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Title:
SORDARIN DERIVATIVES FOR PREVENTING OR TREATING INFECTIOUS DISEASES CAUSED BY PATHOGENIC MICROORGANISMS
Document Type and Number:
WIPO Patent Application WO/2009/131246
Kind Code:
A1
Abstract:
This invention relates to a new sordarin derivative or a pharmaceutically acceptable salt thereof, which has antimicrobial activities (especially, antifungal activities), to process for preparation thereof, to a pharmaceutical composition comprising the same, and to a method for prophylactic and/or therapeutic treatment of infectious diseases in a human being or an animal.

Inventors:
WASHIZUKA KENICHI (JP)
TOMISHIMA MASAKI (JP)
HANADATE TADAATSU (JP)
SHIRAISHI NOBUYUKI (JP)
MATSUYA TAKAHIRO (JP)
MORIKAWA HIROSHI (JP)
TODA AYAKO (JP)
TANABE DAISUKE (JP)
OKADA AKIHIRO (JP)
MAKI KATSUYUKI (JP)
MATSUMOTO SATORU (JP)
OHTAKE HIROAKI (JP)
Application Number:
PCT/JP2009/058437
Publication Date:
October 29, 2009
Filing Date:
April 22, 2009
Export Citation:
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Assignee:
ASTELLAS PHARMA INC (JP)
WASHIZUKA KENICHI (JP)
TOMISHIMA MASAKI (JP)
HANADATE TADAATSU (JP)
SHIRAISHI NOBUYUKI (JP)
MATSUYA TAKAHIRO (JP)
MORIKAWA HIROSHI (JP)
TODA AYAKO (JP)
TANABE DAISUKE (JP)
OKADA AKIHIRO (JP)
MAKI KATSUYUKI (JP)
MATSUMOTO SATORU (JP)
OHTAKE HIROAKI (JP)
International Classes:
C07D307/10; C07C255/47; C07D307/12; C07D307/30; C07D307/54; C07D307/87; C07D309/04; C07D405/12; C07D405/14; C07D407/08; C07D413/06; C07D413/12; C07D487/10; C07D491/10; C07F7/18
Domestic Patent References:
WO1998015178A11998-04-16
Other References:
SERRANO-WU ET AL: "Oxime derivatives of sordaricin as potent antifungal agents", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 12, 2002, pages 943 - 946, XP002535587
HANADATE T ET AL: "FR290581, a novel sordarin derivative: Synthesis and antifungal activity", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 19, no. 5, 22 January 2009 (2009-01-22), pages 1465 - 1468, XP025994296, ISSN: 0960-894X
Attorney, Agent or Firm:
MORITA, Hiroshi et al. (3-11 Nihonbashi-Honcho 2-chom, chuo-ku Tokyo 11, JP)
Download PDF:
Claims:
C LAI M S

1. A compound of Formula (I):

[wherein

R 1 is -CHO, -CO-lower alkyl, cyano, -COOH or lower alkyl substituted with one or more OH(s);

R 2 is -COOH or protected carboxy;

R 3 is

[wherein

R 4 , R 6 and R 7 are each H or lower alkyl optionally substituted with one or more suitable substituent(s);

R 5 is

H 5 lower alkyl optionally substituted with one or more suitable substituent(s), lower alkenyl optionally substituted with one or more suitable substituent(s),

-O-lower alkyl optionally substituted with one or more suitable substituent(s),

-0-lower alkenyl optionally substituted with one or more suitable substituent(s), or cycloalkyl;

X is CHR 10 or O, wherein

R 10 is H, lower alkyl, -COOH or -COO-lower alkyl; and n is an integer of 0 or 1

] and

R 8 , R 9 and R 11 are each lower alkyl

] or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R 2 is -COOH or -COO-lower alkyl; R 3 is

[wherein

R 4 , R 6 and R 7 are each

I) H,

2) lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of

2-1) -OH

2-2) -O-lower alkyl

2-3) -SO 2 -lower alkyl

2-4) -COO-lower alkyl,

2-5) -OCO-amino optionally substituted with one or two lower alkyl(s) optionally substituted with a piperidyl,

2-6) -OCO-piperidyl optionally substituted with a piperidyl,

2-7) -OCO-piperazinyl optionally substituted with one or more lower alkyl(s) optionally substituted with a piperidyl,

2-8) amino optionally substituted with one or two substituent(s) selected from the group consisting of

2-8-1) lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of

-CN, -COOH,

-CO-piperazinyl optionally substituted with one or more lower alkyl(s) optionally substituted with a piperidyl, -0-lower alkyl, -OH, -O-SO 2 -lower alkyl, -OCO-amino optionally substituted with one or two lower alkyl(s) optionally substituted with a piperidyl,

-OCO-piperidyl optionally substituted with one or more lower alkyl(s) optionally substituted with a substituent selected from the group consisting of piperidyl and piperazinyl optionally substituted with a lower alkyl;

-OCO-piperazinyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of

-OH, -0-lower alkylene-OH, amino optionally substituted with one or two lower alkyl(s), -Sθ 2 -phenyl, piperidyl optionally substituted with one or more lower alkyl(s), morpholinyl, phenyl, pyridyl and -CO-morpholinyl; phenyl optionally substituted with a morpholinyl optionally substituted with one or more lower alkyl(s), thiazolyl and pyrimidinyl; amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of cycloalkyl, piperidyl and pyridyl; cycloalkyl, 4,5-dihydroimidazolyl, pyridyl, and quinuclidinyl; cycloalkyl, phenyl optionally sustituted with one or more substituent(s) selected from the group consisting of amino optionally substituted with one or two lower alkyl(s), and lower alkylene-amino optionally substituted with one or two lower alkyl(s) optionally substituted with a pyridyl; heterocyclic group selected from the group consisting of piperidin-2-yl optionally substituted with one or more lower

alkyl(s), pyrrolidin-2-yl optionally substituted with one or more lower alkyl(s), pyridyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of -OH, -O-lower alkyl, amino optionally substituted with one or two lower alkyl(s) optionally substituted with one or two substituent(s) selected from the group consisting of phenyl and pyridyl; piperidyl, and morpholinyl; halogen, -O-lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl and -CO-lower alkyl; -COOH,

-COO-lower alkyl optionally substituted with a phenyl, -CO-amino optionally substituted with a lower alkyl, phenyl, piperidyl, and pyridyl; imidazolyl optionally substituted with one or more lower alkyl(s), furyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiazolyl, benzimidazolyl optionally substituted with one or more lower alkyl(s), isoquinolyl, isoindolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahy dro-2H-pyrido [ 1 ,2-.7]pyrazinyl, octahydropyrrolo [ 1 ,2-α]pyrazinyl, l,3,8-triazaspiro[4,5]decanyl optionally substituted with one or more substituent(s) selected from the group consisting of phenyl and oxo; and

[wherein

Y is -CH 2 -, NH or O; R 12 and R 13 are each H, lower alkyl optionally substituted with a substituent selected from the group consisting of -OH, -0-lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl, lower alkenyl, and phenyl optionally substituted with one or more halogeno lower alkyl(s);

-COO-lower alkyl, -CO-pyrrolidinyl, -CONH-pyridyl, -SO 2 -phenyl, phenyl, naphthyl, pyrrolidinyl optionally substituted with one or more lower alkyl(s), piperidyl optionally substituted with one or more lower alkyl(s) optionally substituted with a -OH, morpholinyl, tetrahydrofuranyl, and pyridyl; lower alkenyl, halogeno lower alkyl, -OH, -O-lower alkyl, halogen, -COOH, -COO-lower alkyl, -CO-amino optionally substituted with one or two lower alkyl(s),

-SO 2 -lower alkyl, cycloalkyl optionally substituted with one or more lower alkyl(s), phenyl optionally substituted with one or more -OH(s), piperidyl optionally substituted with one or more alkyl(s), pyridyl, pyrimidinyl, 1,2-berizisoxazolyl optionally substituted with one or more

halogen(s), or

1,3-dihydrobenzimidazolyl optionally substituted with an oxo; and m is an integer of 0 to 3

] 2-8-2) halogeno lower alkyl,

2-8-3) lower alkenyl optionally substituted with a lower alkynyl, 2-8-4) cycloalkyl,

2-8-5) piperidyl optionally substituted with one or more lower alkyl(s), 2-8-6) quinuclidinyl, 2-8-7) 5,6,7,8-tetrahydroquinolinyl, 2-8-8) 6,7-dihydro-5H-cyclopenta[Z>]pyridinyl, and

2-8-9) pyrrolidinyl optionally substituted with a pyridyl optionally substituted with one or more lower alkyl(s); and

2-9) heterocyclic group selected from the group consisting of imidazolyl optionally substituted with a lower alkyl,

1,2,3,6-tetrahydropyridinyl optionally substituted with one or more substituent(s) selected from the group consisting of cyano, phenyl optionally substituted with an amino optionally substituted with one or two lower alkyl(s), imidazolyl optionally substituted with a lower alkyl, thiazolyl, thienyl, and pyridyl; l-azabicyclo[2.2.1]heρtyl,

1,2,3,4-tetrahydroisoquinolinyl optionally substituted with one or more -O-lower alkyl(s),

2,3,4,5-tetrahydro-lH-3-benzazepinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[l,2-fl]pyrazinyl optionally substituted with one or more alkyl(s), 5 5 6,7,8-tetrahydro-l,6-naphthyridinyl,

octahydropyrrolo[l ,2-α]pyrazinyl, octahydro-2H " -pyrido [ 1 ,2-α]pyrazinyl,

4,5,6,7-tetrahydro[l,3]thiazolo[5,4-c]pyridinyl optionally substituted with a lower alkyl, l,4-dioxa-8-azaspiro[4,5]decanyl optionally substituted with one or more substituent(s) selected from the group consisting of

-COOη, -COO-lower alkyl, and lower alkyl optionally substituted with a piperidyl; l-oxa-8-azaspiro[4,5]decanyl optionally substituted with one or more lower alkyl(s) optionally substituted with a morpholinyl; l-oxa-4,9-diazaspiro[5,5]undecanyl optionally substituted with one or more lower alkyl(s), and

2,7-diazaspiro[4,4]nonanyl optionally substituted with one or more lower alkyl(s); or

[wherein R 14 is η, lower alkyl optionally substituted with a substituent selected from the group consisting of

-OH, -O-lower alkyl, -O-SO 2 -lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of piperidyl, pyridyl and -O-lower alkyl; -OCO-piperazinyl optionally substituted with a lower alkyl,

phenyl, heterocyclic group selected from the group consisting of pyridyl, pyrrolidinyl, piperidyl, piperazinyl, diazepanyl and morpholinyl, each of which is optionally substituted with one or more lower alkyl(s) optionally substituted with a piperidyl; halogen, methylidene, halogeno lower alkyl, lower alkenyl, -OH, oxo, -O-lower alkyl optionally substituted with a substituent selected from the group consisting of -O-lower alkyl and phenyl; -OCO-piperazinyl optionally substituted with a lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of -O-lower alkyl and pyridyl; -COO-lower alkenyl, and

-SO 2 -lower alkyl;

-COOH, -CO-lower alkyl, -COO-lower alkyl, -CO-amino optionally substituted with one or two lower alkyl(s), -CO-piperidyl, -CO-morpholinyl,

-CO-piperazinyl optionally substituted with a lower alkyl, cycloalkyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl and cycloalkyl; phenyl optionally substituted with one or more substituent(s) selected from the group consisting of halogen and morpholinyl optionally substituted with one or more lower alkyl(s); heterocyclic group selected from the group consisting of pyrrolidinyl, piperidyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl, azepanyl, imidazolyl, pyridyl, pyrimidinyl, benzimidazolyl and l,4-dioxa-8-azaspiro[4,5]decanyl, each of which is optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl optionally substituted with a piperidyl, -O-lower alkyl, halogen, phenyl and piperidyl; and -S-tetrazolyl optionally substituted with a lower alkyl;

R 15 is H, lower alkyl, -OH 5 -O-lower alkyl or halogen;

R 16 , R 17 , R 18 and R 19 are each lower alkyl;

R 20 is amino optionally subsituted with one or two lower alkyl(s);

A is lower alkylene; B is CH 2 , NH or O; p is an integer of O to 3; and q is an integer of O to 3, provided that p + q is an integer of O to 3 ; ] and R 5 is H, lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of

-CHO, -COOH, -COO-lower alkyl,

-CO-amino optionally substituted with one or two lower alkyl(s),

-CO-piperidyl,

-OH, -0-lower alkyl, -O-phenyl, cycloalkyl, phenyl, piperidyl and morpholinyl; lower alkenyl optionally substituted with a substituent selected from the group consisting of -COOH and -COO-lower alkyl, halogeno lower alkyl,

-0-lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of cycloalkyl, phenyl, and

-CO-amino optionally substituted with one or two lower alkyl(s); -O-lower alkenyl, or cycloalkyl;

] or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, wherein

R 1 is -CHO;

R 2 is -COOH; R 3 is

[wherein

R 5 is lower alkyl optionally substituted with a cycloalkyl, halogeno lower alkyl, or cycloalkyl;

X is CH 2 ; and n is O;

] or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, as an active ingredient, in association with pharmaceutically acceptable carriers or excipients.

5. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing and/or treating infectious diseases caused by pathogenic microorganisms.

6. An agent for preventing and/or treating infectious diseases caused by pathogenic microorganisms which comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof.

7. A method for the prophylactic and/or therapeutic treatment of infectious diseases caused by pathogenic microorganisms, which comprises administering an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof for curing infectious

diseases caused by pathogenic microorganisms.

9. A process for preparing a pharmaceutical composition for preventing or treating infectious diseases caused by pathogenic microorganisms, which comprises mixing the compound of claim 1 or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable carriers, vehicles or excipients.

10. A commercial package comprising the pharmaceutical composition containing the compound identified in claim 1 and a written matter associated therewith, wherein the written matter states that the compound of claim 1 can or should be used for preventing or treating infectious disease.

Description:

DESCRIPTION

SORDARIN DERIVATIVES FOR PREVENTING OR TREATING INFECTIOUS DISEASES CAUSED BY PATHOGENIC MICROORGANISMS

TECHNICAL FIELD

The present invention relates to a sordarin derivative and a salt thereof, which are useful as a medicament.

BACKGROUND ART Pathogenic fungi causes superficial / cutaneous / subcutaneous mycosis

(dermatophytosis etc.) in skin, hair and nail, and deep-seated infection (disseminated candidiasis and invasive aspergillosis etc.) in several organs. Deep-seated mycosis is a serious fungal infection associated with high rates of mortality and morbidity in severe immunocompromised patients. Therefore, therapeutic efficacy by antifungal drugs against systemic mycosis is relatively poor depending upon the underlying diseases. Furthermore standard antifungals (polyenes and azoles) often have side effects and/or drug-drug interactions, and some organisms are resistant to those antifungals.

Sordarin is an antifungal antibiotic discovered in 1971 as a metabolite of Sordaria araneosa [see Helvetica Chimica Acta 54, 1178 (1971)]. Other compounds having the sordarin skeleton have been reported as antifungal agents: zofimarin (Japanese Kokai

JP62040292) and moriniafungin (WO2003/051889).

Semi-synthetic sordarin derivatives which have antifungal activity have also been reported (WO99/58512, WO2002/022567, WO2003/007878). Japanese Kokai

JP2003/261450 discloses the following compounds:

(For the symbols in the formula, refer to the literature.)

In Bioorganic & Medicinal Chemistry Letters 2002, 12, 943, the following compounds are documented:

(For the symbols in the formula, refer to the literature.)

DISCLOSURE OF INVENTION

The present invention relates to a sordarin derivative and/or a pharmaceutically acceptable salt thereof.

More particularly, it relates to a new sordarin derivative and/or a pharmaceutically acceptable salt thereof, which has antimicrobial activities (especially antifungal activities, in which the fungi may include Aspergillus, Cryptococcus, Candida, Mucor, Actinomyces, Histoplasma, Dermatophyte, Malassezia, Fusarium, and the like).

The object sordarin derivative of the present invention is represented by Formula (I):

wherein

R 1 is -CHO, -CO-lower alkyl, cyano, -COOH or lower alkyl substituted with one or more OH(s);

R 2 is -COOH or protected carboxy;

R 3 is

[wherein

R 4 , R 6 and R 7 are each H or lower alkyl optionally substituted with one or more suitable substituent(s);

R 5 is H, lower alkyl optionally substituted with one or more suitable substituent(s), lower alkenyl optionally substituted with one or more suitable substituent(s), lower alkyl optionally substituted with one or more suitable substituent(s), -0-lower alkenyl optionally substituted with one or more suitable substituent(s) or cycloalkyl; X is CHR 10 or O,

(wherein R 10 is H, lower alkyl, -COOH or -COO-lower alkyl;) n is an integer of O or 1] and

R 8 , R 9 and R 11 are each lower alkyl or a pharmaceutically acceptable salt thereof.

The present invention also relates to a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, in association with pharmaceutically acceptable carriers or excipients.

The present invention further relates to the use of a compound of Formula (I), or its pharmaceutically acceptable salt, for the manufacture of a medicament for preventing and/or treating infectious diseases caused by pathogenic microorganisms.

The present invention still further relates to a method for the prophylactic and/or therapeutic treatment of infectious diseases caused by pathogenic microorganisms, which comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a human being or an animal.

The present invention still further relates to an agent for preventing and/or treating infectious diseases caused by pathogenic microorganisms which comprises the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

The present invention still further relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for curing infectious diseases caused by pathogenic

microorganisms.

The present invention still further relates to a process for preparing a pharmaceutical composition for preventing or treating infectious diseases caused by pathogenic microorganisms, which comprises mixing a compound of Formula (I) or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable carriers, vehicles or excipients.

The present invention still further relates to a commercial package comprising the pharmaceutical composition containing a compound of Formula (I) and a written matter associated therewith, wherein the written matter states that the compound of Formula (I) can or should be used for preventing or treating infectious diseases.

Hereafter, the present invention is explained in detail.

In the above and subsequent descriptions of the present Description, 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.

A "lower alkyl" is a linear or branched alkyl having 1 to 8 carbons (hereinafter abbreviated as C 1-8 ). Non-limiting examples of a lower alkyl include methyl, ethyl, «-propyl, isopropyl, «-butyl, isobutyl, sec-butyl, tert-butyl, rø-pentyl, n-hexy\, n-heptyl, and «-octyl. In some embodiments, the lower alkyl is a methyl, ethyl, «-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, «-pentyl, 3-methylbutyl, 2,2-dimethylpropyl, «-hexyl, 2-ethylbutyl, rc-heptyl, or rø-octyl.

A "lower alkenyl" is a linear or branched C 2-8 alkenyl. Non-limiting examples include vinyl, propenyl, butenyl, pentenyl, 1 -methyl vinyl, l-methyl-2-propenyl, 1,3-butadienyl, and 1,3-pentadienyl. In some embodiments, the lower alkenyl is a C 2-4 alkenyl, in other embodiments 2-propen-l-yl, 2-methyl-2~propen-l-yl, or 3-buten-l-yl.

A "lower alkynyl" is a linear or branched C 2-8 alkynyl. Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl, l-methyl-2-propynyl, 1,3-butadiynyl, and 1,3-pentadiynyl. In some embodiments, the lower alkynyl is a 3,3-dimethylbutyn-l-yl. A "lower alkylene" is a linear or branched C 1-8 alkylene. Non-limiting examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, and

1 , 1 ,2,2-tetramethylethylene.

A "lower alkenylene" is a linear or branched C 2-8 alkenylene. Non-limiting examples include vinylene, ethylidene, propenylene, butenylene, pentenylene, hexenylene, 1,3-butadienylene, and 1,3-pentadienylene.

A "lower alkynylene" is a linear or branched C 2-8 alkynylene. Non-limiting

examples include ethynylene, propynylene, butynylene, pentynylene, hexynylene, 1 ,3 -butadiynylene, and 1 ,3 -pentadiynylene. A "halogen" is F, Cl, Br, or I.

A "halogeno lower alkyl" is a C 1-8 alkyl substituted with one or more halogen atoms. In some embodiments, the halogeno lower alkyl is a C 1-8 alkyl substituted with 1 to 5 halogen atoms, in other embodiments trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, and 4,4,4-trifluorobutyl, chloromethyl, and iodomethyl.

A "cycloalkyl" is a C 3-10 saturated cyclic hydrocarbon group, which may be bridged. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl. In some embodiments, the cycloalkyl is a C 3-8 saturated cyclic hydrocarbon group.

A "cycloalkenyl" is a C 4-15 cycloalkehyl, which may be bridged, and includes a cyclic group fused with a benzene ring at the double bond thereof. Non-limiting examples include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, 1-tetrahydronaphthyl, 1-indenyl, 9-fluorenyl.

An "aryl" is a C 6-14 mono- to tri-cyclic aromatic hydrocarbon group. In some embodiments, the aryl is a phenyl or naphthyl.

A "heterocyclic" group is a cyclic group comprising (i) a monocyclic 3- to

8-membered, in some embodiments 5- to 7-membered, heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen; or (ii) a bicyclic or tricyclic heterocycle containing 1 to 5 heteroatoms selected from oxygen, sulfur, and nitrogen, wherein said monocyclic heterocycle is fused with one or more rings selected from the group consisting of monocyclic heterocycle, benzene ring, C 5-8 cycloalkane, and C 5-8 cycloalkene.

These heterocycles may consist spiro compounds. A sulfur atom(s) or a nitrogen atom(s) constituting the ring may be oxidized to form oxide or dioxide.

Examples of "heterocyclic" groups include the groups described below: (1) Monocyclic saturated heterocyclic groups i) containing 1 to 4 nitrogen atoms, such as azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azocanyl, etc.; ii) containing 1 to 3 nitrogen atoms, and 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms, such as thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl, oxazepanyl, etc.; iii) containing 1 to 2 sulfur atoms, such as tetrahydrothiopyranyl, etc.; iv) containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, such as oxathiolanyl, etc.; or v) containing 1 to 2 oxygen atoms, specifically oxilanyl, oxetanyl, dioxolanyl,

oxolanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, etc.;

(2) Monocyclic unsaturated heterocyclic groups i) containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, dihydroimidazolyl, pyrazolyl, pyridyl, dihydropyridinyl, tetrahydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, triazinyl, dihydrotriazinyl, azepinyl, etc.; ii) containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl, oxazinyl, etc.; iii) containing 1 to 2 sulfur atoms, such as thienyl, thiepinyl, dihydrodithiopyranyl, dihydrodithionyl, etc.; iv) containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, such as dihydrooxathiopyranyl, etc.; or v) containing 1 to 2 oxygen atoms, such as furyl, pyranyl, oxepinyl, dioxolyl, etc.;

(3) Fused polycyclic saturated heterocyclic groups i) containing 1 to 5 nitrogen atoms, such as decahydroquinolinyl, decahydroisoquinolinyl, quinuclidinyl, octahydro-2H-pyrido[l ,2-α]pyrazinyl, octahydropyrrolo[l ,2-α]pyrazinyl, 1 ,3,8-triazaspiro[4,5]decanyl, l-azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl,

3-azabicyclo[3.2.2]nonanyl, 2,7-diazaspiro[4,4]nonanyl, etc.; ii) containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, such as trithiadiazaindenyl, dioxoloimidazolidinyl, 1 -oxa-8-azaspiro[4,5]decanyl, 1 ,4-dioxa-8-azaspiro[4,5]decanyl, l-oxa-4,9-diazaspiro[5,5]undecanyl, etc.; or iii) containing 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, such as 2,6-dioxabicyclo[3.2.2]oct-7-yl, etc.;

(4) Fused polycyclic unsaturated heterocyclic groups i) containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, dihydrobenzimidazolyl, tetrahydrobenzimidazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, tetrahydroisoquinolinyl, indazolyl, imidazopyridinyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, acridinyl, quinoxalinyl, dihydroquinozalinyl, tetrahydroquinoxalinyl, phthalazinyl, dihydroindazolyl, benzopyrimidinyl, naphthylidinyl, quinazolinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[ό]pyridinyl, 2,3 ,4,5-tetrahydro- 1 H-3 -benzazepinyl,

4,5,6,7-tetrahydro-17f-imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[l ,2-α]pyrazinyl, tetrahydronaphthyridinyl, etc.;

ii) containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, such as benzothiazolyl, dihydrobenzothiazolyl, benzothiadiazolyl, imidazothiazolyl, imidazothiadiazolyl, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, benzoxadiazolyl, benzisothiazolyl, benzisoxazolyl, 4,5,6,7-tetrahydro[l,3]thiazolo[5,4-c]pyridinyl, etc.; iii) containing 1 to 3 sulfur atoms, such as benzothiophenyl, benzodithiopyranyl, dibenzo[&,d]thiophenyl, etc.; iv) containing 1 to 3 sulfur atoms and 1 to 3 oxygen atoms, such as benzoxathiopyranyl, phenoxazinyl, etc.; or v) containing 1 to 3 oxygen atoms, such as benzodioxolyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, chromanyl, chromenyl, dibenzo[ό,J]furanyl, methylenedioxyphenyl, ethylenedioxyphenyl, etc.; and the like. An "acyl" includes the following acyl groups: (1) Aliphatic acyl groups, specifically -CHO, -CO-Io wer alkyl, -CO-lower alkenyl, -CO-lower alkylene-O-lower alkyl, -CO-cycloalkyl, -CO-cycloalkenyl, etc.;

(2) Acyl groups containing aryl(s), specifically -CO-aryl, -CO-lower alkylene-aryl, -CO-lower alkenylene-aryl, -CO-lower alkylene-0-aryl, etc.;

(3) Acyl groups containing heterocyclic group(s), specifically -CO-heterocyclic, -CO-lower alkylene-heterocyclic, -CO-lower alkenylene-heterocyclic, etc.; and the like.

A "protected carboxy" includes the following groups:

(1) Esterified carboxyl groups, specifically -CO-O-lower alkyl, -CO-O-lower alkenyl, -CO-0-lower alkynyl, -CO-O-lower alkylene-O-lower alkyl, -CO-O-lower alkylene-aryl, -CO-O-lower alkylene-O-aryl, CO-O-CH(aryl) 2 , etc.;

(2) Amidated carboxyl groups, specifically -CO-NH 2 , -CO-NH-lower alkyl, -CO-N(lower alkyl) 2 , -CO-N(lower alkyl)-aryl, -CO-N(lower alkyl)-(lower alkylene-aryl), -CO-NH-lower alkylene-OH, -CO-NH-lower alkylene-COOH, etc.; and the like. "One or more", in some embodiments, includes the number of 1, 2, 3, 4, and 5, in other embodiments, the number of 1, 2, and 3.

"Optionally substituted" means "unsubstituted" or "substituted." When there are multiple substituents, they may be the same or different.

Non-limiting examples of "suitable substituents" include lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, lower alkenylene, lower alkynylene, halogen, halogeno lower alkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic group, acyl, amino, oxa, oxo, sulfonyl, etc., and the combination of these substituents.

Other embodiments of the compound (I) are as follows: (AA) The compound of Formula (I), wherein

R 1 is -CHO, -CO-lower alkyl, cyano, -COOH or lower alkyl substituted with one or more

OH(s);

R 2 is -COOH or -COO-lower alkyl;

R 3 is

[wherein R 4 , R 6 and R 7 are each

I) H,

2) lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of

2-1) -OH 2-2) -0-lower alkyl

2-3) -SO 2 -lower alkyl 2-4) -COO-lower alkyl,

2-5) -OCO-amino optionally substituted with one or two lower alkyl(s) optionally substituted with a piperidyl, 2-6) -OCO-piperidyl optionally substituted with a piperidyl,

2-7) -OCO-piperazinyl optionally substituted with one or more lower alkyl(s) optionally substituted with a piperidyl,

2-8) amino optionally substituted with one or two substituent(s) selected from the group consisting of 2-8-1) lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of -CN, -COOH,

-CO-piperazinyl optionally substituted with one or more lower alkyl(s) optionally substituted with a piperidyl, -0-lower alkyl, -OH 5 -0-S0 2 -lower alkyl,

-OCO-amino optionally substituted with one or two lower alkyl(s) optionally substituted with a piperidyl,

-OCO-piperidyl optionally substituted with one or more lower alkyl(s) optionally substituted with a substituent selected from the group consisting of piperidyl and piperazinyl optionally substituted with a lower alkyl;

-OCO-piperazinyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of -OH, -0-lower alkylene-OH, amino optionally substituted with one or two lower alkyl(s), -SO 2 -phenyl, piperidyl optionally substituted with one or more lower alkyl(s), morpholinyl, phenyl, pyridyl and -CO-morpholinyl; phenyl optionally substituted with a morpholinyl optionally substituted with one or more lower alkyl(s), thiazolyl and pyrimidinyl; amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of cycloalkyl, piperidyl and pyridyl; cycloalkyl, 4,5-dihydroimidazolyl, pyridyl, and quinuclidinyl; cycloalkyl, phenyl optionally sustituted with one or more substituent(s) selected from the group consisting of amino optionally substituted with one or two lower alkyl(s), and lower alkylene-amino optionally substituted with one or two lower alkyl(s) optionally substituted with a pyridyl; heterocyclic group selected from the group consisting of piperidin-2-yl optionally substituted with one or more lower alkyl(s), pyrrolidin-2-yl optionally substituted with one or more lower alkyl(s), pyridyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected

from the group consisting of -OH, -0-lower alkyl, amino optionally substituted with one or two lower alkyl(s) optionally substituted with one or two substituent(s) selected from the group consisting of phenyl and pyridyl; piperidyl, and morpholinyl; halogen, -O-lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl and -CO-lower alkyl; -COOH, -COO-lower alkyl optionally substituted with a phenyl,

-CO-amino optionally substituted with a lower alkyl, phenyl, piperidyl, and pyridyl; imidazolyl optionally substituted with one or more lower alkyl(s), furyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiazolyl, benzimidazolyl optionally substituted with one or more lower alkyl(s), isoquinolyl, isoindolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-2H-pyrido[l ,2-α]pyrazinyl, octahydropyrrolo [ 1 ,2-α]pyrazinyl, l,3,8-triazaspiro[4,5]decanyl optionally substituted with one or more substituent(s) selected from the group consisting of phenyl and oxo; and

[wherein

Y is -CH 2 -, NH or O; R 12 and R 13 are each H, lower alkyl optionally substituted with a substituent selected from the group consisting of

-OH, -0-lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl, lower alkenyl, and phenyl optionally substituted with one or more halogeno lower alkyl(s);

-COO-lower alkyl, -CO-pyrrolidinyl, -CONH-pyridyl, -SO 2 -phenyl, phenyl, naphthyl, pyrrolidinyl optionally substituted with one or more lower alkyl(s), piperidyl optionally substituted with one or more lower alkyl(s) optionally substituted with a -OH, morpholinyl, tetrahydrofuranyl, and pyridyl; lower alkenyl, halogeno lower alkyl, -OH, -0-lower alkyl, halogen, -COOH, -COO-lower alkyl, -CO-amino optionally substituted with one or two lower alkyl(s), -SO 2 -lower alkyl, cycloalkyl optionally substituted with one or more lower alkyl(s), phenyl optionally substituted with one or more -OH(s), piperidyl optionally substituted with one or more alkyl(s), pyridyl, pyrimidinyl,

1,2-benzisoxazolyl optionally substituted with one or more halogen(s), or

1,3-dihydrobenzimidazolyl optionally substituted with an oxo; and m is an integer of O to 3

]

2-8-2) halogeno lower alkyl,

2-8-3) lower alkenyl optionally substituted with a lower alkynyl, 2-8-4) cycloalkyl, 2-8-5) piperidyl optionally substituted with one or more lower alkyl(s),

2-8-6) quinuclidinyl, 2-8-7) 5 ,6,7,8-tetrahydroquinolinyl, 2-8-8) 6,7-dihydro-5H-cyclopenta[ό]pyridinyl, and 2-8-9) pyrrolidinyl optionally substituted with a pyridyl optionally substituted with one or more lower alkyl(s); and 2-9) heterocyclic group selected from the group consisting of imidazolyl optionally substituted with a lower alkyl, 1,2,3,6-tetrahydropyridinyl optionally substituted with one or more substituent(s) selected from the group consisting of cyano, phenyl optionally substituted with an amino optionally substituted with one or two lower alkyl(s), imidazolyl optionally substituted with a lower alkyl, thiazolyl, thienyl, and pyridyl; l-azabicyclo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolinyl optionally substituted with one or more

-O-lower alkyl(s),

2,3,4,5-tetrahydro-lH-3-benzazepinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl,

5,6,7,8-tetrahydroimidazo[l,2-α]ρyrazinyl optionally substituted with one or more alkyl(s),

5,6,7,8-tetrahydro-l,6-naphthyridinyl, octahydropyrrolo[l ,2-α]pyrazinyl, octahydro-2H-pyrido[l s 2-α]pyrazinyl,

4,5,6,7-tetrahydro[l,3]thiazolo[5,4-c]pyridinyl optionally substituted with a lower alkyl, l,4-dioxa-8-azaspiro[4,5]decanyl optionally substituted with one or more substituent(s) selected from the group consisting of

-COOH, -COO-lower alkyl, and lower alkyl optionally substituted with a piperidyl; l-oxa-8-azaspiro[4,5]decanyl optionally substituted with one or more lower alkyl(s) optionally substituted with a morpholinyl; l-oxa-4,9-diazaspiro[5,5]undecanyl optionally substituted with one or more lower alkyl(s), and

2,7-diazaspiro[4,4]nonanyl optionally substituted with one or more lower alkyl(s); or

[wherein

R 14 Is H, lower alkyl optionally substituted with a substituent selected from the group consisting of -OH, -0-lower alkyl, -O-SO 2 -lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of piperidyl, pyridyl and -0-lower alkyl;

-OCO-piperazinyl optionally substituted with a lower alkyl, phenyl, heterocyclic group selected from the group consisting of pyridyl, pyrrolidinyl, piperidyl, piperazinyl, diazepanyl and morpholinyl, each of which is optionally substituted with one or more lower alkyl(s) optionally substituted with a piperidyl;

halogen, methylidene, halogeno lower alkyl, lower alkenyl, -OH, oxo, -0-lower alkyl optionally substituted with a substituent selected from the group consisting of -0-lower alkyl and phenyl; -OCO-piperazinyl optionally substituted with a lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of -0-lower alkyl and pyridyl; -COO-lower alkenyl, and

-SO 2 -lower alkyl;

-COOH, -CO-lower alkyl, -COO-lower alkyl, -CO-amino optionally substituted with one or two lower alkyl(s), -CO-piperidyl, -CO-morpholinyl, -CO-piperazinyl optionally substituted with a lower alkyl, cycloalkyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl and cycloalkyl; phenyl optionally substituted with one or more substituent(s) selected from the group consisting of halogen and morpholinyl optionally substituted with one or more lower alkyl(s); heterocyclic group selected from the group consisting of pyrrolidinyl, piperidyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl, azepanyl, imidazolyl, pyridyl, pyrimidinyl, benzimidazolyl and l,4-dioxa-8-azaspiro[4,5]decanyl, each of which is optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl optionally substituted with a piperidyl, -O-lower alkyl, halogen, phenyl and piperidyl; and

-S-tetrazolyl optionally substituted with a lower alkyl; R 15 is H, lower alkyl, -OH, -O-lower alkyl or halogen; R 16 , R 17 , R 18 and R 19 are each lower alkyl; R 20 is amino optionally subsituted with one or two lower alkyl(s); A is lower alkylene;

B is CH 2 , NH or O; p is an integer of O to 3;

and q is an integer of 0 to 3, provided that p + q is an integer of 0 to 3;

] and

R 5 is H 3 lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of -CHO, -COOH, -COO-lower alkyl,

-CO-amino optionally substituted with one or two lower alkyl(s), -CO-piperidyl,

-OH, -0-lower alkyl, -O-phenyl, cycloalkyl, phenyl, piperidyl and morpholinyl; lower alkenyl optionally substituted with a substituent selected from the group consisting of -COOH and -COO-lower alkyl, halogeno lower alkyl,

-0-lower alkyl optionally substituted with one or more substiruent(s) selected from the group consisting of cycloalkyl, phenyl, and

-CO-amino optionally substituted with one or two lower alkyl(s); -0-lower alkenyl, or cycloalkyl;

] and

R 8 , R 9 and R 11 are each lower alkyl harmaceutically acceptable salt thereof.

(BB) The compound of Formula (I), wherein R 1 is -CHO;

R 2 is -COOH;

R 3 is

[wherein

R 4 is defined as above (AA);

R 5 is lower alkyl optionally substituted with a cycloalkyl, halogeno lower alkyl, or cycloalkyl;

X is CH 2 ; n is 0

] and

R 8 , R 9 and R 11 are each lower alkyl or a pharmaceutically acceptable salt thereof.

(CC) The compound of Formula (I), wherein R 1 is -CHO; R 2 is -COOH;

R 3 is

[wherein

R 4 Is

[wherein

R 14 Js H, lower alkyl optionally substituted with a substituent selected from the group consisting of

-OH 5 -0-lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of piperidyl, pyridyl and -O-lower alkyl; -OCO-piperazinyl optionally substituted with a lower alkyl, phenyl, heterocyclic group selected from the group consisting of pyridyl, pyrrolidinyl, piperidyl, piperazinyl, diazepanyl and morpholinyl, each of which is optionally substituted with one or two lower alkyl(s) optionally substituted with a piperidyl; halogen, methylidene, halogeno lower alkyl, lower alkenyl, -OH, oxo, -O-lower alkyl optionally substituted with a substituent selected from the group consisting of -O-lower alkyl and phenyl; -OCO-piperazinyl optionally substituted with a lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of -O-lower alkyl and pyridyl; -COO-lower alkenyl, and

-Sθ 2 -lower alkyl; -COOH, -CO-lower alkyl, -COO-lower alkyl,

-CO-amino optionally substituted with one or two lower alkyl(s), -CO-piperidyl, -CO-morpholinyl, -CO-piperazinyl optionally substituted with a lower alkyl, cycloalkyl optionally substituted with a substituent selected from the group consisting of lower alkyl and cycloalkyl; phenyl optionally substituted with a substituent selected from the group consisting of halogen and morpholinyl optionally substituted with one or two lower alkyl(s); heterocyclic group selected from the group consisting of pyrrolidinyl, piperidyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl, azepanyl, imidazolyl, pyridyl, pyrimidinyl, benzimidazolyl and l,4-dioxa-8-azaspiro[4,5]decanyl, each of which is optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a piperidyl, -0-lower alkyl, halogen, phenyl and piperidyl; and

-S-tetrazolyl optionally substituted with a lower alkyl; and

A iS CH 2

]

R 5 is lower alkyl optionally substituted with a cycloalkyl, halogeno lower alkyl, or cycloalkyl;

X is CH 2 ; and n is 0

] and

R 8 , R 9 and R 11 are each lower alkyl or a pharmaceutically acceptable salt thereof.

(DD) The compound of Formula (I), wherein

R 1 is -CHO;

[wherein R 6 is H, lower alkyl optionally substituted with a substituent selected from the group consisting of

-O-lower alkyl, amino optionally substituted with one or two lower alkyl(s), and piperidyl

] and

R 8 , R 9 and R 11 are each lower alkyl, or a pharmaceutically acceptable salt thereof.

(EE) The compound of Formula (I), wherein R 1 is -CHO;

[wherein R 7 is lower alkyl optionally substituted with a substituent selected from the group consisting of amino optionally substituted with one or two lower alkyl(s),

tetrahydroisoquinolinyl, piperidyl optionally substituted with a piperidyl, and morpholinyl ] and

R 8 , R 9 and R 11 are each lower alkyl or a pharmaceutically acceptable salt thereof.

When the substituent on R 4 , R 6 , R 7 , R 14 or R 15 is oxo or methylidene, a double bond can be formed on the bond illustrated as a single one.

The compounds of the present invention may have tautomers and geometric isomers, depending upon the type of substituents. In the present Description, the present invention . encompasses these isomers and also includes isolated isomers or a mixture thereof.

In some cases, compounds of Formula (I) may have asymmetric carbon atom(s) or axial asymmetry, and thus optical isomers such as (R)- and (5)-isomers may be present. The present invention includes all mixtures of those isomers, as well as each isolated isomer.

The present invention further includes pharmaceutically acceptable prodrugs of compounds of Formula (I). Pharmacologically acceptable prodrugs are compounds having a group that can be converted to an amino group, OH, CHO, COOH, etc. of the present invention by solvo lysis or under a physiological condition. Examples of a group that forms a prodrug are the groups mentioned, for example, in Proc. Med. 5, 2157-2161 (1985) and

" Development of Drugs", Vol. 7, Molecular Design, pages 163 to 198 (Hirokawa Shoten, 1990).

The compound of the present invention may form an acid addition salt or may also form a salt with a base, depending on the type of substituent. These salts are also included in the present invention as long as they are pharmaceutically acceptable ones. Specific examples thereof are acid addition salts such as a salt with an inorganic acid, e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, and a salt with an organic acid, e.g. formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamic acid; a salt with an inorganic base, e.g. sodium, potassium, magnesium, calcium or aluminum, and an organic base, e.g. methylamine, ethylamine, ethanolamine, lysine or ornithine; and ammonium salt.

Further, the present invention also includes hydrates, solvates, and crystalline polymorphs of a compound of the present invention, as well as pharmaceutically acceptable salts thereof. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

The compound of the present invention, and the pharmaceutically acceptable salt thereof, can be produced by applying various known synthetic methods, utilizing characteristics based on its basic skeleton or its type of substituents. Depending on the type of functional group, there are cases in which it is effective as a production technique to substitute the functional group with an appropriate protective group (a group that can be easily converted to said functional group) during the raw material-to-intermediate stage. Examples of such functional groups are amino group, OH, CHO, and COOH. These groups can be protected, for example, by the protective groups cited in "Protective Groups in Organic Synthesis (Third Edition, 1999)" by Greene and Wuts, which can be appropriately selected and used according to the reaction conditions. In this method, the protective group is removed if necessary after it has been introduced and the reaction carried out, in order to produce the desired compound.

Further, a prodrug of compound (I) may be manufactured by, as with the aforementioned protective group, introducing a specific group in the raw material-to-intermediate stage, or by causing a reaction using the resulting compound (I). Usually, the reaction may be carried out by applying methods known to persons skilled in the art, such as common esterification, amidation, or dehydration.

Hereunder, representative production processes of the compounds of present invention will be illustrated. Each production process may also be carried out by referring to the references mentioned in the explanation. The process for the production according to the present invention is not limited to the following Examples.

Manufacturing Method 1

[wherein

R 1 is -CHO, -CO-lower alkyl, cyano, -COOH or lower alkyl substituted with one or more OH(s);

R 2 is -COOH or -COO-lower alkyl;

R 5 is

H, lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of

-CHO, -COOH, -COO-lower alkyl,

-CO-amino optionally substituted with one or two lower alkyl(s),

-CO-piperidyl,

-OH, -0-lower alkyl, -O-phenyl, cycloalkyl, phenyl, piperidyl and morpholinyl; lower alkenyl optionally substituted with a substituent selected from the group consisting of -COOH and -COO-lower alkyl, halogeno lower alkyl,

-0-lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of cycloalkyl, phenyl, and

-CO-amino optionally substituted with one or two lower alkyl(s); -0-lower alkenyl, or cycloalkyl;

R 8 , R 9 and R 11 are each lower alkyl; X is CHR 10 or O, wherein

R 10 is H, lower alkyl, -COOH or -COO-lower alkyl;

L is a leaving group (e.g. halogen, methanesulfonyloxy, p-toluenesulfonyloxy); and n is an integer of O or 1 ; r is an integer of 1 to 8; R 101 R 102 NH is as follows: 1) R 101 and R 102 are each 1-I) H,

1-2) lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of

-CN, -COOH,

-CO-piperazinyl optionally substituted with one or more lower alkyl(s) optionally substituted with a piperidyl, -0-lower alkyl, -OH, -OCO-amino optionally substituted with one or two lower alkyl(s) optionally substituted with a piperidyl,

-OCO-piperidyl optionally substituted with one or more lower alkyl(s) optionally substituted with a substituent selected from the group consisting of piperidyl and piperazinyl optionally substituted with a lower alkyl;

-OCO-piperazinyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of

-OH, -0-lower alkylene-OH, amino optionally substituted with one or two lower alkyl(s), -SO 2 -phenyl, piperidyl optionally substituted with one or more lower alkyl(s), morpholinyl, phenyl, pyridyl and -CO-morpholinyl; phenyl optionally substituted with a morpholinyl optionally substituted with one or more lower alkyl(s), thiazolyl and pyrimidinyl; amino optionally .substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of cycloalkyl, piperidyl and pyridyl; cycloalkyl, 4,5-dihydroimidazolyl, pyridyl,

and quinuclidinyl; cycloalkyl, phenyl optionally sustituted with one or more substituent(s) selected from the group consisting of amino optionally substituted with one or two lower alkyl(s), and lower alkylene-amino optionally substituted with one or two lower alkyl(s) optionally substituted with a pyridyl; heterocyclic group selected from the group consisting of piperidin-2-yl optionally substituted with one or more lower alkyl(s), pyrrolidin-2-yl optionally substituted with one or more lower alkyl(s), pyridyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of -OH 5 -0-lower alkyl, amino optionally substituted with one/ or two lower alkyl(s) optionally substituted with one or two substituent(s) selected from the group consisting of phenyl and pyridyl; piperidyl, and morpholinyl; halogen, -0-lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl and -CO-lower alkyl; -COOH,

-COO-lower alkyl optionally substituted with a phenyl, -CO-amino optionally substituted with a lower alkyl, phenyl, piperidyl, and pyridyl; imidazolyl optionally substituted with one or more lower alkyl(s),

furyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiazolyl, benzimidazolyl optionally substituted with one or more lower alkyl(s), isoquinolyl, isoindolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-2H-pyrido[l,2-<2]ρyrazinyl, octahydropyrrolo[l ,2-α]pyrazinyl, l,3,8-triazaspiro[4,5]decanyl optionally substituted with one or more substituent(s) selected from the group consisting of phenyl and oxo; and

[wherein

Y is -CH 2 -, NH or O; R 12 and R 13 are each H, lower alkyl optionally substituted with a substituent selected from the group consisting of -OH, -O-lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl, lower alkenyl, and phenyl optionally substituted with l one or more halogeno lower alkyl(s);

-COO-lower alkyl, -CO-pyrrolidinyl, -CONH-pyridyl, -SCVphenyl, phenyl, naphthyl, pyrrolidinyl optionally substituted with one or more lower alkyl(s), piperidyl optionally substituted with one or more lower alkyl(s) optionally substituted with a -OH, morpholinyl, tetrahydrofuranyl, and pyridyl; lower alkenyl, halogeno lower alkyl, -OH, -O-lower alkyl,

halogen, -COOH, -COO-lower alkyl,

-CO-amino optionally substituted with one or two lower alkyl(s),

-S0 2 -lower alkyl, cycloalkyl optionally substituted with one or more lower alkyl(s), phenyl optionally substituted with one or more -OH(s), piperidyl optionally substituted with one or more alkyl(s), pyridyl, pyrimidinyl, 1,2-benzisoxazolyl optionally substituted with one or more halogen(s), or

1,3-dihydrobenzimidazolyl optionally substituted with an oxo; and m is an integer of 0 to 3

]

1-3) halogeno lower alkyl,

1-4) lower alkenyl optionally substituted with a lower alkynyl, 1-5) cycloalkyl,

1-6) piperidyl optionally substituted with one or more lower alkyl(s), 1-7) quinuclidinyl, 1 -8) 5,6,7,8-tetrahydroquinolinyl, 1 -9) 6,7-dihydro-5iZ-cyclopenta[δ]pyridinyl, and

1-10) pyrrolidinyl optionally substituted with a pyridyl optionally substituted with one or more lower alkyl(s); or

2) R 101 , R 102 , and NH are taken together to form a heterocyclic group selected from the group consisting of imidazolyl optionally substituted with a lower alkyl, 1,2,3,6-tetrahydropyridinyl optionally substituted with one or more substituent(s) selected from the group consisting of cyano, phenyl optionally substituted with an amino optionally substituted with one or two lower alkyl(s), imidazolyl optionally substituted with a lower alkyl,

thiazolyl, thienyl, and pyridyl;

1 -azabicyclo [2.2.1 ]heptyl, 1,2,3,4-tetrahydroisoquinolinyl optionally substituted with one or more

-O-lower alkyl(s),

2,3 ,4,5 -tetrahydro- 1 H-3 -benzazepinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl,

5,6,7,8-tetrahydroimidazo[l,2-α]pyrazinyl optionally substituted with one or more alkyl(s),

5,6,7,8-tetrahydro-l,6-naphthyridinyl, octahydropyrrolo[l ,2-α]pyrazinyl, octahydro-2H-pyrido [ 1 ,2-α]pyrazinyl,

4,5,6,7-tetrahydro[l 5 3]thiazolo[5,4-c]pyridinyl optionally substituted with a lower alkyl, l,4-dioxa-8-azaspiro[4,5]decanyl optionally substituted with one or more substituent(s) selected from the group consisting of

-COOH, -COO-lower alkyl, and lower alkyl optionally substituted with a piperidyl; l-oxa-8-azaspiro[4,5]decanyl optionally substituted with one or more lower alkyl(s) optionally substituted with a morpholinyl; l-oxa-4,9-diazaspiro[5,5]undecanyl optionally substituted with one or more lower alkyl(s), and 2,7-diazaspiro[4,4]nonanyl optionally substituted with one or more lower alkyl(s); or 3) R 101 R 102 N- is

[wherein R 14 Is H, lower alkyl optionally substituted with a substituent selected from the group consisting of

-OH, -0-lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of piperidyl, pyridyl and -O-lower alkyl; -OCO-piperazinyl optionally substituted with a lower alkyl, phenyl, heterocyclic group selected from the group consisting of pyridyl, pyrrolidinyl, piperidyl, piperazinyl, diazepanyl and morpholinyl, each of which is optionally substituted with one or more lower alkyl(s) optionally substituted with a piperidyl; halogen, methylidene, halogeno lower alkyl, lower alkenyl, -OH, oxo, -O-lower alkyl optionally substituted with a substituent selected from the group consisting of -O-lower alkyl and phenyl; -OCO-piperazinyl optionally substituted with a lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of -O-lower alkyl and pyridyl; -COO-lower alkenyl, and

-Sθ 2 -lower alkyl; -COOH, -CO-lower alkyl, -COO-lower alkyl,

-CO-amino optionally substituted with one or two lower alkyl(s), -CO-piperidyl, -CO-morpholinyl, -CO-piperazinyl optionally substituted with a lower alkyl, cycloalkyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl and cycloalkyl; phenyl optionally substituted with one or more substituent(s) selected from the group consisting of

halogen and morpholinyl optionally substituted with one or more lower alkyl(s); heterocyclic group selected from the group consisting of pyrrolidinyl, .piperidyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl, azepanyl, imidazolyl, pyridyl, pyrimidinyl, benzimidazolyl and l,4-dioxa-8-azaspiro[4,5]decanyl, each of which is optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl optionally substituted with a piperidyl, -0-lower alkyl, halogen, phenyl and piperidyl; and

-S-tetrazolyl optionally substituted with a lower alkyl; R 15 is H, lower alkyl, -OH, -O-lower alkyl or halogen; R 16 , R 17 , R 18 and R 19 are each lower alkyl; R is amino optionally subsituted with one or two lower alkyl(s);

B is CH 2 , NH or O; and p is an integer of 0 to 3, q is an integer of 0 to 3, provided that p + q is an integer of 0 to 3] .]

Compound (Ia) of the present invention can be obtained by the reaction of compound (1) with amine (2).

For the reaction, compound (1) and (2) are used in an equimolar amount or in an excessive amount for either of the compounds, and the mixture is stirred in a solvent inert under the reaction conditions, or without solvent, from cooling to reflux conditions, preferably 0°C to 80°C, and generally for 0.1 hours to 5 days. Non-limiting examples of the solvent used here include alcohols such as methanol, ethanol, and 2-propanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof. For the smooth progress of the reaction, it is sometimes advantageous to perform the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, and N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate, and potassium hydroxide.

The each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ia).

Manufacturing Method 2

[wherein R 1 , R 2 , R 8 , R 9 , R 11 , L, r, R 101 , and R 102 are defined as Method L]

Compound (Ib) of the present invention can be obtained by the reaction of compound (3) with amine (2) in a reaction condition similar to Method 1.

The each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ib).

Manufacturing Method 3

[wherein R . 1 1 , τ R>2 z , R r>5\ R\ R y , R 11 , X, and n are defined as Method L]

Compound (Ic) of the present invention can be obtained by a cyclization of compound (4).

For the reaction, compound (4) is stirred in a solvent inert under the reaction conditions, from cooling to reflux conditions, preferably room temperature, and generally for 0.1 hours to 5 days. Non-limiting examples of the solvent used here include alcohols such as methanol, ethanol, and 2-propanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxy ethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof.

The reaction may be performed in the presence of an organic or inorganic acid (e.g. trifluoroacetic acid).

The each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ic).

Manufacturing Method 4

[wherein

R 1 , R 2 , R 8 , R 9 , R 11 , X, and n are defined as Method 1;

R 103 is lower alkyl;

L is a leaving group (e.g. halogen, methanesulfonyloxy, p-toluenesulfonyloxy).]

Compound (Id) of the present invention can be obtained by a cyclization of compound (5) followed by alkylation.

For the first reaction step, compound (5) is stirred in the presence of an equimolar or an excessive amount of base in a solvent inert under the reaction conditions from cooling to reflux conditions, preferably 0°C to 8O 0 C, and generally for 0.1 hours to 5 days. Non-limiting examples of the solvent used here include alcohols such as methanol, ethanol, and 2-propanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1 ,2-dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, water, and mixtures thereof. Examples of the base include organic bases such as triethylamine, N,N-diisopropylethylamine,

1.8-diazabicyclo[5.4.0]-7-undecene, and n-butyllithium; and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, and potassium tert-butoxide. It is sometimes advantageous to perform this reaction in the presence of a phase transfer catalyst such as tetra-n-butylammonium chloride.

For the second reaction step, the intermediate (6) and compound (7) are used in an equimolar amount or in an excessive amount for either of the compounds, and the mixture is stirred in a reaction condition similar to the first step.

The each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Id).

Manufacturing Method 5

[wherein

R 1 , R 2 , R 8 , R 9 , and R 11 are defined as Method 1;

L is a leaving group (e.g. halogen, methanesulfonyloxy, p-toluenesulfonyloxy).]

Compound (Ie) of the present invention can be obtained from compound (8) in a reaction condition similar to Method 4.

The each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ie).

[wherein

R 1 , R 2 , R 5 , R 8 , R 9 , R 11 , X, and n are defined as Method 1; R 104 Is lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of -OH,

-O-lower alkyl optionally substituted with a phenyl, and amino optionally substituted with one or two lower alkyl(s); or -COO-lower alkyl.]

Compound (If) of the present invention can be obtained by the hydrogenation of compound (9).

For the reaction, compound (9) is stirred in the presence of a metal catalyst under a hydrogen atmosphere in a solvent inert under the reaction conditions, and generally for 1 hour to 5 days. This reaction is conducted generally from cooling to heating conditions, preferably room temperature. Non-limiting examples of the solvent used here include alcohols such as methanol, ethanol, and 2-propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, acetic acid, water, ethyl acetate, N,N-dimethylformamide, ,and mixtures thereof. As the metal catalyst, there may be suitably used palladium catalysts such as palladium-carbon, palladium black, palladium hydroxide; platinum catalysts such as platinum plate and platinum oxide; nickel catalysts such as reduced nickel and Raney nickel; rhodium catalysts such as chlorotris(triphenylphosphine)rhodium(I); iron catalysts such as reduced iron; and the like. In place of a hydrogen gas, formic acid or ammonium formate in an amount equimolar or excessive to compound (9) may be used as a

hydrogen source.

The each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (If).

Manufacturing Method 7

[wherein

R 1 , R 2 , R 5 , R 8 , R 9 , R 11 , X, n, and r are defined as Method 1; L 1 is halogen.]

Compound (Ig) of the present invention can be obtained from compound (1) in a reaction condition similar to Method 6.

The each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ig).

Manufacturing Method 8

~%2 τ» 8 Ti .9 r.11 r> 101 π 102 v „ J 1 1

Compound (Ij) of the present invention can be obtained by the reduction of

compound (Ih).

For the reaction, compound (Ih) is treated with an equimolar or excessive amount of a reducing agent in a solvent inert under the reaction conditions, from cooling to heating conditions, preferably -2O 0 C to 8O 0 C, and generally for 0.1- hours to 3 days. Non-limiting examples of the solvent used here include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1 ,2-dimethoxyethane, alcohols such as methanol, ethanol, and 2-propanol, aromatic hydrocarbons such as benzene, toluene, and xylene, N,N-dimethylformarnide, dimethyl sulfoxide, ethyl acetate, and mixtures thereof. As the reducing agent, there may be suitably used hydride reducing agents such as sodium borohydride and diisobutylaluminum hydride; metal reducing agents such as sodium, zinc, and iron.

The each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ij).

[wherein R 2 , R 5 , R 8 , R 9 , R 11 , R 101 , R 102 , X, n, and r are defined as Method 1.]

Compound (Ik) of the present invention can be obtained by the oxidation of compound (Ih) .

For the reaction, compound (Ih) is treated with an equimolar or excessive amount of an oxidizing agent in a solvent inert under the reaction conditions, from cooling to heating conditions, preferably -20 0 C to 8O 0 C, and generally for 0.1 hours to 3 days. Non-limiting examples of the solvent used here include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, water, and mixtures thereof. As the oxidizing agent, there are suitably used, for example, hydrogen peroxide, cumene hydroperoxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, oxone,

activated manganese dioxide, chromic acid, potassium permanganate, sodium periodide, sodium chlorite, and Dess-Martin reagent.

The each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ik).

Manufacturing Method 10

[wherein

R 2j is COOH;

R 5 , R 8 , R 9 , R 11 , R 101 , R 102 , X, n, and r are defined as Method 1; R 105 is lower alkyl;

M is a metal which is used in organometallic reaction (e.g. lithium, magnesium, zinc).]

Compound (Im) of the present invention can be obtained by the reaction of compound (Ih) and (10).

For the reaction, compound (Ih) is treated with an equimolar or excessive amount of compound (10) in a solvent inert under the reaction conditions, from cooling to heating conditions, preferably -20°C to 80°C, and generally for 0.1 hours to 3 days. Non-limiting examples of the solvent used here include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, and mixtures thereof. The compound (10) may be previously prepared or generated in situ.

The each protective group of R may be removed during the reaction, or those on the product can be deprotected to produce the compound (Im).

Manufacturing Method 11

[wherein

R 2k is COOH;

R 5 , R 8 , R 9 , R 11 , R 101 , R 102 , X, n, and r are defined as Method 1;

R 105 is defined as Method 10.]

Compound (In) of the present invention can be obtained from compound (Im) in a reaction condition similar to Method 9.

The each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (In).

Manufacturing Method 12

[wherein

R 1 , R 2 ,R 5 , R 8 , R 9 , R 11 , X, and n are defined as Method 1; R 106 is lower alkyl; s is an integer of 1 to 8; L 2 is a leaving group (e.g. methanesulfonyloxy, p-toluenesulfonyloxy);

R i07 R i08 NH is as follows .

I) R 107 and R 108 are each H, lower alkyl optionally substituted with a substituent selected from the group consisting of cycloalkyl, piperidyl and pyridyl; cycloalkyl, 4,5-dihydroimidazolyl, pyridyl, and quinuclidinyl; or

2) R 107 , R 108 , and NH are taken together to form a heterocyclic group selected from the group consisting of piperidin-2-yl optionally substituted with one or more lower alkyl(s), pyrrolidin-2-yl optionally substituted with one or more lower alkyl(s), pyridyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of

-OH, -0-lower alkyl, amino optionally substituted with one or two lower alkyl(s) optionally substituted with one or two substituent(s) selected from the group consisting of phenyl and pyridyl; piperidyl, and morpholinyl; halogen, -0-lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl and -CO-lower alkyl; -COOH,

-COO-lower alkyl optionally substituted with a phenyl, -CO-amino optionally substituted with a lower alkyl, phenyl, piperidyl, and pyridyl;

imidazolyl optionally substituted with one or more lower alkyl(s), furyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiazolyl, benzimidazolyl optionally substituted with one or more lower alkyl(s), isoquinolyl, isoindolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-2H-pyrido[l,2-α]pyrazinyl, octahydropyrrolo[l ,2-α]pyrazinyl, l,3,8-triazaspiro[4,5]decanyl optionally substituted with one or more substituent(s) selected from the group consisting of phenyl and oxo; and

[wherein

Y is -CH 2 -, NH or O; R 12 and R 13 are each H, lower alkyl optionally substituted with a substituent selected from the group consisting of

-OH, -O-lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl, lower alkenyl, and phenyl optionally substituted with one or more halogeno lower alkyl(s);

-COO-lower alkyl, -CO-pyrrolidinyl, -CONH-pyridyl, -SO 2 -phenyl, phenyl, naphthyl, pyrrolidinyl optionally substituted with one or more lower alkyl(s), piperidyl optionally substituted with one or more lower alkyl(s) optionally substituted with a -OH, morpholinyl, tetrahydrofuranyl, and pyridyl; lower alkenyl, halogeno lower alkyl, -OH, -O-lower alkyl, halogen,

-COOH, -COO-lower alkyl, -CO-amino optionally substituted with one or two lower alkyl(s),

-Sθ 2 -lower alkyl, cycloalkyl optionally substituted with one or more lower alkyl(s), phenyl optionally substituted with one or more -OH(s), piperidyl optionally substituted with one or more alkyl(s), pyridyl, pyrimidinyl,

1,2-benzisoxazolyl optionally substituted with one or more halogen(s), or

1,3-dihydrobenzimidazolyl optionally substituted with an oxo; and m is an integer of 0 to 3].]

Compound (Ir) of the present invention can be obtained by the conversion of hydroxy group in compound (Ip) into a leaving group, followed by a reaction with amine (11).

For the first reaction step, compound (Ip) is treated with an equimolar or excessive amount of a sulfonylating reagent under the reaction conditions similar to Method 1. Examples of the sulfonylating reagent include methanesulfonyl chloride and p-toluenesulfonyl chloride.

For the second reaction step, compound (Ir) of the present invention can be obtained by a reaction of compound (Iq) and amine (11) in a reaction condition similar to Method 1. The each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ir).

[wherein

R 1 , R 2 ,R 5 , R 8 , R 9 , R 11 , X, n, and r are defined as Method 1 ; R 109 R 110 NH is as follows:

1) R 109 and R 110 are each H or lower alkyl optionally substituted with a piperidyl; or

2) R 109 , R 110 , and NH are taken together to form a heterocyclic group selected from the group consisting of piperidyl optionally substituted with a piperidyl, and piperazinyl optionally substituted with one or more lower alkyl(s) optionally substituted with a piperidyl; L 3 is a leaving group comprising halogen, imidazolyl, phenoxy, or 4-nitrophenoxy.]

Compound (Iu) of the present invention can be obtained by conversion of compound

(Is) into carbonate (It), followed by a reaction with amine (12).

The first step is performed by reacting compound (Is) with an equimolar or excessive amount of a carbonylating reagent, in a solvent inert under the reaction conditions, in the presence of a base from cooling to heating conditions, preferably -20°C to 80°C, and generally for 0.1 hours to approximately 1 day.

In the second step, an equimolar or excessive amount of amine (12) for compound (It) is added to the reaction mixture of first step, and the mixture is allowed to be reacted under cooling to heating conditions, preferably -20°C to 80 0 C, and generally for 0.1 hours to approximately 1 day. Non-limiting examples of the solvent used here include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof. Examples of the carbonylating reagent , include diphosgene, triphosgene, l,l'-carbonyldiimidazole, 4-nitrophenyl chloroformate, and phenyl chloroformate. The compound (It) may be isolated for the subsequent reaction after the first step.

The each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Iu).

Manufacturing Method 14

[wherein

R 1 , R 2 ,R 5 , R 8 , R 9 , R 11 , X, and n are defined as Method 1 ; R 106 and s are defined as Method 12; L 3 is defined as Method 13; R 111 R 112 NH is as follows:

1) R 111 and R 112 are each H or lower alkyl optionally substituted with a piperidyl; or

2) R 111 , R 112 , and NH are taken together to form a heterocyclic group selected from the group consisting of piperidyl optionally substituted with one or more lower alkyl(s) optionally substituted with a substituent selected from the group consisting of piperidyl and piperazinyl optionally substituted with a lower alkyl; piperazinyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of

-OH, -0-lower alkylene-OH, amino optionally substituted with one or two lower alkyl(s), -SO 2 -phenyl 5 piperidyl optionally substituted with one or more lower alkyl(s), morpholinyl, phenyl,

pyridyl and -CO-morpholinyl; phenyl optionally substituted with a morpholinyl optionally substituted with one or more lower alkyl(s), thiazolyl and pyrimidinyl.]

Compound (Iv) of the present invention can be obtained from compound (Ip) in a reaction condition similar to Method 13.

The each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Iv).

Manufacturing Method 15

[wherein

R 1 , R 2 , R 8 , R 9 , and R 11 are defined as Method 1; R 6a is H or lower alkyl.]

Compound (Iw) of the present invention can be obtained by a cyclization of compound (15).

For the reaction, compound (15) is treated with an equimolar or excessive amount of an acid or a dehydrating agent in a solvent inert under the reaction conditions, from cooling to heating conditions, preferably 0°C to 80°C, and generally for 0.1 hours to 3 days. Non-limiting examples of the solvent used here include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, acetic acid, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, and mixtures thereof. There may be suitably used acids such as sulfuric acid, phosphoric acid, p-toluenesulfonic acid. As the dehydrating agent, there may be suitably used phosphorus pentoxide, phosphorus pentasulfide.

The each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Iw).

Manufacturing Method 16

[wherein

R 1 , R 2 , R 8 , R 9 , and R 11 are defined as Method 1;

R 6b is an aminomethyl group optionally substituted with one or two lower alkyl(s),

CHO.]

Compound (Iy) of the present invention can be obtained by electrophilic substitution reaction of compound (Ix).

Examples of the electrophilic substitution reaction include the Friedel-Crafts reaction, the Vilsmeier reaction, and aminomethylation described in References below.

[References]

G. A. Olah Ed., "Friedel-Crafts and Related Reactions ," Vol. 3, John Wiley & Sons Inc, 1964.

"The Fifth Series of Experimental Chemistry," Vol.15 Synthesis of Organic Compounds III, edited by the Chemical Society of Japan, Maruzen, 2003.

L. Kurti and B. Czako, "Strategic Applications of Named Reactions in Organic Synthesis,"

Elsevier Inc, 2005, 468-469.

Hereunder, representative production processes of intermediate compounds of present invention will be illustrated.

R lq is cyano, or protected aldehyde; R 5 is H, lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of

-COO-lower alkyl,

-CO-amino optionally substituted with one or two lower alkyl(s), -CO-piperidyl, -O-lower alkyl, -O-phenyl, cycloalkyl, phenyl, piperidyl and morpholinyl; lower alkenyl optionally substituted with a -COO-lower alkyl, halogeno lower alkyl,

-O-lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of cycloalkyl, phenyl, and

-CO-amino optionally substituted with one or two lower alkyl(s); -O-lower alkenyl, or cycloalkyl;

R 8 , R 9 and R 11 are each lower alkyl; X is CHR 10 , wherein R 10 is H or lower alkyl; R 113 is lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of cycloalkyl, phenyl, and -CO-amino optionally substituted with one or two lower alkyl(s); or

-O-lower alkenyl; and n is an integer of 0 or 1 ; PG 1 and PG 2 are each carboxylic acid protective group (e.g. lower alkyl, benzyl, diphenylmethyl) ; PG 3 is hydroxy protective group (e.g. trimethlsilyl, tert-butyldimethylsilyl);

L is a leaving group (e.g. halogen, methanesulfonyloxy, p-toluenesulfonyloxy);

L 1 and Z are each halogen;

M is a metal which is used in organometallic reaction (e.g. lithium, magnesium, zinc).]

Reaction Scheme 1 shows the synthesis of intermediate compounds (Ia), (Ib), (Ic), (4), (5), and (8). Treatment of known compound (16) with compound (17) can give compound (18) (Method A), which can be subjected to halocyclization to afford compound (Ia) (Method B). Epoxidation of compound (18) can give compound (4) (Method C). Compound (Ib) can be prepared in a similar manner to by treatment of compound (16) with compound (19) followed by halocyclization (Method D, B). Exocyclic ether bond can be introduced selectively before halocyclization (Method E, B). Compound (5) is a starting material for Manufacturing Method 4, whose preparation can be carried out in a similar manner to that of compound (4) (Method A, C). Compound (8) is a starting material for Manufacturing Method 5, whose preparation can be carried out in a similar manner by treatment of compound (16) with compound (25) followed by deprotection and conversion to a leaving group (Method A, F).

For Method B, the staring compound is treated with an equimolar or excessive amount of a halogenating agent and a base in a solvent inert under the reaction conditions, from cooling to reflux conditions, preferably room temperature, and generally for 0.1 hours to 5 days. Non-limiting examples of the solvent used here include alcohols such as methanol, ethanol, and 2-propanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, and chloroform, water, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof. As the halogenating agent, there may be suitably used halogens such as iodine, fluorine, chlorine, and bromine, phosphorus trihalides such as phosphorus tribromide and phosphorus trichloride, phosphorus pentahalides such as phosphorus pentachloride and phosphorus pentabromide, phosphoryl chloride, thionyl halides such as thionyl chloride and thionyl bromide, N-halogenosuccinimide such as N-bromosuccinimide, N-chlorosuccinimide and N-iodosuccinimide. As the base, there may be suitably used inorganic base such as (sodium or potassium) alkoxide, hydroxide, carbonate, and bicarbonate, or organic base such as triethylamine, N,N-diisopropylethylamine, and N-methylmorpholine.

For Method A, C, D, and E, these reactions can be carried out in reaction conditions similar to Manufacturing Method 10, 9, 10, and 4 (second step), respectively.

[wherein

R lq , R 8 , R 9 , R 11 , PG 1 , and n are defined as Reaction Scheme 1; R 5 and X are defined as Manufacturing Method 1 ;

R , 104 is defined as Manufacturing Method 6.]

Reaction Scheme 2 illustrates the synthesis of intermediate compound (9aa). Compound (Iaa) can be subjected to oxidation (Method G), followed by Wittig-type reaction

(e.g. Wittig reaction, Horner-Emmons reaction)(Method H).

For the Wittig reaction, alkyl(triphenyl)phosphonium halide is treated with a strong base such as potassium tert-butoxide, potassium or sodium bis(trimethylsilyl)amide, n-butyllithium, or sodium hydride. The aldehyde is added and the reaction mixture is stirred at room temperature for about 4 to 48 hours in a solvent inert under the reaction conditions, from cooling to heating conditions, preferably -20 0 C to 80°C, generally for 0.1 hours to 3 days.

For the Horner - Emmons reaction, alkylphosphonates are used instead of alkyl(triphenyl)phosphonium halides, preferably alkyl (dialkoxyphosphoryl)acetates.

Non-limiting examples of the solvent used here include ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, dimethyl sulfoxide, acetonitrile, and mixtures thereof.

P2009/058437

49

Reaction Scheme 3

[wherein

R lq , R 8 , R 9 , R 11 , PG 1 , L, L 1 , M 5 and Z are defined as Reaction Scheme 1 ;

R 5s is lower alkyl, lower alkenyl, halogeno lower alkyl, or cycloalkyl, each of which is optionally substituted with one or more substituent(s) selected from the group consisting of

-COO-lower alkyl,

-CO-amino optionally substituted with one or two lower alkyl(s),

-CO-piperidyl,

-O-lower alkyl, -O-phenyl, cycloalkyl, phenyl, piperidyl and morpholinyl.]

Reaction Scheme 3 shows a stereoselective synthesis of intermediate compound (Id). An optically active monocrotonated binaphthol (27) can be alkylated stereoselective^ to give compound (29). Reductive cleavage of the chiral auxiliary can give a chiral alcohol (30) which can be transformed to a halide (31) by conventional methods. The halide (31) can be subjected to the reaction with compound (16) (Method A described above), then the halocyclization can afford compound (Id) as a diastereomixture (Method B described above). The desired stereoisomer can be obtained by precipitaion. The diastereoisomers with opposite stereochemistry at R 5s can be obtained in a similar manner by using chiral auxiliary of opposite absolute stereochemistry.

For the stereoselective alkylation step, the monocrotonated binaphthol is treated with an equimolar or excessive amount of strong base in a solvent inert under the reaction conditions, from cooling to heating conditions, preferably -2O 0 C to 8O 0 C, and generally for

0.1 hours to 3 days followed by addition of compound (28). Non-limiting examples of the solvent used here include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, and mixtures thereof. Non-limiting examples of the strong base include lithium diisopropylamide, sodium hexamethyldisilazide, organomagnesium, organolithium, and organozinc.

Compounds of the present invention are isolated and purified as a free compound or as a pharmaceutically acceptable salt, hydrate, solvate or crystalline polymorphorous substance thereof. Pharmaceutically acceptable salts of compounds of Formula (I) of the present invention can be produced by subjecting the compound to a general salt-formation reaction.

Isolation and purification can be carried out by applying general chemical operations such as extraction, fractional crystallization, and various fractional chromatographic techniques.

Various kinds of isomers can be prepared by selecting an appropriate raw material or can be separated by using the difference in physicochemical properties among the isomers.

For example, an optical isomer can be isolated by a general optical resolution (for example, fractional crystallization or chromatography using a chiral column). It is also possible to start from an appropriate optically active compound.

Biological Property

Pharmacological activities of the compounds of the present invention were confirmed by the following tests.

Antimicrobial activity:

In vitro antimicrobial activity of representative compounds of the present invention was determined by minimum inhibitory concentration (MIC) in mouse serum as described below.

Test Method:

The MICs in mouse serum were determined by the microdilution method using

RPMIl 640 buffered with 0.165M MOPS (pH 7.0) and ICR mouse serum buffered with 20 mM HEPES buffer (pH 7.3) as a test medium. Inoculum suspension of 10 6 cells/mL were prepared by a hemocytometric procedure and diluted to obtain an inoculum size of approximately 1.0 x 10 3 cells/mL. Microplates were incubated at 37 0 C for 24 hours in 5%

CO 2 . The MICs were defined as the lowest concentrations at which no visible growth was observed. Representative results are shown in Table 1.

(Ex: Example compound shown in Tables 5-7.)

From the test result, it is confirmed that the compounds of the present invention have antimicrobial activity (especially, antifungal activity).

Furthermore, the antifungal activity, particularly against the following fungi, can be confirmed by the method described above and in vivo animal model.

Acremonium;

Absidia (e.g. Absidia corymbifera, etc.); Aspergillus (e.g. Aspergillus clάvatus, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Aspergillus versicolor, etc.);

Blastomyces (e.g. Blastomyces dermatitidis, etc.);

Candida (e.g. Candida albicans, Candida glabrata, Candida guilliermondii, Candida kejyr,

Candida krusei, Candida parapsilosis, Candida stellatoidea, Candida tropicalis, Candida utilis, etc.);

Cladosporium (e.g. Cladosporium trichloides, etc.);

Coccidioides (e.g. Coccidioides immitis, etc.);

Cryptococcus (e.g. Cryptococcus neoformans, etc.);

Cunninghamella (e.g. Cunninghamella elegans, etc.);

Dermatophyte;

Exophiala (e.g. Exophiala dermatitidis, Exophiala spinifera, etc.);

Epidermophyton (e.g. Epidermophytonfloccosum, etc.); Fonsecaea (e.g. Fonsecaea pedrosoi, etc.);

Fusarium (e.g. Fusarium solani, etc.);

Geotrichum (e.g. Geotrichum candiddum, etc.); '

Histoplasma (e.g. Histoplasma capsulatum var. capsulatum, etc.);

Malassezia (e.g. Malassezia furfur, etc.); Microsporum (e.g. Microsporum canis, Microsporum gypseum, etc.);

M/eor;

Paracoccidioides (e.g. Paracoccidioides brasiliensis, etc.);

Penicillium (e.g. Penicillium marneffei, etc.);

Phialophora; Pneumocystis (e.g. Pneumocystis jiroveci, etc.);

Pseudallescheria (e.g. Pseudallescheria boydii, etc.);

Rhizopus (e.g. Rhizopus microsporus var. rhizopodiformis, Rhizopus oryzae, etc.);

Saccharomyces (e.g. Saccharomyces cerevisiae, etc.);

Scopulariopsis; Sporothrix (e.g. Sporothrix schenckii, etc.);

Trichophyton (e.g. Trichophyton mentagrophytes, Trichophyton rubrum, etc.);

Trichosporon (e.g. Trichosporon asahii, Trichosporon cutaneum, etc.).

The above fungi are well-known to cause various infection diseases in skin, eye, hair, nail, oral mucosa, gastrointestinal tract, bronchus, lung, endocardium, brain, meninges, urinary organ, vaginal portion, oral cavity, ophthalmus, systemic, kidney, heart, external auditory canal, bone, nasal cavity, paranasal cavity, spleen, liver, hypodermal tissue, lymph duct, gastrointestine, articulation, muscle, tendon, interstitial plasma cell in lung, blood, and so on.

Therefore, in some embodiments, the compounds of the present invention are used for preventing and treating various infectious diseases in a human being or an animal, such as dermatophytosis (e.g. trichophytosis, etc.), pityriasis versicolor, candidiasis, cryptococcosis, geotrichosis, trichosporosis, aspergillosis, penicilliosis, fusariosis, zygomycosis, sporotrichosis, chromomycosis, coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, pseudallescheriosis, mycetoma, mycotic keratitis, otomycosis, Pneumocystis pneumonia, fungemia, and so on.

The compounds of the present invention can be used in combination with various preventive or therapeutic medicaments such as azoles (e.g. fluconazole, voriconazole, itraconazole, ketoconazole, miconazole, posaconazole, ER 30346), polyenes (e.g. amphotericin B, nystatin), liposomal and lipid forms thereof (e.g. Abelcet, AmBisome,

Amphocil), purine or pyrimidine nucleotide inhibitors (e.g. flucytosine), polyoxins (e.g. nikkomycines, in particular nikkomycine Z or nikkomycine X), other chitin inhibitors; mannan inhibitors (e.g. predamycin), bactericidal/permeability-inducing (BPI) protein products (e.g. XMP.97, XMP.127), or complex carbohydrate antifungal agents (e.g. CAN-296).

The pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient which is suitable for rectal; pulmonary (nasal or buccal inhalation); ocular; external (topical); oral administration; parenteral (including subcutaneous, intravenous and intramuscular) administrations; insufflation (including aerosols from metered dose inhalator); nebulizer; or dry powder inhalator.

The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers in a solid form such as granules, tablets, dragees, pellets, troches, capsules, or suppositories; creams; ointments; aerosols; powders for insufflation; in a liquid form such as solutions, emulsions, or suspensions for injection; ingestion; eye drops; and any other form suitable for use. And, if necessary, there may be included in the above preparation auxiliary substance such as stabilizing, thickening, wetting, emulsifying and coloring agents; perfumes or buffer; or any other commonly may be used as additives.

A compound of Formula (I) or a pharmaceutically acceptable salt thereof is/are included in the pharmaceutical composition in an amount sufficient to produce the desired antimicrobial effect upon the process or condition of diseases.

For applying the composition to humans, in some embodiments, there are intravenous, intramuscular, pulmonary, oral administration, eye drop administration or insufflation. While the dosage of therapeutically effective amount of the compound of Formula (I) varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01-400 mg of the compound of

Formula (I) per kg weight of human being, in the case of intramuscular administration, a daily dose of 0.1-20 mg of the compound of Formula (I) per kg weight of human being, in case of oral administration, a daily dose of 0.5-50 mg of the compound of Formula (I) per kg weight of human being is generally given for treating or preventing infectious diseases.

For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation form pressurized as powders which may be formulated and the powder compositions may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery system for inhalation is a metered dose inhalation aerosol, which may be formulated as a suspension or solution of compound in suitable propellants such as fluorocarbons or hydrocarbons.

Because of desirability to directly treat lung and bronchi, aerosol administration is a preferred method of administration. Insufflation is also a desirable method, especially where infection may have spread to ears and other body cavities. Alternatively, parenteral administration may be employed using drip intravenous administration.

For administration by intravenous administration, the preferred pharmaceutical composition is the lyophilized form containing the compound of Formula (I) or its pharmaceutically acceptable salt.

The amount of the compound of Formula (I) or its pharmaceutically acceptable salt contained in the composition for a single unit dosage of the present invention is 0.1 to 400 mg, more preferably 1 to 200 mg, still more preferably 5 to 100 mg, specifically 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 and 100 mg.

The process for the production of compounds of the present invention will be illustrated in more detail using the following Examples. The present invention is not limited to the compounds described in the following Examples. The process for the production of Preparation compounds is shown in Preparations.

The following abbreviations will be used in the Examples, Preparations and Tables below.

Table 2. Standard Abbreviations and Acronyms

Preparation 1

To a solution of diphenylmethyl (3aS',4S',4ai?,7i?,7ai?,8aS)-4-(l,3-dioxolan-2-yl)- 8a-formyl-3-isopropyl-7-methyl-4,4a,5,6,7 ; ,7a,8,8a-octahydro-l,4-methano-s-indacene- 3a(lH)-carboxylate (2.0 g) in THF (100 mL) was added a solution of 3-butenylmagnesium bromide in THF (0.5 M, 14.8 mL) at room temperature. The mixture was stirred at room temperature for 3 hrs under nitrogen atmosphere. The mixture was poured into saturated aqueous ammonium chloride, and extracted with AcOEt. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated. Purification by silica-gel column chromatography (10% AcOEt in hexane) gave the compound of Preparation 1 in Table 3 (1.5 g).

Preparation 2

To a solution of the compound of Preparation 177 in Table 3 (6.79 g) in THF (50 mL) were added sodium periodate (3.74 g) in water (40 mL) and microcapsulated osmium tetroxide (1.48 g, 0.4 mmol/g). After stirred at room temperature for 1 hr, the mixture was diluted with AcOEt. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated. Chromatography on silica gel of the residue gave the compound of Preparation 2 in Table 3 (2.00 g).

Preparation 3

To a solution of the compound of Preparation 2 in Table 3 (2.00 g) in THF (20 mL) were added 1.4 M vinylmagnesium chloride in THF (5.37 mL) at -78 Deg. After stirred at the same temperature for 1 hr, the mixture was treated with saturated aqueous ammonium chloride. The solution was extracted with AcOEt. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. Chromatography on silica gel of the residue gave the compound of Preparation 3 in Table 3 (1.04 g).

Preparation 4

To a solution of the compound of Preparation 3 in Table 3 (61.3 mg) in DMF (1.5 mL) were added sodium hydride (6 mg) and pentyl bromide (0.04 mL) at room temperature. After stirred for 1 hr, the mixture was treated with saturated aqueous ammonium chloride. The solution was extracted with AcOEt. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. Chromatography on silica gel of the residue gave the compound of Preparation 4 in Table 3 (58.8 mg).

Preparation 5

To a solution of the compound of Preparation 4 in Table 3 (58.8 mg) in DCM (3 mL)

was added N-iodosuccinimide (29 mg) at room temperature. After stirred for 4 hrs, the reaction mixture was concentrated. The residue was chromatographed on silica gel to give the compound of Preparation 5 in Table 3 (65 mg).

Preparation 6

To a solution of diisopropylamine (0.856 mL) in THF (15 mL) was added n-butyllithium (1.59M in hexane, 4.28 mL) at -78 Deg, and the solution was stirred for 5 Min. To the mixure was added ethyl pent-4-enoate (769 mg) at -78 Deg. After 30 Min, to the solution was added diphenylmethyl (3aS',45',4ai?,7i?,7ai-,8aS)-4-(l,3-dioxolan-2-yl)- 8a-formyl-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro- l,4-methano-s-indacene-

3a(lH)-carboxylate (1.08 g) in THF (5 mL) at -78 Deg. The temperature was gradually raised to 0 Deg, the mixture was stirred at the same temperature for 1 hr. The reaction mixture was treated with saturated aqueous ammonium chloride and AcOEt. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated. Chromatography on silica gel of the residue gave the compound of Preparation 6 in Table 3 (1.33 g).

Preparation 7

To a solution of the compound of Preparation 6 in Table 3 (618 mg) in DCM (20 mL) was added N-iodosuccinimide (374 mg) at room temperature. After stirred for 4 hrs, the reaction mixture was concentrated. The residue was chromatographed on silica gel to give the compound of Preparation 7 in Table 3 (575 mg).

Preparation 8 To a solution of the compound of Preparation 1 in Table 3 (100 mg) in DCM (5 mL) were added potassium carbonate (23 mg) and m-chloroperbenzoic acid (80%, 43 mg) at room temperature. After stirred for 12 hrs, the mixture was treated with aqueous sodium sulfite for 1 hr. The mixture was extracted with AcOEt. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. Chromatography on silica gel of the residue gave the compound of Preparation 8 in Table 3 (69.2 mg).

Preparation 9

To a solution of the compound of Preparation 440 in Table 3 (840.2 mg) in AcOEt (5 mL) was added palladium on charcoal (124.3 mg), then the mixture was stirred under hydrogen atmosphere at room temperature for 3 hrs. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography

(hexane / acetone = 95 / 5 to 75 / 25) to give the compound of Preparation 9 in Table 3 (541.3

mg).

Preparation 10

To a solution of naphthalene (1.97 g) in THF (26 niL) was added lithium wire (110 mg) at room temperature and the mixture was stirred at the same temperature for 3.5 hrs. The solution was cooled to -70 Deg and a solution of 3-(bromomethyl)-4-methylpent-l-ene (1.28 g) in THF (8 mL) was added dropwise. After the addition, the mixture was stirred at the same temperature for 1.5 hrs, then a solution of diphenylmethyl (3aS',45,4ai?,7i?,7ai?,8aS)-4-(l,3-dioxolan-2-yl)-8a-formyl- 3-isopropyl-7-methyl-4,4a,5,6,7,7a, 8,8a-octahydro-l,4-methano-s-indacene-3a(lH)-carboxylate (2.60 g) in THF (8 mL) was added. The solution was stirred at the same temperature for 1 hr, and the reaction was quenched by the addition of saturated aqueous ammonium chloride (50 mL). The mixture was extracted with AcOEt (50 mL, 25 mL). The combined extracts were washed with water (75 mL x 2) and brine (75 mL), and dried over magnesium sulfate. Filtration followed by concentration gave a pale yellow solid (5.05 g) which was chromatographed on silica gel (eluent: hexane / AcOEt) to give the compound of Preparation 10 in Table 3 (760 mg) as a white solid and the compound of Preparation 260 in Table 3 (388 mg) as a white solid.

Preparation 11 To a mixture of iodine (395 mg), sodium hydrogen carbonate (523 mg), and acetonitrile (1.8 mL) was added a solution of the compound of Preparation 260 in Table 3 (368 mg) in acetonitrile (1.8 mL) at room temperature. The mixture was stirred for 1 hr. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate (15 mL), and the mixture was extracted with AcOEt (15 mL, 5 mL). The combined extracts were washed with water (20 mL x 2) and brine (20 mL), and dried over magnesium sulfate. Filtration followed by concentration gave a yellow solid (387 mg) which was chromatographed on silica gel (silica gel 45 g, eluent: hexane/ AcOEt) to give the compound of Preparation 11 in Table 3 (109 mg) as a yellow foam and the compound of Preparation 268 in Table 3 (63.2 mg) as a yellow foam.

Preparation 12

To a solution of the compound of Preparation 52 in Table 3 (50 mg) in MeOH (1 mL) and acetonitrile (1 mL) was added trimethylsilyldiazomethane (2.0M in hexane, 0.05277 mL) at room temperature, and the mixture was stirred at the temperature for 1 hr. After the addition of a small amount of acetic acid, evaporation of the solvent gave the compound of Preparation 12 in Table 3 (51.232 mg).

Preparation 13

To a solution of diphenylmethyl (3ai?,45',4ai?,7i?,7ai?,8aS)-4-foπnyl-8a-

(hydroxymethyl)-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-o ctahydro-l,4-methano-s-indacene-

3a(lH)-carboxylate (1 g), imidazole (410 mg) and (4-dimethylamino)pyridine (24.5 mg) in DMF (10 mL) was added tert-butyldimethylsilyl chloride (363 mg) at ambient temperature.

The mixture was stirred for 1 hr. The reaction mixture was partitioned between AcOEt - diisopropyl ether and water. The organic layer was washed successively with water, saturated aqueous ammonium chloride, water, and brine, dried over sodium sulfate, and filtered. Concentration under reduced pressure gave the compound of Preparation 13 in Table 3 (1.27 g).

Preparation 14

A suspension of the compound of Preparation 13 in Table 3 (1.26 g), hydroxylamine hydrochloride (1.43 g) and sodium hydrogen carbonate (1.90 g) in EtOH (25 mL) was stirred at 60 Deg for 4 hr and diluted with AcOEt. The mixture was washed with water (x 3), saturated aqueous ammonium chloride, and brine, and dried over magnesium sulfate.

Evaporation of the solvent gave the compound of Preparation 14 in Table 3 (1.23 g).

Preparation 15 To a solution of the compound of Preparation 14 in Table 3 (4.5 g) in toluene (60 mL) was added Burgess reagent (4.7 g), and the mixture was stirred at 80 Deg for 1 hr. The mixture was diluted with AcOEt, washed with water, saturated aqueous ammonium chloride, saturated aqueous sodium hydrogen carbonate, and brine, and dried over sodium sulfate. Evaporation of the solvent gave the compound of Preparation 15 in Table 3 (6.0 g).

Preparation 16

To a solution of tetra-n-butyl ammonium fluoride in TηF (IM, 80 mL) was added the compound of Preparation 15 in Table 3 (6.0 g). The mixture was stirred at 60 Deg for 1 hr and diluted with AcOEt. The mixture was washed with water (x 3) and brine, and dried over magnesium sulfate. Evaporation of the solvent gave the compound of Preparation 16 in Table 3 (4.6 g).

Preparation 17

A , suspension of the compound of Preparation 16 in Table 3 (4.6 g), N-methylmorpholine N-oxide (1.72 g), and molecular sieves 4 A (20 g) in DCM (80 mL) was stirred at room temperature for 30 Min. To the mixture was added tetra-n-propylammonium perruthenate (161 mg), and the mixture was stirred at room temperature for 30 Min. After

the insoluble material was filtered off, the filtrate was concentrated. The residue was dissolved in DCM, and to the solution was added silica gel, and the mixture was stirred for 10 Min. Filtration followed by evaporation of the solvent gave the compound of Preparation 17 in Table 3 (3.O g).

Preparation 18

Under nitrogen atmosphere, to a solution of the compound of Preparation 17 in Table 3 (2.47 g) in THF (30 mL) was added 3-butenylmagnesium bromide (0.5M in THF, 15 mL) at room temperature, and the mixture was stirred at the temperature for 2 hrs. The mixture was poured into saturated aqueous ammonium chloride, and extracted with AcOEt. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated to give the compound of Preparation 18 in Table 3 (1.41 g).

Preparation 19 To a suspension of iodine (1.29 g) and sodium hydrogen carbonate (1.07 g) in acetonitrile (30 mL) was added a solution of the compound of Preparation 18 in Table 3 (1.40 g) in acetonitrile (80 mL), and the mixture was stirred at room temperature for 30 Min and diluted with AcOEt. The mixture was washed with saturated aqueous sodium thiosulfate, water (x 2), and brine. The organic layer was dried over magnesium sulfate and concentrated to give the compound of Preparation 19 in Table 3 (590 mg).

Preparation 20

To a solution of l^-anhydro-l-^aiJ^^ai-JiJ^aiJ^a^-Sa-carboxy^-formyl- 3-isopropyl-7-methyl-3a,4,4a,5,6,7,7a,8-octahydro-l,4-methan o-s-indacen-8a(lH)-yl]- 3-cyclohexyl-2,3-dideoxypentitol (200 mg) in DCM (3 mL) were added pyridine (0.1 mL), DIPEA (0.15 mL), and 4-nitrophenyl chloroformate (213 mg) at room temperature. After 2 hrs, the reaction was quenched by addition of water. The mixture was extracted with AcOEt (x 2). The combined organic layer was washed with water and brine, dried over sodium sulfate, then concentrated. The residue was purified by silica gel column chromatography (hexane / acetone = 95 / 5 to 75 / 25) to give the compound of Preparation 20 in Table 3 (229.2 mg).

Preparation 21

To a solution of l,4-anhydro-l-[(3ai-,4S',4ai?,7i?,7ai?,8aS)-3a-carboxy-4-for myl- 3-isopropyl-7-methyl-3a,4,4a,5,6,7,7a,8-octahydro-l,4-methan o-s-indacen-8a(lH)-yl]-

3-cyclohexyl-2,3-dideoxypentitol (450 mg) in DMF (7 mL) were added potassium carbonate (277.3 mg) and benzyl bromide (0.135 mL) at room temperature. The mixture was stirred

for 12 hrs. Resulting mixture was diluted with AcOEt, washed with water and brine, dried over magnesium sulfate, then concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 95 / 5 to 75 / 25) to give the compound of Preparation 21 in Table 3 (305.3 mg).

Preparation 22

To a solution of the compound of Preparation 21 in Table 3 (391.2 mg), ethylene glycol (3 mL), and trimethyl orthoformate (0.4 mL) in MeOH (3 mL) was added p-toluenesulfonic acid monohydrate (6.5 mg) at room temperature. The mixture was stirred for 12 hrs. The reaction was quenched by addition of triethylamine. After concentration, the residue was dissolved in AcOEt. The solution was washed with water and brine, dried over magnesium sulfate, then concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 90 / 10 to 70 / 30) to give the compound of Preparation 22 in Table 3 (306.8 mg).

Preparation 23

To a solution of the compound of Preparation 22 in Table 3 (303.1 mg) in DCM (5 mL) were added N-methylmorpholine N-oxide (126.3 mg) and tetrapropylammonium perruthenate (8.61 mg) at room temperature. After 3 hrs, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 95 / 5 to 85 / 15) to give the compound of Preparation 23 in Table 3 (188.6 mg).

Preparation 24

To a suspension of [3-(dimethylamino)propyl]triphenylphosphonium bromide (90 mg) in THF (0.8 mL) was added n-butyllithium (1.58 M solution in hexane, 0.2 mL) at 4 Deg under nitrogen atmosphere. The white suspension turned to clear orange solution. The mixture was stirred at the temperature for 1 hr then the compound of Preparation 23 in Table 3 (88.3 mg) in THF (0.2 mL) was added. The mixture was allowed to warm to room- temperature. The color changed to pale yellow and a white precipitate was formed. After 2 hrs stirring, the reaction was quenched by addition of water. The mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over magnesium sulfate, then concentrated. The residue was purified by amino-capped silica gel column chromatography (hexane / AcOEt = 90 / 10 to 80 / 20) to give the compound of Preparation 24 in Table 3 (37.5 mg).

Preparation 25

To a solution of naphthalene (2.37 g) in THF (40 mL) was added lithium turnings

(180.6 mg) at room temperature under nitrogen atmosphere. After a few seconds of sonication, the color of the mixture gradually turned to dark green. The mixture was stirred for 3 hrs. The dark green suspension was cooled to -60 Deg then [[4-(bromomethyl)hex-5-en-l-yl]oxy](tert-butyl)dimethylsilan e (4 g) in THF (15 mL) was added dropwise. After 1 hr of stirring, diphenylmethyl (3aS,4SAaRJRJa^,8aS)- 4-(l,3-dioxolan-2-yl)-8a-formyl-3-isopropyl-7-methyl-4,4a,5, 6 5 7,7a,8,8a-octahydro-l,4- methano-s-indacene-3a(lH)-carboxylate (4 g) in THF (15 mL) was added to the mixture at -60 Deg, and stirred for 30 Min at the temperature. To the mixture was added saturated aqueous ammonium chloride at the temperature, and the mixture was warmed to room tempreature. The mixture was extracted with AcOEt (x 3). The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 98 / 2 to 95 / 5) to give the compound of Preparation 25 in Table 3 (4.29 g).

Preparation 26

To a solution of the compound of Preparation 25 in Table 3 (3.2 g) in DCM (50 mL) was added 1-iodosuccinimide (1.42 g) at room temperature. The mixture was stirred for 1 hr.

The resulting mixture was concentrated, and diluted with hexane and toluene. The white precipitate formed was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 80/20) to give the compound of Preparation 26 in Table 3 (3.7 g).

Preparation 27

To a solution of the compound of Preparation 26 in Table 3 (241.4 mg) in DMF (1 mL) was added piperidine (0.3 mL) at room temperature. The mixture was heated at 60 Deg for 24 hrs. After evaporation of the solvent, the yellow oil was diluted with AcOEt. The solution was washed with saturated aqueous sodium hydrogen carbonate, water, and brine, and dried over magnesium sulfate, and concentrated. The residue was purified by amine-capped silica gel column chromatography (hexane / AcOEt = 90/10) to give the compound of Preparation 27 in Table 3 (209.1 mg).

Preparation 28

To a solution of the compound of Preparation 27 in Table 3 (3.52 g) in THF (35 mL) was added 1.0 M tetrabutylammonium fluoride THF solution (9 mL) at room temperature. The mixture was stirred for 18 hrs. The resulting mixture was concentrated, diluted with

AcOEt, washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by amine-capped silica gel column chromatography (hexane / AcOEt =

90 / 10 to 50 / 50) to give the compound of Preparation 28 in Table 3 (2.94 g).

Preparation 29

To a solution of the compound of Preparation 28 in Table 3 (20 mg) in DCM (1 mL) was added (diethylamino)sulfur trifluoride (0.01 mL) at room temperature. The mixture was stirred for 12 hrs. The resulting mixture was directly purified by silica gel column chromatography (chloroform / MeOH = 100 / 0 to 90 / 10 (+0.5% triethylamine)) to give the compound of Preparation 29 in Table 3 (10.1 mg).

Preparation 30

To a solution of the compound of Preparation 28 in Table 3 (50 mg), l,l'-(azodicarbonyl)dipiperidine (53 mg), and phenol (7.9 mg) in THF (1 mL) was added triphenylphosphine (56.1 mg) at 4 Deg. The mixture was stirred for 5 hrs. The resulting mixture was concentrated. The residue was purified by silica gel column chromatography (hexane / acetone = 95 / 5 to 80 / 20) to give the compound of Preparation 30 in Table 3 (30.8 mg).

Preparation 31

To a solution of the compound of Preparation 28 in Table 3 (300 mg) and triethylamine (0.1 mL) in DCM (3 mL) was added methanesulfonyl chloride (0.05 mL) at 4 deg. The mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction was quenched by addition of water. The mixture was extracted with AcOEt (x 2), the organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated to give the compound of Preparation 31 in Table 3 (327.9 mg).

Preparation 32

To a solution of the compound of Preparation 31 in Table 3 (50 mg) in DMF (0.1 mL) was added piperidine (0.05 mL) at room temperature. The mixture was heated at 60 Deg for 12 hrs. The mixture was directly purified by silica gel column chromatography (chloroform/MeOH = 100 / 0 to 80 / 20 (+0.5% triethylamine)) to give the compound of Preparation 32 in Table 3 (40.8 mg).

Preparation 33

To a solution of the compound of Preparation 28 in Table 3 (100 mg) in DCM (5 mL) was added Dess-Martin periodinane (172.4 mg) at room temperature. The mixture was stirred for 3 hrs. The reaction was quenched by addition of 1.0 M aqueous sodium hydroxide.

The mixture was extracted with AcOEt. The organic layer was washed with brine, dried over

magnesium sulfate, and concentrated to give the compound of Preparation 33 in Table 3 (86.9 mg).

Preparation 34 To a solution of the compound of Preparation 33 in Table 3 (20 mg) in DCM (1 mL) was added (diethylamino)sulfur trifluoride (0.02 mL) at room temperature. The mixture was stirred for 12 hrs. The resulting mixture was directly purified by silica gel column chromatography (chloroform / MeOH = 100 / 0 to 90 / 10 (+0.5% triethylamine)) to give the compound of Preparation 34 in Table 3 (9 mg).

Preparation 35

To a suspension of sodium hydride (60% in oil, 10 mg) in THF (2 mL) was added ethyl (diethoxyphosphoryl)acetate (0.05 mL) at room temperature. After 30 Min stirring, the compound of Preparation 33 in Table 3 (100 mg) was added. The mixture was stirred for 2 hrs. The reaction was quenched by addition of saturated aqueous ammonium chloride. The mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over magnesium sulfate, then concentrated. The residue was purified by amine-capped silica gel column chromatography (hexane / AcOEt = 95 / 5 to 80 / 20) to give the compound of Preparation 35 in Table 3 (77.8 mg).

Preparation 36

To a soltion of the compound of Preparation 33 in Table 3 (100 mg) and 2-methyl-2-butene (0.25 mL) in 2-methyl-2-propanol (1.5 mL) and THF (0.75 mL) was added a solution of sodium dihydrogenphosphate (81.5 mg) and sodium chlorite (61.4 mg) in water (0.5 mL) at room temperature. The yellow solution was stirred for 14 hrs. The resulting mixture was diluted with water and extracted with AcOEt (x 2). The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated to give the compound of Preparation 36 in Table 3 (102.1 mg).

Preparation 37

To a solution of the compound of Preparation 36 in Table 3 (32.3 mg), 1-hydroxybenzotriazole (11.6 mg), and diethylamine (0.03 mL) in a DCM - DMF mixed solvent (1 / 1, 1 mL) was added 3-(3-dimethylaminopropyl)-l-ethylcarbodiimide hydrochloride (16.5 mg) at room temperature. The mixture was stirred for 22 hrs. The reaction was quenched by addition of water. The mixture was extracted with AcOEt (x 3), and the organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform /

MeOH = 100 / 0 to 80 / 20 (+0.5% triethylamine)) to give the compound of Preparation 37 in Table 3 (16.9 mg).

Preparation 38 To a solution of sodium iodide (42.3 g) in acetone (200 mL) was added

(3-bromopropoxy)(tert-butyl)dimethylsilane (10.9 g) at room temperature. The mixture was stirred for 12 hrs (the colorless solution changed to a pale yellow suspention). The white precipitate was filtered off, and the filtrate was concentrated. To the residue was added water and the mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 100 / 0 to 95 / 5) to give tert-butyl(3-iodopropoxy)dimethylsilane (12.9 g).

Preparation 39 To a solution of hexamethylphosphoric triamide (14 mL) and lithium diisopropylamide (1.8 M in THF / heptane / ethylbenzene solution, 45 mL) in THF (100 mL) was added ethyl crotonate (10 mL) in THF (80 mL) dropwise at -78 Deg under nitrogen atmosphere. After 30 Min, tørt-butyl(3-iodopropoxy)dimethylsilane (12 g) in THF (20 mL) was added slowly to the mixture and the mixture was stirred at the temperature for 5 hrs. The reaction was quenched by addition of saturated aqueous ammonium chloride. After evaporation of the solvent, the mixture was extracted with AcOEt (x 3). The organic layer was washed with water (x 3) and brine, dried over magnesium sulfate, then concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 100 / 0 to 90/10) to give ethyl 5-[[ter?-butyl(dimethyl)silyl]oxy]-2-vinylpentanoate (6.98 g).

Preparation 40

To a solution of ethyl 5-[[tert-butyl(dimethyl)silyl]oxy]-2-vinylpentanoate (6.98 g) in THF (100 mL) was added lithium aluminum hydride (1 g) at -78 Deg, and the mixture was warmed to room temperature and stirred for 1 hr. The resulting mixture was re-cooled to -78 Deg, and to the mixture were added dropwise water (1 mL), 4.0 M aqueous sodium hydroxide (1 mL), and water (3 mL). The gray suspension was allowed to warm to room temperature and stirring was continued until the color became white. The precipitate was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 95 / 5 to 80 / 20) to give 5-[[tert-butyl(dimethyl)silyl]oxy]- 2-vinylpentan-l-ol (3.99 g).

Preparation 41

To a solution of 5-[[te^butyl(dimethyl)silyl]oxy]-2-vinylpentan-l-ol (3.99 g) and triethylamine (3 mL) in DCM (80 mL) was slowly added methanesulfonyl chloride (1.6 mL) at 4 Deg. The mixture was allowed to warm to room temperature and stirred for 1 hr. The resulting suspension was concentrated then diluted with AcOEt. The mixture was washed with water and brine, dried over magnesium sulfate, then concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 90 / 10 to 80 / 20) to give 5-[[tert-butyl(dimethyl)silyl]oxy]-2-vinylpentyl methanesulfonate (5.2 g).

Preparation 42 To a solution of lithium bromide (8.3 g) and triethylamine (3 mL) in THF (70 mL) was added a solution of 5-[[tert-butyl(dimethyl)silyl]oxy]-2-vinylpentyl methanesulfonate (5.8 g) in THF (30 mL) at room temperature. The mixture was heated at 60 Deg for 3 hrs. The resulting mixture was concentrated. The residual pale yellow suspension was diluted with AcOEt, washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 100 / 0 to 90/10) to give [[4-(bromomethyl)hex-5-en-l-yl]oxy](tert-butyl)dimethylsilan e (3.46 g).

Preparation 43

To a solution of (#)-(+)- l,l'-bi-2-naphthol (75 g) in DCM (500 mL) were added DIPEA (91.3 mL) and (£)-2-butenoyl chloride (26.4 mL) in DCM (250 mL) at 0 Deg. After stirring at room temperature for 1.5 hrs, the mixture was poured into saturated aqueous ammonium chloride at 0 Deg. The mixture was extracted three times with AcOEt. The combined extract was washed with brine, dried over magnesium sulfate, and concentrated to give 2'-hydroxy-l,r-binaphthalen-2-yl (2E)-but-2-enoate (92.8 g) as a brown oil,

Preparation 44

To a solution of lithium diisopropylamide (1.8 M in THF / heptane / ethylbenzene solution, 58.8 mL) in THF (50 mL) was added hexamethylphosphoric triamide (73.6 mL) at -78 Deg, and the mixture was stirred at the same temperature for 30 Min. To the mixture was added 2'-hydroxy-l,l'-binaphthalen-2-yl (2£)-but-2-enoate (15 g) in THF (50 mL) at -78 Deg. After stirring at the same temperature for 30 Min, a solution of (iodomethyl)cyclopentane (40 g) in THF (50 mL) was added to the mixture at -78 Deg. After stirring for 70 Min, the mixture was poured into saturated aqueous ammonium chloride. The mixture was extracted with AcOEt. The combined extract was washed with brine, dried over magnesium sulfate, and concentrated. The residue was triturated with hexane - AcOEt (92 / 8), and the precipitate formed was collected by filtration. The precipitate was dissolved in hot EtOH (140 mL), and the solution was kept without stirring at room temperature for 8 hrs. The

precipitate formed was collected by filtration to give 2'-hydroxy-l,r-binaphthalen-2-yl (2i?)-2-(cyclopentylmethyl)but-3-enoate (16.6 g) as a white solid.

Preparation 45 To a suspension of lithium aluminum hydride (1.15 g) in THF (30 mL) was added slowly a solution of 2'-hydroxy-l,l'-binaphthalen-2-yl (2i?)-2-(cyclopropylmethyl)but- 3-enoate (6.2 g) in THF (30 mL) at - 78 Deg. The mixture was allowed to warm to 0 Deg, and stirring was continued at the temperature for 10 Min. To the mixture was added sodium sulfate decahydrate. The mixture was stirred at room temperature for 2 hrs, filtered, and concentrated. The residue was purified with silica gel column chromatography to give (2i?)-2-(cyclopropylmethyl)but-3-en-l-ol (2.11 g) as a yellow oil.

Preparation 46

To a solution of (2i-)-2-(cyclobutylmethyl)but-3-en-l-ol (4.02 g) in DCM (40 mL) were added DIPEA (5.47 mL) and methanesulfonyl chloride (2.66 mL) at -78 deg. The mixture was allowed to warm to room temperature and stirring was continued for 12 hrs.

The mixture was extracted with AcOEt. The combined extract was washed with brine, dried over magnesium sulfate, and concentrated to give (2i?)-2-(cyclobutylmethyl)but-3-en-l-yl methanesulfonate (6.52 g) as a brown oil.

Preparation 47

To a solution of (2i?)-2-(cyclopropylmethyl)but-3-en-l-yl methanesulfonate (2.57 g) in acetone (25.7 mL) was added lithium bromide (3.28 g) at room temperature, and the mixture was heated to reflux for 3 hrs. After being allowed to cool to room temperature, the mixture was extracted with AcOEt. The combined extract was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified with silica gel column chromatography to give [(2i?)-2-(bromomethyl)but-3-en-l-yl]cyclopropane (1.31 g) as a colorless oil.

Preparation 48

Under nitrogen atmosphere, to a solution of naphthalene (8.52 g) in THF (100 mL) was added lithium turnings (427 mg) at room temperature, and the mixture was stirred at the temperature for 1 hr then cooled to -78 Deg. To the cooled mixture was added dropwise [(2i.)-2-(bromomethyl)but-3-en-l-yl]cyclobutane (5.00 g) in THF (15 mL) at the temperature, and stirring was continued for 1.5 hrs. To the mixture was added dropwise diphenylmethyl (3a5,45,4ai-,7i? 5 7ai-,8aS)-4-(l,3-dioxolan-2-yl)-8a-formyl-3-isopropyl-7-meth yl-4,4a,5,6,7,7a, 8,8a- octahydro-l,4-methano-s-indacene-3a(lH)-carboxylate (20.0 g) in THF (15 mL) at -78

Deg, and stirring was continued at the temperature for 2 hrs. The reaction was quenched via addition of water at -78 Deg. After being allowed to warm to room temperature, the mixture was extracted three times with AcOEt. The combined extract was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the compound of Preparation 48 in Table 3 (5.32 g) as a white solid.

Preparation 49

To a suspension of iodine (8.25 g) and sodium hydrogen carbonate (11 g) in acetonitrile (60 mL) was added a solution of the compound of Preparation 438 in Table 3 (11 g) in acetonitrile (60 mL) at room temperature. A small amount of DCM was added to dissolve the the compound of Preparation 438 in Table 3. Stirring was continued for 1 hr and the reaction was quenched by saturated aqueous sodium thiosulfate. After evaporation of the acetonitrile, the mixture was extracted with AcOEt (x 3). The combined extract was washed with saturated aqueous ammonium chloride and brine, dried over magnesium sulfate, then concentrated. The residue was subjected to silica gel column chromatography (hexane / AcOEt = 100 / 0 to 85 / 15). The white solid obtained was precipitated from hot EtOH to give a solid (1.9 g) containing 80% of the compound of Preparation 49 in Table 3 and 20% of its diastereomers. The mother liquor was concentrated, and the residue was triturated from hexane to give the compound of Preparation 435 in Table 3 (1.45 g) whose diastereomeric ratio was unidentified.

Preparation 50

A 1.2 g of the compound of Preparation 435 in Table 3 was dissolved in hot MeOH - DCM, and the solution was allowed to cool to room temperature without stirring for 8 hrs. The precipitate formed was collected by filtration to give the compound of Preparation 50 in Table 3 (1.00 g) as a white solid.

Preparation 51

A 1.0 g of the compound of Preparation 229 in Table 3 was dissolved in hot MeOH (10 mL) and toluene (2.0 mL), and the solution was allowed to cool to room temperature without stirring for 8 hrs. The precipitate formed was collected by filtration to give the compound of Preparation 51 in Table 3 (362 mg) as a white solid.

Preparation 52 To a mixture of iodine (3.6 g) and sodium hydrogen carbonate (4.7 g) in acetonitrile

(50 mL) was added a solution of the compound of Preparation 175 in Table 3 (4.6 g) in acetonitrile (1 L). The mixture was stirred for 0.5 hrs. Saturated aqueous sodium

thiosulfate and saturated aqueous ammonium chloride were added to the mixture, the mixture was extracted with AcOEt. The extract was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to silica gel column chromatography (hexane / AcOEt / MeOH = 8 / 1 / 0.1). The desired fraction was concentrated, and the residue was precipitated with hexane / AcOEt (10 / 1) to give the compound of Preparation 192 in Table 3 (1.7 g) as a solid. The filtrate was concentrated in vacuo to give the compound of Preparation 52 in Table 3 (1.9 g) as a pale yellow oil.

Preparation 53 To a solution of lithium diisopropylamide (1.8 M in THF / heptane / ethylbenzene solution, 23.4 mL) in THF (20 mL) was added hexamethylphosphoric triamide (7.3 mL) at -78 Deg. After 30 Min, a solution of «-butyl crotonate (5 g) in THF (20 mL) was added dropwise to the mixture at -78 Deg, and stirring was continued for 15 Min at the temperature. (Bromomethyl)cyclohexane (5.9 mL) was added at -78 Deg, and stirring was continued for 1 hr at the temperature. After the mixture was allowed to warm to room temperature, the reaction was quenched by addition of saturated aqueous ammonium chloride. The mixture was extracted with ether, the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in THF (30 mL), and the solution was added to a suspension of lithium aluminum hydride (2.7 g) in THF (50 mL) at 0 Deg, and stirring was continued for 1 hr at the temperature. The reaction was quenched by successive addition of water (2.7 mL), 15% aqueous sodium hydroxide (2.7 mL), and water (8.5 mL). The mixture was filtered and extracted with ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 9 / 1 to 4 / 1) to give the compound of Preparation 53 in Table 3 (l.lg) as a colorless oil.

Preparation 54

To a solution of lithium diisopropylamide (1.8 M in THF / heptane / ethylbenzene solution, 19.6 mL) in THF (16 mL) was added hexamethylphosphoric triamide (6.7 mL) at -78 Deg. After 30 Min, a solution of n-butyl crotonate (5 g) in THF (50 mL) was added dropwise to the mixture at -78 Deg, and stirring was continued for 15 Min at the temperature. (Iodomethyl)cyclopentane (5.9 mL) was added to the mixture at -78 Deg, and stirring was continued for 1 hr at the temperature. After the mixture was allowed to warm to room temperature, the reaction was quenched by addition of saturated aqueous ammonium chloride. The mixture was extracted with ether, and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in THF (50 mL), and the solution was added to a suspension of lithium aluminum hydride (1.1 g) in THF (50

mL) at 0 Deg, and stirring was continued for 1 hr at the temperature. The reaction was quenched by successive addition of water (1 mL), 15% aqueous sodium hydroxide (1 mL), and water (3 mL). The mixture was filtered and extracted with ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in DCM (50 mL), cooled in an ice bath, and to the mixture were added DIPEA (18.3 mL) and methanesulfonyl chloride (4.1 mL). The mixture was stirred for 1 hr. MeOH (20 mL) was added to the mixture, and the mixture was concentrated. The residue was diluted with ether, and the mixture was washed with saturated aqueous ammonium chloride and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 9 / 1 to 4 / 1) to give 2-cyclopentylbut-3-en-l-yl methanesulfonate (2.9g) as a colorless oil.

Preparation 55

To a solution of 5-methyl-2-vinylhexan-l-ol (0.5 g) and DIPEA (1.8 mL) in DCM (5 mL) was added methanesulfonyl chloride (4.1 mL) at 0 Deg. The mixture was stirred for 1 hr. To the mixture was added MeOH (4 mL). The mixture was concentrated in vacuo.

The residue was dissolved in acetone (5 mL), lithium bromide (1.5 g) was added to the solution, and the mixture was heated to reflux for 16 hrs. The mixture was diluted with ether.

The mixture was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography

(hexane only) to give 3-(bromomethyl)-6-methylhept-l-ene (352 mg) as a colorless oil.

Preparation 56

To a suspension of (3ai?,45 r ,4ai?,7i?,7ai-,8aS)-4-formyl-8a-(hydroxymethyl)-3- isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-l,4-methano- s-indacene-3a(lH)-carboxylic acid (20 g) and potassium carbonate (10.8 g) in DMF was added benzyl bromide (10.3 g) dropwise. The mixture was stirred at room temperature for 2 hrs and diluted with AcOEt. The mixture was washed with water (4 times) and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was triturated with 5% AcOEt / n-hexane, collected by filtration, washed with 5% AcOEt / n-hexane and dried to give the compound of Preparation 56 in Table 3 (13.85 g).

Preparation 57

To a solution of the compound of Preparation 56 in Table 3 (106 mg) and tert-butyldimethylchlorosilane (56.7 mg) in DMF (2 mL) were added imidazole (68.3 mg) and

4-(dimethylamino)pyridine (3 mg). The mixture was stirred at room temperature for 1 hr and diluted with AcOEt. The mixture was washed with water (3 times), saturated aqueous

ammonium chloride and brine. The organic layer was dried over magnesium sulfate and concentrated to give the compound of Preparation 57 in Table 3 (130 mg).

Preparation 58 A suspension of the compound of Preparation 57 in Table 3 (130 mg), hydroxylamine hydrochloride (168 mg) and sodium hydrogen carbonate in EtOH (2 mL) was stirred at 60 Deg for 4 hrs and diluted with AcOEt. The mixture was washed with water (3 times), saturated aqueous ammonium chloride, and brine. The organic layer was dried over magnesium sulfate and concentrated to give the compound of Preparation 58 in Table 3 (145 mg).

Preparation 59

To a solution of the compound of Preparation 58 in Table 3 (144 mg) in toluene (2 mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide (311 mg). The mixture was stirred at 80 Deg for 1 hr and diluted with AcOEt. The mixture was washed with water, saturated aqueous ammonium chloride, saturated aqueous sodium hydrogen carbonate, and brine. The organic layer was dried over magnesium sulfate and concentrated to give the compound of Preparation 59 in Table 3 (155 mg).

Preparation 60

To a solution of tetra-«-butyl ammonium fluoride in THF (1 M, 2 mL) was added the compound of Preparation 59 in Table 3 (154 mg). The mixture was stirred at 60 Deg for 1 hr and diluted with AcOEt. The mixture was washed with water (three times) and brine. The organic layer was dried over magnesium sulfate and concentrated to give the compound of Preparation 60 in Table 3 (119 mg).

Preparation 61

A suspension of the compound of Preparation 60 in Table 3 (115 mg), N-methylmorpholine N-oxide (51 mg), and molecular sieves 4A (0.5 g) in DCM (2 mL) was stirred at room temperature for 30 Min. To the mixture was added tetra-n-propylammonium perruthenate (5 mg) and the mixture was stirred at room temperature for 30 Min. The insoluble material was removed by filtration and the filtrate was concentrated. The residue was dissolved in DCM and silica gel was added. The mixture was stirred for 10 Min, then filtered. The filtrate was concentrated to give the compound of Preparation 61 in Table 3 (98 mg).

Preparation 62

Under nitrogen atmosphere, to a solution of the compound of Preparation 61 in Table 3 (418 mg) in THF (5 mL) was added a solution of 3-butenylmagnesium bromide in THF (0.5 M, 3 mL) at room temperature, and the mixture was stirred at the temperature for 2 hrs. The mixture was poured into saturated aqueous ammonium chloride, and extracted with AcOEt. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated to give the compound of Preparation 62 in Table 3 (470 mg).

Preparation 63

Under nitrogen atmosphere, to a solution of the compound of Preparation 65 in Table 3 (2.0 g) in THF (20 mL) was added a 0.5 M solution of 3-butenylmagnesium bromide in THF (13 mL) at room temperature, and the mixture was stirred at the temperature for 2.5 hrs. The mixture was poured into saturated aqueous ammonium chloride and extracted with AcOEt. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 10 / 1) to give the compound of Preparation 63 in Table 3 (1.61 g).

Preparation 64

To a solution of the compound of Preparation 56 in Table 3 (11.0 g) in MeOH (100 mL) were added ethylene glycol (58.1 mL), trimethyl orthoformate (14.2 mL), and p-toluenesulufonic acid monohydrate (248 mg). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with AcOEt. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 10 / 1) to give the compound of Preparation 64 in Table 3 (8.95 g).

Preparation 65

To a solution of oxalyl chloride (3.35 mL) in DCM (70 mL) was added dimethyl sulfoxide (5.45 mL) at -78 Deg. After the mixture was stirred for 5 Min, a solution of the compound of Preparation 64 in Table 3 (8.95 g) in DCM (20 mL) was added dropwise to the mixture and the mixture was stirred for 30 Min at -78 Deg. After Et 3 N (26.7 mL) was added to the mixture, the mixture was warmed to room temperature and stirred for addtional 1 hr.

The mixture was poured into saturated aqueous ammonium chloride and extracted with DCM.

The separated organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified with silica gel column chromatography (hexane /

AcOEt = 10 / 1) to give the compound of Preparation 65 in Table 3 (6.68 g).

Preparation 66

To a solution of the compound of Preparation 177 in Table 3 (30 mg) in DCM (1 mL) was added m-chloroperbenzoic acid, and the mixture was stirred for 2 hrs at room temperature. The mixture was poured into saturated aqueous sodium thiosulfate and sodium hydrogen carbanate, and extracted with AcOEt. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 20% AcOEt in hexane) to give the compound of Preparation 66 in Table 3 (26.0 mg).

Preparation 67

To a solution of the compound of Preparation 178 in Table 3 was added tetrabutylammonium fluoride (1 M solution in THF), and the mixture was stirred for 1 hr at 50 Deg. The mixture was poured into saturated aqueous ammonium chloride, and extracted with AcOEt. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified with preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 50% AcOEt in hexane) to give the compound of Preparation 67 in Table 3 (249.0 mg).

Preparation 68 To a solution of the compound of Preparation 67 in Table 3 (249 mg)and

N,N-diisopropylethylamine (0.361 mL) in DCM (3 mL)was added methanesulfonyl chloride (0.0385 mL) at 0 Deg, and the mixture was stirred at 0 Deg for 1 hr. The mixture was diluted with MeOH and concentrated. The residue was diluted with AcOEt, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous ammonium chloride, and brine, dried over magnesium sulfate, and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 33% AcOEt in hexane) to give the compound of Preparation 68 in Table 3 (152.5 mg).

Preparation 69 To a solution of the compound of Preparation 1 in Table 3 (150 mg) in DCM (2 mL) was added Dess-Martin periodinane (213 mg), and the mixture was stirred at room temperature for 1 hr. To the mixture was added 2-propanol, and the mixture was concentrated. The residue was diluted with ether, filtered, and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 20% AcOEt in hexane) to give the compound of Preparation 69 in Table 3 (79.0 mg).

Preparation 70

A mixture of palladium(II) chloride (14.9 mg) and copper(I) chloride (99.9 mg) in DMF (5 mL) and water (0.5 mL) was stirred for 1 hr under oxygen. To this mixture was added a solution of the compound of Preparation 69 in Table 3 (500 mg) in DMF (5 mL) and water (0.5 mL), and the mixture was stirred for 3 hrs under oxygen. The reaction mixture was diluted with AcOEt and water, and filtered through celite pad. The filtrate was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 20% AcOEt in hexane) to give the compound of Preparation 70 in Table 3 (350 mg).

Preparation 71

A mixture of the compound of Preparation 187 in Table 3 (420 mg), water (0.0268 mL), and p-toluenesulfonic acid monohydrate (141 mg) in THF (5 mL) was stirred for 5 hrs.

To the reaction mixture was added saturated aqueous sodium hydrogen carbonate. The mixture was extracted with AcOEt. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 17% AcOEt in hexane) to give the compound of Preparation 71 in Table 3 (256 mg).

Preparation 72 To a solution of the compound of Preparation 65 in Table 3 (500 mg) and

3-bromo-l-propyne (384 mg) in DMF (5 mL) and diethyl ether (5 mL) was added zinc powder (281 mg), and the mixture was stirred for 5 hrs. The reaction mixture was diluted with AcOEt and filtered. " The filtrate was washed with saturated aqueous ammonium chloride and brine, dried over magnesium sulfate, and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 20% AcOEt in hexane) to give the compound of Preparation 72 in Table 3 (230 mg).

Preparation 73

To a suspension of iodine (1.54 g) and sodium hydrogen carbonate (1.27 g) in acetonitrile (60 mL) was added a solution of the compound of Preparation 63 in Table 3 (1.58 g) in acetonitrile (30 mL), and the mixture was stirred at room temperature for 30 Min and diluted with AcOEt. The mixture was washed with saturated aqueous sodium thiosulfate, water (twice) and brine. The separated organic layer was dried over sodium sulfate and concentrated. The residue was purified with silica gel column chromatography (hexane / AcOEt = 10 / 1) to give the compound of Preparation 73 in Table 3 (1.84 g).

Preparation 74

To a suspension of iodine (108 mg) and sodium hydrogen carbonate (89.4 mg) in acetonitrile (4.0 mL) was added a solution of the compound of Preparation 170 in Table 3 (130 mg) in acetonitrile (1.0 mL). After stirred at room temperature for 30 Min, the mixture was diluted with AcOEt, washed with saturated aqueous sodium thiosulfate, water (x 2), and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 10 / 1) to give the compound of Preparation 74 in Table 3 (41.0 mg).

Preparation 75 To a mixture of the compound of Preparation 61 in Table 3 (100 mg),

3-chloro-l,2-propanediol (0.1 mL), trimethyl orthoformate (0.131 mL) was added p-toluenesulfonic acid monohydrate (2.3 mg). The mixture was stirred at room temperature overnight and diluted with AcOEt. The mixture was washed with saturated aqueous sodium hydrogen carbonate (twice), water, and brine. The organic layer was dried over magnesium sulfate and concentrated to give the compound of Preparation 75 in Table 3 (119 mg).

Preparation 76

To a solution of the compound of Preparation 75 in Table 3 (117 mg) and piperidine (1 mL) in DMF (2 mL) was added potassium iodide (190 mg). The mixture was stirred at 100 Deg for 6 hrs and diluted with AcOEt. The mixture was washed with water (x 3) and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 2 plates, 10% MeOH in DCM) to give the compound of Preparation 76 in Table 3 (17 mg).

Preparation 77

To a suspension of iodine (107 mg) and sodium hydrogen carbonate (142 mg) in acetonitrile (5 mL) was added a solution of the compound of Preparation 62 in Table 3 in acetonitrile (5 mL) and the mixture was stirred at room temperature for 30 Min and diluted with AcOEt. The mixture was washed with saturated aqueous sodium thiosulfate, water (twice) and brine. The organic layer was dried over magnesium sulfate and concentrated. To the residue were added DMF (1 mL) and piperidine (0.2 mL), and the mixture was stirred at 60 Deg for 3 hrs. The mixture was diluted with AcOEt, washed with water (x 3) and brine, dried over magnesium sulfate, and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 2 plates, DCM / MeOH / 28% aqueous ammonia = 100 / 10 / 1) to give the compound of Preparation 77 in Table 3 (38 mg).

Preparation 78

A b solution of the compound of Preparation 73 in Table 3 (100 mg) in piperidine (1.0 mL) was stirred at 60 Deg for 5 hrs. The mixture was diluted with AcOEt, washed with water (x 3) and brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 2 plates, acetone) to give the compound of Preparation 78 in Table 3 (56.0 mg).

Preparation 79

To a solution of the compound of Preparation 73 in Table 3 (100 mg) in DMF (2.0 mL) were added 4-(4-morpholinyl)piperidine (141 mg) and DIPEA (0.15 mL). After stirred at 60 Deg for 5 hrs, the mixture was diluted with AcOEt, washed with water (x 3) and brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 2 plates, DCM / MeOH = 10 / 1) to give the compound of Preparation 79 in Table 3 (63 mg).

Preparation 80

To a solution of the compound of Preparation 71 in Table 3 (50 mg) and anisole (0.057 mL) in THF was added phosphorus pentasulfide (46.6 mg), and the mixture was stirred for 1 hr. To the reaction mixture was added 1 M aqueous sodium hydroxide, and the mixture was stirred for 1 hr. The mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous ammonium chloride, aqueous sodium hydrogen carbonate, and brine, dried over magnesium sulfate, and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 33% AcOEt in hexane) to give the compound of Preparation 80 in Table 3 (30 mg).

Preparation 81

To a solution of the compound of Preparation 188 in Table 3 (100 mg) in acetonitrile (1 mL) was added gold(III) chloride (0.6% (w/v) solution in acetonitrile, 0.1 mL). The mixture was stirred for 30 Min and diluted with AcOEt. The mixture was washed with saturated aqueous ammonium chloride, saturated aqueous sodium hydrogen carbonate, and brine, dried over magnesium sulfate, and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 20% AcOEt in hexane) to give the compound of Preparation 81 in Table 3 (82 mg).

Preparation 82 Phosphoryl chloride (0.0116 mL) was added dropwise to DMF (0.2 mL) at 0 Deg, and the mixture was stirred at the temperature for 30 Min. To the mixture was added a solution of the compound of Preparation 81 in Table 3 (25 mg) in DMF (0.3 mL) at 0 Deg, and

the mixture was stirred at the temperature for 1 hr. The mixture was diluted with AcOEt, and washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 20% AcOEt in hexane) to give the compound of Preparation 82 in Table 3 (20 mg).

Preparation 83

To a solution of the compound of Preparation 82 in Table 3 (60 mg) in MeOH (1 niL) was added sodium borohydride, and the mixture was stirred for 1 hr. To the mixture was added saturated aqueous ammonium chloride. The mixture was diluted with AcOEt, washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was dissolved in DMF. To the solution was added sodium hydride, and the mixture was stirred at 60 Deg for 1 hr then cooled to room temperature. To the mixture was added methyl iodide, and the mixture was stirred for 1 hr. The mixture was poured into saturated aqueous ammonium chloride, and extracted with AcOEt. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 20% AcOEt in hexane) to give the compound of Preparation 83 in Table 3 (45 mg).

Preparation 84 To a solution of the compound of Preparation 82 in Table 3 (30 mg) in THF (1 mL) was added methylmagnesium bromide (8.1 mg), and the mixture was stirred for 1 hr. To the mixture was added saturated aqueous ammonium chloride. The mixture was diluted with AcOEt. The mixture was washed with water and brine, dried over magnesium sulfate, and concentrated. To a solution of the residue in DMF was added sodium hydride, and the mixture was stirred at 60 Deg for 1 hr and then cooled to room temperature. To the mixture was added methyl iodide, and the mixture was stirred for 1 hr. The mixture was poured into saturated aqueous ammonium chloride, and extracted with AcOEt. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 20% AcOEt in hexane) to give the compound of Preparation 84 in Table 3 (15 mg).

Preparation 85

N-ethylquinuclidin-3 -amine hydrochloride was obtained from 3-quinuclidinone hydrochloride and ethylamine by the platinum dioxide-catalyzed reductive animation.

Preparation 86

To a solution of N-ethylquinuclidin-3 -amine hydrochloride (2.00 g) in DMF (40 mL)

was added triethylamine (1.75 mL) at 55 Deg, and the mixture was allowed to cool to room temperature for 8 hrs. The mixture was extracted with chloroform / MeOH (4 / 1). The extract was washed with brine, dried over magnesium sulfate, and concentrated to give N-ethylquinuclidin-3 -amine (2.00 g).

Preparation 87

2-(Isobutylamino)ethanol was obtained from 2-methylpropanal and 2-aminoethanol by the platinum dioxide-catalyzed reductive amination.

Preparation 88

Benzyl (2-hydroxyethyl)methylcarbamate was obtained from 2-(methylamino)ethanol and benzyloxycarbonyl chloride.

Preparation 89 2-[[(Benzyloxy)carbonyl](ethyl)amino]ethyl methanesulfonate was obtained from benzyl ethyl(2-hydroxyethyl)carbamate and methanesulfonyl chloride.

Preparation 90

Benzyl [2-[(2i?*,65' :|: )-2,6-dimethylmorpholin-4-yl]ethyl]ethylcarbamate was obtained from 2-[[(benzyloxy)carbonyl](ethyl)amino]ethyl methanesulfonate and cis-2,6- dimethylmorpholine.

Preparation 91

2-[(2i?*,65'*)-2,6-Dimethylmorpholin-4-yl]-N-ethylethanam ine was obtained from benzyl [2-[(2i?*,65'*)-2,6-dimethylmorpholin-4-yl]ethyl]ethylcarbam ate by catalytic hydrogenation.

Preparation 92

2,2-Dimethyl-N-(2-piperidin-l-ylethyl)propan~l -amine was obtained from pivalaldehyde and 2-(l-piperidinyl)ethylamine by the platinum dioxide-catalyzed reductive amination.

Preparation 93

Benzyl cyclopropyl(2-piperidin-l-ylethyl)carbamate was obtained from N-(2-piperidin- 1 -ylethyl)cyclopropanamine and benzyloxycarbonyl chloride.

Preparation 94

N-methyl-2-piperidin-l-ylethanamine was obtained from benzyl methyl(2-piperidin-l-ylethyl)carbamate by catalytic hydrogenation.

Preparation 95 2-Methyl-N-[2-(l-methylpiperidin-2-yl)ethyl]propan-l-amine was obtained from

2-(2-chloroethyl)-l-methylpiperidine and isobutylamine.

Preparation 96

Benzyl isobutyl[2-(l-methylpiperidin-2-yl)ethyl]carbamate was obtained from 2-methyl-N-[2-(l-methylpiperidin-2-yl)ethyl]propan-l -amine and benzyloxycarbonyl chloride.

Preparation 97

2-Methyl-N-[2-(l-methylpiperidin-2-yl)ethyl]propan-l -amine was obtained from benzyl isobutyl[2-(l -methylpiperidin-2-yl)ethyl] carbamate by catalytic hydrogenation.

Preparation 98

A mixture of ethyl 1-piperidylacetate (5 g) and N,N-dimethylethylenediamine (4.05 g) was heated at 60 Deg under nitrogen atmosphere for 10 days. The resulting mixture was cooled to room temperature and concentrated. The residual yellow oil was diluted with AcOEt, washed with water (x 3) and brine, dried over magnesium sulfate, and concentrated. The residue was purified by amine-capped silica gel column chromatography (hexane / AcOEt = 90 / 10 to 80 / 20) to give N-[2-(dimethylamino)ethyl]-2-piperidin-l-ylacetamide (2 g).

Preparation 99

N,N-dimethyl-N'-(2-piperidin-l-ylethyl)ethane-l,2-diamine was obtained by the reduction of N-[2-(dimethylamino)ethyl]-2-piperidin-l-ylacetamide with lithium aluminum hydride.

Preparation 100

2-Piperidin-l-ylethyl methanesulfonate was obtained from 1-piperidineethanol and methanesulfonyl chloride.

Preparation 101 N-(2-piperidin-l-ylethyl)cyclopropanamine was obtained from 2-piperidin-l-ylethyl methanesulfonate and cyclopropylamine.

Preparation 102

N-(2-piperidin-l-ylethyl)butanamide was obtained from 2-(l-piperidyl)ethylamine and butanoyl chloride.

Preparation 103

N-(2-piperidin-l-ylethyl)butan-l -amine was obtained by the reduction of N-(2-piperidin-l-ylethyl)butanamide with lithium aluminum hydride.

Preparation 104 3-(Ethylamino)propan-l-ol was obtained from 3-chloropropanol and ethylamine.

Preparation 105

N-ethyl-3-piperidin-l-ylpropan-l -amine was obtained from l-(3-chloropropyl)- piperidine and ethylamine hydrochloride.

Preparation 106

Benzyl (3-hydroxypropyl)carbamate was obtained from 3-amino-l-propanol and benzyl chlorocarbonate.

Preparation 107

3-[[(Benzyloxy)carbonyl]amino]propyl methanesulfonate was obtained from benzyl (3-hydroxypropyl)carbamate and methanesulfonyl chloride.

Preparation 108 Benzyl [3 -[bis(pyridin-2-ylmethyl)amino]propyl] carbamate was obtained from

3-[[(benzyloxy)carbonyl]amino]propyl methanesulfonate and 2,2'-dipicolylamine.

Preparation 109

To a solution of benzyl [3-[bis(pyridin-2-ylmethyl)amino]propyl]carbamate (392 mg) and 2-(chloromethyl)pyridine hydrochloride (198 mg) in DMF (5.0 mL) was added sodium hydride in several portions at 0 Deg. The mixture was stirred for 3 hrs at room temperature. Aqueous sodium hydrogen carbonate was added to the mixture, and the whole was extracted with AcOEt. The extract was dried over sodium sulfate. Concentration under reduced pressure and the column chromatography gave benzyl [3-[bis(pyridin-2-ylmethyl)amino]propyl](pyridin-2-ylmethyl) carbamate (412 mg).

Preparation 110

N,N,N'-tris(pyridin-2-ylmethyl)propane- 1,3 -diamine was obtained from benzyl [3-[bis(pyridin-2-ylmethyl)amino]propyl](pyridin-2-ylmethyl) carbamate by catalytic hydrogenation.

Preparation 111

N-methyl-l-(l-methyl-lH-imidazol-4-yl)methanamine was obtained from 1 -methyl- lH-imidazole-4^carboxaldehyde and methylamine by the palladium on carbon-catalyzed reductive animation.

Preparation 112

A mixture of N,N'-dirnethyl-l,3-propanediamine (650 mg), 4,5-dihydro-lH- imidazole-2-sulfonic acid (735 mg), and DIPEA (2.6 mL) in acetonitrile (14.7 mL) was refluxed for 16 hrs. The mixture was made basic, extracted with AcOEt. Evaporation of the solvent gave N-(4,5-dihydro-lH-imidazol-2-yl)-N,N'-dimethylpropane-l,3-di amine (446 mg) as a colorless oil.

Preparation 113

To a suspension of tert-butyl [l-(4-methylpyridin-2-yl)pyrrolidin-3-yl]carbamate (200 mg) in ether (4mL) was added lithium alminum hydride (82 mg) and the mixture was refluxed for 1 hr. To the mixture was added TηF (4 mL), and the mixture was stirred at 50 Deg for 3 hrs, then cooled to room temperature. To the mixture was added sodium fluoride (363mg), then water was added dropwise, and the mixture was stirred for 30 Min. The precipitate was removed by filtration and washed with TηF. The filtrate was concentrated in vacuo to give N-methyl-l-(4-methylpyridin-2-yl)pyrrolidin-3 -amine as a pale yellow oil (134 mg).

Preparation 114

A mixture of 2-fluoropyridine (1.13g) and N,N'-dimethylethylenediamine (4.10 g) was stirred at 100 Deg for 3 hrs. The mixture was diluted with AcOEt and IM hydrochloric acid. The organic layer was separated and extracted with IM hydrochloric acid. The combined aqueous layer was adjusted to pη 10 with IM aqueous sodium hydroxide, and extracted with AcOEt. The organic layer was washed with water and brine. The separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give N,N'-dimethyl-N-pyridin-2-ylethane-l,2-diamine (1.05g) as a yellow oil.

Preparation 115

2-Piperidin-l-yl-N-(2-piperidin-l-ylethyl)ethanamine was obtained by the reduction

of 2-piperidin-l-yl-N-(2-piperidin-l-ylethyl)acetamide with lithium aluminum hydride.

Preparation 116

To a suspension of 2-fluoroethylamine hydrochloride (500 mg) in MeOH (8 mL) were added benzyloxyacetaldehyde (0.65 mL) and sodium triacetoxyborohydride (1.2 g) at room temperature. The mixture was stirred for 4 hrs then concentrated. The residue was diluted with 2.0 M aqueous sodium hydroxyde (20 mL), and to the mixture was added di-/ert-butyl dicarbonate (2.02 g). After 5 hrs stirring, water was added to the mixture, and the mixture was extracted with AcOEt (x 3). The combined organic layer was washed with water and brine, dried over magnesium sulfate, then concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 95/5 to 70/30) to give tert-butyl

[2-(benzyloxy)ethyl](2-fluoroethyl)carbamate (387.4 mg).

Preparation 117 tert-Butyl (2-fluoroethyl)(2-hydroxyethyl)carbamate was obtained from tert-butyl

[2-(benzyloxy)ethyl](2-fluoroethyl)carbamate by catalytic hydrogenation.

Preparation 118

2-[(tert-Butoxycarbonyl)(2-fluoroethyl)amino]ethyl methanesulfonate was obtained from tert-butyl (2-fluoroethyl)(2-hydroxyethyl)carbamate and methanesulfonyl chloride.

Preparation 119 tert-Butyl (2-fluoroethyl)(2-piperidin-l-ylethyl)carbamate was obtained from 2-[(tert-butoxycarbonyl)(2-fluoroethyl)arnino]ethyl methanesulfonate and piperidine.

Preparation 120 tert-Butyl ethyl[2-(4-methylpiperazin-l-yl)-2-oxoethyl]carbamate was obtained from N-(tert-butoxycarbonyl)-N-ethylglycine and N-methylpiperazine.

Preparation 121 l-(2-Piρeridin-4-ylethyl)piperidine dihydrochloride was obtained by the treatment of tert-butyl 4-(2-piperidin-l-ylethyl)piperidine-l-carboxylate with hydrogen chloride in AcOEt.

Preparation 122 To a solution of benzyl ethyl(2-hydroxyethyl)carbamate (500 mg) and pyridine (0.362 mL) in DCM (5 mL) was added 4-nitrophenyl chloroformate (497 mg) at 5 Deg. After stirring at 5 Deg for 10 Min, the mixture was warmed to room temperature and stirred for 4

hrs. To the mixture was added piperidine (0.244 mL), and the whole was stirred for 14 hrs. An additional portion of piperidine (0.244 mL) was added and the mixture was stirred for 5 hrs. The mixture was concentrated in vacuo and the residue was diluted with AcOEt (20 mL). The solution was washed with IM aqueous sodium hydroxide (10 mL x 5) and brine (10 mL), and dried over magnesium sulfate. Filtration followed by evaporation gave an orange paste (752 mg) which was chromatographed on silca gel (hexane / AcOEt) to give 2-[[(benzyloxy)carbonyl](ethyl)amino]ethyl piperidine- 1-carboxylate (618 mg) as a colorless oil.

Preparation 123

2-(Ethylamino)ethyl piperidine- 1-carboxylate was obtained from 2-[[(benzyloxy)carbonyl](ethyl)amino]ethyl piperidine- 1-carboxylate by catalytic hydrogenation.

Preparation 124

Benzyl 4-[2-[(methylsulfonyl)oxy]ethyl]piperazine- 1-carboxylate was obtained from benzyl 4-(2-hydroxyethyi)piperazine- 1-carboxylate and methanesulfonyl chloride.

Preparation 125 Benzyl 4-[2-(4-tert-butylpiperidin-l-yl)ethyl]piρerazine-l-carboxy late was obtained from benzyl 4-[2-[(methylsulfonyl)oxy]ethyl]piperazine-l-carbόxylate and

4-ter/-butylpiperidine.

Preparation 126 3 -Methyl- 1-octylpiperazine was obtained from benzyl 2-methyl-4-octylpiperazine-

1-carboxylate by catalytic hydrogenation.

Preparation 127

Benzyl 2-methyl-4-octylpiperazine- 1-carboxylate was obtained from benzyl 2-methylpiperazine- 1-carboxylate and 1-bromooctane.

Preparation 128

To a solution of 4-methoxypiperidine hydrochloride QSl.1 mg) in a MeOH - THF mixed solvent (1/2, 6 mL) were added benzyl 4-oxo-l-piperazinecarboxylate (549.6 mg) and acetic acid (0.1 mL) at room temperature. The mixture was warmed to 45 Deg for 30 Min.

To the mixture was slowly added sodium triacetoxyborohydride (1.65 g) for 4.5 hrs. After 2 hrs stirring, the reaction was quenched by addition of l.OM aqueous sodium hydroxyde (the

pH was adjusted to 9), then extracted with AcOEt (x 3). The combined organic layer was washed with water and brine, dried over magnesium sulfate, then concentrated. The residual dark red oil was purified by amine-capped silica gel column chromatography (hexane / AcOEt = 90/10 to 80/20) to give benzyl 4-methoxy-l,4'-biρiperidine-l'-carboxylate (137 mg).

Preparation 129

4-Methoxy-l,4'-bipiperidine was obtained from benzyl 4-methoxy-l,4'-bipiperidine- l'-carboxylate by catalytic hydrogenation.

Preparation 130

Benzyl 3-(hydroxymethyl)piperidine-l-carboxylate was obtained from piperidin-3-ylmethanol and benzyl chlorocarbonate.

Preparation 131 Benzyl 3-[[(methylsulfonyl)oxy]methyl]piperidine-l-carboxylate was obtained from benzyl 3-(hydroxymethyl)piperidine-l-carboxylate and methanesulfonyl chloride.

Preparation 132 tert-Butyl 4-(2-piperidin-l-ylethyl)piperidine-l-carboxylate was obtained from tβrt-butyl 4-[2-[(methylsulfonyl)oxy]ethyl]piperidine-l-caxboxylate and piperidine.

Preparation 133 l-(Piperidin-4-ylmethyl)piperidine was obtained from benzyl

4-(piperidin-l-ylmethyl)piperidine-l-carboxylate by catalytic hydrogenation.

Preparation 134

Benzyl 2-(piperidin-l-ylcarbonyl)piperidine-l-carboxylate was obtained from l-(benzyloxycarbonyl)piperidine-2-carboxylic acid and piperidine.

Preparation 135 l-(Piperidin-2-ylcarbonyl)piperidine was obtained from benzyl 2-(piperidin- l-ylcarbonyl)piperidine-l-carboxylate by catalytic hydrogenation.

Preparation 136 l-(Piperidin-2-ylmethyl)piperidine was obtained by the reduction of

1 -(piperidin-2-ylcarbonyl)piperidine with lithium aluminum hydride.

Preparation 137

1 '-Benzyl- 1, 3 '-bipiperidine was obtained from l-benzylpiperidin-3-one hydrochloride and piperidine by the reductive animation using sodium triacetoxyborohydride.

Preparation 138

1,3 '-Bipiperidine was obtained from l'-benzyl- 1,3 '-bipiperidine by catalytic hydrogenation.

Preparation 139 (3i?)-l-Benzylpyrrolidin-3-yl methanesulfonate was obtained from

(3i?)-l-benzylpyrrolidin-3-ol and methanesulfonyl chloride.

Preparation 140 l-[(3S)-l-benzylpyrrolidin-3-yl]piperidine was obtained from (3i?)-l- benzylpyrrolidin-3 -yl methanesulfonate and piperidine .

Preparation 141 l-[(3iS)-Pyrrolidin-3-yl]piperidine was obtained from (3i?)-l-benzylpyrrolidin-3-yl methanesulfonate by catalytic hydrogenation.

Preparation 142

Benzyl (25)-2-(hydroxymethyl)piperidine-l-carboxylate was obtained by the reduction of (25)-l-[(benzyloxy)carbonyl]piperidine-2-carboxylic acid with borane - THF complex.

Preparation 143 v

To a solution of benzyl (2i?)-2-(hydroxymethyl)piperidine-l-carboxylate (500 mg) and pyridine (0.324 mL) in DCM (5 mL) was added 4-nitrophenyl chloroformate (445 mg) at

5 Deg. After stirring at 5 Deg for 10 Min, the mixture was warmed to room temperature and stirred for 1.5 hrs. To the mixture was added N-methylpiperazine (0.486 mL), and the whole was stirred overnight. The mixture was concentrated in vacuo and the residue was diluted with AcOEt (20 mL). The solution was washed with IM aqueous sodium hydroxide (10 mL x 5) and brine (10 mL), and dried over magnesium sulfate. Filtration followed by evaporation gave an oil (781 mg) which was chromatographed on silca gel (hexane / AcOEt, then chloroform / MeOH) to give [(2i?)-l-[(benzyloxy)carbonyl]piperidin-2-yl]methyl

4-methylpiperazine-l-carboxylate (808 mg) as a pale yellow oil.

Preparation 144

Piperidin-4-yl 4-methylpiperazine-l-carboxylate was obtained from l-[(benzyloxy)carbonyl]piperidin-4-yl 4-methylpiperazine-l-carboxylate by catalytic hydrogenation.

Preparation 145

A mixture of cerium trichloride (10 g) in THF (81 mL) was stirred at 0 Deg for 30 Min and stirred at room temperature for 20 hrs. To the solution was added isobutylmagnesium bromide (2.0M solution in diethyl ether)(20.35 mL) at 0 Deg. After 3 hrs, to the solution was added dropwise with stirring tert-butyl 4-oxo-l-piperidinecarboxylate (5.4 g) in THF at 0 Deg. The solution was stirred at 0 Deg for 1 hr. The reaction was quenched with 20% aqueous acetic acid. AcOEt was added to the solution. The organic layer was washed with brine, aqueous sodium hydrogen carbonate, and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / AcOEt) to give tert-butyl 4-hydroxy- 4-isobutylpiperidine-l-carboxylate (6.457 g).

Preparation 146

To a solution of tert-butyl 4-hydroxy-4-isobutylpiperidine-l-carboxylate (11.07 g) in DMF (65 mL) was added sodium hydride (60% dispersion in mineral oil)(1.5g). The solution was stirred at 60 Deg for 1.5 hrs. To the reaction mixture was added iodomethane (4.68 mL). The mixture was stirred for 4 hrs at room temperature. The reaction mixture was added to a mixture of water and AcOEt. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / AcOEt) to give tert-butyl 4-isobutyl- 4-methoxypiperidine-l-carboxylate (5.893 g).

Preparation 147

4-Isobutyl-4-methoxypiperidine trifluoroacetate was obtained by the treatment of tert-butyl 4-isobutyl-4-methoxypiperidine- 1 -carboxylate with trifluoroacetic acid.

Preparation 148

Benzyl 4-[(2i?*,65'*)-2,6-dimethylmorpholin-4-yl]piperidine-l -carboxylate was obtained from benzyl 4-oxopiperidine-l -carboxylate and cis-2,6- dimethylmorpholine by the reductive animation using sodium cyanoborohydride.

Preparation 149

A mixture of phenyl 2'-butyl-l,4'-bipiperidine-r-carboxylate (240 mg) and lithium hydroxide (58.5 mg) in ethylene glycol (2.4 mL) was stirred at 140 Deg for 8 hrs. After cooling to ambient temperature, the reaction mixture was poured into 1.0 M hydrochloric acid and AcOEt. The layers were separated, and to the aqueous layer were added 1.0 M aqueous sodium hydroxide and diethyl ether. The layers were separated, and the organic layer was dried over magnesium sulfate. Evaporation of the solvent gave 2'-butyl-l,4'-bipiperidine (76.8 mg).

Preparation 150 To 4-isobutyl-4-methoxypiperidine trifluoroacetate (500 mg) were added 1.0 M hydrochloric acid and AcOEt. The layers were separated, and to the aqueous layer were added 1.0 M aqueous sodium hydroxide and diethyl ether. The layers were separated, and the organic layer was dried over magnesium sulfate. Evaporation of the solvent gave 4-isobutyl-4-methoxypiperidine (83.6 mg).

Preparation 151

To a solution of magnesium (2.0 g) in THF (40 mL) was added dropwise 3-bromopropoxy(tert-butyl)(dimethyl)silane (18.6 mL) in THF (20 ml). The mixture was stirred at room temperature for 4 hrs and l-tgrt-butoxycarbonyl-4-piperidone (8.0 g) in THF (20 mL) was added dropwise to the mixture. The mixture was stirred at 50 Deg for 2 hrs and the reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with AcOEt, and evaporation of the solvent gave tert-butyl 4-[3-[[tert-butyl(dimethyl)silyl]oxy]propyl]-4-hydroxypiperi dine-l-carboxylate (17.2 g).

Preparation 152 tert-Butyl 4-hydroxy-4-(3-hydroxypropyl)piperidine-l-carboxylate was obtained by the treatment of tert-butyl 4-[3-[[tert~butyl(dimemyl)silyl]oxy]propyl]-4-hydroxypiperid ine- 1-carboxylate with tetrabutylammonium fluoride.

Preparation 153

To a solution of tert-butyl 4-hydroxy-4-(3-hydroxypropyl)piperidine-l-carboxylate (1.37 g) in DCM (15 mL) were added DIPEA (2.0 mL) and methanesulfonyl chloride (0.45 mL). The mixture was stirred at room temperature overnight and diluted with water. The mixture was extracted with DCM. The organic layer was dried over sodium sulfate and concentrated to give tert-butyl 4-hydroxy-4-[3-[(methylsulfonyl)oxy]propyi]piperidine- 1-carboxylate (1.47 g).

Preparation 154

To a solution of tert-butyl 4-hydroxy-4-[3-[(methylsulfonyl)oxy]propyl]piperidine~ 1-carboxylate (1.37 g) in DMF (10 ml) was added sodium hydride (60% dispersion in mineral oil; 220 mg) in several portions. After the mixture was stirred at room temperature for 1 hr, the mixture was diluted with water and extracted with AcOEt. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 10 / 1) to give tert-butyl l-oxa-8-azaspiro[4.5]decane- 8-carboxylate (866 mg).

Preparation 155 l-Oxa-8-azaspiro[4.5]decane was obtained by the treatment of tert-butyl l-oxa-8-azaspiro[4.5]decane-8-carboxylate with hydrogen chloride in AcOEt.

Preparation 156 To a solution of tert-butyl 4-ethyl-4-hydroxypiperidine-l-carboxylate (2.0 g) in DMF

(20 mL) was added sodium hydride (419 mg). The mixture was stirred at room temperature for 30 Min, and methyl iodide (1.63 mL) was added dropwise to the mixture at 0 Deg. After the mixture was stirred at 50 Deg for 3 hrs, the mixture was diluted with water and extracted with AcOEt. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 10 / 1) to give tert-butyl 4-ethyl-4-methoxypiperidine-l-carboxylate (680 mg).

Preparation 157

Benzyl 4-morpholin-4-ylpiperidine-l-carboxylate was obtained from benzyl 4-oxopiperidine-l-carboxylate and morpholine by the reductive animation using titanium tetraisopropoxide.

Preparation 158

4-Piperidin-4-ylmorpholine was obtained from benzyl 4-morpholin-4-ylpiperidine- 1-carboxylate by catalytic hydrogenation.

Preparation 159

Benzyl 2-(chloromethyl)-l ,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate was obtained from benzyl 4-oxopiperidine-l-carboxylate and 3-chloro-l,2-propanediol.

Preparation 160

Benzyl 2-(piperidin-l-ylmethyl)-l ,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate was

obtained from benzyl 2-(chloromethyl)-l,4-dioxa-8-azaspiro[4.5]decane-8-carboxyla te and piperidine.

Preparation 161 Benzyl 3-[(methylsulfonyl)amino]piperidine-l-carboxylate was obtained from benzyl

3-aminopiperidine-l-carboxylate trifluoroacetate and methanesulfonyl chloride.

Example 1

The mixture of the compound of Preparation 7 in Table 3 (52 mg) and piperidine (0.065 mL) in EtOH (1.5 mL) was stirred for 12 hrs at 90 Deg. After concentration of the reaction mixture, the residue was chromatographed on silica gel (10-16% EtOH in DCM (+0.2% Et 3 N)). The desired fractions were concentrated and the residue was treated with anisole (0.5 mL) and TFA (0.5 mL) in DCM (5 mL) overnight. Concentration of the reaction mixture followed by silica gel chromatography (5-20% EtOH in DCM (+0.2% Et 3 N)) gave the compound of Example 1 in Table 5 (22.5 mg) in 63.5% yield.

Example 2

To a solution of the compound of Preparation 8 in Table 3 (60 mg) in DCM (5 mL) were added anisole (0.5 mL) and TFA (0.5 mL). The reaction mixture was stirred at room temperature for 1 hr, then concentrated in vacuo. The residue was chromatographed on silica gel (40-64% EtOAc in hexane) to give 27.5 mg of the compound of Example 2 in Table 5.

Example 3

To a solution of the compound of Preparation 428 in Table 3 (50 mg) in DMF (0.5mL) was added 3-hydroxypiperidine (67.1mg) and the mixture was stirred at 60 Deg for 3 hrs. The mixture was diluted to 3 mL with MeOH and purified by HPLC (Cl 8, 20-100% acetonitrile in water (+0.2% formic acid)). The desired fraction was concentrated, diluted with AcOEt, washed with saturated sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated to give the compound of Example 3 in Table 5 (13 mg).

Example 4 To a solution of the compound of Example 322 in Table 5 (7.5 mg) in THF (0.2 mL) and EtOH (0.1 mL) was added IM aqueous sodium hydroxide (0.1 mL). The mixture was stirred at room temperature for 2 hrs. The mixture was diluted with MeOH (2.6 mL) and purified by HPLC (Cl 8, 20-100% acetonitrile in water (+0.2% formic acid)). The desired fraction was concentrated and diluted with AcOEt, washed with saturated sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated to give the compound of Example 4 in Table 5 (7.0 mg).

Example 5

To an ice-cooled solution of the compound of Example 276 in Table 5 (15 mg) in EtOH (0.15 mL) was added sodium borohydride (1.33 mg). The mixture was stirred at the temperature for 1 hr, then at room temperature for 3 hrs. The mixture was diluted with

EtOAc and poured into water. The organic phase was separated and the aqueous layer was

extracted with AcOEt. The combined extract was washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated. The residue was purified by HPLC (C18, 20-100% acetonitrile in water (+0.2% formic acid)), to give the compound of Example 5 in Table 5 (11 mg).

Example 6

To a solution of the compound of Example 68 in Table 5 (10.0 mg) and 2-methyl-2-butene (0.02 mL) in 2-methyl-2-propanol (0.4 niL) and THF (0.2 mL) was added aqueous sodium dihydrogenphosphate dihydrate (0.2 mL) at room temperature. To the mixture was added sodium chlorite (8.2 mg). The mixture was stirred at room temperature for 2 hrs. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 10% MeOH in DCM) gave the compound of Example 6 in Table 5 (3.8 mg).

Example 7

To an ice-cooled solution of the compound of Example 193 in Table 5 (28 mg) in THF (0.3 mL) was added methyllithium (IM solution in diethyl ether, 0.1 mL), and the mixture was stirred at the temperature for 0.5 hrs. To the mixture was added saturated aqueous ammonium chloride with ice-cooling. The mixture was extracted with AcOEt, the organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by HPLC (Cl 8, 20-100% acetonitrile in water (+0.2% formic acid)). The desired fraction was concentrated, diluted with AcOEt, washed with saturated aqueous odium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated to give the compound of Example 7 in Table 5 (5.2 mg).

Example 8

To a solution of the compound of Example 7 in Table 5 (30 mg) in DCM (0.3 mL) was added Dess-Martin periodinane (57 mg) at room temperature, and the mixture was stirred for 1 hr at the temperature. After the mixture was filtered, the filtrate was diluted with AcOEt, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by HPLC (C 18, 20-100% acetonitrile in water (+0.2% formic acid)). The desired fraction was concentrated, and the residue was diluted with AcOEt. The solution was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated to give the compound of Example 8 in Table 5 (7.6 mg).

Example 9

An EtOH (0.5 mL) solution of the compound of Example 513 in Table 5 (15 mg) was hydrogenated over 10% palladium on carbon (10 mg) at room temperature for 3 hrs. The mixture was filtered, and the filtrate was concentrated to give the compound of Example 9 in Table 5 (7 mg).

Example 10

To a solution of the compound of Preparation 428 in Table 3 (50 mg) in DMF (0.5mL) was added N-butyl-beta-alanine benzyl ester (114.8mg), and the mixture was stirred at 60 Deg overnight. The mixture was diluted to 3mL with MeOH and purified by HPLC (C 18, 20-100% acetonitrile in water (+0.2% formic acid)). The desired fraction was concentrated, and the residue was redissolved with AcOEt. The solution was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated. The residue was dissolved in MeOH (0.5mL) and hydrogenated over 10% palladium on carbon (10 mg) at room temperature for 6 hrs. The solution was filtered, and the filtrate was concentrated to give the compound of Example 10 in Table 5 (8 mg).

Example 11 To a solution of the compound of Example 501 in Table 5 (10 mg) in MeOH (1 mL) was added palladium hydroxide on carbon (0.25 mg). The mixture was stirred under hydrogen atmosphere at room temperature for 5 hrs, filtered, and concentrated in vacuo. The residue was purified by HPLC (C 18, 20-100% acetonitrile in water (+0.2% formic acid)). The desired fraction was concentrated, and the residue was redissolved with AcOEt. The solution was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated to give the compound of Example 11 in Table 5 (10 mg).

Example 12

To a solution of the compound of Preparation 429 in Table 3 (50 mg) in DMF (0.5 mL) was added N-methyl-3-morpholinopropylamine (70 mg), and the mixture was stirred at 60 Deg for 3hrs. The mixture was diluted to 3 mL with MeOH and purified by HPLC (C 18, 20-100% acetonitrile in water (+0.2% formic acid)). The desired fraction was concentrated, and the residue was diluted with AcOEt, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate and concentrated to give the compound of Example 12 in Table 5 (19 mg).

Example 13

To a solution of the compound of Preparation 244 in Table 3 (50 mg) in MeOH (3 niL) and AcOEt (1 mL) was added palladium hydroxide on carbon (5 mg). The mixture was stirred under hydrogen atmosphere at room temperature for 10 hrs, filtered, and concentrated in vacuo. The residue was purified by TLC (silica gel, 10% AcOEt in hexane). The desired fraction was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated to give the compound of Example 13 in Table 5 (18.1 mg).

Example 14

To a solution of the compound of Preparation 28 in Table 3 (20 mg) in DCM (0.6 mL) were added anisole (0.06 mL), TFA (0.07 mL), and water (0.005 mL) at room temperature. After 2 hrs, the reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate. The mixture was extracted with AcOEt three times. The combined extract was washed with water and brine, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel (5-30% MeOH in chloroform) to give the compound of Example 14 in Table 5 (6.2 mg).

Example 15

To a solution of the compound of Example 563 in Table 5 (13.8 mg) in a mixed solvent (THF / EtOH / water = 14 / 7 / 3, 0.4 mL) was added 1.0 M aqueous sodium hydroxide (0.1 mL) at room temperature. The mixture was stirred for 24 hrs, then concentrated. The residue was neutralized by 1.0 M hydrochloric acid (0.1 mL), then concentrated. To the residue was added DCM (2 mL) and insoluble matter was filtered off. The filtrate was concentrated to give the compound of Example 15 in Table 5 (11.9 mg).

Example 16

An EtOH (5 mL) solution of the compound of Example 563 in Table 5 (28.1 mg) was hydrogenated over 10% palladium on carbon (20 mg) at room temperature for 2 hrs. The mixture was filtered, and the filtrate was concentrated to give the compound of Example 16 in Table 5 (24.4 mg).

Example 17

To a solution of the compound of Example 16 in Table 5 (15.4 mg) in a mixed solvent (THF / EtOH / water = 14 / 7 / 3, 0.4 mL) was added 1.0 M aqueous sodium hydroxide (0.1 mL) at room temperature. The mixture was stirred for 24 hrs, then concentrated. The residue was redissolved with THF, neutralized by 1.0 M hydrochloric acid (0.1 mL), then the mixture was concentrated. To the residue was added DCM (2 mL) and insoluble matter was filtered off. The filtrate was concentrated to give the compound of Example 17 in Table 5

(13.8 mg).

Example 18

A solution of the compound of Example 809 in Table 5 (65.0 mg), 1-cyclohexylpiperazine (86.3 mg), and DIPEA (0.0179 mL) in DMF (0.65 mL) was stirred at room temperature for 12 hrs. The mixture was diluted to 3 mL with MeOH and purified by

HPLC (Cl 8, 20-100% acetonitrile in water (+0.2% formic acid)). The desired fraction was concentrated and diluted with AcOEt. The solution was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated to give the compound of Example 18 in Table 6 (18.8 mg).

Example 19

To a mixture of the compound of Example 622 in Table 5 (10 mg), EtOH (0.086 mL), and THF (0.129 mL) was added 5M aqueous potassium hydroxide (0.0037 mL), and the mixture was stirred at room temperature for 2 hrs. The mixture was neutralized by 1.0 M hydrochloric acid and extracted with AcOEt. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give the compound of Example 19 in Table 5 (4 mg).

Example 20

To an ice-cooled solution of the compound of Example 616 in Table 5 (200 mg) in 1,2-dichloroethane (2.0 mL) were added DIPEA (0.183 mL) and methanesulfonyl chloride (0.0598 mL), and the mixture was stirred at room temperature for 4 hrs. Water was added to the mixture, and the mixture was extracted with AcOEt. The extract was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified with silica gel column chromatography to give the compound of Example 20 in Table 5 (121 mg).

Example 21

A solution of the compound of Example 810 in Table 5 (40 mg), piperidine (0.02 mL), and DIPEA (0.07 mL) in N-methylmorpholine (0.4 mL) was stirred at room temperature for 1 hr, then stirred at 50 Deg for 1 hr. The mixture was diluted with MeOH (3 mL) and purified by HPLC (Cl 8, 20-100% acetonitrile in water (+0.2% formic acid)). The desired fraction was concentrated and diluted with AcOEt. The solution was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give the compound of Example 21 in Table 5 (29 mg).

Example 22

To a solution of the compound of Preparation 345 in Table 3 (101.3 mg) in a mixed solvent (MeOH / THF = 1 / 1, 2 mL) was added 10% palladium on carbon (20 mg, wet) at room temperature. The mixture was stirred under hydrogen atmosphere for 3 hrs. The mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel (0-20% acetone in hexane) to give the compound of Example 22 in Table 5 (32.9 mg).

Example 23

To a solution of the compound of Preparation 20 in Table 3 (38.0 mg) in DCM (0.2 mL) was added 4-piperidinopiperidine (50 mg) at room temperature. The mixture was stirred at the temperature for 12 hrs and diluted with AcOEt. The solution was washed with 1.0 M aqueous sodium hydroxide, water, and brine, dried over sodium sulfate, then concentrated. The residue was purified by HPLC (Cl 8, 20-100% acetonitrile in water (+0.2% formic acid)). The desired fraction was concentrated. The residue was diluted with saturated aqueous sodium hydrogen carbonate and extracted with AcOEt three times. The combined organic layer was washed with 1.0 M aqueous sodium hydroxide and brine, dried over sodium sulfate, and concentrated to give the compound of Example 23 in Table 5 (19.1 mg).

Example 24

To a solution of the compound of Example 761 in Table 5 (30.5 mg) in DCM (1 mL) were added 4-nitrophenyl chloroformate (23.7 mg), pyridine (0.01 mL), and DIPEA (0.02 mL) at room temperature. After 2 hrs, l-[2-(l-piperidinyl)ethyl]piperazine (54.1 mg) was added to the solution and the mixture was stirred for 2 hrs. The mixture was concentrated and the residue was dissolved in AcOEt. The solution was washed with 1.0 M aqueous sodium hydroxide four times and brine, dried over sodium sulfate, then concentrated. The residue was purified by HPLC (C18, 20-100% acetonitrile in water (+0.2% formic acid)). The desired fraction was concentrated. The residue was diluted with saturated aqueous sodium hydrogen carbonate and extracted with AcOEt three times. The combined organic layer was washed with 1.0 M aqueous sodium hydroxide and brine, dried over sodium sulfate, and concentrated to give the compound of Example 24 in Table 6 (17.8 mg).

Example 25

To a solution of the compound of Preparation 395 in Table 3 (16.9 mg) and water (0.005 mL) in MeOH (2 mL) was added 10% palladium on carbon (25 mg) at room temperature, and the mixture was stirred under hydrogen atmosphere for 2 hrs. The mixture was filtered and the filtrate was concentrated. The residue was purified by gel permeation

chromatography (Japan Analytical Industry Co., LTD., JAIGEL-IH and JAIGEL-2H, eluted by chloroform) to give the compound of Example 25 in Table 5 (9.8 mg).

Example 26 To a solution of the compound of Preparation 70 in Table 3 (150 mg) and anisole (0.1 mL) and THF (2 mL) was added phosphorus pentasulfide (109 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added IM aqueous sodium hydroxide, and the mixture was stirred for 1 hr and extracted with AcOEt. The organic layer was washed with saturated aqueous ammonium chloride, saturated aqueous sodium hydrogen carbonate, and brine, dried over magnesium sulfate, and concentrated. The residue was purified with preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 33% EtOAc in hexane) to give the compound of Example 26 in Table 5 (8.9 mg).

Example 27 To a solution of the compound of Preparation 66 in Table 3 (60 mg) in DMF (1 mL) was added sodium hydride (8 mg), and the mixture was stirred at 60 Deg for 1 hr. The mixture was poured into saturated aqueous ammonium chloride, and extracted with AcOEt. The organic layer was washed with brine, dried over magnesium sulfate, concentrated, and the residue was redissolved in DMF (1 mL). To the solution was added sodium hydride (8 mg), and the mixture was stirred at 60 Deg for 1 hr and cooled to room temperature. To the mixture was added 1-bromopentane (0.06 mL), and the mixture was stirred at 60 Deg for 1 hr. The mixture was poured into saturated aqueous ammonium chloride, and extracted with AcOEt. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was dissolved in a mixed solvent (anisole / DCM = 54 mg / 1 mL, 1 mL), and to the solution was added 10% TFA in DCM (1 mL) at 0 Deg, and the mixture was stirred at the temperature for 30 Min. To the mixture was added toluene, and the solvent was evaporated. The residue was purified with preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 20% AcOEt in hexane) to give the compound of Example 27 in Table 5 (0.9 mg).

Example 28

To a solution of the compound of Example 36 in Table 5 (10.0 mg) in MeOH (0.2 mL) and acetonitrile (0.2 mL) was added a solution of (trimethylsilyl)diazomethane in diethyl ether (2.0 M, 0.002 mL) at room temperature. The mixture was stirred at the temperature for 1 hr. To the mixture was added acetic acid and the mixture was stirred at room temperature for 10 Min. Evaporation of the solvent followed by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 10% MeOH in DCM) gave the compound of Example 28 in Table 5 (1.0 mg).

Example 29

A mixture of the compound of Preparation 80 in Table 3 (30 mg) and N-methylenepiperidinium chloride (13 mg) in acetonitrile (1 mL) was stirred at 70 Deg for 2 hrs. The reaction mixture was cooled to room temperature, and diluted with AcOEt. The mixture was washed with brine, dried over magnesium sulfate, and concentrated. The residue was dissolved in MeOH (1 mL), and hydrogenated over 10% palladium on carbon (50% wet, 3 mg) at room temperature for 1 hr. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 10% MeOH in DCM) to give the compound of Example 29 in Table 5 (4.5 mg).

Example 30

A mixture of the compound of Preparation 81 in Table 3 (20 mg) and N,N-dimethylmethyleneammonium chloride (14.7 mg) in acetonitrile (1 mL) was stirred at 70 Deg for 2 hrs. The reaction mixture was allowed to cool to room temperature, and diluted with AcOEt. The mixture was washed with brine, dried over magnesium sulfate, concentrated, and the residue was redissolved in THF(I mL). To the solution were added a small amount of water and p-toluenesulfonic acid monohydrate, and the mixture was stirred at room temperature for 2 hrs. To the mixture was added saturated aqueous sodium hydrogen carbonate. The mixture was extracted with AcOEt. The separated organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was dissolved in MeOH (1 mL), and hydrogenated over 10% palladium on carbon (50% wet, 3 mg) for 1 hr. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 10% MeOH in DCM) to give the compound of Example 30 in Table 5 (2.4 mg).

Example 31

To a solution of the compound of Preparation 68 in Table 3 (50 mg) in DMF (1 mL) was added sodium hydride (4.4 mg), and the mixture was stirred at 60 Deg for 1 hr. The mixture was poured into saturated aqueous ammonium chloride, and extracted with AcOEt. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was dissolved in a mixed solvent (anisole / DCM = 1 / 25, 1 mL), and to the solution was added 10% TFA in OCM (1 mL) at 0 Deg, and the mixture was stirred at the temperature for 30 Min. The mixture was diluted with toluene and the solvent was evaporated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 10% MeOH in DCM) to give the compound of Example 31 in Table 5 (14.0 mg).

Example 32

A mixture of the compound of Preparation 81 in Table 3 (35 mg), THF (1 mL), water (0.1 mL), and p-toluenesulfonic acid monohydrate (1.3 mg) was stirred at room temperature for 2 hrs. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate. The mixture was extracted with AcOEt. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was dissolved in MeOH (1 mL), and hydrogenated over 10% palladium on carbon (50% wet, 3 mg) at room temperature for 1 hr. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 10% MeOH in DCM) to give the compound of Example 32 in Table 5 (4.5 mg).

Example 33

To a solution of the compound of Preparation 77 in Table 3 (37 mg) in MeOH (1 mL) was added 10% palladium on carbon (50% wet, 50 mg), and the mixture was stirred under hydrogen atmosphere for 1 hr. The mixture was filtered and the filtrate was concentrated to give the compound of Example 33 in Table 5 (28 mg).

Example 34

To a solution of the compound of Preparation 78 in Table 3 (50 mg) in MeOH (1.0 mL) and THF (1.0 mL) was added 10% palladium on carbon (50% wet, 50 mg), and the mixture was stirred under hydrogen atmosphere for 3 hrs. The mixture was filtered and the filtrate was concentrated. The residue was diluted to 3 mL with MeOH and purified by HPLC (Cl 8, 0.05% TFA in water : 0.05% TFA in acetonitrile, 20% - 100%). The desired fraction was concentrated. The residue was diluted with AcOEt, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated to give the compound of Example 34 in Table 5 (14 mg).

Example 35

To a solution of the compound of Preparation 79 in Table 3 (60 mg) in MeOH (1.0 mL) and THF (1.0 mL) was added 10% palladium on carbon- (50% wet, 20 mg), and the mixture was stirred under hydrogen atmosphere for 2 hrs. The mixture was filtered and the filtrate was concentrated. The residue was diluted to 3 mL with MeOH and purified by HPLC (C 18, 0.05% TFA in water : 0.05% TFA in acetonitrile, 20% - 100%). The desired fraction was concentrated. The residue was diluted with AcOEt, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated to give the compound of Example 35 in Table 5 (26.0 mg).

In the same manner as in the methods of Preparation 1-161, the Preparation compounds 162-456 shown in the following tables were produced using respectively corresponding materials. The structures and production methods thereof are shown in Table 3, production methods and physicochemical data thereof in Table 4. Also, in the same manner as in the methods of Example 1-35, the Example compounds 36-898 shown in the following tables were produced using respectively corresponding materials. Structures of respective Example compounds are shown in Table 5 and 6, production methods and physicochemical data thereof in Table 7.

In addition, the following abbreviations are used in the following tables. PEx: Preparation; Ex: Example; PSyn: production method of the Preparation compounds, which corresponds to Preparation 1-161; Syn: production method of Example compounds, which corresponds to Example 1-35; Str: structure; DATA: physicochemical data; EI: m/z value of EI-MS ((M) + unless otherwise noted); APCI+: m/z value of APCI-MS (cation) ((M+H) + unless otherwise noted); APCI-: m/z value of APCI-MS (anion) ((M-H) " unless otherwise noted); ESI+: m/z value of ESI-MS (cation) ((M+H) + unless otherwise noted); ESI-: m/z value of ESI-MS (anion) ((M-H) " unless otherwise noted); FAB+: m/z value of FAB-MS (cation) ((M+H) + unless otherwise noted); FAB-: m/z value of FAB-MS (anion) ((M-H) " unless otherwise noted); NMRl: δ (ppm) of 1 H NMR in CDCl 3 ; NMR2: δ (ppm) of 1 H NMR in DMSOd 6 ; NMR3: δ (ppm) of 1 H NMR in D 2 O; s: singlet (spectral); d: doublet (spectral); t: triplet (spectral); q: quartet (spectral); m: multiplet (spectral); br: broad (spectral) (e.g. br-s). Also, the HCl in the structural formula represents hydrochloride, and the number before HCl represents molar ratio (e.g. 2HCl represents dihydrochloride).