JP2000026294A - Medicine containing arylurea or arylmethylcarbamoyl derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having excellent inhibiting actions on an acyl-CoA: cholesterol acyltransferase (ACAT). SOLUTION: This compound is represented by formula I [X is a group having CH or N; Y is imino, methylene or the like; R1 is H or a 1-8C alkyl; R2 is a 1-2N 6-membered cyclic heteroaryl; R3 is a (substituted) 6-10C aryl; R4 is H, a halogen, a 1-8C alkyl or the like], e.g. N-[4-butoxy-2-(2-methylphenyl) phenyl]-N'-[2,2-dimethyl-1-(3-pyridyl)propyl]urea. The compound represented by formula I in which Y is imino group is obtained as a compound represented by formula V by reacting a compound represented by formula II with an azidation agent (e.g. sodium azide), providing a compound represented by formula III and reacting the resultant compound represented by formula III with an amino compound represented by formula IV in an inert solvent (e.g. benzene) preferably at 0-150 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an excellent acyl Co
A: Cholesterol acyltransferase (hereinafter, referred to as
Abbreviated as ACAT. A) Arylurea having an inhibitory action and useful as a therapeutic or prophylactic agent for various diseases caused by ACAT, for example, a therapeutic or prophylactic agent for hyperlipidemia, a therapeutic or prophylactic agent for atherosclerosis, etc. Alternatively, the present invention relates to a medicament containing an arylmethylcarbamoyl derivative or a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art Some urea derivatives of o-substituted aniline are known as compounds having an ACAT inhibitory action. For example, Japanese Patent Application Laid-Open No. 7-101940 discloses that
-(O-substituted phenyl) -N '-(4-phenylpyrimidin-5-yl) urea derivatives, N- (o-substituted phenyl) -N'-(6-phenylpyridin-5-yl) urea derivatives, etc. Has been described. Also, Japanese Patent Application Laid-Open No. 62-14 / 1987
No. 9662 discloses N- (2,4-bisaryl-5).
-Pyridyl) -N'-dialkylaminoalkylurea derivatives and the like are described as being useful for the treatment of cerebrovascular disease, but there is no description on ACAT inhibitory action and serum cholesterol lowering action.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have synthesized urea derivatives and the like, and have conducted intensive studies on their pharmacological activities over many years. As a result, an arylurea or arylmethylcarbamoyl derivative having a specific structure has been obtained. ,
It has an excellent ACAT inhibitory activity and is also excellent in oral absorption, and is a therapeutic or prophylactic agent for various diseases caused by ACAT, for example, a therapeutic or prophylactic agent for hyperlipidemia, a treatment for atherosclerosis. The present invention was found to be useful as an agent or a prophylactic agent, and the present invention was completed. The present invention provides an arylurea or arylmethylcarbamoyl derivative or a pharmacologically acceptable derivative thereof having an excellent ACAT inhibitory action, a therapeutic or preventive action for hyperlipidemia or a therapeutic or preventive action for atherosclerosis. A medicament containing a salt is provided.

[0004]

The arylurea or arylmethylcarbamoyl derivative of the present invention has the general formula

[0005]

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[0006]

[0007] In the above formula, X is a formula = CH- or =
Y represents a methylene group or an imino group; R ¹ represents a hydrogen atom or a C ₁ -C ₈ alkyl group; R ² is a 6-membered group containing 1 or 2 nitrogen atoms; A cyclic heteroaryl group, wherein R ³ is an optionally substituted C ₆ -C ₁₀ aryl group (the substituent is a halogen atom,
₁ -C ₆ alkyl group, a halogeno -C ₁ -C ₄ alkyl group, a C ₁ -C ₆ alkoxy or C ₁ -C ₆ alkylthio group shown. R ⁴ represents a hydrogen atom, a halogen atom, a C ₁ -C ₈ alkyl group, a C ₁ -C ₈ alkoxy group,
A C ₁ -C ₈ alkylthio group, an optionally substituted C ₆
-C ₁₀ aryl group (the substituent is a halogen atom, C _1-
C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆
Alkylthio group, C ₁ -C ₆ alkanoyl group, C ₁ -C
_{6 represents an} alkanoylamino group, a cyano group or a nitro group. ), An optionally substituted C ₆ -C ₁₀ aryloxy group (the substituent is the same as the substituent of the C ₆ -C ₁₀ aryl group for R ⁴ ), and may be substituted. C ₆ -C
_{A 10} arylthio group (the substituent is the same as the substituent of the C ₆ -C ₁₀ aryl group of R ⁴ ), an optionally substituted C ₇ -C ₁₂ aralkyl group (the substituent is R ⁴ C
Shows the ₆ -C ₁₀ substituents the same group of the aryl group. ), An optionally substituted C ₇ -C ₁₂ aralkyloxy group (the substituent is the same as the substituent of the C ₆ -C ₁₀ aryl group for R ⁴ ), and may be substituted. A C ₇ -C ₁₂ aralkylthio group (the substituent is the same as the substituent of the C ₆ -C ₁₀ aryl group for R ⁴ ), a di-C ₁ -C ₆ alkylamino group, or an oxygen or sulfur atom And a 3- to 6-membered cyclic amino group which may contain

In the above general formula (I), C _1-of R ¹
The C ₈ alkyl group is a linear or branched alkyl group having 1 to 8 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s
-Butyl, t-butyl, pentyl, isopentyl, t-
Pentyl, hexyl, heptyl, octyl group,
Preferably a C ₁ -C ₅ alkyl group, more preferably, isopropyl, t- butyl or t- pentyl group, particularly preferably a t- butyl group.

The 6-membered cyclic heteroaryl group containing 1 or 2 nitrogen atoms of R ² is, for example, pyridyl, pyrimidyl,
It may be a pyrazinyl or pyridazinyl group, preferably a pyridyl group.

The aryl part of the optionally substituted C ₆ -C ₁₀ aryl group for R ³ can be, for example, a phenyl or naphthyl group, and is preferably a phenyl group. The number of substituents is preferably 1 to 3, more preferably 1 or 2, and particularly preferably 1. Furthermore,
The position of the substituent is preferably at the ortho or meta position,
Particularly preferred is the ortho position.

The halogen atom which is a substituent of the aryl group for R ³ can be, for example, a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom, particularly preferably a fluorine atom. Or a chlorine atom.

C ₁ -C which is a substituent of the aryl group of R ³
_{The 6} alkyl group may be, for example, an alkyl group having 1 to 6 carbon atoms in the C ₁ -C ₈ alkyl group of R ¹ , preferably a C ₁ -C ₄ alkyl group, more preferably ,
It is a methyl or ethyl group, particularly preferably a methyl group.

The halogeno-C ₁ -C ₄ alkyl group which is a substituent of the aryl group for R ³ is an alkyl group having 1 to 4 carbon atoms substituted with a halogen atom, and is, for example, fluoromethyl, chloromethyl , Bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2
- bromoethyl, 2-trifluoroethyl, 3-fluoropropyl, be a 4-fluoro-butyl group, preferably a fluoro -C ₁ -C ₂ alkyl group, particularly preferably, is a trifluoromethyl group .

C ₁ -C which is a substituent of the aryl group of R ³
_{The 6} alkoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms, and may be, for example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy group. It is preferably a C ₁ -C ₄ alkoxy group, more preferably a methoxy or ethoxy group, and particularly preferably a methoxy group.

C ₁ -C which is a substituent of the aryl group of R ³
_{The 6} alkylthio group is a linear or branched alkylthio group having 1 to 6 carbon atoms, and may be, for example, a methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, hexylthio group, It is preferably a C ₁ -C ₄ alkylthio group, more preferably a methylthio or ethylthio group, particularly preferably a methylthio group.

The halogen atom for R ^{4 is the same as} the halogen atom described for the substituent for R ³ .

The C ₁ -C ₈ alkyl group for R ⁴ may be the same as described for R ¹ , preferably C ₂ -C _7.
Alkyl group, more preferably a C ₃ -C ₆ alkyl group, still more preferably a propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl or hexyl group, particularly preferably, A propyl, butyl, pentyl or hexyl group.

The C ₁ -C ₈ alkoxy group R ⁴ is, for example, C ₁ -C ₆ alkoxy groups mentioned in the substituent group R ^3, heptyloxy group which may be octyloxy group, preferably, C ₂ -C ₇ alkoxy group, more preferably C ₃ alkoxy group.
-C ₆ alkoxy, even more preferably, propoxy, isopropoxy, butoxy, isobutoxy, t
-Butoxy, pentoxy or hexyloxy, particularly preferably propoxy, butoxy, pentyloxy or hexyloxy.

The C ₁ -C ₈ alkylthio group for R ⁴ includes, for example, the C ₁ -C ₆ alkylthio group described for the substituent for R ³ ,
A heptylthio group or an octylthio group, preferably
C ₂ -C ₇ alkylthio, more preferably C ₃ -C ₇ alkylthio.
--C ₆ alkylthio, even more preferably propylthio, isopropylthio, butylthio, isobutylthio, t-butylthio, pentylthio or hexylthio, particularly preferably propylthio, butylthio, pentylthio or hexylthio. .

The aryl moiety of the optionally substituted C ₆ -C ₁₀ aryl group R ⁴ is the same as those described in R ^3, the position of the substituent is preferably meta or para position And particularly preferably in the para position.

The halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group or C ₁ -C ₆ alkylthio group which is a substituent of the aryl group of R ⁴ is the same as that described for R ^3. is there.

C ₁ -C which is a substituent of the aryl group of R ⁴
₆ alkanoyl group is a linear or branched alkanoyl group having 1 to 6 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl group,
Preferably it is a C ₁ -C ₃ alkanoyl group, particularly preferably a formyl or acetyl group.

C ₁ -C which is a substituent of the aryl group of R ⁴
C ₁ -C ₆ alkanoyl moiety of ₆ alkanoylamino groups include, but are similar to those described above, particularly preferably an acetyl group.

The aryl moiety and substituent of the aryloxy group may be substituted R ⁴ is the same as the aryl group and a substituent R ^4. The aryl part of the optionally substituted arylthio group of R ⁴ and its substituent are represented by R 4
^{It is the same as} the aryl group of ⁴ and its substituents.

[0025] C ₇ -C ₁₂ aralkyl moiety of the optionally substituted C ₇ -C be the ₁₂ aralkyl group R ⁴ is 1 to 4 carbon atoms which is substituted by the number 6 to 10 aryl group having a carbon
Linear or branched alkyl groups such as benzyl, phenethyl, 3-phenylpropyl,
-Phenylbutyl, naphthylmethyl, 2-naphthylethyl, preferably benzyl, phenethyl or 3
-Phenylpropyl group, more preferably benzyl or phenethyl group, particularly preferably benzyl group. The substituent of the aryl moiety is the same as the substituent of the aryl group of R ⁴ .

[0026] C ₇ -C ₁₂ aralkyl moiety of the optionally substituted C ₇ -C ₁₂ aralkyloxy group R ⁴ is, R ⁴
But preferably a benzyloxy or phenethyloxy group, particularly preferably a benzyloxy group. The substituent of the aryl moiety is the same as the substituent of the aryl group of R ⁴ .

[0027] C ₇ -C ₁₂ aralkyl moiety of the optionally substituted C ₇ -C be the ₁₂ aralkylthio group R ⁴ is of the same as the aralkyl moiety of R ^4, preferably, benzylthio or Fuenechiruchio And particularly preferably,
It is a benzylthio group. The substituent of the aryl moiety is the same as the substituent of the aryl group of R ⁴ .

The C ₁ -C ₆ alkyl moiety of di -C ₁ -C ₆ alkylamino group R ⁴ is, for example, C ₁ -C ₈ of R ¹
The alkyl group may be an alkyl group having 1 to 6 carbon atoms, preferably a C ₁ -C ₄ alkyl group, more preferably a methyl or ethyl group, particularly preferably
It is a methyl group.

The 3- to 6-membered cyclic amino group which may contain an oxygen or sulfur atom for R ⁴ is, for example, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl or 4-thiomorpholinyl. It is preferably a 5- to 6-membered cyclic amino group, more preferably 1-pyrrolidinyl, 1-piperidinyl, 4
-Morpholinyl or 4-thiomorpholinyl, still more preferably 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl, particularly preferably 1-pyrrolidinyl or 1-piperidinyl.

X is preferably a group having the formula = N-.

Y is preferably an imino group.

In the compound represented by the general formula (I), the carbon atom to which R ¹ is bonded may be an asymmetric carbon atom, and there are optical isomers based on the carbon atom and the like. Mixtures are also included in the compounds of the present invention.

Compound (I) is easily converted to a pharmacologically acceptable salt. As their salts, for example,
Salts with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, acetic, propionic, butyric, benzoic, oxalic, malonic, succinic, maleic, fumaric, tartaric, citric A salt with a carboxylic acid such as an acid, a salt with a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
Particularly preferred is the hydrochloride or acetate. Furthermore, hydrates of compound (I) or a salt thereof are also included in the present invention.

In the medicament containing an arylurea or arylmethylcarbamoyl derivative having the above general formula (I) or a pharmaceutically acceptable salt thereof according to the present invention,
Preferably, 1) a drug wherein Y is an imino group, 2) a drug wherein R ¹ is a C ₁ -C ₅ alkyl group, 3) R ¹ is an isopropyl group, a t-butyl group or a t-pentyl group 4) a drug wherein R ¹ is a t-butyl group; 5) a drug wherein R ² is a pyridyl group; 6) a phenyl group wherein R ³ is optionally substituted; fluorine atom, chlorine atom, bromine atom, C ₁ -C ₄ alkyl group, fluoro -C ₁ -C ₂ alkyl group, C ₁ -C ₄
It is an alkoxy group or a C ₁ -C ₄ alkylthio group. )
7) a phenyl group wherein R ³ is an optionally substituted phenyl group (the substituent is a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a methylthio group or 8) a drug wherein R ³ is an optionally substituted phenyl group (the substituent is a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group or a methylthio group) 9) A drug wherein R ³ is a substituted phenyl group (the substituent is a methyl group or a methoxy group) 10) A drug wherein R ⁴ is a hydrogen atom, a fluorine atom, a chlorine atom atom, a bromine atom, C ₂ -C ₇ alkyl group, C ₂ -C ₇ alkoxy group,
A C ₂ -C ₇ alkylthio group, an optionally substituted phenyl, benzyl, phenethyl, 3-phenylpropyl,
A phenoxy, phenylthio, benzyloxy, phenethyloxy, benzylthio or phenethylthio group (the substituent is a fluorine atom, a chlorine atom, a bromine atom, a C ₁ -C ₄
Alkyl group, C ₁ -C ₄ alkoxy group, methylthio group,
Ethylthio group, C ₁ -C ₃ alkanoyl group, C ₁ -C ₃
It is an alkanoylamino group, a cyano group or a nitro group. ), A di-C ₁ -C ₄ alkylamino group or 5 to 6
Medicament that is membered cyclic amino group, 11) R ⁴ is a fluorine atom, a chlorine atom, C ₃ -C ₆ alkyl group, C ₃ -C ₆ alkoxy group, C ₃ -C ₆ alkylthio group, optionally substituted Phenyl, phenoxy, phenylthio, benzyl, phenethyl, benzyloxy or benzylthio group (the substituents are fluorine atom, chlorine atom, methyl group, ethyl group, methoxy group, ethoxy group, methylthio group, ethylthio group, formyl group, acetyl group ,
It is an acetamino group, a cyano group or a nitro group. ), A dimethylamino group, a diethylamino group, a 1-pyrrolidinyl group, a 1-piperidinyl group or a 4-morpholinyl group, 12) R ⁴ is a chlorine atom, a propyl group, an isopropyl group, a butyl group, an isobutyl group, Butyl, pentyl, hexyl, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, hexyloxy, propylthio, isopropylthio, butylthio, isobutylthio, t- Butylthio group, pentylthio group, hexylthio group, optionally substituted phenyl, phenoxy, phenylthio,
A benzyl, benzyloxy or benzylthio group (the substituent is a fluorine atom, a chlorine atom, a methyl group, a methoxy group, a cyano group or a nitro group), a dimethylamino group, a 1-pyrrolidinyl group or a 1-piperidinyl group; pharmaceutical, or, 13) R ⁴ is propyl group, butyl group, a pentyl group, a hexyl group, a propoxy group, a butoxy group, Penchiokishi group, hexyloxy group, propylthio group, butylthio group, pentylthio group, are hexylthio group or a substituted A phenyl, phenoxy, phenylthio or benzyloxy group (the substituent is a fluorine atom, a chlorine atom,
It is a methyl group or a methoxy group. ).

Further, Y is selected from 1), R ¹ is selected from 2) to 4), R ² is selected from 5), and R ³ is 6).
To 9), R ⁴ is selected from 10) to 13), and a drug obtained by arbitrarily combining them is also suitable. 14) X is a group having the formula = CH-, and Y is
R ¹ is a t-butyl group; R ² is an imino group;
Is a 3-pyridyl group, and R ³ is a phenyl group which may be substituted (the substituent is a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group or a methylthio group). Wherein R ⁴ is propyl, butyl, pentyl, hexyl, propoxy, butoxy, pentoxy, hexyloxy, propylthio, butylthio, pentylthio, hexylthio, or substituted. A medicine which is a phenoxy, phenylthio or benzyloxy group (the substituent is a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group or a methylthio group); 15) X is a compound represented by the formula: Y is an imino group, R ¹ is a t-butyl group, and R ² is
A 3-pyridyl group, wherein R ³ is an optionally substituted phenyl group (the substituent is a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group or a methylthio group). , R ⁴ is a propyl group, a butyl group,
Pentyl group, hexyl group, propoxy group, butoxy group,
Pentoxy, hexyloxy, propylthio,
A butylthio group, a pentylthio group, a hexylthio group or an optionally substituted phenoxy, phenylthio or benzyloxy group (the substituent is a fluorine atom, a chlorine atom,
A methyl group, a trifluoromethyl group, a methoxy group or a methylthio group. ) Can be given.

Suitable compounds in the general formula (I) are specifically exemplified in Tables 1 and 2 below. The compounds in Table 1 have a structural formula of Formula (I-1), and the compounds in Table 2 have a structural formula of Formula (I-2).

[0037]

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[0038]

Table 1 Example compound R ¹ R ^Two R ^Three R ^Four X number ──────────────────────────────────── 1-1 i-Pr 3-Pyd- Ph H -= CH- 1-2 t-Bu 3-Pyd- Ph H- = CH- 1-3 t-Pn 3-Pyd- Ph H- = CH- 1-4 i-Pr- 3-Pyd- 2-Me -Ph- H- = CH- 1-5 t-Bu- 3-Pyd- 2-Me-Ph- H- = CH- 1-6 t-Bu-3- 3-Pyd- 2-MeO-Ph- H- = CH- 1-7 t-Bu- 3-Pyd- 2-CF _Three -Ph- H- = CH- 1-8 t-Bu- 3-Pyd- 2-Cl-Ph- H- = CH-1-9 t-Pn-3-Pyd- 2-Me-Ph- H- = CH- 1-10 t-Pn- 3-Pyd- 2-MeO-Ph- H- = CH- 1-11 i-Pr 3-Pyd- Ph F- = CH- 1-12 t-Bu 3-Pyd- Ph F- = CH- 1-13 t-Pn 3-Pyd- Ph F- = CH- 1-14 i-Pr- 3-Pyd- 2-Me-Ph- F- = CH- 1-15 t-Bu -3-Pyd- 2-Me-Ph- F- = CH- 1-16 t-Bu- 3-Pyd- 2-MeO-Ph- F- = CH- 1-17 t-Pn- 3-Pyd-2 -Me-Ph- F- = CH- 1-18 t-Pn- 3-Pyd- 2-MeO-Ph- F- = CH- 1-19 i-Pr 3-Pyd- Ph Cl- = CH- 1- 20 t-Bu 3-Pyd- Ph Cl- = CH- 1-21 t-Pn 3-Pyd- Ph Cl- = CH- 1-22 i-Pr- 3-Pyd- 2-Me-Ph- Cl- = CH- 1-23 t-Bu- 3-Pyd- 2-Me-Ph- Cl- = CH- 1-24 t-Bu-3- 3-Pyd- 2-MeO-Ph- Cl- = CH- 1-25 t -Pn- 3-Pyd- 2-Me-Ph- Cl- = CH- 1-26 t-Pn- 3-Pyd- 2-MeO-Ph- Cl- = CH- 1-27 i-Pr 3-Pyd- Ph Me- = CH- 1-28 t-Bu 3-Pyd- Ph Me- = CH- 1-29 t-Pn 3-Pyd- Ph Me- = CH- 1-30 i-Pr- 3-Pyd- 2 -Me-Ph- Me- = CH- 1-31 t-Bu-3-Pyd- 2-Me-Ph- Me- = CH- 1-32 t-Bu-3-Pyd- 2-MeO-Ph- Me -= CH- 1-33 t-Pn-3- 3-Pyd-2- Me-Ph- Me- = CH- 1-34 t-Pn-3- 3-Pyd-2- MeO-Ph- Me- = CH-1- 35 i-Pr 3-Pyd- Ph Et- = CH- 1-36 t-Bu 3-Pyd- Ph Et- = CH- 1-37 t-Pn 3-Pyd- Ph Et- = C H- 1-38 i-Pr 3-Pyd- 2-Me-Ph- Et- = CH- 1-39 t-Bu 3-Pyd- 2-Me-Ph- Et- = CH-1-40 t-Pn 3-Pyd- 2-Me-Ph- Et- = CH- 1-41 i-Pr 3-Pyd- 2-MeO-Ph- Et- = CH- 1-42 t-Bu 3-Pyd- 2-MeO- Ph- Et- = CH- 1-43 t-Pn 3-Pyd- 2-MeO-Ph- Et- = CH- 1-44 i-Pr 3-Pyd- 2-Cl-Ph- Et- = CH-1 -45 t-Bu 3-Pyd- 2-Cl-Ph- Et- = CH- 1-46 t-Pn 3-Pyd- 2-Cl-Ph- Et- = CH- 1-47 i-Pr 3-Pyd -Ph Pr- = CH- 1-48 t-Bu 3-Pyd- Ph Pr- = CH- 1-49 t-Pn 3-Pyd- Ph Pr- = CH-1-50 i-Pr 3-Pyd- 2 -Me-Ph- Pr- = CH- 1-51 t-Bu 3-Pyd- 2-Me-Ph- Pr- = CH- 1-52 t-Pn 3-Pyd- 2-Me-Ph- Pr- = CH- 1-53 i-Pr 3-Pyd- 2-MeO-Ph- Pr- = CH- 1-54 t-Bu 3-Pyd- 2-MeO-Ph- Pr- = CH- 1-55 t-Pn 3-Pyd- 2-MeO-Ph- Pr- = CH- 1-56 i-Pr 3-Pyd- 2-Cl-Ph- Pr- = CH- 1-57 t-Bu 3-Pyd- 2-Cl- Ph- Pr- = CH- 1-58 t-Pn 3-Pyd- 2-Cl-Ph- Pr- = CH- 1-59 i-Pr 3-Pyd- Ph i-Pr- = CH-1-60 t -Bu 3-Pyd- Ph i-Pr- = CH- 1-61 t-Pn 3-Pyd- Ph i-Pr- = CH- 1-62 i-Pr 3-Pyd- 2-Me-Ph- i- Pr- = CH- 1-63 t-Bu 3-Pyd- 2-Me-Ph- i-Pr- = CH- 1-64 t-Pn 3-Pyd- 2-Me-Ph- i-Pr- = CH -1-65 i-Pr 3-Pyd- 2-MeO-Ph- i-Pr- = CH- 1-66 t-Bu 3-Pyd- 2-MeO-Ph- i-Pr- = CH- 1-67 t-Pn 3-Pyd- 2-MeO-Ph- i-Pr- = CH- 1-68 i-Pr 3-Pyd- 2-Cl-Ph- i-Pr- = CH-1 -69 t-Bu 3-Pyd- 2-Cl-Ph- i-Pr- = CH- 1-70 t-Pn 3-Pyd- 2-Cl-Ph- i-Pr- = CH- 1-71 i- Pr 3-Pyd- Ph Bu- = CH- 1-72 t-Bu 3-Pyd- Ph Bu- = CH- 1-73 t-Pn 3-Pyd- Ph Bu- = CH- 1-74 i-Pr 3 -Pyd- 2-Me-Ph- Bu- = CH- 1-75 t-Bu 3-Pyd- 2-Me-Ph- Bu- = CH- 1-76 t-Pn 3-Pyd- 2-Me-Ph -Bu- = CH- 1-77 i-Pr 3-Pyd- 2-MeO-Ph- Bu- = CH- 1-78 t-Bu 3-Pyd- 2-MeO-Ph- Bu- = CH- 1- 79 t-Pn 3-Pyd- 2-MeO-Ph- Bu- = CH- 1-80 i-Pr 3-Pyd- 2-Cl-Ph- Bu- = CH- 1-81 t-Bu 3-Pyd- 2-Cl-Ph- Bu- = CH- 1-82 t-Pn 3-Pyd- 2-Cl-Ph- Bu- = CH- 1-83 i-Pr 3-Pyd- Ph i-Bu- = CH- 1-84 t-Bu 3-Pyd- Ph i-Bu- = CH- 1-85 t-Pn 3-Pyd- Ph i-Bu- = CH- 1-86 i-Pr 3-Pyd- 2-Me- Ph- i-Bu- = CH- 1-87 t-Bu 3-Pyd- 2-Me-Ph- i-Bu- = CH- 1-88 t-Pn 3-Pyd- 2-Me-Ph- i- Bu- = CH- 1-89 i-Pr 3-Pyd- 2-MeO-Ph- i-Bu- = CH- 1-90 t-Bu 3-Pyd- 2-MeO-Ph- i-Bu- = CH -1-91 t-Pn 3-Pyd- 2-MeO-Ph- i-Bu- = CH- 1-92 i-Pr 3-Pyd- 2-Cl-Ph- i-Bu- = CH- 1-93 t-Bu 3-Pyd- 2-Cl-Ph- i-Bu- = CH- 1-94 t-Pn 3-Pyd- 2-Cl-Ph- i-Bu- = CH- 1-95 i-Pr 3 -Pyd- Ph t-Bu- = CH- 1-96 t-Bu 3-Pyd- Ph t-Bu- = CH- 1-97 t-Pn 3-Pyd- Ph t-Bu- = CH- 1-98 i-Pr 3-Pyd- 2-Me-Ph- t-Bu- = CH- 1-99 t-Bu 3-Pyd- 2-Me-Ph- t-Bu- = CH-1-100 t-Pn 3 -Pyd- 2-Me-Ph- t-Bu- = CH- 1-101 i-Pr 3-Pyd- 2-MeO-Ph- t-Bu- = CH- 1-102 t-Bu 3-Pyd- 2 -MeO-Ph- t-Bu- = CH- 1-103 t-Pn 3-Pyd- 2-MeO-Ph- t-Bu- = CH- 1-104 i-Pr 3-Pyd- 2-Cl-Ph -t-Bu- = CH- 1-105 t-Bu 3-Pyd- 2-Cl-Ph- t-Bu- = CH- 1-106 t-Pn 3-Pyd- 2-Cl-Ph- t-Bu -= CH- 1-107 i-Pr 3-Pyd- Ph Pn- = CH- 1-108 t-Bu 3-Pyd- Ph Pn- = CH- 1-109 t-Pn 3-Pyd- Ph Pn- = CH- 1-110 i-Pr 3-Pyd- 2-Me-Ph- Pn- = CH- 1-111 t-Bu 3-Pyd- 2-Me-Ph- Pn- = CH- 1-112 t-Pn 3-Pyd- 2-Me-Ph- Pn- = CH- 1-113 i-Pr 3-Pyd- 2-MeO-Ph- Pn- = CH- 1-114 t-Bu 3-Pyd- 2-MeO- Ph- Pn- = CH- 1-115 t-Pn 3-Pyd- 2-MeO-Ph- Pn- = CH- 1-116 i-Pr 3-Pyd- 2-Cl-Ph- Pn- = CH-1 -117 t-Bu 3-Pyd- 2-Cl-Ph- Pn- = CH- 1-118 t-Pn 3-Pyd- 2-Cl-Ph- Pn- = CH- 1-119 i-Pr 3-Pyd -Ph Hx- = CH- 1-120 t-Bu 3-Pyd- Ph Hx- = CH- 1-121 t-Pn 3-Pyd- Ph Hx- = CH- 1-122 i-Pr 3-Pyd- 2 -Me-Ph- Hx- = CH- 1-123 t-Bu 3-Pyd- 2-Me-Ph- Hx- = CH- 1-124 t-Pn 3-Pyd- 2-Me-Ph- Hx- = CH- 1-125 i-Pr 3-Pyd- 2-MeO-Ph- Hx- = CH- 1-126 t-Bu 3-Pyd- 2-MeO-Ph- Hx- = CH- 1-127 t-Pn 3-Pyd- 2-MeO-Ph- Hx- = CH- 1-128 i-Pr 3-Pyd- 2-Cl- Ph- Hx- = CH- 1-129 t-Bu 3-Pyd- 2-Cl-Ph- Hx- = CH- 1-130 t-Pn 3-Pyd- 2-Cl-Ph- Hx- = CH-1 -131 i-Pr 3-Pyd- Ph Hp- = CH- 1-132 t-Bu 3-Pyd- Ph Hp- = CH- 1-133 t-Pn 3-Pyd- Ph Hp- = CH- 1-134 i-Pr 3-Pyd- 2-Me-Ph- Hp- = CH- 1-135 t-Bu 3-Pyd- 2-Me-Ph- Hp- = CH- 1-136 t-Pn 3-Pyd-2 -Me-Ph- Hp- = CH- 1-137 i-Pr 3-Pyd- 2-MeO-Ph- Hp- = CH- 1-138 t-Bu 3-Pyd- 2-MeO-Ph- Hp- = CH- 1-139 t-Pn 3-Pyd- 2-MeO-Ph- Hp- = CH- 1-140 i-Pr 3-Pyd- 2-Cl-Ph- Hp- = CH- 1-141 t-Bu 3-Pyd- 2-Cl-Ph- Hp- = CH- 1-142 t-Pn 3-Pyd- 2-Cl-Ph- Hp- = CH- 1-143 i-Pr 3-Pyd- Ph Oc- = CH- 1-144 t-Bu 3-Pyd- Ph Oc- = CH- 1-145 t-Pn 3-Pyd- Ph Oc- = CH- 1-146 i-Pr 3-Pyd- 2-Me-Ph- Oc- = CH- 1-147 t-Bu 3-Pyd- 2-Me-Ph- Oc- = CH- 1-148 t-Pn 3-Pyd- 2-Me-Ph- Oc- = CH- 1-149 i-Pr 3-Pyd- 2-MeO-Ph- Oc- = CH- 1-150 t-Bu 3-Pyd- 2-MeO-Ph- Oc- = CH- 1-151 t-Pn 3-Pyd-2 -MeO-Ph- Oc- = CH- 1-152 i-Pr 3-Py d- 2-Cl-Ph- Oc- = CH- 1-153 t-Bu 3-Pyd- 2-Cl-Ph- Oc- = CH- 1-154 t-Pn 3-Pyd- 2-Cl-Ph- Oc- = CH- 1-155 i-Pr- 3-Pyd- Ph- MeO- = CH- 1-156 t-Bu- 3-Pyd- Ph- MeO- = CH- 1-157 i-Pr- 3- Pyd- 2-Me-Ph- MeO- = CH- 1-158 t-Bu- 3-Pyd- 2-Me-Ph- MeO- = CH- 1-159 t-Bu- 3-Pyd- 2-MeO- Ph- MeO- = CH- 1-160 t-Bu- 3-Pyd- 2-CF _Three -Ph- MeO- = CH- 1-161 t-Bu- 3-Pyd- 2-Cl-Ph- MeO- = CH- 1-162 t-Pn-3- 3-Pyd- 2-Me-Ph- MeO- = CH- 1-163 t-Pn- 3-Pyd- 2-MeO-Ph- MeO- = CH- 1-164 i-Pr- 3-Pyd- Ph-EtO- = CH- 1-165 t-Bu-3 -Pyd- Ph- EtO- = CH- 1-166 i-Pr- 3-Pyd- 2-Me-Ph- EtO- = CH- 1-167 t-Bu- 3-Pyd- 2-Me-Ph- EtO -= CH- 1-168 t-Bu- 3-Pyd- 2-MeO-Ph- EtO- = CH- 1-169 t-Pn-3- 3-Pyd- 2-Me-Ph-EtO- = CH- 1- 170 t-Pn- 3-Pyd- 2-MeO-Ph- EtO- = CH- 1-171 i-Pr- 3-Pyd- Ph- PrO- = CH- 1-172 t-Bu- 3-Pyd- Ph -PrO- = CH- 1-173 i-Pr- 3-Pyd- 2-Me-Ph- PrO- = CH- 1-174 t-Bu-3-Pyd- 2-Me-Ph- PrO- = CH- 1-175 t-Bu- 3-Pyd- 2-MeO-Ph- PrO- = CH- 1-176 t-Pn- 3-Pyd- 2-Me-Ph- PrO- = CH- 1-177 t-Pn -3-Pyd- 2-MeO-Ph- PrO- = CH- 1-178 i-Pr- 3-Pyd- Ph- i-PrO- = CH- 1-179 t-Bu- 3-Pyd- Ph- i -PrO- = CH- 1-180 t-Bu- 3-Pyd- 2-Me-Ph- i-PrO- = CH- 1-181 t-Bu-3- 3-Pyd- 2-MeO-Ph- i-PrO -= CH- 1-182 i-Pr- 3-Pyd- Ph- BuO- = CH- 1-183 t-Bu- 3-Pyd- Ph- BuO- = CH- 1-184 H-3-Pyd- 2 -Me-Ph- BuO- = CH- 1-185 H- 3-Pyd- 2-MeO-Ph- BuO- = CH- 1-186 Me- 3-Pyd- 2-Me-Ph- BuO- = CH- 1-187 Me- 3-Pyd- 2-MeO-Ph- BuO -= CH- 1-188 Et- 3-Pyd- 2-Me-Ph- BuO- = CH- 1-189 Et- 3-Pyd- 2-MeO-Ph- BuO- = CH- 1-190 Pr-3 -Pyd- 2-Me-Ph- BuO- = CH- 1-191 Pr- 3-Pyd- 2-MeO-Ph- BuO- = CH- 1-192 i-Pr- 3-Pyd- 2-Me-Ph -BuO- = CH- 1-193 i-Pr- 3-Pyd- 2-MeO-Ph- BuO- = CH- 1-194 i-Pr- 3-Pyd- 2-CF _Three -Ph- BuO- = CH- 1-195 i-Pr- 3-Pyd- 2-Cl-Ph- BuO- = CH- 1-196 t-Bu- 3-Pyd- 2-Me-Ph- BuO- = CH- 1-197 t-Bu- 3-Pyd- 2-MeO-Ph- BuO- = CH- 1-198 t-Bu- 3-Pyd- 2,4-di-MeO-Ph- BuO- = CH- 1-199 t-Bu- 3-Pyd- 2-CF _Three -Ph- BuO- = CH- 1-200 t-Bu- 3-Pyd- 2-MeS-Ph- BuO- = CH- 1-201 t-Bu- 3-Pyd- 2-F-Ph- BuO- = CH- 1-202 t-Bu- 3-Pyd- 2-Cl-Ph- BuO- = CH- 1-203 t-Pn- 3-Pyd- 2-Me-Ph- BuO- = CH- 1-204 t -Pn- 3-Pyd- 2-MeO-Ph- BuO- = CH- 1-205 t-Pn- 3-Pyd- 2-CF _Three -Ph- BuO- = CH- 1-206 t-Pn- 3-Pyd- 2-Cl-Ph- BuO- = CH- 1-207 i-Pr- 3-Pyd- Ph- i-BuO- = CH- 1-208 t-Bu- 3-Pyd- Ph- i-BuO- = CH- 1-209 t-Bu- 3-Pyd- 2-Me-Ph- i-BuO- = CH- 1-210 t-Bu -3-Pyd- 2-MeO-Ph- i-BuO- = CH- 1-211 i-Pr- 3-Pyd- Ph- t-BuO- = CH- 1-212 t-Bu- 3-Pyd- Ph -t-BuO- = CH- 1-213 t-Bu- 3-Pyd- 2-Me-Ph- t-BuO- = CH- 1-214 t-Bu-3- 3-Pyd- 2-MeO-Ph- t -BuO- = CH- 1-215 i-Pr- 3-Pyd- Ph- PnO- = CH- 1-216 t-Bu- 3-Pyd- Ph- PnO- = CH- 1-217 i-Pr-3 -Pyd- 2-Me-Ph- PnO- = CH- 1-218 t-Bu- 3-Pyd- 2-Me-Ph- PnO- = CH- 1-219 t-Bu- 3-Pyd- 2-MeO -Ph- PnO- = CH- 1-220 t-Pn- 3-Pyd- 2-Me-Ph- PnO- = CH- 1-221 t-Pn- 3-Pyd- 2-MeO-Ph- PnO- = CH- 1-222 i-Pr- 3-Pyd- Ph- HxO- = CH- 1-223 t-Bu- 3-Pyd- Ph- HxO- = CH- 1-224 i-Pr- 3-Pyd- 2 -Me-Ph- HxO- = CH- 1-225 t-Bu- 3-Pyd- 2-Me-Ph- HxO- = CH- 1-226 t-Bu- 3-Pyd- 2-MeO-Ph- HxO -= CH- 1-227 t-Pn- 3-Pyd- 2-Me-Ph- HxO- = CH- 1-228 t-Pn-3- 3-Pyd- 2-MeO-Ph- HxO- = CH- 1- 229 i-Pr- 3-Pyd- Ph- HpO- = CH- 1-230 t-Bu- 3-Pyd- Ph- HpO- = CH- 1-231 i-Pr- 3-Pyd- 2-Me-Ph -HpO- = CH- 1-232 t-Bu- 3-Pyd- 2-Me-P h- HpO- = CH- 1-233 t-Bu-3- 3-Pyd- 2-MeO-Ph- HpO- = CH- 1-234 t-Pn- 3-Pyd- 2-Me-Ph- HpO- = CH -1-235 t-Pn- 3-Pyd- 2-MeO-Ph- HpO- = CH- 1-236 i-Pr- 3-Pyd- Ph- OcO- = CH- 1-237 t-Bu- 3- Pyd- Ph- OcO- = CH- 1-238 i-Pr- 3-Pyd- 2-Me-Ph- OcO- = CH- 1-239 i-Pr- 3-Pyd- 2-MeO-Ph- OcO- = CH- 1-240 t-Bu- 3-Pyd- 2-Me-Ph- OcO- = CH- 1-241 t-Bu-3- 3-Me-Ph- OcO- = CH- 1-242 t-Pn- 3-Pyd- 2-Me-Ph- OcO- = CH- 1-243 t-Pn- 3-Pyd- 2-MeO-Ph- OcO- = CH- 1-244 i-Pr- 3- Pyd- Ph- MeS- = CH- 1-245 t-Bu- 3-Pyd- Ph- MeS- = CH- 1-246 t-Bu- 3-Pyd- 2-Me-Ph- MeS- = CH-1 -247 t-Bu- 3-Pyd- 2-MeO-Ph- MeS- = CH- 1-248 i-Pr- 3-Pyd- Ph- EtS- = CH- 1-249 t-Bu- 3-Pyd- Ph- EtS- = CH- 1-250 t-Bu-3- 3-yd- 2-Me-Ph- EtS- = CH- 1-251 t-Bu-3- 3-Pyd- 2-MeO-Ph- EtS- = CH -1-252 i-Pr- 3-Pyd- Ph- PrS- = CH- 1-253 t-Bu- 3-Pyd- Ph- PrS- = CH- 1-254 t-Bu- 3-Pyd- 2- Me-Ph- PrS- = CH- 1-255 t-Bu- 3-Pyd- 2-MeO-Ph- PrS- = CH- 1-256 i-Pr- 3-Pyd- Ph- i-PrS- = CH -1-257 t-Bu- 3-Pyd- Ph- i-PrS- = CH- 1-258 t-Bu- 3-Pyd- 2-Me-Ph- i-PrS- = CH- 1-259 t- Bu- 3-Pyd- 2-MeO-Ph- i-PrS- = CH- 1-260 i-Pr- 3-Pyd- Ph- BuS- = CH- 1-261 t-Bu- 3-Pyd- Ph- BuS- = CH- 1-262 t-Bu- 3-Pyd- 2-Me-Ph- BuS- = CH- 1-263 t-Bu- 3-Pyd- 2-MeO-Ph- BuS- = CH- 1-264 i-Pr- 3-Pyd- Ph- i-BuS- = CH- 1-265 t-Bu- 3-Pyd- Ph- i-BuS- = CH- 1-266 t-Bu- 3-Pyd- 2-Me-Ph- i-BuS- = CH- 1-267 t-Bu- 3-Pyd- 2-MeO-Ph- i-BuS- = CH- 1-268 i-Pr- 3-Pyd- Ph- t-BuS- = CH- 1-269 t-Bu- 3- Pyd- Ph- t-BuS- = CH- 1-270 t-Bu- 3-Pyd- 2-Me-Ph- t-BuS- = CH- 1-271 t-Bu- 3-Pyd- 2-MeO- Ph- t-BuS- = CH- 1-272 i-Pr- 3-Pyd- Ph- PnS- = CH- 1-273 t-Bu- 3-Pyd- Ph- PnS- = CH- 1-274 t- Bu- 3-Pyd- 2-Me-Ph- PnS- = CH- 1-275 t-Bu- 3-Pyd- 2-MeO-Ph- PnS- = CH- 1-276 i-Pr- 3-Pyd- Ph- HxS- = CH- 1-277 t-Bu- 3-Pyd- Ph- HxS- = CH- 1-278 t-Bu- 3-Pyd- 2-Me-Ph- HxS- = CH- 1-279 t-Bu- 3-Pyd- 2-MeO-Ph- HxS- = CH- 1-280 i-Pr- 3-Pyd- Ph- HpS- = CH- 1-281 t-Bu- 3-Pyd- Ph- HpS- = CH- 1-282 t-Bu-3- 3-yd- 2-Me-Ph- HpS- = CH- 1-283 t-Bu-3- 3-yd- 2-MeO-Ph- HpS- = CH-1 -284 i-Pr- 3-Pyd- Ph- OcS- = CH- 1-285 t-Bu- 3-Pyd- Ph- OcS- = CH- 1-286 t-Bu- 3-Pyd- 2-Me- Ph- OcS- = CH- 1-287 t-Bu- 3-Py d- 2-MeO-Ph- OcS- = CH- 1-288 i-Pr- 3-Pyd- Ph- PhO- = CH- 1-289 t-Bu- 3-Pyd- Ph- PhO- = CH- 1 -290 t-Bu- 3-Pyd- 2-Me-Ph- PhO- = CH- 1-291 t-Bu- 3-Pyd- 2-MeO-Ph- PhO- = CH- 1-292 i-Pr- 3-Pyd- Ph- PhS- = CH- 1-293 t-Bu- 3-Pyd- Ph- PhS- = CH- 1-294 t-Bu- 3-Pyd- 2-Me-Ph- PhS- = CH -1-295 t-Bu- 3-Pyd- 2-MeO-Ph- PhS- = CH- 1-296 i-Pr- 3-Pyd- Ph- Bn- = CH- 1-297 t-Bu- 3- Pyd- Ph- Bn- = CH- 1-298 i-Pr- 3-Pyd- 2-Me-Ph- Bn- = CH- 1-299 t-Bu- 3-Pyd- 2-Me-Ph- Bn- = CH- 1-300 t-Bu- 3-Pyd- 2-MeO-Ph- Bn- = CH- 1-301 t-Bu-3-Pyd- 2-CF _Three -Ph- Bn- = CH- 1-302 t-Bu-3- 3-Pyd- 2-Cl-Ph- Bn- = CH- 1-303 t-Pn-3- 3-Pyd- 2-Me-Ph- Bn- = CH- 1-304 t-Pn- 3-Pyd- 2-MeO-Ph- Bn- = CH- 1-305 i-Pr- 3-Pyd- Ph- PhCH _Two CH _Two -= CH- 1-306 t-Bu- 3-Pyd- Ph- PhCH _Two CH _Two -= CH- 1-307 i-Pr- 3-Pyd- 2-Me-Ph- PhCH _Two CH _Two -= CH- 1-308 t-Bu- 3-Pyd- 2-Me-Ph- PhCH _Two CH _Two -= CH- 1-309 t-Bu- 3-Pyd- 2-MeO-Ph- PhCH _Two CH _Two -= CH- 1-310 t-Bu- 3-Pyd- 2-CF _Three -Ph- PhCH _Two CH _Two -= CH- 1-311 t-Bu- 3-Pyd- 2-Cl-Ph- PhCH _Two CH _Two -= CH- 1-312 t-Pn- 3-Pyd- 2-Me-Ph- PhCH _Two CH _Two -= CH- 1-313 t-Pn- 3-Pyd- 2-MeO-Ph- PhCH _Two CH _Two -= CH- 1-314 i-Pr- 3-Pyd- Ph- BnO- = CH- 1-315 t-Bu- 3-Pyd- Ph- BnO- = CH- 1-316 H-3-Pyd- 2 -Me-Ph- BnO- = CH- 1-317 H- 3-Pyd- 2-MeO-Ph- BnO- = CH- 1-318 Me- 3-Pyd- 2-Me-Ph- BnO- = CH- 1-319 Me- 3-Pyd- 2-MeO-Ph- BnO- = CH- 1-320 Et- 3-Pyd- 2-Me-Ph- BnO- = CH- 1-321 Et- 3-Pyd-2 -MeO-Ph- BnO- = CH- 1-322 Pr-3- 3-Pyd- 2-Me-Ph- BnO- = CH- 1-323 Pr-3- 3-Pyd- 2-MeO-Ph- BnO- = CH- 1-324 i-Pr- 3-Pyd- 2-Me-Ph- BnO- = CH- 1-325 i-Pr- 3-Pyd- 2-MeO-Ph- BnO- = CH- 1-326 i-Pr -3-Pyd- 2-CF _Three -Ph- BnO- = CH- 1-327 i-Pr- 3-Pyd- 2-Cl-Ph- BnO- = CH- 1-328 t-Bu- 3-Pyd- 2-Me-Ph- BnO- = CH- 1-329 t-Bu- 3-Pyd- 2-MeO-Ph- BnO- = CH- 1-330 t-Bu- 3-Pyd- 2,4-di-MeO-Ph- BnO- = CH- 1-331 t-Bu- 3-Pyd- 2-CF _Three -Ph- BnO- = CH- 1-332 t-Bu- 3-Pyd- 2-MeS-Ph- BnO- = CH- 1-333 t-Bu- 3-Pyd- 2-F-Ph- BnO- = CH- 1-334 t-Bu- 3-Pyd- 2-Cl-Ph- BnO- = CH- 1-335 t-Pn-3- 3-Pyd- 2-Me-Ph- BnO- = CH- 1-336 t -Pn- 3-Pyd- 2-MeO-Ph- BnO- = CH- 1-337 t-Pn-3-Pyd- 2-CF _Three -Ph- BnO- = CH- 1-338 t-Pn-3- 3-Pyd- 2-Cl-Ph- BnO- = CH- 1-339 i-Pr- 3-Pyd- 2-Me-Ph- 4-F -BnO- = CH- 1-340 t-Bu- 3-Pyd- 2-Me-Ph- 4-F-BnO- = CH- 1-341 t-Bu- 3-Pyd- 2-MeO-Ph-4 -F-BnO- = CH- 1-342 t-Pn- 3-Pyd- 2-Me-Ph- 4-F-BnO- = CH- 1-343 t-Pn-3-Pyd- 2-MeO-Ph -4-F-BnO- = CH- 1-344 i-Pr- 3-Pyd- 2-Me-Ph- 4-Cl-BnO- = CH- 1-345 t-Bu- 3-Pyd- 2-Me -Ph- 4-Cl-BnO- = CH- 1-346 t-Bu- 3-Pyd- 2-MeO-Ph- 4-Cl-BnO- = CH- 1-347 t-Pn- 3-Pyd-2 -Me-Ph- 4-Cl-BnO- = CH- 1-348 t-Pn- 3-Pyd- 2-MeO-Ph- 4-Cl-BnO- = CH- 1-349 i-Pr- 3-Pyd -2-Me-Ph- 4-Me-BnO- = CH- 1-350 t-Bu- 3-Pyd- 2-Me-Ph- 4-Me-BnO- = CH- 1-351 t-Bu-3 -Pyd- 2-MeO-Ph- 4-Me-BnO- = CH- 1-352 t-Pn- 3-Pyd- 2-Me-Ph- 4-Me-BnO- = CH- 1-353 t-Pn -3-Pyd- 2-MeO-Ph- 4-MeO-BnO- = CH- 1-354 i-Pr- 3-Pyd- 2-Me-Ph- 4-MeO-BnO- = CH- 1-355 t -Bu- 3-Pyd- 2-Me-Ph- 4-MeO-BnO- = CH- 1-356 t-Bu- 3-Pyd- 2-MeO-Ph- 4-MeO-BnO- = CH- 1- 357 t-Pn- 3-Pyd- 2-Me-Ph- 4-MeO-BnO- = CH- 1-358 t-Pn-3- 3-Pyd- 2-MeO-Ph- 4-MeO-BnO- = CH- 1-359 i-Pr- 3-Pyd- 2-Me-Ph- PhCH _Two CH _Two O- = CH- 1-360 t-Bu- 3-Pyd- 2-Me-Ph- PhCH _Two CH _Two O- = CH- 1-361 t-Bu- 3-Pyd- 2-MeO-Ph- PhCH _Two CH _Two O- = CH- 1-362 t-Bu- 3-Pyd- 2-CF _Three -Ph- PhCH _Two CH _Two O- = CH- 1-363 t-Bu- 3-Pyd- 2-Cl-Ph- PhCH _Two CH _Two O- = CH- 1-364 t-Pn-3- 3-Pyd-2- Me-Ph- PhCH _Two CH _Two O- = CH- 1-365 t-Pn-3- 3-Pyd-2- MeO-Ph- PhCH _Two CH _Two O- = CH- 1-366 i-Pr- 3-Pyd- Ph- BnS- = CH- 1-367 t-Bu- 3-Pyd- Ph- BnS- = CH- 1-368 t-Bu- 3- Pyd- 2-Me-Ph- BnS- = CH- 1-369 t-Bu- 3-Pyd- 2-MeO-Ph- BnS- = CH- 1-370 t-Bu- 3-Pyd- 2-Me- Ph- 4-F-BnS- = CH- 1-371 t-Bu- 3-Pyd- 2-MeO-Ph- 4-F-BnS- = CH- 1-372 t-Bu- 3-Pyd- 2- Me-Ph- 4-Cl-BnS- = CH- 1-373 t-Bu- 3-Pyd- 2-MeO-Ph- 4-Cl-BnS- = CH- 1-374 t-Bu- 3-Pyd- 2-Me-Ph- 4-Me-BnS- = CH- 1-375 t-Bu- 3-Pyd- 2-MeO-Ph- 4-Me-BnS- = CH- 1-376 t-Bu- 3- Pyd- 2-Me-Ph- 4-MeO-BnS- = CH- 1-377 t-Bu-3-Pyd- 2-MeO-Ph- 4-MeO-BnS- = CH- 1-378 H- 3- Pyd- 2-Me-Ph- Ph- = CH- 1-379 H- 3-Pyd- 2-MeO-Ph- Ph- = CH- 1-380 Me- 3-Pyd- 2-Me-Ph- Ph- = CH- 1-381 Me- 3-Pyd- 2-MeO-Ph- Ph- = CH- 1-382 Et- 3-Pyd- 2-Me-Ph- Ph- = CH- 1-383 Et- 3- Pyd- 2-MeO-Ph- Ph- = CH- 1-384 Pr-3- 3-Pyd- 2-Me-Ph- Ph- = CH- 1-385 Pr-3-Pyd- 2-MeO-Ph- Ph- = CH- 1-386 i-Pr- 3-Pyd- Ph- Ph- = CH- 1-387 i-Pr- 3-Pyd- 2-MeO-Ph- Ph- = CH- 1-388 i-Pr- 3-Pyd- 2-CF _Three -Ph- Ph- = CH- 1-389 i-Pr- 3-Pyd- 2-Cl-Ph- Ph- = CH- 1-390 t-Bu- 3-Pyd- Ph- Ph- = CH- 1- 391 t-Bu- 3-Pyd- 2-Me-Ph- Ph- = CH- 1-392 t-Bu- 3-Pyd- 2-MeO-Ph- Ph- = CH- 1-393 t-Bu-3 -Pyd- 2,4-di-MeO-Ph- Ph- = CH- 1-394 t-Bu- 3-Pyd- 2-CF _Three -Ph- Ph- = CH- 1-395 t-Bu- 3-Pyd- 2-MeS-Ph- Ph- = CH- 1-396 t-Bu-3-Pyd- 2-F-Ph- Ph- = CH- 1-397 t-Bu- 3-Pyd- 2-Cl-Ph- Ph- = CH- 1-398 t-Pn- 3-Pyd- Ph- Ph- = CH- 1-399 t-Pn-3 -Pyd- 2-Me-Ph- Ph- = CH- 1-400 t-Pn- 3-Pyd- 2-MeO-Ph- Ph- = CH- 1-401 t-Pn- 3-Pyd- 2-CF _Three -Ph- Ph- = CH- 1-402 t-Pn-3-Pyd- 2-Cl-Ph- Ph- = CH- 1-403 t-Bu-3-Pyd- 2-Me-Ph- 3-F -Ph- = CH- 1-404 t-Bu- 3-Pyd- 2-MeO-Ph-3- F-Ph- = CH- 1-405 i-Pr- 3-Pyd- 2-Me-Ph-4 -F-Ph- = CH- 1-406 t-Bu- 3-Pyd- 2-Me-Ph- 4-F-Ph- = CH- 1-407 t-Bu- 3-Pyd- 2-MeO-Ph -4-F-Ph- = CH- 1-408 t-Bu- 3-Pyd- 2-CF _Three -Ph- 4-F-Ph- = CH- 1-409 t-Bu- 3-Pyd- 2-Cl-Ph- 4-F-Ph- = CH- 1-410 t-Pn- 3-Pyd- 2 -Me-Ph- 4-F-Ph- = CH- 1-411 t-Pn- 3-Pyd- 2-MeO-Ph- 4-F-Ph- = CH- 1-412 t-Bu- 3-Pyd -2-Me-Ph- 3-Cl-Ph- = CH- 1-413 t-Bu- 3-Pyd- 2-MeO-Ph- 3-Cl-Ph- = CH- 1-414 i-Pr-3 -Pyd- 2-Me-Ph- 4-Cl-Ph- = CH- 1-415 t-Bu- 3-Pyd- 2-Me-Ph- 4-Cl-Ph- = CH- 1-416 t-Bu -3-Pyd- 2-MeO-Ph- 4-Cl-Ph- = CH- 1-417 t-Bu- 3-Pyd- 2-CF _Three -Ph- 4-Cl-Ph- = CH- 1-418 t-Bu- 3-Pyd- 2-Cl-Ph- 4-Cl-Ph- = CH- 1-419 t-Pn- 3-Pyd- 2 -Me-Ph- 4-Cl-Ph- = CH- 1-420 t-Pn- 3-Pyd- 2-MeO-Ph- 4-Cl-Ph- = CH- 1-421 t-Bu- 3-Pyd -2-Me-Ph- 3-Me-Ph- = CH- 1-422 t-Bu-3-Pyd- 2-MeO-Ph- 3-Me-Ph- = CH- 1-423 i-Pr-3 -Pyd- 2-Me-Ph- 4-Me-Ph- = CH- 1-424 t-Bu- 3-Pyd- 2-Me-Ph- 4-Me-Ph- = CH- 1-425 t-Bu -3-Pyd- 2-MeO-Ph- 4-Me-Ph- = CH- 1-426 t-Bu- 3-Pyd- 2-CF _Three -Ph- 4-Me-Ph- = CH- 1-427 t-Bu- 3-Pyd- 2-Cl-Ph- 4-Me-Ph- = CH- 1-428 t-Pn- 3-Pyd- 2 -Me-Ph- 4-Me-Ph- = CH- 1-429 t-Pn-3-Pyd- 2-MeO-Ph- 4-Me-Ph- = CH- 1-430 t-Bu- 3-Pyd -2-Me-Ph- 3-MeO-Ph- = CH- 1-431 t-Bu-3-Pyd- 2-MeO-Ph- 3-MeO-Ph- = CH- 1-432 i-Pr-3 -Pyd- 2-Me-Ph- 4-MeO-Ph- = CH- 1-433 t-Bu- 3-Pyd- 2-Me-Ph- 4-MeO-Ph- = CH- 1-434 t-Bu -3-Pyd- 2-MeO-Ph- 4-MeO-Ph- = CH- 1-435 t-Bu- 3-Pyd- 2-CF _Three -Ph- 4-MeO-Ph- = CH- 1-436 t-Bu- 3-Pyd- 2-Cl-Ph- 4-MeO-Ph- = CH- 1-437 t-Pn- 3-Pyd-2 -Me-Ph- 4-MeO-Ph- = CH- 1-438 t-Pn- 3-Pyd- 2-MeO-Ph- 4-MeO-Ph- = CH- 1-439 i-Pr- 3-Pyd -2-Me-Ph- Me _Two N- = CH- 1-440 i-Pr- 3-Pyd- 2-MeO-Ph- Me _Two N- = CH- 1-441 t-Bu- 3-Pyd- Ph- Me _Two N- = CH- 1-442 t-Bu- 3-Pyd- 2-Me-Ph- Me _Two N- = CH- 1-443 t-Bu- 3-Pyd- 2-MeO-Ph- Me _Two N- = CH- 1-444 t-Bu- 3-Pyd- 2-CF _Three -Ph- Me _Two N- = CH- 1-445 t-Bu- 3-Pyd- 2-Cl-Ph- Me _Two N- = CH- 1-446 t-Pn- 3-Pyd- 2-Me-Ph- Me _Two N- = CH- 1-447 t-Pn- 3-Pyd- 2-MeO-Ph- Me _Two N- = CH- 1-448 i-Pr- 3-Pyd- 2-Me-Ph- Et _Two N- = CH- 1-449 t-Bu- 3-Pyd- Ph- Et _Two N- = CH- 1-450 t-Bu- 3-Pyd- 2-Me-Ph- Et _Two N- = CH- 1-451 t-Bu- 3-Pyd- 2-MeO-Ph- Et _Two N- = CH- 1-452 t-Pn- 3-Pyd- 2-Me-Ph- Et _Two N- = CH- 1-453 t-Pn-3- 3-Pyd-2- MeO-Ph- Et _Two N- = CH- 1-454 i-Pr-3- 3-Me-Ph- Pyr- = CH- 1-455 i-Pr-3- 3-Me-Ph- Pyr- = CH-1 -456 t-Bu- 3-Pyd- Ph- Pyr- = CH- 1-457 t-Bu- 3-Pyd- 2-Me-Ph- Pyr- = CH- 1-458 t-Bu- 3-Pyd- 2-MeO-Ph- Pyr- = CH- 1-459 t-Bu- 3-Pyd- 2-CF _Three -Ph- Pyr- = CH- 1-460 t-Bu- 3-Pyd- 2-Cl-Ph- Pyr- = CH- 1-461 t-Pn-3- 3-Pyd- 2-Me-Ph- Pyr- = CH- 1-462 t-Pn- 3-Pyd- 2-MeO-Ph- Pyr- = CH- 1-463 i-Pr- 3-Pyd- 2-Me-Ph- Pip- = CH- 1-464 i -Pr- 3-Pyd- 2-MeO-Ph- Pip- = CH- 1-465 t-Bu- 3-Pyd- Ph- Pip- = CH- 1-466 t-Bu- 3-Pyd- 2-Me -Ph- Pip- = CH- 1-467 t-Bu-3-Pyd- 2-MeO-Ph- Pip- = CH- 1-468 t-Bu-3-Pyd- 2-CF _Three -Ph- Pip- = CH- 1-469 t-Bu-3-Pyd- 2-Cl-Ph- Pip- = CH- 1-470 t-Pn-3-Pyd- 2-Me-Ph- Pip- = CH- 1-471 t-Pn- 3-Pyd- 2-MeO-Ph- Pip- = CH- 1-472 i-Pr- 3-Pyd- 2-Me-Ph- Mor- = CH- 1-473 i -Pr- 3-Pyd- 2-MeO-Ph- Mor- = CH- 1-474 t-Bu- 3-Pyd- Ph- Mor- = CH- 1-475 t-Bu- 3-Pyd- 2-Me -Ph- Mor- = CH- 1-476 t-Bu- 3-Pyd- 2-MeO-Ph- Mor- = CH- 1-477 t-Bu- 3-Pyd- 2-CF _Three -Ph- Mor- = CH- 1-478 t-Bu- 3-Pyd- 2-Cl-Ph- Mor- = CH- 1-479 t-Pn-3- 3-Pyd- 2-Me-Ph- Mor- = CH- 1-480 t-Pn- 3-Pyd- 2-MeO-Ph- Mor- = CH- 1-481 t-Bu- 2-Pyd- Ph- H- = CH- 1-482 t-Bu- 2 -Pyd- 2-Me-Ph- H- = CH- 1-483 t-Bu- 2-Pyd- 2-MeO-Ph- H- = CH- 1-484 t-Bu- 2-Pyd- 2-CF _Three -Ph- H- = CH- 1-485 t-Bu- 2-Pyd- 2-Cl-Ph- H- = CH- 1-486 t-Bu- 2-Pyd- Ph- Bu- = CH- 1- 487 t-Bu- 2-Pyd- 2-Me-Ph- Bu- = CH- 1-488 t-Bu- 2-Pyd- 2-MeO-Ph- Bu- = CH- 1-489 t-Bu- 2 -Pyd- 2-Me-Ph- MeO- = CH- 1-490 t-Bu- 2-Pyd- 2-MeO-Ph- MeO- = CH- 1-491 t-Bu- 2-Pyd- Ph- BuO -= CH- 1-492 t-Bu- 2-Pyd- 2-Me-Ph- BuO- = CH- 1-493 t-Bu- 2-Pyd- 2-MeO-Ph- BuO- = CH-1- 494 t-Bu- 2-Pyd- 2-Me-Ph- MeS- = CH- 1-495 t-Bu- 2-Pyd- 2-MeO-Ph- MeS- = CH- 1-496 t-Bu-2 -Pyd- Ph- BuS- = CH- 1-497 t-Bu- 2-Pyd- 2-Me-Ph- BuS- = CH- 1-498 t-Bu- 2-Pyd- 2-MeO-Ph- BuS -= CH- 1-499 t-Bu- 2-Pyd- Ph- PhO- = CH- 1-500 t-Bu- 2-Pyd- 2-Me-Ph- PhO- = CH- 1-501 t-Bu -2-Pyd- 2-MeO-Ph- PhO- = CH- 1-502 t-Bu- 2-Pyd- Ph- PhS- = CH- 1-503 t-Bu- 2-Pyd- 2-Me-Ph -PhS- = CH- 1-504 t-Bu- 2-Pyd- 2-MeO-Ph- PhS- = CH- 1-505 t-Bu- 2-Pyd- Ph- Bn- = CH- 1-506 t -Bu- 2-Pyd- 2-Me-Ph- Bn- = CH- 1-507 t-Bu- 2-Pyd- 2-MeO-Ph- Bn- = CH- 1-508 t-Bu- 2-Pyd -2-CF _Three -Ph- Bn- = CH- 1-509 t-Bu- 2-Pyd- 2-Cl-Ph- Bn- = CH- 1-510 t-Bu- 2-Pyd- Ph- PhCH _Two CH _Two -= CH- 1-511 t-Bu- 2-Pyd- 2-Me-Ph- PhCH _Two CH _Two -= CH- 1-512 t-Bu- 2-Pyd- 2-MeO-Ph- PhCH _Two CH _Two -= CH- 1-513 t-Bu- 2-Pyd- 2-CF _Three -Ph- PhCH _Two CH _Two -= CH- 1-514 t-Bu- 2-Pyd- 2-Cl-Ph- PhCH _Two CH _Two -= CH- 1-515 t-Bu- 2-Pyd- Ph- BnO- = CH- 1-516 t-Bu- 2-Pyd- 2-Me-Ph- BnO- = CH- 1-517 t-Bu -2-Pyd- 2-MeO-Ph- BnO- = CH- 1-518 t-Bu- 2-Pyd- Ph- BnS- = CH- 1-519 t-Bu- 2-Pyd- 2-Me-Ph -BnS- = CH- 1-520 t-Bu- 2-Pyd- 2-MeO-Ph- BnS- = CH- 1-521 t-Bu- 2-Pyd- Ph- Ph- = CH- 1-522 t -Bu- 2-Pyd- 2-Me-Ph- Ph- = CH- 1-523 t-Bu- 2-Pyd- 2-MeO-Ph- Ph- = CH- 1-524 t-Bu- 2-Pyd -2,4-di-MeO-Ph- Ph- = CH- 1-525 t-Bu- 2-Pyd- 2-CF _Three -Ph- Ph- = CH- 1-526 t-Bu- 2-Pyd- 2-MeS-Ph- Ph- = CH- 1-527 t-Bu- 2-Pyd- 2-F-Ph- Ph- = CH- 1-528 t-Bu- 2-Pyd- 2-Cl-Ph- Ph- = CH- 1-529 t-Bu- 2-Pyd- 2-Me-Ph- 3-F-Ph- = CH- 1-530 t-Bu- 2-Pyd- 2-MeO-Ph- 3-F-Ph- = CH- 1-531 t-Bu- 2-Pyd- 2-Me-Ph- 4-F-Ph- = CH- 1-532 t-Bu- 2-Pyd- 2-MeO-Ph- 4-F-Ph- = CH- 1-533 t-Bu- 2-Pyd- 2-CF _Three -Ph- 4-F-Ph- = CH- 1-534 t-Bu- 2-Pyd- 2-Cl-Ph- 4-F-Ph- = CH- 1-535 t-Bu- 2-Pyd- 2 -Me-Ph- 3-Cl-Ph- = CH- 1-536 t-Bu- 2-Pyd- 2-MeO-Ph- 3-Cl-Ph- = CH-1-537 t-Bu- 2-Pyd -2-Me-Ph- 4-Cl-Ph- = CH- 1-538 t-Bu- 2-Pyd- 2-MeO-Ph- 4-Cl-Ph- = CH- 1-539 t-Bu- 2 -Pyd- 2-CF _Three -Ph- 4-Cl-Ph- = CH- 1-540 t-Bu- 2-Pyd- 2-Cl-Ph- 4-Cl-Ph- = CH- 1-541 t-Bu- 2-Pyd- 2 -Me-Ph- 3-Me-Ph- = CH- 1-542 t-Bu- 2-Pyd- 2-MeO-Ph- 3-Me-Ph- = CH- 1-543 t-Bu- 2-Pyd -2-Me-Ph- 4-Me-Ph- = CH- 1-544 t-Bu- 2-Pyd- 2-MeO-Ph- 4-Me-Ph- = CH- 1-545 t-Bu- 2 -Pyd- 2-CF _Three -Ph- 4-Me-Ph- = CH- 1-546 t-Bu- 2-Pyd- 2-Cl-Ph- 4-Me-Ph- = CH-1-547 t-Bu- 2-Pyd-2 -Me-Ph- 3-MeO-Ph- = CH- 1-548 t-Bu- 2-Pyd- 2-MeO-Ph- 3-MeO-Ph- = CH- 1-549 t-Bu- 2-Pyd -2-Me-Ph- 4-MeO-Ph- = CH- 1-550 t-Bu- 2-Pyd- 2-MeO-Ph- 4-MeO-Ph- = CH- 1-551 t-Bu-2 -Pyd- 2-CF _Three -Ph- 4-MeO-Ph- = CH- 1-552 t-Bu- 2-Pyd- 2-Cl-Ph- 4-MeO-Ph- = CH- 1-553 t-Bu- 4-Pyd- Ph -H- = CH- 1-554 t-Bu- 4-Pyd- 2-Me-Ph- H- = CH- 1-555 t-Bu- 4-Pyd- 2-MeO-Ph- H- = CH- 1-556 t-Bu- 4-Pyd- 2-CF _Three -Ph- H- = CH- 1-557 t-Bu- 4-Pyd- 2-Cl-Ph- H- = CH- 1-558 t-Bu- 4-Pyd- Ph- Bu- = CH- 1- 559 t-Bu- 4-Pyd- 2-Me-Ph- Bu- = CH- 1-560 t-Bu- 4-Pyd- 2-MeO-Ph- Bu- = CH- 1-561 t-Bu-4 -Pyd- 2-Me-Ph- MeO- = CH- 1-562 t-Bu- 4-Pyd- 2-MeO-Ph- MeO- = CH- 1-563 t-Bu- 4-Pyd- Ph- BuO -= CH- 1-564 t-Bu- 4-Pyd- 2-Me-Ph- BuO- = CH- 1-565 t-Bu- 4-Pyd- 2-MeO-Ph- BuO- = CH- 1- 566 t-Bu- 4-Pyd- 2-Me-Ph- MeS- = CH- 1-567 t-Bu- 4-Pyd- 2-MeO-Ph- MeS- = CH- 1-568 t-Bu- 4 -Pyd- Ph- BuS- = CH- 1-569 t-Bu- 4-Pyd- 2-Me-Ph- BuS- = CH- 1-570 t-Bu- 4-Pyd- 2-MeO-Ph- BuS -= CH- 1-571 t-Bu- 4-Pyd- Ph- PhO- = CH- 1-572 t-Bu- 4-Pyd- 2-Me-Ph- PhO- = CH- 1-573 t-Bu -4-Pyd- 2-MeO-Ph- PhO- = CH- 1-574 t-Bu- 4-Pyd- Ph- PhS- = CH- 1-575 t-Bu- 4-Pyd- 2-Me-Ph -PhS- = CH- 1-576 t-Bu- 4-Pyd- 2-MeO-Ph- PhS- = CH- 1-577 t-Bu- 4-Pyd- Ph- Bn- = CH- 1-578 t -Bu- 4-Pyd- 2-Me-Ph- Bn- = CH- 1-579 t-Bu- 4-Pyd- 2-MeO-Ph- Bn- = CH- 1-580 t-Bu- 4-Pyd -2-CF _Three -Ph- Bn- = CH- 1-581 t-Bu- 4-Pyd- 2-Cl-Ph- Bn- = CH-1-582 t-Bu- 4-Pyd- Ph- PhCH _Two CH _Two -= CH- 1-583 t-Bu- 4-Pyd- 2-Me-Ph- PhCH _Two CH _Two -= CH- 1-584 t-Bu- 4-Pyd- 2-MeO-Ph- PhCH _Two CH _Two -= CH- 1-585 t-Bu- 4-Pyd- 2-CF _Three -Ph- PhCH _Two CH _Two -= CH- 1-586 t-Bu- 4-Pyd- 2-Cl-Ph- PhCH _Two CH _Two -= CH- 1-587 t-Bu- 4-Pyd- Ph- BnO- = CH- 1-588 t-Bu- 4-Pyd- 2-Me-Ph- BnO- = CH- 1-589 t-Bu -4-Pyd- 2-MeO-Ph- BnO- = CH- 1-590 t-Bu- 4-Pyd- Ph- BnS- = CH-1-591 t-Bu- 4-Pyd- 2-Me-Ph -BnS- = CH- 1-592 t-Bu- 4-Pyd- 2-MeO-Ph- BnS- = CH- 1-593 t-Bu- 4-Pyd- Ph- Ph- = CH- 1-594 t -Bu- 4-Pyd- 2-Me-Ph- Ph- = CH- 1-595 t-Bu- 4-Pyd- 2-MeO-Ph- Ph- = CH- 1-596 t-Bu- 4-Pyd -2,4-di-MeO-Ph- Ph- = CH- 1-597 t-Bu- 4-Pyd- 2-CF _Three -Ph- Ph- = CH- 1-598 t-Bu- 4-Pyd- 2-MeS-Ph- Ph- = CH- 1-599 t-Bu- 4-Pyd- 2-F-Ph- Ph- = CH- 1-600 t-Bu- 4-Pyd- 2-Cl-Ph- Ph- = CH- 1-601 t-Bu- 4-Pyd- 2-Me-Ph- Ph- = CH- 1-602 t -Bu- 4-Pyd- 2-Me-Ph- 3-F-Ph- = CH- 1-603 t-Bu- 4-Pyd- 2-MeO-Ph- 3-F-Ph- = CH- 1- 604 t-Bu- 4-Pyd- 2-Me-Ph- 4-F-Ph- = CH- 1-605 t-Bu- 4-Pyd- 2-MeO-Ph- 4-F-Ph- = CH- 1-606 t-Bu- 4-Pyd- 2-CF _Three -Ph- 4-F-Ph- = CH- 1-607 t-Bu- 4-Pyd- 2-Cl-Ph- 4-F-Ph- = CH- 1-608 t-Bu- 4-Pyd- 2 -Me-Ph- 3-Cl-Ph- = CH- 1-609 t-Bu- 4-Pyd- 2-MeO-Ph- 3-Cl-Ph- = CH- 1-610 t-Bu- 4-Pyd -2-Me-Ph- 4-Cl-Ph- = CH- 1-611 t-Bu- 4-Pyd- 2-MeO-Ph- 4-Cl-Ph- = CH- 1-612 t-Bu- 4 -Pyd- 2-CF _Three -Ph- 4-Cl-Ph- = CH- 1-613 t-Bu- 4-Pyd- 2-Cl-Ph- 4-Cl-Ph- = CH- 1-614 t-Bu- 4-Pyd- 2 -Me-Ph- 3-Me-Ph- = CH- 1-615 t-Bu- 4-Pyd- 2-MeO-Ph- 3-Me-Ph- = CH- 1-616 t-Bu- 4-Pyd -2-Me-Ph- 4-Me-Ph- = CH- 1-617 t-Bu- 4-Pyd- 2-MeO-Ph- 4-Me-Ph- = CH- 1-618 t-Bu-4 -Pyd- 2-CF _Three -Ph- 4-Me-Ph- = CH- 1-619 t-Bu- 4-Pyd- 2-Cl-Ph- 4-Me-Ph- = CH- 1-620 t-Bu- 4-Pyd- 2 -Me-Ph- 3-MeO-Ph- = CH- 1-621 t-Bu- 4-Pyd- 2-MeO-Ph- 3-MeO-Ph- = CH- 1-622 t-Bu- 4-Pyd -2-Me-Ph- 4-MeO-Ph- = CH- 1-623 t-Bu- 4-Pyd- 2-MeO-Ph- 4-MeO-Ph- = CH- 1-624 t-Bu-4 -Pyd- 2-CF _Three -Ph- 4-MeO-Ph- = CH- 1-625 t-Bu- 4-Pyd- 2-Cl-Ph- 4-MeO-Ph- = CH- 1-626 t-Bu- 2-Pyz-2 -Me-Ph- H- = CH- 1-627 t-Bu- 2-Pyz- 2-MeO-Ph- H- = CH- 1-628 t-Bu- 2-Pyz- 2-Me-Ph- Bu -= CH- 1-629 t-Bu- 2-Pyz- 2-MeO-Ph- Bu- = CH- 1-630 t-Bu- 2-Pyz- 2-Me-Ph- MeO- = CH- 1- 631 t-Bu- 2-Pyz- 2-MeO-Ph- MeO- = CH- 1-632 t-Bu- 2-Pyz- Ph- BuO- = CH- 1-633 t-Bu- 2-Pyz-2 -Me-Ph- BuO- = CH- 1-634 t-Bu- 2-Pyz- 2-MeO-Ph- BuO- = CH- 1-635 t-Bu- 2-Pyz- Ph- BnO- = CH- 1-636 t-Bu- 2-Pyz- 2-Me-Ph- BnO- = CH- 1-637 t-Bu- 2-Pyz- 2-MeO-Ph- BnO- = CH-1-638 t-Bu -2-Pyz- Ph- Ph- = CH- 1-639 t-Bu- 2-Pyz- 2-Me-Ph- Ph- = CH- 1-640 t-Bu- 2-Pyz- 2-MeO-Ph -Ph- = CH- 1-641 t-Bu- 2-Pyz- 2-Me-Ph- H- = CH-1-642 t-Bu- 5-Pym- Ph- H- = CH-1-643 t -Bu- 5-Pym- 2-MeO-Ph- H- = CH- 1-644 t-Bu- 5-Pym- 2-Me-Ph- Bu- = CH- 1-645 t-Bu- 5-Pym -2-MeO-Ph- Bu- = CH- 1-646 t-Bu- 5-Pym- 2-Me-Ph- MeO- = CH- 1-647 t-Bu-5-Pym- 2-MeO-Ph -MeO- = CH- 1-648 t-Bu- 5-Pym- Ph- BuO- = CH- 1-649 t-Bu- 5-Pym- 2-Me-Ph- BuO- = CH- 1-650 t -Bu- 5-Pym- 2-MeO-Ph- BuO- = CH- 1-651 t-Bu- 5-Pym- Ph- BnO- = CH- 1-652 t-Bu-5-Pym- 2-Me-Ph- BnO- = CH-1-653 t-Bu-5-Pym-2-MeO-Ph- BnO- = CH -1-654 t-Bu- 5-Pym- Ph- Ph- = CH- 1-655 t-Bu- 5-Pym- 2-Me-Ph- Ph- = CH- 1-656 t-Bu- 5- Pym- 2-MeO-Ph- Ph- = CH- 1-657 t-Bu- 3-Pyzn- 2-Me-Ph- Me- = CH- 1-658 t-Bu- 3-Pyzn- 2-MeO- Ph- Me- = CH- 1-659 t-Bu-3- 3-Pyzn- 2-Me-Ph- Bu- = CH- 1-660 t-Bu-3- 3-Pyzn- 2-MeO-Ph- Bu- = CH -1-661 t-Bu- 3-Pyzn- 2-Me-Ph- MeO- = CH- 1-662 t-Bu- 3-Pyzn- 2-MeO-Ph- MeO- = CH- 1-663 t- Bu- 3-Pyzn- Ph- BuO- = CH- 1-664 t-Bu- 3-Pyzn- 2-Me-Ph- BuO- = CH- 1-665 t-Bu- 3-Pyzn- 2-MeO- Ph- BuO- = CH- 1-666 t-Bu- 3-Pyzn- Ph- BnO- = CH- 1-667 t-Bu-3- 3-Pyzn- 2-Me-Ph- BnO- = CH- 1-668 t-Bu- 3-Pyzn- 2-MeO-Ph- BnO- = CH- 1-669 t-Bu- 3-Pyzn- Ph- Ph- = CH- 1-670 t-Bu-3- 3-Pyzn- 2- Me-Ph- Ph- = CH- 1-671 t-Bu- 3-Pyzn- 2-MeO-Ph- Ph- = CH- 1-672 i-Pr- 3-Pyd- 2-Me-Ph- H- = N- 1-673 t-Bu- 3-Pyd- Ph- H- = N- 1-674 t-Bu- 3-Pyd- 2-Me-Ph- H- = N- 1-675 t-Bu- 3-Pyd- 2-MeO-Ph- H- = N- 1-676 t-Bu- 3-Pyd- 2-CF _Three -Ph- H- = N- 1-677 t-Bu- 3-Pyd- 2-Cl-Ph- H- = N- 1-678 t-Pn- 3-Pyd- 2-Me-Ph- H- = N- 1-679 t-Pn- 3-Pyd- 2-MeO-Ph- H- = N- 1-680 i-Pr- 3-Pyd- 2-Me-Ph- Me- = N- 1-681 t -Bu- 3-Pyd- Ph- Me- = N- 1-682 t-Bu- 3-Pyd- 2-Me-Ph- Me- = N- 1-683 t-Bu- 3-Pyd- 2-MeO -Ph- Me- = N- 1-684 t-Pn- 3-Pyd- 2-Me-Ph- Me- = N- 1-685 t-Pn- 3-Pyd- 2-MeO-Ph- Me- = N- 1-686 i-Pr- 3-Pyd- Ph- Et- = N- 1-687 t-Bu- 3-Pyd- Ph- Et- = N- 1-688 t-Pn- 3-Pyd- Ph -Et- = N- 1-689 t-Bu- 3-Pyd- 2-Me-Ph- Et- = N- 1-690 t-Bu- 3-Pyd- 2-MeO-Ph- Et- = N- 1-691 i-Pr- 3-Pyd- Ph- Pr- = N- 1-692 t-Bu- 3-Pyd- Ph- Pr- = N- 1-693 t-Pn-3- 3-Pyd- Ph- Pr -= N- 1-694 t-Bu- 3-Pyd- 2-Me-Ph- Pr- = N- 1-695 t-Bu-3- 3-Me-Ph- Pr- = N- 1- 696 i-Pr- 3-Pyd- Ph- i-Pr- = N- 1-697 t-Bu- 3-Pyd- Ph- i-Pr- = N- 1-699 t-Bu- 3-Pyd- 2 -Me-Ph- i-Pr- = N- 1-700 t-Bu- 3-Pyd- 2-MeO-Ph- i-Pr- = N- 1-701 i-Pr- 3-Pyd- Ph- Bu -= N- 1-702 t-Bu- 3-Pyd- Ph- Bu- = N- 1-703 t-Pn- 3-Pyd- Ph- Bu- = N- 1-704 t-Bu- 3-Pyd -2-Me-Ph- Bu- = N- 1-705 t-Bu- 3-Pyd- 2-MeO-Ph- Bu- = N- 1-706 i-Pr- 3-Pyd- Ph- i-Bu - = N- 1-707 t-Bu- 3-Pyd- Ph- i-Bu- = N- 1-708 t-Pn- 3-Pyd- Ph- i-Bu- = N- 1-709 t-Bu- 3-Pyd- 2-Me-Ph- i-Bu- = N- 1-710 t-Bu- 3-Pyd- 2-MeO-Ph- i-Bu- = N- 1-711 i-Pr- 3- Pyd- Ph- t-Bu- = N- 1-712 t-Bu- 3-Pyd- Ph- t-Bu- = N- 1-713 t-Pn- 3-Pyd- Ph- t-Bu- = N -1-714 t-Bu- 3-Pyd- 2-Me-Ph- t-Bu- = N- 1-715 t-Bu- 3-Pyd- 2-MeO-Ph- t-Bu- = N- 1 -716 i-Pr- 3-Pyd- Ph- Pn- = N- 1-717 t-Bu- 3-Pyd- Ph- Pn- = N- 1-718 t-Pn- 3-Pyd- Ph- Pn- = N- 1-719 t-Bu- 3-Pyd- 2-Me-Ph- Pn- = N- 1-720 t-Bu- 3-Pyd- 2-MeO-Ph- Pn- = N- 1-721 i-Pr- 3-Pyd- Ph- Hx- = N- 1-722 t-Bu- 3-Pyd- Ph- Hx- = N- 1-723 t-Pn- 3-Pyd- Ph- Hx- = N -1-724 t-Bu- 3-Pyd- 2-Me-Ph- Hx- = N- 1-725 t-Bu- 3-Pyd- 2-MeO-Ph- Hx- = N- 1-726 i- Pr- 3-Pyd- Ph- Hp- = N- 1-727 t-Bu- 3-Pyd- Ph- Hp- = N- 1-728 t-Pn- 3-Pyd- Ph- Hp- = N- 1 -729 t-Bu- 3-Pyd- 2-Me-Ph- Hp- = N- 1-730 t-Bu- 3-Pyd- 2-MeO-Ph- Hp- = N- 1-731 i-Pr- 3-Pyd- Ph- Oc- = N- 1-732 t-Bu- 3-Pyd- Ph- Oc- = N- 1-733 t-Pn- 3-Pyd- Ph- Oc- = N- 1-734 t-Bu- 3-Pyd- 2-Me-Ph- Oc- = N- 1-735 t-Bu- 3-Pyd- 2-MeO-Ph- Oc- = N- 1-736 t-Bu- 3-Pyd- Ph- MeO- = N- 1-737 t-Bu- 3-Pyd- 2-Me-Ph- MeO- = N- 1-738 t-Bu- 3-Pyd- 2-MeO-Ph- MeO- = N- 1-739 t-Bu- 3-Pyd- Ph- EtO- = N- 1-740 t-Bu- 3-Pyd- 2-Me-Ph-EtO- = N- 1-741 t- Bu- 3-Pyd- 2-MeO-Ph- EtO- = N- 1-742 t-Bu- 3-Pyd- Ph- PrO- = N- 1-743 t-Bu- 3-Pyd- 2-Me- Ph- PrO- = N- 1-744 t-Bu- 3-Pyd- 2-MeO-Ph- PrO- = N- 1-745 t-Bu- 3-Pyd- Ph- i-PrO- = N- 1 -746 t-Bu- 3-Pyd- 2-Me-Ph- i-PrO- = N- 1-747 t-Bu- 3-Pyd- 2-MeO-Ph- i-PrO- = N- 1-748 t-Bu- 3-Pyd- Ph- BuO- = N- 1-749 t-Bu- 3-Pyd- 2-Me-Ph- BuO- = N- 1-750 t-Bu- 3-Pyd- 2- MeO-Ph- BuO- = N- 1-751 t-Bu- 3-Pyd- Ph- i-BuO- = N- 1-752 t-Bu- 3-Pyd- 2-Me-Ph- i-BuO- = N- 1-753 t-Bu- 3-Pyd- 2-MeO-Ph- i-BuO- = N- 1-754 t-Bu- 3-Pyd- Ph- t-BuO- = N- 1-755 t-Bu- 3-Pyd- 2-Me-Ph- t-BuO- = N- 1-756 t-Bu- 3-Pyd- 2-MeO-Ph- t-BuO- = N- 1-757 t- Bu- 3-Pyd- Ph- PnO- = N- 1-758 t-Bu- 3-Pyd- 2-Me-Ph- PnO- = N- 1-759 t-Bu- 3-Pyd- 2-MeO- Ph- PnO- = N- 1-760 t-Bu- 3-Pyd- Ph- HxO- = N- 1-761 t-Bu- 3-Pyd- 2-Me-Ph- HxO- = N- 1-762 t-Bu- 3-Pyd- 2-MeO-Ph- HxO- = N- 1-763 t-Bu- 3-Pyd- Ph- HpO- = N- 1-764 t-Bu- 3-Pyd- 2-Me-Ph- HpO- = N- 1-765 t-Bu- 3-Pyd- 2-MeO-Ph- HpO- = N- 1-766 t-Bu -3-Pyd- Ph- OcO- = N- 1-767 t-Bu- 3-Pyd- 2-Me-Ph- OcO- = N- 1-768 t-Bu- 3-Pyd- 2-MeO-Ph -OcO- = N- 1-769 t-Bu- 3-Pyd- Ph- MeS- = N- 1-770 t-Bu- 3-Pyd- 2-Me-Ph- MeS- = N- 1-771 t -Bu- 3-Pyd- 2-MeO-Ph- MeS- = N- 1-772 t-Bu- 3-Pyd- Ph-EtS- = N- 1-773 t-Bu- 3-Pyd- 2-Me -Ph- EtS- = N- 1-774 t-Bu- 3-Pyd- 2-MeO-Ph- EtS- = N- 1-775 t-Bu- 3-Pyd- Ph- PrS- = N- 1- 776 t-Bu- 3-Pyd- 2-Me-Ph- PrS- = N- 1-777 t-Bu- 3-Pyd- 2-MeO-Ph- PrS- = N- 1-778 t-Bu-3 -Pyd- Ph- i-PrS- = N- 1-779 t-Bu- 3-Pyd- 2-Me-Ph- i-PrS- = N- 1-780 t-Bu- 3-Pyd- 2-MeO -Ph- i-PrS- = N- 1-781 t-Bu- 3-Pyd- Ph- BuS- = N- 1-782 t-Bu- 3-Pyd- 2-Me-Ph- BuS- = N- 1-783 t-Bu- 3-Pyd- 2-MeO-Ph- BuS- = N- 1-784 t-Bu- 3-Pyd- Ph- i-BuS- = N- 1-785 t-Bu- 3 -Pyd- 2-Me-Ph- i-BuS- = N- 1-786 t-Bu- 3-Pyd- 2-MeO-Ph- i-BuS- = N- 1-787 t-Bu- 3-Pyd -Ph- t-BuS- = N- 1-788 t-Bu- 3-Pyd- 2-Me-Ph- t-BuS- = N- 1-789 t-Bu- 3-Pyd- 2-MeO-Ph -t-BuS- = N- 1-790 t-Bu- 3-Pyd- Ph- PnS- = N- 1-791 t-Bu- 3-Pyd- 2-Me-Ph- PnS- = N- 1-792 t-Bu- 3-Pyd- 2-MeO-Ph- PnS- = N- 1-793 t-Bu- 3-Pyd- Ph- HxS- = N -1-794 t-Bu- 3-Pyd- 2-Me-Ph- HxS- = N- 1-795 t-Bu- 3-Pyd- 2-MeO-Ph- HxS- = N- 1-796 t- Bu- 3-Pyd- Ph- OcS- = N- 1-797 t-Bu- 3-Pyd- 2-Me-Ph- OcS- = N- 1-798 t-Bu- 3-Pyd- 2-MeO- Ph- OcS- = N- 1-799 t-Bu- 3-Pyd- Ph- PhO- = N- 1-800 t-Bu- 3-Pyd- 2-Me-Ph- PhO- = N- 1-801 t-Bu- 3-Pyd- 2-MeO-Ph- PhO- = N- 1-802 t-Bu- 3-Pyd- Ph- PhS- = N- 1-803 t-Bu- 3-Pyd- 2- Me-Ph- PhS- = N- 1-804 t-Bu- 3-Pyd- 2-MeO-Ph- PhS- = N- 1-805 t-Bu- 3-Pyd- Ph- Me _Two N- = N- 1-806 t-Bu- 3-Pyd- 2-Me-Ph- Me _Two N- = N- 1-807 t-Bu- 3-Pyd- 2-MeO-Ph- Me _Two N- = N- 1-808 t-Bu- 3-Pyd- Ph- Et _Two N- = N- 1-809 t-Bu- 3-Pyd- 2-Me-Ph- Et _Two N- = N- 1-810 t-Bu- 3-Pyd- 2-MeO-Ph- Et _Two N- = N- 1-811 t-Bu- 3-Pyd- Ph- Pyr- N- 1-812 t-Bu- 3-Pyd- 2-Me-Ph- Pyr- = N- 1-813 t-Bu -3-Pyd- 2-MeO-Ph- Pyr- = N- 1-815 t-Bu- 3-Pyd- 2-Me-Ph- Pip- = N- 1-816 t-Bu- 3-Pyd-2 -MeO-Ph- Pip- = N- 1-817 t-Bu- 3-Pyd- Ph- Mor- = N- 1-818 t-Bu- 3-Pyd- 2-Me-Ph- Mor- = N- 1-819 t-Bu- 3-Pyd- 2-MeO-Ph- Mor- = N- 1-820 t-Bu- 3-Pyd- Ph- BnO- = N- 1-821 t-Bu- 3-Pyd -2-Me-Ph- BnO- = N- 1-822 t-Bu- 3-Pyd- 2-MeO-Ph- BnO- = N- 1-823 t-Bu- 3-Pyd- Ph- BnS- = N- 1-824 t-Bu- 3-Pyd- 2-Me-Ph- BnS- = N- 1-825 t-Bu-3- 3-Pyd- 2-MeO-Ph- BnS- = N- 1-826 i -Pr- 3-Pyd- 2-Me-Ph- Bn- = N- 1-827 t-Bu- 3-Pyd- Ph- Bn- = N- 1-828 t-Bu- 3-Pyd- 2-Me -Ph- Bn- = N- 1-829 t-Bu- 3-Pyd- 2-MeO-Ph- Bn- = N- 1-830 t-Bu- 3-Pyd- 2-CF _Three -Ph- Bn- = N- 1-831 t-Bu- 3-Pyd- 2-Cl-Ph- Bn- = N- 1-832 t-Pn- 3-Pyd- 2-Me-Ph- Bn- = N- 1-833 t-Pn- 3-Pyd- 2-MeO-Ph- Bn- = N- 1-834 t-Bu- 3-Pyd- Ph- PhCH _Two CH _Two -= N- 1-835 t-Bu- 3-Pyd- 2-Me-Ph- PhCH _Two CH _Two -= N- 1-836 i-Pr- 3-Pyd- 2-Me-Ph- PhCH _Two CH _Two -= N- 1-837 t-Bu- 3-Pyd- 2-MeO-Ph- PhCH _Two CH _Two -= N- 1-838 t-Bu- 3-Pyd- 2-CF _Three -Ph- PhCH _Two CH _Two -= N- 1-839 t-Bu- 3-Pyd- 2-Cl-Ph- PhCH _Two CH _Two -= N- 1-840 t-Pn- 3-Pyd- 2-Me-Ph- PhCH _Two CH _Two -= N- 1-841 t-Pn- 3-Pyd- 2-MeO-Ph- PhCH _Two CH _Two -= N- 1-842 H- 3-Pyd- 2-Me-Ph- Ph- = N- 1-843 H- 3-Pyd- 2-MeO-Ph- Ph- = N- 1-844 Me- 3 -Pyd- 2-Me-Ph- Ph- = N- 1-845 Me- 3-Pyd- 2-MeO-Ph- Ph- = N- 1-846 Et- 3-Pyd- 2-Me-Ph- Ph -= N- 1-847 Et- 3-Pyd- 2-MeO-Ph- Ph- = N- 1-848 Pr- 3-Pyd- 2-Me-Ph- Ph- = N- 1-849 Pr-3 -Pyd- 2-MeO-Ph- Ph- = N- 1-850 i-Pr- 3-Pyd- 2-Me-Ph- Ph- = N- 1-851 i-Pr- 3-Pyd- 2-MeO -Ph- Ph- = N- 1-852 i-Pr- 3-Pyd- 2-CF _Three -Ph- Ph- = N- 1-853 i-Pr- 3-Pyd- 2-Cl-Ph- Ph- = N- 1-854 t-Bu- 3-Pyd- Ph- Ph- = N- 1- 855 t-Bu- 3-Pyd- 2-Me-Ph- Ph- = N- 1-856 t-Bu- 3-Pyd- 2-MeO-Ph- Ph- = N- 1-857 t-Bu-3 -Pyd- 2,4-di-MeO-Ph- Ph- = N- 1-858 t-Bu- 3-Pyd- 2-CF _Three -Ph- Ph- = N- 1-859 t-Bu- 3-Pyd- 2-MeS-Ph- Ph- = N- 1-860 t-Bu- 3-Pyd- 2-F-Ph- Ph- = N- 1-861 t-Bu- 3-Pyd- 2-Cl-Ph- Ph- = N- 1-862 t-Pn- 3-Pyd- 2-Me-Ph- Ph- = N- 1-863 t -Pn- 3-Pyd- 2-MeO-Ph- Ph- = N- 1-864 t-Pn- 3-Pyd- 2-CF _Three -Ph- Ph- = N- 1-865 t-Pn- 3-Pyd- 2-Cl-Ph- Ph- = N- 1-866 t-Bu- 3-Pyd- 2-Me-Ph- 3-F -Ph- = N- 1-867 t-Bu- 3-Pyd- 2-MeO-Ph-3- F-Ph- = N- 1-868 i-Pr- 3-Pyd- 2-Me-Ph-4 -F-Ph- = N- 1-869 t-Bu- 3-Pyd- 2-Me-Ph- 4-F-Ph- = N- 1-870 t-Bu- 3-Pyd- 2-MeO-Ph -4-F-Ph- = N- 1-871 t-Bu- 3-Pyd- 2-CF _Three -Ph- 4-F-Ph- = N- 1-872 t-Bu- 3-Pyd- 2-Cl-Ph- 4-F-Ph- = N- 1-873 t-Pn- 3-Pyd- 2 -Me-Ph- 4-F-Ph- = N- 1-874 t-Pn- 3-Pyd- 2-MeO-Ph- 4-F-Ph- = N- 1-875 t-Bu- 3-Pyd -2-Me-Ph- 3-Cl-Ph- = N- 1-876 t-Bu- 3-Pyd- 2-MeO-Ph- 3-Cl-Ph- = N- 1-877 i-Pr-3 -Pyd- 2-Me-Ph- 4-Cl-Ph- = N- 1-878 t-Bu- 3-Pyd- 2-Me-Ph- 4-Cl-Ph- = N- 1-879 t-Bu -3-Pyd- 2-MeO-Ph- 4-Cl-Ph- = N- 1-880 t-Bu- 3-Pyd- 2-CF _Three -Ph- 4-Cl-Ph- = N- 1-881 t-Bu- 3-Pyd- 2-Cl-Ph- 4-Cl-Ph- = N- 1-882 t-Pn- 3-Pyd- 2 -Me-Ph- 4-Cl-Ph- = N- 1-883 t-Pn- 3-Pyd- 2-MeO-Ph- 4-Cl-Ph- = N- 1-884 t-Bu- 3-Pyd -2-Me-Ph- 3-Me-Ph- = N- 1-885 t-Bu- 3-Pyd- 2-MeO-Ph- 3-Me-Ph- = N- 1-886 i-Pr-3 -Pyd- 2-Me-Ph- 4-Me-Ph- = N- 1-887 t-Bu- 3-Pyd- 2-Me-Ph- 4-Me-Ph- = N- 1-888 t-Bu -3-Pyd- 2-MeO-Ph- 4-Me-Ph- = N- 1-889 t-Bu- 3-Pyd- 2-CF _Three -Ph- 4-Me-Ph- = N- 1-890 t-Bu- 3-Pyd- 2-Cl-Ph- 4-Me-Ph- = N- 1-891 t-Pn- 3-Pyd- 2 -Me-Ph- 4-Me-Ph- = N- 1-892 t-Pn- 3-Pyd- 2-MeO-Ph- 4-Me-Ph- = N- 1-893 t-Bu- 3-Pyd -2-Me-Ph- 3-MeO-Ph- = N- 1-894 t-Bu- 3-Pyd- 2-MeO-Ph- 3-MeO-Ph- = N- 1-895 i-Pr-3 -Pyd- 2-Me-Ph- 4-MeO-Ph- = N- 1-896 t-Bu- 3-Pyd- 2-Me-Ph- 4-MeO-Ph- = N- 1-897 t-Bu -3-Pyd- 2-MeO-Ph- 4-MeO-Ph- = N- 1-898 t-Bu- 3-Pyd- 2-CF _Three -Ph- 4-MeO-Ph- = N- 1-899 t-Bu- 3-Pyd- 2-Cl-Ph- 4-MeO-Ph- = N- 1-900 t-Pn- 3-Pyd- 2 -Me-Ph- 4-MeO-Ph- = N- 1-901 t-Pn- 3-Pyd- 2-MeO-Ph- 4-MeO-Ph- = N- 1-902 t-Bu- 2-Pyd -2-Me-Ph- H- = N- 1-903 t-Bu- 2-Pyd- 2-MeO-Ph- H- = N- 1-904 t-Bu- 2-Pyd- 2-Me-Ph -Me- = N- 1-905 t-Bu- 2-Pyd- 2-MeO-Ph- Me- = N- 1-906 t-Bu- 2-Pyd- Ph- Bn- = N- 1-907 t -Bu- 2-Pyd- 2-Me-Ph- Bn- = N- 1-908 t-Bu- 2-Pyd- 2-MeO-Ph- Bn- = N- 1-909 t-Bu- 2-Pyd -2-Me-Ph- PhCH _Two CH _Two -= N- 1-910 t-Bu- 2-Pyd- 2-MeO-Ph- PhCH _Two CH _Two -= N- 1-911 t-Bu- 2-Pyd- Ph- Ph- = N- 1-912 t-Bu- 2-Pyd- 2-Me-Ph- Ph- = N- 1-913 t-Bu -2-Pyd- 2-MeO-Ph- Ph- = N- 1-914 t-Bu- 2-Pyd- 2-Me-Ph- 3-F-Ph- = N- 1-915 t-Bu- 2 -Pyd- 2-MeO-Ph- 3-F-Ph- = N- 1-916 t-Bu- 2-Pyd- 2-Me-Ph- 4-F-Ph- = N- 1-917 t-Bu -2-Pyd- 2-MeO-Ph- 4-F-Ph- = N- 1-918 t-Bu- 2-Pyd- 2-Me-Ph- 3-Cl-Ph- = N- 1-919 t -Bu- 2-Pyd- 2-MeO-Ph- 3-Cl-Ph- = N- 1-920 t-Bu- 2-Pyd- 2-Me-Ph- 4-Cl-Ph- = N- 1- 921 t-Bu- 2-Pyd- 2-MeO-Ph- 4-Cl-Ph- = N- 1-922 t-Bu- 2-Pyd- 2-Me-Ph- 3-Me-Ph- = N- 1-923 t-Bu- 2-Pyd- 2-MeO-Ph- 3-Me-Ph- = N- 1-924 t-Bu- 2-Pyd- 2-Me-Ph- 4-Me-Ph- = N- 1-925 t-Bu- 2-Pyd- 2-MeO-Ph- 4-Me-Ph- = N- 1-926 t-Bu- 2-Pyd- 2-Me-Ph- 3-MeO-Ph -= N- 1-927 t-Bu- 2-Pyd- 2-MeO-Ph- 3-MeO-Ph- = N- 1-928 t-Bu-2-Pyd- 2-Me-Ph- 4-MeO -Ph- = N- 1-929 t-Bu- 2-Pyd- 2-MeO-Ph- 4-MeO-Ph- = N- 1-930 t-Bu- 4-Pyd- 2-Me-Ph- H -= N- 1-931 t-Bu- 4-Pyd- 2-MeO-Ph- H- = N- 1-932 t-Bu- 4-Pyd- 2-Me-Ph- Me- = N- 1- 933 t-Bu- 4-Pyd- 2-MeO-Ph- Me- = N- 1-934 t-Bu- 4-Pyd- Ph- Bn- = N- 1-935 t-Bu- 4-Pyd- 2 -Me-Ph- Bn- = N- 1-936 t-Bu- 4-P yd- 2-MeO-Ph- Bn- = N- 1-937 t-Bu- 4-Pyd- 2-Me-Ph- PhCH _Two CH _Two -= N- 1-938 t-Bu- 4-Pyd- 2-MeO-Ph- PhCH _Two CH _Two -= N- 1-939 t-Bu- 4-Pyd- Ph- Ph- = N- 1-940 t-Bu- 4-Pyd- 2-Me-Ph- Ph- = N- 1-941 t-Bu -4-Pyd- 2-MeO-Ph- Ph- = N- 1-942 t-Bu- 4-Pyd- 2-Me-Ph- 3-F-Ph- = N- 1-943 t-Bu- 4 -Pyd- 2-MeO-Ph- 3-F-Ph- = N- 1-944 t-Bu- 4-Pyd- 2-Me-Ph- 4-F-Ph- = N- 1-945 t-Bu -4-Pyd- 2-MeO-Ph- 4-F-Ph- = N- 1-946 t-Bu- 4-Pyd- 2-Me-Ph- 3-Cl-Ph- = N- 1-947 t -Bu- 4-Pyd- 2-MeO-Ph- 3-Cl-Ph- = N- 1-948 t-Bu- 4-Pyd- 2-Me-Ph- 4-Cl-Ph- = N- 1- 949 t-Bu- 4-Pyd- 2-MeO-Ph- 4-Cl-Ph- = N- 1-950 t-Bu- 4-Pyd- 2-Me-Ph- 3-Me-Ph- = N- 1-951 t-Bu- 4-Pyd- 2-MeO-Ph- 3-Me-Ph- = N- 1-952 t-Bu- 4-Pyd- 2-Me-Ph- 4-Me-Ph- = N- 1-953 t-Bu- 4-Pyd- 2-MeO-Ph- 4-Me-Ph- = N- 1-954 t-Bu- 4-Pyd- 2-Me-Ph- 3-MeO-Ph -= N- 1-955 t-Bu- 4-Pyd- 2-MeO-Ph- 3-MeO-Ph- = N- 1-956 t-Bu- 4-Pyd- 2-Me-Ph- 4-MeO -Ph- = N- 1-957 t-Bu- 4-Pyd- 2-MeO-Ph- 4-MeO-Ph- = N- 1-958 t-Bu- 2-Pyz- 2-Me-Ph- H -= N- 1-960 t-Bu- 2-Pyz- 2-Me-Ph- Me- = N- 1-961 t-Bu- 2-Pyz- 2-MeO-Ph- Me- = N- 1- 962 t-Bu- 2-Pyz- Ph- Ph- = N- 1-963 t-Bu- 2-Pyz- 2-Me-Ph- Ph- = N- 1-964 t-Bu- 2-Pyz- 2 -MeO-Ph- Ph- = N- 1-965 t-Bu- 5- Pym- 2-Me-Ph- H- = N- 1-966 t-Bu- 5-Pym- 2-MeO-Ph- H- = N- 1-967 t-Bu-5-Pym- 2-Me- Ph- Me- = N- 1-968 t-Bu- 5-Pym- 2-MeO-Ph- Me- = N- 1-969 t-Bu- 5-Pym- Ph- Ph- = N- 1-970 t-Bu- 5-Pym- 2-Me-Ph- Ph- = N- 1-971 t-Bu- 5-Pym- 2-MeO-Ph- Ph- = N- 1-972 t-Bu- 3- Pyzn- 2-Me-Ph- H- = N- 1-973 t-Bu- 3-Pyzn- 2-MeO-Ph- H- = N- 1-974 t-Bu- 3-Pyzn- 2-Me- Ph- Me- = N- 1-975 t-Bu- 3-Pyzn- 2-MeO-Ph- Me- = N- 1-976 t-Bu- 3-Pyzn- Ph- Ph- = N- 1-977 t-Bu- 3-Pyzn- 2-Me-Ph- Ph- = N- 1-978 t-Bu- 3-Pyzn- 2-MeO-Ph- Ph- = N- 1-979 t-Bu- 3- Pyd- Ph- 1-Np = N- 1-980 t-Bu- 3-Pyd- 2-Me-Ph- 1-Np = N- 1-981 t-Bu- 3-Pyd- 2-MeO-Ph- 1-Np = N- 1-982 t-Bu-3-Pyd- Ph- 2-Np = N- 1-983 t-Bu-3- 3-Pyd-2-Me-Ph- 2-Np = N- 1- 984 t-Bu- 3-Pyd- 2-MeO-Ph- 2-Np = N- ───────────────────────────── ─────.

[0039]

[Table 2] ─────────────────────────────────── Exemplary compound R ¹ R ² R ³ R ⁴ X No.─────────────────────────────────── 2-1 t-Bu- 3-Pyd- Ph- H -= CH- 2-2 t-Bu-3-Pyd- 2-Me-Ph- H- = CH- 2-3 t-Bu-3-Pyd- 2-MeO-Ph- H- = CH- 2- 4 t-Bu- 3-Pyd- Ph- Me- = CH- 2-5 t-Bu- 3-Pyd- 2-Me-Ph- Me- = CH- 2-6 t-Bu- 3-Pyd- 2 -MeO-Ph- Me- = CH- 2-7 t-Bu- 3-Pyd- Ph- Pr- = CH- 2-8 t-Bu- 3-Pyd- 2-Me-Ph- Pr- = CH- 2-9 t-Bu- 3-Pyd- 2-MeO-Ph- Pr- = CH- 2-10 t-Bu- 3-Pyd- Ph- Bu- = CH- 2-11 t-Bu- 3-Pyd -2-Me-Ph- Bu- = CH- 2-12 t-Bu- 3-Pyd- 2-MeO-Ph- Bu- = CH- 2-13 t-Bu- 3-Pyd- Ph- Pn- = CH- 2-14 t-Bu- 3-Pyd- 2-Me-Ph- Pn- = CH- 2-15 t-Bu- 3-Pyd- 2-MeO-Ph- Pn- = CH- 2-16 t -Bu- 3-Pyd- Ph- Hx- = CH- 2-17 t-Bu- 3-Pyd- 2-Me-Ph- Hx- = CH- 2-18 t-Bu- 3-Pyd- 2-MeO -Ph- Hx- = CH- 2-19 t-Bu- 3-Pyd- Ph- Oc- = CH- 2-20 t-Bu- 3-Pyd- 2-Me-Ph- Oc- = CH- 2- 21 t-Bu- 3-Pyd- 2-MeO-Ph- Oc- = CH- 2-22 tB u- 3-Pyd- Ph- MeO- = CH- 2-23 t-Bu- 3-Pyd- 2-Me-Ph- MeO- = CH- 2-24 t-Bu- 3-Pyd- 2-MeO- Ph- MeO- = CH- 2-25 t-Bu-3- 3-Pyd- Ph- PrO- = CH- 2-26 t-Bu-3- 3-Me-Ph- PrO- = CH- 2-27 t-Bu- 3-Pyd- 2-MeO-Ph- PrO- = CH- 2-28 t-Bu- 3-Pyd- Ph- BuO- = CH- 2-29 t-Bu-3- 3-Pyd- 2- Me-Ph- BuO- = CH- 2-30 t-Bu- 3-Pyd- 2-MeO-Ph- BuO- = CH- 2-31 t-Bu- 3-Pyd- Ph- PnO- = CH- 2 -32 t-Bu- 3-Pyd- 2-Me-Ph- PnO- = CH- 2-33 t-Bu- 3-Pyd- 2-MeO-Ph- PnO- = CH- 2-34 t-Bu- 3-Pyd- Ph- HxO- = CH- 2-35 t-Bu- 3-Pyd- 2-Me-Ph- HxO- = CH- 2-36 t-Bu- 3-Pyd- 2-MeO-Ph- HxO- = CH- 2-37 t-Bu- 3-Pyd- Ph- OcO- = CH- 2-38 t-Bu-3- 3-Me-Ph- OcO- = CH- 2-39 t- Bu- 3-Pyd- 2-MeO-Ph- OcO- = CH- 2-40 t-Bu- 3-Pyd- Ph- MeS- = CH- 2-41 t-Bu- 3-Pyd- 2-Me- Ph- MeS- = CH- 2-42 t-Bu-3-Pyd- 2-MeO-Ph- MeS- = CH- 2-43 t-Bu-3-Pyd- Ph- PrS- = CH-2-44 t-Bu- 3-Pyd- 2-Me-Ph- PrS- = CH- 2-45 t-Bu-3- 3-Pyd- 2-MeO-Ph- PrS- = CH- 2-46 t-Bu- 3- Pyd- Ph- BuS- = CH- 2-47 t-Bu- 3-Pyd- 2-Me-Ph- BuS- = CH- 2-48 t-Bu-3-Pyd- 2-MeO-Ph- BuS- = CH- 2-49 t-Bu- 3-Pyd- Ph- PnS- = CH- 2-50 t-Bu- 3- Pyd- 2-Me-Ph- PnS- = CH- 2-51 t-Bu- 3-Pyd- 2-MeO-Ph- PnS- = CH- 2-52 t-Bu- 3-Pyd- Ph- HxS- = CH-2-53 t-Bu-3-Pyd-2-Me-Ph-HxS- = CH-2-54 t-Bu-3-Pyd-2-MeO-Ph-HxS- = CH-2-56 t-Bu- 3-Pyd- 2-Me-Ph- OcS- = CH- 2-57 t-Bu- 3-Pyd- 2-MeO-Ph- OcS- = CH- 2-58 t-Bu- 3- Pyd- Ph- Bn- = CH- 2-59 t-Bu- 3-Pyd- 2-Me-Ph- Bn- = CH- 2-60 t-Bu- 3-Pyd- 2-MeO-Ph- Bn- = CH- 2-61 t-Bu-3- 3-Pyd- Ph- PhCH ₂ CH _2- = CH- 2-62 t-Bu-3- 3-Pyd- 2-Me-Ph- PhCH ₂ CH _2- = CH-2 -63 t-Bu- 3-Pyd- 2-MeO-Ph- PhCH ₂ CH _2- = CH- 2-64 t-Bu- 3-Pyd- Ph- BnO- = CH- 2-65 t-Bu-3 -Pyd- 2-Me-Ph- BnO- = CH- 2-66 t-Bu- 3-Pyd- 2-MeO-Ph- BnO- = CH- 2-67 t-Bu- 3-Pyd- Ph- BnS -= CH- 2-68 t-Bu- 3-Pyd- 2-Me-Ph- BnS- = CH- 2-69 t-Bu-3- 3-Me-Ph- BnS- = CH- 2- 70 t-Bu- 3-Pyd- Ph- Ph- = CH- 2-71 t-Bu- 3-Pyd- 2-Me-Ph- Ph- = CH- 2-72 t-Bu- 3-Pyd- 2 -MeO-Ph- Ph- = CH- 2-73 t-Bu- 3-Pyd- Ph- 4-F-Ph- = CH- 2-74 t-Bu- 3-Pyd- 2-Me-Ph-4 -F-Ph- = CH- 2-75 t-Bu- 3-Pyd- 2-MeO-Ph- 4-F-Ph- = CH- 2-76 t-Bu- 3-Pyd- Ph- 4-Cl -Ph- = CH- 2-77 t-Bu- 3-Pyd- 2-Me-Ph- 4-Cl-Ph- = CH- 2-78 t- Bu- 3-Pyd- 2-MeO-Ph- 4-Cl-Ph- = CH- 2-79 t-Bu- 3-Pyd- Ph- 4-Me-Ph- = CH- 2-80 t-Bu- 3-Pyd- 2-Me-Ph- 4-Me-Ph- = CH- 2-81 t-Bu- 3-Pyd- 2-MeO-Ph- 4-Me-Ph- = CH- 2-82 t- Bu- 3-Pyd- Ph- 4-MeO-Ph- = CH- 2-83 t-Bu- 3-Pyd- 2-Me-Ph- 4-MeO-Ph- = CH- 2-84 t-Bu- 3-Pyd- 2-MeO-Ph- 4-MeO-Ph- = CH- 2-85 t-Bu- 3-Pyd- Ph- PhO- = CH- 2-86 t-Bu- 3-Pyd- 2- Me-Ph- PhO- = CH- 2-87 t-Bu- 3-Pyd- 2-MeO-Ph- PhO- = CH- 2-88 t-Bu- 3-Pyd- Ph- PhS- = CH-2 -89 t-Bu- 3-Pyd- 2-Me-Ph- PhS- = CH- 2-90 t-Bu- 3-Pyd- 2-MeO-Ph- PhS- = CH- 2-91 t-Bu- 3-Pyd- Ph- Me ₂ N- = CH- 2-92 t-Bu- 3-Pyd- 2-Me-Ph- Me ₂ N- = CH- 2-93 t-Bu- 3-Pyd- 2- MeO-Ph- Me ₂ N- = CH- 2-94 t-Bu-3- 3-Pyd- Ph- Pyr- = CH- 2-95 t-Bu-3-Pyd- 2-Me-Ph- Pyr- = CH -2-96 t-Bu- 3-Pyd- 2-MeO-Ph- Pyr- = CH- 2-97 t-Bu- 3-Pyd- Ph- Pip- = CH- 2-98 t-Bu- 3- Pyd- 2-Me-Ph- Pip- = CH- 2-99 t-Bu- 3-Pyd- 2-MeO-Ph- Pip- = CH-2-100 t-Bu- 3-Pyd- Ph- H- = N- 2-101 t-Bu- 3-Pyd- 2-Me-Ph- H- = N- 2-102 t-Bu-3- 3-Pyd- 2-MeO-Ph- H- = N- 2-103 t-Bu- 3-Pyd- Ph- Me- = N- 2-104 t-Bu- 3-Pyd- 2-Me-Ph- Me- = N- 2-105 t-Bu- 3-Pyd- 2-MeO-Ph- Me- = N- 2-106 t-Bu- 3-Pyd- Ph- Pr- = N- 2-107 t-Bu- 3-Pyd- 2-Me-Ph- Pr- = N- 2-108 t-Bu- 3-Pyd- 2-MeO-Ph- Pr- = N- 2-109 t-Bu- 3-Pyd- Ph- Bu- = N- 2-110 t- Bu- 3-Pyd- 2-Me-Ph- Bu- = N- 2-111 t-Bu- 3-Pyd- 2-MeO-Ph- Bu- = N- 2-112 t-Bu- 3-Pyd- Ph- Pn- = N- 2-113 t-Bu-3- 3-Pyd- 2-Me-Ph- Pn- = N- 2-114 t-Bu-3- 3-Pyd- 2-MeO-Ph- Pn- = N -2-115 t-Bu- 3-Pyd- Ph- Hx- = N- 2-116 t-Bu- 3-Pyd- 2-Me-Ph- Hx- = N- 2-117 t-Bu- 3- Pyd- 2-MeO-Ph- Hx- = N- 2-118 t-Bu- 3-Pyd- Ph- Oc- = N- 2-119 t-Bu- 3-Pyd- 2-Me-Ph- Oc- = N- 2-120 t-Bu- 3-Pyd- 2-MeO-Ph- Oc- = N- 2-121 t-Bu- 3-Pyd- Ph- MeO- = N- 2-122 t-Bu- 3-Pyd- 2-Me-Ph- MeO- = N- 2-123 t-Bu- 3-Pyd- 2-MeO-Ph- MeO- = N- 2-124 t-Bu- 3-Pyd- Ph- PrO- = N- 2-125 t-Bu-3-Pyd- 2-Me-Ph- PrO- = N- 2-126 t-Bu-3- 3-Me-Ph- PrO- = N-2 -127 t-Bu- 3-Pyd- Ph- BuO- = N- 2-128 t-Bu- 3-Pyd- 2-Me-Ph- BuO- = N- 2-129 t-Bu- 3-Pyd- 2-MeO-Ph- BuO- = N- 2-130 t-Bu- 3-Pyd- Ph- PnO- = N- 2-131 t-Bu- 3-Pyd- 2-Me-Ph- PnO- = N -2-132 t-Bu- 3-Pyd- 2-MeO-Ph- PnO- = N- 2-133 t-Bu- 3-Pyd- Ph- HxO- = N- 2-134 t-Bu-3-Pyd- 2-Me-Ph- HxO- = N- 2-135 t-Bu-3-Pyd- 2-MeO-Ph- HxO- = N- 2-136 t-Bu- 3-Pyd- Ph- OcO- = N- 2-137 t-Bu- 3-Pyd- 2-Me-Ph- OcO- = N- 2-138 t-Bu- 3-Pyd- 2- MeO-Ph- OcO- = N- 2-139 t-Bu- 3-Pyd- Ph- MeS- = N- 2-140 t-Bu-3-Pyd- 2-Me-Ph- MeS- = N- 2 -141 t-Bu- 3-Pyd- 2-MeO-Ph- MeS- = N- 2-142 t-Bu- 3-Pyd- Ph- PrS- = N- 2-143 t-Bu- 3-Pyd- 2-Me-Ph- PrS- = N- 2-144 t-Bu- 3-Pyd- 2-MeO-Ph- PrS- = N- 2-145 t-Bu- 3-Pyd- Ph- BuS- = N -2-146 t-Bu- 3-Pyd- 2-Me-Ph- BuS- = N- 2-147 t-Bu- 3-Pyd- 2-MeO-Ph- BuS- = N- 2-148 t- Bu- 3-Pyd- Ph- PnS- = N- 2-149 t-Bu- 3-Pyd- 2-Me-Ph- PnS- = N- 2-150 t-Bu- 3-Pyd- 2-MeO- Ph- PnS- = N- 2-151 t-Bu-3- 3-Pyd- Ph- HxS- = N- 2-152 t-Bu-3- 3-Pyd- 2-Me-Ph- HxS- = N- 2-153 t-Bu- 3-Pyd- 2-MeO-Ph- HxS- = N- 2-154 t-Bu- 3-Pyd- Ph- OcS- = N- 2-155 t-Bu- 3-Pyd- 2- Me-Ph- OcS- = N- 2-156 t-Bu- 3-Pyd- 2-MeO-Ph- OcS- = N- 2-157 t-Bu- 3-Pyd- Ph- Bn- = N- 2 -158 t-Bu- 3-Pyd- 2-Me-Ph- Bn- = N- 2-159 t-Bu- 3-Pyd- 2-MeO-Ph- Bn- = N- 2-160 t-Bu- 3-Pyd- Ph- PhCH ₂ CH _2- = N- 2-161 t-Bu- 3-Pyd- 2-Me-Ph -PhCH ₂ CH _2- = N- 2-162 t-Bu- 3-Pyd- 2-MeO-Ph- PhCH ₂ CH _2- = N- 2-163 t-Bu- 3-Pyd- Ph- BnO- = N- 2-164 t-Bu- 3-Pyd- 2-Me-Ph- BnO- = N- 2-165 t-Bu-3- 3-Pyd- 2-MeO-Ph- BnO- = N- 2-166 t -Bu- 3-Pyd- Ph- BnS- = N- 2-167 t-Bu- 3-Pyd- 2-Me-Ph- BnS- = N- 2-168 t-Bu- 3-Pyd- 2-MeO -Ph- BnS- = N- 2-169 t-Bu- 3-Pyd- Ph- Ph- = N- 2-170 t-Bu- 3-Pyd- 2-Me-Ph- Ph- = N- 2- 171 t-Bu- 3-Pyd- 2-MeO-Ph- Ph- = N- 2-172 t-Bu- 3-Pyd- Ph- 4-F-Ph- = N- 2-173 t-Bu-3 -Pyd- 2-Me-Ph- 4-F-Ph- = N- 2-174 t-Bu- 3-Pyd- 2-MeO-Ph- 4-F-Ph- = N- 2-175 t-Bu -3-Pyd- Ph- 4-Cl-Ph- = N- 2-176 t-Bu- 3-Pyd- 2-Me-Ph- 4-Cl-Ph- = N- 2-177 t-Bu-3 -Pyd- 2-MeO-Ph- 4-Cl-Ph- = N- 2-178 t-Bu- 3-Pyd- Ph- 4-Me-Ph- = N- 2-179 t-Bu- 3-Pyd -2-Me-Ph- 4-Me-Ph- = N- 2-180 t-Bu- 3-Pyd- 2-MeO-Ph- 4-Me-Ph- = N- 2-181 t-Bu-3 -Pyd- Ph- 4-MeO-Ph- = N- 2-182 t-Bu- 3-Pyd- 2-Me-Ph- 4-MeO-Ph- = N- 2-183 t-Bu- 3-Pyd -2-MeO-Ph- 4-MeO-Ph- = N- 2-184 t-Bu- 3-Pyd- Ph- PhO- = N- 2-185 t-Bu- 3-Pyd- 2-Me-Ph -PhO- = N- 2-186 t-Bu- 3-Pyd- 2-MeO-Ph- PhO- = N- 2-187 t-Bu- 3-Pyd- Ph- PhS- = N- 2-188 t-Bu- 3-Pyd- 2-Me-Ph- PhS- = N- 2-189 t-Bu- 3-Pyd- 2-MeO-Ph- PhS- = N- 2-190 t-Bu -3-Pyd- Ph- Me ₂ N- = N- 2-191 t-Bu- 3-Pyd- 2-Me-Ph- Me ₂ N- = N- 2-192 t-Bu- 3-Pyd- 2 -MeO-Ph- Me ₂ N- = N- 2-193 t-Bu- 3-Pyd- Ph- Pyr- = N- 2-194 t-Bu-3-Pyd- 2-Me-Ph- Pyr- = N- 2-195 t-Bu- 3-Pyd- 2-MeO-Ph- Pyr- = N- 2-196 t-Bu- 3-Pyd- Ph- Pip- = N- 2-197 t-Bu-3 -Pyd- 2-Me-Ph- Pip- = N- 2-198 t-Bu- 3-Pyd- 2-MeO-Ph- Pip- = N- ────────────── ────────────────────.

In the above table, abbreviations indicate the following groups. Bn: benzyl Bu: butyl Et: ethyl Hp: heptyl Hx: hexyl Me: methyl Mor: morpholino Np: naphthyl Oc: octyl Ph: phenyl Pip: piperidino Pr: propyl Pyd: pyridyl Pym: pyrimidinyl Pyr: pyrrolidinyl Pyz: pyrazinyl Pyzn Pyridazinyl.

In the above table, preferably, compound numbers 1-20, 1-23, 1-24,
1-29, 1-31, 1-32, 1-36, 1-39,
1-42, 1-48, 1-51, 1-54, 1-60,
1-63, 1-66, 1-72, 1-75, 1-78,
1-84, 1-87, 1-90, 1-96, 1-99,
1-102, 1-108, 1-111, 1-114, 1
-120, 1-123, 1-126, 1-132, 1-
135, 1-138, 1-144, 1-147, 1-1
50, 1-156, 1-158, 1-159, 1-16
5, 1-167, 1-168, 1-172, 1-17
4, 1-175, 1-179, 1-180, 1-18
1, 1-183, 1-192, 1-193, 1-19
5, 1-196, 1-197, 1-203, 1-20
4, 1-206, 1-207, 1-208, 1-20
9, 1-210, 1-212, 1-213, 1-21
4, 1-216, 1-218, 1-219, 1-22
3, 1-225, 1-226, 1-230, 1-23
2, 1-233, 1-237, 1-240, 1-24
1, 1-245, 1-246, 1-247, 1-24
9, 1-250, 1-251, 1-253, 1-25
4, 1-255, 1-257, 1-258, 1-25
9, 1-261, 1-262, 1-263, 1-26
5, 1-266, 1-267, 1-269, 1-27
0, 1-271, 1-273, 1-274, 1-27
5, 1-277, 1-278, 1-279, 1-28
1, 1-282, 1-283, 1-285, 1-28
6, 1-287, 1-289, 1-290, 1-29
1, 1-293, 1-294, 1-295, 1-29
7, 1-299, 1-300, 1-306, 1-30
8, 1-309, 1-315, 1-324, 1-32
5, 1-328, 1-329, 1-335, 1-33
6, 1-360, 1-361, 1-367, 1-36
8, 1-369, 1-386, 1-387, 1-39
0, 1-391, 1-392, 1-398, 1-39
9, 1-400, 1-441, 1-442, 1-44
3, 1-449, 1-450, 1-451, 1-45
6, 1-457, 1-458, 1-465, 1-46
6, 1-467, 1-474, 1-475, 1-47
6, 1-486, 1-487, 1-488, 1-49
1, 1-492, 1-493, 1-516, 1-51
7, 1-518, 1-521, 1-522, 1-52
3, 1-558, 1-559, 1-560, 1-56
3, 1-564, 1-565, 1-587, 1-58
8, 1-589, 1-593, 1-594, 1-59
5, 1-681, 1-682, 1-683, 1-68
7, 1-689, 1-690, 1-692, 1-69
4, 1-695, 1-697, 1-699, 1-70
0, 1-702, 1-704, 1-705, 1-70
7, 1-709, 1-710, 1-712, 1-71
4, 1-715, 1-717, 1-719, 1-72
0, 1-722, 1-724, 1-725, 1-72
7, 1-729, 1-730, 1-732, 1-73
4, 1-735, 1-736, 1-737, 1-73
8, 1-739, 1-740, 1-741, 1-74
2, 1-743, 1-744, 1-745, 1-74
6, 1-747, 1-748, 1-749, 1-75
0, 1-751, 1-752, 1-753, 1-75
4, 1-755, 1-756, 1-757, 1-75
8, 1-759, 1-760, 1-761, 1-76
2, 1-763, 1-764, 1-765, 1-76
6, 1-767, 1-768, 1-769, 1-77
0, 1-771, 1-772, 1-773, 1-77
4, 1-775, 1-776, 1-777, 1-77
8, 1-779, 1-780, 1-781, 1-78
2, 1-783, 1-784, 1-785, 1-78
6, 1-787, 1-788, 1-789, 1-79
0, 1-791, 1-792, 1-793, 1-79
4, 1-795, 1-796, 1-797, 1-79
8, 1-799, 1-800, 1-801, 1-80
2, 1-803, 1-804, 1-805, 1-80
6, 1-807, 1-808, 1-809, 1-81
0, 1-811, 1-812, 1-813, 1-81
4, 1-815, 1-816, 1-817, 1-81
8, 1-1819, 1-820, 1-821, 1-82
2, 1-823, 1-824, 1-825, 1-82
6, 1-827, 1-828, 1-829, 1-83
2, 1-833, 1-850, 1-851, 1-85
4, 1-855, 1-856, 1-862, 1-86
3, 1-906, 1-907, 1-908, 1-91
1, 1-912, 1-913, 1-934, 1-93
5, 1-936, 1-939, 1-940, 1-94
1, 2-7, 2-8, 2-9, 2-10, 2-11, 2
-12, 2-13, 2-14, 2-15, 2-16, 2
-17, 2-18, 2-25, 2-26, 2-27, 2
-28, 2-29, 2-30, 2-31, 2-32, 2
-33, 2-34, 2-35, 2-36, 2-33, 2
-44, 2-45, 2-46, 2-47, 2-48, 2
-49, 2-50, 2-51, 2-52, 2-53, 2
-54, 2-58, 2-59, 2-60, 2-64, 2
-65, 2-66, 2-67, 2-68, 2-69, 2
-70, 2-71, 2-72, 2-85, 2-86, 2
-87, 2-88, 2-89, 2-90, 2-106,
2-107, 2-108, 2-109, 2-110, 2
−111, 2-112, 2-113, 2-114, 2-
115, 2-116, 2-117, 2-124, 2-1
25, 2-126, 2-127, 2-128, 2-12
9, 2-130, 2-131, 2-132, 2-13
3, 2-134, 2-135, 2-142, 2-14
3, 2-144, 2-145, 2-146, 2-14
7, 2-148, 2-149, 2-150, 2-15
1, 2-152, 2-153, 2-157, 2-15
8, 2-159, 2-163, 2-164, 2-16
5, 2-166, 2-167, 2-168, 2-16
9, 2-170, 2-171, 2-184, 2-18
5, 2-186, 2-187, 2-188 and 2-18
9 and more preferably Compound Nos. 1-36, 1-39 and 1-4.
2, 1-48, 1-51, 1-54, 1-60, 1-6
3, 1-66, 1-72, 1-75, 1-78, 1-8
4, 1-87, 1-90, 1-96, 1-99, 1-1
02, 1-108, 1-111, 1-114, 1-12
0, 1-123, 1-126, 1-172, 1-17
4, 1-175, 1-179, 1-180, 1-18
1, 1-183, 1-196, 1-197, 1-20
8, 1-209, 1-210, 1-212, 1-21
3, 1-214, 1-216, 1-218, 1-21
9, 1-223, 1-225, 1-226, 1-25
3, 1-254, 1-255, 1-257, 1-25
8, 1-259, 1-261, 1-262, 1-26
3, 1-265, 1-266, 1-267, 1-26
9, 1-270, 1-271, 1-273, 1-27
4, 1-275, 1-277, 1-278, 1-27
9, 1-289, 1-290, 1-291, 1-29
3, 1-294, 1-295, 1-297, 1-29
9, 1-300, 1-315, 1-328, 1-32
9, 1-367, 1-368, 1-369, 1-39
0, 1-391, 1-392, 1-441, 1-44
2, 1-443, 1-456, 1-457, 1-45
8, 1-465, 1-466, 1-467, 1-47
5, 1-692, 1-694, 1-695, 1-69
7, 1-699, 1-700, 1-702, 1-70
4, 1-705, 1-707, 1-709, 1-71
0, 1-712, 1-714, 1-715, 1-71
7, 1-719, 1-720, 1-722, 1-72
4, 1-725, 1-742, 1-743, 1-74
4, 1-745, 1-746, 1-747, 1-74
8, 1-749, 1-750, 1-751, 1-75
2, 1-753, 1-754, 1-755, 1-75
6, 1-757, 1-758, 1-759, 1-76
0, 1-761, 1-762, 1-775, 1-77
6, 1-777, 1-778, 1-779, 1-78
0, 1-781, 1-782, 1-783, 1-78
4, 1-785, 1-786, 1-787, 1-78
8, 1-789, 1-790, 1-791, 1-79
2, 1-793, 1-794, 1-795, 1-79
9, 1-800, 1-801, 1-802, 1-80
3, 1-804, 1-805, 1-806, 1-80
7, 1-811, 1-812, 1-813, 1-81
4, 1-815, 1-816, 1-820, 1-82
1, 1-822, 1-823, 1-824, 1-82
5, 1-827, 1-828, 1-829, 1-85
4, 1-855, 1-856, 2-7, 2-8, 2-
9, 2-10, 2-11, 2-12, 2-13, 2-1
4, 2-15, 2-25, 2-26, 2-27, 2-2
8, 2-29, 2-30, 2-31, 2-32, 2-3
3, 2-43, 2-44, 2-45, 2-46, 2-4
7, 2-48, 2-49, 2-50, 2-51, 2-5
8, 2-59, 2-60, 2-64, 2-65, 2-6
6, 2-67, 2-68, 2-69, 2-70, 2-7
1, 2-72, 2-85, 2-86, 2-87, 2-8
8, 2-89, 2-90, 2-106, 2-107, 2
-108, 2-109, 2-110, 2-111, 2-
112, 2-113, 2-114, 2-124, 2-1
25, 2-126, 2-127, 2-128, 2-12
9, 2-130, 2-131, 2-132, 2-14
2, 2-143, 2-144, 2-145, 2-14
6, 2-147, 2-148, 2-149, 2-15
0, 2-157, 2-158, 2-159, 2-16
3, 2-164, 2-165, 2-166, 2-16
7, 2-168, 2-169, 2-170, 2-17
1, 2-184, 2-185, 2-186, 2-18
7, 2-188 and 2-189, and still more preferably, compound Nos. 1-48, 1-51, 1
-54, 1-72, 1-75, 1-78, 1-108,
1-11, 1-114, 1-120, 1-123, 1
-126, 1-172, 1174, 1-175, 1-
183, 1-196, 1-197, 1-216, 1-2
18, 1-219, 1-223, 1-225, 1-22
6, 1-253, 1-254, 1-255, 1-26
1, 1-262, 1-263, 1-273, 1-27
4, 1-275, 1-277, 1-278, 1-27
9, 1-315, 1-328, 1-329, 1-39
0, 1-391, 1-392, 1-475, 1-69
2, 1-694, 1-695, 1-702, 1-70
4, 1-705, 1-717, 1-719, 1-72
0, 1-722, 1-724, 1-725, 1-74
2, 1-743, 1-744, 1-748, 1-74
9, 1-750, 1-757, 1-758, 1-75
9, 1-760, 1-761, 1-762, 1-77
5, 1-776, 1-777, 1-781, 1-78
2, 1-783, 1-790, 1-791, 1-79
2, 1-793, 1-794, 1-795, 1-82
0, 1-821, 1-822, 1-823, 1-82
4, 1-825, 1-827, 1-828, 1-82
9, 1-854, 1-855, 1-856, 2-10,
2-11, 2-12, 2-28, 2-29, 2-30,
2-46, 2-47, 2-48, 2-70, 2-71,
2-72, 2-109, 2-110, 2-111, 2-
127, 2-128, 2-129, 2-145, 2-1
46, 2-147, 2-169, 2-170 and 2-1
Compound No. 71 is particularly preferable. Compound No. 1-196: N- [4-butoxy-2- (2-methylphenyl) phenyl] -N′-
[2,2-dimethyl-1- (3-pyridyl) propyl]
Urea, Compound No. 1-197: N- [4-butoxy-2- (2-methoxyphenyl) phenyl] -N ′-[2,2-dimethyl-1- (3-pyridyl) propyl] urea, Compound No. 1 -218: N- [4-pentyloxy-2-
(2-methylphenyl) phenyl] -N '-[2,2-
Dimethyl-1- (3-pyridyl) propyl] urea, Compound No. 1-219: N- [4-pentyloxy-2-
(2-methoxyphenyl) phenyl] -N '-[2,2
-Dimethyl-1- (3-pyridyl) propyl] urea, compound number 1-225: N- [4-hexyloxy-2-
(2-methylphenyl) phenyl] -N '-[2,2-
Dimethyl-1- (3-pyridyl) propyl] urea, Compound No. 1-226: N- [4-hexyloxy-2-
(2-methoxyphenyl) phenyl] -N '-[2,2
-Dimethyl-1- (3-pyridyl) propyl] urea, compound number 1-328: N- [4-benzyloxy-2-
(2-methylphenyl) phenyl] -N '-[2,2-
Dimethyl-1- (3-pyridyl) propyl] urea, Compound No. 1-329: N- [4-benzyloxy-2-
(2-methoxyphenyl) phenyl] -N '-[2,2
-Dimethyl-1- (3-pyridyl) propyl] urea, compound number 1-391: N- [2- (2-methylphenyl)
-4-biphenyl-1-yl] -N '-[2,2-dimethyl-1- (3-pyridyl) propyl] urea, compound number 1-392: N- [2- (2-methoxyphenyl) -4 -Biphenyl-1-yl] -N '-[2,2-
Dimethyl-1- (3-pyridyl) propyl] urea, Compound No. 1-475: N- [2- (2-methylphenyl)
-4-morpholinophenyl] -N '-[2,2-dimethyl-1- (3-pyridyl) propyl] urea, compound number 1-749: N- [6-butoxy-4- (2-methylphenyl) pyridine -3-yl] -N '-[2,2
-Dimethyl-1- (3-pyridyl) propyl] urea, compound No. 1-750: N- [6-butoxy-4- (2-methoxyphenyl) pyridin-3-yl] -N ′-[2,
2-dimethyl-1- (3-pyridyl) propyl] urea, compound number 1-758: N- [4- (2-methylphenyl)
-6-pentyloxypyridin-3-yl] -N'-
[2,2-dimethyl-1- (3-pyridyl) propyl]
Urea, compound No. 1-759: N- [4- (2-methoxyphenyl) -6-pentyloxypyridin-3-yl] -N '
-[2,2-dimethyl-1- (3-pyridyl) propyl] urea, compound number 1-761: N- [6-hexyloxy-4-
(2-Methylphenyl) pyridin-3-yl] -N'-
[2,2-dimethyl-1- (3-pyridyl) propyl]
Urea, compound number 1-762: N- [6-hexyloxy-4-
(2-methoxyphenyl) pyridin-3-yl] -N '
-[2,2-dimethyl-1- (3-pyridyl) propyl] urea, compound number 1-855: N- [4- (2-methylphenyl)
-6-phenylpyridin-3-yl] -N '-[2,2
-Dimethyl-1- (3-pyridyl) propyl] urea;
And compound number 1-856: N- [4- (2-methoxyphenyl) -6-phenylpyridin-3-yl] -N'-
[2,2-dimethyl-1- (3-pyridyl) propyl]
And urea compounds.

[0042]

BEST MODE FOR CARRYING OUT THE INVENTION The compound having the general formula (I) of the present invention is easily produced according to the following method.

[0043]

Embedded image

In the above formula, R ¹ , R ² , R ³ , R ⁴ and X
Has the same meaning as described above. Method A is a method for producing compound (Ia) wherein Y in compound (I) is an imino group. Step A1 is a step of producing a compound having the general formula (III), wherein a carboxylic acid compound having the general formula (II), an acid halide thereof or an acid thereof in an inert solvent in the presence or absence of a base. And a mixed acid anhydride obtained from a halogenoformic acid C ₁ -C ₆ alkyl ester with an azidating agent, and then heating the obtained acid azide compound.

The azidating agent used is, for example, di-C ₁ -C ₄ alkylphosphoryl azide such as dimethyl phosphoryl azide, diethyl phosphoryl azide, dibutyl phosphoryl azide; ₆ -C ₁₀ aryl azide; hydrazoic; sodium azide, alkali metal azides, such as potassium azide; or trimethylsilyl azide, triethylsilyl azide, tri C ₁ -C ₄ alkyl such as tri-t- butylsilyl azide it is a silylazide, preferably a di-C ₆ -C ₁₀ aryl azide or an alkali metal azide, particularly preferably a diphenylphosphoryl azide or sodium azide.

Di C ₁ -C ₄ alkyl phosphoryl azide or di C ₆ -C ₁₀ aryl phosphoryl azide can react with carboxylic acid compound (II) in the presence of a base, and hydrogen azide can be reacted with carboxylic acid in the presence of a base. Acid halides (eg, acid chloride, acid bromide or acid iodide, preferably acid chloride) of acid compound (II) or carboxylic acid compound (II)
And halogenoformic acid C ₁ -C ₆ alkyl ester (for example,
Mixed acid anhydride obtained from methyl chloroformate, ethyl chloroformate, ethyl bromate, propyl chloroformate, butyl chloroformate, isobutyl chloroformate, isobutyl bromate or hexyl chloroformate, preferably ethyl chloroformate or isobutyl chloroformate) Alkali metal azide or tri C ₁ -C ₄ alkylsilyl azide is obtained from acid halides of carboxylic acid compound (II) or carboxylic acid compound (II) and halogenoformic acid C ₁ -C ₆ alkyl ester Can react with mixed anhydrides. The acid halides of the carboxylic acid compound (II) used in the above reaction and the mixed acid anhydride obtained from the carboxylic acid compound (II) and the halogenoformic acid C ₁ -C ₆ alkyl ester can be obtained by the following method B
It can be manufactured by the method described in one step.

The base used is, for example, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; sodium bicarbonate Alkali metal bicarbonates such as potassium bicarbonate; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium t-butoxide; or triethylamine, N-methylmorpholine, pyridine, 4-dimethylamino Pyridine,
1,5-diazabicyclo [4.3.0] -5-nonene,
Organic amines such as 1,8-diazabicyclo [5.4.0] -7-undecene may be used, and when phosphoryl azides are reacted, organic amines are preferably used.
More preferably, it is triethylamine, N-methylmorpholine or pyridine. When hydrogen azide is reacted, it is preferably an alkali metal hydroxide or an alkali metal carbonate, more preferably sodium hydroxide. Or or potassium hydroxide. The solvent used is not particularly limited as long as it does not disturb the raw material compound and does not inhibit the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene; dichloromethane, chloroform, carbon tetrachloride Halogenated hydrocarbons such as 1,2-dichloroethane; ethers such as ethyl ether, tetrahydrofuran and dioxane; ketones such as acetone and 2-butanone; nitriles such as acetonitrile; N, N-dimethyl An amide such as formamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone; a sulfoxide such as dimethylsulfoxide; or a mixed solvent thereof. Means hydrocarbons, halogenated hydrocarbons or Ethers, when reacting hydrogen azide or alkali metal azide, preferably halogenated hydrocarbons, ethers or amides, and when reacting trialkylsilyl azides, preferably , Hydrocarbons, halogenated hydrocarbons or ethers, more preferably hydrocarbons or ethers. The reaction temperature varies depending on the starting compound, azidating agent, type of solvent, etc.,
It is usually -10 ° C to 100 ° C, preferably 0 ° C to 50 ° C. The reaction time depends on the starting compound, azidating agent,
Depending on the type of reaction temperature, etc., it is usually 30 minutes to 1
0 hours, preferably 1 hour to 6 hours.

The reaction of heating the obtained acid azide compound is preferably performed in an inert solvent, and the inert solvent used is the same as the above-mentioned solvents. Hydrogens or amides, more preferably aromatic hydrocarbons. The reaction temperature varies depending on the type of the solvent and the like, but is usually 50 ° C. to 150 ° C., preferably 7 ° C.
0 ° C to 140 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually 30 minutes to 10 hours, preferably 1 hour to 6 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent under reduced pressure, and if necessary,
It can be further purified by a conventional method, for example, recrystallization, column chromatography and the like. Further, the target compound obtained in the reaction solution can be used as it is in the next step.

The step A2 is a step of producing the compound (Ia), which is achieved by reacting the compound with an amine compound having the general formula (IV) in an inert solvent. The inert solvent used is the same as the solvent used in Step A1, and is preferably an aromatic hydrocarbon, a halogenated hydrocarbon or an amide. The reaction temperature varies depending on the type of the solvent and the like, but is usually 0 ° C to 150 ° C, preferably 20 ° C to 100 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually 30 minutes to 10 hours, preferably 1 hour to 6 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, it is appropriately neutralized, and the solvent is distilled off under reduced pressure or the solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate. Can be obtained by evaporating the solvent after drying with
If necessary, it can be further purified by a conventional method, for example, recrystallization, column chromatography and the like.

Method B is a method for producing compound (Ib) in which Y is a methylene group in compound (I). The step B1 is a step for producing the compound (Ib), in which a compound having the general formula (V) or a reactive derivative thereof (for example, acid halides, mixed acid anhydrides or active esters) is prepared in an inert solvent. This is achieved by reacting compound (IV) or an acid addition salt thereof (for example, a mineral acid salt such as hydrochloride, nitrate, sulfate), for example, an acid halide method, a mixed acid anhydride method, an active ester method or This is performed by a condensation method.

In the acid halide method, a compound is prepared in an inert solvent.
(V) is reacted with a halogenating agent (eg, thionyl chloride, oxalyl chloride, phosphorus pentachloride, etc.) to produce an acid halide. In the presence or absence of a base,
It is achieved by reacting. The base used is
For example, alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; or triethylamine, N
-Methylmorpholine, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] -5-
Nonene, 1,8-diazabicyclo [5.4.0] -7-
It can be an organic amine such as undecene, preferably
Organic amine.

The inert solvent used is not particularly limited as long as it dissolves the starting compounds and does not inhibit the reaction. For example, hexane, cyclohexane, benzene,
Hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride; ethers such as ethyl ether, tetrahydrofuran and dioxane; or acetone; Ketones such as 2-butanone,
Preferably, hydrocarbons, halogenated hydrocarbons or air
Tells. The reaction temperature varies depending on the types of the starting compounds (V) and (IV) and the solvent, but the reaction between the halogenating agent and the compound (V) and the reaction between the acid halide and the compound (IV) are usually -20 ° C. To 150 ° C., preferably
In the reaction between the halogenating agent and the compound (V), the temperature is −10 ° C. to 50 ° C., and in the reaction between the acid halide and the compound (IV), the temperature is 0 ° C. to 100 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours) for both reactions.

In the mixed acid anhydride method, halogenoformic acid C ₁ -C
_A compound (V) is reacted with a _6- alkyl or C ₆ -C ₁₀ aryl halide formate to produce a mixed anhydride, and the mixed anhydride is reacted with a compound (IV) or an acid addition salt thereof. You. The reaction to produce a mixed acid anhydride is
Halogenoformic acid C ₁ such as methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, hexyl chloroformate;
-C ₆ alkyl (preferably, ethyl chloroformate or isobutyl chloroformate) or chloroformate, phenyl Buromugi acid, chloroformate tolyl, in Harogenogi acid C ₆ -C ₁₀ aryl such as chloroformate naphthyl (preferably the chloroformate The reaction is carried out by reacting the compound (V) with the compound (V), preferably in an inert solvent in the presence of a base.

The base and the inert solvent used are the same as those used in the above-mentioned acid halide method. The reaction temperature varies depending on the type of the starting compound (V) and the solvent, but is usually from -20 ° C to 50 ° C (preferably from 0 ° C to 30 ° C).
° C), and the reaction time varies depending on the reaction temperature and the like.
Usually 15 minutes to 24 hours (preferably 30 minutes to 1 hour
6 hours).

The reaction of the mixed acid anhydride with the compound (IV) or an acid addition salt thereof is preferably carried out in an inert solvent in the presence or absence of a base. The active solvent is the same as that used in the above-mentioned acid halide method. The reaction temperature varies depending on the type of the starting compound (IV) and the solvent, but is usually -20 ° C to 100 ° C (preferably -10 ° C to 50 ° C). The reaction time varies depending on the reaction temperature and the like. , Usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours).

In the active ester method, a condensing agent (for example, dicyclohexylcarbodiimide, carbonyldiimidazo-
Compound (V) in the presence of an active esterifying agent (for example, an N-hydroxy compound such as N-hydroxysuccinimide or N-hydroxybenzotriazole) to produce an active ester. However, this is achieved by reacting the active ester with compound (IV) or an acid addition salt thereof. The reaction for producing the active ester is preferably performed in an inert solvent, and the inert solvent used is
It is the same as that used in the above-mentioned acid halide method. The reaction temperature varies depending on the type of the starting compounds (V) and (IV) and the solvent.
To 50 ° C (preferably -10 ° C to 30 ° C),
In the reaction between the active ester compound and the compound (IV), -2
0 ° C. to 50 ° C. (preferably −10 ° C. to 30 ° C.), and the reaction time varies depending on the reaction temperature and the like. Time).

The condensation method is carried out using a condensing agent [for example, carbodiimides such as dicyclohexylcarbodiimide, 1- (N, N-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; dimethylcyanophosphate, diethylcyanophosphate, dihexyl C ₁ -C ₆ such as cyanophosphoric acid
Alkyl cyanophosphoric acid; diphenylphosphoryl azide,
Di (p- nitrophenyl) phosphoryl azide, di -C ₆ -C ₁₀ aryl phosphite, such as dinaphthyl azide azide; or carbonyl diimidazole, preferably, dicyclohexylcarbodiimide, 1-(N, N
-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, diethylcyanophosphoric acid, diphenylphosphorylazide or carbonyldiimidazole] in the presence of compound (V) and compound (IV) or an acid addition salt thereof. Done. This reaction is carried out in the same manner as the above-mentioned reaction for producing an active ester. After the completion of the reaction, the target substance of each reaction is collected from the reaction mixture according to a conventional method.
For example, after appropriately filtering the insoluble matter, filtering the precipitated crystals or appropriately filtering the insoluble matter, appropriately neutralizing,
After distilling off the solvent, water is added, extracted with a water-immiscible organic solvent such as ethyl acetate, dried, and obtained by distilling off the extraction solvent. , Recrystallization, column chromatography and the like.

The starting compounds (II), (IV) and (V) of the present invention
Is easily manufactured according to the following method.

[0061]

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[0062]

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[0063]

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[0064]

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[0065]

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[0066]

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[0067]

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[0068]

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[0069]

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In the above formula, R ¹ , R ² , R ³ , R ⁴ and X
Have the same meanings as described above, R ¹ a represents a C ₁ -C ₈ alkyl group in R ^1, R ¹ b represents a methyl or ethyl group, R ⁴ a is C in R ⁴ ₁ -C ₈ an alkoxy group or a C ₇ -C ₁₂ aralkyloxy group, R ⁴ b
Represents a C ₆ -C ₁₀ aryl group in R ^4, R ⁴ c
Is C ₁ -C ₈ alkyl group in R ^4, shows a C ₆ -C ₁₀ aryl group or C ₇ -C ₁₂ aralkyl group, R ⁴ d is
A di-C ₁ -C ₆ alkylamino group for R ⁴ ,
R ⁴ e represents a 3- to 6-membered cyclic amino group which may contain an oxygen or sulfur atom in R ⁴ (the group is bonded to a benzene ring via a nitrogen atom), and R ⁴ f represents C ⁴ in R ⁴ indicates ₁ -C ₈ alkylthio group, R ⁵ is, C ₁ -C ₆
An alkyl group or a C ₇ -C ₁₂ aralkyl group (preferably
₁ -C ₄ alkyl group or a C ₇ -C ₈ aralkyl group, more preferably, C ₁ -C ₄ alkyl group or a benzyl group, particularly preferably a methyl or ethyl group), R ⁶ is, R ⁴
C ₁ -C ₈ alkyl moiety of C ₁ -C ₈ alkoxy group in, the C ₇ -C ₁₂ aralkyloxy group in R ⁴ C
₇ -C ₁₂ aralkyl moiety or hydroxyl-protecting radical, R
⁶ a is a protecting group which may benzyl group or a hydroxyl group which may be substituted in R ^6, V represents a leaving group, W is showed good C ₂ -C ₅ alkylene group optionally contain an oxygen or sulfur atom , Z represents a halogen atom (preferably, a chlorine or bromine atom).

The protecting group for the hydroxyl group of R ⁶ is, for example, a cyclic ether or thioether group such as tetrahydrofuranyl, tetrahydropyranyl, 4-methoxytetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl group, methoxyethoxymethyl group or A benzyloxycarbonyl group which may be substituted (the substituent is a C ₁
-C ₄ alkyl, halogen, C ₁ -C ₄ alkoxy or nitro, preferably, methyl, chloro, methoxy or nitro, and particularly preferably a p- chloro or p- methoxy. ), Preferably a tetrahydropyranyl group, a methoxymethyl group, a benzyloxycarbonyl group, a p-chlorobenzyloxycarbonyl group or a p-chlorobenzyloxycarbonyl group.
A methoxybenzyloxycarbonyl group, particularly preferably a benzyloxycarbonyl group. Or R ⁶
C ₇ -C ₁₂ C ₇ aralkyl group in the R ⁴ -
Among the C ₁₂ aralkyl moieties, an optionally substituted benzyl moiety (the substituent is C ₁ -C ₄ alkyl, halogen, C ₁ -C ₄ alkoxy or nitro, preferably methyl, chloro, methoxy Or nitro, particularly preferably p-chloro or p-methoxy.)
It can be a protecting group for a hydroxyl group, preferably a benzyl group, p-
A chlorobenzyl group or a p-methoxybenzyl group,
Particularly preferred is a benzyl group.

The "leaving group" for V is not particularly limited as long as it is a group which is usually eliminated as a nucleophilic residue, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom; Sulfonyloxy group, ethanesulfonyloxy group,
A C ₁ -C ₄ alkanesulfonyloxy group such as a propanesulfonyloxy group or a butanesulfonyloxy group;
Trifluoromethanesulfonyloxy group, 2,2,2-
Trichloroethanesulfonyloxy group, 3,3,3-tribromopropanesulfonyloxy group or 4,4,4
A halogeno C ₁ -C ₄ alkanesulfonyloxy group, such as a trifluorobutanesulfonyloxy group; or a benzenesulfonyloxy group, an α-naphthylsulfonyloxy group, a β-naphthylsulfonyloxy group, a p-toluenesulfonyloxy group, 4-t-butylbenzenesulfonyloxy group, mesitylenesulfonyloxy group or 6-
C, such as an ethyl-α-naphthylsulfonyloxy group
C ₆ -C ₁₀ which may have 1 to 3 _1- C ₄ alkyl
An arylsulfonyloxy group, preferably a halogen atom; a methanesulfonyloxy group, an ethanesulfonyloxy group, a trifluoromethanesulfonyloxy group,
2,2,2-trichloroethanesulfonyloxy group; benzenesulfonyloxy group, toluenesulfonyloxy group or mesitylenesulfonyloxy group, more preferably chlorine atom, bromine atom, iodine atom, methanesulfonyloxy group, trifluoromethanesulfonyl An oxy group,
It is a benzenesulfonyloxy group, a p-toluenesulfonyloxy group or a mesitylenesulfonyloxy group, particularly preferably a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group.

The “C ₂ -C ₅ alkylene group optionally containing an oxygen or sulfur atom” for W is, for example, an ethylene group,
Propylene group, trimethylene group, 2-oxatrimethylene group, 2-thiatrimethylene group, tetramethylene group,
-Oxatetramethylene group, 2-thiatetramethylene group, 1-methyltrimethylene group, 2-methyltrimethylene group, 3-methyltrimethylene group, pentamethylene group,
It may be a 2-oxapentamethylene group, a 2-thiapentamethylene group, a 3-oxapentamethylene group or a 3-thiapentamethylene group, preferably a tetramethylene group, a pentamethylene group or a 3-oxapentamethylene group. is there.

The method C is a method for producing a compound (II) using a 4-substituted salicylic acid or a 6-substituted-4-hydroxypyridine-3-carboxylic acid compound having the general formula (VI) as a raw material. Step C1 is a step of producing a compound having the general formula (VII), which is achieved by esterifying a carboxylic acid having the general formula (VI).

The esterification reaction is carried out in an alcohol which forms an excess ester residue which also serves as a solvent (eg, methanol, ethanol, propanol, butanol, benzyl alcohol, phenethyl alcohol, etc.), and an acid catalyst (eg, hydrochloric acid, sulfuric acid, etc.). Mineral acids such as nitric acid, sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; preferably hydrochloric acid, sulfuric acid or toluenesulfonic acid), halogenotri C ₁ -C ₄ alkyl In the presence of silane (preferably chlorotrimethylsilane or chlorotriethylsilane) or acetyl halide (preferably chloroacetyl or bromoacetyl), the carboxylic acid (VI) is reacted with an alcohol forming an ester residue, 10 ° C to 150 ° C (preferably 10 ° C to 10 ° C C.) for 30 minutes to 36 hours (preferably 1 to 32 hours) or in an inert solvent (for example, aromatic hydrocarbons such as benzene, toluene, xylene, ethyl ether, tetrahydrofuran, Ethers such as dioxane, acetone, 2
Ketones such as butanone, nitriles such as acetonitrile, N, N-dimethylformamide, N, N-
Amides such as dimethylacetamide; preferably aromatic hydrocarbons or amides) in the presence of a base (for example, alkali metal carbonates such as sodium carbonate and potassium carbonate, triethylamine, N-methylmorpholine,
Organic amines such as pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] -5-nonene, and 1,8-diazabicyclo [5.4.0] -7-undecene; Are alkali metal carbonates), carboxylic acids (VI), and halides forming ester residues (eg, methyl iodide, ethyl iodide, propyl iodide, butyl bromide, butyl iodide, benzyl chloride, benzyl bromide, Phenethyl chloride) at −10 ° C. to 150 ° C. (preferably 10 ° C. to 100 ° C.) for 30 minutes to 10 hours (preferably 1 hour to 6 hours).

Step C2 is a step for producing a compound having the general formula (VIII) in an inert solvent (for example, aromatic hydrocarbons such as benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride). Halogenated hydrocarbons such as 1,2-dichloroethane, ethers such as ethyl ether, tetrahydrofuran and dioxane, ketones such as acetone and 2-butanone, and nitriles such as acetonitrile; Hydrocarbons), in the presence of a base (eg, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide,
Alkali metal carbonates such as sodium carbonate and potassium carbonate, triethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo Organic amines such as [5.4.0] -7-undecene; preferably organic amines; more preferably triethylamine, N-methylmorpholine or pyridine),
Carboxylic acid esters (VII) with trifluoromethanesulfonic anhydride, trifluoromethanesulfonic acid halide (preferably trifluoromethanesulfonic anhydride),
At -10 ° C to 50 ° C (preferably 0 ° C to 30 ° C)
10 minutes to 6 hours (preferably 30 minutes to 3 hours)
It is performed by reacting.

Step C3 is a step for producing a compound having the general formula (X) in an inert solvent (for example, benzene,
Aromatic hydrocarbons such as toluene and xylene; ethers such as ethyl ether, tetrahydrofuran and dioxane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidinone Or a mixed solvent of these organic solvents and water;
Preferably, amides) in the presence of a palladium catalyst (for example, palladium-carbon, palladium hydroxide, palladium acetate, tetrakistriphenylphosphine palladium;
Preferably, tetrakistriphenylphosphine palladium) in the presence of a base (for example, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, an alkali metal carbonate such as sodium carbonate or potassium carbonate, triethylamine, N -Methylmorpholine, pyridine, 4-
Organic amines such as dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7-undecene; preferably, organic amine More preferably, triethylamine, N-methylmorpholine or pyridine), a sulfonic acid ester (VIII) and a boron compound having the general formula (IX) are mixed with a boron compound having a general formula (IX) at 20 ° C to 150 ° C (preferably 50 ° C to 1 ° C).
(20 ° C.) for 10 minutes to 6 hours (preferably 30 minutes to 3 hours).

Step C4 is a step of producing compound (II) in an inert solvent (eg, ethers such as ethyl ether, tetrahydrofuran, dioxane, alcohols such as methanol, ethanol, butanol, water or A mixed solvent of these; preferably, a mixed solvent of ethers and alcohols or an aqueous alcohol), compound (X)
With an alkali (eg, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, an alkali metal carbonate such as sodium carbonate or potassium carbonate; preferably an alkali metal hydroxide); 0 ℃ ～ 1
The reaction is carried out at 50 ° C. (preferably 20 ° C. to 100 ° C.) for 30 minutes to 16 hours (preferably 1 hour to 10 hours).

After completion of the reaction, the target compound in each step of Method C is collected from the reaction mixture according to a conventional method. For example, if insolubles are present, they are filtered off as appropriate, or if the reaction solution is acidic or alkaline, they are appropriately neutralized, and the solvent is distilled off under reduced pressure or the solvent is distilled off under reduced pressure. To water, extracted with a water-immiscible organic solvent such as ethyl acetate, dried over anhydrous magnesium sulfate or the like, and can be obtained by distilling off the solvent.If necessary, a conventional method, for example, It can be further purified by recrystallization, column chromatography or the like.

In the method D, starting from 2,4-dihydroxybenzoic acid having the general formula (XI), the compound (II)
X is a group having the formula = CH-, compounds wherein R ⁴ is R ⁴ a (IIa) and X is a group having the formula = CH-, compounds wherein R ⁴ is R ⁴ b and (IIb) It is a manufacturing method. Step D1 is a step of producing a compound having the general formula (XII), which is achieved by esterifying a carboxylic acid having the general formula (XI). Done.

Step D2 is a step of producing a compound having the general formula (XIII), which is achieved by alkylating, aralkylating or protecting the hydroxyl group of the carboxylic acid esters (XII).

The reaction for alkylating or aralkylating a hydroxyl group is carried out in an inert solvent (for example, benzene, toluene,
Aromatic hydrocarbons such as xylene, ethyl ether,
Ethers such as tetrahydrofuran and dioxane,
Acetone, ketones such as 2-butanone, N, N-dimethylformamide, N, N-dimethylacetamide,
Amides such as N-methyl-2-pyrrolidinone; preferably ketones or amides) in the presence of a base (for example, an alkali metal carbonate such as sodium carbonate or potassium carbonate, triethylamine, N-methylmorpholine) ,
Organic amines such as pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7-undecene, hydrogenation Sodium, an alkali metal hydride such as potassium hydride; preferably an alkali metal carbonate), and the corresponding alkyl halide (preferably methyl iodide, ethyl iodide or other alkyl chloride; Bromide or iodide), the corresponding aralkyl halide (preferably benzyl chloride, benzyl bromide or other aralkyl chloride, bromide or iodide), diC ₁ -C
_8- alkyl sulfate, di-C ₇ -C ₁₂ aralkyl sulfate, C ₁ -C ₆ optionally substituted with halogen
Alkanesulfonic acid or C ₆ -C ₁₀ arylsulfonic acid C ₁ -C ₈ alkyl esters (suitable acid moiety, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, p
-Chlorobenzenesulfonic acid or p-nitrobenzenesulfonic acid) or C ₁ -optionally substituted with halogen.
C ₆ alkanoic acid or C ₆ -C ₁₀ arylsulfonic acid C ₇ -C ₁₂ aralkyl esters (suitable acid moiety, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, p- Reaction with chlorobenzenesulfonic acid or p-nitrobenzenesulfonic acid) at -10 ° C to 100 ° C (preferably 10 ° C to 80 ° C) for 30 minutes to 24 hours (preferably 2 hours to 20 hours) It is performed by

The reaction for protecting the hydroxyl group depends on the type of the protecting group, and is carried out by a method well known in organic synthetic chemistry.

When the protecting group for the hydroxyl group is a cyclic ether or thioether group, the reaction for protecting the hydroxyl group is carried out in an inert solvent (for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethyl ether, Ethers such as tetrahydrofuran and dioxane; preferably ethers) in the presence of an acid (eg, a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid) Sulfonic acids such as acids; preferably hydrochloric acid or toluenesulfonic acid), compound (XII) is converted to a dihydrocyclic ether or thioether compound (eg, dihydrofuran, dihydropyran, 4-methoxydihydropyran,
Dihydrothiopyran) at −10 ° C. to 50 ° C. (preferably 10 ° C. to 30 ° C.) for 30 minutes to 10 hours (preferably 1 hour to 5 hours). Also, a large excess of dihydrocyclic ether or thioether compound can be used as the solvent.

When the protecting group for the hydroxyl group is a methoxymethyl group, a methoxyethoxymethyl group or a benzyloxycarbonyl group which may be substituted, the reaction for protecting the hydroxyl group is carried out in an inert solvent in the presence of a base. Compound (XII) is converted to a halide having a protecting group residue (for example, methoxymethyl bromide, methoxymethyl iodide, methoxyethoxymethyl chloride, methoxyethoxymethyl bromide,
Benzyloxycarbonyl chloride, benzyloxycarbonyl bromide, p-chlorobenzyloxycarbonyl chloride, p-methoxybenzyloxycarbonyl chloride), the inert solvent used, the base used and the reaction conditions It is the same as the above-mentioned alkylation or aralkylation reaction.

The step D3 is a step of producing a compound having the general formula (XIV), which is achieved by trifluoromethanesulfonylation of the compound (XIII). Done.

Step D4 is a step of preparing a compound having the general formula (XV), which is achieved by reacting compound (XIV) with compound (IX). The same is done.

[0088] The D5 step is a step for preparing a compound (IIa), in the compound (XV), a group having the formula OR ⁶ is R ⁴ a
Is achieved by alkali hydrolysis of compound (XVa), which is the same as the above-mentioned Method C, Step C4.

[0089] The D6 step is a step for preparing a compound having the general formula (XVI), in the compound (XV), R ⁶ is R ⁶ a
This is achieved by removing the hydroxyl-protecting group of the compound (XVb).

The reaction for removing the hydroxyl group depends on the type of the protecting group and is carried out by a method well known in organic synthetic chemistry.

When the protecting group for the hydroxyl group is a cyclic ether or thioether group, a methoxymethyl group or a methoxyethoxymethyl group, the protective group may be in an inert solvent (for example, alcohols such as methanol or ethanol or water or ethyl ether, Mixed solvents of ethers such as tetrahydrofuran or dioxane and alcohols; preferably alcohols), compound (XV) is converted to an acid (eg, a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid, trifluoromethane) Sulfonic acids such as sulfonic acid, benzenesulfonic acid, and toluenesulfonic acid; preferably hydrochloric acid or toluenesulfonic acid) at -10 ° C to 50 ° C (preferably 10 ° C to 30 ° C) for 10 minutes to By reacting for 10 hours (preferably 30 minutes to 5 hours), a protecting group for a hydroxyl group is obtained. Is carried out.

When the protecting group of the hydroxyl group is a benzyl group which may be substituted or a benzyloxycarbonyl group which may be substituted, an inert solvent (for example, an ether such as ethyl ether, tetrahydrofuran or dioxane) Alcohols such as methanol, ethanol, butanol, formic acid, carboxylic acids such as acetic acid,
Esters such as ethyl acetate and butyl acetate; preferably alcohols) in the presence of a catalytic reduction catalyst (for example, palladium-carbon, palladium-barium sulfate, palladium acetate, palladium hydroxide, platinum oxide, platinum black, rhodium -Alumina, triphenylphosphine-rhodium chloride; preferably palladium-carbon) and compound (XVb) with hydrogen (usually 1 to 5 atm, preferably 1 to 2 atm) at -10 ° C to 100 atm By reacting at 30 ° C. (preferably 10 ° C. to 50 ° C.) for 30 minutes to 10 hours (preferably 1 hour to 5 hours), a reaction for removing a protecting group of a hydroxyl group is performed.

Step D7 is a step of producing a compound having the general formula (XVII), which is achieved by trifluoromethanesulfonylation of the hydroxy compound (XVI). This step is the same as the above-mentioned Method C, Step C2. Done in

Step D8 is a step for producing a compound having the general formula (XIX), which is achieved by reacting the compound (XVII) with a compound having the general formula (XVIII). This is performed in the same manner as in the step C3.

Step D9 is a step of producing compound (IIb), which is achieved by hydrolyzing compound (XIX). This step is carried out in the same manner as in the above-mentioned Method C, Step C4.

After completion of the reaction, the target compound of each step of Method D is collected from the reaction mixture according to a conventional method. For example, if insolubles are present, they are filtered off as appropriate, or, if the reaction solution is acidic or alkaline, they are appropriately neutralized, and the solvent is distilled off under reduced pressure or the solvent is distilled off under reduced pressure,
Water was added to the residue, extracted with a water-immiscible organic solvent such as ethyl acetate, dried over anhydrous magnesium sulfate, and the like.
It can be obtained by evaporating the solvent, and if necessary, can be further purified by a conventional method, for example, recrystallization, column chromatography and the like.

In the method E, the compound (II) in which R ⁴ is R ⁴ c
Wherein X is a group having the formula = N-
c). Step E1 is a step for producing a compound having the general formula (XXII) in an inert solvent (for example, benzene, toluene,
Aromatic hydrocarbons such as xylene, dichloromethane,
Halogenated hydrocarbons such as chloroform, carbon tetrachloride and 1,2-dichloroethane, ethers such as ethyl ether, tetrahydrofuran and dioxane; preferably ethers), in the presence of a copper salt (for example, copper chloride) Copper bromide, copper halides such as copper iodide, copper bromide-dimethyl sulfide, copper halide-dimethyl sulfide complexes such as copper iodide-dimethyl sulfide; preferably copper iodide or copper iodide -Dimethyl sulfide) and C ₁ -C ₆ alkyl halogenoformate or C ₆ -C ₁₀ aryl (for example, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, hexyl chloroformate, phenyl chloroformate, bromate) Phenyl; preferably phenyl chloroformate) and -50 ° C to 10 ° C (preferably -30 ° C).
C. to 0 ° C.) for 10 minutes to 5 hours (preferably 30 minutes).
After reacting for 3 minutes to 3 hours, a Grignard reagent having the general formula (XXI) is reacted with -50 ° C to 10 ° C (preferably-
(30 ° C. to 0 ° C.) for 10 minutes to 5 hours (preferably,
(30 minutes to 3 hours).
Further, the target compound (XXII) in the reaction solution can be used as it is in the next step.

Step E2 is a step for producing a compound having the general formula (XXIII) in an inert solvent (for example, aromatic hydrocarbons such as benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride). , 1,2-dichloroethane, halogenated hydrocarbons such as ethyl ether, tetrahydrofuran, dioxane; preferably, aromatic hydrocarbons), compound (XXII)
With an oxidizing agent (e.g., chloranil such as o-chloranil, p-chloranil, dichlorodicyanoquinone; preferably chloranil) at 0 ° C to 140 ° C (preferably,
(20 ° C. to 120 ° C.) for 30 minutes to 5 hours (preferably 1 hour to 3 hours).

Step E3 is a step of producing a compound having the general formula (XXV), which is achieved by reacting the compound (XXIII) with a compound having the general formula (XXIV). It is performed in the presence or absence in the same manner as in the above-mentioned Step E1.

The step E4 is a step for producing a compound having the general formula (XXVI), which is achieved by reacting the compound (XXV) with an oxidizing agent. This step is carried out in the same manner as the step E2. .

The step E5 is a step of producing the compound (IIc), which is accomplished by hydrolyzing the compound (XXVI). This step is carried out in the same manner as in the above-mentioned Method C, Step C4.

In the compound (II), the compound in which R ⁴ is a hydrogen atom and X is a group having the formula −N- is obtained by hydrolyzing the compound (XXIII) in the same manner as in the above-mentioned Method C, Step C4. Also, it can be manufactured.

After completion of the reaction, the target compound of each step of Method E is collected from the reaction mixture according to a conventional method. For example, if insolubles are present, they are filtered off as appropriate, or, if the reaction solution is acidic or alkaline, they are appropriately neutralized, and the solvent is distilled off under reduced pressure or the solvent is distilled off under reduced pressure,
Water was added to the residue, extracted with a water-immiscible organic solvent such as ethyl acetate, dried over anhydrous magnesium sulfate, and the like.
It can be obtained by evaporating the solvent, and if necessary, can be further purified by a conventional method, for example, recrystallization, column chromatography and the like.

Method F is a method for producing compound (V). Step F1 is a step for preparing a compound having the general formula (XXVII) in an inert solvent (for example, hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, ethyl ether, tetrahydrofuran and dioxane). Ethers, alcohols such as methanol, ethanol, butanol, water or a mixture of water and the above organic solvent; preferably, when the reducing agent described later is lithium aluminum hydride or alkyl aluminum hydride, hydrocarbon When the reducing agent is a borohydride salt, alcohols, water or hydrous alcohols), compound (II) or an ester thereof (compound (II) can be prepared in the same manner as in the above-mentioned Method C, Step C1). And a reducing agent (eg, lithium aluminum hydride, diisobutylaluminum hydride). Alkyl aluminum hydride, such as aluminum, sodium borohydride, borohydride salts such as sodium cyanoborohydride; preferably lithium aluminum hydride, diisobutylaluminum hydride or sodium borohydride); ° C to 1
The reaction is performed at 00 ° C. (preferably 10 ° C. to 50 ° C.) for 10 minutes to 10 hours (preferably 30 minutes to 5 hours).

Step F2 is a step for producing a compound having the general formula (XXVIII) in an inert solvent (for example, aromatic hydrocarbons such as benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride). , 1,2-dichloroethane, halogenated hydrocarbons such as ethyl ether, tetrahydrofuran, dioxane; preferably, halogenated hydrocarbons), compound (X
XVII) is a halogenating agent (for example, thionyl halide such as thionyl chloride, phosphorus trichloride, phosphorus trihalide such as phosphorus tribromide, phosphorus pentachloride, phosphorus pentahalide such as phosphorus pentabromide, Phosphorus oxyhalides such as phosphorus oxychloride and phosphorus oxybromide, triphenylphosphine-tetrahalogen such as triphenylphosphine-carbon tetrachloride, triphenylphosphine-carbon tetrabromide, triphenylphosphine-carbon tetraiodide Carbon bromide, oxalyl chloride; preferably thionyl chloride, phosphorus oxychloride, phosphorus oxybromide or oxalyl chloride) and -1
0 ° C to 100 ° C (preferably 10 ° C to 50 ° C)
The reaction is performed for 10 minutes to 10 hours (preferably, 30 minutes to 5 hours).

Step F3 is a step for producing a compound having the general formula (XXIX) in an inert solvent (for example, aromatic hydrocarbons such as benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride). And halogenated hydrocarbons such as 1,2-dichloroethane, ethers such as ethyl ether, tetrahydrofuran and dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone. Amides, sulfoxides such as dimethyl sulfoxide; preferably amides), compound (XXVIII) is converted to an alkali metal cyanide (eg, lithium cyanide, sodium cyanide, potassium cyanide; preferably sodium cyanide or Potassium cyanide) and 0 ° C to 15
The reaction is carried out at 0 ° C. (preferably 20 ° C. to 100 ° C.) for 30 minutes to 20 hours (preferably 1 hour to 10 hours).

Step F4 is a step of producing compound (V), which is achieved by hydrolyzing compound (XXIX),
This step is performed in the same manner as the above-mentioned Method C, Step C4.

After completion of the reaction, the target compound of each step of Method F is collected from the reaction mixture according to a conventional method. For example, if insolubles are present, they are filtered off as appropriate, or if the reaction solution is acidic or alkaline, it is appropriately neutralized, and the solvent is distilled off under reduced pressure or water or ammonium chloride. After adding an aqueous solution and stirring at room temperature,
If any insolubles are present, they can be obtained by filtering off, extracting with a water-immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate, etc., and then distilling off the solvent. Then, it can be further purified by a conventional method, for example, recrystallization, column chromatography and the like.

Method G is a method for producing compound (IV). Step G1 is a step for producing a compound having the general formula (XXXI) in an inert solvent (for example, alcohols such as methanol, ethanol and butanol, pyridines such as pyridine, lutidine and collidine, N, Amides such as N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone or a mixed solvent thereof; preferably alcohols or pyridines),
Compound (XXX) is combined with hydroxylamine or a salt thereof (for example, a mineral acid salt such as hydrochloride, sulfate or nitrate; preferably hydrochloride) at 0 ° C to 100 ° C (preferably 20 ° C).
To 50 ° C.) for 10 minutes to 6 hours (preferably 30 minutes).
(3 minutes to 3 hours). When a hydroxylamine salt is reacted in an alcohol solvent, a base (an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, lithium carbonate, Alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, or triethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo Organic amines such as [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7-undecene; preferably lithium hydroxide, sodium hydroxide, potassium hydroxide , Triethylamine or N-methylmorpholine).

Step G2 is a step of producing compound (IV) in an inert solvent (for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl ether, etc.). Tetrahydrofuran, ethers such as dioxane, alcohols such as methanol, ethanol, butanol; preferably alcohols), compound (XXXI) is reduced with a reducing agent (for example,
Metal powder such as zinc powder, iron powder, and tin powder, preferably zinc powder) and 10 ° C to 120 ° C (preferably 30 ° C to 1 ° C).
(00 ° C.) for 1 hour to 24 hours (preferably 2 hours to 5 hours).

Compound (IV) may be used in an inert solvent (for example, alcohols such as methanol, ethanol and butanol, fatty acids such as formic acid, acetic acid and propionic acid, or a mixed solvent thereof; Compound (X) in the presence of the catalytic reduction catalyst described in Step D6 of Method D, 1 to 2 atm of hydrogen or formic acid such as formic acid or ammonium formate (preferably ammonium formate).
XX) with an ammonium salt (eg, a salt with a mineral acid such as ammonium chloride, ammonium bromide, a salt with a carboxylic acid such as ammonium formate, ammonium acetate; preferably ammonium chloride or ammonium formate) at 0 ° C. To 100 ° C (preferably, 20 ° C to 6 ° C).
(0 ° C.) for 30 minutes to 10 hours (preferably 1 hour to 5 hours).

After completion of the reaction, the target compound of each step of Method G is collected from the reaction mixture according to a conventional method. For example, if insolubles are present, they are filtered off as appropriate, or, if the reaction solution is acidic or alkaline, they are appropriately neutralized, and the solvent is distilled off under reduced pressure or the solvent is distilled off under reduced pressure,
Water was added to the residue, extracted with a water-immiscible organic solvent such as ethyl acetate, dried over anhydrous magnesium sulfate, and the like.
It can be obtained by evaporating the solvent, and if necessary, can be further purified by a conventional method, for example, recrystallization, column chromatography and the like.

In the compound (IV) produced by the above method, the compound wherein R ¹ is an alkyl group is obtained as a racemic form. This racemate can be resolved by a conventional method, for example, optically active column chromatography; optically active organic acids (for example, tartaric acid, mandelic acid, camphorsulfonic acid, camphoric acid, O, O'-dibenzoyltartaric acid, O , O'-ditoluoyltartaric acid) by a fractional crystallization; or by dehydration-condensation with the above optically active organic acid to form a mixture of diastereoisomers of an optically active carboxamide compound, and diastereoisomers by fractional crystallization Is split and then hydrolyzed to obtain an optically active amine compound.

In the separation by fractional crystallization of a salt with an optically active organic acid, for example, the racemate of compound (IV) may be used in an amount of 0.5 to 1
An equivalent amount of an optically active organic acid is dissolved in a heat-inactive organic solvent to form a salt, and the solution is cooled to precipitate a salt of one of the optically active compounds of compound (IV) as crystals. This is collected by filtration, and the resulting salt is again mixed with a base such as sodium hydroxide solution, and the separated free optically active amine compound is extracted with an organic solvent such as methylene chloride, and further extracted with an organic solvent. The desired optically active amine compound can be obtained by removing the solvent under reduced pressure. The other amine compound
The optically active form (IV) can be obtained in the same manner as described above, using the enantiomer of the optically active organic acid used above.
Further, after the remaining filtrate obtained by filtering the salt is made alkaline with a base such as sodium hydroxide solution, the precipitated amine compound is extracted with an organic solvent such as methylene chloride, and the organic solvent is further distilled under reduced pressure. Then, the obtained mixture containing the other optically active form of the other amine compound (IV) is formed into a salt with the enantiomer of the optically active organic acid used above. By treating with an alkali, extracting with an organic solvent, and further distilling off the organic solvent under reduced pressure, another optically active form of the amine compound (IV) can be easily obtained.

[0115] Process H is the starting compound of Method G in (XXX), a process for preparing compounds wherein R ¹ is R ¹ a a (XXXa). The step H1 is a step for producing a compound having the general formula (XXXIII) in an inert solvent (for example, aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, chloroform, carbon tetrachloride, Halogenated hydrocarbons such as 2-dichloroethane, ethyl ether,
Ethers such as tetrahydrofuran and dioxane;
Preferably, ethers), the general formula (XXXII) Compounds of the formula R ¹ a-Mg-Z (wherein having, R ¹ a and Z are Grignard reagents with.) Indicating the same meanings as described above or the formula R ¹ a-Li (wherein, R ¹ a is. showing the same meanings as defined above) with an alkyl lithium having, -78 ° C. to 50 ° C. (preferably, -30 ° C. to 20 ° C.) The reaction is performed for 10 minutes to 10 hours (preferably, 30 minutes to 5 hours).

Step H2 is a step of producing compound (XXXa) in an inert solvent (for example, hydrocarbons such as hexane, heptane, benzene, toluene and xylene, dichloromethane, chloroform, carbon tetrachloride, and the like). Halogenated hydrocarbons such as 2,2-dichloroethane, ethers such as ethyl ether, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, ketones such as acetone and 2-butanone; , Halogenated hydrocarbons or ketones), compound (XXXIII) with an oxidizing agent (for example, dimethylsulfoxide-oxalyl chloride, dimethylsulfoxide-sulfuric anhydride / pyridine complex, chromic acid-pyridine, manganese dioxide, silver oxide,
1,1,1-triacetoxy-1,1-dihydro-1,
2-benzyliodoxyl-3 (1H) -one (Dess-Martin reagent); preferably chromic acid-pyridine, manganese dioxide or Dess-Martin reagent);
The reaction is carried out at 0 ° C. (preferably 10 ° C. to 60 ° C.) for 30 minutes to 24 hours (preferably 1 hour to 16 hours).

After completion of the reaction, the target compound of each step of Method H is collected from the reaction mixture according to a conventional method. For example, if insolubles are present, they are filtered off as appropriate, or, if the reaction solution is acidic or alkaline, they are appropriately neutralized, and the solvent is distilled off under reduced pressure or the solvent is distilled off under reduced pressure,
Water was added to the residue, extracted with a water-immiscible organic solvent such as ethyl acetate, dried over anhydrous magnesium sulfate, and the like.
It can be obtained by evaporating the solvent, and if necessary, can be further purified by a conventional method, for example, recrystallization, column chromatography and the like.

In method I, R ¹ in compound (XXX) is
This is a method for producing a compound (XXXb) which is a group having the formula C (R ¹ b) ₃ . Step I1 is a step of producing a compound (XXXb) in an inert solvent (for example, aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, chloroform,
Carbon tetrachloride, halogenated hydrocarbons such as 1,2-dichloroethane, ethyl ether, tetrahydrofuran,
Ethers such as dioxane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone; preferably aromatic hydrocarbons) in the presence of a base ( For example, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide, potassium t-
Metal alkoxides such as butoxide, lithium diisopropylamide, alkali metal amides of lithium dicyclohexylamide, triethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine,
1,5-diazabicyclo [4.3.0] -5-nonene,
Organic amines such as 1,8-diazabicyclo [5.4.0] -7-undecene; alkali metal hydrides such as sodium hydride and potassium hydride; preferably potassium t-butoxide); a compound having a (XXXIV), (wherein, R ¹ b and Z,. showing the same meanings as defined above) wherein R ¹ b-Z in the compound having a (preferably, methyl iodide, ethyl bromide or Ethyl iodide)
And -50 ° C to 100 ° C (preferably 0 ° C to 50 ° C).
C.) for 10 minutes to 5 hours (preferably 30 minutes to 3 hours).

After completion of the reaction, the target compound of each step of Method I is collected from the reaction mixture according to a conventional method. For example, it is appropriately neutralized and the solvent is distilled off under reduced pressure or the solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate. After drying, the solvent can be obtained by distilling off the solvent. If necessary, the product can be further purified by a conventional method, for example, recrystallization, column chromatography or the like.

Method J is as follows. In compound (VII), R ⁴ is R
⁴ is a d, compound X is a group having the formula = C-
This is a method for producing (VIIa).

Step J1 is a step of producing a compound having the general formula (XXXVI), which is achieved by esterifying 4-aminosalicylic acid (XXXV).
This is performed in the same manner as the method step C1.

The step J2 is a step of preparing a compound having the general formula (XXXVII), which is accomplished by alkylating, aralkylating or protecting the hydroxyl group of the compound (XXXVI). This is performed in the same manner as in step D2.

Step J3 is a step for preparing a compound having the general formula (XXXVIII) in an inert solvent (for example, amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide, or dimethylsulfoxide). Sulfoxides or the like; preferably hexamethylphosphoramide) in the presence of a base (for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate or sodium hydrogen carbonate;
An alkali metal bicarbonate such as potassium hydrogen carbonate or lithium hydrogen carbonate; preferably an alkali metal bicarbonate), compound (XXXVII) is converted to an alkyl halide compound (eg, methyl iodide, ethyl bromide, ethyl iodide). Propyl bromide, propyl iodide or butyl bromide; preferably an alkyl iodide compound) and 0 ° C to 200 ° C (preferably
(50 ° C. to 150 ° C.) for 10 minutes to 12 hours (preferably 30 minutes to 5 hours).

Step J4 is a step of producing compound (VIIa), which is accomplished by removing the hydroxyl-protecting group of compound (XXXVIII). The reaction for removing the hydroxyl group varies depending on the type of the protecting group, and is carried out by a method well known in synthetic organic chemistry.

After completion of the reaction, the target compound of each step of Method J is collected from the reaction mixture according to a conventional method. For example, it is appropriately neutralized and the solvent is distilled off under reduced pressure or the solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate. After drying, the solvent can be obtained by distilling off the solvent. If necessary, the product can be further purified by a conventional method, for example, recrystallization, column chromatography or the like.

In the method K, the compound (VII) in which R ⁴ is R
⁴ e, wherein X is a group having the formula: ＣC-
This is a method for producing (VIIb).

Step K1 is a step of preparing a compound having the general formula (XXXX) in an inert solvent (for example, amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide, or dimethylsulfoxide). Sulfoxides and the like; preferably hexamethylphosphoramide) in the presence of a base (for example,
Alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate or alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; preferably alkali metal bicarbonates), compounds (XXXVII ) Is a compound having the general formula (XXXIX) (for example, 1,4-diiodobutane, 1,5-diiodopentane or diethylene glycol di-p-tosylate)
And 0 ° C to 200 ° C (preferably 50 ° C to 150 ° C).
C) for 10 minutes to 12 hours (preferably 30 minutes to 5 hours).

Step K2 is a step of producing compound (VIIb), which is accomplished by removing the protecting group for the hydroxyl group of compound (XXXX). The reaction for removing the hydroxyl group varies depending on the type of the protecting group, and is carried out by a method well known in synthetic organic chemistry.

After completion of the reaction, the target compound of each step of Method K is collected from the reaction mixture according to a conventional method. For example, it is appropriately neutralized and the solvent is distilled off under reduced pressure or the solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate. After drying, the solvent can be obtained by distilling off the solvent. If necessary, the product can be further purified by a conventional method, for example, recrystallization, column chromatography or the like.

In the method L, the compound (X) in which R ⁴ is R ⁴ f
Wherein X is a group having the formula = C-
This is a method for producing a).

Step L1 is a step for preparing a compound having the general formula (XXXXII) in an inert solvent (for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethyl ether, tetrahydrofuran, dioxane). Such ethers, formamide, dimethylformamide,
Amides such as dimethylacetamide or hexamethylphosphoramide or a mixed solvent thereof; preferably a mixed solvent of toluene and dimethylformamide) in the presence of a base (for example, an alkali such as sodium hydride or potassium hydride) A metal hydride or the like; preferably sodium hydride) or a compound (XVI) with a compound having the general formula (XXXXI) (eg, N, N-dimethylcarbamoyl chloride or the like) at -50 ° C to 150 ° C (preferably 0 ° C to 1 ° C
(00 ° C.) for 10 minutes to 12 hours (preferably 30 minutes to 5 hours).

The step L2 is a step for producing a compound having the general formula (XXXXIII).
To 300 ° C (preferably 200 ° C to 260 ° C)
The reaction is carried out for 10 minutes to 12 hours (preferably, 30 minutes to 3 hours).

The step L3 is a step for producing a compound having the general formula (XXXXIV), which is accomplished by alkaline hydrolysis of the compound (XXXXIII). Is

The L4 step is a step of producing the compound (Xa), which is accomplished by alkylating the mercapto group of the compound (XXXXIV). This step is carried out in the same manner as the J method, step J3.

After completion of the reaction, the target compound of each step of Method L is collected from the reaction mixture according to a conventional method. For example, it is appropriately neutralized and the solvent is distilled off under reduced pressure or the solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate. After drying, the solvent can be obtained by distilling off the solvent. If necessary, the product can be further purified by a conventional method, for example, recrystallization, column chromatography or the like.

The starting compounds (VI) and (XXXV) are commercially available or can be obtained by a known method [for example, 4-alkylthio or 4-aralkylthio-2-hydroxybenzoic acid such as 4-methylthio-2-hydroxybenzoic acid. Derivatives are published in Journal of Medicinal Chemistry, Vol. 28,
717 (1985) (J. Med. Chem., 28 , 717 (1985))
), Chemical Abstracts, Vol. 50, No. 16701 (1
956) (Chem. Abstr., 50 , 16701 (1956))
4-amino-, such as dimethylamino-2-hydroxybenzoic acid, 4-piperidino-2-hydroxybenzoic acid
2-Hydroxybenzoic acid derivatives can be obtained by N-alkylation of 4-amino-2-hydroxybenzoate, which is well known in organic synthetic chemistry, and 4-aralkyl-2- such as 4-benzyl-2-hydroxybenzoic acid. Hydroxybenzoic acid derivatives are available from Chemistry and Industry 37
Page (1974) (Chem. Ind., 37 (1974)), etc., 6
-Alkyl-4-hydroxynicotinic acid derivatives are described in Chemical Abstracts, Vol. 52, No. 10072 (1958)
(Chem. Abstr., 52 , 10072 (1958)) or 6-
Alkoxy or 6-aralkyloxy-4-hydroxypyridine-5-carboxylic acid derivatives are described in Journal
Of Heterocyclic Chemistry, Vol. 20, No.
1363 (1983) (J. Heterocyclic Chem., 20 , 1363
(1983)), etc., wherein the hydroxyl group at the 6-position of 4,6-dihydroxynicotinic acid methyl ester is selectively alkylated or aralkylated. Further, starting compounds (IX), (XVIII), (XXXIX) and (X
XXXI) is a known or known method [eg, Organic Synthesis Collective Volume IV, Vol.
Page 68 (1963): Organic Syntheses, col. Vol. IV, 6
8 (1963), Journal of Organic Chemistry, vol. 56, p. 3763 (1991): J. Org. Chem., 5
6 , 3763 (1991)].

The compound (I) of the present invention or a pharmaceutically acceptable salt thereof has an excellent ACAT inhibitory activity,
A therapeutic or prophylactic agent for various diseases caused by, for example,
A therapeutic or prophylactic agent for hyperlipidemia (particularly, a therapeutic agent), a therapeutic or prophylactic agent for atherosclerosis (particularly,
It is useful as a therapeutic agent.

When the compound (I) of the present invention or a pharmacologically acceptable salt thereof is used as a therapeutic or prophylactic agent for the above-mentioned diseases, the compound itself or an appropriate pharmacologically acceptable excipient may be used. And diluents and the like, and can be administered orally by tablets, capsules, granules, powders, syrups and the like, or parenterally by injections and the like. These preparations may contain excipients (e.g., sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose). Cellulose derivatives such as low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, and internally cross-linked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate Phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate. Body), binders (eg, the above-mentioned excipients; gelatin; polyvinylpyrrolidone; magrogol, etc.), disintegrants (eg, the above-mentioned excipients; croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone) Chemically modified starch, cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; calcium stearate;
Colloidal silica; Luxes such as veegum, gay wax; Boric acid; Glycol; Carboxylic acids such as fumaric acid, adipic acid; Sodium carboxylate such as sodium benzoate; Sulfuric acid Sulfates such as sodium;
Leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (eg, methyl paraben, propyl paraben) Paraoxybenzoic acid esters; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol; benzalkonium chloride;
Phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc.), flavoring agents (eg, commonly used sweeteners, sour agents, flavors, etc.), diluents, solvents for injections (eg, Water, ethanol, glycerin and the like) are manufactured by a known method using additives. The amount used depends on the symptoms, age, etc., but in the case of oral administration, the lower limit is 10 mg per dose (preferably 50 mg
g), an upper limit of 1000 mg (preferably 500 mg)
In the case of intravenous administration, the lower limit is 0.1 mg (preferably 1 mg) and the upper limit is 500 mg (preferably 100 m
It is desirable to administer g) to an adult 1 to 6 times per day depending on the symptoms. Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples, and Formulation Examples, but the scope of the present invention is not limited thereto.

[0139]

EXAMPLES Example 1 N- [2- (2-methylphenyl) phenyl] -N'-
[2,2-dimethyl-1- (3-pyridyl) propyl]
Urea (Exemplified Compound No. 1-5) 2- (2-methylphenyl) benzoic acid (106 mg, 0.5 mmol) obtained in Reference Example 4 and benzene (2 ml) of diphenylphosphoryl azide (165 mg, 0.6 mmol) To the solution, triethylamine (51 mg, 0.5 mmol) in benzene (1 ml)
The solution was added dropwise and stirred at room temperature for 2.5 hours. To this was added dropwise a solution of 3- (1-amino-2,2-dimethylpropyl) pyridine (82 mg, 0.5 mmol) in benzene (1 ml) obtained in Reference Example 1b, and the mixture was heated to reflux for 2.5. Stirred for hours. A saturated aqueous solution of sodium carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethanol to give the title compound (39 mg: yield
21%). Melting point: 247-248 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.86 and 0.87 (9H, s), 1.97 and 2.0
4 (3H, s), 4.33-4.37 (1H,
m), 5.39-5.42 (1H, m),
6.02 and 6.03 (1H, br.s), 7.09-7.40 (8H, m),
7.93-7.97 (1H, m), 8.27 (1H, br.s), 8.41-8.43 (1H,
m); IR spectrum (KBr) cm ^-1 : 3333, 1638, 1549; Mass spectrum (m / z): 373 (M ⁺ ).

Example 2 N- [2- (2-methylphenyl) -4-biphenyl-
1-yl] -N '-[2,2-dimethyl-1- (3-pyridyl) propyl] urea (Exemplary Compound No. 1-391) Instead of 2- (2-methylphenyl) benzoic acid, Reference Example 5f In addition to using the 2- (2-methylphenyl) -4-phenylbenzoic acid obtained in
A crude product was obtained. The crude product was recrystallized from benzene to give the title compound in 64% yield. Melting point: 213-214 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.87 and
0.88 (9H, s), 2.03 and 2.08 (3H, s), 4.35-4.43 (1
H, m), 5.47-5.52 (1H, m), 6.12-6.13 (1H, m), 7.15-
8.43 (16H, m); IR spectrum (KBr) cm ^-1 : 3358, 1700, 1663, 1524,
762; mass spectrum (m / z): 449 (M ⁺ ).

Example 3 N- [4-methoxy-2- (2-methylphenyl) phenyl] -N '-[2,2-dimethyl-1- (3-pyridyl) propyl] urea (Exemplified Compound No. 1- 158) Instead of using 2- (2-methylphenyl) benzoic acid, 4-methoxy-2- (2-methylphenyl) benzoic acid obtained in Reference Example 6c was used, and in the same manner as in Example 1,
A crude product was obtained. The crude product was recrystallized from ethyl acetate to give the title compound in 41% yield. Melting point: 227-228 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.85 and
0.86 (9H, s), 2.00 and 2.05 (3H, s), 3.80 (3H, s)
s), 4.37-4.43 (1H, m), 5.31-5.37 (1H, m), 5.79 (1
H, br.s), 6.70 (1H, d, J = 3.0Hz), 6.92 (1H, dd, J =
3.0 and 8.8 Hz), 7.06-7.40 (6H, m), 7.68 (1H, dd, J
= 2.8 and 8.8Hz), 8.29 (1H, d, J = 2.0Hz), 8.43 (1H,
dd, J = 1.4 and 4.7 Hz); IR spectrum (KBr) cm ^-1 : 3354, 1648, 1537, 1210
Mass spectrum (m / z): 403 (M ⁺ ).

Example 4 N- [4-butoxy-2- (2-methylphenyl) phenyl] -N '-[2,2-dimethyl-1- (3-pyridyl) propyl] urea (Exemplified Compound No. 1- 196) Instead of using 2- (2-methylphenyl) benzoic acid, 4-butoxy-2- (2-methylphenyl) benzoic acid obtained in Reference Example 7b was used, and in the same manner as in Example 1,
A crude product was obtained. The crude product was recrystallized from benzene to give the title compound in 67% yield. Melting point: 183-185 ° C; ¹ H NMR spectrum (270 MH
z, CDCl ₃ ) δppm: 0.85 and 0.86 (9H, s), 0.97 (3H,
t, J = 7.4Hz), 1.41-1.55 (2H, m), 1.71-1.81 (2H,
m), 1.99 and 2.06 (3H, s), 3.94 (2H, t, J = 6.5H
z), 4.36-4.43 (1H, m), 5.26-5.31 (1H, m), 5.73 (1
H, br.s), 6.70 (1H, d, J = 2.9Hz), 6.91 (1H, dd, J =
2.9 and 8.8 Hz), 7.06-7.40 (6H, m), 7.64 (1H, dd, J
= 3.0 and 8.8Hz), 8.30 (1H, d, J = 2.0Hz), 8.43-8.
45 (1H, m); IR spectrum (KBr) cm ^-1 : 3355, 1645, 1544, 1206
Mass spectrum (m / z): 284 (M ⁺ ).

Example 5 N- [4-benzyloxy-2- (2-methylphenyl) phenyl] -N '-[2,2-dimethyl-1- (3-
Pyridyl) propyl] urea (Exemplary Compound No. 1-32)
8) Instead of 2- (2-methylphenyl) benzoic acid, 4-benzyloxy-2- (2-methylphenyl) benzoic acid obtained in Reference Example 8 was used, and in the same manner as in Example 1, A crude product was obtained. The crude product was recrystallized from ethyl acetate to give the title compound in 33% yield. Melting point: 194-198 ° C .; ¹ H NMR spectrum (270 MH
z, CDCl ₃ ) δppm: 0.85 and 0.86 (9H, s), 1.97 and
2.03 (3H, s), 4.35-4.45 (1H, m), 5.05 (2H, s), 5.
27-5.32 (1H, m), 5.77 (1H, br.s), 6.77-7.44 (13H,
m), 7.63-7.72 (1H, m), 8.29 (1H, br.s), 8.44 (1H, b
rd, J = 4.8Hz); IR spectrum (KBr) cm ^-1 : 3354, 1697, 1649, 1541,
1204; mass spectrum (m / z): 479 (M ⁺ ).

Example 6 N- [4- (2-methylphenyl) pyridin-3-yl] -N '-[2,2-dimethyl-1- (3-pyridyl)
[Propyl] urea (Exemplified Compound No. 1-674) In place of 2- (2-methylphenyl) benzoic acid, 4- (2-methylphenyl) pyridine-3-carboxylic acid obtained in Reference Example 9b is used. A crude product was obtained in the same manner as in Example 1. The crude product was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 20/1 to 10/1) to give the title compound in 90% yield. Melting point: 241-243 ° C .; ¹ H NMR spectrum (270 MH
z, CDCl ₃ ) δppm: 0.87 (9H, s), 2.00 (3H, s), 4.38
-4.50 (1H, m), 5.56 (1H, br.s), 6.19 (1H, br.s),
6.99-7.45 (7H, m), 8.26 (1H, br.s), 8.31 (1H, d, J
= 5.0Hz), 8.37-8.39 (1H, m), 9.30 (1H, s); IR spectrum (KBr) cm ^-1 : 3336, 1703, 1637, 1551,
1415; mass spectrum (m / z): 374 (M ⁺ ).

Example 7 N- [4- (2-methylphenyl) -6-phenylpyridin-3-yl] -N '-[2,2-dimethyl-1-
(3-pyridyl) propyl] urea (Exemplary Compound No. 1
-855) Instead of 2- (2-methylphenyl) benzoic acid, 4- (2-methylphenyl) -6 obtained in Reference Example 10b.
A crude product was obtained in the same manner as in Example 1 except that phenylpyridine-3-carboxylic acid was used. The crude product was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 30/1 to 15/1) and recrystallized from ethyl acetate to give the title compound in 83% yield. Was. Melting point: 226-229 ° C; ¹ H NMR spectrum (270 MH
z, CDCl ₃ ) δppm: 0.88 (9H, s), 2.04 and 2.05 (3H,
s), 4.39-4.50 (1H, m), 5.56-5.59 (1H, m), 6.16-6.
19 (1H, br.s), 7.12-7.47 (9H, m), 7.95 (2H, d, J =
6.7Hz), 8.28 (1H, br.s), 8.39 (1H, dd, J = 1.2 and
4.6Hz), 9.36 (1H, s); IR spectrum (KBr) cm ^-1 : 3335, 1702, 1557, 1532,
1238; Mass Spectrum (m / z): 351 ( M + + H).

Example 8 N- [4- (2-methoxyphenyl) -6-phenylpyridin-3-yl] -N '-[2,2-dimethyl-1-
(3-pyridyl) propyl] urea (Exemplary Compound No. 1
-856) Instead of 2- (2-methylphenyl) benzoic acid, 4- (2-methoxyphenyl) -6 obtained in Reference Example 11c.
A crude product was obtained in the same manner as in Example 1, except that -phenylpyridine-3-carboxylic acid was used. The crude product was recrystallized from ethanol to give the title compound in 84% yield. Mp: 180-183 ℃; ¹ H NMR spectrum (270MH
z, CDCl ₃ ) δppm: 0.88 (9H, s), 3.73 (3H, s), 4.54
(1H, br.d, J = 8.4Hz), 5.30 (1H, br.d, J = 8.4Hz), 6.
31 (1H, br.s), 6.99-7.49 (10H, m), 7.61 (1H, s),
7.97-8.01 (2H, m), 8.36 (1H, d, J = 2.0 Hz), 8.45 (1
H, dd, J = 1.3 and 4.7 Hz), 9.03 (1H, s); IR spectrum (KBr) cm ^-1 : 3339, 1702, 1536, 1497,
1247; Mass Spectrum (m / z): 467 ( M + + H). Mass spectrum (m / z): 467 (M ⁺ H).

Example 9 N- [4- (2-methylphenyl) -6-phenylpyridin-3-yl] -N '-[2,2-dimethyl-1-
(2-pyridyl) propyl] urea (Exemplary Compound No. 1
-912) Instead of 2- (2-methylphenyl) benzoic acid, 4- (2-methylphenyl) -6 obtained in Reference Example 10b.
Using phenylpyridine-3-carboxylic acid, 3- (1-
The title compound was obtained in the same manner as in Example 1 except that 2- (1-amino-2,2-dimethylpropyl) pyridine obtained in Reference Example 2 was used in place of amino-2,2-dimethylpropyl) pyridine. Get.

Example 10 N- [4- (2-methylphenyl) -6-phenylpyridin-3-yl] -N '-[2,2-dimethyl-1-
(4-pyridyl) propyl] urea (Exemplary Compound No. 1
-940) Instead of 2- (2-methylphenyl) benzoic acid, 4- (2-methylphenyl) -6 obtained in Reference Example 10b.
Using phenylpyridine-3-carboxylic acid, 3- (1-
The title compound was obtained in the same manner as in Example 1 except that 4- (1-amino-2,2-dimethylpropyl) pyridine obtained in Reference Example 3 was used instead of amino-2,2-dimethylpropyl) pyridine. Get. Example 11 (S)-(-)-N- [4- (2-methylphenyl)-
6-phenylpyridin-3-yl] -N ′-[2,2-dimethyl-1- (3-pyridyl) propyl] urea (Exemplary Compound No. 1-855) 3- (1-amino-2,2-dimethyl (S)-(-)-obtained in Reference Example 12 instead of (propyl) pyridine.
A crude product was obtained in the same manner as in Example 7, except that 3- (1-amino-2,2-dimethylpropyl) pyridine was used. This crude product was subjected to silica gel column chromatography (elution solvent: methylene chloride / methanol = 10
/ 1) and further recrystallized from ethyl acetate to give the title compound in 54% yield. Melting point: 247-250 ° C; Optical rotation: [α] _D ²⁴ -3.5 ° (c1, ethanol).

Example 12 (R)-(+)-N- [4- (2-methylphenyl)-
6-phenylpyridin-3-yl] -N ′-[2,2-dimethyl-1- (3-pyridyl) propyl] urea (Exemplary Compound No. 1-855) 3- (1-amino-2,2-dimethyl) (R)-(+)-obtained in Reference Example 13 instead of (propyl) pyridine.
A crude product was obtained in the same manner as in Example 7, except that 3- (1-amino-2,2-dimethylpropyl) pyridine was used. This crude product was subjected to silica gel column chromatography (elution solvent: methylene chloride / methanol = 10
The product was purified by using the method described in (1) and further recrystallized from ethyl acetate to give the title compound in a yield of 37%. Melting point: 250-252 ° C .; Optical rotation: [α] _D ²⁴ + 3.8 ° (c 1, ethanol).

Example 13 N- [4-dimethylamino-2- (2-methylphenyl) phenyl] -N '-[2,2-dimethyl-1- (3
-Pyridyl) propyl] urea (Exemplary Compound No. 1-4
42) 4-Dimethylamino-2- (2-) obtained in Reference Example 16
Methylphenyl) benzoic acid (255 mg, 1.0 mmol), diphenylphosphoryl azide (0.258 ml, 1.2 mmol) and triethylamine (0.146 ml, 1.05 mmol) in benzene (3
The resulting mixture was stirred under reflux for 3 hours. 3- (1-Amino-2,2-dimethylpropyl) pyridine (165 mg, 1.0 mmol) obtained in Reference Example 1b was added to the reaction solution, and the mixture was stirred under reflux with heating for 3 hours. Ethyl acetate was added to the reaction solution, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was crystallized in isopropyl ether and collected by filtration to give the title compound (393 mg: yield 94).
%). Melting point: 201-207 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.85 and 0.87 (9H, s), 2.01 and 2.10 (3H, s), 2.96 (6H,
s), 4.51-4.62 (1H, m), 5.25-5.36 (1H, m), 5.57 (1H,
s), 6.55 (1H, d, J = 3.0Hz), 6.77 (1H, dd, J = 3.0
And 9.0Hz), 7.04-7.49 (7H, m), 8.35 (1H, s), 8.46
(1H, d, J = 4.5Hz).

Example 14 N- [2- (2-methylphenyl) -4- (1-pyrrolidinyl) phenyl] -N '-[2,2-dimethyl-1-
(3-pyridyl) propyl] urea (Exemplary Compound No. 1
-457) 2- (2-methylphenyl)-obtained in Reference Example 17c.
The title compound was obtained in a yield of 87% in the same manner as in Example 13 except that 4- (1-pyrrolidinyl) benzoic acid was used instead of 4-dimethylamino-2- (2-methylphenyl) benzoic acid. Melting point: 150-152 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.85 and
0.86 (9H, s), 1.95-2.10 (4H, m), 3.20-3.36 (4H,
m), 4.47-4.55 (1H, m), 5.26-5.34 (1H, m), 5.52 (1
H, s), 6.40 (1H, d, J = 2.5Hz), 6.61 (1H, dd, J = 2.5Hz)
And 8.5Hz), 7.05-7.42 (7H, m), 8.34 (1H, s), 8.4
6 (1H, d, J = 4.0Hz).

Example 15 N- [2- (2-methylphenyl) -4-morpholinophenyl] -N '-[2,2-dimethyl-1- (3-pyridyl) propyl] urea (Exemplified Compound No. 1- 475) 2- (2-Methylphenyl)-obtained in Reference Example 18d.
4-morpholinobenzoic acid is converted to 4-dimethylamino-2-
In place of (2-methylphenyl) benzoic acid, the title compound was obtained in a yield of 88% in the same manner as in Example 13.
I got it. Melting point: 152-154 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.86 and
0.87 (9H, s), 1.99 and 2.06 (3H, s), 3.11-3.16 (4
H, m), 3.80-3.87 (1H, m), 4.36-4.50 (1H, m), 5.31-
5.39 (1H, m), 5.76 (1H, s), 6.70 (1H, d, J = 3.0Hz),
6.93 (1H, dd, J = 2.5 and 8.5Hz), 7.03-7.69 (7H,
m), 8.33 (1H, s), 8.44 (1H, d, J = 3.5Hz). Example 16 N- [2- (2-methylphenyl) -4-piperidinophenyl] -N ′-[2,2-dimethyl-1- (3-pyridyl) propyl] urea (Exemplified Compound No. 1-465 ) 2- (2-Methylphenyl)-obtained in Reference Example 19f.
4-piperidinobenzoic acid is converted to 4-dimethylamino-2-
In place of (2-methylphenyl) benzoic acid, the title compound was obtained in a yield of 99% in the same manner as in Example 13.
I got it. Melting point: 170-179 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.85 and
0.87 (9H, s), 1.51-1.90 (6H, m), 1.99 and 2.07
(3H, s), 3.11-3.19 (4H, m), 4.39-4.49 (1H, m), 5.30
-5.43 (1H, m), 5.70 (1H, s), 6.76 (1H, d, J = 3.0H
z), 6.98 (1H, dd, J = 3.0 and 9.0Hz), 7.02-7.31 (5
H, m), 7.39-7.46 (1H, m), 7.52-7.61 (1H, m), 8.35
(1H, s), 8.42-8.47 (1H, m).

Example 17 N- [2- (2-methylphenyl) -4-methylthiophenyl] -N '-[2,2-dimethyl-1- (3-pyridyl) propyl] urea (Exemplified Compound No. 1- 246) 2- (2-methylphenyl)-obtained in Reference Example 20d
4-methylthiobenzoic acid (258 mg, 1.0 mmol), diphenylphosphoryl azide (0.258 ml, 1.2 mmol) and triethylamine (0.146 ml, 1.05 mmol) were added to toluene (4 m
l) The mixture was stirred under heating and reflux for 1 hour. 3- (1-Amino-2,2-dimethylpropyl) pyridine (165 mg, 1.0 mmol) obtained in Reference Example 1b was added to the reaction solution, and the mixture was stirred under heating and reflux for 1 hour. Ethyl acetate was added to the reaction solution, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was crystallized in isopropyl ether and collected by filtration to give the title compound (325 mg: yield 77).
%). Melting point: 209-211 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.85 and
0.86 (9H, s), 1.99 and 2.02 (3H, s), 2.45 (3H,
s), 4.30-4.41 (1H, br.s), 5.52 (1H, d, J = 8.5Hz),
6.08 (1H, s), 7.01 (1H, d, J = 1.5Hz), 7.03-7.42 (7
H, m), 7.90 (1H, dd, J = 2.5 and 8.5Hz), 8.26 (1H,
s), 8.39 (1H, d, 4.5Hz).

Example 18 N- [4-isopropylthio-2- (2-methylphenyl) phenyl] -N '-[2,2-dimethyl-1- (3
-Pyridyl) propyl] urea (Exemplary Compound No. 1-2
58) 4-Isopropylthio-2- obtained in Reference Example 21b
(2-Methylphenyl) benzoic acid is converted to 4-methylthio-2
A crude product of the title compound was obtained in the same manner as in Example 17, except that it was used in place of-(2-methylphenyl) benzoic acid. This product was subjected to silica gel column chromatography (elution solvent: methylene chloride / methanol = 19/1).
The obtained crystals were washed with isopropyl ether-hexane to give the title compound in a yield of 84%. Melting point: 189-191 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.86 (9H,
s), 1.25 (6H, d, J = 6.5Hz), 1.99 and 2.02 (3H, s),
3.26 (1H, quintet, J = 6.5Hz), 4.29-4.41 (1H, m),
5.41-5.60 (1H, m), 6.10-6.20 (1H, m), 7.04-7.41 (8
H, m), 7.99 (1H, dd, J = 3.5 and 8.5Hz), 8.24 (1H,
s), 8.32-8.41 (1H, m).

Example 19 N- [2,2-Dimethyl-1- (3-pyridyl) propyl] -4-methoxy-2- (2-methylphenyl) phenylacetamide (Exemplified Compound No. 2-23) Reference Example 23c To a solution of 4-methoxy-2- (2-methylphenyl) phenylacetic acid (0.40 g, 1.56 mmol) obtained in the above in dichloromethane (5 ml), oxalyl chloride (0.40 ml,
4.2 mmol) and one drop of dimethylformamide were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in benzene, and concentrated under reduced pressure to remove the remaining oxalyl chloride. The residue was dissolved in dichloromethane (4 ml), and the residue obtained in Reference Example 1b was obtained. (1-amino-2,
2-dimethylpropyl) pyridine (256 mg, 1.56 mmol)
And triethylamine (0.40 ml, 2.9 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and water, ethyl acetate was separated, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20/1) to give the title compound as a foamy solid (0.54 g, yield 86%). ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.79 (9H,
s), 2.01 and 2.04 (3H, s), 3.20 (1H, dd, J = 11.5 and 16.5Hz), 3.37 (1H, dd, J = 6.5 and 16.5Hz), 3.8
4 (3H, s), 4.68 (1H, d, J = 9.0Hz), 5.81 (1H, br.t,
J = 9.0Hz), 6.77 (1H, d, J = 2.5Hz), 6.96 (1H, dd, J = 2.
5 and 8.5Hz), 7.02 and 7.08 (1H, d, J = 7.5Hz), 7.1
3-7.40 (6H, m), 8.32 (1H, s), 8.48 (1H, d, J = 4.5H
z).

Reference Example 1 3- (1-Amino-2,2-dimethylpropyl) pyridine (1a) 3-pivaloylpyridine potassium To a suspension of potassium t-butoxide (74.06 g, 0.66 mol) in toluene (400 ml). Under ice cooling, 3-acetylpyridine (24.20 g, 0.2 mol) was added dropwise. Continue under ice-cooling for 1
After 8-crown-6-ether (0.53 g, 0.002 mol) was added, a solution of methyl iodide (93.68 g, 0.66 mol) in toluene (100 ml) was added dropwise. At this time, the reaction temperature is 10
The dropping speed was adjusted so as to be lower than or equal to ° C. After dropping,
Stirred at room temperature for 1 hour. Water (300 ml) was added to the reaction solution,
The organic layer was separated. The aqueous layer was extracted with ethyl acetate (300 ml), and the obtained extract was combined with the organic layer, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was distilled to obtain the title compound (26.73 g, yield 82%). Boiling ^{point: 75-78 ℃ / 4mmHg; 1 H} NMR spectrum (270 MHz,
CDCl ₃ ) δppm: 1.36 (9H, s), 7.36 (1H, dd, J = 4.7 and 7.9Hz), 7.99 (1H, br.d, J = 7.9Hz), 8.66 (1H, d
d, J = 1.7 and 4.7 Hz), 8.97 (1H, d, J = 1.7 Hz); IR spectrum (KBr) cm ^-1 : 1681, 1584; Mass spectrum (m / z): 164 (M ⁺ ). (1b) 3- (1-Amino-2,2-dimethylpropyl) pyridine Under a nitrogen atmosphere, 3-pivaloylpyridine (16.30 g, 0.1 mol) obtained in Reference Example 1a and ammonium formate (31.50)
g, 0.5 mol) was heated under reflux in methanol (200 ml) for 1 hour. After bringing the reaction solution to room temperature, 5% palladium-
Carbon (2.13 g, 0.001 mol) was added, and oil bath temperature was 40-50 ° C and 4
Heated for hours. After completion of the reaction, palladium-carbon was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. A 15% aqueous sodium hydroxide solution (200 ml) was added to the concentrated residue, and the mixture was extracted twice with methylene chloride (200 ml). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oil was dissolved in ethanol (100 ml), and fumaric acid (11.61
g, 0.1 mol), and the mixture was heated on an oil bath (temperature: 40 ° C.) for 15 minutes, and then left to return to room temperature. The generated crystals were collected by filtration and washed with ethanol (50 ml) to give the corresponding fumarate (26.73 g, melting point: 191-196 ° C.). To this fumarate was added a 15% aqueous sodium hydroxide solution (200 ml), and the mixture was extracted twice with methylene chloride (200 ml). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (10.51 g, yield 64%). ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.91 (9H,
s), 3.75 (1H, s), 7.23 (1H, dd, J = 4.9 and 7.9H
z), 7.67 (1H, br.d, J = 7.9Hz), 8.48 (1H, br.d, J = 4.
8Hz), 8.53 (1H, br.s); IR spectrum (liquid) cm ^-1 : 3376, 1478, 1427, 1364,
718; mass spectrum (m / z): 165 (M ⁺ ).

Reference Example 2 2- (1-amino-2,2-dimethylpropyl) pyridine (2a) 2- (1-hydroxy-2,2-dimethylpropyl) pyridine Under a nitrogen atmosphere, 2-pyridinecarboxaldehyde (1 .
07 g, 10 mmol) in tetrahydrofuran (20 ml) at −78 ° C. with 2 parts of t-butylmagnesium chloride.
M tetrahydrofuran solution (7.5 ml) was added dropwise. The temperature was gradually raised, and the reaction solution was returned to room temperature over about 1 hour. A saturated sodium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 30/1) to give the title compound (0.83 g, yield 50%) as crystals. Melting point: 48-52 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.92 (9H,
s), 4.28 (1H, d, J = 7.1Hz), 4.35 (1H, d, J = 7.1Hz),
7.12-7.21 (2H, m), 8.60-8.66 (1H, m), 8.54-8.57
(1H, m). (2b) 2-pivaloylpyridine oxime 2- (1-hydroxy-2,2- obtained in Reference Example 2a
Dimethylpropyl) pyridine (0.57 g, 3.45 mmol) in methylene chloride (35 ml) at room temperature was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3.
Dess-Martin reagent (1.61 g, 3.80 mmol) consisting of (1H) -one was added and stirred at room temperature for 30 minutes. After completion of the reaction, ether (90 ml) was added to the reaction solution, and the mixture was washed with a 1N aqueous sodium hydroxide solution (39 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the obtained residue, pyridine (5 ml) and hydroxylamine hydrochloride (1.04 g, 15.03 mmol) were added, and the reaction solution was heated to make a homogeneous solution, then left to return to room temperature over about 30 minutes. . The solvent was distilled off from the reaction solution under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure,
The title compound was obtained as crystals. Melting point: 116-120 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.21 (9H,
s) 7.00 (1H, s), 7.18 (1H, d, J = 8.0Hz), 7.25-7.29
(1H, m), 7.70-7.77 (1H, m), 8.70 (1H, br.d, J = 5.7
Hz). (2c) 2- (1-Amino-2,2-dimethylpropyl) pyridine The entire amount of the oxime derivative obtained in Reference Example 2b was dissolved in a mixed solvent of ethanol (3 ml) and acetic acid (3 ml), and the mixture was dissolved at 0 ° C. Zinc powder (0.98 g, 17.25 mmol) was added, and the mixture was stirred under heating and reflux for 2 hours. The reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure. A saturated aqueous sodium carbonate solution was added, and the mixture was extracted with methylene chloride. The extract is dried over anhydrous sodium sulfate,
It was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: methylene chloride / methanol =
10/1) to give the title compound (0.41 g, yield 83%) as a syrup. ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.93 (9H,
s), 1.98 (2H, br.s), 3.72 (1H, s), 7.12-7.21 (2H,
m), 7.56-7.62 (1H, m), 8.55 (1H, br.d, J = 4.4Hz)
; IR spectrum (liquid) cm ^-1 : 3377, 1591, 1570, 1474,
1434, 797, 752; mass spectrum (m / z): 165 (M ⁺ ).

Reference Example 3 4- (1-amino-2,2-dimethylpropyl) pyridine (3a) 4- (1-hydroxy-2,2-dimethylpropyl) pyridine In place of 2-pyridinecarboxaldehyde, In addition to using pyridinecarboxaldehyde, Reference Example 2a
A crude product was obtained in the same manner as described above. The crude product was recrystallized from hexane-ethyl acetate to give the title compound in a yield of 52%.
I got it. Melting point: 111-114 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.93 (9H,
s), 2.22 (1H, m), 4.39 (1H, d, J = 6.3 Hz), 7.22-7.
26 (2H, m), 8.52-8.54 (2H, m). (3b) 4- (1-Amino-2,2-dimethylpropyl) pyridine Instead of 2- (1-hydroxy-2,2-dimethylpropyl) pyridine, 4- (1-hydroxy-2,2-dimethylpropyl) pyridine obtained in Reference Example 3a was used. In the same manner as in Reference Examples 2b and 2c, but using (-2,2-dimethylpropyl) pyridine, the title compound was obtained as an oil in a yield of 51%. ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.91 (9H,
s), 1.65 (2H, br.s), 3.69 (1H, s), 7.23 (2H, d, J
= 6.0Hz), 8.52 (2H, d, J = 6.0Hz); IR spectrum (liquid) cm ^-1 : 3299, 1662, 1600, 829,
563; mass spectrum (m / z): 165 (M ⁺ ).

Reference Example 4 2- (2-methylphenyl) benzoic acid (4a) Methyl 2- (2-methylphenyl) benzoate Methyl salicylate (1.51 g, 5 mmol) and triethylamine (1.39 ml, 10 mmol) To a methylene (10 ml) solution was added trifluoromethanesulfonic anhydride (1.23
ml, 7.5 mmol) was added dropwise and reacted at room temperature for 30 minutes. After completion of the reaction, ethyl acetate and water were added to the reaction solution, the organic layer was separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude sulfonyloxy compound. This crude sulfonyloxy compound was added to dimethylformamide (15 ml
) And dissolved in 2-methylphenylboric acid (1.02 g, 7.5
mmol), triethylamine (2.1 ml, 15 mmol) and tetrakistriphenylphosphine palladium (0.17 mmol).
g, 0.15 mmol) and reacted at an oil bath temperature of 100 ° C. for 1 hour. Ethyl acetate was added to the reaction solution, washed with water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 20/1) to give the title compound as an oil (1.02 g, yield 90%). ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.07 (3H,
s), 3.61 (3H, s), 7.06-7.98 (8H, m); IR spectrum (liquid) cm ^-1 : 1733, 1721, 1291, 1253,
755; mass spectrum (m / z): 226 (M ⁺ ).

(4b) 2- (2-methylphenyl) benzoic acid Methyl 2- (2-methylphenyl) benzoate (1.02 g, 4.5 mmol) obtained in Reference Example 4a and lithium hydroxide monohydrate ( 0.57 g, 13.5 mmol) was added to a mixed solvent of methanol (4 ml), tetrahydrofuran (4 ml) and water (1 ml), and the mixture was heated under reflux for 3 hours. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Hexane was added and the resulting crude crystals were collected by filtration to give the title compound (0.46 g, yield 48%). Melting point: 95-98 [deg.] C. Reference Example 5 2- (2-methylphenyl) -4-phenylbenzoic acid (5a) Methyl 2,4-dihydroxybenzoate 2,4-dihydroxybenzoic acid (15.41 g, 100 mmol)
And a solution of chlorotrimethylsilane (38 ml, 300 mmol) in methanol (100 ml) were heated under reflux for 30 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude crystal. The crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (7.43 g, yield 63%). Melting point: 118-120 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.92 (3H,
s), 5.70 (1H, br.s), 6.36-6.41 (2H, m), 7.73 (1H,
d, J = 8.5Hz), 10.98 (1H, s); IR spectrum (KBr) cm ^-1 : 3344, 1644, 1436, 1282,
773; Mass spectrum (m / z): 168 (M ⁺ ).

(5b) Methyl 4-benzyloxy-2-hydroxybenzoate Methyl 2,4-dihydroxybenzoate (3.40 g, 20.2 mmol) obtained in Reference Example 5a, benzyl bromide (2.65 m
l, 22.2 mmol) and potassium carbonate (3.07 g, 22.2 mmol)
) In 2-butanone (60 ml) was heated under reflux for 1 hour. Insolubles were removed from the reaction solution by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 20/1) to give the title compound as crystals (4.36 g, yield).
83%). Melting point: 101-103 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.91 (3H,
s), 5.08 (2H, s), 6.49-6.53 (2H, m), 7.32-7.43 (5
H, m), 7.74 (1H, d, J = 8.8Hz), 10.98 (1H, s); IR spectrum (KBr) cm ^-1 : 1668, 1621, 1347, 1251,
1218, 1140; mass spectrum (m / z): 258 (M ⁺ ).

(5c) 4-benzyloxy-2- (2
-Methylphenyl) methyl benzoate To a solution of methyl 4-benzyloxy-2-hydroxybenzoate (1.29 g, 5.0 mmol) obtained in Reference Example 5b and pyridine (0.84 ml, 10.5 mmol) in methylene chloride (10 ml). Trifluoromethanesulfonic anhydride (1.
30 ml, 7.9 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour.
Ethyl acetate was added to the reaction solution, and the mixture was washed successively with water, a saturated aqueous solution of sodium carbonate and 1 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude sulfonyloxy compound. This crude sulfonyloxy compound was dissolved in dimethylformamide (20 ml), and 2-methylphenylboric acid (1.02 g, 7.5 mmol) and triethylamine (2.10 ml,
15 mmol) and tetrakistriphenylphosphine palladium (0.17 g, 0.15 mmol) were added and reacted at 100 ° C. for 1 hour. Ethyl acetate was added to the reaction solution, washed with water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The obtained crude product was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 10/1) to give the title compound (1.62 g, yield) as crystals.
97%). Melting point: 73-79 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.05 (3H,
s), 3.59 (3H, s), 5.15 (2H, s), 6.80-7.45 (11H,
m), 7.99 (1H, d, J = 8.8Hz); IR spectrum (KBr) cm ^-1 : 1722, 1595, 1249, 1227,
1139, 1005; mass spectrum (m / z): 332 (M ⁺ ).

(5d) Methyl 4-hydroxy-2- (2-methylphenyl) benzoate 4-benzyloxy-2- (2-
Methylphenyl) methyl benzoate (1.19 g, 3.6 mmol)
Was dissolved in methanol (20 ml), 5% palladium-carbon (0.38 g, 0.18 mmol) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere at 1 atm for 3 hours. The palladium-carbon was removed from the reaction solution by filtration, and the obtained filtrate was concentrated under reduced pressure to give the title compound (0.83 g, yield 96%) as crystals. Melting point: 109-112 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.07 (3H,
s), 3.59 (3H, s), 5.41 (1H, br.s), 6.66 (1H, d, J
= 2.6Hz), 6.85 (1H, dd, J = 2.6 and 9.6Hz), 7.05-7.30
(4H, m), 7.95 (1H, d, J = 8.6Hz); IR spectrum (KBr) cm ^-1 : 3262, 1684, 1567, 1283
Mass spectrum (m / z): 242 (M ⁺ ).

(5e) 2- (2-methylphenyl)-
Methyl 4-phenylbenzoate Methylene chloride (7 ml) of methyl 4-hydroxy-2- (2-methylphenyl) benzoate (0.33 g, 1.4 mmol) obtained in Reference Example 5d and pyridine (0.16 ml, 2.0 mmol) )
To the solution was added dropwise trifluoromethanesulfonic anhydride (0.25 ml, 1.5 mmol) under ice cooling, and the mixture was stirred at the same temperature for 0.5 hour. Ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with water and a saturated aqueous solution of sodium carbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude sulfonyloxy compound. This crude sulfonyloxy compound was dissolved in dimethylformamide (7 ml), and phenylboric acid (0.25 g,
2.0 mmol), triethylamine (0.57 ml, 4.1 mmol)
And tetrakistriphenylphosphine palladium (0.
05 g, 0.04 mmol) and reacted at 100 ° C. for 1 hour. Ethyl acetate was added to the reaction solution, washed with water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 12/1) to give the title compound (0.40 g, yield 97) as a viscous oil.
%). ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.12 (3H,
s), 3.64 (3H, s), 7.12-7.68 (11H, m), 8.06 (1H,
d, J = 8.3Hz); IR spectrum (liquid) cm ^-1 : 1731, 1716, 1600, 1290,
1254, 1097, 757; mass spectrum (m / z): 302 (M ⁺ ).

(5f) 2- (2-methylphenyl)-
4-phenylbenzoic acid 2- (2-methylphenyl) -4 obtained in Reference Example 5e
-Methyl phenylbenzoate (0.40 g, 1.3 mmol) and lithium hydroxide monohydrate (0.28 g, 6.6 mmol) in methanol (4 ml), tetrahydrofuran (4 ml) and water (1 ml)
And the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from cyclohexane to give the title compound (0.24 g, yield 63%). Melting point: 183-184 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.13 (3H,
s), 7.15-7.70 (11H, m), 8.15 (1H, d, J = 8.3Hz); IR spectrum (KBr) cm ^-1 : 1682, 1296, 760; Mass spectrum (m / z): 288 (M ⁺ ).

Reference Example 6 4-methoxy-2- (2-methylphenyl) benzoic acid (6a) Ethyl 2-hydroxy-4-methoxybenzoate 2-hydroxy-4-methoxybenzoic acid (3.36 g, 20 m
mol) 1,8-diazabicyclo [5,4,0] -7-
Undecene (3.04 g, 20 mmol) and ethyl iodide (1.6
ml, 20 mmol) of acetonitrile (40 ml) was stirred for 4 hours while heating under reflux. Ethyl acetate was added to the reaction solution,
Washed sequentially with water and 1N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 20/1) to give the title compound as an oil (3.64 g, yield 93%). ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.40 (3H,
t, J = 7.1Hz), 3.82 (3H, s), 4.37 (2H, q, J = 7.1Hz),
6.41-6.45 (2H, m), 7.75 (1H, d, J = 9.3Hz), 11.05 (1
H, s); IR spectrum (liquid) cm ^-1 : 1668, 1624, 1258, 779
Mass spectrum (m / z): 196 (M ⁺ ).

(6b) Ethyl 4-methoxy-2- (2-methylphenyl) benzoate Ethyl 2-hydroxy-4-methoxybenzoate (0.98 g, 5 mmol) obtained in Reference Example 6a and triethylamine (1.4 ml) , 10 mmol) in methylene chloride (10 ml) was added under ice-cooling to trifluoromethanesulfonic anhydride (1.
2 ml, 7.5 mmol) was added dropwise and stirred at room temperature for 30 minutes.
Ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous solution of sodium carbonate. The organic layer is dried over anhydrous sodium sulfate,
After concentration under reduced pressure, a crude sulfonyloxy compound was obtained. This crude sulfonyloxy compound was dissolved in dimethylformamide (15 ml), and 2-methylphenylboric acid (1.02 g, 7.5 mmo) was dissolved.
l), triethylamine (2.1 ml, 15 mmol) and tetrakistriphenylphosphine palladium (0.17 g, 0.15 g)
mmol) and reacted at 100 ° C. for 1 hour. Ethyl acetate was added to the reaction solution, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 15/1) to give the title compound (0.94 g, yield 70%) as a viscous oil. Was. ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.95 (3H,
t, J = 7.1 Hz), 2.07 (3H, s), 3.85 (3H, s), 4.01 (2
H, q, J = 7.1Hz), 6.72 (1H, d, J = 2.6Hz), 6.93 (1H, d
d, J = 2.6 and 8.7Hz), 7.06-7.28 (4H, m), 7.99 (1H,
d, J = 8.7Hz); IR spectrum (liquid) cm ^-1 : 1706, 1600, 1280, 761
Mass spectrum (m / z): 270 (M ⁺ ).

(6c) Ethyl 4-methoxy-2- (2-methylphenyl) benzoate (0.93 g, 3.4 mmol) of ethyl 4-methoxy-2- (2-methylphenyl) benzoate obtained in Reference Example 6b Lithium hydroxide monohydrate (0.43 g, 10.3 mmol) was added to methanol (4 ml), tetrahydrofuran (4 ml) and water (1 m
The mixture was added to the mixed solvent of l), and heated under reflux for 5 hours. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from hexane-ethyl acetate to give the title compound (0.58 g, yield 70%). Melting point: 149-150 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.07 (3H,
s), 3.85 (3H, s), 6.70 (1H, d, J = 2.6Hz), 6.92 (1
H, dd, J = 2.6 and 8.7Hz), 7.06-7.29 (4H, m), 8.05
(1H, d, J = 8.7 Hz); IR spectrum (liquid) cm ^-1 : 1671, 1597, 1279; Mass spectrum (m / z): 242 (M ⁺ ).

Reference Example 7 4-butoxy-2- (2-methylphenyl) benzoic acid (7a) 4-butoxy-2- (2-methylphenyl)
Methyl benzoate To a solution of methyl 4-hydroxy-2- (2-methylphenyl) benzoate (339 mg, 1.4 mmol) obtained in Reference Example 5d in dimethylformamide (3 ml) was added sodium hydride (3 ml) under ice-cooling. 80 mg, 1.7 mmol) and butyl bromide (230 mg,
1.7 mmol), and the mixture was stirred at room temperature for 18 hours. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain the crude title compound. This compound was used for the next step without purification. (7b) 4-butoxy-2- (2-methylphenyl)
Benzoic acid Total amount of crude product obtained in Reference Example 7a and lithium hydroxide 1
Hydrate (0.18 g, 4.2 mmol) was added to tetrahydrofuran (2 m
l), methanol (2 ml) and water (0.5 ml), and the mixture was stirred under heating and reflux for 7 hours. After completion of the reaction, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the obtained crude product, and the precipitated crystals were collected by filtration to give the title compound (332 mg, yield 83%). Melting point: 113-114 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.97 (3H,
t, J = 7.3Hz), 1.41-1.55 (2H, m), 1.72-1.82 (2H,
m), 2.07 (3H, s), 4.00 (2H, t, J = 6.5Hz), 6.69 (1H,
d, J = 2.6Hz), 6.90 (1H, dd, J = 2.6 and 8.6Hz), 7.06-
7.28 (4H, m), 8.04 (1H, d, J = 8.6Hz); IR spectrum (KBr) cm ^-1 : 1683, 1593, 1294, 1220
Mass spectrum (m / z): 284 (M ⁺ ).

Reference Example 8 4-benzyloxy-2- (2-methylphenyl) benzoic acid 4-benzyloxy-2- (2-
A mixed solvent of methyl (methylphenyl) benzoate (0.44 g, 1.3 mmol) and lithium hydroxide monohydrate (0.28 g, 6.6 mmol) in methanol (4 ml), tetrahydrofuran (4 ml) and water (1 ml) And heated to reflux for 4 hours. The reaction solution is concentrated under reduced pressure,
1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude crystals. The crude crystals were recrystallized from hexane-ethyl acetate to give the title compound (0.28 g, yield 66%). Melting point: 173-177 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.05 (3H,
s), 5.11 (2H, s), 6.79 (1H, d, J = 2.6Hz), 7.00 (1
H, dd, J = 2.6 and 8.7 Hz), 7.06-7.44 (9H, m), 8.06 (1
H, d, J = 8.7Hz); IR spectrum (KBr) cm ^-1 : 1687, 1671, 1593, 1225,
1003, 763; Mass spectrum (m / z): 318 (M ⁺ ).

Reference Example 9 4- (2-methylphenyl) pyridine-3-carboxylic acid (9a) 4- (2-methylphenyl) pyridine-3-
Ethyl carboxylate Ethyl nicotinate (1.51 g, 10 mmol) and a solution of copper iodide dimethylsulfide complex (0.10 g, 0.5 mmol) in tetrahydrofuran (10 ml) at −20 ° C. phenyl chloroformate (1.57 g, 10 mmol) Of tetrahydrofuran (10 m
l) The solution was added dropwise. After completion of the dropwise addition, the mixture was stirred at −20 ° C. for 10 minutes, and at the same temperature, 1M of o-tolylmagnesium chloride
A tetrahydrofuran solution (10 ml) was added dropwise. -20
After stirring at 15 ° C. for 15 minutes, the reaction temperature was gradually returned to room temperature over about 1 hour. A 20% ammonium chloride aqueous solution (50 ml) was added to the reaction solution, and ethyl acetate (100 ml) was added.
Extracted. The extract was washed successively with 1N hydrochloric acid (20 ml) and a saturated aqueous sodium chloride solution (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude dihydropyridine compound. This crude dihydropyridine derivative and o-chloranil (1.51 g, 10 mmol) were dissolved in toluene (50 ml), and the mixture was stirred under heating and refluxing for 2.5 hours. The reaction solution was cooled, ether (150 ml) and 1N aqueous sodium hydroxide solution (83 ml) were added, and the mixture was stirred at room temperature for 10 minutes. Celite was added, and the insolubles were filtered. The filtrate was separated, and the obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product is subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3 /
Purify using 1) to give the title compound (1.65 g, yield 68%)
I got ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.00 (3H,
t, J = 7.0 Hz), 2.08 (3H, s), 4.10 (2H, q, J = 7.0Hz),
7.03-7.34 (5H, m), 8.74 (1H, d, J = 4.9Hz), 9.16 (1
H, s); IR spectrum (liquid) cm ^-1 : 1717, 1589, 1279, 110
8, 762; mass spectrum (m / z): 241 (M ⁺ ).

(9b) 4- (2-methylphenyl) pyridine-3-
Carboxylic acid Ethyl 4- (2-methylphenyl) pyridine-3-carboxylate (452 mg, 1.87 mmol) obtained in Reference Example 9a and lithium hydroxide monohydrate (393 mg, 9.37 mmol) were added to methanol (4 ml), tetrahydrofuran (4 ml) and water (1 ml), and the mixture was heated under reflux for 30 minutes. 1N hydrochloric acid (9.4 ml) was added to the reaction solution, and the mixture was concentrated under reduced pressure. The precipitated crystals were collected by filtration and washed with water. The obtained crude crystals were recrystallized from ethanol to give the title compound (251 mg, yield 63%). Melting point: 203-204 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.04 (3H,
s), 7.05-7.33 (5H, m), 8.74 (1H, d, J = 4.9Hz), 9.00
(1H, s); IR spectrum (KBr) cm ^-1 : 1719, 1271; Mass spectrum (m / z): 213 (M ⁺ ).

Reference Example 10 4- (2-methylphenyl) -6-phenylpyridine-
3-Carboxylic acid (10a) Ethyl 4- (2-methylphenyl) -6-phenylpyridine-3-carboxylate Ethyl 4- (2-methylphenyl) pyridine-3-carboxylate obtained in Reference Example 9a (8.67 g, 35.9 mmol) in tetrahydrofuran (36 ml) at −20 ° C. with phenyl chloroformate (5.91 mmol).
g, 37.7 mmol) in tetrahydrofuran (38 ml) was added dropwise and stirred at -20 ° C for 10 minutes. At the same temperature, a 2M solution of phenylmagnesium bromide in tetrahydrofuran (18.9 ml) was added dropwise, and the mixture was stirred at -20 ° C for 15 minutes, and the reaction temperature was gradually returned to room temperature over about 30 minutes. 20% aqueous ammonium chloride solution is added to the reaction solution,
Extracted with ethyl acetate. The extract was washed successively with 1 N hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude dihydropyridine compound.
This crude dihydropyridine compound and o-chloranil (9.72 g,
39.5 mmol) was dissolved in toluene (180 ml) and stirred for 2 hours while heating under reflux. The reaction solution was cooled, 1N aqueous sodium hydroxide solution (298 ml) was added, and the mixture was stirred at room temperature for 10 minutes. Celite was added, the insolubles were filtered, and the insolubles were washed with isopropyl ether. The filtrate was separated, and the obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product is subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 15 /
Purify using 1) to give the title compound (8.62 g, 76% yield)
I got ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.00 (3H,
t, J = 7.2Hz), 2.12 (3H, s), 4.12 (2H, q, J = 7.2Hz),
7.09-7.51 (7H, m), 7.63 (1H, s), 8.04-8.09 (2H,
m), 9.25 (1H, s); IR spectrum (liquid) cm ^-1 : 1728, 1715, 1591, 1232
Mass spectrum (m / z): 317 (M ⁺ ).

(10b) 4- (2-methylphenyl) -6-phenylpyridine-3-carboxylic acid 4- (2-methylphenyl) obtained in Reference Example 10a
Ethyl-6-phenylpyridine-3-carboxylate (8.62
g, 27.2 mmol) and lithium hydroxide monohydrate (5.70 g,
136 mmol) to a mixed solvent of methanol (54 ml), tetrahydrofuran (54 ml) and water (14 ml).
The mixture was refluxed for 5 hours. The reaction solution was concentrated under reduced pressure, 1N hydrochloric acid (136 ml) was added, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. Isopropyl ether was added to the crude product, and the precipitated crystals were collected by filtration to give the title compound (5.30 g, yield 67%). Melting point: 189-191 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.14 (3H,
s), 7.13 (1H, br.d, J = 7.4Hz), 7.24-7.37 (3H, m),
7.45-7.53 (3H, m), 7.63 (1H, s), 8.04-8.08 (2H, m),
9.32 (1H, s); IR spectrum (KBr) cm ^-1 : 1713, 1596, 1536, 1281,
765; mass spectrum (m / z): 289 (M ⁺ ).

Reference Example 11 4- (2-methoxyphenyl) -6-phenylpyridine-3-carboxylic acid (11a) 4- (2-methoxyphenyl) pyridine-
Using a 1M ether solution of 2-methoxyphenylmagnesium iodide prepared from 2-iodoanisole and magnesium instead of ethyl 6-carboxylate o-tolylmagnesium chloride, the crude product was obtained in the same manner as in Reference Example 9a. Obtained. The crude product was purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give the title compound in the form of a syrup at a yield of 40%. ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.09 (3H,
t, J = 7.2Hz), 3.73 (3H, s), 4.15 (2H, q, J = 7.2Hz),
6.90-7.43 (5H, m), 8.73 (1H, d, J = 5.2Hz), 9.04 (1
H, s); IR spectrum (liquid) cm ^-1 : 1724, 1589, 1278, 1110,
755; mass spectrum (m / z): 257 (M ⁺ ).

(11b) Ethyl 4- (2-methoxyphenyl) -6-phenylpyridine-3-carboxylate Obtained in Reference Example 11a instead of ethyl 4- (2-methylphenyl) pyridine-3-carboxylate 4- (2-
A crude product was obtained in the same manner as in Reference Example 10a using ethyl (methoxyphenyl) pyridine-3-carboxylate.
The crude product was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 5/1) to obtain the title compound in a yield of 85%. ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.10 (3H,
t, J = 7.2Hz), 3.75 (3H, s), 4.16 (2H, q, J = 7.2Hz),
6.93-7.53 (8H, m), 7.68 (1H, s), 8.06 (2H, br.d, J =
7.9Hz), 9.14 (1H, s); IR spectrum (liquid) cm ^-1 : 1719, 1591, 1249, 754
Mass spectrum (m / z): 333 (M ⁺ ).

(11c) 4- (2-methoxyphenyl) -6-phenylpyridine-3-carboxylic acid 4- (2-methylphenyl) -6-phenylpyridine-
The crude product was obtained in the same manner as in Reference Example 10b, using the ethyl 4- (2-methoxyphenyl) -6-phenylpyridine-3-carboxylate obtained in Reference Example 11b instead of ethyl 3-carboxylate. I got The crude product was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 10/1), isopropyl ether was further added, and the precipitated crystals were collected by filtration to give the title compound in a yield of 70%. I got it. Melting point: 158-163 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.75 (3H,
s), 6.93-7.55 (7H, m), 7.70 (1H, s), 8.05 (2H, br.
d, J = 7.9 Hz), 9.20 (1H, s); IR spectrum (KBr) cm ^-1 : 1699, 1593, 1249, 763; Mass spectrum (m / z): 305 (M ⁺ ).

Reference Example 12 (S)-(−)-3- (1-amino-2,2-dimethylpropyl) pyridine (±) -3- (1-amino-2, obtained in Reference Example 1b.
2-dimethylpropyl) pyridine (0.84 g,
5.15 mmol) and D-(-)-tartaric acid (0.77 g,
5.15 mmol) was dissolved in a mixed solution of methanol (10 ml) and water (2 ml) by heating, and allowed to stand at room temperature. (0.74g)
I got This was stirred in a mixed solution of a 15% aqueous solution of sodium hydroxide (10 ml) and methylene chloride (20 ml) to separate a methylene chloride layer. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crystalline title compound (0.33 g, yield
39%). Melting point: 47-49 ° C; Optical rotation: [α] _D ²⁴ -1.9 ° (c 1, methanol).

Reference Example 13 (R)-(+)-3- (1-Amino-2,2-dimethylpropyl) pyridine In Reference Example 12, (S)-(−)-3- (1-amino-2) , 2-Dimethylpropyl) pyridine
(−)-Tartrate salt (0.74 g) was collected by filtration, and the obtained filtrate was concentrated under reduced pressure. This residue was treated with a 15% aqueous solution of sodium hydroxide (1
0ml) and methylene chloride (20ml), and the methylene chloride layer was separated. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crystalline residue (0.4%).
8g) was obtained. L-(+)-tartaric acid (0.44 g, 2.93 mm
ol) and recrystallized from 80% aqueous methanol to give the title compound L-(+)-tartrate (0.74 g). This was stirred in a mixed solution of a 15% aqueous solution of sodium hydroxide (10 ml) and methylene chloride (20 ml) to separate a methylene chloride layer. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crystalline title compound (0.36 g, yield 43%). Melting point: 48-49.5 ° C .; Optical rotation: [α] _D ²⁴ + 3.4 ° (c 1, methanol).

Reference Example 14 (R)-(+)-3- (1-Amino-2,2-dimethylpropyl) pyridine As a separating agent, instead of D-(-)-tartaric acid, L-
(±) -3- (1-amino-2,2-) obtained in Reference Example 1b using (+)-tartaric acid in the same manner as in Reference Example 12.
The title compound was obtained from (dimethylpropyl) pyridine.

Reference Example 15 (S)-(−)-3- (1-Amino-2,2-dimethylpropyl) pyridine As a separating agent, instead of L-(+)-tartaric acid, D-
The title compound was obtained from the filtrate obtained in Reference Example 14 in the same manner as in Reference Example 13 using (-)-tartaric acid.

Reference Example 16 4-dimethylamino-2- (2-methylphenyl) benzoic acid (16a) Methyl 4-amino-2-hydroxybenzoic acid Methanol of 4-amino-2-hydroxybenzoic acid (25 g) (670 ml) Concentrated sulfuric acid (33 ml) was added to the suspension, and the mixture was stirred under reflux for 64 hours. The reaction solution was concentrated, the residue was neutralized by adding a 10% aqueous sodium carbonate solution, and the precipitate was collected by filtration to obtain the title compound (27.3 g).

Melting point: 119-120 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.88 (3H,
s), 4.10 (2H, br.s), 6.15 (1H, d, J = 7.5Hz), 6.16
(1H, s), 7.62 (1H, d, J = 7.5Hz).

(16b) Methyl 4-amino-2-benzyloxybenzoate Methyl 4-amino-2-hydroxybenzoate (4.7 g) obtained in Reference Example (16a), benzyl bromide (2.31 ml) and potassium carbonate (9.75 g) in N, N-dimethylacetamide (50 ml) was stirred at 80 ° C. for 16 hours. The reaction solution was dissolved in ethyl acetate and water, the ethyl acetate layer was separated, washed with water, and the organic layer was dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluting solvent: hexane / hexane).
Purification using ethyl acetate = 1/1) gave the crystalline title compound (2.94 g). Melting point: 126-128 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.84 (3H,
s), 4.02 (2H, br.s), 5.12 (2H, s), 6.23-6.26 (2H,
m), 7.26-7.41 (3H, m), 7.50-7.53 (2H, m), 7.77 (1
H, d, J = 9.0Hz).

(16c) Methyl 2-benzyloxy-4-dimethylaminobenzoate (1.20 g) of methyl 4-amino-2-benzyloxybenzoate obtained in Reference Example (16b), methyl iodide (0.612 ml)
And sodium hydrogen carbonate (1.57 g) were stirred in trimethyl hexamethyl phosphate (20 ml) at 130 ° C. for 2 hours.
After the reaction solution was diluted with ethyl acetate and washed with water, the organic layer was dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give the crystalline title compound (995m
g) was obtained. Melting point: 81-83 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.00 (6H,
s), 3.85 (3H, s), 5.19 (2H, s), 6.18 (1H, d, J = 2.
5Hz), 6.28 (1H, dd, J = 2.5 and 9.0Hz), 7.29-7.41
(3H, m), 7.54 (2H, d, J = 7.5Hz), 7.84 (1H, d, J = 9.0
Hz).

(16d) Methyl 2-hydroxy-4-dimethylaminobenzoate 2-benzyloxy-4- obtained in Reference Example (16c)
Methyl dimethylaminobenzoate (990 mg) and 5% palladium on carbon (500 mg) were stirred in methanol (10 ml) under a hydrogen gas atmosphere at 50 ° C. for 1.5 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give the crystalline title compound (618 mg).
I got Melting point: 82-83 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.02 (6H,
s), 3.88 (3H, s), 6.14 (1H, d, J = 2.5Hz), 6.21 (1
H, dd, J = 2.5 and 9.0Hz), 7.65 (1H, d, J = 9.0Hz).

(16e) Methyl 4-dimethylamino-2- (2-methylphenyl) benzoate Instead of ethyl 2-hydroxy-4-methoxybenzoate, 2-hydroxy-4 obtained in Reference Example (16d) −
A crude product was obtained in the same manner as in Reference Example (6b) except that methyl dimethylaminobenzoate was used. The crude product was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 7/2) to give the title compound as a viscous oil in a yield of 99%. ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.08 (3H,
s), 3.03 (6H, s), 3.58 (3H, s), 6.42 (1H, d, J = 2.
5Hz), 6.66 (1H, dd, J = 2.5 and 9.0Hz), 7.08-7.16
(1H, m), 7.16-7.30 (3H, m), 7.97 (1H, d, J = 9.0H
z).

(16f) 4-dimethylamino-2- (2-methylphenyl) benzoic acid 4-dimethylamino-2- obtained in Reference Example (16e)
Methyl (2-methylphenyl) benzoate (827 mg) and lithium hydroxide monohydrate (1.28 g) were heated to reflux in a mixed solvent of methanol (6 ml), tetrahydrofuran (6 ml) and water (1.5 ml) for 24 hours. . After the reaction solution was concentrated under reduced pressure, 1
The mixture was neutralized by adding normal hydrochloric acid, and the product was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.The residue was crystallized in isopropyl ether and ethyl acetate, and the title compound (526 mg) was collected by filtration.
I got Melting point: 210-211 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.08 (3H,
s), 3.02 (6H, s), 6.37 (1H, d, J = 2.5Hz), 6.64 (1
H, dd, J = 2.5 and 9.0Hz), 7.06-7.12 (1H, m), 7.13-
7.29 (3H, m), 8.01 (1H, d, J = 9.0Hz).

Reference Example 17 2- (2-methylphenyl) -4- (1-pyrrolidinyl) benzoic acid (17a) Methyl 2-benzyloxy-4- (1-pyrrolidinyl) benzoate Obtained in Reference Example 16 (b). 4-
Methyl amino-2-benzyloxybenzoate (598 mg),
Hexamethylphosphoramide (10 ml) of 1,4-diiodobutane (0.31 ml) and sodium bicarbonate (786 mg)
The mixture was stirred at 130 ° C. for 1.5 hours. The reaction solution was dissolved in ethyl acetate and water, the ethyl acetate layer was separated, washed with water, and the organic layer was dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with isopropyl ether-hexane (1: 1) to give
The title compound (501 mg) was obtained. Melting point: 143-144 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.99-2.04
(4H, m), 3.28-3.33 (4H, m), 3.85 (3H, s), 5.18 (2
H, s), 6.05 (1H, d, J = 2.0Hz), 6.15 (1H, dd, J = 2.0
And 9.0Hz), 7.28-7.41 (3H, m), 7.55 (2H, d, J = 8.5
Hz), 7.84 (1H, d, J = 9.0Hz).

(17b) Methyl 2-hydroxy-4- (1-pyrrolidinyl) benzoate 2-benzyloxy-4- obtained in Reference Example (17a)
Methyl (1-pyrrolidinyl) benzoate (1.25 g) and 5% palladium-carbon (0.62 g) were stirred in a mixed solvent of ethanol (12 ml) and tetrahydrofuran (4 ml) under a hydrogen gas atmosphere at 70 ° C. for 1.5 hours. . After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude crystals were washed with isopropyl ether to give the title compound (446 mg). Melting point: 124-126 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.95-2.04
(4H, m), 3.29-3.38 (4H, m), 3.87 (3H, s), 6.01 (1
H, d, J = 2.0Hz), 6.08 (1H, dd, J = 2.0 and 9.0Hz),
7.64 (1H, d, J = 9.0Hz).

(17c) 2- (2-methylphenyl) -4- (1-
Methyl (pyrrolidinyl) benzoate 2-hydroxy-4- obtained in Reference Example (17b) in place of ethyl 2-hydroxy-4-methoxybenzoate
A crude product was obtained in the same manner as in Reference Example (6b), except that methyl (1-pyrrolidinyl) benzoate was used. This was subjected to silica gel column chromatography (elution solvent: hexane /
Purification using ethyl acetate (9/1) afforded the title compound as a viscous oil in 65% yield. ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.98-2.00
(7H, m), 3.29-3.38 (4H, m), 3.58 (3H, s), 6.28 (1
H, d, J = 2.5Hz), 6.52 (1H, dd, J = 2.5 and 9.0Hz),
7.05-7.28 (4H, m).

(17d) 2- (2-methylphenyl) -4- (1-
Pyrrolidinyl) benzoic acid Methyl 2- (2-methylphenyl) -4- (1-pyrrolidinyl) benzoate obtained in Reference Example (17c) (369m
g) and lithium hydroxide monohydrate (524 mg) in methanol
(4 ml), tetrahydrofuran (4 ml) and water (1 ml) in a mixed solvent of 64 hours under reflux. The reaction solution was concentrated under reduced pressure, neutralized by adding 1N hydrochloric acid, and the product was extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate,
After concentration under reduced pressure, the residue was crystallized in isopropyl ether and collected by filtration to give the title compound (157 mg). Melting point: 213-215 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.98-2.14
(7H, m), 3.29-3.42 (4H, m), 6.25 (1H, d, J = 2.5Hz),
6.51 (1H, dd, J = 2.5 and 9.0Hz), 7.08-7.33 (4H,
m), 8.01 (1H, d, J = 8.5Hz).

Reference Example 18 4-morpholino-2- (2-methylphenyl) benzoic acid (18a) methyl 2-benzyloxy-4-morpholinobenzoate 4-amino-2- obtained in Reference Example 16 (b) Methyl benzyloxybenzoate (598 mg), diethylene glycol di-p-tosylate (967 mg) and sodium bicarbonate (7 mg
86 mg) of hexamethylphosphoramide (10 ml) was stirred at 130 ° C. for 1.5 hours. The reaction solution was dissolved in ethyl acetate and water, the ethyl acetate layer was separated, washed with water, and the organic layer was dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 7 /
Purification using 3) yields the crystalline title compound
(267 mg) was obtained. Melting point: 112-114 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.28 (4H,
t, J = 5.0Hz), 3.89 (4H, t, J = 5.0Hz), 3.92 (3H, s),
5.22 (2H, s), 6.47 (1H, d, J = 2.5Hz), 6.53 (1H, dd,
J = 2.5 and 9.0Hz), 7.33-7.47 (3H, m), 7.58 (2H,
d, J = 7.5Hz), 7.90 (1H, d, J = 9.0Hz).

(18b) Methyl 2-hydroxy-4-morpholinobenzoate 2-benzyloxy-4- obtained in Reference Example (18a)
Methyl morpholinobenzoate is converted to 2-benzyloxy-4-
The title compound was obtained in a yield of 95% in the same manner as in Reference Example (16d), except that dimethylaminobenzoic acid was used instead of dimethylaminobenzoic acid. Melting point: 108-109 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.29 (4H,
t, J = 5.0Hz), 3.83 (4H, t, J = 5.0Hz), 3.90 (3H, s),
6.34 (1H, d, J = 2.5Hz), 6.40 (1H, dd, J = 2.5 and
9.0Hz), 7.69 (1H, d, J = 9.0Hz).

(18c) Methyl 2- (2-methylphenyl) -4-morpholinobenzoate Instead of ethyl 2-hydroxy-4-methoxybenzoate, 2-hydroxy-4-morpholino obtained in Reference Example (18b) A crude product was obtained in the same manner as in Reference Example (6b) except that methyl benzoate was used. This was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate =
7/3) to give the title compound as a viscous oil in a 93% yield. ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.07 (3H,
s), 3.28 (4H, t, J = 5.0Hz), 3.60 (3H, s), 3.85 (4
H, t, J = 5.0Hz), 6.64 (1H, d, J = 2.5Hz), 6.87 (1H, d
d, J = 2.5 and 9.0Hz), 7.05-7.10 (1H, m), 7.15-7.30
(3H, m), 7.98 (1H, d, J = 8.5Hz).

(18d) 2- (2-methylphenyl) -4-morpholinobenzoic acid The methyl 2- (2-methylphenyl) -4- (1-pyrrolidinyl) benzoate obtained in Reference Example (18b) was converted to 4 −
A crude product was obtained in the same manner as in Reference Example (16f), except that it was used in place of methyl dimethylamino-2- (2-methylphenyl) benzoate. The obtained crude product was crystallized in isopropyl ether, and the crystals were collected by filtration to give the title compound in a yield of 84%. Melting point: 201-204 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.08 (3H,
s), 3.29 (4H, t, J = 5.0Hz), 3.84 (4H, t, J = 5.0Hz),
6.60 (1H, d, J = 2.5Hz), 6.86 (1H, dd, J = 2.5 and
9.0Hz), 7.05-7.11 (1H, m), 7.15-7.31 (3H, m), 8.03
(1H, d, J = 8.5Hz).

Reference Example 19 2- (2-Methylphenyl) -4-piperidinobenzoic acid (19a) Ethyl 4-amino-2-hydroxybenzoate 4-Amino-2-hydroxybenzoic acid (25 g) and ethyl iodide ( 26.7 g) in a mixture of acetonitrile (250 ml)
8-diazabicyclo [5,4,0] -7-undecene (2
6.1 g) was added, and the mixture was stirred under reflux for 8 hours. The reaction solution was dissolved in ethyl acetate and water, and the ethyl acetate layer was separated.
After washing with water, the organic layer was dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystalline target product was washed with isopropyl ether-ethyl acetate and collected by filtration to obtain the title compound (15.8 g). Melting point: 114-116 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.38 (3H,
t, J = 7.0Hz), 4.12 (1H, br.s), 4.34 (2H, q, J = 7.0H
z), 6.13-6.17 (2H, m), 7.63 (1H, d, J = 9.0H z). The crystal filtrate was further concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1) to give the title compound (6.33 g).

(19b) Ethyl 4-amino-2-benzyloxybenzoate In a mixture of N, N-dimethylacetamide (25 ml) containing 55% oily sodium hydride (1.32 g) and toluene (25 ml), Reference Example 19 was added. 4-Amino-2- obtained in (a)
A solution of ethyl hydroxybenzoate (5 g) in N, N-dimethylacetamide (25 ml) was added dropwise at room temperature, and the mixture was stirred at room temperature for 30 minutes. To this was added benzyl bromide (3.61 ml) with N,
A solution of N-dimethylacetamide (10 ml) was added dropwise at room temperature, and the mixture was further stirred at room temperature for 1.5 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with brine, and then the organic layer was dried using anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
The obtained residue is purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2), and the obtained crystalline target compound is washed with isopropyl ether to give the title compound (3.44). g)
I got Melting point: 124-127 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.32 (3H,
t, J = 7.0Hz), 4.00 (1H, br.s), 4.31 (2H, q, J = 7.0H
z), 5.12 (2H, s), 6.24-6.27 (2H, m), 7.30-7.41 (3
H, m), 7.51 (2H, d, J = 7.0Hz), 7.77 (1H, d, J = 7.0H
z).

(19c) Ethyl 2-benzyloxy-4-piperidinobenzoate (2g) ethyl 4-amino-2-benzyloxybenzoate obtained in Reference Example 19 (b), 1,5-diiodopentane
(1.10 ml) and a mixture of sodium bicarbonate (2.48 g) and hexamethylphosphoramide (30 ml) were stirred at 130 ° C. for 2 hours. The reaction solution was dissolved in ethyl acetate and water, the ethyl acetate layer was separated, washed with water, and the organic layer was dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to obtain a crystalline target compound (1.70 g). . Melting point: 87-89 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.33 (3H,
t, J = 7.0Hz), 1.60-1.73 (6H, m), 3.20-3.33 (4H,
m), 4.31 (2H, q, J = 7.0Hz), 5.15 (2H, s), 6.42 (1H,
d, J = 2.0Hz), 6.48 (1H, dd, J = 2.0 and 9.0Hz), 7.3
0-7.41 (3H, m), 7.54 (2H, d, J = 7.5Hz), 7.82 (1H, d,
J = 9.0Hz).

(19d) Ethyl 2-hydroxy-4-piperidinobenzoate 2-benzyloxy-4- obtained in Reference Example (19c)
Ethyl piperidino benzoate (0.7g) and 5% palladium-
Carbon (70 mg) was stirred in ethanol (70 ml) under a hydrogen gas atmosphere at 70 ° C. for 45 minutes. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (514 mg) as a viscous oil. ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.38 (3H,
t, J = 7.0Hz), 1.52-1.70 (6H, m), 3.26-3.38 (4H,
m), 4.34 (2H, q, J = 7.0Hz), 6.32 (1H, d, J = 2.5Hz),
6.38 (1H, dd, J = 2.5 and 9.0Hz).

(19e) Ethyl 2- (2-methylphenyl) -4-piperidinobenzoate Instead of ethyl 2-hydroxy-4-methoxybenzoate, 2- (2-methylphenyl) -4-piperidino was obtained in Reference Example (19d).
A crude product was obtained in the same manner as in Reference Example (6b) except that ethyl hydroxy-4-piperidinobenzoate was used. This was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 9/1) to give the title compound as a viscous oil in a yield of 33%. ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.94 (3H,
t, J = 7.0Hz), 1.60-1.72 (6H, m), 2.08 (3H, s), 3.2
8-3.37 (4H, m), 4.00 (2H, q, J = 7.0Hz), 6.62 (1H,
d, J = 2.5Hz), 6.86 (1H, dd, J = 2.5 and 9.0Hz), 7.04
-7.28 (4H, m), 7.95 (1H, d, J = 9.0Hz).

(19f) 2- (2-methylphenyl) -4-piperidinobenzoic acid The ethyl 2- (2-methylphenyl) -4-piperidinobenzoate obtained in Reference Example (19e) was converted to 4-dimethylamino- A crude product was obtained in the same manner as in Reference Example (16f), except that methyl 2- (2-methylphenyl) benzoate was used in place of methyl. The obtained crude product was crystallized in isopropyl ether, and the crystals were collected by filtration to give the title compound in a yield of 39%. Melting point: 174-176 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.55-1.72
(6H, m), 2.09 (3H, s), 3.29-3.38 (4H, m), 6.59 (1
H, d, J = 2.5Hz), 6.85 (1H, dd, J = 2.5 and 9.0Hz),
7.09-7.29 (4H, m), 7.99 (1H, d, J = 9.0Hz).

Reference Example 20 2- (2-methylphenyl) -4-methylthiobenzoic acid (20a) 4-dimethylthiocarbamoyloxy-2
Methyl-(2-methylphenyl) benzoate 4-Hydroxy-2- (2-) obtained in Reference Example (5d)
Methylphenyl) methyl benzoate (6.5 g) in a mixed solution of dimethylformamide (32 ml) and toluene (32 ml)
5% oily sodium hydride (1.29 g) was added, and the mixture was stirred at room temperature for 1 hour. A solution of N, N-dimethylthiocarbamoyl chloride (3.76 g) in dimethylformamide (5 ml) was added dropwise to the mixture, and the mixture was stirred at 60 ° C. for 2 hours. Ethyl acetate was added to the reaction solution, the solution was washed with water, and the organic layer was dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1) to give the title compound (8.75) as an oil.
g) was obtained. ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.11 (3H,
s), 3.34 (3H, s), 3.45 (3H, s), 3.61 (3H, s), 6.9
6 (1H, d, J = 2.0Hz), 7.08-7.31 (5H, m), 8.03 (1H,
d, J = 8.5Hz).

(20b) 4-dimethylcarbamoylthio-2- (2
Methyl -methylphenyl) benzoate Methyl 4-dimethylthiocarbamoyloxy-2- (2-methylphenyl) benzoate (8.75 g) obtained in Reference Example (20a) was stirred at 250 ° C for 1 hour. By purifying the product using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1),
The title compound (8.34g) was obtained as an oil. ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.09 (3H,
s), 3.06 (6H, br.s), 3.61 (3H, s), 7.09 (1H, d, J
= 7.0Hz), 7.13-7.31 (3H, m), 7.39 (1H, d, J = 2.0Hz),
7.56 (1H, dd, J = 2.0 and 8.0Hz), 7.95 (1H, d, J = 8.
0Hz).

(20c) Methyl 2- (2-methylphenyl) -4-methylthiobenzoate Methyl 4-dimethylcarbamoylthio-2- (2-methylphenyl) benzoate obtained in Reference Example (20b) (2.
4g) in methanol (20ml)
(1.92 g) and stirred at 50 ° C. for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and water.
After neutralization with N hydrochloric acid, the ethyl acetate layer was separated. After the extract was washed with brine, the organic layer was dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude oily methyl 2- (2-methylphenyl) -4-mercaptobenzoate. Dimethylformamide of this
(20 ml) 1,8-diazabicyclo [5,4,0]
-7-undecene (3.27ml) and methyl iodide (1.81ml)
Was added and stirred at room temperature for 3 hours. After adding ethyl acetate to the reaction solution and washing with water, the organic layer was dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 5: 1) to give the title compound (1.83 g) as an oil. . ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.07 (3H,
s), 2.50 (3H, s), 3.60 (3H, s), 7.03 (1H, d, J = 2.
0Hz), 7.07 (1H, d, J = 7.0Hz), 7.17-7.30 (4H, m), 7.
92 (1H, d, J = 8.0Hz).

(20d) 2- (2-methylphenyl) -4-methylthiobenzoic acid Methyl 2- (2-methylphenyl) -4-methylthiobenzoate (600 mg) obtained in Reference Example (20c) in methanol ( 6 ml) and water (2 ml) in a mixed solution.
Monohydrate (185 mg) was added, and the mixture was stirred at 60 ° C. for 16 hours.
After the reaction solution was concentrated under reduced pressure and neutralized by adding 1N hydrochloric acid, the title compound was extracted with ethyl acetate, the extract was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystalline residue was washed with hexane and a small amount of isopropyl ether to obtain the title compound (500 mg). Melting point: 109-110 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.06 (3H,
s), 2.49 (3H, s), 7.00 (1H, d, J = 1.5Hz), 7.06 (1
H, d, J = 7.5Hz), 7.14-7.30 (4H, m), 7.97 (1H, d, J =
8.5Hz).

Reference Example 21 4-isopropylthio-2- (2-methylphenyl) benzoic acid (21a) Methyl 4-isopropylthio-2- (2-methylphenyl) benzoate Obtained as an intermediate of Reference Example (20c) Methyl 4-mercapto-2- (2-methylphenyl) benzoate (2.00
g) in dimethylformamide (20 ml)
Diazabicyclo [5,4,0] -7-undecene (3.69
ml) and isopropyl iodide (3.28 ml).
Stirred for hours. After adding ethyl acetate to the reaction solution and washing with water, the organic layer was dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1) to give the title compound (2.02 g) as an oil. . ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.35 (6H,
d, J = 6.5Hz), 2.07 (3H, s), 3.60 (3H, s), 3.43-3.6
5 (1H, m), 7.07 (1H, d, J = 7.0Hz), 7.14 (1H, d, J =
2.0Hz), 7.15-7.32 (3H, m), 7.33 (1H, dd, J = 2.0 and 8.0Hz), 7.90 (1H, d, J = 8.0Hz).

(21b) 4-isopropylthio-2- (2-methylphenyl) benzoic acid 4-isopropylthio-2 obtained in Reference Example (21a)
Methyl 2- (2-methylphenyl) benzoate (2.02g)
To a solution of -methoxyethanol (20 ml) was added 85% potassium hydroxide (1.13 g), and the mixture was refluxed for 2.5 hours. The reaction solution was concentrated under reduced pressure, neutralized by adding 1 N hydrochloric acid, and then the title compound was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crystalline residue was washed with hexane and a small amount of isopropyl ether to give the title compound (1.79 mg). Melting point: 91-92 ° C; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.36 (6H,
d, J = 6.5Hz), 2.07 (3H, s), 3.55 (1H, quintet, J =
6.5Hz), 7.07 (1H, d, J = 7.0Hz), 7.12 (1H, d, J = 2.0H
z), 7.15-7.29 (3H, m), 7.32 (1H, dd, J = 2.0 and 8.
5Hz), 7.97 (1H, d, J = 8.5Hz).

Reference Example 22 4-methoxy-2- (2-methylphenyl) phenylacetic acid (22a) 4-methoxy-2- (2-methylphenyl) benzyl alcohol 4-methoxy-2- obtained in Reference Example 6b Ethyl (2-methylphenyl) benzoate (3.
90 g, 14.4 mmol) in tetrahydrofuran (40 ml) at -50 ° C or lower at 1M diisobutylaluminum hydride.
A toluene solution (33 ml) was added dropwise, and the mixture was stirred for 3 hours under ice cooling. Ethyl acetate and a saturated aqueous solution of potassium bisulfate were added to the reaction solution, and the ethyl acetate layer was separated. The extract was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the crystalline residue was washed with isopropyl ether-hexane to obtain the title compound (3.21 g, yield 97%). Melting point: 83.5 ° C .; ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.35 (1H,
br.t, J = 5.5Hz), 2.08 (3H, s), 3.81 (3H, s), 4.28-4.
40 (2H, m), 6.70 (1H, d, J = 2.5Hz), 6.92 (1H, dd, J
= 2.5 and 8.5Hz), 7.15 (1H, d, J = 7Hz), 7.20-7.30
(3H, m), 7.44 (1H, d, J = 8.5Hz).

(22b) 4-methoxy-2- (2-methylphenyl) phenylacetonitrile Dichloromethane of 4-methoxy-2- (2-methylphenyl) benzyl alcohol (2.28 g, 10 mmol) obtained in Reference Example 22a (30 ml) A solution of thionyl chloride (0.80 ml, 11 mmol) in dichloromethane (3 ml) was added dropwise to the solution under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, benzene was added to the residue, and the mixture was concentrated under reduced pressure three times. To a solution of the obtained syrup in dimethylformamide (20 ml) was added sodium cyanide (1.00 g, 20.
After stirring at room temperature for 16 hours and at 60 ° C. for 2 hours, ethyl acetate and water were added, and the ethyl acetate layer was separated. The extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1) to give the title compound as a syrup (1.65 g, yield). 70%). ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.08 (3H,
s), 3.34 (2H, s), 3.82 (3H, s), 6.74 (1H, d, J = 2.5
Hz), 6.94 (1H, dd, J = 2.5 and 8.5Hz), 7.11 (1H, d,
J = 7.0Hz), 7.21-7.35 (3H, m), 7.45 (1H, d, J = 8.5H
z).

(22c) 4-methoxy-2- (2-methylphenyl) phenylacetic acid 4-methoxy-2- (2-methylphenyl) phenylacetonitrile obtained in Reference Example 22b ((1.10 g, 4.64
85% potassium hydroxide (2.00 g, 30.3 mmol) was added to a methoxyethanol (20 ml) solution of the above solution and stirred on a 140 ° C. oil bath for 8 hours. Water (20 ml) was added to the reaction mixture, and the mixture was acidified with 6N hydrochloric acid, and the title compound was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a syrupy title compound (0.84 g, 71%). ¹ H NMR spectrum (270 MHz, CDCl ₃ ) δppm: 2.05 (3H,
s), 3.30 (1H, d, J = 16.5Hz), 3.41 (1H, d, J = 16.5H
z), 3.80 (3H, s), 6.71 (1H, d, J = 2.5Hz), 6.90 (1H,
(dd, J = 2.5 and 8.5Hz), 7.10 (1H, d, J = 7.5Hz), 7.16-
7.30 (4H, m).

Test Example 1 ACAT Inhibitory Activity ACAT inhibitory activity was determined by the in vitro test method of Ross et al. [Ross et al.
Journal of Biological Chemistry, 2
59, 815-819 (1984): AC Ross e
t al., J. Biol. Chem., 259 , 815-819 (198
4)] was measured according to the improved method. That is, rat liver microsomes were spragu
From e-Dawley rats, the method of Ross et al. [Ross et al., Journal of Biological Chemistry, vol.
2453-2459 (1982): AC Ross et al., J.
Biol. Chem., 257 , 2453-2459 (1982)] and used as an enzyme fraction. 100 μM [ ¹⁴ C] oleoyl
(oleoyl) -CoA, 2 mM dithiothreitol and 80 μM
To a 0.15 M potassium phosphate buffer (pH 7.4) containing bovine serum albumin was added 60-100 μg of the microsomal fraction, and 5 μl (2.5% v / v) of a dimethyl sulfoxide solution of a test compound at a constant concentration was added. Was added to make a total volume of 200 μl, and the mixture was heated at 37 ° C. for 4 minutes. Then, add 1 ml of ethanol and stir,
The enzyme reaction was stopped. To this reaction solution, 2 ml of hexane was added, and after stirring, 1 ml of the hexane layer was taken, and the solvent was evaporated under a nitrogen stream. / Diethyl ether / acetic acid = 85
/ 15/1), and its radioactivity was measured.
Active. The inhibition rate (%) was determined from the control activity value and the activity value when a test compound at a certain concentration was used.
The concentration IC ₅₀ of the test compound required to inhibit AT activity by 50% was calculated. Table 3 shows the results.

[0213]

[Table 3] Compound IC ₅₀ (ng / ml)化合物 Compound of Example 2 104 Compound of Example 3 146 Compound of Example 4 72.6 Compound of Example 5 89.8 Compound of Example 7 89.1 Compound of Example 8 137 Example Compound of 11 54.2 Compound of Example 12 105 Compound of Example 13 145 Compound of Example 14 122 Compound of Example 15 129 Compound of Example 16 184 Compound of Example 17 178 Compound of Example 18 114 Compound of Example 19 Compound 120─────────────────────────.

Formulation Example 1 Hard Capsule Each of the standard bipartite hard gelatin capsules was charged with 100 mg of the compound of Example 2 in the form of powder, 150 mg of lactose, 50 m
g of cellulose and 6 mg of magnesium stearate are filled, unit capsules are prepared, washed and dried to obtain hard capsules.

[0215]

EFFECTS OF THE INVENTION The compound of the present invention containing a compound having the above general formula (I) or a pharmacologically acceptable salt thereof has an excellent ACAT inhibitory action and is also excellent in oral absorbability.
A therapeutic or preventive agent for various diseases caused by ACAT,
For example, it is useful as a therapeutic or prophylactic agent (particularly a therapeutic agent) for hyperlipidemia, a therapeutic or prophylactic agent (particularly a therapeutic agent) for atherosclerosis, and the like.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/501 A61K 31/50 601 31/506 31/505 601 // C07D 213/56 C07D 213/56 213 / 64 213/64 213/70 213/70 213/74 213/74 213/75 213/75 401/12 401/12 (72) Inventor Minoru Takamura 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Seiichiro Koga 1-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd.

Claims (18)

[Claims] 1. A compound of the general formula [Wherein, X represents a group having the formula = CH- or = N-, Y represents a methylene group or an imino group, R ¹ represents a hydrogen atom or a C ₁ -C ₈ alkyl radical, R ² represents a 6-membered cyclic heteroaryl group containing 1 or 2 nitrogen atoms; R ³ represents an optionally substituted C ₆ -C ₁₀ aryl group (the substituent is a halogen atom, C ₁ -C ₆ alkyl groups,
Halogeno -C ₁ -C ₄ alkyl group, a C ₁ -C ₆ alkoxy or C ₁ -C ₆ alkylthio group. R ⁴ is a hydrogen atom, a halogen atom, a C ₁ -C ₈ alkyl group, a C ₁ -C ₈ alkoxy group, a C ₁ -C ₈ alkylthio group, an optionally substituted C ₆ -C ₁₀ aryl Group (the substituent is a halogen atom, a C ₁ -C ₆ alkyl group, a C _1-
C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, C _1-
It represents a C ₆ alkanoyl group, a C ₁ -C ₆ alkanoylamino group, a cyano group or a nitro group. ), An optionally substituted C ₆ -C ₁₀ aryloxy group (the substituent is R ⁴
And the same groups as the substituents of the C ₆ -C ₁₀ aryl group. ), An optionally substituted C ₆ -C ₁₀ arylthio group (the substituent is the same as the substituent of the C ₆ -C ₁₀ aryl group for R ⁴ ), and an optionally substituted C ₆ -C ₁₀ arylthio group. ₇ -C
_{A 12} aralkyl group (the substituent is the same as the substituent of the C ₆ -C ₁₀ aryl group of R ⁴ ), an optionally substituted C ₇ -C ₁₂ aralkyloxy group (the substituent is , R ⁴
And the same groups as the substituents of the C ₆ -C ₁₀ aryl group. ), An optionally substituted C ₇ -C ₁₂ aralkylthio group (the substituents are the same as the substituents of the C ₆ -C ₁₀ aryl group for R ⁴ ), di-C ₁ -C ₆ 3 to 6 which may contain an alkylamino group or an oxygen or sulfur atom
A membered cyclic amino group. Or a pharmacologically acceptable salt thereof. 2. The medicament comprising the arylurea or arylmethylcarbamoyl derivative according to claim 1, wherein Y is an imino group, or a pharmacologically acceptable salt thereof. 3. The medicament comprising the arylurea or arylmethylcarbamoyl derivative according to claim 1 or 2, wherein R ¹ is a C ₁ -C ₅ alkyl group, or a pharmaceutically acceptable salt thereof. 4. An arylurea or arylmethylcarbamoyl derivative according to claim 1, wherein R ¹ is an isopropyl group, a t-butyl group or a t-pentyl group, or a pharmacologically acceptable salt thereof. Medicine. 5. The medicament comprising the arylurea or arylmethylcarbamoyl derivative according to claim 1 or 2, wherein R ¹ is a t-butyl group, or a pharmaceutically acceptable salt thereof. 6. A medicament comprising the arylurea or arylmethylcarbamoyl derivative according to claim 1, wherein R ² is a pyridyl group, or a pharmacologically acceptable salt thereof. . (7) R ³ is an optionally substituted phenyl group (the substituent is a fluorine atom, a chlorine atom, a bromine atom, a C _1-
C ₄ alkyl group, fluoro-C ₁ -C ₂ alkyl group, C
₁ -C is a ₄ alkoxy groups or C ₁ -C ₄ alkylthio group. A pharmaceutical comprising the arylurea or arylmethylcarbamoyl derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the claims 1 to 6. 8. A compound according to claim 8, wherein R ³ is an optionally substituted phenyl group (the substituent is a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group,
It is a methylthio group or an ethylthio group. A pharmaceutical comprising the arylurea or arylmethylcarbamoyl derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the claims 1 to 6. 9. The compound according to claim 9, wherein R ³ is an optionally substituted phenyl group (the substituent is a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group or a methylthio group). 7. A medicament comprising the arylurea or arylmethylcarbamoyl derivative or the pharmaceutically acceptable salt thereof according to one of claims 1 to 6. 10. The aryl urea according to claim 1, wherein R ³ is a substituted phenyl group (the substituent is a methyl group or a methoxy group). Alternatively, a medicament containing an arylmethylcarbamoyl derivative or a pharmaceutically acceptable salt thereof. (11) R ⁴ may be a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C ₂ -C ₇ alkyl group, a C ₂ -C ₇ alkoxy group, a C ₂ -C ₇ alkylthio group, A good phenyl, benzyl, phenethyl, 3-phenylpropyl, phenoxy, phenylthio, benzyloxy, phenethyloxy, benzylthio or phenethylthio group (the substituent is a fluorine atom, a chlorine atom, a bromine atom, a C ₁ -C ₄ alkyl group, A C ₁ -C ₄ alkoxy group,
Methylthio group, ethylthio group, C ₁ -C ₃ alkanoyl group, C ₁ -C ₃ alkanoylamino group, a cyano group or a nitro group. ), A di-C ₁ -C ₄ alkylamino group or a 5- to 6-membered cyclic amino group, an arylurea or arylmethylcarbamoyl derivative according to one of claims 1 to 10, or a pharmacologic agent thereof. A medicament containing a pharmaceutically acceptable salt. 12. R ⁴ is a fluorine atom, a chlorine atom, C ₃ -C
₆ alkyl group, C ₃ -C ₆ alkoxy group, C ₃ -C ₆ alkylthio group, a phenyl optionally substituted, phenoxy, phenylthio, benzyl, phenethyl, benzyloxy or benzylthio group (the substituent is a fluorine atom, Chlorine, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, formyl, acetyl, acetamino, cyano or nitro), dimethylamino, diethylamino, 1-pyrrolidinyl 11. A medicament comprising an arylurea or arylmethylcarbamoyl derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is a group, a 1-piperidinyl group or a 4-morpholinyl group. . (13) R ⁴ is chlorine, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, propoxy, isopropoxy, butoxy, isobutoxy, t- Butoxy, pentoxy, hexyloxy, propylthio, isopropylthio, butylthio, isobutylthio,
t-butylthio, pentylthio, hexylthio,
An optionally substituted phenyl, phenoxy, phenylthio, benzyl, benzyloxy or benzylthio group (the substituent is a fluorine atom, a chlorine atom, a methyl group, a methoxy group, a cyano group or a nitro group), a dimethylamino group 11. A medicament comprising an arylurea or arylmethylcarbamoyl derivative or a pharmacologically acceptable salt thereof according to claim 1, which is a 1-pyrrolidinyl group or a 1-piperidinyl group. It is 14. R ^4, propyl group, butyl group, a pentyl group, a hexyl group, a propoxy group, a butoxy group, Penchiokishi group, hexyloxy group, propylthio group, butylthio group, pentylthio group, hexylthio group or substituted 11. The phenyl, phenoxy, phenylthio or benzyloxy group (wherein the substituent is a fluorine atom, a chlorine atom, a methyl group or a methoxy group). A pharmaceutical comprising an arylurea or arylmethylcarbamoyl derivative or a pharmacologically acceptable salt thereof. 15. An N- [4-butoxy-2- (2-methylphenyl) phenyl] -N '-[2,2-dimethyl-1
-(3-pyridyl) propyl] urea, N- [4-butoxy-2- (2-methoxyphenyl) phenyl] -N '-[2,2-dimethyl-1- (3-pyridyl) propyl] urea, N -[4-pentyloxy-2- (2-methylphenyl) phenyl] -N '-[2,2-dimethyl-1- (3
-Pyridyl) propyl] urea, N- [4-pentyloxy-2- (2-methoxyphenyl) phenyl] -N '-[2,2-dimethyl-1- (3
-Pyridyl) propyl] urea, N- [4-hexyloxy-2- (2-methylphenyl) phenyl] -N '-[2,2-dimethyl-1- (3
-Pyridyl) propyl] urea, N- [4-hexyloxy-2- (2-methoxyphenyl) phenyl] -N '-[2,2-dimethyl-1- (3
-Pyridyl) propyl] urea, N- [4-benzyloxy-2- (2-methylphenyl) phenyl] -N '-[2,2-dimethyl-1- (3
-Pyridyl) propyl] urea, N- [4-benzyloxy-2- (2-methoxyphenyl) phenyl] -N '-[2,2-dimethyl-1- (3
-Pyridyl) propyl] urea, N- [2- (2-methylphenyl) -4-biphenyl-
1-yl] -N '-[2,2-dimethyl-1- (3-pyridyl) propyl] urea, N- [2- (2-methoxyphenyl) -4-biphenyl-1-yl] -N'- [2,2-dimethyl-1- (3-
Pyridyl) propyl] urea, N- [2- (2-methylphenyl) -4-morpholinophenyl] -N '-[2,2-dimethyl-1- (3-pyridyl) propyl] urea, N- [6- Butoxy-4- (2-methylphenyl) pyridin-3-yl] -N '-[2,2-dimethyl-1-
(3-pyridyl) propyl] urea, N- [6-butoxy-4- (2-methoxyphenyl) pyridin-3-yl] -N '-[2,2-dimethyl-1-
(3-pyridyl) propyl] urea, N- [4- (2-methylphenyl) -6-pentyloxypyridin-3-yl] -N '-[2,2-dimethyl-
1- (3-pyridyl) propyl] urea, N- [4- (2-methoxyphenyl) -6-pentyloxypyridin-3-yl] -N ′-[2,2-dimethyl-1- (3-pyridyl) ) Propyl] urea, N- [6-hexyloxy-4- (2-methylphenyl) pyridin-3-yl] -N ′-[2,2-dimethyl-1- (3-pyridyl) propyl] urea, N -[6-hexyloxy-4- (2-methoxyphenyl) pyridin-3-yl] -N '-[2,2-dimethyl-1- (3-pyridyl) propyl] urea; N- [4- (2 -Methylphenyl) -6-phenylpyridin-3-yl] -N '-[2,2-dimethyl-1-
(3-pyridyl) propyl] urea and N- [4- (2-methoxyphenyl) -6-phenylpyridin-3-yl] -N '-[2,2-dimethyl-1-
The medicament containing the arylurea or arylmethylcarbamoyl derivative according to claim 1 or a pharmacologically acceptable salt thereof, which is selected from the group consisting of (3-pyridyl) propyl] urea. 16. An ACAT inhibitor comprising the arylurea or arylmethylcarbamoyl derivative according to one of claims 1 to 15 or a pharmacologically acceptable salt thereof as an active ingredient. 17. A therapeutic agent for hyperlipidemia comprising the arylurea or arylmethylcarbamoyl derivative according to one of claims 1 to 15 or a pharmacologically acceptable salt thereof as an active ingredient. Prophylactic agent. 18. A method for treating atherosclerosis, comprising an arylurea or arylmethylcarbamoyl derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. Agent or prophylactic agent.