6,7-DIHYDROIMIDAZO [2,1-b] [1,3]OXAZINE BACTERICIDES

TECHNICAL FIELD

The present invention relates to a 6,7-dihydroimidazo[2,1-b][1,3]oxazine compound.

BACKGROUND ART

Among acid-fast bacilli, Mycobacterium tuberculosis is widely known, and one-third of the human population are said to be infected therewith. In addition to Mycobacterium tuberculosis, Mycobacterium africanum and Mycobacterium bovis are also known to be grouped in the Mycobacterium tuberculosis complex, and are known as mycobacteria, which are highly pathogenic to humans.

The treatment of these tuberculosis uses three agents, i.e., rifampicin, isoniazid, and ethambutol (or streptomycin), or four agents, i.e., the above three agents and pyrazinamide, which serve as first-line drugs.

However, the treatment of tuberculosis requires a distinctly long-term drug administration, which causes poor compliance, often resulting in treatment failure.

Further, the aforementioned agents have been reported to cause side effects as exemplified below: rifampicin causes hepatopathy, flu syndrome, and drug allergy, and is contraindicated for use in combination with other agents due to P450 related enzyme induction; isoniazid causes peripheral neuropathy and induces serious hepatopathy when used in combination with rifampicin; ethambutol causes failing vision due to optic neuropathy; streptomycin causes hearing deterioration due to eighth cranial nerve neuropathy; and pyrazinamide causes hepatopathy, gout attacks accompanied by an increase in the uric acid level, as well as vomiting, and the like (Non-patent Literature 1 and 2).

As a practical matter, cases have been reported where standard chemotherapy could not be performed due to the aforementioned side effects, which account for 70% of the cases where drug administration was discontinued (approximately 23%, 52 cases) of the total number of cases (228 hospital patients surveyed in all) (Non-patent Literature 3).

In particular, out of the above-mentioned five agents, which are used in combination as first-line drugs, rifampicin, isoniazid, and pyrazinamide commonly cause hepatotoxicity, which is known as the most frequently occurring side effect. Meanwhile, tubercle bacilli that are resistant to antituberculosis agents, tubercle bacilli that are resistant to multiple drugs, etc., have been increasing, making treatment more difficult.

A WHO survey (2008) reported that there are 390,000 to 510,000 patients with multidrug-resistant tuberculosis in the world, which account for 3.6% of the total number of tuberculosis patients, and that 5.4% of multidrug-resistant tuberculosis are equal to extensively drug-resistant tuberculosis (Non-patent Literature 4).

Further, one-third of HIV positive patients are suspected of being co-infected with tuberculosis; the number of such patients is said to be 14 million (Non-patent Literature 5). It is also reported that co-infection of HIV and tuberculosis poses a 20 to 37 times greater risk of developing tuberculosis than usual (Non-patent Literature 6).

In view of the above-described current status, examples of the profiles of a desired antituberculosis agent include (1) an agent that is also effective against multidrug-resistant tubercle bacilli; (2) an agent that enables short-term chemotherapy; (3) an agent with few side effects; (4) an agent that shows efficacy against latent infection with tubercle bacilli (latent tuberculosis); (5) an agent that can be administered orally; and the like.

Examples of bacteria known to be pathogenic to humans include pathogens of recently increasing MAC infections (Mycobacterium avium-intracellulare complex infections), such as Mycobacterium avium and Mycobacterium intracellulare; and other atypical acid-fast bacilli, such as Mycobacterium kansasii, Mycobacterium marinum, Mycobacterium simiae, Mycobacterium scrofulaceum, Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium haemophilum, Mycobacterium ulcerans, Mycobacterium shimoidei, Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium smegmatis, and Mycobacterium aurum.

At present, there are few promising therapeutic agents against atypical mycobacteriosis, and the current status is that an antituberculosis agent, such as rifampicin, isoniazid, ethambutol, streptomycin, and kanamycin, is used in combination with a therapeutic agent against general bacterial infections, such as a new quinolone agent, a macrolide antimicrobial agent, an aminoglycoside antimicrobial agent, and a tetracycline antimicrobial agent.

However, compared with the treatment of infections with common bacteria, the treatment of atypical mycobacteriosis requires long-term drug administration, and in some cases, according to reports, atypical mycobacteriosis become intractable, possibly causing death. In order to overcome the current status, the development of a drug with a higher efficacy is in demand.

For example, Patent Literature 1 discloses that a 6-nitro-1,2,3,4-tetrahydro[2,1-b]imidazopyran compound is useful as an antituberculosis agent, because the compound has bactericidal action in vitro against tubercle bacilli (H37Rv strain) and multidrug-resistant tubercle bacilli, as well as because the compound shows, when orally administered, a therapeutic effect on an animal model infected with tuberculosis.

Patent Literature 2 and 3 disclose that a 2,3-dihydroimidazo[2,1-b]oxazole compound has bactericidal action against tubercle bacilli, multidrug-resistant tubercle bacilli, and atypical acid-fast bacilli.

Patent Literature 4 discloses that nitroimidazooxazine and nitroimidazooxazole compounds can be used as a drug against Mycobacterium tuberculosis.

However, the compounds disclosed in the above-mentioned literature have a structure different from that of the compounds of the present invention, and thus are dissimilar compounds.

CITATION LIST
Patent Literature

PTL 1: WO 97/01562 (Japanese Unexamined Patent Publication No. H11-508270)

PTL 2: Japanese Unexamined Patent Publication No. 2004-149527

PTL 3: Japanese Unexamined Patent Publication No. 2005-320316

PTL 4: WO 2011/014776

Non Patent Literature

NPL 1: A Clinician's Guide To Tuberculosis, Michael D. Iseman 2000 by Lippincott Williams & Wilkins, printed in the USA, ISBN 0-7817-1749-3

NPL 2: Kekkaku, Second edition, Fumiyuki KUZE, Takateru IZUMI, Igaku-Shoin, 1992

NPL 3: Kekkaku Vol. 74: 77-82, 1999

NPL 4: Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 Global Report on Surveillance and Response

NPL 5: The Internet Journal of Pulmonary Medicine 2008: Volume 10, Number 1

NPL 6: The Global Plan To Stop TB 2011-2015

SUMMARY OF INVENTION
Technical Problem

An object of the present invention is to provide a compound having excellent bactericidal action against tubercle bacilli and multidrug-resistant tubercle bacilli. It is a further object of the present invention to provide a compound having excellent bactericidal action against atypical acid-fast bacilli.

Solution to Problem

In order to achieve the aforementioned objects, the present inventors conducted extensive research and, as a result, accomplished the synthesis of a novel 6,7-dihydroimidazo[2,1-b][1,3]oxazine compound that has excellent bactericidal action against tubercle bacilli, multidrug-resistant tubercle bacilli, and atypical acid-fast bacilli. The present invention was completed based on such findings.

The present invention provides a compound represented by Formula (1):

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or a salt thereof,

wherein R¹represents tetrahydroisoquinolyl, tetrahydroquinolyl, tetrahydrobenzoazepinyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolinyl, naphthyl, quinolyl, phenyl, biphenylyl, or pyridyl, these groups being optionally substituted,

the phenyl and pyridyl represented by R¹each being substituted directly or via a linker with at least one group selected from the group consisting of tetrahydropyridyl, diazepanyl, diazabicycloheptanyl, tetrahydrotriazolopyrazinyl, tetrahydroimidazopyrazinyl, azabicyclooctanyl, oxazolyl, piperazinyl, piperidyl, and thiazolyl, each of these groups being optionally substituted,

the biphenylyl represented by R¹being substituted directly or via a linker with at least one group selected from the group consisting of tetrahydropyridyl, diazepanyl, diazabicycloheptanyl, tetrahydrotriazolopyrazinyl, tetrahydroimidazopyrazinyl, azabicyclooctanyl, oxazolyl, piperazinyl, piperidyl, thiazolyl, and phenyl, each of these groups being optionally substituted; and

R²represents hydrogen or lower alkyl.

The present invention further provides a compound represented by Formula (1) above, or a salt thereof, wherein R¹is a group represented by Formula (2):

-A-L1-B-L2-C-D (2)

wherein A represents a divalent group selected from (A1) to (A12):

(A1) tetrahydroisoquinolinediyl,

(A2) tetrahydroquinolinediyl,

(A3) tetrahydrobenzoazepinediyl,

(A4) benzoxazolediyl,

(A5) benzothiazolediyl,

(A6) indolediyl,

(A7) isoindolinediyl,

(A8) naphthalenediyl,

(A9) quinolinediyl,

(A10) phenylene,

(A11) biphenyldiyl, and

(A12) pyridinediyl,

these groups (A1) to (A12) being optionally substituted on the ring(s) with at least one group selected from the group consisting of halogen and lower alkyl;

L1 represents a single bond, lower alkylene, —N(lower alkyl)-, —O—, —O-lower alkylene, —O-lower alkylene-O—, lower alkylene-O—, lower alkylene-O-lower alkylene, or lower alkenylene;

B represents a divalent group selected from (B1) to (B11):

(B1) tetrahydropyridinediyl,

(B2) diazepinediyl,

(B3) diazabicycloheptanediyl,

(B4) tetrahydrotriazolopyrazinediyl,

(B5) tetrahydroimidazopyrazinediyl,

(B6) azabicyclooctanediyl,

(B7) oxazolinediyl,

(B8) piperazinediyl,

(B9) piperidinediyl,

(B10) thiazolinediyl, and

(B11) phenylene,

these groups (B1) to (B11) being optionally substituted on the ring(s) with at least one group selected from the group consisting of lower alkyl, halo-lower alkyl, alkenyl, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkenyloxycarbonyl, hydroxy, lower alkylsulfonyl, and halo-lower alkylsulfonyl;

L2 represents a single bond, —CO—, —COO—, —COO-lower alkynylene, —COO-lower alkylene (this lower alkylene is optionally substituted with phenyl), —COO-lower alkenylene, —N(lower alkyl)-, —N(lower alkyl)-lower alkylene, —NH—, —NH-lower alkylene, —O—, —O-lower alkylene, —S—, lower alkylene (this lower alkylene is optionally substituted with optionally protected hydroxy), lower alkylene (this lower alkylene is optionally substituted with optionally protected hydroxy)-O—, lower alkylene-N-(lower alkyl)-, lower alkylene-N(lower alkyl)-lower alkylene, lower alkylene-O-lower alkylene, lower alkylene-S—, or lower alkenylene (this lower alkenylene is optionally substituted with lower alkyl or phenyl);

C represents a divalent group or a single bond selected from (C1) to (C28):

(C1) tetrahydroquinolinediyl,

(C2) dihydrobenzodioxindiyl,

(C3) dihydrobenzoxazolediyl,

(C4) dihydrobenzofurandiyl,

(C5) dihydrobenzoxazinediyl,

(C6) adamantanediyl,

(C7) benzothiophenediyl,

(C8) benzodioxolediyl,

(C9) benzimidazolediyl,

(C10) benzofurandiyl,

(C11) carbazolediyl,

(C12) chromandiyl,

(C13) cyclohexanediyl,

(C14) fluorenediyl,

(C15) furandiyl,

(C16) imidazopyridinediyl,

(C17) imidazolediyl,

(C18) indolediyl,

(C19) naphthalenediyl,

(C20) piperidinediyl,

(C21) pyrazolediyl,

(C22) pyridinediyl,

(C23) pyrrolediyl,

(C24) quinolinediyl,

(C25) thiazolediyl,

(C26) thiophenediyl,

(C27) phenylene, and

(C28) single bond,

these groups (C1) to (C27) being optionally substituted on the ring(s) with at least one group selected from the group consisting of alkoxy, halo-lower alkoxy, alkyl, haloalkyl, halogen, hydroxy, lower alkoxycarbonyl, oxo, lower alkanoylamino, lower alkanoyloxy, nitro, lower alkylthio, halo-lower alkylthio, cyclo-lower-alkyl, cyclo-lower alkoxy, cyano, lower alkoxycarbonylamino, nitro, amino, (mono- or di-lower alkyl)amino, lower alkylsulfonyl, lower alkylsulfonylamino, alkenyloxy, and (mono- or di-lower alkyl)amino lower alkoxy;

D represents a group or an atom selected from (D1) to (D35):

(D1) oxadiazolyl-lower alkoxy,

(D2) triazolyl,

(D3) isoxazolyl-lower alkoxy,

(D4) imidazolyl,

(D5) imidazolyl-lower alkyl,

(D6) thiazolyl-lower alkoxy,

(D7) thienyl,

(D8) thienyl-lower alkoxy,

(D9) furyl-lower alkoxy,

(D10) tetrahydropyranyl,

(D11) pyrazinyl-lower alkoxy,

(D12) piperazinylphenyl,

(D13) pyrazolyl,

(D14) pyridyl,

(D15) pyridyloxy,

(D16) pyridyl-lower alkoxy,

(D17) pyrrolidinyl,

(D18) pyrrolyl,

(D19) phenyl,

(D20) (mono- or di-phenyl)amino,

(D21) phenyl-lower alkyl,

(D22) phenyl-lower alkenyl,

(D23) (phenyl-lower alkyl)(lower alkyl)amino,

(D24) (phenyl-lower alkyl)amino,

(D25) phenyl-lower alkylsulfonyl,

(D26) phenyl-lower alkylsulfinyl,

(D27) phenyl-lower alkylthio,

(D28) phenyl-lower alkenyloxy,

(D29) phenyl-lower alkoxy,

(D30) phenyl-lower alkoxyphenyl,

(D31) phenoxy,

(D32) phenoxy-lower alkyl,

(D33) phenoxypiperidyl,

(D34) morpholinyl-lower alkyl, and

(D35) hydrogen,

these groups (D1) to (D34) being optionally substituted on the ring(s) with at least one group selected from the group consisting of lower alkyl, halo-lower alkyl, lower alkylthio, lower alkoxy, halo-lower alkoxy, and halogen,

with the proviso that when A is group (A10) or (A12), and B is group (B11), C is selected from groups (C1) to (C27).

The present invention provides a pharmaceutical composition comprising a compound represented by Formula (1) (including all subclasses of the compounds of Formula (1) stated in this specification; the same applies hereinafter) or a salt thereof, and a pharmaceutically acceptable carrier.

The present invention provides a prophylactic and/or therapeutic agent for tuberculosis, comprising a compound of Formula (1), or a salt thereof, and a pharmaceutically acceptable carrier.

The present invention provides a compound represented by Formula (1), or a salt thereof, for use in the prevention and/or treatment of tuberculosis.

The present invention provides the use of a compound represented by Formula (1), or a salt thereof, for the production of a pharmaceutical composition.

The present invention provides the use of a compound of Formula (1), or a salt thereof, as a pharmaceutical composition.

The present invention provides a method for preventing and/or treating tuberculosis, comprising administering an effective amount of a compound of Formula (1), or a salt thereof, to a patient.

Advantageous Effects of Invention

The compounds of the present invention have specific efficacy against, in particular, acid-fast bacilli (mycobacterium tuberclosis complex and nontuberculosis mycobacterium complex).

The compounds of the present invention have an excellent effect on multidrug-resistant tubercle bacilli. The compounds of the present invention have an antibacterial action against anaerobic bacteria.

The compounds of the present invention exert the above-described activities not only in vitro but also in oral administration.

The compounds of the present invention do not cause diarrhea, which can be caused by a known antimicrobial agent that has a broad spectrum against general bacteria, such as gram positive and gram negative bacteria. In addition, the compounds of the present invention have fewer side effects than existing drugs. Therefore, the compounds of the present invention can serve as pharmaceutical preparations that can be administered for a long period of time.

The compounds of the present invention can be satisfactorily distributed throughout the lung tissue, which is a main organ infected with mycobacteriosis. In addition, the compounds of the present invention have properties such as sustained drug efficacy and excellent safety. For this reason, the compounds of the present invention are expected to have high therapeutic effects.

Additionally, compared with existing antituberculosis agents, the compounds of the present invention exhibit stronger bactericidal activity against intracellular parasites, such as parasitic tubercle bacillus in human-derived macrophages. Therefore, the compounds of the present invention enable a reduction in the tuberculosis relapse rate and also enable short-term chemotherapy. Further, the compounds of the present invention are also expected to be used as a principal drug for preventive administration that is performed against a mixed infection with HIV and tuberculosis, which has become a serious problem.

The compounds of the present invention exhibit excellent metabolic stability in plasma, and thus have a feature of providing satisfactorily sustained bactericidal action in vivo.

DESCRIPTION OF EMBODIMENTS

The groups represented by R¹, R², A, B, C, D, L1, and L2, and the substituents of these groups, as used herein, are described below.

The term “at least one” means usually one to ten, preferably one to six, and more preferably one to three.

Examples of “alkyl” include straight- or branched-chain alkyl groups having 1 to 12 carbon atoms, such as the “lower alkyl” mentioned below, heptyl, octyl, nonyl, decyl, and dodecyl.

Examples of “lower alkyl” include straight- or branched-chain alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.

Examples of “alkenyl” include straight- or branched-chain alkenyl groups having 2 to 12 carbon atoms, such as the “lower alkenyl” mentioned below, heptenyl, octenyl, nonenyl, decenyl, dodecenyl, and —CH₂CH═C(CH₃) CH₂CH₂CH═C(CH₃)₂.

Examples of “lower alkenyl” include straight- or branched-chain alkenyl groups having 2 to 6 carbon atoms, such as methyl, vinyl, 1-propenyl, allyl, 1-, 2- or 3-butenyl, 1,3-butanedienyl, and 1,2-, 3-, or 4-pentenyl.

Examples of “lower alkylene” include straight- or branched-chain alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, dimethylmethylene, tetramethylene, pentamethylene, and hexamethylene.

Examples of “lower alkenylene” include straight- or branched-chain alkenylene groups having 2 to 6 carbon atoms, such as ethenylene, propenylene, butenylene, pentenylene, and hexenylene.

Examples of “lower alkynylene” include straight- or branched-chain alkynylene groups having 2 to 6 carbon atoms, such as ethynylene, propynylene, butynylene, pentynylene, and hexynylene.

Examples of “cyclo-lower alkyl” include cycloalkyl having 3 to 8, preferably 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, and cyclohexylmethyl.

Examples of “alkoxy” include straight- or branched-chain alkoxy groups having 1 to 12 carbon atoms, such as the “lower alkoxy” mentioned below, n-heptyloxy, n-octyloxy, n-nonyloxy, n-decyloxy, and n-dodecyloxy.

Examples of “lower alkoxy” include straight- or branched-chain alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy.

Examples of “cyclo-lower alkoxy” include cycloalkoxy having 3 to 8, preferably 3 to 7 carbon atoms, such as cyclopropyloxy, cyclobutyloxy, cyclopenthyloxy, cyclohexyloxy, cyclopropylmethyloxy, and cyclohexylmethyloxy.

Examples of “lower alkanoyl” include straight- or branched-chain alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl.

Examples of “lower alkoxycarbonyl” include (straight- or branched-chain alkoxy having 1 to 6 carbon atoms) carbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl.

Examples of “lower alkenyloxycarbonyl” include (straight- or branched chain alkenyloxy having 2 to 6 carbon atoms) carbonyl, such as vinyloxycarbonyl, allyloxycarbonyl, butenyloxycarbonyl, and isobutenyloxycarbonyl.

“Halogen” represents fluorine, chlorine, bromine, and iodine.

Examples of “haloalkyl” include groups in which at least one hydrogen (for example, 1 to whole, 1 to 10, further 1 to 6, in particular 1 to 3 hydrogen atoms) of the above-mentioned “alkyl” is substituted with halogen(s).

Examples of “halo-lower alkyl” include groups in which at least one hydrogen (for example, 1 to 10, further 1 to 6, in particular 1 to 3 hydrogen atoms) of the above-mentioned “lower alkyl” is substituted with halogen(s), such as trihalomethyl (e.g., —CF₃), trihaloethyl (e.g., —CH₂CF₃), pentahaloethyl (e.g., —CF₂CF₃), or nonahalobutyl (e.g., —CF₂CF₂CF₂CF₃).

Examples of “halo-lower alkoxy” include groups in which at least one hydrogen (e.g., 1 to 10, further 1 to 6, in particular 1 to 3 hydrogen atoms) of the above-mentioned “lower alkoxy” is substituted with halogen(s), such as trihalomethoxy (e.g., −OCF₃), pentahaloethoxy (e.g., —OCF₂CF₃), or nonahalobutoxy (e.g., −OCF₂CF₂CF₂CF₃).

Examples of protecting groups of “optionally protected hydroxy” include tetrahydropyranyl, acetyl, trialkylsilyl, (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl), alkyldiphenylsilyl, (e.g., tert-butyldimethylsilyl), and the like.

The present invention provides a 6,7-dihydroimidazo[2,1-b][1,3]oxazine compound represented by Formula (1):

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or a salt thereof,

R²represents hydrogen or lower alkyl.

The pyridyl represented by R¹is preferably substituted directly or via a linker with at least one group selected from the group consisting of piperazinyl and piperidyl, these groups (piperazinyl and piperidyl) being optionally substituted.

In Formula (1), the carbon atom at position 7 is an asymmetric carbon, and the compounds represented by Formula (1) include R—, S—, and racemic forms based on the asymmetric carbon atom, and the mixtures thereof.

In Formula (1), R¹is preferably a group represented by Formula (2):

-A-L1-B-L2-C-D (2)

In this formula, A represents a divalent group selected from (A1) to (A12):

(A1) tetrahydroisoquinolinediyl,

(A2) tetrahydroquinolinediyl,

(A3) tetrahydrobenzoazepinediyl,

(A4) benzoxazolediyl,

(A5) benzothiazolediyl,

(A6) indolediyl,

(A7) isoindolinediyl,

(A8) naphthalenediyl,

(A9) quinolinediyl,

(A10) phenylene,

(A11) biphenyldiyl, and

(A12) pyridinediyl.

These groups (A1) to (A12) are optionally substituted on the ring(s) with at least one group (further 1 to 3, in particular 1 or 2 groups) selected from the group consisting of halogen and lower alkyl.

The “(A1) tetrahydroisoquinolinediyl” represented by A is a divalent group obtained by removing two hydrogen atoms from tetrahydroisoquinoline. Examples of tetrahydroisoquinoline include 1,2,3,4-tetrahydroisoquinoline. Specific examples of tetrahydroisoquinolinediyl include a group represented by:

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Preferable examples thereof include 1,2,3,4-tetrahydroisoquinoline-2,6-diyl and 1,2,3,4-tetrahydroisoquinoline-2,7-diyl.

The “(A2) tetrahydroquinolinediyl” represented by A is a divalent group obtained by removing two hydrogen atoms from tetrahydroquinoline. Examples of tetrahydroquinoline include 1,2,3,4-tetrahydroquinoline. Specific examples of tetrahydroquinolinediyl include a group represented by:

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Preferable examples thereof include 1,2,3,4-tetrahydroquinoline-1,6-diyl.

The “(A3) tetrahydrobenzoazepinediyl” represented by A is a divalent group obtained by removing two hydrogen atoms from tetrahydrobenzoazepine. Examples of tetrahydrobenzoazepine include 2,3,4,5-tetrahydro-1H-benzo[b]azepine and 2,3,4,5-tetrahydro-1H-benzo[c]azepine. Specific examples of tetrahydrobenzoazepinediyl include a group represented by:

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Preferable examples thereof include 2,3,4,5-tetrahydro-1H-benzo[b]azepine-1,7-diyl and 2,3,4,5-tetrahydro-1H-benzo[c]azepine-2,7-diyl.

The “(A4) benzoxazolediyl” represented by A is a divalent group obtained by removing two hydrogen atoms from benzoxazole. Examples of benzoxazole include benzo[d]oxazole. Specific examples of benzoxazolediyl include a group represented by:

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Preferable examples thereof include 2,5-benzo[d]oxazolediyl and 2,6-benzo[d]oxazolediyl.

The “(A5) benzothiazolediyl” represented by A is a divalent group obtained by removing two hydrogen atoms from benzothiazole. Examples of benzothiazole include benzo[d]thiazol. Specific examples of benzothiazolediyl include a group represented by:

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Preferable examples thereof include 2,6-benzo[d]thiazolediyl.

The “(A6) indolediyl” represented by A is a divalent group obtained by removing two hydrogen atoms from indole. Specific examples of indolediyl include a group represented by:

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Preferable examples thereof include 1,5-indolediyl.

The “(A7) isoindolinediyl” represented by A is a divalent group obtained by removing two hydrogen atoms from isoindoline. Specific examples of isoindolinediyl include a group represented by:

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Preferable examples thereof include 2,5-isoindolinediyl.

The “(A8) naphthalenediyl” represented by A is a divalent group obtained by removing two hydrogen atoms from naphthalene. Specific examples of naphthalenediyl include a group represented by:

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Preferable examples thereof include 2,6-naphthalenediyl.

The “(A9) quinolinediyl” represented by A is a divalent group obtained by removing two hydrogen atoms from quinoline. Specific examples of quinolinediyl include a group represented by:

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Preferable examples thereof include 2,6-quinolinediyl.

The “(A10) phenylene” represented by A is a divalent group obtained by removing two hydrogen atoms from benzene. Specific examples of phenylene include 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene, with 1,4-phenylene being preferable.

The “(A11) biphenyldiyl” represented by A is a divalent group obtained by removing two hydrogen atoms from biphenyl. Specific examples of biphenyldiyl include a group represented by:

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Preferable examples thereof include 4,4′-biphenyldiyl.

The “(A12) pyridinediyl” represented by A is a divalent group obtained by removing two hydrogen atoms from pyridine. Specific examples of pyridinediyl include 2,3-pyridinediyl, 2,4-pyridinediyl, 2,5-pyridinediyl, 2,6-pyridinediyl, 3,4-pyridinediyl, and 3,5-pyridinediyl, with 2,5-pyridinediyl being preferable.

L1 represents a single bond or a linker. Specifically, L1 represents a single bond, lower alkylene, —N(lower alkyl)-, —O—, —O-lower alkylene, —O-lower alkylene-O—, lower alkylene-O—, lower alkylene-O-lower alkylene, or lower alkenylene.

B represents a divalent group selected from (B1) to (B11):

These groups (B1) to (B11) are optionally substituted on the ring(s) with at least one group (further 1 to 3, in particular 1 or 2 groups) selected from the group consisting of lower alkyl, halo-lower alkyl, alkenyl, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl, lower alkenyloxycarbonyl, hydroxy, lower alkylsulfonyl, and halo-lower alkylsulfonyl.

The “(B1) tetrahydropyridinediyl” represented by B is a divalent group obtained by removing two hydrogen atoms from tetrahydropyridine. Examples of tetrahydropyridine include 1,2,3,4-tetrahydropyridine and 1,2,3,6-tetrahydropyridine. Specific examples of tetrahydropyridinediyl include a group represented by:

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Preferable examples thereof include 1,2,3,6-tetrahydropyridine-1,4-diyl.

The “(B2) diazepinediyl” represented by B is a divalent group obtained by removing two hydrogen atoms from diazepine. Specific examples of diazepinediyl include a group represented by:

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Preferable examples thereof include 1,4-diazepinediyl.

The “(B3) diazabicycloheptanediyl” represented by B is a divalent group obtained by removing hydrogen atoms from diazabicycloheptane. Examples of diazabicycloheptane include 2,5-diazabicyclo[2,2,1]heptane. Specific examples of diazabicycloheptanediyl include a group represented by:

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The “(B4) tetrahydrotriazolopyrazinediyl” represented by B is a divalent group obtained by removing two hydrogen atoms from tetrahydrotriazolopyrazine. Examples of tetrahydrotriazolopyrazine include 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine. Specific examples of tetrahydrotriazolopyrazinediyl include a group represented by:

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Preferable examples thereof include 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine-3,7-diyl.

The “(B5) tetrahydroimidazopyrazinediyl” represented by B is a divalent group obtained by removing two hydrogen atoms from tetrahydroimidazopyrazine. Examples of tetrahydrotriazolopyrazine include 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine. Specific examples of tetrahydroimidazopyrazinediyl include a group represented by:

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Preferable examples thereof include 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3,7-diyl.

The “(B6) azabicyclooctanediyl” represented by B is a divalent group obtained by removing two hydrogen atoms from azabicyclooctane. Examples of azabicyclooctane include 8-azabicyclo[3,2,1]octane. Specific examples of azabicyclooctanediyl include a group represented by:

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The “(B7) oxazolinediyl” represented by B is a divalent group obtained by removing two hydrogen atoms from oxazoline. Specific examples of oxazolinediyl include a group represented by:

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Preferable examples thereof include 2,4-oxazolinediyl.

The “(B8) piperazinediyl” represented by B is a divalent group obtained by removing two hydrogen atoms from piperazine. Specific examples of piperazinediyl include a group represented by:

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Preferable examples thereof include 1,4-piperazinediyl.

The “(B9) piperidinediyl” represented by B is a divalent group obtained by removing two hydrogen atoms from piperidine. Specific examples of piperidinediyl include a group represented by:

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Preferable examples thereof include 1,4-piperidinediyl.

The “(B10) thiazolinediyl” represented by B is a divalent group obtained by removing two hydrogen atoms from thiazoline. Specific examples of thiazolinediyl include a group represented by:

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Preferable examples thereof include 2,4-thiazolinediyl.

The “(B11) phenylene” represented by B is a divalent group obtained by removing two hydrogen atoms from benzene. Examples of phenylene include 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene, with 1,4-phenylene being preferable.

L2 represents a single bond or a linker. Specifically, L2 represents a single bond, —CO—, —COO—, —COO-lower alkynylene, —COO-lower alkylene (this lower alkylene is optionally substituted with phenyl), —COO-lower alkenylene, —N(lower alkyl)-, —N(lower alkyl)-lower alkylene, —NH—, —NH-lower alkylene, —O—, —O-lower alkylene, —S—, lower alkylene (this lower alkylene is optionally substituted with optionally protected hydroxy), lower alkylene (this lower alkylene is optionally substituted with optionally protected hydroxy)-O—, lower alkylene-N-(lower alkyl)-, lower alkylene-N(lower alkyl)-lower alkylene, lower alkylene-O-lower alkylene, lower alkylene-S—, or lower alkenylene (this lower alkenylene is optionally substituted with lower alkyl or phenyl).

C represents a divalent group or a single bond selected from (C1) to (C28):

These groups (C1) to (C27) are optionally substituted on the ring(s) with at least one group (further 1 to 3, in particular 1 or 2 groups) selected from the group consisting of alkoxy, halo-lower alkoxy, alkyl, haloalkyl, halogen, hydroxy, lower alkoxycarbonyl, oxo, lower alkanoylamino, lower alkanoyloxy, nitro, lower alkylthio, halo-lower alkylthio, cyclo-lower alkyl, cyclo-lower alkoxy, cyano, lower alkoxycarbonylamino, nitro, amino, (mono- or di-lower alkyl)amino, lower alkylsulfonyl, lower alkylsulfonylamino, alkenyloxy, and (mono- or di-lower alkyl)amino-lower alkoxy.

D represents a group or an atom selected from (D1) to (D35):

These groups (D1) to (D34) are optionally substituted on the ring(s) with at least one group (further 1 to 3, in particular 1 or 2 groups) selected from the group consisting of lower alkyl, halo-lower alkyl, lower alkylthio, lower alkoxy, halo-lower alkoxy, and halogen.

In Formula (2), when A is group (A10) or (A12), and B is group (B11), C is preferably selected from groups (C1) to (C27).

In Formula (2), A is preferably

(A1) tetrahydroisoquinolinediyl,

(A2) tetrahydroquinolinediyl,

(A9) quinolinediyl,

(A10) phenylene,

(A11) biphenyldiyl, or

(A12) pyridinediyl,

these groups (A1), (A2), and (A9) to (A12) being optionally substituted on the ring(s) with at least one group (preferably 1, 2, or 3 groups) selected from the group consisting of halogen and lower alkyl.

Among the compounds represented by Formula (1), preferable compounds are those in which R¹is a group represented by Formula (2),

wherein A is

(A1) tetrahydroisoquinolinediyl (preferably 1,2,3,4-tetrahydroisoquinoline-2,6-diyl),

(A2) tetrahydroquinolinediyl (preferably 1,2,3,4-tetrahydroquinoline-1,6-diyl),

(A9) quinolinediyl (preferably 2,6-quinolinediyl),

(A10) phenylene (preferably 1,4-phenylene),

(A11) biphenyldiyl (preferably 4,4′-biphenyldiyl), or

(A12) pyridinediyl (preferably 2,5-pyridinediyl),

these groups (A1), (A2), (A9) to (A12) being optionally substituted on the ring(s) with one or two halogen atoms (preferably fluorine);

L1 is a single bond, lower alkylene, —O—, —O-lower alkylene, or lower alkylene-O—;

B is

(B7) oxazolinediyl (preferably 2,4-oxazolinediyl),

(B8) piperazinediyl (preferably 1,4-piperazinediyl),

(B9) piperidinediyl (preferably 1,4-piperidinediyl),

(B10) thiazolinediyl (preferably 2,4-thiazolinediyl), or

(B11) phenylene (preferably 1,4-phenylene),

these groups (B7) to (B11) being optionally substituted on the ring with at least one or two groups selected from the group consisting of lower alkyl, lower alkoxy, halo-lower alkyl, halo-lower alkoxy, hydroxy, and halo-lower alkylsulfonyl;

L2 is a single bond, —N(lower alkyl)-, —O—, —O-lower alkylene, lower alkylene, lower alkylene-O—, or lower alkenylene;

C is

(C13) cyclohexanediyl,

(C20) piperidinediyl,

(C27) phenylene, or

(C28) single bond,

(with the proviso that when A is (A10) or (A12), and B is (B11), C is (C13), (C20), or (C27)),

these groups (C13), (C20), and (C27) being optionally substituted on the ring with one or two groups selected from the group consisting of halo-lower alkoxy, halo-lower alkyl, hydroxy, and halo-lower alkylthio;

D is

(D21) phenyl-lower alkyl,

(D24) (phenyl-lower alkyl)amino,

(D29) phenyl-lower alkoxy,

(D31) phenoxy, or

(D35) hydrogen,

these groups (D21), (D24), (D29), and (D31) being optionally substituted on the ring with one or two groups selected from the group consisting of halo-lower alkyl and halo-lower alkoxy.

Among the compounds represented by Formula (1), preferable compounds are those represented by Formula (1-1):

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wherein R^Ais halogen or lower alkyl; m is 0, 1, or 2, wherein when m is 2, each R^Amay be the same or different; and R², L1, B, L2, C, and D are the same as defined above.

Among these, R^Ais preferably F.

m is preferably zero.

L1 is preferably lower alkylene (in particular —CH₂—).

B is preferably 1,4-phenylene.

L2 is preferably —O-lower alkylene (in particular —O—CH₂—).

C is preferably phenylene optionally substituted on the ring with one halo-lower alkyl (in particular trifluoromethyl).

D is preferably hydrogen.

Among the compounds represented by Formula (1), preferable compounds are those represented by Formula (1-2):

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wherein R^A, m, R², L1, B, L2, C, and D are the same as defined above.

Among these, m is preferably zero.

L1 is preferably lower alkylene-O— (in particular trimethylene-O—).

B is preferably phenylene optionally substituted on the ring with one halo-lower alkoxy (in particular trifluoromethoxy).

L2 and C each represent a single bond.

D is preferably hydrogen.

Among the compounds represented by Formula (1), preferable compounds are those represented by Formula (1-3):

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wherein R^A, m, R², L1, B, L2, C, and D are the same as defined above.

Among these, m is preferably zero.

L1 is preferably —O-lower alkylene (in particular —O—CH₂—).

B is preferably phenylene optionally substituted on the ring with one halo-lower alkoxy (in particular trifluoromethoxy).

L2 and C each represent a single bond.

D is preferably hydrogen.

Among the compounds represented by Formula (1), preferable compounds are those represented by Formula (1-4):

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wherein E is N or CH; C¹is a divalent group selected from groups (C1) to (C27) above (the substituents on the ring(s) of these groups are the same as defined above); and R^A, m, R², L1, B, L2, and D are the same as defined above.

Among these, R^Ais preferably F.

m is preferably 0 or 1, more preferably 0.

E is preferably CH.

L1 is preferably a single bond.

B is preferably 1,4-piperidinediyl or 1,4-piperazinediyl, each of which is optionally substituted on the ring with one or two substituents selected from the group consisting of lower alkyl (in particular methyl), halo-lower alkylsulfonyl (in particular perfluorobutylsulfonyl), and lower alkoxy (in particular methoxy).

L2 is preferably a single bond, lower alkylene, —O—, lower alkylene-O—, —N(lower alkyl)-, or lower alkenylene.

C is preferably phenylene, cyclohexanediyl, or piperidinediyl, each of which is optionally substituted on the ring with one or two groups selected from the group consisting of halo-lower alkoxy (in particular trifluoromethoxy), halo-lower alkyl (in particular trifluoromethyl), and halo-lower alkylthio (in particular trifluoromethylthio).

D is preferably phenyl-lower alkyl (in particular benzyl), (phenyl-lower alkyl)amino (in particular benzylamino), phenyl-lower alkoxy (in particular benzyloxy), phenoxy, or hydrogen, each of which is optionally substituted on the ring with one or two groups selected from the group consisting of halo-lower alkyl (in particular trifluoromethyl) and halo-lower alkoxy (in particular trifluoromethoxy).

Among the compounds represented by Formula (1), preferable compounds are those represented by Formula (1-5):

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wherein R^A, m, R², L1, B, L2, C, and D are the same as defined above.

Among these, m is preferably zero.

L1 is preferably a single bond.

B is preferably piperidinediyl optionally substituted on the ring with one or two groups selected from the group consisting of halo-lower alkyl (in particular trifluoromethyl) and hydroxy.

L2 is preferably a single bond or —O—.

C is preferably a single bond or phenylene optionally substituted on the ring with one halo-lower alkoxy (in particular trifluoromethoxy).

D is preferably hydrogen or phenoxy optionally substituted on the ring with one halo-lower alkoxy (in particular trifluoromethoxy).

Among the compounds represented by Formula (1), preferable compounds are those represented by Formula (1a) to (1n) shown in Reaction Schemes 1 to 11 below.

Among the compounds represented by Formula (1), those described in Examples 1 to 772, and the salts thereof are furthermore preferable. The compounds described in the Examples 1, 3, 53, 56, 64, 79, 90, 143, 147, 153, 182, 198, 206, 228, 254, 282, 290, 299, 304, 335, 364, 372, 379, 380, 382, 383, 395, 400, 411, 414, 415, 446, 471, and 490, and salts thereof are still furthermore preferable.

In this specification, each of the divalent groups indicated by the letters A, L1, B, L2, and C, or by the structural formulae, in relation to the groups represented by Formula (2) above, can be attached in an arbitrary direction to the two groups on both sides of the divalent group. For example, when L1 is “lower alkylene-O—,” its binding mode with groups A and B represents both “A-(lower alkylene-O)—B” and “A-(O-lower alkylene)-B.” Of these, a preferable binding mode is such that the divalent group is attached as is as stated on the paper to a group represented by Formula (2) (-A-L1-B-L2-C-D) as stated on the paper. For example, when L1 is “lower alkylene-O—,” a binding mode with groups A and B is preferably “A-(lower alkylene-O)—B.”

The 6,7-dihydroimidazo[2,1-b][1,3]oxazine compound represented by Formula (1), or a salt thereof, can be produced, for example, in the following manner.

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wherein R¹and R²are the same as defined above; R³represents lower alkylsulfonyl optionally substituted with halogen, or benzenesulfonyl optionally substituted with lower alkyl or nitro; and X²and X²are the same or different and each represent halogen.

Examples of the lower alkylsulfonyl optionally substituted with halogen represented by R³include C_1-6alkylsulfonyl optionally substituted with 1 to 3 halogen atoms, such as methanesulfonyl, ethanesulfonyl, and trifluoromethanesulfonyl.

Examples of the benzenesulfonyl optionally substituted with lower alkyl represented by R³include benzenesulfonyl optionally substituted with 1 to 3 C_1-6alkyl groups, such as benzenesulfonyl and p-toluenesulfonyl.

Examples of the benzenesulfonyl optionally substituted with nitro represented by R³include benzenesulfonyl optionally substituted with 1 to 3 nitro groups, such as o-nitrobenzenesulfonyl and p-nitrobenzenesulfonyl.

The halogen represented by X²and X²is fluorine, chlorine, bromine, or iodine, with chlorine and bromine being preferable.

(2)+(3)→(4):

In the reaction of Compound (2) and Compound (3), the reaction conditions of a general sulfonylation reaction of alcohol can be widely applied. For example, Compound (4) can be produced by using Compound (2) and Compound (3) without a solvent or by dissolving them in an appropriate solvent (e.g., methylene chloride, acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), or toluene), and allowing a reaction to occur in the presence of a basic compound (e.g., potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, pyridine, triethylamine, diisopropylethylamine, tetramethylethylenediamine (TMEDA), or tetramethylpropylenediamine (TMPDA)).

The basic compound is used in an amount of usually equimolar to excess mole, preferably 1- to 5-fold mol, and more preferably 1- to 2-fold mol, of Compound (2).

Compound (3) is used in an amount of usually equimolar to excess mole, preferably 0.9- to 2-fold mol, and more preferably 0.9- to 1.5-fold mol, of Compound (2).

The reaction temperature is usually −50 to 150° C., preferably −20 to 100° C., and more preferably −10 to 50° C. The reaction time is usually 10 minutes to 24 hours, preferably 10 minutes to 12 hours.

(4)+(5)→(6):

Compound (4) and Compound (5) can be reacted in an appropriate solvent (e.g., methylene chloride, acetonitrile, DMF, or dimethylacetamide (DMAc)) in the presence of a basic compound (e.g., potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, pyridine, triethylamine, diisopropylethylamine, tetramethylethylenediamine (TMEDA), or tetramethylpropylenediamine (TMPDA)). As an activator, an alkali metal iodide, such as sodium iodide or potassium iodide, may also be added to the reaction system, if necessary.

The basic compound is used in an amount of usually equimolar to excess mole, preferably 1- to 5-fold mol, and more preferably 1- to 2-fold mol, of Compound (5).

When an activator is used, the amount of the activator is usually equimolar to excess mole, preferably 1- to 5-fold mol, and more preferably 1- to 2-fold mol, of Compound (5).

Compound (4) is used in an amount of usually 0.5-fold mol to excess mole, further equimolar to excess mole, preferably 0.9- to 2-fold mol, and more preferably 0.9- to 1.5-fold mol, of Compound (5).

The reaction temperature is usually −50 to 150° C., preferably −30 to 100° C., and more preferably −10 to 100° C. The reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours.

(6)→(7):

Compound (7) can be produced by subjecting Compound (6) to a hydrolysis reaction. In the hydrolysis reaction, known reaction conditions generally employed are applicable. For example, the reaction can be performed in an appropriate solvent (e.g., water or a mixed solvent of water with, for example, ethanol or tetrahydrofuran (THF)) in the presence of an acid (e.g., hydrochloric acid or sulfuric acid).

An acid is used in an amount of a catalytic amount to excess mole of Compound (6). The reaction temperature is usually 0 to 50° C. The reaction time is usually 10 minutes to 24 hours.

(7)+(3)→(8):

In the reaction of Compound (7) and Compound (3), the reaction conditions of a general sulfonylation reaction of alcohol can be widely applied. For example, the reaction can be performed under the same reaction conditions for producing Compound (4) from Compound (2) and Compound (3).

(8)+(9)→(10):

Compound (8) and Compound (9) can be reacted in an appropriate solvent in the presence of a basic compound.

Any known solvent can be used as long as it does not hinder the reaction. Examples of such solvents include water; DMF, DMSO, acetonitrile, and like aprotic polar solvents; benzene, toluene, xylene, tetralin, liquid paraffin, cyclohexane, and like hydrocarbon solvents; ethanol, isopropanol, n-butanol, tert-butanol, and like alcohol solvents; THF, dioxane, dipropyl ether, diethyl ether, diglyme, and like ether solvents; ethyl acetate, and like ester solvents; acetone, methylethylketone, and like ketone solvents; mixtures of such solvents; and the like.

Examples of basic compounds include sodium hydride and like alkali metal hydrides; sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and like metal alcoholates; sodium hydroxide, potassium hydroxide, and like alkali metal hydroxides; sodium carbonate, potassium carbonate, cesium carbonate, and like alkali metal carbonates; sodium hydrogen carbonate, potassium hydrogen carbonate, and like alkali metal hydrogen carbonates; tripotassium phosphate and like alkali metal phosphates; sodium amide; sodium acetate, potassium acetate, and like acetates; triethylamine, trimethylamine, diisopropylethylamine, pyridine, dimethylaniline, 1-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and like nitrogen-containing organic bases. These bases can be used singly, or in a combination of two or more in an appropriate ratio.

As a catalyst (or a reaction promoter), for example, an alkali metal halide, such as cesium fluoride, or an alkali metal iodide, such as sodium iodide or potassium iodide, may be added, if necessary.

The basic compound is used in an amount of usually equimolar to excess mole, preferably 1- to 5-fold mol, and more preferably 1- to 2-fold mol, of Compound (8).

Compound (9) is used in an amount of usually 0.5- to 5-fold mol, preferably 0.8- to 2-fold mol, and more preferably 0.9- to 1.5-fold mol, of Compound (8).

When a catalyst is used, the amount of the catalyst is usually a catalytic amount to excess mole, preferably 0.01- to 5-fold mole, and more preferably 0.1- to 2-fold mol, of Compound (8).

The reaction temperature is usually −30 to 150° C., preferably −10 to 100° C., and more preferably −10 to 80° C. The reaction time is usually 10 minutes to 24 hours, preferably 10 minutes to 12 hours, and more preferably 20 minutes to 7 hours.

(10)→(1):

Compound (1) can be produced by subjecting Compound (10) to a ring-closure reaction.

The ring-closure reaction can be performed in an appropriate solvent (e.g., N-methylpyrrolidone (NMP), DMF, or DMAc) in the presence of a basic compound (e.g., sodium hydride or sodium tert-butoxide).

The basic compound is used in an amount of usually equimolar to excess mole, preferably 1- to 5-fold mol, and more preferably 1- to 2-fold mol, of Compound (10).

The reaction temperature is usually −50 to 150° C., preferably −20 to 100° C., and more preferably −10 to 50° C. The reaction time is usually 10 minutes to 100 hours, and preferably 10 minutes to 72 hours.

In the present invention, the reaction mixture obtained by the reaction of Compound (8) and Compound (9) can be subjected to the subsequent ring-closure reaction as is, without isolating Compound (10), to produce target Compound (1). Further, when the reaction is performed at usually −10 to 200° C., and preferably 0 to 100° C., using a basic compound in an amount of equimolar to excess mole of Compound (8), Compound (1) can be produced at once without isolation of the intermediate, i.e., Compound (10).

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wherein R¹, R², R³, X¹, and X²are the same as defined above.

(11)→(12):

Compound (12) can be produced by subjecting Compound (11) to an oxidation reaction. In the oxidation reaction, known reaction conditions generally employed can be widely applied. For example, the reaction can be carried out by reacting Compound (12) with an oxidizing agent (e.g., m-chloroperbenzoic acid (mCPBA) or hydrogen peroxide) in an appropriate solvent.

(12)+(3)→(13):

In the reaction of Compound (12) and Compound (3), the reaction conditions of a general sulfonylation reaction of alcohol can be widely applied. For example, the reaction can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (4) from Compound (2) and Compound (3).

(13)+(5)→(14):

The reaction of Compound (13) and Compound (5) can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (6) from Compound (4) and Compound (5).

(14)+(9)→(10):

The reaction of Compound (14) and Compound (9) can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (10) from Compound (8) and Compound (9).

(10)→(1):

The reaction for producing Compound (1) from Compound (10) can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (1) from Compound (10).

In the present invention, the reaction mixture obtained by the reaction of Compound (14) and Compound (9) can be subjected to the subsequent ring-closure reaction as is, without isolating Compound (10), to produce target Compound (1). Further, when the reaction is performed at usually −10 to 200° C., and preferably 0 to 100° C., using a basic compound in an amount of equimolar to excess mole of Compound (14), Compound (1) can be produced at once without isolation of the intermediate, i.e., Compound (10)

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wherein R¹, R², R³, X¹, and X²are the same as defined above, and X¹⁰represents halogen.

Examples of the halogen represented by X¹⁰include chlorine, bromine, and iodine.

(11)→(15):

Compound (15) can be produced by reacting Compound (11) with a benzyl halide (e.g., benzyl chloride or benzyl bromide) in an appropriate solvent in the presence of a basic compound (an O-benzylation reaction). In the O-benzylation reaction, known reaction conditions generally employed can be widely applied.

(15)→(16):

The reaction for producing Compound (16) from Compound (15) can be performed under the same reaction conditions as employed in Reaction Scheme 2 for producing Compound (12) from Compound (11).

(16)+(9)→(17):

The reaction for producing Compound (17) from Compound (16) and Compound (9) can be performed under the same reaction conditions as employed in Reaction Scheme 2 for producing Compound (10) from Compound (14) and Compound (9).

(17)→(18):

Compound (17) can be produced by subjecting Compound (18) to debenzylation. In the debenzylation reaction, known reaction conditions generally employed can widely be applied. For example, the reaction can be performed by subjecting Compound (17) to catalytic hydrogenation.

(18)+(3)→(19):

In the reaction of Compound (18) and Compound (3), the reaction conditions of a general sulfonylation reaction of alcohol can be widely applied. For example, the reaction can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (4) from Compound (2) and Compound (3).

(19)+(5)→(10):

The reaction of Compound (19) and Compound (5) can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (6) from Compound (4) and Compound (5).

(10)→(1):

The reaction for producing Compound (1) from Compound (10) can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (1) from Compound (10).

In the present invention, the reaction mixture obtained by the reaction of Compound (19) and Compound (5) can be subjected to the subsequent ring-closure reaction as is, without isolating Compound (10), to produce target Compound (1). Further, when the reaction is performed at usually −10 to 200° C., and preferably 0 to 100° C., using a basic compound in an amount of equimolar to excess mole of Compound (19), Compound (1) can be produced at once without isolation of the intermediate, i.e., Compound (10)

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wherein R², R³, and X¹are the same as defined above; R⁴represents a group represented by the above-mentioned —C-D; R⁵represents lower alkyl; R⁵¹represents lower alkyl; and X³represents a leaving group.

Examples of the lower alkyl represented by R⁵include straight- or branched-chain alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.

Examples of the lower alkyl represented by R⁵¹include straight- or branched-chain alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, and neopentyl.

Examples of the leaving group represented by X³include halogen (e.g., chlorine, bromine, and iodine), sulfonyloxy (e.g., p-toluenesulfonyloxy, o- or p-nitrobenzenesulfonyloxy, and methanesulfonyloxy), and the like.

(8)+(20)→(21):

The reaction for producing Compound (21) from Compound (8) and Compound (20) can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (1) through Compound (10) obtained from Compound (8) and Compound (9).

(21)→(22):

The reaction for producing Compound (22) from Compound (21) can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (7) from Compound (6).

(22)+(23)→(1a):

The reaction of Compound (22) and Compound (23) can be performed without a solvent or in an appropriate solvent in the presence of a reducing agent (a reductive amination reaction).

Compound (23) is used in an amount of usually 0.5- to 10-fold mol, preferably 0.6- to 5-fold mol, and more preferably 0.7- to 2-fold mol, of Compound (22).

Examples of solvents include water; methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol, and like lower alcohols; acetonitrile; formic acid, acetic acid, trifluoroacetic acid, and like fatty acids; diethyl ether, THF, dioxane, monoglyme, diglyme, and like ethers; benzene, toluene, xylene, and like aromatic hydrocarbons; dichloromethane, dichloroethane, chloroform, carbon tetrachloride, and like halogenated hydrocarbons; mixtures of such solvents; and the like.

Examples of reducing agents include formic acid, sodium formate, and like alkali metal formates; sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminium hydride, and like hydride reducing agents or mixtures of these hydride reducing agents; palladium black, palladium carbon, platinum oxide, platinum black, Raney nickel, and like catalytic hydrogenation reducing agents.

When formic acid and/or an alkali metal formate is used as a reducing agent, a suitable reaction temperature is usually from about room temperature to 200° C., and preferably about 50 to 150° C. The reaction completes in about 10 minutes to 10 hours. The formic acid and/or alkali metal formate is preferably used in a large excess relative to Compound (22).

When a hydride reducing agent is used, a suitable reaction temperature is usually about −80 to 100° C., and preferably about −80 to 70° C., and the reaction completes in about 30 minutes to 100 hours. A hydride reducing agent may be used in an amount of usually about equimolar to 20-fold mol, and preferably about equimolar to 6-fold mol, of Compound (22). To the reaction system of the reaction may be added an acid, such as acetic acid, formic acid, or tetraisopropoxy titanium; an amine, such as trimethylamine, triethylamine, and N-ethyldiisopropylamine; molecular sieves, such as molecular sieves 3A (MS-3A) and molecular sieves 4A (MS-4A), and the like.

When a catalytic hydrogenation reducing agent is used, the reaction is performed at a temperature of usually about −30 to 100° C., and preferably about 0 to 60° C., in a hydrogen atmosphere at a pressure of usually about atmospheric pressure to 20 atm, and preferably about atmospheric pressure to 10 atm, or in the presence of a hydrogen donor, such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate. The reaction usually completes in about 1 to 12 hours. The catalytic hydrogenation reducing agent is usually used in an amount of about 0.1 to 40 wt %, and preferably about 1 to 20 wt %, of compound (22).

(22)+(24)→(1b):

The reaction of Compound (22) and Compound (24) can be performed under the same reaction conditions as employed in the reaction for producing Compound (1a) from Compound (22) and Compound (23).

(1b)+(25)→(1a):

In the reaction of Compound (1b) and Compound (25), the reaction conditions employed in a general N-alkylation reaction can be widely applied. For example, the reaction can be carried out by reacting Compound (1b) with Compound (25) in an appropriate solvent in the presence of a basic compound.

(1b)+(26)→(1c):

The reaction of Compound (1b) and Compound (26) can be performed under the same reaction conditions as employed in the reaction for producing Compound (1a) from Compound (22) and Compound (23).

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wherein R², R³, and X¹are the same as defined above; A¹is tetrahydroisoquinolinediyl, tetrahydroquinolinediyl, tetrahydrobenzoazepinediyl, or isoindolinediyl (these groups are optionally substituted on the ring(s) with at least one group selected from the group consisting of halogen and lower alkyl) and represents a group in which the atom attached to P¹is nitrogen; R⁷is a group represented by the above-mentioned —C-D; and P¹represents a protecting group of nitrogen.

The protecting group of nitrogen represented by P¹is not particularly limited as long as it does not have an adverse effect on the reaction. Examples thereof include formyl, lower alkyl carbonyl (e.g., acetyl and ethylcarbonyl), phenylcarbonyl, lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl (Boc)), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), and the like. These protecting groups are further optionally substituted with 1 to 5, (e.g., 1 to 3) substituents, such as halogen (fluorine, chlorine, bromine, or iodine) or nitro. Boc is a preferable protecting group of nitrogen.

(8)+(27)→(28):

The reaction for producing Compound (28) from Compound (8) and Compound (27) can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (1) through Compound (10) obtained from Compound (8) and Compound (9).

(28)→(29):

Compound (29) can be obtained by performing deprotection of P¹from Compound (28). A deprotection reaction may be performed in accordance with a general method for deprotection of a nitrogen protecting group, for example, a method disclosed in Green's Protective Groups in Organic Synthesis, -4-th ed. John Wiley & Sons, Inc. For example, when P¹is Boc, Compound (28) can be subjected to a deprotection reaction without a solvent or in an appropriate solvent in the presence of an acid (e.g., hydrochloric acid or trifluoroacetic acid). When P¹is Cbz, the reaction can be performed without a solvent or in an appropriate solvent in the presence of a reducing agent (e.g., an alkali metal formate, a hydride reducing agent, or a catalytic hydrogenation reducing agent). When P¹is Alloc, the deprotection reaction can be performed in the presence of a palladium catalyst.

(29)+(30)→(1d):

The reaction of Compound (29) and Compound (30) can be performed under the same reaction conditions as employed in Reaction Scheme 4 for producing Compound (1a) from Compound (22) and Compound (23).

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wherein A, L1, R², R³, R⁷, X¹and P¹are the same as defined above; R⁶¹represents lower alkyl, halo-lower alkyl, or alkenyl; and m1 represents 0, 1, or 2.

Examples of the lower alkyl represented by R⁶¹include straight- or branched-chain alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.

The halo-lower alkyl represented by R⁶¹is a group in which at least one hydrogen atom (e.g., 1 to 10, further 1 to 6, in particular 1 to 3 hydrogen atoms) of the above-mentioned “lower alkyl” is substituted with halogen(s). Examples thereof include trihalomethyl (e.g., —CF₃), trihaloethyl (e.g., —CH₂CF₃), pentahaloethyl (e.g., —CF₂CF₃), and nonahalobutyl (e.g., —CF₂CF₂CF₂CF₃).

Examples of the alkenyl represented by R⁶¹include straight- or branched-chain alkenyl groups having 2 to 6 carbon atoms, such as methyl, vinyl, 1-propenyl, allyl, 1-, 2-, or 3-butenyl, 1,3-butanedienyl, 1-, 2-, 3-, or 4-pentenyl, heptenyl, octenyl, nonenyl, decenyl, dodecenyl, and —CH₂CH═C(CH₃)CH₂CH₂CH═C(CH₃)₂.

A is preferably phenylene, and more preferably para-phenylene.

L1 is preferably a single bond.

(8)+(31)→(32):

The reaction for producing Compound (32) from Compound (8) and Compound (31) can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (1) through Compound (10) obtained from Compound (8) and Compound (9).

(32)→(33):

Compound (33) can be obtained by performing deprotection of P¹from Compound (32). The deprotection reaction can be performed under the same reaction conditions as employed in Reaction Scheme 5 for producing Compound (29) from Compound (28).

(33)+(30)→(1e):

The reaction of Compound (33) and Compound (30) can be performed under the same reaction conditions as employed in Reaction Scheme 4 for producing Compound (1a) from Compound (22) and Compound (23).

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wherein A, L1, R², R³, R⁷, X¹, and P¹are the same as defined above; R⁶²represents lower alkyl, halo-lower alkyl, alkenyl, lower alkoxy, halo-lower alkoxy, or hydroxy; m2 represents 0, 1, or 2; and the dashed lines indicate that the bond may be a double bond.

The lower alkyl, halo-lower alkyl, and alkenyl represented by R⁶²are the same as defined above for R⁶¹.

Examples of the lower alkoxy represented by R⁶²include straight- or branched-chain alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy.

Examples of the halo-lower alkoxy represented by R⁶²include a group in which at least one hydrogen atom (e.g., 1 to 10, further 1 to 6, in particular 1 to 3 hydrogen atoms) of the above-mentioned “lower alkoxy” is substituted with halogen(s). Examples thereof include trihalomethoxy (e.g., −OCF₃), pentahaloethyl (e.g., −OCF₂CF₃), and nonahalobutyl (e.g., —CF₂CF₂CF₂CF₃).

A is preferably phenylene, and more preferably para-phenylene.

L1 is preferably a single bond.

(8)+(34)→(35):

The reaction for producing Compound (35) from Compound (8) and Compound (34) can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (1) through Compound (10) obtained from Compound (8) and Compound (9).

(35)→(36):

Compound (36) can be obtained by performing deprotection of P¹from Compound (35). The deprotection reaction can be performed under the same reaction conditions as employed in Reaction Scheme 5 for producing Compound (29) from Compound (28).

(36)+(30)→(1f):

The reaction of Compound (36) and Compound (30) can be performed under the same reaction conditions as employed in Reaction Scheme 4 for producing Compound (1a) from Compound (22) and Compound (23).

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wherein A, L1, R², R³, X¹, and P²are the same as defined above; R⁶³and R⁶⁴are the same or different and each represent lower alkyl, halo-lower alkyl, alkenyl, lower alkoxy, halo-lower alkoxy, or hydroxy; m3 and m4 are the same or different and each represent 0, 1, or 2; R⁸¹represents lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, or hydroxy; and

n1 represents an integer of 1 to 5.

The lower alkyl, halo-lower alkyl, alkenyl, lower alkoxy, halo-lower alkoxy, and hydroxy represented by R⁶³, R⁶⁴, or R⁸¹are the same as those defined above for R⁶².

A is preferably phenylene, and more preferably para-phenylene.

L1 is preferably a single bond.

(8)+(37)→(38):

The reaction for producing Compound (38) from Compound (8) and Compound (37) can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (1) through Compound (10) obtained from Compound (8) and Compound (9).

(38)→(39):

Compound (39) can be obtained by performing deprotection of P¹from Compound (38). The deprotection reaction can be performed under the same reaction conditions as employed in Reaction Scheme 5 for producing Compound (29) from Compound (28).

(39)+(40)→(1g):

The reaction of Compound (39) and Compound (40) can be performed under the same reaction conditions as employed in Reaction Scheme 4 for producing Compound (1a) from Compound (22) and Compound (23).

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wherein A, L1, R², R³, R⁷, X¹, and P¹are the same as defined above; R⁶⁵represents lower alkyl or halo-lower alkyl; and m5 represents 0 or 1.

(8)+(41)→(42):

The reaction for producing Compound (42) from Compound (8) and Compound (41) can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (1) through Compound (10) obtained from Compound (8) and Compound (9).

(42)→(43):

Compound (43) can be produced by performing deprotection of P¹from Compound (42). The deprotection reaction can be performed under the same reaction conditions as employed in Reaction Scheme 5 for producing Compound (29) from Compound (28).

(43)+(30)→(1h):

The reaction of Compound (43) and Compound (30) can be performed under the same reaction conditions as employed in Reaction Scheme 4 for producing Compound (1a) from Compound (22) and Compound (23).

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wherein A, L1, R², R⁶¹, and m1 are the same as defined above; R⁸²represents lower alkyl or halo-lower alkyl; R⁸³represents a group represented by —C-D; R⁸⁴represents a group represented by -L2¹-C-D, wherein L2¹represents lower alkynylene, lower alkylene (this lower alkylene is optionally substituted with phenyl), or lower alkenylene; R⁸⁵is a group represented by -L2²-C-D, wherein L2²represents a single bond or lower alkylene-O—; R⁸⁶represents a group represented by -L2-C-D; and X⁴¹, X⁴², X⁴³, and X⁴⁴each represent a leaving group.

Examples of the leaving group represented by X⁴¹include halogen (e.g., chlorine and bromine) and a group represented by O—SO₂R⁸².

Examples of the leaving group represented by X⁴²include halogen (e.g., chlorine and bromine), hydroxy, and the like.

Examples of the leaving group represented by X⁴³include halogen (e.g., chlorine and bromine).

Examples of the leaving group represented by X⁴⁴include halogen (e.g., chlorine and bromine), sulfonyloxy (e.g., p-toluenesulfonyloxy, o- or p-nitrobenzenesulfonyloxy, methanesulfonyloxy, and trifluoromethanesulfonyloxy), and the like.

(33)+(44)→(1i):

In the reaction of Compound (33) and Compound (44), the reaction conditions of a general sulfonylation reaction of amine can be widely applied. For example, Compound (1i) can be produced by using Compound (33) and Compound (44) without a solvent or by dissolving them in an appropriate solvent (e.g., methylene chloride, acetonitrile, DMF, DMSO, or toluene) and allowing a reaction to occur in the presence of a basic compound (e.g., triethylamine or diisopropylethylamine).

The basic compound is used in an amount of usually equimolar to excess mole, preferably 1- to 5-fold mol, and more preferably 1- to 4-fold mol, of Compound (33).

Compound (44) is used in an amount of usually equimolar to excess mole, preferably 1- to 2-fold mol, and more preferably 1- to 1.5-fold mol, of Compound (33).

The reaction temperature is usually −50 to 150° C., preferably −20 to 100° C., and more preferably −10 to 50° C. The reaction time is usually 10 minutes to 24 hours, and preferably 10 minutes to 12 hours.

(33)+(45)→(1j):

In the reaction of Compound (33) and Compound (45), the reaction conditions of a general acylation reaction of amine can be widely applied.

For example, when X⁴²of Compound (45) is halogen, Compound (1j) can be produced by using Compound (33) and Compound (45) without a solvent or by dissolving them in an appropriate solvent (e.g., methylene chloride, acetonitrile, DMF, DMSO, or toluene) and allowing a reaction to occur in the presence of a basic compound (e.g., potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, pyridine, triethylamine, or diisopropylethylamine).

When X⁴²of Compound (45) is hydroxy, Compound (1j) can be produced by using Compound (33) and Compound (45) without a solvent or by dissolving them in an appropriate solvent (e.g., methylene chloride, acetonitrile, DMF, DMSO, or toluene) and allowing a reaction to occur in the presence of a suitable condensing agent (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride/1-hydroxybenzotriazole).

(33)+(46)→(1k):

In the reaction of Compound (33) and Compound (46), the reaction conditions of a general urethanation reaction of amine can be widely applied.

For example, Compound (1k) can be produced by using Compound (33) and Compound (46) without a solvent or by dissolving them in an appropriate solvent (e.g., methylene chloride, acetonitrile, DMF, DMSO, or toluene) and allowing a reaction to occur in the presence of a basic compound (e.g., potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, pyridine, triethylamine, or diisopropylethylamine).

(33)+(47)→(1l):

In the reaction of Compound (33) and Compound (47), the reaction conditions of a ring-opening reaction of epoxy with amine can be widely applied.

For example, Compound (11) can be produced by using Compound (33) and Compound (47) without a solvent or by dissolving them in an appropriate solvent (e.g., methylene chloride, acetonitrile, DMF, DMSO, NMP, or toluene) and allowing a reaction to occur.

(33)+(48)→(1m):

In the reaction for producing Compound (1m) from Compound (33) and Compound (48), the reaction conditions of a general alkylation reaction of amine can be widely applied. For example, the reaction can be performed under the same reaction conditions as employed in Reaction Scheme 4 for producing Compound (1a) from Compound (1b) and Compound (25).

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wherein R², R³, R⁷, X¹, R⁶¹, m1, and L2 are the same as defined above; and W represents N or CH.

(8)+(49)→(50):

The reaction for producing Compound (50) from Compound (8) and Compound (49) can be performed under the same reaction conditions as employed in Reaction Scheme 1 for producing Compound (1) through Compound (10) obtained from Compound (8) and Compound (9).

(50)+(51)→(1n):

The reaction for producing Compound (1n) from Compound (50) and Compound (51) can be performed under the same reaction conditions as employed in Reaction Scheme 4 for producing Compound (1a) from Compound (22) and Compound (23).

The compounds of Formula (1) according to the present invention, the intermediate compounds thereof, and the starting material compounds thereof can be produced by the above-described synthesis processes. They can also be produced based on the synthesis processes described in the Reference Examples and Examples of this specification in light of a technique that is well known or known at the time of the filing of this application.

Before subjecting the starting material compounds and intermediate compounds shown in each of the schemes above to each reaction, the functional groups thereof can be protected with suitable protecting groups using a well known method, if necessary, and, after completion of the reaction, deprotection of the protecting groups can be carried out by a well known method.

Each of the target compounds obtained in accordance with the above schemes can be isolated and purified. For example, after cooling the reaction mixture, an isolation procedure, such as filtration, concentration, or extraction, is performed to separate a crude reaction product, and thereafter, the crude reaction product is subjected to a general purifying procedure, such as column chromatography or recrystallization, thereby enabling isolation and purification from the reaction mixture.

The starting material compounds and the target compounds shown in each scheme above include those in the form of a solvate with a solvent (e.g., hydrate and ethanol solvate).

The compounds of Formula (1) according to the present invention (the final compound), the intermediate compounds obtained in each scheme above, and the starting material compounds thereof include geometrical isomers, stereoisomers, and optical isomers.

Various isomers can be isolated by well known separation methods. For example, a racemic compound can be led to a stereochemically pure isomer by a general optical resolution method (e.g., optical resolution by crystallization, or direct optical resolution by chromatography). Further, an optically active compound can also be produced by the use of a suitable optically active starting material.

The starting material compounds and the target compounds shown in each of the schemes above can be used in the form of an appropriate salt.

The compounds of the present invention include pharmaceutically acceptable salts. Among the compounds of the present invention, those containing a basic group or basic groups can form salts with general pharmaceutically acceptable acids. Examples of such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and like inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citrate, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid, and like organic acids.

Among the compounds of the present invention, those containing an acidic group or acidic groups can form salts with pharmaceutically acceptable basic compounds. Examples of such basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and the like.

In the compounds of the present invention, one or more atoms can be substituted with one or more isotope atoms. Examples of isotope atoms include deuterium (²H), tritium (³H), ¹³C, ¹⁴N, ¹⁸O, and the like.

The following describes pharmaceutical preparations (pharmaceutical compositions) comprising a compound of the present invention as an active ingredient.

Such pharmaceutical preparations are obtained by formulating a compound of the present invention into usual pharmaceutical preparations, using a compound of the present invention and a pharmaceutically acceptable carrier. Examples of such carriers include usually employed diluents and excipients, such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants.

The form of such pharmaceutical preparations can be selected from various forms, depending on the therapeutic purpose. Typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), and the like.

To form tablets, any of various known carriers can be used, including, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and like excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, and like binders; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, and like disintegrants; sucrose, stearin, cacao butter, hydrogenated oils, and like disintegration inhibitors; quaternary ammonium base, sodium lauryl sulfate, and like absorption promoters; glycerin, starch, and other wetting agents; starch, lactose, kaolin, bentonite, colloidal silica, and like adsorbents; purified talc, stearates, boric acid powder, polyethylene glycol, and like lubricants; and the like.

Such tablets may be coated with usual coating materials as required, to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double- or multi-layered tablets.

To form pills, any of various known carriers can be used, including, for example, glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc, and other excipients; gum arabic powder, tragacanth powder, gelatin, ethanol, and other binders; laminaran, agar, and other disintegrants; etc.

To form suppositories, any of various known carriers can be used, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc.

To form an injection, a solution, emulsion, or suspension is sterilized and preferably made isotonic with blood. Any of various known widely used diluents can be employed to prepare the solution, emulsion, or suspension. Examples of such diluents include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, fatty acid esters of polyoxyethylene sorbitan, and the like. In this case, the pharmaceutical preparation may contain sodium chloride, glucose, or glycerin in an amount sufficient to prepare an isotonic solution, and may contain usual solubilizers, buffers, analgesic agents, etc., and may further contain, if necessary, coloring agents, preservatives, flavors, sweetening agents, etc., and/or other medicines.

The proportion of the compound of the present invention in the pharmaceutical preparation is not limited and can be suitably selected from a wide range. It is preferable that the pharmaceutical preparation usually contain the compound of the present invention in a proportion of 1 to 70 wt %.

The route of administration of the pharmaceutical preparation according to the present invention is not limited, and the preparation is administered by a route suitable for the form of the preparation, the patient's age and sex, conditions of the disease, and other conditions. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are administered orally. Injections are intravenously administered singly or as mixed with usual injection transfusions, such as glucose solutions or amino acid solutions, or singly administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, as required. Suppositories are administered intrarectally.

The dosage of the pharmaceutical preparation is suitably selected according to the method of use, the patient's age and sex, severity of the disease, and other conditions, and is usually about 0.01 to 100 mg/kg body weight/day, and preferably 0.1 to 50 mg/kg body weight/day, in single or divided doses.

According to variations of various conditions, there may be cases where a dosage smaller than the above range is sufficient or where a dosage larger than the above range is required.

The compounds of the present invention have specific efficacy against tubercle bacilli, such as acid-fast bacilli (the genera of tubercle bacilli and atypical acid-fast bacilli). The compounds of the present invention have an excellent effect on multidrug-resistant tubercle bacilli. The compounds of the present invention have an antibacterial action against anaerobic bacteria. Accordingly, the compounds of the present invention are useful as a prophylactic and/or therapeutic agent for tuberculosis.

The compounds of the present invention exhibit excellent metabolic stability in plasma, and thus have a feature of providing satisfactorily sustained bactericidal action in vivo.

The compounds of the present invention can be used in combination with other therapeutic agents. Examples of drugs that can be used in combination with the compounds of the present invention include first-line antituberculosis drugs, second-line antituberculosis drugs, quinolone antibacterial drugs, macrolide antibacterial drugs, sulfa drugs, anti-HIV drugs, delamanid, PA-824, which is a drug currently being developed, and the like.

DESCRIPTION OF EMBODIMENTS

The present invention is described in more detail below with reference to Examples. However, the scope of the invention is not limited thereto.

The compounds whose physical property data are not shown in the Reference Examples were used in the subsequent reaction without further purification.

Reference Example 1
Preparation of 2-chloro-1-[2-(2-methyloxiranyl)ethyl]-4-nitro-1H-imidazol

Potassium carbonate (1.16 g) and cesium fluoride (196 mg) were added to a DMF solution (20 ml) of 2-chloro-4-nitro-1H-imidazole (953 mg) and 4-nitrobenzene sulfonic acid 2-(2-methyloxiranyl)ethyl ester (1.856 g), and the mixture was stirred at 60° C. overnight. Thereafter the reaction mixture was cooled to room temperature. Water was added to the reaction solution, and the reaction mixture was then extracted repeatedly with ethyl acetate. The combined organic layer was washed with water and a saturated sodium chloride aqueous solution, and then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to afford the title compound as a yellow oil (1.1 g).

Reference Example 2
Preparation of 2-chloro-4-nitro-1-(2-oxiranylethyl)-1H-imidazole

The title compound was prepared in the same manner as in Reference Example 1 using suitable starting materials.

Yellow Oil
Reference Example 3
Preparation of 2-chloro-1-[2-((R)-2,2-dimethyl[1,3]dioxolan-4-yl)-ethyl]-4-nitro-1H-imidazole

A solution of (4R)-2′-(2,2-dimethyl-[1,3]-dioxolan-4-yl)ethanol (100 g) in acetonitrile (400 ml) at −20° C. was treated with N,N,N′,N′-tetramethyl-1,3-propanediamine (172 ml). A solution of p-toluenesulfonyl chloride (156.5 g) in acetonitrile (350 ml) was added dropwise at 0° C. or less and then the reaction mixture was stirred at 0 to 10° C. for 1 hour. Water was added to the reaction solution, and the reaction mixture was then extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, and then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. Acetonitrile (1,000 ml) was added to the resulting residue. 2-Chloro-4-nitro-1H-imidazole (100.90 g), potassium carbonate (132.35 g) and sodium iodide (122.3 g) were further added, and then the mixture was heated at reflux overnight. Thereafter the reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then subjected to filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1→1:2) and washed with isopropyl ether to afford the title compound as a pale yellow powder (101.35 g).

1H NMR (CDCl3) δ: 1.35 (3H, s), 1.43 (3H, s), 1.95-2.00 (1H, m), 2.00-2.05 (1H, m), 3.63-3.68 (1H, m), 4.00-4.15 (2H, m), 4.18-4.30 (2H, m), 7.83 (1H, m).

Reference Example 4
Preparation of 2-chloro-1-[2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)ethyl]-4-nitro-1H-imidazole

The title compound was prepared in the same manner as in Reference Example 3 using suitable starting materials.

Colorless Columnar
Reference Example 5
Preparation of 2-chloro-1-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)ethyl]-4-nitro-1H-imidazole

The title compound was prepared in the same manner as in Reference Example 3 using suitable starting materials.

Colorless Columnar
Reference Example 6
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-butane-1,2-diol

While stirring a tetrahydrofuran solution (700 ml) of 2-chloro-1-[2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)ethyl]-4-nitro-1H-imidazole (196.2 g) at room temperature, 1.0 M hydrochloric acid ethanol solution (1,100 ml) was added thereto and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, hexane was added to the residue obtained and concentrated under reduced pressure. Thereafter, ethyl acetate was added thereto and concentrated under reduced pressure. Isopropyl ether was added to the resulting solid and stirred for a while. The precipitated crystal was collected by filtration to afford the title compound as a colorless solid (166.5 g).

1H NMR (DMSO-d6) δ: 1.63-1.74 (1H, m), 1.91-2.01 (1H, m), 3.22-3.28 (1H, m), 3.30-3.36 (1H, m), 3.40-3.49 (1H, m), 4.08-4.23 (2H, m), 4.62 (1H, t, J=5.6 Hz), 4.81 (1H, d, J=5.1 Hz), 8.56 (1H, s).

Reference Example 7
Preparation of (S)-4-(2-chloro-4-nitroimidazol-1-yl)butane-1,2-diol

The title compound was prepared in the same manner as in Reference Example 6 using suitable starting materials.

Pale Yellow Solid
Reference Example 8
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)butane-1,2-diol

The title compound was prepared in the same manner as in Reference Example 6 using suitable starting materials.

White Powder
Reference Example 9
Preparation of toluene-4-sulfonic acid (R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester

2-Chloro-1-[4-((R)-1,2-dihydroxy)butyl]-4-nitro-1H-imidazole (166.5 g) was dissolved in pyridine (333 ml) and cooled to −30° C., p-toluenesulfonyl chloride (148.19 g) was gradually added thereto at −10° C. or less, and the mixture was stirred at −10° C. for 2 hours. The reaction mixture was added to a mixture of concentrated hydrochloric acid (430 ml) and water (1,500 ml), followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and subjected to filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=96:4→ethyl acetate) and recrystallized from ethyl acetate-isopropyl ether to afford the title compound as a colorless solid (212.12 g).

1H NMR (CDCl3) δ: 1.83-2.00 (2H, m), 2.47 (3H, s), 2.53-2.73 (1H, m), 3.80-3.90 (1H, m), 3.93-3.98 (1H, m), 4.03-4.08 (1H, m), 4.23-4.28 (2H, m), 7.37 (2H, d, J=8.0 Hz), 7.73-7.80 (3H, m).

Reference Example 10
Preparation of toluene-4-sulfonic acid (S)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester

The title compound was prepared in the same manner as in Reference Example 9 using suitable starting materials.

White Powder
Reference Example 11
Preparation of toluene-4-sulfonic acid 4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-butyl ester

The title compound was prepared in the same manner as in Reference Example 9 using suitable starting materials.

White Solid
Reference Example 12
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxy}butan-2-ol

Toluene-4-sulfonic acid 4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-butyl ester (0.78 g) was suspended in ethanol (12 ml), an ethanol solution (0.68 ml) of 20% sodium ethoxide was added thereto, followed by stirring at room temperature for 1 hour. 4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (0.707 g) and tripotassium phosphate (0.509 g) were added thereto and stirred at 80° C. for 2 hours. The mixture was cooled to room temperature and filtered through Celite to remove insoluble matter and, then the residue was washed with ethyl acetate. The filtrate and liquid were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1→9:1) to afford the title compound as a pale yellow powder (0.314 g).

Reference Example 13
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[N-(4-chlorophenyl)-N-methylamino]piperidin-1-yl}phenoxy)butan-2-ol

2-Chloro-4-nitro-1-(2-oxiranylethyl)-1H-imidazole (810 mg) was suspended in ethanol (20 ml) and 4-{4-[N-(4-chlorophenyl)-N-methylamino]piperidin-1-yl}phenol (982 mg) and tripotassium phosphate (200 mg) were added thereto, followed by stirring at 70° C. overnight. Thereafter the reaction solution was cooled to room temperature, and filtered through Celite to remove insoluble matter and, then the residue was washed with ethyl acetate. The filtrate and liquid were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:1) and recrystallized from methylene chloride-ethyl acetate to afford the title compound as a yellow solid (486 mg).

Reference Example 14
Preparation of 4-{4-[4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenyl}piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 13 using suitable starting materials.

Yellow Amorphous
Reference Example 15
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethylbenzyloxymethyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 13 using suitable starting materials.

Brown Oil
Reference Example 16
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethylphenoxymethyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 13 using suitable starting materials.

Brown Solid
Reference Example 17
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethoxybenzyloxy)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 18
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethoxybenzyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 19
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[N-methyl-N-(4-trifluoromethoxyphenyl)amino]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 20
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 21
Preparation of (S)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 22
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethoxybenzyloxymethyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Brown Powder
Reference Example 23
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethoxyphenoxymethyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 24
Preparation of 1-{4-[4-(4-chlorobenzyloxymethyl)piperidin-1-yl]phenoxy}-4-(2-chloro-4-nitroimidazol-1-yl)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 25
Preparation of 1-{4-[4-(4-chlorobenzyloxy)piperidin-1-yl]phenoxy}-4-(2-chloro-4-nitroimidazol-1-yl)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 26
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Amorphous
Reference Example 27
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethylphenoxy)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 28
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-chlorophenoxy)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 29
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethoxyphenyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 30
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[N-methyl-N-(4-trifluoromethylphenyl)amino]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 31
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(3-trifluoromethylphenoxy)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 32
Preparation of 1-{4-[4-(3,5-bis-trifluoromethylphenoxy)piperidin-1-yl]phenoxy}-4-(2-chloro-4-nitroimidazol-1-yl)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 33
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 34
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[1-(4-trifluoromethylphenyl)piperidin-4-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 35
Preparation of 4-{4-[4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenyl}piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 36
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethylbenzyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 37
Preparation of 1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]phenoxy}-4-(2-chloro-4-nitroimidazol-1-yl)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 38
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[N-(4-chlorophenyl)-N-ethylamino]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Oil

MS (m/z): 547[M+H]⁺

Reference Example 39
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[N-ethyl-N-(4-trifluoromethylphenyl)amino]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Oil

MS (m/z): 582[M+H]⁺

Reference Example 40
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[N-ethyl-N-(4-trifluoromethoxyphenyl)amino]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Oil

MS (m/z): 598[M+H]⁺

Reference Example 41
Preparation of 4-{4-[4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenyl}-[1,4]diazepane-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Amorphous

MS (m/z): 510[M+H]⁺

Reference Example 42
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethoxyphenyl)-oxazol-2-ylmethyl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Powder
Reference Example 43
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[2-(4-trifluoromethoxyphenyl)-oxazol-4-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 44
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[2-(4-trifluoromethoxyphenoxymethyl)-oxazol-4-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Powder
Reference Example 45
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[2-(4-trifluoromethoxyphenoxymethyl)thiazol-4-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 46
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[2-(4-trifluoromethoxyphenyl)thiazol-4-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Powder
Reference Example 47
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 48
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[3-(4-trifluoromethoxyphenoxy)propyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 49
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[3-(4-trifluoromethoxyphenyl)propyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 50
Preparation of 1-{4-[4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenyl}-4-trifluoromethylpiperidin-4-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 51
Preparation of 4-{5-[4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]pyridin-2-yl}piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Red Powder

MS (m/z): 496[M]⁺

Reference Example 52
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[2-(4-trifluoromethoxybenzyl)thiazol-4-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 53
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(5-trifluoromethylpyridin-2-yloxy)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 54
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(5-trifluoromethylpyridin-2-yloxymethyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 55
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-[4-(4-methoxy-4-trifluoromethylpiperidin-1-yl)phenoxy]butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 56
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(5-trifluoromethylpyridin-2-yloxy)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 57
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{6-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]pyridin-3-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Orange Amorphous
Reference Example 58
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{6-[4-(4-trifluoromethoxybenzyl)piperidin-1-yl]pyridin-3-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Amorphous
Reference Example 59
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{6-[4-(4-trifluoromethoxyphenoxymethyl)piperidin-1-yl]pyridin-3-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 60
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(6-{4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidin-1-yl}pyridin-3-yloxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Brown Powder
Reference Example 61
Preparation of (S)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 62
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-[4-(4-propoxy-4-trifluoromethylpiperidin-1-yl)phenoxy]butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 63
Preparation of 4-{4-[(S)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenyl}piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Oil

MS (m/z): 495[M]⁺

Reference Example 64
Preparation of (S)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[N-methyl-N-(4-trifluoromethoxyphenyl)amino]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Dark Red Amorphous
Reference Example 65
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 66
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 68
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[N-methyl-N-(4-trifluoromethoxyphenyl)amino]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Red Amorphous
Reference Example 69
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{6-[4-(4-chlorophenoxy)piperidin-1-yl]pyridin-3-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Amorphous
Reference Example 70
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{6-[4-(4-trifluoromethoxybenzyloxy)piperidin-1-yl]pyridin-3-yloxy]butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 71
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{6-[4-(4-trifluoromethylphenoxy)piperidin-1-yl]pyridin-3-yloxy]butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 73
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[1-(4-trifluoromethoxyphenyl)piperidin-4-ylmethyl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Amorphous
Reference Example 74
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[1-(4-trifluoromethylphenyl)piperidin-4-ylmethyl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 75
Preparation of 4-{4-[4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]benzyl}piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Oil
Reference Example 76
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(6-{4-[3-(4-trifluoromethoxyphenyl)propyl]piperidin-1-yl}pyridin-3-yloxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Oil
Reference Example 77
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-[6-(4-trifluoromethoxybenzyloxymethyl)pyridin-3-yloxy]butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Solid
Reference Example 78
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(4-trifluoromethylphenoxy)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 79
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(4-chlorophenoxy)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 80
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(4-trifluoromethylphenyl)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 81
Preparation of 4-(2-{4-[4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenyl}-ethyl)piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 82
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{2-chloro-4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Amorphous
Reference Example 83
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(4-chlorophenyl)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 84
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[3-(4-trifluoromethylphenyl)propyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 85
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[3-(4-trifluoromethylphenoxy)propyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 86
Preparation of 1-{4-[4-(5-chlorobenzofuran-2-ylmethyl)piperidin-1-yl]phenoxy}-4-(2-chloro-4-nitroimidazol-1-yl)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 87
Preparation of 1-{4-[4-(5-chlorobenzofuran-2-ylmethoxy)piperidin-1-yl]phenoxy}-4-(2-chloro-4-nitroimidazol-1-yl)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 88
Preparation of 4-{4-[4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylbutoxy]phenyl}piperazine-1-carboxylic acid tert-butyl ester

4-{4-[2-Hydroxy-2-methyl-4-(toluene-4-sulfonyloxy)butoxy]phenyl}piperazine-1-carboxylic acid tert-butyl ester (4.69 g, 8.77 mmol), 2-chloro-4-nitro-1H-imidazole (1.55 g, 10.52 mmol), sodium hydrogen carbonate (0.88 g) and dimethylformamide (47 ml) were mixed, and the mixture was stirred at 90 to 100° C. overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. After filtering under reduced pressure, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→3:7) to afford the title compound as a yellow amorphous solid (2.12 g).

MS (m/z): 509[M]⁺

Reference Example 89
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[3-(4-chlorophenoxy)propyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 90
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(5-trifluoromethylbenzofuran-2-ylmethyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 91
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[3-(4-chlorophenyl)propyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 92
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(5-trifluoromethoxybenzofuran-2-ylmethyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 93
Preparation of 1-{4-[4-(5-chlorobenzofuran-2-ylmethoxymethyl)piperidin-1-yl]phenoxy}-4-(2-chloro-4-nitroimidazol-1-yl)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Powder
Reference Example 94
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{1-[3-(4-trifluoromethoxyphenoxy)propyl]-1,2,3,4-tetrahydro-quinolin-6-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Orange Amorphous
Reference Example 95
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{1-[3-(4-trifluoromethoxyphenoxy)propyl]-1,2,3,4-tetrahydro-quinolin-6-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Red Amorphous
Reference Example 96
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{1-[3-(4-trifluoromethoxyphenoxy)propyl]-1H-indole-5-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Red Amorphous
Reference Example 97
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{1-[3-(4-trifluoromethoxyphenoxy)propyl]-1,2,3,4-tetrahydro-quinolin-5-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 98
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{1-[3-(4-trifluoromethoxyphenoxy)propyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Red Amorphous
Reference Example 99
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{1-[4-(4-trifluoromethoxyphenoxy)benzyl]-1,2,3,4-tetrahydro-quinolin-6-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Red Amorphous
Reference Example 100
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{1-[4-(4-trifluoromethoxyphenoxy)benzyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 101
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{2-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]-quinolin-6-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Amorphous
Reference Example 102
Preparation of 4-{6-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]-quinolin-2-yl}piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 103
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{2-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]benzothiazol-6-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 104
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{2-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]benzothiazol-6-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 105
Preparation of 4-{6-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]benzothiazol-2-yl}piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 106
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-[4-(4,4-dimethoxypiperidin-1-yl)phenoxy]butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Orange Amorphous
Reference Example 107
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(6-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}-naphthalen-2-yloxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Solid
Reference Example 108
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 109
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[3-(4-trifluoromethoxyphenyl)propyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 110
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(3,4-dichlorophenoxy)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 111
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(3-chloro-5-trifluoromethylpyridin-2-yloxy)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 112
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(3,5-dichloropyridin-2-yloxy)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Amorphous
Reference Example 113
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(4-chloro-3-trifluoromethylphenoxy)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Amorphous
Reference Example 114
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(tetrahydropyran-2-yloxy)-2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 115
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(2,4-dichlorophenoxy)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Reference Example 116
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[4-(4-trifluoromethoxybenzyloxy)phenyl]piperazin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Solid
Reference Example 117
Preparation of (R)-1-(4-{4-[2-(4-chloro-3-methylphenoxy)ethyl]piperidin-1-yl}phenoxy)-4-(2-chloro-4-nitroimidazol-1-yl)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 118
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(3-trifluoromethylphenoxy)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 119
Preparation of (R)-1-(4-{4-[2-(3-chloro-4-fluorophenoxy)ethyl]piperidin-1-yl}phenoxy)-4-(2-chloro-4-nitroimidazol-1-yl)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 120
Preparation of (4-{4-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenyl}piperazin-1-yl)-carbamic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 121
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[4-(4-trifluoromethoxyphenoxy)phenyl]piperazin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Brown Solid
Reference Example 122
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{2-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]benzooxazol-5-yloxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 123
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[3-(4-trifluoromethoxyphenoxy)propyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 124
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[2-(5-trifluoromethylpyridin-2-yloxy)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 125
Preparation of 4-{4-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenoxy}piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Amorphous
Reference Example 126
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[4-(4-trifluoromethoxyphenoxy)butyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 127
Preparation of 4-{4-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenyl}piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 88 using suitable starting materials.

Orange Amorphous
Reference Example 128
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-[4-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-yl)phenoxy]butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Solid
Reference Example 129
Preparation of (S)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[4-(4-trifluoromethoxybenzyloxy)phenoxy]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Orange Amorphous
Reference Example 130
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[4-(4-trifluoromethoxybenzyloxy)phenoxy]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Amorphous
Reference Example 131
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-[4-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)phenoxy]butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Amorphous
Reference Example 132
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[4-(4-trifluoromethoxyphenoxymethyl)phenyl]piperazin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Amorphous
Reference Example 133
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-[4-(4-{4-[N-methyl-N-(4-trifluoromethylbenzyl)amino]phenyl}piperazin-1-yl)phenoxy]butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Brown Solid
Reference Example 134
Preparation of (S)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[4-(4-trifluoromethylbenzyloxy)phenoxy]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Powder
Reference Example 135
Preparation of 4-{4-[(S)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenoxy}piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Solid
Reference Example 136
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[4-(4-trifluoromethylbenzyloxy)phenoxy]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Red Powder
Reference Example 137
Preparation of 4-{5-[(S)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]benzooxazol-2-yl}piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 138
Preparation of 4-{5-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]benzooxazol-2-yl}piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Powder
Reference Example 139
Preparation of (S)-4-(2-chloro-4-nitroimidazol-1-yl)-1-[4-(4,4-dimethoxypiperidin-1-yl)phenoxy]butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 140
Preparation of 5-[(S)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]-1,3-dihydroisoindole-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Brown Amorphous
Reference Example 141
Preparation of 5-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]-1,3-dihydroisoindole-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Amorphous
Reference Example 142
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[4-(4-trifluoromethoxybenzyloxy)phenoxymethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Powder
Reference Example 143
Preparation of (S)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[4-(4-trifluoromethoxybenzyloxy)phenoxymethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Powder
Reference Example 144
Preparation of (S)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(2-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperidin-1-yl}benzothiazol-6-yloxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 145
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4′-diethoxymethylbiphenyl-4-yloxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Oil
Reference Example 146
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(2-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperidin-1-yl}benzothiazol-6-yloxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 147
Preparation of 7-[(S)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Reference Example 148
Preparation of 7-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Amorphous
Reference Example 149
Preparation of 6-[(S)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 150
Preparation of 6-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 151
Preparation of 7-[(S)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]-1,3,4,5-tetrahydrobenzo[c]azepine-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Amorphous
Reference Example 152
Preparation of 7-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]-1,3,4,5-tetrahydrobenzo[c]azepine-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

White Amorphous
Reference Example 153
Preparation of (2R,5S)-4-{4-[(S)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenyl}-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Reference Example 154
Preparation of (2R,5S)-4-{4-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenyl}-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Amorphous
Reference Example 155
Preparation of 4-{5-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]pyridin-2-yl}piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Brown Amorphous
Reference Example 156
Preparation of 4-{5-[(S)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]pyridin-2-yl}piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Brown Amorphous
Reference Example 157
Preparation of 5-{4-[(S)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Orange Amorphous
Reference Example 158
Preparation of 4-{4′-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]biphenyl-4-yl}piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Solid
Reference Example 159
Preparation of 4-{4′-[(S)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]biphenyl-4-yl}piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Solid
Reference Example 160
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-({N-methyl-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]-amino}-methyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Amorphous
Reference Example 161
Preparation of (S)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-({N-methyl-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]-amino}-methyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Amorphous
Reference Example 162
Preparation of 5-{4-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Amorphous
Reference Example 163
Preparation of 4-{4-[(R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutoxy]phenyl}piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 164
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethylphenoxymethyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Solid
Reference Example 165
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethoxybenzyloxymethyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Oil
Reference Example 166
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-1-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 88 using suitable starting materials.

Brown Amorphous

MS (m/z): 596[M]⁺

Reference Example 167
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethoxybenzyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Reddish Brown Amorphous
Reference Example 168
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethylbenzyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow-Red Amorphous
Reference Example 169
Preparation of (R)-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]phenoxy}-4-(2-chloro-4-nitroimidazol-1-yl)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow-Red Amorphous
Reference Example 170
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethoxyphenyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Orange Amorphous
Reference Example 171
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethylphenyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Orange Amorphous
Reference Example 172
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[1-(4-trifluoromethoxyphenyl)piperidin-4-yloxy]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow Amorphous
Reference Example 173
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[1-(4-trifluoromethylphenyl)piperidin-4-yloxy]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Yellow-Red Amorphous
Reference Example 174
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-1-{4-[4-(4-trifluoromethoxybenzyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 88 using suitable starting materials.

Yellow Oil

MS (m/z): 582[M]⁺

Reference Example 175
Preparation of 4-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-1-(4-{4-[3-(4-trifluoromethoxyphenyl)propyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 88 using suitable starting materials.

Yellow Oil
Reference Example 176
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{4-[3-(4-trifluoromethylphenyl)propyl]piperidin-1-yl}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Brown Oil
Reference Example 177
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(5-trifluoromethylpyridin-2-yloxymethyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 178
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{N-ethyl-N-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]amino}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Pale Yellow Powder
Reference Example 179
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-(4-{N-methyl-N-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]amino}phenoxy)butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Orange Powder
Reference Example 180
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethylbenzyloxymethyl)piperidin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Red Amorphous
Reference Example 181
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(2,2,2-trifluoro-ethyl)piperazin-1-yl]phenoxy}butan-2-ol

The title compound was prepared in the same manner as in Reference Example 12 using suitable starting materials.

Brown Oil

MS (m/z): 477[M]⁺

Reference Example 182
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-[4-(4-{2-[N-methyl-N-(4-trifluoromethoxyphenyl)amino]-ethyl}piperidin-1-yl)phenoxy]butan-2-ol

Toluene-4-sulfonic acid (R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester (988 mg) and 4-(4-{2-[N-methyl-N-(4-trifluoromethoxyphenyl)amino]ethyl}piperidin-1-yl)phenol (1.0 g) were suspended in ethanol (30 ml). Tripotassium phosphate (1.08 g) and sodium iodide (418 mg) were added to the suspension, and the mixture was stirred at 80° C. under a nitrogen atmosphere for 4.5 hours. After being cooled to room temperature, ethyl acetate (20 ml) was added to the reaction mixture, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→methylene chloride:methanol=97:3) to afford the title compound as a reddish brown oil (1.17 g).

Reference Example 183
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-[4-(4-{[N-methyl-N-(4-trifluoromethoxybenzyl)amino]methyl}piperidin-1-yl)phenoxy]butan-2-ol

The title compound was prepared in the same manner as in Reference Example 182 using suitable starting materials.

Orange Amorphous
Reference Example 184
Preparation of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethylsulfanylbenzyl)piperidin-1-yl]phenoxy}butan-2-ol

Sodium tert-butoxide (0.412 g) was added to an ethanol solution (20 ml) of toluene-4-sulfonic acid (R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester (1.671 g) under an argon atomosphere in an ice water bath, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 4-[4-(4-trifluoromethylsulfanylbenzyl)piperidin-1-yl]phenol (1.50 g) and tripotassium phosphate (0.867 g) were added thereto, and then the mixture was heated at reflux for 4 hours. Thereafter the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→0:10) to afford the title compound as a brown oil (1.47 g).

MS (m/z): 584[M]⁺

Reference Example 185
Preparation of (R)-1-{4-[4-(tert-butyl-dimethyl-silanyloxy)-[1,4′]bipiperidinyl-1′-yl]phenoxy}-4-(2-chloro-4-nitroimidazol-1-yl)butan-2-ol

Toluene-4-sulfonic acid (R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester (848 mg) and 4-[4-(tert-butyl-dimethylsilanyloxy)[1,4′]bipiperidinyl-1′-yl]phenol (850 mg) were suspended in ethanol (30 ml). Tripotassium phosphate (1.02 g) and sodium iodide (359 mg) were added to the suspension, and the mixture was stirred at 75° C. for 3 hours under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Insoluble matter that was precipitated by adding isopropyl ether to the residue was collected by filtration to afford the title compound as a pale brown powder (470 mg).

Reference Example 186
Preparation of 4-(4-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester

1-(4-Hydroxyphenyl)piperazine (5.0 g) was suspended in methanol (50 ml). Di-tert-butyl dicarbonate (6.8 ml) was added to the suspension, and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=50:1) to afford the title compound as a white powder (7.88 g).

1H NMR (CDCl3) δ 1.49 (9H, s), 2.95-3.00 (4H, m), 3.55-3.60 (4H, m), 5.77 (1H, s), 6.74-6.86 (4H, m).

Reference Example 187
Preparation of 4-[4-(4-trifluoromethoxybenzyloxy)piperidin-1-yl]phenol

Pyridinium p-toluenesulfonate (81 mg) was added to an ethanol solution (3 ml) of 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-(4-trifluoromethoxybenzyloxy)piperidine (507 mg) and the mixture was stirred at 70 to 80° C. for 24 hours. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the residue, and the result was separated into layers. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. After being concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to afford the title compound as a pale purple solid (305 mg).

1H NMR (CDCl3) δ 1.76-1.90 (2H, m), 2.00-2.10 (2H, m), 2.84 (2H, m), 3.33-3.42 (2H, m), 3.51-3.60 (1H, m), 4.53 (1H, brs), 4.63 (2H, s), 6.74 (2H, d, J=9.0 Hz), 6.87 (2H, d, J=9.0 Hz), 7.48 (2H, d, J=8.1 Hz), 7.60 (2H, d, J=8.2 Hz).

Reference Example 188
Preparation of 4-[4-(4-trifluoromethylbenzyloxy)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Colorless Solid

1H NMR (CDCl3) δ 1.71-1.93 (2H, m), 1.95-2.15 (2H, m), 2.71-2.93 (2H, m), 3.26-3.46 (2H, m), 3.46-3.63 (1H, m), 4.50 (1H, s), 4.57 (2H, s), 6.74 (2H, d, J=9.0 Hz), 6.87 (2H, d, J=8.9 Hz), 7.19 (2H, d, J=8.5 Hz), 7.39 (2H, d, J=8.4 Hz).

Reference Example 189
Preparation of 4-[4-(4-trifluoromethylphenylamino)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Colorless Amorphous

1H NMR (CDCl3) δ 1.56-1.72 (2H, m), 2.13-2.20 (2H, m), 2.77-2.88 (2H, m), 3.44-3.51 (3H, m), 3.92 (1H, d, J=7.94 Hz), 4.86 (1H, s), 6.59-6.63 (2H, m), 6.72-6.79 (2H, m), 6.85-6.92 (2H, m), 7.38-7.42 (2H, m).

Reference Example 190
Preparation of 4-[4-(4-trifluoromethoxyphenoxymethyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Pale Yellow Solid

1H NMR (CDCl3) δ 1.48-1.63 (2H, m), 1.87-1.98 (3H, m), 2.62-2.72 (2H, m), 3.51-3.57 (2H, m), 3.83 (2H, d, J=5.88 Hz), 4.50 (1H, brs), 6.73-6.78 (2H, m), 6.84-6.91 (4H, m), 7.12-7.16 (2H, m).

Reference Example 191
Preparation of 4-[4-(4-trifluoromethoxybenzyl)piperidin-1-yl]phenol

10% palladium on carbon (64 mg) was added to an ethanol solution (13 ml) of 4-(4-trifluoromethoxybenzyl)piperidine (1.28 g) and 1,4-cyclohexanedione (1.19 g), and the mixture was stirred at 70 to 80° C. for 8.5 hours. After being cooled to room temperature, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. After being dissolved in ethyl acetate, the residue was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. After being concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→6:4) to afford the title compound as a black oil (305 mg).

MS (m/z): 351[M]⁺

Reference Example 192
Preparation of 4-[4-(3,4-dichlorobenzyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Brown Oil

MS (m/z): 335[M]⁺

Reference Example 193
Preparation of 4-[4-(4-trifluoromethylbenzyloxymethyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Pale Yellow Oil

1H NMR (CDCl3) δ 1.37-1.54 (2H, m), 1.68-1.90 (3H, m), 2.57-2.68 (2H, m), 3.39 (2H, d, J=6.29 Hz), 3.46-3.52 (2H, m), 4.57 (2H, s), 5.28 (1H, s), 6.67-6.74 (2H, m), 6.83-6.89 (2H, m), 7.43-7.47 (2H, m), 7.58-7.62 (2H, m).

Reference Example 194
Preparation of 4-[3-(4-trifluoromethoxyphenoxy)-8-azabicyclo[3.2.1]oct-8-yl]phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Gray Powder

MS (m/z): 379[M]⁺

Reference Example 195
Preparation of 1-(4-hydroxyphenyl)-4-(4-trifluoromethoxyphenyl)piperidin-4-ol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Black Powder

MS (m/z): 353[M]⁺

Reference Example 196
Preparation of 4-{4-[3-(4-trifluoromethoxyphenyl)propyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Black Oil

MS (m/z): 379[M]⁺

Reference Example 197
Preparation of 4-{4-[2-(4-trifluoromethoxybenzyloxy)ethyl]piperidin-1-yl}phenol

6 N hydrochloric acid (1 ml) was added to an ethanol solution (15 ml) of 1-(4-methoxymethoxyphenyl)-4-[2-(4-trifluoromethoxybenzyloxy)ethyl]piperidine (1.51 g) and stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. A saturated sodium hydrogen carbonate aqueous solution was added to the residue, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound as a pink solid (1.34 g).

1H NMR (CDCl3) δ 1.37-1.66 (5H, m), 1.75-1.81 (2H, m), 2.55-2.65 (2H, m), 3.44-3.50 (2H, m), 3.55 (2H, t, J=6.3 Hz), 4.44 (1H, s), 4.50 (2H, s), 6.72-6.78 (2H, m), 6.83-6.89 (2H, m), 7.18-7.22 (2H, m), 7.35-7.39 (2H, m)

Reference Example 198
Preparation of 4-{4-[2-(4-trifluoromethylbenzyloxy)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Gray Solid

1H NMR (CDCl3) δ 1.35-1.67 (5H, m), 1.76-1.82 (2H, m), 2.55-2.66 (2H, m), 3.44-3.50 (2H, m), 3.57 (2H, t, J=6.3 Hz), 4.38 (1H, s), 4.57 (2H, s), 6.72-6.78 (2H, m), 6.84-6.89 (2H, m), 7.43-7.48 (2H, m), 7.59-7.62 (2H, m)

Reference Example 199
Preparation of 4-[4-(5-trifluoromethylbenzofuran-2-ylmethyl)piperidin-1-yl]phenol

1 N hydrochloric acid was added to an ethanol solution of 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-(5-trifluoromethylbenzofuran-2-ylmethyl)piperidine (2.3 g) and stirred at 80° C. for 1 hour. After being cooled to room temperature, a saturated sodium hydrogen carbonate aqueous solution was added to the mixture and concentrated under reduced pressure. The residue was subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to afford the title compound as a pinkish white amorphous compound (1.15 g).

Reference Example 200
Preparation of 4-[4-(3-trifluoromethylphenoxymethyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Brown Solid
Reference Example 201
Preparation of 4-{4-[2-(4-trifluoromethylphenoxy)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Brown Solid
Reference Example 202
Preparation of 4-{4-[3-(4-trifluoromethylphenoxy)propyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Brown Solid
Reference Example 203
Preparation of 4-[2-(4-chlorophenoxymethyl)oxazol-4-yl]phenol

2-Bromo-1-(4-hydroxyphenyl)ethanone (2.90 g) and 2-(4-chlorophenoxy)acetamide (5.0 g) were added to N-methylpyrrolidone (5 ml), and the mixture was stirred at 100° C. under a nitrogen atmosphere. After being cooled to room temperature, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture and separated into layers. The organic layer was washed with water, dried over sodium sulfate, and then concentrated under reduced pressure. Sodium acetate (11.1 g) in DMF (20 ml) were added to the residue and then stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and the prepared insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) and recrystallized from hexane-ethyl acetate to afford the title compound as a pale yellow powder (1.63 g).

Reference Example 204
Preparation of 4-{4-[2-(4-trifluoromethylphenyl)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

White Powder
Reference Example 205
Preparation of 4-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Brown Powder

MS (m/z): 457[M]⁺

Reference Example 206
Preparation of 4-{4-[2-(4-trifluoromethylphenyl)ethyl]piperazin-1-yl}phenol

1-(4-Benzyloxyphenyl)-4-[2-(4-trifluoromethylphenyl)ethyl]piperazine (0.94 g) was dissolved in ethanol (19 ml) and THF (19 ml). 10% palladium on carbon (94 mg) was added to the mixture and stirred at 50 to 60° C. under a hydrogen atmosphere for 8 hours. After being cooled to room temperature, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to afford the title compound as a gray powder (0.72 g).

MS (m/z): 349[M−H]

Reference Example 207
Preparation of 4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperazin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 206 using suitable starting materials.

Gray Powder

MS (m/z): 366[M]⁺

Reference Example 208
Preparation of 4-{4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Brown Amorphous

MS (m/z): 411[M]⁺

Reference Example 209
Preparation of 3-fluoro-4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 206 using suitable starting materials.

Pale Brown Powder
Reference Example 210
Preparation of 4-{4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Amorphous
Reference Example 211
Preparation of 4-{3,5-dimethyl-4-[3-(4-trifluoromethylphenyl)propyl]piperazin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials. Pale brown powder

MS (m/z): 392[M]⁺

Reference Example 212
Preparation of 4-{(3R,5S)-3,5-dimethyl-4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Brown Amorphous

MS (m/z): 486[M]⁺

Reference Example 213
Preparation of 4′-[4-(4-trifluoromethoxyphenoxy)piperidin-1-ylmethyl]-biphenyl-4-ol

Sodium triacetoxyborohydride (1.69 g) was added to a 1,2-dichloroethane solution (11 ml) of 4′-hydroxybiphenyl-4-carbaldehyde (1.13 g) and 4-(4-trifluoromethoxyphenoxy)piperidine (1.78 g) and stirred at room temperature overnight. A potassium carbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→0:10) to afford the title compound as a yellow powder (1.73 g).

MS (m/z): 443[M]⁺

Reference Example 214
Preparation of 4-{3,5-dimethyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Brown Powder

MS (m/z): 470[M]⁺

Reference Example 215
Preparation of 4-{(R)-3-methyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Brown Amorphous

MS (m/z): 456[M]⁺

Reference Example 216
Preparation of (R)-4-(4-hydroxyphenyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Yellow Oil

MS (m/z): 292[M]⁺

Reference Example 217
Preparation of 4-{(S)-3-methyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Brown Amorphous

MS (m/z): 456[M]⁺

Reference Example 218
Preparation of (S)-4-(4-hydroxyphenyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 206 using suitable starting materials.

Brown Oil

MS (m/z): 292[M]⁺

Reference Example 219
Preparation of 1-(4′-hydroxybiphenyl-4-yl)-4-trifluoromethylpiperidin-4-ol

The title compound was prepared in the same manner as in Reference Example 206 using suitable starting materials.

White Powder
Reference Example 220
Preparation of 4-{4-[3-(3-trifluoromethylphenoxy)propyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Yellow Solid
Reference Example 221
Preparation of 4-{4-[3-(5-trifluoromethylpyridin-2-yloxy)propyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

White Solid
Reference Example 222
Preparation of 4-{4-[4-(4-trifluoromethylbenzyloxy)benzyl]-3,6-dihydro-2H-pyridin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Brown Powder
Reference Example 223
Preparation of 4-[4-(4-trifluoromethoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Pink Powder
Reference Example 224
Preparation of 4-[4-(4-trifluoromethoxybenzyl)-3,6-dihydro-2H-pyridin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Yellow Oil
Reference Example 225
Preparation of 2-hydroxy-4-(4-trifluoromethylbenzyloxy)benzaldehyde

Potassium carbonate (16.51 g) and 4-trifluoromethylbenzylbromide (18.47 ml) were added to an acetone solution of 2,4-dihydroxybenzaldehyde (15 g). The mixture was stirred at room temperature for 15 hours and further stirred at 60° C. for 7 hours. After being cooled to room temperature, the mixture was concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to afford the title compound as a white powder (12.76 g).

Reference Example 226
Preparation of 4-[4-(4-trifluoromethylsulfanylphenoxy)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Yellow Powder

MS (m/z): 369[M]⁺

Reference Example 227
Preparation of 4-[4-(5-trifluoromethylbenzofuran-2-ylmethoxy)piperidin-1-yl]phenol

p-Toluenesulfonic acid monohydrate (0.84 g) was added to an ethanol solution (40 ml) of 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-(5-trifluoromethylbenzofuran-2-ylmethoxy)piperidine (2.1 g) and the mixture was heated at reflux for 1 hour. After being cooled to room temperature, water was added to the reaction mixture and filtered through Celite, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was washed with ether and dried to afford the title compound as a white powder (1.4 g).

1H NMR (CDCl3) δ 1.80-1.87 (2H, m), 2.03-2.09 (2H, m), 2.83 (2H, dt, J=9.5, 2.9 Hz), 3.35-3.39 (2H, m), 3.60-3.66 (1H, m), 4.69 (2H, s), 5.23 (1H, brs), 6.70-6.76 (3H, m), 6.85-6.88 (2H, m), 7.52-7.56 (2H, m), 7.84 (1H, s).

Reference Example 228
Preparation of 4-[4-(4-trifluoromethoxyphenylsulfanyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 227 using suitable starting materials.

White Powder

1H NMR (CDCl3) δ 1.76-1.84 (2H, m), 2.05-2.09 (2H, m), 2.74 (2H, dt, J=9.5, 2.6 Hz), 3.13-3.19 (1H, m), 3.42-3.46 (2H, m), 5.23 (1H, brs), 6.70-6.76 (2H, m), 6.82-6.86 (2H, m), 7.15 (2H, d, J=8.6 Hz), 7.44-7.47 (2H, m).

Reference Example 229
Preparation of 4-{4-[2-(4-trifluoromethoxyphenylsulfanyl)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 227 using suitable starting materials.

White Powder

1H NMR (CDCl3) δ 1.36-1.46 (2H, m), 1.48-1.58 (1H, m), 1.64 (2H, dt, J=7.0, 7.5 Hz), 1.76-1.83 (2H, m), 2.56-2.65 (2H, m), 2.96 (2H, t, J=7.5 Hz), 3.43-3.49 (2H, m), 5.30 (1H, brs), 6.70 (2H, d, J=9.0 Hz), 6.85 (2H, d, J=9.0 Hz), 7.12-7.16 (2H, m), 7.31-7.35 (2H, m).

Reference Example 230
Preparation of 4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]phenol

10% palladium on carbon (350 mg) was added to an ethanol solution (50 ml) of 4-(3,4-dichlorophenoxy)piperidine (7.1 g) and 1,4-cyclohexanedione (6.47 g), and the mixture was stirred at 50 to 60° C. for 5 hours. After being cooled to room temperature, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. After being concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to afford the title compound as a pale brown powder (5.2 g).

1H NMR (CDCl3) δ 1.91-1.98 (2H, m), 2.05-2.13 (2H, m), 2.94-3.01 (2H, m), 3.29-3.34 (2H, m), 4.36-4.41 (1H, m), 5.25 (1H, brs), 6.72-6.79 (3H, m), 6.87-6.90 (2H, m), 7.02 (1H, d, J=0.7 Hz), 7.31 (1H, d, J=8.9 Hz).

Reference Example 231
Preparation of 1-(4-hydroxyphenyl)-4-(4-trifluoromethylphenyl)piperidin-4-ol

1-(4-Benzyloxyphenyl)-4-(4-trifluoromethylphenyl)piperidin-4-ol (2 g) was dissolved in ethanol (20 ml) and ethyl acetate (20 ml). 20% palladium hydroxide on carbon (0.2 g) was added to the mixture and stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The mixture was filtered through Celite to remove the catalyst, and the filtrate was concentrated under reduced pressure. The residue was washed with an ether-hexane mixed solvent to afford the title compound as a pale pink powder (1.43 g).

Reference Example 232
Preparation of 4-[4-methoxy-4-(4-trifluoromethylphenyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 231 using suitable starting materials.

White Powder
Reference Example 233
Preparation of 4-[4-methoxy-4-(4-trifluoromethoxyphenyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 231 using suitable starting materials.

Pale Pink Powder
Reference Example 234
Preparation of 4-[4-(4-hydroxybenzyl)piperidin-1-yl]phenol

48% hydrobromic acid (300 ml) was added to 4-(4-methoxybenzyl)-1-(4-methoxyphenyl)piperidine (10.58 g) and heated at 100° C. for 21 hours. After being cooled to room temperature, the reaction mixture was diluted with water and neutralized by adding a sodium hydroxide aqueous solution and a sodium hydrogen carbonate aqueous solution. The insoluble matter formed was collected by filtration and dried to afford the title compound as a grayish brown powder (10.46 g).

Reference Example 235
Preparation of 4-(4-{1-methyl-1-[4-(4-trifluoromethylbenzyloxy)phenyl]-ethyl}piperazin-1-yl)phenol

The title compound was prepared in the same manner as in Reference Example 227 using suitable starting materials.

White Powder
Reference Example 236
Preparation of 4-{4-[4-(4-trifluoromethylphenoxy)benzyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Pale Red Solid
Reference Example 237
Preparation of 4-[2-(4-trifluoromethoxyphenoxymethyl)thiazol-4-yl]phenol

A solution of 2-Bromo-1-(4-hydroxyphenyl)ethanone (4.09 g) and 4-(4-trifluoromethoxyphenoxy)-thiobutyramide (5.31 g) in ethanol (100 ml) was heated at reflux overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane) to afford the title compound as a yellow oil (2.60 g, 6.57 mmol, 34.6%).

Reference Example 238
Preparation of 4-(4-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 206 using suitable starting materials.

Reference Example 239
Preparation of 4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Reference Example 240
Preparation of 4-[4-(4-chlorophenoxy)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Reference Example 241
Preparation of 4-[4-(4-trifluoromethylphenoxy)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Reference Example 242
Preparation of 4-[4-(4-chlorobenzyloxy)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Reference Example 243
Preparation of 4-{4-[N-(4-chlorophenyl)-N-methylamino]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Reference Example 244
Preparation of 4-[4-(4-trifluoromethoxybenzyloxymethyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Reference Example 245
Preparation of 4-[4-(4-trifluoromethylbenzyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 246
Preparation of 4-[4-(4-chlorobenzyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 247
Preparation of 4-[4-(4-trifluoromethylphenoxymethyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Reference Example 248
Preparation of 4-[4-(4-chlorobenzyloxymethyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Reference Example 249
Preparation of 4-[4-(4-trifluoromethoxyphenyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 250
Preparation of 4-{4-[N-methyl-N-(4-trifluoromethylphenyl)amino]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 251
Preparation of 4-[1-(4-trifluoromethoxyphenyl)piperidin-4-yloxy]phenol

The title compound was prepared in the same manner as in Reference Example 206 using suitable starting materials.

Reference Example 252
Preparation of 4-(4-hydroxyphenoxy)piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 206 using suitable starting materials.

Reference Example 253
Preparation of 4-[1-(4-trifluoromethylphenyl)piperidin-4-yloxy]phenol

The title compound was prepared in the same manner as in Reference Example 206 using suitable starting materials.

Reference Example 254
Preparation of 4-{4-[N-methyl-N-(4-trifluoromethoxyphenyl)amino]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 255
Preparation of 4-{4-[N-(4-chlorophenyl)-N-ethylamino]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 256
Preparation of 4-(4′-hydroxybiphenyl-4-yl)piperazin-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Reference Example 257
Preparation of 4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 258
Preparation of 4-(4-hydroxyphenyl)[1,4]diazepane-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 259
Preparation of 4-(4,4-dimethoxpiperidin-1-yl)phenol

The title compound was prepared in the same manner as in Reference Example 206 using suitable starting materials.

Reference Example 260
Preparation of 4-[4-(5-chlorobenzofuran-2-ylmethyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 261
Preparation of 4-[2-(4-trifluoromethoxyphenyl)oxazol-4-yl]phenol

2-Bromo-1-(4-hydroxyphenyl)ethanone (0.39 g) and 4-trifluoromethoxybenzamide (0.39 g) were dissolved in N,N-dimethylformamide (10 ml) and stirred at 140° C. for 2 hours. After cooling the reaction mixture to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25). The result was concentrated to dryness under reduced pressure to afford the title compound as a pale yellow solid (70 mg).

Reference Example 262
Preparation of 4-[4-(4-trifluoromethoxyphenyl)oxazol-2-ylmethyl]phenol

The title compound was prepared in the same manner as in Reference Example 261 using suitable starting materials.

Reference Example 263
Preparation of [4-(4-hydroxyphenyl)piperazin-1-yl]carbamic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 264
Preparation of 4-[2-(4-trifluoromethoxybenzyl)thiazol-4-yl]phenol

The title compound was prepared in the same manner as in Reference Example 237 using suitable starting materials.

Reference Example 265
Preparation of 4-{4-[2-(4-chlorophenoxy)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 266
Preparation of 4-{4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 267
Preparation of 4-[4-(5-trifluoromethylpyridin-2-yloxymethyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 197 using suitable starting materials.

Reference Example 268
Preparation of 4-[2-(4-trifluoromethoxyphenoxymethyl)oxazol-4-yl]phenol

The title compound was prepared in the same manner as in Reference Example 261 using suitable starting materials.

Reference Example 269
Preparation of 4-{4-[3-(4-trifluoromethoxyphenoxy)propyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 197 using suitable starting materials.

Reference Example 270
Preparation of 4-[4-(5-trifluoromethylpyridin-2-yloxy)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 271
Preparation of 4-{4-[2-(5-trifluoromethylpyridin-2-yloxy)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 272
Preparation of 4-{4-[N-ethyl-N-(4-trifluoromethylphenyl)amino]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 273
Preparation of 4-[4-(3-trifluoromethylphenoxy)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 274
Preparation of 4-[4-(3,5-bis-trifluoromethylphenoxy)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 275
Preparation of 4-{4-[N-ethyl-N-(4-trifluoromethoxyphenyl)amino]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 276
Preparation of 4-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]phenol

The title compound was prepared in the same manner as in Reference Example 234 using suitable starting materials.

Reference Example 277
Preparation of 4-[1-(4-trifluoromethylphenyl)piperidin-4-yl]phenol

The title compound was prepared in the same manner as in Reference Example 234 using suitable starting materials.

Reference Example 278
Preparation of 1-(4-hydroxyphenyl)-4-trifluoromethylpiperidin-4-ol

The title compound was prepared in the same manner as in Reference Example 206 using suitable starting materials.

Reference Example 279
Preparation of 4-[2-(4-trifluoromethoxyphenyl)thiazol-4-yl]phenol

The title compound was prepared in the same manner as in Reference Example 237 using suitable starting materials.

Reference Example 280
Preparation of 4-(4-methoxy-4-trifluoromethylpiperidin-1-yl)phenol

Boron trichloride (1 M dichloromethane solution, 2.3 ml) was added to a solution (50 ml) of 1-(4-benzyloxyphenyl)-4-methoxy-4-trifluoromethylpiperidine (0.7 g) in dichloromethane (50 ml) at 0° C. and stirred for 20 minutes. A sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water and dried over sodium sulfate. The result was concentrated under reduced pressure, and the residue was washed with diethylether and then dried to afford the title compound as a pale yellow powder (508 mg).

Reference Example 281
Preparation of 4-(4-propoxy-4-trifluoromethylpiperidin-1-yl)phenol

The title compound was prepared in the same manner as in Reference Example 206 using suitable starting materials.

Reference Example 282
Preparation of 4-[4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 283
Preparation of 4-[1-(4-trifluoromethoxyphenyl)piperidin-4-ylmethyl]phenol

The title compound was prepared in the same manner as in Reference Example 234 using suitable starting materials.

Reference Example 284
Preparation of 4-(4-hydroxybenzyl)piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 186 using suitable starting materials.

Reference Example 285
Preparation of 4-[1-(4-trifluoromethylphenyl)piperidin-4-ylmethyl]phenol

The title compound was prepared in the same manner as in Reference Example 234 using suitable starting materials.

Reference Example 286
Preparation of 4-{4-[3-(4-trifluoromethylphenyl)propyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 287
Preparation of 4-[2-(4-hydroxyphenyl)ethyl]piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 186 using suitable starting materials.

Reference Example 288
Preparation of 2-chloro-4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 289
Preparation of 4-{4-[2-(4-chlorophenyl)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 290
Preparation of 4-[4-(5-chlorobenzofuran-2-ylmethoxy)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 291
Preparation of 4-{4-[3-(4-chlorophenoxy)propyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 292
Preparation of 4-{4-[3-(4-chlorophenyl)propyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 293
Preparation of 4-[4-(5-trifluoromethoxybenzofuran-2-ylmethyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 294
Preparation of 4-[4-(5-chlorobenzofuran-2-ylmethoxymethyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 295
Preparation of 4-{4-[4-(4-trifluoromethoxybenzyloxy)phenyl]piperazin-1-yl}phenol p-toluenesulfonate

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 296
Preparation of 4-{4-[2-(3,4-dichlorophenoxy)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 297
Preparation of 4-{4-[2-(3-chloro-5-trifluoromethylpyridin-2-yloxy)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 298
Preparation of 4-{4-[2-(3,5-dichloropyridin-2-yloxy)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 299
Preparation of 4-{4-[2-(4-chloro-3-trifluoromethylphenoxy)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 300
Preparation of 4-{4-[2-(2,4-dichlorophenoxy)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 301
Preparation of 4-{4-[2-(tetrahydropyran-2-yloxy)-2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 206 using suitable starting materials.

Reference Example 302
Preparation of 4-{4-[2-(4-chloro-3-methylphenoxy)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 303
Preparation of 4-{4-[2-(3-trifluoromethylphenoxy)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 304
Preparation of 4-{4-[2-(3-chloro-4-fluorophenoxy)ethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 305
Preparation of 4-{4-[4-(4-trifluoromethoxyphenoxy)phenyl]piperazin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 191 using suitable starting materials.

Reference Example 306
Preparation of 4-{4-[4-(4-trifluoromethoxyphenoxy)butyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 307
Preparation of 4-{4-[4-(4-trifluoromethoxyphenoxymethyl)phenyl]piperazin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 197 using suitable starting materials.

Reference Example 308
Preparation of 4-(4-{4-[N-methyl-N-(4-trifluoromethylbenzyl)amino]phenyl}piperazin-1-yl)phenol

The title compound was prepared in the same manner as in Reference Example 197 using suitable starting materials.

Reference Example 309
Preparation of 4-{4-[4-(4-trifluoromethoxybenzyloxy)phenoxy]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 310
Preparation of 4-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-yl)phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 311
Preparation of 4-{4-[4-(4-trifluoromethylbenzyloxy)phenoxy]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 312
Preparation of 4-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)phenol

The title compound was prepared in the same manner as in Reference Example 206 using suitable starting materials.

Reference Example 313
Preparation of 4-{4-[4-(4-trifluoromethoxybenzyloxy)phenoxymethyl]piperidin-1-yl}phenol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

Reference Example 314
Preparation of 4′-diethoxymethylbiphenyl-4-ol

The title compound was prepared in the same manner as in Reference Example 206 using suitable starting materials.

Reference Example 315
Preparation of (2R,5S)-4-(4-hydroxyphenyl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 186 using suitable starting materials.

Reference Example 316
Preparation of (1R,4R)-5-(4-hydroxyphenyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 186 using suitable starting materials.

Reference Example 317
Preparation of 4-[4-([N-methyl-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amino]methyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Reference Example 318
Preparation of 4-[4-(4-trifluoromethylphenyl)piperidin-1-yl]phenol

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

Reference Example 319
Preparation of 4-(4-trifluoromethoxyphenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ol

5′-Benzyloxy-4-(4-trifluoromethoxyphenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (0.93 g) and 10% palladium on carbon (93 mg) were added to ethanol (9.3 ml), and the mixture was stirred at room temperature under a hydrogen atmosphere (atmospheric pressure) for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→6:4). The result was concentrated to dryness under reduced pressure to afford the title compound as a pale yellow powder (0.55 g).

Reference Example 320
Preparation of 4-(4-trifluoromethoxybenzyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ol

The title compound was prepared in the same manner as in Reference Example 319 using suitable starting materials.

Reference Example 321
Preparation of 4-(5-hydroxypyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 319 using suitable starting materials.

Reference Example 322
Preparation of 4-(4-trifluoromethoxyphenoxymethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ol

Pyridinium p-toluenesulfonate (PPTS) (0.917 g) was added to an ethanol solution (20 ml) of 5′-(tetrahydropyran-2-yloxy)-4-(4-trifluoromethoxyphenoxymethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (1.65 g), and the mixture was stirred for 4 hours while heating under reflux. After cooling the reaction mixture to room temperature, a sodium hydrogen carbonate aqueous solution was added thereto, and ethanol was distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off and the precipitated solid was collected by filtration. The solid was then washed with diisopropyl ether and dried to afford the title compound as a yellow powder (0.94 g).

Reference Example 323
Preparation of 4-[2-(4-trifluoromethoxyphenoxy)ethyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ol

The title compound was prepared in the same manner as in Reference Example 322 using suitable starting materials.

Reference Example 324
Preparation of 4-(4-chlorophenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ol

The title compound was prepared in the same manner as in Reference Example 322 using suitable starting materials.

Reference Example 325
Preparation of 4-(4-trifluoromethoxybenzyloxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ol

The title compound was prepared in the same manner as in Reference Example 322 using suitable starting materials.

Reference Example 326
Preparation of 4-(4-trifluoromethylphenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ol

The title compound was prepared in the same manner as in Reference Example 322 using suitable starting materials.

Reference Example 327
Preparation of 4-[3-(4-trifluoromethoxyphenyl)propyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ol

The title compound was prepared in the same manner as in Reference Example 322 using suitable starting materials.

Reference Example 328
Preparation of 6-(4-trifluoromethoxybenzyloxymethyl)pyridin-3-ol

2 N hydrogen chloride-ethyl acetate solution (20 ml) was added to an ethanol solution (20 ml) of 5-methoxymethoxy-2-(4-trifluoromethoxybenzyloxymethyl)pyridine (2.3 g) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and a sodium hydrogen carbonate aqueous solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution and dried over sodium sulfate. The result was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1). The result was concentrated to dryness under reduced pressure to afford the title compound as a white solid (2.4 g).

Reference Example 329
Preparation of 2-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]benzothiazol-6-ol

Methanol (1 ml) and a catalytic amount of acetic acid and sodium triacetoxyborohydride (0.14 g) were added to a 1,2-dichloroethane solution (5 ml) of 2-piperazin-1-yl-benzothiazol-6-ol (0.1 g) and 4-trifluoromethoxybenzaldehyde (0.067 ml) and stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and then concentrated under reduced pressure to afford the title compound as a colorless amorphous compound (80 mg).

Reference Example 330
Preparation of 4-(6-hydroxyquinolin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

2-Chloro-6-(tetrahydropyran-2-yloxy)quinoline (1.00 g) and piperazine-1-carboxylic acid tert-butyl ester (0.76 g) were heated to 140° C. in the absence of solvent under an argon atmosphere and stirred for 2 hours. After cooling the reaction mixture to room temperature, a sodium hydrogen carbonate aqueous solution was added thereto, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The result was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25→67:33). The result was concentrated to dryness under reduced pressure to afford the title compound as a pale yellow amorphous compound (0.55 g).

Reference Example 331
Preparation of 2-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]quinolin-6-ol

The title compound was prepared in the same manner as in Reference Example 330 using suitable starting materials.

Reference Example 332
Preparation of 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

1,2,3,4-Tetrahydro-isoquinolin-6-ol hydrobromide (8.3 g) and sodium hydroxide (4.35 g) were dissolved in a mixed solvent of 1,4-dioxane (50 ml) and water (50 ml). Under ice cooling, di-tert-butyl dicarbonate (Boc₂O) (8.7 g) was added thereto dropwise and stirred at 0 to 10° C. for 2 hours. The result was made hydrochloric acidic, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure to afford the title compound as a brown oil (4.1 g).

Reference Example 333
Preparation of 5-hydroxy-1,3-dihydroisoindole-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 332 using suitable starting materials.

Reference Example 334
Preparation of 2-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]benzothiazol-5-ol

The title compound was prepared in the same manner as in Reference Example 330 using suitable starting materials.

Reference Example 335
Preparation of 1-[3-(4-trifluoromethoxyphenoxy)propyl]-1,2,3,4-tetrahydroquinolin-6-ol

6-Benzyloxy-1-[3-(4-trifluoromethoxy-phenoxy)propyl]-1,2,3,4-tetrahydro-quinoline (2.13 g) was dissolved in ethanol (10 ml). 10% palladium on carbon (0.2 g) was added thereto and stirred at room temperature under a hydrogen atmosphere for 4 hours. The mixture was filtered through Celite to remove the catalyst, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and concentrated under reduced pressure to afford the title compound (1.45 g).

Reference Example 336
Preparation of 1-[3-(4-trifluoromethoxyphenoxy)propyl]-1H-indol-5-ol

The title compound was prepared in the same manner as in Reference Example 335 using suitable starting materials.

Reference Example 337
Preparation of 1-[3-(4-trifluoromethoxyphenoxy)propyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ol

The title compound was prepared in the same manner as in Reference Example 335 using suitable starting materials.

Reference Example 338
Preparation of 1-[3-(4-trifluoromethoxyphenoxy)propyl]-1,2,3,4-tetrahydroquinolin-5-ol

A 1 N hydrochloric acid aqueous solution (10 ml) was added to an ethanol solution (15 ml) of 5-(tetrahydropyran-2-yloxy)-1-[3-(4-trifluoromethoxyphenoxy)propyl]-1,2,3,4-tetrahydroquinoline (1.71 g) and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added thereto, and the mixture was concentrated under reduced pressure. The residue was subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to afford the title compound as a colorless oil (0.62 g).

Reference Example 339
Preparation of 1-[4-(4-trifluoromethoxyphenoxy)benzyl]-1,2,3,4-tetrahydroquinolin-6-ol

The title compound was prepared in the same manner as in Reference Example 335 using suitable starting materials.

Reference Example 340
Preparation of 1-[4-(4-trifluoromethoxyphenoxy)benzyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ol

The title compound was prepared in the same manner as in Reference Example 335 using suitable starting materials.

Reference Example 341
Preparation of 4-(6-hydroxybenzothiazol-2-yl) piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 332 using suitable starting materials.

Reference Example 342
Preparation of 6-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}naphthalen-2-ol

The title compound was prepared in the same manner as in Reference Example 338 using suitable starting materials.

Reference Example 343
Preparation of 2-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]benzooxazol-5-ol hydrochloride

The title compound was prepared in the same manner as in Reference Example 330 using suitable starting materials.

Reference Example 344
Preparation of 4-(5-hydroxybenzoxazol-2-yl)piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 332 using suitable starting materials.

Reference Example 345
Preparation of 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 332 using suitable starting materials.

Reference Example 346
Preparation of 2-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperidin-1-yl}-benzothiazol-6-ol

Potassium carbonate (1.02 g) and 4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperidine were added to an N,N-dimethylformamide solution (10 ml) of 2-chlorobenzothiazol-6-ol (1.37 g) and the mixture was stirred at 80° C. for 2 days. After being cooled to room temperature, the mixture was concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to afford the title compound as a white powder (2.1 g).

Reference Example 347
Preparation of 7-hydroxy-1,3,4,5-tetrahydrobenzo[c]azepin-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 332 using suitable starting materials.

Reference Example 348
Preparation of 2-chloro-6-(tetrahydropyran-2-yloxy)-quinoline

2-Chloroquinolin-6-ol (36 g, 0.20 mol) was dissolved in dichloromethane (500 ml) and tetrahydrofuran (500 ml). 3,4-dihydro-2H-pyran (74 ml, 0.81 mol) and p-toluenesulfonic acid (0.49 g, 0.005 mol) were added to the mixture in ice cooling water bath, followed by stirring at room temperature overnight. A 10% sodium hydroxide aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The result was dried over potassium carbonate and subjected to filtration, and then the filtrate was concentrated under reduced pressure. The crude crystal thus obtained was recrystallized from ethanol to afford the title compound as a colorless granular compound (47 g, yield 89%).

Melting point: 122-124° C.

Reference Example 349
Preparation of (4-trifluoromethoxyphenoxy)acetic acid methyl ester

Bromoacetic acid methyl ester (8 ml, 84.2 mmol) was added to a mixture of 4-(trifluoromethoxy)phenol (10 g, 56.1 mmol) and potassium carbonate (11.6 g, 84.2 mmol) in N,N-Dimethylformamide (50 ml) and stirred at room temperature overnight. The reaction mixture was poured into water and neutralized with a 1 N hydrochloric acid aqueous solution, followed by extraction with diethylether. The result was concentrated and used for the subsequent reaction.

1H NMR (CDCl₃) δ 3.80 (s, 3H), 4.63 (s, 2H), 6.89-6.92 (m, 2H), 7.15-7.16 (m, 2H).

Reference Example 350
Preparation of 2-(4-trifluoromethoxyphenoxy)acetamide

A 25% ammonia aqueous solution (20 ml) was added to (4-trifluoromethoxyphenoxy)acetic acid methyl ester in methanol (40 ml) and the mixture was stirred at room temperature overnight. After distilling the solvent off, the residue was washed with water and dried to afford the title compound as a white solid (12.1 g, yield 91%).

1H NMR (CDCl₃) δ 4.50 (s, 2H), 5.66 (br, 1H), 6.50 (br, 1H), 6.92-6.94 (m, 2H), 7.18-7.20 (m, 2H).

Reference Example 351
Preparation of 1-(3-chloropropoxy)-4-trifluoromethoxybenzene

1-Bromo-3-chloropropane (2.37 ml, 24 mmol), 4-(trifluoromethoxy)phenol (3.56 g, 20 mmol) and potassium carbonate (4.15 g, 30 mmol) were stirred in NMP (30 ml) overnight. After removing potassium carbonate by filtration, water was added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off, and the residue was fractionated and purified by silica gel column chromatography (hexane:ethyl acetate=89:11) to afford the title compound as a colorless oil (5.09 g, yield 99%).

1H NMR (CDCl₃) δ 2.23-2.25 (m, 2H), 3.75 (t, J=6.3 Hz, 2H), 4.11 (t, J=5.8 Hz, 2H), 6.89 (d, J=9.1 Hz, 2H), 7.14 (d, J=8.9 Hz, 2H).

Reference Example 352
Preparation of 4′-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]biphenyl-4-ol

The title compound was prepared in the same manner as in Reference Example 199 using suitable starting materials.

1H NMR (CDCl₃) δ 1.85-2.04 (m, 2H), 2.04-2.22 (m, 2H), 3.07-3.23 (m, 2H), 3.45-3.63 (m, 2H), 4.38-4.53 (m, 1H), 4.74 (s, 1H), 6.81-6.96 (m, 4H), 7.01 (d, J=8.8 Hz, 2H), 7.08-7.20 (m, 2H), 7.38-7.51 (m, 4H).

Reference Example 353
Preparation of 4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester

Sodium hydride (60% in oil, 2.12 g) wad added to an N,N-dimethylformamide solution (100 ml) of 4-trifluoromethoxyphenol (9.0 g) under ice cooling and stirred for 30 minutes. After adding 4-[2-(toluene-4-sulfonyloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (17.7 g), the mixture was heated to room temperature and stirred. The mixture was further stirred at 50° C. for 1 hour. After cooling the reaction mixture to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The result was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=67:33) to afford the title compound as a pale yellow oil (18.64 g).

Reference Example 354
Preparation of 4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidine

Trifluoroacetic acid (40 ml) was added to a dichloromethane solution (40 ml) of 4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (18.6 g), and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure, and ice water was added to the resulting residue. The result was treated with 6 N sodium hydroxide aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was concentrated to dryness under reduced pressure to afford the title compound as a white powder (14 g).

Reference Example 355
Preparation of 6-(4-trifluoromethoxyphenoxy)nicotinic acid ethyl ester

Ethyl 6-chloro nicotinate (5.00 g, 26.9 mmol), 4-(trifluoromethoxy)phenol (5.28 g, 29.6 mmol), potassium carbonate (4.84 g, 35.0 mmol) and N,N-dimethylformamide (50 ml) were mixed and stirred at 100 to 110° C. overnight. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→70:30) to afford the title compound as a colorless oil (7.48 g, 85%).

Mass:[M]⁺=327.

Reference Example 356
Preparation of [6-(4-trifluoromethoxyphenoxy)pyridin-3-yl]methanol

6-(4-Trifluoromethoxyphenoxy)nicotinic acid ethyl ester (7.48 g, 22.9 mmol) was dissolved in tetrahydrofuran (75 ml) and cooled to −78° C. A toluene solution (100.6 ml, 100.6 mmol) of diisobutylaluminium hydride was added thereto and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into a 1 N sodium hydroxide aqueous solution, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The organic layer was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=100:0→0:100) to afford the title compound as a colorless oil (6.15 g, 94%).

Mass:[M]⁺=285.

Reference Example 357
Preparation of 6-(4-trifluoromethoxyphenoxy)pyridine-3-carbaldehyde

{6-[(4-Trifluoromethoxy)phenoxy]pyridine-3-yl}methanol (3.00 g, 10.5 mmol), dimethylsulfoxide (90 ml) and 2-iodoxybenzoic acid (3.53 g, 12.6 mmol) were mixed and stirred at room temperature overnight. After adding water and ethyl acetate to the reaction mixture, insoluble matter was removed and the filtrate was separated into layers. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→70:30) to afford the title compound as a colorless oil (2.96 g, 99%).

Mass:[M]⁺=283

Reference Example 358
Preparation of 5′-(tetrahydropyran-2-yloxy)-4-[2-(4-trifluoromethoxyphenoxy)ethyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

Toluene (15 ml) was added to a mixture of 2-bromo-5-(tetrahydropyran-2-yloxy)pyridine (2.58 g, 10 mmol), 4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidine (3.18 g, 11 mmol) and sodium tert-butoxide (1.35 g, 14 mmol), and then the atmosphere was replaced with nitrogen. Bis(dibenzylideneacetone)palladium (Pd₂(dba)₃complex) (0.23 g, 0.25 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthine (xantphos) (0.36 g, 0.63 mmol) were added to the mixture, and the reaction mixture was heated at 100° C. for 3 hours under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The result was purified by silica gel column chromatography (ethyl acetate:hexane=10:90→25:75) to afford the title compound as a pale brown powder (4.45 g, 95%).

1H NMR (CDCl₃) δ 1.34-1.38 (m, 2H), 1.52-1.85 (m, 10H), 1.97-1.99 (m, 1H), 2.75-2.80 (m, 2H), 3.57-3.60 (m, 1H), 3.91-3.95 (m, 1H), 3.99-4.03 (m, 2H), 4.13-4.16 (m, 2H), 5.21 (s, 1H), 6.62-6.64 (m, 1H), 6.86-6.89 (m, 2H), 7.13-7.14 (m, 2H), 7.28 (m, 1H), 8.04-8.05 (m, 1H).

Reference Example 359
Preparation of 4-[(E)-3-(4-trifluoromethylphenyl)allyl]piperidine-1-carboxylic acid tert-butyl ester

Potassium tert-butoxide (5.78 g, 50.0 mmol) was added to a solution of 4-(trifluoromethyl)benzylphosphonic acid diethyl ester (14.8 g, 50.0 mmol) in tetrahydrofuran solution (40 ml) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Subsequently, a tetrahydrofuran solution (10 ml) of 4-(2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (11.4 g, 50.0 mmol) was added thereto dropwise at 0° C., warmed to room temperature, and then stirred overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=86:14) to afford the title compound as a colorless oil (8.6 g, yield 47%).

1H NMR (CDCl₃) δ 1.10-1.22 (m, 2H), 1.44 (s, 9H), 1.66-1.81 (m, 2H), 2.17-2.25 (m, 2H), 2.60-2.78 (m, 2H), 4.00-4.22 (m, 3H), 6.25-6.33 (m, 1H), 6.37-6.44 (m, 1H), 7.40-7.46 (m, 2H), 7.52-7.56 (m, 2H)

Reference Example 360
Preparation of 4-[3-(4-trifluoromethylphenyl)propyl]piperidine-1-carboxylic acid tert-butyl ester

4-[(E)-3-(4-Trifluoromethylphenyl)allyl]piperidine-1-carboxylic acid tert-butyl ester (13.4 g, 36.2 mmol) and 10% palladium on carbon (1.4 g, 1.3 mmol) were suspended in ethanol (120 ml), followed by stirring under a hydrogen atmosphere (atmospheric pressure) at room temperature for 5 hours. Thereafter the insoluble matter was removed by filtration, and the resulting solution was concentrated to afford the title compound as a colorless oil (crude).

1H NMR (CDCl₃) δ 1.05-1.08 (m, 2H), 1.25-1.30 (m, 2H), 1.37-1.41 (m, 1H), 1.45 (s, 9H), 1.59-1.68 (m, 4H), 2.64-2.67 (m, 4H), 4.11-4.13 (m, 2H), 7.26-7.28 (d, J=9.2 Hz, 2H), 7.52-7.54 (d, J=8.1, 2H).

Reference Example 361
Preparation of 4-[3-(4-trifluoromethylphenyl)propyl]piperidine

4-[3-(4-Trifluoromethylphenyl)propyl]piperidine-1-carboxylic acid tert-butyl ester (13.45 g, 36.2 mmol) prepared in Reference Example 360 was dissolved in dichloromethane (50 ml). Trifluoroacetic acid (25 ml, 324 mmol) was added thereto and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and adjusted to a pH of 10 using a 5 N sodium hydroxide aqueous solution. The mixture was subjected to extraction with dichloromethane 4 times. The result was dried over anhydrous sodium sulfate and then concentrated to afford the title compound as a pale brown oil (10.2 g, quant).

1H NMR (CDCl₃) δ 1.09-1.51 (m, 2H), 1.25-1.29 (m, 2H), 1.37 (m, 1H), 1.61-1.69 (m, 4H), 2.11 (br, 1H), 2.56-2.66 (m, 4H), 3.06-3.08 (m, 2H), 7.27-7.28 (d, J=7.8 Hz, 2H), 7.52-7.53 (d, J=8.1, 2H).

Reference Example 362
Preparation of 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-[3-(4-trifluoromethylphenyl)propyl]piperidine

2-(4-Iodophenoxy)tetrahydropyran (1.12 g, 3.7 mmol) and 4-[3-(4-trifluoromethylphenyl)propyl]piperidine (1 g, 3.7 mmol) were dissolved in degassed anhydrous toluene (10 ml). Sodium tert-butoxide (0.50 g, 5.2 mmol), tri-tert-butylphosphine tetrafluoroborate (tBu₃P.HBF₄) (0.09 g, 0.3 mmol) and palladium acetate (0.03 g, 0.15 mmol) were added thereto, and the mixture was heated at reflux under a nitrogen atmosphere for 5 hours. After being allowed to cool to room temperature, water (10 ml) was added to the mixture, followed by extraction with ethyl acetate. The organic layers were combined and washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After removing insoluble matter by filtration, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20) to afford the title compound as a pale yellow solid (1.42 g, 86%).

1H NMR (CDCl₃) δ 1.32-1.35 (m, 4H), 1.59-1.85 (m, 10H), 1.93-2.05 (m, 1H), 2.58 (t, J=11.7 Hz, 2H), 2.65-2.68 (t, J=7.7 Hz, 2H), 3.50-3.52 (d, J=11.4 Hz, 2H), 3.57-3.59 (m, 1H), 3.92-3.96 (t, J=9.3 Hz, 1H), 5.29-5.30 (m, 1H), 6.87-6.89 (d, J=9.1 Hz, 2H), 6.96-6.97 (d, J=9.1, 2H) 7.28-7.30 (d, J=7.9 Hz, 2H), 7.52-7.54 (d, J=8.05, 2H).

Reference Example 363
Preparation of 4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperidine-1-carboxylic acid tert-butyl ester

tert-Butyl 4-(4-hydroxybenzyl)piperidine-1-carboxylate (1.78 g, 6.1 mmol), potassium carbonate (1.27 g, 9.2 mmol), N,N-dimethylformamide (18 ml) and 4-(trifluoromethyl)benzylbromide (1.75 g, 7.3 mmol) were mixed and stirred at room temperature overnight. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0, 60:40) to afford the title compound as a colorless powder (2.64 g, 96%).

Mass:[M]⁺=449.

Reference Example 364
Preparation of 4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperidine

4-{4-[4-(Trifluoromethyl)benzyloxy]benzyl}piperidine-1-carboxylic acid tert-butyl ester (2.64 g, 5.9 mmol), dichloromethane (5 ml) and trifluoroacetic acid (5 ml) were mixed and stirred at room temperature for 2 hours. After concentrating the reaction mixture, dichloromethane was added to the residue, and 5 N sodium hydroxide was further added, followed by vigorous stirring. The organic layer was separated, washed with water, dried over sodium sulfate, and then concentrated to afford the title compound as a colorless powder (2.06 g, 100%).

Mass:[M]⁺=349.

Reference Example 365
Preparation of 4-(4-benzyloxybenzylidene)piperidine

4-(4-Benzyloxybenzylidene)piperidine-1-carboxylic acid tert-butyl ester (3.80 g, 10 mmol), ethanol (40 ml) and 1 N hydrochloric acid (25 ml) were mixed and stirred at 80° C. for 1 hour. Ethanol was distilled off under reduced pressure and neutralized with sodium hydroxide. The organic layer was dried over sodium sulfate and concentrated to afford the title compound as a pale yellow powder (2.32 g, 83%).

1H NMR (CDCl₃) δ 2.30 (t, J=5.2 Hz, 2H), 2.44 (t, J=5.2 Hz, 2H), 2.84 (t, J=5.5 Hz, 2H), 2.94 (t, J=5.5 Hz, 2H), 5.05 (s, 2H), 6.22 (s, 1H), 6.92-6.94 (m, 2H), 7.13 (d, J=8.6 Hz, 2H), 7.32-7.44 (m, 5H).

Reference Example 366
Preparation of 4-(4-benzyloxybenzylidene)-1-[4-(tetrahydropyran-2-yloxy)phenyl]piperidine

4-[4-(Benzyloxy)benzylidene]piperidine (2.32 g, 8.3 mmol), 1-bromo-4-(tetrahydro-2H-pyran-2-yloxy)benzene (2.35 g, 9.1 mmol), toluene (20 ml), sodium tert-butoxide (1.12 g, 11.6 mmol), palladium acetate (0.075 g, 0.3 mmol) and tri-tert-butylphosphine tetrafluoroborate (0.19 g, 0.7 mmol) were mixed and stirred at 100° C. overnight. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→50:50) to afford the title compound as a colorless powder.

TLC:Rf=0.6 (hexane:ethyl acetate=1:1)

Reference Example 367
Preparation of 6-benzyloxy-1-[3-(4-trifluoromethoxyphenoxy)propyl]-1,2,3,4-tetrahydro-quinoline

6-Benzyloxy-1,2,3,4-tetrahydro-quinoline (1.20 g, 5 mmol), 1-(3-chloropropoxy)-4-trifluoromethoxybenzene (1.42 g, 5.58 mmol), potassium carbonate (1.04 g, 7.5 mmol) and sodium iodide (0.90 g, 6 mmol) were heated and stirred at 90° C. in NMP (10 ml) overnight. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The result was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=75:25) to afford the title compound as a yellow oil (2.13 g, 93%).

1H NMR (CDCl₃) δ 1.91-1.94 (m, 2H), 2.03-2.06 (m, 2H), 2.73 (t, J=6.4 Hz, 2H), 3.21 (t, J=5.6 Hz, 2H), 3.41 (t, J=7.0 Hz, 2H), 4.01 (t, J=5.9 Hz, 2H), 4.96 (s, 2H), 6.53-6.55 (m, 1H), 6.66-6.70 (m, 2H), 6.88-6.90 (m, 2H), 7.13-7.14 (m, 2H), 7.30-7.32 (m, 1H), 7.35-7.38 (m, 2H), 7.41-7.42 (m, 2H).

Reference Example 368
Preparation of 4-{1-[4-(tetrahydropyran-2-yloxy)phenyl]piperidin-4-ylmethyl}phenol

Ethanol (20 ml) and ethyl acetate (10 ml) were added to 4-[4-(benzyloxy)benzylidene]-1-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]piperidine prepared in Reference Example 366. A palladium on carbon (0.378 g) was added to the mixture, and stirred at 50° C. for 4 hours under a hydrogen atmosphere. The insoluble matter was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1→4:1) to afford the title compound as a colorless amorphous compound (1.10 g).

Reference Example 369
Preparation of 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperidine

4-({1-[4-(Tetrahydro-2H-pyran-2-yloxy)phenyl]piperidin-4-yl}methyl)phenol (1.10 g, 3.0 mmol), cesium carbonate (0.977 g, 3.0 mmol), N-methylpyrrolidinone (5 ml), 1-bromo-4-(trifluoromethoxy)benzene (0.723 g, 2.99 mmol) and dipivaloylmethane (0.3 g, 1.5 mmol) were mixed, and the atmosphere was replaced with nitrogen. Copper chloride (0.030 g, 0.3 mmol) was added thereto and stirred at 120° C. for 24 hours. An ammonium chloride aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25) to afford the title compound as a colorless powder (0.84 g, 53%).

TLC:Rf=0.2 (hexane:ethyl acetate=4:1)

Reference Example 370
Preparation of 6-(tetrahydropyran-2-yloxy)-2-(4-trifluoromethoxybenzyloxy)-quinoline

To a solution of (4-(trifluoromethoxy)phenyl)methanol (1.65 ml, 11.4 mmol) in DMF (40 ml) was added 60% sodium hydride (0.46 g, 11.4 mmol) at 0° C. and further stirred for 20 minutes. While stirring the resulting mixture under ice cooling, 2-chloro-6-(tetrahydropyran-2-yloxy)-quinoline (3.0 g, 11.4 mmol) was added thereto and warmed to room temperature, followed by further stirring for 5 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=80:20). The resulting crude crystal was washed with hexane-diethylether to afford the title compound as a white powder (3.84 g, yield 81%).

1H NMR (CDCl₃) δ 1.65-1.94 (m, 6H), 3.45-3.58 (m, 1H), 3.86-3.94 (m, 1H), 5.51 (s, 2H), 5.51-5.53 (m, 1H), 6.92 (d, J=9.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 2H), 7.34 (d, J=3.0 Hz, 1H), 7.39 (dd, J=9.0, 3.0 Hz, 1H), 7.55 (d, J=8.5 Hz, 2H), 7.77 (d, J=9.0 Hz, 1H), 7.92 (d, J=9.0 Hz, 1H)

Reference Example 371
Preparation of 2-(4-trifluoromethoxybenzyloxy)-quinolin-6-ol

A 1 N hydrochloric acid ethanol solution (40 ml) was added to an ethanol (10 ml) solution of 6-(Tetrahydro-2H-pyran-2-yloxy)-2-[4-(trifluoromethoxy)benzyloxy]quinoline (3.5 g, 8.3 mmol) and then stirred at room temperature for 2 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure, and the resulting crude crystal was washed with hexane-diethylether to afford the title compound as a white powder (2.52 g, yield 90%).

1H NMR (CDCl₃) δ 5.17 (brs, 1H), 5.51 (s, 2H), 6.93 (d, J=8.8 Hz, 1H), 7.08 (d, J=2.8 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 7.23 (dd, J=9.1, 2.8 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.57 (d, J=9.1 Hz, 1H), 7.87 (d, J=8.9 Hz, 1H).

Reference Example 372
Preparation of 4-benzyloxy-1-bromo-2-fluorobenzene

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Reference Example 373
Preparation of 1-(4-benzyloxy-2-fluoro-phenyl)-4-(4-trifluoromethoxyphenoxy)piperidine

4-Benzyloxy-1-bromo-2-fluorobenzene (3.55 g, 12.6 mmol), 4-(4-trifluoromethoxyphenoxy)piperidine (3.0 g, 11.5 mmol), sodium tert-butoxide (1.55 g, 16.1 mmol) and toluene (60 ml) were mixed. Palladium acetate (0.10 g, 0.46 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.57 g, 0.92 mmol) were added thereto. The mixture was heated and refluxed under a nitrogen atmosphere for 4 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→60:40), and the resulting crude crystal was washed with hexane-diethylether to afford the title compound as a white powder (3.76 g, yield 71%).

1H NMR (CDCl₃) δ 1.90-2.02 (m, 2H), 2.05-2.15 (m, 2H), 2.89-2.94 (m, 2H), 3.21-3.26 (m, 2H), 4.40-4.45 (m, 1H), 5.01 (s, 2H), 6.65-6.75 (m, 2H), 6.93 (d, J=8.5 Hz, 2H), 6.92-6.98 (m, 1H), 7.14 (d, J=8.5 Hz, 2H), 7.24-7.42 (m, 5H).

Reference Example 374
Preparation of 4-[4-(4-benzyloxy-2-hydroxy-2-methylbutoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester

2-[2-(Benzyloxy)ethyl]-2-methyloxirane (2.60 g, 13.5 mmol), 4-(4-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (4.14 g, 14.9 mmol), tripotassium phosphate (1.15 g, 5.4 mmol) and ethanol (26 ml) were mixed and stirred at 80 to 90° C. overnight. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→30:70) to afford the title compound as a pale yellow oil (6.16 g).

Mass:[M]⁺=470.

Reference Example 375
Preparation of 4-[4-(2,4-dihydroxy-2-methylbutoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester

4-[4-(4-Benzyloxy-2-hydroxy-2-methylbutoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (6.16 g, 13.1 mmol), palladium hydroxide on carbon (0.62 g) and ethanol (62 ml) were mixed and stirred at 50 to 60° C. under a hydrogen atmosphere for 9 hours. The mixture was filtered through Celite to remove the catalyst, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→0:100) to afford the title compound as a colorless powder (3.75 g).

Mass:[M]⁺=380.

Reference Example 376
Preparation of 4-{4-[2-hydroxy-2-methyl-4-(toluene-4-sulfonyloxy)butoxy]phenyl}piperazine-1-carboxylic acid tert-butyl ester

4-[4-(2,4-Dihydroxy-2-methylbutoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (3.75 g, 9.9 mmol), tosyl chloride (2.07 g, 10.8 mmol), dichloromethane (38 ml) and triethylamine (2.75 ml, 19.7 mmol) were mixed and ice-cooled. 1,1,3,3,-Tetramethylpropanediamine (0.16 ml, 1.0 mmol) was added thereto and stirred at room temperature overnight. The reaction mixture was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→40:60) to afford the title compound as a colorless oil (4.69 g, 89%).

Mass:[M]⁺=534.

Reference Example 377
Preparation of 4′-(tetrahydropyran-2-yloxy)biphenyl-4-carbaldehyde

2-(4-Bromophenoxy)tetrahydropyran (3.0 g) was dissolved in N,N-dimethylformamide (30 ml). 4-Formylphenylboronic acid (2.1 g), tetrakis(triphenylphosphine)palladium (0) (1.35 g) and tripotassium phosphate (4.95 g) were added thereto, and the resulting mixture was heated at 90 to 100° C. under a nitrogen atmosphere for 3 hours. After completion of the reaction, ethyl acetate was added to the reaction mixture and filtered through Celite. The filtrate was separated into layers. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→50:50) to afford the title compound as a white powder (1.49 g).

Reference Example 378
Preparation of (R)-4-(4-benzyloxyphenyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

(3R)-1-tert-Butoxycarbonyl-3-methylpiperazine (3.0 g, 15.0 mmol), 4-benzyloxybromobenzene (4.73 g, 18.0 mmol), sodium tert-butoxide (2.02 g, 21.0 mmol) and toluene (30 ml) were mixed, and the atmosphere was replaced with nitrogen. tri-tert-Butylphosphine tetrafluoroborate (0.52 g, 1.8 mmol) and palladium acetate (0.34 g, 1.5 mmol) were added thereto and heated at 90 to 100° C. for 4 hours. Water and ethyl acetate were added to the brown reaction mixture, and insoluble matter was removed by filtration. The filtrate was separated into layers. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→50:50) to afford the title compound as a colorless oil (5.29 g, 92%).

Mass:[M+1]⁺=383.

Reference Example 379
Preparation of (R)-4-(4-benzyloxyphenyl)-2-methylpiperazine-1-carboxylic acid benzyl ester

(R)-2-Methylpiperazine-1-carboxylic acid benzyl ester (4.42 g, 18.9 mmol), 1-benzyloxy-4-bromobenzene (5.95 g, 22.6 mmol), cesium carbonate (8.60 g, 26.4 mmol) and toluene (49 ml) were mixed, and the atmosphere was replaced with nitrogen. Palladium acetate (0.42 g, 1.9 mmol) and tri-tert-butylphosphine tetrafluoroborate (0.66 g, 2.3 mmol) were added thereto and stirred at 90 to 100° C. for 2 days. Water and ethyl acetate were added to the reaction mixture, the mixture was filtered through Celite to remove insoluble matter. The filtrate was separated into layers. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→70:30) to afford the title compound as a brown oil (6.18 g, 79%).

Mass:[M]⁺=416.

Reference Example 380
Preparation of (R)-4-(4-hydroxyphenyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

(R)-4-(4-Benzyloxyphenyl)-2-methylpiperazine-1-carboxylic acid benzyl ester (6.18 g, 14.8 mmol), acetic acid (62 ml) and 10% palladium on carbon (0.62 g) were mixed and stirred at room temperature under the hydrogen pressure of 1 atm for 8 hours. The mixture was filtered through Celite to remove the catalyst, and the filtrate was concentrated. Methanol (62 ml), triethylamine (10 ml) and di-tert-butyl dicarbonate (3.89 g, 17.8 mmol) were added to the residue and stirred at room temperature overnight. The reaction mixture was concentrated, and water was added to the residue, followed by extraction with ethyl acetate.

The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→60:40) to afford the title compound as a pale brown oil (4.65 g, 100%).

Mass:[M]⁺=292.

Reference Example 381
Preparation of 1′-[4-(tetrahydropyran-2-yloxy)phenyl]-[4,4′]bipiperidinyl-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 362 using suitable starting materials.

1H NMR (CDCl₃) δ 1.11-1.32 (m, 4H), 1.38-1.52 (m, 2H), 1.46 (s, 9H), 1.55-1.74 (m, 5H), 1.75-1.89 (m, 4H), 1.95-2.05 (m, 1H), 2.56 (dd, J=12.0, 2.0 Hz, 2H), 2.60-2.75 (m, 2H), 3.52-3.63 (m, 3H), 3.91-4.01 (m, 1H), 4.02-4.22 (m, 2H), 5.31 (d, J=2.0 Hz, 1H), 6.86-6.90 (m, 2H), 6.94-6.98 (m, 2H).

Reference Example 382
Preparation of 1′-(4-hydroxyphenyl)-[4,4′]bipiperidinyl-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Reference Example 187 using suitable starting materials.

1H NMR (CDCl₃) δ 1.08-1.30 (m, 4H), 1.46 (s, 9H), 1.54-1.69 (m, 4H), 1.77-1.85 (m, 2H), 2.59-2.72 (m, 2H), 2.72 (t, J=12.0, 2H), 3.53 (d, J=12.0, 2H), 4.00-4.25 (m, 2H), 6.79 (d, J=9.0 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H).

Reference Example 383
Preparation of 4-trifluoromethylcyclohexane carbaldehyde

After dissolving [cis-4-(trifluoromethyl)cyclohexyl]methanol (2.04 g, 10.2 mmol) in dimethylsulfoxide (30 ml), 2-iodoxybenzoic acid (4.00 g, 14.3 mmol) was added thereto and stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, the insoluble matter was removed by filtration, and then the filtrate was separated into layers. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated to afford the title compound as a colorless oil (2.3 g, 100%).

1H NMR (CDCl₃) δ 1.28-1.39 (m, 2H), 1.53-1.65 (m, 2H), 1.78-1.88 (m, 2H), 1.95-2.10 (m, 1H), 2.30 (dd, J=14.1 Hz, 2.8 Hz, 2H), 2.45-2.52 (m, 1H), 9.71 (s, 1H).

Reference Example 384
Preparation of 1-(4′-benzyloxybiphenyl-4-yl)-4,4′-diethoxy-piperidine

4-(Benzyloxy)-4′-bromobiphenyl (10.0 g, 29.5 mmol), 4,4-diethoxypiperidine (5.62 g, 32.4 mmol), sodium tert-butoxide (3.97 g, 41.3 mmol) and toluene (150 ml) were mixed. Palladium acetate (0.20 g, 0.88 mmol) and tri-tert-butylphosphine tetrafluoroborate (0.39 g, 1.33 mmol) were added thereto and heated and refluxed under a nitrogen atmosphere for 2 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the precipitated crystal was collected by filtration. The obtained crude crystal was washed with acetone-hexane to afford the title compound as a white powder (10.4 g, yield 82%).

Reference Example 385
Preparation of 1-(4′-benzyloxybiphenyl-4-yl)piperidin-4-one

1-(4′-Benzyloxybiphenyl-4-yl)-4,4-diethoxy-piperidine (10.0 g, 23.2 mmol), acetone (100 ml) and a 5 N hydrochloric acid aqueous solution (35 ml) were mixed and heated under reflux for 5 hours. 1 N sodium hydroxide was added to the residue obtained by removing the solvent by distillation, followed by extraction with dichloromethane. The organic layer was washed with water and then dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The resulting crude crystal was washed with diethylether to afford the title compound as a white powder (7.2 g, yield 87%).

1H NMR (CDCl₃) δ 2.57 (t, J=6.1 Hz, 4H), 3.64 (t, J=6.1 Hz, 4H), 5.10 (s, 2H), 7.00-7.06 (m, 4H), 7.33-7.39 (m, 1H), 7.40-7.45 (m, 2H), 7.46-7.52 (m, 6H).

Reference Example 386
Preparation of 4-benzyloxy-2-methyl-1-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxy)butan-2-ol

A tripotassium phosphate (0.44 g, 2.1 mmol) was added to a solution of 2-[2-(Benzyloxy)ethyl]-2-methyloxirane (1.00 g, 5.2 mmol) and 4-{4-[4-(trifluoromethoxy)phenethyl]piperidin-1-yl}phenol (2.28 g, 6.2 mmol) in ethanol (10 ml), and then the mixture was heated at reflux overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→50:50) to afford the title compound as a brown powder (2.43 g, 86%).

1H NMR (CDCl₃) δ 1.32 (s, 3H), 1.34-1.49 (m, 3H), 1.53-1.65 (m, 3H), 1.78-1.89 (m, 2H), 1.89-2.08 (m, 2H), 2.53-2.63 (m, 2H), 2.63-2.70 (m, 2H), 3.42-3.55 (m, 2H), 3.66-3.83 (m, 4H), 4.51 (s, 2H), 6.81 (d, J=9.1 Hz, 2H), 6.90 (d, J=9.1 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.6 Hz, 2H), 7.27-7.41 (m, 5H).

Reference Example 387
Preparation of 3-methyl-4-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxy)butane-1,3-diol

4-Benzyloxy-2-methyl-1-(4-{4-[4-(trifluoromethoxy)phenethyl]piperidin-1-yl}phenoxy)butan-2-ol (2.43 g, 4.5 mmol), ethanol (24 ml) and 20% palladium hydroxide on carbon (0.24 g) were mixed and stirred at 50 to 60° C. under the hydrogen pressure of 1 atm for 4 hours. The mixture was filtered through Celite to remove the catalyst, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→0:100) to afford the title compound as a colorless powder (1.68 g, 80%).

Mass:[M]⁺=467.

Reference Example 388
Preparation of toluene-4-sulfonic acid 3-hydroxy-3-methyl-4-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxy)butyl ester

3-Methyl-4-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxy)butane-1,3-diol (1.68 g, 3.6 mmol), dichloromethane (17 ml), triethylamine (1.00 ml, 7.2 mmol) and p-toluenesulfonyl chloride (0.82 g, 4.3 mmol) were mixed and ice-cooled. 1,1,3,3,-Tetramethylpropanediamine (0.12 ml, 0.7 mmol) was added thereto and stirred at room temperature for 1 hour. The reaction mixture was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0, 50:50) to afford the title compound as a colorless powder (2.03 g, 91%).

Mass:[M]⁺=621.

Reference Example 389
Preparation of 4-[3-(3-trifluoromethylphenoxy)propyl]piperidine-1-carboxylic acid tert-butyl ester

4-(3-Hydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester (15.0 g, 61.6 mmol), 3-trifluoromethylphenol (19.4 g, 64.7 mmol), triphenylphosphine (1.40 g, 73.9 mmol) and tetrahydrofuran (200 ml) were mixed. While stirring the mixture at room temperature, DEAD (21.1 ml, 80.0 mmol) was added thereto dropwise and heated at reflux for 2 days. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=87:13) to afford the title compound as a pale yellow oil (20.5 g, yield 86%).

1H NMR (CDCl₃) δ 1.05-1.21 (m, 2H), 1.40-1.57 (m, 3H), 1.46 (s, 9H), 1.65-1.76 (m, 2H), 1.81-1.89 (m, 2H), 2.65-2.80 (m, 2H), 3.98 (t, J=6.4, 2H), 3.94-4.24 (m, 2H), 7.04 (dd, J=8.3, 2.4

Hz, 1H), 7.11 (d, J=2.4, 1H), 7.19 (d, J=7.7, 1H), 7.38 (ddd, J=8.3, 7.7, 2.4, 1H).

Reference Example 390
Preparation of 1-(4′-benzyloxybiphenyl-4-yl)-4-trifluoromethylpiperidin-4-ol

1-(4′-Benzyloxybiphenyl-4-yl)piperidin-4-one (7.1 g, 19.9 mmol), tetrabutylammonium acetate (0.3 g, 1.0 mmol) and 1,2-dimethoxethane (100 ml) were mixed. While stirring the mixture under ice cooling, trifluoromethyltrimethylsilane (4.11 ml, 27.8 mmol) was added to the mixture and warmed to room temperature, followed by stirring for 6 hours. The residue obtained by distilling off the solvent was dissolved in tetrahydrofuran (100 ml). While stirring at room temperature, 1 mol/l tetrabutylammonium fluoride in tetrahydrofuran (23.8 ml, 23.8 mmol) was added thereto and stirred at room temperature overnight. Water was added to the residue obtained by distilling off the solvent, followed by extraction with dichloromethane. The organic layer was washed with water and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The resulting crude crystal was washed with diethylether to afford the title compound as a white powder (7.6 g, yield 90%).

1H NMR (CDCl₃) δ 1.83 (dd, J=14.0, 2.4 Hz, 2H), 2.08 (dt, J=13.5, 4.5 Hz, 2H), 3.11 (dd, J=12.6, 2.4 Hz, 2H), 3.60-3.66 (m, 2H), 5.10 (s, 2H), 6.99-7.05 (m, 4H), 7.34-7.39 (m, 1H), 7.40-7.46 (m, 2H), 7.47-7.54 (m, 6H).

Reference Example 391
Preparation of 4-[3-(3-trifluoromethylphenoxy)propyl]piperidine

The title compound was prepared in the same manner as in Reference Example 354 using suitable starting materials.

1H NMR (CDCl₃) δ 1.42-1.63 (m, 5H), 1.80-1.90 (m, 4H), 2.75-2.83 (m, 2H), 3.24-3.33 (m, 2H), 3.98 (t, J=6.3, 2H), 7.04 (dd, J=8.2, 2.3 Hz, 1H), 7.10 (d, J=2.3, 1H), 7.19 (d, J=7.7, 1H), 7.39 (ddd, J=8.2, 7.7, 2.3, 1H).

Reference Example 392
Preparation of 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-[3-(3-trifluoromethylphenoxy)propyl]piperidine

The title compound was prepared in the same manner as in Reference Example 362 using suitable starting materials.

1H NMR (CDCl₃) δ 1.37-1.55 (m, 5H), 1.60-1.75 (m, 3H), 1.83-1.90 (m, 6H), 1.95-2.08 (m, 1H), 2.63 (t, J=10.0, 2H), 3.55-3.65 (m, 3H), 3.91-3.98 (m, 1H), 4.00 (t, J=6.5, 2H), 5.31 (t, J=2.0, 1H), 6.87-6.92 (m, 2H), 6.96-6.99 (m, 2H), 7.06 (dd, J=8.3, 2.4 Hz, 1H), 7.13 (d, J=2.4, 1H), 7.20 (d, J=7.7, 1H), 7.38 (ddd, J=8.3, 7.7, 2.4, 1H).

Reference Example 393
Preparation of 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-(4-trifluoromethylsulfanylphenoxy)piperidine

The title compound was prepared in the same manner as in Reference Example 379 using suitable starting materials.

Mass:[M]⁺=453.

Reference Example 394
Preparation of cis-(4-trifluoromethylcyclohexyl)methanol

cis-4-(Trifluoromethyl)cyclohexanecarboxylic acid (1.05 g, 5.4 mmol) and tetrahydrofuran (20 ml) were mixed and ice-cooled. A borane-tetrahydrofuran complex (10.71 ml, 10.7 mmol) was added to the mixture dropwise. After the completion of dropwise addition, the reaction mixture was stirred at room temperature overnight. 1 N hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated to afford the title compound as a colorless oil (0.92 g, 94%).

1H NMR (CDCl₃) δ 1.32 (t, J=4.7 Hz, 1H), 1.48-1.62 (m, 4H), 1.64-1.74 (m, 4H), 1.76-1.82 (m, 1H), 2.05-2.17 (m, 1H), 3.62 (dd, J=4.5 Hz, 7.1 Hz, 2H).

Reference Example 395
Preparation of 1-(4-benzyloxyphenyl)-4-(4-trifluoromethylphenyl)piperidin-4-ol

Isopropylmagnesium chloride (2M tetrahydrofuran solution) (11.73 ml) was added to a tetrahydrofuran solution (20 ml) of 4-iodobenzotrifluoride (3.45 ml, 23.5 mmol) dropwise at −10° C. under an argon atmosphere. The mixture was stirred at the same temperature for 5 minutes and further stirred at room temperature for 2 hours. After cooling the mixture to −10° C., a tetrahydrofuran solution (40 ml) of 1-(4-benzyloxyphenyl)piperidin-4-one (6 g, 21.3 mmol) was added thereto dropwise. While gradually returning to room temperature, the mixture was stirred. After 10 hours, a saturated ammonium chloride aqueous solution/ice water was poured into the mixture, followed by extraction with ethyl acetate. The result was washed with water and a saturated sodium chloride aqueous solution and dried over sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25→66:34). The resultant was washed with a mixed solvent of isopropyl ether and hexane and filtered to afford the title compound as a white powder (6.69 g, 73%).

1H NMR (CDCl₃) δ=1.65 (s, 1H), 1.82-1.88 (m, 2H), 2.31 (dt, J=4.6 Hz, 13.3 Hz, 2H), 3.14 (dt, J=2.5 Hz, 12.3 Hz, 2H), 3.40-3.47 (m, 2H), 5.03 (s, 2H), 6.92-6.96 (m, 2H), 6.96-7.01 (m, 2H), 7.30-7.35 (m, 1H), 7.36-7.41 (m, 2H), 7.42-7.45 (m, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.67 (d, J=8.6 Hz, 2H).

Reference Example 396
Preparation of 1-(4-benzyloxyphenyl)-4-methoxy-4-(4-trifluoromethylphenyl)piperidine

60% sodium hydride (0.225 g, 5.2 mmol) was added to an N,N-dimethylformamide solution (20 ml) of 1-(4-benzyloxyphenyl)-4-(4-trifluoromethylphenyl)piperidin-4-ol (2 g, 4.7 mmol) and iodomethane (0.585 ml, 9.4 mmol) under an argon atmosphere while ice cooling, followed by stirring at the same temperature. After 2 hours, the mixture was poured into ice water, and the precipitate was collected by filtration. The resulting solid was dissolved in ethyl acetate/dichloromethane and dried over sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=100:0→95:5) to afford the title compound as a white powder (1.64 g, 79%).

1H NMR (CDCl₃) δ=2.10-2.18 (m, 4H), 3.02 (s, 3H), 3.05-3.15 (m, 2H), 3.35-3.43 (m, 2H), 5.03 (s, 2H), 6.91-6.94 (m, 2H), 6.94-6.98 (m, 2H), 7.29-7.34 (m, 1H), 7.36-7.41 (m, 2H), 7.42-7.45 (m, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H).

Reference Example 397
Preparation of 2-methyl-2-[4-(4-trifluoromethylbenzyloxy)phenyl]propionic acid

Iodomethane (4.63 ml, 74.0 mmol) was added to an N,N-dimethylformamide solution (80 ml) of [4-(4-trifluoromethylbenzyloxy)phenyl]acetic acid methyl ester (8 g, 24.7 mmol) under an argon atmosphere. Subsequently, sodium hydride (2.37 g, 54.3 mmol) was gradually added thereto under ice cooling. After stirring at the same temperature for 30 minutes, the mixture was further stirred at room temperature. After 2 hours, iodomethane (3.09 ml, 49.3 mmol) was added thereto, and sodium hydride (1.08 g, 24.7 mmol) was further added 1 hour later. Thereafter, the mixture was stirred at room temperature overnight. Because a monomethylated compound still remained, the mixture was ice-cooled again. Sodium hydride (1.08 g, 24.7 mmol) was added thereto and stirred for 5 minutes. Iodomethane (3.09 ml, 49.3 mmol) was added to the mixture and stirred at room temperature. The reaction mixture was poured into a mixture of ice water (500 ml) and acetic acid (6 ml), followed by stirring. Ethyl acetate was added thereto, and the mixture was neutralized with a saturated sodium hydrogen carbonate aqueous solution, followed by extraction with ethyl acetate. The result was washed with water and a saturated sodium chloride aqueous solution and dried over sodium sulfate. After distilling the solvent off, the residue was dissolved in an N,N-dimethylformamide solution (80 ml) again. Sodium hydride (1.08 g, 24.7 mmol) was added to the result under an argon atmosphere while ice cooling, followed by stirring at the same temperature for 30 minutes. Thereafter, iodomethane (3.09 ml, 49.3 mmol) was added to the mixture and stirred while returning the mixture to room temperature. After 10 hours, the reaction mixture was poured into ice water/acetic acid (1.5 ml) and stirred for a while, and the precipitate was collected by filtration. The resulting solid was dissolved in ethyl acetate and dried over sodium sulfate. The solvent was then distilled off.

Because a monomethylated compound still remained, the mixture was dissolved in an N,N-dimethylformamide (80 ml) again, and sodium hydride (1.08 g, 24.7 mmol) was added thereto under an argon atmosphere while ice cooling. The mixture was stirred at the same temperature for 30 minutes, iodomethane (3.09 ml, 49.3 mmol) was added thereto and stirred while returning the mixture to room temperature. After 9 hours, the mixture was poured into ice water/acetic acid (1.5 ml) and stirred for a while. The precipitate was collected by filtration, and the resulting solid was dissolved in ethyl acetate and dried over sodium sulfate. Thereafter, the solvent was distilled off.

Because a monomethylated compound still remained, the mixture was dissolved in an N,N-dimethylformamide (80 ml) again, and sodium hydride (1.08 g, 24.7 mmol) was added thereto under an argon atmosphere while ice cooling. After stirring at the same temperature for 30 minutes, iodomethane (3.09 ml, 49.3 mmol) was added thereto and stirred while returning the mixture to room temperature. After 10 hours, the mixture was poured into ice water/acetic acid (1.5 ml) and the resulting mixture was stirred for a while. Thereafter, the precipitate was collected by filtration. The resulting solid was dissolved in ethyl acetate and dried over sodium sulfate. The solvent was then distilled off.

The resultant was dissolved in methanol (80 ml), and 5 N sodium hydroxide (25 ml) was added thereto and stirred under reflux. After 2 hours, the mixture was returned to room temperature, and the solvent was distilled off. The residue was dissolved in water and washed with hexane. The pH value of the water layer was adjusted to 1 to 2 using a concentrated hydrochloric acid under ice cooling, and the precipitate was collected by filtration. The solid thus obtained was dissolved in ethyl acetate and dried over sodium sulfate. After removing the desiccant by filtration, the solvent was distilled of to afford the title compound as a white powder (7.03 g, 84%).

1H NMR (CDCl₃) δ=1.59 (s, 6H), 5.11 (s, 2H), 6.91-6.95 (m, 2H), 7.32-7.36 (m, 2H), 7.54 (d, J=8.1 Hz, 2H), 7.64 (d, J=8.1 Hz, 2H).

Reference Example 398
Preparation of 1-(2-isocyanatopropan-2-yl)-4-[4-(trifluoromethyl)benzyloxy]benzene

Triethylamine (2.90 ml, 20.8 mmol) and diphenylphosphorylazide (4.48 ml, 20.8 mmol) were added to a 1,4-dioxane solution (70 ml) of 2-methyl-2-[4-(4-trifluoromethylbenzyloxy)phenyl]propionic acid (7.03 g, 10.8 mmol) and heated at reflux. After 2 hours, the solvent was distilled off, and diethylether and water were added to the residue, followed by extraction with diethylether. The result was washed with water and a saturated sodium chloride aqueous solution and dried over sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off to afford the title compound as a pale brown oil (6.89 g, 99%).

1H NMR (CDCl₃) δ=1.70 (s, 6H), 5.13 (s, 2H), 6.90-6.96 (m, 2H), 7.33-7.39 (m, 2H), 7.55 (d, J=8.1 Hz, 2H), 7.65 (d, J=8.1 Hz, 2H).

Reference Example 399
Preparation of 1-methyl-1-[4-(4-trifluoromethylbenzyloxy)phenyl]ethylamine

Concentrated hydrochloric acid (18 ml) was added to an acetic acid solution (24 ml) of 1-(2-isocyanatopropan-2-yl)-4-[4-(trifluoromethyl)benzyloxy]benzene (4.35 g, 13.0 mmol) and stirred at room temperature. After 2.5 hours, the mixture was heated to 80° C. and stirred for 1 hour. The solvent was then distilled off. Ice and a 5 N sodium hydroxide aqueous solution were sequentially added to the residue and stirred, followed by extraction with ethyl acetate. The resultant was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off to afford the title compound as a brown solid (3.3 g, 82%).

1H NMR (CDCl₃) δ=1.48 (s, 6H), 1.76 (brs, 2H), 5.12 (s, 2H), 6.90-6.94 (m, 2H), 7.41-7.46 (m, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.64 (d, J=8.0 Hz, 2H).

Reference Example 400
Preparation of 1-{1-methyl-1-[4-(4-trifluoromethylbenzyloxy)phenyl]ethyl}-4-(toluene-4-sulfonyl]piperazine

N,N-bis-2-(Chloro-ethyl)-4-methylbenzenesulfonamide (4.74 g, 16.0 mmol) was added to a disopropylethylamine suspension (40 ml) of 1-methyl-1-[4-(4-trifluoromethylbenzyloxy)phenyl]ethylamine (3.3 g, 10.7 mmol) and stirred at 130° C. After 24 hours, heating was stopped. The solvent was distilled off, and a dilute sodium hydroxide aqueous solution was added to the residue, followed by extraction with ethyl acetate. The result was washed with water and a saturated sodium chloride aqueous solution and dried over sodium sulfate (30 g of silica gel was added at the same time). After removing the desiccant and silica gel by filtration, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→85:15→80:20) to afford the title compound as a white solid (2.67 g, 47%).

1H NMR (CDCl₃) δ=1.29 (s, 6H), 2.45 (s, 2H), 2.54 (t, J=4.7 Hz, 4H), 2.87-3.02 (m, 4H), 6.82-6.87 (m, 2H), 7.30-7.36 (m, 4H), 7.54 (d, J=8.1 Hz, 2H), 7.60-7.66 (m, 4H).

Reference Example 401
Preparation of 1-{1-methyl-1-[4-(4-trifluoromethylbenzyloxy)phenyl]ethyl}piperazine

Magnesium (1.83 g, 75.0 mmol) was added to a methanol solution (50 ml) of 1-{1-methyl-1-[4-(4-trifluoromethylbenzyloxy)phenyl]ethyl}-4-(toluene-4-sulfonyl]piperazine (2.67 g, 5.0 mmol) and stirred at 60° C. After hours, magnesium (0.61 g, 25.1 mmol) was added thereto and further stirred. After 1 hour, heating was stopped and the solvent was distilled off. Ice and 10% hydrochloric acid (100 ml) were added to the residue and stirred. Ethyl acetate was added and further stirred. The mixture was separated into layers, and the water layer was made basic using a 25% sodium hydroxide aqueous solution. Ethyl acetate was added to the mixture, followed by stirring. The mixture was filtered through Celite to remove the insoluble matter. The filtrate was subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off to afford the title compound as a slightly yellow oil (1.05 g, 55%).

1H NMR (CDCl₃) δ=1.32 (s, 6H), 2.38-2.49 (m, 4H), 2.84 (t, J=4.8 Hz, 4H), 5.11 (s, 2H), 6.87-6.92 (m, 2H), 7.42-7.48 (m, 2H), 7.56 (d, J=8.0 Hz, 2H), 7.64 (d, J=8.0 Hz, 2H).

Reference Example 402
Preparation of 1-{1-methyl-1-[4-(4-trifluoromethylbenzyloxy)phenyl]ethyl}-4-[4-(tetrahydropyran-2-yloxy)phenyl]piperazine

The title compound was prepared in the same manner as in Reference Example 362 using suitable starting materials.

1H NMR (CDCl₃) δ=1.36 (s, 6H), 1.53-1.73 (m, 3H), 1.78-1.90 (m, 2H), 1.94-2.04 (m, 1H), 2.62 (t, J=4.8 Hz, 4H), 3.05 (t, J=4.8 Hz, 4H), 3.54-3.63 (m, 1H), 3.90-3.98 (m, 1H), 5.12 (s, 2H), 5.30 (t, J=3.4 Hz, 1H), 6.83-6.88 (m, 2H), 6.89-6.93 (m, 2H), 6.95-6.99 (m, 2H), 7.45-7.50 (m, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H).

Example 1
Preparation of 2-nitro-7-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

60% sodium hydride (70 mg) was added to an N,N-dimethylformamide solution (10 ml) of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxy}butan-2-ol (0.9 g) under ice cooling, and the mixture was stirred at room temperature for 3 days. A saturated ammonium chloride aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (methylene chloride:ethyl acetate=8:2→methylene chloride:ethyl acetate=2:8) and recrystallized from methylene chloride-ethyl acetate-isopropyl ether to afford the title compound as a pale yellow powder (158 mg).

Melting point: 186.8-187.8° C.

Example 2
Preparation of 4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 199.5-200.3° C.

Example 3
Preparation of 2-nitro-7-{4-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

Trifluoroacetic acid (6.0 ml) was added to 4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (200 mg), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride (2.0 ml) and triethylamine (2.0 ml) were added to the residue, followed by stirring at room temperature for 5 minutes. The reaction mixture was reconcentrated under reduced pressure. 1,2-Dichloroethane (5 ml), 4-(trifluoromethoxy)benzaldehyde (124 μl) and sodium triacetoxyborohydride (185 mg) were added to the residue, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=10:0→methylene chloride:methanol=9:1) and recrystallized from methylene chloride-isopropyl ether to afford the title compound as a white powder (211 mg).

Melting point: 171.8-173.3° C.

Example 4
Preparation of N-(4-chlorophenyl)-N-methyl-N-{1-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}amine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 212.0-213.6° C.

Example 5
Preparation of 2-nitro-7-{4-[4-(4-trifluoromethylbenzyloxymethyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 141-143° C.

Example 6
Preparation of 2-nitro-7-{4-[4-(4-trifluoromethylphenoxymethyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Yellow Solid

Melting point: 199.8-200.8° C.

Example 7
Preparation of 7-{4-[4-(4′-chlorobiphenyl-4-ylmethyl)piperazin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 276.4-277.1° C.

Example 8
Preparation of 2-nitro-7-(4-{4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Brown Powder

Melting point: 164.0-164.4° C.

Example 9
Preparation of 2-nitro-7-{4-[4-(4-trifluoromethoxybenzyloxy)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 189-190° C.

Example 10
Preparation of N-methyl-N-(4-trifluoromethoxyphenyl)-{1-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}amine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 188-189° C.

Example 11
Preparation of 2-nitro-7-{4-[4-(4-trifluoromethoxybenzyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 174-175° C.

Example 12
Preparation of 2-nitro-7-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 204-205° C.

Example 13
Preparation of (S)-2-nitro-7-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 165-166° C.

Example 14
Preparation of 2-nitro-7-{4-[4-(4-trifluoromethoxybenzyloxymethyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 156-157° C.

Example 15
Preparation of 2-nitro-7-{4-[4-(4-trifluoromethoxyphenoxymethyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 202-203° C.

Example 16
Preparation of 7-{4-[4-(4-chlorobenzyloxymethyl)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 149-150° C.

Example 17
Preparation of 7-{4-[4-(4-chlorobenzyloxy)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 200-201° C.

Example 18
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 163-164° C.

Example 19
Preparation of 2-nitro-7-{4-[4-(4-trifluoromethylphenoxy)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 207-209° C.

Example 20
Preparation of 7-{4-[4-(4-chlorophenoxy)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 183-185° C.

Example 21
Preparation of 2-nitro-7-{4-[4-(4-trifluoromethoxyphenyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 214-216° C.

Example 22
Preparation of N-methyl-N-{1-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-(4-trifluoromethylphenyl)amine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 208-209° C.

Example 23
Preparation of 2-nitro-7-{4-[4-(3-trifluoromethylphenoxy)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 189-190° C.

Example 24
Preparation of 7-{4-[4-(3,5-bis-trifluoromethylphenoxy)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 199-200° C.

Example 25
Preparation of 2-nitro-7-(4-{4-[4-(4-trifluoromethoxybenzyl)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 213.9-214.0° C.

Example 26
Preparation of 2-nitro-7-{4-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 200-201° C.

Example 27
Preparation of 2-nitro-7-{4-[1-(4-trifluoromethylphenyl)piperidin-4-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 219-221° C.

Example 28
Preparation of 2-nitro-7-(4-{4-[4-(4-trifluoromethylbenzyl)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 213.3-214.4° C.

Example 29
Preparation of 4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 182-183° C.

Example 30
Preparation of 2-nitro-7-{4-[4-(4-trifluoromethylbenzyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 179-180° C.

Example 31
Preparation of 7-{4-[4-(4-chlorobenzyl)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 175-176° C.

Example 32
Preparation of 7-(4-{4-[4-(4-chlorobenzyl)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 205.7-206.2° C.

Example 33
Preparation of N-(4-chlorophenyl)-N-ethyl-N-{1-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}amine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 195.2° C.

Example 34
Preparation of N-ethyl-N-{1-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-(4-trifluoromethylphenyl)amine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 206.2° C.

Example 35
Preparation of N-ethyl-N-{1-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-(4-trifluoromethoxyphenyl)amine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 184.8-185.3° C.

Example 36
Preparation of 2-nitro-7-{4-[4-(4′-trifluoromethoxybiphenyl-4-ylmethyl)piperazin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 236.0-236.8° C.

Example 37
Preparation of 2-nitro-7-(4-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 196.3-196.8° C.

Example 38
Preparation of 2-nitro-7-(4-{4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 205.2-205.4° C.

Example 39
Preparation of 2-nitro-7-(4-{4-[3-(4-trifluoromethylphenyl)propyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 172.5-173.2° C.

Example 40
Preparation of 2-nitro-7-(4-{4-[(E)-3-(4-trifluoromethoxyphenyl)allyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 203.6-204.3° C.

Example 41
Preparation of 7-(4-{4-[4-(4-chlorobenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 231.3-232.2° C.

Example 42
Preparation of 2-nitro-7-(4-{4-[3-(4-trifluoromethylphenyl)propyl]-[1,4]diazepan-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 157.8-158.0° C.

Example 43
Preparation of 2-nitro-7-(4-{4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 167-168° C.

Example 44
Preparation of 2-nitro-7-(4-{4-[3-(4-trifluoromethoxyphenoxy)propyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 180-181° C.

Example 45
Preparation of 4-{4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-ylmethyl}piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 217.5-217.8° C.

Example 46
Preparation of 4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 176.7-177.1° C.

Example 47
Preparation of 2-nitro-7-{4-[2-(4-trifluoromethoxyphenyl)oxazol-4-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 238-239° C.

Example 48
Preparation of 2-nitro-7-(4-{4-[3-(4-trifluoromethoxyphenyl)propyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 172-174° C.

Example 49
Preparation of 1-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]-4-trifluoromethylpiperidin-4-ol

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 209-211° C.

Example 50
Preparation of 2-nitro-7-(4-{4-[1-(4-trifluoromethylbenzyl)piperidin-4-ylmethyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

Trifluoroacetic acid (1.5 ml) was added to a methylene chloride solution (1.5 ml) of 4-{4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-ylmethyl}piperidine-1-carboxylic acid tert-butyl ester (300 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, methylene chloride (1.5 ml) and triethylamine (1.5 ml) were added to the residue, and the result was stirred at room temperature for 5 minutes. After concentrating the reaction mixture under reduced pressure, methanol (3 ml), 4-(trifluoromethyl)benzaldehyde (130 mg), sodium cyanoborohydride (160 mg) and acetic acid (1 ml) were added to the residue in this order, and the mixture was stirred at room temperature overnight. The resulting reaction mixture was added to a potassium carbonate aqueous solution, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride:methanol=1:0→methylene chloride:methanol=9:1) and recrystallized from methanol to afford the title compound as a pale yellow powder (50 mg).

Melting point: 214.3-217.2° C.

Example 51
Preparation of 7-(4-{4-[1-(4-chlorobenzyl)piperidin-4-ylmethyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 50 using suitable starting materials.

Pale Yellow Powder

Melting point: 211.1-213.2° C.

Example 52
Preparation of 2-nitro-7-(4-{4-[1-(4-trifluoromethoxybenzyl)piperidin-4-ylmethyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 50 using suitable starting materials.

Pale Yellow Powder

Melting point: 207.6° C.

Example 53
Preparation of 2-nitro-7-{4-[2-(4-trifluoromethoxyphenoxymethyl)oxazol-4-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 171-172° C.

Example 54
Preparation of 2-nitro-7-(4-{4-[6-(4-trifluoromethoxyphenoxy)pyridin-3-ylmethyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 190.7° C.

Example 55
Preparation of 2-nitro-7-{4-[2-(4-trifluoromethoxyphenoxymethyl)thiazol-4-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 219-220° C.

Example 56
Preparation of 2-nitro-7-{4-[2-(4-trifluoromethoxyphenyl)thiazol-4-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Slightly Yellow Powder

Melting point: 235-236° C.

Example 57
Preparation of 2-nitro-7-(4-{4-[2-(5-trifluoromethylpyridin-2-yloxy)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 156-158° C.

Example 58
Preparation of 2-nitro-7-{4-[4-(5-trifluoromethylpyridin-2-yloxymethyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 206-207° C.

Example 59
Preparation of 7-[4-(4-methoxy-4-trifluoromethylpiperidin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 167-168° C.

Example 60
Preparation of 2-nitro-7-{4-[4-(4-trifluoromethoxyphenyl)oxazol-2-ylmethyl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 87-89° C.

Example 61
Preparation of 2-nitro-7-{4-[4-(5-trifluoromethylpyridin-2-yloxy)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 186-187° C.

Example 62
Preparation of 2-nitro-7-(4-{4-[6-(4-trifluoromethylphenoxy)pyridin-3-ylmethyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 197.5-197.9° C.

Example 63
Preparation of 7-(4-{4-[6-(4-chlorophenoxy)pyridin-3-ylmethyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 199.1-200.6° C.

Example 64
Preparation of 2-nitro-7-[4-(4-{3-[4-(4-trifluoromethoxyphenoxy)phenyl]propyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 140.6-142.4° C.

Example 65
Preparation of 2-nitro-7-(6-{4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperazin-1-yl}pyridin-3-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 167.0-167.1° C.

Example 66
Preparation of 2-nitro-7-(6-{4-[6-(4-trifluoromethoxyphenoxy)pyridin-3-ylmethyl]piperazin-1-yl}pyridin-3-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 186.0-186.1° C.

Example 67
Preparation of 2-nitro-7-(4-{4-[2-(4-trifluoromethylbenzyloxy)ethyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 156.0-158.2° C.

Example 68
Preparation of 4-[5-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 205.4-205.7° C.

Example 69
Preparation of 2-nitro-7-{4-[2-(4-trifluoromethoxybenzyl)thiazol-4-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

Sodium tert-butoxide (62 mg) was added to a dimethyl formaldehyde solution (5 ml) of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[2-(4-trifluoromethoxybenzyl)thiazol-4-yl]phenoxy}butan-2-ol (334 mg), and the mixture was stirred at room temperature. While confirming the progress of the reaction, sodium tert-butoxide (62 mg) was added 3 times, and the resulting mixture was stirred overnight. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the precipitated solid was sequentially washed with water and diisopropyl ether. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1→ethyl acetate) to afford the title compound as a pale brown powder (69 mg).

Melting point: 222-224° C.

Example 70
Preparation of 2-nitro-7-{6-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]pyridin-3-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

White Powder

Melting point: 181-182° C.

Example 71
Preparation of 2-nitro-7-(4-{4-[3-(5-trifluoromethylpyridin-2-yl)propyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 173.3-173.4° C.

Example 72
Preparation of 2-nitro-7-{6-[4-(4-trifluoromethoxybenzyl)piperidin-1-yl]pyridin-3-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 184-185° C.

Example 73
Preparation of 2-nitro-7-(6-{4-[3-(5-trifluoromethylpyridin-2-yl)propyl]piperazin-1-yl}pyridin-3-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 164.2-164.7° C.

Example 74
Preparation of 2-nitro-7-(4-{4-[3-(5-trifluoromethylpyridin-2-yl)propyl]-[1,4]diazepan-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 177.4° C.

Example 75
Preparation of 7-(4-{4-[5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophen-2-ylmethyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 204.6° C.

Example 76
Preparation of 2-nitro-7-{6-[4-(4-trifluoromethoxyphenoxymethyl)piperidin-1-yl]pyridin-3-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

White Powder

Melting point: 181-182° C.

Example 77
Preparation of 7-{4-[4-(4-benzyloxybenzyl)piperazin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 219.5-220.5° C.

Example 78
Preparation of 2-nitro-7-(4-{4-[2-(4-trifluoromethylphenoxy)ethyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 166.5-168.8° C.

Example 79
Preparation of 2-nitro-7-(6-{4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidin-1-yl}pyridin-3-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

White Powder

Melting point: 140-141° C.

Example 80
Preparation of 2-nitro-7-[4-(4-propoxy-4-trifluoromethylpiperidin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 157-158° C.

Example 81
Preparation of 4-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester

An ethanol solution (25.00 ml) of 20% sodium ethoxide was added to an ethanol solution (250 ml) of toluene-4-sulfonic acid (S)-4-(2-chloro-4-nitro-imidazol-1-yl)-2-hydroxybutyl ester (25.00 g), and the mixture was stirred at room temperature for 30 minutes. 4-(4-Hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (19.63 g) and tripotassium phosphate (13.61 g) were added to the reaction mixture, followed by heating under reflux for 4 hours. The reaction mixture was then concentrated under reduced pressure, and water was added to the residue, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:0→methylene chloride:ethyl acetate=0:1) and concentrated under reduced pressure. Sodium hydride (3.08 g) was added to a dimethylformamide solution (269 ml) of residue and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was dried over magnesium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:0→methylene chloride:ethyl acetate=0:1) to afford the title compound as a yellow powder (16.57 g).

Melting point: 201.0-202.7° C.

Example 82
Preparation of (S)-2-nitro-7-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 201-202° C.

Example 83
Preparation of N-methyl-N-{1-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-(4-trifluoromethoxyphenyl)amine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 186-187° C.

Example 84
Preparation of 7-{4-[4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 185-186° C.

Example 85
Preparation of 7-(4-{4-[5-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)thiophen-2-ylmethyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder (acetone-methanol)

Melting point: 180.3-180.8° C.

Example 86
Preparation of 4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester

An ethanol solution (3.02 ml) of 20% sodium ethoxide was added to an ethanol solution (30 ml) of toluene-4-sulfonic acid (R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester (3.00 g), and the mixture was stirred at room temperature for 30 minutes. 4-(4-Hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (2.36 g) and tripotassium phosphate (1.80 g) were added to the reaction mixture and heated under reflux for 4 hours. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in dimethylformamide (46 ml), sodium hydride (0.31 g) was added thereto, and the resulting mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was dried over magnesium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:0→methylene chloride:ethyl acetate=0:1) and recrystallized from acetone to afford the title compound as a yellow powder (0.72 g).

Melting point: 206.7-208.0° C.

Example 87
Preparation of (S)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 161.2-163.8° C.

Example 88
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 162.6-163.2° C.

Example 89
Preparation of (R)-2-nitro-7-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Needle

Melting point: 201-202° C.

Example 90
Preparation of N-methyl-N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-(4-trifluoromethoxyphenyl)amine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Yellow Needle

Melting point: 186-187° C.

Example 91
Preparation of 2-nitro-7-{6-[4-(4-chlorophenoxy)piperidin-1-yl]pyridin-3-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

White Powder

Melting point: 171-172° C.

Example 92
Preparation of 2-nitro-7-{4-[1-(4-trifluoromethoxyphenyl)piperidin-4-ylmethyl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 193-194° C.

Example 93
Preparation of 7-{4-[4-(5-chlorothiophen-2-yl methyl)piperazin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 182.5-183.3° C.

Example 94
Preparation of 2-nitro-7-{6-[4-(4-trifluoromethoxybenzyloxy)piperidin-1-yl]pyridin-3-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 168-169° C.

Example 95
Preparation of 2-nitro-7-{6-[4-(4-trifluoromethylphenoxy)piperidin-1-yl]pyridin-3-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 199-200° C.

Example 96
Preparation of 2-nitro-7-{4-[1-(4-trifluoromethylphenyl)piperidin-4-ylmethyl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 186-188° C.

Example 97
Preparation of 7-{4-[4-(2,2-difluorobenzo[1,3]dioxol-5-ylmethyl)piperazin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 195.8-196.5° C.

Example 98
Preparation of 2-nitro-7-{4-[1-(4-trifluoromethoxybenzyl)piperidin-4-ylmethyl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 185-186° C.

Example 99
Preparation of 2-nitro-7-{4-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 170.7-171.0° C.

Example 100
Preparation of 7-{4-[4-(4-chlorobenzyl)piperazin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 188.8-189.5° C.

Example 101
Preparation of 2-nitro-7-{4-[1-(4-trifluoromethylbenzyl)piperidin-4-ylmethyl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 180-181° C.

Example 102
Preparation of 2-nitro-7-(4-{1-[4-(4-trifluoromethoxyphenoxy)benzyl]piperidin-4-ylmethyl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 197-198° C.

Example 103
Preparation of 7-{4-[1-(4-chlorobenzyl)piperidin-4-ylmethyl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 194-195° C.

Example 104
Preparation of 2-nitro-7-(6-{4-[3-(4-trifluoromethoxyphenyl)propyl]piperidin-1-yl}pyridin-3-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 162-163° C.

Example 105
Preparation of 7-{4-[4-(4-methylsulfanylbenzyl)piperazin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 191.1-191.5° C.

Example 106
Preparation of 2-nitro-7-{4-[4-(5-trifluoromethylbenzofuran-2-ylmethyl)piperazin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 181.0-181.6° C.

Example 107
Preparation of 2-nitro-7-(4-{4-[3-(4-trifluoromethoxyphenyl)propyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 168.5-168.8° C.

Example 108
Preparation of 2-nitro-7-[6-(4-trifluoromethoxybenzyloxymethyl)pyridin-3-yloxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 105-106° C.

Example 109
Preparation of 2-nitro-7-(4-{4-[2-(4-trifluoromethylphenyl)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 210-211° C.

Example 110
Preparation of 2-nitro-7-(4-{4-[2-(4-trifluoromethylphenoxy)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 171-172° C.

Example 111
Preparation of 7-(4-{4-[2-(4-chlorophenoxy)ethyl]piperidin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 174-175° C.

Example 112
Preparation of 2-{4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-yl}-1-(4-trifluoromethylphenyl)ethanol

1) Trifluoroacetic acid (1.5 ml) and methylene chloride (1.5 ml) were added to 4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (300 mg), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Methylene chloride (1.5 ml) and triethylamine (1.5 ml) were added to the residue, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was reconcentrated under reduced pressure.

2) 2,2,6,6-Tetramethyl-1-piperidinyloxy radical (TEMPO) (13 mg) and trichloroisocyanuric acid (1.93 g) were added to a methylene chloride solution (15 ml) of 4-trifluoromethyl phenethyl alcohol (1.5 g) under ice cooling and the mixture was stirred at the same temperature for 1 hour. After removing insoluble matter by filtration, the filtrate was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0-1; 1) and then concentrated under reduced pressure.

3) The residues obtained in Step 1) and Step 2) above were dissolved in 1,2-dichloroethane (5 ml). Sodium triacetoxyborohydride (0.39 g) was added thereto, and the mixture was stirred at room temperature overnight. After adding methylene chloride, the reaction mixture was washed with a potassium carbonate aqueous solution and water, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→9; 1) and concentrated under reduced pressure. The residue was recrystallized from methanol to afford the title compound as a pale yellow powder (69 mg).

Melting point: 223.8-225.3° C.

Example 113
Preparation of 2-nitro-7-(4-{4-[4-(4-trifluoromethylphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 149.9-151.9° C.

Example 114
Preparation of 7-(4-{4-[4-(4-chlorophenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 134.7° C.

Example 115
Preparation of 2-nitro-7-(4-{4-[4-(4-trifluoromethoxyphenyl)butyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 186.3-186.5° C.

Example 116
Preparation of 7-{2-chloro-4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 108-110° C.

Example 117
Preparation of 7-(4-{4-[2-(4-chlorophenyl)ethyl]piperidin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 212-214° C.

Example 118
Preparation of 2-nitro-7-(4-{4-[3-(4-trifluoromethylphenyl)propyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 180-181° C.

Example 119
Preparation of 2-nitro-7-(4-{4-[3-(4-trifluoromethylphenoxy)propyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 184-185° C.

Example 120
Preparation of 7-{4-[4-(5-chlorobenzofuran-2-ylmethyl)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

White Powder

Melting point: 157-158° C.

Example 121
Preparation of 7-{4-[4-(5-chlorobenzofuran-2-ylmethoxy)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 198-200° C.

Example 122
Preparation of 7-{4-[4-(4-fluoro-naphthalen-1-ylmethyl)piperazin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 182.9-184.4° C.

Example 123
Preparation of 2-nitro-7-(4-{4-[2-(4-trifluoromethylphenyl)ethyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

Toluene-4-sulfonic acid 4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester (1.12 g) was suspended in an ethanol (14 ml). An ethanol solution (1.13 ml) of 20% sodium ethoxide was added to the suspension, and the mixture was stirred at room temperature for 30 minutes. 4-{4-[2-(4-Trifluoromethylphenyl)ethyl]piperazin-1-yl}phenol (0.72 g) and tripotassium phosphate (0.61 g) were added to the reaction mixture and heated for 4 hours under reflux. After the reaction mixture was cooled to room temperature, water was added thereto, followed by extraction with methylene chloride. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→hexane:ethyl acetate=0:1) and recrystallized from methanol to afford the title compound as a pale yellow powder (0.72 g).

Melting point: 213.6-213.7° C.

Example 124
Preparation of 7-(4-{4-[3-(4-chlorophenoxy)propyl]piperidin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

White Powder

Melting point: 196-198° C.

Example 125
Preparation of 2-nitro-7-{4-[3-(4-trifluoromethoxyphenoxy)-8-azabicyclo[3.2.1]oct-8-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 123 using suitable starting materials.

Pale Brown Powder

Melting point: 220.5-222.6° C.

Example 126
Preparation of 2-nitro-7-(4-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 123 using suitable starting materials.

Yellow Powder

Melting point: 214.6° C.

Example 127
Preparation of 2-nitro-7-{4-[4-(5-trifluoromethylbenzofuran-2-ylmethyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

White Powder

Melting point: 171-172° C.

Example 128
Preparation of 7-(4-{4-[3-(4-chlorophenyl)propyl]piperidin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 170-171° C.

Example 129
Preparation of 2-nitro-7-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 123 using suitable starting materials.

White Powder

Melting point: 206.0-206.1° C.

Example 130
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 123 using suitable starting materials.

Pale Yellow Powder

Melting point: 209.5-210.4° C.

Example 131
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 194.0-194.4° C.

Example 132
Preparation of 2-nitro-7-{4-[4-(5-trifluoromethoxybenzofuran-2-ylmethyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

Sodium tert-butoxide (81 mg) was added to an N-methylpyrrolidone solution (5 ml) of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(5-trifluoromethoxybenzofuran-2-ylmethyl)piperidin-1-yl]phenoxy}butan-2-ol (469 mg), and the mixture was stirred at room temperature for 1 hour. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and precipitated solid was sequentially washed with water and diisopropyl ether. The crude product formed was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1→3:1) to afford the title compound as a white powder (181 mg).

Melting point: 142-143° C.

Example 133
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 123 using suitable starting materials.

Pale Yellow Powder

Melting point: 217.0-220.3° C.

Example 134
Preparation of 2-nitro-7-(4-{4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 123 using suitable starting materials.

Pale Yellow Powder

Melting point: 217.2-217.3° C.

Example 135
Preparation of 7-{4-[4-(5-chlorobenzofuran-2-ylmethoxymethyl)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Pale Yellow Powder

Melting point: 130-132° C.

Example 136
Preparation of 7-{4-[4-(4′-fluoro-3′-trifluoromethylbiphenyl-4-ylmethyl)piperazin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 187.4-187.7° C.

Example 137
Preparation of 7-{4-[4-(4′-fluorobiphenyl-4-ylmethyl)piperazin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 232.4-233.0° C.

Example 138
Preparation of 7-{4-[4-(4′-methylsulfanylbiphenyl-4-ylmethyl)piperazin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Brown Powder

Melting point: 258.2-259.1° C.

Example 139
Preparation of 2-nitro-7-(4-{4-[4-(5-trifluoromethylpyridin-2-yl)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 243.0-243.9° C.

Example 140
Preparation of 7-{4-[4-(3-fluoro-4′-trifluoromethoxybiphenyl-4-ylmethyl)piperazin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 179.0-180.4° C.

Example 141
Preparation of 7-{4-[4-(3-fluoro-4′-trifluoromethylbiphenyl-4-ylmethyl)piperazin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 211.6-212.9° C.

Example 142
Preparation of 7-{4-[4-(4′-chloro-3-fluorobiphenyl-4-ylmethyl)piperazin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 234.5-235.1° C.

Example 143
Preparation of 6-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-1-[3-(4-trifluoromethoxyphenoxy)propyl]-1,2,3,4-tetrahydroquinoline

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Pale Yellow Powder

Melting point: 175-176° C.

Example 144
Preparation of 2-nitro-7-(4-{4-[(E)-3-(5-trifluoromethylbenzofuran-2-yl)allyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 196.6-197.4° C.

Example 145
Preparation of 2-nitro-7-{4-[4-(5-trifluoromethoxybenzofuran-2-ylmethyl)piperazin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 185.5-185.6° C.

Example 146
Preparation of 2-nitro-7-(4-{4-[(E)-3-(4-trifluoromethylphenyl)allyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 206.0-206.4° C.

Example 147
Preparation of 7-{3-fluoro-4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

White Powder

Melting point: 186-187° C.

Example 148
Preparation of 7-{3-chloro-4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 143-144° C.

Example 149
Preparation of 7-{3-methyl-4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 199-200° C.

Example 150
Preparation of 7-{2-methyl-4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 156-157° C.

Example 151
Preparation of 6-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[2-(4-trifluoromethoxyphenoxy)ethoxy]quinoline

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 156-157° C.

Example 152
Preparation of 6-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[3-(4-trifluoromethoxyphenoxy)propoxy]quinoline

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 172-173° C.

Example 153
Preparation of 6-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-(4-trifluoromethoxybenzyloxy)quinoline

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 203-204° C.

Example 154
Preparation of 6-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-1-[3-(4-trifluoromethoxyphenoxy)propyl]-1,2,3,4-tetrahydroquinoline

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Pale Yellow Powder

Melting point: 183-185° C.

Example 155
Preparation of (R)-2-nitro-7-{1-[3-(4-trifluoromethoxyphenoxy)propyl]-1H-indol-5-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Pale Yellow Powder

Melting point: 129-131° C.

Example 156
Preparation of 7-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-1-[3-(4-trifluoromethoxyphenoxy)propyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

White Powder

Melting point: 159-160° C.

Example 157
Preparation of 6-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-1-[4-(4-trifluoromethoxyphenoxy)benzyl]-1,2,3,4-tetrahydroquinoline

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Pale Brown Powder

Melting point: 194-196° C.

Example 158
Preparation of 7-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-1-[4-(4-trifluoromethoxyphenoxy)benzyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Powder

Melting point: 133-134° C.

Example 159
Preparation of 6-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]quinoline

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Yellow Powder

Melting point: 193-195° C.

Example 160
Preparation of (R)-7-(2-methyl-4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 181-182° C.

Example 161
Preparation of (R)-7-(2-chloro-4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 160-162° C.

Example 162
Preparation of (R)-2-nitro-7-(6-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}naphthalen-2-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 234-235° C.

Example 163
Preparation of 2-nitro-7-{4-[4-(4′-trifluoromethylbiphenyl-4-ylmethyl)piperazin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 256.9-257.9° C.

Example 164
Preparation of 2-nitro-7-(4-{4-[6-(4-trifluoromethoxyphenyl)pyridin-3-ylmethyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 201.2-203.7° C.

Example 165
Preparation of 6-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]quinoline

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 218-221° C.

Example 166
Preparation of 6-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-{4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperazin-1-yl}quinoline

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 208-211° C.

Example 167
Preparation of 6-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}quinoline

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 226-230° C.

Example 168
Preparation of (R)-2-nitro-7-{2-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]benzothiazol-6-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Yellow Powder

Melting point: 189-191° C.

Example 169
Preparation of (R)-2-nitro-7-{2-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]benzothiazol-6-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

Sodium tert-butoxide (112 mg) was added to a dimethylsulfoxide solution (6 ml) of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{2-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]benzothiazol-6-yloxy}butan-2-ol (662 mg), and the mixture was stirred at room temperature for 3 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and precipitated solid was sequentially washed with water and diisopropyl ether. The crude product was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1→ethyl acetate) to afford the title compound as a pale yellow powder (60 mg).

Melting point: 157-159° C.

Example 170
Preparation of (R)-2-nitro-7-[4-(4-{4-[2-(4-trifluoromethoxyphenyl)ethoxy]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 157.7° C.

Example 171
Preparation of (S)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 193.4-193.9° C.

Example 172
Preparation of (R)-2-nitro-7-(4-{4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 152-153° C.

Example 173
Preparation of 2-nitro-7-(2-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}benzothiazol-6-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 203-205° C.

Example 174
Preparation of (R)-2-nitro-7-[4-(4-{4-[3-(4-trifluoromethoxyphenyl)propoxy]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 158.2-158.4° C.

Example 175
Preparation of (R)-2-nitro-7-[4-(4-{4-[(E)-3-(4-trifluoromethoxyphenyl)allyloxy]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 183.0-183.9° C.

Example 176
Preparation of (R)-7-[4-(4-{4-[2-(4-chlorophenyl)ethoxy]benzyl}piperazin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 150.0-152.2° C.

Example 177
Preparation of (R)-2-nitro-7-[4-(4-{4-[3-(4-trifluoromethylphenyl)propoxy]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 155.0-155.9° C.

Example 178
Preparation of (R)-2-nitro-7-[4-(4-{4-[(E)-3-(4-trifluoromethylphenyl)allyloxy]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 196.1-199.1° C.

Example 179
Preparation of (R)-2-nitro-7-[4-(4-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Solid

Melting point: 168.3-169.5° C.

Example 180
Preparation of N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxyphenoxy)phenyl]amine

1-[4-((R)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-one (700 mg) and 4-(4-trifluoromethoxyphenoxy)phenylamine (557 mg) were suspended in 1,2-dichloroethane (20 ml) and tetrahydrofuran (20 ml). Sodium triacetoxyborohydride (558 mg) and acetic acid (0.13 ml) were added to the suspension, and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the remaining water layer was ice-cooled. A 20% sodium carbonate aqueous solution was added thereto, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (methylene chloride:methanol=100:1→methylene chloride:methanol=40:1) and recrystallized from isopropyl alcohol-isopropyl ether to afford the title compound as a yellow solid (226 mg).

Melting point: 119.6-121° C.

Example 181
Preparation of N-(4′-chlorobiphenyl-4-ylmethyl)-N-methyl-N-{1-[4-NR)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}amine

The title compound was prepared in the same manner as in Example 180 using suitable starting materials.

Colorless Solid

Melting point: 256.5-258° C.

Example 182
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 198.8-200.8° C.

Example 183
Preparation of (R)-7-(4-{4-[4-(4-chlorobenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 225.5-229.0° C.

Example 184
Preparation of (R)-7-(4-{4-[2-(3,4-dichlorophenoxy)ethyl]piperidin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Yellow Powder

Melting point: 152-153° C.

Example 185
Preparation of (R)-7-(4-{4-[2-(3-chloro-5-trifluoromethylpyridin-2-yloxy)ethyl]piperidin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Yellow Powder

Melting point: 140-143° C.

Example 186
Preparation of (R)-2-nitro-7-(4-{4-[3-(4-trifluoromethoxyphenyl)propyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 171-172° C.

Example 187
Preparation of (R)-2-nitro-7-(4-{4-[2-(tetrahydropyran-2-yloxy)-2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 172-175° C.

Example 188
Preparation of 2-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-1-(4-trifluoromethoxyphenyl)ethanol

A 1 N HCl ethanol solution (6 ml) was added to (R)-2-nitro-7-(4-{4-[2-(tetrahydropyran-2-yloxy)-2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.20 g), and the mixture was stirred at room temperature for 3 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the residue obtained by distilling the solvent off, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The crystal thus obtained was washed with methylene chloride-ether and dried to afford the title compound as a white powder (0.16 g).

Melting point: 186-187° C.

Example 189
Preparation of (R)-7-(4-{4-[2-(3,5-dichloropyridin-2-yloxy)ethyl]piperidin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Yellow Powder

Melting point: 143-145° C.

Example 190
Preparation of N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine

Sodium triacetoxyborohydride (0.32 g) and acetic acid (1 ml) were added to a 1,2-dichloroethane solution (8 ml) of 1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-one (0.40 g) and 4-(4-trifluoromethoxybenzyloxy)phenylamine (0.33 g), and the mixture was stirred at room temperature for 5 days. The reaction mixture was diluted with methylene chloride. The result was washed with a potassium carbonate aqueous solution and water in this order, and then dried over magnesium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=1:0→methylene chloride:methanol=9:1) to afford the title compound as a yellow powder (0.46 g).

Melting point: 226.9-228.6° C.

Example 191
Preparation of (R)-7-(4-{4-[2-(4-chloro-3-trifluoromethylphenoxy)ethyl]piperidin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Yellow Powder

Melting point: 116-118° C.

Example 192
Preparation of (R)-2-nitro-7-(4-{4-[3-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 155.6-156.5° C.

Example 193
Preparation of (R)-7-(4-{4-[2-(2,4-dichlorophenoxy)ethyl]piperidin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 164-166° C.

Example 194
Preparation of (R)-7-(4-{4-[2-(4-chloro-3-methylphenoxy)ethyl]piperidin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 166-168° C.

Example 195
Preparation of (R)-2-nitro-7-(4-{4-[2-(3-trifluoromethylphenoxy)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Yellow Powder

Melting point: 148-149° C.

Example 196
Preparation of (R)-2-nitro-7-(4-{4-[3-(4-trifluoromethoxyphenoxy)propyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 176-177° C.

Example 197
Preparation of (R)-2-nitro-7-(4-{4-[2-(5-trifluoromethylpyridin-2-yloxy)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 162-163° C.

Example 198
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxybenzyloxy)phenyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Yellow Solid

Melting point: 261-262° C.

Example 199
Preparation of (R)-7-(4-{4-[2-(3-chloro-4-fluorophenoxy)ethyl]piperidin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Yellow Powder

Melting point: 144-145° C.

Example 200
Preparation of (R)-2-nitro-7-{2-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]benzooxazol-5-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine hydrochloride

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 146-149° C.

Example 201
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxyphenoxy)phenyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Colorless Solid

Melting point: 207.6-208.2° C.

Example 202
Preparation of (R)-2-nitro-7-(4-{4-[3-(4-trifluoromethylphenyl)propyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Brown Powder

Melting point: 190.9° C.

Example 203
Preparation of (R)-7-[4-(4-{4-[(E)-3-(4-chlorophenyl)allyloxy]benzyl}piperazin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 210.6-213.6° C.

Example 204
Preparation of N-{4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-yl}-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)amine

Trifluoroacetic acid (3.0 ml) was added to a mixture of {4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-yl}carbamic acid tert-butyl ester (600 mg) and methylene chloride (3.0 ml), and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure, and methylene chloride (3.0 ml) and triethylamine (3.0 ml) were added to the residue, followed by stirring at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in acetic acid (8 ml). 4′-Trifluoromethylbiphenyl-4-carbaldehyde (316 mg) and sodium cyanoborohydride (239 mg) were added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to a 20% sodium carbonate aqueous solution, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=100:1→methylene chloride:methanol=40:1) and washed with ethyl acetate-isopropyl ether to afford the title compound as a colorless solid (265 mg).

Melting point: 294-295° C.

Example 205
Preparation of (R)-2-nitro-7-{4-[1-(4-trifluoromethoxybenzyl)piperidin-4-yloxy]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 151-152° C.

Example 206
Preparation of (R)-2-nitro-7-(4-{1-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperidin-4-yloxy}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 163-164° C.

Example 207
Preparation of (R)-2-nitro-7-(4-{1-[4-(4-trifluoromethoxyphenoxy)benzyl]piperidin-4-yloxy}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 127-128° C.

Example 208
Preparation of N-methyl-N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine

N-{1-[4-((R)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine (0.30 g) was suspended in methanol (3 ml). A 37% formaldehyde aqueous solution (0.11 g), sodium cyanoborohydride (89 mg) and acetic acid (1 ml) were added to the suspension and stirred at room temperature for 1 day. A 37% formaldehyde aqueous solution (0.22 g), sodium cyanoborohydride (178 mg) and acetic acid (2 ml) were further added to the mixture and stirred at room temperature for 1 day. The reaction mixture was gradually added to a potassium carbonate aqueous solution, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=10:0→methylene chloride:methanol=9:1) and recrystallized from methanol to afford the title compound as a pale brown powder (0.20 g).

Melting point: 142.0-143.7° C.

Example 209
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxyphenoxy)butyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

White Powder

Melting point: 160-162° C.

Example 210
Preparation of (R)-7-[4-(4-{4-[3-(4-chlorophenyl)propoxy]benzyl}piperazin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 200.7-200.9° C.

Example 211
Preparation of (R)-2-nitro-7-[4-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Gray Powder

Melting point: 147.3-150.0° C.

Example 212
Preparation of N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethylbenzyloxy)phenyl]amine

The title compound was prepared in the same manner as in Example 190 using suitable starting materials.

Yellow Powder

Melting point: 233.2-235.6° C.

Example 213
Preparation of N-methyl-N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethylbenzyloxy)phenyl]amine

N-{1-[4-((R)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethylbenzyloxy)phenyl]amine (0.40 g) and methanol (3 ml) were mixed. A 37% formaldehyde aqueous solution (0.47 g), sodium cyanoborohydride (0.36 g) and acetic acid (3 ml) were added to the mixture and stirred at room temperature overnight. The reaction mixture was added to a potassium carbonate aqueous solution, followed by extraction with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=1:0→methylene chloride:methanol=9:1) to afford the title compound as a yellow powder (0.26 g).

Melting point: 170.6° C.

Example 214
Preparation of N-[4-(4-chlorobenzyloxy)phenyl]-N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}amine

The title compound was prepared in the same manner as in Example 190 using suitable starting materials.

Yellow Powder

Melting point: 236.5-237.1° C.

Example 215
Preparation of N-[4-(4-chlorobenzyloxy)phenyl]-N-methyl-N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}amine

The title compound was prepared in the same manner as in Example 213 using suitable starting materials.

Yellow Powder

Melting point: 205.6-206.5° C.

Example 216
Preparation of (R)-2-nitro-7-(4-{4-[3-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Gray Powder

Melting point: 161.9-163.5° C.

Example 217
Preparation of (R)-7-(4-{4-[3-(4-chlorobenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 167.8-167.9° C.

Example 218
Preparation of (R)-2-nitro-7-[4-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 239-240° C.

Example 219
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxyphenoxymethyl)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 174.2-174.4° C.

Example 220
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethylphenoxymethyl)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 207.2-208.2° C.

Example 221
Preparation of 4-[4-(7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester

4-{4-[4-(2-Chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylbutoxy]phenyl}piperazine-1-carboxylic acid tert-butyl ester (2.12 g) was dissolved in dimethylformamide (21 ml). 60% sodium hydride (0.24 g) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, the mixture was subjected to extraction with methylene chloride, and then dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:0→methylene chloride:ethyl acetate=1:1) to afford the title compound as a colorless powder (1.05 g).

Melting point: 208.2-208.8° C.

Example 222
Preparation of (R)-2-nitro-7-[4-(4-{4-[2-(4-trifluoromethylphenyl)ethoxy]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 149.1° C.

Example 223
Preparation of (R)-7-(4-{4-[3-(4-chlorophenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 185.2-186.1° C.

Example 224
Preparation of (R)-2-nitro-7-(4-{1-[4-(4-trifluoromethylbenzyloxy)benzyl]piperidin-4-yloxy}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 177-178° C.

Example 225
Preparation of 7-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 145-146° C.

Example 226
Preparation of 7-methyl-2-nitro-7-(4-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 178.7-178.8° C.

Example 227
Preparation of 7-methyl-2-nitro-7-(4-{4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 162.1-162.7° C.

Example 228
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Gray Powder

Melting point: 143.2-144.9° C.

Example 229
Preparation of (S)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Gray Powder

Melting point: 143.5-146.9° C.

Example 230
Preparation of (S)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxybenzyloxy)phenoxy]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

White Powder

Melting point: 189-191° C.

Example 231
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxybenzyloxy)phenoxy]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 169 using suitable starting materials.

White Powder

Melting point: 190-191° C.

Example 232
Preparation of (S)-2-nitro-7-(4-{4-[4-(3-trifluoromethylphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 155.5-156.4° C.

Example 233
Preparation of (S)-7-(4-{4-[4-(4-chlorophenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 135.7-138.7° C.

Example 234
Preparation of (S)-2-nitro-7-[4-(4-{4-[2-(4-trifluoromethoxyphenyl)ethoxy]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 147.8-149.5° C.

Example 235
Preparation of (S)-2-nitro-7-[4-(4-{4-[2-(4-trifluoromethylphenyl)ethoxy]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 169.8-170.6° C.

Example 236
Preparation of (S)-7-[4-(4-{4-[2-(4-chlorophenyl)ethoxy]benzyl}piperazin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 153.6° C.

Example 237
Preparation of (S)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxyphenoxymethyl)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 174.1-174.5° C.

Example 238
Preparation of (S)-2-nitro-7-(4-{4-[4-(4-trifluoromethylphenoxymethyl)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 208° C.

Example 239
Preparation of (S)-7-(4-{4-[4-(4-chlorophenoxymethyl)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 228.6° C.

Example 240
Preparation of (S)-2-nitro-7-(4-{4-[3-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 156.6-158.3° C.

Example 241
Preparation of (S)-2-nitro-7-(4-{4-[3-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 188.0-188.5° C.

Example 242
Preparation of (R)-7-(4-{1-[4-(4-chlorobenzyloxy)benzyl]piperidin-4-yloxy}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 176-177° C.

Example 243
Preparation of (S)-2-nitro-7-(4-{1-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperidin-4-yloxy}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 162-164° C.

Example 244
Preparation of (S)-2-nitro-7-(4-{1-[4-(4-trifluoromethylbenzyloxy)benzyl]piperidin-4-yloxy}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 156-158° C.

Example 245
Preparation of (S)-7-(4-{1-[4-(4-chlorobenzyloxy)benzyl]piperidin-4-yloxy}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 146-148° C.

Example 246
Preparation of (S)-2-nitro-7-(4-{4-[4-(4-trifluoromethylbenzyloxy)phenoxy]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

White Powder

Melting point: 187-188° C.

Example 247
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethylbenzyloxy)phenoxy]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

White Powder

Melting point: 187-189° C.

Example 248
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxyphenoxymethyl)phenyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Brown Solid

Melting point: 199-201° C.

Example 249
Preparation of N-methyl-N-(4-{4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-yl}phenyl)-N-(4-trifluoromethylbenzyl)amine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Colorless Solid

Melting point: 229-230° C.

Example 250
Preparation of (S)-7-(4-{4-[3-(4-chlorobenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 186.1-186.2° C.

Example 251
Preparation of (S)-2-nitro-7-(2-{4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperazin-1-yl}benzooxazol-5-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 165-167° C.

Example 252
Preparation of (S)-2-nitro-7-(2-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}benzooxazol-5-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 174-176° C.

Example 253
Preparation of (R)-2-nitro-7-(2-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}benzooxazol-5-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 175-176° C.

Example 254
Preparation of (S)-2-nitro-7-(4-{4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Brown Powder

Melting point: 217.9-220.1° C.

Example 255
Preparation of (S)-7-(4-{(3R,5S)-3,5-dimethyl-4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Brown Powder

Melting point: 122.1-122.6° C.

Example 256
Preparation of (R)-7-(4-{(3R,5S)-3,5-dimethyl-4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Brown Powder

Melting point: 125.1° C.

Example 257
Preparation of (S)-2-nitro-7-[4-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 178.0-178.6° C.

Example 258
Preparation of (S)-2-nitro-7-[4-(4-{4-[2-(4-trifluoromethylphenyl)ethyl]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 193.8° C.

Example 259
Preparation of (S)-2-nitro-7-[4-(4-{4-[3-(4-trifluoromethylphenyl)propoxy]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 164.7-164.8° C.

Example 260
Preparation of (S)-7-[4-(4-{4-[3-(4-chlorophenyl)propoxy]benzyl}piperazin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 200.2-200.6° C.

Example 261
Preparation of (S)-2-nitro-7-(4-{4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 208° C.

Example 262
Preparation of (S)-7-(4-{4-[4-(4-chlorobenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 229.9° C.

Example 263
Preparation of N-{1-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Powder

Melting point: 228-229° C.

Example 264
Preparation of (S)-2-nitro-7-[4-(4-{4-[3-(4-trifluoromethoxyphenyl)propoxy]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 159.4-161.7° C.

Example 265
Preparation of (4-{4-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-ylmethyl}phenyl)carbamic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 191.4-191.9° C.

Example 266
Preparation of N-methyl-N-{1-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine

N-{1-[4-((S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine (0.30 g) was suspended in 1,2-dichloroethane (2 ml). A 37% formaldehyde aqueous solution (0.362 ml) and sodium triacetoxyborohydride (149 mg) were added to the suspension and stirred at room temperature overnight. A 37% formaldehyde aqueous solution (0.362 ml) and sodium triacetoxyborohydride (149 mg) were further added thereto and stirred at room temperature for 1 day. A sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1→methylene chloride:methanol=4:1) and crystallized from ether to afford the title compound as a pale yellow powder (130 mg).

Melting point: 143-145° C.

Example 267
Preparation of N-ethyl-N-{1-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine

The title compound was prepared in the same manner as in Example 226 using suitable starting materials.

Pale Yellow Powder

Melting point: 147-150° C.

Example 268
Preparation of (R)-7-(4-{(3R,5S)-3,5-dimethyl-4-[3-(4-trifluoromethylphenyl)propyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Powder

Melting point: 190.6-191.4° C.

Example 269
Preparation of (S)-7-(4-{(3R,5S)-3,5-dimethyl-4-[3-(4-trifluoromethylphenyl)propyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Powder

Melting point: 190.6-191.5° C.

Example 270
Preparation of (S)-2-nitro-7-(4-{4-[5-(4-trifluoromethoxyphenyl)pentyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 165-168° C.

Example 271
Preparation of (R)-2-nitro-7-(4-{4-[5-(4-trifluoromethoxyphenyl)pentyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 166-168° C.

Example 272
Preparation of (S)-2-nitro-7-{2-[4-(4-trifluoromethoxyphenoxy)benzyl]-2,3-dihydro-1H-isoindol-5-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 160-162° C.

Example 273
Preparation of (S)-2-nitro-7-{2-[4-(4-trifluoromethoxybenzyloxy)benzyl]-2,3-dihydro-1H-isoindol-5-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 161-163° C.

Example 274
Preparation of (S)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Powder

Melting point: 210.2-212.2° C.

Example 275
Preparation of N-ethyl-N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine

N-{1-[4-((R)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine (0.47 g) was suspended in 1,2-dichloroethane (5 ml). Acetaldehyde (0.41 ml) and sodium triacetoxyborohydride (0.46 g) were added to the suspension, and the mixture was stirred at room temperature for 3 days. A potassium carbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=10:0→methylene chloride:methanol=9:1) and recrystallized from methanol to afford the title compound as a yellow powder (0.25 g).

Melting point: 95.2-97.0° C.

Example 276
Preparation of N-ethyl-N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethylbenzyloxy)phenyl]amine

The title compound was prepared in the same manner as in Example 275 using suitable starting materials.

Brown Solid

Melting point: 88.7-90.2° C.

Example 277
Preparation of (R)-2-nitro-7-{2-[4-(4-trifluoromethoxyphenoxy)benzyl]-2,3-dihydro-1H-isoindol-5-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 161-164° C.

Example 278
Preparation of (R)-2-nitro-7-{2-[4-(4-trifluoromethoxybenzyloxy)benzyl]-2,3-dihydro-1H-isoindol-5-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 160-163° C.

Example 279
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxybenzyloxy)phenoxymethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 210-215° C.

Example 280
Preparation of (R)-2-nitro-7-[4-(4-{4-[2-(4-trifluoromethylphenyl)ethyl]benzyl}piperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 187.6-188.8° C.

Example 281
Preparation of (R)-2-nitro-7-{4′-[4-(4-trifluoromethoxyphenoxy)piperidin-1-ylmethyl]biphenyl-4-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Brown Powder

Melting point: 200.4-201.4° C.

Example 282
Preparation of (S)-2-nitro-7-{4′-[4-(4-trifluoromethoxyphenoxy)piperidin-1-ylmethyl]biphenyl-4-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Brown Powder

Melting point: 196.9-198.0° C.

Example 283
Preparation of (S)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxybenzyloxy)phenoxymethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Brown Powder

Melting point: 193-196° C.

Example 284
Preparation of (R)-7-(4-{(3R,5S)-3,5-dimethyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Brown Powder

Melting point: 112.8° C.

Example 285
Preparation of (S)-7-(4-{(3R,5S)-3,5-dimethyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Brown Powder

Melting point: 111.5° C.

Example 286
Preparation of (S)-2-nitro-7-(2-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperidin-1-yl}benzothiazol-6-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 190-191° C.

Example 287
Preparation of (R)-2-nitro-7-(2-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperidin-1-yl}benzothiazol-6-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Melting point: 190-191° C.

Example 288
Preparation of 7-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[4-(4-trifluoromethoxyphenoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 147-150° C.

Example 289
Preparation of 7-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[4-(4-trifluoromethoxybenzyloxy)benzyl]-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 150-154° C.

Example 290
Preparation of N-(4-{4-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-ylmethyl}phenyl)-N-(4-trifluoromethylbenzyl)amine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 215.8-217.1° C.

Example 291
Preparation of 7-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[4-(4-trifluoromethoxyphenoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 149-151° C.

Example 292
Preparation of 7-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[4-(4-trifluoromethoxybenzyloxy)benzyl]-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 149-152° C.

Example 293
Preparation of N-methyl-N-(4-{4-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-ylmethyl}phenyl)-N-(4-trifluoromethylbenzyl)amine

The title compound was prepared in the same manner as in Example 213 using suitable starting materials.

White Powder

Melting point: 168.5-169.0° C.

Example 294
Preparation of (R)-7-(4-{4-[4-(2,4-bis-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 185.4-186.3° C.

Example 295
Preparation of (S)-7-(4-{4-[4-(2,4-bis-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 184.5-185.8° C.

Example 296
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxybenzyloxy)phenyl]piperazin-1-ylmethyl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 190 using suitable starting materials.

Yellow Powder

Melting point: 212-214° C.

Example 297
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxyphenoxy)phenyl]piperazin-1-ylmethyl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 190 using suitable starting materials.

Yellow Powder

Melting point: 140-142° C.

Example 298
Preparation of (4-{4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-ylmethyl}phenyl)carbamic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 190.5-190.7° C.

Example 299
Preparation of (R)-7-(4-{(R)-3-methyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Brown Powder

Melting point: 151.0-152.2° C.

Example 300
Preparation of (S)-7-(4-{(R)-3-methyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Brown Powder

Melting point: 156.8-158.3° C.

Example 301
Preparation of 6-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[4-(4-trifluoromethoxyphenoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 196-198° C.

Example 302
Preparation of (R)-3-methyl-4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Brown Powder

Melting point: 196.4° C.

Example 303
Preparation of 6-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[4-(4-trifluoromethoxybenzyloxy)benzyl]-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 212-215° C.

Example 304
Preparation of 6-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[4-(4-trifluoromethylbenzyloxy)benzyl]-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 209-211° C.

Example 305
Preparation of 7-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[4-(4-trifluoromethoxyphenoxy)benzyl]-2,3,4,5-tetrahydro-1H-benzo[c]azepine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 196-198° C.

Example 306
Preparation of 7-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[4-(4-trifluoromethoxybenzyloxy)benzyl]-2,3,4,5-tetrahydro-1H-benzo[c]azepine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 216-218° C.

Example 307
Preparation of N-(4-{4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-ylmethyl}phenyl)-N-(4-trifluoromethylbenzyl)amine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 216.0-217.7° C.

Example 308
Preparation of (R)-7-(4-{(S)-3-methyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Brown Powder

Melting point: 155.9° C.

Example 309
Preparation of (S)-7-(4-{(S)-3-methyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Brown Powder

Melting point: 150.6° C.

Example 310
Preparation of (R)-7-(4-{(R)-2-methyl-4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 164.5° C.

Example 311
Preparation of (R)-7-(4-{(R)-2-methyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 154.3° C.

Example 312
Preparation of (R)-7-(4-{4-[4-(2-fluoro-4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Brown Powder

Melting point: 166.4-167.2° C.

Example 313
Preparation of (S)-7-(4-{4-[4-(2-fluoro-4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Brown Powder

Melting point: 166.4-167.8° C.

Example 314
Preparation of N-(4-{4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-ylmethyl}phenyl)-N-(4-trifluoromethoxybenzyl)amine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 226.3-228.2° C.

Example 315
Preparation of N-methyl-N-(4-{4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-ylmethyl}phenyl)-N-(4-trifluoromethylbenzyl)amine

The title compound was prepared in the same manner as in Example 213 using suitable starting materials.

Yellow Powder

Melting point: 179.6-179.7° C.

Example 316
Preparation of 7-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[4-(4-trifluoromethoxyphenoxy)benzyl]-2,3,4,5-tetrahydro-1H-benzo[c]azepine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 195-196° C.

Example 317
Preparation of 7-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-2-[4-(4-trifluoromethoxybenzyloxy)benzyl]-2,3,4,5-tetrahydro-1H-benzo[c]azepine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 215-217° C.

Example 318
Preparation of (S)-3-methyl-4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Powder

Melting point: 167.6° C.

Example 319
Preparation of (S)-3-methyl-4-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Powder

Melting point: 195.0-195.4° C.

Example 320
Preparation of N-methyl-N-(4-{4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-ylmethyl}phenyl)-N-(4-trifluoromethoxybenzyl)amine

The title compound was prepared in the same manner as in Example 213 using suitable starting materials.

Yellow Powder

Melting point: 184.8-184.9° C.

Example 321
Preparation of (R)-7-(4-{(S)-2-methyl-4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 132.5-132.8° C.

Example 322
Preparation of (R)-7-(4-{(S)-2-methyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 155.6-155.8° C.

Example 323
Preparation of (S)-7-(4-{(S)-2-methyl-4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 148.0-148.3° C.

Example 324
Preparation of (S)-7-(4-{(S)-2-methyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 163.7-164.2° C.

Example 325
Preparation of (R)-2-nitro-7-(4-{4-[4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 172.0-172.5° C.

Example 326
Preparation of (S)-2-nitro-7-(4-{4-[4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 171.9-172.2° C.

Example 327
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethylphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 184.6-184.9° C.

Example 328
Preparation of (R)-7-(4-[(S)-2-methyl-4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperazin-1-yl]phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 147.0-147.4° C.

Example 329
Preparation of (R)-7-(4-[(S)-2-methyl-4-[4-(4-trifluoromethylphenoxy)benzyl]piperazin-1-yl]phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 158.8° C.

Example 330
Preparation of (R)-3-methyl-4-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Powder

Melting point: 164.3-164.9° C.

Example 331
Preparation of N-methyl-N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)benzyl]amine

The title compound was prepared in the same manner as in Example 180 using suitable starting materials.

Pale Yellow Solid

Melting point: 181.4-184.1° C.

Example 332
Preparation of N-methyl-N-{1-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)benzyl]amine

The title compound was prepared in the same manner as in Example 180 using suitable starting materials.

Pale Yellow Solid

Melting point: 181.6-185.2° C.

Example 333
Preparation of (S)-7-(4-{(S)-2-methyl-4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 150.0-150.3° C.

Example 334
Preparation of (S)-7-(4-{(S)-2-methyl-4-[4-(4-trifluoromethylphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 158.0-159.1° C.

Example 335
Preparation of (R)-7-(4-{(R)-2-methyl-4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 150.2-150.6° C.

Example 336
Preparation of (R)-7-(4-{(R)-2-methyl-4-[4-(4-trifluoromethylphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 158.6-160.6° C.

Example 337
Preparation of (R)-2-nitro-7-(6-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}pyridin-3-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Brown Solid

Melting point: 197.7-198.0° C.

Example 338
Preparation of (S)-2-nitro-7-(6-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}pyridin-3-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Brown Solid

Melting point: 197-198° C.

Example 339
Preparation of (S)-7-(4-{(2S,5R)-2,5-dimethyl-4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 95-97° C.

Example 340
Preparation of (S)-7-(4-{(2S,5R)-2,5-dimethyl-4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 127.8-129.8° C.

Example 341
Preparation of (S)-7-(4-{(2S,5R)-2,5-dimethyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Powder

Melting point: 124.2-125.2° C.

Example 342
Preparation of (S)-7-(4-{(R)-2-methyl-4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 145.7-146.3° C.

Example 343
Preparation of (S)-7-(4-{(R)-2-methyl-4-[4-(4-trifluoromethylphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 153.6-154.3° C.

Example 344
Preparation of (S)-7-(4-{(R)-2-methyl-4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 151.0-151.7° C.

Example 345
Preparation of (S)-7-(4-{(R)-2-methyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 155.1-157.2° C.

Example 346
Preparation of (R)-7-(4-{4-[3-methyl-4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 172.9-173.8° C.

Example 347
Preparation of (R)-7-(4-{4-[3-methyl-4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 199.4-206.5° C.

Example 348
Preparation of (S)-7-(4-{4-[3-methyl-4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 169.8-170.2° C.

Example 349
Preparation of (S)-7-(4-{4-[3-methyl-4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

White Powder

Melting point: 161.2-162.8° C.

Example 350
Preparation of (R)-7-(4-{(2S,5R)-2,5-dimethyl-4-[4-(4-trifluoromethoxyphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

Potassium carbonate (135 mg) and sodium iodide (146 mg) were added to an N-methylpyrrolidone solution (6 ml) of (R)-7-[4-((2S,5R)-2,5-dimethyl-piperazin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine trifluoroacetate (343 mg) and 1-(chloromethyl)-4-[4-(trifluoromethoxy)phenoxy]benzene (269 mg), and the mixture was stirred at 60° C. for 3 hours. Sodium tert-butoxide (112 mg) was added to the mixture and stirred at room temperature for 3 hours. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1→ethyl acetate:n-hexane=3:1) to afford the title compound as a pale brown amorphous compound (200 mg).

1H NMR (CDCl3) δ 0.83 (d, J=6.1 Hz, 3H), 1.14 (d, J=6.3 Hz, 3H), 2.04 (t, J=8.9 Hz, 1H), 2.26-2.54 (m, 2H), 2.55-2.73 (m, 2H), 2.82 (dd, J=12.0 Hz, 2.9 Hz, 1H), 2.93-3.17 (m, 2H), 3.22 (d, J=13.4 Hz, 1H), 4.02 (d, J=13.4 Hz, 1H), 4.06-4.35 (m, 4H), 4.65-4.78 (m, 1H), 6.84 (d, J=8.9 Hz, 2H), 6.90-7.11 (m, 6H), 7.18 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.44 (s, 1H).

Example 351
Preparation of (R)-7-(4-{(2S,5R)-2,5-dimethyl-4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 350 using suitable starting materials.

Pale Brown Amorphous

Melting point: 119.5-121.5° C.

1H NMR (CDCl3) δ 0.81 (d, J=6.1 Hz, 3H), 1.13 (d, J=5.9 Hz, 3H), 1.91-2.06 (m, 1H), 2.22-2.54 (m, 2H), 2.54-2.83 (m, 3H), 2.94-3.10 (m, 2H), 3.19 (d, J=13.1 Hz, 1H), 3.89-4.34 (m, 5H), 4.62-4.77 (m. 1H), 5.06 (s, 2H), 6.84 (d, J=8.9 Hz, 2H), 6.93 (d, J=8.6 Hz, 2H), 7.04 (d, J=8.9 Hz, 2H), 7.18-7.32 (m, 4H), 7.40-7.55 (m, 3H).

Example 352
Preparation of (R)-7-(4-{(2S,5R)-2,5-dimethyl-4-[4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 350 using suitable starting materials.

Pale Brown Amorphous

Melting point: 108-110° C.

1H NMR (CDCl3) δ 0.81 (d, J=6.1 Hz, 3H), 1.13 (d, J=6.0 Hz, 3H), 1.93-2.07 (m, 1H), 2.26-2.52 (m, 2H), 2.56-2.83 (m, 3H), 2.92-3.14 (m, 2H), 3.19 (d, J=13.2 Hz, 1H), 3.99 (d, J=13.2 Hz, 1H), 4.05-4.34 (m, 4H), 4.66-4.79 (m, 1H), 5.13 (s, 2H), 6.83 (d, J=8.9 Hz, 2H), 6.93 (d, J=8.6 Hz, 2H), 7.04 (d, J=8.9 Hz, 2H), 7.18-7.28 (m, 2H), 7.45 (s, 1H), 7.56 (d, J=8.2 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H).

Example 353
Preparation of (R)-2-nitro-7-(4′-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}biphenyl-4-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Solid

Melting point: 249.6-252.8° C.

Example 354
Preparation of (S)-2-nitro-7-(4′-{4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}biphenyl-4-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Pale Yellow Solid

Melting point: 222.6-222.9° C.

Example 355
Preparation of N-methyl-N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-ylmethyl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Solid

Melting point: 167.0-170.1° C.

Example 356
Preparation of N-methyl-N-{1-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-ylmethyl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Solid

Melting point: 170-171° C.

Example 357
Preparation of (S)-2-nitro-7-(4-{5-[4-(4-trifluoromethoxyphenoxy)benzyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 350 using suitable starting materials.

Pale Brown Powder

Melting point: 127-129° C.

Example 358
Preparation of (S)-2-nitro-7-(4-{5-[4-(4-trifluoromethoxybenzyloxy)benzyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 350 using suitable starting materials.

Powder

Melting point: 142-145° C.

Example 359
Preparation of (R)-2-nitro-7-(4-{5-[4-(4-trifluoromethoxyphenoxy)benzyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 350 using suitable starting materials.

Pale Brown Powder

Melting point: 165-168° C.

Example 360
Preparation of (R)-2-nitro-7-(4-{5-[4-(4-trifluoromethoxybenzyloxy)benzyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 350 using suitable starting materials.

Pale Brown Powder

Melting point: 172-174° C.

Example 361
Preparation of 7-{4-[2-(4-chlorophenoxymethyl)oxazol-4-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

An ethanol solution (0.45 ml) of 20% sodium ethoxide was added to an ethanol solution (10 ml) of toluene-4-sulfonic acid 4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester (0.52 g), and the mixture was stirred at room temperature for 30 minutes. 4-[2-(4-Chlorophenoxymethyl)oxazol-4-yl]phenol (0.40 g) and tripotassium phosphate (0.34 g) were added to the reaction mixture, and the resulting mixture was heated under reflux for 2 hours. Water was added thereto and the precipitated solid was collected by filtration and dried at 60° C. The residue thus obtained was dissolved in dimethylformamide (3 ml), and sodium hydride (53 mg) was added thereto, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was dried over magnesium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=10:0→methylene chloride:methanol=9:1) to afford the title compound as a pale yellow powder (0.34 g).

Melting point: 199-200° C.

Example 362
Preparation of (R)-7-{4-[2-(4-chlorophenoxymethyl)oxazol-4-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 361 using suitable starting materials.

Pale Yellow Powder

Melting point: 214-215° C.

Example 363
Preparation of (R)-2-nitro-7-{4-[1-(4-trifluoromethoxybenzyl)piperidin-4-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

Trifluoroacetic acid (6 ml) was added to 4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidine-1-carboxylic acid tert-butyl ester (2.0 g), and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure. Methylene chloride (6 ml) and triethylamine (6 ml) were added to the residue, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was reconcentrated under reduced pressure. N-Methylpyrrolidone (6 ml), 4-(trifluoromethoxy)benzaldehyde (0.93 ml) and sodium triacetoxyborohydride (1.39 g) were added to the residue, and the mixture was stirred at room temperature for 3 hours. A 20% sodium carbonate aqueous solution (20 ml) and water (20 ml) were added to the reaction mixture, followed by stirring. The insoluble matter generated was collected by filtration. The residue thus obtained was washed with water and hexane, and then dried. Subsequently, the residue was suspended in ethyl acetate-isopropyl ether (1:1), and the suspension was stirred at room temperature, followed by collection by filtration. The residue was then dried to afford the title compound as a reddish brown solid (2.39 g).

Melting point: 183-184° C.

Example 364
Preparation of 2-nitro-7-{4-[1-(4-trifluoromethoxybenzyl)piperidin-4-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Pale Yellow Solid

Melting point: 178.6-180.2° C.

Example 365
Preparation of N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-(4-trifluoromethylphenyl)amine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellowish Orange Powder

Melting point: 214-216° C.

Example 366
Preparation of (R)-2-nitro-7-(4-{4-[2-(4-trifluoromethylphenoxy)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Solid

Melting point: 172.9-173.1° C.

Example 367
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethylbenzyloxy)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Solid

Melting point: 186.6-197.0° C.

Example 368
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Slightly Yellow Powder

Melting point: 162-164° C.

Example 369
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Pale Yellow Powder

Melting point: 188-189° C.

Example 370
Preparation of N-ethyl-N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-(4-trifluoromethylphenyl)amine

Acetaldehyde (2.2 ml) was added to an acetic acid solution (11 ml) of N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-(4-trifluoromethylphenyl)amine (2.2 g). Subsequently, sodium triacetoxyborohydride (2.52 g) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, and neutralized with a 5 N sodium hydroxide aqueous solution and a saturated sodium hydrogen carbonate aqueous solution. The resulting precipitate was collected by filtration and dried. The solid thus obtained was purified by silica gel column chromatography (methylene chloride:ethyl acetate=50:50) and recrystallized from acetone-ethyl acetate to afford the title compound as a yellow powder (1.96 g).

Melting point: 206° C.

Example 371
Preparation of N-methyl-N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-(4-trifluoromethylphenyl)amine

The title compound was prepared in the same manner as in Example 370 using suitable starting materials.

Yellow Powder

Melting point: 208-209° C.

Example 372
Preparation of (R)-2-nitro-7-(4-{4-[(E)-3-(4-trifluoromethylphenyl)allyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

White Powder

Melting point: 207-210° C.

Example 373
Preparation of N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-(4-trifluoromethoxyphenyl)amine

4-(Trifluoromethoxy)aniline (1.271 ml) was added to a 1,2-dichloroethane solution (50 ml) of 1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-one (2.5 g). Subsequently, sodium triacetoxyborohydride (1.992 g) and acetic acid (0.538 ml) were added thereto and the mixture was stirred at room temperature for 21 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) and recrystallized from ethyl acetate to afford the title compound as a yellow powder (2.55 g).

Melting point: 189-190° C.

Example 374
Preparation of N-ethyl-N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-(4-trifluoromethoxyphenyl)amine

The title compound was prepared in the same manner as in Example 370 using suitable starting materials.

Yellow Powder

Melting point: 184-185° C.

Example 375
Preparation of (R)-2-nitro-7-(4-{4-[(E)-3-(4-trifluoromethoxyphenyl)allyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Slightly Yellow Powder

Melting point: 208-209° C.

Example 376
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethylbenzyloxymethyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Solid

Melting point: 137.7-139.8° C.

Example 377
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethylphenoxymethyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Yellow Solid

Melting point: 198.5-200° C.

Example 378
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethoxybenzyloxymethyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Orange Solid

Melting point: 123-127° C.

Example 379
Preparation of 1-[4′-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)biphenyl-4-yl]-4-trifluoromethylpiperidin-4-ol

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Yellow Powder

Melting point: 225-230° C.

Example 380
Preparation of (R)-2-nitro-7-{4-[4-(nonafluorobutane-1-sulfonyl)piperazin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

Triethylamine (0.35 ml) was added to a methylene chloride suspension (6 ml) of (R)-2-nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.30 g). Subsequently, bis(nonafluoro-1-butanesulfonic)anhydride (0.31 ml) was added thereto dropwise under ice cooling. The mixture was stirred for 7.5 hours while it gradually returned to room temperature. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:1) and recrystallized from acetone-water to afford the title compound as a pale orange powder (0.19 g).

Melting point: 235-236° C.

Example 381
Preparation of (R)-2-nitro-7-[4-(4-trifluoromethanesulfonylpiperazin-1-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 380 using suitable starting materials.

Beige Needle

Melting point: 225-227° C.

Example 382
Preparation of 7-methyl-2-nitro-7-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Yellow Powder

Melting point: 216.6-218.2° C.

Example 383
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethoxybenzyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Solid

Melting point: 172-173° C.

Example 384
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethylbenzyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Solid

Melting point: 178-179° C.

Example 385
Preparation of (R)-7-{4-[4-(4-chlorobenzyl)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Colorless Solid

Melting point: 176.5-178° C.

Example 386
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethoxyphenoxymethyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Orange Solid

Melting point: 199.3-199.5° C.

Example 387
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethoxyphenyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Reddish Yellow Solid

Melting point: 206.5-207.5° C.

Example 388
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethylphenyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Yellow Solid

Melting point: 229-230° C.

Example 389
Preparation of (R)-2-nitro-7-{4-[4-(5-trifluoromethylpyridin-2-yloxy)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

White Powder

Melting point: 183.2-186.6° C.

Example 390
Preparation of (S)-2-nitro-7-(4-{4-[3-(4-trifluoromethoxyphenyl)propyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Yellow Powder

Melting point: 171-173° C.

Example 391
Preparation of 7-methyl-2-nitro-7-{4-[4-(4-trifluoromethoxybenzyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Yellow Powder

Melting point: 170.4-171.6° C.

Example 392
Preparation of (R)-2-nitro-7-{4-[1-(4-trifluoromethoxyphenyl)piperidin-4-yloxy]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Solid

Melting point: 155-157° C.

Example 393
Preparation of (R)-2-nitro-7-{4-[1-(4-trifluoromethylphenyl)piperidin-4-yloxy]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Solid

Melting point: 162.5-164° C.

Example 394
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethoxybenzyloxy)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Powder

Melting point: 180.0-180.3° C.

Example 395
Preparation of (R)-2-nitro-7-(4-{4-[3-(3-trifluoromethylphenoxy)propyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Orange Solid

Melting point: 165.5-166.5° C.

Example 396
Preparation of (R)-2-nitro-7-{4-[4-(3-trifluoromethylphenoxymethyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pink Powder

Melting point: 160.9-161.4° C.

Example 397
Preparation of (R)-2-nitro-7-(4-{4-[3-(4-trifluoromethylphenoxy)propyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Yellow Powder

Melting point: 185-186° C.

Example 398
Preparation of (R)-2-nitro-7-(4-{4-[2-(4-trifluoromethylbenzyloxy)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Solid

Melting point: 154.5-155.2° C.

Example 399
Preparation of (R)-2-nitro-7-(4-{4-[2-(4-trifluoromethoxybenzyloxy)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Orange Solid

Melting point: 147.5-148° C.

Example 400
Preparation of (R)-2-nitro-7-(4-{4-[3-(4-trifluoromethylphenyl)propyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Solid

Melting point: 178-179° C.

Example 401
Preparation of (R)-7-{4-[4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Yellow Powder

Melting point: 161-162° C.

Example 402
Preparation of 7-methyl-2-nitro-7-{4-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 178.8-178.9° C.

Example 403
Preparation of 7-methyl-2-nitro-7-{4-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 155.7-156.4° C.

Example 404
Preparation of 7-methyl-2-nitro-7-(4-{4-[(E)-3-(4-trifluoromethylphenyl)allyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 186.2-186.9° C.

Example 405
Preparation of (R)-2-nitro-7-(4-{4-[3-(5-trifluoromethylpyridin-2-yloxy)propyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Powder

Melting point: 175.0-175.8° C.

Example 406
Preparation of (R)-2-nitro-7-{6-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}pyridin-3-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Yellow Flocculent Crystal

Melting point: 194° C.

Example 407
Preparation of (R)-2-nitro-7-{4-[4-(5-trifluoromethylpyridin-2-yloxymethyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

Melting point: 199.5-199.9° C.

Example 408
Preparation of (R)-2-nitro-7-{4-[1′-(4-trifluoromethoxybenzyl)-4,4′-bipiperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

White Powder

Melting point: 209.8-215.1° C.

Example 409
Preparation of 7-methyl-2-nitro-7-(4-{4-[3-(4-trifluoromethoxyphenyl)propyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Yellow Powder

Melting point: 154.2-156.2° C.

Example 410
Preparation of (R)-2-nitro-7-{6-[4-(4-trifluoromethoxybenzyl)piperidin-1-yl]pyridin-3-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

White Powder

Melting point: 180.7° C.

Example 411
Preparation of 7-methyl-2-nitro-7-(4-{4-[(E)-3-(4-trifluoromethoxyphenyl)allyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 158.3-159.2° C.

Example 412
Preparation of (R)-2-nitro-7-(6-{4-[3-(4-trifluoromethylphenyl)propyl]piperidin-1-yl}pyridin-3-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Yellow Powder

Melting point: 171.7° C.

Example 413
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethyl-cyclohexylmethyl)piperazin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 212.5-213.2° C.

Example 414
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethyl-cyclohexylmethyl)piperazin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 3 using suitable starting materials.

Yellow Powder

Melting point: 214.4-214.8° C.

Example 415
Preparation of (R)-2-nitro-7-{4-[1′-(4-trifluoromethylbenzyl)-4,4′-bipiperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Pale Yellow Powder

Melting point: 223-225° C.

Example 416
Preparation of (R)-2-nitro-7-(4-{4-[2-(4-trifluoromethylphenyl)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Yellow Solid

Melting point: 211.3° C.

Example 417
Preparation of (R)-2-nitro-7-(6-{4-[2-(4-trifluoromethylphenyl)ethyl]piperidin-1-yl}pyridin-3-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Yellow Solid

Melting point: 211.2° C.

Example 418
Preparation of N-ethyl-N-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]-N-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]amine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Powder

Melting point: 166.4-168.1° C.

Example 419
Preparation of N-methyl-N-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]-N-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]amine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Orange Powder

Melting point: 182.1-184.2° C.

Example 420
Preparation of 4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid ethyl ester

Triethylamine (0.31 ml) was added to a methylene chloride suspension (6 ml) of (R)-2-nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.40 g). Subsequently, chloroethyl formate (0.11 ml) was added thereto dropwise under ice cooling, and the mixture was stirred for 14 hours while it gradually returned to room temperature. A 0.5 N hydrochloric acid aqueous solution was then added to the reaction mixture, followed by extraction with methylene chloride. After washing the organic layer with water and a saturated sodium chloride aqueous solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (methylene chloride:methanol=90:10) and recrystallized from acetone-water to afford the title compound as a pale yellow powder (0.36 g).

Melting point: 218° C.

Example 421
Preparation of (2-hydroxy-4-trifluoromethylphenyl)-{4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-yl}methanone

1-Hydroxybenzotriazole (0.19 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.24 g) were added to a DMF solution (5 ml) of (R)-2-nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.40 g) and 4-(trifluoromethyl)salicylic acid (0.25 g), and the mixture was stirred at room temperature for 11 hours. Water was added to the reaction mixture. After stirring the mixture for a while, the precipitate was collected by filtration. The resulting crude product was purified by silica gel column chromatography (methylene chloride:methanol=90:10) and recrystallized from ethanol-acetone to afford the title compound as a white powder (0.42 g).

Melting point: 217-220° C.

Example 422
Preparation of (R)-2-nitro-7-(6-{4-[3-(4-trifluoromethoxyphenyl)propyl]piperidin-1-yl}pyridin-3-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Solid

Melting point: 159.0-159.5° C.

Example 423
Preparation of (R)-2-nitro-7-{4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Yellow Powder

Melting point: 186.5-187.2° C.

Example 424
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Powder

Melting point: 200.5-201.5° C.

Example 425
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethoxybenzyl)-3,6-dihydro-2H-pyridin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Solid

Melting point: 164.8-165.2° C.

Example 426
Preparation of (R)-7-[4-(4-methanesulfonylpiperazin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

Triethylamine (0.31 ml) was added to a methylene chloride suspension (6 ml) of (R)-2-nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.40 g). Subsequently, methanesulfonyl chloride (0.09 ml) was added thereto dropwise under ice cooling, and the mixture was stirred for 14 hours while it gradually returned to room temperature. A 0.5 N hydrochloric acid aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=90:10) and recrystallized from methylene chloride-methanol to afford the title compound as a beige powder (0.15 g).

Melting point: 149-151° C.

Example 427
Preparation of (R)-2-nitro-7-(6-{4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidin-1-yl}pyridin-3-yloxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Yellow Powder

Melting point: 137.6-140.9° C.

Example 428
Preparation of (R)-2-nitro-7-(4-{4-[4-(5-trifluoromethylpyridin-2-yloxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

(R)-2-Nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.50 g), 4-(5-trifluoromethylpyridin-2-yloxy)benzaldehyde (0.41 g), N-methylpyrrolidone (10 ml), and sodium triacetoxyborohydride (0.44 g) were mixed and stirred at room temperature for 16 hours. The reaction mixture was added to a 1 N sodium hydroxide aqueous solution. The precipitated crystal was collected by filtration. The crude crystal was purified by silica gel column chromatography (methylene chloride:ethyl acetate=8:2→methylene chloride:ethyl acetate=2:8) and recrystallized from acetone-ether to afford the title compound as a pale yellow powder (0.55 g).

Melting point: 229-230° C.

Example 429
Preparation of (R)-2-nitro-7-{6-[4-(4-trifluoromethoxyphenoxymethyl)piperidin-1-yl]pyridin-3-yloxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Yellow Powder

Melting point: 182.9-183.3° C.

Example 430
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethoxyphenyl)piperidin-1-ylmethyl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Pale Brown Solid

Melting point: 165-167° C.

Example 431
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethoxybenzyl)piperidin-1-ylmethyl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Pale Brown Solid

Melting point: 159.5-160.5° C.

Example 432
Preparation of (R)-2-nitro-7-{4-[1-(4-trifluoromethylbenzyl)-1,2,3,6-tetrahydropyridin-4-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine hydrochloride

Sodium triacetoxyborohydride (0.631 g) was added to a mixture of (R)-2-nitro-7-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine trifluoroacetate (1.0 g), 4-(trifluoromethyl)benzaldehyde (0.41 ml) and N-methylpyrrolidone (10 ml), and the mixture was stirred at room temperature for 9 hours. A sodium hydrogen carbonate aqueous solution was added to the reaction mixture and stirred for 10 minutes. The precipitate was then collected by filtration. The residue thus obtained was purified by basic silica gel column chromatography (methylene chloride). The resulting product was dissolved in methylene chloride (30 ml), a 1 N hydrochloric acid ethanol solution (1.32 ml) was added thereto and then stirred. Thereafter, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was stirred at room temperature. The precipitate was collected by filtration, and the solid thus obtained was recrystallized using ethanol-water to afford the title compound as a slightly yellow powder (0.52 g).

Melting point: 210-213° C.

Example 433
Preparation of (R)-7-(4-{4-[3-fluoro-4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Pale Brown Solid

Melting point: 150-151° C.

Example 434
Preparation of (R)-7-(4-{4-[2-fluoro-4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Pale Brown Solid

Melting point: 157-158° C.

Example 435
Preparation of (R)-7-(4-{4-[3-methoxy-4-(4-trifluoromethoxybenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Colorless Solid

Melting point: 149.5-150° C.

Example 436
Preparation of (R)-7-{4-[4-((E)-3,7-dimethyl-octa-2,6-dienyl)piperazin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Pale Brown Solid

Melting point: 142.5-144° C.

Example 437
Preparation of (R)-7-(4-{4-[5-(4-chlorophenyl)furan-2-ylmethyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Yellow Solid

Melting point: 222-223.5° C.

Example 438
Preparation of (R)-7-[4-(4-adamantan-2-ylpiperazin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Colorless Solid

Melting point: 245.5-246.5° C.

Example 439
Preparation of 2-{4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-ylmethyl}-5-(4-trifluoromethylbenzyloxy)phenol hydrochloride

The title compound was prepared in the same manner as in Example 432 using suitable starting materials.

Pale Yellow Powder

Melting point: 192-194° C.

Example 440
Preparation of (R)-7-(4-{4-[2-methoxy-4-(4-trifluoromethylbenzyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine hydrochloride

The title compound was prepared in the same manner as in Example 432 using suitable starting materials.

Pale Yellow Powder

Melting point: 214-217° C.

Example 441
Preparation of (R)-2-nitro-7-(4-{4-[5-(4-trifluoromethylphenyl)thiophen-2-ylmethyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Pale Brown Solid

Melting point: 225-226° C.

Example 442
Preparation of (R)-2-nitro-7-(4-{4-[5-(4-trifluoromethoxyphenyl)thiophen-2-ylmethyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Pale Brown Solid

Melting point: 222-224° C.

Example 443
Preparation of (R)-2-nitro-7-(4-{4-[5-(4-trifluoromethylphenyl)furan-2-ylmethyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Pale Yellow Solid

Melting point: 235-237° C.

Example 444
Preparation of (R)-2-nitro-7-(4-{4-[5-(4-trifluoromethoxyphenyl)furan-2-ylmethyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 363 using suitable starting materials.

Pale Yellow Solid

Melting point: 148.5-149.5° C.

Example 445
Preparation of (R)-2-nitro-7-{4-[4-(5-trifluoromethylbenzofuran-2-ylmethyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Yellow Powder

Melting point: 159-161° C.

Example 446
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethylsulfanylphenoxy)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Powder

Melting point: 162.6-163.9° C.

Example 447
Preparation of (R)-2-nitro-7-(4-{1-[4-(4-trifluoromethylbenzyloxy)benzyl]-1,2,3,6-tetrahydropyridin-4-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine hydrochloride

Sodium triacetoxyborohydride (0.63 g) was added to a mixture of (R)-2-nitro-7-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine trifluoroacetate (1.0 g), 4-(4-trifluoromethylbenzyloxy)benzaldehyde (0.72 g) and N-methylpyrrolidone (10 ml), and the mixture was stirred at room temperature for 11 hours. A sodium hydrogen carbonate aqueous solution was added to the reaction mixture and stirred for 10 minutes. The precipitate was collected by filtration. The residue thus obtained was purified by basic silica gel column chromatography (methylene chloride). The resulting product was dissolved in methylene chloride (30 ml), a 4 N hydrochloric acid ethyl acetate solution (0.49 ml) was added thereto, and the mixture was stirred for a while. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The mixture was stirred for 20 minutes and then crystal was collected by filtration. The solid obtained was recrystallized from ethanol-water to afford the title compound as a yellow powder (0.58 g).

Melting point: 212-214° C.

Example 448
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethylbenzylsulfanyl)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine hydrochloride

The title compound was prepared in the same manner as in Example 447 using suitable starting materials.

Slightly Yellow Powder

Melting point: 181-184° C.

Example 449
Preparation of N-methyl-N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-(4-trifluoromethoxybenzyl)amine

The title compound was prepared in the same manner as in Example 180 using suitable starting materials.

Colorless Solid

Melting point: 173-174° C.

Example 450
Preparation of N-methyl-N-(2-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-ethyl)-N-(4-trifluoromethoxyphenyl)amine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Yellow Solid

Melting point: 166.5-167° C.

Example 451
Preparation of N-methyl-N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-ylmethyl}-N-(4-trifluoromethoxybenzyl)amine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Yellow Solid

Melting point: 181.5-182.5° C.

Example 452
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethylsulfanylbenzyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Yellow Powder

Melting point: 191.4-192.6° C.

Example 453
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethylphenylmethanesulfonyl)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine hydrochloride

The title compound was prepared in the same manner as in Example 447 using suitable starting materials.

Slightly Yellow Powder

Melting point: 222-225° C.

Example 454
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethylphenylmethanesulfinyl)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine hydrochloride

The title compound was prepared in the same manner as in Example 447 using suitable starting materials.

Beige Powder

Melting point: 205-208° C.

Example 455
Preparation of (R)-2-nitro-7-{4-[4-(5-trifluoromethylbenzofuran-2-ylmethoxy)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 445 using suitable starting materials.

Pale Yellow Powder

Melting point: 156-158° C.

Example 456
Preparation of (R)-2-nitro-7-{4-[4-(4-trifluoromethoxyphenylsulfanyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 445 using suitable starting materials.

White Powder

Melting point: 161-162° C.

Example 457
Preparation of (R)-2-nitro-7-(4-{4-[2-(4-trifluoromethoxyphenylsulfanyl)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 445 using suitable starting materials.

White Powder

Melting point: 166.7-167.3° C.

Example 458
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethylbenzyloxy)benzyl]-3,6-dihydro-2H-pyridin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 445 using suitable starting materials.

Yellow Powder

Melting point: 183-184° C.

Example 459
Preparation of 1′-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]-[1,4′]piperidinyl-4-01

4-(tert-Butyldimethylsilanyloxy)-1′-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl][1,4′]bipiperidinyl (190 mg) was dissolved in tetrahydrofuran (5 ml). While being stirred at room temperature, 1 M tetra butyl ammonium fluoride (1.11 ml) was added thereto, followed by stirring at 50° C. for 5 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=100:0→methylene chloride:methanol=80:20) and recrystallized from methanol-isopropyl ether to afford the title compound as a yellow solid (40 mg).

Melting point: 234.5-235° C.

Example 460
Preparation of 2-methoxy-4-((E)-3-{4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-yl}propenyl)phenol

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Pale Brown Solid

Melting point: 109-111° C.

Example 461
Preparation of 1-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-ylmethyl}piperidin-4-ol

The title compound was prepared in the same manner as in Example 459 using suitable starting materials.

Colorless Solid

Melting point: 189-190.5° C.

Example 462
Preparation of 1-(4-chlorophenoxy)-3-{4-[4-NR)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-yl}propan-2-ol

(R)-2-Nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (250 mg), 2-(4-chlorophenoxymethyl)oxirane (154 mg) and N-methylpyrrolidone (7 ml) were mixed and stirred at 100° C. for 21 hours. The mixture was cooled to room temperature and water (23 ml) was added thereto, followed by stirring for 5 minutes. The precipitated crystal was collected by filtration and dried at 60° C. The residue thus obtained was purified by silica gel column chromatography (methylene chloride:methanol=100:0→methylene chloride:methanol=97:3) and recrystallized from 1,2-dichloroethane-methanol-ethyl acetate to afford the title compound as a colorless solid (204 mg).

Melting point: 203-205° C.

Example 463
Preparation of 1-{4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-yl}-3-(4-trifluoromethoxyphenoxy)propan-2-ol

The title compound was prepared in the same manner as in Example 462 using suitable starting materials.

Yellow Solid

Melting point: 184.5-185° C.

Example 464
Preparation of (R)-7-{4-[4-(3,4-dichlorobenzyl)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 445 using suitable starting materials.

Pale Yellow Powder

Melting point: 190-192° C.

Example 465
Preparation of (R)-7-(4-{4-[4-((E)-3,7-dimethylocta-2,6-dienyloxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Yellow Solid

Melting point: 145-146.5° C.

Example 466
Preparation of (R)-7-[4-(4-[(E)-3-[4-((E)-3,7-dimethylocta-2,6-dienyloxy)phenyl]allyl]piperazin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Yellow Solid

Melting point: 154-155° C.

Example 467
Preparation of 1′-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)benzyl]-[1,4′]bipiperidinyl-4-ol

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Colorless Solid

Melting point: 164-165° C.

Example 468
Preparation of 1-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)benzyl]piperidin-4-ylmethyl}piperidin-4-ol

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Colorless Solid

Melting point: 174-175° C.

Example 469
Preparation of (R)-7-{4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 445 using suitable starting materials.

Pale Yellow Powder

Melting point: 180-181° C.

Example 470
Preparation of 1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]-4-(4-trifluoromethylphenyl)piperidin-4-ol

A mixture of toluene-4-sulfonic acid (R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester (1.16 g), 1-(4-hydroxyphenyl)-4-(4-trifluoromethylphenyl)piperidin-4-ol (1.0 g), tripotassium phosphate (2.52 g) in ethanol (10 ml) was stirred at 60° C. for 15 hours under an argon atmosphere. The reaction mixture was added to an ammonium chloride aqueous solution, and the mixture was stirred for a while. The precipitated crude crystal was collected by filtration and dried at 60° C. The crude product thus obtained was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:1) and recrystallized from acetone-water to afford the title compound as a beige powder (0.63 g).

Melting point: 201-202° C.

Example 471
Preparation of (R)-7-{4-[4-methoxy-4-(4-trifluoromethylphenyl)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 470 using suitable starting materials.

Slightly Yellow Powder

Melting point: 168-169° C.

Example 472
Preparation of (R)-7-{4-[4-methoxy-4-(4-trifluoromethoxyphenyl)piperidin-1-yl]phenoxymethyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 470 using suitable starting materials.

Pale Yellow Powder

Melting point: 160-161° C.

Example 473
Preparation of 1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]-4-(4-trifluoromethoxyphenyl)piperidin-4-ol

The title compound was prepared in the same manner as in Example 470 using suitable starting materials.

Beige Powder

Melting point: 204-206° C.

Example 474
Preparation of (R)-2-nitro-7-(4-{4-[4-(4-trifluoromethoxyphenoxy)phenoxy]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 470 using suitable starting materials.

Pale Brown Powder

Melting point: 140-142° C.

Example 475
Preparation of (S)-2-nitro-7-{4-[4-(4-trifluoromethoxybenzyl)piperidin-1-yl]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 470 using suitable starting materials.

Pale Yellow Powder

Melting point: 171-172° C.

Example 476
Preparation of (R)-2-nitro-7-{4-[1-(4-trifluoromethoxybenzyl)piperidin-4-ylmethoxy]phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Pale Brown Solid

Melting point: 149.5-150° C.

Example 477
Preparation of (R)-2-nitro-7-(4-{2-[1-(4-trifluoromethoxybenzyl)piperidin-4-yl]-ethoxy}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Pale Brown Solid

Melting point: 132-133° C.

Example 478
Preparation of (R)-2-nitro-7-(4-{(E)-3-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]propenyl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Pale Brown Solid

Melting point: 163-164° C.

Example 479
Preparation of (R)-7-(4-{4-[4-(furan-2-ylmethoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Colorless Solid

Melting point: 190-192° C.

Example 480
Preparation of (R)-2-nitro-7-(4-{4-[4-(pyridin-2-ylmethoxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Colorless Solid

Melting point: 213-214° C.

Example 481
Preparation of (R)-2-nitro-7-(4-{4-[4-(thiophen-2-ylmethoxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Colorless Solid

Melting point: 208-209.5° C.

Example 482
Preparation of (R)-2-nitro-7-[4-(4-{1-[4-(4-trifluoromethylbenzyloxy)phenyl]-ethyl]piperazin-1-yl)phenoxymethyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

(R)-2-Nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.56 g) was added to an N-methylpyrrolidone solution (5 ml) of 1-(1-chloroethyl)-4-(4-trifluoromethylbenzyloxy)benzene (0.54 g). Subsequently, diisopropylethylamine (0.54 ml) was added thereto, and the mixture was stirred at room temperature for 12 hours. Thereafter, the mixture was heated to 60° C. and stirred for 7 hours. Water was added to the reaction mixture and the precipitated solid was collected by filtration. The solid thus obtained was purified by basic silica gel column chromatography (methylene chloride) and recrystallized from acetone-water to afford the title compound as a slightly yellow powder (0.15 g).

Melting point: 190-191° C.

Example 483
Preparation of (R)-2-nitro-7-(4-{4-[4-(pyridin-4-ylmethoxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Colorless Solid

Melting point: 186-187° C.

Example 484
Preparation of (R)-7-(4-{4-[4-(3,5-dimethyl-isoxazol-4-ylmethoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Colorless Solid

Melting point: 122-123.5° C.

Example 485
Preparation of (R)-2-nitro-7-(4-{4-[4-(6-trifluoromethylpyridin-3-ylmethoxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Colorless Solid

Melting point: 191-192° C.

Example 486
Preparation of (R)-2-nitro-7-(4-{4-[4-(pyrazin-2-ylmethoxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Yellow Solid

Melting point: 233-233.5° C.

Example 487
Preparation of (R)-7-(4-{4-[4-(3-methyl-[1,2,4]oxadiazol-5-ylmethoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Colorless Solid

Melting point: 194-195° C.

Example 488
Preparation of (R)-7-(4-{4-[4-(2-methyl-thiazol-4-ylmethoxy)benzyl]piperazin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Colorless Solid

Melting point: 186.5-187° C.

Example 489
Preparation of (R)-2-nitro-7-(4-{4-[4-(pyridin-3-ylmethoxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 428 using suitable starting materials.

Colorless Solid

Melting point: 212.5-213° C.

Example 490
Preparation of (R)-7-[4-(4-{1-methyl-1-[4-(4-trifluoromethylbenzyloxy)phenyl]ethyl}piperazin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 470 using suitable starting materials.

Slightly Yellow Powder

Melting point: 186-187° C.

Example 491
Preparation of (S)-2-nitro-7-(4-{4-[4-(4-trifluoromethylphenoxy)benzyl]piperazin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

4-[4-((S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (300 mg) was suspended in methylene chloride (2 ml). Trifluoroacetic acid (2 ml) was added to the suspension, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Methylene chloride (2 ml) and triethylamine (0.83 ml) were added to the residue and stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure and then dissolved in DMF (2 ml). Potassium carbonate (123 mg) was added thereto and 1-(bromomethyl)-4-(4-trifluoromethylphenoxy)benzene (197 mg) was further added under ice cooling, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The crude product thus obtained was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:0→methylene chloride:ethyl acetate=2:3→methylene chloride:methanol=10:1) and recrystallized from acetone-water to afford the title compound as a pale yellow solid (197 mg).

Melting point: 182.2-185.4° C.

Example 492
Preparation of (S)-2-nitro-7-(4-{4-[4-(4-trifluoromethylphenoxy)benzyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 470 using suitable starting materials.

Yellow Solid

Melting point: 198.0-199.3° C.

Example 493
Preparation of 4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)benzyl]piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

1H NMR (CDCl3) δ 1.06-1.17 (m, 2H), 1.46 (s, 9H), 1.55-1.66 (m, 3H), 2.32-2.42 (m, 1H), 2.46-2.52 (m, 3H), 2.54-2.71 (m, 2H), 3.97-4.24 (m, 5H), 4.28-4.33 (m, 1H), 4.72-4.78 (m, 1H), 6.83 (d, J=8.5 Hz, 2H), 7.06 (d, J=8.5 Hz, 2H), 7.46 (s, 1H).

Example 494
Preparation of 4-{2-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]ethyl}piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

1H NMR (CDCl3) δ 1.05-1.34 (m, 4H), 1.47 (s, 9H), 1.52-1.60 (m, 3H), 2.29-2.37 (m, 1H), 2.44-2.55 (m, 3H), 2.42-2.65 (m, 2H), 3.95-4.20 (m, 5H), 4.25-4.30 (m, 1H), 4.72-4.79 (m, 1H), 6.81 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 7.45 (s, 1H).

Example 495
Preparation of 4-[6-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)quinolin-2-yl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Orange Powder

1H NMR (CDCl3) δ 2.02 (s, 9H), 2.37-2.40 (m, 1H), 2.47-2.50 (m, 1H), 3.66 (br, 4H), 3.68 (br, 4H), 4.12-4.15 (m, 1H), 4.18-4.21 (m, 1H), 4.24-4.27 (m, 1H), 4.34-4.37 (m, 1H), 4.79 (br, 1H), 6.95-6.98 (m, 2H), 7.18-7.20 (m, 1H), 7.43 (s, 1H), 7.64 (d, J=9.1 Hz, 1H), 7.82 (d, J=9.1 Hz, 1H).

Example 496
Preparation of 4-[6-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)benzothiazol-2-yl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

White Powder

1H NMR (CDCl3) δ 1.49 (s, 9H), 2.38-2.40 (m, 1H), 2.48-2.51 (m, 1H), 3.58 (br, 8H), 4.11-4.17 (m, 1H), 4.20-4.24 (m, 2H), 4.32-4.35 (m, 1H), 4.75-4.77 (m, 1H), 6.90-6.92 (m, 1H), 7.18 (d, J=2.5 Hz, 1H), 7.45-7.48 (m, 2H).

Example 497
Preparation of (R)-7-[4-(4,4-dimethoxypiperidin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Yellow Solid

1H NMR (CDCl3) δ 1.90 (t, 4H), 2.17-2.48 (m, 2H), 3.12 (t, J=5.9 Hz, 4H), 3.23 (s, 6H), 4.05-4.18 (m, 3H), 4.18-4.32 (dd, J=10 Hz, 4.2 Hz, 1H), 4.70-4.76 (m, 1H), 6.80-6.95 (m, 4H), 7.45 (s, 1H).

Example 498
Preparation of 1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-one

(R)-7-[4-(4,4-Dimethoxypiperidin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (5.16 g), acetone (100 ml) and water (17 ml) were mixed. A 6 N hydrochloric acid aqueous solution (41 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The remaining water layer was ice-cooled and neutralized by adding a 20% sodium carbonate aqueous solution. After being stirred at the same temperature for 10 minutes, the precipitated crystal was collected by filtration. The crystal thus obtained was dried at 60° C. to afford the title compound as a yellow solid (4.57 g).

1H NMR (CDCl3) δ 2.20 (m, 6H), 3.48 (t, J=5.9 Hz, 4H), 4.05-4.32 (m, 4H), 4.70-4.80 (m, 1H), 6.87 (d, J=9.2 Hz, 2H), 6.96 (d, J=9.1 Hz, 2H), 7.45 (s, 1H).

Example 499
Preparation of {4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-yl}carbamic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Yellow Powder

1H NMR (CDCl3) δ 1.47 (s, 9H), 2.33-2.47 (m, 2H), 2.93-2.97 (m, 4H), 3.18-3.22 (m, 4H), 4.10-4.25 (m, 3H), 4.25-4.35 (dd, J=10 Hz, 4.3 Hz, 1H), 4.65-4.80 (m, 1H), 5.46 (br s, 1H), 6.78-6.92 (m, 4H), 7.45 (s, 1H).

Example 500
Preparation of 4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenoxy]piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

1H NMR (CDCl3) δ 1.46 (s, 9H), 1.65-1.77 (m, 2H), 1.86-1.93 (m, 2H), 2.35-2.54 (m, 2H), 3.29-3.41 (m, 2H), 3.68-3.80 (m, 2H), 4.10-4.38 (m, 5H), 4.74-4.80 (m, 1H), 6.81-6.90 (m, 4H), 7.46 (s, 1H).

Example 501
Preparation of 4-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenoxy]piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

White Powder

1H NMR (CDCl3) δ 1.47 (s, 9H), 1.64-1.77 (m, 2H), 1.83-1.95 (m, 2H), 2.32-2.52 (m, 2H), 3.25-3.37 (m, 2H), 3.65-3.78 (m, 2H), 4.12-4.38 (m, 5H), 4.71-4.78 (m, 1H), 6.80-6.88 (m, 4H), 7.45 (s, 1H).

Example 502
Preparation of 4-[5-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)benzooxazol-2-yl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Yellow Powder

1H NMR (CDCl3) δ 1.49 (s, 9H), 2.38-2.41 (m, 1H), 2.48-2.52 (m, 1H), 3.55-3.57 (m, 4H), 3.65-3.66 (m, 4H), 4.10-4.16 (m, 1H), 4.19-4.22 (m, 2H), 4.30-4.33 (m, 1H), 4.75-4.77 (m, 1H), 6.59-6.61 (m, 1H), 6.91-6.92 (d, J=2.5 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 7.46 (s, 1H).

Example 503
Preparation of 4-[5-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)benzooxazol-2-yl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Yellow Powder

1H NMR (CDCl3) δ 1.49 (s, 9H), 2.38-2.41 (m, 1H), 2.48-2.49 (m, 1H), 3.55-3.57 (m, 4H), 3.65-3.67 (m, 4H), 4.10-4.16 (m, 1H), 4.20-4.23 (m, 2H), 4.30-4.33 (m, 1H), 4.75-4.77 (m, 1H), 6.59-6.61 (m, 1H), 6.91-6.92 (d, J=2.5 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 7.46 (s, 1H).

Example 504
Preparation of (S)-7-[4-(4,4-dimethoxypiperidin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

1H NMR (CDCl3) δ 1.89-1.91 (m, 4H), 2.34-2.38 (m, 1H), 2.46-2.49 (m, 1H), 3.10-3.13 (m, 4H), 3.23 (s, 6H), 4.10-4.22 (m, 3H), 4.26-4.29 (m, 1H), 4.71-4.74 (m, 1H), 6.82-6.84 (m, 2H), 6.89-6.92 (m, 2H), 7.45 (s, 1H).

Example 505
Preparation of 1-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-one

The title compound was prepared in the same manner as in Example 498 using suitable starting materials.

Pale Yellow Powder

1H NMR (DMSO-d6) δ 2.42 (m, 1H), 2.43 (m, 1H), 2.50-2.51 (m, 4H), 3.37-3.46 (m, 5H), 4.10-4.11 (m, 1H), 4.17-4.25 (m, 2H), 4.86-4.88 (m, 1H), 6.90-6.92 (m, 2H), 7.00-7.02 (m, 2H), 8.09 (s, 1H).

Example 506
Preparation of 5-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-1,3-dihydroisoindole-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

1H NMR (CDCl3) δ 1.52 (s, 9H), 2.37-2.41 (m, 1H), 2.48-2.50 (m, 1H), 4.11-4.17 (m, 1H), 4.20-4.24 (m, 2H), 4.30-4.33 (m, 1H), 4.59-4.66 (m, 4H), 4.75-4.77 (m, 1H), 6.77-6.84 (m, 2H), 7.13-7.19 (m, 1H), 7.46 (s, 1H).

Example 507
Preparation of 5-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-1,3-dihydroisoindole-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Yellow Powder

1H NMR (CDCl3) δ 1.52 (s, 9H), 2.37-2.42 (m, 1H), 2.48-2.50 (m, 1H), 4.11-4.17 (m, 1H), 4.19-4.24 (m, 2H), 4.30-4.34 (m, 1H), 4.59-4.66 (m, 4H), 4.74-4.78 (m, 1H), 6.77-6.84 (m, 2H), 7.13-7.19 (m, 1H), 7.46 (s, 1H).

Example 508
Preparation of 7-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

1H NMR (CDCl3) δ 1.49 (s, 9H), 2.36-2.39 (m, 1H), 2.46-2.49 (m, 1H), 2.77 (br, 2H), 3.63 (br, 2H), 4.10-4.23 (m, 3H), 4.28-4.31 (m, 1H), 4.54 (s, 2H), 4.74-4.75 (m, 1H), 6.65 (m, 1H), 6.73-6.75 (m, 1H), 7.05-7.07 (m, 1H), 7.46 (s, 1H).

Example 509
Preparation of 7-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Yellow Powder

1H NMR (CDCl3) δ 1.49 (s, 9H), 2.36-2.39 (m, 1H), 2.46-2.49 (m, 1H), 2.77 (br, 2H), 3.62 (br, 2H), 4.10-4.23 (m, 3H), 4.28-4.31 (m, 1H), 4.53 (s, 2H), 4.73-4.76 (m, 1H), 6.65 (d, J=2.3 Hz, 1H), 6.73-6.75 (m, 1H), 7.05-7.07 (m, 1H), 7.46 (s, 1H).

Example 510
Preparation of 7-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-1,3,4,5-tetrahydrobenzo[c]azepine-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

White Powder

1H NMR (CDCl3) δ 1.39 (s, 9H), 1.76-1.77 (m, 2H), 2.37 (m, 1H), 2.47 (m, 1H), 2.89 (m, 2H), 3.64-3.68 (m, 2H), 4.11-4.22 (m, 3H), 4.30-4.37 (m, 3H), 4.74 (m, 1H), 6.64-6.71 (m, 2H), 7.10-7.11 (m, 1H), 7.45 (s, 1H).

Example 511
Preparation of 6-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

White Powder

1H NMR (CDCl3) δ 1.49 (s, 9H), 2.36-2.39 (m, 1H), 2.46-2.49 (m, 1H), 2.79-2.81 (m, 2H), 3.62 (m, 2H), 4.10-4.22 (m, 3H), 4.29-4.32 (m, 1H), 4.51 (s, 2H), 4.73-4.75 (m, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.74-6.76 (m, 1H), 7.02-7.05 (m, 1H), 7.45 (s, 1H).

Example 512
Preparation of 6-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Pale Yellow Powder

Example 513
Preparation of 7-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)-1,3,4,5-tetrahydrobenzo[c]azepine-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Yellow Powder

Example 514
Preparation of (2R,5S)-2,5-dimethyl-4-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Yellow Powder

1H NMR (CDCl3) δ 0.96 (d, J=6.5 Hz, 3H), 1.26 (d, J=6.8 Hz, 3H), 1.48 (s, 9H), 2.34-2.42 (m, 1H), 2.42-2.53 (m, 1H), 2.94 (m, 1H), 3.22-3.25 (m, 1H), 3.41-3.45 (m, 1H), 3.77-3.85 (m, 2H), 4.11-4.25 (m, 3H), 4.26-4.29 (m, 1H), 4.43 (br, 1H), 4.73 (m, 1H), 6.79-6.84 (m, 4H), 7.44 (s, 1H).

Example 515
Preparation of (2R,5S)-2,5-dimethyl-4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Yellow Powder

Example 516
Preparation of 4-[5-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Brown Solid

1H NMR (CDCl3) δ 1.48 (s, 9H), 2.42-2.44 (m, 2H), 3.39-3.43 (m, 4H), 3.51-3.57 (m, 4H), 4.12-4.27 (m, 4H), 4.65-4.78 (m, 1H), 6.64 (d, J=9.0 Hz, 1H), 7.19 (dd, J=10.0 Hz, 3.3 Hz, 1H), 7.45 (s, 1H), 7.94 (d, J=3.0 Hz, 1H).

Example 517
Preparation of 4-[5-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Brown Solid

1H NMR (CDCl3) δ 1.48 (s, 9H), 2.28-2.50 (m, 2H), 3.36-3.47 (m, 4H), 3.47-3.58 (m, 4H), 4.12-4.27 (m, 4H), 4.65-4.78 (m, 1H), 6.64 (d, J=9.0 Hz, 1H), 7.19 (dd, J=10.0 Hz, 3.3 Hz, 1H), 7.45 (s, 1H), 7.94 (d, J=3.0 Hz, 1H).

Example 518
Preparation of (R)-7-[4-((2S,5R)-2,5-dimethyl-piperazin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine trifluoroacetate

Trifluoroacetic acid (4 ml) was added to a dichloromethane solution (4 ml) of (2R,5S)-2,5-dimethyl-4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (1.31 g), and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure to afford the title compound as a brown amorphous compound (1.35 g).

1H NMR (DMSO-d6) δ 0.84 (d, J=10.2 Hz, 3H), 1.21 (d, J=10.6 Hz, 3H), 2.15-2.40 (m, 2H), 2.71-2.85 (m, 2H), 3.08-3.26 (m, 2H), 3.36-3.40 (m, 2H), 4.11-4.33 (m, 4H), 4.88-4.91 (m, 1H), 6.96-6.99 (d, J=14.8 Hz, 2H), 7.08-7.11 (d, J=14.8 Hz, 2H), 8.10 (s, 1H), 8.89 (br, 1H), 9.21 (br, 1H).

Example 519
Preparation of 5-[4-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 69 using suitable starting materials.

Powder

1H NMR (CDCl3) δ 1.40-1.44 (br, 9H), 1.83-2.08 (m, 2H), 2.32-2.48 (m, 2H), 3.01-3.22 (m, 1H), 3.32-3.65 (m, 3H), 4.07-4.36 (m, 5H), 4.31-4.46 (m, 1H), 4.60 (br, 1H), 6.47-6.50 (m, 2H), 6.82-6.85 (m, 2H), 7.44 (s, 1H).

Example 520
Preparation of 4-[4′-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)biphenyl-4-yl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Solid

1H NMR (DMSO-d6) δ 1.43 (s, 9H), 2.13-2.42 (m, 2H), 3.1-3.15 (t, J=4.9 Hz, 4H), 3.40-3.55 (t, J=5.4 Hz, 4H), 4.04-4.40 (m, 4H), 4.88-4.96 (m, 1H), 7.01 (d, J=8.4 Hz, 2H), 7.04 (J=8.5 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 8.11 (s, 1H).

Example 521
Preparation of 4-[4′-((S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)biphenyl-4-yl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Pale Yellow Solid

Example 522
Preparation of (S)-7-[4-(2,5-diazabicyclo[2.2.1]hept-2-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine trifluoroacetate

The title compound was prepared in the same manner as in Example 518 using suitable starting materials.

Brown Amorphous

1H NMR (DMSO-d6) δ 1.87-1.90 (m, 1H), 2.11-2.29 (m, 3H), 3.13-3.18 (m, 3H), 3.57-3.60 (m, 1H), 4.09-4.21 (m, 4H), 4.41-4.53 (m, 2H), 4.80-4.91 (m, 1H), 6.61-6.64 (d, J=15.0 Hz, 2H), 6.90-6.93 (d, J=15.0 Hz, 2H), 8.10 (s, 1H), 8.52 (br, 1H), 8.96 (br, 1H).

Example 523
Preparation of 5-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 132 using suitable starting materials.

Pale Yellow Powder

1H NMR (CDCl3) δ 1.40-1.44 (br, 9H), 1.83-2.06 (m, 2H), 2.33-2.48 (m, 2H), 3.02-3.22 (m, 1H), 3.32-3.52 (m, 2H), 3.54-3.60 (m, 1H), 4.08-4.31 (m, 5H), 4.46-4.61 (m, 1H), 4.70-4.73 (m, 1H), 6.48-6.50 (m, 2H), 6.82-6.85 (m, 2H), 7.44 (s, 1H).

Example 524
Preparation of (R)-7-[4-(2,5-diazabicyclo[2.2.1]hept-2-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 518 using suitable starting materials.

Brown Amorphous

1H NMR (DMSO-d6) δ 1.64-2.40 (m, 4H), 2.83-4.40 (m, 11H), 4.84 (m, 1H), 6.51-6.53 (d, J=14.8 Hz, 2H), 6.84-6.87 (d, J=14.9 Hz, 2H), 8.09 (s, 1H).

Example 525
Preparation of 4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Reddish Brown Solid

1H NMR (CDCl3) δ 1.48 (s, 9H), 1.51-1.64 (m, 3H), 1.78 (d, J=12.6 Hz, 2H), 2.32-2.42 (m, 1H), 2.44-2.52 (m, 1H), 2.55-2.63 (m, 1H), 2.79 (br s, 2H), 4.10-4.35 (m, 5H), 4.70-4.79 (m, 1H), 6.86 (d, J=8.7 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H), 7.45 (s, 1H).

Example 526
Preparation of (R)-7-[4-(4,4-diethoxypiperidin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Yellow Powder

1H NMR (CDCl3) δ 1.20 (t, J=7.1 Hz, 6H), 1.89-1.95 (m, 4H), 2.31-2.41 (m, 1H), 2.45-2.52 (m, 1H), 3.08-3.17 (m, 4H), 3.51 (q, J=7.1 Hz, 4H), 4.07-4.24 (m, 3H), 4.28 (dd, J=10.1 Hz, 4.2 Hz, 1H), 4.71-4.76 (m, 1H), 6.81-6.85 (m, 2H), 6.88-6.93 (m, 2H), 7.44 (s, 1H).

Example 527
Preparation of (R)-2-nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

A 4 N hydrochloric acid 1,4-dioxane solution (22 ml) was gradually added to a methylene chloride (22 ml) suspension of 4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (4.51 g), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and the precipitate was collected by filtration. The solid thus obtained was subjected to triturate with ethanol, collected by filtration and then dried. Hydrochloride of the title product was dissolved in water and neutralized using a 5 N sodium hydroxide aqueous solution under ice cooling, followed by stirring. The precipitate was collected by filtration and dried at 60° C. to afford the title compound as a yellow powder (3.0 g).

1H NMR (CDCl3) δ 2.31-2.42 (m, 1H), 2.44-2.53 (m, 1H), 3.01-3.08 (m, 8H), 4.08-4.23 (m, 3H), 4.29 (dd, J=10.2 Hz, 4.2 Hz, 1H), 4.69-4.75 (m, 1H), 6.83-6.87 (m, 2H), 6.87-6.91 (m, 2H), 7.45 (s, 1H).

Example 528
Preparation of (R)-2-nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine trifluoroacetate

The title compound was prepared in the same manner as in Example 518 using suitable starting materials.

Pale Brown Powder

1H NMR (DMSO-d6) δ 2.13-2.24 (m, 1H), 2.26-2.34 (m, 1H), 3.16-3.29 (m, 8H), 4.10 (dt, J=5.1 Hz, 12.4 Hz, 1H), 4.14-4.22 (m, 2H), 4.25 (dd, J=11.1 Hz, 3.3 Hz, 1H), 4.84-4.90 (m, 1H), 6.91-6.95 (m, 2H), 6.95-6.99 (m, 2H), 8.10 (s, 1H), 8.77 (brs, 2H).

Example 529
Preparation of 1′-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]-[4,4′]bipiperidinyl-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

Pale Yellow Powder

1H NMR (CDCl3) δ 1.10-1.33 (m, 4H), 1.35-1.45 (m, 2H), 1.46 (s, 9H), 1.65-1.75 (m, 2H), 1.77-1.85 (m, 2H), 2.25-2.48 (m, 2H), 2.49-2.77 (m, 4H), 3.51-3.59 (m, 2H), 4.05-4.23 (m, 5H), 4.24-4.29 (m, 1H), 4.71-4.77 (m, 1H), 6.81-6.85 (m, 2H), 6.88-6.92 (m, 2H), 7.44 (s, 1H).

Example 530
Preparation of 4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 86 using suitable starting materials.

White Powder

1H NMR (CDCl3) δ 1.49 (s, 9H), 2.34-2.44 (m, 1H), 2.44-2.53 (m, 3H), 3.61-3.67 (m, 2H), 4.03-4.09 (m, 2H), 4.09-4.18 (m, 1H), 4.18-4.26 (m, 2H), 4.33 (dd, J=10.2 Hz, 4.2 Hz, 1H), 4.72-4.80 (m, 1H), 5.91-6.02 (m, 1H), 6.85-6.92 (m, 2H), 7.32 (d, J=8.8 Hz, 2H), 7.46 (s, 1H).

Example 531
Preparation of (R)-2-nitro-7-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine trifluoroacetate

The title compound was prepared in the same manner as in Example 518 using suitable starting materials.

Pale Green Powder

1H NMR (DMSO-d6) δ 2.14-2.26 (m, 1H), 2.28-2.38 (m, 1H), 2.61-2.69 (m, 2H), 3.27-3.39 (m, 2H), 3.71-3.78 (m, 2H), 4.10 (dt, J=5.2 Hz, 12.4 Hz, 1H), 4.15-4.22 (m, 1H), 4.28 (dd, J=11.1 Hz, 5.8 Hz, 1H), 4.34 (dd, J=11.1 Hz, 3.2 Hz, 1H), 4.88-4.95 (m, 1H), 6.09-6.13 (m, 1H), 7.01 (d, J=8.9 Hz, 2H), 7.45 (d, J=8.9 Hz, 2H), 8.11 (s, 1H), 8.80 (brs, 2H).

Example 532
Preparation of 4-(tert-butyldimethylsilanyloxy)-1′-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]-[1,4′]piperidinyl

The title compound was prepared in the same manner as in Example 1 using suitable starting materials.

Yellow Powder

1H NMR (CDCl3) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.53-1.96 (m, 7H), 2.31-2.53 (m, 6H), 2.64 (t, J=10.6 Hz, 2H), 2.82 (br s, 2H), 3.59 (d, J=12.1 Hz, 2H), 3.72 (br s, 1H), 4.05-4.22 (m, 3H), 4.22-4.30 (dd, J=10.0 Hz, 4.3 Hz, 1H), 4.68-4.77 (m, 1H), 6.82 (d, J=9.1 Hz, 2H), 6.89 (d, J=9.1 Hz, 2H), 7.45 (s, 1H).

Example 533
Preparation of (R)-7-(4-{4-[4-(tert-butyldimethylsilanyloxy)piperidin-1-ylmethyl]piperidin-1-yl}phenoxymethyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 470 using suitable starting materials.

Reddish Yellow Powder

1H NMR (CDCl3) δ 0.05 (s, 6H), 0.89 (s, 9H), 1.25-1.38 (m, 2H), 1.50-1.65 (m, 3H), 1.73 (br s, 2H), 1.85 (d, J=12.4 Hz, 2H), 2.05-2.25 (m, 4H), 2.28-2.40 (m, 1H), 2.40-2.50 (m, 1H), 2.50-2.70 (m, 4H), 3.52 (d, J=12.0 Hz, 2H), 3.63-3.72 (m, 1H), 4.04-4.21 (m, 3H), 4.21-4.30 (dd, J=10.3 Hz, 4.3 Hz, 1H), 4.65-4.75 (m, 1H), 6.76-6.85 (m, 2H), 6.85-6.94 (m, 2H), 7.44 (s, 1H).

Example 534
Preparation of 4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenoxymethyl]piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 470 using suitable starting materials.

Yellow Solid

1H NMR (CDCl3) δ 1.18-1.30 (m, 2H), 1.46 (s, 9H), 1.81 (d, J=13.1 Hz, 2H), 1.93 (br s, 1H), 2.33-2.44 (m, 1H), 2.44-2.53 (m, 1H), 2.74 (br s, 2H), 3.75 (d, J=6.4 Hz, 2H), 4.06-4.30 (m, 5H), 4.68-4.76 (m, 1H), 6.78-6.87 (m, 4H), 7.45 (s, 1H).

Example 535
Preparation of 4-{2-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenoxy]ethyl}piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 470 using suitable starting materials.

Yellow Solid

1H NMR (CDCl3) δ 1.10-1.21 (m, 2H), 1.46 (s, 9H), 1.64-1.75 (m, 6H), 2.30-2.41 (m, 1H), 2.41-2.53 (m, 1H), 2.70 (br s, 2H), 3.96 (t, J=5.9 Hz, 2H), 4.01-4.24 (m, 4H), 4.24-4.31 (dd, J=10.2 Hz, 4.2 Hz, 1H), 4.68-4.76 (m, 1H), 6.76-6.85 (m, 4H), 7.45 (s, 1H).

Example 536
Preparation of (R)-2-nitro-7-[4-(piperidin-4-ylmethoxy)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 518 using suitable starting materials.

Pale Brown Solid

1H NMR (CDCl3) δ 1.23-1.34 (m, 2H), 1.76-1.97 (m, 5H), 2.31-2.45 (m, 1H), 2.45-2.53 (m, 1H), 2.60-2.75 (m, 2H), 3.14 (d, J=12.1 Hz, 2H), 3.74 (d, J=6.3 Hz, 2H), 4.04-4.32 (m, 3H), 4.68-4.78 (m, 1H), 6.78-6.88 (m, 4H), 7.45 (s, 1H).

Example 537
Preparation of (R)-2-nitro-7-[4-(2-piperidin-4-yl-ethoxy)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

The title compound was prepared in the same manner as in Example 518 using suitable starting materials.

Yellow Solid

1H NMR (CDCl3) δ 1.14-1.30 (m, 2H), 1.61-1.83 (m, 5H), 2.05-2.53 (m, 3H), 2.60-2.70 (m, 2H), 3.10 (d, J=12.1 Hz, 2H), 3.95 (t, J=6.2 Hz, 2H), 4.02-4.31 (m, 4H), 4.70-4.78 (m, 1H), 6.83 (s, 4H), 7.45 (s, 1H).

Example 538
Preparation of 4-{(E)-3-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]allyl}piperazine-1-carboxylic acid tert-butyl ester

The title compound was prepared in the same manner as in Example 470 using suitable starting materials.

Yellow Solid

1H NMR (CDCl3) δ 1.46 (s, 9H), 2.28-2.52 (m, 6H), 3.15 (d, J=6.7 Hz, 2H), 3.46 (br s, 4H), 4.07-4.18 (m, 1H), 4.18-4.27 (m, 2H), 4.30-4.38 (dd, J=10.2 Hz, 4.2 Hz, 1H), 4.70-4.82 (m, 1H), 6.10-6.20 (m, 1H), 6.46 (d, J=15.8 Hz, 1H), 6.86 (d, J=8.6 Hz, 2H), 7.32 (d, J=8.6 Hz, 2H), 7.46 (s, 1H).

Example 539
Preparation of (R)-2-nitro-7-[4-((E)-3-piperazin-1-yl-propenyl)phenoxymethyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine trifluoroacetate

The title compound was prepared in the same manner as in Example 518 using suitable starting materials.

Yellow Powder

1H NMR (CDCl3) δ 2.33 (m, 2H), 2.60 (s, 1H), 3.28-3.56 (m, 4H), 3.56-3.78 (m, 4H), 4.06-4.42 (m, 4H), 4.78-4.88 (m, 2H), 6.05-6.18 (m, 1H), 6.66 (d, J=15.6 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.6 Hz, 2H), 7.62 (s, 1H).

Examples 540 to 772

The following products were prepared in the same manner as in Examples above using suitable starting materials.

TABLE 1

Example No.
R^A
R^B
R^C
R^D
R^E
MS (M + 1)

Example 540
—H
—H
—H
—H
—H
450

Example 541
—H
—H
—C₆H₅
—H
—H
526

Example 542
—H
—H
—OCH₃
—H
—H
480

Example 543
—H
—H
—H
—OCH₃
—H
480

Example 544
—H
—OCH₃
—OCH₃
—OCH₃
—H
540

Example 545
—H
—H
—OH
—H
—H
466

Example 546
—H
—H
—CH₃
—H
—H
464

Example 547
—H
—H
—CH(CH₃)₂
—H
—H
492

Example 548
—H
—H
—C(CH₃)₃
—H
—H
506

Example 549
—H
—H
—NO₂
—H
—H
495

Example 550
—H
—H
—CN
—H
—H
475

Example 551
—H
—H
—NHCOCH₃
—H
—H
507

Example 552
—H
—H
—O(CH₂)₃N(CH₃)₂
—H
—H
551

Example 553
—H
—H
—H
—H
—Cl
484

Example 554
—H
—H
—H
—Cl
—H
484

Example 555
—H
—H
—Cl
—H
—H
484

Example 556
—H
—H
—H
—H
—CF₃
518

Example 557
—H
—H
—H
—CF₃
—H
518

Example 558
—H
—H
—CH₃
—CH₃
—H
478

Example 559
—CH₃
—H
—CH₃
—CH₃
—H
492

Example 560
—H
—Cl
—H
—Cl
—Cl
554

Example 561
—H
—H
—H
—H
—OCF₃
534

Example 562
—H
—H
—CF₃
—H
—H
518

Example 563
—H
—H
—OCH₃
—OCH₃
—H
510

Example 564
—H
—H
—F
—H
—H
468

Example 565
—H
—H
—OC₆H₅
—H
—H
542

Example 566
—H
—H
—OCH₂C₆H₅
—H
—H
556

Example 567
—H
—H
—H
—OCF₃
—H
534

Example 568
—H
—H
—Cl
—Cl
—H
518

Example 569
—H
—H
—O(CH₂)₇CH₃
—H
—H
578

Example 570
—H
—H
—CO₂CH₃
—H
—H
508

Example 571
—H
—Cl
—H
—Cl
—H
518

Example 572
—H
—H
—N(CH₃)₂
—H
—H
493

TABLE 2

Example 573
—H
—H
—OCH₃
—F
—H
498

Example 574
—H
—H
—OCH₃
—CH₃
—H
494

Example 575
—H
—H
—SCH₃
—H
—H
496

Example 576
—H
—H
—OCOCH₃
—H
—H
508

Example 577
—H
—H
—O(CH₂)₃CH₃
—H
—H
506

Example 578
—H
—H
—SO₂CH₃
—H
—H
528

Example 579
—H
—H
—Cl
—CF₃
—H
552

Example 580
—H
—H
—H
—SCF₃
—H
550

Example 581
—H
—H
—Cl
—F
—H
502

Example 582
—H
—H
—CH₂CH(CH₃)₂
—H
—H
506

Example 583
—H
—H
—N(C₆H₅)₂
—H
—H
617

Example 584
—F
—F
—F
—F
—F
540

Example 585
—H
—H
—OCH₂C₆H₅
—OCH₂C₆H₅
—H
662

Example 586
—H
—H
—OCH₂CH═CH₂
—H
—H
506

Example 587
—H
—H
—OCHF₂
—H
—H
516

Example 588
—H
—H
—OCH(CH₃)₂
—H
—H
508

Example 589
—H
—H
—H
—H
—NHSO₂CH₃
543

Example 590
—H
—H
—N(C₄H₉-n)₂
—H
—H
577

Example 591
—H
—H
—OCH₂C₆H₅
—Cl
—H
590

Example 592
—H
—H
—OC(CH₃)₃
—H
—H
522

TABLE 3

Example No.
R^A
R^B
R^C
R^D
R^E
MS (M + 1)

Example 593
—H
—H
—OCH₃

embedded image

—H
564

Example 594
—H
—H

embedded image

—H
—H
519

Example 595
—H
—H

embedded image

—H
—H
517

Example 596
—H
—H

embedded image

—H
—H
516

Example 597
—H
—H

embedded image

—H
—H
533

TABLE 4

Example No.
R^A
R^B
R^C
R^D
R^E
MS (M + 1)

Example 598
—H
—H
—H
—H
—H
476

Example 599
—H
—H
—OCH₃
—H
—H
506

Example 600
—H
—H
—CF₃
—H
—H
544

Example 601
—H
—H
—Cl
—Cl
—H
544

Example 602
—H
—H
—Cl
—H
—H
510

Example 603
—H
—H
—H
—Cl
—H
510

Example 604
—H
—H
—CN
—H
—H
501

Example 605
—H
—H
—H
—Cl
—Cl
544

Example 606
—H
—H
—OCOCH₃
—OCH₃
—H
564

Example 607
—H
—H
—NO₂
—H
—H
521

Example 608
—H
—H
—N(C₂H₅)₂
—H
—H
547

Example 609
—H
—H
—N(CH₃)₂
—H
—H
519

Example 610
—H
—H
—H
—H
—OH
494

Example 611
—H
—OCH₃
—OH
—OCH₃
—H
552

Example 612
—H
—H
—OH
—OCH₃
—H
522

Example 613
—H
—H
—C₂H₅
—H
—H
504

Example 614
—H
—H
—(CH₂)₅CH₃
—H
—H
560

Example 615
—H
—H
—OCH₂C₆H₅
—H
—H
582

Example 616
—H
—H
—OC₆H₅
—H
—H
568

Example 617
—H
—H
—CH(CH₃)₂
—H
—H
518

Example 618
—H
—H
—O(CH₂)₅CH₃
—H
—H
576

Example 619
—H
—H
—OCF₃
—H
—H
560

TABLE 5

Example No.
R^A
R^B
R^C
R^D
R^E
MS (M + 1)

Example 620
—H
—H
—OCH₃
—H
—H
524

Example 621
—H
—H
—CH₃
—H
—H
508

Example 622
—H
—H
—H
—H
—Cl
528

Example 623
—H
—H
—Cl
—H
—H
528

Example 624
—H
—H
—CH(CH₃)₂
—H
—H
536

Example 625
—H
—H
—CO₂CH₃
—H
—H
552

Example 626
—H
—H
—H
—H
—H
494

Example 627
—H
—H
—SCH₃
—H
—H
540

Example 628
—H
—H
—OCH₃
—OCH₃
—H
554

Example 629
—H
—H
—NO₂
—H
—H
539

Example 630
—H
—H
—H
—CF₃
—H
562

Example 631
—H
—H
—H
—Cl
—H
528

Example 632
—H
—H
—O(CH₂)₃CH₃
—H
—H
566

Example 633
—H
—OCH₃
—OCH₃
—OCH₃
—H
584

Example 634
—H
—H
—CH₃
—CH₃
—H
522

Example 635
—H
—H
—H
—H
—NHCOCH₃
551

Example 636
—H
—H
—CF₃
—H
—H
562

Example 637
—H
—H
—Cl
—Cl
—H
562

Example 638
—H
—H
—F
—H
—H
512

Example 639
—H
—H
—OCF₃
—H
—H
578

Example 640
—H
—H
—CH₂C₆H₅
—H
—H
600

Example 641
—H
—H
—C(CH₃)₃
—H
—H
550

Example 642
—H
—H
—OC₂H₅
—H
—H
538

TABLE 6

Example 643
—H
—H
—SCF₃
—H
—H
594

Example 644
—H
—CF₃
—H
—CF₃
—H
630

Example 645
—H
—H
—H
—OCF₃
—H
578

Example 646
—H
—H
—H
—H
—OCF₃
578

Example 647
—F
—F
—F
—F
—F
584

Example 648
—H
—Cl
—H
—Cl
—H
562

Example 649
—H
—H
—C₂H₅
—H
—H
522

Example 650
—H
—H
—C₆H₅
—H
—H
570

Example 651
—H
—H
—H
—H
—CF₃
562

Example 652
—H
—H

embedded image

—H
—H

Example 653
—H
—H

embedded image

—H
—H
559

TABLE 7

Example No.
R^A
R^B
R^C
R^D
R^E
MS (M + 1)

Example 654
—H
—H
—Cl
—Cl
—H
588

Example 655
—H
—H
—Cl
—H
—H
554

Example 656
—H
—H
—CF₃
—H
—H
588

Example 657
—H
—H
—H
—CF₃
—H
588

Example 658
—H
—H
—OCF₃
—H
—H
604

Example 659
—H
—H
—F
—H
—H
538

TABLE 8

Example No.
R^A
R^B
R^C
R^D
R^E
MS (M + 1)

Example 660
—H
—H
—OCF₃
—H
—H
534

Example 661
—H
—H
—H
—OC₆H₅
—H
542

Example 662
—H
—H
—Cl
—H
—Cl
518

Example 663
—H
—H
—H
—H
—OCH₂C₆H₅
556

Example 664
—H
—H
—CH═CHC₆H₅(trans)
—H
—H
552

Example 665
—H
—H
—OCH₂CH₂CH₃
—H
—H
508

Example 666
—H
—H
—Cl
—H
—F
502

Example 667
—H
—H
—H
—OCH₂C₆H₅
—H
556

Example 668
—H
—H
—SC₂H₅
—H
—H
510

TABLE 9

Example No.
R^A
R^B
R^C
R^D
R^E
MS (M + 1)

Example 669
—H
—H

embedded image

—H
—H
595

Example 670
—H
—H
—H

embedded image

—H
576

Example 671
—H
—H
—H

embedded image

—H
516

Example 672
—H
—H

embedded image

—H
—H
549

Example 673
—H
—H

embedded image

—H
—H
572

Example 674
—H
—H

embedded image

—H
—H
576

Example 675
—H
—H
—H

embedded image

—H
560

Example 676
—H
—H

embedded image

—H
—H
530

TABLE 10

Example No.
R^A
R^B
R^C
R^D
R^E
MS (M + 1)

Example 677
—H
—H
—F
—H
—H
544

Example 678
—H
—H
—CF₃
—H
—H
594

Example 679
—H
—H
—OCF₃
—H
—H
610

Example 680
—H
—H
—OCH₃
—H
—H
556

Example 681
—H
—H
—Cl
—H
—H
560

Example 682
—H
—H
—Cl
—Cl
—H
594

Example 683
—H
—H
—Cl
—CH₃
—H
574

Example 684
—H
—H
—SCH₃
—H
—H
572

Example 685
—H
—H
—OCH₂C₆H₅
—H
—H
632

Example 686
—H
—H
—F
—CF₃
—H
612

TABLE 11

Example No.
R^F
MS (M + 1)

Example 687
—CH₂CH═CH₂
458

Example 688
-3-Pyridyl
495

Example 689
-2-Pyridyl
495

Example 690
—CH₂C₆H₅
508

Example 691
—CH₂CH₂C₆H₅
522

Example 692
—CCC₆H₅
518

Example 693
-4-Pyridyl
495

TABLE 12

Example No.
R^F
MS (M + 1)

Example 694

embedded image

542

Example 695

embedded image

565

Example 696

embedded image

544

Example 697

embedded image

611

Example 698

embedded image

645

Example 699

embedded image

563

Example 700

embedded image

538

TABLE 13

Example No.
R^G
MS (M + 1)

Example 701

embedded image

490

Example 702

embedded image

503

Example 703

embedded image

520

Example 704

embedded image

494

Example 705

embedded image

508

Example 706

embedded image

538

Example 707

embedded image

500

Example 708

embedded image

546

Example 709

embedded image

552

TABLE 14

Example 710

embedded image

500

Example 711

embedded image

567

Example 712

embedded image

494

Example 713

embedded image

492

Example 714

embedded image

558

Example 715

embedded image

558

Example 716

embedded image

540

Example 717

embedded image

524

Example 718

embedded image

574

Example 719

embedded image

524

Example 720

embedded image

530

TABLE 15

Example No.
R^G
MS (M + 1)

Example 721

embedded image

501

Example 722

embedded image

516

Example 723

embedded image

550

Example 724

embedded image

631

Example 725

embedded image

490

Example 726

embedded image

533

Example 727

embedded image

567

Example 728

embedded image

563

Example 729

embedded image

549

Example 730

embedded image

466

TABLE 16

Example 731

embedded image

538

Example 732

embedded image

490

Example 733

embedded image

611

Example 734

embedded image

504

Example 735

embedded image

484

Example 736

embedded image

604

Example 737

embedded image

604

Example 738

embedded image

456

Example 739

embedded image

440

Example 740

embedded image

530

TABLE 17

Example 741

embedded image

534

Example 742

embedded image

541

Example 743

embedded image

611

Example 744

embedded image

490

Example 745

embedded image

584

Example 746

embedded image

601

Example 747

embedded image

564

Example 748

embedded image

530

Example 749

embedded image

521

Example 750

embedded image

490

TABLE 18

Example 751

embedded image

557

Example 752

embedded image

539

Example 753

embedded image

593

Example 754

embedded image

501

Example 755

embedded image

523

Example 756

embedded image

612

Example 757

embedded image

628

Example 758

embedded image

578

Example 759

embedded image

464

Example 760

embedded image

506

TABLE 19

Example 761

embedded image

506

Example 762

embedded image

525

Example 763

embedded image

518

Example 764

embedded image

478

Example 765

embedded image

545

Example 766

embedded image

561

Example 767

embedded image

508

Example 768

embedded image

503

Example 769

embedded image

530

Example 770

embedded image

530

TABLE 20

Example No.
R^H
MS (M + 1)

Example 771

embedded image

570

Example 772

embedded image

631

Test Example 1
Antimicrobial Assay (Agar Plate Dilution Method)

The minimum inhibitory concentration of the 2,3-dihydro-6-nitro-imidazo[2,1-b]oxazole compound obtained in Example 228 against Mycobacterium tuberculosis (M. tuberculosis H37Rv) was determined using a 7H11 medium (manufactured by BBL). The above strain had been cultured on a 7H9 medium (manufactured by BBL) and stored by freezing at −80° C. The number of viable cells had been counted. A bacterial suspension with a final viable cell count of approximately 10⁶CFU/ml was prepared by using the bacterial stock mentioned above. Approximately 5 μl of the thus prepared bacterial suspension was inoculated onto the 7H11 agar medium containing the test compound and then cultured at 37° C. for 14 days. Thereafter, the culture was subjected to a test to determine the minimum inhibitory concentration. The minimum inhibitory concentration of the compound against M. tuberculosis H37Rv was ≦0.0004 μg/ml.

Test Example 2
Antimicrobial Assay (Agar Plate Dilution Method)

The minimal inhibitory concentrations against Mycobacterium tuberculosis (M. tuberculosis kurono) of the compounds listed in the table below were determined using a 7H11 medium (manufactured by BBL). M. tuberculosis kurono strain had been cultured on a 7H9 medium (manufactured by BBL) and stored by freezing at −80° C. The number of viable cells had been counted. A bacterial suspension with a final viable cell count of approximately 10⁶CFU/ml was prepared by using a bacterial stock mentioned above. Approximately 5 μl of the thus prepared bacterial suspension was inoculated onto the 7H11 agar medium containing the test compounds and then cultured at 37° C. for 14 days. Thereafter, the culture was subjected to a test to determine the minimum inhibitory concentration.

The results are shown in the table below.

TABLE 21

Minimum

Inhibitory

Concentration

Compound Tested
(μg/ml)

Compound of Example 1
0.024

Compound of Example 3
0.05

Compound of Example 53
0.1

Compound of Example 56
0.012

Compound of Example 64
≦0.006

Compound of Example 79
0.012

Compound of Example 90
0.012

Compound of Example 143
0.1

Compound of Example 147
0.05

Compound of Example 153
0.024

Compound of Example 182
≦0.0015

Compound of Example 198
≦0.0015

Compound of Example 206
≦0.0015

Compound of Example 228
0.0008

Compound of Example 254
0.0008

Compound of Example 282
0.006

Compound of Example 290
0.0008

Compound of Example 299
0.0008

Compound of Example 304
0.012

Compound of Example 335
0.0015

Compound of Example 364
0.024

Compound of Example 372
0.006

Compound of Example 379
0.1

Compound of Example 380
0.012

Compound of Example 382
0.012

Compound of Example 383
0.003

Compound of Example 395
0.003

Compound of Example 400
≦0.0004

Compound of Example 411
0.006

Compound of Example 414
0.006

Compound of Example 415
0.0015

Compound of Example 446
0.003

Compound of Example 471
0.012

Compound of Example 490
0.0008

6,7-DIHYDROIMIDAZO [2,1-b] [1,3]OXAZINE BACTERICIDES

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