JP2002371078A - Quinoline derivative and quinolone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a compound having inhibitory actions on adhesion of synovial membrane cells to collagen and suppressing actions on production of cytokines. SOLUTION: The compound is represented by formula (Ia) (wherein, R<1> is an alkyl or an aryl which can be substituted or R<1> together with R<2> form a single bond; R<2> together with R<1> form a single bond or R<2> together with R<3> denote oxygen atom; R<3> together with R<2> denote oxygen atom or R<3> is a halogen, an alkyl, or the like, which can be substituted; R<4> is a halogen atom, an alkyl, an aryl, or the like, which can be substituted; and R<5> is H, a halogen, or the like) or a pharmacologically acceptable salt, ester or other derivatives thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to quinoline derivatives and quinolone derivatives which are useful as medicaments.

More specifically, it has an effect of inhibiting adhesion between synovial cells and collagen and an effect of suppressing cytokine production, and is used for rheumatoid arthritis, osteoarthritis, asthma, atopic dermatitis, myocardium and brain. Quinoline derivatives useful as prophylactic and / or therapeutic agents for autoimmune diseases such as reperfusion injury, ulcerative enteritis, Crohn's disease, liver and nephritis, and inflammatory diseases, or as pharmaceuticals for suppressing cancer growth and metastasis And quinolone derivatives.

[0003]

2. Description of the Related Art Rheumatoid arthritis (RA) is a chronic inflammatory disease mainly involving the synovium of the joint. From the inflamed synovium, various cytokines, neutral proteases,
Various mediators such as active oxygen and nitric oxide are produced and are involved in pathogenesis.

[0004] In addition, synovial cells express various integrins on the surface thereof, and it is assumed that the integrins are involved in diseases. Is assumed to be involved in

On the other hand, cytokines (TNF-α, IL-
1β) plays an important role in establishing major histopathological changes such as angiogenesis, lymphocyte infiltration and synovial proliferation in the synovium of the joint, and further through activation of osteoclasts. It is presumed to be deeply involved in joint tissue destruction. Recently, anti-human TNF-α targeting RA patients
The results of clinical trials of antibodies have been reported, demonstrating their excellent efficacy and safety (Lancet, 344, 1125, 1).
994; Int. J. Immunopharmac. 1
7, 141, 1995), and TNF-α was found to be an exacerbating factor in the pathogenesis of RA.

Therefore, the action of inhibiting cell adhesion,
Compounds having an effect of inhibiting the production of cytokines are considered to be useful as new types of drugs, particularly as preventive or therapeutic agents for RA, but such compounds have not been found at present.

[0007]

SUMMARY OF THE INVENTION The present inventors have made the above-mentioned 2
As a result of intensive studies on the synthesis of compounds having two actions (ie, the action of inhibiting cell adhesion and the action of suppressing cytokine production) and their pharmacological actions, a quinoline derivative substituted with a 3-oxopropenyl group and The present inventors have found that a quinolone derivative has an excellent cell adhesion inhibitory action and an excellent cytokine production inhibitory action, and completed the present invention.

[0008]

SUMMARY OF THE INVENTION The present invention relates to: (1) A compound having the following general formula (Ia) or a pharmacologically acceptable salt, ester or other derivative thereof:

[0009]

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[In the formula, R ¹ is a lower alkyl group, a lower alkyl group substituted with a group selected from a substituent group α, an aryl group, a group selected from a substituent group α and a substituent group β. A substituted aryl group, an aralkyl group, or an aralkyl group substituted with a group selected from the substituent group α and the substituent group β, or R ¹ forms a single bond together with R ² formed, R ² is either to form a single bond together with R ^1, or, R ² represents an oxygen atom together with R ^3, R ³ together with R ² Represents an oxygen atom, or R ³ is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from a substituent group α, an aryl group, a substituent group α and a substituent group β Selected from an aryl group, a heteroaryl group, a substituent group α and a substituent group β substituted with the selected group. A heteroaryl group, an aralkyl group, a substituent group α and a substituent group β substituted with a selected group;
An aralkyl group or a group substituted with a group selected from:
O—R ⁶ (wherein, R ⁶ is selected from a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from a substituent group α, an aryl group, a substituent group α and a substituent group β. An aryl group substituted with a group, a heteroaryl group, a heteroaryl group substituted with a group selected from a substituent group α and a substituent group β, an aralkyl group, or a substituent group α and a substituent group β an aralkyl group substituted with a group selected from), -.. in S-R ⁶ (wherein, R ⁶ is as defined above) or -NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ is
The same or different, respectively, a hydrogen atom, a lower alkyl group, an aryl group, an aryl group, a heteroaryl group, a substituent group α and a substituent group substituted with a group selected from the substituent group α and the substituent group β a heteroaryl group, an aralkyl group substituted with a group selected from β, or an aralkyl group substituted with a group selected from the substituent group α and the substituent group β, or R ⁷ and R ⁸ Together with the nitrogen atom to which they are attached form a heterocyclyl group or a heterocyclyl group substituted with a group selected from substituent group β. ) Represents a group having
⁴ is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from the substituent group α, an aryl group, an aryl group substituted with a group selected from the substituent group α and the substituent group β , A heteroaryl group, a heteroaryl group substituted with a group selected from substituent group α and substituent group β, an aralkyl group, an aralkyl group substituted with a group selected from substituent group α and substituent group β Or the formula: -O-
R ^{6 ′} (wherein, R ^{6 ′} is a lower alkyl group, a lower alkyl group substituted with a group selected from substituent group α, an aryl group, a group selected from substituent group α and a group selected from substituent group β. An aryl group, a heteroaryl group, a heteroaryl group, an aralkyl group, or a substituent group α and a substituent group β substituted with a group selected from the substituent group α and the substituent group β
An aralkyl group substituted with a group selected from ) -. In S-R ⁶ (wherein, R ^6, the a the same significance) or -NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ have the) as defined above. R ⁵ represents four groups or atoms selected from a hydrogen atom, a substituent group α, a substituent group β, and a substituent group γ.

Wherein R ⁴ is a group represented by the formula: —CO—CH ＝ CH—
When it is Hy (wherein, Hy has the same meaning as described above), R ¹ forms a single bond together with R ² . ]. [Substituent group α] a halogen atom, a hydroxyl group, a thiol group, a lower alkoxy group, a lower alkylthio group, a cyano group, a carboxyl group, a nitro group, a nitrile group, a formula —NR ^a R ^b (where R ^a and R ^b are , The same or different,
Represents a hydrogen atom, a lower alkyl group, or an acyl group, or R ^a and R ^b together with the nitrogen atom to which they are attached form a heterocyclyl group. [Substituent group β] Lower alkyl group; lower alkyl group substituted with a group selected from Substituent group α [Substituent γ] Aryl group; selected from Substituent group α and Substituent group β Aryl group substituted with an aralkyl group; substituent group α
And an aralkyl group substituted with a group selected from the substituent group β. Among the above, preferred compounds include (2) R ¹
Is a lower alkyl group, a lower alkyl group substituted with a group selected from substituent group α, a phenyl group, a phenyl group substituted with a group selected from substituent group α and substituent group β,
An aralkyl group, or an aralkyl group substituted with a group selected from the substituent group α and the substituent group β, or R ¹ is a compound which forms a single bond together with R ² , (3) R ¹ is a lower alkyl group, a lower alkyl group substituted with a group selected from the substituent group α, a benzyl group,
Or a compound in which R ¹ is a benzyl group substituted with a group selected from substituent group α and substituent group β, or R ¹ forms a single bond together with R ² , (4) R ¹ is
An alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a group selected from the substituent group α, or R ¹ is a single group together with R ^2. A compound forming a bond, (5) R ³ together with R ²
Represents an oxygen atom, or R ³ is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from substituent group α, or a formula: —O—R ⁶ , —S—R ⁶ Or a compound which is a group having —NR ⁷ R ⁸ , (6) R
³ represents an oxygen atom together with R ² , or
R ³ is a halogen atom, an alkyl group having 1 to 4 carbon atoms, a carbon atom having 1 carbon atom substituted with a group selected from the substituent group α.
From 4 to 4 alkyl groups, or the formula: -OR ⁶ or-
A compound which is a group having NR ⁷ R ⁸ , (7) R ³ together with R ² represents an oxygen atom, or R ³ is a chlorine atom, methyl, hydroxycarbonylmethyl, isopropyloxy, A compound that is benzyloxy, N′N-dimethylamino, or N-methylhomopiperazino;
(8) R ⁴ is a halogen atom, a phenyl group, a substituent group α
And a phenyl group or heteroaryl group substituted with a group selected from the substituent group β, a heteroaryl group substituted with a group selected from the substituent group α and the substituent group β, or a formula:
Examples thereof include a compound having a group having —OR ⁶ , —SR ^6, or —NR ⁷ R ⁸ , or a pharmacologically acceptable salt, ester, or other derivative thereof.

Another object of the present invention is to provide (9) the compound described in any one of the above (1) to (8), or a pharmaceutically acceptable salt, ester or other compound thereof. An object of the present invention is to provide a pharmaceutical composition containing a derivative as an active ingredient (particularly, a pharmaceutical composition for use as a cell adhesion inhibitor or a cytokine production inhibitor). Further, the present invention provides (10) a compound having the following general formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof for use as a cell adhesion inhibitor or a cytokine production inhibitor. Provide a pharmaceutical composition containing as:

[0013]

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[In the formula, R ¹ is selected from a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from the substituent group α, an aryl group, a substituent group α and a substituent group β. An aryl group, an aralkyl group, or an aralkyl group substituted with a group selected from the substituent group α and the substituent group β, or R ¹ is taken together with R ² a single bond to form, R ² is either to form a single bond together with R ^1, or, R ² represents an oxygen atom together with R ^3, together R ³ is a R ² Represents an oxygen atom, or R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from a substituent group α, an aryl group, a substituent group α And an aryl group, a heteroaryl group, and a substituent group substituted with a group selected from the substituent group β And substituted by a group selected from substituent group β heteroaryl group, an aralkyl group, substituted with a group selected from Substituent group α and Substituent group β aralkyl group, or the formula: -O-R ⁶ ( In the formula, R ⁶ is a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from a substituent group α, an aryl group, a group selected from a substituent group α and a group selected from a substituent group β. Aryl group,
A heteroaryl group, a heteroaryl group substituted with a group selected from substituent group α and substituent group β, an aralkyl group, or an aralkyl substituted with a group selected from substituent group α and substituent group β Represents a group. ), -SR ⁶ (wherein R ⁶ has the same meaning as described above), or -NR ⁷ R
⁸ (wherein, R ⁷ and R ⁸ are the same or different and are each a hydrogen atom, a lower alkyl group, an aryl group, an aryl group substituted with a group selected from a substituent group α and a substituent group β, Heteroaryl group, substituent group α and substituent group β
A heteroaryl group, an aralkyl group, or an aralkyl group substituted with a group selected from the substituent group α and the substituent group β, or R
⁷ and R ⁸ together with the nitrogen atom to which they are attached form a heterocyclyl group or a heterocyclyl group substituted by a group selected from substituent group β. Wherein one of R ⁴ and R ⁹ is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from a substituent group α, an aryl group, a substituent group α
And an aryl group substituted with a group selected from the substituent group β, a heteroaryl group, a heteroaryl group substituted with a group selected from the substituent group α and a group selected from the substituent group β, an aralkyl group, a substituent group α And an aralkyl group substituted with a group selected from substituent group β, or a formula: —O—R ⁶ (wherein R ⁶
Is as defined above. ), -SR ⁶ (wherein, R
⁶ has the same significance as described above. ) Or -NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ have the same meaning as described above), and the other group has the formula: -CO-CH = CH-Hy (where Hy is represented by the formula: Is a heteroaryl group; substituent group α, substituent group β
And a heteroaryl group substituted with a group selected from the substituent group γ. ), And R ⁵ represents four groups or atoms selected from a hydrogen atom, a substituent group α, a substituent group β, and a substituent group γ.

Wherein R ⁴ is a group represented by the formula: —CO—CH ＝ CH—
When it is Hy (wherein, Hy has the same meaning as described above), R ¹ forms a single bond together with R ² . ]. [Substituent group α] a halogen atom, a hydroxyl group, a thiol group, a lower alkoxy group, a lower alkylthio group, a cyano group, a carboxyl group, a nitro group, a nitrile group, a formula —NR ^a R ^b (where R ^a and R ^b are , The same or different,
Represents a hydrogen atom, a lower alkyl group, or an acyl group, or R ^a and R ^b together with the nitrogen atom to which they are attached form a heterocyclyl group. [Substituent group β] Lower alkyl group; lower alkyl group substituted with a group selected from Substituent group α [Substituent γ] Aryl group; selected from Substituent group α and Substituent group β Aryl group substituted with an aralkyl group; substituent group α
And an aralkyl group substituted with a group selected from the substituent group β. Among the pharmaceutical compositions described in (10), preferred are (11) a lower alkyl group in which R ¹ is substituted with a lower alkyl group, a group selected from a substituent group α,
An aryl group, an aryl group substituted with a group selected from the substituent group α and the substituent group β, an aralkyl group, or an aralkyl group substituted with a group selected from the substituent group α and the substituent group β Or R ¹ is a composition which forms a single bond together with R ² , (12) R ³ together with R ² represents an oxygen atom, or R ³ Is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from the substituent group α, an aryl group, an aryl group substituted with a group selected from the substituent group α and the substituent group β, A heteroaryl group, a heteroaryl group substituted with a group selected from substituent group α and substituent group β, an aralkyl group, an aralkyl group substituted with a group selected from substituent group α and substituent group β, or Formula: -OR ⁶ (wherein, R ⁶
Is as defined above. ), -SR ⁶ (wherein, R
⁶ has the same significance as described above. Or a group having —NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ have the same meanings as described above), and (13) one of R ⁴ and R ⁹ is a halogen atom, Lower alkyl group, lower alkyl group substituted with a group selected from substituent group α, aryl group, aryl group substituted with a group selected from substituent group α and substituent group β, heteroaryl group, substitution A heteroaryl group substituted with a group selected from the group α and the substituent group β, an aralkyl group, an aralkyl group substituted with a group selected from the group α and the group β, or a formula: —O -R ^{6 '} (wherein
R ^{6 ′} is a lower alkyl group, a lower alkyl group substituted with a group selected from a substituent group α, an aryl group, a substituent group α
And an aryl group substituted by a group selected from the substituent group β, a heteroaryl group, a heteroaryl group substituted by a group selected from the substituent group α and the substituent group β, an aralkyl group, or a substituent An aralkyl group substituted with a group selected from group α and substituent group β is shown. ), -SR
⁶ (wherein, R ⁶ is as defined above) or -N
R ⁷ R ⁸ (wherein, R ⁷ and R ⁸ are as defined above)
A group having the formula: —CO—CH ＝ CH—
And a group having a group having Hy (wherein, Hy has the same meaning as described above).

[0016] The compositions described in (9) to (13) are particularly preferably used for rheumatoid arthritis, osteoarthritis,
It is used for preventing or treating asthma and / or atopic dermatitis, or for suppressing cancer growth and / or metastasis. In the above general formulas (I) and (Ia),
R ¹ , R ³ , R ⁴ , R ⁶ , R ^{6 ′} , R ⁷ , R ⁸ , R ⁹ , R ^a , R ^b
And “lower alkyl group” in the definition of “substituent group β”, and “substituent group” in the definition of R ¹ , R ³ , R ⁴ , R ⁶ , R ^{6 ′} , R ⁹ and “substituent group β”. The lower alkyl group of the "lower alkyl group substituted with a group selected from α" is methyl, ethyl, propyl, isopropyl, n-
Butyl, isobutyl, s-butyl, tert-butyl, n-
Pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, A straight or branched chain having 1 to 6 carbon atoms such as 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl. Shows a branched alkyl group. Preferably, it is an alkyl group having 1 to 4 carbon atoms, and more preferably, methyl, ethyl, propyl or isopropyl. Most preferably, R ¹ is isopropyl.

Examples of the "halogen atom" in the definition of R ³ , R ⁴ , R ⁹ and the “substituent group α” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Atom, chlorine atom.

R ¹ , R ³ , R ⁴ , R ⁶ , R ^{6 ′} , R ⁷ , R ⁸ , R
^In the definition of ⁹ and `` substituent group γ '', the `` aryl group '' and the aryl group of `` aryl group substituted with a group selected from substituent group α and substituent group β '' include, for example, phenyl, Represents an aryl group having 6 to 14 carbon atoms such as naphthyl, phenanthryl and anthracenyl;
Preferably it is phenyl or naphthyl, most preferably phenyl.

The "aryl group" may be condensed with a cycloalkyl group having 3 to 10 carbon atoms, and examples of such a group include 5-indanyl.

R ¹ , R ³ , R ⁴ , R ⁶ , R ^{6 ′} , R ⁷ , R ⁸ , R
⁹ and “aryl group substituted with a group selected from substituent group α and substituent group β” in the definition of “substituent group γ”
Preferably represents an aryl group substituted with 1 to 4 groups selected from the substituent group α and the substituent group β, more preferably selected from the substituent group α and the substituent group β. Done 1
Or an aryl group substituted with 3 to 3 groups. Examples of suitable groups include 4-fluorophenyl, 3-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 3
Groups such as -trifluoromethylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-cyanophenyl and 4-nitrophenyl.

R ¹ , R ³ , R ⁴ , R ⁶ , R ^{6 ′} , R ⁷ , R ⁸ , R
^In the definition of ⁹ and the “substituent group γ”, the “aralkyl group” and the aralkyl group of the “aralkyl group substituted with a group selected from the substituent group α and the substituent group β” are the aforementioned “aryl group” Represents a group bonded to the above-mentioned "lower alkyl group", and examples of such a group include benzyl,
Indenylmethyl, phenanthrenylmethyl, anthracenylmethyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, piperonyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl,
2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl,
3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl,
4-naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4
-Naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl,
-Naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl and 6-naphthylhexyl. Of these, benzyl, phenanthrenylmethyl, anthracenylmethyl,
α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, 9-anthrylmethyl,
Piperonyl, 1-phenethyl, 2-phenethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-phenylbutyl, 2-phenylbutyl,
3-phenylbutyl and 4-phenylbutyl are preferred.

R ¹ , R ³ , R ⁴ , R ⁶ , R ^{6 ′} , R ⁷ , R ⁸ , R
⁹ and the `` aralkyl group substituted with a group selected from the substituent group α and the substituent group β '' in the definition of the `` substituent group γ '', preferably the aryl moiety is `` substituent group α '' and An aralkyl group substituted with 1 to 4 (more preferably 1 to 3) groups selected from “substituent group β”, and such a substituted aralkyl group includes, for example, 2- Fluorobenzyl, 3-fluorobenzyl,
4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3,5
-Difluorobenzyl, 2,5-difluorophenethyl, 2,6-difluorobenzyl, 2,4-difluorophenethyl, 3,5-dibromobenzyl, 2,5-dibromophenethyl, 2,6-dichlorobenzyl, 2,4-
Dichlorophenethyl, 2,3,6-trifluorobenzyl, 2,3,4-trifluorophenethyl, 3,4,5
-Trifluorobenzyl, 2,5,6-trifluorophenethyl, 2,4,6-trifluorobenzyl, 2,
3,6-tribromophenethyl, 2,3,4-tribromobenzyl, 3,4,5-tribromophenethyl, 2,
5,6-trichlorobenzyl, 2,4,6-trichlorophenethyl, 1-fluoro-2-naphthylmethyl, 2-
Fluoro-1-naphthylethyl, 3-fluoro-1-naphthylmethyl, 1-chloro-2-naphthylethyl, 2-
Chloro-1-naphthylmethyl, 3-bromo-1-naphthylethyl, 3,8-difluoro-1-naphthylmethyl,
2,3-difluoro-1-naphthylethyl, 4,8-difluoro-1-naphthylmethyl, 5,6-difluoro-
1-naphthylethyl, 3,8-dichloro-1-naphthylmethyl, 2,3-dichloro-1-naphthylethyl, 4,
8-dibromo-1-naphthylmethyl, 5,6-dibromo-1-naphthylethyl, 2,3,6-trifluoro-1
-Naphthylmethyl, 2,3,4-trifluoro-1-naphthylethyl, 3,4,5-trifluoro-1-naphthylmethyl, 4,5,6-trifluoro-1-naphthylethyl, 2,4 8-trifluoro-1-naphthylmethyl, bis (2-fluorophenyl) methyl, 3-fluorophenylphenylmethyl, bis (4-fluorophenyl) methyl, 4-fluorophenylphenylmethyl, bis (2-chlorophenyl) methyl, Bis (3-chlorophenyl) methyl, bis (4-chlorophenyl) methyl,
4-chlorophenylphenylmethyl, 2-bromophenylphenylmethyl, 3-bromophenylphenylmethyl, bis (4-bromophenyl) methyl, bis (3,5
-Difluorophenyl) methyl, bis (2,5-difluorophenyl) methyl, bis (2,6-difluorophenyl) methyl, 2,4-difluorophenylphenylmethyl, bis (3,5-dibromophenyl) methyl, 2,
An aralkyl group substituted with a halogen atom such as 5-dibromophenylphenylmethyl, 2,6-dichlorophenylphenylmethyl, bis (2,4-dichlorophenyl) methyl, bis (2,3,6-trifluorophenyl) methyl; 2-trifluoromethylbenzyl, 3-trifluoromethylphenethyl, 4-trifluoromethylbenzyl, 2-trichloromethylphenethyl, 3-dichloromethylbenzyl, 4-trichloromethylphenethyl, 2
-Tribromomethylbenzyl, 3-dibromomethylphenethyl, 4-dibromomethylbenzyl, 3,5-bistrifluoromethylphenethyl, 2,5-bistrifluoromethylbenzyl, 2,6-bistrifluoromethylphenethyl, 2,4-bistriethyl Fluoromethylbenzyl,
3,5-bistribromomethylphenethyl, 2,5-bisdibromomethylbenzyl, 2,6-bisdichloromethylmethylphenethyl, 2,4-bisdichloromethylbenzyl, 2,3,6-tristrifluoromethylphenethyl, 2 , 3,4-tristrifluoromethylbenzyl,
3,4,5-tristrifluoromethylphenethyl,
2,5,6-tristrifluoromethylbenzyl, 2,
4,6-tristrifluoromethylphenethyl, 2,
3,6-tristribromomethylbenzyl, 2,3,4
-Trisdibromomethylphenethyl, 3,4,5-tristribromomethylbenzyl, 2,5,6-trisdichloromethylmethylphenethyl, 2,4,6-trisdichloromethylbenzyl, 1-trifluoromethyl-2-naphthyl Ethyl, 2-trifluoromethyl-1-naphthylmethyl, 3-trifluoromethyl-1-naphthylethyl, 1-trichloromethyl-2-naphthylmethyl, 2-
Dichloromethyl-1-naphthylethyl, 3-tribromomethyl-1-naphthylmethyl, 3,8-bistrifluoromethyl-1-naphthylethyl, 2,3-bistrifluoromethyl-1-naphthylmethyl, 4,8-bistrimethyl Fluoromethyl-1-naphthylethyl, 5,6-bistrifluoromethyl-1-naphthylmethyl, 3,8-bistrichloromethyl-1-naphthylethyl, 2,3-bisdichloromethyl-1-naphthylmethyl, 4,8 -Bisdibromomethyl-1-naphthylethyl, 5,6-bistribromomethyl-1-naphthylmethyl, 2,3,6-tristrifluoromethyl-1-naphthylethyl, 2,3,4
-Tristrifluoromethyl-1-naphthylmethyl,
3,4,5-tristrifluoromethyl-1-naphthylethyl, 4,5,6-tristrifluoromethyl-1-
Naphthylmethyl, 2,4,8-tristrifluoromethyl-1-naphthylmethyl, bis (4-trifluoromethylphenyl) methyl, 4-trifluoromethylphenylphenylmethyl, bis (2-trichloromethylphenyl) methyl, bis (3-trichloromethylphenyl) methyl, bis (4-trichloromethylphenyl) methyl,
2-tribromomethylphenylphenylmethyl, 3-tribromomethylphenylphenylmethyl, bis (4-tribromomethylphenyl) methyl, bis (3,5-bistrifluoromethylphenyl) methyl, bis (2,5-
Bistrifluoromethylphenyl) methyl, bis (2
6-bistrifluoromethylphenyl) methyl, 2,4
-Bistrifluoromethylphenylphenylmethyl, bis (3,5-bistribromomethylphenyl) methyl,
2,5-bistribromomethylphenylphenylmethyl, 2,6-bistrichloromethylphenylphenylmethyl, bis (2,4-bistrichloromethylphenyl)
Aralkyl groups substituted with halogeno lower alkyl groups such as methyl and bis (2,3,6-tristrifluoromethylphenyl) methyl; 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methylphenethyl , 4-methylphenethyl, 2-ethylbenzyl, 3-
Propylphenethyl, 4-ethylbenzyl, 2-butylphenethyl, 3-pentylbenzyl, 4-pentylphenethyl, 3,5-dimethylbenzyl, 2,5-dimethylphenethyl, 2,6-dimethylbenzyl, 2,4-dimethylphenethyl , 3,5-dibutylbenzyl, 2,5-
Dipentylphenethyl, 2,6-dipropylbenzyl,
2,4-dipropylphenethyl, 2,3,6-trimethylbenzyl, 2,3,4-trimethylphenethyl, 3,
4,5-trimethylbenzyl, 2,4,6-trimethylbenzyl, 2,5,6-trimethylphenethyl, 2,
3,6-tributylphenethyl, 2,3,4-tripentylbenzyl, 3,4,5-tributylphenethyl,
2,5,6-tripropylbenzyl, 2,4,6-tripropylphenethyl, 1-methyl-2-naphthylmethyl, 2-methyl-1-naphthylethyl, 3-methyl-1
-Naphthylmethyl, 1-ethyl-2-naphthylethyl,
2-propyl-1-naphthylmethyl, 3-butyl-1-
Naphthylethyl, 3,8-dimethyl-1-naphthylmethyl, 2,3-dimethyl-1-naphthylethyl, 4,8-
Dimethyl-1-naphthylmethyl, 5,6-dimethyl-1
-Naphthylethyl, 3,8-diethyl-1-naphthylmethyl, 2,3-dipropyl-1-naphthylmethyl, 4,
8-dipentyl-1-naphthylethyl, 5,6-dibutyl-1-naphthylmethyl, 2,3,6-trimethyl-1
-Naphthylmethyl, 2,3,4-trimethyl-1-naphthylethyl, 3,4,5-trimethyl-1-naphthylmethyl, 4,5,6-trimethyl-1-naphthylmethyl,
2,4,8-trimethyl-1-naphthylmethyl, bis (2-methylphenyl) methyl, 3-methylphenylphenylmethyl, bis (4-methylphenyl) methyl,
-Methylphenylphenylmethyl, bis (2-ethylphenyl) methyl, bis (3-ethylphenyl) methyl,
Bis (4-ethylphenyl) methyl, 2-propylphenylphenylmethyl, 3-propylphenylphenylmethyl, bis (4-propylphenyl) methyl, bis (3,5-dimethylphenyl) methyl, bis (2,5-
Dimethylphenyl) methyl, bis (2,6-dimethylphenyl) methyl, 2,4-dimethylphenylphenylmethyl, bis (3,5-dipropylphenyl) methyl,
2,5-dipropylphenylphenylmethyl, 2,6-
Aralkyl groups substituted by lower alkyl groups such as diethylphenylphenylmethyl, bis (2,4-diethylphenyl) methyl, bis (2,3,6-trimethylphenyl) methyl; 2-methoxybenzyl, 3-methoxybenzyl 4-methoxybenzyl, 3-methoxyphenethyl, 2-ethoxyphenethyl, 3-propoxybenzyl, 4-ethoxyphenethyl, 2-butoxybenzyl,
3-pentoxyphenethyl, 4-pentoxybenzyl,
3,5-dimethoxyphenethyl, 2,5-dimethoxybenzyl, 2,6-dimethoxyphenethyl, 2,4-dimethoxybenzyl, 3,5-dibutoxyphenethyl, 2,
5-dipentoxybenzyl, 2,6-dipropoxyphenethyl, 2,4-dipropoxybenzyl, 2,3,6-
Trimethoxyphenethyl, 2,3,4-trimethoxybenzyl, 3,4,5-trimethoxyphenethyl, 2,
5,6-trimethoxybenzyl, 2,4,6-trimethoxyphenethyl, 2,3,6-tributoxybenzyl,
2,3,4-tripentoxyphenethyl, 3,4,5-
Tributoxybenzyl, 2,5,6-tripropoxyphenethyl, 2,4,6-tripropoxybenzyl, 1-
Methoxy-2-naphthylmethyl, 2-methoxy-1-naphthylmethyl, 3-methoxy-1-naphthylethyl, 1
-Ethoxy-2-naphthylmethyl, 2-propoxy-1
-Naphthylmethyl, 3-butoxy-1-naphthylethyl, 3,8-dimethoxy-1-naphthylmethyl, 2,3
-Dimethoxy-1-naphthylmethyl, 4,8-dimethoxy-1-naphthylethyl, 5,6-dimethoxy-1-naphthylmethyl, 3,8-diethoxy-1-naphthylmethyl, 2,3-dipropoxy-1-naphthyl Ethyl, 4,
8-dipentoxy-1-naphthylmethyl, 5,6-dibutoxy-1-naphthylmethyl, 2,3,6-trimethoxy-1-naphthylethyl, 2,3,4-trimethoxy-
1-naphthylmethyl, 3,4,5-trimethoxy-1-
Naphthylmethyl, 4,5,6-trimethoxy-1-naphthylethyl, 2,4,8-trimethoxy-1-naphthylmethyl, bis (2-methoxyphenyl) methyl, 3-methoxyphenylphenylmethyl, bis (4-methoxy Phenyl) methyl, 4-methoxyphenylphenylmethyl, bis (2-ethoxyphenyl) methyl, bis (3-
Ethoxyphenyl) methyl, bis (4-ethoxyphenyl) methyl, 2-propoxyphenylphenylmethyl,
3-propoxyphenylphenylmethyl, bis (4-propoxyphenyl) methyl, bis (3,5-dimethoxyphenyl) methyl, bis (2,5-dimethoxyphenyl) methyl, bis (2,6-dimethoxyphenyl) methyl, , 4-Dimethoxyphenylphenylmethyl, bis (3,5-dipropoxyphenyl) methyl, 2,5-dipropoxyphenylphenylmethyl, 2,6-diethoxyphenylphenylmethyl, bis (2,4-diethoxyphenyl) Aralkyl groups substituted by lower alkoxy groups such as methyl, bis (2,3,6-trimethoxyphenyl) methyl; 2-aminophenethyl, 3-aminobenzyl, 4-aminophenethyl, 3,5-diaminobenzyl, 2,5-diaminophenethyl, 2,6-diaminobenzyl, 2,4-di Minophenethyl, 2,3,6-triaminobenzyl, 2,3,4-triaminophenethyl, 3,4,5-triaminobenzyl, 2,5,6-triaminophenethyl, 2,4,6-triamino Aminobenzyl, 1-amino-2-naphthylmethyl, 2-amino-1
-Naphthylethyl, 3-amino-1-naphthylmethyl,
3,8-diamino-1-naphthylmethyl, 2,3-diamino-1-naphthylethyl, 4,8-diamino-1-naphthylmethyl, 5,6-diamino-1-naphthylmethyl, 2,3,6- Triamino-1-naphthylethyl,
2,3,4-triamino-1-naphthylmethyl, 3,
4,5-triamino-1-naphthylmethyl, 4,5,6
-Triamino-1-naphthylethyl, 2,4,8-triamino-1-naphthylmethyl, bis (2-aminophenyl) methyl, 3-aminophenylphenylmethyl, bis (4-aminophenyl) methyl, 4-aminophenyl Phenylmethyl, bis (3,5-diaminophenyl) methyl, bis (2,5-diaminophenyl) methyl, bis (2,6-diaminophenyl) methyl, 2,4-diaminophenylphenylmethyl, bis (2,3 Aralkyl groups substituted with amino groups such as 2,6-triaminophenyl) methyl; 2-nitrophenethyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-nitrophenethyl,
5-dinitrobenzyl, 2,5-dinitrophenethyl,
2,6-dinitrobenzyl, 2,4-dinitrophenethyl, 2,3,6-trinitrobenzyl, 2,3,4-trinitrophenethyl, 3,4,5-trinitrobenzyl, 2,5,6- Trinitrophenethyl, 2,4,6-
Trinitrobenzyl, 1-nitro-2-naphthylmethyl, 2-nitro-1-naphthylethyl, 3-nitro-1
-Naphthylmethyl, 3,8-dinitro-1-naphthylmethyl, 2,3-dinitro-1-naphthylethyl, 4,8
-Dinitro-1-naphthylmethyl, 5,6-dinitro-
1-naphthylmethyl, 2,3,6-trinitro-1-naphthylethyl, 2,3,4-trinitro-1-naphthylmethyl, 3,4,5-trinitro-1-naphthylmethyl, 4,5,6- Trinitro-1-naphthylethyl,
2,4,8-trinitro-1-naphthylmethyl, bis (2
-Nitrophenyl) methyl, 3-nitrophenylphenylmethyl, bis (4-nitrophenyl) methyl, 4-nitrophenylphenylmethyl, bis (3,5-dinitrophenyl) methyl, bis (2,5-dinitrophenyl)
Methyl, bis (2,6-dinitrophenyl) methyl,
2,4-dinitrophenylphenylmethyl, bis (2
Aralkyl groups substituted with nitro groups such as (3,6-trinitrophenyl) methyl; and 2-cyanophenethyl, 3-cyanobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, 4-cyanophenethyl, , 5-dicyanobenzyl, 2,5-dicyanophenethyl, 2,6-dicyanobenzyl, 2,4-dicyanophenethyl, 2,3,6-tricyanobenzyl, 2,
3,4-tricyanophenethyl, 3,4,5-tricyanobenzyl, 2,5,6-tricyanophenethyl, 2,
4,6-tricyanobenzyl, 1-cyano-2-naphthylmethyl, 3-cyano-1-naphthylmethyl, 3,8-
Dicyano-1-naphthylmethyl, 2,3-dicyano-1
-Naphthylethyl, 4,8-dicyano-1-naphthylmethyl, 5,6-dicyano-1-naphthylmethyl, 2,
3,6-tricyano-1-naphthylethyl, 2,3,4
-Tricyano-1-naphthylmethyl, 3,4,5-tricyano-1-naphthylmethyl, 4,5,6-tricyano-1-naphthylethyl, 2,4,8-tricyano-1-
Naphthylmethyl, bis (2-cyanophenyl) methyl,
3-cyanophenylphenylmethyl, bis (4-cyanophenyl) methyl, 4-cyanophenylphenylmethyl, bis (3,5-dicyanophenyl) methyl, bis (2,5-dicyanophenyl) methyl, bis (2,6 −
Examples thereof include an aralkyl group substituted with a cyano group such as dicyanophenyl) methyl, 2,4-dicyanophenylphenylmethyl, and bis (2,3,6-tricyanophenyl) methyl.

"Heteroaryl group" in the definition of R ³ , R ⁴ , R ⁶ , R ^{6 ′} , R ⁷ , R ⁸ , R ⁹ and Hy; R ³ , R ⁴ ,
A heteroaryl group of “heteroaryl group substituted with a group selected from substituent group α and substituent group β” in the definition of R ⁶ , R ^{6 ′} , R ⁷ , R ⁸ and R ⁹ ; The heteroaryl group of the "heteroaryl group substituted with a group selected from the substituent group α, the substituent group β and the substituent group γ" in the definition includes, for example, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl , Isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridonyl, N-oxidepyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, sulfur and oxygen atoms and / or
Or a 5- to 7-membered heteroaryl group containing 1 to 3 nitrogen atoms, preferably furyl, thienyl, pyrrolyl,
5- or 6-membered heteroaryl groups containing one or two sulfur, oxygen and / or nitrogen atoms, such as pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl is there.

Hy is more preferably at least one nitrogen atom such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridonyl, N-oxidepyridyl, pyridazinyl, pyrimidinyl, pyrazinyl. And further contains one sulfur atom, oxygen atom or nitrogen atom.
5 to 6-membered heteroaryl group which may contain 1 or 2 nitrogen atoms such as imidazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyrimidinyl. Membered aromatic heterocyclic group, particularly preferably imidazolyl, pyridyl, pyrazinyl or pyrimidinyl, and most preferably pyridyl.

The "heteroaryl group" may be condensed with another cyclic group (for example, an aryl group). Examples of such a group include indolyl, benzimidazolyl, quinolyl, isoquinolyl, and the like. Examples thereof include quinazolyl, benzopyrazinyl, benzopyridazinyl, benzoxazolyl, benzothiazolyl, benzofuranyl, and benzothienyl.

In the definition of R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ and R ⁹ , the “heteroaryl group substituted by a group selected from the substituent group α and the substituent group β” is preferably Represents a heteroaryl group substituted with 1 to 3 groups selected from the substituent group α and the substituent group β, more preferably 1 selected from the substituent group α and the substituent group β Or a heteroaryl group substituted with two or more groups. A preferred example is
1-methyl-2-imidazolyl, 5-methyl-2-pyridyl, 2-chloro-3-pyridyl, 2-chloro-4-pyridyl, 1-methyl-2-oxopyridin-3-yl,
Examples include groups such as 1-methyl-2-oxopyridin-5-yl and 2-hydroxy-3-pyridyl.

The “heteroaryl group substituted with a group selected from the substituent group α, the substituent group β, and the substituent group γ” in the definition of Hy is preferably a substituent group α, a substituent group β
And a heteroaryl group substituted with 1 to 3 groups selected from the substituent group γ, and more preferably 1 to 3 selected from the substituent group α, the substituent group β, and the substituent group γ. 2
Is a heteroaryl group substituted with two groups. Preferred examples include 1-methyl-2-imidazolyl, 5-methyl-2-pyridyl, 2-chloro-3-pyridyl, 2-chloro-4-pyridyl, 1-methyl-2-oxopyridine-
3-yl, 1-methyl-2-oxopyridin-5-yl, 2-hydroxy-3-pyridyl, 1-phenyl-2
Groups such as -imidazolyl.

A heterocyclyl group of a “heterocyclyl group formed by R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, and a heterocyclyl group substituted by a group selected from substituent group β”; Further, the "heterocyclyl group" formed by R ^a and R ^b together with the nitrogen atom to which they are bonded contains at least one nitrogen atom and further contains a sulfur atom, an oxygen atom or / and a nitrogen atom. A 3- to 7-membered non-aromatic heterocyclic group which may contain 1 to 3 and preferably contains 1 nitrogen atom and further contains 1 oxygen atom, sulfur atom or 1 nitrogen atom Good 5
To a 7-membered non-aromatic heterocyclic group, such as, for example, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, thiazolidinyl, piperidyl, tetrahydropyridyl, dihydropyridyl, piperazinyl, morpholinyl Thiomorpholinyl, homopiperidyl and homopiperazyl. Of these, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperidyl, and homopiperidyl are more preferred.

These groups include the above-mentioned “aryl group”,
"Substituted aryl group selected from substituent group α and substituent group β", "heteroaryl group" or "substituent group α
And a substituted heteroaryl group selected from substituent group β ''.
For example, 1,2,3,4-tetrahydroisoquinolinyl and the like can be mentioned.

The "heterocyclyl group substituted with a group selected from the substituent group β" includes, for example, N-methylhomopiperazyl.

The "lower alkoxy group" in the definition of "substituent group α" refers to a group in which an oxygen atom is bonded to the above "lower alkyl group". It is preferably a straight or branched chain alkoxy group having 1 to 4 carbon atoms, more preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, and particularly preferably methoxy, ethoxy, propoxy. It is.

The "lower alkylthio group" in the definition of the "substituent group α" refers to a group in which a sulfur atom is bonded to the above "lower alkyl group". Preferably, it is a linear or branched alkylthio group having 1 to 4 carbon atoms, more preferably, methylthio, ethylthio, propylthio, isopropylthio, butylthio, and particularly preferably, methylthio, ethylthio, propylthio. It is.

The "acyl group" in the definition of ^Ra and ^Rb includes formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl,
3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl,
Tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl,
Alkanoyl groups such as heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl, henicosanoyl, chloroacetyl, dichloroacetyl,
Trichloroacetyl, a halogenated alkylcarbonyl group such as trifluoroacetyl, a lower alkoxyalkylcarbonyl group such as methoxyacetyl, acryloyl, propioyl, methacryloyl, crotonoyl,
"Aliphatic acyl group" such as an unsaturated alkylcarbonyl group such as isocrotonoyl and (E) -2-methyl-2-butenoyl (preferably a lower aliphatic acyl group having 1 to 6 carbon atoms) Benzoyl, α-naphthoyl, β-
Arylcarbonyl groups such as naphthoyl; halogenated arylcarbonyl groups such as 2-bromobenzoyl, 4-chlorobenzoyl and 2,4,6-trifluorobenzoyl; 2,4,6-trimethylbenzoyl; Lower alkylated arylcarbonyl groups such as toluoyl,
A lower alkoxylated arylcarbonyl group such as 4-anisoyl, a nitrated arylcarbonyl group such as 4-nitrobenzoyl and 2-nitrobenzoyl, a lower alkoxycarbonylated aryl such as 2- (methoxycarbonyl) benzoyl; "Aromatic acyl groups" such as arylcarbonyl groups and arylated arylcarbonyl groups such as 4-phenylbenzoyl; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, s
Lower alkoxycarbonyl groups such as -butoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-
"Alkoxycarbonyl groups" such as lower alkoxycarbonyl groups substituted by halogen or tri-lower alkylsilyl groups such as trimethylsilylethoxycarbonyl can be mentioned. The term “ester or other derivative” refers to a compound obtained by modifying a functional group (eg, a hydroxyl group, a carboxyl group, an amino group, etc.) of a compound of the present invention with a protecting group or the like according to a conventional method.

For example, when the compound of the present invention has a hydroxyl group, the hydroxyl group is a “general protecting group” or a “protecting group that can be cleaved in vivo by a biological method such as hydrolysis”.
Thus, such an “ester or other derivative” can be obtained.

The term "general protecting group" as used herein means a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis. Propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl,
Dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,1
3-dimethyltetradecanoyl, heptadecanoyl, 1
5-methylhexadecanoyl, octadecanoyl, 1-
Alkanoyl groups such as methylheptadecanoyl, nonadecanoyl, eicosanoyl, henicosanoyl, chloroacetyl, dichloroacetyl, trichloroacetyl,
Halogenated alkylcarbonyl groups such as trifluoroacetyl, lower alkoxyalkylcarbonyl groups such as methoxyacetyl, acryloyl, propioyl,
Methacryloyl, crotonoyl, isocrotonoyl,
(E) an "aliphatic acyl group" such as an unsaturated alkylcarbonyl group such as 2-methyl-2-butenoyl (preferably a lower aliphatic acyl group having 1 to 6 carbon atoms); benzoyl Arylcarbonyl groups such as α-naphthoyl and β-naphthoyl; halogenated arylcarbonyl groups such as 2-bromobenzoyl, 4-chlorobenzoyl and 2,4,6-trifluorobenzoyl;
Lower alkylated arylcarbonyl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl, lower alkoxylated arylcarbonyl groups such as 4-anisoyl, 4-nitrobenzoyl and 2-nitrobenzoyl "Aromatics such as natural nitrated arylcarbonyl groups, lower alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, and arylated arylcarbonyl groups such as 4-phenylbenzoyl. Acyl group "; methoxycarbonyl, ethoxycarbonyl,
Lower alkoxycarbonyl groups such as propoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl;
An “alkoxycarbonyl group” such as a lower alkoxycarbonyl group substituted with a halogen or a tri-lower alkylsilyl group such as 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; tetrahydropyran-2-yl; Bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-
"Tetrahydropyranyl or tetrahydrothiopyranyl group" such as yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; like tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl "Tetrahydrofuranyl or tetrahydrothiofuranyl group"; tri-lower alkylsilyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, diphenyl Methylsilyl,
A "silyl group" such as a tri-lower alkylsilyl group substituted with one or two aryl groups such as diphenylbutylsilyl, diphenylisopropylsilyl, and phenyldiisopropylsilyl; methoxymethyl, 1,1-dimethyl-
1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, lower alkoxymethyl groups such as t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl, 2,2, "Alkoxymethyl groups" such as halogeno lower alkoxymethyl such as 2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl;
“Substituted ethyl groups” such as lower alkoxylated ethyl groups such as 1-ethoxyethyl and 1- (isopropoxy) ethyl, and halogenated ethyl groups such as 2,2,2-trichloroethyl; benzyl, α-naphthylmethyl , Β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-
Lower alkyl group substituted with 1 to 3 aryl groups such as naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethyl Benzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2
1 to 3 wherein the aryl ring is substituted by lower alkyl, lower alkoxy, nitro, halogen, cyano groups such as -nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, and 4-cyanobenzyl. An "aralkyl group" such as a lower alkyl group substituted with two aryl groups; an "alkenyloxycarbonyl group" such as vinyloxycarbonyl and allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, “Aralkyloxycarbonyl” in which the aryl ring may be substituted with one or two lower alkoxy or nitro groups such as 4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl Group ".

The term "protecting group which can be cleaved in vivo by a biological method such as hydrolysis" means that it is cleaved in a human body by a biological method such as hydrolysis to produce a free acid or a salt thereof. It refers to a protecting group, and whether such a derivative is administered by intravenous injection to experimental animals such as rats and mice,
It can be determined by examining the body fluid of the subsequent animal and detecting the base compound or a pharmacologically acceptable salt thereof. As such "a protecting group which can be cleaved in vivo by a biological method such as hydrolysis", preferably, formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl Pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pi Baroyloxyethyl, 1-
Valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-
Pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-
Pivaloyloxybutyl, 1-acetoxypentyl, 1
1-("lower aliphatic acyl", such as propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl
Oxy) “lower alkyl group”, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-
1-("cycloalkyl" carbonyloxy) "lower alkyl groups" such as cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl, 1-cyclohexylcarbonyloxybutyl 1- (acyloxy) "lower alkyl groups" such as 1-("aromatic acyl" oxy) "lower alkyl groups" such as benzoyloxymethyl;
Methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, Cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy)
Ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1-
(Isobutoxycarbonyloxy) ethyl, 1- (t-
Butoxycarbonyloxy) ethyl, 1- (pentyloxycarbonyloxy) ethyl, 1- (hexyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) propyl, 1- (cyclohexyl) Oxycarbonyloxy) propyl, 1- (cyclopentyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 1- (methoxycarbonyl Oxy) propyl, 1- (ethoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) propyl, 1- ( Butoxycarbonyl) propyl, 1- (isobutoxycarbonyl) propyl, 1- (pentyloxycarbonyl) propyl, 1- (hexyloxycarbonyl) propyl, 1- (methoxycarbonyloxy) butyl, 1-
(Ethoxycarbonyloxy) butyl, 1- (propoxycarbonyloxy) butyl, 1- (isopropoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (isobutoxycarbonyloxy)
Butyl, 1- (methoxycarbonyloxy) pentyl,
(Lower alkoxycarbonyloxy) alkyl groups such as 1- (ethoxycarbonyloxy) pentyl, 1- (methoxycarbonyloxy) hexyl, 1- (ethoxycarbonyloxy) hexyl; (5-phenyl-2-oxo-1,3 -Dioxolen-4-yl) methyl, [5
-(4-methylphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-methoxyphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5
-(4-chlorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, (2-oxo-1,3-
Dioxolen-4-yl) methyl, (5-methyl-2-
Oxo-1,3-dioxolen-4-yl) methyl,
(5-ethyl-2-oxo-1,3-dioxolen-4
-Yl) methyl, (5-propyl-2-oxo-1,3)
-Dioxolen-4-yl) methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-butyl-2-oxo-1,3-dioxolen-4-yl) methyl "Carbonyloxyalkyl group" such as oxodioxorenylmethyl group; "phthalidyl group" such as phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl: the above "lower aliphatic acyl group":
The above “aromatic acyl group”: “half ester salt residue of succinic acid”: “phosphate ester residue”: “ester forming residue such as amino acid”: carbamoyl group: substituted with one or two lower alkyl groups Carbamoyl group: and “1- (acyloxy) alkyloxycarbonyl group” such as pivaloyloxymethyloxycarbonyl, and preferably “carbonyloxyalkyl group”
It is. "Pharmacologically acceptable salt thereof" means that the compound (I) of the present invention or a pharmaceutically acceptable ester or other derivative thereof reacts with an acid when it has a basic group such as an amino group. When the compound has an acidic group such as a sulfonamide group, it can be converted into a salt by reacting with a base.

The salt based on a basic group is preferably
Inorganic acid salts such as hydrohalides such as hydrochloride, hydrobromide and hydroiodide, nitrates, perchlorates, sulfates and phosphates; methanesulfonate, trifluoromethanesulfonate Salt, lower alkane sulfonate such as ethane sulfonate, benzene sulfonate, aryl sulfonate such as p-toluene sulfonate, acetate, malate, fumarate, succinic acid Organic salts such as salts, citrates, ascorbates, tartrates, oxalates, and maleates; and amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate. Can be mentioned.

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

The compound of the present invention having the general formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof absorbs moisture by being left in the air or recrystallized. In some cases, adsorbed water or hydrates may form, and such hydrates are also included in the present invention.

The compound having the general formula (I) of the present invention may include a geometric isomer (cis, trans isomer), an optical isomer based on an asymmetric center in the molecule, and the like. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all these isomers and mixtures of these isomers in any proportion.

Specific examples of the compound having the general formula (I) of the present invention include the compounds shown in Tables 1 to 3 below.

[0042]

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Table 1 --------------------------------------------- -------------------- Compound number Hy R ³ R ⁴ R ⁵ -------------------- --------------------------------------------- 1-1 4- Py Me MeO H 1-2 4-Py Me MeO 6-Cl 1-3 4-Py Me MeO 6-Me 1-4 4-Py Me MeO 6-MeO 1-5 4-Py Me PhO H 1-6 4 -Py Me PhO 6-Cl 1-7 4-Py Me PhO 6-Me 1-8 4-Py Me PhO 6-MeO 1-9 4-Py Me 4-CN-PhO H 1-10 4-Py Me 4 -CN-PhO 6-Cl 1-11 4-Py Me 4-CN-PhO 6-Me 1-12 4-Py Me 4-CN-PhO 6-MeO 1-13 4-Py Me 4-MeO-PhO H 1-14 4-Py Me 4-MeO-PhO 6-Cl 1-15 4-Py Me 4-MeO-PhO 6-Me 1-16 4-Py Me 4-MeO-PhO 6-MeO 1-17 4- Py Me 3,4-diMeO-PhO H 1-18 4-Py Me 3,4-diMeO-PhO 6-Cl 1-19 4-Py Me 3,4-diMeO-PhO 6-Me 1-20 4-Py Me 3,4-diMeO-PhO 6-MeO 1-21 4-Py Me Ph H 1-22 4-Py Me Ph 6-Cl 1-23 4-Py Me Ph 6-Me 1-24 4-Py Me Ph 6-MeO 1-25 4-Py Me Pip H 1-26 4-Py Me Pip 6-Cl 1-27 4-Py Me Pip 6-Me 1-28 4-Py Me Pip 6-MeO 1-29 2- Cl-4-Py Me MeO H 1-30 2-Cl-4-Py Me MeO 6-Cl 1-31 2-Cl-4-Py Me MeO 6-Me 1-32 2-Cl-4-Py Me MeO 6-MeO 1-33 2-Cl-4-Py Me PhO H 1-34 2 -Cl-4-Py Me PhO 6-Cl 1-35 2-Cl-4-Py Me PhO 6-Me 1-36 2-Cl-4-Py Me PhO 6-MeO 1-37 2-Cl-4- Py Me 4-CN-PhO H 1-38 2-Cl-4-Py Me 4-CN-PhO 6-Cl 1-39 2-Cl-4-Py Me 4-CN-PhO 6-Me 1-40 2 -Cl-4-Py Me 4-CN-PhO 6-MeO 1-41 2-Cl-4-Py Me 4-MeO-PhO H 1-42 2-Cl-4-Py Me 4-MeO-PhO 6- Cl 1-43 2-Cl-4-Py Me 4-MeO-PhO 6-Me 1-44 2-Cl-4-Py Me 4-MeO-PhO 6-MeO 1-45 2-Cl-4-Py Me 3,4-diMeO-PhO H 1-46 2-Cl-4-Py Me 3,4-diMeO-PhO 6-Cl 1-47 2-Cl-4-Py Me 3,4-diMeO-PhO 6-Me 1-48 2-Cl-4-Py Me 3,4-diMeO-PhO 6-MeO 1-49 2-Cl-4-Py Me Ph H 1-50 2-Cl-4-Py Me Ph 6-Cl 1 -51 2-Cl-4-Py Me Ph 6-Me 1-52 2-Cl-4-Py Me Ph 6-MeO 1-53 2-Cl-4-Py Me Pip H 1-54 2-Cl-4 -Py Me Pip 6-Cl 1-55 2-Cl-4-Py Me Pip 6-Me 1-56 2-Cl-4-Py Me Pip 6-MeO 1-57 3-Py Me MeO H 1-58 3 -Py Me MeO 6-Cl 1-59 3-Py Me MeO 6-Me 1-60 3-Py Me MeO 6-MeO 1-61 3-Py Me PhO H 1-62 3-Py Me PhO 6-Cl 1 -63 3-Py Me PhO 6-Me 1-64 3-Py Me PhO 6-MeO 1-65 3-Py Me 4-CN-PhO H 1-66 3-Py Me 4-CN-PhO 6-Cl 1 -67 3-Py Me 4-CN-PhO 6-Me 1-68 3-Py Me 4-CN-PhO 6-MeO 1-69 3-Py Me 4-MeO-PhO H 1-70 3-Py M e 4-MeO-PhO 6-Cl 1-71 3-Py Me 4-MeO-PhO 6-Me 1-72 3-Py Me 4-MeO-PhO 6-MeO 1-73 3-Py Me 3,4- diMeO-PhO H 1-74 3-Py Me 3,4-diMeO-PhO 6-Cl 1-75 3-Py Me 3,4-diMeO-PhO 6-Me 1-76 3-Py Me 3,4-diMeO -PhO 6-MeO 1-77 3-Py Me Ph H 1-78 3-Py Me Ph 6-Cl 1-79 3-Py Me Ph 6-Me 1-80 3-Py Me Ph 6-MeO 1-81 3-Py Me Pip H 1-82 3-Py Me Pip 6-Cl 1-83 3-Py Me Pip 6-Me 1-84 3-Py Me Pip 6-MeO 1-85 2-Cl-3-Py Me MeO H 1-86 2-Cl-3-Py Me MeO 6-Cl 1-87 2-Cl-3-Py Me MeO 6-Me 1-88 2-Cl-3-Py Me MeO 6-MeO 1-89 2-Cl-3-Py Me PhO H 1-90 2-Cl-3-Py Me PhO 6-Cl 1-91 2-Cl-3-Py Me PhO 6-Me 1-92 2-Cl-3-Py Me PhO 6-MeO 1-93 2-Cl-3-Py Me 4-CN-PhO H 1-94 2-Cl-3-Py Me 4-CN-PhO 6-Cl 1-95 2-Cl-3- Py Me 4-CN-PhO 6-Me 1-96 2-Cl-3-Py Me 4-CN-PhO 6-MeO 1-97 2-Cl-3-Py Me 4-MeO-PhO H 1-98 2 -Cl-3-Py Me 4-MeO-PhO 6-Cl 1-99 2-Cl-3-Py Me 4-MeO-PhO 6-Me 1-100 2-Cl-3-Py Me 4-MeO-PhO 6-MeO 1-101 2-Cl-3-Py Me 3,4-diMeO-PhO H 1-102 2-Cl-3-Py Me 3,4-diMeO-PhO 6-Cl 1-103 2-Cl- 3-Py Me 3,4-diMeO-PhO 6-Me 1-104 2-Cl-3-Py Me 3,4-diMeO-PhO 6-MeO 1-105 2-Cl-3- Py Me Ph H 1-106 2-Cl-3-Py Me Ph 6-Cl 1-107 2-Cl-3-Py Me Ph 6-Me 1-108 2-Cl-3-Py Me Ph 6-MeO 1 -109 2-Cl-3-Py Me Pip H 1-110 2-Cl-3-Py Me Pip 6-Cl 1-111 2-Cl-3-Py Me Pip 6-Me 1-112 2-Cl-3 -Py Me Pip 6-MeO 1-113 2-OH-3-Py Me MeO H 1-114 2-OH-3-Py Me MeO 6-Cl 1-115 2-OH-3-Py Me MeO 6-Me 1-116 2-OH-3-Py Me MeO 6-MeO 1-117 2-OH-3-Py Me PhO H 1-118 2-OH-3-Py Me PhO 6-Cl 1-119 2-OH- 3-Py Me PhO 6-Me 1-120 2-OH-3-Py Me PhO 6-MeO 1-121 2-OH-3-Py Me 4-CN-PhO H 1-122 2-OH-3-Py Me 4-CN-PhO 6-Cl 1-123 2-OH-3-Py Me 4-CN-PhO 6-Me 1-124 2-OH-3-Py Me 4-CN-PhO 6-MeO 1-125 2-OH-3-Py Me 4-MeO-PhO H 1-126 2-OH-3-Py Me 4-MeO-PhO 6-Cl 1-127 2-OH-3-Py Me 4-MeO-PhO 6 -Me 1-128 2-OH-3-Py Me 4-MeO-PhO 6-MeO 1-129 2-OH-3-Py Me 3,4-diMeO-PhO H 1-130 2-OH-3-Py Me 3,4-diMeO-PhO 6-Cl 1-131 2-OH-3-Py Me 3,4-diMeO-PhO 6-Me 1-132 2-OH-3-Py Me 3,4-diMeO-PhO 6-MeO 1-133 2-OH-3-Py Me Ph H 1-134 2-OH-3-Py Me Ph 6-Cl 1-135 2-OH-3-Py Me Ph 6-Me 1-136 2 -OH-3-Py Me Ph 6-MeO 1-137 2-OH-3-Py Me Pip H 1-138 2-OH-3-Py Me Pip 6-Cl 1-13 9 2-OH-3-Py Me Pip 6-Me 1-140 2-OH-3-Py Me Pip 6-MeO 1-141 6-Me-2-Py Me MeO H 1-142 6-Me-2- Py Me MeO 6-Cl 1-143 6-Me-2-Py Me MeO 6-Me 1-144 6-Me-2-Py Me MeO 6-MeO 1-145 6-Me-2-Py Me PhO H 1 -146 6-Me-2-Py Me PhO 6-Cl 1-147 6-Me-2-Py Me PhO 6-Me 1-148 6-Me-2-Py Me PhO 6-MeO 1-149 6-Me -2-Py Me 4-CN-PhO H 1-150 6-Me-2-Py Me 4-CN-PhO 6-Cl 1-151 6-Me-2-Py Me 4-CN-PhO 6-Me 1 -152 6-Me-2-Py Me 4-CN-PhO 6-MeO 1-153 6-Me-2-Py Me 4-MeO-PhO H 1-154 6-Me-2-Py Me 4-MeO- PhO 6-Cl 1-155 6-Me-2-Py Me 4-MeO-PhO 6-Me 1-156 6-Me-2-Py Me 4-MeO-PhO 6-MeO 1-157 6-Me-2 -Py Me 3,4-diMeO-PhO H 1-158 6-Me-2-Py Me 3,4-diMeO-PhO 6-Cl 1-159 6-Me-2-Py Me 3,4-diMeO-PhO 6-Me 1-160 6-Me-2-Py Me 3,4-diMeO-PhO 6-MeO 1-161 6-Me-2-Py Me Ph H 1-162 6-Me-2-Py Me Ph 6 -Cl 1-163 6-Me-2-Py Me Ph 6-Me 1-164 6-Me-2-Py Me Ph 6-MeO 1-165 6-Me-2-Py Me Pip H 1-166 6- Me-2-Py Me Pip 6-Cl 1-167 6-Me-2-Py Me Pip 6-Me 1-168 6-Me-2-Py Me Pip 6-MeO 1-169 4-Pym Me MeO H 1 -170 4-Pym Me MeO 6-Cl 1-171 4-Pym Me MeO 6-Me 1-172 4-Pym Me MeO 6-MeO 1-1 73 4-Pym Me PhO H 1-174 4-Pym Me PhO 6-Cl 1-175 4-Pym Me PhO 6-Me 1-1176 4-Pym Me PhO 6-MeO 1-177 4-Pym Me 4-CN -PhO H 1-178 4-Pym Me 4-CN-PhO 6-Cl 1-179 4-Pym Me 4-CN-PhO 6-Me 1-180 4-Pym Me 4-CN-PhO 6-MeO 1- 181 4-Pym Me 4-MeO-PhO H 1-182 4-Pym Me 4-MeO-PhO 6-Cl 1-183 4-Pym Me 4-MeO-PhO 6-Me 1-184 4-Pym Me 4- MeO-PhO 6-MeO 1-185 4-Pym Me 3,4-diMeO-PhO H 1-186 4-Pym Me 3,4-diMeO-PhO 6-Cl 1-187 4-Pym Me 3,4-diMeO -PhO 6-Me 1-188 4-Pym Me 3,4-diMeO-PhO 6-MeO 1-189 4-Pym Me Ph H 1-190 4-Pym Me Ph 6-Cl 1-191 4-Pym Me Ph 6-Me 1-192 4-Pym Me Ph 6-MeO 1-193 4-Pym Me Pip H 1-194 4-Pym Me Pip 6-Cl 1-195 4-Pym Me Pip 6-Me 1-196 4- Pym Me Pip 6-MeO 1-197 2-Pyra Me MeO H 1-198 2-Pyra Me MeO 6-Cl 1-199 2-Pyra Me MeO 6-Me 1-200 2-Pyra Me MeO 6-MeO 1- 201 2-Pyra Me PhO H 1-202 2-Pyra Me PhO 6-Cl 1-203 2-Pyra Me PhO 6-Me 1-204 2-Pyra Me PhO 6-MeO 1-205 2-Pyra Me 4-CN -PhO H 1-206 2-Pyra Me 4-CN-PhO 6-Cl 1-207 2-Pyra Me 4-CN-PhO 6-Me 1-208 2-Pyra Me 4-CN-PhO 6-MeO 1- 209 2-Pyra Me 4-MeO-PhO H 1-210 2-Pyra Me 4 -MeO-PhO 6-Cl 1-211 2-Pyra Me 4-MeO-PhO 6-Me 1-212 2-Pyra Me 4-MeO-PhO 6-MeO 1-213 2-Pyra Me 3,4-diMeO- PhO H 1-214 2-Pyra Me 3,4-diMeO-PhO 6-Cl 1-215 2-Pyra Me 3,4-diMeO-PhO 6-Me 1-216 2-Pyra Me 3,4-diMeO-PhO 6-MeO 1-217 2-Pyra Me Ph H 1-218 2-Pyra Me Ph 6-Cl 1-219 2-Pyra Me Ph 6-Me 1-220 2-Pyra Me Ph 6-MeO 1-221 2- Pyra Me Pip H 1-222 2-Pyra Me Pip 6-Cl 1-223 2-Pyra Me Pip 6-Me 1-224 2-Pyra Me Pip 6-MeO 1-225 2-Py Me MeO H 1-226 2 -Py Me MeO 6-Cl 1-227 2-Py Me MeO 6-Me 1-228 2-Py Me MeO 6-MeO 1-229 2-Py Me PhO H 1-230 2-Py Me PhO 6-Cl 1 -231 2-Py Me PhO 6-Me 1-232 2-Py Me PhO 6-MeO 1-233 2-Py Me 4-CN-PhO H 1-234 2-Py Me 4-CN-PhO 6-Cl 1 -235 2-Py Me 4-CN-PhO 6-Me 1-236 2-Py Me 4-CN-PhO 6-MeO 1-237 2-Py Me 4-MeO-PhO H 1-238 2-Py Me 4 -MeO-PhO 6-Cl 1-239 2-Py Me 4-MeO-PhO 6-Me 1-240 2-Py Me 4-MeO-PhO 6-MeO 1-241 2-Py Me 3,4-diMeO- PhO H 1-242 2-Py Me 3,4-diMeO-PhO 6-Cl 1-243 2-Py Me 3,4-diMeO-PhO 6-Me 1-244 2-Py Me 3,4-diMeO-PhO 6-MeO 1-245 2-Py Me Ph H 1-246 2-Py Me Ph 6-Cl 1-247 2-Py Me Ph 6 -Me 1-248 2-Py Me Ph 6-MeO 1-249 2-Py Me Pip H 1-250 2-Py Me Pip 6-Cl 1-251 2-Py Me Pip 6-Me 1-252 2-Py Me Pip 6-MeO 1-253 1-Me-2-Oxo-3-Py Me PhO H 1-254 1-Me-2-Oxo-3-Py Me PhO 6-Cl 1-255 1-Me-2- Oxo-3-Py Me Ph H 1-256 1-Me-2-Oxo-3-Py Me Ph 6-Cl 1-257 N-Oxide-4-Py Me Ph H 1-258 N-Oxide-4-Py Me Ph 6-Cl 1-259 1-Me-2-Oxo-5-Py Me PhO H 1-260 1-Me-2-Oxo-5-Py Me PhO 6-Cl 1-261 1-Me-2- Imd Me Ph H 1-262 1-Me-2-Imd Me Ph 6-Cl 1-263 4-Py MeOCOCH2O PhO H 1-264 4-Py MeOCOCH2O PhO 6-Cl 1-265 4-Py MeOCOCH2O Ph H 1- 266 4-Py MeOCOCH2O Ph 6-Cl 1-267 4-Py iPrO PhO H 1-268 4-Py iPrO PhO 6-Cl 1-269 4-Py iPrO Ph H 1-270 4-Py iPrO Ph 6-Cl 1 -271 4-Py BnO PhO H 1-272 4-Py BnO PhO 6-Cl 1-273 4-Py BnO Ph H 1-274 4-Py BnO Ph 6-Cl 1-275 4-Py (Me) ₂ N PhO H 1-276 4-Py (Me) ₂ N PhO 6-Cl 1-277 4-Py (Me) ₂ N Ph H 1-278 4-Py (Me) ₂ N Ph 6-Cl 1-279 4- Py N-Me-Hpipa PhO H 1-280 4-Py N-Me-Hpipa
PhO 6-Cl 1-281 4-Py N-Me-Hpipa
Ph H 1-282 4-Py N-Me-Hpipa
Ph 6-Cl 1-283 4-Py Cl
PhOH 1-284 4-PyCl
PhO 6-Cl 1-285 4-Py Cl
Ph H 1-286 4-Py Cl
Ph 6-Cl 1-287 4-Py H
PhOH 1-288 4-Py H
PhO 6-Cl 1-289 4-Py H
Ph H 1-290 4-Py H
Ph 6-Cl 1-291 4-Py Me
4-Me-Ph H 1-292 4-Py Me
4-Me-Ph 6-Cl 1-293 4-Py Me
4-Py H 1-294 4-Py Me
4-Py 6-Cl 1-295 4-Py Me
Me H 1-296 4-Py Me
Me 6-Cl 1-297 4-Py Me
Bn H 1-298 4-Py Me
Bn 6-Cl 1-299 4-Py Me
ClH1-3004-PyMe
Cl 6-Cl 1-301 4-Py Me
H H 1-302 4-Py Me
H 6-Cl 1-303 4-Py Me
PhO 6,7-diMeO 1-304 4-Py Me
PhO 6-NO ₂ 1-305 4-Py Me
PhO 6-AcNH 1-306 4-Py Me
PhO 6-Ph 1-307 4-Py Me
Ph 6,7-diMeO 1-309 4-Py Me Ph 6-AcNH 1-310 4-Py Me Ph 6-Ph ---------------------- -------------------------------------------

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Table 2 --------------------------------------------- -------------------- Compound No.Hy R ¹ R ⁴ R ⁵ -------------------- --------------------------------------------- 2-1 4- Py Me Ph H 2-2 4-Py Me Ph 6-Cl 2-3 4-Py Me Ph 6-Me 2-4 4-Py Me Ph 6-MeO 2-5 4-Py Me Ph 6,7-diMeO 2-6 4-Py Me Ph 6-NO ₂ 2-7 4-Py Me Ph 6-AcNH 2-8 4-Py Me Ph 6-Ph 2-9 4-Py iPr Ph H 2-10 4-Py iPr Ph 6-Cl 2-11 4-Py iPr Ph 6-Me 2-12 4-Py iPr Ph 6-MeO 2-13 4-Py iPr Ph 6,7-diMeO 2-14 4-Py iPr Ph 6-NO ₂ 2-15 4-Py iPr Ph 6-AcNH 2-16 4-Py iPr Ph 6-Ph 2-17 4-Py iPr 4-CN-Ph H 2-18 4-Py iPr 4-CN-Ph 6- Cl 2-19 4-Py iPr 4-CN-Ph 6-Me 2-20 4-Py iPr 4-CN-Ph 6-MeO 2-21 4-Py iPr 4-CN-Ph 6,7-diMeO 2- 22 4-Py iPr 4-CN-Ph 6-NO ₂ 2-23 4-Py iPr 4-CN-Ph 6-AcNH 2-24 4-Py iPr 4-CN-Ph 6-Ph 2-25 4-Py iPr 4-Me-Ph H 2-26 4-Py iPr 4-Me-Ph 6-Cl 2-27 4-Py iPr 4-Me-Ph 6-Me 2-28 4-Py iPr 4-Me-Ph 6 -MeO 2-29 4-Py iPr 4-Me-Ph 6,7-diMeO 2-30 4-Py iPr 4-Me-Ph 6-NO ₂ 2-31 4-Py iPr 4-Me-Ph 6-AcNH 2-32 4-Py iPr 4-Me-Ph 6-Ph 2-33 4-Py iPr 4-MeO-Ph H 2-34 4-Py iPr 4-MeO-Ph 6-Cl 2-35 4-Py iPr 4-MeO-Ph 6-Me 2-36 4-Py iPr 4-MeO-Ph 6- MeO 2-37 4-Py iPr 4-MeO-Ph 6,7-diMeO 2-38 4-Py iPr 4-MeO-Ph 6-NO ₂ 2-39 4-Py iPr 4-MeO-Ph 6-AcNH 2 -40 4-Py iPr 4-MeO-Ph 6-Ph 2-41 4-Py Bn Ph H 2-42 4-Py Bn Ph 6-Cl 2-43 4-Py Bn Ph 6-Me 2-44 4- Py Bn Ph 6-MeO 2-45 4-Py Bn Ph 6,7-diMeO 2-46 4-Py Bn Ph 6-NO ₂ 2-47 4-Py Bn Ph 6-AcNH 2-48 4-Py Bn Ph 6-Ph 2-49 4-Py MeOCOCH2 Ph H 2-50 4-Py MeOCOCH2 Ph 6-Cl 2-51 4-Py MeOCOCH2 Ph 6-Me 2-52 4-Py MeOCOCH2 Ph 6-MeO 2-53 4- Py MeOCOCH2 Ph 6,7-diMeO 2-54 4-Py MeOCOCH2 Ph 6-NO ₂ 2-55 4-Py MeOCOCH2 Ph 6-AcNH 2-56 4-Py MeOCOCH2 Ph 6-Ph 2-57 4-Py H Ph H 2-58 4-Py H Ph 6-Cl 2-59 4-Py H Ph 6-Me 2-60 4-Py H Ph 6-MeO 2-61 4-Py H Ph 6,7-diMeO 2-62 4-Py H Ph 6-NO ₂ 2-63 4-Py H Ph 6-AcNH 2-64 4-Py H Ph 6-Ph 2-65 2-Cl-4-Py iPr Ph H 2-66 2-Cl -4-Py iPr Ph 6-Cl 2-67 2-Cl-4-Py iPr Ph 6-Me 2-68 2-Cl-4-Py iPr Ph 6-MeO 2-69 2-Cl-4-Py iPr Ph 6,7-diMeO 2-70 2-Cl-4-Py iPr Ph 6-NO ₂ 2-71 2-Cl-4-Py iPr Ph 6-AcNH 2-72 2-Cl-4-Py iPr Ph 6-Ph 2-73 3-Py iPr Ph H 2-74 3-Py iPr Ph 6-Cl 2-75 3-Py iPr Ph 6-Me 2-76 3-Py iPr Ph 6-MeO 2-77 3- Py iPr Ph 6,7-diMeO 2-78 3-Py iPr Ph 6-NO ₂ 2-79 3-Py iPr Ph 6-AcNH 2-80 3-Py iPr Ph 6-Ph 2-81 2-Cl-3 -Py iPr Ph H 2-82 2-Cl-3-Py iPr Ph 6-Cl 2-83 2-Cl-3-Py iPr Ph 6-Me 2-84 2-Cl-3-Py iPr Ph 6-MeO 2-85 2-Cl-3-Py iPr Ph 6,7-diMeO 2-86 2-Cl-3-Py iPr Ph 6-NO ₂ 2-87 2-Cl-3-Py iPr Ph 6-AcNH 2- 88 2-Cl-3-Py iPr Ph 6-Ph 2-89 2-OH-3-Py iPr Ph H 2-90 2-OH-3-Py iPr Ph 6-Cl 2-91 2-OH-3- Py iPr Ph 6-Me 2-92 2-OH-3-Py iPr Ph 6-MeO 2-93 2-OH-3-Py iPr Ph 6,7-diMeO 2-94 2-OH-3-Py iPr Ph 6-NO ₂ 2-95 2-OH-3-Py iPr Ph 6-AcNH 2-96 2-OH-3-Py iPr Ph 6-Ph 2-97 2-Me-5-Py iPr Ph H 2-98 2-Me-5-Py iPr Ph 6-Cl 2-99 2-Me-5-Py iPr Ph 6-Me 2-100 2-Me-5-Py iPr Ph 6-MeO 2-101 2-Me-5 -Py iPr Ph 6,7-diMeO 2-102 2-Me-5-Py iPr Ph 6-NO ₂ 2-103 2-Me-5-Py iPr Ph 6-AcNH 2-104 2-Me-5-Py iPr Ph 6-Ph 2-105 2-Py iPr Ph H 2-106 2-Py iPr Ph 6-Cl 2-107 2-Py iPr Ph 6-Me 2-108 2-Py iPr Ph 6-MeO 2-109 2-Py iPr Ph 6,7-diMeO 2-110 2-Py iPr Ph 6- NO ₂ 2-111 2-Py iPr Ph 6-AcNH 2-112 2-Py iPr Ph 6-Ph 2-113 4-Pym iPr Ph H 2-114 4-Pym iPr Ph 6-Cl 2-115 4-Pym iPr Ph 6-Me 2-116 4-Pym iPr Ph 6-MeO 2-117 4-Pym iPr Ph 6,7-diMeO 2-118 4-Pym iPr Ph 6-NO ₂ 2-119 4-Pym iPr Ph 6 -AcNH 2-120 4-Pym iPr Ph 6-Ph 2-121 2-Pyra iPr Ph H 2-122 2-Pyra iPr Ph 6-Cl 2-123 2-Pyra iPr Ph 6-Me 2-124 2-Pyra iPr Ph 6-MeO 2-125 2-Pyra iPr Ph 6,7-diMeO 2-126 2-Pyra iPr Ph 6-NO ₂ 2-127 2-Pyra iPr Ph 6-AcNH 2-128 2-Pyra iPr Ph 6 -Ph ------------------------------------------------ -----------------

[0046]

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Table 3 --------------------------------------------- -------------------- Compound number Hy R ³ R ⁹ R ⁵ -------------------- --------------------------------------------- 3-1 4- Py HHH 3-2 4-Py HH 6-Cl 3-3 4-Py HH 6-Me 3-4 4-Py HH 6-MeO 3-5 4-Py HH 6,7-diMeO 3-6 4-Py HH 6-NO ₂ 3-7 4-Py HH 6-AcNH 3-8 4-Py HH 6-Ph 3-9 4-Py H Cl H 3-10 4-Py H Cl 6-Cl 3-11 4- Py H Cl 6-Me 3-12 4-Py H Cl 6-MeO 3-13 4-Py H Cl 6,7-diMeO 3-14 4-Py H Cl 6-NO ₂ 3-15 4-Py H Cl 6-AcNH 3-16 4-Py H Cl 6-Ph 3-17 4-Py H Me H 3-18 4-Py H Me 6-Cl 3-19 4-Py H Me 6-Me 3-20 4- Py H Me 6-MeO 3-21 4-Py H Me 6,7-diMeO 3-22 4-Py H Me 6-NO ₂ 3-23 4-Py H Me 6-AcNH 3-24 4-Py H Me 6-Ph 3-25 4-Py H MeO H 3-26 4-Py H MeO 6-Cl 3-27 4-Py H MeO 6-Me 3-28 4-Py H MeO 6-MeO 3-29 4- Py H MeO 6,7-diMeO 3-30 4-Py H MeO 6-NO ₂ 3-31 4-Py H MeO 6-AcNH 3-32 4-Py H MeO 6-Ph 3-33 4-Py H Ph H 3-34 4-Py H Ph 6-Cl 3-35 4-Py H Ph 6-Me 3-36 4-Py H Ph 6-MeO 3-37 4-Py H Ph 6,7-diMeO 3-38 4-Py H Ph 6-NO ₂ 3-39 4-Py H Ph 6-AcNH 3-40 4-Py H Ph 6-Ph 3-41 4-Py Cl HH 3-42 4-Py Cl H 6-Cl 3-43 4-Py Cl H 6-Me 3-44 4-Py Cl H 6-MeO 3-45 4- Py Cl H 6,7-diMeO 3-46 4-Py Cl H 6-NO ₂ 3-47 4-Py Cl H 6-AcNH 3-48 4-Py Cl H 6-Ph 3-49 4-Py Me HH 3-50 4-Py Me H 6-Cl 3-51 4-Py Me H 6-Me 3-52 4-Py Me H 6-MeO 3-53 4-Py Me H 6,7-diMeO 3-54 4 -Py Me H 6-NO ₂ 3-55 4-Py Me H 6-AcNH 3-56 4-Py Me H 6-Ph 3-57 4-Py MeO HH 3-58 4-Py MeO H 6-Cl 3 -59 4-Py MeO H 6-Me 3-60 4-Py MeO H 6-MeO 3-61 4-Py MeO H 6,7-diMeO 3-62 4-Py MeO H 6-NO ₂ 3-63 4 -Py MeO H 6-AcNH 3-64 4-Py MeO H 6-Ph 3-65 4-Py Ph HH 3-66 4-Py Ph H 6-Cl 3-67 4-Py Ph H 6-Me 3- 68 4-Py Ph H 6-MeO 3-69 4-Py Ph H 6,7-diMeO 3-70 4-Py Ph H 6-NO ₂ 3-71 4-Py Ph H 6-AcNH 3-72 4- Py Ph H 6-Ph 3-73 2-Cl-4-Py H Ph H 3-74 2-Cl-4-Py Cl HH 3-75 2-Cl-4-Py Me HH 3-76 2-Cl- 4-Py MeO HH 3-77 2-Cl-4-Py Ph HH 3-78 3-Py H Ph H 3-79 3-Py Cl HH 3-80 3-Py Me HH 3-81 3-Py MeO HH 3-82 3-Py Ph HH 3-83 2-Cl-3-Py H Ph H 3-84 2-Cl-3-Py Cl HH 3-85 2-Cl-3-Py Me HH 3-86 2- Cl-3-Py MeO HH 3-87 2-Cl-3-Py Ph HH 3-88 2-OH-3-Py H Ph H 3- 89 2-OH-3-Py Cl HH 3-90 2-OH-3-Py Me HH 3-91 2-OH-3-Py MeO HH 3-92 2-OH-3-Py Ph HH 3-93 2 -Me-5-Py H Ph H 3-94 2-Me-5-Py Cl HH 3-95 2-Me-5-Py Me HH 3-96 2-Me-5-Py MeO HH 3-97 2- Me-5-Py Ph HH 3-98 2-Py H Ph H 3-99 2-Py Cl HH 3-100 2-Py Me HH 3-101 2-Py MeO HH 3-102 2-Py Ph HH 3- 103 4-Pym H Ph H 3-104 4-Pym Cl HH 3-105 4-Pym Me HH 3-106 4-Pym MeO HH 3-107 4-Pym Ph HH 3-108 2-Pyra H Ph H 3- 109 2-Pyra Cl HH 3-110 2-Pyra Me HH 3-111 2-Pyra MeO HH 3-112 2-Pyra Ph HH -------------------- --------------------------------------------- In the table, `` Ac '' Indicates acetyl, `` Bn '' indicates benzyl, `` Hpipa '' indicates homopiperazino, `` Imd '' indicates imidazolyl, `` Me '' indicates methyl, `` Ph '' indicates phenyl, and `` Pip '' Indicates piperidino, "iPr" indicates isopropyl, "Py" indicates pyridyl, "Pym"
Represents pyrimidinyl, and "Pyra" represents pyrazinyl.
In the above table, the preferred compounds are exemplified compound No. 1-
1 to 1-6, 1-9 to 1-37, 1-50 to 1-
52, 1-78, 1-89, 1-106, 1-134,
1-145 to 1-162, 1-173 to 1-19
0, 1-197 to 1-224, 1-229 to 1-2
44, 1-246, 1-253, 1-256, 1-25
8, 1-259, 1-262, 1-266, 1-27
0, 1-274, 1-278, 1-282, 1-28
6, 1-299 to 1-310, 2-1 to 2-48,
2-50, 2-57 to 2-63, 2-65 to 2-7
1, 2-97 to 2-103, 2-105 to 2-11
1, 2-113 to 2-119, 2-121 to 2-1
27, 3-1 to 3-72, and 3-103 to 3-
112, and more preferable compounds are exemplified compound numbers 1-1 to 1-6, 1-9 to 1-37, 1-50 to 1-52, 1-78, and 1-8.
9, 1-106, 1-134, 1-145 to 1-16
2, 1-173 to 1-190, 1-197 to 1-2
24, 1-229 to 1-244, 1-246, 1-2
53, 1-256, 1-258, 1-259, 1-26
2, 1-266, 1-270, 1-274, 1-27
8, 1-282, 1-286, 1-299 through 1-31
0, 2-1 to 2-7, 2-9 to 2-15, 2-17
To 2-23, 2-25 to 2-31, 2-33 to 2
-39, 2-41 to 2-47, 2-50, 2-57 to 2-63, 2-65 to 2-71, 2-97 to 2-
103, 2-105 to 2-111, 2-113 to 2
-119, 2-121 to 2-127, 3-1 to 3-
7, 3-9 to 3-15, 3-17 to 3-23, 3-
25 to 3-31, 3-33 to 3-39, 3-41 to 3-47, 3-49 to 3-55, 3-57 to 3-
63, 3-65 to 3-71, and 3-103 to 3
-112, and more preferable compounds are exemplified compound numbers 1-1, 1-5, 1-9,
1-10, 1-13, 1-17, 1-21, 1-24 to 1-26, 1-33, 1-50, 1-134, 1-1
45, 1-173, 1-218, 1-229, 1-25
6, 1-258, 1-262, 1-274, 1-29
9, 2-1, 2-2, 2-9 to 2-15, 2-42,
2-60, 3-33, 3-41, 3-49, 3-57,
And 3-65 compounds.

[0048]

BEST MODE FOR CARRYING OUT THE INVENTION The compound having the general formula (I) of the present invention can be produced according to the following <Method A> or <Method B>. <Method A> In the method A, R ⁹ in the general formula (I) is a compound represented by the formula: —CO—
This is a method for producing a compound which is a group having CH = CH-Hy (wherein, Hy has the same meaning as described above).

[0049]

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Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and H
y has the same meaning as described above. The first step is a step of producing the compound (Ia) of the present invention by reacting the compound (1) with the heteroaromatic aldehyde (2) in a solvent in the presence of a base in the presence of a catalyst. It is.

The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Preferably, the solvent is methanol, ethanol, n-propanol or n-propanol. Isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,
Alcohols such as diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve
Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; organic solvents such as aromatic hydrocarbons such as benzene, toluene and xylene: or And a mixed solvent of water and an organic solvent. More preferably, methanol, ethanol, tetrahydrofuran, toluene or water and a mixed solvent thereof are used.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but preferably, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and lithium bicarbonate; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; sodium hydroxide, potassium hydroxide, and hydroxide Alkali metal hydroxides such as lithium; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t -Alkali metal alkoxides such as butoxide, lithium methoxide ; Sodium methyl mercaptan, mercaptan alkali metals, such as ethyl mercaptan sodium; N- methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N
-Methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (dimethylamino) pyridine, 2,
6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5
-Ene (DBN), 1,4-diazabicyclo [2.2.
2] Organic bases such as octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide Organometallic bases can be mentioned. More preferably, sodium carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, triethylamine, diisopropylethylamine, pyridine, 4- (dimethylamino) pyridine or 1,4-diazabicyclo [2.2.
2] Octane (DABCO) is used.

As the catalyst, an interlayer transfer catalyst is preferably used, and more preferably, an ammonium halide salt such as tetrabutylammonium bromide or cetyltrimethylammonium bromide is used.

The reaction is carried out at a temperature of from -20 ° C to 100 ° C, preferably from 0 ° C to 80 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually, it is 5 minutes to 2 days, preferably 15 minutes to 3 hours. <Method B> In method B, R ⁴ in the general formula (I) is a compound represented by the formula: —CO—
This is a method for producing a compound which is a group having CH = CH-Hy (wherein, Hy has the same meaning as described above).

[0056]

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(Wherein R ³ , R ⁵ , R ⁹ and Hy have the same meanings as described above.) In the second step, quinoline derivative (3) and pyruvic acid are reacted
This is a step of producing an acetylquinoline derivative (4) by reacting in a solvent in the presence of a silver salt, a persulfate and an acid.

The solvent used is preferably water,
Or a mixed solvent of halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene and water. More preferably, water or a mixed solvent of methylene chloride and water is used.

The silver salt used includes, for example, silver nitrate and silver acetate.

Examples of the persulfate used include ammonium persulfate and potassium persulfate.

The acid used is preferably hydrochloric acid,
Inorganic acids such as hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, nitric acid; or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid; Such organic acids can be mentioned. More preferably, hydrochloric acid, sulfuric acid, nitric acid or trifluoroacetic acid is used.

The reaction is carried out at a temperature of 0 ° C. to 150 ° C., preferably 5 ° C. to 100 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually, it is 5 minutes to 2 days, preferably 30 minutes to 5 hours. In the third step, the acetylquinoline derivative (4) and the heteroaromatic aldehyde (2) are
By reacting in the presence of a catalyst in the presence of a base,
This is a step for producing the compound (Ib) of the present invention, and this step is performed according to the method of the first step. Above <Method A>
Compound (1), compound (2) and compound (3), which are the starting materials in <Method B>, are known or can be produced from known compounds according to known methods. In particular, compound (1) can be produced according to the following <Method C> or <Method D>. <Method C> The method C is a compound (1) in which R ⁴ is substituted with a hydrogen atom, an aryl group, a group selected from a substituent group α and a group selected from a substituent group β, a heteroaryl group,
Alternatively, this is a method for producing a compound which is a heteroaryl group substituted with a group selected from the substituent group α and the substituent group β.

[0064]

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(Wherein R ^1a is selected from a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from the substituent group α, an aryl group, a substituent group α and a substituent group β. An aryl group substituted with a group, an aralkyl group, or an aralkyl group substituted with a group selected from a substituent group α and a substituent group β, R ^3a represents a hydrogen atom, a lower alkyl group, Lower alkyl group and aryl group substituted with a group selected from group α, substituent group α and substituent group β
An aryl group substituted with a group selected from the group consisting of a heteroaryl group, a heteroaryl group substituted with a group selected from a substituent group α and a substituent group β, an aralkyl group, or a substituent group α and a substituent An aralkyl group substituted with a group selected from the group β, wherein R ^3b is a group represented by the formula: —O—R ⁶ (wherein
R ⁶ has the same meaning as described above. ), -SR ⁶ (wherein R ⁶
Is as defined above. ) Or -NR ⁷ R ⁸ (wherein
R ⁷ and R ⁸ are as defined above. And R ^4a represents a hydrogen atom, an aryl group, an aryl group substituted with a group selected from substituent group α and a group selected from substituent group β, a heteroaryl group, or a substituent group α and a substituent A heteroaryl group substituted with a group selected from the group β,
Is a halogen atom (preferably a chlorine atom or a bromine atom)
And Y represents a leaving group.

The “leaving group” in the definition of Y is usually
Represents a group leaving as a nucleophilic residue, for example, a halogen atom such as fluorine, chlorine, bromine or iodine; a trihalogenomethyloxy group such as trichloromethoxy; a lower alkane such as methanesulfonyloxy or ethanesulfonyloxy A sulfonyloxy group; a halogeno lower alkanesulfonyloxy group such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; and an arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy and p-nitrobenzenesulfonyloxy. be able to. Preferably, a halogen atom, a lower alkanesulfonyloxy group,
An arylsulfonyloxy group, particularly preferably a halogen atom, methanesulfonyloxy or p-toluenesulfonyloxy. The fourth step comprises subjecting the aniline derivative (5) and the 1,3-diketo compound (6) to a known method (for example, a Friedlander reaction (J. Heterocy) in the presence or absence of a solvent and in the presence of an acid catalyst.
cle Chem. , 4, 565, 1967, etc.) to produce the compound (7).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol,
Alcohols such as glycerin, octanol, cyclohexanol and methyl cellosolve; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; benzene, toluene and xylene; Organic solvents such as aromatic hydrocarbons: or a mixed solvent of these organic solvents and water.

The acid catalyst is not particularly limited as long as it is used as an acid catalyst in a usual reaction, but is preferably an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid or the like. Acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-
Organic acids such as toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid can be mentioned.

The reaction is carried out at a temperature of 0 ° C. to 200 ° C., preferably 50 ° C. to 150 ° C.

The reaction time mainly depends on the reaction temperature, starting compound,
Depending on the type of reaction reagent or solvent used,
Usually, it is 5 minutes to 2 days, preferably 30 minutes to 5 hours.

When a compound in which R ^3a is a hydrogen atom is produced, such a compound is produced by performing a reaction using acetylacetaldehyde dimethyl acetal instead of the diketo compound (6) in this step. can do. The fifth step is a step of producing the compound (9) by reacting the aniline derivative (5) with the compound (8) in a solvent in the presence of a base.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Hydrogens; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; diethyl ether, diisopropyl ether; Ethers such as tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotrione Ami It can be mentioned amides such as. Particularly preferably, toluene, methylene chloride, dichloroethane, tetrahydrofuran or N, N-
Dimethylformamide is used.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction. Preferably, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and lithium bicarbonate; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; sodium hydroxide, potassium hydroxide, and hydroxide Alkali metal hydroxides such as lithium; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t -Alkali metal alkoxides such as butoxide, lithium methoxide ; Sodium methyl mercaptan, mercaptan alkali metals, such as ethyl mercaptan sodium; N- methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, diisobutyl ethylamine,
Dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (dimethylamino) pyridine, 2,6-di (t-butyl) -4
-Methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-
Diazabicyclo [2.2.2] octane (DABC
O) organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or organic metal bases such as butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide Can be mentioned. Particularly preferably, lithium hydride, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisobutylethylamine, pyridine, 4- (dimethylamino) pyridine, lithium diisopropylamide, lithium bis (trimethylsilyl) amide Is used.

The reaction is carried out at a temperature of from -20 ° C to 150 ° C, preferably from 0 ° C to 100 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually, it is 5 minutes to 10 hours, preferably 15 minutes to 5 hours. The sixth step is a step of reacting the compound (9) with ethyl acetoacetate to produce a 3-acetylquinolone compound (10).

The reaction is carried out at a temperature of 0 ° C. to 200 ° C., preferably 50 ° C. to 150 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually, it is 5 minutes to 2 days, preferably 30 minutes to 3 hours. The seventh step is a step of producing a 3-acetyl-2-hydroxyquinoline compound (11) by reacting the aniline derivative (5) with ethyl acetoacetate, and is carried out according to the method described in the sixth step. You. The eighth step is a step of reacting the 3-acetyl-2-hydroxyquinoline compound (11) with the compound (8) in a solvent in the presence of a base to produce a compound (10). It is carried out according to the method described in the step. The ninth step is
3-acetyl-2-hydroxyquinoline compound (11)
Is reacted with a halogenating agent in the presence or absence of a solvent to give a 3-acetyl-2-haloquinoline compound (12)
This is the step of manufacturing.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Preferably, aromatic solvents such as benzene, toluene and xylene; Methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,
Halogenated hydrocarbons such as dichlorobenzene can be mentioned. Particularly preferably, benzene, toluene,
Xylene, methylene chloride or chloroform is used.

The halogenating agent to be used is not particularly limited as long as it is used as a halogenating agent in a usual reaction, but is preferably a thionyl halide such as thionyl chloride, thionyl bromide or thionyl iodide. Sulfuryl chlorides such as sulfuryl chloride, sulfuryl bromide, and sulfuryl iodide; phosphorus trihalides such as phosphorus trichloride, phosphorus tribromide, and phosphorus triiodide; phosphorus pentachloride, phosphorus pentabromide, Phosphorus pentahalides such as phosphorus iodide or phosphorus oxychloride, phosphorus oxybromide, phosphorus oxyhalide such as phosphorus oxyiodide can be mentioned, and particularly preferably,
Thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride or phosphorus oxychloride is used.

The reaction is carried out at a temperature of 0 ° C. to 200 ° C., preferably 50 ° C. to 150 ° C.

The reaction time mainly depends on the reaction temperature, starting compound,
Depending on the type of reaction reagent or solvent used,
Usually, it is 5 minutes to 2 days, preferably 30 minutes to 3 hours.

The compound (12) can also be produced by halogenating the compound (7) wherein R ^3a is a hydrogen atom according to this step. The tenth step is 3-acetyl-
The 2-haloquinoline compound (12) is reacted with the compound (13) in a solvent in the presence of a base to give the compound (1)
This is a step of manufacturing 4), which is performed according to the method described in the fifth step. In an eleventh step, the 3-acetyl-2-hydroxyquinoline compound (11) is reacted with the compound (15) in a solvent in the presence of a base to give a compound (1).
6), which is performed according to the method described in the fifth step. <Method D> In the method D, R ⁴ is a compound represented by the formula:
—O—R ⁶ (wherein, R ⁶ is as defined above), —S
—R ⁶ (wherein, R ⁶ is as defined above) or —
NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ are as defined above)
This is a method for producing a compound which is a group having

[0083]

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(Wherein, R ^3a and R ⁵ have the same meaning as described above, and R ^4b has the formula: —O—R ⁶ (where R ⁶ has the same meaning as described above), and —S—. A group having R ⁶ (wherein R ⁶ has the same meaning as described above) or —NR ⁷ R ⁸ (where R ⁷ and R ⁸ have the same meanings as above). Is a step of producing a compound (18) by condensing an ethyl anthranilate derivative (17) with a 1,3-diketo compound (6) in the presence or absence of a solvent in the presence of an acid catalyst. It is.

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Preferably, aromatic solvents such as benzene, toluene and xylene are used. Can be mentioned.

The acid catalyst is not particularly limited as long as it can be used as an acid catalyst in a usual reaction, but is preferably an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid. Organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid can be exemplified. More preferably, hydrochloric acid, sulfuric acid, benzenesulfonic acid, p-toluenesulfonic acid or camphorsulfonic acid is used.

The reaction is carried out at a temperature of 0 ° C. to 200 ° C., preferably 50 ° C. to 150 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually, it is 5 minutes to 2 days, preferably 30 minutes to 5 hours. The thirteenth step is to treat compound (18) with a base in a solvent to give 3-acetyl-4-.
This is a step of producing a hydroxyquinoline derivative (19).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,
Alcohols such as diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve
Can be mentioned. Particularly preferably, methanol or ethanol is used.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but preferably, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and lithium bicarbonate; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; sodium hydroxide, potassium hydroxide, and hydroxide Alkali metal hydroxides such as lithium; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t -Alkali metal alkoxides such as butoxide, lithium methoxide ; Sodium methyl mercaptan, mercaptan alkali metals, such as ethyl mercaptan sodium; N- methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, diisobutyl ethylamine,
Dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (dimethylamino) pyridine, 2,6-di (t-butyl) -4
-Methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-
Diazabicyclo [2.2.2] octane (DABC
O) organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or organic metal bases such as butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide Can be mentioned. Particularly preferably, potassium carbonate,
Sodium carbonate, sodium hydroxide, potassium sodium hydroxide methoxide, potassium t-butoxide, triethylamine or DBU is used.

The reaction is carried out at a temperature of 0 ° C. to 200 ° C., preferably 20 ° C. to 150 ° C.

The reaction time mainly depends on the reaction temperature, starting compound,
Depending on the type of reaction reagent or solvent used,
Usually, it is 5 minutes to 2 days, preferably 30 minutes to 10 hours. The fourteenth step is 3-acetyl-4-
A method of producing a 3-acetyl-4-haloquinoline compound (20) by reacting a hydroxyquinoline derivative (19) with a halogenating agent in the presence or absence of a solvent, and the method according to the ninth step. It is carried out according to. Fifteenth
In the step, a 3-acetyl-4-haloquinoline compound (2
0) is reacted with compound (21) in a solvent in the presence of a base to produce compound (21).
It is carried out according to the method described in the step. Compounds (5), (6), (8) and (1) used as starting materials in the above-mentioned <Method C> and <Method D>
5) is known or can be easily synthesized from a known compound. For example, when compound (5) is produced, Org. Chem. , 27,3781,19
62; Synthesis, 677, 1980. After completion of each of the above reactions, the target compound is collected from the reaction mixture according to a conventional method.

For example, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. An organic layer containing the compound is separated, dried over anhydrous magnesium sulfate or the like, and then obtained by distilling off the solvent.

If necessary, the obtained target compound can be obtained by a conventional method.
For example, recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, for example, adsorption column chromatography using a carrier such as silica gel, alumina, and magnesium-silica gel type florisil; Sephadex LH-20 (manufactured by Pharmacia), Amberlite XAD-11 (manufactured by Rohm and Haas),
A method using a synthetic adsorbent such as distribution column chromatography using a carrier such as Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation), a method using ion exchange chromatography,
Alternatively, separation and purification can be carried out by appropriately combining a normal phase / reverse phase column chromatography method with silica gel or alkylated silica gel (preferably high performance liquid chromatography) and eluting with a suitable eluent. . The compound of the present invention having the general formula (I) exhibits excellent cell adhesion inhibitory activity and cytokine production inhibitory activity, and is therefore effective as a medicine. Such drugs include, for example, rheumatoid arthritis (RA), osteoarthritis (OA), asthma, atopic dermatitis, reperfusion injury of myocardium and brain, ulcerative enteritis, Crohn's disease, hepatic / nephritis, etc. Prophylactic or therapeutic agents for autoimmune diseases or inflammatory diseases, or medicaments for suppressing cancer growth and / or metastasis.

The administration form of the compound of the present invention having the general formula (I), a pharmaceutically acceptable salt or derivative thereof includes:
For example, oral administration such as tablets, capsules, granules, powders or syrups, or parenteral administration such as injections or suppositories can be mentioned. These preparations are produced by known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, diluents and the like.

Here, as the excipient, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; corn starch, potato starch, α-
Starch derivatives such as starch, dextrin, carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally cross-linked sodium carboxymethylcellulose; gum arabic; dextran; Organic excipients such as pullulan; and silicate derivatives such as light silicic anhydride, synthetic aluminum silicate, magnesium metasilicate aluminate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; And inorganic excipients such as sulfates.

Examples of the lubricant include metal stearates such as stearic acid, calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as veegum and gay wax; boric acid: adipic acid; Sodium sulfate, DL-leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate, magnesium lauryl sulfate; silicic acids such as silicic anhydride, silicic acid hydrate; And the above-mentioned starch derivatives.

Examples of the binder include polyvinylpyrrolidone, macrogol and the same compounds as the above-mentioned excipients.

Examples of the disintegrant include the same compounds as the above-mentioned excipients and chemically modified starch and cellulose such as croscarmellose sodium, sodium carboxymethyl starch and crosslinked polyvinylpyrrolidone.

As the stabilizer, for example, methyl paraben,
Paraoxybenzoic acid esters such as propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. be able to.

Examples of the flavoring agent include, for example, commonly used sweeteners, sour agents, flavors and the like.

The amount of the compound having the general formula (I) of the present invention, or a pharmacologically acceptable salt or derivative thereof, varies depending on the condition, age, administration method and the like. 0.1m as a minimum per day
g (preferably 0.5 mg), with an upper limit of 2000 m
It is desirable to administer g (preferably 500 mg) once or in several divided doses according to the symptoms. In the case of intravenous administration, the lower limit is 0.1 per day for adults.
01 mg (preferably 0.05 mg), with an upper limit of 2 mg
It is desirable to administer 00 mg (preferably 50 mg) once or in several divided doses according to the symptoms. Hereinafter, the present invention will be described in more detail with reference to Examples, Preparation Examples, and Test Examples, but the present invention is not limited thereto.

[0103]

【Example】

[0104]

Example 1 1- (6-Chloro-2-methyl-4-phenylquinolin-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 1-22) (a) 3-acetyl-6 -Chloro-2-methyl-4-phenylquinoline 2-amino-5-chlorobenzophenone (11.67
g, 50.4 mmol) in acetic acid (50 mL) was added with acetylacetone (5.4 ml, 52.3 mmol) and concentrated sulfuric acid (0.5 mL), and reacted under heating and reflux for 3 hours. The reaction mixture was added to a mixed solution of concentrated aqueous ammonia (70 mL) and iced water (200 mL) with stirring, whereby a solid precipitated. After filtration, washing with water and drying, the title compound (1
(4.77 g, 99%) as a white solid. m. p. 159.0-160.0 ^° C (H ₂ O) High resolution mass spectrum: Found [M] ⁺ 295.0773 Calculated C ₁₈ H ₁₄ ClNO 295.0764 IR (KBr) / νcm ⁻¹ : 3052 1702 ¹ H NMR (270 MHz, CDCl ₃ ) δ: 8.01
(1H, d, J = 8.9 Hz), 7.65 (1H, d
d, J = 8.9, 2.3 Hz), 7.58-7.51
(4H, m), 7.38-7.31 (2H, m), 2.
68 (3H, s), 2.00 (3H, s). (B) 1- (6-chloro-2-methyl-4-phenylquinolin-3-yl) -3- (4-pyridyl) propenone 3-acetyl-6-chloro-2-methyl-4-phenylquinoline (3 0.34 g (11.3 mmol) in methanol (500 mL) at room temperature was added with 28% sodium methoxide methanol solution (5 mL, 30.6 mmol) and pyridine-4-aldehyde (2 mL, 20.4 mmol).
l) was added. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, water and saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane). : Elution with ethyl acetate = 1: 1), washed with isopropyl ether and then the title compound (2.72).
g, 63%) as a white solid. m. p. : 124.0-125.0 ^° C (iPr ₂ O) High-resolution mass spectrum: Observed value [M] ⁺ 384.1030 Calculated value C ₂₄ H ₁₇ ClN ₂ O 384.1029 IR (KBr) / νcm ^-1 : 3434, 3030, 16
54, 1594, 1560 ¹ H NMR (270 MHz, CDCl ₃ ) δ: 8.59
(2H, d, J = 6.1 Hz), 8.07 (1H, d,
J = 8.9 Hz), 7.70 (1H, dd, J = 8.
9, 2.3 Hz), 7.62 (1H, d, 2.3H)
z), 7.51-7.39 (3H, m), 7.35-
7.27 (2H, m), 7.12 (2H, d, J = 6.
1Hz), 7.03 (1H, d, J = 16.4Hz),
6.64 (1H, d, J = 16.4 Hz), 2.70
(3H, s).

[0105]

Example 2 1- (6-Chloro-2-methyl-4-phenylquinolin-3-yl) -3- (3-pyridyl) propenone (Exemplary Compound No. 1-78) 3-Acetyl-6-chloro- 2-Methyl-4-phenylquinoline (32 mg, 0.108 mmol) and pyridine-3-aldehyde (30 μL, 0.323 mmol)
And the reaction was carried out according to the method of Example 1 (b) to obtain the title compound (40 mg, 98%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 384.1025 calculated value C ₂₄ H ₁₇ ClN ₂ O 384.1029 IR (KBr) / νcm ^-1 : 3433, 3057, 16
73, 1650, 1610, 1567 ¹ H NMR (270 MHz, CDCl ₃ ) δ: 8.57
(1H, m), 8.51 (1H, d, J = 2.1H
z), 8.07 (1H, d, J = 8.9 Hz), 7.7
0 (1H, dd, J = 8.9, 2.3 Hz), 7.64
(1H, m), 7.61 (1H, d, J = 2.3H
z), 7.49-7.35 (3H, m), 7.31-
7.21 (3H, m), 7.11 (1H, d, J = 1
6.3 Hz), 6.59 (1H, d, J = 16.3H)
z), 2.71 (3H, s).

[0106]

Example 3 1- (6-Chloro-2-methyl-4-phenylquinolin-3-yl) -3- (2-pyridyl) propenone (Exemplary Compound No. 1-246) 3-acetyl-6-chloro- 2-Methyl-4-phenylquinoline (32 mg, 0.108 mmol) and pyridine-2-aldehyde (30 μL, 0.323 mmol)
And the reaction was carried out according to the method of Example 1 (b) to give the title compound (36 mg, 87%) as a white solid. m. p. : 171.0-172.0 ^° C (iPr ₂ O) High-resolution mass spectrum: actual value [M] ⁺ 384.1031 calculated value C ₂₄ H ₁₇ ClN ₂ O 384.1030 IR (KBr) / νcm ^-1 : 3410, 2922, 16
49, 1610, 1572 ¹ H NMR (270 MHz, CDCl ₃ ) δ: 8.57
(1H, d, J = 4.5 Hz), 8.06 (1H, d,
J = 9.0 Hz), 7.68 (1H, dd, J = 9.
0, 2.4 Hz), 7.66 (1H, m), 7.58
(1H, d, J = 2.4 Hz), 7.47-7.20
(7H, m), 7.11 (1H, d, J = 16.2H
z), 6.98 (1H, d, J = 16.2 Hz), 2.
70 (3H, s).

[0107]

Example 4 1- (2,6-Dimethyl-4-phenylquinolin-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 1-23) (a) 3-acetyl-2,6 -Dimethyl-4-phenylquinoline 2-amino-5-methylbenzophenone (211 mg,
1.0 mmol) and acetylacetone (130 m
g, 1.3 mmol) and reacted according to the method of Example 1 (a) to give the title compound (232 mg, 84%).
I got ¹ H NMR (500 MHz, CDCl ₃ ) δ: 8.00
(1H, d, J = 8.6 Hz), 7.55 (1H, d,
J = 8.6 Hz), 7.52-7.50 (3H, m),
7.35-7.33 (3H, m), 2.68 (3H,
s), 2.42 (3H, s), 1.99 (3H, s). (B) 1- (2,6-dimethyl-4-phenylquinolin-3-yl) -3- (4-pyridyl) propenone 3-acetyl-2,6-dimethyl-4-phenylquinoline (90 mg, 0.32 mmol ) And pyridine-4-
The reaction was carried out using aldehyde (48 mg, 0.45 mmol) according to the method of Example 1 (b) to give the title compound (49 mg, 38%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 364.1577 calculated value C ₂₅ H ₂₀ N ₂ O 364.1572 IR (KBr) / νcm ^-1 : 3399, 2573, 16
61, 1633, 1600, 1499 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.88
(2H, d, J = 6.3 Hz), 8.47 (1H, d,
J = 8.7 Hz), 8.09 (2H, d, J = 6.3H)
z), 7.99 (1H, dd, J = 8.7, 1.1H
z), 7.55 (1H, d, J = 16.6 Hz), 7.
50-7.38 (6H, m), 7.24 (1H, d, J
= 16.6 Hz), 2.84 (3H, s), 2.48
(3H, s).

[0108]

Example 5 1- (2-Methyl-4-phenylquinolin-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 1-21) (a) 3-Acetyl-2-methyl-4 -Phenylquinoline 2-aminobenzophenone (1.97 g, 10 mmol
The reaction was carried out according to the method of Example 1 (a) using 1) and acetylacetone (1 mL, 10 mmol) to obtain the title compound (2.37 g, 91%) as an oil. m. p. : 107.8-111.6 ° C High-resolution mass spectrum: Observed value [M] ⁺ 261.1156 Calculated value C ₁₈ H ₁₅ NO 261.1154 IR (KBr) / νcm ^-1 : 1694 ¹ HNMR (400 MHz, CDCl ₃ ) Δ: 8.09
(1H, d, J = 8.1 Hz), 7.72 (1H, t,
J = 8.1 Hz), 7.62 (1H, d, J = 8.1H)
z), 7.50-7.53 (3H, m), 7.44 (1
H, t, J = 8.1 Hz), 7.35-7.37 (2
H, m), 2.70 (3H, s), 2.01 (3H,
s). (B) 1- (2-methyl-4-phenylquinoline-3-
Yl) -3- (4-Pyridyl) propenone 3-acetyl-2-methyl- obtained in Example 5 (a)
4-phenylquinoline (260 mg, 0.99 mmol
l) and pyridine-4-aldehyde (187 μg,
The reaction was carried out using 1.98 mmol) according to the method of Example 1 (b) to obtain the title compound (50 mg, 14%). m. p. : 170.9-175.1 ° C High-resolution mass spectrum: actually measured value [M] ⁺ 350.1413 calculated value C ₂₄ H ₁₈ N ₂ O 350.1419 IR (KBr) / νcm ^-1 : 2542, 1659, 16
35,1603 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.87
(1H, d, J = 8.6 Hz), 8.80 (2H, d,
J = 6.2 Hz), 8.36 (1 H, d, J = 8.5 H)
z), 8.25 (1H, d, J = 8.6 Hz), 8.1
8 (1H, d, J = 8.6 Hz), 8.10 (2H,
d, J = 6.3 Hz), 7.88-8.02 (2H,
m), 7.50-7.57 (4H, m), 7.14 (1
H, d, J = 16.3 Hz), 3.00 (3H, s).

[0109]

Example 6 1- (6-Methoxy-2-methyl-4-)
Phenylquinolin-3-yl) -3- (4-pyridyl)
Propenone (Exemplary Compound No. 1-24) (a) 3-acetyl-6-methoxy-2-methyl-4-
Phenylquinoline 2-amino-5-methoxybenzophenone (0.52
g, 2.29 mmol) and acetylacetone (0.2
Using 5 ml, 2.29 mmol), the reaction was carried out according to the method of Example 1 (a) to give the title compound (0.47 g, 7
1%) as a white solid. High-resolution mass spectrum: Observed value [M] ⁺ 291.1253 Calculated value C ₁₉ H ₁₇ ClNO ₂ 291.1259 IR (KBr) / νcm ^-1 : 2293, 1705, 16
20,1578 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.98
(1H, d, J = 8.8 Hz), 7.55-7.47
(3H, m), 7.40-7.34 (3H, m), 6.
88 (1H, d, J = 2.9 Hz), 3.73 (3H,
s), 2.66 (3H, s), 1.99 (3H, s). (B) 1- (6-Methoxy-2-methyl-4-phenylquinolin-3-yl) -3- (4-pyridyl) propenone 3-acetyl-6-methoxy-2-methyl-4-phenylquinoline (165 mg) , 0.752 mmol) and pyridine-4-aldehyde (140 μL, 1.50 mmol)
Using l), the reaction was carried out according to the method of Example 1 (b),
The title compound (99 mg, 46%) was obtained as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 380.1513 calculated value C ₂₅ H ₂₀ N ₂ O ₂ 380.1525 IR (film) / νcm ⁻¹ 2961,1653,1
620, 1594, 1563 ¹ H NMR (400 MHz, CDCl ₃ ): 8.58 (2
H, d, J = 5.9 Hz), 8.04 (1H, d, J =
8.8 Hz), 7.45-7.36 (4H, m), 7.
34-7.30 (2H, m), 7.12 (2H, d, J
= 5.9 Hz), 7.02 (1H, d, J = 16.1H)
z), 6.91 (1H, d, J = 2.9 Hz), 6.6
4 (1H, d, J = 16.1 Hz), 3.74 (3H,
s), 2.67 (3H, s).

[0110]

Example 7 1- (6-Chloro-2-methyl-4-phenylquinolin-3-yl) -3- (6-methyl-2-
Pyridyl) propenone (Exemplified Compound No. 1-162) 3-acetyl-6-chloro-2-methyl-4-phenylquinoline (117 mg, 0.369 mmol) and 6-
Methylpyridine-2-aldehyde (90 mg, 0.79
The reaction was carried out using 2 mmol) according to the method of Example 1 (b) to give the title compound (138 mg, 87%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 398.1171 calculated value C ₂₅ H ₁₉ ClN ₂ O 398.1186 IR (KBr) / νcm ^-1 : 3060, 1648, 16
10,1580,1570 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.06
(1H, d, J = 7.3 Hz), 7.68 (1H, d
d, J = 8.8, 2.2 Hz) 7.56 (1H, d, J
= 2.2 Hz), 7.54 (1H, t, J = 7.3H)
z), 7.43-7.36 (3H, m), 7.32-
7.28 (2H, m), 7.14 (1H, d, J = 7.
3 Hz), 7.10 (1H, d, J = 8.8 Hz),
7.07 (1H, d, J = 16.1 Hz), 6.97
(1H, d, J = 16.1 Hz), 2.69 (3H,
s), 2.51 (3H, s).

[0111]

Example 8 1- (6-Chloro-2-methyl-4-phenylquinolin-3-yl) -3- (1-methyl-2-
Imidazolyl) propenone (Exemplary Compound No. 1-26)
2) 3-acetyl-6-chloro-2-methyl-4-phenylquinoline (104 mg, 0.353 mmol) and 1-
Methyl imidazole-2-aldehyde (64 mg, 0.1 mg).
706 mmol) and reacted according to the method of Example 1 (b) to give the title compound (128 mg, 94%) as a white solid. High-resolution mass spectrum: Observed value [M] ⁺ 387.1141 Calculated value C ₂₃ H ₁₈ ClN ₃ O 387.1138 IR (KBr) / νcm ^-1 : 3435, 3060, 16
38, 1619, 1600 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.04
(1H, d, J = 8.9 Hz), 7.67 (1H, d
d, J = 8.9, 2.3 Hz), 7.58 (1H, d,
J = 2.3 Hz), 7.45-7.39 (3H, m),
7.34-7.30 (2H, m), 7.12 (1H,
s), 7.09 (1H, d, J = 15.6 Hz), 6.
96 (1H, s), 6.91 (1H, d, J = 15.6)
Hz), 3.62 (3H, s), 2.71 (3H,
s).

[0112]

Example 9 1- (6-Chloro-2-methyl-4-phenylquinolin-3-yl) -3- (4-pyrimidyl)
Propenone (Exemplified Compound No. 1-190) 3-acetyl-6-chloro-2-methyl-4-phenylquinoline (180 mg, 0.609 mmol) and pyrimidine-4-aldehyde (142 mg, 1.32 mmol)
Using l), the reaction was carried out according to the method of Example 1 (b),
The title compound (82 mg, 35%) was obtained as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 385.0976 calculated value C ₂₃ H ₁₆ ClN ₃ O 385.0982 IR (KBr) / νcm ⁻¹ : 3426, 3048, 16
49, 1573, 1542 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.16
(1H, s), 8.73 (1H, d, J = 5.1H
z), 8.06 (1H, d, J = 8.8 Hz), 7.7
0 (1H, dd, J = 8.8, 2.2 Hz), 7.61
(1H, d, J = 2.2 Hz), 7.45-7.36
(3H, m), 7.32-7.27 (2H, m), 7.
20 (1H, d, J = 5.1 Hz), 7.11 (1H,
d, J = 16.1 Hz), 6.99 (1H, d, J = 1)
6.1 Hz), 2.71 (3H, s).

[0113]

Example 10 1- (6-Chloro-2-methyl-4-)
Phenylquinolin-3-yl) -3- (2-pyrazyl)
Propenone (Exemplified Compound No. 1-218) 3-acetyl-6-chloro-2-methyl-4-phenylquinoline (176 mg, 0.594 mmol) and pyrazine-2-aldehyde (152 mg, 1.19 mmol)
Using l), the reaction was carried out according to the method of Example 1 (b),
The title compound (20 mg, 9%) was obtained as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 385.0984 calculated value C ₂₃ H ₁₆ ClN ₃ O 385.0982 IR (KBr) / νcm ⁻¹ : 3431, 3061, 16
53, 1613, 1567 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.54-
8.48 (3H, m), 8.06 (1H, d, J = 8.
9Hz), 7.70 (1H, dd, J = 8.9, 2.3)
Hz), 7.61 (1H, d, J = 2.3 Hz), 7.
54-7.29 (5H, m), 7.13 (1H, d, J
= 16.0 Hz), 7.06 (1H, d, J = 16.0)
Hz), 2.71 (3H, s).

[0114]

Example 11 1- (6-Chloro-2-methyl-4-)
Phenylquinolin-3-yl) -3- [4- (N-oxide) pyridyl] propenone (Exemplary Compound No. 1-25
8) 3-Acetyl-6-chloro-2-methyl-4-phenylquinoline (99 mg, 0.334 mmol) and pyridine-4-aldehyde-N-oxide (83 mg, 0.1 mg).
669 mmol), and reacted according to the method of Example 1 (b) to give the title compound (70 mg, 52%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 400.0973 calculated value C ₂₄ H ₁₇ ClN ₂ O ₂ 400.0978 IR (KBr) / νcm ^-1 : 3410, 3038, 16
47,1608 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.09
(2H, d, J = 7.3 Hz), 8.06 (1H, d,
J = 8.8 Hz), 7.70 (1H, dd, J = 8.
8, 2.2 Hz), 7.61 (1H, d, J = 2.2H)
z), 7.49-7.37 (3H, m), 7.33-
7.27 (2H, m), 7.14 (2H, d, J = 7.
3 Hz), 6.98 (1H, d, J = 16.1 Hz),
6.49 (1H, d, J = 16.1 Hz), 2.70
(3H, s).

[0115]

Example 12 1- (6-Chloro-2-methyl-4-)
Phenylquinolin-3-yl) -3- (2-chloro-3
-Pyridyl) propenone (Exemplified Compound No. 1-106) 3-acetyl-6-chloro-2-methyl-4-phenylquinoline (101 mg, 0.341 mmol) and 2-
Chloropyridine-3-aldehyde (85 mg, 0.68
Using 3 mmol), the reaction was carried out according to the method of Example 1 (b) to give the title compound (97 mg, 68%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 418.0634 calculated value C ₂₄ H ₁₆ Cl ₂ N ₂ O 418.0640 IR (KBr) / νcm ⁻¹ : 3414, 3058, 16
73, 1654, 1605, 1575, 1559 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.36
(1H, m), 8.07 (1H, d, J = 8.8H
z), 7.70 (1H, dd, J = 8.8, 2.2H
z), 7.64 (1H, m), 7.62 (1H, d, J
= 2.2 Hz), 7.48-7.42 (3H, m),
7.41 (8H, d, J = 16.1 Hz), 7.35−
7.31 (2H, m), 7.22 (1H, dd, J =
7.7, 4.7 Hz), 6.52 (1H, d, J = 1)
6.1 Hz), 2.71 (3H, s)

[0116]

Example 13 1- (6-Chloro-2-methyl-4-)
Phenylquinolin-3-yl) -3- (2-hydroxy-3-pyridyl) propenone (Exemplary Compound No. 1-13
4) 1- (6-Chloro-2-methyl-4-phenylquinolin-3-yl) -3- [3- (2-chloropyridyl)] propenone (105 mg, 0.250 mmol) and 6N
Hydrochloric acid (2 ml) was reacted for 8 hours under reflux. The reaction mixture was returned to room temperature, the reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. Graphy (methylene chloride:
Purification by methanol (eluted with 10: 1) gave the title compound (90 mg, 90%) as a yellow solid. High-resolution mass spectrum: measured value [M] ⁺ 400.0989 calculated value C ₂₄ H ₁₇ ClN ₂ O ₂ 400.079 IR (KBr) / νcm ^-1 : 3435, 3003, 16
50,1600,1547 ¹ H NMR (500 MHz, CDCl ₃ ) δ: 8.05
(1H, d, J = 9.0 Hz), 7.68 (1H, d
d, J = 9.0, 2.3 Hz), 7.56 (1H, d,
J = 2.3 Hz), 7.49 (1H, dd, J = 6.
8, 1.9 Hz), 7.41-7.36 (4H, m),
7.30-7.27 (2H, m) 7.16 (1H, d,
J = 16.2 Hz), 7.11 (1H, d, J = 16.
2Hz), 6.30 (1H, t, J = 6.8Hz),
2.69 (3H, s).

[0117]

Example 14 1- (6-Chloro-2-methyl-4-)
Phenylquinolin-3-yl) -3- (N-methyl-2
-Pyridone-3-yl) propenone (Exemplary Compound No. 1
-256) 3-Acetyl-6-chloro-2-methyl-4-phenylquinoline (78 mg, 0.265 mmol) and 1-methyl-2-pyridone-3-aldehyde (57 mg, 0.5 mg).
413 mmol), and the reaction was carried out according to the method of Example 1 (b) to give the title compound (103 mg, 94%) as a yellow solid. High-resolution mass spectrum: measured value [M] ⁺ 414.1137 calculated value C ₂₅ H ₁₉ ClN ₂ O ₂ 414.1135 IR (KBr) / νcm ^-1 : 3437, 3062, 16
52, 1596, 1580, 1542 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.03
(1H, d, J = 8.8 Hz), 7.66 (1H, d
d, J = 8.8, 2.2 Hz), 7.55 (1H, d,
J = 2.2 Hz), 7.43-7.29 (7H, m),
7.20 (1H, d, J = 16.1 Hz), 7.09
(1H, d, J = 16.1 Hz), 6.18 (1H,
d, J = 6.9 Hz), 3.53 (3H, s), 2.6
7 (3H, s).

[0118]

Example 15 1- (6-Chloro-2-methyl-4-)
Phenylquinolin-3-yl) -3- (2-chloro-4
-Pyridyl) propenone (Exemplified Compound No. 1-50) 3-acetyl-6-chloro-2-methyl-4-phenylquinoline (83 mg, 0.280 mmol) and 2-chloropyridine-4-aldehyde (98 mg, 0.693)
(mmol) to give the title compound (56 mg, 38%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 419.0637 calculated value C ₂₄ H ₁₆ Cl ₂ N ₂ O 419.0640 IR (KBr) / νcm ^-1 : 3438, 3057, 16
56, 1614, 1589, 1561, 1537 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.35
(1H, d, J = 5.1 Hz), 8.06 (1H, d,
J = 8.8 Hz), 7.71 (1H, dd, J = 8.
8, 2.2 Hz), 7.62 (1H, d, J = 2.2H)
z), 7.47-7.41 (3H, m), 7.32-
7.28 (2H, m), 7.15 (1H, s), 7.0
4 (1H, d, J = 5.1 Hz), 6.98 (1H,
d, J = 16.1 Hz), 6.60 (1H, d, J = 1)
6.1 Hz), 2.69 (3H, s).

[0119]

Example 16 1- (4-Chloro-2-methylquinolin-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 1-299) (a) N- (1-methyl-3-) Oxo-1-butenyl)
Ethyl anthranilate Ethyl anthranilate (25m
Acetylacetone (35 mL, 0.34 mol) at 135 ° C. in a toluene (200 mL) solution of 0.17 mol).
l) and p-toluenesulfonic acid (7.3 mg, 0.0
4 mol) and heated for 2 hours and 45 minutes using a Dien-Stark to perform a dehydration reaction. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2. (Eluted at 1: 1) to give the title compound (16.6 g, 40%). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.97
(1H, d, J = 8.8 Hz), 7.46 (1H, t,
J = 8.8 Hz), 7.21 (1H, t, J = 8.1H)
z), 7.14 (1H, d, J = 8.1 Hz), 5.2
3 (1H, s), 4.36-4.41 (2H, m),
2.12 (3H, s), 1.99 (3H, s), 1.3
6 (3H, t, J = 7.3 Hz). (B) 3-acetyl-4-hydroxy-2-methylquinoline Ethyl N- (1-methyl-3-oxo-1-butenyl) anthranilate (16.6) obtained in Example 16 (a)
g, 67 mmol) in methanol at room temperature (28 mL, 73 mL).
7 mmol) and stirred for 30 minutes. After completion of the reaction, amberlite was added to make the mixture acidic, followed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with methylene chloride: methanol = 30: 1) to give the title compound (10.4 g, 77%). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.32
(1H, d, J = 8.1 Hz), 7.58 (1H, t,
J = 8.1 Hz), 7.47 (1H, d, J = 8.8H)
z), 7.32-7.36 (1H, m), 2.69 (3
H, s), 2.57 (3H, s). (C) 3-Acetyl-4-chloro-2-methylquinoline 3-acetyl-4-hydroxy-2-methylquinoline obtained in Example 16 (b) (9.8 g, 49 mmol)
And phosphorus oxychloride (35 mL) were reacted at 80 ° C. for 3 hours. After completion of the reaction, the reaction solution was poured into ice water and made alkaline with aqueous ammonium chloride. This was extracted with ethyl acetate, and the organic layer was separated, washed with saturated saline and dried over anhydrous magnesium sulfate. The concentrated residue is purified with a silica gel column (hexane:
The residue was purified with ethyl acetate = 2: 1) to give the title compound (1
(0.3 g, 96%) as yellow crystals. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.16
(1H, d, J = 8.1 Hz), 8.01 (1H, d,
J = 8.0 Hz), 7.76 (1H, t, J = 8.0)
Hz), 7.61 (1H, t, J = 8.0 Hz), 2.
69 (3H, s), 2.54 (3H, s). (D) 1- (4-chloro-2-methylquinolin-3-yl) -3- (4-pyridyl) propenone 3-acetyl-4-chloro-2-methylquinoline obtained in Example 16 (c) (150mg, 0.68mmo
l) and pyridine-4-aldehyde (127 μL, 1.4
(mmol) to give the title compound (178 mg, 85%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 308.0719 calculated value C ₁₈ H ₁₃ ClN ₂ O 308.0716 IR (KBr) / νcm ^-1 : 1652,756 ¹ HNMR (400 MHz, CDCl ₃ ) δ: 8. 68
(2H, d, J = 5.9 Hz), 8.25 (1H, d,
J = 8.0 Hz), 8.10 (1H, d, J = 8.8H)
z), 7.84 (1H, t, J = 8.8 Hz), 7.6
9 (1H, t, J = 8.0 Hz), 7.37 (2H,
d, J = 5.9 Hz), 7.23 (1H, d, J = 1)
6.8 Hz), 7.18 (1H, d, J = 16.8H)
z), 2.66 (3H, s).

[0120]

Example 17 1- (4-Methoxy-2-methylquinolin-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 1-1) (a) 3-Acetyl-4-methoxy-2 -Methylquinoline 3-acetyl-4-hydroxy-2-methylquinoline obtained in Example 16 (b) (3.0 g, 15 mmol)
Potassium carbonate (4.1 g, 30 mmol) and methyl iodide (4.3) were added to a solution of acetonitrile (50 mL).
mL, 30 mmol) and reacted at 90 ° C. for 4 hours and 30 minutes. After completion of the reaction, the reaction solution was filtered. The filtrate was diluted with methylene chloride, washed with water and saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 30: 1) to obtain the title compound (2.6 g, 81%). High-resolution mass spectrum: measured value [M] ⁺ 215.0942 calculated value C ₁₃ H ₁₃ NO ₂ 215.0938 IR (KBr) / νcm ^-1 : 681,1599,76
0 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.43
(1H, d, J = 8.0 Hz), 7.69 (1H, t,
J = 7.0 Hz), 7.52 (1H, d, J = 8.5H)
z), 7.40 (1H, t, J = 7.2 Hz), 3.7
8 (3H, s), 2.65 (3H, s), 2.53 (3
H, s). (B) 1- (4-methoxy-2-methylquinoline-3-
Yl) -3- (4-Pyridyl) propenone 3-acetyl-4-methoxy-2-methylquinoline obtained in Example 17 (a) (2.15 g, 10 mmol)
And pyridine-4-aldehyde (2.14 g, 20 mm
ol) and the reaction was carried out according to the method of Example 1 (b) to give the title compound (2.02 g, 66%) as a white solid. Mass _{spectrum: C 19 H 16 N 2 O} 2 Found [M] ⁺ 3
04 IR (KBr) / νcm ^-1 : 3486,1671,16
16,1597,1541 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.61
(2H, d, J = 4.9 Hz), 8.46 (1H, d,
J = 7.8 Hz), 7.73 (1H, dt, J = 6.
8, 2.0 Hz), 7.57 (1H, d, J = 8.8H)
z), 7.52 (1H, d, J = 15.6 Hz), 7.
46-7.26 (4H, m), 3.84 (3H, s),
2.59 (3H, s).

[0121]

Example 18 1- (2-Methyl-4-phenoxyquinolin-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 1-5) (a) 3-Acetyl-4-phenoxy-2 -Methylquinoline Sodium hydride (72 mg, 3 mmol) with N, N-
After adding dimethylformamide (3 mL), phenol (282 mg, 3 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. 3-acetyl- obtained in Example 16 (c)
4-chloro-2-methylquinoline (330 mg, 1.5
mmol) N, N-dimethylformamide (4 mL)
After adding the solution and reacting at 80 ° C. for 2 days, water was added to terminate the reaction. This was extracted with ethyl acetate, and the organic layer was separated, washed with saturated saline and dried over anhydrous magnesium sulfate. The concentrated residue was purified by a silica gel column (hexane: ethyl acetate = 4: 1) to give the title compound (310 m
g, 99%) as yellow crystals. m. p. : 132.4-135.9 ° C High-resolution mass spectrum: actual value [M] ⁺ 277.1809 calculated value C ₁₈ H ₁₅ NO ₂ 277.1103 IR (KBr) / νcm ^-1 : 1705, 1591 ¹ H NMR (400 MHz , CDCl ₃ ) δ: 8.07
(1H, d, J = 8.5 Hz), 7.81 (1H, d,
J = 8.4 Hz), 7.72 (1H, t, J = 8.4H)
z), 7.43 (1H, t, J = 8.2 Hz), 7.2
1-7.30 (2H, m), 7.07 (1H, t, J =
8.4 Hz), 6.84 (2H, t, J = 8.5H)
z), 2.71 (3H, s), 2.57 (3H, s). (B) 1- (2-methyl-4-phenoxyquinoline-3
-Yl) -3- (4-pyridyl) propenone 3-acetyl-4- obtained in Example 18 (a) in place of 3-acetyl-2-methyl-4-phenylquinoline
Phenoxy-2-methylquinoline (150 mg, 0.5
mmol) and pyridine-4-aldehyde (102 μL,
(1 mmol), and the reaction was carried out according to the method of Example 1 (b) to give the title compound (40 mg, 20%) as yellow crystals. m. p. : 145.7-148.5 ° C High-resolution mass spectrum: observed value [M] ⁺ 366.1368 calculated value C ₂₄ H ₁₈ N ₂ O ₂ 366.1368 IR (KBr) / νcm ^-1 : 1680,1661,16
10,1590 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.95
(1H, d, J = 6.0 Hz), 8.68 (2H, d,
J = 6.2 Hz), 8.16 (1H, d, J = 8.5H)
z), 7.95 (1H, d, J = 8.5 Hz), 7.8
3 (1H, t, J = 8.3 Hz), 7.76 (1H,
d, J = 6.0 Hz), 7.53 (1H, t, J = 8.
3Hz), 7.21-7.30 (3H, m), 7.12
(1H, d, J = 16.3 Hz), 7.07 (1H,
t. J = 7.4 Hz), 6.84 (2H, d, J = 7.
8 Hz), 2.76 (3H, s).

[0122]

Example 19 1- (6-Chloro-2-methyl-4-)
Phenoxyquinolin-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 1-6) (a) 3-acetyl-6-chloro-4-hydroxy-2
-Methylquinoline methyl 2-amino-5-chlorobenzoate (18.56
g, 100 mmol) and acetylacetone (15.
0g, 150mmol) and reacted according to the method of Example 16 (a) to give 2- (1-methyl-3-oxo-
Methyl 1-butenyl) amino-5-chlorobenzoate was obtained as the crude product. This was further reacted without purification according to the method of Example 16 (b) to give the title compound (17.2 g, 73%) as crystals. High-resolution mass spectrum: Observed value [M] ⁺ 235.0394 Calculated value C ₁₂ H ₁₀ ClNO ₂ 235.4402 IR (film) / νcm ⁻¹ : 2908,1685,1
546, 1509 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.04
(1H, d, J = 2.6 Hz), 7.72 (1H, d
d, J = 8.8, 2.6 Hz) 7.58 (1H, d, J
= 8.8 Hz), 2.50 (3H, s), 2.43 (3
H, s). (B) 3-acetyl-4,6-dichloro-2-methylquinoline 3-acetyl-6-chloro-4-hydroxy-2-methylquinoline (5.02 g, 21.3 mmol) was added to phosphorus oxychloride (18 ml, 193 mmol). ) Was added and reacted under heating and refluxing for 0.75 hours. The reaction mixture was returned to room temperature, ice water was added, and the mixture was stirred for 1 hour. Thereafter, the reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the precipitate was washed with hexane, filtered, and dried under reduced pressure. The compound (4.01 g, 74%) was obtained as a white solid.
(This was used in the next step without purification.) (C) A solution of 3-acetyl-6-chloro-2-methyl-4-phenoxyquinoline phenol (178 mg, 1.82 mmol) in dimethylformamide (5 ml) was added. Sodium hydride (7
(8 mg, 1.75 mmol) and stirred for 20 minutes.
Thereafter, 3-acetyl-4,6-dichloro-2-methylquinoline (371 mg, 1.46 mmol) was added, and 8
The reaction was performed at 0 ° C. for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1).
And eluted with the title compound (285 mg, 6
3%) as a white solid. (This was used in the next step without purification.) (D) 1- (6-Chloro-2-methyl-4-phenoxyquinolin-3-yl) -3- (4-pyridyl) propenone 3- Acetyl-6-chloro-2-methyl-4-phenoxyquinoline (81 mg, 0.259 mmol) and pyridine-4-aldehyde (40 μL, 0.518 mmol)
Using l), the reaction was carried out according to the method of Example 1 (b),
The title compound (22 mg, 21%) was obtained as a yellow solid. High-resolution mass spectrum: measured value [M] ⁺ 400.0972 calculated value C ₂₇ H ₁₇ ClN ₂ O ₂ 400.079 IR (film) / νcm ^-1 : 3030,1656,1
614, 1591, 1555 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.64
(2H, d, J = 5.9 Hz), 8.04 (1H, d,
J = 8.8 Hz) 7.90 (1H, d, J = 2.2H)
z), 7.71 (1H, dd, J = 8.8, 2.2H
z), 7.27-7.20 (5H, m), 7.03 (1
H, d, J = 16.1 Hz), 7.02 (1H, m),
6.83-6.71 (2H, m), 2.68 (3H,
s).

[0123]

Example 20 1- [6-Chloro-2-methyl-4-
(4-cyanophenoxy) quinolin-3-yl] -3-
(4-pyridyl) propenone (Exemplary Compound No. 1-1)
0) (a) 3-acetyl-6-chloro-2-methyl-4-
(4-cyanophenoxy) quinoline 4-cyanophenol (174 mg, 1.20 mmol)
l) and using 3-acetyl-4,6-dichloro-2-methylquinoline (315 mg, 1.22 mmol)
The reaction was carried out according to the method of Example 19 (b) to give the title compound (75 mg, 18%) as a white solid. High-resolution mass spectrum: Observed value [M] ⁺ 336.0658 Calculated value C ₁₉ H ₁₃ ClN ₂ O ₂ 336.0666 IR (KBr) / νcm ^-1 : 3398,3062,22
29, 1703, 1593 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.03
(1H, d, J = 8.8 Hz), 7.70 (1H, d
d, J = 8.8, 1.9 Hz), 7.67 (1H, d,
J = 1.9 Hz), 7.62 (2H, d, J = 8.8H)
z), 6.92 (2H, d, J = 8.8 Hz), 2.7
0 (3H, s), 2.54 (3H, s). (B) 1- [6-Chloro-2-methyl-4- (4-cyanophenoxy) quinolin-3-yl] -3- (4-pyridyl) propenone 3-acetyl-6-chloro-2-methyl-4 -(4-cyanophenoxy) quinoline (69 mg, 0.206 mm
ol) and pyridine-4-aldehyde (40 μL, 0.1 mL).
412 mmol), and the reaction was carried out according to the method of Example 1 (b) to give the title compound (65 mg, 74%) as a yellow solid. m. p. : 88.0-89.0 ^° C (iPr ₂ O) High-resolution mass spectrum: actual value [M] ⁺ 425.0924 calculated value C ₂₅ H ₁₆ ClN ₃ O ₂ 425.0931 IR (KBr) / νcm ^-1 : 3428, 3041, 22
30, 1733, 1656, 1615, 1591 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.69
(2H, d, J = 4.7 Hz), 8.08 (1H,
m), 7.77-7.72 (2H, m), 7.57 (2
H, d, J = 8.9 Hz), 7.33 (2H, d, J =
4.7Hz), 7.25 (1H, d, J = 16.5H)
z), 7.08 (1H, d, J = 16.5 Hz), 6.
86 (2H, d, J = 8.9 Hz), 2.62 (3H,
s).

[0124]

Example 21 1- [2-Methyl-4- (3,4-dimethoxyphenoxy) quinolin-3-yl] -3- (4
-Pyridyl) propenone (Exemplified Compound No. 1-17) (a) Instead of 3-acetyl-4- (3,4-dimethoxyphenoxy) -2-methylquinolinephenol, 3,4-dimethoxyphenol (3
15 mg, 2 mmol) and the 3-acetyl-4-chloro-2-methylquinoline (29) obtained in Example 16 (c).
0 mg, 1.3 mmol) and reacted according to the method of Example 18 (a) to give the title compound (244 mg, 7 mmol).
3%). High-resolution mass spectrum: observed value [M] ⁺ 337.1310 calculated value C ₂₀ H ₁₉ NO ₄ 337.1314 IR (KBr) / νcm ⁻¹ : 1692,1592,15
12 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.05
(1H, d, J = 8.0 Hz), 7.83 (1H, d,
J = 8.1 Hz), 7.72 (1H, t, J = 7.3H)
z), 7.43 (1H, t, J = 7.3 Hz), 6.6
8 (1H, d, J = 8.7 Hz), 6.63 (1H,
s), 6.18 (1H, d, J = 8.8 Hz), 3.8
3 (3H, s), 3.82 (3H, s), 2.70 (3
H, s), 2.54 (3H, s). (B) 1- [2-Methyl-4- (3,4-dimethoxyphenoxy) quinolin-3-yl] -3- (4-pyridyl) propenone 3-acetyl-4 obtained in Example 21 (a) − (3,
4-dimethoxyphenoxy) -2-methylquinoline (1
Pyridine-4-aldehyde (56 μL, 0.6 mm)
ol) and then potassium carbonate (205 mg, 1.5 mg).
mmol) aqueous solution (3 mL) and cetyltrimethylammonium bromide (catalytic amount) were added and reacted for 20 hours. This was extracted with ethyl acetate, and the organic layer was separated, washed with saturated saline and dried over anhydrous magnesium sulfate. The concentrated residue was subjected to a silica gel column (hexane: ethyl acetate = 1: 1).
Purification was performed in 4) to give the title compound (26 mg, 20%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 426.1583 calculated value C ₂₆ H ₂₂ N ₂ O ₄ 426.1580 IR (KBr) / νcm ^-1 : 1654, 1616, 15
93, 1509 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.65
(2H, d, J = 6.6 Hz), 8.11 (1H, d,
J = 8.8 Hz), 7.97 (1H, d, J = 8.8H)
z), 7.79 (1H, t, J = 7.3 Hz), 7.5
0 (1H, t, J = 7.3 Hz), 7.29 (2H,
d, J = 5.9 Hz), 7.21 (1H, d, J = 1)
6.1 Hz), 7.05 (1H, d, J = 16.1H)
z), 6.61 (1H, d, J = 8.8 Hz), 6.5
3 (1H, s), 6.19 (1H, d, J = 8.8H)
z), 3.74 (3H, s), 3.72 (3H, s),
2.69 (3H, s).

[0125]

Example 22 1- [2-Methyl-4- (4-methoxyphenoxy) quinolin-3-yl] -3- (4-pyridyl) propenone (Exemplary Compound No. 1-13) (a) 3-acetyl- 4- (4-methoxyphenoxy)
Instead of 2-methylquinoline phenol, 4-methoxyphenol (246 m
g, 2 mmol) and the 3-acetyl-4-chloro-2-methylquinoline obtained in Example 16 (c) (290 m
g, 1.3 mmol) and reacted according to the method of Example 18 (a) to give the title compound (302 mg, 99 mmol).
%). High resolution mass spectrum: Found [M] ⁺ 307.1210 calcd _{C 19 H 19 NO 3 307.12108 IR} (KBr) / νcm -1: 1702,1504 1 HNMR (400MHz, CDCl 3) δ: 8.05
(1H, d, J = 8.0 Hz), 7.83 (1H, d,
J = 8.1 Hz), 7.72 (1H, t, J = 7.3H)
z), 7.43 (1H, t, J = 7.3 Hz), 6.6
8 (1H, d, J = 8.7 Hz), 6.63 (1H,
s), 6.18 (1H, d, J = 8.8 Hz), 3.8
3 (3H, s), 3.82 (3H, s), 2.70 (3
H, s), 2.54 (3H, s). (B) 1- [2-Methyl-4- (4-methoxyphenoxy) quinolin-3-yl] -3- (4-pyridyl) propenone 3-acetyl-4- (obtained in Example 22 (a) 4-
Methoxyphenoxy) -2-methylquinoline (100 m
g, 0.31 mmol) and pyridine-4-aldehyde (61 μL, 0.6 mmol), and reacted according to the method of Example 21 to give the title compound (12.5 mg, 12.5 mg).
0%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 396.1468 calculated value C ₂₅ H ₂₀ N ₂ O ₃ 366.1368 IR (KBr) / νcm ^-1 : 1679, 1613,
1593, 1505 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.64
(2H, d, J = 6.1 Hz), 8.10 (1H, d,
J = 8.5 Hz), 7.97 (1H, d, J = 8.3H)
z), 7.78 (1H, t, J = 8.3 Hz), 7.4
9 (1H, t, J = 8.1 Hz), 7.28 (2H,
d, J = 5.5 Hz), 7.21 (1H, d, J = 1)
6.3 Hz), 7.03 (1H, d.J = 16.2H)
z), 6.72-6.76 (4H, m), 3.68 (3
H, s), 2.69 (3H, s).

[0126]

Example 23 1- [2-Methyl-4- (4-cyanophenoxy) quinolin-3-yl] -3- (4-pyridyl) propenone (Exemplary Compound No. 1-9) (a) 3-acetyl- 4- (4-cyanophenoxy)-
Example 16 (c) with 4-cyanophenol (240 mg, 2 mmol) in place of 2-methylquinolinephenol
Example 1 using 3-acetyl-4-chloro-2-methylquinoline (290 mg, 1.3 mmol) obtained in Step 1.
The reaction was performed according to the method of 8 (a), and the title compound (94
mg, 24%). High-resolution mass spectrum: measured value [M] ⁺ 302.1046 calculated value C ₁₉ H ₁₄ N ₂ O ₂ 302.1555 IR (KBr) / νcm ^-1 : 2228, 1704, 15
95, 1484 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.09
(1H, d, J = 8.3 Hz), 7.77 (1H, t,
J = 7.2 Hz), 7.68 (1H, d, J = 8.4H)
z), 7.59 (2H, d, J = 8.9 Hz), 7.4
7 (1H, t, J = 7.2 Hz), 6.92 (2H,
d, J = 8.9 Hz), 2.72 (3H, s), 2.5
6 (3H, s). (B) 1- [2-Methyl-4- (4-cyanophenoxy) quinolin-3-yl] -3- (4-pyridyl) propenone 3-acetyl-4- (obtained in Example 23 (a) 4-
(Cyanophenoxy) -2-methylquinoline (94.4 m
g, 0.31 mmol) and pyridine-4-aldehyde (426 μL, 4.5 mmol) according to the method of Example 21 to give the title compound (18.7 mg,
15%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 391.1321 calculated value C ₂₅ H ₁₇ N ₃ O ₂ 391.1321 IR (KBr) / νcm ^-1 : 1656,1595 ¹ HNMR (400 MHz, CDCl ₃ ) δ: 8 .68
(2H, d, J = 5.8 Hz), 8.15 (1H, d,
J = 8.8 Hz), 7.83 (1H, t, J = 8.8H)
z), 7.76 (1H, d, J = 9.6 Hz), 7.5
1-7.57 (3H, m), 7.32 (2H, d, J =
6.6 Hz), 7.27 (1H, d, J = 16.2H)
z), 7.11 (1H, d, J = 16.2 Hz), 6.
87 (2H, d, J = 8.7 Hz), 2.72 (3H,
s).

[0127]

Example 24 1- [6-Methoxy-2-methyl-4-
(3,4-dimethoxyphenoxy) shiquinolin-3-yl] -3- (4-pyridyl) propenone (Exemplary Compound No. 1-20) (a) 2- [1-methyl-3-oxo-1-butenyl]
Methyl amino-5-methoxybenzoate Methyl 2-amino-5-methoxybenzoate (2.45
g, 13.5 mmol) and acetylacetone (2.79)
The reaction was carried out according to the method of Example 16 (a) using the compound of the title (2.24 g, 63 mmol).
%) As an oil. High-resolution mass spectrum: measured value [M] ⁺ 263.1155 calculated value C ₁₄ H ₁₇ NO ₄ 263.1157 IR (Liquid film) / νcm ⁻¹ : 172
0, 1617, 1562 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.45
(1H, s), 7.08 (1H, d, J = 8.8H
z), 7.02 (1H, d, J = 8.8 Hz), 5.2
1 (1H, s), 3.91 (3H, s), 3.84 (3
H, s), 2.11 (3H, s), 1.90 (3H,
s). (B) 3-acetyl-4-hydroxy-2-methyl-6
-Methoxyquinoline Methyl 2- [1-methyl-3-oxo-1-butenyl] amino-5-methoxybenzoate (2.24 g, 8.5 mmol) obtained in Example 24 (a) and 28% sodium methoxy Methanol solution (2.4 mL, 12.8 m
The reaction was carried out according to the method of Example 16 (b) using the compound of formula (13) to obtain the title compound (875 mg, 45%). High-resolution mass spectrum: measured value [M] ⁺ 231.0892 calculated value C ₁₃ H ₁₃ NO ₃ 231.0896 IR (KBr) / νcm ^-1 : 1656,1578,15
41,1517 ¹ H NMR (500 MHz, CDCl ₃ ) δ: 7.67
(1H, s), 7.32 (1H, d, J = 9.3H)
z), 7.19 (1H, d, J = 8.9 Hz), 3.9
0 (3H, s), 2.69 (3H, s), 2.50 (3
H, s). (C) 3-acetyl-4-chloro-2-methyl-6-methoxyquinoline 3-acetyl-4-hydroxy-2-methyl-6-methoxyquinoline obtained in Example 24 (b) (507 m
g, 2.2 mmol) and phosphorus oxychloride (2 mL) according to the method of Example 16 (b) to give the title compound (422 mg, 77%). (D) 3-acetyl-4- (3,4-dimethoxy) phenoxy-2-methyl-6-methoxyquinoline 3-acetyl-4-chloro-2-methyl-6 obtained in Example 24 (c) Methoxyquinoline (422 mg,
Example 18 using 1.69 mmol) and 3,4-dimethoxyphenol (537 mg, 3.4 mmol).
The reaction was carried out according to the method of (a) to give the title compound (156).
mg, 63%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 367.1426 calculated value C ₂₁ H ₂₁ NO ₅ 367.1420 IR (KBr) / νcm ^-1 : 1701, 1590, 15
10 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.96
(1H, d, J = 9.2 Hz), 7.37 (1H, d,
J = 9.2 Hz), 7.07 (1H, s), 6.69
(1H, d, J = 8.7 Hz), 6.63 (1H,
s), 6.22 (1H, d, J = 8.8 Hz), 3.8
3 (3H, s), 3.82 (3H, s), 3.74 (3
H, s), 2.67 (3H, s), 2.52 (3H,
s). (E) 1- [6-Methoxy-2-methyl-4- (3,4-
Dimethoxyphenoxy) shiquinolin-3-yl] -3-
(4-pyridyl) propenone 3-acetyl-4- (3,3) obtained in Example 24 (d).
4-Dimethoxy) phenoxy-2-methyl-6-methoxyquinoline (156 mg, 0.42 mmol) and pyridine-4-aldehyde (79.8 μL, 0.8 mmol)
Then, the reaction was carried out according to the method of Example 21 to obtain the title compound (98 mg, 51%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 456.1689 calculated value C ₂₇ H ₂₄ N ₂ O ₅ 456.1658 IR (KBr) / νcm ^-1 : 1592,1510 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8 .65
(2H, d, J = 5.8 Hz), 8.00 (1H, d,
J = 8.6 Hz), 7.42 (1H, d, J = 8.6H)
z), 7.29 (2H, d, J = 6.6 Hz), 7.2
7 (1H, s), 7.19 (1H, d, J = 16.1H)
z), 7.03 (1H, d, J = 16.1 Hz), 6.
62 (1H, d, J = 8.8 Hz), 6.53 (1H,
s), 6.22 (1H, d, J = 8.8 Hz), 3.8
0 (3H, s), 3.74 (3H, s), 3.72 (3
H, s), 2.65 (3H, s).

[0128]

Example 25 1- [2-Methyl-4-phenoxyquinolin-3-yl] -3- (6-methyl-2-pyridyl) propenone (Exemplified Compound No. 1-145) Produced in Example 18 (a) 3-acetyl-2-methyl-4-phenoxy-quinoline (100 mg, 0.36 m
mol) and 6-instead of pyridine-4-aldehyde
Methylpyridine-2-aldehyde (65.5 mg, 0.
The reaction was carried out according to the method of Example 1 (b) using the compound (54 mmol) to give the title compound (86 mg, 63%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 380.529 calculated value C ₂₅ H ₂₀ N ₂ O ₂ 380.1525 IR (KBr) / νcm ^-1 : 1656, 1203 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8 .10
(1H, d, J = 8.0 Hz), 7.87 (1H, d,
J = 8.0 Hz), 7.76 (1 H, t, J = 8.0 H)
z), 7.58 (1H, t, J = 7.3 Hz), 7.4
5 (1H, t, J = 8.0 Hz), 7.35 (1H,
d, J = 16.1 Hz), 7.25-7.29 (1H,
m), 7.23 (2H, d, J = 8.1 Hz), 7.1
9 (1H, d, J = 7.3 Hz), 7.13 (1H,
d, J = 7.3 Hz), 6.98 (1H, t, J = 8.
1 Hz), 6.81 (2H, d, J = 8.1 Hz). 2.69 (3H, s), 2.54 (3H, s)

[0129]

Example 26 1- (2-Methyl-4-phenoxyquinolin-3-yl) -3- (2-pyridyl) propenone (Exemplified Compound No. 1-229) 3-acetyl produced in Example 18 (a) -2-Methyl-4-phenoxyquinoline (100 mg, 0.36 mm
ol) and pyridine-2-aldehyde (51 μL, 0.1 μL).
The reaction was carried out using 5 mmol) according to the method of Example 1 (b) to give the title compound (71 mg, 54%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 366.1358 calculated value C ₂₄ H ₁₈ N ₂ O ₂ 366.1368 IR (KBr) / νcm ^-1 : 1645, 1484, 12
02 ¹ HNMR (400 MHz, CDCl ₃ ) δ: 8.64
(1H, d, J = 3.7 Hz), 8.10 (1H, d,
J = 8.8 Hz), 7.89 (1H, d, J = 7.3H)
z), 7.68-7.78 (2H, m), 7.46 (1
H, t, J = 8.1 Hz), 7.37-7.41 (2
H, m), 7.27-7.28 (1H, m), 7.19
(2H, d, J = 7.3 Hz), 6.98 (1H, t,
J = 7.3 Hz), 6.81 (2H, d, J = 8.0 H)
z), 2.70 (3H, s).

[0130]

Example 27 1- (2-Methyl-4-phenoxyquinolin-3-yl) -3- (4-pyrimidyl) propenone (Exemplary Compound No. 1-173) 3-acetyl produced in Example 18 (a) -2-Methyl-4-phenoxyquinoline (100 mg, 0.36 mm
ol) and pyrimidine-4-aldehyde (156 μL,
The reaction was carried out using 0.72 mmol) according to the method of Example 21 to obtain the title compound (27.8 mg, 21%) as yellow crystals. High-resolution mass spectrum: Observed value [M] ⁺ 367.1322 Calculated value C ₂₃ H ₁₇ N ₃ O ₂ 367.1320 IR (KBr) / νcm ^-1 : 1572, 1483,
_{^{1206 1 HNMR (400MHz, CDCl 3}} ) δ: 9.23
(1H, s), 8.77 (1H, d, J = 5.2H
z), 8.10 (1H, d, J = 8.1 Hz), 7.9
0 (1H, d, J = 8.0 Hz), 7.78 (1H,
t, J = 8.0 Hz), 7.59 (1H, d, J = 1)
6.1 Hz), 7.48 (1H, t, J = 8.1H)
z), 7.29 (1H, d, J = 5.2 Hz), 7.1
9-7.26 (3H, m), 6.99 (1H, t, J =
7.3 Hz), 6.79 (2H, d, J = 8.8H)
z), 2.71 (3H, s).

[0131]

Example 28 1- (2-Methyl-4-phenoxyquinolin-3-yl) -3- (2-chloro-3-pyridyl) propenone (Exemplary Compound No. 1-90) 3-acetyl-2-methyl- The reaction was carried out according to the method of Example 21 using 4-phenoxyquinoline (139 mg, 0.5 mmol) and 2-chloropyridine-3-aldehyde (141 mg, 1.0 mmol) to give the title compound (172 mg, 86%). Obtained as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 401.1053 calculated value C ₂₄ H ₁₇ ClN ₂ O ₂ 401.1062 IR (KBr) / νcm ^-1 : 3050,1678,16
03,1481,1399 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.39
(1H, dd, J = 4.5, 1.6 Hz), 8.11
(1H, d, J = 8.5 Hz), 7.88 (1H, d,
J = 7.8 Hz), 7.79-7.75 (2H, m),
7.67 (1H, d, J = 16.3 Hz), 7.47
(1H, dt, J = 7.1, 1.0 Hz), 7.27−
7.20 (4H, m), 7.00 (1H, t, J = 7.
6Hz), 6.92 (1H, d, J = 16.3Hz),
6.82 (1H, d, J = 8.4 Hz), 2.73 (3
H, s).

[0132]

Example 29 1- (2-Methyl-4-phenoxyquinolin-3-yl) -3- (1-methyl-2-pyridone-5-yl) propenone (Exemplified Compound No. 1-259) 3-acetyl- 2-methyl-4-phenoxyquinoline (111 mg, 0.4 mmol) and 1-methyl-2-
Pyridone-5-aldehyde (110 mg, 0.8 mmol
The reaction was carried out according to the method of Example 21 using 1) to give the title compound (115 mg, 72%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 396.1472 calculated value C ₂₅ H ₂₀ N ₂ O ₃ 396.1478 IR (KBr) / νcm ^-1 : 3433, 3063, 16
66, 1640, 1619, 1587 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.09
(1H, d, J = 8.8 Hz), 7.87 (1H, d,
J = 7.3 Hz), 7.77 (1H, dt, J = 6.
6, 1.5 Hz), 7.51-7.46 (2H, m),
7.39 (1H, d, J = 2.9 Hz), 7.27-
7.21 (2H, m), 7.07 (1H, d, J = 1
6.1 Hz), 7.01 (1H, t, J = 7.3H)
z), 6.81-6.79 (2H, m), 6.66 (1
H, d, J = 16.1 Hz), 6.58 (1H, d, J)
= 9.6 Hz), 3.52 (3H, s), 2.71 (3
H, s).

[0133]

Example 30 1- (2-Methyl-4-phenoxyquinolin-3-yl) -3- (1-methyl-2-pyridone-3-yl) propenone (Exemplary Compound No. 1-253) 3-acetyl- 2-methyl-4-phenoxyquinoline (111 mg, 0.4 mmol) and 1-methyl-2-
Pyridone-3-aldehyde (110 mg, 0.8 mmol
Using l), the reaction was carried out according to the method of Example 1 (b),
The title compound (118 mg, 74%) was obtained as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 396.1465 calculated value C ₂₅ H ₂₀ N ₂ O ₃ 396.1486 IR (KBr) / νcm ^-1 : 3428, 3081, 16
58, 1645, 1591, 1541 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.08
(1H, d, J = 8.5 Hz), 7.85 (1H, d
d, J = 8.0, 1.0 Hz), 7.72 (1H, d
t, J = 7.3, 1.2 Hz), 7.55 (1H, d,
J = 16.1 Hz), 7.50 (1H, dd, J = 7.
1,1.9 Hz), 7.44-7.37 (2H, m),
7.20 (1H, d, J = 16.0 Hz), 7.19
(1H, d, J = 1.2 Hz), 6.96 (1H, t,
J = 6.9 Hz), 6.82 (1H, t, J = 8.4H)
z), 6.22 (1H, t, J = 7.1 Hz), 3.5
7 (3H, s), 2.68 (3H, s).

[0134]

Example 31 1- (2-Methyl-4-phenoxyquinolin-3-yl) -3- (2-chloro-4-pyridyl) propenone (Exemplary Compound No. 1-33) 3-acetyl-2-methyl- Using 4-phenoxyquinoline (111 mg, 0.4 mmol) and 2-chloropyridine-4-aldehyde (113 mg, 0.8 mmol), the reaction was carried out according to the method of Example 1 (b) to give the title compound (98 mg, 61 mmol). %) As a white solid. High-resolution mass spectrum: Observed value [M] ⁺ 400.0981 Calculated value C ₂₄ H ₁₇ ClN ₂ O ₂ 400.0975 IR (KBr) / νcm ^-1 : 3069, 1660, 16
18, 1588, 1484 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.40
(1H, d, J = 5.1 Hz), 8.11 (1H, d,
J = 8.2 Hz), 7.89 (1H, dd, J = 8.
1,1.0 Hz), 7.78 (1H, dt, J = 7.
8, 1.0 Hz), 7.48 (1H, dt, J = 7.
4,1.0 Hz), 7.26-7.16 (5H, m),
7.06 (1H, d, J = 16.1 Hz), 7.03
(1H, t, J = 7.3 Hz), 6.81-6.78
(2H, m) 2.71 (3H, s).

[0135]

Example 32 1- (2-Methyl-4-piperidylquinolin-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 1-25) (a) 3-Acetyl-2-methyl-4 -Piperidylquinoline 3-acetyl-4-chloro-2-methylquinoline prepared in Example 16 (c) (340 mg, 1.16 mmol)
l) in toluene (1 mL) was added to piperidine (397 μl).
L, 4.64 mmol), reacted at 100 ° C. for 20 hours, and filtered. Water was added to the filtrate, extracted with methylene chloride, and the organic layer was separated, washed with brine, and dried over anhydrous magnesium sulfate. The concentrated residue was washed with hexane to give the title compound (300 mg, 96%) as yellow crystals. m. p. 90.3-29.9 ° C. High-resolution mass spectrum: Observed value [M] ⁺ 268.1579 Calculated value C ₁₇ H ₂₀ N ₂ O 268.1575 IR (KBr) / νcm ^-1 : 1690, 1564 ¹ H NMR (400 MHz , CDCl ₃ ) δ: 8.06
(1H, d, J = 7.9 Hz), 7.98 (1H, d,
J = 8.3 Hz), 7.65 (1H, t, J = 8.3H)
z), 7.46 (1H, t, J = 8.1 Hz), 3.2
8 (4H, s), 2.58 (6H, m), 1.68-
1.77 (6H, m). (B) 1- (2-methyl-4-piperidylquinoline-3)
-Yl) -3- (4-pyridyl) propenone 3-Acetyl-2-methyl-4-piperidylquinoline prepared in Example 32 (a) (150 mg, 0.6 mmol)
l) and pyridine-4-aldehyde (105 μL, 1 mm
ol) in the same manner as in Example 1 (b) to give the title compound (220 mg, 99%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 357.1844 calculated value C ₂₃ H ₂₃ N ₃ O 357.1842 IR (KBr) / νcm ^-1 : 1674, 1631, 16
10,1572 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.72
(2H, d, J = 6.0 Hz), 8.14 (1H, d,
J = 8.3 Hz), 8.07 (1H, d, J = 8.3H)
z), 7.76-7.78 (1H, m), 7.56 (1
H, d, J = 8.3 Hz), 7.34 (2H, d, J =
6.0 Hz), 7.16-7.22 (2H, m), 3.
22-3.31 (4H, m), 2.62 (3H, s),
1.67-1.75 (6H, m).

[0136]

Working Example 33 1- (6-Chloro-2-methyl-4-)
Piperidylquinolin-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 1-26) (a) 3-Acetyl-6-chloro-2-methyl-4-piperidylquinoline In Example 19 (a) The obtained 3-acetyl-4,6-dichloro-2-methylquinoline (300 mg, 1.2 mm
ol) and the reaction was carried out according to the method of Example 32 (a) to obtain the title compound (340 mg, 95%) as yellow crystals. High-resolution mass spectrum: observed value [M] ⁺ 302.192 calculated value C ₁₇ H ₁₉ ClN ₂ O 302.1186 IR (KBr) / νcm ^-1 : 1699,1559 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8. 02
(1H, s), 7.90 (1H, d, J = 8.8H)
z), 7.59 (1H, d, J = 8.8 Hz), 3.2
4 (4H, s), 2.58 (3H, s), 2.56 (3
H, s), 1.70-1.78 (6H, m). (B) 1- (6-chloro-2-methyl-4-piperidylquinolin-3-yl) -3- (4-pyridyl) propenone 3-acetyl-6-chloro- obtained in Example 33 (a) 2-methyl-4-piperidylquinoline (100 mg,
0.3 mmol) and pyridine-4-aldehyde (62 μl)
L, 0.6 mmol), and reacted according to the method of Example 1 (b) to give the title compound (110 mg, 85%)
Was obtained as an oil. High-resolution mass spectrum: measured value [M] ⁺ 391.1456 calculated value C ₂₃ H ₂₂ ClN ₃ O 391.1451 IR (KBr) / νcm ^-1 : 1713,1651,15
95,1563 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.68
(2H, d, J = 5.9 Hz), 8.04 (1H,
s), 7.95 (1H, d, J = 8.8 Hz), 7.6
4 (1H, d, J = 8.8 Hz), 7.36 (2H,
d, J = 5.9 Hz), 7.18 (1H, d, J = 1)
6.1 Hz), 7.13 (1H, d, J = 16.1H)
z), 3.17 (4H, m), 2.54 (3H, s),
1.68-1.73 (6H, m).

[0137]

Working Example 34 1- (6-Chloro-2-methoxycarbonylmethoxy-4-phenylquinolin-3-yl)-
3- (4-pyridyl) propenone (exemplary compound number 1-
266) (a) 3-acetyl-6-chloro-2-methoxycarbonylmethoxy-4-phenylquinoline and 3-acetyl-6-chloro-1-methoxycarbonylmethyl-4-phenyl-2-quinolone 3-acetyl-6 To a solution of -chloro-4-phenyl-2-quinolone (101 mg, 0.340 mmol) in acetonitrile (1 ml) was added bromoacetic acid methyl ester (0.0%).
5 mL, 0.680 mmol) and potassium carbonate (89
mg, 0.680 mmol).
Allowed to react for hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, water and saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane : Ethyl acetate = 2: 1) and purified
-Acetyl-6-chloro-2-methoxycarbonylmethoxy-4-phenylquinoline (38 mg, 30%) and 3
-Acetyl-6-chloro-1-methoxycarbonylmethyl-4-phenyl-2-quinolone (84 mg, 66%)
I got

3-acetyl-6-chloro-2-methoxycarbonylmethoxy-4-phenylquinoline Rf value = 0.80 (hexane: ethyl acetate = 2: 1 (v
/ V)) High-resolution mass spectrum: actual value [M + H] ⁺ 370.0847 calculated value C ₂₀ H ₁₆ ClNO ₄ 370.0846 IR (KBr) / νcm ^-1 : 2954,1761,17
12,1589 ¹ H NMR (270 MHz, CDCl ₃ ) δ: 7.78
(1H, d, J = 8.9 Hz), 7.57 (1H, d
d, J = 8.9, 2.2 Hz), 7.52-7.48
(3H, m), 7.45 (1H, d, J = 2.2H
z), 7.36-7.28 (2H, m), 5.12 (2
H, s), 3.80 (3H, s), 2.27 (3H,
s).

3-acetyl-6-chloro-1-methoxycarbonylmethoxy-4-phenylquinoline Rf value = 0.30 (hexane: ethyl acetate = 2: 1 (v
/ V)) High-resolution mass spectrum: measured value [M + H] ⁺ 370.0860 calculated value C ₂₀ H ₁₆ ClNO ₄ 370.0846 IR (KBr) / νcm ^-1 : 2954,1746,17
07,1643 ¹ H NMR (270 MHz, CDCl ₃ ) δ: 7.52
(1H, dd, J = 9.1, 2.5 Hz), 7.51-
7.47 (3H, m), 7.34-7.27 (2H,
m), 7.26 (1H, d, J = 2.5 Hz), 7.1
1 (1H, d, J = 9.1 Hz), 5.15 (2H,
s), 3.82 (3H, s), 2.23 (3H, s). (B) 1- (6-chloro-2-methoxycarbonylmethoxy-4-phenylquinolin-3-yl) -3- (4-
Pyridyl) propenone 3-acetyl-6-chloro-2-methoxycarbonylmethoxy-4-phenylquinoline (0.36 g, 0.97
4 mmol) and pyridine-4-aldehyde (200 μl)
L, 2.10 mmol) and reacted according to the method of Example 1 (b) to give the title compound (0.20 g, 44
%) As a yellow solid. m. p. : 147.0-148.0 ^° C (iPr ₂ O) High resolution mass spectrum: Found [M + H] ⁺ 459.1100 Calculated C ₂₆ H ₁₉ ClN ₂ O ₄ 459.112 IR (KBr) / νcm ^-1 : 1759, 1658, 15
90 ¹ H NMR (270 MHz, CDCl ₃ ) δ: 8.61
(2H, d, J = 3.9 Hz), 7.83 (1H, d,
J = 8.9 Hz), 7.62 (1H, dd, J = 8.
9, 2.4 Hz), 7.49 (1H, d, J = 2.4H)
z), 7.46-7.42 (3H, m), 7.34-
7.27 (5H, m), 6.90 (1H, d, J = 1
6.5 Hz), 5.11 (2H, s), 3.78 (3
H, s).

[0140]

Example 35 1- (6-Chloro-2-isopropoxy-4-phenylquinolin-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 1-270) (a) 3-acetyl- Instead of 6-chloro-2-isopropoxy-4-phenylquinoline and 3-acetyl-6-chloro-1-isopropyl-4-phenyl-2-quinolone bromoacetic acid methyl ester, isopropyl iodide (0.70 ml, 7 .04 mmol) according to the method described in Example 34 (a).
Chloro-2-isopropoxy-4-phenylquinoline (1.00 g, 81%) and 3-acetyl-6-chloro-
1-isopropyl-4-phenyl-2-quinolone (0.
16g, 13%).

3-acetyl-6-chloro-2-isopropoxy-4-phenylquinoline Rf value = 0.75 (hexane: ethyl acetate = 2: 1 (v
/ V)) High resolution mass spectrum: Found [M ⁺ H] + 339.1031 calcd _{C 20 H 18 ClNO 2 339.1026 IR} (KBr) / νcm -1: 2983,1711,15
90 ¹ H NMR (270 MHz, CDCl ₃ ) δ: 7.78
(1H, d, J = 8.9 Hz), 7.55 (1H, d
d, J = 8.9, 2.4 Hz), 7.50-7.46.
(3H, m), 7.39 (1H, d, J = 2.4H
z), 7.32-7.26 (2H, m), 5.62 (1
H, m), 2.23 (3H, s), 1.41 (6H,
d, J = 6.4 Hz).

3-acetyl-6-chloro-1-isopropyl-4-phenylquinoline Rf value = 0.45 (hexane: ethyl acetate = 2: 1 (v
/ V)) High resolution mass spectrum: Found [M ⁺ H] + 339.1019 calcd _{C 20 H 18 ClNO 2 339.1026 IR} (KBr) / νcm -1: 3015,1710,16
39 ¹ H NMR (270 MHz, CDCl ₃ ) δ: 7.60
(1H, d, J = 9.2 Hz), 7.51-7.45
(4H, m), 7.32-7.27 (2H, m), 7.
23 (1H, d, J = 2.5 Hz), 5.55 (1H,
m), 2.22 (3H, s), 1.69 (6H, d, J
= 9.2 Hz). (B) 1- (6-chloro-2-isopropoxy-4-phenylquinolin-3-yl) -3- (4-pyridyl) propenone 3-acetyl-6-chloro-2-isopropoxy-4-
Phenylquinoline (157 mg, 0.462 mmol)
And pyridine-4-aldehyde (100 μL, 1.15
(mmol), and the reaction was carried out according to the method of Example 1 (b) to give the title compound (138 mg, 70%) as a yellow solid. m. p. : 47.0-48.0 ^° C (iPr ₂ O) High-resolution mass spectrum: actual value [M] ⁺ 428.1287 calculated value C ₂₆ H ₂₁ ClN ₂ O ₂ 428.1291 IR (KBr) / νcm ^-1 : 3432, 2979, 16
62, 1588 ¹ H NMR (270 MHz, CDCl ₃ ) δ: 8.61
(2H, d, J = 5.9 Hz), 7.84 (1H, d,
J = 9.0 Hz), 7.61 (1H, dd, J = 9.
0, 2.3 Hz), 7.45 (1H, d, J = 2.3H)
z), 7.44-7.39 (3H, m), 7.32-
7.21 (4H, m), 7.10 (1H, d, J = 1
6.2 Hz), 6.83 (1H, d, J = 16.2H)
z), 5.63 (1H, m), 1.36 (6H, d, J
= 6.5 Hz).

[0143]

Example 36 1- (2-Benzyloxy-6-chloro-4-phenylquinolin-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 1-274) (a) 3-acetyl- 6-chloro-2-benzoxy-4
-Phenylquinoline and 3-acetyl-6-chloro-1
Example 3 was repeated using benzyl bromide (0.80 ml, 6.73 mmol) instead of -benzyl-4-phenyl-2-quinolone bromoacetic acid methyl ester.
According to the method described in 4 (a), 3-acetyl-6-chloro-2-benzoxy-4-phenylquinoline (0.3
7 g, 26%) and 3-acetyl-6-chloro-1-benzyl-4-phenyl-2-quinolone (1.04 g, 74%).
%).

3-acetyl-6-chloro-2-benzoxy-4-phenylquinoline Rf value = 0.90 (hexane: ethyl acetate = 2: 1 (v
/ V)) High-resolution mass spectrum: actual measured value [M] ⁺ 387.1030 calculated value C ₂₄ H ₁₈ ClNO ₂ 387.1026 IR (KBr) / νcm ^-1 : 3057, 1711, 15
82 ¹ HNMR (500 MHz, CDCl ₃ ) δ: 7.84
(1H, d, J = 8.9 Hz), 7.59 (1H, d
d, J = 8.9, 2.3 Hz), 7.53-7.46.
(5H, m), 7.42 (1H, d, J = 2.3H
z), 7.41-7.35 (2H, m), 7.34-
7.28 (3H, m), 5.61 (2H, s), 2.1
9 (3H, s).

3-acetyl-6-chloro-1-benzyl-4-phenylquinoline Rf value = 0.60 (hexane: ethyl acetate = 2: 1 (v
/ V)) High-resolution mass spectrum: observed value [M] ⁺ 387.1017 calculated value C ₂₄ H ₁₈ ClNO ₂ 387.1026 IR (KBr) / νcm ⁻¹ : 3025, 1709, 16
45 ¹ H NMR (270 MHz, CDCl ₃ ) δ: 7.52-
7.48 (3H, m), 7.39 (1H, dd, J =
9.0, 2.3 Hz), 7.35-7.22 (9H,
m), 5.59 (2H, s), 2.28 (3H, s). (B) 1- (6-Chloro-2-benzoxy-4-phenylquinolin-3-yl) -3- (4-pyridyl) propenone 3-acetyl-2-benzoxy-6-chloro-4-phenylquinoline (143 mg) , 0.369 mmol) and pyridine-4-aldehyde (80 μL, 0.922 mm)
ol) and the reaction was carried out according to the method of Example 1 (b) to give the title compound (106 mg, 61%) as a yellow solid. m. p. _{^{: 144.0-145.0 o C (iPr 2 O}} ) High resolution mass spectrum: Found [M] ⁺ 476.1289 calcd _{C 30 H 21 ClN 2 O 2} 476.1292 IR (KBr) / νcm -1 : 3032, 1660, 15
89 ¹ H NMR (270 MHz, CDCl ₃ ) δ: 8.59
(2H, d, J = 6.0 Hz), 7.90 (1H, d,
J = 8.9 Hz), 7.63 (1H, dd, J = 8.
9, 2.4 Hz), 7.49 (1H, d, J = 2.4H)
z), 7.45-7.38 (5H, m), 7.31-
7.23 (5H, m), 7.14 (2H, d, J = 6.
0 Hz), 7.06 (1H, d, J = 16.3 Hz),
6.80 (1H, d, J = 16.3 Hz), 5.62
(2H, s).

[0146]

Example 37 1- (6-Chloro-2- (N, N-dimethyl) amino-4-phenylquinolin-3-yl)-
3- (4-pyridyl) propenone (exemplary compound number 1-
278) (a) 3-Acetyl-2,6-dichloro-4-phenylquinoline 3-acetyl-6-chloro-4-phenyl-2-quinolone (3.36 g, 11 mmol) was added to phosphorus oxychloride (1
1 mL), and the mixture was reacted under heating and reflux for 2 hours, and then the reaction solution was poured into ice-cold water to terminate the reaction. The reaction solution was made alkaline by adding aqueous ammonia, extracted with acetic acid, washed with saturated saline, and dried over magnesium sulfate. The crystals precipitated after concentration were washed with diisopropyl ether and collected by filtration to obtain the title compound (3.26 g, 91%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 315.0208 calculated value C ₁₇ H ₁₁ Cl ₂ NO 315.0218 IR (KBr) / νcm ^-1 : 1713,1556 ¹ HNMR (400 MHz, CDCl ₃ ) δ: 8. 03
(1H, d, J = 8.8 Hz), 7.72 (1H, d,
J = 9.6 Hz), 7.53-7.57 (4H, m),
7.32-7.34 (2H, m), 2.19 (3H,
s). (B) 3-acetyl-6-chloro-2- (N, N-dimethyl) amino-4-phenylquinoline 3-acetyl-2,6-dichloro-4-phenylquinoline obtained in Example 37 (a) (100mg, 0.3m
mol) of N, N-dimethylformamide (2 mL), a 50% aqueous solution of dimethylamine (500 μL) was added, and the mixture was reacted at room temperature for 5 hours. Water was added to terminate the reaction. This was extracted with ethyl acetate, and the organic layer was separated, washed with saturated saline and dried over anhydrous magnesium sulfate. The concentrated residue is subjected to a silica gel column (hexane: ethyl acetate = 5:
Purification was performed in 1) to give the title compound (76 mg, 73%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 324.1018 calculated value C ₁₉ H ₁₇ ClN ₂ O 324.1030 IR (KBr) / νcm ^-1 : 1703, 1570, 15
45 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.75
(1H, d, J = 8.8 Hz), 7.46-7.52
(4H, m), 7.21-7.25 (3H, m), 3.
06 (6H, s), 2.16 (3H, s). (C) 1- (6-chloro-2- (N, N-dimethyl) amino-4-phenylquinolin-3-yl) -3- (4-
Pyridyl) propenone 3-acetyl-6-chloro-2- (N, N-dimethyl) amino-4-phenylquinoline (50 mg, 0.15 mmol) obtained in Example 37 (b) and pyridine-4-
The reaction was carried out according to the method of Example 1 (b) using aldehyde (28 μL, 0.30 mmol) to obtain the title compound (85 mg, 65%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 413.1304 calculated value C ₂₅ H ₂₀ ClN ₃ O 413.1295 IR (KBr) / νcm ⁻¹ : 3046, 1633, 16
02 ¹ HNMR (400 MHz, CDCl ₃ ) δ: 8.60
(2H, d, J = 5.8 Hz), 7.77 (1H, d,
J = 9.6 Hz), 7.54 (1H, d, J = 9.5H)
z), 7.38-7.44 (3H, m), 7.27 (2
H, m), 7.21-7.24 (2H, m), 7.18
(2H, d, J = 5.8 Hz), 6.78 (1H, d,
J = 16.1 Hz), 3.06 (3H, s).

[0147]

Example 38 1- (6-Chloro-2- (N-methylhomopiperazyl) -4-phenylquinolin-3-yl)
-3- (4-pyridyl) propenone (Exemplary Compound No. 1
-282) (a) 3-Acetyl-6-chloro-2- (N-methylhomopiperazyl) -4-phenylquinoline 3-acetyl-2,6-dichloro-4-phenylquinoline (100 mg, 0.32 mmol) Of pyridine (1.
5 mL) solution with N-methylhomopiperazine (0.2 m
L, 1.78 mmol) and reacted at 130 ° C. for 1 hour. This was extracted with ethyl acetate, and the organic layer was separated, washed with saturated saline and dried over anhydrous magnesium sulfate. The concentrated residue was purified by a silica gel column (methylene chloride: methanol = 19: 1) to give the title compound (92 mg, 7
3%). High-resolution mass spectrum: measured value [M] ⁺ 393.1613 calculated value C ₂₃ H ₂₄ ClN ₃ O 393.1608 IR (KBr) / νcm ^-1 : 1695, 1566, 15
45 ¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.68
(1H, d, J = 8.9 Hz), 7.47-7.50
(4H, m), 7.23-7.26 (2H, m), 7.
18 (1H, s), 3.76-3.79 (2H, m),
3.58-3.61 (2H, m), 2.78-2.81
(2H, m), 2.60-2.62 (2H, m), 2.
39 (3H, s), 2.01-2.04 (2H, m). (B) 1- (6-chloro-2- (N-methylhomopiperazyl) -4-phenylquinolin-3-yl) -3- (4
-Pyridyl) propenone 3-acetyl-6-chloro-2- (N-methylhomopiperazyl) -4-phenylquinoline (92 mg, 0.23 mmol) obtained in Example 38 (a) and pyridine-4
The reaction was carried out using aldehyde (44 μL, 0.46 mmol) according to the method of Example 21 to give the title compound (5
(4 mg, 48%) as yellow crystals. High resolution mass spectrum: Found [M] ⁺ 482.1870 calcd _{C 29 H 27 ClN 4 O 482.1874} IR (KBr) / νcm -1: 1564,1544 1 HNMR (400MHz, CDCl 3) δ: 8. 59
(2H, d, J = 6.1 Hz), 7.72 (1H, d,
J = 8.9 Hz), 7.51 (1H, d, J = 8.9H)
z), 7.36-7.43 (3H, m), 7.22-
7.25 (3H, m), 7.13-7.17 (3H,
m), 6.72 (1H, d, J = 16.0 Hz), 3.
76-3.79 (2H, m), 3.55-3.57 (2
H, m), 2.78-2.80 (2H, m), 2.57
-2.60 (2H, m), 2.36 (3H, s), 1.
97-2.03 (2H, m).

[0148]

Example 39 1- (2,6-Dichloro-4-phenylquinolin-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 1-286) (a) 3-acetyl-2,6 -Dichloro-4-phenylquinoline Phosphorus oxychloride (200 μL, 2.15 mmol) was added to 3-acetyl-6-chloro-4-phenyl-2-quinolone (500 mg, 1.68 mmol), and the mixture was heated under reflux for 2.5 hours. Reacted. The reaction mixture is returned to room temperature, added with ice water and stirred for 1 hour. The precipitate was filtered to give the title compound (530 mg, 100%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 315.0210 calculated value C ₁₇ H ₁₁ Cl ₂ NO 315.0218 IR (KBr) / νcm ^-1 : 3345, 3053, 17
13 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.03
(1H, d, J = 8.9 Hz), 7.71 (1H, d
d, J = 8.9, 2.3 Hz), 7.62-7.50
(4H, m), 7.44 (1H, m), 7.36-7.
30 (2H, m), 2.19 (3H, s). (B) 1- (2,6-Dichloro-4-phenylquinolin-3-yl) -3- (4-pyridyl) propenone 3-acetyl-2,6-dichloro-4-phenylquinoline (55 mg, 0.175 mmol ) And pyridine-4
The reaction was carried out using -aldehyde (50 μL, 0.525 mmol) according to the method of Example 1 (b) to give the title compound (34 mg, 48%) as a yellow solid. High-resolution mass spectrum: measured value [M] ⁺ 404.0488 calculated value C ₂₃ H ₁₄ Cl ₂ N ₂ O 404.0484 IR (KBr) / νcm ⁻¹ : 3417, 3056, 16
60, 1591, 1555 ¹ H NMR (270 MHz, CDCl ₃ ) δ: 8.69 −
8.52 (2H, m), 8.08 (1H, d, J = 9.
0 Hz), 7.76 (1H, dd, J = 9.0, 2.2)
Hz), 7.59 (1H, d, J = 2.2 Hz), 7.
47-7.40 (3H, m), 7.32-7.26 (2
H, m), 7.21 (2H, d, J = 4.6 Hz),
7.10 (1H, d, J = 16.2 Hz), 6.78
(1H, d, J = 16.2 Hz).

[0149]

Working Example 40 1- (6-Chloro-1-methyl-4-)
Phenyl-2-quinolon-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 2-2) (a) 3-acetyl-6-chloro-4-phenyl-2-
Quinolone 2-amino-5-chlorobenzophenone (2.31 g,
Acetoacetic acid ethyl ester (1.3 mL,
10 mmol), and reacted under heating and refluxing for 4 hours.
The reaction mixture was returned to room temperature, diisopropyl ether was added, and the mixture was stirred for 1 hour. The precipitate was filtered to give the title compound (1.53 g, 51%). High-resolution mass spectrum: measured value [M−H] ⁺ 296.0482 calculated value C ₁₇ H ₁₁ ClNO ₂ 296.0478 IR (KBr) / νcm ⁻¹ : 3432, 2998, 17
_{^{04,1651 1 HNMR (270MHz, CDCl 3}} ) δ: 7.41-
7.54 (5H, m), 7.29-7.35 (2H,
m), 7.24 (1H, d, J = 2.0 Hz), 2.2
9 (3H, s). (B) 3-Acetyl-6-chloro-1-methyl-4-phenyl-2-quinolone 3-acetyl-6-chloro-4-phenyl-2-quinolone (200 mg, 0.672 mmol) in acetonitrile (2 ml) To methyl iodide (80 μL, 1.35)
mmol) and potassium carbonate (185 mg, 1.35 m)
mol), and reacted under heating and reflux for 4 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, water and saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane : Ethyl acetate = 1:
And eluted with 1) to afford the title compound (209 mg,
100%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 311.0690 calculated value C ₁₈ H ₁₄ ClNO ₂ 311.0667 IR (KBr) / νcm ^-1 : 3058, 1710, 16
38 ¹ H NMR (270 MHz, CDCl ₃ ): 7.55 (1
H, dd, J = 9.1, 2.4 Hz), 7.52-7.
47 (3H, m), 7.38 (1H, d, J = 9.1H
z), 7.31-7.26 (2H, m), 7.24 (1
H, d, J = 2.4 Hz), 3.77 (3H, s),
2.23 (3H, s). (C) 1- (6-chloro-1-methyl-4-phenyl-
2-quinolon-3-yl) -3- (4-pyridyl) propenone 3-acetyl-6-chloro-1-methyl-4-phenyl-2-quinolone (43 mg, 0.137 mmol) and pyridine-4-aldehyde ( 40μL, 0.410mm
ol) and the reaction was carried out according to the method of Example 1 (1b) to give the title compound (18 mg, 33%) as a yellow solid. High-resolution mass spectrum: Observed value [M] ⁺ 400.0987 Calculated value C ₂₅ H ₂₀ ClN ₂ O ₄ 400.0987 IR (KBr) / νcm ^-1 : 3057, 1638, 15
94,1556 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.60
(1H, dd, J = 8.4, 2.3 Hz), 7.48-
7.40 (4H, m), 7.32-7.17 (6H,
m), 6.86 (1H, d, J = 16.1 Hz), 3.
81 (3H, s).

[0150]

Example 41 1- (6-Chloro-1-methoxycarbonylmethyl-4-phenyl-2-quinolon-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 2-50) Example 34 3-acetyl-6-chloro-1-methoxycarbonylmethyl-4-phenyl-2- obtained in (a)
Quinolone (0.36 g, 0.974 mmol) and pyridine-4-aldehyde (200 μL, 2.10 mmol)
Using l), the reaction was carried out according to the method of Example 1 (b),
The title compound (0.37 g, 82%) was obtained as a yellow solid. m. p. _{^{: 68.0-69.0 o C (iPr 2 O}} ) High resolution mass spectrum: Found [M ⁺ H] + 459.1087 calcd _{C 26 H 19 ClN 2 O 4} 459.1112 IR (KBr) / νcm ^-1 : 1752, 1666, 16
44 ¹ HNMR (270 MHz, CDCl ₃ ) δ: 8.61
(2H, d, J = 2.7 Hz), 7.56 (1H, d
d, J = 9.1, 2.4 Hz), 7.47-7.38
(4H, m), 7.33 (1H, d, J = 2.4H
z), 7.32-7.22 (3H, m), 7.16 (1
H, d, J = 9.1 Hz), 7.10 (1H, m),
6.85 (1H, d, J = 16.4 Hz), 5.18
(2H, s), 3.84 (3H, s).

[0151]

Example 42 1- (6-Chloro-1-isopropyl-4-phenyl-2-quinolon-3-yl) -3- (4
-Pyridyl) propenone (Exemplified Compound No. 2-10) 3-Acetyl-6-chloro-1-isopropyl-4-phenyl-2-quinolone (1) obtained in Example 35 (a)
The reaction was carried out according to the method of Example 1 (b) using 57 mg, 0.461 mmol) and pyridine-4-aldehyde (100 μL, 1.15 mmol) to obtain the title compound (54 mg, 27%) as a yellow solid. . High-resolution mass spectrum: measured value [M] ⁺ 428.1286 calculated value C ₂₆ H ₂₁ ClN ₂ O ₂ 428.1291 IR (KBr) / νcm ^-1 : 3438, 2972, 16
65, 1637, 1594, 1555 ¹ H NMR (270 MHz, CDCl ₃ ) δ: 8.60
(2H, d, J = 5.7 Hz), 7.64 (1H, d,
J = 9.2 Hz), 7.54 (1H, dd, J = 9.
2, 2.2 Hz), 7.46-7.38 (3H, m),
7.31-7.26 (5H, m), 7.25 (1H,
d, J = 16.3 Hz), 6.86 (1H, d, J = 1)
6.3 Hz), 5.54 (1H, m), 1.71 (6
H, d, J = 7.1 Hz).

[0152]

Example 43 1- (1-benzyl-6-chloro-4)
-Phenyl-2-quinolon-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 2-42) 3-Acetyl-1-benzyl-6-chloro- obtained in Example 36 (a) 4-phenyl-2-quinolone (146
mg, 0.375 mmol) and pyridine-4-aldehyde (80 μL, 0.939 mmol), and reacted according to the method of Example 1 (b) to give the title compound (41
mg, 24%) as a yellow solid. High-resolution mass spectrum: measured value [M] ⁺ 476.1287 calculated value C ₃₀ H ₂₁ ClN ₂ O ₂ 476.1292 IR (KBr) / νcm ^-1 : 3031, 1666, 16
38 ¹ H NMR (400 MHz, CDCl ₃ ): 8.61 (2
H, d, J = 5.9 Hz), 7.49-7.41 (4
H, m), 7.39-7.22 (12H, m), 6.9
0 (1H, d, J = 16.1 Hz), 5.62 (2H,
s).

[0153]

Working Example 44 1- (1-Methyl-4-phenyl-2)
-Quinolone-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 2-1) (a) Instead of 3-acetyl-4-phenyl-2-quinolone 2-amino-5-chlorobenzophenone, 2-
The title compound (2.45 g, 93%) was obtained according to the method of Example 40 (a) using aminobenzophenone (1.97 g, 10 mmol). High-resolution mass spectrum: measured value [M] ⁺ 263.0940 calculated value C ₁₇ H ₁₃ NO ₂ 263.0946 IR (KBr) / νcm ^-1 : 1706, 1649 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.55
(1H, t, J = 8.0 Hz), 7.48-7.51
(3H, m), 7.44 (1H, d, J = 8.8H
z), 7.33-7.35 (2H, m), 7.28 (1
H, d, J = 8.0 Hz), 7.15 (1H, t, J =
7.3 Hz), 2.30 (3H, s). (B) 3-acetyl-1-methyl-4-phenyl-2-
Quinolone 3-acetyl-6 obtained in Example 44 (a) in place of 3-acetyl-6-chloro-4-phenyl-2-quinolone
4-phenyl-2-quinolone (395 mg, 1.5 mm
ol) according to the method of Example 40 (b) to give the title compound (390 mg, 94%) as yellow crystals. High resolution mass spectrum: Found [M] ⁺ 277.1082 calcd _{C 18 H 15 NO 2 277.1102 IR} (KBr) / νcm -1: 1711,1631 1 HNMR (400MHz, CDCl 3) δ: 7.61
(1H, t, J = 7.3 Hz), 7.44-7.50
(4H, m), 7.29-7.31 (3H, m), 7.
16 (1H, t, J = 7.3 Hz), 3.80 (3H,
s), 2.24 (3H, s). (C) 1- (1-methyl-4-phenyl-2-quinolon-3-yl) -3- (4-pyridyl) propenone 3-acetyl-1-methyl-4 obtained in Example 44 (b) -Phenyl-2-quinolone (139 mg, 0.5 m
mol) and pyridine-4-aldehyde (94 μL, 1 m
mol)) to give the title compound (100 mg, 55%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 366.1372 calculated value C ₂₄ H ₁₈ N ₂ O ₂ 366.1368 IR (KBr) / νcm ^-1 : 1633,1600,15
90 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.66
(1H, d, J = 8.5 Hz), 7.49 (1H, d,
J = 8.8 Hz), 7.42-7.44 (2H, m),
7.41 (2H, d, J = 5.0 Hz), 7.37 (1
H, d, J = 8.0 Hz), 7.27-7.31 (2
H, m), 7.26 (2H, d, J = 5.0 Hz),
7.23-7.25 (1H, m), 7.21 (1H,
t, J = 8.0 Hz), 7.10 (1H, t, J = 8.
3 Hz), 6.88 (1H, d, J = 16.1 Hz),
3.82 (3H, s).

[0154]

Working Example 45 1- (1-Isopropyl-4-phenyl-2-quinolon-3-yl) -3- (4-pyridyl)
Propenone (Exemplified Compound No. 2-9) (a) 2-Isopropylaminobenzophenone Sodium hydride (183 mg, 7.6) under a nitrogen atmosphere.
mmol) in N, N-dimethylformamide (10 m
L) and then 2-aminobenzophenone (1.0
g, 5.1 mmol) in N, N-dimethylformamide (10 mL) and stirred at room temperature for 30 minutes. Isopropyl iodide (2.03 mL, 12.2 mmol)
N, N-dimethylformamide (4 mL) solution was added and reacted at 80 ° C. for 22 hours, and then water was added to terminate the reaction. This was extracted with ethyl acetate, and the organic layer was separated, washed with saturated saline and dried over anhydrous magnesium sulfate. The concentrated residue is subjected to a silica gel column (hexane: ethyl acetate = 1).
5: 1) to give the title compound (260 mg, 20
%) As an oil. High-resolution mass spectrum: measured value [M] ⁺ 239.1296 calculated value C ₁₆ H ₁₇ NO 239.1310 IR (Liquid film) / νcm ^-1 : 1622
1574, 1518 ¹ H NMR (400 MHz, CDC
l ₃ ) δ: 8.61 (1H, s), 7.59 (2H,
d, J = 6.6 Hz), 7.44-7.58 (5H,
m), 7.36 (1H, t, J = 8.8 Hz), 6.7
9 (1H, d, J = 8.8 Hz), 6.49 (1H,
t, J = 8.1 Hz), 3.80 (1H, d, J = 5.
9Hz), 1.33 (3H, s), 1.31 (3H,
s). (B) 3-Acetyl-1-isopropyl-4-phenyl-2-quinolone Obtained in Example 45 (a) in place of 3-acetyl-6-chloro-1-methyl-4-phenyl-2-quinolone. 2
-Isopropylaminobenzophenone (260 mg,
1.1 mmol) and ethyl acetoacetate (1.3 mL, 1
0.4 mmol) to give the title compound (250 mg, 75%) as yellow crystals according to the method of Example 40 (b). High-resolution mass spectrum: measured value [M] ⁺ 305.1390 calculated value C ₂₀ H ₁₉ NO ₂ 309.1415 IR (KBr) / νcm ^-1 : 1627, 1603, 15
81 ¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.66
(1H, d, J = 8.8 Hz), 7.55 (1H, t,
J = 8.0 Hz), 7.46-7.48 (3H, m),
7.29-7.31 (2H, m), 7.28 (1H,
d, J = 8.8 Hz), 7.12 (1H, t, J = 8.
0 Hz), 2.23 (3H, s), 1.72 (3H,
s), 1.70 (3H, s). (C) 1- (1-isopropyl-4-phenyl-2-quinolon-3-yl) -3- (4-pyridyl) propenone 3-acetyl-1-isopropyl-4 obtained in Example 45 (b) -Phenyl-2-quinolone (100 mg,
0.33 mmol) and pyridine-4-aldehyde (62
(L, 0.6 mmol), and reacted according to the method of Example 1 (b) to give the title compound (70 mg, 61%).
Was obtained as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 394.1683 calculated value C ₂₆ H ₂₂ N ₂ O ₂ 394.1682 IR (KBr) / νcm ⁻¹ : 1663, 1633, 16
00 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.89 −
8.91 (1H, m), 8.59 (2H, d, J = 5.
9Hz), 7.72 (2H, d, J = 5.9Hz),
7.60 (1H, t, J = 8.8 Hz), 7.39-
7.42 (2H, m), 7.36 (1H, d, J = 8.
0 Hz), 7.23-7.30 (4H, m), 7, 16
(1H, t, J = 8.8 Hz), 6.88 (1H, d,
J = 16.1 Hz), 1.74 (3H, s), 1.72
(3H, s).

[0155]

Working Example 46 1- (1-Isopropyl-6-nitro-4-phenyl-2-quinolon-3-yl) -3- (4
-Pyridyl) propenone (Exemplified Compound No. 2-14) (a) 2-Isopropylamino-5-nitrobenzophenone 2-Isopropylamino-4-nitrobenzophenone (5.0 instead of 2-isopropylaminobenzophenone)
g, 206 mmol) and isopropyl iodide (8.42).
The reaction was carried out according to the method of Example 45 (a) using the compound of the title (2.0 g, 34 g).
%) As yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 284.1170 calculated value C ₁₆ H ₁₆ N ₂ O ₃ 284.1161 IR (KBr) / νcm ^-1 : 166,1605,15
77 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.33
(1H, s), 8.50 (1H, d, J = 2.9H)
z), 8.23 (1H, d, J = 9.5 Hz), 7.5
8-7.63 (3H, m), 7.49-7.53 (2
H, d), 6.80 (1H, d, J = 9.5 Hz),
3.90 (1H, d, J = 6.6 Hz), 1.38 (3
H, s), 1.37 (3H, s). (B) 3-acetyl-1-isopropyl-6-nitro-
4-Phenyl-2-quinolone The 2-isopropylamino-5-nitrobenzophenone obtained in Example 46 (a) in place of 3-acetyl-6-chloro-4-phenyl-2-quinolone (2.0 g, 7 m
mol) and ethyl acetoacetate (8.4 mL, 66.5 m)
mol) and the title compound (1.7 g, 70%) was obtained according to the method of Example 40 (b). High-resolution mass spectrum: measured value [M] ⁺ 350.1258 calculated value C ₂₀ H ₁₈ N ₂ O ₄ 350.1266 IR (KBr) / νcm ^-1 : 1713,1647,16
04 ¹ HNMR (400 MHz, CDCl ₃ ) δ: 8.39
(1H, d, J = 9.5 Hz), 8.25 (1H,
s), 7.80 (1H, d, J = 9.5 Hz), 7.5
8-7.59 (3H, m), 7.32-7.37 (2
H, m), 2.28 (3H, s), 1.80 (3H,
s), 1.78 (3H, s). (C) 1- (1-isopropyl-6-nitro-4-phenyl-2-quinolon-3-yl) -3- (4-pyridyl) propenone 3-acetyl-1 obtained in Example 46 (b) -Isopropyl-6-nitro-4-phenyl-2-quinolone (5
Example 1 using 25 mg, 1.5 mmol) and pyridine-4-aldehyde (54 μL, 0.6 mmol).
The reaction was carried out according to the method of (b) to give the title compound (421
mg, 64%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 439.1534 calculated value C ₂₅ H ₂₁ N ₃ O ₄ 439.1532 IR (KBr) / νcm ^-1 : 1668,1649,16
05 ¹ HNMR (400 MHz, CDCl ₃ ) δ: 8.61
(2H, d, J = 5.9 Hz), 8.42 (1H, d,
J = 9.6 Hz), 8.26 (1H, s), 7.79
(1H, d, J = 9.5 Hz), 7.47 (2H, d,
J = 5.8 Hz), 7.24-7.32 (6H, m),
6.85 (1H, d, J = 16.1 Hz), 1.76
(3H, s), 1.74 (3H, s).

[0156]

Example 47 1- (6-acetoamino-1-isopropyl-4-phenyl-2-quinolon-3-yl) -3
-(4-pyridyl) propenone (Exemplary Compound No. 2-1)
5) (a) 3-acetyl-1-isopropyl-6-amino-
4-Phenyl-2-quinolone The 3-acetyl-1-isopropyl-6-nitro-4-phenyl-2-quinolone obtained in Example 46 (b) (5
0 mg, 0.14 mmol) of methanol (1.5 m
L) 10% palladium carbon (20 mg) was added to the solution and hydrogenated. After completion of the reaction, the reaction solution was filtered through celite, and the concentrated residue was purified through a silica gel column (hexane: acetone = 2: 1) to give the title compound (723 mg, 7 mg).
9%). High-resolution mass spectrum: measured value [M] ⁺ 320.511 calculated value C ₂₀ H ₂₀ N ₂ O ₂ 320.1525 IR (KBr) / νcm ^-1 : 1704, 1628, 15
64 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.43-
7.50 (4H, m), 7.27-7.30 (2H,
m), 6.94 (1H, d, J = 9.5 Hz), 6.5
0 (1H, s), 2.22 (3H, s), 1.69 (3
H, s), 1.67 (3H, s). (B) 3-Acetyl-6-acetoamino-1-isopropyl-4-phenyl-2-quinolone 3-acetyl-1-isopropyl-6-amino-4-phenyl-2- obtained in Example 47 (a) Quinolone (2
Acetic anhydride (1 mL) was added to a pyridine (2 mL) solution of 50 mg (0.78 mmol) and reacted for 30 minutes. This was extracted with ethyl acetate, the organic layer was separated, washed with dilute hydrochloric acid and saturated saline, and dried over anhydrous magnesium sulfate to obtain the title compound (269 mg, 95%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 362.1632 calculated value C ₂₂ H ₂₂ N ₂ O ₃ 362.1630 IR (KBr) / νcm ^-1 : 1696,1635 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7 .94
(1H, d, J = 9.5 Hz), 7.62 (1H, d,
J = 9.5 Hz), 7.45-7.50 (3H, m),
7.28-7.31 (2H, m), 7.15 (1H,
s), 2.22 (3H, s), 2.11 (3H, s),
1.70 (3H, s), 1.68 (3H, s). (C) 1- (6-acetoamino-1-isopropyl-4)
-Phenyl-2-quinolon-3-yl) -3- (4-pyridyl) propenone 3-acetyl-6-acetoamino-1-isopropyl-4-phenyl-2-quinolone obtained in Example 47 (b) ( 165 mg, 0.46 mmol) and pyridine-4-
The reaction was carried out using aldehyde (86 μL, 0.9 mmol) according to the method of Example 1 (b), and the title compound (1
(29 mg, 63%) as yellow crystals. High-resolution mass spectrum: measured value [M] ⁺ 451.1906 calculated value C ₂₈ H ₂₅ N ₃ O ₃ 451.1896 IR (KBr) / νcm ^-1 : 166,1631,15
_{^{94,1545 1 HNMR (400MHz, CDCl 3}} ) δ: 8.58
(2H, d, J = 5.9 Hz), 7.98 (1H, d,
J = 9.1 Hz), 7.67 (1H, d, 9.4H)
z), 7.41-7.45 (3H, m), 7.21-
7.31 (6H, m), 7.10 (1H, s), 6.8
7 (1H, d, J = 16.2 Hz), 2.12 (3H,
s), 1.72 (3H, s), 1.71 (3H, s).

[0157]

Working Example 48 1- (6,7-Dimethoxy-1-isopropyl-4-phenyl-2-quinolon-3-yl)-
3- (4-pyridyl) propenone (exemplary compound number 2-
13) (a) 3-Acetyl-6,7-dimethoxy-4-phenyl-2-quinolone 2-amino-4,5-dimethoxybenzophenone (1.
Example 40 using 82 g (7.08 mmol) and acetoacetic acid ethyl ester (4 ml, 30 mmol).
The reaction was carried out according to the method of (b), and the title compound (1.4
9g, 65%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 323.1134 calculated value C ₁₉ H ₁₇ NO ₄ 323.1208 IR (KBr) / νcm ^-1 : 2909, 1705, 16
45,1515 ¹ H NMR (500 MHz, CDCl ₃ ) δ: 7.50 −
7.47 (3H, m), 7.34-7.26 (2H,
m), 6.95 (1H, s), 6.60 (1H, s),
4.00 (3H, s), 3.67 (3H, s), 2.3
1 (3H, s). (B) 3-acetyl-6,7-dimethoxy-1-isopropyl-4-phenyl-2-quinolone 3-acetyl-6,7-dimethoxy-4-phenyl-2
Using -quinolone (1.16 g, 3.6 mmol) and isopropyl iodide (1.70 g, 10 mmol)
The reaction was carried out according to the method of Example 40 (b) to give the title compound (137 mg, 10%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 365.1619 calculated value C ₂₂ H ₂₃ NO ₄ 365.1642 IR (KBr) / νcm ^-1 : 2976, 1698, 16
29,1549,1522 ¹ H NMR (500 MHz, CDCl ₃ ) δ: 7.49 −
7.44 (3H, m), 7.31-7.29 (2H,
m), 7.27 (1H, s), 6.65 (1H, s),
4.03 (3H, s), 3.65 (3H, s), 2.2
4 (3H, s), 1.73 (6H, d, J = 6.8H
z). (C) 1- (6,7-dimethoxy-1-isopropyl-
4-phenyl-2-quinolon-3-yl) -3- (4-
Pyridyl) propenone 3-acetyl-6,7-dimethoxy-1-isopropyl-4-phenyl-2-quinolone (129 mg, 0.35
mmol) and pyridine-4-aldehyde (75 mg,
(0.7 mmol), and the reaction was carried out according to the method of Example 1 (b) to give the title compound (162 mg, 63%) as a white solid. High-resolution mass spectrum: Observed value [M] ⁺ 454.1879 Calculated value C ₂₈ H ₂₆ N ₂ O ₄ 454.1908 IR (KBr) / νcm ^-1 : 3008,1662,16
30, 1594, 1551 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.59
(2H, d, J = 6.6 Hz), 7.44-7.21
(10H, m), 6.93 (1H, d, J = 16.8H
z), 6.71 (1H, s), 4.05 (3H, s),
3.66 (3H, s), 1.74 (6H, d, J = 7.
4 Hz).

[0158]

Working Example 49 1- (6-Methoxy-4-phenyl-)
2-quinolone-3-yl) -3- (4-pyridyl) propenone (Exemplary Compound No. 2-60) (a) 3-acetyl-6-methoxy-4-phenyl-2
-Quinolone 2-amino-5-methoxybenzophenone (283 m
g, 1.24 mmol), and acetoacetic acid ethyl ester (200 μL, 1.24 mmol) was added, and the mixture was reacted under heating and reflux for 3 hours. The reaction mixture was returned to room temperature, diisopropyl ether was added, and the mixture was stirred for 1 hour. The precipitate was filtered to give the title compound (154 mg, 43%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 293.1031 calculated value C ₁₈ H ₁₅ NO ₃ 293.1052 IR (KBr) / νcm ^-1 : 2848, 1704, 16
_{^{50,1621 1 HNMR (400MHz, CDCl 3}} ) δ: 7.53-
7.46 (3H, m), 7.44 (1H, d, J = 8.
8 Hz), 7.36-7.32 (2H, m), 7.19
(1H, dd, J = 8.8, 2.9 Hz), 6.68
(1H, d, J = 2.9 Hz), 3.67 (3H,
s), 2.31 (3H, s). (B) 1- (6-Methoxy-4-phenyl-2-quinolon-3-yl) -3- (4-pyridyl) propenone 3-acetyl-6-methoxy-4-phenyl-2-quinolone (112 mg, 0 .386 mmol) and pyridine-4-aldehyde (70 μL, 0.772 mmol), and the reaction was carried out according to the method of Example 1 (b) to give the title compound (91 mg, 63%) as a yellow solid. High-resolution mass spectrum: measured value [M] ⁺ 382.1317 calculated value C ₂₄ H ₁₈ N ₂ O ₃ 382.1318 IR (KBr) / νcm ^-1 : 3027, 1650, 16
21,1596 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.60
(2H, d, J = 5.9 Hz), 7.47-7.38
(4H, m), 7.35-7.25 (5H, m), 7.
13 (1H, dd, J = 8.8, 2.2 Hz), 6.9
2 (1H, d, J = 16.1 Hz), 6.72 (1H, d, J = 16.1 Hz)
d, J = 2.2 Hz), 3.66 (3H, s).

[0159]

Working Example 50 1- (1-Isopropyl-6-methoxy-4-phenyl-2-quinolon-3-yl) -3-
(4-pyridyl) propenone (Exemplary Compound No. 2-1)
2) (a) 2-Isopropylamino-5-methoxybenzophenone 2-amino-5-methoxybenzophenone (504 m
g, 2.22 mmol) of dimethylformamide (10
sodium hydride (180 mg, 3.33
mmol) and stirred for 20 minutes. Thereafter, isopropyl iodide (330 μL, 3.33 mmol) was added,
The reaction was performed for 20 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate: methylene chloride = 10: (1: 1 elution) to give the title compound (48 mg, 8%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 269.1421 calculated value C ₁₇ H ₁₉ NO ₂ 269.1416 IR (film) / νcm ^-1 : 3319, 2968, ¹
631, 1610, 1575, 1516 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.21
(1H, m), 7.63 (2H, d, J = 6.6H
z), 7.53-7.41 (3H, m), 7.08 (1
H, dd, J = 9.6, 2.9 Hz), 7.01 (1
H, d, J = 2.9 Hz), 6.76 (1H, d, J =
9.6 Hz), 3.79 (1H, m), 3.64 (3
H, s), 1.30 (6H, d, J = 5.9 Hz). (B) 3-Acetyl-1-isopropyl-6-methoxy-4-phenyl-2-quinolone 2-isopropylamino-5-methoxybenzophenone (47 mg, 0.174 mmol) in ethyl acetoacetate (130 μL, 1.05 mmol) And the reaction was carried out according to the method of Example 49 (a) to obtain the title compound (52 mg, 90%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 335.1519 calculated value C ₂₁ H ₂₁ NO ₃ 335.1522 IR (KBr) / νcm ^-1 : 2970, 1711, 16
35, 1564 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.60
(1H, d, J = 9.5 Hz), 7.50-7.42
(3H, m), 7.32-7.27 (2H, m), 7.
17 (1H, dd, J = 9.5, 2.9 Hz), 6.7
2 (1H, d, J = 2.9 Hz), 3.66 (3H,
s), 2.23 (3H, s), 1.69 (6H, d, J
= 7.3 Hz). (C) 1- (1-isopropyl-6-methoxy-4-phenyl-2-quinolon-3-yl) -3- (4-pyridyl) propenone 3-acetyl-1-isopropyl-6-methoxy-4-
Phenyl-2-quinolone (52 mg, 0.155 mmol
l) and pyridine-4-aldehyde (20 μL, 0.3
Using 10 mmol), the reaction was carried out according to the method of Example 1 (b) to give the title compound (43 mg, 66%) as a yellow solid. High-resolution mass spectrum: measured value [M] ⁺ 424.1779 calculated value C ₂₇ H ₁₈ N ₂ O ₃ 424.1787 IR (film) / νcm ^-1 : 3007, 1664, ¹
632, 1594 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.59
(2H, d, J = 7.0 Hz), 7.65 (1H, d,
J = 9.4 Hz) 7.44-7.37 (3H, m),
7.32-7.24 (5H, m), 7.22 (2H, d
d, J = 9.4, 3.0 Hz), 6.88 (1H, d,
J = 16.2 Hz), 6.79 (1H, d, J = 3.0)
Hz), 3.68 (3H, s), 1.71 (6H, d,
J = 7.1 Hz).

[0160]

Working Example 51 1- (1-Isopropyl-6-methyl-4-phenyl-2-quinolon-3-yl) -3- (4
-Pyridyl) propenone (Exemplified Compound No. 2-11) (a) 2-isopropylamino-5-methoxybenzophenone 2-amino-5-methylbenzophenone (480 mg,
2.27 mmol) and isopropyl iodide (340 μl)
L, 3.41 mmol) and reacted according to the method of Example 50 (a) to give the title compound (75 mg, 13 mg).
%) As a white solid. High-resolution mass spectrum: measured value [M] ⁺ 253.1462 calculated value C ₂₇ H ₁₉ NO 253.1467 IR (film) / νcm ^-1 : 3306, 2968, ¹
628, 1574, 1521 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.42
(1H, m), 7.59 (2H, d, J = 7.3H
z), 7.50 (1H, t, J = 7.3 Hz), 7.4
4 (2H, t, J = 7.3 Hz), 7.26 (1H,
d, J = 2.2 Hz), 7.19 (1H, dd, J =
8.1, 2.2 Hz), 6.72 (1H, d, J = 8.
1Hz), 3.77 (1H, m), 2.15 (3H,
s), 1.30 (6H, d, J = 6.6 Hz). (B) 3-acetyl-1-isopropyl-6-methyl-
4-Phenyl-2-quinolone 2-isopropylamino-5-methylbenzophenone (69 mg, 0.272 mmol) was reacted with ethyl acetoacetate (220 μL, 1.63 mmol) according to the method of Example 49 (a). To give the title compound (72 mg, 83%) as a white solid. High-resolution mass spectrum: measured value [M] ⁺ 319.1572 calculated value C ₂₁ H ₂₁ NO ₂ 319.1572 IR (film) / νcm ^-1 : 2972,1710,1
_{^{636,1564 1 HNMR (400MHz, CDCl 3}} ) δ: 7.55
(1H, d, J = 8.8 Hz), 7.49-7.44
(3H, m), 7.36 (1H, dd, J = 8.8,
1.5 Hz), 7.32-7.27 (2H, m), 7.
04 (1H, d, J = 1.5 Hz), 2.27 (3H,
s), 2.22 (3H, s), 1.69 (6H, d, J
= 6.6 Hz). (C) 1- (1-isopropyl-6-methyl-4-phenyl-2-quinolon-3-yl) -3- (4-pyridyl) propenone 3-acetyl-1-isopropyl-6-methyl-4-phenyl -2-quinolone (68 mg, 0.214 mmol
l) and pyridine-4-aldehyde (40 μL, 0.4
Using 28 mmol), the reaction was carried out according to the method of Example 1 (b) to give the title compound (52 mg, 59%) as a yellow solid. High-resolution mass spectrum: measured value [M] ⁺ 408.1843 calculated value C ₂₇ H ₂₄ N ₂ O ₂ 408.1838 IR (KBr) / νcm ⁻¹ : 2971, 1664, 16
33, 1593, 1563 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.59
(2H, d, J = 5.9 Hz), 7.60 (1H, d,
J = 8.8 Hz) 7.45-7.39 (4H, m),
7.30-7.20 (5H, m), 7.11 (1H,
m), 6.87 (1H, d, J = 16.1 Hz), 2.
30 (3H, s), 1.71 (6H, d, J = 7.3H
z).

[0161]

Example 52 1- (2-Phenylquinolin-4-yl) -4- (4-pyridyl) propenone (Exemplary Compound No. 3-65) (a) 4-acetyl-2-phenylquinoline 2-phenylquinoline ( 2.07 g, 10 mmol) in methylene chloride (100 mL) and water (100 mL), and pyruvic acid (2.64 g, 30 mmol), silver nitrate (135 mg, 0.8 mmol), ammonium peroxosulfate (3.42 g, 15 mmol) at room temperature. , And trifluoroacetic acid (3.42 mL, 30 mmol) were added, followed by stirring at 40 ° C. for 6.5 hours. After completion of the reaction, the mixture was made alkaline with a 1N aqueous sodium hydroxide solution, diluted with methylene chloride, and the organic layer was separated, washed with saturated saline and dried over anhydrous magnesium sulfate. The concentrated residue was purified by a silica gel column (hexane: ethyl acetate = 12: 1) to obtain the title compound (690 mg, 28%). High-resolution mass spectrum: measured value [M] ⁺ 247.1005 calculated value C ₁₇ H ₁₃ NO 247.1003 IR (KBr) / νcm ^-1 : 1682, 1339,
1248 ¹ H NMR (400 MHz, CDCl ₃ ): 8.41 (1
H, d, J = 8.5 Hz), 8.21 (1H, d, J =
7.7 Hz), 8.17 (2H, d, J = 6.9H)
z), 8.06 (1H, s), 7.77 (1H, t, J
= 8.4 Hz), 7.48-7.63 (4H, m),
2.80 (3H, s). (B) 1- (2-phenylquinolin-4-yl) -4-
(4-pyridyl) propenone The method of Example 21 using 4-acetyl-2-phenylquinoline (100 mg, 0.40 mmol) obtained in Example 52 (a) and pyridine-4-aldehyde (190 μL, 2 mmol). The title compound (108 mg, 80%) was obtained. High-resolution mass spectrum: measured value [M] ⁺ 336.1256 calculated value C ₂₃ H ₁₆ N ₂ O 336.1263 IR (KBr) / νcm ^-1 : 1593,1549,13
44 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.70
(2H, d, J = 5.1 Hz), 8.27 (1H, d,
J = 8.0 Hz), 8.20 (2H, d, J = 6.6H)
z), 8.09 (1H, d, J = 7.3 Hz), 7.9
9 (1H, s), 7.81 (1H, t, J = 8.8H)
z), 7.47-7.62 (5H, m), 7.42 (2
H, d, J = 5.9 Hz), 7.39 (1H, s).

[0162]

Example 53 1- (2-Chloroquinolin-4-yl) -4- (4-pyridyl) propenone (Exemplary Compound No. 3-41) (a) 4-Acetyl-2-chloroquinoline 2-phenylquinoline Instead, 2-chloroquinoline (4.89 g, 30 mmol) and pyruvic acid (7.92)
g, 90 mmol) and silver nitrate (408 mg, 2.4 mm)
ol), ammonium peroxosulfate (10.3 g, 4
5 mmol), and trifluoroacetic acid (10.3 mL, 9
0 mmol) to carry out a reaction according to the method of Example 52 (a) to obtain the title compound (271 mg, 4%). High-resolution mass spectrum: measured value [M] ⁺ 205.0297 calculated value C ₁₁ H ₈ ClNO 205.0294 IR (KBr) / νcm ^-1 : 1690, 1106, 76
8 ¹ H NMR (500 MHz, CDCl ₃ ) δ: 8.38 (1 H, d, J = 8.5 Hz), 8.07 (1
H, d, J = 8.5 Hz), 7.79 (1H, t, J =
8.4 Hz), 7.65 (1H, t, J = 8.4H)
z), 7.60 (1H, s), 2.75 (3H, s). (B) 1- (2-chloroquinolin-4-yl) -4-
(4-pyridyl) propenone Example 21 using 4-acetyl-2-chloroquinoline (100 mg, 0.48 mmol) obtained in Example 52 (a) and pyridine-4-aldehyde (183 μL, 1.92 mmol). The reaction was carried out according to the method described above to obtain the title compound (100 mg, 71%). High-resolution mass spectrum: observed value [M] ⁺ 294.0560 calculated value C ₁₇ H ₁₁ ClN ₂ O 294.0560 IR (KBr) / νcm ^-1 : 1655,764 ¹ HNMR (400 MHz, CDCl ₃ ) δ: 8. 72
(2H, d, J = 5.8 Hz), 8.12 (1H, d,
J = 8.1 Hz), 8.06 (1H, d, J = 8.8H)
z), 7.83 (1H, t, J = 8.0 Hz), 7.6
4 (1H, t, J = 8.8 Hz), 7.52 (1H,
s), 7.49 (1H, s), 7.42 (2H, d, J
= 5.9 Hz), 7.33 (1H, d, J = 16.1H)
z).

[0163]

Example 54 1- (2-Methylquinolin-4-yl) -4- (4-pyridyl) propenone (Exemplary Compound No. 3-49) (a) 4-Acetyl-2-methylquinoline 2-phenylquinoline Replace with quinaldine (1.43m
L, 10 mmol) and pyruvic acid (2.64 g, 30 m
mol), silver nitrate (135 mg, 0.8 mmol), ammonium peroxosulfate (3.42 g, 15 mmol)
l) and trifluoroacetic acid (3.42 mL, 30 mmol)
The reaction was carried out using 1) according to the method of Example 52 (a) to give the title compound (214 mg, 11%). High-resolution mass spectrum: measured value [M] ⁺ 185.0841 calculated value C ₁₂ H ₁₁ NO 185.0841 IR (KBr) / νcm ^-1 : 1684,1238,77
1 ¹ H NMR (500 MHz, CDCl ₃ ) δ: 8.37
(1H, d, J = 8.1 Hz), 8.06 (1H, d,
J = 8.8 Hz), 7.73 (1 H, t, J = 8.0 H)
z), 7.57 (1H, t, J = 8.0 Hz), 7.4
9 (1H, s), 2.81 (3H, s), 2.73 (3
H, s). (B) 1- (2-methylquinolin-4-yl) -4-
(4-pyridyl) propenone Example 21 using 4-acetyl-2-methylquinoline (100 mg, 0.54 mmol) obtained in Example 54 (a) and pyridine-4-aldehyde (203 μL, 2.16 mmol). The reaction was carried out according to the method described above to obtain the title compound (75 mg, 51%). High-resolution mass spectrum: measured value [M] ⁺ 274.1110 calculated value C ₁₈ H ₁₄ N ₂ O 274.1106 IR (KBr) / νcm ^-1 : 1658, 1596, 12
38 ¹ H NMR (500 MHz, CDCl ₃ ) δ: 8.73
(2H, d, J = 8.2 Hz), 8.15 (1H, d,
J = 8.5 Hz), 8.08 (1H, d, J = 8.4H)
z), 7.78 (1H, t, J = 7.8 Hz), 7.5
9 (1H, t.J = 8.1 Hz), 7.51 (1H,
d, J = 16.2 Hz), 7.44-7.47 (3H,
m), 7.38 (1H, d, J = 16.2 Hz), 2.
86 (3H, s).

[0164]

Example 55 1- (2-Methoxyquinolin-4-yl) -4- (4-pyridyl) propenone (Exemplified Compound No. 3-57) (a) 4-acetyl-2-methoxyquinoline Example 53 (a) 4-acetyl-2-chloroquinoline (205 mg, 1 mmol) obtained in
A solution of 28% sodium methoxide in methanol (0.38 mL, 2 mmol) was added to the solution, and the mixture was reacted at 70 ° C. for 2 hours and 30 minutes. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
(Eluted at 9: 1) to give the title compound (103 m
g, 51%). High-resolution mass spectrum: measured value [M] ⁺ 201.0786 calculated value C ₁₂ H ₁₁ NO ₂ 201.00789 IR (KBr) / νcm ^-1 : 1678, 1601, 13
32,1238 ¹ H NMR (500 MHz, CDCl ₃ ) δ: 8.29
(1H, d, J = 9.5 Hz), 7.89 (1H, d,
J = 9.5 Hz), 7.66 (1H, t, J = 8.8H)
z), 7.45 (1H, t, J = 8.8 Hz), 7.1
5 (1H, s), 4.10 (3H, s), 2.70 (3
H, s). (B) 1- (2-methylquinolin-4-yl) -4-
(4-pyridyl) propenone Example 21 using 4-acetyl-2-methoxyquinoline (100 mg, 0.5 mmol) obtained in Example 55 (a) and pyridine-4-aldehyde (141 μL, 1.5 mmol). The reaction was carried out according to the method described above to obtain the title compound (75 mg, 5%). High-resolution mass spectrum: measured value [M] ⁺ 290.050 calculated value C ₁₈ H ₁₄ N ₂ O ₂ 290.1055 IR (KBr) / νcm ^-1 : 1655,1598,13
83,1352,1235 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.69
(1H, d, J = 5.8 Hz), 7.95 (1H, t,
J = 8.8 Hz), 7.69 (1H, t, J = 8.8H)
z), 7.48 (1H, d, J = 16.1 Hz), 7.
44 (1H, d.J = 8.8 Hz), 7.40 (2H,
d, J = 5.9 Hz), 7.31 (1H, d, J = 1)
6.8 Hz), 7.05 (1H, s), 4.13 (3
H, s).

[0165]

Example 56 1- (3-Phenylquinolin-4-yl) -4- (4-pyridyl) propenone (Exemplified Compound No. 3-33) (a) 3-Phenylquinoline 3-bromoquinoline (1.0 g, 5 mmol) of 1,2
Phenylboronic acid (671 mg, 5.5 mmol) in a mixed solvent of dimethoxyethane (30 mL) and water (10 mL).
l), cesium carbonate (3.3 g, 15 mmol) and dichlorobis (triphenylphosphine) palladium (I
I) (175 mg, 0.25 mmol) was added, and the mixture was reacted at 80 ° C. for 1 hour and 30 minutes. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3). : Eluting with 1: 1) to give the title compound (9
(88 mg, 96%). High-resolution mass spectrum: measured value [M] ⁺ 205.09898 calculated value C ₁₅ H ₁₁ N 205.0891 IR (Liquid film) / νcm ^-1 : 149
4,762 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.18
(1H, s), 8.23 (1H, s), 8.14 (1
H, d, J = 8.8 Hz), 7.86 (1H, d, J =
8.1 Hz), 7.69-7.73 (3H, m), 7.
49-7.60 (3H, m), 7.40-7.45 (1
H, m). (B) 4-acetyl-3-phenylquinoline 3-phenylquinoline obtained in Example 56 (a) instead of 2-phenylquinoline (987 mg, 4.8 mmol)
l) and pyruvic acid (1.27 g, 14.4 mmol),
The reaction was carried out according to the method of Example 52 (a) using silver nitrate (65 mg, 0.38 mmol), ammonium peroxosulfate (3.3 g, 14.4 mmol), and trifluoroacetic acid (1.6 mL, 14.4 mmol). The title compound (130 mg, 11%) was obtained. High resolution mass spectrum: Found [M] ⁺ 247.0997 calcd _{C 17 H 13 NO 247.0997 IR (} Liquid film) / νcm -1: 170
4,1195,764 ¹ H NMR (400 MHz, CD
Cl ₃ ) δ: 9.05 (1H, s), 8.24 (1H,
d, J = 8.7 Hz), 7.79-7.84 (2H,
m), 7.66 (1H, t, J = 8.8 Hz), 7.4
7-7.55 (5H, m), 2.15 (3H, s). (C) 1- (3-phenylquinolin-4-yl) -4-
(4-pyridyl) propenone 4-acetyl-3-phenylquinoline obtained in Example 56 (b) (130 mg, 0.53 mmol) and pyridine-4-aldehyde (148 μL, 2.12 mmol)
The reaction was carried out according to the method of Example 21 using to give the title compound (55 mg, 31%). High-resolution mass spectrum: measured value [M] ⁺ 336.1256 calculated value C ₂₃ H ₁₆ N ₂ O 336.1263 IR (KBr) / νcm ^-1 : 1653,1593,76
6 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.13
(1H, s), 8.60 (2H, d, J = 6.0H)
z), 8.28 (1H, d, J = 8.2 Hz), 7.6
9-7.90 (2H, m), 7.66 (1H, t, J =
8.2 Hz), 7.42-7.51 (5H, m), 7.
13-7.14 (3H, m), 6.80 (1H, d, J
= 16.2 Hz). The preparation of the present invention containing the compound having the general formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof as an active ingredient can be produced, for example, by the following method.

[0166]

Formulation Example 1 Powder 5 g of the compound of Example 2, 895 g of lactose and 100 g of corn starch were mixed with a blender.
A powder is obtained.

[0167]

Formulation Example 2 Granules 5 g of the compound of Example 4, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose were mixed, and then mixed with a 10% aqueous solution of hydroxypropylcellulose 30
Add 0 g and knead. This is granulated using an extrusion granulator and dried to obtain a granule.

[0168]

Formulation Example 3 Capsules 5 g of the compound of Example 6, lactose 115 g, corn starch 58 g and magnesium stearate
After mixing 2 g using a V-type mixer, 180 mg is filled into No. 3 capsules to obtain capsules.

[0169]

Formulation Example 4 Tablets 5 g of the compound of Example 8, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate are mixed in a blender and then tableted with a tablet machine to obtain tablets.

[0170]

[Test example]

[0171]

[Test Example 1] Cell adhesion inhibition test (1) Coating of plate with extracellular matrix Phosphate Buffered in each well of 96-well plate
Add 50 μL of Saline (PBS), and add 100 μg /
Type II collagen (Wako Pure Chemical Industries, Ltd.) or fibronectin (Si
gma Chemical Co.) was added and left at room temperature.
One hour later, the liquid was removed by suction, and 1% bovine seru
Calcium / Magne containing m albumin (Sigma Chemical Co.)
100 μL of sium-containing PBS (hereinafter referred to as “PBS (+)”) was added to each well, and the mixture was allowed to stand at room temperature for 30 minutes. After aspirating and removing this solution, 100 μL of PBS was added to each well, allowed to stand at room temperature for 10 minutes, and then aspirated to remove the solution. This washing with PBS was repeated three times. (2) Preparation of cells The culture medium was removed from the flask in which the synovial cells were cultured in a monolayer by suction, and PBS was added thereto at a ratio of 3 mL / 25 cm ² . After washing the cell surface, the PBS was removed by suction, and 0.25% Trypsin was added to the flask at 1 mL / 25 cm.
² were added. 0.25 before cells begin to float
Pipette off 10% Trypsin and 10% Fetal bovi
Dulbecco's modified Eagle's medium (DMEM) containing ne serum (FBS) was added and suspended, and the cells were collected. 80
After centrifugation at 0 × g to remove the supernatant, the cells were suspended in DMEM. After centrifugation again at 800 × g to remove the supernatant, the cells were suspended in DMEM. (3) Adhesion experiment 100 μL (2 × 10 ⁵ cells / weld) of the cell suspension prepared in the operation of (3) was added to the plate prepared in the operation of (1).
l) was added and left at 37 ° C. for 45 minutes, and then the test compound was added. Thereafter, the liquid was removed by suction, and the operation of adding 100 μL of PBS (+) to each well and immediately removing the liquid by suction was repeated twice. Next, 0.1% crystal violet was used to stain the cells adhered to the plate.
(Wako Pure Chemical Industries, Ltd.)
Left for 5 minutes. After removing the crystal violet solution, each well was washed with 100 μL of H ₂ O. This washing was repeated five times. After drying the wells at room temperature, 0.5% S
Add 50 μL of odium dodesyl sulfate (Nacalai Tesque, Inc.) to each well to extract crystal violet,
The absorbance in nm was measured. A well containing no cells was prepared, and the absorbance was subtracted from each measured value as a background.

Based on these, the concentration (IC ₅₀ ) at which cell adhesion was inhibited by 50% was determined. Table 4 --------------------------------- Test compound IC ₅₀ (μM) -------- ------------------------- Compound of Example 1 2.42 Compound of Example 2 2.9 Compound of Example 3 2.67 Compound of Example 4 2.82 Example Compound of Example 5 0.73 Compound of Example 6 1.32 Compound of Example 7 2.02 Compound of Example 8 1.35 Compound of Example 9 1.82 Compound of Example 10 0.71 Compound of Example 11 1.43 Compound of Example 12 1.78 Example 13 Compound 1.43 Compound of Example 14 1.62 Compound of Example 15 1.02 Compound of Example 16 0.85 Compound of Example 17 0.62 Compound of Example 18 0.51 Compound of Example 19 1.67 Compound of Example 20 1.13 Compound of Example 21 0.87 Example 22 compound 0.79 Example 23 compound 0.98 Example 24 compound 1.84 Example 25 compound 0.69 Example 26 compound 1.34 Example 27 compound 0.95 Example 28 compound 2.01 Example 29 compound 2.63 Example Compound of Example 30 2.37 Compound of Example 31 0.93 Compound of Example 32 1.01 Compound of Example 33 1.41 Compound of Example 34 1.73 Compound of Example 35 1.74 Compound of Example 36 1.42 Compound of Example 37 1.98 Compound of Example 38 1.94 Compound of Example 39 2.18 Example Compound of Example 40 2.12 Compound of Example 41 1.89 Compound of Example 42 0.39 Compound of Example 43 1.31 Compound of Example 44 1.09 Compound of Example 45 1.46 Compound of Example 46 0.56 Compound of Example 47 0.75 Example 48 Compound 0.73 Compound of Example 49 1.5 Compound of Example 50 0.56 Compound of Example 51 0.36 Compound of Example 52 1.04 Compound of Example 53 1.39 Compound of Example 54 1.08 Compound of Example 55 1.22 Compound of Example 56 0.93 --------------------------------- As is clear from Table 4 above, the compound of the present invention is excellent. Cell adhesion inhibitory effect.

[0173]

[Test Example 2] Adjuvant arthritis onset suppression test Winder et al.'S method (CV Winder, LA Lembke and MD
The experiment was performed according to Stephens: Arthritis Rheum., 12, 472, 1957).

The adjuvant was Mycobacterium butyricum
Liquid paraffin (Wako Pure Chemical Industries, Ltd., first-class) which was heat-killed by heating (Difco Laboratories, Lot 679123), refined in an agate mortar, and then sterilized by dry heat to 2 mg / mL.
And sonicated.

This adjuvant (100 μg / 0.05 mL / paw as heat-killed cells) was injected into the right hind paw of the rat.
Was injected to induce arthritis. Day of injection of adjuvant (0
The test substance solution was intraperitoneally administered twice a day from the day 0) to the 20th day to give 3, 5, 7, 10, 13, 15, 18, 18, and 2
The volume of the non-injected paw (left paw) on day 1 was measured, and the swelling volume (hind paw volume of the adjuvant-injected animal-hind paw volume of the healthy group) was calculated. Further, the swelling inhibition rate of the test substance administration group with respect to the test substance non-administration control group was calculated by the following equation. Swelling inhibition rate (%) = {1− (swelling volume of animal to which test substance is administered) / (swelling volume of control group to which no test substance is administered)} × 100 The paw volume is measured by a rat paw volume measuring device (Plethysmometer, U
go Basile) and measured from the hairline of the hind limb to the apex of the hind limb in the tank of the measuring device.

In this test, the compound of the present invention showed an excellent swelling inhibitory action.

[0177]

[Test Example 3] Cytokine production suppression test U937 cells (Dainippon Pharmaceutical) were prepared using 10% FBS (Hyclo
ne Laboratories, Inc.)
(Gibco Laboratories), and the cells were adjusted to 2 × 10 ⁶ / mL before the experiment.

A sample solution (2 μL) was added to 100 μL of the cell suspension added to the 96-well microplate [DMSO and FB
Solution of a 1: 9 mixture of S], 10 μM Phorbol myris
DMSO and FBS of tateacetate (PMA, Calbiochem)
2 μL of a 1: 9 mixed solution of 200 μg / mL Lipo
10 μL of poly saccharide (LPS, Difco) solution, 6
μL of FBS and 80 μL of RPMI-1640 were added, and the cells were cultured at 37 ° C. for 24 hours in a CO ₂ incubator. In addition, a group without LPS and PMA was placed as a blank. After completion of the culture, the supernatant is recovered, and the cytokine in the supernatant is used as an ELISA kit for human IL-1β and human TNFα.
(Biosource International, Inc.).

In addition, cytotoxicity was examined by the Alamar blue method. After 21 hours of culture, Alamar blue (Bi
osource International, Inc.), and after culturing for 3 hours, the fluorescence intensity in the supernatant was measured using a fluorescence multiplate reader (CYTOFLUOR Multi-well Plate Reader, Persepti
ve Biosystems) (excitation wavelength = 560 ± 20).
nm, emission wavelength = 590 ± 35 nm). From these measured values, the inhibition rate of cytokine production was calculated, and the 50% inhibitory concentration (IC ₅₀ ) was determined. As is clear from Table 5, the compounds of the present invention exhibited an excellent inhibitory effect on cytokine production.

[0180]

EFFECTS OF THE INVENTION The compounds of the present invention exhibit excellent cell adhesion inhibitory effects and cytokine production inhibitory effects, and are therefore useful in medicine (eg, rheumatoid arthritis (RA), osteoarthritis (OA), asthma, atopic skin To prevent or treat autoimmune diseases or inflammatory diseases such as inflammation, rehepatic flow disorder of myocardium and brain, ulcerative enteritis, Crohn's disease, hepatic / nephritis, or to suppress cancer growth and / or metastasis As a medicine).

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61P 1/04 A61P 1/04 9/10 9/10 11/06 11/06 19/02 19/02 29/00 29 / 00 101 101 35/00 35/00 37/00 37/00 37/06 37/06 43/00 105 43/00 105 C07D 401/14 C07D 401/14 (72) Inventor Seiichiro Kumakura Shinagawa-ku, Tokyo 1-58, Tachi-cho F-term in Sankyo Co., Ltd. (Reference) 4C063 AA01 AA03 BB01 BB04 CC14 CC22 CC29 CC31 CC34 CC36 DD10 DD12 DD15 EE01 4C086 AA01 AA03 BC17 BC21 BC28 BC36 BC42 BC48 BC50 BC53 MA01 MA04 NA14 ZA75 ZA68 ZA96 ZB11 ZB13 ZB15 ZB26

Claims (19)

[Claims] 1. A compound having the following general formula (Ia) or a pharmacologically acceptable salt, ester or other derivative thereof: Wherein R ¹ is a lower alkyl group, a lower alkyl group substituted with a group selected from a substituent group α, an aryl group, a substituent group α
And an aryl group substituted with a group selected from the substituent group β, an aralkyl group, or an aralkyl group substituted with a group selected from the substituent group α and the substituent group β, or R ¹ , R ² together form a single bond, R ² together with R ¹ form a single bond, or
R ² represents an oxygen atom together with R ^3, R ³ together with R ^2, or an oxygen atom, or, R ³ is a halogen atom, a lower alkyl group, substituent group a lower alkyl group substituted with a group selected from α, an aryl group, an aryl group substituted with a group selected from the substituent group α and a group selected from the substituent group β, a heteroaryl group, a substituent group α
And an aralkyl group substituted with a group selected from the group of substituents β, an aralkyl group, an aralkyl group substituted with a group selected from the group of substituents α and β, or a formula: —O
-R ⁶ (wherein, R ⁶ is a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from substituent group α,
Aryl group, aryl group substituted with a group selected from substituent group α and substituent group β, heteroaryl group, heteroaryl group substituted with a group selected from substituent group α and substituent group β, An aralkyl group or an aralkyl group substituted with a group selected from the substituent group α and the substituent group β is shown. ) -. In S-R ⁶ (wherein, R ⁶ is in the a the same meaning) or -NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ are the same or different, each represents a hydrogen atom, A lower alkyl group, an aryl group, an aryl group substituted with a group selected from the substituent group α and the substituent group β, a heteroaryl group, a group selected from the substituent group α and the group selected from the substituent group β A heteroaryl group, an aralkyl group, or an aralkyl group substituted with a group selected from substituent group α and substituent group β, or R ⁷ and R ⁸ represent a nitrogen atom to which they are bonded. Together with a heterocyclyl group or a heterocyclyl group substituted with a group selected from the substituent group β). R ⁴ is a halogen atom, a lower alkyl group, a substituent group lower alkyl substituted with a group selected from α Group, aryl group, aryl group substituted with a group selected from substituent group α and substituent group β, heteroaryl group, heteroaryl substituted with a group selected from substituent group α and substituent group β A aralkyl group substituted with a group selected from a group, an aralkyl group, a substituent group α and a substituent group β, or a formula: —O—
R ^{6 ′} (wherein, R ^{6 ′} is a lower alkyl group, a lower alkyl group substituted with a group selected from substituent group α, an aryl group, a group selected from substituent group α and a group selected from substituent group β. An aryl group, a heteroaryl group, a heteroaryl group, an aralkyl group, or a substituent group α and a substituent group β substituted with a group selected from the substituent group α and the substituent group β
An aralkyl group substituted with a group selected from ) -. In S-R ⁶ (wherein, R ^6, the a the same significance) or -NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ have the) as defined above. R ⁵ represents a hydrogen atom, four groups or atoms selected from a substituent group α, a substituent group β, and a substituent group γ. Provided that R ⁴ is represented by the formula: —CO—CH ＝ CH—Hy (wherein, H
y has the same meaning as described above. ), R ¹ together with R ² forms a single bond. ] [Substituent group α] halogen atom, hydroxyl group, thiol group, lower alkoxy group, lower alkylthio group, cyano group, carboxyl group, nitro group, nitrile group, formula -NR ^a R ^b (where R ^a and R ^b Are the same or different,
Represents a hydrogen atom, a lower alkyl group, or an acyl group, or R ^a and R ^b together with the nitrogen atom to which they are attached form a heterocyclyl group. [Substituent group β] Lower alkyl group; lower alkyl group substituted with a group selected from Substituent group α [Substituent γ] Aryl group; selected from Substituent group α and Substituent group β Aryl group substituted with an aralkyl group; substituent group α
And an aralkyl group substituted with a group selected from the substituent group β. 2. The method according to claim 1, wherein¹But lower-grade archi
Lower group substituted with a group selected from the group consisting of
Alkyl group, phenyl group, substituent group α and substituent group β
A phenyl group, an aralkyl group,
Or a group selected from substituent group α and substituent group β.
A substituted aralkyl group, or R ¹Is R^TwoAnd one
Compounds that form a single bond in the beginning, or their pharmacology
Salts, esters or other derivatives that are acceptable. 3. The method according to claim 1, wherein R ¹ is a lower alkyl group, a lower alkyl group substituted with a group selected from a substituent group α, a benzyl group, or a substituent group α and a substituent group β. A benzyl group substituted with a selected group,
Alternatively, R ¹ is a compound forming a single bond together with R ² , or a pharmaceutically acceptable salt, ester or other derivative thereof. 4. The method according to claim 1, wherein R ¹ is an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms substituted with a group selected from the substituent group α. ,
Alternatively, R ¹ is a compound forming a single bond together with R ² , or a pharmaceutically acceptable salt, ester or other derivative thereof. 5. The method according to claim 1, wherein R ³ is an oxygen atom together with R ² , or R ³ is a halogen atom or a lower alkyl group. Or a lower alkyl group substituted with a group selected from the substituent group α, or a formula: —O—R ⁶ , —S—R ^6, or —NR.
^A compound which is a group having ⁷ R ⁸ , or a pharmacologically acceptable salt, ester or other derivative thereof. 6. The method according to claim 1, wherein R ³ is an oxygen atom together with R ² , or R ³ is a halogen atom, a carbon atom having 1 carbon atom. To 4 alkyl groups, an alkyl group having 1 to 4 carbon atoms substituted with a group selected from the substituent group α, or a formula: -O-
A compound which is a group having R ⁶ or —NR ⁷ R ⁸ , or a pharmacologically acceptable salt, ester or other derivative thereof. 7. The method according to claim 1, wherein R ³ together with R ² represents an oxygen atom, or R ³ is a chlorine atom, methyl, hydroxy A compound that is carbonylmethyl, isopropyloxy, benzyloxy, N′N-dimethylamino, or N-methylhomopiperazino, or a pharmaceutically acceptable salt thereof;
Esters or other derivatives. 8. The phenyl group according to any one of claims 1 to 7, wherein R ⁴ is substituted with a halogen atom, a phenyl group, a group selected from a substituent group α and a group selected from a substituent group β. A heteroaryl group, a heteroaryl group substituted with a group selected from substituent group α and substituent group β,
Or ^{formula: -O-R 6, -S-} R 6 or -NR ⁷ compound is a group having R ^8, or a pharmacologically acceptable salt, ester or other derivative. 9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. 10. A cell adhesion inhibitor comprising the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. Pharmaceutical compositions for use as cytokine production inhibitors. 11. A medicament containing a compound having the following general formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient for use as a cell adhesion inhibitor or a cytokine production inhibitor. Composition: [Wherein, R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from substituent group α, an aryl group,
An aryl group substituted with a group selected from the substituent group α and the substituent group β, an aralkyl group, or an aralkyl group substituted with a group selected from the substituent group α and the substituent group β, or R ¹ is a single bond to form together with R ^2, R ² is either to form a single bond together with R ^1, or,
R ² represents an oxygen atom together with R ^3, R ³ together with R ^2, or an oxygen atom, or, R ³ is a hydrogen atom, a halogen atom, a lower alkyl group, A lower alkyl group substituted with a group selected from substituent group α, an aryl group, an aryl group substituted with a group selected from substituent group α and a group selected from substituent group β, a heteroaryl group, a substituent group α and A heteroaryl group or an aralkyl group substituted with a group selected from the substituent group β, an aralkyl group substituted with a group selected from the substituent group α and a group selected from the substituent group β, or a formula: —O—R ⁶ (formula Wherein R ⁶ is a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from a substituent group α, an aryl group, a substituent group α and a substituent group β
An aryl group substituted with a group selected from the group consisting of a heteroaryl group, a heteroaryl group substituted with a group selected from a substituent group α and a substituent group β, an aralkyl group, or a substituent group α and a substituent Represents an aralkyl group substituted with a group selected from the group β. ^{), -. S-R 6} ( wherein, R ^6, the a the same significance) or -NR ⁷ R ⁸ (wherein, R ⁷
And R ⁸ are the same or different and are a hydrogen atom, a lower alkyl group, an aryl group, an aryl group substituted with a group selected from the substituent group α and the substituent group β, a heteroaryl group, and a substituent group, respectively. A heteroaryl group substituted with a group selected from α and the substituent group β, an aralkyl group, or an aralkyl group substituted with a group selected from the substituent group α and the substituent group β, or R ⁷ and R ⁸ are
Together with the nitrogen atom to which they are attached, they form a heterocyclyl group or a heterocyclyl group substituted by a group selected from substituent group β. One of R ⁴ and R ⁹ is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from a substituent group α, an aryl group, a substituent group α And substituent group β
Aryl group, heteroaryl group, heteroaryl group, aralkyl group, substituent group α and substituent group β substituted with a group selected from groups selected from Or an aralkyl group substituted with a group selected from the group consisting of: -OR ⁶ (wherein R ⁶ has the same meaning as described above), -SR ⁶ (where R ⁶ is .) or -NR ⁷ R ⁸ (wherein as defined above, R ⁷ and R ^8,
The meaning is as defined above. ), The other being
Formula: -CO-CH = CH-Hy (wherein, Hy is a heteroaryl group; a heteroaryl group substituted with a group selected from Substituent Group α, Substituent Group β, and Substituent Group γ)
R ⁵ represents a hydrogen atom, four groups or atoms selected from a substituent group α, a substituent group β, and a substituent group γ. Provided that R ⁴ is represented by the formula: —CO—CH ＝ CH—Hy (wherein, H
y has the same meaning as described above. ), R ¹ together with R ² forms a single bond. ] [Substituent group α] halogen atom, hydroxyl group, thiol group, lower alkoxy group, lower alkylthio group, cyano group, carboxyl group, nitro group, nitrile group, formula -NR ^a R ^b (where R ^a and R ^b Are the same or different,
Represents a hydrogen atom, a lower alkyl group, or an acyl group, or R ^a and R ^b together with the nitrogen atom to which they are attached form a heterocyclyl group. [Substituent group β] lower alkyl group; lower alkyl group substituted with a group selected from substituent group α [substituent γ] aryl group; selected from substituent group α and substituent group β An aryl group substituted with an aralkyl group; a substituent group α
And an aralkyl group substituted with a group selected from the substituent group β. 12. The method according to claim 11, wherein R ¹ is a lower alkyl group, a lower alkyl group substituted with a group selected from a substituent group α, an aryl group, a substituent group α and a substituent group β.
An aryl group, an aralkyl group, or an aralkyl group substituted with a group selected from the substituent group α and the substituent group β, or R ¹ is R ²
A composition which forms a single bond together with 13. The method according to claim 11, wherein
³ represents an oxygen atom together with R ² , or
R ³ is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a group selected from the substituent group α, an aryl group, an aryl substituted with a group selected from the substituent group α and the substituent group β. Group, heteroaryl group, heteroaryl group substituted with a group selected from substituent group α and substituent group β, aralkyl group, aralkyl substituted with a group selected from substituent group α and substituent group β Group or Formula: -OR
⁶ (wherein, R ⁶ has the same meaning as described above.), -SR ⁶
(Wherein, R ⁶ is as defined above) or -N
R ⁷ R ⁸ (wherein, R ⁷ and R ⁸ are as defined above)
A composition which is a group having the formula: 14. A method selected from claims 11 to 13.
In any one of the terms, R ^FourAnd R⁹One of them is a halogen source
A lower alkyl group, a group selected from the substituent group α.
Substituted lower alkyl group, aryl group, substituent group α and
An aryl group substituted with a group selected from substituent group β,
Heteroaryl group, selected from substituent group α and substituent group β
Heteroaryl group, aralkyl substituted with
Group, substituted with a group selected from substituent group α and substituent group β
Aralkyl group, or a formula: -OR^{6 '}(Where R^{6 '}
Is a lower alkyl group or a group selected from substituent group α.
Substituted lower alkyl group, aryl group, substituent group α and
An aryl group substituted with a group selected from substituent group β,
Heteroaryl group, selected from substituent group α and substituent group β
Heteroaryl group, aralkyl substituted with
Group or a group selected from substituent group α and substituent group β
Represents an aralkyl group substituted with ), -SR⁶(formula
Medium, R⁶Has the same significance as described above. ) Or -NR⁷R
⁸(Where R⁷And R ⁸Has the same significance as described above. )
And the other is of the formula: -CO-CH = CH-Hy
(In the formula, Hy is as defined above.)
Some compositions. 15. The composition according to any one of claims 10 to 14 for preventing or treating rheumatoid arthritis. 16. The composition according to any one of claims 10 to 14, for preventing or treating osteoarthritis. 17. The composition according to any one of claims 10 to 14, for preventing or treating asthma. 18. The composition according to any one of claims 10 to 14 for preventing or treating atopic dermatitis. 19. The composition according to any one of claims 10 to 14, for suppressing cancer growth and / or metastasis.