TW201247215A - Polypeptide compound - Google Patents

Abstract

To provide an antibacterial agent, particularly a novel polypeptide compound having an antifungal activity or a salt thereof. The present inventors considered a novel antibacterial agent and found that excellent antifungal activity can be achieved by introducing a benzoyl group having a cyclic substituent at the carbonyl ortho position, as a partial structure for a natural polypeptide compound, thereby completing the present invention. This polypeptide compound has excellent antifungal activity and can be used as a prophylactic and/or a therapeutic agent for various fungal infections.

Description

201247215 VI [Description of the Invention] The present invention relates to a pharmaceutical, a novel polypeptide compound having antifungal activity, or a pharmaceutically acceptable salt thereof. [Prior Art]

Fungal infections are broadly classified into superficial skin fungus (white fungus, etc.) from skin infections and deep-seated fungi (yeast, aspergillus, etc.) from respirators or oral infections. Deep fungal disease occurs in patients with various risk factors such as immunodeficiency or anticancer agents, and is often refractory to a single disease and has a poor prognosis. In particular, in the case of invasive pulmonary aspergillosis, the mortality rate is 58% of the total disease, especially in bone marrow transplant patients. However, effective treatments or drugs are less, and even the standard drug Voriconazole or Ambisome is less than 60% efficient. Therefore, an antifungal agent having a new strong activity is pursued. In the case of an antifungal compound, for example, Patent Document 1 discloses a compound of the following formula. 201247215 【化1】

In the formula, R1 is H, R2 is a fluorenyl group, R3 is OH or the like, R4 is OH or the like, R5 is ruthenium or the like, and R6 is ruthenium or the like.) Patent Documents 2, 3, 5 and 6 are the same as Patent Document 1 The above-mentioned group of R2 is defined as a fluorenyl group, and R2 is a compound of various benzamidine groups. However, in terms of the substituent of the benzamidine group, a compound having a substituted ring group at the ortho position of the carbonyl group is not revealed. Patent Document 4 discloses a compound in which the group defined by R2 is a benzamidine group or a compound in which the carbonyl group is a methyl group, but a compound in which a carbonyl group is substituted with a ring group is not disclosed. [Prior Art Document] [Patent Document 1] US Patent No. 5,569,646 [Patent Document 2] International Publication No. WO 02/068456 [Patent Document 3] International Publication No. WO 03/068807 [Patent Document 4] International Publication WO 99/401 08 [Patent Document 5] International Publication No. WO098/236377 No. 201247215 [Patent Document 6] International Publication No. WO 09 9/11210 [Summary of the Invention] [Problems to be Solved by the Invention] Providing a pharmaceutical composition, in particular A compound which can be used as an active ingredient of a pharmaceutical composition for the prevention and/or treatment of fungi.

[Means for Solving the Problems] As a result of intensive studies on the prevention and/or treatment of excellent fungal diseases, the present inventors have found that the compound of the formula (I) has excellent antifungal activity and has completed the present invention. The compound is characterized in that the specific carbon atom on the B ring of the compound of the formula (I) has the following formula:

—X-^a"^-RA The compound represented by the radical. That is, the present invention relates to a compound of the formula (I) or a salt thereof, and a pharmaceutical composition comprising the compound of the formula U) or a salt thereof, and an excipient. 201247215 【化3】 Ra

Wherein R1 is -NH2, -OH, -NH-lower alkyl-NH2, -lower alkyl-NH.lower alkyl,lower alkyl-N(lower alkyl)2, -NH- Lower alkylene-C(=0)0H, or -NHCH(0H)C(=0)0H, R2 is -S(=0)20H, -CH2CH(OH)CH2OH,-lower alkyl-C ( = 0) 0H, lower alkyl, or hydrazine, anthracene ring is a nitrogen-containing heterocyclic ring, an aryl group, or a cycloalkyl group,

RA is hydrazine, lower alkyl, lower alkyl-NH2, lower alkyl-NH-lower alkyl, lower alkyl-N (lower alkyl) 2, lower alkyl-OH, - lower alkylene-0-lower alkyl, lower alkylene-C(=0)OH, lower alkyl-S(=0) 2OH, lower alkyl-S(= 0)20 - lower alkyl, -C(=0)0. lower alkyl, -C(=0)-lower alkyl-NH2, -C(=0). lower alkyl-NH-lower alkyl, - C(=0)-lower alkyl hydrazine (lower alkyl) 2, lower alkyl-OH, -C(=NH)-NH2, -CH which can be substituted by -C(=0)-NH2 (lower alkyl-hydrazine H) 2, or cycloalkyl, X is a single bond, lower alkylene, -NH-, or -N (lower alkyl) - • 8 - 201247215 is a sputum or dentate, ruler 8 and RC are each the same or different Β ring is the following formula (II), ίττΐ } watt (nI" a), or formula (III-b) [Chemical 4]

The base represented,

* indicates the position of the X bond in the formula (I), ** is the position bonded to rB in the formula (1), the ring D is a nitrogen-containing heteroaryl group or an aryl group, and RD is a formula (IV) to (VI) ) 【化5】 ^21

RZ1 R22

—L

(VI)

R

The group represented by or a group represented by -L- 0-R1Q1, L is a lower alkyl group, a higher alkyl group, a fluorene-, a fluorene-low alkyl group, or a single bond, and the E ring is a heterocyclic ring. The base, the F ring and the F1 ring are each the same or different and are a cycloalkyl group,

The Fg ring is a cycloalkyl group, or an aryl group,

The Efg ring is a heterocyclic group, a cycloalkyl group, or an aryl group, RE is a hydrazine, a lower alkyl group, a-0.lower alkyl group or a halogen, R1 is a lower alkyl group, a lower alkyl group-cycloalkyl group, Or - higher alkylene-9 - 201247215 yl-cycloalkyl, RZ1 or RZ2 are each the same or different and are fluorene, halogen, aryl, lower alkyl, higher alkyl, which may be substituted by halogen or lower alkyl, · 0. lower alkyl, - fluorene - higher alkyl, - fluorene-cycloalkyl, -0-aryl, -0-lower alkyl-aryl, - higher alkyl-hydrazine-lower alkyl, Cycloalkyl, or -c(=o)o_lower alkyl-aryl. )

Further, the present invention relates to a pharmaceutical composition for preventing and/or treating fungi containing a compound of the formula (I) or a salt thereof, that is, a prophylactic agent for fungi containing the compound of the formula (I) or a salt thereof And / or therapeutic agents. Further, the present invention relates to the use of the compound of the formula (I) or a salt thereof for the production of a fungal disease prevention and/or therapeutic pharmaceutical composition, and the use of the formula (I) for the prevention or treatment of fungal infections The use of the compound or a salt thereof, and a method for preventing and/or treating a fungal disease comprising administering an effective amount of the compound of the formula (I) or a salt thereof to a patient. Further, the present invention relates to a compound of the formula (I) used in the treatment of fungal diseases.

[Effects of the Invention] The compound of the formula (I) or a salt thereof has antifungal activity and can be used as a prophylactic or therapeutic agent for fungi. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present specification will be described in detail. In the present specification, "lower alkyl group" means a straight or branched carbon number of -10-201247215 1 to 6 (hereinafter abbreviated as Cu), such as methyl, ethyl, η-propyl, Isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl, η-pentyl, isopentyl, η-hexyl, and the like. The preferred embodiment is an alkyl group, and more preferably a C, _3 alkyl group. A more preferred aspect is methyl or ethyl. The "lower alkyl group" is a divalent group (C!.6 alkylene group) obtained by removing any one of the above-mentioned "lower alkyl groups", and is in the form of a Ci-4 alkylene group. A preferred embodiment is a methylene group or an ethyl group.

"Advanced alkyl" means a straight or branched alkyl group having 7 to 12 carbon atoms (hereinafter, abbreviated as C7.12), for example, heptyl, 1-propylbutyl, octyl, decyl,癸 base, twelve base. A preferred embodiment is a C7.8 alkyl group. More preferred are heptyl and octyl groups. The "higher alkylene group" is a divalent group (C7-12 alkylene group) obtained by removing any one of the above-mentioned "higher alkyl groups", and is a C7_1() stretching group. The preferred embodiment is heptanediyl, octanediyl ° "halogen" is F, Cl, Br, I. "Cycloalkyl" means a saturated hydrocarbon ring group of Cm and may have crosslinks. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl 'adamantyl and the like. A preferred embodiment is a C 3.8 cycloalkyl group. More preferred are cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, adamantyl. "Aryl" means a monocyclic to tricyclic aromatic hydrocarbon ring group of C6.14, such as phenyl 'naphthyl, preferably phenyl. "Heterocyclic" group means i) a monocyclic heterocyclic ring containing 1-4 members of 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen, preferably 5 to 7 members, -11 - 201247215 and ii) the monocyclic heterocyclic ring is formed by condensing a ring of one or two rings selected from the group consisting of a monocyclic heterocyclic ring, a benzene ring, a C5.1Q cycloalkane, and a C5.1Q cycloalkenene. Further, it contains 1 to 5 heterocyclic atoms selected from oxygen, sulfur and nitrogen, and a selected tricyclic ring. Sulfur or nitrogen of the ring atoms can be oxidized to form oxides or dioxides. The "heterocyclic" group can be, for example, the following: (1) Monocyclic saturated heterocyclic group

(a) Containing 1 to 4 nitrogen atoms, such as azepanyl, diazepine, azacyclopropyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidin a pyridyl group, a pyrazolyl group, a piperazinyl group, an arucarbyl group or the like; (b) a compound having 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms, for example, a sulfur group Morpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl, etc.; (c) those having 1 to 2 sulfur atoms, such as tetrahydrothiopyranyl;

(d) those having 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, such as oxathiolane; (e) those having 1 to 2 oxygen atoms, such as an oxiranyl group or an oxocyclic ring. Butyl, dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxin, etc.; (2) monocyclic unsaturated heterocyclic group (a) having 1 to 4 nitrogen atoms For example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, tetrahydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, triazinyl, dihydrogen Triazinyl, azirretyl, 1,2,3,6-tetrahydropyridyl, etc.; -12- 201247215 (b) containing 1 to 3 nitrogen atoms, and 1 to 2 sulfur atoms and/or 1 to 2 An oxygen atom, such as thiazolyl, isothiazolyl, thiadiazole, dihydrothiazinyl, oxazolyl, isooxazolyl, oxadiazolyl, oxazinyl, etc.; (c) contains 1~ 2 sulfur atoms, such as thienyl, thiepinyl, dihydrodithiopyranyl, dihydrodisulfite, etc.; (d) containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, specifically , such as dihydrooxathiopyranyl, etc.;

(e) those having 1 to 2 oxygen atoms, such as furyl, pyranyl, heptyl, dioxolyl, etc.; (3) condensed polycyclic saturated heterocyclic group (a) containing 1~ 5 nitrogen atoms, such as quinuclidinyl, 7-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.2]fluorenyl, etc.: (b) containing 1 to 4 nitrogen atoms, And 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, such as trithiadiindenyl, dioxoimidazolidinyl, etc.; (c) containing 1 to 3 sulfur atoms and/or 1 to 3 An oxygen atom, such as 2,6-dioxabicyclo[3.2.2]oct-7-yl, etc.; (4) a condensed polycyclic unsaturated heterocyclic group (a) having 1 to 5 nitrogen atoms, For example, fluorenyl, isodecyl, fluorene, fluorenyl, benzoxanthene, diazabenzimidyl, tetrahydrobenzimidazolyl, quinolyl, tetrahydrogen Quinolinyl, isoquinolyl, tetrahydroisophyllinyl, oxazole, imidazopyridyl 'benzotriazolyl, tetrazolopyridazinyl, oxazolyl, acridinyl, quinoxalinyl, Dihydroquinoxalinyl, tetrahydroquinoxaline, indole, indoline, benzopyrene, naphthalene steep-13-2012472 a group having a quinazolinyl group or a pyridazin group; And thiazolyl, benzothiadiazole, imidazothiazolyl, imidazothiadiazole, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, benzoxazole Base, benzisothiazolyl, benzisooxazolyl, imidazo[2,1·b][l,3,4]thiadiazole, etc.;

(c) those having 1 to 3 sulfur atoms, such as benzothienyl, benzodithiopyranyl, dibenzo[b,d]thienyl, etc.; (d) containing 1 to 3 sulfur atoms and 1 to 3 oxygen atoms, such as benzooxathiopyranyl, phenoxazinyl, etc.; (e) those having 1 to 3 oxygen atoms, such as benzodioxan, benzofuranyl, Hydrobenzofuranyl, isobenzofuranyl, chromanyl, chromenyl, dibenzo[b,d]furanyl, methylenedioxyphenyl, ethylidene Oxygen 碁本卷寺,

Wait. The "nitrogen-containing heterocyclic ring" group means (l) (a), (l) (b), (2) (a), (2) (b), (3) (a) in the above "heterocyclic" group. ), (3), (b), (4) (a) and (4) (b), etc., which contain at least one nitrogen atom. The "heteroaryl group" means an aromatic monocyclic or condensed polycyclic heterocyclic group in the above (heterocyclic) group (2) and (4). For example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, iso Oxazozolyl, thiadiazole, oxadiazolyl, thiophene-14 - 201247215, furyl, monocyclic heteroaryl, fluorenyl, isodecyl, benzimidazolyl, carbazole, quinoline , isopipelinyl, oxazolinyl, quinoxalinyl, imidazopyridyl, pyrazolopyridyl, pyridazinyl, benzothiazolyl, benzisothiazolyl, benzothiadiazole, benzene Andoxazolyl, imidazothiazolyl, benzisooxazolyl, benzofuranyl, imidazo[2, lb][l,3,4]thiadiazole, benzothienyl, imidazothiazide Diazole, isocyclic heteroaryl,

a tricyclic heteroaryl group such as a carbazolyl group, a dibenzo[b,d]furanyl group or a dibenzo[b,d]thienyl group, preferably a pyridyl group, a pyrimidinyl group, a thiazolyl group or an oxazole , isooxazolyl, thiadiazole, oxadiazolyl, imidazopyridyl, pyrazolopyridyl, benzothiadiazole, benzoxazolyl, imidazothiazolyl, imidazothiazide More preferably, the pyrazole is pyrimidinyl, oxazolyl, imidazo[2,1-13][1,3,4]thiadiazole or imidazothiadiazole. The "nitrogen-containing heteroaryl group" is a monocyclic or condensed polycyclic ring containing at least one nitrogen atom in the above "heteroaryl group". For example, an aspect such as imidazothiadiazole, pyrimidinyl or oxadiazolyl. Further, in another aspect, such as imidazo[2,l-b][l,3,4]thiadiazole, pyrimidine, hydrazine, oxadiazole. The "monocyclic nitrogen-containing heteroaryl group of 5 or 6 members" has the above-mentioned monocyclic "nitrogen-containing heteroaryl group" which constitutes 5 or 6 atoms of the ring, and examples thereof include a pyridyl group, a pyrimidinyl group, and a thiazole group. Base, thiadiazole, oxazole or oxadiazolyl. "5-member-5-membered condensed polycyclic nitrogen-containing heteroaryl group or 5-member-6-membered condensed polycyclic nitrogen-containing heteroaryl group" can be exemplified by the above-mentioned "nitrogen-containing heteroaryl group" Diazole, hydrazine, benzoxazole, imidazo[2, i_b][l,3,4] thiadiazole and the like. -15- 201247215 "Heterocycloalkyl" means («)(a) 'OHb), (3)(a), (3)(b) or the above-mentioned "heterocyclic" group of the above-mentioned "heterocyclic" group. (2) (a), (2) (b),

And (4) (b), a heterocyclic group having no aromaticity. For example, azacycloheptyl, diazepanyl, azacyclopropyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, 1,2,3,6-tetra Hydropyridyl, pyrazolyl, piperazinyl, arucarbyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl, tetrahydropyridyl, dihydrogen a bicyclic heterocycloalkyl group such as a monocyclic heterocycloalkyl group such as a pyridyl group or a tetrahydropyridyl group, a quinuclidyl group or a 7-azabicyclo[2.2.1]heptyl group. The "nitrogen-containing heterocycloalkyl group" means a group containing at least one nitrogen atom in the above "heterocycloalkyl group". In one aspect, it is a piperidinyl group, a piperazinyl group, a tetrahydropyridyl group or the like. Further, the preferred embodiment is 1,2,3,6-tetrahydropyridyl" "6-membered nitrogen-containing heterocycloalkyl group" means that the number of atoms constituting the ring is 6 in the above "nitrogen-containing heteroalkyl group". . In one embodiment, it is a piperidinyl group, a piperazinyl group, a tetrahydropyridyl group or the like. Still another preferred aspect is 1,2,3,6-tetrahydropyridyl.

The "single-ring heterocyclic ring of 6 members" means that the number of atoms constituting the ring in the above (!) and (2) is six. In one aspect, it is piperidinyl, piperazinyl, mi tetrahydropyridyl, pyridyl, pyrimidinyl, pyrazinyl and the like. The "ring group" means a cyclic group such as a nitrogen-containing heteroaryl group, a nitrogen-containing heterocyclic compound group, an aryl group or a cycloalkyl group in the above definition, and when it has two bonding bonds, it is a divalent group. In the present specification, '"substitutable" means "unsubstituted" or has 5 substituents. Further, when a plurality of substituents are present, the substituents may be the same or different from each other. -16- 201247215 One of the compounds of the present invention represented by the formula (1) or a pharmaceutically acceptable salt thereof is as follows. (1) A ring is a compound of a monocyclic saturated heterocyclic group. (2) A ring-ring compound of 6-membered monocyclic heterocyclic group. (3) A compound wherein the ring A is a monocyclic unsaturated heterocyclic group or a condensed polycyclic unsaturated heterocyclic group. (4) The A ring is a compound containing a nitrogen heterocycloalkyl group. (5) The A ring is a compound of 6 members containing a nitrogen heterocycloalkyl group.

(6) A ring is a compound represented by a 1,2,3,6-tetrahydropyridyl group or a piperidinyl group. (7) The B ring is a compound represented by the formula (II). (8) The B ring is a compound of the formula represented by the formula (ΙΙΙ-a) or the formula (ΙΙΙ-b). (9) The D ring is a compound containing a nitrogen-containing heteroaryl group. (10) The D ring is a compound selected from a monocyclic nitrogen-containing heteroaryl group or a condensed polycyclic nitrogen-containing heteroaryl group.

(1 1) The ring of 5 is a combination of a monocyclic nitrogen-containing heteroaryl group

(12) The D ring is a 5-member-5-membered condensed polycyclic nitrogen-containing heteroaryl group or a 5-member-6-membered condensed polycyclic nitrogen-containing heteroaryl group. (1 3 ) The D ring is an imidazothiadiazole, pyridyl, pyrimidinyl or dioxadiyl compound" (14) The D ring is imidazo[2,1-13][1,3,4] A compound of thiadiazole. (15) RD is a compound of the formula represented by the formula (V) or the formula (VI). (16) The E ring in RD is a monocyclic saturated heterocyclic group or a monocyclic unsaturated compound of -17-201247215 and a heterocyclic group. (17) The E ring in RD is a compound containing a nitrogen heterocycloalkyl group. (18) The E ring in RD is a compound of 6 members containing a nitrogen heterocycloalkyl group. (19) The compound in which the ring is 1,2,3,6-tetrahydropyridyl, piperazinyl or piperidinyl. (20) The Efg ring in RD is a compound containing a nitrogen-containing heterocycloalkyl group. (21) The Efg ring in RD is a compound of 6 members containing a nitrogen heterocycloalkyl group. (22) A compound in which the Fg ring in RD is a cycloalkyl group or an aryl group.

(23) Ri is -NH2, -OH, -NHCH2CH2NH2 ' -NHCH2C( = 0)0H, or -NHCH(0H)C( = 0)0H (24) R2 is -S( = 0)20H, -CH2CH(OH)CH2OH, -CH2C(=0)0H, lower alkyl, or hydrazine compound. (25) RA is Η 'lower alkyl, -lower alkyl-ΝΗ2,-lower alkyl-hydrazine, lower alkyl-indole-lower alkyl, lower alkyl-C(=0) 0H, -lower alkyl-S(=0)0H, -C(=0)OH,

-c( = o)o-lower alkyl, -c( = o)-lower alkyl-nh2, -c( = o)ch(nh2)ch2oh, -ch(cn)-nh2, -CH(- A compound of lower alkyl-OH) 2 or a cycloalkyl group. (26) X is a compound of a single bond. (2 7) A compound wherein L is a single bond, a lower alkyl group, -0-, or -〇-lower alkyl group. (28) L is a compound of a single bond, -CH2CH2-, -0-, or -0-CH2-. (29) RA is a compound of -lower alkyl-OH, -C(=0)-lower alkyl -18-201247215 -NH2, cycloalkyl, lower alkyl, or hydrazine. (30) RA is a compound of -CH2CH2-OH. (31) RA is a compound of a methyl group. (32) 111 is a compound of -NH2. (3 3) A compound wherein R 2 is -S( = 0)20H or a methyl group. (34) A compound wherein R2 is -S(=0)20H (35) is a compound of hydrazine.

(36) A compound of two or more of the groups represented by the compounds of the above (1) to (35). Examples of specific compounds encompassed by the present invention include the following compounds (37) to (84) or their pharmaceutically acceptable salts. (37) A compound represented by the compound of (3) and a compound represented by the compound of (1). (3) A compound represented by the compound of (4) and a compound represented by the compound of (10). (39) A compound represented by the compound of (5) and a compound represented by the compound of (10). (40) a group represented by the compound of (3), and a compound of the group represented by the compound of (1) (41) a group represented by the compound of (4), and a compound represented by the compound of (1 1) (42) A compound represented by the compound of (5) and a compound represented by the compound of (1). (43) A group represented by the compound of (3), and a compound of (12) The compound represented by the formula -19-201247215. (44) The group represented by the compound of (4) and the compound represented by the compound of (12). (45) The group represented by the compound of (5), And a compound represented by the compound of (12), (46) a group represented by the compound of (3), a group represented by the compound of (7), and a compound represented by the compound of (10).

(47) A compound represented by the compound of (4), a group represented by the compound of (7), and a compound represented by the compound of (10). (48) A compound represented by the compound of (5), a group represented by the compound of (7), and a compound represented by the compound of (10). (49) A compound represented by the compound of the group '(7) and a group represented by the compound of (11) represented by the compound of (3). (5) a compound represented by the compound of (4), a group represented by the compound of (7), and a compound represented by the compound of (11).

(5) A compound represented by the compound of (5), a group represented by the compound of (7), and a compound represented by the compound of (11). (52) A compound represented by the compound of (3), a group represented by the compound of (7), and a compound represented by the compound of (12). (53) a group represented by the compound of (4), a group represented by the compound of (7), and a group of a compound represented by the compound of (I2) (54) (5) A compound represented by the compound of (7) and a compound represented by the compound of (12). (55) The compound represented by the compound of (6) and the compound of (1〇) are represented by the compound of -20-201247215. (5 6) A compound represented by the compound of (6) and a compound represented by the compound of (1 1). (57) A compound represented by the compound of (6) and a compound represented by the compound of (12). (58) A compound represented by the compound of the group '(7) and a group represented by the compound of (10) represented by the compound of (6).

(59) A compound represented by the compound of (6), a group represented by the compound of (?), and a compound represented by the compound of (11). (60) A compound represented by the compound of (6), a group represented by the compound of (7), and a compound represented by the compound of (12). (6 1) A compound represented by the compound of (7) and a compound represented by the compound of (10). (62) A compound represented by the compound of (7) and a compound represented by the compound of (1). (63) a compound represented by the compound of (7) and a compound represented by the compound of (12). (64) a compound represented by the compound of (3) and a compound represented by the compound of (15). (65) A compound represented by the compound of (4), a group represented by the compound of (7), a group represented by the compound of (11), and a compound represented by the compound of (15). (66) a group represented by the compound of (4), a group represented by the compound of (7), a group represented by the compound of (1), and a compound of -21,472,215, represented by the compound of (18). . (67) The group represented by the compound of (4), the group represented by the compound of the formula (11) represented by the compound of (7), and the compound of the group represented by the compound of (21). (68) A compound represented by the compound of (4), a group represented by the compound of (7), a group represented by the compound of (12), and a compound represented by the compound of (5).

(69) A compound represented by the compound of (4), a group represented by the compound of (7), a group represented by the compound of (12), and a compound represented by the compound of (18). (70) A compound represented by the compound of (4), a group represented by the compound of (7), a group represented by the compound of (12), and a compound represented by the compound of (21). (71) A compound represented by the compound of (4), a group represented by the compound of (7), a group represented by the compound of (13), and a compound represented by the compound of (18).

(72) A compound represented by the compound of (4), a group represented by the compound of (?), a group represented by the compound of (13), and a compound represented by the compound of (21). (73) A compound represented by the compound of (4), a group represented by the compound of (7), a group represented by the compound of (14), and a compound represented by the compound of (18). (74) The group represented by the compound of (4), the group represented by the compound of (7), the group represented by the compound of (14), and the compound of the group of -22-201247215 represented by the compound of (21). (75) A compound represented by the compound of (6) and a compound represented by the compound of (9).

(7 6)111 is -NH2, R2 is -S(=0)2〇H, A ring is 1,2,3,6-tetrahydropyridin-4-yl, X is a single bond, and B ring is a formula The base represented by (π), rb is 11,11. The ring of 1^,0 is imidazo[2,1-1)][1,3,4]thiadiazole, pyridyl, pyrimidinyl or 1,2,4-oxadiazolyl, RD is a formula ( The group represented by V) is a compound wherein the E ring is a pyridazinyl group or an acridinyl group, L is -CH2CH2., and the Fg ring is a phenyl group. (77) 111 is -NH2, R2 is -S(=0)2〇H, and A ring is 1,2,3,6-tetrahydropyridin-4-yl' 11 VIII-(^2(:1 ^2-0^1, X is a single bond, B ring is a group represented by formula (II) 'RB is H' Re is H, D ring is imidazo[2,1-b][l,3,4 a thiadipine, a succinyl group, a fluorene D group, or a 1,2,4-D oxadiyl group, and RD is a group represented by the formula (V): the ring E is a piperazinyl group or a piperidinyl group, and l is -CH2CH2-, a compound in which the Fg ring is a phenyl group. (78) R1 is -NH2, R2 is -S(=0)2〇H, and the A ring is 1,2,3,6-tetrahydropyridin-4- a group, X is a single bond, B ring is a group represented by formula (η), rb is H' Re is H, Rd is a group represented by formula (V), e ring is piperazinyl, and Fg ring is phenyl (79) R1 is -NH2 ' R2 is -S( = 0)2〇h, and A ring is 1,2,3,6-tetrahydro-peptidyl-4-yl' as -(:112( : 112-(^, X is a single bond, the b ring is a group represented by the formula (π), and is H, R. is h, and rD is a group represented by the formula (v): the E ring is piperidinyl 'L A single bond, the Fg ring is a cycloalkyl compound. (80) R is -NH2, R2 is -S( = 0)2〇h, and a ring is 1,2,3,6-tetra-23- 201247215 hydrogen Pyridyl-4 group, 11 eight _(^2(:1^2-011, X is a single bond, B ring is the base represented by formula (Π) RBm H, Re is H, D ring is oxadiazolyl, Rd is formula (V) The group represented, the e ring is piperidinyl, L is -CH2CH2-, and the Fg ring is a cycloalkyl compound.

(81) R1 is -NH2' R2 is -s( = 〇)2〇h, a ring is 1,2,3,6-tetrahydropyridin-4-yl, X is a single bond, and b ring is a formula ( II) The group represented, Rb is H, R. The ring of H, D is an oxadiazolyl group, rd is a group represented by the formula (v), the ring E is a piperidinyl group, wherein L is a single bond, and the Efg ring is a compound of piperazine or piperidine. (82) R1 is -NH2, R2 is -S(= 〇)2〇h, ring A is 1,2,3,6-tetrahydropyridin-4-yl, RA is methyl, and X is a single bond. The b ring is a group represented by the formula (II), wherein H'Re is h, the D ring is a pyrimidinyl group, RD is a group represented by the formula (VI), L is -0-CH2-, and the Efg ring is a phenyl group. Compound.

(83) R1 is -NH2' R2 is Me, A ring is 1,2,3,6-tetrahydropyridyl-4.yl' X is a single bond' B ring is a group represented by formula (II), rb η, Re is Η, RD is a group represented by the formula (V), an anthracene ring is a piperidinyl group, 1 is a single bond, and the Fg ring is a cycloalkyl compound. (84) R1 is -NH2, R2 is Me, A ring is 1,2,3,6-tetrahydropyridyl-4-yl' 1^ is oxime, X is a single bond, and B ring is a formula (II) The group represented by RB is Η 'Re is Η, D ring is pyrimidine, RD is a group represented by the formula, E ring is piperazinyl, L is -CH2CH2-, and Fg ring is phenyl compound. Examples of the specific compound to be encompassed by the present invention include the compound selected from the group represented by the following (8 5) to (88) or a pharmaceutically acceptable salt thereof. -24- 201247215 (85) Hydrogen sulfate 5-{(2R)-2-[(2R,6S,9S,llR,14aS,15S,16S,20S,23S,25aS)-20-[(lR)-3- Amine-1-hydroxy-3-oxopropyl]-2,11,15-trihydroxy-6.-[(111)-1-hydroxyethyl]-9-(3-[1-(2-hydroxyl) Ethyl)-1,2,3,6-tetrahydropyridin-4-yl]-4'-{2-[4-(2-phenylethyl)piperazin-1-yl]imidazo[2, 1-1^[1,3,4]thiadiazole-6-yl}[1,1'-biphenyl]-4-carboxamide)-16-methyl-5,8,14,19, 22,25-hexaoxytetrasylhydrogen-1H-dipyrrole [2,lC:2',l'-l][l,4,7,10,13,16]hexazacyclohexyl 21 Benzyl-23-yl]-2-hydroxyethyl}-2-hydroxyphenyl ester

(86) Hydrogen sulphate 5-{(2R)-2-[(2R,6S,9S,llR,14aS,15S,16S,20S,23S,25aS)-20-[(lR)-3-amine-1- Hydroxy-3-oxopropyl]-2,11,15-trihydroxy-6-[(111)-1-hydroxyethyl]-9-(3-[1-(2-hydroxyethyl)-l ,2,3,6-tetrahydropyridin-4-yl]-4'-{5-[4-(2-phenylethyl)piperazine-l-yl]pyrimidin-2-yl}[l,l '-Biphenyl]-4-carboxyguanamine)-16-methyl-5,8,14,19,22,25-hexaoxytetradecylhydro-lH-dipyrrole [2, lc: 2 ',13,16] hexazacyclohetero-21-yl-23-yl]-2-hydroxyethyl b-hydroxyphenyl ester. (87) Hydrogen sulphate 5-[(2R)-2-{(2R,6S,9S,llR,14aS,15S,16S, 2〇3,2 35,2533)-2 0-[(111)-3- Amine-1-hydroxy-3-oxopropyl]-9-{4'-(5-{4-[(4,4-dimethylcyclohexyl)oxy]piperidin-1-yl}-1 ,2,4-oxathiazol-3-yl)-3-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl][1,1'_ Biphenyl]-4-carboxyguanamine}-2,11,15-trihydroxy-6-[(lR)-l-hydroxyethyl]-16-methyl-5,8,14,19,22, 25-hexaoxytetradecylhydro-1H-dipyrrole [2,le:2',i'-i][i,4,7,10,13,16]hexazacyclohetero-i-yl - 23-yl}- 2 hydroxyethyl]-2-hydroxyphenyl ester. -25- 201247215 (88)N-{(2R,6S,9S,llR,14aS,15S,16S,20S,23S,25aS)-20-[(111)-3-amine-1-hydroxy-3-oxo Propyl]-2,11,15-trihydroxy-6-[(1R)-1-hydroxyethyl]-23-[(lR)-l-hydroxy-2-(4-hydroxy-3-methoxy) Phenyl)ethyl]-16-methyl- 5,8,14,19,22,25-hexaoxytetradecylhydrogen-lH·dipyrrole [2, lc: 2', l'-l ]Π,4,7,10,13,16]hexazacycloheterosuccinyl-9-yl}-4'-(5-{4-[2-(4-ethoxyphenyl)ethyl Piperazine-l-yl}pyrimidin-2-yl)-3-(1,2,3,6-tetrahydropyridin-4-yl)[1,1biphenyl]-4-carboxamide.

Among the compounds of the formula (I), geometric isomers may exist depending on the kind of the substituent. The compound of the formula (I) in the present specification describes only one form of the isomer, but the present invention also includes other isomers, purified persons of the isomers, or a mixture thereof. Further, in the case of the compound of the formula (I), there is a case where the asymmetric carbon atom or the axis is asymmetric, and based on this, an optical isomer may exist. The present invention comprises the optical isomers of the isolated compounds of formula (I), or mixtures thereof.

Further, the present invention also encompasses a pharmaceutically acceptable prodrug of the compound represented by the formula (I). The pharmaceutically acceptable prodrug means a compound which is decomposed by a solvent or has a group which can be converted into an amine group, a hydroxyl group, a carboxyl group or the like under physiological conditions. For the formation of a precursor drug, for example, Prog. Med., 5, 2 1 5 7-2 1 6 1 (1 985) or "Development of Pharmaceuticals" (Guangchuan Bookstore, 1990), Volume 7, Molecular Design 163- The basis of 198 records. Further, the salt of the compound of the formula (I) refers to a pharmaceutically acceptable salt of the compound of the formula (I), which may be an acid addition salt or a salt with a base depending on the kind of the substituent. Specifically, such as hydrochloric acid, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids or formic acid, acetic acid, propionic acid, oxalic acid, -26-

201247215 Malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, succinic acid, tartaric acid, diphenylmethyl tartaric acid, xylene decyl alcoholic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid 'p _toluenesulfonic acid, succinic acid and other organic acid acid addition salts, and sodium, potassium, and other inorganic bases, methylamine, ethylamine, ethanolamine, lysine organic salt, and acetonitrile white ammonia A salt or an ammonium salt of various amino acids such as an acid. Further, the present invention also encompasses a compound of the formula (1), a hydrate or a solvate thereof, and a crystalline polymorph. Further, the compound of the formula (I) and the salt thereof, which are labeled with various radioactive or non-radioactive isotopes, can be produced by various conventional synthetic methods using the characteristics based on the types of the basic groups. This functional group is sometimes substituted by a protecting group (a group which is easily convertible into the functional group) from a raw material to an intermediate. Such a protection base may be, for example, Wuts) and T. W. Greene, "Greene"

Groups in Organic Synthesis (4th edition, 2006: protecting group, etc., depending on such reaction conditions, the method can be suitably selected, and after the reaction group is introduced and reacted, the desired compound can be obtained by removing the protecting group. The compound of the formula (I) is pre-drug-extracted, and the specific base is introduced at the stage of the raw material to the intermediate, and the specific base is introduced, the fruit acid, the almond acid, the citric acid, the magnesium aspartate, the calcium, the aluminum, the avian amine. Amino acid such as an acid is derived from various salts thereof, and is also a compound of the present invention. Structure or substitution. At this time, the stage of the factor may be described in the "Technology" ("G. Μ. Protective Abandonment"). If necessary, the protecting group can be produced by further reacting with a compound of the formula (I) obtained in -27 to 201247215. The reaction can be carried out by a conventional method such as esterification, amidation, dehydration or the like. Hereinafter, a representative production method of the compound of the formula (I) will be described. The respective production methods can also be carried out with reference to the attached references. Further, the production method of the present invention is not limited to the following examples. 1) of [6]

The compound (I) of the present invention can be produced by the reaction of the compound (Q) with the compound (P-1). This reaction is a condensation reaction of an amine group of the compound (Q) with a carboxylic acid corresponding to (P-1). In the present reaction, the compound (Q) and the compound (P-1) are used in an equivalent amount or in an excess amount, and the mixture is reacted in an inert solvent in the presence of a condensing agent, and cooled to heating, preferably -20 ° C to 60 ° C, 0.1 hour to 5 days of stirring. Examples of the solvent are not particularly limited, and examples thereof include aromatic hydrocarbons (such as toluene or xylene) and halogenated hydrocarbons (for example, DCM or DCE or An example of a condensing agent, such as chloroform or the like, an ether (for example, diethyl ether, THF or dioxane, etc.), an aprotic solvent (for example, DMF, DMSO, EtOAc, MeCN), or water, and a mixed solvent thereof. For example, BOP, HBTU, EDCI, DPPA, and phosphorus oxychloride may be mentioned, but are not limited thereto. Additives (such as HOBt, etc.) are sometimes used to facilitate the reaction. Sometimes 28 - 201247215 The reaction is carried out in the presence of an organic base (e.g., TEA, DIPEA or NMM, etc.) or an inorganic base (e.g., K2C03 or KOH, etc.) to facilitate smooth reaction.

Further, the compound (I) can also be obtained by temporarily purifying the compound (p-1) as a reactive derivative and then reacting it with the compound (Q). Examples of the reactive derivative of the carboxylic acid (P-1) include, for example, an acid halide obtained by reacting with a halogenating agent (for example, phosphorus oxychloride or a sulfite group), and chloroformic acid. A mixed acid anhydride obtained by a reaction such as butyl ester or an active ester obtained by condensation with HOBt or the like. The reaction of the compound (P-1) with a reactive derivative may be carried out in a reaction inert solvent such as DMF, halogenated hydrocarbons, aromatic hydrocarbons or ethers, under cooling to heating, preferably at -20 ° C. ~60t is carried out. Further, the reaction in the presence of a base (e.g., NMM 'TEA, DIPEA, DMAP, pyridine, methylpyridine, lutidine, etc.) may facilitate the smooth progress of the reaction. Further, pyridine can also serve as a solvent. [Documents] SR Sandler and W. Karo, "Organic Functional Group Preparations", 2nd Edition, Vol. 1, Academic Press Inc., 1991 Chemical Society of Japan, "Experimental Chemistry Lecture (5th Edition)", Volume 16 ( 2005) (Jiushan) (general method 2 -1) -29- 201247215 【化7】

(wherein R is _CH(-R')-R, '.R, or R,, the same or different represents Η, or lower alkyl. However, RA1 is _CH(_R')_R, in the base The total number of carbon atoms is 1 to 6. The compound (1) of the present invention can be obtained by reacting a compound (p_2) with a compound (pgq). In this reaction, the compound (P_2) and the compound (Pdd) are used in an equal amount or in an excess amount to make the mixture in the presence of a reducing agent in a reaction inert solvent at -45 ° C to reflux under heating, preferably. For 〇°c~ room temperature, it is usually stirred for 1 hour to 5 days. Examples of the solvent which can be used herein are not particularly limited, and examples thereof include alcohols such as Me Ο Η and E t Η 、, ethers such as diethyl ether, DMF, halogenated hydrocarbons, and the like. The reducing agent may, for example, be NaBH(OAc)3, NaBH3CN or NaBH4. Examples of the compound (ρ-3-1) include, for example, an aldehyde represented by the general formula 0 = C(-R')-R'' or -30-201247215

In addition to the ketone, 1,4-dioxane-2,5-diol or the like can also be used. It is preferred to carry out the reaction in the presence of a dehydrating agent such as a molecular sieve or an acid such as AcOH, hydrochloric acid or titanium (IV) isopropoxide complex. The condensation of the compound (P-2) with the compound (P-3-1) may cause an imine due to the reaction, and may be purified as a stable intermediate. In this case, the compound (I) can be obtained by a reduction reaction of the imine intermediate. Further, instead of the treatment with the reducing agent, a reducing catalyst (for example, palladium carbon, Raney nickel, etc.) may be used in the presence of an acid such as MeOH, EtOH or EtOAc, or in the presence or absence of an acid such as AcOH or hydrochloric acid. reaction. In this case, it is preferred to carry out the reaction under a hydrogen atmosphere at a normal pressure of -50 atmospheres and under cooling to heating. [Documentation] AR Katritzky and RJK Taylor, "Comprehensive Organic Functional Group Transformations II", Volume 2, Elsevier Pergamon, 2005 Chemical Society of Japan, "Experimental Chemistry Lecture (5th Edition)", Volume 14 (2005) (9 Good) (general method 2-2) -31 - 201247215 H, [Chem. 8]

(wherein Lvg is the leaving group.)

Further, the compound (1-2) of the present invention can also be obtained by alkylating a compound of (P-2) with a compound of (P-3-2). Here, in the example of the leaving group Lvg, 'halogen, methanesulfonyloxy group, p-toluenesulfonyloxy group or the like is contained. In this reaction, the compound (P·2) and the compound (p_3_2) are used in an equal amount or in an excess amount, and the mixture is allowed to react in a reaction inert solvent or without a solvent under cooling to reflux under heating, preferably Hey. (A) is usually stirred for 0.1 to 5 days. The solvent to be used herein is not particularly limited, and examples thereof include aromatic hydrocarbons such as toluene and xylene, dioxane, THF, and the like. Ethers, or halogenated hydrocarbons such as DCM or chloroform, DMF, DMSO, EtOAc, MeCN, and the like, in the presence of an organic base such as Et3N or DIPEA, or an inorganic-32-201247215 base such as K2C03, Na2CO3 or KOH. The reaction sometimes facilitates the smooth progress of the reaction. [Document] S. R. S and 1 er and W · Kar, "0 rganic F uncti ο na 1 Group Preparations", 2nd edition, Vol. 1, Academic Press Inc., 199 1 曰本化学化学, "Experimental Chemistry Lecture (5th Edition)", Volume 14 (2005) (Jiushan)

(general method 3)

【化9】

(1-3) or a salt thereof (wherein X1 is a single bond or -CH2. Lvg is as defined above.) The compound (1-3) is a compound of which the compound (I) X is X1. The compound Π-1) can be produced from the compound (P-4) and the compound (P-5). This reaction is a method of producing a compound (1-1) by reacting an aryl compound (P-4) with a boric acid compound (P-5) and coupling it by a so-called Suzuki. The reaction can be carried out in a solvent-free manner, an aromatic hydrocarbon, an ether, a halogenated hydrocarbon, an aprotic solvent or the like in a reaction inert solvent at room temperature to reflux under heating. The reaction is carried out in the presence of palladium, a phosphine ligand and a metal base. Palladium can be used as a divalent palladium such as Pd(OAc)2 or -33- 201247215

0-valent palladium such as Pd2(dba)3. As the phosphine ligand, a 2-dental ligand such as BINAP' DPPF or a single-dentate ligand such as P(BUt)3 can be used. As the metal base, K2C03, Cs2C03, potassium phosphate, NaOBu1 or the like can be used. Here, the leaving group Lvg contains a halogen, a trifluoromethanesulfonyloxy group or the like. ("General method 4" [Chemical 10]

(I -4) X = X 2 or a salt thereof (wherein X2 is NH or N(Me).)

The compound (1-4) is a compound of the compound (I) wherein X is X2. Compound (1-2) can be obtained by reacting compound (P-4) with compound (P-6). In this reaction, the compound (P-4) and the compound (P-6) are used in an equal amount or in an excess of 'such that in a reaction inert solvent or in the absence of a solvent, under cooling to reflux under heating, Good for 〇t~8 〇t, usually carried out for 〇.1 hour~5 days stirring. Examples of the solvent which can be used herein are not particularly limited, and examples thereof include aromatic hydrocarbons such as toluene and xylene, ethers such as diethyl ether, THF, dioxane and DME, and DCM and 1,2-di. Halogenated hydrocarbons such as chloroethane, chloroform, DMF, DMSO, EtOAc, MeCN, and mixtures thereof. The reaction in the presence of an organic base such as Et3N, DIPEA or NMM or an inorganic base such as k2C03, NhCO3 or K0H may sometimes facilitate the smooth progress of the reaction. -34- 201247215 [Document] by SR Sandler and W. Karo, "Organic Functional G roup P reparati ο ns", 2nd Edition, Volume 1, Academic Press In c., edited by the Japanese Chemical Society in 1979 "Experimental Chemistry Lecture (5th Edition)", Vol. 14 (2005) (Nine Good) In the compound of formula (I), the nitrogen atom of ring A forms a quaternary ammonium salt.

The product can be produced by subjecting a nitrogen-containing heterocycloalkyl group of the compound of the present invention to an N-alkylation reaction. The N-alkylation reaction can be carried out by a conventional N-alkylation reaction, but specifically, a sufficient amount of alkylation can be carried out by subjecting the compound of the present invention to alkylation of the amine group of the A ring. In DMF, CHC13, MEK,

The reaction is carried out in an inert solvent such as MeCN or THF, under ice cooling to room temperature, or occasionally under heating. The alkylating agent may, for example, be an alkyl halide or a lower alkyl methanesulfonate. (Intermediate Production Method 1)

(P-1) or a salt thereof (wherein R is a protecting group of a carboxyl group.) The compound (P-1) can be produced by deprotection of a carboxyl group of the compound (P-7). For example, it can be deprotected by hydrolysis reaction. -35- 201247215 (Intermediate Process 2) [Chemical 12]

(P-7-1) X=^ or its salt (P-7-2) X=X2 or its salt (P-6) or its salt

The compound (P-7-1) is a compound wherein X of the compound (p-7) is a compound, and the compound (P-7-2) is a compound of the compound (1)-7) which is further X2. This reaction is carried out by reacting the compound (P-8) with a compound (p-5) or a compound (p-6). Thus, the compound (pjq) and the compound (p-7-2) can be produced separately. Regarding the reaction conditions, the desired compound can be produced under the same conditions as in the general production method 3 or the general production method 4. [化13] ra

(P-9)

(P-10)

Further, the compound (P-7) can be produced by reacting the compound (p_9) with (P-10), wherein either Y and Z are Lvg, and the other is borous acid or borane. The desired compound can be produced under the same conditions as in General Process 3. Further, all of the above reactions may be carried out by the method of the production example or the examples of the present specification, or according to the method, the compound may be produced by the conventional method of 36-201247215, the method of the manufacturer, or the manufacture of the present specification. The method described in the examples or the examples, or produced according to the method. (Manufacturing method of raw materials)

The raw material compound represented by the general formula (Q) which can be used in the production of the compound of the present invention can be combined with International Publication No. WO97/32975, International Publication No. WO99/40 1 08, International Publication No. WO2000/064927, International Publication WO2002/ The method shown in No. 072621, International Publication No. WO2003/068807, International Publication No. WO2009/057568, or the method described therein is similarly manufactured. The compound of the formula (I) can be purified and purified into a free compound, a salt thereof, a hydrate, a solvate or a crystalline polymorph. The salt of the compound of the formula (I) can also be produced by a conventional salt-forming reaction. Purification and purification can be carried out by usual chemical operations such as extraction, separate crystallization, and various fractionation chromatography. The various isomers can be produced by selecting an appropriate starting material compound or by utilizing the difference in physicochemical properties between the isomers. For example, the optical isomer may be subjected to a general optical division method of a racemate (for example, conversion to a non-mirromeric isomer of an optically active base or an acid, and chromatography using a separate crystallizing or palm column, etc.) Alternatively, it can be made from a suitable optically active starting material compound. The pharmacological activity of the compound of formula (I) is confirmed by the following test. Test Example 1: Determination of the sensitivity of C. glabrata; Echinocandin resistant strain, smoothing -37- 201247215 Candida glabrata FP2135 strain

The MIC (minimum inhibitory concentration) in human serum was determined by using a human serum buffered with 2〇11^-1^?3 buffer (?117.3) as a test medium by a micro-liquid dilution method. The suspension having a cell number of 106 cells/mL was prepared by a hematocrit plate to obtain an inoculum size of about 5 M 03 to 2 χ 10 4 cells/mL. The microplates were incubated at 37t for 24 hours in a 5% CO2 environment. The MIC of this strain is defined as the lowest concentration of test compound whose proliferation is completely prevented. The MICs of the Echinocandins (Caspofungin, Anidulafungin, and Micafungi η) listed in the plant were all > 64 pg/mL. Test Example 2: Toxicity of Aspergillus fumigatus strain was measured using Aspergillus fumigatus, the same as Test Example 1. Ground measurement.

With respect to several representative compounds of the present invention, the test results of the above Test Example 1 are shown in Table I below. In the table, Ex is the embodiment number. The multiplication of the MEC of the clinical isolates (A. fumigatus 20030, 20024, and 200293 strains) of the MICs of C. glabrata (Echinocandin resistant strain) and A. fumigatus (C. glabrata; Echinocandin resistant strain)値Expression" -38- 201247215 [Table 1]

Ex C.glabrata FP2135 pg/mL Aspergillus pg/mL 32 4 0.25 36 4 0.2 126 4 0.25 155 8 0.4 183 8 0.4 289 8 0.25

Test Example 3: Determination of antifungal susceptibility in human serum

The MIC (minimum inhibitory concentration) in human serum was determined by a micro-liquid dilution method using human serum buffered with 20 mM-HEPES buffer (pH 7.4) as a test medium. A suspension of cells of 1 〇 7 cells/mL was prepared by a blood cell calculation plate to obtain an inoculum size of about 2.5 χΙΟ 3 to 2 M 05 cells/mL. The microplate was cultured at 37 ° C for 24 hours in a 5% CO 2 atmosphere. The lowest concentration of the test compound for the MIC of Candida is completely inhibited, and the MEC for the genus Aspergillus is defined as the lowest concentration of the test compound whose proliferation is sufficiently inhibited compared to developmental control. MIC, C. sphaeroides (C. glabrata; Echinocandin resistant strain), Candida albicans FP 1 943 and clinical isolate 1 against C. parapsilosis 20001 A. fumigatus) shows the multiplicative mean 値 of MEC of 3 clinical isolates (A. fumigatus 20030, 20024' and 200293 strains). -39 - 201247215 [Table 2] Ex C. glabrata FP2135 μβ/ml C. alibicans pg/ml C. parapsilosis gg/ml fumigatus pg/ml 13 8 0.5 8 0.5 16 4 0.5 4 0.32 17 4 0.5 4 0.32 23 4 0.5 4 0.4 25 8 0.5 4 0.2 32 4 0.5 8 0.25 36 4 0.5 4 0.2 37 4 0.5 4 0.4 41 4 0.25 4 0.13 43 8 0.5 8 0.2 47 4 0.25 4 0.13 49 8 0.5 8 0.25 52 8 0.5 4 0.32 55 4 0.5 8 0.32 64 4 1 8 0.4 65 4 0.25 4 0.32 79 2 0.25 4 0.32 100 8 0.5 8 0.25 107 4 0.5 4 0.4 114 8 0.5 8 0.25 118 8 0.5 8 0.2 126 4 0.25 4 0.13 128 4 0.25 4 0.32 131 8 0.5 8 0.2 137 8 0.5 8 0.32 144 2 0.25 2 0.25 155 8 0.5 4 0.4 156 8 0.5 4 0.4 157 8 0.5 4 0.25 164 8 0.25 2 0.16 170 8 0.5 8 0.25 178 8 0.5 8 0.2

-40- 201247215

[Table 3] Ex C. glabrata FP2135 pg/ml C.alibicans pg/ml C.parapsilosis pg/ml A.fumigatus pg/ml 183 8 1 8 0.4 186 8 0.5 8 0.25 187 8 1 8 0.5 190 4 0.5 8 0.25 193 8 0.5 2 0.25 206 8 1 8 0.32 217 8 0.5 8 0.5 218 8 0.5 8 0.63 222 8 0.5 8 0.4 224 8 0.5 8 0.32 230 4 1 4 0.32 231 8 1 4 0.32 233 8 0.5 8 0.2 239 4 0.5 4 0.4 240 4 1 8 0.63 242 8 1 8 0.25 248 8 1 8 0.5 263 8 1 8 0.4 272 8 0.5 8 0.32 273 8 0.5 8 0.4 275 8 0.5 8 0.32 285 8 0.5 8 0.2 289 8 0.5 8 0.25 290 8 0.5 8 0.16 Compound A > 32 1 > 32 2 Compound B > 32 16 > 32 32 Compound c > 32 > 32 > 32 > 32 Compound D > 32 4 > 32 3.18 -41 - 201247215 The compounds are as follows. Compound A is the compound of Example 19 of U.S. Patent No. 5,569,646.

Compound 8 is the compound of Example 8 of W098/23637. Compound C is the compound of Example 100 of W09 6/11210. Compound D is a compound of Example 94 of W09 9/4 0108. The above test results confirm that the compound of the formula (I) represented by the table has antifungal activity. Moreover, the compound has antifungal activity not only for C. alibicans, A. fumigatus, but also for C. p ar ap s i 1 o s i s, and further C. glabrata; Echinocandin resistant strain. From this result, it was confirmed that the antifungal activity was excellent as compared with the conventional compound. Thus, the compound of the formula (I) can be used as a prophylactic or therapeutic agent for various fungal infections, particularly infectious diseases of the following fungi. Acremonium:

Aspergillus (eg Aspergillus clavatus, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans 'Aspergillus niger, Aspergillus terreus, Aspergillus versicolor, etc.); Buds (eg Blastomyces dermatitidis, etc.); Yeast (eg Candida albicans, Candida glabrata, Candida guilliermondii, Candida kefyr , Candida krusei, Candida parapsilosis, Candida stellatoidea, Candida tropicalis, Candida utilis, etc.; Cladosporium (eg Cladosporium trichoides, etc.); -42- 201247215 Coccidioides (eg Co ccidioides immitis, etc.); H. sinensis (eg Cunninghamella) Elegance, etc.;; filamentous fungus; outer mold (eg Exophiala dermatitidis, Exophiala spinifera, etc.); epidermal bacteria (eg Epidermophyton floccosum, etc.); colored buds (eg Fonsecaea pedrosoi, etc.);

Bacillus cerevisiae (eg Geotrichum candidum, etc.); tissue bacterium (eg Histoplasma capsulatum variant capsulatum, etc.); Malassezia (eg Malasseziafurfur, etc.); Microsporum (eg Microsporum canis, Microsporum gypseum, etc.); Paraspora (eg Paracoccidioides brasiliensis, etc.); Penicillium (eg Penicillium marneffei, etc.); Bottle mold; Pneumocystis (eg Pneumocystis jiroveci, etc.); Pu Shou De Shili (eg Pu Shou De Shili Phuket, etc.); Yeast ( For example, Saccharomyces cerevisiae, etc.;; Phytophthora sojae; sporotrichosis (such as S ρ 〇r 〇thri X schenckii, etc.); Trichophyton (such as Trichophyton mentagrophytes,

Trichophyton rubrum, etc. 0 In another aspect, the compound of the formula (I) can be used as a prophylactic or therapeutic agent for the following fungal sensation-43-201247215 infection or fungal infection disease. Aspergillus (eg Aspergillus clavatus, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Aspergillus versicolor, etc.); Yeast (eg Candida albicans, Candida glabrata,

Candida gui 11 iermοndii, Candida kefyr, Candida krusei,

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

Pulmonary worms (such as Pneumocystis jiroveci, etc.); Pu Shou Xueli (such as Pu Shou de Shili Phuket, etc.); yeast (such as Saccharomyces cerevisiae, etc.).

The above fungi are known in the kitchen, eye, hair, nail, oral mucosa, gastrointestinal tube, bronchus, lung, endocardium, brain, medulla, urinary tract, vagina, mouth, eyeball, whole body, kidney, palpitations, external auditory canal, Bone, nasal cavity, paranasal cavity, spleen, liver, subcutaneous tissue, lymphatic vessels, gastrointestinal, joint, muscle, tendon, interstitial cells of the lung, blood vessels, etc. cause various infections. Therefore, the compound of formula (I) can be used for Various infectious diseases, such as Pichia sclerotia (such as chalk disease), discoloration of rubella, yeast, Geotrichum, sand hair, Aspergillosis, Penicillosis, sporotrichosis, chromogenic mold Symptoms, coccidioidomycosis, histoplasmosis, blastomy, paracoccal disease, A. licheniformis, foot edema, fungal keratitis, ear fungus, card lung worm, fungal blood Prevention and/or treatment of a disease or the like. One or two or more compounds containing a compound of the formula (I) or a salt thereof can be used as a pharmaceutical composition having a therapeutic ingredient of -44 to 201247215 by using an excipient which is generally used in the field. Use the excipients for pharmaceutical use or The drug carrier or the like is prepared by a usual method. The administration may be oral administration of a lozenge, a nine-dose, a capsule, a granule, a powder, a liquid, or the like, or an intra-articular, intravenous, intramuscular injection, a sitting agent, an eye-dropping agent, an ophthalmic ointment, a transdermal Any form of non-oral administration such as liquid preparation, ointment, percutaneous patch, transmucosal solution, transmucosal patch, and inhalation.

As the solid composition for oral administration, for example, a tablet, a powder, a granule or the like can be used. In such a solid composition, one or more active ingredients may be combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyethylene. Pyrrolidone, and/or magnesium aluminosilicate, and the like are mixed. The composition may contain an inert additive such as a magnesium stearate-like lubricant or a sodium carboxymethyl starch such as a disintegrating agent, a stabilizer, or a dissolution aid. The lozenge or the nine doses may be coated with a film of a sugar-coated or stomach-soluble or enteric material as necessary. The liquid composition for oral administration contains an emulsion, a solution, a suspending agent, a syrup or an elixir which is acceptable for the drug, and a generally usable inert diluent 'for example, contains purified water or ethanol. The liquid composition may contain a solubilizing agent, a wetting agent, a suspending agent-like auxiliary agent, a sweetener, a flavoring agent, a fragrance, and a preservative in addition to the inert diluent. Injections for non-administration include sterile aqueous or non-aqueous solutions, suspensions or opacifiers. The aqueous solvent contains, for example, distilled water for injection or physiological saline. The non-aqueous solvent may, for example, be propylene glycol, poly-45-201247215 ethylene glycol or olive oil-like vegetable oil, ethanol-like alcohol, or polysorbate 80 (office name). Such a composition may further contain an isotonic agent, a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizer, or a dissolution aid. Such as, for example, sterilizing by filtration through a bacterial filter, collocation or irradiation of a bactericide, or a sterile solid composition, which can be dissolved or suspended in sterile water or a sterile injectable solvent before use. Use after turbidity. The external preparation comprises an ointment, a plaster, a cream, a gel, a patch, a spray, a lotion, an eye drop, an eye ointment and the like. It includes a soft binder, a lotion base, an aqueous or non-aqueous liquid, a suspension, an emulsion, and the like which are generally used. For example, an ointment or lotion base may, for example, be polyethylene glycol, propylene glycol, white petrolatum, beeswax, polyoxyethylene hardened castor oil, glyceryl monostearate, stearyl alcohol, hexadecanol, polyglycerol, Loss of sorbitol sesquioleate and the like. A transmucosal agent such as an inhalant or a nasal spray can be used in a solid, liquid or semi-solid form, and can be produced by a conventional method. For example, a conventional excipient or a pH adjuster, a preservative, a surfactant, a lubricant, a stabilizer or a tackifier may be added as appropriate. A device for proper inhalation or insufflation can be used for administration. For example, by using a conventional device such as a metered administration inhalation device or a nebulizer, the compound may be administered as a solution or suspension in combination with a powder of the prescribed mixture or in combination with a pharmaceutically acceptable carrier. The dry powder inhaler or the like may be a single or multiple administration, a dry powder or a powder-containing capsule may be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable expelling agent such as a preferred gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide. -46- 201247215 Particularly, in the case of prevention and/or treatment of fungal infections, it is preferred to use the above-mentioned parenteral injection or inhalation or transnasal agent. Usually, when administered orally, the dosage for one day is about 0.001 to 100 mg/kg, preferably 10 to 30 mg/kg', more preferably 0.1 to 10 mg/kg, which is 1 time or It is divided into 2 times to 4 times. In the case of intravenous administration, the dosage on the 1st day is about 0.0001~10 mg/kg.

1曰1 times~ divided into several times. Further, the mucosa is administered in an amount of about 0.001 to 100 mg/kg on a single day to several times. The dose, the age, the sex, and the like are appropriately determined depending on the occasion. The compound of the formula (I) can be used together with various prophylactic or therapeutic agents for the disease showing the effectiveness of the compound of the above formula (I). The application may be administered at the same time, or separately, or at intervals. At the same time, the formulation can be formulated as a collateral or as a separate formulation. [Embodiment] [Examples] Hereinafter, the production method of the compound of the formula (I) will be further described in detail based on the examples. Further, the present invention is not limited to the compounds described in the following examples. Further, the production methods of the raw material compounds are each shown in the production examples. Further, the method for producing the compound of the formula (I) is not limited to the production method of the specific embodiment shown below, and the compound of the formula (I) can be produced by a combination of the above-mentioned production methods or a method known to the manufacturer. . Further, in the present specification, examples, production examples, and tables to be described later, the following abbreviations are used. -47- 201247215

Ag20=silver oxide, AgOTf=silver trifluoromethanesulfonate, BINAP=1,1'-binaphthyl-2,2'.diylbis(diphenylphosphine), BOC or boc = tert-butoxycarbonyl , BOP = benzotriazole-1-oxyxyl (dimethylamine) iron, B0C2O = ditert-butyl dicarbonate, Bn = benzyl, DBU = 1,8-diazabicyclo[ 5.4_0] eleven-7-ene, CH2C12 or DCM = dichloromethane, CO = - carbon oxide, DCE = dichloroethane, DIPEA = N, N-diisopropylethylamine, DMAc = N, N - dimethyl acetamide, DMF = N, N-dimethylformamide, DMI = 1,3 - dimethyl-2-imidazolidinone, DMSO = dimethyl hydrazine, DPPA = diphenyl Azide phosphate, DPPP = 1,3-bis(diphenylphosphino)propane, EDCI, WSC = 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide, Et3N=three Ethylamine, EtOAc = ethyl acetate, EtOH = ethanol, FMOC = mercaptomethoxycarbonyl, HBTU = o-benzotriazole-1^, meaning; ^', >^'-tetramethyl-urea Key-hexafluorophosphate, 1^081=1-hydroxybenzotriazole, Hex=hexane, Κ3Ρ04 = potassium phosphate, K0Ac=potassium acetate, LHMDS = lithium bistrimethyldecyl decylamine, Mel=methyl Iodide , MS3A = molecular decoration 3Sngstr0m, MeCN = acetonitrile, MgS04 = anhydrous magnesium sulfate, NIS = N-iodosuccinimide, NMM = N-methylmorpholine, NMP = N-methylpyrrolidone, NaBH3CN = cystization Sodium borohydride, NaBH(OAc)3=Sodium triethyloxyborohydride, NaBH4=sodium borohydride, Na2S203=sodium thiosulfate, Na2SO4=anhydrous sodium sulfate, NaBH(OAc)3=triethoxynitride Sodium hydride, NaHC03 = sodium bicarbonate, NaOtBu = sodium tert butoxide, Pd/C = pin carbon, Pd2 (dba) 3 = gin (dibenzylideneacetone) dipalladium (〇), ? (1(:丨2((^?=(1)-bis(diphenylphosphino)ferrocene-palladium(Π) dichloride methylene chloride complex, TBAI = four-48- 201247215 butylammonium iodide, TEA or EtsN = triethylamine, TFA = trifluoroacetic acid 'THF = tetrahydrofuran, TfOH = trifluoromethyl acid extension, AcOH = acetic acid, brine = saturated brine, n-BuOH = n-butanol, n-=positive, sat. = saturated, tert- = third. Also, especially in the formula, 'the following abbreviations are used.

B〇C = third butoxycarbonyl, Bn = benzyl, Et = ethyl, FMOC = mercaptomethoxycarbonyl, methyl, OMe = methoxy, 〇Bn = benzyloxy, OEt = B Oxy, 〇Me=methoxy, 0iPr=isopropoxy, 〇nBu=n-butoxy, 〇nPn=n-pentyloxy, OnPr=n-propoxy, 〇tBu=third butoxy, Tf = trifluoromethanesulfonate, Cbz = benzyloxycarbonyl, iPr = isopropyl, nBu = n-butyl, nHep = n-heptyl, nHex = n-hexyl, nOct = n-octyl, nPn = n-pentyl , nPr = n-propyl, tBu- = tert-butyl. In the following table, (HC1) indicates purification to the hydrochloride salt. Preparation Example 1 6-Chloro-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-1,3-benzothiazole (0.501 g) in toluene (5 mL) Add 4-cyclohexyl-4-methoxypiperidine (343 mg), Pd2(dba)3 (66.3 mg), 2'-(dichlorohexylphosphino)-N,N-dimethylbiphenyl Base-2-amine (42.7 mg) and NaOtBu (0,195 g) were irradiated in a microwave at 1 60 ° C for 1 hour. To the reaction mixture, 0.1 M of HCl was added, followed by stirring for several minutes. The organic layer was washed with brine, dried with MgS04, and concentrated under reduced pressure. Purification by cerium oxide colloidal column chromatography (eluent; Hexane: CHCl3 = 50:50 to 30:70) -49 - 201247215 to give 6-(4-cyclohexyl-4-methoxypiperidine- 1-yl)-2-[4·(tetrahydro-2Η-pyran-2-yloxy)phenyl]-1,3-benzothiazole (734 mg). The compound of Production Example 1-1 to Production Example 1-7 shown in the table below was produced in the same manner as in the method of Production Example 1. Manufacturing Example 2

Methyl 4'-{2-[4-(2-phenylethyl)piperazin-1-yl]imidazo[2,1-1>][1,3,4]thiadipine-6- }}-3-(1,2,3,6-tetrahydropyridin-4-yl)biphenyl-4-carboxylate (201 mg) dissolved in CH2C12 (4.26 mL) MeOH (2, 13 mL) The mixed solvent was added to 1,4-dioxin-2,5-diol (79.8 mg) and NaBH(OAc)3 (140 mg) under ice cooling, and the mixture was stirred at room temperature for 1 hour. An aqueous solution of sat. NaHC03 was added to the reaction solution at 〇 ° C, and extracted with CHC13. The organic layer was washed with brine, dried with MgS 4 and concentrated under reduced pressure. The obtained residue was washed with MeCN to give methyl (ethyl)-ethyl)-1,2,3,6-tetrahydroindole/dt-4-yl]-4'-{2-[4-(2-benzene White ethyl) pyridazin-1-yl]imiphtho[2,lb][l,3,4]thiadiazole-6-yl}biphenyl-4-resulphonate (164 mg) as a white solid . The compound of Production Example 2-1 to Production Example 2-48 shown in the table below was produced in the same manner as in the method of Production Example 2. Production Example 3 Addition of 2-(-bromo-6-(4-bromo-based)midoxime [2,i_b][i,3,4]-exposed dioxime (54 g) in DMAc (840 mL) 2·Phenylethyl)piperazine (34 3 g), E13 N (3 6 · 5 g), was carried out at a bath temperature of 90 ° C; and stirred for B hours. After the mixture was allowed to cool, the reaction was allowed to stand for 3 hours, and the resulting precipitate was suspended in water and then filtered off. The precipitate was washed with water and a small amount of MeCN to obtain 6-(4-bromophenyl). -2-[4-(2-Phenylethyl)piperazine-1-yl]imidazo[2,1-b][l,3,4]thiadiazole (64.7 g). The compound of Production Example 3-1 to Production Example 3-4 shown in the table below will be produced in the same manner as in the method of Production Example 3. Manufacturing Example 4

Piperazine (2.66 g), 130, was added to a solution of 3-bromo-5-(4-bromophenyl)-4,5-dihydro-1,2-oxazole (4.70 g) in NMP (70.5 mL). (:, stirring for 3 hours. Water and EtOAc were added to the reaction mixture for partitioning. The organic layer was washed with brine and concentrated under reduced pressure to give a crude product. The residue was dissolved in CH.sub.2C. Boc20 (4.3 7 g) and stirred at room temperature. Water and E10 A c were added to the reaction mixture, and the mixture was concentrated and concentrated under reduced pressure. The obtained residue was purified by EtOAc (EtOAc). =98:2) Purified to give tert-butyl 4-[5-(4-bromophenyl)-4,5-dihydro-1,2-oxazol-3-yl]piperazine-1-carboxylic acid Ester (3.3 g).

Production Example 5A is 6-(4-bromophenyl)-2-[4-(2-phenylethyl)piperazin-1-yl]imidazo[2,lb][l,3,4]thiadipine Azole (2〇g), {3-[l-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-4-(methoxycarbonyl)phenyl} K3P〇4 (22.6g), 1,2,3,4,5-pentaphenyl-1'- in a mixed solution of boronic acid (2 3.1 g) in dioxane (600 mL) and water (60 mL) (di-161^-butylphosphino) two 201247215

A mixture of ferrocene (1.58 g) was replaced with nitrogen. Pd2(dba)3 (48 8.7 mg) was added, and the inside of the system was again decompressed and replaced with nitrogen. Under a nitrogen atmosphere, the mixture was stirred at 1 Torr for 24 hours. The reaction solution was allowed to cool and the precipitate was filtered. The obtained precipitate was suspended in water (500 mL) and then filtered. Suspended in MeCN (300 mL), stirred under heating and reflux for 30 minutes, and allowed to cool. The precipitate was filtered and washed with a small amount of acetonitrile to give tert-butyl 4-[4-(methoxycarbonyl). -4'-{2-[4-(2-Phenylethyl)piperazin-1-yl]imidazo[2,1-1?][1,3,4]thiadiazole-6-yl} Biphenyl-3-yl]-3,6-dihydropyridine-1(2H)-carboxylate (25.3 g). Production Example 5A shown in the following table was produced in the same manner as in Production Example 5A. 1 to the compound of Production Example 5A-47.

Manufacturing Example 5 B

4,4,4,,4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaboron (1 ·2 g), K〇AC (750 mg), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-U2H)-carboxylate (1.6 g), Dioxane (2 〇 mL) degassed by ultrasonic for 20 minutes was added. Nitrogen was substituted three times in the reaction system. In the reaction system, mg) and dicyclohexyl (2',6'-dimethoxybiphenyl-2-yl)phosphine (245 mg) were added, and the reaction system was again substituted with nitrogen three times. The reaction mixture was at 1 1 Torr. (: (internal temperature 95. 〇 stirring for 3 hours. Return to room temperature, add methyl 2_chloro_4_(tetrahydro-2H-|] than oxa-2-yloxy) benzoate (1 g ), K3P〇4 (750 mg), H2〇 (2 mL) 'At 1 10 ° C (internal temperature 95. 〇 stirring for 2 hours. After diluting the reaction mixture with Et〇Ac, add water to wash) The organic layer was separated into -52-201247215, washed with brine, dried with MgS04, and concentrated under reduced pressure. The residue was purified by succinite column chromatography (Hexane/EtOAc). , tert-butyl 4-[2-(methoxycarbonyl)-5-(tetrahydro-2H-pyran-2-yloxy)phenyl]_3,6-dihydroxypyridine-1 (2H) An orange oil of a carboxylic acid ester (1.3 g). The compound of Production Example 5 B-1 to Production Example 5 B -1 5 shown in the following Table was produced in the same manner as in the method of Production Example 5B.

Production Example 5C 1-[3-(4-Bromophenyl)-1,2,4-oxadiazole-5-yl]-4.[(4,4-dimethylcyclohexyl)oxy] Piperidine (243 mg), {3-[l-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-4-(methoxycarbonyl)phenyl} Boric acid (22 3 mg), Κ3Ρ〇4 (3 5 6 mg), palladium acetate (1 2.6 mg), tricyclohexylphosphine (15.7 mg) of dioxane (4.86 mL)-water (1.22 mL) The mixed solution was stirred at room temperature for 1 hour. After adding EtOAc and water to the reaction mixture, it was filtered over Celite. The filtrate was dispensed and the organic layer was washed with brine. The organic layer was dried with MgS 04 and concentrated under reduced pressure. The obtained residue was purified by cerium oxide colloidal column chromatography (Hexane/EtOAc) to give tert-butyl 4-[4'-(5-{4-[(4,4-dimethyl) ring Hexyl)oxy]piperidin-1-yl}-1,2,4-oxadiazol-3-yl)-4-(methoxycarbonyl)biphenyl-3-yl]-3,6- White solid of dihydroxypyridine-1(2H)-carboxylate (220 mg)

The compound of Production Example 5C-1 to Production Example 5C-27 shown in the table below was produced in the same manner as in the method of Production Example 5C. -53- 201247215

Manufacturing Example 5D

Add tert-butyl 4-[2.(methoxycarbonyl)-5-{[(trifluoromethyl)sulfonyl]oxy}phenyl]-3,6-dihydropyridine_1 (211 )-Carboxylic acid vinegar (441 mg), 4,4,4',4',5,5,5',5'-octamethyl-2,2,-bis-^,2-dioxaborane A reaction vessel of a mixture of (277 mg), triphenylphosphine (33_3 mg), KOAc (279 mg), and a mixture of two chews (5 mL) was subjected to nitrogen reduction in the reaction vessel. After the addition of PdCh(PPh3)2, the nitrogen substitution was repeated, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was returned to room temperature, water was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine. After drying the MgS04, it was concentrated under reduced pressure, and the residue was purified by ruthenium dioxide colloidal column chromatography to obtain tert-butyl 4-[2-(methoxycarbonyl)-5-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (480 mg).

The compound of Production Example 5D-1 to Production Example 5D-6 shown in the table below was produced in the same manner as in the method of Production Example 5D.

Production Example 5E Mixing 4-{5-[4-(2-phenylethyl)piperazin-1-yl]pyrimidin-2-yl}phenyltrifluoromethanesulfonate (2.1 g), [3-chloro 4-(methoxycarbonyl)phenyl]boronic acid (1.1 g), 2.0 M Na2CO3 aqueous solution (5.4 mL), triphenylphosphine palladium (0), DME (2 1 mL), after blowing nitrogen, Stirring was carried out for 2 hours under heating under reflux. After adding the reaction liquid to water, the resulting solid was collected by filtration, washed with water and MeCN, and dried under reduced pressure at 40 ° C to give methyl 3--54-201247215 chloro-4'-{5-[ 4-(2-Phenylethyl)piperazin-1-yl]pyrimidin-2-yl}biphenyl·4carboxylate (1.95 g). The compound of Example 5E-1 to Production Example 5E-29 described later was produced in the same manner as in the method of Production Example 5E.

Production Example 5F was carried out in 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxa shed

垸 (0.125 g), DIPEA (0.16 mL) and tert-butyl 4-[3_(methoxybenzyl)-7-{[(difluoromethyl)minenonyloxy]oxy}-2 - To the naphthyl]-aminopyridine-(2H)-carboxylate (0-22 g), dioxane (2 mL) was degassed by ultrasonication for 2 Torr. The reaction system was substituted with nitrogen three times. Biphenyl-2-yl(dicyclohexyl)phosphine (〇.03 2 g) and Pd(0 Ac) 2 (5 mg) were added to the reaction system, and the reaction system was again substituted with nitrogen three times. The reaction mixture was stirred at 80 ° C for 1 hour. Return to room temperature, add water (0.8 mL), K3P〇4 (0.28 g), tricyclohexylphosphine (〇〇25 g), Pd(OAc)2 (5 mg) and l-[3-(4- Bromophenyl)-l,2,4-oxadiazole-5-yl]-4-[2-(4-fluorophenyl)ethyl]oxime (0.19 g), stirred overnight at 80 °C . After the reaction mixture was diluted with CHC13 (30 mL), water (2 mL) was added and washed. The organic layer was separated, dried over MgS04 and concentrated under reduced pressure. The obtained residue was purified by ruthenium dioxide colloidal column chromatography (CHCl3/MeOH) to afford tert-butyl 4-{7-[4-(5-{4-[2-(4-fluorophenyl)) Ethyl]piperazine-1·yl}-i,2,4-oxadiazole-3-yl)phenyl]-3-(methoxycarbonyl)-2-naphthyl}-3,6-di Hydropyridine-(2H)-carboxylate (0.074 mg) as a yellow solid. -55- 201247215

Manufacturing Example 5 G

Add 0.5 M 9-boron bicyclo[3·3·1]壬 to a solution of tert-butyl 4-methylenepiperidine-1-carboxylate (240 mg) in THF (1.2 mL) under nitrogen. The alkane THF solution (5.00 mL) was heated to reflux for 1 hour. To the reaction solution were added methyl 4-chloro-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (323 mg), Κ3Ρ〇4 (538 mg), PdCL2(dppf)CH2CL2 ( 62.0 mg), water (0·84 5 mL), and stirred at 80 ° C for 12 hours. The reaction solution was added with water and extracted with EtOAc. After washing with brine and drying with MgS04, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex: EtOAc) to give tert-butyl 4_[5·chloro·2 - (Methoxy group) alkaloid] piperazine-1-residate (184 mg) as a thin yellow oil. Manufacturing Example 6

Tert-butyl 4-[5-hydroxy-2-(methoxycarbonyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (5.33 g), 1,1,1 -Trifluoro-N-phenyl-N-[(tri-gasmethyl)-enriched base] A-line amine (6.30 g), and DIPEA (d = 0.742, 8 mL) in DMF (50 mL) Stirring was carried out for 5 hours at room temperature. The reaction solution was extracted by adding EtOAc. The organic layer was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex/EtOAc) to afford tert-butyl 4- [2-(Methoxycarbonyl)-5-{[(trifluoromethyl)sulfonyl]oxy}phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (6.7 g) yellow oil. -56-201247215 In the same manner as in the method of Production Example 6, the compounds of Production Example 6-1 to Production Example 6-26 shown in the following Table were produced. Manufacturing Example 7

5-[4-(2-Phenylethyl)piperazine-1·yl]-1,3-thiazol-2-amine (4 < 75 mg) and 2-bromo-1-(4-bromophenyl) Ethyl ketone (460 mg) was stirred in n-BuOH (6 mL) at 90 ° C for 1 hour. After the reaction mixture was cooled to room temperature, EtOH (5 mL) was added, and the precipitate was collected by filtration. The obtained solid was washed with EtOH and dried at 40 ° C under reduced pressure to give 6-(4-bromophenyl) a purple solid of 2-[4-(2-phenylethyl)piperazin-1-yl]imidazo[2,lb][l,3]thiazole (731 mg). Production Example 8 In a solution of 5-fluoro-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidine (7.20 g) in DMSO (72 mL), 1-(2) -Phenylethyl)piperazine (9.93 «11〇 and K2C03 (7.26 g), stirred at 140 ° C for 20 hours. After cooling to room temperature, water (100 mL) was added to the reaction mixture and filtered. The resulting precipitate was washed with IP E and dried overnight at 40 ° C under reduced pressure to give 5-[4-(2-phenylethyl)piperazin-1-yl]-2- [4-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidine (10.06 g). Production Example 8-1 to Production Example shown in the following Table was produced in the same manner as in Production Example 8. Compound of 8-26" Manufacturing Example 9 -57- 201247215

Add (2R)-2-methylperidine to a solution of 5-fluoro-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidine (500 mg) in NMP (2.5 mL) The azine (547 mg) and K2C03 (1.26 g) were stirred at 140 ° C for 6 hours. Further, (2R)-2-methylpiperazine (547 mg) and K2C03 (1.26 g) were added, and the mixture was stirred overnight. Brine (10 mL) and water (10 mL) were added to the mixture, and the mixture was applied with EtOAc. The organic layer was washed four times with brine, dried with MgS04, and concentrated under reduced pressure. To the obtained residue CH2C12 solution (3.5 mL), phenylacetaldehyde (245 μ! 〇, NaBH(OAc) 3 (502 mg) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was slowly added to sat. The aqueous solution of NaHC03 was extracted twice with CH2C12. The organic layer was dried over MgS04, and the residue was purified (Hexane: CHCl3:EtOAc = 1:1:1 to 0:70:30) to give 5-[(3R)- 3-Methyl-4-(2-phenylethyl)piperazin-1-yl]-2-[4-(tetrahydro-2H-pyranyloxy)phenyl]pyrimidine (600 mg).

The compound of Production Example 9-1 shown in the following Table was produced in the same manner as in the method of Production Example 9. Production Example I 3- 3-[l-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-4'-{2-[4-(2-phenyl Ethyl)piperazin-1-yl]imidazo[2,lb][l,3,4]thiadiazole-6-yl}biphenyl-4-carboxylic acid (1 g), BOP (768 mg) , DMF, DIPEA (d = 0.742 662 μ! 混合物 mixture was stirred at room temperature for 1 hour. Add the compound of Example No. 169 (1.5 〇g) of International Publication WO99/40 1 08, overnight at room temperature Stirring. Add -58- 201247215 to the reaction solution.

EtOAc (10 mL) was obtained, and the resulting precipitate was filtered and dried under reduced pressure for 3 hours. After dissolving the powder in a solvent (MeCN: H20 = 1:1), a 1 M aqueous NaOH solution was added thereto, and the mixture was diluted with water while stirring. This solution was purified by ODS medium pressure column chromatography, and then freeze-dried to obtain the compound (1.76 g) of Production Example 10.

In the same manner as in the method of Production Example 10, the compounds of Production Examples 10-1 to 10-24 and Production Examples 1 - 2 6 to 10 - 33 shown in the following Table were produced. Production Example 10-25 was obtained by subjecting a condensation reaction according to the method of Production Example 10, followed by cyclization by the method of Production Example 18. For purification and purification, general chemical operations such as extraction, separate crystallization, various fractionation chromatography (for example, ODS column chromatography or cerium oxide colloidal column chromatography), and production examples or examples of the present specification can be used. The method described or according to the method suitable for the compound in the method. Production Example 11 A mixture of the compound of Example 33-25 (451 mg), BOP (328 mg), DMF (6.77 mL), and DIPEA (d = 0.742, 282.0 μm) was stirred at room temperature for 1 hour. The compound (642 mg) of Example No. 169 of International Publication No. WO99/40 1 08 was added, and stirred overnight at room temperature. EtOAc (300 mL) was added to the reaction mixture, and the resulting precipitate was collected by filtration. A MeOH solution of Pd/C (2 2 5.5 mg) was added to the solution of Me0H-H20, and the mixture was stirred for 9 hours in an H2 atmosphere, and Pd/C (90.0 mg) was further added to the reaction mixture for 7 hours. The reaction solution was washed with diatomaceous earth (Η 2 Ο : M eCN = 1 : 1), -59-201247215. After the solvent was distilled off under a reduced pressure, H20:MeCN = 80 was added to the obtained solution: 20 and 1 M NaOH aqueous solution were purified by 〇ds column chromatography (H20:MeCN = 80:20 to 20:80) to obtain the compound of Example n (356 mg).

2-(4-Bromopyridin-2-yl)-1-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]ethanone oxime (1.6 g) in CH2C12 (16.0 mL) DIPEA (d = 0.726, 1.71 mL) was added to the turbid liquid, and TFAA (d=l_49, 865 μ! 〇 dripping) was allowed to make the reaction mixture at 7 ° C to 10 ° C for 1 hour and water cooling for 2 hours. After stirring, the reaction solution was washed with 50 ml of water, and the organic layer was dried with MgS 4 and then concentrated under reduced pressure. Chromatography column chromatography (eluent; Hexane: Ett) Purification with Ac = 80:20) gives 4-bromo-2-{3-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2H-argiline-2-yl Pyridine (1.38 g) oily substance.

Production Example 1 3 Under a nitrogen atmosphere, 5·bromo-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyridine (1.20 g), 4-cyclohexyl-4-methyl Pd(dba)2, (413 mg), BINAP (671 mg) were added at room temperature in a solution of oxypiperidine hydrochloride (1.26 g) and Cs2C03 (5.26 g) in toluene (12 mL). The solution was refluxed overnight. After cooling to room temperature, CHC13 water was added to the reaction mixture to carry out partitioning. The organic layer was washed with brine, dried with MgS04, and concentrated under reduced pressure. The obtained solid was suspended in IPE and stirred for 30 minutes. The solid was washed and pulverized with -60 - 201247215 IPE to give 5-(4-cyclohexyl-4-methoxypiperidin-1-yl)-2-[4-(tetrahydro-2H-indole-pyran- 2-Ethyloxy)phenyl]pyrene is an orange solid with η (632 mg).

Manufacturing Example 14A

Tert-butyl 4-{4-(methoxyoxy)-4'-[5-(indol-1-yl)pyrimidin-2-yl]biphenyl-3-yl}-3,6 -dihydropyridine-1(2H)-carboxylate (400 mg)' 1-(2-bromoethyl)-2-methylbenzene (215 mg), K2C03 (1 99 mg), NaI (162 mg), The mixture of DMI (13.3 mL) was stirred at 140 ° C for 20 hours. After cooling, it was diluted with EtOAc, washed with a sat. NaH.sub.3 aqueous solution and dried over MgSO. After concentrating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent; CHCl3:EtOAc = 100:0 to 3:1) to afford tert-butyl 4-[4- (methoxycarbonyl)-4'-(5-{4-[2_(2-methylphenyl)ethyl]piperazine-l-yl}pyrimidin-2-yl)biphenyl-3-yl] -3,6-Dihydropyridine-1(2H)-carboxylate (160 mg). The compound of Production Example 14A-1 to Production Example 14A-15 shown in the table below was produced in the same manner as in the method of Production Example 14A. General chemical operations such as purification, purification, extraction, crystallization, various fractionation chromatography (for example, ODS column chromatography or cerium oxide colloidal column chromatography), and manufacturing examples or examples of the present specification The method described or according to the method suitable for the compound in the method.

Manufacturing Example 1 4 B -61 - 201247215

Under ice cooling, trans-4-[3-(4-bromophenyl)-l,2,4-oxadiazol-5-yl]cyclohexanol (200 mg), CH2C12 (2 mL)' AgOTf (310.06 mg), 2,6-diter-tert-butylpyridine (d = 0.870, 306.2 μ! 加入 added a mixture of 1-iodopropane (d = 1.743, 109 μΙ〇, stirred for 10 minutes. Back The mixture was stirred at room temperature for 1 hour. After the reaction mixture was filtered through celite, the broth was washed with 1 Μ hydrochloric acid water, sat. NaHC 3 water, water, brine, dried with MgS04, and concentrated under reduced pressure. The residue was purified by ruthenium dioxide colloidal column chromatography (eluent; EtOAc/Hexane) to give 3-(4-bromophenyl)-5-(trans-4-propoxycyclohexyl)-1 White solid of 2,4-oxadiazole (168 mg). The compound of Production Example 14B-1 to Production Example 14B-4 shown in the following Table was produced in the same manner as in the method of Production Example 14B.

Manufacturing Example 14C

Trans-4-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl]cyclohexanol (200 mg) with 1.0 M triethyloxonium tetrafluoro A mixture of the boric acid ester in dichloromethane (1 mL) was stirred overnight at room temperature. Water was added to the reaction mixture and extracted with E10 A c . The organic layer was washed with water and brine, dried over MgS04, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent; Hexane/EtOAc) to give the object 3 -(4-Bromophenyl)-5-(trans-4-ethoxycyclohexyl)-1,2,4-oxadiazole (1 73.2 mg) as a white solid. Production Example 15 - 62 - 201247215 tert-butyl 4-carbazide-bry residue (3 〇〇mg) in THF (3 · 0 1111 〇 solution in '〇. 〇, added 八 82 〇 (69 〇 111 §), a solution of 6-bromo-; 3,3-dimethylcyclohexene (640 mg) in THF was added. After stirring overnight at room temperature, the mixture was filtered and the filtrate was washed with EtOAc. The mixture was dried over MgS 〇 4 and concentrated under reduced pressure. Purified by cerium dioxide colloidal chromatography (eluent; Hexane/EtOAc) to give tert-butyl 4-[(4,4-dimethyl A colorless transparent solid of hexyl-2-ene-byl)oxy]piperidine-i-carboxylate (121 mg).

Tert-butyl 4-[4-(tert-butoxycarbonyl)-4'-cyanobiphenyl-3-yl]-3,6-dihydropyridine-1(2H)-carboxylate (3.2 g) A mixture of hydroxylamine hydrochloride (1 03 8 mg), NaHC03 (1 75 1 mg) and MeOH (48 mL) was stirred at 80 ° C for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over MgS04, and concentrated under reduced pressure to give tert-butyl 4-{4'-[amine (hydroxyimino)methyl]-4-(tert-butyl) Oxycarbonyl)biphenyl-3-yl}-3,6-dihydropyridine-1(2H)-carboxylate (3.2 g) as a white solid. In the same manner as in the production of 16, the compounds of Production Example 16-1 to Production Example 16-3 shown in the following Table were produced. Production Example 1 7 1-[4-(Benzyloxy)phenyl]-2-bromoethane (2.48 g), 5-bromo-2-pyridinamine (155 g), and 95% EtOH (20 mL) The reaction mixture was refluxed at 3 - 63 - 201247215 hours, and further stirred at 60 ° C for 12 hours. After allowing to cool, the precipitate was collected by filtration to give 2-[4-(benzyloxy)phenyl]-6-bromoimido[1,2-a]pyridine (2.76 g) as a solid. Production Example 18 A mixture of 4-bromo-indolyl-({[4-(4-chlorophenyl)cyclohexyl)carbonyl]oxy)phenylcarboxyimine decylamine (862 mg) and DMAc (8.62 mL) Stir at 120 ° C for 6 hours. The reaction solution was returned to room temperature. Water was added and stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to give 3-(4-bromophenyl)-5-[4-(4-chlorophenyl)cyclohexyl]-1,2,4-oxadiazole (732.9 mg) ) beige powder. In the same manner as in the method of Production Example 18, the compound of Production Example 18-1 to Production Example 18-22 shown in the following Table was produced. Production Example 19 Under a nitrogen atmosphere, in 4-bromo-2-{3-[4 -(Tetrahydro-2H-pyran-2-yloxy)phenyl]-2H-agilt-2-yl}pyridine (1.36 g) in MeCN (13.6 mL), FeCl2 (46.1 g) The mixture was heated and stirred for 2 hours in an oil bath (60 ° C). After cooling to room temperature, MeCN was concentrated under reduced pressure. The residue obtained was dissolved in CHC13 (200 mL) and water (1 mL) was added. The insoluble matter was removed by filtration through diatomaceous earth. The organic layer of the filtrate was separated and the aqueous layer was extracted with CHC 13 (50 mL). The extracts were combined, dried with MgS04, and subjected to activated carbon treatment. After filtration, the solvent of the filtrate was distilled off. The crude product was subjected to cerium oxide colloidal column chromatography (eluent; -64-201247215)

Hexane: CHCl3 = 2:1) was purified to give 5-bromo-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrazolo[l,5-a]pyridine (8 60 mg) ° Manufacturing Example 20

a reaction mixture of 4-bromo-indolyl-[(trans-4-methylcyclohexyl)carbonyl]benzoindole (300 mg), P2S5 (216 mg) and THF (6 mL) at 5 ° C. Stir for 5 hours. Water, a 1 M aqueous NaOH solution (420 μί) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The resulting precipitate was collected by filtration, dried under reduced pressure and purified by silica gel column chromatography (eluent; CHCl3:EtOAc = 20:1) to give 2-(4-bromophenyl)-5- (trans-4-methylcyclohexyl)-1,3,4-thiadiazole (223 mg) as a white solid. In the same manner as in the method of Production Example 20, a compound of Production Example 20-1 shown in the following Table was produced. Production Example 2 1 4-Bromo-N-[2-(4-cyclohexyl-4-methoxypiperidin-1-yl)-2-oxoethyl]phenylguanamine (1.67 g), pyridine ( A mixture of 16.7 mL) and P2S5 (1.70 g) was stirred at 100 ° C for 6 hours. Water was added to the reaction mixture, and the mixture was made alkaline with a 1 NaOH aqueous solution, and stirred for 15 minutes. The reaction solution was extracted with CHC13, washed twice with 1M EtOAc, and then washed with water and EtOAc. MeOH was added to the obtained residue, and the precipitate was collected by filtration. The residue was washed with MeOH and dried under reduced pressure to give 1-[2-(4-bromophenyl)-1,3-thiazol-5-yl]-4-cyclohexyl--65-201247215 4- A beige solid of oxypiperidine (1.25 g). Manufacturing Example 22

Anhydrous CeCl3 (7.62 g) was finely pulverized in a glove box in a three-diameter flask filled with nitrogen gas. The flask was taken out of the glove box and replaced with argon. Anhydrous THF was added to the flask, and the reaction mixture was stirred vigorously overnight at room temperature. In the reaction system, a 2.0 Μ diethyl ether solution (15.5 mL) of η-pentyl magnesium bromide was added over 10 minutes, and the internal temperature was maintained at 1 〇 ° C or less using an ice bath. The reaction mixture was stirred at room temperature for 3 hours. The THF solution of tert_butyl 4-oxopiperidine-1-carboxylate was added to the reaction mixture over a period of 15 minutes, and the internal temperature was maintained at 1 °C or less using an ice bath. The reaction mixture was stirred at 4 ° C for 1.5 hours. 10% acetic acid was slowly added to the reaction mixture, and the reaction mixture was extracted twice with EtOAc. The organic layer was washed with water and brine and dried with MgS04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by ruthenium dioxide colloidal column chromatography (120 g of ruthenium dioxide colloid; eluate; Hexane: EtOAc = 95:5 to 75:25) to give tert-butyl 4-hydroxy-4-pentyl. Piperidine-1-carboxylate (5.16 g) as a white solid. In the same manner as in the method of Production Example 22, the compounds of Production Example 22-1 to Production Example 22_4 shown in the following Table were produced. Production Example 23 In a solution of 2-(4-bromophenyl)-1,3,4-oxadiazole in acetic acid, bromine (251.8 μ! 花费 was added at room temperature for 1 Torr. 1.5 small-66- 201247215

Stir when. The reaction solution was heated to 5 and stirred for 1.5 hours, and bromine (1 14.5 μM was added thereto, and stirred at 50 ° C for 5 hours. Bromine was added to the reaction solution (1 14 · 5 μM at 50 ° C). The reaction mixture was stirred for 5 hours. The reaction mixture was taken to room temperature, then 1M aqueous EtOAc (200 mL), EtOAc (200 mL) was evaporated. The organic layer was separated and washed with 1M NaOH aqueous solution (100 mL) with 10% Na2S2O3 After washing with water and brine, it was dried over MgS04 and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hexane. 'EtOAc) to give 2-bromo-5- (4) a white solid of -bromophenyl)-1,3,4-oxadiazole (404 mg). In the same manner as in the method of Production Example 23, Production Example 23-1 to Production Example 23-2 shown in the following Table were produced. Preparation Example 2 4 In a mixture of 4-(4-bromophenyl)-1,3.oxazole (787 mg) and THF (17.3 mL) under an argon atmosphere, the internal temperature was -65 to -60. C. LHMDS (4.7 mL) was dripped for 8 minutes. The reaction mixture was stirred in an MeCN/dry ice bath at an internal temperature of -43 ° C for 30 minutes. Hexachloroethane (1.66 g) was added and the mixture was warmed to room temperature. get on Stir in the night. Add EtOAc and water to the reaction mixture. The organic layer was separated, washed with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc Hexane/EtOAc is a white solid of 4-(4-diphenyl)-2-chloro-1,3-Doxan (630 mg). Manufactured from 25-67-201247215

White suspension of MeOH at 〇 °C of benzylidene-4-[3-(4.bromophenyl)-l,2,4-oxadiazole-5-yl]pyridine iron bromide (1.24 g) Turbid, a small amount of NaBH4 (198 mg) was added in small portions. The yellow reaction suspension was stirred at the same temperature for 1 hour. Solid nh4ci was added to the reaction mixture, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was subjected to EtOAc: THF = 4:1. The organic layer was washed with brine, dried over MgS04, and concentrated under reduced pressure. The residue was purified by ruthenium dioxide colloidal column chromatography (eluent; Hexane: EtOAc = 80:20 to 60:40) to give 1-benzyl- 4-[3-(4-bromophenyl)- 1,2,4-oxadiazol-5-yl]-1,2,3,6-tetrahydropyridine (0.39 g) as a yellow oil. Manufacturing Example 26

a suspension of 5-bromo-1,3,4-thiadiazol-2-amine (26 g), 2-bromo-1-(4-bromophenyl)ethanone (40.1 g) in n-BuOH (780 mL) was stirred at 125 t: for 20 hours. After the reaction mixture was allowed to stand for cooling, EtOH (1 600 mL) was poured and stirred for 2 hours, and the precipitated solid was collected by filtration. The solid was washed with EtOH to give 2-bromo-6-(4-bromophenyl)imidazo[2,1-1]][1,3,4]thiadiazole as a white powder (38.3 g). Production Example 27 2-[(6-Bromo-1-chloro-2-naphthalenyl)oxy]tetrahydro-2H-pyran (54.5 g) and triisopropyl borate (44 mL) were mixed under a nitrogen atmosphere. THF (550 mL). A 2.76 M n-BuLi-hexane solution (69.4 mL) was added dropwise at an internal temperature of -65 to -60 ° C for 30 minutes, and the mixture was stirred for 1 hour while warming to room temperature. Anti-68- 201247215 Add MeOH (30 mL) to the solution for 1 hour. Add brine (400 mL) and adjust to pH = 4 with 1 M hydrochloric acid. Extraction with EtOAc (1 000 mL, 500 mL). The organic layer was washed with brine (400 mL) and dried over MgSO4, and concentrated under reduced pressure. hexane (600 mL) was added to the residue and the precipitate was collected by filtration. Then, it was dried under reduced pressure to give [5-chloro-6-(tetrahydro-2H-pyran-2-yloxy)-2-naphthalenyl]boronic acid (46.7 g) as a white solid.

Preparation Example 28 In a solution of hydroxycarbodiimide dibromide (5.00 g) in DMF (25 mL), 1 -bromo-4-vinylbenzene (5.41 g) was added at 5 ° C, followed by

An aqueous solution of NaHC03 (6.16 g) was added dropwise and stirred overnight. Water was added to the reaction mixture, and the mixture was evaporated. The residue obtained was purified by ruthenium dioxide colloidal column chromatography (eluent; Hexane: EtOAc = 90:10) to give 3-bromo-5-(4-bromophenyl)-4,5-dihydroiso Oxazole (7.14 g). Production Example 29 In an aqueous solution of sodium periodate (95 7 mg) and ammonium acetate (3 45 mg), tert-butyl 4-[2-(methoxycarbonyl)-5-(4,4,5 was added. ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]_3,6-dihydropyridine-1(2H)-carboxylate (1.32 g) in EtO Ac solution Stir for 3 days. The precipitate was collected by filtration and washed with EtO Ac. After the combined filtrate and the washing liquid were separated, the organic layer was washed with a 5% Na2S203 7jc solution and brine, dried over MgS04, and concentrated under reduced pressure -69-201247215 to give a crude product. The crude product was purified by ruthenium dioxide colloidal column chromatography (eluent: CHCl3: MeOH = 100:0 to 90:10) to afford {3-[l-(tert-butoxycarbonyl)-1,2 , 3,6-tetrahydropyridin-4-yl]-4-(methoxycarbonyl)phenyl}boronic acid (860 mg) ^ In the same manner as in the method of Production Example 29, Production Example 2 shown in the table below was produced. 9-1 compound. Manufacturing Example 3 0

Tert-butyl 4-{3-[4-(5-chloro-6-{[(trifluoromethyl)sulfonyl)oxy-2-naphthyl)phenyl]-1,2,4- Oxadiazole-5-yl}piperazine-1-carboxylate (850 mg), D Μ 1 (5 6.7 mL), Pd(OAc) 2 (3 4 mg) ' Et3N (d = 0.726,93 5 Μΐ^), propane-1,3-diylbis(diphenylphosphine (125 mg)

The reaction mixture with MeOH (22.6 mL) was charged with carbon monoxide. The reaction mixture was stirred under a carbon monoxide atmosphere at 5 hours and 95 °C. The reaction mixture was allowed to cool to room temperature and water (200 mL) was added. The reaction mixture was filtered, and the obtained solid was washed with water. The solid was dissolved in CHC13. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by ruthenium dioxide colloid chromatography (eluent: Hexane: CHC13 = 50:50~ Et?Ac: CHCl3 = 15:75) to give tert-butyl 4-(3-(4-[5 -Chloro-6-(methoxycarbonyl)-2-naphthyl]phenyl}-1,2,4-oxadiazole-5-yl) piperazine-1-carboxylate (440 mg) white In the same manner as in the method of Production Example 30, the compound of Production Example 30-1 shown in the table below was produced. -70-201247215 Production Example 3 1

Dissolve tert-butyl 4_hydroxy-4_pentylpiperidine-oxime carboxylate ("ο mg) in THF 'under cold, add NaH (60% oily suspension, 1 30 mg) at room temperature Stir for 1 hour. The reaction solution was ice-cooled, and iodomethane (0.925 g) was added thereto for stirring for 5 minutes, and further stirred at room temperature for 5 hours. Water was added to the reaction mixture, which was partitioned between EtOAc and water. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to afford tert-butyl 4-methoxy-4-pentylpiperidine-1-carboxylate (590 mg) A colorless, transparent oily substance. In the same manner as in the method of Production Example 31, the compound of Production Example 31-1 to Production Example 31-5 was shown in the following Table. Production Example 3 2 6-Ethoxy-2-naphthoic acid (5 g), TBAI (12 g) and

NIS (5 g) was added to a solution of Pd(OAc) 2 (500 mg) in DMF (100 mL). The reaction solution was stirred at 45 ° C for 8 hours. To the reaction mixture, NIS (5 g)' was added and stirred at 45 ° C for 12 hours. NIS (5 g) and Pd(0Ac) 2 (1 〇〇 mg) were added to the reaction mixture, and after stirring for 20 hours, Pd(OAC) 2 (100 mg) and NIS (5 g) were added, followed by stirring for 48 hours. The reaction mixture was cooled to 〇 ° C and K 2 C 〇 3 was added. In the reaction solution, M e I ' was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc. The organic layer was washed twice with an aqueous solution of Na2S2?3, aq. iM NaOH, H.sub.2, and 0.05M of HCl, and then washed with <RTI ID=0.0>> The obtained residue was purified by ruthenium dioxide colloidal column chromatography (eluent: CHC13, Hexane/EtOAc) to give methyl 6-acetoxy-3·iodo-2-naphthalate (6.37 g). a yellow solid mixed with impurities. Manufacturing Example 33

Methyl 3-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-4'-{2-[4-(2-phenylethyl) Piperazine-1-yl]imidazo[2,1-15][1,3,4]thiadiazol-6-yl}biphenyl-4-carboxylate (164 mg) in dioxane A 1 M aqueous NaOH solution (2.52 mL) was added, and stirred at 100 ° C for 5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and then water and 1 hydr. The precipitate was collected by filtration. The obtained solid was washed with 丨ρ , to give 3-[1-(2-hydroxyethyl)-indole, 2,3,6-tetrahydropyridin-4-yl]-4,-{2-[4- (2-Phenylethyl)piperazin-1-yl]imidazo[2,lb][l,3,4]thiadiazole-6-yl}biphenyl-4-residic acid (151 mg).

In the same manner as in the method of Production Example 3 3, the compound of Production Example 3 3 -1 to Production Example 3 3 - 1 3 5 shown in the table below was produced. However, the compound of Production Example 3 3 _ 2 5 was obtained by hydrolyzing it according to the method of Production Example 3 3, adding water to the reaction liquid, and filtering the resulting precipitate. Purification, purification, extraction, and crystallization, respectively, various chemical operations such as various fractionation chromatography (for example, ODS column chromatography or cerium oxide colloidal column chromatography), and manufacturing examples or examples of the present specification The method described or according to the method suitable for the compound in the method. Manufacturing Example 3 4 -72- 201247215

〇°(:, 2-(3-isopropoxyphenyl)ethanol (20 〇 11^) (: 112 (: 12 solution (2 mL), added Dess-Martin Periodinane (565 mg), room Stirring was carried out for 2 hours at a temperature. In the reaction mixture, aqueous solution of sat. NaHC〇3 (5 mL) and aqueous solution of sat. Na2S203 (5 mL) were added, and extracted twice with CH2C12 (5 mL). Concentration under reduced pressure. The residue was purified by silica gel column chromatography (eluent; Hexane: EtOAc = 90:10 to 70:30) to give (3·isopropoxyphenyl) Colorless oily substance of furfural (175 mg). The compound of Production Example 34-1 to Production Example 34-3 shown in the following Table was produced in the same manner as in the method of Production Example 34. Production Example 3 5 DMF (2 mL) The reaction mixture of the compound of Example 1 61 (丨丨〇mg), B0C20 (19.9 mg) and DIPEA (d = 0.742, 31.8 μιη) was stirred at 25 ° C for 4 hours. (20 mL) was diluted to give a precipitate, which was filtered, and the obtained solid was washed with Et EtOAc to give the compound of the compound of Example 3 (1 02 mg). Preparation Example 36 dCh (65 mL) Mixture of methyl 2-chloro-4-hydroxybenzoic acid vinegar (8.73 g), 3,4-dihydro-2H-pyran (1 1.98 6 g) and PPTS (4 g) at room temperature 1 8 The reaction mixture was diluted with E t Ο A c and washed with a sat. NaHCO 3 aqueous solution. The separated organic layer was washed with brine. After drying with MgS 4 , the residue was concentrated under reduced pressure to give residue. 73- 201247215 Separation of ruthenium dioxide column chromatography (Hexane: EtOAc = 9:1) to give methyl 2-chloro-4-(tetrahydro-2H-pyran-2-yloxy)benzoic acid A yellow oil of the ester (1 〇·6 g) was produced in the same manner as in the method of Production Example 36, and the compound of Production Example 36-1 to Production Example 3-6-3 shown in the following Table was produced.

Under ice cooling, trans-4-[3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl]cyclohexanol (4 丨〇mg), benzyl 2,2 TfOH (0.0553 mL) was added to a mixture of 2-trichloroethane sulfimine (545 mg) and CH2C12 (6.15 mL). The temperature was raised to room temperature and stirred for 2 hours. The reaction was diluted with EtOAc and sat. NaHC03 7-K solution was added. The organic layer was washed with brine, dried over MgS04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; Hexane: EtOAc) to give 5-[trans- White solid of 4-(benzyloxy)cyclohexyl]-3-(4-bromophenyl)-1,2,4-oxadiazole (293 mg). Production Example 3 8 2-[4- (benzyloxy)phenyl]-6-[4-(2-phenylethyl)piperazin-1-yl]imidazo[l,2-a]pyridine (270 mg), 10% Pd/C (294 mg),

A mixture of MeOH (8.1 mL) and THF (5.4 mL) was stirred overnight at room temperature under 3 atmospheres of hydrogen. The solvent was concentrated under reduced pressure to give 4-{6-[4-(2-phenyl A gray solid of ethyl)piperazin-1-yl]imidazo[1,2-a]pyridin-2-yl}phenol (1,94 mg). -74-201247215 The same as the method of Production Example 38 The compound of Example 3 8 -1 was not produced in the table. Manufacturing Example 3 9

Benzyl trans-4-(3-methylbutoxy)cyclohexanil residual acid vinegar (700 mg), EtOAc (19.5 mL), and Pd/C 10% (50% wet under atmospheric hydrogen atmosphere) A mixture of 70 mg) was stirred at room temperature for 5 hours. The reaction solution was filtered through Celite to remove Pd/C, and the filtrate was concentrated under reduced pressure to give a white solid of trans-4-(3-methoxybutoxy)cyclohexanecarboxylic acid (470 mg). . The compound of Production Example 39-1 to Production Example 39-3 shown in the following Table was produced in the same manner as in the method of Production Example 39. Preparation Example 40 Preparation of tert-butyl 4-[4-(methoxycarbonyl)-4'-{2-[4-(2-phenylethyl)piperazin-1-yl]imidazo[2,lb ][l,3,4]thiadiazole-6-yl}biphenyl-3-yl]-3,6-dihydropyridine-l(2H)-carboxylate (28 7 mg) dissolved in dioxins Alkane (3.5 mL) was added to 4M EtOAc / EtOAc (3 mL) and stirred at room temperature for one hour. The reaction mixture was diluted with IP E, and the precipitate was filtered, washed with IPE and dried under reduced pressure. CH2C12 was added to the obtained powder. The organic layer was washed with NaHC03 and brine, and the organic layer was concentrated under reduced pressure to give methyl 4,-{2-[4-(2-phenylethyl)indolyl] and [2, lb] [l,3,4]thiadiazole-6-yl}-3-(1,2,3,6-tetrahydropyridin-4-yl)biphenyl-4-carboxylate (201 mg). -75-201247215 The compound of Production Example 40-1 to Production Example 40-23 shown in the following Table was produced in the same manner as in the method of Production Example 40. Production Example 4〇-2 After the reaction was carried out in accordance with Production Example 40, the reaction mixture was concentrated under reduced pressure to give a residue powder. The compounds of Production Examples 40-1 to 40-23 were reacted according to Production Example 40, and the hydrochloride salt compound was purified according to the method of Production Example 40-2, and the other compounds were purified according to the method of Production Example 40. And get it.

Manufacturing Example 4 1

Tert-butyl 4-{4-(1^(-butoxycarbonyl)-4'-[5-(trans-4-butoxycarbonyl)-1,2,4-oxadiazole- A mixture of 3-yl]biphenyl-3-ylbu- 3,6-dihydropyridine-1(2H)-carboxylate (135 mg) and 4M HCl/EtOAc (3 mL) Stirring was carried out for 5 hours. To the residue was added dioxane, 2M aqueous Na2CO3 (0.41 mL), and 9H-purin-9-ylmethyl chlorocarbonate (5 5.7 mg). After stirring for 4 hours, water was added to the reaction mixture, and the mixture was adjusted to ρ Η = 2 with 1 Μ hydrochloric acid water, and extracted with EtOAc. The mixture was washed with water and brine. The organic layer was dried with MgSO 4 and concentrated under reduced pressure to give 4 '-[5-(trans-4-butoxycyclohexyl)-1,2,4-oxadiazole-3-yl]-3-{1-[(9Η-芴-9-ylmethoxy) a white blister solid of carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}biphenyl-4-carboxylic acid (150 mg), which was produced in the same manner as in the method of Production Example 41. Production Example 4 1 -1 to Production Example 4 1 - 2 Compound" - 76 - 201247215 Production Example 42

Pd/C 10%, 50% wet (1.19 g) was added to a solution of the compound of Example 10-2 (2.38 g) in MeOH/H.sub.2 (23.8 mL / 23.8 mL), and the mixture was stirred for 7 hours. The reaction solution was filtered through celite. After the filtrate was distilled off under reduced pressure, a H20:MeCN = 80:20 solution and 1M aqueous NaOH solution were added to the obtained solution, and purified by ODS column chromatography (H20:MeCN = 80:20 to 20:80). MeCN, which was subjected to fractionation, was distilled off under reduced pressure, and then freeze-dried to give the compound of Example 42 (470 mg). In the same manner as in the method of Production Example 42, the compound of Production Example 42-1 to Production Example 4-2-4 shown in the following Table was produced. Purification and purification using general chemical operations such as extraction, crystallization, various fractionation chromatography (ODS column chromatography or cerium oxide colloid chromatography), and the production examples or examples of the present specification Method or according to suitable compounds in the method

Preparation Example 43 'Et; (N (15.3 mL) with 2-nitrophenylsulfonyl chloride in a solution of tert-butylpiperazine-1-carboxylate (17 g) in CH2C12 (3 40 mL) (22.3 g) Under ice-cooling, add '5 minutes at the same temperature, and stir for 4.5 hours at room temperature. In the reaction mixture, (TC, add water (150 mL) and extract three times with EtOAc. The layers were washed with brine and dried with MgSO4. The solvent was concentrated under reduced pressure and the residue was chromatographed with EtOAc-77-201247215 (Hexane: EtOAc = 70:30 to 20: 80% elution) refining. The concentration was concentrated under reduced pressure, and the residue was powdered by IPE to obtain tert-butyl 4-[(2-nitrophenyl)sulfonyl]piperazine-1-carboxylate. (31.8 g). Manufacturing Example 44

Tert-butyl 4-[4-(methoxycarbonyl)-4'-(5-{4-[(2-nitrophenyl)sulfonyl]piperazin-1-yl}-1,2 , 4-oxathiazol-3-yl)biphenyl-3-yl]-3,6-dihydropyridine-1(2H)-carboxylate (22.5 g) was dissolved in DMF (225 mL) K2C03 (12_8 g) and 4-methylbenzenethiol (4.59 g) were stirred overnight at room temperature. Water was added to the reaction mixture, and extraction was carried out twice with CH2C12. The organic layer was washed with water and brine, dried over MgS04, and concentrated under reduced pressure. The residue was dissolved in EtOAc (1 L), washed with water for 6 times, washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by medium pressure cerium oxide colloidal column chromatography (eluent; Hexane: EtOAc = 1:1, followed by CHCl3:MeOH = 95:5) to afford tert-butyl 4-[4- (Methoxycarbonyl)-4'-(5-piperazine-l-yl-1,2,4-oxadiazol-3-yl)biphenyl-3-yl]-3,6-dihydro Pale-1(2H)-carboxylate (16.0 g) as a pale brown foam. Production Example 45 on 5-[4-(2-phenylethyl)piperazin-1-yl]-2-[4-(tetrahydro-2-pyran-2-yloxy)phenyl]pyrimidine ( In a suspension of 10.05 g of dioxane (100 mL), 6M hydrochloric acid (18.8 mL) was added under ice cooling, and stirred at room temperature for 2 hours -78 to 201247215. The reaction mixture was made into a pH = 8 with aq. NaOH aqueous solution and then filtered, and the solid was collected and washed with MeCN to give 4-{5-[4-(2-phenylethyl)piperazine-indole- A milky yellow powder of pyrimidine-2-yl}phenol (8.06 g). In the same manner as in the method of Production Example 45, the compound of Production Example 45-1 to Production Example 45-1-9 shown in the table below was produced. Manufacturing Example 46

Tert-butyl 4-[2-(methoxycarbonyl)-5-(tetrahydro-2H-pyran-2-yloxy)phenyl]-3,6-dihydropyridine-1 (2H) A mixture of a carboxylate (2.65 g), 4-methylbenzenesulfonic acid (328 mg), MeOH (27 mL) was stirred at room temperature for 3 hours. The reaction mixture was poured into water (EtOAc) (EtOAc) Brine was added to the aqueous layer and extracted again with EtOAc. The organic layer was combined, washed with brine, dried over MgS04, and concentrated under reduced pressure to give tert-butyl 4-[5-hydroxy-2-(methoxycarbonyl)phenyl]-3,6- Dihydropyridine-1(2H)-carboxylate (2.04 g). In the same manner as in the method of Production Example 46, the compounds of Production Example 46-1 to Production Example 46-5 shown in the following Table were produced. Preparation Example 47 6-{4-[5-(Benzyloxy)pyrimidin-2-yl]phenyl}-1-chloro-2-naphthyltrifluoromethanesulfonate (200 mg), Pd (OAc ) 2 (8.0 mg) and DPPP (15 mg) in DMSO / MeOH (16 mL / 4 mL) solution, Et3N (d = 0.726, 150 μ! 〇 added at room temperature. CO environment, -79- 201247215, stirred at 90 ° C for 4 hours. After adding water to the reaction solution, the precipitate was collected by filtration, washed with water, and dried under reduced pressure to give a crude powder. The crude powder was chromatographed by ruthenium dioxide colloid (column; CHCl3) :MeOH = 99:1) Purified to give methyl 6-{4-[5-(benzyloxy)pyrimidin-2-yl]phenyl b!-chloro-2-naphthoate (143 mg) The compound of Production Example 47-1 to Production Example 47-3 shown in the following Table was produced in the same manner as in the method of Production Example 47. Production Example 48 was methyl 4-(tetrahydro-2H-pyran-2-yl). To a solution of oxy)benzene (1.37 g), 4-bromo-2-methylpyridine (1 g) in THF (20 mL), 1M LHMDS (11.6 mL). After adding water and EtOAc, the mixture was extracted, and the organic layer was dried over MgS04 and concentrated under reduced pressure to give residue Purification by hydrazine column chromatography to give 2-(4-bromopyridin-2-yl)-indole-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]ethanone (1 .91 g). Preparation of 49 (meth). The reaction mixture was stirred at 25 ° C for 18 hours at 4 ° C for 8 hours. A 1 M aqueous NaOH solution (698.7 μM) was added to the reaction mixture, and the reaction mixture was stirred overnight at room temperature. Neutralization, dilution with water (100 mL), elution by ODS column chromatography (pH 6.8 201247215 buffer, washed with water, 5 〇% MeCN), concentrated under reduced pressure, and then freeze-dried to obtain a product. Compound of Example 49 (157 mg). Production Example 50

In a solution of tert-butyl 4-[(4,4-dimethylcyclohex-2-en-1-yl)oxy]piperidine-1-carboxylate (810 mg) in MeOH (8 mL) Add 10% Pd/C (50% wet, 50 mg) and carry out contact reduction at room temperature for 5 hours under hydrogen atmosphere. The reaction solution was filtered through celite, and then filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-[(4,4-dimethylcyclohexyl)oxy]piperidin-1- A colorless oil of the carboxylic acid ester (500 mg). In the same manner as in the method of Production Example 50, the compound of Production Example 5 0-1 shown in the following Table was produced. Production Example 51 A mixture of 4-bromo-2-chlorobenzoic acid (15 g), DIB0C (16.7 g), DMAP (3 90 mg), THF (23 0 mL), t-BuOH (75 mL) at room temperature Stir for 24 hours. The reaction mixture was poured with EtOAc (300 mL). The organic layer was washed successively with water, 0.1M aqueous hydrochloric acid and brine, dried over MgS04, and concentrated under reduced pressure to give tert-butyl 4-bromo-2-chlorobenzoate (17 g). Color oily substance. Example 1 3-{1-[(9Η-芴-9-ylmethoxy)carbonyl]-1,2,3,6-tetrahydropyridine - •81 - 201247215

4-yl}-4'-[5-(trans-4-isobutoxycyclohexyl)-1,2,4-oxadiazole-3-yl]biphenyl-4-carboxylic acid (402 A mixture of mg), HBTU (221.2 mg), DMF (6. 〇〇mL), DIPEA (0.237 mL) was stirred at room temperature for 30 minutes. The compound (57 7 mg) of Example No. 169 of International Publication WO 9 9/40 1 08 was added and stirred at room temperature for 5 hours. In TLC, it was confirmed that the active ester disappeared. Piperidine (709.3 mg) was added and stirred at room temperature for 30 minutes. EtO Ac was added to the reaction solution, and the resulting precipitate was collected by filtration. Suspended in water and added 1 M NaOH water until dissolved. The mixture was purified by ODS (filled with water-substituted ODS cerium oxide colloid 80 mL, and then subjected to staged dissolution with 10, 20, 30, 40% MeCN water), and then freeze-dried to obtain the compound of Example 1. (472 mg) of white powder. The compounds of Examples 2 to 6 were produced in the same manner as in the method of Example 1. Example 7

To a solution of the compound of Example 42-1 (50 mg) in DMF (0.75, 3-methoxybenzaldehyde (14 mg), AcOH (5 μί), NaBH (OAc) 3 (15 mg), nitrogen atmosphere The mixture was stirred for 15 hours at room temperature, and EtOAc was added to the reaction mixture, and the resulting precipitate was collected by filtration. The obtained mixture was added to the mixture, THF (0.5 mL), and the mixture was stirred at the same temperature for 0.5 hour. In NaOH aqueous solution (6.7 mL)-H20 (200 mL), the reaction mixture was slowly added under ice-cooling, and directly purified by ODS column chromatography (H20:MeCN = 80:20 to 20:80). The separated MeCN was distilled off under reduced pressure and dried to give a compound of Example 7. - 82 - 201247215 The compound of Examples 8 to 3 was produced in the same manner as in Example 7. The compounds of Examples 33 to 36 and The method of Production Example 1 was produced in the same manner. Example 3 7

3-[1-(161^-butoxymethyl)-1,2,3,6-tetrahydroindole ratio 11-1,4-yl]-4'-{2-[4-(2-benzene Base ethyl) piperazin-1-yl]imidazo[2,l-bni,3,4]thiadiazole-6-yl}biphenyl-4-carboxylic acid (10.6 g), BOP (8_14 g) A mixture of DMF (212 mL) and DIPEA (d = 0.742, 7.01 mL) was stirred at room temperature for 1 hour. The compound (1 5.967 g) of Example No. 169 of International Publication WO99M0108 was added and stirred overnight at room temperature. The reaction mixture was poured into EtOAc (3 L), and the obtained precipitate was collected by filtration, washed with IPE, and dried under reduced pressure for 3 hours. The obtained powder was added to TFA (d = 1.480, 130 mL) under ice cooling, and stirred for 2 hours. Add CH2C12 (1 L) to the reaction solution under ice cooling,

Et3N (d = (K726' 3 20.8 mL) was carefully and slowly dripped at an internal temperature of 15 ° C or less. The reaction solution was concentrated under reduced pressure, and the resulting oil was stirred under ice cooling while being added to 1 M. NaOH aqueous solution (30 mL) in water (4 L). Further '1 M aqueous NaOH (20 mL) was added to make pH = l 1. The solution was subjected to 0DS column chromatography (purified by h2, MeCN: pH 7) Buffer solution = 2% to 42%) Refined. Divide the target substance into water and dilute it by adding NaOH aqueous solution to dissolve. The solution was washed with ODS column chromatography (with h2〇, MeCN: H20 = 4: 1) De-83-201247215 The salt was concentrated under reduced pressure and dried to dryness to give the compound of Example 3 (16.89 g). Compounds of Examples 38 to 153 and 295 were produced in the same manner as in Example 37. Example 154

The compound of Production Example 35 (1 mg) was suspended in MeOH (1. The reaction was diluted with MeOH and EtOAc was filtered and evaporated. After the combined filtrate and washings were concentrated under reduced pressure, EtOAc was evaporated and evaporated. After the powder was dried, it was suspended in CHiCh, and ice-cooled, and TFA was added. The mixture was stirred for 3 hours while warming to room temperature. Under ice cooling, Et3N was added to stop the reaction. After concentration under reduced pressure, water was added to the obtained residue. Further, in the suspension, 1 M aqueous NaOH solution was added, and 10%-MeCN/H20' was dissolved. The mixture was refined with hydrazine DS (condition: ODS cerium oxide 15 5 m L, after charging, b u f f e r, 10%, 20%, 30%, 40% MeCN/buffer (10R each)). After the concentration was concentrated, it was diluted with H2 、 and filled (the eluate; in order, h2o, 10% MeCN/H20, 50% MeCN/H2O). It was freeze-dried to give a white powder of the object (45 mg). Example 1 5 5 Production Example 3 3 - 5 5 compound (50.0 mg), HBTU (30.2 -84 - 201247215

Mg), DMF (75 0 μΐ^), D IP EA (d = 0.7 4 2 -3 7.2 μ! 混合物 mixture was stirred at room temperature for 1 hour. The compound of Production Example 20 of International Publication No. WO 03/068807 was added. (63.8 mg), stirring at room temperature for 6 hours. EtOAc was added to the reaction mixture, and the resulting precipitate was collected by filtration. The solid obtained after drying under reduced pressure was added with TFA (d = 1.480, 2.00 mL). The mixture was stirred for 3 hours. The reaction was dropped to 7% MeCN water (100 mL). The mixture was purified by 〇DS cerium oxide colloidal chromatography (filled with water-substituted 0DS cerium oxide colloid 20 After the mL, sequentially, 〇, 5, 10' 15, 20% pH 2.0 hydrochloric acid: MeCN was dissolved), and dried to give a yellow solid of the compound of Example 155 (4 7.3 mg). The compound of 56 to 1 64 was produced in the same manner as in the method of Example 1 5 5. Example 165 'Addition of ethyl 3-bromopropionate (5.45) to a solution of the compound of Example 55 (60 mg) in DMF (450 μm) pL), powder K2C03 (11.6 mg) and Nal (6.3 mg) were stirred for 4 days at room temperature. The resulting precipitate was added by adding EtOAc to the reaction mixture. A white powder of crude ethyl ester intermediate (84.3 mg) was obtained. The crude ethyl ester intermediate was dissolved in water (600, 1 M aqueous NaOH solution (420 μM, stirred at room temperature for 2 hours) with 1 Μ hydrochloric acid After neutralization, it was purified by 〇DS cerium oxide colloidal chromatography (eluent: MeCN: pH 6.86buffer = 27.5:72.5). The concentration of the target substance was concentrated, diluted with water to about 2 times, and then 〇DS. Desalting by column chromatography 'Me CN was concentrated under reduced pressure, and then freeze-dried to obtain a white amorphous material of the compound (15.0 mg) of Example-85-201247215 165. Example 166

Add 1,3-propane sultone (9 mg) to the 750 μΙ〇 solution of the compound of Example 55 (1 〇〇mg), stir at room temperature for 20 hours, and add 1,3-propane sulfonate. The ester (9 mg) was stirred at room temperature for 20 hours, and further 1,3-propane sultone (9 mg) was added thereto, and the temperature was raised to 50 ° C, and the mixture was stirred for 3 Torr. After the reaction solution was allowed to cool to room temperature, Water (50 mL) was added, and purified by ODS cerium oxide colloidal chromatography (eluent; MeCN: pH 6.86 1>1^丨6^25:75~27.5:72.5). After diluting to about 2 times, it was desalted by ODS column chromatography, and MeCN was concentrated under reduced pressure, and then evaporated to dryness to give white crystals of the compound of Example 166 (8.46 mg). Example 1 6 7

TFA was added to the compound of Example 10-19 (115 mg), stirred at room temperature for 1 hour, and Et3N was added under ice cooling. The mixed solution was concentrated under reduced pressure, and a 20% MeOH solution was added to obtain a suspension, and a 1 M aqueous NaOH solution was added thereto to prepare a pH of about 9.5 to completely dissolve. The aqueous solution was purified by ODS column chromatography (eluent; MeCN: pH 6.8 buffer = 20: 80 to 80: 20). The resulting aqueous solution was again subjected to 〇DS column chromatography to remove the salt, and the solvent was replaced with M e C N . The obtained solution was concentrated under reduced pressure. The residual aqueous solution was freeze-dried to give a white powder of the compound (89 mg) of Example -86-201247215 The compounds of Examples 168 to 178 were produced in the same manner as in Example 167. Example 1 8 0

A solution of the compound of Example 37 (50 mg) in MeOH ( 1.5 mL) The reaction mixture was stirred at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained solid was evaporated and evaporated. The precipitate was filtered, washed with EtOAc then dried The compounds of Examples 1 and 79 were produced in the same manner as in the method of Example 1 80. Example 1 8 2 The compound of Example 1 5 6 (50 mg), 1 Η-pyrazole-1 -carboxylate hydrochloride (12.9 mg), DMF (250 μL), DIPEA (d = The mixture of 0.742, 24·6 μΙ〇 was stirred overnight at room temperature. Water was added to the reaction solution, and MeCN was added until dissolved. The mixture was subjected to 〇DS cerium oxide colloid chromatography (ODS cerium oxide colloid). 15 mL, the eluate; 〇%~6 5 % p Η 2.0 hydrochloric acid:M e CN)), purified by freeze drying to give a white powder of the compound of Example 182 (34.2 mg). Example 1 8 3 a mixture of the compound of Example 55 (103 mg), 1,4-dioxane-2,5-diol (17.3 mg), CHC13 (3 mL), MeOH (1 mL), MS3A (154.5 -87 - 201247215 mg) NaBH3CN (10 mg) and AcOH (14 μM) were added. The mixture was stirred at room temperature for 3 hours. MS3A was filtered and concentrated under reduced pressure. The residue was suspended in MeCN:H20 = about 1:1. In a solution of hydrazine, adjust to pH 8 to 9 (pH test paper) with 1 M NaOH to dissolve. The solution was subjected to ODS medium pressure column chromatography (washing: MeCN: H20 = 1:9, MeCN: ( pH 6.86 standard buffer solution

Liquid) = 1:9, dissolution: MeCN: (pH 6.86 standard buffer solution) = 1:4, 3:7) Refined. The fractions containing the target substance were collected and diluted to about 1.5 times with H20, and desalted by ODS medium pressure column chromatography (washing solution: MeCN: H20 = 1:9, eluate; MeCN: H20 = 4:1). Concentrate under reduced pressure. The fractions containing the title compound were concentrated under reduced pressure, and the aqueous residue was freeze-dried to give a powder of the compound of Example 183 (73.8 mg). The compounds of Examples 184 to 294 were produced in the same manner as in Example 183. Among them, Example 1 99 is a hydrochloride obtained by salt formation.

In the same manner as in the above examples or production examples, the compounds of the examples and the production examples shown in the tables below were produced. Regarding the production example compound and the example compound, each represents a structure, a physical chemical data, and a production method. In the table, Pr is a manufacturing example number, and Ex is an embodiment number. Ref-Pr is a reference to a manufacturing example number that can be manufactured, and Ref-Ex is a reference to an example number that can be manufactured. However, in Ref-Pr, the number of the embodiment which can be manufactured by reference is also described. In the Ref-Ex, the manufacturing example number that can be manufactured by reference is also described, and the Pr number is used at this time. In the STR column, the construct is represented. The DAT column describes W-NMR and/or MS data. -88- 201247215 NMRl = chemical shift 1H-NMR measured in d6-DMSO δ (δ), NMR2 = chemical shift 1 (δ) of 1H-NMR measured in d6-DMSO + D20, NMR3 = determination in CDC13 The chemical shift δ(δ) of W-NMR. ESI and EI are each a mass analysis of the electrospray ionization method, a mass analysis of the electron ionization method, and a positive or negative case of the ESI and EI data. APCI is the mass spectrometry mass spectrometry mass analysis, and APCI/ESI is the mass analysis of the simultaneous determination of APCI and ESI.

[Industrial Applicability] The compound of the formula (I) or a salt thereof has antifungal activity and can be used as various infectious diseases such as skin filamentous fungi (for example, chalk disease, etc.), discoloration of pityriasis, yeast, cryptococcal disease. , Geotricepsy, sand hair disease, Aspergillosis, Penicillium, sputum bacterium, zygomycete, sporotrichosis, chromogenic fungus, coccidioidomycosis, histoplasmosis, germination, Prophylactic agents and/or therapeutic agents such as paraspora, A. serrata, foot edema, fungal keratitis, ear fungal disease, pneumocystis, fungal disease. -89 - 201247215 [Table 4] Pr STR 1 OMe 1-1 1-2 1-3 Γ> Γ, ν <^Ο"0ΕΙ 1-4 , <ηχτ^ 1-5 c|-i>NOcbz 1~ 6 -mxx0?) 1-7 2 ΗΟ^Ν-λ -90 - 201247215

[Table 5] 2-1 BOC Cl ^ Me(f\=/\=/\=/ V_y 2-2 BOC t) ^ Me0' WWW V_y 2-3 boc c| MeC/^=AA=/^A= /^ \_v 2-4 BOC N~v MeO_ Me(/ WWW V_y 2-5 BOC Nx Cl %yy^-y^-y^y^ MeC/ WWW u 2-6 BOC Q Me〇HQ MeC/ WWW V_y 2-7 BOC MeO 03y^y, NyN^S MeC/ WWW V_y 2-8 -91 - 201247215 [Table 6]

-92- 201247215

[Table 7] 2-16 BOC iPrO 2-17 MeO 2-18 OiPr 2-19 BOC 〇iprt)-o 2-20 2-21 ho^-Q g 0k>O^">C^ MeO x= / N-^ N~' 2-22 BOC lPr^ q rN』 2-23 -93- 201247215

[Table 8] 2-24 BOC. 疒 Hirose Hex 2-47 BOC Q rfHep °K>^Y MeO X==/ N〆. 2-48 BOC 2-25 BOC Q wide N'n〇Ct 2-26 BOC Q 2-27 BOC 0 2-28 boc, n Me~L Μβ0Μ=ΑΛ_/Λ-ο 2-29 BOC

-94- 201247215

[Table 9] 2-30 BOC 2-31 BOC MeO^=^ N-0 2-32 BOC 2-33 BOC 2-34 BOC MeO x=/ M-0 2-35 BOC Q 2-36 BOC Q 2- 37 BOQ q 〇-°>7 -95- 201247215 [Table 1 2-] 2-38 2-39 2-40 Boc-r/^N—( | 2-41 Η(ΓΛι /=, O LrMe MeO χ= / W』 2-42 广 广, ex 2-43 BOC 2-44 Me B〇hr, 』 2-45 B〇h rN^

-96 - 201247215

[Table 1 1J 2-46 B〇h 3 3-1 -o^xK>o- 3-2 3-3 f V-OMe 3-4 B\Vn^n-^O 4 BXVv. I />-N N-BOC °'N ^ 5A BOC 5A-1 BOC /Ν~λ OMe -97- 201247215 [Table 1 2] 5A-2 boc, n, 5A-3 Ο 〇·^ΚΧΤ〇Βη 5A-4 BOC Λλ OMe 5A-5 BOC 5A-47 BOC ^<y<y<"Xj^〇MeO \=/ \=/ 5A-6 B°b , 5A-7 B〇CN °K>^ '>〇-c- MeO x=/ N-7

-98 - 201247215

[Table 1 3]

-99- 201247215 [Table 1 4]

-100- 201247215

[Table 1 5]

-101 - 201247215 [Table 1 6]

-102- 201247215

[Table 1 7]

-103- 201247215 [Table 1 8]

-104- 201247215

[Table 1 9]

-105- 201247215 [Table 2 0]

-106- 201247215 [Table 2 1]

5C-5 BOC 5C-6 BOC Μθ〇^\==/Λ_/^ νό 5C-7 BOC MeO \=/ n〆0 508 BOC OMe Q rWMe 5C-9 BOC 5C-10 B〇CKi 0 N〇2 iW # 5C-11 Cl 5C-12 BOC /N~\ OMe -107- 201247215 [Table 2 2]

-108- 201247215

[Table 2 3] 5C - 20 BOC 5C-21 MeO 5C-22 Cr°^〇^ 5C-23 BOC /Ν"Λ OMe rj^(CH2)8〇Me 5C-24 BOC Q r/> O^y -fy/Y^ MeC/A=rW^crN 5C-25 BOC . Me Q NX> 5C-26 BOC 0 £T Me0M=^/~vi 5C-27 BOC Q rTe -109- 201247215

[Table 2 4] 5D household oc factory N Ο 5D-1 Me Me” Me〆fKHXT Ae 5D-2 Me\ Me— Me Ae _ t>^:xr °^3 5D-3 ( Me me K) 5D-4 :3⁄4 rhyme xtn〇f〇5D-5 jO mXb-〇-<;XJ Me 5D-6 Me Mevi Λ /\KI,B0C Me^T-0 [| N Me ^^^COOMe 5E

-110- 201247215

[Table 2 5] 5EH 5E-2 5E-3 5E-4 ( ΜΘ}^〇ΛΐΝν/ DMe 5E-5 ( DMe 5E-6 c )Me Ό 5E-7 c 〕Me Ho 5E-8 c Μ:^^ Ι0 〕Me 5E-9 -111 - 201247215

[Table 2 6] 5E-10 C )Me 5E-11 ci r"yB0C 5E-12 a0!^>o-<r>cS 5E-13 5E-14 5E-15 q: Recognition: acl 5E-16 〇) ^0^_^N^N.cbz 5E-17 Cl NXbZ 5E-18 5E-19 MeO x=/ x=/ N-0 μ6 -112- 201247215

[Table 2 7] 5E-20 5E-21 5E-22 jpN'B〇C Cl 5E-23 . /y°c Cl 5E-24 a^o^ro^〇5E-25 Guangguang cq:^〇^N” 5E-26 5E-27 c ci<K!nJ F )Me 5E-28 CC^>o - -113- 201247215

[Table 2 8] 5F BOC F 5G JVboc OMe N 6 BOC Ν-Λ VfVoif 6-1 OMe Tf〇-^^>Ncy〇6-2 Tra^-{>NCN-^ 6-3 TM<Hxrn 6-4 OMe 6-5 ^i〇rC?) 6-6 Tfo-^^—(^^)-N^N-Cbz 6-7 -114- 201247215

[Table 2 9] 6-8 6-9 6-10 TfO 乂二^N-Cbz 6-11 广 N'Cbz 6-12 f N』OC ^^^COOMe 6-13 6-14 6-15 r^ N』〇C 6-16 Tra_〇^>〇J〇6-17 TfO-^^—/^-OBn -115- 201247215

[Table 3 0] BOC 6-18 f BOC 6-19 6-20 f BOC 6-21 6-22 6-23 Λ=/Λ=Λ ηΛΌ Me '~' 6-24 BOC 6-25 Q Vfy〇Tf MeO ^==/ 7 Br-〇-<I>0^_Q -116- 201247215

[Table 3 1] 8 8-1 Brtw Force N-0 8-2 n _ 〇Me ^lsrN^b 8-3 8-4 ^ OMe BOv^>〇8-5 ^ OMe BOwC^ 8-6 OMe b /H>〇8-7 BrO^vCTB0C NN 8-8 G0_^_/^.N^N.Cb2 N 8-9 Η2Ύ>0^° -117- 201247215

[Table 3 2] 8-10 \=/ N=/ \f 〇Me 8-11 α〇-〇^;>0〇^ 8-12 Dr OMe ^VO^Me N-0 8-13 Br-f ^N-BOC ON 8-14 Br^v〇h N-0 \^J 8-15 Brt^_v〇^° 8-16 Brt^vO"0C N-0 8-17 ΒΓΊΧν〇°Ό N-0 8 -18 〇2Nv^\ BO^r〇# N-0 8-19 BOwCf^Me -118- 201247215

[Table 3 3] 8-20 NO. 8-21 N-0 8-22 OMe N-0 8-23 „ 八z9Me Me Br^vO^ N-0 8-24 N-0 8-25 Br^ya° 〇Me Me 8-26 Me Br'^O^v〇^^ N-0 9 〇o^ry^^y.^ O 9-1 f=\ -119- 201247215 [Table 3 4]

-120- 201247215

[Table 3 5] 10-3 BOC h; ^Hh M 0H Hbz HO oso3h 10-4 Br_O^H2 }·"0^Μθ 10-5 BrO^0 0>".O^Me 10-6 -~ chn_H>〇h N^f nh2 O 10-7 10-8 10-9 Me Br_^NV〇.„〇^Me X=/ nh2o vy -121 - 201247215 [Table 3 6] 10-10 BOC M ?H 0 Η2Ν^ίΗΗ 0^〇Η HO 0S03H r J OEt 10-11 V(CH2)7OMe x=/ nh2 0 10-12 /,~Λ .N _〇ΒΓ<Ηη2〇^-〇10-13 /)-~ \ N _0 Br \ Γ~\ >-(CH2)8〇Me X=/ nh2〇10-14 /}~λ .N—0 W NH2 〇10-15 BOC 10-16 W NH2〇Me 10-17 n=\ Me x=/ nh2 0

-122- 201247215 [Table 3 7] 10-18 10-19

10-20

EΜ, ,ο 10-21 10-22

e Μ -123- 201247215 [Table 3 8] 10-23 BOC ?H 〇rS >-^NH H1 OH h2n 〇=< h 〇yS'' ^^νΝΌ Q 6h〇HJ〇h Λ HO 0S03H Me^ ^/^OMe Me 10-24 BOC M ?h 0 rS Η2Ν^ί h 0^〇〇HH〇〇s〇3H fy^ iPrO 10-25 BOC Me 10-26

-124- 201247215 [Table 3 9]

HO 0S03H

-125- 201247215 [Table 4 0] 10-30 10-31 10-32

卩OC

Br

O-N,

O H2N

N-Bn

O-N

O H2N

Br

OMe 10-33

-126- 201247215

[Table 4 1] 13 广9 OMe 14A BOC Q 十ν〇-ο-<">ο^ MeO \==/ N-^ 14A-1 BOC 0 14A-2 BOC 0 14A-3 Br~^ Q^\}~〇Bn 14A-4 14A-5 ?H 0 HO >=〇^ 〇Bn °5^>Λη hn 〇h2n . Heart 〇γ\, ΟΗ ^Nv? Me /=\ OH〇 U, M 〇 0H Bn〇 °^OtBu 14A-6 Br-/~V〇 /=x n=/ -127- 201247215 [Table 4 2]

-128- 201247215

[Table 4 3] 14A-14 BOC V〇-〇^°^y=\ MeO N-^ d/-Me 14A-15 BrOVvO'Bn N-0 Br 14B , ',.,0〇^Me N-0 14B-1 ~Me BnO N-'14B-2 Me J'"·/ BnO N—' 14B-3 BnO N_/ 14B-4 BnO ^~^ Me 14C ',,. 'Cr〇』e N- 0 15 BOC-〇~〇-〇Ce 16 BOC V/V^fV/'0H tBuO^^==/^-^^NH2 16-1 H0V a0o^Br -129- 201247215

[Table 4 4] 16-2 N^"Vjh2 16-3 BOC \~\ /=\ /=\ .ΝΌΗ 〇^〇-<N MeO ^=7 17 CrBr 18 Br<KN^3^c, N -0 18-1 ΒΑν〇.'Μβ N-0 18-2 -.ctoh N-0 18-3 BrOvW N-0 18-4 Me B"0^v〇,'0^^Me N-0 18- 5 B"''O^ifV(CH2)7〇Me N-0 18-6 BOC MeO x=/ -130- 201247215

[Table 4 5]

18-7 N-0 18-8 N-0 18-9 BOC. S>O^vC>0nBU tBuO x=/ x—^ N-0 18-10 Br'^OScV(CH2)e〇Me N-0 18-11 Br^iNr^O^Me 18-12 BOC ιΒυ}^Κ>ιΧ^ 18-13 BOwt>B0C ON 18-14 Br^KvC〇N-0 18-15 Me N-0 18-16 B" OVW〇rEt N-0 18-17 BOwCr ON -131 - 201247215

[Table 4 6] 18-18 N-〇18-19 N-0 1/ 18-20 BOC MeO 18-21 BOC MeO 18-22 BOC MeO 19 ^〇-o-caBr 20 βΧ}^τ〇· NN 20 -1 BrO^v〇,, NN 21 ( b^:tn0 )Me -132- 201247215

[Table 4 7] 22 B0c-〇^Me 22-1 BOC-N^Y" N^/ (CH2)8OMe 22-2 boc-n^YH N^/ (CH2)7OMe 22-3 BOC-N^X ^x/^N^Me 22-4 23 Biv〇^Br NN 23-1 ^!r〇Br 23-2 H.叙 24 25 β“·ΌυΆν N-〇 26 Br^CX>Br 27 cro^6aB,〇H OH -133- 201247215

[Table 4 8] 28 -wOBr N-0 29 boc, n' 9h MeOOC^^ 29-1 B0C, ni ?h 30 wide n, b〇c MeO 31 /~\ OMe B〇C_〇^_Me 31- 1 /\ OMe BOC-N X ^/ (CH2)8〇Me 31-2 /~\ OMe BOC-N XN^f (CH2)7OMe 31-3 /~\ OMe Β00_Νν^)\^Ν^Μθ Me 31 -4 BOC-N二)<^^Me 31-5 /\ OMe B〇C-VXX^Me 32 Ι·γΎ^Ο 丫Me MeOOC^^^ 0 -134- 201247215

[Table 4 9]

-135- 201247215 [Table 5 0]

-136- 201247215

[Table 5 1] 33-14 BOC, Guangfei OMe 33-15 BOC, Ql Q ry 33-16 Β〇ςΝ-Λ Hv〇^;xx0/ 33-17 BOC H:^^CCr0 33-18 OEt B〇 Cna H&^:xr°N 33-19 BOC -137- 201247215 [Table 5 2]

-138- 201247215

[Table 5 3]

-139- 201247215 [Table 5 4]

-140- 201247215

[Table 5 5]

-141 - 201247215 [Table 5 6]

-142- 201247215

[Table 5 7]

-143- 201247215 [Table 5 8]

-144- 201247215

[Table 5 9] 33-63 BOC /Ν~λ HO \=/ 33-64 Β〇ς r^Y〇iPr Q 33-65 BOC iPrO Q q HO WW \=/ W 33-66 BOC O ipr〇- ^QH〇/ w W,=/ u 33-67 BOC 33-68 BOC °K>〇-〇-〇Bn HO X=/ N-^ -145- 201247215 [Table 6 0]

-146- 201247215

[Table 6 1]

-147- 201247215 [Table 6 2]

-148- 201247215

[Table 6 3 I

-149- 201247215 [Table 6 4] 33-96 BOC 33-97 BOC ηοΓΛ=ΑΛ=/, N=/ w Me 33-98 BOC HCf\=/\=/ λΝ=/ Me 33-99 η(ΓΛ飞O 广/心 33-100 BOC Ο ^Ν^ηΗθΡ Λη>*ν". 33-101 BOC :3>^ίΟΧ] 33-102 BOC O Wide N'n0ct fb^cr1

-150- 201247215

[Table 6 5] 33-103 BOC 33-104 BOC 33-105 BOC q rN^0 33-106 BOC person Q 33-107 BOC 91 Q r^0 : ib-o^: xN^ 33-108 BOC 33- 109 BOC (/ ^\9Me Me -151 - 201247215 [Table 6 6] 33-110 BOC N-\ Me 33-111 BOC 33-112 B〇<\l 广Me 广N^々Me 33-113 BOC, Q rN-〇33-114 B〇C r-\ Q rr° 33-115 BOC 33-116 BOC Me

-152- 201247215

[Table 6 7] 33-117 BOC Q Hfb~o^:xN" 33-118 Me B〇CQ Ηί〇-^;ϊ 33-119 BOC 33-120 O 〇〇33-121 BOC /-Ji-Me Q rN^J Hv〇-〇^;:r^ 33-122 BOC /~\ Q rN^ 33-123 Δχρ^〇Η -153- 201247215

[Table 6 8] 33-124 BOC η〇-^Λ=/Λ=^〇-ν 33-125 BOC HO \=/ \=/ NO 33-126 BOC γ ^N-0 33-127 BOC 〇rr^ 7 33-128 BOC /N-\ MeO 33-129 BOC N Fly MeO

-154- 201247215

[Table 6 9] 33-130 BOC 33-131 BOC η^〇λϊν〇^〇ρ 33-132 B0CV| Me 0Q 33-133 B〇\ Me 0 rx> 33-134 BOC HM>^NTN^^ HO \ =/ \=/ |S|〆. 34 Me 丫 Me 〇 34-1 Me Me^jY 34-2 Me^rxH Me -155- 201247215

[Table 7 Ο] 34-3 ^caH 35 BOC ?; q0h0^〇h 0 HO OS〇3H 0Me 36 ίτ0Όζ〇Μθ 0 36-1 36-2 Cr°^0aBr 37 BrO^,,,··.Cr〇Bn N-0 38 38-1 BOC

-156- 201247215

[Table 7 1 I 39 HO Nf 39-1 HO N^' 39-2 HO 39-3 °>-<〇〇^rMe HO N' Me 40 MeO \==/ \==/ N into S ^ ~/ 40-1 OEt <>〇40-2 H〇Cy:cl 40-3 HN V /—Me N~' HCI 40-4 ΒΑν〇ΗΗα N-0 40-5 〇w,° no2 H0^ ^0 HC, 40-6 Cl Wide NH MeO x==/ 1ST. -157- 201247215 [Table 7 2] 40-7 Η Q 40-8 Q hci 40-9 /~\ xOMe . HOC^Me (10) Me 40-10 40-11 μθ〇^-^λΧΧ^ hc. 40-12 /~~\ OMe HV_)C^^Me HCI 40-13 Q hc, 40-14 Cl Guang NH 八1

-158- 201247215

[Table 7 3] 40-15 Η Q 广 - 40-16 hci Ηα多40-17 /~\ OMe HCI HN XN/ (CH2)8OMe 40-18 /~\ OMe hci hn XN/ (CH2)7〇Me 40-19 HCI ON 40-20 HNC^N^0 HCI Me 40-21 BrO^V〇H Η. O-N 40-22 Guang NH MeO 40-23 41 FMOC ,O0nBU HO x=/ N~/ N-0 -159- 201247215

[Table 7 4] 41-1 FMOC 0Κ>〇1ΝΤ^ HO Ν~f Ν-0 41-2 FMOC Me 42 h2n 〇=< h % HO 0S03H H 42-1 〇H 〇BOC Me..<tVXHp 〇Qbrf5Hj〇HQ HO OSO3H

-160- 201247215

[Table 7 5] 42-2 BOC 42-3 BOC 42-4 〇H 〇 HOvJ". 1 hoH^ 〇H 43 °〇 no2 B0C-0N^ 44 BOC Q γψ 45 hohQh^-n^n^q 45-1 OMe ηο^^>νΟΌ -161 - 201247215

[Table 7 6] 45-2 OMe 45-3 Η〇·€ΗΧΤη 45-4 45-5 45-6 45-7 Η〇-(^)~(( 3~NCyN~CbZ 45-8 H〇^^ n^NCN_cbz 45-9 Wide N'Cbz 45-10 〇Η〇·〇~〇-〇·.- 45-11 Η Rhyme-162- 201247215

[Table 7 7]

45-12 -°3⁄4 45-13 -OBn 45-14 ^B〇C 45-15 η〇Ό-<^>ν R:>〇45-16 Η0Ό~{}Ν: 45-17 η〇 -〇Λ-0 45-18 -me r. 45-19 46 BOC Ν-χ MeO ^=7 46-1 八'B〇C r>N -163- 201247215 [Table 7 8]

-164- 201247215 [Table 7 9] 9 -0:0

e BOC,

50-1

BOC

oO 0

5A-47

OBn -165 201247215 [Table 8 0]

-166- 201247215

[Table 8 1] Pr Ref-Pr DAT 1 1 ESI+: 507_3 1-1 1 ESI+: 501.6 1-2 1 ESI+: 484.4 1-3 1 ESI+: 604.4 1-4 1 ESI+: 530.4 1-5 1 ESI+: 354.2 [M+Na]+ 1-6 1 ESI+: 489.1 1-7 1 ESI+: 483.3 2 2 ESI+: 649.3 2-1 2 ESI+: 693.2 2-2 2 ESI+: 693.2 2-3 2 FAB+:679.2 2-4 2 ESI+: 675.3 2-5 2 ESI+: 679.2 2-6 2 ESI+:689.3 2-7 2 ESI+:689.3 2-8 2 ESI+: 412.1, 414.1 2-9 2 ESI+: 675.3 2-10 2 ESI+: 674.4 2-11 2 ESI+: 659.3 2-12 2 ESI+: 674.3 2-13 2 ESI+: 694.3 2-14 2 ESI+.704.4 2-15 2 FAB+: 704.1 2-16 2 ESI+: 718.3 2-17 2 ESI+: 553.3 2-18 2 ESI+: 561 2-19 2 ESI+: 718.3 2-20 2 ESI+: 549.3 2-21 2 ESI+: 604.3 2-22 2 ESI+: 708.4 2-23 2 ESI+: 503.3 2-24 2 ESI+.630.3 2-47 2 ESI+ :644.3 2-48 2 I ESI+: 642_3 -167- 201247215 [Table 8 2] 2-25 2 ESI+: 658.3 2-26 2 ESI+: 678.3 2-27 2 ESI+: 628.3 2-28 2 ESI+: 644.4 2-29 2 ESI+: 656.3 2-30 2 ESI+: 642.3 2-31 2 ESI+: 692.3 2-32 2 ESI+: 642.2 2-33 2 ESI+: 678.3 2-34 2 ESI+: 656.3 2-35 2 ESI+: 628.3 2-36 2 ESI+: 656.3 2-37 2 ESI+: 690.3 2-38 2 ESI+: 418.4, 420.4 2- ESI+:297.3 2-42 2 -46 2 ESI+: 684.2 3 3 ESI+: 468.1, 470.1 3-1 3 ESI+: 460.1, 462.1 3-2 3 ESI+: 499.1 3-3 3 ESI+: 484.2, 486.1 3-4 3 ESI+: 352_3 4 4 ESI+: 410.2 , 412.2 5A 5A ESI+: 705.3 5A-1 5A ESI+: 672.5 5A-2 5A ESI+: 594.4 [M+Na]+ 5A-3 5A ESI+: 418.2 5A-4 .5A ESI+:722.4 5A-5 5A ESI+:633.4 5A -5 5A ESI+: 716.8 5A-6 5A ES Bu: 683,1

-168- 201247215

◎ [Table 8 3] 5A-7 5A ESI+: 690.2 5A-8 5A ESI+: 650.2 [M+Na]+ 5A-9 5A ESI+: 600.2 [M+Na]+ 5A-10 5A ESI+.745.4 5A-11 5A ESI+: 596.3 [M+Na]+ 5A-12 5A ESI+: 580.3 [M+Na]+ 5A-13 5A ESI+.709.9 5A-14 5A ESI+: 384.2 5A-15 5A ESI+: 666 5A-16 5A ESI+:704_3 5A-17 5A ESI+.735.3 5A-18 5A ESI+: 696.6 5A-19 5A ESI+: 721.3 5A-20 5A ESI+: 698_9 5A-21 5A ESI+: 610.3 [M+Na]+ 5A-22 5A NMR-CDCI3: 8.50 (2H, s), 8.42 (2H, d, J = 8.0 Hz), 7.96 (1H, d, J = 8.0 Hz), 7.7 3 (2H, d, J = 8.0 Hz), 7.63 (1 H, dd, J=8.0, 2.0 Hz), 7.50 (1 H, d, J=2.0 Hz), 7.28-7.35 (2H, m), 6.93-7.05 (3H, m), 5_69 (1H, s), 4_07 (2H, m), 3.87(3H, s), 3_55- 3.75(4H,m), 3.28-3.35(2H,m)l2.39(2HIm)l2.00-2.18(4H,m) 5A-23 5A ESI+:671 5A-24 5A ESI+: 652.5fM+Na]+ 5A-25 5A ESI+: 649.3 5A-26 5A ESI+: 700.3 5A-27 5A ESI+: 708 5A-28 5A ESI+: 533.3 [M+Nal+ 5A-29 5A ESI+: 592_4 5A-30 5A ESI+:577_2 5A-31 5A ESI+:476.2 5A-32 5A ESI+:698.3 5A-33 5A ESI+:461_3 5A-34 5A ESI+:572_4 5A-35 5A ESI+:696.1 5A-36 5A ESI+:681.2 5A-37 5A ESI+: 665.3 5A-38 5A ESI+: 650.3 5A-39 5A FA B+: 674.4 -169- 201247215 [Table 8 4] 5Α·40 5A ESI+; 674.4 5Α-41 5A ESI+: 656.4 5Α-42 5A ESI+.700.3 5Α-43 5A ESI+:667 5Α-44 5A ESI+: 676.1, 678, 1[M+Na]+ 5Α-45 5A ESI+: 653.4 5Α-46 5 A ESI+: 624.3fM+Na]+ 5Β 5B ESI+:440.4[M+Na1+ 5Β-1 5B ESI+:660.4 5Β-2 5B ESI+:695.3 [M+Na]+ 5Β-3 5B ESI+: 694.5 [M+Na]+ 5Β-4 5B ESI+: 679.3iM+Na1+ 5Β·5 5B ESI+: 678.4 [M+Na]+ 5Β-6 5B NMR3:1_51( 9H, s >, 2.39 (2H, brs), 3.67 (2H, m), 3.88 (3H, s), 4.07 (2 H, brs), 5.13 (2H, s), 5.59 (1H, brs), 7〇 7(2Hld, J=8.8Hz), 7.32- 7.48(6H,m), 7.56-7.69(7H,m), 7.96(1H,d,J=8.1Hz) 5-7-7 5B ESI+:679.3[M+ Na]+ 5Β-8 5B ESI+:690_3 5Β-9 5B ESI+:674.3 5Β-10 5B ESI+:699.2 5Β-11 5B ESI+:820.1 5Β-12 5B ESI+:711.2iM+Na]+ 5Β-13 5B ESI+:618.2 5Β-14 5B ESI+.649.3 5Β-15 5B ESI+: 477_1 5C 5C ESI+: 671.5 5C-1 5C ESI+: 703.6 5C-2 5C FAB+:710.4 5C-3 5C ESI+.499 5C-4 5C ESI+:612_0 5C-5 5C ESI+: 643.4 5C-6 5C ESI+: 588.3iM+Nal+ 5C-7 5C ESI+: 580.3iM+Na]+ 5C-8 5C ESI+:645.3 5C-9 5C ESI+:604.4 5C-10 5C FAB+:731.3 5C- 11 5C ESI+.499.2

-170- 201247215

[Table 8 5] 5012 5C ESI+: 643.5 5C-13 5C ESI+: 631.5 5C-14 5C FAB+: 650.3 5C-15 5C ESI+: 580.1 5C-16 5C ESI+: 580.1 5C-17 5C ESI+: 594.1 5C-18 5C ESI+ : 633.3 5C-19 5C ESI+: 657.5 5C-20 5C ESI+: 633.3 5C-21 5C ESI-: 204.1 5C-22 5C ESI+:269.2[M+Na]+ 5C-23 5C ESI+:717.6 5C-24 5C ESI+: 655.4 5025 5C ESI+: 654.3 5C-26 5C ESI+: 480.3fM-BOC+Hr 5C-27 5C ESI+: 659.5 5D 5D ESI+: 466.1 [M+Na]+ 5D-1 5D ESI+: 444.2 5D-2 5D ESI+.494.4 5D-3 5D ESI+: 483_3 5D-4 5D ESI+: 533_1 5D-5 5D ESI+: 526.4 5D-6 5D ESI+: 516.2 [M+Na]+ 5E 5E ESI+: 513.3 5E-1 5E NMR3: 3.96 (3H, s ), 5.13(2Hls)l7.08(2H,d,J=8.9Hz), 7.32- 7.48(5H,m), 7.56- 7.59(3H,m), 7.65(4H,s),7.73(1 H. Brd, J=1,8Hz), 7.94(1 H,d,J=8.2 Hz) 5E-2 5E ESI+:425.1 5E-3 5E ESI+:275.2 5E-4 5E ESI+:548.2,550.2[M+Na]+ 5E-5 5E ESI+: 525.3 5E-6 5E ESI+: 525_4 5E-7 5E ESI+: 532.3, 534.2 [M+Na]+ 5E-8 5E ESI+: 531.4 [M+Na]+ 5E-9 5E ESI+:346.1 5E -10 5E ESI+: 391.3 -171 - 201247215

[Table 8 6] 5E-11 5E ESI+: 537.3 [M+Na]+ 5E-12 5E ESI+: 604.7 5E-13 5E ESI+: 403.2 5E-14 5E ESI+: 522.8 5E-15 5E ESI+: 330_1 5E-16 5E ESI+: 474.2 5E-17 5E ESI+.599.2 5E-18 5E ESI+: 565.2 [M+Nal+ 5E-19 5E ESI+: 483.2 5E-20 5E ESI+: 502.3 5E-21 5E ESI+: 362.2 5E-22 5E ESI+: 544.2 5E -23 5E ESI+: 545.1 5E-24 5E ESI+: 384.1, 386.1 5E-25 5E ESI+: 591_3 5E-26 5E ESI+: 336.1 [M+Na]+ 5E-27 5E ESI+: 409.1 5E-28 5E ESI+: 386.1 iM +Nal+ 5F 5F ESI+: 718.3 5G 5G ESI+: 390.1 [M+Na]+ 6 6 ESI+: 488.0 [M+Na]+ 6-1 6 6-2 6 ESI+:493.1 6-3 6 ESI+:466.1 6-4 6 ESI+: 555.2 6-5 6 ESI+: 548.2 6-6 6 ESI+: 545.0 [M+Na]+ 6-7 6 ES!+:533.4 6-8 6 FAB+: 653.3 6-9 6 ESI+:653.5 6-10 6 ESI+: 544.2 [M+Na]+ 6-11 6 ESI+: 578.1 6-12 6 ESI+: 537.9 [M+Nal+ 6-13 6 ESI+: 531.3 6-14 6 ESI+:486.0 6-15 6 ESI+:639.2 I -172- 201247215

[Table 8 7] 6-16 6 ESI+: 480.1 6-17 6 ESI+: 410.1 6-18 6 ESI+: 581.1fM+Na]+ 6-19 6 ESI+: 524.1 6-20 6 ESI+: 531.1 6-21 6 ESI+ : 525.1 6-22 6 ESI+: 507.2 6-23 6 ESI+: 507.2 6-24 6 ESI+: 570.6 6-25 6 ESI+: 490.1 [M+Naf 7 7 ESI+: 467.3, 469.2, [Μ+Η+2Γ 8 8 ESI+: 445.2 8-1 8 ESI+: 420.2, 422.2 8-2 8 ESI-: 435.1, 437.0 8-3 8 ESI+: 419.2, 421.1 8-4 δ ESI+: 420.1, 422.2 8-5 8 ESI+: 420.1, 422.1 8 -6 8 ESI+: 359.2, 361.1 8-7 δ ESI+: 447.1, 449.0 [M+Na]+ 8-8 8 ESI+: 497.2 [M+Na]+ 8-9 8 ESI+:289.1 8-10 8 ESI+:437.0 8-11 8 ESi+: 432 8-12 8 ESI+: 408.2, 410.2 8-13 8 ESI+: 408.1, 410.1 8-14 8 ESI+: 434 8-15 8 ESI+: 412.4, 414.1 8-16 8 ESI+: 409 8- 17 8 ESI+: 406, 408 8-18 8 ESI+: 494.0 8-19 8 ESI+: 408.0 8-20 8 ESI+: 480.2 8-21 8 ESI+: 466.0 8-22 8 ESI+: 406.1, 408.1 8-23 8 ESI+: 394.2, 396.1 8-24 8 ESI+: 422.2, 424.2 -173- 201247215 [Table 8 8] 8-25 8 ESI+: 434.3, 436.3 8-26 8 ESI+: 419.2, 421.1 9 9 ESI+: 459.3 9-1 9 ESI+: 459.3 10 10 ESI-: 1577.4 10-1 10 ESI+: 377.4 [M+Nal+ 10-2 10 ESI-:1559.00 [M-H1- 10-3 10 ESI-: 1561.6rM-Hl- 10-4 10 ESI+: 361.1.363.1 [M+Na1+ 10-5 10 ESI+: 361.1, 363.1 [M+Nal+ 10-6 10 ESI+:341.1 , 343.0 10-7 10 ESI+: 426.1, 428.1 10·8 10 ESI+: 383.1, 385.1 10-9 10 ESI+: 411.0, 413.0 10-10 10 ESI-: 1541 10-11 10 ESI+: 371.1 10-12 10 ESI+: 347_0,349_0 10-13 10 ESI+:385.2 10-14 .10, ESI+:361.1 10-15 10 ESI+:604.0 10-16 10 ESI+:361.1,363.1 10-17 10 ESI+:375_1,377.1 10-18 10 10- 19 10 ESI-: 1579 10-20 10 ESI+: 670.0 10-21 10 ESI+: 676.6 10-22 10 ESI-: 1513.7 10-23 10 ESI-: 1515.8 10-24 10 ESI-: 1579.2 10-25 10 ESI+: 680.4[M+Nal+ 10-26 10 ESI+:434.9,437.0 10-27 10 FAB-: 1562.8 10-28 10 FAB-: 1548.6 10-29 10 FAB-: 1526.6 10-30 10 FAB-: 1498.6 10-31 10 ESI+: 414.1, 416.1 -174- 201247215

[Table 8 9] 10-32 10 ESI+: 320.0, 322.0 10-33 10 ESI+: 459.1, 461.0 11 11 ESI-: 1482.1 12 12 ESI+: 373.3, 375.1 13 13 ESI+: 451.0 14A 14A ESI+: 674.4 14A-1 14A ESI+: 608.4 14A-2 14A ESI+: 607.3 14A-3 14A ESI+: 341.2, 343.2 14A-4 14A ESI+: 326.2 14A-5 14A ESI+: 1163.3 14A-6 14A ESI+: 264.0, 266.0 [M+2+H]+ 14A-7 14A ESI+: 625.3 14A-8 14A ESI+: 445.1 14A-9 14A ESI+: 591.3 14A-10 14A El: 535.4 14A-11 14A ESI+: 592.2 14A-12 14A ESI+: 592.2 14A-13 14A ESI+: 591.3 14A -14 14A ESI+: 591.2 14A-15 14A ESI+: 392.2, 394.2 14B 14B ESI+: 365.1, 367.1 14B-1 14B El+: 276.1 14B-2 14B ESI+: 327.2 [M+Na]+ 14B-3 14B El:290.2 14B ESI+:311.2[M+Na]+ 14C 14C ESI+:351.1,353.0 15 15 ESI+:332.2[M+Na]+ 16 16 ESI+:494.4 16-1 16 ESI+:391.1,393.3 16-2 16 ESI+: 232.1 16-3 16 ESI+: 502.2 17 17 ESI+: 379.1, 381.1 18 18 ESI+: 417.0, 419.1 18-1 18 ESI+: 321.1, 323.2 18-2 18 ESI+: 323.1, 325.0 -175- 201247215 [Table 9 0] 18 -3 18 FAB+: 408.0, 410.0 18-4 18 El: 392.2, 394.3 18-5 18 ESI+: 353 18-6 18 ESI+: 674.3 fM+Na]+ 18-7 18 ESI+: 329.0 18-8 18 ESI+: 321.1, 323.1 18-9 18 ESI+: 658.4 18-10 18 ESI+: 367.1 18-11 18 ESI+: 343.1 18-12 18 ESI+: 608.3 [ M+Na]+ 18-13 18 ESI+: 409.1, 411.1 18-14 18 ESI+: 343.1, 345.0 18-15 18 ESI+: 343.0, 345.0 18-16 18 ESI+: 357.1, 359.1 18-17 18 FAB+: 396.1, 398.1 18-18 18 ESI+: 302.0, 304.0 18-19 18 ESI+: 369.1, 371.1 18-20 18 ESI+: 697.3 18-21 18 ESI+: 699.4 18-22 18 ESI+: 623.3 19 19 ESI+: 373.0, 375.0 20 20 ESI+ : 337.1, 339.1 20-1 20 ESI+: 381.1, 383.1 21 21 ESI+: 435.1, 437.2 22 22 ESI+: 272.3 22-1 22 ESI+: 344.3 22-2 22 ESI+: 330.3 22-3 22 22-4 22 ESI+: 258.2 23 23 ESI+: 325.0, 327.0 [M+Nar 23-1 23 ESI+: 318.0, 319.9 23-2 23 El: 256.1, 258.1 24 24 ESI+: 256.9, 259.0 25 25 ESI+: 396.2, 398.2 26 26 ESI+: 359.1, 361.1 27 27 ESI+: 329.1 fM+Nal+

-176- 201247215

[Table 9 1] 28 28 El: 304.9 29 29 ESI+: 362.1 29-1 29 ESI+: 412.2 30 30 ESI+: 549.3 31 31 ESI+: 286.2 31-1 31 ESI+: 358.3 31-2 31 ESI+: 344_1 31-3 31 ESI+: 286.3 31-4 31 ESI+.272.2 31-5 31 ESI+: 300_3 32 32: ESI+: 371.0 33 33 ESI+: 635.3 33-1 33 ESI-: 644.3 33-2 33 ESI-: 657.4, 659.3 33-3 33 ESI-: 656.3 33-4 33 ESI-: 641.5 33-5 33 ESI-: 640.5 33-6 33 ESI-: 656.5 33-7 33 ESI-: 560.3 33-8 33 ESI-: 556.5 33-9 33 ESI+: 708.3 33-10 33 ESI-: 641.5 33-11 33 ESI-: 674.3 33-12 33 ESI+: 619.3 33-13 33 ESI-: 499.1 33-14 33 33-15 33 ESI+: 701.3 33-16 33 ESI+: 669.5 33-17 33 ESI+: 685.4 33-18 33 ESI+: 806.6 33-19 33 ESI+: 691.3 33-20 33 ESI-: 673.3 33-21 33 ESI-: 673.3 33-22 33 ESI-: 612.3 33-23 33 ESI -: 562.2 33-24 33 ESI+: 731_3 - 177 - 201247215 [Table 9 2] 33-25 33 ESI-: 558.4 33-26 33 ESI-: 542.3 33-27 33 ESI-: 678.4 33-28 33 ESI-: 694.5 33-29 33 ESI+: 652_0 33-30 33 ESI+: 679.3 33-31 33 ESI+: 665.2 33-32 33 ESI+: 661.3 33-33 33 ESI+: 665.2 33-34 33 ESI+: 675.3 33-35 33 FAB-: 638.3, 640.3 33-36 33 ESI+: 675.3 33-37 33 ESI-: 1577.6 33-38 33 ESI+: 683.3 33-39 33 ESI+: 610.3fM+Na]+ 33-40 33 ESI+: 707_3 33- 41 33 ESI+: 690.3 33-42 33 ESI+: 635.3 33-43 33 ESI+: 604.4 33-44 33 FAB-: 572.3 33-45 33 ESI+: 696.3 33-46 33 ESI+: 684.4 33-47 33 ESI+: 721.3 33- 48 ESI+: 661.3 33-49 33 ESI+: 660.4 33-50 33 ESI+.686.3 33-51 33 ESI+: 633.0 33-52 33 ESI+: 645.3 33-53 33 ESI+: 660.3 33-54 33 ESI+:680.3 33-55 33 FAB+: 690.3 33-56 33 ESI+: 639.0 33-57 33 ESI+: 690.5 33-58 33 ESI+: 657 33-59 33 ESI+: 653.3 33-60 33 ESI+: 638.4 [M+Nal+

-178- 201247215

◎ [Table 9 3] 33-61 33 ESI+: 635.3 33-62 33 ESI+.704.6 33-63 33 ESI+: 686.6 33-64 33 ESI+: 694 33-65 33 ESI+: 704'3 33-66 33 ESI+: 704.3 33-67 33 ESI+: 598.2 [M+Na]+ 33-68 33 ESI+: 563.2 33-69 33 ESI+: 578.3 33-70 33 ESI+: 660.3 [M+Na]+ 33-71 33 ESI+:682.1 33-72 33 ESI+: 684.3 33-73 33 ESI+: 629.4 33-74 33 ESI+: 577.2 33-75 33 NMR-CDCI3: 8.13 (2H, d, J = 8.8 Hz), 7_97 (1H, d, J = 8.0 Hz), 7.69 (2H, d, J=8, 8 Hz), 7.53 (1 H, d, J = 8.0 Hz), 7.45 (1 H, s), 7.20-7/35 (5H, m), 5.61 (1H, s ), 3.95-4.09 (2H, m), 3.65-3.52 (2H, m), 3.29-3.19 (4H, m), 2.48-2.34 (2H, m), 2.14 (1 H, brs), 1.45 (9H, s) 33-76 33 ESI+: 631.4 33-77 33 ESI+: 566_3 [M+Na]+ 33-78 33 ESI+: 611.1 33-79 33 ESI+: 667.3 33-80 33 ESI+: 651.3 33-81 33 ESI+: 590.3 33-82 33 ESI+: 685.4 33-83 33 ESI+: 590.4 33-84 33 ESI+: 588.3 33-85 33 ESI+: 578.3 33-86 33 ESI+: 577.2 33-87 33 ESI+: 577.2 33-88 33 ESI+: 578.3 33 -89 33 ESI+: 694.3 33-90 33 ESI+: 604.3 33-91 33 ESI+: 609.3 33-92 33 ESI+: 594.4 33-93 33 ESI+: 593.2 -179- 201247215 [Table 9 4] 33-94 33 ESI+: 658.3 [M+Na]+ 33-95 33 ESI+: 667.2fM+Na]+ 33-96 33 ESI+: 636.3 33-97 33 FAB+: 660_4 33-98 33 ESI+: 660.3 33-99 33 ESI+: 560.3 33 -100 33 ESI+: 630.3 33-101 33 ESI+: 628.3 33-102 33 ESI+: 644.3 33-103 33 ESI+: 664.3 33-104 33 ESI+: 614.3 33-105 33 ESI+: 650.3 33-106 33 ESI+: 654.2 33- 107 ESI+: 670.2 33-108 33 ESI-: 627.5 33-109 33 ESI+: 639.22 [M+Na]+ 33-110 33 33-111 33 ESI+: 602_3[M+Na]+ 33-112 33 ESI+:630.3 33-113 33 ESI+: 642.3 33-114 33 ESI+: 628.3 33-115 33 ESI+: 588.2 [M+Nal+ 33-116 33 ESI+: 678_3 33-117 33 ESI+: 643.3 33-118 33 ESI+: 664.2 33-119 33 ESI+: 642.3 33-120 33 ESI+: 614.3 33-121 33 ESI+: 642_3 33-122 33 ESI+: 628.3 33-123 33 33-124 33 ESI+: 619.1 33-125 33 ESI+: 619.2 33-126 33 ESI+: 592.1 [ M+Na]+ 33-127 33 ESI+: 676.3 33-128 33 ESI+: 689.5 33-129 33 ESI+: 703.5 .

-180- 201247215

[Table 9 5] 33-130 33 ESI+: 679.2 [M+Na]+ 33-131 33 ESI+: 706.3 33-132 33 ESI+: 641.2 33-133 33 ESI+: 639.4 33-134 33 ESI+: 642.3 34 34 El+: 178.1 34-1 34 EI+.162.1 34-2 34 El+: 148.1 34-3 34 El+: 160_0 35 35 36 36 ESI+: 293.2, 295.1 [M+Na]+ 36-1 36 ESI+: 357,359 [M+Na]+ 36-2 36 ESI+: 363.0, 365.0 [M+Na]+ 37 37 ESI+: 413.1, 415.1 38 38 ESI+:399_3 38-1 38 ESI+:487.1 39 39 ESI+:215.1 39-1 39 El+:186.1 39-2 39 El+:200_1 39-3 39 El+:200.1 40 40 ESI+: 605.2 40-1 40 ESI+:212 40-2 40 ESI+:186.1 40-3 40 ESI+:172.1 40-4 40 ESI+.-308.1,310.1 40-5 40 ESI+: 272.1 40-6 40 ESI+: 399 40-7 40 ESI+: 567.2 40-8 40 ESI+: 560.2 40-9 40 ESI+: 186.2 40-10 40 ESI+: 444.2 40-11 40 ESI+: 445.1 40-12 40 ESI+ : 200.2 40-13 40 ESI+.574.3 40-14 40 APCI/ESI+: 399.2 40-15 40 ESI+: 530.2 *181 - 201247215 [Table 9 6] 40-16 40 ESI+: 212.2 40-17 40 ESI+: 258.3 40- 18 40 ESI+: 244.1 40-19 40 ESI+: 308.0, 310.0 40-20 40 ESI+: 197.3 40-21 40 ESI+: 306.1, 308.1 40-22 40 40-23 40 ESI+: 255.4 41 41 ESI+ : 746.4 [M+Na] + 41-1 41 NMR-CDCI3: 8.20 (2H, d, J = 8.5 Hz), 8.09 (1H, d, J = 8.2 Hz), 7.72 - 7.79 (4H, m) l7. 58-7.66(3Hlm), 7.47-7.51(1H,m), 7.28- 7.44(4H,m),5.57-5.69(1H,m),4.41 to 4.50(2H,m), 4.27(1H,m), 4.05-4.12(2Hlm)l3.62- 3.69(2H,m)l3.04(1H,m), 2.32-2.50(2Hlm)l2.12- 2.22(2H,m),1.84-1,94(2H, m), 1.67-1.80 (3H, tn), 1.30- 1.50 (3H, m) 41-2 41 ESI+: 746.4 [M+Na]+ 42 42 ESI-: 1425.19 42-1 42 ESI-: 1427.7 42-2 42 ESI+: 555.3 42-3 42 ESI+: 556.2 42-4 42 ESI+: 939.3 43 43 ESI+: 394.1 [M+Na]+ 44 44. ESI+: 546.5 45 45 ESI+: 361.3 45-1 45 ESI+: 367.0 45-2 45 ESI+: 423.3 45-3 45 ESI+: 334.2 45-4 45 ESI-.519.2 45-5 45 ESI+: 400.3 45-6 45 ESI-: 437.2 45-7 45 ESI+:391_3 45-8 45 ESI+:390.2 45- 9 45 ES Bu: 446.1 45-10 45 ESI+: 348.0 45-11 45 ESI+: 353.0 45-12 45 ESI+: 399_3 45-13 45 ESI+: 278.1 45-14 45 ESI+: 392.2

-182- 201247215

[Table 9 7] 45*15 45 ESI+: 375.3 45-16 45 ESI+: 375.3 45-17 45 ESI+: 416.1 45-18 45 ESI+: 520_4 45-19 45 ESI+: 163.1 46 46 ESI-: 334.3 46-1 46 ESI+.507.2 46-2 46 ESI-: 425.1 46-3 46 ESI+: 392.2 46-4 46 ESI+: 488.4 47 47 ESI+.480.9 47-1 47 ESI+: 563.3 47-2 47 ESI+: 491.2 [M+Na]+ 48 ESI+: 376.1, 378.1 49 49 ESI-: 772 (MH) 72 50 50 ESI+: 312.2 50-1 50 ESI+442.3 [M+Nar 51 51 EI+-.290.0,292.0 33-135 33 ESI+: 637.2 5A- 47 5A ESI+: 651.1 47-3 47 ESI+: 370.1 6-26 6 ESI+: 460.1 46-5 46 ESI+: 328.1 5B-16 5B ESI+: 412.4 36-3 36 ESI+: 310.1

-183- 201247215

[Table 9 8] Ex STR 1 Μ ?H 〇 A HO 0— X〇 2 °^: h2n 〇< h 〇VS IP . b HO 0S03H 0nBu 3 άά, - /Λ:^ΜΘ yj 〇Η HO 0S03H

-184- 201247215

[Table 9 9] 4 Λ Μ ?Η ο Η^Ν /νΛ η2ν 〇={ η 〇yS'' Me X HO 〇'一i Me^Me W 〇H HO 0S03H 5 h2n^Y° Μ6^〇Ν^ Ηη C5 h〇v>〇h νΝγΛ °y^\H Hfjl 〇H h2n o=<^h 〇yS'' W vJs Me /=<^io O^O, (N_\ OH ^-/〇Me HO OSO3H i~\ 6 H2N^T〇M ?H 0 rNvi OVrOHH 9 ν^ΝΗ ηΛη〇h2n 〇=( h °vS'' ^rN〇v HO OSO3H 〇Bn -185- 201247215 ο ο

HN

8

HN 9

-186 201247215

[Table 1 ο 1] 10 Η 9Η 〇 [Ν] ^ ι〇ν^ν_. ΗζΝ Ά HO 0S03H 11 r 9H 〇门V/^C〇N /=< HOO VJ, Ν-Λ Q 〇H 〇HO OSO3H \ Me_^0 12 h〇Hs〇3h oh 〇r -187- 201247215

[Table 1 Ο 2 I

13 Η Me^v ώ V^JH , 〇H h2n K h 〇^r IJLn-, Μ Λ HO 0S03H Me 14 Η 〇Η η/^Η ◦, Ο) M fV H〇OSO3H *^Μβ 15 〇^ 0 ηΛ MeH〇h2NK>h ^ oh HO OSO3H -188- 201247215

[Table 1 ο 3]

-189- 201247215 [Table 1 Ο 4] 19 ηΧ Cl^d η2ν 〇=<_η °yS'' Hi Μθ 〇Η HO 0S03H 20 m ?H 〇 rS . Fen? H2nK>ho^oh ao HO OSO3H 21 Jl^Me 〇, hoHso3h 〇H Φ OMe

-190 - 201247215 [Table 1 Ο 5]

=~T9t 201247215 [Table 1 Ο 6] 25 η2ν 〇=< η J 1 h〇Hso3h fj0 26 OH ί% μΆ,,. ηηλΥ οΗ〇ΧΗ^ΝΛν. a〇, hoHso, * ^ 27 η;^Ϊη ^:; a-\ HO 0S03H EtO^5^ -192- 201247215

[Table 1 Ο 7] 28 Yes. 〇 a〇, hoHso3h 〇H OBn 29 ,Ηί H hoHso3h 〇H φ σ° -193- 201247215 Μ 30

-194- 201247215 [Table 1 ο 8]

-195- 201247215

-196 - 201247215

[Table 1 1 0]

-197- 201247215

-198- 201247215

[Table 1 1 2] 43 /=^ H〇〇|sj Q 〇H ^ 〇HO 0S03H r )| N 44 A 9H 0 Gate, '.·άν〇也°>K0 ¥ 0=Ck°τ^' 々rfiK 0 )_( 0Η Me 乂V Η〇0S°3H (o^Q^Q, 45 Η 〇H 〇H2N 〇=< H 〇yS''〇H ΧλγΝ Q 0H 〇HO OSO3H 0^3 -199 - 201247215 [Table 1 1 3] 46 〇A ho 〇s〇3h y~^ '~7^~Me Me 47 〇[N] H2N 〇心〇^γ〇Η ^Υ°·Ν Me N( Q 0H W HO OSO3H S^~Me Me

-200- 201247215

48

OMe -201 - 201247215

[Table 1 1 4] 49 Me^〇N^-H 6 h〇^V〇h Η2^^ίΗΗ r? along sn y_^ OH X-^OMe HO 0S03H /( 50 q〇. HO OSO3H /~( 51 Jckr 〇O OH S^〇Me HO OSO3H

-202- 201247215

-203- 201247215 [Table 1 1 6]

55 T〇〇H ^ 〇H HO 0S03H 56 heart ''name HCV h0 1 N hn 〇〇h h2n 〇=< h JckT W 0H HO OSO3H 57 HO, >〇X ^,〇Me hK^h to 0 W 〇H HO OSO3H -204- 201247215

[mi 17] 58 〇H 0 Gate μ /=\ HO 0 \__·( /N, M 0H Q HO 0S03H 59 V>^H 0 u (10) h2n 〇KH 〇yS''〇H > νλMe /=&lt ; HOO VJ, W 〇H HO OSO3H 60 Me^W0H HA$ h. WN_Vx hh 〇h ^i3i ¥ 〇(H 〇yS', VV^N JV/N, Me FM /^0 O^U (ΝΛ y_^ 〇H W-〇Me HO OSO3H /~\ -205- 201247215 [Table 1 1 8]

-206- 201247215 [Table 1 1 9]

HO 0S03H -207- 201247215 [Table 1 2 0]

-208- 201247215

[Table 1 2 1] 70 μ ?h 〇 A H2H^h. UXXCN1 Μ Λ HO OSO?HI II 71 η,ν^-^η o^oh O^o ^:^ΜΘ npr oh HO OS〇3H 72 Me,,^W〇H hoHso3h 〇HM〇iJ -209- 201247215 [Table 1 2 2] 73 η2ν ο=^Η 〇^γ, ΟΗ 1 ^o^Me SO, Q tV HO 0S03H 74 M; h>〇oh a. H2N 〇={ H 〇yS'' np/ JoKT \_J OH HO OSO3H 75 h〇Hso3h (9

-210- 201247215 [Table 1 2 3]

-211 - 201247215

-212- 201247215

[Table 1 2 5] 82 HO 0S03H EtO^^ 83 〇A h2n 〇=< η °υ^·λ〇η Me hoHso3h 〇HQ Or1 84 Me^VH η〇λ〇η ^Λα hoHso, 〇H 6 - 213- 201247215

[Table 1 2 6] 85 N0, hoHso, 〇H EV 86 <Η;Ηί°τ^η h2n 〇=< h °yS''〇H ^Sf^S Me νΛο, hoHso3h 〇H x9 iPrO^^ 87 H Me Ο, yj OH iPrOy^J HO 0S03H K^J

-214- 201247215 [Table 1 2 7]

-215- 201247215

[Table 1 2 8] 91 M ?H 〇0 H〇〇s〇3h {^y~^ 92 H ?H ◦ /N °>^ίΗ〇HO 〇S〇3H np> 93 N\ HL λΝΗ n~ 'λ一·' N-^ HO )=〇\ V^Jnh hn 〇〇h h2n 〇=< H 〇V^S' Me /=\ ho 0 V4 W OH HO OSO3H

-216- 201247215 [Table 1 2 9] -

Cl -217- 201247215 [Table 1 3 0] 97 τ °〇hu h2n 〇=< H >νλMe /=\ HO〇V-4 yj oh HO 0S03H 98 hX Me-o h2n 〇={ h 〇V\ '' Jckr yj oh HO OSO3H 99 H η2ΝΚ^Ά,〇η Jy N\ n Me Νν^Ν^γΜβ /=(^0 0^\Dy ^Nv] h〇Hs〇3h oh cr

-218- 201247215

[Table 1 3 1] 100 Η h2n 〇=< η 〇Λ'〇Η (j W OH HO 0S03H 101 HO >=〇\ Γ ) V^NH 〇H "〇Bn h2n 〇=κΓ h °vS '' 〇H HO OSO3H 102 <H; ηΛη d- h2n 〇={ h °Va' \_J 〇H HO OSO3H -219- 201247215 [Table 1 3 2]

103 <Ηη° ηΛη 0 H2N 〇K_H 〇yS'' Me W OH HO 0S03H 104 VVfH hX Q-Me h2n 〇=< h 〇V\'' 〇H HO OSO3H 105 P H2N 0=< H Me W 〇h HO OSO3H -220- 201247215

[Table 1 3 3] 106 Hr?"〇jQ| h2n”o{Hh ο&,ΟΗ ^ V,Me yj oh HO OS〇3H 107 Me'-0^N^〇HS? m rr HO OSO3H 108 H HO^ >=〇%yin ηΛ u h2n 〇=( h ^NV>N. Me /=^m〇\J, W 〇H HO OSO3H -221 - 201247215

[Table 1 3 4] 109 \ hn^o nHep H2N 〇=^H 〇^r'〇H ^ V,Me oh HO 〇S〇3H 110 Me,,CV^N^^0H h2n 〇=( h 〇ySm ^ Q hoHso3h 〇H ^ 111 〇^H〇<〇〇H "n〇Ct Me y_^ oh HO 0S03H

-222- 201247215

-223- 201247215

[Table 1 3 6] 115 °>_7Λη hn 〇h Q oh〇^〇h Q HO 〇S〇3H MeO ηΗθΧ 116 H2H^h. Right H Μ 0Η VoMe HO 0S03H ΓΛ 117 ～ Η ?Η 0 '^χ«λ9 η2ν 〇={ η 〇yS'n ^Vn〇 Μ 〇Η VnBu HO OSO3H MeO

-224- 201247215 [Table 1 3 7]

HO 0S03H -225- 201247215 [Table 1 3 8]

121 〇HO h^h 0] W 0H HO 0S03H 122 u ?H 0 Λ^?μθ εΛ; oh HO OS03H 123 OH 〇Ν-λ^ Μβ^Ν^Η h2n 〇=( h 〇yS'' [fV y_ ( 〇H HO 0S03H 226- 201247215

[Table 1 3 9] 124 OH 〇 Ν-λ HO 0S03H 125 9*~* 〇 N Fly hkU^^n a. Yj oh HO OSO3H 126 m ?H 〇 h2nK>ho^oh Me M 0-〇HJ〇h 0 HO OSO3H -227- 201247215

[Table 1 4 0] 127 M ?H 0 , Ν-λ h2n 〇=(_ h 〇yS'' (il 〇H ^ HO 0S03H 128 ?H 〇A ΜΘ,,.0^〇'〇ΗΗ 0 9 h2n 〇=< η °γΝΛ〇Η '^TN0 M 〇HW Eight Me HO OSO3H 0-^^ 129 ?H 0 H!N>CCMe HO OSO3H

-228- 201247215

-229- 201247215

[Table 3 3 9 I

-230- 201247215

[Table 1 4 3] 136 <?H 〇A °^° H2N o' h 〇vV 0 〇HQ HO OSO.HN, 137 \J( 0H W HO 〇S〇3H (3-^ 138 A 〇H 0 Γ Ί Me"Cr"«X«-Vi 0 H〇〇s〇3H -231 - 201247215

-232- 201247215

[Table 1 4 5]

142 H2N 0< Η Βη /=\ OHO \—( 〇Η HO 0S03H 143 Η; 〇 3 Me (7 〇Η f HO 0S03H 144 Vr<NH HN^O hoHso3h 〇H -233- 201247215 [Table 1 4 6]

145. Hey. X ο h2^hh Me /=\ OHO \( W 0H HO 0S03H 146 H2N>p^- Q 0ho^〇h 〇 HO OSO3H 147 : Suppressing goods '$ HO OSO3H -234- 201247215

[Table 1 4 7] 148 Me^N^-HQN ί Also On, h2n 〇=< h Ί K^Me v yj( 〇H ii HO 0S03H 149 h2n^VHh 〇^〇H λ ^ΝΊ V 〇H HO OSO3H 150 H : Dog t , Ηί H ^1V0 \_J 0H Sv-7^-0Me HO OSO3H (CH2)7OMe -235- 201247215

[Table 1 4 8] 151 η2ν 〇=( Η 0 ^νλΜθ η' /=\ OHO vJ; / \ 0Η ^-y~〇Me HO 0S03H (CH2)8OMe 152 Η rfCoHJ, 〇HO 0S03H 〇153 Η〇ν&gt ;〇ΗVj:H Η2Ν 0=< Η 0^/1' Ν=( _T\)i Me (CH2)8〇Me /=( όΗΟ7^—( oh HO OSO3H

-236- 201247215

[Table 1 4 9]

-237- 201247215 [Table 1 5 0] 157 _ νΛ〇ν Q 〇Η Γ) HO OMe J ηρ 158 η〇Η^〇Η :: 0 0Η 〇Ρ 159 Office, % Η〇 OMe Door Ν>

-238- 201247215

[Table 1 5 1] 160 M ?H0 6 〇HVh \ Μ >-VnH ^ 〇Η (HCI) \J h2n 〇<H yj oh HO OMe 161 <Hh〇H^〇Me-^ H2N"0 ={HH Ο^ΙγΟΗ (HCI) W \J 〇H HO OMe 162 ?H o 〔K] HO )=〇H LN'^n^jL 〇^NH T 〇H〇l0L N h2n 〇={ h 〇yS&quot ; ^ /=^0^Me - νΛ〇, M ,0H HO OMe -239- 201247215 [Table 1 5 2] 163 0^; "Ν Nl U° v〇H 164 Μθ,-- ί^νΛΜ/\ Χ〇ΗΧ〇Η h H^H -3⁄4 H〇〇Me (HCI) · fy 165 : Doing h2H^h ΝΛ ΝΛα, hoHso3h 〇H 〇?

-240- 201247215

[Table 1 5 3] 166 ho3s^^ Μβ.. Κ Κ hoHso, οη σ 167 ηλ9 〇>η>: Rabbit Me ΝΚ〇γ_( 〇Η , ] HO OSO.H iPr-O1^ 168 οηη 6 0n>〇H\:vb^;i η〇Κ=(Ά,〇η Q— 〇〇H HO 0S03- Na+ -241 - 201247215 [Table 1 5 4]

-242- 201247215

[Table 1 5 5] 172 M 〇HV〇Me H〇〇— Me-T^ Me 173 VHNh ηΛ U HzN °>We iPr-°ry \J oh HO 0S03H 174 HH° r(^>U s 〇 QI) HO 0S03H Γ 丫-243- 201247215

[Table 1 5 6] 175 Μ~Ι>\,,,〇ΗΗ i? 9 °^NH Ht| 〇H h2n 〇=< h 〇yS'n ^T'o /=\ OHO V4 Ν-Λ M 〇H Me-<MeW HO 0S03H W\ \ 176 OH 〇Ν-λ External. 〇 Η2Ν 〇< Η Me^IJ y \ ) OH Me HO OSO3H 177 Me"^W〇H〇^V^A H2N 0< Η S Me ό W 0H HO OSO3H

-244- 201247215

-245- 201247215 [Table 1 5 8] 181 h2nKJHh 〇yS*'oh 0 Nb h"h 182 HN 丫NH2 ?H 〇& 2HC, s>. HO OMe Γ~\ 183 HO^j M ?h 〇rNi H2n 〇\h °^l''〇H *^ΎΝ<!1 νΛο, M ho 〇s〇3h y 1

-246- 201247215

-247- 201247215 [Table 1 6 0]

89

-248- 201247215

-249- 201247215

[Table 1 6 2] 193 HO^l 9Η Tuen Mun 194 HO^l 9H 〇HzN >Cv: HO 〇S〇3H 〇·^ 195 Me ς)Η 〇人 Me", OV〇L^ v5-fH° κ 0H QH〇os〇3H

-250- 201247215

[Table 1 6 3]

-251 - 201247215 [Table 1 6 4] 199 HO^ V^-ζ0 ij 〇Η (HCI) HO^OMe N\ oP 200 OH 〇H0 factory}1Λ W 〇H HO OSOjH 201 HO^l 狮文^〇x hoHso, 〇HC|i)

-252- 201247215

[Table 1 6 5] 202 HO^ M ?H 〇Λ h2nK>ho^oh 'CLn. yj oh ^ ^ HO 0S03H j^j| Cl 203 M ?H HO) Si ^〇V?Me y_^ 〇HC\ y^J HO OSO3H 204 H〇/T> vVfH° hX Me〇-〇h2n 〇={ H 〇yS'' yj oh HO OSO3H -253- 201247215 [Table 1 6 6] 205 HO^ ?H 0 : h;^hh 〇^h ^Sn hoHso3h 〇H λ 206 OH Η〇^ΝΛ H;〇a9p yj oh HO 0S03H 207 9H 0 H〇H°,Η α;σ

-254- 201247215

-255- 201247215 [Table 1 6 8] 211 HO^| h2n 〇< h Me h〇Hs〇3h oh rr MeO^^ 212 HO^| ?H 〇rN^ hoRso3h 〇h (^f Cl 213 HO^| M ?H 〇r"S HcS^^-TrS o^Ch h1 〇h° ^Vl ^νλΜθ Up /=\ 〇H〇V-4 >\/N, hoRso3h 〇H Me^ -256 - 201247215

-257- 201247215

-258- 201247215

[Table 1 7 1] 220 HO. HO >=〇H VN H Li H2N 〇=f h 〇yS"〇H r< Me M X.乂 o HO 〇S〇3H 221 HO^| Me N A, /===\H〇 O^VJ ^Ns hoHso, 〇H EV 222 HO, M ?H 0 crtrrv? 〆 >. Rabbit 1 h2nK>h o^oh Me J /=< HO〇 V4 k/N. hoHso, 〇H 孑 iPrO 〆 -259- 201247215

[Table 1 7 2] 223 ΗΟ^| 0H 〇Λ Me''AUL 〇hh 丫°Λ〇N η2νΜ〇=/Ηη 0^0Η 1 HO 0S03H 224 OH 〇Η〇Λ~)Ν·\ uj, ηΛ 0 Οο η2ν ο^ηΟ^ 〇"Bu W 〇Η HO 0S03H 225 ΟΗ Η〇/~^ ΗΟ )=〇γ 〇\=/ \=/ 'Ν:ίΙ^τ^Ν U> ηΛοη u;0 η2ν 〇= < η °Υ^Ί' ( Me MeV OH HO OSO3H

-260- 201247215

[Table 1 7 4] 226 Y ?Η 〇rN^ MetVWHHf?V 〇y_J\jH H1 OH N h2n 〇=< h 〇yS'' ^Sr /=G〇o^〇M HO 0S03H [IJ 227 ho^ Y^oh ?H 0 rNsi 1 Me /=< HO〇V4 M fV ho 0SO3H |l Ί 228 HO), <?H 〇f 1 Me,,0V<HNlX %H; ^ Y, h2N^o= Th〇^h T Me ~Ν.〇R 〇HN HO OSO3H \__N〆-261 - 201247215 [Table 1 7 4]

229 Me„, 〇 H〇 0 h^c〇h H0 Household 0 \’NH /5 HO 0S03H \^/~^ 230 HO^| hoHso3h 〇H . 231 HO^| κ ή HO OSO3H -262- 201247215

[Table 1 7 5] 232 HO^ Η2Ν^ί Η 〇^〇〇Η 0 η, Q0H - QnHex HO 0S03H MeO 233 HO^| M ?h 〇r, ΟΛ 丫η Y 〇HOJ^° xN0^u^ h2N ^h Q〇H〇MJ〇h 0 HO 0S03H )—\ leMe 234 HO^| rCioHJ, 〇M 0H — HO OSO3H -263- 201247215

[Table 1 7 6] 235 Me HO 0S03H 0nPr 236 hcT>A Xx OH W_ hK^H. Yj oh HO OSO3H 237 Me H;〇 yj oh HO OSO3H

-264- 201247215

[Table 1 7 7] 238 ς)Η 〇HO factory^ 〇H V_/ h2N^JHh o^h Me^ yj oh HO OSOgH 239 Me H corpse 0 heart 〇^Y〇H Me^C) >νλMe /= \ HO 0 ( yj oh HO OSO3H 240 Me, ηΛ h2n 〇K_H 〇yS" yj oh HO OSO3H -265- 201247215

[Table 1 7 8] 241 ?H 〇O °>κ; q, —〇心〇yS, y_^ 〇h HO 0S03H 242 OH 〇H〇l H" ^CVe HO OSO3H nPn 243 h2n^2NHh o^' Oh V0Me W OH HO OSO3H

-266- 201247215

[Table 1 7 9] 244 Me, OH 〇, N fly) ^NJ, Me 9 rCbno^, nBu W 0H HO 0S03H 245 Me L 〇Λ==/Λ=/^ΝίνΝ as 'W 〇H HO OSO3H 246 HO , •Ά,,,〇η \ Cl -267- 201247215

-268- 201247215

[Table 1 8 1] 250 ΗΟ^ι M ?h 〇rNi h2n 〇kh Me N into ^Me M HO 0S03H [I^J 251 ΗΟ^Ν-λ hX o-Me h2n 〇=(_h 0yS° yj oh HO OSO3H 252 °^:; >〇OH P H2N 0=< H Me /=\ HO〇VJ, yj oh HO OSO3H -269- 201247215

[Table 1 8 2] 253 ΗζΝ ^0^Me i° rdooH^ -Λμθ y_^ oh HO 0S03H 254 Me HzN i° rCicHJ, -People-oh HO OSO3H 255 Me hK^H. Office W 0H HO OSO3H

-270 - 201247215

[Table 1 8 3] 256 Me 〇η〇Λ° W OH HO 0S03H 257 Me, h2^h 0^ P y( 〇H HO OSO3H 258 He/~, H-λ w=w=v H〇V〇H VNT<>〇-i>0) hK^h. D- \J OH HO 0S03H -271 - 201247215 [Table 1 8 4]

-272- 201247215

[Table 1 8 5] 262 HO. Hh_〇0 H2N 0K H °Y^''〇H *^>N /=\ OHO V-( /N, H〇Hso3H 〇H 263 HO^| H〇J>〇H Wl Ηκϋ ^xv. Batch J] HO 0S03H 〈 \—/ 264 HO) H〇OSO3H ^-yj -273- 201247215 [Table 1 8 6] 265 HO^| ?Η ο γΝΊ Ηκϋ ^〇v·. >Nv Me N=< minutes 'Q HO 0S03H n0ct 266 OH Η. ] :P^H 〇^^°^x0 Me Me 267 HO. . Year ^tx 0 HO OSO3H ^

-274- 201247215

-275- 201247215

-276 - 201247215 [Table 1 8 9]

274 HO, μ ?Η 〇 丫 Still η η 9 vHh〇 Η2Ν 〇{Η 〇^,,. Η ^^ΟγΝ.ο /-γ w%Me QOH〇nj〇H 〇>—( vV1〇Me HO 0S03H 275 HO, ..9H 0 ^nn Hr〇〇H^V\ N H2N Q όΗ0^〇Η Q, HO OSO3H yw 276 hoHso, 〇H -277 201247215

-278- 201247215

•279- 201247215

•280· 201247215 [Table 1 9 3]

HO 0S03H HO^,

-281 - 201247215

[Table 1 9 4] 291 M ?H 〇H0 Factory)ΝΛ Me ^°XJ oh HO 0S03H 292 HO) 0^=° HXKx^ H!N^: HO OSO3H Me 293 Me vHh h2N o^hO^ ^0 r (i>U 〇^ 〇HS^OMe HO OSO3H /^Λ 294 Me ^ V)Me /=\ HOO V-4 yj oh HO OSO3H

-282- 201247215

[Table 1 9 5]

-283- 201247215 [Table 1 9 6] Ex Ref -Ex DAT 1 1 ESI-: 1386.6 2 1 ESI-: 1386.7 3 1 ESI+: 1338.8 [M+Na]+ 4 1 ESI+: 1467.3 [M+Na]+ 5 1 ESI-: 1499.4 6 1 ESI+: 1502.2 [M+Na] + 7 7 ESI-: 1446.6 8 7 ESI+: 1476.2 9 7 ESI-: 1478.6 10 7 ES1-:1485.5 11 7 ESI-: 1486.1 12 7 ESI-: 1429.4 13 7 ESI-: 1430, 3 14 7 ESI-: 1444.3 15 7 ES!-: 1444.4 16 7 ESI-: 1464.4 17 7 ESI-: 1460.5 18 7 ESI-: 1430.3 19 7 ESI-: 1464.3 20 7 ESI- : 1450.3 21 7 ESI-: 1446.4 22 7 ESI-: 1434.6 23 7 ESI-: 1458.6 24 7 ESI-: 1450.4 25 7 ESI-: 1434.4 26 7 ESI-: 1448.3 27 7 ESI-.1461.4 28 7 ESI-: 1522.3 29 7 ESI-: 1508.5 30 7 ESI-: 1461.4 31 7 ESI-: 1522.4 32 7 ESI+: 1519.5 33 Pr10 ESI+: 1512.3 [M+Na]+ 34 Pr10 FAB+: 1468.9 [M+Nal+ 35 Pr10 ESI-: 1495.3

-284- 201247215

[Table 1 9 7] 36 Pr10 ESI-: 1520.6 NMR2; 0.98 (3H, d, J = 6.4 Hz), 1.08 (3H, d, J = 6.0 Hz), 1.48-2.48 (9H, m), 2.64-4.44 (38H, m), 4.82-4.90 (2H, m), 5.68 (1H, m), 6.71-6.82 (2H, m), 6.98-6.99 (1H, m), 7.18-7.37 (5H, m), 7_49 - 7.56 (2H, m), 7.70-7.74 (3H, m), 7.90-7.92 (2H, m), 8.40 (1H, s). 37 37 ESI-: 1475.8 38 37 ESI--.1519.6 39 37 ESI- : 1419.8 40 37 ESI+: 752.4 [(M+2H)/21+ 41 37 ESI-: 1486.6 42 37 ESI-: 1454.5 43 37 ESI+.1471.1 44 37 ESI+: 1591.8 45 37 ESI-: 1469.5 46 37 FAB-: 1425.7 47 37 FAB-: 1423.6 48 37 ESI-: 1443.4 49 37 ESI-: 1442.3 50 37 ESI-: 1427.5 51 37 ESI-: 1426.8 52 37 ESI-: 1442.3 53 37 ESk1346.3 54 37 ESI-: 1342.4 55 37 ESI -: 1430.3 56 37 ESI-: 1348.5 57 37 ESI-: 1427.3 58 37 ESI-: 1493.7 59 37 ESI-: 1404.2 60 37 ESI-: 1460.3 61 37 ESI-: 1444.4 62 37 ESI-: 1398.2 63 37 ESI+: 1468.3 [M+Nal+ 64 37 ESI-: 1463.3 65 37 ESI-: 1344.4 66 37 ESk1328.3 67 37 ESI+: 1473.2 [M+Na]+ 68 37 ESI-: 1463.40 69 37 ESI+: 1462.1 70 37 ESI+: 1469.3 [M +Na]+ -285- 201247215 [Table 1 9 8] 71 37 ESI+: 1374.7 72 37 ESI+: 148 4.3fM+Na]+ 73 37 ESI-: 1474.7 74 37 ESI-: 1388.7 75 37 ESI-: 1481.1fM-H]· 76 37 ESI+: 1469.4 [M+Na]+ 77 37 ESI+: 713.5f (M+2H ) / / / / / / / / / / / / / / / / / / / / / ]··················· 2H)/21+ 91 37 ESI+: 1473.5 92 37 ESk1422.7 93 37 ESI-: 1347.6 94 37 ESI+: 1363.3 95 37 ESI-: 1362.7 Θ6 37 ESI+: 1448.2 [M+Na]+ 97 37 ESI-: 1337.6 98 37 ESI-: 1361.6 99 37 ESI+: 1468.2fM+Na]+ 100 37 ESI-: 1469.8 [MH]· 101 37 ESI+: 1444.3 [M+Na]+ 102 37 ESk1362.7 103 37 ESk1362.9 104 37 ESI- : 1361.2 105 37 ESI+: 1363.2 106 37 ESI-: 1350.6 107 37 ESI-: 1444.8 108 37 FAB+: 1395.8 109 37 ESI+: 1438.3 [M+Nal+

-286- 201247215

[Table 1 9 9] 110 37 ESI+: 1436.4 [M+Naf 111 37 ESI+: 1452.5 [M+Na] + 112 37 ESI-: 1377 113 37 ESI+: 1402.1 [M+Na]+ 114 37 FAB-:1448.7 115 37 ESI+: 1453.3 [M+Na]+ 116 37 ESI+: 1437.3 [M+Na]+ 117 37 ESI-: 1402.2 118 37 ESI+: 1422.3fM+Na]+ 119 37 FAB+: 1416.8 120 37 FAB-: 1426.6 121 37 FAB-: 1412.7 122 37 ESI+: 1388.2 [M+Na]+ 123 37 ESI+: 1374.2 [M+Na]+ 124 37 ESI+: 1374.2 [M+Na]+ 125 37 ESI+: 1451.3 [M+Na]+ 126 37 FAB+: 1414.6 127 37 FAB-: 1376.8 128 37 ESI-: 1441.6 [MH]- 129 37 FAB-: 1450.4 130 37 ESI+: 747.0 [(M+2H)/2]+ 131 37 FAB-: 1426.7 132 37 ESI- : 1464.3 133 37 ESI-: 1506.6 134 37 ESI+: 1493.1 135 37 ESI-: 1467.8 136 37 ESI-: 1468.9 137 37 ESI-: 1466.8 138 37 ESk1436.6 139 37 ESI-: 1452.6 140 37 FAB-: 1421.0 141 37 FAB-: 1403.5 142 37 FAB-.1403.3 143 37 FAB-: 1438.5 144 37 ESI-: 1480.4 145 37 ESk1329_8 -287- 201247215 [Table 2 Ο 0] 146 37 ESI-: 1426.4 147 37 ESI-: 1434.7 148 37 FAB -: 1454.3 149 37 FAB-: 1460.7 150 37 FAB-: 1473.5 151 37 FAB-: 1487.7 152 37 ESI- : 1501 15 3 37 ESI+: 1376.0 154 37 ESI-: 1517 155 37 ESI+: 1410.5 NMR 2; 0.97 (3H, d, J = 6.9 Hz), 1.08 (3H, d, J = 6.1 Hz), 1.32 (3H, t, J = 6.9 Hz), 1.74-4.50 (46H, m), 4.01 (2H, q, J=6.9Hz), 4.78- 4.92 (2H, m), 5.73 (1 H, m), 6.58 (1 H, dd, J =1.4, 8.1 Hz), 6.65- 6.72 (1 H, overlapping), 6.68 (1 H, d, J = 8.1 Hz), 6.91 (1 H, d, J = 8.7 Hz), 7_22 ( 1H, d, J =8.7 Hz), 7.48-7_62 (2H, overlapping), 7_74- 7.82 (1H.m)) 7.84 (2H, d, J = 8.5 Hz), 8.41 (2H.d, J = 8.5 Hz), 8.71 (2H) , s) 156 37 ESI+: 1378.6 157 37 ESI+: 684.0f(M+2H)/2]+ 158 37 ESI+: 1481.6 159 37 ESI+: 1421.3 160 37 ESI+: 683.7RM+2H)/2]+ 161 37 ESI+: 691.1[(M+2H)/2]+ 162 37 ESI+:701.1f(M+2H)/2l+ 163 37 ESI+:1405.5 164 37 ESI-:1410.2 165 165 ESI+:753.1[(M+2H)/2]+ 166 165 ESI+: 778.1 [(M+2H)/2]+ 167 165 ESI-: 1479 168 167 ESI-: 722 [(M-1)/21- 169 167 ESI-: 1441 170 167 ESI-: 1413.8 171 167 ESI-: 1415.7 172 167 ESI+: 1417.8 173 167 ESI-: 1478.7 174 167 ESI-: 1477.5 -288- 201247215

[Table 2 Ο 1] 175 167 FAB-: 1462.2 176 167 FAB-: 1448.6 177 167 FAB-: 1426.5 178 167 FAB-: 1398.5 179 179 ESI+: 1441.4 180 179 ESI+: 1397_4 181 179 ESI+.1392.4 182 182 ESI+:711 〇r(M+2H)/2r 183 183 ESI-: 1474.4 NMR2; 0.98 (3H, d, J = 6.8 Hz), 1.08 (3H, d, J = 5.8 Hz), 1.70-4.60 (47H, m) 14.82-4.92(2H,m), 5.65- 5.72(1 H,m), 6.74(1 H,d,J=8.2Hz), 6.80(1 H,dd,J=1,8,8.2Hz),7.01 (1 H, d, J = 1.8 Hz), 7.16 - 7.34 (5H, m), 7_51 (1H, brd, J = 8.0 Hz), 7.59 (1H, brs >, 7.74 (1H, brd, J = 8.0 Hz) ), 7.84 (2H, d, J = 8.5 Hz), 8.38 (2Hld, J = 8.5 Hz), 8.61 (2H, s). 184 183 ESI-: 1376.5 185 183 ESI-: 1486.4 186 183 ESI-: 1456.4 187 183 ESI-: 1392.4 188 183 ESI-: 1456.4 189 183 ESk1486.6 190 183 ESI-: 1444.4 191 183 ESI-: 1458.4 192 183 ESI-: 1501.4 193 183 ESI-: 1530.3 194 183 ESI-: 1514_3 195 183 ESI- : 1484_3 196 183 ESI-: 1490.4 197 183 ESI-: 1529.3 198 183 ESI-: 1508.1 199 183 ESI+: 1465.1 200 183 ESI-: 1442.3 201 183 ESI-: 1493.9, 1495.9 202 183 ESI-: 1493.9, 1495.9 203 183 ESI -: 1507.9, 1509.9 204 183 ESI+: 1527.3 [M+Na]+ 205 1 83 ESI+: 1513.3 [M+Na]+ 206 183 ESI-: 1416.8 -289- 201247215 [Table 2 Ο 2] 207 183 ESI-: 1507.50 208 183 ESI-: 1503.50 209 183 ESI+: 1456.4 [M+Na]+ 210 ESI ESI-: 1550.6 211 183 ESI-: 1504.8 212 183 ESI-: 1508.6 213 183 ESI-: 1488.8 214 183 ESI+: 1533.4 [M+Na]+ 215 183 ESI+: 1528.4 [M+Na]+ 216 183 ESI-: 1512.4 217 183 ESI-: 1482.3 218 183 ESI-: 1489.7 219 183 ESI-: 1518.8 220 183 ESI-: 1514.7 221 183 ESI+: 1542.1 222 183 ESI+: 1556.2 [M+Na]+ 223 183 ESI+:1556_2[M+Na ] + 224 183 ESI-: 1430.8 225 183 ESI-: 1444.7 226 183 ESI+: 737.1 [(M+2H)/21+ 227 183 ESI-: 1504.8 228 183 ESI+: 1556.3 [M+Na]+ 229 183 ESI+: 1516.4 230 183 ESI+: 1548.4 [M+Na]+ 231 183 ESI-: 1481.9 232 183 ESI+: 1497.3 [M+Na]+ 233 183 FAB-: 1470.8 234 183 ESI+: 1490.4 [M+Na]+ 235 183 ESI-: 1437.7 236 183 ESI-: 1391.6 237 183 ESI-: 1362.6 238 183 ESI-: 1406.6 239 183 ESI-: 1376.7 240 183 ESI-: 1361.5 241 183 ESI-: 1480.7 242 183 ESI+: 1461.1 243 183 ESI+: 1461.2 -290 - 201247215

[Table 2 Ο 3] 244 183 ESI+: 1424.4 [M+Na]+ 245 183 ESI-: 1386.9 246 183 ESI-: 1468.6, 1470.6 247 183 ESI-: 1405.5 248 183 ESI-: 1375.7 249 183 ESI+: 1352.3 [M +Na]+ 250 183 ESI+: 1512.3 [M+Na]+ 251 183 ESI-: 1406.7 252 183 ESI-: 1406.3 253 183 ESI+: 1454.3 [M+Na]+ 254 183 ESI+: 1424.4 [M+Na]+ 255 183 ESI-: 1376.7 256 183 ESI-: 1375.4 257 183 ESk1375.3 258 183 ESI-: 1405.6 259 183 ESI+: 1547.1 [M+Na]+ 260 183 ESI-:1405.7 261 183 ESI-:1488.9 262 183 ESI+:1482.4 [M+Na]+ 263 183 ESI+: 1481.3 [M+Na]+ 264 183 FAB-: 1513.1 265 183 FAB-: 1473.0 266 183 FAB-: 1492.8 267 183 ESI+: 1466.3 [M+Na]+ 268 183 FAB- : 1421.6 269 183 FAB-: 1457.7 270 183 FAB-: 1391.5 271 183 FAB-.1392.6 272 183 FAB-: 1470.9 273 183 FAB-: 1456.7 274 183 FAB-: 1471.8 275 183 FAB-: 1506.7 276 183 FAB-.1471.4 277 183 FAB-: 1442.6 278 183 ESI-: 1469.5 279 183 ESI+: 1469.0 280 183 ESI+: 1418.3 [M+Na]+ -291 - 201247215

[Table 2 Ο 4] 281 183 ESI+: 1442.4 [M+Na]+ 282 183 ESI+: 1469.3 [M+Na]+ 283 183 ESI+: 1367.4 284 183 FAB-:1408.5 285 183 FAB-: 1394.7 286 183 FAB-: 145 。 。 。 。 。 。 。 。 。 。 。 , 0.93 - 4.46 (50H, m), 4.75 - 4.95 (2H, m), 5.68 (1 H, m), 6.72 (1 H, d, J = 8.4 Hz), 6.78 (1 H, dd, J = 2.4 , 8.4 Hz), 6.99 (1H, d, J = 2.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 8_02 (2H, d, J = 8.4 Hz), 7.20 - 8.8 (7H, m) 290 183 FAB·: 1494.8 291 183 FAB-: 1534.5 292 183 FAB-: 1470.6 293 183 ESI-: 1441.7 294 183 ESI-: 1375.7 295 37 ESI-: 1421.8

-292-

Claims (1)

201247215 VII. Patent application scope 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, [Chem. 14] RA (wherein R1 is -NH2, -OH, -NH-lower alkyl-NH2, -lower alkyl-NH-lower alkyl, -lower alkyl-N (lower alkyl)" -NH-lower alkylene-C(=0)0H, or -NHCH(0H)C(=0)0H, R2 is -S(=0)20H, -CH2CH(OH)CH2OH,-lower alkyl -C(= 0)0H, lower alkyl, or hydrazine, anthracene ring is nitrogen-containing heterocyclic group, aryl group or cycloalkyl group, RA is hydrazine, -lower alkyl group -lower alkyl group-NH2, - Lower alkyl-NH-lower alkyl, lower alkyl-N (lower alkyl) 2, lower alkyl-OH, lower alkyl-lower alkyl, lower alkyl _ C( = 0)0H, -lower alkyl-S(=0)20H,-lower alkyl-S(=0)20-lower alkyl, -c(=o)o-lower alkyl, -C( = 0)-lower alkyl-NH2, ·(:( = 0)-lower alkyl-NH-lower alkyl, -C(=0)-lower alkyl-N (lower alkyl 2' can be -C(=0)-NH2 substituted lower alkyl-OH, -C(=NH)-NH2, -CH(lower alkyl-OH)2, or ring-293- 201247215 fluorenyl And X is a single bond, a lower alkyl group, -NH_, or -N (lower alkyl)-RB & 6 are each the same or different, and are halo or halogen, and the anthracene ring is represented by the following formula (II): (ΙΙΙ-a), or formula (III-b), [化15] 氺 The indicated group, * represents the X bonding position in the formula (I), ** represents the 118 bonding position in the formula (I), the D ring is a nitrogen-containing heteroaryl group, and rd is the following formula (iv)~ (vi) [Chem. 16] The group represented, or a group represented by -L-0-R1()1, L is a lower alkyl group, a higher alkyl group, a-0-, a-0-lower alkyl group, or a single bond, an E ring Is a heterocyclic group, the F ring and the F1 ring are each the same or different and are a cycloalkyl group, the Fg ring is a cycloalkyl group, or an aryl group, and the -294-201247215 Efg ring is a heterocyclic group, a cyclodecyl group, or an aryl group. , RE is hydrazine, lower alkyl, - hydrazine lower alkyl, or halogen, R1q1 is lower alkyl, - lower alkyl-cycloalkyl, or - higher alkyl-cycloalkyl, RZI or RZ2 are each the same or different and are fluorene, halogen, aryl, lower alkyl, higher alkyl, -0-lower alkyl, -fluorene-higher alkyl, which may be substituted by halogen or lower alkyl. 0-cycloalkyl,-0-aryl, -fluorene-lower alkyl-aryl higher alkyl-hydrazine-lower alkyl, cycloalkyl, or -c(=o)o-lower alkyl -Aryl). 2. The compound according to claim 1, wherein the ring A is a monocyclic saturated heterocyclic group or a monocyclic unsaturated heterocyclic ring, or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 2, wherein the ring A is a 6-membered nitrogen-containing heterocycloalkyl group, or a pharmaceutically acceptable salt thereof. 4. The compound of claim 2 or 3, wherein the D ring is a monocyclic nitrogen-containing heteroaryl group or a condensed polycyclic nitrogen-containing heteroaryl group, or a pharmaceutically acceptable salt thereof. 5. The compound of claim 2 or 3, wherein the D ring is a 5- to 6-membered monocyclic nitrogen-containing heteroaryl group, or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 2 or 3, wherein the D ring is a 5-membered 5-membered condensed polycyclic nitrogen-containing heteroaryl group or a 5-membered-6-membered condensed polycyclic ring. A nitrogen-containing heteroaryl group. 7. The compound according to any one of claims 1 to 6, wherein the ring B is a group represented by the formula (Π), or a pharmaceutically acceptable salt thereof. The compound of any one of the above-mentioned items, wherein the ring B is a group represented by the formula (11), and the ring D is a monocyclic nitrogen group, and the pharmaceutically acceptable salt thereof. Heterocyclyl or condensed polycyclic vapor-containing heteroaryl. 9. The compound according to any one of claims 1 to 3, wherein the ring B is a group represented by the formula (π), and the ring D is a 5-member-5-condensed salt, or a pharmaceutically acceptable salt thereof. Polycyclic nitrogen-containing heteroaryl. 10. The compound of claim 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the ring is a group represented by formula (II), and the ring D is a 5- to 6-membered monocyclic nitrogen-containing heteroaryl group. base. 11. The compound according to claim 2, wherein the RD is a group represented by the formula (V), or a pharmaceutically acceptable salt thereof. The compound according to claim 2, wherein the RD is a group represented by the formula (VI), or a pharmaceutically acceptable salt thereof. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the E ring in RD is a nitrogen-containing heterocycloalkyl group. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein the E ring in RD is a 6-membered nitrogen-containing saturated heterocycloalkyl group. 15.-Lithium hydrogen sulfate 5-{(2R)-2-[(2R,6S,9S,l lR,14aS, 15S,16S,20S,23S,25aS)-20-[(lR)-3 -amine 1-hydroxy-3-oxopropyl]-2,11,15-trihydroxy-6-[(lR)-l-hydroxyethyl]-9-(3-[l-(2-hydroxyethyl) -1,2,3,6-tetrahydropyridin-4-yl]-4'- {2-[4-(2-phenylethyl)piperazin-1-yl]imidazo[2,lb] [l,3,4]thiadiazole-6-yl}[1,1'-biphenyl]-4-carboxyguanamine)-16-methyl-5,8,14,19,22,25- Hexaoxodisuccinyl-hydrogen-111-dipyrrole [2,1-〇:2',1'-1][1,4,7,10,13,16]hexazacyclopentadiene i-- 296- 201247215 benzyl-23-yl]-2-hydroxyethyl}-2-hydroxyphenyl ester, hydrogen sulfate 5-{(2R)-2-[(2R,6S,9S,llR,14aS,15S,16S , 20S, 23S, 25aS)-20-[(lR)-3-amine-1-hydroxy-3-oxopropyl]- 2,11,15-Trihydroxy-6-[(111)-1-hydroxyethyl]-9-(3-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridine 4-yl]-4'-{5-[4-(2-phenylethyl)piperazin-1-yl]pyrimidin-2-yl}[1,1'-biphenyl]-4-carboxylate Indoleamine-16-methyl-5,8,14,1 9,22,25-hexaoxytetradecylhydrogen-1H-dipyrrole [2,1-<^2',1'-1 ][1,4,7,10,13,16]hexazacyclohexa-~1"-yl-23-yl]-2-hydroxyethyl}-2-hydroxyphenyl ester, hydrogen sulfate 5-[( 2R)-2-{(2R,6S,9S,llR,14aS,15S,16S,20S,23S,25aS)-20-[(lR)-3-amine-1-hydroxy-3-oxopropyl] -9-{4,-(5-{4-[(4,4-Dimethylcyclohexyl)oxy]piperidin-1-yl}-1,2,4-oxadiazole-3-yl )-3-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl][1,1,-biphenyl]-4-carboxydecylamine}-2 ,11,15-trihydroxy-6-[(lR)-i-hydroxyethyl]-16-methyl-5,8,14,19,22,25-hexaoxytetradecylhydrogen-lH- Dipyrrole [2, lc: 2', l'-l] [l, 4, 7, 10, 13, 16] hexazacyclotetrakisyl-2-yl}-2-hydroxyethyl]-2 -hydroxyphenyl ester and N-{(2R,6S,9S,llR,i4aS,15S,16S,20S,23S,25aS)-20-[(lR)-3-amine-1-hydroxyl Base-3_ oxopropyl 2,11,15-trihydroxy-6-[(1 ))-1-hydroxyethyl]-23-[(111)-1-hydroxy-2-(4-hydroxy- 3-methoxyphenyl)ethyl]-16-methyl-5,8,14,19,22,25-hexaoxytetradecylhydrogen-1H-dipyrrole [2,10,13,16 Hexazacycloheterosuccinyl-9-yl}-4'-(5-{4-[2-(4.ethoxyphenyl)ethyl]piperidin-l-yl}candane-2 a compound selected from the group consisting of -3(1,2,3,6-tetrahydroindole ratio steep-4 -yl)[I,〗, _biphenyl]_4_carboxamide Pharmacologically -297- 201247215 Xu salt. A pharmaceutical composition comprising the compound of claim 1 or a salt thereof, and a pharmaceutically acceptable excipient. 17. The pharmaceutical composition according to claim 16, which is a pharmaceutical composition for the prevention or treatment of fungal infections. Use of the compound of claim 1 or a salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of fungal infections. 19. Use of a compound of claim 1 or a salt thereof for the prevention or treatment of a fungal infection. The compound according to claim 1, or a salt thereof, for use in the prevention or treatment of a fungal infection. A method for preventing or treating a fungal infection characterized by administering an effective amount of the compound or the salt thereof as claimed in claim 1 to a subject. -298- 201247215 IV. Designated representative map: (1) The representative representative of the case is: None (2) The symbol of the representative figure is simple: No 201247215 V. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: Equation 1