WO2014119617A1

WO2014119617A1 - Amidine compound and salt thereof

Info

Publication number: WO2014119617A1
Application number: PCT/JP2014/051966
Authority: WO
Inventors: 正弘竹林; 康裕筒井; 歩夢森; 加藤　智也; 宣知藤野
Original assignee: 富山化学工業株式会社
Priority date: 2013-01-30
Filing date: 2014-01-29
Publication date: 2014-08-07

Abstract

A compound that can be represented by general formula or a salt of such a compound is useful as an antifungal agent. (In the formula, R¹ and R² may be the same as or different from each other and each represent a halogen atom, a C_1-6 alkyl group that may be substituted, or the like; R³ represents an indanyl group that may be substituted, an indenyl group that may be substituted, a dihydronaphthyl group that may be substituted, a tetrahydronaphthyl group that may be substituted, or the like; R⁴ and R⁵ may be the same as or different from each other and each represent a hydrogen atom, a C_1-6 alkyl group that may be substituted, or the like; X¹ represents a C_1-6 alkylene group or the like; Z¹ and Z² may be the same as or different from each other and each represent a nitrogen atom, the group represented by the formula CH, or the like; and Z³ represents a nitrogen atom, the group represented by the formula CH, or the like.)

Description

Amidine compound or salt thereof

The present invention relates to a novel amidine compound having an antifungal activity or a salt thereof, and an antifungal agent containing them.

Serious deep mycosis such as invasive candidiasis is often a fatal disease. Originally, the main defense mechanism on the host organism side against fungi such as Candida is considered to be due to non-specific immunity by neutrophils. If this defense mechanism is functioning normally, there is little risk of infection with fungi. In recent years, however, the number of patients with underlying diseases such as malignant tumors and AIDS that cause a decline in the immune function of this living body, frequent use of anticancer drugs and immunosuppressants, heavy use of antibacterial antibiotics and steroid hormones, and long-term focus There is an increased risk of suffering from deep mycosis due to the use of parenteral nutrition and intravenous catheters (Non-patent Document 1).

There are only nine such drugs for deep mycosis: amphotericin B, flucytosine, miconazole, fluconazole, itraconazole, voriconazole, posaconazole, caspofungin and micafungin. Amphotericin B has a very strong bactericidal action, but has side-effects such as nephrotoxicity and is limited in clinical use. Since flucytosine has problems such as resistance, it is rarely used alone at present. Caspofungin and Micafungin are weakly active against the genus Cryptococcus. All other drugs are collectively referred to as azole antifungal agents, and their bactericidal action tends to be generally inferior to that of amphotericin B, but is currently most frequently used due to the balance between efficacy and safety. (Non-Patent Document 2).

Currently, fluconazole-resistant Candida albicans is frequently detected in the oropharyngeal candidiasis lesions of AIDS patients who have been repeatedly administered fluconazole. Moreover, many resistant strains are also cross-resistant to itraconazole and other azole drugs. Furthermore, isolation of resistant strains has also been reported for non-AIDS patients who developed chronic mucocutaneous candidiasis or deep candidiasis (Non-patent Document 3). The problem of resistance has a serious impact on the management of patients with deep mycosis, which is steadily increasing (Non-patent Document 3).

On the other hand, onychomycosis caused by ringworm is a kind of superficial mycosis and is an intractable disease that requires 3 to 6 months for its treatment. Currently, itraconazole and terbinafine are used for the treatment.
However, both drugs cannot be said to have a sufficient cure rate, and recurrence has been observed (Non-patent Documents 4 and 5). Terbinafine must be taken every day for 6 months, and it has been pointed out that medication compliance is poor due to long-term administration (Non-patent Document 6). Furthermore, side effects were observed in approximately 10% or more of both drugs, and abnormal laboratory values such as liver function test values were confirmed in about 5% of patients. Itraconazole is known to show drug interactions with many other drugs.

There is a strong need for antifungal agents that have better cure rates, lower recurrence rates, shorter administration periods, and improved safety and drug interactions than existing drugs.
The amidine compounds of the present invention or salts thereof having antifungal activity against pathogenic fungi, and antifungal agents containing them have never been known so far.

International Publication No. 00/46184 Pamphlet International Publication No. 2004/037239 Pamphlet

An object of the present invention is to provide a novel compound that exhibits excellent antifungal activity against pathogenic fungi including Candida, Aspergillus, and ringworm, and is useful as a pharmaceutical.

Under such circumstances, the present inventors have conducted extensive studies, and as a result, the general formula [1]

In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _{2- 6} alkenyl group, optionally substituted C _2-6 alkynyl group, optionally substituted C _3-8 cycloalkyl group, optionally substituted C _1-6 alkoxy group, optionally substituted A C _1-6 alkylamino group, an optionally substituted di (C _1-6 alkyl) amino group, an optionally substituted C _1-6 alkylthio group, an optionally substituted aryloxy group, a substituted Arylthio group which may be substituted, aryl group which may be substituted, monocyclic heterocyclic group which may be substituted, bicyclic heterocyclic group which may be substituted, protected Good amino group, An optionally protected hydroxyl group or an optionally protected carboxyl group;
R ³ is an optionally substituted dihydrobenzocyclobutenyl group, an optionally substituted indanyl group, an optionally substituted indenyl group, an optionally substituted tetrahydronaphthyl group, an optionally substituted Good dihydronaphthyl group, optionally substituted benzocycloheptyl group, optionally substituted dihydro-5H-benzocycloheptenyl group, optionally substituted 5H-benzocycloheptenyl group, substituted May be a hexahydrobenzocyclooctenyl group, an optionally substituted tetrahydrobenzocyclooctenyl group, an optionally substituted dihydrobenzocyclooctenyl group, an optionally substituted tetrahydromethanonaphthyl group or a substituted An optionally tetrahydroethanonaphthyl group;
R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or an optionally substituted C _{2− A 6} alkynyl group, an optionally substituted C _3-8 cycloalkyl group, an optionally substituted aryl group or an optionally substituted monocyclic heterocyclic group; or
R ⁴ and R ⁵ are an optionally substituted cyclic amino group formed together with the nitrogen atom to which they are attached;
X ¹ represents a sulfur atom, a C _1-6 alkylene group or a general formula NR ^a , wherein R ^a represents a hydrogen atom, an optionally substituted C _1-6 alkyl group or an imino protecting group. The group represented;
Z ¹ and Z ² are the same or different and are each a nitrogen atom or a general formula CR ^c wherein R ^c is a hydrogen atom, a halogen atom, a cyano group, a nitro group, or an optionally substituted C _1-6 alkyl. A group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _3-8 cycloalkyl group, an _optionally substituted C _{1 -6} alkoxy group, optionally substituted C _1-6 alkylamino group, optionally substituted di (C _1-6 alkyl) amino group, optionally substituted C _1-6 alkylthio group, substituted Aryloxy group which may be substituted, arylthio group which may be substituted, aryl group which may be substituted, monocyclic heterocyclic group which may be substituted, bicyclic which may be substituted Heterocyclic A group represented by a group, an optionally protected amino group, an optionally protected hydroxyl group or an optionally protected carboxyl group;
Z ³ represents a nitrogen atom or a group represented by the general formula CR ^b wherein R ^b represents a hydrogen atom, a halogen atom or an optionally substituted C _1-6 alkyl group. It has been found that the compound represented by the above or a salt thereof has excellent antifungal activity and is useful as an antifungal agent.

Furthermore, as a result of intensive studies, the present inventors have found that in the general formula [1],
R ¹ and R ² are the same or different and are each a halogen atom, a cyano group, a nitro group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, a substituted An optionally substituted C _2-6 alkynyl group, an optionally substituted C _3-8 cycloalkyl group, an optionally substituted C _1-6 alkoxy group, an optionally substituted C _1-6 alkylamino group , An optionally substituted di (C _1-6 alkyl) amino group, an optionally substituted C _1-6 alkylthio group, an optionally substituted aryloxy group, an optionally substituted arylthio group, Aryl group which may be substituted, monocyclic heterocyclic group which may be substituted, bicyclic heterocyclic group which may be substituted, amino group which may be protected, protected May A hydroxyl group or an optionally protected carboxyl group;
R ³ is an optionally substituted indanyl group, an optionally substituted indenyl group, an optionally substituted tetrahydronaphthyl group, an optionally substituted dihydronaphthyl group, an optionally substituted benzocyclo group. A heptyl group, an optionally substituted dihydro-5H-benzocycloheptenyl group or an optionally substituted 5H-benzocycloheptenyl group;
R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or an optionally substituted C _{2− A 6} alkynyl group, an optionally substituted C _3-8 cycloalkyl group, an optionally substituted aryl group or an optionally substituted monocyclic heterocyclic group; or
An optionally substituted cyclic amino group formed by R ⁴ and R ⁵ together with the nitrogen atom to which they are attached;
X ¹ is a sulfur atom, a methylene group, or a group represented by the general formula NR ^a , wherein R ^a represents a hydrogen atom, an optionally substituted C _1-6 alkyl group or an imino protecting group. ;
Z ¹ and Z ² are the same or different and are a nitrogen atom or a group represented by the formula CH;
A compound in which Z ³ is a nitrogen atom or a group represented by the general formula CR ^b , wherein R ^b represents a hydrogen atom, a halogen atom or an optionally substituted C _1-6 alkyl group, or The salt was found to have excellent antifungal activity and useful as an antifungal agent, and the present invention was completed.

The compound represented by the general formula [1] or a salt thereof has excellent antifungal activity and is useful as an antifungal agent. In another embodiment, the compound represented by the general formula [1] or a salt thereof is excellent in safety and is useful as an antifungal agent against Candida, Aspergillus, and Trichophyton.

The present invention is described in detail below.
In this specification, unless otherwise stated, each term has the following meaning.
A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
C _1-6 alkyl group means, for example, linear or branched C ₁ such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups. _-6 means an alkyl group.
The C _1-6 alkylene group means a linear or branched C _1-6 alkylene group such as methylene, ethylene, propylene, butylene and hexylene groups.
C _2-6 alkenyl group means, for example, linear or branched C _2-6 alkenyl such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl groups Means a group.
The C _2-6 alkynyl group, for example, ethynyl, propynyl, butynyl, straight or branched C _2-6 alkynyl group such as pentynyl and hexynyl groups.
C _3-8 cycloalkyl group means a C _3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
An aryl group means, for example, a phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, dihydronaphthyl, benzocycloheptyl, dihydro-5H-benzocycloheptenyl or 5H-benzocycloheptenyl group.
The Al _{C 1-6} alkyl group, for example, refers to a benzyl, diphenylmethyl, trityl, Al _{C 1-6} alkyl groups such as phenethyl and naphthylmethyl groups.

C _1-6 alkoxy group means, for example, linear or branched C groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups Means a _1-6 alkyloxy group;
The al C _1-6 alkoxy group means an al C _1-6 alkyloxy group such as benzyloxy, phenethyloxy and naphthylmethyloxy groups.
An aryloxy group means, for example, a phenoxy or naphthyloxy group.
The C _1-6 alkoxy C _1-6 alkyl group means, for example, a C _1-6 alkyloxy C _1-6 alkyl group such as methoxymethyl and 1-ethoxyethyl group.
The ar C _1-6 alkoxy C _1-6 alkyl group means an ar C _1-6 alkyloxy C _1-6 alkyl group such as benzyloxymethyl and phenethyloxymethyl groups.

The C _2-12 alkanoyl group, for example, means acetyl, propionyl, valeryl, a linear or branched C _2-12 alkanoyl group such as isovaleryl and pivaloyl groups.
An aroyl group means, for example, a benzoyl or naphthoyl group.
The heterocyclic carbonyl group means, for example, nicotinoyl, thenoyl, pyrrolidinocarbonyl or furoyl group.
The (α-substituted) aminoacetyl group is, for example, an amino acid (glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine. , Phenylalanine, tyrosine, tryptophan, proline and hydroxyproline and the like.) The N-terminus derived from (α-substituted) aminoacetyl group may be protected.
Acyl group means, for example, 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.

Acyl _{C 1-6} alkyl group, for example, means an acyl _{C 1-6} alkyl group such as acetyl, methyl, benzoyl methyl and 1-benzoyl ethyl.
And acyloxy C _1-6 alkyl group, for example, means acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, a benzoyloxy methyl and 1- acyloxy C _1-6 alkyl group such as (benzoyloxy) ethyl.
C _1-6 alkoxycarbonyl group means, for example, linear or branched C _1-6 such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and 1,1-dimethylpropoxycarbonyl groups. Means an alkyloxycarbonyl group;
The al C _1-6 alkoxycarbonyl group means an al C _1-6 alkyloxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl groups.
An aryloxycarbonyl group means, for example, a phenyloxycarbonyl or naphthyloxycarbonyl group.

The C _1-6 alkylamino group is, for example, a linear or branched group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino and hexylamino groups. It means a branched C _1-6 alkylamino group.
Examples of the di (C _1-6 alkyl) amino group include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di (tert-butyl) amino, dipentylamino, dihexylamino, (ethyl) (methyl) By linear or branched di (C _1-6 alkyl) amino groups such as amino and (methyl) (propyl) amino groups are meant.

The C _1-6 alkylthio group means, for example, a C _1-6 alkylthio group such as methylthio, ethylthio and propylthio groups.
An arylthio group means, for example, a phenylthio or naphthylthio group.
The C _1-6 alkylsulfonyl group means, for example, a C _1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl and propylsulfonyl groups.
An arylsulfonyl group means, for example, a benzenesulfonyl, p-toluenesulfonyl or naphthalenesulfonyl group.
The C _1-6 alkylsulfonyloxy group means a C _1-6 alkylsulfonyloxy group such as methylsulfonyloxy, trifluoromethylsulfonyloxy and ethylsulfonyloxy groups.
The arylsulfonyloxy group means, for example, benzenesulfonyloxy or p-toluenesulfonyloxy group.

A silyl group means, for example, a trimethylsilyl, triethylsilyl or tributylsilyl group.

Monocyclic nitrogen-containing heterocyclic groups include, for example, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, dihydropyrrolyl, piperidyl, tetrahydropyridyl, pyridyl, homopiperidinyl, octahydroazosinyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, It means a monocyclic nitrogen-containing heterocyclic group containing only a nitrogen atom as a hetero atom forming the ring, such as pyrazolyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, homopiperazinyl, triazinyl, triazolyl and tetrazolyl groups.
The monocyclic oxygen-containing heterocyclic group means, for example, a tetrahydrofuranyl, furanyl, tetrahydropyranyl or pyranyl group.
The monocyclic sulfur-containing heterocyclic group means, for example, a thienyl group.
The monocyclic nitrogen-containing / oxygen heterocyclic group is, for example, a monocyclic nitrogen-containing / oxygen containing only a nitrogen atom and an oxygen atom as hetero atoms forming the ring, such as oxazolyl, isoxazolyl, oxadiazolyl and morpholinyl groups. Means a heterocyclic group.
A monocyclic nitrogen-containing / sulfur heterocyclic group forms the ring such as thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxidethiomorpholinyl and 1,1-dioxidethiomorpholinyl groups This means a monocyclic nitrogen-containing / sulfur heterocyclic group containing only nitrogen and sulfur atoms as hetero atoms.
The monocyclic heterocyclic group is a monocyclic nitrogen-containing heterocyclic group, a monocyclic oxygen-containing heterocyclic group, a monocyclic sulfur-containing heterocyclic group, or a monocyclic nitrogen-containing / oxygen heterocyclic group. It means a group or a monocyclic nitrogen-containing / sulfur heterocyclic group.

Bicyclic nitrogen-containing heterocyclic groups include, for example, indolinyl, indolyl, isoindolinyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, tetrahydroquinolinyl, quinolyl, tetrahydroisoquinolinyl, isoquinolinyl, Bicyclic nitrogen-containing heterocyclic groups containing only a nitrogen atom as a hetero atom forming the ring, such as quinolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, purinyl, pteridinyl and quinuclidinyl groups Means.
Examples of the bicyclic oxygen-containing heterocyclic group include 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3- It means a bicyclic oxygen-containing heterocyclic group containing only an oxygen atom as a hetero atom forming the ring, such as benzodioxanyl and 1,4-benzodioxanyl groups.
The bicyclic sulfur-containing heterocyclic group is, for example, a bicyclic sulfur-containing heterocyclic ring containing only a sulfur atom as a hetero atom forming the ring, such as 2,3-dihydrobenzothienyl and benzothienyl groups. Means a formula group.
Bicyclic nitrogen-containing / oxygen heterocyclic groups include, for example, benzoxazolyl, benzisoxazolyl, benzooxadiazolyl, benzomorpholinyl, dihydropyranopyridyl, dihydrodioxynopyridyl and dihydropyridyl. It means a bicyclic nitrogen-containing / oxygen heterocyclic group containing only a nitrogen atom and an oxygen atom as the hetero atoms forming the ring, such as a dooxazinyl group.
Bicyclic nitrogen-containing / sulfur heterocyclic groups are, for example, bicyclic compounds containing nitrogen and sulfur atoms as hetero atoms forming the ring such as benzothiazolyl, benzisothiazolyl and benzothiadiazolyl groups. This means a nitrogen-containing / sulfur heterocyclic group.
A bicyclic heterocyclic group is a bicyclic nitrogen-containing heterocyclic group, a bicyclic oxygen-containing heterocyclic group, a bicyclic sulfur-containing heterocyclic group, or a bicyclic nitrogen-containing group. -An oxygen heterocyclic group or a bicyclic nitrogen-containing / sulfur heterocyclic group.

The heterocyclic group means a monocyclic heterocyclic group or a bicyclic heterocyclic group.

Cyclic amino groups include, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, thiazolinyl, thiazolidinyl, dihydrothiadiazyl, Including one or more nitrogen atoms as a hetero atom forming the ring, such as homomorpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzomorpholinyl, dihydropyridoxazinyl and quinuclidinyl, Means a 3-, 4-, 5-, 6- or 7-membered, fused or bridged cyclic amino group which may contain one or more oxygen or sulfur atoms .

Amino protecting groups and imino protecting groups include all groups that can be used as protecting groups for conventional amino and imino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-926, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, an ar C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, an acyl group, a C _1-6 alkoxycarbonyl group, an ar C _1-6 alkoxycarbonyl group, an aryloxycarbonyl group, Examples thereof include a C _1-6 alkylsulfonyl group, an arylsulfonyl group, and a silyl group.

Hydroxyl protecting groups include all groups that can be used as protecting groups for conventional hydroxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 16-299, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, for example, a C _1-6 alkyl group, a C _2-6 alkenyl group, an ar C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, an ar C _1-6 alkoxy C _{1- 1 6} alkyl group, acyl group, C _1-6 alkoxycarbonyl group, al C _1-6 alkoxycarbonyl group, C _1-6 alkylsulfonyl group, arylsulfonyl group, silyl group, tetrahydrofuranyl group or tetrahydropyranyl group .

The carboxyl protecting group includes all groups that can be used as protecting groups for ordinary carboxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 533-643, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, a C _1-6 alkyl group, a C _2-6 alkenyl group, an aryl group, an ar C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, an ar C _1-6 alkoxy C _{1 Examples} include a _-6 alkyl group, an acyl C _1-6 alkyl group, an acyloxy C _1-6 alkyl group, and a silyl group.

Examples of the leaving group include a halogen atom, a C _1-6 alkylsulfonyloxy group or an arylsulfonyloxy group.

Examples of the aliphatic hydrocarbons include pentane, hexane, cyclohexane, and decahydronaphthalene.
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.
Examples of the esters include methyl acetate, ethyl acetate, propyl acetate, and butyl acetate.
Examples of amides include N, N-dimethylformamide, N, N-dimethylacetamide, and 1-methyl-2-pyrrolidone.
Examples of aromatic hydrocarbons include benzene, toluene, and xylene.

In the present specification, each substituent group has the following meaning.

Substituent group A1:
Halogen atom, a cyano group, a nitro group, one or more C _1-6 alkyl carbamoyl group which may be substituted with a group, optionally substituted with one or more groups selected from Substituent Group A2 C _{1 A -6} alkoxy group, a C _1-6 alkylamino group optionally substituted with one or more groups selected from Substituent Group A2, and a substituent substituted with one or more groups selected from Substituent Group A2 A good di (C _1-6 alkyl) amino group, an aryl group which may be substituted with one or more groups selected from Substituent Group B1, and one or more groups selected from Substituent Group B1 A monocyclic heterocyclic group which may be substituted, a bicyclic heterocyclic group which may be substituted with one or more groups selected from substituent group B1, an amino group which may be protected, a protected group Optionally imino groups, optionally protected hydro A xyl group, an optionally protected carboxyl group.

Substituent group A2:
A halogen atom, a cyano group, a carbamoyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, an optionally protected amino group, an optionally protected hydroxyl group, and an optionally protected carboxyl group;

Substituent group B1:
A halogen atom, a cyano group, a nitro group, an oxo group, a carbamoyl group that may be substituted with one or more C _1-6 alkyl groups, and a substituent that is substituted with one or more groups selected from Substituent Group A2. A C _1-6 alkyl group, which may be substituted with one or more groups selected from the substituent group A2, and a C _1-6 alkoxy group which may be substituted with one or more groups selected from the substituent group A2. An _optionally substituted C _1-6 alkylamino group, a di (C _1-6 alkyl) amino group _optionally substituted with one or more groups selected from Substituent Group A2, an optionally protected amino group, An imino group which may be protected, a hydroxyl group which may be protected, a carboxyl group which may be protected.

Substituent group C1:
A halogen atom, a cyano group, a nitro group, an oxo group, a carbamoyl group that may be substituted with one or more C _1-6 alkyl groups, and a substituent that is substituted with one or more groups selected from Substituent Group A2. A C _1-6 alkyl group, a C _2-6 alkenyl group optionally substituted with one or more groups selected from Substituent Group A2, and one or more groups selected from Substituent Group A2 A C _2-6 alkynyl group which may be optionally substituted with one or more groups selected from substituent group A2, and a C _1-6 alkoxy group which may be substituted with one or more groups selected from substituent group A2. A C _1-6 alkylamino group which may be substituted, a di (C _1-6 alkyl) amino group which may be substituted with one or more groups selected from the substituent group A2, and a substituent group A2. C optionally substituted with one or more groups _1-6 alkylthio group, C _3-8 cycloalkyl group optionally substituted with one or more groups selected from substituent group C2, substituted with one or more groups selected from substituent group C2 Or an aroyl group, an al C _1-6 alkyl group which may be substituted with one or more groups selected from substituent group C2, and one or more groups selected from substituent group C2. A good aryloxy group, an arylthio group which may be substituted with one or more groups selected from substituent group C2, an aryl group which may be substituted with one or more groups selected from substituent group C2, A monocyclic heterocyclic group which may be substituted with one or more groups selected from group C2, and a bicyclic complex which may be substituted with one or more groups selected from substituent group C2. Cyclic groups, optionally protected amino groups, Which may be an imino group, a protected or unprotected hydroxyl groups, protected or unprotected carboxyl group.

Substituent group C2:
Substituted with one or more groups selected from a halogen atom, a cyano group, a nitro group, an oxo group, an adamantyl group, a carbamoyl group optionally substituted with one or more C _1-6 alkyl groups, and substituent group A2. An optionally substituted C _1-6 alkylsulfonyl group, one or more groups selected from substituent group A2 and a C _2-12 alkanoyl group optionally substituted by one or more groups selected from substituent group A2. A C _1-6 alkyl group which may be substituted with one or more, a C _2-6 alkenyl group which may be substituted with one or more groups selected from substituent group A2, and one or more selected from substituent group A2 A C _2-6 alkynyl group which may be substituted with one group, a C _1-6 alkoxy group which may be substituted with one or more groups selected from substituent group A2, and a group selected from substituent group A2 Substituted with two or more groups A C _1-6 alkylamino group which may be _optionally substituted with one or more groups selected from substituent group A2, and a di (C _1-6 alkyl) amino group which may be substituted with 1 or more groups selected from substituent group A2. A C _1-6 alkylthio group which may be substituted with one or more groups, a C _3-8 cycloalkyl group which may be substituted with one or more groups selected from substituent group B1, and a substituent group B1 An aryloxy group optionally substituted with one or more selected groups, an arylthio group optionally substituted with one or more groups selected from substituent group B1, and one or more selected from substituent group B1 An aryl group which may be substituted with the above group, an al C _1-6 alkoxy group which may be substituted with one or more groups selected from substituent group B1, and one or more groups selected from substituent group B1 Monocyclic optionally substituted with groups A cyclic group, a bicyclic heterocyclic group optionally substituted with one or more groups selected from substituent group B1, an amino group which may be protected, an imino group which may be protected A hydroxyl group which may be protected, a carboxyl group which may be protected.

Substituent group D1:
A halogen atom, a cyano group, a nitro group, an oxo group, a carbamoyl group that may be substituted with one or more C _1-6 alkyl groups, and a substituent that is substituted with one or more groups selected from Substituent Group A2. A C _1-6 alkyl group, a C _2-6 alkenyl group optionally substituted with one or more groups selected from Substituent Group A2, and one or more groups selected from Substituent Group A2 A C _2-6 alkynyl group which may be optionally substituted with one or more groups selected from substituent group A2, and a C _1-6 alkoxy group which may be substituted with one or more groups selected from substituent group A2. A C _1-6 alkylamino group which may be substituted, a di (C _1-6 alkyl) amino group which may be substituted with one or more groups selected from substituent group A2, and a substituent group B1 C optionally substituted with one or more groups _3-8 cycloalkyl group, amino group which may be protected, imino group which may be protected, hydroxyl group which may be protected, carboxyl group which may be protected.

C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxy group, C _1-6 alkylamino group, di (C _1-6 alkyl) of R ¹ and R ² The amino group and the C _1-6 alkylthio group may be substituted with one or more groups selected from the substituent group A1.
The C _3-8 cycloalkyl group, aryloxy group, arylthio group, aryl group, monocyclic heterocyclic group and bicyclic heterocyclic group represented by R ¹ and R ² are selected from the substituent group B1. It may be substituted with more than one group.

R ³ dihydrobenzocyclobutenyl, indanyl, indenyl, tetrahydronaphthyl, dihydronaphthyl, benzocycloheptyl, dihydro-5H-benzocycloheptenyl, 5H-benzocycloheptenyl, hexahydrobenzo The cyclooctenyl group, tetrahydrobenzocyclooctenyl group, dihydrobenzocyclooctenyl group, tetrahydromethanonaphthyl group and tetrahydroethanonaphthyl group may be substituted with one or more groups selected from the substituent group C1.

The C _1-6 alkyl group, C _2-6 alkenyl group and C _2-6 alkynyl group of R ⁴ and R ⁵ may be substituted with one or more groups selected from the substituent group A1.
The C _3-8 cycloalkyl group, aryl group and monocyclic heterocyclic group of R ⁴ and R ⁵ may be substituted with one or more groups selected from substituent group B1.
The cyclic amino group of R ⁴ and R ⁵ may be substituted with one or more groups selected from the substituent group D1.

The C _1-6 alkyl group of R ^a may be substituted with one or more groups selected from Substituent Group A1.

The C _1-6 alkyl group of R ^b may be substituted with one or more groups selected from Substituent Group A1.

A C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-6 alkoxy group, a C _1-6 alkylamino group, a di (C _1-6 alkyl) amino group of R ^c and The C _1-6 alkylthio group may be substituted with one or more groups selected from Substituent Group A1.
The C _3-8 cycloalkyl group, aryloxy group, arylthio group, aryl group, monocyclic heterocyclic group and bicyclic heterocyclic group of R ^c are one or more selected from the substituent group B1. It may be substituted with a group.

In the compound of the general formula [1] of the present invention, preferable compounds include the following compounds.

R ¹ and R ² are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or a substituted The compound is an optionally substituted C _2-6 alkynyl group, an optionally substituted C _3-8 cycloalkyl group, an optionally substituted C _1-6 alkoxy group or an optionally substituted aryl group. Compounds are preferred.
R ¹ and R ² are the same or different and are each a halogen atom, a cyano group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or an optionally substituted A compound that is a compound having a C _2-6 alkynyl group, an optionally substituted C _3-8 cycloalkyl group, or an optionally substituted C _1-6 alkoxy group is more preferable.
More preferred is a compound wherein R ¹ and R ² are the same or different and each is a halogen atom, an optionally substituted C _1-6 alkyl group or an optionally substituted C _3-8 cycloalkyl group.
R ¹ and R ² may be the same or different and each may be a halogen atom, a cyano group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-8 cycloalkyl group or an optionally substituted More preferred are compounds that are good C _1-6 alkoxy groups.
R ¹ and R ² are the same or different and each is a halogen atom, a C _1-6 alkyl group which may be substituted with one or more halogen atoms, or C ₃ which may be substituted with one or more halogen atoms _Even more preferred are compounds that are _-8 cycloalkyl groups.

R ³ is an optionally substituted dihydrobenzocyclobutenyl group, an optionally substituted indanyl group, an optionally substituted tetrahydronaphthyl group, an optionally substituted benzocycloheptyl group, a substituted A compound which is an optionally substituted hexahydrobenzocyclooctenyl group or an optionally substituted tetrahydromethanonaphthyl group is preferred.
A compound in which R ³ is an optionally substituted indanyl group, an optionally substituted tetrahydronaphthyl group or an optionally substituted benzocycloheptyl group is more preferable.
In another embodiment, R ³ is represented by the general formula [X]

"Wherein R ⁶ is the same or different and is a group selected from substituent group C1; R ⁷ is the same or different and is a group selected from substituent group C1; n is an integer of 2 to 6 M1 represents an integer of 0 to 10; m2 represents an integer of 0 to 3. ”is more preferable.

m 1 R ^{6 s} are the same or different and each is a halogen atom, a C _1-6 alkyl group which may be substituted with one or more groups selected from Substituent Group A2, or one selected from Substituent Group A2 A compound which is a C _1-6 alkoxy group which may be substituted with the above groups is preferred.
A compound in which m1 R ^{6 s} are the same or different and each is a halogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group is more preferable.
m1 pieces of ^{R 6} are the same or _different, compounds which are _{C 1-6} alkyl group is more preferred.

m2 R ^{7 s} are the same or different and each is a halogen atom, a C _1-6 alkyl group which may be substituted with one or more groups selected from Substituent Group A2, or one selected from Substituent Group A2 A compound which is a C _1-6 alkoxy group which may be substituted with the above groups is preferred.
A compound in which m 2 R ^{7 s} are the same or different and each is a halogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group is more preferable.

A compound in which m1 represents an integer of 0 to 4 is preferable.
A compound in which m1 represents an integer of 0 to 2 is more preferable.

A compound in which m2 is 0 or 1 is preferable.
A compound in which m2 is 0 is more preferable.

Compounds in which n is 3, 4 or 5 are preferred.
A compound in which n is 3 or 4 is more preferable.
More preferred are compounds wherein n is 3.

R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or an optionally substituted C _{2− A} compound which is a ₆ alkynyl group or an optionally substituted C _3-8 cycloalkyl group is preferred.
A compound in which R ⁴ and R ⁵ are the same or different and each is a C _1-6 alkyl group which may be substituted with a hydrogen atom or one or more groups selected from substituent group A1 is more preferable.
More preferred are compounds in which R ⁴ and R ⁵ are the same or different and are a hydrogen atom or a C _1-6 alkyl group.

A compound in which X ¹ is a C _1-6 alkylene group or a group represented by the general formula NR ^a , wherein R ^a has the same meaning as described above is preferable.
More preferred is a compound in which X ¹ is a methylene group or a group represented by the general formula NR ^a1 , wherein R ^a1 represents a hydrogen atom or an imino protecting group.
A compound in which X ¹ is a methylene group is more preferable.

A compound in which Z ¹ and Z ² are the same or different and is a group represented by the general formula CR ^c "wherein R ^c has the same meaning as described above" is preferable.
Z ¹ and Z ² may be the same or different and have the general formula CR ^c1 , wherein R ^c1 is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C _1-6 alkyl group, a substituted An optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _3-8 cycloalkyl group, an optionally substituted C _1-6 alkoxy group or a substituted group The aryl group which may be made is a group represented by "is more preferable.
Z ¹ and Z ² are the same or different and have the general formula CR ^c2 "wherein R ^c2 is a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group or an optionally substituted C 1 _A compound represented by the formula “ _3-8 cycloalkyl group” is more preferred.
Z ¹ and Z ² are the same or different and have the general formula CR ^c3 , wherein R ^c3 is a hydrogen atom, a halogen atom, a C _1-6 alkyl group which may be substituted with one or more halogen atoms, or A compound having a group represented by “denotes a C _3-8 cycloalkyl group which may be substituted with one or more halogen atoms” is even more preferable.
Most preferred are compounds wherein Z ¹ and Z ² are groups represented by the formula CH.

A compound in which Z ³ is a group represented by the general formula CR ^b "wherein R ^b has the same meaning as described above" is preferable.
A compound in which Z ³ is a group represented by the formula CH is more preferable.

As another aspect, in the compound of the general formula [1] of the present invention, preferable compounds include the following compounds.
R ^1, ^R 2, two of ^{Z 1} of ^{R c} and ^{Z 2} of ^{R c} are the same or different, a halogen atom, a cyano group, an optionally substituted _{C 1-6} alkyl group, optionally substituted A compound having an optionally substituted C _3-8 cycloalkyl group or an optionally substituted C _1-6 alkoxy group, and the other two being a hydrogen atom is preferable.
R ^1, ^R 2, two of ^{Z 1} of ^{R c} and ^{Z 2} of ^{R c} are the same or different, substituted is also _{C 1-6} alkyl group, the other two are hydrogen atom The compound which is is more preferable.
R ¹ and ^{R 2} are the same or _different, a _{C 1-6} alkyl group, ^{R c} and ^{Z 2} of ^{R c} of ^{Z 1} is, compounds and more preferably a hydrogen atom.

As another aspect, in the compound of the general formula [1] of the present invention, preferable compounds include the following compounds.
N ′-(5-Bromo-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl)- N-ethyl-N-methylimidoformamide, N ′-(5-cyclopropyl-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3- Thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide, N ′-(2,5-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalene-2) -Yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-methylimidoformamide, N ′-(2,5-dimethyl-4-((4- (5,6,7,8- Tetrahydronaphthalen-2-yl) -1,3-thiazole- 2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide, N ′-(2,5-dimethyl-4-((5-methyl-4- (5,6,7,8-tetrahydronaphthalene) -2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide, N ′-(4-((4- (indan-5-yl) -1 , 3-thiazol-2-yl) methyl) -2,5-dimethylphenyl) -N-ethyl-N-methylimidoformamide, N ′-(2,5-dimethyl-4-((4- (benzocycloheptane -2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide, N ′-(2,5-dimethyl-4-((4- (5 6,7,8-tetrahydronaphthalene-2- Yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-methyl-N- (propan-2-yl) imidoformamide, N ′-(5-chloro-2-methyl-4-(( 4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide, N ′-(5- (Difluoromethoxy) -2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl -N-methylimidoformamide, N-ethyl-N '-(5-methoxy-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3- Thiazol-2-yl) methyl) phenyl -N-methylimidoformamide, N-ethyl-N-methyl-N '-(2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3- Thiazol-2-yl) methyl) -5- (trifluoromethyl) phenyl) imidoformamide, N-ethyl-N ′-(5-ethynyl-2-methyl-4-((4- (5,6,7, 8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-methylimidoformamide, N-ethyl-N-methyl-N ′-(2-methyl-5- ( Propan-2-yl) -4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) imidoformamide, N′- (5- (difluoromethyl)- -Methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide N ′-(2,5-dimethyl-4-((4- (1,2,3,4-tetrahydro-1,4-methanonaphthalen-6-yl) -1,3-thiazol-2-yl) Methyl) phenyl) -N-ethyl-N-methylimidoformamide, N ′-(2,5-dimethyl-4-((4- (2-methyl-2,3-dihydro-1H-inden-5-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide, N ′-(4-((4- (2,2-dimethyl-2,3-dihydro-1H -Inden-5-yl) -1,3-thiazole-2- L) methyl) -2,5-dimethylphenyl) -N-ethyl-N-methylimidoformamide, N ′-(4-((4- (bicyclo [4.2.0] octa-1,3,5- Trien-3-yl) -1,3-thiazol-2-yl) methyl) -2,5-dimethylphenyl) -N-ethyl-N-methylimidoformamide, N-ethyl-N ′-(4-(( 4- (5,6,7,8,9,10-hexahydrobenzo [8] annulen-2-yl) -1,3-thiazol-2-yl) methyl) -2,5-dimethylphenyl) -N -Methylimidoformamide.

An antifungal agent means a substance capable of acting on a pathogenic fungus and suppressing or sterilizing its growth. It may be something that suppresses fungal growth or kills some fungi to reduce their number.

Examples of pathogenic fungi include yeast-like fungi, filamentous fungi, and zygomycetes. Examples of yeast-like fungi include Candida (Candida albicans, Candida glabrata, Candida giermondii, Candida crusei, Candida parapsilosis, Candida tropicalis, etc.), Cryptococcus genus (such as Cryptococcus neoformans), Examples include the genus Malassezia (such as Malassezia fullfur) and the genus Trichosporon (such as Trichosporon and Asahi). As the filamentous fungi, for example, Aspergillus (Aspergillus fumigatus, Aspergillus tereus, Aspergillus niger, Aspergillus flavus, etc.) , Genus Fusarium (such as Fusarium solani), genus Schedosporum (such as skedosporum apiospermum) and genus Microsporium (such as Microsporum canis). Examples of the zygomycete include the genus Mucor (Mucor plum plumus, etc.), the genus Rhizopus (such as Rhizopus oryzae), and the genus Absidia (such as Absidia cholinebifera).
The antifungal agent of the present invention exhibits an excellent antifungal action against bacterial species such as Candida, Aspergillus and ringworm, and more excellent antifungal action against ringworm .
In another aspect, the antifungal agent of the present invention is a bacterial species such as Candida albicans, Aspergillus fumigatus, Trichophyton rubulum, Trichophyton mentagrophytes, Malassezia furfur, and Cryptococcus neoformans. Excellent antifungal activity.

The compound represented by the general formula [1] or a salt thereof exhibits excellent safety. Safety is evaluated by various tests, for example, cytotoxicity test, hERG test, repeated dose toxicity test, cytochrome P450 (CYP) activity inhibition test, metabolism-dependent inhibition test, in vivo mouse micronucleus It can be evaluated by various safety tests selected from a test and an in vivo rat liver UDS test.

Examples of the salt of the compound represented by the general formula [1] include a salt of a commonly known basic group such as amino group or acidic group such as hydroxyl or carboxyl group.

Examples of salts in basic groups 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 Is mentioned.

Salts in acidic groups include, for example, 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.

In the compound of the general formula [1] or a salt thereof, when isomers (for example, optical isomers, geometric isomers, tautomers, etc.) exist, the present invention includes those isomers, It includes solvates, hydrates and crystals of various shapes.

Next, the manufacturing method of this invention compound is demonstrated.
The compound of the present invention is produced by combining methods known per se, and can be produced, for example, according to the production method shown below.

[Production Method 1]

“Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , Z ¹ , Z ² and Z ³ have the same meaning as described above.

N-ethyl-N-methylformamide, N-methylformamide, and the like are known as compounds of the general formula [3].
The compound of the general formula [1] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [3] in the presence of an activator.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides , Aromatic hydrocarbons and water, and these may be used as a mixture. Preferable solvents include halogenated hydrocarbons.
Examples of the activator used in this reaction include oxalyl chloride, phosphoryl chloride and p-toluenesulfonyl chloride.
The amount of the activator used may be 1 to 20 times mol, preferably 1 to 5 times mol, of the compound of the general formula [2].
The amount of the compound of the general formula [3] used may be 1 to 20 times mol, preferably 1 to 5 times mol for the compound of the general formula [2].
This reaction may be carried out at −50 to 200 ° C., preferably 0 to 50 ° C., for 10 minutes to 48 hours.

[Production Method 2]

“Wherein L ¹ represents a leaving group; R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^b , X ¹ , Z ¹ and Z ² have the same meaning as described above.

Compounds of general formula [5] include 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone and 2-bromo-1- (2,3-dihydro-1H-indene- 5-yl) ethanone is known.
The compound of the general formula [1a] can be produced by reacting the compound of the general formula [4] with the compound of the general formula [5].
This reaction may be carried out by the method described in International Publication No. 05/115382 pamphlet and US Patent No. 20060052420 or a method based thereon.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides , Aromatic hydrocarbons and water, and these may be used as a mixture. Preferred solvents include alcohols.
The amount of the compound of the general formula [5] used may be 1 to 20 times mol, preferably 1 to 5 times mol for the compound of the general formula [4].
This reaction may be carried out at −50 to 200 ° C., preferably 0 to 150 ° C., for 10 minutes to 48 hours.

The thus obtained compounds of the general formulas [1a] and [1] or salts thereof are known per se such as, for example, condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis. By subjecting to a reaction or by appropriately combining these reactions, it can be derived into other compounds of the general formula [1] or salts thereof.

Next, a method for producing a raw material for producing the compound of the present invention will be described.

[Production method A]

“Wherein R ¹ , R ² , R ³ , R ^b , L ¹ , X ¹ , Z ¹ and Z ² have the same meaning as described above.

(A-1)
The compound of the general formula [Ab] can be produced by reacting the compound of the general formula [Aa] with dithiophosphoric acid O, O′-diethyl or the like in the presence of an acid.
This reaction is the method described in WO 06/137658 and the Journal of Medicinal Chemistry, 1990, Vol. 33, p.2715-2720, or a similar method. Just do it.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides , Aromatic hydrocarbons and water, and these may be used as a mixture. Preferable solvents include esters.
Examples of acids used in this reaction include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrogen chloride and hydrogen bromide; organic carboxylic acids such as acetic acid, trichloroacetic acid and trifluoroacetic acid; and methanesulfonic acid and Examples thereof include organic sulfonic acids such as p-toluenesulfonic acid. A preferred acid is hydrogen chloride.
The amount of the acid used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [Aa].
The amount of dithiophosphoric acid O, O′-diethyl used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of general formula [Aa].
This reaction may be carried out at −50 to 200 ° C., preferably 0 to 50 ° C., for 10 minutes to 48 hours.

(A-2)
The compound of general formula [Ac] can be manufactured according to the manufacturing method 2.

(A-3)
The compound of the general formula [2a] can be produced by reducing the compound of the general formula [Ac]. This reaction was performed by Richard C. Richard C. Larock et al., Comprehensive Organic Transformations, 2nd edition, pages 823-827, 1999, John Wiley & Sons , INC.) Or a method similar thereto. Specific examples include a catalytic hydrogenation reaction using a metal catalyst and a reduction reaction using a metal such as iron or zinc.

When the compound of the general formula [Ac] is subjected to a catalytic hydrogenation reaction, the solvent used is not particularly limited as long as it does not adversely affect the reaction. For example, water, halogenated hydrocarbons, alcohols , Ethers, ketones, esters, amides, aromatic hydrocarbons, nitriles such as acetonitrile, carboxylic acids such as acetic acid, heteroaromatics such as pyridine, and water, which are used as a mixture May be.
Examples of the metal catalyst used in this reaction include palladium metal such as palladium-carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; nickel metal such as Raney nickel; and platinum salts such as platinum oxide. Can be mentioned. The amount of the metal catalyst used may be 0.001 to 5 times (w / w), preferably 0.01 to 1 times (w / w) of the compound of the general formula [Ac].
Examples of the hydrogen source include hydrogen; formic acid; formate salts such as sodium formate, ammonium formate and triethylammonium formate; cyclohexene; and cyclohexadiene. The amount of the hydrogen source used may be 2 to 100 times mol, preferably 2 to 10 times mol, of the compound of the general formula [Ac].
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C. for 1 minute to 24 hours.

When the compound of the general formula [Ac] is subjected to a reduction reaction using a metal, the solvent used is not particularly limited as long as it does not adversely affect the reaction, but water, halogenated hydrocarbons, alcohols, Examples include ethers, ketones, esters, amides, aromatic hydrocarbons, nitriles such as acetonitrile, and water, and these may be used as a mixture.
Examples of the metal used in this reaction include iron, zinc, tin, and tin (II) chloride. The amount of the metal used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound of the general formula [Ac].
Examples of the acid that is optionally used in this reaction include hydrogen chloride, hydrogen bromide, acetic acid, and ammonium chloride. The amount of the acid used may be 0.001 to 100 times (v / w), preferably 0.01 to 20 times (v / w) of the compound of the general formula [Ac].
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C. for 1 minute to 24 hours.

[Production method B]

“Wherein R ¹ , R ² , R ⁴ , R ⁵ , X ¹ , Z ¹ and Z ² have the same meaning as described above.

(B-1)
The compound of the general formula [Ba] can be produced according to production method A-3.

(B-2)
The compound of general formula [Bb] can be manufactured according to the manufacturing method 1.

(B-3)
The compound of the general formula [4a] can be produced according to production method A-1.

[Production Method C]

“Wherein R ^d represents an amino group which may be protected; R ¹ , R ² , R ^b , L ¹ , X ¹ , Z ¹ and Z ² have the same meaning as described above.

(C-1)
The compound of the general formula [Cb] can be produced according to production method A-1.

(C-2)
The compound of the general formula [Cc] can be produced according to Production Method 2.

(C-3)
When R ^d is a protected amino group, the compound of the general formula [2a] can be produced by deprotecting the amino protecting group of the compound of the general formula [Cc].
Deprotection of amino protecting groups is described, for example, in W.W. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-868, 2007, John Wiley & Sons (John Wiley & Sons, INC.).

[Production Method D]

“Wherein L ² represents a leaving group or an arylthio group; R ¹ , R ² , Z ¹ and Z ² have the same meaning as described above.

As compounds of the general formula [Da], 1,4-dimethyl-2-nitrobenzene, 4-bromo-1-methyl-2-nitrobenzene and the like are known.
As compounds of the general formula [Db], chloroacetonitrile, (phenylthio) acetonitrile, 4-chlorophenoxyacetonitrile, 2-((cyanomethyl) sulfanyl) benzoic acid and the like are known.
The compound of the general formula [Aaa] can be produced by reacting the compound of the general formula [Da] with the compound of the general formula [Db] in the presence of a base.
This reaction is carried out by a method described in US 2003229130 and The Journal of Organic Chemistry, 1984, Vol. 49, p. Just do it.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides , Aromatic hydrocarbons, sulfoxides such as dimethyl sulfoxide and water, and these may be used as a mixture. A preferred solvent is dimethyl sulfoxide.
Examples of the base used in this reaction include organic bases such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, pyridine, dimethylaminopyridine and triethylamine; sodium hydride, sodium hydroxide, potassium hydroxide, Examples thereof include inorganic bases such as sodium hydrogen carbonate, potassium carbonate and sodium carbonate. Preferred bases include sodium hydroxide and potassium hydroxide.
The amount of the base used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound of the general formula [Da].
The amount of the compound of the general formula [Db] used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [Da].
This reaction may be carried out at −50 to 200 ° C., preferably 0 to 50 ° C., for 10 minutes to 48 hours.

[Production Method E]

“Wherein L ³ represents a leaving group; R ¹ , R ² , R ^d , Z ¹ and Z ² have the same meaning as described above.

(E-1)
As compounds of general formula [Ea], N- (4-iodo-2,5-dimethylphenyl) acetamide, (4-iodo-2,5-dimethylphenyl) amine and N- (4-bromo-2,5- Dimethylphenyl) acetamide and the like are known.
The compound of the general formula [Eb] is produced by reacting the compound of the general formula [Ea] with acrylonitrile in the presence or absence of a base, in the presence or absence of a ligand, and in the presence of a palladium catalyst. Can do.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides, aromatic hydrocarbons. Nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide, and water, and these may be used as a mixture.
Examples of the base optionally used in this reaction include inorganic bases such as sodium hydride, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate; sodium acetate, potassium acetate, sodium = tert-butoxide And organic bases such as triethylamine, diisopropylethylamine, tributylamine and N, N-dicyclohexylmethylamine.
The amount of the base used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [Ea].

The ligands optionally used in this reaction include trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphine such as triphenylphosphine and tritolylphosphine Trialkyl phosphites such as trimethyl phosphite, triethyl phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; triaryl phosphites such as triphenyl phosphite; 1,3- Imidazolium salts such as bis (2,4,6-trimethylphenyl) imidazolium chloride; acetylacetone and octafluoroacetylacetate Diketones such as trimethylamine, triethylamine, tripropylamine and triisopropylamine; 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1 '-Binaphthyl, 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, 2- (di-tert-butylphosphino)- Examples thereof include 2 ′, 4 ′, 6′-triisopropylbiphenyl and 2- (di-tert-butylphosphino) biphenyl, and these may be used in combination.
The amount of the ligand used may be 0.00001 to 1-fold mol, preferably 0.001 to 0.1-fold mol based on the compound of the general formula [Ea].

Examples of the palladium catalyst used in this reaction include metal palladium such as palladium-carbon and palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine) palladium (0), Bis (tri-tert-butylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride, (E) -di ( μ-Acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium (II) and tris (dibenzylideneacetone) dipalladium (0) (II And polymer supported di (acetato) such as a polymer immobilized organopalladium complex such as dicyclohexylphenylphosphine palladium (II) and the like, may be used these in combination.
The amount of the palladium catalyst used may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol for the compound of the general formula [Ea].

The amount of acrylonitrile used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of general formula [Ea].
This reaction is preferably carried out at 40 to 170 ° C. for 1 minute to 24 hours in an inert gas (eg, nitrogen, argon) atmosphere.

(E-2)
The compound of the general formula [Caa] can be produced by reducing the compound of the general formula [Eb].
Examples of the reduction reaction include a catalytic hydrogenation reaction using a metal catalyst.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides, aromatic hydrocarbons. , Nitriles such as acetonitrile, carboxylic acids such as acetic acid, heteroaromatics such as pyridine and water, and these may be used as a mixture.
Examples of the metal catalyst used in this reaction include palladium metal such as palladium-carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; nickel metals such as Raney nickel and platinum salts such as platinum oxide. It is done. The amount of the metal catalyst used may be 0.001 to 5 times (w / w), preferably 0.01 to 1 times (w / w) of the compound of the general formula [Eb].
Examples of the reducing agent include hydrogen; formic acid; formate salts such as sodium formate, ammonium formate and triethylammonium formate; cyclohexene and cyclohexadiene. The amount of the reducing agent used may be 2 to 100 times mol, preferably 2 to 10 times mol, of the compound of the general formula [Eb].
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C. for 1 minute to 24 hours.

[Production Method F]

“Wherein R ^e represents an optionally substituted C _1-6 alkyl group or an optionally substituted C _2-6 alkenyl group; R ¹ , R ² , R ^d , L ³ , Z ¹ and Z ² has the same meaning as described above.

(F-1)
As a compound of the general formula [Fa], ethyl cyanoacetate or methyl cyanoacetate is known.
The compound of the general formula [Fb] is produced by reacting the compound of the general formula [Ea] with the compound of the general formula [Fa] in the presence of a base, in the presence or absence of a ligand, and in the presence of a palladium catalyst. can do.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides, aromatic hydrocarbons. Nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide, and water, and 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 and tripotassium phosphate; organic bases such as triethylamine and diisopropylethylamine. The amount of the base used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [Ea].

The ligands optionally used in this reaction include trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphine such as triphenylphosphine and tritolylphosphine Trialkyl phosphites such as trimethyl phosphite, triethyl phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; triaryl phosphites such as triphenyl phosphite; 1,3- Imidazolium salts such as bis (2,4,6-trimethylphenyl) imidazolium chloride; acetylacetone and octafluoroacetylacetate Diketones such as trimethylamine, triethylamine, tripropylamine and triisopropylamine; 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1 '-Binaphthyl, 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, 2- (di-tert-butylphosphino)- Examples include 2 ', 4', 6'-triisopropylbiphenyl, 2- (di-tert-butylphosphino) biphenyl, and tri-tert-butylphosphonium tetrafluoroborate, which may be used in combination. .
The amount of the ligand used may be 0.00001 to 1-fold mol, preferably 0.001 to 0.1-fold mol based on the compound of the general formula [Ea].

Examples of the palladium catalyst used in this reaction include metal palladium such as palladium-carbon and palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine) palladium (0), Bis (tri-tert-butylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride and tris (dibenzylideneacetone) Organopalladium complexes such as dipalladium (0) and polymer-supported bis (acetate) triphenylphosphine palladium (II) and polymer-supported di (acetate) dicyclohexylphenylphosphine palladium (II) A mer-immobilized organic palladium complex may be used, and these may be used in combination.
The amount of the palladium catalyst used may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol for the compound of the general formula [Ea].

The amount of the compound of the general formula [Fa] used may be 1 to 50 times mol, preferably 1 to 2 times mol for the compound of the general formula [Ea].
This reaction is preferably carried out at 40 to 170 ° C. for 1 minute to 96 hours in an inert gas (eg, nitrogen, argon) atmosphere.

(F-2)
The compound of the general formula [Cab] can be produced by subjecting the compound of the general formula [Fb] to a decarboxylation reaction.
This reaction is carried out by a method known per se, for example, the method described in New Experimental Chemistry Course, Vol. 15, [II], edited by The Chemical Society of Japan, pages 808-811 (1977, Maruzen) or a method analogous thereto. Just do it.

In the compounds used in the above production method, a compound that can take the form of a salt can also be used as a salt. Examples of such salts include the same salts as the salts of the compound of the general formula [1].

In the compounds used in the above production method, when there are isomers (for example, optical isomers, geometric isomers, tautomers, etc.), these isomers can also be used. Also, when solvates, hydrates and crystals of various shapes are present, these solvates, hydrates and crystals of various shapes can also be used.

In addition, in the compounds used in the above-described production method, a compound having a substituent that can be protected, such as an amino group, a hydroxyl group, or a carboxyl group, is previously protected with a normal protecting group. In addition, after the reaction, these protecting groups can be removed by a method known per se.

When the compound of the general formula [1] of the present invention is used as a medicine, formulation adjuvants such as excipients, carriers and diluents usually used for formulation may be appropriately mixed. These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, It can be administered orally or parenterally in the form of a patch, ointment or injection. In addition, the administration method, the dosage, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. In general, for adults, oral administration or parenteral administration (for example, injection, infusion, administration to the rectal site, etc.), 0.01 to 1000 mg / kg daily may be divided into 1 to several doses. Good.

Next, the usefulness of the representative compounds of the present invention will be explained by the following test examples.

Test Example The susceptibility test of fungi to the test substance was performed by a micro liquid dilution method according to the Clinical and Laboratory Standards Institute method. The microplate was prepared by the following method.
The medium used for the sensitivity test was RPMI1640 (RPMI / MOPS) adjusted to pH 7.0 with 0.165 mol / L morpholinepropanesulfonic acid (MOPS) and 50% sodium hydroxide. The test substance was dissolved in DMSO, diluted 2-fold serially with DMSO on a 96-well microplate, and then dispensed at 1 μL into a 96-well microplate. Candida albicans TIMM 1623 cultured overnight at 35 ° C. on a Sabouraud agar medium was suspended in sterile physiological saline. The number of cells was counted with a biological microscope, and the bacterial suspension was diluted with RPMI / MOPS to prepare an inoculated bacterial solution (about 1 × 10 ³ cells / mL). Alternatively, C. albicans TIMM 1623 stored at −80 ° C. was diluted with RPMI / MOPS to prepare an inoculum (about 1 × 10 ³ CFU / mL). Aspergillus fumigatus TIMM 0063 stored at 5 ° C. was diluted with RPMI / MOPS to prepare an inoculum (about 1 × 10 ⁴ CFU / mL). Trichophyton rubrum NBRC 5467 stored at −80 ° C. was diluted with RPMI / MOPS to prepare an inoculum (about 2 × 10 ³ CFU / mL). 199 μL of the inoculum solution was dispensed into each well to prepare a microplate containing a predetermined concentration of the test substance, medium and cells.
C. albicans and A. fumigatus were cultured at 35 ° C. for 2 days. T. rubrum was cultured at 35 ° C for 4 days. After completion of the culture, the MIC was visually determined. The MIC of C. albicans and A. fumigatus was the lowest concentration at which about 50% growth inhibition was observed compared to the growth control without addition of the test substance. The MIC of T. rubrum was set to the lowest concentration at which about 80% growth inhibition was observed compared to the growth control with no test substance added. The results are shown in Tables 1 to 3.

Next, the present invention will be described with reference examples and examples, but the present invention is not limited thereto.

Unless otherwise specified, the carrier in silica gel column chromatography is Kanto Chemical Co., Inc., silica gel 60 (spherical, 63-210 μm); the carrier in DIOL type silica gel chromatography is Chromatrex DIOL MB 100- manufactured by Fuji Silysia Chemical Ltd. 75/200; The carrier in DNH silica gel chromatography is Chromatrex DNHDMB 100-75 / 200 (110 μm) manufactured by Fuji Silysia Chemical Ltd.

The mixing ratio in the eluent is a volume ratio.

In each example, each abbreviation has the following meaning.
DMSO: dimethyl sulfoxide DMSO-d ₆ : heavy dimethyl sulfoxide s: singlet d: doublet dd: double doublet m: multiplet

Reference example 1

Under a nitrogen atmosphere, a solution of 4.6 mL of (phenylthio) acetonitrile in 26 mL of dimethyl sulfoxide was added dropwise at 30 ° C. or lower to a mixture of 10.4 g of sodium hydroxide, 5.5 g of 4-bromo-1-methyl-2-nitrobenzene and 26 mL of dimethyl sulfoxide. For 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 90: 10-50: 50], diisopropyl ether was added, and the solid was collected by filtration to give a green solid (2-bromo 2.5 g of -5-methyl-4-nitrophenyl) acetonitrile was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.61 (3H, s), 3.88 (2H, s), 7.56 (1H, s), 8.24 (1H, s).

Reference example 2

A mixture of 2.5 g of (2-bromo-5-methyl-4-nitrophenyl) acetonitrile, 2.3 mL of dithiophosphoric acid O, O′-diethyl and 7.5 mL of a 4.9 mol / L hydrogen chloride-ethyl acetate solution was stirred at room temperature for 1 day. . The solid was collected by filtration to obtain 2.1 g of 2- (2-bromo-5-methyl-4-nitrophenyl) ethanethioamide as a yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 2.59 (3H, s), 4.19 (2H, s), 6.79-6.98 (1H, broad), 7.38-7.50 (1H, broad), 7.46 (1H, s), 8.24 (1H, s).

Reference example 3

Under nitrogen atmosphere, 2- (2-bromo-5-methyl-4-nitrophenyl) ethanethioamide 1.0 g, 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone 0.96 g A mixture of methanol and 5.0 mL was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then activated carbon was added. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to give 2- (2-bromo-5-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalene) as a brown oil. 1.6 g of -2-yl) -1,3-thiazole was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.78-1.87 (4H, m), 2.54 (3H, s), 2.75-2.88 (4H, m), 4.55 (2H, s), 7.11 (1H, d, J = 8.0Hz), 7.33 (1H, s), 7.36 (1H, s), 7.55-7.63 (2H, m), 8.25 (1H, s).

Reference example 4

2- (2-Bromo-5-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole 200 mg, ethanol 2.0 mL and water 2.0 mL To the mixture, 76 mg of iron powder and 72 mg of ammonium chloride were added and heated to reflux for 30 minutes. Ethanol 2.0mL was added to the reaction mixture, and it heated and refluxed for 30 minutes. The reaction mixture was cooled to room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the insoluble material was removed by filtration. The organic layer of the filtrate was separated, 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: ethyl acetate = 3: 1], and yellow oil 5-bromo-2-methyl-4-((4- (5,6,7,8 -Tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline 136 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.75-1.86 (4H, m), 2.10 (3H, s), 2.73-2.87 (4H, m), 3.58-3.73 (2H, broad), 4.39 (2H, s ), 6.91 (1H, s), 7.05 (1H, s), 7.10 (1H, d, J = 7.8Hz), 7.25 (1H, s), 7.55-7.59 (1H, m), 7.62 (1H, s) .

Reference Example 5

Method A: 200 mg of 2- (2-bromo-5-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole under nitrogen atmosphere To a mixture of 3.8 mL of toluene and 0.2 mL of water were added 61 mg of cyclopropylboronic acid, 340 mg of tripotassium phosphate and 33 mg of bis (tricyclohexylphosphine) palladium (II) dichloride, and the mixture was heated to reflux for 6 hours. The reaction mixture was cooled to room temperature, toluene and water were added, and the insoluble material was removed by filtration. The organic layer of the filtrate was separated and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.25 g of a brown oil.
Method B: 200 mg of 2- (2-bromo-5-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole under nitrogen atmosphere To a mixture of 3.8 mL of toluene and 0.2 mL of water, 61 mg of cyclopropylboronic acid, 340 mg of tripotassium phosphate, 5.1 mg of palladium (II) acetate and 18 mg of 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl were added. Heated to reflux for hours. The reaction mixture was cooled to room temperature, toluene and water were added, and the insoluble material was removed by filtration. The organic layer of the filtrate was separated and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.27 g of a brown oil.
The brown oils obtained in Methods A and B were combined and purified by silica gel column chromatography [hexane: ethyl acetate gradient elution = 99: 1-94: 6] to give 2- (2-cyclopropyl) as a brown oil. There was obtained 0.38 g of -5-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole.
¹ H-NMR (CDCl ₃ ) δ value: 0.67-0.73 (2H, m), 0.96-1.03 (2H, m), 1.78-1.86 (4H, m), 1.95-2.03 (1H, m), 2.56 (3H , s), 2.75-2.87 (4H, m), 4.59 (2H, s), 7.11 (1H, d, J = 8.0Hz), 7.24 (1H, s), 7.30 (1H, s), 7.55-7.59 ( 1H, m), 7.60 (1H, s), 7.69 (1H, s).

Reference Example 6

2- (2-Cyclopropyl-5-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole as in Reference Example 4 From 0.19 g, 5-cyclopropyl-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline 90 mg Got.
¹ H-NMR (CDCl ₃ ) δ value: 0.54-0.60 (2H, m), 0.80-0.86 (2H, m), 1.79-1.89 (5H, m), 2.14 (3H, s), 2.76-2.86 (4H , m), 3.40-3.80 (2H, broad), 4.44 (2H, s), 6.38 (1H, s), 6.98 (1H, s), 7.10 (1H, d, J = 8.0Hz), 7.23 (1H, s), 7.55-7.60 (1H, m), 7.62 (1H, s).

Reference Example 7

To a suspension of 81.5 g of sodium hydroxide in 900 mL of dimethyl sulfoxide, 88.0 g of 2,5-dimethylnitrobenzene and 110 g of (phenylthio) acetonitrile were added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate and water were added to the reaction mixture under ice cooling, and the pH was adjusted to 7.9 with concentrated hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and washed successively with 10% aqueous potassium carbonate, 1 mol / L hydrochloric acid and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 82.4 g of (2,5-dimethyl-4-nitrophenyl) acetonitrile as a brown solid.
¹ H-NMR (CDCl ₃ ) δ value: 2.38 (3H, s), 2.59 (3H, s), 3.71 (2H, s), 7.37 (1H, s), 7.85 (1H, s).

Reference Example 8

In the same manner as in Reference Example 2, 512 mg of 2- (2,5-dimethyl-4-nitrophenyl) ethanethioamide was obtained from 500 mg of (2,5-dimethyl-4-nitrophenyl) acetonitrile.
¹ H-NMR (CDCl ₃ ) δ value: 2.37 (3H, s), 2.58 (3H, s), 4.11 (2H, s), 6.43-6.72 (1H, broad), 7.18 (1H, s), 7.41 7.68 (1H, broad), 7.86 (1H, s).

Reference Example 9

Mixture of 0.23 g of 2- (2,5-dimethyl-4-nitrophenyl) ethanethioamide, 0.26 g of 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone and 5.2 mL of methanol Was heated to reflux for 2 hours. To the reaction mixture, 0.05 g of 2- (2,5-dimethyl-4-nitrophenyl) ethanethioamide was added and heated to reflux for 1 hour. The reaction mixture is cooled to room temperature, toluene is added, the solid is collected by filtration, and the dark brown solid 2- (2,5-dimethyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydro 0.29 g of naphthalen-2-yl) -1,3-thiazole was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.72-1.78 (4H, m), 2.38 (3H, s), 2.48 (3H, s), 2.70-2.79 (4H, m), 4.46 (2H, s ), 7.09 (1H, d, J = 8.3Hz), 7.45 (1H, s), 7.59-7.63 (2H, m), 7.87 (1H, s), 7.89 (1H, s).

Reference Example 10

To a 1.2 mL water suspension of 0.29 g 2- (2,5-dimethyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole, Ethanol 4.8mL, iron powder 0.11g and ammonium chloride 20mg were added, and it heated and refluxed for 2 hours. The reaction mixture was cooled to room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the insoluble material was removed by filtration. The organic layer of the filtrate was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give 2,5-dimethyl-4-((4- ( There was obtained 172 mg of 5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline.
¹ H-NMR (CDCl ₃ ) δ value: 1.79-1.84 (4H, m), 2.14 (3H, s), 2.21 (3H, s), 2.76-2.86 (4H, m), 3.52-3.60 (2H, broad ), 4.24 (2H, s), 6.55 (1H, s), 6.96 (1H, s), 7.10 (1H, d, J = 8.0Hz), 7.22 (1H, s), 7.54-7.59 (1H, m) , 7.62 (1H, s).

Reference Example 11

160 mL of ethanol, 14.1 g of iron powder and 13.5 g of ammonium chloride were added to a suspension of 16.0 g of (2,5-dimethyl-4-nitrophenyl) acetonitrile in 160 mL of water, and the mixture was heated to reflux for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, insolubles were filtered off, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the resulting solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A 25% aqueous ethanol solution was added to the obtained residue, and the solid was collected by filtration to obtain 12.9 g of (4-amino-2,5-dimethylphenyl) acetonitrile as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 2.13 (3H, s), 2.23 (3H, s), 3.54 (2H, s), 3.50-3.68 (2H, broad), 6.52 (1H, s), 6.98 ( 1H, s).

Reference Example 12

To a solution of 3.81 g of N-ethyl-N-methylformamide in 15 mL of chloroform was added 3.75 mL of oxalyl chloride under ice cooling, and the mixture was stirred at 20 ° C. for 1 hour. To the reaction mixture, a solution of 5.00 g of (4-amino-2,5-dimethylphenyl) acetonitrile in 20 mL of chloroform was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [DIOL type silica gel, hexane: ethyl acetate = 3: 1]. To the obtained oil were added 5.1 mL / L hydrogen chloride-ethyl acetate solution (80 mL) and dithiophosphoric acid O, O′-diethyl (7.34 mL), and the mixture was stirred at room temperature for 7 hours. To the reaction mixture, 1.47 mL of dithiophosphoric acid O, O′-diethyl was added and stirred for 5 days. The upper layer of the reaction mixture was removed, ethyl acetate was added, the solid was collected by filtration, and light gray solid 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethane. 8.70 g of thioamide hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.21-1.29 (3H, m), 2.25-2.32 (6H, m), 3.22-3.30 (3H, m), 3.58-3.70 (2H, m), 3.82 (2H, s), 7.10-7.16 (1H, m), 7.17 (1H, s), 8.25-8.43 (1H, m), 9.33-9.44 (1H, broad), 9.49-9.61 (1H, broad), 10.67 -10.88 (1H, m).

Reference Example 13

A mixture of 0.50 g of N- (4-iodo-2,5-dimethylphenyl) acetamide, 20 mg of tetrakis (triphenylphosphine) palladium (0), 482 μL of triethylamine, 136 μL of acrylonitrile and 5 mL of N, N-dimethylformamide was added under a nitrogen atmosphere. And heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and water and chloroform were added. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the resulting residue, and the solid was collected by filtration to obtain 0.29 g of N- (4- (2-cyanoethenyl) -2,5-dimethylphenyl) acetamide as a white solid.
¹ H-NMR (CDCl ₃ ) δ value: 2.22 (3H, s), 2.25 (3H, s), 2.37 (3H, s), 5.73 (1H, d, J = 16.5 Hz), 6.92-7.07 (1H, broad), 7.28 (1H, s), 7.61 (1H, d, J = 16.5Hz), 7.88 (1H, s).

Reference Example 14

A mixture of 150 mg of N- (4- (2-cyanoethenyl) -2,5-dimethylphenyl) acetamide, 20 mg of 10% palladium-carbon, 5 mL of ethanol and 5 mL of N, N-dimethylformamide was stirred at room temperature for 2 hours under a hydrogen atmosphere. Stir. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 115 mg of white solid N- (4- (2-cyanoethyl) -2,5-dimethylphenyl) acetamide.
¹ H-NMR (CDCl ₃ ) δ value: 2.20 (3H, s), 2.22 (3H, s), 2.28 (3H, s), 2.55 (2H, t, J = 7.6 Hz), 2.91 (2H, t, J = 7.6Hz), 6.84-6.94 (1H, broad), 6.98 (1H, s), 7.59 (1H, s).

Reference Example 15

A mixture of 113 mg of N- (4- (2-cyanoethyl) -2,5-dimethylphenyl) acetamide, 165 μL of dithiophosphoric acid O, O′-diethyl and 2 mL of 5 mol / L hydrogen chloride-ethyl acetate solution was stirred at room temperature for 14 hours. did. To the reaction mixture, 248 μL of dithiophosphoric acid O, O′-diethyl was added and stirred for 5 hours. To the reaction mixture, 248 μL of dithiophosphoric acid O, O′-diethyl was added and stirred for 5 hours. To the reaction mixture were added ethyl acetate, chloroform and 10% aqueous potassium carbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 114 mg of N- (4- (3-amino-3-thioxopropyl) -2,5-dimethylphenyl) acetamide as a light gray solid. It was.
¹ H-NMR (CDCl ₃ ) δ value: 2.19 (3H, s), 2.20 (3H, s), 2.30 (3H, s), 2.86 (2H, t, J = 7.7 Hz), 3.05 (2H, t, J = 7.7Hz), 6.79-6.95 (2H, broad), 7.02 (1H, s), 7.20-7.35 (1H, broad), 7.46 (1H, s).

Reference Example 16

N- (4- (3-amino-3-thioxopropyl) -2,5-dimethylphenyl) acetamide 100 mg, 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone A mixture of 101 mg and 5 mL of ethanol was stirred at 70 ° C. for 2 hours. The reaction mixture was cooled to room temperature and ethyl acetate and 10% aqueous potassium carbonate solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid matter was collected by filtration. 134 mg of -2-yl) -1,3-thiazol-2-yl) ethyl) phenyl) acetamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.78-1.86 (4H, m), 2.16-2.24 (6H, m), 2.30 (3H, s), 2.74-2.88 (4H, m), 3.04-3.16 (2H , m), 3.23-3.33 (2H, m), 6.77-6.87 (1H, broad), 7.03 (1H, s), 7.11 (1H, d, J = 7.9Hz), 7.25 (1H, s), 7.54 ( 1H, s), 7.58 (1H, d, J = 7.9Hz), 7.62 (1H, s).

Reference Example 17

N- (2,5-dimethyl-4- (2- (4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) ethyl) phenyl) acetamide 100 mg A mixture of 2 mL of dioxane, 1 mL of concentrated hydrochloric acid and 1 mL of water was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and ethyl acetate and 10% aqueous potassium carbonate solution were added. The organic layer was separated and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to give 2,5-dimethyl-4- (2- (4- (5,6,7,8) as a pale yellow oil. -Tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) ethyl) aniline (113 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.77-1.86 (4H, m), 2.12 (3H, s), 2.23 (3H, s), 2.75-2.88 (4H, m), 2.98-3.06 (2H, m ), 3.22-3.29 (2H, m), 3.41-3.55 (2H, broad), 6.51 (1H, s), 6.89 (1H, s), 7.10 (1H, d, J = 8.0Hz), 7.25 (1H, s), 7.58 (1H, d, J = 8.0Hz), 7.62 (1H, s).

Reference Example 18

5-bromo-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline 0.26 g, zinc cyanide A mixture of 0.22 g, 64 mg of bis (tri-tert-butylphosphine) palladium (0) and 2.6 mL of N, N-dimethylformamide was stirred at 120 to 130 ° C. for 4 hours under a nitrogen atmosphere. To the reaction mixture, 64 mg of bis (tri-tert-butylphosphine) palladium (0) was added, and the mixture was stirred at 140 to 150 ° C. for 4 hours and 30 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, ethyl acetate, methanol and water were added, and insoluble materials were removed by filtration. The organic layer of the filtrate was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 17: 3-1: 1], and 5-amino-4-methyl-2-((4- (5 , 6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) benzonitrile (0.20 g).
¹ H-NMR (DMSO-d ₆ ) δ value: 1.70-1.78 (4H, m), 2.10 (3H, s), 2.68-2.80 (4H, m), 4.33 (2H, s), 5.38 (2H, s ), 6.94 (1H, s), 7.06-7.13 (1H, m), 7.17 (1H, s), 7.58-7.65 (2H, m), 7.84 (1H, s).

Reference Example 19

A mixture of 1.72 g of 4-chloro-1-methyl-2-nitrobenzene, 1.68 g of potassium hydroxide, 2.89 g of 2-((cyanomethyl) sulfanyl) benzoic acid and 5 mL of dimethyl sulfoxide was stirred at room temperature for 2 hours. To the reaction mixture, 1.68 g of potassium hydroxide was added and stirred for 2 hours and 30 minutes. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, 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: ethyl acetate gradient elution = 9: 1-4: 1] to give a red solid (2-chloro-5-methyl-4-nitrophenyl) acetonitrile 0.90. g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.64 (3H, s), 3.89 (2H, s), 7.56 (1H, s), 8.08 (1H, s).

Reference Example 20

In the same manner as in Reference Example 2, 0.76 g of 2- (2-chloro-5-methyl-4-nitrophenyl) ethanethioamide was obtained from 0.90 g of (2-chloro-5-methyl-4-nitrophenyl) acetonitrile. .
¹ H-NMR (CDCl ₃ ) δ value: 2.61 (3H, s), 4.17 (2H, s), 6.74-7.06 (1H, broad), 7.38-7.62 (1H, broad), 7.46 (1H, s), 8.08 (1H, s).

Reference Example 21

A mixture of 245 mg of 2- (2-chloro-5-methyl-4-nitrophenyl) ethanethioamide, 253 mg of 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone and 3 mL of methanol The mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to give 2- (2-chloro-5-methyl-4-nitrobenzyl) -4- (5,6,7,8- 360 mg of tetrahydronaphthalen-2-yl) -1,3-thiazole was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.77-1.86 (4H, m), 2.61 (3H, s), 2.74-2.94 (4H, m), 5.35 (2H, s), 7.21 (1H, d, J = 8.1Hz), 7.51 (1H, s), 7.75 (1H, dd, J = 8.1, 2.2Hz), 7.87-7.91 (1H, m), 8.08 (1H, s), 8.17 (1H, s).

Reference Example 22

In the same manner as in Reference Example 10, 2- (2-chloro-5-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole 100 mg Thus, 92 mg of 5-chloro-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline was obtained. .
¹ H-NMR (CDCl ₃ ) δ value: 1.76-1.88 (4H, m), 2.11 (3H, s), 2.70-3.00 (4H, m), 3.50-3.82 (2H, broad), 4.37 (2H, s) ), 6.73 (1H, s), 7.03 (1H, s), 7.09 (1H, d, J = 7.8Hz), 7.24 (1H, s), 7.53-7.60 (1H, m), 7.62 (1H, s) .

Reference Example 23

In the same manner as in Reference Example 19, 0.52-g of (2-fluoro-5-methyl-4-nitrophenyl) acetonitrile was obtained from 2.32 g of 4-fluoro-1-methyl-2-nitrobenzene.
¹ H-NMR (CDCl ₃ ) δ value: 2.62 (3H, s), 3.84 (2H, s), 7.49 (1H, d, J = 7.1 Hz), 7.79 (1H, d, J = 9.2 Hz).

Reference Example 24

A mixture of 0.40 g of (2-fluoro-5-methyl-4-nitrophenyl) acetonitrile, 0.49 mL of dithiophosphoric acid O, O′-diethyl and 2 mL of 5 mol / L hydrogen chloride-ethyl acetate solution was stirred at room temperature for 12 hours and 30 minutes. did. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 9: 1-2: 1] to give 2- (2-fluoro-5-methyl-4-nitrophenyl) as a red solid. Ethanethioamide 400 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.60 (3H, s), 4.07 (2H, s), 6.69-7.11 (1H, broad), 7.41 (1H, d, J = 7.3 Hz), 7.38-7.58 ( 1H, broad), 7.79 (1H, d, J = 9.3Hz).

Reference Example 25

In the same manner as in Reference Example 9, 228 mg of 2- (2-fluoro-5-methyl-4-nitrophenyl) ethanethioamide and 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) From 253 mg of ethanone, 294 mg of 2- (2-fluoro-5-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.76-1.87 (4H, m), 2.60 (3H, s), 2.74-2.93 (4H, m), 5.27 (2H, s), 7.21 (1H, d, J = 7.8Hz), 7.52 (1H, s), 7.75 (1H, dd, J = 7.8,1.7Hz), 7.80 (1H, d, J = 9.3Hz), 7.88 (1H, s), 8.06 (1H, d , J = 7.3Hz).

Reference Example 26

In the same manner as in Reference Example 10, 2- (2-fluoro-5-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole 90 mg Thus, 82 mg of 5-fluoro-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline was obtained. .
¹ H-NMR (CDCl ₃ ) δ value: 1.78-1.88 (4H, m), 2.10 (3H, s), 2.73-2.90 (4H, m), 3.58-3.80 (2H, broad), 4.27 (2H, s ), 6.42 (1H, d, J = 11.2Hz), 6.98 (1H, d, J = 8.2Hz), 7.09 (1H, d, J = 8.2Hz), 7.25 (1H, s), 7.56 (1H, dd , J = 7.8, 1.9Hz), 7.61 (1H, s).

Reference Example 27

2- (2-Bromo-5-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole 100 mg, tetrakis (triphenylphosphine) palladium A mixture of (0) 13 mg, phenylboric acid 30 mg, potassium carbonate 62 mg, dioxane 5 mL and water 2 mL was heated to reflux under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 100: 0-10: 1] to obtain a pale yellow oil. In the same manner as in Reference Example 10, 4-methyl-6-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole- 86 mg of 2-yl) methyl) biphenyl-3-amine were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.76-1.86 (4H, m), 2.20 (3H, s), 2.73-2.86 (4H, m), 3.58-3.72 (2H, m), 4.21 (2H, s ), 6.63 (1H, s), 7.08 (1H, d, J = 7.7Hz), 7.11 (1H, s), 7.21 (1H, s), 7.23-7.38 (5H, m), 7.53 (1H, d, J = 7.7Hz), 7.57 (1H, s).

Reference Example 28

A mixture of 5.5 g of sodium hydroxide, 3.2 g of 2-((cyanomethyl) sulfanyl) benzoic acid and 18 mL of dimethyl sulfoxide was stirred at 30 ° C. for 5 minutes. To the reaction mixture was added 2.8 g of 4- (difluoromethoxy) -1-methyl-2-nitrobenzene in 10 mL of dimethyl sulfoxide, and the mixture was stirred at 30 ° C. for 1 hour. Ice water, toluene and ethyl acetate were added to the reaction mixture, and the insoluble material was removed by filtration. The organic layer of the filtrate was separated and the aqueous layer was extracted with toluene. The organic layer and the extract were combined, washed sequentially with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then activated carbon was added. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 1.6 g of (2- (difluoromethoxy) -5-methyl-4-nitrophenyl) acetonitrile as a brown oil.
¹ H-NMR (CDCl ₃ ) δ value: 2.63 (3H, s), 3.82 (2H, s), 6.65 (1H, t, J = 71.8 Hz), 7.53 (1H, s), 7.85 (1H, s) .

Reference Example 29

A mixture of 0.36 g of (2- (difluoromethoxy) -5-methyl-4-nitrophenyl) acetonitrile, 0.14 mL of dithiophosphoric acid O, O′-diethyl and 3.0 mL of 4 mol / L hydrogen chloride-ethyl acetate solution was added at room temperature to 4 Stir for hours. The solvent was distilled off under reduced pressure to obtain a brown oil. A mixture of the obtained brown oil, 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone (0.46 g) and ethanol (4 mL) was heated to reflux for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 19: 1-17: 3] to give 2- (2- (difluoromethoxy) -5-methyl-4 as a brown oil. -Nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole (0.23 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.77-1.86 (4H, m), 2.57 (3H, s), 2.74-2.86 (4H, m), 4.48 (2H, s), 6.62 (1H, t, J = 72.8Hz), 7.11 (1H, d, J = 7.8Hz), 7.31 (1H, s), 7.37 (1H, s), 7.51-7.60 (2H, m), 7.87 (1H, s).

Reference Example 30

In the same manner as in Reference Example 4, 2- (2- (difluoromethoxy) -5-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3 -From 0.23 g of thiazole, 5- (difluoromethoxy) -2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) 80 mg of methyl) aniline were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.77-1.86 (4H, m), 2.11 (3H, s), 2.74-2.86 (4H, m), 3.69 (2H, s), 4.29 (2H, s), 6.46 (1H, t, J = 74.2Hz), 6.50 (1H, s), 7.03 (1H, s), 7.09 (1H, d, J = 8.1Hz), 7.20-7.40 (1H, m), 7.53-7.58 (1H, m), 7.60 (1H, s).

Reference Example 31

A mixture of 0.84 g of 4-methoxy-1-methyl-2-nitrobenzene, 1.20 g of sodium hydroxide, 1.45 g of 2-((cyanomethyl) sulfanyl) benzoic acid and 5 mL of dimethyl sulfoxide was stirred at room temperature for 6 hours. Water and toluene were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 9: 1-4: 1] to give (2-methoxy-5-methyl-4-nitrophenyl) acetonitrile as a pale yellow solid. 0.14 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.57 (3H, s), 3.73 (2H, s), 3.93 (3H, s), 7.37 (1H, s), 7.53 (1H, s).

Reference Example 32

In the same manner as in Reference Example 15, 102 mg of 2- (2-methoxy-5-methyl-4-nitrophenyl) ethanethioamide was obtained from 0.12 g of (2-methoxy-5-methyl-4-nitrophenyl) acetonitrile.
¹ H-NMR (CDCl ₃ ) δ value: 2.56 (3H, s), 3.95 (3H, s), 4.08 (2H, s), 7.21-7.35 (2H, broad), 7.32 (1H, s), 7.58 ( 1H, s).

Reference Example 33

In the same manner as in Reference Example 21, 100 mg of 2- (2-methoxy-5-methyl-4-nitrophenyl) ethanethioamide and 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) From 105 mg of ethanone, 140 mg of 2- (2-methoxy-5-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.69-1.80 (4H, m), 2.44 (3H, s), 2.65-2.83 (4H, m), 3.88 (3H, s), 4.37 (2H, s ), 7.06-7.12 (1H, m), 7.47 (1H, s), 7.58-7.67 (3H, m), 7.83 (1H, s).

Reference Example 34

In the same manner as in Reference Example 4, 2- (2-methoxy-5-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole 140 mg Thus, 75 mg of 5-methoxy-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline was obtained. .
¹ H-NMR (CDCl ₃ ) δ value: 1.76-1.85 (4H, m), 2.09 (3H, s), 2.72-2.88 (4H, m), 3.53-3.71 (2H, broad), 3.77 (3H, s ), 4.25 (2H, s), 6.29 (1H, s), 6.95 (1H, s), 7.08 (1H, d, J = 7.8Hz), 7.20 (1H, s), 7.56 (1H, dd, J = 8.0, 1.7Hz), 7.62 (1H, s).

Reference Example 35

To a mixture of 1.0 g of 1-methyl-2-nitro-4- (trifluoromethyl) benzene, 0.30 mL of chloroacetonitrile and 20 mL of N, N-dimethylformamide, 1.1 g of potassium tert-butoxide was added at −15 to −10 ° C. The mixture was stirred at -20 to -10 ° C for 1 hour and 50 minutes. To the reaction mixture, 90 μL of chloroacetonitrile was added and stirred at 0 to 10 ° C. for 1 hour. Water and toluene were added to the reaction mixture, and the pH was adjusted to 2 with 6 mol / L hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 49: 1-4: 1] to give (5-methyl-4-nitro-2- (trifluoromethyl) as a brown oil. 0.19 g of phenyl) acetonitrile was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.74 (3H, s), 4.01 (2H, s), 7.73 (1H, s), 8.34 (1H, s).

Reference Example 36

In the same manner as in Reference Example 24, from 0.19 g of (5-methyl-4-nitro-2- (trifluoromethyl) phenyl) acetonitrile, 2- (5-methyl-4-nitro-2- (trifluoromethyl) phenyl ) 0.116 g of ethanethioamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.70 (3H, s), 4.20 (2H, s), 6.60-6.90 (1H, broad), 7.35-7.54 (1H, broad), 7.67 (1H, s), 8.33 (1H, s).

Reference Example 37

In the same manner as in Reference Example 31, from 2.20 g of 4-methyl-3-nitrophenyl = propan-2-yl ether, (5-methyl-4-nitro-2- (propan-2-yloxy) phenyl) acetonitrile 1.03 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.40 (6H, d, J = 6.1 Hz), 2.56 (3H, s), 3.70 (2H, s), 4.61-4.71 (1H, m), 7.35 (1H, s), 7.52 (1H, s).

Reference Example 38

A mixture of 0.50 g of (5-methyl-4-nitro-2- (propan-2-yloxy) phenyl) acetonitrile, 0.51 mL of dithiophosphoric acid O, O′-diethyl and 5.0 mL of 5 mol / L hydrogen chloride-ethyl acetate solution The mixture was stirred at room temperature for 1 hour and 15 minutes and allowed to stand for 14 hours. The reaction mixture was evaporated under reduced pressure. A mixture of the obtained brown oily substance, 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone (0.65 g) and ethanol (5.0 mL) was heated to reflux for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 100: 0-3: 1] to obtain 0.73 g of a yellow oily substance. A mixture of 0.40 g of the obtained yellow oil, 30 mg of ammonium chloride, 0.16 g of iron powder, 8.0 mL of ethanol and 2.0 mL of water was heated to reflux for 3 hours. To the reaction mixture were added 0.33 g of the obtained yellow oil, 30 mg of ammonium chloride and 0.16 g of iron powder, and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, insolubles were filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane: ethyl acetate = 4: 1] to give 2-methyl-5- (propan-2-yloxy) -4-((4- ( 240 mg of 5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.27 (6H, d, J = 6.1 Hz), 1.76-1.86 (4H, m), 2.09 (3H, s), 2.72-2.88 (4H, m), 3.50- 3.76 (2H, broad), 4.24 (2H, s), 4.40-4.51 (1H, m), 6.96 (1H, s), 7.09 (1H, d, J = 8.0Hz), 7.20 (1H, s), 7.56 (1H, d, J = 8.1Hz), 7.62 (1H, s).

Reference Example 39

5-Bromo-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline 0.10 g, trimethylsilylacetylene 43 μL , Sodium tetrachloropalladium (II) trihydrate 2.1 mg, tri-tert-butylphosphonium tetrafluoroborate 3.5 mg, copper (I) iodide 2.3 mg and N, N, N ′, N′-tetramethyl A mixture of 0.5 mL of ethylenediamine was treated using a microwave reactor at 130 ° C. for 10 minutes and 140 ° C. for 20 minutes. To the reaction mixture, 0.13 mL of trimethylsilylacetylene, 2.1 mg of sodium tetrachloropalladium (II) trihydrate, 3.5 mg of tri-tert-butylphosphonium tetrafluoroborate and 2.3 mg of copper (I) iodide were added. Treated at 140 ° C. for 20 minutes using a reactor. Ethyl acetate and water were added to the reaction mixture, and the insoluble material was removed by filtration. The organic layer of the filtrate was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, potassium carbonate (0.10 g) and methanol (2.0 mL) were added, stirred for 30 minutes, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 9: 1-67: 33], and 5-ethynyl-2-methyl-4-((4- ( 5,6,7,8-Tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline 57 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.78-1.85 (4H, m), 2.15 (3H, s), 2.74-2.87 (4H, m), 3.18 (1H, s), 3.56-3.70 (2H, broad) ), 4.46 (2H, s), 6.86 (1H, s), 7.05 (1H, s), 7.10 (1H, d, J = 8.0Hz), 7.24 (1H, s), 7.54-7.59 (1H, m) , 7.62 (1H, s).

Reference Example 40

4-Bromo-2-methyl-5- (propan-2-yl) aniline 0.50 g, ethyl cyanoacetate 0.70 mL, bis (tri-tert-butylphosphine) palladium (0) 56 mg, tripotassium phosphate 1.40 g and toluene 10 mL of the mixture was heated to reflux under a nitrogen atmosphere for 3 hours 30 minutes. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, a 4 mol / L hydrogen chloride-ethyl acetate solution was added, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration. Hydrochloric acid of ethyl = (4-amino-5-methyl-2- (propan-2-yl) phenyl) (cyano) acetate as a pale yellow solid 0.58 g of salt was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.21-1.32 (9H, m), 2.59 (3H, s), 3.06-3.15 (1H, m), 4.17-4.35 (2H, m), 4.94 (1H, s ), 7.39 (1H, s), 7.63 (1H, s), 10.10-10.90 (3H, broad).

Reference Example 41

A mixture of 0.50 g of ethyl = (4-amino-5-methyl-2- (propan-2-yl) phenyl) (cyano) acetate, 0.74 g of sodium chloride, 1 mL of water and 16 mL of dimethyl sulfoxide at 150 ° C. Stir for 40 minutes. The reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, 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: ethyl acetate = 4: 1], 4 mol / L hydrogen chloride-ethyl acetate solution was added, and the solid was collected by filtration to give a pale yellow solid (4- 206 mg of amino-5-methyl-2- (propan-2-yl) phenyl) acetonitrile hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.18 (6H, d, J = 6.8 Hz), 2.31 (3H, s), 3.05-3.17 (1H, m), 4.04 (2H, s), 7.27 ( 1H, s), 7.41 (1H, s), 9.70-10.50 (3H, broad).

Reference Example 42

A mixture of 150 mg of hydrochloride of (4-amino-5-methyl-2- (propan-2-yl) phenyl) acetonitrile, 158 μL of dithiophosphoric acid O, O′-diethyl and 3 mL of 5 mol / L hydrogen chloride-ethyl acetate solution, The mixture was stirred at room temperature for 5 hours and then allowed to stand for 14 hours. To the reaction mixture, 84 μL of dithiophosphoric acid O, O′-diethyl was added and stirred for 3 hours. To the reaction mixture, 84 μL of dithiophosphoric acid O, O′-diethyl was added and stirred for 2 hours. To the reaction mixture, 316 μL of dithiophosphoric acid O, O′-diethyl was added and stirred for 14 hours. To the reaction mixture, 316 μL of dithiophosphoric acid O, O′-diethyl was added and stirred for 10 hours. A 10% aqueous potassium carbonate solution and ethyl acetate were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, a 4 mol / L hydrogen chloride-ethyl acetate solution was added, and the solid was collected by filtration to give 2- (4-amino-5-methyl-2- (propan-2-yl) as a light brown solid. 166 mg of phenyl) ethanethioamide hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.14 (6H, d, J = 6.6 Hz), 2.27 (3H, s), 3.17-3.25 (1H, m), 3.85 (2H, s), 7.13 ( 1H, s), 7.27 (1H, s), 9.26-9.38 (1H, broad), 9.50-9.59 (1H, broad), 9.60-10.20 (3H, broad).

Reference Example 43

2- (4-amino-5-methyl-2- (propan-2-yl) phenyl) ethanethioamide hydrochloride 100 mg, 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl ) A mixture of 88 mg ethanone and 3 mL ethanol was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and ethyl acetate and 10% aqueous potassium carbonate solution were added. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 10: 1-5: 1], a 4 mol / L hydrogen chloride-ethyl acetate solution was added, and the solid was collected by filtration. 2-methyl-5- (propan-2-yl) -4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) as a white solid 137 mg of methyl) aniline hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.12 (6H, d, J = 6.8 Hz), 1.71-1.79 (4H, m), 2.31 (3H, s), 2.66-2.80 (4H, m), 3.19-3.31 (1H, m), 4.41 (2H, s), 7.09 (1H, d, J = 7.8Hz), 7.30 (1H, s), 7.41 (1H, s), 7.59-7.64 (2H, m) , 7.83 (1H, s), 9.80-10.30 (3H, broad).

Reference Example 44

To a solution of 5- (tert-butyl) -2-methylaniline hydrochloride (1.50 g) in chloroform (20 mL) was added trimethylphenylammonium bromide (2.82 g) under ice cooling, and the mixture was stirred at room temperature for 8 hours and 30 minutes. A sodium thiosulfate aqueous solution was added to the reaction mixture. The organic layer was separated, 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: ethyl acetate = 5: 1] to obtain 1.63 g of red oil 4-bromo-5- (tert-butyl) -2-methylaniline.
¹ H-NMR (CDCl ₃ ) δ value: 1.46 (9H, s), 2.09 (3H, s), 3.49-3.62 (2H, broad), 6.75 (1H, s), 7.25 (1H, s).

Reference Example 45

4-bromo-5- (tert-butyl) -2-methylaniline 0.50 g, ethyl cyanoacetate 0.66 mL, bis (tri-tert-butylphosphine) palladium (0) 53 mg, tripotassium phosphate 1.31 g and toluene 10 mL The mixture was heated to reflux under a nitrogen atmosphere for 3 hours 30 minutes. To the reaction mixture, 0.66 mL of ethyl cyanoacetate, 53 mg of bis (tri-tert-butylphosphine) palladium (0), 10 mL of toluene and 3 mL of dioxane were added, and the mixture was heated to reflux for 6 hours under a nitrogen atmosphere. To the reaction mixture was added 53 mg of bis (tri-tert-butylphosphine) palladium (0), and the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 5: 1-3: 1], and ethyl of pale yellow oil = (4-amino-2- (tert-butyl) 300 mg of -5-methylphenyl) (cyano) acetate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.28 (3H, t, J = 7.1 Hz), 1.41 (9H, s), 2.13 (3H, s), 3.58-3.72 (2H, broad), 4.19-4.35 ( 2H, m), 5.27 (1H, s), 6.70 (1H, s), 7.15 (1H, s).

Reference Example 46

In the same manner as in Reference Example 41, from 300 mg of ethyl = (4-amino-2- (tert-butyl) -5-methylphenyl) (cyano) acetate, (4-amino-2- (tert-butyl) -5- 130 mg of methylphenyl) acetonitrile hydrochloride was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.42 (9H, s), 2.57 (3H, s), 3.96 (2H, s), 7.38 (1H, s), 7.71 (1H, s), 10.30-10.70 ( 3H, broad).

Reference Example 47

In the same manner as in Reference Example 42, a pale yellow solid was obtained from 100 mg of hydrochloride of (4-amino-2- (tert-butyl) -5-methylphenyl) acetonitrile. From the obtained pale yellow solid and 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone 100 mg, in the same manner as in Reference Example 43, 5- (tert-butyl) -2 120 mg of 4-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.37 (9H, s), 1.71-1.79 (4H, m), 2.29 (3H, s), 2.66-2.81 (4H, m), 4.60 (2H, s ), 7.10 (1H, d, J = 7.6Hz), 7.28 (1H, s), 7.54 (1H, s), 7.60-7.66 (2H, m), 7.83 (1H, s), 9.90-10.30 (3H, broad).

Reference Example 48

Bis (2-methoxyethyl) aminosulfur trifluoride (3.1 mL) was added to a chloroform (28 mL) solution of 4-methyl-3-nitrobenzaldehyde (1.4 g), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oily 4- (difluoromethyl) -1-methyl-2 -1.6 g of nitrobenzene were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.66 (3H, s), 6.69 (1H, t, J = 56.3 Hz), 7.47 (1H, d, J = 7.6 Hz), 7.66 (1H, d, J = 7.6Hz), 8.13 (1H, s).

Reference Example 49

Reaction A: To a suspension of 1.6 g of sodium hydroxide in 4.4 mL of dimethyl sulfoxide, 0.77 mL of (phenylthio) acetonitrile and 2.9 mL of dimethyl sulfoxide in 0.73 g of 4- (difluoromethyl) -1-methyl-2-nitrobenzene were added, After stirring at room temperature for 15 minutes, toluene was added to obtain reaction mixture A.
Reaction B: To a suspension of 0.11 g of sodium hydroxide in 0.30 mL of dimethylsulfoxide was added 53 μL of (phenylthio) acetonitrile and 0.20 mL of dimethylsulfoxide in 50 mg of 4- (difluoromethyl) -1-methyl-2-nitrobenzene at room temperature. After stirring for 20 minutes, toluene and water were added to obtain reaction mixture B.
Reaction mixture A and reaction mixture B were added to ice water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 19: 1-3: 1] to give (2- (difluoromethyl) -5-methyl-4-nitro as a yellow oil) 0.28 g of phenyl) acetonitrile was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.71 (3H, s), 4.02 (2H, s), 6.73 (1H, t, J = 54.4 Hz), 7.65 (1H, s), 8.14 (1H, s) .

Reference Example 50

In the same manner as in Reference Example 24, from 0.28 g of (2- (difluoromethyl) -5-methyl-4-nitrophenyl) acetonitrile, 2- (2- (difluoromethyl) -5-methyl-4-nitrophenyl) ethane 0.23 g of thioamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.67 (3H, s), 4.20 (2H, s), 6.70-7.50 (2H, m), 6.86 (1H, t, J = 54.9 Hz), 7.54 (1H, s), 8.20 (1H, s).

Reference Example 51

0.10 g 2- (2- (difluoromethyl) -5-methyl-4-nitrophenyl) ethanethioamide, 0.15 g 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone and A mixture of 2.0 mL of ethanol was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, iron powder (64 mg), ammonium chloride (12 mg) and water (0.50 mL) were added, and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, ethyl acetate, methanol and saturated aqueous sodium hydrogen carbonate solution were added, and the insoluble material was removed by filtration. The organic layer of the filtrate was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and activated carbon was added. The insoluble material was removed by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 9: 1-3: 1] to give a brown oil Of 5- (difluoromethyl) -2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline Obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.77-1.86 (4H, m), 2.17 (3H, s), 2.74-2.87 (4H, m), 3.62-3.82 (2H, broad), 4.36 (2H, s ), 6.88 (1H, t, J = 55.6Hz), 6.90 (1H, s), 7.06 (1H, s), 7.10 (1H, d, J = 7.8Hz), 7.25 (1H, s), 7.54-7.59 (1H, m), 7.60 (1H, s).

Reference Example 52

In the same manner as in Reference Example 19, 0.62-g of (5-fluoro-2-methyl-4-nitrophenyl) acetonitrile was obtained from 2.32 g of 1-fluoro-4-methyl-2-nitrobenzene.
¹ H-NMR (CDCl ₃ ) δ value: 2.40 (3H, s), 3.74 (2H, s), 7.40 (1H, d, J = 11.0 Hz), 7.94 (1 H, d, J = 7.3 Hz).

Reference Example 53

In the same manner as in Reference Example 15, 600 mg of 2- (5-fluoro-2-methyl-4-nitrophenyl) ethanethioamide was obtained from 600 mg of (5-fluoro-2-methyl-4-nitrophenyl) acetonitrile.
¹ H-NMR (CDCl ₃ ) δ value: 2.38 (3H, s), 4.08 (2H, s), 6.42-6.74 (1H, broad), 7.19 (1H, d, J = 11.2 Hz), 7.28-7.64 ( 1H, broad), 7.93 (1H, d, J = 7.3Hz).

Reference Example 54

In the same manner as in Reference Example 9, 228 mg of 2- (5-fluoro-2-methyl-4-nitrophenyl) ethanethioamide and 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) From 253 mg of ethanone, 300 mg of 2- (5-fluoro-2-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.78-1.87 (4H, m), 2.43 (3H, s), 2.74-2.90 (4H, m), 4.60-4.80 (2H, broad), 7.16 (1H, d , J = 7.9Hz), 7.29 (1H, s), 7.39 (1H, s), 7.63 (1H, d, J = 7.9Hz), 7.70 (1H, s), 7.94 (1H, d, J = 7.3Hz ).

Reference Example 55

In the same manner as in Reference Example 10, 2- (5-fluoro-2-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole 90 mg Thus, 85 mg of 2-fluoro-5-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline was obtained. .
¹ H-NMR (CDCl ₃ ) δ value: 1.76-1.86 (4H, m), 2.20 (3H, s), 2.72-2.88 (4H, m), 3.63-3.75 (2H, broad), 4.23 (2H, s ), 6.63 (1H, d, J = 9.0Hz), 6.91 (1H, d, J = 11.5Hz), 7.10 (1H, d, J = 8.1Hz), 7.24 (1H, s), 7.56 (1H, dd , J = 8.1, 2.0Hz), 7.61 (1H, s).

Reference Example 56

A mixture of 6.48 g of sodium hydroxide, 10 g of 1-bromo-4-methyl-2-nitrobenzene, 11.6 g of 2-((cyanomethyl) sulfanyl) benzoic acid and 50 mL of dimethyl sulfoxide was stirred at room temperature for 88 hours. To the reaction mixture, 13 g of potassium tert-butoxide was added under ice cooling, and the mixture was stirred for 2 hours under ice cooling. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with 10% aqueous potassium carbonate solution, 1 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, 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: ethyl acetate gradient elution = 4: 1-2: 1] to give (5-bromo-2-methyl-4-nitrophenyl) acetonitrile 1.12 as a brown solid. g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.39 (3H, s), 3.72 (2H, s), 7.74 (1H, s), 7.77 (1H, s).

Reference Example 57

In the same manner as in Reference Example 15, 0.42 g of 2- (5-bromo-2-methyl-4-nitrophenyl) ethanethioamide was obtained from 500 mg of (5-bromo-2-methyl-4-nitrophenyl) acetonitrile.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.31 (3H, s), 3.94 (2H, s), 7.73 (1H, s), 7.87 (1H, s), 9.35-9.49 (1H, broad), 9.61-9.73 (1H, broad).

Reference Example 58

A mixture of 300 mg of 2- (5-bromo-2-methyl-4-nitrophenyl) ethanethioamide, 263 mg of 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone and 5 mL of methanol The mixture was heated to reflux for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate and ethyl acetate were added. The organic layer was separated, 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: ethyl acetate = 5: 1]. Diisopropyl ether and hexane were added to the obtained oil, and the solid was collected by filtration to give 2- (5-bromo-2-methyl-4-nitrobenzyl) -4- (5,6,7, 390 mg of 8-tetrahydronaphthalen-2-yl) -1,3-thiazole was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.78-1.87 (4H, m), 2.40 (3H, s), 2.75-2.88 (4H, m), 4.39 (2H, s), 7.11 (1H, d, J = 7.8Hz), 7.31 (1H, s), 7.56 (1H, d, J = 7.8H), 7.59 (1H, s), 7.64 (1H, s), 7.74 (1H, s).

Reference Example 59

2- (5-Bromo-2-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole 0.10 g, zinc cyanide 79 mg, tetrakis A mixture of 27 mg of (triphenylphosphine) palladium (0) and 2.0 mL of N, N-dimethylformamide was treated for 10 minutes at 140 ° C. using a microwave reactor under a nitrogen atmosphere. To the reaction mixture, 13 mg of tetrakis (triphenylphosphine) palladium (0) was added and treated at 140 ° C. for 5 minutes. Toluene and water were added to the reaction mixture, and insoluble materials were removed by filtration. The organic layer of the filtrate was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 9: 1-67: 33], and 4-methyl-2-nitro-5-((4- ( There was obtained 73 mg of 5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) benzonitrile.
¹ H-NMR (CDCl ₃ ) δ value: 1.78-1.85 (4H, m), 2.58 (3H, s), 2.75-2.86 (4H, m), 4.47 (2H, s), 7.11 (1H, d, J = 7.6Hz), 7.34 (1H, s), 7.51-7.57 (2H, m), 7.79 (1H, s), 8.17 (1H, s).

Reference Example 60

In the same manner as in Reference Example 10, 4-methyl-2-nitro-5-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl ) From 73 mg of benzonitrile, 2-amino-4-methyl-5-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) benzo 52 mg of nitrile was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.78-1.86 (4H, m), 2.33 (3H, s), 2.74-2.90 (4H, m), 4.26 (2H, s), 5.50-5.80 (2H, broad ), 6.55 (1H, s), 7.10 (1H, d, J = 8.1Hz), 7.24-7.30 (2H, m), 7.54-7.64 (2H, m).

Reference Example 61

In the same manner as in Reference Example 31, 140 mg of (5-chloro-2-methyl-4-nitrophenyl) acetonitrile was obtained from 0.86 g of 1-chloro-4-methyl-2-nitrobenzene.
¹ H-NMR (CDCl ₃ ) δ value: 2.41 (3H, s), 3.73 (2H, s), 7.60 (1H, s), 7.77 (1H, s).

Reference Example 62

In the same manner as in Reference Example 15, 150 mg of 2- (5-chloro-2-methyl-4-nitrophenyl) ethanethioamide was obtained from 140 mg of (5-chloro-2-methyl-4-nitrophenyl) acetonitrile.
¹ H-NMR (CDCl ₃ ) δ value: 2.38 (3H, s), 4.08 (2H, s), 6.40-6.80 (1H, broad), 7.41 (1H, s), 7.42-7.58 (1H, broad), 7.77 (1H, s).

Reference Example 63

In the same manner as in Reference Example 21, 150 mg of 2- (5-chloro-2-methyl-4-nitrophenyl) ethanethioamide and 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) From 156 mg of ethanone, 180 mg of 2- (5-chloro-2-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.66-1.80 (4H, m), 2.39 (3H, s), 2.64-2.82 (4H, m), 4.52 (2H, s), 7.09 (1H, d , J = 8.3Hz), 7.56-7.64 (2H, m), 7.75 (1H, s), 7.90 (1H, s), 8.00 (1H, s).

Reference Example 64

In the same manner as in Reference Example 10, 2- (5-chloro-2-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole 90 mg Thus, 37 mg of 2-chloro-5-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline was obtained. .
¹ H-NMR (CDCl ₃ ) δ value: 1.76-1.86 (4H, m), 2.21 (3H, s), 2.74-2.88 (4H, m), 3.88-4.06 (2H, broad), 4.23 (2H, s ), 6.63 (1H, s), 7.10 (1H, d, J = 7.8Hz), 7.16 (1H, s), 7.24 (1H, s), 7.56 (1H, dd, J = 7.8, 1.7Hz), 7.61 (1H, s).

Reference Example 65

In the same manner as in Reference Example 31, 0.62 g of (5-methoxy-2-methyl-4-nitrophenyl) acetonitrile was obtained from 0.84 g of 1-methoxy-4-methyl-2-nitrobenzene.
¹ H-NMR (CDCl ₃ ) δ value: 2.32 (3H, s), 3.73 (2H, s), 3.99 (3H, s), 7.15 (1H, s), 7.73 (1H, s).

Reference Example 66

In the same manner as in Reference Example 15, 0.53 g of 2- (5-methoxy-2-methyl-4-nitrophenyl) ethanethioamide was obtained from 0.62 g of (5-methoxy-2-methyl-4-nitrophenyl) acetonitrile. .
¹ H-NMR (CDCl ₃ ) δ value: 2.30 (3H, s), 3.96 (3H, s), 4.12 (2H, s), 6.48-6.70 (1H, broad), 6.72 (1H, s), 7.42 7.63 (1H, broad), 7.73 (1H, s).

Reference Example 67

In the same manner as in Reference Example 21, 240 mg of 2- (5-methoxy-2-methyl-4-nitrophenyl) ethanethioamide and 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) From 253 mg of ethanone, 310 mg of 2- (5-methoxy-2-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.70-1.80 (4H, m), 2.29 (3H, s), 2.64-2.82 (4H, m), 3.90 (3H, s), 4.48 (2H, s ), 7.09 (1H, d, J = 7.6Hz), 7.44 (1H, s), 7.58-7.66 (2H, m), 7.78 (1H, s), 7.88 (1H, s).

Reference Example 68

In the same manner as in Reference Example 10, 90 mg of 2- (5-methoxy-2-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole As a result, 77 mg of 2-methoxy-5-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline was obtained. .
¹ H-NMR (CDCl ₃ ) δ value: 1.77-1.86 (4H, m), 2.19 (3H, s), 2.73-2.88 (4H, m), 3.68-3.80 (2H, broad), 3.82 (3H, s ), 4.26 (2H, s), 6.58 (1H, s), 6.72 (1H, s), 7.10 (1H, d, J = 7.8Hz), 7.23 (1H, s), 7.56 (1H, dd, J = 7.8, 1.7Hz), 7.62 (1H, s).

Reference Example 69

In the same manner as in Reference Example 31, from 2.66 g of 4-methyl-2-nitrophenyl = propan-2-yl ether, (2-methyl-4-nitro-5- (propan-2-yloxy) phenyl) acetonitrile 1.80 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.40 (6H, d, J = 6.1 Hz), 2.30 (3H, s), 3.70 (2H, s), 4.63-4.76 (1H, m), 7.14 (1H, s), 7.65 (1H, s).

Reference Example 70

A mixture of 0.60 g of (2-methyl-4-nitro-5- (propan-2-yloxy) phenyl) acetonitrile, 0.61 mL of dithiophosphoric acid O, O′-diethyl and 6.0 mL of 5 mol / L hydrogen chloride-ethyl acetate solution The mixture was stirred at room temperature for 1 hour and 15 minutes and allowed to stand for 12 hours. The solvent of the reaction mixture was distilled off under reduced pressure to obtain a yellow solid. A mixture of the obtained yellow solid, 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone 0.78 g and ethanol 6.0 mL was heated to reflux for 2 hours 30 minutes. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to give 2- (2-methyl-4-nitro-5- (propan-2-yloxy) benzyl) -4- (5, a pale yellow solid. There was obtained 1.14 g of 6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29 (6H, d, J = 6.1 Hz), 1.69-1.82 (4H, m), 2.28 (3H, s), 2.68-2.82 (4H, m), 4.45 (2H, s), 4.58-4.90 (1H, m), 7.06-7.14 (1H, m), 7.45 (1H, s), 7.59-7.68 (2H, m), 7.71 (1H, s), 7.87 ( 1H, s).

Reference Example 71

In the same manner as in Reference Example 4, 2- (2-methyl-4-nitro-5- (propan-2-yloxy) benzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl)- From 0.50 g of 1,3-thiazole, 5-methyl-2- (propan-2-yloxy) -4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3- 320 mg of thiazol-2-yl) methyl) aniline were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.33 (6H, d, J = 6.1 Hz), 1.74-1.89 (4H, m), 2.19 (3H, s), 2.68-2.90 (4H, m), 3.60- 3.86 (2H, broad), 4.24 (2H, s), 4.42-4.55 (1H, m), 6.59 (1H, s), 6.75 (1H, s), 7.10 (1H, d, J = 8.2Hz), 7.23 (1H, s), 7.56 (1H, d, J = 8.2Hz), 7.62 (1H, s).

Reference Example 72

A mixture of 2.54 g of 1- (difluoromethoxy) -4-methyl-2-nitrobenzene, 5.00 g of sodium hydroxide, 2.90 g of 2-((cyanomethyl) sulfanyl) benzoic acid and 25 mL of dimethyl sulfoxide is stirred at 30 to 40 ° C. for 2 hours. Stir. The reaction mixture was ice-cooled, water and ethyl acetate were added, and the insoluble material was removed by filtration. The organic layer of the filtrate was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane: ethyl acetate = 3: 1] to obtain 2.07 g of (5- (difluoromethoxy) -2-methyl-4-nitrophenyl) acetonitrile as a brown oil. It was.
¹ H-NMR (CDCl ₃ ) δ value: 2.42 (3H, s), 3.74 (2H, s), 6.62 (1H, t, J = 72.8Hz), 7.44 (1H, s), 7.82 (1H, s) .

Reference Example 73

In the same manner as in Reference Example 29, from 0.68 g of (5- (difluoromethoxy) -2-methyl-4-nitrophenyl) acetonitrile, 2- (5- (difluoromethoxy) -2-methyl-4-nitrobenzyl)- There was obtained 0.73 g of 4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole.
¹ H-NMR (CDCl ₃ ) δ value: 1.78-1.87 (4H, m), 2.44 (3H, s), 2.76-2.88 (4H, m), 4.54 (2H, s), 6.61 (1H, t, J = 73.3Hz), 7.12 (1H, d, J = 7.8Hz), 7.31 (1H, s), 7.52-7.60 (2H, m), 7.78 (1H, s), 7.81 (1H, s).

Reference Example 74

2- (5- (difluoromethoxy) -2-methyl-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole 0.73 g, ethanol 12 mL and To a mixture of 3 mL of water, 0.33 g of iron powder and 54 mg of ammonium chloride were added and heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature, insolubles were filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 7: 1-3: 1], and 2- (difluoromethoxy) -5-methyl-4-(( 460 mg of 4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.77-1.86 (4H, m), 2.22 (3H, s), 2.74-2.88 (4H, m), 3.49 (2H, s), 4.24 (2H, s), 6.44 (1H, t, J = 74.5Hz), 6.64 (1H, s), 6.98 (1H, s), 7.10 (1H, d, J = 8.0Hz), 7.23-7.30 (1H, m), 7.53-7.59 (1H, m), 7.60 (1H, s).

Reference Example 75

4-bromo-5-methyl-2- (propan-2-yl) aniline 500 mg, ethyl cyanoacetate 702 μL, bis (tri-tert-butylphosphine) palladium (0) 56 mg, tripotassium phosphate 1.40 g and toluene 10 mL The mixture was heated to reflux under a nitrogen atmosphere for 5 hours. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, 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: ethyl acetate = 4: 1], and light yellow oily ethyl = (4-amino-2-methyl-5- (propan-2-yl) phenyl ) 470 mg of (cyano) acetate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.15-1.31 (9H, m), 2.28 (3H, s), 2.77-2.90 (1H, m), 3.68-3.76 (2H, broad), 4.16-4.32 (2H , m), 4.76 (1H, s), 6.51 (1H, s), 7.15 (1H, s).

Reference Example 76

A mixture of ethyl = (4-amino-2-methyl-5- (propan-2-yl) phenyl) (cyano) acetate 460 mg, sodium chloride 0.74 g, water 1 mL and dimethyl sulfoxide 16 mL was stirred at 140 ° C. for 4 hours. . The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, 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: ethyl acetate = 5: 1], 4 mol / L hydrogen chloride-ethyl acetate solution was added, and the solid was collected by filtration to give a yellow solid (4-amino 110 mg of hydrochloride of -2-methyl-5- (propan-2-yl) phenyl) acetonitrile was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.18 (6H, d, J = 6.8 Hz), 2.26 (3H, s), 3.01-3.12 (1H, m), 3.96 (2H, s), 7.07 ( 1H, s), 7.34 (1H, s).

Reference Example 77

A mixture of 110 mg of hydrochloride of (4-amino-2-methyl-5- (propan-2-yl) phenyl) acetonitrile, 116 μL of dithiophosphoric acid O, O′-diethyl and 3 mL of 5 mol / L hydrogen chloride-ethyl acetate solution at room temperature For 19 hours. To the reaction mixture, 116 μL of dithiophosphoric acid O, O′-diethyl was added and stirred for 6 hours. Ethyl acetate and 10% aqueous potassium carbonate solution were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. A 4 mol / L hydrogen chloride-ethyl acetate solution was added to the obtained residue, and the solid was collected by filtration. Ethyl acetate and 10% aqueous potassium carbonate solution were added to the obtained solid. The organic layer was separated and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to give 2- (4-amino-2-methyl-5- (propan-2-yl) phenyl) ethanethioamide as a brown solid. 91 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.24 (6H, d, J = 6.8 Hz), 2.16 (3H, s), 2.80-2.91 (1H, m), 3.60-3.72 (2H, broad), 4.03 ( 2H, s), 6.55 (1H, s), 6.66-6.78 (1H, broad), 6.88 (1H, s), 7.35-7.48 (1H, broad).

Reference Example 78

A mixture of 2- (tert-butyl) -5-methylphenol (2.0 g), trifluoromethanesulfonic anhydride (2.4 mL), pyridine (1.47 mL) and methylene chloride (25 mL) was stirred for 2 hours and 30 minutes under ice cooling. 2 mol / L hydrochloric acid was added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution, 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] to obtain 3.42 g of colorless oily 2- (tert-butyl) -5-methylphenyl = trifluoromethanesulfonate.
¹ H-NMR (CDCl ₃ ) δ value: 1.40 (9H, s), 2.35 (3H, s), 7.06-7.10 (1H, m), 7.14-7.16 (1H, m), 7.34 (1H, d, J = 8.0Hz).

Reference Example 79

2- (tert-butyl) -5-methylphenyl = trifluoromethanesulfonate 3.0 g, benzophenone = imine 2.04 mL, palladium (II) acetate 68 mg, 2,2′-bis (diphenylphosphino) -1,1′- A mixture of 284 mg of binaphthyl, 4.62 g of cesium carbonate and 30 mL of dioxane was heated to reflux for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 100: 0-25: 1], and N- (2- (tert-butyl) -5-methylphenyl) as a yellow solid As a result, 3.04 g of 1,1-diphenylmethanimine was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.47 (9H, s), 1.96 (3H, s), 5.97-6.00 (1H, m), 6.67-6.72 (1H, m), 7.05-7.49 (9H, m ), 7.76-7.82 (2H, m).

Reference Example 80

A mixture of N- (2- (tert-butyl) -5-methylphenyl) -1,1-diphenylmethanimine (3.0 g), 2 mol / L hydrochloric acid (2.5 mL) and tetrahydrofuran (30 mL) was stirred at room temperature for 4 hours and 30 minutes. To the reaction mixture, 2 mL of 6 mol / L hydrochloric acid was added and stirred for 9 hours. To the reaction mixture was added 2 mL of 6 mol / L hydrochloric acid, and the mixture was allowed to stand for 15 hours. Toluene and water were added to the reaction mixture. The aqueous layer was separated, and the organic layer was extracted with 1 mol / L hydrochloric acid. The aqueous layer and the extract were combined, and 10% aqueous potassium carbonate solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.78 g of 2- (tert-butyl) -5-methylaniline as a pale red oil.
¹ H-NMR (CDCl ₃ ) δ value: 1.40 (9H, s), 2.23 (3H, s), 3.57-3.94 (2H, broad), 6.46-6.50 (1H, m), 6.53-6.58 (1H, m ), 7.12 (1H, d, J = 7.8Hz).

Reference Example 81

In the same manner as in Reference Example 44, 650 mg of 4-bromo-2- (tert-butyl) -5-methylaniline was obtained from 0.78 g of 2- (tert-butyl) -5-methylaniline.
¹ H-NMR (CDCl ₃ ) δ value: 1.39 (9H, s), 2.26 (3H, s), 6.61 (1H, s), 7.33 (1H, s).

Reference Example 82

In the same manner as in Reference Example 75, from 400 mg of 4-bromo-2- (tert-butyl) -5-methylaniline, ethyl = (4-amino-5- (tert-butyl) -2-methylphenyl) (cyano) Acetate 502 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.16-1.41 (3H, m), 1.40 (9H, s), 2.26 (3H, s), 3.79-3.94 (2H, m), 4.19-4.32 (2H, m ), 4.75 (1H, s), 6.47 (1H, s), 7.24 (1H, s).

Reference Example 83

In the same manner as in Reference Example 76, from 500 mg of ethyl = (4-amino-5- (tert-butyl) -2-methylphenyl) (cyano) acetate, (4-amino-5- (tert-butyl) -2- 150 mg of methylphenyl) acetonitrile hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.35 (9H, s), 2.21 (3H, s), 3.88 (2H, s), 6.89 (1H, s), 7.27 (1H, s).

Reference Example 84

In the same manner as in Reference Example 42, from 150 mg of hydrochloride of (4-amino-5- (tert-butyl) -2-methylphenyl) acetonitrile, 2- (4-amino-5- (tert-butyl) -2- 50 mg of methylphenyl) ethanethioamide hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.36 (9H, s), 2.25 (3H, s), 3.80 (2H, s), 7.03 (1H, s), 7.34 (1H, s), 9.24 9.35 (1H, broad), 9.46-9.56 (1H, broad).

Reference Example 85

To a mixture of 318 mg of 1,4-difluoro-2-nitrobenzene, 402 mg of 4-chlorophenoxyacetonitrile and 4.0 mL of N, N-dimethylformamide at −20 to −10 ° C., 561 mg of potassium tert-butoxide and N, N-dimethylformamide 4.0 mL was added and stirred at −20 to −10 ° C. for 15 minutes. To the reaction mixture was added ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 4: 1-2: 1] to obtain a black oily substance. A mixture of the obtained black oily substance, 0.47 mL of dithiophosphoric acid O, O′-diethyl and 4 mL of 5 mol / L hydrogen chloride-ethyl acetate solution was stirred at room temperature for 19 hours. To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 9: 1-2: 1] to give 2- (2,5-difluoro-4-nitrophenyl) ethanethioamide as a yellow solid 60 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 4.05 (2H, s), 7.43 (1H, dd, J = 10.6, 6.0 Hz), 7.85 (1H, dd, J = 8.7, 6.0 Hz).

Reference Example 86

A mixture of 60 mg of 2- (2,5-difluoro-4-nitrophenyl) ethanethioamide, 72 mg of 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone and 2 mL of methanol Heated to reflux for hours. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 99: 1-9: 1] to give 2- (2,5-difluoro-4-nitrobenzyl) -4 as a yellow solid. 66 mg of (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.76-1.88 (4H, m), 2.72-2.90 (4H, m), 4.46 (2H, s), 7.11 (1H, d, J = 7.8Hz), 7.32 7.40 (2H, m), 7.52-7.63 (2H, m), 7.84 (1H, dd, J = 8.5,6.1Hz).

Reference Example 87

In the same manner as in Reference Example 4, from 66 mg of 2- (2,5-difluoro-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole, 42 mg of 2,5-difluoro-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.76-1.86 (4H, m), 2.72-2.88 (4H, m), 3.68-3.92 (2H, broad), 4.27 (2H, d, J = 1.0Hz), 6.51 (1H, dd, J = 10.4,7.4Hz), 6.96 (1H, dd, J = 11.0,6.8Hz), 7.10 (1H, d, J = 7.8Hz), 7.27 (1H, s), 7.56 (1H , dd, J = 7.8,1.7Hz), 7.60 (1H, s).

Reference Example 88

In the same manner as in Reference Example 19, 0.31 g of (2,5-dichloro-4-nitrophenyl) acetonitrile was obtained from 1.92 g of 1,4-dichloro-2-nitrobenzene.
¹ H-NMR (CDCl ₃ ) δ value: 3.91 (2H, d, J = 0.5 Hz), 7.78 (1H, s), 8.01 (1H, s).

Reference Example 89

In the same manner as in Reference Example 24, 0.28 g of 2- (2,5-dichloro-4-nitrophenyl) ethanethioamide was obtained from 0.30 g of (2,5-dichloro-4-nitrophenyl) acetonitrile.
¹ H-NMR (CDCl ₃ ) δ value: 4.14 (2H, s), 6.76-7.04 (1H, broad), 7.32-7.60 (1H, broad), 7.68 (1H, s), 7.98 (1H, s).

Reference Example 90

In the same manner as in Reference Example 21, 133 mg of 2- (2,5-dichloro-4-nitrophenyl) ethanethioamide and 127 mg of 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone As a result, 190 mg of 2- (2,5-dichloro-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.78-1.88 (4H, m), 2.76-2.94 (4H, m), 5.41 (2H, s), 7.22 (1H, d, J = 8.1 Hz), 7.52 ( 1H, s), 7.75 (1H, dd, J = 8.1, 1.9Hz), 7.89 (1H, s), 8.00 (1H, s), 8.40 (1H, s).

Reference Example 91

In the same manner as in Reference Example 10, from 90 mg of 2- (2,5-dichloro-4-nitrobenzyl) -4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole, 72 mg of 2,5-dichloro-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.76-1.86 (4H, m), 2.72-2.90 (4H, m), 4.02-4.16 (2H, broad), 4.37 (2H, s), 6.83 (1H, s ), 7.10 (1H, d, J = 8.0Hz), 7.22-7.30 (2H, m), 7.56 (1H, dd, J = 8.0, 2.0Hz), 7.61 (1H, s).

Reference Example 92

To a solution of 1.09 g of N-ethyl-N-methylformamide in 5 mL of methylene chloride was added 1.07 mL of oxalyl chloride under ice cooling, and the mixture was stirred at room temperature for 30 minutes. A solution of 1.00 g of (4-amino-3,5-dimethylphenyl) acetonitrile in 5 mL of methylene chloride was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and ice water. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, ethyl acetate, acetone and a 4 mol / L hydrogen chloride-ethyl acetate solution were added, and the solid was collected by filtration to give N ′-(4- (cyanomethyl) -2,6-dimethylphenyl as a white solid. ) 1.51 g of hydrochloride salt of -N-ethyl-N-methylimidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.22-1.29 (3H, m), 2.27 (6H, s), 3.25-3.30 (3H, m), 3.56-3.76 (2H, m), 4.02 (2H , s), 7.18 (2H, s), 8.12-8.30 (1H, m), 10.87-11.08 (1H, m).

Reference Example 93

1.40 g of N ′-(4- (cyanomethyl) -2,6-dimethylphenyl) -N-ethyl-N-methylimidoformamide hydrochloride, 40 mL of 5 mol / L hydrogen chloride-ethyl acetate solution and dithiophosphoric acid O, O ′ -A mixture of 1.25 mL of diethyl was stirred at room temperature for 5 hours and allowed to stand for 14 hours. Chloroform and 10% aqueous potassium carbonate solution were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [DIOL-type silica gel, hexane: ethyl acetate gradient elution = 4: 1-1: 1], and light brown solid 2- (4-((((ethyl (methyl 690 mg of amino) methylene) amino) -3,5-dimethylphenyl) ethanethioamide were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.21 (3H, t, J = 7.1 Hz), 2.12 (6H, s), 2.99 (3H, s), 3.18-3.52 (2H, broad), 4.00 (2H, s), 6.71-6.81 (1H, broad), 6.87 (2H, s), 7.17 (1H, s), 7.41-7.57 (1H, broad)

Reference Example 94

4-bromo-2,3-dimethylaniline 2.00 g, ethyl cyanoacetate 3.20 mL, tris (dibenzylideneacetone) dipalladium (0) 275 mg, tri-tert-butylphosphonium tetrafluoroborate 348 mg, tripotassium phosphate 6.37 g The mixture of toluene and 40 mL was heated to reflux for 4 hours and 10 minutes under a nitrogen atmosphere. To the reaction mixture was added 260 mg of bis (tri-tert-butylphosphine) palladium (0), and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and ice water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with 1 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue, a 4 mol / L hydrogen chloride-ethyl acetate solution was added, and the solid matter was collected by filtration, and the yellow solid ethyl = (4-amino-2,3-dimethylphenyl) (cyano) acetate hydrochloride 2.11 g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.19 (3H, t, J = 7.1 Hz), 2.21 (3H, s), 2.23 (3H, s), 4.13-4.28 (2H, m), 5.86 ( 1H, s), 7.17-7.29 (2H, m), 8.80-10.80 (3H, broad).

Reference Example 95

In the same manner as in Reference Example 76, from 0.50 g of ethyl = (4-amino-2,3-dimethylphenyl) (cyano) acetate hydrochloride, 180 mg of (4-amino-2,3-dimethylphenyl) acetonitrile hydrochloride Got.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.23 (3H, s), 2.24 (3H, s), 4.03 (2H, s), 7.25-7.28 (2H, m), 9.40-10.40 (3H, broad ).

Reference Example 96

A mixture of 150 mg of (4-amino-2,3-dimethylphenyl) acetonitrile hydrochloride, 181 μL of dithiophosphoric acid O, O′-diethyl and 3 mL of 5 mol / L hydrogen chloride-ethyl acetate solution was stirred at room temperature for 5 hours, and 12 hours Left to stand. To the reaction mixture, 97 μL of dithiophosphoric acid O, O′-diethyl was added and stirred for 3 hours, and 97 μL of dithiophosphoric acid O, O′-diethyl was added and stirred for 2 hours. To the reaction mixture was added 362 μL of dithiophosphoric acid O, O′-diethyl, and the mixture was stirred for 14 hours. To the reaction mixture, 362 μL of dithiophosphoric acid O, O′-diethyl was added and stirred for 10 hours. A 10% aqueous potassium carbonate solution and ethyl acetate were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 3: 1-0: 100], a 4 mol / L hydrogen chloride-ethyl acetate solution was added, and the solid was collected by filtration. 83 mg of 2- (4-amino-2,3-dimethylphenyl) ethanethioamide hydrochloride as a light brown solid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.18-2.22 (6H, m), 3.87 (2H, s), 7.11-7.23 (2H, m), 9.21-9.33 (1H, broad), 9.51-9.59 (1H, broad), 9.68-10.19 (3H, broad).

Reference Example 97

Mixture of 70 mg of 2- (4-amino-2,3-dimethylphenyl) ethanethioamide hydrochloride, 77 mg of 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone and 5 mL of ethanol Was heated to reflux for 1 hour 30 minutes. The reaction mixture was cooled to room temperature and ethyl acetate and 10% aqueous potassium carbonate solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 15: 1-4: 1] to give 2,3-dimethyl-4-((4- (5 , 6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.78-1.85 (4H, m), 2.11 (3H, s), 2.21 (3H, s), 2.74-2.86 (4H, m), 3.55-3.65 (2H, broad ), 4.31 (2H, s), 6.59 (1H, d, J = 7.8Hz), 6.99 (1H, d, J = 8.0Hz), 7.10 (1H, d, J = 8.0Hz), 7.22 (1H, s) ), 7.54-7.59 (1H, m), 7.60-7.64 (1H, m).

Reference Example 98

To a mixture of 0.40 g of 1,2,3,4-tetrahydro-1,4-methanonaphthalene, 0.26 mL of bromoacetyl bromide and 8 mL of methylene chloride, 0.44 g of aluminum chloride was added under ice cooling, and the mixture was heated at 0-10 ° C. Stir for hours. The reaction mixture and chloroform were added to ice water. The organic layer was separated, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 100: 0-90: 10] to give 2-bromo-1- (1,2,3,4-tetrahydro-1 , 4-Methanonaphthalen-6-yl) ethanone 0.57 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.15-1.21 (2H, m), 1.52-1.61 (1H, m), 1.75-1.82 (1H, m), 1.92-2.00 (2H, m), 3.40-3.46 (2H, m), 4.44 (2H, s), 7.24-7.28 (1H, m), 7.73-7.80 (2H, m).

Reference Example 99

To a solution of 0.22 g of 2-methyl-2,3-dihydro-1H-indene in 2.2 mL of methylene chloride were added 0.16 mL of bromoacetyl bromide and 0.26 g of aluminum chloride under ice cooling, and the mixture was stirred at room temperature for 2 hours. Ice and chloroform were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2-bromo-1- (2-methyl-2,3-dihydro-1H-inden-5-yl as a white solid. ) 0.47 g of ethanone was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.12-1.20 (3H, m), 2.50-2.68 (3H, m), 3.02-3.17 (2H, m), 4.44 (2H, s), 7.26-7.31 (1H , m), 7.75-7.83 (2H, m).

Reference Example 100

5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene 0.10 g, butyl vinyl ether 0.15 mL, potassium carbonate 0.08 g, (1,1′-bis (diphenylphosphino) ferrocene) dichloropalladium (II ) A mixture of 8.7 mg, water 0.2 mL and N, N-dimethylformamide 1.8 mL was treated at 100 ° C. for 20 minutes and 120 ° C. for 20 minutes using a microwave reactor. To the reaction mixture was added ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, N-bromosuccinimide (0.12 g), tetrahydrofuran (1.0 mL) and water (1.0 mL) were added, and the mixture was stirred at room temperature for 10 minutes. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 99: 1-9: 1], and colorless oily 2-bromo-1- (2,2-dimethyl-2, 3-Dihydro-1H-inden-5-yl) ethanone 53 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.16 (6H, s), 2.77 (4H, s), 4.44 (2H, s), 7.25-7.28 (1H, m), 7.74-7.81 (2H, m).

Reference Example 101

To a solution of 0.22 g of bicyclo [4.2.0] octa-1,3,5-triene in 2.0 mL of methylene chloride was added 0.20 mL of bromoacetyl bromide and 0.34 g of aluminum chloride under ice cooling, and the mixture was stirred at room temperature for 3 hours. did. Ice and chloroform were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 99: 1-93: 7] to give 1- (bicyclo [4.2.0] octa-1,3 as a white solid. , 5-trien-3-yl) -2-bromoethanone was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.24 (4H, s), 4.44 (2H, s), 7.17 (1H, d, J = 7.6 Hz), 7.67 (1H, s), 7.87 (1H, dd, J = 7.6,1.4Hz).

Reference Example 102

To a solution of 0.40 g of 5,6,7,8,9,10-hexahydrobenzo [8] annulene-2-carboxylic acid in 4.0 mL of chloroform was added 0.20 mL of oxalyl chloride and 10 μL of N, N-dimethylformamide for 1 hour. Heated to reflux for 20 minutes. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. To the obtained residue, 0.80 mL of toluene and 1.1 mL of 2,2,7,7-tetramethyl-4-((trimethylsilyl) oxy) -3,6-dioxa-2,7-disilaoct-4-ene were added. The mixture was stirred at 90-100 ° C. for 1 hour. To the reaction mixture was added 0.12 mL of 2,2,7,7-tetramethyl-4-((trimethylsilyl) oxy) -3,6-dioxa-2,7-disilaoct-4-ene, and the mixture was stirred at 90-100 ° C. for 3 hours. Stir for 30 minutes. To the reaction mixture, 1.6 mL of dioxane and 0.80 mL of 1 mol / L hydrochloric acid were added, and the mixture was stirred at 70 to 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature, adjusted to pH 2 with a 1 mol / L aqueous sodium hydroxide solution, and ethyl acetate was added to the reaction mixture. The organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 47: 3-4: 1] to give 1- (5,6,7,8,9,10-hexa of white solid. 0.19 g of hydrobenzo [8] annulen-2-yl) -2-hydroxyethanone was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.40 (4H, m), 1.66-1.76 (4H, m), 2.78-2.86 (4H, m), 3.40-3.74 (1H, broad), 4.86 (2H , s), 7.18-7.24 (1H, m), 7.66-7.70 (1H, m), 7.83-7.88 (1H, m).

Reference Example 103

Reaction A: 1- (5,6,7,8,9,10-Hexahydrobenzo [8] annulen-2-yl) -2-hydroxyethanone 20 mg of acetonitrile in a suspension of 0.16 mL under ice cooling Then, 27 mg of triphenylphosphine and 33 mg of carbon tetrabromide were added, and the mixture was stirred for 10 minutes under ice-cooling and at room temperature for 15 minutes, and then ethyl acetate and water were added to obtain a reaction mixture A.
Reaction B: 1- (5,6,7,8,9,10-hexahydrobenzo [8] annulen-2-yl) -2-hydroxyethanone in a suspension of 170 mg of acetonitrile in 1.4 mL of acetonitrile under ice cooling Then, 0.23 g of triphenylphosphine and 0.28 g of carbon tetrabromide were added, and the mixture was stirred for 20 minutes under ice-cooling and for 15 minutes at room temperature, and then ethyl acetate and water were added to obtain a reaction mixture B.
Reaction mixture A and reaction mixture B were combined. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 49: 1-9: 1] to give 2-bromo-1- (5,6,7,8, 0.26 g of 9,10-hexahydrobenzo [8] annulen-2-yl) ethanone was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.80 (8H, m), 2.77-2.87 (2H, m), 4.45 (2H, s), 7.16-7.24 (1H, m), 7.70-7.78 (2H , m).

Example 1

Under a nitrogen atmosphere, 54 μL of oxalyl chloride was added to a solution of N-ethyl-N-methylformamide 55 mg in chloroform 1.0 mL, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 131 mg of 5-bromo-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline. A chloroform 1.0 mL solution was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [DIOL type silica gel, hexane: ethyl acetate = 10: 1], 0.17 mL of a 4.9 mol / L hydrogen chloride-ethyl acetate solution was added, and the solid was collected by filtration. N ′-(5-Bromo-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) as a white solid Phenyl) -N-ethyl-N-methylimidoformamide hydrochloride 115 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.22-1.30 (3H, m), 1.71-1.79 (4H, m), 2.30-2.35 (3H, m), 2.69-2.80 (4H, m), 3.23 -3.31 (3H, m), 3.55-3.68 (2H, m), 4.48 (2H, s), 7.10 (1H, d, J = 7.8Hz), 7.51 (1H, s), 7.60-7.65 (2H, m ), 7.77-7.81 (1H, m), 7.86 (1H, m), 8.32-8.50 (1H, m), 10.78-11.05 (1H, m).

Example 2

In the same manner as in Example 1, 5-cyclopropyl-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl ) Methyl) aniline from 90 mg, N ′-(5-cyclopropyl-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole-2) 70 mg of hydrochloride of -yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 0.57-0.69 (2H, m), 0.87-0.96 (2H, m), 1.37-1.53 (3H, m), 1.79-1.90 (5H, m), 2.46-2.62 (3H, m), 2.76-2.91 (4H, m), 3.36-3.48 (1H, m), 3.63-3.77 (3H, m), 4.16-4.28 (1H, m), 4.93-5.02 (2H, m) , 6.88-6.99 (1H, m), 7.17-7.23 (2H, m), 7.45-7.54 (1H, m), 7.71-7.87 (3H, m), 8.50-8.85 (1H, m).

Example 3

2,5-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline 0.13 g and N-methylformamide 2.6 To the mL mixture, 0.11 g of p-toluenesulfonyl chloride was added and stirred at room temperature for 16 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [DIOL type silica gel, hexane: ethyl acetate = 3: 1], 0.20 mL of 4 mol / L hydrogen chloride-ethyl acetate solution and acetone were added, and the solid was collected by filtration. N ′-(2,5-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl as a white solid ) -N-methylimidoformamide hydrochloride 60 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.72-1.79 (4H, m), 2.26-2.35 (6H, m), 2.69-2.81 (4H, m), 2.98-3.15 (3H, m), 4.33 -4.41 (2H, m), 7.07-7.34 (3H, m), 7.60-7.65 (2H, m), 7.82-7.88 (1H, m), 8.24-8.62 (1H, m), 8.90-10.30 (1H, m), 10.77-11.29 (1H, m).

Example 4

In the same manner as in Example 3, 2,5-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) From 114 mg of aniline to N ′-(2,5-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl as a white solid 66 mg of phenyl) -N-ethylimidoformamide hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.11-1.27 (3H, m), 1.71-1.79 (4H, m), 2.15-2.36 (6H, m), 2.69-2.80 (4H, m), 3.33 -3.57 (2H, m), 4.33-4.42 (2H, m), 7.07-7.36 (3H, m), 7.60-7.65 (2H, m), 7.82-7.88 (1H, m), 8.16-8.70 (1H, m), 9.07-10.38 (1H, m), 10.93-11.46 (1H, m).

Example 5

2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride 200 mg, 2-bromo-1- (5,6,7,8-tetrahydronaphthalene A mixture of -2-yl) ethanone 186 mg and methanol 2 mL was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the pH was adjusted to 9.5 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [DNH type silica gel, hexane: ethyl acetate = 8: 1], 0.20 mL of a 4.9 mol / L hydrogen chloride-ethyl acetate solution was added, and the solid was collected by filtration. N ′-(2,5-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) as a white solid 252 mg of hydrochloride salt of -N-ethyl-N-methylimidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.22-1.29 (3H, m), 1.70-1.79 (4H, m), 2.28-2.32 (6H, s), 2.67-2.81 (4H, m), 3.23 -3.30 (3H, m), 3.58-3.74 (2H, m), 4.37 (2H, s), 7.10 (1H, d, J = 8.0Hz), 7.21-7.25 (1H, m), 7.28 (1H, s ), 7.60-7.64 (2H, m), 7.84 (1H, s), 8.27-8.46 (1H, m), 10.82-11.05 (1H, m).

Example 6

According to the same procedure as in Example 5, 0.36 g of 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride, 2-bromo-1- ( From 0.48 g of 5,6,7,8-tetrahydronaphthalen-2-yl) propan-1-one to N ′-(2,5-dimethyl-4-((5-methyl-4- (5,6 , 7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide hydrochloride 0.25 g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.22-1.28 (3H, m), 1.71-1.79 (4H, m), 2.27-2.32 (6H, m), 2.44 (3H, s), 2.70-2.79 (4H, m), 3.22-3.29 (3H, m), 3.46-3.84 (2H, m), 4.27 (2H, s), 7.09-7.14 (1H, m), 7.20-7.23 (1H, m), 7.27 (1H, s), 7.30-7.34 (2H, m), 8.26-8.44 (1H, m), 10.80-11.01 (1H, m).

Example 7

In the same manner as in Example 5, 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride 100 mg, 2-bromo-1- (5 , 5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) ethanone from 108 mg of white solid N ′-(2,5-dimethyl-4-((4- (5 Of 5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide 142 mg of hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.21-1.32 (15H, m), 1.63-1.69 (4H, m), 2.31 (3H, s), 2.33 (3H, s), 3.23-3.30 (3H , m), 3.58-3.73 (2H, m), 4.39 (2H, s), 7.21-7.25 (1H, m), 7.29 (1H, s), 7.36 (1H, d, J = 8.2Hz), 7.64 ( 1H, dd, J = 8.2,1.9Hz), 7.86 (1H, d, J = 1.9Hz), 7.90 (1H, s), 8.26-8.44 (1H, m), 10.82-11.04 (1H, m).

Example 8

In the same manner as in Example 5, 200 mg of 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride, 2-bromo-1- (indane -5-yl) ethanone to 175 mg of light yellow solid N ′-(4-((4- (indan-5-yl) -1,3-thiazol-2-yl) methyl) -2,5-dimethylphenyl) 245 mg of hydrochloride salt of -N-ethyl-N-methylimidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.22-1.28 (3H, m), 1.98-2.09 (2H, m), 2.28-2.35 (6H, m), 2.83-2.93 (4H, m), 3.21 -3.30 (3H, m), 3.58-3.68 (2H, m), 4.37 (2H, s), 7.21-7.25 (1H, m), 7.27 (1H, d, J = 7.7Hz), 7.29 (1H, s ), 7.69 (1H, d, J = 7.7Hz), 7.78 (1H, s), 7.85 (1H, s), 8.27-8.45 (1H, m), 10.69-10.94 (1H, m).

Example 9

In the same manner as in Example 5, 100 mg of 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride, 2-bromo-1- (benzo From 94 mg of cycloheptan-2-yl) ethanone to N ′-(2,5-dimethyl-4-((4- (benzocycloheptan-2-yl) -1,3-thiazol-2-yl) methyl as a white solid 124 mg of phenyl) -N-ethyl-N-methylimidoformamide hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.21-1.30 (3H, m), 1.51-1.65 (4H, m), 1.75-1.86 (2H, m), 2.26-2.35 (6H, m), 2.73 -2.85 (4H, m), 3.20-3.30 (3H, m), 3.58-3.66 (2H, m), 4.38 (2H, s), 7.16 (1H, d, J = 7.8Hz), 7.21-7.25 (1H , m), 7.29 (1H, s), 7.61 (1H, dd, J = 7.8, 1.7Hz), 7.66-7.69 (1H, m), 7.85 (1H, s), 8.27-8.46 (1H, m), 10.67-10.88 (1H, m).

Example 10

0.12 mL of oxalyl chloride was added to a 2.4 mL chloroform solution of 0.14 g N-isopropyl-N-methylformamide and stirred at room temperature for 20 minutes. To the reaction mixture, 2,5-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline 0.24 g of chloroform was added. 2.4 mL solution was added and stirred at room temperature for 4 hours. The solvent of the reaction mixture was distilled off under reduced pressure. Ethanol was added to the obtained residue, and the solvent was distilled off under reduced pressure. Diethyl ether and ethyl acetate were added to the obtained residue, the solid was collected by filtration, washed with acetone, and white solid N ′-(2,5-dimethyl-4-((4- (5,6 , 7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-methyl-N- (propan-2-yl) imidoformamide 0.17 g of Z hydrochloride Obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.25-1.31 (6H, m), 1.70-1.79 (4H, m), 2.30 (3H, s), 2.32 (3H, s), 2.66-2.80 (4H , m), 3.12-3.18 (3H, m), 4.08-4.17 (1H, m), 4.37 (2H, s), 7.10 (1H, d, J = 8.6Hz), 7.22-7.31 (2H, m), 7.59-7.65 (2H, m), 7.84 (1H, s), 8.23-8.46 (1H, m), 10.63-10.93 (1H, m).

Example 11

In the same manner as in Example 1, 2,5-dimethyl-4- (2- (4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) N '-(2,5-dimethyl-4- (2- (4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole-2) from 82 mg of ethyl) aniline 87 mg of hydrochloride of -yl) ethyl) phenyl) -N-ethyl-N-methylimidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.20-1.30 (3H, m), 1.71-1.80 (4H, m), 2.23-2.32 (6H, m), 2.67-2.82 (4H, m), 3.02 -3.12 (2H, m), 3.20-3.33 (5H, m), 3.48-3.70 (2H, m), 7.07-7.18 (2H, m), 7.22 (1H, s), 7.61-7.68 (2H, m) 7.84 (1H, s), 8.22-8.43 (1H, m), 10.68-10.91 (1H, m).

Example 12

To a solution of N-ethyl-N-methylformamide 48 mg in chloroform 1.0 mL was added oxalyl chloride 48 μL, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added 5-amino-4-methyl-2-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) benzonitrile 0.10. A solution of g in chloroform (3.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction mixture was distilled off under reduced pressure. Ethyl acetate and acetone were added to the obtained residue, and the solid matter was collected by filtration, and N ′-(5-cyano-2-methyl-4-((4- (5,6,7,8- 88 mg of hydrochloride of tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.23-1.33 (3H, m), 1.71-1.80 (4H, m), 2.42-2.51 (3H, m), 2.65-2.81 (4H, m), 3.25 -3.34 (3H, m), 3.59-3.75 (2H, m), 4.58 (2H, s), 7.09 (1H, d, J = 8.3Hz), 7.59-7.64 (3H, m), 7.91 (1H, s ), 7.96-8.04 (1H, m), 8.34-8.53 (1H, m), 10.93-11.16 (1H, m).

Example 13

To a solution of 33 mg of N-ethyl-N-methylformamide in 1 mL of chloroform was added 32 μL of oxalyl chloride, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture, 92 mg of 5-chloro-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline A 2 mL solution of chloroform was added, and the mixture was stirred at room temperature for 15 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid matter was collected by filtration, and a pale yellow solid N ′-(5-chloro-2-methyl-4-((4- (5,6,7,8-tetrahydro 102 mg of the hydrochloride salt of naphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.20-1.31 (3H, m), 1.67-1.81 (4H, m), 2.34 (3H, s), 2.65-2.81 (4H, m), 3.20-3.32 (3H, m), 3.55-3.77 (2H, m), 4.48 (2H, s), 7.10 (1H, d, J = 8.3Hz), 7.51 (1H, s), 7.56-7.68 (3H, m), 7.86 (1H, s), 8.30-8.54 (1H, m).

Example 14

30 μL of oxalyl chloride was added to 1 mL of chloroform in 30 mg of N-ethyl-N-methylformamide, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 82 mg of 5-fluoro-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline. A 2 mL solution of chloroform was added, and the mixture was stirred at room temperature for 10 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid substance was collected by filtration, and a light yellow solid N-ethyl-N ′-(5-fluoro-2-methyl-4-((4- (5,6,7 , 8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-methylimidoformamide hydrochloride 95 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.21-1.30 (3H, m), 1.69-1.81 (4H, m), 2.33 (3H, s), 2.65-2.83 (4H, m), 3.21-3.34 (3H, m), 3.56-3.80 (2H, m), 4.40 (2H, s), 7.09 (1H, d, J = 7.6Hz), 7.38-7.50 (2H, m), 7.57-7.67 (2H, m ), 8.29-8.51 (1H, m), 11.00-11.33 (1H, m).

Example 15

To a solution of 36 mg of N-ethyl-N-methylformamide in 5 mL of methylene chloride was added 36 μL of oxalyl chloride under ice cooling, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added 85 mg of 4-methyl-6-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) biphenyl-3-amine. Methylene chloride (2 mL) was added, and the mixture was stirred at room temperature for 3 hours. Ice water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. A 5 mol / L hydrogen chloride-ethyl acetate solution was added to the obtained residue, and the solid substance was collected by filtration, and a light yellow solid N-ethyl-N-methyl-N ′-(4-methyl-6-((4 There was obtained 82 mg of hydrochloride salt of-(5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) biphenyl-3-yl) imidoformamide.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.21-1.29 (3H, m), 1.70-1.79 (4H, m), 2.35-2.41 (3H, m), 2.66-2.80 (4H, m), 3.21 -3.29 (3H, m), 3.54-3.70 (2H, m), 4.33 (2H, s), 7.08 (1H, d, J = 8.3Hz), 7.33-7.49 (7H, m), 7.53-7.59 (2H , m), 7.80 (1H, s), 8.31-8.51 (1H, m), 10.64-10.87 (1H, m).

Example 16

34 μL of oxalyl chloride was added to 1 mL of chloroform in 34 mg of N-ethyl-N-methylformamide, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, 5- (difluoromethoxy) -2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) A solution of 79 mg of aniline in 1 mL of chloroform was added, and the mixture was stirred at room temperature for 30 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Ethyl acetate and acetone were added to the obtained residue, and the solid substance was collected by filtration, and N ′-(5- (difluoromethoxy) -2-methyl-4-((4- (5,6, 73 mg of 7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.23-1.30 (3H, m), 1.71-1.79 (4H, m), 2.29-2.34 (3H, m), 2.66-2.80 (4H, m), 3.22 -3.31 (3H, m), 3.60-3.70 (2H, m), 4.37 (2H, s), 7.09 (1H, d, J = 7.8Hz), 7.23 (1H, t, J = 73.7Hz), 7.35 ( 1H, s), 7.45 (1H, s), 7.58-7.64 (2H, m), 7.85 (1H, s), 8.30-8.49 (1H, m), 10.72-10.90 (1H, m).

Example 17

To a solution of 27 mg of N-ethyl-N-methylformamide in 1 mL of chloroform was added 26 μL of oxalyl chloride, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 75 mg of 5-methoxy-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline. Chloroform 2mL solution was added and stirred at room temperature for 5 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid substance was collected by filtration, and a pale yellow solid N-ethyl-N ′-(5-methoxy-2-methyl-4-((4- (5,6,7 , 8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-methylimidoformamide hydrochloride 97 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.21-1.33 (3H, m), 1.66-1.82 (4H, m), 2.20-2.30 (3H, m), 2.63-2.83 (4H, m), 3.20 -3.36 (3H, m), 3.57-3.73 (2H, m), 3.84 (3H, s), 4.29 (2H, s), 7.02-7.18 (2H, m), 7.28 (1H, s), 7.57-7.69 (2H, m), 7.80 (1H, s), 8.26-8.53 (1H, m), 10.70-11.01 (1H, m).

Example 18

2- (5-Methyl-4-nitro-2- (trifluoromethyl) phenyl) ethanethioamide 0.12 g, 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl) ethanone 0.16 g A mixture of ethanol and 2.0 mL was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. Hexane was added to the obtained residue, and the solid was collected by filtration to obtain a light brown solid. A mixture of the obtained light brown solid, water 0.6 mL, ethanol 2.4 mL, iron powder 58 mg and ammonium chloride 11 mg was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the insoluble material was removed by filtration. The organic layer of the filtrate was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and activated carbon was added. The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure to give a yellow oil. 17 μL of oxalyl chloride was added to a 1.0 mL chloroform solution of 18 mg N-ethyl-N-methylformamide and stirred at room temperature for 10 minutes. To the reaction mixture was added a 1.0 mL solution of the obtained yellow oil in chloroform, and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction mixture was distilled off under reduced pressure. Diethyl ether and ethyl acetate were added to the obtained residue, and the solid was collected by filtration, washed with acetone, and pale yellow solid N-ethyl-N-methyl-N ′-(2-methyl-4-(( 4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) -5- (trifluoromethyl) phenyl) imidoformamide hydrochloride 24 mg was obtained. .
¹ H-NMR (DMSO-d ₆ ) δ value: 1.23-1.31 (3H, m), 1.71-1.79 (4H, m), 2.42 (3H, s), 2.65-2.82 (4H, m), 3.24-3.31 (3H, m), 3.60-3.72 (2H, m), 4.54 (2H, s), 7.10 (1H, d, J = 7.8Hz), 7.59-7.65 (3H, m), 7.86 (1H, s), 7.88 (1H, s), 8.35-8.55 (1H, m), 10.88-11.09 (1H, m).

Example 19

To a solution of 107 mg of N-ethyl-N-methylformamide in 1.5 mL of chloroform was added 105 μL of oxalyl chloride, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added 2-methyl-5- (propan-2-yloxy) -4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl. ) Methyl) aniline (240 mg) in chloroform (1.5 mL) was added, and the mixture was stirred at room temperature for 20 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. A 5 mol / L hydrogen chloride-ethyl acetate solution was added to the obtained residue, and the solvent was distilled off under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue, the solid was collected by filtration, and a light brown solid N-ethyl-N-methyl-N ′-(2-methyl-5- (propan-2-yloxy) 220 mg of hydrochloride of -4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) imidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.20-1.32 (9H, m), 1.70-1.82 (4H, m), 2.20-2.32 (3H, m), 2.74-2.84 (4H, m), 3.20 -3.34 (3H, m), 3.57-3.71 (2H, m), 4.26 (2H, s), 4.59-4.72 (1H, m), 7.06-7.14 (2H, m), 7.28 (1H, s), 7.58 -7.68 (2H, m), 7.80 (1H, s), 8.24-8.46 (1H, m), 10.64-10.84 (1H, m).

Example 20

To a solution of N-ethyl-N-methylformamide 27 mg in 1 mL of chloroform was added 27 μL of oxalyl chloride, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture, 56 mg of 5-ethynyl-2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline Chloroform 1mL solution was added and stirred at room temperature for 30 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Acetone, ethyl acetate and diethyl ether were added to the obtained residue, and the solid was collected by filtration, and N-ethyl-N ′-(5-ethynyl-2-methyl-4-((4- (5 , 6,7,8-Tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-methylimidoformamide hydrochloride 45 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.22-1.30 (3H, m), 1.72-1.79 (4H, m), 2.32-2.37 (3H, m), 2.65-2.81 (4H, m), 3.20 -3.31 (3H, m), 3.58-3.72 (2H, m), 4.50 (2H, s), 4.53 (1H, s), 7.10 (1H, d, J = 8.0Hz), 7.45 (1H, s), 7.60-7.65 (3H, m), 7.85 (1H, m), 8.32-8.50 (1H, m), 10.58-10.76 (1H, m).

Example 21

To a solution of 42 mg of N-ethyl-N-methylformamide in 1 mL of methylene chloride was added 42 μL of oxalyl chloride under ice cooling, and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added 2-methyl-5- (propan-2-yl) -4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3- under ice cooling. A solution of thiazol-2-yl) methyl) aniline hydrochloride (100 mg) in methylene chloride (10 mL) was added, and the mixture was stirred at room temperature for 50 minutes. Chloroform and 10% aqueous potassium carbonate solution were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 2: 1-0: 100], a 5 mol / L hydrogen chloride-ethyl acetate solution was added, and the solid was collected by filtration. White solid N-ethyl-N-methyl-N ′-(2-methyl-5- (propan-2-yl) -4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) 87 mg of hydrochloride salt of) -1,3-thiazol-2-yl) methyl) phenyl) imidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.16 (6H, d, J = 6.8 Hz), 1.23-1.30 (3H, m), 1.70-1.79 (4H, m), 2.28-2.31 (3H, m ), 2.66-2.79 (4H, m), 3.22-3.31 (4H, m), 3.59-3.77 (2H, m), 4.42 (2H, s), 7.09 (1H, d, J = 8.0Hz), 7.28- 7.34 (2H, m), 7.59-7.65 (2H, m), 7.83 (1H, s), 8.22-8.43 (1H, m), 10.67-10.89 (1H, m).

Example 22

Reaction A: To 1 mL of methylene chloride in 41 mg of N-ethyl-N-methylformamide was added 40 μL of oxalyl chloride under ice cooling, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was stirred under ice cooling with 5- (tert-butyl) -2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole- 2-yl) methyl) aniline hydrochloride (100 mg) in methylene chloride (10 mL) was added, and the mixture was stirred at room temperature for 50 minutes. To the reaction mixture, 130 μL of triethylamine was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour and 30 minutes to obtain reaction mixture A.
Reaction B: 40 μL of oxalyl chloride was added to 2 mL of methylene chloride in 41 mg of N-ethyl-N-methylformamide, and the mixture was stirred at room temperature for 20 minutes to obtain a reaction mixture B.
Under ice-cooling, reaction mixture B was added to reaction mixture A and stirred at room temperature for 10 minutes. Chloroform and 10% aqueous potassium carbonate solution were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [DNH type silica gel, hexane: toluene gradient elution = 100: 0-20: 1], 5 mol / L hydrogen chloride-ethyl acetate solution was added, and the solid was filtered. N ′-(5- (tert-butyl) -2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazole) 67 mg of hydrochloride of -2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.23-1.29 (3H, m), 1.40 (9H, s), 1.71-1.79 (4H, m), 2.25-2.29 (3H, m), 2.65-2.81 (4H, m), 3.21-3.31 (3H, m), 3.60-3.72 (2H, m), 4.62 (2H, s), 7.10 (1H, d, J = 7.8Hz), 7.27-7.32 (2H, m ), 7.61-7.66 (2H, m), 7.83 (1H, s), 8.27-8.47 (1H, m), 10.68-10.87 (1H, m).

Example 23

To a 1.0 mL chloroform solution of 26 mg N-ethyl-N-methylformamide was added 26 μL oxalyl chloride, and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture, 5- (difluoromethyl) -2-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) A solution of aniline (58 mg) in chloroform (1.0 mL) was added, and the mixture was stirred at room temperature for 20 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Ethyl acetate and acetone were added to the obtained residue, and the solid matter was collected by filtration, and N ′-(5- (difluoromethyl) -2-methyl-4-((4- (5,6, There was obtained 28 mg of hydrochloride salt of 7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide.
¹ H-NMR (CD ₃ OD) δ value: 1.34-1.41 (3H, m), 1.78-1.86 (4H, m), 2.41 (3H, m), 2.73-2.86 (4H, m), 3.20-3.40 ( 3H, m), 3.63-3.73 (2H, m), 4.56 (2H, s), 7.08 (1H, d, J = 7.8Hz), 7.18 (1H, t, J = 54.8Hz), 7.48 (1H, s ), 7.53-7.58 (2H, m), 7.60 (1H, s), 7.63 (1H, s), 8.22-8.39 (1H, m).

Example 24

To a solution of N-ethyl-N-methylformamide 32 mg in 1 mL of chloroform was added 31 μL of oxalyl chloride, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 85 mg of 2-fluoro-5-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline. A 2 mL solution of chloroform was added, and the mixture was stirred at room temperature for 10 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid matter was collected by filtration, and light yellow solid N-ethyl-N ′-(2-fluoro-5-methyl-4-((4- (5,6,7 , 8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-methylimidoformamide hydrochloride 92 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.20-1.30 (3H, m), 1.67-1.80 (4H, m), 2.32 (3H, s), 2.64-2.82 (4H, m), 3.22-3.34 (3H, m), 3.58-3.75 (2H, m), 4.43 (2H, s), 7.10 (1H, d, J = 8.3Hz), 7.38-7.48 (2H, m), 7.58-7.65 (2H, m ), 7.87 (1H, s), 8.43-8.64 (1H, m), 11.15-11.39 (1H, m).

Example 25

To a solution of N-ethyl-N-methylformamide 25 mg in 1 mL of chloroform was added 25 μL of oxalyl chloride, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was charged with 2-amino-4-methyl-5-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) benzonitrile 52 mg. In chloroform (2 mL) and stirred at room temperature for 2 hours. To the reaction mixture, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of hexane: ethyl acetate = 4: 1-1: 1], and N ′-(2-cyano-5-methyl-4- ( 8 mg of (4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.22-1.29 (3H, m), 1.78-1.86 (4H, m), 2.31 (3H, s), 2.76-2.87 (4H, m), 3.01-3.11 (3H , m), 3.31-3.63 (2H, m), 4.30 (2H, s), 6.77-6.87 (1H, m), 7.10 (1H, d, J = 8.0Hz), 7.25-7.29 (1H, m), 7.43 (1H, s), 7.53-7.69 (3H, m).

Example 26

To a solution of N-ethyl-N-methylformamide 13 mg in 1 mL of chloroform was added 13 μL of oxalyl chloride, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 37 mg of 2-chloro-5-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline. Chloroform 2mL solution was added and stirred at room temperature for 5 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid substance was collected by filtration, and the pale yellow solid N ′-(2-chloro-5-methyl-4-((4- (5,6,7,8-tetrahydro 27 mg of hydrochloride of naphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.22-1.30 (3H, m), 1.70-1.80 (4H, m), 2.35 (3H, s), 2.66-2.81 (4H, m), 3.22-3.33 (3H, m), 3.60-3.80 (2H, m), 4.45 (2H, s), 7.10 (1H, d, J = 8.6Hz), 7.49 (1H, s), 7.57-7.65 (3H, m), 7.87 (1H, s), 8.38-8.60 (1H, m), 10.95-11.18 (1H, m).

Example 27

27 μL of oxalyl chloride was added to 1 mL of chloroform in 28 mg of N-ethyl-N-methylformamide, and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture, 77 mg of 2-methoxy-5-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline A 2 mL solution of chloroform was added, and the mixture was stirred at room temperature for 10 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid matter was collected by filtration, and light yellow solid N-ethyl-N ′-(2-methoxy-5-methyl-4-((4- (5,6,7 , 8-Tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-methylimidoformamide hydrochloride 93 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.19-1.28 (3H, m), 1.70-1.80 (4H, m), 2.27 (3H, s), 2.65-2.81 (4H, m), 3.18-3.31 (3H, m), 3.57-3.68 (2H, m), 3.85 (3H, s), 4.41 (2H, s), 7.10 (1H, d, J = 7.6Hz), 7.22-7.29 (2H, m), 7.59-7.66 (2H, m), 7.84 (1H, s), 8.34-8.54 (1H, m), 10.62-10.84 (1H, m).

Example 28

To a 2.0 mL solution of 84 mg of N-ethyl-N-methylformamide in chloroform was added 82 μL of oxalyl chloride, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 5-methyl-2- (propan-2-yloxy) -4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl. ) 206 mg of methyl) aniline hydrochloride was added and stirred at room temperature for 20 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Acetone and diisopropyl ether are added to the obtained residue, and the solid is collected by filtration to give N-ethyl-N-methyl-N ′-(5-methyl-2- (propan-2-yloxy) -4 as a white solid. 216 mg of hydrochloride of-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) imidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.20-1.34 (9H, m), 1.70-1.81 (4H, m), 2.26 (3H, s), 2.68-2.86 (4H, m), 3.20-3.32 (3H, m), 3.58-3.70 (2H, m), 4.39 (2H, s), 4.56-4.68 (1H, m), 7.10 (1H, d, J = 7.8Hz), 7.20-7.32 (2H, m ), 7.59-7.67 (2H, m), 7.84 (1H, s), 8.32-8.54 (1H, m), 10.56-10.71 (1H, m).

Example 29

To a 1.5 mL chloroform solution of 101 mg N-ethyl-N-methylformamide was added 100 μL oxalyl chloride, and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added 2- (difluoromethoxy) -5-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) A solution of aniline 233 mg in chloroform 1.5 mL was added, and the mixture was stirred at room temperature for 40 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate and a 5 mol / L hydrogen chloride-ethyl acetate solution were added to the obtained residue, and the solvent was distilled off under reduced pressure. Ethyl acetate, acetone and diisopropyl ether were added to the obtained residue, and the solid matter was collected by filtration, and light yellow solid N ′-(2- (difluoromethoxy) -5-methyl-4-((4- (5 , 6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide hydrochloride 196 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.20-1.30 (3H, m), 1.70-1.80 (4H, m), 2.35 (3H, s), 2.68-2.82 (4H, m), 3.20-3.34 (3H, m), 3.56-3.80 (2H, m), 4.44 (2H, s), 7.00-7.24 (1H, m), 7.38-7.46 (2H, m), 7.58-7.65 (2H, m), 7.87 (1H, s), 8.38-8.58 (1H, m), 10.92-11.10 (1H, m).

Example 30

Reaction A: 2- (4-Amino-2-methyl-5- (propan-2-yl) phenyl) ethanethioamide 90 mg, 2-bromo-1- (5,6,7,8-tetrahydronaphthalen-2-yl ) A mixture of 97 mg ethanone and 5 mL methanol was heated to reflux for 50 minutes. The reaction mixture was cooled to room temperature and ethyl acetate and 10% aqueous potassium carbonate solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. A 4 mol / L hydrogen chloride-ethyl acetate solution was added to the obtained residue, and the solid was collected by filtration to give a pale yellow solid.
Reaction B: 70 μL of oxalyl chloride was added to 2 mL of methylene chloride in 71 mg of N-ethyl-N-methylformamide, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 2 mL of a methylene chloride solution of light yellow solid obtained in Reaction A and 28 μL of triethylamine were added under ice cooling, and the mixture was stirred for 25 minutes under ice cooling. Chloroform and 10% aqueous potassium carbonate solution were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [DNH type silica gel, hexane: toluene gradient elution = 100: 0-10: 1], 5 mol / L hydrogen chloride-ethyl acetate solution was added, and the solid was filtered. N-ethyl-N-methyl-N ′-(5-methyl-2- (propan-2-yl) -4-((4- (5,6,7,8-tetrahydronaphthalene) 100 mg of hydrochloride of -2-yl) -1,3-thiazol-2-yl) methyl) phenyl) imidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.18 (6H, d, J = 6.8 Hz), 1.22-1.28 (3H, m), 1.70-1.79 (4H, m), 2.31 (3H, s), 2.66-2.80 (4H, m), 3.17-3.29 (4H, m), 3.57-3.70 (2H, m), 4.41 (2H, s), 7.10 (1H, d, J = 8.0Hz), 7.20 (1H, s), 7.45 (1H, s), 7.59-7.65 (2H, m), 7.83 (1H, s), 8.27-8.45 (1H, m), 10.83-10.98 (1H, m).

Example 31

Reaction A: 2- (4-Amino-5- (tert-butyl) -2-methylphenyl) ethanethioamide hydrochloride 50 mg, 2-bromo-1- (5,6,7,8-tetrahydronaphthalene-2- Yl) A mixture of 44 mg of ethanone and 5 mL of ethanol was stirred at 70 ° C. for 2 hours. The reaction mixture was cooled to room temperature and ethyl acetate and 10% aqueous potassium carbonate solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. A 4 mol / L hydrogen chloride-ethyl acetate solution was added to the obtained residue, and the solid was collected by filtration to give a pale yellow solid.
Reaction B: To 1 mL of methylene chloride in 12 mg of N-ethyl-N-methylformamide was added 12 μL of oxalyl chloride, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to a mixture of the pale yellow solid obtained in reaction A, 12 μL of triethylamine and 1 mL of methylene chloride, and stirred at room temperature for 30 minutes to obtain reaction mixture B.
Reaction C: 12 μL of oxalyl chloride was added to 1 mL of methylene chloride in 12 mg of N-ethyl-N-methylformamide, and the mixture was stirred at room temperature for 15 minutes to obtain a reaction mixture C.
Reaction mixture C was added to reaction mixture B and stirred at room temperature for 30 minutes. A 10% aqueous potassium carbonate solution was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [DNH type silica gel, hexane], 5 mol / L hydrogen chloride-ethyl acetate solution was added, the solid was collected by filtration, and N ′-(2- (2- ( tert-butyl) -5-methyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl 14 mg of hydrochloride salt of -N-methylimidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.21-1.29 (3H, m), 1.34 (9H, s), 1.72-1.78 (4H, m), 2.32 (3H, s), 2.66-2.79 (4H , m), 3.19-3.29 (3H, m), 3.54-3.66 (2H, m), 4.43 (2H, s), 7.10 (1H, d, J = 7.6Hz), 7.15-7.19 (1H, m), 7.55 (1H, s), 7.59-7.65 (2H, m), 7.83 (1H, s), 8.26-8.44 (1H, m), 10.53-10.64 (1H, m).

Example 32

15 μL of oxalyl chloride was added to a solution of N-ethyl-N-methylformamide 15 mg in 1 mL of chloroform and stirred at room temperature for 10 minutes. To the reaction mixture, 2,5-difluoro-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline 41 mg chloroform 2 mL The solution was added and stirred at room temperature for 20 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid matter was collected by filtration, and light yellow solid N ′-(2,5-difluoro-4-((4- (5,6,7,8-tetrahydronaphthalene- 40 mg of hydrochloride of 2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.18-1.35 (3H, m), 1.69-1.84 (4H, m), 2.65-2.84 (4H, m), 3.25-3.39 (3H, m), 3.61 -3.78 (2H, m), 4.45 (2H, s), 7.09 (1H, d, J = 8.3Hz), 7.56-7.73 (4H, m), 7.90 (1H, s), 8.47-8.70 (1H, m ), 11.35-11.65 (1H, m).

Example 33

24 μL of oxalyl chloride was added to 1 mL of chloroform in 24 mg of N-ethyl-N-methylformamide, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture, 2,5-dichloro-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) aniline 72 mg chloroform 2 mL The solution was added and stirred at room temperature for 15 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid matter was collected by filtration, and N ′-(2,5-dichloro-4-((4- (5,6,7,8-tetrahydronaphthalene-2) was obtained as a brown solid. 90 mg of hydrochloride of -yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.20-1.32 (3H, m), 1.67-1.80 (4H, m), 2.64-2.81 (4H, m), 3.20-3.34 (3H, m), 3.58 -3.73 (2H, m), 4.54 (2H, s), 7.10 (1H, d, J = 7.8Hz), 7.56-7.66 (2H, m), 7.85-7.94 (2H, m), 8.42-8.65 (1H , m).

Example 34

2- (4-((((Ethyl (methyl) amino) methylene) amino) -3,5-dimethylphenyl) ethanethioamide 100 mg, 2-bromo-1- (5,6,7,8-tetrahydronaphthalene-2- Yl) A mixture of 98 mg of ethanone and 5 mL of methanol was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. To the obtained residue, ethyl acetate and 10% aqueous potassium carbonate solution were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, a 5 mol / L hydrogen chloride-ethyl acetate solution was added, and the solid matter was collected by filtration, freeze-dried, and light yellow solid N ′-(2,6-dimethyl-4-((4- 148 mg of (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.20-1.29 (3H, m), 1.71-1.79 (4H, m), 2.25 (6H, s), 2.66-2.81 (4H, m), 3.22-3.28 (3H, m), 3.54-3.69 (2H, m), 4.35 (2H, s), 7.10 (1H, d, J = 8.3Hz), 7.22 (2H, s), 7.60-7.65 (2H, m), 7.85 (1H, s), 8.12-8.30 (1H, m), 10.56-10.73 (1H, m).

Example 35

To a solution of 42 mg of N-ethyl-N-methylformamide in 5 mL of methylene chloride was added 42 μL of oxalyl chloride under ice cooling, and the mixture was stirred at room temperature for 40 minutes. To the reaction mixture was added 2,3-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl) under ice cooling. A solution of 85 mg of aniline in 5 mL of methylene chloride was added, and the mixture was stirred for 1 hour and 30 minutes under ice cooling. Chloroform and 10% aqueous potassium carbonate solution were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [DNH type silica gel, hexane: chloroform gradient elution = 100: 0-15: 1], 5 mol / L hydrogen chloride-ethyl acetate solution was added, and the solid was filtered. N ′-(2,3-dimethyl-4-((4- (5,6,7,8-tetrahydronaphthalen-2-yl) -1,3-thiazol-2-yl) methyl as a white solid 97 mg) of phenyl) -N-ethyl-N-methylimidoformamide hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.26 (3H, t, J = 7.1 Hz), 1.71-1.80 (4H, m), 2.22-2.29 (6H, m), 2.66-2.82 (4H, m ), 3.22-3.31 (3H, m), 3.62 (2H, q, J = 7.1Hz), 4.45 (2H, s), 7.09 (1H, d, J = 7.7Hz), 7.20-7.26 (1H, m) , 7.33 (1H, d, J = 7.7Hz), 7.60-7.66 (2H, m), 7.83 (1H, s), 8.24-8.44 (1H, m), 10.75-11.23 (1H, m).

Example 36

0.10 g of hydrochloride of 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide, 2-bromo-1- (1,2,3,4-tetrahydro A mixture of 0.11, 4-methanonaphthalen-6-yl) ethanone and 2.0 mL of methanol was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate and ethyl acetate were added. The organic layer was separated, dried over anhydrous magnesium sulfate, and activated carbon was added. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. To the obtained residue, a 4 mol / L hydrogen chloride-ethyl acetate solution was added, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [DIOL type silica gel, hexane: ethyl acetate gradient elution = 100: 0-1: 3], a 4 mol / L hydrogen chloride-ethyl acetate solution was added, and the mixture was reduced under reduced pressure. The solvent was distilled off. Acetone and ethyl acetate are added to the obtained residue, and the solid matter is collected by filtration, and N ′-(2,5-dimethyl-4-((4- (1,2,3,4-tetrahydro 63 mg of hydrochloride of 1,4-methanonaphthalen-6-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.04-1.11 (2H, m), 1.22-1.29 (3H, m), 1.49-1.55 (1H, m), 1.62-1.68 (1H, m), 1.89 -1.96 (2H, m), 2.26-2.33 (6H, m), 3.20-3.71 (7H, m), 4.37 (2H, s), 7.14-7.25 (2H, m), 7.28 (1H, s), 7.62 (1H, dd, J = 7.6,1.5Hz), 7.72 (1H, s), 7.80 (1H, s), 8.26-8.45 (1H, m), 10.63-10.82 (1H, m).

Example 37

0.12 g of 2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride, 2-bromo-1- (2-methyl-2,3-dihydro A mixture of −1 g-inden-5-yl) ethanone and 2.0 mL methanol was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, purified by silica gel column chromatography [DIOL type silica gel, hexane: ethyl acetate gradient elution = 100: 0-4: 1], 4 mol / L hydrogen chloride-ethyl acetate solution was added, and the pressure was reduced. The solvent was distilled off under. Acetone, ethanol and ethyl acetate are added to the obtained residue, and the solid is collected by filtration, and N ′-(2,5-dimethyl-4-((4- (2-methyl-2,2, 70 mg of hydrochloride of 3-dihydro-1H-inden-5-yl) -1,3-thiazol-2-yl) methyl) phenyl) -N-ethyl-N-methylimidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.11 (3H, d, J = 6.3 Hz), 1.22-1.29 (3H, m), 2.26-2.35 (6H, m), 2.45-2.58 (3H, m ), 2.98-3.11 (2H, m), 3.22-3.29 (3H, m), 3.58-3.71 (2H, m), 4.37 (2H, s), 7.14-7.32 (3H, m), 7.66-7.70 (1H) , m), 7.74 (1H, s), 7.83 (1H, s), 8.26-8.45 (1H, m), 10.72-10.92 (1H, m).

Example 38

2- (4-(((ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride 67 mg, 2-bromo-1- (2,2-dimethyl-2,3- A mixture of 53 mg of dihydro-1H-inden-5-yl) ethanone and 2.0 mL of methanol was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [DIOL type silica gel, hexane: ethyl acetate gradient elution = 99: 1-17: 3], a 4 mol / L hydrogen chloride-ethyl acetate solution was added, and the mixture was reduced under reduced pressure. The solvent was distilled off. Ethanol, acetone and ethyl acetate were added to the obtained residue, and the solid was collected by filtration, and white solid N ′-(4-((4- (2,2-dimethyl-2,3-dihydro-1H -Inden-5-yl) -1,3-thiazol-2-yl) methyl) -2,5-dimethylphenyl) -N-ethyl-N-methylimidoformamide hydrochloride 40 mg was obtained.
¹ H-NMR (CD ₃ OD) δ value: 1.16 (6H, s), 1.34-1.41 (3H, m), 2.33-2.38 (6H, m), 2.74 (2H, s), 2.76 (2H, s) , 3.26-3.38 (3H, m), 3.63-3.72 (2H, m), 4.42 (2H, s), 7.18-7.22 (2H, m), 7.31 (1H, s), 7.58-7.66 (3H, m) , 8.16-8.34 (1H, m).

Example 39

2- (4-(((Ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride 0.29 g, 1- (bicyclo [4.2.0] octa-1,3 , 5-trien-3-yl) -2-bromoethanone and 4.4 mL of methanol were heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [DIOL type silica gel, hexane: ethyl acetate gradient elution = 99: 1-4: 1], and white solid N ′-(4-((4- (bicyclo [4.2.0] octa-1,3,5-trien-3-yl) -1,3-thiazol-2-yl) methyl) -2,5-dimethylphenyl) -N-ethyl-N-methyl 0.16 g of imidoformamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.21 (3H, t, J = 7.1 Hz), 2.24 (3H, s), 2.25 (3H, s), 2.99 (3H, s), 3.20 (4H, s) , 3.27-3.47 (2H, m), 4.28 (2H, s), 6.59 (1H, s), 7.05 (1H, s), 7.08 (1H, d, J = 8.0Hz), 7.20 (1H, s), 7.44 (1H, s), 7.57 (1H, s), 7.74 (1H, dd, J = 8.0,1.5Hz).

Example 40

2- (4-((((Ethyl (methyl) amino) methylene) amino) -2,5-dimethylphenyl) ethanethioamide hydrochloride 0.14 g, 2-bromo-1- (5,6,7,8,9 , 10-hexahydrobenzo [8] annulen-2-yl) ethanone and a mixture of methanol 2.0 mL were heated to reflux for 1 hour 35 minutes. The reaction mixture is cooled to room temperature, 0.13 g of 2-bromo-1- (5,6,7,8,9,10-hexahydrobenzo [8] annulen-2-yl) ethanone and 2.0 mL of methanol are added, and 1 Heated to reflux for hours. The reaction mixture was cooled to room temperature, and saturated aqueous sodium hydrogen carbonate solution, saturated aqueous sodium chloride solution and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [DIOL type silica gel, hexane: ethyl acetate gradient elution = 99: 1-17: 3], a 4 mol / L hydrogen chloride-ethyl acetate solution was added, and the mixture was reduced under reduced pressure. The solvent was distilled off. Ethanol and ethyl acetate were added to the obtained residue, and the solid was collected by filtration. Acetone was added to the obtained solid substance, and the mixture was collected by filtration. 61 mg of hydrochloride of annulen-2-yl) -1,3-thiazol-2-yl) methyl) -2,5-dimethylphenyl) -N-methylimidoformamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.22-1.36 (7H, m), 1.58-1.68 (4H, m), 2.27-2.34 (6H, m), 2.71-2.80 (4H, m), 3.20 -3.29 (3H, m), 3.35-3.67 (2H, m), 4.38 (2H, s), 7.16 (1H, d, J = 7.6Hz), 7.21-7.25 (1H, m), 7.30 (1H, s ), 7.65-7.69 (2H, m), 7.85 (1H, s), 8.26-8.44 (1H, m), 10.56-10.72 (1H, m).

Claims

General formula

In the formula, R 1 and R 2 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 2- 6 alkenyl group, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl group, optionally substituted C 1-6 alkoxy group, optionally substituted A C 1-6 alkylamino group, an optionally substituted di (C 1-6 alkyl) amino group, an optionally substituted C 1-6 alkylthio group, an optionally substituted aryloxy group, a substituted Arylthio group which may be substituted, aryl group which may be substituted, monocyclic heterocyclic group which may be substituted, bicyclic heterocyclic group which may be substituted, protected Good amino group, An optionally protected hydroxyl group or an optionally protected carboxyl group;
R 3 is an optionally substituted dihydrobenzocyclobutenyl group, an optionally substituted indanyl group, an optionally substituted indenyl group, an optionally substituted tetrahydronaphthyl group, an optionally substituted Good dihydronaphthyl group, optionally substituted benzocycloheptyl group, optionally substituted dihydro-5H-benzocycloheptenyl group, optionally substituted 5H-benzocycloheptenyl group, substituted May be a hexahydrobenzocyclooctenyl group, an optionally substituted tetrahydrobenzocyclooctenyl group, an optionally substituted dihydrobenzocyclooctenyl group, an optionally substituted tetrahydromethanonaphthyl group or a substituted An optionally tetrahydroethanonaphthyl group;
R 4 and R 5 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 2− A 6 alkynyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group or an optionally substituted monocyclic heterocyclic group; or
R 4 and R 5 are an optionally substituted cyclic amino group formed together with the nitrogen atom to which they are attached;
X 1 represents a sulfur atom, a C 1-6 alkylene group or a general formula NR a , wherein R a represents a hydrogen atom, an optionally substituted C 1-6 alkyl group or an imino protecting group. The group represented;
Z 1 and Z 2 are the same or different and are each a nitrogen atom or a general formula CR c wherein R c is a hydrogen atom, a halogen atom, a cyano group, a nitro group, or an optionally substituted C 1-6 alkyl. A group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1 -6 alkoxy group, optionally substituted C 1-6 alkylamino group, optionally substituted di (C 1-6 alkyl) amino group, optionally substituted C 1-6 alkylthio group, substituted Aryloxy group which may be substituted, arylthio group which may be substituted, aryl group which may be substituted, monocyclic heterocyclic group which may be substituted, bicyclic which may be substituted Heterocyclic A group, an amino group which may be protected, a hydroxyl group which may be protected or a carboxyl group which may be protected;
Z 3 represents a nitrogen atom or a group represented by the general formula CR b wherein R b represents a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group. Or a salt thereof.
R 1 and R 2 are the same or different and are each a halogen atom, a cyano group, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, a substituted An optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkylamino group , An optionally substituted di (C 1-6 alkyl) amino group, an optionally substituted C 1-6 alkylthio group, an optionally substituted aryloxy group, an optionally substituted arylthio group, Aryl group which may be substituted, monocyclic heterocyclic group which may be substituted, bicyclic heterocyclic group which may be substituted, amino group which may be protected, protected May A hydroxyl group or an optionally protected carboxyl group;
R 3 is an optionally substituted indanyl group, an optionally substituted indenyl group, an optionally substituted tetrahydronaphthyl group, an optionally substituted dihydronaphthyl group, an optionally substituted benzocyclo group. A heptyl group, an optionally substituted dihydro-5H-benzocycloheptenyl group or an optionally substituted 5H-benzocycloheptenyl group;
R 4 and R 5 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 2− A 6 alkynyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group or an optionally substituted monocyclic heterocyclic group; or
An optionally substituted cyclic amino group formed by R 4 and R 5 together with the nitrogen atom to which they are attached;
X 1 is a sulfur atom, a methylene group, or a group represented by the general formula NR a , wherein R a represents a hydrogen atom, an optionally substituted C 1-6 alkyl group or an imino protecting group. ;
Z 1 and Z 2 are the same or different and are a nitrogen atom or a group represented by the formula CH;
Z 3 is a nitrogen atom or a group represented by the general formula CR b , wherein R b represents a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group. 2. The compound or a salt thereof according to 1.
Z 1 and Z 2 may be the same or different and have the general formula CR c , wherein R c is a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted C 1-6 alkyl group, a substituted group An optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, optionally substituted C 1-6 alkylamino group, optionally substituted di (C 1-6 alkyl) amino group, an optionally substituted C 1-6 alkylthio group, substituted An aryloxy group which may be substituted, an arylthio group which may be substituted, an aryl group which may be substituted, a monocyclic heterocyclic group which may be substituted, a bicyclic heterocyclic ring which may be substituted Formula group, protected The compound or a salt thereof according to claim 1, which is a group represented by “an amino group which may be protected, a hydroxyl group which may be protected or a carboxyl group which may be protected.”
The compound or a salt thereof according to claim 1 or 2, wherein Z 1 and Z 2 are a group represented by the formula CH.
R 1 and R 2 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or a substituted 2. An optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, or an optionally substituted aryl group. 5. The compound or a salt thereof according to any one of 3 and 4.
R 1 and R 2 may be the same or different and each may be a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group or an optionally substituted The compound or a salt thereof according to any one of claims 1 to 4, which is a good C 1-6 alkoxy group.
X 1 represents a C 1-6 alkylene group or a general formula NR a , wherein R a represents a hydrogen atom, an optionally substituted C 1-6 alkyl group or an imino protecting group. The compound or a salt thereof according to any one of claims 1, 3, 4, 5, and 6, which is a group.
The compound according to any one of claims 1 to 6, wherein X 1 is a methylene group or a group represented by the general formula NR a1 , wherein R a1 represents a hydrogen atom or an imino protecting group. Or its salt.
The compound or a salt thereof according to any one of claims 1 to 6, wherein X 1 is a methylene group.
R 4 and R 5 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 2− The compound or a salt thereof according to any one of claims 1 to 9, which is a 6 alkynyl group or an optionally substituted C 3-8 cycloalkyl group.
The compound or a salt thereof according to any one of claims 1 to 9, wherein R 4 and R 5 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group.
R 3 is an optionally substituted dihydrobenzocyclobutenyl group, an optionally substituted indanyl group, an optionally substituted tetrahydronaphthyl group, an optionally substituted benzocycloheptyl group, a substituted The compound or a salt thereof according to any one of claims 1 and 3 to 11, which is an optionally substituted hexahydrobenzocyclooctenyl group or an optionally substituted tetrahydromethanonaphthyl group.
The compound according to any one of claims 1 to 11, wherein R 3 is an optionally substituted indanyl group, an optionally substituted tetrahydronaphthyl group, or an optionally substituted benzocycloheptyl group. Its salt.
An antifungal agent comprising the compound according to any one of claims 1 to 13 or a salt thereof.