TW201414725A - Novel pyrazole derivative - Google Patents

Abstract

The present invention provides a novel treatment means for Alzheimer's disease. This includes a compound represented by the following general formula (I) [In the formula, Ar1 represents 2-methoxy-4-(2-pyridylmethoxy) phenyl and the likes, Ar2 represents 1H-indol-6-yl and the likes.] or a salt thereof.

Description

Novel pyrazole derivatives

The present invention relates to a novel compound, and a Tau agglutination inhibitor, a β-secretase inhibitor, a β-amyloid protein agglutination inhibitor, and a pro-prevention or A pharmaceutical composition for treating diseases such as dementia and Alzheimer's disease.

In recent years, senile dementia has become a major medical and social problem with the advent of a rapidly aging society, and is eager for effective anti-dementia drugs. There is a lot of research on Alzheimer's disease, but the cause has not been revealed. Aricept, a therapeutic drug for Alzheimer's disease, is based on the inhibition of acetylcholinesterase and is very useful as a symptomatic treatment, but not a radical therapeutic.

The cause of Alzheimer's disease is considered to be agglutination of β-amyloid protein (hereinafter, also referred to as A β) or agglutination of Tau. Therefore, substances that inhibit the aggregation of these proteins may become the fundamental therapeutic drugs for Alzheimer's disease.

Yang et al. report that curcumin has an Aβ aggregation inhibitory action, agglutination Aβ decomposition, and the like (Non-Patent Document 1). In addition, the present inventors have shown that curcumin or a derivative thereof has an action of inhibiting the secretion of aβ by the production of Aβ (Patent Document 1 and Patent Document 2). Again, there is Narlawar et al. have synthesized a derivative in which a 1,3-dicarbonyl moiety of curcumin is substituted with a pyrazole ring, and these compounds have a report of inhibition of Tau aggregation (Non-Patent Document 2).

[Advanced technical literature] [Patent Literature]

Patent Document 1: WO2008/066151

Patent Document 2: WO2009/145219

[Non-patent literature]

Non-Patent Document 1: Fusheng Yang et al., J. Biol. Chem. 2005, Feb 18; 280(7) 5892-5901

Non-Patent Document 2: Rajeshwar Narlawar et al., ChemMedChem 2008, 3, 165-172

As described in the above literature, the derivative of curcumin can be a powerful candidate for the fundamental therapeutic drug for Alzheimer's disease. Against this technical background, the present invention is directed to providing novel treatments for Alzheimer's disease.

The present inventors succeeded in the creation of a novel compound different from the known compound, and it was found that the compound had superior pharmacological activity and was repeatedly studied to complete the present invention.

In order to solve the above problems, the present inventors have conducted intensive studies and found that at least one of the 1,3-carbonyl moiety of curcumin is substituted with a pyrazole ring and the 4-hydroxy-3-methoxyphenyl group at both ends is synthesized. Replacement with other substitutions The curcumin derivative has a strong Tau agglutination inhibitory effect. Further, it has been found that the derivative has high brain mobility, and the derivative has a β-secretase inhibitory action or an Aβ agglutination inhibitory action.

Non-Patent Document 2 and the like describe a curcumin derivative in which a 1,3-carbonyl moiety of curcumin is substituted with a pyrazole ring. Further, in Patent Documents 1 and 2, at least one of 4-hydroxy-3-methoxyphenyl groups at both ends of curcumin is substituted with a derivative of another substituent. However, curcumin derivatives having a pyrazole ring and having at least one of the 4-hydroxy-3-methoxyphenyl groups at both ends substituted with other substituents are not disclosed in the novel compounds of the publicly known literature.

The derivative of curcumin having a Tau aggregation inhibitory action is described in Non-Patent Document 2. However, in this document, a nitrogen atom at the 1-position of the pyrazole ring is introduced into a plurality of groups, and the Tau aggregation inhibition effect of each derivative greatly changes depending on the group to be introduced. On the other hand, the benzene ring at both ends is not changed, and the synthesized derivative has a 4-hydroxy-3-methoxyphenyl group similarly to curcumin. Because of this, those who read Non-Patent Document 2 will think that the introduction group of the pyrazole ring plays an important role in Tau agglutination inhibition, and the 4-hydroxy-3-methoxyphenyl group at both ends has no correlation with the inhibition of Tau agglutination. Without considering that the 4-hydroxy-3-methoxyphenyl group was not substituted with another substituent.

The present invention has been completed on the basis of the above findings.

That is, the present invention relates to the following invention.

[1] A compound represented by the following formula (I) or a salt thereof Wherein R represents hydrogen, a chain-like or cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and Ar ¹ and Ar ² may be the same or different and each represents a homocyclic group which may have a substituent; Or a heterocyclic group. However, except that R is hydrogen, and Ar ¹ and Ar ² are all 4-hydroxy-3-methoxyphenyl groups].

[2] The compound according to the above [1] or a salt thereof, wherein R of the above formula (I) is hydrogen.

[3] The compound according to the above [1] or [2], wherein Ar ¹ of the above formula (I) is a phenyl group which may have a substituent.

[4] The above [1] or [2] The compound according or a salt thereof, wherein, Ar in the general formula (I) of ^a phenyl group having an alkyl group of _1-3 may have a substituent group of C.

[5] The compound of the above formula (1) or a salt thereof, wherein Ar ¹ of the above formula (I) is a C _1-3 alkyl group substituted with a heterocycloalkyl group which may have a substituent the phenyl group, an alkyl group having _1-3 via the phenyl may have a substituent of the cycloalkyl substituted C, alkyl group having _1-3 via the heteroaryl may have a substituent group of the aryl group substituted with C the phenyl group, an alkyl group having _1-3 may have a substituent by the aryl group of the substituted phenyl group of the C _1-3 alkyl group, a substituted of the dialkylamino group of the by substituent may have C a phenyl group, a phenyl group having a C _1-3 alkyloxy group substituted with an alkyl group which may have a substituent, or a benzene having a C _1-3 alkyloxy group substituted with an alkyl group which may have a substituent base.

[6] The compound according to the above [1] or [2], wherein Ar ¹ of the above formula (I) is tetrahydrofuran-3-ylmethoxy or tetrahydrofuran-2-ylmethoxy, 2-(piperidin-1-yl)ethoxy, 2-(4-methylpiperidine Ethyloxy, 2-(4-benzylidene) Ethyloxy, 2-morpholinylethoxy, 2-pyrrolidylethoxy, β-D-glucopyranosyloxy, 2-[4-(t-butoxycarbonyl)per -1-yl]ethoxy, 2-[4-(methylsulfonyl)per -1-yl]ethoxy or 2-[4-(2-hydroxyethyl)per -1-yl] ethoxyl phenyl.

[7] The compound according to the above [1] or [2] wherein the Ar ¹ of the above formula (I) is 2-methoxy-4-(tetrahydrofuran-3-ylmethoxy)benzene , 2-methoxy-4-(tetrahydrofuran-2-ylmethoxy)phenyl, 2-methoxy-4-[2-(piperidin-1-yl)ethoxy]phenyl, 2 -methoxy-4-[2-(4-methylperazine) Ethyloxy]phenyl, 2-methoxy-4-(2-morpholinylethoxy)phenyl, 4-(β-D-glucopyranosyl)oxy-2-methoxy Phenyl, 4-(tetrahydrofuran-3-ylmethoxy)phenyl, 4-(tetrahydrofuran-2-ylmethoxy)phenyl, 3-methoxy-4-(tetrahydrofuran-3-ylmethoxy) Phenyl, 3-methoxy-4-(tetrahydrofuran-2-ylmethoxy)phenyl, 2-[2-(4-benzylmethyl) Ethyl]-4-methoxyphenyl, 4-diethylamino-2-(2-morpholinylethoxy)phenyl, 4-dimethylamino-2-(2 -morpholinylethoxy)phenyl, 4-diethylamino-2-(2-morpholinylethoxy)phenyl, 4-diethylamino-2-(2-pyrrolidinyl) Ethoxy)phenyl or 4-diethylamino-2-[2-(piperidin-1-yl)ethoxy]phenyl.

The compound according to the above [1] or [2], wherein Ar ¹ of the above formula (I) has a pyridin-2-ylmethoxy group, a pyridin-3-ylmethoxy group, A phenyl group of pyridin-4-ylmethoxy or 1-pyrrolylmethoxy.

[9] The compound according to the above [1] or [2] or a salt thereof, wherein Ar ¹ of the above formula (I) is 4-(pyridin-2-ylmethoxy)phenyl, 2-methoxy 4--4-pyridin-2-ylmethoxy)phenyl, 2-[2-(piperidin-1-yl)ethoxy]-4-(pyridin-2-ylmethoxy)phenyl, 2-(2-morpholinylethoxy)-4-(pyridin-2-ylmethoxy)phenyl, 2-(2-pyrrolidinylethoxy)-4-(pyridin-2-ylmethyl) Oxy)phenyl, 2-[2-(4-methylper Ethyl]-4-(pyridin-2-ylmethoxy)phenyl, 3-methoxy-4-(pyridin-2-ylmethoxy)phenyl, 2-hydroxy-4-( Pyridin-2-ylmethoxy)phenyl, 3-(pyridin-2-ylmethoxy)phenyl, 2-methoxy-3-(pyridin-2-ylmethoxy)phenyl, 4- Methoxy-3-(pyridin-2-ylmethoxy)phenyl, 3-methoxy-5-(pyridin-2-ylmethoxy)phenyl, 2-methoxy-5-(pyridine -2-ylmethoxy)phenyl, 2-(pyridin-2-ylmethoxy)phenyl, 4-methoxy-2-(pyridin-2-ylmethoxy)phenyl, 5-methyl Oxy-2-(pyridin-2-ylmethoxy)phenyl, 2-nitro-5-(pyridin-3-ylmethoxy)phenyl, 4-diethylamino-2-(pyridine -3-ylmethoxy)phenyl or 2-methoxy-2-(1-pyrrolylmethoxy)phenyl.

The compound of the above formula (I) or the salt thereof, wherein Ar ² of the above formula (I) is a bicyclic homocyclic group or a heterocyclic group which may have a substituent.

[11] The compound of the above formula (I), wherein Ar ² is a bicyclic heterocyclic group which may have a substituent, or a salt thereof, according to any one of the above [1] to [9].

[12] The compound according to the above [11] or a salt thereof, wherein Ar ² of the above formula (I) is indol-2-yl, indol-3-yl, indol-4-yl or anthracene -5-yl, indol-6-yl, indol-7-yl, benzotriazol-5-yl, benzimidazol-5-yl, quin Polin-6-yl, benzofuran-2-yl, benzothiophen-2-yl, 1H-indazol-5-yl, 7-indol-3-yl, quinolin-2-yl, quinoline -5-yl, quinoline-8-yl, 1,4-benzoic Alkan-6-yl, 1,3-benzoic Zyrid-5-yl, chromone-3-yl, coumarin-6-yl, 7-methoxycoumarin-4-yl or 4-methoxycoumarin-6-yl.

[13] [11] above or a salt thereof according to the compound, wherein, Ar in the general formula (I) having the ² methyl, ethyl, benzyl, acetyl group, benzoyl group, t-butoxide A bicyclic heterocyclic group of an oxycarbonyl group, a methanesulfonyl group, a p-toluenesulfonyl group, a hydroxyl group or a nitro group.

[14] The compound according to the above [11] or a salt thereof, wherein Ar ² of the above formula (I) is 1-methyl-indol-6-yl or 1-methylindol-2-yl, 1-methylindol-3-yl, 1-ethylindol-6-yl, 1-benzylmethylindol-3-yl, 1-phenylmethylindol-6-yl, 1-ethylindole吲哚-3-yl, 1-ethylindolyl-6-yl, 1-benzylidenyl-3-yl, 1-tert-butoxycarbonylindole-5-yl, 1- Methanesulfonyl-3-yl, 1-methylsulfonyl-6-yl, 1-p-toluenesulfonyl-3-yl, 1-p-toluenesulfonylhydrazone- 6-yl, 4-hydroxyindol-3-yl or 4-nitroindol-3-yl.

[15] A Tau agglutination inhibitor, which comprises the compound according to any one of the above [1] to [14] or a salt thereof as an active ingredient.

[16] A β-secretase inhibitor, which comprises the compound according to any one of the above [1] to [14] or a salt thereof as an active ingredient.

[17] A β-amyloid protein agglutination inhibitor, which comprises the compound according to any one of the above [1] to [14] or a salt thereof as an active ingredient.

[18] A pharmaceutical composition comprising the compound according to any one of the above [1] to [14] or a salt thereof as an active ingredient.

[19] Use of the pharmaceutical composition according to the above [18] for preventing or treating a disease in which Tau, β-secretase or β-amyloid protein is involved.

[20] Use of the pharmaceutical composition according to the above [18] for the prevention or treatment of Alzheimer's disease.

[21] An oral or parenteral preparation comprising the compound according to any one of the above [1] to [14] or a salt thereof, and one or more pharmacologically acceptable carriers.

[22] A compound represented by the following formula (II) or a salt thereof; [In the formula, Ar ³ and Ar ⁴ may be the same or different and each represents a homocyclic group or a heterocyclic group which may have a substituent. (I) (i) Ar ³ is an aryl or heteroaryl group which may have a substituent, and Ar ⁴ is a phenyl group which may have a substituent having an electron-withdrawing group at the 2-position, and may have a substituent 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl or 1H-indole -7-yl and (ii) Ar ³ are phenyl which may be substituted by hydroxy, methoxy or ethoxylated, and Ar ⁴ is phenyl, 4-chlorophenyl, 2-methoxyphenyl, 3- Methoxyphenyl, 4-methoxyphenyl, 3-hydroxyphenyl, 4-ethylguanidinophenyl, 3,4-difluorophenyl, 2,4-dichlorophenyl, 2, 3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dihydroxyphenyl , 3-fluoro-4-hydroxyphenyl, 2-hydroxy-5-methoxyphenyl, 3-hydroxy-4-methoxyphenyl, 3-hydroxy-5-methoxyphenyl, 3-methyl Oxy-4-nitrophenyl, 4-ethenyloxy-3-methoxyphenyl, 4-dimethylamino-3-methoxyphenyl, 4-hydroxy-3-nitrobenzene , 2-methoxynaphthalen-1-yl, 6-methoxynaphthalen-2-yl, 1H-pyrrol-2-yl, pyridin-2-yl, 1H-imidazol-2-yl, 1-methyl -1H-pyrrol-2-yl 9-Ethyl-9H-carbazol-3-yl, 1-methyl-1H-indol-3-yl, 1H-indol-3-yl, 1H-indol-5-yl or 1H-indole Except for -6-base)].

Since the compound of the present invention has a Tau agglutination inhibitory action, a β-secretase inhibitory action, an Aβ agglutination inhibitory action, and the like, and has high mobility in the brain, it is useful as a therapeutic drug for Alzheimer's disease or the like.

Fig. 1 is an electron micrograph showing a thioflavin S sample prepared in Pharmacological Test Example 1. The left panel shows the results when only DMSO was added, the middle panel shows the results of the addition of 0.1 μM of the compound of Example 2, and the right panel shows the results of the addition of 1 μM of the compound of Example 2.

Fig. 2 is a graph showing changes in blood concentration when the compound of Example 2 and the compound of Example 2 (2) were administered orally.

Fig. 3 is a graph showing the amount of insoluble and soluble Aβ 1-42 in the brain of the mouse to which the compound of Example 2 was administered. The left panel shows the amount of insoluble A β 1-42, and the right panel shows the amount of soluble A β 1-42.

Fig. 4 is a graph showing the amount of insoluble Tau in the brain of the mouse to which the compound of Example 2 was administered.

Hereinafter, the present invention will be described in detail.

R in the above formula (I) represents hydrogen, a chain-like or cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and preferably represents hydrogen. The above-mentioned chain or cyclic hydrocarbon group is not particularly limited as long as it does not impair the effects of the present invention, and examples thereof include an alkyl group such as a methyl group, an ethyl group, a propyl group, and an isopropyl group (preferably C _1-6 ); An alkenyl group (preferably C _1-6 ); an aryl group such as a phenyl group or a naphthyl group (preferably C _6-12) or the like. The heterocyclic group is not particularly limited as long as it does not inhibit the effects of the present invention, and examples thereof include a heterocyclic group having 1 to 3 oxygen atoms, a sulfur atom and a nitrogen atom, and specific examples thereof include pyrrolyl and pyrroline. Base, imidazolyl, pyrazolyl, pyridyl, furyl, thienyl, Azolyl and the like. Further, the above-mentioned substituent is not particularly limited as long as it does not impair the effects of the present invention, and examples thereof include an alkyl group such as a methyl group or an ethyl group (preferably C _1-6 ); an aralkyl group such as a benzyl group (preferably C) _7-10 ); an oxime group such as an acetamyl group or a benzhydryl group (preferably C _2-7 ); an alkylcarbonyl group such as a third butoxycarbonyl group (preferably C _2-7 ); a methanesulfonyl group; An alkylsulfonyl group such as p-toluenesulfonyl (preferably C _1-6 ); a hydroxyl group, a nitro group or the like.

Ar ¹ and Ar ² in the above formula (I) may be the same or different and each represents a homocyclic group or a heterocyclic group which may have a substituent. The "homocyclic group" is not particularly limited as long as it does not impair the effects of the present invention, and examples thereof include a vinyl group, a phenyl group, and a naphthyl group. The "heterocyclic group" is not particularly limited as long as it does not impair the effects of the present invention, and examples thereof include a pyrrolyl group, a pyrrolinyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a furyl group, a thienyl group, and the like. Azolyl and the like. The "bicyclic allocyclic group" is not particularly limited as long as it does not impair the effects of the present invention, and examples thereof include a naphthyl group and the like. Further, the above-mentioned substituent is not particularly limited as long as it does not impair the effects of the present invention, and examples thereof include an alkyl group such as a methyl group or an ethyl group (preferably C _1-6 ); an aralkyl group such as a benzyl group (preferably C) _7-10 ); an oxime group such as an acetamyl group or a benzhydryl group (preferably C _2-7 ); an alkylcarbonyl group such as a third butoxycarbonyl group (preferably C _2-7 ); a methanesulfonyl group; An alkylsulfonyl group such as p-toluenesulfonyl (preferably C _1-6 ); a hydroxyl group, a nitro group or the like.

Ar ^{1 is} preferably a phenyl group which may have a substituent. Here, the substituent of the phenyl group is not particularly limited as long as it does not impair the effects of the present invention, and (1) a C _1-3 alkyloxy group which may have a substituent, and (2) a aryl group which may have a substituent are preferably exemplified. a oxy group, a (3) disubstituted amine group (two substituents may form a ring together), (4) an aryl group which may have a substituent or a heteroaryl group which may have a substituent, (5) a bromine atom, (6) An alkyl group which may have a substituent, an alkenyl group which may have a substituent or an alkynyl group which may have a substituent, (7) a nitro group, a (8) anthracenyl group, a (9) alkylcarbonylamino group, a sulfonyl group, Sulfosyl, sulfonyloxy and the like.

(1) C _1-3 alkyloxy group which may have a substituent

May be exemplified _"C1-3 alkyl group may have a substituent group of C" (1a) substituted by a heterocyclic group of the alkyl-substituted C _1-3 alkyl group, (1b) of the via may have a substituent a cycloalkyl-substituted C _1-3 alkyloxy group, (1c) a C _1-3 alkyloxy group substituted with a heteroaryl group which may have a substituent, (1d) substituted with an aryl group which may have a substituent a C _1-3 alkyloxy group, (1e) a C _1-3 alkyloxy group substituted with a dialkylamino group which may have a substituent, (1f) a C substituted by an alkyloxy group which may have a substituent _1-3 alkyloxy group, (1 g) C _1-3 alkyloxy group substituted with an alkyl group which may have a substituent, and the like.

(1a) a C _1-3 alkyloxy group substituted with a heterocycloalkyl group which may have a substituent

The "C _1-3 alkyloxy group substituted by a heterocycloalkyl group which may have a substituent" is exemplified by tetrahydrofuran-3-ylmethoxy, tetrahydrofuran-2-ylmethoxy, 2-(piperidin-1- Ethyloxy, 2-(4-methylperidyl) Ethyloxy, 2-(4-benzylidene) Ethyloxy, 2-morpholinylethoxy, 2-pyrrolidylethoxy, β-D-glucopyranosyloxy, 2-[4-(t-butoxycarbonyl)per -1-yl]ethoxy, 2-[4-(methylsulfonyl)per -1-yl]ethoxy, 2-[4-(2-hydroxyethyl)per -1-yl]ethoxy and the like.

The "phenyl group having a C _1-3 alkyloxy group substituted with a heterocycloalkyl group which may have a substituent" is exemplified by 2-methoxy-4-(tetrahydrofuran-3-ylmethoxy)phenyl, 2 -methoxy-4-(tetrahydrofuran-2-ylmethoxy)phenyl, 2-methoxy-4-[2-(piperidin-1-yl)ethoxy]phenyl, 2-methoxy -4-[2-(4-methylperazine) Ethyloxy]phenyl, 2-methoxy-4-(2-morpholinylethoxy)phenyl, 4-(β-D-glucopyranosyl)oxy-2-methoxy Phenyl, 4-(tetrahydrofuran-3-ylmethoxy)phenyl, 4-(tetrahydrofuran-2-ylmethoxy)phenyl, 3-methoxy-4-(tetrahydrofuran-3-ylmethoxy) Phenyl, 3-methoxy-4-(tetrahydrofuran-2-ylmethoxy)phenyl, 2-[2-(4-benzylmethyl) Ethyl]-4-methoxyphenyl, 4-diethylamino-2-(2-morpholinylethoxy)phenyl, 4-dimethylamino-2-(2 -morpholinylethoxy)phenyl, 4-diethylamino-2-(2-morpholinylethoxy)phenyl, 4-diethylamino-2-(2-pyrrolidinyl) Ethoxy)phenyl, 4-diethylamino-2-[2-(piperidin-1-yl)ethoxy]phenyl, and the like.

(1b) C _1-3 alkyloxy group substituted by a cycloalkyl group which may have a substituent

The "C _1-3 alkyloxy group substituted with a cycloalkyl group which may have a substituent" may, for example, be a cyclohexylmethoxy group or the like.

"By having a group of the cycloalkyl substituent may have a substituent group of the phenyl C _1-3 alkyl group" 4-cyclohexyl-2-methoxy phenyl, 2-cyclohexyl group can be exemplified methoxy group 4-hydroxyphenyl, 2-cyclohexylmethoxy-3-fluorophenyl, 2-cyclohexylmethoxy-5-fluorophenyl, 5-chloro-2-cyclohexylmethoxyphenyl, 2 , 4-di(cyclohexylmethoxy)phenyl, and the like.

(1c) a C _1-3 alkyloxy group substituted with a heteroaryl group which may have a substituent

The "C _1-3 alkyloxy group substituted with a heteroaryl group which may have a substituent" may, for example, be pyridin-2-ylmethoxy, pyridin-3-ylmethoxy or pyridin-4-ylmethoxy. 1-pyrrolylmethoxy and the like.

The "phenyl group having a C _1-3 alkyloxy group substituted with a heteroaryl group which may have a substituent" is exemplified by 4-(pyridin-2-ylmethoxy)phenyl group, 2-methoxy-4- (pyridin-2-ylmethoxy)phenyl, 2-[2-(piperidin-1-yl)ethoxy]-4-(pyridin-2-ylmethoxy)phenyl, 2-(2 -morpholinylethoxy)-4-(pyridin-2-ylmethoxy)phenyl, 2-(2-pyrrolidinylethoxy)-4-(pyridin-2-ylmethoxy)benzene Base, 2-[2-(4-methylperazine) Ethyl]-4-(pyridin-2-ylmethoxy)phenyl, 3-methoxy-4-(pyridin-2-ylmethoxy)phenyl, 2-hydroxy-4-( Pyridin-2-ylmethoxy)phenyl, 3-(pyridin-2-ylmethoxy)phenyl, 2-methoxy-3-(pyridin-2-ylmethoxy)phenyl, 4- Methoxy-3-(pyridin-2-ylmethoxy)phenyl, 3-methoxy-5-(pyridin-2-ylmethoxy)phenyl, 2-methoxy-5-(pyridine -2-ylmethoxy)phenyl, 2-(pyridin-2-ylmethoxy)phenyl, 4-methoxy-2-(pyridin-2-ylmethoxy)phenyl, 5-methyl Oxy-2-(pyridin-2-ylmethoxy)phenyl, 2-nitro-5-(pyridin-3-ylmethoxy)phenyl, 4-diethylamino-2-(pyridine -3-ylmethoxy)phenyl, 2-methoxy-2-(1-pyrrolylmethoxy)phenyl, and the like.

(1d) C _1-3 alkyloxy group substituted with an aryl group which may have a substituent

The "C _1-3 alkyloxy group substituted with an aryl group which may have a substituent" may, for example, be a phenethyloxy group, a benzyloxy group, a 1-naphthylmethoxy group, a diphenylmethoxy group, or 4 a methoxybenzyloxy group, a 2-chloro-6-fluorobenzyloxy group, a 2,4-dichlorobenzyloxy group, a 4-tert-butylbenzyloxy group, or the like.

"Having the via may have a substituent of a substituted aryl group of a phenyl C _1-3 alkyl group" can be exemplified by 2-methoxy-4-phenethyloxy-phenyl, 4-benzyloxy - 2-methoxyphenyl, 4-(1-naphthylmethoxy)-2-methoxyphenyl, 4-diphenylmethoxy-2-methoxyphenyl, 2-benzyl Oxy-4-hydroxyphenyl, 2-benzyloxy-4-chlorophenyl, 2-benzyloxy-3-fluorophenyl, 2-benzyloxy-3,5-di Chlorophenyl, 5-benzyloxy-2-nitrophenyl, 5-(4-methoxybenzyloxy)-2-nitrophenyl, 5-(2-chloro-6- Fluorobenzyloxy)-2-nitrophenyl, 5-(2,4-dichlorobenzyloxy)-2-nitrophenyl, 5-(4-t-butylbenzyl) Oxy)-2-nitrophenyl, 4-benzyloxy-2-bromophenyl, 4-benzyloxy-2-phenylphenyl, 2-benzyloxy-5- Bromophenyl, 2-benzyloxy-5-phenylphenyl, 2-benzyloxy-5-(indol-6-yl)phenyl, 2-benzyloxy-4- Dimethylaminophenyl, 2-benzyloxy-4-diethylaminophenyl, 4-diethylamino-2-(4-methoxybenzyloxy)phenyl 4-Diethylamino-2-(2-chloro-6-fluorobenzyloxy)phenyl, 4-diethyl Amino-2-(2,4-dichlorobenzyloxy)phenyl, 4-diethylamino-2-(4-t-butylbenzyloxy)phenyl, and the like.

(1e) a C _1-3 alkyloxy group substituted with a dialkylamino group which may have a substituent

The "C _1-3 alkyloxy group substituted with a dialkylamino group which may have a substituent" is exemplified by 2-dimethylaminoethoxy group, 3-dimethylaminopropyloxy group, 2-di Methylamino-1-methylethoxy, 2-dimethylamino-1-methylethoxy, and the like.

The "phenyl group having a C _1-3 alkyloxy group substituted with a dialkylamino group which may have a substituent" is exemplified by 4-(3-dimethylaminopropyloxy)phenyl group, 2-chloro- 4-(3-dimethylaminoethoxy)phenyl, 2-bromo-5-(3-dimethylaminoethoxy)phenyl, 2-(2-dimethylaminoethoxy) 4-methoxyphenyl, 4-diethylamino-2-(2-dimethylamino-1-methylethoxy)phenyl and the like.

(1f) a C _1-3 alkyloxy group substituted with an alkyloxy group which may have a substituent

"Having the substituent may have a substituent group of alkyloxy C _1-3 alkyl group" can be exemplified by methoxyethoxy, benzyloxy ethoxy.

The "phenyl group having a C _1-3 alkyloxy group substituted with an alkyloxy group which may have a substituent" is exemplified by 2-methoxy-4-methoxyethoxyphenyl group and 2-benzyl group. Oxyethoxy-4-methoxyphenyl and the like.

(1 g) C _1-3 alkyloxy group substituted by an alkyl group which may have a substituent

The "C _1-3 alkyloxy group substituted with an alkyl group which may have a substituent" may, for example, be an isopropoxy group, a 2-methylpropoxy group or a 3-methyl-2-butenyloxy group.

The "phenyl group having a C _1-3 alkyloxy group substituted with an alkyl group which may have a substituent" is exemplified by 4-hydroxy-2-isopropoxyphenyl group, 4-isopropoxy-2-methoxy group. Phenyl, 2-methoxy-4-(2-methylpropoxy)phenyl, 3-fluoro-2-(2-methylpropoxy)phenyl, 2,5-di(2- Methylpropoxy)phenyl, 2,4-bis(2-methylpropoxy)phenyl, 4-diethylamino-2-isopropoxyphenyl, 4-diethylamino -2-(3-methyl-2-butenyloxy)phenyl and the like.

(2) an aryloxy group which may have a substituent

The aryloxy group which may have a substituent may, for example, be a phenoxy group.

The "phenyl group having an aryloxy group which may have a substituent" may, for example, be 2-phenoxyphenyl, 3-phenoxyphenyl or 4-phenoxyphenyl.

(3) Disubstituted amine groups

The "disubstituted amine group" may, for example, be a dimethylamino group or a diethylamino group. In the "disubstituted amine group", an imidazole-1-yl group or a pyrazole can be exemplified as the two substituents form a ring group together. -1-yl, triazol-2-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-benzylpiperidin-1-yl, morpholin-4-yl, piperidin -1-yl, 4-methylperidazole -1-yl, 4-benzylidene -1-yl, 4-phenylperidine -1-yl, 4-(t-butoxycarbonyl)peri -1-yl, 4-(methylsulfonyl)perazine -1-yl, 4-(2-hydroxyethyl)peri -1-yl, 1,4-diazepane-1-yl, 1,4-diazepane-1-yl, 4-methyl-1,4-diazepan-1-yl 4-benzyl-1,4-diazepane-1-yl, 4-(t-butoxycarbonyl)-1,4-diazepan-1-yl, and the like.

"Phenyl group having a disubstituted amino group (the two substituents may form a ring together)" is exemplified by 4-dimethylaminophenyl group, 4-dimethylamino-2-methoxyphenyl group, 4- Diethylamino-2-hydroxyphenyl, 4-diethylamino-2-methoxyphenyl, 2-dimethylaminophenyl, 4-bromo-2-dimethylaminobenzene , 5-bromo-2-dimethylaminophenyl, 2-dimethylamino-5-trifluoromethylphenyl, 2-dimethylamino-4-phenylphenyl, 2- Dimethylamino-5-phenylphenyl, 4-dimethylamino-3-methoxyphenyl, 4-dimethylamino-2-nitrophenyl, 4-dimethylamine 2-chlorophenyl, 4-dimethylamino-2-methoxymethoxyphenyl, 4-dimethylamino-2-trifluoromethylphenyl, 5-dimethylamine Benzyl-2-nitrophenyl, 2-benzylideneoxy-4-diethylaminophenyl, 4-diethylamino-2-ethoxycarbonyloxyphenyl, 4-di Ethylamino-2-ethylaminocarbonyloxyphenyl, 4-diethylamino-2-(2-hydroxyethoxy)phenyl, 4-(imidazol-1-yl)phenyl, 4 -(pyrazol-1-yl)phenyl, 4-(triazol-2-yl)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(piperidin-1-yl)phenyl , 4-(morpholin-4-yl)phenyl, 4-(piperidin -1-yl)phenyl, 4-(4-methylpiperidin -1-yl)phenyl, 4-(4-benzylidene) -1-yl)phenyl, 2-(pyrrolidin-1-yl)phenyl, 2-(piperidin-1-yl)phenyl, 2-(morpholin-4-yl)phenyl, 2-[ 4-(t-butoxycarbonyl)piperidin -1-yl]phenyl, 2-[4-(methylsulfonyl)per -1-yl]phenyl, 2-[4-(2-hydroxyethyl)peri -1-yl]phenyl, 2-bromo-4-(piperidin-1-yl)phenyl, 2-bromo-4-(4-phenylmethylpiperidin-1-yl)phenyl, 2-bromo -4-(morpholin-4-yl)phenyl, 2-bromo-4-(4-methylpiperidin -1-yl)phenyl, 2-bromo-4-(4-benzylidene) -1-yl)phenyl, 2-bromo-4-(4-phenylperidine -1-yl)phenyl, 2-bromo-4-(pyrrolidin-1-yl)phenyl, 2-bromo-4-[4-(t-butoxycarbonyl)per -1-yl]phenyl, 2-bromo-4-(piperidin -1-yl)phenyl, 2-bromo-4-[4-(methylsulfonyl)per -1-yl]phenyl, 2-bromo-4-[4-(2-hydroxyethyl)peri -1-yl]phenyl, 4-(1,4-diazepan-1-yl)phenyl, 4-(4-methyl-1,4-diazepane-1- Phenyl, 4-(4-benzyl-1,4-diazepane-1-yl)phenyl, 4-[4-(t-butoxycarbonyl)-1,4- Diazaheptan-1-yl]phenyl, 2-bromo-4-(1,4-diazepan-1-yl)phenyl, 2-bromo-4-(4-methyl -1,4-diazepan-1-yl)phenyl, 2-bromo-4-(4-benzyl-1,4-diazepane-1-yl)phenyl, 2-bromo-4-[4-(t-butoxycarbonyl)-1,4-diazepan-1-yl]phenyl, 5-hydroxy-2-(pyrrolidin-1-yl) Phenyl, 5-hydroxy-2-(piperidin-1-yl)phenyl, 5-hydroxy-2-(morpholin-4-yl)phenyl, 2-(4-phenylmethylpiperidin-1- 5-)-5-hydroxyphenyl, 5-hydroxy-2-[4-(2-hydroxyethyl)per -1-yl]phenyl, 5-hydroxy-2-(piperidin -1-yl)phenyl, 2-[4-(t-butoxycarbonyl)peri -1-yl]-5-hydroxyphenyl, 5-hydroxy-2-(4-phenylperidine -1-yl)phenyl, 5-hydroxy-2-(4-methylpiperidin -1-yl)phenyl, 2-(1,4-diazepan-1-yl)-5-hydroxyphenyl, 5-hydroxyphenyl-2-(4-methyl-1,4 -diazepan-1-yl)yl, 2-(4-benzyl-1,4-diazepan-1-yl)-5-hydroxyphenyl, 2-[4- (t-butoxycarbonyl)-1,4-diazepan-1-yl]-5-hydroxyphenyl, 5-bromo-2-[4-(2-hydroxyethyl)per -1-yl]phenyl and the like.

(4) an aryl group which may have a substituent or a heteroaryl group which may have a substituent

The "aryl group which may have a substituent" may, for example, be a phenyl group, a 2-methylphenyl group, a 2-ethoxyphenyl group, a 1-naphthyl group or a 2-naphthyl group, or a "heteroaryl group which may have a substituent". Either 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazol-1-yl, 1H-1,2,4-triazol-1-yl, 4-ethoxycarbonyl-1H-1,2 ,3-triazol-1-yl, 5-ethoxycarbonyl-1H-1,2,3-triazol-1-yl, 1-benzyl-1H-1,2,3-triazole-4 -yl, 1-benzyl-1H-1,2,3-triazol-5-yl, 1-ethoxycarbonylmethyl-1H-1,2,3-triazol-4-yl, 1- Ethoxycarbonylmethyl-1H-1,2,3-triazol-5-yl, 1H-benzimidazol-1-yl, 1H-tetrazol-5-yl, 1-phenylmethyl-1H-tetra Zyrid-5-yl, 1-ethoxycarbonylmethyl-1H-tetrazol-5-yl and the like.

The "phenyl group having a aryl group which may have a substituent or a heteroaryl group which may have a substituent" may, for example, be a 2-phenylphenyl group, a 3-phenylphenyl group or a 4-phenylphenyl group. 5-hydroxy-2-phenylphenyl, 5-fluoro-2-phenylphenyl, 5-chloro-2-phenylphenyl, 5-hydroxy-2-(2-methylphenyl)phenyl, 2-(2-ethoxyphenyl)-5-hydroxyphenyl, 2-(1-naphthyl)phenyl, 2-(2-naphthyl)phenyl, 5-hydroxy-2-(1-naphthalene) Phenyl, 2-(2-pyridyl)phenyl, 2-(3-pyridyl)phenyl, 2-(4-pyridyl)phenyl, 4-(2-pyridyl)phenyl, 4 -(imidazol-1-yl)phenyl, 4-(1H-benzimidazol-1-yl)phenyl, 2-(1H-1,2,4-triazol-1-yl)phenyl, 2- (4-ethoxycarbonyl-1H-1,2,3-triazol-1-yl)phenyl, 2-(5-ethoxycarbonyl-1H-1,2,3-triazol-1-yl Phenyl, 2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl, 2-(1-benzyl-1H-1,2,3-triazole -5-yl)phenyl, 2-(1-ethoxycarbonylmethyl-1H-1,2,3-triazol-4-yl)phenyl, 2-(1-ethoxycarbonylmethyl- 1H-1,2,3-triazol-5-yl)phenyl, 2-(1H-tetrazol-5-yl)phenyl, 2-(1-benzyl-1H-tetrazol-5-yl Phenyl, 2-(1-ethoxycarbonylmethyl-1H-tetrazol-5-yl)phenyl, and the like.

(5) Bromine atom

The "phenyl group having a bromine atom" is exemplified by 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-bromo-3-hydroxyphenyl, 2-bromo-4-hydroxyphenyl, 2- Bromo-5-hydroxyphenyl, 2-bromo-5-methoxyphenyl, 2-bromo-5-methoxymethoxyphenyl, 4-bromo-2-fluorophenyl, 5-bromo-2 -fluorophenyl, 2-bromo-4-hydroxy-5-methoxyphenyl, 2-bromo-5-hydroxy-4-methoxyphenyl, 2,4-dibromo-5-hydroxyphenyl, 2,3-dibromo-4-hydroxy-5-methoxyphenyl and the like.

(6) an alkyl group which may have a substituent, an alkenyl group which may have a substituent or an alkynyl group which may have a substituent

The "alkyl group which may have a substituent, the alkenyl group which may have a substituent, or the alkynyl group which may have a substituent" can be exemplified by isopropyl group, hydroxymethyl group, n-propyl group, 2- Cyclopropylethyl, 2-(methoxymethyl)ethyl, 2-(dimethylaminomethyl)ethyl, 2-(diethylaminomethyl)ethyl, phenethyl, 2- (pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-methylvinyl, 2-cyclopropylvinyl, 2 -(methoxymethyl)vinyl, 2-(dimethylaminomethyl)vinyl, 2-(diethylaminomethyl)vinyl, styryl, 2-(pyridin-2-yl) Vinyl, 2-(pyridin-3-yl)vinyl, 2-(pyridin-4-yl)vinyl, 1-propynyl, cyclopropylethynyl, methoxymethylethynyl, 2-( Dimethylaminomethyl)ethynyl, 2-(diethylaminomethyl)ethynyl, phenylethynyl, pyridin-2-ylethynyl, pyridin-3-ylethynyl, pyridin-4-ylacetylene Base.

The "phenyl group having an alkyl group which may have a substituent, an alkenyl group which may have a substituent or an alkynyl group which may have a substituent" may be exemplified by 4-isopropylphenyl group, 2-(hydroxymethyl)phenyl group, 2 -methoxy-4-(n-propyl)phenyl, 4-(2-cyclopropylethyl)-2-methoxyphenyl, 2-methoxy-4-[2-(methoxy Methyl)ethyl]phenyl, 4-[2-(dimethylaminomethyl)ethyl]-2-methoxyphenyl, 4-[2-(diethylaminomethyl)ethyl] 2-methoxyphenyl, 2-methoxy-4-phenylethylphenyl, 2-methoxy-4-[2-(pyridin-2-yl)ethyl]phenyl, 2-methyl Oxy-4-[2-(pyridin-3-yl)ethyl]phenyl, 2-methoxy-4-[2-(pyridin-4-yl)ethyl]phenyl, 2-styryl Phenyl, 2-methoxy-4-(2-methylvinyl)phenyl, 4-(2-cyclopropylvinyl)-2-methoxyphenyl, 2-methoxy-4- [2-(Methoxymethyl)vinyl]phenyl, 4-[2-(dimethylaminomethyl)vinyl]-2-methoxyphenyl, 4-[2-(diethylamine) Methyl)vinyl]-2-methoxyphenyl, 2-methoxy-4-styrylphenyl, 2-methoxy-4-[2-(pyridin-2-yl)vinyl Phenyl, 2-methoxy-4-[2-(pyridin-3-yl)vinyl]phenyl, 2-methoxy-4-[2-(pyridyl) 4-yl) ethenyl] phenyl, 2-methoxy-4- (1-propynyl) benzene , 4-(2-cyclopropylethynyl)-2-methoxyphenyl, 2-methoxy-4-[2-(methoxymethyl)ethynyl]phenyl, 4-[2 -(dimethylaminomethyl)ethynyl]-2-methoxyphenyl, 4-[2-(diethylaminomethyl)ethynyl]2-methoxyphenyl, 2-methoxy 4-(phenylethynyl)phenyl, 2-methoxy-4-[2-(pyridin-2-yl)ethynyl]phenyl, 2-methoxy-4-[2-(pyridine- 3-yl)ethynyl]phenyl, 2-methoxy-4-[2-(pyridin-4-yl)ethynyl]phenyl and the like.

(7) Nitro

The "phenyl group having a nitro group" can be exemplified by 2-nitrophenyl group, 4-hydroxy-3-nitrophenyl group, 3-methoxy-4-nitrophenyl group, 5-methoxy-2-nitrate. Phenyl, 5-methoxymethoxy-2-nitrophenyl, 5-fluoro-2-nitrophenyl, 5-hydroxy-2-nitrophenyl, 5-chloro-2-nitro Phenyl, 2-chloro-5-nitrophenyl, 4,5-dimethoxy-2-nitrophenyl, and the like.

(8) 醯基

The "phenyl group having a mercapto group" is exemplified by 2-hydroxycarbonylphenyl group, 3-hydroxycarbonylphenyl group, 2-methoxycarbonylphenyl group, 3-methoxycarbonylphenyl group, 4-methoxycarbonylphenyl group. , 2-dimethylaminocarbonylphenyl, 3-(di-n-propylaminocarbonyl)phenyl, and the like.

(9) Alkylcarbonylamino group, etc.

A phenyl group having an alkylcarbonylamino group, a sulfonyl group, a sulfinyl group or a sulfonyloxy group is also contained in the above-mentioned "phenyl group which may have a substituent".

The number of the substituents in the above (1) to (9) is not particularly limited, and a plurality of substituents of the same kind or different kinds may be introduced, but it is preferred to introduce one substituent. Further, the position of the substituent of the above (1) to (9) on the phenyl group is not particularly limited, and it can be introduced into any of the ortho position, the meta position, and the para position, and is preferably introduced into the para position. The phenyl group represented by Ar ¹ may have a substituent such as a hydroxyl group, a methoxy group or a halogen atom other than a bromine atom, in addition to the substituents of the above (1) to (9).

With respect to Ar ² in the above formula (I), it is preferred to represent a homocyclic group or a heterocyclic group which may have a substituent, and preferably a bicyclic allocyclic group or a heterocyclic group which may have a substituent. Most preferred is a bicyclic heterocyclic group which may have a substituent.

The "bicyclic heterocyclic group" is not particularly limited as long as it does not impair the effects of the present invention, and is preferably exemplified by an indol-2-yl group, an indol-3-yl group, an indol-4-yl group, an anthracene-5-yl group. , 吲哚-6-yl, 吲哚-7-yl, benzotriazol-5-yl, benzimidazol-5-yl, quin Polin-6-yl, benzofuran-2-yl, benzothiophen-2-yl, 1H-indazol-5-yl, 7-indol-3-yl, quinolin-2-yl, quinoline -5-yl, quinoline-8-yl, 1,4-benzoic Alkan-6-yl, 1,3-benzoic Zyrid-5-yl, chromone-3-yl, coumarin-6-yl, 7-methoxycoumarin-4-yl, 4-methoxycoumarin-6-yl and the like. The substituent of the bicyclic heterocyclic group may, for example, be a methyl group, an ethyl group, a benzyl group, an ethyl fluorenyl group, a benzamidine group, a third butoxycarbonyl group, a methylsulfonyl group, a p-toluenesulfonyl group, a hydroxyl group or a nitrate. Base.

The "bicyclic heterocyclic group which may have a substituent" is not particularly limited as long as it does not impair the effects of the present invention, and preferably, in addition to the unsubstituted bicyclic heterocyclic group, a bicyclic heterocyclic group substituted with a group: 1-methyl-indol-6-yl, 1-methylindol-2-yl, 1-methylindol-3-yl, 1-ethylindol-6-yl, 1-benzylmethyl Indole-3-yl, 1-benzylmethylindol-6-yl, 1-ethylindolizin-3-yl, 1-ethylindolyl-6-yl, 1-benzylformamidinium Indole-3-yl, 1-t-butoxycarbonylindole-5-yl, 1-methylsulfonylindol-3-yl, 1-methylsulfonylpurin-6-yl, 1-pair -toluenesulfonylindole-3-yl, 1-p-toluenesulfonylpurin-6-yl, 4-hydroxyindol-3-yl, 4-nitroindol-3-yl, etc.; A group (for example, C _1-6 or the like), an aralkyl group (for example, C _7-10 or the like), a fluorenyl group (for example, C _2-10 or the like), a hydroxyl group, a nitro group or the like.

The compound represented by the above formula (I) preferably has the following structure from the viewpoint of inhibition of Tau aggregation and the like.

In the above formula (I), Ar ^{1 is} particularly preferably a phenyl group having the above substituent (1), more preferably a phenyl group having the above substituent (1a) or (1c), and more preferably 2-A. Oxy-4-(pyridin-2-ylmethoxy)phenyl.

In the above formula (I), Ar ^{2 is} particularly preferably an inden-2-yl group which may have a substituent, an indole-3-yl group which may have a substituent, an indol-4-yl group which may have a substituent, An inden-5-yl group which may have a substituent, an inden-6-yl group which may have a substituent, an inden-7-yl group which may have a substituent, a benzotriazol-5-yl group which may have a substituent, a benzimidazole-5-yl group which may have a substituent, a quinine which may have a substituent a phenyl-6-yl group, a benzofuran-2-yl group which may have a substituent or a benzothiophen-2-yl group which may have a substituent, more preferably an indol-2-yl group, an indole-3-yl group, an anthracene哚-6-yl, 1-methyl-indol-6-yl, benzotriazol-5-yl, benzimidazol-5-yl, quin Orolin-6-yl, benzofuran-2-yl or benzothiophen-2-yl, more preferably 吲哚-6-yl.

Salts of the compounds represented by the above formula (I) are also included in the present invention. Such a salt is preferably a pharmacologically acceptable salt, and examples thereof include a hydrogen halide such as a hydrofluoride, a hydrochloride, a hydrobromide or a hydroiodide; a sulfate, a nitrate, and a perchlorate. , inorganic salts of phosphates, carbonates, bicarbonates, etc.; organic carboxylates such as acetates, oxalates, maleates, tartrates, fumarates; methanesulfonates, triflate , organic sulfonates such as ethanesulfonate, besylate, tosylate, camphorsulfonate; aspartate, bran An amine salt such as an amine salt; a salt of an amine such as a trimethylamine salt, a triethylamine salt, a procaine salt, a pyridinium salt or a phenethylbenzylamine salt; a base such as a sodium salt or a potassium salt; A metal salt; an alkaline earth metal salt such as a magnesium salt or a calcium salt, etc., preferably a hydrochloride or an oxalate.

The compound represented by the above formula (I) can be produced, for example, by the methods described in Rajeshwar Narlawar et al., Chem Med Chem 2008, 3, 165-172, International Publication No. 2008/066151, International Publication No. 2009/145219, or the like. Specifically, it can be manufactured through the following steps 1 and 2.

In the above formula, Ar ¹ and Ar ² have the same meanings as described above.

Step 1 is a step of reacting an aldehyde represented by the formula (A) with a compound represented by the formula (B) in the presence of a solvent and a catalyst to obtain a diketone represented by the formula (C). The diketone represented by the formula (C) or a salt thereof is also included in the present invention. Further, in the above formula, the aldehyde represented by the formula (A) has Ar ¹ , the compound represented by the formula (B) has Ar ² , and the aldehyde represented by the formula (A) having Ar ² may have an Ar ¹ The compound represented by the formula (B) is reacted to obtain a diketone represented by the formula (C).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction, and examples thereof include ethyl acetate, N,N-dimethylacetamide, N,N-dimethylformamide, and N-methylpyrrolidone. Dimethyl hydrazine, tetrahydrofuran, acetonitrile, and the like. Such dissolution The agents may be used singly or in combination of two or more kinds as appropriate in an appropriate ratio.

The catalyst to be used is not particularly limited, and examples thereof include a base such as a primary amine and a secondary amine, and more specifically, n-butylamine, ethanolamine, piperidine, morpholine or the like.

Further, in order to capture water generated by the reaction, a water scavenger may be added. The water-trapping agent may, for example, be an alkyl borate, an alkyl phosphate or an orthoester. Specific examples thereof include trimethyl orthoformate and tri-n-butyl borate.

The ratio of the amount of the aldehyde represented by the formula (A) to the compound represented by the formula (B) is not particularly limited, but is preferably from 0.5 to 10 mol, more preferably from 0.5 to 2, with respect to 1 mol of the former. Moor.

The reaction temperature is not particularly limited, but is preferably from 0 to 200 ° C, more preferably from 50 to 100 ° C.

The reaction time is also not particularly limited, but is preferably from 0.5 to 48 hours, more preferably from 1 to 24 hours.

The aldehyde represented by the formula (A) or the compound represented by the formula (B) used in the step 1 may be a commercially available product or a known method (for example, the method described in International Publication No. 2008/066151, International Publication No. 2009/145219). Synthesizer.

Step 2 is a step of reacting a diketone represented by the formula (C) with hydrazine or a derivative thereof in the presence of a solvent to obtain a compound represented by the above formula (I). Step 2 is a compound which is obtained by reacting a diketone represented by the above formula (C) with hydrazine or a derivative thereof (a compound represented by H ₂ N-NHR or a salt thereof, etc.). The step of substituting.

The use is not particularly limited, and examples thereof include hydrazine monohydrate, an aqueous hydrazine solution, anhydrous hydrazine, hydrazine acetate, hydrazine monohydrochloride or the like.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction, and examples thereof include protic solvents such as acetic acid, methanol, ethanol, and water; and aprotic solvents such as ethyl acetate, toluene, tetrahydrofuran, dichloromethane, and chloroform. These solvents may be used singly or in combination of two or more kinds as appropriate in an appropriate ratio.

The ratio of the amount of the diketone to hydrazine represented by the formula (C) is not particularly limited, but the latter is preferably from 1 to 50 mol, more preferably from 2 to 10 mol, relative to 1 mol of the former.

The reaction temperature is not particularly limited, but is preferably from 20 to 120 ° C, more preferably from 50 to 80 ° C.

The reaction time is also not particularly limited, but is preferably from 1 to 24 hours, more preferably from 1 to 6 hours.

The compound of the present invention may be administered alone or in combination with one or more compounds other than the present invention, or may be administered in combination with one or more compounds other than the compound of the present invention. The compound of the present invention can also be administered as a preparation in which one or more pharmacologically acceptable carriers are formulated. The effective amount and the number of administrations vary depending on the form of administration, the age, body weight, symptoms, and the like of the patient, and are usually from about 0.01 to 100 mg/kg per day, more preferably from about 1 to 50 mg/kg.

When a preparation containing the compound of the present invention as an active ingredient is administered, the form thereof is not particularly limited, and oral administration can be carried out by a usual method or Not administered by mouth. For example, it can be formulated into tablets, powders, granules, capsules, liquids, emulsions, elixirs, suspensions, syrups, troches, inhalants, suppositories, injections, ointments. A preparation such as an oral preparation or a non-oral preparation such as an agent, an ophthalmic ointment, an eye drop, a nasal spray, an ear lotion, a cataplasm or a lotion is administered. The pharmaceutical dosage amount according to the present invention can be appropriately selected in accordance with the degree of symptoms, age, sex, body weight, administration form, type of salt, specific type of disease, and the like.

Since the compound of the present invention has Tau aggregation inhibition, β-secretase inhibition, and A β aggregation inhibition, diseases involving Tau, β-secretase or A β, such as Alzheimer's disease (familial AIDS) Hyperthermia and sporadic Azheimer's disease, Alzheimer's disease, Down Syndrome, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral ridge The prevention and treatment of sclerosis, diabetic neuropathy, Huntington's Chorea, and multiple sclerosis are effective. Among these neurological diseases, it is particularly effective for the prevention and treatment of Alzheimer's disease.

The compound of the present invention can be formulated into a tablet, a powder, a fine granule, a granule, a coated tablet, a capsule, a liquid, an emulsion, an elixir, a suspension, a syrup, a throat lozenge, etc. by a conventional method. Inhalation, suppository, injection, ointment, eye ointment, eye drop, nose, ear lotion, loach, lotion, etc. An agent, a binder, a lubricant, a colorant, a flavoring agent, and a stabilizer, an emulsifier, an absorption enhancer, a surfactant, which are generally used for formulation, may be used. pH adjuster, preservative, antioxidant, etc., formulated for general use as a pharmaceutical The ingredients used in the preparation raw materials are formulated by a usual method. For example, in the manufacture of an oral preparation, the crystalline or non-crystalline compound of the present invention and an excipient, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, etc., are prepared according to a conventional method. Powders, fine granules, granules, lozenges, coated tablets, capsules, and the like. Examples of such components include animal and vegetable oils such as soybean oil, tallow, and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane, and paraffin wax; ester oils such as octyldode myristate and isopropyl myristate. ; higher alcohol such as cetearyl alcohol, behenyl alcohol; oxime resin; eucalyptus oil; polyethylene oxide fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyethylene oxide sorbitan Surfactant such as fatty acid ester, polyethylene oxide hardened castor oil, polyethylene oxide polypropylene oxide block copolymer; hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl group Water-soluble polymer such as cellulose phthalate, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, methyl cellulose; lower alcohol such as ethanol or isopropanol; glycerin, propylene glycol, Polyhydric alcohols such as dipropylene glycol and sorbitol; sugars such as glucose and sucrose; inorganic powders such as phthalic anhydride, aluminum magnesium niobate, and aluminum citrate; and purified water. As the excipient, for example, lactose, corn starch, white sugar, glucose, mannitol, sorbit, crystalline cellulose, cerium oxide, or the like can be used; for example, polyvinyl alcohol, polyvinyl ether, methyl fiber can be used as the binder. , ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol-polycyclic Oxyethane-block copolymer, meglumine, etc.; for disintegrating agent, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, paste Fine, pectin, carboxymethyl cellulose-calcium, etc.; lubricants such as magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil, etc. can be used; colorants can be used to allow for the addition of pharmaceuticals. For the flavoring agent, cocoa powder, menthol, aroma powder, peppermint oil, borneol, cinnamon powder, or the like can be used. Such lozenges/granules may be suitably coated with a sugar coating or coated as needed. Further, when a liquid preparation such as a syrup, an emulsion, an elixir, a suspension, or an injection preparation is prepared, a pH adjusting agent, a dissolving agent, an emulsifier, a dispersing agent, an isotonic agent, or the like may be added to the compound of the present invention as needed. An adjuvant, a stabilizer, and the like are formulated by a conventional method. The method for producing the external preparation is not particularly limited and can be produced by a usual method. In other words, as a base material used in the formulation, it is generally used for various raw materials such as pharmaceuticals, quasi drugs, and cosmetics. Specific examples of the base material to be used include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, eucalyptus oils, surfactants, phospholipids, alcohols, polyols, and high water solubility. Molecular, clay minerals, refined water and other raw materials, in addition, pH adjusting agent, antioxidant, chelating agent, antiseptic and antifungal agent, coloring material, perfume, etc. may be added as needed, but the base material of the external agent of the present invention is added. Not limited to this. Further, a component having a differentiation-inducing action, a blood flow promoter, a bactericide, an anti-inflammatory agent, a cell activating agent, a vitamin, an amino acid, a moisturizer, a keratolytic agent, and the like may be formulated as needed. Moreover, the amount of the base material to be added is usually the amount of the concentration set when the external preparation is produced.

The compounds of the present invention are useful in the treatment of diseases in which Tau, β-secretase or A β is involved. Specific methods can exemplify the following (a) to (c).

(a) A method of treating a disease in which Tau is involved, which comprises The compound represented by the formula (I) or a salt thereof is administered to a patient suffering from a disease in which Tau is involved.

(b) A method for treating a disease in which β-secretase is involved, which comprises the step of administering a compound represented by the above formula (I) or a salt thereof to a patient suffering from a disease in which β-secretase is involved.

(c) A method for treating a disease in which Aβ is involved, which comprises the step of administering a compound represented by the above formula (I) or a salt thereof to a patient suffering from a disease in which Aβ is involved.

The compound of the present invention can also be used in a method for inhibiting aggregation of Tau, a method for inhibiting β-secretase, and a method for inhibiting aggregation of Aβ. The specific method can exemplify the following (d) to (i).

(d) A method for inhibiting Tau agglutination, which comprises the step of administering a compound represented by the above formula (I) or a salt thereof to a human, and inhibiting Tau agglutination in a human body.

(e) A Tau agglutination inhibiting method comprising the step of contacting a compound represented by the above formula (I) or a salt thereof with Tau.

(f) A method for inhibiting β-secretase, which comprises the step of administering a compound represented by the above formula (I) or a salt thereof to a human, and inhibiting β-secretase in humans in vivo.

(g) A method for inhibiting β-secretase, which comprises the step of contacting a compound represented by the above formula (I) or a salt thereof with β-secretase.

(h) A method for inhibiting Aβ aggregation, which comprises the step of administering a compound represented by the above formula (I) or a salt thereof to a human, and inhibiting Aβ aggregation in a human body.

(i) A method for inhibiting aggregation of Aβ, which comprises the step of bringing a compound represented by the above formula (I) or a salt thereof into contact with Aβ.

Further, in the above, the salt may be a pharmacologically acceptable salt.

[Examples]

In the following, the present invention will be described in more detail by way of examples, and the present invention is not limited to the embodiments, and various modifications can be made by those skilled in the art within the technical idea of the present invention.

Further, as described below, the synthetic compound of the example having the structure represented by R = hydrogen atom of the formula (I) is based on the measurement conditions of 1H NMR as the mutual formula (I) and the formula (I') The isomer is detected, and the general formula (I) is the same as the general formula (I'). Therefore, the synthetic compound in the examples can be named according to any one of the formula (I) and the formula (I').

The compound represented by the following formula (II) corresponds to the compound represented by the above formula (C) and is a synthetic intermediate contained in the present invention. The compound represented by the formula (II) has the mutual variability of the keto form and the alcohol form, but is the same substance. Therefore, it can be named according to any one of the general formula (II), the general formula (II'), and the general formula (II". Further, the melting point can be expressed by the degree of mixing of the crystal system or the impurity. Values different from those shown in the examples.

[Example 1] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-tetrahydrofuran) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) Synthesis of 2-methoxy-4-(2-tetrahydrofurylmethoxy)benzaldehyde

24.5 g (161 mmol) of 4-hydroxy-2-methoxybenzaldehyde was dissolved in 160 mL of N-methylpyrrolidone, and 63 g (0.19 mol) of cesium carbonate and 40 g (0.24 mol) of tetrahydrofuran methyl bromide were added at room temperature. Stir at 80 ° C for 22 hours. Water (800 mL) was added to the obtained reaction solution under ice-cooling, and extracted with diethyl ether (500 mL × 3 times). The combined organic layers were washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained crude product was purified from basic alumina (hexane / ethyl acetate = 50 / 50 → 0/100) to give a pale yellow powder which had the following properties. The title compound was 23.7 g (yield: 62%).

¹ H NMR (δ, acetone-d ₆ ): 1.7-2.0 (M, 4H), 3.74 (M, 1H), 3.84 (M, 1H), 3.97 (s, 3H), 4.10 (M, 2H), 4.21. (M, 1H), 6.64 (ddd, J = 0.8, 2.2, 8.5 Hz, 1H), 6.71 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 10.27 (d, J = 0.8 Hz, 1H). Melting point 73.3 ° C.

(2) (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)phenyl]heptane-1.6-di Synthesis of ene-3,5-dione

6-(1H-吲哚-6-yl)hex-5-ene-2,4-dione 19.3 mg (85.0 μmol) and boron oxide 22 mg (0.32 mmol) were placed in a 20 mL reaction vessel with acetic acid B The ester 0.4 mL was dissolved. 20 mg (85 μmol) of 2-methoxy-4-(2-tetrahydrofurylmethoxy)benzaldehyde and 32 μL (0.14 mmol) of triisopropyl borate were sequentially added to the mixture stirred at 70 °C. After stirring at the same temperature for 1 hour, piperidine 18 μL (0.18 mmol) was added, and the mixture was further stirred for 1 hour. A 1 : 1 solution of hydrochloric acid and saturated brine (2 mL) was added to the reaction mixture at room temperature, and the mixture was stirred for 5 minutes to 1 hour (otherwise, neutralized with a saturated aqueous solution of sodium hydrogencarbonate). The obtained organic phase was purified by hydrazine column chromatography (hexane/ethyl acetate or methylene chloride/methanol) to give the title compound (10.2 mg (yield 27) %).

¹ H NMR (δ, acetone-d ₆ ): 1.7-2.0 (M, 4H), 3.74 (M, 1H), 3.84 (M, 1H), 3.95 (s, 3H), 4.05 (M, 2H), 4.21. (M, 1H), 6.00 (s, 1H), 6.53 (br d, J = 3 Hz, 1H), 6.62 (dd, J = 2.2, 8.5 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H ), 6.78 (d, J = 16 Hz, 1H), 6.82 (d, J = 16 Hz, 1H), 7.44 (dd, J = 1.7, 8.5 Hz, 1H), 7.47 (M, 1H), 7.63 (d) , J = 8.3 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.74 (br s, 1H), 7.78 (d, J = 16 Hz, 1H), 7.93 (d, J = 16 Hz, 1H), 10.5 (br s, NH). Melting point 159-161 ° C, MS (ESI+) m/z 446.3 (M+1).

(3) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-tetrahydrofuranyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

(1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)phenyl]heptane-1,6-di 400 mg (0.898 mmol) of the ene-3,5-dione was dissolved in 4.5 mL of acetic acid, and 0.45 g (9.0 mmol) of hydrazine monohydrate was added thereto at room temperature, and the mixture was stirred at 60 ° C for 3 hours. The obtained reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate aqueous solution and brine, and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate or dichloromethane/methanol), and the obtained solid was washed with an organic solvent. The title compound 298 mg (yield 75%) of the title compound was obtained as a yellowish white powder.

¹ H NMR (δ, acetone-d ₆ ): 1.7-2.0 (M, 4H), 3.74 (M, 1H), 3.84 (M, 1H), 3.92 (s, 3H), 4.01 (d, J = 5.0 Hz , 1H), 4.21 (M, 1H), 6.47 (br d, J = 3 Hz, 1H), 6.58 (dd, J = 2.2, 8.5 Hz, 1H), 6.62 (d, J = 2.2 Hz, 1H), 6.70(s,1H),7.06(d,J=17 Hz,1H), 7.10(d,J=17 Hz,1H),7.32(d,J=17 Hz,1H),7.34(dd,J=1.7 , 8.5 Hz, 1H), 7.35 (M, 1H), 7.39 (d, J = 17 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.59 (br s, 1H), 10.3 (br s, NH). Melting point 218-220 ° C, MS (ESI+) m/z 442.2 (M+1).

[Example 2] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) Synthesis of 2-methoxy-4-(2-pyridylmethoxy)benzaldehyde

4-hydroxy-2-methoxybenzaldehyde 8.00g (52.6mmol), potassium carbonate 14.5g (105mmol) and 2-chloromethylpyridine hydrochloride 9.06g (55.2mmol) with N,N-dimethyl 53 mL of formamide was dissolved and stirred at 50 ° C for 4 hours. After 260 mL of water was added to the reaction solution at room temperature, the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (1.

¹ H NMR (δ, acetone-d ₆ ): 3.97 (s, 3H), 5.31 (s, 2H), 6.74 (ddd, J = 0.8, 2.2, 8.5 Hz, 1H), 6.84 (d, J = 2.2 Hz) , 1H), 7.34 (M, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.84 (dt, J = 1.9, 7.7 Hz, 1H), 8.60 (br d, J = 5 Hz, 1H), 10.28 (d, J = 0.8 Hz, 1H). Melting point 93.6 ° C.

(2) (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

By replacing 20 mg (85 μmol) of 2-methoxy-4-(2-tetrahydrofurylmethoxy)benzaldehyde of Example 1 (2) with 2-methoxy-4-(2-pyridylmethoxy) 21 mg (85 μmol) of benzaldehyde, and the same synthesis operation was carried out to obtain 12.4 mg (yield: 32%) of the title compound of the title compound.

¹ H NMR (δ, acetone-d ₆ ): 3.95 (s, 3H), 5.27 (s, 2H), 6.00 (s, 1H), 6.53 (brd, J = 3 Hz, 1H), 6.71 (dd, J=2.2, 8.5 Hz, 1H), 6.78 (d, J=16 Hz, 1H), 6.79 (d, J=2.2 Hz, 1H), 6.82 (d, J=16 Hz, 1H), 7.33 (M, 1H), 7.44 (dd, J = 1.7, 8.5 Hz, 1H), 7.47 (M, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.64 ( d, J = 8.5 Hz, 1H), 7.74 (br s, 1H), 7.78 (d, J = 16 Hz, 1H), 7.84 (dt, J = 1.7, 7.7 Hz, 1H), 7.93 (d, J = 16 Hz, 1H), 8.60 (br d, J = 5 Hz, 1H), 10.5 (br s, NH). Melting point 165-168 ° C, MS (ESI+) m/z 453.2 (M+1).

(3) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)benzene of Example 1 (3) 400 mg (0.898 mmol) of hexyl-1,6-diene-3,5-dione was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy 4-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 400 mg (0.884 mmol), and subjected to the same synthetic procedure to give a yellowish white powder The title compound 239 mg (yield 60%) was obtained.

¹ H NMR (δ, acetone-d ₆ ): 3.92 (s, 3H), 5.24 (s, 2H), 6.47 (brd, J = 3 Hz, 1H), 6.67 (dd, J = 2.2, 8.5 Hz, 1H), 6.70 (s, 1H), 6.75 (d, J = 2.2 Hz, 1H), 7.07 (d, J = 17 Hz, 1H), 7.11 (d, J = 17 Hz, 1H), 7.32 (d, J=17 Hz, 1H), 7.30-7.38 (M, 3H), 7.39 (d, J=17 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.55-7.59 (M, 2H), 7.59(br s,1H), 7.84 (dt, J=1.7, 7.7 Hz, 1H), 8.60 (br d, J=5 Hz, 1H), 10.3 (br s, NH). Melting point 237-239 ° C, MS (ESI+) m/z 449.2 (M+1).

[Example 3] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-hydroxy-4-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

(1) Synthesis of 2-hydroxy-4-(2-pyridylmethoxy)benzaldehyde

16.4 g (100 mmol) of 2-chloromethylpyridine hydrochloride was dissolved in 50 mL of water, and 50 mL of chloroform was added. After neutralizing the solution with a saturated aqueous solution of sodium hydrogencarbonate at room temperature, the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 250 mL of acetonitrile was added to the residue to obtain 2-chloromethylpyridine in acetonitrile.

13.8 g (100 mmol) of 2,4-dihydroxybenzaldehyde was dissolved in 250 mL of acetonitrile, and 32.5 g (100 mmol) of cesium carbonate was added at room temperature. A pre-prepared 2-chloromethylpyridine solution in acetonitrile was added dropwise to the solution at 50 ° C for 4 hours, and stirred for additional 11 hours. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified (jjjjjjjjjjjjjjjjj 27%).

¹ H NMR (δ, chloroform-d): 5.25 (s, 2H), 6.53 (d, J = 2.5 Hz, 1H), 6.65 (dd, J = 2.6, 8.1 Hz, 1H), 7.25 (M,1H), 7.45 (M, 2H), 7.73 (dt, J = 1.9, 7.7 Hz, 1H), 8.61 (d, J = 4.8 Hz, 1H), 9.73 (s, 1H), 11.4 (s, 1H). Melting point 89.2-89.7 ° C, MS (EI) m / z 229 (M ⁺ ).

(2) (1E,6E)-1-(1H-indol-6-yl)-7-[2-hydroxy-4-(2-pyridylmethoxy)phenyl]heptan-1,6-di Synthesis of ene-3,5-dione

By using 2-methoxy-4-(2-tetrahydrofuranylmethoxy) of Example 1 (2) 20 mg (85 μmol) of benzaldehyde was substituted with 908 mg (3.96 mmol) of 3-hydroxy-4-(2-pyridylmethoxy)benzaldehyde, and the synthesis operation was carried out in the same amount to obtain an orange powder having the following The title compound was 356 mg (yield 21%).

¹ H NMR (δ, DMSO-d ₆ ): 5.19 (s, 2H), 6.08 (s, 1H), 6.48 (M, 1H), 6.55-6.59 (M, 2H), 6.79 (d, J = 16 Hz , 1H), 6.86 (d, J = 16 Hz, 1H), 7.35-7.37 (M, 1H), 7.41-7.43 (M, 1H), 7.47-7.50 (M, 2H), 7.58-7.60 (M, 2H) ), 7.70 (s, 1H), 7.74 (d, J = 16 Hz, 1H), 7.81 (d, J = 16 Hz, 1H), 3.14 (dt, J = 2.0, 7.7 Hz, 1H), 8.59 (M , 1H), 10.4 (s, 1H), 11.4 (s, 1H), 16.4 (br s, 1H). Melting point 187.6-189.5 ° C.

(3) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-hydroxy-4-(2-pyridylmethoxy) Synthesis of phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)benzene of Example 1 (3) 400 mg (0.898 mmol) of hexyl-1,6-diene-3,5-dione was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-hydroxy- 4-(2-Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 700 mg (1.61 mmol), and the same operation was carried out to obtain a yellowish white powder. The title compound 226 mg (yield 32%) was obtained.

¹ H NMR (δ, acetone-d ₆ ): 5.17 (s, 2H), 6.46 (M, 1H), 6.58-6.60 (M, 1H), 6.60 (s, 1H), 6.68 (s, 1H), 7.09 (d, J = 16 Hz, 1H), 7.10 (d, J = 17 Hz, 1H), 7.29-7.34 (M, 3H), 7.30 (d, J = 17 Hz, 1H), 7.40 (d, J = 16 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.58 (s, 1H), 7.81 (dt, J = 1.8, 7.7 Hz, 1H), 8.58 (M, 1H), 10.2 (br s, 1H). Melting point 202.5-203.5 ° C, MS (EI) m/z 434 (M ⁺ ). EI- HRMS m/z calcd for C ₂₇ H ₂₂ N ₄ O ₂ (M ⁺ ) 434.1743, found 434.1740.

[Example 4] 3-[(1E)-2-(1H-indol-5-yl)vinyl]-5-[(1E)-2-[4-(2-pyridylmethoxy)benzene Synthesis of vinyl]-1H-pyrazole

(1) Synthesis of 4-(2-pyridylmethoxy)benzaldehyde

4-hydroxybenzaldehyde 611 mg (5.00 mmol) was dissolved in 5.0 mL of N,N-dimethylformamide, and 3.26 g (10.0 mol) of cesium carbonate and 0.98 g of 2-chloromethylpyridine hydrochloride were added at room temperature. (6.0 mmol), stirred at 50 ° C overnight. The obtained reaction solution was diluted with ethyl acetate (100 mL), washed with water and brine (30 mL each), and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by chromatography (hexane/ethyl acetate=80/20→50/50). 77%).

(2) Synthesis of 6-(1H-indol-5-yl)hex-5-ene-2,4-dione

In a 300 mL eggplant-shaped flask equipped with a cooling tube, 15.5 mL of ethyl acetate, 15.9 mL (155 mmol) of 2.4-pentanedione, and 3.24 g (46.5 mmol) of boron oxide were placed, and 1H-吲哚 was added dropwise at 70 ° C with stirring. 4.50 g (31.0 mmol) of 5-carboxycarboxaldehyde and 7.2 mL (31 mmol) of triisopropyl borate in ethyl acetate (31 mL). After stirring at 70 ° C for 30 minutes, drip n-butylamine 3.68 mL (37.2 mmol) in ethyl acetate (9.3 mL). After stirring at 85 ° C for 1 hour, it was cooled to 50 ° C, and 3N hydrochloric acid (22 mL) was added. After stirring at the same temperature for 10 minutes, it was neutralized with saturated sodium hydrogencarbonate. The obtained solution was diluted with ethyl acetate, and then washed twice with brine and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→70/30) and crystallization (ethyl acetate/hexane) The title compound was obtained as a yellow powder (yield: 49%).

¹ H NMR (δ, acetone-d ₆ ): 2.11 (s, 3H), 5.81 (s, 1H), 6.53 (d, J = 3.1 Hz, 1H), 6.63 (d, J = 16 Hz, 1H), 7.38 (M, 1H), 7.47 (M, 2H), 7.73 (d, J = 16 Hz, 1H), 7.87 (s, 1H), 10.49 (br s, NH). Melting point 136-137 ° C.

(3) (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3, Synthesis of 5-diketone

6-(1H-indol-5-yl)hex-5-ene-2,4-dione 31.0 mg (136 μmol) and boron oxide 13.2 mg (0.190 mmol) were placed in a 20 mL reaction vessel with acetic acid The ester was dissolved in 0.88 mL. Further, 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) and 62 μL (0.27 mmol) of triisopropyl borate were sequentially added to the mixture stirred at 70 °C. After stirring at the same temperature for 1 hour, a solution of 2.7 μL (27 μmol) of piperidine in ethyl acetate (0.135 mL) was added and stirred for 1 hour. A 1 : 1 solution of hydrochloric acid and saturated brine (0.4 mL) was added to the reaction mixture at room temperature, and the mixture was stirred for 5 minutes to 1 hour (otherwise, neutralized with a saturated aqueous solution of sodium hydrogencarbonate). Purification by hydrazine column chromatography directly on the obtained organic phase (hexane/ethyl acetate or methylene chloride) The title compound (37.1 mg (yield: 65%))

(4) 3-[(1E)-2-(1H-Indol-5-yl)vinyl]-5-[(1E)-2-[4-(2-pyridylmethoxy)phenyl] Synthesis of vinyl]-1H-pyrazole

(1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3,5- 15 mg (35 μmol) of diketone was dissolved in 0.34 mL of acetic acid, and 34 μL (0.70 mmol) of hydrazine monohydrate was added thereto at room temperature, and the mixture was stirred at 60 ° C for 3 hours. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The obtained organic layer was washed with brine and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate or dichloromethane/methanol). The yellowish white powder had the title compound 3.5 mg (yield: 24%).

¹ H NMR (δ, acetone-d ₆ ): 5.22 (s, 2H), 6.48 (d, J = 3.1 Hz, 1H), 6.70 (s, 1H), 7.03 (d, J = 17 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 17 Hz, 1H), 7.16 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.26- 7.35 (M, 2H), 7.41 (dd, J = 1.5, 8.7 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.55 (br d, J = 7.7 Hz, 1H), 7.72 (br s, 1H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H), 10.3 (br s, NH) Melting point 95-102 ° C, MS (ESI +) m / z 419.4 (M + 1).

[Example 5] 3-[(1E)-2-(1H-indol-5-yl)vinyl]-5-[(1E)-2-[3-methoxy-4-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) Synthesis of 3-methoxy-4-(2-pyridylmethoxy)benzaldehyde

611 mg (5.00 mmol) of 4-hydroxybenzaldehyde of Example 4 (1) was replaced with 4-hydroxy-3-methoxybenzaldehyde 761 mg (5.00 mmol), and the same synthesis operation was carried out to obtain pale green crystals. The title compound was 1.016 g (yield: 84%).

(2) (1E,6E)-1-(1H-indol-5-yl)-7-[3-methoxy-4-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 4 (3) with 3-methoxy-4-(2-pyridylmethoxy)benzaldehyde 33 mg The title compound (42.3 mg (yield: 69%).

(3) 3-[(1E)-2-(1H-Indol-5-yl)vinyl]-5-[(1E)-2-[3-methoxy-4-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-5-yl)-7-[3-methoxy-4-(2- 15 mg (33 μmol) of pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione, and the same synthetic procedure was carried out to give the title compound: (yield 34%).

¹ H NMR (δ, acetone-d ₆ ): 3.93 (s, 3H), 5.20 (s, 2H), 6.48 (d, J = 3.2 Hz, 1H), 6.70 (s, 1H), 6.99-7.09 (M , 4H), 7.15 (d, J = 17 Hz, 1H), 7.25-7.36 (M, 4H), 7.40 (dd, J = 1.4, 8.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H) , 7.60 (br d, J = 7.7 Hz, 1H), 7.71 (br s, 1H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 8.57 (br d, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 96-101 ° C, MS (ESI+) m/z 449.4 (M+1).

[Example 6] 3-[(1E)-2-(1H-indol-5-yl)vinyl]-5-[(1E)-2-[4-methoxy-3-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) Synthesis of 4-methoxy-3-(2-pyridylmethoxy)benzaldehyde

611 mg (5.00 mmol) of 4-hydroxybenzaldehyde of Example 4 (1) was replaced with 3-hydroxy-4-methoxybenzaldehyde 761 mg (5.00 mmol), and the same synthesis operation was carried out to obtain pale green crystals. The title compound was 989 mg (yield 81%).

(2) (1E,6E)-1-(1H-indol-5-yl)-7-[4-methoxy-3-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 4 (3) with 4-methoxy-3-(2-pyridylmethoxy)benzaldehyde 33 mg The title compound (38.9 mg (yield: 63%).

(3) 3-[(1E)-2-(1H-Indol-5-yl)vinyl]-5-[(1E)-2-[4-methoxy-3-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) Substitution with (1E,6E)-1-(1H-indol-5-yl)-7-[4-methoxy-3-(2-pyridylmethoxy)phenyl]heptan-1,6- 15 mg (33 μmol) of the diene-3,5-dione, and the same synthetic procedure was carried out to give 3.8 mg (yield: 26%) of the title compound as a yellowish white powder.

¹ H NMR (δ, acetone-d ₆ ): 3.87 (s, 3H), 5.26 (s, 2H), 6.49 (d, J = 2.9 Hz, 1H), 6.75 (s, 1H), 7.00 (d, J) =8.3 Hz, 1H), 7.02 (d, J=17 Hz, 1H), 7.05 (d, J=17 Hz, 1H), 7.11 (dd, J=2.0, 8 Hz, 1H), 7.13 (d, J =17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.27-7.36 (M, 3H), 7.41 (dd, J = 1.4, 8.3 Hz, 1H), 7.43 (d, J = 8.3 Hz) , 1H), 7.64 (br d, J = 7.9 Hz, 1H), 7.71 (br s, 1H), 7.83 (dt, J = 1.8, 7.7 Hz, 1H), 8.59 (br d, J = 5 Hz, 1H ), 10.3 (br s, NH). Melting point 109-118 ° C, MS (ESI+) m/z 449.3 (M+1).

[Example 7] 3-[(1E)-2-(1H-indol-5-yl)vinyl]-5-[(1E)-2-[3-(2-pyridylmethoxy)benzene Synthesis of vinyl]-1H-pyrazole

(1) Synthesis of 3-(2-pyridylmethoxy)benzaldehyde

By substituting 611 mg (5.00 mmol) of 4-hydroxybenzaldehyde of Example 4 (1) with 611 mg (5.00 mmol) of 3-hydroxybenzaldehyde, and performing the same synthetic procedure, the title compound 772 mg (yield 72%).

(2) (1E,6E)-1-(1H-indol-5-yl)-7-[3-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3, Synthesis of 5-diketone

By 4-(2-pyridylmethoxy)benzaldehyde 29 mg of Example 4 (3) (0.14 mmol) was replaced with 3-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol), and the title compound was obtained (yield: 43%).

(3) 3-[(1E)-2-(1H-Indol-5-yl)vinyl]-5-[(1E)-2-[3-(2-pyridylmethoxy)phenyl] Synthesis of vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-5-yl)-7-[3-(2-pyridylmethoxy) Phenyl]heptane-1,6-diene-3,5-dione 15 mg (35 μmol), and the same synthetic procedure was carried out to give the title compound 9.4 mg (yield: 63%) ).

¹ H NMR (δ, acetone-d ₆ ): 5.25 (s, 2H), 6.49 (d, J = 2.9 Hz, 1H), 6.75 (s, 1H), 6.95 (ddd, J = 1, 2.5, 8.1 Hz , 1H), 7.07 (d, J = 17 Hz, 1H), 7.17 (br d, J = 8 Hz, 1H), 7.18 (M, 2H), 7.25-7.36 (M, 5H), 7.41 (dd, J = 1.5, 8.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.58 (br d, J = 7.9 Hz, 1H), 7.72 (br s, 1H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 8.59 (br d, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 183-186 ° C, MS (ESI+) m/z 419.3 (M+1).

[Example 8] 3-[(1E)-2-(1H-indol-5-yl)vinyl]-5-[(1E)-2-[2-(2-pyridylmethoxy)benzene Synthesis of vinyl]-1H-pyrazole

(1) Synthesis of 2-(2-pyridylmethoxy)benzaldehyde

611 mg (5.00 mmol) of 4-hydroxybenzaldehyde of Example 4 (1) was replaced with 2-hydroxybenzaldehyde 611 mg (5.00 mmol), and the same synthetic procedure was carried out to give the title compound 882 mg Rate 83%).

(2) (1E,6E)-1-(1H-indol-5-yl)-7-[2-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3, Synthesis of 5-diketone

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 4 (3) with 2-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol), The same synthetic operation was carried out to give the title compound (yield: 63%).

(3) 3-[(1E)-2-(1H-Indol-5-yl)vinyl]-5-[(1E)-2-[2-(2-pyridylmethoxy)phenyl] Synthesis of vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-5-yl)-7-[2-(2-pyridylmethoxy) Phenyl]heptane-1,6-diene-3,5-dione 15 mg (35 μmol), and the same synthetic procedure was carried out to give the title compound 9.9 mg (yield 67%) .

^{1 H NMR (δ, DMSO-} d 6): 5.30 (s, 2H), 6.44 (br s, 1H), 6.69 (s, 1H), 6.9-7.4 (M, 10H), 7.49 (d, J = 17 Hz, 1H), 7.58 (br d, J = 7.9 Hz, 1H), 7.64 (br d, J = 8 Hz, 1H), 7.66 (br s, 1H), 7.88 (br t, J = 7.7 Hz, 1H ), 8.60 (br d, J = 5 Hz, 1H), 11.2 (br s, NH). Melting point 220-223 ° C, MS (ESI+) m/z 419.3 (M+1).

[Example 9] 3-[(1E)-2-(1H-indol-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-5-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) Synthesis of 2-methoxy-5-(2-pyridylmethoxy)benzaldehyde

By substituting 611 mg (5.00 mmol) of 4-hydroxybenzaldehyde of Example 4 (1) with 761 mg (5.00 mmol) of 5-hydroxy-2-methoxybenzaldehyde, and performing the same synthesis operation, white amorphous The title compound was 1.018 g (yield: 84%).

(2) (1E,6E)-1-(1H-indol-5-yl)-7-[2-methoxy-5-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 4 (3) to 2-methoxy-5-(2-pyridylmethoxy)benzaldehyde 33 mg The title compound (30.6 mg (yield: 50%)).

(3) 3-[(1E)-2-(1H-indol-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-5-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-5-yl)-7-[2-methoxy-5-(2- 15 mg (33 μmol) of pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione, and subjected to the same synthetic procedure to give the title compound as a yellowish white powder 9.2 mg (yield 62%).

¹ H NMR (δ, acetone-d ₆ ): 3.85 (s, 3H), 5.20 (s, 2H), 6.49 (d, J = 3.1 Hz, 1H), 6.73 (s, 1H), 6.94 (dd, J = 2.6, 9.0 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.19 (d, J = 17 Hz, 1H), 7.33 (d, J) =17 Hz,1H), 7.26-7.36 (M,3H), 7.41 (dd, J=1.5, 8.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.45 (d, J=17 Hz) , 1H), 7.58 (br d, J = 7.7 Hz, 1H), 7.73 (br s, 1H), 7.81 (dt, J = 1.8, 7.7 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H ), 10.3 (br s, NH). Melting point 116-122 ° C, MS (ESI+) m / z 449.3 (M + 1).

[Example 10] 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[4-(2-pyridylmethoxy)benzene Synthesis of vinyl]-1H-pyrazole

(1) Synthesis of 6-(1H-indol-3-yl)hex-5-ene-2,4-dione

By substituting 4.50 g (31.0 mmol) of 1H-indole-5-carboxycarboxaldehyde of Example 4 (2) for 1H-indole-3-carboxycarboxaldehyde 4.50 g (31.0 mmol), and performing the same synthesis operation, The title compound was obtained as a yellow powder (yield: 30%).

¹ H NMR (δ, acetone-d ₆ ): 2.08 (s, 3H), 5.81 (s, 1H), 6.66 (d, J = 16 Hz, 1H), 7.1-7.3 (M, 2H), 7.51 (M , 1H), 7.85 (s, 1H), 7.89 (d, J = 16 Hz, 1H), 8.00 (M, 1H). Melting point 155-158 ° C.

(2) (1E,6E)-1-(1H-indol-3-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3, Synthesis of 5-diketone

6-(1H-indol-3-yl)hex-5-ene-2,4-dione 31.0 mg (136 μmol) and boron oxide 13.2 mg (0.190 mmol) were placed in a 20 mL reaction vessel. It was dissolved in 0.88 mL of ethyl acetate. Further, 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) and 62 μL (0.27 mmol) of triisopropyl borate were sequentially added to the mixture stirred at 70 °C. After stirring at the same temperature for 1 hour, a solution of 2.7 μL (27 μmol) of piperidine in ethyl acetate (0.135 mL) was added and stirred for 1 hour. A 1 : 1 solution of hydrochloric acid and saturated brine (0.4 mL) was added to the reaction mixture at room temperature, and the mixture was stirred for 5 minutes to 1 hour (otherwise, neutralized with a saturated aqueous solution of sodium hydrogencarbonate). The title compound (25.4 mg (yield: 45%)) was obtained as the title compound (yield: hexane/ethyl acetate/methanol/methanol).

(3) 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[4-(2-pyridylmethoxy)phenyl] Synthesis of vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-3-yl)-7-[4-(2-pyridylmethoxy) Phenyl]heptane-1,6-diene-3,5-dione 15 mg (35 μmol), and the same synthetic procedure was carried out to give the title compound 5.8 mg (yield 39%) .

¹ H NMR (δ, acetone-d ₆ ): 5.21 (s, 2H), 6.46 (dd, J = 1, 3.0 Hz, 1H), 6.69 (s, 1H), 7.02 (d, J = 17 Hz, 1H) ), 7.05 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 17 Hz, 1H), 7.15 (d, J = 17 Hz, 1H), 7.1-7.2 (M, 2H), 7.32 (M , 1H), 7.43 (d, J = 17 Hz, 1H), 7.46 (M, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.53-7.60 (M, 2H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 7.96 (M, 1H), 8.58 (br d, J = 5 Hz, 1H), 10.5 (br s, NH). Melting point 196-199 ° C, MS (ESI+) m/z 419.3 (M+1).

[Example 11] 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[3-methoxy-4-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-3-yl)-7-[3-methoxy-4-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 10 (2) with 3-methoxy-4-(2-pyridylmethoxy)benzaldehyde 33 mg (0.14 mmol), and the title compound was obtained (yield: 47%).

(2) 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[3-methoxy-4-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-3-yl)-7-[3-methoxy-4-(2- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (33 μmol), and subjected to the same synthetic procedure to give the title compound 8.4 Mg (yield 57%).

¹ H NMR (δ, acetone-d ₆ ): 3.93 (s, 3H), 5.20 (s, 2H), 6.69 (s, 1H), 7.0-7.13 (M, 5H), 7.1-7.2 (M, 2H) , 7.27 (d, J = 2 Hz, 1H), 7.30 (M, 1H), 7.43 (d, J = 17 Hz, 1H), 7.47 (M, 1H), 7.60 (s, 1H), 7.61 (d, J=7 Hz, 1H), 7.82 (dt, J=1.7, 7.7 Hz, 1H), 7.96 (M, 1H), 8.56 (br d, J=5 Hz, 1H), 10.5 (br s, NH). Melting point 120-130 ° C, MS (ESI +) m / z 449.3 (M + 1).

[Example 12] 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[4-methoxy-3-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-3-yl)-7-[4-methoxy-3-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 10 (2) with 4-methoxy-3-(2-pyridylmethoxy)benzaldehyde 33 mg (0.14 mmol), and the title compound was obtained (yield: 43%).

(2) 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[4-methoxy-3-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-3-yl)-7-[4-methoxy-3-(2- Pyridylmethoxy)phenyl]heptane-1,6-diene-3,5-dione 15 mg (33 μmol), and subjected to the same synthetic procedure to give the title compound 5.9 Mg (yield 40%).

¹ H NMR (δ, DMSO-d ₆ ): 3.80 (s, 3H), 5.23 (s, 2H), 6.64 (s, 1H), 6.94 (d, J = 17 Hz, 1H), 6.9-7.2 (M) , 6H), 7.30 (br s, 1H), 7.32 (d, J = 17 Hz, 1H), 7.35 (M, 1H), 7.42 (br d, J = 7.4 Hz, 1H), 7.56 (br d, J =7.6 Hz,1H), 7.63(br s,1H),7.88(br t,J=7.7 Hz,1H),7.87(br d,J=8 Hz,1H),8.59(br d,J=5 Hz , 1H), 11.4 (br s, NH). Melting point 232-243 ° C, MS (ESI+) m/z 449.3 (M+1).

[Example 13] 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[3-(2-pyridylmethoxy)benzene Synthesis of vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-3-yl)-7-[3-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3, Synthesis of 5-diketone

By substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 10(2) to 3-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol), The same synthetic operation was carried out to give the title compound (yield: 27%) of orange powder.

(2) 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[3-(2-pyridylmethoxy)phenyl] Synthesis of vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-3-yl)-7-[3-(2-pyridylmethoxy) Phenyl]heptane-1,6-diene-3,5-dione 15 mg (35 μmol), and the same synthetic procedure was carried out to give the title compound 5.7 mg (yield 38%) ).

¹ H NMR (δ, acetone-d ₆ ): 5.25 (s, 2H), 6.73 (s, 1H), 6.94 (ddd, J = 1, 2.6, 8.2 Hz, 1H), 7.10 (d, J = 17 Hz) , 1H), 7.11-7.21 (M, 5H), 7.25-7.30 (M, 2H), 7.33 (M, 1H), 7.44 (d, J = 17 Hz, 1H), 7.46 (M, 1H), 7.56- 7.62 (M, 2H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 7.96 (M, 1H), 8.59 (br d, J = 5 Hz, 1H), 10.5 (br s, NH). Point 198-201 ° C, MS (ESI+) m / z 419.4 (M + 1).

[Example 14] 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-(2-pyridylmethoxy)benzene Synthesis of vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-3-yl)-7-[2-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3, Synthesis of 5-diketone

By substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 10 (2) to 2-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol), The same synthetic operation was carried out to give the title compound (34.6 mg (yield: 60%)).

(2) 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-(2-pyridylmethoxy)phenyl] Synthesis of vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-3-yl)-7-[2-(2-pyridylmethoxy) Phenyl]heptane-1,6-diene-3,5-dione 15 mg (35 μmol), and subjected to the same synthetic procedure to give the title compound as a yellowish white powder 7.8 mg (yield 53%).

¹ H NMR (δ, acetone-d ₆ ): 5.31 (s, 2H), 6.71 (s, 1H), 6.99 (dd, J = 7, 7 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H) ), 7.10 (d, J = 17 Hz, 1H), 7.1-7.2 (M, 2H), 7.23 (d, J = 17 Hz, 1H), 7.25 (M, 1H), 7.32 (M, 1H), 7.44 (d, J = 17 Hz, 1H), 7.46 (M, 1H), 7.57-7.65 (M, 3H), 7.67 (dd, J = 1.4, 7.8 Hz, 1H), 7.85 (dt, J = 1.8, 7.7) Hz, 1H), 7.97 (M, 1H), 8.60 (br d, J = 5 Hz, 1H), 10.5 (br s, NH). Melting point 114-125 ° C, MS (ESI+) m/z 419.4 (M +1).

[Example 15] 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy-5-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-3-yl)-7-[2-methoxy-5-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 10 (2) with 2-methoxy-5-(2-pyridylmethoxy)benzaldehyde 33 mg The title compound (38.0 mg (yield: 62%)).

(2) 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy-5-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E, 6E)-1-(1H-indol-5-yl)-7-[4-(2-) of Example 4(4) 15 mg (35 μmol) of pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione was substituted with (1E,6E)-1-(1H-indol-3-yl)-7 -[2-Methoxy-5-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (33 μmol), and the same synthetic operation was carried out to give The title compound 7.3 mg (yield: 49%) of the title compound.

¹ H NMR (δ, acetone-d ₆ ): 3.85 (s, 3H), 5.20 (s, 2H), 6.71 (s, 1H), 6.93 (dd, J = 2.6, 8.9 Hz, 1H), 6.96 (d) , J=8.9 Hz, 1H), 7.10 (d, J=17 Hz, 1H), 7.1-7.2 (M, 2H), 7.19 (d, J=17 Hz, 1H), 7.31 (M, 1H), 7.34 (d, J = 2.6 Hz, 1H), 7.44 (d, J = 17 Hz, 1H), 7.46 (d, J = 17 Hz, 1H), 7.46 (M, 1H), 7.56-7.62 (M, 2H) , 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 7.97 (M, 1H), 8.58 (br d, J = 5 Hz, 1H), 10.5 (br s, NH). Melting point 233-238 ° C, MS (ESI+) m/z 449.3 (M+1).

[Example 16] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[4-(2-pyridylmethoxy)benzene Synthesis of vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3, Synthesis of 5-diketone

6-(1H-吲哚-6-yl)hex-5-ene-2,4-dione 31.0 mg (136 μmol) and boron oxide 13.2 mg (0.190 mmol) were placed in a 20 mL reaction vessel with acetic acid The ester was dissolved in 0.88 mL. Further, 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) and 62 μL (0.27 mmol) of triisopropyl borate were sequentially added to the mixture stirred at 70 °C. Add the pipeper after stirring at the same temperature for 1 hour. A solution of 2.7 μL (27 μmol) of ethyl acetate (0.135 mL) was stirred and stirred for 1 hour. A 1 : 1 solution of hydrochloric acid and saturated brine (0.4 mL) was added to the reaction mixture at room temperature, and the mixture was stirred for 5 minutes to 1 hour (otherwise, neutralized with a saturated aqueous solution of sodium hydrogencarbonate). The title compound (41.3 mg (yield: 72%))

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[4-(2-pyridylmethoxy)phenyl] Synthesis of vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[4-(2-pyridylmethoxy) Phenyl]heptane-1,6-diene-3,5-dione 15 mg (35 μmol), and the same synthetic procedure was carried out to give the title compound 5.2 mg (yield 35%) ).

¹ H NMR (δ, acetone-d ₆ ): 5.21 (s, 2H), 6.46 (dd, J = 1, 3.0 Hz, 1H), 6.71 (s, 1H), 7.03 (d, J = 17 Hz, 1H) ), 7.05 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 17 Hz, 1H), 7.16 (d, J = 17 Hz, 1H), 7.26-7.36 (M, 4H), 7.52 (d) , J=8.8 Hz, 2H), 7.53-7.6 (M, 3H), 7.82 (dt, J=1.8, 7.7 Hz, 1H), 8.58 (br d, J=5 Hz, 1H), 10.3 (br s, NH). Melting point 211-214 ° C, MS (ESI+) m / z 419.3 (M + 1).

[Example 17] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[3-methoxy-4-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[3-methoxy-4-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 3-methoxy-4-(2-pyridylmethoxy)benzaldehyde 33 mg The title compound (29.7 mg (yield: 48%)).

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[3-methoxy-4-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[3-methoxy-4-(2- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (33 μmol), and subjected to the same synthetic procedure to give the title compound 9.3 Mg (yield 63%).

¹ H NMR (δ, DMSO-d ₆ ): 3.86 (s, 3H), 5.17 (s, 2H), 6.41 (br s, 1H), 6.70 (s, 1H), 6.94-7.1 (M, 5H), 7.17-7.30 (M, 3H), 7.31-7.38 (M, 2H), 7.47-7.55 (M, 3H), 7.84 (br d, J = 8 Hz, 1H), 8.57 (br d, J = 4 Hz, 1H), 11.2 (br s, NH). Melting point 236-243 ° C, MS (ESI+) m/z 449.3 (M+1).

[Example 18] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[4-methoxy-3-(2-pyridine) Combination of methoxy)phenyl]vinyl]-1H-pyrazole to make

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[4-methoxy-3-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 4-methoxy-3-(2-pyridylmethoxy)benzaldehyde 33 mg (0.14 mmol), and the title compound was obtained (yield: 52%).

(2) 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[4-methoxy-3-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[4-methoxy-3-(2- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (33 μmol), and the same synthetic procedure was carried out to give the title compound 9.9 as a yellowish white powder. Mg (yield 67%).

¹ H NMR (δ, acetone-d ₆ ): 3.87 (s, 3H), 5.26 (s, 2H), 6.46 (dd, J = 0.8, 3.2 Hz, 1H), 6.70 (s, 1H), 7.00 (d) , J = 8.3 Hz, 1H), 7.02 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.11 (M, 1H), 7.13 (d, J = 17 Hz, 1H) ), 7.25-7.38 (M, 5H), 7.53-7.58 (M, 2H), 7.64 (d, J = 7.9 Hz, 1H), 7.83 (dt, J = 1.7, 7.7 Hz, 1H), 8.58 (br d , J=5 Hz, 1H), 10.3 (br s, NH). Melting point 110-117 ° C, MS (ESI+) m/z 449.3 (M+1).

[Example 19] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[3-(2-pyridylmethoxy)benzene Synthesis of vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[3-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3, Synthesis of 5-diketone

By disposing 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1), 3-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol), The same synthetic operation was carried out to give the title compound (yield: 41%) (yield: 41%).

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[3-(2-pyridylmethoxy)phenyl] Synthesis of vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[3-(2-pyridylmethoxy) Phenyl]heptane-1,6-diene-3,5-dione 15 mg (35 μmol), and the same synthetic procedure was carried out to give the title compound 10.7 mg (yield: 72%) .

¹ H NMR (δ, acetone-d ₆ ): 5.25 (s, 2H), 6.46 (dd, J = 0.8, 3.2 Hz, 1H), 6.76 (s, 1H), 6.95 (ddd, J = 1, 2.6, 8.1 Hz, 1H), 7.10 (d, J = 17 Hz, 1H), 7.17 (br d, J = 8 Hz, 1H), 7.18 (M, 2H), 7.23 - 7.38 (M, 6H), 7.53 - 7.62 (M, 3H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 8.59 (br d, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 193-195 ° C, MS ( ESI+)m/z 419.4(M+1).

[Example 20] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-(2-pyridylmethoxy)benzene Synthesis of vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[2-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3, Synthesis of 5-diketone

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 2-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol), The same synthetic operation was carried out to give the title compound (yield: 64%).

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-(2-pyridylmethoxy)phenyl] Synthesis of vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-(2-pyridylmethoxy) Phenyl]heptane-1,6-diene-3,5-dione 15 mg (35 μmol), and the same synthetic procedure was carried out to give the title compound 9.7 mg (yield: 65%) .

¹ H NMR (δ, acetone-d ₆ ): 5.31 (s, 2H), 6.46 (dd, J = 0.9, 3.1 Hz, 1H), 6.74 (s, 1H), 6.99 (dd, J = 7.4, 7.4 Hz , 1H), 7.08 (dd, J = 0.9, 8.2 Hz, 1H), 7.10 (d, J = 17 Hz, 1H), 7.22 (M, 1H), 7.23 (d, J = 17 Hz, 1H), 7.28 -7.36 (M, 4H), 7.54 - 7.59 (M, 2H), 7.62 (d, J = 17 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.67 (dd, J = 1.7, 7.8 Hz, 1H), 7.85 (dt, J = 1.8, 7.7 Hz, 1H), 8.60 (br d, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 113-120 ° C, MS (ESI+ ) m / z 419.3 (M + 1).

[Example 21] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-5-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-5-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16 (1) to 2-methoxy-5-(2-pyridylmethoxy)benzaldehyde 33 mg (0.14 mmol), and the title compound was obtained (yield: 68%).

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-5-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-5-(2- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (33 μmol), and subjected to the same synthesis operation to obtain a yellowish white powder having the following physical properties The title compound was 11.6 mg (yield 78%).

¹ H NMR (δ, acetone-d ₆ ): 3.85 (s, 3H), 5.19 (s, 2H), 6.46 (dd, J = 0.8, 3.1 Hz, 1H), 6.73 (s, 1H), 6.94 (dd , J=2.6, 9.0 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 7.10 (d, J=17 Hz, 1H), 7.19 (d, J=17 Hz, 1H), 7.27-7.38 (M,5H), 7.45 (d, J=17 Hz, 1H), 7.53-7.62 (M, 3H), 7.81 (dt, J=1.8, 7.7 Hz, 1H), 8.58 (br d, J=5 Hz , 1H), 10.3 (br s, NH). Melting point 111-120 ° C, MS (ESI+) m/z 449.4 (M+1).

[Example 22] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-3-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) Synthesis of 2-methoxy-3-(2-pyridylmethoxy)benzaldehyde

611 mg (5.00 mmol) of 4-hydroxybenzaldehyde of Example 4 (1) was replaced with 3-hydroxy-2-methoxybenzaldehyde 100 mg (0.657 mmol), and the synthesis operation was carried out in the same amount relationship. The title compound was 66.8 mg (yield: 42%).

(2) (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-3-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) to 2-methoxy-3-(2-pyridylmethoxy)benzaldehyde 33 mg (0.14 mmol), and the same synthesis operation was carried out to obtain orange powder The title compound was 40.6 mg (yield: 66%).

(3) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-3-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-3-(2- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (33 μmol), and the same synthetic procedure was carried out to give the title compound 8.4 mg (Yield 57%).

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.25 (s, 2H), 6.46 (dd, J = 0.8, 3.2 Hz, 1H), 6.78 (s, 1H), 7.0-7.06 (M, 2H), 7.11 (d, J = 17 Hz, 1H), 7.19 (d, J = 17 Hz, 1H), 7.27-7.38 (M, 5H), 7.50 (d, J = 17 Hz, 1H) , 7.54-7.60 (M, 2H), 7.64 (d, J = 7.9 Hz, 1H), 7.84 (dt, J = 1.8, 7.7 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 109-114 ° C, MS (ESI+) m/z 449.3 (M+1).

[Example 23] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[4-methoxy-2-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) Synthesis of 4-methoxy-2-(2-pyridylmethoxy)benzaldehyde

611 mg (5.00 mmol) of 4-hydroxybenzaldehyde of Example 4 (1) was replaced with 2-hydroxy-4-methoxybenzaldehyde 100 mg (0.657 mmol), and the same The amount of the mixture was subjected to a synthetic operation to give the title compound (yield: 43%) as white powder.

(2) (1E,6E)-1-(1H-indol-6-yl)-7-[4-methoxy-2-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

Substituting 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 4-methoxy-2-(2-pyridylmethoxy)benzaldehyde 33 mg (0.14) The title compound was obtained as an orange powder (yield: 69%).

(3) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[4-methoxy-2-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[4-methoxy-2-(2- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (33 μmol), and the same synthetic procedure was carried out to give a yellow-white powder of the title compound 7.5 mg. (Yield 50%).

¹ H NMR (δ, acetone-d ₆ ): 3.79 (s, 3H), 5.30 (s, 2H), 6.46 (brd, J = 3 Hz, 1H), 6.59 (dd, J = 2, 8.6 Hz, 1H), 6.67 (d, J = 2 Hz, 1H), 6.68 (s, 1H), 7.09 (d, J = 17 Hz, 1H), 7.10 (d, J = 17 Hz, 1H), 7.29 (d, J = 17 Hz, 1H), 7.29-7.36 (M, 3H), 7.52 (d, J = 17 Hz, 1H), 7.53 - 7.58 (M, 2H), 7.57 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.85 (br t, J = 7.7 Hz, 1H), 8.60 (br d, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 107- 115 ° C, MS (ESI+) m / z 449.4 (M + 1).

[Example 24] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[5-methoxy-2-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) Synthesis of 5-methoxy-2-(2-pyridylmethoxy)benzaldehyde

611 mg (5.00 mmol) of 4-hydroxybenzaldehyde of Example 4 (1) was replaced with 2-hydroxy-5-methoxybenzaldehyde 100 mg (0.657 mmol), and the synthesis operation was carried out in the same amount relationship. The title compound of the white powder was 77.3 mg (yield: 48%).

(2) (1E,6E)-1-(1H-indol-6-yl)-7-[5-methoxy-2-(2-pyridylmethoxy)phenyl]heptan-1,6 Synthesis of -diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16 (1) to 5-methoxy-2-(2-pyridylmethoxy)benzaldehyde 33 mg (0.14 mmol), and the title compound was obtained (yield: 48%).

(3) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[5-methoxy-2-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[5-methoxy-2-(2- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (33 μmol), and subjected to the same synthesis operation to obtain a yellowish white powder having the following physical properties The title compound was 7.0 mg (yield 47%).

¹ H NMR (δ, DMSO-d ₆ ): 3.75 (s, 3H), 5.22 (s, 2H), 6.41 (br s, 1H), 6.71 (s, 1H), 6.81 (brd, J = 9 Hz) , 1H), 7.01 (d, J = 9 Hz, 1H), 7.01 (d, J = 17 Hz, 1H), 7.18 (d, J = 17 Hz, 1H), 7.17-7.6 (M, 9H), 7.87 (dd, J = 1.6, 7.7 Hz, 1H), 8.59 (br d, J = 5 Hz, 1H), 11.2 (br s, NH). Melting point 119-124 ° C, MS (ESI+) m/z 449.4 ( M+1).

[Example 25] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[3-methoxy-5-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) Synthesis of 3-methoxy-5-(2-pyridylmethoxy)benzaldehyde

611 mg (5.00 mmol) of 4-hydroxybenzaldehyde of Example 4 (1) was replaced with 3-hydroxy-5-methoxybenzaldehyde 100 mg (0.657 mmol), and the synthesis operation was carried out in the same amount relationship. The title compound was white powder (85.6 mg, yield 54%).

(2) (1E,6E)-1-(1H-indol-6-yl)-7-[3-methoxy-5-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 3-methoxy-5-(2-pyridylmethoxy)benzaldehyde 33 mg The title compound (22.8 mg (yield: 37%)).

(3) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[3-methoxy-5-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[3-methoxy-5-(2- 15 mg (33 μmol) of pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione, and the same synthetic procedure was carried out to give the title compound: 8.5 mg (Yield 57%).

¹ H NMR (δ, acetone-d ₆ ): 3.82 (s, 3H), 5.23 (s, 2H), 6.46 (brd, J = 3 Hz, 1H), 6.54 (dd, J = 2.2, 2.2 Hz, 1H), 6.75 (s, 1H), 6.76 (br s, 1H), 6.86 (br s, 1H), 7.10 (d, J = 17 Hz, 1H), 7.13 (d, J = 17 Hz, 1H), 7.18 (d, J = 17 Hz, 1H), 7.27-7.38 (M, 4H), 7.51-7.60 (M, 3H), 7.85 (dt, J = 1.8, 7.7 Hz, 1H), 8.58 (br d, J =5 Hz, 1H), 10.3 (br s, NH). Melting point 88-93 ° C, MS (ESI+) m/z 449.4 (M+1).

[Example 26] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-piperidin) Synthesis of pyridylethoxy)phenyl]vinyl]-1H-pyrazole

(1) Synthesis of 2-methoxy-4-(2-piperidinylethoxy)benzaldehyde

By dissolving 4-hydroxy-2-methoxybenzaldehyde 304 mg (2.00 mmol), potassium carbonate 0.55 g (4.0 mmol) and tetrabutylammonium bromide 64 mg (0.20 mmol) in N,N-dimethyl group Guanamine 2.0 mL, adding 1-(2-chloroethyl) piperidine hydrochloride Salt 0.74 g (4.0 mmol) was stirred at 100 ° C overnight. The obtained reaction solution was diluted with ethyl acetate (100 mL), washed with water and brine (20 mL each) and dried over magnesium sulfate. After the filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) to afford Rate 16%).

(2) (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-piperidinylethoxy)phenyl]heptane-1, Synthesis of 6-diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 2-methoxy-4-(2-piperidinylethoxy)benzaldehyde 36 mg (0.14 mmol), and the same synthetic procedure was carried out to give the title compound 46.3 mg (yield 75%).

(3) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-piperidinyl) Synthesis of ethoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2- Piperidinylethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (32 μmol), and the same synthetic procedure was carried out to give the title compound as a yellowish white powder. 7.7 mg (yield 52%).

¹ H NMR (δ, acetone-d ₆ ): 1.41 (M, 2H), 1.54 (M, 4H), 2.47 (M, 4H), 2.69 (t, J = 6.0 Hz, 2H), 3.90 (s, 3H) ), 4.12 (t, J = 6.0 Hz, 2H), 6.46 (dd, J = 0.8, 3.1 Hz, 1H), 6.56 (d, J = 2.4, 8.4 Hz, 1H), 6.59 (d, J = 2.4 Hz) , 1H), 6.68 (s, 1H), 7.04 (d, J = 17 Hz, 1H), 7.08 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.3-7.38 (M, 2H), 7.38 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.54-7.60 (M, 2H), 10.3 (br s, NH). Melting point 150 - 155 ° C, MS (ESI+) m/z 469.4 (M+1).

[Example 27] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-? Synthesis of phenyl ethoxy)phenyl]vinyl]-1H-pyrazole

(1) Synthesis of 2-methoxy-4-(2-morpholinylethoxy)benzaldehyde

By replacing 0.74 g (4.0 mmol) of 1-(2-chloroethyl)piperidine hydrochloride of Example 26(1) with 4-(2-chloroethyl)morpholine hydrochloride 0.74 g (4.0 The same synthesis was carried out to give the title compound (yield: 56%).

(2) (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-morpholinylethoxy)phenyl]heptane-1, Synthesis of 6-diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) to 2-methoxy-4-(2-morpholinylethoxy)benzaldehyde The title compound (50.1 mg (yield: 82%)).

(3) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-morpholinyl) Synthesis of ethoxy)phenyl]vinyl]-1H-pyrazole

By (1E, 6E)-1-(1H-indol-5-yl)-7-[4-(2-) of Example 4(4) 15 mg (35 μmol) of pyridylmethoxy)phenyl]heptane-1,6-diene-3,5-dione was substituted with (1E,6E)-1-(1H-indol-6-yl)-7 -[2-Methoxy-4-(2-morpholinylethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (32 μmol), and subjected to the same synthesis operation, The title compound (9.2 mg (yield: 62%)) was obtained as the yellowish white powder.

¹ H NMR (δ, acetone-d ₆ ): 2.52 (t, J = 4.6 Hz, 4H), 2.74 (t, J = 5.8 Hz, 2H), 3.61 (t, J = 4.6 Hz, 4H), 3.90 ( s, 3H), 4.16 (t, J = 5.8 Hz, 2H), 6.46 (dd, J = 1, 3.1 Hz, 1H), 6.57 (dd, J = 2.4, 8.4 Hz, 1H), 6.60 (d, J) =2.4 Hz, 1H), 6.68 (s, 1H), 7.04 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.30-7.36 (M, 2H), 7.37 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.53-7.60 (M, 2H), 10.3 (br s, NH). Melting point 113-122 ° C, MS (ESI+) m / z 471.4 (M + 1).

[Example 28] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-[2-( 4-methylperazine Synthesis of ethoxy]phenyl]vinyl]-1H-pyrazole

(1) 2-methoxy-4-[2-(4-methylperidine) Synthesis of ethoxy]benzaldehyde

To a solution of 4-hydroxy-2-methoxybenzaldehyde 304 mg (2.00 mmol) in N,N-dimethylformamide (4.0 mL) was added 105 mg (55%, 2.40 mmol). After stirring at room temperature for 30 minutes, ethylene dibromide 0.69 M1 (8.0 mmol) was added. Add 1-methylpiperider after stirring at 80 ° C for 7 hours 2.2 mL (20 mmol). After stirring overnight at 80 ° C, water was added to the reaction solution under ice cooling, and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→40/60). Rate 20%).

(2) (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-[2-(4-methylpiperidin) Synthesis of ethoxy]phenyl]heptan-1,6-diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) to 2-methoxy-4-[2-(4-methylpiperidine) 38 mg (0.14 mmol) of ethoxy]benzaldehyde, and the same synthetic procedure was carried out to give the title compound 40.9 mg (yield: 65%).

(3) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-[2-(4- Methylpiper Synthesis of ethoxy]phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-[2- (4-methylperidazole Ethyl]phenyl]heptane-1,6-diene-3,5-dione 15 mg (31 μmol), and subjected to the same synthetic procedure to give the title compound 8.8 mg (Yield 59%).

¹ H NMR (δ, acetone-d ₆ ): 2.18 (s, 3H), 2.37 (br s, 4H), 2.55 (br s, 4H), 2.74 (t, J = 5.9 Hz, 2H), 3.90 (s) , 3H), 4.13 (t, J = 5.9 Hz, 2H), 6.46 (br d, J = 3.1 Hz, 1H), 6.56 (dd, J = 2.3, 8.4 Hz, 1H), 6.59 (d, J = 2.3 Hz, 1H), 6.68 (s, 1H), 7.04 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.31 (d, J = 17 Hz, 1H), 7.30- 7.36 (M, 2H), 7.37 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.53 - 7.59 (M, 2H), 10.3 (br s, NH). Melting point 134-142 ° C, MS (ESI+) m / z 484.4 (M + 1).

[Example 29] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[4-[(β-D-glucopyranose) Synthesis of yloxy]-2-methoxyphenyl]vinyl]-1H-pyrazole

(1) Synthesis of 2-methoxy-4-[(2,3,4,6-tetra-O-ethinyl-β-D-glucopyranosyl)oxy]benzaldehyde

666 mg (4.38 mmol) of 4-hydroxy-2-methoxybenzaldehyde and 1.50 g of 2,3,4,6-tetra-O-ethylidene-α-D-glucopyranose for 4-hydroxy-2-methoxybenzaldehyde at room temperature A solution of (3.65 mmol) and tetrabutylammonium bromide (1.18 g, 3.66 mmol) in chloroform (11 mL) was evaporated. The reaction solution was extracted with ethyl acetate, and then washed with saturated aqueous sodium hydrogen carbonate and brine and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=75/25→60/40) to give a white powder of 2-methoxy- 4-[(2,3,4,6-tetra-O-ethinyl-β-D-glucopyranosyl)oxy]benzaldehyde 606 mg (yield 40%).

(2) (1E,6E)-1-(1H-吲哚-6-yl)-7-[2-methoxy-4-[(2,3,4,6-tetra-O-) Synthesis of acetyl-β-D-glucopyranosyloxy]phenyl]heptan-1,6-diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 2-methoxy-4-[(2,3,4,6-tetra- O-Ethyl-β-D-glucopyranosyloxy)benzaldehyde 65 mg (0.14 mmol) was obtained from the title compound (yield: 92%).

(3) 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[4-[(β-D-glucopyranosyl) Synthesis of oxy]-2-methoxyphenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-[(2) ,3,4,6-tetra-O-ethinyl-β-D-glucopyranosyl)oxy]phenyl]heptan-1,6-diene-3,5-dione 15 mg (22 μmol) And performing the same synthesis operation to obtain 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[4-[(2,3, The crude product of 4,6-tetra-O-ethinyl-β-D-glucopyranosyl)oxy]-2-methoxyphenyl]vinyl]-1H-pyrazole was 14.7 mg.

14.7 mg of the above compound was dissolved in 1.0 mL of tetrahydrofuran, and a solution of 5.4 mg (0.10 mmol) of methanol (1.0 mL) of sodium methoxide was added at room temperature. After stirring at the same temperature for 1 hour, it was neutralized with 100 μL (0.10 mmol) of 1N hydrochloric acid. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane/methanol=95/5→70/30) to give the title compound 5.9 mg (2 stage yield 53%).

¹ H NMR (δ, DMSO-d ₆ ): 3.84 (s, 3H), 4.64 (M, 1H), 4.90 (M, 1H), 5.07 (M, 1H), 5.14 (M, 1H), 5.34 (M) , 1H), 6.41 (br s, 1H), 6.65 (br d, J = 9 Hz, 1H), 6.69 (s, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.99 (br d, J =17 Hz, 2H), 7.20-7.40 (M, 4H), 7.47-7.60 (M, 3H), 11.2 (br s, NH). Melting point 194-199 ° C, MS (ESI+) m/z 520.3 (M +1).

[Example 30] 3-[(1E)-2-(1H-benzotriazol-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2) Synthesis of -pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

(1) Synthesis of 6-[2-methoxy-4-(2-pyridylmethoxy)phenyl]hex-5-ene-2,4-dione

Substituting 4.50 g (31.0 mmol) of 1H-indole-5-carboxycarboxaldehyde of Example 4 (2) to 2-methoxy-4-(2-pyridylmethoxy)benzaldehyde 10.0 g (41.1 The title compound (5.65 g (yield: 42%)) of the title compound was obtained as a yellow white powder.

¹ H NMR ^(δ, acetone _{-d 6): 2.10 (s,} 3H), 3.92 (s, 3H), 5.25 (s, 2H), 5.75 (s, 1H), 6.63 (d, J = 16 Hz, 1H ), 6.67 (dd, J = 2.4, 8.6 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 7.32 (M, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.60 (d) , J=8.6 Hz, 1H), 7.82 (dt, J=1.8, 7.8 Hz, 1H), 7.85 (d, J=16 Hz, 1H), 8.58 (M, 1H). Melting point 81-82°C, MS (ESI+) m/z 326.2 (M+1).

(2) (1E,6E)-1-(1H-benzotriazol-5-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptane-1 Synthesis of 6-diene-3,5-dione

6-[2-methoxy-4-(2-pyridylmethoxy)phenyl]hex-5-ene-2,4-dione 44.3 mg (136 μmol) and oxidized in a 20 mL reaction vessel 13.2 mg (0.190 mmol) of boron was dissolved in 0.88 mL of ethyl acetate. 1 H-benzotriazole-5-carboxycarboxaldehyde 20 mg (0.14 mmol) and 62 μL (0.27 mmol) of triisopropyl borate were sequentially added to the mixture stirred at 70 °C. After stirring at the same temperature for 1 hour, a solution of 2.7 μL (27 μmol) of piperidine in ethyl acetate (0.135 mL) was added and stirred for 1 hour. A 1 : 1 solution of hydrochloric acid and saturated brine (0.4 mL) was added to the reaction mixture at room temperature, and the mixture was stirred for 5 minutes to 1 hour (otherwise, neutralized with a saturated aqueous solution of sodium hydrogencarbonate). The title compound (5.9 mg (yield: 10%)) (yield: 10%).

(3) 3-[(1E)-2-(1H-benzotriazol-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-benzotriazol-5-yl)-7-[2-methoxy-4-( 2-Pyridylmethoxy)phenyl]heptane-1,6-diene-3,5-dione 15 mg (33 μmol), and subjected to the same synthetic procedure to give a yellowish white powder title title: Compound 1.7 mg (yield 11%).

Melting point 113-120 ° C, MS (ESI+) m / z 451.2 (M + 1).

[Example 31] 3-[(1E)-2-(1H-benzimidazol-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2- Synthesis of pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-benzimidazol-5-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptane-1, Synthesis of 6-diene-3,5-dione

By replacing 1H-benzotriazol-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30 (2) with 1H-benzimidazole-5-carboxycarboxaldehyde 20 mg (0.14 mmol), and performing the same synthesis operation The title compound was obtained as an orange powder (15.1 mg (yield: 24%).

(2) 3-[(1E)-2-(1H-Benzimidazole-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridyl) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-benzimidazol-5-yl)-7-[2-methoxy-4-(2) -pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (33 μmol), and the same synthetic procedure was carried out to give the title compound as a yellowish white powder. 4.8 mg (yield 32%).

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.65 (dd, J = 2.3, 8.6 Hz, 1H), 6.71 (s, 1H), 6.74 (d) , J=2.3 Hz, 1H), 7.06 (d, J=17 Hz, 1H), 7.13 (d, J=17 Hz, 1H), 7.28-7.4 (M, 2H), 7.39 (d, J=17 Hz) , 1H), 7.45-7.75 (M, 5H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 8.15 (s, 1H), 8.58 (br d, J = 5 Hz, 1H), 11.6 (br s, NH). Melting point 135-142 ° C, MS (ESI +) m / z 450.3 (M + 1).

[Example 32] 3-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-5-[(1E)-2-(quinine Synthesis of porphyrin-6-yl)vinyl]-1H-pyrazole

(1) (1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(quin Synthesis of porphyrin-6-yl)heptane-1,6-diene-3,5-dione

By replacing 1H-benzotriazole-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30 (2) with quinolin 21 mg (0.14 mmol) of the oxo-6-carboxycarboxaldehyde, and the same synthetic procedure was obtained to give the title compound 19.

(2) 3-[(1E)-2-[2-Methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-5-[(1E)-2-(quinine Synthesis of porphyrin-6-yl)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-( Quino Phenyl-6-yl)heptane-1,6-diene-3,5-dione 15 mg (32 μmol), and the same synthetic procedure was carried out to give the title compound: 27%).

^{1 H NMR (δ, DMSO-} d 6): 3.86 (s, 3H), 5.22 (s, 2H), 6.65 (dd, J = 2,8 Hz, 1H), 6.74 (d, J = 2 Hz, 1H ), 6.79 (s, 1H), 6.99 (d, J = 17 Hz, 1H), 7.29 (d, J = 17 Hz, 1H), 7.30-7.46 (M, 3H), 7.50 (M, 1H), 7.54 (d, J = 8 Hz, 1H), 7.85 (d, J = 1.8, 7.7 Hz, 1H), 8.06 (d, J = 9.1 Hz, 1H), 8.12 (br s, 1H), 8.18 (br s, 1H), 8.59 (br d, J = 5 Hz, 1H), 8.88 (d, J = 1.7 Hz, 1H), 8.93 (d, J = 1.7 Hz, 1H). Melting point 205-213 ° C, MS (ESI+ ) m / z 462.2 (M + 1).

[Example 33] 3-[(1E)-2-(benzofuran-2-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridyl) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(benzofuran-2-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptan-1,6- Synthesis of diene-3,5-dione

By arranging 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxycarboxaldehyde of Example 30 (2) to 186 μL (1.54 mmol) of benzofuran-2-carboxycarboxaldehyde, and synthesizing in the same amount relationship The title compound (169 mg (yield: 24%) of

¹ H NMR (δ, deuterated chloroform): 3.88 (s, 3H), 5.25 (s, 2H), 5.86 (s, 1H), 6.59-6.61 (M, 2H), 6.65 (d, J = 16 Hz, 1H), 6.77 (d, J = 15 Hz, 1H), 6.91 (s, 1H), 7.21-7.25 (M, 2H), 7.34 (M, 1H), 7.46-7.51 (M, 4H), 7.57 (d) , J = 7.2 Hz, 1H), 7.73 (dt, J = 1.6, 7.7 Hz, 1H), 7.93 (d, J = 16 Hz, 1H), 8.61 (M, 1H), 15.9 (br s, 1H). Melting point 125.8-127.7 ° C, MS (EI) m / z 453 (M ⁺ ). EI-HRMS m / z theory for C ₃₂ H ₃₂ N ₄ O (M ⁺ ) 453.1576, found 453.1576.

(2) 3-[(1E)-2-(benzofuran-2-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy) Synthesis of phenyl)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(benzofuran-2-yl)-7-[2-methoxy-4-(2-pyridine) 100 mg (0.221 mmol) of methoxy)phenyl]heptane-1,6-diene-3,5-dione, and the synthesis operation was carried out in the same amount to obtain the title of the following physical properties of the pale brown powder. Compound 21.0 mg (yield 21%).

¹ H NMR (δ, deuterated chloroform): 3.86 (s, 3H), 5.24 (s, 2H), 6.56-6.62 (M, 3H), 6.69 (s, 1H), 6.95 (d, J = 17 Hz, 1H), 7.00 (d, J = 16 Hz, 1H), 7.17-7.30 (M, 3H), 7.24 (d, J = 16 Hz, 1H), 7.31 (d, J = 17 Hz, 1H), 7.42 7.47 (M, 2H), 7.52 (d, J = 11 Hz, 2H), 7.72 (dt, J = 1.9, 7.7 Hz, 1H), 8.61 (M, 1H). Melting point 199.4-200.9 ° C, MS (EI m/z 449 (M ⁺ ). EI-HRMS m/z calcd for C ₂₈ H ₂₃ N ₃ O ₃ (M ⁺ ) 449.1739, found 449.1743.

[Example 34] 3-[(1E)-2-(benzothiophen-2-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridyl) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(benzothiophen-2-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptan-1,6- Synthesis of diene-3,5-dione

By using 1H-benzotriazole-5-carboxycarboxaldehyde of Example 30(2) 20 mg (0.14 mmol) was replaced with 150 μL (0.923 mmol) of benzothiophene-2-carboxycarboxaldehyde, and the title compound was obtained as a yellow powder.

¹ H NMR ^(δ, deuterochloroform): 3.88 (s, 3H) , 5.25 (s, 2H), 5.82 (s, 1H), 6.46 (d, J = 15 Hz, 1H), 6.6 1-6 .58 (M, 2H), 6.64 (d, J = 16 Hz, 1H), 6.91 (s, 1H), 7.23 - 7.25 (M, 2H), 7.34 - 7.36 (M, 1H), 7.44 (s, 1H), 7.47-7.52 (M, 2H), 7.71-7.80 (M, 3H), 7.82 (d, J = 15 Hz, 1H), 7.92 (d, J = 16 Hz, 1H), 8.61 (M, 1H), 15.9 (m, 1H). melting point 187.7-188.4 ℃, MS (EI) m / z 469 (m +) .EI-HRMS m / z theory _{for C 32 H 32 N 4 O} (m +) 469.1348, found 469.1351.

(2) 3-[(1E)-2-(benzothiophen-2-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy) Synthesis of phenyl)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(benzothiophen-2-yl)-7-[2-methoxy-4-(2-pyridine) 40 mg (0.085 mmol) of methoxy)phenyl]heptane-1,6-diene-3,5-dione, and the synthesis operation was carried out in the same amount to obtain a yellowish white powder having the following physical properties. The title compound was 8.0 mg (yield 20%).

¹ H NMR (‧, DMSO-d ₆ ): 3.86 (s, 3H), 5.22 (s, 2H), 6.63-6.77 (M, 3H), 6.86-7.01 (M, 2H), 7.23-7.37 (M, 4H), 7.42-7.56 (M, 4H), 7.77-7.93 (M, 2H), 7.85 (dt, J = 1.9, 7.7 Hz, 1H), 8.59 (M, 1H), 13.0 (M, 1H). Point 231.1-232.1 ° C, MS (EI) m / z 465 (M ⁺ ). EI-HRMS m / z theory for C ₂₈ H ₂₃ N ₃ O ₂ S (M ⁺ ) 465.1511, found 465.1509.

[Example 35] 3-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-5-[(1E)-2-(1) Synthesis of -methyl-1H-indol-6-yl)vinyl]-1H-pyrazole

(1) (1E, 6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(1-methyl-1H-indol-6-yl) Synthesis of G-1,6-diene-3,5-dione

By replacing 1H-benzotriazol-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30 (2) with 1-methyl-1H-indole-6-carboxycarboxaldehyde 391 mg (2.46 mmol), The same amount of the relationship was subjected to a synthetic operation to obtain 367 mg (yield: 32%) of the title compound (yield: 32%).

¹ H NMR ^(δ, deuterochloroform): 3.83 (s, 3H) , 3.88 (s, 3H), 5.25 (s, 2H), 5.83 (s, 1H), 6.48 (d, J = 3.1 Hz, 1H) , 6.59-6.60 (M, 2H), 6.63 (d, J = 16 Hz, 1H), 6.66 (d, J = 16 Hz, 1H), 7.12 (d, J = 3.1 Hz, 1H), 7.23 - 7.25 ( M,1H), 7.37 (dd, J=1.0, 8.2 Hz, 1H), 7.47-7.52 (M, 3H), 7.60 (d, J = 8.2 Hz, 1H), 7.73 (dt, J = 2.1, 7.7 Hz) , 1H), 7.81 (d, J = 16 Hz, 1H), 7.90 (d, J = 16 Hz, 1H), 8.61 (M, 1H), 16.1 (br s, 1H).

Melting point 190.6-191.6 ℃, MS (EI) m / z 466 (M +) .EI-HRMS m / z Theory _{for C 32 H 32 N 4 O} (M +) 466.1893, found 466.1891.

(2) 3-[(1E)-2-[2-Methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-5-[(1E)-2-(1-A Synthesis of keto-1H-indol-6-yl)vinyl]-1H-pyrazole

(1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptan-1,6- of Example 4(4) 15 mg (35 μmol) of diene-3,5-dione was replaced by (1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(1- Methyl-1H-indol-6-yl)heptane-1,6-diene-3,5-dione 130 mg (0.279 mmol), and subjected to a synthetic operation in the same amount to give a yellow powder having the following The title compound was 48 mg (yield: 37%).

¹ H NMR (δ, acetone-d ₆ ): 3.86 (s, 3H), 3.91 (s, 3H), 5.23 (s, 2H), 6.42 (M, 1H), 6.66 (dd, J = 2.6, 8.4 Hz , 1H), 6.69 (s, 1H), 6.75 (d, J = 2.6 Hz, 1H), 7.07 (d, J = 17 Hz, 1H), 7.15 (d, J = 17 Hz, 1H), 7.23 (d , J = 2.9 Hz, 1H), 7.30-7.37 (M, 3H), 7.39 (d, J = 17 Hz, 1H), 7.52 - 7.58 (M, 4H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 8.58 (m, 1H ), 11.9 (br s, 1H). melting point 172.0-174.0 ℃, MS (EI) m / z 462 (m +) .EI-HRMS m / z for C ₂₉ H theory ₂₆ N ₄ O ₂ (M ⁺ ) 462.2056, found 462.2060.

[Example 36] 3-[(1E)-2-(1H-indol-2-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-2-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

By replacing 1H-benzotriazole-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30 (2) with 1H-indole-2-carboxycarboxaldehyde 220 mg (1.54 mmol), The synthesis operation was carried out in the same amount to give the title compound (yield: 9.2%).

¹ H NMR (δ, deuterated chloroform): 3.87 (s, 3H), 5.25 (s, 2H), 5.79 (s, 1H), 6.40 (d, J = 15 Hz, 1H), 6.57-6.61 (M, 2H), 6.62 (d, J = 16 Hz, 1H), 6.83 (M, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.23 - 7.27 (M, 2H), 7.35 (d, J = 8.2) Hz, 1H), 7.47-7.52 (M, 2H), 7.60-7.65 (M, 2H), 7.92 (d, J = 16 Hz, 1H), 8.29 (br s, 1H), 8.61 (M, 1H), 15.8(s,1H).

Melting point 177.7-179.4 ° C, MS (EI) m / z 452 (M ⁺ ). EI-HRMS m / z theory for C ₃₂ H ₃₂ N ₄ O (M ⁺ ) 452.1736, found 452.1737.

(2) 3-[(1E)-2-(1H-indol-2-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-2-yl)-7-[2-methoxy-4-(2- Pyridylmethoxy)phenyl]heptane-1,6-diene-3,5-dione 100 mg (0.221 mmol), and subjected to a synthetic operation in the same amount to obtain a yellowish white powder having the following properties. The title compound was 49 mg (yield: 49%).

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.23 (s, 2H), 6.59 (M, 1H), 6.66 (dd, J = 2.6, 8.7 Hz, 1H), 6.69 (s) , 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.99 (M, 1H), 7.06 (d, J = 17 Hz, 1H), 7.10 (M, 1H), 7.11 (d, J = 17 Hz) , 1H) 7.24 (d, J = 16 Hz, 1H), 7.30-7.37 (M, 2H), 7.39 (d, J = 16 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.52 ( d, J = 8.7 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.82 (dt, J = 2.0, 7.7 Hz, 1H), 8.59 (M, 1H), 10.5 (br s, 1H) , 12.1 (br s, 1H). Melting point 150.8-151.6 ° C, MS (EI) m / z 448 (M ⁺ ). EI-HRMS m / z theoretical value for C ₂₈ H ₂₄ N ₄ O ₂ (M ⁺ ) 448.1899, measured value 448.1897.

[Example 37] 3-[(1E)-2-(2-Benzyloxy-4-diethylaminophenyl)vinyl]-5-[(1E)-2-(1H-indole) Synthesis of 哚-6-yl)vinyl]-1H-pyrazole

(1) (1E,6E)-1-(2-Benzyloxy-4-diethylaminophenyl)-7-(1H-indol-6-yl)heptane-1,6-di Synthesis of ene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 2-benzyloxy-4-diethylaminobenzaldehyde 411 mg (1.45) The title compound 482 mg (yield 74%) of the title compound was obtained as a black powder.

¹ H NMR (δ, acetone-d ₆ ): 1.14 (t, J = 7.2 Hz, 3H), 3.45 (q, J = 7.2 Hz, 4H), 5.28 (s, 2H), 5.85 (s, 1H), 6.35-6.40 (M, 2H), 6.51 (M, 1H), 6.65 (d, J = 16 Hz, 1H), 6.74 (d, J = 16 Hz, 1H), 7.34 - 7.46 (M, 5H), 7.41 (d, J = 8.7 Hz, 1H), 7.54 - 7.56 (M, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.70 (s, 1H), 7.72 (d, J = 15 Hz, 1H) , 8.01 (d, J = 16 Hz, 1H), 10.4 (br s, 1H), 16.7 (br s, 1H). Melting point 160.1-162.9 ° C, MS (EI) m / z 492 (M ⁺ ).

(2) 3-[(1E)-2-(2-Benzyloxy-4-diethylaminophenyl)vinyl]-5-[(1E)-2-(1H-吲哚- Synthesis of 6-yl)vinyl]-1H-pyrazole 38

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(2-benzyloxy-4-diethylaminophenyl)-7-(1H-吲哚-6-yl)heptane-1,6-diene-3,5-dione 300 mg (0.609 mmol), and the same synthetic procedure was carried out to give a pale brown powder of the title compound 11.4 mg ( Yield 3.83%).

¹ H NMR (δ, acetone-d ₆ ): 1.11 (t, J = 7.2, 3H), 3.39 (q, J = 7.2, 4H), 5.25 (s, 2H), 6.33-6.53 (M, 2H), 6.46(M,1H), 6.60(s,1H), 6.97(d,J=17 Hz,1H), 7.10(d,J=16 Hz,1H), 7.28(d,J=16 Hz,1H), 7.39-7.45 (M, 3H), 7.46 (d, J = 17 Hz, 1H), 7.54 - 7.58 (M, 4H), 10.3 (s, 1H), 11.9 (br s, 1H). Melting point 78.1-80.0 °C, MS (EI) m / z 488 (M ⁺ ). EI-HRMS m/z calc. for C ₃₂ H ₃₂ N ₄ O (M ⁺ ) 488.2576, found 488.2574.

[Example 38] 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-3-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

By replacing 1H-benzotriazole-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30 (2) with 1H-indole-3-carboxycarboxaldehyde 40 mg (0.27 mmol), and in the same amount relationship Synthesis operation, titled brown powder The compound was 81.2 mg (yield 67%).

(2) 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-3-yl)-7-[2-methoxy-4-(2- 15 mg (35 μmol) of pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione, and the same synthetic procedure was carried out to give the title compound 4.8 as a yellowish white powder. Mg (yield 32%).

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.64 (dd, J = 2.4, 8.4 Hz, 1H), 6.65 (s, 1H), 6.73 (d) , J=2.4 Hz, 1H), 7.05 (d, J=17 Hz, 1H), 7.09 (d, J=17 Hz, 1H), 7.11-7.19 (M, 2H), 7.31 (dd, J=5.1, 7.2 Hz, 1H), 7.37 (d, J = 17 Hz, 1H), 7.43 (d, J = 17 Hz, 1H), 7.45 (dd, J = 1.4, 6.8 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.59 (s, 1H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 7.97 (br d, J = 7.2 Hz, 1H) ), 8.58 (br d, J = 4 Hz, 1H), 10.5 (br s, NH). Melting point 112-116 ° C, MS (ESI+) m/z 449.2 (M+1).

[Example 39] 3-[(1E)-2-(1H-indol-4-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-4-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptan-1,6 Synthesis of -diene-3,5-dione

By replacing 1H-benzotriazole-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30 (2) with 1H-indole-4-carboxycarboxaldehyde 40 mg (0.27 mmol), and in the same amount relationship The title compound (32.9 mg (yield: 27%).

(2) 3-[(1E)-2-(1H-Indol-4-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-4-yl)-7-[2-methoxy-4-(2- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (35 μmol), and the same synthetic procedure was carried out to give the title compound 5.8 mg (Yield 39%).

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.22 (s, 2H), 6.65 (dd, J = 2.4, 8.5 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H) ), 6.78 (s, 1H), 6.88 (d, J = 3 Hz, 1H), 7.07 (d, J = 17 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 7.29 (d, J) =17 Hz, 1H), 7.29-7.44 (M, 5H), 7.53 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 17 Hz, 1H) ), 7.82 (dt, J = 1.7, 7.7 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H), 10.4 (br s, NH). Melting point 108-113 ° C, MS (ESI+) m/ z 449.1 (M+1).

[Example 40] 3-[(1E)-2-(1H-indol-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-5-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptan-1,6 Synthesis of -diene-3,5-dione

By replacing 1H-benzotriazole-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30 (2) with 1H-indole-5-carboxycarboxaldehyde 40 mg (0.27 mmol), and in the same amount relationship The title compound was obtained as a yellow powder (yield: 89%).

(2) 3-[(1E)-2-(1H-indol-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-5-yl)-7-[2-methoxy-4-(2- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (35 μmol), and the same synthetic procedure was carried out to give the title compound 4.6 of Mg (yield 31%).

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.48 (d, J = 3.0 Hz, 1H), 6.65 (dd, J = 2.4, 8.6 Hz, 1H ), 6.67 (s, 1H), 6.73 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 17 Hz, 1H), 7.05 (d, J = 17 Hz, 1H), 7.28-7.34 (M , 3H), 7.37 (d, J = 17 Hz, 1H), 7.41 (M, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.72 (s , 1H), 7.81 (dt, J = 1.7, 7.7 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 98-104 ° C, MS (ESI+) m/z 449.2 (M+1).

[Example 41] 3-[(1E)-2-(1H-indol-7-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-7-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

By replacing 1H-benzotriazole-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30 (2) with 1H-indole-7-carboxycarboxaldehyde 20 mg (0.14 mmol), and performing the same synthesis operation, The title compound was obtained as a brown powder (yield: 28%).

(2) 3-[(1E)-2-(1H-indol-7-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-7-yl)-7-[2-methoxy-4-(2- 15 mg (35 μmol) of pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione, and the same synthetic procedure was carried out to give the title compound 6.1. Mg (yield 41%).

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.22 (s, 2H), 6.51 (d, J = 3.1 Hz, 1H), 6.65 (dd, J = 2.4, 8.6 Hz, 1H ), 6.74 (s, 1H), 6.74 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.23 (d, J) =17 Hz, 1H), 7.31 (dd, J=5,7 Hz, 1H), 7.38 (d, J=17 Hz, 1H), 7.38 (br d, J=3.1 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 17 Hz, 1H), 7.82 (dt, J = 1.7, 7.7 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H), 10.6 (br s, NH). Melting point 99-110 ° C, MS ( ESI+)m/z 449.0(M+1).

[Example 42] 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(3-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-3-yl)-7-[2-methoxy-4-(3-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 10 (2) to 2-methoxy-4-(3-pyridylmethoxy)benzaldehyde 33 mg (0.14 mmol), and the same synthetic procedure was carried out to give the title compound (20.7 mg (yield: 34%) of

(2) 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(3-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-3-yl)-7-[2-methoxy-4-(3- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (35 μmol), and subjected to the same synthesis operation to obtain a yellowish white powder having the following physical properties The title compound was 2.7 mg (yield 18%).

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.66 (s, 1H), 6.68 (dd, J = 2.3, 8.6 Hz, 1H), 6.71 (d) , J=2.3 Hz, 1H), 7.06 (d, J=17 Hz, 1H), 7.09 (d, J=17 Hz, 1H), 7.1-7.2 (M, 2H), 7.37 (d, J=17 Hz) , 1H), 7.40 (M, 1H), 7.42 (d, J = 17 Hz, 1H), 7.45 (dd, J = 1.7, 5.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H) 7.59 ( s, 1H), 7.89 (br d, J = 7.8 Hz, 1H), 7.97 (br d, J = 6.8 Hz, 1H), 8.55 (dd, J = 2.5, 4.8 Hz, 1H), 8.72 (d, J = 1.7 Hz, 1H), 10.5 (br s, NH). Melting point 129-137 ° C, MS (ESI+) m/z 449.1 (M+1).

[Example 43] 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(4-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-3-yl)-7-[2-methoxy-4-(4-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 10 (2) with 2-methoxy-4-(4-pyridylmethoxy)benzaldehyde 33 mg (0.14 mmol), and the same synthetic operation was carried out to obtain 61 mg (yield of the yield) of the title compound of the following material.

(2) 3-[(1E)-2-(1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(4-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E, 6E)-1-(1H-indol-5-yl)-7-[4-(2-) of Example 4(4) 15 mg (35 μmol) of pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione was substituted with (1E,6E)-1-(1H-indol-3-yl)-7 -[2-Methoxy-4-(4-pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (35 μmol), and the same synthetic operation was carried out to obtain The title compound 3.4 mg (yield 23%) of the title compound was obtained as a yellowish white powder.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.24 (s, 2H), 6.64 (dd, J = 2.3, 8.5 Hz, 1H), 6.65 (s, 1H), 6.73 (d) , J=2.3 Hz, 1H), 7.05 (d, J=17 Hz, 1H), 7.09 (d, J=17 Hz, 1H), 7.1-7.2 (M, 2H), 7.37 (d, J=17 Hz) , 1H), 7.43 (d, J = 17 Hz, 1H), 7.43 - 7.46 (M, 3H), 7.54 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 7.97 (br d, J = 7.2 Hz, 1H), 8.59 (dd, J = 1.4, 4.4 Hz, 2H), 10.5 (br s, NH). Melting point 128-139 ° C, MS (ESI+) m/z 449.2 (M+1).

[Example 44] 3-[(1E)-2-(1H-indol-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(3-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-5-yl)-7-[2-methoxy-4-(3-pyridylmethoxy)phenyl]heptan-1,6 Synthesis of -diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 4 (3) to 2-methoxy-4-(3-pyridylmethoxy)benzaldehyde 33 mg (0.14 mmol), and the same synthetic procedure was carried out to give the title compound (32.4 mg (yield: 53%)).

(2) 3-[(1E)-2-(1H-Indol-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(3-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-5-yl)-7-[2-methoxy-4-(3- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (35 μmol), and subjected to the same synthetic procedure to give the title compound 2.8 Mg (yield 19%).

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.48 (d, J = 3.0 Hz, 1H), 6.67 (dd, J = 2.4, 8.5 Hz, 1H ), 6.68 (s, 1H), 6.71 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 17 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.28-7.34 (M , 3H), 7.38 (d, J = 17 Hz, 1H), 7.38-7.42 (M, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.72 (s, 1H), 7.89 (br d, J = 7.9 Hz, 1H), 8.55 (dd, J = 1.4, 4.7 Hz, 1H), 8.71 (br s, 1H), 10.3 (br s, NH). Melting point 127-135 ° C, MS (ESI+) m/ z 449.1 (M+1).

[Example 45] 3-[(1E)-2-(1H-indol-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(4-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-5-yl)-7-[2-methoxy-4-(4-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 4 (3) to 2-methoxy-4-(4-pyridylmethoxy)benzaldehyde 33 mg (0.14 mmol), and the same synthetic operation was carried out to give the title compound (30.4 mg (yield 50%) of

(2) 3-[(1E)-2-(1H-Indol-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(4-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-5-yl)-7-[2-methoxy-4-(4- 15 mg (35 μmol) of pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione, and the same synthetic procedure was carried out to give the title compound 2.9 as a yellowish white powder. Mg (yield 19%).

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.24 (s, 2H), 6.48 (d, J = 2.7 Hz, 1H), 6.65 (dd, J = 2.4, 8.5 Hz, 1H ), 6.67 (s, 1H), 6.73 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 17 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.28-7.36 (M , 3H), 7.38-7.46 (M, 4H), 7.53 (d, J = 8.5 Hz, 1H), 7.72 (s, 1H), 8.58 (br d, J = 4 Hz, 2H), 10.3 (br s, NH). Melting point 133-141 ° C, MS (ESI+) m / z 449.0 (M + 1).

[Example 46] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(3-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(3-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) to 2-methoxy-4-(3-pyridylmethoxy)benzaldehyde 33 mg The title compound (31.0 mg (yield: 51%)) was obtained as a brown powder.

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(3-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(3- 15 mg (35 μmol) of pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione, and the same synthetic procedure was carried out to give the title compound: Mg (yield 33%).

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.45 (dd, J = 0.7, 3.0 Hz, 1H), 6.67 (dd, J = 2.4, 8.4 Hz , 1H), 6.69 (s, 1H), 6.72 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d) , J = 17 Hz, 1H), 7.31 (dd, J = 1.3, 8.2 Hz, 1H), 7.34 (M, 1H), 7.38 (d, J = 17 Hz, 1H), 7.40 (dd, J = 4.8, 7.2 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.57 (br s, 1H), 7.89 (br d, J = 7.8 Hz, 1H) , 8.55 (dd, J = 1.5, 4.7 Hz, 1H), 8.72 (d, J = 1.8 Hz, 1H), 10.3 (br s, NH). Melting point 90-95 ° C, MS (ESI+) m/z 449.2 (M+1).

[Example 47] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2- Synthesis of [2-methoxy-4-(4-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(4-pyridylmethoxy)phenyl]heptan-1,6 Synthesis of -diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) to 2-methoxy-4-(4-pyridylmethoxy)benzaldehyde 33 mg (0.14 mmol), and the same synthetic operation was carried out to give the title compound 42.0 mg (yield 69%) of the following material.

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(4-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(4- 15 mg (35 μmol) of pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione, and the same synthetic procedure was carried out to give the title compound: Mg (yield 33%).

¹ H NMR ^(δ, acetone _{-d 6): 3.90 (s,} 3H), 5.24 (s, 2H), 6.45 (br d, J = 3 Hz, 1H), 6.65 (dd, J = 2.4,8.6 Hz, 1H), 6.68 (s, 1H), 6.73 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d, J=17 Hz, 1H), 7.31 (dd, J=1.4, 8.2 Hz, 1H), 7.34 (M, 1H), 7.37 (d, J=17 Hz, 1H), 7.45 (br d, J=5 Hz , 2H), 7.53 (d, J = 8 Hz, 1H), 7.55 (d, J = 8 Hz, 1H), 7.57 (br s, 1H), 8.59 (dd, J = 1.4, 4.5 Hz, 2H), 10.3 (br s, NH). Melting point 103-118 ° C, MS (ESI+) m/z 449.2 (M+1).

[Example 48] 3-[(1E)-2-(1H-indol-4-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(3-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-4-yl)-7-[2-methoxy-4-(3-pyridylmethoxy)phenyl]heptan-1,6 Synthesis of -diene-3,5-dione

6-(1H-indol-4-yl)hex-5-ene-2,4-dione 31.0 mg (136 μmol) and boron oxide 13.2 mg (0.190 mmol) were placed in a 20 mL reaction vessel with acetic acid The ester was dissolved in 0.88 mL. To the mixed solution which was stirred at 70 ° C, 33 mg (0.14 mmol) of 2-methoxy-4-(3-pyridylmethoxy)benzaldehyde and 62 μL (0.27 mmol) of triisopropyl borate were sequentially added. After stirring at the same temperature for 1 hour, a solution of 2.7 μL (27 μmol) of piperidine in ethyl acetate (0.135 mL) was added and stirred for 1 hour. A 1 : 1 solution of hydrochloric acid and saturated brine (0.4 mL) was added to the reaction mixture at room temperature, and the mixture was stirred for 5 minutes to 1 hour (otherwise, neutralized with a saturated aqueous solution of sodium hydrogencarbonate). The title compound (42.8 mg (yield: 70%)) (yield: 70%).

(2) 3-[(1E)-2-(1H-indol-4-yl)vinyl]-5-[(1E)-2-[2-methoxy Synthesis of -4-(3-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-4-yl)-7-[2-methoxy-4-(3- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (35 μmol), and subjected to the same synthetic procedure to give the title compound 6.4 Mg (yield 43%).

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.22 (s, 2H), 6.68 (dd, J = 2.4, 8.4 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H) ), 6.78 (s, 1H), 6.88 (br d, J = 3 Hz, 1H), 7.08 (d, J = 17 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 7.29 (d, J=17 Hz, 1H), 7.32 (d, J=6.9 Hz, 1H), 7.36-7.42 (M, 4H), 7.55 (d, J=8.5 Hz, 1H), 7.64 (d, J=17 Hz, 1H), 7.89 (br d, J = 7.8 Hz, 1H), 8.56 (dd, J = 1.6, 4.7 Hz, 1H), 8.72 (d, J = 1.8 Hz, 1H), 10.4 (br s, NH). Melting point 109-114 ° C, MS (ESI+) m / z 449.1 (M + 1).

[Example 49] 3-[(1E)-2-(1H-indol-4-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(4-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-4-yl)-7-[2-methoxy-4-(4-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

By using 2-methoxy-4-(3-pyridylmethoxy) of Example 49(1) 33 mg (0.14 mmol) of benzaldehyde was substituted with 2-methoxy-4-(4-pyridylmethoxy)benzaldehyde 33 mg (0.14 mmol), and the same synthetic operation was carried out to obtain an orange powder having the following physical properties. The title compound was 56.0 mg (yield: 92%).

(2) 3-[(1E)-2-(1H-Indol-4-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(4-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-4-yl)-7-[2-methoxy-4-(4- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (35 μmol), and subjected to the same synthetic procedure to give the title compound 9.1 Mg (yield 61%).

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.24 (s, 2H), 6.65 (dd, J = 2.4, 8.5 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H) ), 6.78 (s, 1H), 6.88 (d, J = 3 Hz, 1H), 7.08 (d, J = 17 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 7.29 (d, J) =17 Hz, 1H), 7.32-7.42 (M, 4H), 7.46 (br d, J = 5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 17 Hz, 1H), 8.59 (br d, J = 5 Hz, 2H), 10.4 (br s, NH). Melting point 207-215 ° C, MS (ESI+) m/z 449.1 (M+1).

[Example 50] 3-[(1E)-2-(1H-indol-7-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(3-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-7-yl)-7-[2-methoxy-4-(3-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

6-[2-methoxy-4-(3-pyridylmethoxy)phenyl]hex-5-ene-2,4-dione 88 mg (0.27 mmol) and oxidized in a 20 mL reaction vessel 26.4 mg (0.380 mmol) of boron was dissolved in 1.76 mL of ethyl acetate. 1H-indole-7-carboxycarboxaldehyde 40 mg (0.27 mmol) and triisopropyl borate 124 μL (0.54 mmol) were sequentially added to the mixture stirred at 70 °C. After stirring at the same temperature for 1 hour, a solution of 5.4 μL (54 μmol) of piperidine in ethyl acetate (0.27 mL) was added and stirred for 1 hour. A 1 : 1 solution of hydrochloric acid and saturated saline (0.8 mL) was added to the reaction mixture at room temperature, and the mixture was stirred for 5 minutes to 1 hour (otherwise, neutralization with a saturated aqueous solution of sodium hydrogencarbonate). The title compound (21.6 mg (yield: 18%)) was obtained as a yellow powder.

(2) 3-[(1E)-2-(1H-indol-7-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(3-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-7-yl)-7-[2-methoxy-4-(3- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (35 μmol), and subjected to the same synthetic procedure to give a yellow-white powder title Compound 7.2 mg (yield 48%).

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.22 (s, 2H), 6.52 (d, J = 3.2 Hz, 1H), 6.68 (dd, J = 2.3, 8.5 Hz, 1H) ), 6.73 (d, J = 2.3 Hz, 1H), 6.74 (s, 1H), 7.06 (t, J = 7.7 Hz, 1H), 7.07 (d, J = 17 Hz, 1H), 7.23 (d, J) =17 Hz, 1H), 7.38 (d, J = 17 Hz, 1H), 7.40 (M, 1H), 7.38 (br d, J = 3.4 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H) , 7.53 (d, J = 8 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 17 Hz, 1H), 7.89 (br d, J = 7.8 Hz, 1H), 8.56 (br d, J = 5 Hz, 1H), 8.71 (br s, 1H), 10.6 (br s, NH). Melting point 122-129 ° C, MS (ESI+) m/z 449.1 (M+1).

[Example 51] 3-[(1E)-2-(1H-indol-7-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(4-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-7-yl)-7-[2-methoxy-4-(4-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

6-[2-methoxy-4-(4-pyridylmethoxy)phenyl]hex-5-ene-2,4-dione 88 mg (0.27 mmol) and oxidized in a 20 mL reaction vessel 26.4 mg (0.380 mmol) of boron was dissolved in 1.76 mL of ethyl acetate. 1H-indole-7-carboxycarboxaldehyde 40 mg (0.27 mmol) and triisopropyl borate 124 μL (0.54 mmol) were sequentially added to the mixture stirred at 70 °C. After stirring at the same temperature for 1 hour, 5.4 μL (54 μmol) of ethyl acetate of piperidine was added. (0.27 mL) solution was stirred for an additional 1 hour. A 1 : 1 solution of hydrochloric acid and saturated saline (0.8 mL) was added to the reaction mixture at room temperature, and the mixture was stirred for 5 minutes to 1 hour (otherwise, neutralization with a saturated aqueous solution of sodium hydrogencarbonate). The title compound (43.5 mg (yield: 36%)) (yield: 36%) was obtained as a yellow powder.

(2) 3-[(1E)-2-(1H-indol-7-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(4-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-7-yl)-7-[2-methoxy-4-(4- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (35 μmol), and subjected to the same synthetic procedure to give the title compound 3.4 Mg (yield 23%).

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.25 (s, 2H), 6.52 (brd, J = 3.2 Hz, 1H), 6.65 (dd, J = 2.4, 8.5 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.74 (s, 1H), 7.06 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.23 (d, J=17 Hz, 1H), 7.38 (d, J=17 Hz, 1H), 7.38 (br d, J=3.2 Hz, 1H), 7.43 (d, J=7.3 Hz, 1H), 7.46 (br d, J=5.8 Hz, 2H), 7.52 (d, J=7.4 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.70 (d, J=17 Hz, 1H), 8.59 (br d, J =5 Hz, 2H), 10.7 (br s, NH). Melting point 201-206 ° C, MS (ESI+) m/z 449.2 (M+1).

[Example 52] 3-[(1E)-2-(1H-indol-2-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(3-pyridine) Combination of methoxy)phenyl]vinyl]-1H-pyrazole to make

(1) (1E,6E)-1-(1H-indol-2-yl)-7-[2-methoxy-4-(3-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

40 mg (0.27 mmol) of 1H-indole-7-carboxycarboxaldehyde of Example 51 (1) was replaced with 1H-indole-2-carboxycarboxaldehyde 40 mg (0.27 mmol), and the same synthetic procedure was carried out to obtain brown. The title compound of the powder was 44.4 mg (yield 36%).

(2) 3-[(1E)-2-(1H-indol-2-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(3-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-2-yl)-7-[2-methoxy-4-(3- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (35 μmol), and the same synthetic procedure was carried out to give the title compound 6.3 mg (Yield 42%).

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.58 (s, 1H), 6.68 (dd, J = 2.3, 8.6 Hz, 1H), 6.69 (s) , 1H), 6.72 (d, J = 2.3 Hz, 1H), 6.98 (t, J = 7 Hz, 1H), 7.04-7.14 (M, 3H), 7.24 (d, J = 17 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 17 Hz, 1H), 7.40 (dd, J = 5, 7 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.89 (br d, J = 7.8 Hz, 1H), 8.56 (dd, J = 1.4, 4.7 Hz, 1H), 8.71 (d, J = 1 Hz, 1H), 10.6 (br s, NH). Melting point 126-138 ° C, MS (ESI+) m/z 449.1 (M+1).

[Example 53] 3-[(1E)-2-(1H-indol-2-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(4-pyridine) Synthesis of methoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-2-yl)-7-[2-methoxy-4-(4-pyridylmethoxy)phenyl]heptane-1,6 Synthesis of -diene-3,5-dione

6-(1H-indol-2-yl)hex-5-ene-2,4-dione 31.0 mg (136 μmol) and boron oxide 13.2 mg (0.190 mmol) were placed in a 20 mL reaction vessel with acetic acid The ester was dissolved in 0.88 mL. To the mixture which was stirred at 70 ° C, 33 mg (0.14 mmol) of 2-methoxy-4-(4-pyridylmethoxy)benzaldehyde and 62 μL (0.27 mmol) of triisopropyl borate were sequentially added. After stirring at the same temperature for 1 hour, a solution of 2.7 μL (27 μmol) of piperidine in ethyl acetate (0.135 mL) was added and stirred for 1 hour. A 1 : 1 solution of hydrochloric acid and saturated brine (0.4 mL) was added to the reaction mixture at room temperature, and the mixture was stirred for 5 minutes to 1 hour (otherwise, neutralized with a saturated aqueous solution of sodium hydrogencarbonate). The title compound (47.3 mg (yield: 78%)) (yield: 78%).

(2) 3-[(1E)-2-(1H-indol-2-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(4-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-2-yl)-7-[2-methoxy-4-(4- Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 15 mg (35 μmol), and subjected to the same synthetic procedure to give the title compound 2.8 Mg (yield 19%).

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.24 (s, 2H), 6.58 (s, 1H), 6.65 (dd, J = 2.4, 8.5 Hz, 1H), 6.69 (s) , 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.98 (br t, J = 7 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.09 (M, 1H), 7.10 ( d, J = 17 Hz, 1H), 7.23 (d, J = 17 Hz, 1H), 7.34 (d, J = 8 Hz, 1H), 7.38 (d, J = 17 Hz, 1H), 7.46 (br d , J=5 Hz, 2H), 7.48 (d, J=8 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 8.58 (dd, J=1.4, 4.4 Hz, 2H), 10.5 (br s, NH). Melting point 124-134 ° C, MS (ESI+) m / z 449.1 (M + 1).

[Example 54] 3-[(1E)-2-(2,4-dimethoxyphenyl)ethenyl]-5-[(1E)-2-(1H-indol-6-yl)ethene Synthesis of thiol-1H-pyrazole

(1) (1E,6E)-1-(2,4-dimethoxyphenyl)-7-(1H-indol-6-yl)heptan-1,6-diene-3,5-di Ketone synthesis

By disposing 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1), 2,4-dimethoxybenzaldehyde 21 mg (0.14 mmol), and the same Synthetic operation to obtain an orange powder with the next The title compound of the title compound was 43.6 mg (yield: 87%).

(2) 3-[(1E)-2-(2,4-Dimethoxyphenyl)vinyl]-5-[(1E)-2-(1H-indol-6-yl)vinyl] -1H-pyrazole synthesis

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(2,4-dimethoxyphenyl)-7-(1H-indol-6-yl) Hg-1,6-diene-3,5-dione 15 mg (40 μmol), and the same synthetic procedure was carried out to give the title compound 8.6 mg (yield: 57%) of yellowish white powder.

¹ H NMR (δ, acetone-d ₆ ): 3.82 (s, 3H), 3.89 (s, 3H), 6.45 (dd, J = 1, 3 Hz, 1H), 6.56 (dd, J = 2.3, 8.5 Hz , 1), 6.58 (d, J = 2.3 Hz, 1H), 6.67 (s, 1H), 7.04 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d , J=17 Hz, 1H), 7.30-7.35 (M, 2H), 7.37 (d, J=17 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.4 Hz) , 1H), 7.57 (br s, 1H), 10.3 (br s, NH). Melting point 121-133 ° C, MS (ESI+) m/z 372.2 (M+1).

[Example 55] 3-[(1E)-2-[4-(Ethylamino)phenyl]vinyl]-5-[(1E)-2-(1H-indol-6-yl) Synthesis of vinyl]-1H-pyrazole

(1) (1E,6E)-1-[4-(Ethylamino)phenyl]-7-(1H-indol-6-yl)heptan-1,6-diene-3,5- Diketone synthesis

By using 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) 29 mg (0.14 mmol) was replaced with 4-(ethylideneamino)benzaldehyde (22 mg) (0.14 mmol), and the title compound (yield: 81%) .

(2) 3-[(1E)-2-[4-(Ethylamino)phenyl]vinyl]-5-[(1E)-2-(1H-indol-6-yl)vinyl Synthesis of -1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-[4-(ethylideneamino)phenyl]-7-(1H-indol-6-yl) Glycid-1,6-diene-3,5-dione 15 mg (40 μmol), and the same synthetic procedure was carried out to give the title compound 5.4 mg (yield 36%) of the crude material as white powder.

¹ H NMR (δ, acetone-d ₆ ): 2.07 (s, 3H), 6.45 (dd, J = 1, 3 Hz, 1H), 6.72 (s, 1H), 7.06 (d, J = 17 Hz, 1H) ), 7.09 (d, J = 17 Hz, 1H), 7.15 (d, J = 17 Hz, 1H), 7.29 (d, J = 17 Hz, 1H), 7.31 (dd, J = 2, 8 Hz, 1H) ), 7.34 (d, J = 3 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8 Hz, 1H), 7.57 (br s, 1H), 7.66 (d, J = 8.6 Hz, 2H), 10.3 (br s, NH). Melting point > 300 ° C, MS (ESI+) m / z 369.2 (M + 1).

[Example 56] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-(4-phenoxyphenyl)vinyl]- Synthesis of 1H-pyrazole

Synthesis of (1)(1E,6E)-1-(1H-indol-6-yl)-7-(4-phenoxyphenyl)heptan-1,6-diene-3,5-dione

By substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16 (1) to 4-phenoxybenzaldehyde 27 mg (0.14 mmol), and performing the same synthesis operation, There was obtained 40.1 mg (yield: 73%) of the title compound (yield: 73%).

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-(4-phenoxyphenyl)vinyl]-1H- Synthesis of pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-(4-phenoxyphenyl)heptane-1 , 6-diene-3,5-dione 15 mg (37 μmol), and the same synthetic procedure was carried out to give the title compound 6.9 mg (yield 46%) of the crude material as a yellowish white powder.

¹ H NMR (δ, acetone-d ₆ ): 6.45 (br d, J = 3 Hz, 1H), 6.74 (s, 1H), 7.01 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8 Hz, 2H), 7.09 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 17 Hz) , 1H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.2, 8.2 Hz, 1H), 7.34 (d, J = 3.1 Hz, 1H), 7.40 (t, J = 8 Hz) , 2H), 7.55 (d, J = 8 Hz, 1H), 7.57 (br s, 1H), 7.58 (d, J = 9 Hz, 2H), 10.3 (br s, NH). Melting point 175-182 ° C , MS (ESI+) m/z 404.2 (M+1).

[Example 57] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[4-(methylsulfonyl)phenyl]ethene Synthesis of thiol-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[4-(methylsulfonyl)phenyl]heptan-1,6-diene-3,5-di Ketone synthesis

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 4-(methylsulfonyl)benzaldehyde 25 mg (0.14 mmol), and performing the same The title compound (14.4 mg (yield: 28%)) of

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[4-(methylsulfonyl)phenyl]vinyl] -1H-pyrazole synthesis

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[4-(methylsulfonyl)phenyl] Gly-l,6-diene-3,5-dione 12 mg (31 μmol), and the synthesis operation was carried out in the same amount to give the title compound 4.8 mg (yield 40%) ).

¹ H NMR (δ, acetone-d ₆ ): 3.12 (s, 3H), 6.46 (brd, J = 3 Hz, 1H), 6.82 (s, 1H), 7.11 (d, J = 17 Hz, 1H) , 7.30 (d, J = 17 Hz, 1H), 7.30-7.36 (M, 3H), 7.38 (d, J = 17 Hz, 1H), 7.56 (d, J = 8 Hz, 1H), 7.58 (br s , 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 10.3 (br s, NH). Melting point 260-268 ° C, MS (ESI+) m/z 390.2 (M+1).

[Example 58] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-(5-methoxy-2-nitrophenyl) Synthesis of vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-(5-methoxy-2-nitrophenyl)heptan-1,6-diene-3,5 -dione synthesis

By substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16 (1) to 5-methoxy-2-nitrobenzaldehyde 25 mg (0.14 mmol), The same synthetic procedure gave the title compound (24.0 mg (yield 46%) of

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-(5-methoxy-2-nitrophenyl)ethene Synthesis of thiol-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-(5-methoxy-2-nitrobenzene 18 mg (47 μmol) of heptane-1,6-diene-3,5-dione, and the synthesis operation was carried out in the same amount to give the title compound 14.1 mg (yield 78%). ).

¹ H NMR (δ, acetone-d ₆ ): 4.00 (s, 3H), 6.46 (brd, J = 3 Hz, 1H), 6.81 (s, 1H), 7.04 (dd, J = 2.8, 9.1 Hz, 1H), 7.11 (d, J = 17 Hz, 1H), 7.21 (d, J = 17 Hz, 1H), 7.32 (dd, J = 1.4, 8 Hz, 1H), 7.33 - 7.38 (M, 3H), 7.56 (d, J = 8.2 Hz, 1H), 7.58 (br s, 1H), 7.67 (d, J = 17 Hz, 1H), 8.05 (d, J = 9.1 Hz, 1H), 10.3 (br s, NH) ) melting point 104-109 ° C, MS (ESI) m / z 387.0 (M + 1).

[Example 59] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2- Synthesis of [2-(3-pyridyl)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[2-(3-pyridyl)phenyl]heptan-1,6-diene-3,5-di Ketone synthesis

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) into 2-(3-pyridyl)benzaldehyde 25 mg (0.14 mmol), and the same The title compound (51.1 mg (yield: 96%) of

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-(3-pyridyl)phenyl]vinyl] -1H-pyrazole synthesis

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-(3-pyridyl)phenyl] Gly-1,6-diene-3,5-dione 20 mg (52 μmol), and the same operation was carried out to give the title compound 10.8 mg (yield: 54%) .

¹ H NMR (δ, acetone-d ₆ ): 6.45 (dd, J = 0.8, 3.1 Hz, 1H), 6.56 (s, 1H), 7.06 (d, J = 17 Hz, 1H), 7.08 (d, J) =17 Hz,1H), 7.14 (d, J=17 Hz, 1H), 7.25 (d, J=17 Hz, 1H), 7.29 (dd, J=1.2, 8 Hz, 1H), 7.34 (d, J =3.1 Hz, 1H), 7.33-7.6 (M, 6H), 7.69 (M, 1H), 7.79 (ddd, J = 1.8, 2.2, 7.9 Hz, 1H), 7.85 (br d, J = 7.7 Hz, 1H ), 8.61 (d, J = 1.7 Hz, 1H), 10.3 (br s, NH). Melting point 248-255 ° C, MS (ESI+) m/z 389.0 (M+1).

[Example 60] 3-[(1E)-2-(2-bromo-5-hydroxy-4-methoxyphenyl)ethenyl]-5-[(1E)-2-(1H-indole- Synthesis of 6-yl)vinyl]-1H-pyrazole

(1) (1E, 6E)-1-(2-bromo-5-hydroxy-4-methoxyphenyl)-7-(1H-indol-6-yl)heptane-1,6-diene- Synthesis of 3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) to 2-bromo-5-hydroxy-4-methoxybenzaldehyde 31 mg (0.14 mmol) And the same synthetic operation was carried out to obtain a yellow powder of the title compound (20.7 mg (yield: 35%)).

(2) 3-[(1E)-2-(2-Bromo-5-hydroxy-4-methoxyphenyl)vinyl]-5-[(1E)-2-(1H-吲哚-6- Synthesis of vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(2-bromo-5-hydroxy-4-methoxyphenyl)-7-(1H-indole -6-yl)heptane-1,6-diene-3,5-dione 15 mg (34 μmol), and the same synthetic procedure was carried out to give the title compound 5.2 mg (yield) 35%).

¹ H NMR (δ, acetone-d ₆ ): 3.89 (s, 3H), 6.46 (brd, J = 3 Hz, 1H), 6.75 (s, 1H), 6.94 (s, 1H), 6.99 (d, J = 17 Hz, 1H), 7.10 (d, J = 17 Hz, 1H), 7.14 (s, 1H), 7.29 (d, J = 17 Hz, 1H), 7.32 (dd, J = 1.2, 8 Hz, 1H), 7.35 (M, 1H), 7.37 (d, J = 17 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.58 (br s, 1H), 10.3 (br s, NH). Melting point 137-142 ° C, MS (ESI+) m / z 435.9 (M + 1).

[Example 61] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-(4-phenylphenyl)vinyl]-1H -pyrazole synthesis

(1) Synthesis of (1E,6E)-1-(1H-indol-6-yl)-7-(4-phenylphenyl)heptan-1,6-diene-3,5-dione

By substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16 (1) with 25 mg (0.14 mmol) of 4-phenylbenzaldehyde, and performing the same synthesis operation, The title compound (33.3 mg (yield: 64%) of

(2) 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-(4-phenylphenyl)vinyl]-1H-pyridyl Synthesis of azole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-(4-phenylphenyl)heptane-1. 6-Diene-3,5-dione 20 mg (52 μmol), and the synthesis operation was carried out in the same amount to give the title compound 3.9 mg (yield 20%) of the crude material as a yellowish white powder.

¹ H NMR (δ, acetone-d ₆ ): 6.46 (dd, J = 1, 3 Hz, 1H), 6.78 (s, 1H), 7.11 (d, J = 17 Hz, 1H), 7.22 (d, J) =17 Hz,1H), 7.26 (d, J=17 Hz, 1H), 7.32 (d, J=17 Hz, 1H), 7.32 (dd, J=1.5, 8 Hz, 1H), 7.32-7.38 (M , 2H), 7.46 (dd, J = 7.4, 7.8 Hz, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.58 (br s, 1H), 7.65-7.7 (M, 6H), 10.3 (br) s, NH). Melting point 273-276 ° C, MS (ESI+) m / z 388.1 (M + 1).

[Example 62] 3-[(1E)-2-[2-bromo-4-(4-methylpiperidin) Synthesis of -1-yl)phenyl]vinyl]-5-[(1E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazole

(1) (1E, 6E)-1-[2-bromo-4-(4-methylpiperidine) Synthesis of -1-yl)phenyl]-7-(1H-indol-6-yl)heptane-1,6-diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) to 2-bromo-4-(4-methylpiperidine) -1-yl)benzaldehyde 38 mg (0.14 mmol), which was obtained from the title compound (5.

(2) 3-[(1E)-2-[2-bromo-4-(4-methylpiperidine) Synthesis of -1-yl)phenyl]vinyl]-5-[(1E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-[2-bromo-4-(4-methylpiperidin -1-yl)phenyl]-7-(1H-indol-6-yl)heptane-1,6-diene-3,5-dione 20 mg (41 μmol), and the synthesis operation is carried out in the same amount relationship The title compound (8.1 mg (yield: 41%) of the title compound of

¹ H NMR (δ, acetone-d ₆ ): 2.25 (s, 3H), 2.48 (t, J = 5.0 Hz, 2H), 3.24 (t, J = 5.0 Hz, 2H), 6.45 (dd, J=1) , 3 Hz, 1H), 6.73 (s, 1H), 6.97 (d, J = 17 Hz, 1H), 7.01 (dd, J = 2.3, 8.8 Hz, 1H), 7.10 (d, J = 17 Hz, 1H) ), 7.12 (d, J = 2.3 Hz, 1H), 7.32 (d, J = 17 Hz, 1H), 7.32 (dd, J = 1.4, 8.4 Hz, 1H), 7.34 (M, 1H), 7.39 (d) , J=17 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.58 (br s, 1H), 7.66 (d, J=8.8 Hz, 1H), 10.3 (br s, NH). Point 120-124 ° C, MS (ESI+) m / z 488.1 (M + 1).

[Example 63] 3-[(1E)-2-(4-Benzyloxy-2-methoxyphenyl)ethenyl]-5-[(1E)-2-(1H-indole- Synthesis of 6-yl)vinyl]-1H-pyrazole

(1) (1E,6E)-1-(4-Benzyloxy-2-methoxyphenyl)-7-(1H-indol-6-yl)heptane-1,6-diene- Synthesis of 3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 4-benzyloxy-2-methoxybenzaldehyde 33 mg (0.14 mmol) The same synthesis operation was carried out, and the title compound (59.2 mg (yield: 98%) of

(2) 3-[(1E)-2-(4-Benzyloxy-2-methoxyphenyl)vinyl]-5-[(1E)-2-(1H-吲哚-6- Synthesis of vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(4-benzyloxy-2-methoxyphenyl)-7-(1H-indole -6-yl)heptane-1,6-diene-3,5-dione 20 mg (45 μmol), and the same The amount of the title compound was 10.4 mg (yield: 51%) of the title compound.

¹ H NMR ^(δ, acetone _{-d 6): 3.89 (s,} 3H), 5.15 (s, 2H), 6.45 (dd, J = 1,3 Hz, 1H), 6.64 (dd, J = 2.4,8.5 Hz , 1H), 6.68 (s, 1H), 6.69 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d) , J=17 Hz, 1H), 7.31 (dd, J=1.4, 8 Hz, 1H), 7.32-7.36 (M, 3H), 7.40 (d, J=7.2, 7.5 Hz, 2H), 7.49 (d, J=7.0 Hz, 2H), 7.53 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.57 (br s, 1H), 10.3 (br s, NH). Melting point 86-91 ° C, MS (ESI+) m / z 448.1 (M + 1).

[Example 64] 3-[(1E)-2-[4-(diphenylmethoxy)-2-methoxyphenyl]ethenyl]-5-[(1E)-2-(1H- Synthesis of 吲哚-6-yl)vinyl]-1H-pyrazole

(1) (1E,6E)-1-[4-(diphenylmethoxy)-2-methoxyphenyl]-7-(1H-indol-6-yl)heptan-1,6- Synthesis of diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 4-(diphenylmethoxy)-2-methoxybenzaldehyde 43 mg ( The title compound (59.9 mg (yield: 85%) of

(2) 3-[(1E)-2-[4-(Diphenylmethoxy)-2-methoxyphenyl]ethenyl]-5-[(1E)-2-(1H-吲哚Synthesis of -6-yl)vinyl]-1H-pyrazole

By (1E, 6E)-1-(1H-indol-5-yl)-7-[4-(2-) of Example 4(4) 15 mg (35 μmol) of pyridylmethoxy)phenyl]hepta-1,6-diene-3,5-dione was replaced by (1E,6E)-1-[4-(diphenylmethoxy)- 2-methoxyphenyl]-7-(1H-indol-6-yl)heptane-1,6-diene-3,5-dione 20 mg (38 μmol), and the synthesis operation was carried out in the same amount relationship The title compound (12.5 mg (yield: 63%) of the title compound was obtained as a yellow white powder.

¹ H NMR (δ, acetone-d ₆ ): 3.83 (s, 3H), 6.45 (brd, J = 3 Hz, 1H), 6.52 (s, H), 6.61 (dd, J = 2.3, 8.6 Hz, 1H), 6.65 (s, 1H), 6.73 (d, J = 2.3 Hz, 1H), 7.00 (d, J = 17 Hz, 1H), 7.07 (d, J = 17 Hz, 1H), 7.24 - 7.38 ( M, 10H), 7.43 (d, J = 8.6 Hz, 1H), 7.53 - 7.57 (M, 5H), 7.57 (br s, 1H), 10.3 (br s, NH). Melting point 114-119 ° C, MS (ESI+) m/z 524.2 (M+1).

[Example 65] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-(4-isopropoxy-2-methoxy Synthesis of Phenyl)vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-(4-isopropoxy-2-methoxyphenyl)heptane-1,6-diene-3 Synthesis of 5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 4-isopropoxy-2-methoxybenzaldehyde 26 mg (0.14 mmol), The same synthesis operation was carried out to give the title compound (44.7 mg (yield: 83%) of

(2) 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-(4-isopropoxy-2-methoxyphenyl) Synthesis of vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-(4-isopropoxy-2-methoxy Phenyl)heptane-1,6-diene-3,5-dione 20 mg (50 μmol), and the synthesis operation was carried out in the same amount to give the title compound 11.1 mg (yield: The rate is 56%).

¹ H NMR (δ, acetone-d ₆ ): 1.30 (d, J = 6.0 Hz, 6H), 3.88 (s, 3H), 4.66 (tt, J = 6.0, 6.0 Hz, 1H), 6.45 (dd, J =1, 3 Hz, 1H), 6.52-6.56 (M, 2H), 6.67 (s, 1H), 7.03 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.4, 8.2 Hz, 1H), 7.34 (M, 1H), 7.37 (d, J = 17 Hz, 1H), 7.49 (M, 1H) , 7.55 (d, J = 8.4 Hz, 1H), 7.57 (br s, 1H), 10.3 (br s, NH). Melting point 107-113 ° C, MS (ESI+) m/z 400.2 (M+1).

[Example 66] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-A) Synthesis of oxyethoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-methoxyethoxy)phenyl]heptane-1, Synthesis of 6-diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) to 2-methoxy-4-(2-methoxyethoxy)benzaldehyde 28mg (0.14mmol), and the same synthesis operation, to obtain brown powder The title compound having the following physical properties was 50.2 mg (yield: 90%).

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-methoxy) Synthesis of ethoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2- Methoxyethoxy)phenyl]heptan-1,6-diene-3,5-dione 20 mg (48 μmol), and the synthesis operation was carried out in the same amount to obtain a yellow-white powder having the following physical properties. The title compound was 11.8 mg (yield 59%).

¹ H NMR (δ, acetone-d ₆ ): 3.36 (s, 3H), 3.70 (t, J = 4.7 Hz, 2H), 3.89 (s, 3H), 4.15 (t, J = 4.7 Hz, 2H), 6.45 (dd, J = 1, 3 Hz, 1H), 6.56 (d, J = 2.3, 8.5 Hz, 1H), 6.59 (d, J = 2.3 Hz, 1H), 6.67 (s, 1H), 7.04 (d , J=17 Hz, 1H), 7.09 (d, J=17 Hz, 1H), 7.30 (d, J=17 Hz, 1H), 7.31 (dd, J=1.4, 8.2 Hz, 1H), 7.34 (M , 1H), 7.37 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.57 (br s, 1H), 10.3 ( Br s, NH). Melting point 90-96 ° C, MS (ESI+) m / z 416.1 (M + 1).

[Example 67] 3-[(1E)-2-(2-bromo-5-methoxyphenyl)ethenyl]-5-[(1E)-2-(1H-indol-6-yl) Synthesis of vinyl]-1H-pyrazole

(1) (1E,6E)-1-(2-bromo-5-methoxyphenyl)-7-(1H-indol-6-yl)heptan-1,6-diene-3,5- Diketone synthesis

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) into 2-bromo-5-methoxybenzaldehyde 29 mg (0.14 mmol), and the same The title compound (35.2 mg (yield: 62%) of

(2) 3-[(1E)-2-(2-Bromo-5-methoxyphenyl)vinyl]-5-[(1E)-2-(1H-indol-6-yl)vinyl Synthesis of -1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(2-bromo-5-methoxyphenyl)-7-(1H-indol-6-yl) Gly-l,6-diene-3,5-dione 20 mg (48 μmol), and the synthesis operation was carried out in the same amount to give the title compound 9.0 mg (yield 45%) of yellowish white powder. .

¹ H NMR (δ, acetone-d ₆ ): 3.87 (s, 3H), 6.46 (brd, J = 3 Hz, 1H), 6.80 (s, 1H), 6.82 (dd, J = 3.0, 8.8 Hz, 1H), 7.11 (d, J = 17 Hz, 1H), 7.19 (d, J = 17 Hz, 1H), 7.32 (dd, J = 1.4, 8 Hz, 1H), 7.34 (d, J = 17 Hz, 1H), 7.33-7.37 (M, 2H), 7.44 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.58 ( Br s,1H), 10.3 (br s, NH). Melting point 103-109 ° C, MS (ESI+) m/z 420.0 (M+1).

[Example 68] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(4-A) Synthesis of oxybenzyloxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(4-methoxybenzyloxy)phenyl]heptane- Synthesis of 1,6-diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 2-methoxy-4-(4-methoxybenzyloxy) The title compound (20.1 mg (yield 31%)) of the title compound was obtained as an orange powder of 37 mg (0.14 mmol).

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(4-methoxy) Synthesis of benzyloxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(4- 18 mg (38 μmol) of methoxybenzyloxy)phenyl]heptan-1,6-diene-3,5-dione, and the synthesis operation was carried out in the same amount to obtain a white powder having the following physical properties. The title compound was 4.2 mg (yield 23%).

¹ H NMR (δ, acetone-d ₆ ): 3.80 (s, 3H), 3.89 (s, 3H), 5.06 (s, 2H), 6.45 (dd, J = 1, 3 Hz, 1H), 6.63 (dd , J=2.3, 8.4 Hz, 1H), 6.66 (d, J=2.3 Hz, 1H), 6.68 (s, 1H), 6.95 (d, J=8.8 Hz, 2H), 7.04 (d, J=17 Hz , 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.3, 8 Hz, 1H), 7.34 (M, 1H), 7.37 (d, J = 17 Hz, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.57 (br s, 1H), 10.3 (br s, NH). Melting point 211-214 ° C, MS (ESI+) m/z 478.1 (M+1).

[Example 69] 3-[(1E)-2-(quinolin-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridyl) Synthesis of oxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(quinolin-5-yl)heptan-1,6-di Synthesis of ene-3,5-dione

By substituting 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxycarboxaldehyde of Example 30 (2) to 40 mg (0.27 mmol) of quinoline-5-carboxycarboxaldehyde, the synthesis operation was carried out in the same amount relationship. The title compound was obtained as an orange powder (yield: 19%).

(2) 3-[(1E)-2-[2-Methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-5-[(1E)-2-(quinoline- Synthesis of 5-yl)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-( 18 mg (39 μmol) of quinoline-5-yl)heptane-1,6-diene-3,5-dione, and subjected to a synthetic operation in the same amount to give the title compound as a yellowish white powder 4.6 mg (yield 26%).

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.22 (s, 2H), 6.66 (dd, J = 2.4, 8.5 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H) ), 6.91 (s, 1H), 7.08 (d, J = 17 Hz, 1H), 7.28 (d, J = 17 Hz, 1H), 7.32 (dd, J = 5, 7 Hz, 1H), 7.41 (d) , J=17 Hz, 1H), 7.52-7.58 (M, 3H), 7.77 (t, J=7.9 Hz, 1H), 7.82 (dt, J=1.8, 7.7 Hz, 1H), 7.96 (d, J= 7.2 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 17 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H), 8.82 (d, J = 8.5 Hz, 1H), 8.93 (dd, J = 1.6, 4.0 Hz, 1H). Melting point 107-120 ° C, S (ESI +) m / z 461.2 (M + 1).

[Example 70] 3-[(1E)-2-(1-Benzyl-1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy- Synthesis of 4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1-Benzyl-1H-indol-6-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl Synthesis of Geng-1,6-diene-3,5-dione

By replacing 1H-benzotriazol-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30 (2) with 1-benzyl-1H-indole-6-carboxycarboxaldehyde 32 mg (0.14 mmol), The same synthetic operation was carried out to give the title compound (yield: 44%).

(2) 3-[(1E)-2-(1-Benzyl-1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4- Synthesis of (2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1-benzyl-1H-indol-6-yl)-7-[2-methoxy 4-(2-pyridylmethoxy)phenyl]heptane-1,6-diene-3,5-dione 20 mg (37 μmol), and the synthesis operation was carried out in the same amount to obtain a yellowish white powder. The title compound having the following physical properties was 8.4 mg (yield: 42%).

¹ H NMR (δ, acetone-d ₆ ): 3.89 (s, 3H), 5.21. (s, 2H), 5.49 (s, 2H), 6.50 (dd, J = 1, 3 Hz, 1H), 6.65 (dd , J=2.4, 8.5 Hz, 1H), 6.66(s, 1H), 6.73 (d, J=2.4 Hz, 1H), 7.04 (d, J=17 Hz, 1H), 7.09 (d, J=17 Hz) , 1H), 7.21-7.28 (M, 4H), 7.28-7.34 (M, 4H), 7.36 (d, J = 17 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.56 (d, J=8 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.58 (br s, 1H), 7.82 (dt, J=1.8, 7.7 Hz) , 1H), 8.58 (br d, J = 5 Hz, 1H). Melting point 89-93 ° C, MS (ESI+) m / z 539.2 (M + 1).

[Example 71] 3-[(1E)-2-[2-bromo-4-(morpholin-4-yl)phenyl]ethenyl]-5-[(1E)-2-(1H-indole) Synthesis of -6-yl)vinyl]-1H-pyrazole

(1) (1E,6E)-1-[2-bromo-4-(morpholin-4-yl)phenyl]-7-(1H-indol-6-yl)heptane-1,6-diene Synthesis of -3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) to 2-bromo-4-(morpholin-4-yl)benzaldehyde 36 mg (0.14 mmol) And the same synthesis operation was carried out to obtain 62.6 mg (yield 98%) of the title compound of the title compound.

(2) 3-[(1E)-2-[2-Bromo-4-(morpholin-4-yl)phenyl]vinyl]-5-[(1E)-2-(1H-吲哚-6 Synthesis of -based)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) Substitution with (1E,6E)-1-[2-bromo-4-(morpholin-4-yl)phenyl]-7-(1H-indol-6-yl)heptan-1,6-diene- 35 mg (74 μmol) of 3,5-diketone, and the synthesis operation was carried out in the same amount to give the title compound 16.4 mg (yield: 47%) of the crude material as white powder.

¹ H NMR (δ, acetone-d ₆ ): 3.20 (t, J = 5 Hz, 2H), 3.77 (t, J = 5 Hz, 2H), 6.46 (dd, J = 1, 3 Hz, 1H), 6.74 (s, 1H), 6.99 (d, J = 17 Hz, 1H), 7.00 (dd, J = 2.5, 8.4 Hz, 1H), 7.10 (d, J = 17 Hz, 1H), 7j.14 (d , J=2.5 Hz, 1H), 7.32 (d, J=17 Hz, 1H), 7.32 (dd, J=1.5, 8.4 Hz, 1H), 7.34 (M, 1H), 7.40 (d, J=17 Hz) , 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.58 (br s, 1H), 7.67 (d, J = 8.9 Hz, 1H), 10.3 (br s, NH). Melting point 143-148 ° C , MS (ESI+) m / z 475.3 (M + 1).

[Example 72] 3-[(1E)-2-[2-bromo-4-(4-methyl-1,4-diazepan-1-yl)phenyl]vinyl]-5 Synthesis of -[(1E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazole

(1) (1E,6E)-1-[2-bromo-4-(4-methyl-1,4-diazepan-1-yl)phenyl]-7-(1H-indole Synthesis of -6-yl)heptane-1,6-diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) to 2-bromo-4-(4-methyl-1,4-diazacyclocycle Heptane-1-yl)benzaldehyde 40 mg (0.14 mmol) was obtained from the title compound (yield: 87%).

(2) 3-[(1E)-2-[2-Bromo-4-(4-methyl-1,4-diazepan-1-yl)phenyl]vinyl]-5-[ Synthesis of (1E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-[2-bromo-4-(4-methyl-1,4-diazepane-1 -phenyl)-7-(1H-indol-6-yl)heptane-1,6-diene-3,5-dione 35 mg (70 μmol), and the synthesis operation was carried out in the same amount relationship to obtain The title compound (7.0 mg (yield 20%)) of

¹ H NMR (δ, acetone-d ₆ ): 1.96 (tt, J = 5.6, 6.2 Hz, 2H), 2.30 (s, 3H), 2.50 (t, J = 5.6 Hz, 2H), 2.66 (t, J) = 4.9 Hz, 2H), 3.50 (t, J = 6.2 Hz, 2H), 3.58 (t, J = 5.0 Hz, 2H), 6.45 (dd, J = 1, 3 Hz, 1H), 6.70 (s, 1H) ), 6.79 (dd, J = 2.5, 8.9 Hz, 1H), 6.90 (d, J = 17 Hz, 1H), 6.91 (d, J = 2.6 Hz, 1H), 7.09 (d, J = 17 Hz, 1H) ), 7.31 (d, J = 17 Hz, 1H), 7.32 (dd, J = 1.3, 8 Hz, 1H), 7.34 (M, 1H), 7.39 (d, J = 17 Hz, 1H), 7.55 (d) , J = 8.3 Hz, 1H), 7.57 (br s, 1H), 7.60 (d, J = 8.9 Hz, 1H), 10.3 (br s, NH). Melting point 132-136 ° C, MS (ESI+) m / z 502.2 (M+1).

[Example 73] 3-[(1E)-2-(1-Ethyl-1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy- Synthesis of 4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1-Ethyl-1H-indol-6-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl Synthesis of Geng-1,6-diene-3,5-dione

By replacing 1H-benzotriazol-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30(2) with 1-ethylindenyl-1H-indole-6-carboxycarboxaldehyde 40 mg (0.21 mmol), The synthesis operation was carried out in the same amount to give the title compound (yield: 24%).

(2) 3-[(1E)-2-(1-Ethyl-1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4- Synthesis of (2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1-ethylindenyl-1H-indol-6-yl)-7-[2-methoxy 4-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 20 mg (40 μmol), and the synthesis operation was carried out in the same amount to obtain a yellowish white powder. The title compound having the following physical properties was 9.6 mg (yield: 48%).

¹ H NMR (δ, acetone-d ₆ ): 2.69 (s, 3H), 3.90 (s, 3H), 5.22 (s, 2H), 6.65 (dd, J = 2.3, 8.5 Hz, 1H), 6.69 (dd , J = 1, 3.8 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H), 6.77 (s, 1H), 7.06 (d, J = 17 Hz, 1H), 7.18 (d, J = 17 Hz) , 1H), 7.31 (dd, J = 5, 7 Hz, 1H), 7.35 (d, J = 17 Hz, 1H), 7.39 (d, J = 17 Hz, 1H), 7.53 (d, J = 8.6 Hz) , 1H), 7.53-7.58 (M, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.76 (d, J = 3.8 Hz, 1H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H) , 8.58 (br d, J = 5 Hz, 1H), 8.60 (br s, 1H). Melting point 182-187 ° C, MS (ESI+) m/z 491.3 (M+1).

[Example 74] 3-[(1E)-2-(1-methylsulfonyl-1H-indol-6-yl)vinyl] Synthesis of 5-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1-methylsulfonyl-1H-indol-6-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)benzene Synthesis of ke]-1,6-diene-3,5-dione

By replacing 1H-benzotriazole-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30 (2) with 1-methanesulfonyl-1H-indole-6-carboxycarboxaldehyde 30 mg (0.13 mmol), The synthesis was carried out in the same amount to give the title compound 14.1 mg (yield 20%) as a yellow powder.

(2) 3-[(1E)-2-(1-Methanesulfonyl-1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4 Synthesis of -(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1-methylsulfonyl-1H-indol-6-yl)-7-[2-methoxy 12-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 12 mg (23 μmol), and subjected to a synthetic operation in the same amount to give a white powder The title compound having the following physical properties was 4.6 mg (yield 38%).

¹ H NMR (δ, acetone-d ₆ ): 3.38 (s, 3H), 3.90 (s, 3H), 5.22 (s, 2H), 6.65 (dd, J = 2.3, 8.5 Hz, 1H), 6.74 (d) , J = 2.3 Hz, 1H), 6.77 (s, 1H), 6.80 (dd, J = 1, 3.7 Hz, 1H), 7.06 (d, J = 17 Hz, 1H), 7.21 (d, J = 17 Hz) , 1H), 7.31 (dd, J=5,7 Hz, 1H), 7.37 (d, J=17 Hz, 1H), 7.39 (d, J=17 Hz, 1H), 7.51-7.57 (M, 3H) , 7.58 (d, J = 1.3, 6.4 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.82 (dt, J = 1.7, 7.7 Hz, 1H), 8.04 (br s, 1H), 8.58 (br d, J=5 Hz, 1H). Melting point 212-214 ° C, MS (ESI+) m/z 527.3 (M+1).

[Example 75] 3-[(1E)-2-(7-Aza-1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy-4 Synthesis of -(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(7-Aza-1H-indol-3-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl] Synthesis of G-1,6-diene-3,5-dione

By replacing 1H-benzotriazole-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30 (2) with 7-aza-1H-indole-3-carboxycarboxaldehyde 40 mg (0.27 mmol), The same amount of the relationship was subjected to a synthetic operation to give the title compound (yield: 63%) of orange powder.

(2) 3-[(1E)-2-(7-Aza-1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-( Synthesis of 2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(7-aza-1H-indol-3-yl)-7-[2-methoxy- 4-(2-Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 30 mg (66 μmol), and the synthesis operation was carried out in the same amount to obtain a yellowish white powder. The title compound having the following physical properties was 18.0 mg (yield 60%).

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.65 (dd, J = 2.3, 8 Hz, 1H), 6.66 (s, 1H), 6.73 (d) , J=2.3 Hz, 1H), 7.05 (d, J=17 Hz, 1H), 7.11 (d, J=17 Hz, 1H), 7.16 (dd, J=4.7, 7.9 Hz, 1H), 7.31 (dd , J=5,7 Hz,1H), 7.37 (d, J=17 Hz, 1H), 7.39 (d, J=17 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.56 (d , J = 7.7 Hz, 1H), 7.71 (s, 1H), 7.82 (dt, J = 1.7, 7.7 Hz, 1H), 8.28 (dd, J = 1.5, 4.7 Hz, 1H), 8.35 (dd, J = 1.5, 7.9 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H), 10.8 (br s, NH). Melting point 219-223 ° C, MS (ESI+) m/z 450.2 (M+1).

[Example 76] 3-[(1E)-2-[4-[2-(Dimethylamino)ethoxy]-2-methoxyphenyl]vinyl]-5-[(1E)- Synthesis of 2-(1H-indol-6-yl)vinyl]-1H-pyrazole

(1) (1E,6E)-1-[4-[2-(Dimethylamino)ethoxy]-2-methoxyphenyl]-7-(1H-indol-6-yl)g Synthesis of -1,6-diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 4-[2-(dimethylamino)ethoxy]-2-methoxy 31 mg (0.14 mmol) of the base benzaldehyde, and the same synthesis operation was carried out to obtain the title compound (34.9 mg (yield: 59%) of

(2) 3-[(1E)-2-[4-[2-(Dimethylamino)ethoxy]-2-methoxyphenyl]vinyl]-5-[(1E)-2- Synthesis of (1H-吲哚-6-yl)vinyl]-1H-pyrazole

By (1E, 6E)-1-(1H-indol-5-yl)-7-[4-(2-) of Example 4(4) 15 mg (35 μmol) of pyridylmethoxy)phenyl]heptane-1,6-diene-3,5-dione was substituted with (1E,6E)-1-[4-[2-(dimethylamino) Ethoxy]-2-methoxyphenyl]-7-(1H-indol-6-yl)hepta-1,6-diene-3,5-dione 25 mg (58 μmol), and the same The amount of the title compound was subjected to a synthetic operation to give the title compound (11.7 mg (yield: 47%) of the title compound.

¹ H NMR (δ, acetone-d ₆ ): 2.25 (s, 6H), 2.67 (brt, J = 6 Hz, 1H), 3.89 (s, 3H), 4.11 (t, J = 5.9 Hz, 1H) , 5.22 (s, 2H), 6.45 (br d, J = 3 Hz, 1H), 6.56 (dd, J = 2.3, 8.5 Hz, 1H), 6.59 (d, J = 2.3 Hz, 1H), 6.68 (s , 1H), 7.04 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.4, 8 Hz) , 1H), 7.34 (M, 1H), 7.37 (d, J = 17 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.57 (br s, 1H), 10.3 (br s, NH). Melting point 109-112 ° C, MS (ESI+) m/z 429.4 (M+1).

[Example 77] 3-[(1E)-2-(1,3-benzoic acid) Synthesis of oxazol-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E, 6E)-1-(1,3-benzoic acid) Synthesis of oxazol-5-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione

By replacing 1H-benzotriazol-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30(2) with 1,3-benzoic acid 40 mg (0.27 mmol) of azole-5-carboxycarboxaldehyde, and the title compound was obtained as a brown powder (yield: 20%).

(2) 3-[(1E)-2-(1,3-benzoic acid) Synthesis of oxazol-5-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1,3-benzoic acid) Zyrid-5-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 20 mg (44 μmol), The synthesis operation was carried out in the same amount to give the title compound 3.6 mg (yield: 18%) of the title compound as the yellow white powder.

¹ H NMR (δ, acetone-d ₆ ): 3.90 (s, 3H), 5.22 (s, 2H), 6.01 (s, 2H), 6.64 (dd, J = 2.4, 8.6 Hz, 1H), 6.65 (s) , 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 17 Hz, 1H), 7.00 (dd, J = 1.6, 8.0 Hz , 1H), 7.04 (d, J = 17 Hz, 1H), 7.14 (d, J = 17 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 7.31 (dd, J = 5, 7 Hz) , 1H), 7.36 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.56 (br d, J = 8.2 Hz, 1H), 7.82 (dt, J = 1.7, 7.7 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H). Melting point 218-220 ° C, MS (ESI+) m/z 454.3 (M+1).

[Example 78] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-(4-isopropylphenyl)vinyl]- Synthesis of 1H-pyrazole

(1) Synthesis of (1E,6E)-1-(1H-indol-6-yl)-7-(4-isopropylphenyl)heptan-1,6-diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 4-isopropylbenzaldehyde 20 mg (0.14 mmol) in the same amount relationship The title compound (27.9 mg (yield: 57%).

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-(4-isopropylphenyl)vinyl]-1H- Synthesis of pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-(4-isopropylphenyl)heptane-1 The 6-diene-3,5-dione 30 mg (84 μmol) was subjected to a synthetic operation in the same manner to give the title compound (22.2 mg (yield: 74%) of the title compound of the product of the white crystals.

¹ H NMR (δ, acetone-d ₆ ): 1.23 (d, J = 6.9 Hz, 6H), 2.90 (tt, J = 6.9, 6.9 Hz, 1H), 6.46 (dd, J = 1, 3 Hz, 1H) ), 6.74 (s, 1H), 7.10 (d, J = 17 Hz, 1H), 7.11 (d, J = 17 Hz, 1H), 7.18 (d, J = 17 Hz, 1H), 7.25 (d, J) = 8.2 Hz, 2H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.4, 8 Hz, 1H), 7.34 (M, 1H), 7.48 (d, J = 8.2 Hz, 2H ), 7.56 (d, J = 8.6 Hz, 1H), 7.57 (br s, 1H), 10.3 (br s, NH). Melting point 208-212 ° C, MS (ESI+) m/z 354.2 (M+1) .

[Example 79] 3-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-5-[(1E)-2-(4) Synthesis of -nitro-1H-indol-6-yl)vinyl]-1H-pyrazole

(1) (1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(4-nitro-1H-indol-6-yl) Synthesis of G-1,6-diene-3,5-dione

By replacing 1H-benzotriazol-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30 (2) with 4-nitro-1H-indole-6-carboxycarboxaldehyde 52 mg (0.27 mmol), The same amount of the relationship was subjected to a synthetic operation to give the title compound (yield: 15%) as a yellow powder.

(2) 3-[(1E)-2-[2-Methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-5-[(1E)-2-(4-nitro Synthesis of keto-1H-indol-6-yl)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-( 4-nitro-1H-indol-6-yl)heptane-1,6-diene-3,5-dione 15 mg (30 μmol), and the synthesis operation was carried out in the same amount to obtain an orange powder. The title compound was 7.8 mg (yield 52%).

¹ H NMR ^(δ, acetone _{-d 6): 3.90 (s,} 3H), 5.22 (s, 2H), 6.62 (s, 1H), 6.64 (dd, J = 2.3,8.6 Hz, 1H), 6.73 (d , J=2.3 Hz, 1H), 6.81 (d, J=17 Hz, 1H), 7.07 (d, J=17 Hz, 1H), 7.31 (dd, J=7.9, 8.0 Hz, 1H), 7.32 (M , 1H), 7.38 (d, J = 17 Hz, 1H), 7.49 (d, J = 17 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.56 (br d, J = 7.8 Hz, 1H), 7.81 (dt, J = 1.7, 7.7 Hz, 1H), 7.81 (dd, J = 0.7, 7.9 Hz, 1H), 7.81 (dd, J = 0.7, 8.0 Hz, 1H), 8.02 (s, 1H) ), 8.58 (br d, J = 5 Hz, 1H), 11.3 (br s, NH). Melting point 125-131 ° C, MS (ESI+) m/z 494.3 (M+1).

[Example 80] 3-[(1E)-2-[4-(cyclohexylmethoxy)-2-methoxyphenyl]ethenyl]-5-[(1E)-2-(1H-indole) Synthesis of 哚-6-yl)vinyl]-1H-pyrazole

(1) (1E,6E)-1-[4-(cyclohexylmethoxy)-2-methoxyphenyl]-7-(1H-indol-6-yl)heptan-1,6-di Synthesis of ene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 4-(cyclohexylmethoxy)-2-methoxybenzaldehyde 67 mg (0.27) The title compound (84.1 mg (yield: 70%)) of

(2) 3-[(1E)-2-[4-(Cyclohexylmethoxy)-2-methoxyphenyl]ethenyl]-5-[(1E)-2-(1H-indole- Synthesis of 6-yl)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-[4-(cyclohexylmethoxy)-2-methoxyphenyl]-7-(1H-吲哚-6-yl)heptane-1,6-diene-3,5-dione 30 mg (66 μmol), and the synthesis operation was carried out in the same amount to obtain the title compound having the following physical properties as a yellowish white powder. 7.0 mg (yield 23%).

¹ H NMR (δ, acetone-d ₆ ): 1.02-1.38 (M, 6H), 1.64-1.92 (M, 5H), 3.83 (d, J = 6.3 Hz, 2H), 3.90 (s, 3H), 6.45 (br d, J = 3 Hz, 1H), 6.54 (dd, J = 2.3, 8.5 Hz, 1H), 6.58 (d, J = 2.3 Hz, 1H), 6.67 (s, 1H), 7.03 (d, J =17 Hz,1H), 7.09 (d, J=17 Hz, 1H), 7.30 (d, J=17 Hz, 1H), 7.31 (dd, J=1.4, 8.2 Hz, 1H), 7.34 (M, 1H) ), 7.37 (d, J = 17 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.57 (br s, 1H), 10.3 (br s , NH). Melting point 104-108 ° C, MS (ESI +) m / z 454.4 (M + 1).

[Example 81] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-[2-( Synthesis of pyrrol-1-yl)ethoxy]phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-[2-(pyrrol-1-yl)ethoxy]phenyl] Synthesis of G-1,6-diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) to 2-methoxy-4-[2-(pyrrol-1-yl)ethoxylate 66 mg (0.27 mmol) of benzaldehyde, and the synthesis operation was carried out in the same amount to give 60.5 mg (yield: 50%) of the title compound.

(2) 3-[(1E)-2-(1H-Indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-[2-(pyrrole- Synthesis of 1-yl)ethoxy]phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-[2- (pyrrole-1- 30 mg (66 μmol) of ethoxy]phenyl]heptane-1,6-diene-3,5-dione, and the synthesis operation was carried out in the same amount to obtain a yellowish white powder having the following physical properties. The title compound was 14.7 mg (yield: 49%).

¹ H NMR (δ, acetone-d ₆ ): 3.88 (s, 3H), 4.31 (M, 4H), 6.01 (t, J = 2.1 Hz, 2H), 6.45 (dd, J = 1, 3 Hz, 1H) ), 6.55 (dd, J = 2.3, 8.5 Hz, 1H), 6.58 (d, J = 2.3 Hz, 1H), 6.67 (s, 1H), 6.80 (t, J = 2.1 Hz, 2H), 7.04 (d , J=17 Hz, 1H), 7.08 (d, J=17 Hz, 1H), 7.30 (d, J=17 Hz, 1H), 7.31 (dd, J=1.4, 8 Hz, 1H), 7.34 (M , 1H), 7.36 (d, J = 17 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.57 (br s, 1H), 10.3 ( Br s, NH). Melting point 102-110 ° C, MS (ESI +) m / z 451.4 (M + 1).

[Example 82] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(1,3) Synthesis of -thiazol-2-ylmethoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E, 6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(1,3-thiazol-2-ylmethoxy)phenyl] Synthesis of G-1,6-diene-3,5-dione

Substituting 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde of Example 16(1) to 2-methoxy-4-(1,3-thiazol-2-ylmethoxy) 71 mg (0.27 mmol) of benzaldehyde, and a synthetic operation was carried out in the same amount to give the title compound 52.6 mg (yield: 43%).

(2) 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(1,3-thiazole) Synthesis of -2-ylmethoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(1, 3-thiazol-2-ylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 30 mg (66 μmol), and subjected to a synthetic operation in the same amount to obtain a yellow-white powder The title compound of the following properties was 17.4 mg (yield: 58%).

¹ H NMR (δ, acetone-d ₆ ): 3.91 (s, 3H), 5.29 (s, 2H), 6.45 (brd, J = 3 Hz, 1H), 6.68 (s, 1H), 6.68 (dd, J=2.4, 8.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 7.06 (d, J=17 Hz, 1H), 7.09 (d, J=17 Hz, 1H), 7.30 (d, J = 17 Hz, 1H), 7.31 (dd, J = 1.4, 8 Hz, 1H), 7.34 (M, 1H), 7.38 (d, J = 17 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.57 (br s, 1H), 7.69 (br d, J = 2.0 Hz, 1H), 9.03 (d, J = 2.0 Hz, 1H), 10.3 ( Br s, NH). Melting point 229-237 ° C, MS (ESI+) m / z 455.3 (M + 1).

[Example 83] 3-[(1E)-2-(1,4-benzoic acid) Synthesis of alk-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E, 6E)-1-(1,4-benzoic acid) Synthesis of alk-6-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione

By replacing 1H-benzotriazol-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30(2) with 1,4-benzoic acid Alkyl-6-carboxycarboxaldehyde (44 mg, 0.27 mmol) was obtained from the title compound (yield: 20%).

(2) 3-[(1E)-2-(1,4-benzoic acid) Synthesis of alk-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(1,4-benzoic acid) Alkan-6-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 20 mg (42 μmol), The synthesis operation was carried out in the same amount to give the title compound 7.7 mg (yield 39%) of the crude material as a yellowish white powder.

¹ H NMR (δ, acetone-d ₆ ): 3.89 (s, 3H), 4.27 (s, 4H), 5.22 (s, 2H), 6.64 (dd, J = 2.4, 8.5 Hz, 1H), 6.65 (s) , 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 17 Hz, 1H), 7.00-7.05 (M, 2H), 7.04 (d, J = 17 Hz, 1H), 7.09 (d, J = 17 Hz, 1H), 7.31 (dd, J = 5, 7 Hz, 1H), 7.36 (d, J = 17 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.56 (br d, J = 8 Hz, 1H), 7.81 (dt, J = 1.7, 7.7 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H) Melting point 153-155 ° C, MS (ESI +) m / z 468.3 (M + 1).

[Example 84] 3-[(1E)-2-[2-bromo-5-(2-pyridylmethoxy)phenyl]vinyl]-5-[(1E)-2-(1H-indole) Synthesis of 哚-6-yl)vinyl]-1H-pyrazole

(1) (1E,6E)-1-[2-bromo-5-(2-pyridylmethoxy)phenyl]-7-(1H-indol-6-yl)heptan-1,6-di Synthesis of ene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with 2-bromo-5-(2-pyridylmethoxy)benzaldehyde 78 mg (0.27) The title compound ( 28.1 mg (yield 21%)) was obtained as a brown powder.

(2) 3-[(1E)-2-[2-Bromo-5-(2-pyridylmethoxy)phenyl]vinyl]-5-[(1E)-2-(1H-indole- Synthesis of 6-yl)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-[2-bromo-5-(2-pyridylmethoxy)phenyl]-7-(1H-吲哚-6-yl)heptane-1,6-diene-3,5-dione 20 mg (40 μmol), and the synthesis operation was carried out in the same amount to obtain the title compound having the following physical properties as a yellowish white powder. 3.4 mg (yield 17%).

¹ H NMR (δ, acetone-d ₆ ): 5.28 (s, 2H), 6.46 (brd, J = 3 Hz, 1H), 6.80 (s, 1H), 6.93 (dd, J = 3.0, 8.8 Hz, 1H), 7.11 (d, J = 17 Hz, 1H), 7.20 (d, J = 17 Hz, 1H), 7.29-7.38 (M, 4H), 7.44 (d, J = 17 Hz, 1H), 7.50 ( d, J = 3.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.58 (br s, 1H), 7.59 (br d, J = 8 Hz, 1H), 7.83 (dt, J = 1.7, 7.7 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H), 10.3 (br s, NH). Melting point 100-106 ° C, MS (ESI+ ) m / z 497.3 (M + 1).

[Example 85] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-tetrahydrofuran) Methoxy)phenyl]vinyl]-1-phenyl-1H-pyrazole and 5-[(1E)-2-(1H-indol-6-yl)vinyl]-3-[(1E Synthesis of -2-[2-methoxy-4-(2-tetrahydrofurylmethoxy)phenyl]vinyl]-1-phenyl-1H-pyrazole

(1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)phenyl]heptane-1,6-di 10 mg (22 μmol) of the ene-3,5-dione was dissolved in 0.22 mL of toluene and 11 μL of trifluoroacetic acid, and phenyl hydrazine 7.3 mg (66 μmol) was added thereto at room temperature, and the mixture was stirred at 100 ° C for 1 hour. The reaction mixture was diluted with EtOAc. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate or dichloromethane/methanol), and the obtained solid was washed with an organic solvent. The title compound 3.1 mg (yield 27%) of the title compound was obtained as a yellowish white powder.

¹ H NMR (δ, acetone-d ₆ ): 1.7-2.0 (M, 4H), 3.71 (M, 1H), 3.83 (M, 1H), 3.88 (s, 3H x 0.5), 3.91 (s, 3H x 0.5), 3.99 (d, J = 5.3 Hz, 1H x 0.5), 4.00 (d, J = 5.3 Hz, 1H x 0.5), 4.2 (M, 1H), 6.45 (M, 1H), 6.53 (dd, J =2,8 Hz,1H x 0.5), 6.58 (dd, J=2.4, 8.5 Hz, 1H x 0.5), 6.61 (d, J=3 Hz, 1H x 0.5), 6.62 (d, J=3 Hz, 1H x 0.5), 6.97 (d, J = 17 Hz, 1H x 0.5), 7.00 (d, J = 17 Hz, 1H x 0.5), 7.01 (s, 1H), 7.08 (d, J = 17 Hz, 1H) x 0.5), 7.12 (d, J = 17 Hz, 1H x 0.5), 7.23 (dd, J = 2, 8.2 Hz, 1H x 0.5), 7.32 - 7.62 (M, 11H + 1H x 0.5), 10.3 (br s, NH). Melting point 90-95 ° C, MS (ESI+) m / z 518.2 (M + 1).

[Example 86] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridine) Methoxy)phenyl]vinyl]-1-phenyl-1H-pyrazole and 5-[(1E)-2-(1H-indol-6-yl)vinyl]-3-[(1E Synthesis of 2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1-phenyl-1H-pyrazole

By (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)phenyl]g of Example 85 -1,6-diene-3,5-dione 10 mg (22 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4- (2-Pyridylmethoxy)phenyl]heptane-1,6-diene-3,5-dione 10 mg (22 μmol), and the synthesis operation was carried out in the same amount to obtain a yellowish white powder. The title compound was 7.7 mg (yield 66%).

¹ H NMR (δ, acetone-d ₆ ): 3.88 (s, 3H x 0.5), 3.92 (s, 3H x 0.5), 5.21 (s, 2H x 0.5), 5.23 (s, 2H x 0.5), 6.46 ( Br d, J=3 Hz, 1H), 6.62 (dd, J=2.5, 8.7 Hz, 1H x 0.5), 6.66 (dd, J=2.5, 8.7 Hz, 1H x 0.5), 6.73 (d, J=3) Hz, 1H x 0.5), 6.74 (d, J = 3 Hz, 1H x 0.5), 6.95 (d, J = 17 Hz, 1H x 0.5), 7.01 (br s, 1H), 7.02 (d, J = 17) Hz, 1H x 0.5), 7.09 (d, J = 17 Hz, 1H x 0.5), 7.13 (d, J = 17 Hz, 1H x 0.5), 7.23 (dd, J = 2, 8 Hz, 1H x 0.5) , 7.26-7.63 (M, 13H+1H x 0.5), 7.82 (M, 1H), 8.57 (M, 1H), 10.3 (br s, NH). Melting point 96-104 ° C, MS (ESI+) m/z 525.0 (M+1).

[Example 87] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-tetrahydrofuran) Methoxy)phenyl]vinyl]-1-nitrophenyl-1H-pyrazole and 5-[(1E)-2-(1H-indol-6-yl)vinyl]-3-[ Synthesis of (1E)-2-[2-methoxy-4-(2-tetrahydrofurylmethoxy)phenyl]vinyl]-1-nitrophenyl-1H-pyrazole

(1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)phenyl]heptane-1,6-di 20 mg (45 μmol) of the ene-3,5-dione was dissolved in 0.44 mL of toluene and 22 μL of trifluoroacetic acid, and 21 mg (0.14 mmol) of 4-nitrophenylhydrazine was added thereto at room temperature, and the mixture was stirred at 80 ° C for 1 hour. The reaction mixture was diluted with EtOAc. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate or dichloromethane/methanol). The yellow powder had the title compound 5.7 mg (yield 23%).

¹ H NMR (δ, acetone-d ₆ ): 1.7-2.0 (M, 4H), 3.73 (M, 1H), 3.85 (M, 1H), 3.93 (s, 3H x 0.5), 3.94 (s, 3H x 0.5), 4.02 (d, J = 5 Hz, 1H x 0.5), 4.03 (d, J = 5 Hz, 1H x 0.5), 4.2 (M, 1H), 6.49 (M, 1H), 6.57 (dd, J =2.4, 8.5 Hz, 1H x 0.5), 6.60 (dd, J = 2.4, 8.5 Hz, 1H x 0.5), 6.65 (d, J = 2.5 Hz, 1H x 0.5), 6.66 (d, J = 2.5 Hz, 1H x 0.5), 7.10 (d, J = 17 Hz, 1H x 0.5), 7.11 (d, J = 17 Hz, 1H x 0.5), 7.12 (s, 1H), 7.16 (d, J = 17 Hz, 1H) x 0.5), 7.17 (d, J = 17 Hz, 1H x 0.5), 7.34 (dd, J = 1.4, 8.4 Hz, 1H x 0.5), 7.39 (M, 1H), 7.41 (dd, J = 1.4, 8.4 Hz, 1H x 0.5), 7.45-7.61 (M, 4H), 7.65 (br s, 1H x 0.5), 7.66 (br s, 1H x 0.5), 7.94 (br d, J = 9.2 Hz, 2H x 0.5) , 7.95 (br d, J = 9.2 Hz, 2H x 0.5), 8.47 (br d, J = 9.2 Hz, 2H x 0.5), 8.48 (br d, J = 9.2 Hz, 2H x 0.5), 10.4 (br s , NH). Melting point 94-101 ° C, MS (ESI +) m / z 563.2 (M + 1).

[Example 88] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridine) Methoxy)phenyl]vinyl]-1-nitrophenyl-1H-pyrazole and 5-[(1E)-2-(1H-indol-6-yl)vinyl]-3-[ Synthesis of (1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1-nitrophenyl-1H-pyrazole

By (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)phenyl]g of Example 87 -1,6-diene-3,5-dione 20 mg (45 μmol) was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4- (2-Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 20 mg (44 μmol), and subjected to a synthetic operation in the same amount to obtain a yellow powder 20.5 mg (yield 81%) of the title compound.

¹ H NMR (δ, acetone-d ₆ ): 3.93 (s, 3H x 0.5), 3.94 (s, 3H x 0.5), 5.25 (s, 2H), 6.49 (M, 1H), 6.66 (dd, J = 2.4, 9 Hz, 1H x 0.5), 6.69 (dd, J = 2.4, 9 Hz, 1H x 0.5), 6.77 (d, J = 2.5 Hz, 1H x 0.5), 6.78 (d, J = 2.5 Hz, 1H x 0.5), 7.10 (d, J = 17 Hz, 1H x 0.5), 7.12 (d, J = 17 Hz, 1H x 0.5), 7.13 (br s, 1H), 7.16 (d, J = 17 Hz, 1H x 0.5), 7.17 (d, J = 17 Hz, 1H x 0.5), 7.30-7.42 (M, 3H), 7.45-7.54 (M, 2H), 7.54-7.67 (M, 3H), 7.65 (br s, 1H x 0.5), 7.66 (br s, 1H x 0.5), 7.83 (dt, J = 1.7, 7.8 Hz, 1H x 0.5), 7.84 (dt, J = 1.7, 7.8 Hz, 1H x 0.5), 7.94 (br d, J = 9.2 Hz, 2H x 0.5), 7.95 (br d, J = 9.2 Hz, 2H x 0.5), 8.46 (br d, J = 9.2 Hz, 2H x 0.5), 8.48 (br d, J = 9.2 Hz, 2H x 0.5), 8.60 (br d, J = 6 Hz, 1H), 10.4 (br s, NH). Melting point 107-112 ° C, MS (ESI+) m/z 570.2 (M+1).

[Example 89] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridine) Methoxy)phenyl]vinyl]-1-methyl-1H-pyrazole and 5-[(1E)-2-(1H-indol-6-yl)vinyl]-3-[(1E Synthesis of 2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1-methyl-1H-pyrazole

(1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptane-1,6-di Ethylene-3,5-dione 20 mg (44 μmol) dissolved in 0.22 mL of acetic acid was added, and 7.0 μL (0.13 mmol) of methyl hydrazine was added thereto at room temperature, and the mixture was stirred at 80 ° C for 1 hour. The reaction mixture was diluted with EtOAc. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate or dichloromethane/methanol). The yellow powder had the title compound 2.1 mg (yield 10%).

¹ H NMR (δ, acetone-d ₆ ): 3.80 (s, 3H x 0.5), 3.90 (s, 3H x 0.5), 3.92 (s, 3H x 0.5), 3.93 (s, 3H x 0.5), 5.22 ( s, 2H x 0.5), 5.23 (s, 2H x 0.5), 6.44 (dd, J = 1, 3 Hz, 1H x 0.5), 6.46 (dd, J = 1, 3 Hz, 1H x 0.5), 6.64 ( Dd, J = 2.3, 9 Hz, 1H x 0.5), 6.65 (dd, J = 2.3, 9 Hz, 1H x 0.5), 6.72 (d, J = 2.4 Hz, 1H x 0.5), 6.74 (br s, 1H +1H x 0.5), 6.98 (d, J = 17 Hz, 1H x 0.5), 7.02 (d, J = 17 Hz, 1H x 0.5), 7.09 (d, J = 17 Hz, 1H x 0.5), 7.12 ( d, J = 17 Hz, 1H x 0.5), 7.26 (d, J = 17 Hz, 1H x 0.5), 7.27-7.37 (M, 4H), 7.40 (dd, J = 1.3, 8.4 Hz, 1H x 0.5) , 7.51-7.60 (M, 3H), 7.63 (br s, 1H), 7.81 (dt, J = 1.8, 7.7 Hz, 1H x 0.5), 7.82 (dt, J = 1.8, 7.7 Hz, 1H x 0.5), 8.58 (br d, J=5 Hz, 1H), 10.28 (br s, NH x 0.5), 10.33 (br s, NH x 0.5). Melting point 80-85 ° C, MS (ESI+) m/z 463.1 (M +1).

[Example 90] 1-t-butyl-3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy 4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole and 1-tert-butyl-5-[(1E)-2-(1H-indol-6-yl) Vinyl]-3-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H- Synthesis of pyrazole

By substituting 7.0 μL (0.13 mmol) of the methyl hydrazine of Example 89 into a third butyl hydrazine 16 mg (0.13 mmol), and performing the same synthesis operation (reaction time: 14 hours), a yellowish white powder was obtained. The title compound was 2.5 mg (yield 11%).

¹ H NMR (δ, acetone-d ₆ ): 1.69 (s, 9H x 0.5), 1.71 (s, 9H x 0.5), 3.90 (s, 3H x 0.5), 3.93 (s, 3H x 0.5), 5.22 ( s, 2H x 0.5), 5.23 (s, 2H x 0.5), 6.44 (dd, J = 1, 3 Hz, 1H x 0.5), 6.46 (dd, J = 1, 3 Hz, 1H x 0.5), 6.64 ( Dd, J = 2.5, 9 Hz, 1H x 0.5), 6.65 (dd, J = 2.5, 9 Hz, 1H x 0.5), 6.72 (d, J = 2.5 Hz, 1H x 0.5), 6.761 (d, J = 2.5 Hz, 1H x 0.5), 6.764 (br s, 1H), 6.99 (d, J = 17 Hz, 1H x 0.5), 7.04 (d, J = 17 Hz, 1H x 0.5), 7.17 (d, J = 17 Hz, 1H x 0.5), 7.22 (d, J = 17 Hz, 1H x 0.5), 7.26-7.38 (M, 4H + 1H x 0.5), 7.44 (d, J = 17 Hz, 1H x 0.5), 7.52 -7.58 (M, 3H), 7.62 (br s, 1H), 7.81 (dt, J = 1.8, 7.7 Hz, 1H x 0.5), 7.82 (dt, J = 1.8, 7.7 Hz, 1H x 0.5), 8.58 ( Br d, J=5 Hz, 1H), 10.25 (br s, NH x 0.5), 10.31 (br s, NH x 0.5). Melting point 76-84 ° C, MS (ESI+) m/z 505.3 (M+1 ).

[Example 91] 1-Hydroxyethyl-3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy- 4-(2-pyridylmethoxy)phenyl]vinyl]- 1H-pyrazole and 1-hydroxyethyl-5-[(1E)-2-(1H-indol-6-yl)vinyl]-3-[(1E)-2-[2-methoxy- Synthesis of 4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

By substituting 7.0 μL (0.13 mmol) of the methyl hydrazine of Example 89 into 2-hydroxyethyl hydrazine 9.0 μL (0.13 mmol), and performing the same synthesis operation (reaction time: 2 hours), a yellowish white powder was obtained. The title compound having the following physical properties was 10.2 mg (yield: 47%).

¹ H NMR (δ, acetone-d ₆ ): 3.88-3.94 (M, 2H), 3.90 (s, 3H x 0.5), 3.91 (s, 3H x 0.5), 4.31 (d, J = 5.6 Hz, 2H x 0.5), 4.34 (d, J = 5.6 Hz, 2H x 0.5), 5.22 (s, 2H x 0.5), 5.23 (s, 2H x 0.5), 6.45 (dd, J = 1, 3 Hz, 1H x 0.5) , 6.46 (dd, J = 1, 3 Hz, 1H x 0.5), 6.64 (dd, J = 2.5, 9 Hz, 1H x 0.5), 6.66 (dd, J = 2.5, 9 Hz, 1H x 0.5), 6.73 (d, J = 2.5 Hz, 1H x 0.5), 6.74 (d, J = 2.5 Hz, 1H x 0.5), 6.76 (br s, 1H), 7.00 (d, J = 17 Hz, 1H x 0.5), 7.05 (d, J = 17 Hz, 1H x 0.5), 7.16 (d, J = 17 Hz, 1H x 0.5), 7.20 (d, J = 17 Hz, 1H x 0.5), 7.28 (d, J = 17 Hz, 1H x 0.5), 7.27-7.40 (M, 4H+1H x 0.5), 7.52-7.59 (M, 3H), 7.60 (d, J = 8.7 Hz, 1H x 0.5), 7.62 (br s, 1H x 0.5) , 7.82 (br dt, J = 2, 8 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H), 10.29 (br s, NH x 0.5), 10.33 (br s, NH x 0.5). Point 94-97 ° C, MS (ESI+) m / z 493 (M + 1).

[Example 92] 1-Benzyl-3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy- 4-(2-Pyridylmethoxy)phenyl]vinyl]-1H-pyrazole and 1-benzyl-5-[(1E)-2-(1H-indol-6-yl)vinyl Synthesis of -3-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

By substituting 7.0 μL (0.13 mmol) of methyl hydrazine of Example 89 with benzyl hydrazine 21 mg (0.13 mmol), and performing the same synthesis operation (reaction time: 10 hours), a yellowish white powder was obtained. The title compound of the title compound was 11.2 mg (yield: 47%).

¹ H NMR (δ, acetone-d ₆ ): 3.88 (s, 3H x 0.5), 3.90 (s, 3H x 0.5), 5.21 (s, 2H x 0.5), 5.22 (s, 2H x 0.5), 5.50 ( s, 2H x 0.5), 5.54 (s, 2H x 0.5), 6.44 (M, 1H), 6.61 (dd, J = 2.3, 8.6 Hz, 1H x 0.5), 6.64 (dd, J = 2.4, 8.6 Hz, 1H x 0.5), 6.72 (d, J = 2.4 Hz, 1H x 0.5), 6.73 (d, J = 2.4 Hz, 1H x 0.5), 6.84 (br s, 1H), 7.03 (d, J = 17 Hz, 1H x 0.5), 7.07 (d, J = 17 Hz, 1H x 0.5), 7.12 (d, J = 17 Hz, 1H x 0.5), 7.14 (d, J = 17 Hz, 1H x 0.5), 7.22 - 7.35 (M,9H+1H x 0.5), 7.39 (d, J=17 Hz, 1H x 0.5), 7.47 (d, J=8.7 Hz, 1H x 0.5), 7.51-7.57 (M, 2H+1H x 0.5) , 7.57 (br s, 1H x 0.5), 7.58 (br s, 1H x 0.5), 7.81 (dt, J = 1.8, 7.7 Hz, 1H x 0.5), 7.82 (dt, J = 1.8, 7.7 Hz, 1H x 0.5), 8.57 (M, 1H), 10.29 (br s, NH x 0.5), 10.32 (br s, NH x 0.5). Melting point 80-86 ° C, MS (ESI+) m/z 539.2 (M+1) .

[Example 93] 1-Cyclohexyl-3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4 -(2-Pyridylmethoxy)phenyl]vinyl]-1H-pyrazole and 1-cyclohexyl-5-[(1E)-2-(1H-indol-6-yl)vinyl]- Synthesis of 3-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

By substituting 7.0 μL (0.13 mmol) of methyl hydrazine of Example 89 with cyclohexyl hydrazine 20 mg (0.13 mmol) and performing the same synthesis operation (reaction time: 12 hours), a yellowish white powder was obtained having the following The title compound was 3.6 mg (yield 15%).

¹ H NMR (δ, acetone-d ₆ ): 1.2-2.0 (M, 10H), 3.90 (s, 3H x 0.5), 3.92 (s, 3H x 0.5), 4.43 (M, 1H), 5.22 (s, 2H x 0.5), 5.23 (s, 2H x 0.5), 6.44 (br d, J = 3 Hz, 1H x 0.5), 6.46 (br d, J = 3 Hz, 1H x 0.5), 6.65 (br dd, J =2,9 Hz,1H),6.72 (d,J=2.4 Hz,1H x 0.5), 6.74 (br s,1H), 6.75 (d, J=2.4 Hz, 1H x 0.5), 7.02 (d, J =17 Hz, 1H x 0.5), 7.06 (d, J = 17 Hz, 1H x 0.5), 7.16 (d, J = 17 Hz, 1H x 0.5), 7.20 (d, J = 17 Hz, 1H x 0.5) , 7.25 (d, J = 17 Hz, 1H x 0.5), 7.27-7.38 (M, 4H), 7.40 (dd, J = 1.3, 8.4 Hz, 1H x 0.5), 7.52 - 7.58 (M, 3H), 7.60 (d, J = 8.7 Hz, 1H x 0.5), 7.61 (br s, 1H x 0.5), 7.81 (br dt, J = 2, 8 Hz, 1H), 8.58 (br d, J = 4 Hz, 1H) , 10.29 (br s, NH x 0.5), 10.32 (br s, NH x 0.5). Melting point 101-115 ° C, MS (ESI+) m/z 531.3 (M+1).

[Example 94] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridine) Methoxy)phenyl]vinyl]-1-(2-pyridyl)-1H-pyrazole and 5-[(1E)-2-(1H-indol-6-yl)vinyl]-3 Synthesis of [[1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1-(2-pyridyl)-1H-pyrazole

By substituting 7.0 μL (0.13 mmol) of methyl hydrazine of Example 89 into 2-pyridyl hydrazine 15 mg (0.13 mmol), and performing the same synthetic operation, the title compound 18.2 of the following property was obtained as a yellowish white powder. Mg (yield 78%).

¹ H NMR (δ, acetone-d ₆ ): 3.92 (s, 3H x 0.5), 3.93 (s, 3H x 0.5), 5.23 (s, 2H x 0.5), 5.24 (s, 2H x 0.5), 6.47 ( Br d, J=3 Hz, 1H), 6.66 (dd, J=2.5, 8.5 Hz, 1H x 0.5), 6.67 (dd, J=2.3, 8.5 Hz, 1H x 0.5), 6.75 (d, J=2) Hz, 1H x 0.5), 6.76 (d, J = 2 Hz, 1H x 0.5), 7.11 (d, J = 17 Hz, 1H x 0.5), 7.102 (br s, 1H x 0.5), 7.106 (br s, 1H x 0.5), 7.14 (d, J = 17 Hz, 1H x 0.5), 7.30-7.61 (M, 9H), 7.63 (br s, 1H x 0.5), 7.64 (br s, 1H x 0.5), 7.818 ( Dt, J = 1.8, 7.7 Hz, 1H x 0.5), 7.822 (dt, J = 1.8, 7.7 Hz, 1H x 0.5), 7.94 - 8.02 (M, 2H), 8.12 (d, J = 17 Hz, 1H x 0.5), 8.16 (d, J = 17 Hz, 1H x 0.5), 8.52-8.60 (M, 2H), 10.3 (br s, NH). Melting point 91-97 ° C, MS (ESI+) m/z 526.2 ( M+1).

[Example 95] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-1-(4-methoxyphenyl)-5-[(1E)-2-[ 2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole and 5-[(1E)-2-(1H-indol-6-yl)vinyl ]-1-(4-methoxyphenyl)-3-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H- Synthesis of pyrazole

By substituting 7.0 μL (0.13 mmol) of methyl hydrazine of Example 89 with 4-methoxyphenyl hydrazine 23 mg (0.13 mmol), and performing the same synthesis operation, a yellowish white powder having the following physical properties was obtained. The title compound was 7.9 mg (yield 32%).

¹ H NMR (δ, acetone-d ₆ ): 3.878 (s, 3H x 0.5), 3.883 (s, 3H x 0.5), 3.90 (s, 3H x 0.5), 3.91 (s, 3H x 0.5), 5.21. s, 2H x 0.5), 5.23 (s, 2H x 0.5), 6.45 (M, 1H), 6.61 (dd, J = 2.4, 8.5 Hz, 1H x 0.5), 6.66 (dd, J = 2.4, 8.5 Hz, 1H x 0.5), 6.73 (d, J = 3 Hz, 1H x 0.5), 6.74 (d, J = 3 Hz, 1H x 0.5), 6.88 (d, J = 17 Hz, 1H x 0.5), 6.94 (d , J=17 Hz, 1H x 0.5), 6.97 (br s, 1H), 7.07 (d, J=17 Hz, 1H x 0.5), 7.08-7.14 (M, 2H+1H x 0.5), 7.21 (dd, J = 1.4, 8.4 Hz, 1H x 0.5), 7.28-7.60 (M, 10H), 7.61 (br s, 1H x 0.5), 7.81 (dt, J = 1.7, 7.8 Hz, 1H x 0.5), 7.82 (dt , J = 1.8, 7.8 Hz, 1H x 0.5), 8.57 (M, 1H), 10.3 (br s, NH). Melting point 92-99 ° C, MS (ESI+) m/z 555.1 (M+1).

[Example 96] 3-[(1E)-2-(1H-indol-6-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridine) Methoxy)phenyl]vinyl]-1-(2-methylphenyl)-1H-pyrazole and 5-[(1E)-2-(1H-indol-6-yl)vinyl] -3-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1-(2-methylphenyl)-1H-pyrazole Synthesis

By substituting 7.0 μL (0.13 mmol) of methyl hydrazine of Example 89 with 2-methylphenylhydrazine 21 mg (0.13 mmol), and performing the same synthesis operation, the title of the following property was obtained as a yellowish white powder. Compound 21.4 mg (yield 74%).

¹ H NMR (δ, acetone-d ₆ ): 2.04 (s, 3H x 0.5), 2.10 (s, 3H x 0.5), 3.81 (s, 3H x 0.5), 3.91 (s, 3H x 0.5), 5.18 ( s, 2H x 0.5), 5.22 (s, 2H x 0.5), 6.43 (br d, J = 3 Hz, 1H x 0.5), 6.45 (br d, J = 3 Hz, 1H x 0.5), 6.56 (d, J=17 Hz, 1H x 0.5), 6.57 (dd, J=2.4, 8.3 Hz, 1H x 0.5), 6.60 (d, J=17 Hz, 1H x 0.5), 6.66 (dd, J=2.4, 8.6 Hz) , 1H x 0.5), 6.69 (d, J = 2.4 Hz, 1H x 0.5), 6.74 (d, J = 2.3 Hz, 1H x 0.5), 6.99 (br s, 1H), 7.01 (d, J = 7.4 Hz) , 1H x 0.5), 7.08 (d, J = 17 Hz, 1H x 0.5), 7.11 (d, J = 7.4 Hz, 1H x 0.5), 7.12 (d, J = 17 Hz, 1H x 0.5), 7.26- 7.61 (M, 12H), 7.79 (dt, J = 1.7, 7.8 Hz, 1H x 0.5), 7.82 (dt, J = 1.7, 7.8 Hz, 1H x 0.5), 8.56 (br d, J = 5 Hz, 1H) x 0.5), 8.57 (br d, J = 5 Hz, 1H x 0.5), 10.27 (br s, NH x 0.5), 10.31 (br s, NH x 0.5). Melting point 94-100 ° C, MS (ESI+) m/z 539.3 (M+1).

[Example 97] 3-[(1E)-2-[4-diethylamino-2-[2-(1-piperidinyl)ethoxy]phenyl]vinyl]-5-[( Synthesis of 1E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazole

Synthesis of (1) 4-Diethylamino-2-[2-(1-piperidinyl)ethoxy]benzaldehyde

2.8 g (14.6 mmol) of 4-diethylaminosulphonic acid was dissolved in 90 mL of acetonitrile, and 14.3 g (43.8 mmol) of cesium carbonate and 2.8 g of 1-(2-chloroethyl)piperidine hydrochloride were added at room temperature. (15.3 mmol) and stirred at 80 ° C for 4 hours. Water (150 mL) was added to the obtained reaction solution, and extracted with ethyl acetate (100 mL×3×). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title compound 4.5 g.

¹ H NMR (δ, deuterated chloroform): 1.21 (t, J = 7.1 Hz, 6H), 1.43-1.48 (M, 2H), 1.59-1.64 (M, 4H), 2.52-2.58 (M, 4H), 2.83-2.86 (M, 2H), 3.39-3.44 (M, 4H), 4.17-4.21 (M, 2H), 6.04 (d, J = 2.3 Hz, 1H), 6.28 (dd, J = 1.7 Hz, 9.0 Hz , 1H), 7.71 (d, J = 9.2 Hz, 1H), 10.16 (s, 1H). Melting point 70-72 ° C, MS (EI) m / z 304 (M +).

(2) (1E,6E)-1-[4-Diethylamino-2-[2-(1-piperidinyl)ethoxy]phenyl]-7-(1H-indole-6- Synthesis of g)-1,6-diene-3,5-dione

By replacing 20 mg (85 μmol) of 2-methoxy-4-(2-tetrahydrofurylmethoxy)benzaldehyde of Example 1 (2) with 4-diethylamino-2-[2-(1) 215 mg (0.97 mmol) of -piperidinyl)ethoxy]benzaldehyde, and the title compound was obtained by the title compound (yield: 31%).

¹ H NMR (δ, DMSO-d ₆ ): 1.14 (t, J = 7.1 Hz, 6H), 1.37-1.46 (M, 2H), 1.51-1.57 (M, 4H), 2.48-2.51 (M, 4H, DMSO over lapped), 2.73-2.76 (M, 2H), 3.40-3.45 (M, 4H), 4.15-4.18 (M, 2H), 5.95 (s, 1H), 6.22 (d, J = 2.6) Hz, 1H), 6.33 (dd, J = 2.0 Hz, 9.0 Hz, 1H), 6.46-6.48 (M, 1H), 6.65 (d, J = 15.4 Hz, 1H), 6.79 (d, J = 16.0 Hz, 1H), 7.37-7.40 (M, 1H), 7.45-7.48 (M, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.65-7.69 (M, 2H), 7.79 (d, J = 16.1 Hz) , 1H), 11.31 (s, 1H), 16.61 (br s, 1H). MS (EI) m / z 513 (M +).

(3) 3-[(1E)-2-[4-Diethylamino-2-[2-(1-piperidinyl)ethoxy]phenyl]vinyl]-5-[(1E) Synthesis of -2-(1H-indol-6-yl)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-[4-diethylamino-2-[2-(1-piperidinyl)ethoxy] benzene 4-[1-H-indol-6-yl)heptane-1,6-diene-3,5-dione 400 mg (0.78 mmol), and the title compound 196 mg (Yield 49%).

1H NMR (δ, DMSO-d6): 1.12 (t, J = 7.1 Hz, 6H), 1.37-1.44 (M, 2H), 1.52-1.58 (M, 4H), 2.52-2.59 (M, 4H), 2.76 -2.82 (M, 2H), 3.35-3.40 (M, 4H), 4.12-4.16 (M, 2H), 6.24 (d, J = 2.6 Hz, 1H), 6.30 (dd, J = 2.3 Hz, 8.7 Hz, 1H), 6.42 (s, 1H), 6.57 (s, 1H), 6.85 (d, J = 16.7 Hz, 1H), 7.00 (d, J = 16.6 Hz, 1H), 7.18-7.28 (M, 3H), 7.31-7.37 (M, 2H), 7.48-7.54 (M, 2H), 11.10 (s, 1H), 12.68 (br s, 1H). Melting point 102-104 ° C, MS (EI) m/z 509 (M+ ).

[Example 98] 3-[(1E)-2-[4-diethylamino-2-(2-morpholinylethoxy)phenyl]vinyl]-5-[(1E)-2 Synthesis of -(1H-吲哚-6-yl)vinyl]-1H-pyrazole

Synthesis of (1) 4-diethylamino-2-(2-morpholinylethoxy)benzaldehyde

2.8 g (15.3 mmol) of 1-(2-chloroethyl)piperidine hydrochloride of Example 97 (1) was replaced by 1-(2-chloroethyl)morpholine hydrochloride 5.1 g (27.2) The synthesis operation was carried out in the same amount relationship to give the title compound (yield: 89%).

¹ H NMR (δ, deuterated chloroform): 1.22 (t, J = 7.4 Hz, 6H), 2.58-2.63 (M, 4H), 2.85-2.88 (M, 2H), 3.39-3.45 (M, 4H), 3.71-3.75 (M, 4H), 4.18-4.21 (M, 2H), 6.03 (d, J = 2.3 Hz, 1H), 6.30 (dd, J = 1.8 Hz, 8.7 Hz, 1H), 7.71 (d, J) = 9.2 Hz, 1H), 10.15 (s, 1H). Melting point 107-109 ° C, MS (EI) m / z 306 (M +).

(2) (1E,6E)-1-[4-Diethylamino-2-(2-morpholinoethoxy)phenyl]-7-(1H-indol-6-yl)heptane- Synthesis of 1,6-diene-3,5-dione

By replacing 20 mg (85 μmol) of 2-methoxy-4-(2-tetrahydrofurylmethoxy)benzaldehyde of Example 1 (2) with 4-diethylamino-2-(2-morpholine) 1.5 g (4.8 mmol) of benzyloxy)benzaldehyde, and the same operation was carried out to give the title compound 1.2 g (yield: 53%).

¹ H NMR (δ, DMSO-d ₆ ): 1.14 (t, J = 6.8 Hz, 6H), 2.52-2.55 (M, 4H), 2.77-2.81 (M, 2H), 3.40-3.45 (M, 4H) , 3.60-3.63 (M, 4H), 4.18-4.21 (M, 2H), 5.95 (s, 1H), 6.23 (d, J = 2.6 Hz, 1H), 6.34 (dd, J = 2.0 Hz, 9.0 Hz, 1H), 6.46-6.48 (M, 1H), 6.66 (d, J = 15.3 Hz, 1H), 6.80 (d, J = 16.0 Hz, 1H), 7.38-7.41 (M, 1H), 7.44-7.49 (M , 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.65-7.70 (M, 2H), 7.80 (d, J = 16.1 Hz, 1H), 11.31 (s, 1H), 16.62 (br s, 1H) ).MS(EI)m/z 515(M+).

(3) 3-[(1E)-2-[4-Diethylamino-2-(2-morpholinylethoxy)phenyl]vinyl]-5-[(1E)-2-( Synthesis of 1H-吲哚-6-yl)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-[4-diethylamino-2-(2-morpholinylethoxy)phenyl]- 7-(1H-indol-6-yl)heptane-1,6-diene-3,5-dione 712 mg (1.38 mmol), The synthesis was carried out in the same amount to give the title compound 446 mg (yield: 63%).

¹ H NMR (δ, DMSO-d ₆ ): 1.12 (t, J = 7.1 Hz, 6H), 2.53-2.58 (M, 4H), 2.78-2.83 (M, 2H), 3.34 - 3.40 (M, 4H) , 3.60-3.63 (M, 4H), 4.14 - 4.18 (M, 2H), 6.25 (d, J = 1.9 Hz, 1H), 6.30 (dd, J = 2.0 Hz, 9.0 Hz, 1H), 6.42 (s, 1H), 6.57 (s, 1H), 6.87 (d, J = 16.7 Hz, 1H), 7.00 (d, J = 16.7 Hz, 1H), 7.18-7.28 (M, 3H), 7.31-7.36 (M, 2H) ), 7.49-7.54 (M, 2H), 11.10 (s, 1H), 12.69 (br s, 1H). Melting point 96-99 ° C, MS (EI) m / z 511 (M +).

[Example 99] 3-[(1E)-2-(5-fluoro-1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy-4- Synthesis of (2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(5-fluoro-1H-indol-3-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]g Synthesis of -1,6-diene-3,5-dione

By replacing 1H-benzotriazole-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30 (2) with 5-fluoro-1H-indole-3-carboxycarboxaldehyde 111 mg (0.68 mmol), and The amount of the relationship was subjected to a synthesis operation to give the title compound (yield: 20%).

¹ H NMR (δ, DMSO-d ₆ ): 3.89 (s, 3H), 5.26 (s, 2H), 6.11 (s, 1H), 6.69-6.78 (M, 4H), 7.05-7.10 (M, 1H) , 7.35-7.38 (M, 1H), 7.46-7.50 (M, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 15.4) Hz, 1H), 7.80-7.88 (M, 3H), 8.02 (s, 1H), 8.59-8.60 (M, 1H), 11.89 (s, 1H), 16.50 (br s, 1H). Melting point 183-186 °C, MS (EI) m / z 470 (M +).

(2) 3-[(1E)-2-(5-Fluoro-1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy-4-(2) Synthesis of -pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(5-fluoro-1H-indol-3-yl)-7-[2-methoxy-4 -(2-Pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 40 mg (85 μmol), and the same operation was carried out to give the title compound 20 mg (yield 50%).

¹ H NMR (δ, DMSO-d ₆ ): 3.86 (s, 3H), 5.23 (s, 2H), 6.6 _{1 -} 6.67 (M, 2H), 6.74 (s, 1H), 6.90 (d, J = 16.7) Hz, 1H), 6.93-7.06 (M, 2H), 7.18-7.37 (M, 3H), 7.38-7.44 (M, 1H), 7.47-7.56 (M, 2H), 7.60-7.64 (M, 1H), 7.69-7.71 (M, 1H), 7.85 (dt, J = 1.9, 7.7 Hz, 1H), 8.58-8.60 (M, 1H), 11.30-11.47 (M, 1H), 12.55-12.75 (M, 1H). Melting point 209-213 ° C, MS (EI) m / z 466 (M +).

[Example 100] 3-[(1E)-2-(5-Methoxy-1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy- Synthesis of 4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(5-methoxy-1H-indol-3-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl Synthesis of Geng-1,6-diene-3,5-dione

By arranging 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxycarboxaldehyde of Example 30 (2) to 5-methoxy-1H-indole-3-carboxycarboxaldehyde 119 mg (0.68 mmol), The synthesis operation was carried out in the same amount to give the title compound 142 mg (yield: 48%).

¹ H NMR (δ, DMSO-d ₆ ): 3.86 (s, 3H), 3.89 (s, 3H), 5.26 (s, 2H), 6.08 (s, 1H), 6.67-6.71 (M, 2H), 6.73 -6.78 (M, 2H), 6.87 (dd, J = 2.3 Hz, 8.7 Hz, 1H), 7.35-7.38 (M, 2H), 7.42 (d, J = 2.6 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 16.1 Hz, 1H), 7.85 (dt, J = 1.9 Hz, 7.7 Hz, 1H), 7.88-7.93 (M , 2H), 8.59-8.60 (M, 1H), 11.70 (s, 1H), 16.58 (br s, 1H). MS (EI) m/z 482 (M+).

(2) 3-[(1E)-2-(5-Methoxy-1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy-4- Synthesis of (2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(5-methoxy-1H-indol-3-yl)-7-[2-methoxy 4-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 40mg (83μ The synthesis operation was carried out in the same amount relationship to give the title compound 22 mg (yield 55%).

^{1 H NMR (δ, DMSO-} d 6): 3.84 (s, 3H), 3.86 (s, 3H), 5.22 (s, 2H), 6.6 1-6 .68 (M, 2H), 6.73 (s, 1H ), 6.78-6.90 (M, 2H), 6.97 (d, J = 16.7 Hz, 1H), 7.20-7.72 (M, 8H), 7.85 (dt, J = 1.9, 7.7 Hz, 1H), 8.58-8.60 ( M, 1H), 11.07-11.24 (M, 1H), 12.63-12.72 (M, 1H). Melting point 189-195 ° C, MS (EI) m / z 478 (M +).

[Example 101] 3-[(1E)-2-(5-Benzyloxy-1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy Synthesis of 4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(5-Benzyloxy-1H-indol-3-yl)-7-[2-methoxy-4-(2-pyridylmethoxy) Synthesis of phenyl]heptane-1,6-diene-3,5-dione

By replacing 1H-benzotriazol-5-carboxycarboxaldehyde 20 mg (0.14 mmol) of Example 30 (2) with 5-benzyloxyinden-3-carboxycarboxaldehyde 170 mg (0.67 mmol), The same amount of the relationship was subjected to a synthetic operation to give the title compound 94 mg (yield: 27%).

¹ H NMR (δ, DMSO-d ₆ ): 3.88 (s, 3H), 5.21 (s, 2H), 5.26 (s, 2H), 6.07 (s, 1H), 6.66 (d, J = 16.0 Hz, 1H) ), 6.70 (dd, J = 2.2 Hz, 8.7 Hz, 1H), 6.73-6.78 (M, 2H), 6.95 (dd, J = 2.0 Hz, 9.0 Hz, 1H), 7.32-7.44 (M, 5H), 7.52-7.55 (M, 4H), 7.64 (d, J = 9.0 Hz, 1H), 7.74 (d, J = 16.1 Hz, 1H), 7.83-7.92 (M, 3H), 8.58-8.60 (M, 1H) , 11.71 (s, 1H), 16.58 (br s, 1H). MS (EI) m / z 558 (M +).

(2) 3-[(1E)-2-(5-Benzyloxy-1H-indol-3-yl)vinyl]-5-[(1E)-2-[2-methoxy- Synthesis of 4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(5-benzyloxy-1H-indol-3-yl)-7-[2- Oxy-4-(2-pyridylmethoxy)phenyl]heptan-1,6-diene-3,5-dione 100 mg (0.18 mmol), and the same operation was carried out to obtain the title Compound 42 mg (yield 43%).

¹ H NMR (δ, DMSO-d ₆ ): 3.86 (s, 3H), 5.17 (s, 2H), 5.22 (s, 2H), 6.61-6.68 (M, 2H), 6.73 (s, 1H), 6.84 -6.92 (M, 2H), 6.98 (d, J = 16.0 Hz, 1H), 7.21-7.37 (M, 5H), 7.39-7.43 (M, 2H), 7.46-7.72 (M, 6H), 7.84 (dt , J=1.9, 7.7 Hz, 1H), 8.59-8.60 (M, 1H), 11.10-11.26 (M, 1H), 12.63-12.72 (M, 1H). MS (EI) m/z 554 (M+).

[Example 102] 5-[(1E)-2-(1H-indol-6-yl)vinyl]-3-[(1E)-2-[4-(4-methylpiperidin Synthesis of -1-yl)phenyl]vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[4-(4-methylpiperidin Synthesis of -1-yl)phenyl]heptan-1,6-diene-3,5-dione

By replacing 20 mg (85 μmol) of 2-methoxy-4-(2-tetrahydrofurylmethoxy)benzaldehyde of Example 1 (2) with 4-(4-methylpiperidine) 1,4-glycol benzaldehyde 0.45 g (2.2 mmol), and the same synthetic procedure was carried out to give the title compound 0.47 g (yield 52%).

1H NMR (δ, DMSO-d ₆ ): 2.22 (s, 3H), 2.42 - 2.45 (M, 4H), 3.25 - 3.33 (M, 4H, H2O overlap), 6.09 (s, 1H), 6.46-6.49 ( M,1H), 6.68 (d, 1H, J = 16.0 Hz), 6.82 (d, 1H, J = 16.0 Hz), 6.97 (d, 2H, J = 9.0 Hz), 7.41 (dd, 1H, J = 1.3) Hz, 8.4 Hz), 7.46-7.48 (M, 1H), 7.52-7.60 (M, 4H), 7.68-7.76 (M, 2H), 11.33 (s, 1H), 15.7-17.1 (br, 1H). Point 65-77 ° C, MS (EI) m / z 413 (M ⁺ ).

(2) 5-[(1E)-2-(1H-indol-6-yl)vinyl]-3-[(1E)-2-[4-(4-methylpiperidyl) Synthesis of -1-yl)phenyl]vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)benzene of Example 1 (3) 400 mg (0.898 mmol) of hexyl-1,6-diene-3,5-dione was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[4-(4 -methylperazine -1-yl)phenyl]heptan-1,6-diene-3,5-dione 0.45 g (1.09 mmol), and the same synthetic procedure was carried out to give the title compound 175 mg (yield 39). %).

1H NMR (δ, DMSO-d ₆ ): 2.22 (s, 3H), 2.43-2.47 (M, 4H), 3.15-3.21 (M, 4H), 6.42 (s, 1H), 6.67 (s, 1H), 6.81-7.13 (M, 5H), 7.16-7.31 (M, 2H), 7.32-7.43 (M, 3H), 7.49-7.57 (M, 1H), 7.50 (s, 1H), 11.10 And 11.12 (eAch s, totAl 1H), 12.78 And 12.79 (eAch s, totAl 1H). Melting point 192-198 ° C, MS (EI) m / z 409 (M ⁺ ).

[Example 103] 5-[(1E)-2-(1H-indol-6-yl)vinyl]-3-[(1E)-2-(4-morpholinylphenyl)vinyl]- Synthesis of 1H-pyrazole

(1) Synthesis of (1E,6E)-1-(1H-indol-6-yl)-7-(4-morpholinylphenyl)heptan-1,6-diene-3,5-dione

20 mg (85 μmol) of 2-methoxy-4-(2-tetrahydrofurylmethoxy)benzaldehyde of Example 1 (2) was replaced with 4-morpholinylbenzaldehyde 0.42 g (2.2 mmol), and The same synthesis operation was carried out to obtain 0.60 g (yield: 68%) of the title compound.

1H NMR (δ, DMSO-d ₆ ): 3.22-3.28 (M, 4H), 3.72-3.76 (M, 4H), 6.10 (s, 1H), 6.47-6.49 (M, 1H), 6.70 (d, 1H) , J = 16.0 Hz), 6.83 (d, 1H, J = 16.0 Hz), 6.98 (d, 2H, J = 9.0 Hz), 7.41 (dd, 1H, J = 1.3 Hz, 8.4 Hz), 7.45-7.48 ( M, 1H), 7.53-7.61 (M, 4H), 7.69-7.71 (M, 1H), 7.73 (d, 1H, J = 16.0 Hz), 11.34 (s, 1H), 15.82-17.02 (br, 1H) Melting point 93-97 ° C, MS (EI) m / z 400 (M ⁺ ). (2) 5-[(1E)-2-(1H-吲哚-6-yl)vinyl]-3-[ Synthesis of (1E)-2-(4-morpholinylphenyl)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)benzene of Example 1 (3) 400 mg (0.898 mmol) of hexyl-1,6-diene-3,5-dione was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-(4-morpholine Phenyl)g-heptyl-1,6-diene-3,5-dione 0.50 g (1.25 mmol), and the same synthetic procedure was carried out to give the title compound 0.26 g (yield 53%).

1H NMR (δ, DMSO-d ₆ ): 3.12-3.17 (M, 4H), 3.72-3.76 (M, 4H), 6.42 (s, 1H), 6.68 (s, 1H), 6.83-7.13 (M, 3H) ), 6.94 (d, 2H, J = 7.7 Hz), 7.17-7.39 (M, 3H), 7.42 (d, 2H, J = 7.7 Hz), 7.49-7.56 (M, 1H), 7.51 (s, 1H) , 11.05-11.17 (M, 1H), 12.80 (s, 1H). Melting point 236-238 ° C, MS (EI) m / z 396 (M ⁺ ).

[Example 104] 3-[(1E)-2-(4-Diethylamino-2-methoxyphenyl)ethenyl]-5-[(1E)-2-(1H-indole- Synthesis of 6-yl)vinyl]-1H-pyrazole

(1) (1E,6E)-1-(4-Diethylamino-2-methoxyphenyl)-7-(1H-indol-6-yl)heptane-1,6-diene- Synthesis of 3,5-dione

By replacing 20 mg (85 μmol) of 2-methoxy-4-(2-tetrahydrofurylmethoxy)benzaldehyde of Example 1 (2) with 4-(diethylamino)-2-methoxybenzene Formaldehyde 0.46 g (2.2 mol) was subjected to the same synthetic procedure to give the title compound (yield: 75%).

1H NMR (δ, DMSO-d ₆ ): 1.14 (t, 6H, J = 7.1 Hz), 3.40-3.46 (M, 4H), 3.88 (s, 3H), 5.99 (s, 1H), 6.20 (d, 1H, J=1.9 Hz), 6.34 (dd, 1H, J=2.6 Hz, 9.0 Hz), 6.46-6.48 (M, 1H), 6.58 (d, 1H, J = 16.0 Hz), 6.81 (d, 1H, J=16.0 Hz), 7.39 (dd, 1H, J=1.3 Hz, 8.3 Hz), 7.44-7.47 (M, 1H), 7.50 (d, 1H, J=9.0 Hz), 7.58 (d, 1H, J= 8.3 Hz), 7.66-7.68 (M, 1H), 7.68 (d, 1H, J = 16.0 Hz), 7.81 (d, 1H, J = 16.0 Hz), 11.31 (s, 1H), 16.00-17.20 (br, 1H). Melting point 61-65 ° C, MS (EI) m / z 416 (M ⁺ ).

(2) 3-[(1E)-2-(4-Diethylamino-2-methoxyphenyl)vinyl]-5-[(1E)-2-(1H-吲哚-6- Synthesis of vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)benzene of Example 1 (3) 400 mg (0.898 mmol) of hexyl-1,6-diene-3,5-dione was replaced by (1E,6E)-1-(4-diethylamino-2-methoxyphenyl)- 7-(1H-Indol-6-yl)heptane-1,6-diene-3,5-dione 0.59 g (1.42 mmol), and the same synthetic procedure was carried out to give the title compound: (Yield 9.4%).

1H NMR (δ, DMSO-d ₆ ): 1.12 (t, 6H, J = 7.1 Hz), 3.38 (q, 4H, J = 7.1 Hz), 3.85 (s, 3H), 6.23 (br s, 1H), 6.27-6.33 (M, 1H), 6.40-6.43 (M, 1H), 6.62 (s, 1H), 6.82 (d, 1H, J = 16.7 Hz), 6.99 (d, 1H, J = 16.1 Hz), 7.19 -7.28(M,3H),7.32-7.38(M,2H),7.49-7.51(M,1H),7.52(d,1H,J=8.4 Hz),11.10(s,1H),12.27-13.07(br , 1H). Melting point 104-108 ° C, MS (EI) m / z 412 (M ⁺ ).

[Example 105] 3-[(1E)-2-(4-dimethylaminophenyl)vinyl]-5-[(1E)-2-(1H-indol-6-yl)vinyl Synthesis of -1H-pyrazole

(1) (1E,6E)-1-(4-Dimethylaminophenyl)-7-(1H-indol-6-yl)heptan-1,6-diene-3,5-dione Synthesis

By replacing 20 mg (85 μmol) of 2-methoxy-4-(2-tetrahydrofurylmethoxy)benzaldehyde of Example 1 (2) with 4-dimethylaminobenzaldehyde 0.33 g (2.2 mol) The same synthesis operation was carried out to obtain 0.63 g (yield: 36%) of the title compound.

1H NMR (δ, DMSO-d ₆ ): 3.00 (s, 6H), 6.07 (s, 1H), 6.47-6.48 (M, 1H), 6.62 (d, 1H, J = 16.0 Hz), 6.74 (d, 2H, J=9.0 Hz), 6.81 (d, 1H, J = 16.0 Hz), 7.40 (dd, 1H, J = 1.3 Hz, 8.3 Hz), 7.45-7.48 (M, 1H), 7.55 (d, 2H, J=9.0 Hz), 7.56 (d, 1H, J = 16.0 Hz), 7.58 (d, 1H, J = 8.3 Hz), 7.68-7.70 (M, 1H), 7.71 (d, 1H, J = 16.0 Hz) , 11.33 (s, 1H), 15.70-17.20 (br, 1H). Melting point 112-119 ° C, MS (EI) m / z 358 (M ⁺ ).

(2) 3-[(1E)-2-(4-Dimethylaminophenyl)vinyl]-5-[(1E)-2-(1H-indol-6-yl)vinyl]- Synthesis of 1H-pyrazole

By (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)benzene of Example 1 (3) 400 mg (0.898 mmol) of hexyl-1,6-diene-3,5-dione was replaced by (1E,6E)-1-(4-dimethylaminophenyl)-7-(1H-indole哚-6-yl)heptane-1,6-diene-3,5-dione 243 mg (0.68 mmol), and the title compound (yield: 28%).

1H NMR (δ, DMSO-d ₆ ): 2.93 (s, 6H), 6.42 (s, 1H), 6.66 (s, 1H), 6.73 (d, 2H, J = 8.3 Hz), 6.75-6.91 (M, 1H), 6.94-7.10 (M, 2H), 7.14-7.31 (M, 2H), 7.32-7.41 (M, 1H), 7.38 (d, 2H, J = 8.3 Hz), 7.49-7.51 (M, 1H) , 7.53 (d, 1H, J = 7.1 Hz), 11.04-11.07 (M, 1H), 12.68-12.80 (M, 1H). Melting point 224-227 ° C, MS (EI) m / z 354 (M ⁺ ) .

[Example 106] 3-[(1E)-2-(4-diethylaminophenyl)vinyl]-5-[(1E)-2-(1H-indol-6-yl)vinyl Synthesis of -1H-pyrazole

(1) (1E,6E)-1-(4-Diethylaminophenyl)-7-(1H-indol-6-yl)heptan-1,6-diene-3,5-dione Synthesis

By replacing 20 mg (85 μmol) of 2-methoxy-4-(2-tetrahydrofurylmethoxy)benzaldehyde of Example 1 (2) with 4-diethylaminobenzaldehyde 0.39 g (2.2 mol) The same synthesis operation was carried out to obtain 0.63 g (yield: 37%) of the title compound.

1H NMR (δ, DMSO-d ₆ ): 1.12 (t, 6H, J = 7.1 Hz), 3.41 (q, 4H, J = 7.1 Hz), 6.06 (s, 1H), 6.46-6.49 (M, 1H) , 6.57 (d, 1H, J = 16.0 Hz), 6.70 (d, 2H, J = 9.0 Hz), 6.81 (d, 1H, J = 16.0 Hz), 7.40 (d, 1H, J = 8.3 Hz), 7.45 -7.47 (M, 1H), 7.51 (d, 2H, J = 9.0 Hz), 7.54 (d, 1H, J = 16.0 Hz), 7.58 (d, 1H, J = 8.3 Hz), 7.68-7.73 (M, 2H), 11.33 (s, 1H), 15.68-17.27 (br, 1H). Melting point 110-118 ° C, MS (EI) m / z 386 (M ⁺ ).

(2) 3-[(1E)-2-(4-Diethylaminophenyl)vinyl]-5-[(1E)-2-(1H-indol-6-yl)vinyl]- Synthesis of 1H-pyrazole

By (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)benzene of Example 1 (3) 400 mg (0.898 mmol) of hexyl-1,6-diene-3,5-dione was replaced by (1E,6E)-1-(4-diethylaminophenyl)-7-(1H-indole哚-6-yl)heptane-1,6-diene-3,5-dione 264 mg (0.68 mmol), m.

1H NMR (δ, DMSO-d ₆ ): 1.10 (t, 6H, J = 7.1 Hz), 3.36 (q, 4H, J = 7.1 Hz), 6.42 (s, 1H), 6.65 (s, 1H), 6.66 (d, 2H, J = 8.3 Hz), 6.71-6.88 (M, 1H), 6.93-7.09 (M, 2H), 7.15-7.30 (M, 1H), 7.27 (d, 1H, J = 8.3 Hz), 7.32-7.38 (M, 3H), 7.50 (s, 1H), 7.53 (d, 1H, J = 8.3 Hz), 11.10 (s, 1H), 12.72 (s, 1H). Melting point 201-204 ° C, MS (EI)m/z 382(M ⁺ ).

[Example 107] 5-[(1E)-2-(1H-indol-6-yl)vinyl]-3-[(1E)-2-[4-(1-piperidinyl)phenyl] Synthesis of vinyl]-1H-pyrazole

(1) (1E,6E)-1-(1H-indol-6-yl)-7-[4-(1-piperidinyl)phenyl]heptan-1,6-diene-3,5- Diketone synthesis

By replacing 20 mg (85 μmol) of 2-methoxy-4-(2-tetrahydrofurylmethoxy)benzaldehyde of Example 1 (2) with 4-(1-piperidinyl)benzaldehyde 0.42 g (2.2 mol), and the same synthesis operation was carried out to obtain the title compound (yield: 74%).

1H NMR (δ, DMSO-d ₆ ): 1.56-1.62 (M, 6H), 3.23 - 3.34 (M, 4H, H ₂ O), 6.08 (s, 1H), 6.47-6.49 (M, 1H), 6.65 (d, 1H, J = 16.0 Hz), 6.82 (d, 1H, J = 16.0 Hz), 6.94 (d, 2H, J = 9.0 Hz), 7.41 (dd, 1H, J = 1.3 Hz, 8.4 Hz) , 7.46-7.48 (M, 1H), 7.52-7.60 (M, 4H), 7.68-7.71 (M, 1H), 7.73 (d, 1H, J = 16.0 Hz), 11.33 (s, 1H), 15.94-17.05 (br, 1H). Melting point 91-96 ° C, MS (EI) m / z 398 (M ⁺ ).

(2) 5-[(1E)-2-(1H-Indol-6-yl)vinyl]-3-[(1E)-2-[4-(1-piperidinyl)phenyl]vinyl Synthesis of -1H-pyrazole

By (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)benzene of Example 1 (3) 400 mg (0.898 mmol) of hexyl-1,6-diene-3,5-dione was replaced by (1E,6E)-1-(1H-indol-6-yl)-7-[4-(1 -piperidinyl)phenyl]heptan-1,6-diene-3,5-dione 580 mg (1.46 mmol), and the same synthetic procedure was carried out to give the title compound 144 mg (yield 25%) ).

1H NMR (δ, DMSO-d ₆ ): 1.52-1.58 (M, 2H), 1.58-1.64 (M, 4H), 3.16-3.22 (M, 4H), 6.40-6.44 (M, 1H), 6.67 (s) , 1H), 6.79-7.10 (M, 3H), 6.92 (d, 2H, J = 9.0 Hz), 7.16-7.30 (M, 1H), 7.26 (d, 1H, J = 7.7 Hz), 7.31-7.41 ( M, 3H), 7.49-7.51 (M, 1H), 7.53 (d, 1H, J = 7.7 Hz), 11.10 (s, 1H), 12.77 (s, 1H). Melting point 189-191 ° C, MS (EI )m/z 394(M ⁺ ).

[Example 108] 3-[(1E)-2-[4-diethylamino-2-(2-pyridylmethoxy) Synthesis of Phenyl]vinyl]-5-[(1E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazole

Synthesis of (1) 4-Diethylamino-2-(2-pyridylmethoxy)benzaldehyde

2.8 g (15.3 mmol) of 1-(2-chloroethyl)piperidine hydrochloride of Example 97 (1) was replaced with 1.8 g (10.9 mmol) of 2-chloromethylpyridine hydrochloride, and The same amount of the relationship was subjected to a synthesis operation to obtain a quantitative title compound of 2.9 g.

¹ H NMR (δ, deuterated chloroform): 1.16 (t, J = 7.1 Hz, 6H), 3.36-3.41 (M, 4H), 5.38 (s, 2H), 6.13 (d, J = 2.3 Hz, 1H) , 6.31 (dd, J = 2.1 Hz, 9.0 Hz, 1H), 7.30-7.33 (M, 1H), 7.70-7.74 (M, 2H), 7.81-7.85 (M, 1H), 8.59-8.61 (M, 1H) ), 10.26 (s, 1H). Melting point 78-81 ° C, MS (EI) m / z 284 (M +).

(2) (1E,6E)-1-[4-Diethylamino-2-(2-pyridylmethoxy)phenyl]-7-(1H-indol-6-yl)heptane-1 Synthesis of 6-diene-3,5-dione

By replacing 20 mg (85 μmol) of 2-methoxy-4-(2-tetrahydrofurylmethoxy)benzaldehyde of Example 1 (2) with 4-diethylamino-2-(2-pyridyl) 0.39 g (1.4 mmol) of methoxy)benzaldehyde, and the same synthetic procedure was carried out to give the title compound (yield: 90%).

1H NMR (δ, DMSO-d ₆ ): 1.05 (t, 6H, J = 7.1 Hz), 3.36 (q, 4H, J = 7.1 Hz), 5.33 (s, 2H), 5.96 (s, 1H), 6.25 (d, 1H, J = 2.6 Hz), 6.34 (dd, 1H, J = 2.6 Hz, 9.0 Hz), 6.46-6.48 (M, 1H), 6.66 (d, 1H, J = 16.0 Hz), 6.81 (d) , 1H, J = 16.0 Hz), 7.35-7.39 (M, 1H), 7.40 (dd, 1H, J = 1.3 Hz, 8.3 Hz), 7.44 - 7.47 (M, 1H), 7.51 - 7.55 (M, 2H) , 7.58 (d, 1H, J = 8.3 Hz), 7.66-7.71 (M, 2H), 7.86-7.93 (M, 2H), 8.60-8.63 (M, 1H), 11.32 (s, 1H), 16.00-17.20 (br, 1H). Melting point 92-96 ° C, MS (EI) m / z 493 (M ⁺ ).

(3) 3-[(1E)-2-[4-Diethylamino-2-(2-pyridylmethoxy)phenyl]vinyl]-5-[(1E)-2-(1H Synthesis of -吲哚-6-yl)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofurylmethoxy)benzene of Example 1 (3) 400 mg (0.898 mmol) of hexyl-1,6-diene-3,5-dione was replaced by (1E,6E)-1-[4-diethylamino-2-(2-pyridylmethoxy) Benzyl]-7-(1H-indol-6-yl)hepta-1,6-diene-3,5-dione 280 mg (0.57 mmol), and the same synthetic operation was carried out to give the following The title compound was 24 mg (yield 8.6%).

1H NMR (δ, DMSO-d ₆ ): 1.03 (t, 6H, J = 7.7 Hz), 3.30 (t, 4H, J = 7.7 Hz), 5.29 (s, 2H), 6.23-6.26 (M, 1H) , 6.27-6.32 (M, 1H), 6.4 _1-6 .43 (M, 1H), 6.61 (s, 1H), 6.87 (d, 1H, J = 16.7 Hz), 7.00 (d, 1H, J = 16.7) Hz), 7.20-7.41 (M, 6H), 7.48-7.52 (M, 1H), 7.52 (d, 1H, J = 8.4 Hz), 7.55-7.59 (M, 1H), 7.87 (dt, 1H, J = 1.9 Hz, 7.7 Hz), 8.58-8.62 (M, 1H), 11.10 (s, 1H), 12.33-13.13-(br, 1H). MS (EI) m/z 489 (M ⁺ ).

[Example 109] 3-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-5-[(1E)-2-phenyl Synthesis of vinyl]-1H-pyrazole

(1) (1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-phenylheptan-1,6-diene-3,5- Diketone synthesis

By substituting 20 mg (0.14 mmol) of 1H-benzotriazole-5-carboxycarboxaldehyde of Example 30 (2) to benzaldehyde 15 mg (0.14 mmol), and performing the same synthetic procedure to give the title compound 3.9 mg. Rate 7%).

(2) 3-[(1E)-2-[2-Methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-5-[(1E)-2-phenylvinyl Synthesis of -1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-benzene 13 mg (31 μmol) of hexyl-1,6-diene-3,5-dione, and the same synthetic procedure was carried out to give the title compound 8.6 mg (yield: 67%) of the title compound as a yellowish white powder.

¹ H NMR (δ, acetone-d ₆ ): 5.22 (s, 2H), 6.65 (dd, J = 2.4, 8.5 Hz, 1H), 6.71 (s, 1H), 6.74 (d, J = 2.4 Hz, 1H) ), 7.06 (d, J = 17 Hz, 1H), 7.15 (d, J = 17 Hz, 1H), 7.23 (d, J = 17 Hz, 1H), 7.22 - 7.42 (M, 5H), 7.53 (d) , J = 8.5 Hz, 1H), 7.54 - 7.59 (M, 2H), 7.82 (dt, J = 1.7, 7.7 Hz, 1H), 8.58 (br d, J = 5 Hz, 1H). Melting point 143-146 °C, MS (ESI+) m/z 410 2 (M+1).

[Example 110] 3,5-bis[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy) Synthesis of phenyl]vinyl]-1H-pyrazole

In Example 30 (1), a by-produced (1E,6E)-1,7-bis[2-methoxy-4-(2-pyridylmethoxy)phenyl]heptane-1,6-di was obtained. Alkene-3,5-dione 149 mg.

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1,7-bis[2-methoxy-4-(2-pyridylmethoxy)phenyl]g -1,6-Diene-3,5-dione 27.5 mg (50.0 μmol), and the same synthetic procedure was carried out to give the title compound (yield: 13%) of the title compound.

¹ H NMR (δ, acetone-d ₆ ): 5.22 (s, 4H), 6.63 (s, 1H), 6.68 (dd, J = 2.4, 8.3 Hz, 2H), 6.73 (d, J = 2.4 Hz, 2H ), 7.05 (d, J = 17 Hz, 2H), 7.31 (M, 2H), 7.37 (d, J = 17 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.56 (M, 2H) ), 7.82 (dt, J = 1.7, 7.7 Hz, 2H), 8.58 (br d, J = 5 Hz, 2H). Melting point 195-197 ° C, MS (ESI+) m/z 547.3 (M+1).

[Example 111] 3-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-5-[(1E)-2-(3) Synthesis of -amino-4-hydroxy-phenyl)vinyl]-1H-pyrazole

(1) (1E, 6E)-1-(Benzene Synthesis of oxazol-5-yl)-7-(1H-indol-6-yl)heptane-1,6-diene-3,5-dione

By replacing 4-(2-pyridylmethoxy)benzaldehyde 29 mg (0.14 mmol) of Example 16 (1) with benzo The azole-5-carboxycarboxaldehyde 40 mg (0.27 mmol) was subjected to a synthetic operation in the same amount to give the title compound 10.1 mg (yield 8%).

(2) 3-[(1E)-2-(3-Amino-4-hydroxyphenyl)vinyl]-5-[(1E)-2-(1H-indol-6-yl)vinyl] -1H-pyrazole synthesis

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1-(benzo Oxazol-5-yl)-7-(1H-indol-6-yl)hepta-1,6-diene-3,5-dione 8.0 mg (18 μmol), and the synthesis operation is carried out in the same amount relationship. There was obtained 3.4 mg (yield: 44%) of the title compound as white powder.

¹ H NMR (δ, acetone-d ₆ ): 3.89 (s, 3H), 5.21. (s, 2H), 6.61 (s, 1H), 6.64 (dd, J = 2.2, 8.5 Hz, 1H), 6.66 (dd , J = 1.7, 8 Hz, 1H), 6.71 (d, J = 8 Hz, 1H), 6.73 (d, J = 2 Hz, 1H), 6.85 (d, J = 17 Hz, 1H), 6.94 (d , J = 1.8 Hz, 1H), 7.02 (d, J = 17 Hz, 1H), 7.03 (d, J = 17 Hz, 1H), 7.31 (dd, J = 5, 7 Hz, 1H), 7.35 (d , J=17 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.56 (br d, J=7.8 Hz, 1H), 7.81 (dt, J=1.7, 7.7 Hz, 1H), 8.58 ( Br d, J=5 Hz, 1H). Melting point 123-126 ° C, MS (ESI+) m/z 441.3 (M+1).

[Example 112] Synthesis of 3,5-bis[(1E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazole

By (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]heptane-1 of Example 4(4), 6-diene-3,5-dione 15 mg (35 μmol) was replaced by (1E,6E)-1,7-bis(1H-indol-6-yl)heptane-1,6-diene-3,5 -1,1 mg (50.0 μmol) of the diketone, and the same synthetic procedure was carried out to give the title compound 9.2 mg (yield: 53%) of the title compound.

¹ H NMR (δ, acetone-d ₆ ): 6.46 (dd, J = 0.9, 3.1 Hz, 2H), 6.74 (s, 1H), 7.10 (d, J = 17 Hz, 2H), 7.30 (d, J) =17 Hz, 2H), 7.32 (d, J = 1.6, 8.4 Hz, 2H), 7.35 (d, J = 3.1 Hz, 2H), 7.56 (d, J = 8 Hz, 2H), 7.57 (br s, 2H), 10.3 (br s, 2NH). Melting point 289-291 ° C, MS (ESI+) m/z 351.1 (M+1).

[Pharmacological Test Example 1] Determination of Tau Agglutination Inhibition

The recombinant protein of the Tau microtubule domain repeat sequence (3R-MBD) was expressed, purified and used using Escherichia coli (E. coli). The purified Tau solution was diluted with 50 mM Tris-HCl buffer (pH 7.6) to a final concentration of 10 μM. The test compound was prepared by dimethyl hydrazine (DMSO) to a final concentration of 20 times and added as 5% DMSO. Heparin was added at a final concentration of 10 μM, and after standing at 37 ° C for 16 hours, thioflavin T was added in a manner of 10 μM, and a fluorescence plate reader was used (Bajin Love) The fluorescence intensity (excitation wavelength 440 nm, measurement wavelength 480 nm) was measured.

The final concentration at the time of measurement of each compound was set to 0.1, 0.3, 1, 3, and 10 μM. As a negative contrast, when only DMSO was added, the effect of inhibiting the fluorescence intensity was set to 0%, and the 50% inhibitory concentration (IC50) of each compound hindrance was determined. The test results are shown in Table 1. Further, the inhibitory actions of the compounds of Example 109, Example 110, and Example 112 at 1 μM were 0%, 0%, and 24%, respectively.

Further, a part of the sample which was allowed to stand for 16 hours after the addition of heparin was observed with an electron microscope. The sample was added to a grid, washed with distilled water, washed with a 1 mM aqueous solution of phosphotungstic acid, and dried overnight to observe. The result is shown in Fig. 1. When the sample to which the compound of Example 2 was added was compared with the sample to which only DMSO was added, the aggregation of Tau was small and aggregation was suppressed.

[Pharmacological Test Example 2] Determination of β-secretase inhibition

The β-secretase inhibitory action was measured using a BACE-1 ENER assay kit (Invitrogen). The test compound was prepared by dissolving DMSO to 30 times the final concentration and then dissolving it in 10%. In this solution, human recombinant β-secretase (1 U/mL) and fluorescent matrix peptide (2.5 nM) dissolved in assay buffer were added in equal amounts each time, and allowed to stand for 1 hour. The fluorescence intensity (excitation wavelength 545 nM, measurement wavelength 590 nM) was measured by a disk fluorescence analyzer.

The final concentration of each compound was determined to be 0.1, 0.3, 1, 3, 10, or 0.3, 1, 3, 10, 30, or 1, 3, 10, 30, 100 μM. As a negative control, only DMSO was added, and the effect of inhibiting the fluorescence intensity was set to 0%, and the 50% inhibitory concentration (IC50) of each compound was calculated. Fluorescent matrix peptide The amino acid sequence of Ser-Glu-Val-Asn-Leu-Asp-Ala-Glu-Lys-Arg, and the Ser residue of the first residue is identified by the fluorescent donor (Cy3), respectively, in the ninth Lys is identified by a fluorescent extinction (Cy5Q). The 50% inhibitory concentration (IC50) of each compound was calculated. The test results are shown in Table 1. The hindrance effects of the compounds of Example 109, Example 110, and Example 112 at 1 μM were 12%, 12%, and 30%, respectively.

[Pharmacological Test Example 3] Determination of Aβ agglutination inhibition

Aβ 1-42 (manufactured by Peptide Research Institute) was dissolved in 0.3% ammonia water to be 0.5 mM, and then diluted to 20 μM with PBS. The test compound was adjusted to 2% of the final concentration in DMSO. The Aβ solution was mixed with the test compound solution in equal amounts and incubated at 37 ° C for 24 hours. In addition, a thioflavin T solution adjusted to 6 μM in 100 mM Tris-glycine buffer (pH 8.5) was added in an equal amount, and the fluorescence intensity (excitation wavelength) was measured by a disk type fluorescence analyzer. 440 nM, measurement wavelength 480 nM).

The final concentration at the time of measurement of each compound was set to 0.1, 0.3, 1, 3, and 10 μM. As a negative control, only DMSO was added, and the effect of inhibiting the fluorescence intensity was set to 0%. The 50% inhibitory concentration (IC50) of each compound was calculated by the effect of blocking the fluorescence intensity at 0%. The test results are shown in Table 1. Further, the blocking effect of the compound of Example 112 at 3 μM was 17%.

The compound having the structure represented by the above formula (I) as described above is compared with the curcumin which does not have a pyrazole ring, and the like, in the inhibition of Tau agglutination protein, the inhibition of β-secretase, and the inhibition of A β aggregation. At least one of them exhibits a remarkable superior effect, so that its structural system is considered to be closely related to the inhibition of Tau agglutination protein.

[Pharmacological Test Example 4] Evaluation of drug body dynamics

Oral administration of test compound 50 mg/kg-bw (po) or intravenous administration of 1 mg/kg-bw (iv) in SD mice (male, 7 weeks old), measured in blood and brain after 3 hours concentration. The medium was administered as an 80% aqueous solution of PEG400. Blood was collected under isoflurane inhalation anesthesia, and brain extraction was further performed after death. In the blood, the plasma was separated, and the brain was added with 3 times the amount of PBS and homogenized, and then methanol was added to adjust the sample for measurement. The measurement was carried out by LC-MS/MS (Applied Biosystems and Waters Corporation).

Compound of Example 2 (2) ((1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl The concentration of blood in the case of orally administered (po) of the compound of Example 2 and the compound of Example 2 is shown in Figure 2, intravenously administered (iv) The change in brain concentration at the time of oral administration (po) is shown in Table 2. The compound of Example 2 was higher in the blood concentration and the brain concentration than the compound of Example 2 (2).

[Pharmacological Test Example 5] Determination of Aβ agglutination inhibition and production inhibition in mice by oral administration

The compound of Example 2 was orally administered in APPswe/PS1dE9 Tg mice (male, 10 to 12 months old, n = 8 to 10), and the Aβ concentration in the brain was measured. The medium was administered as an 80% PEG400 aqueous solution, and the dosage was adjusted to 10 mL/kg-bw/day, and the amount was adjusted to 25 mg/kg-bw/day and 50 mg/kg-bw/day. The vehicle group was administered with an 80% PEG400 aqueous solution at 10 mL/kg-bw/day. The administration was continued by oral administration for 4 weeks using an oral nasogastric tube (manufactured by Sakae Machine Co., Ltd.). After the end of the administration period, the brain after death was anesthetized with pentobarbital anesthesia, and 10 times the amount of phosphate buffer (pH 7.4) was added and homogenized, and the homogenate was 16,000 g. Centrifuge at 4 ° C for 1 hour. The centrifuged supernatant was used as a soluble protein sample. The pellet was resuspended with 70% formic acid and neutralized by adding a 20-fold amount of 0.9 M Tris buffer (pH 12.0) as a sample of insoluble protein. The measurement of Aβ was carried out using a β-amyloid protein 1-42 ELISA kit (manufactured by Wako Pure Chemical Industries, Ltd.). 100 μL of each of the sample diluted with the standard dilution and the standard dilution series of the standard curve was added to the primary antibody solid phase plate, and allowed to stand overnight at 4 ° C. After washing 5 times with the washing buffer, 100 μL of the HRP-labeled secondary antibody solution was added, and the mixture was allowed to stand at 4 ° C for 1 hour. After washing again with washing buffer 5 times, the TMB solution was added, and a color reaction was carried out for 20 minutes. The color reaction was stopped by adding 100 μL of the reaction stop solution. The absorbance at 450 nm was measured with a micro disk analyzer (manufactured by Bio-Rad Co., Ltd.). The Aβ concentration was calculated based on the measured value of the standard dilution series.

The test results are shown in Figure 3. It was confirmed that the administration group of the compound of Example 2, the insoluble and soluble A β 1-42 amount in the brain decreased with the amount (the graph value is the mean ± SEM, **p < 0.01, and the significant difference test was used. One Way ANOVA method).

[Pharmacological Test Example 6] Determination of Tau Agglutination Inhibition Effect in Oral Administration of Mice

The compound of Example 2 was orally administered to TauN279K Tg mice (male, 8 months old, n=8), and the Tau concentration in the brain was measured. The medium was administered as an 80% PEG400 aqueous solution, and the dosage was adjusted to 10 mL/kg-bw/day, and the dosage was adjusted to 10, 20, 40 mg/kg-bw/day. The vehicle liquid group was administered with an 80% PEG400 aqueous solution at 10 mL/kg-bw/day. The positive control compound group was adjusted to adjust methylene blue (MB; Methylene Blue) to 40 mg/kg-bw/day and administered. The administration was continued by oral administration for 4 weeks using an oral nasogastric tube (manufactured by Sakae Machine Co., Ltd.). At the end of the administration period, the brain after death was anesthetized with pentobarbital, and a 5-fold high-salt buffer (0.8 M sodium chloride, 1 mM EGTA, 10 mM Tris-HCl, 10%) was added. Sucrose was homogenized, and sodium N-dodecyl sarcosinate (Sarcosyl) was added to make it 1%, and after incubation at 37 ° C for 1 hour, it was centrifuged at 100 ° 000 g for 1 hour at 4 ° C. The pellet was resuspended in extraction buffer (4 M guanidine, 50 mM Tris-HCl) and diluted with 50 mM Tris-HCl buffer as a sample of N-dodecyl sarcosinate insoluble protein. The measurement of Tau was performed using a human ELISA kit (manufactured by Invitrogen). 100 μL of each of the sample diluted with the standard dilution and the standard dilution series for the standard curve was added to the primary antibody immobilization plate, and allowed to stand at 4 ° C overnight. After washing with washing buffer, add secondary antibody solution 100μ L, allowed to stand at 4 ° C for 1 hour. After washing again, the HRP-labeled anti-IgG antibody solution was added and allowed to stand for 30 minutes. After washing again, the TMB solution was added to carry out a color reaction for 20 minutes. 100 μL of the reaction stop solution was added to stop the color reaction, and the absorbance at 450 nm was measured with a microplate reader. The Tau concentration was calculated based on the measured value of the standard dilution series.

The results of the test regarding the amount of insoluble Tau in the brain of mice are shown in Fig. 4. It was confirmed that in the administration group of the compound of Example 2, the amount of N-dodecyl sarcosinate-insoluble Tau in the brain decreased with the amount (the graph value is mean ± SEM, **p < 0.01, significant difference) The assay uses a single factor analysis of variance).

(the possibility of industrial use)

Since the compound of the present invention is used as a prophylactic or therapeutic drug for Alzheimer's disease, the present invention can be utilized in industrial fields such as pharmaceuticals.

Since the diagram of this case is an electron micrograph of the sample, a blood concentration shift diagram of the compound, a graph of the amount of A β 1-42 in the mouse brain, and the amount of insoluble Tau, it is not representative of the technical characteristics of the case, and is not representative of the case. Figure. Therefore, there is no designated representative map in this case.

Claims (22)

a compound represented by the following formula (I) or a salt thereof, Wherein R represents hydrogen, a chain-like or cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and Ar ¹ and Ar ² may be the same or different and each represents a homocyclic group which may have a substituent; Or a heterocyclic group; except that R is hydrogen, and Ar ¹ and Ar ² are all 4-hydroxy-3-methoxyphenyl groups. The compound of the above formula (I) or a salt thereof, wherein R of the above formula (I) is hydrogen. The compound of the above formula (I) or a salt thereof, wherein Ar ¹ of the above formula (I) is a phenyl group which may have a substituent. The compound of the above formula (I) or the salt thereof, wherein Ar ¹ of the above formula (I) is a phenyl group having a C _1-3 alkyloxy group which may have a substituent. The compound of the above formula (I) or the salt thereof, wherein Ar ¹ of the above formula (I) is a C _1-3 alkyl group substituted with a heterocycloalkyl group which may have a substituent the phenyl group, an alkyl group having _1-3 via the phenyl may have a substituent of the cycloalkyl substituted C, alkyl group having _1-3 via the heteroaryl may have a substituent group of the aryl group substituted with C the phenyl group, an alkyl group having _1-3 may have a substituent by the aryl group of the substituted phenyl group of the C _1-3 alkyl group, a substituted of the dialkylamino group of the by substituent may have C a phenyl group, a phenyl group, an alkyl group of _1-3 or a phenyl group having a substituent of the via may have the alkyl group substituted by C _1-3 alkyl group may have a substituent of substituent group of the alkyl group C . The compound of the above formula (I), wherein Ar ¹ has a tetrahydrofuran-3-ylmethoxy group, a tetrahydrofuran-2-ylmethoxy group, or a salt thereof, according to the above formula (I), 2-(piperidin-1-yl)ethoxy, 2-(4-methylpiperidine Ethyloxy, 2-(4-benzylidene) Ethyloxy, 2-morpholinylethoxy, 2-pyrrolidylethoxy, β-D-glucopyranosyloxy, 2-[4-(t-butoxycarbonyl)per -1-yl]ethoxy, 2-[4-(methylsulfonyl)per -1-yl]ethoxy or 2-[4-(2-hydroxyethyl)per -1-yl] ethoxyl phenyl. The compound of the above formula (I) or the salt thereof, wherein Ar ¹ of the above formula (I) is 2-methoxy-4-(tetrahydrofuran-3-ylmethoxy)benzene , 2-methoxy-4-(tetrahydrofuran-2-ylmethoxy)phenyl, 2-methoxy-4-[2-(piperidin-1-yl)ethoxy]phenyl, 2 -methoxy-4-[2-(4-methylperazine) Ethyloxy]phenyl, 2-methoxy-4-(2-morpholinylethoxy)phenyl, 4-(β-D-glucopyranosyl)oxy-2-methoxy Phenyl, 4-(tetrahydrofuran-3-ylmethoxy)phenyl, 4-(tetrahydrofuran-2-ylmethoxy)phenyl, 3-methoxy-4-(tetrahydrofuran-3-ylmethoxy) Phenyl, 3-methoxy-4-(tetrahydrofuran-2-ylmethoxy)phenyl, 2-[2-(4-benzylmethyl) Ethyl]-4-methoxyphenyl, 4-diethylamino-2-(2-morpholinylethoxy)phenyl, 4-dimethylamino-2-(2 -morpholinylethoxy)phenyl, 4-diethylamino-2-(2-morpholinylethoxy)phenyl, 4-diethylamino-2-(2-pyrrolidinyl) Ethoxy)phenyl or 4-diethylamino-2-[2-(piperidin-1-yl)ethoxy]phenyl. The compound of the above formula (I), wherein Ar ¹ has a pyridin-2-ylmethoxy group, a pyridin-3-ylmethoxy group, or a salt thereof, or a salt thereof. A phenyl group of pyridin-4-ylmethoxy or 1-pyrrolylmethoxy. The compound of the above formula (I) or the salt thereof, wherein Ar ¹ of the above formula (I) is 4-(pyridin-2-ylmethoxy)phenyl, 2-methoxy 4--4-pyridin-2-ylmethoxy)phenyl, 2-[2-(piperidin-1-yl)ethoxy]-4-(pyridin-2-ylmethoxy)phenyl, 2-(2-morpholinylethoxy)-4-(pyridin-2-ylmethoxy)phenyl, 2-(2-pyrrolidinylethoxy)-4-(pyridin-2-ylmethyl) Oxy)phenyl, 2-[2-(4-methylper Ethyl]-4-(pyridin-2-ylmethoxy)phenyl, 3-methoxy-4-(pyridin-2-ylmethoxy)phenyl, 2-hydroxy-4-( Pyridin-2-ylmethoxy)phenyl, 3-(pyridin-2-ylmethoxy)phenyl, 2-methoxy-3-(pyridin-2-ylmethoxy)phenyl, 4- Methoxy-3-(pyridin-2-ylmethoxy)phenyl, 3-methoxy-5-(pyridin-2-ylmethoxy)phenyl, 2-methoxy-5-(pyridine -2-ylmethoxy)phenyl, 2-(pyridin-2-ylmethoxy)phenyl, 4-methoxy-2-(pyridin-2-ylmethoxy)phenyl, 5-methyl Oxy-2-(pyridin-2-ylmethoxy)phenyl, 2-nitro-5-(pyridin-3-ylmethoxy)phenyl, 4-diethylamino-2-(pyridine -3-ylmethoxy)phenyl or 2-methoxy-2-(1-pyrrolylmethoxy)phenyl. The compound of the above formula (I), wherein Ar ² is a bicyclic homocyclic ring group or a heterocyclic group which may have a substituent, is a compound of the above formula (I) or a salt thereof. The compound of the above formula (I), wherein Ar ² is a bicyclic heterocyclic group which may have a substituent, or a salt thereof, according to any one of the above claims. The compound of the above formula (I) or the salt thereof, wherein Ar ² of the above formula (I) is indole-2-yl, indol-3-yl, indol-4-yl, anthracene -5-yl, indol-6-yl, indol-7-yl, benzotriazol-5-yl, benzimidazol-5-yl, quin Polin-6-yl, benzofuran-2-yl, benzothiophen-2-yl, 1H-indazol-5-yl, 7-azaindole-3-yl, quinolin-2-yl, quin Porphyrin-5-yl, quinoline-8-yl, 1,4-benzoic Alkan-6-yl, 1,3-benzoic Zyrid-5-yl, chromone-3-yl, coumarin-6-yl, 7-methoxycoumarin-4-yl or 4-methoxycoumarin-6-yl. The compound of the above formula (I) or the salt thereof, wherein the Ar ² of the above formula (I) has a methyl group, an ethyl group, a benzyl group, an ethyl fluorenyl group, a benzamidine group, and a third group. A bicyclic heterocyclic group of an oxycarbonyl group, a methanesulfonyl group, a p-toluenesulfonyl group, a hydroxyl group or a nitro group. The compound of the above formula (I) or the salt thereof, wherein Ar ² of the above formula (I) is 1-methyl-indol-6-yl or 1-methylindol-2-yl, 1-methylindol-3-yl, 1-ethylindol-6-yl, 1-benzylmethylindol-3-yl, 1-phenylmethylindol-6-yl, 1-ethylindole吲哚-3-yl, 1-ethylindolyl-6-yl, 1-benzylidenyl-3-yl, 1-tert-butoxycarbonylindole-5-yl, 1- Methanesulfonyl-3-yl, 1-methylsulfonyl-6-yl, 1-p-toluenesulfonyl-3-yl, 1-p-toluenesulfonylhydrazone- 6-yl, 4-hydroxyindol-3-yl or 4-nitroindol-3-yl. A Tau agglutination inhibitor, which comprises the compound according to any one of claims 1 to 14 or a salt thereof as an active ingredient. A β-secretase inhibitor, which contains the first item of the patent application scope to The compound according to any one of the items 14 or a salt thereof as an active ingredient. A β-amyloid agglutination inhibitor, which comprises the compound of any one of the above-mentioned items of claim 1 or a salt thereof as an active ingredient. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 or a salt thereof as an active ingredient. A pharmaceutical composition according to claim 18, which is for use in the prevention or treatment of a disease in which Tau, β-secretase or β-amyloid is involved. A pharmaceutical composition according to claim 18, which is for use in the prevention or treatment of Alzheimer's disease. An oral or parenteral preparation, which is a compound according to any one of claims 1 to 14, or a salt thereof, and one or more pharmacologically acceptable carriers. a compound represented by the following formula (II) or a salt thereof, [wherein, Ar ³ and Ar ⁴ may be the same or different and each represents a homocyclic group or a heterocyclic group which may have a substituent, (i), (i) Ar ³ is an aryl or heteroaryl group which may have a substituent, Ar ⁴ is a phenyl group having a substituent having an electron withdrawing group at the 2-position, a 1H-inden-2-yl group of the substituent, a 1H-indol-3-yl group, a 1H-indol-4-yl group, 1H-indol-5-yl, 1H-indol-6-yl or 1H-indol-7-yl, and (ii) Ar ³ is phenyl which may be substituted by hydroxy, methoxy or ethoxylated oxy group Ar ⁴ is phenyl, 4-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-hydroxyphenyl, 4-ethenylamino Phenyl, 3,4-difluorophenyl, 2,4-dichlorophenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxy Phenyl, 3,5-dimethoxyphenyl, 3,4-dihydroxyphenyl, 3-fluoro-4-hydroxyphenyl, 2-hydroxy-5-methoxyphenyl, 3-hydroxy- 4-methoxyphenyl, 3-hydroxy-5-methoxyphenyl, 3-methoxy-4-nitrophenyl, 4-ethyloxy-3-methoxyphenyl, 4- Dimethylamino-3-methoxyphenyl, 4-hydroxy-3-nitrophenyl, 2-methoxynaphthalen-1-yl, 6-methoxynaphthalen-2-yl, 1H-pyrrole -2-yl, pyridin-2-yl, 1H-imidazol-2-yl, 1-methyl-1H-pyrrol-2-yl, 9-ethyl-9H-carbazol-3-yl, 1-methyl Except for -1H-indol-3-yl, 1H-indol-3-yl, 1H-indol-5-yl or 1H-indol-6-yl).