WO2004072047A1

WO2004072047A1 - Indoles, benzimidazoles or naphhimidazoles as histone deacetylase (hdac) inhibitors

Info

Publication number: WO2004072047A1
Application number: PCT/JP2004/001438
Authority: WO
Inventors: Yasuharu Urano; Mitsuru Hosaka; Takayuki Inoue; Kazuhiko Osoda; Kozo Sawada; Akio Kuroda
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 2003-02-11
Filing date: 2004-02-10
Publication date: 2004-08-26
Also published as: AU2003900608A0; WO2004072047A8

Abstract

A compound of the following formula (I):whereinR1 is acyl, R2 is hydrogen, orR1 and R2 are linked together to form a heterocyclic ring, R5 is hydroxy, hydroxylamino, lower alkyl, lower alkoxy, halo(lower)alkyl or hydroxy(lower)alkyl, Q is lower alkylene or lower alkenylene, andG is a substituent selected from the following formulas and wherein R3 and R4 are each independently hydrogen, halogen, halo(lower)alkyl, cyano, aryl or aryl(lower)alkyl optionally substituted with one or more suitable substituent(s), or R3 and R4 are linked together to form an aromatic ring, and X is NH, O or S, or a salt thereof. The compound is useful as an inhibitor of histone deacetylase.

Description

INDOLES, BENZIMIDAZOLES OR NAPHHIMIDAZOLES AS HISTONE DEACETYLASES (HDAC) INHIBITORS

TECHNICAL FIELD

The present invention relates to a compound, which is useful as a medicament, and to a pharmaceutical composition comprising the same.

BACKGROUND ART Histone deacetylase (hereinafter also referred as HDAC) is known to play an essential role in the transcriptional machinery for regulating gene expression, induce histone hyperacetylation and to affect the gene expression. Therefore, it is useful as a therapeutic or prophylactic agent for diseases caused by abnormal gene expression, such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL) , organ transplant rejections, autoimmune diseases, protozoal infections, tumors and the like.

SMϋRΪ OF THE IMUE1TIOH The present invention relates to a novel compound, which is useful as a medicament, and to a pharmaceutical composition comprising the same.

More particularly, the present invention relates to a compound, which has a potent inhibitory effect on the activity of histone deacetylase. The inventors of the present invention have also found that a histone deacetylase inhibitor, such as compound of formula (I) (hereinafter compound [I] ) , has a potent immunosuppressive effect and potent antitumor effect. Therefore, a histone deacetylase inhibitor such as compound [I] is useful as an active ingredient of an immunosuppressant and an antitumor agent, and useful as a therapeutic or prophylactic agent for diseases such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, autoimmune diseases, protozoal infections, tumors and the like. Accordingly, one object of the present invention is to provide a compound, which has biological activities for treating or preventing the diseases as stated above.

Another object of the present invention is to provide a pharmaceutical composition containing the compound [I] as an active ingredient.

A further object of the present invention is to provide use of the histone deacetylase inhibitors, such as the compound [I] , for treating or preventing the diseases as stated above. A yet further object of the present invention is to provide a commercial package comprising the pharmaceutical composition containing the compound [I] and a written matter associated therewith, the written matter stating that the pharmaceutical composition may or should be used for treating or preventing the diseases as stated above.

Thus, the present invention provides [ 1] a compound of the formula (I) %

wherein

R¹ is acyl, R² is hydrogen, or

R¹ and R² are linked together to form a heterocyclic ring, R⁵ is hydroxy, hydroxylamino, lower alkyl, lower alkoxy, halo(lower)alkyl or hydroxy(lower)alkyl, Q is lower alkylene or lower alkenylene, and G is a substituent selected from the following formulas

wherein

R³ and R⁴ are each independently hydrogen, halogen, halo(lower)alkyl, cyano, aryl or aryl(lower)alkyl optionally substituted with one or more suitable substituent( s) , or

R³ and R⁴ are linked together to form an aromatic ring, and X is NH, 0 or S, or a salt thereof;

[2] the compound of the above-mentioned [ 1] , wherein R¹ is acyl selected from the group consisting of arylcarbonyl in which the aryl portion is optionally substituted with one or more suitable substituent(s) ; heterocyclic carbonyl; lower alkyl- carbonyl; carbamoyl in which the amino portion is optionally mono- or di-substituted with suitable substituent(s) ; lower alkyl-carbonyloxy(lower)alk lcarbonyli lower alkoxycarbonyl; lower alkylsulfonyl; and arylsulfonyl, R² is hydrogen, or

R¹ and R² are linked together to form a heterocyclic ring, R³ and R⁴ are each independently hydrogen; halogen; halo(lower)alkyl; cyano; aryl; or aryl(lower)alkyl in which the alkyl portion is optionally substituted with hydroxy or lower alkoxy, or

R³ and R⁴ are linked together to form a benzene ring, R⁵ is hydroxylamino, halo(lower)alkyl or hydrox (lower)alkyl, X is NH, and

Q is lower alkylene, or a salt thereof;

[3] the compound of the above-mentioned [2] , wherein R¹ is arylcarbonyl in which the aryl portion is optionally substituted with one or more substituent(s) selected from the group consisting of lower alkoxycarbonyl; carboxy; lower alkylcarbamoyl; N, N-di( lower)alkylamino; lower alkyl; hydroxy; and cyano, or a heterocyclic carbonyl,

R³ and R⁴ are each independently hydrogen, or

R³ and R⁴ are linked together to form a benzene ring,

R⁵ is hydroxylamino, halo(lower)alkyl or hydroxy(lower)alkyl,

X is NH, and

Q is lower alkylene, or a salt thereof;

[4] A compound of the following formula (I ' ) :

wherein

R¹ is acyl,

R² is hydrogen, or

R¹ and R² are linked together to form a heterocyclic ring,

R³ and R⁴ are each independently hydrogen, halogen, halo(lower)alkyl, cyano, aryl or aryl(lower)alkyl optionally substituted with one or more suitable substituent(s) , or R³ and R⁴ are linked together to form an aromatic ring, R⁵ is hydroxylamino, halo( lower)alkyl or hydroxy(lower)alkyl, 1 is NH, O or S, and Q is lower alkylene or lower alkenylene, or a salt thereof;

[5] the compound of the above-mentioned [4] , wherein R¹ is acyl selected from the group consisting of arylcarbonyl in which the aryl portion is optionally substituted with one or more suitable substituent( s) ; heterocyclic carbonyl; lower alkyl- carbonyl; carbamoyl in which the amino portion is optionally mono- or di-substituted with suitable substituent(s) ; lower alky1-carbonyloxy(lower)alkylcarbonyl; lower alkoxycarbonyl; lower alkylsulfonyl; and arylsulfonyl,

R² is hydrogen, or

R³ and R⁴ are linked together to form a benzene ring, R⁵ is hydroxylamino,

X is NH, and

Q is lower alkylene, or a salt thereof;

[6 ] the compound of the above-mentioned [5] , wherein R¹ is arylcarbonyl in which the aryl portion is optionally substituted with one or more substituent( s) selected from the group consisting of lower alkoxycarbonyl; carboxy; lower alkylcarbamoyl; N, N-di( lower)alk lamino lower alkyl; hydroxy; and cyano, R³ and R⁴ are linked together to form a benzene ring,

R⁵ is hydroxylamino,

X is NH, and

Q is lower alkylene, or a salt thereof, etc.

Of the above-mentioned compounds, the compounds represented by the formula (I^f) (compound [I^f]) is also encompassed in the scope of the compound represented by the formula (I) .

Hereinafter "compound [I]" also encompasses "compound [I']". The above-mentioned compounds and salts thereof can be prepared by the processes as illustrated in the following reaction schemes or by the methods disclosed in the Preparations and Examples.

In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.

The compound [I] or a salt thereof can be prepared by the process as illustrated in the following reaction schemes. In the following processes, Compounds [1-1], [1-2], [1-3], [1-3'] (Compound [1-3] wherein R⁵ is lower alkoxy), [1-4], [1-5] and [1-6] are encompassed in the scope of the Compound [I] , and Compounds [II-l] to [11-10] are encompassed in the scope of Compound [II]. Compounds [III-l] and [III-2] are encompassed in the scope of the Compound [III], and Compounds [V-1] and [V-2] are encompassed in the scope of the Compound [V] .

Process A

(A-3)

(A-4)

deprotection

[II-l]

Process B

(A-6) ;ιι-2]

Process C

(C-0) (C-l)

[II-3] Process D

(A-6) [II-4]

Process E

(A-β) [II-5]

Process F

(A-β) [II-6] Process G

(A-3') (G-l)

deprotection of amino protective

(G-3)

(G-5)

deprotection of carboxy deprotection of protective group imidasole protective group

Step 7 or Step 8

(G-7) (G-8) deprotection of deprotection of

Step 9 imidazole protective Step 10 carboxy protective group group

[ II-7 ]

Process H

Process I

[II-8]

Process J

(J-0) (J-l)

(J-2)

(J-3)

(J-4)

(J-5)

Step 6

(J-6)

(J-7)

(J-8)

(J-10)

(K-0) (K-l)

(K-2)

Process L

[1-4] [11-10] Process M

(M-l)

[III-2]

Process N

R^b— N COOR^a

(J-6) (N-l)

Deprotection of 0. amino protective group

Q' d (removal of R )

R^b— N COOR^a

Step 2 I H

(N-2)

(N- 3)

(N-4)

Deprotection

Process o

(0-7)

(0-8)

Process P

wherein

R¹, R², R³, R⁴, R⁵, Q and X are as defined above,

R⁵' is lower alkylene such as methylene, methylmethylene, ethylmethylene, ethylene, propylene and the like, R⁶ is a group such as lower alkyl (e.g., methyl, ethyl, propyl and the like), aryl (e.g., phenyl, benzyl and the like) and the like,

R⁷ is a group such as lower alkyl (e.g., methyl, ethyl, propyl and the like) and the like, R⁸ is a group such as lower alkyl (e.g., ethyl, propyl, butyl and the like), aryl (e.g., optionally substituted phenyl and the like) and the like,

R⁹ is a group such as lower alkyl (e.g., isopropyl, butyl and the like), lower alkoxy (e.g., ethoxy, isobutoxy and the like), lower alkoxycarbonyl(lower)alkyl (e.g., ethoxycarbonylmethyl and the like), optionally substituted amino (e.g., N,M-d_Lmethylamino and the like), optionally substituted aryl (e.g., 3-methylphenyl and the like) and the like,

R¹⁰ is lower alkyl such as methyl, ethyl, propyl, tert-butyl and the like,

Y is amino, thiol or hydroxy, w is an integer of 2 to 6,

2 is alkylene represented by the formula -(CH₂)_m-,

Z ' is alkylene represented by the formula -(CH₂)_(m_i₎-, (wherein m is an integer of 1 to 6), ' is alkenylene group,

R^a is carboxy protective group,

R^c and R^e are each hydroxy protective group, and

R^b, R^d and R^f are each amino protective group. In the above-mentioned Processes A, B, C, D, E, F, G, H,

I, J, K, L, M, N, O and P, each of the starting compounds can be prepared, for example, according to the procedures as illustrated in Preparations in the present specification or in a manner similar thereto. For example, the compounds (A-l), (A-2), (A-3), (A-4), (A-5) and (A-6) can be obtained by the procedures as illustrated in Preparations 1, 2, 3, 4, 5 and 6, respectively; the compound (C-l) can be obtained by the procedure as illustrated in Preparation 23; and the compounds (G-l), (G-2), (G-3), (G-4), (G-5), (G-6), (G-7) and (G-9) can be obtained by the procedures as illustrated in Preparations 77, 78, 79, 80, 81, 82, 83, 84, 85, 86 and 87; and the compound (J-l), (J-2), (J-3), (J-4), (J-5), (J-6), (J-7), (J-8), (J-9), and (J-10) can be obtained by the procedures as illustrated in Preparations 94, 95, 96, 97, 98, 99, 100, 101, 102 and 103; and the compound (K-l) and (K-2), can be obtained by the procedures as illustrated in

Preparations 105 and 106; and the compound (M-l) can be obtained by the procedures as illustrated in Preparation 109; and the compound (N-l), (N-2), (N-3), (N-4) and (N-5) can be obtained by the procedures as illustrated in Preparations 111, 112, 113, 114, and 115; and the compounds (0-1), (0-2), (0-3), (0-4), (0-5), (0- 6), (0-7), (0-8), (0-9) and (O-10) can be obtained by the procedures as illustrated in Preparations 118, 119, 120, 121, 122, 124, 126, 128, 130 and 135; the compound (P-l) can be obtained by the procedures as illustrated in Preparation 133, respectively. The compounds [II-l], [II-2], [II-3], [II-4], [II-5], [II-6], [II-7], [II-8J, [II-9] and [11-10] can be obtained by, for example, the procedures as illustrated in Preparations 7, 9, 24, 44, 45, 48, 86, 72, 76 and 108, respectively. The compounds [III-l], [III-2], [IV], [V-1], [V-2] and [VI] can be obtained by, for example, the procedures as illustrated in Preparations 104, 110, 107, 116, 140 and 138,respectively.

The compound [I] of the present invention is obtained from compound [II] according to, for example, the following process. Preparation of the compound [I] of the present invention Process 1

[II] [1-1]

wherein

R¹, R², R³, R⁴, R^c, Q and X are as defined above.

The compound [1-1] is obtained by deprotecting the hydroxy protective group of the compound [II]

The reaction may be carried out in the presence of a catalyst for hydrogenation and under the atmosphere of hydrogen.

Suitable catalysts for the hydrogenation include, for example, palladium-BaS0 (Pd-BaS0₄), palladium on carbon (Pd-C), Pd(0H)₂ on carbon and the like.

Alternatively, when the hydroxy protective group is hydroxypyranyl, the deprotection of the hydroxy group is carried out in the presence of an acid. Suitable acids include, for example, hydrochloric acid and the like. The deprotection may be carried out in a conventional solvent which does not adversely influence the reaction, which is exemplified by methanol, ethyl acetate, ethanol, 1,4-dioxane and the like.

The temperature of the reaction is not critical and the reaction is usually carried out from under cooling to heating.

The Process 1 is exemplified by, for example, Examples 1, 8 and the like. Process 2

wherein R¹, R³, R⁴, R⁵, Q and X are as defined above.

The compound [1-2] is obtained by cyclization of the compound [III] .

In this reaction, the compound [III] includes the compounds [III-l] and [III-2].

The reaction may be carried out in the presence of a catalyst for cyclization.

Suitable catalysts for the cyclization include, for example, acids such as hydrochloric acid, acetic acid and the like.

The cyclization may be carried out in a conventional solvent which does not adversely influence the reaction, which is exemplified by methanol, ethanol and the like.

The Process 2 is exemplified by Examples 53 and 57.

Process 3

wherein

R¹, R³, R⁴, R⁵,and Q are as defined above.

The compound [1-3] is obtained by reaction of the compound [IV] with R^x-OH.

The reaction may be carried out, for example, in the presence of reagents such as HOAT, HOBT, WSCD and the like.

The reaction may be carried out in a conventional solvent which does not adversely influence the reaction, which is exemplified by N,N-d_Lmethylformamide, dichloromethane and the like.

The temperature of the reaction is not critical and the reaction is usually carried out from under cooling to heating. The Process 3 is exemplified by Example 54.

Process 4

wherein R¹, R³, R⁴, R¹⁰, and Q are as defined above.

The compound [1-4] is obtained by deprotecting the hydroxy protective group of the compound [1-3'].

In this reaction, the compound [1-3'] is the compound [1-3] wherein R⁵ is lower alkoxy represented by the formula -OR¹⁰ (wherein R¹⁰ is lower alkyl such as methyl, ethyl, propyl, tert- butyl and the like) . The reaction may be carried out by heating in the presence of water and a catalyst for ester hydrolysis.

Suitable catalysts for the ester hydrolysis include, for example, bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. The ester hydrolysis may be carried out in a conventional solvent which does not adversely influence the reaction, which is exemplified by methanol, ethanol and the like. The temperature of the reaction is not critical and the reaction is usually carried out from under cooling to heating.

The Process 4 is exemplified by Example 55. Process 5

wherein

R¹, R³, R⁴, R^5', R^c, R^e, Q and X are as defined above.

The compound [1-5] is obtained by deprotecting the hydroxy protective group of the compound [V] .

The deprotection reaction may be carried out in the presence of a catalyst for elimination reaction of trisubstituted silyl group.

Suitable catalysts for the elimination reaction include, for example, catalysts such as tetrabutylammonium fluoride, hydrogen fluoride, hydrogen fluoride-pyridine complex, acetic acid, hydrochloric acid, sodium hydroxide and the like.

The deprotection may be carried out in a conventional solvent which does not adversely influence the reaction, which is exemplified by ether such as tetrahydrofuran and the like.

The temperature of the reaction is not critical and the reaction is usually carried out from under cooling to heating. The Process 5 is exemplified by Example 58. Process 6

Deprotection of imidazole protective group

wherein

R¹, R³, R⁴, R⁵, R^d and Q are as defined above.

The compound [1-6] is obtained by deprotecting the imidazole protective group of the compound [VI]

The reaction may be carried out in the presence of a catalyst for deprotection reaction of imidazole deprotective group.

Suitable catalysts for the deprotection reaction include, for example, diaramonium cerium nitrate, 2,3-dichloro-5,β-dicyano- 1, —benzoquinone and the like.

The deprotection may be carried out in a conventional solvent which does not adversely influence the reaction, which is exemplified by dichloromethane, mixed solvent of acetonitrile, methanol and water, and the like.

The temperature of the reaction is not critical and the reaction is usually carried out from under cooling to heating. The Process 6 is exemplified by Example 60. When the compound [I] has stereoiso ers, such isomers are also encompassed in the present invention.

The compound [I] may form a salt, which is also encompassed in the present invention. For example, when a basic group such as an amino group is present in a molecule, the salt is exemplified by an acid addition salt (e.g., a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like, a salt with an organic acid such as methanesulfonic acid, fumaric acid, aleic acid, mandelic acid, citric acid, salicylic acid and the like), and when an acidic group such as carboxyl group is present, the salt is exemplified by a basic salt (e.g., a salt with a metal such as sodium, potassium, calcium, magnesium, aluminium and the like, a salt with an amino acid such as lysine and the like) and the like. In addition, solvates of the compound [I] such as hydrate, ethanolate and the like, are also encompassed in the present invention.

Suitable examples and illustration of the various definitions in the above and subsequent descriptions, which the present invention intends to include within its scope, are explained in detail as follows:

Each of the "halogen", "halo" and "Hal" includes fluorine, chlorine, bromine and iodine.

The "lower" used in the description is intended to mean 1 to 6 carbon atom(s), unless otherwise indicated.

The "one or more" as used herein mean the number of 1 to 6, preferably 1 to 3.

Suitable examples of the "lower alkyl" include a straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, neopentyl, hexyl, isohexyl and the like. Suitable "lower alkyl" as substituents of the "arylcarbonyl" for R¹ includes methyl, isopropyl and the like. Suitable examples of the "lower alkyl" for R⁵ include ethyl and the like. Suitable examples of the "lower alkoxy" include a straight or branched one having 1 to 6 carbon atom(s), such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert- butoxy, pentyloxy, tert-pentyloxy, neopentyloxy, hexyloxy, isohexyloxy and the like. Suitable examples of the "lower alkoxy" as substituents of the "aryl(lower)alkyl" for R³ and/or R⁴ include methoxy and the like. Suitable examples of the "lower alkoxy" for R⁵ include ethoxy and the like.

Suitable examples of the "aryl" include a C₆-C₁₆ aryl such as phenyl, naphthyl, anthryl, pyrenyl, phenanthryl, azulenyl and the like. Suitable examples of the "aryl" for R³ and/or R⁴ include phenyl and the like.

Suitable examples of the "halo(lower)alkyl" include a lower alkyl substituted with 1 to 3 halogen atom(s), such as monochloromethyl, dichloromethyl, trichloromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monobromomethyl, dibromomethyl, tribromomethyl, monochloroethyl, dichloroethyl, trichloroethyl, monofluoroethyl, difluoroethyl, trifluoroethyl and the like. Suitable examples of the "halo(lower)alkyl" for R³ and/or R⁴ include, such as trifluoromethyl and the like, and suitable examples of the

"halo(lower)alkyl" for R⁵ include fluoromethyl, difluoromethyl and the like.

Suitable examples of the "hydroxy(lower)alkyl" include a lower alkyl substituted with hydroxy, such as hydroxymethyl, 1- hydroxyethyl, 2-hydroxymethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1-hydroxybutyl, 1-hydroxypentyl, 1-hydroxyhexyl and the like. Suitable examples of the "hydrox (lower)aIkyl" for R⁵ include hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl and the like. The "acyl" as used herein includes, for example, alkanoyl [e.g., formyl, lower alkyl-carbonyl (e.g., acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, pivaloyl, 2,2- di ethylpropanoyl, hexanoyl and the like), heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadeσanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl and the like] ; alkoxycarbonyl [e.g., lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl and the like) and the like]; lower alkyl-carbonyloxy(lower)alkyIcarbonyl (e.g. acetyloxyacetyl, ethylcarbonyloxyacetyl and the like); arylcarbonyl [e.g., C₆_ιo arylcarbonyl (e.g., benzoyl, toluoyl, naphthoyl, fluorenyIcarbonyl and the like)]; arylalkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl and the like) , naphthyl(lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl and the like) and the like]; arylalkenoyl [e.g., aryl(C₃-C₆)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl and the like) and the like) ] ; naphthylalkenoyl [e.g., naphthyl(C₃-C₆)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, naphthyl ethacryloyl, naphthylpentenoyl, naphthylhexenoyl and the like) and the like]; arylalkoxycarbonyl [e.g., aryl(lower)alkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl and the like) , fluorenyl( lower)alkoxycarbonyl (e.g., fluorenylmethyloxycarbonyl and the like) and the like]; aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl and the like) ; aryloxyalkanoy1 [e.g., aryloxy(lower)aIkano 1 (e.g., phenoscyacetyl, phenoxypropionyl and the like) and the like]; heterocyclic acyl (e.g., heterocycliccarbonyl and the like); heterocycliσalkanoyl [e.g., heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl and the like) and the like]; heterocyclicalkenoyl [e.g., heterocyclic(lower)alkenoyl

(e.g., heterocyclicpropεnoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl and the like)]; carbamoyl; alkylcarbamoyl [e.g., lower alkylcarbamoy1 (e.g., methylcarbamoy1, ethylcarbamoyl and the like) ] ; alkoxycarbamoyl [e.g., lower alkoxycarbamoyl (e.g., methoxycarbamoyl, ethoxycarbamoyl and the like) ] and the like; arylcarbamoy1 [e.g., C₆_ιo arylcarbamoyl (e.g., phenylcarbamoyl, naphthylcarbamoyl and the like) and the like]; arylthiocarbamoyl [e.g., C₆_ι₀ arylthiocarbamoyl (e.g., phenylthiocarbamoyl, naphthylthiocarbamoyl and the like) and the like]; alkylsulfonyl [e.g., lower alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl and the like)]; alkoxysulfonyl [e.g., lower alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl and the like) ] and the like; arylsulfonyl (e.g., phenylsulfonyl and the like); arylglyoxyloyl [e.g., C₆-ιo arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl and the like) and the like]; heterocyclicglyoxyloyl; and the like. Each of these acyl is optionally substituted by one or more suitable substituent(s) . Suitable "acyl" for R¹ is as follows: (1) arylcarbonyl in which the aryl portion is optionally substituted with one or more suitable substituent(s) ;

(2) heterocyclic carbonyl;

(3) lower alkyl-carbonyl;

(4) carbamoyl in which the amino portion is optionally mono- or di-substituted with suitable substituent(s) ;

(5) lower alk 1-carbon loxy(lower)alkyIcarbonyl;

(6) lower alkoxycarbonyl;

(7) lower all∑ylsulfonyl;

(8) arylsulfonyl and the like. The "lower alkyl" in each of the "(3) lower alkyl-carbonyl", "(5) lower alky1-carbonyloxy(lower)alkyIcarbonyl" and "(7) lower alkylsulfonyl" has the same meaning as that of the above- mentioned "lower alkyl". Suitable examples of the "(3) lower alkyl-carbonyl" include acetyl, n-butyIcarbonyl, n-butyIcarbonyl, n-pentyIcarbonyl, n-hexyIcarbonyl and the like. Suitable examples of the "(5) lower aIky1-carbonyloxy( lower)alkyIcarbonyl" include acetyloxyacetyl, ethylcarbonyloxyacetyl and the like. Suitable examples of the "(7) lower alkylsulfonyl" for R¹ include methylsulfonyl and the like. The "lower alkoxy" in the "(6) lower alkoxycarbonyl" has the same meaning as that of the above-mentioned "lower alkoxy". Suitable examples of the "(6) lower alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl and the like.

The "aryl" in the "(1) arylcarbonyl in which the aryl portion is optionally substituted with one or more suitable substituent(s)" has the same meaning as that of the above- mentioned "aryl". Suitable examples of the "arylcarbonyl" include benzoyl, naphthoyl and the like. Preferably, the "(1) arylcarbonyl in which the aryl portion is optionally substituted with one or more suitable substituent(s) " is benzoyl in which the phenyl portion is optionally substituted with one or more substituent(s) selected from the group consisting of lower alkoxycarbonyl (e.g., methoxycarbonyl and the like); carboxy; lower alkylcarbamoyl (e.g., methylcarbamoyl and the like); N,N- di(lower)alkylamino (e.g., N,N-dimethylamino and the like); lower alkyl (e.g., methyl, isopropyl and the like); hydroxy; and cyano.

The "aryl" in the "(8) arylsulfonyl" has the same meaning as that of the above-mentioned "aryl". Suitable examples of the "(8) arylsulfonyl" include phenylsulfonyl and the like. Suitable "heterocyclic" as used herein includes a 5- or 6- membered heteromonocyclic group or a condensed heterocyclic group, each of which contains at least one heteroatom selected from a sulfur atom, an oxygen atom and a nitrogen atom besides carbon atoms and one or more carbon atom(s) is/are optionally replaced with oxo group(s).

Suitable examples of the "heteromonocyclic group" include pyridyl, dihydropyridyl, azepinyl (e.g., IH-azepinyl and the like) , pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, 1H- 1,2,3-triazolyl, 2H-l,2,3-triazolyl and the like), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl and the like), perhydroazepinyl (e.g., perhydro-lH-azepinyl and the like), pyrrolidinyl, imidazolidinyl, piperidyl, piperadinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, 1,2,5-oxadiazolyl and the like), morpholinyl, sydnonyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3- thiazidiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5- thiadiazolyl and the like) , dihydrothiazinyl, thiazolidinyl, furyl, dihydrooxatiinyl, N-succinimidyl and the like. Suitable examples of the "condensed heterocyclic group" include indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, quinoxalinyl, imidazopyridyl (e.g., imidazo[ 4, 5-c]pyridyl and the like) , tetrahydroimidazopyridyl (e.g., 4,5,6, 7-tetrahydro[4,5-c]pyridyl and the like), 7-azabicyclo[2.2.1]heptyl, 3- azabicyclo[3.2.2]nonanyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzodithiinyl, benzoxathiinyl and the like.

Suitable "heterocyclic ring" for R¹ and R² include N- succinimidyl and the like.

Suitable "(2) heterocyclic carbonyl" include pyridyIcarbonyl, pyradinyIcarbonyl, furyIcarbonyl, indolyIcarbonyl and the like.

Suitable examples of the "(4) carbamoyl in which the amino portion is optionall mono- or di- substituted with suitable substituent(s)" include N,N-dimethylcarbamoyl and the like. Suitable examples of the "aryl(lower)alkyl" include a phenyl(Cι-C₅)alkyl such as benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylhexyl and the like, a naphthyl(Cι-C₆)alkyl such as naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphtylhexyl and the like. Suitable examples of the "aryl(lower)alkyl optionally substituted with one or more suitable substituent( s) " for R³ and/or R⁴ include an aryl(lower)alkyl in which the alkyl portion is optionally substutituted with one or more substituent(s) such as hydroxy, lower alkoxy (e.g., methoxy, ethoxy) and the like, such as (hydroxyphenyl)methyl, (methoxyphenyl)methyl and the like.

Suitable examples of the "aromatic ring" for R³ and R⁴ include benzene ring and the like. Suitable examples of the "lower alkylene" include a straight or branched alkylene having 1 to 6 carbon atom(s), such as ethylene, propylene, 1-methylpropylene, butylene, 1- methylbutylene, 2-methylbutylene, 1-ethylbutylene, 2- ethylbutylene, pentylene, 1-methylpentylene, 2-methylpentylene, hexylene and the like. Suitable examples of the "lower alkylene" for Q include pentylene and the like.

Suitable examples of the "lower alkenylene" include a straight or branched alkenylene having 1 to 6 carbon atom(s), such as vinylene, 1-methylvinylene, 2-methylvinylene, 1- propenylene, 2-propenylene, 2-methyl-l-propenylene, 2-methyl-2- propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1- pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 1- hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5- hexenylene and the like. Suitable examples of the "lower alkenylene" for Q include 1-pentenylene and the like.

Suitable examples of the "carboxy protective group" include: lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like) ; mono(or di or tri)halo(lower)alkyl (e.g. 2-iodoethyl, 2,2,2- trichloroethyl and the like), preferably 2,2,2-trichloroethyl; lower alkanoylαxy(lower)alkyl (e.g. acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, hexanoyloxymethyl, l(or 2)-acetoxyethyl, l(or 2 or 3)-acetoxypropyl, l(or 2 or 3 or 4)-acetoxybutyl, l(or 2)- propionyloxyethyl, l(or 2 or 3)-propionyloxypropyl, l(or 2)- butyryloxyethyl, l(or 2)-isobutyryloxyethyl, l(or 2)- pivaloylox ethyl, 1(or 2 )-hexanoyloxyethyl, isobutyryloxymethyl, 2-ethylbutyryloxymethyl, 3,3-dimethylbutyryloxymethyl, l(or 2)- pentanoyloxyethyl and the like) ; lower alkanesulfonyl( lower)alkyl (e.g. 2-mesylethyl and the like) ; lower alkoxycarbonyloxy( lower)alkyl (e.g. methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 2- methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1- isopropoxycarbonyloxyethyl and the like) ;

[5-(lower)alky1-2-oxo-l,3-dioxol-4-yl](lower)alkyl (e.g. (5- methyl-2-oxo-l, 3-dioxol-4-yl)methyl, (5-ethyl-2-oxo-l,3-dioxol-4- yl)methyl, (5-propyl-2-oxo-l,3-dioxol-4-yl)methyl and the like); aryl optionally substituted with one or more suitable substituent(s) (e.g. phenyl, o(or m or p)-chlorophenyl, tolyl, o(or m or p)-t-butylphenyl, xylyl, mesityl, cumenyl and the like) ; ar(lower)alkyl in which the aryl portion is optionally substituted with one or more suitable substituent(s) (e.g. benzyl, p-methoxybenzyl, o(or p)-nitrobenzyl, phenethyl, trityl, benzhydryl, bis(methoxyphenyl)methyl, m,p-d:Lmethoxybenzyl, 4- hydroxy-3,5-di-t-butylbenzyl and the like); arylcarbonyl(lower)alkyl in which the aryl portion is optionally substituted with one or more suitable substituent(s) (e.g. phenacyl and the like) ; cyclo(lower)alkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like); lower alkenyl (e.g. vinyl, allyl and the like); lower alkynyl (e.g. ethynyl, propynyl and the like); trisubstituted silyl such as tri( lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, tributylsilyl, tert- butyldimethylsilyl, tri-tert-butylsilyl and the like), lower alkyldiarylsilyl (e.g. methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenylsilyl, and the like) and the like; tri(lower)alkylsilyl( lower)alkyl (e.g. 2-(trimethylsilyl)ethyl and the like);

1-(lower)alkyl-2, 6, 7-trioxabicyclo[2.2.2]oct-4-yl (e.g. 1-methyl- 2,6,7-trioxabicyclo[2.2.2]oct-4-yl, l-ethyl-2,6,7- trioxabicyclo[2.2.2]oct-4-yl, and the like); and the like. Suitable examples of the "hydroxy protective group" include: lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like); lower alkoxy(lower)alkyl (e.g., methoxymethyl, 1-ethoxyethyl and the like) ; lower alkoxy(lower)alkoxy(lower)alkyl (e.g., 2- methoxyethoxymethyl and the like) ; aryl(lower)alkyl in which the aryl portion is optionally substituted with one or more suitable substituent(s) (e.g., benzyl, p-methoxybenzyl, m,p-dimethoxybenzyl and the like); aryl(lower)alkoxy(lower)alkyl in which the aryl portion is optionally substituted with one or more suitable substituent(s) (e.g., benzyloxymethyl, p-methoxybenzyloxymethyl and the like); lower alkylthio(lower)alkyl (e.g., methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl and the like) ; heterocyclic group (e.g., tetrahydropyranyl and the like); trisubstituted silyl [e.g., tri( lower)alkylsilyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tert- butyldimethylsilyl (TBDMS), tri-tert-butylsilyl and the like), lower alkyldiarylsilyl (e.g., methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenylsilyl (TBDPS) and the like) and the like]; acyl as described above; lower alkenyl (e.g., vinyl, allyl and the like); and the like.

Suitable examples of the "amino protective group" include: acyl as described above; aryl( lower)alkyl in which the aryl portion is optionally substituted with one or more suitable substituent(s) (e.g., benzyl, p-methoxybenzyl, o(or p)-nitrobenzyl, phenethyl, trityl, benzhydryl, bi (methoxyphenyl)methyl, m,p-dimethoxybenzyl, 4- hydroxy-3,5-di-t-butylbenzyl and the like);

[5-( lower)alkyl-2-oxo-l,3-dioxol-4-yl] (lower)alkyl (e.g., (5- methyl-2-oxo-l,3-dioxol-4-yl)methyl, (5-ethyl-2-oxo-l,3-dioxol-4- yl)methyl, (5-propyl-2-oxo-l,3-dioxol-4-yl)methyl and the like); and the like. Suitable examples of the "imidazole protective group" include those exemplified for the "amino protective group" described above and the like.

The following abbreviations are also used in the present specification: Boc (t-butyloxycarbonyl) ; HOBT (1- hydroxybenzotriazole); WSCD (l-ethyl-3-(3'-dimethylaminopropyl)- carbodiimide); DMF (N,N-dimethylformamide) ; aq. (aqueous solution); Me (methyl); MeOH (methanol); Et (ethyl); EtOH (ethanol); tBu (t-butyl); t-Boc (t-butoxycarbonyl); TsCl (p- toluenesulfonyl chloride); Ac (acetyl); AcOH (acetic acid); Ph (phenyl); DIEA (diisopropylethylamine) ; Bn (benzyl); Bz (benzoyl); TBAI (tetrabutylammonium iodide); TBAF (tetrabutylammonium fluoride); CAN (cerium ammonium nitrate); THP (tetrahydropyranyl) ; IPE (diisopropyl ether); HOAT ( 1-hydroxy-7- azabenzotriazole) ; TBDPS (t-butyl(diphenyl)silyl); TBDMS (t- butyl(dimethyl) sily1) . Test Method

In order to show the usefulness of the compound [I] of the invention, the pharmacological test result of the representative compound of the present invention is shown in the following. Test 1: Determination of histone deacetylase inhibitory activity The partial purification of human histone deacetylase, the preparation of [³H] acetyl histones, and the assay for histone deacetylase activity were performed as follows basically according to the method as proposed by Yoshida et al. Partial purification of human histone deacetylase

The human histone deacetylase was partially purified from human T cell leukemia Jurkat cells. Jurkat cells (5 x 10⁸ cells) were suspended in 40 mL of the EDA buffer consisting of 15 mM potassium phosphate (pH 7.5), 5% glycerol and 0.2 mM EDTA. After homogenization, nuclei were collected by centrifugation (35,000 x g, 10 min) and homogenized in 20 mL of the same buffer supplemented with 1 M (NH₄)₂Sθ₄. The viscous ho ogenate was sonicated and clarified by centrifugation (35,000 x g, 10 min), and the deacetylase was precipitated by raising the concentration of (NH₄)₂S0₄ to 3.5 M. The precipitated protein was dissolved in 10 mL of the HDA buffer and dialyzed against 4 liters of the same buffer. The dialyzate was then loaded onto a DEAE-cellulose (Whatman DE52) column (25 x 85 mm) equilibrated with the same buffer and eluted with 300 mL of a linear gradient (0-0.6 M) of NaCl. A single peak of histone deacetylase activity appeared between 0.3 and 0.4 M NaCl. Preparation of [³H] acetyl histone

To obtain [³H] acetyl-labeled histone as the substrate for the histone deacetylase assay, 1 x 10⁸ cells of Jurkat in 20 mL of RPMI-1640 medium (supplemented with 10% FBS, penicillin (50 units/mL) and streptomycin (50 μg/mL) ) were incubated with 300 MBq [³H] sodium acetate in the presence of 5 mM sodium butyrate for 30 min in 5% C0₂-95% air atmosphere at 37°C in a 75 cm² flask, harvested into a centrifuge tube (50 mL), collected by centrifugation at 1000 rpm for 10 min, and washed once with phosphate-buffered saline. The washed cells were suspended in 15 mL of ice-cold lysis buffer (pH 6.5, 10 mM Tris-HCl, 50 mM sodium bisulfite, 1% Triton X-100, 10 mM MgCl₂, 8.6% sucrose). After Dounce homogenization (30 stroke), the nuclei were collected by centrifugation at 1000 rpm for 10 min, washed 3 times with 15 mL of the lysis buffer, and once with 15 mL of ice-cooled washing buffer (pH 7.4, 10 mM Tris-HCl, 13 mM EDTA) successively. The pellet was suspended in 6 mL of ice-cooled water using a mixer, and 68 μl of H₂S0₄ was added to the suspension to give a concentration of 0.4 N. After incubation at 4°C for 1 hr, the suspension was centrifuged for 5 min at 15,000 rpm, and the supernatant was taken and mixed with 60 mL of acetone. After overnight incubation at -20°C, the coagulated material was collected by microcentrifugation, air-dried, and stored at -80°C. Assay for histone deacetylase activity

For the standard assay, 10 μl of [³H] acetyl-labeled histones were added to 90 μl of the enzyme fraction, and the mixture was incubated at 25°C for 30 min. The reaction was stopped by addition of 10 μl of HCl. The released [³H] acetic acid was extracted with 1 mL of ethyl acetate, and 0.9 mL of the solvent layer was taken into 10 mL of toluene scintillation solution for determination of radioactivity. Test 2: Determination of T-cell growth inhibitor activity The T lymphocyte blastogenesis test was performed in microtiter plates with each well containing 1.5 x 10⁵ splenic cells of Lewis rats in 0.1 mL RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), 50 mM 2-mercaptoethanol, penicilln ( 100 units/mL) and streptomycin ( 100 μg/mL) , to which Concanavalin A (1 μg/mL) was added. The cells were incubated at 37°C in a humidified atmosphere of 5% C0₂ for 72 hr. After the culture period, suppressive activities of the test compounds in T lymphocyte blastogenesis were quantified by AlamarBlue (trademark) Assay. The test samples were dissolved in DMSO and further diluted with RPMI-1640 medium and added to the culture. The activities of the test compounds were expressed as IC₅₀. The results of those tests are shown in the Table 1.

Table 1: HDAC inhibitory activity and T-cell growth inhibitory activity of the compound of the present invention

Examples Test 1: Test 2:

HDAC T-cell inhibitory growth activity inhibitory

IC50 (nM) activity

Compound El <10 <4

Compound E3 <10 <4

Compound E4 <10 <4

Compound E5 <10 <4

The pharmaceutical composition of the present invention comprising histone deacetylase inhibitor such as the compound [I] is useful as a therapeutic or prophylactic agent for diseases caused by abnormal gene expression, such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), protozoal infection and the like. Further, it is useful as an antitumor agent or immunosuppressant, which prevents an organ transplant rejection and autoimmune diseases as exemplified below.

Rejection reactions by transplantation of organs or tissues (e.g., heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small, intestine, limb, muscle, nerve, intervertebral disc, trachea, myoblast, cartilage and the like) and the like; graft-versus-host reactions following bone marrow transplantation; autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes and the like); infections caused by pathogenic microorganisms (e.g., Aspergillus fumigatus, Fusarium oxysporum, Trichophyton asteroides and the like) ; and the like.

Furthermore, pharmaceutical preparations of the histone deacetylase inhibitor, such as the compound [I], are useful for the therapy or prophylaxis of the following diseases.

Inflammatory or hyperproliferative skin diseases or cutaneous manifestations of immunologically-mediated diseases (e.g., psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, erythema, dermal eosinophilia, lupus erythematosus, acne, alopecia areata and the like) ; autoimmune diseases of the eye (e.g., keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy and the like); reversible obstructive airway diseases [e.g., asthma (e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma), particularly chronic or inveterate asthma (e.g., late asthma, airway hyper-responsiveness and the like), bronchitis and the like]; mucosal or vascular inflammations (e.g., gastric ulcer, ischemic or thrombotic vascular injury, ischemic bowel diseases, enteritis, neσrotizing enterocolitis, intestinal damages associated with thermal burns, leukotriene B4-mediated diseases and the like) ; intestinal inflammations/allergies (e.g., coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis and the like); food-related allergic diseases with symptomatic manifestation remote from the gastrointestinal tract (e.g., migrain, rhinitis, eczema and the like) ; renal diseases (e.g., intestitial nephritis, Goodpasture' s syndrome, hemolytic uremic syndrome, diabetic nephropathy and the like); nervous diseases (e.g., multiple myositis, Guillain-Barre syndrome, Meniere's disease, multiple neuritis, solitary neuritis, cerebral infarction, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), radiculopathy and the like); cerebral ischemic diseases [e.g., head injury, hemorrhage in brain (e.g., subarachnoid hemorrhage, intracerebral hemorrhage and the like), cerebral thrombosis, cerebral embolism, cardiac arrest, stroke, transient ischemic attack (TIA), hypertensive encephalopathy and the like]; endocrine diseases (e.g., hyperthyroidism, Basedow's disease and the like); hematic diseases (e.g., pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia and the like); bone diseases (e.g., osteoporosis and the like); respiratory diseases (e.g., sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia and the like); skin diseases (e.g., dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photosensitivity, cutaneous T-cell lymphoma and the like); circulatory diseases (e.g., arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis and the like); collagen diseases (e.g., scleroderma, Wegener's granuloma, Sjδgren's syndrome and the like); adiposis; eosinophilic fasciitis; periodontal diseases (e.g., damage to gingiva, periodontium, alveolar bone or substantia ossea dentis and the like); nephrotic syndrome (e.g., glomerulonephritis and the like); male pattern alopecia, alopecia senile; muscular dystrophy; pyoderma and Sezary syndrome; chromosome abnormality-associated diseases (e.g., Down's syndrome and the like) ;

Addison's disease; active oxygen-mediated diseases {e.g., organ injury [e.g., ischemic circulation disorders of organs (e.g., heart, liver, kidney, digestive tract and the like) associated with preservation and transplantation and the like], ischemic diseases (e.g., thrombosis, cardial infarction and the like), intestinal diseases (e.g., endotoxin shock, pseudomemforanous colitis, drug- or radiation-induced colitis and the like), renal diseases (e.g., ischemic acute renal insufficiency, chronic renal failure and the like), pulmonary diseases [e.g., toxicosis caused by pulmonary oxygen or drugs (e.g., paracort, bleomycin and the like), lung cancer, pulmonary emphysema and the like], ocular diseases (e.g., cataracta, iron-storage disease (siderosis bulbi), retinitis, pigmentosa, senile plaques, vitreous scarring, corneal alkali burn and the like), dermatitis (e.g., erythema multiforme, linear immunoglobulin A bullous dermatitis, cement dermatitis and the like), other diseases [e.g., gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (e.g., air pollution and the like) , aging, carcinogen, metastasis of carcinoma, hypobaropathy and the like] and the like}; diseases caused by histamine release or leukotriene C4 release; restenosis of coronary artery following angioplasty and prevention of postsurgical adhesions; autoimmune diseases and inflammatory conditions [e.g., primary mucosal edema, autoimmune atrophic gastritis, premature menopause, male sterility, juvenile diabetes mellitus, pemphigus vulgaris, pemphigoid, sympathetic ophthalmitis, lens-induced uveitis, idiopathic leukopenia, active chronic hepatitis, idiopathic cirrhosis, discoid lupus erythematosus, autoimmune orchitis, arthritis (e.g., arthritis deformans and the like), polychondritis and the like] ;

Human Immunodeficiency Virus (HIV) infection, AIDS; allergic conjunctivitis; hypertrophic cicatrix and keloid due to trauma, burn, surgery and the like; and the like.

Therefore, the pharmaceutical composition of the present invention is useful for the therapy and prophylaxis of liver diseases [e.g., immunogenic diseases (e.g., chronic autoimmune liver diseases such as autoimmune hepatic diseases, primary biliary cirrhosis, sclerosing cholangitis and the like), partial liver resection, acute liver necrosis (e.g., necrosis caused by toxins, viral hepatitis, shock or anoxia and the like), hepatitis B, non-A non-B hepatitis, hepatocirrhosis, hepatic failure (e.g., fulminant hepatitis, late-onset hepatitis and "acute-on-chronic" liver failure (acute liver failure on chronic liver diseases) and the like) and the like] .

The pharmaceutical composition of the present invention can be used in the form of pharmaceutical preparation, for example, in a solid, semisolid or liquid form, which contains the histone deacetylase inhibitor, such as the compound [I], as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral administrations. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, injections, ointments, liniments, eye drops, lotion, gel, cream, and any other form suitable for use.

The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in a solid, semisolid, or liquid form. Additionally, auxiliary, stabilizing, thickening, solubilizing and coloring agents and perfumes may be used in combination with the carrier.

For application to human, the composition is preferably applied by intravenous, intramuscular, topical or oral administration, or by a vascular stent impregnated with the compound [I] . While the dosage of therapeutically effective amount of the histone deacetylase inhibitor, such as the compound [I] , varies depending upon the age and condition of each individual patient to be treated, when an individual patient is to be treated, in the case of intravenous administration, a daily dose of 0.01-10 mg of the histone deacetylase inhibitor, such as the compound [I], per kg weight of human being, in the case of intramuscular administration, a daily dose of 0.1-10 mg of the histone deacetylase inhibitor, such as the compound of the formula [I], per kg body weight of human being, and in the case of oral administration, a daily dose of 0.5-50 mg of the histone deacetylase inhibitor, such as the compound [I], per kg body weight of human being, is generally given for treatment.

During the preparation of the above-mentioned pharmaceutical administration forms, the compound [I] or a salt thereof can be also combined together with other immunosuppressive substances, such as repamycin, mycophenoliσ acid, cyclosporin A, tacrolius and brequinar sodium.

Hereinafter the reactions in respective Preparations and Examples for preparing the compound [I] of the present invention are explained in more detail. The invention should not be restricted by the following Preparations and Examples in any way. Preparation 1

To a stirred suspension of (2S)-2-amino-8-(benzyloxy)-8- oxσoctanoic acid (150 mg) in dioxane (3 mL) were added di-tert- butyldicarbonate (176 mg) in dioxane (1 mL) and lN-sodium hydroxide (0.8 mL), and the mixture was stirred at ambient temperature for 13 hr. The solvent was evaporated in vacuo. The residue was diluted with water and washed with diethyl ether. The aqueous layer was acidified with IN-hydrogen chloride to pH 2, and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give Compound (1) as a colorless oil (188 mg).

^-NMR (300 MHz, DMSO-de, δ) : 1.28-1.50 (4H, m) , 1.45 (3x3H, S),

1.56-1.73 (IH, m), 1.84 (IH, m) , 2.36 (2H, t, J=7.3 Hz), 4.28 (IH, m), 4.98 (IH, br-d, J=8 Hz), 5.11 (2H, s), 7.28-7.41 (5H, ) ; MASS (ES-): m/e 378. Preparation 2

To a stirred solution of Compound (1) (182 mg) in N,N- dimethylformamide (4 mL) were added 1-hydroxybenzotriazole (HOBT, 78 mg) , l-eth l-3-(3 '-dimethylaminopropyl)carbodiimide hydrochloride (WSCD-HC1, 110 mg) and 1,2-diaminonaphthalene (83.5 mg), and the mixture was stirred at ambient temperature for 18 hr. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogencarbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by preparative thin layer chromatography (hexane:ethyl acetate = 1:1) to give Compound (2) as a brown oil (197 mg).

^-NMR (300 MHz, CDC1₃, δ) : 1.32-1.54 (4H, m) , 1.48 (3x3H, s), 1.57-1.78 (3H, m) , 1.96 (IH, m) , 2.37 (2H, t, J=7.3 Hz), 4.19 (IH, dt, J=7, 6.5 Hz), 4.43 (2H, br-s), 5.12 (2H, s), 5.12 (IH, m) , 7.21-7.50 (9H, m) , 7.72-7.81 (2H, m) , 7.93 (IH, s); MASS (ES+): m/e 520. Preparation 3

A solution of Compound (2) (10.1 g) in a mixed solvent of toluene (108 mL) and acetic acid (12 mL) was stirred at 55°C for 30 min. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography (eluting with a mixture of hexane and ethyl acetate=2:l) to give Compound (3) as a brown amorphous (9.75 g) .

^Η-NMR (300 MHz, DMSO-dβ, δ) : 1.19-1.46 (4H, m) , 1.40 (3x3H, s), 1.48-1.62 (2H, m) , 1.85 (IH, m) , 1.96 (IH, m) , 2.35 (2H, t, J=7.3 Hz), 4.82 (IH, m), 5.07 (2H, s), 7.26-7.74 ( 10H, m) , 7.97 (IH, m) , 8.38 (IH, m), 12.47 (0.6H, s), 13.00 (0.4H, s); MASS (ES+) : m/e 502. Preparation 4

A mixture of Compound (3) (282 mg) and 10% palladium on carbon (30 mg) in methanol (6 mL) was stirred under hydrogen atmosphere at ambient temperature for 1 hr. The catalyst was filtered off through a pad of Celite® and the solvent was evaporated in vacuo to dryness to give Compound (4) as a white amorphous (285 mg).

'Η-NMR (300 MHz, CDC1₃, δ) : 1.18-1.74 (6H, m) , 1.42 (3x3H, s), 2.13 (2H, m), 2.38 (2H, m) , 5.01 (IH, m) , 6.62 (IH, d, J=8 Hz), 7.34-7.58 (4H, m) , 7.82 (IH, d, J=7.5 Hz), 8.17 (IH, br); MASS (ES+) : m/e 412. Preparation 5

To a stirred solution of Compound (4) (242 mg) in N,N- dimethylformamide (4 mL) were added 0-benzylhydroxylamine hydroσhloride (141 mg), HOBT (119 mg) and l-ethyl-3-(3 ' - dimethylaminopropyl)carbodiimide (WSCD, 137 mg) and the mixture was stirred at ambient temperature for 15 hr. The reaction mixture was diluted with ethyl acetate and washed successively with water, saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogencarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol = 10:1) to give Compound (5) as a pale yellow amorphous (257 mg) . ^- MR (300 MHz, CDC1₃, δ) : 1.16-1.65 (6H, m) , 1.43 (3x3H, s), 1.70-2.25 (4H, m) , 4.69-5.00 (3H, m) , 5.52-5.75 (IH, m) , 7.24- 8.18 (10H, m), 8.53 (IH, br), 9.10-9.30 ( IH, br) ; MASS (ES+): m/e 517. Preparation 6 To a stirred solution of Compound (5) (244 mg) in dioxane (6 mL) was added 4N-hydrogen chloride in dioxane (2 mL) , and the mixture was stirred at ambient temperature for 2 hr. The solvent was evaporated in vacuo to give Compound (6) hydrochloride as a pale yellow amorphous (254 mg) . ^Η-NM (300 MHz, DMSO-dβ, δ) : 1.16-1.54 (6H, m) , 1.93 (2H, t, J=7 Hz), 2.14 (2H, m), 4.72 (IH, m) , 4.75 (2H, s), 7.28-7.42 (5H, m) , 7.57 (IH, dd, J=8, 7 Hz), 7.69 ( IH, dd, J=8, 7 Hz), 7.78-7.88 (2H, m), 8.08 (IH, d, J=8 Hz), 8.48 (IH, d, J=8 Hz), 8.94 (2H, br), 10.99 (IH, br); MASS (ES+): m/e 417. Preparation 7

To a stirred solution of Compound (6) (218 mg) in N,N- dimethylformamide (5 mL) were added HOBT (78 mg), WSCD (90 mg) and 4-(methoxycarbonyl)benzoic acid (95 mg), and the resulting mixture was stirred at ambient temperature for 15 hr. This mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed successively with water, saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogencarbonate solution and brine. The organic phase was dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate

(2:1 to 1:1) to give Compound (7) as a pale yellow amorphous (193 mg) . The obtained Compound (7) was used in Example 1. ^XH-NMR (300 MHz, DMSO-d₆, δ) : 1.24-1.60 (6H, m) , 1.95 (2H, t, J=6.5 Hz), 2.06 (IH, m) , 2.21 (IH, m) , 3.89 (3H, S), 4.76 (2H, s), 5.40 (IH, m), 7.28-7.50 (6H, m) , 7.52-7.78 (3H, m) , 7.97 ( IH, m) , 8.03-8.15 (4H, m) , 8.40 ( IH, m) , 9.19 (IH, d, J=8 Hz), 10.94 (IH, s), 12.61 (0.5H, s), 13.11 (0.5H, s); MASS (ES+): m/e 579. Preparation 8

To a stirred solution of Compound (7) (133 mg) in methanol (3 mL) was added lN-sodium hydroxide (0.46 mL), and the mixture was stirred at ambient temperature for 7 hr. The mixture was neutralized with IN-hydrogen chloride and extracted with ethyl acetate. The organic phase was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give Compound (8) (115 mg). The obtained Compound (8) was used in Example 2. ^Η- MR (300 MHz, DMSO-d₆, δ) : 1.22-1.60 (6H, m) , 1.85-2.30 (4H, m) , 4.77 (2H, s), 5.41 (IH, m) , 7.26-7.50 (6H, m) , 7.52-7.78 (3H, m) , 7.92-8.14 (5H, m) , 8.40 (IH, br-d, J=7 Hz), 9.17 (IH, d, J=7.5 Hz), 10.95 (IH, s), 12.64 (0.5H, s), 13.18 (0.5H, S); MASS (ES+) : m/e 563. Preparation 9

To a stirred solution of (7S)-7~amino-N-(benzyloxy)-7-(3H- naphtho[l,2-d]imidazol-2-yl)heptanamide (111 mg) in dichloromethane (3 mL) were added triethylamine (0.045 mL) and then methanesulfonyl chloride in dichloromethane (1 ml) at 0°C. The mixture was stirred at the same temperature for 1 hr and left at ambient temperature for 15 hr. The resulting mixture was washed successively with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogencarbonate solution and brine. The organic phase was dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by preparative thin layer chromatography to give Compound (9) as a pale yellow amorphous (114 mg) . The obtained Compound (9) was used in Example 3.

^Η-NMR (300 MHz, DMSO-d₆, δ) : 1.16-1.58 (6H, m) , 1.85-2.05 (4H, m) , 2.74 (3x0.4H, S), 2.81 (3x0.6H, s), 4.65 (IH, m) , 4.76 (2H, S), 7.28-7.42 (5H, ) , 7.46 (IH, m) , 7.54-7.84 (5H, m) , 7.99 (IH, dd,

J=7.5, 7.5 Hz), 8.35 (0.4H, d, J=8 Hz), 8.42 (0.6H, d, J=8 Hz),

10.93 (IH, br-s), 12.61 (0.6H, s), 13.13 (0.4H, s);

MASS (ES+): m/e 495. Preparation 10

Compound (10) (338 mg) was obtained in a manner similar to

Preparation 7. The obtained Compound (10) was used in Example 4.

^-MR (300 MHz, DMSO-de, δ) : 1.26-1.60 (6H, m) , 1.96 (2H, t,

J=6.5 Hz), 2.07 (IH, m) , 2.22 (IH, m) , 3.90 (3H, S), 4.76 (2H, s), 5.42 (IH, ), 7.28-7.50 (6H, m) , 7.53-7.76 (4H, m) , 7.98 (IH, d,

J=7, 7 Hz), 8.13 (IH, d, J=8 Hz), 8.25 (IH, d, J=8 Hz), 8.40 ( IH, m), 8.58 (IH, m), 9.24 (IH, d, J=7.5 Hz), 10.94 (IH, s), 12.61

(0.6H, s), 13.11 (0.4H, s);

MASS (ES+): m/e 579. Preparation 11

Compound (11) (659 mg) was obtained in a manner similar to

Preparation 2.

^Η-NMR (300 MHz, CDC1₃, δ): 1.30-1.52 (4H, m) , 1.47 (3x3H, s),

1.55-1.77 (3H, m) , 1.95 ( IH, m) , 2.37 (2H, t, J=7 Hz), 3.97 (2H, br), 4.17 (IH, dt, J=7, 7 Hz), 5.05 (IH, d, J=7 Hz), 5.11 (0.5H, s), 5.12 (0.5H, s), 6.83 (0.5H, d, J=8 Hz), 6.96-7.03 (IH, m) ,

7.22-7.58 (11.5H, m) 7.91 (0.5H, s), 7.96 (0.5H, s);

MASS (ES+): m/e 546.

Preparation 12 Compound (12) (591 mg) was obtained in a manner similar to

Preparation 3.

^^•H-NMR ( 300 MHz, DMSO-ds, δ) : 1.21-1.46 ( 4H, m) , 1.40 ( 3x3H, s) ,

1.48-1.62 (2H, m) , 1.70-1.84 ( 2H, m) , 1.86-2.00 ( 2H, m) , 2.35 (2H, t, J=7.3 Hz ) , 4.75 ( IH, m) , 5.07 (2H, s) , 7.28-7.84 ( 14H, m) , 12 .22 ( IH, br) ;

MASS (ES+) : m/e 528.

Preparation 13

Compound (13) (478 mg) was obtained in a manner similar to

Preparation 3. ^XH-NMR (300 MHz, DMSO-dg, δ) : 1.20-1.55 (6H, m) , 1.40 (3x3H, S), 1.70-2.00 (2H, m), 2.19 (2H, t, J=7 Hz), 4.75 (IH, m) , 7.27-7.38

(2H, m), 7.40-7.86 (7H, m) ;

MASS (ES+): m/e 438.

Preparation 14 Compound (14) (456 mg) was obtained in a manner similar to

Preparation 5.

^Η-NMR (300 MHz, DMSO-de, δ) : 1.16-1.54 (6H, m) , 1.40 (3x3H, s),

1.70-2.01 (4H, m), 4.74 ( IH, m) , 4.77 (2H, s), 7.27-7.82 ( 14H, m) ,

10.94 (IH, s), 12.21 (0.5H, s), 12.22 (0.5H, s); MASS (ES+): m/e 543.

Preparation 15

Compound (15) (353 mg) was obtained in a manner similar to

Preparation 6.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.14-1.56 (6H, m) , 1.69 (IH, m) , 1.81 (IH, m), 1.93 (2H, m) , 4.01 (IH, m) , 4.77 (2H, s), 7.28-7.80

(13H, m), 11.95 (IH, br);

MASS (ES+): m/e 443.

Preparation 16

Compound (16) (173 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (16) was used in Example 5.

^-NMR (300 MHz, DMSO-d₆, δ) : 1.20-1.58 (6H, m) , 1.95 (3H, t,

J=7.3 Hz), 2.00 (IH, m) , 2.14 (IH, m) , 4.77 (2H, s), 5.32 (IH, m) ,

7.29-7.72 (15.5H, m) , 7.83 (0.5H, s), 7.97 (2H, d, J=7.7 Hz),

8.91 (IH, d, J=8 Hz), 10.95 (IH, s), 12.31 (0.5H, s), 12.34 (0.5H, s) ;

MASS (ES+): m/e 547.

Preparation 17

Compound (17) (53 mg) was obtained in a manner similar to

Preparation 5. The obtained Compound (17) was used in Example 6. ^-NMR (300 MHz, CDC1₃, δ) : 1.18-1.60 (6H, m) , 1.64-2.02 (2H, m) ,

2.04-2.39 (2H, m) , 4.86 (2H, s), 5.45 (IH, m) , 7.18-7.46 ( 12H, m) ,

7.62 (IH, d, J=8.5 Hz), 7.82 (2xlH, d, J=7.5 Hz), 7.85 (IH, d,

J=9 Hz), 9.23 (IH, br) ; MASS (ES+): m/e 521. Preparation 18

A solution of Compound (10) (116 mg) in 40% methylamine in methanol (6 mL) was stirred at ambient temperature for 3 hr. The solvent was evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol = 10:1) to give Compound (18) as a pale yellow amorphous (126 mg) . The obtained Compound (18) was used in Example 7.

^-NMR (300 MHz, DMSO-d₆, δ) : 1.26-1.58 (6H, m) , 1.90-2.42 (4H, m) , 2.80 (3H, d, J=4.5 Hz), 4.71-4.94 (2H, m) , 5.41 (IH, m) , 7.28-

7.76 (10H, m), 7.90-8.13 (3H, m) , 8.31-8.58 (3H, m) , 9.06 (IH, m) ,

10.94 ( IH, m) , 12.61 (0.6H, S) , 13.12 ( 0.4H, s) ;

MASS (ES+) : m/e 578.

Preparation 19 Compound (19) (531.6 mg) was obtained in a manner similar to Preparation 2.

¹H-NMR (300 MHz, CDCl₃, δ) : 1.32-1.51 (4H, m) , 1.46 (9H, s), 1.60-

1.75 (3H, ), 1.86-2.00 (IH, m) , 2.37 (2H, t, J=7.3 Hz), 4.07- 4.17 (IH, m), 4.25 (2H, s), 5.04-5.11 (IH, m) , 5.11 (2H, s), 6.75 (IH, d, J=8.1 Hz), 7.23-7.31 (2H, m) , 7.30-7.42 (5H, m) , 7.48 (IH, s), 7.97 (IH, s);

MASS (ES+): m/e 538.22 (M-KL).

Preparation 20

Compound (20) (663 mg) was obtained in a manner similar to Preparation 3.

^XH-NMR (300 MHz, CDC1₃, δ) : 1.28-1.51 (4H, m) , 1.45 (9H, s), 1.57-

1.76 (4H, m), 1.87-2.06 (IH, m) , 2.10-2.26 (IH, m) , 2.34 (2H, t, J=7.4 Hz), 4.76-4.88 (IH, m) , 5.10 (2H, s), 5.29 (IH, d, J=7.7 Hz), 7.28-7.40 (5H, m) , 7.40-7.52 (2H, m) , 7.60-7.83 (IH, m) , 7.99 (0.4H, s) , 10.74-10.63 (0.6H, br);

MASS (ES+): m/e 520.21 (M+l) .

Preparation 21

Compound (21) (629 mg) was obtained in a manner similar to

Preparation 6. ^- MR (300 MHz, CDC1₃, δ) : 0.85-1.14 (2H, m) , 1.16-1.56 (4H, m) , 2.24 (2H, t, J=7.0 Hz), 2.29-2.44 (2H, m) , 3.71 (2H, s), 5.03 (2H, s), 5.53 (IH, br), 7.25-7.41 (5H, m) , 7.71 ( IH, d, J=8.4 Hz), 7.90 (IH, d, J=8.4 Hz), 8.11 ( IH, s), 9.12-9.80 (IH, br) ; MASS (ES+): m/e 420.10 (free). Preparation 22

Compound (22) (473 mg) was obtained in a manner similar to Preparation 7.

^-NR (300 MHz, CDC1₃, δ) : 1.17-1.67 (6H, m) , 1.79 (IH, brs), 2.03-2.39 (2H, m) , 2.82 (2H, t, J=7.6 Hz), 5.07 (2H, s) , 5.33- 5.47 (IH, m), 7.25-7.55 (10H, m) , 7.66-7.88 (IH, m) , 7.80 (2H, d, J=8.4 Hz), 7.86 (0.5H, s), 11.58-11.85 (0.5H, m) ; MASS (ES+): m/e 524.39 (M+l) . Preparation 23

To a solution of benzyl (7S)-7-(benzoylamino)-7-[5- (trifluoromethyl)-lH-benzimidazol-2-yl]heptanoate (473 mg) in methanol (5 mL) was added 10% palladium on barium sulfate (48 mg) and the mixture was stirred under hydrogen atmosphere at ambient temperature for 2 hr. The catalyst was filtered off through a pad of Celite®. The solvent was evaporated in vacuo, and the residue was purified by preparative thin layer chromatography (hexane:ethyl acetate = 10:1) to give Compound (23) (397 mg) .

^XH-NMR (300 MHz, DMSO-de, δ) : 1.27-1.60 (6H, m) , 1.94-2.26 (2H, m) , 2.19 (2H, t, J=7.3 Hz), 5.27-5.39 ( IH, m) , 7.44-7.61 (4H, m) , 7.63-7.77 (IH, m) , 7.79-7.93 ( IH, m) , 7.96 (IH, d, J=8.1 Hz), 8.98 (2H, d, J=8.1 Hz), 11.84-12.92 (IH, br) ; MASS (ES+) : m/e 434.39 (M+l). Preparation 24

To a solution of Compound (23) (394 mg) in N,N- dimethylformamide (6 mL) were added HOBT (160 mg) and WSCD-HC1 (227 mg), and the mixture was stirred for 1 hr. To the mixture was added tetrahydropyranyloxyamine (160 mg) and the mixture was stirred for 1 hr. To the mixture were added additional tetrahydropyranyloxyamine (1.5 equivalents) , HOBT (1.3 equivalent) and WSCD-HC1 (1.3 equivalents), and the mixture was stirred for 3 hr. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:l) to give Compound

(24) (568 mg). The obtained Compound (24) was used in Example 8.

^XH-NMR (300 MHz, DMSO-de, δ) : 1.24-1.76 ( 12H, m) , 1.92-2.22 (4H, m), 3.44-3.54 (IH, m) , 3.84-3.96 (IH, m) , 4.79 (IH, s), 5.27-5.39 (IH, m), 7.44-7.61 (5H, m) , 7.61-7.83 (IH, m) , 7.92-8.03 (3H, m) ,

8.32 (0.2H, s), 8.96 (IH, d, J=8.1 Hz), 10.90 (0.8H, s);

MASS (ES+) : m/e 533.38 (M+l) .

Preparation 25

Compound (25) (596.3 mg) was obtained in a manner similar to Preparation 2. -NMR (300 MHz, CDCl₃, δ) : 1.49-1.55 (5H, m) , 1.62-1.76 (3H, m) ,

1.84-2.01 (IH, m), 2.37 (2H, t, J=7.3 Hz), 4.05-4.20 (3H, m) ,

4.95-5.06 (IH, m) , 5.12 (2H, s), 6.51 (IH, dd, J=9.2, 8.1 Hz),

6.84-6.93 (IH, m) , 7.29-7.41 (5H, m) , 7.84 (IH, s); MASS (ES+) : m/e 506.15 (M+l).

Preparation 26

Compound (2β) (600 mg) was obtained in a manner similar to

Preparation 3.

^- MR (300 MHz, CDC1₃, δ) : 1.34-1.46 (4H, m) , 1.44 (6H, s), 1.45 (3H, s), 1.57-1.72 (2H, m) , 1.88-2.06 (IH, m) , 2.10-2.29 (IH, m) ,

2.34 (IH, t, J=7.3 Hz), 2.35 (IH, t, J=7.3 Hz), 4.70-4.84 (IH, m) ,

5.11 (2H, s), 5.12-5.31 (IH, m) , 7.00-7.11 (2H, m) , 7.31-7.42 (5H m), 10.40-10.57 ( IH, m) ;

MASS (ES+): m/e 488.15 (M+l). Preparation 27

Compound (27) (521 mg) was obtained in a manner similar to

Preparation 6. -NMR (300 MHz, CDC1₃, δ) : 0.92-1.57 (6H, m) , 2.12-2.40 (4H, m) ,

3.71 (IH, s), 5.04 (2H, s), 5.26-5.42 (IH, m) , 7.21-7.38 (7H, m) , 7.45-7.57 (IH, m) ;

MASS (ES+) : m/e 388 .09 ( free) .

Preparation 28

Compound (28) (397 mg) was obtained in a manner similar to

Preparation 7. ^-NMR (300 MHz, CDC1₃, δ) : 1.11-1.67 (6H, m) , 2.08-2.37 (2H, m) , 2.25 (2H, t, J=7.3 Hz) , 5.06 (2H, s) , 5.32-5.52 ( IH, m) , 6.92- 7.11 (2H, m) , 7.24-7.42 (7H, m) , 7.47 (2H, dd, J=6.2, 7.3 Hz) , 7.55-7.69 ( 0.4H, m) , 7.77-7.94 ( 0.6H, m) , 7.81 ( IH, d, J=7.7 Hz) , 8.16-8.21 ( 0.1H, m) , 11.88-12.00 (0.7H, m) , 12.04-12.27 ( 0.2H, m) ;

MASS (ES+): m/e 492.24 (M+l). Preparation 29

Compound (29) (327 mg) was obtained in a manner similar to Preparation 23. -NMR (300 MHz, CDC1₃, δ) : 1.26-1.58 (6H, m) , 1.91-2.25 (2H, m) ,

2.19 (2H, t, J=7.0 Hz), 5.23-5.34 ( IH, m) , 7.14-7.34 (2H, m) ,

7.45-7.65 (3H, m) , 7.96 (2H, d, J=8.4 Hz), 8.90-9.07 (IH, m) ,

11.92-12.27 (0.4H, ) , 12.69 (0.6H, brs);

MASS (ES-): m/e 400.20 (M-l). Preparation 30

Compound (30) (116 mg) was obtained in a manner similar to

Preparation 24. The obtained Compound (30) was used in Example 9.

^XH-NMR (300 MHz, DMSO-d₅, δ) : 1.22-1.73 (12H, m) , 1.92-2.19 (2H, m), 1.97 (2H, t, J=6.6 Hz), 3.42-3.53 (IH, m) , 3.85-3.95 (IH, m) , 4.79 (IH, S), 5.22-5.32 ( IH, m) , 7.16-7.30 (2H, m) , 7.46-7.60 (3H, m), 7.93-8.01 (2H, ) , 8.92-9.00 (IH, m) , 10.88-10.95 (0.6H, m) ,

12.65-12.72 (0.4H, m) .

Preparation 31

Compound (31) (104.8 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (31) was used in Example

10.

^Η-NMR (300 MHz, CDC1₃, δ) s 1.22-1.60 (6H, m) , 1.88-2.32 (4H, m) ,

4.77 (2H, s), 5.34-5.47 ( IH, m) , 7.29-7.78 (11H, m) , 7.94-8.02

(IH, m), 8.30 (IH, d, J=8.4 Hz), 8.34-8.45 (IH, m) , 8.71-8.78 (IH, m), 9.13 (IH, s), 9.21 (IH, d, J=8.4 Hz), 10.95 (0.6H, s), 12.62

(0.2H, s), 13.11 (0.2H, s);

MASS (ES+): m/e 522.35 (M+l).

Preparation 32

Compound (32) (109.5 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (32) was used in Example 11.

^-NMR (300 MHz, DMSO-d₆, δ) : 1.25-1.59 (6H, m) , 1.91-2.14 (IH, m) , 1.95 (2H, t, J=7.3 Hz), 2.15-2.31 (IH, m) , 4.77 (2H, s), 5.30- 5.43 (IH, m), 7.25-7.40 (5H, m) , 7.41-7.50 (IH, m) , 7.52-7.77 (3H, ), 7.85-7.91 (2H, m) , 7.94-8.02 (IH, m) , 8.33-8.47 (IH, m), 8.73-8.81 (2H, m) , 9.31 (IH, d, J=8.1 Hz), 10.95 (0.5H, brs), 12.64 (0.3H, brs), 13.13 (0.2H, brs); MASS (ES+): m/e 522.18 (M+l). Preparation 33 Compound (33) (116 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (33) was used in Example 12. ^- R (300 MHz, DMSO-d₆, δ) : 1.20-1.55 (6H, m) , 1.82-2.24 (4H, m) ,

4.75 (2H, s), 5.38-5.50 (IH, m) , 7.28-7.42 (5H, m) , 7.42-7.51 ( IH, m), 7.53-7.79 (4H, m) , 7.94-8.15 (4H, m) , 8.23-8.50 (IH, m) , 8.72 (IH, dd, J=4.8, 1.1 Hz), 9.05-9.22 (IH, m) , 10.93 (0.6H, brs),

12.70 (0.2H, brs), 13.19 (0.2H, brs);

MASS (ES+)s m/e 522.32 (M+l).

Preparation 34

Compound (34) (432.1 mg) was obtained in a manner similar to Preparation 2.

^XH-NMR (300 MHz, CDC1₃, δ) : 1.31-1.53 (4H, m) , 1.46 (9H, s) , 1.53-

1.76 (3H, m), 1.85-2.01 (IH, m) , 2.39 (IH, t, J=7.3 Hz), 4.07 (IH, dt, J=8.1, 6.2 Hz), 4.51 (2H, brs), 5.03 (IH, d, J=6.2 Hz), 5.12 (2H, s), 6.72 (IH, d, J=8.4 Hz), 7.31-7.41 (5H, m) , 7.31 (IH, dd, J=8.4, 1.8 Hz), 7.52 ( IH, d, J=1.8 Hz), 7.86 ( IH, s); MASS (ES+): m/e 495.19 (M+l). Preparation 35

Compound (35) (467 mg) was obtained in a manner similar to Preparation 3. ^-NMR (300 MHz, CDC1₃, δ) : 1.33-1.51 (4H, m) , 1.45 (9H, s), 1.56- 1.74 (2H, m), 1.90-2.07 (IH, m) , 2.08-2.27 (IH, m) , 2.35 (2H, t, J=7.3 Hz), 4.75-4.86 (IH, m) , 5.11 (2H, s), 5.17-5.29 (IH, m) , 7.29-7.39 (6H, m) , 7.40-7.52 (2H, m), 8.04 (0.6H, s), 10.62-10.74 (0.4H, m); MASS (ES+) : m/e 477.20 (M+l ) . Preparation 36

Compound (36) (474 mg) was obtained in a manner similar to Preparation 6. -NMR (300 MHz, DMSO-de, δ) : 1.18-1.37 (4H, m) , 1.44-1.58 (2H, m) , 1.93-2.09 (2H, m) , 2.32 (2H, t, J=7.3 Hz), 4.56-4.70 (IH, m) ,

5.05 (2H, s), 7.30-7.41 (5H, ) , 7.65 (IH, dd, J=8.4, 1.5 Hz),

7.79 (IH, d, J=8.4 Hz), 8.21 (IH, s), 8.72-8.86 (3H, m) ;

MASS (ES+): m/e 377.14 (free).

Preparation 37 Compound (37) (411 mg) was obtained in a manner similar to

Preparation 7.

^- MR (300 MHz, CDC1₃, δ) : 1.20-1.69 (6H, m) , 1.72-2.39 (2H, m) ,

2.29 (2H, t, J=7.3 Hz), 5.07 (2H, s), 5.36-5.51 (IH, m) , 7.25-

7.62 (11H, m), 7.66-7.88 (IH, m) , 7.80 (2H, d, J=7.7 Hz), 7.99 (0.6H, s), 11.83-12.04 (0.4H, m) ;

MASS (ES+) : m/e 481.19 (M+l ) .

Preparation 38

Compound (38) (302 mg) was obtained in a manner similar to

Preparation 23. ^-NMR (300 MHz, DMSO-d₆, δ) s 1.25-1.59 (6H, m) , 1.92-2.23 (2H, m) ,

2.19 (2H, t, J=7.3 Hz), 5.31 (IH, dt, J=8.1, 5.5 Hz), 7.43-7.60

(5H, m), 7.66 ( IH, d, J=8.1 Hz), 7.96 (2H, d, J=8.4 Hz), 8.05 (IH, brs), 8.99 (IH, d, J=8.1 Hz);

MASS (ES+) : m/e 391.12 (M+l). Preparation 39

Compound (39) (339 mg) was obtained in a manner similar to

Preparation 24. The obtained Compound (39) was used in Example

13.

^-NMR (300 MHz, DMSO-dg, δ) : 1.14-1.74 (12H, m) , 1.90-2.22 (4H, m), 3.42-3.45 ( IH, m) , 3.82-3.96 (IH, m) , 4.79 (IH, s), 5.26-5.38 (IH, m), 6.00 (IH, br), 7.46-7.79 (5H, m), 7.93-8.19 (2.5H, m) , 8.95 (IH, d, J=8.1 Hz), 10.75 (0.3H, brs), 12.79 (0.2H, br); MASS (ES+): m/e 490.21 (M+l). Preparation 40 Compound (40) (102 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (40) was used in Example 14. ^XH-NMR (300 MHz, DMSO-de, δ) : 1.23-1.60 (6H, m) , 1.88-2.29 (2H, m) , 1.94 (2H, t, J=7.3 Hz), 2.97 (6H, s), 4.76 (2H, s), 5.31-5.44 (IH, m), 6.72 (2H, d, J=9.2 Hz), 7.28-7.49 (6H, m) , 7.52-7.78 (3H, m) , 7.84 (2H, d, J=9.2 Hz), 7.92-8.01 (IH, m) , 8.35-8.43 (IH, m) ,

8.50-8.59 ( IH, m) , 10.94 ( 0.5H, S) , 12.51 ( 0.3H, S) , 13.06 ( 0.2H, s);

MASS (ES+) : m/e 564.32 (M+l).

Preparation 41 Compound (41) (154 mg) was obtained in a manner similar to

Preparation 7. The obtained Compound (41) was used in Example 15. -NMR (300 MHz, DMSO-d₆, δ) : 1.22-1.60 (6H, m) , 1.95 (2H, t,

J=7.0 Hz), 1.97-2.31 (2H, m) , 4.77 (2H, s), 5.36-5.50 (IH, m) ,

7.04 (IH, dd, J=7.3, 7.0 Hz), 7.20 (IH, dd, J=8.1, 7.3 Hz), 7.27- 7.40 (7H, m), 7.40-7.49 (2H, ) , 7.53-7.77 (5H, m) , 7.93-8.03 ( IH, m), 8.34-8.45 ( IH, m) , 8.95 (IH, d, J=7.3 Hz), 10.94 (0.7H, s),

11.61 (IH, s), 12.64 (0.2H, brs), 13.15 (0.1H, brs);

MASS (ES+): m/e 560.29 (M+l).

Preparation 42 Compound (42) (117 mg) was obtained in a manner similar to

Preparation 7. The obtained Compound (42) was used in Example 16.

¹H-NMR (300 MHz, DMSO-de, δ) : 1.20-1.57 (6H, m) , 1.93 (2H, d, J=7.0 Hz), 2.00-2.29 (2H, m) , 4.75 (2H, s), 5.38-5.49 (IH, m) , 7.26-7.40 (5H, m) , 7.45 (IH, dd, J=7.7, 7.7 Hz), 7.58 (IH, dd, J=7.7, 7.7 Hz), 7.63-7.79 (2H, m) , 7.98 ( IH, d, J=7.7 Hz), 8.27- 8.47 (IH, m), 8.80 (IH, d, J=2.6 Hz), 8.92 (IH, d, J=2.6 Hz), 9.18-9.37 (IH, m) , 9.25 (IH, s), 10.93 (0.7H, brs), 12.65 (0.2H, brs), 13.12 (0.1H, brs); MASS (ES+): m/e 523.26 (M+l). Preparation 43

Compound (43) (139 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (43) was used in Example 17. ^- MR (300 MHz, DMSO-dg, δ) : 0.83 (3H, t, J=6.6 Hz), 1.16-1.42 (8H, m), 1.41-1.62 (4H, m) , 1.77-2.30 (6H, m) , 4.77 (2H, s), 5.07-5.22 (IH, m) , 7.28-7.40 (5H, m) , 7.40-7.49 (IH, m) , 7.52- 7.75 (2H, m), 7.65 (IH, s), 7.93-8.01 (IH, m) , 8.32-8.44 (2H, m) , 10.94 (0.5H, s), 12.51 (0.3H, s), 13.06 (0.2H, s); MASS (ES+): m/e 515.22 (M+l). Preparation 44 To a stirred solution of (7S)-amino-N-(benzyloxy)-7-(3H- naphtho[l,2-d]imidazol-2-yl)heptanamide (120 mg) in methylene chloride (2 mL) were added acetic anhydride (0.054 mL) and pyridine (0.047 mL) , and the mixture was stirred at ambient temperature for 2 hr. The mixture was poured into water and extraxted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate solution, water and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo. The residue was purified by preparative thin layer chromatography (CHCl₃:methano1=9:1) to give Compound (44) (120 mg). The obtained Compound (44) was used in Example 18.

¹H-MMR (300 MHz, DMSO-d₆, δ) : 1.20-1.55 (6H, m) , 1.75-2.13 (2H, m) , 1.91 (3H, s), 1.93 (2H, t, J=7.3 Hz), 4.77 (2H, s), 5.04-5.19 (IH, m), 7.30-7.40 (5H, ) , 7.40-7.50 (IH, m) , 7.52-7.79 (2H, m) , 7.65 (IH, s), 7.93-8.02 (IH, m) , 8.32-8.44 (IH, m) , 8.46 ( IH, d, J=8.4 Hz), 10.94 (0.5H, brs), 12.53-12.59 (0.3H, m) , 13.05-13.13 (0.2H, m);

MASS (ES+) : m/e 459.19 (M+l).

Preparation 45

To a stirred solution of (7S)-amino-N-(benzyloxy)-7-(3H- naphtho[l,2-d]imidazol-2-yl)heptanamide (120 mg) in chloroform (3 mL) was added a solution of phenyl isocyanate (41.2 mg) in chloroform (0.5 mL) . The mixture was stirred for 2 hr. The solvent was evaporated, and the residue was triturated with diisopropyl ether and dried to give Compound (45) as a white powder (153 mg) . The obtained Compound (45) was used in Example 19.

^Η-NMR (300 MHz, DMSO-de, δ) : 1.20-1.61 (6H, m) , 1.82-2.07 (2H, ) , 1.93 (2H, t, J=7.3 Hz), 4.75 (2H, s), 4.98-5.14 (IH, m) , 6.82 ( IH, d, J=7.7 Hz), 6.89 (2H, dd, J=7.3, 7.3 Hz), 7.22 (2H, dd, J=7.3, 7.3 Hz), 7.27-7.43 (7H, m) , 7.46 (IH, dd, J=8.1, 7.7 Hz), 7.59 ( IH, dd, J=8.1, 7.7 Hz) , 7.62-7.78 (2H, m) , 7.99 ( IH, d, J=8.1 Hz) , 8.33-8 .45 ( IH, m) , 8.68 ( IH, s) , 10.92 ( IH, s) ; MASS (ES+) : m/e 536.25 (M+l) . Preparation 46 Compound ( 46 ) ( 161 mg) was obtained in a manner similar to

Preparation 7. The obtained Compound (46 ) was used in Example 20.

^Η-NMR ( 300 MHz, DMSO-dg, δ) : 1.00-2.31 ( 20H, m) , 4.77 (2H, s) , 5.06-5.20 ( IH, m) , 7.28-7.50 ( 6H, m) , 7.74-7.52 ( 3H, m) , 7.93- 8.02 ( 2H, m) , 8 .25 ( IH, d, J=8 .0 Hz ) , 8 .31-8.43 ( IH, m) ; MASS (ES+): m/e 527.33 (M+l). Preparation 47

Compound (47) (142 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (47) was used in Example 21. ^XH-NMR (300 MHz, DMSO-d₆, δ) : 0.82 (3H, t, J=6.6 Hz), 1.13-1.40 (10H, m), 1.39-1.61 (4H, m) , 1.77-2.10 (4H, m) , 2.08-2.30 (2H, m) , 4.77 (2H, s), 5.08-5.22 (IH, m), 7.28-7.40 (5H, m) , 7.40-7.50 ( IH, m), 7.51-7.74 (3H, ) , 7.65 (IH, s), 7.94-8.01 (IH, m) , 8.32-8.43 (2H, m), 10.94 (0.5H, s), 12.51 (0.3H, s), 13.06 (0.2H, s); MASS (ES+) : m/e 529.36 (M+l). Preparation 48

Compound (48) (96 mg) was obtained in a manner similar to Preparation 44. The obtained Compound (48) was used in Example 22. -NMR (300 MHz, DMSO-d₆, δ) : 1.10-1.37 (4H, m) , 1.38-1.57 (2H, m) , 1.84-2.16 (4H, m) , 2.86 (6H, s), 4.77 (2H, a ) , 4.98-5.07 (IH, m) ,

6.66 (IH, s, J=9.2 Hz), 7.29-7.41 (5H, m) , 7.40-7.70 (3H, m) ,

7.76 (IH, s), 7.94-8.06 (IH, m) , 8.35-8.44 (2H, m) , 10.90-11.00

(IH, m);

MASS (ES+): m/e 488.26 (M+l). Preparation 49

Compound (49) (101 mg) was obtained in a manner similar to

Preparation 44. The obtained Compound (49) was used in Example

23.

^-NMR (300 MHz, DMSO-dg, δ) : 0.99 (3H, t, J=7.0 Hz), 1.15-1.35 (6H, m), 1.38-1.56 (2H, m) , 1.72-2.04 (4H, m) , 2.97-3.09 (IH, m) , 4.76 (2H, s), 4.92-5.06 (IH, m) , 6.00 (IH, t, J=5.5 Hz), 6.37- 6.47 (IH, m), 7.26-7.41 (6H, ) , 7.40-7.49 (IH, m) , 7.52-7.75 (3H, m), 7.92-8.02 (IH, m) , 8.29-8.44 (IH, m) , 10.92 (0.6H, s), 12.56 (0.3H, s), 13.09 (0.1H, s); MASS (ES+): m/e 488.22 (M+l). Preparation 50

Compound (50) (160 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (50) was used in Example 24. ^- MR (300 MHz, DMSO-dg, δ) : 1.23-1.59 (6H, m) , 1.88-2.29 (4H, m) , 2.36 (3H, s), 4.76 (2H, S), 5.31-5.46 ( IH, m) , 7.29 (2H, d, J=8.1 Hz), 7.32-7.39 (5H, m) , 7.40-7.49 (IH, m) , 7.51-7.68 (2H, m) , 7.64 (IH, s), 7.72 (IH, d, J=9.2 Hz), 7.88 (2H, d, J=8.1 Hz), 7.92-8.02 (IH, m) , 8.34-8.43 (IH, m) , 8.82-8.90 (IH, m) , 10.94 (0.5H, s), 12.55 (0.3H, s), 13.08 (0.2H, s); MASS (ES+): m/e 535.31 (M+l). Preparation 51

Compound (51) (62.8 mg) was obtained in a manner similar to Preparation 9. The obtained Compound (51) was used in Example 25. ¹H-NMR (300 MHz, DMSO-d₆, δ) : 0.89-1.22 (4H, m) , 1.21-1.40 (2H, m) , 1.67-1.93 (4H, m) , 4.41-4.53 (IH, m) , 4.75 (2H, s) , 7.24-7.49 (9H, m), 7.50-7.67 (3H, m) , 7.67-7.80 (2H, m) , 7.93-7.99 (IH, m) , 8.23-8.43 (2H, m) , 10.90 (0.6H, s), 12.47 (0.3H, S), 12.94 (0.1H, s);

MASS (ES+): m/e 557.24 (M+l). Preparation 52

Compound (52) (62.8 mg) was obtained in a manner similar to Preparation 48. The obtained Compound (52) was used in Example

26.

^-NMR (300 MHz, DMSO-dg, δ) : 1.15-1.41 (6H, m) , 1.18 (3H, t, J=6.6 Hz), 1.40-1.57 (2H, m) , 1.77-2.11 (2H, m) , 1.94 (2H, t, J=7.3 Hz), 3.93-4.10 (2H, m) , 4.77 (2H, s), 4.78-4.92 ( IH, m) , 7.28-7.51 (6H, m) , 7.51-7.79 (4H, m) , 7.97 (IH, dd, J=7.7, 6.2 Hz), 8.38 (IH, dd, J=8.1, 7.7 Hz), 10.94 (0.5H, s), 12.51 (0.3H, s), 13.02 (0.2H, s); MASS (ES+): m/e 489.20 (M+l). Preparation 53

Compound (53) (116 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (53) was used in Example 27. ^-NMR (300 MHz, DMSO-dg, δ) : 1.10-1.59 (6H, m) , 1.22 (6H, d, J=6.6 Hz), 1.89-2.30 (2H, m) , 1.95 (2H, t, J=7.7 Hz), 2.87-3.03 (IH, m), 4.76 (2H, S), 5.32-5.46 (IH, m) , 7.27-7.40 (7H, m) , 7.51-7.69 (2H, m) , 7.65 ( IH, s), 7.73 (IH, d, J=8.8 Hz), 7.91 (2H, d, J=8.1 Hz), 7.97 (IH, dd, J=7.7, 7.0 Hz), 8.39 (IH, dd, J=7.7, 7.3 Hz), 8.81-8.90 (IH, m) , 10.94 (0.5H, s), 12.53 (0.3H, s), 13.06 (0.2H, s);

MASS (ES+): m/e 563.30 (M+l). Preparation 54

Compound (54) (116 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (54) was used in Example 28. ^- MR (300 MHz, DMSO-d₆, δ) : 1.21-1.61 (6H, m) , 1.85-2.40 (4H, m) , 2.35 (IH, s), 2.36 (2H, s), 4.77 (2H, s), 5.27-5.43 (IH, m) , 7.19-7.51 (10H, m) , 7.52-7.77 (2H, m) , 7.67 (IH, s), 7.73 (IH, d, J=7.7 Hz), 7.92-8.04 (IH, m) , 8.35-8.45 ( IH, m) , 8.73-8.83 (IH, m), 10.95 (0.5H, s) , 12.56 (0.3H, s), 13.12 (0.2H, s); MASS (ES+): m/e 535.35 (M+l). Preparation 55

Compound (55) (149 mg) was obtained in a manner similar to Preparation 48. The obtained Compound (55) was used in Example 29. ^- MR (300 MHz, DMSO-dg, δ) : 1.22-1.59 (6H, m) , 1.95 (2H, t,

J=7.3 Hz), 1.98-2.29 (2H, m) , 2.37 (3H, s), 4.76 (2H, s), 5.33- 5.45 (IH, m), 7.29-7.40 (4H, m) , 7.41-7.49 (IH, m) , 7.52-7.61 (IH, m), 7.62-7.80 (3H, m) , 7.97 (IH, d, J=8.1 Hz), 8.32 (0.6H, s), 8.40 (IH, d, J=8.4 Hz), 8.89 ( IH, d, J=8.1 Hz), 10.93 (0.4H, s); MASS (ES+): m/e 535.31 (M+l). Preparation 56

Compound (56) (252 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (56) was used in Example 30.

^-NMR (300 MHz, DMSO-d₆, δ) : 1.20-1.41 (4H, m) , 1.41-1.59 (2H, m) , 1.80-2.01 (3H, ) , 2.00-2.31 (IH, ) , 2.09 (3H, s), 4.56 (2H, dd, J=17.9, 2.9 Hz), 4.77 (2H, s), 5.10-5.24 (IH, m) , 7.27-7.41 (6H, m), 7.41-7.51 (IH, m) , 7.53-7.76 (3H, ) , 7.97 (IH, d, J=7.7 Hz), 8.31-8.44 (IH, m) , 8.59-8.69 ( IH, m) , 10.93 (0.5H, s), 12.59 (0.3H, s), 13.07 (0.2H, s); MASS (ES+): m/e 517.21 (M+l). Preparation 57

Compound (57) (147 mg) was obtained in a manner similar to Preparation 7.

^XH-NMR (300 MHz, DMSO-de, δ) : 1.19-1.40 (4H, m) , 1.40-1.57 (2H, m) , 1.78-2.00 (3H, m) , 1.99-2.24 (IH, ) , 2.09 (3H, s), 4.56 (2H, s), 4.76 (2H, s), 5.09-5.24 (IH, m) , 7.28-7.40 (6H, m) , 7.40-7.50 (IH, m), 7.52-7.77 (3H, m) , 7.97 (IH, d, J=7.7 Hz), 8.30-8.45 (IH, m) , 8.57-8.70 (IH, m) , 10.93 (0.5H, s), 12.58 (0.3H, s), 13.06 (0.2H, s); MASS (ES+): m/e 517.22 (M+l).

Preparation 58

Compound (58) (80 mg) was obtained in a manner similar to

Preparation 8. The obtained Compound (58) was used in Example 31.

¹H-NMR (300 MHz, DMSO-dg, δ) s 1.13-1.39 (4H, m) , 1.39-1.56 (2H, m) , 1.86-2.12 (2H, m) , 1.93 (2H, t, J=7.3 Hz), 3.93 (2H, s) , 4.76 (2H, s), 5.19-5.32 (IH, m) , 7.27-7.43 (6H, m) , 7.45-7.55 (IH, m) ,

7.58-7.68 (IH, m) , 7.68-7.79 (2H, m) , 8.02 (IH, d, J=8.4 Hz),

8.15-8.24 (IH, m) , 8.41 ( IH, d, J=8.4 Hz), 10.94 ( IH, s);

MASS (ES+): m/e 475.27 (M+l). Preparation 59

Compound (59) (143 mg) was obtained in a manner similar to

Preparation 7. The obtained Compound (59) was used in Example 32.

^- MR (300 MHz, DMSO-dg, δ) : 1.19-1.4 (4H, m) , 1.40-1.57 (2H, m) ,

1.82-2.13 (2H, m), 1.93 (2H, t, J=7.0 Hz), 3.40 (3H, s), 3.92 (2H, s), 4.76 (2H, s), 5.16-5.29 (IH, m) , 7.27-7.41 (6H, m), 7.41-7.51

(IH, m), 7.53-7.75 (2H, m) , 7.66 (IH, s), 7.93-8.02 (IH, m) ,

8.14-8.27 (IH, m) , 8.29-8.44 (IH, m) , 10.93 (0.5H, s), 12.57

(0.3H, s), 13.07 (0.2H, s);

MASS (ES+): m/e 489.20 (M+l). Preparation 60

Compound (60) (82 mg) was obtained in a manner similar to

Preparation 7. The obtained Compound (60) was used in Example 33.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.16-1.40 (4H, m) , 1.40-1.58 (2H, m) , 1.81-2.10 (4H, m) , 2.24 (3H, s), 2.26 (3H, s), 2.88-3.04 (2H, m) ,

4.76 (2H, s), 5.15-5.27 (IH, m) , 7.28-7.41 (6H, m) , 7.41-7.51 (IH, m), 7.53-7.77 (2H, m) , 7.66 (IH, s), 7.94-8.03 (IH, m) , 8.11-8.23

(IH, m), 8.27-8.43 (IH, m) , 10.93 (0.5H, S), 12.60 (0.3H, s),

13.10 (0.2H, s); MASS (ES+) : m/e 502.27 (M+l).

Preparation 61

Compound (61) (75 mg) was obtained in a manner similar to

Preparation 48. The obtained Compound (61) was used in Example

34. ^-NMR (300 MHz, DMSO-dg, δ) : 0.89 (6H, d, J=6.6 Hz), 1.18-1.41

(4H, m), 1.41-1.57 (2H, m) , 1.68-2.09 (5H, m) , 3.66-3.85 (2H, m) ,

4.68-4.92 (IH, m) , 4.77 (2H, s), 7.28-7.51 (7H, m) , 7.52-7.79 (3H, m), 7.65 (IH, s), 7.92-8.02 (IH, m) , 8.33-8.44 (IH, ) , 10.94

( 0.5H, s) , 12.52 ( 0.3H, s) , 13.04 ( 0.2H, s) ; MASS (ES+) : m/e 517.29 (M+l ) .

Preparation 62

Compound (62) (131.4 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (62) was used in Example

35. ^- R (300 MHz, DMSO-dg, δ) : 1.01 (3H, d, J=6.3 Hz), 1.06 (3H, d,

J=6.6 Hz), 1.18-1.39 (4H, m) , 1.40-1.56 (2H, m) , 1.78-2.12 (5H, m), 4.76 (2H, s), 5.07-5.22 (IH, m) , 7.28-7.40 (6H, m) , 7.40-7.50

(IH, m), 7.52-7.76 (3H, m) , 7.65 (IH, s), 7.94-8.01 (IH, m),

8.28-8.43 (2H, m) , 10.93 (0.5H, s), 12.51 (0.3H, s), 13.08 (0.2H, s);

MASS (ES+): m/e 487.30 (M+l). Preparation 63

Compound (63) (124.7 mg) was obtained in a manner similar to Preparation 48. The obtained Compound (63) was used in Example 36. -NMR (300 MHz, DMSO-de, δ) : 1.16 (9H, S), 1.21-1.39 (4H, m) ,

1.40-1.57 (2H, m) , 1.86-2.14 ( 4H, m) , 4.77 (2H, s) , 5.13-5.28 ( IH, m) , 7.29-7.49 (6H, m) , 7.51-7.77 (3H, m) , 7.79-7.89 ( IH, m) , 7.93-8.02 ( IH, m) , 8.30-8.45 ( IH, m) , 10.94 ( 0.5H, s) , 12 .50 (0.3H, s) , 13.14 (0.2H, s) ; MASS (ES+) : m/e 501.27 (M+l). Preparation 64

Compound (64) (124.7 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (64) was used in Example 37. ^Η-NMR (300 MHz, DMSO-d₆, δ) : 1.11-1.35 (4H, m) , 1.35-1.56 (2H, m) , 1.71-2.10 (2H, m), 1.93 (2H, t, J=7.3 Hz), 2.37-2.59 (2H, m) , 2.76-2.93 (2H, m) , 4.77 (2H, s), 5.07-5.22 (IH, ) , 7.08-7.27 (5H, m), 7.28-7.50 (6H, ) , 7.52-7.76 (3H, m) , 7.93-8.02 (IH, m) , 8.30-8.48 (2H, m) , 10.94 (0.5H, s), 12.53 (0.3H, s), 13.07 (0.2H, s) ;

MASS (ΞS+): m/e 549.34 (M+l). Preparation 65

Compound (65) (311 mg) was obtained in a manner similar to Preparation 48. The obtained Compound (65) was used in Example 38. -NMR (300 MHz, DMSO-dg, δ) : 1.16 (3H, t, J=7.0 Hz), 1.21-1.56 (6H, m), 1.79-2.14 (2H, m) , 1.94 (2H, t, J=7.3 Hz), 3.29 ( IH, d, J=15.4 Hz), 3.39 (IH, d, J=15.4 Hz), 4.07 (2H, q, J=7.0 Hz), 4.76 (2H, s), 5.07-5.21 (IH, m) , 7.28-7.41 (5H, m) , 7.41-7.51 (IH, m) , 7.53-7.78 (3H, m) , 7.94-8.02 (IH, m) , 8.41 (IH, d, J=8.1 Hz),

8.72 ( IH, d, J=8.1 Hz) , 10.93 ( 0.5H, s) , 12.60 ( 0.3H, s) , 13.10

( 0.2H, s) ;

MASS (ES+) : m/e 531.33 (M+l ) .

Preparation 66 Compound (66) (115 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (66) was used in Example 39.

^XH-NMR (300 MHz, DMSO-de, δ) : 1.13-1.35 (4H, m) , 1.36-1.53 (2H, m) ,

1.74-2.11 (4H, m), 2.83 (6H, s), 4.76 (2H, s) , 5.04-5.21 (IH, m) ,

6.64 (2H, d, J=8.1 Hz), 7.09 (IH, d, J=8.1 Hz), 7.12 (IH, d, J=8.1 Hz), 7.28-7.40 (6H, m) , 7.40-7.51 (IH, m) , 7.53-7.77 (3H, m), 7.94-8.02 (IH, m) , 8.30-8.45 (IH, m) , 8.51-8.59 (IH, m) ,

10.92 (0.5H, s), 12.57 (0.3H, S), 13.09 (0.2H, s);

MASS (ES+) : m/e 578.39 (M+l).

Preparation 67 Compound (67) (141 mg) was obtained in a manner similar to

Preparation 7. The obtained Compound (67) was used in Example 40.

^-NMR (300 MHz, DMSO-d₆, δ) : 1.21-1.57 (6H, m) , 1.88-2.29 (2H, m) ,

1.95 (2H, t, J=7.0 Hz), 4.76 (2H, s), 5.28-5.40 ( IH, m) , 6.96 (IH, s), 7.31-7.51 (6H, m) , 7.52-7.82 (4H, m) , 7.94-8.03 ( IH, m) , 8.29 (IH, s), 8.34-8.45 ( IH, m) , 8.70 (IH, d, J=8.1 Hz), 10.94 (0.5H,

S), 12.60 (0.3H, S), 13.12 (0.2H, S);

MASS (ES+): m/e 511.17 (M+l).

Preparation 68

Compound (68) (146.9 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (68) was used in Example

41. -HMR (300 MHz, DMSO-dg, δ) : 1.24-1.44 (4H, m) , 1.43-1.57 (2H, m) ,

1.87-2.31 (4H, m) , 4.76 (2H, s), 5.27-5.41 (IH, m) , 6.65 (IH, dd,

J=3.7, 1.5 Hz), 7.24 (IH, d, J=3.7 Hz), 7.28-7.41 (6H, m) , 7.40- 7.51 (IH, m), 7.53-7.78 (3H, m) , 7.88 (IH, d, J=1.5 Hz), 7.94-

8.02 (IH, ), 8.32-8.49 (IH, m) , 8.76-8.88 (IH, m) , 10.94 (0.7H, s), 12.58 (0.2H, s), 13.09 (0.1H, s);

MASS (ES+) : m/e 511.19 (M+l).

Preparation 69 Compound (69) (136.8 mg) was obtained in a manner similar to Preparation 8. The obtained Compound (69) was used in Example

42. -NMR (300 MHz, DMSO-dg, δ) : 1.12-1.56 (6H, m) , 1.78-2.12 (2H, m) , 1.93 (2H, t, J=6.6 Hz), 3.22 (IH, d, J=15.0 Hz), 3.31 (IH, d, J=15.0 Hz), 4.76 (2H, s), 5.08-5.19 (IH, m) , 7.29-7.41 (5H, m) , 7.45 (IH, dd, J=7.7, 8.1 Hz), 7.58 (IH, dd, J=7.7, 8.1 Hz), 7.62- 7.76 (2H, m), 7.98 (IH, d, J=7.7 Hz), 8.34-8.42 (IH, m) , 8.69 ( IH, d, J=7.7 Hz), 10.92 (IH, s); MASS (ES+): m/e 503.23 (M+l). Preparation .70

Compound (70) (87.2 mg) was obtained in a manner similar to Preparation 9. The obtained Compound (70) was used in Example 43.

^-NMR (300 MHz, DMSO-dg, δ) : 0.98-1.11 (3H, m) , 1.14-1.54 (6H, m) ,

1.84-2.02 (4H, m) , 2.69-2.94 (2H, m) , 4.54-4.69 (IH, m) , 4.76 (2H, s), 7.26-7.39 (5H, m) , 7.42-7.51 (IH, m) , 7.53-7.85 (4H, m) ,

7.93-8.03 (IH, m) , 8.30-8.46 (IH, m) , 10.94 (0.5H, s), 12.62

(0.3H, s), 13.15 (0.2H, s);

MASS (ES+): m/e 509.23 (M+l).

Preparation 71 Compound (71) (91.1 mg) was obtained in a manner similar to

Preparation 9. The obtained Compound (71) was used in Example 44.

^^■H-NMR (300 MHz, DMSO-dg, δ) : 0.69 (3H, t, J=7.3 Hz), 1.17-1.61 (8H, m), 1.84-2.03 (2H, m) , 1.93 (2H, t, J=7.3 Hz), 2.59-2.97 (2H, m), 4.55-4.66 (IH, m) , 4.76 (2H, s), 7.29-7.42 (6H, m) , 7.41-7.51 (IH, m), 7.53-7.77 (3H, m) , 7.80 (IH, d, J=8.4 Hz), 7.98 ( IH, dd, 3=1.1, 7.3 Hz), 8.30-8.46 ( IH, m) , 10.93 (0.5H, s), 12.62 (0.3H, s), 13.14 (0.2H, s); MASS (ES+): m/e 523.24 (M+l). Preparation 72 To a solution of (7S)-7-amino-N-(benzyloxy)-7-(3H- naphtho[ 1,2-d]imidazol-2-y1)heptanamide ( 120 mg) in dichloromethane (2 mL) were added succinic anhydride, molecular sieves (4A, powder) and triethylamine (87.5 mg), and the mixture was refluxed for 15 hr. To the reaction mixture was added 10% aqueous citric acid solution and extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, water and brine and concentrated in vacuo to give Compound (72) as a gummy substance. The obtained

Compound (72) was used in Example 45. ^XH-NMR (300 MHz, DMSO-dg, δ) : 1.18-1.40 (4H, m) , 1.39-1.55 (2H, m) , 1.76-2.12 (4H, m) , 2.32-2.56 (4H, m) , 4.76 (2H, s), 5.05-5.19 (IH, m), 7.32-7.51 (7H, m) , 7.53-7.83 (3H, m) , 7.94-8.02 (IH, m) , 8.31-8.51 (IH, m), 8.45 (IH, d, J=7.7 Hz), 10.93 (0.8H, s), 12.02-12.22 (IH, br), 12.48 (0.1H, s), 1.98 (0.1H, s); MASS (ES+): m/e 517.26 (M+l).¹ Preparation 73

Compound (73) (148.7 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (73) was used in Example 46. ^-NMR (300 MHz, DMSO-dg, δ) : 1.23-1.58 (6H, m) , 1.86-2.34 (4H, m) ,

4.76 (2H, s), 5.29-5.43 (IH, m) , 6.81 (2H, d, J=8.8 Hz), 7.26- 7.41 (6H, m), 7.39-7.49 (IH, m) , 7.51-7.77 (3H, m) , 7.84 (2H, d, J=8.8 Hz), 7.92-8.01 (IH, m) , 8.34-8.44 ( IH, m) , 8.61-8.70 (IH, m), 10.01 (IH, s), 10.94 (0.5H, s), 12.51 (0.3H, s), 13.05 (0.2H, S);

MASS (ES+): m/e 537.25 (M+l).

Preparation 74

Compound (74) (116 mg) was obtained in a manner similar to

Preparation 7. The obtained Compound (74) was used in Example 47. ¹H- MR (300 MHz, CDC1₃, δ) : 1.14-1.37 (4H, m) , 1.32 (6H, s), 1.37-

1.52 (2H, m), 1.80-2.05 (2H, ) , 1.91 (2H, t, J=6.6 Hz), 4.75 (2H, s), 5.10-5.21 (IH, ), 7.27-7.39 (5H, m) , 7.41-7.51 (IH, m) ,

7.54-7.76 (3H, m) , 7.94-8.09 (2H, m) , 8.23-8.44 (IH, m) , 10.93

(0.5H, s), 12.62 (0.3H, s), 13.15 (0.2H, s); MASS (ES+): m/e 503.23 (M+l).

Preparation 75

Compound (75) (138 mg) was obtained in a manner similar to

Preparation 7. The obtained Compound (75) was used in Example 48.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.19-1.59 (6H, m) , 1.95 (2H, t, J=7.3 Hz), 1.97-2.12 (IH, m) , 2.13-2.30 (IH, m) , 4.76 (2H, s),

5.32-5.47 (IH, ) , 7.29-7.41 (6H, m) , 7.40-7.49 (IH, m) , 7.52-

7.77 ( 3H, m) , 7.99 ( IH, d, J=8.1 Hz ) , 7.99 ( IH, d, J=8.4 Hz) , 8.12 (2H, d, J=8.4 Hz) , 8.33-8.44 ( IH, m) , 9.26 ( IH, d, J=8.4 Hz) , 10.94 ( 0.5H, s) , 12.63 ( 0.3H, s) , 13.12 ( 0.2H, s) ; MASS (ES+) : m/e 546.22 (M+l) . Preparation 76

Compound (76) (28 mg) was obtained in a manner similar to Preparation 7. The obtained Compound (76) was used in Example 49. ^-NMR (300 MHz, DMSO-dg, δ) : 1.11-1.43 (4H, m) , 1.42-1.61 (2H, m) , 1.81-2.07 (2H, m) , 2.09-2.47 (2H, m) , 2.74 (3H, brs), 2.89 (IH, brs), 4.79 (2H, s), 5.33-5.46 (IH, m) , 7.29-7.52 (7H, m) , 7.52-

7.82 (3H, m), 7.90-8.07 (IH, m) , 8.29-8.49 (IH, m) , 10.96 (0.5H, S), 12.60 (0.3H, S), 12.85 (0.2H, S);

MASS (ES+): m/e 499.18 (M+l). Preparation 77

To a solution of benzyl (lS)-5-(tert- butyldimethylsilyl)oxy-1-(5-phenyl-lH-benzimidazol-2-yl)- pentylcarbamate (3.0 g) in N,N-dimethylformamide (50 mL) was added potassium t-butoxide (805 mg) under ice-cooling, and the mixture was stirred at 0°C for 30 min. To the mixture were added 3, 4-dimethoxybenzyl bromide (1.91 g) and tetrabutylammonium iodide (TBAI, 408 mg) , and the mixture was stirred at 0°C for 3 hr. The reaction was quenched by adding saturated aqueous ammonium chloride solution, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over sodium sulfate. The dried mixture was filtered, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluting with CHC1₃:ethyl acetate=95:5 then 9:1). The resulting solid was triturated with diethyl ether to give Compound (77) (1.64 g).

^-NMR (300 MHz, CDC1₃, δ) : 0.01 (6H, S), 0.85 (9H, s), 1.19-1.54 (4H, m), 1.88-2.06 (2H, m) , 3.50 (2H, t, J=5.9 Hz), 3.77 (3H, s) ,

3.83 (3H, s), 5.00 (IH, d, J=12.1 Hz), 5.04-5.18 ( IH, ) , 5.10 (IH, d, J=12.1 Hz), 5.40-5.59 (IH, m) , 5.50 (IH, d, J=16.5 Hz), 5.53 (IH, d, J=16.5 Hz), 6.63 (IH, dd, J=8.4, 1.3 Hz), 6.73 (IH, d, J=1.4 Hz),¹ 6.75 (IH, d, J=8.4 Hz), 7.23-7.38 (6H, m) , 7.39- 7.64 (5H, m), 7.53 (IH, d, J=8.4 Hz), 7.80 (IH, d, J=8.4 Hz); MASS (ES+): m/e 694.46 (M+l). Preparation 78 A suspension of benzyl (lS)-5-{[tert- butyldimethylsilyl]oxy}-l-[ l-( 3, 4-dimethoxybenzyl)-5-phenyl-lH- benzimidazol-2-yl]pentylcarbonate (2.73 g) and 10% palladium on carbon (270 mg) in methanol (50 mL) and acetic acid (12 mL) was stirred under hydrogen atmosphere at ambient temperature for 30 min. The catalyst was removed through a pad of Celite®, and the solvent was evaporated. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution (x3), water and brine, and dried over sodium sulfate. The mixture was filtered and the solvent was evaporated to give Compound (78) (1.89 g).

^XH-NMR (300 MHz, CDC1₃, δ): 0.01 (6H, S), 0.85 (9H, s), 1.21-1.58 (4H, m), 1.76-2.06 (2H, m) , 3.55 (2H, t, J=5.9 Hz), 3.78 (2H, s), 3.78 (IH, s), 3.83 (2H, s), 3.84 (IH, S), 4.06-4.17 (IH, m) , 5.35-5.51 (2H, m) , 6.52-6.62 (IH, m) , 6.66-6.72 (IH, m) , 6.72- 6.80 (IH, m), 7.23-7.37 (IH, m) , 7.38-7.68 (5H, m) , 7.51 (IH, d, J=8.4 Hz), 7.82 (IH, d, J=8.4 Hz); MASS (ES+): m/e 560.24 (M+l). Preparation 79

Compound (79) (1.97 mg) was obtained in a manner similar to Preparation 7.

^XH-NMR (300 MHz, DMSO-d₆, δ) : 0.03 (6H, s), 0.82 (9H, s), 1.29- 1.57 (4H, m), 2.03-2.23 (2H, m) , 3.51-3.58 (2H, m) , 3.63 (3H, s), 3.67 (2H, s), 3.69 (IH, s), 5.51-5.65 (IH, m) , 5.56 (IH, d, J=16.1 Hz), 5.66 (IH, d, J=16.1 Hz), 6.65-6.71 (IH, m) , 6.80-6.88 (IH, m), 6.89-6.97 (IH, m) , 7.32-7.58 (7H, ) , 7.65-7.76 (3H, m) , 7.76-7.94 (3H, m) , 9.04-9.12 (IH, m) ; MASS (ES+): m/e 664.41 (M+l). Preparation 80

To a solution of Compound (79) (1.97 g) in tetrahydrofuran (20 mL) was added tetrabutylammonium fluoride (TBAF, 5.34 g) and the mixture was stirred for 2 hr. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and filtered. The solvent was evaporated to give a crude compound. The compound was crystallized from hexane to give Compound (80) (1.48 g) .

^-NMR (300 MHz, DMSO-dg, δ) : 1.25-1.69 (6H, m) , 2.06-2.21 (2H, m) , 3.65 (3H, s), 3.68 (2H, S), 3.70 (IH, S), 4.40 (IH, t, J=5.1 Hz), 5.52-5.71 (IH, m) , 5.58 (IH, d, J=16.1 Hz), 5.62 ( IH, d, J=16.1 Hz), 6.68-6.75 (IH, m) , 6.82-6.88 (IH, m) , 6.90-6.96 (IH, m) , 7.32-7.40 (IH, m) , 7.42-7.59 (6H, m) , 7.66-7.79 (4H, m) , 7.84- 7.94 (2H, m), 9.05-9.13 (IH, m) ; MASS (ES+) : m/e 550.21 (M+l). Preparation 81 Compound (80) was dissolved in a mixture of methylene chloride (10 ml) and dimethyl sulfoxide (4 ml) with heating in a water bath. To the solution were added periodinane (702 mg) and sodium hydrogencarbonate (139 mg) and the mixture was stirred at ambient temperature for 3 hr. The reaction was quenched by adding a 20% solution of sodium thiosulfate in saturated aqueous sodium hydrogencarbonate solution under ice-cooling. The mixture was stirred for 15 min under ice-cooling and extracted with ethyl acetate. The aqueous layer was separated, and the organic layer was washed with a 20% solution of sodium thiosulfate in saturated aqueous sodium hydrogencarbonate solution, saturated aqueous sodium hydrogencarbonate solution, water and brine, and dried over sodium sulfate. The mixture was filtered and the solvent was evaporated to give Compound (81) (700 mg). ^- MR (300 MHz, DMSO-dg, δ) : 9.62 (IH, s), 9.06 (IH, d, J=8.1 Hz), 7.78-7.91 (2H, m) , 7.62-7.77 (4H, ) , 7.39-7.54 (6H, m) , 7.29-

7.36 (IH, m), 6.85-6.91 (IH, m) , 6.77-6.82 (IH, m) , 6.62-6.68 (IH, m), 5.62 (IH, d, J=16.1 Hz), 5.52 (IH, d, J=16.1 Hz), 5.48-5.62 (IH, m), 3.66 (IH, s), 3.64 (2H, S), 3.59 (2H, s), 3.59 ( IH, s), 2.39-2.50 (2H, m) , 2.04-2.19 (2H, m) , 1.51-1.71 (2H, m) ; MASS (ES+): m/e 548.16 (M+l). Preparation 82

To a solution of Compound (82) (700 mg) in tetrahydrofuran (30 mL) was added methyl(triphenylphosphoranylidene)acetate, and the mixture was stirred for 6 hr and left standing for a week. The solvent was evaporated, and the residue was purified by a silica gel column (CHCl₃:methanol=95:5 then 9:1) and triturated with diisopropyl ether to give Compound (82) (783 mg).

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.42-1.59 (2H, m) , 2.05-2.30 (4H, m) ,

3.60 (3H, s), 3.63 (4H, s), 3.66 (2H, s), 5.47 (IH, d, J=16.5 Hz), 5.47-5.63 ( IH, m) , 5.63 (IH, d, J=16.5 Hz), 5.80-5.90 (IH, m) ,

6.61-6.68 (IH, m) , 6.77-6.94 (3H, m) , 7.29-7.78 (11H, m) , 7.80- 7.91 (2H, m), 9.05-9.14 (IH, m) ; MASS (ES+): m/e 604.27 (M+l). Preparation 83 Compound (83) (232 mg) was obtained in a manner similar to Preparation 8. ^- MR (300 MHz, DMSO-dg, δ) : 1.34-1.56 (2H, m) , 2.05-2.23 (4H, m) ,

3.61 (3H, s), 3.64 (2H, S), 3.66 (IH, s), 5.46-5.65 (2H, m) , 5.71-5.78 (IH, ) , 6.64-6.68 (IH, m) , 6.78-6.94 (3H, m) , 7.40- 7.94 (13H, m), 9.04-9.14 (IH, m) ; MASS (ES+) : m/e 590.17 (M+l). Preparation 84

A solution of Compound (83) (227 mg) in a mixed solvent (acetonitrile (2.8 mL) , methanol (0.6 mL) and water (0.6 mL) ) was added cerium ammonium nitrate (CAN, 633 mg) and the mixture was stirred at ambient temperature overnight. To the mixture was added additional CAM (3 equivalent) and stirred at ambient temperature for 3 hr. The solvent was evaporated, and the residue was dissolved in methanol. To the solution was added IN aqueous sodium hydroxide solution under ice-cooling and the mixture was stirred for 2 days. The mixture was neutralized with IN aqueous hydrogen chloride solution and extracted with ethyl acetate. The extract was washed with water and brine, and purified by thin layer chromatography (CHCl₃:methano1=9:1) to give Compound (84) (65.4 mg) .

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.33-1.67 (2H, m) , 1.94-2.45 (4H, m) , 5.28-5.40 (IH, m) , 5.79 (IH, d, J=15.8 Hz), 6.83 (IH, dt, J=15.8, 7.0 Hz), 7.29-7.38 (IH, m) , 7.40-7.89 (8H, m) , 7.67 (2H, d, J=7.3 Hz), 7.97 (2H, d, J=7.3 Hz), 8.91-9.00 (IH, m) , 12.07-12.45 (IH, m); MASS (ES+): m/e 440.14 (M+l). Preparation 85

Compound (85) (64.3 mg) was obtained in a manner similar to Preparation 8. ^- MR (300 MHz, DMSO-d₆, δ) : 1.33-1.68 (2H, m) , 1.94-2.45 (4H, m) , 5.27-5.40 (IH, m) , 5.79 (IH, d, J=15.8 Hz), 6.84 (IH, dt, J=15.8, 7.0 Hz), 7.29-7.37 (IH, m) , 7.41-7.87 (8H, m) , 7.67 (2H, d, J=7.7 Hz), 7.97 (2H, d, J=7.0 Hz), 8.90-9.00 (IH, m) , 12.12-12.42 (IH, m); MASS (ES+): m/e 440.12 (M+l). Preparation 86

Compound (86) (82 mg) was obtained in a manner similar to Preparation 24. The obtained Compound (86) was used in Example 50. ¹H-N R (300 MHz, DMSO-d₆, δ) : 1.21-1.74 (8H, m) , 1.88-2.32 (4H, m) , 3.44-3.58 (IH, m) , 3.84-3.97 (IH, m) , 4.77-4.86 (IH, m) , 5.28- 5.40 (IH, ), 5.76-5.85 (IH, m) , 6.65-6.77 (IH, m) , 7.29-7.37 (IH, m), 7.41-7.79 (10H, m) , 7.97 (2H, d, J=8.1 Hz), 8.89-9.00 (IH, m) , 10.95-11.07 (0.4H, m) , 12.29-12.41 (0.6H, m) ; MASS (ES+): m/e 539.22 (M+l). Preparation 87

Benzyl (7S)-7-( 5-benzoyl-lH-benzimidazol-2-yl)-7-[ (tert- butoxycarbonyl)amino]heptanoate (1.6 g) was added 10% hydrogen chloride in methanol (48 mL) under ice-cooling, and the mixture was stirred at ambient temperature 24 hr. The solvent was evaporated. The residue was dissolved in methanol and the solvent was evaporated (these steps were repeated several times) to remove excess hydrogen chloride. The residue was dried in a vacuum dryer to give Compound (87) (1.64 g). ^XH-NMR (300 MHz, DMSO-d₆, δ) : 1.19-1.36 (4H, m) , 1.40-1.57 (2H, m) , 1.95-2.11 (2H, m), 2.27 (2H, t, J=7.3 Hz), 3.56 (3H, s), 4.57- 4.69 (IH, m), 7.55-7.63 (2H, m) , 7.66-7.80 (5H, m) , 7.99 (IH, s), 8.82 (2H, br); MASS (ES+) : m/e 380.11 (free). Preparation 88

Compound (88) (403 mg) was obtained in a manner similar to Preparation 7.

^XH-NMR (300 MHz, DMSO-de, δ) : 1.28-1.48 (4H, m) , 1.47-1.61 (2H, m) , 1.94-2.08 (IH, m) , 2.08-2.23 (IH, m) , 2.29 (2H, t, J=7.3 Hz), 3.56 (3H, s), 5.32 (IH, dt, J=8.8, 5.9 Hz), 7.46-7.78 (11H, m) , 7.83 (0.4H, s), 7.90-8.01 (2H, m) , 8.92-9.00 (IH, m) , 12.59 (0.3H, s), 12.69 (0.3H, s); MASS (ES+): m/e 484.17 (M+l). Preparation 89

A solution of methyl (7S)-7-(benzoylamino)-7-(5-benzoyl-lH- benzimidazol-2-yl)heptanoate (398 mg) in a mixed solvent (methanol (3.6 mL) and acetic acid (0.4 mL) ) was hydrogenated for 20 hr. The mixture was filtered through a pad of Celite® and the filtrate was reduced again with a catalytic amount of palladium on carbon at room temperature at 3 atm for 2 days. The solvent was evaporated, and the residue was extracted with ethyl acetate and water. The organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution, water and brine, and dried over sodium sulfate. The mixture was filtered, and the solvent was evaporated to give Compound (89) (277 mg) .

^-NMR (300 MHz, DMSO-dg, δ) : 1.26-1.45 (4H, m) , 1.45-1.59 (2H, m) , 1.88-2.02 (IH, m), 2.02-2.17 (IH, m) , 2.28 (2H, t, J=7.3 Hz), 3.55 (3H, s), 5.25 (IH, dt, J=8.4, 6.2 Hz), 5.77 (0.5H, d, J=4.0 Hz), 5.78 (0.5H, d, J=4.0 Hz), 5.81 (0.5H, d, J=4.0 Hz), 5.84

(0.5H, d, J=4.0 Hz), 7.08-7.22 (2H, m) , 7.23-7.33 (2H, m) , 7.33- 7.40 (2H, m), 7.41-7.59 (5H, m) , 7.94 (2H, d, J=8.1 Hz), 8.84 (IH, d, J=8.4 Hz), 12.15 ( IH, s); MASS (ES+): m/e 487.17 (M+l). Preparation 90

Compound (90) (207 mg) was obtained in a manner similar to Preparation 8.

^XH- MR (300 MHz, DMSO-dg, δ) : 1.22-1.43 (4H, m) , 1.43-1.57 (2H, m) , 1.89-2.03 (IH, m), 2.03-2.14 (IH, m) , 2.18 (2H, t, J=7.3 Hz), 5.78 (IH, d, J=4.0 Hz), 5.84 (IH, d, J=4.0 Hz), 7.10-7.22 (2H, m) , 7.23-7.33 (2H, m) , 7.34-7.44 (2H, m) , 7.43-7.59 (5H, m) , 7.94 (2H, d, J=7.0 Hz ) , 8.85 ( IH, d, J=8.1 Hz ) , 11.98 ( IH, s) , 12.26 ( IH, br) ;

MASS (ES+): m/e 472.15 (M+l). Preparation 91

Compound (91) (190 mg) was obtained in a manner similar to Preparation 24. The obtained Compound (91) was used in Example 51. ^-NMR (300 MHz, DMSO-dg, δ) : 1.21-1.71 ( 12H, m) , 1.87-2.17 (2H, m), 1.96 (2H, t, J=7.3 Hz), 3.42-3.52 (IH, m) , 3.84-3.95 (IH, m) , 4.79 (IH, s), 5.25 (IH, dt, J=8.1, 6.2 Hz), 5.75-5.87 (2H, ) , 7.08-7.22 (2H, m) , 7.23-7.33 (2H, m) , 7.33-7.40 (2H, m) , 7.40- 7.59 (5H, m), 7.94 (2H, d, J=7.0 Hz), 8.85 (IH, d, J=8.1 Hz), 10.90 (0.5H, s), 12.16 (0.5H, s); MASS (ES+) : m/e 571.23 (M+l). Preparation 92

To a solution of dimethyl methylphosphonate (58.5 g) in tetrahydrofuran (708 mL) was added dropwise a solution of n- buthyllithium (1.59 M hexane solution, 326 mL) over 1 hr at -78°C. After stirring for 30 min, ethyl fluoroacetate (50 g) was added dropwise over 1 hr at -78°C. After stirring for 30 min, the reaction mixture was warmed to room temperature, and water (78.5 mL) was added thereto and the mixture was and stirred for 20 min. The reaction mixture was acidified with concentrated hydrochloric acid to pH 3 and was extracted with dicholoromethane ten times. The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by distillation under reduced pressure (90-93°C/ 0.3 mmHg) to give Compound (92) as a colorless oil (54 g). The obtained compound (92) was used in Preparation 100.

^XH-NMR (300 MHz, CDC1₃, δ) : 2.25 (2H, dd, J=22.7, 3.7 Hz), 3.80 (3H, s), 3.84 (3H, s), 4.84 (IH, d, J=l Hz), 5.00 ( IH, d, J=l Hz). Preparation 93

To a solution of 1,2-benzenediamine (34.7 g) in methylene chloride (500 mL) was added dropwise a solution of 1- (( (benzyloxy)carbonyl)oxy)-2,5-pyrrolidinedione (40 g) in methylene chloride (150 mL) over 1 hr with cooling in an ice bath. The reaction mixture was stirred at ambient temperature for 2 hr. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with aqueous 0.lN-hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The solid formed was washed with diethyl ether to give Compound (93) as a white solid (30 g) . The obtained compound (93) was used in Preperation 102.

^XH-NMR (300 MHz, CDC1₃, δ) : 3.50-3.90 ( IH, brs), 5.20 (2H, s), 6.30-6.50 (IH, brs), 6.77-6.83 (2H, m) , 7.03 (IH, ddd, J=7.3, 1.5, 1.5 Hz), 7.28-7.45 (7H, m) . Preparation 94 To a solution of 6-hydroxy-L-norleucine (50.17 g), benzyl chloroformate (37.8 g) in dioxane-water (500 mL - 500 mL) was added sodium bicarbonate (74.5 g) with cooling in an ice bath. The reaction mixture was stirred at ambient temperature for 2 hr, and benzyl chloroformate (37.8 g) and sodium bicarbonate (37.2 g) were added to the reaction mixture with cooling in an ice bath.

The reaction mixture was stirred at ambient temperature for 12 hr. The residue was partitioned between ethyl ether and water. Excess benzyl chloroformate was removed by extraction (100 L, twice). The aqueous layer was acidified with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with lN-hydrochloric acid and brine, dried over sodium sulfate, and concentrated in vacuo to give Compound (94) as a colorless oil (95 g) . The obtained crude product was used in Preparation 95 without further purification. ^XH-NMR (300 MHz, CDC1₃, δ) : 1.37-1.66 (4H, m) , 1.68-1.96 (2H, m) , 3.24 (IH, brs), 3.64 (2H, t, J=6.22 Hz), 4.36-4.44 ( IH, m) , 5.08 (IH, d, J=11.0 Hz), 5.12 (IH, d, J=11.0 Hz), 5.48 (IH, brd, J=7.7 Hz), 7.30-7.39 (5H, m) . Preparation 95 To a solution of Compound (94) (127 g) and cesium carbonate (73.5 g) in N,N-dimethyl formamide (1000 mL) was added dropwise (bromomethyl)benzene (78.8 g) with cooling in an ice bath. The reaction mixture was stirred at ambient temperature for 12 hr. The mixture was concentrated in vacuo, and the residue was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo to give Compound (95) as a colorless oil (125 g) . Water was azeotropically removed with toluene twice, and the crude residue was used in Preparation 96 without further purificatiuon.

^XH-NMR (300 MHz, CDC1₃, δ) : 1.20-1.95 (6H, m) , 3.58 (2H, t, J=5.9

Hz), 5.08-5.24 (4H, m) , 5.33 (IH, brd, J=8.4 Hz), 7.28-7.4 (10H, brs);

MASS (ES+): m/e 372.2 (M+l). Preparation 96

To a solution of Compound (95) (83 g) and pyridinium p- toluenesulfonate (1.12 g) in methylene chloride (600 mL) was added dropwise a solution of 1-ethoxyethylene (17.7 g) with cooling in an ice bath. The reaction mixture was stirred at ambient temperarute for 1 hr. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of chloroform and ethyl acetate (9:1) to give Compound (96) as a colorless oil (83 g).

^XH-NMR (300 MHz, CDC1₃, δ) : 1.19 (3H, t, J=7.0 Hz), 1.28 (3H, d,

J=5.5 Hz), 1.34-1.93 (6H, m) , 3.32-3.64 (4H, m) , 4.43 (IH, dd, J=7.3, 12.0 Hz), 4.64 (IH, q, J=5.5 Hz), 5.11 (2H, s) , 5.15 ( IH, d, J=12.5 Hz), 5.20 (IH, d, J=12.5 Hz), 5.31 ( IH, brd, J=7.7 Hz),

7.25-7.40 (10H, m) ;

MASS (ES+): m/e 466.4 (M+Na).

Preparation 97 To a solution of Compound (96) (83 g) and 4-(N,N- dimethylamino)pyridine (2.29 g) in acetonitrile (600 mL) was added dropwise a solution of di(tert-butyl) dicarbonate (65.4 g) over 30 min with cooling in an ice bath. The reaction mixture was stirred at ambient temperature for 12 hr. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of hexane and ethyl acetate (9:1) to give Compound (97) as an oil (84.3 g) .

^XH-NMR (300 MHz, CDC1₃, δ) : 1.19 (3H, t, J=7.0 Hz), 1.28 (3H, d, J=5.1 Hz), 1.32-1.46 (2H, m) , 1.39 (9H, s), 1.50-1.64 (2H, m) , 1.86-2.00 (IH, m), 2.08-2.23 (IH, m) , 3.30-3.70 (4H, m) , 4.64 (IH, q, J=5.3 Hz), 4.97 ( IH, dd, J=9.9, 5.1 Hz), 5.07 (IH, d, J=12.5 Hz), 5.12 (IH, d, J=12.5 Hz), 5.14 (IH, d, J=12.1 Hz), 5.20 ( IH, d, J=12.1 Hz), 7.24-7.38 (10H, m) ; MASS (ES+): m/e 566.4 (M+Ma) . Preparation 98 To a solution of Compound (97) (41 g) in ethanol (300 mL) was added pyridinium p-toluenesulfonate (2.84 g) with cooling in an ice bath. The reaction mixture was stirred at ambient temperature for 10 hr. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of hexane and ethyl acetate (7:3) to give Compound (98) as a pale yellow oil (35.8 g) . ^XH-NMR (300 MHz, CDC1₃, δ) : 1.35-1.45 (3H, m) , 1.39 (9H, s), 1.48- 1.61 (3H, m), 1.85-2.02 (IH, m) , 2.06-2.22 (IH, m) , 3.58 (2H, dd, J=12.1, 6.2 Hz), 4.97 (IH, dd, J=9.5, 5.1 Hz), 5.08 (IH, d, J=12.5 Hz) , 5.12 (IH, d, J=12.5 Hz), 5.14 (IH, d, J=12.5 Hz), 5.20 (IH, d, J=12.5 Hz), 7.24-7.38 (10H, m) ; MASS (ES+) : m/e not detected. Preparation 99

To a solution of Compound (98) (26 g) in methylene chloride (110 mL) was added 2,2,5,5-tetramethyl pyrolidine N-oxide (862 mg) at 0°C, and then iodobenzene diacetate (19.5 g) and acetic acid (1.37 mL) were added to the mixture. The reaction mixture was stirred at ambient temperature for 12 hr. The mixture was concentrated in vacuo, diluted with ethyl acetate, poured into 20% sodium thiosulfate in saturated aqueous sodium bicarbonate solution. The product was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to give Compound (99) as a pale yellow oil (25.9 g) . The product was dried by azotropic removal of water with toluene (twice) . The crude product was dried by pump (1 hr), which was used in Preparation 100 without further purification.

^XH-NMR (300 MHz, CDC1₃, δ) : 1.39 (9H, s), 1.58-1.72 (2H, m) , 1.86- 2.03 (IH, m), 2.08-2.22 (IH, m) , 2.32-2.53 (2H, m) , 4.97 (IH, dd, J=9.5, 5.1 Hz), 5.07 (IH, d, J=12.1 Hz), 5.12 ( IH, d, J=12.1 Hz), 5.15 (IH, d, J=12.1 Hz), 5.20 (IH, d, J=12.1 Hz), 7.24-7.39 (10H, m), 9.70 (IH, t, J=1.54 Hz); MASS (ES+) s m/e not detected. Preparation 100

To a solution of Compound (92) (20.3 g) and cesium carbonate (34.1 g) in isopropyl alcohol (260 mL) was added dropwise a solution of Compound (99) (25.9 g) in tetrahydrofuran (5 mL) with cooling in an ice bath. The reaction mixture was stirred at 0°C for 90 min. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and sodium phosphate buffer solution (pH=6.86). The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of hexane and ethyl acetate (9:1) to give Compound (100) as a colorless oil (21.7 g) .

^XH-NMR (300 MHz, CDC1₃, δ) : 1.39 (9H, S), 1.43-1.63 (2H, m) , 1.82- 2.00 (IH, m), 2.40-2.70 (3H, m) , 4.92 (2H, d, J=47.3 Hz), 4.97 (IH, dd, J=9.5, 5.5 Hz), 5.07 (IH, d, J=12.1 Hz), 5.12 ( IH, d, J=12.1 Hz), 5.15 (IH, d, J=12.1 Hz), 5.20 (IH, d, J=12.1 Hz), 6.31 (IH, dddd, J=15.8,2.9, 1.5, 1.5 Hz), 6.95 (IH, ddd, J=15.8, 6.6 Hz), 7.24-7.38 (10H, m) ; MASS (ES+) : m/e not detected. Preparation 101

A solution of Compound (100) (21.7 g) and 10% palladium- carbon powder (4.34 g) in dioxane (170 mL) was stirred for 1 hr under hydrogen atomosphere (3 atm) . The mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give Compound (101) as a colorless oil (12.6 g) . ^XH-NM (300 MHz, CDC1₃, δ) : 1.28-1.52 (5H, m) , 1.45 (9H, s) , 1.56- 1.75 (3H, m), 1.80-1.94 (IH, m) , 2.55 (2H, ddd, J=7.3, 7.3, 2.6 Hz), 4.22-4.36 (IH, m) , 4.80 (2H, d, J=47.6 Hz), 5.02 (IH, brd, J=8.0 Hz);

MASS (ES+): m/e 306.3 (M+l). Preparation 102

To a solution of Compound (101) (6.0 g), Compound (93) (5.0 g) and HOBT (2.92 g) in methylene chloride (60 mL) was added WSCD hydrochloride (4.14 g) with cooling in an ice bath. The reaction mixture was stirred at ambient temperature for 12 hr. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with 0.lN-hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was triturated with diethyl ether to give Compound (102) as a white needle crystal (6.95 g) . The obtained compound (102) was used in Preparations 103 and 109.

^XH-NMR (300 MHz, CDC1₃, δ) : 1.28-1.46 (4H, m) , 1.43 (9H, s), 1.52- 1.70 (3H, m), 1.86-1.98 ( IH, m) , 2.52 (2H, ddd, J=7.3, 7.3, 2.6 Hz), 4.09-4.20 (IH, m) , 4.76 (2H, d, J=47.6 Hz), 4.90-5.02 ( IH, m), 5.21 (2H, s), 7.10-7.46 (9H, m) , 7.58-7. (IH, brs), 8.30-8.40 (IH, brs); MASS (ES+): m/e 552.6 (M+Na); m.p. 117-118°C. Preparation 103

(1) To a solution of Compound (102) (6.95 g) in dioxane (35 mL) was added 4N hydrogen chloride dioxane solution (60 mL) at

0 °C, and the mixture was stirred at ambient temperature for 1 hr. Solvent was removed under reduced pressure and dried by pump for 2 hr to give a hydrochloride salt as a white powder.

(2) To a suspension of the hydrochloride salt (6.95 g) in methylene chloride (70 mL) were added benzoic acid (1.85 g), HOBT (2.48 g) and WSCD (2.85 g) with cooling in an ice bath. The reaction mixture was stirred at ambient temperature for 90 min. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with IN hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo to form a solid. The solid was collected with diethyl ether to give Compound (103) (4.1 g).

^XH-KMR (300 MHz, DMSO-dg, δ) s 1.22-1.56 (6H, m) , 1.75-1.95 (2H, m) , 2.40 (2H, ddd, J=7.3, 1.5, 1.5 Hz), 4.48-4.58 ( IH, m) , 5.02 (2H, d, J=46.9 Hz), 5.03 (2H, s), 7.08-7.24 (2H, m) , 7.30-7.60 (13H, m), 7.93 (2H, d, J=7.0 Hz), 8.71 (IH, d, J=7.0 Hz), 8.81 (IH, brs) ;

MASS (ES+) s m/e 534.6 (M+l). Preparation 104

To a suspension of Compound (103) (8.0 g) in acetic acid (30 mL) was added 33% hydrogen bromide acetic acid solution (30.0 mL) at 0°C with cooling in a cooling bath, and the cooling bath was removed immediately. The reaction mixture was stirred for 40 min, water (100 mL) and diethyl ether (100 mL) was added and inpurity was removed by extraction (100 mL, twice). The combined organic layer was extracted with water (2 mL, 10 times) and the combined aqueous layer was poured into saturated aqueous sodium bicarbonate solution (500 mL) - ethyl acetate (200 mL) . The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting solid was collected with diethyl ether to give Compound (104) (4.5 g) . The obtained compound (104) was used in Example 53.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.28-1.58 (6H, m) , 1.76-1.88 (2H, m) , 2.42 (2H, t, J=7.3 Hz), 4.48-5.48 (IH, m) , 4.89 (2H, brs), 5.04 (2H, d, J=46.9 Hz), 6.53 (IH, dd, J=7.7, 7.7 Hz), 6.71 (IH, d, J=7.7 Hz), 6.92 (IH, dd, J=7.7, 7.7 Hz), 7.10 ( IH, d, J=7.7 Hz), 7.42-7.60 (3H, m) , 7.90-7.98 (2H, d, J=7.0 Hz), 8.58 (IH, brd, J=7.0 Hz), 9.34 (IH, brs); MASS (ES+): m/e 400.4 (M+l). Preparation 105

To a solution of indole (1.11 g) in dichloromethane (20 mL) were added tin(IV) chloride (1 M solution in dichloromethane) and ethyl 6-(chloroformyl)hexanoate (2.16 g), and the mixture was stirred at ambient temperature for 1 hr. The resulting mixture was diluted with chloroform, washed successively with hydrochloric acid, and diluted sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of chloroform and ethyl acetate (4:1) to give Compound (105) (996 mg) as a solid.

^XH-FMR (300 MHz, DMSO-dg, δ) : 1.16 (3H, t, J=7Hz), 1.34 (2H, m) , 1.50-1.70 (4H, m), 2.28 (2H, t, J=7Hz), 2.83 (2H, t, J=7Hz), 4.03 (2H, q, J=7Hz), 7.10-7.23 (2H, m) , 7.45 ( IH, m) , 8.17 (IH, m) , 8.32 (IH, S);

MASS: m/z 286 (M-l) . Preparation 106

To a solution of Compound (105) (200 g) in ethanol (5 mL) and water (1 mL) were added hydroxylamine hydrochloride (121 mg) and sodium acetate (149 mg), and the mixture was stirred at reflux temperature for 1 hr. The resulting mixture was evaporated in vacuo, diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (2:1) to give Compound (106) (160 mg) .

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.15 (3H, t, J=7Hz), 1.37 (2H, m) , 1.48-1.60 (4H, m), 2.29 (2H, t, J=7Hz), 2.68 (2H, t, J=7Hz), 4.02 (2H, q, J=7Hz), 7.03 (IH, m) , 7.12 (IH, m) , 7.37 (IH, d, J=8Hz), 7.65 (IH, d, J=3Hz), 8.12 ( IH, d, J=8Hz); MASS: m/z 303 (M+l). Preparation 107

To a solution of Compound (106) (248 mg) in ethanol (5 mL) were added 10% hydrogen chloride in methanol and 10% palladium- charcol (60 mg), and the mixture was stirred under hydrogen atomosphere (4 atm) for 1 hr. The resulting mixture was filtered through Celite® and washed with ethanol. The filtrate and washings were evaporated in vacuo to give Compound (107). The obtained compound was immediately used in Example 54 without further purification. Preparation 108

To a stirred solution of Compound E55 (63 mg, described later in Example 55) in N,N-dimethylformamide (2 mL) was added O- benzylhydroxylamine hydrochloride (36 mg), HOAT (38 mg) and WSCD (43 mg), and the resulting mixture was stirred at ambient temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and washed successively with 10% sodium dihydrogenphosphate solution, saturated sodium hydrogen carbonate solution, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform : methanol = 19 : 1) to give Compound (108) (60 mg). The obtained compound (108) was used in Example 56. ^XH-NMR (300 MHz, DMSO-dg, δ) : 1.22-1.57 (6H, m) , 1.90-2.05 (4H, m) , 4.76 (2H, s), 5.38 (IH, q, J=7Hz), 6.94 ( IH, t, J=8Hz), 7.05 (IH, t, J=8Hz), 7.27-7.52 (9H, m) , 7.63 (IH, d, J=8Hz), 7.85 ( IH, dd, J=2, 8Hz), 8.03 (IH, d, J=8Hz) . Preparation 109

Compound (102) (300 mg) was dissolved in 1,4-dioxane (3 mL), and 4N-HC1 in 1,4-dioxane (3 mL) was added thereto at 20°C. After stirring at 20°C for 3 hr, the solvent was removed by evaporation, and the residue was dissolved in methylene chloride (3 mL). The solution was cooled to 0°C, and diisopropylethylamine (220 mg) and mesyl chloride (78 mg) were added thereto. After stirring at 20°C for 3 hr, the mixture was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of EtOAc and hexane (1:5) to give Compound (109) (223 mg) as an oil. ^XH-NMR (300 MHz, DMSO-dg, δ) : 1.30-1.90 (8H, m) , 2.49 (2H, t, J=7 Hz), 2.97 (3H, s), 4.05-4.15 (IH, m) , 5.11 (2H, d, J= 47 Hz), 5.24 (2H, s), 7.20-7.35 (2H, m) , 7.40-7.55 (4H, m) , 7.55-7.60 2H, m), 7.70 (IH, d, J= 10 Hz), 8.92 (IH, brs), 9.73 (IH, brs). Preparation 110 Compound (109) (200 mg) was dissolved in AcOH (1 mL), and 30% HBr in AcOH (2 mL) was added thereto at 0°C. After stirring at 20°C for 3 hr, the mixture was partitioned between EtOAc and aq NaHC0₃. The organic layer was separated, washed with water and brine, dried over sodium sulfate, and evaporated to give Compound (110) (143 mg) as an oil. The obtained compound (110) was used in Example 57.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.30-1.90 (8H, m) , 2.51 (2H, t, J=7 Hz), 3.00 (3H, s), 4.05-4.15 (IH, m) , 5.12 (2H, d, J= 47 Hz), 6.66 (IH, t, J=8 Hz), 6.82 (IH, d, J=8 Hz), 7.03 (IH, t, J=8 Hz), 7.21 (IH, d, J=8 Hz), 7.60 ( IH, d, J=8 Hz), 9.43 (IH, s) . Preparation 111

To a stirred suspension of dimethyl (3R)-3-( (tert- butyl(diphenyl) silyl)oxy)-2- oxobutylphosphonate (4.91 g), lithium chloride (479m g) and N,N- diisopropylethylamine (1.64 mL) in dry acetonitrile (70 mL) was added a solution of benzyl (2S)-2-(bis(tert- butoxycarbonyl)amino)-6- oxohexanoate (4.1 g) in dry acetonitrile (24 mL) at room temperature. The reaction mixture was stirred at room temperature for 38 hr under nitrogen atmosphere. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel using n-hexane-ethyl acetate (4:1) as an eluant to give Compound (111) (3.98 g) as a colorless oil. ^XH-NMR (300 MHz, DMSO-d₆, δ) : 1.02 (9H, S), 1.17 (3H, d, J=7.0 Hz), 1.32-1.47 (2H, m) , 1.37 (18H, s), 1.75-1.89 (IH, m) , 1.93-2.07 (IH, m), 2.17-2.30 (2H, m) , 4.27 (IH, q, J=7.0 Hz), 4.88 (IH, dd, J=10.0, 5.5 Hz), 5.11 (2H, s), 6.46 ( IH, d, J=16.0 Hz), 6.77 (IH, dt, J=16.0, 7.0 Hz), 7.31-7.70 (15H, m) ; MASS: 766(M+Na)⁺. Preparation 112

Compound (111) (700 mg) was dissolved in acetonitrile (7 mL) , and then magnesium chloride (17.9 mg) was added to the solution at room temperature. The reaction mixture was stirred at 50°C for 2.5 hr, and poured into 5% potassium hydrogensulfate. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give Compound (112) (593.1 mg) as a colorless oil.

^XH-NMR (300 MHz, DMSO-d₆, δ) : 1.02 (9H, s), 1.17 (3H, d, J=7.0 Hz), 1.22-1.45 (2H, m) , 1.37 (9H, S), 1.52-1.69 (2H, m) , 2.09-2.19 (2H, m), 3.95-4.03 (IH, m) , 4.28 (IH, q, J=7.0 Hz), 5.07 ( IH, d, J=13.0 Hz), 5.14 (IH, d, J=13.0 Hz), 6.44 (IH, d, J=16.0 Hz), 6.76 (IH, dt, J=16.0, 7.0 Hz), 7.28-7.48 (12H, m) , 7.52-7.62 (4H, m);

MASS: 644(M+1)⁺. Preparation 113

A solution of Compound (112) (580 mg) in methanol (6 mL) was hydrogenated over 10% palladium carbon (58 mg) at ambient temperature under atmospheric pressure for 6 hr. The reaction mixture was filtered through a pad of Celite®, and the filtrate was concentrated in vacuo to give Compound (113) (551.6 mg) as a colorless oil. ^XH-NMR(300 MHz, DMSO-d₆, δ) : 1.02-1.41 (6H, m) , 1.04 (9H, s), 1.16 (3H, d, J=6.5 Hz), 1.37 (9H, s), 1.45-1.63 (2H, m) , 2.37-2.46 (2H, m), 3.77-3.87 (IH, m) , 4.18 (IH, q, J=6.5 Hz), 7.01 (IH, d, J=7.5 Hz), 7.38-7.52 (6H, m) , 7.54-7.62 (4H, m) ; MASS: 556(M+1)⁺. Preparation 114

A mixture of Compound (113) (600 mg), 1,2-phenylenediamine (117 mg), HOBT (160 mg) and WSCD hydrochloride (217 mg) in N,N- dimethylformamide (12 mL) was stirred at ambient temperature for 14 hr. The reaction mixture was poured into saturated sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over a silica gel with n-hexane / ethyl acetate (1:1) as an eluant to give Compound (114) (443.1 mg) as a colorless amorphous.

^XH-NMR (300 MHz, DMSO-dg, δ) s 1.00-1.69 (8H, m) , 1.04 (9H, s) , 1.16 (3H, d, J=6.5 Hz), 1.39 (9H, s), 2.40-2.47 (2H, m) , 3.96- 4.07 (IH, m), 4.18 ( IH, q, J=6.5 Hz), 4.84 (2H, S), 6.53 (IH, t, J=7.0 Hz), 6.69 ( IH, d, J=7.0 Hz), 6.91 ( IH, t, J=7.0 Hz), 7.03 (IH, d, J=7.0 Hz), 7.07 (IH, d, J=7.0 Hz), 7.37-7.48 (6H, m) , 7.53-7.62 (4H, m) , 9.17 (IH, s); MASS: 644(M-1)⁺. Preparation 115 Compound (114) (420 mg), xylene (4.2 mL) and acetic acid (0.42 mL) were combined. The mixture was refluxed for 4 hr with azeotropic removal of water and allowed to cool. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with a n-hexane / ethyl acetate (1:1) as eluant to give Compound (115) (351.9 mg) as a pale yellow oil. The obtained compound (115) was used in Preparations 116 and 117.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.02 (9H, S), 1.12-1.46 (6H, ) , 1.14 (3H, d, J=7.0 Hz), 1.39 (9H, s), 1.65-1.81 (IH, m) , 1.82- 1.96 (IH, m), 2.41 (2H, t, J=7.0 Hz), 4.17 (IH, q, J=7.0 Hz), 4.65-4.77 (IH, m) , 7.08-7.16 (2H, ) , 7.27 (IH, d, J=7.5 Hz), 7.34-7.61 (12H, m), 12.25 (IH, s); MASS: 626(M-1)⁺. Preparation 116 Compound (115) (160 mg) was dissolved in dichloromethane (1 mL) , and then 4N-solution of hydrochloric acid in 1,4-dioxane (1 mL) was added to the solution under nitrogen atmosphere. The mixture was stirred at ambient temperature for 1.5 hr. The solvent was concentrated in vacuo. A mixture of the residual solid, benzoic acid (31.1 mg), HOBT (37.9 mg) and WSCD (41.5 mg) in dichloromethane (1 mL) was stirred at ambient temperature for 66 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative silica gel column chromatography with a chloroform / methanol (40:1) as eluant to give Compound (116) (70.9 mg) as a colorless amorphous. The obtained compound (116) was used in Example 58. ^XH-NMR (300 MHz, DMSO-d₆, δ) : 1.00 (9H, s), 1.14 (3H, d, J=7.0

Hz), 1.15-1.41 (6H, m) , 1.88-2.02 (IH, m) , 2.03-2.17 (IH, m) , 2.41 (2H, t, J=7.0 Hz), 4.16 (IH, q, J=7.0 Hz), 5.23-5.34 (IH, m) , 7.11-7.16 (2H, m), 7.36-7.61 (15H, m) , 7.97 (2H, d, J=7.5 Hz), 8.87 (IH, d, J=7.5 Hz), 12.34 ( IH, s); MASS: 632(M+1)⁺. Preparation 117

Compound (117) (107.5 mg) was obtained from Compound (115) (140 mg) in manner similar to Preparation 116. The obtained compound (117) was used in Example 59. ^XH-NMR (300 MHz, DMSO-d₆, δ) : 0.99 (9H, s), 1.13 (3H, d, J=7.0 Hz), 1.15-1.42 (6H, m), 1.87-2.02 (IH, m) , 2.06-2.20 (IH, m) , 2.41 (2H, t, J=7.0 Hz), 4.15 (IH, q, J=7.0 Hz), 5.26-5.37 ( IH, m) , 7.04 (IH, t, J=7.5 Hz), 7.08-7.17 (2H, ) , 7.20 (IH, d, J=7.5 Hz), 7.31 ( IH, s), 7.34-7.50 (8H, m) , 7.51-7.60 (5H, m) , 7.62 ( IH, d, J=7.5 Hz), 8.86 (IH, d, J=7.5 Hz), 11.61 (IH, s), 12.30 ( IH, s); MASS: 671(M+1)⁺. Preparation 118

To a solution of (2S)-2-{[ (benzyloxy)carbonyl]amino}-6- hydroxyhexanoic acid (5.85 g) in N,N-dimethylformamide (60 mL) were added isobutyl chloroformate (2.84 g), 4-methylmorpholine N- oxide (2.66 g) and 3,5-dichloro-l,2-benzenediamine (3.68 g), and the mixture was stirred for 30 min under ice-cooling. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give Compound (118) (6.93 g) as a solid.

^XH-NMR (300 MHz, CDC1₃, δ) : 1.20-1.79 (6H, m) , 3.28-3.43 (2H, m) , 4.09-4.19 (IH, m), 4.39 (IH, t, J=5.4 Hz), 4.99-5.33 (2H, m) , 5.27 (IH, s), 7.23-7.26 ( IH, m) , 7.27-7.50 (6H, m) , 7.65 (IH, d, J=7.3 Hz), 9.48 (IH, s); MS (ES+) m/e 440.06 (M+l). Preparation 119

A mixture of Compound (118) (7.12 g) and IN hydrochloric acid in ethanol (120 mL) was refluxed for 4 hr. The reaction mixture was concentrated in vacuo, and the concentrate was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was separated, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was triturated with diisopropyl ether to give Compound (119) (6.03 g).

^XH-NMR (300 MHz, CDC1₃, δ) : 1.35-2.27 (6H, m) , 2.64 (IH, brs), 3.66 (IH, brs), 4.83-5.18 (3H, m) , 5.80-6.10 (IH, m) , 7.11-7.44 (7H, m), 7.56 (1x0.5H, s), 11.05 (1x0.2H, s), 11.21 (1x0.3H, s); MS (ES+) m/e 422.07 (M+l). Preparation 120

To a solution of Compound (119) (6.03 g) in N,N- dimethylformamide (100 mL) were added tert-butyldimethylsilyl chloride (2.26 g) and imidazole (1.07 g), and the mixture was stirred at ambient temperature for 3 hr. The resulting mixture was diluted with ethyl acetate, washed successively with water and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol (4:1) to give ethyl Compound (120) (6.93 g).

^XH-NMR (300 MHz, CDC1₃, δ) : 0.01 (6H, s), 0.85 (9H, S), 1.32-1.66 (4H, m), 1.93-2.31 (2H, m) , 3.52-3.63 (2H, m) , 4.76-4.95 (IH, m) , 5.03-5.19 (2H, m) , 5.45-5.71 (IH, m) , 7.18-7.40 (7H, m) , 7.59 (1x0.5H, d, J=1.5 Hz), 10.36 (1x0.2H, s), 10.55 (1x0.3H, S); MS (ES+) m/e 536.21 (M+l). Preparation 121

To a solution of Compound (120) (6.93 g) in N,N- dimethylformamide (60 mL) was added potassium tert-butoxide (1.88 g) under ice-cooling, and the mixture was stirred for 30 min. To the mixture were added 3,4-dimethoxybenzyl bromide (4.48 g) and n-tetrabutylammonium iodide (954 mg) under ice-cooling, and the mixture was stirred for 3 hr. The resulting mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (chloroform : ethyl acetate = 9 : 1) to give Compound (121) (3.99 g) .

The obtained Compound (121) was used in Preparation 123. ^XH-NMR (300 MHz, CDC1₃, δ) : 0.01 (6H, s), 0.84 (9H, S), 1.16-1.52 (4H, m), 1.79-2.05 (2H, m) , 3.50 (2H, t, J=6.2 Hz), 3.78 (3H, s), 3.85 (3H, s), 4.96-5.13 (IH, m) , 5.01 (IH, d, J=12.5 Hz), 5.10 (IH, d, J=12.5 Hz), 5.34 ( IH, d, J=16.5 Hz), 5.46 (IH, d, J=16.5 Hz), 5.62 (IH, d, J=9.2 Hz), 6.58 (IH, d, J=8.1 Hz), 6.67 (IH, s), 6.78 (IH, d, J=8.1 Hz), 7.19 (IH, s), 7.25-7.39 (6H, m) ; MS (ES+) m/e 686.35 (M+l). Preparation 122

A solution of benzyl {(lS)-5-{[tert- butyl(dimethyl) silyl]oxy}-1-[3-(3,4-dimethoxybenzyl)-3H- naphtho[l,2-d]imidazol-2-yl]pentyl}carbamate (10.0 g) in a mixture of methanol and acetic acid (4 :1 v/v, 200mL) was hydrogenated over 10% palladium carbon (1.0 g) at ambient temperature under hydrogen atomosphere (3 atm) for 3 hr. The reaction mixture was filtered through a pad of Celite®, and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water, and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give Compound (122) (8.25 g) as a pale yellow oil. The obtained Compound (122) was used in Preparation 124. ^XH-NMR (300 MHz, CDC1₃, δ) : 0.01 (6H, s), 0.84 (9H, s), 1.29-2.07 (6H, m), 3.47-3.58 (2H, m) , 3.74 (3H, s), 3.83 (3H, s), 4.23 (IH, t, J=6.6 Hz), 5.51 (IH, S), 6.50-6.57 (IH, m) , 6.63-6.66 (IH, m) , 6.69-6.79 (IH, m) , 7.38 (IH, d, J=8.8 Hz), 7.48 (IH, dd, J=8.1,7.0 Hz), 7.57-7.67 ( IH, m) , 7.63 (IH, d, J=8.8 Hz), 7.91 (IH, d, J=8.1 Hz), 8.65 (IH, d, J=8.8 Hz); MS (ES+) m/e 534.33 (M+l). Preparation 123

Compound (123) (233 mg) was obtained from Compound (121) in a manner similar to Preparation 122. The obtained Compound (123) was used in Preparation 125.

^XH-NMR (300 MHz, CDC1₃, δ) s 0.01 (6H, s), 0.85 (9H, s), 1.22-1.57 (6H, m), 1.74-2.02 (2H, m) , 3.48-3.58 (2H, m) , 3.79 (IH, s), 3.85 (IH, s), 4.10-4.20 (IH, m) , 5.35-5.45 (IH, ) , 6.48-6.56 ( IH, m) , 6.60-6.67 (IH, m) , 6.73-6.80 ( IH, m) , 7.13 (IH, s, J=1.8 Hz), 7.28 (IH, d, J=1.8 Hz);

MS (ES+) m/e 552.21 (M+l). Preparation 124

To a stirred solution of Compound (122) (8.0 g) in N,N- dimethylformamide (100 mL) were added benzoic acid (1.92 g), HOBT (2.43 g) and WSCD hydrochloride (3.45 g), and the resulting mixture was stirred at ambient temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (chloroform : ethyl acetate = 9 : 1) to give Compound (124) (7.6 g) . The obtained Compound (124) was used in Preparation 126.

^XH-NMR (300 MHz, CDC1₃, δ) : 0.01 (3H, s), 0.03 (3H, s), 0.83 (9H, s), 1.33-1.60 (4H, m) , 2.10-2.23 (2H, m) , 3.53 (2H, t, J=6.6 Hz), 3.75 (3H, s), 3.82 (3H, s), 5.54 (IH, d, J=16.5 Hz), 5.65-5.78 (IH, m), 5.69 (IH, d, J=16.5 Hz), 6.60-6.68 (IH, m) , 6.69-6.80 (2H, m), 7.39-7.57 (5H, m) , 7.61-7.74 (2H, m) , 7.76-7.84 (2H, m) , 7.95 (IH, d, J=8.1 Hz), 8.65 (IH, d, J=7.0 Hz); MS (ES+) m/e 638.31 (M+l). Preparation 125

Compound (125) (1.62g) was obtained from Compound (123) in a manner similar to Preparation 124. The obtained Compound (125) was used in Preparation 127. ^XH-NMR (300 MHz, CDCl₃, δ) : 0.010 (3H, s), 0.024 (3H, S), 0.83 (9H, s), 1.22-1.56 (4H, m) , 1.95-2.21 (2H, m) , 3.52 (2H, t, J=5.9 Hz), 3.80 (3H, s), 3.85 (3H, s), 5.40 (IH, d, J=16.1 Hz), 5.55-5.68 (IH, m), 5.60 (IH, d, J=16.1 Hz), 6.57-6.63 (IH, m) , 6.70-6.79 (2H, ), 7.00 (IH, d, J=9.1 Hz), 7.25 (IH, d, J=1.8 Hz), 7.32 (IH, d, J=1.8 Hz), 7.38-7.56 (3H, m) , 7.70-7.78 (2H, m) ; MS (ES+) m/e 656.47 (M+l). Preparation 126

To a stirred solution of Compound (124) (7.6 g) in tetrahydrofuran (80 mL) was added tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 24 mL) under ice-cooling, and the mixture was stirred at ambient temperature for 3 hr. Additional tetrabutylammonium fluoride (8 mL) was added thereto, and the mixture was stirred for 1 hr. The reaction mixture was diluted with water (400 mL) and extracted with chloroform (750 mL) . The organic layer was washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give Compound (126) (6.08 g). The obtained Compound (126) was used in Preparation 128. ^XH-NMR (300 MHz, DMSO-dg, δ) : 1.25-1.53 (4H, m) , 2.05-2.30 (2H, m) , 3.27-3.42 (2H, m) , 3.57 (3H, s), 3.65 (3H, s), 4.38 (IH, t, J=5.5 Hz), 5.53-5.71 (3H, m) , 6.60-6.69 (IH, m) , 6.76-6.88 (2H, m) , 7.37-7.53 (4H, m) , 7.57-7.76 (3H, m) , 7.80-7.88 (2H, m) , 7.97 (IH, d, J=8.1 Hz), 8.46 (IH, d, J=7.0 Hz), 9.11 ( IH, d, J=8.4 Hz); MS (ES+) m/e 524.31 (M+l). Preparation 127

Compound (127) (1.39 g) was obtained from Compound (125) in a manner similar to Preparation 126. The obtained Compound (127) was used in Preparation 129.

^XH-NMR (300 MHz,CDCl₃,δ): 1.17-2.03 (6H,m), 2.03-2.16 (lH,m), 3.48-3.60 (2H,m), 3.77 (3H,s), 3.83 (3H,s), 5.38 (lH,d,J=16.5 Hz), 5.52-5.68 (lH,m), 5.59 (lH,d,J=16.5 Hz), 6.55-6.63 (lH,m), 6.68- 6.79 (2H,m), 7.18 (lH,d,J=8.8 Hz), 7.25 (lH,d,J=1.5 Hz), 7.30 (lH,d,J=1.5 Hz), 7.36-7.45 (2H,m), 7.45-7.54 (lH,m), 7.70-7.81 (2H,m); MS (ES+) m/e 542.15 (M+l). Preparation 128

To a stirred solution of Compound (126) (6.08 g) in methylene chloride (80 mL) were added l,l,l-triacetoxy-l,l- dihydro-l,2-benziodoxol-3(lH)-one (Dess-Martin periodinane) (6.4 g) and sodium hydrogen carbonate (1.27 g) under ice-cooling. The mixture was stirred at ambient temperature for 2 hr. The reaction was quenched with a solution of 20% sodium thiosulfate in saturated sodium hydrogen carbonate (100 mL) under ice-cooling, then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and brine, dried over sodium sulfate, and concentrated in vacuo to give Compound (128) (580 mg) as an amorphous solid. The obtained Compound (128) was used in Preparations 130, 131, 132 and 133. ^XH-NMR (300 MHz, CDC1₃, δ) : 2.07-2.27 (2H, m) , 2.28-2.51 (2H, m) , 3.74 (3H, s), 3.81 (3H, s), 5.54 (IH, d, J=15.8 Hz), 5.60-5.77 (IH, m), 5.67 (IH, d, J=15.8 Hz), 6.56-6.64 (IH, m) , 6.64-6.78 (2H, m), 7.18-7.30 (IH, m) , 7.36-7.56 (5H, m) , 7.59-7.82 (4H, m) , 7.95 (IH, d, J=7.7 Hz), 8.63 (IH, d, J=8.1 Hz), 9.66 (IH, s); MS (ES+) m/e 522.24 (M+l). Preparation 129

Compound (129) (609 mg) was obtained from Compound (127) in a manner similar to Preparation 128. The obtained Compound (129) was used in Preparation 134. ^XH-NMR (300 MHz, CDC1₃, δ) : 1.28-1.69 (4H, m) , 1.96-2.19 (2H, m) , 3.79 (3H, s), 3.75-3.84 (2H, m) , 3.83 (3H, s), 5.38 (IH, d, J=16.5 Hz), 5.54-5.66 (IH, m) , 5.59 (IH, d, J=16.5 Hz), 6.52-6.62 (IH, m), 6.70-6.77 (2H, m) , 7.16 (IH, d, J=8.8 Hz), 7.25 ( IH, d, J=1.8 Hz), 7.30 (IH, d, J=1.8 Hz), 7.37-7.46 (2H, m) , 7.47-7.54 (IH, m), 7.73-7.80 (2H, m) , 9.65 (IH, s); MS (ES+) m/e 540.10 (M+l). Preparation 130

To a stirred solution of dimethyl ( (3R)-3-{[tert- butyl(diphenyl)silyl]oxy}-2-oxopentyl)phosphonate (516 mg) in a mixed solvent of tetrahydrofuran and water (40:1 v/v, 7.5 mL) was added barium hydroxide octahydrate (242 mg) in an ice bath, and the resulting mixture was stirred at ambient temperature for 45 min. To this mixture was added Compound (128) (500 mg) in the same solvent (3 mL) in an ice bath, and the mixture was stirred at ambient temperature for 2 hr. To the mixture was added 10% aqueous citric acid (50 mL), and the mixture was extracted with ethyl acetate (30 mL) . The organic phase was washed with saturated sodium hydrogen carbonate solution (50 mL) and brine (50 mL) . The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (eluted with ethyl aσetate- hexane 1:2 v/v) to give Compound (130) as a colorless foam (430 mg) . The obtained Compound (130) was used in Preparation 135. ^XH-NMR (300 MHz, CDC1₃, δ) : 0.77 (3H, t, J=7.3 Hz), 1.02 (3x3H, s), 1.36-1.66 (4H, m) , 1.99-2.26 (4H, m), 3.72 (3H, s), 3.78 (3H, s), 4.11 (IH, t, J=5.8 Hz), 5.51 (IH, d, J=16.8 Hz), 5.63 (IH, d, J=16.8 Hz), 5.70 (IH, m) , 6.47 ( IH, d, J=15.8 Hz), 6.55 ( IH, dd, J=8, 1.8 Hz), 6.64-6.78 (3H, m) , 7.15-7.81 (20H, m) , 7.93 (IH, d, J=7.7 Hz), 8.62 (IH, d, J=8.3 Hz); MS (ES+) m/e 844. Preparation 131

Compound (131) (614 mg) was obtained from Compound (128) in a manner similar to Preparation 130. The obtained Compound (131) was used in Preparation 136. ^XH-NMR (300 MHz, CDC1₃, δ) : 1.01 (9H, s), 1.19 (3H, d, J=6.5 Hz),

1.40-1.54 (2H, m), 2.04-2.28 (4H, m) , 3.72 (3H, s), 3.78 (3H, s),

4.23 (IH, q, J=6.5 Hz), 5.51 ( IH, d, J=16.5 Hz), 5.64 ( IH, d,

J=16.5 Hz), 5.71 (IH, m) , 6.46-6.60 (2H, m) , 6.64-6.85 (3H, m) ,

7.16 (IH, d, J=9 Hz), 7.22-7.80 (20H, m) , 7.93 (IH, d, J=9 Hz). Preparation 132

Compound (132) (458 mg) was obtained from Compound (128) in a manner similar to Preparation 130. The obtained Compound (132) was used in Preparation 137.

^XH-NMR (300 MHz, CDC1₃, δ) : 1.04 (9H, s), 1.38-1.52 (2H, m) , 1.98- 2.28 (4H, m), 3.71 (3H, s), 3.76 (3H, s), 4.28 (2H, s), 5.50 ( IH, d, J=17 Hz), 5.63 (IH, d, J=17 Hz), 5.70 (IH, m) , 6.32 (IH, d,

J=16 Hz), 6.56 ( IH, dd, J=8, 1.5 Hz), 6.62-6.86 (3H, m) , 7.16-

7.80 (20H, m), 7.93 (IH, d, J=8 Hz), 8.61 (IH, d, J=8.5 Hz).

Preparation 133 Compound (133) (393 mg) was obtained from Compound (128) in a manner similar to Preparation 130. The obtained Compound (133) was used in Preparation 138.

^XH-NMR (300 MHz, CDC1₃, δ) : 1.06 (3H, t, J=7.3 Hz), 1.37-1.53 (2H, m), 2.00-2.30 (4H, m) , 2.50 (2H, q, J=7.3 Hz), 3.73 (3H, s), 3.79 (3H, s), 5.52 (IH, d, J=16.5 Hz), 5.66 (IH, d, J=16.5 Hz), 5.70

(IH, m), 6.00 (IH, d, J=16 Hz), 6.56-6.78 (4H, m) , 7.18 (IH, d,

J=9 Hz), 7.37-7.82 (9H, m) , 7.94 (IH, d, J=8 Hz), 8.03 (IH, d,

J=8 Hz).

Preparation 134 Compound (134) (596 mg) was obtained from Compound (129) in a manner similar to Preparation 130. The obtained Compound (134) was used in Preparation 139.

^XH-NMR (300 MHz, CDC1₃, δ) : 1.07 (9H, S), 1.21 (3H, d, J=6.6 Hz),

1.35-1.50 (2H, m), 1.97-2.21 (4H, m) , 3.77 (3H, s), 3.81 (3H, s), 4.24 (IH, q, J=6.6 Hz), 5.38 (IH, d, J=16.5 Hz), 5.57-5.68 (IH, m), 5.58 (IH, d, J=16.5 Hz), 6.46-6.57 (2H, m) , 6.68-6.80 (3H, m) , 7.03 (IH, d, J=9.2 Hz), 7.22-7.77 (17H, m) ; MS (ES+) m/e 848.16 (M+l). Preparation 135 A solution of Compound (130) (566 mg) in a mixed solvent of methanol and dioxane (1:1 v/v 30 mL) was added 10% palladium on carbon, and the mixture was stirred at ambient temperature under hydrogen atomosphere (3 atm) for 4 hr. The catalyst was filtered off through a pad of Celite® and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (1:1) to give Compound (135) (628 mg) as a white foam. The obtained Compound (135) was used in Preparation 140.

^XH-NMR (500 MHz, CDC1₃, δ) : 0.76 (3H, t, J=7.3 Hz), 1.06 (3x3H, S), 1.08-1.36 (6H, m) , 1.55 (IH, dq, J=7.3, 6 Hz), 1.98-2.42 (4H, m) , 3.72 (3H, s), 3.78 (3H, s), 4.06 (IH, t, J=6 Hz), 5.52 (IH, d, J=16.5 Hz), 5.65 (IH, m) , 5.67 (IH, d, J=16.5 Hz), 6.59 ( IH, dd, J=8, 2 Hz), 6.69 (IH, d, J=8 Hz), 6.72 (IH, d, J=2 Hz), 7.18-7.70 (18H, m), 7.77 (2H, ) , 7.93 (IH, d, J=8.8 Hz), 8.63 (IH, d, J=8.3 Hz);

MS (ES+) m/e 846. Preparation 136

Compound (136) (613 mg) was obtained from Compound (131) in a manner similar to Preparation 135. The obtained Compound (136) was used in Preparation 141.

^XH-NMR (300 MHz, CDC1₃, δ) s 1.04 (9H, s), 1.14 (3H, d, J=6.5 Hz), 1.20-1.42 (4H, m), 2.00-2.23 (4H, m) , 2.42 (2H, m) , 3.72 (3H, s), 3.78 (3H, s), 4.14 ( IH, m) , 5.32 (IH, d, J=16.5 Hz), 5.66 (IH, d, J=16.5 Hz), 5.66 (IH, m) , 6.59 ( IH, m) , 6.66-6.76 (2H, m) , 7.19 (IH, d, J=8 Hz), 7.28-7.80 (19H, m) , 7.93 (IH, d, J=8.8 Hz), 8.63 (IH, d, J=8 Hz). Preparation 137

Compound (137) (494 mg) was obtained from Compound (132) in a manner similar to Preparation 135. The obtained Compound (137) was used in Preparation 142. ^XH-NMR (300 MHz, CDC1₃, δ) : 1.06 (9H, S), 1.14-1.50 (6H, m) , 2.00- 2.22 (2H, m), 2.38 (2H, m) , 3.71 (3H, S), 3.77 (3H, s), 4.06-4.16 (2H, m), 5.52 (IH, d, J=16 Hz), 5.60-5.72 (2H, m) , 6.59 (IH, dd, J=8.5, 2 Hz), 6.65-6.74 (2H, m) , 7.20 (IH, d, J=9 Hz), 7.30-7.80 (19H, m), 7.93 (IH, d, J=8 Hz), 8.62 (IH, d, J=8.5 Hz). Preparation 138

Compound (138) (398 mg) was obtained from Compound (133) in a manner similar to Preparation 135. The obtained Compound (138) was used in Example 60. ^XH-NMR (300 MHz, CDC1₃, δ) : 1.00 (3H, t, J=7 Hz), 1.14-1.52 (6H, m), 2.00-2.40 (6H, m) , 3.73 (3H, s), 3.80 (3H, s), 5.53 (IH, d, J=16.5 Hz), 5.61-5.73 (2H, m) , 6.60 (IH, dd, J=8, 1.5 Hz), 6.66- 6.76 (2H, m), 7.17 (IH, d, J=8.5 Hz), 7.37-7.54 (5H, m) , 7.60- 7.71 (2H, m), 7.72-7.82 (2H, m) , 7.93 (IH, d, J=8 Hz), 8.62 (IH, d, J=8 Hz).

Preparation 139

Compound (139) (414 mg) was obtained from Compound (134) in a manner similar to Preparation 135. The obtained Compound (139) was used in Preparation 143. ^XH-NMR (300 MHz, CDC1₃, δ) s 1.07 (9H, s), 1.15 (3H, d, J=6.6 Hz),

1.22-1.42 (4H, m) , 1.79-2.17 (4H, m) , 2.37-2.50 (2H, m) , 3.78 (3H, s), 3.81 (3H, s), 4.07-4.22 (IH, m) , 5.39 (IH, d, J=16.5 Hz), 5.48-5.67 (IH, m) , 5.72 ( IH, d, J=16.5 Hz), 6.54-6.67 ( IH, m) , 6.69-6.83 (2H, m) , 7.23-8.22 (18H, m) ; MS (ES+) m/e 850.36 (M+l). Preparation 140

To a stirred solution of Compound (135) (530 mg) in a mixed solvent of acetonitrile, methanol and water (14 : 3 : 3 v/v, 20mL) was added diammonium cerium nitrate (1.03 g) under ice- cooling, and the resulting mixture was stirred at ambient temperature for 1 hr. Additional diammonium cerium nitrate (350 mg) was added thereto, and the mixture was stirred for 1 hr. To this mixture were added saturated sodium hydrogen carbonate solution and ethyl acetate and the mixture was stirred vigorously for 10 min. The insoluble material was filtered off through a pad of Celite®, and the filtrate was extracted with ethyl acetate.

The organic phase was washed with water (twice) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate : chloroform 1:5 v/v) to give

Compound (140) as a yellow foam (285 mg) . The obtained Compound

(140) was used in Example 61.

^XH-NMR ( 300 MHz, CDC1₃, δ) : 0.78 (3H, t, J=7.5 Hz) , 1.06 ( 3x3H, S) ,

1.14-1.44 ( 6H, m) , 1.56 ( IH, dq, J=7.5, 5.7 Hz ) , 2.13-2.44 ( 4H, m) , 4.06 ( IH, t, J=5.7 Hz) , 5.40 ( IH, br) , 7.22-7.68 ( 18H, ) ,

7.84 ( 2xlH, d, J=8.5 Hz) , 7.91 ( IH, d, J=8.5 Hz ) ;

MS (ES+) m/e 696.

Preparation 141

Compound (141) (377 mg) was obtained from Compound (136) in a manner similar to Preparation 140. The obtained Compound (141) was used in Example 62.

^XH-NMR (300 MHz, CBC1₃, δ) : 1.04 (9H, S), 1.13 (3H, d, J=7 Hz),

1.18-1.48 (6H, m), 2.15-2.48 (4H, m) , 4.13 ( IH, m) , 5.44 (IH, m) ,

7.23-7.68 (19H, m) , 7.81-7.94 (3H, m) . Preparation 142

Compound (142) (219 mg) was obtained from Compound (137) in a manner similar to Preparation 140. The obtained Compound ( 142 ) was used in Example 63.

^XH-NMR (300 MHz, CDCl₃, δ) : 1.05 (9H, s), 1.18-1.50 (6H, m) , 2.12- 2.46 (4H, m) , 4.09 (2H, s), 5.42 (IH, br), 7.30-7.68 (18H, ) ,

7.80-7.94 (3H, m) , 8.53 (IH, br) .

Preparation 143

Compound (143) (136 mg) was obtained from Compound (139) in a manner similar to Preparation 140. The obtained Compound (143) was used in Example 64.

^XH-NMR (300 MHz, CDC1₃, δ) : 1.07 (9H, S), 1.16 (3H, d, J=6.6 Hz),

1.21-1.54 (4H, m), 2.08-2.41 (4H, m) , 2.39-2.55 (2H, m) , 4.16 (IH, q, J=6.6 Hz), 5.20-5.38 (IH, m) , 6.97-7.06 (IH, m) , 7.20-7.64

(15H, m), 7.75-7.84 (2H, m) , 9.86 (1x0.5H, S), 11.03 (1x0.2H, brs), 11.37 (1x0.3H, brs); MS (ES+) m/e 700.31 (M+l).

Example 1

A mixture of Compound (7) (57 mg) and 10% palladium on barium sulfate (10 mg) in methanol (3 mL) was stirred under hydrogen atmosphere at ambient temperature for 2 hr. The catalyst was filtered off through the pad of Celite® and the solvent was evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chlorofor :methanol = 10:1) to give Compound El as an orange powder (40 mg) .

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.20-1.60 (6H, m) , 1.95 (2H, m) , 2.06 (IH, m), 2.22 (IH, m) , 3.89 (3H, s), 5.40 (IH, m) , 7.45 ( IH, m), 7.52-7.80 (3H, m) , 7.98 (IH, d, 3=1, 1 Hz), 8.02-8.18 (4H, m) , 8.40 (IH, dd, 3=1, 1 Hz), 8.67 ( IH, s), 9.19 (IH, br-d, J=8 Hz), 10.34 (IH, s), 12.62 (0.6H, s), 13.13 (0.4H, s); MASS (ES+): m/e 489. Example 2

Compound E2 (90 g) was obtained from Compound (8) in a manner similar to Example 1. ^XH-NMR (300 MHz, DMSO-dg, δ) : 1.26-1.60 (6H, m) , 1.95 (2H, t,

J=7.5 Hz), 2.08 (IH, m) , 2.22 (IH, m) , 5.42 (IH, m) , 7.47 (IH, dd, J=7.5, 7.5 Hz), 7.60 (IH, dd, J=7.5, 7.5 Hz), 7.66-7.76 (2H, m) , 8.00 (IH, d, J=7.5 Hz), 8.04 (2xlH, d, J=8.5 Hz), 8.08 (2xlH, d, J=8.5 Hz), 8.42 (IH, d, J=8.5 Hz), 8.68 (IH, br), 9.20 (IH, d, 3=1 Hz), 10.35 (IH, s), 13.24 (IH, br); MASS (ES+): m/e 475. Example 3

Compound E3 (78 mg) was obtained from Compound (9) in a manner similar to Example 1. ^XH-NMR (300 MHz, DMSO-d₆, δ) : 1.15-1.55 (6H, m) , 1.84-2.08 (4H, m) , 2.86 (3H, s), 4.75 (IH, m) , 7.53 (IH, dd, J=7.5, 7.5 Hz), 7.66 (IH, dd, J=7.5, 7.5 Hz), 7.72-7.84 (2H, m) , 7.91 (IH, br-d, J=6 Hz), 8.05 (IH, d, J=7.5 Hz), 8.45 ( IH, d, J=7.5 Hz), 10.34 (IH, s); MASS (ES+): m/e 405. Example 4

Compound E4 (65 mg) was obtained from Compound (10) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-de, δ) : 1.26-1.60 (6H, m) , 1.95 (2H, t, 3=1 Hz), 2.10-2.32 (2H, m) , 3.90 (3H, s), 5.50 (IH, m) , 7.59-7.88 (4H, m), 7.94 (IH, br-d, 3=9 Hz), 8.10-8.20 (2H, m) , 8.28 (IH, d, J=8

Hz), 8.53-8.63 (2H, m) , 9.45 (IH, br-d, J=8 Hz), 10.36 ( IH, s);

MASS (ES+): m/e 489.

Example 5 Compound E5 (77 mg) was obtained from Compound (16) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-de, δ) : 1.20-1.58 (6H, m) , 1.94 (2H, t, 3=1

Hz), 2.00 (IH, m), 2.14 (IH, m) , 5.31 (IH, m) , 7.28-7.74 (10.5H, m), 7.83 (0.5H, S), 7.97 (2H, d, 3=1 Hz), 8.67 (IH, s), 8.92 (IH, br-d, 3=6 Hz), 10.35 (IH, s), 12.34 (IH, br) ;

MASS (ES+): m/e 457.

Example 6

Compound E6 (34 mg) was obtained from Compound (17) in a manner similar to Example 1. ^XH-HMR (300 MHz, DMSO-d₆, δ) : 1.10-1.64 (6H, m) , 1.86-2.32 (4H, m) ,

5.40 (IH, m), 7.38-7.80 (7H, m) , 7.86-8.10 (3H, m) , 8.41 (IH, m) ,

8.69 (IH, br), 9.01 ( IH, br), 10.36 (IH, br) , 12.66 (0.6H, br) ,

13.24 (0.4H, br);

MASS (ES+): m/e 431. Example 7

Compound E7 (98 mg) was obtained from Compound (18) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.26-1.60 (6H, m) , 1.95 (2H, t, 3=1

Hz), 2.04-2.32 (2H, m) , 2.81 (3H, d, J=4.5 Hz), 5.41 (IH, m) , 7.50-7.86 (6H, m) , 7.96-8.16 (3H, m) , 8.45-8.68 (3H, m) , 9.24 ( IH, br-d, 3=1 Hz), 10.36 (IH, br-s);

MASS (ES+): m/e 488.

Example 8

Compound (24) was dissolved in a small amount of dioxane, and 4N hydrogen chloride in dioxane (4 mL) was then added thereto and the mixture was stirred at ambient temperature for 3 hr. The mixture was purified using a silica gel column (CHCl₃:MeOH=9:l) to give Compound E8 (173 mg).

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.22-1.59 (6H, m) , 1.87-2.31 (4H, m) , 5.26-5.39 (IH, m) , 7.43-7.82 (6H, m) , 7.90-8.02 ( IH, m) , 7.96 (2H, d, J=7.3 Hz), 8.67 (IH, s), 8.96 (IH, d, J=7.0 Hz), 10.33 (IH, s), 12.70 (IH, br); MASS (ES+) : m/e 449.39 (M+l). Example 9 Compound E9 (38 mg) was obtained from Compound (30) in a manner similar to Example 8.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.20-1.57 (6H, m) , 1.86-2.31 (2H, m) ,

1.94 (2H, t, J=7.3 Hz), 5.21-5.34 ( IH, m) , 7.14-7.32 (2H, m) ,

7.45-7.62 (3H, m) , 7.95 (2H, d, J=6.6 Hz), 8.66 (IH, s), 8.96 (IH, d, J=7.3 Hz), 10.32-10.39 (0.6H, m) , 12.65-12.73 (0.4H, m) ;

MASS (ES+) : m/e 417.08 (M+l ) .

Example 10

Compound E10 (57.9 mg) was obtained from Compound (31) in a manner similar to Example 1. H-NMR (300 MHz, DMSO-dg, δ) : 1.22-1.59 (6H, m) , 1.87-2.31 (4H, m) ,

5.35-5.46 (IH, m) , 7.40-7.78 (4H, m) , 7.98 (IH, d, J=8.4 Hz),

8.28-8.49 (2H, ) , 8.64-8.79 (2H, m) , 9.13 (IH, s), 9.20-9.29 (IH, m), 10.37 (0.5H, s), 12.66 (0.3H, s), 13.15 (0.2H, s);

MASS (ES+) : m/e 432.27 (M+l). Example 11

Compound Ell (51 mg) was obtained from Compound (32) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 0.98-1.59 (6H, m) , 1.87-2.32 (4H, m) ,

5.28-5.47 (IH, m) , 7.37-7.78 (3H, m) , 7.82-8.06 (3H, m) , 8.31- 8.48 (IH, m), 8.64-8.87 (3H, m) , 9.27-9.38 ( IH, m) , 10.34 (0.5H, brs), 12.64 (0.3H, brs), 13.14 (0.2H, brs);

MASS (ES+) : m/e 432.16 (M+l).

Example 12

Compound E12 (58 mg) was obtained from Compound (33) in a manner similar to Example 1. ^XH-NMR ( 300 MHz, DMSO-dg, δ) : 1.21-1.57 ( 6H, m) , 1.87-2.30 ( 4H, m) ,

5.39-5.52 ( IH, m) , 7.43-7.84 ( 4H, m) , 7.94-8.21 ( 3H, m) , 8.27-

8.52 ( IH, ) , 8.63-8.87 (2H, m) , 9.04-9.29 ( IH, m) , 10.32 ( 0.7H, brs) , 12.70 (0.2H, br) , 13.19 ( 0.1H, br) ; MASS (ES+) : m/e 432.13 (M+l) .

Example 13

Compound E13 (155 mg) was obtained from Compound (39) in a manner similar to Example 8.

^XH-NMR (300 MHz, DMSO-de, δ) : 1.22-1.58 (6H, m) , 1.87-2.29 (2H, m) , 1.94 (2H, t, J=7.0 Hz), 5.26-5.37 (IH, m) , 7.46-7.82 (6H, m) ,

7.92-8.22 (IH, m) , 7.95 (2H, d, J=7.7 Hz), 8.32 (0.2H, s), 8.67

(IH, brs), 8.96 (IH, d, J=8.1 Hz), 10.31-10.40 (0.4H, m) , 12.83

(0.4H, br);

MASS (ES+) : m/e 406.14 (M+l). Example 14

Compound E14 (48 mg) was obtained from Compound (40) in a manner similar to Example 8.

^XH-NMR (300 MHz, DMSO-d₆, δ) : 1.22-1.59 (6H, m) , 1.89-2.32 (2H, m) ,

1.94 (2H, t, J=7.3 Hz), 5.30-5.44 (IH, m) , 6.73 (2H, d, J=8.8 Hz), 7.43-7.54 (IH, m) , 7.56-7.66 (IH, m) , 7.66-7.76 (2H, m) , 7.85 (2H, d, J=8.8 Hz), 8.01 (IH, d, J=7.7 Hz), 8.43 (IH, d, J=7.7 Hz),

8.57-8.80 (2H, m) , 10.34 ( IH, s);

MASS (ES+) : m/e 474.23 (M+l).

Example 15 Compound E15 (65.6 mg) was obtained from Compound (41) in a manner similar to Example 8.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.27-1.62 (6H, m) , 1.89-2.34 (4H, m) ,

5.34-5.48 (IH, m) , 7.04 ( IH, dd, J=8.6, 7.0 Hz), 7.19 (IH, dd,

J=8.4, 7.0 Hz), 7.32 (IH, s), 7.38-7.50 (2H, m) , 7.52-7.76 (4H, m), 7.93-8.01 ( IH, m) , 8.32-8.45 (IH, m) , 8.66 (IH, s), 8.91-9.01

( IH, m) , 10.33 ( 0.7H, s) , 11.61 ( IH, s) , 12.64 ( 0.2H, brs) , 13.16

(0.1H, brs) ;

MASS (ES+) : m/e 470.15 (M+l).

Example 16 Compound E16 (55 g) was obtained from Compound (42) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.21-1.56 (6H, m) , 1.92 (2H, t, J=7.0 Hz), 1.97-2.35 (2H, m) , 5.37-5.52 (IH, m) , 7.37-7.50 ( IH, m), 7.53-7.78 (3H, m) , 7.93-8.02 (IH, m) , 8.27-8.46 (IH, m), 8.65 (IH, s), 8.78-8.83 (IH, m) , 8.92 (IH, d, J=2.2 Hz), 9.17-9.34 (IH, m), 9.25 (IH, s), 10.32 (0.7H, brs), 12.64 (0.2H, brs), 13.12 (0.1H, brs);

MASS (ES+) : m/e 433.12 (M+l). Example 17 Compound E17 (65.3 mg) was obtained from Compound (43) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 0.84 (3H, t, J=6.6 Hz), 1.14-1.41 (8H, m), 1.40-1.61 (4H, m), 1.76-2.30 (6H, m) , 5.06-5.22 ( IH, m) , 7.40-7.50 (IH, m), 7.52-7.76 (3H, m) , 7.92-8.02 (IH, m) , 8.29- 8.46 (2H, m), 8.67 ( IH, s), 10.34 (0.5H, S), 12.53 (0.3H, s), 13.05 (0.2H, s); MASS (ES+): m/e 425.17 (M+l). Example 18

Compound E18 (65.0 mg) was obtained from Compound (44) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-d₆, δ) : 1.19-1.41 (4H, m) , 1.41-1.57 (2H, m) , 1.76-2.16 (4H, m) , 1.92 (3H, s), 4.98-5.19 (IH, m) , 7.38-7.50 (IH, m), 7.50-7.76 (3H, m) , 7.91-8.02 (IH, m) , 8.30-8.53 (2H, ) , 8.67 (IH, s), 10.33 (0.5H, s), 12.54 (0.3H, s), 13.06 (0.2H, s); MASS (ES+): m/e 369.12 (M+l). Example 19

Compound E19 (77 mg) was obtained from Compound (45) in a manner similar to Example 1. ^XH-NMR (300 MHz, DMSO-d₆, δ) : 1.19-1.54 (6H, m) , 1.78-2.07 (4H, m) , 5.02-5.16 (IH, m) , 6.74-6.86 (IH, m) , 6.89 (IH, dd, J=7.0, 7.0 Hz), 7.22 (2H, dd, J=8.1, 7.0 Hz), 7.40 (2H, d, J=8.1 Hz), 7.42- 7.51 (IH, m), 7.54-7.77 (3H, m) , 7.98 (IH, dd, 3=1 .1, 7.0 Hz), 8.29-8.45 (IH, m) , 8.65 (IH, s), 10.32 (0.7H, brs) , 12.69 (0.2H, brs), 13.18 (0.1H, brs); MASS (ES+): m/e 446.17 (M+l). Example 20

Compound E20 (48 mg) was obtained from Compound (46) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-de, δ) : 1.07-1.52 ( 12H, m) , 1.56-1.82 (4H, m), 1.83-2.12 (3H, m) , 2.17-2.35 (IH, ) , 5.06-5.20 (IH, m) ,

7.46-7.57 (IH, m) , 7.59-7.82 (3H, m) , 8.04 (IH, d, J=8.0 Hz),

8.30-8.48 (2H, m) , 10.34 (IH, s);

MASS (ES+): m/e 437.14 (M+l).

Example 21 Compound E21 (96 mg) was obtained from Compound (47) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-de, δ) : 0.83 (3H, t, J=6.6 Hz) , 1.12-1.41

( 10H, m) , 1.41-1.61 ( 4H, m) , 1.78-2.10 ( 4H, m) , 2.08-2.29 (2H, m) ,

5.07-5.23 ( IH, m) , 7.41-7.50 ( IH, m) , 7.53-7.75 (2H, m) , 7.65 ( IH, s) , 7.93-8.02 ( IH, m) , 8.32-8.44 (2H, m) , 8.67 ( IH, s) , 10.33

(0.5H, s) , 12.51 (0.3H, s) , 13.06 ( 0.2H, s) ;

MASS (ES+) : m/e 439.17 (M+l ) .

Example 22

Compound E22 (23 mg) was obtained from Compound (48) in a manner similar to Example 1.

^XH-NM (300 MHz, DMSQ-de, δ) : 1.18-1.56 (6H, m) , 1.82-2.13 (4H, m) , 2.86 (6H, s), 4.97-5.10 (IH, m) , 6.60-6.71 (IH, m) , 7.40-7.49 (IH, m), 7.52-7.77 (2H, m) , 7.65 (IH, s) , 7.93-8.01 (IH, m) , 8.34-8.46 (2H, m), 8.67 (IH, S), 10.35 (0.5H, s), 12.38 (0.3H, s), 12.95 (0.2H, s);

MASS (ES+): m/e 398.16 (M+l). Example 23

Compound E23 (60.2 mg) was obtained from Compound (49) in a manner similar to Example 1. ^XH-NMR (300 MHz, DMSO-dg, δ) : 0.99 (IH, dt, J=7.0, 2.6 Hz), 1.17-

1.37 (4H, m), 1.38-1.52 (2H, m) , 1.69-2.04 (4H, ) , 2.97-3.09 (2H, m), 4.92-5.06 (IH, m) , 5.95-6.05 (IH, m) , 6.36-6.47 (IH, ) , 7.40-7.50 (IH, m), 7.50-7.74 (3H, m) , 7.97 (IH, dd, J=8.1, 7.0 Hz), 8.29-8.43 (IH, m) , 8.66 (IH, s), 10.33 (0.6H, s), 12.56 (0.3H, s), 13.09 (0.1H, s); MASS (ES+): m/e 398.17 (M+l). Example 24

Compound E24 (86 mg) was obtained from Compound (50) in a manner similar to Example 1. ^XH-NMR (300 MHz, DMSO-dg, δ) : 1.22-1.59 (6H, m) , 1.88-2.29 (2H, m) , 1.94 (2H, t, J=6.6 Hz), 2.37 (3H, s), 5.32-5.47 ( IH, m) , 7.30 (2H, d, J=7.7 Hz), 7.40-7.49 (IH, m) , 7.52-7.79 (3H, m) , 7.65 (IH, s), 7.89 (2H, d, J=7.7 Hz), 7.93-8.04 (IH, m) , 8.34-8.48 (IH, m) , 8.68 (IH, s), 8.82-8.96 (IH, m) , 10.35 (IH, s); MASS (ES+): m/e 445.20 (M+l). Example 25

Compound E25 (48 mg) was obtained from Compound (51) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 0.91-1.20 (4H, m) , 1.20-1.40 (2H, m) , 1.68-1.92 (2H, m) , 1.83 (2H, t, J=7.0 Hz), 4.42-4.52 (IH, m) , 7.26-7.49 (4H, m) , 7.52-7.84 (5H, m) , 7.96 (IH, d, J=8.1 Hz), 8.24-8.49 (IH, m) , 8.57-8.79 (IH, m) , 10.30 (0.7H, s), 12.48 (0.2H, S), 12.97 (0.1H, s); MASS (ES+): m/e 467.13 (M+l). Example 26

Compound E26 (65.2 mg) was obtained from Compound (52) in a manner similar to Example 1.

^XH-1MMR (300 MHz, DMSO-dg, δ) : 1.11-1.57 (9H, m) , 1.74-2.14 (4H, m) ,

3.92-4.12 (2H, m) , 4.77-4.92 (IH, m) , 7.36-7.49 (IH, m) , 7.51- 7.73 (3H, m) , 7.92-8.00 (IH, m) , 8.34-8.42 (IH, m) , 8.66 (IH, s),

10.33 (0.5H, s), 12.52 (0.3H, s), 13.02 (0.2H, s);

MASS (ES+): m/e 399.14 (M+l).

Example 27

Compound E27 (83.2 mg) was obtained from Compound (53) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.22 (6H, d, J=7.0 Hz), 1.28-1.57 (6H, m), 1.89-2.30 (2H, m) , 1.94 (2H, t, J=6.6 Hz), 2.89-3.01 (IH, m), 5.33-5.46 (IH, m) , 7.35 (2H, d, J=8.4 Hz), 7.40-7.48 ( IH, m) , 7.52-7.69 (2H, m) , 7.65 (IH, s), 7.72 (IH, d, J=8.8 Hz), 7.91 (2H, d, J=8.4 Hz), 7.93-8.01 (IH, m) , 8.34-8.44 (IH, m) , 8.66 (IH, s), 8.81-8.92 ( IH, m) , 10.33 ( 0.5H, s) , 12.53 (0.3H, s) , 13.06 ( 0.2H, s);

MASS (ES+): m/e 473.24 (M+l).

Example 28 Compound E28 (67 mg) was obtained from Compound (54) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-de, δ) : 1.22-1.56 (6H, m) , 1.90-2.41 (2H, m) ,

1.96 (2H, t, J=7.0 Hz), 2.35 ( IH, s), 2.36 (2H, s), 5.28-5.40 ( IH, m), 7.20-7.30 (2H, m) , 7.29-7.39 (IH, m) , 7.40-7.52 (2H, m) , 7.54-7.78 (2H, m) , 7.67 ( IH, s), 7.73 (IH, d, J=9.9 Hz), 7.94-

8.03 (IH, m), 8.35-8.45 (IH, m) , 8.67 (IH, s), 8.74-8.84 ( IH, m) ,

10.34 (0.5H, s) , 12.56 (0.3H, s) , 13.12 ( 0.2H, s) ;

MASS (ES+): m/e 445.23 (M+l).

Example 29 Compound E29 (102 mg) was obtained from Compound (55) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.20-1.59 (6H, m) , 1.85-2.35 (4H, m) , 2.37 (3H, s), 5.32-5.46 (IH, m) , 7.33-7.50 (4H, m) , 7.52-7.85 (3H, m), 7.65 (IH, s), 7.93-8.02 (IH, m) , 8.34-8.44 (IH, m) , 8.65-8.95 (IH, m), 8.66 (IH, s), 10.34 (0.5H, s), 12.56 (0.3H, s), 13.11 (0.2H, s);

MASS (ES+)§ m/e 445.24 (M+l). Example 30

Compound E30 (80 mg) was obtained from Compound (56) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.17-1.41 (4H, m) , 1.41-1.56 (2H, m) , 1.77-1.99 (3H, m) , 1.98-2.18 (IH, m) , 2.09 (3H, a) , 4.56 (2H, s), 5.05-5.24 (IH, m) , 7.41-7.51 (IH, m) , 7.53-7.81 (3H, m) , 7.98 (IH, dd, J=8.1, 7.3 Hz), 8.31-8.45 (IH, m) , 8.59-8.73 (IH, m) , 8.67 (IH, S), 10.33 (0.5H, S), 12.59 (0.3H, s), 13.07 (0.2H, s);

MASS (ES+): m/e 427.13 (M+l).

Example 31

Compound E31 (42 mg) was obtained from Compound (58) in a manner similar to Example 1. ^XH-NM (300 MHz, DMSO-dg, δ) : 1.19-1.40 (4H, m) , 1.40-1.56 (2H, m) , 1.83-2.15 (2H, m) , 1.93 (2H, t, J=7.3 Hz), 3.93 (2H, s), 5.20- 5.33 (IH, m), 5.62 (IH, brs), 7.47-7.56 (IH, m) , 7.59-7.69 (IH, m), 7.70-7.82 (2H, m) , 8.03 (IH, d, J=8.1 Hz), 8.23 (IH, d, J=8.8 Hz), 8.43 (IH, d, J=8.1 Hz), 8.55-8.78 (IH, m) , 10.33 (IH, s); MASS (ES+): m/e 385.15 (M+l). Example 32

Compound E32 (86 mg) was obtained from Compound (59) in a manner similar to Example 1. ^XH-NMR (300 MHz, DMSO-dg, δ) : 1.16-1.40 (4H, m) , 1.40-1.56 (2H, m) , 1.80-2.15 (2H, m) , 1.93 (2H, t, J=7.0 Hz), 3.36 (3H, s), 3.92 (2H, s), 5.15-5.30 (IH, m), 7.41-7.51 (IH, m) , 7.53-7.79 (2H, m) , 7.66 (IH, s), 7.93-8.04 ( IH, m) , 8.14-8.29 ( IH, m) , 8.29-8.46 (IH, m) , 8.66 (IH, S), 10.33 (0.5H, s), 12.57 (0.3H, S), 13.07 (0.2H, s); MASS (ES+): m/e 399.16 (M+l). Example 33

Compound E33 (47 mg) was obtained from Compound (60) in a manner similar to Example 1.

^XH-MMR (300 MHz, DMSO-dg, δ) : 1.19-1.39 (4H, m) , 1.39-1.55 (2H, m) , 1.81-2.11 (2H, m), 1.92 (2H, t, J=6.6 Hz), 2.26 (6H, s), 2.91- 3.03 (2H, m), 3.31 (IH, s) , 5.15-5.28 (IH, m) , 7.41-7.51 ( IH, m) ,

7.54-7.77 (2H, m) , 7.66 ( IH, S), 7.93-8.02 (IH, m) , 8.12-8.25 (IH, m), 8.27-8.42 (IH, m) , 8.66 (IH, s), 10.33 (0.5H, s), 12.61 (0.3H,

MASS (ES+): m/e 412.20 (M+l). Example 34

Compound E34 (48 mg) was obtained from Compound (61) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 0.89 (6H, d, J=6.2 Hz), 1.19-1.42

(4H, m), 1.40-1.55 (2H, m) , 1.68-2.08 (3H, m) , 1.93 (2H, t, J=7.0 Hz), 3.68-3.86 (2H, m) , 4.79-4.91 ( IH, m) , 7.41-7.51 (IH, m) ,

7.53-7.61 (IH, m) , 7.61-7.78 (3H, m) , 7.97 (IH, d, J=7.7 Hz),

8.39 (IH, d, J=7.7 Hz), 8.68 (IH, brs);

MASS (ES+): m/e 427.18 (M+l).

Example 35 Compound E35 (96 mg) was obtained from Compound (62) in a manner similar to Example 1.

^XH-NMR (300 MHZ, CDCl₃-CD₃OD, δ) : 1.01 (3H, d, J=7.0 Hz), 1.07 (3H, d, J=7.0 Hz), 1.13-1.58 (6H, m) , 1.82-2.12 (3H, m) , 1.93 (2H, t, J=7.0 Hz), 5.12-5.23 (IH, m) , 7.52-7.63 ( IH, m) , 7.65-7.91 (4H, m), 7.95 (IH, s), 8.08 (IH, d, J=7.3 Hz), 8.45-8.85 (IH, m) , 8.49 (IH, d, J=7.3 Hz), 10.36 (IH, s); MASS (ES+): m/e 397.16 (M+l). Example 36

Compound E36 (77.4 mg) was obtained from Compound (63) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.16 (9H, s), 1.20-1.40 (4H, m) , 1.41-1.56 (2H, m), 1.81-2.30 (2H, m) , 1.93 (2H, t, J=6.6 Hz), 5.12-5.28 (IH, m) , 7.40-7.50 (IH, m) , 7.53-7.77 (3H, m) , 7.80- 7.90 (IH, m), 7.94-8.05 (IH, m) , 8.31-8.45 (IH, m) , 8.66 (IH, s), 10.34 (0.5H, s), 12.40 (0.3H, s), 13.04 (0.2H, S); MASS (ES+) : m/e 411.23 (M+l). Example 37

Compound E37 (88.7 mg) was obtained from Compound (64) in a manner similar to Example 1. ^XH-NMR (300 MHz, DMSO-dg, δ) : 1.13-1.37 (4H, m) , 1.38-1.54 (2H, m) , 1.78-2.30 (2H, m) , 1.93 (2H, t, J=7.3 Hz), 2.35-2.57 (2H, m) , 2.85 (2H, t, J=7.3 Hz), 5.10-5.20 (IH, m) , 7.10-7.30 (5H, m) , 7.49-7.59 (IH, m) , 7.61-7.70 (IH, m) , 7.70-7.86 (IH, m) , 8.04 (IH, d, J=8.4 Hz), 8.44 (IH, d, J=8.4 Hz), 8.50-8.80 (2H, m) , 10.34 (IH, s);

MASS (ES+): m/e 459.19 (M+l). Example 38

Compound E38 (88.7 mg) was obtained from Compound (65) in a manner similar to Example 1. ^XH-NMR (300 MHz, DMSO-dg, δ) : 1.16 (3H, t, J=7.0 Hz), 1.21-1.57 (6H, m), 1.81-2.14 (2H, m) , 1.94 (2H, t, J=7.3 Hz), 3.30 ( IH, d, J=15.4 Hz), 3.42 (IH, d, J=15.4 Hz), 4.07 (2H, q, J=7.0 Hz), 5.12-5.24 (IH, m) , 7.48-7.58 (IH, m) , 7.60-7.69 (IH, m) , 7.69- 7.87 (2H, ), 8.03 (IH, d, J=7.7 Hz), 8.42 (IH, d, J=7.7 Hz), 8.67 (IH, br), 8.76-8.86 (IH, m) , 10.34 (IH, s); MASS (ES+): m/e 441.18 (M+l). Example 39

Compound E39 (66 mg) was obtained from Compound (66) in a manner similar to Example 1. ^XH-NMR (300 MHz, DMSO-d₆, δ) : 1.09-1.36 (4H, m) , 1.37-1.52 (2H, m) , 1.76-2.11 (4H, m), 2.83 (6H, s), 5.04-5.17 (IH, ) , 6.64 (2H, d, J=8.1 Hz), 7.09 (IH, d, J=8.1 Hz), 7.12 (IH, d, J=8.1 Hz), 7.40- 7.51 (IH, m), 7.53-7.77 (3H, m) , 7.93-8.03 (IH, m) , 8.31-8.48 (IH, m), 8.51-8.62 (IH, m) , 8.66 (IH, s), 10.32 (0.5H, s), 12.58 (0.3H, s), 13.10 (0.2H, s);

MASS (ES+): m/e 488.23 (M+l). Example 40

Compound E40 (91 mg) was obtained from Compound (67) in a manner similar to Example 1. ^XH-NMR (300 MHz, DMSO-d₆, δ) : 1.22-1.58 (6H, m) , 1.85-2.34 (2H, m) , 1.94 (2H, t, J=7.0 Hz), 5.22-5.40 (IH, m) , 6.96 (IH, s), 7.39- 7.49 (IH, m), 7.52-7.78 (3H, m) , 7.74 (IH, s), 7.91-8.01 (IH, m) , 8.29 (IH, s), 8.34-8.45 (IH, m) , 8.63-8.74 (IH, m) , 10.34 (0.5H, s), 12.60 (0.3H, s), 13.13 (0.2H, s); MASS (ES+): m/e 421.15 (M+l). Example 41

Compound E41 (85 mg) was obtained from Compound (68) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.20-1.43 (4H, m) , 1.43-1.60 (2H, m) , 1.88-2.10 (IH, m) , 1.94 (2H, t, J=7.3 Hz), 2.10-2.32 (IH, m) ,

5.25-5.39 (IH, m) , 6.65 (IH, dd, J=2.9, 1.1 Hz), 7.24 (IH, d,

J=2.9 Hz), 7.39-7.50 (IH, m) , 7.52-7.79 (3H, m) , 7.93-8.02 (IH, m), 8.66 (IH, s), 8.76-8.90 (IH, m) , 10.33 (0.7H, s), 12.59 (0.2H, s), 13.10 (0.1H, s); MASS (ES+): m/e 421.18 (M+l).

Example 42

Compound E42 (51.5 mg) was obtained from Compound (69) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.17-1.41 (4H, m) , 1.41-1.55 (2H, m) , 1.76-2.33 (2H, m) , 1.93 (2H, t, J=7.0 Hz), 2.94-3.53 (2H, m) , 5.09-5.19 ( IH, m) , 7.45 ( IH, dd, J=8.4, 7.7 Hz) , 7.58 ( IH, dd, J=8.4, 7.7 Hz) , 7.62-7.76 ( IH, m) , 7.98 ( IH, d, J=7.7 Hz) , 8.39 ( IH, d, J=8.4 Hz) , 8.68 ( IH, d, J=8.4 Hz) , 10.33 ( IH, s) ; MASS (ES+) : m/e 413.15 (M+l) . Example 43

Compound E43 ( 55.6 mg) was obtained from Compound ( 70 ) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.09 ( 3H, t, J=7.3 Hz) , 1.18-1.56 (6H, m) , 1.87-2.05 (2H, m) , 1.92 (2H, t, J=7.3 Hz ) , 2.81-3.01 (2H, m), 4.62-4.75 (IH, m) , 7.52 (IH, dd, 3=1.1 , 7.0 Hz), 7.65 (IH, dd, J=7.7, 7.0 Hz), 7.71-7.82 (2H, m) , 7.85-7.97 (IH, m) , 8.03 (IH, d, J=8.1 Hz), 8.42 (IH, d, J=8.1 Hz), 10.34 (IH, s); MASS (ES+): m/e 419.16 (M+l). Example 44 Compound E44 (58.2 mg) was obtained from Compound (71) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 0.62-0.73 (3H, m) , 1.15-1.62 (8H, m) , 1.85-2.05 (2H, m) , 1.92 (2H, t, J=7.3 Hz), 2.58-2.96 (2H, m) , 4.53-4.68 (IH, m) , 7.41-7.51 (IH, m) , 7.53-7.78 (3H, m) , 7.80 (IH, d, J=8.1 Hz), 7.94-8.03 (IH, m) , 8.30-8.45 ( IH, m) , 8.66 (IH, s), 10.33 (0.5H, s), 12.62 (0.3H, s), 13.15 (0.2H, s); MASS (ES+): m/e 433.15 (M+l). Example 45

Compound E45 (17 mg) was obtained from Compound (72) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-d₆, δ) : 1.18-1.41 (4H, m) , 1.40-1.55 (2H, m) , 1.76-2.14 (4H, m) , 2.35-2.62 (4H, m) , 5.06-5.19 (IH, m) , 7.40- 7.51 (IH, m), 7.53-7.79 (3H, m) , 7.93-8.03 (IH, m) , 8.33-8.56 (IH, m), 8.45 (IH, d, J=8.8 Hz), 8.66 (IH, s), 10.33 (0.7H, s), 12.09 (IH, brs), 12.49 (0.2H, s), 12.99 (0.1H, s); MASS (ES+): m/e 427.14 (M+l). Example 46

Compound E46 (112 mg) was obtained from Compound (73) in a manner similar to Example 1. ^XH-NMR (300 MHz, DMSO-dg, δ) : 1.22-1.59 (6H, m) , 1.94 (2H, t, J=7.7 Hz) , 1.97-2.30 (2H, m) , 5.28-5.43 ( IH, m) , 6.81 (2H, d,

J=8.8 Hz) , 7.44 ( IH, dd, J=7.7, 7.7 Hz) , 7.56 ( IH, dd, J=7.7, 7.3

Hz) , 7.60-7.76 (2H, m) , 7.84 (2H, d, J=8.8 Hz) , 7.92-8.03 ( IH, m) ,

8.34-8.44 ( IH, m) , 8.61-8.72 ( IH, ) , 10.01 ( IH, s) , 10.34 (0.7H, s) , 12.52 ( 0.2H, s) , 13.07 ( 0.1H, s) ;

MASS (ES+): m/e 447.14 (M+l).

Example 47

Compound E47 (71 mg) was obtained from Compound (74) in a manner similar to Example 1. ^XH-NMR (300 MHz, DMSO-dg, δ) : 1.13-1.41 (4H, m) , 1.27 (3H, S) ,

1.32 (3H, s), 1.40-1.57 (2H, m) , 1.85-2.33 (2H, m) , 1.93 (2H, t,

J=7.0 Hz), 5.20-5.32 (IH, m) , 7.55-7.64 (IH, m) , 7.67-7.93 (3H, m), 8.09 (IH, d, J=8.8 Hz), 8.20-8.34 (IH, m) , 8.48 (IH, d, J=8.8

Hz), 10.35 (IH, s); MASS (ES+): m/e 413.14 (M+l).

Example 48

Compound E48 (45 mg) was obtained from Compound (75) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-d₆, δ) : 1.26-1.60 (6H, m) , 1.94 (2H, t, J=7.3 Hz), 1.97-2.14 (IH, m) , 2.14-2.33 ( IH, m) , 5.29-5.43 (IH, m), 7.39-7.49 (IH, ) , 7.51-7.79 (3H, m) , 7.99 ( IH, d, J=8.1 Hz),

7.99 (IH, d, J=8.4 Hz), 8.13 (2H, d, J=8.4 Hz), 8.33-8.45 (IH, m) ,

8.66 (IH, s), 9.26 (IH, d, J=8.4 Hz), 10.34 (0.5H, s), 12.63

(0.3H, s), 13.12 (0.2H, s); MASS (ES+): m/e 456.17 (M+l).

Example 49

Compound E49 (16 mg) was obtained from Compound (76) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.19-1.43 (4H, m) , 1.42-1.62 (2H, m) , 1.87-2.03 (2H, m) , 2.16-3.03 (6H, m) , 5.32-5.47 (IH, m) , 7.42-

7.53 (IH, m), 7.53-7.83 (3H, m) , 7.92-8.07 (IH, m) , 8.34-8.47 (IH, m), 8.62-8.79 (IH, m), 10.37 (IH, s);

MASS (ES+): m/e 409.13 (M+l).

Example 50 Compound E50 (35 mg) was obtained from Compound (86) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.35-1.62 (2H, m) , 1.92-2.32 (4H, m) , 3.46-3.60 (IH, m) , 5.29-5.40 (IH, m) , 5.71-5.80 (IH, m) , 6.61- 6.72 (IH, m), 7.28-8.18 (13H, m) , 8.73-8.87 (IH, m) , 8.89-9.01 (IH, m), 10.38-10.42 (0.2H, m) , 10.50-10.58 (0.3H, m) , 12.30- 12.40 (0.5H, m); MASS (ES+): m/e 455.11 (M+l). Example 51

Compound E51 (14.5 mg) was obtained from Compound (91) in a manner similar to Example 1.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.21-1.56 (6H, m) , 1.85-2.30 (4H, m) , 5.22-5.33 (IH, m) , 5.76-5.97 (2H, m) , 7.13-7.24 (2H, m) , 7.24- 7.33 (2H, m), 7.32-7.42 (2H, m) , 7.42-7.61 (5H, m) , 7.95 (2H, d, J=7.0 Hz), 8.60-8.75 (IH, m) , 8.87-9.05 (IH, m) , 10.34 (IH, s); MASS (ES+): m/e 487.18 (M+l). Example 52

Compound E52 (14.7 mg) was obtained from Compound (91) as a by-product of Example 51.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.10-1.54 (6H, m) , 1.88-2.22 (4H, m) , 3.27 (2H, s), 3.31 (IH, s), 5.20-5.30 (IH, m) , 5.39 (0.4H, s), 5.41 (0.6H, s), 7.08-7.16 ( IH, m) , 7.17-7.25 (IH, m) , 7.26-7.43 (4H, m), 7.44-7.60 (5H, m) , 7.94 (2H, d, J=7.3 Hz), 8.66 (0.4H, s), 8.80-8.91 (IH, m), 10.33 (0.3H, s), 12.18-12.31 (0.3H, m) ; MASS (ES+): m/e 501.21 (M+l). Example 53

A suspension of Compound (104) (4.5 g) in ethanol (150 mL) - IN hydrochloric acid (25 mL) was refluxed for 90 min. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (50:1) to give N-[ (lS)-l-(lH-benzimidazol-2-yl)-8-fluoro-7-oxooσtyl]benzamide as a pale yellow amorphous solid. This solid was treated with minimum amount of dry ethyl acetate to form a pale yellow crystal. The crystal was collected with diethyl ether to give Compound E53 as a light yellow crystal (3.98 g) .

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.26-1.56 (6H, m) , 1.92-2.06 (IH, m) , 2.08-2.22 (IH, m) , 2.40 (2H, ddd, J=7.7, 7.7, 2.2 Hz), 5.02 (2H, d, J=46.9 Hz), 5.24-5.35 (IH, m) , 7.10-7.18 (2H, m) , 7.40-7.60 (5H, m), 7.96 (2H, dd, J=8.4, 1.8 Hz), 8.88 ( IH, brd, J=8.1 Hz), 12.2 (IH, brs); MASS (ES+): m/e 382.3 (M+l). Example 54

To a stirred solution of Compound (107) (249 mg) in N,N- dimethylformamide (5 mL) were added benzoic acid (112 mg) , HOAT (167 mg) and WSCD (190 mg), and the resulting mixture was stirred at ambient temperature for 12 hr. The reaction mixture was diluted with ethyl acetate and washed successively with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform : ethyl acetate = 4 : 1) to give Compound E54 (286 mg). The obtained compound E54 was also used in Example 55.

^XH-NMR (300 MHz, DMSO-dg, δ):1.15 (3H, t, 3=1 Hz), 1.30-1.45 (4H, m), 1.52 (2H, m), 1.98 (2H, m), 2.26 (2H, t, 3=1 Hz), 4.02 (2H, q, 3=1 Hz), 5.39 (IH, q, 3=1 Hz), 6.94 (IH, t, J=8 Hz), 7.05 (IH, t, J=8 Hz), 7.28 (IH, d, 3=2 Hz), 7.34 (IH, d, J=8 Hz), 7.40-7.52

(3H, m), 7.64 (IH, d, J=8 Hz), 7.85 (IH, dd, 3=2, 8 Hz), 8.03 (IH, d, J=8 Hz) ;

MASS: m/z 363 (M-l) .

Example 55 To a stirred solution of Compound E54 (277 mg) in ethanol (3 mL) was added lN-sodium hydroxide (0.85 mL), and the mixture was stirred at 50°C for 90 min. The mixture was concentrated, neutralized with lN-hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The resulting solid was triturated with ethyl acetate to give Compound E55 (220 mg) . The obtained compound E55 was also used in preparation 108. ^XH-NMR (300 MHz, DMSO-dg, δ) : 1.28-1.57 (6H, m) , 1.99 (2H, m) , 2.18 (2H, t, J=7 Hz), 5.38 (IH, q, 3=1 Hz), 6.94 (IH, t, J=8 Hz), 7.05 (IH, t, J=8 Hz), 7.28 ( IH, d, 3=2 Hz), 7.34 (IH, d, J=8 Hz), 7.40-7.52 (2H, m) , 7.63 (IH, d, J=8 Hz), 7.85 (IH, dd, 3=2 , 8 Hz), 8.03 (IH, d, J=8 Hz). Example 56

A mixture of Compound (108) (57 mg) and 10% palladium on barium sulfate (10 mg) in methanol (5 mL) was stirred at ambient temperature under hydrogen atmosphere (1 atm) for 3 hr. The catalyst was filtered off through a pad of Celite® and the filtrate was evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform : methanol = 19 : 1) to give Compound E56 (35 mg) .

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.26-1.57 (6H, m) , 1.90-2.05 (4H, m), 5.38 (IH, q, 3=1 Hz), 6.94 (IH, t, J=8 Hz), 7.05 (IH, t, J=8 Hz), 7.28 (IH, d, 3=2 Hz), 7.34 ( IH, d, J=8 Hz), 7.40-7.52 (2H, m), 7.63 (IH, d, J=8 Hz), 7.85 (IH, dd, 3=2, 8 Hz), 8.53 (IH, d, J=8 Hz), 8.66 (IH, s) . Example 57

A mixture of Compound (110) (127 g) and IN HC1 in EtOH (3 ml) was heated at 50°C for 2 hr, then partitioned between EtOAc and aqueous NaHC0₃. The organic layer was separated, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on a silica gel eluting with a mixture of EtOAc and hexane (1:5) to give Compound E57 (83 mg) as an oil. ^XH-NMR (300 MHz, DMSO-dg, δ) : 1.30-1.45 (4H, m) , 1.50-1.60 (2H, m) , 1.90-2.05 (2H, m) , 2.47 (2H, t, 3=1 Hz), 2.87 (3H, s), 4.10-4.20 (IH, m), 5.10 (2H, d, J=47 Hz), 7.25 (2H, brd, J=8 Hz), 7.55-7.70 (2H,m), 7.83 (IH, d, J=8 Hz). Example 58

Compound (116) (70 mg) was dissolved in tetrahydrofuran (1 mL) , and then 1.0 M solution (0.332 mL) of tetrabutylammonium fluoride in tetrahydrofuran was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 1 hr, and concentrated in vacuo. The residue was purified by preparative silica gel column chromatography using a mixture of chloroform / methanol (20:1) as an eluant. The amorphous residue was solidified with isopropyl ether to give Compound E58 (15 mg) as a colorless solid.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.13 (3H, d, J=7.0 Hz), 1.22-1.54

(6H, m), 1.88-2.19 (2H, m) , 2.50 (2H, t, J=7.0 Hz), 3.94-4.05 (IH, m), 5.23-5.34 (IH, m) , 5.27 (IH, d, J=5.5 Hz), 7.08-7.18 (2H, m) ,

7.41-7.60 (5H, m) , 7.96 (2H, d, J=7.5 Hz), 8.88 (IH, d, J=7.5 Hz),

12.24 (IH, s);

MASS: 394(M+1)⁺; mp. 101-102°C. Example 59

Compound E59 (16.2 mg) was obtained from Compound (117) in a manner similar to Example 58.

^XH-NMR (300 MHz, DMSO-dg, δ) : 1.13 (3H, d, J=7.0 Hz), 1.24-1.58

(6H, m), 1.90-2.23 (2H, m) , 2.39-2.60 (2H, m) , 3.94-4.05 ( IH, ) , 5.25 (IH, d, J=5.5 Hz), 5.28-5.39 (IH, m) , 7.04 ( IH, t, J=7.5 Hz),

7.09-7.24 (3H, m) , 7.30 (IH, s), 7.44 (2H, d, J=7.5 Hz), 7.57 (IH, d, J=7.5 Hz), 7.63 (IH, d, J=7.5 Hz), 8.86 (IH, d, J=7.5 Hz),

11.60 (IH, s), 12.30 (IH, s) .

MASS: 433(M+1)⁺; mp. 218-219°C.

Example 60

Compound E60 (160 mg) was obtained from Compound (138) in a manner similar to Preparation 140.

^XH-NMR (300 MHz, DMSO-dg, δ) : 0.88 (3H, t, 3=1 Hz), 1.25-1.54 (6H, m), 1.97-2.46 (6H, m) , 5.39 ( IH, m) , 7.41-7.76 (7H, m) , 7.94-8.04

(3H, m), 8.39 (IH, m), 8.95 (IH, m) , 12.58 (0.5H, br), 13.09

(0.5H, br).

Example 61

Compound E61 (82 mg) was obtained from Compound (140) in a manner similar to Example 58. ^XH-NMR (300 MHz, DMSO-dg, δ) : 0.81 (3H, t, J=7.3 Hz), 1.24-1.64 (8H, m), 2.06 (IH, m), 2.20 (IH, m) , 2.42-2.56 (2H, m) , 3.81 (IH, m), 5.20 (IH, d, J=5.5 Hz), 5.40 (IH, m) , 7.40-7.77 (7H, m) , 7.91-8.04 (3H, m) , 8.39 (IH, dd, J=8.5, 8.5 Hz), 8.96 (IH, m) , 12.57 (5/8H, s), 13.08 (3/8H, s); MS (ES+) m/e 458. Example 62

Compound E62 (144 mg) was obtained from Compound (141) in a manner similar to Example 58. ^XH-NMR (300 MHz, CDC1₃, δ) : 1.22-1.58 (6H, m) , 1.27 (3H, d, 3=1 Hz), 2.13-2.48 (4H, m) , 3.54 ( IH, br) , 4.10 (IH, m) , 5.44 (IH, br), 7.35-8.14 (12H, m) . Example 63

Compound E63 (60 mg) was obtained from Compound (142) in a manner similar to Example 58.

^XH-NMR (300 MHz, DMSO-d₆, δ) : 1.26-1.56 (6H, m) , 2.13 (2H, m) , 2.39 (2H, m), 4.03 (2H, d, 3=6 Hz), 5.04 (IH, t, J=6 Hz), 5.38 (IH, m), 7.40-8.04 ( 10H, m) , 8.39 (IH, m) , 8.96 (IH, m) . Example 64 Compound E64 (93 mg) was obtained from Compound (143) in a manner similar to Example 58.

^XH-NMR (300 MHz, CDC1₃, δ) s 1.29 (3H, d, J=7.3 Hz), 1.38-1.78 (6H, m), 2.09-2.44 (4H, ) , 3.48-3.60 (IH, m) , 4.15 (IH, brs), 5.25- 5.48 (IH, m), 7.15-7.24 (2H, ) , 7.26-7.60 (4H, m) , 7.75-7.85 (2H, m) , 7.95 (IxO.SH, brs), 11.74 (lx0.3H, brs), 12.44 (lx0.2H, brs); MS (ES+) m/e 462.07 (M+l).

The compounds obtained by the above-mentioned Preparations and Examples are listed in the following Table 2 (including Tables 2-1 to 2-18) and Table 3 (including Tables 3-1 to 3-8). Table 2

Table 2-1

Table 2-2

Compound (9) Compound (10)

Compound (11) Compound (12)

Compound (13) Compound (14)

Compound (15) Compound (16)

Table 2-3

Compound (17) Compound (18)

Compound (19) Compound (20)

Compound (21) Compound (22)

Compound (23) Compound (24)

Table 2-4

Compound (25) Compound (26)

Compound (27) Compound (28)

Compound (29) Compound (30)

Compound (31) Compound (32)

Table 2-5

Compound (33) Compound (34)

Compound (35) Compound (36)

Compound (37) Compound (38)

Compound (39) Compound (40;

Table 2-6

Compound (41) Compound (42)

Compound (43) Compound (44)

Compound (45) Compound (46)

Compound (47) Compound (48)

Table 2-7

Table 2-8

Compound (57) Compound (58)

Compound (59) Compound (60)

Compound (61) Compound (62)

Compound (63 ) Compound (64)

Table 2-9

Table 2-10

Table 2-11

Compound (81) Compound (82)

Compound (83) Compound (84)

Compound (85) Compound (86)

Compound (87) Compound (88)

Table 2-12

Compound (89) Compound (90)

Compound (91) Compound (92)

Compound (93) Compound (94)

Compound (95) Compound (96)

Table 2-13

Compound (97) Compound (98)

Compound (99) Compound (100)

Compound (101) Compound (102)

Compound (103) Compound (104)

Table 2-14

Compound (105) Compound (106)

Compound (107) Compound (108)

Compound (109) Compound (110)

Compound (111) Compound (112)

Table 2-15

Table 2-16

Table 2-17

Compound (129) Compound (130)

Compound (131) Compound (132)

Compound (133) Compound (134)

Compound (135) Compound (136)

Table 2-18

Table 3

Table 3-1

Compound El Compound E2

Compound E3 Compound E4

Compound E5 Compound E6

Compound E7 Compound E8

Table 3-2

Compound E9 Compound ElO

Compound Ell Compound El2

Compound E13 Compound El

Compound E15 Compound El6

Table 3-3

Compound El7 Compound El8

Compound El9 Compound E20

Compound E21 Compound E22

Compound E23 Compound E2

Table 3-4

Compound E25 Compound E26

Compound E27 Compound E28

Compound E29 Compound E30

Compound E31 Compound E32

Table 3-5

Table 3-6

Compound E41 Compound E42

Compound E43 Compound E4

Compound E45 Compound E46

Compound E47 Compound E48

Table 3-7

Compound E49 Compound E50

Compound E51 Compound E52

Compound E53 Compound E54

Compound E55 Compound E56

Table 3-8

Compound E57 Compound E58

Compound E59 Compound E60

Compound E61 Compound E62

Compound E63 Compound E6

INDUSTRIAL APPLICABILITY

According to the invention, a compound having a potent inhibitory effect on the activity of histone deacetylase and a pharmaceutical composition containing said compound as an active ingredient can be provided. The compound is useful as an active ingredient of an immunosuppressant and an antitumor agent, and useful as a therapeutic or prophylactic agent for diseases such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, autoimmune diseases, protozoal infections, tumors, etc.

This application is based on the patent application No. 2003900608 filed in Australia, and the contents of which are incorporated hereinto by reference.

Claims

1. A compound of the following formula (I) :

wherein R^x is acyl,

R² is hydrogen, or

R^x and R² are linked together to form a heterocyclic ring,

R⁵ is hydroxy, hydroxylamino, lower alkyl, lower alkoxy, halo(lower)alkyl or hydrox (lower)alkyl, Q is lower alkylene or lower alkenylene, and

G is a substituent selected from the following formulas

wherein

K and are each independently hydrogen, halogen halo(lower)alkyl, cyano, aryl or aryl(lower)alkyl optionally substituted with one or more suitable substituent(s), or R³ and R⁴ are linked together to form an aromatic ring, and X is NH, 0 or S, or a salt thereof.

2. The compound of claim 1, wherein

R^x is acyl selected from the group consisting of arylcarbonyl in which the aryl portion is optionally substituted with one or more suitable substituent(s) ; heterocyclic carbonyl; lower alkyl- carbonyl; carbamoyl in which the amino portion is optionally mono- or di-substituted with suitable substituent(s) ; lower alky1-carbonyloxy(lower)alkyIcarbonyl; lower alkoxycarbonyl; lower alkylsulfonyl; and arylsulfonyl, R² is hydrogen, or

R^x and R² are linked together to form a heterocyclic ring, R³ and R⁴ are each independently hydrogen; halogen; halo(lower)alkyl; cyano; aryl; or aryl(lower)alkyl in which the alkyl portion is optionally substituted with hydroxy or lower alkoxy, or

R³ and R⁴ are linked together to form a benzene ring, R⁵ is hydroxylamino, halo(lower)alkyl or hydroxy(lower)alkyl, X is NH, and

Q is lower alkylene, or a salt thereof.

3. The compound of claim 2, wherein R¹ is arylcarbonyl in which the aryl portion is optionally substituted with one or more substituent(s) selected from the group consisting of lower alkoxycarbonyl; carboxy; lower alkylcarbamoyl; N, N-di( lower)aIk lamino; lower alkyl; hydroxy; and cyano, or a heterocyclic carbonyl, R³ and R⁴ are each independently hydrogen, or

R³ and R⁴ are linked together to form a benzene ring,

R⁵ is hydroxylamino, halo(lower)alkyl or hydroxy(lower)alkyl,

X is NH, and

Q is lower alkylene, or a salt thereof.

4. A compound of the following formula (I ' ) s

wherein R^x is acyl, R² is hydrogen, or

R¹ and R² are linked together to form a heterocyclic ring, R³ and R⁴ are each independently hydrogen, halogen, halo(lower)alkyl, cyano, aryl or aryl(lower)alkyl optionally substituted with one or more suitable substituent(s), or R³ and R⁴ are linked together to form an aromatic ring, R⁵ is hydroxylamino, halo(lower)alkyl or hydroxy(lower)alkyl, X is NH, O or S, and

Q is lower alkylene or lower alkenylene, or a salt thereof.

5. The compound of claim 4, wherein

R¹ is acyl selected from the group consisting of arylcarbonyl in which the aryl portion is optionally substituted with one or more suitable substituent( s) ; heterocyclic carbonyl; lower alkyl- carbonyl; carbamoyl in which the amino portion is optionally mono- or di-substituted with suitable substituent(s) ; lower aIky1-carbonylox (lower)alkyIcarbonyl; lower alkoxycarbonyl; lower alkylsulfonyl; and arylsulfonyl, R² is hydrogen, or

R¹ and R² are linked together to form a heterocyclic ring,

R³ and R⁴ are each independently hydrogen; halogen; halo(lower)alkyl; cyano; aryl; or aryl(lower)alkyl in which the alkyl portion is optionally substituted with hydroxy or lower alkoxy, or

R³ and R⁴ are linked together to form a benzene ring,

R⁵ is hydroxylamino,

X is NH, and

Q is lower alkylene, or a salt thereof.

6. The compound of claim 5, wherein

R^x is arylcarbonyl in which the aryl portion is optionally substituted with one or more substituent(s) selected from the group consisting of lower alkoxycarbonyl; carboxy; lower alkylcarbamoyl; N, N-di(lower)aIkylamino; lower alkyl; hydroxy; and cyano,

R³ and R⁴ are linked together to form a benzene ring, R⁵ is hydroxylamino, X is NH, and Q is lower alkylene, or a salt thereof.

7. A histone deacetylase inhibitor comprising the compound of claim 1 or 4.

8. A method for inhibiting histone deacetylase, comprising using the compound of claim 1 or 4.

9. Use of the compound of claim 1 or 4 for the manufacture of a medicament for inhibiting histone deacetylase.

10. A pharmaceutical composition for treating or preventing inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, autoimmune diseases, protozoal infections or tumors, which comprises the compound of claim 1 or 4 as an active ingredient:

11. A method for treating or preventing inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, autoimmune diseases, protozoal infections or tumors, which comprises administering an effective amount of the compound of claim 1 or 4 to a human being or an animal.

12. Use of the compound of claim 1 or 4 for the manufacture of a medicament for treating or preventing inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, autoimmune diseases, protozoal infections or tumors.

13. A commercial package comprising the pharmaceutical composition of claim 10 and a written matter associated therewith, the written matter stating that the pharmaceutical composition may or should be used for treating or preventing inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, autoimmune diseases, protozoal infections or tumors.