JP2014214118A - Pyrazole derivative or salt thereof and pharmaceutical composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel compound and a pharmaceutical composition useful for treatment and/or prevention of HIV virus infections.SOLUTION: Provided is a pyrazole derivative represented by the general formula (I) or a salt thereof (in the formula, Ris a Calkyl group, Ccycloalkyl group, a phenyl or naphthyl group which may have a substituent; Ris a hydrogen atom, a Calkyl group, or a phenyl group; Ris a hydrogen atom, a cyano group, or a Calkoxycarbonyl group; Rand Rare each independently a hydrogen atom, a halogen atom, a Calkyl group, or a Cacylamino group, a Calkylaminocarbonyl group, or a phenyl group or an indazolyl group which may have a Calkoxy group; and Xis *-CH=CH-**, *-CH-NH-**, *-NH-CH-**, or *-N=N-**), and a pharmaceutical composition containing the same.

Description

  The present invention relates to a pyrazole derivative or a salt thereof and a pharmaceutical composition containing them, and in particular, a pyrazole derivative useful for treatment such as treatment and / or prevention of a viral infection such as human immunodeficiency virus (HIV). Or its salt and pharmaceutical composition containing them.

  In the treatment of HIV infection, certain effects have been recognized by HAART therapy combined with reverse transcriptase inhibitors and protease inhibitors. A typical example of a drug having an action mechanism different from that of a reverse transcriptase inhibitor or a protease inhibitor is Fuzeon, which is a commercially available membrane fusion inhibitor. A pyrazole derivative compound having a pharmacological action against HIV has also been reported (see Patent Document 1).

JP-A-8-245384

  Since HIV tends to acquire drug resistance due to mutations and is often difficult to treat with conventional drugs, the mechanism of action differs from that of existing products such as reverse transcriptase inhibitors and protease inhibitors. There is a need to develop drugs with an introductory. In addition, Fuzeon, a membrane fusion inhibitor, is a peptidic compound, and therefore has problems in terms of in vivo stability and absorbability, so the development of low molecular weight compounds with similar or alternative actions is hoped for. It is rare. So far, in addition to the pyrazole derivative compounds described in Patent Document 1, researches on the search for novel anti-HIV active compounds with compounds having various skeletons have been conducted. There are few examples.

  Accordingly, an object of the present invention is to provide a novel compound and a pharmaceutical composition useful for treatment such as treatment and / or prevention of viral infection.

（上記式中、
Ｒ^１は、C_１−６アルキル基；C_３−８シクロアルキル基；置換基群αから選択される少なくとも１つの置換基を有してもよいフェニル基もしくはナフチル基；または；フェニル基を有してもよいチアゾリル基、ピリジル基、キノリル基もしくはイソキノリル基を表し、
ここで、置換基群αは、ハロゲン原子；シアノ基；ニトロ基；ハロゲン原子を有してもよいC_１−６アルキル基；ハロゲン原子を有してもよいC_１−６アルコキシ基（結合する炭素原子およびそれに隣接炭素原子と一緒になって、ハロゲン原子を有してもよい1,3−ベンゾジオキソール環を形成してもよい）； C_１−６アシルアミノ基；または；ハロゲン原子、C_１−６アルキル基、C_１−６アルコキシ基および（Ｎ−C_１−６アルキル）C_１−６アルキルスルホニルアミノ基からなる群から選択される少なくとも１つの置換基を有してもよいフェニル基、ナフチル基、ピリジル基もしくはキノリル基；であり、
Ｒ^２は、水素原子、C_１−３アルキル基またはフェニル基を表し、
Ｒ^３は、水素原子、シアノ基またはC_１−６アルコキシカルボニル基を表し、
Ｒ^４およびＲ^６は、それぞれ独立に、水素原子；ハロゲン原子；C_１−６アルキル基；C_１−６アシルアミノ基；C_１−６アルキルアミノカルボニル基；または；C_１−６アルコキシ基を有してもよいフェニル基；を表し、但し、Ｒ^４およびＲ^６の少なくとも一方は、水素原子以外の置換基であり、
Ｒ^５は、水素原子、水酸基またはC_１−６アルコキシ基を表し、但し、Ｒ^５と、Ｒ^４もしくはＲ^６と、それぞれが結合する炭素原子と一緒になって、インダゾール環を形成してもよく、
Ｘ^１は、＊−CH＝CH−＊＊、＊−CH₂−NH−＊＊、＊−NH−CH₂−＊＊または＊−N＝N−＊＊を表し、ここで、＊は上記式中のピラゾール環側との結合、＊＊は上記式中のフェニル環側との結合である）で表されるピラゾール誘導体またはその塩を提供する。 As a result of continual research to solve the above problems, the present inventors have found that a pyrazole derivative having a specific structure or a salt thereof is useful for treatment such as treatment and / or prevention of viral infections. As a result, the present invention has been completed.
That is, the present invention provides the following general formula (I),

(In the above formula,
R ¹ is a C _1-6 alkyl group; a C _3-8 cycloalkyl group; a phenyl group or a naphthyl group which may have at least one substituent selected from the substituent group α; or; Represents a thiazolyl group, pyridyl group, quinolyl group or isoquinolyl group,
Here, the substituent group α is a halogen atom; a cyano group; a nitro group; a C _1-6 alkyl group that may have a halogen atom; a C _1-6 alkoxy group that may have a halogen atom (bonded). A carbon atom and a carbon atom adjacent thereto may form a 1,3-benzodioxole ring which may have a halogen atom); a C _1-6 acylamino group; or a halogen atom, Phenyl optionally having at least one substituent selected from the group consisting of a C _1-6 alkyl group, a C _1-6 alkoxy group, and an (N—C _1-6 alkyl) C _1-6 alkylsulfonylamino group A group, naphthyl group, pyridyl group or quinolyl group;
R ² represents a hydrogen atom, a C _1-3 alkyl group or a phenyl group,
R ³ represents a hydrogen atom, a cyano group or a C _1-6 alkoxycarbonyl group,
R ⁴ and R ⁶ each independently have a hydrogen atom; a halogen atom; a C _1-6 alkyl group; a C _1-6 acylamino group; a C _1-6 alkylaminocarbonyl group; or a C _1-6 alkoxy group. An at least one of R ⁴ and R ⁶ is a substituent other than a hydrogen atom;
R ⁵ represents a hydrogen atom, a hydroxyl group or a C _1-6 alkoxy group, provided that R ⁵ and R ⁴ or R ⁶ may be combined with the carbon atom to which each is bonded to form an indazole ring. Often,
X ¹ represents * —CH═CH — **, * —CH ₂ —NH — **, * —NH—CH ₂ — ** or * —N = N — **, where * is the above In the formula, a bond with the pyrazole ring side, and ** is a bond with the phenyl ring side in the above formula), or a salt thereof.

  The present invention also provides a pharmaceutical composition containing the pyrazole derivative of the present invention or a salt thereof. The pharmaceutical composition of the present invention is suitably used as a pharmaceutical composition for treatment such as treatment and / or prevention of viral infections, and particularly as a pharmaceutical composition in which the virus is human immunodeficiency virus (HIV). Preferably used.

  Furthermore, the present invention provides a method for treating and / or preventing a viral infection. Preferably, a method comprising the step of administering a therapeutically effective amount of the above-mentioned pyrazole derivative or a salt thereof to mammals including mammals or mammals, a method for treating human immunodeficiency virus (HIV), wherein the pyrazole derivative or A method is provided comprising the step of administering a therapeutically effective amount of the salt to a mammal, including a human, or a mammal. The present invention further relates to the use of the pyrazole derivatives or salts thereof of the present invention for the manufacture of pharmaceutical compositions, in particular for the treatment such as treatment and / or prevention of viral infections such as human immunodeficiency virus (HIV). There is provided the use of a pyrazole derivative of the present invention or a salt thereof for the manufacture of a pharmaceutical composition.

  The pyrazole derivative of the present invention or a salt thereof is excellent in the effect of treatment such as treatment and / or prevention of a viral infection, and the pharmaceutical composition of the present invention contains the pyrazole derivative of the present invention or a salt thereof, It is a pharmaceutical composition excellent in the effect of treatment, such as treatment and / or prevention. In particular, it is excellent in the effect of treatment such as treatment and / or prevention of RNA virus, human immunodeficiency virus (HIV).

Hereinafter, the compound of the present invention will be described in detail.
In the present specification, unless otherwise specified, the following definitions are used.
A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The C _1-6 alkyl group is a linear or branched C _1-6 such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups. An alkyl group is meant.
C _1-3 alkyl group means a methyl, ethyl, propyl or isopropyl group.
A C _3-8 cycloalkyl group means a C _3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
The C _1-6 alkoxy group is a linear or branched C _1- group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups. ₆ means an alkyloxy group.
The acyl group means formyl group, succinyl group, glutaryl group, maleoyl group, phthaloyl group, C _2-12 alkanoyl group, aroyl group, heterocyclic carbonyl group or (α-substituted) aminoacetyl group.
The C _1-6 acylamino group means a substituent represented by —NHC (O) R, wherein R is a C _1-6 alkyl group (the carbon number does not include the carbon number of the carbonyl group). Here, the C _1-6 alkyl group is as described above.
The C _1-6 alkylaminocarbonyl group means a substituent represented by —C (O) NHR, wherein R is a C _1-6 alkyl group (the carbon number does not include the carbon number of the carbonyl group). Here, the C _1-6 alkyl group is as described above.

Aliphatic hydrocarbons include pentane, hexane or cyclohexane.
Examples of halogenated hydrocarbons include methylene chloride, chloroform or dichloroethane.
Examples of alcohols include methanol, ethanol, propanol, 2-propanol, butanol, and 2-methyl-2-propanol.
Examples of ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether.

Examples of ketones include acetone, 2-butanone, and 4-methyl-2-pentanone.
Esters include methyl acetate, ethyl acetate, propyl acetate or butyl acetate.
Examples of amides include N, N-dimethylformamide, N, N-dimethylacetamide, and 1-methyl-2-pyrrolidone.
Examples of the sulfoxides include dimethyl sulfoxide.
Aromatic hydrocarbons include benzene, toluene or xylene.

  Examples of the salt of the compound of the general formula (I) include a salt in a basic group such as a commonly known amino group or an acidic group such as a hydroxyl or carboxyl group.

  Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.

Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N- Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
Among the above-mentioned salts, preferred salts include pharmacologically acceptable salts.

で表されることを特徴とするものである。 The pyrazole derivative of the present invention has the following general formula (I),

It is characterized by being represented by.

R ¹ is a C _1-6 alkyl group; a C _3-8 cycloalkyl group; a phenyl group or a naphthyl group which may have at least one substituent selected from the substituent group α; or; It may be a thiazolyl group, a pyridyl group, a quinolyl group or an isoquinolyl group. R ¹ is preferably a C _3-8 cycloalkyl group; a phenyl group or naphthyl group which may have at least one substituent selected from substituent group α; or; may have a phenyl group A thiazolyl group, a pyridyl group, a quinolyl group or an isoquinolyl group, more preferably a phenyl group which may have at least one substituent selected from the substituent group α; or; a quinolyl group, more preferably A phenyl group having at least one substituent selected from substituent group α; or; a quinolyl group.
Examples of the C _1-6 alkyl group, for example, there may be mentioned methyl group, ethyl group and propyl group preferably, more preferably a methyl group.
The C _3-8 cycloalkyl group is preferably a cyclohexyl group.

The substituent group α includes a halogen atom; a cyano group; a nitro group; a C _1-6 alkyl group that may have a halogen atom; a C _1-6 alkoxy group that may have a halogen atom (bonded carbon atoms and It may be combined with adjacent carbon atoms to form a 1,3-benzodioxole ring which may have a halogen atom); a C _1-6 acylamino group; or; a halogen atom, C _{1- A} phenyl group optionally having at least one substituent selected from the group consisting of a ₆ alkyl group, a C _1-6 alkoxy group and a (N—C _1-6 alkyl) C _1-6 alkylsulfonylamino group, naphthyl Group, pyridyl group or quinolyl group. Substituent group α is preferably a halogen atom; a C _1-6 alkyl group; a C _1-6 alkoxy group; or; a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group and (N—C _{1 -6} alkyl) C _1-6 at least one substituent a phenyl group which may have a selected from the group consisting of alkylsulfonylamino group, more preferably a halogen atom, C _1-6 alkyl groups, C It is a phenyl group which may have at least one substituent selected from the group consisting of a _1-6 alkoxy group and a (N—C _1-6 alkyl) C _1-6 alkylsulfonylamino group.
Here, as a halogen atom, a fluorine atom, a chlorine atom, and a bromine atom can be mentioned suitably, More preferably, it is a chlorine atom. As the halogen atom to be substituted with C _1-6 alkyl group, preferably a fluorine atom.
As the C _1-6 alkyl group, for example, there may be mentioned methyl group, ethyl group and propyl group preferably, more preferably a methyl group.
As a _C1-6 alkoxy group, a methoxy group and an ethoxy group can be mentioned suitably, for example, More preferably, it is a methoxy group.
The C _1-6 acylamino group preferably has 1 to 3 carbon atoms (not including the carbon number of the carbonyl group), more preferably 1 to 2, still more preferably 1.

When R ¹ is a phenyl group having at least one substituent selected from substituent group α, the substitution position of the substituent selected from substituent group α that is substituted on the phenyl group is preferably 3 And / or the 5-position, more preferably the 3-position. The substituent selected from the substituent group α to be substituted with the phenyl group is preferably at least one substituent selected from the group consisting of a halogen atom, a C _1-6 alkyl group and a C _1-6 alkoxy group. It is a phenyl group which may have.
Here, the halogen atom is preferably a chlorine atom.
As the C _1-6 alkyl group, for example, there may be mentioned methyl group, ethyl group and propyl group preferably, more preferably a methyl group.
As a _C1-6 alkoxy group, a methoxy group and an ethoxy group can be mentioned suitably, for example, More preferably, it is a methoxy group.

（＊は結合位置）が好ましい。 When R ¹ is a quinolyl group,

(* Is a bonding position) is preferable.

R ² is a hydrogen atom, a C _1-3 alkyl group or a phenyl group. R ² is preferably a hydrogen atom or a C _1-3 alkyl group, more preferably a C _1-3 alkyl group, still more preferably a methyl group or an ethyl group, and particularly preferably a methyl group. is there.

R ³ is a hydrogen atom, a cyano group or a C _1-6 alkoxycarbonyl group. R ³ is preferably a hydrogen atom or a cyano group, more preferably a cyano group.
Here, as a _C1-6 alkoxycarbonyl group, a methoxycarbonyl group and an ethoxycarbonyl group can be mentioned suitably, for example, More preferably, it is an ethoxycarbonyl group.

R ⁴ and R ⁶ each independently have a hydrogen atom; a halogen atom; a C _1-6 alkyl group; a C _1-6 acylamino group; a C _1-6 alkylaminocarbonyl group; or a C _1-6 alkoxy group. It may be a phenyl group. Here, at least one of R ⁴ and R ⁶ is a substituent other than a hydrogen atom.
R ⁴ and R ⁶ are each independently preferably a halogen atom, a C _1-6 acylamino group or a C _1-6 alkylaminocarbonyl group, more preferably a halogen atom or a C _1-6 acylamino group. . More preferably, one of R ⁴ and R ⁶ is a halogen atom, and the other is a C _1-6 acylamino group.
Here, the halogen atom is preferably a chlorine atom.
As the C _1-6 alkyl group, for example, there may be mentioned methyl group, ethyl group and propyl group preferably, more preferably a methyl group.
The C _1-6 acylamino group preferably has 1 to 5 carbon atoms (not including the carbon number of the carbonyl group), more preferably 1 to 3, and still more preferably 1 to 2.
The C _1-6 alkylaminocarbonyl group preferably has 1 to 3 carbon atoms (not including the carbon number of the carbonyl group), more preferably 1 to 2, still more preferably 2.
Preferred examples of the C _1-6 alkoxy group substituted on the phenyl group include a methoxy group and an ethoxy group, and a methoxy group is more preferable.

R ⁵ is a hydrogen atom, a hydroxyl group or a C _1-6 alkoxy group. Here, R ⁵ , R ⁴ or R ⁶ and the carbon atom to which each is bonded may form an indazole ring.
R ⁵ is preferably a hydroxyl group or a C _1-6 alkoxy group, and more preferably a hydroxyl group. Here, as a _C1-6 alkoxy group, an ethoxy group and a methoxy group can be mentioned suitably, for example, More preferably, it is a methoxy group.

X ¹ is * —CH═CH — **, * —CH ₂ —NH — **, * —NH—CH ₂ — ** or * —N = N — **. Here, * represents a bond to the pyrazole ring side in the above formula, and ** represents a bond to the phenyl ring side in the above formula. X ¹ is preferably * —CH ₂ —NH — **, * —NH—CH ₂ — ** or * —N═N — **, more preferably * —NH—CH ₂ — *. * Or * -N = N-**, and more preferably * -NH-CH ₂ -**.

（上記式中、
Ｒ^７は、ハロゲン原子、C_１−６アルキル基およびC_１−６アルコキシ基からなる群から選択される少なくとも１つの置換基を有してもよいフェニル基を有するフェニル基；または；キノリル基を表し、
Ｒ^８は、C_１−３アルキル基を表し、
Ｒ^９およびＲ^１０は、一方が、ハロゲン原子であり、もう一方が、C_１−６アシルアミノ基を表す。） The pyrazole derivative of the present invention is preferably a pyrazole derivative represented by the following general formula (II).

(In the above formula,
R ⁷ represents a phenyl group having a phenyl group which may have at least one substituent selected from the group consisting of a halogen atom, a C _1-6 alkyl group and a C _1-6 alkoxy group; or; a quinolyl group Represent,
R ⁸ represents a C _1-3 alkyl group,
One of R ⁹ and R ¹⁰ represents a halogen atom, and the other represents a C _1-6 acylamino group. )

When R ⁷ is a phenyl group having a phenyl group which may have at least one substituent selected from the group consisting of a halogen atom, a C _1-6 alkyl group and a C _1-6 alkoxy group, the substitution The substitution position of the group is preferably the 3-position and / or 5-position, and more preferably the 3-position.
Here, the halogen atom is preferably a chlorine atom.
As the C _1-6 alkyl group, for example, there may be mentioned methyl group, ethyl group and propyl group preferably, more preferably a methyl group.
As a _C1-6 alkoxy group, a methoxy group and an ethoxy group can be mentioned suitably, for example, More preferably, it is a methoxy group.

（＊は結合位置）が好ましい。 When R ⁷ is a quinolyl group,

(* Is a bonding position) is preferable.

R ⁸ is a C _1-3 alkyl group, preferably a methyl group or an ethyl group, and more preferably a methyl group.

One of R ⁹ and R ¹⁰ is a halogen atom, the other is a C _1-6 acylamino group, the halogen atom is preferably a chlorine atom, and the C _1-6 acylamino group is preferably Has 1-5 carbon atoms (not including the carbon number of the carbonyl group), more preferably 1-3, and still more preferably 1-2.

In the pyrazole derivative of the general formula (I) of the present invention, preferable compounds include the following compounds.
(E) -N- (3-chloro-5-((4-cyano-1-cyclohexyl-3-methyl-1H-pyrazol-5-yl) diazenyl) -2-hydroxyphenyl) propionamide -N- (3-chloro-2-hydroxy-5-((1-phenyl-1H-pyrazol-5-yl) diazenyl) phenyl) propionamide. (E) -N- (3-chloro-5-(( 4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) diazenyl) -2-hydroxyphenyl) propionamide N- (3-chloro-5-(((4-cyano-3-methyl -1-phenyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide N- (3-chloro-5-(((4-cyano-3-methyl-1- (quinoli) -7-yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) butanamide · N- (5-(((1-((1,1′-biphenyl) -3-yl) -4-cyano-3-methyl-1H-pyrazol-5-yl) amino) methyl) -3-chloro-2-hydroxyphenyl) butanamide N- (3-chloro-5-(((4-cyano-3 -Methyl-1- (3-methylphenyl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide N- (5-(((1- (3-bromophenyl)- 4-cyano-3-methyl-1H-pyrazol-5-yl) amino) methyl) -3-chloro-2-hydroxyphenyl) propionamide N- (3-chloro-5-(((4-cyano-3 -Methyl-1- 3- (Trifluoromethyl) phenyl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide N- (3-chloro-5-(((4-cyano-1- ( 3-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide N- (3-chloro-5-(((4-cyano-1- ( Quinolin-2-yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide N- (3-chloro-5-(((4-cyano-3-methyl-1- (Pyridin-2-yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide N- (5-(((1-([1,1′-biphenyl] 3-yl) -4-cyano-3-methyl-1H-pyrazol-5-yl) amino) methyl) -3-chloro-2-hydroxyphenyl) propionamide N- (3-chloro-5-((( 4-cyano-3-methyl-1- (3- (quinolin-3-yl) phenyl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide N- (3-chloro -5-(((4-cyano-3-methyl-1- (2'-methyl- [1,1'-biphenyl] -3-yl) -1H-pyrazol-5-yl) amino) methyl) -2 -Hydroxyphenyl) propionamide N- (3-chloro-5-(((1- (2'-chloro- [1,1'-biphenyl] -3-yl) -4-cyano-3-methyl-1H -Pyrazol-5-yl) amino) methyl 2-hydroxyphenyl) propionamide N- (3-chloro-5-(((1- (3′-chloro- [1,1′-biphenyl] -3-yl) -4-cyano-3-methyl -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide N- (3-chloro-5-(((1- (4'-chloro- [1,1'-biphenyl] -3-yl) -4-cyano-3-methyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide N- (3-chloro-5-(((4-cyano -1- (2'-methoxy- [1,1'-biphenyl] -3-yl) -3-methyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide N- (3-Chloro-5-(((4- Ano-1- (3′-methoxy- [1,1′-biphenyl] -3-yl) -3-methyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide N -(3-Chloro-5-(((4-cyano-1- (4'-methoxy- [1,1'-biphenyl] -3-yl) -3-methyl-1H-pyrazol-5-yl) amino ) Methyl) -2-hydroxyphenyl) propionamide. (E) -N- (3-chloro-5- (2- (4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) vinyl ) -2-Hydroxyphenyl) propionamide N- (3-chloro-5-(((4-cyano-3-methyl-1- (3- (naphthalen-2-yl) phenyl) -1H-pyrazole-5) -Yl) amino) methyl) -2- Hydroxyphenyl) propionamide

上記反応式中、Ｒ^１、Ｒ^２およびＲ^３は、それぞれ、前記と同様の意味であり、Ａｒは、一般式（Ｉ）中の、特定の置換基を有するフェニル基を意味する。 Next, the manufacturing method of the pyrazole derivative which is the compound of this invention is demonstrated.
[Production Method 1]

In the above reaction formula, R ¹ , R ² and R ³ each have the same meaning as described above, and Ar represents a phenyl group having a specific substituent in the general formula (I).

(1-1)
The compound represented by the general formula A3 can be produced by reacting the compound represented by the general formula A1 with the compound represented by the general formula A2 in the presence or absence of an acid.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, acetonitrile, and the like. These may be used as a mixture.

Examples of the acid used in this reaction include sulfonic acids such as paratoluenesulfonic acid monohydrate, pyridinium paratoluenesulfonate, camphorsulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid, and carboxylic acids such as acetic acid and formic acid. Examples include acids.
The amount of the acid used is 1 to 10 times mol, preferably 1 to 2, and more preferably 0.1 to 1 times mol for the compound represented by formula A1.

This reaction is preferably carried out in an inert gas (for example, nitrogen, argon) atmosphere at room temperature to the boiling point of the solvent for 10 minutes to 24 hours.
(1-2)
The compound represented by the general formula A4 can be produced by reacting the compound represented by the general formula A3 with a reducing agent in the presence or absence of an acid.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, acetonitrile, water and the like. These may be used as a mixture. Preferred solvents include methanol, ethanol, tetrahydrofuran and methylene chloride.

  Examples of the reducing agent used include sodium borohydride, sodium triacetoxyborohydride, lithium borohydride, sodium cyanoborohydride, and lithium aluminum hydride. Preferred reducing agents include sodium borohydride, sodium triacetoxyborohydride, and lithium borohydride.

  An acid may be used as a solvent. Examples of the acid include acetic acid. The reduction reaction may be carried out at 0 to 150 ° C., preferably 0 to 110 ° C. for 10 minutes to 24 hours.

上記反応式中、Ｒ^１、Ｒ^２、Ｒ^３およびＡｒは、それぞれ、前記と同様の意味であり、Ｌｖは脱離基を意味する。 [Production Method 2]

In the above reaction formula, R ¹ , R ² , R ³ and Ar each have the same meaning as described above, and Lv means a leaving group.

The compound represented by the general formula A3-1 is a compound represented by the general formula A4-1 in the presence of a base, in the presence of a copper catalyst or a palladium catalyst, in the presence or absence of a ligand. It can manufacture by making it react with the compound represented or the compound represented by general formula A6.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, acetonitrile and water. These may be used as a mixture.

Examples of the base used in this reaction include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium acetate and tripotassium phosphate, and 1,8-diazabicyclo And organic bases such as [5.4.0] -7-undecene, triethylamine and N, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine.
The usage-amount of a base is 1-50 times mole with respect to the compound represented by general formula A4-1, Preferably, it is 1-10 times mole, More preferably, it is 2-5 times mole.

Examples of the copper catalyst used in this reaction include copper (II) acetate and copper (I) iodide. The usage-amount of the copper catalyst used for this reaction is 0.00001-5 times mole with respect to the compound represented by general formula A4-1, Preferably, it is 0.1-2 times mole.
The amount of the ligand used as desired in this reaction is 0.00001 to 5 times mol, preferably 0.1 to 2 times mol, of the compound represented by Formula A4-1.

Examples of the palladium catalyst used in this reaction include palladium (II) acetate, tris (benzalacetone) dipalladium (0), and the like. The usage-amount of the palladium catalyst used for this reaction is 0.00001-1 times mole with respect to the compound represented by general formula A4, Preferably, it is 0.001-0.1 times mole.
The ligand used in this reaction is 2-di-tert-butylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene. Etc. The amount of the ligand used optionally in this reaction is 0.00001 to 1-fold mol, preferably 0.001 to 0.1-fold mol based on the compound represented by Formula A4-1.

  The usage-amount of the compound represented by general formula A5 or A6 is 1-50 times mole with respect to the compound represented by general formula A4, Preferably, it is 1-2 times mole.

  This reaction is preferably carried out in an inert gas (for example, nitrogen, argon) atmosphere at room temperature to 250 ° C. for 10 minutes to 24 hours.

上記反応式中、Ｒ^１、Ｒ^２、Ｒ^３およびＡｒは、それぞれ、前記と同様の意味である。 [Production Method 3]

In the above reaction formula, R ¹ , R ² , R ³ and Ar each have the same meaning as described above.

The compound represented by the general formula A7 can be produced by diazotizing the compound represented by the general formula A1 in the presence of an acid and then reacting with the compound represented by the general formula A8.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, alcohols, amides, sulfoxides, acetonitrile and water. These may be used as a mixture.

Examples of the acid used in this reaction include hydrochloric acid, hydrobromic acid, acetic acid, formic acid, phosphoric acid and the like. These may be used in combination.
The amount of the acid used may be used as a 1-fold mole to a solvent relative to the compound represented by formula A1, and is preferably used as a solvent.

Examples of the diazotizing agent include sodium nitrite and isoamyl nitrite.
The amount of the diazotizing agent used is 1 to 10 moles, preferably 1 to 5 moles, more preferably 1 to 2 moles relative to the compound represented by Formula A1. is there.

  This reaction is preferably carried out in an inert gas (for example, nitrogen, argon) atmosphere at −20 ° C. to room temperature for 10 minutes to 24 hours.

上記反応式中、Ｒ^１、Ｒ^２、Ｒ^３およびＡｒは、それぞれ、前記と同様の意味である。 [Production Method 4]

In the above reaction formula, R ¹ , R ² , R ³ and Ar each have the same meaning as described above.

The compound represented by General Formula A10 can be produced by reacting the compound represented by General Formula A8 with the compound represented by General Formula A9 in the presence of a base.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. Examples thereof include aliphatic hydrocarbons, ethers, alcohols, sulfoxides, aromatic hydrocarbons and the like. These may be used as a mixture.

Examples of the base used in this reaction include n-butyllithium, lithium diisopropylamide, sodium methoxide, sodium t-butoxide, potassium t-butoxide, sodium hydride and the like.
The amount of the base used is 1 to 5 times mol, preferably 1 to 2 times mol for the compound represented by formula A8.

  This reaction is preferably carried out in an inert gas (for example, nitrogen, argon) atmosphere at −80 ° C. to room temperature for 10 minutes to 24 hours.

上記反応式中、Ｒ^１、Ｒ^２、Ｒ^３およびＡｒは、それぞれ、前記と同様の意味である。 [Production Method 5]

In the above reaction formula, R ¹ , R ² , R ³ and Ar each have the same meaning as described above.

  The compound represented by General Formula A14 can be synthesized from the compound represented by General Formula A11 and the compound represented by General Formula A12 by the same method as Production Method 1.

Next, the manufacturing method of the compound represented by general formula A1 which is a raw material for manufacturing the compound of the present invention will be described.
[Production method A]

上記反応式中、Ｒ^１、Ｒ^２およびＲ^３は、それぞれ、前記と同様の意味である。

In the above reaction formula, R ¹ , R ² and R ³ each have the same meaning as described above.

  As a compound represented by the general formula B1, for example, 2- (1-ethoxyethylidene) malononitrile is known. For example, aniline is known as a compound represented by the general formula B2.

The compound represented by the general formula A1 can be produced by reacting the compound represented by the general formula B1 with the compound represented by the general formula B2 in the presence or absence of an acid.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. Examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, acetonitrile, and the like. These may be used as a mixture. Preferred solvents include alcohols.

  Examples of the acid used in this reaction include inorganic acids such as hydrochloric acid, paratoluenesulfonic acid monohydrate, pyridinium paratoluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid and the like, Examples thereof include carboxylic acids such as acetic acid and formic acid. The amount of the acid used is 1 to 10 times mol, preferably 1 to 2 and more preferably 0.1 to 1 times mol for the compound represented by the general formula B1.

  This reaction is preferably carried out in an inert gas (for example, nitrogen, argon) atmosphere at room temperature to the boiling point of the solvent for 10 minutes to 24 hours.

  The compound obtained by the above-described production method can be subjected to a reaction known per se such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or the reaction can be appropriately performed. In combination, it can be derived into other compounds.

The pharmaceutical composition of the present invention comprises the pyrazole derivative of the present invention or a salt thereof. The pharmaceutical composition of the present invention can be suitably used as a pharmaceutical composition for treatment such as treatment and / or prevention of viral infection.
In particular, it can be suitably used as a pharmaceutical composition for treatment such as treatment and / or prevention of HIV, which is an RNA virus, and HSV, which is a DNA virus.

  In the pyrazole derivative represented by the general formula (I) or a salt thereof, when there are isomers (for example, optical isomers, geometric isomers, tautomers, etc.), the present invention relates to all of these isomers. And also includes hydrates, solvates and all crystalline forms.

The compound of the present invention comprises excipients, binders, disintegrants, disintegration inhibitors, caking / adhesion inhibitors, lubricants, absorption / adsorption carriers, solvents, extenders, tonicity agents, solubilizers, emulsifiers. , Suspending agent, thickener, coating agent, absorption accelerator, gelation / coagulation accelerator, light stabilizer, preservative, moisture-proofing agent, emulsification / suspension / dispersion stabilizer, anti-coloring agent Oral preparations (tablets) containing various pharmaceutical additives such as oxygen / antioxidants, flavoring / flavoring agents, coloring agents, foaming agents, antifoaming agents, soothing agents, antistatic agents, buffer / pH regulators, etc. , Capsules, powders, granules, fine granules, pills, suspensions, emulsions, solutions, syrups, etc.), injections, eye drops and the like.
The above various drugs are formulated by ordinary methods.

Oral solid preparations such as tablets, powders and granules include, for example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, anhydrous dicalcium phosphate, partially pregelatinized starch, corn starch and alginic acid. Excipients; simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, sodium alginate, gum arabic, hydroxypropylmethylcellulose, hydroxypropylcellulose, water and Binders such as ethanol; dried starch, alginic acid, candy powder, starch, crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose nato Disintegrants such as calcium, carboxymethylcellulose calcium and sodium starch glycolate; disintegration inhibitors such as stearyl alcohol, stearic acid, cocoa butter and hydrogenated oil; aluminum silicate, calcium hydrogen phosphate, magnesium oxide, talc, silicic anhydride Anti-caking and anti-adhesive agents such as carnauba wax, light anhydrous silicic acid, aluminum silicate, magnesium silicate, hardened oil, hardened vegetable oil derivative, sesame oil, white beeswax, titanium oxide, dry aluminum hydroxide gel, stearic acid, steer Lubricants such as calcium phosphate, magnesium stearate, talc, calcium hydrogen phosphate, sodium lauryl sulfate and polyethylene glycol; absorbents such as quaternary ammonium salts, sodium lauryl sulfate, urea and enzymes Accelerators: Conventional methods using pharmaceutical additives for solid formulation such as absorption / adsorption carriers such as starch, lactose, kaolin, bentonite, silicic anhydride, hydrous silicon dioxide, magnesium aluminate metasilicate and colloidal silicic acid It may be prepared according to

Furthermore, the tablets can be made into tablets with ordinary coatings, for example, sugar-coated tablets, gelatin-encapsulated tablets, gastric-coated tablets, enteric-coated tablets, and water-soluble film-coated tablets as necessary.
Capsules are prepared by mixing with the various pharmaceuticals exemplified above and filling hard gelatin capsules and soft capsules.
In addition, using the various liquid formulation additives described above such as solvents, extenders, tonicity agents, solubilizers, emulsifiers, suspending agents, thickeners, etc. Oily suspensions, solutions, syrups and elixirs may be used.

  Injections include, for example, diluents such as water, ethyl alcohol, macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid and sodium hydroxide; sodium citrate, sodium acetate and sodium phosphate PH adjusters and buffers such as; sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid and thiolactic acid and other stabilizers; isotonic agents such as sodium chloride, glucose, mannitol or glycerin; sodium carboxymethylcellulose, propylene glycol, Solubilizers such as sodium benzoate, benzyl benzoate, urethane, ethanolamine, glycerin; soothing agents such as calcium gluconate, chlorobutanol, glucose, benzyl alcohol; and liquids such as local anesthetics Using pharmaceutical additives for formulation, it may be prepared according to a conventional method.

  Eye drops include, for example, preservatives such as chlorobutanol, sodium dehydroacetate, benzalkonium chloride, cetylpyridinium chloride, phenethyl alcohol, methyl paraoxybenzoate and benzethonium chloride; borax, boric acid and potassium dihydrogen phosphate Thickeners such as methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, sodium carboxymethylcellulose and chondroitin sulfate; solubilizers such as polysorbate 80 and polyoxyethylene hydrogenated castor oil 60; sodium edetate And a stabilizer such as sodium hydrogen sulfite; and an isotonic agent such as sodium chloride, potassium chloride and glycerin as appropriate. It may be prepared according to

Although the administration method of the said formulation is not specifically limited, It determines suitably according to the form of a formulation, a patient's age, sex, other conditions, and the grade of a patient's symptom.
The dose of the active ingredient of the preparation of the present invention is appropriately selected according to the usage, patient age, sex, disease form, other conditions, etc. What is necessary is just to divide and administer several times, Preferably, what is necessary is just to divide and administer 40-500 mg a day in 1 to several times.

The present invention will be described with reference to examples and test examples, but the present invention is not limited thereto.
Unless otherwise specified, purification by column chromatography uses an automatic purifier ISOLERA (Biotage) or medium pressure liquid chromatograph YFLC W-prep 2XY (Yamazen Co., Ltd.), and the carrier in silica gel column chromatography is SNAP Use KPSilCartridge (Biotage), Hi-Flash column W001, W002, W003, W004 or W005 (Yamazen Co., Ltd.), NH silica using SNAP KP-NH Cartridge (Biotage), preparative thin layer silica gel chromatography The graphy uses PLC glass plate silica gel F60 (Merck), the microwave reactor uses Initiator Sixty (Biotage), and the flow-type hydrogenation reactor uses H-Cube (ThalesNano). For reverse phase preparative HPLC, the Waters 2998 Photodiode Array (PDA) Detector (Waters) and Waters 600 Controller (Waters), Waters 2767 Sample M Anager (Waters) complete set and YMC-Actus ProC18,30X50mm column (YMC) are used, MS spectrum is ACQUITY SQD LC / MS System (Waters, ionization method: ESI (Electro Spray Ionization, electrospray ionization) method) Alternatively, LCMS-2010EV (Shimadzu Corporation, ionization method: ESI and APCI (Atomospheric Pressure Chemical Ionization)) was measured using an ionization method in which atmospheric pressure chemical ionization was performed simultaneously.

The NMR spectrum was calculated using Bruker AV300 (Bruker) using tetramethylsilane as an internal standard.
The total δ value was expressed in ppm.
Abbreviations in NMR measurements have the following meanings.
s: Singlet
br: Broad
d: Doublet
dd: Double doublet
t: Triplet
q: Quartet
m: Multiplet
DMSO-d ₆ : Heavy dimethyl sulfoxide

The abbreviations in Reference Examples and Examples have the following meanings.
Ac: Acetyl
Bn: benzyl
Et: ethyl
Me: methyl
Ph: Phenyl
Pr: Propyl

２−クロロ−６−ニトロフェノール(2g)、活性炭(100mg)、塩化鉄（III）六水和物(18mg)のイソプロパノール(8.2mL)懸濁液に室温でヒドラジン一水和物(0.76mL)を加え、20分攪拌した。90℃に加熱し、イソプロパノール(8mL)を加え、5時間攪拌した。塩化鉄（III）六水和物(10mg)とヒドラジン一水和物(0.3mL)を加え、90℃でさらに終夜攪拌した。反応液に脱気した水、酢酸エチル、トルエンを加えて抽出し、有機層を無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して橙色固体を得た。得られた橙色固体のテトラヒドロフラン(30mL)溶液に塩酸(4.0mol/L、１，４−ジオキサン溶液、4mL)を加え、析出した固体をろ取して、２−アミノ−６−クロロフェノール塩酸塩(化合物０００１−１、1.36g)を白色固体として得た。
MSm/z(M+H):144. [Example 1]

Hydrazine monohydrate (0.76 mL) at room temperature in a suspension of 2-chloro-6-nitrophenol (2 g), activated carbon (100 mg), iron (III) chloride hexahydrate (18 mg) in isopropanol (8.2 mL) And stirred for 20 minutes. The mixture was heated to 90 ° C., isopropanol (8 mL) was added, and the mixture was stirred for 5 hours. Iron (III) chloride hexahydrate (10 mg) and hydrazine monohydrate (0.3 mL) were added, and the mixture was further stirred at 90 ° C. overnight. The reaction solution was extracted by adding degassed water, ethyl acetate and toluene, and the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain an orange solid. Hydrochloric acid (4.0 mol / L, 1,4-dioxane solution, 4 mL) was added to a solution of the obtained orange solid in tetrahydrofuran (30 mL), and the precipitated solid was collected by filtration to give 2-amino-6-chlorophenol hydrochloride. (Compound 0001-1, 1.36 g) was obtained as a white solid.
MSm / z (M + H): 144.

２−アミノ−６−クロロフェノール塩酸塩(化合物０００１−１、5.4g)のテトラヒドロフラン(150mL)溶液にピリジン(5.3mL)を加え、氷冷した後塩化プロピオニル(2.6mL)を加え、0℃で3時間攪拌した。徐々に室温に昇温し、17.5時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、室温で1時間攪拌した後、一晩静置した。反応液にジクロロメタン、酢酸エチル、水を加えて分液し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた固体をジクロロメタンに溶かし、塩酸で洗浄後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)にて精製して得られた固体をメタノールに溶かし、飽和炭酸水素ナトリウム水溶液を加えた後、酢酸エチルと飽和塩化アンモニウム水溶液を加えて分液し、有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去して、Ｎ−（３−クロロ−２−ヒドロキシフェニル）プロピオンアミド(化合物０００１−２、3.74g)を得た。
MSm/z(M+H):200.

To a solution of 2-amino-6-chlorophenol hydrochloride (compound 0001-1, 5.4 g) in tetrahydrofuran (150 mL) is added pyridine (5.3 mL), ice-cooled, and then propionyl chloride (2.6 mL) is added. Stir for 3 hours. The temperature was gradually raised to room temperature and stirred for 17.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour, and then allowed to stand overnight. Dichloromethane, ethyl acetate, and water were added to the reaction solution, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was dissolved in dichloromethane, washed with hydrochloric acid, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane). The solid obtained was dissolved in methanol, saturated aqueous sodium hydrogen carbonate solution was added, and then ethyl acetate and saturated aqueous ammonium chloride solution were added for separation. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain N- (3-chloro-2-hydroxyphenyl) propionamide (Compound 0001-2, 3.74 g).
MSm / z (M + H): 200.

Ｎ−（３−クロロ−２−ヒドロキシフェニル）プロピオンアミド(化合物０００１−２、1.72g)の酢酸(19.9mL)溶液を窒素雰囲気下で110℃に加熱し、ヘキサメチレンテトラミン(2.79g)を加えて2時間攪拌した後、130℃で終夜攪拌した。反応液を室温に冷却した後、酢酸エチルと水を加えて分液し、有機層を飽和食塩水と飽和塩化アンモニウム水溶液で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して粗生成物を得た。シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)で精製し、Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミド(化合物０００１−３、0.60g)を黄色固体として得た。
MSm/z(M-H):228.

A solution of N- (3-chloro-2-hydroxyphenyl) propionamide (compound 0001-2, 1.72 g) in acetic acid (19.9 mL) is heated to 110 ° C. under a nitrogen atmosphere, and hexamethylenetetramine (2.79 g) is added. The mixture was stirred for 2 hours and then stirred at 130 ° C. overnight. After cooling the reaction solution to room temperature, ethyl acetate and water were added for liquid separation, and the organic layer was washed successively with saturated brine and saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To obtain a crude product. Purification by silica gel column chromatography (ethyl acetate-hexane) gave N- (3-chloro-5-formyl-2-hydroxyphenyl) propionamide (Compound 0001-3, 0.60 g) as a yellow solid.
MSm / z (MH): 228.

シクロヘキシルヒドラジン塩酸塩(51mg)のエタノール(2.5mL)溶液にトリエチルアミン(0.14mL)を加え、室温で10分攪拌した後、２−（１−エトキシエチリデン）マロノニトリル(69mg)を加えて室温で1時間攪拌した。減圧下溶媒を留去した後、析出した固体をろ別し、氷冷したエタノールで洗浄して、５−アミノ−１−シクロヘキシル−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル(化合物０００１−４、55mg)を得た。
MSm/z(M+H):205.

Triethylamine (0.14 mL) was added to a solution of cyclohexylhydrazine hydrochloride (51 mg) in ethanol (2.5 mL) and stirred at room temperature for 10 minutes, and then 2- (1-ethoxyethylidene) malononitrile (69 mg) was added for 1 hour at room temperature. Stir. After evaporating the solvent under reduced pressure, the precipitated solid was filtered off and washed with ice-cooled ethanol to give 5-amino-1-cyclohexyl-3-methyl-1H-pyrazole-4-carbonitrile (compound 0001- 4, 55 mg) was obtained.
MSm / z (M + H): 205.

５−アミノ−１−シクロヘキシル−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル(化合物０００１−４、20mg)のりん酸(0.5mL)懸濁液を超音波処理し、水(0.05mL)を加えた。Ｎ−（３−クロロ−２−ヒドロキシフェニル）プロピオンアミド(化合物０００１−３、18.6mg)、りん酸(0.5mL)を加え、超音波処理した後、懸濁液を-5℃に冷却し、亜硝酸イソアミル(13μL)を加えて1時間攪拌した。反応液に水を加えて析出した固体をろ取し、得られた粗生成物を分取薄層クロマトグラフィー(メタノール−クロロホルム)で精製し、（Ｅ）−Ｎ−（３−クロロ−５−（（４−シアノ−１−シクロヘキシル−３−メチル−１Ｈ−ピラゾール−５−イル）ジアゼニル）−２−ヒドロキシフェニル）プロピオンアミド(3.5mg)を得た。
¹H-NMR(CDCl₃)δ:7.98(1H,d,J=2.0Hz),7.89(1H,s),7.83(1H,d,J=2.0Hz),4.89-4.84(1H,m),2.57(2H,q,J=7.5Hz),2.43(3H,s),2.05-1.16(13H,m).
MSm/z(M+H):415.

A suspension of 5-amino-1-cyclohexyl-3-methyl-1H-pyrazole-4-carbonitrile (Compound 0001-4, 20 mg) in phosphoric acid (0.5 mL) was sonicated and water (0.05 mL) was added. added. N- (3-Chloro-2-hydroxyphenyl) propionamide (Compound 0001-3, 18.6 mg), phosphoric acid (0.5 mL) was added and sonicated, then the suspension was cooled to -5 ° C, Isoamyl nitrite (13 μL) was added and stirred for 1 hour. Water was added to the reaction solution and the precipitated solid was collected by filtration. The resulting crude product was purified by preparative thin layer chromatography (methanol-chloroform), and (E) -N- (3-chloro-5- ((4-Cyano-1-cyclohexyl-3-methyl-1H-pyrazol-5-yl) diazenyl) -2-hydroxyphenyl) propionamide (3.5 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.98 (1H, d, J = 2.0 Hz), 7.89 (1 H, s), 7.83 (1 H, d, J = 2.0 Hz), 4.89-4.84 (1 H, m), 2.57 (2H, q, J = 7.5Hz), 2.43 (3H, s), 2.05-1.16 (13H, m).
MS m / z (M + H): 415.

１−フェニル−１Ｈ−ピラゾール−５−アミン（20mg）を酢酸（1mL）、濃塩酸（10μL）に溶かし、氷冷下、亜硝酸ナトリウム（8.6mg）水溶液（40μL）を加え、同温度で1.5時間攪拌した。反応液にＮ−（３−クロロ−２−ヒドロキシフェニル）プロピオンアミド（25mg）のエタノール溶液（125μL）を加えた後、室温に昇温し、40分間攪拌した。反応混合物を氷水に注ぎ、水層をクロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去し、得られた残留物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）で精製し、（Ｅ）−Ｎ−（３−クロロ−２−ヒドロキシ−５−（（１−フェニル−１Ｈ−ピラゾール−５−イル）ジアゼニル）フェニル）プロピオンアミド（4.2mg）を得た。
¹H-NMR(CDCl₃)δ:8.54-8.51(1H,brs),8.10(1H,d,J=2.3Hz),7.77-7.73(3H,m),7.68(1H,d,J=2.3Hz),7.63-7.41(4H,m),6.70(1H,d,J=2.3Hz),2.53(2H,q,J=7.0Hz),1.30(3H,t,J=7.2Hz).
MSm/z(M+H):370. [Example 2]

1-Phenyl-1H-pyrazol-5-amine (20 mg) is dissolved in acetic acid (1 mL) and concentrated hydrochloric acid (10 μL). Under ice-cooling, an aqueous solution of sodium nitrite (8.6 mg) (40 μL) is added, and 1.5 ° C. Stir for hours. After adding an ethanol solution (125 μL) of N- (3-chloro-2-hydroxyphenyl) propionamide (25 mg) to the reaction solution, the mixture was warmed to room temperature and stirred for 40 minutes. The reaction mixture was poured into ice water, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (E) -N- (3-chloro-2 -Hydroxy-5-((1-phenyl-1H-pyrazol-5-yl) diazenyl) phenyl) propionamide (4.2 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.54-8.51 (1H, brs), 8.10 (1H, d, J = 2.3Hz), 7.77-7.73 (3H, m), 7.68 (1H, d, J = 2.3Hz ), 7.63-7.41 (4H, m), 6.70 (1H, d, J = 2.3Hz), 2.53 (2H, q, J = 7.0Hz), 1.30 (3H, t, J = 7.2Hz).
MSm / z (M + H): 370.

実施例２において、１−フェニル−１Ｈ−ピラゾール−５−アミンに代わりに５−アミノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いたこと以外は実施例２と同様の方法で、（Ｅ）−Ｎ−（３−クロロ−５−（（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）ジアゼニル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
MSm/z(M+H):409. [Example 3]

Example 2 was the same as Example 2 except that 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile was used instead of 1-phenyl-1H-pyrazol-5-amine. (E) -N- (3-chloro-5-((4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) diazenyl) -2-hydroxyphenyl) propionamide Obtained.
MSm / z (M + H): 409.

氷冷下、濃硝酸(1.6mL)に濃硫酸(12mL)を加え、0℃で5分攪拌した。３−クロロ安息香酸(3g)を5分かけて加え、室温に昇温して1時間攪拌した。氷冷した水に反応液を滴下し、析出した固体をろ取し、水で洗浄して、３−クロロ−５−ニトロ安息香酸(化合物０００４−１、2.65g)を白色固体として得た。
MSm/z(M+H):200. [Example 4]

Concentrated sulfuric acid (12 mL) was added to concentrated nitric acid (1.6 mL) under ice cooling, and the mixture was stirred at 0 ° C. for 5 minutes. 3-Chlorobenzoic acid (3 g) was added over 5 minutes, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was added dropwise to ice-cooled water, and the precipitated solid was collected by filtration and washed with water to give 3-chloro-5-nitrobenzoic acid (Compound 0004-1, 2.65 g) as a white solid.
MSm / z (M + H): 200.

イソプロパノール(78mL)、水(20mL)の混合溶液に塩化アンモニウム(0.18g)、還元鉄(1.07g)を加え、90℃で1時間攪拌した後、３−クロロ−５−ニトロ安息香酸(化合物０００４−１、1.1g)をゆっくり加え、90℃で3時間攪拌した。反応液を室温に冷却した後ろ過し、メタノールで洗浄してろ液を減圧下溶媒留去して粗生成物を得た。シリカゲルカラムクロマトグラフィー(メタノール−クロロホルム)で精製して、３−アミノ−５−クロロ安息香酸(化合物０００４−２、368mg)を淡褐色固体として得た。
MSm/z(M+H):172.

Ammonium chloride (0.18 g) and reduced iron (1.07 g) were added to a mixed solution of isopropanol (78 mL) and water (20 mL), and the mixture was stirred at 90 ° C. for 1 hour, and then 3-chloro-5-nitrobenzoic acid (compound 0004 −1, 1.1 g) was slowly added and stirred at 90 ° C. for 3 hours. The reaction solution was cooled to room temperature and then filtered, washed with methanol, and the filtrate was evaporated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (methanol-chloroform) gave 3-amino-5-chlorobenzoic acid (Compound 0004-2, 368 mg) as a light brown solid.
MSm / z (M + H): 172.

３−アミノ−５−クロロ安息香酸(化合物０００４−２、130mg)のテトラヒドロフラン(3.8mL)溶液に、トリエチルアミン(0.32mL)を加え、氷冷した。塩化プロピオニル(0.15mL)を加え、室温に昇温し、1時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて1時間撹拌し、一晩静置した。5.0mol/L水酸化ナトリウム水溶液(0.6mL)を加えて1.5時間攪拌し、さらに5.0mol/L水酸化ナトリウム水溶液(1mL)を加えて30分攪拌した。6.0mol/L塩酸(3mL)を加え、次いで酢酸エチルと水を加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して粗生成物を得た。シリカゲルカラムクロマトグラフィー(メタノール−クロロホルム)で精製し、３−クロロ−５−プロピオンアミド安息香酸(化合物０００４−３、92mg)を得た。
MSm/z(M+H):228.

To a solution of 3-amino-5-chlorobenzoic acid (compound 0004-2, 130 mg) in tetrahydrofuran (3.8 mL) was added triethylamine (0.32 mL), and the mixture was ice-cooled. Propionyl chloride (0.15 mL) was added, the temperature was raised to room temperature, and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, stirred for 1 hour, and allowed to stand overnight. 5.0 mol / L sodium hydroxide aqueous solution (0.6 mL) was added and stirred for 1.5 hours, and 5.0 mol / L sodium hydroxide aqueous solution (1 mL) was further added and stirred for 30 minutes. 6.0mol / L hydrochloric acid (3mL) was added, then ethyl acetate and water were added for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product. Got. Purification by silica gel column chromatography (methanol-chloroform) gave 3-chloro-5-propionamide benzoic acid (Compound 0004-3, 92 mg).
MS m / z (M + H): 228.

３−クロロ−５−プロピオンアミド安息香酸(化合物０００４−３、92mg)のテトラヒドロフラン(1.1mL)溶液にトリエチルアミン(56μL)を加え、-10℃に冷却した。クロロぎ酸エチル(39μL)を加え、30分攪拌した。反応液をろ過し、テトラヒドロフランで洗浄した。ろ液に水素化ホウ素ナトリウム(48.8mg)を加え、メタノール(0.26mL)を加えて1時間攪拌した。反応液に10%塩酸を加え、さらに酢酸エチルと水を加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒留去して粗生成物を得た。シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)で精製し、Ｎ−（３−クロロ−５−（ヒドロキシメチル）フェニル）プロピオンアミド(化合物０００４−４、18mg)を白色固体として得た。
MSm/z(M+H):213.

Triethylamine (56 μL) was added to a solution of 3-chloro-5-propionamide benzoic acid (Compound 0004-3, 92 mg) in tetrahydrofuran (1.1 mL) and cooled to −10 ° C. Ethyl chloroformate (39 μL) was added and stirred for 30 minutes. The reaction solution was filtered and washed with tetrahydrofuran. Sodium borohydride (48.8 mg) was added to the filtrate, methanol (0.26 mL) was added, and the mixture was stirred for 1 hr. To the reaction mixture was added 10% hydrochloric acid, and ethyl acetate and water were further added to separate the layers. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. . Purification by silica gel column chromatography (ethyl acetate-hexane) gave N- (3-chloro-5- (hydroxymethyl) phenyl) propionamide (Compound 0004-4, 18 mg) as a white solid.
MS m / z (M + H): 213.

Ｎ−（３−クロロ−５−（ヒドロキシメチル）フェニル）プロピオンアミド(化合物０００４−４、18mg)のジクロロメタン(4.3mL)溶液に、クロロクロム酸ピリジニウム(56mg)を加え、窒素雰囲気下、室温で1.5時間攪拌した。減圧下溶媒を留去し、粗生成物を得た。シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)で精製し、Ｎ−（３−クロロ−５−ホルミルフェニル）プロピオンアミド(化合物０００４−５、15mg)を得た。
MSm/z(M+H):212.

To a solution of N- (3-chloro-5- (hydroxymethyl) phenyl) propionamide (Compound 0004-4, 18 mg) in dichloromethane (4.3 mL) was added pyridinium chlorochromate (56 mg) and at room temperature under a nitrogen atmosphere. Stir for 1.5 hours. The solvent was distilled off under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (ethyl acetate-hexane) gave N- (3-chloro-5-formylphenyl) propionamide (Compound 0004-5, 15 mg).
MS m / z (M + H): 212.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルの代わりに、５−アミノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを、Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミドの代わりに３−クロロ−Ｎ−エチル−５−ホルミルフェニルプロピオンアミドを用いること以外は実施例５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）フェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:7.56-7.28(8H,m),4.99-4.96(1H,m),4.56(2H,d,J=5.9Hz),2.41(2H,q,J=7.7Hz),2.32(3H,s),1.29-1.20(3H,m).
MSm/z(M+H):394.

In Example 5, instead of 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile was replaced with N- ( N- (3) was prepared in the same manner as in Example 5, except that 3-chloro-N-ethyl-5-formylphenylpropionamide was used instead of 3-chloro-5-formyl-2-hydroxyphenyl) propionamide. -Chloro-5-(((4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) amino) methyl) phenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.56-7.28 (8H, m), 4.99-4.96 (1H, m), 4.56 (2H, d, J = 5.9Hz), 2.41 (2H, q, J = 7.7Hz) ), 2.32 (3H, s), 1.29-1.20 (3H, m).
MS m / z (M + H): 394.

５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル(19.3mg)、Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミド(化合物０００１−３、14.8mg)、パラトルエンスルホン酸ピリジニウム(20.1mg、約1.0当量)のトルエン(10mL)溶液を2.5時間加熱還流後、溶媒を減圧下留去した。得られた淡黄色固体にエタノール(0.66mL)を加え、0℃、窒素下で水素化ホウ素ナトリウム(7.5mg)のエタノール(0.66mL)溶液を滴下した後、徐々に室温に昇温して1時間攪拌した。反応液にアセトンを加え、減圧下溶媒を留去した後、得られた固体に酢酸エチル、水を加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して粗生成物を得た。分取薄層クロマトグラフィー(酢酸エチル−ヘキサン)で精製し、得られた固体をエタノール(0.66mL)に溶かし、0℃、窒素下で水素化ホウ素ナトリウム(5mg)のエタノール(0.4mL)溶液を滴下した後、徐々に室温に昇温して1時間攪拌した。反応液にアセトンを加え、減圧下溶媒を留去した後、得られた固体に酢酸エチル、水を加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して、Ｎ−（３−クロロ−５−（（（４−シアノ−１−フェニル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミド(3.2mg)を橙色固体として得た。
¹H-NMR(CDCl₃)δ:7.73(1H,s),7.66(1H,s),7.57-7.44(6H,m),7.09(1H,d,J=2.0Hz),4.64-4.62(1H,m),4.57(2H,d,J=5.3Hz),2.48(2H,q,J=7.5Hz),1.31-1.27(3H,m).
MSm/z(M+H):396. [Example 5]

5-amino-1-phenyl-1H-pyrazole-4-carbonitrile (19.3 mg), N- (3-chloro-5-formyl-2-hydroxyphenyl) propionamide (compound 0001-3, 14.8 mg), para A toluene (10 mL) solution of pyridinium toluenesulfonate (20.1 mg, about 1.0 equivalent) was heated under reflux for 2.5 hours, and then the solvent was distilled off under reduced pressure. Ethanol (0.66 mL) was added to the obtained pale yellow solid, a solution of sodium borohydride (7.5 mg) in ethanol (0.66 mL) was added dropwise at 0 ° C. under nitrogen, and the temperature was gradually raised to room temperature. Stir for hours. Acetone was added to the reaction solution, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the obtained solid to separate the solution, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then under reduced pressure. The solvent was distilled off to obtain a crude product. Purified by preparative thin layer chromatography (ethyl acetate-hexane), the obtained solid was dissolved in ethanol (0.66 mL), and a solution of sodium borohydride (5 mg) in ethanol (0.4 mL) was added at 0 ° C. under nitrogen. After the dropwise addition, the mixture was gradually warmed to room temperature and stirred for 1 hour. Acetone was added to the reaction solution, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the obtained solid to separate the solution, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then under reduced pressure. The solvent was distilled off to give N- (3-chloro-5-(((4-cyano-1-phenyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide (3.2 mg ) Was obtained as an orange solid.
¹ H-NMR (CDCl ₃ ) δ: 7.73 (1H, s), 7.66 (1H, s), 7.57-7.44 (6H, m), 7.09 (1H, d, J = 2.0Hz), 4.64-4.62 (1H , m), 4.57 (2H, d, J = 5.3Hz), 2.48 (2H, q, J = 7.5Hz), 1.31-1.27 (3H, m).
MSm / z (M + H): 396.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−１−シクロヘキシル−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル(化合物０００１−４)を用いたこと以外は実施例５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−１−シクロヘキシル−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:7.88-7.85(2H,m),7.58-7.55(1H,m),7.13(1H,d,J=1.3Hz),4.50(2H,d,J=5.9Hz),4.24-4.21(1H,m),3.68-3.66(1H,m),2.48(2H,q,J=7.5Hz),2.24(3H,s),1.90-1.17(13H,m).
MSm/z(M+H):416. [Example 6]

In Example 5, instead of using 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile, 5-amino-1-cyclohexyl-3-methyl-1H-pyrazole-4-carbonitrile (compound 0001- 4) was used in the same manner as in Example 5 except that N- (3-chloro-5-(((4-cyano-1-cyclohexyl-3-methyl-1H-pyrazol-5-yl) amino was used. ) Methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.88-7.85 (2H, m), 7.58-7.55 (1H, m), 7.13 (1H, d, J = 1.3Hz), 4.50 (2H, d, J = 5.9Hz) ), 4.24-4.21 (1H, m), 3.68-3.66 (1H, m), 2.48 (2H, q, J = 7.5Hz), 2.24 (3H, s), 1.90-1.17 (13H, m).
MS m / z (M + H): 416.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（３’−メチル−[１,１’−ビフェニル]−３−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００５４−１)を、Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミドを用いた代わりに３−クロロ−４−ヒドロキシベンズアルデヒドを用いたこと以外は実施例５と同様の方法で、５−（（３−クロロ−４−ヒドロキシベンジル）アミノ）−３−メチル−１−（３’−メチル−[１，１’−ビフェニル]−３−イル）−１Ｈ−ピラゾール−４−カルボニトリルを得た。
¹H-NMR(CDCl₃)δ:7.61-7.65(2H,m),7.55(1H,t,J=7.6Hz),7.35-7.36(4H,m),7.28(1H,d,J=2.0Hz),7.22(1H,d,J=4.0Hz),7.14(1H,dd,J=8.6,2.0Hz),6.99(1H,d,J=7.9Hz),5.54(1H,s),4.54-4.60(3H,m),2.42(3H,s),2.35(3H,s).
MSm/z(M+H):429. [Example 7]

In Example 5, instead of using 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1- (3′-methyl- [1,1′-biphenyl] -3-yl) -1H-pyrazole-4-carbonitrile (compound 0054-1) was replaced with 3-chloro-4 instead of N- (3-chloro-5-formyl-2-hydroxyphenyl) propionamide. 5-((3-Chloro-4-hydroxybenzyl) amino) -3-methyl-1- (3′-methyl- [1,1] in the same manner as in Example 5 except that -hydroxybenzaldehyde was used. '-Biphenyl] -3-yl) -1H-pyrazole-4-carbonitrile was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.61-7.65 (2H, m), 7.55 (1H, t, J = 7.6Hz), 7.35-7.36 (4H, m), 7.28 (1H, d, J = 2.0Hz ), 7.22 (1H, d, J = 4.0Hz), 7.14 (1H, dd, J = 8.6,2.0Hz), 6.99 (1H, d, J = 7.9Hz), 5.54 (1H, s), 4.54-4.60 (3H, m), 2.42 (3H, s), 2.35 (3H, s).
MSm / z (M + H): 429.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いたこと以外は実施例５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミド(3.0mg)を得た。
¹H-NMR(CDCl₃)δ:7.70-7.66(1H,brs),7.70(1H,d,J=2.0Hz),7.55-7.41(5H,m),7.09(1H,d,J=2.0Hz),4.63-4.58(1H,brm),4.55(2H,d,J=5.3Hz),2.48(2H,q,J=7.5Hz),2.33(3H,s),1.27(4H,t,J=7.6Hz).
MSm/z(M+H):410. [Example 8]

In Example 5, instead of using 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile was used. Except for N- (3-chloro-5-(((4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) amino) methyl) -2- Hydroxyphenyl) propionamide (3.0 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.70-7.66 (1H, brs), 7.70 (1H, d, J = 2.0Hz), 7.55-7.41 (5H, m), 7.09 (1H, d, J = 2.0Hz) ), 4.63-4.58 (1H, brm), 4.55 (2H, d, J = 5.3Hz), 2.48 (2H, q, J = 7.5Hz), 2.33 (3H, s), 1.27 (4H, t, J = 7.6Hz).
MSm / z (M + H): 410.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに３−メチル−１−フェニル−１Ｈ−ピラゾール−５−アミンを用いたこと以外は実施例５と同様の方法で、Ｎ−（３−クロロ−２−ヒドロキシ−５−（（（３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）フェニル）プロピオンアミド(3.0mg)を得た。
¹H-NMR(CDCl₃)δ:7.76-7.73(1H,brs),7.64(1H,s),7.54-7.42(4H,m),7.34-7.31(1H,m),7.12(1H,d,J=2.0Hz),5.31(1H,s),4.16(2H,d,J=5.0Hz),4.12-4.07(1H,brs),2.47(2H,q,J=7.5Hz),2.22(3H,s),1.27(3H,t,J=7.2Hz).
MSm/z(M+H):385. [Example 9]

Example 5 Example 5 except that 3-methyl-1-phenyl-1H-pyrazol-5-amine was used instead of 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile N- (3-Chloro-2-hydroxy-5-(((3-methyl-1-phenyl-1H-pyrazol-5-yl) amino) methyl) phenyl) propionamide (3.0 mg) Got.
¹ H-NMR (CDCl ₃ ) δ: 7.76-7.73 (1H, brs), 7.64 (1H, s), 7.54-7.42 (4H, m), 7.34-7.31 (1H, m), 7.12 (1H, d, J = 2.0Hz), 5.31 (1H, s), 4.16 (2H, d, J = 5.0Hz), 4.12-4.07 (1H, brs), 2.47 (2H, q, J = 7.5Hz), 2.22 (3H, s), 1.27 (3H, t, J = 7.2Hz).
MSm / z (M + H): 385.

Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミド(化合物０００１−３、840mg)のトルエン（5mL）溶液にパラトルエンスルホン酸一水和物（10mg）を加え、3時間加熱還流した。反応混合物を室温に冷却し、これに塩化アンモニウム水溶液を加えた。酢酸エチルで分液後、有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。得られた残留物をカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製し、７−クロロ−２−メチルベンゾ[ｄ]オキサゾール−５−カルバルデヒド（化合物００１０−１、480mg）を得た。
MSm/z(M+H):210. [Example 10]

To a toluene (5 mL) solution of N- (3-chloro-5-formyl-2-hydroxyphenyl) propionamide (Compound 0001-3, 840 mg) was added paratoluenesulfonic acid monohydrate (10 mg) and heated for 3 hours. Refluxed. The reaction mixture was cooled to room temperature, and aqueous ammonium chloride solution was added thereto. After liquid separation with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain 7-chloro-2-methylbenzo [d] oxazole-5-carbaldehyde (Compound 0010-1, 480 mg).
MS m / z (M + H): 210.

７−クロロ−２−メチルベンゾ[ｄ]オキサゾール−５−カルバルデヒド（化合物００１１−１、140mg）、５−アミノ−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル（122mg）を酢酸（1.1mL）と塩化メチレン（2.2mL）の混合溶媒に溶かし、これに水素化トリアセトキシホウ素ナトリウム（212mg）を加え、マイクロウェーブ反応装置で130℃、2.5時間攪拌した。反応混合物を室温に冷却後、塩化アンモニウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−テトラヒドロフラン）で精製し、５−（（（７−クロロ−２−メチルベンゾ[ｄ]オキサゾール−５−イル）メチル）アミノ）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００１０−２、81mg）を得た。
MSm/z(M+H):316.

7-chloro-2-methylbenzo [d] oxazole-5-carbaldehyde (compound 0011-1, 140 mg), 5-amino-3-methyl-1H-pyrazole-4-carbonitrile (122 mg) and acetic acid (1.1 mL) And methylene chloride (2.2 mL) were dissolved in a mixed solvent, sodium triacetoxyborohydride (212 mg) was added thereto, and the mixture was stirred in a microwave reactor at 130 ° C. for 2.5 hours. The reaction mixture was cooled to room temperature, poured into an aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-tetrahydrofuran) to give 5-(((7-chloro-2-methylbenzo [d] oxazol-5-yl) methyl) amino) -3-methyl-1H. -Pyrazole-4-carbonitrile (Compound 0010-2, 81 mg) was obtained.
MSm / z (M + H): 316.

５−（（（７−クロロ−２−メチルベンゾ[ｄ]オキサゾール−５−イル）メチル）アミノ）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００１０−２、30mg）、ベンゾ[ｄ][１，３]ジオキソール−５−イルボロン酸（31mg）を塩化メチレン（2mL）とピリジン（15μL）に溶かし、これにモレキュラーシーブス４Aと酢酸銅（II）を加え、室温で終夜攪拌した。反応混合物を水に注ぎ、酢酸エチルで抽出後、溶媒を減圧下留去した。残留物を分取薄層シリカゲルクロマトグラフィー（ヘキサン−酢酸エチル）で精製し、１−（ベンゾ[ｄ][１，３]ジオキソール−５−イル）−５−（（（７−クロロ−２−メチルベンゾ[ｄ]オキサゾール−５−イル）メチル）アミノ）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００１０−３、16mg）を得た。
MSm/z(M+H):436.

5-(((7-chloro-2-methylbenzo [d] oxazol-5-yl) methyl) amino) -3-methyl-1H-pyrazole-4-carbonitrile (compound 0010-2, 30 mg), benzo [d ] [1,3] dioxol-5-ylboronic acid (31 mg) was dissolved in methylene chloride (2 mL) and pyridine (15 μL), and molecular sieves 4A and copper (II) acetate were added thereto, followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel chromatography (hexane-ethyl acetate) to give 1- (benzo [d] [1,3] dioxol-5-yl) -5-(((7-chloro-2- Methylbenzo [d] oxazol-5-yl) methyl) amino) -3-methyl-1H-pyrazole-4-carbonitrile (Compound 0010-3, 16 mg) was obtained.
MSm / z (M + H): 436.

１−（ベンゾ[ｄ][１，３]ジオキソール−５−イル）−５−（（（７−クロロ−２−メチルベンゾ[ｄ]オキサゾール−５−イル）メチル）アミノ）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル（16mg）をエタノール（1mL）に溶かし、これに濃塩酸（33μL）を加え、室温で10時間攪拌した。反応混合物を塩化アンモニウム水溶液に注ぎ、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残留物を分取薄層シリカゲルクロマトグラフィー（ヘキサン−酢酸エチル）で精製し、Ｎ−（５−（（（１−（ベンゾ[ｄ][１，３]ジオキソール−５−イル）−４−シアノ−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−３−クロロ−２−ヒドロキシフェニル）プロピオンアミド（5.3mg）を得た。
¹H-NMR(THF-d₈)δ:9.68-9.51(1H,brs),9.22-9.16(1H,brs),7.50(1H,d,J=2.0Hz),7.10(1H,d,J=2.0Hz),6.95-6.91(3H,m),6.14(1H,t,J=6.4Hz),6.01(2H,s),4.50(2H,d,J=6.6Hz),2.42(2H,q,J=7.0Hz),2.15(3H,s),1.18(3H,t,J=7.2Hz).
MSm/z(M+H):454.

1- (Benzo [d] [1,3] dioxol-5-yl) -5-(((7-chloro-2-methylbenzo [d] oxazol-5-yl) methyl) amino) -3-methyl-1H -Pyrazole-4-carbonitrile (16 mg) was dissolved in ethanol (1 mL), concentrated hydrochloric acid (33 μL) was added thereto, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was poured into an aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative thin layer silica gel chromatography (hexane-ethyl acetate) to give N- (5-(((1- (benzo [d] [1,3 ] Dioxole-5-yl) -4-cyano-3-methyl-1H-pyrazol-5-yl) amino) methyl) -3-chloro-2-hydroxyphenyl) propionamide (5.3 mg) was obtained.
¹ H-NMR (THF-d ₈ ) δ: 9.68-9.51 (1H, brs), 9.22-9.16 (1H, brs), 7.50 (1H, d, J = 2.0Hz), 7.10 (1H, d, J = 2.0Hz), 6.95-6.91 (3H, m), 6.14 (1H, t, J = 6.4Hz), 6.01 (2H, s), 4.50 (2H, d, J = 6.6Hz), 2.42 (2H, q, J = 7.0Hz), 2.15 (3H, s), 1.18 (3H, t, J = 7.2Hz).
MS m / z (M + H): 454.

実施例１において、塩化プロピオニルの代わりにブタン酸クロリドを用いたこと以外は実施例１と同様の方法で、Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）ブチルアミド（化合物００１１−１）を得た。
MSm/z(M+H):242. [Example 11]

In Example 1, N- (3-chloro-5-formyl-2-hydroxyphenyl) butyramide (Compound 0011-1) was prepared in the same manner as in Example 1, except that butanoic chloride was used instead of propionyl chloride. )
MS m / z (M + H): 242.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（キノリン−２−イル）−１Ｈ−ピラゾール−４−カルボニトリル（化合物００４１−１）を、Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミドの代わりにＮ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）ブタンアミド（化合物００１１−１）を用いたこと以外は実施例５と同様の方法で、Ｎ−（３−クロロ−５−(((４−シアノ−３−メチル−１−（キノリン−２−イル）−１Ｈ−ピラゾール−５−イル)アミノ)メチル)−２−ヒドロキシフェニル）ブタンアミドを得た。
¹H-NMR(CD₃OD)δ:8.46(1H,d,J=8.9Hz),8.30(1H,brs),8.11(1H,d,J=8.9Hz),7.91(1H,s),7.79-7.726(1H,m),7.65-7.55(3H,m),7.30(1H,d,J=2.3Hz),4.89(1H,s),4.86(2H,d,J=2.3Hz),2.40(2H,t,J=7.4Hz),2.30(3H,s),1.70-1.65(2H,m),0.95(3H,t,J=7.4Hz).
MSm/z(M+H):475.

In Example 5, instead of using 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1- (quinolin-2-yl) -1H-pyrazole-4- Carbonitrile (compound 0041-1) was replaced with N- (3-chloro-5-formyl-2-hydroxyphenyl) butanamide (compound) instead of N- (3-chloro-5-formyl-2-hydroxyphenyl) propionamide. N- (3-Chloro-5-(((4-cyano-3-methyl-1- (quinolin-2-yl) -1H) was prepared in the same manner as in Example 5, except that 0011-1) was used. -Pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) butanamide was obtained.
¹ H-NMR (CD ₃ OD) δ: 8.46 (1H, d, J = 8.9Hz), 8.30 (1H, brs), 8.11 (1H, d, J = 8.9Hz), 7.91 (1H, s), 7.79 -7.726 (1H, m), 7.65-7.55 (3H, m), 7.30 (1H, d, J = 2.3Hz), 4.89 (1H, s), 4.86 (2H, d, J = 2.3Hz), 2.40 ( 2H, t, J = 7.4Hz), 2.30 (3H, s), 1.70-1.65 (2H, m), 0.95 (3H, t, J = 7.4Hz).
MSm / z (M + H): 475.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに１−（（１，１'−ビフェニル）−３−イル）−５−アミノ−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００４４−１）を、Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミドの代わりにＮ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）ブタンアミド（化合物００１１−１）を用いたこと以外は実施例５と同様の方法で、Ｎ−（５−（（（１−（（１，１'−ビフェニル）−３−イル）−４−シアノ−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−３−クロロ−２−ヒドロキシフェニル）ブタンアミドを得た。
¹H-NMR(CDCl₃)δ:7.65-7.58(7H,m),7.48-7.36(4H,m),7.11(1H,d,J=2.0Hz),4.66(1H,t,J=6.3Hz),4.56(2H,d,J=5.9Hz),2.40(2H,t,J=7.4Hz),2.34(3H,s),1.82-1.70(2H,m),1.01(3H,t,J=7.4Hz).
MSm/z(M+H):500. [Example 12]

In Example 5, instead of using 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile, 1-((1,1′-biphenyl) -3-yl) -5-amino-3-methyl -1H-pyrazole-4-carbonitrile (compound 0044-1) is replaced with N- (3-chloro-5-formyl-2 instead of N- (3-chloro-5-formyl-2-hydroxyphenyl) propionamide N- (5-(((1-((1,1′-biphenyl) -3-yl) was prepared in the same manner as in Example 5 except that -hydroxyphenyl) butanamide (Compound 0011-1) was used. -4-Cyano-3-methyl-1H-pyrazol-5-yl) amino) methyl) -3-chloro-2-hydroxyphenyl) butanamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.65-7.58 (7H, m), 7.48-7.36 (4H, m), 7.11 (1H, d, J = 2.0Hz), 4.66 (1H, t, J = 6.3Hz ), 4.56 (2H, d, J = 5.9Hz), 2.40 (2H, t, J = 7.4Hz), 2.34 (3H, s), 1.82-1.70 (2H, m), 1.01 (3H, t, J = (7.4Hz).
MSm / z (M + H): 500.

３−クロロ−２−ヒドロキシ安息香酸(307mg)のジクロロメタン(4.5mL)懸濁液にトリエチルアミン(0.25mL)、四臭化炭素(0.6g)、エチルアミン(0.9mL)、トリフェニルホスフィン(0.47g)を加え、室温で終夜攪拌した。減圧下溶媒を留去して得られた固体に酢酸エチル、ヘキサンを加えてろ過した後、ろ液を減圧下溶媒留去して粗生成物を得た。シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)で精製し、３−クロロ−Ｎ−エチル−２−ヒドロキシベンズアミド（化合物００１３−１、36mg）を白色固体として得た。
MSm/z(M+H):200. [Example 13]

To a suspension of 3-chloro-2-hydroxybenzoic acid (307 mg) in dichloromethane (4.5 mL), triethylamine (0.25 mL), carbon tetrabromide (0.6 g), ethylamine (0.9 mL), triphenylphosphine (0.47 g) And stirred at room temperature overnight. Ethyl acetate and hexane were added to the solid obtained by evaporating the solvent under reduced pressure, followed by filtration. The filtrate was evaporated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (ethyl acetate-hexane) gave 3-chloro-N-ethyl-2-hydroxybenzamide (Compound 0013-1, 36 mg) as a white solid.
MSm / z (M + H): 200.

実施例１において、Ｎ−（３−クロロ−２−ヒドロキシフェニル）プロピオンアミドを用いた代わりに３−クロロ−Ｎ−エチル−２−ヒドロキシベンズアミド(化合物００１３−１)を用いること以外は実施例１と同様の方法で、３−クロロ−Ｎ−エチル−５−ホルミル−２−ヒドロキシベンズアミド（化合物００１３−２）を白色固体として得た。
MSm/z(M+H):228.

In Example 1, Example 1 was used except that 3-chloro-N-ethyl-2-hydroxybenzamide (Compound 0013-1) was used instead of N- (3-chloro-2-hydroxyphenyl) propionamide. In the same manner, 3-chloro-N-ethyl-5-formyl-2-hydroxybenzamide (Compound 0013-2) was obtained as a white solid.
MS m / z (M + H): 228.

５−アミノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル(9.2mg)、３−クロロ−Ｎ−エチル−５−ホルミル−２−ヒドロキシベンズアミド(化合物００１３−２、6.6mg)、パラトルエンスルホン酸一水和物(8.8mg、約1.0当量)のトルエン(4mL)溶液を3時間加熱還流後、減圧下溶媒を留去した。室温に冷却し、得られた淡黄色固体にエタノール(0.29mL)を加え、0℃、窒素下で水素化ホウ素ナトリウム(3.3mg)のエタノール(0.26mL)溶液を滴下した後、徐々に室温に昇温して1時間攪拌した。室温で一晩静置した後、0℃で水素化ホウ素ナトリウム(3.3mg)のエタノール(0.26mL)溶液を加え、再度室温に昇温し、1時間攪拌した。反応液にアセトンを加え、減圧下溶媒を留去した後、得られた固体に酢酸エチル、水を加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して粗生成物を得た。分取薄層クロマトグラフィー(酢酸エチル−ヘキサン)で精製し、３−クロロ−５−（（（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−Ｎ−エチル−２−ヒドロキシベンズアミド(4.7mg)を得た。
¹H-NMR(CDCl₃)δ:12.97(1H,s),7.57-7.35(7H,m),6.67(1H,s),4.76(1H,t,J=6.3Hz),4.51(2H,d,J=6.6Hz),3.54-3.45(2H,m),2.31(3H,s),1.30-1.26(3H,m).
MSm/z(M+H):410.

5-Amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile (9.2 mg), 3-chloro-N-ethyl-5-formyl-2-hydroxybenzamide (Compound 0013-2, 6.6 mg) Then, a toluene (4 mL) solution of paratoluenesulfonic acid monohydrate (8.8 mg, about 1.0 equivalent) was heated under reflux for 3 hours, and then the solvent was distilled off under reduced pressure. After cooling to room temperature, ethanol (0.29 mL) was added to the resulting pale yellow solid, and a solution of sodium borohydride (3.3 mg) in ethanol (0.26 mL) was added dropwise at 0 ° C. under nitrogen, and then gradually brought to room temperature. The mixture was warmed and stirred for 1 hour. After standing at room temperature overnight, a solution of sodium borohydride (3.3 mg) in ethanol (0.26 mL) was added at 0 ° C., and the mixture was warmed to room temperature and stirred for 1 hour. Acetone was added to the reaction solution, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the obtained solid to separate the solution, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then under reduced pressure. The solvent was distilled off to obtain a crude product. Purification by preparative thin layer chromatography (ethyl acetate-hexane) yields 3-chloro-5-(((4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) amino) methyl)- N-ethyl-2-hydroxybenzamide (4.7 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 12.97 (1H, s), 7.57-7.35 (7H, m), 6.67 (1H, s), 4.76 (1H, t, J = 6.3Hz), 4.51 (2H, d , J = 6.6Hz), 3.54-3.45 (2H, m), 2.31 (3H, s), 1.30-1.26 (3H, m).
MSm / z (M + H): 410.

５−アミノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル(285mg)、４−ヒドロキシ−３−ニトロベンズアルデヒド(150mg)、パラトルエンスルホン酸一水和物(273mg、約1.0当量)のトルエン(15mL)溶液を1時間加熱還流後、減圧下溶媒を留去した。得られた橙色固体にエタノール(9mL)を加え、0℃、窒素下で水素化ホウ素ナトリウム(103mg)のエタノール(8.2mL)溶液を滴下した後、徐々に室温に昇温して2.5時間攪拌した。水素化ホウ素ナトリウム(34mg)を0℃で加え、再度室温に昇温し、1時間攪拌した後、さらに水素化ホウ素ナトリウム(34mg)を加え、40℃で30分攪拌した。反応液にアセトンを加え、減圧下溶媒を留去した後、得られた固体に酢酸エチル、水を加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して粗生成物を得た。シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)で精製し、得られた固体をジクロロメタンに溶解させ、5.0mol/L水酸化ナトリウム水溶液を加えて分液した。得られた水層に塩酸を加えて中和し、析出した固体をろ取した後、水で洗浄し、５−（（４−ヒドロキシ−３−ニトロベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００１４−１、84mg)を淡黄色固体として得た。
MSm/z(M+H):350. [Example 14]

5-Amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile (285 mg), 4-hydroxy-3-nitrobenzaldehyde (150 mg), p-toluenesulfonic acid monohydrate (273 mg, about 1.0 equivalents) ) In toluene (15 mL) was heated under reflux for 1 hour, and then the solvent was distilled off under reduced pressure. Ethanol (9 mL) was added to the obtained orange solid, a solution of sodium borohydride (103 mg) in ethanol (8.2 mL) was added dropwise at 0 ° C. under nitrogen, and the mixture was gradually warmed to room temperature and stirred for 2.5 hours. . Sodium borohydride (34 mg) was added at 0 ° C., the temperature was raised again to room temperature, and the mixture was stirred for 1 hour, further sodium borohydride (34 mg) was added, and the mixture was stirred at 40 ° C. for 30 minutes. Acetone was added to the reaction solution, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the obtained solid to separate the solution, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then under reduced pressure. The solvent was distilled off to obtain a crude product. The product was purified by silica gel column chromatography (ethyl acetate-hexane), the obtained solid was dissolved in dichloromethane, and 5.0 mol / L aqueous sodium hydroxide solution was added to separate the layers. The resulting aqueous layer was neutralized by adding hydrochloric acid, and the precipitated solid was collected by filtration and then washed with water to give 5-((4-hydroxy-3-nitrobenzyl) amino) -3-methyl-1- Phenyl-1H-pyrazole-4-carbonitrile (Compound 0014-1, 84 mg) was obtained as a pale yellow solid.
MSm / z (M + H): 350.

実施例１において、２−クロロ−６−ニトロフェノールを用いた代わりに５−（（４−ヒドロキシ−３−ニトロベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００１４−１)を用いたこと以外は実施例１と同様の方法で、５−（（３−アミノ−４−ヒドロキシベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル塩酸塩(化合物００１４−２）を得た。
MSm/z(M+H):320.

In Example 1, instead of using 2-chloro-6-nitrophenol, 5-((4-hydroxy-3-nitrobenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile 5-((3-Amino-4-hydroxybenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4 was prepared in the same manner as in Example 1 except that (Compound 0014-1) was used. -Carbonitrile hydrochloride (compound 0014-2) was obtained.
MS m / z (M + H): 320.

５−（（３−アミノ−４−ヒドロキシベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル塩酸塩(化合物００１４−２、16mg)のＮ，Ｎ−ジメチルホルムアミド(0.23mL)溶液に、プロピオン酸(5μL)、Ｎ，Ｎ−ジイソプロピルエチルアミン(23μL)、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩(11mg)を加え、45℃で19時間攪拌した。プロピオン酸(5.4μL)、Ｎ，Ｎ−ジイソプロピルエチルアミン(23μL)、１−ヒドロキシベンゾトリアゾール一水和物(1mg)、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩(11mg)を加え、45℃で1.5時間攪拌した後、60℃で終夜攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて1.5時間攪拌した後、40℃で30分攪拌した。反応液に5.0mol/L水酸化ナトリウム水溶液(0.1mL)を加えて45分攪拌し、6.0mol/L塩酸で酸性にした後、酢酸エチルを加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して粗生成物を得た。分取薄層クロマトグラフィー(酢酸エチル−ヘキサン)で精製し、Ｎ−（５−（（（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミド(2.7mg)を得た。
¹H-NMR(CDCl₃)δ:8.81(1H,s),7.49-7.42(6H,m),7.04(1H,s),7.00-6.99(2H,m),4.55(3H,s),2.49(2H,t,J=7.6Hz),2.32(3H,s),1.31-1.24(3H,m).
MSm/z(M+H):376.

5-((3-amino-4-hydroxybenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile hydrochloride (compound 0014-2, 16 mg) in N, N-dimethylformamide ( 0.23 mL) solution was added propionic acid (5 μL), N, N-diisopropylethylamine (23 μL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (11 mg) and stirred at 45 ° C. for 19 hours. did. Propionic acid (5.4 μL), N, N-diisopropylethylamine (23 μL), 1-hydroxybenzotriazole monohydrate (1 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (11 mg) In addition, the mixture was stirred at 45 ° C. for 1.5 hours, and then stirred at 60 ° C. overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and stirred for 1.5 hours, and then stirred at 40 ° C. for 30 minutes. To the reaction solution was added 5.0 mol / L aqueous sodium hydroxide solution (0.1 mL), and the mixture was stirred for 45 minutes, acidified with 6.0 mol / L hydrochloric acid, separated by adding ethyl acetate, and the organic layer was washed with saturated brine. After washing and drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product. Purification by preparative thin layer chromatography (ethyl acetate-hexane) and N- (5-(((4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) amino) methyl) -2 -Hydroxyphenyl) propionamide (2.7 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.81 (1H, s), 7.49-7.42 (6H, m), 7.04 (1H, s), 7.00-6.99 (2H, m), 4.55 (3H, s), 2.49 (2H, t, J = 7.6Hz), 2.32 (3H, s), 1.31-1.24 (3H, m).
MS m / z (M + H): 376.

実施例１において、Ｎ−（３−クロロ−２−ヒドロキシフェニル）プロピオンアミドを用いた代わりに２−クロロ−６−ニトロフェノールを用いること以外は実施例１と同様の方法で、３−クロロ−４−ヒドロキシ−５−ニトロベンズアルデヒド（化合物００１５−１）を黄色固体として得た。
MSm/z(M+H):202. [Example 15]

In Example 1, in the same manner as in Example 1 except that 2-chloro-6-nitrophenol was used instead of N- (3-chloro-2-hydroxyphenyl) propionamide, 3-chloro- 4-Hydroxy-5-nitrobenzaldehyde (Compound 0015-1) was obtained as a yellow solid.
MS m / z (M + H): 202.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを、Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミドを用いた代わりに３−クロロ−４−ヒドロキシ−５−ニトロベンズアルデヒド（化合物００１５−１）を、水素化ホウ素ナトリウムの代わりに水素化ホウ素リチウムを用いること以外は実施例５と同様の方法で、５−（（３−クロロ−４−ヒドロキシ−５−ニトロベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００１５−２）を得た。
MSm/z(M+H):384.

In Example 5, instead of using 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile was replaced with N- Instead of (3-chloro-5-formyl-2-hydroxyphenyl) propionamide, 3-chloro-4-hydroxy-5-nitrobenzaldehyde (compound 0015-1) was hydrogenated instead of sodium borohydride. 5-((3-Chloro-4-hydroxy-5-nitrobenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4- is the same as Example 5 except that lithium boron is used. Carbonitrile (Compound 0015-2) was obtained.
MSm / z (M + H): 384.

実施例１において、２−クロロ−６−ニトロフェノールを用いた代わりに５−（（３−クロロ−４−ヒドロキシ−５−ニトロベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００１５−２）を用いること以外は実施例１と同様の方法で、５−（（３−アミノ−５−クロロ−４−ヒドロキシベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル塩酸塩（化合物００１５−３）を褐色固体として得た。
MSm/z(M+H):354.

In Example 1, instead of using 2-chloro-6-nitrophenol, 5-((3-chloro-4-hydroxy-5-nitrobenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole- 5-((3-Amino-5-chloro-4-hydroxybenzyl) amino) -3-methyl-1- was prepared in the same manner as in Example 1 except that 4-carbonitrile (Compound 0015-2) was used. Phenyl-1H-pyrazole-4-carbonitrile hydrochloride (Compound 0015-3) was obtained as a brown solid.
MS m / z (M + H): 354.

実施例１４において、５−（（３−アミノ−４−ヒドロキシベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル塩酸塩を用いた代わりに５−（（３−アミノ−５−クロロ−４−ヒドロキシベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル塩酸塩（化合物００１５−３）を、プロピオン酸を用いた代わりに酢酸を用いること以外は実施例１４と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）アセトアミドを得た。
¹H-NMR(CDCl₃)δ:7.87(1H,s),7.69(1H,s),7.61(1H,s),7.54-7.50(2H,m),7.43-7.42(3H,m),7.08(1H,d,J=2.0Hz),4.66(1H,t,J=6.3Hz),4.53(2H,d,J=6.6Hz),2.31(3H,s),2.24(3H,s).
MSm/z(M+H):396.

In Example 14, instead of using 5-((3-amino-4-hydroxybenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile hydrochloride, 5-((3- Amino-5-chloro-4-hydroxybenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile hydrochloride (compound 0015-3) using acetic acid instead of propionic acid Except that, N- (3-chloro-5-(((4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) amino) methyl) -2 was prepared in the same manner as in Example 14. -Hydroxyphenyl) acetamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.87 (1H, s), 7.69 (1H, s), 7.61 (1H, s), 7.54-7.50 (2H, m), 7.43-7.42 (3H, m), 7.08 (1H, d, J = 2.0Hz), 4.66 (1H, t, J = 6.3Hz), 4.53 (2H, d, J = 6.6Hz), 2.31 (3H, s), 2.24 (3H, s).
MSm / z (M + H): 396.

実施例４において、３−クロロ安息香酸を用いた代わりに４−ヒドロキシ−３−メチルベンズアルデヒドを用いること以外は実施例４と同様の方法で、４−ヒドロキシ−３−メチル−５−ニトロベンズアルデヒド（化合物００１６−１）を得た。
MSm/z(M+H):182. [Example 16]

In Example 4, 4-hydroxy-3-methyl-5-nitrobenzaldehyde (in the same manner as in Example 4 except that 4-hydroxy-3-methylbenzaldehyde was used instead of 3-chlorobenzoic acid) Compound 0016-1) was obtained.
MSm / z (M + H): 182.

実施例１５において、３−クロロ−４−ヒドロキシ−５−ニトロベンズアルデヒドを用いた代わりに４−ヒドロキシ−３−メチル−５−ニトロベンズアルデヒド（化合物００１６−１）を用いること以外は実施例１５と同様の方法で、５−（（４−ヒドロキシ−３−メチル−５−ニトロベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００１６−２）を得た。
MSm/z(M+H):364.

Example 15 is the same as Example 15 except that 4-hydroxy-3-methyl-5-nitrobenzaldehyde (Compound 0016-1) is used instead of 3-chloro-4-hydroxy-5-nitrobenzaldehyde. In this manner, 5-((4-hydroxy-3-methyl-5-nitrobenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile (Compound 0016-2) was obtained.
MSm / z (M + H): 364.

実施例１において、２−クロロ−６−ニトロフェノールを用いた代わりに５−（（４−ヒドロキシ−３−メチル−５−ニトロベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００１６−２）を用いること以外は実施例１と同様の方法で、５−（（３−アミノ−４−ヒドロキシ−５−メチルベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル塩酸塩（化合物００１６−３）を褐色固体として得た。
MSm/z(M+H):334.

In Example 1, instead of using 2-chloro-6-nitrophenol, 5-((4-hydroxy-3-methyl-5-nitrobenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole- 5-((3-Amino-4-hydroxy-5-methylbenzyl) amino) -3-methyl-1- was prepared in the same manner as in Example 1 except that 4-carbonitrile (Compound 0016-2) was used. Phenyl-1H-pyrazole-4-carbonitrile hydrochloride (Compound 0016-3) was obtained as a brown solid.
MS m / z (M + H): 334.

実施例１４において、５−（（３−アミノ−４−ヒドロキシベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル塩酸塩を用いた代わりに５−（（３−アミノ−４−ヒドロキシ−５−メチルベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル塩酸塩（化合物００１６−３）を用いること以外は実施例１４と同様の方法で、Ｎ−（５−（（（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシ−３−メチルフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:8.76(1H,s),7.48-7.42(6H,m),6.90(1H,s),6.84-6.83(1H,m),4.51(3H,s),2.50(2H,q,J=7.5Hz),2.33(3H,s),2.26(3H,s),1.33-1.24(3H,m).
MSm/z(M+H):390.

In Example 14, instead of using 5-((3-amino-4-hydroxybenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile hydrochloride, 5-((3- Amino-4-hydroxy-5-methylbenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile hydrochloride (compound 0016-3) To give N- (5-(((4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxy-3-methylphenyl) propionamide.
¹ H-NMR (CDCl ₃ ) δ: 8.76 (1H, s), 7.48-7.42 (6H, m), 6.90 (1H, s), 6.84-6.83 (1H, m), 4.51 (3H, s), 2.50 (2H, q, J = 7.5Hz), 2.33 (3H, s), 2.26 (3H, s), 1.33-1.24 (3H, m).
MSm / z (M + H): 390.

５−（（３−クロロ−４−ヒドロキシ−５−ニトロベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００１５−２、58mg）をＮ，Ｎ−ジメチルホルムアミド（0.8mL）に溶かし、これに炭酸カリウム（62mg）とヨウ化メチル（10.3μL）を加え、室温で終夜攪拌した。反応混合物を水に注ぎ、酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残留物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）で精製し、５−（（３−クロロ−４−メトキシ−５−ニトロベンジル）アミノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００１７−１、27.7mg）を得た。
MSm/z(M+H):398. [Example 17]

5-((3-Chloro-4-hydroxy-5-nitrobenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile (compound 0015-2, 58 mg) was converted to N, N-dimethyl. Dissolved in formamide (0.8 mL), potassium carbonate (62 mg) and methyl iodide (10.3 μL) were added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 5-((3-chloro-4-methoxy-5-nitrobenzyl) amino-3-methyl. -1-Phenyl-1H-pyrazole-4-carbonitrile (Compound 0017-1, 27.7 mg) was obtained.
MS m / z (M + H): 398.

実施例１において、２−クロロ−６−ニトロフェノールを用いた代わりに５−（（３−クロロ−４−メトキシ−５−ニトロベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００１７−１）を用いること以外は実施例１と同様の方法で、５−（（３−アミノ−４−メトキシ−５−クロロベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル塩酸塩（化合物００１７−２）を黄色固体として得た。
MSm/z(M+H):368.

In Example 1, instead of using 2-chloro-6-nitrophenol, 5-((3-chloro-4-methoxy-5-nitrobenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole- 5-((3-Amino-4-methoxy-5-chlorobenzyl) amino) -3-methyl-1- was prepared in the same manner as in Example 1 except that 4-carbonitrile (Compound 0017-1) was used. Phenyl-1H-pyrazole-4-carbonitrile hydrochloride (Compound 0017-2) was obtained as a yellow solid.
MSm / z (M + H): 368.

５−（（３−アミノ−４−メトキシ−５−クロロベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル塩酸塩（化合物００１７−２、15mg）をテトラヒドロフラン（0.2mL）に溶かし、これにトリエチルアミン（13μL）とプロピオニルクロリド（3.5μL）を加え、室温で終夜攪拌した。反応混合物を塩化アンモニウム水溶液に注ぎ、塩化メチレンで抽出し、有機層を無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残留物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）で精製し、Ｎ−（５−（（（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−メトキシ−３−クロロフェニル）プロピオンアミド(1.5mg)を得た。
¹H-NMR(CDCl₃)δ:8.32(1H,d,J=2.0Hz),7.76(1H,s),7.56-7.39(5H,m),7.08(1H,d,J=2.3Hz),4.62-4.55(3H,brs),3.89(3H,s),2.45(2H,q,J=7.6Hz),2.33(3H,s),1.27(3H,t,J=7.5Hz).
MSm/z(M+H):424.

5-((3-Amino-4-methoxy-5-chlorobenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile hydrochloride (Compound 0017-2, 15 mg) was added to tetrahydrofuran (0.2 To this, triethylamine (13 μL) and propionyl chloride (3.5 μL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into an aqueous ammonium chloride solution, extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and N- (5-(((4-cyano-3-methyl-1-phenyl-1H- Pyrazol-5-yl) amino) methyl) -2-methoxy-3-chlorophenyl) propionamide (1.5 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.32 (1H, d, J = 2.0Hz), 7.76 (1H, s), 7.56-7.39 (5H, m), 7.08 (1H, d, J = 2.3Hz), 4.62-4.55 (3H, brs), 3.89 (3H, s), 2.45 (2H, q, J = 7.6Hz), 2.33 (3H, s), 1.27 (3H, t, J = 7.5Hz).
MSm / z (M + H): 424.

実施例１４において、５−（（３−アミノ−４−ヒドロキシベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル塩酸塩を用いた代わりに５−（（３−アミノ−４−ヒドロキシ−５−メチルベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル塩酸塩(化合物００１６−３、12mg)を、プロピオン酸の代わりに酪酸を用いること以外は実施例１４と同様の方法で、Ｎ−（５−（（（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシ−３−メチルフェニル）ブタンアミドを得た。
¹H-NMR(CDCl₃)δ:7.68(2H,d,J=1.7Hz),7.70-7.63(1H,brs),7.55-7.41(5H,m),7.10(1H,d,J=2.0Hz),4.64-4.57(1H,brm),4.55(2H,d,J=5.0Hz),2.42(2H,t,J=7.4Hz),2.32(3H,s),1.84-1.72(2H,m),1.02(3H,t,J=7.4Hz).
MSm/z(M+H): 424. [Example 18]

In Example 14, instead of using 5-((3-amino-4-hydroxybenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile hydrochloride, 5-((3- Amino-4-hydroxy-5-methylbenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile hydrochloride (compound 0016-3, 12 mg) using butyric acid instead of propionic acid Except for this, N- (5-(((4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxy-3 was prepared in the same manner as in Example 14. -Methylphenyl) butanamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.68 (2H, d, J = 1.7Hz), 7.70-7.63 (1H, brs), 7.55-7.41 (5H, m), 7.10 (1H, d, J = 2.0Hz ), 4.64-4.57 (1H, brm), 4.55 (2H, d, J = 5.0Hz), 2.42 (2H, t, J = 7.4Hz), 2.32 (3H, s), 1.84-1.72 (2H, m) , 1.02 (3H, t, J = 7.4Hz).
MSm / z (M + H): 424.

実施例１４において、５−（（３−アミノ−４−ヒドロキシベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル塩酸塩を用いた代わりに５−（（３−アミノ−４−ヒドロキシ−５−メチルベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル塩酸塩(化合物００１６−３、15mg)を、プロピオン酸の代わりにヘキサン酸を用いること以外は実施例１４と同様の方法で、Ｎ−（５−（（（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシ−３−メチルフェニル）ヘキサンアミド(7.9mg)を得た。
¹H-NMR(CDCl₃)δ:7.72(1H,s),7.64(1H,d,J=1.7Hz),7.54-7.37(5H,m),7.09(1H,d,J=2.0Hz),4.64-4.58(1H,brm),4.54(2H,d,J=5.9Hz),2.43(2H,t,J=7.4Hz),2.32(3H,s),1.79-1.69(2H,m),1.40-1.32(4H,m),0.92(3H,t,J=7.2Hz).
MSm/z(M+H):452. [Example 19]

In Example 14, instead of using 5-((3-amino-4-hydroxybenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile hydrochloride, 5-((3- Amino-4-hydroxy-5-methylbenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile hydrochloride (compound 0016-3, 15 mg), hexanoic acid instead of propionic acid N- (5-(((4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxy- is the same as in Example 14 except for using. 3-Methylphenyl) hexanamide (7.9 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.72 (1H, s), 7.64 (1H, d, J = 1.7Hz), 7.54-7.37 (5H, m), 7.09 (1H, d, J = 2.0Hz), 4.64-4.58 (1H, brm), 4.54 (2H, d, J = 5.9Hz), 2.43 (2H, t, J = 7.4Hz), 2.32 (3H, s), 1.79-1.69 (2H, m), 1.40 -1.32 (4H, m), 0.92 (3H, t, J = 7.2Hz).
MSm / z (M + H): 452.

メチルヒドラジン(89μL)のエタノール(0.8mL)溶液に２−（１−エトキシエチリデン）マロノニトリル(150mg)を加えて90℃で30分攪拌した。反応液を氷冷し、析出した固体をろ取し、５−アミノ−１，３−ジメチル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００２０−１、92mg）を得た。
¹H-NMR(CDCl₃)δ:4.20-4.10(2H,brs),3.58(3H,s),2.24(3H,s). [Example 20]

2- (1-Ethoxyethylidene) malononitrile (150 mg) was added to a solution of methyl hydrazine (89 μL) in ethanol (0.8 mL), and the mixture was stirred at 90 ° C. for 30 minutes. The reaction solution was ice-cooled, and the precipitated solid was collected by filtration to obtain 5-amino-1,3-dimethyl-1H-pyrazole-4-carbonitrile (Compound 0020-1, 92 mg).
¹ H-NMR (CDCl ₃ ) δ: 4.20-4.10 (2H, brs), 3.58 (3H, s), 2.24 (3H, s).

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−１，３−ジメチル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００２０−１）を用いたこと以外は実施例５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−１，３−ジメチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
MSm/z(M+H):348.

Instead of using 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile in Example 5, 5-amino-1,3-dimethyl-1H-pyrazole-4-carbonitrile (Compound 0020-1) N- (3-Chloro-5-(((4-cyano-1,3-dimethyl-1H-pyrazol-5-yl) amino) methyl)-in the same manner as in Example 5 except that 2-Hydroxyphenyl) propionamide was obtained.
MSm / z (M + H): 348.

マロノニトリル(1g)にオルトプロピオン酸トリエチル(3.3mL)を加え、90℃で1.5時間攪拌した。室温まで冷却した後、減圧下溶媒を留去して、２−（１−エトキシプロピリデン）マロノニトリル（化合物００２１−１、2.54g）を得た。
¹H-NMR(CDCl₃)δ:4.47(2H,q,J=6.8Hz),2.67(2H,q,J=7.5Hz),1.46(3H,t,J=6.9Hz),1.30-1.24(3H,m). [Example 21]

Triethyl orthopropionate (3.3 mL) was added to malononitrile (1 g), and the mixture was stirred at 90 ° C. for 1.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure to obtain 2- (1-ethoxypropylidene) malononitrile (compound 0021-1, 2.54 g).
¹ H-NMR (CDCl ₃ ) δ: 4.47 (2H, q, J = 6.8Hz), 2.67 (2H, q, J = 7.5Hz), 1.46 (3H, t, J = 6.9Hz), 1.30-1.24 ( 3H, m).

２−（１−エトキシプロピリデン）マロノニトリル(化合物００２１−１、0.31g)のエタノール(10.3mL)溶液にフェニルヒドラジン(0.34mL)を加え、室温で6.5時間攪拌した。減圧下溶媒を留去し、得られた固体に酢酸エチルと水を加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して粗生成物を得た。シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)で精製し、５−アミノ−３−エチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２１−２、0.33g)を得た。
MSm/z(M+H):213.

Phenylhydrazine (0.34 mL) was added to a solution of 2- (1-ethoxypropylidene) malononitrile (Compound 0021-1, 0.31 g) in ethanol (10.3 mL), and the mixture was stirred at room temperature for 6.5 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the resulting solid for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. I got a thing. Purification by silica gel column chromatography (ethyl acetate-hexane) gave 5-amino-3-ethyl-1-phenyl-1H-pyrazole-4-carbonitrile (Compound 0021-2, 0.33 g).
MS m / z (M + H): 213.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−エチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２１−１)を用いること以外は実施例５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−エチル−１−フェニル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CD₃OD)δ:7.60-7.46(6H,m),7.09(1H,d,J=2.0Hz),4.49(2H,s),2.62-2.60(2H,m),2.48-2.46(2H,m),1.26-1.21(6H,m).
MSm/z(M+H):424.

In Example 5, instead of using 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile, 5-amino-3-ethyl-1-phenyl-1H-pyrazole-4-carbonitrile (compound 0021- N- (3-chloro-5-(((4-cyano-3-ethyl-1-phenyl-1H-pyrazol-5-yl) amino) in the same manner as in Example 5 except that 1) was used. Methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CD ₃ OD) δ: 7.60-7.46 (6H, m), 7.09 (1H, d, J = 2.0Hz), 4.49 (2H, s), 2.62-2.60 (2H, m), 2.48- 2.46 (2H, m), 1.26-1.21 (6H, m).
MSm / z (M + H): 424.

マロノニトリル(0.17g)にフェニルトリエトキシメタン(0.5mL)、無水酢酸(0.94mL)を加え、140℃で終夜攪拌した。反応液を室温まで冷却した後、減圧下溶媒を留去して粗生成物を得た。シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)で精製し、２−（エトキシ（フェニル）メチレン）マロノニトリル(化合物００２２−１、334mg)を得た。
¹H-NMR(CD₃OD)δ:7.69-7.59(5H,m),4.20(2H,q,J=7.0Hz),1.34(3H,t,J=7.3Hz). [Example 22]

Phenyltriethoxymethane (0.5 mL) and acetic anhydride (0.94 mL) were added to malononitrile (0.17 g), and the mixture was stirred at 140 ° C. overnight. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (ethyl acetate-hexane) gave 2- (ethoxy (phenyl) methylene) malononitrile (Compound 0022-1, 334 mg).
¹ H-NMR (CD ₃ OD) δ: 7.69-7.59 (5H, m), 4.20 (2H, q, J = 7.0Hz), 1.34 (3H, t, J = 7.3Hz).

２−（エトキシ（フェニル）メチレン）マロノニトリル(化合物００２２−１、334mg)のエタノール(5.1mL)溶液にフェニルヒドラジン(0.15mL)を加え、室温で終夜攪拌した。減圧下溶媒を留去して、粗生成物を得た。シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)で精製し、５−アミノ−１，３−ジフェニル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２２−２、0.22g)を得た。
MSm/z(M+H):261.

Phenylhydrazine (0.15 mL) was added to a solution of 2- (ethoxy (phenyl) methylene) malononitrile (Compound 0022-1, 334 mg) in ethanol (5.1 mL), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (ethyl acetate-hexane) gave 5-amino-1,3-diphenyl-1H-pyrazole-4-carbonitrile (Compound 0022-2, 0.22 g).
MSm / z (M + H): 261.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−１，３−ジフェニル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２２−２)を用いること以外は実施例５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−１，３−ジフェニル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CD₃OD)δ:7.85-7.82(2H,m),7.61-7.55(6H,m),7.46-7.41(3H,m),7.13(1H,d,J=2.0Hz),4.59-4.55(2H,m),2.47(2H,q,J=7.5Hz),1.26-1.18(3H,m).
MSm/z(M+H):472

Instead of using 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile in Example 5, 5-amino-1,3-diphenyl-1H-pyrazole-4-carbonitrile (Compound 0022-2) N- (3-Chloro-5-(((4-cyano-1,3-diphenyl-1H-pyrazol-5-yl) amino) methyl) -2 in the same manner as in Example 5 except that -Hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CD ₃ OD) δ: 7.85-7.82 (2H, m), 7.61-7.55 (6H, m), 7.46-7.41 (3H, m), 7.13 (1H, d, J = 2.0 Hz), 4.59-4.55 (2H, m), 2.47 (2H, q, J = 7.5Hz), 1.26-1.18 (3H, m).
MSm / z (M + H): 472

実施例２２において、マロノニトリルを用いる代わりにシアノ酢酸エチルを、フェニルトリエトキシメタンを用いる代わりにオルトぎ酸トリエチルを用いること以外は実施例２２と同様の方法で、エチル ２−シアノ−３−エトキシ−２−ブテノアート(化合物００２３−１)をE/Z混合物として得た。
MSm/z(M+H):184. [Example 23]

In Example 22, ethyl 2-cyano-3-ethoxy- was prepared in the same manner as in Example 22 except that ethyl cyanoacetate was used instead of malononitrile and triethyl orthoformate was used instead of phenyltriethoxymethane. 2-Butenoate (Compound 0023-1) was obtained as an E / Z mixture.
MS m / z (M + H): 184.

実施例２２において、２−（エトキシ（フェニル）メチレン）マロノニトリルを用いる代わりにエチル エチル ２−シアノ−３−エトキシブト−２−エノアート（化合物００２３−１）を用いること以外は実施例２２と同様の方法で、エチル ５−アミノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボキシラート(化合物００２３−２)を得た。
MSm/z(M+H):246.

In Example 22, the same method as in Example 22 except that ethyl ethyl 2-cyano-3-ethoxybut-2-enoate (compound 0023-1) was used instead of 2- (ethoxy (phenyl) methylene) malononitrile. To give ethyl 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (Compound 0023-2).
MSm / z (M + H): 246.

エチル ５−アミノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボキシラート(化合物００２３−２、16.2mg)、Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミド(化合物０００１−３、17.9mg)、パラトルエンスルホン酸ピリジニウム(16.6mg)のトルエン(10mL)溶液を2時間加熱還流後、減圧下溶媒を留去した。得られた淡黄色固体にエタノール(0.66mL)を加え、0℃、窒素下で水素化ホウ素ナトリウム(7.4mg)のエタノール(0.66mL)溶液を滴下した後、徐々に室温に昇温して1時間攪拌した。水素化ホウ素ナトリウム(8.2mg)のエタノール(0.6mL)溶液を追加し、40分攪拌した後、室温で一晩静置した。さらに水素化ホウ素ナトリウム(8.0mg)のエタノール(0.6mL)溶液を追加し、1時間攪拌した。反応液にアセトンを加え、減圧下溶媒を留去した後、得られた固体に酢酸エチル、水を加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して黄色オイルを得た。得られた黄色オイルにテトラヒドロフラン(0.66mL)を加え、窒素雰囲気下で水素化ホウ素リチウム(3.0mol/L、テトラヒドロフラン溶液、66μL)を加え、室温で1時間攪拌した。反応液にアセトンを加え、減圧下溶媒を留去した後、得られた固体に酢酸エチル、水を加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して粗生成物を得た。分取薄層クロマトグラフィー(酢酸エチル−ヘキサン)で精製し、エチル ５−（（３−クロロ−４−ヒドロキシ−５−プロピオンアミドベンジル）アミノ）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボキシラート(3.4mg)を得た。
¹H-NMR(CD₃OD)δ:7.52-7.42(5H,m),7.17(1H,s),6.68(1H,d,J=2.0Hz),4.31(2H,q,J=7.0Hz),3.86(2H,s),2.44(2H,q,J=7.5Hz),2.32(3H,s),1.37-1.15(8H,m).
MSm/z(M+H):457.

Ethyl 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (compound 0023-2, 16.2 mg), N- (3-chloro-5-formyl-2-hydroxyphenyl) propionamide ( A toluene (10 mL) solution of compound 0001-3, 17.9 mg) and pyridinium paratoluenesulfonate (16.6 mg) was heated under reflux for 2 hours, and then the solvent was distilled off under reduced pressure. Ethanol (0.66 mL) was added to the obtained pale yellow solid, a solution of sodium borohydride (7.4 mg) in ethanol (0.66 mL) was added dropwise at 0 ° C. under nitrogen, and the temperature was gradually raised to room temperature. Stir for hours. A solution of sodium borohydride (8.2 mg) in ethanol (0.6 mL) was added, stirred for 40 minutes, and allowed to stand overnight at room temperature. Further, a solution of sodium borohydride (8.0 mg) in ethanol (0.6 mL) was added and stirred for 1 hour. Acetone was added to the reaction solution, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the obtained solid to separate the solution, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then under reduced pressure. The solvent was distilled off to obtain a yellow oil. Tetrahydrofuran (0.66 mL) was added to the obtained yellow oil, lithium borohydride (3.0 mol / L, tetrahydrofuran solution, 66 μL) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. Acetone was added to the reaction solution, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the obtained solid to separate the solution, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then under reduced pressure. The solvent was distilled off to obtain a crude product. Purification by preparative thin layer chromatography (ethyl acetate-hexane) and ethyl 5-((3-chloro-4-hydroxy-5-propionamidobenzyl) amino) -3-methyl-1-phenyl-1H-pyrazole- 4-Carboxylate (3.4 mg) was obtained.
¹ H-NMR (CD ₃ OD) δ: 7.52-7.42 (5H, m), 7.17 (1H, s), 6.68 (1H, d, J = 2.0Hz), 4.31 (2H, q, J = 7.0Hz) , 3.86 (2H, s), 2.44 (2H, q, J = 7.5Hz), 2.32 (3H, s), 1.37-1.15 (8H, m).
MSm / z (M + H): 457.

ｐ−トリルヒドラジン塩酸塩(0.56g)のエタノール(11.8mL)懸濁液にトリエチルアミン(0.5mL)を加え、室温で20分攪拌した。２−（１−エトキシエチリデン）マロノニトリル(150mg)を加えてさらに1時間攪拌した後、減圧下溶媒を留去した。得られた固体を酢酸エチルに溶かし、水を加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して粗生成物を得た。得られた粗生成物を結晶化(酢酸エチル−ヘキサン)で精製し、５−アミノ−３−メチル−１−（４−メチルフェニル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２４−１、0.41g)を得た。
MSm/z(M+H):213. [Example 24]

Triethylamine (0.5 mL) was added to a suspension of p-tolylhydrazine hydrochloride (0.56 g) in ethanol (11.8 mL), and the mixture was stirred at room temperature for 20 minutes. 2- (1-Ethoxyethylidene) malononitrile (150 mg) was added and further stirred for 1 hour, and then the solvent was distilled off under reduced pressure. The obtained solid was dissolved in ethyl acetate, water was added for liquid separation, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by crystallization (ethyl acetate-hexane) to give 5-amino-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carbonitrile (compound 0024-1, 0.41 g) was obtained.
MS m / z (M + H): 213.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（ｐ−トリル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２４−１)を用いたこと以外は実施例５と同様な方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（４−メチルフェニル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CD₃OD)δ:7.52(1H,s),7.35(4H,q,J=8.4Hz),7.07(1H,d,J=1.3Hz),4.47(2H,s),2.46(2H,t,J=7.6Hz),2.42(3H,s),2.21(3H,s),1.21(3H,t,J=7.3Hz).
MSm/z(M+H):424.

Instead of using 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile in Example 5, 5-amino-3-methyl-1- (p-tolyl) -1H-pyrazole-4-carbonitrile N- (3-Chloro-5-(((4-cyano-3-methyl-1- (4-methylphenyl)-) was obtained in the same manner as in Example 5 except that (Compound 0024-1) was used. 1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CD ₃ OD) δ: 7.52 (1H, s), 7.35 (4H, q, J = 8.4Hz), 7.07 (1H, d, J = 1.3Hz), 4.47 (2H, s), 2.46 (2H, t, J = 7.6Hz), 2.42 (3H, s), 2.21 (3H, s), 1.21 (3H, t, J = 7.3Hz).
MSm / z (M + H): 424.

実施例２４において、ｐ−トリルヒドラジン塩酸塩を用いた代わりにｍ−トリルヒドラジン塩酸塩を用いること以外は実施例２４と同様の方法で、５−アミノ−１，３−ジメチル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（３−メチルフェニル）−１Ｈ−ピラゾール−４−カルボニトリル（化合物００２５−１)を得た。
MSm/z(M+H):213. [Example 25]

In Example 24, 5-amino-1,3-dimethyl-1H-pyrazole was prepared in the same manner as in Example 24 except that m-tolylhydrazine hydrochloride was used instead of p-tolylhydrazine hydrochloride. Instead of using 4-carbonitrile, 5-amino-3-methyl-1- (3-methylphenyl) -1H-pyrazole-4-carbonitrile (Compound 0025-1) was obtained.
MS m / z (M + H): 213.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（３−メチルフェニル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２５−１)を用いること以外は実施例５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（３−メチルフェニル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CD₃OD)δ:7.54(1H,s),7.44-7.41(1H,m),7.32-7.26(3H,m),7.07(1H,s),4.48(2H,s),2.48-2.45(2H,m),2.42(3H,s),2.22(3H,s),1.23-1.21(3H,m).
MSm/z(M+H):424.

In Example 5, instead of using 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1- (3-methylphenyl) -1H-pyrazole-4-carbo N- (3-Chloro-5-(((4-cyano-3-methyl-1- (3-methylphenyl)-) was used in the same manner as in Example 5 except that nitrile (Compound 0025-1) was used. 1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CD ₃ OD) δ: 7.54 (1H, s), 7.44-7.41 (1H, m), 7.32-7.26 (3H, m), 7.07 (1H, s), 4.48 (2H, s), 2.48-2.45 (2H, m), 2.42 (3H, s), 2.22 (3H, s), 1.23-1.21 (3H, m).
MSm / z (M + H): 424.

実施例２４において、ｐ−トリルヒドラジン塩酸塩を用いた代わりにｏ−トリルヒドラジン塩酸塩を用いること以外は実施例２４と同様の方法で、５−アミノ−３−メチル−１−（２−メチルフェニル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２６−１)を得た。
MSm/z(M+H):213. [Example 26]

In Example 24, 5-amino-3-methyl-1- (2-methyl) was prepared in the same manner as in Example 24 except that o-tolylhydrazine hydrochloride was used instead of p-tolylhydrazine hydrochloride. Phenyl) -1H-pyrazole-4-carbonitrile (Compound 0026-1) was obtained.
MS m / z (M + H): 213.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（２−メチルフェニル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２６−１)を用いること以外は実施例５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（２−メチルフェニル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CD₃OD)δ:7.46-7.37(5H,m),7.05(1H,s),4.44(2H,s),4.09(1H,q,J=7.3Hz),2.47(2H,q,J=7.5Hz),2.23(3H,s),2.07(3H,s),1.29-1.19(3H,m).
MSm/z(M+H):424.

In Example 5, instead of using 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carbo N- (3-Chloro-5-(((4-cyano-3-methyl-1- (2-methylphenyl)- 1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CD ₃ OD) δ: 7.46-7.37 (5H, m), 7.05 (1H, s), 4.44 (2H, s), 4.09 (1H, q, J = 7.3Hz), 2.47 (2H, q, J = 7.5Hz), 2.23 (3H, s), 2.07 (3H, s), 1.29-1.19 (3H, m).
MSm / z (M + H): 424.

実施例２４において、ｐ−トリルヒドラジン塩酸塩を用いた代わりに（３−ブロモフェニル）ヒドラジン塩酸塩を用いること以外は実施例２４と同様の方法で、５−アミノ−３−メチル−１−（３−ブロモフェニル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２７−１)を得た。
MSm/z(M+H):277,279. [Example 27]

In Example 24, in the same manner as in Example 24 except that (3-bromophenyl) hydrazine hydrochloride was used instead of p-tolylhydrazine hydrochloride, 5-amino-3-methyl-1- ( 3-Bromophenyl) -1H-pyrazole-4-carbonitrile (Compound 0027-1) was obtained.
MSm / z (M + H): 277, 279.

５−アミノ−３−メチル−１−（３−ブロモフェニル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２７−１、18mg)、Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミド(化合物０００１−３、18mg)にトルエン(10mL)を加え、加熱還流下30分攪拌した。トルエン(5mL)、パラトルエンスルホン酸ピリジニウム(16.3mg)を加え、10分間加熱還流後、減圧下溶媒を留去した。得られた固体にテトラヒドロフラン(0.66mL)を加え、窒素雰囲気下、0℃で水素化ホウ素リチウム(3.0mol/L、テトラヒドロフラン溶液、66μL)を加え、室温で1時間攪拌した。反応液にアセトンを加え、減圧下溶媒を留去した後、得られた固体に酢酸エチル、水を加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して粗生成物を得た。シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)で精製し、Ｎ−（５−（（（１−（３−ブロモフェニル）−４−シアノ−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−３−クロロ−２−ヒドロキシフェニル）プロピオンアミド(18mg)を得た。
¹H-NMR(CDCl₃)δ:7.77(2H,d,J=5.9Hz),7.68-7.67(4H,m),7.30-7.26(1H,m),7.10(1H,d,J=2.0Hz),4.56-4.54(3H,m),2.48(2H,q,J=7.5Hz),2.33(3H,s),1.29-1.19(3H,m).
MSm/z(M+H):488,490.

5-Amino-3-methyl-1- (3-bromophenyl) -1H-pyrazole-4-carbonitrile (Compound 0027-1, 18 mg), N- (3-chloro-5-formyl-2-hydroxyphenyl) Toluene (10 mL) was added to propionamide (Compound 0001-3, 18 mg), and the mixture was stirred with heating under reflux for 30 minutes. Toluene (5 mL) and paratoluenesulfonic acid pyridinium (16.3 mg) were added, and the mixture was heated to reflux for 10 minutes, and the solvent was evaporated under reduced pressure. Tetrahydrofuran (0.66 mL) was added to the obtained solid, lithium borohydride (3.0 mol / L, tetrahydrofuran solution, 66 μL) was added at 0 ° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. Acetone was added to the reaction solution, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the obtained solid to separate the solution, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then under reduced pressure. The solvent was distilled off to obtain a crude product. Purification by silica gel column chromatography (ethyl acetate-hexane) and N- (5-(((1- (3-bromophenyl) -4-cyano-3-methyl-1H-pyrazol-5-yl) amino) methyl ) -3-Chloro-2-hydroxyphenyl) propionamide (18 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.77 (2H, d, J = 5.9Hz), 7.68-7.67 (4H, m), 7.30-7.26 (1H, m), 7.10 (1H, d, J = 2.0Hz ), 4.56-4.54 (3H, m), 2.48 (2H, q, J = 7.5Hz), 2.33 (3H, s), 1.29-1.19 (3H, m).
MSm / z (M + H): 488,490.

実施例２４において、ｐ−トリルヒドラジン塩酸塩を用いた代わりに（３−（トリフルオロメチル）フェニル）ヒドラジン塩酸塩を用い、再結晶溶媒に酢酸エチル−ヘキサンを用いた代わりにヘキサンを用いること以外は実施例２４と同様の方法で、５−アミノ−３−メチル−１−（３−（トリフルオロメチル）フェニル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２８−１)を得た。
MSm/z(M+H):267. [Example 28]

In Example 24, (3- (trifluoromethyl) phenyl) hydrazine hydrochloride was used instead of p-tolylhydrazine hydrochloride, and hexane was used instead of ethyl acetate-hexane as the recrystallization solvent. In the same manner as in Example 24, 5-amino-3-methyl-1- (3- (trifluoromethyl) phenyl) -1H-pyrazole-4-carbonitrile (Compound 0028-1) was obtained.
MSm / z (M + H): 267.

実施例２７において、５−アミノ−３−メチル−１−（３−ブロモフェニル）−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（３−（トリフルオロメチル）フェニル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２８−１)を用いること以外は実施例２７と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（３−（トリフルオロメチル）フェニル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:7.77(2H,d,J=5.9Hz),7.68(3H,d,J=1.3Hz),7.63(1H,s),7.10(1H,d,J=2.0Hz),4.56-4.54(3H,m),2.48(2H,q,J=7.5Hz),2.33(3H,s),1.28-1.23(4H,m).
MSm/z(M+H):478.

In Example 27, instead of using 5-amino-3-methyl-1- (3-bromophenyl) -1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1- (3- (tri Fluoromethyl) phenyl) -1H-pyrazole-4-carbonitrile (Compound 0028-1) was used in the same manner as in Example 27 except that N- (3-chloro-5-(((4-cyano- 3-Methyl-1- (3- (trifluoromethyl) phenyl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.77 (2H, d, J = 5.9 Hz), 7.68 (3 H, d, J = 1.3 Hz), 7.63 (1 H, s), 7.10 (1 H, d, J = 2.0 Hz), 4.56-4.54 (3H, m), 2.48 (2H, q, J = 7.5Hz), 2.33 (3H, s), 1.28-1.23 (4H, m).
MSm / z (M + H): 478.

実施例２４において、ｐ−トリルヒドラジン塩酸塩を用いた代わりに（３，５−ジクロロフェニル）ヒドラジン塩酸塩を用いること以外は実施例２４と同様の方法で、５−アミノ−３−メチル−１−（３，５−ジクロロフェニル）−１Ｈ−ピラゾール−４−カルボニトリルを得た。
MSm/z(M+H):267. [Example 29]

In Example 24, in the same manner as in Example 24 except that (3,5-dichlorophenyl) hydrazine hydrochloride was used instead of p-tolylhydrazine hydrochloride, 5-amino-3-methyl-1- (3,5-dichlorophenyl) -1H-pyrazole-4-carbonitrile was obtained.
MSm / z (M + H): 267.

実施例２７において、５−アミノ−３−メチル−１−（３−ブロモフェニル）−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（３，５−ジクロロフェニル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２９−１)を用いること以外は実施例２７と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−１−（３，５−ジクロロフェニル）−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:7.74-7.66(2H,m),7.40-7.39(3H,m),7.10(1H,d,J=2.0Hz),4.60-4.56(3H,m),2.47(2H,q,J=7.5Hz),2.30(3H,s),1.26(3H,m,J=9.2,5.9Hz).
MSm/z(M+H):480.

In Example 27, instead of using 5-amino-3-methyl-1- (3-bromophenyl) -1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1- (3,5- N- (3-Chloro-5-(((4-cyano-1- ( 3,5-Dichlorophenyl) -3-methyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.74-7.66 (2H, m), 7.40-7.39 (3H, m), 7.10 (1H, d, J = 2.0Hz), 4.60-4.56 (3H, m), 2.47 (2H, q, J = 7.5Hz), 2.30 (3H, s), 1.26 (3H, m, J = 9.2,5.9Hz).
MSm / z (M + H): 480.

実施例２４において、ｐ−トリルヒドラジン塩酸塩を用いた代わりに（３−メトキシフェニル）ヒドラジン塩酸塩を用いること以外は実施例２４と同様の方法で、５−アミノ−１−（３−メトキシフェニル）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３０−１)を得た。
MSm/z(M+H):229. [Example 30]

In Example 24, 5-amino-1- (3-methoxyphenyl) was prepared in the same manner as in Example 24 except that (3-methoxyphenyl) hydrazine hydrochloride was used instead of p-tolylhydrazine hydrochloride. ) -3-Methyl-1H-pyrazole-4-carbonitrile (Compound 0030-1) was obtained.
MSm / z (M + H): 229.

実施例２７において、５−アミノ−３−メチル−１−（３−ブロモフェニル）−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−１−（３−メトキシフェニル）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３０−１)を用いること以外は実施例２７と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−１−（３−メトキシフェニル）−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:7.82(1H,s),7.45-7.42(2H,m),7.37-7.34(1H,m),7.09-7.04(3H,m),4.52(3H,s),3.84(3H,s),2.46(2H,q,J=7.5Hz),2.31(3H,s),1.26(4H,td,J=7.4,1.8Hz).
MSm/z(M+H):440.

In Example 27, instead of using 5-amino-3-methyl-1- (3-bromophenyl) -1H-pyrazole-4-carbonitrile, 5-amino-1- (3-methoxyphenyl) -3- N- (3-Chloro-5-(((4-cyano-1- (3) was used in the same manner as in Example 27 except that methyl-1H-pyrazole-4-carbonitrile (Compound 0030-1) was used. -Methoxyphenyl) -3-methyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.82 (1H, s), 7.45-7.42 (2H, m), 7.37-7.34 (1H, m), 7.09-7.04 (3H, m), 4.52 (3H, s) , 3.84 (3H, s), 2.46 (2H, q, J = 7.5Hz), 2.31 (3H, s), 1.26 (4H, td, J = 7.4, 1.8Hz).
MSm / z (M + H): 440.

実施例２４において、ｐ−トリルヒドラジン塩酸塩を用いた代わりに（３−ニトロフェニル）ヒドラジン塩酸塩を用いること以外は実施例２４と同様の方法で、５−アミノ−３−メチル−１−（３−ニトロフェニル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３１−１)を得た。
MSm/z(M+H):244. [Example 31]

In Example 24, in the same manner as in Example 24 except that (3-nitrophenyl) hydrazine hydrochloride was used instead of p-tolylhydrazine hydrochloride, 5-amino-3-methyl-1- ( 3-Nitrophenyl) -1H-pyrazole-4-carbonitrile (Compound 0031-1) was obtained.
MS m / z (M + H): 244.

実施例２７において、５−アミノ−３−メチル−１−（３−ブロモフェニル）−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（３−ニトロフェニル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３１−１)を用いること以外は実施例２７と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（３−ニトロフェニル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:8.38(1H,t,J=2.3Hz),8.26-8.24(1H,m),7.89(1H,d,J=7.9Hz),7.75-7.71(2H,m),7.12(1H,d,J=2.0Hz),4.58(3H,s),2.49(2H,q,J=7.5Hz),2.34(3H,s),1.28-1.25(4H,m).
MSm/z(M+H):455.

Instead of using 5-amino-3-methyl-1- (3-bromophenyl) -1H-pyrazole-4-carbonitrile in Example 27, 5-amino-3-methyl-1- (3-nitrophenyl) ) -1H-pyrazole-4-carbonitrile (Compound 0031-1) was used in the same manner as in Example 27 except that N- (3-chloro-5-(((4-cyano-3-methyl- 1- (3-Nitrophenyl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.38 (1H, t, J = 2.3Hz), 8.26-8.24 (1H, m), 7.89 (1H, d, J = 7.9Hz), 7.75-7.71 (2H, m ), 7.12 (1H, d, J = 2.0Hz), 4.58 (3H, s), 2.49 (2H, q, J = 7.5Hz), 2.34 (3H, s), 1.28-1.25 (4H, m).
MSm / z (M + H): 455.

１−ナフチルヒドラジン塩酸塩(0.59g)のエタノール(10mL)懸濁液にトリエチルアミン(0.42mL)を加え、室温で20分攪拌した。２−（１−エトキシエチリデン）マロノニトリル(274mg)を加えてさらに1時間攪拌した後、減圧下溶媒を留去した。得られた固体を酢酸エチルに溶かし、水を加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して粗生成物を得た。シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)で精製し、５−アミノ−３−メチル−１−（ナフタレン−１−イル）−１Ｈ−ピラゾール−４−カルボニトリル(0.33g)を得た。
MSm/z(M+H):249. [Example 32]

Triethylamine (0.42 mL) was added to a suspension of 1-naphthylhydrazine hydrochloride (0.59 g) in ethanol (10 mL), and the mixture was stirred at room temperature for 20 minutes. 2- (1-Ethoxyethylidene) malononitrile (274 mg) was added and the mixture was further stirred for 1 hour, and then the solvent was distilled off under reduced pressure. The obtained solid was dissolved in ethyl acetate, water was added for liquid separation, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (ethyl acetate-hexane) gave 5-amino-3-methyl-1- (naphthalen-1-yl) -1H-pyrazole-4-carbonitrile (0.33 g).
MSm / z (M + H): 249.

実施例２７において、５−アミノ−３−メチル−１−（３−ブロモフェニル）−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（ナフタレン−１−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３２−１)を用いること以外は実施例２７と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（ナフタレン−１−イル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:8.00-7.95(2H,m),7.62-7.53(4H,m),7.46(1H,s),7.40-7.39(1H,m),6.96(1H,d,J=2.0Hz),4.48(2H,d,J=6.6Hz),4.27(1H,t,J=6.6Hz),2.46(2H,q,J=7.5Hz),2.37(3H,s),1.32-1.19(5H,m).
MSm/z(M+H):460.

Instead of using 5-amino-3-methyl-1- (3-bromophenyl) -1H-pyrazole-4-carbonitrile in Example 27, 5-amino-3-methyl-1- (naphthalene-1- Yl) -1H-pyrazole-4-carbonitrile (compound 0032-1) was used in the same manner as in Example 27 except that N- (3-chloro-5-(((4-cyano-3-methyl -1- (Naphthalen-1-yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.00-7.95 (2H, m), 7.62-7.53 (4H, m), 7.46 (1H, s), 7.40-7.39 (1H, m), 6.96 (1H, d, J = 2.0Hz), 4.48 (2H, d, J = 6.6Hz), 4.27 (1H, t, J = 6.6Hz), 2.46 (2H, q, J = 7.5Hz), 2.37 (3H, s), 1.32 -1.19 (5H, m).
MSm / z (M + H): 460.

実施例３２において、１−ナフチルヒドラジン塩酸塩を用いた代わりに（３−フルオロフェニル）ヒドラジン塩酸塩を用いること以外は実施例３２と同様の方法で、５−アミノ−１−（３−フルオロフェニル）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３３−１)を得た。
MSm/z(M+H):217. [Example 33]

In Example 32, 5-amino-1- (3-fluorophenyl) was prepared in the same manner as in Example 32 except that (3-fluorophenyl) hydrazine hydrochloride was used instead of 1-naphthylhydrazine hydrochloride. ) -3-Methyl-1H-pyrazole-4-carbonitrile (Compound 0033-1) was obtained.
MSm / z (M + H): 217.

実施例２７において、５−アミノ−３−メチル−１−（３−ブロモフェニル）−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−１−（３−フルオロフェニル）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３３−１)を用いること以外は実施例２７と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−１−（３−フルオロフェニル）−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:7.77(1H,s),7.63(1H,s),7.51-7.46(1H,m),7.21-7.13(3H,m),4.62-4.57(3H,m),2.48(2H,q,J=7.5Hz),2.32(3H,s),1.30-1.24(5H,m).
MSm/z(M+H):427.

In Example 27, instead of 5-amino-3-methyl-1- (3-bromophenyl) -1H-pyrazole-4-carbonitrile, 5-amino-1- (3-fluorophenyl) -3- N- (3-Chloro-5-(((4-cyano-1- (3) was used in the same manner as in Example 27 except that methyl-1H-pyrazole-4-carbonitrile (Compound 0033-1) was used. -Fluorophenyl) -3-methyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.77 (1H, s), 7.63 (1H, s), 7.51-7.46 (1H, m), 7.21-7.13 (3H, m), 4.62-4.57 (3H, m) , 2.48 (2H, q, J = 7.5Hz), 2.32 (3H, s), 1.30-1.24 (5H, m).
MSm / z (M + H): 427.

１−ヒドラジノイソキノリン塩酸塩(385mg)のエタノール(8mL)懸濁液に、２−（１−エトキシエチリデン）マロノニトリル(220mg)を加えて、室温で1時間、50℃で1時間攪拌した。反応液を室温に戻し、固体をろ取、エタノールで洗浄して、５−アミノ−１−（イソキノリン−１−イル）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３４−１、82mg)を白色固体として得た。
MSm/z(M+H):250. [Example 34]

2- (1-Ethoxyethylidene) malononitrile (220 mg) was added to a suspension of 1-hydrazinoisoquinoline hydrochloride (385 mg) in ethanol (8 mL), and the mixture was stirred at room temperature for 1 hour and at 50 ° C. for 1 hour. The reaction solution is returned to room temperature, and the solid is collected by filtration and washed with ethanol to give 5-amino-1- (isoquinolin-1-yl) -3-methyl-1H-pyrazole-4-carbonitrile (Compound 0034-1, 82 mg) was obtained as a white solid.
MSm / z (M + H): 250.

実施例２７において、５−アミノ−３−メチル−１−（３−ブロモフェニル）−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−１−（イソキノリン−１−イル）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３４−１)を用いること以外は実施例２７と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−１−（イソキノリン−１−イル）−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:9.02(1H,d,J=8.6Hz),8.26(2H,t,J=5.0Hz),7.86(2H,t,J=5.6Hz),7.78-7.60(5H,m),7.20(1H,d,J=2.0Hz),4.73(2H,d,J=6.6Hz),2.47(2H,q,J=7.5Hz),2.40(3H,s),1.26(3H,t,J=7.6Hz).
MSm/z(M+H):461.

In Example 27, 5-amino-1- (isoquinolin-1-yl) -3 instead of 5-amino-3-methyl-1- (3-bromophenyl) -1H-pyrazole-4-carbonitrile N- (3-Chloro-5-(((4-Cyano-1-((1))) except that -methyl-1H-pyrazole-4-carbonitrile (Compound 0034-1) was used. Isoquinolin-1-yl) -3-methyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 9.02 (1H, d, J = 8.6Hz), 8.26 (2H, t, J = 5.0Hz), 7.86 (2H, t, J = 5.6Hz), 7.78-7.60 ( 5H, m), 7.20 (1H, d, J = 2.0Hz), 4.73 (2H, d, J = 6.6Hz), 2.47 (2H, q, J = 7.5Hz), 2.40 (3H, s), 1.26 ( (3H, t, J = 7.6Hz).
MSm / z (M + H): 461.

２−（１−エトキシプロピリデン）マロノニトリル(化合物００２１−１、0.14g)のエタノール(4.8mL)溶液に２−ヒドラジノイソキノリン(227mg)を加え、室温で1時間攪拌した。固体をろ取し、エタノールで洗浄して、５−アミノ−３−エチル−１−（キノリン−２−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３５−１、216mg)を得た。
MSm/z(M+H):264. [Example 35]

2-Hydrazinoisoquinoline (227 mg) was added to a solution of 2- (1-ethoxypropylidene) malononitrile (Compound 0021-1, 0.14 g) in ethanol (4.8 mL) and stirred at room temperature for 1 hour. The solid was collected by filtration and washed with ethanol to give 5-amino-3-ethyl-1- (quinolin-2-yl) -1H-pyrazole-4-carbonitrile (Compound 0035-1, 216 mg).
MSm / z (M + H): 264.

５−アミノ−３−エチル−１−（キノリン−２−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３５−１、35mg)、Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミド(化合物０００１−３、30mg)、ナトリウムトリアセトキシボロヒドリド(36mg)のジクロロメタン(1.2mL)、酢酸(0.1mL)混合溶液を、マイクロウェーブ反応装置を用いて110℃で60分、次いで110℃で30分反応させた。反応液に酢酸エチル及び水を加えて分液し、有機層を飽和食塩水で洗浄した後、有機層を無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して粗生成物を得た。分取薄層クロマトグラフィー(酢酸エチル−ヘキサン)、シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)で精製し、Ｎ−（３−クロロ−５−（（（４−シアノ−３−エチル−１−（キノリン−２−イル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミド(1.6mg)を得た。
¹H-NMR(DMSO-d₆)δ:10.04(2H,s),9.82(1H,s),8.57(1H,d,J=8.6Hz),8.11-8.05(2H,m),7.61(1H,s),7.49(1H,s),7.27(1H,s),4.79(2H,d,J=5.9Hz),2.73(2H,s),2.62(2H,d,J=7.3Hz),1.26(3H,t,J=7.6Hz),1.05(3H,t,J=7.6Hz).
MSm/z(M+H):475.

5-Amino-3-ethyl-1- (quinolin-2-yl) -1H-pyrazole-4-carbonitrile (Compound 0035-1, 35 mg), N- (3-chloro-5-formyl-2-hydroxyphenyl) ) Propionamide (compound 0001-3, 30 mg), sodium triacetoxyborohydride (36 mg) in dichloromethane (1.2 mL), acetic acid (0.1 mL) was mixed in a microwave reactor at 110 ° C. for 60 minutes, then The reaction was carried out at 110 ° C. for 30 minutes. Ethyl acetate and water were added to the reaction solution for separation, and the organic layer was washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. Purification by preparative thin layer chromatography (ethyl acetate-hexane), silica gel column chromatography (ethyl acetate-hexane), and N- (3-chloro-5-(((4-cyano-3-ethyl-1- ( Quinolin-2-yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide (1.6 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 10.04 (2H, s), 9.82 (1H, s), 8.57 (1H, d, J = 8.6Hz), 8.11-8.05 (2H, m), 7.61 (1H , s), 7.49 (1H, s), 7.27 (1H, s), 4.79 (2H, d, J = 5.9Hz), 2.73 (2H, s), 2.62 (2H, d, J = 7.3Hz), 1.26 (3H, t, J = 7.6Hz), 1.05 (3H, t, J = 7.6Hz).
MSm / z (M + H): 475.

実施例３５において、２−（１−エトキシプロピリデン）マロノニトリルを用いた代わりに２−（エトキシメチレン）マロノニトリルを用いる以外は実施例３５と同様の方法で、５−アミノ−１−（キノリン−２−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３６−１)を得た。
MSm/z(M+H):236. [Example 36]

In Example 35, 5-amino-1- (quinoline-2) was prepared in the same manner as in Example 35 except that 2- (1-ethoxypropylidene) malononitrile was used instead of 2- (1-ethoxypropylidene) malononitrile. -Yl) -1H-pyrazole-4-carbonitrile (compound 0036-1) was obtained.
MSm / z (M + H): 236.

実施例３５において、５−アミノ−３−エチル−１−（キノリン−２−イル）−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−１−（キノリン−２−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３６−１)を用いる以外は実施例３５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−１−（キノリン−２−イル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(DMSO-d₆)δ:10.03(1H,t,J=10.0Hz),9.81(1H,s),8.60(1H,d,J=9.2Hz),8.15-8.05(4H,m),7.83(1H,t,J=6.9Hz),7.63(1H,t,J=6.9Hz),7.50(1H,s),7.27(1H,s),4.81(2H,d,J=5.9Hz),2.40(2H,q,J=7.5Hz),1.05(3H,t,J=7.6Hz).
MSm/z(M+H):447.

In Example 35, instead of 5-amino-3-ethyl-1- (quinolin-2-yl) -1H-pyrazole-4-carbonitrile, 5-amino-1- (quinolin-2-yl)- N- (3-Chloro-5-(((4-cyano-1- (quinoline-2-one)) was used in the same manner as in Example 35 except that 1H-pyrazole-4-carbonitrile (Compound 0036-1) was used. Yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide.
¹ H-NMR (DMSO-d ₆ ) δ: 10.03 (1H, t, J = 10.0Hz), 9.81 (1H, s), 8.60 (1H, d, J = 9.2Hz), 8.15-8.05 (4H, m ), 7.83 (1H, t, J = 6.9Hz), 7.63 (1H, t, J = 6.9Hz), 7.50 (1H, s), 7.27 (1H, s), 4.81 (2H, d, J = 5.9Hz) ), 2.40 (2H, q, J = 7.5Hz), 1.05 (3H, t, J = 7.6Hz).
MS m / z (M + H): 447.

３−アミノベンゾニトリル(100mg)の塩酸(0.85mL)懸濁液に、氷冷下で亜硝酸ナトリウム(64mg)の水(0.23mL)溶液を加え、15分攪拌した。塩化すず（ＩＩ）(670mg)の水溶液(0.37mL)を加え、さらに1時間攪拌した。反応液を室温に昇温し、固体をろ取し、水、酢酸エチルで洗浄し、３−ヒドラジニルベンゾニトリル塩酸塩(化合物００３７−１、118mg)を得た。
MSm/z(M+H):134. [Example 37]

A solution of sodium nitrite (64 mg) in water (0.23 mL) was added to a suspension of 3-aminobenzonitrile (100 mg) in hydrochloric acid (0.85 mL) under ice cooling, and the mixture was stirred for 15 minutes. An aqueous solution (0.37 mL) of tin (II) chloride (670 mg) was added, and the mixture was further stirred for 1 hour. The reaction solution was warmed to room temperature, and the solid was collected by filtration and washed with water and ethyl acetate to obtain 3-hydrazinylbenzonitrile hydrochloride (Compound 0037-1, 118 mg).
MS m / z (M + H): 134.

３−ヒドラジニルベンゾニトリル塩酸塩(化合物００３７−１、100mg)のエタノール(2mL)溶液にトリエチルアミン(82μL)、２−（１−エトキシエチリデン）マロノニトリル(54mg)を加え、室温で2.5時間、40℃で1時間、50℃で終夜攪拌した。反応液を室温に戻し、減圧下溶媒を留去して粗生成物を得た。シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)で精製し、さらに得られた固体を結晶化(クロロホルム−ヘキサン)し、５−アミノ−１−（３−シアノフェニル）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３７−２、12mg)を得た。
MSm/z(M+H):224.

To a solution of 3-hydrazinylbenzonitrile hydrochloride (Compound 0037-1, 100 mg) in ethanol (2 mL) were added triethylamine (82 μL) and 2- (1-ethoxyethylidene) malononitrile (54 mg). The mixture was stirred at 50 ° C for 1 hour and at 50 ° C overnight. The reaction solution was returned to room temperature, and the solvent was distilled off under reduced pressure to obtain a crude product. The product was purified by silica gel column chromatography (ethyl acetate-hexane), and the obtained solid was crystallized (chloroform-hexane) to give 5-amino-1- (3-cyanophenyl) -3-methyl-1H-pyrazole- 4-carbonitrile (Compound 0037-2, 12 mg) was obtained.
MS m / z (M + H): 224.

５−アミノ−１−（３−シアノフェニル）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３７−２、12mg)、Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミド(化合物０００１−３、12mg)、ナトリウムトリアセトキシボロヒドリド(15mg)のジクロロメタン(0.48mL)、酢酸(53μL)混合溶液を、マイクロウェーブ反応装置を用いて110℃、30分の条件で4回反応させた。反応液に酢酸エチル及び水を加えて分液し、有機層を飽和食塩水で洗浄した後、有機層を無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して固体を得た。得られた固体をエタノール(0.5mL)に溶かし、0℃、窒素雰囲気下、水素化ホウ素ナトリウム(6mg)のエタノール(0.5mL)溶液を加え、室温に昇温して2時間反応させた後、水素化ホウ素ナトリウム(6.5mg)のエタノール(0.5mL)溶液を加え、さらに3.5時間反応させた。さらに水素化ホウ素ナトリウム(6mg)のエタノール(0.5mL)溶液を加え、室温で1時間反応させた。反応液にアセトンを加え、減圧下溶媒を留去した後、得られた固体に酢酸エチル及び水を加えて分液し、有機層を飽和食塩水で洗浄した後、有機層を無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して粗生成物を得た。シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)で精製し、Ｎ−（３−クロロ−５−（（（４−シアノ−１−（３−シアノフェニル）−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミド(4.2mg)を得た。
¹H-NMR(CDCl₃)δ:7.87-7.63(5H,m),7.07(1H,d,J=15.2Hz),4.56(2H,t,J=5.3Hz),2.48(2H,dd,J=15.2,7.9Hz),2.32(3H,s),1.32-1.26(3H,m).
MSm/z(M+H):435.

5-Amino-1- (3-cyanophenyl) -3-methyl-1H-pyrazole-4-carbonitrile (Compound 0037-2, 12 mg), N- (3-chloro-5-formyl-2-hydroxyphenyl) Propionamide (compound 0001-3, 12 mg), sodium triacetoxyborohydride (15 mg) in dichloromethane (0.48 mL) and acetic acid (53 μL) were mixed in a microwave reactor at 110 ° C. for 30 minutes. Reacted once. Ethyl acetate and water were added to the reaction solution for separation, and the organic layer was washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a solid. The obtained solid was dissolved in ethanol (0.5 mL), a solution of sodium borohydride (6 mg) in ethanol (0.5 mL) was added at 0 ° C. under a nitrogen atmosphere, and the mixture was allowed to warm to room temperature and reacted for 2 hours. A solution of sodium borohydride (6.5 mg) in ethanol (0.5 mL) was added, and the mixture was further reacted for 3.5 hours. Further, a solution of sodium borohydride (6 mg) in ethanol (0.5 mL) was added and reacted at room temperature for 1 hour. Acetone was added to the reaction solution, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the obtained solid to separate the solution, and the organic layer was washed with saturated brine, and then the organic layer was washed with anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (ethyl acetate-hexane) and N- (3-chloro-5-(((4-cyano-1- (3-cyanophenyl) -3-methyl-1H-pyrazol-5-yl ) Amino) methyl) -2-hydroxyphenyl) propionamide (4.2 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.87-7.63 (5H, m), 7.07 (1H, d, J = 15.2Hz), 4.56 (2H, t, J = 5.3Hz), 2.48 (2H, dd, J = 15.2,7.9Hz), 2.32 (3H, s), 1.32-1.26 (3H, m).
MSm / z (M + H): 435.

実施例３７において、３−ヒドラジニルベンゾニトリル塩酸塩の代わりに６−ヒドラジニルキノリン塩酸塩を用いる以外は実施例３７と同様の方法で、５−アミノ−３−メチル−１−（キノリン−６−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３８−１)を得た。
MSm/z(M+H):250. [Example 38]

In Example 37, 5-amino-3-methyl-1- (quinoline) was prepared in the same manner as in Example 37 except that 6-hydrazinylquinoline hydrochloride was used instead of 3-hydrazinylbenzonitrile hydrochloride. -6-yl) -1H-pyrazole-4-carbonitrile (Compound 0038-1) was obtained.
MSm / z (M + H): 250.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（キノリン−６−イル）−１Ｈ−ピラゾール−４−カルボニトリル（化合物００３８−１）を用いること以外は実施例５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（キノリン−６−イル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CD₃OD)δ:8.93-8.95(1H,m),8.53(1H,d,J=7.3Hz),8.21(1H,d,J=8.6Hz),8.14(1H,d,J=2.6Hz),7.88(1H,dd,J=9.2,2.6Hz),7.61-7.67(2H,m),7.11(1H,d,J=2.0Hz),4.52(2H,s),2.48(2H,q,J=7.5Hz),2.26(3H,s),1.22(3H,t,J=7.5Hz).
MSm/z(M+H):461

In Example 5, instead of using 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1- (quinolin-6-yl) -1H-pyrazole-4- N- (3-Chloro-5-(((4-cyano-3-methyl-1- (quinolin-6-yl) was prepared in the same manner as in Example 5 except that carbonitrile (Compound 0038-1) was used. ) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CD ₃ OD) δ: 8.93-8.95 (1H, m), 8.53 (1H, d, J = 7.3Hz), 8.21 (1H, d, J = 8.6Hz), 8.14 (1H, d, J = 2.6Hz), 7.88 (1H, dd, J = 9.2,2.6Hz), 7.61-7.67 (2H, m), 7.11 (1H, d, J = 2.0Hz), 4.52 (2H, s), 2.48 ( 2H, q, J = 7.5Hz), 2.26 (3H, s), 1.22 (3H, t, J = 7.5Hz).
MSm / z (M + H): 461

実施例３７において、３−ヒドラジニルベンゾニトリル塩酸塩の代わりに２−ヒドラジニルピリジン塩酸塩を用いる以外は実施例３７と同様の方法で、５−アミノ−３−メチル−１−（ピリジン−２−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００３９−１)を得た。
MSm/z(M+H):200. [Example 39]

In Example 37, 5-amino-3-methyl-1- (pyridine) was prepared in the same manner as in Example 37 except that 2-hydrazinylpyridine hydrochloride was used instead of 3-hydrazinylbenzonitrile hydrochloride. -2-yl) -1H-pyrazole-4-carbonitrile (Compound 0039-1) was obtained.
MSm / z (M + H): 200.

実施例３７において、５−アミノ−１−（３−シアノフェニル）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（ピリジン−２−イル）−１Ｈ−ピラゾール−４−カルボニトリル（化合物００３９−１）を用いること以外は実施例３７と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（ピリジン−２−イル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:9.56(1H,t,J=6.4Hz),8.34-8.31(1H,m),7.91(1H,d,J=8.3Hz),7.86-7.79(2H,m),7.64-7.60(1H,brm),7.61(1H,s),7.21(1H,d,J=2.0Hz),7.17-7.12(1H,m),4.73(2H,d,J=6.3Hz),2.48(2H,q,J=7.6Hz),2.31(3H,s),1.27(3H,t,J=7.6Hz).
MSm/z(M+H):411.

In Example 37, instead of using 5-amino-1- (3-cyanophenyl) -3-methyl-1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1- (pyridine-2- Yl) -1H-pyrazole-4-carbonitrile (Compound 0039-1) was used in the same manner as in Example 37 except that N- (3-chloro-5-(((4-cyano-3-methyl -1- (Pyridin-2-yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 9.56 (1H, t, J = 6.4Hz), 8.34-8.31 (1H, m), 7.91 (1H, d, J = 8.3Hz), 7.86-7.79 (2H, m ), 7.64-7.60 (1H, brm), 7.61 (1H, s), 7.21 (1H, d, J = 2.0Hz), 7.17-7.12 (1H, m), 4.73 (2H, d, J = 6.3Hz) , 2.48 (2H, q, J = 7.6Hz), 2.31 (3H, s), 1.27 (3H, t, J = 7.6Hz).
MS m / z (M + H): 411.

実施例３７において、３−ヒドラジニルベンゾニトリル塩酸塩の代わりに３−ヒドラジニルピリジン塩酸塩を用いる以外は実施例３７と同様の方法で、５−アミノ−３−メチル−１−（ピリジン−３−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００４０−１)を得た。
MSm/z(M+H):200 [Example 40]

In Example 37, 5-amino-3-methyl-1- (pyridine) was prepared in the same manner as in Example 37, except that 3-hydrazinylpyridine hydrochloride was used instead of 3-hydrazinylbenzonitrile hydrochloride. -3-yl) -1H-pyrazole-4-carbonitrile (compound 0040-1) was obtained.
MSm / z (M + H): 200

実施例３７において、５−アミノ−１−（３−シアノフェニル）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（ピリジン−２−イル）−１Ｈ−ピラゾール−４−カルボニトリル（化合物００３９−１）を用いること以外は実施例３７と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（ピリジン−２−イル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:8.75(1H,d,J=2.3Hz),8.64(1H,d,J=4.8Hz),7.88-7.83(1H,m),7.80-7.75(1H,brs),7.75(1H,s),7.48(1H,dd,J=8.3,4.6Hz),7.09(1H,d,J=2.0Hz),4.69-4.62(1H,brs),4.56(2H,d,J=5.9Hz),2.47(2H,q,J=7.5Hz),2.33(3H,s),1.25(3H,t,J=7.5Hz).
MSm/z(M+H):411.

In Example 37, instead of using 5-amino-1- (3-cyanophenyl) -3-methyl-1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1- (pyridine-2- Yl) -1H-pyrazole-4-carbonitrile (Compound 0039-1) was used in the same manner as in Example 37 except that N- (3-chloro-5-(((4-cyano-3-methyl -1- (Pyridin-2-yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.75 (1H, d, J = 2.3 Hz), 8.64 (1 H, d, J = 4.8 Hz), 7.88-7.83 (1 H, m), 7.80-7.75 (1 H, brs ), 7.75 (1H, s), 7.48 (1H, dd, J = 8.3, 4.6Hz), 7.09 (1H, d, J = 2.0Hz), 4.69-4.62 (1H, brs), 4.56 (2H, d, J = 5.9Hz), 2.47 (2H, q, J = 7.5Hz), 2.33 (3H, s), 1.25 (3H, t, J = 7.5Hz).
MS m / z (M + H): 411.

実施例３７において、３−ヒドラジニルベンゾニトリル塩酸塩の代わりに２−ヒドラジニルキノリンを用い、トリエチルアミンを用いないこと以外は実施例３７と同様の方法で、５−アミノ−３−メチル−１−（キノリン−２−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００４１−１)を得た。
MSm/z(M+H):250. [Example 41]

In Example 37, in the same manner as in Example 37 except that 2-hydrazinylquinoline was used instead of 3-hydrazinylbenzonitrile hydrochloride and triethylamine was not used, 5-amino-3-methyl- 1- (Quinolin-2-yl) -1H-pyrazole-4-carbonitrile (Compound 0041-1) was obtained.
MSm / z (M + H): 250.

実施例３７において、５−アミノ−１−（３−シアノフェニル）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（キノリン−２−イル）−１Ｈ−ピラゾール−４−カルボニトリル（化合物００３９−１）を用いること以外は実施例３７と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（キノリン−２−イル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(DMSO-d₆)δ:10.04(1H,t,J=6.6Hz),10.00(1H,s),9.83(1H,s),8.57(1H,d,J=8.6Hz),8.15(1H,d,J=8.3Hz),8.06(1H,d,J=9.2Hz),8.02(1H,d,J=7.5Hz),7.82(1H,ddd,J=7.8,7.0,1.5Hz),7.61(1H,ddd,J=7.9,6.9,1.6Hz),7.48(1H,d,J=1.5Hz),7.26(1H,d,J=1.7Hz),4.79(2H,d,J=6.6Hz),2.40(2H,q,J=7.5Hz),2.24(3H,s),1.05(3H,t,J=7.6Hz).
MSm/z(M+H):461.

In Example 37, instead of using 5-amino-1- (3-cyanophenyl) -3-methyl-1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1- (quinoline-2- Yl) -1H-pyrazole-4-carbonitrile (Compound 0039-1) was used in the same manner as in Example 37 except that N- (3-chloro-5-(((4-cyano-3-methyl -1- (Quinolin-2-yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 10.04 (1H, t, J = 6.6Hz), 10.00 (1H, s), 9.83 (1H, s), 8.57 (1H, d, J = 8.6Hz), 8.15 (1H, d, J = 8.3Hz), 8.06 (1H, d, J = 9.2Hz), 8.02 (1H, d, J = 7.5Hz), 7.82 (1H, ddd, J = 7.8,7.0,1.5Hz ), 7.61 (1H, ddd, J = 7.9, 6.9, 1.6Hz), 7.48 (1H, d, J = 1.5Hz), 7.26 (1H, d, J = 1.7Hz), 4.79 (2H, d, J = 6.6Hz), 2.40 (2H, q, J = 7.5Hz), 2.24 (3H, s), 1.05 (3H, t, J = 7.6Hz).
MSm / z (M + H): 461.

実施例３７において、３−ヒドラジニルベンゾニトリル塩酸塩の代わりに２−ヒドラジニル−４−フェニルチアゾールを用い、トリエチルアミンを用いないこと以外は実施例３７と同様の方法で、５−アミノ−３−メチル−１−（４−フェニルチアゾール−２−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００４２−１)を得た。
MSm/z(M+H):282. [Example 42]

In Example 37, except that 2-hydrazinyl-4-phenylthiazole was used in place of 3-hydrazinylbenzonitrile hydrochloride and triethylamine was not used, 5-amino-3- Methyl-1- (4-phenylthiazol-2-yl) -1H-pyrazole-4-carbonitrile (Compound 0042-1) was obtained.
MS m / z (M + H): 282.

実施例３７において、５−アミノ−１−（３−シアノフェニル）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（４−フェニルチアゾール−２−イル）−１Ｈ−ピラゾール−４−カルボニトリル（化合物００４２−１）を用いること以外は実施例３７と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（４−フェニルチアゾール−２−イル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(THF-d₆)δ:9.88-9.78(1H,br.s),9.26-9.24(1H,br.s),8.72-8.66(1H,br.m),7.76-7.71(2H,m),7.54(1H,d,J=2.3Hz),7.52(1H,s),7.39-7.25(4H,m),4.79(2H,d,J=5.6Hz),2.42(2H,q,J=7.6Hz),2.26(3H,s),1.15(3H,t,J=7.4Hz).
MSm/z(M-H₂O+H):475.

In Example 37, instead of using 5-amino-1- (3-cyanophenyl) -3-methyl-1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1- (4-phenylthiazole -2-yl) -1H-pyrazole-4-carbonitrile (Compound 0042-1) was used in the same manner as in Example 37 except that N- (3-chloro-5-(((4-cyano- 3-Methyl-1- (4-phenylthiazol-2-yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (THF-d ₆ ) δ: 9.88-9.78 (1H, br.s), 9.26-9.24 (1H, br.s), 8.72-8.66 (1H, br.m), 7.76-7.71 (2H , m), 7.54 (1H, d, J = 2.3Hz), 7.52 (1H, s), 7.39-7.25 (4H, m), 4.79 (2H, d, J = 5.6Hz), 2.42 (2H, q, J = 7.6Hz), 2.26 (3H, s), 1.15 (3H, t, J = 7.4Hz).
_{MSm / z (MH 2 O +} H): 475.

実施例３７において、３−アミノベンゾニトリルの代わりにＮ−（３−アミノフェニル）アセトアミドを用いること以外は実施例３７と同様の方法で、Ｎ−（３−ヒドラジニルフェニル）アセトアミド(化合物００４３−１)を得た。
MSm/z(M+H):166. [Example 43]

In Example 37, N- (3-hydrazinylphenyl) acetamide (Compound 0043) was prepared in the same manner as in Example 37, except that N- (3-aminophenyl) acetamide was used instead of 3-aminobenzonitrile. -1) was obtained.
MS m / z (M + H): 166.

実施例３７において、３−ヒドラジニルベンゾニトリル塩酸塩の代わりにＮ−（３−ヒドラジニルフェニル）アセトアミド(化合物００４３−１)を用い、トリエチルアミンを用いないこと以外は実施例３７と同様の方法で、Ｎ−（３−（５−アミノ−４−シアノ−３−メチル−１Ｈ−ピラゾール−１−イル）フェニル）アセトアミド(化合物００４３−２)を得た。
MSm/z(M+H):256.

In Example 37, N- (3-hydrazinylphenyl) acetamide (Compound 0043-1) was used in place of 3-hydrazinylbenzonitrile hydrochloride, and triethylamine was not used. By the method, N- (3- (5-amino-4-cyano-3-methyl-1H-pyrazol-1-yl) phenyl) acetamide (Compound 0043-2) was obtained.
MSm / z (M + H): 256.

実施例３７において、５−アミノ−１−（３−シアノフェニル）−３−メチル−１Ｈ−ピラゾール−４−カルボニトリルの代わりにＮ−（３−（５−アミノ−４−シアノ−３−メチル−１Ｈ−ピラゾール−１−イル）フェニル）アセトアミド(化合物００４３−２)を用いたこと以外は実施例３７と同様の方法で、Ｎ−（５−（（（１−（３−アセトアミドフェニル）−４−シアノ−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−３−クロロ−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:8.67(1H,s),8.41(1H,s),8.04(1H,s),7.86-7.81(2H,m),7.66(1H,d,J=7.6Hz),7.50(1H,t,J=8.0Hz),4.86(1H,t,J=6.5Hz),4.62(2H,d,J=6.3Hz),2.54(2H,q,J=7.6Hz),2.29(3H,s),2.26(3H,s),1.32(3H,t,J=7.6Hz).
MSm/z(M+H):467.

In Example 37, instead of 5-amino-1- (3-cyanophenyl) -3-methyl-1H-pyrazole-4-carbonitrile, N- (3- (5-amino-4-cyano-3-methyl) 1-H-pyrazol-1-yl) phenyl) acetamide (Compound 0043-2) was used in the same manner as in Example 37, except that N- (5-(((1- (3-acetamidophenyl)- 4-Cyano-3-methyl-1H-pyrazol-5-yl) amino) methyl) -3-chloro-2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.67 (1H, s), 8.41 (1H, s), 8.04 (1H, s), 7.86-7.81 (2H, m), 7.66 (1H, d, J = 7.6Hz ), 7.50 (1H, t, J = 8.0Hz), 4.86 (1H, t, J = 6.5Hz), 4.62 (2H, d, J = 6.3Hz), 2.54 (2H, q, J = 7.6Hz), 2.29 (3H, s), 2.26 (3H, s), 1.32 (3H, t, J = 7.6Hz).
MSm / z (M + H): 467.

５−アミノ−３−メチル−１−（３−ブロモフェニル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００２７−１、100mg)、フェニルボロン酸(88mg)、ビス（ジベンジリデンアセトン）ジパラジウム（０）(10mg)、トリシクロヘキシルホスフィン(13mg)、りん酸カリウム(130mg)に１，４−ジオキサン(1mL)、水(0.5mL)を加え、窒素雰囲気下、100℃で2時間攪拌した。反応液を室温まで冷却した後、酢酸エチルと水を加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して粗生成物を得た。シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン)で精製し、１−（［１，１’−ビフェニル］−３−イル）−５−アミノ−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００４４−１、71mg)を淡緑色固体として得た。
MSm/z(M+H):275. [Example 44]

5-amino-3-methyl-1- (3-bromophenyl) -1H-pyrazole-4-carbonitrile (Compound 0027-1, 100 mg), phenylboronic acid (88 mg), bis (dibenzylideneacetone) dipalladium ( 0) (10 mg), tricyclohexylphosphine (13 mg) and potassium phosphate (130 mg) were added 1,4-dioxane (1 mL) and water (0.5 mL), and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. After cooling the reaction solution to room temperature, ethyl acetate and water were added for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product. . Purification by silica gel column chromatography (ethyl acetate-hexane) and 1-([1,1′-biphenyl] -3-yl) -5-amino-3-methyl-1H-pyrazole-4-carbonitrile (Compound 0044) -1,71 mg) as a pale green solid.
MSm / z (M + H): 275.

実施例２７において、５−アミノ−３−メチル−１−（３−ブロモフェニル）−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに１−（［１，１’−ビフェニル］−３−イル）−５−アミノ−３−メチル−１Ｈ−ピラゾール−４−カルボニトリル(化合物００４４−１)を用いること以外は実施例２７と同様の方法で、Ｎ−（５−（（（１−（［１，１’−ビフェニル］−３−イル）−４−シアノ−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−３−クロロ−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:7.66-7.58(7H,m),7.48-7.33(4H,m),7.10(1H,d,J=2.0Hz),4.66(1H,t,J=6.3Hz),4.55(2H,d,J=5.9Hz),2.45(2H,q,J=7.5Hz),2.34(3H,s),1.40-1.19(4H,m).
MSm/z(M+H):486.

In Example 27, instead of using 5-amino-3-methyl-1- (3-bromophenyl) -1H-pyrazole-4-carbonitrile, 1-([1,1′-biphenyl] -3-yl ) -5-amino-3-methyl-1H-pyrazole-4-carbonitrile (compound 0044-1) was used in the same manner as in Example 27 except that N- (5-(((1-([ 1,1′-biphenyl] -3-yl) -4-cyano-3-methyl-1H-pyrazol-5-yl) amino) methyl) -3-chloro-2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.66-7.58 (7H, m), 7.48-7.33 (4H, m), 7.10 (1H, d, J = 2.0Hz), 4.66 (1H, t, J = 6.3Hz ), 4.55 (2H, d, J = 5.9Hz), 2.45 (2H, q, J = 7.5Hz), 2.34 (3H, s), 1.40-1.19 (4H, m).
MSm / z (M + H): 486.

Ｎ−（５−（（（１−（３−ブロモフェニル）−４−シアノ−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−３−クロロ−２−ヒドロキシフェニル）プロピオンアミド(実施例２７参照、20mg)、４−ピリジンボロン酸(10.1mg)、ビス（ジベンジリデンアセトン）パラジウム（０）(1.3mg)、トリシクロヘキシルホスフィン(1.4mg)、りん酸カルシウムｎ水和物(15.3mg)の１，４−ジオキサン(0.11mL)/水(0.06mL)混合溶液を、窒素雰囲気下100℃で1時間攪拌した。反応液を室温まで冷却した後、酢酸エチルと水を加えて分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して粗生成物を得た。シリカゲルカラムクロマトグラフィー(メタノール−クロロホルム)で精製し、得られた固体を結晶化(クロロホルム−ヘキサン)で精製し、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（３−（ピリジン−４−イル）フェニル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミド(4.6mg)を得た。
¹H-NMR(MeOD)δ:8.62-8.60(2H,m),7.89-7.85(2H,m),7.74-7.71(3H,m),7.64-7.60(2H,m),7.11-7.10(1H,m),4.51(2H,s),2.46-2.43(2H,m),2.25(3H,s),1.18(3H,t,J=12.9Hz).
MSm/z(M+H):487. [Example 45]

N- (5-(((1- (3-bromophenyl) -4-cyano-3-methyl-1H-pyrazol-5-yl) amino) methyl) -3-chloro-2-hydroxyphenyl) propionamide ( See Example 27, 20 mg), 4-pyridineboronic acid (10.1 mg), bis (dibenzylideneacetone) palladium (0) (1.3 mg), tricyclohexylphosphine (1.4 mg), calcium phosphate n-hydrate (15.3 mg) of 1,4-dioxane (0.11 mL) / water (0.06 mL) mixed solution was stirred at 100 ° C. for 1 hour under a nitrogen atmosphere. After cooling the reaction solution to room temperature, ethyl acetate and water were added for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product. . Purification by silica gel column chromatography (methanol-chloroform), the resulting solid was purified by crystallization (chloroform-hexane), and N- (3-chloro-5-(((4-cyano-3-methyl-1 -(3- (Pyridin-4-yl) phenyl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide (4.6 mg) was obtained.
¹ H-NMR (MeOD) δ: 8.62-8.60 (2H, m), 7.89-7.85 (2H, m), 7.74-7.71 (3H, m), 7.64-7.60 (2H, m), 7.11-7.10 (1H , m), 4.51 (2H, s), 2.46-2.43 (2H, m), 2.25 (3H, s), 1.18 (3H, t, J = 12.9Hz).
MSm / z (M + H): 487.

実施例４５において、４−ピリジンボロン酸を用いた代わりに３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）キノリンを用いること以外は実施例４５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（３−（キノリン−３−イル）フェニル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(DMSO-d₆)δ:9.71(1H,s),9.33(1H,d,J=2.0Hz),8.75(1H,d,J=2.6Hz),8.07-8.02(4H,m),7.83-7.49(5H,m),7.37(1H,t,J=6.6Hz),7.13(1H,d,J=2.0Hz),4.47(2H,d,J=6.6Hz),2.38(2H,q,J=7.7Hz),2.17(3H,s),1.01(3H,t,J=7.6Hz).
MSm/z(M+H):537. [Example 46]

Example 45 Example 45 except that 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline was used instead of 4-pyridineboronic acid. N- (3-Chloro-5-(((4-cyano-3-methyl-1- (3- (quinolin-3-yl) phenyl) -1H-pyrazol-5-yl) amino ) Methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 9.71 (1H, s), 9.33 (1H, d, J = 2.0Hz), 8.75 (1H, d, J = 2.6Hz), 8.07-8.02 (4H, m ), 7.83-7.49 (5H, m), 7.37 (1H, t, J = 6.6Hz), 7.13 (1H, d, J = 2.0Hz), 4.47 (2H, d, J = 6.6Hz), 2.38 (2H , q, J = 7.7Hz), 2.17 (3H, s), 1.01 (3H, t, J = 7.6Hz).
MSm / z (M + H): 537.

実施例４５において、４−ピリジンボロン酸を用いた代わりにｏ−トリルボロン酸を用いること以外は実施例４５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（２’−メチル−［１，１’−ビフェニル］−３−イル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミド(2.9mg)を得た。
¹H-NMR(CDCl₃)δ:7.62-7.55(4H,m),7.41-7.39(3H,m),7.22-7.20(2H,m),7.09(1H,d,J=2.0Hz),4.63(1H,t,J=5.3Hz),4.56(2H,d,J=5.9Hz),2.46(2H,q,J=7.5Hz),2.32(3H,s),2.24(3H,s),1.26(3H,t,J=7.6Hz).
MSm/z(M+H):500. [Example 47]

In Example 45, except that o-tolylboronic acid was used instead of 4-pyridineboronic acid, N- (3-chloro-5-(((4-cyano-3 -Methyl-1- (2'-methyl- [1,1'-biphenyl] -3-yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide (2.9 mg) Obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.62-7.55 (4H, m), 7.41-7.39 (3H, m), 7.22-7.20 (2H, m), 7.09 (1H, d, J = 2.0Hz), 4.63 (1H, t, J = 5.3Hz), 4.56 (2H, d, J = 5.9Hz), 2.46 (2H, q, J = 7.5Hz), 2.32 (3H, s), 2.24 (3H, s), 1.26 (3H, t, J = 7.6Hz).
MSm / z (M + H): 500.

実施例４５において、４−ピリジンボロン酸を用いた代わりに２−クロロフェニルボロン酸を用い、マイクロウェーブ反応装置の反応条件を80℃、5分とする以外は実施例４５と同様の方法で、Ｎ−（３−クロロ−５−（（（１−（２’−クロロ−［１，１’−ビフェニル］−３−イル）−４−シアノ−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:7.76(2H,d,J=27.1Hz),7.60-7.57(2H,m),7.51-7.44(4H,m),7.34-7.30(3H,m),7.11(1H,d,J=2.0Hz),4.75(1H,t,J=6.3Hz),4.57(2H,d,J=5.9Hz),2.46(2H,q,J=7.7Hz),2.32(3H,s),1.32-1.19(3H,m).
MSm/z(M+H):520. [Example 48]

In Example 45, 2-chlorophenylboronic acid was used instead of 4-pyridineboronic acid, and the reaction conditions of the microwave reactor were set to 80 ° C. for 5 minutes. -(3-Chloro-5-(((1- (2'-chloro- [1,1'-biphenyl] -3-yl) -4-cyano-3-methyl-1H-pyrazol-5-yl) amino ) Methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.76 (2H, d, J = 27.1Hz), 7.60-7.57 (2H, m), 7.51-7.44 (4H, m), 7.34-7.30 (3H, m), 7.11 (1H, d, J = 2.0Hz), 4.75 (1H, t, J = 6.3Hz), 4.57 (2H, d, J = 5.9Hz), 2.46 (2H, q, J = 7.7Hz), 2.32 (3H , s), 1.32-1.19 (3H, m).
MS m / z (M + H): 520.

実施例４５において、４−ピリジンボロン酸を用いた代わりにｍ−トリルボロン酸を用いる以外は実施例４５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（３’−メチル−［１，１’−ビフェニル］−３−イル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:7.65-7.56(5H,m),7.37-7.32(4H,m),7.20(1H,d,J=6.6Hz),7.09(1H,d,J=2.0Hz),4.66(1H,t,J=6.6Hz),4.55(2H,d,J=5.9Hz),2.46(2H,q,J=7.6Hz),2.45(3H,s),2.33(3H,s),1.27-1.24(3H,m).
MSm/z(M+H):500. [Example 49]

In Example 45, in the same manner as in Example 45 except that m-tolylboronic acid was used instead of 4-pyridineboronic acid, N- (3-chloro-5-(((4-cyano-3- Methyl-1- (3′-methyl- [1,1′-biphenyl] -3-yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.65-7.56 (5H, m), 7.37-7.32 (4H, m), 7.20 (1H, d, J = 6.6Hz), 7.09 (1H, d, J = 2.0Hz) ), 4.66 (1H, t, J = 6.6Hz), 4.55 (2H, d, J = 5.9Hz), 2.46 (2H, q, J = 7.6Hz), 2.45 (3H, s), 2.33 (3H, s) ), 1.27-1.24 (3H, m).
MSm / z (M + H): 500.

実施例４５において、４−ピリジンボロン酸を用いた代わりに３−クロロフェニルボロン酸を用い、マイクロウェーブ反応装置の反応条件を100℃、10分とする以外は実施例４５と同様の方法で、Ｎ−（３−クロロ−５−（（（１−（３’−クロロ−［１，１’−ビフェニル］−３−イル）−４−シアノ−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:7.73-7.56(6H,m),7.45-7.37(5H,m),7.12-7.09(1H,m),4.62-4.57(3H,m),2.46(2H,q,J=7.3Hz),2.34(3H,s),1.28-1.23(3H,m).
MSm/z(M+H):520. [Example 50]

In Example 45, 3-chlorophenylboronic acid was used instead of 4-pyridineboronic acid, and the reaction conditions of the microwave reactor were changed to 100 ° C. for 10 minutes. -(3-Chloro-5-(((1- (3'-chloro- [1,1'-biphenyl] -3-yl) -4-cyano-3-methyl-1H-pyrazol-5-yl) amino ) Methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.73-7.56 (6H, m), 7.45-7.37 (5H, m), 7.12-7.09 (1H, m), 4.62-4.57 (3H, m), 2.46 (2H, q, J = 7.3Hz), 2.34 (3H, s), 1.28-1.23 (3H, m).
MS m / z (M + H): 520.

実施例４５において、４−ピリジンボロン酸を用いた代わりにｐ−トリルボロン酸を用いる以外は実施例４５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（４’−メチル−［１，１’−ビフェニル］−３−イル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:7.65-7.62(4H,m),7.56(1H,t,J=7.9Hz),7.47(2H,d,J=7.9Hz),7.38-7.34(1H,m),7.24(1H,s),7.10(1H,d,J=2.0Hz),4.64(1H,t,J=5.9Hz),4.55(2H,d,J=5.9Hz),2.45(2H,q,J=7.5Hz),2.40(3H,s),2.33(3H,s),1.27-1.24(3H,m).
MSm/z(M+H):500. [Example 51]

In Example 45, except that p-tolylboronic acid was used instead of 4-pyridineboronic acid, N- (3-chloro-5-(((4-cyano-3- Methyl-1- (4′-methyl- [1,1′-biphenyl] -3-yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.65-7.62 (4H, m), 7.56 (1H, t, J = 7.9Hz), 7.47 (2H, d, J = 7.9Hz), 7.38-7.34 (1H, m ), 7.24 (1H, s), 7.10 (1H, d, J = 2.0Hz), 4.64 (1H, t, J = 5.9Hz), 4.55 (2H, d, J = 5.9Hz), 2.45 (2H, q , J = 7.5Hz), 2.40 (3H, s), 2.33 (3H, s), 1.27-1.24 (3H, m).
MSm / z (M + H): 500.

実施例４５において、４−ピリジンボロン酸を用いた代わりに４−クロロフェニルボロン酸を用い、マイクロウェーブ反応装置の反応条件を100℃、10分とする以外は実施例４５と同様の方法で、Ｎ−（３−クロロ−５−（（（１−（４’−クロロ−［１，１’−ビフェニル］−３−イル）−４−シアノ−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:7.65-7.47(11H,m),7.09(1H,d,J=2.0Hz),4.65(1H,t,J=6.3Hz),4.55(2H,d,J=5.9Hz),2.46(2H,q,J=7.5Hz),2.33(3H,s),1.26-1.21(3H,m).
MSm/z(M+H):520. [Example 52]

In Example 45, 4-chlorophenylboronic acid was used instead of 4-pyridineboronic acid, and the reaction conditions of the microwave reactor were changed to 100 ° C. for 10 minutes. -(3-Chloro-5-(((1- (4'-chloro- [1,1'-biphenyl] -3-yl) -4-cyano-3-methyl-1H-pyrazol-5-yl) amino ) Methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.65-7.47 (11H, m), 7.09 (1H, d, J = 2.0Hz), 4.65 (1H, t, J = 6.3Hz), 4.55 (2H, d, J = 5.9Hz), 2.46 (2H, q, J = 7.5Hz), 2.33 (3H, s), 1.26-1.21 (3H, m).
MS m / z (M + H): 520.

実施例４５において、４−ピリジンボロン酸を用いた代わりに３，４−ジクロロフェニルボロン酸を用い、マイクロウェーブ反応装置の反応条件を80℃、5分とする以外は実施例４５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−１−（３’，４’−ジクロロ−［１，１’−ビフェニル］−３−イル）−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミド(1.3mg)を得た。
¹H-NMR(CDCl₃)δ:7.74-7.35(9H,m),7.08(1H,d,J=2.0Hz),4.64(1H,t,J=5.9Hz),4.55(2H,d,J=5.9Hz),2.49-2.42(2H,m),2.33(3H,s),1.27-1.24(4H,m).
MSm/z(M+H):554,556. [Example 53]

In Example 45, the same method as in Example 45 was used, except that 3,4-dichlorophenylboronic acid was used instead of 4-pyridineboronic acid, and the reaction conditions of the microwave reactor were 80 ° C. and 5 minutes. N- (3-Chloro-5-(((4-cyano-1- (3 ′, 4′-dichloro- [1,1′-biphenyl] -3-yl) -3-methyl-1H-pyrazole- 5-yl) amino) methyl) -2-hydroxyphenyl) propionamide (1.3 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.74-7.35 (9H, m), 7.08 (1H, d, J = 2.0Hz), 4.64 (1H, t, J = 5.9Hz), 4.55 (2H, d, J = 5.9Hz), 2.49-2.42 (2H, m), 2.33 (3H, s), 1.27-1.24 (4H, m).
MSm / z (M + H): 554,556.

実施例４４において、フェニルボロン酸の代わりにｍ−トリルボロン酸を用いる以外は実施例４４と同様の方法で、５−アミノ−３−メチル−１−（３’−メチル−［１，１’−ビフェニル］−３−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００５４−１)を得た。
MSm/z(M+H):289. [Example 54]

In Example 44, 5-amino-3-methyl-1- (3′-methyl- [1,1′-] was prepared in the same manner as in Example 44 except that m-tolylboronic acid was used instead of phenylboronic acid. Biphenyl] -3-yl) -1H-pyrazole-4-carbonitrile (compound 0054-1) was obtained.
MS m / z (M + H): 289.

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（３’−メチル−［１，１’−ビフェニル］−３−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００５４−１)を、Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミドを用いた代わりに１Ｈ−インダゾール−５−カルバルデヒドを用いたこと以外は実施例５と同様の方法で、５−（（（１Ｈ−インダゾール−５−イル）メチル）アミノ）−３−メチル−１−（３’−メチル−［１，１’−ビフェニル］−３−イル）−１Ｈ−ピラゾール−４−カルボニトリルを得た。
¹H-NMR(CDCl₃)δ:8.04(1H,s),7.71(1H,s),7.63-7.60(2H,m),7.54-7.48(2H,m),7.36-7.31(5H,m),7.21-7.20(1H,m),4.80(2H,d,J=5.9Hz),4.64(1H,t,J=5.9Hz),2.39(3H,s),2.35(3H,s).
MSm/z(M+H):419.

In Example 5, instead of using 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1- (3′-methyl- [1,1′-biphenyl] -3-yl) -1H-pyrazole-4-carbonitrile (compound 0054-1) was replaced with 1H-indazole-5 instead of N- (3-chloro-5-formyl-2-hydroxyphenyl) propionamide. -5-(((1H-indazol-5-yl) methyl) amino) -3-methyl-1- (3'-methyl- [1] in the same manner as in Example 5 except that carbaldehyde was used. , 1′-biphenyl] -3-yl) -1H-pyrazole-4-carbonitrile was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.04 (1H, s), 7.71 (1H, s), 7.63-7.60 (2H, m), 7.54-7.48 (2H, m), 7.36-7.31 (5H, m) 7.21-7.20 (1H, m), 4.80 (2H, d, J = 5.9Hz), 4.64 (1H, t, J = 5.9Hz), 2.39 (3H, s), 2.35 (3H, s).
MSm / z (M + H): 419.

実施例３４において、１−ヒドラジニルイソキノリン塩酸塩を用いた代わりに２−ナフチルヒドラジン塩酸塩を用いる以外は実施例３４と同様の方法で、５−アミノ−３−メチル−１−（ナフタレン−２−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００５５−１)を得た。
MSm/z(M+H):249. [Example 55]

In Example 34, in the same manner as in Example 34 except that 2-naphthylhydrazine hydrochloride was used instead of 1-hydrazinylisoquinoline hydrochloride, 5-amino-3-methyl-1- (naphthalene- 2-yl) -1H-pyrazole-4-carbonitrile (Compound 0055-1) was obtained.
MSm / z (M + H): 249.

実施例２７において、５−アミノ−３−メチル−１−（３−ブロモフェニル）−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（ナフタレン−２−イル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００５５−１)を用いること以外は実施例２７と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（ナフタレン−２−イル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:8.00(1H,d,J=9.2Hz),7.95-7.88(3H,m),7.76(1H,s),7.63-7.52(4H,m),7.39(1H,s),7.10(1H,d,J=2.0Hz),4.72(1H,t,J=6.3Hz),4.57(2H,d,J=5.9Hz),2.48(2H,q,J=7.7Hz),2.35(3H,s)1.28(3H,t,J=7.3Hz).
MSm/z(M+H):460.

In Example 27, instead of using 5-amino-3-methyl-1- (3-bromophenyl) -1H-pyrazole-4-carbonitrile, 5-amino-3-methyl-1- (naphthalene-2- Yl) -1H-pyrazole-4-carbonitrile (Compound 0055-1) was used in the same manner as in Example 27 except that N- (3-chloro-5-(((4-cyano-3-methyl -1- (Naphthalen-2-yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.00 (1H, d, J = 9.2Hz), 7.95-7.88 (3H, m), 7.76 (1H, s), 7.63-7.52 (4H, m), 7.39 (1H , s), 7.10 (1H, d, J = 2.0Hz), 4.72 (1H, t, J = 6.3Hz), 4.57 (2H, d, J = 5.9Hz), 2.48 (2H, q, J = 7.7Hz) ), 2.35 (3H, s) 1.28 (3H, t, J = 7.3Hz).
MSm / z (M + H): 460.

実施例４５において、４−ピリジンボロン酸を用いた代わりに２−メトキシフェニルボロン酸を用いる以外は実施例４５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−１−（２’−メトキシ−［１，１’−ビフェニル］−３−イル）−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:7.81(1H,s),7.61-7.56(5H,m),7.41-7.29(3H,m),7.12(1H,d,J=2.0Hz),7.06-6.97(2H,m),4.80(1H,t,J=6.3Hz),4.58(2H,d,J=6.6Hz),3.73(3H,s),2.46(2H,q,J=7.7Hz),2.33(3H,s),1.26(3H,t,J=7.6Hz).
MSm/z(M+H):516. [Example 56]

In Example 45, in the same manner as in Example 45 except that 2-methoxyphenylboronic acid was used instead of 4-pyridineboronic acid, N- (3-chloro-5-(((4-cyano- 1- (2′-methoxy- [1,1′-biphenyl] -3-yl) -3-methyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.81 (1H, s), 7.61-7.56 (5H, m), 7.41-7.29 (3H, m), 7.12 (1H, d, J = 2.0Hz), 7.06-6.97 (2H, m), 4.80 (1H, t, J = 6.3Hz), 4.58 (2H, d, J = 6.6Hz), 3.73 (3H, s), 2.46 (2H, q, J = 7.7Hz), 2.33 (3H, s), 1.26 (3H, t, J = 7.6Hz).
MSm / z (M + H): 516.

実施例４５において、４−ピリジンボロン酸を用いた代わりに３−メトキシフェニルボロン酸を用いる以外は実施例４５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−１−（３’−メトキシ−［１，１’−ビフェニル］−３−イル）−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:7.66-7.54(6H,m),7.40-7.35(2H,m),7.16-7.11(3H,m),6.93(1H,dd,J=9.2,2.6Hz),4.62(1H,d,J=5.3Hz),4.56(2H,d,J=5.9Hz),3.86(3H,s),2.46(2H,q,J=7.5Hz),2.34(3H,s),1.26(3H,t,J=7.6Hz).
MSm/z(M+H):516. [Example 57]

In Example 45, except that 3-methoxyphenylboronic acid was used instead of 4-pyridineboronic acid, N- (3-chloro-5-(((4-cyano- 1- (3′-methoxy- [1,1′-biphenyl] -3-yl) -3-methyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.66-7.54 (6H, m), 7.40-7.35 (2H, m), 7.16-7.11 (3H, m), 6.93 (1H, dd, J = 9.2,2.6Hz) , 4.62 (1H, d, J = 5.3Hz), 4.56 (2H, d, J = 5.9Hz), 3.86 (3H, s), 2.46 (2H, q, J = 7.5Hz), 2.34 (3H, s) , 1.26 (3H, t, J = 7.6Hz).
MSm / z (M + H): 516.

実施例４５において、４−ピリジンボロン酸を用いた代わりに４−メトキシフェニルボロン酸を用いる以外は実施例４５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−１−（４’−メトキシ−［１，１’−ビフェニル］−３−イル）−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミド(実施例５８の化合物)と、Ｎ−（５−（（（４−シアノ−１−（４’−メトキシ−［１，１’−ビフェニル］−３−イル）−３−メチル−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシ−４’−メトキシ−［１，１’−ビフェニル］−３−イル）プロピオンアミド(実施例５９の化合物)を得た。
実施例５８の化合物
¹H-NMR(CDCl₃)δ:7.66(1H,d,J=2.0Hz),7.63-7.50(7H,m),7.34(1H,d,J=7.9Hz),7.11(1H,d,J=2.0Hz),6.98(2H,dd,J=6.6,2.0Hz),4.63(1H,d,J=5.9Hz),4.56(2H,d,J=5.9Hz),3.86(3H,s),2.46(2H,q,J=7.5Hz),2.34(3H,s),1.26(t,J=7.6Hz,3H).
MSm/z(M+H):516.
実施例５９の化合物
¹H-NMR(CDCl₃)δ:7.69-7.68(2H,m),7.61-7.31(10H,m),7.02-6.91(5H,m),4.61(2H,d,J=5.3Hz),3.84(6H,s),2.47(2H,q,J=7.5Hz),2.34(3H,s),1.26(3H,t,J=7.6Hz).
MSm/z(M+H):588. [Example 58], [Example 59]

In Example 45, in the same manner as in Example 45 except that 4-methoxyphenylboronic acid was used instead of 4-pyridineboronic acid, N- (3-chloro-5-(((4-cyano- 1- (4′-Methoxy- [1,1′-biphenyl] -3-yl) -3-methyl-1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide (Example 58) Compound) and N- (5-(((4-cyano-1- (4′-methoxy- [1,1′-biphenyl] -3-yl) -3-methyl-1H-pyrazol-5-yl ) Amino) methyl) -2-hydroxy-4′-methoxy- [1,1′-biphenyl] -3-yl) propionamide (the compound of Example 59).
Compound of Example 58
¹ H-NMR (CDCl ₃ ) δ: 7.66 (1H, d, J = 2.0Hz), 7.63-7.50 (7H, m), 7.34 (1H, d, J = 7.9Hz), 7.11 (1H, d, J = 2.0Hz), 6.98 (2H, dd, J = 6.6, 2.0Hz), 4.63 (1H, d, J = 5.9Hz), 4.56 (2H, d, J = 5.9Hz), 3.86 (3H, s), 2.46 (2H, q, J = 7.5Hz), 2.34 (3H, s), 1.26 (t, J = 7.6Hz, 3H).
MSm / z (M + H): 516.
Compound of Example 59
¹ H-NMR (CDCl ₃ ) δ: 7.69-7.68 (2H, m), 7.61-7.31 (10H, m), 7.02-6.91 (5H, m), 4.61 (2H, d, J = 5.3Hz), 3.84 (6H, s), 2.47 (2H, q, J = 7.5Hz), 2.34 (3H, s), 1.26 (3H, t, J = 7.6Hz).
MSm / z (M + H): 588.

実施例４５において、４−ピリジンボロン酸を用いた代わりにＮ−メチル−Ｎ−（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル）メタンスルホンアミドを用い、マイクロウェーブ反応装置の反応条件を90℃、10分とする以外は実施例４５と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（４’−（Ｎ−メチルメタンスルホンアミド）−［１，１’−ビフェニル］−３−イル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミド(9.4mg)を得た。
¹H-NMR(CDCl₃)δ:7.74(1H,s),7.62-7.56(6H,m),7.47-7.41(4H,m),7.10(1H,d,J=2.0Hz),4.56(3H,d,J=4.0Hz),3.37(3H,s),2.88(3H,s),2.47(2H,q,J=7.7Hz),2.34(3H,s),1.26(3H,t,J=7.9Hz).
MSm/z(M+H):593. [Example 60]

In Example 45, instead of using 4-pyridineboronic acid, N-methyl-N- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) N- (3-Chloro-5-(((4-cyano-3- Methyl-1- (4 ′-(N-methylmethanesulfonamido)-[1,1′-biphenyl] -3-yl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propion Amide (9.4 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.74 (1H, s), 7.62-7.56 (6H, m), 7.47-7.41 (4H, m), 7.10 (1H, d, J = 2.0Hz), 4.56 (3H , d, J = 4.0Hz), 3.37 (3H, s), 2.88 (3H, s), 2.47 (2H, q, J = 7.7Hz), 2.34 (3H, s), 1.26 (3H, t, J = 7.9Hz).
MS m / z (M + H): 593.

５−（クロロメチル）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル（50mg）とトリフェニルホスフィン（79mg）をトルエン（1mL）に溶かし、終夜加熱還流した。生成した固体をろ取し、固体をヘキサン−酢酸エチル混合溶媒で洗浄し、塩化（（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）メチル）トリフェニルホスホニウム（化合物００６１−１、60.5mg）を黄色固体として得た。
MSm/z(M+H):232. [Example 61]

5- (Chloromethyl) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile (50 mg) and triphenylphosphine (79 mg) were dissolved in toluene (1 mL) and heated to reflux overnight. The produced solid was collected by filtration, and the solid was washed with a mixed solvent of hexane-ethyl acetate, and ((4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) methyl) triphenylphosphonium (compound) 0061-1, 60.5 mg) was obtained as a yellow solid.
MS m / z (M + H): 232.

Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミド(化合物０００１−３、30mg)をクロロホルム（2mL）−メタノール（0.5mL）混合溶媒に溶かし、これに炭酸カリウム（59mg）、ベンジルブロミド（14μL）を加え、60℃で12.5時間攪拌した。反応混合物を室温に冷却し、不溶物をろ過し、ろ液を減圧下濃縮した。残留物をシリカゲルカラムクロマトグラフィーで精製し、Ｎ−（２−（ベンジルオキシ）−３−クロロ−５−ホルミルフェニル）プロピオンアミド（化合物０００６２−３、34.7mg）を得た。
¹H-NMR(CDCl₃)δ:9.90(1H,s),8.81(1H,d,J=1.7Hz),7.71(1H,d,J=1.8Hz),7.50-7.46(1H,brs),7.46-7.37(5H,m),5.16(2H,s),2.08(2H,q,J=7.5Hz),1.07(3H,t,J=7.6Hz).

N- (3-Chloro-5-formyl-2-hydroxyphenyl) propionamide (Compound 0001-3, 30 mg) was dissolved in a mixed solvent of chloroform (2 mL) -methanol (0.5 mL), and potassium carbonate (59 mg) was dissolved therein. Benzyl bromide (14 μL) was added and stirred at 60 ° C. for 12.5 hours. The reaction mixture was cooled to room temperature, insolubles were filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain N- (2- (benzyloxy) -3-chloro-5-formylphenyl) propionamide (Compound 00062-3, 34.7 mg).
¹ H-NMR (CDCl ₃ ) δ: 9.90 (1H, s), 8.81 (1H, d, J = 1.7Hz), 7.71 (1H, d, J = 1.8Hz), 7.50-7.46 (1H, brs), 7.46-7.37 (5H, m), 5.16 (2H, s), 2.08 (2H, q, J = 7.5Hz), 1.07 (3H, t, J = 7.6Hz).

塩化（（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）メチル）トリフェニルホスホニウム（化合物００６１−１、18mg）にテトラヒドロフラン（0.5mL）を加え、これに氷冷下で1.6mol/Lのｎ−ブチルリチウム（26μL）を加え、同温度で30分間攪拌した。反応混合物にＮ−（２−（ベンジルオキシ）−３−クロロ−５−ホルミルフェニル）プロピオンアミド（化合物００６１−２、12mg）のテトラヒドロフラン溶液（0.5mL）を加え、室温に昇温し、終夜攪拌した。反応混合物にメタノールを加え、減圧下溶媒を留去した。残留物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）で精製し、（Ｅ）−Ｎ−（２−（ベンジルオキシ）−３−クロロ−５−（２−（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）ビニル）フェニル）プロピオンアミド（化合物００６１−３、8.8mg）を白色固体として得た。
MSm/z(M+H):497.

Tetrahydrofuran (0.5 mL) was added to ((4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) methyl) triphenylphosphonium chloride (Compound 0061-1, 18 mg), and this was followed by cooling with ice. Then, 1.6 mol / L of n-butyllithium (26 μL) was added and stirred at the same temperature for 30 minutes. To the reaction mixture was added a tetrahydrofuran solution (0.5 mL) of N- (2- (benzyloxy) -3-chloro-5-formylphenyl) propionamide (Compound 0061-2, 12 mg), warmed to room temperature, and stirred overnight. did. Methanol was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) and (E) -N- (2- (benzyloxy) -3-chloro-5- (2- (4-cyano-3-methyl-1). -Phenyl-1H-pyrazol-5-yl) vinyl) phenyl) propionamide (Compound 0061-3, 8.8 mg) was obtained as a white solid.
MSm / z (M + H): 497.

（Ｅ）−Ｎ−（２−（ベンジルオキシ）−３−クロロ−５−（２−（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）ビニル）フェニル）プロピオンアミド（化合物００６１−３、8.8mg）をアセトニトリルに溶かし、これにヨードトリメチルシラン（25μL）を加え、50℃で９時間、80℃で14時間攪拌した。反応混合物を室温に冷却後、亜硫酸水素ナトリウム水溶液に注ぎ、酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残留物をシリカゲルクロマトグラフィー（ヘキサン−酢酸エチル）で精製し、（Ｅ）−Ｎ−（３−クロロ−５−（２−（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）ビニル）−２−ヒドロキシフェニル）プロピオンアミド（4.6mg）を得た。
¹H-NMR(CDCl₃)δ:8.21-8.18(1H,brm),7.61(1H,d,J=2.0Hz),7.58-7.42(7H,m),7.25(1H,d,J=2.3Hz),6.66(1H,d,J=16.5Hz),2.49(2H,q,J=7.6Hz),2.46(3H,s),1.28(3H,t,J=7.6Hz).
MSm/z(M+H):407.

(E) -N- (2- (benzyloxy) -3-chloro-5- (2- (4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) vinyl) phenyl) propionamide (Compound 0061-3, 8.8 mg) was dissolved in acetonitrile, iodotrimethylsilane (25 μL) was added thereto, and the mixture was stirred at 50 ° C. for 9 hours and at 80 ° C. for 14 hours. The reaction mixture was cooled to room temperature, poured into an aqueous sodium hydrogen sulfite solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to give (E) -N- (3-chloro-5- (2- (4-cyano-3-). Methyl-1-phenyl-1H-pyrazol-5-yl) vinyl) -2-hydroxyphenyl) propionamide (4.6 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.21-8.18 (1H, brm), 7.61 (1H, d, J = 2.0Hz), 7.58-7.42 (7H, m), 7.25 (1H, d, J = 2.3Hz ), 6.66 (1H, d, J = 16.5Hz), 2.49 (2H, q, J = 7.6Hz), 2.46 (3H, s), 1.28 (3H, t, J = 7.6Hz).
MSm / z (M + H): 407.

（Ｚ）−３−アミノ−２−（２，２−ジクロロアセチル）−２−ブテンニトリル（386mg）とパラトルエンスルホン酸一水和物（10mg）をメタノール（10mL）に溶かし、これにフェニルヒドラジンを加え、60℃で終夜攪拌した。反応混合物を減圧下濃縮後、水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去し、得られた残留物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）で精製し、５−（ジクロロメチル）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル（260mg）を得た。
MSm/z(M+H):266. [Example 62]

(Z) -3-Amino-2- (2,2-dichloroacetyl) -2-butenenitrile (386 mg) and paratoluenesulfonic acid monohydrate (10 mg) were dissolved in methanol (10 mL), and phenylhydrazine was dissolved therein. And stirred at 60 ° C. overnight. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the resulting residue is purified by silica gel column chromatography (hexane-ethyl acetate) to give 5- (dichloromethyl) -3-methyl-1 -Phenyl-1H-pyrazole-4-carbonitrile (260 mg) was obtained.
MSm / z (M + H): 266.

５−（ジクロロメチル）−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルを20%硫酸水溶液（4.5mL）に溶かし、100℃で５時間、120℃で８時間、130℃で９時間攪拌した。反応混合物を室温に冷却し、クロロホルムで抽出し、有機層を炭酸水素ナトリウムで洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、残留物をシリカゲルクロマトグラフィー（ヘキサン−酢酸エチル）で精製し、５−ホルミル−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００６２−２、23mg）を得た。
¹H-NMR(CDCl₃)δ:9.89(1H,s),7.59-7.42(5H,m),2.53(3H,s).

5- (Dichloromethyl) -3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile is dissolved in a 20% aqueous sulfuric acid solution (4.5 mL) and dissolved at 100 ° C for 5 hours, 120 ° C for 8 hours, and 130 ° C. Stir for 9 hours. The reaction mixture was cooled to room temperature, extracted with chloroform, and the organic layer was washed with sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (hexane-ethyl acetate), and 5-formyl-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile (compound 0062-2, 23 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 9.89 (1H, s), 7.59-7.42 (5H, m), 2.53 (3H, s).

実施例５において、５−アミノ−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリルの代わりに５−ホルミル−３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボニトリル（化合物００６２−２）を、Ｎ−（３−クロロ−５−ホルミル−２−ヒドロキシフェニル）プロピオンアミドの代わりにＮ−（３−アミノフェニル）アセトアミドを用いる以外は実施例５と同様の方法で、Ｎ−（３−（（（４−シアノ−３−メチル−１−フェニル−１Ｈ−ピラゾール−５−イル）メチル）アミノ）フェニル）アセトアミドを得た。
¹H-NMR(CDCl₃)δ:7.57-7.45(5H,m),7.09-7.04(1H,m),7.08(1H,t,J=8.0Hz),6.92(1H,s),6.76(1H,d,J=7.9Hz),6.25(1H,dd,J=8.3,1.7Hz),4.45(2H,d,J=6.3Hz),4.03(1H,t,J=6.2Hz),2.41(3H,s),2.14(3H,s).
MSm/z(M+H):346.

In Example 5, 5-formyl-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile (Compound 0062-2) instead of 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile In the same manner as in Example 5 except that N- (3-aminophenyl) acetamide is used instead of N- (3-chloro-5-formyl-2-hydroxyphenyl) propionamide. (((4-Cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) methyl) amino) phenyl) acetamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.57-7.45 (5H, m), 7.09-7.04 (1H, m), 7.08 (1H, t, J = 8.0Hz), 6.92 (1H, s), 6.76 (1H , d, J = 7.9Hz), 6.25 (1H, dd, J = 8.3, 1.7Hz), 4.45 (2H, d, J = 6.3Hz), 4.03 (1H, t, J = 6.2Hz), 2.41 (3H , s), 2.14 (3H, s).
MSm / z (M + H): 346.

実施例４４において、フェニルボロン酸を用いた代わりに２−ナフチルボロン酸を用いること以外は実施例４４と同様の方法で、５−アミノ−３−メチル−１−（３−（ナフタレン−２−イル）フェニル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００６３−１)を得た。
MSm/z(M+H):325. [Example 63]

In Example 44, in the same manner as in Example 44 except that 2-naphthylboronic acid was used instead of phenylboronic acid, 5-amino-3-methyl-1- (3- (naphthalene-2- Yl) phenyl) -1H-pyrazole-4-carbonitrile (compound 0063-1) was obtained.
MSm / z (M + H): 325.

実施例２７において、５−アミノ−３−メチル−１−（３−ブロモフェニル）−１Ｈ−ピラゾール−４−カルボニトリルを用いた代わりに５−アミノ−３−メチル−１−（３−（ナフタレン−２−イル）フェニル）−１Ｈ−ピラゾール−４−カルボニトリル(化合物００６３−１)を用いること以外は実施例２７と同様の方法で、Ｎ−（３−クロロ−５−（（（４−シアノ−３−メチル−１−（３−（ナフタレン−２−イル）フェニル）−１Ｈ−ピラゾール−５−イル）アミノ）メチル）−２−ヒドロキシフェニル）プロピオンアミドを得た。
¹H-NMR(CDCl₃)δ:8.04(1H,s),7.94-7.41(13H,m),7.11(1H,d,J=1.3Hz),4.68(1H,t,J=5.9Hz),4.57(2H,d,J=5.9Hz),2.41(2H,q,J=7.6Hz),2.35(3H,s),1.28-1.19(3H,m).
MSm/z(M+H):536.

Instead of using 5-amino-3-methyl-1- (3-bromophenyl) -1H-pyrazole-4-carbonitrile in Example 27, 5-amino-3-methyl-1- (3- (naphthalene) -2-yl) phenyl) -1H-pyrazole-4-carbonitrile (Compound 0063-1) was used in the same manner as in Example 27 except that N- (3-chloro-5-(((4- Cyano-3-methyl-1- (3- (naphthalen-2-yl) phenyl) -1H-pyrazol-5-yl) amino) methyl) -2-hydroxyphenyl) propionamide was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.04 (1H, s), 7.94-7.41 (13H, m), 7.11 (1H, d, J = 1.3Hz), 4.68 (1H, t, J = 5.9Hz), 4.57 (2H, d, J = 5.9Hz), 2.41 (2H, q, J = 7.6Hz), 2.35 (3H, s), 1.28-1.19 (3H, m).
MSm / z (M + H): 536.

<Test Example 0001>
The anti-HIV activity of the present invention was evaluated according to the method described in [Journal of Clinical Microbiology, 2008, 46, 792-795]. That is, NCK45-β-Gal / SEAP cells were seeded at 1 × 10 ⁴ cells / well in a 96-well flat bottom plate, cultured for 24 hours, and then replaced with a medium containing an appropriate dilution of the compound synthesized above. did. Subsequently, HIV-1 (IIIB strain) was infected with 60 NCK units. After 48 hours of culture, HIV-1 infected cells were stained with X-gal and counted. Anti-HIV-1 activity of various compounds was calculated as EC ₅₀ (50% effective concentration), the concentration that inhibits HIV-1 infection by 50%. The EC50 values obtained using the example compounds synthesized above are shown in Table 1 as A (100 nM or less), B (100 nM or more and less than 1000 nM), C (1000 nM or more and less than 10000 nM), and D (10000 nM or more).

Claims (12)

The following general formula (I),

(In the above formula,
R ¹ is a C _1-6 alkyl group; a C _3-8 cycloalkyl group; a phenyl group or a naphthyl group which may have at least one substituent selected from the substituent group α; or; Represents a thiazolyl group, pyridyl group, quinolyl group or isoquinolyl group,
Here, the substituent group α is a halogen atom; a cyano group; a nitro group; a C _1-6 alkyl group that may have a halogen atom; a C _1-6 alkoxy group that may have a halogen atom (bonded). A carbon atom and a carbon atom adjacent thereto may form a 1,3-benzodioxole ring which may have a halogen atom); a C _1-6 acylamino group; or a halogen atom, Phenyl optionally having at least one substituent selected from the group consisting of a C _1-6 alkyl group, a C _1-6 alkoxy group, and an (N—C _1-6 alkyl) C _1-6 alkylsulfonylamino group A group, naphthyl group, pyridyl group or quinolyl group;
R ² represents a hydrogen atom, a C _1-3 alkyl group or a phenyl group,
R ³ represents a hydrogen atom, a cyano group or a C _1-6 alkoxycarbonyl group,
R ⁴ and R ⁶ each independently have a hydrogen atom; a halogen atom; a C _1-6 alkyl group; a C _1-6 acylamino group; a C _1-6 alkylaminocarbonyl group; or a C _1-6 alkoxy group. An at least one of R ⁴ and R ⁶ is a substituent other than a hydrogen atom;
R ⁵ represents a hydrogen atom, a hydroxyl group or a C _1-6 alkoxy group, provided that R ⁵ and R ⁴ or R ⁶ may be combined with the carbon atom to which each is bonded to form an indazole ring. Often,
X ¹ represents * —CH═CH — **, * —CH ₂ —NH — **, * —NH—CH ₂ — ** or * —N = N — **, where * is the above A pyrazole derivative or a salt thereof, which is represented by a bond to the pyrazole ring side in the formula, and ** is a bond to the phenyl ring side in the above formula). R ¹ represents a C _3-8 cycloalkyl group; a phenyl group or a naphthyl group which may have at least one substituent selected from substituent group α; or; a thiazolyl group which may have a phenyl group The pyrazole derivative or a salt thereof according to claim 1, which is a pyridyl group or a quinolyl group. The substituent group α is at least selected from the group consisting of a halogen atom; a C _1-6 alkyl group; a C _1-6 alkoxy group; or a halogen atom, a C _1-6 alkyl group and a C _1-6 alkoxy group The pyrazole derivative or a salt thereof according to claim 1 or 2, which is a phenyl group which may have one substituent. The pyrazole derivative or a salt thereof according to any one of claims 1 to 3, wherein R ² is a hydrogen atom or a C _1-3 alkyl group. Said R < ³ > is a hydrogen atom or a cyano group, The pyrazole derivative or its salt as described in any one of Claims 1-4. The R ⁴ and R ⁶ are each independently a halogen atom, a C _1-6 acylamino group, or a C _1-6 alkylaminocarbonyl group, or a pyrazole derivative according to any one of claims 1 to 5 or its salt. Wherein R ⁵ is a pyrazole derivative or salt thereof according to any one of claims 1 to 6 is a hydroxyl group or a C _1-6 alkoxy group. The pyrazole according to claim 1, wherein X ¹ is * —CH ₂ —NH — **, * —NH—CH ₂ — **, or * —N═N — **. Derivatives or salts thereof. The following general formula (II),

(In the above formula,
R ⁷ represents a phenyl group having a phenyl group which may have at least one substituent selected from the group consisting of a halogen atom, a C _1-6 alkyl group and a C _1-6 alkoxy group; or; a quinolyl group Represent,
R ⁸ represents a C _1-3 alkyl group,
One of R ⁹ and R ¹⁰ is a halogen atom, and the other is a C _1-6 acylamino group), or a pyrazole derivative or a salt thereof.   The pharmaceutical composition containing the pyrazole derivative or its salt as described in any one of Claims 1-9.   11. A pharmaceutical composition according to claim 10 for treatment and / or prevention of viral infections.   The pharmaceutical composition according to claim 11, wherein the virus is human immunodeficiency virus (HIV).