JP2005350363A - 4-trifluoromethylpyrimidine derivative as inducing or induction accelerator of hemoxygenase - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new inducing agent or inducing accelerator of hemoxygenase. <P>SOLUTION: This 4-trifluoromethylpyrimidine derivative expressed by general formula (1) [wherein, X is phenyl having a substituent, a heteroaromatic ring which may have a substituent, general formula (1a) or general formula (1b)(in the specification); Y is hydroxy, a 2-6C cyclic or non-cyclic amino group which may have a substituent or general formula (1c)(in the specification); Z is -CH=CH-, -C≡C-, -CH<SB>2</SB>CH<SB>2</SB>-, -CH<SB>2</SB>O- and -CONH-] and the inducing agent or inducing accelerator of the hemoxygenase containing the same as an active ingredient are provided. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

で表される４−トリフルオロメチルピリミジン誘導体およびそれらの薬理学的に許容しうる塩並びにその水和物およびこれら４−トリフルオロメチルピリミジン誘導体、その塩、その水和物のうちの少なくとも一種類以上を有効成分として含有するヘムオキシゲナーゼの誘導剤または誘導促進剤に関する。 The present invention relates to an inducer or inducer of heme oxygenase, and in detail, the following general formula (1)

4-trifluoromethylpyrimidine derivatives represented by the above and their pharmacologically acceptable salts and hydrates thereof, and at least one of these 4-trifluoromethylpyrimidine derivatives, salts and hydrates thereof The present invention relates to heme oxygenase inducers or inducers containing the above as active ingredients.

Heme oxygenase (hereinafter abbreviated as HO) is a rate-limiting enzyme that works in the first stage of heme metabolism, and is an enzyme that breaks down intracellular free heme into carbon monoxide, iron, and biliverdin. Biliverdin is further converted to bilirubin by biliverdin reductase. Three isozymes of HO-1, HO-2 and HO-3 are known for HO. HO-1 is an inducible enzyme that is induced by a wide range of compounds and pathological conditions, such as oxidative stress, heat shock, cytokines, metalloporphyrins, heavy metals, xenobiotics, hormones, etc. It is thought to play an important role in the maintenance and recycling of iron. HO-1 is widely present in mammalian tissues, but is known to be induced at sites of oxidative stress during inflammation and ischemia reperfusion. Furthermore, HO-1 induction is considered to be part of the intrinsic defense mechanism against cell damage, based on studies in various inflammation models. Biliverdin and bilirubin produced by HO have anti-oxidant and anti-complement effects, CO functions as an intracellular transmitter, and iron functions as a gene regulator. Is considered.
HO-2 is a non-inducible enzyme that is present in large amounts in the brain and testis, and is not induced except by glucocorticoids.
HO-3 is structurally related to HO-2, but details are not disclosed. The activity as a catalyst is relatively weak and is considered to be involved in the binding of hemes.
Several reports have been made on the relationship between induction of HO-1 and pathological conditions. When HO-1 is induced with iron protoporphyrin, which is an HO-1 inducer, increase in pleural effusion volume and number of inflammatory cells in pleural effusion is suppressed in the carrageenan pleurisy model. In contrast, it has been reported that the inflammatory reaction is exacerbated by the administration of tin protoporphyrin, which is an HO inhibitor (Non-patent Document 1). It has been reported that overexpression of HO-1 suppresses neutrophil infiltration into the airway and improves airway hypersensitivity in a mouse model of airway inflammation caused by ozone exposure (Non-patent Document 2). In addition, epidemiological survey results have been reported that humans with low genetic expression of HO-1 are likely to develop chronic obstructive pulmonary disease (hereinafter abbreviated as COPD) (Non-patent Document 3). It has also been reported that the increase in the number of eosinophils is suppressed by induction of HO-1 in a mouse asthma model (Non-patent Document 4). Furthermore, the expression of HO-1 acts as a tissue protective effect during high oxygen load (Non-Patent Document 5), heart transplantation (Non-Patent Document 6), and cerebral vasospasm (Non-Patent Document 7), which is advantageous for the living body. Has been reported to work.

In recent years, a congenital HO-1 deficiency, which is the world's first human case, has been reported (Non-patent Document 8). Patient reported various clinical symptoms such as persistent fever, hepatic hypertrophy, joint pain, rash, hemolytic anemia, abnormal coagulation and fibrinolysis system, etc. from around 2 years old, and reported death at the age of 6 with hypertension and intracranial hemorrhage Has been. On the other hand, Poss et al. Produced and analyzed HO-1 knockout mice (Non-patent Document 9). HO-1 knockout mice showed anemia due to impaired iron reuse, iron deposition in tissues, and impaired growth. In addition, it was considered that this mouse had a very high fetal mortality rate and markedly reduced resistance to infection stress. Based on these information, HO-1 plays an important role in the defense of the body, and it is assumed that this deficiency causes not only oxidative stress but also the defense mechanism of the body, resulting in various complications.
By the way, there has been no report that a 4-trifluoromethylpyrimidine derivative induces HO-1. Compounds that show induction of HO-1 include leminoprazole (Patent Document 1), nicotinamide derivatives (Patent Document 2), prostaglandin A and agonists thereof, vitamin B12, hemin and fragments and analogs thereof (Patent Document 3). ) And pyridine derivatives and imidazole derivatives have been reported (Non-Patent Document 10), both of which are different in structure from 4-trifluoromethylpyrimidine derivatives.
Moreover, although antiviral agents and cancer chemotherapeutic agents (Non-Patent Documents 11 and 12) are known as pyrimidine derivatives, there is no description regarding HO-1 activation, and the structure is also different.

JP 2000-119182 A WO 0168094 WO 9609038 Willis, D, et al: Nature Medicine 2, 87-90 (1996) Hisada, T, et al: Eur. J. Pharmacol., 399, 229-234 (2000) Yamada, N. et al: Am. J. Hum. Genet., 66, 187-195 (2000) Suzuki, M. et al: Breathing, Vol. 19, No. 2, S37-S38 (2000) Otterbein L. E. et al: J. Clin. Invest., 103, 1047-1054 (1999) Coito, A. J. et al: Lab. Invest., 82, 61-70 (2002) Tunoda, H. et al: Journal of Japanese Pharmacology 114, Suppl1, 55-59 (1999) Yachie, A. et al: J. Clin. Invest., 103, 129-135 (1999) Poss, K. D. et al: Proc. Natl. Acad. Sci. USA, 94, 10919-10924 (1997) Kobayashi, Y, et al: Jpn. J. Toxicol. Environ. Health. 42, 468-478 (1996) Kundu, N. G. and Das, P .: J. Chem. Soc., Chem. Commun., 99-100 (1995) Kundu, N. G. et al: Bioorg. Med. Chem., 5, 2011-2018 (1997)

  The present invention is to provide a novel HO inducer or induction promoter.

[式中、Xは置換基を有していても良いフェニル基、置換基を有していても良いヘテロ芳香環、または一般式(１ａ)

（式中ｍは１または２を表し、Ｑは置換基を有していても良いフェニル基または置換基を有していても良いヘテロ芳香環を表し、Ｒａは、水素、トリフルオロメチル基、トリフルオロメトキシ基、炭素数１〜４の低級アルキル基、炭素数１〜４の低級アルコキシル基、炭素数２〜６の置換基を有していてもよい環状または非環状アミノ基、ハロゲン原子、カルボキシル基、アセチル基を表す）、または一般式（１ｂ）

（式中、Ａは結合または−Ｏ−を表し、Ｒａ，Ｑは上述の通り）を表し、
Yはヒドロキシル基、炭素数２〜６の置換基を有してもよい環状または非環状アミノ基、または一般式（１ｃ）

（式中Ｅは−ＣＨ_２Ｏ−，−ＣＨ_２ＮＨ−，−ＣＨ_２ＣＨ_２ＮＨ−を表し、Ｑは上述の通り）を表し、Zは−CH=CH-、−C≡C−、−CH₂CH₂-、−CH₂O-、−CONH-を表す]で表されることを特徴とする４−トリフルオロメチルピリミジン誘導体およびそれらの薬理学的に許容しうる塩並びにその水和物、

２） 一般式（１ｄ）

［式中Xaは、一般式（１ｅ）

（式中Ｒｂは、フッ素、トリフルオロメチル基、トリフルオロメトキシ基、炭素数１〜４の低級アルキル基、炭素数１〜４の低級アルコキシル基、炭素数２〜６の置換基を有していてもよい環状または非環状アミノ基「ただし、ジメチルアミノ基とピロリジン−１−イル基を除く」、または一般式（１ｆ）

（式中Ｑａは、一般式（１ｇ）

（式中Ｒｃはクロル基、トリフルオロメチル基、トリフルオロメトキシ基、炭素数１〜４の低級アルキル基、炭素数１〜４の低級アルコキシル基、炭素数２〜６の置換基を有していてもよい環状または非環状アミノ基）、または置換基を有してもよいヘテロ芳香環）、または一般式（１ｈ）

（式中、Ｑｂは置換基を有するフェニル基、または置換基を有してもよいヘテロ芳香環、Ｒａは上述の通り）、または一般式（１ｉ）

（式中、ＱおよびＲａは上述の通り）］で表される、１）記載の４−トリフルオロメチルピリミジン誘導体およびそれらの薬理学的に許容しうる塩並びにその水和物、

３） 前記一般式（１）で表される化合物が、下記（１）から（４）
（１） ２−ヒドロキシ−４−［トランス−（４−トリフルオロメトキシフェニル）エテニル］−６−トリフルオロメチルピリミジン
（２） ２−ヒドロキシ−４−［トランス−（４−ビフェニル）エテニル］−６−トリフルオロメチルピリミジン
２−ヒドロキシ−４−［トランス−（４−フェノキシフェニル）エテニル］−６−トリフルオロメチルピリミジン
（４） ２−ヒドロキシ−４−［トランス−（４−（４−トルイル）フェニル）エテニル］−６−トリフルオロメチルピリミジン
のいずれか一つである、１）記載の４−トリフルオロメチルピリミジン誘導体およびそれらの薬理学的に許容しうる塩並びにその水和物、

４） １）記載の４−トリフルオロメチルピリミジン誘導体およびそれらの薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分として含有する、ヘムオキシゲナーゼの誘導剤または誘導促進剤、

５） １）記載の４−トリフルオロメチルピリミジン誘導体およびそれらの薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分として含有する、急性肺傷害（ALI, ARDS）治療剤、

６） １）記載の４−トリフルオロメチルピリミジン誘導体およびそれらの薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分として含有する、慢性閉塞性肺疾患（COPD）治療剤、

７） １）記載の４−トリフルオロメチルピリミジン誘導体およびそれらの薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分として含有する、喘息治療剤、

８） １）記載の４−トリフルオロメチルピリミジン誘導体およびそれらの薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分として含有する、移植臓器の保護剤、
に関するものである。 The present invention is 1) General formula (1)

[Wherein X is a phenyl group which may have a substituent, a heteroaromatic ring which may have a substituent, or a group represented by the general formula (1a)

(In the formula, m represents 1 or 2, Q represents a phenyl group which may have a substituent or a heteroaromatic ring which may have a substituent, and Ra represents hydrogen, a trifluoromethyl group, A trifluoromethoxy group, a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxyl group having 1 to 4 carbon atoms, a cyclic or acyclic amino group which may have a substituent having 2 to 6 carbon atoms, a halogen atom, Represents a carboxyl group or an acetyl group), or general formula (1b)

(Wherein A represents a bond or —O—, and Ra and Q are as described above),
Y is a hydroxyl group, a cyclic or acyclic amino group which may have a substituent having 2 to 6 carbon atoms, or a general formula (1c)

(Wherein E is _{-CH 2 O -, - CH 2} NH -, - CH 2 CH 2 NH- represents, Q is as defined above) represents, Z is -CH = CH -, - C≡C-, _{-CH 2 CH 2 -, - CH} 2 O -, - CONH- characterized by being represented by at representing] 4-trifluoromethyl pyrimidine derivatives and their pharmacologically acceptable salts and hydrated thereof Stuff,

2) General formula (1d)

[Wherein Xa represents the general formula (1e)

(In the formula, Rb has fluorine, a trifluoromethyl group, a trifluoromethoxy group, a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxyl group having 1 to 4 carbon atoms, and a substituent having 2 to 6 carbon atoms. A cyclic or acyclic amino group which may be excluded, except for the dimethylamino group and the pyrrolidin-1-yl group, or the general formula (1f)

(Where Qa is the general formula (1g)

(Wherein Rc has a chloro group, a trifluoromethyl group, a trifluoromethoxy group, a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxyl group having 1 to 4 carbon atoms, and a substituent having 2 to 6 carbon atoms. A cyclic or acyclic amino group which may be substituted), or a heteroaromatic ring which may have a substituent, or a compound represented by the general formula (1h)

(Wherein Qb is a phenyl group having a substituent, or a heteroaromatic ring optionally having a substituent, Ra is as described above), or general formula (1i)

(Wherein Q and Ra are as described above)], the 4-trifluoromethylpyrimidine derivatives described in 1) and pharmacologically acceptable salts thereof and hydrates thereof,

3) The compound represented by the general formula (1) is the following (1) to (4)
(1) 2-hydroxy-4- [trans- (4-trifluoromethoxyphenyl) ethenyl] -6-trifluoromethylpyrimidine (2) 2-hydroxy-4- [trans- (4-biphenyl) ethenyl] -6 -Trifluoromethylpyrimidine 2-hydroxy-4- [trans- (4-phenoxyphenyl) ethenyl] -6-trifluoromethylpyrimidine (4) 2-hydroxy-4- [trans- (4- (4-toluyl) phenyl 1) ethenyl] -6-trifluoromethylpyrimidine, the 4-trifluoromethylpyrimidine derivative according to 1), a pharmacologically acceptable salt thereof, and a hydrate thereof,

4) An inducer or inducer of heme oxygenase containing, as an active ingredient, at least one of the 4-trifluoromethylpyrimidine derivatives described in 1) and their pharmacologically acceptable salts and hydrates thereof. ,

5) Acute lung injury (ALI, ARDS) treatment comprising as an active ingredient at least one of the 4-trifluoromethylpyrimidine derivatives described in 1) and their pharmacologically acceptable salts and hydrates thereof. Agent,

6) Treatment of chronic obstructive pulmonary disease (COPD) comprising as an active ingredient at least one of the 4-trifluoromethylpyrimidine derivatives described in 1) and pharmacologically acceptable salts thereof and hydrates thereof. Agent,

7) A therapeutic agent for asthma, comprising as an active ingredient at least one of the 4-trifluoromethylpyrimidine derivatives according to 1) and their pharmacologically acceptable salts and hydrates thereof,

8) A transplanted organ protective agent comprising, as an active ingredient, at least one of the 4-trifluoromethylpyrimidine derivatives described in 1) and pharmacologically acceptable salts thereof and hydrates thereof,
It is about.

[式中、Ｘ，Ｙ，Zは上述の通り]で示される本発明の４−トリフルオロメチルピリミジン誘導体は、病態時に生体防御的に作用するHOの発現を誘導または促進し、病態の緩和を促進することができる。
このような４−トリフルオロメチルピリミジン誘導体はHOの誘導剤または誘導促進剤として有用であり、様々な疾患の治療剤として、例えば急性肺傷害治療剤、慢性閉塞性肺疾患治療剤、喘息治療剤、移植臓器の保護剤などとして、様々な酸化的ストレスに対する生体防御剤として提供することができる。 General formula (1)

The 4-trifluoromethylpyrimidine derivative of the present invention represented by the formula [wherein X, Y, Z are as described above] induces or promotes the expression of HO that acts as a biodefense at the time of pathological condition, and alleviates the pathological condition. Can be promoted.
Such 4-trifluoromethylpyrimidine derivatives are useful as HO inducers or inducers, and as therapeutic agents for various diseases, for example, acute lung injury therapeutic agents, chronic obstructive pulmonary disease therapeutic agents, asthma therapeutic agents. As a protective agent for transplanted organs, it can be provided as a biological defense agent against various oxidative stresses.

[式中、Ｘ，Ｙ，Zは上述の通りである]で示される本発明の化合物の薬理学的に許容できる塩とは、塩酸塩、臭化水素酸塩、酢酸塩、トリフルオロ酢酸塩、クエン酸塩のような酸付加塩、またはナトリウム塩、カリウム塩のようなアルカリ金属塩が挙げられる。
また、一般式（１）における「置換基を有してもよいフェニル基」、「置換基を有してもよいヘテロ芳香環」、および「置換基を有するフェニル基」における「置換基」とは、たとえばトリフルオロメチル基、炭素数1〜４の低級アルキル基、ハロゲン、アセチル基、カルボキシル基、炭素数１〜４の低級アルコキシル基、炭素数２〜６の置換基を有してもよい環状または非環状アミノ基等が挙げられ、「置換基を有してもよいヘテロ芳香環」における「ヘテロ芳香環」とは、５員もしくは６員の窒素、酸素または硫黄原子を含む複素環およびその縮合環を表し、たとえばピリジル基、インドリル基、キノリル基等が挙げられ、「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子を表し、「炭素数１〜４の直鎖または分枝低級アルキル基」とは、たとえばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｔ−ブチル基などを表し、「炭素数１〜４の低級アルコキシル基」とは、たとえばメトキシ基、エトキシ基、イソプロピルオキシ基などを表し、「置換基を有してもよい炭素数２〜６の環状または非環状アミノ基」の「炭素数２〜６の環状または非環状アミノ基」とは、例えばシクロプロピルアミノ基、ピロリジル基、ピペリジル基、モルホリル基などの環状アミノ基やジメチルアミノ基、ジエチルアミノ基、エチルアミノ基等の非環状アミノ基を表し、「置換基を有してもよい炭素数２〜６の環状または非環状アミノ基」の「置換基」とは、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシル基、炭素数２〜６の環状または非環状アミノ基を表す。ここで言う「炭素数１〜４のアルキル基」、「炭素数１〜４のアルコキシル基」および「炭素数２〜６の環状または非環状アミノ基」とは上記で説明したものと同一である。
本発明で包含される化合物は例えば以下の方法により製造することができる。 General formula (1)

The pharmacologically acceptable salt of the compound of the present invention represented by the formula: wherein X, Y and Z are as described above, is hydrochloride, hydrobromide, acetate, trifluoroacetate , Acid addition salts such as citrates, or alkali metal salts such as sodium salts and potassium salts.
Further, “substituent” in “phenyl group optionally having substituent”, “heteroaromatic ring optionally having substituent”, and “phenyl group having substituent” in general formula (1) May have, for example, a trifluoromethyl group, a lower alkyl group having 1 to 4 carbon atoms, a halogen, an acetyl group, a carboxyl group, a lower alkoxyl group having 1 to 4 carbon atoms, or a substituent having 2 to 6 carbon atoms. Examples thereof include a cyclic or acyclic amino group, and the “heteroaromatic ring” in the “optionally substituted heteroaromatic ring” means a heterocyclic ring containing a 5-membered or 6-membered nitrogen, oxygen or sulfur atom and The condensed ring is represented, and examples thereof include a pyridyl group, an indolyl group, a quinolyl group, and the like. “Halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Or low branch The “primary alkyl group” represents, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a t-butyl group, and the like, and the “lower alkoxyl group having 1 to 4 carbon atoms” includes, for example, a methoxy group, ethoxy group Group, isopropyloxy group and the like, and “cyclic or non-cyclic amino group having 2 to 6 carbon atoms which may have a substituent” means “cyclic or non-cyclic amino group having 2 to 6 carbon atoms”, for example, It represents a cyclic amino group such as cyclopropylamino group, pyrrolidyl group, piperidyl group, morpholyl group, or acyclic amino group such as dimethylamino group, diethylamino group, ethylamino group, etc. The "substituent" of "6 to 6 cyclic or acyclic amino group" means an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, or a cyclic or acyclic amino group having 2 to 6 carbon atoms. A representative. The “alkyl group having 1 to 4 carbon atoms”, the “alkoxyl group having 1 to 4 carbon atoms”, and the “cyclic or acyclic amino group having 2 to 6 carbon atoms” are the same as those described above. .
The compound included in the present invention can be produced, for example, by the following method.

スキーム1で、一般式（３）

［式中、X₁はフェニル基、4-トリフルオロメチルフェニル基、4-メチルフェニル基、４−フルオロメチル基、４−ビフェニル基、3-クロロフェニル基、2-クロロフェニル基、４−フェノキシフェニル基、４−ベンジルオキシフェニル基、２−ナフチル基、３,４,５-トリメトキシフェニル基、または３，５−ビスベンジルオキシフェニル基］で表される化合物は、文献公知の４-クロロ−２−メチルチオ−６−トリフルオロメチルピリミジン（Gershon, H. et al, J. Heterocyclic Chem., 24, 205 (1987); Gershon, H., et al, J Heterocyclic Chem., 24, 1243 (1987)）(2)

と一般式（５）

［式中、X₁は上述の通り］で表されるビニルホウ酸誘導体を反応させることにより製造する事ができる（工程１）。
工程１の反応は、テトラキストリフェニルホスフィンパラジウムなどのパラジウム触媒の存在下、ジオキサン、THF、DMFなどの有機溶媒中、またはトルエン−水等の混合溶媒中、常温〜加熱還流、好適には加熱還流にて行うことができる。
スキーム１で、一般式（４）

［式中、X₁は上述の通り］で表される化合物は、一般式（３）で表される化合物を酸化することによって製造することができる（工程２）。
工程２の反応は、３−クロロ過安息香酸（ｍCPBA）やオキソン、３０％過酸化水素水等の酸化剤の存在下、塩化メチレン等の有機溶媒中で、０℃〜加熱還流、好適には０℃〜常温にて行うことができる。
スキーム１で、一般式（１−２）

［式中、X₁は上述の通り］で表される化合物は、一般式（４）で表される化合物を、加水分解することにより製造することができる（工程３）。
工程３の反応は、水酸化ナトリウム、水酸化カリウム等の塩基の存在下、水やTHF、DMFなどの溶媒中で、０℃〜加熱還流、好適には常温にて行うことができる。
また一般式（５）

［式中X₁は上述の通り］で表される化合物は、以下の方法で製造することができる。 <Scheme 1>

In scheme 1, the general formula (3)

[Wherein, X ₁ is a phenyl group, 4-trifluoromethylphenyl group, 4-methylphenyl group, 4-fluoromethyl group, 4-biphenyl group, 3-chlorophenyl group, 2-chlorophenyl group, 4-phenoxyphenyl group , 4-benzyloxyphenyl group, 2-naphthyl group, 3,4,5-trimethoxyphenyl group, or 3,5-bisbenzyloxyphenyl group] is a 4-chloro-2 known in the literature. -Methylthio-6-trifluoromethylpyrimidine (Gershon, H. et al, J. Heterocyclic Chem., 24, 205 (1987); Gershon, H., et al, J Heterocyclic Chem., 24, 1243 (1987)) (2)

And general formula (5)

[Wherein X ₁ is as described above] can be produced by reacting with a vinyl boric acid derivative (Step 1).
The reaction of Step 1 is carried out in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium, in an organic solvent such as dioxane, THF, and DMF, or in a mixed solvent such as toluene-water, preferably from room temperature to heating reflux, preferably heating reflux. Can be done.
In scheme 1, the general formula (4)

[Wherein X ₁ is as described above] can be produced by oxidizing the compound represented by the general formula (3) (step 2).
The reaction in Step 2 is carried out in the presence of an oxidizing agent such as 3-chloroperbenzoic acid (mCPBA), oxone or 30% hydrogen peroxide in an organic solvent such as methylene chloride, preferably at 0 ° C. to reflux with heating, preferably It can carry out at 0 degreeC-normal temperature.
In scheme 1, the general formula (1-2)

[Wherein X ₁ is as described above] can be produced by hydrolyzing the compound represented by the general formula (4) (step 3).
The reaction in Step 3 can be performed in the presence of a base such as sodium hydroxide or potassium hydroxide in a solvent such as water, THF, or DMF at 0 ° C. to heating under reflux, preferably at room temperature.
Moreover, general formula (5)

The compound represented by [wherein X ₁ is as described above] can be produced by the following method.

スキーム２で、一般式（７）

［式中R１、R2は共に臭素原子またはR1、R2の一方が塩素原子かつ他方が水素で、X₁は上述の通り］で表される化合物は、一般式（６）
X_１−CHO （６）
［式中X₁は上述の通り］で表されるアリールアルデヒド誘導体から製造することができる（工程４）。
工程４の反応は、トリフェニルホスフィン−四臭化炭素、またはトリフェニルホスフォラニリデンクロロメチルを用い、THFや塩化メチレン等の有機溶媒中、−７８℃〜加熱還流、好適には０℃〜室温にて行うことができる。
スキーム２で、一般式（８）

［式中X₁は上述の通り］で表される化合物は、一般式（７）で表される化合物から製造することができる（工程５）。
工程５の反応は、ｎ−ブチルリチウム、ｔ−ブチルリチウム等の塩基の存在下、ＴＨＦ、ジエチルエーテル等の有機溶媒中、−７８℃〜室温で行うことができる。
スキーム２で、一般式（５）

［式中X₁は上述の通り］で表される化合物は、一般式（８）で表される化合物をヒドロホウ素化することにより製造することができる（工程６）。
工程６の反応は、カテコールボラン、またはHBBr₂等のボラン誘導体を用い、THF等の有機溶媒中、−２０℃〜加熱還流、好適には加熱還流にて行うことができる。
また、一般式（３a）

［式中X₂は３−クロロフェニル基、４−ホルミルフェニル基、４−ヒドロキシメチルフェニル基または４−アセチルフェニル基］で表される化合物は、以下の方法によっても製造することができる。 <Scheme 2>

In scheme 2, the general formula (7)

[While a chlorine atom and the other is hydrogen Both wherein R1, R2 bromine atom or R1, R2, X ₁ is as defined above] a compound represented by the general formula (6)
X ₁ -CHO (6)
[Wherein X ₁ is as described above] (Step 4).
The reaction in Step 4 uses triphenylphosphine-carbon tetrabromide or triphenylphosphoranylidene chloromethyl and is in an organic solvent such as THF or methylene chloride at −78 ° C. to heating under reflux, preferably 0 ° C. to It can be performed at room temperature.
In Scheme 2, the general formula (8)

The compound represented by [wherein X ₁ is as described above] can be produced from the compound represented by the general formula (7) (Step 5).
The reaction in Step 5 can be carried out in the presence of a base such as n-butyllithium or t-butyllithium in an organic solvent such as THF or diethyl ether at −78 ° C. to room temperature.
In scheme 2, the general formula (5)

The compound represented by [wherein X ₁ is as described above] can be produced by hydroborating the compound represented by the general formula (8) (step 6).
The reaction in Step 6 can be carried out using catecholborane or a borane derivative such as HBBr _{2 in} an organic solvent such as THF at −20 ° C. to heating under reflux, preferably under heating under reflux.
In addition, the general formula (3a)

The compound represented by [wherein X ₂ is 3-chlorophenyl group, 4-formylphenyl group, 4-hydroxymethylphenyl group or 4-acetylphenyl group] can also be produced by the following method.

スキーム３で、構造式

で表される化合物（９）は、上述の化合物（２）とビニルホウ酸ピナコールエステルから製造することができる（工程７）。
工程7の反応は、テトラキストリフェニルホスフィンパラジウムやPdCl2（dppf）等のパラジウム触媒存在下、THF、DMF、1,4−ジオキサン等の有機溶媒中またはトルエン−水などの２層溶媒を用い、0℃〜加熱還流、好適には加熱還流にて行うことができる。
スキーム３で、一般式（３a）で表される化合物は、一般式（９）で表される化合物とアリールほう酸誘導体から製造することができる（工程８）。
工程８の反応は、酢酸パラジウム等のパラジウム触媒存在下、THF、DMF、1,4−ジオキサン等の有機溶媒中またはトルエン−水などの２層溶媒を用い、反応液中に空気または酸素を吹き込みながら、0℃〜加熱還流、好適には４０℃〜５０℃にて行うことができる。
次に、一般式（１）で表される化合物のうち一般式（１−３）

［式中Z1は、−C≡C-、−CH₂CH₂-、−CONH-、−CH₂O−、−CH₂NH-］で表される化合物は、以下の方法によって、製造することができる。 <Scheme 3>

In Scheme 3, the structural formula

(9) can be produced from the above-mentioned compound (2) and vinyl borate pinacol ester (step 7).
The reaction in Step 7 is carried out using an organic solvent such as THF, DMF, 1,4-dioxane, or a two-layer solvent such as toluene-water in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium or PdCl2 (dppf). The reaction can be carried out at a temperature of from ° C to heating reflux, preferably heating reflux.
In Scheme 3, the compound represented by the general formula (3a) can be produced from the compound represented by the general formula (9) and an aryl boric acid derivative (Step 8).
In the reaction of Step 8, air or oxygen is blown into the reaction solution in the presence of a palladium catalyst such as palladium acetate in an organic solvent such as THF, DMF, 1,4-dioxane, or a two-layer solvent such as toluene-water. However, it can be carried out at 0 ° C. to reflux with heating, preferably at 40 ° C. to 50 ° C.
Next, among the compounds represented by the general formula (1), the general formula (1-3)

[Wherein Z1 represents —C≡C—, —CH ₂ CH ₂ —, —CONH—, —CH ₂ O—, —CH ₂ NH—] by the following method. Can do.

スキーム４で一般式（１０）

［式中Z1は上述の通り］で表される化合物は、文献公知の化合物（２）と４−クロロベンジルアミン、４−クロロベンジルアルコール、４−クロロベンズアミド、４−クロロフェニルアセチレンまたは４−クロロスチレンから製造することができる（工程９）。
工程９の反応は、４−クロロベンジルアミン、４−クロロベンジルアルコールまたは４−クロロベンズアミドを用いた場合には、トリエチルアミン、水素化ナトリウム等の塩基の存在下、DMF、THF等の有機溶媒中、−２０℃〜加熱還流、好適には０℃〜室温にて行うことができ、４−クロロアセチレンを用いた場合には、テトラキストリフェニルホスフィンパラジウムなどのパラジウム触媒、ヨウ化銅等の銅触媒、トリエチルアミン等の塩基の存在下、DMF、THFなどの有機溶媒中、０℃〜加熱還流、好適には室温にて行うことができ、４−クロロスチレンを用いた場合には、４−クロロスチレンを９−ボラビシクロ［３．３．１］ノナン（9−BBN）と反応させた後、ジクロロパラジウム（II）−ｄｐｐｆ錯体（PdCl₂(dppf)）等のパラジウム触媒と化合物（２）を加え、THF、DMFなどの有機溶媒または水―トルエン等の混合溶媒中、０℃〜加熱還流、好適には加熱還流に行うことができる。
スキーム４で一般式（１１）

［式中Z1は上述の通り］で表される化合物は、一般式（１０）で表される化合物を酸化することによって製造することができる（工程１０）。
工程１０の反応は、３−クロロ過安息香酸（ｍCPBA）やオキソン、３０％過酸化水素水等の酸化剤の存在下、塩化メチレン等の有機溶媒中で、０℃〜加熱還流、好適には０℃〜常温にて行うことができる。
スキーム４で、一般式（１−３）

［式中Z1は上述の通り］で表される化合物は、一般式（１１）で表される化合物を加水分解することによって製造することができる（工程１１）。
工程１１の反応は、水酸化ナトリウム、水酸化カリウム等の塩基の存在下、水やTHF、DMFなどの溶媒中で、０℃〜加熱還流、好適には室温にて行うことができる。
次に、一般式（１）で表される化合物のうち一般式（１−４）

［式中Y₁はピロリジン−１−イル基、モルホリン−４−イル基、ピペリジン−１−イル基、４-メチルピペラジン−１−イル基、（４−ピロリジル）ピペリジン−１−イル基、N,N,N’−トリメチルエチレンジアミノ基、４−トリフルオロメチルベンジルオキシ基、４−クロロベンジルアミノ基、エチルアミノ基、フェネチルアミノ基］で表される化合物は、以下の方法で製造することができる。 <Scheme 4>

In scheme 4, the general formula (10)

[Wherein Z1 is as described above] is a compound known from the literature (2) and 4-chlorobenzylamine, 4-chlorobenzyl alcohol, 4-chlorobenzamide, 4-chlorophenylacetylene or 4-chlorostyrene. (Step 9).
In the reaction of Step 9, when 4-chlorobenzylamine, 4-chlorobenzyl alcohol or 4-chlorobenzamide is used, in the presence of a base such as triethylamine or sodium hydride in an organic solvent such as DMF or THF, -20 ° C to heating reflux, preferably 0 ° C to room temperature. When 4-chloroacetylene is used, a palladium catalyst such as tetrakistriphenylphosphine palladium, a copper catalyst such as copper iodide, In the presence of a base such as triethylamine, the reaction can be carried out in an organic solvent such as DMF or THF at 0 ° C. to heating under reflux, preferably at room temperature. When 4-chlorostyrene is used, After reacting with 9-borabicyclo [3.3.1] nonane (9-BBN), combined with a palladium catalyst such as dichloropalladium (II) -dppf complex (PdCl ₂ (dppf)) The product (2) is added, and the reaction can be carried out in an organic solvent such as THF and DMF or a mixed solvent such as water-toluene at 0 ° C. to heating to reflux, preferably heating to reflux.
In scheme 4, the general formula (11)

The compound represented by [wherein Z1 is as described above] can be produced by oxidizing the compound represented by the general formula (10) (step 10).
The reaction of Step 10 is carried out in the presence of an oxidizing agent such as 3-chloroperbenzoic acid (mCPBA), oxone, and 30% hydrogen peroxide in an organic solvent such as methylene chloride, preferably at 0 ° C. to reflux with heating, preferably It can carry out at 0 degreeC-normal temperature.
In scheme 4, the general formula (1-3)

The compound represented by [wherein Z1 is as described above] can be produced by hydrolyzing the compound represented by the general formula (11) (step 11).
The reaction in Step 11 can be performed in the presence of a base such as sodium hydroxide or potassium hydroxide in a solvent such as water, THF, or DMF at 0 ° C. to heating under reflux, preferably at room temperature.
Next, among the compounds represented by the general formula (1), the general formula (1-4)

Wherein Y ₁ is a pyrrolidin-1-yl group, morpholin-4-yl group, piperidin-1-yl group, 4-methylpiperazin-1-yl group, (4-pyrrolidyl) piperidin-1-yl group, N , N, N′-trimethylethylenediamino group, 4-trifluoromethylbenzyloxy group, 4-chlorobenzylamino group, ethylamino group, phenethylamino group] can be produced by the following method. it can.

スキーム５で構造式（１２）で表される化合物は、上述の化合物（２）と２−（４−クロロフェニル）ビニルホウ酸から製造することができる（工程１２）。
工程１２の反応は、テトラキストリフェニルホスフィンパラジウムなどのパラジウム触媒の存在下、ジオキサン、THF、DMFなどの有機溶媒中、またはトルエン−水等の混合溶媒中、室温〜加熱還流、好適には加熱還流にて行うことができる。
スキーム５で構造式（１３）で表される化合物は、化合物（１２）を酸化することにより、製造することができる（工程１３）。
工程１３の反応は、３−クロロ過安息香酸（ｍCPBA）やオキソン、３０％過酸化水素水等の酸化剤の存在下、塩化メチレン等の有機溶媒中で、０℃〜加熱還流、好適には０℃〜室温にて行うことができる。
スキーム５で、一般式（１−４）で表される化合物は、化合物（１３）と各種アミンまたはアルコールより製造することができる（工程１４）。
工程１４の反応は、水素化ナトリウム、炭酸カリウム、トリエチルアミン、ピリジン等の塩基の存在下、DMF、THF等の有機溶媒中、０℃〜加熱還流、好適には０℃〜室温にて、行うことができる。
次に一般式（１）で表される化合物のうち、一般式（１−５）

［式中R3は、３，５−ビストリフルオロメチルベンジル基、４-ニトロベンジル基、４−トリフルオロメトキシベンジル基、４−イソプロポキシフェニル基、４-トルイル基、４−メトキシベンジル基、４−クロロフェニル基または４−トリフルオロメチルフェニル基］であらわされる化合物は、以下の方法で製造することができる。 <Scheme 5>

The compound represented by the structural formula (12) in Scheme 5 can be produced from the above-mentioned compound (2) and 2- (4-chlorophenyl) vinyl boric acid (Step 12).
The reaction in Step 12 is performed in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium, in an organic solvent such as dioxane, THF, and DMF, or in a mixed solvent such as toluene-water, preferably at room temperature to heating to reflux, preferably heated to reflux. Can be done.
The compound represented by Structural Formula (13) in Scheme 5 can be produced by oxidizing compound (12) (step 13).
The reaction in the step 13 is carried out in the presence of an oxidizing agent such as 3-chloroperbenzoic acid (mCPBA), oxone, and 30% hydrogen peroxide water in an organic solvent such as methylene chloride, preferably at 0 ° C. to heating under reflux, preferably It can be performed at 0 ° C. to room temperature.
In Scheme 5, the compound represented by the general formula (1-4) can be produced from the compound (13) and various amines or alcohols (Step 14).
The reaction of step 14 is carried out in the presence of a base such as sodium hydride, potassium carbonate, triethylamine, pyridine and the like in an organic solvent such as DMF and THF at 0 ° C. to heating under reflux, preferably 0 ° C. to room temperature. Can do.
Next, among the compounds represented by the general formula (1), the general formula (1-5)

[Wherein R3 represents 3,5-bistrifluoromethylbenzyl group, 4-nitrobenzyl group, 4-trifluoromethoxybenzyl group, 4-isopropoxyphenyl group, 4-toluyl group, 4-methoxybenzyl group, 4- The compound represented by [chlorophenyl group or 4-trifluoromethylphenyl group] can be produced by the following method.

スキーム６で構造式（１４）で表される化合物は、上述一般式（３）で表される化合物のうち、X₁が（４−ベンジルオキシ）フェニル基である化合物と同一のものである。したがって、化合物（１４）は工程１と同様な方法で製造することができる。
スキーム６で構造式（１５）で表される化合物は、化合物（１４）で表される化合物を用いて製造することができる（工程１６）。
工程１６の反応は、三フッ化ホウ素（BF₃）や塩化アルミニウム（AlCl₃）等のルイス酸とエタンチオール、ジメチルスルフィド等の求核剤の存在下、塩化メチレン等の有機溶媒中で、−２０℃〜加熱還流、好適には加熱還流にて行うことができる。
スキーム６で一般式（１６）

［式中R3は上述の通り］で表される化合物は、化合物（１５）とベンジルブロミド誘導体、アリールメチルブロミド誘導体またはフェニルホウ酸誘導体を用いて製造することができる（工程１７）。
工程１７の反応は、ベンジルブロミド誘導体またはアリールメチルブロミド誘導体を用いた場合には、水素化ナトリウム、炭酸カリウムまたはトリエチルアミン等の塩基の存在下、塩化メチレン、THF、DMF等の有機溶媒中、０℃〜加熱還流、好適には室温にて行うことができる。またフェニルホウ酸誘導体を用いた場合には、酢酸銅等の銅触媒、トリエチルアミン等の塩基、モリキュラーシーブス４Aの存在下、塩化メチレン、THF等の有機溶媒中、０℃〜加熱還流、好適には室温にて行うことができる。
スキーム６で一般式（１７）

［式中R3は上述の通り］で表される化合物は、一般式（１６）で表される化合物を酸化することによって製造することができる（工程１８）。
工程１８の反応は、３−クロロ過安息香酸（ｍCPBA）やオキソン、３０％過酸化水素水等の酸化剤の存在下、塩化メチレン等の有機溶媒中で、０℃〜加熱還流、好適には０℃〜室温にて行うことができる。
スキーム６で一般式（１−５）で表される化合物は、一般式（１７）で表される化合物を加水分解することによって製造することができる（工程１９）。
工程１９の反応は、水酸化ナトリウム、水酸化カリウム等の塩基の存在下、水やTHF、DMFなどの溶媒中で、０℃〜加熱還流、好適には室温にて行うことができる。
次に、一般式（１）で表される化合物のうち、Ｘが４−モルホリノフェニル基、Ｙがヒドロキシル基、Ｚが−ＣＨ＝ＣＨ−である化合物（１−６）

は、以下の方法で製造することができる。 <Scheme 6>

The compound represented by Structural Formula (14) in Scheme 6 is the same as the compound represented by General Formula (3) described above, wherein X ₁ is a (4-benzyloxy) phenyl group. Therefore, compound (14) can be produced by the same method as in step 1.
The compound represented by Structural Formula (15) in Scheme 6 can be produced using the compound represented by Compound (14) (Step 16).
The reaction in Step 16 is carried out in an organic solvent such as methylene chloride in the presence of a Lewis acid such as boron trifluoride (BF ₃ ) or aluminum chloride (AlCl ₃ ) and a nucleophile such as ethanethiol or dimethyl sulfide. The reaction can be carried out at 20 ° C. to heating reflux, preferably heating reflux.
In scheme 6, the general formula (16)

The compound represented by the formula [wherein R3 is as described above] can be produced using compound (15) and a benzyl bromide derivative, an arylmethyl bromide derivative or a phenylboric acid derivative (step 17).
In the case of using a benzyl bromide derivative or an arylmethyl bromide derivative, the reaction of Step 17 is carried out in the presence of a base such as sodium hydride, potassium carbonate or triethylamine in an organic solvent such as methylene chloride, THF or DMF at 0 ° C. ~ Heating under reflux, preferably at room temperature. When a phenylboric acid derivative is used, a copper catalyst such as copper acetate, a base such as triethylamine, and molecular sieves 4A, in an organic solvent such as methylene chloride and THF, preferably at 0 ° C. to reflux under heating, preferably It can be performed at room temperature.
In scheme 6, the general formula (17)

The compound represented by [wherein R3 is as described above] can be produced by oxidizing the compound represented by the general formula (16) (step 18).
The reaction in Step 18 is carried out in the presence of an oxidizing agent such as 3-chloroperbenzoic acid (mCPBA), oxone, and 30% hydrogen peroxide in an organic solvent such as methylene chloride, preferably at 0 ° C. to heating under reflux, preferably It can be performed at 0 ° C. to room temperature.
The compound represented by General Formula (1-5) in Scheme 6 can be produced by hydrolyzing the compound represented by General Formula (17) (Step 19).
The reaction in Step 19 can be carried out in the presence of a base such as sodium hydroxide or potassium hydroxide in a solvent such as water, THF or DMF at 0 ° C. to heating under reflux, preferably at room temperature.
Next, among the compounds represented by the general formula (1), a compound (1-6) in which X is a 4-morpholinophenyl group, Y is a hydroxyl group, and Z is —CH═CH—.

Can be produced by the following method.

スキーム７中、化合物（１８）は、上述の化合物（１２）とモルホリンから製造することができる（工程２０）。
工程２０の反応は、トリ−ｔ−ブチルホスフィン等のホスフィン配位子、酢酸パラジウム等のパラジウム触媒、ナトリウムｔ−ブトキシド等の塩基の存在下、ＴＨＦ，ＤＭＦ、トルエン、キシレン等の有機溶媒中、室温〜加熱還流、好適には加熱還流にて行うことができる。
スキーム７中化合物（１９）は、化合物（１８）を酸化することによって製造することができる（工程２１）。
工程２１の反応は、３−クロロ過安息香酸（ｍCPBA）やオキソン、３０％過酸化水素水等の酸化剤の存在下、塩化メチレン、メタノール等の有機溶媒中で、０℃〜加熱還流、好適には０℃〜室温にて行うことができる。
スキーム７中、化合物（１−６）は、化合物（１９）を加水分解することにより製造することができる（工程２２）。
工程２２の反応は、水酸化ナトリウム、水酸化カリウム等の塩基の存在下、水やTHF、DMFなどの溶媒中で、０℃〜加熱還流、好適には室温にて行うことができる。
次に一般式（１）で表される化合物のうち、Ｘが４−ピロリジルメチルフェニル基、Ｙがヒドロキシル基、Ｚが−ＣＨ＝ＣＨ−である化合物（１−７）

は、以下の方法で製造することができる。 <Scheme 7>

In scheme 7, compound (18) can be produced from compound (12) and morpholine described above (step 20).
The reaction of step 20 is carried out in the presence of a phosphine ligand such as tri-t-butylphosphine, a palladium catalyst such as palladium acetate, a base such as sodium t-butoxide in an organic solvent such as THF, DMF, toluene, xylene, The reaction can be carried out at room temperature to heating reflux, preferably heating reflux.
Compound (19) in Scheme 7 can be produced by oxidizing compound (18) (step 21).
The reaction in Step 21 is carried out at 0 ° C. to heating under reflux in an organic solvent such as methylene chloride and methanol in the presence of an oxidizing agent such as 3-chloroperbenzoic acid (mCPBA), oxone, and 30% hydrogen peroxide. Can be performed at 0 ° C. to room temperature.
In scheme 7, compound (1-6) can be produced by hydrolyzing compound (19) (step 22).
The reaction in step 22 can be carried out in the presence of a base such as sodium hydroxide or potassium hydroxide in a solvent such as water, THF, or DMF at 0 ° C. to heating under reflux, preferably at room temperature.
Next, among the compounds represented by the general formula (1), a compound (1-7) wherein X is a 4-pyrrolidylmethylphenyl group, Y is a hydroxyl group, and Z is —CH═CH—.

Can be produced by the following method.

スキーム８中、構造式（２０）で表される化合物は、上述の化合物（９）と４−ヒドロキシメチルフェニルほう酸から製造することができる（工程２３）。
工程２３の反応は、酢酸パラジウム等のパラジウム触媒存在下、THF、DMF、1,4−ジオキサン等の有機溶媒中またはトルエン−水などの２層溶媒を用い、空気または酸素の存在下、0℃〜加熱還流、好適には４０℃〜５０℃にて行うことができる。
スキーム８中構造式（２１）で表される化合物は、化合物（２０）とメシルクロリドから製造することができる（工程２４）。
工程２４の反応は、トリエチルアミン、ピリジン等の塩基の存在下、ＴＨＦ、塩化メチレン等の有機溶媒中、−２０℃〜加熱還流、好適には０℃にて行うことができる。
スキーム８中構造式（２２）で表される化合物は、化合物（２１）とピロリジンから製造することができる（工程２５）。
工程２５の反応は、トリエチルアミン等の塩基の存在下、塩化メチレン等の有機溶媒中で、−２０℃〜加熱還流、好適には０℃にて行うことができる。
スキーム８中一般式（２３）

［式中、ｎは１または２］で表される化合物は、化合物（２２）を酸化することによって製造することができる（工程２６）。
工程２６の反応は、３−クロロ過安息香酸（ｍCPBA）やオキソン、３０％過酸化水素水等の酸化剤の存在下、塩化メチレン、メタノール等の有機溶媒中で、０℃〜加熱還流、好適には０℃〜室温にて行うことができる。
スキーム８で構造式（１−７）で表される化合物は、一般式（２３）で表される化合物を加水分解することにより製造することができる（工程２７）。
工程２７の反応は、水酸化ナトリウム、水酸化カリウム等の塩基の存在下、水やTHF、DMFなどの溶媒中で、０℃〜加熱還流、好適には室温にて行うことができる。
次に、一般式（１）で表される化合物のうち、Xが４−カルボキシフェニル基、Yがヒドロキシル基、Zが−CH=CH-の化合物（１−８）は、以下の方法にて製造することができる。 <Scheme 8>

In scheme 8, the compound represented by the structural formula (20) can be produced from the above-mentioned compound (9) and 4-hydroxymethylphenyl boric acid (step 23).
The reaction in Step 23 is carried out in the presence of a palladium catalyst such as palladium acetate, in an organic solvent such as THF, DMF, 1,4-dioxane, or a two-layer solvent such as toluene-water, in the presence of air or oxygen at 0 ° C. Heating to reflux, preferably 40 ° C to 50 ° C.
The compound represented by Structural Formula (21) in Scheme 8 can be produced from Compound (20) and mesyl chloride (Step 24).
The reaction in Step 24 can be carried out in the presence of a base such as triethylamine or pyridine in an organic solvent such as THF or methylene chloride at −20 ° C. to heating under reflux, preferably 0 ° C.
The compound represented by Structural Formula (22) in Scheme 8 can be produced from Compound (21) and pyrrolidine (Step 25).
The reaction in step 25 can be carried out in the presence of a base such as triethylamine in an organic solvent such as methylene chloride at −20 ° C. to heating under reflux, preferably 0 ° C.
General formula (23) in scheme 8

The compound represented by [wherein n is 1 or 2] can be produced by oxidizing compound (22) (step 26).
The reaction in Step 26 is carried out at 0 ° C. to heating under reflux in an organic solvent such as methylene chloride and methanol in the presence of an oxidizing agent such as 3-chloroperbenzoic acid (mCPBA), oxone, and 30% hydrogen peroxide. Can be performed at 0 ° C. to room temperature.
The compound represented by Structural Formula (1-7) in Scheme 8 can be produced by hydrolyzing the compound represented by General Formula (23) (Step 27).
The reaction in step 27 can be performed in the presence of a base such as sodium hydroxide or potassium hydroxide in a solvent such as water, THF, or DMF at 0 ° C. to heating under reflux, preferably at room temperature.
Next, among the compounds represented by the general formula (1), a compound (1-8) in which X is a 4-carboxyphenyl group, Y is a hydroxyl group, and Z is —CH═CH— is obtained by the following method. Can be manufactured.

スキーム９で一般式（２４）

［式中ｎは１または２］で表される化合物は、上述の化合物（２０）を酸化することによって製造することができる（工程２８）。
工程２８の反応は、３−クロロ過安息香酸（ｍCPBA）やオキソン、３０％過酸化水素水等の酸化剤の存在下、メタノール中で、０℃〜加熱還流、好適には０℃〜室温にて行うことができる。
スキーム９で構造式（１−８）で表される化合物は、一般式（２４）で表される化合物を加水分解することにより製造することができる（工程２９）。
工程２９の反応、水酸化ナトリウム、水酸化カリウム等の塩基の存在下、水やTHF、DMFなどの溶媒中で、０℃〜加熱還流、好適には室温にて行うことができる。 <Scheme 9>

In scheme 9, the general formula (24)

The compound represented by [wherein n is 1 or 2] can be produced by oxidizing the above-mentioned compound (20) (step 28).
The reaction in the step 28 is carried out in the presence of an oxidizing agent such as 3-chloroperbenzoic acid (mCPBA), oxone or 30% hydrogen peroxide in methanol at 0 ° C. to heating under reflux, preferably 0 ° C. to room temperature. Can be done.
The compound represented by Structural Formula (1-8) in Scheme 9 can be produced by hydrolyzing the compound represented by General Formula (24) (Step 29).
The reaction in Step 29 can be carried out in the presence of a base such as sodium hydroxide or potassium hydroxide in a solvent such as water, THF or DMF at 0 ° C. to heating under reflux, preferably at room temperature.

  Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

２−クロロベンズアルデヒド (420mg, 2.99mmol) とトリフェニルホスフィン (3.15g, 12.0 mmol) をジクロロメタン(10mL)に溶かし、氷冷下で四臭化炭素 (1.98g, 5.97 mmol) を加えた。0℃で15分攪拌後、反応液に少量の水を加え反応を終了させた。適量のシリカゲルをヘキサンに懸濁し、そこに反応液を加えた。シリカゲルを濾去し、濾液を濃縮した。黄色油状物として、目的物 (875mg, 99%)を得た。
¹H-NMR (CDCl₃) δ: 7.28-7.29 (2H, m), 7.39-7.40 (1H, m), 7.57 (1H, s), 7.64-7.64 (1H, m). <Reference Example 1>
β, β-Dibromo-2-chlorostyrene

2-Chlorobenzaldehyde (420 mg, 2.99 mmol) and triphenylphosphine (3.15 g, 12.0 mmol) were dissolved in dichloromethane (10 mL), and carbon tetrabromide (1.98 g, 5.97 mmol) was added under ice cooling. After stirring at 0 ° C. for 15 minutes, a small amount of water was added to the reaction solution to terminate the reaction. An appropriate amount of silica gel was suspended in hexane, and the reaction solution was added thereto. Silica gel was removed by filtration and the filtrate was concentrated. The target product (875 mg, 99%) was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 7.28-7.29 (2H, m), 7.39-7.40 (1H, m), 7.57 (1H, s), 7.64-7.64 (1H, m).

<Reference Examples 2-6>
The compounds shown in Table 1 were synthesized in the same manner as in Reference Example 1.

参考例１の化合物 (875mg, 2.95 mmol) をTHF(20mL)に溶かし、-78℃に冷却した。そこにn-BuLi (1.58mol/L ヘキサン溶液を3.80mL, 6.00mmol)を滴下した。-78℃で一時間攪拌した後、反応液を常温に戻し更に一時間攪拌した。水を加え、酢酸エチルで希釈した。有機層を水と飽和食塩水で洗浄し,無水硫酸ナトリウムで乾燥後、濃縮した。残渣をヘキサンに溶かし、シリカゲルカラムクロマトグラフィー（ヘキサン）で精製した。淡黄色油状物として目的物 (323mg, 80%) を得た。
¹H-NMR (CDCl₃) δ: 3.37 (1H, s), 7.22 (1H, td, J = 7.5, 1.4 Hz), 7.29 (1H, td, J = 7.5, 1.8 Hz), 7.41 (1H, dd, J = 7.5, 1.4 Hz), 7.53 (1H, dd, J = 7.5, 1.8 Hz). <Reference Example 7>
2-chlorophenylacetylene

The compound of Reference Example 1 (875 mg, 2.95 mmol) was dissolved in THF (20 mL) and cooled to -78 ° C. N-BuLi (1.58 mol / L hexane solution 3.80 mL, 6.00 mmol) was added dropwise thereto. After stirring at -78 ° C for 1 hour, the reaction solution was returned to room temperature and further stirred for 1 hour. Water was added and diluted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in hexane and purified by silica gel column chromatography (hexane). The target product (323 mg, 80%) was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 3.37 (1H, s), 7.22 (1H, td, J = 7.5, 1.4 Hz), 7.29 (1H, td, J = 7.5, 1.8 Hz), 7.41 (1H, dd , J = 7.5, 1.4 Hz), 7.53 (1H, dd, J = 7.5, 1.8 Hz).

<Reference Examples 8-12>
The compounds shown in Table 2 were synthesized in the same manner as in Reference Example 7.

参考例７の化合物 (323mg, 2.36mmol) をジクロロメタン（5mL）に溶かし、0℃に冷却した。そこに二臭化ボラン−ジメチルスルフィド錯体（HBBr₂-Me₂S） (2.4mL の 1mol/L ジクロロメタン溶液, 2.40mmol) を加え、常温に戻して1日攪拌した。反応液を水酸化ナトリウム水溶液（3mL の1.7mol/L水酸化ナトリウム水溶液） に氷冷下で滴下し、常温に戻して2時間攪拌した。希塩酸で酸性にし、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝3 : 1 ^v/_v） で精製し、淡黄色固体の目的物 (40mg, 9%) を得た。
¹H -NMR (CDCl₃) δ: 4.32 (2H, s), 6.16 (1H, d, J = 18.3 Hz), 7.23-7.31 (2H, m), 7.37-7.39 (1H, m), 7.63-7.71 (2H, m). <Reference Example 13>
Trans-2- (2-chlorophenyl) vinyl boric acid

The compound of Reference Example 7 (323 mg, 2.36 mmol) was dissolved in dichloromethane (5 mL) and cooled to 0 ° C. Borane dibromide-dimethyl sulfide complex (HBBr ₂ -Me ₂ S) (2.4 mL of a 1 mol / L dichloromethane solution, 2.40 mmol) was added thereto, and the mixture was returned to room temperature and stirred for 1 day. The reaction solution was added dropwise to an aqueous sodium hydroxide solution (3 mL of a 1.7 mol / L aqueous sodium hydroxide solution) under ice-cooling, and returned to room temperature and stirred for 2 hours. Acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 ^v / _v ) to obtain the desired product (40 mg, 9%) as a pale yellow solid.
¹ H -NMR (CDCl ₃ ) δ: 4.32 (2H, s), 6.16 (1H, d, J = 18.3 Hz), 7.23-7.31 (2H, m), 7.37-7.39 (1H, m), 7.63-7.71 (2H, m).

参考例８の化合物 (653mg, 3.36mmol) をTHF（5mL）に溶かし、0℃に冷却した。そこにカテコールボラン (3.4mL の 1mol/L THF溶液, 3.40mmol) を加え、8時間加熱還流した。反応液を希塩酸にあけ、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝2 : 1 ^v/_v） で精製し、淡黄色固体の目的物 (227mg, 28%) を得た。
¹H-NMR (CDCl₃) δ: 5.18 (2H, s), 6.38 (1H, d, J = 18.5 Hz), 6.80-7.59 (9H, m), 7.74 (1H, d, J = 18.5 Hz). <Reference Example 14>
Trans-2- (4-Phenoxyphenyl) vinyl boric acid

The compound of Reference Example 8 (653 mg, 3.36 mmol) was dissolved in THF (5 mL) and cooled to 0 ° C. Catecholborane (3.4 mL of 1 mol / L THF solution, 3.40 mmol) was added thereto, and the mixture was heated to reflux for 8 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 ^v / _v ) to obtain the desired product (227 mg, 28%) as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 5.18 (2H, s), 6.38 (1H, d, J = 18.5 Hz), 6.80-7.59 (9H, m), 7.74 (1H, d, J = 18.5 Hz).

文献公知の４−クロロ−２−メチルチオ−6−トリフルオロメチルピリミジン(Gershon, H, et al, J. Heterocyclic Chem., 24, 205 (1987); Gershon, H., et al, J. Heterocyclic Chem., 24, 1243 (1987))(77mg, 0.34mmol)とトランス−２−フェニルビニルほう酸 (50mg, 0.34mmol)とテトラキストリフェニルフォスフィンパラジウム(Pd(Ph₃P)₄) (35mg, 0.03mmol)をトルエン(3mL)に懸濁し、1mol/L Na₂CO₃ 水溶液 (2mL)を加え、2時間加熱還流した。反応液を水にあけ、酢酸エチルで抽出した後、有機層を水と飽和食塩水で洗浄した。硫酸ナトリウムで乾燥した後、濃縮し、残渣をシリカゲルカラム（ヘキサン：酢酸エチル＝30:1 ^v/_v）で精製した。黄色固体として目的物(82mg, 82%)を得た。
¹H-NMR(CDCl₃ 400MHz) δ： 2.65 (3H, s), 7.06(1H, d, 15.9Hz), 7.26 (1H, s), 7.39-7.45 (3H, m), 7.60-7.63(2H,m), 7.94 (1H, d, 15.9Hz). <Reference Example 15>
2-methylthio-4- (trans-2-phenylethenyl) -6-trifluoromethylpyrimidine

4-Chloro-2-methylthio-6-trifluoromethylpyrimidine (Gershon, H, et al, J. Heterocyclic Chem., 24, 205 (1987); Gershon, H., et al, J. Heterocyclic Chem , 24, 1243 (1987)) (77 mg, 0.34 mmol), trans-2-phenylvinyl boric acid (50 mg, 0.34 mmol) and tetrakistriphenylphosphine palladium (Pd (Ph ₃ P) ₄ ) (35 mg, 0.03 mmol) ) Was suspended in toluene (3 mL), 1 mol / L Na ₂ CO ₃ aqueous solution (2 mL) was added, and the mixture was heated to reflux for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate, and then the organic layer was washed with water and saturated brine. After drying over sodium sulfate, the mixture was concentrated and the residue was purified with a silica gel column (hexane: ethyl acetate = 30: 1 ^v / _v ). The target product (82 mg, 82%) was obtained as a yellow solid.
¹ H-NMR (CDCl ₃ 400 MHz) δ: 2.65 (3H, s), 7.06 (1H, d, 15.9 Hz), 7.26 (1H, s), 7.39-7.45 (3H, m), 7.60-7.63 (2H, m), 7.94 (1H, d, 15.9Hz).

<Reference Examples 16-23>
The compounds shown in Table 3 were synthesized in the same manner as in Reference Example 15.

参考例９の化合物 (490mg, 2.35mmol) をTHF（10mL）に溶かし、そこにカテコールボラン (5mL の 1mol/L THF溶液, 5.00mmol) を加え、8時間加熱還流した。反応液を希塩酸にあけ、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して濃縮した。残渣と４−クロロ−２−メチルチオ−6−トリフルオロメチルピリミジン( 540 mg, 2.38 mmol)と Pd(Ph₃P)₄ (200mg)をトルエン(20mL)に懸濁し、1mol/L Na₂CO₃ 水溶液 (20mL)を加え、4時間加熱還流した。反応液を水にあけ、酢酸エチルで抽出した後、有機層を水と飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝20 : 1 ^v/_v）で精製した。黄色アモルファスの目的物 (750mg 79% （２工程）)を得た。
¹H-NMR (CDCl₃) δ: 2.64 (3H, s), 5.12 (2H, s), 6.92 (1H, d, J = 16.5 Hz), 7.01 (2H, d, J = 9.0 Hz), 7.21 (1H, s), 7.35-7.42 (5H, m), 7.56 (2H, d, J = 9.0 Hz), 7.90 (1H, d, J = 15.9 Hz). <Reference Example 24>
2-Methylthio-4- [trans-2- (4-benzyloxyphenyl) ethenyl] -6-trifluoromethylpyrimidine

The compound of Reference Example 9 (490 mg, 2.35 mmol) was dissolved in THF (10 mL), catecholborane (5 mL of 1 mol / L THF solution, 5.00 mmol) was added thereto, and the mixture was heated to reflux for 8 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue, 4-chloro-2-methylthio-6-trifluoromethylpyrimidine (540 mg, 2.38 mmol) and Pd (Ph ₃ P) ₄ (200 mg) were suspended in toluene (20 mL), and 1 mol / L Na ₂ CO ₃ was suspended. Aqueous solution (20 mL) was added and heated to reflux for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate, and then the organic layer was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 ^v / _v ). A yellow amorphous target product (750 mg 79% (2 steps)) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.64 (3H, s), 5.12 (2H, s), 6.92 (1H, d, J = 16.5 Hz), 7.01 (2H, d, J = 9.0 Hz), 7.21 ( 1H, s), 7.35-7.42 (5H, m), 7.56 (2H, d, J = 9.0 Hz), 7.90 (1H, d, J = 15.9 Hz).

<Reference Examples 25-27>
In the same manner as in Reference Example 24, the compounds shown in Table 4 were synthesized using the compounds of Reference Examples 10-12.

４−クロロ−２−メチルチオ−6−トリフルオロメチルピリミジン(740 mg, 3.24 mmol)とビニルほう酸ピナコールエステル (500 mg, 3.25 mmol)と PdCl₂(dppf) (50mg)をトルエン(10mL)に懸濁し、1mol/L Na₂CO₃ 水溶液 (10mL)を加え、15時間加熱還流した。反応液を水にあけ、酢酸エチルで抽出した後、有機層を水と飽和食塩水で洗浄した。硫酸ナトリウムで乾燥した後、濃縮し、残渣をシリカゲルカラム（ヘキサン：酢酸エチル=20:1 ^v/_v）で精製した。黄色油状物として目的物(593mg, 83%)を得た。
¹H-NMR(CDCl₃ 400MHz) δ： 2.61 (3H, s), 5.81 (1H, d, 10.5Hz), 6.57 (1H, d, 17.5Hz), 6.74 (1H, dd, 10.5Hz and 17.5Hz), 7.21 (1H, s). <Reference Example 28>
2-methylthio-4-trifluoromethyl-6-vinylpyrimidine

4-Chloro-2-methylthio-6-trifluoromethylpyrimidine (740 mg, 3.24 mmol), vinyl boric acid pinacol ester (500 mg, 3.25 mmol) and PdCl ₂ (dppf) (50 mg) were suspended in toluene (10 mL). 1 mol / L Na ₂ CO ₃ aqueous solution (10 mL) was added, and the mixture was heated to reflux for 15 hours. The reaction solution was poured into water and extracted with ethyl acetate, and then the organic layer was washed with water and saturated brine. After drying over sodium sulfate, the mixture was concentrated and the residue was purified with a silica gel column (hexane: ethyl acetate = 20: 1 ^v / _v ). The target product (593 mg, 83%) was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ 400 MHz) δ: 2.61 (3H, s), 5.81 (1H, d, 10.5Hz), 6.57 (1H, d, 17.5Hz), 6.74 (1H, dd, 10.5Hz and 17.5Hz) , 7.21 (1H, s).

参考例２８の化合物 (100mg, 0.45mmol) と ３−クロロフェニルほう酸 (240mg, 1.53mmol)をDMF(5mL)に溶解し、酢酸パラジウム (60mg) と Na₂CO₃ (500mg) を加え、空気を吹き込みながら50℃で10時間攪拌した。反応液を水にあけ、酢酸エチルで抽出した後、有機層を水と飽和食塩水で洗浄した。硫酸ナトリウムで乾燥した後、濃縮し、残渣をシリカゲルカラム（ヘキサン：酢酸エチル＝２０：1 ^v/_v）で精製した。黄色固体として目的物 (76mg, 50%)を得た。
¹H-NMR(CDCl₃ 400MHz) δ： 2.63 (3H, s), 7.02(1H, d, 15.9Hz), 7.22 (1H, s), 7.30-7.36 (2H, m), 7.45-7.47 (2H, m), 7.58 (1H, brs), 7.86 (1H, d, 15.9Hz). <Reference Example 29>
2-Methylthio-4- [trans-2- (3-chlorophenyl) ethenyl] -6-trifluoromethylpyrimidine

The compound of Reference Example 28 (100 mg, 0.45 mmol) and 3-chlorophenylboric acid (240 mg, 1.53 mmol) are dissolved in DMF (5 mL), palladium acetate (60 mg) and Na ₂ CO ₃ (500 mg) are added, and air is blown into the mixture. The mixture was stirred at 50 ° C. for 10 hours. The reaction solution was poured into water and extracted with ethyl acetate, and then the organic layer was washed with water and saturated brine. After drying over sodium sulfate, the mixture was concentrated and the residue was purified with a silica gel column (hexane: ethyl acetate = 20: 1 ^v / _v ). The target product (76 mg, 50%) was obtained as a yellow solid.
¹ H-NMR (CDCl ₃ 400 MHz) δ: 2.63 (3H, s), 7.02 (1H, d, 15.9 Hz), 7.22 (1H, s), 7.30-7.36 (2H, m), 7.45-7.47 (2H, m), 7.58 (1H, brs), 7.86 (1H, d, 15.9Hz).

<Reference Examples 30 to 32>
The compounds shown in Table 5 were synthesized in the same manner as in Reference Example 29.

アルゴン雰囲気下、ナトリウムｔ−ブトキシド（NaO^tBu） (45 mg , 0.04 mmol)、酢酸パラジウム (9 mg , 0.04 mmol)、トリ-t-ブチルホスフィン (10 mg, 0.05 mmol) をキシレン 2 mL に懸濁し、参考例２３の化合物 (132 mg, 0.40 mmol) を加えた。さらに、モルホリン(40 mg , 0.46 mmol) を加え、120℃で4時間攪拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥、濾過し、濃縮した。シリカゲルカラムクロマトグラフィー (ヘキサン：酢酸エチル＝1：1 ^v/_v) で分離精製し、黄色油状物 として目的物 (50 mg, 34 %) を得た。(cis:trans=1:3の混合物)
¹H -NMR (CDCl₃) δ: 2.52 (1H, s, cis isomer), 2.64 (3H, s, trans isomer), 3.21 (1H, t, J = 4.9 Hz, cis isomer), 3.27 (4H, t, J = 4.9 Hz, trans isomer), 3.85-3.89 (5H, m, trans isomer), 6.38 (1H, d, J = 12.2 Hz, cis isomer), 6.81 (1H, d, J = 8.6 Hz, cis isomer), 6.87-6.93 (3H, m, trans isomer), 6.98 (1H, d, J = 12.2 Hz, cis isomer), 7.12 (0H, s, cis isomer), 7.20 (1H, s, trans isomer), 7.31 (1H, d, J = 8.6 Hz, cis isomer), 7.53 (2H, d, J = 8.6 Hz, trans isomer), 7.87 (1H, d, J = 15.9 Hz, trans isomer). <Reference Example 33>
2-Methylthio-4- [trans-2- (4- (morpholin-4-yl) phenyl) ethenyl] -6-trifluoromethylpyrimidine

Suspend sodium t-butoxide (NaO ^t Bu) (45 mg, 0.04 mmol), palladium acetate (9 mg, 0.04 mmol), tri-t-butylphosphine (10 mg, 0.05 mmol) in 2 mL of xylene under an argon atmosphere. It became cloudy and the compound of Reference Example 23 (132 mg, 0.40 mmol) was added. Furthermore, morpholine (40 mg, 0.46 mmol) was added, and the mixture was stirred at 120 ° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. Separation and purification by silica gel column chromatography (hexane: ethyl acetate = 1: 1 ^v / _v ) gave the desired product (50 mg, 34%) as a yellow oil. (mixture of cis: trans = 1: 3)
¹ H -NMR (CDCl ₃ ) δ: 2.52 (1H, s, cis isomer), 2.64 (3H, s, trans isomer), 3.21 (1H, t, J = 4.9 Hz, cis isomer), 3.27 (4H, t , J = 4.9 Hz, trans isomer), 3.85-3.89 (5H, m, trans isomer), 6.38 (1H, d, J = 12.2 Hz, cis isomer), 6.81 (1H, d, J = 8.6 Hz, cis isomer) ), 6.87-6.93 (3H, m, trans isomer), 6.98 (1H, d, J = 12.2 Hz, cis isomer), 7.12 (0H, s, cis isomer), 7.20 (1H, s, trans isomer), 7.31 (1H, d, J = 8.6 Hz, cis isomer), 7.53 (2H, d, J = 8.6 Hz, trans isomer), 7.87 (1H, d, J = 15.9 Hz, trans isomer).

参考例３１の化合物 (80 mg, 0.25 mmol) をジクロロメタン(8 mL)に溶解し、メチルスルホニルクロリド (0.06 mL)、トリエチルアミン (0.08 mL) を加え常温で3時間攪拌した。水に注ぎ、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、濾過し濃縮した。シリカゲルカラムクロマトグラフィー (ヘキサン：酢酸エチル＝2：1 ^v/_v)で分離精製し、淡黄色結晶としてメタンスルホニル化された化合物 (70 mg, 71 %)を得た。この化合物をテトラヒドロフラン (5 mL) に溶解し、ピロリジン (0.06 mL, 0.72 mmol)、トリエチルアミン (0.10 mL) を加え室温で3時間攪拌した。水に注ぎ、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、濾過し濃縮した。シリカゲルカラムクロマトグラフィー (NH-シリカ、ヘキサン：酢酸エチル＝3：2 ^v/_v)で分離精製し、淡黄色油状物 として目的物(50 mg, 76 %)を得た。
¹H -NMR (CDCl₃)δ: 1.78-1.82 (4H, m), 2.50-2.55 (4H, m), 2.64 (3H, s), 3.65 (2H, s), 7.04 (1H, d, J = 15.9 Hz), 7.24 (1H, s), 7.39 (2H, d, J = 7.9 Hz), 7.56 (2H, d, J = 7.9 Hz), 7.93 (1H, d, J = 15.9 Hz). <Reference Example 34>
2-Methylthio-4- [trans-2- (4- (pyrrolidin-1-ylmethyl) phenyl) ethenyl] -6-trifluoromethylpyrimidine

The compound of Reference Example 31 (80 mg, 0.25 mmol) was dissolved in dichloromethane (8 mL), methylsulfonyl chloride (0.06 mL) and triethylamine (0.08 mL) were added, and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. Separation and purification by silica gel column chromatography (hexane: ethyl acetate = 2: 1 ^v / _v ) gave a methanesulfonylated compound (70 mg, 71%) as pale yellow crystals. This compound was dissolved in tetrahydrofuran (5 mL), pyrrolidine (0.06 mL, 0.72 mmol) and triethylamine (0.10 mL) were added, and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated. Separation and purification by silica gel column chromatography (NH-silica, hexane: ethyl acetate = 3: 2 ^v / _v ) gave the desired product (50 mg, 76%) as a pale yellow oil.
¹ H -NMR (CDCl ₃ ) δ: 1.78-1.82 (4H, m), 2.50-2.55 (4H, m), 2.64 (3H, s), 3.65 (2H, s), 7.04 (1H, d, J = 15.9 Hz), 7.24 (1H, s), 7.39 (2H, d, J = 7.9 Hz), 7.56 (2H, d, J = 7.9 Hz), 7.93 (1H, d, J = 15.9 Hz).

参考例２４の化合物 (238mg, 0.59 mmol) をジクロロメタン(5mL)に溶かし、室温でジメチルスルフィド(1mL)と三フッ化ホウ素−ジエチルエーテル錯体（BF₃-Et₂O）(1mL)を加えた。20時間加熱還流した後、反応液を水にあけ、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、硫酸ナトリウムで乾燥して、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝3 : 1 ^v/_v）で精製した。黄色固体の目的物 (140mg, 76% )を得た。
¹H -NMR (CDCl₃) δ: 2.63 (3H, s), 5.95 (1H, br s), 6.88 (2H, d, J = 9.2 Hz), 6.90 (1H, d, J = 15.9 Hz), 7.21 (1H, s), 7.50 (2H, d, J = 9.2 Hz), 7.87 (1H, d, J = 15.9 Hz). <Reference Example 35>
2-Methylthio-4- [trans-2- (4-hydroxyphenyl) ethenyl] -6-trifluoromethylpyrimidine

The compound of Reference Example 24 (238 mg, 0.59 mmol) was dissolved in dichloromethane (5 mL), and dimethyl sulfide (1 mL) and boron trifluoride-diethyl ether complex (BF ₃ -Et ₂ O) (1 mL) were added at room temperature. After heating to reflux for 20 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 ^v / _v ). The target product (140 mg, 76%) was obtained as a yellow solid.
¹ H -NMR (CDCl ₃ ) δ: 2.63 (3H, s), 5.95 (1H, br s), 6.88 (2H, d, J = 9.2 Hz), 6.90 (1H, d, J = 15.9 Hz), 7.21 (1H, s), 7.50 (2H, d, J = 9.2 Hz), 7.87 (1H, d, J = 15.9 Hz).

参考例３５の化合物(119mg, 0.38 mmol) をDMF(5mL)に溶かし、常温で炭酸カリウム(300mg, 2.17mmol)と３，５−ビストリフルオロメチルベンジルブロミド(0.09mL, 0.49mmol)を加えた。反応液を常温で1.5時間攪拌後、反応液を水にあけ、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、硫酸ナトリウムで乾燥して、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝10 : 1 ^v/_v）で精製し、目的物を得た。
¹H-NMR (CDCl₃) δ: 2.64 (3H, s), 5.21 (2H, s), 6.95 (1H, d, J = 15.9 Hz), 7.03 (2H, d, J = 9.2 Hz), 7.22 (1H, s), 7.60 (2H, d, J = 8.6 Hz), 7.85-7.90 (4H, m). <Reference Example 36>
2-Methylthio-4- [trans-2- (4- (3,5-bistrifluoromethylbenzyloxy) phenyl) ethenyl] -6-trifluoromethylpyrimidine

The compound of Reference Example 35 (119 mg, 0.38 mmol) was dissolved in DMF (5 mL), and potassium carbonate (300 mg, 2.17 mmol) and 3,5-bistrifluoromethylbenzyl bromide (0.09 mL, 0.49 mmol) were added at room temperature. After stirring the reaction solution at room temperature for 1.5 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 ^v / _v ) to obtain the desired product.
¹ H-NMR (CDCl ₃ ) δ: 2.64 (3H, s), 5.21 (2H, s), 6.95 (1H, d, J = 15.9 Hz), 7.03 (2H, d, J = 9.2 Hz), 7.22 ( 1H, s), 7.60 (2H, d, J = 8.6 Hz), 7.85-7.90 (4H, m).

<Reference Examples 37 to 40>
The compounds shown in Table 6 were synthesized in the same manner as in Reference Example 36.

参考例３５の化合物(50mg, 0.16mmol)、4−クロロフェニルほう酸(60mg, 0.38mmol)、酢酸銅(II)(30mg, 0.17mmol)、モリキュラーシーブス４A(200mg)を塩化メチレン(2mL)に懸濁させ、トリエチルアミン(0.12mL)を加えた。反応液を常温で15時間撹拌した後、反応液をセライトを通してろ過し、濾液を濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝50 : 1 ^v/_v）で精製し、黄色アモルファスの目的物(41mg, 61%)を得た。
¹H-NMR (CDCl₃) δ: 2.64 (3H, s), 6.96 (1H, d, J = 15.9 Hz), 7.00-7.01 (4H, m), 7.22 (1H, s), 7.34 (2H, d, J = 8.6 Hz), 7.58 (2H, d, J = 8.6 Hz), 7.91 (1H, d, J = 15.9 Hz). <Reference Example 41>
2-Methylthio-4- [trans-2- (4- (4-chlorophenoxy) phenyl) ethenyl] -6-trifluoromethylpyrimidine

The compound of Reference Example 35 (50 mg, 0.16 mmol), 4-chlorophenylboric acid (60 mg, 0.38 mmol), copper (II) acetate (30 mg, 0.17 mmol), and molecular sieves 4A (200 mg) were suspended in methylene chloride (2 mL). Turbid and triethylamine (0.12 mL) was added. After stirring the reaction solution at room temperature for 15 hours, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1 ^v / _v ) to obtain a yellow amorphous target product (41 mg, 61%).
¹ H-NMR (CDCl ₃ ) δ: 2.64 (3H, s), 6.96 (1H, d, J = 15.9 Hz), 7.00-7.01 (4H, m), 7.22 (1H, s), 7.34 (2H, d , J = 8.6 Hz), 7.58 (2H, d, J = 8.6 Hz), 7.91 (1H, d, J = 15.9 Hz).

<Reference Examples 42 and 43>
The compounds shown in Table 7 were synthesized in the same manner as in Reference Example 41.

４−クロロフェニルアセチレン(207mg, 1.52mmol) と4−クロロ−２−メチルチオ−６−トリフルオロメチルピリミジン(300mg, 1.31mmol) をトリエチルアミン(5mL)に溶かし、PdCl₂(Ph₃P)₂ (30mg) と ヨウ化銅（I） (30mg) を加え、常温で一晩攪拌した。反応液を希塩酸にあけ、酢酸エチルにて抽出した。有機層を水と飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝40:1 ^v/_v）で精製し、茶色固体の目的物(126 mg, 25%) を得た。
¹H-NMR(CDCl₃ 400MHz) δ： 2.53 (3H, s), 7.28 (1H, s), 7.30 (2H, d, 8.6Hz), 7.47 (2H, d, 8.6Hz). <Reference Example 44>
2-Methylthio-4- [2- (4-chlorophenyl) ethynyl] -6-trifluoromethylpyrimidine

4-Chlorophenylacetylene (207 mg, 1.52 mmol) and 4-chloro-2-methylthio-6-trifluoromethylpyrimidine (300 mg, 1.31 mmol) were dissolved in triethylamine (5 mL), and PdCl ₂ (Ph ₃ P) ₂ (30 mg) And copper iodide (I) (30 mg) were added and stirred overnight at room temperature. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 40: 1 ^v / _v ) to obtain the desired product (126 mg, 25%) as a brown solid.
¹ H-NMR (CDCl ₃ 400 MHz) δ: 2.53 (3H, s), 7.28 (1H, s), 7.30 (2H, d, 8.6Hz), 7.47 (2H, d, 8.6Hz).

４−クロロスチレン (180 mg, 1.30 mmol) をTHF(10mL)に溶かし、氷冷下9-BBN(0.5mol/L in THF, 2.60mL, 1.30mmol)を滴下した。常温で一晩攪拌した後、反応液に4−クロロ−２−メチルチオ−６−トリフルオロメチルピリミジン(300mg, 1.31mmol)とPdCl₂(dppf) (100mg)とK₂CO₃(500mg)とDMF(5mL)と水（0．7mL）を加え、５０℃で2.5時間攪拌した。反応液を水にあけ、酢酸エチルにて抽出した。有機層を水と飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝40:1 ^v/_v）で精製し、黄色油状物の目的物(79 mg, 18%) を得た。
¹H-NMR(CDCl₃ 400MHz) δ： 2.59(3H, s), 3.06 (4H, s), 7.03 (1H, s), 7.11 (2H, d, 7.5Hz), 7.25 (2H, d, 7.5Hz). <Reference Example 45>
2-Methylthio-4- [2- (4-chlorophenyl) ethyl] -6-trifluoromethylpyrimidine

4-Chlorostyrene (180 mg, 1.30 mmol) was dissolved in THF (10 mL), and 9-BBN (0.5 mol / L in THF, 2.60 mL, 1.30 mmol) was added dropwise under ice cooling. After stirring overnight at room temperature, the reaction solution was mixed with 4-chloro-2-methylthio-6-trifluoromethylpyrimidine (300 mg, 1.31 mmol), PdCl ₂ (dppf) (100 mg), K ₂ CO ₃ (500 mg) and DMF. (5 mL) and water (0.7 mL) were added, and the mixture was stirred at 50 ° C. for 2.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 40: 1 ^v / _v ) to obtain the desired product (79 mg, 18%) as a yellow oil.
¹ H-NMR (CDCl ₃ 400 MHz) δ: 2.59 (3H, s), 3.06 (4H, s), 7.03 (1H, s), 7.11 (2H, d, 7.5Hz), 7.25 (2H, d, 7.5Hz ).

４−クロロベンズアミド (250 mg, 1.61 mmol) をDMF（5mL）に溶かし、氷冷下６０％水素化ナトリウム (55mg, 1.38 mmol) を加えた。常温で１５分攪拌した後、4−クロロ−２−メチルチオ−６−トリフルオロメチルピリミジン(300 mg, 1.31 mmol)のジクロロメタン溶液を滴下した。常温で2時間攪拌した後、反応液を希塩酸にあけ酢酸エチルにて抽出した後、有機層を水と飽和食塩水で洗浄し、硫酸ナトリウムで乾燥して濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝20:1 ^v/_v）で精製し、白色固体として目的物 (137mg, 30%)を得た。
¹H-NMR(CDCl₃ 400MHz) δ： 2.60 (3H, s), 7.52 (2H, d, 8.3Hz), 7.87 (2H, d, 8.3Hz), 8.31 (1H, s), 8.66 (1H, brs). <Reference Example 46>
4-Chloro-N- (2-methylthio-6-trifluoromethylpyrimidin-4-yl) benzamide

4-Chlorobenzamide (250 mg, 1.61 mmol) was dissolved in DMF (5 mL), and 60% sodium hydride (55 mg, 1.38 mmol) was added under ice cooling. After stirring at room temperature for 15 minutes, a dichloromethane solution of 4-chloro-2-methylthio-6-trifluoromethylpyrimidine (300 mg, 1.31 mmol) was added dropwise. After stirring at room temperature for 2 hours, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 ^v / _v ) to obtain the desired product (137 mg, 30%) as a white solid.
¹ H-NMR (CDCl ₃ 400 MHz) δ: 2.60 (3H, s), 7.52 (2H, d, 8.3Hz), 7.87 (2H, d, 8.3Hz), 8.31 (1H, s), 8.66 (1H, brs ).

<Reference Example 47>
4- (4-Chlorobenzyloxy) -2-methylthio-6-trifluoromethylpyrimidine

４−クロロベンジルアルコール (150 mg, 1.05 mmol) をDMF（2mL）に溶かし、氷冷下６０％水素化ナトリウム (35mg, 0.88mmol) を加えた。０℃で30分攪拌した後、4−クロロ−２−メチルチオ−６−トリフルオロメチルピリミジン(200 mg, 0.87 mmol)のジクロロメタン溶液を滴下した。常温で5時間攪拌した後、反応液を水にあけ酢酸エチルにて抽出した後、有機層を水と飽和食塩水で洗浄し、硫酸ナトリウムで乾燥して濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝20:1 ^v/_v）で精製し、無色油状物として目的物 (252mg, 87%)を得た。
¹H-NMR(CDCl₃ 400MHz) δ： 2.56 (3H, s), 5.42 (2H, s), 6.73 (1H, s), 7.35 (4H, s).

4-Chlorobenzyl alcohol (150 mg, 1.05 mmol) was dissolved in DMF (2 mL), and 60% sodium hydride (35 mg, 0.88 mmol) was added under ice cooling. After stirring at 0 ° C. for 30 minutes, a dichloromethane solution of 4-chloro-2-methylthio-6-trifluoromethylpyrimidine (200 mg, 0.87 mmol) was added dropwise. After stirring at room temperature for 5 hours, the reaction solution was poured into water and extracted with ethyl acetate, and then the organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 ^v / _v ) to obtain the desired product (252 mg, 87%) as a colorless oil.
¹ H-NMR (CDCl ₃ 400 MHz) δ: 2.56 (3H, s), 5.42 (2H, s), 6.73 (1H, s), 7.35 (4H, s).

4−クロロ−２−メチルチオ−６−トリフルオロメチルピリミジン(230 mg, 1.00 mmol)をジクロロメタン（3mL）に溶かし、４−クロロベンジルアミン (320 mg, 2.56 mmol)のジクロロメタン溶液を室温で滴下した。室温で5時間攪拌した後、反応液を水にあけ酢酸エチルにて抽出して、有機層を水と飽和食塩水で洗浄し、硫酸ナトリウムで乾燥して濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝10:1 ^v/_v）で精製し、白色固体として目的物 (195mg, 58%)を得た。
¹H-NMR(CDCl₃ 400MHz) δ： 2.50 (3H, s), 4.61 (2H, br), 5.34 (1H, br), 6.34 (1H, s), 7.25 (2H, d, 7.9Hz), 7.33 (2H, d, 7.9Hz). <Reference Example 48>
4- (4-Chlorobenzylamino) -2-methylthio-6-trifluoromethylpyrimidine

4-Chloro-2-methylthio-6-trifluoromethylpyrimidine (230 mg, 1.00 mmol) was dissolved in dichloromethane (3 mL), and a dichloromethane solution of 4-chlorobenzylamine (320 mg, 2.56 mmol) was added dropwise at room temperature. After stirring at room temperature for 5 hours, the reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 ^v / _v ) to obtain the desired product (195 mg, 58%) as a white solid.
¹ H-NMR (CDCl ₃ 400 MHz) δ: 2.50 (3H, s), 4.61 (2H, br), 5.34 (1H, br), 6.34 (1H, s), 7.25 (2H, d, 7.9 Hz), 7.33 (2H, d, 7.9Hz).

参考例１５の化合物 (10mg, 0.034mmol) をジクロロメタン(2mL)に溶かし、常温でmCPBA(18mg, 0.104mmol)を加えた。2時間攪拌後、反応液を亜硫酸水素ナトリウム水溶液にあけ、酢酸エチルで抽出した。有機層を亜硫酸水素ナトリウム水溶液と飽和重曹水と飽和食塩水で洗浄し、硫酸ナトリウムで乾燥して、濃縮した。残渣をシリカゲルカラムクロマトグラフィー （ヘキサン：酢酸エチル＝3:1 ^v/_v）で精製し、黄色固体の目的物 (8mg,72％)を得た。
¹H-NMR (CDCl₃, 400MHz) δ: 3.45(3H, s), 7.23(1H, d, 16.2Hz), 7.43-7.47(3H, m), 7,64-7.68(2H, m), 7.75 (1H, s), 8.19 (1H, d, 16.2Hz). <Reference Example 49>
2-Methanesulfonyl-4- (trans-2-phenylethenyl) -6-trifluoromethylpyrimidine

The compound of Reference Example 15 (10 mg, 0.034 mmol) was dissolved in dichloromethane (2 mL), and mCPBA (18 mg, 0.104 mmol) was added at room temperature. After stirring for 2 hours, the reaction solution was poured into an aqueous sodium hydrogen sulfite solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bisulfite solution, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 ^v / _v ) to obtain the desired product (8 mg, 72%) as a yellow solid.
¹ H-NMR (CDCl ₃ , 400MHz) δ: 3.45 (3H, s), 7.23 (1H, d, 16.2Hz), 7.43-7.47 (3H, m), 7,64-7.68 (2H, m), 7.75 (1H, s), 8.19 (1H, d, 16.2Hz).

<Reference Examples 50-71>
Using the compounds of Reference Examples 16 to 27, 29, 36 to 38, 42, and 44 to 48, the compounds shown in Tables 8 to 11 were synthesized in the same manner as in Reference Example 44.

参考例３９の化合物(60mg, 0.137mmol)をメタノール(30mL)に溶解し、OXONE(250mg, 0.41mmol)を加えた。４０℃で3時間撹拌した後、反応液を飽和重曹水に加え、酢酸エチルにて抽出した。有機層を水と飽和食塩水で洗浄し、硫酸ナトリウムで乾燥して、濃縮した。黄色アモルファスの目的物(56mg, 90%)を得た。
¹H-NMR (CDCl₃) δ: 3.03 (3H, s), 5.09 (2H, s), 7.01 (2H, d, J = 9.0 Hz), 7.10 (1H, d, J = 15.9 Hz), 7.37 (4H, s), 7.59 (1H, s), 7.60 (2H, d, J = 9.0 Hz), 8.12 (1H, d, J = 15.9 Hz). <Reference Example 72>
2-Methylsulfoxy-4- [trans-2- (4- (4-chlorobenzyloxy) phenyl) ethenyl] -6-trifluoromethylpyrimidine

The compound of Reference Example 39 (60 mg, 0.137 mmol) was dissolved in methanol (30 mL), and OXONE (250 mg, 0.41 mmol) was added. After stirring at 40 ° C. for 3 hours, the reaction solution was added to saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. A yellow amorphous target product (56 mg, 90%) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 3.03 (3H, s), 5.09 (2H, s), 7.01 (2H, d, J = 9.0 Hz), 7.10 (1H, d, J = 15.9 Hz), 7.37 ( 4H, s), 7.59 (1H, s), 7.60 (2H, d, J = 9.0 Hz), 8.12 (1H, d, J = 15.9 Hz).

<Reference Examples 73 to 78>
Using the compounds of Reference Examples 32-34, 40, 41 and 43, the compounds shown in Table 12 were synthesized in the same manner as in Reference Example 72.

<Reference Example 79>
2-Methylsulfoxy-4- [trans-2- (4-methyloxycarbonylphenyl) ethenyl] -6-trifluoromethylpyrimidine

参考例３０の化合物(50mg, 0.16mmol)をメタノール(30mL)に溶解し、OXONE(300mg, 0.49mmol)を加えた。５０℃で２時間撹拌した後、反応液にチオ硫酸ナトリウム水溶液を加え、飽和重曹水中に注ぎ、酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥して、濃縮した。淡黄色粉末の目的物をスルホキシド体・スルホン体の混合物として得た(30mg)。
スルホキシド体（ｎ＝１)； ¹H -NMR (CDCl₃) δ: 3.05 (3H, s), 3.95 (3H, s), 7.32 (1H, d, J = 15.9 Hz), 7.67 (1H, s), 7.72 (2H, d, J = 8.6 Hz), 8.11 (2H, d, J = 8.6 Hz), 8.21 (1H, d, J = 15.9 Hz).

スルホン体（ｎ＝２）； ¹H -NMR (CDCl₃) δ: 3.46 (3H, s), 3.95 (4H, s), 7.31 (1H, d, J = 15.9 Hz), 7.73 (2H, d, J = 8.6 Hz), 7.78 (1H, s), 8.12 (2H, d, J = 8.6 Hz), 8.23 (1H, d, J = 15.9 Hz).

The compound of Reference Example 30 (50 mg, 0.16 mmol) was dissolved in methanol (30 mL), and OXONE (300 mg, 0.49 mmol) was added. After stirring at 50 ° C. for 2 hours, an aqueous sodium thiosulfate solution was added to the reaction solution, poured into saturated sodium bicarbonate water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. A light yellow powder was obtained as a mixture of sulfoxide and sulfone (30 mg).
Sulfoxides body ^{(n = 1); 1 H} -NMR (CDCl 3) δ: 3.05 (3H, s), 3.95 (3H, s), 7.32 (1H, d, J = 15.9 Hz), 7.67 (1H, s) , 7.72 (2H, d, J = 8.6 Hz), 8.11 (2H, d, J = 8.6 Hz), 8.21 (1H, d, J = 15.9 Hz).

Sulfone (n = 2); ¹ H-NMR (CDCl ₃ ) δ: 3.46 (3H, s), 3.95 (4H, s), 7.31 (1H, d, J = 15.9 Hz), 7.73 (2H, d, J = 8.6 Hz), 7.78 (1H, s), 8.12 (2H, d, J = 8.6 Hz), 8.23 (1H, d, J = 15.9 Hz).

<Example 1>
4- [trans-2- (4-chlorophenyl) ethenyl] -2- (pyrrolidin-1-yl) -6-trifluoromethylpyrimidine

参考例５７の化合物(30mg, 0.083 mmol)を１,４−ジオキサン (2mL)に溶かし、ピペリジノメチル−ポリスチレン (50mg) とピロリジン (0.02mL: 0.24mmol) を加え、50℃で2時間攪拌した。ポリスチレン−イソシアネート (50mg) を加え、更に30分攪拌した後、固体を濾去し、濾液を濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル＝20 : 1 ^v/_v)で精製し、黄色固体として目的物（8 mg, 27 ％）を得た。
高分解能質量分析 (EI) : 計算値.: 353.0907, 実測値 353.0871.

The compound of Reference Example 57 (30 mg, 0.083 mmol) was dissolved in 1,4-dioxane (2 mL), piperidinomethyl-polystyrene (50 mg) and pyrrolidine (0.02 mL: 0.24 mmol) were added, and the mixture was stirred at 50 ° C. for 2 hours. Polystyrene-isocyanate (50 mg) was added and the mixture was further stirred for 30 minutes, and then the solid was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 ^v / _v ) to obtain the desired product (8 mg, 27%) as a yellow solid.
High resolution mass spectrometry (EI): Calculated value: 353.0907, measured value 353.0871.

<Examples 2 to 9>
In the same manner as in Example 1, using the compound of Reference Example 57, the compounds shown in Table 13 were synthesized.

４−トリフルオロメチルベンジルアルコール(25 mg, 0.147 mmol) をDMF（2mL）に溶かし、６０％水素化ナトリウム (6mg, 0.15 mmol) を加えた。室温で20分攪拌した後、参考例５７の化合物(48mg, 0.132 mmol)のジクロロメタン溶液を滴下した。室温で一晩攪拌した後、反応液を希塩酸にあけ酢酸エチルにて抽出した後、有機層を水と飽和食塩水で洗浄し、硫酸ナトリウムで乾燥して濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル=20:1 ^v/_v）で精製し、黄色油状物として目的物 (31 mg, 51%)を得た。
高分解能質量分析(FAB) ； 計算値：459.0699, 実測値：459.0661. <Example 10>
4- [trans-2- (4-chlorophenyl) ethenyl] -2- (4-trifluoromethylbenzyloxy) -6-trifluoromethylpyrimidine

4-Trifluoromethylbenzyl alcohol (25 mg, 0.147 mmol) was dissolved in DMF (2 mL) and 60% sodium hydride (6 mg, 0.15 mmol) was added. After stirring at room temperature for 20 minutes, a dichloromethane solution of the compound of Reference Example 57 (48 mg, 0.132 mmol) was added dropwise. After stirring overnight at room temperature, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 ^v / _v ) to obtain the desired product (31 mg, 51%) as a yellow oil.
High resolution mass spectrometry (FAB); Calculated value: 459.0699, Actual value: 459.0661.

参考例４９の化合物(7mg, 0.021mmol)をTHF(2mL)に溶かし、１mol/L 水酸化ナトリウム水溶液(1mL)と触媒量のテトラブチルアンモニウムクロリドを加え、室温で2時間撹拌した。反応液を希塩酸に加え、酢酸エチルにて抽出した。有機層を水と飽和食塩水により洗浄し、硫酸ナトリウムで乾燥した後、濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル＝2:1 ^v/_v)で精製し、黄色固体の目的物(4mg, 70%)を得た。
高分解能質量分析（FAB）： 計算値：267.0745 実測値：267.0760 <Example 11>
2-Hydroxy-4- (trans-2-phenylethenyl) -6-trifluoromethylpyrimidine

The compound of Reference Example 49 (7 mg, 0.021 mmol) was dissolved in THF (2 mL), 1 mol / L aqueous sodium hydroxide solution (1 mL) and a catalytic amount of tetrabutylammonium chloride were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 ^v / _v ) to obtain the desired product (4 mg, 70%) as a yellow solid.
High resolution mass spectrometry (FAB): Calculated value: 267.0745 Actual value: 267.0760

<Examples 12 to 40>
The compounds shown in Tables 14 to 18 were synthesized in the same manner as in Example 11 using the compounds of Reference Examples 50 to 56 and 58 to 79.

<Experimental example 1> Measurement of HO activity in human umbilical vein endothelial cells (HUVEC)
HUVECs were subcultured in EB-2 medium containing 2% FCS, and those in the 6th to 9th generations were used for experiments. 4.5 mL of HUVEC (1 × 10 ⁵ cell / mL) was seeded in a collagen type I-coated 6 cm dish, dissolved in DMSO, and 0.5 mL of a test compound diluted 100-fold with a medium was added. After incubation for 24 hours in a 37 ° C. CO ₂ incubator, the cells were collected. Cells were disrupted by freezing and thawing, protein quantification was performed, and 60 to 100 μg was used as a sample.
The HO activity was measured according to the method of Taylor, JL et al. (Am. J. Physiol. 274, L582-L590, 1998). Sample contains 2 mg of rat liver supernatant protein, 20 μM hemin, 2 mM glucose 6-phosphate, 0.016 U / μL glucose 6-phosphate dehydrogenase, 0.8 mM nicotinamide adenine dinucleotide phosphate (hereinafter abbreviated as NADPH) After 450 μL of the reaction solution was added and stirred, the mixture was reacted for 1 hour. After adding 700 μL of chloroform and stirring well, the mixture was centrifuged at 9000 rpm and 4 ° C. for 5 minutes, and the absorbance (453 nm and 530 nm) of the lower layer (chloroform layer) was measured. The amount of bilirubin produced was calculated from the difference in absorbance between 453 nm and 530 nm, and was defined as HO activity.
The activation ratio was calculated using the following formula.

以上のように、一般式（１）で表される本発明化合物は、HO-1の活性化作用を持つことが確認された。

As described above, it was confirmed that the compound of the present invention represented by the general formula (1) has an HO-1 activation action.

[式中、Ｘ，Ｙ，Zは前述の通りである]で示される４−トリフルオロメチルピリミジン誘導体が上記実験例１で示したヒト臍帯静脈内皮細胞を用いた実験から、HOの誘導または誘導促進作用を有することが明らかになった。即ち、本発明の４−トリフルオロメチルピリミジン誘導体はHO-1のmRNAを上昇させることをし、HO-1 mRNAの誘導を介してHO活性を上昇させていることが判明した。
従って、本は発明の４−トリフルオロメチルピリミジン誘導体は、病態時に生体防御的に作用するHOの発現を誘導または促進する。
このような４−トリフルオロメチルピリミジン誘導体はHOの誘導剤または誘導促進剤として有用であり、様々な疾患の治療剤として、例えば急性肺傷害治療剤、慢性閉塞性肺疾患治療剤、喘息治療剤、移植臓器の保護剤などとして、様々な酸化的ストレスに対する生体防御剤として提供することができる。 General formula (1) of the present invention

From the experiment using human umbilical vein endothelial cells shown in Experimental Example 1 above, the 4-trifluoromethylpyrimidine derivative represented by the formula [wherein X, Y and Z are as described above] was induced or induced. It became clear that it had a promoting action. That is, it was found that the 4-trifluoromethylpyrimidine derivative of the present invention increases HO-1 mRNA and increases HO activity through induction of HO-1 mRNA.
Therefore, the 4-trifluoromethylpyrimidine derivative of the present invention induces or promotes the expression of HO acting as a biodefense at the time of pathology.
Such 4-trifluoromethylpyrimidine derivatives are useful as HO inducers or inducers, and as therapeutic agents for various diseases, for example, acute lung injury therapeutic agents, chronic obstructive pulmonary disease therapeutic agents, asthma therapeutic agents. As a protective agent for transplanted organs, it can be provided as a biological defense agent against various oxidative stresses.

Claims (8)

The following general formula (1)

[Wherein X is a phenyl group which may have a substituent, a heteroaromatic ring which may have a substituent, or a group represented by the general formula (1a)

(In the formula, m represents 1 or 2, Q represents a phenyl group which may have a substituent or a heteroaromatic ring which may have a substituent, and Ra represents hydrogen, a trifluoromethyl group, A trifluoromethoxy group, a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxyl group having 1 to 4 carbon atoms, a cyclic or acyclic amino group which may have a substituent having 2 to 6 carbon atoms, a halogen atom, Represents a carboxyl group or an acetyl group), or general formula (1b)

(Wherein A represents a bond or —O—, and Ra and Q are as described above),
Y is a hydroxyl group, a cyclic or acyclic amino group which may have a substituent having 2 to 6 carbon atoms, or a general formula (1c)

(Wherein E is _{-CH 2 O -, - CH 2} NH -, - CH 2 CH 2 NH- represents, Q is as defined above) represents, Z is -CH = CH -, - C≡C-, 4-trifluoromethylpyrimidine derivatives represented by —CH ₂ CH ₂ —, —CH ₂ O—, —CONH—] and their pharmacologically acceptable salts and hydrates thereof. General formula (1d)

[Wherein Xa represents the general formula (1e)

(In the formula, Rb has fluorine, a trifluoromethyl group, a trifluoromethoxy group, a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxyl group having 1 to 4 carbon atoms, and a substituent having 2 to 6 carbon atoms. A cyclic or acyclic amino group which may be excluded, except for the dimethylamino group and the pyrrolidin-1-yl group, or the general formula (1f)

(Where Qa is the general formula (1g)

(Wherein Rc has a chloro group, a trifluoromethyl group, a trifluoromethoxy group, a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxyl group having 1 to 4 carbon atoms, and a substituent having 2 to 6 carbon atoms. A cyclic or acyclic amino group which may be substituted), or a heteroaromatic ring which may have a substituent, or a compound represented by the general formula (1h)

(Wherein Qb is a phenyl group having a substituent, or a heteroaromatic ring optionally having a substituent, Ra is the same as in the case of general formula (1)), or general formula (1i)

(Wherein Q and Ra are the same as those in the case of the general formula (1)). 4. The 4-trifluoromethylpyrimidine derivatives according to claim 1, pharmaceutically acceptable salts thereof and hydration thereof Stuff. The compound represented by the general formula (1) is the following 1) to 4)
1) 2-hydroxy-4- [trans- (4-trifluoromethoxyphenyl) ethenyl] -6-trifluoromethylpyrimidine 2) 2-hydroxy-4- [trans- (4-biphenyl) ethenyl] -6-tri Fluoromethylpyrimidine 3) 2-hydroxy-4- [trans- (4-phenoxyphenyl) ethenyl] -6-trifluoromethylpyrimidine 4) 2-hydroxy-4- [trans- (4- (4-toluyl) phenyl) The 4-trifluoromethylpyrimidine derivatives according to claim 1, which are any one of ethenyl] -6-trifluoromethylpyrimidine, pharmacologically acceptable salts thereof, and hydrates thereof. A heme oxygenase inducer or inducer comprising at least one of the 4-trifluoromethylpyrimidine derivatives shown in claim 1 and pharmacologically acceptable salts thereof and hydrates thereof as an active ingredient. . Acute lung injury (ALI, ARDS) containing at least one or more of 4-trifluoromethylpyrimidine derivatives and their pharmacologically acceptable salts and hydrates thereof as claimed in claim 1 as active ingredients Therapeutic agent. The treatment of chronic obstructive pulmonary disease (COPD) comprising at least one of the 4-trifluoromethylpyrimidine derivatives shown in claim 1 and pharmacologically acceptable salts thereof and hydrates thereof as an active ingredient. Agent. A therapeutic agent for asthma, comprising as an active ingredient at least one of the 4-trifluoromethylpyrimidine derivatives shown in claim 1 and their pharmacologically acceptable salts and hydrates thereof. A protective agent for transplanted organs containing at least one of the 4-trifluoromethylpyrimidine derivatives shown in claim 1 and their pharmacologically acceptable salts and hydrates thereof as an active ingredient.