g, eluent:
Hexane / ethyl acetate (1/10))
42.36 g of β-dibromo-5-bromo-2,3-methylenedioxystyrene was obtained. ¹ H NMR (CDCl ₃ ): δ = 6.00 (s, 2
H), 6.93 (d, 1H), 7.39 (s, 1H),
7.43 (d, 1H)

Β, β-dibromo-5-bromo-2,3-
42.36 g of methylenedioxystyrene (0.11 mol
l) 100 ml of diethylene glycol, 60 ml of water,
32 g (0.485 mol) of 85% potassium hydroxide was added, and the mixture was stirred with heating under reflux for 2 hours. The reaction solution was poured into ice water, extracted with toluene, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was ethyl acetate (80 ml)
-Hexane (300 ml) was recrystallized to give 5-bromo-2,
25.35 g of 3-methylenedioxyphenylacetic acid was obtained. ¹ H NMR (CDCl ₃ ): δ = 3.59 (s, 2
H), 5.98 (m, 2H), 6.80-6.95
(M, 2H)

To a solution of 13.75 g (53.1 mmol) of 5-bromo-2,3-methylenedioxyphenylacetic acid in 180 ml of methylene chloride, 8.0 ml of thionyl chloride (1
10 mmol) and 0.5 ml of N, N-dimethylformamide were added, and the mixture was stirred with heating under reflux for 5 hours. The methylene chloride and excess thionyl chloride were distilled off, the residue was dissolved in methylene chloride (40 ml), and this solution was added to n-pentylamine (6.3 ml, 54.3 mmol) and triethylamine (7.5 ml) in methylene chloride (50 ml) under ice-cooling. It was added dropwise over a period of minutes. After stirring at room temperature for 2 hours, the reaction solution was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (Wakogel C-300: 180 g, eluent: methanol / chloroform (1/50)).
8.61 g of pentyl- (5-bromo-2,3-methylenedioxyphenyl) acetamide was obtained.

¹ H NMR (CDCl ₃ ): δ = 0.8
8 (t, 3H), 1.10 to 1.35 (m, 4H),
1.47 (q, 2H), 3.23 (q, 2H), 3.4
5 (s, 2H), 5.40-5.60 (bs, 1H),
5.99 (s, 2H), 6.85 to 6.95 (m, 2
H) N-pentyl- (5-bromo-2,3-methylenedioxyphenyl) acetamide 4.65 g (14.8 mmo)
1.11 g (16.3 mmol) of imidazole in 1),
2.78 g (20.1 mmol) of potassium carbonate, 0.31 g (3.1 mmol) of cuprous chloride and 25 ml of N-methylpyrrolidone were added, and the mixture was stirred at 200 ° C. for 10 hours. The reaction solution was cooled, 30 ml of ethyl acetate was added, and the precipitate was separated by filtration. The ethyl acetate layer was washed with 10% aqueous ammonia and then saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography (Wakogel C-300: 100 g, eluent: methanol / chloroform (1/50 to 1/20)) to give an oily N-
2.13 g of pentyl- (5-imidazolyl-2,3-methylenedioxyphenyl) acetamide was obtained. ¹ H NMR (CDCl ₃ ): δ = 0.88 (t, 3
H), 1.20-1.40 (m, 4H), 1.49
(Q, 2H), 3.23 (q, 2H), 3.52 (s,
2H), 5.60 to 5.80 (bs, 1H), 6.06
(S, 2H), 6.70-6.90 (m, 2H), 7.
10 to 7.20 (m, 2H), 7.75 (s, 1H)

2.34 g of sodium borohydride (6
1.9 mmol) and 25 ml of tetrahydrofuran with heating under reflux, N-pentyl- (5-imidazolyl-2,3-
2.13 g of methylenedioxyphenyl) acetamide
(6.75 mmol), 3.5 ml of acetic acid (61.1 mm
80 ml of a tetrahydrofuran solution of ol) was added dropwise over 20 minutes, and the mixture was further stirred with heating under reflux for 2 hours. Under ice cooling, 150 ml of water and 25 ml of concentrated hydrochloric acid were added dropwise, and the mixture was stirred at 60 ° C. for 2 hours. 100 ml of ethyl acetate and water 1
50 ml was added, and the mixture was separated. The aqueous layer was made alkaline with sodium hydroxide and then extracted with toluene. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 1.52 g of oily N-pentyl-2- (5-imidazolyl-2,3-methylenedioxyphenyl) ethylamine. ¹ H NMR (CDCl ₃ ): δ = 0.89 (t, 3
H), 1.20-1.40 (m, 4H), 1.49
(Q, 2H), 2.64 (t, 2H), 2.81 (t,
2H), 2.92 (t, 2H), 6.03 (s, 2
H), 6.70-6.75 (m, 2H), 7.16
(S, 2H), 7.73 (s, 1H)

The following amine derivative (VI-F) was synthesized in the same manner as in Reference Example 3. N-pentyl-2- (3-imidazolylphenyl) ethylamine N-pentyl-2- (4-imidazolylphenyl) ethylamine N-pentyl-2- (5-imidazolyl-2-methoxyphenyl) ethylamine N-pentyl-2- ( 4-Pyrazolylphenyl) ethylamine N-pentyl-2- (4-triazolylphenyl) ethylamine

Reference Example-4 (Production Method G) Synthesis of N-heptyl-2- (2-benzyloxy-3-methoxyphenyl) ethylamine 2-benzyloxy-3-methoxybenzaldehyde 4
Nitromethane 100m in 2.2g (0.17mol)
1, 13.4 g (0.17 mol) of ammonium acetate,
Toluene (500 ml) was added, and the mixture was stirred with heating under reflux for 8 hours. The reaction solution was cooled, washed twice with water, washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was chromatographed on silica gel (Wako Gel C-3
00: 250 g, eluent: hexane / ethyl acetate (4 /
1)) to obtain 2-nitro- (2-benzyloxy-3-methoxy) vinylbenzene (47.2 g). ¹ H NMR (CDCl ₃ ): δ = 3.93 (s, 3
H), 5.10 (s, 2H), 6.90-7.45
(M, 8H), 7.55 (d, 1H), 8.09 (d,
1H)

14.0 g of lithium aluminum hydride
(0.38 mol), 1 l of ether was added, and this was added to 20
1.5 hours while maintaining at ~ 25 ° C.
47.2 g of (2-benzyloxy-3-methoxy) vinylbenzene were added little by little. After stirring with heating under reflux for 1 hour, the mixture was cooled to 5 to 6 ° C, and 50 ml of ethyl acetate and subsequently 100 ml of 3% sodium hydroxide were added dropwise. The precipitated salt was filtered, extracted with methylene chloride and washed with saturated saline. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (Wakogel C-300: 850 g, eluent: chloroform) to obtain 19.6 g of 2- (2-benzyloxy-3-methoxyphenyl) ethylamine. ¹ H NMR (CDCl ₃ ): δ = 2.71 (t, 2
H), 2.87 (t, 2H), 3.88 (s, 3H),
5.01 (s, 2H), 6.70 to 7.50 (m, 8
H)

2- (2-benzyloxy-3-methoxyphenyl) ethylamine 10.0 g (0.039 mo)
100 ml of methylene chloride, 40 ml of water and 5.4 g (0.039 mol) of potassium carbonate were added to 1) and the mixture was cooled to 5 to 6 ° C.
A solution obtained by adding 12 ml of methylene chloride to (0.0427 mol) was added dropwise while keeping the temperature at 10 ° C or lower. 1 at room temperature
After stirring for an hour, the reaction solution was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue is subjected to silica gel chromatography (Wakogel C-300: 1).
Purification with 60 g, eluent: hexane / ethyl acetate (2/1)) gave 5.0 g of N- [2- (2-benzyloxy-3-methoxyphenyl) ethyl] heptamide. ¹ H NMR (CDCl ₃ ): δ = 0.86 (t, 3
H), 1.21 (m, 6H), 1.48 (m, 2H),
1.98 (t, 2H), 2.76 (t, 2H), 3.4
0 (q, 2H), 3.90 (s, 3H), 5.02
(S, 3H), 5.84 (bs, 1H), 6.75
(D, 1H), 6.84 (d, 1H), 7.03 (t,
1H), 7.33-7.49 (m, 5H)

3.0 g (8.1) of N- [2- (2-benzyloxy-3-methoxyphenyl) ethyl] heptamide
2 mmol) and add 45 ml of tetrahydrofuran to 5
Cooled to 6 ° C. To this solution, 1.1 g (29.1 mmol) of sodium borohydride was added, and 4.8 ml (39 mmol) of a boron trifluoride etherate was slowly added dropwise. After stirring the reaction solution for 2 hours while heating under reflux, 5
The mixture was cooled to -6 ° C, 25 ml of 6N hydrochloric acid aqueous solution was added, and the mixture was stirred with heating under reflux for 1 hour. 35 ml of 25% aqueous sodium hydroxide solution was added, the reaction solution was made alkaline, extracted with toluene, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (Wakogel C-300: 40 g, eluent: hexane / ethyl acetate (4/1)) to give N-heptyl-2- (2-benzyloxy-3-methoxyphenyl) ethylamine 1
9.6 g were obtained. ¹ H NMR (CDCl ₃ ): δ = 0.87 (t, 3
H), 1.25 (m, 8H), 1.45 (m, 2H),
2.55 (t, 2H), 2.80 (s, 4H), 3.8
8 (s, 3H), 5.01 (s, 2H), 6.81
(M, 2H), 7.01 (t, 1H), 7.32-7.
49 (m, 5H)

The following amine derivative (IV-G) was synthesized in the same manner as in Reference Example 4. N-heptyl-2- [2- (2-pyridylmethyloxy) -3-methoxyphenyl] ethylamine N-pentyl-2- [2- (2-pyridylmethyloxy) -3-methoxyphenyl] ethylamine

Reference Example-5 (Production Method H, Production Method I) 1-Amino-5,6,7,8-tetrahydro-2- [3
Synthesis of-(4-phenyl-1-piperazyl) propoxy] naphthalene 5,6,7,8-tetrahydro-2-naphthol 50 g
400 ml of ether was added to (0.337 mol) and 28 ml of 60% nitric acid was added while keeping the reaction temperature below 15 ° C.
(0.368 mol) was added dropwise, and then the mixture was stirred at 15 to 20 ° C for 1 hr. Water (500 ml) was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was chromatographed on silica gel (Wakogel C-300: 900 g, eluent: hexane / ethyl acetate (500 / 1-60 /
1)) and purified by 2-hydroxy-5,6,7,8-
21.2 g of tetrahydro-1-nitronaphthalene was obtained. ¹ H NMR (CDCl ₃ ): δ = 1.77 (m, 4
H), 2.74 (bs, 2H), 2.97 (bs, 2)
H), 6.92 (d, 1H), 7.21 (d, 1H),
9.74 (s, 1H)

2-Hydroxy-5,6,7,8-tetrahydro-1-nitronaphthalene 17.6 g (0.091 m)
180 ml of N, N-dimethylformamide, 37.8 g (0.273 mol) of potassium carbonate, 1,3-
93 ml (0.916 mol) of dibromopropane was added, and the mixture was stirred at 70 ° C for 4 hours. The precipitated salt was filtered, the solvent was evaporated, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (Wakogel C-300: 500 g, eluent: ethyl acetate / hexane (1/20)), and 5,6,7,8-tetrahydro-1-nitro-2- (3- 19.4 g of bromopropoxy) naphthalene was obtained. ¹ H NMR (CDCl ₃ ): δ = 1.79 (m, 4
H), 2.28 (m, 2H), 4.64 (bs, 2)
H), 4.74 (bs, 2H), 3.55 (t, 2)
H), 4.17 (m, 2H), 6.83 (d, 1H),
7.12 (d, 1H)

4.8 g of 5,6,7,8-tetrahydro-1-nitro-2- (3-bromopropoxy) naphthalene
(15.3 mmol) to 1-phenylpiperazine 2.
77 g (17.1 mmol), potassium carbonate 7.1 g
(51.4 mmol) and 30 ml of N, N-dimethylformamide were added, and the mixture was stirred at 60 ° C for 8 hours. 80 ml of water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel chromatography (Wakogel C-300: 200 g, eluent: hexane / ethyl acetate (7/1 to 3/1)) to give 5,6,7,8-tetrahydro-1-nitro-2. -[3- (4-phenyl-
5.5 g of 1-piperazinyl) propoxy] naphthalene was obtained. ¹ H NMR (CDCl ₃ ): δ = 1.77 (m, 4
H), 1.99 (m, 2H), 2.53 (t, 2H),
2.63 (m, 6H), 2.73 (bs, 2H), 3.
20 (t, 4H), 4.11 (t, 2H), 6.80-
6.88 (m, 3H), 6.93 (d, 1H), 7.1
0 (d, 1H), 7.23 to 7.29 (m, 2H)

5.5 g (13.9 mmol) of 5,6,7,8-tetrahydro-1-nitro-2- [3- (4-phenyl-1-piperazinyl) propoxy] naphthalene
In addition, 15 g (0.27 mol) of iron, 45 ml of isopropyl alcohol, 11 ml of water, and 1.5 ml of acetic acid (26.2).
mmol) was added and the mixture was stirred with heating under reflux for 2 hours. After cooling the reaction solution, potassium carbonate (10 g) dissolved in a small amount of water was added, and after stirring for several minutes, ethyl acetate was added and the precipitate was filtered off. The filtrate was concentrated, the residue was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off.
1-amino-5,6,7,8-tetrahydro-2- [3
There was obtained 4.9 g of-(4-phenyl-1-piperazinyl) propoxy] naphthalene. ¹ H NMR (CDCl ₃ ): δ = 1.72 to 1.85
(M, 4H), 2.04 (q, 2H), 2.48 (t,
2H), 2.58 to 2.72 (m, 8H), 3.22
(T, 4H), 3.76 (bs, 2H), 4.06
(T, 2H), 6.48 (d, 1H), 6.65 (d,
1H), 6.85-6.96 (m, 3H), 7.27.
(M, 2H)

An aniline derivative (II-H) shown below was synthesized in the same manner as in Reference Example 5. 2- {3- (4-phenyl-1-piperazinyl) propoxy} -6-methylaniline 2- {2- (4-phenyl-1-piperazinyl) ethoxy} -6-methylaniline 2- {3- (4- Methyl-1
-Piperazinyl) propoxy} -6-methylaniline 2
-[3- {4- (2-pyridyl) -1-piperazinyl}
Propoxy] -6-methylaniline

Example 1 (Production method A)

Embedded image

2- {3- (4-phenyl-1-piperazinyl) propoxy} -6-methylaniline 7.0 g (2
220 ml of methylene chloride was added to 1.5 mmol), and 5
Cool to ６6 ° C. Bis (trichloromethyl) carbonate 2.
1 g (7.08 mmol) was added little by little, and further 6.5 g (64.2 mmol) triethylamine was added dropwise so that the temperature was kept at 10 ° C or lower. After stirring at 10 to 20 ° C for 1 hour, 5.88 g (21.5 mmo) of N-pentyl- (5-imidazolyl-2-methoxyphenyl) methylamine
1) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution is water 300
The extract was washed twice with ml, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (Wakogel C-300: 70 g, eluent: methanol / chloroform (1/100 to 1/50)), and further ethyl acetate / n-heptane (1 / 2.46: 226).
recrystallized from N- {5- (1-imidazolyl)-
2-Methoxyphenyl} methyl-N- (1-pentyl)
-N '-[2- {3- (4-phenyl-1-piperazinyl) propoxy} -6-methylphenyl] urea 11.
7 g were obtained. ¹ H NMR (CDCl ₃ ): δ = 0.91 (t, 3
H), 1.36 (m, 4H), 1.84 (m, 4H),
2.25 (s, 3H), 2.43 (t, 2H), 2.5
4 (t: 4H), 3.18 (t, 4H), 3.40
(T, 2H), 3.91 (s, 3H), 3.98 (t,
2H), 4.64 (s, 2H), 6.18 (s, 1
H), 6.71-7.03 (m, 7H), 7.18-
7.34 (m, 6H), 7.77 (s, 1H)

Embodiment 2

Embedded image

N- {5- (1-imidazolyl) -2-methoxyphenyl} methyl-N- (1-pentyl) -N '
11.7 g of-[2- {3- (4-phenyl-1-piperazinyl) propoxy} -6-methylphenyl] urea
175 ml of ethyl acetate was added to (0.0187 mol). 16 ml (0.064 mol) of 4N HCl ethyl acetate solution was added dropwise with stirring at room temperature, 100 ml of ether was added after stirring at room temperature for 1 hour, and further stirred at room temperature for 1 hour. The precipitated amorphous crystals were collected by filtration under a nitrogen atmosphere, dried under reduced pressure at 60 ° C. and N- {5- (1-imidazolyl) -2-methoxyphenyl} methyl-N- (1-pentyl) -N ′-[. 13.15 g of 2- {3- (4-phenyl-1-piperazinyl) propoxy} -6-methylphenyl] urea trihydrochloride was obtained. ¹ H NMR (DMSO-d ₆ ): δ = 0.85 (t,
3H), 1.27 (m, 4H), 1.59 (m, 2
H), 2.08 (m, 5H), 3.20 to 3.46.
(M, 6H), 3.89 (s, 3H), 3.99 (t,
2H), 4.31 (bs, 4H), 4.54 (s, 2
H), 6.78 (d, 1H), 6.85 (m, 2H),
6.97 to 7.05 (m, 3H), 7.23 to 7.28
(M, 3H), 7.44 (d, 1H), 7.56 (s,
1H), 7.67 (m, 1H), 7.93 (d, 1
H), 8.14 (d, 1H), 9.72 (s, 1H),
11.54 (bs, 1H)

Embodiment 3

Embedded image

N- {5- (1-imidazolyl) -2-methoxyphenyl} methyl-N- (1-pentyl) -N '
-[2- {3- (4-phenyl-1-piperazinyl) propoxy} -6-methylphenyl] urea 5.0 g
(8.0 mmol) in acetone 84 ml and water 8.4 ml
Was added. While stirring at room temperature, 1.5 ml of concentrated hydrochloric acid (1
(7 mmol) was added dropwise, seed crystals were added, and the mixture was stirred under ice cooling for 3 hours, then the precipitated crystals were collected by filtration and dried under reduced pressure at 60 ° C.
-{5- (1-Imidazolyl) -2-methoxyphenyl} methyl-N- (1-pentyl) -N '-[2- {3
-(4-phenyl-1-piperazinyl) propoxy}-
6-Methylphenyl] urea dihydrochloride
5.1 g were obtained. ¹ H NMR (DMSO-d ₆ ): δ = 0.85 (t,
3H), 1.27 (m, 4H), 1.59 (m, 2
H), 2.08 (m, 5H), 3.17-3.38 (b
m, 12H), 3.89 (s, 3H), 3.99 (t,
2H), 4.54 (s, 2H), 6.80 (d, 1
H), 6.85 (m, 2H), 6.97-7.05
(M, 3H), 7.23-7.28 (m, 3H), 7.
44 (d, 1H), 7.56 (s, 1H), 7.68
(M, 1H), 7.90 (d, 1H), 8.11 (d,
1H), 9.65 (s, 1H)

The following Example Compounds 4-63 and Example Compounds 72-75 were synthesized in the same manner as in Examples 1-3. Among these compounds, those with high hygroscopicity will absorb water when left in the air, and the substances of the following formula:

Embedded image (R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , k, l, and Y are as defined above, a is 0 or any integer, or any fraction, and b is It represents any integer or any fraction). For example, N- {5- (1-imidazolyl) -2-methoxyphenyl} methyl-N- (1-pentyl) -N '-[2- obtained in Example 3
After {3- (4-phenyl-1-piperazinyl) propoxy} -6-methylphenyl] urea dihydrochloride was left in the atmosphere for 2 days, the weight was measured by the Karl Fischer method, and it was 3.3%. An increase in weight was observed.

Example 4 ¹ H NMR DMSO-d ₆ δ = 0.84 (t, 3H), 1.27 (m, 4H), 1.58 (m, 2H), 2.08
(m, 5H), 3.14-3.46 (m, 12H), 3.87 (s, 3H), 3.99 (t, 2
H), 4.53 (s, 2H), 6.78-7.06 (m, 6H), 7.19-7.28 (m, 3
H), 7.36 (d, 1H), 7.52-7.58 (m, 3H), 7.82 (s, 1H), 8.
86 (s, 1H) Example 5 ¹ H NMR CDCl ₃ δ = 0.91 (t, 3H), 1.34 (m, 4H), 1.71 (m, 2H), 1.88
(m, 2H), 2.23 (s, 3H), 2.47 (s, 2H), 2.59 (t, 2H), 2.
70 (t, 4H), 3.22 (t, 4H), 3.40 (t, 2H), 3.90 (s, 3H),
3.96 (t, 2H), 4.64 (s, 2H), 6.20 (m, 2H), 6.72 (d, 1
H), 6.88-7.03 (m, 6H), 7.18-7.83 (m, 6H), 7.84 (s, 1
H) Example 6 ¹ H NMR CDCl ₃ δ = 0.90 (t, 3H), 1.35 (m, 4H), 1.71 (m, 2H), 1.91
(m, 2H), 2.22 (s, 3H), 2.46 (s, 4H), 2.72 (t, 2H), 2.
84 (t, 4H), 3.26 (t, 4H), 3.40 (t, 2H), 3.90 (s, 3H),
3.95 (t, 2H), 4.63 (s, 2H), 6.24 (s, 1H), 6.71 (d, 1
H), 6.81 (d, 1H), 6.89-6.97 (m, 4H), 7.04 (t, 1H), 7.
20-7.34 (m, 6H), 7.71 (bs, 2H), 7.91 (s, 1H)

Example 7 ¹ H NMR DMSO-d ₆ δ = 0.85 (t, 3H), 1.27 (m, 4H), 1.59 (m, 2H), 2.04-
2.08 (m, 5H), 2.35 (s, 6H), 3.16-3.37 (m, 12H), 3.89
(s, 3H), 4.01 (t, 2H), 4.55 (s, 2H), 6.78-6.89 (m, 3
H), 6.98-7.07 (m, 3H), 7.25 (m, 3H), 7.43 (d, 1H), 7.
53 (s, 1H), 7.67 (m, 1H), 7.91 (s, 1H), 8.08 (s, 1H),
9.54 (s, 1H) Example 8 ¹ H NMR CDCl ₃ δ = 0.87 (t, 3H), 1.24 (bs, 8H), 1.55-1.72 (m, 6H),
1.90 (m, 2H), 2.45 (t, 2H), 2.56 (m, 6H), 2.70 (m, 2
H), 3.16-3.28 (m, 6H), 3.91-3.96 (m, 5H), 4.42 (s, 2
H), 5.05 (s, 2H), 5.82 (s, 1H), 6.64 (d, 1H), 6.83-6.
94 (m, 6H), 7.09 (t, 1H), 7.21-7.39 (m, 7H) Example 9 ¹ H NMR CDCl ₃ δ = 1.72 (bs, 4H), 1.86 (m, 4H), 2.40 (t, 2H), 2.47-
2.61 (m, 8H), 2.68 (d, 2H), 3.14 (t, 4H), 3.31 (t, 2
H), 3.91 (m, 5H), 4.41 (s, 2H), 5.05 (s, 2H), 5.80 (s,
1H), 6.64 (d, 1H), 6.83-6.93 (m, 6H), 7.06-7.38 (m,
(13H)

Example 10 ¹ H NMR CDCl ₃ δ = 0.90 (m, 3H), 1.27-1.40 (m, 4H), 1.76-1.96 (m, 8
H), 2.25-2.63 (m, 6H), 2.71 (d, 4H), 3.17 (m, 4H), 3.3
6 (t, 2H), 4.00 (m, 2H), 4.63 (d, 2H), 5.97 (d, 1H), 6.
67 (t, 1H), 6.71-6.94 (m, 4H), 7.19-7.30 (m, 4H), 7.3
7-7.52 (m, 4H), 7.87 (d, 1H) Example 11 ¹ H NMR CDCl ₃ δ = 0.92 (t, 3H), 1.37 (m, 4H), 1.93 (m, 4H), 2.28
(s, 3H), 2.50-2.59 (m, 6H), 3.18 (m, 4H), 3.36 (t, 2
H), 4.02 (m, 2H), 4.65 (s, 2H), 6.10 (s, 1H), 6.72-7.
05 (m, 6H), 7.20-7.52 (m, 8H), 7.86 (s, 1H) Example 12 ¹ H NMR CDCl ₃ δ = 0.91 (t, 3H), 1.37 (m, 4H), 1.92 (m, 4H), 2.28
(s, 3H), 2.50 (m, 6H), 3.36 (t, 2H), 3.52 (t, 4H), 4.
01 (m, 2H), 4.65 (s, 2H), 6.09 (s, 1H), 6.61-6.85 (m,
4H), 7.05 (m, 1H), 7.29 (m, 2H), 7.37-7.52 (m, 5H),
7.87 (d, 1H), 8.20 (d, 1H)

Example 13 ¹ H NMR CDCl ₃ δ = 1.73 (m, 6H), 2.35 (t, 2H), 2.50 (t, 4H), 2.63-
2.70 (m, 4H), 3.16 (t, 4H), 3.84 (s, 3H), 3.91 (t, 2
H), 4.68 (s, 4H), 6.13 (s, 1H), 6.67 (d, 1H), 6.86-6.
95 (m, 5H), 7.20-7.38 (m, 11H), 7.75 (s, 1H) Example 14 ¹ H NMR CDCl ₃ δ = 1.72 (m, 2H), 2.24 (s, 3H), 2.34 (t, 2H), 2.49
(t, 4H), 3.16 (t, 4H), 3.85 (s, 3H), 3.91 (t, 2H), 4.
69 (s, 4H), 6.25 (s, 1H), 6.75 (d, 1H), 6.83-7.02 (m,
6H), 7.19-7.74 (m, 11H), 7.75 (s, 1H) Example 15 ¹ H NMR CDCl ₃ δ = 0.88 (t, 3H), 1.28 (m, 4H), 1.58 (m, 2H), 1.96
(m, 2H), 2.25 (s, 3H), 2.51 (t, 2H), 2.58 (t, 4H), 3.
20 (m, 6H), 4.03 (t, 2H), 4.42 (s, 2H), 6.06 (s, 1H),
6.74 (d, 1H), 6.75-7.10 (m, 6H), 7.24-7.62 (m, 8H)

Example 16 ¹ H NMR CDCl ₃ δ = 0.99 (t, 3H), 1.75 (m, 2H), 1.89 (m, 2H), 2.26
(s, 3H), 2.47 (t, 2H), 2.55 (t, 4H), 3.18 (t, 4H), 3.
34 (t, 2H), 3.87 (s, 3H), 3.92 (s, 3H), 4.00 (t, 2H),
4.69 (s, 2H), 6.22 (s, 1H), 6.73 (d, 1H), 6.81-7.03
(m, 7H), 7.18-7.29 (m, 4H), 7.79 (s, 1H) Example 17 ¹ H NMR CDCl ₃ δ = 0.91 (t, 3H), 1.36 (m, 4H), 1.76-1.86 (m , 4H),
2.25 (s, 3H), 2,41 (t, 2H), 2.48 (t, 4H), 3.40 (t, 2
H), 3.51 (t, 4H), 3.90 (s, 3H), 3.98 (t, 2H), 4.64 (s,
2H), 6.17 (s, 1H), 6.62-6.65 (m, 2H), 6.72 (d, 1H),
6.82 (d, 1H), 6.94 (d, 1H), 7.02 (t, 1H), 7.19 (d, 2
H), 7.26 (m, 1H), 7.34 (d, 1H), 7.47 (m, 1H), 7.77 (s,
1H), 8.19 (d, 1H) Example 18 ¹ H NMR CDCl ₃ δ = 0.90 (t, 3H), 1.34 (m, 4H), 1.70 (m, 2H), 2.25
(s, 3H), 2.56 (t, 4H), 2.63 (t, 2H), 3.12 (t, 4H), 3.
40 (t, 2H), 3.78 (s, 3H), 4.08 (t, 2H), 4.64 (s, 2H),
6.32 (s, 1H), 6.85 (d, 1H), 6.87-6.95 (m, 5H), 7.03
(t, 1H), 7.17-7.28 (m, 5H), 7.34 (d, 1H), 7.77 (s, 1
H)

Example 19 ¹ H NMR CDCl ₃ δ = 0.96 (t, 3H), 1.67-1.86 (m, 4H), 2.25 (s, 3H),
2.43 (t, 2H), 2.54 (t, 4H), 3.18 (t, 4H), 3.38 (t, 2
H), 3.90 (s, 3H), 4.00 (t, 2H), 4.65 (s, 2H), 6.18 (s,
1H), 6.73 (d, 1H), 6.84 (q, 2H), 6.93 (t, 3H), 7.02
(t, 1H), 7.16-7.29 (m, 6H), 7.34 (d, 1H), 7.77 (s, 1
H) Example 20 ¹ H NMR CDCl ₃ δ = 0.91 (t, 3H), 1.39 (m, 4H), 1.77 (m, 2H), 2.23
(s, 3H), 2.40 (m, 2H), 3.40 (m, 2H), 3.60 (m, 2H), 3.
72 (m, 2H), 3.82-4.00 (m, 8H), 4.15 (m, 4H), 4.42 (t,
2H), 4.72 (s, 2H), 6.65 (m, 2H), 6.81 (m, 1H), 7.00
(m, 2H), 7.33-7.66 (m, 7H), 10.30 (bs, 1H) Example 21 ¹ H NMR CDCl ₃ δ = 0.98 (t, 3H), 1.78 (m, 4H), 2.24 (s, 3H ), 2.35
(s, 3H), 2.35-2.43 (m, 10H), 3.37 (t, 2H), 3.90 (s, 3
H), 3.94 (t, 2H), 4.63 (s, 2H), 6.18 (s, 1H), 6.70 (d,
1H), 6.81 (d, 1H), 6.93-7.01 (m, 2H), 7.21 (d, 2H),
7.27 (m, 1H), 7.33 (d, 1H), 7.76 (s, 1H)

Example 22¹ H NMR CDCl_Three  δ = 1.02 (t, 3H), 1.82 (m, 2H), 2.23 (s, 3H), 2.35
(m, 2H), 2.90 (s, 3H), 3.40 (t, 2H), 3.60-3.73 (m, 4
H), 3.90-4.05 (m, 9H), 4.17 (t, 2H), 4.66 (s, 2H), 6.6
5 (d, 1H), 6.72 (d, 1H), 6.99 (m, 2H), 7.27 (m, 1H),
7.38 (s, 1H), 7.47 (s, 1H), 7.65 (s, 1H), 10.31 (s, 1
H) Example 23¹ H NMR CDCl_Three δ = 1.01 (t, 3H), 1.73-1.92 (m, 4H), 2.25 (s, 3H),
2.47 (t, 2H), 2.55 (t, 4H), 3.18 (t, 4H), 3.36 (t, 2
H), 4.00 (t, 2H), 4.61 (s, 2H), 6.06 (s, 2H), 6.18 (s,
 1H), 6.79-6.94 (m, 7H), 7.03 (t, 1H), 7.16 (d, 2H),
7.26 (m, 2H), 7.73 (s, 1H) Example 24¹ H NMR CDCl_Three δ = 0.92 (t, 3H), 1.38 (m, 4H), 1.74 (m, 2H), 1.89
(m, 2H), 2.25 (s, 3H), 2.46 (t, 2H), 2.55 (t, 4H), 3.
18 (t, 4H), 3.38 (t, 2H), 4.01 (t, 2H), 4.61 (s, 2H),
6.06 (s, 2H), 6.17 (s, 1H), 6.72-6.93 (m, 7H), 7.04
(t, 1H), 7.15 (d, 2H), 7.27 (t, 2H), 7.73 (s, 1H)

Example 25 ¹ H NMR CDCl ₃ δ = 0.87 (t, 3H), 1.29 (m, 4H), 1.61 (m, 2H), 1.87
(t, 2H), 2.20 (s, 3H), 2.45 (t, 2H), 2.55 (t, 4H), 3.
17 (t, 4H), 3.34 (t, 2H), 3.87 (s, 3H), 3.95 (t, 2H),
4.62 (s, 2H), 5.19 (s, 2H), 6.11 (s, 1H), 6.69 (d, 1
H), 6.78-7.10 (m, 9H), 7.26 (t, 2H), 7.57 (d, 1H), 7.
65 (t, 1H), 8.52 (d, 1H) Example 26 ¹ H NMR CDCl ₃ δ = 0.86 (t, 3H), 1.28 (m, 4H), 1.63 (m, 2H), 2.17
(s, 3H), 2.27 (m, 2H), 3.41 (m, 4H), 3.67 (d, 2H), 3.
82 (d, 2H), 3.88 (s, 3H), 4.11 (m, 4H), 4.67 (t, 2H),
4.88 (s, 2H), 5.66 (s, 2H), 6.73 (d, 1H), 6.81 (d, 1
H), 6.97 (d, 2H), 7.06 (t, 1H), 7.15 (t, 1H), 7.50 (m,
3H), 7.78 (t, 1H), 7.91 (m, 2H), 8.27 (d, 1H), 8.40
(t, 1H), 8.65 (d, 1H) Example 27 ¹ H NMR CDCl ₃ δ = 0.86 (t, 3H), 1.28 (m, 4H), 1.66-1.72 (m, 8H),
1.87 (m, 2H), 2.45 (t, 2H), 2.55 (m, 4H), 2.70 (t, 2
H), 3.17 (t, 4H), 3.33 (t, 2H), 3.87 (s, 3H), 3.94 (t,
2H), 4.62 (s, 2H), 5.19 (s, 2H), 6.00 (s, 1H), 6.65
(d, 1H), 6.83-7.13 (m, 8H), 7.26 (t, 2H), 7.57 (d, 1
H), 7.66 (m, 1H), 8.53 (d, 1H)

Example 28 ¹ H NMR CDCl ₃ δ = 0.87 (t, 3H), 1.30 (m, 4H), 1.62-1.71 (m, 6H),
2.22 (m, 2H), 2.61 (bs, 2H), 2.68 (bs, 2H), 3.36 (m, 4
H), 3.62 (m, 4H), 3.88 (m, 5H), 4.06 (t, 2H), 4.43 (t,
2H), 4.84 (s, 2H), 5.66 (s, 2H), 6.64 (d, 1H), 6.67
(bs, 1H), 6.88-6.97 (m, 3H), 7.16 (t, 1H), 7.37 (t, 1
H), 7.46 (t, 2H), 7.68 (d, 2H), 7.75 (t, 1H), 8.33-8.
39 (m, 2H), 8.58 (d, 1H) Example 29 ¹ H NMR CDCl ₃ δ = 0.90 (t, 3H), 1.33 (m, 4H), 1.68-1.82 (m, 4H),
2.25 (s, 3H), 2.41 (t, 2H), 2.52 (t, 4H), 3.16 (t, 4
H), 3.42 (t, 2H), 3.96 (t, 2H), 4.76 (s, 2H), 5.29 (s,
2H), 6.19 (s, 1H), 6.84 (d, 1H), 6.89-7.03 (m, 5H),
7.18-7.26 (m, 7H), 7.38 (d, 1H), 7.50 (d, 1H), 7.71
(t, 1H), 7.76 (s, 1H), 8.60 (d, 1H) Example 30 ¹ H NMR CDCl ₃ δ = 0.90 (t, 3H), 1.37 (m, 4H), 1.76 (m, 2H), 2.21-
2.31 (m, 5H), 3.19 (m, 2H), 3.27 (t, 2H), 3.41-3.68
(m, 8H), 3.93 (t, 2H), 4.84 (s, 2H), 5.61 (s, 2H), 6.6
2 (d, 1H), 6.85 (d, 1H), 6.94 (t, 3H), 7.05 (t, 1H),
7.27 (m, 3H), 7.43 (m, 2H), 7.55 (d, 2H), 7.65 (d, 1
H), 7.91 (d, 1H), 8.05 (t, 1H), 8.32 (d, 1H), 9.86 (s,
1H)

Example 31 ¹ H NMR CDCl ₃ δ = 0.88 (t, 3H), 1.36 (m, 4H), 1.74 (m, 2H), 2.23-
2.70 (m, 5H), 3.41 (m, 2H), 3.57 (t, 2H), 3.75 (d, 2
H), 3.94 (m, 6H), 4.37 (m, 2H), 4.95 (s, 2H), 5.98 (s,
2H), 6.59 (d, 1H), 6.83 (d, 1H), 7.03 (t, 1H), 7.38-
7.56 (m, 6H), 7.70-7.76 (m, 6H), 8.25 (bs, 1H), 8.37
(d, 1H), 8.50 (t, 1H), 9.94 (s, 1H) Example 32 ¹ H NMR CDCl ₃ δ = 0.88 (t, 3H), 1.31 (m, 4H), 1.69 (m, 2H), 1.84
(t, 2H), 2.23 (s, 3H), 2.42 (t, 2H), 2.54 (t, 4H), 3.
17 (t, 4H), 3.42 (t, 2H), 3.94 (t, 2H), 4.73 (s, 2H),
5.26 (s, 2H), 6.16 (s, 1H), 6.68 (d, 1H), 6.78-7.02
(m, 7H), 7.22-7.29 (m, 4H), 7.36 (d, 1H), 7.48 (d, 1
H), 7.67 (t, 1H), 8.58 (d, 1H) Example 33 ¹ H NMR CDCl ₃ δ = 0.90 (t, 3H), 1.32 (m, 4H), 1.64 (m, 2H), 1.91
(m, 2H), 2.24 (s, 3H), 2.47 (t, 2H), 2.56 (t, 4H), 3.
17 (t, 4H), 3.34 (t, 2H), 3.99 (t, 2H), 4.54 (s, 2H),
5.20 (s, 2H), 6.04 (s, 1H), 6.72 (d, 1H), 6.82-6.91
(m, 7H), 7.22-7.28 (m, 5H), 7.52 (d, 1H), 7.68 (t, 1
H), 8.58 (d, 1H)

Example 34 ¹ H NMR CDCl ₃ δ = 0.90 (t, 3H), 1.34 (m, 4H), 1.68 (m, 2H), 2.22
(s, 3H), 2.29 (m, 2H), 3.24 (t, 2H), 3.42 (t, 2H), 3.
62 (m, 6H), 4.15 (m, 4H), 4.58 (s, 2H), 5.75 (s, 2H),
6.13 (s, 1H), 6.71 (d, 1H), 6.82 (d, 1H), 7.03 (t, 1
H), 7.18-7.49 (m, 9H), 7.81 (t, 1H), 8.12 (d, 1H), 8.
36 (t, 1H), 8.76 (d, 1H) Example 35 ¹ H NMR CDCl ₃ δ = 0.90 (t, 3H), 1.33 (m, 4H), 1.66 (m, 2H), 1.89
(m, 2H), 2.25 (s, 3H), 2.45 (t, 2H), 2.54 (t, 4H), 3.
17 (t, 4H), 3.36 (t, 2H), 3.98 (t, 2H), 4.58 (s, 2H),
5.20 (s, 2H), 6.05 (s, 1H), 6.71 (d, 1H), 6.69-7.01
(m, 8H), 7.23-7.28 (m, 4H), 7.52 (d, 1H), 7.70 (t, 1
H), 8.58 (d, 1H) Example 36 ¹ H NMR CDCl ₃ δ = 0.90 (t, 3H), 1.34 (m, 4H), 1.69 (m, 2H), 2.10
(s, 3H), 2.27 (m, 2H), 3.33 (t, 2H), 3.47 (m, 2H), 3.
63 (d, 2H), 3.75 (d, 2H), 3.90 (t, 2H), 4.15 (t, 2H),
4.50 (t, 2H), 4.65 (s, 2H), 5.74 (s, 2H), 6.26 (s, 1
H), 6.72 (d, 1H), 6.78 (d, 1H), 7.02 (m, 3H), 7.25 (s,
1H), 7.31-7.48 (m, 4H), 7.70 (m, 3H), 8.09 (d, 1H),
8.38 (t, 1H), 8.74 (d, 1H)

Example 37 ¹ H NMR CDCl ₃ δ = 0.91 (t, 3H), 1.38 (m, 4H), 1.77 (m, 2H), 2.22
(s, 3H), 2.46 (m, 2H), 3.44 (m, 2H), 3.65-3.87 (m, 6
H), 4.12 (m, 4H), 4.33 (m, 2H), 4.77 (s, 2H), 6.66-6.
82 (m, 3H), 7.00 (t, 2H), 7.31-7.60 (m, 9H), 7.79 (s,
1H), 10.31 (s, 1H) Example 38 ¹ H NMR CDCl ₃ δ = 0.92 (t, 3H), 1.35 (m, 4H), 1.72 (m, 2H), 1.95
(t, 2H), 2.28 (s, 3H), 2.47-2.59 (m, 6H), 3.18 (t, 4
H), 3.36 (t, 2H), 4.02 (t, 2H), 4.65 (s, 2H), 6.10 (s,
1H), 6.74 (d, 1H), 6.82-6.93 (m, 4H), 7.05 (t, 1H),
7.19-7.30 (m, 4H), 7.37-7.48 (m, 4H), 7.87 (s, 1H) Example 39 ¹ H NMR CDCl ₃ δ = 0.91 (t, 3H), 1.35 (m, 4H), 1.71 ( bs, 2H), 2.20
(s, 3H), 2.34 (bs, 2H), 3.47 (m, 4H), 3.51 (m, 2H), 3.
64 (m, 4H), 4.21-4.33 (m, 4H), 4.77 (s, 2H), 6.71 (m,
3H), 6.93 (t, 1H), 7.26-7.75 (m, 10H), 9.75 (s, 1H)

Example 40¹ H NMR CDCl_Three  δ = 0.88 (t, 3H), 1.31 (m, 4H), 1.68 (m, 2H), 1.84
(m, 2H), 2.23 (s, 3H), 2.42 (t, 2H), 2.53 (t, 4H), 3.
16 (t, 4H), 3.39 (t, 2H), 3.77 (s, 3H), 3.93 (t, 2H),
4.65 (s, 2H), 5.22 (s, 2H), 6.20 (s, 1H), 6.54 (m, 2
H), 6.68 (d, 1H), 6.78-7.00 (m, 5H), 7.20 (m, 1H), 7.
23-7.29 (m, 3H), 7.48 (d, 1H), 7.63 (t, 1H), 8.56 (d, 1
H) Example 41¹ H NMR CDCl_Three δ = 0.91 (t, 3H), 1.34 (m, 4H), 1.69 (m, 2H), 2.22
(s, 3H), 2.30 (m, 2H), 3.23 (t, 2H), 3.43 (t, 2H), 3.
59 (m, 6H), 3.88 (s, 3H), 4.13 (m, 4H), 4.58 (s, 2H),
5.73 (s, 2H), 6.10 (s, 1H), 6.72 (d, 1H), 6.83 (d, 1
H), 6.90 (m, 2H), 7.04 (t, 1H), 7.20 (d, 2H), 7.37 (d,
 4H), 7.79 (t, 1H), 8.21 (d, 1H), 8.38 (t, 1H), 8.71
(d, 1H) Example 42¹ H NMR CDCl_Three δ = 0.90 (t, 3H), 1.32 (m, 4H), 1.64 (m, 2H), 1.89
(m, 2H), 2.23 (s, 3H), 2.46 (t, 2H), 2.54 (t, 4H), 3.
18 (t, 4H), 3.30 (t, 2H), 3.90 (s, 3H), 3.98 (t, 2H),
4.49 (s, 2H), 5.27 (s, 2H), 6.03 (s, 1H), 6.70 (d, 1
H), 6.79-7.01 (m, 8H), 7.20-7.28 (m, 3H), 7.57 (d, 1
H), 7.67 (t, 1H), 8.57 (d, 1H)

Example 43 ¹ H NMR CDCl ₃ δ = 0.90 (t, 3H), 1.34 (m, 4H), 1.67 (m, 2H), 2.08
(s, 3H), 2.35 (m, 2H), 3.27-3.47 (m, 6H), 3.60 (t, 4
H), 3.89 (m, 5H), 4.16 (t, 2H), 4.55 (s, 2H), 5.70 (s,
2H), 6.16 (s, 1H), 6.73 (d, 1H), 6.79 (d, 1H), 6.94
(d, 1H), 7.01-7.36 (m, 8H), 7.67 (t, 1H), 8.15 (d, 1
H), 8.32 (t, 1H), 8.60 (d, 1H) Example 44 ¹ H NMR CDCl ₃ δ = 0.90 (t, 3H), 1.33 (m, 4H), 1.66 (m, 2H), 1.90
(m, 2H), 2.25 (s, 3H), 2.47 (t, 2H), 2.56 (t, 4H), 3.
18 (t, 4H), 3.34 (t, 2H), 3.90 (s, 3H), 3.99 (t, 2H),
4.53 (s, 2H), 5.27 (s, 2H), 6.07 (s, 1H), 6.72 (d, 1
H), 6.80-7.02 (m, 8H), 7.23-7.28 (m, 3H), 7.57 (d, 1
H), 7.68 (t, 1H), 8.57 (d, 1H) Example 45 ¹ H NMR CDCl ₃ δ = 0.90 (t, 3H), 1.34 (m, 4H), 1.69 (m, 2H), 2.12
(m, 2H), 2.28 (s, 3H), 3.42-3.61 (m, 8H), 3.83 (m, 7
H), 4.34 (m, 2H), 4.85 (s, 2H), 5.98 (s, 2H), 6.54 (m,
2H), 6.85 (d, 1H), 7.02 (m, 2H), 7.20 (d, 1H), 7.41-
7.51 (m, 4H), 7.61 (t, 1H), 7.79 (d, 2H), 8.08 (bs, 1
H), 8.33-8.41 (m, 2H)

Example 46 ¹ H NMR CDCl ₃ δ = 0.91 (t, 3H), 1.34 (m, 4H), 1.66 (m, 2H), 2.16
(s, 3H), 2.39 (bs, 2H), 3.05 (t, 2H), 3.33 (t, 2H),
3.47 (m, 2H), 3.65 (m, 6H), 3.80 (d, 2H), 4.20 (m, 4H),
6.52 (s, 1H), 6.73 (t, 2H), 6.95 (t, 1H), 7.20 (bs, 1
H), 7.35-7.57 (m, 10H), 9,46 (s, 1H) Example 47 ¹ H NMR CDCl ₃ δ = 0.90 (t, 3H), 1.34 (m, 4H), 1.74 (m, 4H) , 2.25
(s, 3H), 2.36 (t, 2H), 2.49 (t, 4H), 3.15 (t, 4H), 3.
43 (t, 2H), 3.90 (s, 5H), 4.65 (s, 2H), 6.20 (s, 1H),
6.44 (t, 1H), 6.68 (d, 1H), 6.79-7.04 (m, 7H), 7.23-
7.30 (m, 1H), 7.58-7.69 (m, 3H), 7.85 (d, 1H) Example 48 ¹ H NMR CDCl ₃ δ = 0.89 (t, 3H), 1.33 (m, 4H), 1.69 (m, 2H), 2.23
(m, 5H), 2.77 (t, 2H), 2.95 (t, 2H), 3.30 (d, 2H), 3.
41-3.55 (m, 6H), 3.90 (s, 3H), 4.05 (t, 2H), 4.63 (s,
2H), 6.23 (s, 1H), 6.48 (t, 1H), 6.71 (d, 1H), 6.83-
7.10 (m, 7H), 7.23-7.30 (m, 1H), 7.55 (d, 1H), 7.68
(d, 1H), 7.75 (d, 1H), 7.88 (d, 1H)

Example 49 ¹ H NMR CDCl ₃ δ = 0.91 (t, 3H), 1.36 (m, 4H), 1.70-1.86 (m, 4H),
2.25 (s, 3H), 2.42 (t, 2H), 2.53 (t, 4H), 3.17 (t, 4
H), 3.42 (t, 2H), 3.92 (s, 3H), 3.97 (t, 2H), 4.65 (s,
2H), 6.19 (s, 1H), 6.72 (d, 1H), 6.80-7.06 (m, 7H),
7.23-7.30 (m, 1H), 7.54-7.60 (m, 2H), 8.07 (s, 1H),
8.46 (s, 1H) Example 50 ¹ H NMR CDCl ₃ δ = 0.90 (t, 3H), 1.37 (m, 4H), 1.74 (t, 2H), 2.23
(s, 3H), 2.31 (bs, 2H), 3.24 (t, 2H), 3.54-3.77 (m, 8
H), 3.93 (s, 3H), 4.12 (t, 2H), 4.26 (t, 2H), 4.66 (s,
2H), 6.41 (s, 1H), 6.71 (d, 1H), 6.84 (d, 1H), 7.05
(m, 2H), 7.28 (m, 2H), 7.39-7.52 (m, 4H), 7.66 (d, 1
H), 7.75 (d, 1H), 8.25 (s, 1H) Example 51 ¹ H NMR CDCl ₃ δ = 0.87 (t, 3H), 1.26 (m, 4H), 1.59 (m, 2H), 1.95
(m, 2H), 2.20 (s, 3H), 2.53 (m, 6H), 3.05 (t, 2H), 3.
14 (t, 4H), 3.26 (t, 2H), 3.50 (t, 2H), 3.84 (s, 3H),
3.95 (t, 2H), 5.17 (s, 2H), 6.20 (s, 1H), 6.66 (d, 1
H), 6.79-6.91 (m, 6H), 6.97-7.06 (m, 3H), 7.25 (t, 2
H), 7.49 (t, 1H), 7.53 (d, 1H), 8.04 (d, 1H)

Example 52 ¹ H NMR CDCl ₃ δ = 0.88 (t, 3H), 1.30 (m, 4H), 1.59 (m, 2H), 2.13
(s, 3H), 2.36 (bs, 2H), 3.10 (t, 2H), 3.39 (t, 2H),
3.45-3.68 (m, 6H), 3.80 (s, 3H), 3.91 (bs, 4H), 4.13
(bs, 2H), 4.43 (t, 2H), 5.58 (s, 2H), 6.71 (t, 3H),
6.89 (m, 2H), 7.01 (t, 1H), 7.10 (t, 1H), 7.37 (t, 1H),
7.45 (t, 2H), 7.58 (bs, 1H), 7.69 (d, 2H), 8.10 (m, 2
H), 8.39 (bs, 1H) Example 53 ¹ H NMR CDCl ₃ δ = 0.92 (t, 3H), 1.35 (m, 4H), 1.71 (m, 2H), 1.97
(m, 2H), 2.23 (s, 3H), 2.55 (m, 6H), 2.98 (t, 2H), 3.
17 (t, 4H), 3.32 (t, 2H), 3.61 (t, 2H), 4.03 (t, 2H),
6.03 (s, 2H), 6.13 (s, 1H), 6.75-6.92 (m, 7H), 7.04
(t, 1H), 7.14 (d, 2H), 7.25 (t, 2H), 7.72 (s, 1H) Example 54 ¹ H NMR CDCl ₃ δ = 0.89 (t, 3H), 1.33 (m, 4H), 1.65 (bs, 2H), 2.15
(s, 3H), 2.27 (bs, 2H), 3.04 (bs, 2H), 3.43 (bs, 4H),
3.62 (m, 4H), 3.76 (bs, 4H), 4.10 (m, 4H), 6.10 (s, 2
H), 6.69 (m, 2H), 6.91 (m, 2H), 7.21 (m, 2H), 7.36 (m,
5H), 7.56 (s, 2H), 9.51 (s, 1H)

Example 55 ¹ H NMR CDCl ₃ δ = 0.90 (t, 3H), 1.35 (m, 4H), 1.71 (m, 2H), 2.05
(m, 2H), 2.22 (s, 3H), 2.95 (m, 2H), 3.48 (m, 6H), 3.
90 (m, 5H), 4.04 (t, 2H), 4.50 (t, 2H), 4.62 (s, 2H),
6.20 (s, 1H), 6.34 (s, 2H), 6.73 (d, 1H), 6.84 (d, 1
H), 6.98-7.11 (m, 4H), 7.37-7.51 (m, 5H), 7.73 (d, 2
H) Example 56 ¹ H NMR CDCl ₃ δ = 0.91 (t, 3H), 1.34 (m, 4H), 1.68 (m, 2H), 1.96
(m, 2H), 2.27 (s, 3H), 2.51 (m, 6H), 3.13 (m, 6H), 3.
36 (t, 2H), 3.53 (t, 2H), 3.82 (s, 3H), 4.04 (t, 2H),
6.56 (s, 1H), 6.76 (d, 1H), 6.83-6.91 (m, 5H), 7.06
(t, 1H), 7.19-7.28 (m, 6H), 7.76 (s, 1H) Example 57 ¹ H NMR CDCl ₃ δ = 0.88 (t, 3H), 1.28 (m, 4H), 1.58 (m, 2H ), 1.95
(m, 2H), 2.26 (s, 3H), 2.49 (t, 2H), 2.57 (t, 4H), 3.
17-3.25 (m, 6H), 3.84 (s, 3H), 4.03 (t, 2H), 4.35 (s,
2H), 6.08 (s, 1H), 6.75 (d, 1H), 6.85-6.94 (m, 5H),
7.04-7.08 (m, 3H), 7.17-7.56 (m, 4H), 7.56 (s, 1H)

Example 58 ¹ H NMR CDCl ₃ δ = 0.91 (t, 3H), 1.35 (m, 4H), 1.71 (m, 2H), 1.91
(m, 2H), 2.26 (s, 3H), 2.48 (t, 2H), 2.56 (t, 4H), 3.
18 (t, 4H), 3.34 (t, 2H), 3.84 (s, 3H), 4.01 (t, 2H),
4.58 (s, 2H), 6.10 (d, 1H), 6.74 (d, 1H), 6.85-6.93
(m, 4H), 7.02-7.05 (m, 2H), 7.16-7.29 (m, 6H), 7.80
(s, 1H) Example 59 ¹ H NMR CDCl ₃ δ = 0.91 (t, 3H), 1.34 (m, 4H), 1.69 (m, 2H), 1.99
(m, 2H), 2.27 (s, 3H), 2.55 (m, 6H), 3.00 (t, 2H), 3.
18 (m, 4H), 3.26 (t, 2H), 3.58 (t, 2H), 4.05 (t, 2H),
6.07 (s, 1H), 6.44 (d, 1H), 6.76 (d, 1H), 6.82-6.91
(m, 4H), 7.04 (t, 1H), 7.22-7.34 (m, 4H), 7.63 (d, 2
H), 7.71 (s, 1H), 7.89 (s, 1H) Example 60 ¹ H NMR CDCl ₃ δ = 0.92 (t, 3H), 1.35 (m, 4H), 1.69 (m, 2H), 2.01
(m, 2H), 2.25 (s, 3H), 2.58 (m, 6H), 3.02 (t, 2H), 3.
17 (m, 4H), 3.25 (t, 2H), 3.59 (t, 2H), 4.05 (t, 2H),
6.06 (s, 1H), 6.76 (d, 1H), 6.83-6.92 (m, 4H), 7.04
(t, 1H), 7.25 (m, 2H), 7.39 (d, 2H), 7.61 (d, 2H), 8.
09 (s, 1H), 8.52 (s, 1H)

Example 61 ¹ H NMR CDCl ₃ δ = 1.09 (s, 9H), 1.84 (m, 2H), 2.17 (s, 3H), 2.44
(t, 2H), 2.56 (t, 4H), 3.19 (t, 4H), 3.31 (s, 2H), 3.
89 (s, 3H), 3.95 (t, 2H), 4.72 (s, 2H), 6.25 (s, 1H),
6.70-7.05 (m, 6H), 7.17-7.30 (m, 7H), 7.75 (s, 1H) Example 62 ¹ H NMR CDCl ₃ δ = 1.11 (s, 9H), 2.19 (s, 3H), 2.35 ( m, 2H), 3.38
(m, 2H), 3.52 (s, 2H), 3.68-3.91 (m, 7H), 4.11 (m, 4
H), 4.32 (t, 2H), 4.72 (s, 2H), 6.59 (bs, 1H), 6.65
(d, 1H), 6.77 (d, 1H), 6.98 (t, 2H), 7.32-7.54 (m, 9
H), 10.10 (s, 1H) Example 63 ¹ H NMR CDCl ₃ δ = 0.92 (t, 3H), 1.34 (m, 4H), 1.67 (m, 2H), 1.98
(m, 2H), 2.24 (s, 3H), 2.50-2.60 (m, 6H), 3.03 (t, 2
H), 3.18 (t, 4H), 3.26 (t, 2H), 3.60 (t, 2H), 4.04 (t,
2H), 6.07 (s, 1H), 6.74 (d, 1H), 6.83-6.93 (m, 4H),
7.05 (t, 1H), 7.19-7.29 (m, 7H), 7.41 (t, 1H), 7.85
(s, 1H)

[0098]

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[0099]

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[0100]

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[0101]

[Chemical 21]

[0102]

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[0103]

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[0104]

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Example 64

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1.16 g (5.91 mmol) of 1-amino-5,6,7,8-tetrahydro-2- {3- (4-phenyl-1-piperazinyl) propoxy} naphthalene
60 ml of methylene chloride was added to, and bis (trichloromethyl) carbonate 0.75 g (2.5
3 mmol) and 1.62 g of triethylamine (16
mmol). After stirring for 1.5 hours with heating under reflux, the mixture was cooled to room temperature and N-heptyl-2- (2-benzyloxy-3-methoxyphenyl) ethylamine 2.16 g
(6.08 mmol) was added, and the mixture was reacted overnight at room temperature.
Part of the solvent was distilled off, and silica gel chromatography (Wakogel C-300: 150 g, eluent: ethyl acetate /
Hexane (1/1)), N- {2- (2-benzyloxy-3-methoxy) phenyl} ethyl-N-
(1-heptyl) -N '-[5,6,7,8-tetrahydro-2- {3- (4-phenyl-1-piperazinyl)
Propoxy} naphthyl] urea was obtained. To this, 120 ml of ethyl alcohol, 10% palladium / carbon 0.4
5 g was added and hydrogenated at 50 ° C. for 6 hours. After filtering the catalyst, the solvent was distilled off, and the residue was purified by silica gel chromatography (Wakogel C-300: 150 g, eluent: chloroform / methanol (100/1)), N- {2-.
(2-Hydroxy-3-methoxyphenyl) ethyl}-
1.0 g of N- (1-heptyl) -N '-[5,6,7,8-tetrahydro-2- {3- (4-phenyl-1-piperazyl) propoxy} naphthyl] urea was obtained. ¹ H NMR (CDCl ₃ ): δ = 0.88 (t, 3
H), 1.30 (m, 8H), 1.63 to 1.74.
(M, 4H), 1.96 (m, 2H), 2.51 (m,
6H), 2.72 (bs, 4H), 3.01 to 3.14.
(M, 6H), 3.37 (t, 2H), 3.51 (t,
2H), 3.84 (s, 3H), 4.01 (t, 2)
H), 6.57 (bs, 1H), 6.67 to 6.91.
(M, 8H), 7.26 (m, 2H)

Example 65

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N- {2- (2-hydroxy-3-methoxy) phenyl} ethyl-N- (1-heptyl) -N '
-[5,6,7,8-tetrahydro-2- {3- (4-
Phenyl-1-piperazyl) propoxy} naphthyl] urea (1.0 g, 1.5 mmol) and potassium carbonate (1.0)
g (7.2 mmol), 2-chloromethylpyridine hydrochloride 0.56 g (3.4 mmol), N, N-
Add 30 ml of dimethylformamide and add 12 at 100 ° C.
Stirred for hours. After cooling, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography (Wako Gel C-300: 80 g, eluent: ethyl acetate), and N- [2- {2- (2-
Pyridylmethyloxy) -3-methoxyphenyl} ethyl] -N- (1-heptyl) -N '-[5,6,7,8
-Tetrahydro-2- {3- (4-phenyl-1-piperazyl) naphthyl}] urea was obtained. To this, methyl alcohol and concentrated hydrochloric acid 0.15 ml (1.7 mmol)
Was added, and the solvent was concentrated and crystallized from ether to give N- [2- {2- (2-pyridylmethyloxy)
-3-Methoxy} phenyl] ethyl-N- (1-heptyl) -N '-[5,6,7,8-tetrahydro-2-
{3- (4-phenyl-1-piperazyl) propoxy}
Naphthyl} urea trihydrochloride 0.23g
I got ¹ H NMR (CDCl ₃ ): δ = 0.86 (t, 3
H), 1.27 (m, 8H), 1.57 to 1.67
(M, 6H), 2.37 (m, 2H), 2.52 (b
s, 2H), 2.64 (bs, 2H), 3.14 (t,
2H), 3.36 (t, 2H), 3.47 to 3.64.
(M, 6H), 3.79 (s, 3H), 3.83 (b
s, 4H), 4.15 (bs, 2H), 4.35 (b
s, 2H), 5.62 (s, 2H), 6.46 (s, 1
H), 6.62 (d, 1H), 6.83 to 6.91.
(M, 3H), 7.10 (s, 1H), 7.28 (m,
1H), 7.31 to 7.56 (m, 5H), 8.06
(Bs, 2H), 8.50 (d, 1H)

In the same manner as in Examples 64 to 65, the following No. Compounds 66-71 were synthesized. Example 66 ¹ H NMR CDCl ₃ δ = 0.86 (t, 3H), 1.28 (m, 8H), 1.72 (m, 6H), 1.88
(t, 2H), 2.43 (t, 2H), 2.54 (t, 4H), 2.68 (m, 4H), 3.
17 (t, 4H), 3.41 (t, 2H), 3.93 (t, 2H), 4.73 (s, 2H),
5.25 (s, 2H), 6.06 (s, 1H), 6.64 (d, 1H), 6.84-6.95
(m, 6H), 7.02 (t, 1H), 7.17-7.29 (m, 3H), 7.38 (d, 1
H), 7.49 (d, 1H), 7.69 (t, 1H), 8.57 (d, 1H) Example 67 ¹ H NMR CDCl ₃ δ = 1.72-1.84 (m, 6H), 2.01 (m, 2H), 2.39 (t, 2H),
2.48 (t, 4H), 2.62-2.70 (m, 6H), 3.12 (t, 4H), 3.49
(t, 2H), 3.91 (t, 2H), 4.72 (s, 2H), 5.24 (s, 2H), 6.0
6 (s, 1H), 6.65 (d, 1H), 6.84-6.95 (m, 6H), 7.02 (t, 1
H), 7.16-7.33 (m, 9H), 7.47 (d, 1H), 7.64 (t, 1H), 8.
56 (d, 1H) Example 68 ¹ H NMR CDCl ₃ δ = 0.93 (t, 3H), 1.70 (m, 6H), 1.85 (m, 2H), 2.44
(t, 2H), 2.54 (t, 4H), 2.64-2.70 (m, 4H), 3.17 (t, 4
H), 3.39 (t, 2H), 3.93 (t, 2H), 4.73 (s, 2H), 5.25 (s,
2H), 6.07 (s, 1H), 6.65 (d, 1H), 6.84-6.95 (m, 5H),
7.03 (t, 1H), 7.20-7.29 (m, 4H), 7.38 (d, 1H), 7.50
(d, 1H), 7.67 (d, 1H), 8.56 (d, 1H)

Example 69 ¹ H NMR CDCl ₃ δ = 0.94 (t, 3H), 1.72 (m, 6H), 1.86 (m, 2H), 2.44
(t, 2H), 2.55 (t, 4H), 2.64-2.71 (m, 4H), 3.18 (t, 4
H), 3.39 (t, 2H), 3.94 (t, 2H), 4.71 (s, 2H), 5.13 (s,
2H), 6.03 (s, 1H), 6.67 (d, 1H), 6.85-6.94 (m, 7H),
7.04 (t, 1H), 7.23-7.38 (m, 4H), 8.60 (m, 2H) Example 70 ¹ H NMR CDCl ₃ δ = 0.91 (t, 3H), 1.70 (m, 6H), 1.88 (m, 2H), 2.47
(t, 2H), 2.57 (m, 6H), 2.70 (m, 2H), 3.19 (t, 4H), 3.
36 (t, 2H), 3.94 (t, 2H), 4.64 (s, 2H), 5.11 (s, 2H),
6.00 (s, 1H), 6.66 (d, 1H), 6.84-6.98 (m, 5H), 7.08
(t, 1H), 7.23-7.30 (m, 4H), 7.42 (d, 1H), 7.79 (d, 1
H), 8.60 (m, 1H), 8.68 (d, 1H) Example 71 ¹ H NMR CDCl ₃ δ = 1.72 (m, 4H), 1.85 (m, 2H), 2.43 (t, 2H), 2.53
(t, 4H), 2.68 (m, 4H), 3.10 (s, 3H), 3.16 (t, 4H), 3.
93 (t, 2H), 4.74 (s, 2H), 5.25 (s, 2H), 6.17 (s, 1H),
6.65 (d, 1H), 6.85-6.97 (m, 5H), 7.03 (t, 1H), 7.18-
7.36 (m, 5H), 7.48 (d, 1H), 7.64 (t, 1H), 8.54 (d, 1H)

Example 72 ¹ H NMR DMSO-d ₆ δ = 1.39-1.60 (m, 6H), 1.93 (m, 2H), 2.10 (m, 5H),
3.21-3.48 (m, 10H), 3.91 (s, 3H), 4.00 (t, 2H), 4.44
(s, 2H), 4.58 (q, 1H), 6.76-7.05 (m, 6H), 7.21-7.36
(m, 4H), 7.61-7.67 (m, 2H), 7.92 (s, 1H), 8.06 (s, 1
H), 9.62 (s, 1H) Example 73 ¹ H NMR DMSO-d ₆ δ = 0.94 (d, 6H), 2.06 (m, 6H), 3.05-3.80 (m, 12H),
3.89 (s, 3H), 3.97 (t, 2H), 4.56 (s, 2H), 6.76-7.05
(m, 6H), 7.27 (m, 3H), 7.40 (d, 1H), 7.69 (s, 1H), 7.
70 (m, 1H), 7.96 (s, 1H), 8.16 (s, 1H), 9.76 (s, 1H) Example 74 ¹ H NMR DMSO-d ₆ δ = 1.14 (m, 6H), 2.07 (m, 5H), 3.11-3.78 (m, 10H),
3.91 (s, 3H), 3.99 (t, 2H), 4.44 (s, 2H), 4.56 (m, 1
H), 6.76-6.89 (m, 3H), 6.99-7.05 (m, 3H), 7.22-7.29
(m, 3H), 7.44 (d, 1H), 7.54 (s, 1H), 7.64-7.67 (m, 1
H), 7.95 (s, 1H), 8.11 (s, 1H), 9.68 (s, 1H) Example 75 ¹ H NMR DMSO-d ₆ δ = 1.48 (s, 9H), 2.19 (m, 5H), 3.13 -3.74 (m, 10H),
3.91 (s, 3H), 4.09 (m, 4H), 6.80-6.87 (m, 2H), 6.94
(d, 2H), 7.04 (t, 1H), 7.23 (t, 2H), 7.31 (d, 1H), 7.
85 (d, 1H), 7.92 (s, 1H), 8.29 (t, 2H), 9.36 (bs, 2H),
9.72 (s, 1H)

[0112]

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[0113]

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Test Example Test Example 1: AC of HepG2 cells derived from human liver cancer cells
AT inhibitory activity The ACAT inhibitory activity of the compounds of the present invention was measured by the following method. ACAT activity was measured using HepG2 cells derived from human liver cancer cells. A radiolabeled oleic acid-bovine serum albumin complex was added to the culture medium of the cells, and the amount of radiolabeled cholesterol oleate formed from radiolabeled oleic acid in the cells was determined. The activity of a compound of the present invention that inhibits ACAT was based on the amount of cholesterol oleate produced in a control group to which no test drug was added, and what percentage of the enzyme activity was reduced by adding each concentration (μM) of the test drug. Was determined, and the IC ₅₀ value (the concentration of the test compound required to inhibit the enzyme activity by 50%) was determined from the results. Table 2 shows the results.

Test Example 2: ACA of foamed macrophages
T Inhibitory Activity The macrophage ACAT inhibitory activity of the compounds of the present invention was measured by the following method. Acetylated low-density lipoprotein was added to macrophages collected from the abdominal cavity of ddY female mice and cultured overnight to obtain foamed macrophages. The cell accumulates a large amount of cholesterol (ester) in the cell and is considered as a model of arteriosclerotic lesion. The ACAT activity of the cells was determined by adding a radiolabeled oleic acid-bovine serum albumin complex to the culture medium and measuring the amount of radiolabeled cholesterol oleate formed from radiolabeled oleic acid in the cells. I asked. The activity of a compound of the present invention that inhibits ACAT was based on the amount of cholesterol oleate produced in a control group to which no test drug was added, and what percentage of the enzyme activity was reduced by adding each concentration (μM) of the test drug. Was determined, and the IC ₅₀ value (the concentration of the test compound required to inhibit the enzyme activity by 50%) was determined from the results. Table 2 shows the results.

[0116]

[Table 2]

Test Example 3: Cholesterol-lowering effect in rats fed a high-cholesterol diet WISTAR rats 6-week-old males were fed with a solid high-cholesterol diet (Oriental Yeast Co., Ltd .: cholesterol 1).
%, Cholic acid 0.5%), and 0.2 mg aqueous solution of the test substance (compound of Example 3) was given to 7 animals per group once a day, 1 mg / kg, 3 mg / kg, 10 mg / kg,
Alternatively, it was orally administered by gavage at a dose of 30 mg / kg for 5 days. On the other hand, 7 rats of the same group were fed with the same high-cholesterol diet and used as a control group. 3.5 hours after the final administration, blood was collected from the abdominal vena cava, and total cholesterol in serum was measured. The total cholesterol lowering rate was expressed as a ratio with the control (7 animals) to which no drug was administered, and was assayed by the probit method. Table 3 shows the results.

[0118]

[Table 3]

[0119]

INDUSTRIAL APPLICABILITY The compound of the present invention has an excellent ACAT inhibitory activity, and is an active ingredient of a medicine for the prevention and / or treatment of hyperlipidemia and the prevention and / or treatment of atherosclerosis. Is useful as

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07D 231/12 C07D 231/12 E 249/08 513 249/08 513 295/08 295/08 A 401 / 12 233 401/12 233 403/12 233 403/12 233 405/04 231 405/04 231 233 233 249 249 // C12N 9/99 C12N 9/99 (C07D 401/12 213: 30 233: 61) ( (C07D 401/12 213: 74 233: 61) (C07D 403/12 233: 61 239: 42) (C07D 405/04 231: 12 317: 48) (C07D 405/04 233: 61 317: 48) (C07D 405 (04 249: 08 317: 48) (72) Inventor Kazuo Suzuki 1000 Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa Mitsubishi Chemical Corporation Yokohama Research Institute (72) Inventor Chisuko Takahashi 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa Address Mitsubishi Chemical stock Company Yokohama Research Institute (72) Inventor Mizue Kawai 1000 Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa Mitsubishi Chemical Corporation Yokohama Research Institute (72) Inventor Masayuki Mitsuya 1000 Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa Mitsubishi Chemical Corporation Company Yokohama Research Institute

Claims (16)

[Claims] 1. A compound represented by the following general formula (I) (In the general formula (I), R ₁ , R ₂ and R ₃ are each independently a hydrogen atom, a hydroxyl group, a C ₁ -C ₃ alkoxy group, Het- (CH ₂ ) _m- O- (Het Represents a heterocyclic residue having 1 to 2 nitrogen atoms and a total number of atoms of 5 to 6, and m represents an integer of 1 to 3), a C _{7 to} C ₉ aralkyloxy group, or a nitrogen atom. Represents a heterocyclic residue having 1 to 4 total atoms and having 5 to 6 atoms, and R ₁ and R ₂ together form —O— (CH ₂ ) _n —O— (n is 1 to 3). Represents an integer.) R ₄ is a C ₁ -C ₇ alkyl group, a C ₃ -C ₇ cycloalkyl group, Ar- (CH
_{2) p} - (Ar represents an aryl group of C ₆ ~C _10, p represents represents) an integer of 1 to 3.. R ₅ and R ₆ each independently represent a hydrogen atom or a C ₁ -C ₃ alkyl group, but when R ₅ and R ₆ are taken together, — (CH ₂ ) _q —
(Q represents an integer of 3 to 5) may be represented. Y is C
_{It represents a 1 to} C ₃ alkyl group, a heterocyclic residue containing 1 to 4 nitrogen atoms and having a total of 5 to 6 atoms, or a C _{6 to} C ₁₀ aryl group. k represents an integer of 1 to 3, and l represents an integer of 2 to 4. ) Or a salt thereof, or a hydrate or solvate thereof. 2. R ₁ , R ₂ and R ₃ are each independently a hydrogen atom, a hydroxyl group, a C ₁ -C ₃ alkoxy group, Het- (CH ₂ ) _m —O— (Het is a pyrrolyl group, Imidazolyl group, pyrazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidyl group, or piperazinyl group, m is 1 to 3 Represents an integer of), a phenyl- (C ₁ -C ₃ ) alkoxy group
Pyrrolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group,
A pyrrolidinyl group, a pyrrolinyl group, an imidazolidinyl group,
It represents an imidazolinyl group, a pyrazolidinyl group, a pyrazolinyl group, a piperidyl group, a piperazinyl group, a triazolidinyl group, a triazolyl group, a triazinyl group, a tetrazolyl group, or a tetrazinyl group, but R ₁ and R ₂ together form -O- (CH ₂ ) _N- O- (n represents an integer of 1 to 3) may be represented; R ₄ is a C _{1 to} C ₇ alkyl group, a C _{3 to} C ₇ cycloalkyl group, or Ar- (CH
₂ ) _p- (Ar represents a phenyl group, a tolyl group, or a naphthyl group, and p represents an integer of 1 to 3); R ₅ and R ₆ are each independently a hydrogen atom or C _1- . C
₃ represents an alkyl group, but when R ₅ and R ₆ are taken together,
(CH ₂ ) _q- (q represents an integer of 3 to 5); Y represents a C _{1 to} C ₃ alkyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group, Pyrimidinyl group, pyridazinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group, triazolidinyl group, triazolyl group, triazinyl group, tetrazolyl group, tetrazinyl group, phenyl group, phenyl group Or represents a naphthyl group; k
Represents an integer of 1 to 3, and l represents an integer of 2 to 4;
Or a hydrate or solvate thereof. 3. R ₁ , R ₂ and R ₃ are each independently a hydrogen atom, a hydroxyl group, a C ₁ -C ₃ alkoxy group, Het- (CH ₂ ) _m- O- (Het is a pyridyl group. , M is an integer of 1 to 3), phenyl-
Represents a (C ₁ -C ₃ ) alkoxy group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, or a triazolyl group.
₁ and R ₂ together form -O- (CH ₂ ) _n -O- (n
Represents an integer of 1 to 3. ) May be represented; R ₄ is C ₁
Alkyl group -C _7, cycloalkyl group C ₃ -C _7,
Or _{Ar- (CH 2) p - (} Ar represents a phenyl group,
p represents an integer of 1 to 3. R ₅ and R ₆ each independently represent a hydrogen atom or a C ₁ -C ₃ alkyl group, but when R ₅ and R ₆ are taken together, — (CH ₂ )
_q- (q represents an integer of 3 to 5) may be represented; Y
Represents an alkyl group of ₁ to ₃ carbon atoms, a pyridyl group, or a phenyl group; k represents an integer of 1 to 3 and 1 represents an integer of 2 to 4; A compound or a salt thereof, or a hydrate or solvate thereof. 4. R ₁ , R ₂ and R ₃ are each independently a hydrogen atom, a C ₁ -C ₃ alkoxy group, Het-
(CH _{2) m} -O- (Het represents a 2-pyridyl, 3-pyridyl, or 4-pyridyl group, m represents 1.) Phenylmethyl group, 1-pyrrolyl group, 1
Represents an imidazolyl group, a 1-pyrazolyl group, or a 1-triazolyl group, wherein R ₁ and R ₂ together form -O-
(CH _{2) n} -O- _(n is 1.) May represent; R ₄ is an alkyl group of C ₁ -C _7, cyclopentyl, or _{Ar- (CH 2) p - (} Ar is phenyl Represents a group, p represents 1 or 3); R ₅ is C ₁ -C.
₃ represents an alkyl group, R ₆ represents a hydrogen atom, but R ₅
And R ₆ together _{- (CH 2) q - (} . Q is representative of the 4) may represent a; Y represents a 2-pyridyl group or a phenyl group; k represents 1 or 2, l Represents 3;
The compound or salt thereof according to claim 1, or a hydrate or solvate thereof, which is characterized in that: 5. At least one of R ₁ , R ₂ and R ₃ is Het- (CH ₂ ) _m- O- (Het represents a 2-pyridyl group or a 3-pyridyl group, and m represents 1). 1
-Represents an imidazolyl group or a 1-triazolyl group;
R ₄ is n- propyl group, n- pentyl group, a cyclopentyl group, or _{Ar- (CH 2) p, -} (Ar represents phenyl group, p is representative of 1 or 3.) Represents a; R ₅ is a methyl group R ₆ represents a hydrogen atom, but R ₅ and R ₆ together may represent — (CH ₂ ) _q — (q represents 4); Y represents a phenyl group; k represents 1 or 2, and 1 represents 3 .; The compound of Claim 1, its salt, or those hydrates or solvates, characterized by the above-mentioned. 6. N- {5- (1-imidazolyl) -2-
Methoxyphenyl} methyl-N- (1-pentyl)-
The compound or salt thereof according to claim 1, which is N ′-[2- {3- (4-phenyl-1-piperazinyl) propoxy} -6-methylphenyl] urea, or a hydrate or solvate thereof. Stuff. 7. A medicine comprising the compound according to any one of claims 1 to 6 or a salt thereof, or a hydrate or solvate thereof. 8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable carrier. 9. A hyperlipidemic agent comprising the compound according to any one of claims 1 to 6 or a salt thereof, or a hydrate or solvate thereof as an active ingredient. 10. A method for preventing and / or treating hyperlipidemia, which comprises the compound according to any one of claims 1 to 6 and salts thereof, and hydrates and solvates thereof. A method comprising the step of administering to a hyperlipidemic patient an effective amount of a substance selected from the group. 11. An anti-atherosclerotic agent comprising the compound according to claim 1 or a salt thereof, or a hydrate or solvate thereof as an active ingredient. 12. A method for preventing and / or treating arteriosclerosis, which comprises the compound according to any one of claims 1 to 6 and salts thereof, and hydrates and solvates thereof. A method comprising the step of administering to a patient with arteriosclerosis an effective amount of a substance selected from 13. A cholesterol-lowering agent comprising the compound according to any one of claims 1 to 6 or a salt thereof, or a hydrate or solvate thereof as an active ingredient. 14. A method for preventing and / or treating hypercholesterolemia, which comprises the compound according to any one of claims 1 to 6 and salts thereof, and hydrates and solvates thereof. A method comprising the step of administering an effective amount of a substance selected from the group to a patient with hypercholesterolemia. 15. A neutral fat lowering agent comprising the compound according to any one of claims 1 to 6 or a salt thereof, or a hydrate or solvate thereof as an active ingredient. 16. A method for preventing and / or treating high neutral steatosis, which comprises the compound according to any one of claims 1 to 6 and a salt thereof, and a hydrate and a solvate thereof. A method comprising the step of administering an effective amount of a substance selected from the group to a patient with hypertriglyceridosis.