TW200410948A - Water soluble triazole compounds - Google Patents

Abstract

The present invention relates to a trizol compound of the following formula (I): [wherein, L1: C1-C6 alkylene, etc, L2: single bond, L3: C1-C6 alkylene, etc, A: carboxyl group, -OSO3H, -OSO3H, -SO2NH2, -OPO3H2, etc, R1: hydrogen atom or C1-C6 alkyl group, etc, Ar: C6-C10 aryl group or a C6-C10 aryl group consisting 1 to 3 same or different substitute groups selecting from halogen atom or C1-C6 haloalkyl group, or, Ra: organic group], or the pharmaceutically acceptable salt or ester thereof.

Description

200410948 发明, Description of the invention: [Technical field to which the invention belongs] The present invention relates to a novel water-soluble tri-D compound and its pharmacologically acceptable salt, which has excellent drug dynamics and antifungal activity as medical music (especially injections), and its Medicines that are active ingredients (especially antifungals). [Prior art] Live true infections? Oral therapeutic agents have been reported on various types of three wow compounds, for example, in Japanese Patent Application Laid-Open No. 8-333350, Japanese Patent Application No. 11-8〇135, Japanese Patent Application No. 10-279567, Japanese Patent Application No. 2000-342187 W002 / 40472 describes a triazole compound of a tertiary hydroxyl group. Japanese Patent Application Laid-Open No. 62-14766 describes 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) -2-propanol ( Fluconazol). Japanese Patent Application Laid-Open No. 8-53426 describes 3-[4- (4-cyanophenyl) thiazole-2-yl] -2- (2,4-difluorophenyl) -1- (1H-1,2,4 -Trimile-i-yl) -2-butanol (rabuconazole). Publication W099 / 45008 describes 2- (2,5-difluorophenyl) -3- [4- (4-one · cut / benzyl) exo-2-yl] -1- (1H-1, 2,4-diwa-1-yl) -2-butanol (R000948 1 5). Patent Publication No. 2 62 5 5 84 describes 2 · (2, 4-difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1- (1Η-1,2,4-triazole- (Bulkyl) -2-butanol (Porinconazole). Japanese Patent Application Laid-Open No. 9- 1 8 3 7 6 9 describes 1 · [(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1Η-1 , 2,4-triazol-1-yl) propyl] -3- [4- (1Η_1-tetrazole) phenyl] -2-imidazolidinone (TAK-4 5 6). Japanese Patent Application Laid-Open No. 1 1-2 4 0 8 7 1 describes 2- (2,4-difluorophenyl) -1- (ethanesulfonyl) -1,1-difluoro-3- (1H-1, 2,4-triazol-1-yl) -2-propanol (SS750). W098 / 31675 describes (2R, 3R) -2- (2,4-difluorophenyl) -3- [4- [4- 200410948 [3-oxo 2- (4-trifluoromethoxybenzyl ) -2H-1,2,4-triazol-4-yl] phenyl] -1 -piperidinyl] -bu (1 Η -1,2,4-triazole-:!-Yl) -2- Butanol (Syn-2869). No. W097 / 05130, g., 7-chloro-3-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl- 3- (1Η-1 , 2,4-triazol-1 -yl) propoxy] quinazolin-4 (3 Η) -one (UR-9 8 2 5). EP1083175A2 describes (2R, 3R) -3-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadiene-1- Yl] -1,3-dicropin-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) 2-butanol. Others, Patent Publication No. 3 0 5 0 9 8 2, Lu WO 9 5/2 5 1 07, WOOO / 2 7 8 5 2, WO 0 1/6 6 5 5 1, and WOO The 1/79 1 96 publication describes a triazole compound having a tertiary hydroxyl group. The therapeutic agent for mycotic infections is administered in different forms depending on the type of fungus to be targeted and the appearance of the infection. The administration forms include oral administration and injection. These administration methods have one strength and one shortcoming. Therefore, the fungal infection treatment agent should be able to be administered orally and by injection. The above-mentioned therapeutic agents for triazole fungal infections have excellent antifungal activity, but because of their low water solubility, they have the disadvantage of being administered by injection. The improvement of low water solubility can be considered to convert the hydroxyl group to an ester group with high water solubility. However, the common hydroxyl group of these fungal infection treatment agents is a tertiary hydroxyl group, which has low reactivity, so the ester group is in vivo after administration. Can not be quickly split, there is regret that can not show activity. The compound 'for the purpose of solving this inconvenience' is disclosed in WO 00/3 0 65 5 and WO 9 9/6 1017, which have carbonyl esters of ethyl carbonate derivatives having substituted benzylfluorenyl groups on the side chains. However, in terms of physical properties, chemical stability, in vivo dynamics, safety, and ease of synthesis, these compounds are not sufficient for medicine (note 200410948 antifungal agents for injection). The compounds of the present invention differ from these compounds by having an aliphatic fluorenyl group in the side chain. In woo 0/3 0 6 5 5 and WO 0 9 9/6 1 01 7, there is neither disclosure nor suggestion of carbonyl carbonate esters having aliphatic fluorenyl groups. The water-soluble triazole derivatives are, for example, the ethyl ester derivatives described in Japanese Patent Application Laid-Open No. 2002-3 22 1 76. These compounds differ from the carbonyl ester derivative of the present invention in which the carbonyl ester is adjacent to one oxygen atom. Furthermore, WOO 1/5 6 3 5 8 discloses a compound in which a pesticide compound is chemically modified with a carbonyl ester of ethyl carbonate (donating group). However, these compounds differ from the compounds of the present invention in that their active substance is a pesticide compound. Moreover, the donor base is a base giving physical properties suitable for pesticides, and is different from the donor base of the compound of the present invention modified with a base suitable for injection with an antifungal agent. Therefore, the disclosed compounds are not suitable for use as medicine (antifungal agents for injection) in terms of antifungal activity (especially strong antibacterial spectrum), physical properties (particularly water-soluble and chemical stability), in vivo dynamics, and safety. . In W 0 0 1/5 6 3 5 8 ', the chemical modification of pharmaceuticals (antifungal agents for injection) is neither disclosed nor implied. [Summary of the Invention] In view of this, the problem to be solved by the present invention is to provide a high water solubility, the active body can be split quickly and with high conversion rate in the body, the organ selectivity is excellent, and the conversion rate is excellent. Stable tertiary hydroxyethyl carbonate, triazole compound for injection. The present inventors have worked hard to solve the above-mentioned problems, and thus synthesized the ethyl carbonate compound of the present invention ' The compound of the present invention can be used as medicine (especially an antibacterial agent for injection), and finally completed the present invention. 200410948 The present invention relates to: (1) a compound of formula (I) or a pharmacologically acceptable salt thereof 0 R1 0, everyone

Ar L1- (f) In the formula, L1 is a C3-C7 cycloalkyl group, Cl_c6 alkylene group or c2-C6 alkylene group G is a single bond and a double bond, -〇 · '-ΝΗ · ε (= 〇) ... · N ((: Η3) < (= 〇) _, · (:( = 〇) -ΝΗc (= 〇) _N (CH3) ·, carbonyl group, -0-C (= ο) _, or -c ( = 〇) _ 〇, L 2 is a single bond, a double bond, c 3-c 7 cycloalkyl, or a 4- to 7-membered heterocyclic group, L 3 is a single bond, a double bond, C] -C 6 alkylene Or c 2-C 6 alkenyl, A is a carboxyl group, -0S03H group '-0s〇3h group ... s〇2NH2 group, · 〇ρ〇3Η2 group, a nitrogen-containing heterocyclic group, and is selected from the substituent group α And the substituent group points are the same or different substituents substituted with 1 or 2 nitrogen-containing heterocyclic groups, or the formula _nr2r2, (Wuzhong, thought of a hydrogen atom, a methyl group,! -Iminoethyl, IA group There is a fluorenyl group substituted with 1 or 2 of the same or different substituents selected from the substituent group, Cl-C6_Chemical group 'c6-Cl. Aryl' or c7_c] 4Aromatic group C6 R2 is a gas atom 'C, -C6 alkyl group' has an alkyl group substituted by 1 or 2 of the same substituent group of substituent group 1, r, halogenated alkyl group), R is a hydrogen atom or c "c6 alkyl group, ar is C6- C1G aryl, or [Eta] $ is selected from a halogen atom and a C 1 - C 6 halogenated hospital group of the same or different substituent groups of Bu 3 c6-cu aryl group,

Ra _ organic group (but the formula (u OH

(») The compound has antifungal activity)], < Substituent group α > Methoxyl, 1-iminoethyl, Cl-C6, which have the same meaning or I I said before; Self-substituting group

U or i or 2 substituted U alkyl with different substituents, c Γ 醉 醉 宜 1 0 1 < 61 ，, c] -c6 _ servant c "c4k fluorenyl, C6-ClG aryl ^ ^, generation group c7-c] 4-party alkynyl. Hydroxyl, sulfhydryl, cyano, N_ (Cup # Lu I λ 7 1 Carboxyl) amino, N-(c, radical) -n- (C2-C "end Amidino) amine (c% group. Limamyl and amidomethyl) The compound of the above formula (I) or a pharmacologically acceptable salt thereof is preferably (widely: phenyl 'or' has selected from the group consisting of a tooth atom and three Chloromethyl phase-substituted phenyl compounds or pharmacologically acceptable salts thereof, (3) Ar is 2,4-difluorobenzene or even 9, < ~ ^ ~~ fluorophenyl compound or: a drug. Permissible salt, () is a compound of 4-monofluorobase or a pharmacologically acceptable salt thereof, (5) is selected from the compound or a pharmacologically acceptable salt thereof according to any one of the items (η to (4) above, wherein Ra is below Formula Η (6) A compound or a drug-implantable salt thereof as described in any one of items (1) to (4 ·) above, wherein Ra is the following formula -10-200410948

(7) A compound or a pharmacologically acceptable salt thereof selected from any one of items (1) to (4) above, wherein Ra is a group of the formula ch3 f

(8) A compound or a pharmacologically acceptable salt thereof selected from any one of items (1) to (4) above, wherein Ra is a group of the formula

1 ™™ / ^ j \ = | sj (9) selected from the compounds of any one of (1) to (4) above or a pharmacologically acceptable salt thereof, wherein Ra is a base of the formula (10) selected from the above (1) ) A compound according to any one of (4) or a pharmacologically acceptable salt thereof, wherein

(1 1) A compound selected from any one of the items (1) to (4) above or a pharmacologically acceptable salt thereof, wherein

(1 2) A compound or a pharmacologically acceptable salt thereof selected from any one of the items (1) to (4) above, wherein Ra is the following formula (III) R3 {Π1) Ρ ^^ [wherein R3 and R4 are each A hydrogen atom or an alkyl group, Al 2 is a phenyl group, and there are 1 to 5 substituted phenyl groups selected from the same or different substituents of the substituent group r, a monocyclic heteroaryl group, and a group selected from the substituent group r 1 to 5 substituted monocyclic heteroaryl groups with the same or different substituents, naphthyl, 1 to 5 substituted naphthyl groups with the same or different substituents selected from substituent group 7, fused bicyclic heteroaryl Or a fused bicyclic heteroaryl group having 1 to 5 substitutions of the same or different substituents selected from the substituent group r, E1 is a methylene group, or a formula -S (O) nl- (wherein , Nl is an integer from 0 to 2), E2 is a C 4 -C 7 cycloalkyl or heterocyclic group, and E3 is a group of the formula (Ga): — (GO) p- (R5C ^ OR ^ q- {CsQr ^ tR7C ^ CR \ ™ (Ga) (wherein R5, R6, R7 and R8 are each a hydrogen atom, a C! -C6 alkyl group, or a C1-C6 haloalkyl group, and P is 0 or 1, -12 -qA, rA (1 4) as the base: 200410948 q is an integer of 0 to 3, and r and s are each an integer of 0 to 2), or the base of the following formula (Gb): —Ar3-COMR9 T — ㈣) (where 'AP is phenylene, which has the same or different substituents selected from the same or different substituents of (oxygen and chlorogen), and has the same or Non- or 2-substituted naphthyl, R9 is a hydrogen atom or Cl-c6 alkyl, τ is a single bond, or Cl-C8 alkyl)), (13) A compound such as (12) or a pharmacologically acceptable salt thereof, Its base, "1 v" Wu Yun, ~ Ar2 is a phenyl group, has a phase selected from the group of substituents-the basic group substituted by them, and the monocyclic heteroaryl group has one of the same or different substituents. ~ 5 substituted monocyclic parent E3 is the formula -S (0) η1 · (wherein, ... is 0 ~ E is the following formula (GaA) group: (where '^' ^ '^ and ^ are each a nitrogen atom EC is a C 6 halogenated alkyl group, P is 0 or 1, and sA is each an integer of 0 to 2), a compound of (1 2) or a pharmacologically acceptable salt thereof) of a substituent group, a naphthyl group, or the same substituent 1 in R3 is the phase of C] -C4 with the substituent group of the first-generation group r; j ”), the spring (GaA) 'C 1-C 6 courtyard base' _zhong Ra is the following formula 200410948

Group I5) or a pharmacologically acceptable salt thereof as in (12), wherein El is methylene E2 is selected from the group

E3 is a group of the following formula (GaB): (< 3aB) and sB are each an integer of 0 to 2. but

(In the formula, qB is an integer of 0 to 3, and the sum of E qB, rB, and sB is 3 or less), (1 6) a compound such as (1 2) τ $ or a pharmacologically acceptable salt thereof, wherein Ra is the following formula base:

Ar2 is naphthyl, and there are 1 to 5 substituted naphthyl and bicyclic heteroaryl groups with the same or different substituents of substituent group 7, or white, or k. Or different n ^ heteroaryl "substituents with 1 to 5 substituted fused dipics-14-200410948 E1 is a formula -S (0) nl- (where E3 is a group of the following formula (Gac): η 1 is 0 ~ 2 integer), or (wherein R5C, R6C C 1-C 6 haloalkyl, PC is 0 or 1, R ^ and R8C are each a hydrogen atom, C!-C 6 alkyl, q

-tT (18) A compound such as (M12) or a pharmacologically acceptable salt thereof, wherein y is hydrogen

Ar is a base group; there are 1 to 5 substituted phenyl groups, naphthyl groups, or other groups substituted for a certain A group 7 or different substituents; or Qiu Baiqian you # ~ 卞 土 4 有1 to 5 substituted naphthyl groups which are the same or different substituents from the substituent group γ, Ε is a methylene 'or a sulfur atom, and E3 is a group of the following formula (Gb):-Ar3_CCHNR points-τ-(Qb) (In the formula, Ar3 is a phenyl group, and there are i or 2 substituted phenyl groups selected from the same or different substituents of the (fluoro and chloro ~~) substituent group, and ′ is substituted by (fluorine and chlorine atoms). The same or different group of the naphthyl group is substituted by one or two, the group is 1 R9 舄 hydrogen atom or c] -c6 alkyl group, T is a single bond, or Cl-c8 alkylene group, &lt; substituent group r &gt;, ',' atoms, alkoxy, sulfhydryl, nitro, amine, cyano * succinyl Gorky, Q .; Wutuo 'is selected from (halogen, hydroxyl, cyano, and C] , C 1 1 6 h oxygen group) 200410948 The same or different substituent group M group, fluorenyloxy group, has a phase selected from (substitute atom, «, ^ = · 6 alkyloxy) group nn π and c ^ c6 cc generate 1 of oxygen and its different substituents ~ 5 substituted groups 'C1-C6 fluorenyl group, which are the same or selected from ~ _ 5 substituted Cl-C6 groups, which are selected from the group of (_atom, aryl, cyano' and CrC, alkoxy) | ^ 1 atom of the same generation group, the furnace of which ... C6 courtyard oxygen group, (there are 1 ~ from the same or different substituents selected from the group of (halogen ', Gongtuo' and Cl-C6 alkoxy) substituents 5 substitutions 丨 ″ 2 Γ Γ ^ _ instead of c2-c6k 醯 oxy, C2_c7 oxygen oxygen soil 2- 5 1 carbamoylamine, formula -C (0) -nr10rh (where 'Rl0 and R11 each Is a hydrogen atom or a Cl-C6i end group, or a group of 4 to 7 nitrogen-containing heterocyclic groups formed by r1q and Rll and the associated atom, and the formula · s (= (where "1" is an integer of 0 to 2, R &quot; is a Cl-C6 alkyl group, and has a group selected from the same or different substituents of the (halogen atom and mesityl) substituent group, and has ~~ $ substituted c] -c6 alkyl groups.), The formula _s ( 〇) ”_r14 (wherein '^ 〇 ~ 2 integers' R" is c "c6 radical, there are i ~ 5 substituted c's of the same or different substituents selected from the group of (dental atom and vial) substituents ] _C6alkyi.) Of the base 'Formula-SCO) &quot; 3-Ru (In the formula, # 3 is an integer of 0 ~ 2, == C ^ C6 alkyl Or a group selected from the same or different substituents of the (halogen atom and hydroxyl group) substituent group (5 substituted Cl_C6 groups), an imidazolyl group, or one of the same or different substituent groups selected from the substituent group 5 ~ 2 substituted imidazolyl, aryl, 1 ~ 2 substituted pyrazolyl, triazolyl with the same or different substituents selected from the substituent group δ Or 1 to 2 substituted triazolyl 'tetrazolyl groups with different substituents, the same or different substituents of the optional substituent group <5, substituted quatyl groups, ^^ dilute' c2-c〆yne Group, c3-c6 ring group, and C3-C6_end group ^ -16-200410948 C! -C6 alkyl group, &lt; substituent group 5 &gt; CrL alkyl group, selected from the same or different halogens 1 to 5 substituted C! -C4 alkyl groups, and a halogen atom, (19) selected from the compound or a pharmacologically acceptable salt thereof according to any one of the items (1) to (18) above, wherein R1 is A hydrogen atom or a methyl group, (20) selected from the compound or a pharmacologically acceptable salt thereof according to any one of the items (1) to (18) above, wherein R1 is a methyl group, and (21) is selected from the above (1) to (2) 〇) Compound or a pharmacologically acceptable salt thereof, wherein L1 is an alkylene or C2-C6 alkenyl group, and (22) is selected from the compound or a pharmacologically acceptable salt thereof according to any one of the items (1) to (20) above, wherein L1 Is C2-C6 alkylene or -CH = CH-, (2 3) is selected from the compounds according to any one of (1) to (20) above or a pharmacologically acceptable salt thereof, wherein L1 is C2 alkylene or- CH di-CH-, (24) is selected from the compound or a pharmacologically acceptable salt thereof according to any one of the items (1) to (20) above, wherein L1 is C2 alkylene or (2 5) is selected from the group consisting of (1) A compound or a pharmacologically acceptable salt thereof according to any one of (24), wherein G is a single bond, -0-, -NH-C (= 0)-, -C (= O) -NH-, -C ( = 0) -N (CH3)-, carbonyl, or -C (= 0) -0-, (26) selected from the compound or a pharmacologically acceptable salt thereof according to any one of the items (1) to (24) above, wherein G is -NH-C (= 0)-, -C (= 0) -N (CH3) -5 iron group 'or -C (= 0) (2 7) is selected from the above items (1) to (24) The compound according to any one or a pharmacologically acceptable salt thereof, wherein G is -C (= 0) -NH- or a carbonyl group, and (2 8) is selected from the compound according to any one of the above (1) to (24) or its Pharmacological tolerance A salt in which G is -C (= 0) -NH ·, -17- 200410948 (2 9) is selected from the compound according to any one of the items (1) to (2 8) or a pharmacologically acceptable salt thereof, wherein L2 is Single bond, double bond 'or' 4- to 7-membered heterocyclic group, (3 0) selected from the compound or a pharmacologically acceptable salt thereof according to any one of the items (1) to (2 8) above, wherein L2 is a single bond, (3 1) A compound or a pharmacologically acceptable salt thereof selected from any one of (1) to (30) above, wherein L3 is a single bond, a double bond, or Cl_C6 alkylene, and (3 2) is selected from The compound of any one of (1) to (30) or a pharmacologically acceptable salt thereof, wherein L3 is a single bond, a double bond '-CH2-or -CH2CH2-, and (3 3) is selected from the above (1) to ( 3) The compound according to any one of the above items, or a pharmacologically acceptable salt thereof, wherein L3 is a single bond, or -CH2CH2-, and (3 4) is selected from the compounds according to any one of the items (1) to (30) above, or Its pharmacologically tolerable salt, wherein L3 is -CH2- or -CH2CH2-, (35) is selected from the above (J) Musically tolerated salt 'wherein L3 is · CH2_, and (36) is selected from the above (1) to (35) A compound of any one or | a pharmacologically acceptable salt, of which eight is Group, -SO3H group, -OS03H group, -SO2NH group '-OPP 0 Η 9 even, rtv Γ butidyl, pyrrolidinyl, piperidinyl, piperidinyl, morpholinyl, substituted 〇 S 〇 Η 1 1 Substitute carbamidine (the substituent: methyl, • OS〇3H group or-〇〇〇〇3Η2) So, one 1 guarana stem, which should be taken $ 〇ρ 〇3Η2 group) 'with substituents, yi: to glycan substituent: methyl, · 〇ς ^ 2 :)' 1 with substituents substituted eridinyl (substituted piperidinyl group, -S02NH2 group-ΟΟΟ

Hydrazone (this substituent, sodium: sulphonyl 'substituent is substituted Cn group or -NMe2 group 3 group, os3H (37) is selected from pharmacologically acceptable _, its φ or, NV [(A The compound of any one of (35) or 03H group, -0s〇3h group, · 〇ρ〇3 200410948 group, 1-azetidinyl, 1-pyrrolidinyl, piperidinyl (ie 1-piperidinyl Pyridyl), morpholinyl (ie 4-morpholinyl), 1-methyl-3-azetidinyl, 3-(sulfonyloxy) -1-azetidinyl, 3-(sulfonyloxy) -1 -Azetidinyl, 4-methyl-4-piperidinyl ^ 1-methyl-4-imidinyl 5 3- (mineral acidoxy) -1-warmpyridinyl ^ 3- (phenylamino) -1 -Piperidinyl, 4-methyl-b piperidinyl, 4- (2-hydroxyethyl) -bupiperinyl, 4- [2- (sulfonyloxy) ethyl] -bupiperinyl, 4- [2- (phosphonoethoxy) ethyl] -bupipenyl or -NMe2 group, (38) selected from the compound or a pharmacologically acceptable salt thereof according to any one of the items (1) to (35) above, Wherein A is a carboxyl group, -S03H group, -0P03 基 2 group, 4-methyl-bupiperinyl group or 4- (2-hydroxyethyl) -bupiperinyl group, and (3 9) is selected from the group consisting of (1) ~ ( 35) the transformation of any of the items Or a pharmacologically acceptable salt thereof, wherein A is a carboxyl group, -S03H group or -OP03Η2 group, and (40) is selected from a compound or a pharmacologically acceptable salt thereof according to any one of the items (1) to (35) above, wherein A is Carboxyl, (4 1) The compound or a pharmacologically acceptable salt thereof as described above, wherein Ra is a group of the formula

Ar is 2,4-difluorophenyl, R] is a hydrogen atom or a methyl group, L1 is a C2-C6 alkylene group or-CH = CH-, and G is -C (= 0) -NH-, -C ( = 0) -N (CH3)-, carbonyl, or -C (= 0) -0-, L2 is a single bond, L3 is a single bond, -ch2- or -ch2ch2-, a is a carboxyl group,-so3h group,- oso3h group, -opo3h2 group, 1-azetidinyl group, 1-pyrrolidinyl group, piperidinyl group, morpholinyl group, p-methyl-3-azetidinyl group, 3-(sulfonyloxy) -buazetidinyl group, 3-( Phosphoniumoxy) -1 -azetidinyl, 1 -methyl-4 -piperidinyl, methyl 4 -piperidinyl, 3-19- 200410948 (mineral oxygen) -i-Pigpyridinyl, (Phosphatinooxy) group · 1 · piperidinyl, 4- (2 · hydroxyethyl) · pipendyl) ethyl] -1-piperidyl, 4_ [2_ -NMe2 group, pyrimidinyl group, 4-methyl-4, [2- (sulfonamidoethyl) -1-piperin (42) as described above or a pharmacologically acceptable salt thereof, wherein 玟 CHe

Ar is 2,4-difluorophenyl, R1 is a hydrogen atom, or A is a radical of the following formula or -CH = CH ... g is -C (= 0) -NH- or a bond, L3 is a single bond,- CH-Ch2CH2-, A is a carboxyl group, -0 S Ο 3 fluorenyl group '-Ο P 〇3 η 2 group, azetidinyl group, 1 group, morpholinyl group, 1-methyl-3 ^ butylidene group , Pyridinyl, 3- (phosphofluorenyloxy) methyl-4-piperidinyl, 3- ^ L is C2-L6, L2 is mono-so3h, _pyridinyl, piperidine (sulfo (Fluorenyloxy) -brazidin-1-azetidinyl, methyl, C-piperidinyl, methyl (sulfofluorenyl) -1-piperidinyl, 3- (phosphofluorenyloxy) -1-piperidinyl, 4-methyl well group, 4 · (2-hydroxyethyl) · piperidinyl group '4- [2- (Shibei fermentoxy) ethyl] -1_piperidinyl Ethyl] -1-piperazinyl or NMe2 group, (43) The compound or a pharmacologically acceptable salt thereof as described above, wherein

A * is 2 '4-difluorophenyl, R1 is a hydrogen atom or a methyl group, Li is a c2-C6 alkylene group or -CH = CH ·, G is -C (= 〇) -NH · or a carbonyl group, L2 Is a single bond, L3 is a single bond ... CH2- or -Ch2CH2-, A is a carboxyl group, -S03H group, -20- 200410948 -OS Ο 3 fluorenyl group, -0 Ρ Ο 3 fluorenyl 2 group, 1-azetidinyl group, 1 -Pyrrolidinyl, piperidinyl, morpholinyl, 1 -methyl-3 -azetidinyl, 3- (sulfofluorenyloxy) · 1-azetidinyl, 3- (phosphofluorenyloxy) -1-azetidinyl , Methyl-4-piperidinyl, 1-methyl-4-piperidinyl, 3- (sulfofluorenyloxy) -piperidinyl, 3- (phosphofluorenyloxy) -1 -piperidinyl, 4-methyl-buperithionyl, 4- (2-hydroxyethyl) -1-piperidyl, 4- [2- (sulfonyloxy) ethyl] -1-piperidyl, 4- [ 2- (phosphonoethoxy) ethyl] -1-piperidinyl or -NMe2 group, (44) the compound or a pharmacologically acceptable salt thereof as described above, wherein Ra is a group of the formula

Ar is 2,4-di · phenyl, R1 is a hydrogen atom or a methyl group, L1 is a C 2 alkylene group, G is -C (di0) -NH- or a carbonyl group, L2 is a single bond, and L3 is a single bond , -Ch2- or -ch2ch2-, a is a carboxyl group,-so3h group,-oso3h group,-opo3h2 group, 1-azetidinyl group, pyrrolidinyl, piperidinyl, morpholinyl, 1-methyl-3- Acridinyl, 3- (sulfofluorenyloxy) -buaziridinyl, 3- (phosphofluorenyloxy) -1-azetidinyl, methyl-4-methylpiperidinyl, 1-methyl-4-piperidinyl , 3- (sulfofluorenyloxy) -1-piperidinyl, 3- (phosphofluorenyloxy) -piperidinyl, 4-methyl-buperithinyl, 4- (2-hydroxyethyl)- 1-piperidinyl, 4- [2- (sulfofluorenyloxy) ethyl] -1-piperidinyl, 4- [2- (phosphofluorenyloxy) ethyl] -1-piperidinyl or -NMe2 (4 5) The compound or a pharmacologically acceptable salt thereof as described above, wherein Ra is a group of the formula

-21-200410948

Ar is 2,4-difluorophenyl, R1 is a hydrogen atom or a methyl group, L1 is a C2 alkylene group, G is -C (= 0) -NH- or a carbonyl group, L2 is a single bond, and L3 is -CH2- Or -CH2CH2-, A is a carboxyl group, -S03H group, · OP03Η2 group, 4-methyl-1-piperidinyl group or 4- (2-hydroxyethyl) -buperithionyl, (4 6) a compound as described above Or a pharmacologically acceptable salt thereof, wherein Ra is a base

Ar is 2,4-difluorophenyl, R1 is a hydrogen atom or a methyl group, L1 is a C2 alkylene group, G is -C (= 0) -NH-, L2 is a single bond, and L3 is -CH2- or- CH2CH2-, A is a carboxyl group, -S03H group or -OP03 (2 group, (4 7) The compound or a pharmacologically acceptable salt thereof as described above, wherein Ra is a group of the formula

Ar is 2,4-difluorophenyl, R1 is a hydrogen atom or a methyl group, L1 is a C2 alkylene group, G is -C (= 0) -NH-, L2 is a single bond, L3 is a single bond, and A is Carboxylic acid, (48) hydroglutaric acid 1 _ [[(111,21〇-2-[[trans-2-[(to, 3 £) -4- (4-oxy-2-truncated) -1 '3 -Ding_ * susceptible group] -1' 3 -—Recruiting House-5 · yl] thio group] -1-(2,4-difluorophenyl) -1-[(1 Η -1,2, 4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl, 1-[4- [1-[[(1R, 2R) -2-[[trans- 2-[(ΙΕ ， 3Ε) -4- (4-Amino- 2-¾phenyl) -1 '3 -butyroyl] -1' 3 -monoethoxy-5-yl] thio] -1- (2 , 4-difluorophenyl) -1-[(111-1,2,4-triazol-1-yl) -22- 200410948 methyl] propoxy] mineoxy] ethoxy] -4- Oxybutyryl] -4-warm hydrazine residual acid, [[4- [1-[[(1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano -2 -fluorophenyl) -1,3 -butadienyl] -1,3-dioxane-5 -yl] thio] -1- (2 '4-1 ^ trunkenyl) -1 -[(1H-1 '2' 4 -Di-D-S-1) -methyl] propoxy] Oxy] ethoxy] -4-oxobutyryl] amino] acetic acid, 3-[[4- [1-[[(1R, 2R) -2-[[trans- 2-[(IE, 3E)- 4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluoro Phenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutanyl] amino] propionic acid, [N- [4-[[[(1R, 2R) -2-[[trans-2-[(IE, 3E) -4- (4-muryl-2-p-phenylene) -1 '3- Ding Yi "Askyl] -1 '3-1 * 1% Yuan-5-yl] Thiyl] -1 · (2,4-difluorophenyl) -1-[(1H-1,2,4- Triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutanyl] methylamino] acetic acid, hydroglutaric acid [(1R, 2R) -2- [[trans -2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl, l- [4-[[(lR, 2R) -2 -[[Trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3- Butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(111-1,2,4-triazole- 1-yl) methyl] propoxy] carbonyloxymethoxy] -4 -oxobutynyl] -4-piperidinecarboxylic acid, -23- 200410948 [[4-[[(1R, 2R) -2- [ [Trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] sulfur Yl] -1- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4 -Oxobutynyl] amino] acetic acid, 3-[[4-[[(lR, 2R) -2 · [[trans- 2-[(lE, 3E) -4- (4-cyano-2-fluorobenzene Group) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1.2, 4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutanyl] amino] propanoic acid, [N- [4-[[(lR, 2R) -2- [[Trans-2-[(1E, 3E) -4- (4-Cyclo-2-chlorophenyl) -1'3-butanyl] -1'3-Yipinyuan-5-yl] Thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl Methyl] propoxy] carbonyloxymethoxy] -4-oxobutanoyl] -N-methylamino] acetic acid, 5- [l-[[(lR, 2R) -2-[[trans- 2- [ (1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-diseno-5-yl] thio] -1- ( 2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -5-oxo-bu Heptanesulfonic acid, 6- [l-[[(lR, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2 -fluorophenyl) -1,3 -Butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazole -1-yl) methyl] propoxy] carbonyloxy] ethoxy] -6-oxo-hexanoic acid, 5-[[((lR, 2R) -2 · [[trans- 2-[( 1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-diDf alkyl-5-yl] thio] -b (2, 4-difluorophenyl) 2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -5 -oxo-1 -heptanesulfonic acid, -24- 200410948 6-[[ (LR, 2R) -2-[[Trans-2-[(IE, 3E) -4- (4-cyano-2- 2-benzyl) -1 '3- Dingyi · Diphenyl] -1 '3-— • Yunyuan-5 -yl] thio] -1_ (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole -1-yl) methyl] propoxy] carbonyloxymethoxy] -6-oxo-1-hexanesulfonic acid, [[4- [1-[[(1R, ZR) -2-[[trans- 2-[(IE, 3E) -4- (4-trunkyl-2-Tibenyl) -1,3-butanyl] -1 '3 -one · crocodile-5-yl] thio]]- 1- (2,4-difluorophenyl) -1-[(1Η · 1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4- Oxetramethyl] oxy] acetic acid, [[4-[[(1R, 2R) -2-[[trans-2-[(ΙΕ, 3Ε) -4- (4-cyano-2 -chlorobenzyl)- 1 »3 -butane-alkynyl] -1 '3-1 ^ %%-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2 , 4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutanyl] oxy] acetic acid or a pharmacologically acceptable salt thereof, (49) [(4- (1-[ [(1 R ^ 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1, 3-diDf alkyl-5-yl] thio] -1- (2,4-difluorophenyl) -l- (1H-1,2,4-triazole-blyl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutyryl] amino] acetic acid, 3-[[4- [Bu [ [(1R, 2R) -2-[[Trans- 2-[(IE, 3E) -4- (4-cyano-2 -fluorophenyl) -1,3 -butadienyl] -1,3 -Dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[((Π9Η-1,2,4-triazol-1-yl) methyl] propoxy Group] carbonyloxy] ethoxy] -4-oxobutanyl] amino] propanoic acid, [[4-[[((1R, 2R) -2--2-[[trans- 2-[(IE, 3E) -4 -(4-cyano-25- 200410948-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4 -Difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutanyl] amino] acetic acid, 3-[[4-[[(lR, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2 -fluorophenyl) -1,3 -butane Alkenyl] -1,3 -diseno-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1.2,4-triazol-1-yl) Methyl] propoxy] carbonyloxymethoxy] 4-oxobutynyl Amine] propionic acid or pharmacologically acceptable salt thereof, (50) a pharmaceutical composition containing a triazole compound or a pharmacologically acceptable salt thereof selected from any one of (1) to (49) as an effective ingredient, (5 1) an antifungal agent containing a triazole compound or a pharmacologically acceptable salt selected from any one of (1) to (4 9) as an active ingredient, (5 2)-a method for preparing a pharmaceutical composition, Use of a triazole compound or a pharmacologically acceptable salt thereof according to any one of (1) to (4 9), (5 3) —an antifungal preparation method, using any of (1) to (4 9) Item of the triazole compound or its pharmacologically acceptable salt, (5 4)-a preventive or therapeutic method, which is administered an effective amount of the triazole compound or its pharmacologically acceptable salt of any one of (1) to (49) For warm-blooded animals, (5 5) The method according to (5 4), wherein the warm-blooded animals are humans. The above-mentioned "alkyl" is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, third butyl, n-pentyl, isopentyl, 2-methyl Butyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3 ' 3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2, Cl ~ 6 straight or branched chain alkyl groups such as 3-dimethylbutyl, 2-ethyl-26- 200410948 butyl, etc., preferably ci ~ 4 straight or branched chain alkyl groups, more preferably, the above-mentioned " Ci-C6 is halogenated and burned; "rr may be a redundant group" as the base "has the same or different 5 ~ 5 halogen atom substituted groups, for example, trifluoromethyl, trichloromethyl, difluoromethyl , Dichloromethyl, dibromomethyl, fluoromethyl, 2,2 '2-trifluoroethyl' 2 '2' 2-trichloroethyl, 2-bromoethyl, 2 • chloroethyl, 2 —Gas ethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6—iodohexyl, 2, dibromoethyl, etc., preferably fluoromethyl. The "C6-C1Garyl group" is, for example, a C6 to i0 aromatic hydrocarbon group such as phenyl, indenyl, or naphthyl, and is preferably a phenyl group. The above "c7-c14 $ alkyl" is a group in which the above "c6_c1 () aryl" is combined with the above "alkyl", for example, benzyl 'α' naphthylmethylningmethyl, benzyl, 1-phenylethyl , 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl '3-phenylpropyl, 1-naphthylpropyl, 2-caproyl, 3 naphthylpropyl Methyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, phenylbutyl, naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, etc., preferably Section base. "C3-C7 cycloalkyl" in L1 and L2 above, "C4-C7 cycloalkyl" in E2, "CrC6 cycloalkyl" in substituent group 7, and "c3-C6 cycloalkyl" in substitution group τ In the "C I-c6 courtyard substituted", "cyclic courtyard" is a saturated cyclic hydrocarbon group which may have fused rings, and "C4-C6 cycloalkyl" is, for example, cyclobutyl, cyclopentyl, cyclohexyl, etc., " "C4-c7 cycloalkyl" includes cycloheptyl and the like, and "C3-C6 cycloalkyl" includes cyclopropyl and the like. The "C3-C7 cycloalkyl" in L1 and L2 is preferably a c4-C6 cycloalkyl group, and more preferably cyclohexyl. The above "alkylene" is, for example, methylene, methylmethylene, ethylene, propyl, trimethylene, tetramethylene, methyltrimethylene, 2--27- 200410948 methyltrimethylene C1 ~ 6 straight or branched chain alkylene groups such as 3-methyltrimethylene, pentamethylene, hexamethylene, etc., L1 is preferably C2 ~ 6 straight or branched chain alkylene groups, more preferably For C2 straight or branched chain alkylene, L3 is preferably methylene or ethylene, more preferably methylene. The above "C i-C 8 alkylene" is, for example, methylene, methylmethylene, ethylene, propyl, trimethylene, tetramethylene, methyltrimethylene, 2-methyltrimethylene Methyl, 3-methyltrimethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, etc. C1 ~ 8 straight or branched chain alkylene, preferably C2 ~ 6 straight Chain or branched chain alkylene, more preferably C2 straight or branched chain alkylene, more preferably methylene or ethylene, most preferably methylene. The above "C 2 -C 6 alkenyl" is, for example, C1 ~ 6 straight or branched alkenyl, such as vinyl, propenyl, butenyl, hexenyl, etc., preferably ci ~ 4 straight The chain or branched chain alkenyl group is more preferably a vinyl group. "C2-C4 alkyl" in the above substituent group α, "N- (c2-c7 alkyl) amino" in the substituent group / 3, and "N- (Cl_c6 alkyl) in the substituent group ^ In "N- (C2-C? Alkylfluorenyl) amino group", the "alkylsulfonyl group" is a straight or branched chain alkylsulfonyl group, and the "CpC4 alkylfluorenyl group" is, for example, an ethylfluorenyl group, a propanyl group, or a butanyl group. "Ding Yiji and other 'C2-C7 Yuan Yiji" also contains amyl, isoamyl, hexamyl, heptyl and so on. The "C ^ C: 7 alkylfluorenyl" is preferably a C2 to 4 straight chain or a bivalent bond, and more preferably an acetate group. "C2_C4 courtyard brewing base" should be ethyl. The aforementioned "halogen atom" is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine, and more preferably fluorine. The above "4- to 7-membered heterocyclic group" is a 4- to 7-membered heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms, and / or nitrogen atoms, such as furyl, thienyl, pyrrolyl, -28, 200410948. Heptyl, 1: 1 to 1: 1 radicals, 'imid alpha radicals, Df alpha radicals, isomer p radicals, thi radicals, isothiazolyl radicals, 1,2,3-oxadiazolyl radicals, Triazolyl, thiadiazolyl, pyridyl, hydrazyl, hydrazone, aryl, [j-pyranyl, and other aromatic heterocyclic groups, pyrrolinyl, imidyl, pyridyl Partially reduced heterocyclic groups such as phosphono, and fluorenylcyclo, tetrahydrofuryl'tetrahydropyranyl, azetidinyl, morpholinyl, thiomorpholinyl'laloylpyridyl ', Completely reduced type groups such as p-p-type, p-π-type, perhydroazepine, piperazine, homopiperazine, etc., are preferably 5 to 7 containing more than one nitrogen atom and may contain oxygen or sulfur atoms. Heterocyclyl, such as larolyl, azepinyl, fluorenyl, imidazolyl, isothiol, isoxylazolyl, thiazolyl, isothiazolyl

, 2,3-Df oxadiazolyl, triazolylthiodi d ring group and radical, imidazolium, etc., preferably the above-mentioned nitrogen azolyl group, triazolyl pyrazolyl oxaloxinyl, Aromatic heteroazetidinyl groups such as butidyl, piperidinyl, pyridyl, pyridyl, pyrimidinyl, pyridyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolidazolyl, imidazole Partially or completely reduced groups such as pyridyl, pyridinyl, pyrazolinyl, piperidinyl, heptyl 'piperazinyl, homopiperidinyl are 卩 I7 butanyl'morpholinyl'piperidine Group, piperazinyl.

"Nitrogen-containing heterocyclyl" is one of the above-mentioned "4- to 7-membered heterocyclyl", such as pyrrolyl, azepinyl, pyrazolyl, imidazolyl, slogan iso-Dfazolyl, thiazolyl, iso Thiazolyl, 2,3,3-diadiazolyl, tetrazolyl, thiadiazolyl, pyridyl, dalyl, pyrimidinyl, and other aromatic heterocyclic groups and butidyl, morpholinyl, thiomorpholine Partially or completely reduced groups such as pyrrolidinyl, imidazolyl, imidazolyl, imidazolyl, pyridinyl, piperazinyl, piperidinyl, etc., preferably acripyridinyl, piperidinyl, piperidin Radicals, morpholinyl, etc. are completely reduced and they are each other, 1-P Υ but π π is 1 r J 卩 疋 1-pyrrolidinyl, piperidinyl (ie 1-) 'morpholinyl (ie 4 -morpholinyl ). -29- 200410948 The above-mentioned "Substituent Group 1 has a substituent selected from 1 or 2: Substituted for the piperidine substituent as a substituted C -so2nh2 azetidinyl-1-azetidine D (sulfonyloxy-bupi The above is "ethyl", the above "" alkyl "," the above "," N- (group "has 1 above", "] azaheptyl isothiazolyl, and pyran sulfur atoms have * selected from Substitute a π or 2 Substitute =; and the substituents are the same or different and take the substituent cyclic group "instead of the above" nitrogen-containing heterocyclic group "and the same or different substituents of the substituent group-preferably as , The substituent is a 1-substituted heart group (there is: 0 alkyl or-), and the substituent is taken from this (the substituent is a methyl group, a -0s〇3H group or a -0ρ〇3Η2 group), 1-substituted piperidinyl group [the substituent: methyl, the substituent is! 2_C6 alkyl (the substituent: —s03H group, —s03H &quot; group, the group -OP3 # 2 or -NMe2 group )], Preferably, __methyl small '3' (extended oxy) berberyl butyridyl, 3 · (phosphoryloxy), ^ methyl-4 · piperidyl, 1-methyl-4 -Piperidinyl, 3-alkyl) -bpiperidinyl, 3- (phosphonium ) · Piperidinyl, cardiomethyl, (2-hydroxyethyl) -piperidinyl, 〇 [2 · (sulfofluorenyloxy] -1-carotoxy group, 4 · [2_ (phosphoranyloxy) Ethyl] I piperidinyl Cmethyl-1-piperazinyl or 4- (2-hydroxyethyl) 1 piperazinyl. 4 (Usperyl) amino "is an amino group having the above-mentioned" c2_C7 1 substitution " The nitrogen atom of M- (K6alkyl) -N- (c2-C7alkylfluorenyl) amino group "is a CrC7alkylfluorenyl) amino group has the above-mentioned" Ci_C6 alkyl substitution " Is preferably acetomethylamino. Monocyclic heteroaryl "is, for example, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,,: I, 2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl 'pyridyl, datralyl, pyrimidinyl, pyrazolyl, etc. containing 1 to 4, oxygen atom or / and nitrogen atom Among 5 to 7-membered aromatic heterocyclic groups, -30-200410948 is preferably pyridyl. The above-mentioned "fused bicyclic heteroaryl" is a fused bicyclic aromatic heterocyclic group having 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur atoms, such as isobenzofluorenyl and benzofuranyl. , 9-membered polycyclic heteroaryl groups such as isobenzothienyl, benzothienyl, indoxyl, isoindolyl, indolyl, benzoxazolyl, benzoxazolyl and the like; and 10-membered polycyclic heteroaryl groups, such as fluorinyl, quinolyl, quinazolinyl, etc., are preferably quinolyl, benzothienyl, or indolyl. The above "1 or 2 substituted CrQ alkyl groups having the same or different substituents selected from the substituent group / 5" is the same or different substituents selected from the substituent group / 3 of the "Ci_C6 alkyl group" described above 丨Or 2 substituted groups, preferably cyanomethyl, 2 cyano 2 (ethylamido) ethyl, 2- (N-ethylamido-N-methylamino) ethyl, carbamoylmethyl, 2 _Aminomethyl ethyl or 2_ (Aminomethyloxy) ethyl, and preferably 2_ (ethylamido) ethyl or carbamoylmethyl. The above-mentioned "C6-Cl ° aryl group having 1 to 3 substituents having the same or different substituents from a halogen atom &amp; Cl_C6 alkylation alkyl group" is the above-mentioned "c6-Cl. There are 1 to 3 above" "Atom" or the above-mentioned W chemical industry group, preferably a phenyl group, or a phenyl group substituted with 1 to 3 selected from a halogen atom and a trifluoromethyl group or 2, 5, j, and 2, 4, 2 Fluorophenyl, fluorophenyl, and preferably 2, *-difluorophenyl. Substitute ^ _ has the same or different substituent t 1 ~ 5 substituents from the substituent group 7. "Stomach phenyl group is the same or different from the substituent group r. Dichlorobenzene di ~ 5 Substituent 'should be fluorophenyl, chlorophenyl, difluorophenyl,' (difluoromethyl) phenyl, (trichloromethyl) phenyl, cistrimethyl; methyl (one (2 $ soil '(Monofluoromethoxy) phenyl, (trifluoromethoxy) phenyl,' 2 '2 · trifluoromethoxy) phenyl, hydrazone, 1,2,2-tetrafluoroethoxy;)- 31- 200410948 phenyl 5 (2, 2, 3 &gt; 3-tetrafluoropropoxy) phenyl, fluoro- (2, 2, 3, 3-tetrafluoropropoxy), nitrophenyl, fluoro- Nitrophenyl, cyanophenyl, cyano-fluorophenyl, chloro-cyano (methylthio) phenyl, (methylsulfonyl) phenyl, (methylsulfanyl) phenyl, 1 [trifluoromethylthio ) Phenyl, (trifluoromethanesulfinyl) phenyl or (difluoromethanesulfinyl) phenyl, preferably 4-fluorophenyl, 4-chlorophenyl 2, 4 ~ monofluorophenyl, 2 4-dichlorophenyl, 4- (trifluoromethyl) phenyl 5 4- (dichloromethyl) phenyl, 2- Fluoro-4- (trifluoromethyl) phenyl, 4- (difluoromethoxy) phenyl, 3- (trifluoromethoxy) phenyl, 4- (trifluoromethoxy) phenyl 5 4 k (2,2,2-Diacetoxy) phenyl, 4- (1,2,2, '2-tetrafluoroZroxy.yl:) phenyl, 4 · (2'2,3, 3-tetrafluoropropoxy) phenyl 2-fluoro-4_ (2,2 3,3-tetrafluoropropoxy) phenyl, 4-nitrophenyl, 2-fluoro-4 -nitrophenyl 4. cyanide Phenyl, 4-cyano: 2-fluorophenyl, 4-cyano-3-fluorophenyl, 2-chloro-4 · benzyl, 4- (methylthio) phenyl, 4- (methylidene) Sulfonyl) phenyl 4- (methylsulfonyl) phenyl, 4- (tri: fluoromethylthio) phenyl, 4- (difluoromethylidene) phenyl, 4- (trifluoromethanesulfonyl) Fluorenyl) phenyl, more preferably 4, chlorophenyl 5 4-cyano-2-fluorophenyl, 4-cyano-3-fluorophenyl, 4- (trifluoromethylthio) benzyl, 4 -(Trifluoromethanesulfonyl) phenyl '4-(= fluoromethyl) phenyl &gt; 4. (.trifluoromethoxy) phenyl, 4-(1'1'2,2 tetrafluoroethyl Oxy) phenyl or 4- (2, 2, 3, 3-horsepower) Gas-propoxy) phenyl, 4-cyano should Laid-fluoro-phenyl. The above-mentioned ^ ~ substituted monocyclic heteroaryl having the same or different substituents from the substituent group 7 mentioned above are 1 to 5 of the same or different substituents having the optional group r in the above-mentioned "monocyclic heteroaryl". G p ^ M substituted group, preferably. The aforementioned "naphthyl group having the same or four substituted groups selected from the substituent group r" is a naphthyl group having 1 to 5 substituted groups selected from the substituent group 1 to 5 substituted groups, preferably For the same or different radicals of r, 6-oxy · 2-zirconyl, _naphthyl, 6-methyl-2-naphthalene DffL, 6_ (difluoromethyl group ^ oxygen _)-2 · naphthalene , 6 · (2,2,3 ^, 6 '(trifluoromethyl 6-[(difluoromethyl) -tetrafluoropropoxy) · 2-naphthyl, (monofluoromethyl) thio]] Octaphthylnaphthyl, and also U ~ fluoromethyl) sulfofluorenyl] ^ 乂 and is naphthyl or 6_ (yl) _2-naphthyl. 1 2,3,3-tetrafluoropropoxy The above "fused or substituted #fused fused groups ^ same or different substituents of the 5 selected from the substituted fluorene group" is the above-mentioned "fused bicyclic The "heteroaryl" group is preferably the same or different substituents of m 6 to group 7 &amp; 1 to 5 substituted-2 -quinolinyl, 7 1 benzo ... sulfanyl, 2 'phenylfluorene ["thiophene + Thiophene_2-yl, 2 sulfofluorenyl) benzo '"pyrenemethyl" benzo [b] thiophen-6-yl) benzofluorene ["thiophen-2-yl, 5- (2,2, 3,3-tetrafluoropropoxy L 乜] mouth plug stage 0 Cargo_2-indolyl, 3, ~ ... earth, 5-bromoindolyl, 5- (trifluoromethyl) benzazole, 2. Its, chloro] -methyl, indolyl, 6- (one-one, 3,3-tetrafluoropropoxy (: methyl) benzothiazole I-yl benzimidazole, 2- its ^) benzothiazole 1 group, 6_ (trifluoromethyl) -1Η · 2,3,3, or 5 · bromo] &amp; benzimidazole, preferably 6- (2, oxy) -2-quinylenyl,% (2,2,3,3-tetrafluoropropylmethyl-2 -D indolyl (trifluoromethoxychlorooctaquinolinyl, (trifluoromethyl) -2-quinolinyl, 6-s 0M ^ ^ 2. 嗤 Linki '6 a (2, 2, 3, 3-tetrafluoropropoxy Radical) p-methyl) -3-isoquinolyl, 5- (trifluoromethyl) fluoromethyl) benzo [b] furan-6-fluoromethyl) benzo [b], 5- (methylfluoro (Methyl), 6- (2,2, oxy) -2-quinolinyl, 5oxy) benzene, "k, &gt; (2, 2 [b] phen-2-yl, 3, 5- Dichloromethane • 33, 200410948 or 6 · (2,2,3, tetrafluoropropoxy) benzoxazol-2-yl group. The above "fluorenyl group" is 4-7 containing more than one nitrogen, oxygen, and sulfur. A membered aliphatic heterocyclic group, preferably azetidin, _pyridine, 1, dioxane, 丨, 4,5,6 · tetrahydropyrimidine, tetrahydropyridine or 丨, 3-dithia_, and preferably γ Butidine, piperidine, 1 '3-two dihymn' 1 '4,5' 6 -tetrahydropyridine, tetrahydropyridine, or 3_dithia ring, more preferably piperidine or I, 3- Dihumane, particularly preferably, 丨, 3-two crocodile courtyard. The above "having the same or different substituents selected from the (fluorine and chlorine atom) ear substitution groups] or 2 substituted phenylene" is Among the phenylene groups, the same group selected from the (fluorine and chlorine atom) substituent groups and substituted with the same substituent $ is preferably 2-fluoro-phenyl 4-phenylene, 3-1, 4-phenylene Radical, chlorine] 4-phenylene, 3-chloro] '4-phenylene, 2, 6-difluoro], 4, phenyl, or 2,6-dichloro-1,4-phenylene. "2,6 -Chloro-1 '4-phenylene is the group of the following formula (Gb) ~ CO-NR9-T-P Plant The same or different from the above-mentioned "with a (fluorine and chlorine atom) substituent group A 1 or 2 substituted naphthyl group of a substituent group is a group of 1 or 2 ^ substituted with the same or different substituents selected from the group consisting of (face atom and chlorine atom), preferably 1- Fluoro-2,6-naphthyl. The above "1-fluoro-2,6-naphthyl" is the base of the following formula (Gb) / ~ \)-GONR9-T- -34- 200410948 Among the above G, L2 and L3, the "single bond" is 2 More than "-single button-single button-." And "-single button-single button-single button-" are represented by one single button. In the above G, L2, and L3, two or more of "-double-bond-double-bond-_" and "-double-bond-double-bond-double-bond-" in "double bond" are represented by one double bond. In the above G, L2 and L3, the "single bond" and "double bond" are not continuous. The "organic residue" in Ra above refers to a carbon-containing group, as long as Ra contains the following formula (Π)

The compound is a compound having antifungal activity, but is not particularly limited. In the above formula (I), Ra is preferably the following formula

In the above formula (I), Am · is preferably 2,4-difluorophenyl or 2,5-difluorophenyl, and A: • is preferably 2,4-difluorophenyl. In the above formula (I), R1 is preferably a hydrogen atom or a methyl group, and R1 is preferably a methyl group. In the above formula (I), 1 ^ is preferably Ci-Q alkylene or C2-C6 alkylene, and L1 is preferably C2-C6 alkylene or -CH = CH-, and more preferably L1 is C2. Alkylene or -CH = CH-, most preferably L1 is C2 alkylene. In the above formula (I), G is preferably a single bond, -0-, -NH-C (= 0)-, -C (= 0) -NH-, -C (= 0) -N (CH3)- , Carbonyl, or -C (= Ο) -〇-, and G should be -C (= 0) -NH-, -C (= 0) -N (CH3) -35- 200410948 (= 0) More preferably, G is -C (= 0) -NH- 'Base group' is most preferably-0) -NH-. In the above formula (I), L2 is preferably a single bond, a double bond, or a 4- to 7-membered heterocyclic group, and L2 is a single bond. In the above formula (I), it is preferable to use L3 as a single bond, a double bond, or CrQ alkylene, and it is also preferable to use L3 as a single bond, a double bond, -CH2- or -CH2CH2-, and it is more preferable to use L3 as a single bond. -CH2- or -CH2CH2-, particularly preferably L3 as -CH2- or -CH2CH2-, most preferably L3 as -CH2- In the above formula (I), A is preferably a carboxyl group, -S03H group, -0S03H group, -S02NH group, -0P03Η2 group, azetidinyl, pyrrolidinyl, piperidinyl, piperidinyl, morpholinyl, 1 substituted azetidinyl group (substituent: methyl, -0S03H group or -0P03Η2 group ), 1 substituted piperidinyl (substituent: methyl, -0S03H group or-(^ (^: ^ group), 1 substituted substituted piperinyl 1 is substituted by c 2 -C 6 alkyl (substituent: -so3h group,-oso3h group,-so2nh group,-opo3h2 group or -MNe2- group)] or-MNe2- group, preferably A is carboxyl group,- S03H group, -0 S Ο 3 fluorenyl group, -0 Ρ Ο 3 fluorenyl 2 group, 1-azetidinyl group, 1-pyrrolidinyl group, piperidinyl group, morpholinyl group, 1-methyl-3-azetidinyl group, 3- (sulfofluorenyloxy) -1 -azetidinyl, 3- (phosphofluorenyloxy) -1-azetidinyl, 1-methyl-4- Pyridyl, p-methyl-4-piperidinyl, 3- (sulfonyloxy) -1-piperidinyl, 3- (phosphofluorenyloxy) -1 -piperidinyl, 4-methyl-piperidine 4-, 2- (2-hydroxyethyl) -bumainzyl'4- [2- (extended oxy) ethyl] -1-veinyl'4- [2- (phenyloxy) ethyl Group] -1-piperidinyl or -MNe2-, more preferably A as a carboxyl group, -S03H group, -OP03Ρ2 group, 4-methyl-1-piperidinyl group or 4- (2 · hydroxyethyl)- 1-piperidinyl, especially A as carboxyl group, -S03H group or -0P03H2g, most 200410948 should be A as carboxyl group. "Antifungal activity" refers to deep mycosis, deep skin mycosis, expressive Mycotic infections (mycosis) such as mycosis can be expected to have a therapeutic effect, and if a specific compound has an effect, as long as the practitioner is, for example, it can be easily judged according to the following methods. For example, according to the US National Committee for Clinical Laboratory Standards (NCCLS) Standardized assays (M27-A, M38-P) or assays described in the literature (Journal of Clinical Microbiology, v 38, ρ · 34 1 -344 (2 000)) to measure representative fungal diseases · Candida, Aspergillus, New The MIC (minimum growth inhibitory concentration) of Cryptococcus or Trichophyton can be judged as having antifungal activity when the concentration is below a predetermined threshold (preferably 64 // / ml). In the compounds of the present invention, the "pharmacologically acceptable salt j" is an acidic group such as a carboxyl group in the formula (I), -P (= 〇) (0 Η) 2 group and -S 0 3 fluorenyl group, and a triazolyl group, an amine group, a piperazine Basic salts such as pyridyl are commonly used in pharmaceutical compounds. Salts of acidic groups in formula (I) are, for example, sodium salts, potassium salts, lithium salts and other alkali metal calcium salts, magnesium salts and other alkaline earth metal salts; aluminum salts, Iron salts, zinc salts, copper salts, nickel salts, cobalt salts and other metal salts; inorganic salts such as ammonium salts; tertiary octylamine salt, bisamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester Salt, ethylenediamine salt, N-methylglucamine salt, guanidinium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, Ν, Ν, -di-T-ethylenediamine salt, cloproca Organic salts, organic salts such as procaine salt, diethanolamine salt, N-fluorenyl-N-phenethylamine salt, piperidine salt, tetramethylammonium salt, ginsyl (hydroxymethyl) aminomethane salt, etc. Basic salts are, for example, hydrofluoride, hydrochloride, hydrobromide, hydrocorate, and other hydrohalates; nitrate, perchlorate, sulfate, phosphate-37-200410948 and other inorganic acids Salt methanesulfonate Low alkane sulfonates such as sulfonate and ethane sulfonate; aromatic sulfonates such as benzene sulfonate and p-toluene sulfonate; amino acid salts such as runitine acid salt and glutamate; and fumarate Acid salts, succinate salts, citrate salts, tartrate salts, oxalate salts, maleic acid salts and the like. When the compound of the present invention is placed or recrystallized in the atmosphere, it can absorb water, adsorb water, and form In the case of hydrates. The triazole compounds and pharmacologically acceptable salts of the present invention also include these water compounds. Furthermore, the compounds of the present invention and other solvents can be absorbed to obtain solvents and compounds. The triazole compounds of the present invention and their pharmacology Permissible salts also include these solvents and compounds. The compounds of the present invention include various isomers. For example, when stereoisomers based on asymmetric carbon atoms in the molecule of formula (I) are present. Also the former formula (I) There are also cases where asymmetric carbon atoms or C = C double bonds exist in various stereoisomers. Therefore, the present invention also includes these isomers and mixtures of isomers in any proportion. Such stereoisomers can be used stereo Specific raw materials, or asymmetric synthesis or The symmetric derivatization method is used to synthesize the compound of the present invention, or to separate the synthesized compound of the present invention by ordinary optical division method or separation method if necessary. The compounds of the present invention are exemplified by the compounds in Tables 1 to 9 below, but the present invention is not limited thereto. The abbreviations in Tables 1 to 9 below are as follows.

Ac is ethenyl, l-Azt is 1-azetidinyl, 3-Az 1 is 3 · azetidinyl, 1,3-Azt is 1,3-azetidinyl, -38- 200410948 0 3 , 1-A ζ t is 3,1-azetidindiyl tBu is a third butyl,

Car is carbamoyl,

Hx is hexyl, c Η X is cyclohexyl, 1,4-cHX is 1,4 · cyclohexyl, Et is ethyl,

Me is methyl, 4-Mor is 4-morpholinyl, Ph is phenyl, 1-Pip is 1-piperidinyl, 4-Pip is 4-piperidinyl, and 1,4-Pip is 1 , 4-piperidinediyl

4, I-Pip is 4,1-piperidinediyl,

4,4-Pip is 4-piperidinyl, 200410948 l-Pyrd is 1-pyrrolidinyl, 1-P i z is 1-piperidinyl, 1,4-Piz is 1,4-piperidinyl,

Pr is propyl and iPr is isopropyl. -It is a single key. Two or more single keys, namely "-single key-single key-" and "-single key-single key-single key-" are all represented by one single key. . = Is a double bond. 3 or more double bonds, ie "-double bond-double bond-double bond-" are all represented by 1 double bond. Single and double bonds are not continuous. Table 1

Exemplified R1 -L Compound No. 40- 200410948 1-1 Me -CH2--One-'' C00H 1-2 Me -CH2--One-so3h 1-3 Me _CH2--— — -OSO3H 5 1-4 Me -CH2-----opo3h2 1-5 Me -CH2--One-one 1-Azt 1-6 Me -CH2- — One-Pyrd 1-7 Μθ ~ CH2 ~-One-one 1-Pip 1 -8 Me -CHr---4-Pip 10 1-9 Me -CHr--1-Me-4-Pip 1-10 Me -CH2--— —. (CH2CH2OH) -4-Pip 1-11 Me -CH2- -One-one 1-Piz 1-12 Me -CHr--4-Me ~ l-Piz 1-13 Me -CH2--One-one 4- (CH2CH20H) -l-Piz 15 1-14 Me -CHr.-- I. 4- (CH2CH2 _) + Pi 1-15 Me -CH2---4-Mor 1-16 Me -CHr-I-nh2 1-17 Me -CH2-----NHMe 1 -18 Me -CH2 --—-~ NMθ2 20 1-19 Me -CH2--1,4-cHx--NMe2 1-20 Me -CH2CH factory-One --- C00H 1-21 Me -CH2CH2--~--S03H 1- 22 Me -CH2CHr-one one -OSO3H 1-23 Me -CH2CH2--one one-so2nh2 25 1-24 Me -CH2CH2- _ — one • -〇p〇3h2 1-25 Me -CH2CHr-one one l-Azt 1-26 Me -CH2CH2 ——- — — 1-Pyrd 1-27 Me -CH2CHr-— one 1-Pip 1-28 Me -CH2CHr-~ one 4-Pip 3 0 1-29 Me -CH2CH 「--l-Me-4-Pip -41-200410948 ίο 15 20 25 1-30 Me -CH2CHr l- (CH2CH20H) -4_Pip 1-31 Me _CH2CH2- — — ~ 1- Piz 1-32 Me -CH2CHr — — — 4-Me-l-Piz 1-33 Me -CH2CHr — — — 4-(CH2CH20H) -HPiz 1-34 Me -CH2CHr --- 4-Mor 1-35 Me- CH2CHr — — — — nh2 1-36 Me -CH2CHr---· -NHMe 1-37 Me -CH2CHr --- -NMe2 1-38 Me -CH2CH2--1,4-cHx-, e2 1-39 Me- (CH2) 3- --- -C00H 1-40 Me: (CH2) 3- — ~ — -S03H · 1-41 Me-(CH2) 3----0S03H 1-42 _ Me-(CH2) 3 -―One-so2nh2 1-43 Me-(CH2) 3- — — — -〇〇〇〇3h2 1-44 Me-(CH2) 3- --- 1-Azt 1-45 Me-(CH2) 3- One ~ · t ~ 1-Pyrd 1-46 Me-(CH2) 3- — — — 1-Pip 1-47 Me-((¾) 3- One One. _ 1-Me-4-Pip 1-48 Me -(CH2) 3 ~ _ ~ — 1-(CH2CH2OH) -4-Pip · 1-49 Me-(CH2) 3- — — — 1 -Piz 1-50 Me '(CH2) 3- One. One One Four -Me-Bu Pi z 1-51 Me-(CH2) 3- — — — 4_ (CH2CH20H) -Bu Piz 1-52 Me-(CH2) 3- One-One 4-Mor 1-53 Me-(CH2) 3- one one one-circle e2 1-54 Me _ (CH2) 3--1, 4-cHx ~-NMe2 1-55 Me-(CH2) 4_ One — One 4-Me-Bu Piz 1-56 Me-(CH2) 4- One One • One 4- (CH2CH20H) -l-Piz 1-57 Me-(CH2) 4----4-Mor 1-58 Me-(CH2) 4- ~ ~ — .-NMe2 1-59 Me -CH2CHr -C (= 0)-one- 1-Azt

-42- 30 200410948 1-60 Me -CH2CH2- -c (= o)-— .. -3-(0H) + Azt 1-61 Me -CH2CHr-c (= o)---3-(0Car) + Azt 1-62 Me ~ CH2CHr -CH)---l ~ Pyrd 1-63 Me -CH2CH2- -CH)---1-Pip 5 64 Me -CH2CHr-CH)---4-(OH) + P ip 1-65 Me -CH2CH2- -C (= 0)---4-Car-l-Pip 1-66 Me -CH2CH2--C (= 0)-—-4- (OCar) -l- Pip Bu 67 Me -CH2CHr -C (= 0)-One- 1-Piz 1-68 Me -CH2CH2- -C (= 0)-One- 4- [C (= NH) NH2] _ Bu Piz 10 1- 69 Me -CH2CHr ~ C (= 0)-a- 4- [C (= NH) CH3] -1-Piz 1-70 Me -CH2CHr a.-4-Me-1-Piz 1-71 Me -CH2CHr- CH)-One- 2,6-d.iMe-l-Piz 7.2 Me -CH2CHr -C (= 0)-One- 3,5-diMe-l-Piz 1-73 Me -CH2CHr -c (= 0 )-— -4- (CH2CH2OH) + Piz 15 Bu 74 Me -CH2CHr -CH)-1- 4- (CH2CH2NHAc) -l-Piz 1-75 Me -CH2CHr-C (= 0)-1- 4- ( CH2CH2NMeAc) -Bu Piz 1-76 Me -CH2CHr-c (= o)-1-2, 4, 6-triMe-HPiz 1-77 .Me -CH2CHr-C (= 0)---3, 4,5 -triMe- 1-Piz 1-78 Me -CH2CHr-c (= 〇)-mono-4- (CH2CH20H) -2,6-diMe-l-Piz 20 1-79 Me -CH2CH2- -〇 (= 〇) ---4-(CH2CH20H) -3,5-diMe + Piz 1-80 Me -CH2CHr-c (= 0)-—-4-(CH2CN) + Piz 1-81 Me -CH2CH2--C (= 0)-one-4-(CH2CH2CN) + Piz 1-82 Me- CH2CHr -c (= 0) ~ One- 4- (CH2Car) -1 -Piz 83 Me -CH2CHr-C (= 0)-One-4- (CH2CH20Car) + Piz 25 1-84 Me -CH2CHr-C ( = 0)-One-4- (CH2CH2F) -l-Piz 1-85 Me -CH2CHr -CH)---4-Car-: HPiz 1-86 Me -CH2CH2--C (= 0)-One-4 -Mor Bu 87 Me -CH2CHr -CH)-1,4-cHx--Li e2 1-88 Me -CH2CHr _C㈣- 1,3-Azt--C00H 30 1-89 Me -CH2CHr -C (= 0)- 1,3 ~ Az t--oso3h

-43 200410948

1-90 Me -CH2CHr -c (1,3-Azt--〇p〇3h2 1-91 Me -CH2CHr -c (= 〇)-1,3-Azt-1-Azt * 1-92 Me -CH2CH2 --C (= 0)-1,3-Az t-1-Pyrd 1-93 Me -CH2CHr -C (= 0)-1,3 ~ Az t-1-Piz 5 1-94 Me -CH2CH2-- CH)-1,3-Az t — 1-Pip 95 Me -CH2CHr -c (= 0)-1,3-Az t-4-Me-1-Piz 1-96 Me -CH2CH2--C (= 0)-1,3 ~ Az t-4- (CH2CH20H) ~ l-Piz 1-97 Me -CH2CH2_-C (= 0)-1,3-Az t-4-Mor 1-98 Me -CH2CHr -c (= 〇)-1,3-Az t--NHMe 10 1-99 Me -CH2CH2--c (= o)-1,3 ~ Az t--Li e2. 1-100 Me -CH2CH 「-c ( = o)-1,3-Az t--Li eCH2CH2OH 101 Me -CH2CHr-c (= o)-1,3-Azt-, eCH2CH2CN 1-102 Me -CH2CH2- -c (= o)-1, 3-Azt--wake up eCH2Car 1-103 Me -CH2CHr-c (= o)-1,3-Az t--plane eCH2CH2Car 15 1-104 Me _CH2CHr-c (= o)-1,3-Azt-- ECH2CH2OCar. Bu 105 Me -CH2CH2- -c (= o)-1,3-Az t--N (CH2CH20H) 2 1-106 Me -CH2CHr -c (= 0)-1,4-Pip--C00H 1-107 Me -CH2CHr -C (= 0)-1,4-Pip--so3h 1-108 Me -CH2CHr-c. (= O)-1,4-Pip ~-oso3h 20 109 Me -CH2CHr- c (= o)-1,4-Pip --〇p〇3h2 Bu 110 Me -CH2CHr-c (= o)-1,4-Pip-1-Azt 1-111 Me -CH2CHr-c (= o)-1,4-Pip-1-Pyrd 1 -1.12 Me -CH2CH2--(: (= 0)-1,4-Pip-1-Pip 1-113 Me -CH2CHr-c (= o)-1,4-Pip-1-Piz 25 1-114 Me -CH2CHr -C (= 0)-l, 4 ~ Pip-4-Me-HP iz 1-115 Me -CH2CH2--c (= o)-1,4-Pip-4-(CH2CH2OH) _l -Piz 1 -116 Me -CH2CHr -c (= o)-1,4-Pip-4-Mor 1-117 Me -CH2CHr-(: (= 0)-1,4-Pip--NHMe 1-118 Me -CH2CH2- -c (= o)-1, 4-Pip--Bandit2 30 1-119 Me -CH2CH2- -C (= 0) ~ 1,4-Pip--Li eCH2CH20H -44- 200410948 Bu 120 Me -CH2CHr- CH)-1? 4-Pip Di-NMeCH2CH2CN 1-121 Me -CH2CHr -CH)-1,4-Pip--NMeCH2Car 1-122 Me -CH2CHr -c (= 0)-1,4-Pip--NMeCH2CH2Car 1-123 Me -CH2CHr -CH)-1,4-Pip--NMeCH2CH2OCar 5 1-124 Me -CH2CH2- -C (= 0)-1,4-Pip a-N (CH2CH20H) 2 1-125 Me- CH2CHr-c (= o)-1,4-Pip -CHr-C00H 1-126 Me -CH2CHr -CH)-1,4-Pip one CHr-S03H 1-127 Me -CH2CHr -c (= o)-1 , 4-Pip -ch2- _oso3h 1-128 Me -CH2CHr -c (= 〇)-1,4-Pip-ch2- -〇P〇A 10 1-129 Me -CH2C Hr-C (= 0)-1,4-Pip -ch2- 1-Azt Bu 130 Me -CH2CHr-CH)-1,4-Pip -CHr 1-Pyrd Bu 131 Me -CH2CH2- -c (= o) -1,4-Pip -ch2- 1-Pip 1-132 Me -CH2CHr -c (= o)-1, 4-Pip-CH 「1-Piz H33 Me -CH2CHr -C (= 0)-1,4 -Pip -ch2- 4-Me-l-Piz. 15 1-134 Me -CH2CH2--c (= o)-1,4-Pip-ch2- 4- (CH2CH20H) + Piz 1-135 Me ~ CH2CHr- C (= 0)-1,4-Pip -ch2- 4-Mor 1-136 Me -CH2CHr -c (= 〇)-1,4-Pip Mai 1-137 Me -CH2CHr -c (= 0)-1 , 4-Pip -CHr ~ NHMe (138 Me -CH2CHr -CH)-1,4-Pip -ch2-, e2 20 1-139 Me -CH2CH2- -c (= 〇)-1,4-Pip-CHr- MeCH2CiI2OH 1-140 Me -CH2CHr-coo)-1,4-Pip -ch2- -N (CH2CH20H) 2 1-141 Me -CH2CHr -C (= 0) ~ 1,4-P iz a-so2nh2 1-142 Me -CH2CHr -C (= 0)-1,4-P iz-ch2ch2- 1-Azt 1-143 Me -CH2CHr -c (= 0)-1,4-P iz-ch2ch2 ·-HPyrd 25 1-144 Me -CH2CHr-c (= 〇)-1,4-P iz-ch2ch2. _ L-Pip 145 Me -CH2CHr -c (= 0)-1, 4-Piz-ch2ch2.-4-Me-l- Piz Bu 146 Me -CH2CHr -c (= 0)-1,4-Piz-ch2ch2.-4- (CH2CH2OH)-Bu Piz 1-147 Me -CH2CH2- -C (= 0) ~ 1,4-Piz- ch2ch2. 4-Mor 1-148 Me -CH2CHr-c (= 0)-1,4-P iz -ch2ch2 · -NHCH2CH2OH 30 149 Me -CH〇CHr -c (= 0)-1,4-Piz-ch2ch2_- NHMe -45- 200410948

1-150 Me -CH2CHr-C (= 0)-1,4-Piz ~ CH2CHr -NMe2 1-151 Me ~ CH2CHr -c (= o)-1,4-Piz -CH2CHr -Li eCH2CH20H 1-152 Me- CH2CHr -c 0 = 0)-1,4-Piz -CH2CHr -N (CH2CH2OH) 2 1-153 Me -CH = CH- -c (= o)-—-1-Piz 5 1-154 Me -CH = CH- _c (= o)--4-(C (= NH) NH2) -1 -Piz 1-155 Me -CH = CH--c (= o)--4- (C (= NH) CH3) -1-Piz 1-156 Me -CH-CH--c (= o)--4-Me-HPiz 1-157 Me _CH = CH- -c (= o)--2,6-diMe-l- Piz 1-158 Me -CH = CH--c (= o)-—-3, 5-diMe-HPiz 10 1-159 Me -CH di CH--c (= o)--4- (CH2CH2OHH-Piz 1-160 Me -CH = CH- -c (= o)-— — 4- (CH2CH2CN) -l-Piz 1-161 Me -CH = CH--c (= o)---4- (CH2Car) + Piz 1-162 Me -CH = CH- -c (= o)-one-four- (CH2CH20Car)-; HPiz 1-163 Me -CH = CH--c (= o)-4- (CH2CH2F)- l-Piz 15 164 Me -CH = CH--c (= o)---4-Mor '1-165 Me -CH = CH- -c (= o)-1,3-Azt--C00H 1 -166 Me -CHsubstituted- (: (= 0)-1, 3 ~ Az t--so3h 1-167 Me -CH = CH- -c (= o)-1,3-Az t--oso3h 1- 168 Me -CH = CH- -c (= o)-1,3-Az t--〇p〇A 20 1-169 Me -CH di CH- -c (= o)-1,3 ~ Az t _ 1- Azt 1-170 Me -CH = CH--c (= o)-1, 3 ~ Az t ~ 1-Pyrd 1-171 Me -CH = CH- ~ C (= 0)-1, 3 ~ Az t- 1-Pip 1-172 Me -CH = CH- -c (= o)-1,3-Az t.-Piz 1-173 Me -CH = CH--c (= o)-1,3-Azt -4-Me-1-Piz 25 1-174 Me -CH = CH--c (= o)-l, '3_Azt-4- (CH2CH20H) -l-Piz 1-175 Me -CH = CH- -c (= o)-1, 3 ~ Az t ~ 4-Mor 1-176 Me -CH = CH- -c (= o)-1,3-Az t--NHMe 1-177 Me -CH = CH-- c (= o)-1,3-Azt--_e2 1-178 Me -CH = CH- -c (= o)-1,3-Az t--NMeCH2CH20H 30 1-179 Me -CH = CH-- c (= o)-1,3-Azt--NMeCH2CH2CN -46 200410948 1-180 Me -CH = CH--C (= 0)-1,3-Az t —-NMeCH2Car 1-181 Me -CH = CH --c (= 0)-1,3-Az t one-Li eCH2CH2Car 1-182 Me -CH = CH--C (= 0)-1, .3-Azt one-NMeCH2CH20Car 1-183 Me -CH = CH- _c (= 〇)-1,3-Azt--N (CH2CH2OH) 2 5 1 -184 Me -CH = CH--c (= 〇)-1,4-Pip--C00H 1-185 Me- CH = CH--c (= 〇)-1,4-Pip a- S03H 186 Me -CH = CH- -c (= 0)-1,4-: Pip a-0S03H 1-187 Me -CH = CH--c (= o)-1,4-Pip a- 〇p〇3h2 1-188 Me -CH = CH--C (= 0)-1,4-Pip-1-Azt 10 1-189 Me -CH = CH- -c (= 0)-1,4-Pip a 1-Pyrd 1-190 Me -CH = CH- -c (= 0)-1,4-Pip a l- Pip 1-191 Me -CH = CH- _C (= 0)-1,4-Pip-1-Piz 1-192 Me -CH = CH--C (= 0)-1,4-Pip a 4-Me -l-Piz 1-193 Me -CH = CH- -c (= 0)-1,4-Pip-4- (CH2C_ + Piz 15 1-194 Me -CH = CH--C (= 0)-1 , 4-Pip a 4-Mor BU 195 Me -CH = CH--c (= o)-1,4-Pip a-NHMe 1-196 Me-CH = CH- -c (= 0)-1,4 -Pip--_e2 1-197 Me -CH = CH- -c (= 0)-1,4-Pip a -NMeCH2CH2OH 1-198 Me -CH = CH— -c (= o)-1, 4-Pip -NMeCH2CH2CN 20 1-199 Me -CH = CH- -c (= o)-1, 4-Pip--NMeCH2Car 1-200 Me -CH = CH- -c (= o)-1,4-Pip- -NMeCH2CH2Car 1-201 Me -CH = CH--c (= o)-.1,4-Pip a -NMeCH2CH2OCar 1-202 Me -CH = CH- -c (= 0)-1,4-Pip-- N (CH2CH2OH) 2 1-203 Me -CH = CH--c (= 0)-1, 4-Pip-CH2--C00H. 25 1-204 Me -CH = CH- -C (= 0)-1 , 4-Pip-ch2- -OSO3H 1-205 Me -CH = CH--c (= 0)-1,4-Pip-ch2- -〇p〇3h2 206 Me -CH = CH- -c (= 0)-1,4-Pip-ch2-1-Azt Bu 207 Me -CH = CH- -C (= 0)-1,4-Pip-ch2- Bu Pyrd 1-208 Me -CH = CH-- C (= 0)-1,4-Pip ·-CH 「1-Pip 30 1-209 Me -CH = CH- -C (= 0)-1,4-Pip-ch2- 4-Me-HP iz- 47- 200410948

1-210 Me -CH = CH- -C (= 0)-1,4-Pip-ch2- 4- (CH2CH20H) -l-Piz 1-211 Me -CH = CH- -CH)-1,4- Pip-ch2- 4-Mor 1-212 Me -CH = CH--c (= 〇)-1,4-Pip-ch2--νη2 1-213 Me _CH = CH- -C (= 0)-1, 4-Pip-CH``-· Me 5 1-214 Me _CH = CH--c (= 〇)-1,4-Pip _CHr __e2 1-215 Me -CH = CH- -c (= 0)-1, 4-Pip-CH 「-Circle eCH2CH2OH 1-216 • Me -CH = CH- -C (= 0)-1,4 ~ Pip-CH「 -N (CH2CH2OH) 2 1-217 Me -CH2CHr -C (= 0)-1,4-Piz--SO wind 1-218 Me -CH = CH- -c (= o)-1,4-Piz • -ch2ch2. • 1-Azt 10 1-219 Me -CH = CH -1,4-Piz-ch2ch2- 1-Pyrd 1-220 Me -CH = CH- -c (= 0)-1,4-Piz-CH2CH2- 1-Pip 1-221 Me -CH = CH- -c (= 〇)-1,4-Piz -ch2ch2- -Bu Piz 1-222 Me -CH = CH- -C (= 0)-1,4-Piz-ch2ch2 4-Me-l-Piz 1-223 Me -CH = CH- ~ C (= 0)-1,4-Piz-ch2ch2.-4- (CH2CH20H) -1 -Piz 15 1-224 Me -CH = CH- -c (= o)-1, 4-Piz-ch2ch2 · 4-Mor 1-225 Me -CH = CH- -c (= o)---4-(CH2CH2NHAc) + Piz 1-226 Me -CH = CH--coo)-1,4 -Piz -ch2ch2 · -NHMe 1-227 Me -CH = CH- -C (= 0)-1,4-Piz _ch2ch2 1 ·-NMe2 1-228 Me -CH = CH --c (= 〇)-1,4-Piz .-ch2ch2 -NMeCH2CH20H 20 1-229 Me -CH = CH- -c (= 0)-1,4-Piz-ch2ch2 -N (CH2CH20H) 2 1- 230 Me _CHr-0---1-Me-3-Azt 1-231 Me -CH2_ -0--one 1-(CH2CH20H) -3-Azt 1-232 Me -CHr _0-one-1-(CH2CH2NHAc) -3-Azt 1-233 Me -CHr -0-one one 4-P ip 25 1-234 Me -CH2- -0-one one 1-Me-4-Pip 1-235 Me -CHr -0--. -L- (CH2CH20H) -4-Pip Bu 236 Me -CHr -0-l- (CH2CH2NHAc) -4-Pip 1-237 Me -CHr-0---CH Factory-COOH Bu 238 Me -CHr -CH2CH2 --C00H 30 1-239 Me -CHr -0--ch2ch 2 ~-S03H -48- 200410948

1-240 Me _CHr--CH2CH2- -OSO3H 1-241 Me -CH2 ~--ch2ch 「-so2nh2 .1-242 Me &quot; CH2 * · -0- 一 -CH2CHr-0P03h2 1-243 Me -CHr.- 〇--~ CH2CHr 1-Azt 5 1-244 Me * &quot; CH2 ~ -0---CH2CH2- 1-Pyrd 1-245 Me -CH2 ~~-0--_CH2CH2- 1-Pip 1-246 Me- CH2- _0- one-CH2CHr 1-Piz 1-247 Me -CH〗---ch2ch2- 4-Me-l-Piz 1-248 Me -CH2- -0---ch2ch2- 4- (CH2CH20H)-1 -Piz 10. 1-249 Me -CH2- -0---CH2CHr •. 4-Mor Bu 250 Me ~ CH2- a-ch2ch2--NMe2 1-251 Me -CH 「_0---ch2ch」-NMeCH2CH2OH 1 -252 Me ~ CH2 ~ 〇 一--CH2CHr -N (CH2CH20H) 2 1-253 Me ~ CH2 ~ -0- 1,4-cHx ~-NMe2 15 1-254 Me -CHr -0- 1,4- cHx--NMeCH2CH20H 1-255 Me ~ CH2 ~ -0-1, 4, 4-cHx--N (CH2CH2OH) 2 1-256 Me -CH2-. -0-3,1-Azt--so2nh2 257 Me ~ CH2 ~ -0- 3, Azt-3-Azt 1-258 -Me ~ CH2 ~ -0-3,1 -Azt-l-Me-3-Azt 20 1-259 Me -CH2--0- 3, 1-Azt-Bu (CH2CH2OH) -3, Azt 1-260 Me -CHr -0- 3,1-Azt-4-Pip 1-261 Me -CH2- -0-3,1 -Azt-l-Me- 4-Pip 1-262 Με &quot; &quot; CH 2 ~ -0- 3,1-Azt 1-(CH2CH20H)-4-Pip 1-263 Me &quot; · 0Η2 ~-0- 3, 1 -Azt -CH2CH2- 1-Azt 25 1-264 Me -CHr- 0- 3, l ~ Azt -CH2CH2- 1-Pyrd 265 Me -CH2- -0- 3,1 -Azt -CH2CHr 1-Pip 1-266 Me -CH2- -0-_ 3,1 -Azt -CH2CH2 -Bu Piz Bu 267 Me -CH2_ -0-3,1 -Azt ~ CH2CH2 * &quot; 4-Me-l-Piz Bu 268 Me -CH2- -0-3, l ~ Azt ~ CH2CH2 *-4- (CH2CH20H ) -l-Piz 30 Bu 269 Me —CH2_-0- 3, Bu Azt -CH2CH2- 4-Mor -49 200410948 1-270 Me ~ CHr -0- 3,1 -Azt -CH2CHr -NHMe 1-271 Me- CHr-0- 3,1 -Azt -ch2ch2- -Li e2 1-272 Me -CH2 '-0- 3,1 -Azt -ch2ch 「-NMeCH2CH2OH 1-273 Me -CHr-0- 3,1 -Az t -ch2ch2- -N (CH2CH2OH) 2 5 1-274 Me _CHr -0- 4,1-Pip a-so2nh2 1-275 Me -CH2- ·-0- 4,1-Pip a 3 ~ Az t 1-276 Me -CHr -0- 4,1-Pip -1-Me-3-Azt 1-277 Me -CHr-0- 4,1-Pip-l- (CH2CH20H) -3-Azt 1-278 Me -CHr- 0- 4,1-Pip-4-Pip 10 1-279 Me -CHr -0- 4,1-Pip-l-Me-4-Pip 1-280 Me -CHr -0- 4,1-Pip-1 ~ (CH2CH20H) -4-Pip 1-281 Me -CHr -0- 4,1-Pip -ch2ch2- 1-Azi 1-282 Me -CHr -0- 4,1-Pip- CH2CHr 1-Pyrd 1-283 Me -CHr-0- 4,1-Pip -ch2ch2- 1-Pip 15 1-284 Me -CHr -0- 4, l ~ Pip-ch2ch 「Piz 1-285 Me -CHr -0- 4,1-Pip -ch2ch2-4-Me-HPiz 1-286 Me rCHr -0- 4,1-Pip -CH2CH2-4-(CH2CH20H) -Bu Piz 1-287 Me -CHr-0- 4 , 1 ~ P ip- -ch2ch2- 4-Mor 1-288 Me -CH2_-0- 4,1-Pip-CH2CHr-· Me 20 289 Me -CHr -0-.4,1-Pip-CH2CHr-NMe2 1-290 Me -CHr -0- 4,1-Pip-CH2CHr -calendar eCH2CH2OH 1-291 Me -CHr 4,1-Pip -CH2CHr -_2CH2OH) 2 1-292 Me -CHr -NHC (= 0)-1 -CH 「-C00H 1-293 Me -CH2- -NHC (= 0)-One- ch2--so3h 25 294 Me -CHr -NHC (= 0)-One- ch2--oso3h 1-295 Me -CHr -NHC〇 = 0)---CH2--0P03h2 1-296 Me -CHr -NHC (= 0)-a-ch2- 1-Azt 297 Me -CH2- -NHC (= 0)-a- CH 「 1-Pyrd 1-298 Me -CHr-NHC (= 0)---ch2- 1-Pip 30 1-299 Me -CH9- -NHC (= 0)---CHr 4-Me-l-Piz 50- 200410948 1-300 Me -CHr 1-301 Me -CHr 1-302 Me -CHr 1-303 Me -CHr 5 1-304 Me _CHr 1-305 Me -CHr 1-306 Me -CHr 1-307 Me -CHr 1 -308 Me ~ CHr 10 1-309 Me -CHr 1-310. Me -CHr 1-311 Me -CHr 1-312 Me -CHr 1-313 Me -CHr 15 1-314 Me · -CHr 1-315 Me -CHr 1-316 Me -CHr 1-317 Me- CHr 1-318 Me -CHr 20 1-319 Me -CHr 1-320 Me -012- 1-321 Me -CHr 1-322: Me -CHr 1-323 Me -CHr 25 1-324 Me -CHr 325 Me -CHr Bu 326 Me -CHr 1-327 Me -CHr 1-328 Me -CHr 30 Bu 329 Me -CH Factory-ch2--ch2- -CHr-CHr -CH2CHr-CH2CH2--CH2CHr-CH2CH 「-CH2CHr -CH2CHr -CH2CH2--CH2CHr-CH2CHr -CH2CHr-CH2CH2--CH2CHr-CH2CHr -CH2CHr -CH2CHr-CH2CHr-CH2--CV-ch2--ch2--ch2 --ch2- -CHr -NHC (= 0) ~--- CHr -NHC (= 0) --- NHC (= 0) --- NHC (= 0)-~ NHC (= 0) --- NHC (= 0) --- NHC (= 0) --- NHC (: 0)---NHC 0 = 〇) --- Li C (= 0) --- NHC (= 0)--NHC (= 0) --- NHC (= 0) --- NHC (= 0)---NHC (= 0)--NHC (= 0)---NHC (= 0) --- NHC (= 0) --- NHC (= 0)-~ -NHCOO)- --NHC (= 0)--NMeC (= 0) --_ iiMeC (= 0)--NMeC (= 0) --- Li eC (= 0) --- Li eC (= 0)-- -Li eC (: 0) —— -NMeC (= 0)---NMcC (= 0)-~ _CH2 ~ -NMeCbO)--~ CH2- 4 1 (CH2CH20H) -Bu Piz 4-Mor -None e2

-NMeCH2CH20H -N (CH2CH2〇H) 2 -C00H ·

-S03H-oso3h-〇p〇3h2 Azt HPyrd 1-Pip 4-Pip 1-Me-4-Pip HPiz 4-Me-1-Piz 4-(CH2CH2OH) -l -Piz 4-Mor -Li e2

-Li eCli2CH2OH-N (CH2CH20H) 2

-C00H ~ S03H-oso3h, 〇3h2 l-Azt 1-Pyrd 1-Pip '4-Me-1-Piz 4- (CH2CH20H) -l-Piz 200410948 1-330 Me _CH2_-CHr 4-Mor 1-331 Μθ -CH2 ~ -Li eC (= 0)----CHr -Li e2 1-332 Me -CHr -NMeC (= 0)--CH2- -Li eCH2CH20H 333 Μθ ~ CH2- -fiMeC (= 0)- --CHr -N (CH2CH20H) 2 5 1-334 Me -CHr -Li eC (= 0)----CH2CHr-C00H 1-335 Me -CHr -Wake eC (= 0)----CH2CHr -S03H 1- 336 Me -CHr -Wake eC (= 0)---ch2ch2- -oso3h 1-337 Me -CH2- -Li eC (= 0)--ch2ch2- -opo3h2 1-338 Me -CHr -Beat eCH)- --CH2CH2- 1-Azt 10 1-339 Me -CH2--Bandit eC (= 0)--CH2CH2- 1-Pyrd 1-340 Me -CH2- -Li eC (= 0)---CH2CHr HP ip 1-341 Me -CH2--Li has. (= 0)--CH2CH2- 1-Piz 1-342 Me -CH2- -Li eC (= 0)--CH2CHr 4-Me + Piz 1-343 Me -CHr -Li eC (= 0)-- -CH2CHr 4- (CH2CH20H) -l-Piz 15 1-344 Me -CHr -Circular eC (= 0)--CH2CH2 ~ 4-Mor 1-345 Me -CHr -Li eC (= 0)--CH2CH2_ -iiMe2 .1-346 Me -CHr -Band eC (= 0)--CH2CHr -NMeCH2CH2OH 347 Me -CHr-NMeC (= 0)--CH2CH2- -N (CH2CH20H) 2 1-348 Me -CH2CHr -C (= 0) NH---CH2- -C00H 20 1-349 Me -CH2CHr -C (= 0) NH---CH2CHr-C00H 1-350 Me -CH2CHr -C (= 0) NH---- ch2ch2- ~ so3h 1-351 Me -CH2CHr-CH) NH---ch2ch2- -oso3h 1-352 Me -CH2CHr ~ C (= 0) NH-- -ch2ch2- -opo3h2 1-353 Me -CH2CH2 ~-C (= 0) Li--~ CH2CH2 ~ 1-Azt 25 1-354 Me -CH2CHr-C (= 0) NH-- -CH2CHr Pyrd 1-355 Me -CH2CHr -C (= 0) NH---CH2CH2_ 1-Pip 1-356 Me -CH2CH2--C (= 0) NH--.-CH2CHr 4-Me + Piz 1-357 Me -CH2CHr-(: (two 0) Li--CH2CH2- 4- (CH2CH20H ) -1 -Pi: 1-358 Me -CH2CH2--C (= 0) NH---CH2CHr 4-Mor 30 1-359 Me -CH2CHr ~ C (-0) NH---CH2CH2_ -Lie2 -52 -200410948

1-360 Me -CH2CHr -C (: 0) NH-- -ch2ch2- -NMeCH2CH20H 1-361 Me -CH2CHr -C (= 〇) NH-- -ch2ch2- -N (CH2CH2OH) 2 1-362 Me -CH2CH2_ -C (= 〇) Li e---CHr--C00H 1-363 Me -CH2CHr-C (two 0) _e —-CH2CHr -C00H 5 1-364 Me ~ CH2GHr -C (= 0) plane e-- -CH2CH2--S03H 1-365 Me -CH2CHr -C (= 0) Li e---CH, CHr-oso3h 1-366 Me -CH2CHr -C (= 0) circle e---CH2CHr-opo3h2 1-367 Me -CH2CH2- -C (= 〇) Lie----CH2CHr 1-Azt 1-368 Me -CH2CH2- -C (= 0) Lie----CH2CHr 1-Pyrd 10 1-369 Me _CH2CH2- -C (= 0) Li e---c_2- 1-Pip 1-370 Me -CH2CHr -C (= 0) NMe---CH2CH2- 1-Piz 1-371 Me -CH2CHr -CO0) Li e- _ -CH2CHr 4-Me-1-Piz 1-372 Me -CH2CHr-C (= 0) NMe—— -CH2CHr 4- (CH2CH20H) -l-Piz 1-373 Me -CH2CH2- -C (= 0) NMe---- CH2CHr 4-Mor 15 1-374 Me -CH2CHr -C (O) Li e---ch2ch2- -NHMe 1-375 Me -CH2CH 「-C (= 0) wake up e--CH2CHr -NMe2 1-376 Me -CH2CH2--C (= 0) iiMe---CH2CH2- -NMeCH2CH20H 1-377 Me -CH2CH2- -C (= 0) NMe----CH2CHr-N (CH2CH2OH) 2 1-378 Me -CH = = = = 1-Me-4, 4-Pip 20 1-379 Me -CH = two = = l- (CH2CH 2〇H) -4,4-Pip 1-380 H -CHr--C00H 1-381 H -CHr----so3h 1-382 H-CHr---0S03H 1-383 H -CHr--opo3h2 25 1-384 H -CH 「— —-1-Azt 1-385 H -CHr — one-1-Pyrd 1-386 H -CHr one one-1-Pip BU 387 H -CH2---4-Pip 1 -388 H -CHr 1--l-Me-4-Pip 30 1-389 H -CHr — — — l- (CH2CH2OH) -4-Pip 53- 200410948 1-390 Η -CH2--— — 1-Piz 1-391 Η -ch2---4-Me-l-Piz 1-392 Η _ch2---4- (CH2CH20H) -l-Piz 1-393 Η chch---4- (CH2CH2NHAc) -l-Piz 5 1-394 Η -ch2---4-M or 1-395 Η -CH2--— —-nh2 1-396 Η -CH2----NHMe 1-397 Η-ch2----NMe2 1- 398 Η-CH2--1,4 ~ cHx--Circle e2 10 1-399 Η-CH2CHr---C00H 1-400: Η -CHzCHr--~-S03H 1-401 Η-CH2CHr----oso3h 1 -402 Η -CH2CHr----so2nh2 1-403 Η-CH2CH2----opo3h2 15 1-404 Η -ch2ch2---1-Azt 1-405 • Ή -CH2CH2 ~--One 1-Pyrd 1- 406 Η -CH2CHr-One HPip 1-407 Η -CH2CH2---4-Pip 1-408 Η -CH2CHr-One l-Me-4-Pip 20 1-409 Η -CH2CHr ~ 一 1- (CH2CH20H) -4-Pip 1-410 Η-CH2CHr-— 1-1-Piz 1-411 Η -CH2CHr-~ · 4-4-Me-l-Piz 1-412 Η-CH2CH2---4- (CH2CH20H) -l ~ Piz 1-413 Η -CH2CH2----4-Mor 25 1-414 Η-CH2CHr-一-nh2 1-415 Η -ch2ch 「-— — -NHMe 1-416 Η -CH2CH2---, e2 1-417 Η -ch2ch2--. 1,4-cHx--face e2 1-418 Η-(ch2) 3----C00H 30 1-419 Η -(CH2) 3-— one--so3h -54-200410948 1-420 H-(CH2) 3-1-421 H-(CH2) 3-1-422 H-(ch2) 3- 1-423 H, ) Γ 5 1-424 H-(ch2) 3- .1-425 H-(CH2) 3- 1-426 H-(CH2) 3- 1-427 H) r 1-428 H-(CH2) 3 -10. 1-429 H-(CH2) 3-1-430 H-(CH2) 3- 1-431 H-(CH2) r 1-432 H-(CH2) 3- 1-433 H-(CH2) r 15 1-434 H-(ch2) 4- 1-435 H-(ch2) 4- 1-436 H-(ch2) 4- 1-437 H-(CH2) 4- 1-438 H-CH2CHr 20 1 -439 H -ch2ch2- 1-440 H -ch2ch2- 1-441 H -CH2CHr 1-442 H -CH2CHr 1-443 H -CH2CHr 25 1-444 H -CH2CHr 1-445 H -CH2CHr 1-446 H -CH2CHr 1-447 H -ch2ch2- 1-448 H -ch2ch2- 30 1- 449 H -CH2CHr l, 4-cHx--C (= 0)--C (= 0) --- C (two 0)----C (= 0)--C (= 0)- _c (= 〇) --- c (= o)--C (= 0)---C (= 0) --- C (-0)--c (= 〇) --- c ( -〇)--oso3H-S02NH2. -Opo3h2 · 1-Azt 1-Pyrd 1-Pip l_Me-4-Pip. Bu (CH2CH20H) -4-Pip Bu Piz 4-Me-l-Piz 4- (CH2CH20H) -HPiz 4-Mor -Li e2., E2 '4-Me-1-Piz 4- (CH2CH20H) + Piz 4-Mor -Li e2 l ~ Azt 3- (0H) + Azt 3- (0Car) -l- Azt 1-Pyrd 1-Pip 4- (OH) -1-Pip 4- Car-l-Pip 4- (0Car) -l-Pip 1-Piz 4- (C (= NH) NH2) -l-Piz 4 -(C (= NH) CH3) -1-Piz 4-Me-l-Piz

55 200410948

1-450 H -CH2CHr -c (= 0)-one-2,6-diMe-l-Piz 1-451 H -CH2CHr -c (= 0)---3,5-diMe-l-Piz 1- 452 H -CH2CHr -c (= 0)---4- (CH2CH20H) -l-Piz 1-453 H -CH2CHr -c (= 0)-one-4 ~ (CH2CH2NHAc) -l-Piz 5 1-454 H -CH2CHr -c (= 〇)-— -4- (CH2CH2NMeAc) -l-Piz 1-455 H -CH2CHr -c (= 0)-one-2, 4, 6-triMe-1-Piz 1-456 H -CH2CH2- ~ C (= 0)---3,4,5-triMe-l-Piz 1-457 H -CH2CHr -C (= 0)-one- 4- (CH2CH2OH) -2,6-diMe -Bu Piz 1-458 H -CH2CH2- -c (= o)---4- (CH2CH20H) -3,5-diMe-l-Piz 10 1-459 H -CH2CH2- -C (= 0)-a -4- (CH2CN) -l-Piz 1-460 H -CH2CH2- -c (= 0)-one- 4- (CH2CH2CN) -HPiz 1-461 H -CH2CH2--c (= 0)-one-4 -(CH2Car) + Piz 1-462 H-CH2CH2_-c (= 〇)-a-4- (CH2CH20Car) + Piz 1-463 H -CH2CHr-c (= o)-— -4- (CH2CH2F) ~ l -Piz 15 1-464 H -CH2CHr -c (= 0)-a- 4-Car-1-Piz 1-465 H -CH2CH2--c (= 〇)---4-Mor 1-466 • H- CH2CHr ~ C (= 0) ~ 1,4-cHx--Li e2 1-467 H -CH2CHr -C (= 0 &gt;-1, 3 ~ Az t--C00H 1-468 H -CH2CHr -c (= 0 )-1,3-Az t--0S03H 20 1-469 H -CH2CHr -0 (= 0)-1,3 ~ Az t--opo3h2 1-470 H -CH2CHr -c (= 0)-1,3 ~ Az t-1-Azt 1-471 H -CH2CHr-C (= 0)-1,3-Az t-1- Pyrd 1-472 H -CH2CHr -C (= 0)-1,3-Az t-HPiz 1-473 H -CH2CH2- -c (= 0)-1, 3-Azt-1-Pip 25 1-474 H -CH2CHr -c (= 〇)-1,3-Azt-4-Me-1-Piz 1-475 H -CH2CH2--c (= 〇)-1,3-Az t-4- (CH2CH20H) -l -Piz \ 1-476 H -CH2CHr-C (= 0)-1,3_Az t-4-Mor 1-477 H -CH2CHr -c (= o)-1, 3-Azt--NHMe 1-478 H- CH2CH2- -c (= 〇)-1,3-Azt--NMe2 30 1-479 H -CH2CHr -c (= 0)-1,3-Azt--plane eCH2CH2OH -56 200410948 1-480 Η-CH2CHr- C (= 0)-1,3-Azt 1-NMeCH2CH2CN 1-481 H -CH2CHr-coo)-1,3-Azt--bandeCH2Car_ 1-482 H -CH2CHr -c (= o)-1,3- Az t —-NMeCH2CH2Car 1-483 H -CH2CHr -c (= o)-1, 3-Azt--wake up eCH2CH20Car 5 1-484 H -CH2CHr -C (= 0)-1, 3-Azt-one N ( CH2CH20H) 2 1-485 H-CH2CHr -c (= o)-1,4-Pip--C00H '1-486 H -CH2CH2- -C (= 0) ~ 1,4-Pip one- so3h 1-487 H -CH2CHr-c (= 〇)-1,4-Pip — -OSO3H 1-488 H -CH2CH2- -c (= 0)-1,4-Pip one-opo3h2 10 1-489 H -CH2CHr- c (= o)-1,4-Pip-1-Azt 1.-490 H -CH2CHr -C (= 0)-1,4-Pip-l'Pyrd 1-491 H -CH2CH 「-c (= 0 )-1,4-Pip-Pip 1-492 H -CH2CH2- -c (= o)-1,4-Pip-1-Piz 1-493 H -CH2CHr -c (= 0)-1,4- Pip-4-Me-1-Piz 15 1-494 H -CH2CHr -c (= 〇)-1,4-Pip-4- (CH2CH20H) + Piz 1-495 H-CH2CH2-~ C (= 0) ~ 1,4-Pip-4-Mor. 1-496 H -CH2CHr -c (= 0)-1,4-Pip a-MMe 1-497 H -CH2CH2- -c (= 0)-1,4-Pip I-Li e2 1-498 H -CH2CHr -c (= o)-1,4-Pip--Li eCH2CH20H 20 1-499 H-CH2CH "-c (= o)-1,4-Pip I-NMeCH2CH2CN · 1-500 H -CH2CHr -C (= 0) ~ 1,4-Pip one-wake eCH2Car 1-501 H -CH2CHr -CH))-1,4-Pip —-NMeCH2CH2Car 1-502 H -CH2CHr -C ( = 0)-1,4-Pip--eCH2CH2OCar 1-503 H -CH2CHr -c (= 0)-1,4-Pip--_2CH20H) 2 25 1-504 H -CH2CH2- -c (= 0) -1,4-Pip-ch2- -C00H 1-505 H -CH2CH2- -C (= 0)-1,4-Pip -ch2- -SO3H 1-506 H -CH2CH2- -c (= o)-1 , 4-Pip -ch2- --oso3h 1-507 H -CH2CHr -c (= 〇)-1,4-Pip -ch2- -〇p〇3h2 1-508 H -CH2CHr -C (= 0)-1 , 4-Pip -ch2- 1-Azt 30 1-509 H-CH2CH2- -C (= 0)-1,4-Pip -ch2- 1-Pyrd -57- 200410948 1-510 H -CH2CHr -c (= 0)-1,4-Pip -ch2-1-Pip 1-511 H -CH2CHr -c㈣- 1,4-Pip -ch2- 1-Piz 1-512 H -CH2CHr -c㈣- 1,4-Pip-CHr 4-Me-l-Piz 1-513 H -CH2CH2--COO)-1, 4-Pip -CH Factory 4-(CH2CH2OH) -1-Piz 5 1-514 H -CH2CHr -c (= 0)-1,4-Pip -ch2- 4-Mor 1-515 H -CH2CH2- -c ( = 0)-1,4-Pip-CHr -nh2 1-516 H -CH2CHr -c (= 0)-1,4-Pip -ch2- -NHMe 1-517 H -CH2CHr -C (= 0)-1 , 4-Pip-ch2- ~ NMe2 1-518 H -CH2CHr -c (= 〇)-1,4-Pip Mai-NMeCH2CH2OH 10 1-519 H -CH2CHr -c (= 0)-1,4-Pip- CHr -_2CH20H) 2 1-520 H -CH2CHr-c (= 0)-1,4-Piz--S02 Li 2 1-521 H -CH2CHr -c. (= 0)-1,4-Piz -ch2ch2- 1-Azt 1-522 H-CH2CHr -c (= 〇)-1,4-Piz -ch2ch2- 1-Pyrd 1-523 H -CH2CHr -c (= o)-1,4-Piz -CH2CH2 &quot; · 1 -Pip 15 1-524 H -CH2CHr -c (= o)-1,4-Piz -CH2CHr 4-Me-l-Piz 1-525 H -CH2CH2- -〇 (= 〇)-1,4-Piz- CH2CHr 4- (CH2CH20H) -l-Piz 1-526 H -CH2CH2- -c (= 0)-1,4-Piz -CH2CH2- 4-Mor 1-527 H -CH2CHr -c (= 0)-1, 4-Piz -ch2ch2- -NHCH2CH2OH 1-528 H-CH2CHr -C (= 0)-1,4-Piz-ch2ch2--NHMe 20 1-529 H -CH2CHr -c (= 0)-1,4-Piz -ch2ch`` -Circle e2 1-530 H -CH2CHr -c (= 0)-1,4-Piz -ch2ch2- -LiCH2CH2OH 1-531 H -CH2CHr -C (= 0)-1,4-Piz -CH2CHr -N (CH2CH2OH) 2 1-532 H -CH = CH -~ c (= 0)-One- 1-Piz 1-533 H -CH = CH--c (= 0)-One-one 4-(C (= NH) NH2) -1-Piz 25 Bu 534 H- CH = CH--c (= 0)---4-(C (,) CH3) + Piz 1-535 H -CH = CH- -0 (= 0)---4-Me-HP iz BU 536 H -CH = CH--C (= 0)---2,6-diMe-l-Piz 1-537 H -CH = CH--c (= o)-one-3,5-diMe-l- Piz 1-538 H _CH = CH- -c (= 〇)---4- (CH2CH20H) -l-Piz 30 1-539 H -CH di-CH- -c (= 0)---4- (CH2CH2CN ) -l-Piz

-58- 200410948 1-540 Η -CH-CH- -C (= 0)-— _ 4- (CH.2Car) + Piz 1-541 Η -CH = CH- -c (= 0)---4 -(CH2CH20Car) -l-Piz 1-542 Η -CH = CH--C (= 0)--4-(CH2CH2F) -Bu Piz 1-543 Η -CH = CH- -C (= 0)-- 4-Mor 5 1-544 Η -CH = CH--c (= 0)-1,3-Azt--C00H 1-545 Η -CH = CH- -c (= 〇)-1,3-Az t --so3h 1-546 Η -CH = CH- 1,3-Azt--0S03H 1-547 Η -CH = CH- -C (= 0)-1,3-Azt--〇P〇A 1-548 Η -CH = CH- -c (= 0)-1,3-Azt-1-Azt 10 1-549 Η -CH = CH- -C (= 0)-1,3-Azt-1-Py.rd 1-550 Η -CH = CH--C (= 0)-1,3-Azt-1-Pip 1-551 Η-CH = CiK -c (= 0)-1,3-Azt-1-Piz 1 -552 Η -CH = CH- -C (= 0)-1,3-Az t-4-Me-l-Piz 1-553 Η -CH = CH- -c (= 0)-1,3-Az t-4-(CH2CH2OH) + Piz 15 1-554 Η -CH = CH- -c (= 0)-1,3-Azt-4-Mor 1-555 Η -CH = CH- -c (= 0) -1,3-Azt--MMe 1-556 Η. -CH = CH--c (= 0)-1,3-Az t--NMe2 1-557 Η -CH = CH--c (= o) -1,3-Az t — -Li eCH2CH2OH 1-558 Η -CH = CH--c (= 〇)-1,3-Azt--Li eCH2CH2CN 20 1-559 Η -CH di CH--c (= o)-1,3-Az t--Li eCH2Car 1-56 0 Η -CH = CH--c (= o)-1,3-Azt--NMeCH2CH2Car 1-561 Η -CH = CH- _ (:( ♦ 1,3-Az t-4iMeCH2CH20Car 1-562 Η -CH = CH- _c (= o)-1, 3 ~ Az t--_2CH20H) 2 1-563 Η -CH = CH- -c (= 0)-1,4-Pip--C00H 25 1-564 Η- CH = CH- _c (= o)-1,4-Pip--so3h 1-565 Η -CH = CH--c (= o)-1,4-Pip--oso3h 1-566 Η -CH: CH --c (= 0)-1,4-Pip--opo3h2 1-567 Η -CH = CH--c (= 〇)-1,4-Pip-1-Azt 1-568 Η -CH = CH- -C (= 0)-1,4-Pip-1-Pyrd 30 1-569 Η-c (: 〇)-1,4-Pip-1-Pip

-59- 200410948 1-570 H -CH = CH- -CH)-1,4-Pip-1-Piz 1-571 H -CH = CH- -CH)-1,4-Pip-4-Me-l -Piz 1-572 H -CH = CH- -C (= 0)-1,4-Pip-4- (CH2CH20H) -l-Piz 1-573 H -eH = CH- -C (= 0)-1 , 4-Pip-4-Mor 5 1-574 H -CH = CH- -c (= 0)-1,4-Pip--NHMe 1-575 H -CH = CH- -c (= 0)-1 , 4-Pip--Li e2 1-576 H -CH = CH- -c (= o)-1,4-P ip--NMeCH2CH2OH 1-577 H -CH = CH- -c (= o)-1 ? 4-P ip--NMeCH2CH2CN 1-578 H -CH = CH- -c (= 0)-1,4-Pip--eCH2Car 10 1-579 H -CH = CH- -c (= o)- 1,4-Pip--NMeCH2CH2Car 1-580 H -CH = CH- -C (= 0)-1,4-Pip--Li eCH2CH2OCar 1-581 H -CH = CH- -c (= 〇)-1 , 4-Pip--N (CH2CH2OH) 2 1-582 H -CH = CH- -c (= 0)-1,4-Pip -CH2--C00H 1-58.3 H -CH = CH- -c (= 0)-1,4-Pip -CH2--0S03H 15 1-584 H -CH = CH- _C (= 0)-1,4-Pip ~ CHr -0P03H2 1-585 H -CH = CH- -c ( = 0)-1,4-Pip -CH2:-1-Azt 1-586 H -CH = CH- -C (= 0)-1,4-Pip -CH2:-1-Pyrd 1-587 · H- CH = CH- -c (= 0)-1,4-Pip -CH2-1-Pip 1-58.8 H -CH = CH- ~ C (= 0)-1,4-Pip -CH2 「4-Me- HPiz 20 1-589 H -CH = CH- -c (= 0)-1,4-Pip -CH2 r 4- (CH2CH20H) -l-Piz 1-590 H ~ CH = CH- -c (= 0)-1,4-Pip -CH, factory 4-Mor 1-591 H -CH = CH--c ( = 〇)-1,4-Pip -CH, factory -nh2 1-592 H -CH = CH- -c (= o)-1,4-Pip-(¾ r -NHMe 1-593 H -CH = CH --c (= 0)-1,4 ~ Pip -CE 「~ NMe2 25 .1-594 H -CH = CH--c (= 〇)-1,4-Pip -CH: r. -LiCH2CH2OH _ 1-595 H -CH = CH--C (= 0)-1,4-Pip -CH: r • -N (CH2CH2OH) 2 1-596 H -CH2CHr ~ C (= 0)-1,4-Piz -, 2Li 2 1-597 H -CH = CH- -C (= 0)-1,4-Piz -CH2CHr 1-Azt 1-598 H -CH = CH- -c (= 0)-1,4 -Piz -CH2CH2- 1-Pyrd 30 1-599 H -CH-CH- -c (two 0)-1,4-Piz -CH2CHr 1-Pip.

-60- 200410948 1-600 H -CH = CH- -c (= o)-1,4-Piz -CH2CHr 1-Piz 1-601 H -CH = CH- -c (= o)-1,4- Piz -CH2CHr 4-Me-l-Piz 1-602 H -CH di CH- -CH)-1,4-Piz -CH2CHr 4- (CH2CH20H) -l-Piz 1-603 Η -CH di CH- -C (= 0)-1,4-Piz -CH2CHr 4-Mor 5 1-604 H -CH = CH- -CH)---4- (CH2CH2NHAc) -l-Piz • 1-605 H -CH = CH- -CH))-1,4-Piz -CH2CHr -NHMe 1-606 Η -CH: CH- -CH)-1,4-Piz -CH2CHr -NMe2 1-607 H _CH = CH- -C (= 0) -1,4-Piz -CH2CHr .- NMeCH2CH20H 1-608 H -GH = CH- -c (= 0)-1,4-Piz -CH2CHr -N (CH2CH2OH) 2 10 1-609 Η -CH2--0 -One- l-Me-3-Azt 1-610 Η -CHr-0---Bu (CH2CH2OH) -3-Azt Bu 611 CH -CHr -0---l- (CH2CH2NHAc) -3-Azt 1- 612 Η -CHr -0---4-Pip. 1-613 Η-CH2--0---Bu Me-4-Pip 15 1-614 H -CH2- -0- one,-1- (CH2CH20H) -4-Pip 1-615 H -CH2 ~ -0-.--L- (CH2CH2NHAc) -4-Pip 1-616 H -CHr, -0---ch2--C00H 1-617 H -CH2-- 0---CH2CHr -C00H 1-618 H -CHr-0- -CH2CHr -so3h 20 '1-619 H-CH2- -0----CH2CH factory-0S03H 1-620 H -CHr-0- one- CH2CHr-SO wind 1 621 H -CHr -0---CH2CHr -opo3h2 1-622 H -CHr -0- one-CH2CHr 1-Azt 1-623 H -CH2--0---CH2CHr 1-Pyrd 25 1-624 H-CH2 --0- 1 ~ CH2CHr 1-Pip 1-625 H -CH2- -0- — -CH2CHr 1-Piz 1-626 H -CHr-0---CH2CHr 4-Me-l-Piz 1-627 H- CH2- -0--CH2CHr _ 4- (CH2CH2OH)-1-Piz 1-628 H -CH2- -0---CH2CHr 4-Mor 30 1-629 H -CH2--0---CH2CHr-NMe2- 61-200410948 1-630 H -CHr -0---CH2CH2- -NMeCH2CH2OH 1-631 Η -CHr -0-one-CH2CH2- -N (CH2CH2OH) 2 1-632 Η -CHr -0- 1,4- cHx--NMe2 1-633 Η -CHr -0- 1,4-cHx _ -NMeCH2CH2OH · 5 1-634 Η -CHr -0-1,4-cHx--N (CH2CH20H) 2 1-635 Η -CHr -0- 3,1 -Azt--so2nh2 1-636 Η _CHr -0- 3,1 -Az t-3-Azt 1-637 Η -CHr -0-3,1 -Azt-1-Me-3- Azt 1-638 Η-CHr -0-3,1 -Azt-l- (CH2CH20H) -3-Azt .10 i 1-639 H-CHr-0- 3,1 -Az t-4-Pip · 1- 640 H _CHr -0- 3,1-Azt-l-Me-4-Pip 1-641 Η -CHr -0-3,1-Az t-1- (CH2CH20H) -4-Pip 1-642 Η -CHr -0-3,1 -Azt-CH2CH2-'1-Azt 1-643 Η -CHr -0- 3 ,. 1-Azt -CH2 CHr 1-Pyrd 15 1-644 Η -CHr -0-3,1-Az t-CH2CH2- 1-Pip 1-645 Η -CHr-0- 3,1 -Azt -CH2CH2 ~ '1-Piz 1-646 Η-CHr -0-3,1 -Az t-CH2CH2- 4-Me -1 -P iz 1-647 H -CHr-0- 3, l ~ Az t -CH2CHr 4- (CH2CH20H) -l-Piz 1_648 H -CH2--0- 3,1-Az t -CH2CH2- 4-Mor. I 20 1-649 H -CH2- -0- 3,1-Azt -CH2CH2- -NHMe 1-650 H _CHr -0- 3,1 -Az t-CH2CH2- -NMe2 1-651 H -CHr -0-3, · 1-Azt -CH2CH2- -surface eCH2CH20H. 1-652 H-CH2--0-3, l ~ Az t- CH2CH factory_N (CH2CH2OH) 2 1-653 H-CHr -0-4,1-Pip--so2nh2 25 1-654 H -CHr -0-4,1-Pip-3-Azt 1-655 H _CH2- -0-4,1-Pip-1-Me-3-Azt 1-656 H-CHr -0-4,1-Pip-Bu (CH2CH2OH)-3-Azt Bu 657 H -CHr -0-4,1 -Pip-4-Pip 1-658 H-CH2 ~ -0-4,1-Pip-1-Me-4-Pip 30 1-659 H -CHr -0-4, 1-Pip-l- (CH2CH2OH) -4-Pip -62- 200410948 1-660 H -CHr -0- 4,1-Pip one ch2ch2- 1-Azt 1-661 H ~ CH2 ~-0- 4,1-Pip -ch2ch2- 1-Pyrd 1 -662 H -CHr.-0- 4,1-Pip -ch2ch2- 1-Pip 1-663 H -CHr -0- 4,1-Pip -CH2CHr HPiz 5 1-664 H -CHr -0- 4,1 -Pip -CH 2CHr 4-Me-l-Piz 1-665 H -CHr 4,1-Pip -ch2ch2- 4- (CH2CH20H) -l-Piz 1-666 H -CHr 4,1-Pip -ch2ch2- 4-Mor 1- 667 H -CHr -0- 4,1-Pip-CH2CHr-NHMe 1-668 H -CHr -0-4,1-Pip -CH2CH2- -NMe2 10 1-669 H -CHr -0- 4,1-Pip -ch2ch factory-LiCH2CH2OH 1-670 H -CHr -0- 4,1-Pip-CH2CHr-N (CH2CH2OH) 2 671 H -CHr -NHC (= 0)-—-ch2- -C00H 1-672 H -CHr -NHC (= 0)-One-CHr -so3h 1-673 H -CHr-NHCO0)-One- CH2- -0S03H 15 1-674 H-CHr-NHC (= 0)-One- ch2--〇 p〇3h2 1-675 H-CH2--NHC (= 0)---ch2- 1-Azt 1-676 H -CHr-NHCO0)--CHR 1-Pyrd 1-677 H ~ CH2 * ·-NHC (= 0)---ch2- 1-Pip 1-678 H -CHr-NHC (= 0)--CHr 4-Me-l-Piz 20 1-679 H -CHr -NHC (= 0)--- CH2- 4-(CH2CH2OH) -l-Piz 1-680 H -CHr -NHC H)---CH2-4-Mor 1-681 H -CHr -NHC (= 0)-one-CH2- · -circle e2 1-682 H -CHr -NHC (= 0)-mono-CHr. -Band eCH2CH2OH 1-683 H -CHr, -NHC (= 0)---CHr -N (CH2CH2OH) 2 25 1-684 H -CHr -NHC (= 0)---ch2ch2- .-C00H 1-685 H -CHr-NHC (= 0)---CH2CHr -SO3H 1-686 H -CHr -NHC (-0)----CH2CHr -OSO3H 1-687 H -CHr-NHC (= 0)---ch2ch2- -opo3h2 1-688 H-CHr -NHC (= 0)-one-ch2ch 「 1-Azt 30 1-689 H -CHr -NHC (= 0)-a-ch2ch2- 1-Pyrd 63- 200410948

1-690 Η -CHr -Li c (= 〇)---ch2ch2- 1-Pip 1-691 Η Female-Li c (= o)--ch2ch2- 4-Pip 1-692 Η-ch2- -NHCH )--ch2ch2- 1-Me-4-Pip 1-693 Η -ch2- -NHC (= 0) ---- -ch2ch2- 1-Piz 5 1-694 Η-ch2--NHC (= 0)-- -CH2CHr 4-Me-l-Piz 1-695 Η -CHr -Li C (two)-.-CH2CHr 4-(CH2CH2OH) -Bu Piz 1-696 Η -CHr -NHC (= 0)-- CH2CHr 4-Mor 1-697 Η -cv-NHC (= 0)--One ch2ch2- -Li e2 1-698 Η One CHr -NHC (= 0)--ch2ch2- -Li eCH2CH2OH 10 1-699 Η- CHr -NHC (= 0)--ch2ch2- -N (GH2CH2OH) 2 1-700 Η -CH2--wake up eC (= 0)----CHr -C00H 1-701 Η -ch2- -Li eC (= 0)--CH2--so3h 1-702 Η-ch2_ -NMeC (= 0)--CHr-oso3h 1-703 Η -ch2- -Li eCOO)--ch2- -〇p〇3h2 15 1 -704 Η-CHr -Li eC (= 0)--. Mai 1-Azt 1-705 Η -ch2- -Li eC (= 0)--ch2- 1-Pyrd 1-706 Η-ch2_ -Li eC (= 0)--Dance 1 -Pip 1-707 Η-ch2- -Circle eC (= 0)---CHr 4-Me-l-Piz 1-708 Η -ch2-jMeCOO)-One CH2- 4 -(CH2CH20H) -1 Piz 20 1-709 Η -CH2- -Li eC (= 0)---ch2- 4-Mor 1-710 Η-ch2-, MeC (= 0)- --ch2--NMe2 1-711 Η -ch2- -Li eC (= 0)---ch2- -Li eCH2CH2OH 1-712 Η -ch2- -NMeC (= 0)--ch2- -N (CH2CH20H ) 2 1-713 Η -ch2- -Li eCOO)--~ CH2CHr-C00H 25 1-714 Η -ch2- -Bae eC (= 0)---CH2CHr -so3h 1-715 Η ~ ch2- -NMeC ( = 0)---CH2CHr -0S03H 1-716 Η -ch2- -NMeC (Service--CH2CHr -0P0A 1-717 Η-ch2--匪 eC (= 0)---CH2CH2- 1-Azt 718718718 Η -ch2- -NMeC (two 0)---ch2ch 「1-Pyrd 30 1-719 Η -CHr -Circle eC (= 0)--ch2ch2- 1-Pip 64-200410948 1-720 Η -ch2-- Rei eC (= 0)---CH2CHr 1-Piz 1-721 Η -ch2- -Circle eC (= 0)---ch2ch2- 4-Me-l-Piz 1-722 Η-ch2- -Li eC ( 0)---ch2ch2- 4- (CH2CH20H) -1-Piz 1-723 Η-ch2- -band eC (= 0)--ch2ch2- 4-Mor 5 1-724 Η-ch2--Li eC (Tue 0)----ch2ch2- -NMe2 1-725 Η -CHr-Bandit eC (= 0)--ch2ch2- -iiMeCH2CH20H 1-726 Η _CH2--Li eC (= 0)---CH2CHr -N (CH2CH2OH) 2 1-727 Η-ch2ch factory_C (= 0) NH---ch2- -C00H 1-728 Η -CH2.CHr -CH) NH-- -CH2CHr -C00H 10 1-729 Η -ch2ch2 --C (= 0) Li--ch2ch2- -so3h 1-730 Η-CH2CHr -C (= 0)-- -CH2CHr -0S03H 1-731 Η -CH2CH2--C (= 0) NH---CH2CHr -〇p〇3h2 1-732 Η ~ CH2CHr-C (= 0) NH---ch2c.h2- 1-Azt 1-733 Η -ch2ch2- -C (= 0) NH---ch2ch2- 1-Pyrd 15 1-734 Η -ch2ch2- -C (= 0) NH---CH2CHr • 1-Pip 1-735 Η- CH2CHr-C (= 0) NH-- -CH2CH2- 4-Me-l-Piz 1-736 Η -CH2CH2--C (= 0) album--ch2ch2- 4- (CH2CH20H) -l-Piz 1- 737 Η -ch2ch2--C (= 0) NH-- -ch2ch factory 4-Mor 1-738 Η -ch2ch2- -C (= 0) NH---ch2ch2_ -Li e2 20 1-739 Η-CH2CHr -C (= 0) NH-- -CH2CHr -BaeCH2CH2OH 1-740 Η -ch2ch2--C (= 0) NH-- -CH2CHr -N (CH2CH2OH) 2 1-741 Η-CH2CHr _C (= 0) NMe-- -CHr-C00H 1-742 Η -ch2ch2- -C (= 0) wake up e---CH2CHr-C00H 1-743 Η One ch2ch factory -C (= 0) circle e----CH2CHr -SO3H 25 1-744 Η-CH2CHr _C (= 0) NMe_--CH2CHr -oso3h BU745 Η -CH2CH2- -C (= 0) NMe— -CH2CHr-〇p〇3h2 1-746 Η -ch2ch2_-C (= 0) NMe-- -CH2CHr 1-Azt 1-747 Η ~ CH2CHr -CHWMe——-CH2CHr 1-Pyrd 1-748 Η -ch2ch2- -C (two 0) NMe—— -CH2CH2- 1-Pip 30 1-749 Η -CH2CHr- C (-0) NMe-- -ch2ch2- 1-P iz 65- 200410948

1-750 Η -ch2ch2- -CHMMe- _ -ch2ch2- 4-Me-l-Piz 1-751 Η -CH2CHr -C (= 0) Li e---CH2CH2- 4- (CH2CH20H) -l-Piz 1 -752 Η -CH2CHr -C (= 0) Li e-- -ch2ch2- 4-Mor 1-753 Η -CH2CHr -C (= 0) turn e---ch2ch2- -NHMe 5 1-754 Η -CH2CHr- C (= 0) _e_--ch2ch2- -NMe2 • 1-755 Η -CH2CH2- -C (= 0) plane e---ch2ch2- -Li eCH2CH20H 1-756 Η -ch2ch2- -C (= 0) e—— -ch2ch 「-N (CH2CH2OH) 2 1-757 Η -CH- = 2. =: l-Me-4,4-Pip 1-758 Η -CH = = = = 1-(CH2CH20H) -4 , 4-Pip 10 1-759 Me 1,4-cHx----C00H 1-760 Me 1,4-cHx —---so3h 1-761 Me 1,4-cHx. —--0S03H 1- 762 Me 1,4-cHx — — one-so2nh2. 1-763 Me 1,4-cHx one one--opo3h2 15 1-764 Me 1,4-cHx one one-1-Azt 1-765 Me 1,4 -cHx--1-Pyrd 1-766 Me 1,4-cHx .One.--1-Pip 1-767 Me 1 ,. 4-cHx-One 4-Pip 1-768 Me 1,4-cHx-One l-Me-4-Pip 20 1-769 Me 1,4-cHx one one-i- (CH2CH2OH)-4 -Pip 1-770 Me 1,4-cHx one-one 1-Piz 1-771 Me 1, 4-cHx — — 4-Me-1-Piz 1-772 Me 1,4-cHx-one one 4- (CH2CH20H) -l-Piz. 1-7 73 Me 1,4-cHx — —-4-Mor 25 1-774 Me 1,4-cHx .---nh2 1-775 Me 1, 4 ~ cHx---NHMe 1-776 Me 1, 4-cHx One — one_NM62 1-777 H 1,4-cHx-— -C00H 1-778 H 1,4-cHx — —--so3h 30 1-779 H 1,4-cHx — —--OSO3H 200410948

1-780 Η 1,4-cHx--· '-s〇2 Rei 2 1-781 Η 1,4-cHx-----0Ρ0Α 1-782 Η · 1,4-cHx--1-Azt 1-783 Η 1,4-cHx 1--1-Pyrd 5 1_784 Η 1,4-cHx---1-Pip 1-785 Η 1,4-cHx---4-Pip 1-786 Η 1, 4-cHx---l-Me-4-Pip 1-787 Η 1,4-cHx---l- (CH2CH2OH) -4-Pip 1-788 Η 1,4-cHx---HPiz 10 1- 789 Η 1,4-cHx--one 4-Me-l-Piz 1-790 Η 1,4-cHx--one 4- (CH2CH2OH) -l-Piz 1-791 Η 1,4-cHx--one 4-Mor 1-792 Η .1,4-cHx--— -nh2 1-793 Η 1,4-cHx----NHMe 15 1-794 Η 1,4-cHx----Calendar e2 1- 795 Me-(CH2) 4-----C00H 1-796 Me-(ch2) 4----SO3H 1-797 .Me-(ch2) 4- ·---OSO3H 1-798 Me-. ( CH2) 4 ~----〇p〇3h2 20 1-799 Me One (ch2) 5-- One- -C00H 1-800 Me-(ch2) 5---One-SO3H 1-801 Me-(ch2 ) 5----OSO3H 1-802 Me-(CH2) 5--—-〇P〇3H2 1-803 Me-(CH2) 3- -C (= 0) NMe-- .-ch2ch 「-so3h 25 1 ~ 804 Me-(CH2) r -C (= 0) NMe-- -ch2ch2- -so3h 1-805 Me-(CH2) 5- -C (= 0) NMe---ch2ch2- -S03H 1-806 M e-(CH2) 6- -C (= 0) Li e---ch2ch2- -S03H 1-807 H ~ (CH2) 4----C00H 1-808 H-(CH2) r----S03H 30 1-809 H-(ch2) 4-----OSO3H 67- 200410948

1-810 Η-(ch2) 4- one — one-〇p〇3h2 1-811 Η-(CH2) 5---one-c_ 1-812 Η-(CH2) 「one-one. -So3h, 1 -813 Η-(ch2) 5-one by one-0S03H 5 1-814 Η-(CH2) 5- one by one-0P03h2 1-815 Η-(ch2) 3- -C (= 0) plane e-- -ch2ch 「-so3h 1-816 Η-(CH2) 4- -C (= 0) PiMe---CHzCHr-so3h 1-817 Η-(ch2) 5- -C (= 0) Me-- -CH2CHr- so3h 1-818 Η-(ch2) 6- -CH) NMe- ~ -CH2CHr-so3h 10 1-819 Me-ch2- -0C (= 0)-one one 4-Pip 1-820 Me -ch2- -0C (-0)-1-Me-4-Pip 1-821 Me-ch2- -0C (= 0)-. -CHr -C00H 1-822 Me-CH`` -0C (= 0)---- CH2--so3h 1-823 Me -ch2--0C (= 0)---ch2- -OSO3H 15 1-824 Me -CHr -0C (= 0)--ch2- -〇p〇3h2 1-825 Me-ch2_ -0C (= 0)---ch2- 1-Azt 1-826 Me -CHr-oc (= o)---ch2- 1-Pyrd 1-827 Me-ch2- -0C (= 0) --ch2-Pip 1-828 Me -ch2_-oc (= 0)----CH factory 4-Pip 20 1-829 Me -CHr -0.C (= 0)---ch2--Pip 1 -830 Me-CH2--ocH)--CV 1-Piz 1-831 Me-ch2--oc (: 〇)----CHr 4-Me-l-Piz 1-832 Me -CH 「_oc (= 0)- --CHr 4- (CH2CH20H) -l-Piz 1-833 Me-ch2_ -oc (: o)---ch2- 4-Mor 25 1-834 Me-ch2- -0C (= 0)--ch2 --Li e2 1-835 Me-CHr -0C (= 0)--ch2- -Circle eCH2CH20H 1-836 Me -CHr -0C (= 0)--ch2- -N (CH2CH2OH) 2 1-837 Me-ch2- -OCH)--ch2ch2--C00H 1-838 Me -ch2- -oc (= 0)---ch2ch2- -SO3H 30 1-839 Me -CHr -oc (-〇)---- CH2CHr -OSO3H 200410948

1-840 Me -CHr -oc (= 0)---ch2ch2--opo3h2 1-841 Me -CHr -oc (= 0)-one-ch2ch2- 1-Azt 1-842 Me -CHr -oc (two 0 )-_-ch2ch2- -1-Pyrd 1-843 Me -CHr -oc (= 0)--ch2ch2- 1-Pip 5 1-844 Me ~ CH2 ~ -oc (= 〇)--ch2ch2- 4 -Pip 1-845 Me-CH2--oc (= 〇)--ch2ch2- l-Me-4-Pip 1-846 Me ~ &quot; CH2 &quot; ~ -oc (= 〇)--ch2ch 「1- Piz 1-847 Me -CH2-.-Oc (= 〇)--CH2CHr 4-Me-1-Piz ί-848 Me -CHr-oc (= 〇)--CH2CHr 4- (CH2CH20H) -l- Piz 10 1-849 Me -CH〗--oc (= 0)---CH2CHr -4-Mor 1-850 Me -CHr -OC (= 0)---CH2CHr -NMe2 1-851 Me -CHr -OC (= 0)---ch2ch2--BanditCH2CH2OH 1-852 Me-CH2- -OC (= 0)-.. ~ CH2CHr -N (CH2CH2OH) 2. 1-853 Me -CH2CH2- -OC (= 0 )---4-Pip 15 1-854 Me -CH2CH2--oc (= o)---1-Me-4-Pip 1-855 Me -CH2CHr -oc (= 0)---ch2--COOH 1-856 Me -CH2CH2- -OC (= 0)-one-ch2- -so3h 1-857 Me -CH2CH2--oc (= o)---ch2- -0S03H 1-858 Me -CH2CHr-0CH)- --ch2- -〇p〇3h2 20 1-859 Me -CH2CH 「-oc (= o)---CH2-1-Azt 1_860 Me -CH2CH「 -0C (= 0)---CHr 1-Pyrd 1-861 Me -CH2CHr-0C (= 0) _.--CHr ip Pip 1-862 Me-CH2CHr -0C (= 0)----CH2-4-Pip 1-863 Me -CH2CHr-oc (= o)---ch2- l-Me-4-Pip 2 ^ 5 1-864 Me -CH2CHr -oc (= o)--ch2- 1-Piz 1-865 Me -CH2CHr -oc (= o)---ch2- 4-Me-1-Piz 1-866 Me -CH2CH 「-oc (= o)--CH2- 4- (CH2CH2OH) -bu Piz 1-867 Me -CH2CH2- -0CH)---ch2- 4-Mor 1-868 Me -CH2CHr -0CH)---ch2--NMe2 30 1-869 Me -CH2CHr -0C (: 0)---ch2-- NMeCH2CH2OH 69- 200410948 1-870 Me -CH2CHr -0C (= 0)-— -CHr -N (CH2CH20H) 2 1-871 Me -CH2CHr -oc (= 0)---ch2ch2--COOH 1-872 Me- CH2CHr -oc (= 〇)-— -CH2CHr-S03H 1-873 Me -CH2CHr -oc (= 0)---ch2ch2--oso3h 5 1-874 Me -CH2CH2- -oc (= o)-one-ch2ch2 --opo3h2 1-875 Me -CH2CHr -OCH)---ch2ch2- 1-Azt 1-876 Me -CH2CHr -oc (= o)---CH2CHr l ~ Pyrd 1-87.7 Me -CH2CHr -oc (= o )-·--CH2CHr P Pip .1-878 Me -CH2CHr -oc (= o)---CH2CHr 4-Pip 10 1-879 Me -CH2CH2--oc (= 0)---CH2CHr • l-Me -4-Pip .1-880 Me -CH2CHr -ocoo)-1 ~ CH2CHr 1-Piz 1-881 Me -CH2CH2- -oc (= o)-mono-CH2CHr 4-Me-l-Piz '1-882 Me -CH2CH 「-oc (= o)-mono-CH2CHr 4- (CH2CH2OH) -1- Piz 1-883 Me -CH2CH2- -〇C (= 0)-one-CH2CHr 4-Mor 15 1-884 Me-CH2CH2- -0C (= 0)---CH2CHr -plane e2 1-885 Me -CH2CH2- _0C (= 0) ~ one- CH2CH 「-NMeCH2CH2OH 1-886 Me -CH2CH2--oc (= 0)-one-ch2ch2- -N (CH2CH2OH) 2 1-887 Me-(CH2) 3- -0C (= 0)--4-Pip. 1-888 Me-(CH2) 3- -OC (= 0)---Bu Me-4-Pip 20 1-889 Me-(CH2) 3--oc (= o) -One- ch2--COOH 1-890 Me-(CH2) 3--oc (: 0)-One-CHr -so3h 1-891 Me-(CH2) 3- -oc (= 0)---ch2- -oso3h 1-892 Me-(CH2) 3- -0C (two 0)-one -CHr-opo3h2 1-893 Me-(CH2) 3- -0C (= 0)---CHr 1-Az t 25 1 -894 Me-(CH2) 3 * ~ -oc (= 〇)---ch2-1-Pyrd 1-895 Me-(CH2) 3--oc (= o)---ch2- 1-Pip 1- 896 Me-(CH2) 3--oc (= o)--Mai 4-Pip 1-897 Me-(CH2) 3- -oc (= 0)---ch2- 1-Me-4-Pip 1- 898 Me-(CH2) 3--oc (= 0)---ch2- 1-Piz 30 1-899 Me-(CH2) 3- -0C (= 0)---ch2- 4-Me-l- Piz 70- 200410948 1-900 Me-(CH2) 3- -〇C (-0)-— -CH2- 4-(CH2CH2OH) -1 -Piz 1-901 Me-(ch2) 3- -OCH)--.-CH 「4-Mor 1-902 Me- (CH2) 3- -OC (= 0)---ch2- -NMe2 1-903 Me-(CH2) 3 ~ ~ 0C (= 0) ~--CHr -Li eCH2CH20H 5 1-904 Me ~ (CH2) 3 ~ ~ 0C (= 0)---CHr -N (CH2CH2OH) 2 1-905 Me-(CH2) 3 ~ ~ 0C (-0)-— -ch2ch2- -C00H 1-906. Me-(CH2) 3 ~ _0C (-0)---CH2CHr -S03H 1-907 Me-(ch2) 3- -oc (二 〇)---CH2CHr-oso3h '1-908 Me-(CH2) 3 ~ ~ OC (= 0)---CH2CHr-〇p〇3h2 10 1-909 Me-(CH2) 3--0C (= 0)---CH2CHr 1-Azt 1-910 Me-(CH2) 3 ~ ~ 0C (= 0 ) ~--ch2ch2- 1-Pyrd 1-911 Me-(CH;) 3_ -〇C (= 0)-One-ch2ch 「1-Pip 1-912 Me-(CH2) 3--〇C (= 0 )-— -CH2CHr 4-Pip 1-913 Me-(CH2) 3 ~ ~ 0C (= 0)---CH2CH2-l-Me-4-Pip 15 1-914 Me-(CH2) 3- -oc ( = 0)-a-ch2ch2- 1-Piz 1-915 Me-(CH2) 3 ~ ~ 0C (= 0) ~--CH2CHr 4-Me-1-Piz 1-916 Me-(CH2) 3 ~ -0C (= 0)-a-ch2ch2- 4- (CH2CH20H) -HPiz 1-917 Me-(CH2) 3 ~ ~ 0C (= 0)--. -CH2CHr 4-Mor 1-918 Me-(ch2) 3- -oc (= o)-—-CH2CHr-_e2 20 1-919 Me-(CH2) 3 ~ &quot; OC (= 0)--_CH2CH2 ~ • -NMeCH2CH2OH 1-920 Me-(CH2) 3--0C (= 0)-One- CH2CHr -N (CH2CH20H) 2 1-921 Me-(CH2) 4 ~ -0C (= 0)-—-4-Pip 1-922 Me-(CH2) 4- -0C (= 0)---1-Me-4-Pip 1-923 Me-(ch2) 4—— och)---ch2--C00H 25 1-924 Me-(CH2) 4- -〇C (= 0) -one-CHr -so3h 1-925 Me-(CH2) 4- ~ 0C (= 0)- --ch2- -0S03H 1-926 Me-(CH2) 4——0CH)--One CHr-opo3h2 1-927 Me-(CH2) 4 ~ ~ * 0C (-0) ~ One-ch2- 1-Azt 1-928 Me-(CH2) 4- -0C (= 0)----CHr 1-Pyrd 30 1-929 Me-(CH2) 4- -oc (two 0)----CHr 1-Pip -71- 200410948

1-930 Me-(ch2) 4--oc (= 0)--ch2- 4-Pip 1-931 Me ~ (ch2) 4- -oc (= 〇)-.-CHr l-Me-4 -Pip 1-932 Me-(ch2) 4- -oc (= o)----CHr 1-Piz 1-933 Me-(ch2) 4-- • OC (= 0)---CHr-4-Me -l-Piz 5 1-934 Me ~ (ch2) 4- -0C (= 0)---CHr 4- (CH2CH20H) -lP.iz 1-935 Me-(ch2) 4--oc (= 〇) ---CHr 4-Mor 1-936 Me-(ch2) 4--OC (= 〇)---ch2- -Circle e2 1-937 Me-(CH2) 4--oc (= 0)---- CHr -NMeCH2CH2OH 1-938 Me-(ch2) 4- -oc (= 〇)--CHr -Ca 2CH2OH) 2 10 1-939 Me (ch2) 4- -OC (= 0)--ch2ch2-- C00H 1-940 Me-(ch2) 4- -oc (= 〇)---ch2ch2- -so3h 1-941 Me-(CH2) r-oc (= 〇)---ch2ch2--oso3h 1-942 Me '-(CH2) 4--oc (= 0)--CH2CHr -〇p〇3h2 1-943 Me-(CH2) 4--oc (= 〇)--CH2CHr 1-Azt 15 1-944 Me ~ (ch2) 4- -oc (= 〇)---ch2ch2- 1-Pyrd 1-945 Me-(ch2) 4--oc (= 〇)---ch2ch2-1-Pip 1-946 Me-( CH2) 4--OCH)--CH2CH2- 4-Pip 1-947 Me-(ch2) r -OC (= 0)---ch2ch2- 1-Me-4-Pip 1-948 Me-(CH2) 4- -oc (= 〇)---ch2ch 「1-Piz 20 1-949 Me-(ch2) 4- -OC (= 0) ---ch2ch2- 4-Me-l-Piz 1-950 Me-(ch2) 4--OCH)--ch2ch2- 4- (CH2CH2OH) -1-Piz 1-951 Me-(ch2) 4-- oc (= 0)---ch2ch2- 4-Mor 1-952 Me ~ (ch2) 4- -oc (= 〇)--ch2ch2- .length 2 1-953 Me-(CH2) 4--oc ( 20) --- CH2CHr -NMeCH2CH20H '25 1-954 Me-(CH2) 4- -oc (= 〇)---CH2CHr -N (CH2CH2OH) 2 1-955 Me -ch = ch-ch2 r -oc (= 0)--4-Pip 1-956 Me -ch = ch-ch5 --oc (= 0) -.--l-Me-4-Pip 1-957. Me -CH ^ CH-CH, r -〇C (= 0)--CHr -C00H 1-958 Me-CH two CH-CH: "-0C (= 0)---ch2_ -so3h 30 1-959 Me -CH two CH-CH; ,-〇C (= 〇)---ch2- -0S03H -72- 200410948 1-960 Me -CH = CH-CH2- -0CH)---ch2--opo3h2 1-961 Me -CH = CH- CHr -oc (= 0)-— _ch2- 1-Azt 1-962 Me -CH = CH-CHr -OCH)--CH2- 1-Pyrd 1-963 Me -CH = CH-CHr -oc (= 〇 )---CHr 1-Pip 5 1-964 Me -CH = CH-CHr -OCH)---CHr 4-Pip 1-965 Me -CH = CH-CHr-00 (= 0)-One-CHr 1 -Me-4-Pip 1-966 Me -CH = CH-CHr -OC (= 0)---CH Factory 1-Piz '1-967 Me -CH = CH-CHr-OC (= 0) _ A- CH2-4-Me-l-Piz 1-968 Me -CH = CH-CH2- -oc (= o)---CH2- 4- (CH2CH20H) -Bu Piz 10 1-969 Me -CH = CH-CH2- -0C (= 0)-—-ch2- 4-Mor 1-970 · Me -CH = CH-CH2- -oc (= o)-a-ch2-, e2 1-971 Me -CH = CH-CHr -0C (= 0)---CHr -NMeCH2CH2OH 1-972 Me -CH = CH-CH2 --oc (= 〇)----CH2- -N (CH2CH2OH) 2 1-973 Me -CH = CH-CHr -OCH)--_ch2ch2_ -COOH 15. · 1-974 Me -CH = CH-CHr -OC (= 0)-— -ch2ch2_ -so3h 1-975 Me -CH = CH-CHr -oc (= 0)-one-CH2CHr -oso3h 1-976 Me -CH = CH-CH2- -och)-- .-ch2ch2_-〇p〇A 1-977 Me -CH = CH-CHr -oc (= 0)-i--CH2CHr 1-Azt 1-978 Me -CH = CH-CHr -oc (= 〇)-- ch2ch2- 1-Pyrd · 20 1-979 Me ~ CH = CH-CHr-oc (= o)---ch2ch2- 1-Pip 1-980 Me -CH = CH-CH2--oc (: 〇)-- -ch2ch2- 4-Pip 1-981 Me-CH = CH-CH2- -0C (= 0) ~--CH2CHr 1-Me-4-Pip .1-982 Me -CH = CH ~ CHr -OCH)-a -CH2CHr 1-Piz 1-983 Me -CH = CH-CHr -oc (= o)-One- CH2CH2- 4-Me ~ l-Piz 25 1-984 Me -CH = CH-CHr -OC (= 0) ---CH2CHr 4 ~ (CH2CH20H) -1-Piz 1-985 Me -CH = CH-CHr -OC (= 0)---CH2CHr 4-Mor 1-986 Me -CH = CH-CHr -〇C ( = 0)-one -ch2ch2- -NMe2 1-987 Me -CH = CH-CHr -oc (= 〇)---CH2CHr -Li eCH2CH2OH 1-988 Me -CH = CH-CHr -OC (= 0)---CH2CH2- -N (CH2CH2OH) 2 30 1-989 Me -CH2CH2- .. -CH) 0- One- 4-Pip 73- 200410948 1-990 Me -CH2CHr -C (= 0) 0---1-Me-4-Pip 1-991 Me -CH2CHr -c (= o) o---CHr -C00H 1-992 Me -CH2CHr -c (= o) o---CHr 4-Pip 1-993 Me -CH2CHr-c (: 〇) 〇-- -ch2- l-Me-4-Pip 5 1_994 Mg -CH2CHr -c (= o) o--CH2CHr-COOH 1-995 Me -ch2ch2- -c (: o) o---ch2ch2--so3h 1 -996 Me -ch2ch2--C (= 0) 0--ch2ch2- -oso3h 1-997 Me -CH2CHr-C (= 0) 0---ch2ch2--〇p〇3h2 1-998 Me -CH2CHr -C (= 0) 〇---ch2ch2- 1 -Az t 10 1-999 Me -ch2ch2--C (= 0) 0---ch2ch 「1-Pyrd 1-1000 Me -ch2ch2--C (= 0) 0---ch2ch2- 1-Pip 1-1001 Me -ch2ch2--C (= 0) 0-&quot; -ch2ch2- 4-Pip 1-1002 Me -ch2ch2- -C (= 0) 〇 ~--GH2CHr 1-Me-4-P ip 1-1003 Me-c.h2ch2--C (= 0) 0-~ -ch2ch2- 1-Piz 15 1-1004 Me-ch2ch 「-C (= 0) 0--- CH2CHr 4-Me-1-Piz 1-1005 Me -ch2ch2--C 00) 0---CH2CH2-4-(CH2CH2OH) + Pi 1-1006 Me-CH2CHr-C (= 0) 0---ch2ch2- 4-Mor 1-1007. Me-CH2CHr-c (= o) o-- -CH2CHr, e2 1-1008 Me -ch2ch2--C (=, 0) 0- —-CH2CHr-ReeCH2CH2OH 20 1-1009 Me -ch2ch2--c (= 〇) 〇---CH2CHr -N (CH2CH2OH) 2 1-1010 Me-(CH2) 3--C (= 〇 ) 〇-- 4-Pip 1-1 Gil Me-(CH2) 3- -C (= 0) 〇---l-Me-4-Pip 1-1012 Me-(CH2) 3- -C (= 0 ) 0---ch2--COOH 1-1013 Me ~ (ch2) 3--C (= 0) 0-~ -CHr 4-Pip 25 1-1014 Me ~ (CH2) 3 ~-C (= 0) 0---CH 「1-Me-4-Pip 1-1015 Me-(CH2)」-C (= 0) 0---ch2ch2- -COOH ί-1016 Me-(CH2) 3--C (= 0) 0 ~--CH2CHr -so3h 1-1017 Me-(CH2) 3- -C (-0) 〇---CH2CHr -0S03H 1-1018 Me-(ch2) 3- -C (= 0) 0- --CH2CHr -opo3h2 30 1-1019 Me-(CH2) 3- -CH) 0---CH2CHr 1-Azt 74- 200410948 1-1020 Me-(CH2) 3--C (: 〇) 〇-- -ch2ch2- 1-Pyrd Bu 1021 Me-(CH2) 3- -c (= o) o-- -CH2CH2_ .1-Pip 1-1022 Me-(CH2) 3- -C (= 0) 0--- ch2ch2- 4-Pip 1-1023 Me-(CH2) 3 ~ -C (= 0) 0---CH2CHr l-Me-4-Pip 5 1-1024 Me-(CH2) 3- -C (= 0) 0---ch2ch2- 1-Piz 1-1025 Me-(CH 2) 3- -C (= 0) 0-- -CH2CHr 4-Me-1-Piz 1-1026 Me-(CH2) 3- -C (= 0) 0---CH2CHr 4- (CH2CH20H) -Bu Piz 1-1027 Me-(CH2) 3- -c (= o) o---ch2ch2- 4-Mor 1-1028 Me-(CH2) 3--c (= o) o---ch2ch2- -Li e2 10 1-1029 Me-(CH2) 3- -C (two 0) 0- one- CH2CHr -band eCH2CH20H 1-1030 Me-(CH2) 3- -C (= 0) 0---CH2CHr -N ( CH2CH20H) 2 1-1031 Me -CH = CH--c (= o) o---4-Pip 1-1032 Me -CH = CH--C (= 0) 0---l_Me-4-Pip 1 -1033 Me -CH = CH- -C (= 0) 〇---ch2- -C00H 15 1-1034 Me -CH = CH- -C (-0) 〇 ~--ch2-4-Pip 1-1035 Me -CH = CH- -C (= 0) 〇--One CH2-l-Me-4-Pip 1-1036 Me -CH = CH--C (= 0) 0---ch2ch2- -C00H 1- 1037 Me-CH = CH- -C (= 0) 0---CH2CHr -S03H 1-1038 Me -CH = CH--c (= o) o---CH2CHr -0S03H 20 1-1039 Me -CH = CH- -C (: 0) 0---CH2CHr -0Ρ0Α 1-1040 Me -CH = CH- -C (= 0) 0---CH2CHr 1-Azt 1-1041 Me -CH = CH- -C ( = 0) 0---CH2CHr l ~ Pyrd 1-1042 Me _CH = CH--C (= 0) 〇- One-CH2CHr 1-Pip 1-1043 Me -CH = CH--C (two 0) 0- --CH2CHr 4-Pip 25 1-1Q44 Me -CH = CH--C (= 0) 0--CH2CHr 1-M e-4-Pip 1-1045 Me -CH = CH--C (= 0) 〇---CH2CH2- 1-Piz 1-1046 Me -CH = CH- -C (= 0) 〇-- -CH2CHr 4 -Me-1-Piz 1-1047 Me -CH = CH- -C (= 〇) 〇---CH2CHr 4- (CH2CH20H) -l-Piz 1-1048 Me -CH = CH- -〇 (= 〇) 〇-- -CH2CHr 4-Mor 30 1-1049 Me · -CH = CH— -C (-0) 0 ~--ch2ch2-, e2 75- 200410948 1-1050 Me -CH = CH- -C (= 0 ) 0- One- CH2CHr -Li eCH2CH2OH 1-1051 Me -CH: CH--C (= 0) 0- One-ch2ch2- -N (CH2CH2OH) 2 1-1052 Η -CHr -oc (= o)-- -4-Pip 1-1053 Η -ch2- -oc (= 0)-One- 1-Me-4-Pip 5 1-1054 Η-CHr -0CH)---CH 「-COOH 1-1055 Η -CHr -oc (= o)---CH 「-so3h 1-1056 Η-CH2--OCH)-_ -ch2- -OSO3H 1-1057 Η-ch2- -oc (= 〇)-one-ch2--〇 p〇3h2 1-1058 Η-ch2--oc (= o)---CHr 1-Az t. 10 1-1059 Η -ch2--oc (= 〇)---ch2- 1-Pyrd BU 1060 Η -CHr -oc (= 〇)---ch2-1-Pip. 1-1061 Η-CHr -oc (= o)---CH2- 4-Pip 1-1062 Η -CH2--oc (= 〇) ---ch2- 1-Me-4-Pip 1-1063 Η -ch2- -oc (= o)-one-ch2- 1-Piz 15 1-1064 Η -ch2- -OC (= 0)-one- ch2- 4-Me-l- Piz 1-1065 Η -CH 「-oc (= o)---CHr 4- (CH2CH20H) -l-Piz 1-1066 Η -ch2- -0C (= 0)-one- ch2- 4-Mor 1- 1067 Η -ch2- -OC (= 0)---ch2- 1-1068 Η-ch2- -OC (= 0)-one- ch2- -LiCH2CH2OH 20 1-1069 Η -ch2 ~ -oc (= o )-A-ch2--N (CH2CH2OH) 2 1-1070 Η -ch2--OC (= 0)-— -CH2CHr -COOH 1-1071 Η -ch2--oc (= 〇)-a-ch2ch2-- so3h 1-1072 Η-CH2--OC (-0)---CH2CHr-oso3h 1-1073 Η-CH2--oc (= o)---CH ^ CH〗-, 〇3H2 25 1-1074 Η- ch2- _oc (= o)---ch2ch2- 1-Azt 1-1075 Η -ch2- -oc (= 〇)---ch2ch2- 1-Pyrd 1-1076 Η-ch2--0C (= 0)- -ch2ch2- 1-Pip 1-1077 Η -CHr-oc (= 〇)-one-ch2ch2- 4-Pip 1-1078 Η-ch2- -OC (-0)---ch2ch2- l-Me-4- Pip 30 1-1079 Η -ch2- -OG (-0)---ch2ch2- 1-Piz 76- 200410948 1-1080 H -CH2- -oc (= 0)---CH2CHr 4-Me-HPiz 1- 1081 H -CHr -OC (= 0)---ch2ch2- 4- (CH2CH20H) -l-Piz 1-1082 H-CHr -oc (= 0)-one-ch2ch2- 4-Mor 1-1083 H -CHr _0C (= 0)-one-ch2ch2- -plane e2. 5 1-1084. H-CHr -OC (= 0)-one-CH2CHr-N MeCH2CH20H 1-1085 H -CHr -〇C (= 〇)-one-CH2CHr -N (CH2CH2OH) 2 1086 H -CH2CH2- -0C (= 0)---. '4-Pip 1-1087 H -CHAV -0C (= 0) -l-Me-4-Pip BU 1088 H -CH2CH``-oc (: 〇)---ch2- -C00H 10 1-1089 H-CH2CH``-oc (= o)- --CHr-so3h 1-1090 H-CH2CH 「-0C (= 0)-One-ch2- -0S03H 1-1091 H -CH2CH2- -0C (= 0)-—-CV-opo3h2 1-1092 H -CH2CHr -oc (= o)-— .-ch2- 1-Azt 1-1093 H -CH2CH2- -〇C (= Q)-— -CHr HPyrd 15 1-1094 H -CH2CHr -0C (= 0)-one- ch2- 1-Pip 1-1095 H -CH2CH2--oc (= 〇)-one-CHr 4-Pip 1-1096 H -CH2CHr -oc (= 〇)---ch2- 1-Me-4-Pip 1 -1097 H -CH2CHr -oc (= 0)---ch2-1-Piz 1-1098 H-CH2CH2--oc (= o)-— -ch2-4-Me-1-Piz 20 1-1099 H- CH2CH2- -OC (two 0)-one -CHr 4- (CH2CH20H) -1 -Piz 1-1100 H-CH2CH2- -OC (-O)--CH2-4-Mor 1-1101 H -CH2CH2- -0C (= 0)--ch2--ying e2 1102 H -CH2CH2- -OC (= 0)---ch2- -circle eCH2CH2OH 1-1103 H -CH2CHr-oc (= 〇)-— -CHr -N ( CH2CH20H) 2 25 1-1104 H -CH2CHr -〇C (= 0)-one -ch2ch2-- C00H 1-1105 H -CH2CH2- -〇C (= 0)---CH2CHr-S03H 1-1106 H -CH2CHr -oc (= o)---CH2CHr -OSO3H 1-1107 H -CH2CH2--oc (= 〇)---ch2ch2- -0P03H2 · 1-1108 H -CH2CHr-OC (= 0)---CH2CHr 1-Azt 30 1-1109 H -CH2CH2--oc (two)--* -ch2ch2- 1 -Pyrd 200410948

1-1110 H -CH2CH2- -0C (= 0)---ch2ch2- 1-Pip 1-1111 H -CH2CH2- -〇C (= 0) ~--ch2ch2- 4-Pip 1-1112 h -ch2ch 「 -oc (two 0)---ch2ch2- 1-Me-4-P ip 1-1113 H -CH2CHr -0C (= 0)---ch2ch2- 1-Piz 5 1-1114 h-ch2ch2--oc ( = o)---ch2ch2- 4-Me-l-Piz '1-1115 H -CH2CHr -OC (= 0)----CH2CHr 4- (CH2CH20H) -Bu Piz 1-1116 H -CH2CH2- -OC ( = 0)---CH2CHr 4-Mor 1-1117 H -CH2CHr -OC (= 〇)---ch2ch2--NMe2 1-1118 H -CH2CHr -OC (= 0)---CH2CHr -NMeCH2CH20H 10 1- 1119 H -CH2CH2- -OC (= 0)---ch2ch2- -N (CH2CH2OH) 2 1-1120 H-(CH2) 3- -OC (= 0)-one-4-Pip 1-1121 H-( CH2) 3- -〇C (= 0)---1-Me-4-Pip 1-1122 H-(CH2) 3- -0C (= 0)---CH2--C00H 1-1123 H-( CH2) 3--OC (= 〇)---CHr-S03H 15 1-1124 H-(CH2) 3- -OC (= 0)---CH2--0S03H — 1-1125 H ~ (CH2) 3_ ~ 0C (= 0)-a-ch2--〇p〇3h2 1-1126 H-(CHZ) 3 ~ ~ 0C (= 0) · *--ch2- 1-Azt 1-1127 H-(CH2) 3 ~ -OC (= 0)-~ ·-ch2-1-Pyrd. 1-1128 H-(CH2) 3--0C (= 0)-—-ch2- 1-Pip 20 1-1129 H-(CH2) "-0C (= 0)---ch2- 4- Pip Bu 1130 H-(CH2) 「-0C (= 0)---ch2- l-Me-4-P.ip 1-1131 H-(CH2) 3--0C (= 0)--.-CHr 1-Piz 1-1132 h- (ch2) 3--oc (= o)---CHr 4-Me-HPiz 1-1133 H-(CH2) 3- -0C (= 0)-one-ch2_ 4- (CH2CH20H) -1-Piz 25 1-1134 H-(CH2) 3--0CH)---ch2_ 4-Mor 1-1135 H-(CH2) 3- -oc (= 〇)-one-CHr -Li e2 1-1136 H-(CH2) 3- -0C (= 0)---ch2_ -Li eCH2CH2OH 1-1137 H-(CH2) 3 * ~ -〇C (= 0) ~--ch2_ -N (CH2CH2OH ) 2 1-1138 H-(CH2) 3--0C (= 0)-One-ch2ch2 · -C00H 30 1-1139 H ~ (CH2) 3 ~ -0C (-0)---ch2ch2- -SO3H 78 -200410948 1-1140 Η-(ch2) 3- -OCH)---ch2ch2- -0S03H 1-1141 Η-(CH2) 3- -OCH)----CH2CHr -opo3h2 1-1142 Η-(CH2) 3--OCH)-—-CH2CHr 1-Azt 1-1143 Η-(CH2) 3--OCH)-—-CH2CHr 1-Pyrd 5 1-1144 Η-(ch2) 「-OCH)-one-ch2ch2- 1-Pip 1-1145 Η-(CH2) 3---ch2ch2- 4-Pip 1-1146 Η-， (ch2) 「--ch2ch2- 1-Me-4 ~ * Ρ ip 1-1147 Η-(CH2 ) 3--OCH)---ch2ch2- 1-Piz 1-1148 Η-(CH2) 「-OCH)---CH2CH2-4-Me-l-Piz 10 1-1149 Η-(CH2) 3-- OCH )---CH2CHr 4- (CH2CH20H) -l-Piz 1-1150 Η-(ch2) 3--oc (Service- -CH2CHr 4-Mor 1-1151 Η-(CH2) 「-oc (= o)- 1-CH2CHr -NMe2 1-1152 Η-(CH2) 3--OCH)-1-CH2CHr -NMeCH2CH2OH 1-1153 Η-(ch2) 3--oc (= 〇)---CH2CHr -n (ch2ch2oh) 2 15 1-1154 Η-(CH2) 4--0C (= 0)-one one 4-Pip 1-1155 Η-(ch2) 4- -oc (= o)-one-l-Me-4-Pip 1 -1156 Η-(ch2) 4--oc (= o)---ch2--COOH 1-1157 Η-(CH2) r-OCH)--ch2 '-SO3H 1-1158 Η •-(CH2) 4--OCH)-1-CHr -OSO3H 20 1-1159 Η-(CH2) 4- -OCH)----ch2- -〇p〇3h2 1-1160 Η-(ch2) 4- -0C (= 0 )---CHr 1-Azt 1-1161 Η ~ (ch2) 4- -0C (= 0) ~--ch2-l ~ Pyrd 1-1162 Η-(ch2) 4- -oc (= o)-— -CH2- Bu Pip 1-1163 Η-(ch2) 4--oc (= o)-One- ch2- 4-Pip 25 1-1164 Η-(CH2) 4- -OCH)---CHr l-Me -4-Pip 1-1165 Η (ch2) 4- -oc (= 〇)-one-CHr 1-Piz 1-1166 Η-(ch2) 4--oc (= o)-one-CH2-4-Me -HPiz 1-1167 Η-(CH2) r-oc (= o)---CHr 4- (CH2CH20H) -l-Piz 1-1168 Η-(ch2) 4- -OCH)---CH2- 4- Mor 30 1-1169 Η-(ch2) 4--0C (= 0)----CHr -Li e2 79- 200410948 1-1170 Η) Γ _oc (= o)---CHr -NMeCH2CH2OH 1-1171 Η- (CH Hill- -oc (= 0)--CH2- -N (CH2CH2OH) 2 1-1172 Η-(CH2) 4- -0CH)---CH2CHr -C00H 1-1173 Η-(CH2) r- 0CH)---CH2CHr-so3h 5 1-1174 Η パ CH2) 「-oc (= 0)--ch2ch2- oso3h 1-1175 Η-(ch2) 4- ~ 0C (= 0)--'一 ch2ch2_ -〇p〇3h2 '1-1176 Η-(called 4- -oc (= 0)-one-CH2CHr 1-Azt 1-1177 Η-(CH2) 4- -oc (= 0)-one-ch2ch2- 1 -Pyrd BU 1178 Η-(CH2) 4--0C (= 0)---ch2ch2- 1-Pip 10 1-1179 Η-(CH2) r -oc (= 0)--ch2ch2- 4-Pip 1 -1180 Η-(CH2) 4--oc (= o)-—— -CH2CHr 1-Me + Pip 1-1181 Η-(ch2) 4--oc (= o)---CH2CH2- 1-Piz 1 -1182 Η-(ch2) 4- -oc (= 0)---ch2ch 「4-Me-l-Piz 1-1183 Η (ch2) 4- -oc (= o)-.--Ch2ch2- 4- (CH2CH20H) -l-Piz 15 Bu 1184 Η-(CH2) 4- -oc (= o)----ch2ch2- 4-Mor 1-1185 Η-(CH2) r-oc (= o)-one-ch2ch2 --Bae2 1-1186 Η -Wr.-Oc (= o) _--ch2ch2- -LiCH2CH20H bu 1187 Η-(ch2) 4--oc (= o)---ch2ch 「- N (CH2CH20H) 2 1-1188 Η -CH = CH-CH r -oc (= 0)-a 4-Pip 20 1-1189 Η -CH = CH-CH 2- -0C (= 0)--- 1-Me-4-Pip 1-1190 Η -CH = CH-CH r -0C (= 0)--ch2- -C00H 1-1191 Η -CH = CH-CH 2--oc (= o)- --CHr-so3h 1-1192 Η -CH = CH-CH r -oc (= 0)---CHr-oso3h 1Ί193 Η -CH = CH-CH 2- -oc (= 0)--CHr-〇 p〇3h2 25 1-1194 Η -CH = CH-CH r -oc (= 0)--CH2-1-Azt 1 1195 Η -CH = CH-CHr -0C (= 0)---ch2- HPyrd 1-1196 Η -CH = CH-CH r -oc (= 0) -.--ch2- 1-Pip 1-1197 Η -CH-CH-CH r -oc (= 0)--CHr 4-Pip 1-1198 Η -CH = CH-CH r -0CH)--CHr l-Me-4-Pip 30 1-1199 Η -CH = CH-CH 2 ~ -oc (= o)---ch2- 1 -Piz -80 200410948

1-1200 Η -CH = CH_CH2--0C (= 0)-~ -CHr 4-Me-l-Piz 1-1201 Η -ch = ch-ch2- -oc (= o)---ch2- 4 ~ (CH2CH2OH) -l-Piz 1-1202 Η -CH CHCH-CHr -0CH)---CHr 4-Mor 1201203 CH -CH CHCH-CHr -0C (二 0)--ch2- ._NMe2 5 1-1204 Η -CH = CH-CH2--〇C (= 0)-~ -CHr-wake eCH2CH20H 1-1205 Η -CH-CH-CHr -OC (= 0)--ch2- -N (CH2CH20H ) 2 1-1206 Η -ch = ch-ch2- -OC (= 0)---ch2ch2 · --C00H Bu 1207, Η-CH = CH_CH2_ -0C (= 0)--ch2ch2 --so3h 1- 1208 Η-ch = ch-ch2--0C (= 0) -— -ch2ch2- -0S03H 10 1-1209 Η -CH = CH_CH2-—0C (= 0)---ch2ch2.-1-1210 Η- CH = CH-CHr -0C (= 0)---ch2ch2 ·-1-Azt 1-1211 Η -CH = CH-CHr -0C (= 0)---ch2ch2_-HPyrd 1-1212 Η -CH = CH -CH2-_0C (= 0)---ch2ch2- 1-Pip BU 1213 Η -CH = CH-CHr -0C (= 0)---ch2ch2_ 4-Pip 15 1-1214 ΗCH = CH-CH2- -0C (= 0)--ch2ch2 ·-l-Me-4-Pip BU 1215 Η -CH = CH-CH2- -0C (= 0)--ch2ch2_ 1-Piz 1-1216 Η -ch = ch -ch2- -oc (= 0)---ch2ch2. 4-Me-l-Piz BU 1217 Η -CH = CH-CHr ~ 0C (= 0)--ch2ch2. -4- (CH2CH2OH) + Piz 1 -1218 Η -C H = CH-CHr -0C (= 0)---ch2ch2 ·-4-Mot 20 1-1219 Η -CH = CH-CHr -0C (= 0)---ch2ch2. --Ye2 1-1220 应-CH = CH-CHr -0C (= 0)--ch2ch2 · -NMeCH2CH2OH 1-1221 Η-CH = CH-CHr -0C (two 0)---ch2ch2 · -N (CH2CH20H) 2 1-1222 Η -CH2CHr -C (= 0) 0---4-Pip 1-1223 Η-CH2CH2--C (= 0) 0---1-Me-4-Pip 25 1-1224 Η-CH2CH2--C ( = 0) 〇---CHr-j C00H 1-1225 Η ~ CH2CHr -C (= 0) 0- -CH2- 4-Pip 1-1226 Η -CH2CH2-: c (= o) o---CH2 -1-Me-4-Pip 1-1227 Η -CH2CHr-C (= 0) 0---CH2CHr -C00H 1-1228 Η -CH2CH2--C (two 0) 0---CH2CH2- -SO3H 30 1 -1229 Η • ~ CH2CH2 ~ ~ c (-〇) 〇-- -ch2ch2- -OSO3H 200410948 1-1230 H -CH2CHr _C (= 0) 0-- -ch2ch2- -opo3h2 1-1231 H -CH2CH2--C (= 0) 0---ch2ch2- 1-Azt 1-1232 H-CH2CHr -C (= 0) 0---ch2ch2- 1-Pyrd 1-1233 H -CH2CH2- -C (= 0) 0-- -ch2ch2- 1-Pip 5 1-1234 H -CH2CHr -c 〇0) 0---ch2ch2- 4-Pip 1-1235 H-CH2CH "-c (= o) o---ch2ch2- l-Me- 4-Pip 1-1236 H -CH2CHr-C (= 0) 0-one -ch2ch2- l ~ Piz 1-1237 H-CH2CH2_ -C (= 0) 0---c h2ch2- 4-Me-l-Piz 1-1238 H -CH2CHr -c (= o) o---CH2CHr 4-(CH2CH20H) -HPiz 10 1-1239 H -CH2CH2- -c (= o) o-- -CH2CHr 4-Mor 1-1240 H -CH2CHr -C (= 0) 〇---CH2CHr-NMe2 1-1241 H -CH2CHr -C (= 0) 0-- -ch2ch2- -plane eCH2CH20H 1-1242 H _CH2CH2 --C (= 0) 0---ch2ch 「-n (ch2ch2oh) 2 1-1243 H-(CH2) 3--c (= o) o---4-Pip 15 1-1244 H-(CH2 ) 3--c (= o) o---l-Me-4-Pip 1-1245 H-(CH2) 3- -c (= o) o---CHr -C00H 1-1246 H-(CH2 ) 3- -C (= 0) 0---ch2- 4-Pip 1-1247 H-(CH2) 3- -C (= 0) 0---ch2- 1-Me-4-Pip BU 1248 H -(CH2) r-C (= 0) 0-— -CH2CHr-C00H 20 1-1249 H-(CH2) 3--c (= o) o---CH2CH2--so3h 1-1250 H-(CH2 ) 3_ -c (= o) o-- -CH2CHr -0S03H 1-1251 H-(CH2) 3--C (= 0) 0- _ -CH2CHr -〇p〇3h2. · 1-1252 H-(CH2 ) "-C (= 0) 0_--ch2ch2- 1-Azt 1-1253 H-(CH2)" -c (= o) o---ch2ch2- 1-Pyrd 25 1-1254 H-(CH2) r -C (= 0) 0---ch2ch2- 1-Pip BU 1255 H-(CHI- -c (= o) o---ch2ch2- 4-Pip BU 1256 H-(CH2) 3--c (: o) o---CH2CHr 1-Me-4-Pip 1-1257 H-(CH 2) 3- -c (: o) o---CH2CHr 1-Piz 1-1258 H-(CH2) 3--C (= 0) 0---CH2CHr 4-Me-l-Piz 30 BU 1259 H -(CH2) 3- -c (= o) o---ch2ch2- 4- (CH2CH20H) -HPiz -82- 200410948 1-1260 Η-(CH2) 3- -C (= 0) 0- one-CH2CHr 4-Mor 1-1261 Η-(CH2) 3- -CH) 〇---ch2ch2- -NMe2 1-1262 Η-(CH2) 3- -C (= 0) 0---ch2ch2- -NMeCH2CH2OH 1- 1263 Η-(CH2) 3--c (= o) o- a-ch2ch2- -N (CH2CH2OH) 2 5 .1-1264 Η -CH di CH- -C (-0) 〇--a 4-Pip 1-1265 Η -CH = CH--CH) 0--1-Me-4-Pip 1-1266 Η -CH = CH- -C (= 0) 0---CHr-C00H 1-1267 Η -CH = CH- -C (= 0) 0---CHr 4-Pip 1-1268 Η -CH = CH- -c (= 0) 0-.--Ch2- 1-Me-4-Pip 10 1-1269 Η -CH = CH- -c (= o) o---ch2ch2--COOH 1-1270 Η -CH = CH--C (two 0) 0- one-CH2CHr-so3h 1-1271 Η -CH = CH --C (= 0) 0---ch2ch2- -0S03H 1-1272 Η -CH = CH- -C (= 0) 0---ch2ch2--0P03H2. 1-1273 Η-CH = CH '-C (= 0) 〇---CH2CHr 1-Azt 15 1-1274 Η -CHtCH- -C (= 0) 0---CH2CHr 1-Pyrd 1-1275 Η -CH = CH--C (two 0) 0 -One -ch2ch2- 1-Pip BU 1276 Η -CH = CH- -C (= 0) 0-one- CH2CHr '4-Pip 1-1277 Η -CH = CH- -C (= 0) 0 ~ One -CH2CHr l-Me-4-Pip 1-1278 Η -CH = CH--C (= 0) 0-One -CH2CHr 1-Piz 20 1-1279 Η -CH = CH- -c (= o) o--CH2CHr 4-Me-HP iz 1-1280 Η -CH = CH- -C (= 0) 0- One- CH2CHr 4- (CH2CH20H) -l-Piz 1-1281 Η -CH di CH_ -C (= 0) 〇- mono-CH2CH2-4-Mor. 1-1282 Η -CH = CH- -c (= o) o -One-CH2CH2- -NMe2 1-1283 Η -CH = CH--C (= 0) 0- One-ch2ch2--NMeCH2CH2OH 25 1-1284 Η -CH = CH- ~ C (= 0) 0 ~-- ch2ch〆-N (CH2CH20H) 2 1-1285 Me-CH2CHr -CH)-1,4-Pip -CH2CHr -NHMe 1-1286 Η-CH2CHr ~ C (= 0)-1,4-Pip-CH2CHr -NHMe 30 Table 2 -83- 200410948 〇R1〇

〇A〇A〇Al1_g_l2_l3_a 5 Exemplified R1 -L1- Compound No.-G--L2--L3-. -A 2-1 Me -CH2----1-Pyrd 2-2 Me -CHr---1- Pip 2-3 Me -CHr--1-Me-4-Pip 10 2-4 Me -CHr-1-l- (CH2CH2OH) -4-Pip 2-5 Me -CHr-1- 4-Me-1 -Piz 2-6 Me -CHr-One one 4-(CH2CH2OH) -Bu Piz 2-7 Me -CHr---4-Mor 2-8 Me -CHr-One one -nh2 15 2-9 Me -CHr ----NHMe 2-10 Me -CH2-----awake e2 2-11 Me -CH2CH2-----C00H 2-12 Me -CH2CH2-----〇〇〇〇 2-13 Me- CH2CH2-- one_-l-Pyrd 20 2-14 Me -CH2CH2-- — one-Pip 2-15 Me ~ CH2CH2-- one- l-Me-4-Pip 2-16 Me -CH2CHr-one-1 -(CH2CH20H) -4-Pip 2-17 Me -CH2CH2-- one, one 4-Me-l-Piz 2-18 Me -CH2CHr--one 4- (CH2CH20H) -l-Piz 25 2-19 Me- CH2CH2-- Mon- 4-Mor 84- 200410948 2-20 Me -CH2CHr — 2-21 Me -CH2CHr — 2-22 Me -CH2CHr-2-23 Me-(CH2) 3- — 5 2-24 Me-( CH2) 3--2-25 Me -CH2CHr -c (= 0)-2-2 6 Me -CH2CHr -C (-0)-2-27 Me -CH2CH2--c (= 〇)-2-28 Me -CH2CH2- -c (= 0)-1 0 2-29 Me -CH2CHr -c (= o)-2-30 Me -CH2CHr -c (= o)-2-31 Me -CH2CH2_ -c (= o)-2-32 Me -CH2CHr -c (, -2-33 Me -CH2CHr-c (= 〇)-15 2-34 Me -CH2CHr-c (= o)-2 ^ 35 Me -CH2CHr.-CH)-2-36 Me -CH2CHr -c (= o )-2-37 Me -CH2CHr -c (= 0)-2-38 Me -CH2CHr -c (= 〇)-20 2-39 Me -CH2CHr -c (= 0)-2-40 Me -CH2CHr -c (= 〇)-2-41 Me -CH2CHr -C (= 0)-2-42 Me -CH2CH2_-c (= o)-2-43 Me -CH2CHr -C (= 0)-25 2-44 Me- CH2CHr -c (= o)-2-45 Me -CH2CHr -c (= 〇)-2-46 Me -CH2CHr -c (= 0)-2-47 Me -CH2CHr -c (= 〇)-2-48 Me -CH2CHr -C (= 0)-30 2-49 Me -CHoCHo- -c (= 0)-— — -nh2 —-NHMe — —, e2---C00H-1-〇P〇A — — l -Piz one 4 ~ (C (^ NH) .NH2) -1-Piz one-. 4- (C (= NH) CH3) -1-Piz one 4- 4-Me-l-Piz one one 4- ( CH2CH20H) -l-Piz--4- (CH2CH2NHAc) -l-Piz -4- (CH2Car) + Piz-4- (CH2CH20Car) -l-Piz —-4- (CH2CH2F) -Bu Piz 1,3- Azt--C00H 1,3-Azt--0S03H 1,3-Az t--OPO3H2 1,4-Pip--C00H 1,4-Pip--so3h 1,4-Pip--OSO3H 1,4-Pip --〇p〇3h2 1,4-Pip-1-Pyrd 1,4-Pip-1-Pip 1,4-Pip-4-Me-HP iz 1,4-Pip-4-(CH2CH2OH) -Bu Piz 1,4-Pip-4-Mor 1,4-Pip-.-NHMe 1,4-Pip--Li e2 1,4-Pip--Li eCH2CH2OH 1,4-Pip--N (CH2CH2OH) 2- 85- 200410948

2-50 Me * ~ CH2CH2--. (Tue 0)-1,4-Pip-ch2--C00H 2-51 Me -CH2CHr -CH)-1,4-Pip -ch2--so3h 2-52 Me -CH2CH2- -C (= 0)-1 , 4-Pip -CH2- -0S03H 2-53 Me -CH2CH2——C (= 0)-1,4-Pip -ch2- -opo3h2 5 2-54 Me -CH2CH2 · &quot; -C (= 0)- 1,4-Pip-CHr 4-Mor 2-55 Me -CH2CH2—C (= 0)-1,4-Pip -ch2- -nh2 2-56 Me -CH2CH2- -C (= 0)-1,4 -Pip-ch2- -NHMe 2-57 Me -CH2CH2- ~ C (= 0)-1,4-Pip -CHr, Me2 2-58 Me -CH2CHr -C (= 0)-1,4-Pip -CHr -NMeCH2CH2OH 10 2-59 Me -CH2CHr -C (= 0)-1,4-Pip -ch2- -N (CH2CH20H) 2 2-60 Me -CH2CHr -C (= 0)-1,4-P iz a -so2nh2 2-61 Me -CH2CHr -C (= 0)-1,4-Piz-ch2ch2- 1-Azt 2-62 Me -CH2CHr -C (= 0)-1,4-Piz -ch2ch 「1-Pyrd 2-63 Me -CH2CHr -C (= 0)-1,4-Piz-CH2CHr 1-Pip 15 2-64 Me -CH2CH2- -C (= 0)-1,4-P iz-CH2CH2- 4-Me -l-Piz 2-65 Me -CH2CHr -C (= 0)-1,4-Piz -CH2CHr 4- (CH2CH20H) -l-Pi: 2-66 Me -CH2CH2- -C (= 0)-1, 4-Piz -ch2ch2- 4-Mor 2-67 Me -CH2CHr ~ C (= 0)-1,4-Piz -ch2ch2- -NHMe 2-68 Me -CH2CH2--. (= 0)-1,4- Piz -ch2ch2- -NMe2 20 2-69 Me -CH2CHr -C (= 0) ~ 1,4-Piz -CH2CHr -Li eCH2CH20H 2-70 Me-CH2CH2——C (= 0)-1,4-Piz -ch2ch2- -N (CH2CH20H) 2 2-71 Me -CH = CH- -C ( = 0)---1-Piz 2-72 Me -CH = CH- -C (= 0) ~ 1- 4- (C (= NH) NH2) -l-Piz 2-73 Me -CH = CH- -C (= 0)-One- 4- (C (= NH) CH3) -1-Piz 25 2-74 Me -CH = CH- -C (= 0)-One- 4-Me-HPiz 2-75 Me _CH = CH- _C (= 0)--4- (CH2CH2OH) -1-Piz 2-76 Me -CH-CH- -C (= 0)-a-4-. (CH2CH2NHAc) -l-Piz 2 -77 Me -CH = CH- -C (= 0)-one-4- (CH2Car) -l ~ Piz. 2-78 Me-CH = CH——C (= 0)-—-4- (CH2CH20Car) -l-Piz 30 2-79 Me -CH-CH- -C (= 0)-1,3-Az t--C00H -86- 200410948

2-80 Me -CH = CH- _C (two 0)-1, 3 ~ Az t--oso3h 2-81 Me -CH = CH- -C (= 0)-1,3-Azt--opo3h2 2- 82 Me -CH = CH--C (= 0)-1,4-Pip — -C00H 2-83 Me -CH = CH--0 (= 0)-1,4-Pip -SO3H 5 2-84 Me -CH = CH--C (= 0)-1,4-Pip--OSO3H 2-85 Me -CH = CH- -C (= 0)-1,4-Pip--opo3h2 2-86 Me -CH = CH- -C (= 0)-1,4-Pip-1-Pyrd 2-87 Me -CH = CH- -C (= 0)-1,4-Pip-1-Pip 2-88 Me-CH = CH——C (= 0)-1,4-Pip-4-Me-1-Piz 10 2-89 Me -CH = CH- -C (= 0)-1,4-Pip 4- (CH2CH20H) -l-Piz 2-90 Me -CH = CH- -C (= 0)-1,4-Pip-4- (CH2CH2NHAc) -l-Piz 2-91 Me -CH = CH- -C (= 0) -1,4-Pip-4-Mor 2-92 Me -CH = CH- -C (= 0)-1,4-Pip--NHMe 2-93 Me -CH = CH- -C (= 0)- 1,4-Pip I-iiMe2 15 2-94 Me -CH = CH- -COO)-1,4-Pi.p I-Li eCH2CH2OH 2-95 Me -CH ^ CH- -C (= 0)-1 , 4-Pip a-N (CH2CH20H) 2 2-96 Me -CH = CH- -C (= 0)-1,4-Pip Mai-C00H 2-97 Me -CH = CH- -C (= 0) -1,4-Pip ~ ch2- -OSO3H 2-98 Me -CH = CH- -C (= 0)-1,4-Pip -ch2_ -〇p〇3h2 20 2-99 Me -CH = CH-- C (= 0)-1,4-Pip-ch2-4-Mor 2-100 Me -CH = CH- -C (= 0)-1,4-Pip -CH r 2-101 Me -CH = CH- -C (= 0)-1,4-Pip-CHr -NHMe 2-102 Me -CH = CH——C (= 0)-1,4-Pip-ch2- -NMe2 2-103 Me -CH = CH- -C (= 0)-1,4-Pip-ch2--BanditCH2CH20H ， 25 2-104 Me -CH: CH- -C (= 0)-1,4 -Pip -ch2- -N (CH2CH2OH) 2 2-105 Me -CH2CHr -C (= 0)-1,4-Piz--so2nh2 2-106 Me -CH = CH- -C (= 0)-1, 4-Piz -CH2CHr 4-Mor 2-107 Me -CH = CH- -C (= 0)-1,4-Piz-CH2CH2- -NHMe 2-108 Me -CH di CH- -C (: 0)- 1,4-Piz -ch2ch2- -NMe2 30 2-109 Me -CH = CH- -CH)-1,4-Piz -ch2ch2- -NMeCH2CH2OH -87- 200410948 2-110 Me -CH: CH- -C ( = 0)-1,4-Piz -CH2CHr -N (CH2CH20H) 2 2-111 Me -CHr -NHC (= 0)---CHr 4-Me-l-Piz 2-112 Me -CHr -NHC (= 0)---CHr .4- (CH2CH20H) -Bu Piz 2-113 Me -CH2- · -Li C (= 0)--One CH2- -Li e2 5 2-114 Me -CHr -NMeCH)-One -CH〗-4-Me-l_Piz 2-115 Me -CHr -NMeC (= 0)-.- -CH2- 4- (CH2CH20H) -l -Piz 2-116 Me -CH2- -Li eC (= 0) ---CHr -NMe2 2-117 Me -CH2CH2- -C (= 0) Li e---ch2ch2- -cooh 2-118 Me -CH2CH2- -C (= 0) Li e- ·--ch2ch2-- so3h 10 2-119 Me -CH2CHr -C (= 0),---CH2CH2- -N Me2 2-120 H -CHr---1-Pyrd 2-121 H -CH2- ·---1-Pip 2-122 H-CHr---1-Me-4-Pip 2-123 H -CHr- -1- (CH2CH20H) -4-Pip 15 2-124 H -CHr---4-Me-l-Piz 2-125 H -CHr--4- (CH2CH20H) -Bu Piz 2-126 H -CHr- --4-Mor 2-127 Ή -CHr----nh2 2-128 Η -CHr--*--ΝΗΜθ 20 2-129 H-CHr----NMe2 2-130 H-CH2CH2----- -C00H 2-131 H -CH2CHr----〇P〇3H2 2-132 H -CH2CHr---1-Pyrd 2-133 H -CH2CHr---1-Pip 25 2-134 H -CH2CHr-one- l-Me-4-Pip 2-135 H -CH2CH2----1- (CH2CH20H) -4-Pip 2-136 H -CH2CHr---4-Me-1-Piz 2-137 H -CH2CHr-- -4- (CH2CH20H)-1-Piz 2-138 H -CH2CH2----4-Mor 30 2-139 H -CH2CH2——---Leg 2 88- 200410948 2-140 H -CH2CH2----- -NHMe 2-141 Η -CH2CH2-----circle e2 2-142 Η-(CH2) 3-- one- -C00H 2-143 h- (ch2) 3-----〇p〇3h2 5 2 -144 H -CH2CHr -C (= 0)----l-Piz 2-145 H -CH2CH2- -C (= 0)-—-4-(C (= NH) NH2) + Piz 2-146 H- CH2CH2- -C (= 0)-a- 4- (C (= NH) CH3) -1-Piz 2-147 H-CH2CH2—COO)- -4-Me-l-Piz 2-148 H -CH2CH2——C (= 0)----4- (CH2CH20H) -l-Piz 10 2-149 H -CH2CH2- -C (= 0)-one- 4- (CH2CH2NHAc) -1-Piz 2-150 H -CH2CHr -C (= 0)-one- 4- (CH2Car) ~ l-Piz 2-151 h-ch2ch2--coo)---4- (CH2CH20Car ) -l-Piz 2-152 H -CH2CH2- -C (: 0)-a-4- (CH2CH2F) -l-Piz 2-153 • H -CH2CHr -C (= 0)-1,3-Az t --C00H 15 2-154 H -CH2CH2- -C (= 0)-1, 3 ~ Az t--0S03H 2-155 H -CH2CH2- -C. (: 0)-1, 3 * ~ Az t- -〇p〇3h2 2-156 H -CH2CH2- -C (= 0)-1, 4-Pip--C00H 2-157 H -CH2CHr -C (= 0)-1,4-P ip--S03H 2-158 H -CH2CH2--C (= 0)-. 1,4-Pip--oso3h 20 2-159 H -CH2CHr -C (= 0)-1,4-Pip--〇P〇3H2.2. 2 -160 h-ch2ch2--c (= o)-1,4-Pip-1-Pyrd. 2-161 H -CH2CHr -C (= 0)-1,4-Pip-1-Pip 2-162 H- CH2CHr -C (= 0)-1,4-Pip-4-Me-l-Piz 2-163 H -CH2CHr ~ CH) ~ 1,4-Pip-4- (CH2CH20H) -1-Piz 25 2-164 H -CH2CHr -C (= 0)-1,4-Pip-4-Mor 2-165 H -CH2CHr -C (= 0)-1,4-Pip--NHMe 2-166 H -CH2CHr -C (= 0) ~ 1,4-Pip--NMe2 2-167 H _CH2CH2- -C (= 0)-1,4-Pip--NMeCH2CH2OH 2-168 『-CH 2CH2- -C (two 0)-1, 4-Pip--N (CH2CH20H) 2 30 2-169 H -CH2CHr -C (two 0)-1, 4-Pip -ch2- -cooh -89- 200410948

2-170 H -CH2CHr -C (= 0)-1,4-Pip -ch2- -so3h 2-171 H -CH2CHr -C (-0)-1, 4-Pip -ch2- -oso3h 2-172 H -CH2CHr -C (= 0)-1,4-Pip -ch2--〇P〇3H2 2-173 H -CH2CHr -C (= 0)-1,4-Pip _CHr 4-Mor 5 2-174 H- CH2CH2- -C (= 0)-1,4-Pip _ch2- -nh2 2-175 H -CH2CHr -C (= 0)-1,4-Pip-ch2--NHMe 2-176 H -CH2CH2——C (= 0)-1,4-Pip -CHr -NMe2 2-177 H -CH2CHr -C (= 0)-1, 4-Pip-CHr .-LiCH2CH2OH 2-178 H -CH2CH2——CH)-1 , 4-Pip -CHr -N (CH2CH2OH) 2 10 2-179 H -CH2CHr -C (= 0)-1,4-Piz--so2nh2 2-180 H -CH2CHr -C (= 0)-1,4 -Piz -ch2ch2- 1-Azt 2-181 H -CH2CHr -C (= 0)-1,4-Piz -ch2ch2- 1-Pyrd 2-182 H -CH2CHr -C (= 0)-1,4-Piz -CH2CHr 1-Pip 2-183 H -CH2CH2--C (= 0)-1,4-Piz-CH2CH 「4-Me-1-Piz 15 2-184 H -CH2CH2- -CH)-1,4- Piz-ch2ch 「4- (CH2CH20H) -1-Piz 2-185 H -CH2CHr -C (= 0)-1,4-Piz -ch2ch2- 4-Mor 2-186 H -CH2CH2- -C (= 0) -1,4-Piz -ch2ch2_ -NHMe 2-187 H -CH2CH2--C (= 0)-1,4-Piz -CH2CHr, e2 2-188 .H -CH2CHr -C (= 0)-1,4 -Piz -CH2CHr -NMeCH2CH20H 20 2-189 H -CH2CHr -C (= 0)-1,4-Piz -ch2ch2- -N (CH2CH20H) 2 2-190 H -CH-CH- -C (= 0)-one- 1-Piz 2-191 H -CH = CH --C (= 0)---4- (C (= NH) NH2) -l-Piz 2-192 H -CH = CH- -C (= 0)---4- (C (= NH) CH3) -1-Piz 2-193 H -CH = CH- -C (= 0)-One_4_Me-1-P iz 25 2-194 H -CH = CH——C (= 0)---4 -(CH2CH2OH) -l-Piz 2-195 H _CH = CH- -CH)-one-4- (CH2CH2NHAc) -l-Piz 2-196 H -CH = CH- -C (= 0)--one 4 -(CH2Car) -1-Piz 2-197 H -CH = CH- -C (= 0)----4- (CH2CH20Car) -l-Piz 2-198 H -CH: CH- -C (two 0) -1,3-Az t--C00H 30 2-199 H -CH: CH- -CH)-1,3 ~ Az i -OSO3H

-90 200410948 2-200 Η -CH = CH- -C (= 0)-1,3-Azt--opo3h2 2-201 H -CH = CH- -C (= 0)-1,4-Pip-- C00H 2-202 H -CH = CH- -C (= 0)-1,4-Pip-_so3h 2-203 H -CH = CH- -C (= 0)-1,4-Pip — -oso3h 5 2 -204 H -CH = CH——C (= 0)-1,4-Pip a-opo3h2 • 2-205 H -CH = CH- -C (-0)-1,4-Pip a · 1-Pyrd 2-206 H-CH = CH ---- C (: 0) _ 1,4-Pip-1-Pip 2-207 H -CH = CH- -C (= 0)-1,4-Pip-4-Me -1-Piz 2-208 H -CH = CH- -C (= 0)-1,4-Pip-4- (CH2CH20H) -HPiz 10 2-2.09 H -CH = CH——C (= 0)- 1,4-Pip-4- (CH2CH2NHAc) -l-Piz 2-210 H -CH = CH- -C (= 0)-1,4-Pip a 4-Mor 2-211 H -CH = CH- ~ C (= 0)-1,4-Pip ·--NHMe 2-212 H -CH two CH- -C (= 0)-1,4-Pip--Li e2 .2-213 H -CH = CH— --C (= 0)-1,4-Pip--BanditCH2CH2OH 15 2-214 H -CH = CH- -C (= 0)-1,4-Pip--N (GH2CH20H) 2 2-215 H- CH = CH- -C (= 0)-1,4-Pip -ch2- -C00H 2-216 H -CH = CH- -C (= 0)-1,4-Pip -ch2--oso3h 2-217 H -CH = CH- -C (= 0)-1,4-Pip -ch2--opo3h2 2-218 H-CH = CH--C (= 0)-1,4-Pip -ch2- 4-Mor 20 2-219 H -CH = CH- _C (= 0)-· 1,4-Pip-ch2--NH2 2-220 Ή _CH = CH- -C (= 0)-1,4-Pip -CHr -NHMe, 2-221 H -CH = CH- -C (= 0)-1,4-Pip-ch2-, e2 2-222 H -CH = CH- -C (= 0)-1,4-Pip-ch2- -Wake eCH2CH2OH 2-223 H -CH = CH- -C (= 0)-1,4-Pip- CHr -N (CH2CH2OH) 2 25 2-224 H -CH2CHr -C (= 0)-1,4-Piz a -so2nh2 2-225 H ~ CH = CH- -C (= 0)-1,4-Piz -ch2ch2- 4-Mor 2-226 H -CH = CH- -C (= 0)-1,4-Piz -ch2ch2--NHMe 2-227 H -CH: CH——C (: 0)-1, 4-Piz -ch2ch2--NMe2 2-228 H -CH two CH ---- C (two 0) _ 1,4-Piz -ch2ch2- -Li eCH2CH20H 30 2-229 H -CH two CH- -C (: 0 )-1,4-Piz-ch2ch2- -N (CH2CH2OH) 2 200410948 2-230 H -CHr -NHC (= 0)---CHr 2-231 H -CHr -NHC (= 0)---CHr 2 -232 H-CH2-~ NHC (= 0)----CHr 2-233 H-CH2--Li eC (= 0)---CHr 5 2-234 H -CH2- -Li eC (= 0)- --CHr 2-235 H -CH2- -NMeC (= 0)--ch2-2-236 H: CH2CH2- -C (= 0) NMe-- -ch2ch2- 2-237 H -CH2CHr -C (= 0) Bandit--ch2ch 「2-238 H -CH2CH2- -C (= 0) Lie--ch2ch2- 10 2-239 Me 1,4-cHx--2-240 Me 1,4- cHx .---2-241 Me 1,4-cHx---2-242 Me 1,4-cHx a- -2-243 Me 1,4-cHx One--15 2-244 Me 1,4-cHx--One 2-245 Me 1,4-cHx--One 2-246 Me 1,4-cHx —-One 2-247 Me 1,4 ~ cHx---2-248 Me 1,4-cHx---20 2-249 Me 1,4-cHx---2-250 Me 1,4-cHx-—-2 -251 H 1,4-cHx---2-252 H 1,4-cHx---2-253 H 1,4-cHx---25 2-254 H 1,4-cHx--2-255 H 1,4-cHx---2-256 H 1,4-cHx--one 2-257 H 1,4-cHx —--2-258 H 1,4-cHx one--30 2-259 H 1,4-cHx---4-Me-l-Piz 4-(CH2CH20H) -Bu Piz-NMe2 4-Me-l-Piz 4- (CH2CH20H) + Piz-NMe2

-C00H-S03H -NMe2-COOH _0P03H2 1-Pyrd 1-Pip Me-4-Pip 1- (CH2CH20H) -4-Pip .4-Me-l-Piz 4- (CH2CH20H) -l-Piz 4-Mor -NHMe -Li e2

-COOH -0P03H2 1-Pyrd 1-Pip l-Me-4-Pip (CH2CH2OH) -4-Pip 4-Me-l-Piz 4- (CH2CH20H) -l-Piz 4-Mor -92- 200410948

2-260 H l, 4-cHx one one one-nh2 2-261 Η 1,4-cHx _ one — -NHMe 2-262 Η 1,4-cHx — — one-turn e2 2-263 Me-(CH2 ) r — one — -C00H 5 2-264 Me-(CH2) 4- — one — -SO3H 2-265 Me _ (CH2) 4- — one — -OSO3H 2-266 Me-(CH2) 4 ~ — — Mon-〇p〇3h2 2-267 Me-(CH2) 5- Mon- -C00H 2-268 Me-(CH2) 5- — Mon- -SO3H 10 2-269 Me-(CH2) 5- —-- -OSO3H 2-270 Me-(CH2) 5- one by one-〇p〇3h2 2-271 Me-(CH2) 3_ -CO0) brain e---ch2ch "-SO3H 2-272 Me-(CH2) 4 --C (= 0) Li e---ch2ch2--S03H 2-273 Me-(CH2) 5- _C (= 0) NMe---ch2ch2- -so3h 15 2-274 Me-(CH2) 6- -C (= 0) Li e-- -ch2ch2- -S03H 2-275 H-(CH2) r — —--C00H 2-276 H-(CH2) 4-one_ one one -SO3H 2-277 H- (CH2) 4-— — — -oso3h 2-278 H-(CH2) r one by one -〇p〇3h2 20 2-279 H-(CH2) 5-----C00H 2-280 H-(CH2 ) 5- — —--SO3H 2-281 H-(CH2) 5- One---OSO3H 2-282 H-(CH2) 5-One-one-0P0A 2-283 H-(CH2) 3--C (= 0) Me-- -ch2ch2- -S03H 25 2-284 H-(CH2) r -C (= 0) NMe ~-- CH2CHr-so3h 2-285 H ~ (CH2) r-C (= 0) Li e—— -CH2CHr -so3h 2-286 H-(CH2) 6--C (= 0) Li e-- -CH2CHr -S03H 2-287 Me -CH2CH2- .-0C (-0)--·-l-Me-4-Pip 2-288 Me -CH2CH2--0CH)---CH2- -C00H 30 2-28.9 Me -CH2CH2- -0CH)---ch2--SO3H 93- 200410948 2-290 Me -CH2CHr -0CH)---CHr -0P03h2 2-291 Me -CH2CHr-OC (= 0)-one- ch2- 1-Azt 2- 292 Me -CH2CHr -oc (two 0)-one-CH "1-Pyrd 2-293 Me -CH2CH2- -oc (: 0)-one -CHr 1-Pip 5 2-294 Me -CH2CH2- -oc (= o)---ch2- 1-Me-4-Pip 2-295 Me ~ CH2CHr-ocoo)-one-CHr 4-Me-1-Piz 2-296 Me -CH2CHr -0C (= 0)-one, dance 4-(CH2CH2OH) —Bu Piz 2-297 Me -CH2CHr -0C (= 0)----CHr 4-Mor 2-298 Me -CH2CHr -oc (= 〇)---CHr -NMe2 10 2-299 Me -CH2CH2--oc (= o)-1-ch2- -eCH2CH2OH 2-300 Me -CH2CHr-oc (= 〇)-1 0)-One- ch2ch2- ——COOH. 2-302 Me -CH2CH2- -OC (= 0)-One-ch2ch2- --S03H 2-303 Me -CH2CHr-OC (= 0)-One-ch2ch2.- -〇p〇3h2 15 2-304 Me -CH2CH r -OC (= 0)---ch2ch2- l ~ Azt 2-305 Me -CH2CHr -0C (= 0)-one. -ch2ch2- -1-Pyrd 2-306 Me -CH2CHr -〇C (= 0) -One-ch2ch2 · -1-Pip 2-307 Me -CH2CH 「-oc (= 0)-One: ch2ch2--1-Me-4-Pip 2-308 Me -CH2CHr-oc (= o)-One- ch2ch2 ·-4-Me-1-Piz 20 2-309 Me -CH2CHr-oc (= o)---ch2ch2 · -4- (CH2CH20H) -l-Piz 2-310 Me -CH2CH2- -oc (= 0 )-One-ch2ch2 · -4-Mor 2-311 Me -CH2CH2- -oc (= 0)-One-ch2ch2 · --Li e2 2-312 Me -CH2CHr -0C (= 0)-One-ch2ch2 ·- -Li eCH2CH2OH 2-313 Me -CH2CH2- -oc (= 〇)-One-ch2ch2 · --N (CH2CH2OH) 2 25 2-314 Me-(CH2) 3- -0C (= 0)-One- 1- Me-4_Pip 2-315 Mc-(CH2) 3 ~ -OC (-O)---ch2- -C00H 2-316 Me-(CH2) 3- -oc (= o)-one-ch2- -S03H 2 -317 Me-(CH2) 3- -0C (= 0)-one-CHr -〇p〇3h2 2-318 Μθ-(CH2) 3 ~ -oc (= 0)-one- CHr 1-Azt 30 2- 319 Me-(CH2) 3- -oc (-〇)--_ch2- 1-Pyrd 94- 200410948 • 2-320 Me-(CH2) 3 ~ -0CH)--CHr 1-Pip 2-321 Me- (CH2) r -OCH)-— -CHr l-Me-4-Pip 2-322 Me-(CH2) 3- -0C (= 0)-one-ch2-4-Me-1-P iz 2-323 Me-(CH2) 3- -OC (= 0)---CHr 4- (CH2CH20H) -l-Piz 5 2-324 Me-(CH2) 3--oc (= 0)-one &gt; CHr. 4-Mor 2-325 Me-(CH2) 3- -OC (= 0) ~ One- ch2- -Circle e2 2-326 Me-(CH2) 3- -OC (= 0)-One- CHr -NMeCH2CH? OH 2-327 Me- (CH2) 3 di-oc (= o)-mono-ch2- -N (CH2CH20H) 2 2-328 Me-(CH2) 3- -oc (= 0)-— -CH2CHr-COOH 10 2-329 Me- (CH2) r -OC (= 0)-— .-CH2CH2- -so3h 2-330 Me-(CH2) 3- -oc (= 〇)---ch2ch2--〇p〇3h2 2-331 Me-( CH2) 3- -0C (= 0)-One-CH2CHr 1-Azt 2-332 Me _ (CH2) 3- -0C (= 0)-One-ch2ch2- 1-Pyrd 2-333 Me-(CH2) 3 --〇C (= 0)-One.-ch2ch2- 1-Pip 15 2-334 Me-(CH2) 3- -oc (= 0)-One- CH2CHr 1-Me-4-Pip 2-335 Me- (CH2) 3--OCH)--CH2CHr 4-Me-l-Piz 2-336 Με-(CH2) 3 ~-oc (= 0)---CH2CH2- 4-(CH2CH2OH) + Piz 2- 337 Me-(CH2) 3--0C (= 0)---CH2CHr 4-Mor 2-338 Me _ (CH2) 3- -0C (= 0)--CH2CH2- -NMe2 20 2-339 Me- (CH2) 3--oc (= o)-—. —Ch2ch2--banditCH2CH2OH 2-340 Me-(CH2) 3_ -OC (= 0)-.- -ch2ch2- -N (CH2CH2OH) 2 2-341 Me -CH2CHr -c (= o) o-. L-Me- 4 ~ Pip 2-342 Me -CH2CHr -C (= 0) 0---CHr -COOH 2-343 Me -CH2CHr-C (= 0) 0---CH2-l-Me-4-Pip 25 2- 344 Me -CH2CHr -C (= 0) 0---CH2CH2-.-COOH 2-345 Me -CH2CHr -c (= o) o---ch2ch2- -so3h 2-346 Me -CH2CHr -CH) 0- --CH2CHr-opo3h2 2-347 Me -CH2CHr-c (: o) o----CH2CH2- 1-Azt 2-348 Me -CH2CH2- -CH) 0---ch2ch2- 1-Pyrd 30 2-349 Me -CH2CHr -c (two) 〇---CH2CHr 1-Pip 95- 200410948 2-350 Me -CH2CHr -C (= 0) 0---ch2ch2- l-Me-4-Pip 2-351 Me -CH2CH2 --C (= 0) 0-- -ch2ch2- 4-Me-l-Piz 2-352 Me -CH2CH2- -C 〇0) 0---CH2CHr 4- (CH2CH20H) -1-Piz 2-353 Me -CH2CH2- -C (= 0) 0---ch2ch2- 4-Mor 5 2-354 Me -CH2CH2- -C (= 0) 0---ch2ch2- -NMe2 2-355 Me -CH2CH2--C ( = 0) 0---CH2CHr -Li eCH2CH2OH 2-356 Me -CH2CHr -C (= 0) 0-- -ch2ch2- -N (CH2CH20H) 2 2-357 Me -CH = CH- -c (= o) o--.-l-Me-4-Pip 2-358 Me -CH = CH- -c (= o) o---CHr -C00H 10 2-358 Me -CH = CH- -C (= 0) 0-- -ch2- 1-Me-4-Pip 2-35.9 Me -CH = CH- -c (: 0) 0-one.-CH2CHr -C00H 2-360 Me -CH = CH- -C (= 0 ) 0-- -ch2ch2- -so3 h 2-361 Me -CH = CH- -c (= o) o-- -ch2ch2--opo3h2 2-362 Me -CH = CH- -c (= o) o---CH2CHr 1-Azt 15 2- 363 Me -CH = CH- -C (= 0) 0---ch2ch2- 1-Pyrd 2-364 Me -CH = CH- -c (= o) o-one-ch2ch2- HP ip 2-365 Me- CH = CH- -C (= 0) 0---ch2ch2- l-Me-4-Pip 2-366 Me -CH = CH- -C (= 0) 0---ch2ch2- 4-Me-l- Piz 2-367 Me -CH = CH--c (= o) o---ch2ch 「4- (CH2CH20H) -l -Piz 20 2-368 Me -CH = CH--C (= 0) 0-- -ch2ch2- 4-Mor 2-369 Me -CH = CH--C (= 0) 0---ch2ch2- -NMe2 2-370 Me -CH = CH- -〇 (= 〇) 〇---CH2CHr- ReiCH2CH2OH 2-371 Me -CH = CH- -C (= 0) 〇---ch2ch2- -N (CH2CH2OH) 2 2-372 H-CH2CHr-oc (= o)---1-Me-4- Pip 25 2-373 H -CH2CH2- -0C (= 0) ~--CHr -C00H 2-374 H -CH2CH2- -oc (= o)---CH2--so3h 2-375 H -CH2CHr _oc (= 〇)-·--ch2- -OPOA 2-376 H -CH2CH "-oc (= o)---CHr 1-Azt 2-377 H -CH2CH2- -0 (: (♦--ch2- 1-Pyrd 30 2-378 H -CH2CH2- -〇c (二 〇)---ch2-1-Pip 96-200410948 2-379 Η-CH2CH2- -oc (= 0)-— -CHr l-Me-4-Pip 2-380 H -CH2CH2- -oc (= o)---CHr 4-Me -l-Piz 2-381 H -CH2CHr -0C (= 0)---CHr 4- (CH2CH20H) -l-Piz 2-382 H -CH2CH2- -0C (= 0)----CH Factory 4-Mor 5 2-383 H -CH2CHr -oc (= o)--• -ch2-, e2 • 2-384 H -CH2CH2- -oc (= 〇)-— -ch2- -Awake eCH2CH2OH 2-385 H-CH2CH2- -00 (= 0)---CHr -N (CH2CH20H) 2 2-386 H -CH2CH 「-oc (= 0)---CH2CHr -C00H 2-387 H-CH2CH2- -〇C (= 0)- 1-ch2ch 「-so3h 10 2-388 H -CH2CH2- -0C (= 0)---ch2ch2--〇p〇3h2 2-389 H -CH2CH2- -oc (= o)--ch2ch2_ l-Azt 2 -390 H -C.H2CH 「-oc (= o)-One-ch2ch「 1-Pyrd 2-391 H -CH2CH2- -0C (= 0)-One-CH2CHr 1-Pip 2-392 H -CH2CH 「- OC (= 0)---ch2ch2- l-Me-4-Pip 15 2-393 H -CH2CH2--oc (= o)---ch2ch2- 4-Me-l-Piz 2-394 H -CH2CH2- -0C (= 0)---CH2CHr 4- (CH2CH20H) -l-Piz 2-395 H -CH2CHr-oc (= 0)---CH2CHr 4-Mor 2-306 H, -CH2CH2- -OCH)- Mon- _e2 2-397 H -CH2CHr -oc (= o)---CH2CHr-_eCH2CH20H 20 2-398 H -CH2CHr -0C (= 0)-Mon-CH2CH2--N (CH2CH2OH) 2 2-399 Me- (CH2) 3- -oc (= 〇)---1-Me-4-Pip 2-400 Me-(CH2) 3--oc (= o)--~ CH r-C00H 2-401 Mc-(CH2) 3 ~ -oc (= o)---CHr-so3h 2-402 Me-(CH2) 3--oc (= 〇)-one- ch2- -opo3h2 25 2 -403 Me-(CH2) 3- -oc (= o)---CHr l-Azt 2-404 Me-(CH2) 3--oc (= 〇)-one.-CHr 1-Pyrd 2-405 Me -(CH2) 3--oc (= o)-_CH2-1-Pip 2-406 Me-(CH2) 3- -oc (= 〇)----CHr l-Me-4-Pip · 2- 407 Me-(CH2) 3- -oc (-0)-— -CH Factory 4-Me-l-Piz 30 2-408 Me-(CH2) 3- -oc (-0)---CHr 4- ( CH2CH20H) -l-Piz -97- 200410948 2-409 Me-(CH2) 3--oc (= o)-—-CHr 2-410 Me-(CH2) 3- -oc (= 0)---CHr 2-411 Me-(CH2) 3--〇C (= 0)---ch 2- 2-412 Me-(CH2) 3--oc (= 0)----CHr 5 2-413 Me-(CH2 ) 3--oc (= 0)---CH2CHr 2-414 Me-(CH2) 3--oc (= 0)---ch2ch2- 2-415 Me-(CH2) 3--oc (: o) -— (-Ch2ch2- 2-416 Me-(CH2) 3- -0C (-0)---ch2ch2- 2-417 Me-(CH2) 3- -oc (= 〇)---CH2CHr 10 2- 418 Me -Pei) 3--oc (= 0)--, -ch2ch2- 2-419 Me ~ (CH2) 3--0C (= 0) _--CH2CHr 2-420 Me-(CH2) 3-- oc (= 0)--CH2GHr 2-421 • Me-(CH2) 3- -0C (= 0)--ch2ch2_ 2-4 22 Me-(CH2) 3- -oc (= 〇)----CH2CHr 15 2-423 Me-(CH2) 3--oc (= 〇)-_ -CH2CHr 2-424 Me-(CH2) "-oc (= 0)---CH2CHr 2-425 Me-(CH2) 3--oc (= 〇)--ch2ch2- 2-426 H -CH2CHr -C (= 0) 0 ~ —-2-427 H- CH2CHr -c (= o) o--Dance 20 2-428 H -CH2CHr -c (= o) o----CHr 2-429 H -CH2CHr-C (= 0) 0---CH2CHr 2-430 H -CH2CHr-C (= 0) 0---CH2CHr 2-431 H -CH2CHr -c (= o) o----CH2CHr 2-432 H -ch2ch2- _c (= 〇) 〇_--CH2CH2- 25 2 -433 H -CH2CHr -C (= 0) 0---CH2CHr 2-434 H -CH2CHr-C (= 0) 0---CH2CHr 2-435 H-CH2CHr _C (two 0) 0---CH2CHr 2 -436 H-CH2CHr-C (= 0) 0---CH2CH2- 2-437 H -CH2CHr -CH) 0---ch2ch2- 30 2-438 H -CH2CHr -c (= o) o-- -ch2ch2 -4-Μογ -NMe2.

-Li eCH2CH2OH -N (CH2CH2OH) 2 -C00H -S03H-〇〇〇〇3h2 1-Azt 1-Pyrd 1-Pip l-Me-4-Pip 4-Me-l-Piz 4- (CH2CH20H) -l-Piz 4-Mor-NMe2 -Li eCH2CH2OH -N (CH2CH20H) 2 l-Me-4-Pip -C00H 1-Me-4-Pip

-COOH

-S03H -〇p〇3h2 1-Azt 1-Pyrd 1-Pip 1-Me-4_Pip 4-Me-l-Piz 4- (CH2CH20H) -l-Piz 4-Mor 200410948 2-439 H -CH2CHr -CH) 0-- -CH2CHr 2-440 H -CH2CHr -C (= 0) 0---ch2ch2- 2-441 H -CH2CHr-c (o) o----CH2CHr 2-442 · H -CH = CH-- C (= 0) 0---5 2-443 H -CH = CH- -C (= 0) 0---ch2- 2-444 H -CH = CH- -CH) 0-- -ch2- 2 -445 H -CH = CH- -c (= o) o-- -ch2ch2- 2-446 H -CH = CH- · -C (-0) 0-- -ch2ch2- 2-447 H -CH = CH --c (= o) o--_CH2CHr 10 2-448 H -CH: CH- -C (= 0) o---CH2CHr 2-449 H -CH = CH--C (= 0) 0-- -CH2CH 「2-450 H -CH = CH--c (= o) o-- -ch2ch2- 2-451 H -CH = CH- -C (= 0) 0---ch2ch2- 2-452 H. -CH = CH- -C (= 0) o--. -Ch2ch2- 15 2-453 H -CH = CH- -c (: 〇〉 〇-- .- CH2CHr 2-454 H -CH di-CH-- CH) 0---CH2CHr 2-455 H -CH = CH--C (= 0) 0---CH2CH2- 2-456 H -CH = CH--C (= 0) 0---CH2CHr 2- 457 H -CH = CH- -c (= o) o---CH2CH2— 20 -bande2

-NMeCH2CH2OH -N (CH2CH20H) 2 l-Me-4-Pip-C00H l-Me-4-Pip-C00H -S03H -〇p〇3h2 1-Azt 1-Pyrd 1-Pip l-Me-4-Pip 4 -Me-l-Piz 4- (CH2CH2OH) -l-Piz 4-Mor -NMe2 -Li eCH2CH2OH -N (CH2CH2OH) 2 Table 3 O R1 Ο

〇A〇A〇Al1-G—l2-L3-A

-L3--A 25 Exemplified R1-L1- -G--L2- -99- 200410948 Compound No. 3-1 Me -CHr-mono- 1-Pyrd 5 3-2 Me -CHr mono--1-Pip 3- 3 Me _CH2--one-one 1-Me-4-Pip 3-4 Me -CHr one--l- (CH2CH2OH) -4-Pip 3-5 Me -CHr--one 4-Me-l-Piz 3- 6 Me -CHr---4- (CH2CH20H) + Piz 10 3-7 Me -CHr---4-Mor 3-8 Me -CHr-一一 -nh2 3-9 Me -CHr-one -NHMe .3-10 Me -CH plant.-1--NMe2 • 3-11 Me -CH2CHr----C00H. 15 3-12 Me -CH2CHr-—--opo3h2 3 -13 Me -CH2CHr-— 1. 1 -Pyrd 3-14 Me -CH2CHr one by one Pip 3-15 Me -CH2CH2--one — 1-Me-4-Pip 3-16 Me -CH2CHr-one-1- (CH2CH20H) -4-Pip 20 3 -17 Me -CH2CHr---4-Me-1-P iz 3-18 Me -CH2CHr one--4-(CH2CH2OH) + Piz 3-19 Me -CH2CHr —-4-Mor 3-20 Me -CH2CH2- -~-3-21 Me -CH2CHr One---NHMe 25 3-22 Me -CH2CHr One---^ e2 3-23 Me-(CH2) 3--One--COOH 3-24 Me-(CH2) 3- one- one- 〇P〇3H2 3-25 Me ~ CH2CHr-C (= 0)-one- 1-Piz 3-26 Me -CH2CH2- -C (= 0), --4- (C (= NH) NH2) -l-Piz 30 3-27 Me -CH2CHr-C (= 0)-4- (C (: _ CH3) + Piz -100- 200410948 3-28 Me -CH2CHr -c (= o)-— — 4-Me-l-Piz 3-29 Me -CH2CH2- -c (= 0)----4- (CH2CH20H) -l-Piz 3-30 Me -CH2CHr- c (= 0)---4- (CH2CH2NHAc) -l-Piz 3-31 Me -CH2CHr-c (= o)-~-4- (CH2Car) -l-Piz 5 3-32 Me -CH2CH2-- C (= 0)---4- (CH2CH20Car) -l-Piz 3-33 Me -CH2CH2- -c (= 0)----4- (CH2CH2F) -l-Piz 3-34 Me -CH2CH2-- C (-0) 1,3-Az t--C00H 3-35 Me -CH2CHr -c (= 0)-1,3 ~ Az t ~ -0S03H 3-36 Me -CH2CHr -c (= 0)-1 , 3 ~ Az t--opo3h2 10 3-37 Me -CH2CH2- -C (= 0)-1,4-Pip--COOH 3-38 Me -CH2CH2--C (two 0)-1,4-Pip -/ -SO3H 3-39 Me -CH2CH2--c (= o)-1,4-Pip--OSOgH 3-40 Me -CH2CH2- -c (= 〇)-1,4-Pip-• -〇p 〇3h2 3-41 Me -CH2CHr -c (= 0)-1,4-Pip-l-Pyrd 15 3-42 Me -CH2CH2- -c (= 〇)-1,4-Pip-Bu Pip 3-43 Me -CH2CH2--C (= 0)-1,4-Pip-4-Me-1-Piz 3-44 Me -CH2CH2- -c (= o)-1,4-Pip-4- (CH2CH20H)- l ~ Piz 3-45 Me -CH2CH2- -c (= o)-1,4-Pip-4-Mor 3-46 Me -CH2CHr-c ( = o)-1,4-Pip--NHMe 20 3-47 Me -CH2CH2—-c (= 〇)-1,4-Pip--NMe2 3-48 Me -CH2CH2- -c (= o)-1 , 4-Pip--NMeCH2CH2OH 3-49 Me -CH2CH2- -c (= 0)-1,4-Pip ~ -N (CH2CH20H) 2 3-50 Me -CH2CHr -c (= 〇)-1,4- Pip-CH2--COOH 3-51 Me -CH2CHr -c (: 〇)-1,4-Pip -CH2--so3h 25 3-52 Me -CH2CHr -c (= o)-1,4-Pip -CH2 --oso3h 3-53 Me -CH2CH2- -C (= 0)-1,4-Pip -CH2--〇p〇3h2 3-54 Me -CH2CH2- -C (= 0)-. l, 4 ~ Pip .-CH2-4-Mor 3-55 Me -CH2CH2- ~ C (= 0) ~ 1,4 ~ Pip -CH2--νη2 3-56 Me -CH2CHr ~ C (= 0)-1,4-Pip- CH2 --NHMe 30 3-57 Me -CH2CH2--c (= 〇)-1,4-Pip -CH2 -circle e2 -101-200410948 3-58 Me -CH2CHr -C (= 0)-1,4- Pip-CH 「-NMeCH2CH20H 3-59 Me -CH2CHr -C (= 0)-1,4-Pip -CH「 -N (CH2CH2OH) 2 3-60 Me -CH2CH2- -C (= 0)-1,4 -Piz. I- so2nh2 3-61 Me -CH2CHr -C (= 0)-1,4-Piz -ch2ch2- l-Azt 5 3-62 Me -CH2CH2- -C (= 0)-1,4-Piz -CH2CHr 1-Pyrd 3-63 Me -CH2CH2--C (= 0)-1,4-Piz-CH2CHr 1-Pip 3-64 Me -CH2CH2- -C (= 0)-1,4-Piz -CH2CHr 4-Me-HP iz 3-65 Me -CH2CHr -C (= 0)-1,4-Piz -CH2CHr 4- (CH2CH20H) -l-Piz 3-66 Me -CH2CHr -C (= 0)-1,4-Piz -CH2CHr 4-Mor 10 3-67 Me- CH2CH2- -C (= 0)-1,4-Piz -CH2CH2- • -_e 3-68 Me -CH2CH2- -C (= 0)-1,4-Piz -CH2CHr, e2 3-69 Me -CH2CH2- -C (= 0)-1,4-Piz -CH2CHr-BanditCH2CH2OH 3-70 Me -CH2CHr -C (= 0)-1,4-Piz -CH2CH2--N (CH2CH2OH) 2 3-71 Me _CH = CH- -C (= 0)---1-Piz 15 3-72 Me -CH = CH- -C (= 0)-one- 4- (C (= M) NH2) + Piz 3-73 Me- CH = CH- -C (= 0)---4- (C (= NH) CH3) -l ~ Piz 3-74 Me -CH = CH- -C (= 0)-one-4-Me-l -Piz 3-75 Me -CH = CH- -C (= 0)-One-4- (CH2CH2OH) -Bu Piz 3-76 Me _CH = CH- -C (= 0)---4- (CH2CH2NHAc) -l-Piz 20 3-77 Me _CH = CH- _C (= 0)---4- (CH2Car) -1-Piz 3-78 Me -CH = CH- -C (= 0)-one- 4- (CH2CH20Car) -Bu Piz 3-79, Me -CH = CH- -C (= 0)-1,3-Az t a- C00H 3-80 Me -CH = CH- -C (= 0) ~ 1, 3-Azt one -0S03H 3-81 Me -CH = CH- -C (= 0)-1, 3 ~ Az t one-〇p〇3h2 25 3-82 Me ~ CH = CH- -C (= 0) -1,4-Pip —-C00H 3-83 Me -CH = CH- -C (= 0)-1,4-Pip ·--so3h 3-84 Me -CH = CH- -C (= 0)- 1, 4-Pip —-os o3h 3_85 Me -CH = CH- -C (= 0)-1,4-Pip--〇p〇3h2 3-86 Me -CH = CH- -C (= 0)-1, 4-Pip -Pyrd 30 3-87 Me -CH = CH- -C (= 0)-1,4-Pip a 1-Pip 200410948

3-88 Me -CH = CH- -C (= 0)-• 1,4-Pip 4-Me-l-Piz 3-89 Me -CH-CH- -C (= 0)-1,4-Pip -4- (CH2CH20H) -l-Pi.z 3-90 Me -CH = CH- -C (= 0)-1,4-Pip.-4- (CH2CH2NHAc) -l-Piz 3-91 Me -CH = CH- -C (= 0)-1,4-Pip a 4-Mor 5 3-92 Me -CH = CH- ~ C (= 0)-1,4-Pip a -NHMe 3-93 Me -CH = CH- -C (= 0)-1,4-Pip--NMe2 3-94 Me -CH = CH- -C (= 0)-1, 4-Pip-_fiMeCH2CH20H 3-95 Me -CH = CH- -C (= 0)-1,4-Pip--N (CH2CH2OH) 2 3-96 Me -CH = CH- -C (= 0)-1,4-Pip -CHr -C00H 10 3-97 Me- CH = CH- -C (= 0)-1, 4-Pip -ch2- -0S03H · 3-98 Me -CH = CH- _C (= 0)-1,4-Pip -ch2--〇p〇3h2 3-99 Me .-CH = CH- -C (= 0)-1,4-Pip-ch2- 4-Mor 3-100 Me -CH = CH- -C (= 0)-1, 4-Pip- ch2-, 3-101 Me -CH = CH- -C (= 0)-1,4-Pip-CH factory-NHMe 15 3-102 Me -CH = CH- -C (= 0)-1,4- Pip-CHr-NMe2 3-103 Me -CH = CH- -C (= 0)-1, 4-Pip-CH factory--wake eCH2CH20H 3-104 Me -CH = CH- -C (= 0)-1 , 4-Pip-CHr-N (CH2CH2OH) 2 3-105 Me -CH2CH2--C (= 0)-1,4-Piz — -so2nh2 3-106 Me -CH = CH- -C (= 0)- 1,4-Piz-CH2CHr 4-Mor 20 3-107 Me -CH = CH- -C ( = 0) _ 1,4-Piz-ch2ch2_ -NHMe 3-108 Me -CH = CH- ~ C (= 0)-1,4-Piz-CH2CHr -Bae2 3-109 Me -CH = CH- -C (= 0)-1,4-Piz -CH2CHr-NMeCH2CH20H 3-110 Me -CH = CH- -C (= 0)-1,4-Piz-CH2CH 「-N (CH2CH2OH) 2 3-111 Me -CHr -NHC (= 0)-One-CHr 4-Me-l-Piz 25 3-112 Me -CHr -NHC (= 0)-One- ch2- 4-(CH2CH2OH) -l -Piz 3-113 Me -CHr -NHC (= 0) ~ 1-CHr-NMe2 3-114 Me -CHr -Draw eC (= 0)--~ ch2- 4-Me-1-Piz 3-115 Me ~ CHr -NMeCOO)---ch2 ~ 4-(CH2CH2OH) + Piz 3-116 Me -CH2-, eC (= 0)-one-ch2- -NMe2 30 3-117 Me -CH2CH2- -C (= 0) NMe----CH2CHr -C00H 103 -200410948 3-118 Me -CH2CHr -C (= 0) NMe- _ -ch2ch2---so3h 3-119 Me —CH2CH2—-C (= 0) NMe-- -ch2ch2- --NMe2 3-120 H- CHr — * ~ 1-Pyrd 3-121 H -CHr — 1- 1-Pip 5 3-122 H -CHr — ~ •-1-Me-4-Pip 3-123 H -CHr —-1 1-( CH2CH20H) -4HPip 3-124 H -CHr---4-Me-l-Piz 3-125 H -CH2---4- (CH2CH20H) -l ~ Piz 3-126 H -CHr-4-Mor 10 3-127 H -CH 「— —--nh2 3-128 H -CHr-—-_e 3-129 H-CHr ---NMe2 3-130 H -CH2CHr one-one-C00H t 3-131 H -CH2CH2_----10p〇3h2 15 3-132 H -CH2CHr one-one HPyrd 3-133 H ~ CH2CHr one-one 1-Pip. 3-134 H -CH2CHr---1-Me-4-Pip 3-135 H -CH2CH2-One-by-one 1- (CH2CH20H) -4-Pip: 3-136 H -CH2CHr--4- Me-1-Piz 20 3-137 H -CH2CHr — One-one 4- (CH2CH20H) -Bu Piz 3-138 H -CH2CH2_ ~ — 4-Mor 3-139 H -CH2CHr.-—--Nh2 3-140 H -CH2CHr---NHMe 3-141 H-CH2CHr--NMe2 25 3-142 H-(CH2) r -one--C00H 3-143 H-(CH2) 3-one-one--〇p〇3h2 3 -144 H -CH2CHr-c (= o)---1-Piz 3-145 H-CH2CHr -C (= 0)----4- (C (= NH) NH2) -1-Piz 3-146 H -CH2CH2- -C (= 0)---4-(C (= NH) CH3) -Bu Piz 30 3-147 H -CH2CHr -c (= o)---4-Me-HPi z -104- 200410948 1,3-Az t -1, 3 ~ Az t -1,3 ~~ Az t -1,4-Pip-1.4- Pip-1.4- Pip -1, 4-Pip-1.4- Pip-1.4- Pip -1,4-Pip -1,4-Pip-1,4-Pip -1,4-Pip-1.4- Pip-1.4- Pip-1.4- Pip-l, .4 ~ Pip -CHr 1.4- Pip -CH2 -1.4- Pip -CHr 1.4- Pip -C H2-l, 4 ~ Pip ~ CH2 ~ 1.4- Pip -CHr 1.4- Pip -CHr 1.4- Pip -CHr 1.4- Pip -CHr

-4- (CH2CH20H) -l-Piz-4- (CH2CH2NHAc) -HPiz-4-(CH2Car) + Piz -4- (CH2CH20Car) -l-Piz-4- (CH2CH2F) -1-Piz-COOH 3- 148 Η 3-149 Η 3-150 Η 3-151 Η 5 3-152 Η 3-153 Η 3-154 Η 3-155 Η 3-156 Η) 10 3-157 Η 3-158 Η 3-159 Η. 3-160 tt 3-161 Η 15 3-162 Η 3-163 Η 3-164 Η 3-165 Η 3-166 Η) 20 3-167 Η 3-168 Η 3-169 Η 3-170 Η 3-171 Η 25 3-172 Η 3-173 Η 3-174 Η 3-175 Η 3-176 Η 30 3-177 Η-CH2CH2--C (= 0) --CH2CHr -C (= 0)-CH2CHr -C (= 0)-CH2CH2- -C (= 0)-CH2CHr-C (= 0)-CH2CHr-C (= 0)-CH2CH2- -C (= 0)--CH2CHr -C (= 0 )-CH2CHr -C (= 0)-CH2CHr -C (= 0)-CH2CH2- -C (= 0)-CH2CHr -C (= 0)-CH2CHr -C (= 0)-CH2CH2 --C (= 0) --CH2CHr -C (= 0)-CH2CH2- -C (= 0) --CH2CH2- -c (= o) --CH2CHr -C (= 0)-CH2CH2-- c (= o)--ch2ch2- -c (= 〇)--CH2CH2- _c (= o) --CH2CH2- -c (= o) --CH2CHr -c (= 0)-CH2CHr -C (= 0)-CH2CHr -C (= 0)-CH2CH2- -C (= 0) --CH2CHr -C (= 0)-CH2CHr -C (= 0)-~ CH2CHr -C (= 0)- CHXHo- ~ C (-0)--oso3h -〇p〇3h2

-COOH

-S03H

-0S03H

-〇p〇A l-Pyrd 1-Pip 4-Me-1-Piz 4-(CH2CH2OH) -HPiz 4-Mor -NHMe, e2

-NMeCH2CH2OH -N (CH2CH20H) 2 -COOH -SO3H

-0S03H

-〇p〇A 4-Mor-nh2 -NHMe-丽 e2

-Li eCH2CH20H -105-200410948 3-178 H -CH2CHr -C (= 0)-1,4-Pip-CHr -N (CH2CH20H) 2 3-179 H -CH2CHr -C (= 0)-1,4- Piz--so2nh2 3-180 H _CH2CH2- -C (= 0)-1,4-Piz-ch2ch 「1-Azt 3-181 H -CH2CH2_ -C (= 0)-1,4-Piz -ch2ch2- 1 -Pyrd 5 3-182 H -CH2CHr -C (= 0)-1,4-Piz -CH2CHr 1-Pip 3-183 H -CH2CH2- -C (= 0)-1,4-Piz-CH2CHr 4-Me -l-Piz 3-184 H -CH2CH2--C (= 0)-1,4-Piz-CH2CHr 4- (CH2CH20H) -Bu Piz 3-185 H -CH2CH2--C (= 0) _ 1,4 -Piz -ch2ch2- 4-Mor 3-186 H -CH2CHr -C (= 0)-1,4-Piz -ch2ch2- -NHMe 1.0 3-187 H -CH2CH2--(: (♦ 1,4-P iz -ch2ch 「-NMe2 3-188 H -CH2CH2- -C (= 0)-1,4-Piz -CH2CHr -LiCH2.CH2OH 3-189 H -CH2CH2- -C (= 0)-1,4-Piz -CH2CHr -N (CH2CH2OH) 2 3-190 H -CH = CH——C (= 0) _ one one · HPiz 3-191 H -CH = CH- -C (= 0)-one one 4- ( C (= NH) NH2) ~ l ~ Piz 15 3-192 H -CH = CH--. (= 0)---4-(C (= NH) CH3) + Piz 3-193 H_CH = CH—— C (: 0)-Mon- 4 -Me-HPiz 3-194 H -CH = CH- -C (= 0)-Mon-4- (CH2CH20H) ~ l-Piz 3-195 H -CH = CH-- C (= 0)-one-4- (CH2CH2NHAc) -l-Piz 3-196 H -CH = CH——C (= 0)--— 4 — (CH2Car) -l-Piz 20 3-197 H -CH = CH- _C (= 0)-one-4-(CH2CH20Car) + Piz 3 -198 H -CH = CH- -C (= 0)-1, 3 ~ Az t--C00H 3-199 H -CH = CH- -C (= 0)-1, 3-Az t one -0S03H 3 -200 H -CH = CH--C (= 0)-1,3_Az t one -〇P〇3h2 3-201 H -CH = CH- -C (= 0)-1,4-Pip one -C00H 25 3-202 H -CH = CH 1, 4-Pip--so3h 3-203 H -CH = CH- -C (: 0)-1, 4-Pip--OSO3H 3-204 H -CH = CH-- C (two 0)-• 1,4-Pip--〇p〇3h2 3-205 H _CH = CH- -C (= 0)-1,4-Pip — 1-Pyrd 3-206 H -CH = CH --C (= 0)-1,4-Pip-Pip 30 3-207 H -CH = CH- -C (= 0)-1,4-Pip-4: One Me -1-Pi z -106 -200410948

3-208 H -CH = CH- -C (= 0)-1,4-Pip-4- (CH2CH20H) -l-Piz 3-209 H -CH = CH- -C (= 0)-1, 4 -Pip-4- (CH2CH2NHAc) -l-Piz 3-210 H -CH = CH- -C (= 0)-1,4-Pip-4-Μογ 3-211 H -CH = CH- -C (= 0)-1,4-Pip-~ NHMe 5 3-212 H -CH = CH- -C (= 0)-1,4-Pip--Li e2 3-213 H -CH = CH- -C (= 0)-1,4-Pip--NMeCH2CH20H 3-214 H -CH = CH- -C (= 0)-1,4-Pip--Ca 2CH2OH) 2 3-215 H-CH = CH——C ( = 0)-1,4-Pip ~ CHr -C00H 3-216 H-CH = CH--C (= 0)-1,4-Pip -CH2--oso3h 10 3-217 H -CH = CH-- C (= 0)-Ί, 4-Pip -CH2--0Ρ03η2 3-218 H_CH = CH--C (= 0)-1,4-Pip -CHr 4-Mor 3-219 H -CH = CH—— C (= 0)-1,4-Pip -CHr-nh2 3-220 H -CH = CH- -C (= 0)-l, 4_Pip -CH2 ~ -NHMe 3-221 H _CH = CH_ -C (= 0)-1,4-Pip -CH2--_e2 15 3-222 H -CH = CH- -C (= 0)-1,4-Pip-CHr -eCH2CH20H 3-223 H -CH = CH-- C (= 0)-1,4-fip -CHr ~ N (CH2CH2OH) 2 3-224 H -CH2CHr -C (= 0)-1,4-Piz--so2nh2 3-225 H -CH = CH—— C (= 0)-1,4-Piz -CH2CHr 4-Mor 3-226 H-CH = CIi--C (= 0)-1,4-Piz -CH2CHr-NHMe 20 3-227 H -CH = CH_ -C (= 0)-1,4-Piz -CH2CIi2--wake up e2 3-228 H -CH = CH——C (= 0)-1,4-Piz -CH2CHr -surface eCH2CH2OH 3-229 H -CH = CH- -C (= 0) _ 1,4-Piz -CH2CH2 --N (CH2CH2OH) 2 3-230 H -CHr -NHC (= 0)---ch2-4-Me-1-Piz 3-231 H -CHr -NHC (: 0)---ch2- 4- (CH2CH20H) -Bu Piz 25 3-232 H -CHr -NHC (= 0)---CHr • Yili e2 3-233 H -CHr -Li eC (= 0)-— -CHr 4-Me-1- P iz 3-2¾ H -CHr -Yes eC (= 0)---ch2- 4- (CH2CH20H) -l-Piz 3-235 H -CHr -NMeC (= 0)-— -CHr -NMe2 3-236 H -CH2CHr -C (= 0) NMe---ch2ch2- -C00H 30 3-237 H -CH2CH2- -C (= 0) Li e---ch2ch2--S03H -107- 200410948 3-238 H -CH2CHr -C (= 0) Lie-3-239 Me 1,4-cHx-3-240 Me 1, 4-cHx — 3-241 Me 1,4-cHx-5 3-242 Me 1, 4-cHx- 3-243 Me 1,4-cHx-3-244 Me 1,4-cHx-3-245 Me 1,4-cHx-3-246 Me 1,4-cHx-10 3-247 Me 1,4-cHx One 3-248 Me 1,4-cHx One 3-249 Me 1,4-cHx-3-250 Me 1,4-cHx 1 3-251 H 1,4-cHx One 15 3-252 H 1,4 -cHx -3-253 H 1,4-cHx -3-254 H 1,4-cHx -3-255 H 1,4-cHx-3-256 H 1,4-cHx — 20 3-257 H 1, 4-cHx one 3-258 H 1,4-cHx-3-259 H 1,4-cHx-3-260 H 1,4-cHx -3-261 H 1,4-cHx -25 3-262 H 1,4-cHx -3-263 Me-(CH2) 4--3-264 Me-(CH2) 4--3-265 Me-(ch2) 4--3-266 Me-(ch2) 4--3.0 3-267 Me -(ch2) 5---CH2CHr -draw e2

--COOH--〇p〇3h2-1-Pyrd-1-Pip-l-Me-4-Pip

I-Bu (CH2CH20H) -4-Pip a 4-Me-l-Piz-4- (CH2CH20H) -l-Piz-4-Mor a •-· 2--NHMe--surface

--COOH--0P03H2-1-Pyrd-Pip

I-1-Me-4-Pip-1- (CH2CH20H) -4-Pip-4-Me-l-Piz-4- (CH2CH20H) + Piz-4-Mor--NH2--NHMe--NMe2

--COOH

-~ S03H

Mon-0S03H--opo3h2

--COOH -108-200410948 3-268 Me-(CH2) 「---so3h 3-269 Me _ (CH2)」-one--oso3h 3-270 Me-(CH2) 5- one one one-〇P 〇3H2 3-271 Me-(CH2) 3- -COO) surface e-- -ch2ch2--so3h 5 3-272 Me-(CH2) 4- -C (= 0) bande---CH2CHr -so3h 3 -273 Me-(CH2) 5- -C (= 〇) Li e- _ -CH2CHr-S03H 3-274 Me-(CH2) 6- _C (= 0) _e----CH2CHr -so3h 3-275 H- (CH2) 4--one- C00H 3-276 H-(CH2) 4-— ~ one-S03H 10 3-277 H-(CH2) 4---*-• -oso3h 3-278 H-(CH2) 4- ~ one-one-0P〇3hz 3-279 H _ (CH2) 5-----C00H 3-280 H, (CH2) 5- one-one-S03H 3-281 H _ (CH2) 5-- ---OS03H 15 3-282 H-(CH2) r one-to-one-0Ρ0Α 3-283 H-(CH2) 3--CH) NMe---CH2CHr -S03H 3-284 H — (CH2) 4-- C (= 0) NMe—— ~ CH2CHr-S03H 3-285 H-(CH2) 5-~ C (= 0) NMθ ~---CH2CH2--so3h 3-286 H-(CH2) 6--C (= 0) NMe---ch2ch2- -so3h 20 3-287 Me -CH2CH2--oc (= o)-~ 1-Me-4 two Pip 3-288 Me _CH2CH 「-oc (= 0)---ch2 --C00H 3-289 Me -CH2CH2- -oc (= 0)---CHr -SO3H 3-290 Me -CH2CH2--oc (= 〇) ---CH 「-opo3h2 3-291 Me -CH2CHr-0C (= 0)---ch2- 1 -Az t 25 3-292 Me -CH2CHr -〇C (= 0)---ch2-1-Pyrd 3-293 Me -CH2CHr -0C Η)---ch2- 1-Pip 3-294 Me -CH2CHr-oc (= o)---ch2-Bu Me-4-Pip 3-295 Me -CH2CHr -0C ( = 0)---CHr 4-Me-l-Piz 3-296 Me -CH2CH2- -0CH)---CHr 4- (CH2CH20H) -lP.iz 30 3-297 Me -CHoCHo- -0CH)-- -ch2- 4-Mor -109-200410948 3-298 Me -CH2CHr ~ 0C (= 0)-one- CHr -Li e2 3-299 Me -CH2CHr-oc (= 〇)-one one ch2--wake up eCH2Ci ^ 20H 3-300 Me -CH2CH2--oc (two 0)-one-CH "-N (CH2CH2OH) 2 3-301 Me -CH2CH factory -oc (= 〇)-one-ch2ch2- ——COOH 5 3-302 Me -CH2CH2- -oc (= o)---ch2ch2- ——so3h .3-303 Me -CH2CH2--oc (= o)---ch2ch2- --〇p〇3h2 3-304 Me -CH2CHr- oc (= o)-one-ch2ch2- -1-Azt 3-305 Me -CH2CHr -oc (= o)---ch2ch2- -1-Pyrd 3-306 Me _CH2CH2- -oc (= o)-one- ch2ch2 -1-Pip 10 3-307 Me -CH2CHr -0C (= 0)----ch2ch2- -l-Me-4-Pip 3-308 Me -CH2CHr-oc (= 0)-one-ch2ch2-- 4-Me-HPiz 3-309 Me -CH2CHr. -Oc (: o)- -ch2ch2- -4- (CH2CH2OH) -l-Piz 3-310 Me -CH2CHr -oc (= o)-one-ch2ch2- -4-Mor 3-311 Me -CH2CHr-oc (= 〇)-one-ch2ch2 ---NMe2. 15 3-312 Me -CH2CH2- -0C (= 0)---ch2ch2 · --NMeCH2CH2OH 3-313 Me -CH2CHr-oc (: 0)-one-ch2ch2- --N (CH2CH2OH) 2 3-314 Me-(CH2) 3--oc (= o)--Yibu Me-4-Pip 3-315 Me-(CH2) 3- -oc (= o)-One-CHr-COOH 3- 316 Me-(CH2) r-oc (= o)---CH2- -so3h 20 3-317 Me-(CH2) 3 ~ -OC (= 0)---CH Factory-〇p〇3h2 3-318 Me-(CH2) 3- -oc (= o)-. One- CH2- '1-Azt 3-319 Me _ (CH2) 3--oc (= o)-One- ch2- 1-Pyrd 3-320 Me-(CH2) r -0C (= 0) ~--CHr 1-Pip 3-321 Me-(CH2) 3- -0C (= 0)---CHr 1-Me-4-Pip 25 3-3.22 Me _ (CH2) 3- -oc (= o)-one- CH2-4-Me-1-Piz 3-323 Me-(CH2) 3--oc (= o)-one_ch2- 4-(CH2CH2OH ) -Bu Piz 3-324 Me-(CH2) 3- -oc (= o)-One- CH 「4-Mor 3-325 Me-(CH2) 3--OCH)-One- CH2--NMe2 3- 326 Me-(CH2) 3_ -OC (= 0)-—-CHr-NMeCH2CH2OH 30 3-327 Me-(CH2) 3- -0C (= 0)--CHr-N (CH2CH2OH) 2 110- 200410948 3 -328 M e ~ (CH2) 3 ~ -0C (= 0)--CH2CHr -C00H 3-329 Me-(CH2) 3_-OC (= 0)----CH2CHr-so3h 3-330 Me-(CH2) 3- -0C (= 0)--CH2CHr-opo3h2 3-331 Me-(CH2) 3- -OC (= 〇)--CH2CHr l ~ Azt 5 3-332 Me .- (CH2) 3- -OC ( Service--CH2CHr 1-Pyrd .3-333 Me-_3--0C (= 0)----CH2CHr 1-Pip 3-334 Me-(CH2) 3- -OC (= 0)--CH2CHr -4-Pip 3 ~ 335 Mo ~ (0Η2) 3 ~-0C (= 0)---CH2CH2- 4-Me-1-Piz 3-336 Me-(CH2) 3- -OC (= 0)-- -CH2CHr 4- (CH2CH20H) -l-Piz 10 3-337 Me-(CH2) 3--oc (= o)----CH2CH factory 4-Mor 3-338 Me-(CH2) 3- -OC (= 0)--ch2ch2--NMe2 3-339 Me-(CH2) 3- -OC (= 0)--CH2CHr -NMeCH2CH2OH '3-340 Me-(CH2) 3--OC (= 〇)- -CH2CHr -_2CH2OH) 2 3-341 Me -CH2CH2--C (= 0) 0-one one 1-Me-4-Pip 15 3-342 Me -CH2CH2--c (= o) o---ch2- -COOH 3-343 Me -ΠΙΑ--C (= 0) 0---ch2- 1-Me-4-Pip 3-344 Me -CH2CH2--C (= 0) 0---ch2ch2--COOH 3 -345 Me -CH2CH2--C (= 0) 0---ch2ch2--so3h 3-346 Me -CH2CH``-C (= 0) 0---CH2CHr-〇p〇3h2 20 3-347 Me -CH2CH2_ -C (= 0) 0-- -CH2CH2- 1-Azt 3-348 Me -CH2CH2--C (= 0) 0---CH2CHr HPyrd 3-349 Me -CH2CHr-C (: 0) 0----CH2CHr 1-Pip 3-350 Me- CH2CH2--C (= 0) 0---CH2CHr Me-4-Pip 3-351 Me -CH2CHr -c (= o) o---CH2CHr 4-Me-HPiz 25 3-352 Me -CH2CHr-c (= o) o---CH2CHr 4- (CH2CH20H) ~ l-Piz 3-353 Me -CH2CHr-C (= 0) 0---CH2CHr 4-Mor 3-354 Me -CH2CHr ~ C (= 0) 〇 ~--ch2ch2- -NMe2 3-355 Me —CH2CH2- -c (= o) o---ch2ch2--LiCH2CH2OH 3-356 Me -CH2CHr-c (= o) o---CH2CHr-N ( CH2CH2OH) 2 30 3-357 Me -CH = CH--C (= 0) 0---l-Me-4 ~ Pip -111- 200410948

3-358 Me -CH = CH--C (= 0) 0---CHr -C00H 3-358 Me -CH = CH- -C (= 0) 0---CHr l-Me-4-Pip 3 -359 Me -CH = CH- -C (= 0) 0 ~--ch2ch2--COOH 3-360 Me -CH = CH--c (= o) o-- -CH2CHr-S03H 5. 3-361 Me -CH = CH--C (= 0) 0-One -CH2CH2-• -opo3h2 3-362 Me -CH = CH- -0 (= 0) 0----CH2CHr 1-Azt 3-363 Me -CH = CH--C (= 0) 0---CH2CHr HPyrd 3-364 · Me -CH = CH- _c (= o) o----CH2CHr 1-Pip 3-365 Me -CH = CH- -C (= 0) 0 »--CH2CHr 1-Me-4-Pip 10 3-366 Me -CH = CH- -c (= o) o---CH2CH2-4-Me-1-Piz 3-367 Me -CH = CH--C (= 0) 0---CH2CH 「4- (CH2CH2OH) '-l -Piz 3-368 Me -CH = CH- _c (= o) o---ch2ch2- 4-Mor 3-369 Me -CH = CH- -c (= o) o---ch2ch2--NMe2 3-370 Me -CH = CH--c (: o) o---CH2CHr-NMeCH2CH2OH 15 3-371 Me -CH = CH- • -C (= 0) 0---CH2CHr -N (CH2CH2OH) 2 3-372 H ~ CH2CHr-oc (= o)---1-Me-4-Pip 3-373 H -CH2CHr -00 (= 0)--CHr -COOH 3-374 H -CH2CHr -oc (= o) _.--CH2--so3h 3-375 H -CH2CHr-oc (= o)---CHr-〇p〇 3h2 20. 3-376 H -CH2CHr-0CH))---ch2- 1-Azt 3-377 H -CH2CH2- -oc (= o)---ch2-1-Pyrd 3-378 H-CH2CHr-oc (= o)--CH 「1-Pip 3-379 H -CH2CHr-0C (= Q)-one-ch2 -Bu Me-4-Pip 3-380 H -CH2CH2--oc (= o)---ch2- 4-Me-1-Piz 25 3-381 H -CH2CHr-oc (= o)--ch2- 4-(CH2CH2OH) -1 -Piz 3-382 H -CH2CH factory-oc (= o)---ch2- 4-Mor 3-383 H-CH2CHr -oc (= o)---CHr -NMe2 3- 384 H -CH2CHr-oc (= o)---CHr-NMeCH2CH2OH 3-385 H -CH2CH factory -〇〇 (= 〇)--ch2--N (CH2CH2OH) 2 30 3-386 H -CHzCHr-oc (= o) _--ch2ch2 ——COOH 112- 200410948 3-387 Η-CH2CHr ~ 0C (= 0)-one.-CH2CHr-so3h 3-388 H -CH2CH2_ ~ 0C (= 0)---CH2CHr- opo3h2 3-389 H -CH2CH2- -0C (= 0)-one.-CH2CHr 1-Azt 3-390 Η-CH2CHr-oc (= 0)-one-CH2CHr 1-Pyrd 5 .3-391 H -CH2CHr- oc (= o)-— -ch2ch2- Bu Pip .3-392 H -CH2CH2--oc (= 0)-— -ch2ch 「l-Me-4-Pip 3-393 H-CH2CHr-OCH)-1- CH2CHr 4-Me-Bu Pi z 3-394 H -CH2CHr -OC (= 0)-One-CH2CHr 4- (CH2CH20H) -l ~ Piz 3-395 H -CH2CH2- -0C (= 0)-One- CH2CHr 4-Moi &quot; 10 3-306 H -CH2CHr-OC (= 0)- Mon-CH2CHr-_e2 3-397 H-CH2CH2--oc (= o)-— -CH, CHr-NMeCH2CH20H 3-398 H-CH2CH〆-oc (= 〇)-Mon-CH2CHr-N (CH2CH20H) 2 3 -399 Me-(CH2) 3- -0C (= 0)-one-l-Me-4-Pip 3-400 Me-(CH2) 3--oc (: o)-one-CH``-COOH 15 3 -401 Me _ (CH2) 3--oc (= o)-one-ch2- -so3h 3-402 Me _ (CH2) 3--OCH)-one -ch2--〇p〇3h2 3-403 Me- (CH2) 3-.-Oc (= o)-one- ch2- 1-Azt 3-404 Me _ (CH2) r-oc (= 0)-one-ch2-. 1-Pyrd 3-405 Me-( CH2) r-oc (= o)-one ~ ch2 ~ 1-Pip 20 3-406 Me-(CH2) 3-.-Oc (= o)-one- ch2- l-Me-4-Pip 3-407 .Me ， 2) r-oc (= o)-one- ch2-4-Me-l-Piz 3-408 Me-(CH2) 3--oc (= o)---CH2- 4- (CH2CH20H) -l-Piz 3-409 Me-(CH2) 3- -〇C (= 0) &quot; ·--CH2-4-Mor 3-410 Me-(CH2) 3_ -0C (= 0) ~ one-ch2 --NMe2 25 3-411 Me-(CH2) 3--oc (= 0)-one-CHr -NMeCH2CH20H 3-412 Me-(CH2) 3- -OC (= 0)-one.-CHr-N ( CH2CH2OH) 2 3-413 Me _ (CH2) 3--oc (= 〇)-one-CH2CHr -COOH 3-414 Me _ (CH2) 3--oc (= o)---CH2CHr-so3h 3-415 Me-(CH2) 3--OCH)) -One-CH2CHr, o3h2 30 3-416 Me-(CH2) 3--oc (= o)---CH2CH2- 1-Azt -113- 200410948 3-417 Me-(CH2) 3- -0CH)-- -CH2CHr 1-Pyrd 3-418 Me-(CH2) 3--0C (= 0)----CH2CHr 1-Pip 3-419 Me-(ch2) 「-0C (= 0) _--ch2ch2- 1- Me-4-Pip 3-420 Me-(CH2) 3--OCH)---CH2CHr 4-Me-Bu Piz 5 3-421 Me-(CH2) 3--0C (= 0)---CH2CHr 4 -(CH2CH2OH) -HPiz 3-422 Me-(CH2) 3- -0C (= 0)---CH2CHr 4-Mor 3-423 Me-(CH2) 3--0C (= 0)---CH2CH2- -NMe2 3-424 Me-(CH2) 「-0C (= 0)---ch2ch2--NMeCH2CH2OH 3-425 Me _ (CH2) 3--0C (= 0)--. Ch2ch2- -N (CH2CH2OH ) 2. 10 3-426 H -CH2CHr _c (= o) o---l-Me-4-Pip 3-427 H-CH2CHr -c (= o) o---ch2--COOH 3-428 H -ch2ch factory-C (= 0) 0---ch2-1-Me-4-Pip 3-429 H-CH2CHr -C (= 0) 0- one-ch2ch2--COOH 3-430 H -CH2CHr -c (= o) o---ch2ch2- -so3h 15 3-431. H -ch2ch2- -c (= o) o--_ch2ch2--〇p〇3h2 3-432 H-CH2CHr-C (= 0) 0---ch2ch2- 1-Azt 3-433 H-CH2CHr -c (: o) o---CH2CHr 1-Pyrd 3-434 H-CH2CH 「-C (= 0) 0---ch2ch2 -1-Pip 3-4.35, H -ch2ch2- -c (= o) o---CH2CHr 1-Me-4-Pip 20 3-436 H-ch2ch2--C (= 0) 0---ch2ch2- 4-Me-HPiz 3-437 H-CH2CHr-C (= 0) 0---ch2ch2- 4-(CH2CH2OH) -HPiz 3-438 H-CH2CHr-c (= o) o---ch2ch2- 4- Mor 3-439 H -ch2ch2--C (= 0) 0---CH2CHr -NMe2 3-440 H-CH2CHr-c (= o) o---CH2CH2--NMeCH2CH2OH 25 3-441 H-CH2CHr -C (= 0) 0---ch2ch2- -N (CH2CH2OH) 2 3-442 H -CH = CH--c (= o) o--. -L-Me-4-Pip 3-443 H -CH = CH--C (: 0) 0---CHr-COOH 3-444 H -CH = CH--C (= 0) 0- a-ch2- l-Me-4-Pip 3-445 H -CH two CH- -C (= 0) 0---ch2ch2--COOH 30 3-446 H -CH = CH- -C (= 0) 0----CH2CHr-so3h

114- 200410948 3-447 H -CH = CH--C (= 0) 0-- .-CH2CHr-〇p〇3h2 3-448 Η -CH = CH- -C (= 0) 0-- ~ CH2CHr 1 -Azt 3-449 H -CH = CH--C (= 0) 0--, -CH2CHr 1-Pyrd 3-450 Η -CH = CH- -C (= 0) 0---CH2CHr 1-Pip 3 -451 Η -CH = CH- _c (= 〇) 〇---CH2CHr 1-Me-4-Pip 3-452 Η -CH = CH- _c (= o) o---CH2CHr 4-Me-1- Piz 3-453 Η -CH = CH- -c (= 0) 0- --CH2CHr 4- (CH2CH20H) -l-Piz 3-454 H -CH = CH--C (= 0) 0---CH2CH2 -4-Mor 3-455 H -CH = CH--c (= o) o-- -CH2CHr-NMe2 3-456 H -CH = CH- -c (= o) o---CH2CH2- -LiCH2CH2OH 3-457 H -CH = CH- -c (= o) o---ch2ch2- -N (CH2CH2OH) 2 Table 4 · O R1〇〇A〇A〇Al1-G_l2_l3_a

20

Exemplified R1 -L1- -G- -L2_ -L3- -A Compound No. 4-1 Me -CHr-One 1 -Pyrd 4-2 Me -CHr-One-1-Pip 4-3 Me -CHr-Bu Me -4-Pip 4-4 Me ~ CH2--a l- (CH2CH2OH) -4-Pip 4-5 Me -CHr--4-Me-1-Piz 4 a 6 Me -CH factory-one a 4- ( CH2CH20H)-: HPiz 25 200410948

4-7 Me -CHr---4-Mor 4-8 Me. -CHr-One--nh2 4-9 Me -CH2-----NHMe 4-10 Me -CH Plant-One--NMe2 5 4 -11 Me -CH2CH2-- one-C00H 4-12 Me -CH2CH2----, 〇3h2 4-13 Me -CH2CHr---1-Pyrd 4-14 Me -CH2CHr-one-1-Pip 4-15 Me -CH2CH2-- —-l-Me-4-Pip 10 4-16 Me -CH2CHr---l- (CH2CH2OH) -4-Pip 4-17 .Me -CH2CH2——--4-Me-l- Piz 4-18 Me -CH2CHr--4- (CH2CH20H) -l-Piz 4-19 Me -CH2CH2——--4-Mor 4-20 Me -CH2CHr-.---Nh2 15 4-21 Me- CH2CH2--Mon- -NHMe 4-22 Me -CH2CH2---_ -NMe2 4-23 Me _ (CH2) r--_ -C00H 4-24 Me-(CH2) 3 ~ ~ Mon- -〇〇〇 3h2 4-25 Me -CH2CH2——C (= 0)-1- 1-Piz 20 4-26 Me -CH2CH2- -C (= 0)-—-4- (C_NH2) + Piz 4-27 Me -CH2CH2 ——C (= 0)-One-4-(C (= NH) CH3)-l-Piz 4-28 Me -CH2CHr -C (= 0)-One-4-Me-HP iz 4-29 Me ~ CH2CHr -C (= 0)---4-(CH2CH2OH) + Piz 4-30 • Me -CH2CH2- _C (= 0)---4- (CH2CH2NHAc) -l-Piz 25 4-31 Me -CH2CH2- -C (= 0)-one- 4 one (CH2Car) -HPiz 4-32 Me -CH2CH2- -C (= 0)---4- (CH2CH2OCar) -HPiz 4-33 Me -CH2CHr -C (= 0)-one-four- (CH2CH2F) -1 -Piz 4-34 Me -CH2CHr -C (= 0) -1,3-Az t--C00H 4-35 Me -CH2CHr -C (= 0)-1,3-Az t--0S03H 30 4-36 Me ~ CH2CHr -C (= 0)-1,3- Azt-_〇P〇A -116-200410948 4-37 Me -CH2CHr-c (= o)-1,4-Pip--C00H 4-38 Me -CHzCHr _C (= 0)-1,4-Pip 1 _S03H _ 4-39 Me -CH2CHr-C (= 0)-1,4-Pip-_0S03H '4-40 Me -CH2CHr-c (= o)-1,4-Pip--opo3h2 5 4-41 Me -CH2CH2- _c (= o)-1,4-Pip a 1-Pyrd 4-42 Me _CH2CH2--c (= o)-.1,4-Pip-HPip 4-43 Me -CH2CHr -c (= o )-1,4-Pip-4-Me-HP iz. '4-44 Me -CH2CH 「-c (= 0)-1,4-Pip-4-(CH2CH2OH) + Piz 4-45 Me _CH2CH2-- c (= 〇)-1,4-Pip a 4-Mor 10 4-46 Me -CH2CH2- -c (= 0)-1,4-Pip a -NHMe 4-47 Me _CH2CH2- -C (= 0) -1,4-Pip a-wake e2. 4-48 Me -CH2CH2--c (= o)-1,4-Pip a-NMeCH2CH2OH 4-49 • Me -CH2CH 「-c (= o)-1, 4-Pip mono-N (CH2CH2OH) 2 4-50 Me -CH2CHr -c (= 0)-1,4-Pip-CH2--C00H 15 4-51 Me _CH2CHr-c (= 〇)-1,4- Pip -ch2-_so3h 4-52 • Me -CH2CHr-c (= o)-1,4-Pip -CH2- -OSO3H 4-5 3 Me -CH2CHr -c (= 0)-1, .4-Pip-ch2--0P0A 4-54 Me -CH2CHr -c (= 〇)-1,4-Pip-CHr 4-Mor 4-55 Me -CH2CHr -C (= 〇)-1,4-Pip-CHr -nh2 20 4-56 Me -CH2CH2-- c (= o)-1,4-Pip -ch2--NHMe 4-57 Me _CH2CH2- -c (= 0)-1,4-Pip -ch2--NMe2 4-58 Me -CH2CHr -C (= 0 )-1, 4-Pip -CHr -Wake eCH2CH2OH 4-59 Me -CH2CH2- -C (= 0)-1, 4-Pip-CH 「-_2ch2oh) 2 4-60 Me -CH2CHr -C (= o) -1, 4-P iz--so2nh2 25 4-61 Me -CH2CHr-C (= 0) _ 1,4-Piz -ch2ch2-1-Azt 4-62 Me -CH2CHr -C (= 0)-1, 4-Piz-ch2ch2-l ~ Pyrd 4-63 Me -CH2CHr -c (= 0)-1,4-Piz -ch2ch2-.1-Pip 4-64 Me -CH2CHr-C (= 0)-1,4 -Piz-ch2ch2-. 4-Me-1 -Pi of 4-65 Me -CH2CH2- -c (= 0)-1,4-Piz-ch2ch2-4- (CH2CH2OH) -l-Piz 30 4-66 Me -CH2CHr -C (= 0)-1,4-Piz -ch2ch2-4-Mor -117- 200410948 4-67 Me -CH2CHr -C (= 0)-1,4-Piz -CH2CHr-NHMe 4-68 Me -CH2CH2- -C (= 0)-1,4-Piz -CH2CH2-, Me2 4-69 Me -CH2CH2——C (= 0)-1,4-Piz-CH2CH2- -LiCH2CH20H 4-70 Me -CH2CHr -C (= 0)-1,4-Piz.-CH2CH2- -N (CH2CH2OH) 2 5 4-71 Me -CH = CH- .-C (= 0)-one- 1-Piz 4- 72 Me -CH = CH- -C (= 0)-one-4- (C (= NH) NH2) -1-Piz 4-73 Me -CH = CH——C (= 0)---4- (C (= NH) CH3) -1-Piz 4-74 Me _CH = CH- -C (= 0)---4-Me-1-Piz 4-75 Me -CH = CH--C (= 0 )---4- (CH2CH20H) -l-Piz 10 4-76 Me -CH = CH- -C (= 0)---4- (CH2CH2NHAc) -l -Piz 4-77 Me -CH = CH- -C (= 0)--4- (CH2Car) -l-Piz 4-78 Me -CH = CH- -C (= 0)----4- (CH2CH20Car) -l-Piz 4-79 Me -CH = CH- -C (= 0)-1,3_Az t --C00H 4-80 Me -CH = CH- -C (= 0)-1,3-Az t--oso3h 15 .4-81 Me _CH = CH- -C (= 0)-1,3 "Az t-~ 〇P〇3H2 4-82 Me -CH = CH- -C (= 0)-1,4-Pip--C00H 4-83 Me- CH = CH- -C (= 0)-1,4-Pip _ _S03H 4-84 Me -CH = CH——C (= 0)-1,4-Pip--0S03H 4-85 Me _CH = CH- -C (= 0)-1, 4-Pip--〇p〇3h2 20 4-86 Me -CH = CH- -C (= 0)-1,4-Pip-1-Pyrd 4-87 Me -CH = CH- -C (= 0)-1, 4-Pip-1-Pip 4-88 Me -CH = CH- -C (= 0)-.1,4-Pip-4-Me-1-Piz 4 -89 Me -CH = CH- -C (= 0)-1,4-Pip-4- (CH2CH20H)-HPiz 4-90 Me -CH = CH--C (= 0)-1,4-Pip-4- (CH2CH2NHAc) -l-Piz 25 4-91 Me -CH = CH- -C (= 0)-1, 4-Pip-4- Mor 4-92 _CH = CH- -C (= 0)-1,4-Pip--NHMe 4-93 Me -CH = CH- -C (= 0)-1,4-Pip--NMe2 4-94 Me -CH = CH——C (= 0)-1,4-Pip--NMeCH2CH2OH 4-95 Me -CH di CH- -C (= 0)-1,4-Pip--N (CH2CH20H) 2 30 4-96 Me -CH = CH- -C (= 0)-1, 4-Pip-ch2- -cooh .-118 200410948 4-97 Me -CH = CH- ~ C (= 0)-1,4- Pip -CHr-oso3h 4-98 Me -CH = CH- ~ C (= 0)-1,4-Pip -CHr-opo3h2 4-99 Me -CH = CH--c (= 〇)-1,4- Pip ~ CHr 4-Μογ · 4-100 Me -CH = CH--C (= 0)-1,4-Pip -CHr-νη2 5 4-101 Me -CH = CH--c (= 〇)-1 , 4-Pip -CHr -NHMe 4-102 Me -CH = CH '-c (= 0)-1,4-Pip ~ CHr, e2 4-103 Me -CH = CH- -c (= 0)-l , 4 ~ Pip ~ CH2 ~-NMeCH2CH2OH 4-104 Me -CH = CH--C (= 0)-1,4-P ip -CH2- -N (CH2CH20H) 2 4 -105 Me -CH2CHr _C (= 0 )-1,4-Piz--so2nh2 10 4-106 Me -CH = CH--c (= o)-1,4-Piz -CH2CHr 4-Mor 4-107 Me -CH = CH- -c (= o)-1,4-Piz -CH2CH2- -NHMe 4-108 Me -CH = CH- -c (= 0)-1,4-Piz -CH2CH2- .-NMe2 4-109 Me _CH = CH --c (= 0 &gt;-1,4-Piz -CH2CH2- -NMeCH2CH2OH 4-110 Me -CH = CH--c (= 〇)-1,4-Piz -CH2CHr -N (CH2CH20H) 2 15 4- 111 Me ~ CH2 ~ -NHC (= 0)---ch2-4-Me-HPiz 4-112 Me -CH2- -NHC (= 0)---ch2- 4-(CH2CH2OH) + nz 4-113 Me -CHr -NHC (= 0)-Yiwu- NMe2 4-114 Me -CHr-NMeC (= 0)---ch2- 4-Me-1-Piz 4-115 Me -CH2- -NMeC (= 0) ---CHr 4-(CH2CH2OH) -Bu Piz 20 4-116 Me -CHr -NMeC (= 0)-_ One CHr -NMe2 4-117 Me -CH2CH2--C (= 0) Lie---ch2ch2 --C00H 4-118 Me -CH2CHr _C (= 0) NMe---CH2CHr -so3h 4-119 Me -CH2CHr-_CH2CHr-NMe2 4-120 H-CHr One--1-Pyrd 25 4-121 H -CHr — One-to-one 1 -P ip 4-122 H-CHr One-to-one 1-Me-4-Pip 4-123 H-CHr One-_ 1- (CH2CH20H) -4-Pip 4-124 H -CH2-—- 4-Me-Bu Pi z 4-125 H -CH2-One-_ 4- (CH2CH20H) -1-Piz 30 4-126 H -CH9-— One 4 ~ Mor -119- 200410948

4-127 Η-CH2----nh2 4-128 H -CHr---_e 4-129 H -CHr---e2 .4-130 Η -CH2CHr----C00H 5 4- 131 H -CH2CH 「----〇〇〇〇〇3H2 .4-132 H-CH2CH2-----1-Pyrd 4-133 H -CH2CH2—— a-1-Pip 4-134 Η -CH2CH2- _ a- 1-Me-4-Pip 4-135 H -CH2CHr--1- (CH2CH20H) -4-Pip 10 4-136 Η-CH2CH2——--4 ~ Me-l-Piz 4-137 H -CH2CHr-1 -4- (CH2CH20H) + Piz 4-138 H -CH2CHr---4-Mor 4-139 H -CH2CH2----νη2 4-140 H -CH2CH2------NHMe • 15 4-141 H -CH2CH 「---_NMe2 4-142 H _ (CH2) 3-- one- -C00H 4-143 H-(CH2) 3— one- -〇〇〇〇3H2 4-144 H; -CH2CHr -C (= 0)-One- 1-Piz 4-145 H-CH2CH 「-C (= 0)-One- 4- (C (= NH) NH2) -l-Piz 20 4-146 H -CH2CHr-C (= 0 )---4- (C (= NH) CH3) + Piz 4-147 H -CH2CHr -C (= 0)-•--4 -Me-HPiz 4-148 H -CH2CHr -C (: 0)- Mon-4- (CH2CH20H) -l-Piz 4-149 H -CH2CH2- -COO)-Mon-4- (CH2CH2NHAc) -l-Piz 4-150 H-CH2CH2--C (= 0)-Mon-4 -(CH2Car) -1 -Piz 25 4-151 H -CH2CHr -C (= 0)-a-4- (CH2CH20Car ) -l-Piz 4-152 H -CH2CH2- -C (= 0)--~ 4- (CH2CH2F) -l-Piz 4-153 H-CH2CH2--C (= 0)-1,3-Azt- -C00H 4-154 H -CH2CHr ~ C (= 0)-1,3-Azt--0S03H 4-155 H, CH2CH2- -C (= 0)-1,3-Az t-_〇p〇3h2 30 4-156 H -CH? CH?-C (= 0)-1,4-Pip--C00H -120- 200410948 4-157 H -CH2CHr-C (two 0) _ 1,4-Pip,-- so3h 4-158 Η -CH2CHr -c (= o)-1,4-Pip--0S03H 4-159 Η -CH2CHr -c (= o)-1,4-Pip one-〇P〇3H2 4-160 Η -CH2CHr -c (= 0)-1,4-Pip -l ~ Pyrd 5 4-161 Η -CH2CH2- -c (= 0)-1,4-Pip 1 :: Pip • 4-162 H -CH2CHr- C (= 0)-1,4-Pip-4-Me-1-Piz 4-163 H -CH2CH`` -C (= 0)-1,4-Pip-4- (CH2CH20H) -Bu Piz 4-164 H-CH2CHr -C (= 0)-1,4-Pip-4-Mor 4-165 H -CH2CHr-c (= o)-1,4-Pip--NHMe 10 4-166 H _CH2CH 「-c ( = 0)-1,4-Pip — • -NMe2 4-167 H -CH2CHr -C (= 0)-1,4-Pip —-NMeCH2CH20H 4-168 H -CH2CH2- -C (= 0)-1, 4-Pip one-N (CH2CH20H) 2 4-169 H-CH2CHr -c (= o)-1,4-Pip -CHr-C00H 4-170 H -CH2CHr -c (= 〇)-1,4-Pip -CH2--S03H 15 4-171 H -CH2CH factory-C (= 0)- 1,4-Pip-ch2--oso3h 4-172 H -CH2CHr -C (= 0)-1,4-Pip -CH 「-〇p〇3h2 4-173 H-CH2CH2--C (= 0)- 1,4-Pip -ch2-4-Mor 4-174 H -CH2CHr-CH)-1,4-Pip -CH2_ ·--nh2 4-175 H -CH2CHr-c (= o)-1,4-Pip- CHr -NHMe 20 4-176 H -CH2CH2--c (= o)-'1,4-Pip-ch2- -NMe2 4-177 H-CH2CHr -c (= 0)-1,4-Pip -CHr- NMeCH2CH20H 4-178 H-CH2CHr -c (= 0)-1,4-Pip-CH2--N (CH2CH2OH) 2 4-179 H -CH2CH2--C (= 0)-1,4-Piz--so2nh2 4-180 H -CH2CHr -C (= 0)-1,4-Piz-CH2CHr l-Azt 25 4-181 H -CH2CH2- -C (= 0)-1,4-Piz -CH2CHr 1-Pyrd 4- 182 H-CH2CHr-c (= o)-1,4-Piz-CH2CHr 1-Pip 4-183 H-CH2CHr -C (= 0)-1,4-Piz-CH2CHr 4-Me-HPiz 4-184 H -CH2CHr -c (= o)-1,4-Piz -CH2CH2-4- (CH2CH20H) -l -Piz 4-185 H -CH2CH2--C (= 0)-1,4-Piz-CH2CHr 4-Mor 30 4-186 H -CH2CHr-C (= 0)-1,4-Piz -CH2CH2- • -NHMe. -121-200410948 4-187 H -CH2CHr -C (= 0)-1, 4-P iz- CH2CH plant 4Me2 4-188 H-CH2CH2--C (= 0)-1,4-Piz-CH2CH2- -NMeCH2CH2OH 4-189 H -CH2CHr-. (= 0)-1,4-Piz -CH2CHr -N (CH2CH2OH) 2 4-190 H -CH = CH- -C (= 0)---BU Piz 5 4-191 H -CH = CH--€ (= 0)-—-4- (C (= NH) NH2) -l-Piz 4-192 H -CH = CH- -C (= 0)----4- (C (= M) CH3)- l-Piz 4-193 H -CH = CH- -C (= 0)-. --Me-l-Piz 4-194 H -CH = CH ~ -C (= 0)---4-( CH2CH2OH) -HPiz 4-195 H -CH = CH- -C (= 0)-One- 4- (CH2CH2NHAc) -l-Piz 10 4-196 H -CH = CH- _C (= 0)-One-. 4- (CH2Car) -l ~ Piz 4-197 H ~ CH = CH- -C (= 0)--4- (CH2CH20Car) -l ~ Piz 4-198 H ~ CH = CH- -C (= 0 )-1,3-Az t -C00H 4-199 H -CH = CH- _C (= 0)-1,3 * ~ Az t--0S03H 4-200 H -CH = CH- -C (= 0) -1,3-Az t-_〇p〇3h2 15 4-201 H -CH = CH_ -C (= 0)-1,4-Pip--C00H 4-202 H -CH = CH- -C (= 0)-1,4-Pip-_S03H 4-203 H -CH = CH- -C (= 0)-1,4-Pip--0S03H 4-204 H -CH = CH- -C (= 0)- 1,4-Pip _ -_3h2 4-205 H -CH = CH- -C (= 0)-1,4-Pip-1-Pyrd 20 4-206 H -CH = CH- -C (= 0)- 1,4-Pip-1-Pip 4-207 H -CH = CH- -C (= 0)-1,4-Pip — 4-Me-1-Piz 4-20.8 H -CH = CH- -C ( = 0)-1,4-Pip-4- (CH2CH20H) -l-Piz 4-2.09 H -CH = CH- -C (= 0)-1,4-Pip-4- (CH2CH2N HAc) -l-Piz 4-210 H -CH = CH- -C (= 0)-1,4-Pip-4-Mor 25 4-211 H _CH = CH- -C (= 0)-1,4 -Pip--NHMe 4-212 H _CH = CH- -C (two 0)-1,4-Pip--NMe2 .. 4-213 H -CH = CH——C (= 0)-1,4- Pip--LiCH2CH2OH 4-214 H -CH = CH- -C (= 0)-1,4-Pip One-N (CH2CH2OH) 2 4-215 H -CH = CH- -C (= 0)-1 , 4-Pip -ch2--cooh 30 4-216 H -CH = CH——C (= 0)-1,4-Pip-CH2- -OSO3H. -122- 200410948 4-217 H-CH = CH- -C (= 0) _ 1, 4-Pip-CHr -〇p〇3h2 4-218 H -CH = CH- -C (= 0)-1,4-Pip -CH2- 4-Μογ 4-219 H -CH = CH- -C (= 0)-1,4-Pip ~ CHr-νη2 4-220 H -CH = CH- _C (= 0)-1,4-Pip -CHr-_e 5 4-221 H -CH = CH- -C (= 0)-1,4-Pip -CHr-NMe2 .4-222 H -CH = CH- _C (= 0)-1,4-Pip -CH2- -NMeCH2CH20H 4-223 H -CH = CH- -C (= 0)-1,4-Pip -CHr -N (CH2CH20H) 2 4-224 H -CH2CH2_ -C (= 0)-1,4-P iz--so2nh2 4- 225 H -CH = CH- -C (two 0)-1,4-Piz ~ -CH2CH2-4-Μογ 10 4-226 H -CH = CH- -C (= 0)-1,4-Piz -CH2CHr -NHMe 4-227 H -CH = CH- -C (= 0)-1,4-Piz -CH2CHr -.e2 4-228 H -CH = CH- -C (= 0)-1,4-Piz ~ CH2CHr -NMeCH2CH20H 4-229 H-CH = CH- -C (= 0) _ 1,4-Piz -CH2CHr -N (CH2CH2OH) 2 4-230 H -CHr -NHC (= 0)---ch2-4-Me-l-Piz 15 4- 231 H -CH2- -NHC (= 0)---ch2-4-(CH2CH2OH) -Bu Piz 4-2.32 H -CH2-, -NHC (= 0)--CHr .-NMe2 4-233 H- CHr -NMeC (= 0)---ch2- 4-Me-1-Piz 4-234 H -CHr -NMeC (= 0)-one. One CHr 4- (CH2CH20H) -1 -Piz 4-235 H- CHr -NMeC (= 0)----CHr -NMe2 20 4-236 H -CH2CH2- -C (= 0) NMe----CH2CHr-C00H 4-237 H -CH2CHr -C (= 0) NMe---- CH2CHr-S03H 4-238 H _CH2CHr -C (= 0),--CH2CHr -NMe2 4-239 Me 1,4-cHx-— -C00H 4-240 Me 1,4-cHx-one -0p〇 3h2 25 4-241 Me 1,4-cHx-one one 1-Pyrd 4-242 Me 1,4-cHx one — ~ 1-Pip 4-243 Me 1,4-cHx-— ~ 1-Me-4- Pip 4-244 Me 1,4-cHx---1-(CH2CH20H) -4-Pip 4-245 Me 1,4-cHx-— -4-Me-l-Piz 30 4-246 Me 1,4- cHx-one-four- (CH2CH20H) -l-Piz 123- 200410948

4-247 Me 1,4-cHx--— 4-Mor 4-248 Me 1,4-cHx one one one-νη2 4-249 Me 1,4 ~ cHx — one one -NHMe 4-250 Me 1,4 -cHx-— One-NMe2 5 4-251 Ή 1,4-cHx ~ —--C00H .4-252 H 1,4-cHx-.-· -0-003Η2 4-253 H 1,4-cHx One one I. Pyrd 4-254 H 1,4-cHx — —-1-Pip '4-255 H 1,4-cHx — —-l * ~ Me-4-P ip 10 4-256 H 1,' 4- cHx one one — 1- (CH2CH20H) -4-Pip 4-257. H • 1, 4-cHx — —-4-Me-l-Piz 4-258 H 1,4-cHx — — one 4- (CH2CH20H ) -l-Piz 4-259 H 1,4-cHx---4-Mor 4-260 H · 1, 4-cHx — — one-nh2 15. 4-261 H 1,4-cHx — — one- NHMe 4-262 H 1,4-cHx---NMe2 4-263 Me-(ch2) 4- — —--C00H 4-264 Me-(ch2) 4-one-to-one-so3tf 4-265 Me-( CH2) r One---0S03H 20 4-266 Me-(CH2) 4-----0P03h2 4-267 Me-(CH2) 5--One-C00H 4-268 Me-(CH2) 5--~ --so3h 4-269 Me-(CH2) 5--~--OSO3H 4-270 Me-(CH2) 5-one by one-0P03h2 25 4-271 Me-(CH2) 3- -C (= 0) fiMe-- -ch2ch2 ~ -so3h. 4-272 Me-(C H2) 4--C (= 0) NMe----CH2CHr -S03H 4-273 Me-(CH2) 5- -C (= 0) NMe----CH2CH2--so3h 4-274 Me-(ch2) 「 -C (= 0), --- CH2CHr -so3h 4-275 H-(ch2) 4--111 -C00H 30 4-276 H-(CH2) 4-~---SO3H -124- 200410948 4- 277 Η-(CH2) 4- — one one.-Oso3h 4-278 Η-(ch2) 4-— one--0P03h2 4-279 Η-(ch2) 「one —---C00H-4-280 Η-( ch2) 5-one one--so3h 5 4-281 Η-(ch2) 5- one----oso3h 4-282 Η-(ch2) 5--one one -〇P〇3H2 4-283 Η-(CH2 ) r-C (= 0) -CH2CHr -so3h 4-284 Η-(ch2) 4- -C (= 0) NMe---CH2CH2--S03H 4-285 Η-(ch2) 5- -C (= 0) NMe---CH2CHr -so3h 10 4- 286 · Η-(CH2) 6_ -C (= 0) NMe---CH2CHr -S03H 4-287 Me-CH2CHr -0C (= 0)--I. Bu Me-4-Pip 4-288 Me-CH2CHr -oc (= 〇)--ch2- -C00H 4-289 Me -CH2CHr _oc (: o)----CHr -SO3H 4-290 Me _ch2ch2- -OC ( -0)--CHr -〇p〇3h2 15 4-291 Me -ch2ch2--oc (= 0)--CH2-1-Azt 4-292 Me -ch2ch2- -OC (= 0)--- ch2- 1-Pyrd .4-293 Me -ch2ch2--oc (= o)---ch2 -1-Pip 4-294 Me lCH2CH2--oc (= 〇)---ch2- 1-Me-4-P ip 4-295 Me -CH2CHr -0C (= 0)-one-ch2- 4-Me- HPiz 20 4-296 Me-CH2CHr -oc (= o)---ch2-4- (CH2CH2OH) -l · 4-297 Me -CH2CHr _oc (= o)---ch2- 4-Mor 4-298 Me -CH2CHr -oc (= o) _-CHr -NMe2 4-299 Me -CH2CHr -0C (= 0)--_ch2- -Li eCH2CH2OH 4-300 Me -CH2CHr-oc (= o)----CHr- N (CH2CH2OH); 25 4-301 Me -CH2CHr-0C (= 0)---ch2ch2 ——C00H 4-302 Me -CH2CHr _oc (= o)---ch2ch2 ——S03H 4-303 Me-ch2civ _oc (= o)---ch2ch2-, 〇3h2 4-304 Me -CH2CHr _oc (= o)--_ch2ch2-1-Azt 4-305 Me-CH2CHr-oc (= o)---ch2ch2:-1- Pyrd 30 4-306 Me -CHXHr -〇〇 (= 〇)--ch2ch2 -1-Pip 125- 200410948 4-307 Me _CH2CH2- -0C (= 0)---ch2ch2- l-Me-4-Pip 4-308 Me -CH2CHr -0C (= 0)-— -CH2CHr 4-Me-l-Piz 4-309 Me -CH2CHr -OC (two 0)---CH2CH2-4-(CH2CH2OH) + Piz 4-310 Me -CH2CHr -0C (= 0)---ch2ch 「4-Mor -5. 4-311 Me -CH2CH2- -0C (= 0)---ch2ch2--NMe2 .4-312 Με ~ CH2CH2 ~-oc (= 0)-one-CH2CHr -NMeCH2CH2OH 4-313 Me -CH2CH2--OC (= 0)-one -CH2CHr -N (CH2CH2OH) 2 4-314 Me-(CH2) r -oc (= 0)-one-Bu Me-4-Pip 4 -315 Me-(CH2) 3_ -OC (= 〇)----CH2--COOH 10 4-316 Me-(CH2) r -〇C (= 0)---ch2--so3h 4-317 Me- (CH2) 3- -oc (= o)-----CHr -〇p〇3h2 4-318 Me-(CH2) 3- -oc (= o)-a-ch2-1-Azt 4-319 Me- (CH2) 3--OC (= 〇)--CH2-1-Pyrd 4-320 Me-(CH2) 3--oc (= o)---CHr 1-Pip 15 4-321 Me-(CH2) 3--oc (= o)---CH 「1-Me-4-Pip 4-.322 Me-(CH2)」 -oc (= o)---CH 「4-Me-l-Piz 4- 323 Me-(CH2) 3- -0C (= O)---CH2_ 4- (CH2CH2OH) -HPiz 4-324 Me-(CH2) 3- -oc (= o)-—-ch2- 4-Mor 4 -325 Me-(CH2) 3- -0C (= 0)-One- CHr -NMe2 20 4-326 Me-(CH2) 3- -OC (= 0)-One-CHr -NMeCH2CH2OH 4-327 Me-( CH2) r -0C (= O) ~--CH "-N (CH2CH2OH) 2 4-328 Me _ (CH2) 3--OC (= 〇)----CH2CHr-COOH 4-329 Me-(CH2) 3--oc (= o)---CH2CHr -so3h · 4-330 Me-(CH2) r-OC (= 〇)--CH2CHr-〇p〇3h2 25 4-331 Me-(CH2) 3- -oc (= o)-one-CH2CHr 1 -Azt 4-332 Μθ-(CH2) 3 ~ -OC (= 〇)-One- CH2CHr HPyrd 4-333 Me-(CH2) 3- -OC (= 0)-One- CH2CHr 1-Pip 4-334 Me , (CH2) 3_ -OC (= 0)-One-CH2CHr 1 -Me-4 · -Pip 4-335 Me-(CH2) r -OC (= 0)-One-CH2CH2- 4-Me ~ l ~ Piz 30 4-336 Me-(CH2) 3- -OC (= 〇)---CH2CHr 4-(CH2CH2OH) + Piz 126- 200410948 4-337 Me ~ (CH2) 3 &quot; ~-0C (= 0)-- ~ CH2CHr 4-Mor 4-338 Me-(CH2) 3--0C (= 0)---ch2ch 「-丽 e2 4-339 Me _ (CH2) r -oc (= 0)----CH2CHr -NMeCH2CH2OH 4-.340 Me '(CH2) 3- -0C (= 0)---CH2CHr-N (CH2CH2OH) 2 5 4-341 Me -CH2CH2- -c (= o) o---1-Me-4 -Pip .4-342 Me -CH2CHr-c (= o) o---CH 「-C00H 4-343 Me -CH2CH2 ~--c (= o) o---CHr 1-Me-4-Pip. 4 -344 Me -CH2CHr -c (= o) o---CH2CHr -C00H 4-345 Me -CH2CHr-c (= 〇) 〇---CH2CHr-S03H 10 4-346 Me -CH2CHr -c 0 = 0) 0---CH2CHr -opo3h2 4-347 Me -CH2CHr-c (= o) o---ch2ch2- 1-Azt 4-348 Me -CH2CHr-C (= 0) 0--one ch2ch2— 1-Pyrd 4 -349 Me -CH2CHr-c (= o) o----CH2CHr 1-Pip '4-350 Me -CH2CHr -c (= o) o---CH2CHr .1-Me-4 -Pip 15 4-351 Me -CH2CH 「-C (= 0) 0---CH2CHr 4-Me-HPiz 4-352 Me -CH2CHr-C (= 0) 0---CH2CHr 4- (CH2CH2OH)-: HPiz 4-353 Me -CHzCHr-c (= o) o-- -CH2CHr 4-Mor 4-354 Me -CH2CH2- -C (= 0) 0---CH2CHr-NMe2 4-355 Me -CH2CHr -c ( : o) o- -CH2CHr -NMeCH2CH2OH 20 4-356 Me -CH2CHr-C (= 0) 0----CH2CHr-N (CH2CH2OH) 2 4-357 Me -CH = CH--C (= 0) 0- -1-Me-4-Pip 4-358 Me -CH = CH--c (= o) o--~ ch2- -C00H 4-358 Me -CH = CH- -c (= o) o-- -CH 「l-Me-4-Pip 4-359 Me _CH = CH--C (= 0) 0--.-CH2CH2--C00H 25 4-360 Me _CH = CH--c (= o) o- --CH2CHr -S03H 4-361 Me -CH = CH- -c (= o) o---CH2CHr-〇P〇A 4-362 Me -CH = CH- -C (= 0) 0---CH2CHr 1-Azt 4-363 Me _CH = CH--C (= 〇) 〇---CH2CH2-1-Pyrd 4-364 Me -CH = CH- -C (= 0) 0---CH2CHr Pip 30 4 -365 Me -CH = CH- -c (= o) o---CH2CH2- 1-Me + Pip 127- 200410948 4-366 Me -CH = CH- -C (= 0) 0---CH2CHr 4- Me-l-Piz 4-367 Me _CH = CH--C (= 0) 0-One -CH2CHr 4- (CH2CH20H) -Bu Piz 4-368 Me -CH = CH- -C (= 0) 0- — -ch2ch2- 4-Mor 4-369 Me- CH = CH-. -C (= 0) 0- —-ch2ch2- -NMe2 5 4-370 Me -CH di-CH--c (= 〇) 〇-.--CH2CHr-round eCH2CH2OH .4-371 Me- CH = CH--c (= 0) 0- -ch2ch2- -N (CH2CH2OH) 2 4-372 H-CH2CHr-oc (= o)---1-Me-4-Pip 4-373 H -ch2ch2- -oc (= 〇)-one- CH2--C00H 4-374 H '-ch2ch``-oc (= o)-one. one CHr -S03H 1.0 4-375 H -CH2CHr-oc (= 0)---- ch2- -〇p〇3h2 4-376 H-CH2CH2--oc (= o)-— -CHr 1-Az t 4-377 H -ch2ch2- -oc (= 0)-one-CHr 1-Pyrd 4- 378 H -ch2ch2--oc (= o)--· .-CHr 1-Pip 4-379 H-CH2CH2- -oc (= 〇)---ch2- l-Me-4-Pip 15 4-380 H -CH2CHr -0C (= 0)-a-ch2- 4-Me-l-Piz 4-381 H -CH2CHr-oc (= 〇)---ch2- 4- (CH2CH20H) -l-Piz 4-382 H -CH2CHr ~ 0C (= 0)---CHr 4 ~ Mor 4-383 H-CH2CH 「. _Oc (= o)----CH2--NMe2 4-384 H-CH2CHr -0C (= 0)---- CH2-• -NMeCH2CH2OH 20 4-385 H -CH2CHr-oc (: 〇)-a-ch2- -N (CH2CH2OH) 2. 4-386 H-CH2CHr -0C (= 0)-a- ch2ch2 -C00H 4- 387 H -CH2CHr -oc (= 〇)---ch2ch2 --S03H 4-388 H-CH2CH2--OC (= 0) ~ 1 -ch2ch2--opo3h2 4-389 H-CH2CH 「_oc (= 〇)-a_ch2ch2 -1-Azt 25 4-390 H-CH2CHr-oc (= o)--.-ch2ch2 -1-Pyrd 4-391 H-ch2ch2- -oc (= o)---ch2ch2 -1-Pip 4-392 H-CH2CHr-oc (= o)-one-ch2ch2-1-Me-4-Pip 4-393 H-CH2CH "- oc (= o)---ch2ch2-4-Me-H? iz 4-394 H -CH2CHr -oc (= 〇)-a-ch2ch2 -4- (CH2CH20H) ~ l ~ Pi 30 4-395 H -CH2CHr -oc (= 〇)-one- ch2ch2-4-Mor 128- 200410948 4-306 Η-CH2CH2- -0C (= 0)-one- CH2CHr-NMe2 4-397 H-CH2CHr -0C (= 0)-one -ch2ch 「-bandeCH2CH2OH 4-398 Η-CH2CHr -OCH)---ch2ch「 -N (CH2CH2OH) 2. 4-399 Me-(CH2) 3--oc (= 〇)-one- l-Me- 4-Pip 5 4-400 Me-(CH2) 3- -0C (= 0)---CH Factory-COOH .4-401 Me _ (CH2) "-0C (= 0)-One-ch2--so3h 4-402 Me-(CH2) 3- -OCH)-Imai-〇p〇3h2 4-403 Me-(CH2) Factory-OC (= 0)-.- One CHr 1-Azt 4-404 Me-( CH2) 3- -oc (= o)-—-ch2- 1-Pyrd 10 4-405 Me-(CH2) 3- -OCH)---ch2-1-Pip 4-406 Me-(CH2) 3- -oc (= o)-— -CHr l-Me-4-Pip 4-407 • Me-(CH2) 3- -0C (= 0)-1 -CH Factory 4-Me-l-Piz 4-408 Me _ (CH2) 3--OCH)-One-CHr 4- (CH2CH20H) -l-Piz 4-409 Me-(CH2) 3--oc (= 〇)-One- CH 「4-Mor 15 4-410 Me _ (CH2) 3--oc (= o)-One- ch2- -Li e2. 4-411 Me-(CH2) 3- -0C (= 0)---ch2- -NMeCH2CH2OH 4-412 Me _ (CH2) 3- -oc (= o)-one-to-one CHr-N (CH2CH2OH) 2 4-413 Me ~ (CH2) 3 ~ -OC (= 0 )-1-CH2CH 「-COOH 4-414 Me _ (CH2) 3--oc (= o)---ch2ch「-so3h 20 4-415 Me _ (CH2) 3_-OC (= 0)--- CH2CHr -〇p〇3h2 4-416 Me _ (CH2) "-oc (= o)--CH2CHr 1-Azt 4-417 Me-(CH2) r -0C (= 0)----CH2CHr Pyrd 4 -418 Me-(CH2) r-oc (= o)---CH2CHr 1-Pip 4-419 Me-(CH2) 3--OCH)-— -CH2CHr l-Me-4-Pip 25 4-420 Me _ (CH2) 3- -OC (= 0)--CH2CHr 4-Me-l-Piz 4-421 Me-(CH2) 3--oc (= o)--CH2CH 「4- (CH2CH2OH) -HPiz 4 -422 Me _ (CH2) 3--OC (= 0)--one CH2CHr 4-Mor 4-423 Me _ (CH2) 3_ -OCH)-one -CH2CHr-NMe2 4-424 Me-(CH2) 3- -OCH)-1-CH2CHr-Li eCH2CH2OH 30 4-425 Me-(CH2) 3--oc (= o)---CH2CH2- -N (CH2CH2OH) 2 129- 200410948 4-426 Η -CH2CH2_ -C (= 0) 0 -.- -1-Me-4_Pip 4-427 H -CH2CH2--C (= 0) 0---ch2- -C00H 4: 428 Η -CH2CHr -c (= o ) o-- -CHr 1-Me-4-Pip 4-429 Η -CH2CH2--c (= 0) 0_--ch2ch2--COOH 5 4-430 Η -CH2CHr -c (= o) o---- CH2CHr-S03H 4-431 Η -CH2CHr -c (= o) o---ch2ch 「-〇p〇3h2 4-432 H -CH2CHr-C (= 0) 0---ch2ch「 1-Azt 4-433 H-CH2CHr-C (= 0) 0---ch2ch2- 1-Pyrd 4-434 H -CH2CHr -C (= 0) 0-- -ch2ch2- 1-Pip 10 4-435 Η -CH2CH 「-C ( = 0) 0---CH2CHr l-Me-4-Pip 4-436 Η-CH2CHr-C (: 0) 0---CH2CH2-4-Me-l-Piz 4-437 H -CH2CHr-c (= o) o---ch2ch2- 4-(CH2CH2OH) -Bu Piz 4-438 Η -CH2CH 「-C (= 0) 0---ch2ch2- 4-Mor 4-439 H -CH2CHr _c (= o) o --CH2CHr -NMe2 15 4-440 H -CH2CHr-C (= 0) 0---ch2ch2- -LiCH2CH20H 4-441 H ~ CH2CHr-C (= 0) 0--.-CH2CHr -N (CH2CH2OH ) 2 4-442 H -CH = CH- -c (= o) o --- Me-4-Pip 4-443 H _CH-CH--C (= 〇) 〇- ~ -CH2--COOH 4 -444 H -CH = CH--c (= o) o----CH factory 1-Me-4-Pip 20 4-445 H -CH = CH- -C (= 0) 0-- -CH2CHr-COOH 4-44 6 H -CH = CH- -c (= o) o---ch2ch2- -so3h 4-447 H -CH = Cl · -C (= 0) 0---CH2CHr-〇P〇3H2 4-448 H -CH = CH--C (: 〇) 〇---CH2CHr 1-Azt 4-449 H -CH = CH--C (= 0) 0---CH2CHr 1-Pyrd 25 4-450 H -CH = CH--C (= 0) 0--One ch2ch2- 1-Pip 4-451 H -CH = CH--C (= 0) 0---CH2CHr l-Me-4-Pip 4-452 H -CH = CH_-C (: 〇) ό-_ -CH2CHr 4-Me-l-Piz 4-453 H -CH = CH--C (= 0) 0---CH2CHr 4- (CH2CH20H) -l-Piz 4 -454 H -CH = CH--C (= 0) 0---CH2CHr 4-Mor 30 4-455 H -CH = CH- general 0) 0---CH2CH2- -NMe2 130- 200410948

4-456 Η -CH = CH- -C (= 0) 0---CH2CHr -NMeCH2CH2OH 4-457 H -CH = CH- -C (= 0) 0- --CH2CH2_ -N (CH2CH2OH) 2 5 Table 5 O R1 0 〇A〇A〇Al1-_g_l2_l3_a 10 Exemplified R1-L1- Compound No. -G--L2- -V--A 5-1 Me -CHr-1-Pyrd 5-2 Me -CH Factory-11-Pip 5-3 Me -CHr-11-l-Me-4-Pip 15 5-4 Me -CHr--C 1- (CH2CH20H) -4-Pip 5-5 Me -CHr--- 4-Me-1-Piz 5-6 Me -CHr---'4 ~ (CH2CH20H) -1-Piz 5-7 Me -CHr---4-Mor 5-8 Me -CH2--one one -nh2 _ 20 5-9 Me -CHr-—--NHMe 5-10 Me -CH2----Li-e2 5-11 Me -CH2CH "----C00H 5 -12 Me -CH2CHr--1-〇P 〇3H2 5-13 Me -CH2CHr--1-Pyrd 25 5-14 Me -CH2CHr-1-Pip

-131-200410948 5-15 Me -CH2CHr---l-Me-4-Pip 5-16 Me ~ CH2CH2-- one one l ~ (CH2CH2OH) -4-Pip 5-17 Me -CH2CHr-one-4- Me-HP iz 5 -18 Me -CH2CH2----4- (CH2CH20H) -l-Piz 5 5 -19 Me -CH2CH2-- a- 4-Mor .5-20 Me -CIi2CH2-- a-, .. ; 5-21 Me -CH2CH2---· -NHMe 5-22 Me -CH2CH2----_-NMe2 5-23 Me-(CH2) 3 ~---C00H 10 .5-24 Me-(CH2 ) 3_---opo3h2 5-25 Me -CH2CHr -C (= 0)---1-Piz 5-26 Me -CH2CH2 ~ ~ C (= 0)---4- (C (= NH) NH2) -1-Piz 5-27 Me -CH2CH2--C (= 0)---4- (C (= NH) CH3) -HPiz. 5-28 Me -CH2CH2-—C (= 0)-one — 4- Me-1-Piz 15 5-29 Me -CH2CHr -C (= 0)-One- 4- (CH2CH20H) -1 -Piz 5-30 Me -CH2CH2——C (= 0)-One-4-(CH2CH2NHAc ) -Bu Piz 5-31 Me ~ CH2CHr -C (= 0)-—-4- (CH2Car) + Piz 5-32 Me -CH2CHr -C (= 0)--4- (CH2CH20Car) -HPiz 5-33 Me -CH2CH2- -C (= 0) _--4- (CH2CH2F) -l-Piz 20 5-34 Me -CH2CH2——C (: 0)-1,3-Azt--C00H 5-35 Me- CH2CH2--C (= 0)-1,3-Azt--oso3h 5-36 Me -CH2CHr -C (= 0)-1,3-Az t-, 〇3h2 5- 37 Me -CH2CHr -C (= 0)-1,4-Pip--C00H 5-38 Me -CH2CHr ~ C (= 0)-1,4-Pip--SO3H 25 5-39 Me ~ CH2CHr ~ C ( = 0)-1,4-Pip--oso3h 5-40 Me -CH2CHr -CH))-1,4-Pip-~ 〇p〇3h2 5-41 Me -CH2CH2--C (= 0)-1, 4-Pip-1-Pyrd 5-42 Me -CH2CH2- -C (= 0)-1,4-Pip-1-Pip 5-43 Me -CH2CH2——C (= 0)-1,4-Pip- 4-Me-1-Piz 30 5-44 Me -CH2CH2- -C (= 0)-1,4-Pip-4- (CH2CH20H)-; l-Piz -132- 200410948 5-45 Me .-CH2CHr- c (= 0)-1,4-Pip a 4-Mor 5-46 Me -CH2CHr ~ C (= 0) ~ 1,4-: Pip a -NHMe .5-47 Me -CH2CHr-c (= 0) -1,4-Pip--NMe2 5-48 Me _CH2CHr -c (= o)-1,4-Pip One-wake eCH2CH20H 5 5-49 Me ~ CH2CH2- -c (= o〉 _ 1,4-Pip -N (CH2CH2OH) 2 5-50 Me -CH2CHr -c (= 0)-1,4 ~ Pip-CH 「-C00H 5-51 Me -CH2CHr _c (= o)-1,4-Pip -CH factory -S03H 5-52 Me -CH2CH2- -c (= o)-1,4-Pip-ch2--oso3h 5-53 Me -CH2CH2_-c (= 〇)-1,4-Pip -CHr-〇p〇 3h2 10 5-54 Me -CH2CH2- -c (= 〇)-1,4-Pip-ch2- 4-Mor 5-55 Me -CH2CH 「-c (= 0)-1,4-Pip bone-nh2 5 -56 Me -CH2CHr -c (= 0)-1,4-Pip dance-NHMe 5-57 Me -CH2CHr -c (= 0)-.1,4-Pip-ch2- -_2 5-58 Me -CH2CHr -C (= 0)-1,4-Pip -CHr • -Li eCH2CH2OH 15 5 -59 Me -CH2CH2- -c (= 0)-1,4-Pip -CHr -N (CH2CH2OH) 2 5-60 Me -CH2CH2- -c (= 0)-1,4-Piz one- so2nh2 5- 61 Me-CH2CHr -C (= 0) ~ 1,4-Piz -CH2CHr 1-Azt 5-62 Me -CH2CH2--c (= 〇)-1,4-Piz-CH2CHr 1-Pyrd 5-63 Me -CH2CHr -c (= o)-1,4-Piz-CH2CHr 1-Pip 20 5-64 Me -CH2CHr -c (= 0)-1,4-Piz-CH2CHr 4-Me-l-Piz 5-65 Me -CH2CH2- -C (= 0)-1,4-Piz-CH2CH 「4- (CH2CH20H) -1-Piz 5-66 Me -CH2CH2--C (= 0)-1,4-Piz -ch2ch2- 4-Mor 5-67 Me -CH2CHr -c (= 0)-1,4-Piz -ch2ch2- -NHMe 5-68 Me -CH2CHr-C (= 0)-1,4-Piz -ch2ch2- -NMe2 25 5-69 Me -CH2CHr -c (= 0)-1,4-Piz -CH2CHr • -Li eCH2CH20H 5-70 Me -CH2CHr ~ C (= 0)-1,4-Piz-CH2CHr -N (CH2CH20H) 2 5-71 Me -CH two CH--C (= 0)-one HPiz 5-72 Me -CH = CH- -C (= 0)---4- (C (= NH) NH2) -l- Piz 5-73 Me -CH = CH- -C (= 0)----4- (C (= NH) CH3) -1-Piz 30 5-74 Me _CH = CH- -c (= 0)-- A 4-Me ~ l-Piz -133- 200410948 5-75 Me -CH = CH-( (= 0)-1 4-(CH2CH20H) -Bu Piz 5-76 Me -CH = CH- -C (= 0)-— — 4- (CH2CH2NHAc) + Piz 5-77 Me-CH = CH-- C (= 0)--4- (CH2Car) -l-Piz 5-78 Me -CH = CH- -C (= 0) _ — — 4- (CH2CH20Car) -Bu Piz 5 5-79 Me -CH = CH- -C (= 0)-1,3-Az t--C00H 5-80 Me -CH = CH- -C (= 0)-1,3-Az t--0S03H 5-81 Me -CH = CH- -C (= 0)-1,3-Az t--〇p〇3h2 5-82 Me -CH = CH- -C (= 0)-1,4-Pip--C00H 5-83 Me- CH = CH- -C (= 0)-.1,4-Pip--so3h 10 5-84 Me -CH = CH- -C (= 0)-1,4-Pip--OSO3H 5-85 Me- CH = CH- -C (= 0)-1,4-Pip--0P03H2. 5-86 Me -CH = CH--C (= 0)-1? 4-Pip-1-Pyrd 5-87 Me- CH = CH- -C (= 0)-1,4-Pip-1-Pip 5-88 Me -CH = CH- -C (= 0)-1,4-Pip-4-Me-1-Piz 15 5-89 Me -CH = CH- -C (= 0)-1,4-Pip-4-(CH2CH2OH) -l-Piz 5-90 Me -CH = CH--C (= 0)-1,4 -Pip-4- (CH2CH2NHAc) -l-Piz 5-91 Me -CH = CH- -C (= 0)-.1,4-Pip-4-Mor 5-92 Me -CH = CH- -C ( = 0)-1,4-Pip--NHMe · 5-93 Me -CH = CH_ -C (= 0)-1,4-Pip--NMe2 20 5-94 Me -CH = CH- -C (= 0)-1,4-Pip--NMeCH2CH2OH. 5-95 Me -CH = CH- -C (= 0)-1,4 -Pip--N (CH2CH2OH) 2 5-96 Me -CH = CH- -C (= 0)-1,4-Pi.p -CHr -C00H 5-97 Me -CH = CH- -C (= 0 )-1,4-Pip -CHr-oso3h 5-98 Me -CH = CH- -C (= 0)-l, 4 ~ Pip &quot; &quot; CH2 ~ -opo3h2 25 5-99 Me -CH = CH- -C (= 0)-l, 4 ~ Pip -CHr 4-Mor 5-100 Me -CH = CH- ~ C (= 0)-1,4-Pip -CHr -nh2 5-101 Me -CH = CH --C (= 0)-1,4-Pip -CH2- -NHMe .5-102 Me -CH = CH- -C (= 0)-1,4-Pip -CHr -NMe2 5-103 Me -CH = CH--C (= 0)-1,4-Pip -CHr-NMeCH2CH2OH 30 5-104 Me -CH = CH- -C (= 0)-1,4-Pip ~ CH2- -N (CH2CH20H) 2 -134- 200410948 5-105 Me -CH2CHr -C (= 0)-1,4-Piz--so2nh2 5-106 Me -CH-CH- -C (-0)-1,4-Piz -CH2CH2- 4 -Mor 5-107 Me -CH = CH- -C (two 0)-1,4-Piz -CH2CH2- -NHMe 5-108 Me -CH ^ CH- ~ C (= 0)-1,4-Piz- CH2CH2- -NMe2 5 5-109 .Me -CH-CH- -C (-0)-. 1,4-Piz -CH2CH2---circle eCH2CH20H 5-110 Me -CH-CH- -C (-0) -1,4-Piz -CH2CH2- -N (CH2CH2OH) 2 5-111 Me -CHr -NHC (two 0)---ch2- 4-Me-l-Piz 5-112 Me -CHr -NHC (= 0 )---ch2- -4- (CH2CH20H) -lP 5-113 Me -CHr -NHC (= 0)----ch2- --bande2 10 5-114 Me -CH2- -NMeC (= 0)---ch2- 4-Me-l-Piz 5-115 Me -CHr -Li eC (two 0)--~ ch2- -4- (CH2CH20H) -lP 5-116 Me -CH2- -Li eC (= 0 )---CH2- -NMe2 5-117 Me -CH2CH2- -C〇 = 0) Bandit---CH2CH2- -C00H 5-118 Me -CH2CH2--C (= 0) ^ e- -ch2ch2-- SO3H 15 5-119 Me -CH2CHr -C (= 0) Lie----ch2ch2- -NMe2 5-120 H -CH2----1-Pyrd 5-121 H -CHr---1-Pip 5- 122 H -CHr-l-Me-4-Pip 5-123 H -CHr---1- (CH2CH20H) -4-Pip 20 5-124 H -CHr-— — 4-Me-l-Piz 5-125 H -CHr---4- (CH2CH20H) -l-Piz 5-126 Η-CH2---'—— 4-Mor 5-127 H _CHr-one--nh2 5-128 H-CHr-— —- NHMe 25 5-129 H -CHr one one -band 2 -130 H -CH2CH2----'-C00H 5-131 H -CH2CH2----opo3h2 5-132 H -CH2CHr-_ 1-Pyrd 5- 133 H ~ CH2CHr--1-Pip 30 5-134 H -CHXHr--l-Me-4-Pip mm 135-200410948 5-135 H -CH2CH`` 5-136 H -ch2ch2_ 5-137 H -ch2ch2- 5 -138 H -CH2CHr 5 5-139 H -CH2CH2- .5-140 H -ch2ch2- 5-141 H -ch2ch2- 5-142 H-(CH2) 3- 5-143 H-(CH2) 3- 10 5 -144 • H -ch2ch2- 5-145 H-ch2ch 「 5-146 H -CH2CHr 5-147 H -CH2CH2- 5-148 H -CH2CHr 15 5-149 H -CH2CH2- 5-150 H -CH2CHr 5-151 H -CH2CH2- 5-152 H -CH2CHr 5-153 H -ch2ch2- 20 5-154 H-CH2CHr 5-155 H -CH2CH2- 5-156 H -CH2CHr 5-157 H -CH2CH2 ~ 5-158 H -ch2ch2- 25 5-159 H-ch2ch 「5-160 H _CH2CHr 5-161 H -CH2CH2- 5-162 H -CH2CHr 5-163 H -ch2ch2- 30 5-164 H -ch9ch9--C (= 0)---c (= 〇)-one- C (= 0) ---C (= 0)-one-c (= 〇)-one- c (= 0)-one-c (= 0)----C (= 0)-one- CH)-one- c ( = 〇)-1,3-Az t -c (= 0)-1,3-Azt -c (= 0)-1,3-Azt-c (= 0)-1,4-Pip-c (= o)-1,4-Pip-c (= 〇)-1,4-Pip -c (= 0)-1,4-Pip-c (= 〇)-1,4-Pip-c (= o) -1,4-Pip-CH)-1,4-Pip-CH)-1,4-Pip -c (= 0)-1,4-Pip l- (CH2CH20H) -4-Pip 4-Me]- Pi z 4-(CH2C_ + Piz 4-Mor -NHMe • -NMe2 -COOH -0P03H2 1-Piz 4- (C (= NH) NH2) -HPiz 4- (C (= NH) CH3) -1-Piz 4 -Me-1-Piz 4- (CH2CH20H) -l-Piz 4- (CH2CH2NHAc) -l-Piz 4-(CH2Car)-1_P iz 4- (CH2CH20Car) -l ~ Piz 4-(CH2CH2F) + Piz

-COOH

-0S03H-〇p〇3h2

-COOH -S03H-oso3h -OPOA l ~ Pyrd 1-Pip 4-Me-HPiz 4-(CH2CH2OH)-Bu; Piz 4-Mor -136- 200410948

V 5-165 H -CH2CHr -C (-0) ~ 1,4-Pip--_e 5-166 H -CH2CHr -C (= 0)-1,4-Pip -NMe2 5-167 H -CH2CHr -C (= 0)-1,4-Pip-.- wake up eCH2CH2OH 5-168 H -CH2CH2- -C (= 0)-1,4-Pip--N (CH2CH20H) 2 5 5-169 H -CH2CH2-- C (: 0)-1,4-Pip-ch2--C00H .5-170 H -CH2CH2--C (= 0)-1,4-Pip-ch2- -so3h 5-171 H -CH2CHr -C ( = 0)-1,4-Pip -ch2- -oso3h · 5-172 H -CH2CH2- -C (= 0)-1,4-Pip -ch2-.-〇p〇3h2 5-173 H -CH2CHr- C (= 0)-1,4-Pip -CH2-4-Mor 10 5-174 H -CH2CHr -C (= 0)-.1,4-Pip -CH2- -nh2. 5-175 H -CH2CHr- C (= 0)-1,4-Pip-ch2- •-臓 e 5-176 H -CH2CH2- -C (= 0)-1,4-Pip -CH factory '-NMe2 5-177 H -CH2CH2- -C (= 0)-1,4-Pip Mai-NMeCH2CH20H, 5-178 H-CH2CHr-C (= 0)-1,4-Pip -ch2- -N (CH2CH20H) 2 15 5-179 H -CH2CH2 --C (= 0)-1,4-P iz a -so2nh2 5-180 H -CH2CHr -C (= 0)-1,4-Piz -ch2ch2- 1-Azt 5-181 H -CH2CH2- -C (= 0)-1,4-P iz -CH2CHr 1-Pyrd 5-182 H -CH2CH2- -C (= 0)-1,4-Piz-CH2CH2-1-Pip 5-183 H -CH2CH2- -C (= 0)-1,4-Piz-CH2CH2-4-Me-HPiz. 20 5-184 H -CH2CHr -C (= 0)-1,4-Piz -CH2CHr 4- (CH2CH20H) -HPiz 5-185 H -CH2CHr ~ C (= 0)-1,4-Piz -CH2CHr 4-Mor 5-186 H -CH2CHr -C (= 0)-1,4-Piz -CH2CH2- -NHMe 5-187 H -CH2CH2- -C (= 0)-1,4-Piz-CH2CHr-NMe2 5-188 H -CH2CH2- _C (= 0) -1,4-Piz -CH2CHr-NMeCH2CH2OH 25 5-189 H -CH2CHr -C (= 0)-1,4-Piz-CH2CHr-N (CH2CH2OH) 2 5-190 H -CH = CH- -C (= 0)--— HPiz 5-191 H -CH = CH- -C (= 0)-—-4- (C (= NH) NH2) -l-Piz 5-192 H -CH = CH- -C ( = 0)---4 ~ (C (= NH) CH3) -1-Piz 5-193 H -CH = CH- -C (= 0)-one-four-Me-1-Piz 30 5-194 H -CH = CH- -C (= 0)-a- 4- (CH2CH20H) -l-Piz '137 200410948 5-195 H ~ CH = CH- -C (= 0)-one-to-four-(CH2CH2NHAc) + Piz 5-196 H -CH = CH-CH)-one-four- (CH2Car)-l-Piz 5-197 H -CH = CH- -C (= 0)-one-four- (CH2CH20Car) -l ~ Piz 5-198 H -CH = CH- -CH))-1,3-Az t one-C00H 5 5-199 H-CH = CH--C (= 0)-1,3-Az t--oso3h 5-200 H -CH = CH- ~ C (= 0)-1,3-Az t--opo3h2 5-201 H -CH = CH—C (= 0)-1,4-Pip--C00H 5- 202 H -CH = CH- -C (= 0)-1,4-Pip--so3h 5-203 H -CH = CH- -G (= 0)-1,4-Pip 1 -oso3h 10 5-204 H -CH = CH- -C (= 0)-1, 4-Pip- a-〇p〇3h2 5-205 H-CH = CH——C (= 0)-1,4 -Pip-1-Pyrd 5-206 H -CH = CH- -C (= 0)-1,4-Pip-1-Pip 5-207 H _CH = CH- -C (= 0)-1,4- Pip-4-Me-HPiz 5-208 H -CH = CH- -C (= 0)-1,4-Pip-4- (CH2CH20H) -1 -Piz 15 5-209 H -CH = CH- ~ C (= 0)-1,4 ~ Pip a 4- (CH2CH2NHAc)-HPiz 5-210 H -CH = CH- -C (= 0)-1,4-Pip-4-Mor 5-211 H -CH = CH——C (= 0)-1,4-Pip--NHMe 5-212 H -CH = CH- -C (= 0)-1,4-Pip--NMe2 5-213 H -CH = CH- -C (= 0)-1,4-Pip--NMeCH2CH2OH 20 5-214 H -CH = CH- -C (= 0)-1,4-Pip--N (CH2CH2OH) 2 5-215 H -CH = CH- -C (= 0)-1,4-Pip-ch2- -C00H 5-216 H ~ CH = CH- ~ C (= 0)-1,4-Pip-ch2- -0S03H 5-217 H -CH = CH ~ *-C (= 0)-1,4-Pip-ch2 · -〇p〇3h2 5-218 H -CH = CH- -C (= 0)-1,4-Pip-ch2 · -4-Mor 25 .5-219 H -CH = CH- -C (= 0)-1,4-Pip-ch2- -nh2 5-220 H -CH = CH--CH)-1,4-Pip -ch2- -NHMe 5-221 H -CH = CH- -C (= 0)-1,4-Pip -ch2- --NMe2. 5-222 H -CH = CH- -C (= 0)-1 , 4-Pip -ch2 · -NMeCH2CH2OH 5-223 H -CH = CH- -C (= 0)-1,4-Pip -ch2 · -N (CH2CH20H) 2 30 5-224 H-CH2CH2——CH)-1,4-Piz a- so2nh2 -138- 200410948 5-225 H -CH = CH- -CH)-1,4- Piz -CH2CHr 4-Mor 5-226 H -CH = CH- ~ C (= 0)-1,4-Piz ~ CH2CHr -NHMe 5-227 H -CH = CH- -C (= 0)-1,4 -Piz -CH2CHr -NMe2

5-228 H -CH-CH- -C (= 0)-1,4-Piz -CH2CHr -NMeCH2CH2OH 5 5-229 H -CH = CH- -C (= 0)-1,4-Piz -CH2CHr- N (CH2CH20H) 2 5-230 Η-CH2--NHC (= 0)-5-231 Η-CH 「· -NHC (= 0)-5-232 Η -CHr -NHC (= 0)-5-233 Η-ch2- ·-NMeC (= 0)-10 5-234 Η -ch2- -Li eC (= 0)-5-235 Η-CH 「-NMeC (= 0)-5-236 Η -CH2CHr -C (= 0) i ^ e- 5-237 Η-ch2ch2--(: (= 0 »-5-238. Η -CH2CHr-C (= 0) Li e- 15. 5-239 Me 1,4-cHx One 5-240 Me 1,4-cHx One 5-241 Me 1,4-cHx One 5-242 Me 1,4-cHx-5-243 Me 1,4-cHx — 20 5-244 Me 1,4- cHx-5-245 Me 1,4-cHx-5-246 Me l, 4-cHx-5-247 Me 1,4-cHx-5-248 Me 1,4-cHx -25 5-249 • Me 1, 4-cHx-5-250 Me 1,4-cHx-5-251 H 1,4-cHx -5-252 H l, 4_cHx -5-253 H .1,4-cHx -30 5-254 H 1, 4-cHx mono-CHr 4-Me -1 -Piz -CHr 4 ~ (CH2CH20H) -1-Piz -CH2- .-NMc2-CHr 4-Me + Piz -CHr 4- (CH2CH20H) -l-Piz-CH2 --NM62

-CH2CHr-C00H

-CH2CHr · —S03H -CH2CH2- -NMe2

-'-COOH--0Ρ03Η2-1-Pyrd-1-Pip -1-Me-4-Pip-Bu (CH2CH20H) -4-Pip-4-Me-HPiz-4-(CH2CH2OH)-Bu Piz-4- Mor I-nh2--NHMe--NMe2

--COOH a -〇P〇3H2-1-Pyrd-1-Pip 139- 200410948

5-255 H 1,4-cHx — — One 1-Me_4-Pip 5-256 Η 1,4r-cHx One one one (CH2CH20H) -4-Pip 5-257 Η 1,4-cHx — One-4 -Me-HPiz 5-258 Η 1,4-cHx — ~-4-(CH2CH20H) -Bu Piz 5 5-259 Η 1,4-cHx — — 4-Mor .5-260 Η 1,4-cHx — — — -Νη2 5-261 Η 1,4-cHx — —--NHMe 5-262 Η 1,4-cHx-1--NMe2 5-263 Me _ (CH2) 4--1-C00H 10 5- 264 Me-(ch2) 4-—---so3h 5-265 Me-called 4- r- — --0S03H 5-266 Me ~ (CH2) r — —--opo3h2 5-267 Me _ (CH2) 5 -— One--C00H 5-268 Me-(ch2) 5-----SO3H 15 5-269 Me-(CH2) 5----0S03H 5-270 Me-(CH2) 5----- -〇p〇3h2 5-271 Me-(CH2) 3- -C (= 0) NMe—— -CH2CHr -SO3H 5-272 Me-(ch2) 4--C (= 0) NMe—— -ch2ch2_ • -so3h 5-273 Me-(ch2) 5- -C (= 0) NMe-- -ch2ch2- -so3h 20 5-274 Me _ (CH2) 6_ -C (= 0〉 NMe----CH2CHr -S03H 5 -275 H-(ch2> 4- — — •--C00H 5-276 H ~ (CH2) r — — one-so3h 5-277 H-(CH2) r one one one -OSO3H 5-278 H-(CH2 ) r — — —-0P03 h2 25 5-279 H-(ch2) 「—.--C00H 5-280 H-(ch2)「 ―One--SO3H 5-281 H-(ch2) 5-―One--OSO3H 5-282 H -(ch2) 5-one one--〇〇〇〇〇3H2 5-283 H-(CH2) 「-C (= 0) NMe— -ch2ch2- -SO3H 30 5-284 H-(ch2) 4--C ( = 0) NMe---CH2CHr -SO3H -140- 200410948 5-285 H-(CH2) 5--C (= 0) _---CH2CHr-so3h 5-286 Η-(CH2) 6--C ( = 0) NMe---CH2CHr-so3h 5-287 Me -CH2CHr -0C (= 0)-One 1-Me-4-Pip 5-288 Me -CH2CH2--0C (= 0)-One-CHr- C00H 5 5-289 Me -CH2CHr -0C (= 0)---CH2--so3h 5-290 Me -CH2CH2--0C (= 0)---CH "-〇P〇3H2 5-291 Me -CH2CHr -0C (= 0)-• one-CHr 1-Azt 5-292 Me -CH2CHr -0C (= 0)-• one- CHr HPyrd 5-293 Me -CH2CHr -oc (= 〇)-one- ch2- HPip 10 5-294 Me -CH2CH2--oc (= o)-One-CHr 1-Me-4-Pip 5-295 Me -CH2CH2--oc (= o)-One-CHr 4-Me-1-Piz 5 -296 Me -CHXIL- UL -0C (= 0)---CHr 4- (CH2CH20H) -l-Piz 5-297 Me ~ CH2CHr -oc (= 〇)----CHr 4-Mor 5-298 Me- CH2CHr-oc (= o)---ch2- -Li e2 15 5-299 Me -CH2CHr -0C (= 0)---CH r-NM_eCH2CH20H 5-300 Me -CH2CH2- -oc (= 〇)-one-ch2- -N (CH2CH2OH) 2 5-301 Me -CH2CHr-oc (= o)---CH2GH2 ~ -C00H 5-302 Me -CH2CHr -0C (= 0) ~--CH2CHr-so3h 5-303 Me -CH2CHr-oc (= o)-'--CH2CHr-〇p〇3h2 20 5-304 Me -CH2CH2--oc (: 0) -One- CH2CH2-1-Azt 5-305 Me ~ CH2CH2 ~ · -OC (= 0)---CH2CH 「HPyrd 5-306 Me -CH2CHr-0C (= 0)-One-by-two CH2CHr Pip 5-307 Me -CH2CHr -oc (= o)-One- CH2CHr 1-Me-4-Pip 5-308 Me -CH2CH2--oc (= o)---CH2CHr 4-Me-HPiz 25 5-309 Me -CH2CH2-- oc (二 〇)-mono-CH2CH2- 4- (CH2CH20H)-: HPiz 5-310 Me -CH2CH2- -0C (= 0)---ch2ch2- 4-Mor 5-311 Me -CH2CHr-oc (= o )---CH2CHr-NMe2 5-312 Me -CH2CHr -OC (= 0) ~ One-CH2CHr -NMeCH2CH20H-5-313 Me -CH2CHr-oc (= 〇)-One-CH2CHr-N (CH2CH2OH) 2 30 5 -314 Me-(CH2)-oc (= o)---l-Me-4-Pip -141-200410948

5-315 Me _ (CH2) 3- -0C (= 0)-— .-CHr -C00H 5-316 Me _ (CH2) 3--0C (= 0)---ch2--so3h 5-317 Me _ (CH2) 3--oc (= o)-·--ch2-. -〇p〇3h2 5-318 Me-(CH2) r-OCH)-.a.- CHr 1-Azt 5 .5-319 Me-(CH2) 3- -OC (= 0)-one, ch2- 1-Pyrd .5-320 Me-(CH2) 3--oc (= 〇)-one dance 1-Pip. 5-321 Me- (CH2) 3--OC (= 0)---CHr 1-Me-4-Pip 5-322 Me-(CH2) 3--OC (= 0)---CHr 4-Me "l-Piz 5 -323 Me-(CH2) 3--OC (= 0)-one- CHr 4-(CH2CH2OH) + Piz 10 5-324 Me-(CH2) r -〇C (= 0)-one-ch2- 4- Mor 5-325 Me-(CH2) 「-oc (= o)-•--CHr, -_2 5-326 Me-(CH2) 3- -OC (= 0)---CH「-NMeCH2CH2OH 5-327 Me-(CH2) 3- -OCH)---ch2- -N (CH2CH20H) 2 5-328 Me-(CH2) 「-OC (= 0)---CH2CHr _C00H 15 • 5-329 Me _ (CH2 ) 3- -OC (= 0)---CH2CHr -S03H 5-330 Me-(CH2) r _oc (= o)---CH2CHr -OPO3H2 5-331 Me _ (CH2) `` -OC (= 0) -One.One CH2CH2- l-Azt 5-332 Me _ (CH2) 3- -OC (= 0)-One-CH2CHr HPyrd ... 5-333 Me-(CH2) 3--oc (= 0)- -*-CH2CH2- .1-Pip 20 5-334 Me _ (C H2) r-oc (= o)---CH2CHr 1-Me-4-Pip 5-335 Me -_3- -OC (= 0)-— -CH2CHr 4-Me-: HP iz 5-336 Me _ ( CH2) 3- -0C (= 0)---CH2CH2- 4- (CH2CH2OH) -l-Piz 5-337 Me-(CH2) 3- -〇C (= 0)---CH2CHr 4-Mor 5- 338 Me-(CH2) 3- -OCH)-One-CH2CHr -Li e2 25 5-339 Me-(CH2) r -oc (= 0)-— -CH2CHr-NMeCH2CH2OH 5-340 Me-(CH2) 3- -oc (= o)-one- CH2CHr -N (CH2CH2OH) 2 5-341 Me -CH2CH2- -c (= 0) 0--1-Me-4-Pip 5-342 Me -CH2CHr-C (= 0 ) 0-One-CH2--C00H 5-343 Me -CH2CHr-C (= 0) 0-One -CHr 1-Me-4-Pip 30 5-344 Me -CH2CHr -C (= 0) 0--- CH2CHr-COOH -142- 200410948

5-345 Me -CH2CH2--c (= o) 〇---CH2CH factory-S03H 5-346 Me -CH2CHr -CH) 0---ch2ch2- -0P03h2 5-347 Me -CH2CHr-C (= 0) 0---ch2ch2- 1-Azt 5-348 Me -CH2CHr-C (= 0) 〇---CH2CHr 1-Pyrd 5 5-349 Me -CH2CHr-C (= 0) 0---CH2CHr 1-Pip • 5-350 Me -CH2CHr-C (= 0) 0---ch2ch2- 1-Me-4-Pip 5-351 Me -CH2CHr -C (二 ◦) 0---ch2ch2- 4-Me-1- Piz 5-352 Me -CH2CHr-c (= 〇) o---ch2ch2_ 4- (CH2CH20H) -l-Piz 5-353 Me -CH2CHr -C (= 0) 0---ch2ch`` 4-Mor 10 5 -354 Me -CH2CHr-c (= o) o---CH2CHr -Li e2 5-355 Me -CH2CHr-C (= 0) 0---ch2ch2- -Li eCH2CH20H 5-356 Me -CH2CH2- -c ( = o) o---ch2ch2--N (CH2CH20H) 2 5-357 Me -CH = CH--C (= 0) 0--I-4-Pip 5-358 Me -CH = CH-- c (= o) o---CH2--C00H 15 5-358 Me -CH = CH- -C (= 0) 0-- -ch2- l-Me-4-Pip 5-359 Me -CH = CH -~ C (= 0)--CH2CHr -C00H 5-360 Me -CH = CH--c (= o) o- _ -CH2CH2--so3h 5-361 Me -CH = CH--c (: o) o---ch2ch 「5-362 Me -CH = CH- -C (= 0) 0---ch2ch2- 1-Az t 20 5-363 Me -CH = CH- .-c (= o) o- --ch 2ch2_ 1-Pyrd 5-364 Me -CH = CH- -c (= o) o---ch2ch 「1-Pip 5-365 Me -CH = CH--c (= o) o-- -CH2CHr 1- Me-4-Pip. 5-366 Me -CH = CH--C (= 0) 0----CH2CH2-4-Me-1-Piz 5-367 Me -CH = CH--C 0 = 0) 0 ---ch2ch2- 4-(CH2CH2OH) -Bu Piz 25 5-368 Me -CH = CH--C (= 0) 0---CH2CHr 4-Mor 5-369 Me -CH = CH- -c (= o) o---CH2CHr -NMe2 5-370 Me -CH = CH--c (: o) o---ch2ch2- -LiCH2CH2OH 5-371 Me -CH = CH--C (= 0) 0- --CH2CHr -N (CH2CH2OH) 2 5-372 H -CH2CH2_-oc (= o) _--1-Me-4-Pip 30 5-373 H -CH2CHr _oc (= o) _--CHr -C00H- 143- 200410948 5-374 Η -CH2CH2--oc (= o)--'-CHr -so3h 5-375 Η -CH2CHr -0CH)--CHr -〇P〇3H2. 5-376 Η-CH2CHr -0C (= 0)-One-CHr 1-Azt 5-377 Η -CH2CHr -OC (= 0)-One- CH2- 1-Pyrd 5 5-378 Η -CH2CHr -OC (= 0)-One_CH2- Bu Pip 5-379 Η -CH2CHr-oc (= 0)---ch2-Bu Me-4-Pip 5-380 Η-CH2CHr -0C (= 0)---CHr 4-Me-HPiz 5-381 Η- CH2CHr -〇C (= 0)-one-CH2- 4-(CH2CH2OH) -l-Piz 5-382 Η -CH2CHr -OC (= 0)-one -CHr 4-Mor 10 5-383 Η -ch 2ch2- ~ 0C (= 0) ~ one-ch2- -NMe2 5-384 Η-CH2CHr -oc (= 〇)-one, -ch2- -NMeCH2CH2OH 5-385 Η -ch2ch2--OC (= 0)-. Mon-ch2_ -N (CH2CH20H) 2 5-386 Η-CH2CHr-oc (= 〇)----CH2CHr-COOH 5-387 Η -CH2CHr -OC (= 0)-Mon -ch2ch`` -S03H 15 5-388 Η-CH2CHr -oc (= 〇)---CH2CHr-opo3h2 5-389 Η -CH2CHr -〇C (= 0)----CH2CHr l-Azt 5-390 Η-CH2CHr-oc (= 0)--·· -CH2CHr 1-Pyrd 5-391 Η-CH2CH2--OC (= 0)-One -CH2CHr 1-Pip. 5-392 Η-ch2ch2- -OC (= 0)-One -CH2CH2-1-Me-4- Pip 20 5-393 Η-CH2CHr -oc (= 〇)----CH2CHr 4-Me-HP iz 5-394 Η -ch2ch2--OC (= 0)--• -CH2CHr 4- (CH2CH20H) ~ l- Piz 5-3.95 Η, -CH2CHr -oc (= 〇)-1-CH2CHr 4-Mor 5-306 Η-CH2CHr -〇C (= 0)-— -ch2ch2--NMe2 5-397 Η -CH2CHr -〇C (= 0)-—-CH2CHr -NMeCH2CH2OH 25 5-398 Η -CH2CH2--oc (= 〇)---CH2CHr-N (CH2CH2OH) 2 5-399 Me-(CH2) 3--oc (= o) -One — .1 -Me-4 -Pip 5-400 Me-(CH2) 3- -oc (= o)-One · -CHr-COOH 5-401 Me-(CH2) r-oc (= o)- One -CH Factory-so3h 5-402 Me _ (CH2) 3- -OC (= 0)-— one CHr-〇p〇3h2 30 5-403 Me-(CH2) 3--oc (= 〇)--one CHr 1-Azt 144- 200410948 5-404 Me-(CH2) 3- -0C (= 0)-'— 5-405 Me-(CH2> 3--0C (= 0)--5-406 Me-( CH2) 3--0C (= 0)-,-5-407 Me-(CH2) 3 ~ -0C (Tue 0)-One 5 5-408 Me _ (CH2〉 「-OCH)--5-409 Me _ (CH2> 3- -0C (= 0)-one 5-410 Me _ (CH2) 3- -OC (= 0)--5-411 Me ~ (CH2) 3 ~-0C (= 0)-one 5-412 Me _ (CH2) 3- -oc (= 〇)--10 5-413 Me-(CH2) 3- ~ 0C (= 0)--5-414 Me-(CH2). 3--oc (= o)-— 5-415 Me-(CH2) 3--oc (two 0)--5-416 Me ~ (CH2) 3 ~ -0C (= 0)-.-5-417 Me-(CH2 ) 3 ~, oc (= 〇)--15 5-418 Me-(CH2) 3- _oc (= o)--5-419 Me-(CH2) 3- -oc (= o)-one 5-420 Me _ (CH2> 3--oc (= 〇)--5-421 Με-(CH2) 3 ~-oc (= o)--5-422 Me-(CH2) 3- -oc (= o)- -20 5-423 Me-(CH2) 3 ~ -oc (= o)--5-424 Me _ (CH2) r -00 (= 0)--5-425 Me _ (CH2) 3--oc ( = o)-One 5-426 H -CH2CHr -C (= 0) 0- One 5-427 H -CH2CHr -c (= o) o--25 5- 428 H -CH2CHr-c (= o) o--5-429 H -CH2CHr -c (= o) o--5-430 H -CH2CHr -C (= 0) 0--5-431 H -CH2CH2- -c (: 0) 0--5-432 H -CH2CHr -C (= 0) 0-one 30 5-433 H _CH? CHr -c (= o) o-one-CH2- l-Pyrd-CHr 1 -Pip -CHr l_Me-4-Pip-CH2- 4-Me-HPiz-CHr 4- (CH2CH20H) + Piz

-ch2- 4-Mor -CHr-NMe2-ch2- -NMeCH2CH20H.-CHr -N (CH2CH20H) 2-ch2ch 「-COOH-CH2CHr -SO3H-CH2CHr -〇p〇3h2 _ch2ch「 l-Azt-CH2CHr l-Pyrd -CH2CHr • Pip-ch2ch 「l-Me-4-Pip -CH2CHr 4-Me-1-Piz -CH2CHr 4- (CH2CH2OH) -l-Piz -CH2CHr 4-Mor-CH2CHr-NMe2 -CH2CHr -NMeCH2CH2OH -CH2CHr -N (CH2CH2OH) 2-l-Me-4-Pip-CHr-COOH-CHr 1-Me-4-Pip -CH2CHr-COOH-CH2CHr -SO3H.-CH2CHr-0P〇3H2-CH2CHr 1-Azt-CH2CHr l ~ Pyrd 145-

20041094S 5-434 Η-ch2ch2--C (two 0) 0---CH2CHr 1-Pip 5-435 Η -ch2ch2- -C (two 0) 0---ch2ch2- 1-Me-4-Pip 5- 436 Η -CH2CHr ~~ C (-0) 0 ~--CH2CHr 4-Me-l-Piz • 5-437 Η-CH2CHr -C (二 〇) 〇-.-.-CH2CHr 4- (CH2CH20H) ~ l ~ Piz 5 5-438 Η -CH2CHr -C (two 0) 0---ch2ch2- 4-Mor 5-439 Η -ch2ch2- -C (two 0) 0---ch2ch 「-NMe2 5-440 Η- GH2CHr -C (: 〇) 〇-- -CH2CHr -NMeCH2CH20H 5-441 Η -CH2CHr -c (= o) o----CH2CHr -N (CH2CH2OH) 2 5-442 Η -CH = CH--C (two 0) 0---1-Me-4-Pip ΙΟ 5-443 Η -CH = CH- -C (two) 0--ch2- -C00H 5-444 Η -CH di CH- -C (= 〇) 〇---ch2- l-Me-4-Pip, 5-445. Η -CH di CH- .-C (two 0) 0-- -ch2ch2- -COOH 5-446 Η -CH = CH- -C (= 0) 0---ch2ch2- -so3h 5-447 Η -CH di CH--C (two 0) 0--ch2ch2- -〇p〇3h2 15 5-448 Η -CH = CH- -CH) 0-- -ch2ch2- 1-Azt 5-449 Η -CH = CH--C (= 0) 0---CH2CHr 1-Pyrd 5 ~ 450 Η -CH = CH- -C (= 0) 0-~ -CH2CHr 1-Pip 5-451 Η -CH: CH- -C (= 0) 0-- -ch2ch2- 1-Me-4-Pip 5-452 Η -CH = CH--C (= 0 ) 0---ch2ch 2- 4-Me-l-Piz 20 5-453 Η -CH = CH--C (two 0) 0---ch2ch2- 4- (CH2CH20H) -l ~ Piz 5-454 Η -CH: CH-- c (: o) o---ch2ch2- 4-Mor 5-455 Η -CH = CH--C (0) 0---ch2ch2- ， e2 5-456 Η -CH = CH- -c (= o ) o---ch2ch2- -Li eCH2CH2OH 5-457 Η -CH di CH- -C (-0) 0-- -CH2CHr -N (CH2CH2OH) 2 Table 6 -146-25 200410948

5 Examples. Compound No. R 丨 -L1--G- 6-1 Me -CH2--6-2 Me -CHr-6-3 Me -CH2---10 6-4 Me -CHr-- 6-5 Me -CHr--6-6 Me -CHf--6-7 Me -CHr--6-8 Me -CH2---15 6-9 Me -CH2---6-10 Me -CHf- -6-11 Me -CH2CH 「--6-12 Me -CH2CHr--6-13 Me -CH2CHr--20 6-14 Me -CH2CH2---, 6-15 Me -CH2CH2——-6-16 Me -CH2CH2---6-17 Me -CH2CHr--6 ~ 18 Me -CH2CH2---25 6-19 Me -CH? CH,--

-L2--L3- -A β -1-Pyrd ·-1-Pip-1-Me-4-Pip 1- (CH2CH20H) -4-Pip-4-Me-1-Piz-4- (CH2CH20H)- l-Piz-4-Mor--νη2--NHMe--NMe2, paralysis

--COOH--opo3h2-Bu Pyrd 1-Pip-l-Me-4-Pip-Bu (CH2CH2OH)-4-Pip-4-Me-l ~ Piz-4- (CH2CH20H) -l-Piz One 4- Mor -147- 200410948 6-20 Me -CH2CHr--one -NH2 6-21 Me -CH2CH2- one-one -NHMe 6-22 Me -CH2CH2--one one, e2 6-23 Me-(CH2) "one -One- C00H 5 6-24 Me-(CH2) 3_-One-one-〇P〇3H2 6-25 Me -CH2CH2- -c (= 0)-One-one 1-Piz 6-26 Me -CH2CH2- -c (= 〇)-One 4- (C (= NH) NH2) -1-Piz 6-27 Me -CH2CH2- -c (= o)---4-(C (DiNH) CH3) + Piz 6 -28 Me ~ CH2CHr-c (= 0)---4-Me-l-Piz 10 6-29 Me -CH2CH2--c (= o)---4- (CH2CH20H) ~ l-Piz 6-30 Me -CH2CHr -c (= o)-one 4- (CH2CH2NHAc) -l ~ Piz 6-31 .Me -GH2.CH2--c (= o)-one-4 ~ (CH2Car) -l-Piz 6- 32 Me -CH2CH2--c (= o)---4- (CH2CH20Car) + Piz 6-33 Me -CH2CHr -c (= 0)---4- (CH2CH2F) -l-Piz 15 6-34 Me ~ CH2CHr -C (= 0)-1,3-Az t — -C00H 6-35 Me -CH2CH2--c (= 〇)-1,3 ~ Az t --0S03H 6-36 Me -CH2CH2- -c (= 0)-1,3-Azt one- opo3h2 6-37 Me -CH2CHr -c (= 0)-1,4-Pip one.-COOH 6-38 Me -CH2CHr-C ( = 0)-1,4-Pip a -SO3H 20 6-39 Me -CH2CH2--c (= o)-1,4-Pip a -OSO3H 6-40 Me -CH2CH2--c (= o)-1 , 4-Pip a- opo3h2 6-41 Me ~ CH2CHr -c (= 0)-1,4-Pip a 1-Pyrd 6-42 Me -CH2CHr-c (= o)-1,4-Pip-1- Pip 6-43 Me -CH2CH2- -c (= 0)-1,4-Pip-4-Me-1-Piz 25 6-44 Me -CH2CH2- -C (= 0)-1,4-Pip one 4 -(CH2CH20H) -l-Piz 6-45 Me -CH2CH2- -C (= 0)-1,4-Pip one 4-Mor 6-46 Me -CH2CHr -C (= 0)-1,4-Pip one -NHMe 6-47 Me -CH2CHr ~ c (= 〇)-1,4-Pip--Li e2 6-48 Me -CH2CH 「-c (= 0)-1,4-Pip--Draw eCH2CH2OH 30 6- 49 Me -CH2CHr -c (= 〇)-1,4-Pip one ~ N (CH2CH2OH) 2 -148- 200410948

6-50 Me -CH2CHr -C (= 0)-1,4-Pip-ch2- -C00H 6-51 Me -CH2CHr -C (= 0)-1,4-Pip-CHr -so3h 6-52 Me- CH2CHr -C (= 0)-1,4-Pip-CH2- -OSO3H 6-53 Me -CH2CH2- -C (two 0)-1,4-Pip-ch2--〇P〇3H2 5 6-54 Me -CH2CH2- -C (= 0)-1,4-Pip-ch2- 4-Mor 6-55 Me -CH2CH2--C (= 0)-· 1,4-Pip -ch2-6-56 'Me- CH2CHr -C (= 0)-1,4-Pip -CH2--MMe 6-57 Me ~ CH2CHr -C (= 0)-1,4-Pip -CH2--NMe2 6-58 Me -CH2CHr -C ( = 0)-1,4-Pip-ch2- -NMeCH2CH20H 10 6-59 Me -CH2CH2--(: (♦. 1,4-Pip -ch2--_2CH2OH) 2 6-60 Me -CH2CHr -C (= 0)-1,4-Piz one- so2nh2 6-61 Me -CH2CH2——C (two 0)-1,4-Piz-CH2CHr 1-Azt 6-62 Me -CH2CHr -C (= 0) ~ 1, 4-Piz -CH2CHr 1-Pyrd 6-63 Me-CH2CH2——C (= 0)-1,4-Piz-ch2ch2-1-Pip 15 6-64 Me -CH2CHr -C (= 0)-1,4 -Piz-CH2CHr 4-Me-1-Piz .6-65 Me -CH2CHr -C (= 0)-1,4-Piz-CH2CHr 4-(CH2CH2OH) _l -Piz 6-66 Me -CH2CHr -C (= 0)-1,4-Piz-CH2CHr 4-Mor 6-67 Me -CH2CHr -C (= 0)-1,4-Piz -CH2CHr -NHMe 6-68 Me -CH2CH2- -C (= 0)-1 , 4-Piz-CH2CHr -NMe2 20 6-69 Me -CH2CH2——C, (= 0)-1,4-Piz-CH2CHr-NMeCH2CH2OH 6-70 Me -CH2CHr -C (= 0)-1,4-Piz-CH2CHr-N ( CH2CH2OH) 2 6-71 Me -CH = CH- -C (= 0)-one 1-Piz 6-72 Me -CH = CH- -C (= 0)-. One one 4- (C (= NH ) NH2) -1-Piz 6-73 Me -CH = CH-_C (= 〇K a-4- (C (= NH) CH3) -1-Piz 25 6-74 Me -CH = CH- -C ( = 0)---4-Me-1-Piz '6-75 Me -CH = CH- -C (= 0)-a- 4- (CH2CH20H) -HPiz 6-76 Me -CH = CH- -C (= 0)---4- (CH2CH2NHAc) -1-Piz 6-77 Me -CH = CH- -C (= 0)-_ 4-(CH2Car) -Bu Piz 6-78. Me -CH = CH- -C (= 0)---4-(CH2CH2OCar) + Piz 30 6-79 Me -CH = CH- -C (= 0)-1,3-Azt One-C00H -149- 200410948

6-80 Me -CHNCH- -C (= 0)-1,3-Az t one-oso3h 6-81 Me -CH = CH- -C (= 0)-1,3-Az t--opo3h2 6- 82 Me -CH = CH- -C (= 0)-1,4-Pip--COOH 6-83 Me -CH = CH- _C (two 0)-1,4-Pip--so3h 5 6-84 Me -CH = CH——C (= 0)-1,4-Pip — -oso3h 6-85 Me -CH = CH- -C (= 0)-1,4-Pip a-〇P〇3H2 _: 6 -86 Me -CH = CH- -C (= 0)-1,4-Pip a 1-Pyrd 6-87 Me -CH = CH——C (= 0)-1,4-Pip a 1-Pip 6 -88 Me -CH = CH- -C (= 0)-1,4-Pip — i 4-Me-HPiz 10 6-89 Me -CH = CH- -C (= 0)-1,4-Pip — i 4 ~ (CH2CH2OH) -l-Piz 6-90 Me ~ CH = CH- -C (= 〇)-1,4-Pip-4 ~ (CH2CH2NHAc) ~ l ~ Piz 6-91 Me -CH = CH— --C (= 0)-1,4-Pip-4-Mor 6-92 Me -CH = CH- -C (= 0)-. .1,4-Pip--NHMe 6-93 Me -CH = CH --C (= 0) ~ 1,4-Pip —, e2 15 6-94 Me -CH = CH- -C (= 0)-1,4-Pip — -Li eCH2CH2OH 6-95 Me -CH = CH --C (= 0)-1,4-Pip a-N (CH2CH20H) 2 6-96 Me -CH = CH——C (= 0)-1,4-Pip-CHr -COOH 6-97 Me- CH = CH- -C (= 0)-1,4-Pip -CH 「-OSO3H 6-98 Me -CH = CH--C (= 0)-1,4-Pip-CHr -〇p〇3h2 20 6-99 Me -CH = CH——C (= 0) _ 1,4-Pip- CHr 4-Mor 6-100 Me -CH = CH- -C (= 0.)-1,4-Pip-CHr 6-101 Me -CH = CH ~ -C (= 0)-1,4-Pip- CH2--NHMe 6-102 Me -CH = CH- -C (= 0)-1,4-Pip -CHr-NMe2 6-103 Me -CH = CH- -C (= 0)-1,4-Pip -CHr -Noodle eCH2CH20H 25 6-104 Me -CH = CH- -C (= 0)-1,4-Pip -ch2- -N (CH2CH20H) 2 6-105 Me -CH2CH2--C (= 0)- l, 4 ~ Piz--so2nh2 6-106 Me -CH = CH- -C (= 0)-1,4-Piz-ch2ch: 2- 4-M0r 6-107 Me -CH = CH- -C (= 0)-'· 1,4-Piz -ch2ch; Γ -NHMe 6-108 Me -CH = CH- -0 (= 0)-1,4-P iz -ch2cr Γ -Li e2 30 6-109 Me- CH = CH- -C (= 0)-1, 4HPiz -ch2ch Γ. -NMeCH2CH2OH -150- 200410948

6-110 Me -CH = CH- -C (= 0)-1,4-Piz-CH2CH2- -N (CH2CH2OH) 2 6-111 Me -CHr -MCH)---CHr 4-Me-HPiz 6- 112 Me -CH2- -NHC (= 0)---CHr 4- (CH2CH20H) -l-Piz 6-113 Me -CHr -NHC (= 0)---CHr, Me2 5 6-114 Me -CH2- -Draw eC (= 0)---CH2- 4-Me-l-Piz 6-115 Me -CH2- ~ NMeC (= 0)--CH2- 4- (CH2CH20H) ~ l-Piz 6-116 Me -CH2- -fiMeC (= 0)----CHr-NMe2 6-117 Me -CH2CH2- -C (= 0) NMe_--ch2ch2- -cooh 6-118 Me -CH2CH2- -C (= 0) wake up --ch2ch2- -so3h 10 6-119 Me ~ CH2CH2 ~ ~ C (= 0) NM6 ~-CH2CH2- -NM62 6-120 H -CHr---1-Pyrd 6-121 H -CHr--1- Pip 6-122 H -CHr---1-Me-4-Pip 6-123 H-CHr _--Bu (CH2CH2OH)-4-Pip 15 6-124 H -CHr---4-Me-l- Piz 6-125 H -CHr-~-4- (CH.2CH20H) -l-Piz 6-126 Η -CHr--4-Mor 6-127 Η -CHr---nh2 6-128 H -CHr-- --NHMe 20 6-129 H ~ CHr _----e2 6-130 H -CH2CH2——---COOH 6-131 H -CH2CH2——---〇〇〇〇3h2 6-132 H -CH2CHr-- -1-Pyrd 6-133 H -CH2CH2——--1-Pip 25 6-134 H -CH2CH2-----l-Me-4-Pip 6-135 H -CH2CH 「-· _ -l- (CH2CH2OH) -4-Pip 6-136 H -CH2CH2-----4-Me-HPiz 6-137 H -CH2CH2-- -4- (CH2CH20H) -l -Piz 6-138 H -CH2CH2— —--4: -Mor 30 6-139 H _CH? CH factory one by one nh2 -151-200410948

6-140 H -CH2CHr one one--NHMe 6-141 Η -CH2CIV----bande2 6-142 Η-(CH2) 3- one---C00H 6-143 Η-(CH2) 3--one --〇p〇3h2 5 6-144 • H -CH2CHr-C (= 0)-One-1-Piz 6-145 Η -CH2CH2- -c (= 0)-One-4- (C (= NH) NH2) -HPiz 6-146. H-CH2CHr -c (= 0)-one:-4- (C (= NH) CH3) -l-Piz 6-147 H _CH2CH "-c (= 0)-one- 4-Me-HPiz 6-148 Η -CH2CH2- -C (= 0)-—-4- (CH2CH20H) -Bu Piz 10 6-149 Η ~ CH2CHr -C (= 0)-one-4- (CH2CH2NHAc) -l-Piz 6-150 Η-CH2CHr -C (= 0)-Mon-4-(CH2Car) + Piz 6-151 Η -CH2CH factory-C (= 0)-— -4- (CH2CH20Car) -l- Piz 6-152 H -CH2CH2-• ~ C (= 0)---4- (CH2CH2F) -l ~ Piz 6-153 Η -CH2CH2- -C (= 0)-1,3-Azt--C00H 15 6-154 Η ~ CH2CHr -c (= 0)-1, 3_Az t--0S03H 6-155 Η -CH2CHr -c 0 = 0)-1, 3_Az t -〇P〇3H2 6-156 Η -CH2CH 「- C (= 0)-1,4-Pip--C00H 6-157 Η -CH2CHr -c (= 0)-1,4-Pip--SO3H 6-158 Η -CH2CHr -c (= 〇)-1, 4-Pip--oso3h 20 6-159 Η -CH2CH2- -C (= 0)-1,4-Pip-_〇p〇3h2 6-160 H-CH2CHr-c (= 0)-1,4-Pip-1-Pyrd 6-161 Η-CH2CH2- -C (= 0)-1,4-Pip-1-Pip 6-162 H-CH2CHr -C (= 0)-1,4-Pip-4-Me- 1-Piz 6-163 H -CH2CH2_-C (= 0)-1,4-Pip-4- (CH2CH20H) -l-Piz 25 6-164 Η-CH2CH2- -coo)-1,4-Pip one 4 -Mor 6-165 H -CH2CHr -c (= o)-1,4-Pip--NHMe 6-166 H -CH2CHr-c (= 0)-1,4-Pip--NMe2 6-167 H-CH2CH2 -_c (= o)-1,4-Pip--plane eCH2CH2OH 6-168 H -CH2CHr-c (= 〇)-1,4-Pip.- -N (CH2CH2OH) 2 30 6-169 H -CH2CHr- c (= 〇)-1,4-Pip -CHr -C00H -152- 200410948

6-170 Η -CH2CHr -C (: 0)-1,4-Pip -CHr-S03H 6-171 Η -CH2CHr -C (= 0)-1,4-Pip Mai-oso3h 6-172 Η ~ CH2CHr- C (= 0)-1,4-Pip-CH2--opo3h2 6-173 Η -CH2CHr -C (= 0) _ 1, 4-Pip-CH 「4-Μογ 5 6-174 Η -CH2CHr -C ( = 0)-1,4-Pip-ch2- -νη2 6-175 Η -CH2CH2- -C (= 0) .- 1,4-Pip -ch2--_e 6-176 Η -CH2CHr-C (= 0 )-1,4-Pip -CH2- -NMe2 6-177 Η -CH2CHr -C (= 0)-1,4-Pip -CHr ~ NMeCH2CH2OH 6-178 Η -ch2ch2——c (= o)-1, 4-Pip-ch2- -N (CH2CH2OH) 2 10 6-179 Η -ch2ch2——c (= o)-1,4-Piz one- so2nh2 6-180 Η-ch2ch2——c (= o)-1 , 4-Piz-CH2CHr 1-Az t 6-181 Η -CH2CH〇r -C (= 0)-1,4-Piz -CH2CHr 1-Pyrd 6-182 Η -CH2CH2- -C (= 0)-• 1,4-Piz-CH2CHr 1-Pip 6-183 Η -CH2CHr -C (= 0)-1,4-Piz -CH2CHr 4-Me-l-Piz 15 6-184 Η -ch2ch2——c (= o ) _ 1, 4-P iz-CH2CHr 4- (CH2CH20H) -l-Piz 6-185 Η -CH2CHr -C (= 0)-1,4-Piz -CH2CHr 4-Mor 6-186 Η -CH2CH factory- C (= 0)-1,4-Piz-CH2CHr _NHMe 6-187 Η -CH2CHr -C (= 0)-1,4-Piz-CH2CHr _NMe2 6-188 Η -CH2CHr -C (= 0)-l, 4 ~ Piz-CH2CH Factory-NMeCH2CH20H 20 6-189 Η -CH2CHr -C (= 0)-1,4-Piz-CH2CHr • -N (CH2CH20H) 2 6-190 Η -CH = CH--C (= 0 )-1 — 1-Piz 6-191 Η -CH = CH- -C (= 0)--1-4- (C (= NH) NH2) -l-Piz 6-192 Η -CH = CH- -C (= 0)-One-four- (C (= NH) CH3) ~ 1-Piz 6-193 Η -CH = CH ~ -C (= 0)-One-four-Me-Bu Piz 25 6-194 Η -CH = CH——C (= 0)-One- 4-(CH2CH2OH) -1 -Piz 6-195 Η -CH = CH- -C (= 0)-One-4- (CH2CH2NHAc) -l-Piz 6-196 Η -CH = CH- -C (= 0)-1-4- (CH2Car) + Piz 6-197 Η -CH = CH- -C (= 0)--— 4- (CH2CH20Car) -l -Piz 6-198 Η -CH = CH--C (= 0)-1,3-Azt--C00H 30 6-199 Η -CH = CH- -C (= 0)-1,3 ~ Az t- -0S03H -153- 200410948 6-200 Η -CH di CH- -CO0)-1,3-Az t--〇p〇3h2 6-201 H -CH = CH- -C (= 0)-1,4 -Pip--C00H 6-202 H -CH = CH- -C (= 0)-1,4-Pip--so3h 6-203 H -CH = CH- -COO)-1,4-Pip a-oso3h 5 6-204 H _CH = CH——C (: 0)-1,4-Pip —-〇p〇3h2 .6-205 H -CH = CH- -C (= 0)-1,4-Pip — 1-Pyrd 6-206 H -CH = CH- -C (= 0)-1,4-Pip-1-Pip 6-207 H-CH = CH——C (= 0)-1,4-Pip- 4-M e-1-Piz 6-208 H -CH = CH- -C (= 0)-1,4-Pip-4- (CH2CH20H) -Bu Piz 10 6-209 H -CH = CH- -C (= 0 )-1,4-Pip-4- (CH2CH2NHAc) -Bu Pi 6-210 、 H -CH = CH--C (= 0)-1,4-Pip a 4-Mor 6-211 H-CH = CH ——C (= 0) _ 1,4-Pip a- NHMe 6-212 H -CH = CH- -C (= 0)-1,4-Pip a-Li e2 6-213 H-CH = CH— --C (= 0)-1,4-Pip--Li eCH2CH20H 15 6-214 H -CH = CH- -C (= 0)-1,4-Pip a- N (CH2CH20H) 2 6-215 H- CH = CH- -C (= 0)-1,4-Pip _CH 「-C00H 6-216 H-CH = CH——C (= 0)-1,4-Pip-ch2--oso3h 6-217 H -CH = CH-_C (= 0)-1,4-Pip -ch2- -opo3h2 6-218 H -CH = CH——C (= 0)-1,4-Pip-ch2- 4-Mor 20 6 -219 H -CH = CH- -C (= 0)-1,4-Pip -ch2- -nh2 6-220 H -CH = CH- -C (= 0)-1,4-Pip-ch2-- NHMe 6-221 H -CH = CH- -C (= 0)-1,4-Pip-ch2- -Li e2 6-222 H -CH = CH- -C (= 0)-1,4-Pip- ch2--BanditCH2CH20H 6-223 H-CH = CH ---- C (= 0)-1,4-Pip -CH``-N (CH2CH2OH) 2 25 6-224 H -CH2CH2- -C (= 0)- 1,4-Piz a-so2nh2 6-225 H -CH = CH- -C (= 0)-1,4-Piz-CH2CHr 4-Mor 6-226 H -CH = CH- -C (= 0)- 1,4-Piz-CH2CHr -NHMe 6-227 H -CH = CH——C (= 0)-1,4-Piz -CH2CHr -Li e2 6-228 H -CH = CH- -C (= 0)-1,4-Piz -CH2CHr -Li eCH2CH2OH 30 6-229 H-CH: CH——C (= 0)-1,4-Piz-CH2CH2--N (CH2CH20H) 2

# -154- 200410948 6-230 Η -CHr -NHC (= 0)---CHr 4-Me-l ~ Piz 6-231 Η -CH2- -NHC (= 0)---ch2- 4- (CH2CH2OH ) -Bu Piz 6-232 Η -CHr. -NHC (= 0)--_CHr -NMe2 6-233 Η -CHr-wake eC (= 0)---ch2- 4-Me-l-Piz 5 6- 234 Η -CH2- -NMeC (= 0)--ch2- 4- (CH2CH20H) -l-Piz 6-235 Η -CH2- -NMeCOO)---CHr -Lie2 6-236 Η -CH2CH2- _C (= 0) Li e-- -ch2ch2- -C00H 6-237 Η -CH2CH2--C (= 0) NMe---ch2ch2--S03H 6-238 Η -CH2CHr -C (= 0) NMe--- CH, CHr-NMe2 10 6-239 Me 1,4-cHx----C00H 6-240 Me 1,4-cHx-one--0P03H2 6-241 Me 1,4-cHx-.--1-Pyrd 6-242 Me 1,4-cHx---1-Pip 6-243 Me 1,4-cHx 'a-a 1-Me-4-Pip 15 6-244 Me 1,4-cHx---l- (CH2CH2OH) -4-Pip 6-245 Me 1,4-cHx---4-Me-1-Piz 6-246 Me 1,4-cHx---4- (CH2CH20H) -l-Piz 6-247 Me 1,4-cHx---4-Mor 6-248 Me 1,4-cHx--a-nh2 20 6-249 Me 1,4-cHx----NHMe 6-250 Me 1,4-cHx ----NMe2 6-251 H 1,4-cHx----C00H 6-252 H 1,4-cHx----〇〇〇〇3H2 6-253 H 1,4-cHx---1-Pyrd 25 6-254 H • 1,4-cHx---1-Pip 6-255 H 1,4-cHx---1-Me-4-Pip 6-256 H 1,4-cHx---• l- (CH2CH2OH)- 4-Pip 6-257 H 1,4 ~ cHx---4-Me-l_Piz 6-258 H 1,4-cHx---4 ~ (CH2CH2OH) ~ l-Piz 30. 6-259 H 1,4 -cHx-· 4-Mor

Φ 155- 200410948

6-260 Η 1,4-cHx ~-one-nh2 6-261 H 1,4-cHx---NHMe 6-262 H 1,4-cHx one one-•-wake e2 6-263 Me-(CH2 ) 4-----C00H 5 6-264 Me-(CH2) r-one--so3h .6-265 Me-(CH2) 4- one---0S03H 6-266 Me .- (CH2) 4- — — One-〇P〇3H2 6-267 Me-(CH2) 5- — — One -C00H 6-268 Me-(CH2) 5- — One--so3h 10 6-269 Me-(CH2) 5- • — — One-OS03H 6-270 Me-(CH2) 5-----〇P〇3H2 6-271 Me _ (CH2) 3- -C (= 0) f ^ Me-- -ch2ch2--so3h 6 -272 Me-(CH2) 4- -C (= 0) NMe----CH2CHr -so3h 6-273 Me _ (CH2) 「-C (= 0) 丽 e-- -CH2CH「 -so3h 15 6-274 Me _ (CH2) 6- -C (= 0) Li e-- -ch2ch2_ -S03H 6-275 H _ (CH2) 4--one-one-C00H 6-276 H _ (CH2) r — one-one-so3h 6-277 H _ (CH2) 4- — One —-oso3h 6-278 H-(CH2) r — —-0P03h2 20 6-279 H-(CH2) 5- One —--C00H 6-280 H-( CH2) 5-1-so3h 6-281 H-(CH2) 「— —--oso3h 6-282 H-(CH2) 5- — ~--〇〇〇〇〇3H2 6-283 H-(CH2) 3-- C (= 0) NMe-- -CH2CH2--so3h 25 6-284 H _ (CH2) 4--C (O) Li e-- -ch2ch 2- -so3h 6-285 H-(CH2) 5--C (= 0) wake up e-- -ch2ch2--so3h 6-286 H _ (CH2) 6_ -C (= 0) NMe---CH2CHr- so3h 6-287 Me _CH2CHr -〇C (= 0)---1-Me-4-Pip 6-288 Me -CH2CH2- -0CH)---CHr-C00H 30 6-289 Me -CH2CH2- -0CH) ---CHr -SO3H 0 \ · -156- 200410948 6-290 Me -CH2CH2- -〇C (= 0)-— -ch2- -〇P〇A 6-291 Me -CH2CH2- -oc (= 0) -One- ch2- 1-Azt 6-292 Me -CH2CHr-OC (= 0)-One-CH2-1-Pyrd 6-293 Me -CH2CH2- -oc (= 0)-One-CHr 1-Pip 5 6 -294 Me -CH2CHr-OC (= 0)-—-ch2- l-Me-4-Pip 6-295 Me ~ CH2CHr ~ 0C (= 0)-one-ch2-4-Me-l-Piz 6-296 Me -CH2CH 「-OC (= 0)-One-CHr 4- (CH2CH20H) -l-Piz 6-297 Me -CH2CHr-OC (= 0)-One-CHr 4-Mor 6-298 Me -CH2CHr -0 (: (♦ —-CH "-NMe2 10 6-299 Me -CH2CHr -0C (= 0)-one-ch2--NMeCH2CH2OH '• 6-300 Me -CH2CH2_ -OCH)-, one -ch2--N ( CH2CH2OH) 2 6-301 Me -CH2CHr-OCH)---CH2CHr-COOH 6-302 Me -CH2CHr -OC (= 0)-—-ch2ch2- -so3h 6-303 Me -CH2CHr-OCH)-. —- CH2CHr -opo3h2 15 6-304 Me -CH2CHr -OC (= 0) -One ~ CH2CHr 1-Azt 6-305 Me -CH2CHr-OC (= 0)-—-ch2ch2- 1-Pyrd 6-306 Me -CH2CHr-oc (= o)-One-CH2CHr 1-Pip 6-307 Me -CH2CH2- -OC (= 〇)---CH2CH "l-Me-4-Pip 6-308 Me -CH2CH2--OC (鲁 一 -ch2ch2- 4-Me-HP iz 20 6-309 Me -CH2CHr- OCH)-One.-CH2CHr 4-(CH2CH2OH)-Bu Piz 6-310 Me -CH2CHr-OC (= 0)-One-CH2CHr 4-Mor 6-311 Me -CH2CHr-oc (= o)-One -CH2CHr .-NMe2 6-312 Me -CH2CHr -OCH)-One-CH2CHr-NMeCH2CH2OH 6-313 Me -CH2CHr -OC (= 〇)-One -CH2CH2--N (CH2CH2OH) 2 25 6-314 Me-(CH2) 3- -0C (= 0)-one-one 1-Me-4-Pip 6-315 Me _ (CH2) 3- -OC (= 0)-one- CHr-COOH 6-316 Me-(CH2) 3- -0C (= 0)--CH 「-so3h 6-317 Me _ (CH2)」-OC (= 0)---ch2- -〇p〇3h2 6-318 Me-(CH2) 3--OC ( = 〇)---ch2- 1-Azt 30 6-319 Me-(CH2) 3--OCH)-one CHr l ~ Pyrd 200410948 6-320 Me-(CH2) 3_-0C (two 0)-· -~ ch2- 1-Pip 6-321 Me-(CH2) 3--0C (= 0)---ch2- 1-Me-4-Pip 6-322 Me-(CH2) 3 ~ -0C (= 0 )-1-CIV 4-Me-1-Piz 6-323 Me ~ (CHZ) 3 ~-0C (= 0)-One-CH2- 4- (CH2CH2OH) -Bu Piz 5 6-324 Me _ (CH2) 3- -0C (= 0)-One- CH2-4-Mor 6-325 Me-(CH2) 3- -0C (Tue 0)-One-ch2- -NMe2 .. 6-326 Me--(CH2) 3--0C (K))---ch2--NMeCH2CH2OH. 6-327 Me-(CH2) 3- -0CH)-One- CH2-_N (CH2CH20H) 2 '6-328 Me _ (CH2) 3---CH2CHr -C00H 10 6-329 Me-(CH2) 3- -oc (= o)-— -CH2CHr -so3h 6-330 Me-(CH2) 3--oc (= o)-—-CH2CHr-〇p〇3h2 6-331 Me _ (CH2) 3- -0C (= 0) ~ -CH2CHr 1-Azt 6-332 Me-(CH2) 3--0 (: (= 0)-One- CH2CHr 1-Pyrd 6-333 Me-(CH2) 3 ~ -oc (= o)-One-CH2CHr 1-Pip 15 6 -334 Me ~ (CH2) 3 ~-oc (= o)-One- CH2CHr 1-Me-4-Pip 6-335 Me-(CH2) 3--0C (= 0)-One- CH2CHr 4-Me- HPiz 6-336 Me-(CH2) 3---CH2CH2- 4- (CH2CH20H) -l-Piz 6-337 Me .- (CH2) 3--00 (= 0) _ a-ch2gh2- 4-Mor 6 -338 Me _ (CH2) 3--oc (= o)-one- CH2CHr-NMe2 20 6-339 Me-(CH2) 3- -oc (= o)-one-CH2CHr-NMeCH2CH2OH 6-340 Me-( CHI- -QC (= 0)---ch2ch2- -N (CH2CH2OH) 2 6-341 Me -CH2CH2--C (= 0) 0---Bu Me-4-Pip 6-342 Me -CH2CHr-C (= 0) 0--'-CHr-COOH 6-343 Me -CH2CHr -c (= o) o---CHr 1-Me-4-Pip 25 6-344 Me -CH2CHr-C ( = 0) 0-one-CH2CHr-COOH 6-345 Me -CH2CHr -c (= o) o---CH2CHr -SO3H 6-346 Me _CH2CHr -C (= 0) 0-one -CH2CHr-〇p〇3h2 6-347 Me -CH2CH2- -c (= o) o---CH2CHr 1-Azt 6-348 Me -CH2CH2--C 00) 0---CH2CHr • 1-Pyrd 30 6-349 Me -CH2CHr-C (= 0) 0-1-CH2CH, Pip f%

-158- 200410948

6-350 Me -CH2CHr -C (-0) 〇---ch2ch2- Bu Me-4-Pip 6-351 Me -CH2CHr-C (= 0) 0---ch2ch2- 4-Me-1-Piz 6 -352 Me -CH2CH2 ~ -c (= o) o---CH2CHr 4- (CH2CH2OH) -l-Piz 6-353 Me -CH2CH2--c (= 0) 0_--ch2ch 「4-Mor 5 6- 354 Me -CH2CH2--C (= 0) 0---ch2ch 「-Li e2 6-355 Me -CH2CH2--C (= 0) 0---ch2ch「 -NMeCH2CH20H 6-356 Me -〇Η / Η〗 --C (= 0) 0---CH2CHr -N (CH2CH2OH) 2 6-357 Me -CH = CH- ~ C (= 0) 0- Yibu Me-4-Pip .6-358 Me -CH = CH--C (= 0) 0-One-CH 「-COQH 10 6-358 Me -CH = CH--C (= 0) 0-L-ch2- l-Me-4-Pip 6-359 Me- CH = CH--C (= 0) 0---CH2CHr-C00H 6-360 Me -CH = CH_-C (= 0) 0---ch2ch2- -S03H 6-361 Me _CH = CH--C ( = 0) 0---CH2CHr ._〇p〇3h2 6-362 Me -CH = CH- -c (= o) o---CH2CHr 1-Azt 15 6-363 Me.-CH = CH--C (= 0) 0---CH2CHr l_Pyrd 6-364 Me -CH = CH- -c (= o) o----CH2CHr 1-Pip 6-365 Me -CH = CH- -c (= o) o- --CH2CH2- l-Me-4-Pip 6-366 Me -CH = CH--C (= 0) 0---ch2ch2- .4-Me -1 -Piz 6-367 Me -CH = CH-- C (= 0) 0---ch2ch2- 4- (GH2CH20H) -l-Pi z 20 6-368 Me _CH = CH--C (= 0) 0---CH2CHr 4-Mor 6-369 Me -CH = CH- -〇 (= 〇) 〇---CH2CHr _NMe2 6-370 Me- CH = CH--c (= o) o---CH2CH2--NMeCH2CH2OH 6-371 Me -CH = CH- -c (= o) o---CH2CHr -N (CH2CH2OH) 2 6-372 H -CH2CH2_ -0C (= 0)---Bu Me-4-Pip 25 6-373 H -CH2CH "-oc (= o)---ch2--C00H 6-374 H -CH2CH2- _〇〇 ('= 〇 )--.-CHr-S03H 6-375 H _CH2CH 「-oc (= o)---ch2--〇P〇A 6-376 H -CH2CHr -0C (Service- -CH「 1-Azt 6-377 H _CH2CH``-oc (= o)----CHr 1-Pyrd 30 6-378 H -CH2CH2--0C (= 0)--CH2-1-Pip 159- 200410948 6-379 ΗCH2CHr-OCH) ---ch2- 1-Me-4-Pip 6-380 Η-CH2CHr -0C (= 0)-One-CHr 4-Me-l-Piz 6-381 Η-CH2CHr -0C (= 0)---- ch2- 4- (CH2CH20H) -l-Piz 6-382 Η -ch2ch2--oc (= 〇)-one-ch2- 4-Mor 5 6-383 Η -CH2CHr -oc (= o)---CHr- Rei e2 6-384 Η -CH2CHr -OC (= 0)-One-CHr -Li eCH2CH20H 6-385 Η-CH2CHr ~ 0C (= 0) ~--ch2- -_2ch2oh) 2 6-386 Η-CH2CHr-oc (= 〇)-one -ch2ch2- _ -COOH 6-387 Η-CH2CHr-OC (= 0)-one -ch2ch2_ --so3h 10. 6-388 Η -CH2CHr -oc (= o)-— -ch2ch2----〇P〇A 6-389 Η-CH2CHr -0C (= 0)---ch2ch2- -1- Azt 6-390 Η-CH2CHr -0C (= 0) ~ —-ch2ch2 * -i-Pyrd 6-391 Η-CH2CHr -0C (= 0)---ch2ch2_ -1-Pip 6-392 Η-CH2CHr -oc (: o)--ch2ch2_ -l-Me-4-Pip 15 6-393 Η-ch2ch2--oc (= 〇)---ch2ch2 · -4-Me-l-Piz 6-394 Η -CH2CHr-oc (= 〇)---ch2ch2--4- (CH2CH20H) + Piz 6-395 Η -ch2ch2- • -OCH)---ch2ch2- 4 ~ Mor 6-306 Η -ch2ch2--oc (= o)- --Ch2ch2. --NMe2 6-397 Η-CH2CHr -OC (= 0)---ch2ch2. --NMeCH2CH2OH 20 6-398 Η-ch2ch2- -oc (= o)---ch2ch2 · --N ( CH2CH20H) 2 6-399 Me-(ch2) 「-oc (= 0)-one-l-Me-4-Pip 6-400 Me one (CH2) 3--oc (= 〇)-one- ch2-- C00H 6-401 Me-(ch2) 3--OC (= 0)-—-CHr -so3h 6-402 Me-(CH〗) 3--oc (= o)---CH 「-〇P〇3H2 25 6-403 Me-(CH2) r -oc (= 〇)---CHr 1-Azt 6-404 Me-(CH2) 3--OC (= 0) ~ •--ch2- 1-Pyrd 6- 405 Me-(CH2) 3--oc (= 〇)-one-CHr 1-Pip 6-406 Me (ch2) 3 --0C (= 0)-One-CHr 1-Me-4-Pip 6-407 Me-(ch2) 3- -0C (= 0)-One- CHr 4-Me-l-Piz 30 6-408 Me -(CH2) 3- -0C (-0)-—-CHr 4-(CH2CH20H) -HPiz 160- 200410948 6-409 Me-(CH2) 3--00 (= 0)---CH2-4-Mor 6-410 Me-(ch2) 「-0C (= 0)-_ -CHr, e2 6-411 Me-(CH2) 3--OCH)---CHr -NMeCH2CH2OH 6-412 Me-(ch2) 3- -OC (= 0)--CH2--N (CH2CH2OH) 2 5 6-413 Me-(ch2) 3- -0C (= 0)---CH2CHr -C00H 6-414 Me-(ch2) 3- -0C (= 0)---ch2ch2_ -S03H 6-415 Me-(ch2) 3- -0C (= 0)---ch2ch2- -〇p〇3h2 6-416 Me-(ch2) 3- -0C (= 0)--CH2CHr 1-Azt .6-417 Me-(CH2) 3--oc (= 0)---CH2CHr 1-Pyrd 10 6-418 Me-(CH2) 3--OCH)- _ -CH2CHr 1-Pip 6-419 Me-(ch2) 3- -OC (= 0)---ch2ch2- l-Me-4-Pip 6-420 Me-(CH2) 3--OCH)---- ch2ch2- 4-Me-l-Piz 6-421 Me-(CH2) 3- -OC (= 0)----CH2CHr 4- (CH2CH20H) -l-Piz 6-422 Me-(CH2) 3- -OC (= 0)---CH2CHr 4-Mor 15 .6-423 Me-(CH2) 3--oc (= 〇)-_ -CH2CH2- -Lie2 6-424 Me-(CH2) 「-OC (= 0)--ch2ch 「, eCH2CH2OH 6-425 Me-(CH2) 3--oc (= 0)-- -CH2CHr -N (CH2CH2OH) 2 6-426 H -ch2ch2--c (= o) o---1-Me-4-Pip 6-427 H -ch2ch2- -c (= o) o---ch2 --C00H 20 6-428 H-ch2ch2--C (= 0) 0---ch2-1-Me-4-P ip 6-429 H -CH2CHr-C (= 0) 0---CH2CHr -C00H 6-430 H -CH2CHr -c (= o) o---CH2CH 「-so3h 6-431 H -ch2ch2--C (= 0) 0---CH2CHr -〇p〇3h2 6-432 H -CH2CHr- c (= o) o---CH2CHr 1-Azt 25 6-433 H -CH2CHr -c (= o) o---CH2GHr 1-Pyrd 6-434 H -CH2CHr -C (= 〇) 〇--- CH2CHr 1-Pip 6-435 H-CH2CH2--C (= 0) 0--.-ch2ch2- l-Me-4-Pip 6-436 H -ch2ch2- -〇 (-〇) 〇-- -CH2CHr 4 -Me-l-Piz 6-437 H-ch2ch2- -C (-0) 〇-- -CH2CH2- 4- (CH2CH20H) -l-Piz 30 6-438 H -ch2ch2- -C (= 0) 0- --ch2ch2- 4-Mor -161-200410948 6-439 H -CH2CHr-C (= 0) 0---CH2CHr -Yes e2 6-440 H -CH2CH2--CH) 0---ch2ch2- -NMeCH2CH20H 6 -441 H _CH2CHr-CH) 0--.-ch2ch2- -N (CH2CH2OH) 2 6-442 H -CH-CH- -C (two 0) 0---l-Me-4-Pip 5 6-443 H -CH = CH--CH) 〇---CHr -C00H 6-444 H -CH = CH--C (= 0) 0---ch2- 1-Me-4-Pip 6-445 H -CH = CH- -C (: 0) 0---ch2ch2- -C00H 6-446 H -CH = CH- -C (= 0) 0---ch2ch2- -so3h 6-447 H -CH = CH- -C (= 0) 0---CH2CHr-〇p〇3h2; 10 6-448 H -CH = CH- -c (= o) o---ch2ch 「1-Azt 6-449 H -CH = CH--c (= o ) o---ch2ch 「1-Pyrd 6-450 H -CH = CH- -c (= o) o-- -ch2ch2- 1-Pip 6-451 H -CH = CH--C (= 0) 0 -1-CH2CHr l-Me-4-Pip 6-452 H -CH = CH--c (= o) o---ch2ch2_ 4-M'e-l-Piz 15 6-453 H -CH: CH- -c (= o) o---ch2ch2- 4- (CH2CH20H) -l-Piz 6.-454 H -CH = CH--C (= 0) 0---ch2ch 「4-Mor 6-455 H -CH = CH- -C (= 0) 0---CH2CHr -Li e2 6-456 H _CH = CH--c (= o) o- -CH2CHr -Li eCH2CH20H 6-457 H -CH = CH- -c (= o) o-- -ch2ch2- -N (CH2CH2OH) 2 20

O R1 〇 〇A〇J \ 〇AL1_G_L2-L3-A Table 7

25 Exemplified R1 -L1- -G- -L2- -L3- -A -162- 200410948 Compound No. 10 15 20 25 7-1 Me -CH2---7-2 Me.-CH2---7-3 Me -CHr--7-4 Me -CHr--7-5 Me -CHr-— 7-6 Me -CHr--7-7 Me -CHr--7-8 Me -CI ^---7-9 Me -CHr-One 7 -10 Me -CH2---7-11 Me -CH2CHr--7-12 Me -CH2CHr-One 7-13 Me -CH2CHr-One 7-14 Me -CH2CHr-One 7-15 Me- CH2CHr-One 7-16 Me -CH2CH2--One 7 -17 Me -CH2CH2--One 7-18 Me -CH2CH2---7-19 Me -CH2CHr-One 7-20 Me _CH2CH2---7-21 Me -CH2CHr--7-22 Me -CH2CHr-one 7-23 Me-(CH2) 3---7-24 Me-(CH2) 3---7-25 Me -CH2CHr -C (= 0)-one 7-26 Me -CH2CHr -CH)-1 7-27 Me -CH〇CHr -CH)-1-1-Pyrd-1 -P ip-1-Me-4-Pip-1- (CH2CH20H) -4- Pip-4-Me-1-Piz-4-(CH2CH20H)-: HPiz-4-Mor ·---NH2--NHMe--surface e2

--C00H one -〇P〇3H2-1-Pyrd-1-Pip-1-Me-4-Pip-Bu (CH2CH2OH) -4-Pip-4-Me-1-Piz-4- (CH2CH20H) -l -Piz-4-Mor I-nh2--NHMe--Ι ^ 2

--C00H

--〇p〇A-l-Piz-4- (C (= NH) NH2) -l-Piz 4- (C (= NH) CH3) -l-Piz -163- 30 200410948 7-28 .Me- CH2CHr-CH)-— — 4-Me-l-Piz 7-29 Me -CH2CHr -c (= o)-One to four-(CH2CH20H) -HPiz 7-30 Me -CH2CHr-c (= 〇)-- — 4- (CH2CH2NHAc) -l-Piz 7-31 Me ~ CH2CHr -C (-0)-one 4- (CH2Car) -l-Piz 5 7-32 Me -CH2CHr-c (= 〇)---- 4- (CH2CH20Car) + Piz. 7-33 Me -CH2CHr-c (= 〇)--4- (CH2CH2F) -l ~ Piz 7-34 Me -CH2CHr -c (= 0)-1, 3-Azt- -C00H 7-35 Me -CH2CHr -C (= 0)-1,3-Az t--oso3h 7-36 Me -CH2CHr-c (= 〇)-1,3-Azt--〇p〇3h2 10 7 -37 Me -CH2CH2--C (= 0)-1,4-Pip--C00H 7-38 Me -CH2CH2- -c (= o)-1,4-Pip--so3h 7-39 Me _CH2CH2-- C (= 0)-1,4-Pip--OSO3H 7-40 Me -CH2CH2--C (= 0)-1,4-Pip--0P03H2 7-41 Me -CH2CHr -c (= o)-1 , 4-Pip-1-Pyrd 15 • 7-42 Me -CH2CHr -c (= 0)-1,4-Pip-1-Pip 7-43 Me -CH2CHr _c (= o)-1,4-Pip * ~ 4-Me-HPiz 7-44 Me -CH2CPxr -c (= 0)-l, 4 ~ Pip-4- (CH2CH20H) -l-Piz 7-45 Me -CH2CHr -c (= 0)-1,4 -Pip-4-Mor 7-46 Me -CH2CHr _c (= 0)- 1,4-Pip--NHMe 20 7-47 Me -CH2CH2- -c (1,4-Pip--_e2 7-48 Me -CH2CHr-c (= o)-l, 4_Pip--NMeCH2CH2OH 7-49 Me -CH2CH2--(:( ♦ 1,4-Pip--N (CH2CH20H) 2 7-50 Me -CH2CH2--c (= o)-1,4-Pip _CH2--C00H 7-51 Me -CH2CHr -c (= 〇)-1,4-Pip -CH2 ~ -so3h 25 7-52 Me -CH2CHr-c (= o)-1,4-Pip -CHr -0S03H 7-53 Me -CH2CHr -c (= 0)-1,4-Pip -CH2--opo3h2 7-54 Me -CH2CHr -c (= 〇)-1,4-Pip -CH2 「4-Mor 7-55 Me -CH2CH2--c (= o) -1,4-Pip -CH, Γ, 7-56 Me -CH2CH2- -c (= 0)-1,4-Pip -CH, r -NHMe 30 7-57 Me -CH2CHr -c (= 〇)- 1,4-Pip -CH, 「-NMe2 -164- 200410948 7-58 Me -CH2CH2- -C (= 0)-1,4-Pip -ch2- -Wake eCH2CH2OH 7-59 Me -CH2CH2- -C ( = 0)-1,4-Pip-ch2- -N (CH2CH2OH) 2 7-60 Me -CH2CHr -C (= 0)-1,4-Piz a -so2nh2 7-61 Me -CH2CHr -C (-0 )-1,4-Piz-CH2CHr 1-Azt 5 7-62 Me -CH2CH2- -C (= 0)-1,4-Piz-CH2CHr HPyrd • 7-63 Me -CH2CH2-, C (= 0)- 1,4-Piz -CH2CH2-HPip 7-64 Me -CH2CH2--C (= 0)-1,4-Piz-CH2CH 「4-Me-1-Piz 7-65 Me -CH2CH Factory-C (= 0 )-1,4-Piz- CH2CHr 4-(CH2CH20H) -1 -Piz 7-66 Me -CH2CHr -C (= 0)-1,4-Piz -CH2CHr 4-Mor 10 7-67 Me -CH2CHr -C (= 0)-1,4 -Piz -CH2CHr-NHMe 7-68 Me _CH2CH2——C (= 0)-1,4-Piz -CH2CHr -NMe2 7-69 Me -CH2CHr -C (-0)-1,4-Piz-CH2CH 「- ReiCH2CH20H 7-7.0 Me -CH2CHr -C (= 0)-1,4-Piz-ch2ch2--N (CH2CH2OH) 2 7-71 Me -CH = CH- -C (= 0)--1-Piz 15 7-72 Me -CH = CH- -C (= 0)--— 4- (C (= NH) NH2) -HPiz 7-73 Me -CH = CH- -C (= 0)-—-. 4- (C '(= NH) CH3) -HPiz 7-74 Me -CH = CH- ~ C (= 0) -one 4-Me-1-Piz 7-75 Me -CH = CH- -C ( = 0) -A-4- (CH2CH20H) -l-Piz 7-76 Me -CH = CH- -C (= 0)-A-4- (CH2CH2NHAc) -l-Piz 20 7-77 Me -CH = CH- -C (= 0)-a 4- (CH2Car) -1-Piz 7-78 Me -CH = CH- -C (= 0)-a- · 4-(CH2CH2OCar) + Piz 7-79 Me- CH = CH- -C (= 0)-1,3-Azt 1-C00H 7-80 Me ~ CH = CH ~ -C (= 0)-1,3 ~ Az t — -0S03H 7-81 Me -CH = CH- -C (= 0)-1, 3_Az t one-opo3h2 25 7-82 Me -CH = CH- -C (= 0)-1,4-Pip one-C00H 7-83 Me -CH = CH --C (= 0)-1,4-Pip a -SO3H 7-84 Me -CH = CH- -C (= 0)-1,4-Pip — -OSO3H 7-8 5 Me -CH = CH- -C (= 0)-1,4-Pip a-opo3h2 .7-86 Me -CH = CH- -C (= 0)-1,4-Pip a HPyrd 30 7-87 Me -CH = CH- _C (= 0)-1,4-Pip a 1-Pip 200410948

7-88 Me -CH di CH- -C (Service 1,4-Pip-4-Me-l-Piz 7-89 Me -CH = CH- -CH)-1,4-Pip-4- (CH2CH20H) -l-Piz 7-90 Me -CH = CH- -C (= 0)-1,4-Pip-4- (CH2CH2NHAc) -l-Piz 7-91 Me -CH = CH- -C (two 0) 1,4-Pip-4-Mor 5 7-92 Me -CH = CH- -C (= 0)-1,4-Pip--NHMe 7-93 Me -CH = CH- -C (= 0) -· 1,4-Pip a-NMe2 7-94 Me -CH: CH- -C (= 0)-· 1,4-Pip a -NMeCH2CH2OH 7-95 Me -CH = CH--(:( ♦ · 1,4-Pip--N (CH2CH2OH) 2 7-96 Me -CH = CH——C (= 0)-1,4-Pip-ch2--C00H 10 7-97 Me -CH = CH- -C (= 0)-1,4-Pip-ch2--0S03H 7-98 Me -CH = CH- -C (= 0)-1,4-Pip -CH2- -〇p〇3h2 7-99 Me -CH = CH- -C (= 0)-1,4-Pip -ch2- 4-Mor 7-100 Me -CH = CH- -C (= 0)-1,4-Pip -ch2--nh2 7-101 Me -CH = CH——C (= 0)-1,4-Pip-ch2--NHMe · 15 7-102 Me -CH = CH- -C (= 0)-'1,4-Pip -CHr, e2 7-103 Me -CH = CH- -C (= 0)-1,4-Pip -CHr -Li eCH2CH20H 7-104 Me -CH = CH- -C (= 0)-1,4-Pip Mai- N (CH2CH20H) 2 7-105 Me. -CH2CH2- -CH)-1,4 ~ P iz.--So2nh2 7-106 Me -CH = CH- -C (= 0)-1,4-Piz -ch2ch2 -4-Mor 20 7-107 Me -CH = C H- -C (: 0)-1,4-Piz-CH2CHr -NHMe 7-108 Me -CH = CH- -C (= 0)-1,4-Piz-CH2CH 「-面 e2 7-109 Me- CH = CH- -C (= 0)-1,4-Piz -ch2ch2- -NMeCH2CH20H. 7-110 Me -CH = CH- -C (= 0)-1,4-Piz -ch2ch 「-N (CH2CH20H ) 2 7-111 Me -CH Factory -NHC (= 0)-1-CHr 4-Me-l-Piz 25 7-112 Me -CHr -Li C (= 0)---CHr 4- (CH2CH20H)- l-Piz 7-113 Me -CH2- -Li C (= 0)----CH2--Li e2 7-114 Me -CHr -Band eC (= 0)-One-ch2- 4-Me-l-Piz 7-115 Me -CH2- -NMeC (-0)-A-ch2- 4- (CH2CH20H) -Bu Piz 7-116 Me -CH2- -Li eC (= 0)---CHr -Li e2 30 7- 117 Me -CH2CHr -C (two 0) NMe- —-ch2ch2- -C00H

166-200410948 7-118 Me -CH2CHr -C (= 0) NMe-- -ch2ch2 · --so3h 7-119 Me -CH2CH2- -C (= 0) just e---ch2ch2 ·--NMe2 7-120 H-CHr---l ~ Pyrd 7-121 H -CHr---1-Pip 5 7-122 H-CHr---l-Me-4-Pip 7-123 H -CHr--Yibu (CH2CH20H ) -4-Pip 7-124 H -CHr ------4-Me-l-Piz 7-125 H-CHr-~-4- (CH2C_ + Piz 7-126 H .-CH2---.- 4-Mor 10 7-127 H -CHr _---nh2 7-128 H-CHr--one-_e 7-129 H -CHr----NMe2 7 -130 H -CH2CH2——-one-C00H 7 -131 Η -CH2CHr----〇〇〇〇〇3H2 15 7-132 Η-CH2CH factory---1-Pyrd 7-133 Ή -CH2CH2——--1-Pip 7-134 H -CH2CHr-one one one -Me-4-Pip 7-135 Η --CH2CHr---l- (CH2CH2OH) -4-Pip 7-136 H -CH2CH2——--4-Me-HPiz 20 .7-137 H -CH2CHr--- 4-(CH2CH2OH) + Piz 7-138 H -CH2CH2——--4-Mor 7-139 Η-CH2CH factory-1-nh2 7-140 H -CH2CHr----NHMe 7-141 H -CH2CHr _ --, E2 25 7-142 H-(CH2) 3------C00H 7-143 H _ (CH2) r----opo3h2 7-144 H -CH2CHr -C (= 0)---1 -Piz 7- 145 H -CH2CHr -C (= 0)---4- (C (= NH) NH2) -l-Piz 7-146 H -CH2CHr-C (= 0)--4- (C (-NH). CH3) -1-Piz 30 7-147 H -CH2CHr -C (-0)----4-Me-l-Pi z -167- 200410948

7-148 H _CH2CH2_ -C (= 0)---4- (CH2CH20H) -l-Piz 7-149 Η -CH2CH2- -C (= 〇)---4-(CH2CH2NHAc) -1 -Piz 7- 150 Η -CH2CH 「-C (= 0)---4-(CH2Car) + Piz 7-151 Η -CH2CHr -C (= 0)---4- (CH2CH20Car) -l-Piz 5 7-152 Η -CH2CHr -c (= 0)---4- (CH2CH2F) -Bu Piz 7-153 Η = CH2CH2--C (= 0)-1,3-Az t — -C00H 7-154 Η -CH2CH2_-Cd 1, 3 ~ Az t --0S03H 7-155 Η -CH2CHr -CH)-1, 3 ~ Az t--opo3h2 7-156 Η -CH2CH2- -c (= 〇)-1,4-Pip--C00H 10 7-157 Η -CH2CHr -C (= 0)-1,4-Pip--SO3H 7-158 Η. -CH2CHr -c (= 〇)-1,4-Pip a-OSO3H 7-159 Η -CH2CHr -C (= 0)-1,4-Pip a -〇p〇3h2 7-160 Η -CH2CH2- _C (= 0)-1,4-P * ip — 1-Pyrd 7-161 H -CH2CHr-C (= 0)-1,4-Pip-1-Pip 15 7-162 H -CH2CH2- -c (= 〇)-1,4-Pip-4-Me-HPiz 7-163 H -CH2CHr -C (= 0)-1,4-Pip -4- (CH2CH2OH) -l-Piz 7-164 H -CH2CH2- -C (= 0)-1,4-Pip-4-Mor 7-165 H -CH2CH2--C (= 0)-1,4-Pip a- NHMe 7-166 H -CH2CH2--C (= 0)-1,4-Pip a- NMe2 20 7-167 H -CH2CHr-c (= o)-1 , 4-Pi p — · -NMeCH2CH2OH 7 -168 H ~ CH2CHr-c (= 〇)-1,4-Pip--N (CH2CH2OH) 2 7-169 H -CH2CHr-c (= o)-1,4-Pip-ch2 --C00H 7-170 H -CH2CHr-cd 1,4-Pip-ch2--so3h 7-171 H -CH2CHr-c (= o)-1,4-Pip -ch2--OSO3H 25 7-172 H- CH2CHr-c (= o)-1,4-Pip-ch2!--Opo3h2 7-173 H -CH2CHr-. (= 〇)-1,4-Pip -CHj r 4-Mor 7-174 H -CH2CHr _C (= 0)-1,4-Pip-CH: Γ -nh2 7-175 H -CH2CH2- -C (= 0)-1,4-Pip -CH;--NHMe 7-176 H -CH2CH "-C (= 〇)-1,4-P-ip -CH. Γ -Experiment 2 30 7-177 H -CH2CHr -C (: 0)-1, 4-Pip -CH. R -NMeCH2CH2OH ^ 168- 200410948 7-178 H -CH2CHr -C (= 0)-1,4-Pip -CHr -N (CH2CH20H) 2 7- 179 H -CH2CHr -C (= 0)-1,4-Piz--so2nh2 7-180 H -CH2CHr -C (= 0)-1,4-P iz -CH2CHr 1-Azt 7-181 H -CH2CHr- C (= 0)-1,4-Piz -ch2ch2- 1-Pyrd 5 7-182 H -CH2CHr -C (= 0)-1,4-Piz-ch2ch2- 1-Pip .7-183 H -CH2CHr- C (= 0)-1,4-Piz -CH2CHr 4-Me ~ l-Piz 7-184 H -CH2CH2--C (= 0)-1,4-Piz ~ CH2CHr 4-(CH2CH20H) + Piz 7- 185 H -CH2CHr -C (= 0)-1,4-Piz -CH2CHr 4-Mor 7-186 H -CH2CHr -C (= 0)-1,4-Piz -CH2CHr -NHMe 10 7-187 H -CH2CH2 --C (= 0)-1,4-Piz -CH2CHr-NMe2 7-188 H -CH2CHr -C (= 0)-1,4-Piz -ch2ch2- -Li eCH2CH20H. 7-189 H -CH2CHr -C (= 0)-1,4-Piz -ch2ch2- -N (CH2CH20H) 2 7-190 H -CH = CH- -C (= 0)--. ~ '1-Piz 7-191 H -CH = CH --C (= 0)--_-4- (C (= NH) NH2) -1-Piz 15 7-1 92 H -CH = CH ~ -C (= 0)---4- (C (= NH) CH3) ~ 1-Piz 7-193 H -CH = CH ~ -C (= 0)---4 -Me-1-Piz 7-194 H -CH = CH- -C (= 0)-a-4-(CH2CH2OH) + Piz 7-195 H -CH = CH—C (= 0)---4- (CH2CH2NHAc) -Bu Piz 7-196 H-CH = CH——C (= 0) _ A-4- (CH2Car) -P iz 20 7-197 H -CH = CH——C (= 0)-- -4- (CH2CH20Car) -l-Piz 7-198 H -CH = CH- -C (= 0)-1,3-Az t one -C00H 7-199 H ~ CH = CH- -C (= 0) -1,3-Az t one -0S03H 7-200 H -CH = CH- -C (two 0)-1,3-Azt one -〇p〇3h2 7-201 H -CH = CH- -C (= 0)-1,4-Pip a- C00H 25 7-202 H -CH = CH- -C (= 0)-1,4-Pip a-so3h 7-203 H -CH = CH- -C (= 0 )-1,4-Pip a-OSO3H 7-204 H -CH = CH- -C (= 0)-1,4-Pip a-opo3h2 7-205 H -CH = CH- -C (= 0)- 1,4-Pip -1-Pyrd 7-206 H -CH = CH- -C (= 0)-1, 4-Pip-HPip 30 7-207 H -CH = CH- -C (-0)-1 , 4-Pip — 4-Me-l_Piz -169-200410948 7-208 Η -CH: Cfih -CH)-1,4-Pip-4- (CH2CH20H) -l-Piz 7-209 Η -CH = CH- -C (= 0)-1,4-Pip-4- (CH2CH2NHAc) -Bu Piz 7-210 H -CH = CH- -C (= 0)-1,4-Pip- 4-Μογ, 7-211 H -CH di CH- -C (= 0)-1,4-P ip--NHMe 5 7-212 H -CH = CH- -c (= 0)-1,4-Pip-~ NMe2 7-213 H -CH = CH--c (= o)-1,4-Pip --NMeCH2CH20H 7-214 H -CH: CH- -c (= 0)-1,4-Pip--N (CH2CH2OH) 2. 7-215 H -CH = CH- -c (= 0)-l, 4_Pip ~ CH2 ~ -C00H 7-216 H -CH = CH- -C (= 0)-1,4-Pip ~ CH2 ~-0S03H 10 7-217 H -CH = CH- -C (= 0)-1 , 4-Pip -CHr -〇p〇3h2 7-218 H -CH = CH- -c (= 0)-1,4-Pip -CHr 4-Mor 7-219 H -CH = CH- -c (= 0)-1,4-Pip -CHr-nh2 7-220 H -CH = CH--C (= 0)-1,4-Pip -CHr -NHMe 7-221 H -CH di CH- -c (= o)-1,4-Pip -CHr -Wake e2 15 7-222 H -CH = CH--c (= 〇)-1,4-Pip -CHr. -Li eCH2CH20H 7-223 H -CH = CH- -c (= o)-1,4-Pip -CHr-N (CH2CH20H) 2 7-224 H -CH2CHr -C (= 0)-1,4-Piz--so2nh2 7-225 H -CH = CH- -c (= 〇)-1,4-Piz -CH2CH2- 4-Mor 7-226 H -CH di-CH- -c (= o)-1,4-Piz -CH2CH2- -NHMe 20 7-227 H _CH : CH--c (= 〇)-1,4-Piz -CH2CH2- -iiMe2 7-228 H -CH = CH- -c (= 0)-1,4-Piz · -CH2CH2- -Li eCH2CH2OH 7- 229 H. -CH = CH--c (= 〇)-1,4-Piz -CH2CH2--N (CH2CH2OH) 2 7-230 H -CHr -NHC (= 0)---ch2- 4-Me- l-Piz 7-231 H -CHr -NHC (= 0)---ch2-4- (CH2CH20H) -l-Piz 25 7-232 H -CHr -NHC (= 0)---ch2- -NMe2 7-233 H -CHr-NMeC (= 0)--_CH2-4-Me-l-Piz 7-234 H -CHr-Bandit eC (= 0)---ch2- 4-(CH2CH2OH) -l-Piz 7-235 H -CHr -Li eC (= 0)--~ ch2--Bandit e2 7-236 H -CH2CHr -C (= 0) NMe---CH2CHr-C00H 30 7-237 H -CH2CH2- -C (= 0) ^ e-- ~ CH2CH2 ~-so3h 170- 200410948

7-238 Η -CH2CHr-C (= 0) NMe-- -ch2ch2- -NMe2 7-239 Me 1,4-cHx----C00H 7-240 Me 1,4-cHx--~ 〇p〇3h2 7-241 Me 1,4-cHx-1-Pyrd 5 7-242 Me 1,4-cHx-1-Pip 7-243 Me 1,4-cHx---l-Me-4-Pip 7- 244 Me 1,4-cHx-one — l- (CH2CH20H) -4-Pip 7-245 Me 1,4-cHx one —-4-Me-l-Piz 7-246 Me 1,4-cHx — — — 4- (CH2CH20H) -l-Piz 10 7-247 Me 1,4-cHx ~ —-4-Mor 7-248 Me 1,4-cHx * — — one-nh2 7-249 Me 1,4_cHx one one- -NHMe. 7-250 Me 1,4-cHx One. _NMe2. 7-251 H 1,4-cHx — — One-C00H 15 7-252 H 1,4-cHx — One-, 03H2 7-253 H 1 , 4-cHx one one-1-Pyrd 7-254 H 1,4-cHx one one — 1-Pip 7-255 H 1,4-cHx-— '1-Me-4-Pip 7-256 H 1, 4-cHx one one-1- (CH2CH20H) -4-Pip 20 7-257 H 1,4-cHx-.--4-Me-l-Piz 7-258 H 1,4-cHx — — one 4- (CH2CH2OH) + Piz 7-259 H 1, -4-cHx One-One 4-Mor 7-260 H 1,4-cHx-One-nh2 7-261 H 1,4-cHx — — One-NHMe 25 7 -262 H 1,4-cHx-one--NMe2 7-263 Me-(CH2) 4-one one one-C00H 7-264 Me-(CH2) r — —-.-so3h 7-265 Me-(ch2) 4_ — one one -0S03H 7-266 Me-(ch2) 4- ~ —--0P03H2 30 7-267 Me — (CH2) 5--ONE-C00H -171-200410948 7-268 Me _ (CH2) 5- ONE-ONE-so3h 7-269 Me-(CH2) 5---ONE-oso3h 7-270 Me-(CH2) 5- — —--Opo3h2 7-271 Me _ (CH2) 3- _C (= 0) NMe---ch2ch2--so3h 5 7-272 Me _ (CH2) 4- -C (= 0) circle e--- ch2ch2- -so3h 7-273 Me _ (CH2) 「-C (= 0) Li e---ch2ch2--so3h 7-274 Me-(CH2) 6- -C (= 0) Li e-- -ch2ch2 --so3h 7-275 H-(CH2) 4- one----C00H 7-276 H _ (CH2) 4-one · one--so3h 10 7-277 H-(CH2) 4--~ one -oso3h 7-278 H-(CH2) 4-one ~-opo3h2 7-279 H-(CH2) 5- — one--C00H 7-280 H-(CH2) 5--one -so3h 7-281 H-(CH2 ) r one by one -oso3h 15 7-282 H-(CH2) 5- — ~ -opo3h2 7-283 H-(CH2) 3- -CHMMe——.-CH2CHr _so3h 7-284 H, 2) 4- -C (= 0) Bandit-- -ch2ch2--so3h 7-285 H-(CH2) 5- -C (= 0) Lie- _-CH2CHr-so3h 7-286 H-(CH2) 「-C (= 0) iiMe-- -CH2CHr -so3h 20 7-287 Me -CH2CH2--oc (= o)- -1-Me-4-Pip 7-288 Me -CH2CH2--oc (= o)---ch2- -C00H 7-289 Me -CH2CHr-〇c (= o)---CHr-so3h 7- 290 Me -CH2CHr -oc (= o)---ch2- -〇p〇3h2 7-291 Me -CH2CHr-oc (= o)---ch2- Azt 25 7-292 Me -CH2CH2- -0C ( = 0)---ch2- 1-Pyrd 7-293 Me -CH2CHr -00 (= 0)----CHr 1-Pip 7-294 Me -CH2CHr -0C (= 0)--CHr 1-Me- 4-Pip 7-295 Me -CH2CH2_-oc (= o)--ch2- 4-Me-l-Piz 7-296 Me -CH2CH2- -0C (= 〇)---CHr 4- (CH2CH20H)- 1-Piz 30 7-297 Me -CH2CHr -0C (-0)---CHr 4-Mor 200410948 7-298 Me -CH2CHr-0C (two 0)---CHr -Bae2 7-299 Me ~ CH2CHr- oc (Service one -CHr .-NMeCH2CH2OH 7-300 Me -CH2CHr -0 (: (♦ one-ch2- -N (CH2CH2OH) 2 7-301 Me -CH2CH2_ -0C (= 0)-one -ch2ch2. COOH 5 7-302 Me -CH2CHr-0C (= 0)---ch2ch2-_S03H 7-303 Me -CH2CHr -0CH)---ch2ch2--opo3h2 7-304 Me -CH2CHr -0C (= 0)-1 -ch2ch2-1-Azt 7-305 Me -CH2CHr -OCH)---ch2ch2 -1-Pyrd 7-306 Me -CH2CHr -OC (= 0)-a-ch2ch2 -1-Pip 10 7-307 Me -CH2CHr .-oc (= o)-a-ch2ch2-l-Me-4-Pi p 7-308 Me -CH2CH2- -oc (= o)---ch2ch2 -4-Me-HPiz 7-309 Me -CH2CHr -oc (= o)---ch2ch2-4- (CH2CH20H) -l-Piz 7-310 Me -CH2GHr -oc (= o)---ch2ch2-4-Mor 7-311 Me -CH2CHr -OC (= 0)-one-ch2ch2--NMe2 15 7-312 Me factory CH2CHr -oc (= o)-—-ch2ch2-_NMeCH2CH2OH 7-313 Me -CH2CH2- • -oc (= o)-one -ch2ch2--N (CH2CH2OH) 2 7-314 Me _ (CH2) 3- -oc (= 〇)- 1-Me-4-Pip 7-315 Me-(CH2) r -oc (= 0)-—-ch2--COOH 7-316 Me-(CH2) 3--oc (= o)-1- ch2--so3h 20 7-317 Me — (CH2) 3--oc (= o)---CHr-〇p〇3h2 7-318 Me _ (CH2) 3--oc (= o)-one-ch2 -1-Azt 7-319 Me-(CH2) r -0C (= 0)---ch2- 1-Pyrd 7-320 Me-(CH2) 3- -oc (= o) _--ch2-1- Pip 7-321 Me ~ (CH2) 3- -OCH)--One CHr 1-Me-4-Pip 25 7-322 Mc-(CH2) 3 ~-oc (= o)-One-CHr 4-Me- 1-Piz 7-323 Me-(CH2) 3- -OC (= 0)---ch2- 4- (CH2CH20H) -l-Piz 7-324 Me-(CH2) r -OC (= 0)-- -CHr 4-Mor 7-325 Me- (CH2) r ~ 0C (= 0) —-ch2-., E2 7-326 Mc-(CH2) 3 ~-oc (= 〇)---CHr-NMeCH2CH2OH 30 7-327 Me-(CH 2) r-OCH)--CHr-N (CH2CH2OH) 2 173- 200410948 7-328 Me-(CH2) 3- -0C (= 0)---CH2CHr 7-329 Me-(CH2) 3-- 0C (= 0)-one -CH2CHr 7-330 Me-(CH2) 3- -0C (= 0)--CH2CHr 7-331 Me-(CH2) 3- -0C (= 0)-_ .-CH2CHr 7-332 Me-(CH2) 3--oc (= 〇)--CH2CHr. 7-333 Me-(CH2) 3- -0C (= 0)--CH2CHr 7-334 Me-(CH2) 3 --oc (= o)---CH2CHr 7-335 Me-(CH2) 3--oc (= 〇)--ch2ch2- 7-336 Me-(CH2) 3- _oc (= o)--- CH2CHr 7-337 Me-(CH2) 3_ ~ 0C (= 0)----CH2CHr 7-338 Me-(CH2) 3 -0C (= 0)---CH2CHr 7-339 Me-(CH2) 3- _0C (= 0)---CH2CHr 7-340 Me-(CH2) 3_ -0C (= 0)---CH2CHr 7-341 Me -CH2CH2- -C (= 0) 0---7-342 Me- CH2CH2- -C (= 0) 0---ch2- 7-343 Me -CH2CH2- -C (= 0) 0---CHr 7-344 Me -CH2CH2--C (= 0) 0---ch2ch2 -7-345 Me -CH2CH2--C (= 0) 〇-- -ch2ch2- 7-346 Me -CH2CHr -c (= o) o---CH2CHr '7-347 Me _CH2CHr -C (= 0) 0 --CH2CHr 7-348 Me -CH2CH2--CH) 0--CH2CHr 7-349 Me -CH2CH2- -C (= 0) 0---CH2CHr 7-350 Me -CH2CH2--c (= o) o---CH2CHr 7-351 Me -CH2CH2_- c (= 〇) 〇-- -ch2ch2- Γ 7-352 Me -CH2CH2--C (= 0) 0---ch2ch2- 7-353 Me -CH2CHr -c (= o) o- -CH2CHr 7- 354 Me -CH2CHr-c (= o) o---CH2CH2-7-355 Me -CH2CH2--C (= 0) 0---CH2CHr 7-356 Me -CH2CHr -G (-0) 0 ~-- CH2CHr) 7-357 Me -CH = CH--C (= 〇) 〇- 一-

-C00H

-S03H -opo3h2 1-Azt 1-Pyrd 1-Pip 1-Me-4_P ip 4-Me-l-Piz 4- (CH2CH20H) -l-Piz 4-Mor -face e2 -NMeCH2CH2OH -N (CH2CH2OH) 2 1 -Me-4-Pip -C00H 1-Me-4-Pip

-C00H

-S03H-opo3h2 1-Az t 1-Pyrd 1-Pip -Me-4-Pip -174- 200410948 7-358 Me -CH = CH--c (= 0) 0---ch2- 7-358 Me -CH = CH_-C (= 0) 0---ch2_ 7-359 Me -CH = CH- -C (= 0) 0---ch2ch2- 7-360 Me ~ CH = CH--c (= 0) 0_--ch2ch2- 5 7-361 Me -CH = CH --c (; o) o----CH2CHr 7-362 Me -CH = CH- -C (= 0) 0---ch2ch2- 7-363 Me -CH = CH--C (= 0) 0 ---ch2ch2- 7-364 Me -CH = CH- -C (= 0) 〇-—-ch2ch 「7-365 Me -CH = CH--C (= 0) 0_--CH2CHr t 10 7-366 Me -CH = CH- -C (= 0) 0---CH2CHr 7-367 Me -CH = CH--C (= 0) 0---ch2ch2- 7-368 Me -CH = CH--C ( = 0) 0---ch2ch2- 7-369 Me -CH = CH- -c (= o) o---ch2ch2- 7-370 Me -CH = CH--C (= 0) 0---ch2ch2 -15 7-371 Me -CH = CH--C (= 0) 0---ch2ch2-7-372 H -CH2CHr -OCH)---7-373 H -CH2CHr-oc (= o)-- CHr 7-374 H-CH2CHr -oc (: 〇)---ch2- 7-375 H-CH2CHr-0 (: (= 0)--ch2- 20 7-376 H -CH2CH2--0C (= 0 )---CHr 7-377 H-CH2CHr-oc (= o)---ch 2- 7-378 H -CH2CHr-oc (= o)---CHr 7-379 H -CH2CHr-oc (= o)--ch2- 7-380 H -CH2CHr-0C (= 0)--- ch2- 25 7-381 H -CH2CHr-0C (= 0)--ch2- 7-382 H -CH2CHr-oc (= o)-, -ch2- 7-383 H -CH2CHr -oc (= o) -1-CHr 7-384 H -CH2CH2--0C (= 0)-~ -CH2-7-385 H-CH2CHr -OCH)---CH2-. 30 7-386 H -CH2CHr -oc (= o) --ch2ch2.

-COOH l-Me-4-Pip

-COOH

-S03H-〇P〇3H2 1-Azt. 1-Pyrd 1-Pip l-Me-4-Pip 4-Me + Piz 4- (CH2CH20H)-1-Piz 4-Mor -Bande2

-Wake eCH2CH2OH -N (CH2CH2OH) 2 l-Me-4-Pip -COOH

-S03H

-〇p〇A 1-Azt 1-Pyrd 1-Pip l-Me-4-Pip 4-Me-l ~ * Piz 4- (CH2CH2OH) -1-Piz 4-Mor -NMe2

-Band eCH2CH2OH

-N (CH2CH2OH) 2 --COOH 200410948 7-387 Η -CH2CHr -oc (= 0)---ch2ch2- -SO3H 7-388 Η-CH2CHr -oc (two 0)---ch2ch2-, 03H2 7- 389 Η-CH2CHr _oc (= o)----CH2CHr 1-Azt 7-390 Η -ch2ch2- -0CH)-— -CH2CHr 1-Pyrd 5 7-391 Η-ch2ch2- -OC (= 0)-one- ch2ch2- 1-Pip 7-392 Η -ch2ch2--oc (= 〇)-.- -ch2ch2- l-Me-4-Pip 7-393 Η. -ch2ch2- -oc (= 0)---ch2ch2- 4-Me-1-Piz 7-394 Η -CH2CHr-oc (= o)-mono-ch2ch2- 4- (CH2CH2OH) -l-Piz 7-395 Η -CH2CHr-oc (= o)---ch2ch2- 4-Mor 10 7-306 Η -CH2CH2- -oc (= 〇)-— -CH2CHr -NMe2 7-397 Η-CH2CHr -oc (= o)-— -CH2CHr -Li eCH2CH20H 7-398 Η -CH2CH2-- 0C (= 0)---ch2ch 「-N (CH2CH2OH) 2 7-399 Me-(CH2) 3- -0C (= 0)-— -l-Me-4-Pip 7-400 Me-(CH2) 3--0C (= 0)-—-CH2--C00H 15 7-401 Me-(CH2) 3- -oc (= 〇)---CH 「-SO3H 7-402 Me-(CH2)「 -oc (= o)-1-ch2--〇p〇3h2 7-403 Me-(CH2) 3- -OC (= 0)-• -ch2-1-Azt 7-404 Me-(CH2) 3--oc (= 0)---CHr l-Pyrd · 7-405. Me-(CH2) r-oc (= o)-a-c h2-1-Pip 20 7-406 Me ~ (ch2) 3- -OC (= 0)--CHr 1-Me -'4-Pip 7-407 Me ~ (CH2) 3- -〇C (= 0 )--CH Factory 4-Me-1-Piz 7-408 Me-(ch2) 3--oc (= 〇)--CHr 4- (CH2CH20H) -l ~ Piz 7-409 Me-(CH2) 3 --oc (= o)---CH2-4-Mor 7-410 Me-(CH2) 3- -oc (= o)---ch2--NMe2 25 7-411 Me-(CH2) 3-- OC (= 0)--Brother · -eCH2CH2OH 7-412 Me ~ (ch2) 3- -oc (= 0)-one -ch2- -N (CH2CH2OH) 2 7-413 Me ~ (ch2) 3- ~ 0C (= 0)-One-ch2ch2--C00H 7-414 Me-(CH2) 3- ~ 0C (= 0) ~ One- CH2CHr -SO3H 7-415 Me-(CH2) r-OC (= 0)- — -CH2CH2- -opo3h2 30 7-416 Me-(CH2) 3- -oc (: 〇)---CH2CHr 1-Azt 200410948 7-417 Me-(ch2) "-oc (= o)---CH2CHr 1-Pyrd 7-418 Me-(CH2) 3--oc (two 0)--ch2ch2- 1-Pip 7-419 Me-(CH2) 3- -oc (= 0)---CH2CHr Bu Me- 4-Pip 7-420 Me-(CH2) 3--oc (= 0)---ch2ch2- 4-Me-l-Piz 5. 7-421 Me-(CH2) 3- -OC (= 0)- --CH2CHr 4- (CH2CH2OH) -l-Piz 7 * 422 Me-(CH2) 3- -OC (= 0)----CH2CHr 4-Mor 7-423 Me-(CH2) r -OC (= 0) --One ch2ch2— -NMe2 7-424 Me _ (CH2) 3- -OC (= 0)--CH2CHr -Yes eCH2CH20H 7-425 Me-(CH2) 3- -OC (= 0)---ch2ch2- -N (CH2CH2OH) 2 10 7-426 H-CH2CHr- c (= o) o-- I. Me-4-Pip. 7-427 H -CH2CHr-C (= 0) 0---CHr-COOH 7-428 H -CH2CH2--C (= 0) 0- --CHr l-Me-4-Pip 7-429 H -CH2CHr -c (= o) o---CH2CHr -COOH 7-430 H-CH2CHr -c (= o) o---ch2ch2- -so3h 15 7-431 H-CH2CHr -c (= o) o---ch2ch2- -〇p〇3h2 7-432 H -CH2CHr-C (= 0) 0---CH2CHr 1-Azt 7-433 H-CH2CHr- c (= o) o---CH2CH2-1-Pyrd 7-434 H-CH2CHr-c (= o) o---ch2ch 「1-Pip 7-435 H-CH2CH2- · ~ C (= 0) 0 --ch2ch2- 1-Me-4-Pip 20 7-436 H-CH2CHr -c (= o) o---ch2ch2- 4-Me-HPiz 7-437 H-CH2CHr-C (= 0) 〇- --ch2ch2- 4- (CH2CH20H) -l-Piz 7-438 H -CH2CHr -c (= o) o---CH2CHr 4-Mor 7-439 H -ch2ch2- -c (= o) o---- CH2CHr -Li e2 '7-440 H-ch2ch2- -C (= 0) 0---CH2CH2- -NMeCH2CH2OH 25 7-.441 H -CH2CHr -C (= 0) 0---ch2ch2- -N (CH2CH2OH ) 2 7-442 H -CH = CH- -0 (= 0) 0---l-Me-4-Pip 7-443 H -CH = CH- -C (= 0) 0---CH2-- COOH 7-444 H ~ CH = CH--C (= 0) 0--_CH2-l-Me-4-Pip 7-445 H -CH = CH- -CH) 0-- -ch2ch2- -COOH 30 7-446 H -CH-CH- -c (: 〇) 〇---ch2ch2_ -so3h 200410948 7-447 Η -CH: CH- -C (two 0) 0-- -CH2CHr-opo3h2 7-448 Η -CH = CH- -C (= 0 ) 0-- -CH2CHr Azt 7-449 Η -CH = CH--C (two 0) 0---CH2CHr 1-Pyr.d 7-450 Η -CH = CH- -c (= o) o- --CH2CHr 1-Pip 5 7-451 Η -CH = CH- -C (= 0) 0---CH2CHr l-Me-4-Pip 7-452 Η -CH = CH--C (= 0) 0 ---CH2CHr 4-Me-l-Piz 7-453 Η -CH = CH- -C (= 0) 0---CH2CHr 4-(CH2CH2OH) -HPiz 7-454 Η -CH = CH--c ( = o) o-- -CH2CH2- 4-Mor 7-455 Η -CH = CH- -c (= o) o---ch2ch2- -NMe2 10 7-456 Η -CH: CH- -C (-0 ) 0-- -CH2CHr-NMeCH2CH2OH 7-457 Η -CH = CH- -c (= o) o-.-~ CH2CHr -N (CH2CH20H) 2 Table 8

Exemplified R1 -L1- Compound No.-G ~-L2- -L3--A 8-1 Me -CHr-One HPyrd 8-2 Me -CH2--—-1-Pip 8-3 Me -CHr-One one 1 -Me-4-Pip 8-4 Me -CH2----1- (CH2CH20H) -4-Pip 178- 20 200410948 8-5 Me -CHr-8-6 Me -CH2--8-7 Me -CH 〖--8-8 Me ~ &quot; CH2 ~ _ 5 8 ~ 9 Me -CHr-• 8-10 Me -CH2- 8-11 Me -CH2CHr-8-12 Me -CH2CHr-8-13 Me -CH2CHr- 10 8-14 Me -CH2CH2--8-15 Me -CH2CH factory-8-16 Me -CH2CHr-8-17 Me -CH2CHr-8-18 Me -CH2CHr-15 8-19 Me -CH2CHr-8-20 Me -CH2CH2--8-21 Me -CH2CHr-8-22 Me -CH2CH2—— 8-23 Me-(CH2) 3--20 8-24 Με-(CH2) 3- _ 8-25 Me -CH2CH2_ -C (= 0)-8-26 Me -CH2CH2- -C (= 0)-8-27 Me _CH2CH2- -C (= 0)-8-28 Me -CH2CH2- -C (= 0)-25 8-29 Me -CH2CH2- -C (= 0)-8-30 Me -CH2CHr-(: (♦ 8-31 Me -CH2CHr -C (= 0)-8-32 Me -CH2CH2- -C (= 0)-8 -33 Me -CH2CHr -C (-0)-30 8-34 Me -CH2CHr -C (= 0)----4-Me-1-Piz--4- (CH2CH2OH) -l-Piz-one 4- Mor--ΝΗ2---NHMe---NMe2

---C00H--.-_ 3h2--1-Pyrd--1-Pip--1-Me-4 ~ Pip--l- (CH2CH2OH) -4-Pip--. 4-Me- HPiz--4 -(CH2CH20H) -l-Piz--4-Mor-·--ΝΗ2 1- -NHMe---NMe2

---C00H---〇p〇3h2-_ 1-Piz--4- (C (= NH) NH2) -l-Piz--4- (C (= NH) CHS) -1-Piz-- 4-Me-l-Piz--4- (CH2CH20H)-HPiz--4 ~ (CH2CH2NHAc) -1-Piz--4-(CH2Car) + Piz--4- (CH2CH20Car) -l-Piz-"4 -(CH2CH2F) -1 -Piz

1,3-Azt--COOH -179- 200410948 8-35 Me -CH2CHr -c (= o)-1,3-Azt- -oso3h 8-36 Me -CH2CHr-c (= 〇)-1,3- Az t--〇p〇3H2 8-37 Me -CH2CH2- -C (= 0)-1,4-Pip a-C00H 8-38 Me -CH2CHr -C (= 0)-1,4-Pip a- S03H 5 8-39 Me -CH2CHr -c (= 0)-1,4-Pip a-OS03H .8-40 Me -CH2CH2- ~ C (= 0)-1,4-Pip a-〇p〇3H2 8 -41 Me -CH2CHr -C (= 0)-1,4-Pip -1-Pyrd 8-42 Me -CH2CHr -C (= 0)-1,4-Pip -1-Pip 8-43 Me -CH2CHr- c (= o)-1,4-Pip-4-Me-l-Piz 10 8-44 Me -CH2CHr -c (= 0)-.1,4-Pip-4- (CH2CH20H) -HPiz 8-45 Me -CH2CHr -c (= 0)-.1, 4-Pip-4-Mor 8-46 Me -CH2CHr -C (= 0)-1,4-Pip a -NHMe 8-47 Me -CH2CH2- -c (= 〇)-1,4-Pip--Li e2 8-48 Me -CH2CH2- -c (= o)-1,4-Pip I-wake eCH2CH2OH 15 8-49 Me —CH2CH2—-c (= o )-1,4-Pip -N (CH2CH20H) 2 8-50 Me -CH2CHr -c (= o)-1,4-Pip-CH 「-C00H 8-51 Me -CH2CHr -c (= 0)- 1,4-Pip-CHr -SO3H 8-52 Me -CH2CH2--c (= o)-1,4-Pip.-CH2-&quot; OSO3H 8-53 Me -CH2CHr-c (= 〇)-1, 4-Pip -ch2- -〇p〇3h2 2 0 8-54 Me -CH2CHr-c (= o)-1,4-Pip-ch2- 4-Mor 8-55 Me -CH2CH2- -c (= 〇)-1,4-Pip-ch2- -nh2 8 -56 Me -CH2CHr-ct (= o)-1,4-Pip-ch2--NHMe 8-57 Me ~ CH2CHr -c (= 0)-1,4-Pip-ch2- -Li e2 8-58 Me -CH2CHr-c (= o)-1,4-Pip-CHr -NMeCH2CH2OH 25 8-59 Me -CH2CHr -C (= 0)-1,4-Pip-ch2--N (CH2CH2OH) 2 8-60 Me -CH2CHr-c (= 〇)-1,4-Piz a -so2nh2 8-61 Me -CH2CH2- -c (= o)-1,4-Piz-CH2CHr 1-Azt 8-62 Me -CH2CH2- -C (= 0)-1,4-Piz -CH2CH2- 1-Pyrd 8-63 Me -CH2CH2- -c (= 0)-1,4-Piz -ch2ch 「1-Pip 30 8-64 Me -CH2CH2-- C (-0) ~ 1,4-Piz -ch2ch2- 4-Me-l-Piz -180- 200410948

8-65 Me -CH2CH2--C (: 0)-1,4-P iz-CH2CH2- 4- (CH2CH20H) -l-Piz 8-66 Me -CH2CH2 — (:( ♦ 1,4-P iz- CH2CH2- 4-Mor 8-67 Me -CH2CHr -C (= 0)-1,4-P iz-CH2CHr -NHMe 8-68 Me -CH2CH2—C (= 0)-1,4-P iz -CH2CHr- Li e2 5 8-69 Me -CH2CH2--C (= 0)-1,4-Piz -CH2CHr -NMeCH2CH20H 8-70 Me -CH2CHr -C (= 0)-1, 4-P iz-CH2CHr -N (CH2CH2OH) 2 8-71 Me -CH = CH- -C (= 0)---1-Piz 8 ~ 72 Me-CH = CH——C (= 0)-a- 4- (C (= NH ) NH2) -1-Piz 8-73 Me-CH = CH--C (= 0)---4- (C (= NH) CH3) -1-Piz 10 8-74 Me -CH = CH—— C (= 0)---4-Me-l-Piz 8-75 Me -CH = CH--C (= 0)-a-4- (CH2CH20H) -l-Piz 8-76 Me -CH = CH --C (= 0)---4- (CH2CH2NHAc) -l-Piz 8-77 Me -CH = CH- -C (= 0)-1- 4- (CH2Car) -Bu Piz 8-78 Me- CH = CH--C (= 0)---4- (CH2CH20Car) -l ~ Piz 15 8-79 Me-CH = CH--C (= 0)-1,3-Azt--C00H. 8- 80 Me -CH = CH- -C (= 0)-1,3-Az t--0S03H 8-81 Me -CH = CH——C (= 0)-1,3-Az t--〇p〇 3h2 8-82 Me -CH = CH ~ -C (= 0)-1, 4-Pip--C00H 8-83 Me _CH = CH- -C (: 0)-1,4-Pip--so3h 20 8 ~ 84 Me -CH = CH-- C (= 0)-1,4-Pip--0S03H 8-85 Me -CH = CH- -C (= 0) — 1, 4-Pip -〇p〇3h2 8-86 Me _CH = CH- -C (= 0)-1,4-Pip-1-Pyrd 8-87 Me -CH = CH- -C (= 0)-1,4-Pip-1-Pip 8-88 Me -CH = CH- -C (= 0)-1,4-Pip-4-Me-l-Piz 25 8-89 Me _CH = CH- -C (= 0)-1,4-Pip-4- (CH2CH20H) + Piz 8-90 Me ~ CH ~ CH_ _C (-0)-1,4-Pip-4- (CH2CH2NHAc) -l-Piz 8_91 Me -CH = CH- -C (= 0)-1,4-Pip-4-Mor 8 -92 Me -CH-CH- -C (= 0)-1,4-Pip--NHMe 8-93 Me -CH-CH- -C (= 0)-1,4-Pip--NMe2 30 8- 94 Me -CH = CH——C (: 0) _ 1,4-Pip--wake up eCH2CH2OH -181-200410948

8-95 Me -CH = CH- -C (= 0)-1,4-Pip--_2ch2oh) 2 8-96 Me -CH = CH- -C (= 0)-1,4-Pip -ch2- -C00H 8-97 Me -CH = CH- -C (= 0)-1,4-Pip -ch2- -0S03H 8-98 Me -CH = CH--C (= 0)-1,4-Pip- ch2--0P0A 5 8-99 Me -CH = CH- -C (= 0)-1,4-Pip-CH 「4-Mor 8-100 Me -CH = CH- -C (= 0)-1, 4-Pip-CHr, 8-101 Me -CH = CH- -C (= 0)-1,4-Pip -ch2--NHMe 8-102 Me -CH = CH- -C (= 0)-1, 4-Pip -CH 「-NMe2 8-103 Me -CH = CH- -C (= 0)-1,4-Pip -ch2- -NMeCH2CH2OH 10 8 * ~ 104 Me -CH = CH- -C (-0 )-_1,4-Pip -ch2- -N (CH2CH2OH) 2 8-105 Me -CH2CH2- -C (= 0)-1,4-Piz--so2nh2 8-106 Me -CH = CH- -C ( = 0)-1,4-Piz -ch2ch2- 4-Mor 8-1.07 Me.-CH = CH--C (= 0)-1, 4-P iz -ch2ch2- -NHMe 8-108 Me -CH = CH- -C (= 0)-1,4-Piz-ch2ch2- 15 8-109 Me-CH = CH--C (= 0)-1,4-Piz -ch2ch2---Li eCH2CH20H 8-110 Me -CH = CH- -C (= 0)-1,4-P iz-ch2ch2- ~ N (CH2CH20H) 2 8-111 Me -CHr -NHC (= 0)-. --Ch2- 4-Me-l -Piz 8-112 Me -CHr -NHC (= 0)-one-ch2- -4- (CH2CH20H) -l-Piz 8-113 Me -CHr -NHC (= 0)-one- ch2- --1 ^ 2 20 8-114 Me -CH2- -Li eC (= 0)- 1- ch2- 4-Me-l-Piz 8-115 Me -CHr -Li eC (= 0)---ch2- -4- (CH2CH20H) -1-Piz 8-116 Me -CH2- -Li eC ( = 0)-One-ch2- -NMe2 8-117 Me -CH2CH2- _C (= 0) Li e---ch2ch2- -C00H 8-118 Me -CH2CH Factory-C (= 0) Li e- one-ch2ch2 --so3h 25 8-119 Me -CH2CH2- -C (= 0) circle e_ a-ch2ch2- -Li e2 8-120 H-CH2-.---1-Pyrd 8-121 H -CHr---1 -Pip 8-122 H -CHr .---l-Me-4-Pip 8-123 H-CH2---1-(CH2CH20H) -4-Pip 30 8-124 H -CH〇- — —- 4-Me-l-Piz 182- 200410948 8-125 H -CHr-8-126 H -CHr-8-127 H -CHr 8-128 H -CHr-5 8-129 H -CHr-8-130 H- CH2CH2-- 8-131 H -CH2CH2—— 8-132 H -CH2CHr-8-133 H -CH2CH2-- 10 8-134 H -CHzCHr-8-135 H -CH2CH2—— 8-136 H -CH2CHr-8 -137 H -CH2CHr-8-138 H -CH2CHr-15 8-139 H -CH2CHr-8-140 H -CH2CHr-8-14Ϊ H -CH2CHr-8-142 h- (ch2) 3- 8-143 H, (CH2) 3— 20 8-144 H ~ CH2CHr -C (= 0)-8-145 H -CH2CHr -C (= 0)-8-146 H -CH2CHr -C (= 0)-8-147 h- ch2ch2--c (= o)-8-148 h_ch2ch2--c (= o)-25 8-149 H -CH2C H2- -C (= 0)-8-150 H -CH2CH2- -C (= 0)-8-151 H-CH2CHr-Cd 8-152 H -CH2CHr -C (= 0)-8-153 H -CH2CHr -C (= 0) * 30 8-154 H -CH2CH2——C (= 0)---4- (CH2CH20H) -l-Piz ~-4 ~ Mor---NH2---NHMe---NMe2

One-C00H-.One-0P03Η2--1-Pyrd--1-Pip--1-Me-4-Pip One-l- (CH2CH2OH) -4-Pip--4-Me-l-Piz--4 -(CH2CH20H) -l-Piz--4-Mor--~ NH2 ~ ~ -NHMc---NMe2

---COOH--&quot; 〇p〇3h2-1-Piz-one 4- (C (= NH) NH2) -1-Piz--4- (C (= NH) CH3) -1-Piz-one 4-Me-1-Piz--4- (CH2CH2OH) -l-Piz--4-(CH2CH2NHAc) -Bu Piz--4- (CH2Car)-1-Piz--4 ~ (CH2CH2OCar) ~ 1-P iz--4 ~ (CH2CH2F) ~ 1-Piz

1.3- Azt--COOH

1.3- Azt-~ 0S03H -183- 200410948 8-155 Η -CH2CH2- -c (= 0)-1,3-Az t--〇〇〇〇3h2 8-156 Η -CH2CH2--c (two 0)- 1,4-Pip a-C00H 8-157 Η -CH2CHr ~ C (= 0)-1,4-Pip--so3h 8-158 Η -CH2CHr-c (= 〇)-. 1,4-Pip-- oso3h 5 8-159 Η-CH2CH2- -C (= 0)-1,4-Pip • — ·-0P03H2 8-160 H-CH2CHr-c (= 0)-1,4-Pip-1-Pyrd 8- 161 H -CH2CHr ~ C (= 0)-1,4-Pip -1-PiP, 8-162 H -CH2CH2- -C (= 0)-1,4-Pip-4-Me-1-Piz 8- 163 H -CH2CH2- -C (= 0)-1,4-Pip-4- (CH2CH20H) + Piz 10 8-164 H -CH2CH2- -c (= 0)-1,4-Pip one 4-Mor 8 -165 H -CH2CH2- -c (= 〇)-1,4-Pip a-NHMe 8-166 H -CH2CH2- -c (= 0)-1,4-Pip--Bae2 8-167 H -CH2 .CH2- -C (= 0)-1,4-Pip--fiMeCH2CH2OH 8-168 H -CH2CHr -c (= o)-1,4-Pip--N (CH2CH2OH) 2 15 8-169 H -CH2CH2 --c (= 0)-1,4-Pip -ch2- -C00H 8-170 H -CH2CH2--c (= o)-1,4-Pip-ch2- · -SO3H 8-171 H ~ CH2CH2- -c (= o)-1,4-Pip-ch2- -OSO3H 8-172 H -CH2CHr -c (= o)-1,4-Pip-ch2- -〇P〇A 8-173 H -CH2CHr- c (= 〇)-1,4-Pip -ch2-4-Mor 20 8-174 H -CH 2CH2- -c (= o)-1,4-PIp-CH2--nh2 8-175 H -CH2CHr -c (= 0)-1,4-Pip-CH2--NHMe 8-176 H-CH2CHr -C (= 0)-1,4-Pip-CH2--Li e2 8-177 H -CH2CHr-c (= o)-1,4-Pip-ch2- -Li eCH2CH2OH 8-178 H -CH2CHr-c (= o)-1,4-Pip-ch2- -_2ch2oh) 2 25 8-179 H-CH2CHr-c (= o)-1,4-Piz a -so2nh2 8-180 H -CH2CHr -C (= 0)- 1,4-Piz -CH2CHr 1-Azt 8-181 H -CH2CHr -c (= o)-1,4-Piz -CH2CHr 1-Pyrd 8-182 H -CH2CH2- -c (= 0)-1,4 -Piz -CH2CHr 1-Pip 8-183 H -CH2CH2- -c (= 0)-1,4-Piz -ch2ch2- 4-Me-1-Piz 30 8-184 H -CH2CH2- -c (= 0) -1,4-Piz -ch2ch2- 4- (CH2CH20H) -l-Piz -184-200410948 8-185 H -CH2CH2- -C (= 0)-1,4-P iz -CH2CH2- 4-Mor 8- 186 H -CH2CH2- -C (= 0)-1,4-Piz -CH2CHr -NHMe 8-187 H -CH2CH2——C (= 0)-1,4-Piz -CH2CHr -NMe2 8_188 H -CH2CHr -C (= 0)-1,4-Piz -CH2CHr -NMeCH2GH2OH 5 8-189 H -CH2CHr -C (= 0)-1,4-Piz -CH2CHr -N (CH2CH20H) 2 8-190 H -CH = CH- -C (= 0)---1-Piz 8-191 H -CH two CH——C (= 0) _ one- 4- (C (= NH) NH2) -l-Piz 8-192 H-CH : CH——C (= 0)-1- 4- (C (= NH) CH3) -1-Piz 8-193 H -CH = CH- -C (= 0)--4-Me-HPiz 10 8-194 H -CH = CH- -C (= 0)-1- 4- (CH2CH20H) 'Bu Piz 8 -195 H -CH = CH- -C (= 0)-.A-4- (CH2CH2NHAc)-1-Piz 8-196 H -CH = CH- -C (= 0)--4- (CH2Car)- l-Piz 8-197 H -CH = CH- -C (= 0)---4-(CH2CH2OCar) -Bu Piz. 8-198 H -CH = CH- -C (= 0)-1, 3- Az t-C00H 15 8-199 H -CH = CH- -C (= 0)-1,3-Az t--oso3h .8-200 H -CH: CH- -C (= 0)-1 , 3-Az t--〇p〇3h2 8-201 H -CH = CH——C (= 0)-1,4-Pip--C00H 8-202 H -CH = Cl · -COO)-1, 4-Pip--so3h 8-203 H -CH = CH- -C (= 0)-1,4-Pip--oso3h 20 8-204 H -CH = CH--C (= 0)-1,4 -Pip--〇p〇3h2 '8-205 H-CH = CH--C (= 0)-1,4-Pip-1-Pyrd 8-206 H-CH = CH ---- C (= 0)- 1,4-Pip-1-Pip 8-207 H -CH = CH- -C (= 0)-1,4-Pip-4-Me-l-Piz 8-208 H -CH = CH- -C ( = 0)-1,4-Pip-4-(CH2CH20H) -Bu Piz 25 8-209 H -CH = CH- -C (= 0)-1,4-Pip-4- (CH2CH2NHAc) -l-Piz 8-210 H -CH = CH--C (= 0)-1,4-Pip-4-Mor 8-211 H -CH = CH- -C (= 0)-1,4-Pip--NHMe 8 -212 H -CH = CH- -C (= 0)-1,4-Pip--NMe2 8-213 H -CH = CH- -C (= 0)-1,4-Pip--NMeCH2CH20H 30 8-214 H -CH di CH- -C (two 0)-1,4-Pip--N (CH2CH2OH) 2 -185- 200410948 8-215 Η -CH = CH- -C (= 0)-1,4-Pip -CHr -C00H 8-216 H -CH = CH- -C (= 0)-1,4-Pip -CHr-0S〇3H 8- 217 H -CH = CH- -C (= 0)-1,4-Pip-ch2- -opo3h2 8-218 H -CH = CH- -C (= 0)-1,4-Pip -CH 「4- Μογ 5 8-219 · HL -C (= 0)-1,4-Pip-ch2- -leg 2 8-220 H -CH = CH- -C (: 0)-1,4-Pip -ch2-- NHMe 8-221 H -CH = CH- -C (= 0)-1,4-Pip -CH2- -NMe2 8-222 H-CH = CH--C (= 0)-1,4-Pip -ch2 --NMeCH2CH2OH 8-223 H -CH = CH- -C (= 0)-1,4-Pip-ch2- -_2CH2OH) 2 10 8-224 H -CH2CH2- -C (= 0)-1,4- Piz--so2nh2 '8-225 H -CH di CH- -C (= 0)-1,4-Piz -CH2CHr 4-Mor 8-226 H -CH = CH- -C (= 0)-1,4 -Piz -CH2CHr -NHMe 8-227 H -CH = CH- -C (= 0)-1,4-Piz -CH2CHr -Lie2 8-228 H -CH = CH- -C (= 0)-1, 4-Piz -CH2CHr -NMeCH2CH2OH 15 8-229 H -CH = CH- -C (two 0)-1,4-Piz -CH2CHr-N (CH2CH20H) 2 8-230 H -CH2- -NHC (= 0) -One- ch2- 4-Me-l-Piz 8-231 H -CH2- -NHC (= 0)----CHr 4- (CH2CH20H)-H 8-232 H -CH`` -NHC (= 0)- One One CHr -NMe2 8-233 H -CH2--Li eC (= 0)-One-CHr 4-Me-l-Piz 20 8-234 H ~ CHr-NMeC (= 0)-One-ch2- 4- ( CH2CH20H) -1-8-235 H -CHr -Li eC (= 0)-a-ch2-, e2 8-236 H -CH2CHr -C (= 0) NMe----CH2CHr-C00H 8-237 H -CH2CHr -C (= 0) Li e---ch2ch2- -so3h 8-238 H -CH2CHr -C (= 0) NMe- one -ch2ch "-wake e2 25 8-239 Me 1,4-cHx--one- C00H 8-240 Me 1,4-cHx-one--〇〇〇〇3H2 8-241 Me 1,4-cHx--one -Pyrd 8-242 Me 1,4-cHx-one one 1-Pip 8- 243 Me 1,4-cHx-one-1-Me-4-Pip 30 8-244 Me 1,4-cHx--one l- (CH2CH2OH) 186- 200410948 8-245 Me 1,4-cHx-— 4 -Me-l-Piz 8-246 Me 1,4-cHx one-to-one 4-(CH2CH2OH) -l -Piz 8-247 Me 1,4-cHx — —-4-Mor 8-248 Me 1,4- cHx---νη2 5 8-249 Me 1,4-cHx-—--NHMe 8-250 Me 1,4-cHx — —--Li-e2 8-251 H 1,4-cHx----C00H 8-252 H 1,4-cHx — —--〇〇〇〇 3H2 8-253 H 1,4-cHx-one — l-Pyrd 10 8-254 H 1,4-cHx one. One-1-Pip 8 -255 H 1,4-cHx one one-1-Me-4-Pip 8-256 H 1,4-cHx--one l- ( CH2CH2OH) -4-Pip 8-257 H 1,4-cHx 1 — — 4-Me-l-Piz 8-258 H 1,4-cHx-—-4- (CH2CH20H) -l-Piz 15 8-259 H 1,4-cHx,-— — 4-Mor 8-260 H 1,4-cHx-one -nh2 8-261 H 1,4-cHx-one-• -NHMe 8-262 H 1,4-cHx — — One-NMe2 8-263 Me-(ch2) 4-One one one-C00H 20 8-264 Me _ (CH2) 4- — — One-so3h 8-265 Me-(ch2) 4_--One -0S03H 8-266 .Me-(ch2) 4- — —--0P03h2 8-267 Me-(ch2) 5- one-to-one-C00H 8-268 Me-(CH2) 5- —---SO3H 25 8- 269 Me-(ch2) 5----OSO3H 8-270 Me-(CH2) 5-----opo3h2 8-271 Me-(CH2) r -C (: 0_e—— -CH2CHr -so3h 8-272 Me-(ch2) 4- -C (= 0) fiMe—— _CH2CH2--so3h 8-273 Me-(CH2) 5--C (= 0) Li e--.-Ch2ch2--so3h 30 8-274 Me-(CH2) 6--C (= 0) plane e-- -ch2ch2- -so3h 187- 200410948 8-275 H-(CH2) 4----C00H 8-276 Η-(CH2) 4_ one one Mono-so3h 8-277 Η-(CH2) 4- — — mono-oso3h 8-278 Η-(CH2) 4- .----opo3h2. 5 8-279 Η _ (CH2) 5---- -C00H 8-280 Η-(CH2) 5- — —_--S03H 8-281 Η-(CH2) 5-----OS03H 8-282 _ _ (CH2) 5- — — --0P0A 8-283 Η-(CH2) 3--C (= 0) NMe-- -ch2ch2-- S03H 10 8-284 Η-(CH2) 4--C (= 0) NMe-- -ch2ch2- -S03H 8-285 H-(CH2) 5- -CHMMe——-CH2CHr -so3h 8-286 H-( CH2) 6- -C (= 0) wake up e---ch2ch2- -S03H 8-287 Me -CH2CH2- -OC (= 0)--l-Me-4-Pip 8-288 Me -CH2CHr -0C (= 0)--ch2- -C00H 15 8-289 Me -CH2CH2--0C (= 0)---CHr. -SO3H 8-290 Me -CH2CHr -0C (= 0)---CH2-- opo3h2 8-291 Me -CH2CH2- -0C (= 0) ~--ch2- 1-Azt 8-292 Me -CH2CH2- -0C (= 0)-one-CHr 1-Pyrd 8-293 Me -CH2CHr-oc (= 0)--ch2- 1-Pip 20 8-294 Me -CH2CHr -oc (= 0)--CHr 1-Me-4-Pip 8-295 Me -CH2CHr -oc (= 0)- -CHr 4-Me-l-Piz 8-296 Me -CH2CH2- -oc (= 0)---CHr 4- (CH2CH20H) -l-Piz 8-297 Me -CH2CH2- -0C (= 0)- -ch2- 4-Mor 8-298 Me -CH2CH2- -oc (= 〇)---ch2- -Li e2 25 8-299 Me -CH2CH2- -oc (= 0)-one-CHr -NMeCH2CH2OH: 8- 300 Me -CH2CH2- -〇C (= 0)---CHr -N (CH2CH20H) 2 8-301 Me -CH2CH2- -oc (= 〇)--ch2ch2 ·---C00H 8-302 Me -CH2CH2- -oc (= 0)---ch2ch2- --SO3H 8-303 Me -CH2CHr -oc (= 0)--ch2ch2_--0P03H2 30 8-304 Me -CH2CH2- -0C (-0) ~-- ch2ch2 · l ~ Azt 188- 200410948 8-305 Me -CH2CH2--0C (= 0)----CH2CHr 1-Pyrd 8-306 Me -CH2CH2- -0 (: (♦--CH2CHr 1-Pip 8-307 Me -CH2CH2- -0C (= 0)-One-ch2ch2- Bu Me-4-Pip 8-308 Me -CH2CHr-oc (= o)-One-CH2CHr 4-Me-l-Piz 5 8-309 Me- CH2CHr-OCH)---CH2CHr 4- (CH2CH20H) -l-Piz 8-310 Me -CH2CHr -OCH)---CH2CHr 4-Mor 8-311 Me ~ CH2CHr -OC (= 0)-one-CH2CHr- NMe2 8-312 Me -CH2CHr -oc (= o)---CH2CHr -Li eCH2CH20H 8-313 Me -CH2CH2- -oc (= 0)-a-ch2ch2--N (CH2CH2OH) 2 10 8-314 Me- (CH2) r -oc (= 0)-1-Me-4-Pip 8-315 Me-(CH2) 3- .-OCH)---CH 「-C00H 8-316 Me-(CH2) 3 --OC (= 0)-One-ch2--S03H '8-317 Me _ (CH2) 3- -OC (= 0)---CHr -〇p〇3h2 8-318 Me-(CH2) 3- -OC (= 0)---CHr 1-Azt 15 8-319 Me-(CH2) 3- -0C (= 0)---CH2- 1-Pyrd 8-320 Me-(CH2) 3_-oc ( = 〇)---ch2- 1-Pip .8-321 Me-(CH2) 3 ~ -oc (= o)---ch2-l-Me-4 -P ip 8-322 Me-(CH2) 3- -oc (= 〇)---CHr 4-Me-l-Piz 8-323 Me-(CH2) 3--oc (= o)--CH2 -4- (CH2CH2OH) -Bu Piz 20 8-324 Me _ (CH2) 3- -OC (= 0)-One-CHr 4 -Mor 8-325 Me-(CH2) 3- -oc (= 〇)- — -CHr -Li e2 8-326 Me-(CH2) "-oc (= o)---ch2- -_eCH2CH2OH 8-327 Me-(CH2) r -0C (= 0) ~--ch2--N (CH2CH2OH) 2 8-328 Me-(CH2) 3- -oc (= 〇)--~ CH2CHr-C00H 25 8-329 Me-(CH2) 「-oc (= 0)----CH2CHr -so3h 8- 330 Me-(CH2) 3- -〇C (-0) ~ one-CH2CHr -〇p〇3h2 8-331 Me _ (CH2) 3- -0C (= 0) ~ one-CH2CHr 1-Azt 8-332 Me-(CH2) 3- -0C (= 0)---CH2CHr 1-Pyrd 8-333 Me-(CH2) 3- -oc (= 〇)---CH2CHr 1-Pip 30 8-334 Me-( CH2) 3- -oc (= 〇)---ch2ch2- l-Me-4-Pip -189- 200410948 8-335 Με-(CH2) 3 &quot; &quot; -0C (= 0)---ch2ch2- 4 -Me-l-Piz 8-336 Me- (CH2) 3--OCH)---CH2CHr 4- (CH2CH20H) -l-Piz 8-337 Me-(CH2) r-OC (= 0)---- ch2ch 「4-Mor 8-338 Me-(CH2 &gt; 3- -OC (= 0)---ch2ch2- -NMe2 5 8-339. Me-(CH2) 3- -0C (= 0)--CH2CHr -NMeCH2CH2OH • 8-340 Me-(C H2) 3- -OCH)---ch2ch2- -N (CH2CH2OH) 2 8-341 Me -CH2CHr-C (= 0) 〇- -l-Me-4-Pip 8-342 Me -CH2CHr -C ( 0) 0---ch2- -C00H 8-343 Me -CH2CHr-C (= 0) 0--_ch2- 1-Me-4-Pip 10 8-344 Me -CH2CHr -C (= 0) 0- --CH2CHr-C00H 8-345 Me -CH2CH2- -C (= 0) 0- --ch2ch2- -so3h 8-346 Me -CH2CHr-C (= 0) 0---CH2CHr -〇p〇3h2 8- 347 Me -CH2CH2--CK0O--rCH2CHr 1-Azt 8-348 Me -CH2CHr-c (= o) o---CH2CHr 1-Pyrd 15 8-349 Me -CH2CHr-C (= 0) 0--- ch2ch2- 1-Pip 8-350 Me -CH2CHr -C (= 〇) 〇---CH2CHr Bu Me-4-Pip 8-351 Me -CH2CHr -C (= 0) 0----CH2CHr 4-Me-1 -Piz 8-352 Me -CH2CHr -C (= 0) 0---CH2CHr 4- (CH2CH20H) -l-Piz 8-353 Me -CH2CHr-C (= 0) 0---CH2CHr 4-Mor 20 8 -354 Me -CH2CHr-c (= o) o-- -CH2CH2_ -Li e2 8-355 Me -CH2CHr-c (= o) o---ch2ch2- -Li eCH2CH20H 8-356 Me -CH2CHr-C (= 0) 0---CH2CHr -N (CH2CH2OH) 2 8-357 Me -CH = CH- -C (= 0) 0---l-Me-4-Pip 8-358 Me -CH = CH- -C (= 0) 0---ch2--C00H 25 8-358 Me -CH = CH--C (= 0) 0--~ ch2 ~ l-Me-4-Pip 8-359 Me -CH = CH--C (= 0) 0---ch2ch``-C00H 8-360 Me -CH = CH- -c (= o) o---CH2CHr -so3h 8-361 Me- CH = CH- -C (= 0) 0---CH2CHr -opo3h2 8-362 Me -CH = CH--C (= 〇) 〇- ~ -CH2CHr 1-Azt 30 8-363 Me -CH di-CH- -C (-0) 0 ~--CH2CHr 1-Pyrd 200410948 8-364 Me -CH = CH- -0 (= 0) 0---CH2CHr 1-Pip 8-365 Me -CH-CH- -0 ( = 0) 0---CH2CHr l-Me-4-Pip 8-366 Me -CH = CH- _c (= o) o---ch2ch2- 4-Me-l-Piz 8-367 Me -CH = CH --C (= 0) 0---CH2CHr 4- (CH2CH20H) -l-Piz 5 8-368 Me -CH = CH- -c (= o) o---CH2CHr 4-Mor 8-369 Me- CH = CH- -C (= 0) 0---CH2CHr -NMe2 8-370 Me -CH = CH--c (= o) o---CH2CHr -Li eCH2CH2OH 8-371 Me -CH = CH-- C (: 0) 0---CH2CHr -n (ch2ch2oh) 2 8-372 H-CH2CHr -oc (= o)---1-Me-4-Pip 10 8-373 H -CH2CHr-oc (= o )---CH2--C00H 8-374 H -CH2CH2--oc (= o)---ch2 ~ -so3h 8-375 H -CH2CHr-OCN))---ch2- -〇p〇3h2 8- 376 H -CH2CHr-oc (: o)---ch2- 1-Azt 8-377 H -CH2CHr -0C (= 0)---CHr 1-Pyrd 15 8-378 H-CH2CHr -0C (= 〇) --ch2- 1-Pip 8-379 H -CH2CHr -0C (= 0 )--ch2- l-Me-4-Pip 8-380 H-CH2CHr -oc (= o)---ch2- 4-Me-1-Piz 8-381 H-CH2CHr-oc (= o)- --CHr 4-(CH2CH2OH) —HPiz 8-382 H -CH2CH2- -0C (= 0)----ch2- 4-Mor 20 8-383 H-CH2CH2--oc (= o)---CHr- NMe2 8-384 H -CH2CHr-OCH)---ch2-, -Li eCH2CH20H 8- 385. H -CH2CHr-oc (= o)---ch2- -N (CH2CH2OH) 2 8-386 H -CH2CH2- -0C (= 0)---CH2CHr-C00H 8-387 H -CH2CH2- -OCH)---CH2CHr -S03H 25 8-388 H -CH2CHr-oc (= o)---CH2CHr -〇p〇3h2 8-389 H -CH2CH2_ -oc (= o)--CH2CH2- 1-Azt • 8-390 H -CH2CHr-oc (= o)---CH2CHr 1-Pyrd 8-391 H-CH2CHr-oc (= o)---CH2CHr 1-Pip 8-392 H-CH2CHr-0C (two 0)---CH2CHr l-Me-4-Pip 30 8-393 H -CH2CHr -0C (-0)---CH2CHr 4 -Me ~~ lP iz 200410948 8-394 H -CH2CHr -oc (= 0)-one-ch2ch2- 4- (CH2CH20H) -l-Piz 8-395 H -CH2CH2--0C (= 0)-one- ch2ch2 -4-Mor 8-306 H -CH2CHr -0C (= 0)-One-ch2ch ", e2 8-397 H-CH2CHr-oc (= 0)-One -ch2ch2- -NMeCH2CH2OH 5 8-398 H -CH2CHr- 〇C (= 0)-a-ch2ch2- -N (CH2CH2 OH) 2 8-399 Me-(CH2) 3- -0C (= 0)---1-Me-4-Pip 8-400 Me-(CH2) 3- -0C (= 0)-one ~ ch2- -C00H 8-401 Me-(CH2) 3--oc (= o) _--CHr -so3h 8-402 Me ~ (CH2) 3 ~ -oc (= o)---ch2--〇p〇3h2 10 8-403 Me-(CH2) 3- -0CO0)-— -ch2- 1-Azt 8-404 Me-(CH2) 3_-oc (= 〇)---CH 「1-Pyrd 8-405 Me- (CH2) 3--oc (= o)-One- CH2-1-Pip 8-406 Me '(CH2) 3- -0C (= 0)---CHr 1-Me-4-Pip 8-407 Me _ (CH2) 3--ocoo)-•--CH 「4-Me-l-Piz 15 8-408 Me-(CH2) 3- -0 (: (= 0)---CHr 4- (CH2CH20H) -l-Piz 8-409 Me-(CH2) 3- -0C (= 0)---CHr 4-Mor 8-410 Me-(CH2) 3- -oc (= 〇)-one-CH2--wake up e2 8-411 Me-(CH2) 3- -oc (= 0)--Mai-Li eCH2CH2OH 8-412 Me-(CH2) 3--oc (= 〇)---CHr -N (CH2CH20H) 2 20 8-413 Μθ-(CH2) 3 ~ -0C (= 0)-—-ch2ch2--COOH 8-414 Me-(CH2) 3- -0C (= 0)-one-ch2ch2--so3h 8-41.5 Me _ (CH2) 3- -00 (= 0)-— one ch2ch2- -〇p〇3h2 8-416 Me-(CH2) 3- -oc (= 〇)-one-ch2ch2- 1-Azt 8-417 Me -(CH2) 3- -oc (= 0)----CH2CHr 1-Pyrd 25 8-418 Me-(CH2) 3- -OCH)-1-ch2ch2- bu Pip 8-419 Me-(CH2) r -oc (Service 1-ch2ch 「l-Me-4-Pip 8-420 Me ~ (CH2) 3- -oc (= 〇) -One-ch2ch2- 4'Me-lP iz 8-421 Me-(CH2) 3- -0 (:( ♦ One-ch2ch2- 4- (CH2CH2OH) -l-Pi2 8-422 Me-(CH2) 3- -oc (= 0)--CH2CHr 4-Mor 30 8-423 Me-(CH2) 3- -oc (: 〇)---ch2ch2- -NMe2 200410948 8-424 Me-(CH2) 3--OC ( = 0)--ch2ch2- 8-425 Me-(CH2) 3- ~ 0C (-0) ~-one ch2ch2 8-426 H -CH2CHr: one C (= 0) 0- one-8-427 H -CH2CH2--c (: 0) 0---CH 「5 8-428 H -CH2CHr _c (= o) o----CHr 8-429 H -CH2CHr -C (= 0) 〇 -.- -CH2CHr 8-430 H -CH2CH2--C (= 0) 0---CH2CHr 8-431 H-CH2CHr-C (= 0) 0---CH2CHr 8-432 H -CH2CH2--c (= o) o- --CH2CHr 10 8-433 H -CH2CH2- -c (= o) o---CH2CHr 8 ~ 434 H -CH2CHr -c (= o) o----CH2CHr 8-435 H-CH2CHr -C (= 0 ) 0---CH2CHr 8-436 H, CH2CHr-c (= o) o---ch2ch 「8-437 H-CH2CH「 -c (= o) o--:-ch2ch2-15 8-438 H- CH2CHr -C (= 0) 0 ~---CH2CHr 8-439 H -CH2CH2--C (= 0) 0---CH2CHr 8-440 H-CH2CHr -c (= o) o--- CH2CH2- 8-441 H-CH2CHr-COO) 0---CH2CHr 8-442 H -CH = CH--C (= 0) 0---20 8-443 H -CH = CH--C (= 0 ) 0---ch2-8-444 H -CH = CH--C (= 0) 0---CH2-8-445 H -CH = CH- -c (= o) o---ch2ch2- 8 -446 H -CH = CH--C (= 0) 0---CH2CHr 8-447 H ~ CH = CH--C (= 0) 0---CH2CHr 25 8-448 H -CH = CH-- C (= 〇) 〇'--CH2CHr 8-449 H -CH di-CH--c (= 〇) 〇---CH2CHr 8-450 H -CH = CH--C (= 0) 0--~ CH2CH2 ~ * 8-451 H -CH = CH- -c (= o) o---ch2ch2- 8-452 H -CH2CH--C (= 0) 0---ch2ch 「30 8-453 H- CH two CH- -C (-0) 0 ~--ch2ch2- -NMeCH2CH2OH -N (CH2CH2OH) 2 l-Me-4-Pip -C00H 1-Me-4-Pip -COOH -S03H -OPOA 1-Azt 1 -Pyrd 1-Pip 1-Me-4-Pip 4-Me-HPiz 4- (CH2CH20H) -l-Piz 4-Mor, e2

-NMeCH2CH2OH ~ N (CH2CH2OH) 2 1-Me-4-Pip-COOH l-Me-4-Pip -COOH-S03H -〇p〇3h2 1-Azt 1-Pyrd 1-Pip 1-Me-4-Pip 4 -Me-1-Piz 4- (CH2CH20H) -l-Piz -193- 200410948 8-454 Η -CH = CH--C (= 0) 0---CH2CHr 4-Μογ 8-455 Η -CH = CH --C (= 0) 0---CH2CHr -NMe2 8-456 Η -CH = CH- -CH) 〇---CH2CHr-NMeCH2CH2OH 8-457 Η -CH = CH- -C (= 0) 0- --CH2CHr-N (CH2CH2OH): Table 9 O R1 〇, 〇A〇A.〇Al1_g_l2_l3_a

10 exemplified R1-L1--G- compound number-L2--L3--A 9-1 Me -CH2_--1 -Pyrd 15 9-2 Me -CHr--1 -Pip 9-3 Me. -CH2 ~-— — 1-Me-4-Pip 9-4 Me -CH2-----l- (CH2CH2OH) -4-Pip 9-5 Me -CH factory-.— — 4-Me-l-Piz 9-6 Me -CH2--One-4- (CH2CH20H) -l-Piz 20 9-7 Me -CHr-One- 4-Mor 9-8 Me -CHr-One--nh2 9-9 Me -CHr- --NHMe 9-10 Me -CH 「-— -NMe2 9-11 Me -CH2CHr---C00H 25 9-12 Me -CH2CHr----opo3h2 -194-200410948 9-13 Me -CH2CH2- -9- 14 Me -CH2CHr-9-15 Me -CH2CH2--9-16 Me -CH2CH2--5 9-17 Me -CH2CHr a. 9-18 Me -CH2CHr-9-19 Me -CH2CH2- — 9-20 Me- CH2CHr-9-21 Me -CH2CHr — 10 9-22 Me -CH2CHr-9-23 Me _ (CH2) 3--9-24 Mc-(CH2) 3- — 9-25 Me -CH2CHr-C (= 0 )-9-26 Me -CH2CHr-c (= o)-15 9-27 Me -CH2CH2- -c (= o)-9-28 Me -CH2CHr-c (= o)-9-29 Me -CH2CHr- c (= o)-9-30 Me -CH2CH2- -C (= 0)-9-31 Me -CH2CHr-c (= o)-20 9-32 Me -CH2CH2--c (= o)-9- 33 Me -CH2CHr-C (= 0)-9-34 Me -CH2CHr-c (= o)-9-35 Me -CH2CH2- ~ C (= 0)-9-36 Me -CH2CHr -c (= 0)-25 9-37 Me -CH2CHr-c (= o) -9-38 Me -CH2CHr -CH)-9-39 Me -CH2CHr-c (= o)-9-40 Me -CH2CH2- -c (= o)-9-41 Me -CH2CH2- -CH))- 30 9-42 Me -CH? CH9- -c (= o)--l-Pyrd-1-Pip-1-Me-4-Pip-HCH2CH20H)-4-Pip-4-Me-l-Piz-4 -(CH2CH20H) -l-Piz-4-Mor I, 2--NHMe--Li e2

--C00H--〇p〇3h2-1-Piz-. 4- (C (= NH) NH2) -l-Piz-4- (C (= NH) CH3) -1-Piz-4-Me-l -Piz -4-. (CH2CH20H) -l-Piz-4- (CH2CH2NHAc) -l-Piz-4- (CH2Car) -l-Piz-4- (CH2CH2OCar) -Bu Piz — — 4- (CH2CH2F)- l-Piz 1,3-Az t--C00H 1,3-Az t-.-OSO3H 1,3-Az t-, 〇3h2 1,4-Pip--C00H 1,4-Pip--SO3H 1, 4-Pip--OSO3H 1,4-Pip--opo3h2 1,4-Pip-1-Pyrd 1,4-Pip-1-Pip -195-200410948 9-43 Me -CH2CHr -CH)-1,4- Pip a 4-Me-l-Piz 9-44 Me -CH2CH2- -C (= 0)-1,4-Pip-4- (CH2CH20H) -l-Piz 9-45 Me -CH2CHr -C (= 0) -1,4-Pip-4-Mor 9-46 Me —CH2CH2- —C (= 0)-1,4-Pip--Leg Me 5 9-47 Me -CH2CHr -C (= 0)-1,4 -Pip a__e2 .9-48 Me -CH2CHr -C (= 0) ~ 1,4-Pip-'-NMeCH2CH20H 9-49 Me -CH2CHr -C (= 0)-1,4-Pip a-N ( CH2CH2OH) 2 9-50 Me -CH2CH2- -C (= 0)-1,4-Pip-ch2- -C00H 9-51 Me -CH2CHr -C (= 0)-1,4-Pip-ch2- -so3h 10 9-52 Me -CH2CHr -C (= 0)-1,4-Pip -ch2- -0S03H 9-53 Me -CH2CH2- -C (= 0)-1,4-Pip-CH "-〇p〇 3h2 9-54 Me—CH2CH2——C〇0)-1,4-Pip ~ CHr 4-Mo r 9-55 Me-CH2CH2--C (= 0)-1,4-Pip -ch2--nh2 9-56 Me —CH2CH2— _C (= 0) — 1,4-Pip-ch2- -NHMe 15 9 -57 Me -CH2CH2- -C (= 0)-1,4-Pip-ch2- -Li e2 9-58 Me -CH2CH2--C (= 0)-1,4-Pip-CHr -Li eCH2CH2〇H 9-59 Me ~ CH2CHr -C (= 0)-1,4-Pip-ch2- -N (CH2CH20H) 2 9-60 Me -CH2CHr -C (= 0)-1,4-Piz a-so2nh2 9- 61 Me -CH2CH2--CO0)-ί, 4-P iz -CH2CHr 1-Azt 20 9-62 Me -CH2CHr ~ C (= 0) ~ 1,4-Piz -CH2CH 「1-Pyrd 9-63 Me- CH2CHr ~ C (= 0)-1,4-Piz-ch2ch2- 1-Pip 9-64 Me -CH2CH2- -C (= 0)-1,4-Piz-ch2ch2- 4-Me-l-Piz 9- 65 Me, CH2CH2--C (= 0)-1,4-Piz -CH2CHr 4- (CH2CH20H) -l-Piz 9-66 Me -CH2CHr -C (= 0)-1,4-Piz-CH2CH2- 4 -Mor 25 9-67 Me -CH2CHr -C (= 0)-1,4-Piz -ch2ch2- -NHMe 9-68 Me -CH2CH2- -C (Service 1,4-Piz-ch2ch2--NMe2 9-69 Me -CH2CH2- -C (= 0)-1,4-Piz-CH2CHr -NMeCH2CH2OH 9-70 Me -CH2CH2— —C (= 0)-1,4-Piz-CH2CH2- -N (CH2CH2OH) 2 9- 71 Me _CH = CH- -C (= 0)-_ 1-Piz 30 9-72 Me -CH-CH- -C (= 0)---4- (C (= NH) NH2) -l- Piz -196-200410948 9-73 Me -CH = CH- -C (= 0) -9-74 Me -CH = CH- -C (= 0)-9-75 Me -CH = CH- -C (= 0)-9-76 Me -CH = CH— (: (♦ 5 9-77 Me -CH = CH- -C '(= 0)-9-78 Me -CH = CH——C (= 0)-9-79 Me -CH: CH——C (= 0)-9-80 Me _CH = CH- -C (= 0)-9-81 Me -CH = CH- -C (= 0)-10 9-82 Me -CH = CH- -C (= 0)-9-83 Me-CH = CH——C (= 0)-9-84. Me -CH = CH- -C (= 0)-9-85 Me -CH = CH——C (= 0)-9-86 Me -CH = CH- -C (= 0)-15 9-87 Me -CH = CH- -C (= 0)-9-88 Me -CH = CH- -C (= 0)-9-89 Me -CH = CH ~ -C (= 0)-9-90 Me -CH = CH- -C (= 0)-9-91 Me -CH = CH- -C (= 0)-20 9-92 Me -CH = CH- _C (= 0)-9-93 Me -CH = CH- -C (= 0)-9-94 Me -CH = CH- -C (= 0)-9-95 Me -CH = CH——C ( = 0)-9-96 Me-CH = CH——C (= 0)-25 9-97 Me -CH = CH——C (= 0)-9-98 Me -CH = CH- -C (two 0)-9-99 Me -CH = CH- -C (= 0)-9-100 Me -CH = CH- -C (= 0)-9-101 Me -CH = CH- -C (= 0) -30 9-102 Me -CH di CH- -C (di 0)-4- (C (= NH) CH3) + Piz 4-Me- * l-Piz one-4- (CH2CH2OH) ~ l-Piz- -4- (CH2CH2NHAc) -l-Piz one-4- (CH2Car) + Piz — one 4-(CH2CH2OCar) -l-Piz 1,3_Az t one-C00H 1,3-Az t--0 S03H 1,3_Az t--opo3h2 1,4-Pip one .-COOH 1,4-Pip one-so3h 1,4-Pip--OSO3H 1,4-Pip--opo3h2 1,4-Pip one 1-Pyrd 1,4-Pip -1-Pip 1,4-Pip -4-Me-l ~ P iz 1,4-Pip-4- (CH2CH20H) -l-Piz 1,4-Pip-4- (CH2CH2NHAc)- l-Pi 1,4-Pip one 4-Mor 1,4-Pip one -NHMe 1,4-Pip -Li e2 1,4-Pip--NMeCH2CH2OH 1,4-Pip one -N (CH2CH2OH) 2 1, 4-Pip -ch2- -COOH 1,4-Pip -ch2- -OSO3H 1,4-Pip-ch2- -〇p〇3h2 1,4-Pip -ch2- 4-Mor 1,4-Pip · -ch2 ---nh2 1,4-P ip -ch2- -NHMe 1,4-Pip -ch2- -NMe2

-197-200410948 9-103 Me -CH = CH- -C (= 0)-1,4-Pip -CHr -round eCH2CH20H 9-104 Me -CH di-CH- -C (= 0)-1,4- Pip -CHr -N (CH2CH2OH) 2 9-105 Me -CH2CH2--C (: 0)-1,4-Piz-, 2 Li 2 9-106 Me -CH = CH——C (= 0) _ 1 , 4-Piz -CH2CHr 4-Mor 5 9-107 Me -CH = CH- -C (= 0)-1,4-Piz -CH2CHr -e 9-108 Me -CH = CH- -C (= 0 )-l, 4 ~ Piz -CH2CHr -NMe2 9-109 Me -CH = CH- (= 0)-1,4-Piz ~ CH2CHr -SaeCH2CH20H 9-110 Me ~ CH = CH- -C (= 0) -• 1,4-Piz ~ CH2CHr -N (CH2CH2OH) 2 9-111 Me -CH2- ~ NHC (= 0)---CHr 4-Me-l-Piz 10 · 9-112 Me -CHr -NHC ( = 0)---ch2- 4-(CH2CH2OH) -Bu Piz 9-113 Me -CH2- ~ NHC (= 0)-*--ch2--Circle e2 9-114 Me -CHr -Circle eCOO)-- -ch2- 4-Me-1-Piz 9-115 Me -CHr -Li eCOO)-_-CH2- 4- (CH2CH20H) -l-Piz 9-116 Me ~ CHr -Li eC (= 0)---- CH2- _ -NMe2 15 9-117 Me -CH2CH2- -C (= 0) ^ e---CH2CHr-C00H 9-118 Me -CH2CH2_ -C (= 0) NMe----CH2CHr -so3h 9-119. Me -CH2CH2- -C (= 0) Li e---CH2CH2--Bandit2 9-120 H -CHr-1 — 1-Pyrd 9-121 H -CHr--...-1-Pip 20 9- 122 H -CHr-— — 1-Me-4 -Pip 9-123 H -CHr-One- l- (CH2CH2OH) -4-Pip 9-124 H -CHr--4-Me-1-Piz 9-125 H -CHr---4 ~ (CH2CH20H)- l ~ Piz 9-126 H -CHr---4_Mor 25 9-127 H -CHr----nh2 9-128 H -CHr-— —-NHMe 9-129 H -CHr 1 — ~, e2 9-130 H -CH2CHr---C00H 9-131 H -CH2CHr---0P03H2 30 9-132 H -CHoCHo---1-Pyrd

198- 200410948 9-133 H -CH2CHr-one-1-Pip 9-134 Η -CH2CHr-one-l-Me-4-Pip 9-135. H -CH2CHr-one *-1- (CH2CH20H) -4- Pip 9-136 H -CH2CHr-Mon-4-Me-l-Piz 5 9-137 H -CH2CHr-Mon-4- (CH2CH20H) -l-Piz 9-138 Η -CH2CH2----4-Mor 9 -139 Η -CH2CH2- '---nh2 9-140 H -CH2CHr-one--NHMe 9-141 H -CH2CH2-----N &quot; Me2 10 9-142 Η-(CH2) 3—--- C00H 9-143 H _ (CH2) 3-- I.--〇〇〇-9-144 H -CH2CHr ~ C (= 0)---l-Piz 9-145 H -CH2CHr -C (: 0) ---4- (C (= NH) NH2) -l-Piz 9-146 H -CH2CH2- -C (= 0)-one- 4- (C (= NH) CH3) -1-Piz 15 9- 147. H -CH2CH2- -C (= 0)-1-4-Me-l-Piz 9-148 H -CH2CH2——C (= 0)-—-4- (CH2CH20H) -l-Piz 9-149 H -CH2CH2- -C (= 0)-— -4 ~ (CH2CH2NHAc) -l-Piz 9-150 H -CH2CHr -C (= 0)-one-4- (CH2Car) -l ~ Piz 9-151 H -CH2CHr --C (= 0)---4- (CH2CH20Car) -l-Piz 20 9-152 H -CH2CH2- -C (= 0)-a-4- (CH2CH2F) -l-Piz 9-153 H -CH2CHr -C (= 0)-1,3 ~ Az t--C00H 9-154 H -CH2CH2- -C (= 0)-1,3-Azt--0S03H 9-155 H ~ CH2CHr -C ( = 0)-1,3-Az t--〇p〇3h2 9-156 H -CH2CH2_ -C (= 0)-.1,4-Pip--C00H 25 9-157 H -CH2CH2—C (= 0)-1,4-Pip-- so3h 9-158 H -CH2CHr -C (= 0)-1,4-Pip--OSO3H 9-159 H -CH2CHr -C (= 0)-1,4-Pip a -〇p〇3h2 9-160 H ~ CH2CHr -C (= 0)-1,4-Pip-l-Pyrd 9-161 H -CH2CHr -C (= 0)-1,4-Pip-1-Pip 30 9-162 H -CH2CH2- -CH )-1,4-Pip-4-Me-HP iz

-199- 200410948

9-163 Η -ch2ch2- -CH))-1,4-Pip-4- (CH2CH20H) -l-Piz 9-164 Η -CH2CHr-C (= 0)-1,4-Pip-4-Mor 9 -165 Η -CH2CHr -C (= 0)-1, .4-Pip-~ NHMc 9-166 Η -CH2CH2- -c (= 0)-1,4-Pip — -NMe〗 5 9-167 Η- CH2CHr -c (= 0)-1,4-Pip a-NMeCH2CH20H 9-168 Η -ch2ch2- -C (= 〇)-1,4-Pip a-N (CH2CH20H) 2 9-169 Η -CH2CHr-c (= 〇)-1,4-Pip -CH2- -C00H 9-170 Η -CH2CHr -C (= 0)-1,4-Pip -CHr-S03H 9: 171 Η -CH2CH 「-C (= 0) -1,4-Pip -ch2--oso3h 10 9-172 Η -ch2ch2- '-c (= 〇)-1,4-Pip-ch2- -〇p〇3h2 9-173 Η -ch2ch2- -c ( = 〇)-1,4-Pip-ch2-4-Mor 9-174 Η -ch2ch2- -C (= 0)-1,4-Pip -CH2- -nh2 9-175 Η -ch2ch2- -C (= 0)-1,4-Pip -CHr -NHMe 9-176 Η ~ ch2ch2--c (= o)-1,4-Pip -ch2- -Li e2 15 9-177 Η -CH2CHr -C (= 〇) -1,4-Pip-ch2- -Li eCH2CH2OH 9-178 Η -ch2ch2- -c (= 0)-1,4-Pip -ch2- -N (CH2CH2OH) 2 9-179 Η -CH2CHr -c (= 0)-1,4-Piz a-so2nh2 9-180 Η-CH2CHr-c (= 〇)-1,4-Piz-ch2ch2- 1-Azt 9-181 Η-CH2CHr -C (= 0) ~ 1, 4-Piz -ch2ch2- 1-Pyrd 20 9-182 Η -CH2CH2- -c (= 0)-1,4-Piz-ch2ch 「1-Pip 9-183 Η-CH2CHr -c (= 〇)-1,4-Piz -ch2ch2- 4-Me- l-Piz 9-184 Η -CH2CH2--c (= 0)-1,4-Piz-ch2ch2- 4- (CH2CH20H) -l-Piz 9-185 Η -CH2CHr-c (= 〇)-1,4 -Piz -ch2ch2- 4-Mor 9-186 Η -ch2ch2- -c (= 0)-1,4-Piz -ch2ch2- -Book Me 25 9-187 Η -CH2CHr -C (= 0)-1,4 -Piz -ch2ch2- -Li e2 9-188 Η -CH2CHr -C (= 〇)-1,4-Piz -ch2ch2- -Li eCH2CH2OH 9-189 Η-CH2CHr -c (= 0)-1,4-Piz -ch2ch2--N (CH2CH2OH) 2 9-190 Η -CH = CH--C (= 0)-one-1-Piz 9-191 Η -CH = CH- -C (= 0)-— — 4- (C (= fiH) Wi2) -PPiz 30 9-192 Η -CH = CH- -c (: 0)-—-4-(C (DiNH) CH3) + Piz -200-200410948

9-193 H -CH = CH- -C (= 0)-1 — 4-Me-l-Piz 9-194 H -CH = CH——C (= 0)-1-4-(CH2CH2OH) -1 -Piz 9-195 H -CH = CH- -C (= 0)---4- (CH2CH2NHAc) -l-Piz 9-196 H -CH = CH- -C (= 0)---4-( CH2Car) + Piz 5 9-197 H -CH = CH- ~ C (= 0)-one- 4- (CH2CH20Car) -l-Piz 9-198 H -CH = CH- -C (= 0)-1, 3-Az t -C00H 9-199 H -CH = CH- -C (= 0)-1,3-Azt--0S03H 9-200 H -CH = CH- -C (-0)-1,3 ~ Az t--o.po3h2 9-201 H-CH: CH——C (= 0)-1,4-Pip--COOH 10 9-202 H-CH = CH——C (= 0) -1, 4-Pip one -SO3H 9-203 H -CH = CH- -C (= 0)-. 1., 4-Pip--OSO3H 9-204 H -CH = CH- -C (= 0)-1, 4-Pip a-〇P〇3H2 9-205 H -CH = CH- -C (= 0)-1,4-Pip a 1-Pyrd 9-206 H-CH = CH——C (= 0)- 1,4-Pip one.1-Pip 15 9-207 H-CH = CH——C (= 0)-1,4-Pip one 4-Me-l-Piz 9-208 H ~ CH = CH-- C (= 0)-1,4 ~ Pip a 4- (CH2CH20H) -l-Piz 9-209 H-CH = CH——C (= 0)-1,4-Pip a 4-(CH2CH2NHAc) -bu Piz 9-210 H -CH = CH- -C (= 0)-l, 4-Pip a 4-Mor 9-211 H -CH = CH- -C (= 0)-1,4-Pip a-NHMe 20 9-212 H -CH = CH- _C (= 0)-.1,4-Pip I.-Li e2 9-213 H -CH = CH- -C (two 0)-1,4-Pip one-NMeCH2CH2OH 9-214 H -CH = CH- -C (= 0)-1,4-Pip-.-N (CH2CH2OH) 2 9-215 H -CH = CH- -C (= 0)-1,4 ~ Pip -ch2_ -COOH 9-216 H-CH = CH——C (= 0)-1,4-Pip -ch2- -OSO3H 25 9-217 H -CH = CH- -C (= 0)-1,4-Pip -ch2- -〇p〇3h2 9-218 H -CH = CH- -C (= 0) -1,4-Pip -ch2- 4-Mor 9-219 H -CH = CH- -C (= 0)-1,4-Pip -ch2 · Yilili 2. 9-220 H -CH = CH- -C (= 0)-1,4-Pip-ch2 · '-NHMe 9-221 H -CH = CH- -C (: 0)-1,4-Pip -ch2.' •-丽 e2 30 9- 222 H -CH = CH- -C (: 0)-1,4-Pip -ch2 · -NMeCH2CH2OH 200410948 9-223 H -CH = CH- -C (-0)-l, 4_Pip -CH2_ -N (CH2CH2OH ) 2 9-224 H -CH2CH2- -C (= 0)-1,4-Piz--so2nh2 9-225 H -CH = CH- -C (= 0)-1,4-Piz -CH2CHr • 4- Mor 9-226 H -CH = CH- -C (= 0)-1,4-Piz -CH2CH2- -NHMe 5 9-227 H -CH = CH- -C (= 0)-1,4-Piz- CH2CH2- -NMe2 9-228 H -CH = CH- -C (= 0)-1,4 ~ Piz -CH2CH2- ~ NMeCH2CH2OH 9-229 H -CH = CH- -C (= 0)-1,4- Piz -CH2CHr -N (CH2CH2OH) 2 9-230 H -CHr -NHC (= 0)---〇Hr 4-Me-l-Piz 9-231 H -CHr -NHC (two 0)---CHr 4 -(CH2CH 2OH) -lP.iz 10 9-232 H -CHr -NHC (= 0)---CH2-, e2 9-233 H -CH2--Li eC (= 0) _-_ch2-4-Me-l- Piz 9-234 H -CHr -Li eC (= 0)-—-ch2- 4- (CH2CH20H) -l-Piz 9-235 H -CHr -Li eC (= 0)---CH2_ -Li e2 9- 236 H -CH2CHr -C〇0) NMe---ch2ch2--C00H 15 9-237 H -CH2CH2- -C (= 0) plane θ---CH2CHr .-S03H 9-238 η -CH2CHr -C (= 0) NMe---CH2CH2 ~, e2 9-239 Me 1,4-cHx-----C00H 9-240 Me 1,4-cHx one---〇〇〇-〇Me 9-241 Me 1,4-cHx -One — l-Pyrd 20 9-242 Me 1,4-cHx-. One-1-Pip 9-243 Me 1,4-cHx-— — l-Me-4-Pip 9-244 Me 1,4- cHx--Bu (CH2CH2OH)-4-Pip 9-245 Me 1,4-cHx-one-four-Me-l-Piz 9-246 Me 1,4-cHx-one-four- (CH2CH20H) -l- Piz 25 9-247 Me 1,4-cHx-1-4-Mor 9-248 Me 1,4-cHx-1--nh2 9-249 Me 1,4-cHx-~ _ -NHMe 9-250 Me 1 , 4-cHx-_--NMe2 9-251 H 1,4-cHx-one--C00H 30 9-252 H 1,4-cHx-one--opo3h2 -202 ^ 200410948 9-253 Η 1,4- cHx — — 1 1-Pyrd 9-254 Η 1,4-cHx 1 — — 1-Pip 9-255 Η 1,4-cHx 1 —-Bu Me- 4-Pip 9-256 Η 1,4-cHx one-by-one (CH2CH20H) -4-Pip 5 9-257 Η 1,4-cHx — —-4-Me-1-Piz 9-258 Η 1,4 -cHx — —-4- (CH2CH20H) -l-Piz 9-259 Η 1,4-cHx---4-Mor 9-260 Η 1,4-cHx ~ —. -nh2 9-261 Η 1, 4-cHx — one-to-Me 10 9-262 Η 1,4-cHx one-to- -NMe2 9-263 Me-(CH2) 4- one-to-one-C00H 9-264 Me-(ch2) 4-- --so3h 9-265 Me-(ch2) 4--\---0S03H. 9-266 Me-(CH2) 4- one one one -〇p〇3h2 15 9-267 Me-(CH2) 5- ~ —--C00H 9-268 Me-(CH2) 「One---SO3H 9-269 Me-(CH2) 5- One-One-OSO3H 9-270 Me-(CH2) 5- One--〇p〇3h2 9-271 Me-(CH2) 3- -C (= 0) Lie----ch2ch2- -SO3H 20 9-272 Me-(CH2) 4- DiCCMe---CH2CHr-so3h 9-273 Me- (ch2) 5- -C (= 0) Li e---CH2CH2 ''-so3h 9-274 Me-(CH2) r-C (= 0) Li e—— -ch2ch2--so3h 9-275 H-( CH2) 4---C00H 9-276 H-(CH2) 4-----S03H 25 9-277 H-(ch2) 4-----OS03H 9-278 H-(ch2) 4-- One One-0P03H2 9-279 H-(CH2) 5--One--C00H 9-280 H-(ch2) 「One one --SO3H 9-281 H-(ch2) 5----OSO3H 30 9-282 H-(CH2) 5----opo3h2 -203-200410948 9-283 H-(CH2) 3--C (= 0) NMe- a-ch2ch2- -so3h 9-284 Η-(CH2) r -C (= 0) _e---ch2ch2--S03H-9-285 Η-(CH2) 5--C (= 0) Ree-a-ch2ch2- -S03H 9-286 H-(CH2) 6--C (= 0_e- one-ch2ch2- -S03 [5 9-287 Me -CH2CH2- -0C (= 0)-one-. l-Me-4-Pip 9-288 Με ~ CH2CH2 ~ ~ 0C (= 0) ~ --CHr -C00H 9-289 Me -CH2CHr -0C (= 0)---CHr -SO3H 9-290 Me -CH2CHr -0C (= 0)-One-CHr -opo3h2 9-291 Me -CH2CHr -0C (= 0)-One- CH2- 1-Azt 10 9-292 Me -CH2CH2- -0CH)-One-ch2- 1- Pyrd 9-293-Me -CH2CH2--oc (= 〇)---ch2- 1-Pip 9-294 Me -CH2CH2- -oc (= 〇)-a-ch2-l-Me-4-Pip 9- 295 Me -CH2CH2- -oc (two)-Imai 4-Me-l-Piz 9-296 Me -CH2CHr -ocH)---CHr 4- (CH2CH20H) -l-Piz 15 9-297 Me -CH2CHr -oc (two)---ch2- 4-Mor 9-298 Me -CH2CHr -oc (two 0)---CHr -NMe2 9-299 Me -CH2CHr -oc (= o)-• one-ch2- -NMeCH2CH20H 9-300 Me -CH2CHr -oc (= o)---ch2- -N (CH2CH2OH) 2 9-301 Me -CH2CHr- oc (= o)---ch2ch2--COOH 20 9-302 Me -CH2CHr-oc (= 〇)---CH2CHr -SO3H 9-303 Me -CH2CHr-oc (= o)---CH2CHr-opo3h2 9 -304 Me -CH2CHr -0C (= 0)----CH2CHr 1-Azt 9-305 Me -CH2CH2- -0C (= 0)---CH2CH2- 1-Pyrd 9-306 Me -CH2CHr-oc (= 〇 )-A-ch2ch2- 1-Pip 25 9-307 Me -CH2CH2- -〇C (= 0)-a-ch2ch2- 1-Me-4-Pip 9-308 Me -CH2CHr -0C (= 0)-- -CH2CH2- 4-Me-l-Piz 9-309 Me -CH2CHr -〇C (= 0) ~ 1-ch2ch2- 4-(CH2CH2OH) -HPiz 9-310 Me -CH2CHr -0C (= 0)---- ch2ch2- 4-Mor 9-311 Me -CH2CHr-oc (= 〇)-a-ch2ch2- -NMe2 30 9-312 Me -CH2CHr -oc (= 0)--~ CH2CH2 ~ -NMeCH2CH2OH -20 buckle 200410948

9-313 Me -CH2CHr -0CH)--One CH2CHr -N (CH2CH2OH) 2 9-314 Me-(CH2) 3--0C (two 0)----l-Me-4-Pip 9-315 Me- (CH2) 3- -oc (= 〇)----CHr -C00H 9-316 Me-(CH2) r -0C (two 0)---CHr-so3h 5 9-317 Me- (CH2) r -0CH )-A-ch2- · -〇p〇3h2 .9-318 Me-(CH2) 3- -0C (= 0) ~ a-CHr 1-Azt 9-319 Me-(CH2) 3 ~ -oc (= 〇)---CH ". 1-Pyrd 9-320 Me- (CH2) 3- -oc (: 〇)-— -CHr 1-Pip 9-321 Me-(CH2) r -0C (= 0)- 1-ch2- 1-Me-4-P ip 10 9-322 Me-(CH2) 3- -oc (= o)---ch2-4-Me-l-Piz. 9-323 Me-(CH2) 3- -oc (= 〇)-.- -CHr 4-(CH2CH2OH) + Piz 9-324 Me-(CH2) 3- -oc (= o)---CHr 4-Mor 9-325 Me-(CH2 ) 3- -0C (Earth 0)---ch2--l ^ e2 9-326 Me-(CH2) 3- -oc (= o)---ch2 '-Band CH2CH2OH 15 9-327 Me-(CH2 ) 3- -oc (= 〇)-mono-CHr-N (CH2CH20H) 2 9-328 Me-(CH2) 3- -oc (= 〇)-mono-ch2ch2_ -C00H 9-329 Me _ (CH2) r -oc (= o)-one.-ch2ch2--so3h 9-330 Me-(CH2) 3- -oc (= o)----CH2CHr 9-331 Me-(CH2) 3--oc (= 〇) ---CH2CHr 1-Azt 20 9-332 Me-(CH2) 3--oc (= o)--~ CH2CHr HPyrd 9-333 Me-(CH2) 3--oc (= o)---CH2CHr 1-Pip 9-334 Me-(CH2) 3- —OC (= 0)---CH2CHr l-Me-4- Pip 9-335 Me-(CH2) 3--oc (= 〇)-mono-ch2ch2- 4-Me-1-Piz 9-336 Me-(CH2) r -〇C (= 〇)---CH2CHr 4 -(CH2CH20H) -HPiz 25 9-337 Me-(CH2) 3- -oc (= o)---ch2ch2- 4-Mor 9-338 Me-(CH2) 3- -0C (= 0)---- ch2ch2-, e2 9-339 Me-(CH2) 3- -oc (= 0)---ch2ch2- -NMeCH2CH20H 9-340 Me-(CH2) 3--oc (= 〇)---CH2CHr -N ( CH2CH2OH) 2 9-341 Me ~ CH2CHr .-C (two 0) 0---l-Me-4-Pip 30 9-342 Me -CHoCHo- -C (two 0) 0---ch2_ -C00H 205- 200410948 9 ~ 343 Me -CH2CHr -C (= 0) 0---CHr 1-Me-4-Pip 9-344 Me (-CH2CHr -C (= 0) 0---ch2ch2- -C00H 9-345. Me -CH2CHr -C (; 〇) 〇-- -ch2ch2- -so3h 9-346 Me -CH2CH2- -C (= 0) 0-- -ch2ch2--opo3h2 5 9-347 Me -CH2CHr-C (= 0 ) 0---ch2ch2- 1-Azt 9-348 Me -CH2CHr -C (-0) 〇- -ch2ch2- l ~ Pyrd 9-349 Me -CH2CH 「-c (= o) o---ch2ch2- 1 -Pip 9-350 Me -CH2CHr-c (= o) o-- -CH2CHr Me-4-Pip 9-351 Me ~ CH2CHr-C (= 0) 0-a-ch2ch2- 4-Me-l-Piz 10 9-352 Me -C H2CHr-C (= 0) 0---ch2ch2- 4- (CH2CH2OH) -i-Piz 9-353 Me -CH2CHr-C (= 0) 0---ch2ch2- 4 "Mor 9-354 Me -CH2CH2_- C (= 0) 0---ch2ch2--wake up e2. 9-355 Me -CH2CHr-C (= 0) 0---ch2ch2- -NMeCH2CH2OH 9-356 Me -CH2CHr -C (= 0) 0-- -ch2ch2- -N (CH2CH2OH) 2 15 9-357 Me -CH = CH- -c (= o) o---l-Me-4-Pip 9-358 Me -CH = CH--C (= 0 ) 0---CH2-,-COOH 9-35.8. Me -CH = CH--c (= o) o----CHr l-Me-4-Pip 9-359 Me -CH = CH--C ( = 0) 0---ch2ch2--COOH 9-360 Me -CH = CH- -c (= o) o---ch2ch2- -so3h 20 9-361 Me -CH = CH--C (= 0) 0---CH2CHr -〇p〇3h2 9-362 Me -CH = CH--c (= o) o-- -ch2ch2- 1-Azt 9-363 Me _CH = CH--C (= 0) 0- --CH2CHr 1-Pyrd 9-364 Me -CH = CH- -c (= o) o---CH2CHr 1-Pip 9-365 Me -CH = CH- -C (= 0) 0---CH2CHr l -Me-4-Pip 25 9-366 Me -CH = CH--c (= 〇) 〇---CH2CHr 4-Me-l-Piz 9-367 Me -CH = CH--C (= 0) 0 --ch2ch2- 4- (CH2CH20H) -l-Piz 9-368 Me -CH = CH--c (= o) o--• -CH2CHr 4-Mor 9-369 Me -CH = CH--C ( 0) 0 ----- -ch2ch2- -NMe2 9-370 Me -CH = CH- -c (= o) o-- -ch2ch2 --NMeCH2CH2OH 30 '9-371 Me -CH = CH- -CH) 0-- -CH2CHr -N (CH2CH2GH) 2 m

206-200410948 9-372 H _CH2CHr -0C (= 0)-— one l-Me-4-Pip 9-373 Η _CH2CH2- -0C (-0)-one -ch2--COOH 9-374 Η -CH2CHr- OC (= 0)-mono-ch2--so3h 9-375 Η -CH2CH2- -oc (= o)-mono-CHr -〇p〇3h2 5 9-376 Η -CH2CHr-oc (two)--- ch2- 1-Azt 9-377 Η -CH2CHr -oc (= o)---ch2-1-Pyrd 9-378 Η -CH2CHr -OC (= 0)----CHr 1-Pip 9-379 Η -CH2CHr -oc (= 〇)-one-CH2- l-Me-4-Pip 9-380 h-ch2ch2--OC (= 0)---ch2- 4-Me-l-Piz 10 9-381 H -CH2CH2 --oc (= o)---CH2- 4- (CH2CH20H) -l-Piz 9-382 H -CH2CH 「. -OC (-O)-—-CH「 4-Mor 9-383 H -CH2CH2- -0C (= 0 &gt;-one-CH2--NMe2 9-384 H -CH2CH2- -oc (= 0)-one-ch2- -LiCH2CH2OH 9-385 H -CH2CHr -oc (= 〇)-one-CHr -N (CH2CH2OH) 2. 15 9-386 H -CH2CH2--OC (= 0)---CH2CHr -C00H 9-387 H -CH2CHr -OC (= 0)---ch2ch2--S03H 9-388 H -CH2CH2--OC (= 0)---ch2ch2- -〇p〇3h2 9-389 H -CH2CH2- ~ 0C (= 0)---ch2ch2- 1-Azt 9-390 H -CH2CH2- -0C ( = 0)-one-ch2ch2- 1-Pyrd 20 9-391 H -CH2CHr-oc (= 〇)---ch2ch2- • 1-Pip 9-392 H -CH2CHr-oc (= o)-One-ch2ch2- l-Me-4-Pip 9-393 H -CH2CHr -0C (= 0)-One-ch2ch2- 4-Me ~ l- Piz 9-394 H -CH2CHr -0C (= 0)---ch2ch2- 4- (CH2CH20H) + Piz 9-395 H -CH2CHr -oc (= o)---CH2CHr 4-Mor 25 9-306 H- CH2CHr -oc (= 〇)-one -ch2ch2- • -NMe2 9-397 H -CH2CH2- -OC (= 0)---ch2ch2- -NMeCH2CH20H 9-398 H -CH2CHr-oc (: 0)-one. -ch2ch2- -_2CH2OH) 2 9-399 Me-(CH2) 3--OC (two 0)-—-l-Me-4-Pip 9-400 Me-(CH2) 3--oc (: 0)- -. -CHr-C00H 30 9-401 Me-(CH2) 3- -oc (-〇)----CHr -so3h -207-200410948 9-402 Me-(CH2) 3--OCH)-~ ch2- -0P0A 9-403 Me-(CH2) 3- -OCH)--~ ch2 ~ 1-Azt 9-404 Me-(CH2) 3- -OCH)---CHr 1-Pyrd 9-405 Me-(CH2 ) 3- -0C (= 0)-one-ch2- HPip 5 9-406 Me-(CH2) 3- -0C (= 0)---ch2-1-Me-4-P ip 9-407 Me- (CH2) 3--oc (= o)-mono-ch2- 4-Me-1-Piz 9-408 Me _ (CH2) 3--OCH)---ch2- 4- (CH2CH20H) -l-Piz 9-409 Me _ (CH2) 3--oc (= 〇)---CHr 4-Mor 9-410 Me ~ (CH2) 3 ~ -OC (= 0)---CHr-NMe2 10 9-411 Me ~ (CH2) 3_- oc (= 0)-mono-CH2- -Li eCH2CH2OH 9-412 Me-(CH2) 3--oc (= 〇)---ch2--n (ch2ch2oh) 2 | 9-413 Me-(CH2) 「 -oc (= o)---ch2ch2- ——COOH 9-414 Me-(CH2) 3- -oc (= o) _--ch2ch2- ——so3h 9-415 Me _ (CH2) 3--oc (= 〇)---ch2ch2- --opo3h2 15 .9-416 Me _ (CH2) 3- -oc (= o)---ch2ch2- -1-Azt 9-417 Me-(CH2) 「-oc (= 0)-one- ch2ch2- -1-Pyrd 9-418 Me-(CH2) 3- &lt; -0C (= 0)----c_2 · -1-Pip 9-419 Me-(CH2) 3 ' -0C (= 0)-•--ch2ch2- -l-Me-4-Pip 9-420 Me-(CH2) 「-oc (: o)---ch2ch2 ·-4-Me-1-Piz 20 9 -421 Me-(CH2) 3- -OCH)---ch2ch2--4- (CH2CH20H) -Bu Piz 9-422 Μθ-(CH2) 3 ~ -oc (= 〇)-one-ch2ch2 · -4- Mor 9-423 Me-(CH2) 「-oc (= 〇)--ch2ch2. --Li e2 9-424 Me-(CH2) 3- -oc (= 〇)---ch2ch2. --Li eCH2CH20H 9 -425 Me-(Cri2) r-oc (= 〇)---ch2ch2 --N (CH2CH2OH) 2 25 9-426 H -CH2CHr -C (= 0) 0-one-l-Me-4-Pip 9 -427 H-CH2CH2- -CH) 0---CHr-C00H 9-428 Ή -CH2CHr -C (= 0) 0- — -CHr 1-Me-4-Pip 9-429 H -CH2CH2- -C ( = 0) 0---ch2c h2- -C00H 9-430 H -CH2CHr -c (= o) o- 1 ~ CH2CHr -so3h 30 9-431 H -CH2CHr -c (= o) o----CH2CHr -opo3h2 200410948 9-432 H -CH2CHr -C (= 0) 0---CH2CHr • 1-Azt 9-433 H -CH2CHr-CH) 0---CH2CHr 1-Pyrd 9-434 H -CH2CHr-C (= 0) 0---CH2CHr 1 -Pip 9-435 H -CH2CH2--C (= 0) 0-- -CH2CHr 1-Me-4-Pip 5 9-436 H -CH2CHr -C (= 0) 0_--CH2CHr 4-Me-l- Piz 9-437 H -CH2CH2--C (= 〇) 〇-- -CH2CHr 4- (CH2CH2OHM -Piz 9-438 H -CH2CHr -C (= 0) 0---ch2ch2- 4-Mor 9-439 H -CH2CH2--C (= 0) 0---ch2ch2-, e2 9-440 H -CH2CH2--C (= 0) 0---ch2ch2--YeCH2CH2OH 10 9-441 H -CH2CHr -c (= 〇) o---ch2ch2- • -N (CH2CH2OH) 2 9-442 H -CH = CH- -c (= o) o--. -1-Me-4-Pip * 9-443 H -CH = CH- -c (= o) o---ch2- -C00H 9-444 H -CH = CH--C, (= 0) 0---ch2- 1-Me-4-Pip 9-445 H- CH = CH- -c (= o) o---CH2CHr-C00H 15 9-446 H -CH: CH- -C (= 0) 0---CH2CHr-S03H * 9-447 H -CH = CH- -c (= o) o---CH2CHr 〇3h2 9-448 H -CH = CH- -C (= 0) 0-- -ch2ch2- 1-Azt 9-449 H -CH = CH--c ( : o) o--'-ch2ch2- 1 -Pyrd 9-450 H -CH = CH--C (= 0) 0-- -CH2CHr 1-Pip 20 9-451 H -CH = CH- -c (= o) o---CH2CH2- 1-Me -4-Pip 9-452 H -CH = CH--C (= 〇) 〇---CH2CHr 4-Me-1-Piz 9-453 H -CH = CH- -C (= 0) 0--- CH2CH2- 4-(CH2CH2OH) -1 -Piz 9-454 H -CH = CH- -c (= o) o--~ CH2CHr 4-Mor 9-455 H -CH = CH- -C (= 0) 0 ---ch2ch2_ -Li e2. 25 9-456 H -CH = CH- -C (= 0) 0---ch2ch2- -NMeCH2CH2OH 9-457 H _CH = CH- -c (= o) o---- ch2ch2--N (CH2CH2OH) 2 Among the above exemplified compounds, suitable compounds are compound numbers 1-9, 1-20, 1-21, 1-24, 132, 1-33, 1-39, 1-47, 1-59, 1-62, 1-63, Bu 64, 1-67, Bu 65, 1-70, 1-71, 1-72, 1-73, 30 1-74, 1-80, 1-82 , 1-83, 1-86, 1-88, 1-89, 1-90, 1-91, 1-92, 1-94, 1-95, 1-96, -209-200410948 BU 97, BU 99 , 1-106, 1-107, 1-108, Bu 109, Bu 11◦, Bu 111, 1-112, Bu 114, Bu 115, Bu 116, H17, Bu 118, 1-125, Bu 126, 1- 127, 1-128, H29, H30, H31, 1-132, 1 -133, 1-134, Bu 135, 1 -136, 1-137, 1 -138, H39, Bu 140 , Bu 142, H43, 1-144, 1-145, Bu 146, 1-147, 1 -150, 1 -156, 1-159, 1 -164, 1_165, Bu 166, 1-168, 1 -169, 5 1-170, Bu 171, 1-173, 1-174, 1 -175, 1 -177, H84, Bu 185, Bu 187, H88, 1-189, 1-190, 1-192, 1-193, 1-194, 1-196, 1-203, 1-204, 1-205, 1-206, 1-207, 1-208, .1-209, 1-210, 1-211, 1-214, 1-218, 1-219, Bu 220, 1-222, 1-223, 1-224, 1-227, 1-237, 1-238, 1-292, Bu 293, 1-295, Bu 302, 1 -305, 1-321, 1-328, 1-334, 1-348, 1-349, 1-350, 1-351, 1-352, 1-353, Bu 354, 1-355, 1-356, 1-357, 1-358, 1-359, 10 1-360, 1-361, 1-362, Bu 363, .1-364, 1-365, 1-366, Bu 367, 1-368, 1- 369, 1-370, 1-371 '1-372, 1-373, 1-375, 1-378, 1-388, 1-399, 1-400, 1-403, 1-411, 1-412, 1-418, Bu 426,1-438, Bu 441,1-442, Bu 443,1-444, 1-446 ,:! -449,1-450,1-451, 1-452, 1-453, BU 459, 1-461, 1-462, 1-465, BU 467 1-468, Bu 469, 1-470, 1-471, 1-473, 1-474, Bu 475, 1-476, 1-478, Bu 485, 1-486, Bu 487, 1-488, 1- 489, 1-490, 15 BU 491, 1-493, 1-494, 1-495, 1-496, 1-497, 1-504, BU 505, 1-506, 1-507, 1-508, BU 509, 1 -510, 1-511, 1 -512, 1 -51.3, 1 -514, 1 -515, 1 -516, 1_517, 1-518, 1 -519, 1-521, 1 -522, 1- 523, 1-524, 1-525, 1-526, 1-529, Bu 535, 1-538, 1-543, 1-544, 1-545, 1-547, 1-548, 1-549, 1 550, 1 552, 1 553, 1 554, 1 556, 1-563, 1-564, 1-566, Bu 571, 1-572, Bu 573, 1-575, 1-582, 1 1 583, .1 -584, 1-585,; 1-586, 1-587, 20 1-588, 1-589, 1-590, 1-593, 1-597, 1-598, 1-599, 1-601, 1-602, 1-603, Bu 606, 1-616, 1-617, 1-671, Bu 672, 1-674, Bu 681, 1-684, Bu 700, 1-707, 1- 713, 1-727, 1-728, 1-729, 1-730, 1-731, 1-732, 1-733, 1-734, 1-735, Bu 736, 1-737, Bu 738, Bu 739 , 1-74 0, 1-741, Bu 742, 1-743, 1-744, 1-745, Bu 746, 1-747, 1-748, 1-749, Bu 750, 1-751, 1-752, 1 -754 , 1-757, 1-759, 1-777, 1-795, 1-796, Bu 797, Bu 799, 25 1-800, 1-806, Bu 807, Bu 808, 1-811, 1-812 , 1-818, Bu 821, Bu 855, 1-856, 1-857, 1 -859, 1 860, 1-861, 1 -865, 1-866, Bu 867, 1 -868 ,; 1 -871 , 1-872, 1-881, 1-882, 1-889, 1-890, 1-892, 1-905, 1-923, 1-924, BU 926, 1-939, 1-957, 1- 990, 1-991, 1-992, 1-993, 1-994, 1-995, 1-996, 1-997, 1-998, Bu 999, Bu 1000, Bu 1001, Bu 1002, 1-1003, 1-1004, 1-1005, 1-1006, 1-1007, 1-1012, 1-1014, 1-1015, 1-1016, 1-1018, 30 1-1025, BU 1026, BU 1033, 1-1034 1-1035, 1036, 1-1037, 1038, 1038, 1039, 1040, 210-200410948, 1041, 1042, 1046, 1 1047, 1048, 1049, 1054, 1088, 1 -1089, Bu 1090, .H092, Bu 1093, Bu 1094, Bu 1098, Bu 1099, H100, H101, H104, Bu 1105, Bu 1114, Bu 1115, 1122, Bu 1123, 'Bu 1125, Bu 1138, Bu 1156, Bu 1157, H159, H172, Bu 1190, 1-1223, 1-1224, 1-1225, 1-1226, 1-1227, 1-1228, 1 -1229, 1-1230, 1-123K 1-1232, 5 BU 1 233, H234, BU 1235, BU 1 236, H237, BU 1238, BU 1 239, BU 1240, 1-1245, BU 1247, • 1 1 1248, Bu 49, 1-1251, 1-1258, Bu 1259, Bu 1 266, Bu 1267, M268, Bu 1269, Bu 1270, 1 1271, Bu 1 272, 1 1273, Bu 1274, 1-1 275 , Bu 1279, Bu 1280, Bu 1281, Bu 1 282, 1-1285 or 1-2 8 6 Compounds are particularly preferred Compound Nos. 1-9, 1-20,: 1 -21, Bu 24, Bu 39, 1-47 , Bu 59, 1-62, 1-63, 10 Bu 70, 1-73, Bu 74, 1-82, 1-83, 1-86, 1-88, 1-91, 1-92, Bu 94, 1-95, .1-96, 1-97, BU 99, BU 106, BU 107, 1-109, 1 -110, 1-111, BU 112, H14, BU 115, BU 116, 1 -118, BU 125, Bu126, Bu127, 1-128, 1-129, Bu130, 1-131, Bu132, H33, 1-134, H35, Bu138, Bu142, 1-143, 1-144, 1- 145, 1-146, 1-147, [[150, Bu 156, Bu 15 9, 1-165, Bu 166, 1-168, Bu 169, 1-170, 1-171, Bu 175, M77, 1-184, 1-185, 1-187, Bu 188, 15 20 25 1-189 , 1-210, 1-349, 1-360, BU 372, 1-441, 1-473, 1-493, 1-511, 1-529, BU 573, 1-593, 1-730, 1-741 , 1-754, 1-818, 1-196, 222, 1-352, 1-363, 1-378, 1-452, 1-476, 1-497, 1-514, 1-544, 1- 58.3, 1-616, 1-733, 1-744, 1-777, 1-858, 1-203, 223, 1-353, 1-364, 1-388, 1-453, 1-478, 1 -504, 1-517, 545, 1-584, 1-671, 1-734, 1-745, 1-795, 1-865, 1-190, 1-194, 1-211, 1-214, 1-350, 1-351, 1-361, 1-362, 1-373, 1-375, 1-442, 1-449, 1-474, 1-475, 1-494, 1-495, 1- 512, BU 513, BU 535, 1-538, BU 575, 1-582, BU 601, 1-602, 1-731, 1-732, 1-742, 1-743, BU 757, 1-759, 1 -855, 1-856, 1-204, 1-205, 1-237, 1-292, 1-354, 1-355, 1-365, 1-366, 1-399, 1-400, 1-461 , 1-462, 1-485, 1-486, 1-505, 1-506, 1-52 1, 1-522, BU 547, 1-554, BU 585, 1-586, 1-681, 1-707, 1-735, 1-736, 1-746, 1-747, 1-796, 1- 800, 1-866, 1-871, 1-206, 1-207, 1-302, 1-328, 1-356, 1-357, 1-367, 1-368, 1-403, .1-418 , 1-465, 1-467, 1-488, 1-489, 1-507, 1-508, 1-523, Bu 524, 1-556, 1-563, Bu 587, 1-588, 1-713 , 1-727, 1-737, 1-738, 1-748, 1-750, 1-806, 1_807, 1-872, 1-889, 1-208, 1-209, 1-334, 1-348 , 1-358, 1-359, 1-369, 1-371, 1-426, 1-438, 1-470, 1-471, 1-490, H91, 1-509, 1-510, Bu 525, 1-526, 1-564, 1-566, 1-589, Bu 590, 1-728, 1-729, 1-739, 1-740, 1-751, 1-752, 1-808, 1-812 , 1-923, 1-991, -2JJ-30 200410948 1-992, 1-993, 1-994, 1-995, 1-996, 1-997, 1-998, 1-999, 1-1000, 1-1004, 1-1005, M006, 1-1007, 1-1012, 1-1015, 1-1016, M018, 1- 1033, 1-1035, 1-1036, 1-1037, M039, M046, 1- 1047, 1-1088, 1-1089, M091, 1-1098, 1-1099, 1-1104, 1-1105, 1-1122, 1-1156, M224, 1-1225, 1-1226, 1- 1227, '1-1228, 1-1229, 1-1230, 1-1231, 1-1232, 1-1233, 1-1237, 1-1238 ., H239, 1-1240, 1-1245, 1-1248, M249, 1-125 and M266, H268, H269, M270, 1-1272, M279 or 1-1280 compounds,

Particularly preferably, (1-methyl4-piperidinyl) acetic acid 1-[[2-[[2-[4-(4 -amino-2-chlorophenyl) -1 '3-butanyl group ] -1, 3-Mono-Sullyin-5-yl] thio]] 1-(2,4-difluorophenyl) -1-[(1 Η-1,2,4 -triwa-bu (Methyl) propoxy] carbonyloxy] ethyl (exemplified compound numbers 1-9), hydrosuccinic acid 1-[[2-[[2- [4- (4-cyano-2-fluoro Phenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1 Η- 1,2,4-triazole-1 -yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound numbers 1-2 0),

Hydroglutaric acid 1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5- []] Thio]-[(2,4-difluorophenyl) -1-[(1,2-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl (Exemplified compound number 1-3 9), 4- (4-methyl-1 · piperidyl) -4-oxobutanoic acid [[2-[[2- [4- (4-cyano-2 -fluoro Phenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1 , 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound number 1-70), 4- [4- (2-hydroxyethyl) piperidyl ] -4-oxobutanoic acid [[2-[[2-[4- (4-cyano-2 -fluorophenyl) -1,3-butadienyl] -1,3-di-alkane- 5 -yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) -212- 200410948 methyl] propoxy ] Carbonyloxy] ethyl ester (exemplified compound number 1-7), 1-4- [1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1, 3-butanethiol] -1 '3-Yipinyuan-5-yl,] thio]- 1- (2 '4 -mono * 1 ^ phenyl) -1_ [(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4 -Oxetinoyl] -3-azetidinic acid (exemplified compound number 1-8 8), 4-[3 (buazetidinyl) 1-azetidinyl]-4-oxobutanoic acid 1-[[2-[[ 2-[4-(4 -cyano-2 -fluorophenyl)-1, 3 -butadienyl]-1, 3 -dioxane-5 -yl] thio]-1-(2,4 -Difluorophenyl) -1-[(1 Η -1,2,4-triazole-1 -yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound No. 91), 4- Oxy-4- [3- (1-pyrrolopyridyl) -1-pyrimidine, butyl fluorenyl] butanoic acid 1-[[2- [[2- [4- (4-amino-2-amino The main group) -1 '3-butanyl] -1' 3-one. Pinane-5 -yl] thio] 1-(2,4-difluorophenyl)-[(1 fluorene-1, 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound No. 9 2), 4-oxo-4- (3-piperidinyl-1-azetidinyl ) Butanoic acid 1-[[2-[[2- [4- (4-cyano-2 -fluorophenyl) -1,3-butadienyl] -1,3-di Alk-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1 Η -1,2,4 · triazole-1 -yl) methyl] propoxy] Carbonyloxy] ethyl ester (exemplified compound No. 9 4), 4-(3-morpholinyl-1 -azetidinyl) -4 -oxobutanoic acid 1-[[2-[[2-[4-(4 -Cyano-2 -fluorophenyl) -1,3 · butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl)- 1-[(1 Η -1,2,4-triazole-1 -yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound number 1-9 7), 4-[3-(di Methylamino) -1-azetidinyl] -4-oxobutanoic acid 1-[[2-[[2-ί 4-(4 -cyano-2 -fluorophenyl)-1, 3 -butadienyl ]-1, 3-difluorenfane-5 -yl] thio]-1-(2,4-difluorophenyl)-]-[(1 Η-1,2,4-triazole-213- 200410948

-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound number 1-99), 1- [4- [1-[[2-[[2- [4- (4- Phenyl-2-aminophenyl) -13-butane. Alkenyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1- [ (1H-1,2,4-tri-D-sit-1-yl) methyl] propoxy] ferrooxy] ethoxy] -4-oxobutanyl] -4-piperidinecarboxylic acid (Exemplified compound number 1 -106), 1- [4- [1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3- Dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy ] Carbonyloxy] ethoxy] -4-oxobutyryl] -4-piperidinesulfonic acid (exemplified compound number 1-107), dihydrogen phosphate [4- [1-[[2-[[2- [ 4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 -yl] thio] -b (2,4-difluorobenzene Yl) -1-C (1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutyryl] -4-piperidine ester ( Exemplified compound numbers 1-1 0 9),

4-[4-(1 -Acridinedinyl) piperidinyl]-4 -oxobutanoic acid 1-[[2-[[2-[4- (4-cyano-2-fluorophenyl) -1,3 -Butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole -1 -yl) methyl] propoxy] carbonyloxy] ethyl ester (Exemplified compound No. 1 1 0), 4-[4-(1 -pyrrolidinyl) piperidinyl] butanoic acid 1- [[2-[[2-[4- (4-Cyano-2-fluorophenyl) -1,3 · butadienyl] -1,3-dioxan-5-yl] thio]] 1- (2,4-difluorophenyl) -1-[(1H-1,2,4: triazole-butyl) methyl] propoxy] carbonyloxy] ethyl ester (Exemplified compound number 1- Π 1), 4-oxo-4-(4-piperidinopiperidinyl) butanoic acid 1-[[2-[[2-[4-(4-cyano-2 -fluorophenyl) -1, 3 -butadienyl] -1,3-dioxane-5 -yl] thio-214-200410948 group] -l- (2,4-difluorophenyl) -1-[(1H-1,2 , 4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound number 1-1 1 2), 4-(4-morpholinopiperidinyl)-4-oxo Butyric acid 1-[[ 2-[[2-[4-(4 -Amino-2-¾phenyl) -1 '3-butaneyl] -1' 3-Yiyuan-5-yl] thio] -1- ( 2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound number 1-1 1 6), 4-[4-( Dimethylamino) piperidinyl] -4 -oxobutanoic acid 1-[[2-[[2-[4 · (4-oxy-2-zophenyl) -1 '3-butaneyl] -1 '3-_ • Waiyuan-5 · yl] thio]]-1- (2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy Yl] ethyl ester (exemplified compound number 1-1 1 8), [1- [4- [1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1, 3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -l-[(1H-1,2,4-tri Azole-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4 -oxobutyryl] -4-piperidinyl] acetic acid (Exemplified compound number 1-125),

[1- [4- [1-[[2-[[2- [4- (4-Cyclo-2-phenylphenyl) -1'3-butadienyl] -1,3-dicyclone -5 -yl] thio] -1-(2,4-difluorophenyl) -bu [(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy ] Ethoxy] -4-oxobutanyl] -4-piperidinyl] methanesulfonic acid (exemplified compound; number 1-1 2 6), hydrosulfuric acid [1-[4-[Bu [[2-[[2 -[4-(4 -cyano-2 -fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 -yl] thio]-1-(2,4- Difluorophenyl) 2,4-triazole-butyl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutyryl] -4-piperidinyl] methyl ester (Exemplified compound number 1 -1 2 7), -215- 200410948 — ^ Pyroscale acid [l- [4- [l-[[2-[[2- [4- (4 -Amino-2 -aerophenyl) -1, 3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] Propoxy] carbonyloxy] ethoxy] -4-oxobutanyl] -4-piperidinyl] methyl ester (exemplified compound number 1-1 2 8), 1- [4- [1-[[2- 〔〔2 -[4- (4-cyano-2-fluorophenyl) _1,3-butane

Dienyl] -1,3-diDfalk-5-yl] thio] -1-(2,4-difluorophenyl) -l-[(1H-1,2,4-triazole-1 -Yl) methyl] propoxy] carbonyloxy] ethoxy] -4 -oxo-2 -butyridyl] -3 -azetidincarboxylic acid (exemplified compound number 1-165), 4- [3- ( 1-Hydroxybutyridyl) -1-Hydroxybutyryl] -4-oxo-2-butanoic acid 1-[[2-[[2- [4- (4-amino-2-truncated Phenyl) -1 '3-butanyl] -1' 3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1 1 -1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound 1-1 6 9), 4-oxo-4-[3-(1 -pyrrole Pyridinyl) -buazetidinyl] -2 -butenoic acid [[2-[[2- [4- [4- (4-cyano (yl-2-aminophenyl) -1'3-butane · alkynyl] -1 '3-_ ^ yinyuan -5 -yl] thio]-1-(2' 4-monobenzyl)-1-[(1H-1 '2,4-triazol-1-yl) a [Propyl]] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-1 7 0), 4-oxo-4-(3-piperidinyl-butazetidinyl) -2-butenoate [[2- 〔〔2-〔4- (4 -cyano-2- Phenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1 H- 1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-1 7 1), 4-(3 -morpholinyl-1 -azetidinyl) -4 -Oxygen-2 -butenoic acid 1-[[2-[[2--216- 200410948 [4- (4-cyano-2 -fluorophenyl) -1,3-butadienyl]- 1,3-dioxan-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazole-1 -yl) methyl [Propyl]] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-1 7 5), 4- [3 (dimethylamino) 1-azetidinyl] -4-oxo-2-butenoic acid 1- [ [2-[[2- [4- (4-Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 -yl] thio] -1 -(2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (Exemplified compound 177) , 1- [4- [1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane -5 -yl] thio] -1-(2,4-difluorobenzene ) -1-[(1,2-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxo-2-butanyl] -4-piperidine Carboxylic acid (Exemplified compound number 1-184), 4- [4- (1-Acridinedinyl) piperidinyl] -4-oxo-2-butenoic acid 1-[[2-[[2- [4- ( 4 -truncated group-2-per base) -1 '3 -butanyl group] -1' 3 -—.  Oxane-5 -yl] thio] -b (2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazole-1 -yl) methyl] propoxy] Carbonyloxy] ethyl ester (exemplified compound 1-188), 4-oxo-4-[4-(1 -pyrrolidinyl) piperidinyl] -2 -butenoic acid 1-[[2-[[2- [4- (4-Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-di Fluorophenyl) -1-[(1H-1,2,4-triazole-1 "yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound 1-189), 4-oxo-4 -(4 · D D and D D) -2-butyric acid 1-[[2-[[2- [4- (4-cyano-2 -fluorophenyl) -1,3-butane Alkenyl] -1,3-dioxane-5 -yl] -217-200410948 Thiyl] -1-(2,4-difluorophenyl) -1-[(1 Η -1,2,4- Triazole-1 -yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-1 9 0), 4-(4-morpholinopiperidinyl)-4-oxo-2 -butane Enoic acid 1-[[2-[[2-[4-(4-cyano-2 -fluorophenyl) -1,3-butadienyl] -1,3-diDfalk-5-yl] Thio] -1- (2 '4-1 iil Group) -l-[(1H-1'2'4-diiso-1--1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1 -1 9 4), 4-[4 -(Dimethylamino) piperidinyl] -4-oxo-2-butenoic acid 1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3 -Butadienyl] -1,3-dioxane-5-yl] thio]] [(2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound 1-196), [1- [4-'[1-[[2-[[2- [4- (4-cyan Phenyl-2-fluorophenyl) -1,3-butadienyl] -1,3-diDfalk-5-yl] thio] -b (2,4-difluorophenyl) -b [( 1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy: 1 ethoxy] -4 -oxo-2 -butanyl] -4-piperidinyl] acetic acid (exemplified Compound 1-2 0 3), Hydrogen Sulfate [4-[1-[[2-[[2-[4-(4 -cyano-2 -fluorophenyl) -1, 3 -butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl Yl] propoxy] carbonyloxy 丨 ethoxy] -4- -2-Butanyl] -4-piperidinyl ester (exemplified compounds 1-2 0 4), dihydrogen phosphate 1-[4-[1-[[2-[[2-[4-(4 -cyano-2 -Fluorophenyl | -1,3-butadienyl] -1,3-dioxane-5 -yl] thio] -1-(2,4 difluorophenyl) -1-[(1H- 1,2,4-triazol-1-yl) methyl] propoxycarbonyloxy] ethoxy] -4-oxo-2-butylfluorenyl] -4-piperidine ester (exemplified compound 1-2 0 5 ), [1 [2- [1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1, -918-200410948 butadienyl] -1,3 -Dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazole-1 -yl) methyl] propane Oxy] carbonyloxy] ethoxy] -2-oxoethyl] -N-methylamino] -4-oxobutanoic acid (exemplified compound number 1-3 3 4), [[4- [1- [ [2-[[2- [4- (4-Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio], 1 -(2,4-difluorophenyl) -1-[(1 Η-1,2,4-triazole-butyl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxy Butanyl] amino] acetic acid (exemplified Compounds 1-3 4 8),. 3-[[4- [l-[[2-[[2- [4- (4 ·· cyano-2-fluorophenyl) -l, 3-butadienyl] -1,3-difluorene Alk-5-yl] thio] -l- (2,4-difluorophenyl) -bu [(1,1,2,4-triazole-buyl) methyl] propoxy] carbonyloxy ] Ethoxy] -4-oxobutanyl] amino] propionic acid (exemplified compounds 1-3 4 9), 2-[[4- [1-[[2- [[2- [4- (4- -cyano Phenyl-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1- [(1Η-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutanyl] amino] ethanesulfonic acid (Exemplified Compounds 1-3 5 0), hydrosulfuric acid 2-[[4- [1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1 , 3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-U1H-1,2,4-triazol-1-yl) methyl] propoxy Group] carbonyloxy] ethoxy] -4 -oxobutynyl] amino] ethyl ester (exemplified compound 1-351), dihydrogen phosphate 2-[[4- [1-[[2-[[2- [ 4- (4-cyano-2-fluorophenyl) -1,3-butane Alkenyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] propoxy] Carbonyloxy] ethoxy] -4-oxobutanyl] amino] ethyl (exemplified compound -219- 200410948 1-352), 4-[[2- (1-azetidinyl) ethyl] amino]- 4-oxobutanoic acid 1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] · 1,3-dioxane-5 -Yl] thio] -1- (2,4-difluorophenyl) -1-[(1Η-1 '2' 4-triazol-1-yl) methyl] propoxy] carbonyloxy] Ethyl ester (exemplified compound 1-353), 4-oxo-4-[[2- (1-pyridyl) ethyl] amino] butanoic acid 1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-di-n-alkane-5-yl] thio] -1- (2,4-difluorophenyl ) -1-[(1H-1,2,4-triazole-butyl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-3 5 4), 4-oxo-4- [ (2-Midinoethyl) amino] butanoic acid 1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl]- 1,3-dioxan-5-yl] sulfur Group] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified Compound 1 -3 5 5), 4-[[2- (4-methyl-1-piperidyl) ethyl] amino] -4-oxobutanoic acid 1-[[2-[[2- [4 -(4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-diDf alkyl-5-yl] thio] -1- (2,4-difluorobenzene Group) -l-[(1H-1, 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound BU 3 5 6), 4-[[2- [4- (2-hydroxyethyl) -1-piperidyl] ethyl] amino] -4-oxobutanoic acid [[2-[[2- [4- (4-cyano-2-fluoro Phenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -bu (2,4-difluorophenyl) -1-[(1H-1, 2,4-triazol · 1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-3 5 7), -220- 200410948 4-[(2 -morpholinyl) amino ] -4-oxobutanoic acid l-[[2-[[2- [4- (4-cyano-2 -fluorophenyl) -1,3-butadienyl] -1,3-dioxane -5 -yl] thio] · 1- (2,4-difluorophenyl) -1-[(1H-1,2,4 -Triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-3 5 8), 4-[[2-(monomethylamino) ethyl] amino] -4 -oxobutanoic acid 1-[[2-[[2 · [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane- 5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy ] Ethyl ester (exemplified compound 1-359), [^ [4- [1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadiene Yl] -1,3-difluorenfalkyl-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazole-1- Group) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutenyl. ] Methylamino] acetic acid (exemplified compound 1-362) ^ 3-[] ^-[4- [1-[[2-[[2- [4- (4-amino-2-chlorophenyl) -1 '3-butadienyl] -1,3-diDf alkyl-5 -yl] thio] -1-(2,4-difluorophenyl) -l-[(1H-1,2, 4- Triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4 -oxobutyryl] -N -methylamino] propionic acid (exemplified compound 1-363), 2-[^ [ 4- [1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl ] Thio] -b (2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy ] -4-oxobutanyl] -N-methylamino] ethanesulfonic acid (exemplified compound 1-364), dihydrogen phosphate 2-["[4- [1-[[2-[[2- [4- [ 4-cyano-2-fluorophenyl) -1,3-butaneyl] -1 '3 -one lyre-6-5-yl] thio] -1- (2' -221-200410948 4- Difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutanyl] -methylamino ] Ethyl ester (exemplified compounds 1-3 6 6) (1-methyl-4-piperidinyl) acetic acid 1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl]- 1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl ] Propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-3 7 8), (; 1-methyl-4-piperidinyl) acetic acid [2-[[2- [4- (4-cyano 2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -l- [ (1H-1,2,4-triazol-1-yl) methyl] propoxy] methyl carbonyloxy (exemplified compound number 1-3 8 8), hydrosuccinic acid [2-[[2- [ 4- (4-cyano-2-fluorophenyl) -1,3-butanediyl] -1,3-dioxin-5-yl] thio] -1- (2 '4 -a Chlorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] mineoxymethyl ester (exemplified compound number 1 -3 99), hydroglutaric acid [ 2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl ] Propoxy] carbonyloxymethyl ester (exemplified compound numbers 1-4 1 8), 4- (4-methyl-1-piperidyl) -4-oxobutanoic acid [2-[[2- [4 -(4-cyano-2 -fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 -yl] thio] -1- (2,4-difluorobenzene Group) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl ester (exemplified compound number 1-449), [[2- [4- ( 4-cyano-2-fluorophenyl) -1 '3 · butadienyl] -1,3-dicropin-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2, -222- 200410948 4-triazole-butyl) methyl] propoxy] carbonyloxymethyl = 4- [4- (2-hydroxyethyl) -1- Piperinyl] -4-oxobutyrate (exemplified compound number 1-4 5 2), 1- [4- [1-[[2-[[2- [4- (4-Cyclo-2-chloro) Phenyl) -1'3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1 , 2,4-trisino-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutanyl] -3-azetidincarboxylic acid (Exemplified compound number 1-467), 4 -[3-(1-azetidinyl) -1-azetidinyl 4-oxobutanoic acid [2--[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1 '3-dioxane-5-yl ] Thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl (exemplified Compound No. 1-4 7 0), 4-oxo-4- [3-(1-pyrrolidinyl) -1-azetidinyl] butanoic acid [2-[[2- [4- (4-cyano-2 -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -bu [(1H- 1,2 '4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl ester (Exemplified compound number 1-471), 4-oxo-4-(3-piperidinylbuazetinyl) Butyric acid [2-[[2-[4--(4-cyano-2 -fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 -yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl (Exemplified compound number 1- 473), 4- (3-morpholinyl-1-azetidinyl) -4-oxobutanoic acid [2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3- Butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl (Exemplified compound number 1- 476), [2--[2- (4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio ] -1- (2,4-difluorophenyl) -1-[(1H-1, 2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl = 4- [3 -(Dimethyl-223-200410948 amino) -buazetidinyl] -4-oxobutanoate (exemplified compound number 1-47 8), 1- [4-[[2-[[2- [4- [ 4 -fluorenyl-2-aminophenyl) -1 '3 -butanyl'flammyl] -1,3 -mono-Shuyuan-5 -yl] thio] -1- (2' 4 -monophenyl ) -1_ [(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy]-4-oxobutyryl] -4-piperidinecarboxylic acid (exemplified compound number 1 -4 8 5), 1- [4-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3- Yishuyuan-5-yl] thio] -1- (2 '4-chlorochloro) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy ] Carbonyloxymethoxy] -4-oxobutanyl] -4-piperidinesulfonate (Exemplified compound number 1-4 8 6), dihydrogen phosphate 1- [4-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1, 3-butadiene Yl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] propoxy] carbonyl Oxymethoxy] -4-oxobutyryl] -4-piperidinyl ester (exemplified compound number 1-4 8 8), [2-[[2-[4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1, 2, 4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl-4- [4- (1-azetidinyl) piperidinyl] -4-oxobutanoate (exemplified compound; number 1- 4 8 9), 4 -oxo-4- [4- (1-branyl D-base) and D-base] butanoic acid [2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1 （-1,2 , 4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl (exemplified compound number 1-490), 4-oxo-4- (4-piperidinopiperidinyl) butanoic acid [2 -[[2- [4- (4-cyano-2-fluorobenzene Group) -1,3-butadienyl] -1,3-dicropin-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1Η-1, 2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl ester (exemplified compound number 1_491), 200410948 4- (4-morpholinopiperidinyl) -4-oxobutanoic acid [2 -[[2- [4- (4-Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-diDfalk-5-yl] thio] -1- ( 2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl (Exemplified compound number 1-4 9 5) , 4- [4- (dimethylamino) piperidinyl] -4-oxobutanoic acid [2--[[2--[4- (4-cyano-2 -fluorophenyl) -1,3-butane Dienyl] -1,3-difluorenfane-5-yl] thio] -1- (2,4-difluorophenyl)-; 1-[(1H-1,2,4-triazole -1-yl) methyl] propoxy] carbonyloxymethyl (exemplified compound number 1-497), [1- [4-[[2-[[2- [4- (4-cyano-2- Fluorophenyl) -1,3-butanediyl] -1 '3-Yipinyuan-5-yl] thio] -1- (2' 4 -One win phenyl) -l-[(1H- 1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl Group] -4-oxobutanyl] -4-piperidinyl] acetic acid (exemplified compound number 1-5 04), [1- [4-[[2-[[2- [4- (4-cyano-2 -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -l-[(1H -1,2,4-tri_-1-yl) methyl] propoxy] mineoxymethoxy] -4-oxobutanyl] -4-piperidinyl] methanesulfonic acid (Exemplified compound numbers 1-5 0 5), hydrosulfuric acid [1- [4-[[2-[[2- [4- (4-cyano-2 -fluorophenyl) -1, 3-butanediyl] -1, 3- Yipinyuan-5-yl] thio] -1- (2 '4-tritylphenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy ] Carbonoxymethoxy] -4-oxobutanyl] -4-piperidinyl] methyl ester (Exemplified compound number 1-5 0 6) »Dihydrogen phosphate [1- [4-[[2-[[2- [4- (4-Cyano-2-fluorophenyl) -1,3-butanediyl] -1,3-Yipinyuan-5-yl] thio] -1- (2 '4-1 Per phenyl)-; 1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutyryl] -4-piperidinyl 〕 Methyl ester (exemplified Compound No.-225-200410948 1-5 0 7), 1- [4-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadiene Group] -1,3-diDf alkyl-5 -yl] thio] -1-(2,4-difluorophenyl)-: [-[(1H-1,2,4-triazole-1- (Methyl) propoxy] carbonyloxymethoxy] -4-oxo-2-butylfluorenyl] -3-azetidincarboxylic acid (exemplified compound number 1-5 4 4), 4- [3-(1 -D-Yadine D-Dynyl) -1-D-Yadine D-Dynyl] -4-oxo-2-butyric acid [2-[[2- [4- (4-cyano-2-fluorophenyl) -1 , 3-butadienyl] -1,3-di-slogan courtyard-5-yl] thio] -1- (2 '4 -monophenyl) -1-[(1H-1' 2 '4- Triazol-1-yl) methyl] propoxy] carbonyloxymethyl ester (exemplified compounds 1-5 4 8), 4-oxo-4- [3-(1-D than slightly D-Amino) -1- 卩Yardine B adenyl] -2-butanoic acid [2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dial f alk-5 -yl] thio] -bu (2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazole-bulyl) methyl] propoxy] carbonyl Oxomethyl ester (exemplified compounds 1-5 4 9) Acetyl D adenyl) -2-butanedioic acid [2-[[2- [4-_ (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane -5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazole-1 -yl) methyl] propoxy] carbonyl Oxymethyl ester (exemplified compounds 1-5 50), 4-(3-morpholinyl-1-pyridine D amidinyl)-4-oxo-2-butanoic acid [2-[[2- [4_ ( 4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1,2-1,2,4-triazole ·:!-Yl) methyl] propoxy] carbonyloxymethyl (exemplified compounds 1-5 5 4), 4- [3- (dimethylformate Amine) -1-azetidinyl] -4-oxo-2-butenoic acid [2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl ] -1,3-di harmonican-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazole-butyl) Methyl] propoxy] carbonyloxymethyl (exemplified compound 1-556), -226- 200410948 1- [4-[[2-[[2- [4- (4, cyano-2-fluorophenyl) ) -1,3-butane: yl] -1,3-dioxane-5 -yl] thio] -1- (2,4-difluorophenyl) [(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy !! 4-oxo-2-butanyl]- 4-Piperidinecarboxylic acid (Exemplified compound No. 1-563) 4- [4- (1- (Hydroxybutyridinyl) pyridinyl] -4-oxo-2-butanoic acid [2-1 丨 [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-difluorenyl] thio] -1- (2,4-difluorophenyl) -1 -[(1H-1,2,4--1-yl) methyl] propoxy] carbonyloxymethyl ester (exemplified compound 1-5 6 7) '4 _ oxygen _ 4-[4-(1 -pyrrole Pyridyl) piperidinyl] -2 -butenoic acid [2- I [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-difluorenyl G []] Thio]-: 1-(2,4-difluorophenyl) -1-[(1 Η-1,2,4--1-yl) methyl] propoxy] carbonyloxymethyl ( Exemplified compounds 1-5 6 8> · 4-oxo-4- (4-Hyridinyl and D-Dynyl) -2-butyric acid [2-[[2- [4-cyano-2 -fluorophenyl ) -1,3-butadienyl] -1,3-dioxane-5 -S group] -1- (2,4-difluorophenyl) -1-[(1Η-1,2,4 -Triazole-1-Mmethyl] propoxy] carbonyloxymethyl (exemplified compounds 1- 5 6 9), 4- (4-morpholinopiperidinyl) -4-oxo-2-butenoic acid [2-[[2- [4 · cyano-2 -fluorophenyl)- 1,3-butadienyl] -1,3-dioxane-5 U group] -1-(2,4-difluorophenyl) -1-[(1 Η -1,2,4 -tri Azole-methyl methyl] propoxy] carbonyloxymethyl ester (exemplified compounds 1-5 7 3), 4- [4- (monomethylamino) phosphonium] -4-oxo-2-butanyl Acid [2 ~ [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-diIf'yl] thio] -1- (2,4- Difluorophenyl) -1-[(1H-1,2,4--1-yl) methyl] propoxy] carbonyloxymethyl (exemplified compound 1-57 s [1-[4-[[2- [[2-[4-(4 -Cyano-2 -fluorophenyl) -1,1-227-200410948 alkenyl] -1,3-dioxane-5 -yl] thio]] 1-( 2,4-difluorophenyl) -bu [(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4 -oxo-2 -butanyl] -4 -piperidinyl] acetic acid (exemplified compounds 1-5 8 2), chlorosulfuric acid 1- [4-[[2-[[2- [4- (4-amino-2 -carbophenyl) -1 ' 3 -butadienyl] -1,3 -dioxane- 5 -yl] thio] -1-(2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl Oxy] -4 -oxo-2 -butyridinyl]-4-piperidinyl ester (exemplified compound bu 5 8 3), dichlorodic acid 1-[4- [[2- [[2- [4- (4- Fluorenyl-2-phenylene) -1'3-butadienyl] -1,3-diDf alkyl-5-yl] thio] -1-(2,4-difluorophenyl) -1 -[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxo-2-butylfluorenyl] -4-piperidine ester (Exemplary Compound 1 -5 8 4), [] ^-[2-[[2-[[2- [4- (4-amino-2-p-phenylene) -1'3-butane.  Alkenyl] -1,3 -dioctane-5 -yl] thio]-1-(2,4-difluorophenyl) -bu [(1H-1 '2,4 -dimile-1-yl ) Methyl] propoxy] carboxymethoxy] -2-oxoethyl] -N-methylamino] -4-oxobutanoic acid (exemplified compound No. 7 1 3), [[4-[[ 2-[[2- [4- (4-Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dienyl-5-yl] thio] -1- (2 '4-Phenylphenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutanyl] amine Yl] acetic acid (exemplified compounds 1-727), 3-[[4-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl [Propyl]] propoxy] carbonyloxymethoxy] -4-oxobutanyl] amino] propanoic acid (exemplified compounds 1-72 8),-228-200410948 2-[[4-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-di Fluorophenyl) -1-[(1H-1,2,4-triazol-1-yl Methyl] propoxy] carbonyloxymethoxy] _ 4-oxobutyryl] amino] ethanesulfonic acid (exemplified compound 1. 7 2 9), gas sulfuric acid 2-[[4-[[2-[[2 -[4- (4-Gas-2-ylphenyl) -1'3-butadienyl] -1,3-dioxane-5-yl] thio] -b (2,4-di Fluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutanyl] amino] ethyl ester (exemplified Compounds 1-7 3 0), — «chlorodic acid 2-[[4-[[2-[[2- [4- (4 -fluorenyl-2- ¾phenyl) -1 ^ 3 -butadiene Yl] -1,3-difluorenfane-5 -yl] thio]] [(2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl ) Methyl] propoxy] carbonyloxymethoxy] -4-oxobutyryl] amino] ethyl (exemplified compound 1-731), 4-[[2- (1-azetidinyl) ethyl] amino ] -4-oxobutanoic acid 1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane -5 -yl] thio] -1-(2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazole-1 -yl) methyl] propoxy] carbonyl oxygen Yl] ethyl ester (exemplified compound 1 -7 3 2) ^ 4-oxo-4-[[2- (plpyrrolidinyl) ethyl] amino] butanoic acid -Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl)- Bu [(1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl (exemplified compound Bu 7 3 3), 4-oxo-4-[(2-piperazine Pyridinyl) amino] butanoic acid [2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane- 5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl Ester (exemplified compound 1-734), 200410948 4-[[2- (4-methyl-1-piperidyl) ethyl] amino] -4-oxobutanoic acid [2-[[2- [4- (4-cyano (yl-2-trunkyl) -1'3-butanyl) -1 '3-one.  Pinane-5-yl] thio] -1 · (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] Carbooxymethyl ester (exemplified compound 1-73 5), 4-[[2- [4- (2-hydroxyethyl) -piperazinyl] ethyl] amino] -4-oxobutanoic acid 1- [ [2-([2- [4- (4-Cyano-2-fluorophenyl) -1,3-butanediyl] -1,3-Yipinyuan-5-yl] thio] -1 -(2 '4 -p-phenylene) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1 -7 3 6), 4-[(2-morpholinethyl) amino] -4-oxobutanoic acid [2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3 -Butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole -1-yl) methyl] propoxy] carbonyloxymethyl (exemplified compounds 1- 7 3 7), 4-[[2- (dimethylamino) ethyl] amino] -4-oxobutanoic acid [2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1 -(2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy Carbonyloxymethyl ester (exemplified compounds 1-7 3 8), [1 ^-[4-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butane Dienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1H-1,2,4-triazole-1 -Yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutylamyl] -N-methylamino] acetic acid (exemplified compound 1-741), 3- [N- [4-[[2- [[2- [4- (4-Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 -yl] thio] -1-(2 , 4-difluorophenyl) -1-[(1H-1,2,4-triazole-butyl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutanyl] -N-formyl Amine] propionic acid (exemplified compounds 1-742), 200410948 2- [N- [4-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3- Butanyl] -1 '3-1 * 1% fluoren-5-yl] thio] -1- (2' 4 -monochlorophenyl) _1-[(1H-1,2,4 -tri Azole-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutyryl] -N-methylamino] ethanesulfonic acid (exemplified compounds 1-7 4 3), mono-aerobic acid 2- [N- [4-[[2-[[2- [4- (4-Amino-2-dailyl) -1,3-butadienyl] -1,3-difluorenef-alk-5-yl] thio] 1-(2,4-difluorobenzene Group) 2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutanyl] -N-methylamino] ethyl ester (exemplified compounds 1-7 4 5) , (1-methyl-4 -Vinyl D amidinyl) acetic acid [2-[[2- [4- (4- (4-amino-2-fluorophenyl) -1,3-butadienyl] -1, 3-dioctane-5-yl] thio] -b (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy Group] carbonyloxymethyl ester (exemplified compound 1- 7 5 7), hydrogen 1,4-cyclohexyldicarboxylic acid [[2-[[2- [4_ (4-cyano-2-fluorophenyl)- 1 '3 -Butyl-diluted] -1' 3-Yipinyuan-5-yl] thio] -1- (2 '4-difluorophenyl) -bu [(1H-1, 2, 4 -Triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-7 5 9), hydrogen 1,4-cyclohexyldicarboxylic acid [2-[[2- [4 -(4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-diDf alkyl-5 -yl] thio] -1-(2,4-difluorobenzene Yl) -1-[(1H-1,2,4-triazol-1-yl ) Methyl] propoxy] carbonyloxymethyl ester (exemplified compound 1_777), 5-[1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3 -Butadienyl] -1,3-difluorenfane-5 -yl] thio] -1-(2,4-difluorophenyl) -1-[(1H-1,2,4-tri Azole-1-yl) methyl] propoxy] carbonyloxy] ethoxy 200410948 group] -5-oxo-1-pentanesulfonic acid (exemplified compounds 1-7 9 6), 6- [1-[[2 -[[2- [4- (4-Cryptyl-2-perphenyl) -1,3- butane_. Alkyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1H-1,2,4, triazole-1- (Methyl) propoxy] carbonyloxy] ethoxy] -6-oxo-1-hexanesulfonic acid (exemplified compounds 1-8 00), 2-* [N · [8- [1- [[ 2-[[2- [4- (4-Cyano-2-fluorophenyl) -1, 3-butanecanyl] -1 '3-Yipinyuan-5-yl] thio] -1- (2,4-diphenyl)-[[1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -8-oxoctyl] -N -methylamino] ethanesulfonic acid (Exemplified compound 1-8 0 6) ^ 5- [[2-[[2- [4- (4- -Amino-2-propenyl) -1,3- Butanyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1, 2,4-triazole- 1-yl) methyl] propoxy] carbonyloxymethoxy] -5-oxo-1-pentanesulfonic acid (exemplified compound 1- 8 0 8), 6- [[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 -yl] thio] -1-(2,4-difluorophenyl ) -1-[(111-1,2,4-tri-D-s-1-yl) methyl] propoxy] Oxymethoxy] -6-oxy-1-hexanesulfonic acid (exemplified compounds 1-8 1 2), [心 [8 [[2-[[2 [4- (4-cyano-2-fluorophenyl ) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1H-1,2 , 4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -8-oxooctyl] -N-methylamino] ethanesulfonic acid (exemplified compound 1-818), hydropropane Acid 3-[[[2-[[2-[4- (4-cyano-2-fluorophenyl) -1, 3-butadienyl] -1,3-dioxan-5- Group] thio] -1-(2,4-difluorophenyl) · 1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] • 232-200410948 ethoxy] -3 -oxypropyl ester (exemplified compounds 1-8 5 5), 2- [3- 1, [[2- [4- (4-cyano-2-fluorophenyl)- 1,3-butadienyl] -1,3-dioxane-5 -yl] thio] -1-(2,4-difluorophenyl) -1-[(1 fluorene -1,2, 4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -3 -oxopropoxy] -2-oxoethanesulfonic acid (exemplified compounds 1-8 5 6), two Hydrogen phosphoric acid 2 · 〔3- 〔1 · [2-[[2- [4- (4-Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 -yl] thio] -1 -(2,4-difluorophenyl) -1-[(1,2-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -3-oxy Propoxy] -2-oxoethyl ester (exemplified compounds 1-8 5 8), hydrosuccinic acid 3- [b [[2-[[2-[4- (4-cyano-2-fluorophenyl ) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2 , 4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] 3-oxopropyl ester (exemplified compounds 1-8 7 1), [[4- [1-[[ 2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutanyl] oxy] acetic acid (Exemplary Compound 1 -991), (4-methyl-1-piperidyl) methyl = succinic acid 1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1, 3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2, 4-difluorophenyl) -1-[(1H_1,2,4-triazole-butyl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-9 9 3), 3- [ [4- [1-[[2-[[2- [4- (4-Amino-2-phenylene) -1'3-butadienyl] -1,3-dioxane-5 · Group] thio] -1-(2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy]- 233-200410948 ethoxy] -4-oxobutanyl] oxy] propionic acid (exemplified compounds 1-9 94), 2-[[4- [1-[[2-[[2- [4- (4- (4- Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 -yl] thio] -1-(2,4-difluorophenyl) -1 -[(1H-1,2,4.triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4 -oxobutanyl] oxy] ethanesulfonic acid (Exemplary Compound 1- 9 9 5), —chlorochloroic acid 2-[[4- [1-[[2-[[2- [4- (4-Cityl 2- 2- ¾phenyl) • 1,3-butadienyl ] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) 2,4-triazole-butyl) methyl] propoxy] carbonyloxy ] Ethoxy] -4-oxy Fluorenyl] oxy] ethyl ester (exemplified compound Bu 99 7), 2- (4-methyl-1-piperidinyl) ethyl = succinic acid 1-[[2-[[2- [4- ( 4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dicropin-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound 1-4), succinic acid 1- [ [2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1 -(2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl 2- [4- ( 2-hydroxyethyl) -1-piperidinyl] ethyl ester (exemplified compounds 1-1 00 5), [[5- [卜 [[2-[[2- [4- (4-cyano-2- Fluorophenyl) -1,3-butadienyl] -1,3-dioxanfane-5 -yl] thio] -1-(2,4-difluorophenyl) -1-[(1H -1,2,4-triazole-butyl) methyl] propoxy] carbonyloxy] ethoxy] -5-oxopentyl] oxy] acetic acid (exemplified compound 1-1012), 3- [[5- [1-[[2-[[2- [4- (4-cyan 2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -l- [ (1H-1,2,4-triazole-butyl) methyl] propoxy] carbonyloxy]-234-200410948 ethoxy] -5 -oxopentyl] oxy] propionic acid (exemplified compounds 1-1015), [[4- [1-[[2-[[2- [4- (4-cyano-2_fluorophenyl) -1,3-butadienyl] -1,3 -di Pinane-5 -yl] thio] -1-(2,4-difluorophenyl) -1-[(1H-1,2,4-triazole-butyl) methyl] propoxy] carbonyl Oxy] ethoxy] -4 -oxo-2 -butylfluorenyl] oxy] acetic acid (exemplified compounds 1-1 0 3 3), 3-[[4- [1-[[2-[[2- [4 -(4 -fluorenyl-2-phenylene) -1 '3-butadienyl] -1,3-diflfalkyl-5-yl] thio] -b (2,4-difluorophenyl ) -L-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxo-2-butanyl] oxy] propionic acid (Exemplified compound 1-1 03 6), 2-[[4- [1-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadiene Yl] -1,3-dioxan-5-yl] thio ] -1- (2,4-difluorophenyl) -l-[(1H-1 '2' 4-Difluoren-1-yl) methyl] propoxy] mineoxy] ethoxy]- 4-oxo-2-butanyl] oxy] ethanesulfonic acid (exemplified compounds 1-1 0 3 7) ^ dihydrogen phosphate 2-[[4- [1-[[2-[[2- [4- (4 (4 -Cyano-2-fluorophenyl) -1,3 -butadienyl] -1,3-dioctane-5 -yl] thio] -1-(2,4-difluorophenyl)- 1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxo-2-butylfluorenyl] oxy] ethyl ester (exemplified Compound 1-1039) &gt; Hydromalonic acid 3-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3 -Dioctane-5 -yl] thio] -1-(2,4-difluorophenyl) -1-[(1H-1,2,4-triazole-butyl) methyl] propoxy ] Carbonyloxymethoxy] 3-oxopropyl ester (exemplified compound 1-1 0 8 8), 2- [3-[[2-[[2- [4- (4-oxy-2- ) -1'3-butanyl group] -1,3-di-Dfalk-5-yl] thio] -1-(2,4-difluorophenyl) -Bu-235-200410948 [(1H -1,2,4-triazol-1-yl) methyl] propane Yl] carbonyloxymethoxy] -3 -oxopropyl]-2-oxosulfonic acid (exemplified compounds 1-1 0 8 9), -amino acid 2- [3- [[2- [[2- [4- (4-Gas-2-chlorophenyl) · 1'3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-di Fluorophenyl) -1-[(1,2-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -3-oxopropyl] -2-oxoethyl (Exemplified compound 1-1091), hydrosuccinic acid 3-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1, 3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -bu [(1,1,2,4-triazol-1-yl) methyl] propoxy Yl] carbonyloxymethoxy] -3-oxopropyl ester (exemplified compound 1-11 〇4), [[4-[[2-[[2- [4- (4-cyano-2-fluorophenyl ) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1H-1,2 , 4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutanyl] oxy] acetic acid (exemplified compounds 1-1 224), succinic acid [2-[[ 2- [4- (4-cyano-2-fluorophenyl ) -1,3-butadienyl] -1''3-crocodyl] thio] -1- (2 '4-truncated phenyl) -I- ^ ΙΗ-1, 2, 4- Triazol-1-yl) methyl] propoxy] methyl carbonyloxy (4-methyl-1-piperidyl) methyl ester (exemplified compound 1-226), 3-[[4-[[2 -[[2- [4- (4-Cyano-2-fluorophenyl) -1,3-butanediyl], 3-Yipinyuan-5-yl] thio] -1- (2 ' 4- (1- (2-phenyl) phenyl) -1 _ [(1H-1,2,4-trisino-1-yl) methyl] propoxy] mineoxymethoxy] -4-oxobutanyl] oxy] Propionic acid (exemplified compounds 1 2 2 7), 2-[[4-[[2 — [2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl ] -1,3-Dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) Methyl] propoxy] carbonyloxymethoxy]-236-200410948 -4 -oxobutynyl] oxy] ethanesulfonic acid (exemplified compound 1-1 2 2 8), -oxo acid 2-[[4- [[2-[[2- [4-(4 -fluorenyl-2 -perphenyl) -1 '3-butadienyl] -1,3-dioxan-5-yl] thio]- 1- (2,4-difluorophenyl) -1-[(1Η-1,2,4-triazole · butyl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutanyl] oxy] ethyl ester (Exemplary compounds 1-1 2 3 0), succinic acid [2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] · 1,3-Yipinyuan-5- Yl] thio] -1- (2 '4 -monophenyl) -l-γί 1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl 2 -(4-methyl-1-piperidyl) ethyl ester (exemplified compound 1-1 23 7), succinic acid [2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-Yipinyi-5-yl] thio] -1- (2,4-monochlorophenyl) -1-K 1H-1, 2, 4 -Triazole-butyl) methyl] propoxy] carbonyloxymethyl 2- [4- (2-hydroxyethyl) -1-piperidinyl] ethyl ester (exemplified compounds 1-1 2 3 8), [ [5-[[2-[[2- [4- (4-Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] sulfur Group] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -5 -Oxopentyl] oxy] acetic acid (exemplified compound 1- 1 24 5), 3-[[5-[[2-[[2- [4- (4-amino-2-chlorophenyl) -1'3-but _.  Alkenyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1α 1H-1,2,4-triazol-1-yl) formyl Group] propoxy] carbonyloxymethoxy] -5-oxopentyl] oxy] propionic acid (exemplified compounds 1-1 2 4 8), [[4-[[2-[[2- [4 -(4-cyano · 2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorobenzene Group) -1-[(1Η-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxo-2-butanyl] oxy] acetic acid (exemplified Compound 1-1266),-237-200410948 3-[[4-[[2-[[2- [4- (4-cyano-2-fluorophenyl) -1,3-butadienyl]- 1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl ] Propoxy] carbonyloxymethoxy] -4 -oxo-2 · butylfluorenyl] oxy] propionic acid (exemplified compound 1-1269), 2-[[4-[[2-[[2- [4- (4-amino-2-p-phenylene) -1'3-butane-meryl] -1'3-yipinyuan-5-yl] thio] -1- (2'4-peptylphenyl) -1-[(1H-1,2,4-triazole-1- ) Methyl] propoxy] carbonyloxymethoxy] -4-oxo-2-butylfluorenyl] oxy] ethanesulfonic acid (exemplified compound Bu 1 2 7 0), or dihydrogen phosphate 2-[[4- [ [2-[[2- [4- (4-cyano-2-fluorophenyl) -1, 3-butadienyl] -1,3-dioxan-5-yl] thio]] (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxo-2- Butanyl) oxy. ] Ethyl ester (exemplified compounds 1-1 272). Particularly preferred compounds are compound numbers 1-39, 1-88, 1-106, 1-125, Bu 126, M28, 1-203, 1-204, 1-205, 1-348, 1-349, 1 -350, 1-351, 1-352, 1-353, 1-354, 1-356, 1-357, 1-358, 1-359, 1-362, 1-363, 1-364, 1-366 , 1-418,1-467,1-485,1-504,1-505, 1-507,1-582,1-583,1-584,1-727,1-728,1-729,1 -730, 1-73, 1-732, 1-733, 1-735, 1-736, 1-737, 1-738, 1-741, 1-742, 1-743, 1-745, 1-796 , 1-800, 1-808, 1-812, Bu 855, 1-991, 1-994, 1-995, 1-997, M012, 1-033, 1-1036, 1-1088, 1-1224, 1-1227, M228, 1-1230, 1-1245, 1-1266, or 1-1269, more preferably compound numbers 1-39, 1-106, 1-125, 1-126, 1-128, 1 -203, Bu 348 '1-349, 1-350, 1-352, 1-356, 1-357, 1-362, 1-363, 1-418, 1-485, 1-504, 1-505, 1-507, 1-582 ^ 1-727 ^ 1-728 ^ 1-729 ^ 1-731 »1-735 ^ 1-736 ^ 1-741 ^ 1-742 ^ 1-796» 1-800 ^ 1- 808 »1- 812, 1-991, 1-994, 1-033, 1-1224, 1- 1227 or 1-1266 compounds, more preferably compound number 1-39, 1-106, 1-348, 1-349, Bu 350, 1-352, 1-362, 1-418, 1-485, 1-727, 1-728, 1-729, 1-731 , 1-741, 1-796, 1-800, 1-808, 1-812, 1-991-238-200410948 or 1-1224, most preferably compound numbers 1-348, 1-349, 1- 727 or 1-728 compounds. The compound of the present invention can be produced by the following method A.

(VI) ‘0 person In the above, R1, Ra, A, Ar’ L1 to L3 and G are as defined above. (Method A) (A-1 process) This process is to prepare a compound (11) prepared by a known method and then react it with a compound (IV) prepared by a known method to prepare a compound ( V) works. Among the above compounds, the known production method of the 'compound (11)' and the compound (IV) is as follows. Compound (II) is known or can be easily prepared according to a known compound production method. For example, Ra is the following formula: Time

-239- 200410948 According to the method of JP 62- 1 47 66, Ra is based on the following formula

According to the method described in JP 8- 5 3 4 2 6 or WO 9 9/4 5 0 0 8, Ra is based on the following formula:

According to the method described in Patent Publication No. 2625 5 84, Ra is the base time Λ 如下 as follows: χ s / ------ f \ = jg According to the method described in Japanese Patent Publication No. 9-1 8 3 7 69, Ra When it is based on

Mm * ti Γ ch2ch3-^ S〇2

According to the method described in Japanese Patent Application Laid-Open No. Π-24 0 8 71, Ra is based on the following formula:

According to the method described in WO 98/3 1 67 5, Ra is based on the following formula -240- 200410948

According to the method described in WO 9 7/0 5 1 3 0, when Ra is based on the following general formula (1 Η), it is disclosed in JP-A-Heisei 8-3 3 3 3 5 0, JP-A-Hei 1 0- 2 7 No. 9 5 6 No. 7 beta 'Japanese Unexamined Patent Publication No. 11-80135, epi 0883175A2, or the method described in Japanese Unexamined Patent Publication No. 200 1-3 42 1 8, especially r3 is a Cu4 alkyl group, and R4 is Hydrogen atom or alkyl,

Ar2 is a phenyl group having 1 to 5 substituted phenyl groups having the same or different substituents selected from the substituent group r or 1 to 5 substituted mono groups having the same or different substituents selected from the substituent group r Ring heteroaryl, E1 is a group of the formula -S (0) ηι- (where η is an integer of 0 to 2), and E3 is a group of the following formula (GaA):

(In the formula, R, R6A, R7A and R8 are each a hydrogen atom, Ci-C6 alkyl group, or C 丨 -C 6 halogenated alkyl group, PA is 0 or 1, qA, rA and sA are each an integer of 0 to 2) At the time, according to the method described in JP-A-8_3 3 3 3 5 0, Ra is based on the following formula

According to the method described in EP 1 0 8 3 1 7 5 A2, El is methylene and E2 is selected from the group consisting of the following formula, 200410948

(Ga®) E3 is the base of the following formula (GaB) — {HC ^ CH) q8 ^ c = C) tB— (HC = rCH) se— b (where qB is an integer of 0 to 3, and rB and sb are each It is an integer of 0 to 2. When the sum of ^ and rB and sb is 3 or less), according to the method described in the Japanese Patent Publication No. 1 '5, r3 is a hydrogen atom,

Ar is naphthyl and has a substituent group selected

代 _ 之 1 self-substituted bicyclic heteroaryl ——... / t 口 口 ... | 5 substituted naphthyl, fused bicyclic heteroaryl, or 5 with the same or different substituents of group τ Substituted fused group, or E is the formula .SCO) In the formula, m oE3 is the following formula (Gac) group: 2 integer) (where R5C, r6c c 丨 -C 6 haloalkyl, R7C and r8C Each is a hydrogen atom, Ci-C6 courtyard,

When pC is 0 or 1, q and each integer is 0 to 2), the method described in JP-A-Hei 10-279 5 67, R4 is a hydrogen atom, and Ar2 is a base group. Phenyl group, 1 of the same or different substituent group _ _ group r, or 1 to 5 substituted naphthyl groups with the same or -242- 200410948 different substituents selected from group 7, E1 is methylene Group, or sulfur atom, E3 is a group of the following formula (Gb):-Ai ^ -OOHNF ^ -T- (Gb) (wherein Ar3 is a phenyl group, and is selected from the group consisting of (fluorine and chlorine atoms) substituents 1 or 2 substituted phenyl, 1 or 2 substituted with the same or different substituents, or 1 or 2 substituted naphthyl substituted with the same or different substituents selected from the group of (fluorine and chlorine atoms), R9 is Hydrogen atom or alkyl group, T is a single bond, or alkylene group), the method described in JP-A 200 1-3 4 2 1 8 7 is disclosed, and the others are patent 3305 0 9 8 2 , W09 5/2 5 1 0 7, W000 / 2 7 8 5 2, W00 1/6 6 5 5 1, or the method described in W 0 0 1/7 9 1 9 6 . Compound (IV) can be found in the literature (Tetrahedron Lett., Vol. 30, 2033 (1989), Synthesis, 1159 (1990), J. Chem. Phys., 21, 1049 (1953), J. Mol. Struct., 198, 2 39 (1989)). The solvents used are, for example, aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, dioxane Ethers such as ethylene glycol dimethyl ether; nitriles such as acetonitrile, isobutyronitrile; formamidine, N, N -dimethylformamide, N, N -dimethylacetamide, N -methyl-2 -Pyrrolidone, hexamethylphosphonium triamine and the like amines, preferably ethers or amines, but also dimethoxyethane, tetrahydrofuran or N, N-dimethylformamide. The alkali used may be alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, etc. 243-200410948; alkali metal oxychlorides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkaline earth such as palladium hydroxide Metal hydroxides; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium methoxide and other metal alkoxides; butyllithium, lithium diisopropylamide, Organometallic bases such as bis (trimethylsulphonate base) lithium amidoamine are preferably alkali metal hydrides, and also sodium hydride or potassium hydride. Furthermore, if necessary, after the alkali is added, in order to complete the oxidation reaction, the ultrasonic irradiation may be performed. The reaction temperature may vary depending on the raw material compounds and reaction reagents, and it is generally carried out at _50 ~ 50 ° C, preferably 0 ° C ~ 25 ° C. The reaction time may vary depending on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but it is usually 10 minutes to 4 hours, preferably 30 minutes to 1 hour. After completion of the reaction, the target compound of the present reaction can be, for example, a saturated sodium bicarbonate aqueous solution, an immiscible organic solvent such as ethyl acetate, and the organic layer is washed with water and a saturated sodium bicarbonate aqueous solution, and then the organic layer containing the target compound is separated. After being dried over anhydrous magnesium sulfate, etc., the solvent is distilled off. The obtained compound may be purified by a conventional method, for example, recrystallization, reprecipitation, and silica gel column chromatography. (A-2 process) This process is to make the compound (V) obtained from the F 1 process, and perform halogen conversion (A-2 a) if necessary, and then compound with a compound that is easy to manufacture by a known method or by the method b to D described later. (VI) The process of reacting to obtain compound (I) (a-2b). (A-2a) The solvents used are aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, petroleum ether; aromatic hydrocarbons such as benzene'toluene, xylene; ethyl formate, ethyl acetate, acetic acid-244-200410948 C酉 vinegars such as' butyl acetate 'diethyl carbonate; ethers, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and other ethers; acetone, methyl 2-ketone' Ketones such as methyl isobutyl ketone, isophorone, cyclohexanone; nitriles such as ethenyl isobutyronitrile; formamidine, N, N-dimethylformamide, N, N-monomethyl Acetamide, N-methyl · 2-pyrrolidone, hexamethylphosphonium triamine, and the like amines are preferably aromatic hydrocarbons, amines or nitriles, and also acetone, N, N-di Methylformamide or acetonitrile. If necessary, a small amount of crown ethers should be added (preferably 18-crown-6). The reagents used are alkali metal iodides such as sodium iodide, potassium iodide, thallium iodide, and iodide; tetraalkylammonium iodides such as tetrabutylammonium iodide, etc., preferably alkali metal iodides and sodium iodide . The reaction temperature may vary depending on the starting compound's reaction reagent, and it is generally carried out at 50 to 120 ° C, preferably 80t: to 1200c. The reaction time varies depending on the reaction temperature, the starting compound, the reaction reagent, or the type of solvent used. It is usually 1 hour to 48 hours, and preferably 3 hours to 24 hours. After the reaction is completed, the target compound of the reaction can be concentrated by adding an immiscible organic solvent such as water and ethyl acetate, and after washing with water, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate, and then distilled off. Derived from solvents. The obtained compound may be purified according to ordinary methods, for example, recrystallization, re-sinking, and silica gel column chromatography. (A-2b) The solvents used are aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; ethyl formate, ethyl acetate, acetic acid-245-200410948 C Ester 'butyl acetate, diethyl carbonate and other esters; ether, isopropyl ether, enantane' dioxane 'dimethoxyethane, diethylene glycol dimethyl ether and other ethers; propyl methyl ethyl ketone' a Ketonitrile such as isobutyl ketone, isophorone, cyclohexanone, and nitriles such as isobutyronitrile; formamidine, N, N -dimethylformamide, N dimethylacetamide, N- Methyl-2-pyrrolidone and hexamethylphosphonium triamine amines are preferably ethers or amines, and also tetrahydrofuran, N, N-dimethylamine or N, N-dimethylethyl Lamine. In addition, if necessary, less ethers (preferably 18-crown · 6) are added. Examples of the base to be used are, for example, sodium carbonate, potassium carbonate, lithium carbonate, and metal carbonate carbonates; alkali hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, and lithium hydrogen carbonate; and alkali metals such as lithium hydride, sodium hydride, and potassium hydride. Alkali metal compounds such as hydride sodium hydroxide, potassium hydroxide, lithium hydroxide, and hydroxide planer; earth test metal hydroxides such as hydroxide hydroxide, etc., are preferably alkalis and carbonate planers. In this reaction, when the compound (VI) is a carboxylic acid salt of a base, the preparation method is a method of preparing in vitro before the reaction, or the base and the compound (VI) are mixed with alcohol such as water and ethanol, and then distilled. In addition to the solvent, the pre-reaction temperature may vary depending on the raw material compounds and the reaction reagents. Generally, the reaction is performed at ~ 80 ° C, preferably 2 5 t: ~ 4 0 t. The reaction time varies depending on the reaction temperature, the type of the starting compound, the reaction reagent or the solvent, but it is usually 1 hour to 48 hours, preferably 1 hour. After the reaction is completed, the target compound of the reaction can be mixed and shrunk by adding an immiscible organic solvent such as water and ethyl acetate. After washing with water, the organic layer containing the target compound is separated. , Alkaline metals such as B'N- and other methyl groups, crowns, and salt salts such as hydrogen and oxygen. 2 5 ° C use ～ 24 substance concentration, distilled off -246- 200410948

Derived from solvents. The obtained compound may be purified by silica gel column chromatography and the like. After the above reaction is completed, the functional group may be changed. Protective Groups Peter G. M. Wuts% Publication) may be used for transformation. Next. It is prepared by the compound used in the above method A, for example, according to the following method. TWGreen, f '1999, conducted by AWiley-Interscience). Hydroxyl ethyl phosphate ^ (allyloxy) (diisopropylamino) phosphine, inactive solvents such as &amp; dichloromethane In the process, the ice-cold substance (VI) is known or can be prepared according to known methods and convenient methods ~ D.-247-200410948 ο β ^ ι y

H—HO L1-G ^ L2 ^ t3 &quot; A m 〇 〇 (Vi)

PgO person L person Lv (V «Ii) 0 HO person L1-G-dA (VI) Η2Ν—l3 &quot; L3, A (IX) 01 O 0

PgCT ^ L1 person Lv {VII!}

In the above, 'A, L1 to L3, and G are as defined above, Pg is a carboxy protecting group, and Lv is a leaving group. The carboxy-protecting group of P g is not limited to those that can protect the carboxyl group. Specifically, it refers to a protecting group that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis, such as methyl, ethyl, and propyl. Group, isopropyl, butyl, isobutyl, second butyl, third butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl'buethylpropyl, hexyl 'isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, plant dimethylbutyl, 1, 1 -"Alkyl" such as dimethylbutyl, 1,2-dimethylbutyl, 1,3 ~ dimethylbutyl '2,3-dimethylbutyl, 2-ethylbutyl; ethylene Group, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, methyl, 248-200410948-1-propenyl, 2-methyl-propenyl, 2-methyl- 2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3 -Methyl-2-butenyl, ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl -3-butenyl 1-pentanyl ^ 2-pentanyl ^ 1-methyl-2-pentanyl '2-methyl-2-pentanyl' 3-pentenyl, 1-methyl-3-pentenyl , 2-methyl-3-pentenyl, 4-pentenyl; 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexene "Alkenyl", 3-hexenyl, 4-hexenyl, 5-hexenyl, etc .; ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl 2-propynyl, 2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 1-ethyl 2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl Methyl, 2-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4 -Pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl "Alkynyl"; "Alkyl" such as acetomethyl; "lower alkyl"; benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, ten-naphthylmethyl, di Benzyl, trityl, 6-phenylhexyl, α-naphthyl diphenylmethyl 9-Onion methyl and other 1 to 3 aryl-substituted lower alkyl groups, and 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl Methyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzylbenzyl , Bis (2-nitrophenyl) methyl, sunfloweryl, 4-methoxycarbonylbenzyl and other lower alkyl, lower alkoxy, nitro, halogen atom, cyano, alkoxycarbonyl and other aromatic rings are substituted 1 to 3 aryl-substituted lower alkyls such as "aralkyl"; trimethylsilyl, triethylsilyl, isopropylsilyl, third butyldimethylsilyl, -249-200410948 methyl Diisopropylsilyl'methyltri-tert-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, cumylsilyl, butyldiphenylsilyl, benzenediisopropylsilyl And so on.

The leaving group of Lv is not limited to those that can be removed to obtain functional groups in the condensation reaction. This # group is, for example, a meridian group; the above-mentioned "halogen atom"; "Alkanesulfonyloxy"; trifluoromethanesulfonyloxy and the like, "halogen substituted low alkylsulfonyloxy"; arylsulfonyloxy such as benzenesulfonyloxy, and low alkylation such as p-toluenesulfonyloxy Halogens such as aromatic sulfonyloxy and p-chlorobenzenesulfonyloxy are substituted with "aromatic sulfonyloxy" such as aromatic sulfonyloxy. (Method B) _ In this project, the compound (V11) obtained by a known method is condensed (B-1 a) with the compound (V III) obtained by a known method, and then the carboxy protecting group is deprotected (B-1 b) the process of obtaining compound (VI) (G = carbonyl). 〔B-la〕 This project is not limited in accordance with customary condensation methods. For example, (i) reaction in the presence of a condensing agent and (i i) reaction in the absence of a condensing agent. (i) Reaction in the presence of a condensing agent This reaction is performed by reacting the above-mentioned compound (VIII) with a condensing agent, and then adding a compound (VII). The solvents used are, for example, halogenated hydrocarbons such as dichloromethane, chloroform; ethers such as diethyl ether, tetrahydrofuran; fluorenamines such as dimethylformamide, dimethylacetamide; and nitriles such as acetonitrile. The condensing agents used are, for example, N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornenyl-2,3-dicarboxyimine; and dipyridine; The active esterification reaction of disulfide compounds such as disulfide is preferably -250- 200410948. Dicyclohexylcarbodiimide, carbonyldiimidazole, or triphenylphosphine are used in the presence of a condensing agent. The reaction temperature is from -10 ° C to 100 t under the reaction of the condensing agent, and then at room temperature. The reaction time for the second reaction is from 30 minutes to 80 hours. After the reaction is completed, the target compound of the reaction can be concentrated by adding the water and ethyl acetate immiscible organic solvent. After washing with water, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate, and then distilled off. Derived from solvents. The obtained compound may be purified according to ordinary methods, for example, recrystallization, re-sinking, silica gel column chromatography, and the like. (ii) Reaction in the absence of a condensing agent. The solvents used are, for example, ethers such as diethyl ether, tetrahydrofuran; fluorene amines such as dimethylformamide, dimethylacetamide; and nitriles such as acetonitrile. The reaction is preferably carried out in the presence of organic amines such as triethylamine, N-methylmorpholine, etc. The reaction temperature is -10 ° to 50 ° C, and the reaction time is 30 minutes to 20 hours. After the reaction is completed, the target compound of the reaction can be concentrated by adding the immiscible organic solvent such as water and ethyl acetate to the reaction mixture. After washing with water, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate, and then distilled off. Derived from solvents. The obtained compound may be purified according to a conventional method, for example, by recrystallization 'reprecipitation, silica gel column chromatography, or the like. (B-1b) Carboxyl protecting group When a lower alkyl group or aryl group is used, it can be removed by treatment with an acid or a base. Acid can use hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, alkali should be suitable for the compound. • 251-2200410948 There are no special restrictions on other parts, and it should be sodium carbonate, potassium carbonate, carbonate shavings and other alkali metal carbonates; hydroxide Alkali metal hydroxides such as sodium and potassium hydroxide or concentrated ammonia-methanol solutions. When a base is used, it can be carried out according to the method of (A-2b). The product of this reaction can be used in the (A-2b) reaction without purification. The solvent used is usually a user of the hydrolysis reaction, as long as it does not affect the reaction, such as water or a mixed solvent of alcohols such as methanol, ethanol, n-propanol, and the like, or organic solvents such as tetrahydrofuran and ether. The reaction temperature and reaction time may vary depending on the starting material, solvent, and reagents used. There is no specific limit to suppress side reactions. The reaction is usually performed at 0 ° C to 150 ° C for 1 hour to 10 hours. When the carboxy-protecting group is an alkoxyaryl group such as p-methoxybenzyl or a di- or triaryl-substituted methyl group such as diphenylmethyl or trityl, it is usually removed by treatment with an acid in a solvent. The solvent used is preferably an aromatic hydrocarbon such as anisole, and the acid used may be a fluorinated organic acid such as trifluoroacetic acid. The reaction temperature and reaction time may vary depending on the starting material, solvent, and acid used, and it is usually 30 minutes to 10 hours at room temperature. When the carboxy-protecting group is an aralkyl group or a haloalkyl group, it is usually removed by reduction in a solvent. When the carboxy protecting group is a halogen-lower alkyl group, the reduction method is preferably a chemical reduction method such as zinc · acetic acid. When it is an aralkyl group, a catalyst such as palladium-carbon or platinum is preferably used for the contact reduction method, or using Alkali metal sulfides such as potassium sulfide and sodium sulfide are implemented by a chemical reduction method. The solvents used are not limited to those who do not participate in the reaction, such as methanol, ethanol, etc. -252-200410948 hydrazones; ethers such as tetrahydrofuran, di-Dfane; mixed solvents of fatty acids such as acetic acid or organic solvents and water. The reaction temperature and reaction time may vary depending on the starting material, solvent, and reduction method. Usually, the reaction is performed at 0 ° C to room temperature for 5 minutes to 2 hours. When the carboxy protecting group is an alkoxymethyl group, it is usually removed by treating with a solvent and acid. The acid used is not particularly limited to conventional Brienzide deacidifiers, and is preferably an inorganic acid such as hydrochloric acid or sulfuric acid; or an organic acid such as acetic acid or p-toluenesulfonic acid. The solvent used is not limited to those who do not participate in the reaction, such as alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; or mixed solvents of organic solvents and water. The reaction temperature and reaction time may vary depending on the starting material, the solvent and the type of acid used, etc., and the reaction is usually performed at 0 to 50 ° C for 10 minutes to 18 hours. When the carboxy-protecting group is 2-propenyl, 2-butenyl and the like which can be substituted, 2-propene is usually removed by treatment with a metal complex and a nucleophilic (reducing) agent in a solvent. The solvent used is not limited to those who do not participate in the reaction, and is preferably a hydrocarbon such as toluene; an ether such as tetrahydrofuran; a halogenated hydrocarbon such as dichloromethane. The metal complexes used are palladium (triphenylphosphine) palladium, bis (triphenylphosphine) palladium dichloride, and other palladium complexes. The amount of the metal complex is 0.0 01 to 0 · 1 mol equivalent to the raw material. The nucleophilic (reducing) agents used are, for example, amines such as pyrrolidine; carboxylates such as potassium 2-ethylhexanoate; tin hydrides such as tributyltin hydride; and formic acid or a salt thereof. The reaction temperature and reaction time may vary depending on the starting material, solvent, heavy metal complex and nucleophile (reducing) agent, etc., and the reaction is usually performed at 0 ° C ~ 50 ° C 200410948 10 minutes ~ 5 hours. In addition, the removal of the protecting group can be carried out by treatment with ammonia water and ammonium by a conventional method. In addition, if necessary, according to a normal method, the above-mentioned mixed carboxylic acid produced in an immiscible organic solvent such as water and ethyl acetate is dissolved, and alkali metals such as aqueous sodium hydrogen carbonate solution and potassium carbonate aqueous solution are added at 0 ° C to room temperature. A carbonate or bicarbonate aqueous solution can be filtered and precipitated at p Η 7 to produce an alkyl metal salt. (Method C) In this project, the compound (IX) obtained by a known method is condensed (C-la) with the compound (VIII) obtained by a known method, and the carboxy protecting group is deprotected (C-1b). The process of obtaining the amidine compound (v I) (G =-C (= Ο) N Η-). Furthermore, when an epianol compound represented by the formula HO-L2-L3-A in the starting compound (IX) is used, an ester compound (VI) (-C (20) 0-) can be obtained. (C-la) This project is implemented according to customary contraction laws. For example, according to the method of (B-1 a) above, (i) react in the presence of a condensing agent, (i 丨) in the absence of a condensing agent. Take a reaction to implement. (C-lb) This project can be implemented in accordance with the customary carboxy deprotection method. For example, it can be implemented according to the method of (B · 1 b) above. That is, when a protecting group is a low alkyl group or an aryl group, the protecting group can be removed by treatment with an acid or a base. When the protecting group is a methyl group substituted with an alkoxyaryl group such as p-methoxybenzyl or a di or triaryl group such as benzyl or trityl, the protecting group is usually removed by treatment with an acid in a solvent. When the protecting group is an aralkyl group or a halogenoalkyl group, the protecting group is usually removed by reduction in a solvent. When the protecting group is alkoxymethyl-254-200410948, the protecting group is usually removed by treating with a solvent and acid. When the protecting group is 2-propenyl, 2-butenyl and the like, which can be substituted, the 2-propylene is usually removed in a solvent by treatment with a metal complex and a nucleophilic (reducing) agent. The removal of the carboxy-protecting group can be carried out by treatment with ammonia water and ammonium by a conventional method. If necessary, according to the normal method, the above mixed carboxylic acid produced by dissolving the carboxylic acid in water and ethyl acetate and other immiscible organic solvents is added at 0 ° C to room temperature. A salt or bicarbonate aqueous solution can be filtered and precipitated at pH 7 to produce an alkyl metal salt. (Method D) · In this project, the compound (X) obtained by a known method is condensed (D -1 a) with the compound (V 111) obtained by a known method, and then the carboxy protecting group is deprotected (D-lb ) To obtain the amidine compound (VI) (G-NHC (= 0)-). In addition, when the epigol compound represented by Pg0-C (= O) · υ-ΟΗ in the raw material compound (X) is used, an ester compound (V I) (G =:-0 C (= 0)-) can be obtained. (D-1 a) This project is implemented in accordance with customary contraction laws. For example, according to the method of the above (B-la) project, (i) react in the presence of a condensing agent, (π) in the absence of a condensing agent Take a reaction to implement. (D-lb) This project can be implemented in accordance with the customary carboxy deprotection method. For example, it can be implemented according to the method of (B-1 b) above. The compound (I) of the present invention or a pharmacologically acceptable salt thereof has an antifungal activity in vivo. In addition, the compound (I) of the present invention has excellent in vivo dynamics such as absorption, in vivo distribution, blood half-life, and the like, and has low toxicity to organs such as the kidney and liver. Since-255-200410948, the compound (i) of the present invention can be used as medicine, especially for the treatment or prevention of fungal infections. When the compound of the present invention is used as the above-mentioned disease preventive or therapeutic agent, it is possible that the compound of the above formula (I), or a pharmacologically acceptable salt thereof, alone or mixed with appropriate pharmacologically acceptable excipients, diluents, etc., can be obtained as a tablet Oral administration such as capsules, granules, powders or sugar prizes, or parenteral administration forms such as injections, drips, suppositories or patches, or external preparations. The dosage form is preferably a solution form such as an injection or an instillation. The triazole (I) and its pharmacologically acceptable salt of the present invention have high water solubility, can be quickly cracked in the body as medicine (especially injections), and exhibit excellent antifungal activity. Mucor, Histoplasma, Bacillus, Coccus, Paracoccus, Hairy's Epidermophytes, Microspora, Leptospira, Nematodes Genus' Cladosporium, Alternaria, Shembophyte, Helminthosporium, Micrococcus, Calicospora, Echinoderm, Coprinus, Ear mold, Rana spp., Fungi such as Penicillium, Limonium, Yeast, Cephalosporum, Rhizopus, Rhizopus, etc. have excellent antifungal activity. The dosage varies depending on the symptoms of the patient (warm-blooded animals, especially humans), the age and weight of the method of administration (intravenous, intramuscular, subcutaneous injection, etc.), etc. For example, when administered intravenously, the lower limit of body weight per kg per adult 0.0 0 2mg (preferably 0.0 1 mg / kg body weight), the upper limit is 10mg / kg body weight (preferably, 8mg / kg body weight), and it should be administered 1 to 6 times per day according to symptoms. [Embodiment] Examples, reference examples, test examples, and formulation examples' will be described in detail below, but the present invention is not limited thereto. -256- 200410948 Example 1 4-oxo-4-[4-(1 -pyrrolidinyl) piperidinyl] butanoic acid 1-[[(1 R, 2 R) -2-[[trans-2- [ (IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 · yl] thio] -1-( 2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound 1-1 1 1 ) (la) 1-chloroethyl carbonate (1R, 2R) -2-[[trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3- Butadienyl] -1,3-dioxane-5-yl] thio] -1_ (2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] propyl ester Potassium hydride (dispersed in 30% mineral oil; 0.50 g, 3 · 8 mm ο 1) dissolved in tetrahydrofuran (18ml), and under ice cooling, 4-[(IE, 3E) -4 was added -[Trans-5-[[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1 · methyllO Η-1, 2, 4-triazole-1 -yl ) Propoxy] thio] -1, 3 -dioxane-2-yl] -1,3-butadienyl] -3 -fluorobenzonitrile (European Patent Publication EP1083175A2 (publication: 2001 ) Already contained in the statement; 1.09g, 2.0mmol), stirred at square ° C 1 hour. At the same temperature, add chloroformic acid (1-chloroethyl) (429mg, 3.0mmol), and stir for 10 minutes. Under ice cooling, a saturated aqueous sodium hydrogen carbonate solution (20 m 1) was added, and the resultant was extracted with ethyl acetate. The organic layers were combined, washed with a saturated sodium bicarbonate aqueous solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 80: 20-20: 80, V / V, silica gel 10g) to obtain the title compound (1.22g, yield 94%) Colorless amorphous solid (diastereomeric ratio-257-200410948 = about 1: 1). IR (CHC13) vmax2233, 1766, 1616, 1505, 1277, 1256, 1140cm.1; hNMR (CDC13, 400MHz): 51.25 (3Hx (1/2), d, J = 7Hz), 1.27 (3Hx (1 / 2), d, J = 7Hz), 1.86 (3Hx (1/2), d, J = 6Hz), 1.87 (3Hx (1/2), d, J = 6Hz), 2.98-3.09 (1H, m ), 3.49 (lHx (1/2), t, J = llHz), 3.50 (lHx (1/2), t, J = llHz), 3.52 (1H x (1/2), t, J = llHz), 3.53 (lHx (1/2), t, J = llHz), 3.88 (lHx (1/2), q, J = 7Hz), 3.93 (lHx (1/2), q, J = 7Hz), 4.18 (1H, ddd, J = ll, 5, 2Hz), 4.28 (lHx (1/2), ddd ,, 5, 2Hz), 4.30 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.98 (IHx (1/2), d, J = 4Hz), 4.99 (1Ηχ (1/2), d, J = 4Hz), 5.39 (2H, brs), 5. · 86 (1Η, dd, J = 16, 4Hz), 6.37 (lHx (1/2), like q, J = 6Hz), 6.38 (lHx (1/2), like q, J = 6Hz), 6.59 (1H, dd, J = 16, 11Hz), 6.75 (1H, d, J = 16Hz), 6.85-6.95 (2H, m), 6.93 (1H, d, J = 16, 11Hz), 7.33 (1H, dd , J = 10, 1Hz), 7.40 (1H, d, J = 8Hz), 7.4-7.5 (1H, m), 7.57 (1H, t, J = 8Hz), 7.94 (1H, s), 7.98 ( ΙΗχ (1/2), s), 8 · 02 (lHx (1/2), s); MS (FAB) m / z: 649 ((M + H) +). (lb) 4-oxo-4- [4- (1-pyrrolidinyl) piperidinyl] butanoic acid 4-(1 -pyridinyl) _ Π (1 · 1 7 g, 7 · 2 1 mm ο 1) was dissolved in dichloromethane (10 ml), succinic anhydride (0.72 g, 7.21 m mol) was added, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure to obtain a crude title compound (1.91 g, quantitative yield) as a yellow amorphous solid. 4 NMR (CDC13, 400MHz): (51.20 (1H, br q, J = 13Hz), 1.34 (1H, br q, J = 13Hz), 1.64-1.71 (4H, m), 1.72 (2H, brt, J = 13Hz), 2.18-2.25 (1H, m), 2,38-2.43 (2H, m), 2.47-2.54 (6H, m), 2.72 (1H, Id, J = 13, 3Hz), 3.05 (1H, br t, J = 13Hz), 3.79 (1H, brd, J = 13Hz), 4.15 (1H, brd, J = 13Hz); MS (El) m / z: 254 (M +) 0-258-200410948 (lc) 4 -Oxy · 4- [4- (1-pyrrolidinyl) piperidinyl] butyrate [[(1R, 2R) -2-[[trans-2-[(IE, 3E) -4- (4- Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -bu [(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound) 4-oxo-4- produced in Example 1 (lb) [4- (Pyridoridinyl) piperidinyl] butyric acid (763 mg, 3 mmol) was dissolved in N, N-dimethylformamide (10 ml). '18, Crown-6 (793 mg, 3 mmol) was added ) And carbonate shavings (456mg, 1.4mmol). After stirring at room temperature for 1.5 hours, 1-chloroethyl carbonate (1) produced in Example 1 (1a) was added. , 21〇-2-[[trans-2-[(1 £, 3 £) -4, (4-cyano-2-aminophenyl) -1'3-butane-fluoryl] -1'3 -Yishuyuan-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazole-butyl) methyl] propyl ester ( Diastereomer ratio = about 1: 1; 650 mg, 1 mm ο 1), and stirred at room temperature for 40 hours. Under ice-cooling, a phosphate buffer solution was added to the reaction solution, and the resulting product was ethyl acetate Ester extraction 3 times. The organic layer was combined, washed with water (20 m 1 X 3), saturated brine (30 m 1 X 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title. Compound: The obtained crude title compound was subjected to cyclic separation by HPLC [LC-908; manufactured by Japan Analytical Industries; GPC columns JAIGEL-1H (20mm idx600mm) and JAIGEL-2H (20mm idx600mm) were used in series; a solvent, Chloroform] was purified to obtain the title object compound (356.1 mg, yield 41%) as a pale yellow amorphous solid (diastereomeric ratio = about 1: 1). IR (CHC13) z ^ max 2233, 1765, 164, 1505, 1276, 11411, 1055cm · 1; hNMR (CDC13, 400MHz): 61.36 (3H, dd, J = 7; 2Hz), 1.54 (3Hx (1 / 2), like 200410948 d, J = ca. 5Hz), 1.55 (3Hx (1/2), like d, J = ca. 5Hz), 1.5-1.9 (8H, m), 2.5-2.75 (1 OH, m), 2.99-3.13 (2H, m), 3.48 (lHx (1/2), t, 11Hz), 3.49 (lHx (1/2), t, J = 11Hz), 3.49 (lHx ( 1/2), t, J = 11Hz, overlap): 3.50 (lHx (1/2), t, J = 11Hz), 3.79-3.92 (2H, n) '4.18 (1H, ddd, J = ll, 5 , 2Hz), 4.44-4.54 (1H, m), 4.97 (lHx (1/2), d, J = 4Hz) '4.98 (lHx (1/2)' d 'J = 4Hz), 5.34 (lHx (1 / 2), br d 'J = 15Hz), 5.37 (1H, s), 5.45 (lHx (1/2), dd, J = 15, 5Hz), 5.86 (1H, dd, J = 15, 4Hz), 6.58 (1H, dd, J = 15, 11Hz), 6.74 (1H, d, J = 16Hz), 6.72-6.76 (lHx (1/2), m), 6.81 (lHx (1/2), q , J = 5Hz), 6.84-6.95 (2H, m), 6.93 (1H, dd, 16, 11Hz), 7.33 (1H, dd, J = 10, 1Hz), 7.40 (1H, dd, J = 8 , 1Hz), 7.43 (1H, td, J = 9, 6Hz), 7.57 (1H, t, J = 8Hz) '7.91 (lHx (1/2), s), 7.95 (lHx (1/2), s), 8.02 (lHx (1/2), like d), 8.19 &amp; 8.24 (lHx (1 / 2) All, relative strength 2: 1: 1, each s); MS (FAB) m / z: 8 67 ((M + H) +). The title compound (diastereomeric ratio = about 1: 1; 3 3 3.1 mg, 0.3 8 mmol) prepared above was dissolved in dichloromethane (10 ml), and under ice cooling, hydrogen chloride (4N acetic acid) was added. Ethyl acetate solution; 96.1 // 1, 0.3 8 mm ο 1), and stirred at the same temperature for 5 minutes. The solvent was distilled off under reduced pressure to obtain 1 hydrochloride salt of the title object compound (3 3 9.6 mg, yield 98%) as a pale yellow amorphous solid (diastereomer ratio = about 1: 1). IR (KBr) vmax 2230, 1765, 1648, 1504, 1275, 1141, 1056, 973cm · 1; iHNMR (DMSO-d6 '400MHz): δΐ.25 (3Hx (1/2), dd, J = 7, 2Hz ), 1.27 (3Hx (1/2), 10dd, J = 7, 2Hz), 1.45 (3Hx (1/2), d, J = 5Hz), 1.49 (3Hx (1/2), d, J = 5Hz ), 1.3-1.5 (2H, m), 1.8-2.1 (6H, m), 2.45-2 · 67 (7H, m), 2.85-3.07 (4H, m), 3.4-3.5 (1H, m) , 3.42 (lHx (1/2), t, J = llHz), 3.44 (lHx (1/2), t, J = llHz), 3.44 (lHx (1/2), t, J = llHz, overlap) , 3.46 (1Ηχ (1/2), t, J = llHz), 3.56 (lHx (1/2), 200410948 q, J = 7Hz), 3.74 (ΙΗχ (1/2), brq, J = 7Hz), 3.96-4.06 (2H, m), 4.08-4.14 (1H, m) '4.4-4.5 (1H, m)' 5.03 (lHx (1/2) 'd' J = 4Hz) '5.04 (lHx (1/2), d, J = 4Hz), 5.24 (lHx (1/2), d, J-16Hz), 5.28 (lHx (1/2), d, J = 16Hz), 5.43 (lHx (1 / 2), d, J = 14Hz), 5.46 (lHx (1/2), d, J = 14Hz), 5.88 (lHx (1/2), dd, J = 16, 4Hz), 5.89 (lHx (1 / 2), dd, J = 16, 4Hz), 6.55-6.62 (lHx (1/2), m), 6.57 (1H, dd, J = 16, 11Hz), 6.68 (lHx (1/2) q, J = 5Hz), 6.83 (1H, d, J = 16Hz), 7.15-7.20 (1H, m), 7.19 (1H, dd, J = 16, 11Hz), 7.31-7.38 (1H, m) = 7.42-7.51 (1H, m), 7.68 (1H, dd, J = 8, 2Hz), 7.85 (1H, dd, J = 10, 2Hz), 7.87 (1Η, t, J = 8Hz), 8.06 (lHx (l / 2), s), 8.06 (lHx (1/2), s, overlap), 8.36 (lHx (1/2), like d), 8.48 (lHx (1/2) , S); MS (FAB) m / z: 867 ((non-hydrochloric acid portion + H) +). Example 2 4 -Oxygen 4- (4- Warm B-Ding and D-Dingyl) Butyric Acid 1-[[((1R, 2R) -2-[[Trans-2-[(1E, 3E) -4- ( 4-cyano-2-fluorophenyl) -1,3-butadienyl] -1., 3-dioxan-5-yl] thio] -1-(2,4-difluorophenyl ) -1-[(1 Η -1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound 1-1 1 2) (2a) 4-oxo 4- (4-piperidinopiperidinyl) butyric acid 4-Piperidine and piperidinyl (3.70 g, 22.0 mmol) were dissolved in dichloromethane (10 ml), and succinic anhydride (2.16 g, 21.6mm〇l), and stirred at room temperature for 3.5 hours. The solvent was distilled off under reduced pressure to obtain a crude title compound (5.88 g, quantitative yield) as a light brown amorphous solid. HNMR (CDC13, 400MHz): 51.20 (1H, qd, J = 12, 3Hz), 1.32-1.41 (3H, m), 1.41-1.50 (4H, m), 1.72 (2H, brt, J = 13Hz), 2.37-2.53 (9H, m), 2.94 (1H, brt, J = 13Hz), 3.88 (1H, dd, J = 13, 2Hz), 4.37 (lHbrd, J = 13Hz); 200410948 MS (EI) m / z : 254 (M +). (2 b) 4-oxo-4-(4-piperidinopiperidinyl) butanoic acid 1-[[(1 R, 2 R) -2-[[trans-2-[(IE, 3E) -4 -(4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] (2,4-difluorophenyl)- 1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound) 4-Oxide produced in Example 2 (2a)- 4- (4-piperidinopiperidinyl) butyric acid (805 mg, 3 mmol) was dissolved in N, N-dimethylformamide (10 ml), and 1 8-crown-6 (7 9 3 mg , 3 mmol) and carbonate shavings (4 5 6 mg, 1.4 mmol). After stirring at room temperature for 1.5 hours, 1-chloroethyl carbonate (1R, 2R) produced in Example 1 (1a) was added. 2-[[Trans- 2-[(1E, 3E) -0 (4- Cyano-2 -fluorophenyl) -1,3-butadienyl] · 1,3-dioxane-5 -yl] thio] -1- (2,4-difluorophenyl) .- 1-[(1H-1,2,4-triazol-1-yl) methyl] propyl ester (diastereomeric ratio = about 1: 1; 650 mg, 1 mmol), stirred at room temperature for 2 0 hours. Under ice cooling, a phosphate buffer solution was added to the reaction solution, and the resultant was extracted three times with ethyl acetate. The organic layer was combined, washed with water (20m 1x3), saturated brine (3 Om 1 X 1), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude title compound. The obtained crude title compound was subjected to cyclic separation by HPLC [LC-9 0 8; manufactured by Japan Analytical Industries; GPC column JAIGEL-1H (20mm idx600mm) and JAIGEL-2H (20mm idx600mm) were used in series; solvent, chloroform] Purification gave the title object compound (330 mg, 36% yield, 38%) as a pale yellow amorphous solid (diastereomeric ratio = about 1: 1). IR (CHCh) ^ Sa 2233, 1765, 1640, 1505, 1276, 1141, 1055, 974cm · 1; -262- 200410948 bNMR (CDC13, 400MHz): ά 1.36 (3H, dd, J = 7, 2Hz), 1 · 54 (3Hx (1/2), d, J = 5Hz), 1.55 (3Hx (1/2), d, J = 5Hz), 1.4-1.7 (10H, m), 2.45-2.75 (10H, m) , 2.97-3.06 (2H, m), 3.45 (IHx (1/2), t, J = llHz), 3.46 (lHx (1/2), t, J = llHz), 3.46 (lHx (1/2) , T, J = llHz, overlap), 3.47 (lx (1/2), t, J = llHz), 3.9-4.0 (2H, m), 4.15-4.21 (1H, m), 4.26-4.33 (1H, m), 4.60 (1H, brd, J = 14Hz), 4.98 (1H, d, J = 4Hz), 5.32 (lHx (1/2), d, J = 15Hz), 5.37 (1H, s), 5.45 ( lHx (1/2), dd, J = 15, 3Hz), 5.86 (1H, dd, J = 16, 4Hz), 6.58 (1H, dd, J = 16, 11Hz), 6.74 (lHx (1 / 2), qd, J = 5, 2 Hz), 6.74 (1H, d, J = 16 Hz, overlapping), 6, 81 (lHx (1/2), q, J = 5 Hz), 6.84-6 · 94 (2H, m), 6.93 (1H, dd, J = 16, 11Hz), 7.33 (1H, dd, J = 10, 1Hz), 7.40 (1H, dd, J = 8, 1Hz), 7.38-7.46 (1H, m), 7.57 (1H, t, J = 8Hz), 7.91 (lHx (1/2), s). 7.95 (IHx (1/2), s), 8.02 (lHx (1/2), s), 8.21 &amp; 8.25 (lHx (1/2) all, relative intensity = 1: 1, each s); MS (FAB) m / z: 881 ((M + H) +). The title compound of interest (diastereomeric ratio = about 1: 1; 321-4 mg, 0.36 mmol) prepared above was dissolved in dichloromethane (10 ml), and under ice cooling, hydrogen chloride (4N ethyl acetate solution; 87 // 1, 0.3 5 mmol), and stirred at the same temperature for 5 minutes. The solvent was distilled off under reduced pressure to obtain the title object compound 1 hydrochloride (322.2 mg, yield 96%) as a pale yellow amorphous solid (diastereomer ratio = about 1: 1). IR (KBr)]; max 2230, 1765, 1504, 1275, 1141, 1060, 973 cnf1;

bNMR (DMSO-d6, 400MHz): 5 1.25 (3Hx (1/2), dd, J = 7, 2Hz), 1.27 (3Hx (1/2), dd, J = 7, 2Hz), 1.3-1.8 ( 10H, m), 1.45 (3Hx (1/2), d, J = 5Hz), 1.48 (3H x (1/2), d, J = 5Hz), 2.3-2.7 (8H, m), 2.85-3.05 (4H, m), 3.41 (IHx (1/2), t, J = llHz), 3.43 (IHx (1/2), t, J = 13Hz), 3.44 (IHx (1/2), t, J = llHz), 3.46 (1H -263-200410948 x (1/2), t, J = llHz), 3.57 (ΙΗχ (1/2), q, J = 7Hz), 3.72-3.76 (ΙΗχ (1/2 ), M), 4.02-4.07 (2H, m), 4.08-4.13 (1H, n), 4.4-4.5 (1H, m), 5.03 (lHx (1/2), d, J = 4Hz), 5.04 ( lHx (1/2), d, J = 4Hz), 5.24 (lHx (1/2), d, 15Hz), 5.28 (lHx (1/2), d, J = 15Hz), 5.43 ( lHx (1/2), d, J = 13Hz), 5.46 (lHx (1/2), d, J = 13Hz), 5.88 (lHx (1/2), dd, J = 16, 4Hz), 5.89 ( lHx (1/2), dd, J = 16, 4Hz), 6.57 (lHx (1/2), dd, J = 16, llHz), 6.58 (lHx (1/2), dd, J = 16, 11Hz ), 6.56-6.64 (lHx (1/2), m), 6.68 (lHx (1/2), q, J-2 5Hz), 6.82 (1H, d, J-2 16Hz), 7.12-7.20 (1H, m ), 7.19 (1H, dd, 16.11Hz), 7.31- 7.37 (1H, m), 7.42-7.51 (1H, m), 7.68 (1H, dd, J = 8, 1Hz), 7.85 (1H, dd, J = 11, 1Hz), 7.87 (1H, t, J = 8Hz), 8.06 (lHx (1/2), s), 8.06 (1H x (1/2), s, overlap), 8.35 & 8.36 (lHx (1/2) all, relative intensity = 1: 1. Each is s), 8.48 Lu (IΗχ (1/2), s); MS (FAB) m / z: 881 ((non-hydrochloric acid portion + H) +). Example 3 4- [4- (Dimethylamino) piperidinyl] -4-oxobutanoic acid 1-[[(111,21〇-2-[[trans-2-[(IE, 3E) -4 -(4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-difluorenylfalkyl-5-yl] thio] -1- (2,4-difluoro Phenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound 1-Π 8) · (3a) 4- (Dimethylamino) -1- (third-butoxycarbonyl) piperidine 1- (third-butoxycarbonyl) _4-piperidone (J. Med. Chem., 35, p. 4118 (1992) Record; 6.33g, 32mmol) was dissolved in ethanol (100ml), dimethylamine hydrochloride (12.95g, 159mmol) and molecular sieve 3 A (5g) were added, and stirred at room temperature for 1.5 hours. Sodium cyanoborohydride was added. (2.07g, 3 3 mmol), and stirred at room temperature for 1 hour. At room temperature, the insoluble matter was filtered through diatomaceous earth, and the solid matter was washed with ethanol. He-264- 200410948 倂 filtrate and washing solution, concentrated under reduced pressure, the resulting residue The layers were separated in water and ether. The organic layer was combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude title compound. The obtained crude title compound was purified by silica gel column chromatography (methanol: ethyl acetate, 10: 90- 50:50, V / V, 60 g of silica gel) to obtain the title compound (2.3 8 g, yield 3). 2%) colorless oily substance. IR (CHC13) ^ sink 1682, 1428, 1367, 1247, 1161cm.1; WNMR (CDC13, 400MHz): 1.37 (2H, qd, J = 12, 4Ηζ), 1 46 (9H, s), 1.79 (2H, d, J = 12Hz), 2.2-2.3 (1H, n), 2.28 (6H, s), 2.71 (2H, brt, J = 12Hz), 4.08 -4.18 ( 2H, br); your MS (FAB) m / z: 229 ((M + H) +). (3b) 4- [4- (dimethylamino) piperidinyl] -4-oxobutanoic acid ethyl ester 4- (dimethylamino) -1- (third butoxycarbonyl) piperidine (1.55 3 g, 6.8 mmol) produced in Example 3 (3a) was dissolved in dichloromethane (10 ml) Under ice cooling, trifluoroacetic acid (10 m 1) was added. After the mixture was stirred at room temperature for 15 minutes, the solvent was distilled off under reduced pressure, toluene was added and the solvent was distilled off twice to obtain crude 4- (dimethylamine). Trifluoroacetic acid salt of piperidine. The crude 4- (dimethylamino) piperidine trifluoroacetate salt prepared above was dissolved in dichloromethane (20 m 1). Amine (3.4 4 g, 3 4 m m ο 1) and 4-chloro-4-oxobutyrate (i.ii9g, 6.8mm〇l), stirred at room temperature for 2.5 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the product was extracted with dichloromethane. The organic layer was combined, washed with saturated brine, and the solvent was evaporated under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (methanol: acetic acid-265-200410948 ethyl ester, 10: 90-20: 80, V / V, silica gel 50 g) to obtain the title compound (1.01 g , Yield 58%), a colorless oily substance. IR (CHC13) vmax 1727, 1647, 1455, 1377, 1180, 1153cm · 1; bNMR (CDC13, 400MHz): (5 1.27 (3H, t, J = 7Hz), 1.45 (1H, qd, J = 12, 4Hz ) '1.54 (1H, qd, J = 12, 4Hz), 1.92 (1H, brd, J = 13Hz), 2.01 (1H, brd, J = 12Hz), 2.48 (6H, s), 2.56-2.69 ( 6H, n), 3.06 (1H, br t, J = 12Hz), 4.00 (1H, br d, J = 13Hz), 4.15 (2H, q, J = 7Hz), 4.71 (1H, brd, J = 13Hz) MS (El) m / z: 256 (M +). (3c) 4- [4- (dimethylamino) piperidinyl] -4-oxobutanoic acid 1-[[(1R, 2R) -2- [[Trans-2-[(IE, 3E) -4- (4-amino-2-aminobenzyl) -1 '3-butanyl]]-1' 3 · 一 ^ 聘 院 -5-yl] Thio] -1- (2 '4 -monophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester ( The title object compound) Ethyl 4- [4- (dimethylamino) piperidinyl] -4-oxobutanoate (1 · 0 1 g, 3 · 9 4 mm) manufactured in Example 3 (3b) 1 ) Dissolved in water (3 5 m 1), carbonic acid shaver (609.8 mg, 1.87 mmol) was added, and after stirring at 70 ° C for 8 hours, the solvent was distilled off under reduced pressure to obtain crude 4- 4- (dimethylamino) piperidinyl] -4-oxobutyric acid. The crude 4- [4- (dimethylamino) piperidinyl] -4-oxobutyric acid prepared in the above was dissolved in N , N-dimethylformamide (30 m 1), added to the dichloroethyl carbonate (1R, 2R) produced in Example 1 (1 a) -2-[[Trans- 2-[(1E, 3E ) -4- (4 · cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-difluorenf-alkyl-5-yl] thio] -1- (2,4 -Difluorophenyl) 2,4-triazole-1 -yl) methyl] propyl ester (diastereomer ratio = about 1: 1; 1 · 1 2 g, 1 · 7 3 mm ο 1) And stirred at 40 ° C for 20 hours. -266- 200410948 Under ice cooling, a phosphate buffer was added to the reaction solution, and the resultant was extracted three times with ethyl acetate. The organic layer was combined, washed with water (30 m 1 X 3), saturated brine (50 m 1 X 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (methanol: ethyl acetate, 5: 95-20: 80, V / V, silica gel 25 g) to obtain the title target compound (58 1.1 mg, product Yield 36%), brown amorphous solid (diastereomer ratio = about 1: 1). IR (KBr) ^ max2230, 1765, 1720, 1644, 1504, 1275, 1142, 1058 cm · 1;! HNMR (CDC13, 400MHz): (51.36 (3H, dd, J = 7, 2Hz), 1.30-1.49 ( 2H, m), ^ 1.54 (3Hx (1/2), d, J = 5Hz), 1.55 (3Hx (1/2), d, J = 5Hz), 1.81-1.90 (2H, m), 2.28 (6Hx (1/2), s), 2.28 (6Hx (1/2), s, overlap), 2.54-2.77 (6H, m), 2.98-3.19 (2H, m), 3.48 (lHx (1/2 ), T, J = llHz), 3.49 (lHx (1/2), t, J ^ llHz), 3.49 (lHx (1/2), t, J = llHz, overlap), 3.50 (lHx (1/2 ), T, J = llHz), 3.80- 3.97 (2H, m), 4.14 (1H x (1/2), ddd ,, 5, 2Hz), 4.17 (lHx (1/2), ddd, J = n , 5, 2Hz), 4.25-4.33 (1H, m), 4.57 (1H, brd, J = 13Hz), 4.98 (1H, d, J = 4Hz), 5.32 (lHx (1/2), d, J 15Hz), 5.37 (1H, s), 5.45 (lHx (1/2), dd, J = 15, 4Hz), 5.85 (1H, dd, J = 16, 4Hz), 6.58 (1H, dd, 16, 11Hz ), 6.73 (lHx (1/2), qd, J = 5, 2Hz), 6.74 (1H, · d, J = 16Hz), 6.81 (lHx (1/2), q, J = 5Hz), 6.84-6.95 (2H, m), 6.93 (1H, dd, J = 16, 11Hz), 7.33 (1H, dd, J = 10, 1Hz), 7,40 (1H, dd, J = 8, 1Hz), 7.43 (1H, td, J = 9, 6Hz), 7.57 (1H, t, J = 8Hz), 7.91 (lHx (1/2), s), 7.95 (lHx (1/2), s). 8.02 &amp; 8.03 (all lHx (1/2), relative intensity = 1: 1, each for s)), 8.21 &amp; 8 · 26 (lHx (1/2) all, relative intensity = 1: 1, each s)); MS (FAB) m / z: 841 ((M + H) +). The title compound (diastereomer ratio = about 1: 1, · -267- 200410948, 470 mg, 0.56 mmol) produced in the above was dissolved in dichloromethane (10 ml), and under ice cooling, hydrogen chloride ( 4N ethyl acetate solution; 140 # 1, 0.56 mmol), and stirred at the same temperature for 5 minutes. The solvent was distilled off under reduced pressure to obtain the title object compound 1 hydrochloride (466 mg 'yield 95%) as a pale yellow amorphous solid (diastereomer ratio = about 1: 1). IR (CHC13) hiax2230, 1765, 1646, 1504 ′ 1275, 1142, 1055cm.];

NMR (DMSO-d6, 400MHz): 61 · 24 (3Hx (1/2), dd, J = 7, 2Hz), 1.27 (3Hx (1/2), dd, J = 7, 2Hz), 1.2-1.36 (2H, m); 1.45 (3Hx (1/2), d, J = 5Hz), 1.48 (3H x (1/2), d, J = 5Hz), 1.84-2.00 (2H, m), 2.5 · 2 · 7 (5H, m), 2.90 (lHx (1/2), tt,, 5Hz), 2.91 (lHx (1/2), tt, J = 11, 5Hz), 3.00 (2H, brt, J = 12Hz), 3.26-3.35 (2H, m), 3.41 (lHx (1/2), t, J = llHz), 3.42 (lHx (1/2), t, J = llHz), 3.44 (1H x (1/2), t, J = llHz), 3.44 (lHx (1/2), t, J = ll, overlap), 3.57 (lHx (1/2), q, J = 7Hz), 3.72-3.78 (lHx (1/2), m), 3.95-4.06 (2H, m), 4.07-4.14 (1H, m), 4.43 (1H, brd, J = 12Hz), 5.03 (lHx (l / 2) , D, J = 4Hz), 5.04 (lHx (1/2), d, J = 4Hz),

5.24 (lHx (1/2), d, J = 15Hz), 5.28 (lHx (1/2), d, J = 15Hz), 5.44 (lHx (1/2), d, J = 15Hz), 5.46 ( lHx (1/2), d, J = 15Hz), 5.88 (lHx (1/2), dd, J = 16, 4Hz), 5.89 (lHx (1/2), dd, J = 16, 4Hz), 6.57 (1H, dd, J = 16, 11Hz), 6.56-6.63 (lHx (1/2), m), 6.68 (lHx (1/2), q, J = 5Hz), 6.82 (1H, d , J = 16Hz), 7.14-7.20 (1H, m), 7.19 (1H, dd, J = 16, 11Hz), 7.31-7.37 (1H, m), 7.42-7.51 (1H, m), 7 · 68 (1H, dd, J = 8, 1Hz), 7.85 (1H, dd, J = 10, 1Hz), 7.87 (1H, t, J = 8Hz), 8.06 (1H, s), 8.35 &amp; 8.37 (lHx (1/2) all, relative strength = 1: 1, s), 8.48 (lHx (1/2), s); MS (FAB) m / z: 841 ((non-hydrochloric acid Each part is + H) +). Example 4 4- [4- (Methylamino) piperidinyl] -4 -oxobutanoic acid 1-[[(1R, 2R) -2-[[trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1, · 3-butadiene-268-200410948 group] -1,3-difluorenylfalkyl-5-yl] thio]-; ι_ (2, 4-difluorophenyl) -1-[(1H-1,2 '4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-11 7) (4a ) 4- [N- (allyloxycarbonyl) -N-methylamino]-丨 _ (third butoxycarbonyl) piperidine will be 1- (didioxoyl) -4- (methylamino) Piperidine (J. Med. Chem., 42 巻, page 6 93 (1999); 9.0 g, 42 mmol) was dissolved in water (100 ml) and ice-cooled, and acetic acid (5.46 g, 45.3) was added. mmol), and 4- (dimethylamino) pyridine (5.5 4 g, 4 5 · 3 mm ο 1), and stirred at room temperature for 30 minutes. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added, and the resultant was extracted with ethyl acetate (80 m 1 X 3). The organic layer was combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 80: 20-50: 50, V / V, silica gel 50g) to obtain the title compound (7.3 g, yield 58%) ) Colorless oily substance. IR (CHC13) max 1683, 1428, 1317, 1156, 1013cm · 1;! HNMR (CDC13, 400MHz): ά 1.46 (9H, s), 1.58-1 · 66 (4H, br), 2.7-2.82 ( 3H, br), 2.79 (3H, s), 4.14-4.25 (2H, br), 4.60 (2H, d, J = 5Hz), 5.21 (1H, dd, J = 10, 1Hz), 5.30 (1H , D, J = 17Hz), 5.95 (1H, ddt, J = 17, 10, 5Hz); MS (FAB) m / z: 299 ((M + H) +). (4b) 4- [N- (allyloxycarbonyl) -N-methylamino] piperidine [N- (allyloxycarbonyl) -N-methylamino] -1 produced in Example 4 (4a) -(Third butoxycarbonyl) piperidine (2.6 g, 8.7 mmol) was dissolved in ethyl-269-200410948 ethyl acetate (5 m 1), and hydrogen chloride (4N ethyl acetate solution; 10 m) was added at 0 ° C. 1), the mixture was stirred at room temperature for 30 minutes. After the solution of the mixture diluted with water was washed twice with ethyl acetate, sodium bicarbonate was added thereto, and the resultant was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.9 1 g, yield 53%) as a light brown oily substance. IR (CHC13) u orbital 1686, 145, 1410, 1319, 1165cm1;] HNMR (CDC13, 400MHz): 5 1.59-1.72 (4H, m), 2.6-2.8 (1H, br), 2.69 (2H, brt , J = 12Hz), 2.82 (3H, s), 3.14 (2H, brd, J = 12Hz), 4.60 (2H, d, J = 5Hz), 5.21 (1H, d, J = llHz), 5.30 ( 1H, d, J = 17Hz), 5.96 (1H, ddt, J = 17, 11 5Hz); MS (El) m / z: 198 (M +). (4c) 4- [4- [N- (Allyloxycarbonyl) -N-methylamino] piperidinyl] -4-oxobutanoic acid 4- [N- (ene) produced in Example 4 (4b) Propoxycarbonyl) -N-methylamino] pididine (0.90 g, 4.59 mmol) was dissolved in dichloromethane (15 ml). Under ice cooling, succinic anhydride (45 0.3 mg, 4.5 mmol) was added. Stir at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure. The obtained residue was diluted with an aqueous sodium hydrogen carbonate solution, washed twice with ethyl acetate, 2N hydrochloric acid was added, and the resultant was extracted with ethyl acetate. The organic layer was combined, washed with saturated brine, and the solvent was evaporated under reduced pressure to obtain the crude title compound (1.33 g, yield 96%) as a colorless solid.

Mp 85-87〇C IR (CHC13) v orbital 1713,169, 1645,1452,1317,1157,1011cm -1.82 (2H, m), 2.6-2.8 (5H, n), 2.79 (3H, s), 3.13 (2H, brt, J = 13Hz), 3.95 (1H, brd, J = 14Hz), 4. · 61 (2H, 200410948 d, J = 5Hz), 4.74 (1H, br d, J = 11Hz), 5.22 (1H, d, J = 10Hz), 5.30 (1H, d, J = 17Hz), 5.95 (1H, ddt, J 2: 17, 10, 5 Hz); MS (FAB) m / z: 299 ((M + H) +). (4d) 4- [4- [N- (allyloxycarbonyl) -N-methylamino] piperidinyl] -4-oxobutanoic acid l-[[(lR, 2R) -2-[[trans · 2-[(lE, 3E) -4- (4-cyano-2-fluorophenyl) -l, 3-butadienyl] -1,3-diDf alkyl-5-yl] thio]- 1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester Example 4 ( 4c) 4- [4- [N- (allyloxycarbonyl) -N-methylamino] piperidinyl] -4-oxobutanoic acid (1.32 g, 4.4 mmol) was dissolved in N, N-di Methylformamide (iOmi), 18-crown-6 (0.79 g, 3 mmol) and carbonate shavings (0.46 g, 1.5 mmol) were added. After stirring at room temperature for 2 hours, 1-chloroethyl carbonate (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyanocarbonate) produced in Example 1 (la) was added. Phenyl-2-fluorophenyl) -1,3-butadienyl] -1,3-difluorenyl] thio]-丨 _ (2,4-difluorophenyl) (1H-1, 2 '4-Triazole-1 -yl) methyl] propyl ester (diastereomer ratio of about 1: 1; 0-65 g, 1 mmol) was stirred at room temperature for 40 hours. Under ice cooling, a phosphate buffer solution was added to the reaction solution, and the resultant was extracted three times with ethyl acetate. The organic layer was combined, washed with water (20 m 1 X 3), and then with saturated brine (30 melons) χ 1 :), dried under anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. . The obtained crude title compound was purified by silica gel column chromatography (hexane · ethyl acetate, 25: 75-10: 90, V / V, silica gel 25 g) to obtain the title compound (0.56 g, yield 44%) as colorless. Amorphous solid (diastereoisomer ratio = about 1: 1) 〇200410948 IR (KBr) ymax 2230, 1765, 1700, 1644, 1504, 1275, 1143 cm · 1;! HNMR (CDC13, 400MHz) ·· 51.36 (3H, dd, J = 7, 2Hz), 1.54 (3Hx (1/2), d, J = 5Hz), 1.56 (3Hx (1/2), d, J = 5Hz), 1.5-1.8 (4H , M), 2.54 · 2 · 76 (5H, m), 2.77 (3H, s), 3.10-3.15 (3H, m), 3.48 (lHx (1/2), t, J = 11H), 3.49 (lHx (1/2), t, J = llHz), 3.49 (lHx (1/2), t, J = llHz 'overlap), 3.50 (lHx (1/2), t, J = llHz), 3.83 (lHx (1/2), q, J = 7Hz), 3.88 (lHx (1/2), q, J = 7Hz), 3.91-4 · 04 (1H, m), 4.15-4 · 20 (1H, m), 4.28 (lHx (1/2), ddd, J = U, 5, 2Hz), 4.29 (lHx (1/2), ddd, J = ll,

5, 2Hz), 4.60 (2H, d, J = 5Hz), 4.70 (1H, brd, J = 13Hz), 4.98 (1H, d, J = 4Hz), 5.22 (1H, d, J = 10Hz), 5.30 (1H, br d, J = 17Hz), 5.31 (lHx (1/2), dd, J = 15, 4Hz), 5.37 (1H, s), 5.45 (lHx (1/2), d , J = 15Hz), 5.85 (1H, dd, J = 16, 4Hz), 5.95 (1H, ddt, J = 17, U, 5Hz), 6.58 (lHx (1/2), dd, J = 16, 11Hz ), 6.58 (lHx (1/2), dd, J = 16, 11Hz, overlap), 6.74 (lHx (1/2), q, J = 6Hz), 6.74 (1H, d, J = 16Hz, overlap) , 6.81 (lHx (1/2), q, J = 6Hz), 6.85-6.95 (2H, m), 6.93 (1H, dd, J = 16, 11Hz), 7.33 (1H, dd, J = 10, lHz ), 7.40 (1H, dd, J = 7, 1Hz), 7.38-7 · 46 (1H, m), 7.57 (1H, t, J = 8Hz), 7.90 (lHx (1/2), s) , 7.95 (lHx (1/2), s), 8.02 (lHx (l / 2), s), 8.24 &amp; 8.25 (lHx (l / 2) all, relative strength = 1: 1, each s); MS (FAB) m / z: 939 ((M + H) +). (4e) 4- [4- (methylamino) piperidinyl] · 4-oxobutanoic acid 1-[[(1R, 2R) -2-[[trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5yl] thio] -1- (2,4-difluorophenyl )-L-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound) 4- prepared in Example 4 (4d) [4- [N- (allyloxycarbonyl) -N-methylamino] piperidinyl] -4-oxobutanoic acid 1-[[(1R, 2R) -2-[[trans-2- [(IE , 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1, -272- 200410948 3-dioxan-5-yl] thio] -1 -(2, 4-difluorophenyl) -l-[(1H-1, .2,4 · triazole-1 -yl) methyl] propoxy] carbonyloxy] ethyl ester (diastereomers Structure ratio = about 1: 1: 0.55 g, 0.60 mm ο 1) dissolved in dichloromethane (15 m 1), and under ice cooling, bis (triphenylphosphine) dichloropalladium was added (21.2 mg, 0.03 mmol) and tributyltin hydride (175.7 mg, 0.79 mmol), and stirred at room temperature under nitrogen for 20 minutes.

The reaction solution was purified by silica gel column chromatography (ethyl acetate-methanol, 100: 0-7 5 · 25, V / V, and silica gel 20 g) to obtain the title object compound (2 97.2 mg, yield 60%). ) Pale yellow amorphous solid (diastereomeric ratio = about 1: 1). IR (KBr) 2; max 2230, 1765, 1643, 1504, 1275, 1141 cm.1;! HNMR (CDC13, 400MHz): (51.16-1.30 (2H, m), 1.36 (3H, dd, J = 7, 2Hz), 1.54 (3Hx (1/2), d, J = 6Hz), 1.55 (3Hx (1/2), d, J = 6Hz), 1.86-1.97 (2H, m), 2.44 ( 3H, s), 2.6-2.8 (6H, m), 3.0-3.15 (2H, m), 3.49 (lHx (1/2), t, J = llHz),

13.50 (lHx (1/2), J = llHz), 3.50 (lHx (1/2), t, J = llHz, overlap), 3.51 (lHx (1/2), t, J = 11Hz), 3.82 -3.91 (2H, m), 4.18 (1H, ddd, J = ll, 5, 2Hz), 4.28 (1H x (1/2), ddd, J = ll, 5, 2Hz), 4.30 (lHx (1 / 2), ddd, J = 1I, 5, 2Hz), 4.41 (1H,

brd, J = 13Hz), 4.97 (1H, d, J = 4Hz), 5.32 (lHx (1/2), d, J = 15Hz), 5.37 (lH.s), 5.43 (lHx (1/2), dd, J = 15, 4Hz), 5.85 (1H, dd, J = 16, 4Hz), 6.58 (1H, dd, J = 16, 11Hz), 6.73 (lHx (1/2), q, J = 5Hz), 6.74 (1H, d, J = 16Hz), 6.80 (lHx (1/2), q 'J = 5Hz), 6.84-6.92 (2H, m), 6.93 (1H, dd, J = 16 , 11Hz), 7.33 (1H, dd, J = 10, 1Hz), 7.40 (1H, dd, J = 8, 1Hz), 7.37-7.44 (1H, m), 7.57 (1H, t, J = 8Hz ), 7.91 (lHx (1/2), s), 7.95 (lHx (1/2), like d), 8.02 (lHx (1/2), s), 8.21 &amp; 8.25 (1H x (1/2) ) All, relative strength = 1: 1, each s); MS (FAB) m / z827 (M + 1) + 〇 will be the above titled target compound (diastereomeric ratio = about 1 ··-- 273-200410948 1; 2 8 8 · 2 mg, 0 · 3 5 mm ο 1) dissolved in dichloromethane (5 m 1), and under ice cooling, add hydrogen chloride (4N ethyl acetate solution; 87 // 1 , 0.3 5 mmol), and stirred at the same temperature for 5 minutes. The solvent was distilled off under reduced pressure to obtain the title object compound 1 hydrochloride (290 mg, yield 96%) as a pale yellow amorphous solid (diastereomer ratio = about 1: 1). IR (KBr) max 2231, 1765, 1646, 1616, 1504, 1275, 114, 1055, 974 cnf1;

々NMR (CDC13, 400MHz): (5 1 · 36 (3H, dd, J = 7, 2Hz), 1.54 (3Hx (1/2), d, J = 5Hz), 1.57 (3Hx (1/2 ), D, J = 5Hz), 1.6-1.8 (2H, m), 2.1-2.25 (2H, m), 2.6 (3H, s), 2.6-2.8 (6H, m), 3.0-3.15 (2H, m ), 3.49 (lHx (1/2), t, J = llHz), 3.50 (lHx (1/2), t, J = llHz), 3.51 (lHx (1/2), t, J = llHz), 3.51 (lHx (1/2), t, J = llHz, overlap), 3.8-3.9 (lHx (1/2), m), 3.89 (lHx (1/2), q, J = 7Hz), 3.95 4.05 (1H, m), 4.18 (1H, ddd, J = ll, 5, 2Hz), 4.25-4.35 (1H, m), 4.63 (1H, brd, J = 13Hz), 4.98 (lHx (1 / 2), d, J = 4Hz), 4.99 (lHx (1/2), d, J = 4Hz), 5.3-5.4 (2H, m), 5.85 (1H, dd, J = 16, 4Hz), 6.58 ( 1H, dd, J = 16, 11Hz), 6.71-6.79 (1H, m), 6.75 (1H, d, J = 10Hz), 6.84-6.94 (2H, m), 6.94 (1H, dd, J = 16, 11Hz), 7.33 (1H, dd, 10, 1Hz), 7.40 (1H, dd, J = 8, 1Hz), 7.37-7.43 (1H, m), 7.57 (1H, t, J = 8Hz) , 7.92 (lHx (1/2), s), 7.95 (lHx (1/2), like d), 8.02 (lHx (1/2), s), 8.21 &amp; 8.26 (lHx (1/2) all ,relatively Intensity = 1: i, each s); MS (FAB) m / z ·· 827 ((M + H) +). Example 5 4-[4-[2-(methylamino) ethyl] piperazine Pyridyl] -4-oxobutanoic acid 丨-[[(; [r, 21〇-2-[[trans-2-[(: ^, 3 £) -4- (4-cyano-2-fluorobenzene Group) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1 ' 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound 1-1 2 8 5)-274-200410948 (5a) l- (second butoxy group ) -4- [2- (mesylateoxy) ethyl] piperidine 1- (third butoxycarbonyl) -4- (2-hydroxyethyl) piperidine (6.14 g '26.8 mmol) Dichloromethane (80 m 1), under ice-cooling, add diethylamine (2.71g, 26.8mmol), 4- (dimethylamino) pyridine Bidine (327.4mg '2.6 8mmol), and methanesulfonate醯 Chlorine (3 · 37 g, 2 9.5 mm ο 1), and stirred at the same temperature for 1 hour.

The reaction solution was diluted with dichloromethane, and the organic layer was washed with a saturated ammonium chloride aqueous solution 'and then with a saturated saline solution. The organic layer was dried under anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain a crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 50:50, V / V, silica gel 150 g) to obtain the title compound (6.80 g, yield 8). 3%), colorless solid.

Mp 80-82 ° C; iHNMR (CDC13, 400MHz): c5 1.12-1.16 (2H, m), 1.56 (9H, s), 1.61-1.73 (5H, m), 2.70 (2H, br t, J = 12Hz ), 3.01 (3H, s), 4.05-4.15 (2H, br), 4.29 (2H, t, J = 6Hz),

(5b) 1- (Third butoxycarbonyl) -4- [2- [N- (allyloxycarbonyl) -N-methylamino] ethyl] piperidine N- (allyloxycarbonyl) methylamine (Angew · Chem ·, 93 巻, 115 pages (1981); 1.266g, 11mmol) was dissolved in N, N-dimethylformamide (30ml), and sodium hydride (dispersed in 55% mineral oil; 0.48) g, 11 mmol), and stirred at room temperature for 1 hour. Introduce 1- (third butoxycarbonyl) -4 · [2- (methanesulfonyloxy) ethyl] piperidine (3.07 g, 10 mmol) produced in Example 5 (5a) at 70 ° C. Stir for 1 hour. -275-200410948 Water was added to the reaction solution at room temperature, and the product was washed with ethyl acetate. The organic layer was combined, washed with water (3 times) and then with saturated brine (1 time), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 67:33, V / V, silica gel 75 g) to obtain the title compound (3.19 g, yield 98%), as a colorless oil. Like substance. IR (CHC13) 1686, 1428, 1279, 1248, 1158 cm · 1;

hNMR (CDC13, 400MHz): 1.12 (2H, qd, J = 12, 4Hz), 1.45 (9H, s), 1.35-1.7 (5H, m), 2.67 (2H, brt, J = 12Hz), 2.90 ( 3H, s), 3.31 (2H, brt, J = 7Hz), 4.03-4.11 (2H, br), 4.58 (2H, d, J = 5HZ), 5.20 (1H, dd, J = 10, 1Hz), 5.29 (1H, dd, J = 17.2 Hz), 5.93 (1H, ddt, J = 17, 11, 5 Hz); MS (FAB) m / z · 327 ((M + H) +) 〇 (5c) 4- [2- [N- (Allyloxycarbonyl) -N-methylamino] ethyl] piperidine 1- (Third-butoxycarbonyl) -4-[2 · produced in Example 5 (5b) [N- (allyloxycarbonyl) -N-methylamino] ethyl] piperidine (3.15 g, 9.1 mmol) was dissolved in dichloromethane (5 m 1), and under ice cooling, trifluoroacetic acid (5 .m 1), and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and water (30 ml) was added to the obtained residue. Sodium bicarbonate was added, and the resultant was extracted with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude title compound (2.7 1 g, quantitative yield) as a light brown oily substance. IR (CHC13) 2; surface 1686, 1406, 1248, 1180, 1141 cm · 1;! HNMR (CDC13, 400MHz): (5 1.45-1.53 (5H, br), 1.83-1.97 (2H, br), 2.75- 2.85-276- 200410948 (2H, br), 2.90 (3H, s), 3.33 (4H, d, J = 12Hz), 4.58 (2H, d'J-2 6Hz), 5.21 ( 1H, d, J = 10Hz), 5.30 (1H, d, J = 17Hz), 5.89-5.97 (1H, m); MS (El) m / z ·· 226 (M +). (5d) 4- [2 -[N- (dilute propoxy-based) -N-methylamino] ethyl] oxidinyl-4-oxobutanoic acid 4- [2- [N- (allyl) produced in Example 5 (5c) Oxygen-based) methylamino] ethyl] piperidine (1.245 g, 5.5mmol) was dissolved in dichloromethane (25ml), succinic anhydride (500.4mg, 5mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to obtain a residue. An aqueous solution of sodium bicarbonate was added, and the mixture was washed with ethyl acetate. 2N Hydrochloric acid was added, and the product was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine. Drying under anhydrous magnesium sulfate and distilling off the solvent under reduced pressure, the title compound (0.84 g, yield 47%) was obtained as a light brown oily substance. IR (CHC13) max 1691, 1645, 1600, 14 52, 1317, 1157, 1011 cm · 1;! H NMR (CDC13, 400MHz): (51.13-1.23 (2H, m), 1.45-1.55 (3H, br), 1 · 7 · 1 · 9 (2H, br ), 2.61 (1H, brt, J = 13Hz), 2.71 (4H, s) '2.91 (3H, s), 3.04 (1H, brt, J = 13Hz), 3.33 (2H, brt, J = 7Hz), 3.85 (1H, brd, J = 13Hz), 4.56-4.61 (1H, br): See 4.59 (2H, d, J = 6Hz), 5.22 (1H, d, J = 10Hz), 5.30 (1H, d, J = 16Hz), 5.90-5.97 (1H, m); MS (FAB) m / z · 299 ((M + H) +). (5e) 4- [4- [2- [N- (allyloxycarbonyl) ) -N-methylamino] ethyl] piperidinyl] -4-oxobutanoic acid [[(1R, 2R) -2-[[trans- 2-[(IE, 3E) -4- (4- Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1 -[(1 Η -1,2,4 -tri-D-Sat-277-200410948-1-yl) methyl] propoxy] carbonyloxy] ethyl ester 4- [2 produced in Example 5 (5d) -[N- (allyloxycarbonyl) -N-methylamino] ethyl] piperidinyl-4 · oxobutyric acid (913mg, 2.80mmol) dissolved in &gt; ^ '&gt; ^ dimethylacetamidamine (15) 111), add the third potassium butoxide (2 8 2.5 nig, 2.52 mmol), and stirred at the same temperature for 2 hours. ^ Chloroethyl carbonate (ir, 2R) produced in Example 1 (la) was added _2 _ [[trans-2 _ [(π, 3E) -4- (4-cyano-2-fluorophenyl) -1,3 -Butadienyl] -1,3-diseno-5-yl] thio] (2,4-difluorophenyl)-; ^ "; ^-;!,:, # -Triazole-1 -Yl) methyl] propyl ester (diastereomer ratio = about; 1 ··; [; i · 〇 丨 g, 1 · 4ιηιηο 1), and stirred at 50 ° C for 22 hours. Under ice cooling To the reaction solution, a phosphate buffer solution was added, and the resultant was extracted three times with ethyl acetate. The organic layer was combined, washed with water (30 m 1 x 3), and then washed with saturated brine (50 Om 1 X 1), and then dried in anhydrous sulfuric acid. The crude title compound was obtained by drying under magnesium and distilling off the solvent under reduced pressure. The obtained crude title compound was purified by silica gel column chromatography (hexane · ethyl acetate, 2 5: 7 5 to 10: 90, V / V, Silica gel 25g) to obtain the title compound (0.5 6g, yield 38%) as a colorless amorphous solid (diastereomer ratio = about 1 ·· 1). IR (KBr) vmax 2230, 1765, 1699, 1644, 1504, 1275, 1143, 1056, 973 cm · 1; hNMlUCDCb, 400MHz): (5 1.06-1.20 (2H, m), 1.36 (3H, d, J = 7Hz), 1.4-1.6 (3H, m), 1.54 (3Hx (1/2), d, J = 5Hz), 1.55 (3Hx (1/2), d, J = 5Hz), 1.66- 1.83 (2H, m), 2.49- 2.75 (6H, m), 2.89 (3H, s), 2.98-3.07 (1H, m), 3.28-3.34 (2H, br), 3.48 (lHx (1/2), t, J = llHz), 3.49 (lHx (1/2), t 'J = llHz), 3.50 (lHx (1/2), t, J = 11Hz), 3.52 (lHx (1/2), t, J = llHz), 3.8-3.92 (2H, m), 4.15-4.21 (1H, m), 4.27 (lHx (1/2), ddd, J = n, 5, 2Hz), 4.30 (lHx (1/2 ), Ddd, J = n, 5, 2Hz); 200410948 4.52-4.58 (1H, br), 4.58 (2H, dd, J = 5, 1Hz), 4.98 (1H, d, J = 4Hz), 5.20 (1H, d, J = 10Hz), 5.29 (1H, d, J = 17Hz), 5.32 (lHx (1/2), d, J = 15Hz), 5.38 (lH.s) '5.45 (lHx (1 / 2), dd, 15, 3Hz), 5.86 (1H, dd 'J = 15, 4Hz), 5.90-5.94 (1H, m), 6.58 (1H, dd, J = 15, 11Hz), 6.73 (lHx (1/2), qd, J = 5, 1Hz), 6.74 (1H, d, J = 16Hz), 6.81 (lHx (1/2), q, J = 5Hz), 6.85-6.94 (2H, m), 6.93 (1H, dd, J = 16, 11Hz), 7.36 (1H, dd, J = 10, 1Hz), 7.40 (1H, dd, J = 8, 1Hz), 7.43 (1H, td, J = 9.6Hz), 7.57 (1H, t, J = 8Hz), 7.91 (lHx (1/2), s), 7.95 (lHx (1/2), s), 8.02 (lHx ( 1/2), s), 8.22 &amp; 8.55 (lHx (1/2) all, relative intensity = 1: 1, each s), MS (FAB) m / z: 939 ((M + H) +) 〇 (5f) 4- [4- [2- (methylamino) ethyl] piperidinyl] -4-oxobutanoic acid 1-[[(1R, 2R) -2-[[trans-2-[( IE, 3E) -4- (4-amino-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2 , 4-difluorophenyl) -l-[(1H-1,2,4-triazole-butyl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound)

4- [4- [2- [N- (allyloxycarbonyl) -N-methylamino] ethyl] piperidinyl] -4 -oxobutanoic acid produced in Example 5 (5e) [[( 1R, 2R) -2-[[trans-2-[(1 £, 3 £) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3 -Dioxanfane-5 -yl] thio] -bu (2'4-difluorophenyl)-;!-[(1H-1,2,4-triazole-bulyl) methyl] propoxy Group] carbonyloxy] ethyl ester (diastereoisomer ratio = about 1: 1; 5 57 · 3 mg, 0.59 mm ο 1) was dissolved in dichloromethane (10 m 1), and Under ice cooling, add triphenylphosphine palladium (34.3 mg, 0.03 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (124.7 mg, 0.8 9 mmol) under nitrogen at room temperature. Stir for 2 hours. The reaction solution was purified by silica gel column chromatography (ethyl acetate · methanol, 100: 0-75: -279- 200410948 25, V / V, 20 g of silica gel) to obtain the title object compound (3 27.9 mg, yield 6). 5%) light yellow amorphous solid (diastereoisomer ratio = about 1: 1). IR (KBr) max 2230, 1765, 1642, 1504, 1275, 114, 1054, 972 cm · 1;! HNMR (CDC13, 400MHz): 5 51.15-1.2 (2H, m), 1.36 (3H, dd ' J = 7, 2Hz), 1.4_1 · 5 (2H, m), 1.54 (3Hx (1/2), d, J = 5Hz), 1.55 (3Hx (1/2), d, J = 5Hz), 1.5 -1.6 (1H, m), 1.65-1.7 (2H, m), 2.44 (3H, s), 2.5-2.8 (7H, m), 2.97-3.06 (2H, m), 3.48 (lHx (1 / 2), t, J = llHz), 3.49 (lHx (1/2), t, J = llHz), 3.49 (lHx (1/2), t, J = llHz, overlap), 3.50 (lHx (1 / 2), t, J = llHz), 3.81-3.92 (2H, m), 4.14-4.21 (1H, m), 4.28 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.30 ( lHx (1/2), ddd, J = ll, 5, 2Hz), 4.54 (1H, brd, J = 13Hz), 4.97 (1H, d, J = 4Hz), 5.31 (lHx (1/2), d , J = 15Hz), 5.37 (1H, s), 5.44 (lHx (1/2), dd, J = 15, 4Hz), 5.85 (1H, dd, J = 16, 4Hz), 6.58 (1H, dd, J = 16, 11Hz), 6.73 (lHx (1/2), m), 6.74 (1H, d, J = 16Hz), 6.81 (1H x (1/2), q, J = 5Hz) , 6.85-6.95 (2H, m), 6.93 (1H, dd 'J = 16, 11Hz), 7.33 (1H, dd, J = 10, 1Hz), 7.40 (1H, dd, J = 8, 1Hz), 7.43 (1H.dd: J = 8, 1Hz), 7.57 (1H, t, J = 8Hz), 7.91 (lHx (1/2), s), 7.94 (lHx (1/2), s) , 8.02 (lHx (1/2), s), 8.21 &amp; 8.25 (lHx (1/2) all, relative intensity = i: i, each s); MS (FAB) m / z: 855 ( (M + H) +). The title object compound (diastereomer ratio = about i: 1; 3 1 0 mg '0 · 3 3 mm ο 1) prepared above was dissolved in dichloromethane (5 m !), Add hydrogen chloride (4 N ethyl acetate solution; 8 2 // 1.3 mm ο 1) under ice cooling, and stir at the same temperature for 5 minutes. The solvent was distilled off under reduced pressure. The obtained oily residue was dissolved in water (5 m 1) at 0 ° C., the insoluble matter was filtered off, and the obtained aqueous solution was freeze-dried to obtain the title target compound hydrochloride (120.2 mg, yield). 37%) light yellow amorphous solid (diastereomeric ratio = about 1: 1). -280- 200410948 IR (KBr) vmax 2230, 1765, 1640, 1504, 1275, 1142, 972 cm * 1;】 HNMR (CDC13, 400MHz): (51.05-1.15 (2H, m), 1.31 (3Hx (1 / 2), dd, J = 7, 2Hz), 1.33 (3Hx (1/2), dd, J = 7, 2Hz), 1.52 (3Hx (1/2), d, J = 5Hz), 1.53 ( 3H x (1/2), d, J = 5Hz), 1.58-1.64 (3H, m), 1.71-1.82 (2H, m), 2.67 (3H, s), 2.6-2.75 (5H, m), 2.95 -3.05 (3H, m), 3.08 (1H, br t, J = 13Hz), 3.48 (lHx (1/2), t, J = llHz), 3.48 (lHx (1/2), t, J = llHz, overlap), 3.49 (lHx (1/2), t, J = llHz), 3.51 (lHx (1/2), t, J, ΠΗζ), 3.81 (lHx (1/2), q, J = 7Hz), 3.87 (lHx (1/2), q, J 2 7Hz), 3.96-4.04 (1H, m), 4.11 (1H, ddd, J = n, 5, 2Hz), 4.26 (1H, ddd, J =

11, 5, 2 Hz), 4.48 (1H, brd, J = 13Hz), 5.01 (1H, d, J = 4Hz), 5.43 (lHx (1/2),

d, J = 15Hz), 5.45 (1H, s), 5.50 (lHx (1/2), dd, J = 15, 3Hz), 5.87 (1H, dd, J

= 16, 11Hz), 6.59 (1H, dd, J = 16, 11Hz), 6.69 (lHx (1/2), q, J = 5Hz), 6.75-6.80 (lHx (1/2), m) , 6.80 (1H, d, J = 16Hz), 7.02-7.10 (2H, m), 7.10 (1H, dd, J = 16, 11Hz), 7.50-7.55 (3H, m), 7.78 (1H, t, J = 8Hz), 8.03 (lHx (1/2), s), 8.04 (lHx (1/2), s), 8.39 &amp; 8.41 (lHx (1/2) all, relative intensity: 1, each s) , 8.42 (1H x (1/2), S); MS (FAB) m / z: 855 ((non-hydrochloric acid portion + H) +). Example 6 Hydrosuccinic acid 1-[[(111,21〇-2-[[trans-2-[(1 £, 3 £) -4- (4-cyano-2 -fluorophenyl) -1 , 3-butadienyl] -1,3-diDfalk-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4- Triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-20) (6a) allyl succinate 1-[[(1R, 2R) -2-[[ Trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio ] -1-(2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazole-1 -yl) methyl] propoxy] carbonyloxy] ethyl ester -281 -200410948 Dissolved propyl hydrogen succinate (J. P harm. Sci., 50ci, page 487 (1961); 1.12§, 7.1 ^ 1111〇1) in 1 ^,: ^-dimethyl Formamidine (301011) was added with 18-crown-6 (1.88 g, 7.1 mm ο 1) and carbonic acid (1.10 g, 3.4 mm ο 1). Stir at room temperature. For 3 hours, add 1 · chloroethyl carbonate (1R, 2R) produced in Example 1 (1 a) -2-[[trans- 2-[(1Ε, 3Ε) -4- (4-cyano-2- 2- Fluorophenyl) _1, 3-butadienyl] -1,3-diDfalk-5-yl] thio]]-10], 4-difluorophenyl) -1-U1H-1, 2, 4-triazole-1- Group) methyl] propyl ester (diastereoisomer ratio = about 1: 1; 1 · 95 g, 3 mm ο 1), and stirred at room temperature for 14 hours. _ Under ice cooling, a phosphate buffer solution (60 m 1) was added to the reaction solution, and the crude product was extracted with ethyl acetate (50 m 1 X 3). Combine the organic layers, wash with water (30 m 1 x 3) and then with saturated brine (50 m 1 X 1), dry under anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure to obtain the residue containing the title compound. . · The residue was purified by silica gel column chromatography (hexane: ethyl acetate '5 0:50-2 0: 80, V / V, 75 g of silica gel) to obtain the crude title compound (total = 2.4 g, The content of the title compound = about 1.6 g, the yield of the title compound is about 7.2%, and the impurities and 4-[(1 E, 3 E)-4-[trans-5-[[(1 R, 2 R) _-2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1Η-1,2,4-triazole-1 -yl) propyl] thio] -1 , 3-dioxane-2-yl] -1,3-butadienyl] -3 -fluorobenzonitrile, a colorless amorphous solid (diastereomer ratio = about 1: 1 ·). It may not be Purified and used in the next process (6b). (6b) Hydrosuccinic acid 1-[[((1R, 2R) -2-[[trans- 2-[(IE, 3E) -4- (4-cyano -2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -bu (2,4-difluorophenyl) -bu [(1 Η-1,2,4-triazole-1 -yl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound)-282-200410948 The crude succinic acid produced in Example 6 (6 a) Acid allyl ester 1-[[(1 R, 2R) -2-[[trans- 2-[(1Ε , 3E) -4- (4-cyano-2-fluorophenyl) -1, 3-butadienyl] -1,3-difluorenylf 垸 -5-yl] thio] -1- (2 '4-Gas phenyl) -l-[(1H-1,2,4-tri-II-s--1-yl) methyl] propoxy] mineoxy] ethyl ester (content about 0.69 g, About 0 · 9 mm ο 1; diastereomeric ratio of about 1: 1) dissolved in dichloromethane (20ml), and added with ice (triphenylphosphine) f bar (52mg, 0.045 mmol) under ice cooling ) And 5,5 · dimethyl-1,3-cyclohexanedione (63.1 mg, 0.45 mmol), and stirred at room temperature under nitrogen for 50 minutes. The reaction solution was purified by silica gel column chromatography (ethyl acetate-methanol, 〇〇: 〇-9 0: 10, V / V, 20 g of silicon rubber), the title object compound (4 6 8.2 mg, yield about 72%) was obtained as a pale yellow amorphous solid (diastereomeric ratio = Approximately 1: 1) IR (KBr) 2231, 1765, 1615, 1504, 1418, 1277, 1141 cm · 1;】 HNMR (CDC13, 400MHz) ·· δ 1.35 (3H; dd, J = 7, 2Hz) , 1.53 (3Hx (1/2), d, J = 5Hz), 1.57 (3Hx (1/2), d, J = 5Hz), 2.64-2.78 (4H, m), 3.47 (lHx (1/2) , T, J = llHz), 3.13 (lHx (1/2), tt, J = ll, 5Hz), 3.02 (lHx (1/2) ′ tt, J = n, 5Hz), 3.47

(lHx (1/2), t, J = llHz), 3.47 (lHx (1/2), t, J = llHz, overlap), 3.52 (lHx (1/2) 't, J = 11Hz), 3.53 (lHx (1/2), t, J = llHz), 3.66 (lHx (1/2), q 'J = 7Hz), 3.94 (1H x (1/2), t, J = 7Hz), 4.14- 4.17 (lHx (1/2), m), 4.19 (lHx (1/2), ddd, J 2 11.5, 2Hz), 4.26 (lHx (1/2), ddd, J = n, 5, 2Hz), 4.34 (lHx (1/2), ddd, J2, 5, 2Hz), 4..97 (lHx (1/2), d, J = 4Hz), 5.02 (lHx (1/2), d, J2 4Hz), 5.31 (lHx (1/2) 'dd, 15' 2Hz), 5.35 (lHx (1/2), d, 15Hz), 5.43 (lHx (1/2), dd, 15, 2Hz) , 5.44 (IHx (1/2), d, J = 15Hz), 5.86 (1H, dd, J = 16, 4Hz), 6.59 (1H, dd, J = 16, 11Hz), 6.74 (1H, d, J = 16Hz), 6.80 (lHx (1/2), q, J = 4Hz), 6.81 (lHx (1/2), q, J 2 4Hz), 6.84-6 · 96 (2H, m) , 6.93 (1H, dd, = 16, 11Hz), 7.33 (1H, dd, J = 10, 1Hz), 7.33-7.43 (1H, m), 7.40 (1H, d, J = 8Hz), 7.57 (lHx ( 1/2), s), 7.83 (lHx-283-200410948 (1/2), s), 8.00 (ΙΗχ (1/2), s), 8.10 (ΙΗχ (1/2), s), 8.31 (ΙΗχ (1/2) , S); MS (FAB) m / z: 731 ((M + 1)). Example 7 1- [4- [1-[[(1R, 2R) -2-[[trans-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3 -Butadienyl] -1,3dioxan-5-yl] thio] -1- (2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] propoxy Group] carbonyloxy] ethoxy] -4-oxobutanyl] -4-piperidine carboxylic acid (exemplified compound 1 -1 〇6) (7a) 1- (third butoxycarbonyl) -4-piperidinecarboxylic acid Acid allyl esters 1- (Third-butoxy-based) -4-piperidinidine residual acid (Bioorg. Med. Chem. Lett., 10 巻, page 79 (2000); 6.92 g, 30.18 mmol) Dissolved in N, N-dimethylformamide (60 m 1), added dicyclohexylamine (6.5 7 g, 3 6.2 2 mm ο 1) »and propyl hydrazone (6.08 g, 36.22 mmol), Stir under nitrogen at 90 ° C for 1 hour. Water (100 ml) was added at room temperature, and the precipitated solid was filtered through celite, and the solid was washed with ethyl acetate (100 m 1). The mixture of the mother liquor and the washing solution was separated in water-ethyl acetate, and the organic layer was combined, washed with water (100m 1x3), and then saturated brine (100m 1X1), and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 25:75, V / V, 150 g of silica gel) to obtain the crude title compound (7.42 g, yield 9 1%) as a yellow oil. Like substance. IR (CHC13) umax 1730, 1685, 1427, 1367, 1165, 1127, 1039 cm-1; bNMR (CDC13, 400MHz): 51.46 (9H, s), 1.61 (1H, dd, J = ll, 4Hz), 1.67 (1H, dd, J, 2H, 4Hz), 1.89 (2H, d, J = 11Hz), 2.48 (1H, tt, J = 1, 4Hz), 2.84 200410948 (2H, t, J ^ llHz), 4.01- 4.10 (2H, brs), 4.59 (2H, d, J = 6Hz), 5.24 (1H, d, J = 12Hz), 5.31 (1H, dd, J = 17, 2Hz), 5.91 (1H, ddt, J = 17, 12, 6 Hz); MS (FAB) m / z: 270 ((M + H) +). (7b) Hydrochloride salt of allyl 4-piperidinecarboxylate The allyl 1- (third butoxycarbonyl) -4-piperidinecarboxylate (4.05) produced in Example 7 (7a) g, 15.0 mm ο 1) dissolved in ethyl acetate (3 m 1), and hydrogen chloride (4N ethyl acetate solution; 15 ml, about 60 mmol) was added at 0 ° C. After the mixture was stirred at room temperature for 20 minutes, the solvent was distilled off under reduced pressure. The obtained solid was washed with diethyl ether (30 m 1) to obtain the title compound (2.25 @, yield 73%) as a colorless solid.

Mpl25-127〇C IR (KBr) ^ Orbital 2962, 2806, 1720, 1582, 1284, 1247 (^ 1-1;) HNMR (DMS〇-d6, 400MHz): (51.72 (1H, dd, J = ll, 4Hz), 1.79 (1H, dd, J = 11, 4Hz), 2.00 (2H, d, J = 11Hz), 2.73 (1H, tt, J = ll, 4Hz), 2.91 (2H, td, J = (12, 2 Hz), 3.23 (2H, d, J = 12Hz), 4.58 (2H, d, J = 6Hz), 5.23 (1H, d, J = 10Hz), 5.30 (1H, d 'J = 17Hz), 5.93 (1H, ddt, J = 17, 10, 6 Hz); MS (El) m / z: 169 (M +) 〇 (7 c) 4-[4-(allyloxycarbonyl) piperidinyl] -4-oxo Butyric acid The hydrochloride salt of allyl 4-piperidinecarboxylate (2.24 g, 10.89 mmol) produced in Example 7 (7b) was dissolved in dichloromethane (25 ml), and succinic anhydride was added under ice cooling. (1.90 g, 10 · 8 9 mm ο 1) and N, N-diisopropylethylamine (1.4 1 g, 10 · 8 9 mm ο 1), and stirred at room temperature for 2 hours Water (30 m 1) was added, and the product was extracted with ethyl acetate (50 m 1 X 3). The organic layer was combined, washed with 2N hydrochloric acid, water, and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the crude title compound -285-2 00410948 (2.8 7 g, yield 98%) light yellow oily substance. IR (KBr) vmax 1731,] 637, 1598, 1450, 1270, 1250, 1175, 1038 cm-1;] HNMR (CDC13, 400MHz) : 5 1.65-1.80 (2H, m), 1.99 (2H, m), 2.62 (1H, m), 2.7] (4H, m), 2.9] (1H, t, J = 12Hz), 3.19 () H, t, J = 12Hz), 3.86 (1H, brd, J = 13Hz), 4.40 (1H, d, J = 14Hz), 4.63 (2H, d, J = 5Hz), 5.27 (1H, d, J = 10Hz), 5.34 (1H, d, J = 17Hz), 5.93 (1H, ddt, J = 17, 10, 5Hz); MS (FAB) m / z: 270 ((M + H) +). (7d) 1- [4- [1-[[(1R ^ 2R) -2-[[trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1 , 3-butadienyl] -1,3-dioxane-5-φyl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4 -Triazol-1-yl) methyl] propoxy] mineoxy] ethoxy] -4 * • oxobutanoyl] 4-piperidinecarboxylic acid allyl ester Manufactured in Example 7 (7c) 4- [4- (Allyloxycarbonyl) piperidinyl] -4-oxobutanoic acid (2.60g, 4.0mmol) was dissolved in N, N-dimethylformamide (20ml), and the 18-crown -6 (2.80 g, 10.58 mmol) and carbonic acid (1.63 g, 5.0 mm ο 1). The mixture was stirred at room temperature for 2 hours, and dichloroethyl carbonate (1R, 2R) produced in Example i (ia) was added. 2-[[Trans_2-[(IE, 3E) -4-φ (4-cyano -2-fluorophenyl) -1,3-butadienyl] q, 3-diamidinoalkyl] thio] -bu (2,4-difluorophenyl) -1-[(1Η-1, 2,4-triazol-1-yl) methyl] propyl ester (diastereomer ratio = about 1: 1; 2 · 6 g, 4 mm ο 1), and stirred at room temperature for 18 hours. Under ice-cooling, a phosphate buffer solution (60 m 1) was added to the reaction solution, and the crude product was extracted with ethyl acetate (50 m 1 × 3). The organic layer was combined, washed with water (30 mi x 3) and then with saturated saline (50 m 1 X 1), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude title compound. -286-200410948 The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 60: 40-0: 100, V / V, silica gel 75g) to obtain the title compound (2.) 8 g , Yield 6 2%) colorless amorphous solid (diastereomeric ratio = about 1: 1). IR (KBr) vmax 2233, 1765, 732, 1643, 105, 176, 1141, 1055 cm-];

] HNMR (CDC13, 400MHz): (51.36 (3H, d, J = 7Hz), 1.54 (3Hx (1/2), d, J = 6Hz), 1.55 (3Hx (1/2), d, J = 6Hz ), 1.63-1.74 (1H, m), 1.9H.98 (2H, m), 2.54-2.88 (7H, m), 3.00-3.06 (1H, m), 3.10-3.16 (1H, m), 3. · 45 (] Hx (1/2), t, J = 11Hz), 3.49 (lHx (1/2), t, 11Hz), 3.49 (lHx (1/2), t, 11Hz), 3.50 (lHx (1 / 2), t, 11 Hz), 3.81-3.91 (2H, m), 4.15-4.19 (1H, m), 4.26-4.31 (1H, m), 4.34-4 · 38 (1H, 10 m) , 4.59 (2H, brd, J = 5Hz), 4.97 (1H, d, J = 4Hz), 5.24 (1H, brd, J = 10Hz), 5.31 (1H, br d, J = 17Hz), 5.30-5.42 ( 2H, m), 5.85 (1H, dd, J = 16, 4Hz), 5.90 (1H, ddt, J = 16, 11, 5Hz), 6.58 (1H, dd, J = 16, 11Hz), 6.73 ( 1H, d, J = 16Hz), 6.74 (lHx (1/2), q, J = 5Hz), 6.81 〇Hx (1/2), q, J = 5Hz), 6.83-6.93 (2H, m), 6.93 (1H, dd, 16, 11Hz), 7.33 (1H, d, J = 10Hz), 7.39-7.44 (2H, m), 7.57 (1H, t, J = 8Hz), 7.91 (lHx ( 1/2), s), 7.95 (lHx (1/2), s), 8.02 (lHx (1/2), s), 8.20 &amp; 8.24 (ΙΗχ (1/2) all Relative intensity = 1: l, each s); MS (FAB) m / z: 882 ((M + H) +). (7e) l- [4- [l-[[(lR, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1 , 3-butadienyl] -1,3-difluorenf-alkyl-5-yl] thio] -1- (2,4-difluorophenyl)-! _ [〇Η ·〗, 2, 4 -Triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4 -oxobutanyl] -4-piperidinecarboxylic acid (the title object compound) was prepared in Example 7 (7d) 1- [3- [1-[[(1R, 2R) -2-[[trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) 25 -1,3 -But-287-200410948 dienyl] -1,3-dioxan-5-yl] thio] (2 · 4-difluorophenyl) _] — [(1 Η_], 2, cardiotriazole- 1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutyryl] allyl piperidinecarboxylate (diastereomer ratio = about 1 ·]; 526.] mg (0.60mmol) was dissolved in dichloromethane (1) 5), and under cooling with ice, tris (triphenylphosphine) palladium (3 4 · 5 mg, 0.0 2 9 8 mm ο 1) and 5 '5-2 were added. Methyl _], 3_cyclohexanedione (42.lmg, 0.30mmol), and stirred at room temperature under nitrogen for 40 minutes. The reaction solution was purified by silica gel column chromatography (ethyl acetate-methanol, 1 00: 0-80:

20, V / V, 20 g of silicon rubber) to obtain the title compound (489.9 mg, yield 98%) as a pale yellow amorphous solid (diastereomer ratio = about 1: 1). IR (KBr) max 2934, 2230, 1765, 1644, 1615, 1504, 1275, 1141, 1055, 973 cm-]:

iHNMR (CDC13, 400MHz) ·· 5 1 · 36 (3H, dd, J = 7, 2Hz), 1.54 (3Hx (1/2), d, J = 5Hz), 1.55 (3Hx (1/2), d , J = 5Hz), 1.60-L78 (2H, m) '1.88-2.00 (2H, m), 2.53-2 / 78 (5H, m), 2 · 81-2 · 89 (1H, m), 3.03 ( 1H, tt, J = ll, 5Hz), 3.15 (1H, td, 11, 3Hz), 3.48 (lHx (1/2), t, J = llHz), 3.49 (lHx (1/2), t, J = llHz), 3.49 (lHx (1/2), t, J = llHz), 3.50 (1Ηχ (1/2), 3.79-3.86 (1H, m), 3.86 (lHx (1/2) , Q, J = 7Hz), 3.88 (lHx (1/2), q, J = 7Hz), 4.18 (1H, ddd, J2 11, 5, 2Hz), 4.25-4.27 (2H, η ), 4.98 (1H, d, J = 4Hz), 5.38 (2H, brs), 5.85 (1H, dd, J = 15, 4Hz), 6.58 (1H, dd, J = 15, 11Hz) ), 6.73 (1H, d, J = 16Hz), 6.74 (lHx (1/2), q, J = 5Hz), 6.80 (] Hx (1/2), q, J ^ SHz), 6.85 6.95 (2H, m), 6.93 (1H, dd, J = 16, 11Hz), 7.33 (1H, dd, J = 10, 1Hz), 7.39-7.44 (2H, m), 7.57 (1H, t, J2 8Hz), 7.92 (ΙΗχ (1/2), 5), 7.98 (1 of (1/2), 5), 8.06 &amp; 8.07 (11 ^ (1/2) full 咅 15, relative intensity = 1: 1 , Each S) 8.32 (1H, s); MS (FAB) m / z: 842 (M + H) +). The title compound (diastereomer ratio = about 1: 1; -288-200410948 3 6 6 · 8 mg, 0.4 3 6 mmol) prepared above was dissolved in tetrahydrofuran (5 m 1), and sodium bicarbonate ( 3 4 · 7 mg, 0 · 4] 4 mm ο]) in water (5 m 1) solution, and stirred at room temperature for 5 minutes. After distilling off tetrahydrofuran under reduced pressure, the insoluble matter was filtered off with membrane filter paper, and the aqueous solution was freeze-dried to obtain the sodium salt of the title object compound (3 4 0.1 mg, yield 90%) as a colorless amorphous solid (diastereoisomer The ratio is about 1: 1. IR (KBr) vmax 2230, 1764, 1636, 1616, 1576, 1504, 1417, 1276, 1142, 1055, 973 cm-1

] HNMR (DMSOd6, 400MHz): 5 1.33 (3H, dd, J = 7, 2Hz), 1.45 (3Hx (1/2), d, J = 5Hz), 1.48 (3Hx (1/2), d , J = 5Hz), 1.60-1.73 (2H, m), 1.93-1.99 (1H, m), 2.52-2.60 (4H, m), 2.70-2.79 (1H, ni), 2.86-2.96 (1H, m) , 3.02 (1H, br t, J = 13Hz), 3.41 (lHx (1/2), t, J = 13Hz), 3.41 (lHx (1/2), t, J = llHz), 3.44 (lHx (1 / 2), t, J = llHz), 3.44 (lHx (1/2), t, J = llHz), 3.46 (lHx (1/2), t, J =] lHz), 3.46 (1H x (1 / 2), t, J = llHz), 3.57 (lHx (1/2), q, J = 7Hz), 3.65-3.75 (1H, m), 3.98 (1H x (1/2), q, J = 7Hz), 3.96-4.08 (2H, m), 4.11 (1H, ddd, J = ll, 5, 2Hz), 5.03 (1H x (1/2), d, J = 4Hz) ' 5.04 (lHx (1/2), d, J = 4Hz), 5.28 (IHx (1/2), d, 15Hz),

5.31 (lHx (1/2), d, J = 15Hz), 5.43 (lHx (1/2), d, J = 10Hz), 5.46 (lHx (1/2), d, J = 10Hz), 5. · 88 (lHx (1/2), dd, J = 15, 4Hz), 5.89 (lHx (1/2), dd, J = 15, 4Hz), 6.57 (] Hx (1/2), dd, J = 16, 11Hz), 6.58 (lHx (1/2), dd, J = 16, 11Hz), 6.66 (1H x (1/2), q, J = 6Hz), 6.68 (lHx (1/2), q , J = 6Hz), 6.82 (1H, d, J = 16Hz), 7.19 (1H, dd, J = 16, 11Hz), 7.15-7.21 (1H, m), 7.30-7.36 (1H, m), 7.41- 7.48 (1H, m), 7.67 (1H, dd, J = 2, 1HZ), 7.84 (1H, dd, J = 10, 1Hz), 7.88 (1H, td, J = 8, 2Hz), 8.04 (lHx ( 1/2), s), 8.05 (lHx (1/2), S), 8.35 &amp; 8.36 (lHx (1/2) total 咅 B, relative intensity = 1: 1, each s); all, relative Intensity = 1: 1, each s), 8.47 (ΙΗχ (1/2), s);-289-200410948 MS (FAB) m / z: 864 ((M + H) +) 〇Example 8 2- [N- [4- [1-[[(1R '2R) -2-[[trans- 2-[(IE, 3E) (4- cyano-2 -fluorophenyl) -1,3 -butane Alkenyl] -1,3 -dioctane-5_yl] thio]-1-(2,4-difluorophenyl)-[-((1H-1,2,4-trisyl)] _ ) Methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutylammonium] -N-methylamino] ethanesulfonic acid (Exemplary Compound 1 -364) (8a) 2- [N- (Third Butoxycarbonyl) -N-methylamino] isobutyl ethanesulfonate N-methylaminoethanesulfonic acid (4.1 8g, 30m mol) was dissolved in water (20ml), and tetrabutylammonium hydroxide (40% by weight in water) was added. 21.41 g, 33 m mol), and then added di-tert-butyl carbonate (6.55 g, 30 mmol), and stirred at room temperature for 5 hours. Water (60 ml) was added to the reaction solution, and the crude product was extracted with dichloromethane. The organic layer was combined, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude 2- [N- (third-butoxycarbonyl) -N-methylamino] tetrabutylammonium ethanesulfonate as a colorless oily substance. The above-prepared crude 2- [N- (third-butoxycarbonyl) methylamino] tetrabutylammonium ethanesulfonate was dissolved in dichloromethane (80m 1), and under ice cooling, phosgene (4.60g, 15.5m mol) was added. ) And N, N-dimethylformamide (〇ιιηιΐ), and stirred under nitrogen at the same temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain crude 2- [N- (third-butoxycarbonyl) -N-methylamino] ethanesulfonyl chloride. Isobutanol (3.71 g, 50 mmol) was dissolved in pyridine (50 ml), and the crude h [N- (third-butoxycarbonyl) -N-methylamino] ethanesulfonyl chloride produced above was added under ice cooling, Stir at room temperature for 1 hour. -290-200410948 Under ice cooling, a phosphate buffer solution (100 m) was added to the reaction solution, and the crude product was extracted with dichloromethane. The combined organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate '1 00: 20, V / V, 75 g of silica gel) to obtain the title compound (6.33 g, yield 71%) as a colorless oily substance. . IR (CHC13) 1688, 1479, 1394, 1368, 1168 cm_1;] HNMR (CDC13, 400MHz): 50.99 (6H, d, J = 7Hz), 1.47 (9H, s), 2.01 (1H, m), 2 · 93 (2H, s), 3.25-3 · 40 (2H, m), 3.67 (2H, t, J = 7Hz), 4.00 (2H, d, J = 7Hz); MS (FAB) m / z: 296 ((M + H) +) ° (8b) 2- (methylamino) isobutyl ethanesulfonate 2- [N- (third butoxycarbonyl) produced in Example 8 (8a) ) -N-methylamino] isobutyl ethanesulfonate (3.0 g, 10.2 mm ο 1) was dissolved in dichloromethane (15 m 1), and trifluoroacetic acid (5 m 1 ), And stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained oil was added with water (20 m 1) and washed with ethyl acetate. A saturated aqueous sodium hydrogen carbonate solution was added to the aqueous solution, and the resultant was extracted with dichloromethane (3 Om 1 x 4). The organic layer was combined, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude title compound (360 mg, yield 20%) as a yellow oily substance. IR (CHC13) vmax 1688, 1479, 1394, 1368, 1168cm-1; hNMR (CDC13, 400MHz): (50.99 (6H, d, J = 7Hz), 3.04 (1H, m), 2.47 (3H , S), 3.09 (2H, t, J = 6Hz), 3.30 (2H, t, J = 6Hz), 4.01 (2H, d, J = 6Hz); MS (FAB) m / z: 196 ((M + H) +). (8c) 4- [N- [2- (Isobutoxysulfonyl) ethyl] -N-methylamino] -291-200410948 4-oxobutanoic acid Example 8 (8b ) 2- (methylamino) isobutyl ethanesulfonate (36 mg, 2.0 3 mm ο 1) was dissolved in dichloromethane (10 in 1), and succinic anhydride (2 0 2.9 mg, 2 · 0 3 mm 〇]), and stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure to obtain crude 4- [N- [2- (isobutoxycarbonyl) ethyl] -N-methylamine group. ] 4-Oxybutyric acid (620.6mg, quantitative yield) Yellow oily substance. IR (CHC13) vmax 1748, 1715, 1650, 1356, 1171 cm-1; b NMR (CDC13, 400MHz): δ 0 · 99 (6H, d, J = 7Hz), 1.99-2.07 (1H, m), 2.61-2.73 (4H, m), 3.14 (3H, s), 3.39 (2H, t, J = 7Hz), 3. · 87 (2H, t, J = 7Hz), 4.00 (2H.d, J = 7Hz); MS (FAB) m / z: 296 ((M + H) +). (8d) 4- [N- [2- (Isobutoxysulfonyl) ethyl] -N-methylamino] -4-oxobutanoic acid 1-[[(1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 -Yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] Ethyl ester 4- [N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -4-oxobutanoic acid (620 mg, 2 mmol) prepared in Example 8 (8c) was dissolved in N, N-dimethylformamide (10 ml), 18-crown-6 (528.6 mg, 2 mmol) and carbon shavings (293.2 mg, 0.9 mmol) were added by force. Stir at room temperature for 30 minutes, 1-chloroethyl carbonate (1 R '2R) produced in Example 1 (la) was added -2-[[trans-2-[(1 E, 3 E) -4- (4 -truncyl-2-proline The base) -1 '3-butane · storyl] -1,3-dioxan-5-yl] thio] -1- (2, 4-difluorophenyl) -1-[(1H- 1,2,4-triazol-1-yl) methyl] propyl ester (diastereomer ratio = about 1: 1; -292-200410948 8 0 6 · 3 mg, 1.2 mm ο 1) , And stirred at room temperature for 21 hours. Under ice-cooling, a phosphate buffer solution (30 m 1) was added to the reaction solution, and the resultant was extracted with ethyl acetate (30 m 1 × 3). The organic layer was combined, washed with water (10m 1x3), and then saturated brine (30ml xl), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 50: 100-0: 100, V / V, silica gel 25g) to obtain the title compound (3 9 6.3 mg, yield 3 5 %) Colorless amorphous solid (diastereomeric ratio = about 1: 1). IR- (KBr) vmax 1765, 1652, 1616, 1504, 1418, 1275, 1142 cm-1; hNMR (CDC13, 400MHz): (50.96 (6Hx (1/2), d, J 2 6Hz), 0.97 (6Hx (1/2), d, J = 6Hz), 1.36 (3H, dd, J = 7, 2Hz), 1.54 (3H, dd, J = 6Hz), 1.99-2.04 (1H, m), 2.6-2.820 (4H, m), 2.98-3.08 (1H, m), 3.13 (3Hx (1/2), s), 3.15 (3Hx (1/2),

s), 3.33-3.39 (2H, m), 3.45-3.53 (2H, η, 3.77 (2H, t, J = 7Hz), 3.76- 3.90 (1H, m), 3.96 (2H x (1/2 ), D, J = 7Hz), 3.98 (2Hx (1/2), d, J = 7Hz), 4.17 (1H, ddd, J = ll, 5, 2Hz), 4.28 (1H, ddd, J = ll, 5, 2Hz), 5.97 (lHx (1/2), d, J = 4Hz), 4.98 (lHx (1/2), d, J = 4Hz), 5.29-5.46 (2H, m), 5.86 ( 1H, dd, 16, 4Hz), 6.58 (1H, dd, 16, 11Hz), 6.72-6.76 (lHx (1/2), m), 6.74 (1H, d, J2 16Hz), 6.80 (lHx (1/2), q, J = 5 Hz), 6.84-6.93 (2H, m), 6.93 (1H, dd, J = 16, 11Hz), 7.33 (1H, tt, J = 10, 1Hz) , 7.38-7.43 (1H, m), 7.40 (1H, dd, J = 8, 1Hz), 7.57 (1H, t, J = 8Hz), 7.90 (1H x (1/2), s), 7.95 (lHx (1/2), s) '8.02 (lHx (1/2), s), 8.20 (lHx (1/2), s); MS (FAB) m / z: 908 ((M + H) +) 〇 (8e) 2- [N- [4- [1-[[(1R, 2R)-[[trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane- 5--293-200410948 group] thio] -1-(2,4-difluorophenyl) -1 — [(1 Η -1, 2, 4 -Triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutanyl] -N-methylamino] ethanesulfonic acid (the title object compound) Example 8 (8d ) 4- [N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -4-oxobutanoic acid l-[[(lR, 2R) -2-[[trans -2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1, 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (diastereomer Isomer ratio = about 1: 1; 3 96 mg, 0.43 mm ο 1) dissolved in acetone (10 m 1), and sodium iodide (6 4 3 · 8 mg, 4.3 mm ο 1) , And stirred at 40 ° C for 5 hours. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to Cosmosil 75 C18-PREP (manufactured by Nakaraitesc) reverse phase column chromatography (methanol: water, 20: 80-60: 40, V / V, using Cosmosil 75 C18-PREPP 25g )purification. It was concentrated and lyophilized to obtain the title object compound (diastereomeric ratio = about 1: 1) sodium salt (colorless amorphous solid, 21 1.7 mg, yield 56%). IR (KBr)] &gt; max 2230, 1764, 1641, 1504, 1418, 1275, 1258, 1207, 1142 cm-1; hNMR (DMSO-d6, 400MHz): (5 1.24 (3Hx (1/2), dd , J = 7, 2Hz), 1.27 (3Hx (1/2), dd, J = 7, 3Hz), 1.45 (3Hx (l / 2), d, J = 5Hz), 1.48 (3Ηχ ( 1/2), d, J 2 5Hz), 2.48-2.71 (6H, m), 2.88-2.97 (1H, m), 2.76 (3Hx (1/2), s), 2.94 (3Hx (1/2) , S), 3.36-3.60 (4H, m), 3.55-3.60 (lHx (1/2), m), 3.74-3.78 (lHx (1/2), m), 4.01-4Ό8 (1H, m), 4.11 (lHx (1/2), ddd, J = ll, 5, 2Hz), 5.04 (1H, d, J = 4Hz), 5.25 (1H x (1/2), d, J = 15Hz), 5.29 (lHx (1/2), d, J = 15Hz), 5.42 (lHx (1/2), d, J = 13Hz), 5.46 (lHx (1/2), d, J = 13Hz), 5.88 ( lHx (1/2), dd, J = 16, 5Hz), 5.90 (lHx (1/2), dd, J2, 16, 5Hz), 6.58-6.63 (lHx (1/2), m), 6.57 ( lHx (1/2), dd, 16, 11Hz), 6.58 (lHx (1/2), dd, J = 16, 11Hz), 6.68 (lHx (1/2), qd, J = 5, 1Hz), 6.82 (1H, 200410948 d, J = 16Hz), 7.13-7.23 (1H, π〇, 7.18 (1Η, dd, J = 16, 1) Ηζ), 7.29-7.37 (1H, m), 7.41-7.51 (1H, m), 7.67 (1H, d, J = 8Hz), 7.84 (1H, dd, 10, 1Hz), 7.88 (1H, td, J = 8.3Hz), 8.04 (] Hx 〇 / 2 ), S), 8Ό5 &amp; 8.06 (lHx (1/2) all, relative intensity = 1 ·· 1, each s), 8.34 &amp; 8 · 35 (ΙΗχ (1/2) all, relative intensity = 1 : 1, each s), 8.48 (IΗχ (1/2), s); MS (FAB) m / z: 874 ((M + H) +) Example 9 4-(cis-2, 6-dimethyl-1-piperidinyl) -4-oxobutanoic acid 1-1 [(1R, 2R) -2-[[trans-2-[(IE, 3E) -4- (4-cyano 2-fluorophenyl) -1,3-butadienyl] -1,3-difluorenylfalkyl-5-yl] thio] -1- (2,4-difluorophenyl) 2,4 -Triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound 1-71) (9a) cis-1-(allyloxycarbonyl) -3,5-dimethylpiperine Dissolve the cis-2,6-dimethylpiperazine (3.4 3 g, 30 mm ο 1) in water (50 m 1), and add sodium carbonate (3.18 g, 30 mm) under ice cooling. 1) and allyl chloroformate (3.62 g, 30 mm), and stirred at room temperature for 2.5 hours. Under ice cooling, 2N hydrochloric acid (30 ml) was added to the reaction solution, and the aqueous layer was washed once with ethyl acetate. A saturated aqueous sodium hydrogen carbonate solution was added to the aqueous layer, and extraction was performed 4 times with dichloromethane. The organic layer was combined with water, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (2.23 g, yield 37%) as a colorless oily substance. IR (CHCI3) yniax 1686, 1456, 1262, 1144, 1125 cm1; 4 NMR (CDC13, 400MHz): (5 1.07 (6H, d, J = 6Hz), 2.35-3.43 (2H, br), 2.78- 2.83 (2H, m), 3.9-4 · 1 (2H, bi ·), 4.60 (2H, d, J = 6Hz), 5.21 (1H, d, J = 10Hz), 5.30 (1H, brd, J = 17Hz), 5.95 (1H, ddt, J-2, 17), 0, 6Hz); 200410948 MS (EI) m / z: 198 (M1). (9b) 4- [cis-4- (stripe propionite based) ) -2,6-dimethyl-]-piperidinyl] -4-oxobutanoic acid The cis-1-(allyloxycarbonyl) -3,5-dimethyl produced in Example 9 (9a) A pipe trap (2 · 12 g, 10.7 m mo 1) was dissolved in acetonitrile (30 m 1), and succinic anhydride (1. .07 g, 10.7 mmol) was added under ice cooling, and the mixture was stirred at 50 ° C for 1 5 hours. At room temperature, 2N hydrochloric acid was added to the reaction solution, and the resultant was extracted with dichloromethane. The organic layer was washed with water and then with saturated brine, and the solvent was distilled off under reduced pressure to obtain the title compound (2.5 4 g, Yield 80%) light yellow oily substance. IR (liquid film) ν_Π85, 1734, 1704, 1645, 1436, 1148 cm-1; 4 NMR (CDC13, 400MHz): (51.3-1.4 (6H, br), 2.6-2.8 (4H, br), 3 03 (2H, br), 4.10 (3H, br), 4.65 (3H, br s), 5.24 (1H, dd, J = 10, 1Hz), 5.32 (1H, dd, J = 17, 2Hz ), 5.95 (1H, ddt, J = 17, 11, 6 Hz); MS (El) m / z: 298 (M +) 0 (9c) 4-[cis-4-(allyloxycarbonyl) -2,6 -Dimethyl-1-piperidyl] -4-oxobutanoic acid [[(〗 R, 2R) -2- [[trans- 2-[(1E, 3E) -4- (4-cyano- 2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[( ih-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl 4- [cis-4- (allyloxycarbonyl) produced in Example 9 (9b) -2, 6-dimethyl-1-pyridyl] -4-oxobutanoic acid (1.51g, 5.1mmol) was dissolved in N, N-dimethylformamide (20nil), and 18-crown -6 (134g, 5.1mmol) and carbonic acid planer (7 8 5.2 mg, 2.4 1 mm ο 1). After stirring at room temperature for 1 hour, 1-chloroethyl carbonate (ir, 2R)-2-[[trans200410948 -2- [(] E, 3E) -4- (yl- 2-fluorophenyl) -1,3-butadienyl]-], 3-dioxan-5-yl] thio]-]-(2, difluorophenyl)-]-[(1H- 1,2,4-triazole-b-yl) methyl] propyl ester (diastereomer ratio of about 1: 1;] .3] g, 1.9 1 mm ο 1), stirred at room temperature 1 1 hour. Under ice-cooling, a phosphate buffer solution (60 m 1) was added to the reaction solution, and the crude product was extracted with ethyl acetate (50 m 1 × 3). The organic layer was combined, washed with water (30 ml X 3) and then with saturated brine (50 m 1 X 1), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 60: 40-0: 100, V / V, silica gel 60g) to obtain the title compound (109g, yield 59%), which was colorless. Amorphous solid (diastereomeric ratio = about 1; 1). IR (KBr) ^ max2230, 1765, 1703, 1644, 1504, 1419, 1275, 1145, 1057cm · 1;

iHNMR (CDC13, 400MHz) ♦ δ 1.1-1.2 (6H, m), 1.23 (3H, dd, J = 7, 2Hz), 1.55 (3Hx (1/2), d, J = 6Hz), 1.56 (3Hx (1/2), d, J = 6Hz), 2.6-2.8 (4H, m), 2.9-3.1 (3H, m), 3.48 (lHx (1/2), t, J = llHz), 3.50 (lHx (1/2), t, J = llHz), 3.50 (1H x (1/2), t, J = llHz, overlap), 3.51 (IHx (1/2), t, J = llHz) , 3.80-3.85 (lHx (1/2), br), 3.89 (lHx (1/2), q, J = 7Hz), 3.95-4.10 (3H, br), 4.18 (lHx (1/2), ddd , J = 11, 5, 2 Hz), 4.19 (1Ηχ (1/2), ddd, J = 11, 5, 2 Hz), 4.26-4.32 (lH, m), 4.6 (3H, brs), 4.97 ( lHx (1/2), d, J = 4Hz), 4.98 (lHx (1/2), d, J = 4Hz), 5.23 (1H, brd, J = llHz), 5.32 (1H, bi · d , J = 17Hz), 5.32 (lHx (1/2), d, J = 15Hz, overlap), 5.38 (1H, s), 5.45 (lHx (1/2), d, J = 15Hz), 5.95 〇Hx (1/2), ddt, J2 17, 11, 5Hz), 6.59 (1H, dd, J = 15, 11Hz), 6.74 (lHx (1/2), q, J = 6Hz), 6.74 ( 1H, d, J = 16Hz, overlap), 6.82 (lHx (1/2), q, J = 6Hz), 6.85-6 · 96 (2H, m), 6.94 (1H, dd, J = 16, 11Hz), 7.34 (1H, d d, J = 10, 2Hz), 7.40 (1H, dd, J = 8, 2Hz), 7.38-7.46 (1H, m),-297-200410948 7.58 (1H, t, J = 8Hz), 7.91 (] Ηχ (1/2), s), 7.95 (] Hx (1/2), s), 8.03 (ΙΗχ (1/2), s), 8.23 (lHx (1/2), s); MS (FAB) m / z: 9]] ((M + H) +). (9 d) 4-(cis-2,6-dimethyl-piperidyl) -4-oxobutanoic acid 1-[[(1 R, 21〇-2-[[trans-2-[(^, 3 £) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -b (2,4 -Difluorophenyl) -1-[(1H-1,2,4-triazole-; 1-yl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound) Example 9 ( 9c) 4- [cis-4- (allyloxycarbonyl) -2, 6-dimethyl-1-piperidyl] 4-oxobutanoic acid 1-[[(1R, 2R) -2- [[Trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] Thio] -1- (2,4-difluorophenyl) -l-[(1H-1, 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester ( Diastereomer ratio = about 1: 1; 443.6 mg, 0.49 mmol) was dissolved in dichloromethane (10 ml), and under ice cooling, tris (triphenylphosphine) palladium (28.1 mg, 0.024 m mol) was added And 5,5-dimethyl-1,3-cyclohexanedione (81.9 mg, 0.5 8 mmol), and stirred under nitrogen at Ot: for 1 hour. The reaction solution was purified by silica gel column chromatography (ethyl acetate : Methanol, 100: 0-80: 20, V / V, 20 g of silica gel) to obtain the title compound (25 5.8 mg, yield 64%) as a pale yellow amorphous solid (diastereomeric ratio = about 1 :) 1) IR (KBr) vmax 2230, 1765, 1634, 1504, 1419, 1276, 1141, 1061, 973 cm · 1; WNMR (CDC13, 400MHz) ·· δ 1.3-1.4 (6H, br), 1.36 (3H , D, J = 7Hz), 1.54 (3H x (1/2), d, J = 5Hz), 1.55 (3Hx (] / 2), d, J = 5Hz), 2.6-2.9 (8H, m), 3.02 (lHx (1/2), tt, J = ll, 5Hz), 3.03 (lHx (1/2), tt, J = 11, 5Hz), 3.49 (lHx (1/2), t, J = llHz ), 3.49 (lHx (l / 2), t, J = llHz, overlap), 3.49 (1Ηχ (1/2), t ,: [two 11Hz, overlap), 200410948 3.50 (IΗχ (1/2) , T 'J = llHz), 3.8] (ΙΗχ (1/2), q, J = 7Hz), 3.88 (IHx (1/2), q,

J = 7Hz), 3.8-4.0 (] H, br), 4.17 (] Hx (] / 2), ddd, J = 11, 5, 2Hz), 4.18 (lHx () / 2), ddd, JII , 5, 2Hz), 4.28 (IHx (1/2), ddd, J =] 1, 5, 2Hz), 4.30 (lHx (1/2), ddd, 11, 5, 2Hz), 4.4-4.5 (1H , Br), 4.98 (1H, d, J = 4Hz), 5.32 (lHx 〇 / 2), dd, J = 15, 3Hz), 5.38 (1H, s), 5.44 (lHx (1/2), d, J = 15Hz), 5.86 (1H, dd, J = 15, 4Hz), 6.58 (1H, dd, J = 15, 11Hz), 6.73 (lHx (1/2), q, J = 5Hz), 6.73 (1H, d, J = 16Hz), 6.82 (lHx (1/2), q, J = 5Hz), 6.84-6.93 (2H, m), 6.93 (1H, dd, J 2: 16 , 11Ηζ), 7.33 (1H, dd, J = 10, 1Ηζ), 7.39 (1Η, dd, J = 8, 1Ηζ), 7.38-7 · 46 (] Η, m), 7.57 ( 1H, t, J = 8Hz), 7.91 (IHx (1/2), s), 7.94 (IHx (1/2), s), 8.02 (lHx (1/2), s), 8.21 (lHx (1/2), s); MS (FAB) m / z: 827 ((M + H) +). The title compound (diastereomer ratio of about 1: 1; 250.0mg, 0.30mmol) prepared above was dissolved in dichloromethane (5ml), and under ice-cooling, hydrogen chloride (4N ethyl acetate solution) was added. 75 · 7 // 1, 0.30 mmol), and stirred at the same temperature for 5 minutes.

The solvent was distilled off under reduced pressure to obtain the title object compound hydrochloride (262.2 mg, quantitative yield) as a pale yellow amorphous solid (diastereomer ratio = about 1: 1). IR (KBr) v Yan 2230, 1765, 1504, 1419, 1276, 1141, 1066, 973 cm-1;] HNMR (DMSO-d6, 400MHz): 5 1 · 2-1 · 4 (6Η, η), 1 · 25 (3Hx (1/2), dd, J = 7, 2Hz), 1.27 (3Ηχ (1/2), dd, J = 7, 2Hz), 1.45 (3Ηχ (1/2), d, J = 5Hz), 1.48 (3Η x (1/2), dJ = 5Hz), 2.5-2.7 (6H, m), 2.85-2.95 (3H, m), 3.05 (1H, brd, J = 13Hz) , 3.42 (lHx (1/2), t, J = llHz), 3.43 (lHx (1/2), t, J = llHz), 3.44 (lHx (1/2), t, J = llHz), 3.46 (lHx (1/2), t, J = 11HZ), 3.57 (lHx (1/2), q, J = 7Hz), 3.64 (1H x (1/2), q, J = 7Hz), 4.03- 4.08 (1H, m), 4.KM.15 (1H, m), 5.03 (lHx (1/2), d, J = 5Hz), 5.04 (lHx (1/2), d, J = 5Hz), 5.22 (lHx (1/2), d, J = 15Hz), 5.28 (lHx-299-200410948 (1/2), d, J = 15Hz), 5.43 (ΙΗχ (] / 2), d, J = 13Hz ), 5.46 (IΗχ (1/2), d, J = 13Hz), 5.88 (IHx (1/2), dd, J = 16, 5¾), 5.89 (lHx (] / 2), dd , J = 16, 5Hz), 6.58-6.62 (lHx (] / 2), m), 6.57 (lHx (] / 2), dd, J =] 6, llHz), 6.59 (lHx () / 2), dd, J = 16, nHz), 6.68 (lHx (1/2) q, J 2 5Hz), 6.82 (1H, d, J = 16Hz), 7.12-7.20 (1H, m), 7.19 (1H, dd, 16, 11Hz), 7.30-7.37 (1H, m), 7.41-7.50 (1H, m), 7.68 (1H, dd, J = 8, 1Hz), 7.85 (1H, dd, J = ll, 1Hz), 7,87 (1H, t, J = 8Hz), 8.05 (1H , S), 8.35 (IHx (1/2), s), 8.48 (IHx (1/2), s); MS (FAB) m / z: 827 ((non-hydrochloric acid portion + H) +). Example] 〇4- (cis-3 '5- · methyl-1-pulsadol) 4-oxobutanoic acid 1-[[(1R' 2R) -2-[[trans-2- [ (IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butanediyl] -1,3-Yipinyuan-5-yl] thio] -1- ( 2 '4-Yifan / phenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (Exemplified compound BU 72) ( 10a) cis-1- (allyloxycarbonyl) -4- (third butoxycarbonyl) -2,6-dimethylpipen, cis (third butoxycarbonyl) -3,5-dimethylpipeline ( He] V · Chi m · Acta ·, 73 巻, page 839 (1990); 3.76 g, 17.55 mmol) were dissolved in water (50 m 1), and sodium carbonate (2 · 2 0 was added under ice cooling). g'20 mm) and allyl chloroformate (2.4 lg, 20 mmol), and stirred at room temperature for 2.5 hours. Water was added to the reaction solution under ice-cooling, and the resultant was extracted with ethyl acetate. The organic layer was combined with water, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (Keinin: acetic acid • 300-200410948 ethyl ester, 1: 5-1: 2, V / V, silica gel 7 5 g) to obtain the title compound (4 · 7 4 g, yield 91 1%) is a colorless oily substance. IR (CHC13) 2Λ1ιαχ] 686, 1430, 1408, 1150, imcnf1;] H NMR (CDC13, 400MHz) · 51.24 (6H, d, J = 7Hz), 1.58 (9H, s), 2.90-3Ό8 (2H, br), 3.83-3.92 (1H, br), 3.92-4, 01 (1H, br), 4.18-4.26 (2H, br), 4.61 (2H, dt, J = 5, 2Hz), 5.21 (1H, dd) , J = 11, 2Hz), 5.30 (1H, dd, J2 17, 2Hz), 5.94 (1H, ddt, J = 17, Π, 5Hz); MS (FAB) m / z: 299 ((M + H ) +). (10b) cis-1- (allyloxycarbonyl) -2,6-dimethyl pipe trap Example 10 (100-1 cis-1- (allyloxycarbonyl) -4- (third butoxy Carbonyl) -2,6-dimethylpiperazine (4.72g, 15.8mmol) was dissolved in dichloromethane (10m 1), and under ice cooling, trifluoroacetic acid (15 m 1) was added, and at room temperature It was stirred for 30 minutes. The solvent was distilled off under reduced pressure. Toluene was added to the obtained oily residue. The solvent was distilled off under reduced pressure to remove volatile components (3 times) by azeotropy. Under ice cooling, an aqueous sodium hydrogen carbonate solution was added. Extracted with dichloromethane, combined the organic layers, washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated the solvent under reduced pressure to obtain the title compound (3.04 g, yield 97%) as a colorless oily substance. DR ( CHC13) ^ max 1684, 1409, 1316, 1106 cm-1:] HNMR (CDC13 '400MHz): (Π.29 (6H, d, J = 7Hz), 2.81 (2H, d, J = 12Hz), 2 · 87 (2H, dd, 4Hz) '4.11 (2H, qd, J = 7, 4Hz), 4.61 (2H, d, J = 5Hz), 5.20 (1H, d, J = 11Hz), 5.30 (1H , D, J = 17Hz), 5.95 (1H, ddt, 17, 11, 5Hz); MS (FAB) m / z: 199 ((M + H), (1 0 c) 4- [cis-4-(allyloxycarbonyl) -3,5-dimethyl-1-piperidinyl] -4-oxobutanoic acid-301-200410948 Example 1 〇 (] 〇b ) The obtained cis-bu (allyloxycarbonyl) -2,6-dimethylpiperazine (3.02 g, 15 · 23 m ni 〇]) was dissolved in dichloromethane (30 m)), Succinic anhydride (1.45 g, 14.47 m mol) was added under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure to obtain the title compound (4.53 g, quantitative yield) as a colorless amorphous solid. IR (CHC13) ^ Gu 1692, 1649, 1408, 1336, 1309, 1103, 1093cm-1;! H NMR (CDC13, 400MHz): 51.21 (3H, d, J = 7Hz), 1.30 (3H, d, J = 7Hz), 2.65 -2.81 (4H, m), 2.85 (1H, dd, J = 13, 5Hz), 3.34 (1H, dd, J = 13, 5Hz), 3.68 (1H, d, J = 13Hz), 4.28 -4 · 34 (2H, m), 4 · 44 (1H, d, J = 13Hz), 4 · 63 (2H, d, J · = 15Hz), 5 · 23 (1H, dd, 10, 1Hz), 5.31 (1H, dd, 17, 2Hz), 5.94 ° H, ddt, J2 17,10, 5Hz); MS (FAB) m / z: 299 ((M + H) +). (10d) 4- [cis-4- (allyloxycarbonyl) -3,5-dimethyl-1-piperidinyl] -4-oxobutanoic acid]-[[(1R, 2R) -2 -[[Trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl ] Thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl φ 4- [cis-4- (allyloxycarbonyl) -3 '5-dimethyl-1-piperidyl] -4-oxobutanoic acid (1.28 g, 4.3 mmol) was dissolved in N'N-dimethylformamide (15 ml) 'and 18-crown-6 (1.13 g, 4.3 mmol) and carbonic acid (6 2 8.8 mg, 1.93 m mol) were added. Stir at 40 ° C for 1 hour. 'Add chloroethyl carbonate (1 R' 2 R) _ 2-[[Trans-2-[(1 £, 3 £) -4 -(4-cyano-2-fluorophenyl) -1,3-butadienyl] "1,3-dioxane-5 -yl] thio]-丨-(2,4-difluorobenzene Radical) -1-[(1 H -1,2,4-triazol-1-yl) methyl] propyl ester (diastereomer ratio of about 2: 1 · '-302-200410948 1.1 ] g, 1 · 7 2π ^ ο 1), and stirred at room temperature for one hour. Under ice cooling, a phosphate buffer solution (60 m) was added to the reaction solution, and the crude product was extracted with ethyl acetate (50 m] X 3). The organic layer was combined, washed with water (300 mm x 3) 'and then with saturated brine (500 m), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 60: 40-20 ·· 80, V / V, silica gel 25g) to obtain the title compound (9 07.3 mg, yield 65%) Colorless amorphous solid (diastereomeric ratio = about 1: 1)

IR (KBr) 2; legs 2230, 1765, 1695, 1651, 1504, 1275, 1061 cm_1; hNMR (CDC13, 400MHz): (Π.17-1.21 (3H, m), 1.28-1 · 31 (3Η , Π〇, 1.36 (3H, dd, J = 7, 2Hz), 1.54 (3Hx (1/2), d, J = 6Hz), 1.56 (3Hx (1/2), d, J = 6Hz) , 2.6-2.7 (2H, m), 2.7-2.85 (4H, m), 2.99-3.07 (1H, m), 3.28 · 3.34 (1H, m), 3.48 (lHx (1/2), t, J ^ UHz), 3.49 (lHx (1/2), t, J = llHz), 3.50 (lHx (1/2), t, J ^ llHz), 3.68 (lHx (1/2), d, J = 14Hz), 3.2-3 / 78 (lHx (1/2), m), 3.78-3.85 (lHx (1/2), m), 3.88 (lHx (1/2), q, J = 7Hz), 4.17 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.18 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.25- 4.31 (3H, m), 4.40 ( ] H, d, J = 13Hz), 4.62 (2H, br d, J = 6Hz), 4.97 (lHx (1/2), d, J = 4Hz), 4.98 (lHx (1/2), d , J = 4Hz), 5.22 (1H, bi.d, J = 10Hz), 5.30 (1H, brd, J = 17Hz), 5.29-5.33 (lHx (1/2), m), 5.37 (1H, s), 5.43 (lHx (1/2), d, J = 15Hz), 5.85 (1H, dd, J = 16, 4Hz), 5.94 (1H, ddt, J = 17, 10, 5Hz), 6.58 〇H , Dd, J = 16 , 11Hz), 6.73 (1H, d, J = 16Hz), 6.72-6.75 (] Hx (1/2), m), 6.82 (IHx (1/2), q, J = 5Hz), 6.85-6.94 ( 2H, m), 6.93 (1H, dd, J = 16, 11Hz), 7.33 (1H, dd, J = 8, 1Hz), 7.40 (1H, dd, J = 8, 1Hz), 7.43 (1H, td, J = 9, 6Hz), 7.57 (1Π, t, J = 8Hz), 7.90 (1H, s), 7.94 (1H x (1/2), s), 8.20 (lHx (1/2), s );-303-200410948 MS (FAB) m / z: 911 ((M + H) +) 0 (] Oe) 4- (cis-3,5-dimethyl-: l-piperidinyl) -4 -Oxobutanoic acid b [[(1 R, 2 R)-2-[[trans-2-[(1 E, 3 E)-4-(4 -cyano-2 -fluorophenyl)-], 3 -Butadienyl] 3-dioxan-5-yl] thio] -l- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazole-butyl ) Methyl] propoxy] carbonyloxy] ethyl ester (the title object compound) 4- [cis-4- (allyloxycarbonyl) -3,5-di-diene produced in Example 10 (10d) Methyl-bupergyl] -4-oxobutanoic acid]-[[(1R, 2R) -2-[[trans-2-[(IE, 3E) -4- (4-cyano-2-fluoro Phenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorobenzene ) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (diastereomer ratio of about 2: 1: 1; 〇. 88g, 1.15mmol) was dissolved in dichloromethane (20ml), and under cooling with ice, tris (triphenylphosphine) osmium (6 6 · 4 mg, 0.0 5 8 mm ο 1) and 5,5-dimethyl- 1,3-cyclohexanedione (129.3 mg, 0.922 mmol), stirred under nitrogen for 45 minutes. The reaction solution was purified by silica gel column chromatography (ethyl acetate: methanol, 1 00: 0-80: 20, V / V, 15 g of silica gel) to obtain the title compound (7 6 1 · 9 mg, yield 9 5%) of a light brown amorphous solid (diastereoisomer ratio = about 1: 1). IR (KBr) umax 2230, 1765, 1644, 1504, 1275, 1142, 1067, 973 cm-1;] HNMR (CDC13, 400MHz): 5 1Ό4-1Ό7 (3H, m), 1.09 (3H, d, J = 6Hz), 1.36 (3H, d, J = 7Hz), 1.54 (3Hx (1/2), d, J = 6Hz), 1.55 (3Hx (1/2), d, J = 6Hz), 2 · 6_2 · 8 (6H, m), 3.03 (lHx (1/2), tt, J = ll, 5Hz), 3.03 (IHx (1/2), tt, J = 11, 5Hz, overlap), 3.47 (lHx (1/2), t, 11Hz), 3.48 (Ιχχ (1/2), t, 11Hz), 3.49 (1H x (1/2), t, J ^ llHz), 3.50 (lHx (1 / 2), t, J = llHz), 3.67 (IHx (1/2), br d, J = 13Hz), 3.74 (lHx (1/2), brd, J = 13Hz), 3.82 (lHx (1/2 ), Like q, J = ca. 7Hz), 3.88 200410948 (IΗχ (] / 2), q, J- = 7Hz), 4 ·] 6 (IΗχ (1/2), ddd, J = 11, 5, 2Hz), 4.18 (IHx (1/2), ddd, J = ll, 5, 2Hz), 4.28 (IHx (1/2), ddd, J = l], 5, 2Hz), 4.30 (lHx (1 / 2), ddd, J2]], 5, 2Hz), 4.45 (] H, brd, J2 13Hz), 4.97 (1H, brs), 5.32 〇Hx (1/2), dd, J =] 5, 3Hz), 5.37 (] H, s), 5.44 (lHx (1/2), d, J = 15Hz), 5.85 (] H, dd, J = 16, 4Hz), 6.58 (1H dd, J = 16, 11Hz), 6.73 (1H, d, J =) 6Hz), 6.74 (IHx (1/2), q-like, J = ca.5Hz), 6.82 (lHx (1/2) , Like q, J = ca. 5Hz), 6.84-6.95 (1H, m), 6.93 (1H, dd, J = 16, 11Hz), 7.33 (1H, dd, J = 10, 1Hz), 7.38_7 · 44 (1H, m), 7.40 (1H, dd, J = 8, 1Hz), 7.57 (1H, t, J = 8Hz), 7.91 (lHx (1/2), s), 7.95 (lHx (1/2 ), S), 8.02

(lHx (1/2), like d), 8.22 (lHx (1/2), s); MS (FAB) m / z: 827 (M + H) +). The title object compound (diastereomeric ratio = about 1: 1; 4 0 7.0 mg, 0.49 mm ο I) prepared above was dissolved in dichloromethane (5 m 1), and under ice cooling, Add hydrogen chloride (4N ethyl acetate solution; 123 μ 1, 0.49 mmol), and stir at the same temperature for 5 minutes. The solvent was evaporated under reduced pressure to obtain the title object compound hydrochloride (417.7 mg, yield 98%) as a pale yellow amorphous solid (diastereomer ratio = about 1: 1).

IR (KBr) vmax 1765, 1655, 1504, 1275, 1141, 1648, 973 cm_1;

bNMR (DMSO-d6 '400MHz): δ 1 · 1-1 · 2 (6H, br), 1.25 (3Hx (1/2), dd, J = 7, 2Hz), 1.27 (3Hx (1/2), dd, J = 7, 2Hz), 1.46 (3Hx (1/2), d, J = 5Hz), 1.48 (3H x (1/2), d, J = 5Hz), 2.3-3.0 (8H, m) , 3 ·· 0-3.1 (1H, m), 3.42 (lHx (1/2), t, J = llHz), 3.44 (lHx (1/2), t, J = llHz), 3.44 (lHx (1 / 2), 1, J = llHz, overlap), 3.47 (lHx (1/2), 1, J = llHz), 3.58 (lHx (1/2), q, J = 7Hz), 3.71-3.74 (lHx (1/2), m), 3.94498 (1H, m), 4.04-4.07 (1H, m), 4.1 (M.13 (1H, m), 4.37-4.40 (1H, m), 5.03 (lHx (1/2), d, J = 4Hz), 5.04 (lHx (1/2), d, J = 4Hz), 5.24 (lHx (1/2), d, J = 16Hz), 5.28 (lHx (1 / 2), d, J = 16Hz), 5.43 (lHx (1/2), cTJ = 12Hz), 5.46 (1H-305-200410948 x (1/2), d, J2) 2Hz), 5.88 (IΗχ (1/2), dd, J = 15, 4Hz), 5.89 (IΗχ (1/2), dd, J = 15, 4Hz), 6.57 (1Hx (1/2), dd, J = 15, 11Hz), 6.58 (IHx (] / 2), dd, J = 15, l] Hz), 6.62 (lHx (1/2), q, J = 5Hz), 6.68 (] Hx (] / 2), q , J = 5Hz), 6.82 (1H, d, J = 16Hz), 7.11-7.21 (1H, m), 7.18 (1Ηχ〇 / 2), dd, J =] 6, 11Ηζ), 7.19 (1Ηχ〇 / 2), dd, 16, 11Hz), 7.307.37 ( 1H, m), 7.41-7.51 (1H, m), 7.68 (1H, dd, J2 8, 1Hz), 7.84 (1H, dd, J2 10, 1Hz), 7.87 (1H, t, J = 8Hz) , 8.05 (lHx (1/2), s), 8.06 (lHx (1/2), s), 8.35 (lHx (1/2), like d), 8.46 &amp; 8.47 (lHx (1/2) all , Relative strength two 1: 1, each S); MS (FAB) m / z: 8 27 ((non-hydrochloric acid portion + H) +). Example 1 1 4- (4-Hydroxypiperidinyl) -4-oxobutanoic acid 1-[[(1 foot, 2 &amp;)-2-[[trans-2 [(IE, 3E) -4- (4 -Cyano-2-fluorophenyl) -1,3-butanediyl] -1, 3--1% 1--5-yl] thio] -1- (2 '4 -monochlorophenyl) -l-[(1H-1'2,4-triazole-butyl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound Bu 6 4) (11a) 4- (4-hydroxypiperidine 4-oxobutanoic acid Dissolve 4-piperidine (3.03 g, 30 mm ο 1) in dichloromethane (10 m 1), and add succinic anhydride (3.00 g, 3 Omm ο]), and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure to obtain a crude title compound (3.11 g, yield 52%) as a colorless solid.

Mp 105-112 ° C iHNMiUCDCb, 400MHz): δ 1.52-1.62 (2H, m), 1.87-1.95 (2H, m), 2.72 (4H, s). 3.72-3 / 79 (2H, m), 3.954.08 (3H, m): MS (El) m / z: 201 (M +). (] lb) 4- (4-hydroxypiperidinyl) -4-oxobutanoic acid 1-[[(1R, 2R) -2-200410948 [[trans-2-[(IE, 3E) -4- (4 -Cyano-2-fluorophenyl) -I, 3-butadienyl] -1,3-dioxan-5-yl] thio] _; [-(2,4-difluorophenyl) -Bu 2,4-triazolyl) methyl] propoxy] carbonyloxy] ethyl ester (the title objective compound) Example 11 (4- (4-hydroxypiperidinyl) -made from ΠΟ) -heart Oxybutyric acid (6 0 3 · 6 mg, 3 mm ο 1) was dissolved in N, N -dimethylformamide (1 0 m 1), and 1 8 -crown-6 (7 9 3 mg '3 mm ο 1) and carbonic acid planer (4.6 5 mg 'I. 4 mm ο 1). Stir at room temperature for 1 hour, and add 1_chloroethyl carbonate (1R, 2R) -2 produced in Example 1 (1 a). -[[Trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl ] Thio] _ ((2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazole-1 -yl) methyl] propyl ester (diastereomeric ratio = About]: 1; 78 mg, 1.2 mmol), and stirred at room temperature for 7 hours. Under ice cooling, water was added to the reaction solution, and the product was acetic acid Ester extraction three times. Combine the organic layers, wash with water (20 m 1 X 3), and then with saturated brine (30 m 1 X 1), dry under anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure. The crude title compound was obtained. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 2 5 ·· 7 5-0: 100, V / V, silica gel 2 5 g) to obtain the title. The target compound (6〗 9mg, yield 60%) is a colorless amorphous solid (diastereomer ratio = about 1: 1). IR (KBr) vmax 2230, 1765, 1641, 1504, 1275, 1141, 1068, 973 cm · 1;] HNMR (CDC13, 400MHz): 5 1.36 (3H, dd, J = 7.2Hz), 1.4-1.6 (2H, m), 1.54 (3Hx (1/2), dd, J = 6, 3Hz), 1.56 (3Hx (1/2), d, J = 6Hz), 1,82-1.98 (2H, m), 2.6-2.8 (4H, m), 3.0-3Ό8 (1H, m) , 3.12-3.24 (2H, m), 3.48 (IHx (1/2), t, J = 200410948]] Hz), 3.49 (mx (] / 2), t, J = llHz), 3.49 (lH, t , J = l 1Hz, overlap), 3.51 (1Ηχ (1/2), t, J =] lHz), 3.72-3.75 (ΙΗχ (1/2), m), 3.76-3.85 (1H, m), 3.88 (IHx (] / 2), q, J = 7Hz), 3.89-3.94 (1H, m), 4 .03-4.12 (1H, m), 4.15 (] Hx (] / 2), ddd, J =] l, 5, 2Hz), 4.18 (] Hx (] / 2), ddd, J =] l, 5 , 2Hz), 4.25-4.30 (IHx (] / 2), m), 4.30 (] H x (1/2) 'ddd, J =] l, 5, 2Hz), 4.97 (IHx (1 / 2), d, J two Hz), = 98 (lHx (1/2), d, J = 4Hz), 5.32 (lHx (1/2), brd, J two 15Hz), 5.38 (1H, s) , 5.46 (lHx (1/2), ddd, J = 15, 6Hz), 5.85 (1H, dd, J = 15, 4Hz), 6.58 (1H, dd, J = 15, 11Hz), 6.73 (lHx (1 / 2), q, J = 6Hz), 6.74 (1H, d, J = 16Hz), 6.80 (lHx (1/2), q, J = 6Hz), 6.84-6.95 (2H, m), 6.93 (1H , Dd, J = 16, 11Hz), 7.33 (1H, dd, J = 10, 1Hz), 7.40 (1H, dd 'J 2 8, 1Hz), 7.37-7.45 (1H' m), 7.57 (1H , T, J = 8HZ), 7.90 (lHx (1/2), s), 7.95 &amp; 7.96 (lHx (1/2) all, relative strength = i: i, each s), 8 · 0 2 & amp 8.03 (1Ηχ (1/2) all, relative intensity 1, each for s), 8.21 &amp; 8.04 (ΙΗχ (W2) all, relative intensity = 1: 1, each for s); MS (FAB) m / z: 8 14 ((M + H) +). Example 1 2

Monohydrogen phosphate 1- [4- [1-[[(1 &amp;, 2] ^)-2 _ [[trans_2 _ [(1] 5, 3E) -4- (4-cyano-2-fluorobenzyl ) · 1,3-butadienyl] _1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) _b [(1H-1,2, I Triazole_ ^ yl) methyl] propoxy] · oxy] ethoxy] _ 'oxobutyryl] -4-piperidine ester (exemplified compound; ^ 109) &gt; (12a) monoallyl phosphate l- [4 — [^ [[(,, 2r) -2 _ [[trans-2-[(1E, 3E) -4- (4-cyano-fluorophenyl) ", 3 • butadienyl] -1,3 -one-yin;): yuan-5-yl] thio] 2,4-difluorophenyl) ^, 2, trimethyl-1-yl) methyl] propoxy] carbonyloxy ] Ethoxy] -4-oxobutanyl] -4-piperidinyl ester-308-200410948 4-(4-hydroxypiperidinyl)-4-oxobutanoic acid 1-produced in Example π (1 1 b) [[(1R, 2R) -2-[[trans-2-[(] E, 3E) -4- (4-cyano-2-fluorophenyl)-], 3 -butadienyl] -1 , 3-dioxane-5-yl] thio] -2, 4-difluorophenyl) -bu [(1 Η -1,2,4-triazole-buyl) methyl] propoxy] Carbonyloxy] ethyl ester (diastereomer Material ratio = about 1: 1; 6 15 mg, 0.76 mmo 1) dissolved in dichloromethane, and under ice cooling, tetrazole (133.1 mg, 1.9 mmol), bis (allyloxy) (diisopropylamine) ) Phosphine (Tetrahedron Lett., 30 巻, page 4219 (1989); 27 8.1 mg, 1.13 mmol), and stirred at room temperature for 1 hour. A third butyl peroxide (0.3 ml) was added to the reaction solution, and after stirring for 20 minutes, an aqueous sodium hydrogen carbonate solution, an aqueous sodium thiosulfate solution and dichloromethane were added, and the mixture was partitioned between ethyl acetate and water. The organic layer was combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (methanol: ethyl acetate, 0: 100-5 · 95, V / V, 30 g of silica gel) to obtain the title compound (5 90 blood g, yield 80%). Colorless amorphous solid (diastereoisomer ratio = about 1 ·· 1) 〇IR (KBr) vmax 2230, 1765, 1647, 1504, 1275, 1142, 1054, 1018 cm · 1;] HNMR (CDC13 ^ 400MHz ): (5 L36 (3H ^ d ^ J-7Hz) ^ 1.54 (3Hx (1/2) »d Ί = 6Hz), 1.55 (3Hx (1/2), d, J = 6Hz), 1.7-2.0 ( 4H, m), 2.59-2.77 (4H, m), 3.03 (1H x (1/2), tt, J = ll, 5Hz), 3.03 (lHx (1/2), tt, J = ll, 5Hz) , 3.48 (lHx (1/2), t, J = llHz), 3.49 (lHx (1/2), t, J = llHz), 3.49 (lHx (1/2), t, J = llHz, overlap) , 3.50 (lHx 〇 / 2), t, J = 11Hz), 3.34-3.59 (2H, m), 3.62-3.77 (2H, m), 3.77-3.85 (lHx (1/2), m), 3.86 ( IHx (1/2), q, J 2 6Hz), 4.15-4.20 (1H, m), 4.25- 4.32 (1H, m), 4.54 (4H, t, J = 6Hz), 4.61-4.67 (1H, m ), 4.97 (lHx (1/2), d, J = 4Hz), 4.98 200410948 (] Ηχ (1/2), d, J = 4Hz), 5.27-5.50 (2H, m), 5.26 (2H, d , J ] 0Ηζ), 5.37 (2H, d, J =] 7Hz), 5.85 (] H, dd, J = 15, 4Hz), 5.94 (2H, ddt, J = 17,]], 6Hz), 6.58 ( 1H, dd, J = 16, 11Hz), 6.74 (IHx (] / 2), q, J = 5Hz), 6.74 (] H, d, J =] 6Hz), 6.81 (] Hx (1/2), q, J = 5Hz), 6.85-6.95 (2H, m), 6.93 (1H, dd, J = 16, l) Hz), 7.33 (lH.dd, 10, 1Hz), 7.40 (1H, dd, J = 10, 1Hz), 7.43 (1H, td, J = 9, 6Hz), 7.57 (1H, t 'J = 8Hz), 7.90 (IHx (1/2), s), 7.95 (IHx (1/2), s), 8.02 (lHx (1/2), s), 8.22 &amp; 8 · 24 (lHx (1/2) all, relative intensity = 1: 1, each for s); MS (FAB) m / z : 97 3 ((M + H) +). (12b) dihydrogen phosphate 1- [4- [1-[[(11,2 &amp;)-2-[[trans-2- φ [(ΙΕ, 3Ε) -4- (4-cyano-2-fluoro Phenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1 Η- 1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutanyl] piperidine ester (the title object compound) Manufactured in Example 12 (12a) Diallyl phosphate 1- [4-[[[(1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl)] -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1: [(111-1,2, 4-triazol-1-yl) methyl] propoxy] carbonyloxy] φ ethoxy] -4-oxobutanyl] -4-piperidinyl ester (diastereomer ratio of about 1: 1) 576.7 mg, 0.59 mmol) was dissolved in dichloromethane (10 ml), and bis (triphenylphosphine) palladium dichloride (2 0 · 8 mg, 0 · 0 3 mm 〇1) and tributyltin hydride (3 4 3 · 5 mg, 1 · 19 mm ο 1), stir for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was partitioned between an aqueous sodium hydrogen carbonate solution and hexane. The water layer was combined and the solvent was distilled off under reduced pressure to obtain a crude title object compound. The obtained crude title compound was subjected to reverse phase column chromatography (acetonitrile: water, 20: -310- 200410948 80-30: 70, V / V, using Cosmosi) 75 C18-PREPP using Cosmosil 75 Ci8-PREP (manufactured by Nakaraitesc). 25g) purified. Concentrated and lyophilized to obtain the title compound (diastereomer ratio = about 1:]) of sodium salt (colorless amorphous solid, 147 · 5 mg, yield 26%). 1R (KBr) 2ΛLi 223], 1764, 1636, 1504, 1418,] 276, 114], 977 cm · 1;] HNMR (CDCI3, 400MHz): 51.32 (3Hx (] / 2), dd, J = 7 , 2Hz), 1.33 (3Hx (1/2), dd, J 2 7, 2Hz), 1.52 (3Hx (1/2), d, J = 5Hz), 1.53 (3Hx (1/2), d, J = 5Hz), 1.63-1.70 (1H, m), 1.73-1.80 (] H, m), 1.83-1 · 90 (1Η, m), 1.92-1.98 (1H, m), 2.6-2.8 (4H , M), 2.98 (1H, tt, J = ll, 5Hz), 3.35-3.45 (2H, m), 3.51 (1H, t, J = llHz), 3.52 (1H, t, J = llHz), 3.75-3.86 (3H, m), 4.12 (1H, ddd, JII 11, 5, 2Hz), 4.244.30 (1H, m), 4.31-4.38 (1H, m), 5.01 (1H, d, J = 4Hz), 5.45 (2H, brs), 5.86 (1H, dd, J = 15, 4Hz), 6.58 (1H, dd, J = 15, 11Ηζ), 6.68 (1Ηχ (1/2), q , J = 5Hz), 6.78-7.82 (lHx (1/2), m), 6.79 (1H, d, J = 16Hz), 7.01-7.10 (2H, m), 7.09 (1H, dd, J 2: 16. ] lHz), 7.49-7.56 (3H, ni), 7.78 (1H, t, J = 8Hz), 8.02 (lHx (1/2), s), 8.03 (lHx (1/2), s), 8.37 &amp; 8 · 38 (lHx (1/2) all, relative strength 2: 1: 1, each s), 8.42 (1Ηχ (1/2), s); ^^ (? 8 6) 111 / 2: 938 ((2 sodium salts overall +1 ^) +). Example 1 3 4- [4- (Aminemethyl)] piperidinyl] -4-oxobutanoic acid [[(1 foot, 2 feet) [[trans-2-[(〗 E, 3E) -4 -(4-amino-2-fluoro / phenyl) -1'3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorobenzene Group) -1-[(1H-1,2,4-triazolyl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound 1-〖3 6) (13a) 4-(allyloxy Carboxamide methyl) -1- (third butoxycarbonyl) piperidine 4- (amine methyl tertiary butoxycarbonyl) piperidine (J. Med. Chem. 39 -311-200410948 巻, p. 4 87 (1996) records; 5.61 people, 26.2111171〇1) dissolved in water (8〇111]), added sodium carbonate (3.0 5 g, 2 8.8 mm ο 1), and allyl chloroformate (3.47 g , 2 8.8 mm ο 1), and stirred at room temperature for 15 hours. At room temperature, ethyl acetate was added to extract the product (80 ml x 3), and the organic layer was combined, washed with water, and then washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the crude title compound. . The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 80 ·· 20-1: 1, V / V, silica gel 100 g) to obtain the title compound (5 · 10 g, yield 6). 5%) colorless oily substance. IR (CHC13) vmax 1720, 1682, 1515, 1427, 1171, 1147〇1 ^;] HNMR (CDC13, 400MHz): 51.11 (2H, qd, J = 12, 4Hz), 1.45 (9H, s), 1.6- 1.7 (1H, m), 1.67 (2H, brd, J = 12Hz), 2.68 (2H, brt, J = 12Hz), 3.08 (2H, brt, J = 5Hz), 4.054.15 (2H, br) , 4.56 (2H, d, J = 5Hz), 4.76 = 4.82 (1H, br), 5.22 (1H, d, J = 10Hz), 5.30 (1H, dd, J = 17, 1Hz), 5.92 (1H, ddt , J = 17, 11, 5 Hz) MS (FAB) m / z: 299 ((M + H) +). (13b) 4- (allyloxycarbonylaminomethyl) piperidine 4- (allyloxycarbonylaminomethyl) -1-(third butoxycarbonyl) piperidine produced in Example 13 (13a) Pyridine (5.lg, 17,1 mm) was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (10 m 1) was added at 0 ° C. After stirring at room temperature for 15 minutes, the solvent was distilled off under reduced pressure, and toluene and the solvent were distilled off under reduced pressure twice to obtain an oily residue. The obtained oily residue was dissolved by adding water, sodium hydroxide (3 g) was added, and the resultant was extracted with dichloromethane. The organic layer was dried under anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound (3 〇3 g, yield 89%) colorless oily substance. -312- 200410948 IR (CHC13) ^] Amount 1720, 1680, 1515, 1246, 1185, 1142 cm ·];】 HNMR (CDC13, 400MHz): 5 U3 (2H, qd, J =] 2, 4Hz),] 55-1 · 64 (3H, m), 2.58 (2H, td, J = 12, 3Hz), 3.05-3.10 (4H, m), 4.56 (2H, d, J = 5Hz), 4.75 -4.85 (lH.br), 5.21 (1H, dd, 10, 1Hz), 5.30 (] H, dd, 17, 2Hz), 5.92 (1H, ddt, J2 17, 11, 5Hz); MS (El) m / z: 1 9 8 (M +) 〇 (13c) 4- [4- (allyloxycarbonylaminomethyl) piperidinyl] -4-oxobutanoic acid Manufactured from Example 1 3 (1 3b) 4- (allyloxycarbonylaminomethyl) piperidine (3.03 g, 15.2 mmol) was dissolved in dichloromethane (15 ml), and under ice cooling, succinic anhydride (1.33 g, 13.2 mmol) was added, and the solution was kept at room temperature. Stir for 2 hours. The solvent was distilled off under reduced pressure to obtain a crude title compound (4.30 g, yield 98%) as a colorless oily substance. ER (CHC13) vmax 1790, 1718, 1634, 1596, 1515, 1449 cm · 1; 4 NMR (CDC13, 400MHz): (Π.11-1.22 (2H, m), 1.78 (2H, br t, J = 13Hz), 1.78 (1H, m, overlap), 2.61 (1H, brt, J = 13Hz), 2.64-2.71 (4H, m), 3.01-3.15 (3H, m), 3.88 (1H, br d, 13Hz ), 4.56 (2H, d, J = 5Hz), 4.63 (1H 'br d, J = 13Hz), 4.82-4.87 (1H, b] · s), 5.22 (1H, d, 10Hz), 5.31 ( 1H, dd, J (2, 17Hz), 5.92 (1H 'ddt, J = 17, 11, 5Hz); MS (FAB) m / z: 299 ((M + H) +). (13d) 4- [ 4- (allyloxycarbonylaminomethyl) piperidinyl] oxobutanoic acid 1-[[((111,21〇-2-[[trans-2-[(1 £, 3 £) -4_ (4-cyan Phenyl-2-fluorophenyl 丨, 3-butadienyl] -1,3-dioxan-5-yl] thio] -b (2,4-difluorophenyl) -l-[(1H -1 '2, 4-triazole-butyl) methyl] propoxy] carbonyloxy] ethyl ester 4-[4-(allyloxycarboxamide) produced in Example 1 3 (1 3 c) Group) -313-200410948 piperidinyl] -oxobutanoic acid (]. 50 g, 5.0 mmol) was dissolved in N, N -dimethylformamide (20 m 1), and 1 8 -crown- 6 (1 · 6 6 g, 6.3 valence m ο 1) and carbonic acid (0.7 4 g, 2 · 3 mm ο〗). Stir at room temperature for 2 hours, and add 1-chlorocarbonic acid carbonate produced in Example 1 (la). Ethyl ester (1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1, 3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -bu [(1 H-1,2,4-triazole-buyl) methyl] propyl ester (Diastereomer ratio = about 1: 1; 1.3 g, 1. 8 mmol), and stirred at room temperature for 13 hours. Under ice cooling, a phosphate buffer solution was added to the reaction solution, and the resulting product was ethyl acetate The ester was extracted three times. The organic layer was combined, washed with water (30m 1x3), and then saturated brine (50m 1 X1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 60: 40-60: 10, V / V, silica gel 30g) to obtain the title compound (1.12g, yield 68%) Colorless amorphous solid (diastereomeric ratio = about 1: 1). IR (KBr) vmax 2230, 1765, 1720, 1643, 1504, 1275, 1257, 1141 cnf1;

iHNMR (CDC13, 400MHz): (5 1.UM.20 (2H, m), 1.36 (3H, dd, J = 7, 2Hz), 1.54 (3Hx (1/2), d, J = 6Hz), 1.55 (3Hx (1/2), d, J = 6Hz), 1.66-1.78 (3H, m), 2.49-2.75 (6H, m), 2.96-3.13 (4H, m), 3.49 (lHx ( 1/2), t, J ^ llHz), 3.50 (lHx (1/2), t, J = llHz), 3.50 (lHx (1/2), t, J = llHz, overlap), 3.52 ( lHx (1/2), t, J = llHz), 3.79-3.94 (2H, m), 4.19 (1H, m), 4.24-4.32 (1H, m), 4.54 (2H, brd, J = 5Hz), 4.57-4.61 (1H, m), 4.79-4.84 (1H, m), 4.98 (1H, d, J = 4Hz), 5.22 (1H, dd, J = 10, 2Hz), 5.35 (1H, dd, J = 17, 2Hz), 5.25-5.47 (2H, m), 5.85 (1H, dd, J = 16.5Hz), 5.88-5.94 (1H, m), 6.58 (lHx (1/2), dd, 16, 11Hz), 6.58 (1H 200410948 x (1/2), dd, J = 16, 1] Ηζ, overlapping), 6.73 (] Ηχ (] / 2), q, J = 5Hz), 6.73 (m, d, J =] 6Hz), 6.80 (lHx (] / 2), q, J = 5Hz), 6.84-6.95 (2H, m), 6.93 (] H, dd, 16, 11Hz), 7.33 (1H, dd , J = 10, 1Hz), 7.40-7; 46 (] H, m), 7.40 (1H, dd, J = 8,] Hz), 7.57 (1H, t, J = 8Hz ), 7.9] (IHx (] / 2), s), 7.95 (lHx (] / 2), s), 8.02 (] Hx (1/2), s), 8.22 (IHx (1/2), s ); MS (FAB) m / z: 911 ((M + H) +). (1 3 e) 4-[4-(Aminomethyl) piperidinyl] -4 -oxobutanoic acid 1-[[( 1 R, 2R) -2-[[trans-2-[(lE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3- Dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy ] Carbonyloxy] ethyl ester (the title object compound) 4- [4- (allyloxycarbonylaminomethyl) piperidinyl] -4 -oxobutanoic acid produced in Example 13 (13d)-[[( 1R, 2R) -2-[[trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-di Pinane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] Carbonyloxy] ethyl ester (diastereomeric ratio = about 1: 1 · 1 · 10 g, 1 · 2 1 mm ο 1) dissolved in dichloromethane (1 5 m 1) and cooled in ice (Triphenylphosphine) pin (6 9.8 mg, 0.06 mm ο 1) and 5, 5-monomethyl- 1 '3 -cyclohexanedione (118.7 mg' 0.85 mol) was stirred under nitrogen and room temperature for 40 minutes. The resulting reaction solution was purified by silica gel column chromatography (ethyl acetate-methanol, 100: 0-40: 60, V / V 'silica gel 30 g) to obtain the title object compound (777.2 mg, yield 78%) Pale yellow amorphous solid (diastereoisomer ratio of about two !: i). IR (KBr) vmax 2230, Π65, 1641, 1617, 1503, 1275, 1141 cnf1;

WnMR (CDC13, 400MHz): 51.08-1.20 (3H, m), 1.36 (3H, d, J = 7Hz), 1.53 200410948

(3Hx (1/2), d, J = 5Hz), 1.55 (3Hx (] / 2), d, J-2 5Hz), 1. 67-1.82 (2H, m), 2.49-3.07 (7H, m), 3.48 (IHx (1/2), t, J = 7Hz), 3.49 (] Hx (1/2), t, J = 7Hz), 3.49 (IHx (1/2), t, J = 7Hz , Overlap), 3.50 (lHx (] / 2) 't,] =]] Hz), 3.80-3 · 92 (2H, m), 4.154.20 (1H, m), 4.28 () Hx (1 / 2), ddd, J = 1, 5, 2Hz), 4.30 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.25-4.33 (1H, m), 4.59 (1H, br d, J = 13Hz), 4.98 (1H, d, J = 4Hz), 5.32 (lHx (1/2), d, J = 15Hz), 5.38 (1H, s), 5.44 (lHx (1/2 ), Dd, J = 15, 4Hz), 5.86 (1H, dd, 16, 4Hz), 6.58 (1H, dd, 16, 11Hz), 6.72-6.77 (lHx (1/2), m) , 6.73 (1H, d, J = 16Hz), 6.81 (lHx (1/2), q, J = 4Hz), 6.82-6.94 (2H, m), 6.93 (1H, dd, J = 16 , 11Hz), 7.40 (1H, dd, J = 7, 1Hz), 7.41-7.52 (2H, m), 7.57 (1H, t 'J = 8Hz), 7.91 (lHx (1/2), s), 7.95 〇Hx (1/2), s), 8.02 (lHx (1/2), s), 8.21 &amp; 8.24 (lHx (1/2) all, relative intensity = 1: 1, each s); MS ( FAB) m / z 827 (M + 1 ) + 〇 Example 1 4 4- (4-methyl-1-piperidinyl) -4-oxobutanoic acid [[(111,21〇-2-[[trans-2-[(1E, 3E)- 4- (4-cyano-2_fluorophenyl) _1,3-butadienyl] -1,3-dioxan-5-yl] thio] -i_ (2,4-difluorophenyl 1H-1,

2′xintril-1-yl) methyl] propoxy] carbonyloxy] methyl ester (exemplified compounds 1-4 4 9) (14a) chloromethyl carbonate (1R, 2R) -2 _ [[trans- 2-[(ie, 3E) -4- (4-cyano-2-fluorophenyl) -1,3 · butadienyl]-丨, 3-dioxan-5-yl] thio] -1 -(2,4-difluorophenyl) -bu [(i η -1,2,4-triazol-1-yl) methyl] propyl ester potassium hydride (dispersed in 30% mineral oil; 0.5 〇§, 3.8111111〇1) was dissolved in tetrahydrofuran (18ml), and under ice cooling, [(1 ε, 3Ε) -4- [trans-5-[[(lR, 2R) _2- (2,4,2 Fluorophenyl) hydroxy-p-methyl_3_ -316- 200410948 (1H-1,2,4-triazol-yl) propoxy] thio] -1,3-dioxane-2-yl] -1, 3-butadienyl] -3-fluorobenzonitrile (described in European Patent Publication No. EP1083175A2 (publication: 200) years; 1.09 g, 2.0 mmo]), and stirred at 0 ° C.] hours. At the same temperature, chloromethyl chloroformate (387 mg, 3.0 mm ο 1) was added and stirred for 15 minutes. Under ice cooling, a phosphate buffer solution (10 m 1) was added to the reaction solution, and the resultant was extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution, and then with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 90: 10-40: 60, V / V, silica gel 10g) to obtain the title compound (1.11g, yield 8). 7%) is a colorless amorphous solid. ER (CHC13) vmax 2233, 1769, 1732, 1617, 1504, 1277, 1257, 1140 cm · 1;】 HNMR (CDC13, 400MHz): 5 1 · 37 (3H, dd, J = 7, 2Hz), 3.04 ( 1Η, tt, J = ll, 5Hz), 3.49 (1H, t, J = llHz), 3.51 (1H, t, J = llHz), 3.92 (1H, q, J = 7Hz), 4.18 ( 1H, ddd, J = ll, 5, 2Ηζ), 4.29 (1H, ddd, J = ll, 5, 2Hz), 4.98 (1H, d, J = 4Hz), 5.36 (1H, dd, J = 15, 2Hz), 5.42 (1H, d, J = 15Hz), 5.69 (1H, d, J = 6Hz), 5.76 (1H, d, J = 6Hz), 5.86 (1H, d, J = 15) , 4Hz), 6.59 (1H, dd, J = 15, 11Hz), 6.74 (1H, d, J = 16Hz), 6.87-6.97 (2H, m), 6.93 (1H, dd, 16, 11Hz), 7.33 ( 1H, dd, J = 10, 2Hz), 7.40 (1H, dd, J = 8, 2Hz), 7.43 (1H, td, J = 8, 6Hz), 7.57 (1H, t, J = 8Hz), 7.96 (1H, s), 8Ό0 (1H, s); MS (FAB) m / z: 6 3 5 ((M + H) +). (14b) 4- (4-methyl-1-piperidyl) -4-oxobutanoic acid [[((1R, 2R) -2-[[trans-2-[(IE, 3E) -4- (4 -Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 -yl] thio] -1-(2,4-difluorophenyl)- 317- 200410948 -1-[(1H-1,2. Cardiotriazol-1-yl) methyl] propoxy] carbonyloxy] methyl ester (the title object compound) -4 -oxobutanoic acid (Bioorg. Med. Chem., 8 巻, page 2 693 (2000) words have been included; 6 0 · 7 mg, 3 m] η ο 1), Dissolved in N, N-dimethylformamide (10 ml), added carbonic acid (4 5 6.1 mg, 1.4 mmol), 1 8-crown-6 (7 9 3.0 mg, 3 mm ο 1) , And stirred at room temperature for 1 hour. To the mixture was added chloromethyl carbonate (1R, 2R) manufactured in Example 14 (14a). 2-[[Trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl)] -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2, 4-Triazol-1-yl) methyl] propyl ester (952.5 mg, 1.5 mmol) was stirred at room temperature for 2.5 hours. Under ice-cooling, a phosphate buffer solution (20 m 1) was added, and the resultant was extracted with ethyl acetate (30 m 1 × 3). The organic layer was combined, washed with water (20 ml x 3), and then washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title object compound. The obtained crude title compound was purified by silica gel column chromatography (ethyl acetate: methanol, 100: 0-90: 10, V / V, silica gel 20g) to obtain the title compound (1 009.7 mg, yield 84%). Crystalline solid. IR (KBr) vmax 2230, 1767, 1645, 1504, 1258, 1142 cm · 1; NMR (CDC13, 400MHz): 51 · 37 (3H, dd, J = 7, 2Hz), 2.30 (3H, s), 2.36 (2H, t, J = 5Hz), 2.41 (2H, t, J = 5Hz), 2.68 (1H, t, J = 7Hz), 2.70 (1H, t, J = 7Hz), 2.79 ( 1H, t, J = 7Hz), 2.80 (1H, t, J = 7Hz), 3.03 (1H, tt, 11, 5Hz), 3.47-3.53 (2H, br), 3.49 (1H, t, J = llHz) , 3.50 (1H, t, J = llHz), 3.62 (2H, brt, J = 5Hz), 3.90 (1H, q, J = 7Hz), 4.17 (1H, ddd, J = ll, 5, 2Hz), 4.27 (1H, ddd, J = 11, 5, 2Hz), 4.98 (1H, d, J = 4Hz), 5.35 (1H, dd, J = 15, 3Hz), 5.42 (1H, d, 200410948 J2] 5Hz), 5,74 (] Η, d, J2 6Hz), 5.84 (1H, d, J = 4Hz), 5.86 (1H, dd, J2] 1, 4Hz), 6.59 (] H, dd, 16, l] Hz), 6.74 (1H, d, J = 16 Hz), 6.85-6.96 (2H, m), 6.93 (] H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10,] Hz), 7.40 (1H, dd, J = 8, 1 Hz), 7.44, td, J = 9, 6 Hz), 7.57 (m, t, J = 8 Hz) , 7.93 (] H, s), 8.04 (] H, s MS (FAB) m / z: 7 9 9 ((M + H) +). 4- (4-methyl-1-piperidyl) -4-oxobutanoic acid [[(1R, 2R) -2-[[trans-2-[(lE, 3E ) -4- (4-cyano-2-fluorophenyl)-], 3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4- Difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] methyl ester (3 00.1 mg, 0.3 7 5 mm) Dissolve in dichloromethane (5ml), add ice-cold hydrogen chloride (4N ethyl acetate solution; 93.5 // 1, 0.3 7 4 mm ο 1) under ice cooling, and stir at the same temperature for 5 minutes. The solvent was distilled off under reduced pressure to obtain the title compound 1 hydrochloride (31 1 mg, yield 99%) as a pale yellow amorphous solid. IR (KBr) vmax 2230, 1767, 1653, 1504, 1418, 1142, 1976 cm · 1; 4 NMR (CDC13, 400MHz): 5 1.26 (3H, d, J = 7, 2Hz), 2.5-2.7 (9H, n〇, 2.8-3.1 (4H, br), 2.92 (lH, tt, J = ll, 5Hz), 3.43 (m, t, J = llHz), 3.43 (lH, t, J = 11Hz), 3.5-3.7 (2H, br), 3.63 (1H, q, J = 7Hz), 4.03-4.10 (2H, m), 5; 03 (1H, d, J = 5Hz), 5.28 (1H, d, J = 15Hz), 5.47 (1H, d, J = 15Hz), 5.71 (1H, d, J = 7Hz), 5.73 (1H, d, J = 7Hz), 5.88 (1H, dd, J = 16, 11Hz), 6.57 (1H, dd, J = 16, 11Hz), 6.82 (1H, d, J = 16Hz), 7.15-7, 22 (1H, m), 7.19 · (1H, dd, J = 16,) lHz ), 7.32-7.38 (1H, m), 7.49 (1H, td, J = 9, 6Hz), 7.68 (1H, dd, J = 8, 1Hz), 7.85 (1H, dd, J = n, 1Hz), 7.87 (1H, t, J = 8Hz), 8.06 (1H, s), 8.44 (1H, s); MS (FAB) m / z: 7 9 9 ((non-hydrochloric acid portion + H) +). -319- 200410948 Example 1 5 (4-methyl-]-piperidyl) acetic acid 1-[[1 R '2 R]-2-[[trans-2.-[(1 E, 3E) -4- (4 -Cyano-2-fluorophenyl) -1,3-butadienyl]- ], 3-Dioxan-5-yl] thio]-]-(2,4-difluorophenyl)-]-[(1 Η-], 2,4-triazole-1 -yl) methyl [Propyl]] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-9) (4-methyl-1-piperidyl) acetic acid (J. Med · Chem · '43 巻, page 1489 (2000) Words; 2.5 g, 15.8 mmol) were dissolved in water (30 ml), and stirred at 0 ° C. Carbonic acid (2 · 5 7 g, 7.9 mm ο 1) was added and stirred at room temperature for 1 hour. Distilled off under reduced pressure Water can be used to obtain crude (4-methyl-1-piperazyl) acetic acid (4.49 g, yield 98%) as a pale yellow solid. (670 mg, 2.3 mm ο 1) dissolved in N, N -dimethylformamide (5 m 1), and 1-chloroethyl carbonate (1R, 2R) -2-[ [Trans-1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1 -(2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] propyl ester (diastereomer ratio = about 1: 1; 50 mg, 0.77 mmol) of N , N-dimethylformamide (3ml) solution, and crown-6 (6 1 1 mg, 2.3 mm ο 1). The reaction solution was stirred at room temperature for 12 hours, and ethyl acetate (150 ml) and brine (50 ml) were added under ice-cooling. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate (x3). The organic layer was combined, washed with saturated brine (50m 1 X 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was subjected to cyclic separation by HPLC [LC-908; manufactured by Japan Analytical Industries; GPC column JAIGEL-1 Η (20 mmi. D. X 600 mm) and JA IG EL-2 H ( 2 0mm i. D. X 600 mm) used in series; solvent, chloroform] refined to obtain 200410948 title compound of interest (〖6] mg, yield 28%) light yellow oily substance (diastereomer The ratio is about 1: 1.

] HNMR (CDC13, 400MHz): 51.34 (3Hx (1/2), d, J = 7Hz), 1.36 (3Hx (1/2), d, J = 7Hz), 1.55 (3Hx (1/2), d , J = 5Hz), 1.57 (3Hx (1/2), d, J = 6Hz), 2.29 (3H, s), 2.48 (4H, brs), 2.61 (4H, brs), 2.99 -3.19 (1H, m), 3.26 (1H, s), 3.30 (1H x (1/2), s), 3.34 (lHx (1/2), s), 3.48 (1H, t, J = 13Hz), 3.50 (1H, t, J = 12Hz), 3.80 (] Hx (1/2), q, J = 7Hz), 3.87 (lHx (1/2), q, J = 8Hz) , 4.14-4.20 (1H, m), 4.25-4.28 (1H, m), 4.96 (lHx (1/2), d, J = 4Hz), 4.97 (lHx (1/2), d, J = 4Hz) , 5.31 -5.42 (2H, m), 5.85 (1H, dd, J = 15, 4Hz), 6.54-6.62 (1H, m), 6.68-6.81 (2H, m), 6.85-7.06 (3H, m), 7.33 (1H, dd, J = 10, 2Hz), 7.38-7.47 (2H, m), 7.57 (1H, t, J = 8Hz), 7.93 (lHx (1/2), s), 7.94 (lHx (1/2), s), 7.99 (lHx (1/2), s), 8.05 (lHx (1/2), s); MS (FAB) m / z: 77 1 ((M + H) +). HRMS (ESI +) m / z: C37H42F3N607S ((M + H) +) Calculated 値: 771.2788, Measured 値: 771.2761. The ethyl acetate (4 ml) solution of the title object compound (diastereomer ratio = about 1: 1; 148 mg, 0.20 mmol) prepared above was cooled at 0 ° C, and hydrogen chloride (4N ethyl acetate was added under stirring). Ester solution; 50 // 1, 0.20 mmol). The solvent was distilled off under reduced pressure to obtain an oily substance, which was dissolved in water (10 m 1) at 0 ° C. The insoluble matter was filtered off with a filter membrane, and the obtained aqueous solution was freeze-dried to obtain the hydrochloride salt of the title object compound (1 54 mg). Pale yellow amorphous solid (diastereomeric ratio = about 1: 1). ] Η NMR (DMSO-d6, 500MHz): (Π.24 (3Hx (1/2), d, J = 7Hz), 1.26 (3Hx (1/2), d, J = 7Hz), 1.48 (3Hx ( 1/2), d, J = 5Hz), 1.51 (3Hx (1/2), d, J = 5Hz), 2.36-3.51 (16H, m) '3.56 (lHx (1/2), q, J = 7Hz), 3.67 (lHx (1/2), q, J = 7Hz), 4.04-4.12 -321-200410948 (2H, m), 5.02 (ΙΗχ (1/2), d, J = 5Hz), 5. · 03 (ΙΗχ (] / 2), d, J = 5Hz), 5.23 (1H x (l / 2), d, J = 15Hz), 5.27 () Hx (; l / 2), d, J =] 5Hz ), 5.44 (lHx (] / 2), d, J =] 5Hz), 5.47 (lHx (1/2), d, J = 5Hz), 5.89 (1H, dd, J =] 6, 5Hz), 6.56 (] H, dd, J = 15,] 3Hz), 6.66 (] Hx (] / 2), q, J = 6Hz), 6.72 (] Hx 〇 / 2), q, J = 6Hz), 6.82 ( ] H, d, J = 16Hz), 7.16-7.22 (2H, m), 7.35 (1H, t, 11Hz), 7.42-7.50 (1H, m), 7.68 (1H, d, J = 8Hz), 7.84- 7.89 (2H, m), 8.06 (] Hx (1/2), s), 8.34 (lHx (1/2), s), 8.49 (lHx (1/2), s), 9.58 (lHx (1 / 2), s); MS (FAB) m / z: 771 ((M + H) +). HRMS (ESI +) m / z: C37H42F3N607S ((M + H) +) Calculate 値: 7 7 1.2788, practical collar!] {Straight: 771.2797 ° Example 1 6 4- (4-methyl-bupergyl) Butyric acid 1-[[(1R, 2R) -2-[[trans-2 [(IE '3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazole-butyl) methyl [Propyl]] propoxy] carbonyloxy] ethyl ester (exemplified compound B 4 7) 4- (4-methyl-1-piperidinyl) butanoic acid (J. Med. Chem., 43 巻, p. 1489 ( 2000) Yan Ji Zai; 502 mg, 2.7 mmo 1) Dissolved in N, N -dimethylformamide (5ml), added carbon shavings (43 6mg, 1.3mmol) and 1 8-crown-6 (7 1 4 mg, 2 · 7 mm ο 1). After the reaction solution was cooled at 0 ° C, dichloroethyl carbonate (ir, 2R) produced in Example 1 (la) was added. 2-[[Trans-2-[(1E, 3E) -4- (4- Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 -yl] thio] _ 1 _ (2,4-difluorophenyl) -1 -[(1 Η -1,2,4-triazol-1-yl) methyl] propyl ester (diastereomer ratio of about 丨:}; 7 0 0 mg, 1 · 1 mm ο 1) , And stirred at room temperature for 24 hours. Under ice cooling,-322-200410948 reaction solution was added with ethyl acetate (150 m), and brine (50 m). After the organic layer was separated, the aqueous layer was extracted with ethyl acetate (] ⑽m 1 x 3). The organic layer was combined, washed with saturated brine (50 m] X1), and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude title compound. The crude title compound thus obtained was subjected to HPLC [LC-908; manufactured by Japan Analytical Industries; GPC column JAIGEL-1H (20mm idx600mm) and JAIGEL-2H (20mm idx 600mm) were used in series; solvent, chloroform] was refined, The title object compound (23 3 mg, yield 27%) was obtained as a pale yellow oily substance (diastereomeric ratio = about 1: 1). · IR (KBr) i; max 3428, 2938, 2797, 2230, 1763, 1615, 1504, 1277 cm-1; bNMR (CDC13, 400MHz): 51.36 (3Hx (1/2), d, J = 7Hz), 1 · 36 (3Hx (1/2), d, J = 7Hz), 1.54 (3Hx (1/2), d, J = 5Hz), 1.54 (3Hx (1/2), d, J = 5Hz), 1.76-1.89 (2H, no, 2.26 (3Hx (1/2), s), 2.27 (3Hx (1/2), s), 2.33-2.50 (12H, m), 2.98-3.05 ( 1H, η), 3.48 (1H, t, J = llHz), 3.50 (1H, t, J = llHz), 3.77 (lHx (1/2), q, J = 7Hz), 3.88 (lHx (1 / 2), q, J = 7Hz), 4,10-4.20 (1H, m), 4.25-4.29 (1H, m), 4.97 (1H, d, J = 5Hz), 5.30-5.45 (2H, m) , 5.85 (1H, dd, J = 15, 4Hz), 6.58 (lH, dd, J = 15, 11Hz), 6.66-6.80 (2H, m), 6.85-7Ό0 (3H, m), 7.33 (1H , Dd, J = 10, 2Hz), φ 7.38-7.47 (2H, m), 7.52-7.59 (1H, m), 7.93 (1H, s), 7.99 (lHx (1/2), s), 8.03 (lHx (1/2), s); MS (FAB) m / z: 799 ((M + H) +). HRMS (ESI +) m / z: C 3 9 H 4 5 F 3 N 6 0 7 SN a ((M + N a) +) Calculated 値 8 2 1.29 20 ^ Measured 値: 8 2 1 .28 9 6 〇 Will include the title purpose of the above manufacturing A compound (diastereomer ratio = about 1: 1; 2 30 mg, 0.2 9 mm ο 1) in ethyl acetate (4 m 1) was cooled at 0 ° C, and hydrogen chloride (4N acetic acid) was added under stirring. Ethyl acetate solution; 72 ι,-323-200410948 0.20 m mol), the solvent was distilled off under reduced pressure, and the obtained oily residue was dissolved in water (5 m) at 0 ° C, and the insoluble matter was filtered through a membrane, The obtained aqueous solution was freeze-dried to obtain 234 mg of hydrochloride of the title object compound as a colorless amorphous solid (diastereomeric ratio of about 2: 1). IR (KBr) vmax 3412, 2939, 2797, 2230, 1764, 1615, 1504, 1276 cm-1;

4 NMR (DMSO-d6, 500MHz): 5 1.24 (3Hx (1/2), d, J = 7Hz), 1.26 (3Hx (1/2), d, J = 7Hz), 1.47 (3Hx (1/2 ), D, J = 5Hz), 1.48 (3Hx (1/2), d, J = 5Hz), 1.67-1.72 (2H, m), 2.32-3.51 (18H, m), 3.56 (lHx (1/2 ), Q, J = 7Hz), 3.70 (lHx (1/2), q, J = 7Hz), 4Ό4-4.12 (2H, m), 5.02 (lHx (1/2), d, J = 4Hz ), 5.04 (lHx (1/2), d, J = 4Hz), 5.24 (lHx (1/2), d, J = 15Hz), 5.27 (lHx 〇 / 2), d, J = 15Hz), 5.43 (lHx (1/2), d, J = 14Hz), 5.46 (lHx (1/2), d, J = 14Hz), 5.87 (lHx (1/2), dd, 15, 4Hz), 5.88 (lHx (1/2), dd, 15, 4Hz), 6.54-6.64 (1H, m), 6.62 (lHx (1/2), q, J = 5Hz), 6.70 (lHx (1/2), q , J = 5Hz), 6.81 (lH.d, J = 17Hz), 7.16-7.21 (2H, m), 7.31-7.34 (1H, m), 7.42-7.49 (1H, m), 7.67 (1H, d, J = 8Hz), 7.84-7.88 (2H, m), 8.04 (lHx (1/2), s), 8.06 (lHx (1/2), s), 8.30 (lHx (1/2) , S), 8.48 (lHx (1/2), s);

MS (FAB) m / z: 7 99 ((M + H) +). HRMS (ESI +) m / z: C39H45F3N607S ((M + H) +) Calculate 値 ·· 7 9 9 · 3 1 0 1, measured 値: 7 9 9.3 1 0 2 C39H45F3N607 S- (1/2) HC1-H20 Calculate 値: C, 56.09; Η, 5.73; N, 10.06; F, 6.82; α, 2.12; S, 3.84; Measured 値: C, 55.79; Η , 5.51; N, 9.95; F, 6.74; α, 2.05; S, 3.84. Example 1 7 4-(4-Aminomethylpiperidinyl) -4-oxobutanoic acid 1-[[(] R, 2R) -2-[[trans-2-[(1Ε, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -324-200410948 -1 '3-Yipinyuan-5-yl] thiol] -1- (2' 4- Dichlorophenyl) -1-[(1H-1'2,4-triazol-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound) -6 5) Succinic anhydride (3 0 g, 30 mm ο 1) dissolved in a mixed solvent of anhydrous tetrahydrofuran (50 m 1) and N, N -dimethylformamide (15 m), and stirred at room temperature. A solution of isopiperidinecarboxamide (3.9 g, 30 m mol) in anhydrous tetrahydrofuran (50 ml) was added, and the mixture was stirred at room temperature for 24 hours. The precipitate was collected by filtration to obtain crude 4- (4-aminomethyl piperidinyl D) oxybutyric acid (6.4 g, yield 94%) as a colorless solid. The obtained 4- (4-aminomethylpiperidinyl) -4-oxobutanoic acid (97 2 mg, 2.3 mmol) was dissolved in N, N-dimethylformamidine (20 ml), and carbonic acid planer (5 6 5 mg, 1.7 mmol) and 18-crown-6 (918 mg, 3.5 mmol). After the reaction solution was cooled at 0 ° C, 1-chloroethyl carbonate (1 R, 2R) produced in Example 1 (1 a) was added. 2-[[Trans- 2-[(1E, 3E) -4- ( 4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole-butyl) methyl] propyl ester (diastereomer ratio = about 1 ·· 1; 7 50 mg, 1.2 mm ο 1), Stir at room temperature for 3 days. Under ice-cooling, ethyl acetate (150 m 1) and brine (50 ml) were added to the reaction solution. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate (100m 1x3). The organic layer was combined, washed with saturated brine (50 m 1 X 1), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude title compound. The obtained crude title compound was subjected to cyclic separation by HPLC [LC-908; manufactured by Japan Analytical Industries; GPC column JAIGEL-1H (20mm idx600mn〇 and JAIGEL-2 Η (20 mmi · d. X 60 0 in m) Use in series; solvent, chloroform] Refine to obtain the title object compound (42 3 mg, yield 47%) as a colorless oily 200410948 substance (diastereoisomer ratio = about i:]). IR (KBr) vmax 3439, 3354, 2938, 2856, 2230, 1765, 1679, 1640, 1617, 1504, 1276 cm'1:

iHNMR (CDC13, 400MHz): (51.36 (3Hx (1/2), d, J = 6Hz), 1.36 (3Hx (1/2), d, J = 6Hz), 1.54 (3Hx (1/2), d , J = 5Hz), 1.55 (3Hx (1/2), d, J = 5Hz), L58-1.77 (2H, m), 1.83-1.99 (2H, m), 2.35-2.45 (1H, m), 2.56 -2.80 (6H, m), 3.00-3.18 (2H, m), 3.45-3.55 (1H, m), 3.49 (1H, t, J = llHz), 3.50 (1H, t, J ^ llHz), 3.79- 4.00 (2H, m), 4.KM.19 (1H, m), 4.22-4.29 (lHx (1/2), m), 4.464.60 (lHx (1/2), m), 4.98 (1H, d, J = 3Hz), 5.26-5.48 (3H, m), 5.85 (1H, dd, J = 15, 4Hz), 6.58 (1H, dd, J = 15, 11Hz), 6.74 (1H, d, J = 16Hz), 6.72-6.81 (1H, m), 6.84-7.00 (3H, m), 7.33 (1H, dd, J = 10, 2Hz), 7.38-7.46 (2H, m), 7.57 (1H, t, J = 7Hz), 7.90 (lHx (1/2), s), 7.95 (lHx (1/2), s), 8.02 (lHx (1/2), like d), 8.20 &amp; 8.24 (1H x ( 1/2) All, relative intensity = 1: 1, each s); MS (FAB) m / z: 841 ((M + H) +). HRMS (ESI +) m / z: C4〇44F3N609S ((M + H) +) Calculated 値: 841.2843, Measured 値: 841.2835 〇

Example 1 8 (Methyl-4-piperidinyl). Acetic acid 1-[[((1R, 2R) -2-[[trans-2 [(IE, 3E) -4- (4 ~ cyano-2- Fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl)-[(, 2, 4 _Triazole-butyl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-3 7 8) (18a) (bumethyl-4-piperidinyl) tert-butyl acetate 1-methyl Base, 4-piperidone (4.20g, 37.1mmol) and tert-butyl diethylphosphonium acetate (10.3g, 40.8mmol) were dissolved in tetrahydrofuran (150ml), -326-200410948 was added under cooling with stirring Potassium oxide (4.57 g '4 0 · 8 mm 01). Stir at room temperature for 1 hour 'and then stir at 3 5 ~ 4 5 ° C for 1 hour' to obtain a binding liquid mixture. The resulting mixture was cooled, and then partitioned between ethyl acetate and water. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude title compound. The obtained crude title compound was purified by silica gel column chromatography (ethyl acetate: methanol, 100: 0_80: 20, V / V, silica gel 50 g) to obtain the title compound (6.9 g, yield 88%) Colorless oil. IR (CHC13) vniax 2945, 2796, 1702, 1651, 1387, 1368, 1279, 1252, 1156, 1138 cm];] HNMR (CDC13, 400MHz): 51.475 (9H, s), 2.290 (3H, s) i2. 317 (2H, td, J = 6, 1Hz), 2.462 (2H, t, J = 6Hz), 2.477 (2H, t, J = 6Hz), 2.968 (2H, t, J = 6Hz), 5.578 ( m, s); MS (El) m / z: 211 (M +), 154, 110, 44; HRMS (ESI +) m / z: C12H21N02 (M +) Calculated 値: 211.1573, Measured 値: 211.1582. (18b) (1-methyl-4-piperidinyl) acetic acid hydrochloride The (1-methyl-4-piperidinyl) acetic acid tertiary butyl produced in Example 18 (18a) The ester (1.0 g, 4.7 mm) was dissolved in ethyl acetate (6 ml), and hydrogen chloride (4 N ethyl acetate solution; 6 m 1, 2 4 mm ο 1) was added under stirring, and the mixture was stirred at room temperature for 2 hours. . Add ethyl acetate (6 m 1) and hydrogen chloride (4 N ethyl acetate solution; 6 m 1, 2 4 m m ο 1), and stir at 40 to 50 ° C for 7 hours. The volatile components were distilled off under reduced pressure, and the residue was vacuum-pumped. Ethyl acetate was added to the obtained solid, and the volatile components were distilled off under reduced pressure to obtain the crude hydrochloride-327-200410948. The obtained crude hydrochloride was recrystallized from a mixed solvent of ethyl acetate-methanol to obtain pure hydrochloride (730 mg, yield 81%) as colorless needles. M p is about 1 8 5 ° C slowly sublimes, melting at 19 5 ° C; IR (KBr) ^ Yan 2721, 1721, 1714, 1659, 1206 ^ 1144 cm'1;] HNMR (CD3OD, 400MHz): 02.628 (2H , T, J = 6Hz), 2.902 (3H, s) '3.2-3.4 (6H, m), 5.888 (1H, s); MS (El) m / z: 155 ((non-hydrochloric acid part) +); HRMS (El) C8H13N02 ((non-hydrochloric acid part) +) Calculated 値 · 1 3 3.0947, found 値: 1 5 5.0 9 4 5 C 8 H i 3 Ν 2-H C 1 Calculate 値: C, 50.14; Η, 7.36; N, 7.31; Cl, 18.50. Measured radon: C, 49.81; Rhenium, 7.48; N, 7.24; Cl, 18.73. (18c) (1-methyl-4-piperidinyl) acetic acid 1-[[((1R, 2R) -2-[[trans-2-[(IE, 3E)-(4-cyano-2- Fluorophenyl) -1,3-butadienyl] -1,3-difluorenfane-5 -yl] thio] -1-(2,4-difluorophenyl) -1-[(1H -1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound) Piperidinyl) acetic acid hydrochloride (575 mg, 3.0 mol) was dissolved in methanol (12 ml), and carbonic acid (97 7 mg, 3.0 mmol) was added, followed by stirring at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and the residue was vacuum-pumped to obtain a crude methyl-4-piperidinyl) acetic acid-containing planed solid containing chloride. The obtained crude (1-methyl-4 -piperidinyl) acetic acid (full amount), 1-chloroethyl carbonate (1 R, 2 R)-2-[[trans -2-1 (IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1, 200410948 3-Ershuyuan-5-yl] thio ] -L- (2,4-difluorophenyl) -l-[(1H-1 '2,4-triazole- 丨 _yl) methyl] propyl ester (diastereomeric ratio = about 1 : 1; 1 · 30 g, 2 · 0 mm ο 1), and a mixture of N, N -dimethylacetamide (20 m 1), and stirred at room temperature for 94 hours. Ethyl acetate and 0% sodium chloride were added to the reaction mixture to separate the layers. The resulting organic layer was separated, washed with 10% saline (5 times), and then saturated brine (1 times), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude mixture of two diastereomers of the title object compound (diastereomer ratio = about 1: 1). The resulting mixture was purified by silica gel column chromatography (silica gel 3 3 g), and dissolved in a mixed solvent of ethyl acetate: methanol (94: 6-90: 10, V / V) to obtain the title compound of low polarity. Enantiomer A (205 mg, 13% yield) as a pale yellow amorphous solid. Dissolve in a mixed solvent of ethyl acetate: methanol (88:12, V / V) to obtain a mixture of low-polar diastereomer A and high-polar diastereomer B of the title object compound (50 mg , Yield 3%) light yellow amorphous solid. Redissolve in a mixed solvent of ethyl acetate: methanol (8 4: 1 6- 80: 20, V / V) to obtain the highly polar diastereomer B (90 mg, yield 6%) of the title object compound. Yellow amorphous solid. Diastereomer A (low polarity) spectral data: IR (CHC13) 2; max 2233, 1759, 1732, 1649, 1616, 1505, 1388, 1277, 1139 cm · 1;】 H NMR (CDC13, 400MHz) : 5 1.361 (3H, dd, J = 7, 2Hz), 1.553 (3H, d, J = 5Hz), 2.303 (3H, s), 2.37-2.40 (2H, m), 2.45-2.55 (4H, m) , 2.9-3.1 (3H, m), 3.486 (2H, t, J = 11Hz), 3.892 (1H, q, J = 7Hz), 4.180 (1H, ddd, J = ll, 5, 2Hz), 4.285 (1H , Ddd, J 2:11, 5, 2Hz), 4.968 (1H, d, J = 5Hz), 5.37 (1H, dd, J = 16, 3Hz), 5.40 (1H, d, J = 16Hz), 5.644 (1H , S), 5.855 (1H, dd, J = 16, 5Hz), 6.582 200410948 (1H, dd, J = 16,] 1Ηζ), 6.74 (1Η, d, J =) 6Hz), 6.753 (1H, q, J = 5Hz), 6.8-7.0 (2H, m), 6.92 (1H, dd, J =] 6,] lHz), 7.334 (1H, dd, J = 10, 1Hz), 7.400 (1H, dd, J = 8, 1Hz), 7.445 (1H, td, J = 8, 6Hz), 7.569 (] H, t, J = 8Hz), 7.916 (1H, s), 8.0] 8 (m, s); MS (FAB) m / z: 768 ((M + H) +); HRMS (ESI +) m / z: C38H41F3N5〇7SSi ((M + H) +) Calculated 値: 768.2679, measured 値: 76 8.2675. Diastereomer B (high polarity) spectral data: IR (CHC13) vmax 2233, 1760, 1731, 1649, 1616, 1505, 1388, 1277, 1140 cm-1;

4 NMR (CDC13, 400MHz): 5 1.367 (3H, dd, J = 7, 2Hz), 1.554 (3H, d, J = 5Hz), 2.3-2.6 (6H, m), 2.9-3.1 (3H, m) , 3.474 (1H, t, J = llHz), 3.496 (1H, t, J = llHz), 3.771 (1H, q, J = 7Hz), 4.16 (1H, ddd, 11, 5, 2Hz), 4.277 (m, ddd, J = ll, 5, 2Hz), 4.965 (1H, d, J = 4Hz), 5.37 (1H, dd, J = 16, 3Hz), 5.41 (1H, d, J = 16Hz), 5.728 (1H, s), 5.854 (1H, dd, 15, 4Hz), 6.585 (1H, d, J = 15, 10Hz), 6.723 (1H, d, J = 16Hz), 6.805 (1H, q, J = 5Hz), 6.85-7.0 (3Η, m), 7.332 (1H, dd, J = 10, 2Hz), 7.399 (1H, dd, J = 8, 2Hz), 7.39-7.44 (1H, m ), 7.567 (1H, t, J = 8Hz), 7.940 (1H, s), 8.038 (1H, s);

MS (FAB) m / z: 768 ((M + H) +); HRMS (ESI +) m / z: C38H41F3N507SSi ((M + H) +) Calculated 値: 768.2679, measured 値: 768.2687. A mixture of about 1: 1 diastereomer A and diastereomer B of the title object compound (total 3 45 mg, 0.445 mmol) was dissolved in ethyl acetate (4 0 m 1) at -4 Hydrogen chloride (1 N ethyl acetate solution; 0.6 m 1, 0.6 mm ο 1) was added dropwise under cooling and stirring at 0 ° C. The solvent was distilled off under reduced pressure, and the residue was dissolved in water (20 m 1) and filtered. The filtrate was freeze-dried to obtain 1 hydrochloride salt (320 mg) of the title object compound as a pale yellow solid (diastereomeric ratio = About 1:

-330-200410948 Example 1 9 4-(4-methyl-1 -piperidinyl) -4 -oxobutanoic acid 1-[[(1 R, 2 R)-2-[[Trans-2-[( IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1 '3-yibo-5-yl] thio]-i- (2 , 4-mono-phenyl) -1-[(]. H-], 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-7 0 ) 4- (4-methyl-1-fluorenyl) -4-oxobutanoic acid (Bioorg · Med · Chem · Let., 88 '2877 (1998)); 925mg, 4.6 mmol ) Dissolved in water (5ml), added carbonic acid planer (7 5 3 mg, 2.3mmol), and freeze-dried the resulting aqueous solution to obtain 4- (4-methyl-1-piperidyl) -4-oxobutanoic acid planer salt. The obtained planed salt (full amount) was dissolved in N, N-dimethylformamide (7 m 1), and dichloroethyl carbonate (1R, 2R) -2-[[trans ^ · 2-[(lE'3E) -4- (4-amino-2-chlorophenyl) -1'3-butanediyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propyl ester (diastereomer ratio = about 1: 1; 1.0 g, 1.5 mmoI) and 18-crown-6 (1.2 g, 4.6 mmol). After stirring at room temperature for 15 hours, ethyl acetate (150 m 1) and brine (50 m 1) were added to the reaction solution under ice-cooling. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate (100 m 1 X 3). The organic layer was combined, washed with saturated brine (50 m 1 X), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was subjected to cyclic separation by HPLC [LC-908; GPC column JAIGEL-1H (20 mm i.d. X 600 mm) and JAIGEL-2H (20mm idx600mm) Continuous use; solvent, chloroform] to produce '' the title target compound (3 20 mg, yield 26%) light brown oily substance (diastereoisomer ratio of about 1: 1.). 200410948] HNMR (CDC) 3, 400MHz: 51.36 (3Hx (1/2), d, J = 7Hz), 1.36 (3Hx (1/2), d, J = 7Hz), 1.54 (3Hx (1/2 ), D, J = 5Hz), 1.55 (3Hx (] / 2) 'd, J = 5Hz), 2.29 (3H x (1/2), s), 2.30 (3Hx (1/2), s ). 2.33-2.41 (4H, m), 2.56-2.75 (4H, m), 3Ό0-3Ό6 (1H, m), 3.45-3.53 (4H, m), 3.60-3.64 (2H, m), 3.83 (lHx (1 / 2), q, J = 7Hz), 3.88 (lHx (1/2), q, J = 7Hz), 4.15-4.20 (1H, m), 4.26-4.32 (1H, m), 4.97 (1H, d , J = 3Hz), 5.29-5 · 46 (2H, m), 5.85 (1H, dd, J = 15, 4Hz), 6.58 (1H, dd, J =] 5, 11Hz), 6.73 (1H, d, J = 16Hz), 6.73 (lHx (1/2), q, J = 5Hz), 6.81 (lHx (1/2), q,

J = 5Hz), 6.84_6 · 96 (3H, m), 7.33 (1H, dd, J = 10, 2Hz), 7.38_7.46 (2H, m), 7.57 (lHx (1/2), t, J = 8Hz), 7.58 (lHx (1/2), t, J = 8Hz), 7.91 (lHx (1/2), s), 7.95 (lHx (1/2), s), 8.02 (lHx (1 / 2), s), 8.23 (lHx (1/2), s); MS (FAB) m / z: 813 ((M + H) +). HRMS (ESI +) m / z: C39H44F3N608S ((M + H) +) Calculated 値: 813.2894, Measured 値: 813.2886.

An ethyl acetate (10 ml) solution containing the title compound of interest (diastereomeric ratio = about 1: 1; 320 mg, 0.39 mmol) was cooled at 0 ° C, and hydrogen chloride (4N ethyl acetate) was added with stirring. Ester solution; 9 8 // 1, 0.3 9 mmol), and the solvent was distilled off under reduced pressure to obtain an oil, which was dissolved in water (1 5 m 1) at 0 ° C, and the insoluble matter was removed by membrane filtration, and the obtained aqueous solution was frozen After drying, 3,19 mg of the hydrochloride salt of the title object compound was obtained as a pale yellow amorphous solid (diastereomeric ratio = about 1: 1). IR (KBr) ^ max 3437, 2938, 2230, 1765, 1651, 1616, 1504, 1275 cnV1; 4 NMR (DMSO-d6, 500MHz): δ 1.24 (3Hx (1/2), d, J = 8Hz), 1.26 (3Hx (1/2), d, J = 8Hz), 1.46 (3Hx (1/2), d, J = 6Hz), 1.47 (3Hx (1/2), d, I 3 6Hz), 2.36- 3.60 (18H, m), 3.57 (lHx (1/2), q, J = 7Hz), 3.73 (lHx (1/2), q, J = 7Hz), 4.04-4.12 (2H, m), 5.03 ( lHx (1/2), d, J = 5Hz), 5.04 (lHx (1/2), d, I 竽 Hz), 5.24 (lHx (1/2), d, J = 15Hz), 5.27 (lHx ( 1/2), d, J = 15Hz), 5.43 (lHx (1/2), d, J = 15Hz) '-332-200410948 5.45 (IHx (] / 2), d, J =] 5Hz) , 5.88 (ΙΗχ (1/2), dd, J = 15, 4Hz), 5.89 (IHx (1/2), dd, 15, 4Hz), 6.54-6.63 (] H, m), 6.62 (IHx (] / 2), q, J = 5Hz), 6.68 (] Hx (] / 2), q, J = 5Hz), 6.82 (1H, d, 15Hz), 7.14-7.21 (2H, m), 7.31-7.36 ( 1H, m), 7.42-7.50 (1H, m), 7.68 (1H, d, J = 8Hz), 7.84-7.89 (2H, m), 8.05 (lHx (1/2), s), 8.06 ( lHx (1/2), s), 8.35 (lHx (1/2), s), 8.47 (lHx (1/2), s), 10.09 (1H, brs); MS (FAB) m / z: 813 ((M + H) +). HRMS (ESI +) m / z: C39H43F3N608SNa ((M + Na) +) Calculated: 835.2713. Found 値: 835.2711. C39H43F3N608S · (2/3) HC1 · (9/4) H20: C, 53 · 37; Η, 5.53; N, 9.58; Cl, 2.69; F, 6.49; S, 3.65. Found 値: C, 53.15; H, 5.30; N, 9.39; Cl, 2.81; F, 6.47; S.3.59. Example 2 0 4- [4- (2-Acetylaminoethyl) -1-piperazyl] -4-oxobutanoic acid 1-[[(1 foot, 2R) -2-[[trans-2- [(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butane-1-yl] -1 '3 -_Yuan-5-yl] thio] -1- ( 2 '4 -monochlorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-7 4) (20a) (benzyloxycarbonyl) -4- [2- (benzyloxycarbonylamino) ethyl] piperidine Dissolve 1- (2-aminoethyl) piperidine (4.0g, 31mmol) in water (60ml .), Stir at room temperature. Add sodium carbonate (7.8 g, 74 mm) and benzyl chloroformate (30% toluene solution; 4 3 m 1, 68 m m ο 1), and stir at room temperature for 12 hours. Hydrochloric acid was added to bring the reaction solution to pH = 10, and the resultant was extracted with ethyl acetate (80 ml x 4). The organic layer was combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate-333-200410948 ester, 50:50, V / V) to obtain the title compound (2.1 g, yield〗 7%) , Colorless oily substance. IR (liquid film) u max 3342, 2946, 1703,] 530, 1455, 1432, 124] cm · 1; 1Η NMR (CDC13, 400MHz): 5 2.40 (4H, br s), 2.48 (2H, t, J = 6Hz), 3.30 (2H, brt, J = 6Hz), 3.48-3.50 (4H, m), 5.10 (2H, s), 5.13 (2H, s), 5.21 (1H, brs), 7.29-7.52 (10H, m); MS (FAB) m / z: 398 ((M + H) +). HRMS (ESI +) m / z: C22H28N304 ((M + H) +) Calculated 値: 398.2080, Measured 値: 398.2069. (20b) l- [2- [N-Ethyl-N- (benzyloxycarbonyl) amino] ethyl] -4- (benzyloxycarbonyl) pipe trap 1- (produced in Example 20 (20a) Benzyloxycarbonyl) -4- [2- (benzyloxycarbonylamino) ethyl] piperidine (1.9g, 4.8mmol) was dissolved in N, N-dimethylformamide (15ml) and stirred at ° C Add a suspension of sodium hydride (dispersed in 55% mineral oil; 2 3 1 mg, 5 · 3 mm ο 1) in N, N -dimethylformamide (1 5 m 1), and stir at room temperature for 1 hour . After cooling at -78 ° C, a solution of N, N-dimethylformamide (10 ml) in acetamyl chloride (0.82 ml, 11.6 m mol) was added and stirred at room temperature for 15 hours. After the reaction solution was cooled at 0 ° C, an aqueous solution of sodium hydrogencarbonate (50 ml) was added, and the mixture was extracted with ethyl acetate (80 m 1x4). The organic layer was combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 60:40, V / V) to obtain the title compound (1.0 g, yield 48%) as a yellow oily substance. IR (liquid film) u max 2949, 2813, 1738, 1703, 1431, 1346cm · 1;】 HNMR (CDC13, 400MHz): (5 2.36 (4H, s), 2.45 (2H, t, J = 7Hz) , 2.49 (3H, s), 3.39-3.40 (4H, ni), 3.86 (2H, t, J = 7Hz), 5.12 (2H, s), 5.22 (2H, s), 7.30 200410948 -7.42 (10H, n0; MS (FAB) m / z: 440 ((M + H) +). HRMS (ESI +) m / z: C24H300N305 ((M + H) +) Calculated 値: 440.2186, found 値: 440.2] 90. (20c) 4-[4-(2 -Ethylamidoethyl) _ 1 -piperidinyl]-4-oxobutanoic acid 1-[[(1R, 2R) -2- [[trans -2 — [(IE, 3E) -4- (4-cyano-2-chlorophenyl)-] '3-butanyl group] -1' 3-Secondary Institute-5-yl] thio group ] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (Title Purpose Compound) 1- [2- [N-Ethyl-N- (benzyloxy) amino] ethyl] -4- (oxybenzyl) 卩 jg produced in Example 20 (20b) ( 1.0 g, 2.3 mmol) was dissolved in ethanol (25 ml), palladium hydroxide-carbon catalyst (20%; 300 mg) was added, and the mixture was stirred under hydrogen (normal pressure) and room temperature for 6 hours. The reaction solution was filtered through diatomaceous earth, and the solid matter was washed with dichloromethane (50 m 1). The solvent was distilled off under reduced pressure to obtain a crude 1-(2-acetamidoethyl) pipette. Dissolved in N, N-dimethylformamide (8 m 1), and a solution of succinic anhydride (228mg, 2.3mmol) in N, N-dimethylformamide (3ml) was added under stirring at 0 ° C, and the mixture was stirred at room temperature. 12 hours. The solvent was distilled off under reduced pressure to obtain crude 4- [4- (2- (acetamidoethyl) -1-piperidyl] -4-oxobutanoic acid. It was dissolved in N, N-dimethylformate. Methylformamide (12inl), add carbon shavings (3 4 8 mg, 1.1 mm 1 ο 1) and 18-crown-6 (5 6 5 mg, 2 · 1 mm ο 1) with stirring at 0 ° C. ), And then added in Example 1 (1-chloroethyl carbonate (1R, 2R) -2- [[trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl ) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -bu [(1H-1,2,4 _Triazol-1-yl) methyl] propyl ester (diastereomeric ratio = about 1: 1; 770 mg; 1.2 mmol). After being stirred at room temperature for 2 days, ethyl acetate (150 m 1) and brine (50 m) were added to the reaction solution under ice cooling in 200410948. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate (100m; 1 × 3). The organic layer was combined, washed with saturated brine (50 m 1 χ 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was circulated and separated. PLC [LC-9 0 8; manufactured by Japan Analytical Industries; GPC columns JAIGEL-1H (20mm idx600mm) and JAIGEL-2H (20mm idx600mm) were used in series; solvent, chloroform ] Refined, the title object compound (338 mg, yield 32%) was obtained as a pale yellow oily substance (diastereoisomer ratio = about 1: 1). IR (liquid film) v max 3327, 3002, 2232, 1765, 1645, 1505, 1276cm · 1;] HNMR (CDC13, 400MHz) ·· 51.36 (3Hx (1/2), d, J = 7Hz), 1 · 36 (3Hx (1/2), d, J = 7Hz), 1.54 (3Hx (1/2), d ,; T = 6Hz), 1.55 (3Hx (1/2), d, J = 6Hz), 2.00 (3H, s), 2.40-2.41 (2H, m), 2.47-2.51 (4H, m), 2.59-2.76 (4H, m), 3.00-3.06 (1H, m), 3.35- 3.36 (2H, m) , 3.48 (1H, t, J = llHz), 3.49 (1H, t, J = llHz), 3.45-3 · 53 (2H, m), 3.61-3 · 69 (2Η, m), 3 · 83 (1Ηχ (1/2), q, J = 7Hz), 3.88 (lHx (l / 2), q, J = 7Hz), 4.16-4.20 (1H, m), 4.26-4.32 (1H, m) , 4.98 (1H, br s), 5.29-5.47 (2H, m), 5.86 (1H, dd, J = 15, 5Hz), 5.88 (1H, brs), 6.59 (1H, dd, J = 15, 10Hz), 6.74 (1H, d, J = 15Hz), 6.74 (lHx (1/2), q, J = 7Hz), 6.81 (lHx (1/2), q, J = 7Hz), 6.83 7.00 (3H, m), 7.33 (1H, dd, J = 11, 2Hz), 7.37-7.44 (2H, m), 7.57 (1H't, J = 7Hz), 7.91 (lHx ( 1/2), s), 7.95 (lHx (1/2), s), 8.02 (lHx (1/2), s), 8.25 (lHx (1/2), s); MS (FAB) ni / z: 884 (( M + H) +). HRMS (ESI +) m / z: C42H49F3N7〇9S ((M + H) +) Calculated 884.3265, measured 値: 884.3281. The ethyl acetate (8 m 1) solution containing the title compound of the title (diastereomer ratio = about 1: 1; 3 2 8 mg, 0.37 mm ο 1) was cooled at 0 ° C,- 336-200410948 Hydrogen chloride (4N ethyl acetate solution; 93 // 1; 0.3 7 mmol) was added under stirring, and the solvent was distilled off under reduced pressure. J. The obtained oily residue was dissolved in water (8 m ]), The insoluble matter was removed by membrane filtration, and the obtained aqueous solution was freeze-dried to obtain the hydrochloride salt of the title object compound, 332 mg, as a colorless amorphous solid (diastereoisomer ratio = about: 1). IR (KBr) vmax 3284, 2936, 2230, 1765, 1655, 1616, 1504, 1276 cm-1;

hNMR (DMSO-d6, 400MHz): 5 1.24 (3Hx (1/2), d, J = 7Hz), 1.26 (3Hx (1/2), d, J = 7Hz), 1.45 (3Hx (1/2) , D, J = 5Hz), 1.48 (3Hx (1/2), d, J = 5Hz), 1.84 (3H, br s), 2.33-3.64 (19H, m), 3.57 (lHx (1/2 ), Q, J = 7Hz), 3.76 (lHx (1/2), q, J = 7Hz), 3.93-4.10 (2H, m), 5.03 (lHx (1/2), d, J = 5Hz), 5.04 (lHx (1/2), d, J = 5Hz), 5.24 (lHx (1/2), d, J = 16Hz), 5.28 (lHx (1/2), d, J = 16Hz), 5.43 (1H x (1/2), d, J = 13Hz), 5.46 (lHx (1/2), d, J = 16Hz), 5_87 (1H, dd, J = 15, 4Hz ), 6.56 (1H, dd, 15, 11Hz), 6.60 (lHx (1/2), q, J = 6Hz), 6.66 (] Hx (1/2), q, J = 6Hz), 6.82 (1H, d, J = 16Hz), 7.16-7.22 (2H, m), 7.29-7.35 (1H, m), 7.41-7.51 (1H, m), 7.67 (1H, d, J = 8Hz), 7.84 -7.89 (2H, m) '8.06 (lHx (1/2), s), 8.06 (lHx (1/2), s), 8.18 (1H, brs), 8.35 (lHx (1/2), s) , 8.47 (lHx (1/2), s), 9.54 (1H, brs); MS (FAB) m / z: 884 ((M + H) +). HRMS (ESI +) m / z: C42H49F3N702S ((M + H) +) Calculated 値: 884.3264, Measured 値: 884.3279. C42H49F3N702S · (2/3) HC1 · H20: C, 53.42; Η, 5.62; N, 10.38; F, 6.04; α, 2.50; S, 3.40. Found 値: C, 53.50; H, 5.47; N, 10.29; F, 6.04; Cl, 2.20; S, 3.37. Example 2 1 4- [4- (cyanomethyl) = 1-piperidyl] -4-oxobutanoic acid 1-[[(111,21〇-2-[[trans-2 [(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dicyclopentane-5-yl] thio] -1-(2,4-di Fluorophenyl)--337-200410948 [(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-8 0) (2) a) [4- (benzyloxycarbonyl) -bupiperinyl] acetonitrile Dissolve 1- (benzyloxycarbonyl) piperin (4.0 g, 18 mm ο 1) in N, N-dimethylformamidine Amine (20ml), stirred at (TC. Add triethylamine (3.8ml, 27 mm ο 1), petrified sodium (1.4 g, 9.1 mm ο 1) and bromoacetonitrile (1.5 m 1, 2 2 mm ο 1), and stirred at room temperature for 4 hours. Under ice cooling, the reaction solution was added with ethyl acetate (150 ml) and brine (50 ml). After the organic layer was separated, the aqueous layer was treated with acetic acid. Extract with ethyl acetate (100m 1x3). Combine the organic layers, wash with saturated brine (50m1X1), dry under anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure to obtain the crude title compound. Crude the obtained crude product title The compound was purified by silica gel column chromatography (hexane: ethyl acetate, 33:67, V / V) to obtain the title compound (4.4 g, yield 92%) as a colorless solid. IR (liquid membrane) v max 2943, 2824, 1700, 1430, 1242cm · 1; WNMR (CDC13, 400MHz): 52.56 (4H, brs), 3.54 (2H, s), 3.55-3.60 (4H, m), 5.14 (2H, s), 7.31 -7.40 (5H, m); MS (EI) m / z: 259 (M +). HRMS (ESI +) m / z: C14H17N302 (M +) Calculated 値: 259.1321, Measured 値: 259.1324. (21b) 4- [4- (cyanomethyl) -1-piperidyl] -4-oxobutanoic acid 1-[[(1R, 2R) -2-[[trans-2-[(IE, 3E) -4- (4 -Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-diseno-5-yl] thio] -b (2,4-difluorophenyl)-l -[(1H-1,2,4-triazolyl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound) [4--(Benzyl) produced in Example 2 1 (2 1 a) Oxycarbonyl) -1-piperazinyl] acetonitrile (856 mg, 3.3 mm) is dissolved in ethanol (2.5 ml), and hydroxide-338-200410948 palladium-carbon catalyst (20%; 2000 mg), stirred for 8 hours at room temperature under hydrogen (normal pressure)The reaction solution was filtered through celite, and the solid matter was washed with dichloromethane (50 m 1). Distilling and dissolving the hydrazone under reduced pressure can obtain the crude 1- (cyanomethyl) pigon. This was dissolved in N, N-dimethylformamide (100 m 1) 'and stirred at 0 ° C. Add a solution of succinic anhydride (32411 ^, 3.21101111) to dimethylformamide (3 1111), and stir at room temperature for 16 hours. The solvent was evaporated under reduced pressure to remove the solvent 'to obtain crude 4- [4- (cyanomethyl) -1-piperidinyl] -4-oxobutanoic acid. This was dissolved in N, N-dimethylformamide (15 m 1) and stirred at 0 ° C. Carbonic acid (492 mg, 1.5 mmol) and 18-crown-6 (799 mg '3.0 mmol)' were added at room temperature, and dichloroethyl carbonate (1 R, 2R) produced in Example 1 (100) was added at room temperature -2-[[ Trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propyl ester (diastereomer ratio = about 1: 1; 700 mg, 1.1 mm ο 1). After stirring at room temperature for 1 day, under ice cooling, the reaction solution was added with ethyl acetate (150 m 1) and brine (50 ml). The organic layer was After the layers were separated, the aqueous layer was extracted with ethyl acetate (100m 1x3). The organic layer was combined, washed with saturated brine (50mlxl), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude title object compound. HP LC [LC-908; manufactured by Japan Analytical Industries; GPC column JAIGEL-1H (20mm idx600mm) and JAIGEL-2H (20mm idx600mm) were used in series; the solvent and chloroform] were used to obtain the crude title compound obtained by recycling. To give the title object compound (3 66 mg, yield 41%) is colorless Substance (diastereoisomer ratio = about 1: 1). IR (KBr) max 3429, 2938, 2230, 1765, 1649, 1504, 1275 cm · 1; hNMR (CDC13, 400MHz): (5 1.36 ( 3Hx (1/2), d, J = 7Hz), 1.36 (3Hx (1/2), 200410948 d, J = 7Hz), 1.54 (3Hx (1/2), d, J = 5Hz), 1.55 (3Hx (1/2), d, J = 5Hz), 2.54-2.56 (2H, m), 2.59-2.61 (2H, m), 2.60-2.79 (4H, m), 3.02-3.06 (1H, m) , 3.48 (] H, t, J =] lHz), 3.49 (1H, t, J =] lHz), 3.45-3.58 (4H, m), 3.53 (1H, s), 3.54 (] H, s), 3.82 (lHx (1/2), q, J = 7Hz), 3.88 (IHx (1/2), q, J = 7Hz), 4.15-4.19 (1H, m), 4.26-4.31 (1H, m), 4.97 (IHx (1/2), d, J = 3Hz), 4.98 (lHx (1/2), d, J = 3Hz), 5.29-5.47 (2H, m), 5.85 (1H, dd, J = 15 , 4Hz), 6.58 (1H, dd, J = 15, 11Hz), 6.73 (1H, d 'J = 16Hz), 6.74 (lHx (1/2), q, J = 5Hz), 6.81 ( lHx (1/2), q, J = 5Hz), 6.84-7.00 (3H, m), 7.33 (1H, dd, J = 10, 2Hz), 7.39-7.46 (2H, m), 7.57 (1H , T, J = 8Hz), 7.91 (lHx (1/2), s), 7.95 (lHx (1/2), s), 8.02 (lHx (1/2) ), S), 8.23 (1H x (1/2), s); MS (FAB) m / z: 838 ((M + H) +); HRMS (ESI +) m / z: C40H42F3N7O8SNa ((M + Na ) +) Calculate 値: 860.2666, Measured 値: 860.2681. Example 2 2 4- [4- (2-Amino-2-oxoethyl) -1-piperidinyl,]-4-oxobutanoic acid 1-[[(1R, 2R) -2-[[trans -2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (Exemplary Compound 1 -8 2) (22a) 2- [4- (benzyloxycarbonyl) -1-piperidyl] acetamide dissolves 1-(benzyloxycarbonyl) piperon (4.0 g, 18 mm ο 1) Stir at N, N-dimethylformamide (2 5 m 1) at 0 ° C. Add triethylamine (3.8 m 1; 27 mmol), sodium iodide (1.4 g, 9.1 mmol), and 2-bromoacetamide (3.0 g, 2 2 mm ο 1), and stir at room temperature for 2 days. Under ice-cooling, ethyl acetate (150 m 1) and brine (50 m 1) were added to the reaction solution. After the organic layer was separated-340-200410948, the aqueous layer was extracted with ethyl acetate (100 m 1 x 3). The organic layer was combined, washed with saturated brine (50 m 1 X 1) and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (ethyl acetate: methanol, 95 · 5, V / V) to obtain the title compound (4.6 g, yield 91%) as a pale yellow solid. IR (KBr) max 3354, 3170, 1694, 1655, 1433, 1241 cm-1; bNMR (CDC13, 400MHz): ά 2.53 (4H, s), 3.03 (2H, s), 3.53-3 56 (4H, m), 5.14 (2H, s), 5.43 (1H, brs), 6.94 (1H, brs), 7.31-7.52 (5H, m); MS (FAB) m / z: 278 ((M + H) +) 〇HRMS (ESI +) m / z: C14H2GN303 ((M + H) +) Calculated: 278.1505, measured: 278.15 (H. C14H20N3O3 calculated: C, 60.63; 値, 6.91 Ν, 15.15, measured 値: C, 60.53; Η, 6.74; Ν · 15 · 18. (2 2b) 4- [4- (2-Amino-2-oxoethyl) -1-piperidyl] 4-oxobutanoic acid 1-[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3- Butadienyl] -1,3-dioxan-5-yl] thio] -1- (2 5 4 --- truncated radical) · 1-[(1H-1,2 '4 -difluorenyl -1 -yl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound) 2- [4- (benzyloxycarbonyl) -1-piperidinyl] ethyl produced in Example 22 (22a) Amidine (915mg, 3.3mmol) was dissolved in ethanol (30ml), palladium hydroxide carbon catalyst (20% ·, 200mg) was added, and the mixture was stirred under hydrogen (normal pressure) and room temperature 2 The reaction solution was filtered through diatomaceous earth, and the solid matter was washed with dichloromethane (50 ml). The solvent was distilled off under reduced pressure to obtain crude 2- (1-piperidyl) acetamidamine. It was dissolved in N, N-dimethylformamide (10ml), stirred at 0 ° C. Add succinic anhydride (327mg, 3.3mmol) in N, N-dimethylformamide (3ml) -341-200410948 solution at room temperature It was stirred for 1 day. The solvent was distilled off under reduced pressure to obtain 4- [4- (2-amino-2-oxoethyl) -1-piperidyl] -4 · oxobutanoic acid. Dissolved in N, N-dimethylformamide (5 m 1), and stirred at 0 ° C. Introduce carbonic acid (5 0 2 mg, 1 · 5 mm ο 1) and] 8 -crown-6 (8 1 5 mg, 3.0 mm ο 1) 'At room temperature, the 1-chloroethyl carbonate (1 R, 2R) produced in Example 1 (1 a) was added -2-[[Trans-2-[(IE, 3E ) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-difluoren | alkyl-5-yl] thio] -1- (2,4 -Difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propyl ester (diastereomer ratio = about 1: 1; 7 1 4 mg, 1 · 1 mm ο 1). After stirring at room temperature for 4 days, ethyl acetate (150 m 1) · and brine (50 ml) were added to the reaction solution under ice-cooling. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate (100m 1x3). The organic layer was combined, washed with saturated brine (50 ml x 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The crude title compound thus obtained was subjected to HPLC [LC-908; manufactured by Analytical Industries, Japan; GPC column JAIGEL-1H (20mm idx600mm) and JAIGEL-2H (20mm idx600mm) were used in series; solvent, chloroform] was purified, The title object compound (279 mg, yield 30%) was obtained as a colorless oily substance (diastereomer ratio = about 1: 1). IR (KBr) vmax 3446, 2939, 2853, 2230, 1765, 1687, 1647, 1504, 1276 cm · 1;

bNMR (CDC13, 400MHz): (51.36 (3Hx (1/2), d, J = 7Hz), 1.36 (3Hx (1/2), d; J = 7Hz), 1.54 (3Hx (1/2) , D, J = 5Hz), 1.55 (3Hx (1/2), d, J = 5Hz), 2.52-2.53 (2H, m), 2.57-2.58 (2H, m), 2.61-2.78 (4H, m) , 3.00-3.07 (3H, m), 3.48 (1H, t 'J = llHz), 3.49 (1H, t, J = llHzl3.45-3.57 (2H, m), 3.63 (2H, brs) , 3.82 (1H x (1/2), q, J = 7Hz), 3.88 (lHx (1/2), q, J = 7Hz), 4.16-4.20 (1H, m), 4.26-4.31 (1H, m ), 4.97 (1H, s), 5.28-5.47 (2H, m), 5.41 (1H, br s), 5.85 (1H, dd, J 200410948 = 16, 4Hz), 6.59 (1H, dd, J = ] 6, 10Hz), 6.74 (1H, d, J = 16Hz), 6.74 (ΙΗχ (1/2), q, J = 5Hz), 6.81 (IHx (1/2), q, J = 5I- Iz), 6.83-7.00 (4H, in), 7.33 (1H, dd, J = 10, 2Hz), 7.37-7.46 (2H, m), 7.57 (] H, t ,; [two 8Hz), 7.90 (lHx (1/2), s), 7.95 (lHx (1/2), s), 8.02 (lHx (1/2), s), 8.24 (lHx (1/2), s); MS (FAB) m / z: 856 ((M + H) +).

HRMS (ESI +) m / z: C40H45F3N7O9S ((M + H) +) Calculated 値: 856.2951, Measured 値: 856.2975. A solution of the title compound of interest (diastereomer ratio = about 1: 1; 137 mg, 0.16 mmol) in ethanol (5 ml) prepared above was cooled at 0 ° C, and 1-ascorbic acid (28 mg, 0.16 mmol) was added under stirring, The solvent was distilled off under reduced pressure to obtain an oily residue, which was dissolved in water (10 ml) at 0 ° C, and the insoluble matter was removed by membrane filtration. The obtained aqueous solution was freeze-dried to obtain ascorbate (172 mg) of the title object compound as a colorless amorphous solid (diastereomeric ratio of about 1: 1). IR (KBr) ^ max 3371, 2230, 1763, 1686, 1646, 1616, 1504, 1277 cm · 1; NMR (DMSO-d6, 400MHz) ·· 51 · 24 (3Hx (1/2), d, J = 7Hz), 1 · 26 (3Hx (1/2), d, J = 7Hz), 1.45 (3Ex (1/2), d, J = 5Hz), 1.48 (3Hx (1/2), d, J = 5Hz), 2.35 (2H.s), 2.42 (2H, s), 2.51-2.61 (4H, m), 2.86 (1H, s), 2.87 (1H, s), 2.86-2.96 (1H, m ), 3.27-3,51 (25Hx (1/2), m), 3.56 (lHx (1/2), q, J = 8Hz), 3.70-3.76 (1H, m), 4.03-4.10 (1H, m ), 4.1CM.18 (1H, m), 4.69 (lHx (1/2), s), 4.70 (lHx (1/2), s), 4.85 (1H, br s), 5.02 (lHx (1 / 2), d, J = 5Hz), 5.03 (lHx (1/2), d, J = 5Hz), 5.25 (lHx (1/2), d, J = 15Hz), 5.28 (lHx (1/2) , D, J = 15Hz), 5.43 (lHx (1/2), d, J = 15Hz), 5.45 (lHx (1/2), d, J = 15Hz), 5.88 (lHx (1 / 2), dd, J = 15, 4Hz), 5.88 (lHx (1/2), dd, J = I5, 4Hz), 6.53-6.66 (1H, m), 6.61 (lHx (1/2), q, J = 5Hz), 6.67 (lHx (1/2), q, J = 5Hz), 6.82 (1H, d, J = 16Hz), 7.13-7.24 (3H, m), 7.34-7.41 (1H, m), 7.4 3-7.48 (1H, m), 7.67 (1H, d, J = 8Hz), 7.83-7.89 (2H, m), 8.05 (lHx (1/2), s), 8.06 (lHx (1/2 ), S), 8.35 (lHx (1/2), s), 8.47 (lHx (1/2), s);-343-200410948 MS (FAB) m / z · 856 ((M + H) + ). HRMS (ESI +) m / z: C40H44F3N7O9S-C6H8〇6 ((M + H) +) Calculated 値: 856.2951, Measured 85: 856.2953. C4〇H44F3N7〇9S_C6H8〇6 · (5/3) H20 Calculate 値: C, 52.02; Η, 5.25; N, 9.23; F, 5.37; S, 3.02. Measured 値: C, 51.84; Η; 5.16; N, 9.07; F, 5.26; S, 2.96. Example 2 3

4- [4-[(2- (Aminemethyloxy) ethyl) -l-piperidyl] oxobutanoic acid 1-[[((1R '2R) -2-[[Trans- 2-[(1Ε , 3E) -4- (4-Chloro-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] _b (2,4- Difluorophenyl)-; 1-[(1,1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound 1-83) (23a) (Benzyloxycarbonyl) -4- [2- (benzyloxycarbonyloxy) ethyl] pigon Dissolve 1- (2-transethyl) eghen (4.0 g, 31 mmol) in water (60 mi). Stir at room temperature. Add sodium carbonate (7.8 g, 74 mm) and benzyl chloroformate (30% toluene solution; 43 ml, 68 mmol), and stir at room temperature for 12 hours. Adjust pΗ = 10 with hydrochloric acid, and extract with ethyl acetate (80 m 1 X 4). The organic layer was combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate · 66: 33, V / V) to obtain the title compound (7.8 g, yield 63%) as a pale yellow oil. IR (liquid film) V max 2950, 1746, 1702, 1456, 1431, 1242cm · 1; 4 NMR (CDC13, 400MHz): ά 2.45 (4H, s), 2.66 (2H, t, J = 6Hz), 3.46 -3.49 (4H, m), 4.26 (2H, t, J = 6Hz), 5.13 (2H, s), 5.16 (2H, s), 7.31-7 · 39 (10H,-344- 200410948 MS (FAB) m / z: 399 ((M + H) +). HRMS (ESI +) m / z: C22H27N203 ((M + H) +) Calculated 値: 399.1920, Measured 399: 399 1906. ( 23b) 1- (benzyloxycarbonyl) -4- (2-hydroxyethyl) pipeline

(Benzyloxycarbonyl) -4- [2- (oxybenzyloxy) ethyl] hydrazone (7.8g, 20m mol) produced in Example 23 (23a) was dissolved in ethanol (80ml), Stir at room temperature. Add potassium hydroxide (2N solution; 2.0 ml, 3.9 mmol) and stir at room temperature for 2 hours. After the reaction solution was cooled at 0 ° C, an aqueous ammonium chloride solution (1000 m 1) was added, and the reaction solution was extracted with ethyl acetate (100 m 1 X 4). The organic layer was combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (4.1 g, yield 74%) as a colorless oily substance. IR (liquid film) V max 3449 '2944, 2816' 1702, 1433, 1241; 4 NMR (CDC13, 400MHz): δ2 · 48 (4H, s), 2.56 (2H, t, J = 5Hz), 3.52 -3.54 (4H, m), 3.63 (2H, t, J = 5Hz), 5.14 (2H, s), 7.30-7.39 (5H, m); Φ MS (FAB) m / z: 265 ((M + H) +). HRMS (ESI +) m / z: C14H21N203 ((M + H) +) Calculated 値: 265.1552, Found 値: 265.1563. (23c) 4- [4-[(2- (Aminomethyloxy) ethyl) -1-piperidyl] -4-oxobutanoic acid 1-[[(1R, 2R) -2-[[trans -2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound ) The 1- (benzyloxycarbonyl) -4- (2-hydroxyethyl) pipe trap (2.4g, 8.4mmol) produced in Example 23 (23b) was dissolved in anhydrous dichloromethane (40ml),-345-200410948 Stir at 0 ° C. Trichloroethyl isocyanate (1.75 g, 9 · 3 m m ο 1) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was placed in aluminum for 2 hours, the reaction solution was filtered through celite, and the solid matter was washed with ethyl acetate (00 m 1). Combine the filtrate and washing solution, wash with saturated brine, dry under anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure to obtain the crude (benzyloxycarbonyl) [2- (aminoformamyloxy) ethyl] pipe trap. (2 · 1 g, yield 80%), colorless oily substance. The obtained 1- (benzoxanthyl-based) limbicyloxy) ethyl] P mass trap (1.0 g, 3.3 mmol) was dissolved in a mixed solvent of ethanol (20 ml) and ethyl acetate (20 ml), and palladium hydroxide was added Carbon catalyst (20%; 25 Omg), stirred under hydrogen (normal pressure) and room temperature for 6 hours. The reaction solution was filtered through celite, and the solid matter was washed with dichloromethane (50 ml). The solvent was distilled off under reduced pressure to obtain crude 1- [2- (aminomethyloxy) ethyl] piperon. This was dissolved in N, N-dimethylformamide (8 m 1) and stirred at 0 ° C. A solution of succinic anhydride (327 mg, 3.3 mmol) in N, N-dimethylformamide (4 ml) was added, and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure to remove the solvent 'to obtain crude 4-[(2- (aminomethylamidooxy) ethyl) -1-piperidinyl] -4-oxobutanoic acid. This was dissolved in N, N-dimethylformamide (15 m 1) and stirred at 0 ° C. Carbonic acid (502 mg, 1.5 mmol) and 18-crown-6 (815 mg, 3.1 mmol) were added, and 1-chloroethyl carbonate (1 R '2R) -2- produced in Example 1 (1 a) was added at room temperature. [[Trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] Thio] -1- (2,4-difluorophenyl) -1-[(1 Η 1,2,4-triazole-1 -yl) methyl] propyl ester (diastereomer ratio = About 1 ·· 1; 7 1 4 mg, 1 · 1 mm ο 1). After stirring at room temperature for 1 day, ethyl acetate (150 ml) and common salt-346-200410948 water (50 m 1) were added to the reaction solution under ice cooling. After the organic layer was separated, the aqueous layer was taken with ethyl acetate (100 nl x 3). The organic layer was combined, washed with saturated brine (50 m) x 1, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude title compound. The obtained crude title compound was circulated and collected. PLC [LC-98; manufactured by Japan Analytical Industries; GPC column JAIGEL-lH (20mmi.d.x600mm) and JAIGEL-2H (20mm idx600mm) were used in series; solvent , Chloroform] was purified to obtain the title object compound (460 mg, yield 47%) as a pale yellow oily substance (diastereomeric ratio = about 1: 1).

IR (liquid film) v max 3358, 3008, 2232, 1764, 1726, 1643, 1617, 1505, 1276 cm'1; bNMR (CDC13, 400MHz) · (Π.36 (3Ηχ (1/2), d, J = 7Hz), 1.36 (3Hx (1/2), d, J = 7 Hz), 1.54 (3Hx (1/2), d, J = 5Hz), 1.55 (3Hx (1/2), d, J = 5Hz), 2.44-2.47 (2H, m), 2.51 (2H, s), 2.51-2.82 (6H, m), 3.00-3.05 (1H, m), 3.48 (1H, t, J = llHz), 3.49 (1H, t, J = llHz), 3.45-3.53 (2H, m), 3.60-3.62 (2H, m), 3.82 (1H x (1/2), q, J = 7Hz), 3.88 (lHx (1/2), q, J = 7Hz); 4.15-4.21 (3H, m), 4.27-4.31 (1H, m), 4.61 (1H, br s), 4.97 (1H, s), 5.30-5.46 ( 2H, m), 5.85 (1H, dd, J = 15, 4Hz), 6.57 (1H, dd, J = 15, 10Hz), 6.73 (1H, d, J = 15Hz), 6.73 (lHx (l / 2), q, J = 5Hz), 6.81 (lHx (1/2), q, J = 5Hz), 6.85-7.00 (4H, m), 7.33 (1H, dd, J = 10, 2Hz), 7.39- 7.46 (2H, m), 7.57 (1H, t, J = 8Hz), 7.91 (lHx (1/2), s), 7.95 (lHx (1/2), s), 8.02 (lHx (1/2) , S), 8.23 (lHx (1/2), s); MS (FAB) m / z: 886 ((M + H) +). HRMS (ESI +) m / z: C41H47F3N701 () S ((M + H) +) Calculated 値: 886.3057, measured 实 886.3055. The title object compound (diastereomeric ratio == about 1: 1; 444 mg, 0.5 0 mmol) prepared above was The ethyl acetate (12ml) solution was cooled at 0 ° C, and hydrogen chloride (4N ethyl acetate solution; 125 // 1,-347-200410948 0.5 0m mol) was added under stirring, and the solvent was distilled off under reduced pressure. The residue was dissolved in water (12 m 1) at 0 t: the insoluble matter was removed by membrane filtration, and the obtained aqueous solution was freeze-dried to obtain the hydrochloride salt (443 mg) of the title object compound as a colorless amorphous solid (non- Enantiomeric ratio = about]: 1). IR (KBr) 2 ^ 3428, 2938, 2231, 1764, 1732, 1648, 1616, 1504, 1276 cm · 1;

] Η NMR (DMSO-d6, 400MHz): 5] · 24 (3Hx (1/2), d, J = 8Hz), 1.26 (3Hx (1/2), d, J = 8Hz), 1.45 (3Hx ( 1/2), d, J = 5Hz), 1.48 (3Hx (1/2), d, J = 5Hz), 2.20-2.80 (10H, m), 2.80-3.62 (7H, m), 3.57 ( ] Hx (1/2), q, J = 7Hz), 3.63-3.80 (lHx (1/2), m), 3.80-4.50 (5H, in) '5.03 (lHx (] / 2), d , J = 5Hz), 5.04 (lHx (1/2), d, J = 5Hz), 5.24 (lHx (1/2), d, J = 15Hz), 5.27 (lHx (1/2), d , J = 15Hz), 5.43 (lHx (1/2), d, J = 14Hz), 5.46 (lHx (1/2), d, J = 14Hz), 5.88 (lHx (1/2), dd, J = 14, 4Hz), 5.88 (lHx (1/2), dd, J = 14, 4Hz), 6.30-6.70 (3H, m), 6.82 (1H, d, J = 16Hz), 7.15-7.22 (2H, m), 7.30-7.41 (1H, m), 7.43-7.51 (1H, in), 7.67 (1H, dd, J = 8, 2Hz), 7.83-7.89 (2H, m), 8.05 (lHx (1/2), s), 8.06 (lHx (1/2), s), 8.35 (lHx (1/2), s), 8.47 (IHx (1/2), s); MS (FAB) m / z: 886 ((M + H) +).

HRMS (ESI +) m / z: C41H47F3N701 () S ((M + H) +) Calculated 値: 886.3057, Measured 値: 886.3054. Example 24 4- [4- [2- (Dimethylamino) ethyl] -piperazinyl] -4-oxobutanoic acid 1-[[(111,21〇-2-[[trans-2- (1 £, 3 £) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] 5-yl] thio] (2,4-difluorophenyl) 1 , 3-Secondary School-[(1H-1,2,254-triazole-butyl) methyl] propoxy] carbonyloxy] ethyl ester (Exemplary compounds 1-1 5 0) (24a) 1- (Benzyloxycarbonyl) -4- [2- (dimethylamino) ethyl] piperidine Dissolve 1- (benzyloxycarbonylhydrazone) piperin (4.0g, 18mmol) in N, N-di • 348-200410948 Methylformamide (20 m 1), stirred at 0 ° C. Triethylamine (6.3 m 1, 4 6 mm ο 1), sodium iodide (] · 4 g, 9.1 mm ο 1) were added. And 2-(dimethylamino) ethyl chloride hydrochloride (3 ·] 5 g, 22m m ο 1) N, N -dimethylformamide (5ml), stirred at 65 ° C for 5 After hours, ethyl acetate (150 ml) and brine (50 ml) were added to the reaction solution under ice cooling. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate (100 ml x 3). The layers were washed with saturated saline (50ml xl) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the crude title compound. The crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 50:50, V / V) to obtain the title compound (2.3 g). , Yield 44%), yellow oily substance. IR (liquid film) v max 2945, 2817,] 703, 1429, 1241 cm · 1;] HNMR (CDC] 3, 400 MHz): 52.24 (6H, s), 2.40-2.50 (4H, m), 2.48 (2H, t, J = 5Hz), 3.48 (2H, t, J = 5Hz), 3.51-3.54 (4H, m), 5.13 (2H, s), 7.30-7.36 (5H, MS (El) m / z: 291 = M +). HRMS (ESI +) m / z: C 〖6H25N302 (M +) Calculate 値: 29U947, measured 値 ·· 29U948.

(24b) 4- [4- [2 · (dimethylamino) ethyl] -l-piperidinyl] ... cardiobutyric acid 1-[[(1R, 2R) [[trans- 2-[(1Ε , 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dimorphan-5-yl] thio] -1- (2, 4-difluorophenyl) 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound) 1- (benzyloxy) produced in Example 24 (24a) Carbonyl) -4- [2- (dimethylamino) ethyl] pyridine (962mg, 3.3m mol) was dissolved in ethanol (20 ml), and palladium hydroxide carbon catalyst (20%; 20 Omg) was added, Stir under hydrogen and room temperature for 1 day. The reaction solution was filtered through diatomaceous earth, and the solid matter was washed with dichloromethane ′ 349-200410948 (50 ml). The solvent was distilled off under reduced pressure to obtain crude 1- [2- (dimethylaminoethyl) piperine. This was dissolved in N, N-dimethylformamide (10 m 1) and stirred at 0 ° C. Add a solution of succinic anhydride (324m g, 3.2m mol) in N, N-dimethylformamide (3 in 1), and stir at room temperature for 3 days. The solvent was distilled off under reduced pressure to obtain crude 4- [4- [2- (dimethylamino) ethyl] -bupiperinyl] -4-oxobutanoic acid. This was dissolved in N, N-dimethylformamide (15 ml) and stirred at 0 ° C. Add AiiMifeC 492mg ^ 1.5mm 01) ¾ 18-crown-6 (799mg, 3.0mmol), and add the dichloroethyl carbonate (1 R '2R) produced in Example 1 (1 a) at room temperature -2-[[ Trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio ] -Bu (2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazole-;!-Yl) methyl] propyl ester (diastereomer ratio = about 1: 1; 700 mg, 1.1 mmol). After stirring at room temperature for 2 days, ethyl acetate (150 m 1) and brine (50 ml) were added to the reaction solution under ice-cooling. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate (100 m 1 × 3). The organic layer was combined, washed with saturated brine (50m 1x1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was subjected to cyclic separation by HPLC [LC-908; manufactured by Japan Analytical Industries; GPC column JAIGEL-1H (20mm idx600mm) and JAIGEL-2H (20mm idx600mm) were used in series; solvent, chloroform] was purified The title object compound (235 mg, yield 25%) was obtained as a yellow oily substance (diastereomeric ratio = about 1: 1). IR (KBr) v max 3421, 2940, 2230, 1765, 1646, 1504, 1276 cm.1; 々NMR (CDC13, 400MHz): 51.36 (3Hx (1/2), d, J = 7Hz), 1.36 (3Hx (1/2), d, J = 7Hz), 1.54 (3Hx (1/2), d, J = 5Hz), 1.55 (3Hx (1/2), d, J = 5Hz), 2.26 (3H, 200410948 s), 2.26 (3H, s), 2.41-2 · 51 (6H, m), 2.51-2 · 77 (4Η, m), 3.00-3.07 (] H, m), 3.35-3.66 (8H, m), 3.82 (ΙΗχ (] / 2), q, J = 7Hz), 3.88 (IHx (1/2), q, J = 7Hz), 4 · 13-4 · 20 (1H, m), 4.26-4.32 (1H, m), 4.97 (1H, d, J = 4Hz), 5.29-5.46 (2H, m), 5.85 (1H, dd, J = 15, 4Hz), 6.57 〇H, dd, J = 15, 11Hz), 6.73 (1H, d, J = 15Hz), 6.73 (1H x (1/2), q, J = 5Hz), 6.81 (lHx (1/2), q, J = 5Hz) , 6.84-7 · 00 (3H, m), 7.33 (1H, dd, J = 10, 2Hz), 7.39-7.46 (2H, m), 7.57 (1H, t, J = 8Hz), 7.91 (lHx (1/2), s), 7.95 (lHx (1/2), s), 8.02 (lHx (1/2), s), 8.23 (lHx (1/2), s); MS (FAB) m / z: 870 ((M + H) +) 〇HRMS (ESI +) m / z: C42H51F3N708S ((M + H) +) Calculate 870.3472, measured 値: 870.3500.

A solution of the above-obtained title compound (diastereomer ratio = about 1 ·· 1; 197 mg, 0.23 mmol) in ethyl acetate (5 ml) was dissolved in (TC), and hydrogen chloride ( 4N ethyl acetate solution; 56.5 &quot; 1, 0.2 3 mmol), and the solvent was evaporated under reduced pressure to obtain an oily residue, which was dissolved in water (5 m 1) at 0 ° C, and the insoluble matter was removed by membrane filtration. The obtained aqueous solution was lyophilized to obtain the hydrochloride (198 mg) of the title object compound as a pale yellow amorphous solid (diastereomeric ratio = about 1: 1).

IR (KBr) max3425, 2938, 2230, 1765, 1644, 1504, 1276 cm · 1; JHNMR (DMSO-d6, 400MHz): (Π · 24 (3Hx (1/2), d, J = 7Hz), 1.27 (3Hx (1/2), d, lJ = 7Hz), 1.45 (3Hx (1/2), d, J = 5Hz), 1.47 (3Hx (1/2), d; J = 5Hz), 2.34-3.58 (25H, m), 3.56 (lHx (1/2), q, J = 7Hz), 3.74 (lHx (1/2), q, J = 7Hz), 4.04-4.12 (2H, m), 5.02 (lHx (1/2), d, J = 5Hz), 5.03 (lHx (1/2), d, J = 5Hz), 5.24 (1H x (1/2), d, 16Hz), 5.28 (lHx (1 / 2), d, 16Hz), 5.42 (lHx (1/2), d, 14 Hz), 5.45 (lHx (1/2), d, 14Hz), 5.88 (lHx (1/2), dd, J = 15, 4Hz), 5.88 (1H x (1/2), dd, J = 15, 4Hz), 6.53-6.67 (1H, m), 6.61 (lHx (1/2), q, J = 5Hz) , 6.67 (lHx (1/2), q, J = 5Hz), 6.82 (1H, d, J = 16Hz), 7.13-7.22 (2H, m), 7.30-7.35 (1H. M), -351- 200410948 7.41- 7.48 (1H, m), 7.67 (1H, d ,: Γ = 7Ηζ), 7.84-7.89 (2H, m), 8.05 (ΙΗχ (1/2), s), 8.06 (lHx (1 / 2), s), 8.36 (lHx (1/2), s), 8.48 (lHx (] / 2), s); MS (FAB) m / z: 870 ((M + H) +). HRMS ( ESI +) nVz: C42H51F3N708S ((M + H) +) Calculated tritium: 870.3472, found tritium: 870.3448. Example 25 4- (4-methyl-1-piperidyl) -4-oxocrotonic acid 1- [1 (1R , 2R) -2-[[trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3 -di Epinene-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] Carbonyloxy] ethyl ester (exemplified compound 1-1 5 6) (25a) 4- (4-methyl-bupiperinyl) -4-oxocrotonate ethyl hydrogen fumarate (4.0 g, 28 mmol) was dissolved in anhydrous dichloromethane (20 ml), and stirred at 0 ° C. Chloramphenicol (3.6ml, 42mmol) and N, N-dimethylformamide (2 drops) were added by mouth. After stirring at 35 ° C for 15 minutes, the solvent was distilled off under reduced pressure to obtain crude 4-chloro- Ethyl 4-oxycrotonate. It was dissolved in anhydrous dichloromethane (20 ml) and stirred at 0 ° C. 1-Mepigen (3.3 g, 33 mm) was added, and the mixture was stirred at room temperature for 12 hours. Under ice-cooling, an aqueous sodium hydrogen carbonate solution (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml x 5). The organic layer was combined, washed with saturated brine (50 ml x 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude title compound (5.47 g, yield 87%) as an orange oily substance. IR (KBr) vmax 2939, 2793, 1722, 1653, 1628, 1442, 1295 cm · 1; NMR (CDC13, 400MHz): (5 1 · 32 (3H, t, J = 7Hz), 2.32 (3H, s) , 2.41-2.44 (4H, m), 3.60 (2H, t, J = 5Hz), 3.72 (2H, t, J = 5Hz), 4.25 (2H, q, J = 7Hz), 6.76 (lH.d, J = 15Hz), 7.38 (1H, d, J = 15Hz);-352-200410948 MS (EI) n / z: 226 (M +). HRMS (ESI +) m / z: CnHaN: ^ (M +) Calculate 値: 226.1317, Measured 226.1323. (25b) 4- (4-methyl-1-velocyl) -4-oxocroton]-[[(1R, 2R) -2-[[Trans-2- [ (IE, 3E) -4- (4-cyano-2-fluorophenyl)-], 3-butadienyl] -1,3-dioxan-5-yl] thio] -1- ( 2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] acetic acid (the title object compound) Example 25 (25a) Ethyl 4- (4-methyl-bupergyl) -4-oxocrotonate (733 mg, 3.2 mmol) was dissolved in water (10 ml), and carbonic acid (517 mg, 1. 6 mmol), and after stirring at 70 ° C. for 7 hours, the aqueous solution was freeze-dried. The obtained shaved salt was dissolved in N, N-dimethylformamide (5 ml), and Stir at ° C. Add the 1-chloroethyl carbonate (1 R, 2R) produced in Example 1 (1 a) -2-[[Trans- 2-[(1E, 3E) -4- (4-cyano- 2-fluorophenyl) -1,3-butadienyl] -1,3-diseno-5-yl] thio] -1- (2,4-difluorophenyl) -1-[( 1 Η -1,2,4-triazole-1 -yl) methyl] propyl ester (diastereomeric ratio = about 1: 1; 700 mg, 1.1 mmol) and 18-crown-6 (910 mg, 3.2 mmol). After stirring at room temperature for 2 days, ethyl acetate (150 ml) and brine (50 ml) were added to the reaction solution under ice-cooling. After the organic layer was separated, the aqueous layer was ethyl acetate (1.0). 〇mlx3) extraction. The organic layer was combined, washed with saturated brine (50m 1 X 1), dried under anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was recycled. HPLC [LC-908; manufactured by Japan Analytical Industries; GPC column JAIGEL-1H (20mni idx600mm) and JAIGEL-2H (20mm id x 6 00mm) were used in series; solvent, chloroform] was purified to obtain the title target compound ( 6 2 2 mg, yield 71%) colorless oily substance (diastereomer ratio 20041094 8 = about 1: 1) IR (KBr) 2940, 2849, 2796, 2230, 1763, 1620, 1504, 1279 cm-]; bNMR (CDC13, 400MHz): δ 1.35 (3Hx (1/2), d, J 2 8Hz), 1.36 (3Hx (1/2), d, J = 8Hz),] · 60 (3Hx (1/2), d, J = 6Hz), 1.60 (3Hx (1/2), d, J-2 6Hz), 2.32 (3H, s), 2.42-2.48 (4H, m), 2.98-3Ό7 (1H, m), 3.49 (1H, t, J = llHz), 3.50 (1H, t , J = llHz), 3.52-3.60 (2H, m), 3.66-3.73 (2H, m), 3.87 (1H, q, J = 7Hz), 4.18 (1H, ddd, J = ll, 5, 2Hz), 4.27 (1H, ddd, J = 11, 5, 2Hz), 4.97 (1H, d, J = 4Hz), 5.35 (1H, d, J = 15Hz), 5.38 (1H, d, J = 15Hz) ), 5.85 (1H, dd, J = 15, 4Hz), 6.58 (1H, dd, J = 15, 11Hz), 6.74 (1H, d, J = 16Hz), 6.75 (1H, d, J = 15Hz) ), 6.80 (1H, q, J = 5Hz), 6.82-6.96 (3H, m), 7.33 (1H, dd, J = 10, 2Hz), 7.39-7.44 (2H, m), 7.42 (lH, d, J = 15Hz), 7.57 (lH, t, J = 8Hz), 7.92 (lH, s), 8.00 (lH.s); MS (FAB) m / z: 811 (M + H) + ° HRMS (ESI +) m / z: C39H42F3N608S ((M + H) +) Calculate 値 · 811.2737, Measured 値: 811 · 2754 〇 Ethyl acetate (15 ml) solution containing the title object compound (diastereoisomer ratio = about 1: 1; 611 mg, 0.75 mmol) was cooled at 0 ° C, and hydrogen chloride (4 N) was added under stirring. Ethyl acetate solution; 1 8 8 // 1, 0 · 7 5 mm ο 1), and the solvent was distilled off under reduced pressure to obtain an oily residue. It was dissolved in water (25 m 1) below, insoluble matter was removed by membrane filtration, and the obtained aqueous solution was freeze-dried to obtain the hydrochloride (595 mg) of the title object compound as a pale yellow amorphous solid (diastereomer). Than about 2: 1). ER (KBr) ^ dirty 3434, 2940; 2230, 1763, 1656, 1617, 1504, 1276 cm · 1;

4 NMR (DMSO-d6, 400MHz): 5 1.25 (3Hx (1/2), d, J = 7Hz), 1.26 (3Hx (1/2), d, J = 7Hz), 1.54 (3Hx (1/2 ), D, J = 5Hz), 1.56 (3Hx (1/2), d, J = 5Hz), 2.33-3.57 (14H, m), 3.56 (lHx (1/2), q, J = 7Hz), 3.72 (lHx (1/2), q, J = 7Hz), 4.02-4.14 (2H, m), 5.01 (lHx (1/2), d, J = 5Hz), 5.04 (lHx (1/2 ), D 'J = 5Hz), 5.23 (1H 200410948 x (1/2), d, J = I6Hz), 5.28 (ΙΗχ (1/2), d, J = 16Hz), 5.43 (ΙΗχ (1 / 2), d, J = 16Hz), 5.47 (IHx (1/2), d, J = 16Hz), 5.88 (IHx (1/2), dd, J = 15, 5Hz), 5.88 (lHx (1 / 2), dd,] = 15,5Hz), 6.55 (1H, dd, J = 15, 10Hz), 6.59 (IHx (1/2), d, J = 15Hz), 6.63 () Hx (1/2 ), D, J = 15Hz), 6.74 (lHx (1/2), q, J = 5Hz), 6.79 (lHx (1/2), q, J = 5Hz), 6.82 (1H, d , J = 17Hz), 7.15-7.22 (2H, m), 7.29-7.35 (1H, m), 7.38-7.51 (1H, m), 7.56 (IHx (1/2), d, 15Hz), 7.59 (lHx (1/2), d, J = 15Hz), 7.68 (1H, dd, J = 8, 2Hz), 7.84-7.89 (2H, m), 8.05 (lHx (1/2), s), 8.06 (lHx (1/2), s), 8.31 (lHx (1/2), s), 8.49 (lHx (1/2), s); MS (FAB) m / z: 811 (M + H) + 〇HRMS (ESI +) m / z: C39H42F3N608S ( (M + H) +) Calculated 値: 811.2736, Measured 値: 811.2776 〇C39H42F3N608S · (4/5) HC1 · 2H20 · · C, 53 · 47; Η, 5.27; N, 9.59; F, 6.51; Cl, 3.24 S, 3.66. Found 値: C, 53.61; H, 5.15; N, 9.62; F, 6.51; Cl, 3.28; S, 3.67. Example 2 6 [[(dimethylamino) ethenyl] amino] acetic acid 1-[[(1R, 2R) -2-[[trans-2-[(IE, 3E) -4- (4- Cyano-2-fluorophenyl) -1,3-butadienyl] 1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl M (1H- 1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-3 0 2) (26a) [[(dimethylamino) ethenyl] Amine] Ethyl acetate Dissolve N, N-dimethylglycine (2.2g, 22mmol) in anhydrous dichloromethane (50ml) and stir at 0 ° C. Add grasshopper chlorine (5.7g, 45mmol) And N, N-dimethylformamide (2 5 m 1), and after stirring at room temperature for 30 minutes, the solvent was distilled off under reduced pressure to obtain crude (dimethylamino) acetamidine chloride. This was dissolved in Anhydrous tetrahydrofuran (25 m 1), stirred at 0 ° C. Trimethylamine (6.2 nm, 45 mmol) and ethyl glycine hydrochloride (2.5 g, 18 mmol) 200410948 N, N-dimethylformamide were added. Amidine (10 ml) was stirred at room temperature for 12 hours. Under ice-cooling, an aqueous solution of sodium bicarbonate (50 m 1) was added to the reaction solution, and the mixture was extracted with ethyl acetate (700 m 1 X 5).倂 The organic layer was washed with saturated brine (50 m 1 X 1) and dried over anhydrous magnesium sulfate to obtain the crude title compound. The crude title compound was purified by silica gel column chromatography (ethyl acetate) to obtain The title compound (884 mg, yield 26%), brown oily substance. IR (liquid film) w Hi a X 3367, 2982, 2947, 2782, 1751, 1675, 1524, 1200 cm-1; hNMR (CDC13, 400MHz) : δ 1.29 (3H, t, J = 7Hz), 2.33 (6H, s), 3.00 (2H, s), 4.07 (2H, d, J = 6Hz), 4.21 (2H, q, J = 7Hz), 7.61 (1H, brs); MS (El) m / z: 188 (M +). HRMS (ESI +) m / z: C8H16N203 (M +) Calculated 値: 188.1161, Measured 値: 188.1160. (2 6b ) [[(Dimethylamino) ethenyl] amino] acetic acid 1-[[(1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano- 2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1-(2,4-difluorophenyl) -l-[( 1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound) [[(dimethylamino)) produced in Example 26 (26a) B Fluorenyl] amino] ethyl acetate (508 mg, 2.7 mmol) was dissolved in water (10 ml), and aq. Hydroxide (50% (W / W) aqueous solution; 795 mg, 2.7 mmol) was added at 70 ° C. After stirring for 2 hours, the aqueous solution was freeze-dried. The obtained planed salt was dissolved in N, N-dimethylformamide (5 m 1) and stirred at 0 ° C. Add the dichloroethyl carbonate (1R, 2R) produced in Example 1 (1 a) -2-[[Trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl)] -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2, 4 · Triazole-methyl) methyl] propyl ester (diastereomeric ratio = about 1: 1; 700 mg '200410948] · 1 mm ο 1) and 1 8-crown-6 (7 1 5 mg, 2.7 mm ο 1). After stirring at room temperature, ethyl acetate (150 m 1) and brine (50 m) were added to the reaction solution under ice cooling. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate (100 m 1 X 3). The organic layer was combined, washed with saturated brine (5 Om 1 X 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude title compound. The obtained crude title compound was subjected to cyclic separation by HPLC [LC-908; manufactured by Analytical Industries Japan; GPC column JAIGEL, 1H (20mmi.d.x600mm) and JAIGEL-2H (20mm idx600mm) were used in series; solvent, chloroform] By purification, the title object compound (294 mg, yield 38%) was obtained as a pale yellow oily substance (diastereomer ratio = about 1: 1). IR (KBr) ^ max 3371, 2851, 2230, 1770, 1681, 1505, 1275 cm · 1; JHNMR (CDC13, 500MHz) ·· (51.36 (3Hx (1/2), d, J = 7Hz), 1 · 36 (3Hx (1/2), d, J = 7Hz), 1.55 (3Hx (1/2), d, J = 6Hz), 1.57 (3Hx (1/2), d, J = 6Hz), 2.34 ( 3H, s), 2.34 (3H, s), 3.02 (2H, s), 2.98-3.07 (1H, m), 3.49 (1H, t, J = llHz), 3.49 (1H, t, J = 11Hz ), 3.87 (lHx (1/2), q, J = 7Hz), 3.89-4.00 (lHx (1/2), m), 4.16-4.22 (3H, m), 4.24-4.29 (1H, m ), 4.98 (1H, d, J = 4Hz), 5.30-5.42 (2H, m), 5.86 (lHx (1/2), dd, J = 15, 4Hz), 5.86 (lHx (1/2) , Dd, J = 15, 4Hz), 6.58 (1H, dd, J = 15, 10Hz), 6.74 (1H, d, J = 15Hz), 6.74 (lHx (1/2), q, J = 6Hz ), 6.85 (1H x (1/2), q, J = 6Hz), 6.83-6.95 (3H, m), 7.33 (1H, d, J = 10Hz), 7.39-7.47 (2H. M), 7.57 ( lH, t, J = 8Hz), 7.63 (lHx (1/2), brs), 7.78 (lHx (1/2), brs), 7.94 (1H, s), 7.98 (lHx (1/2) , S), 8.08 (lHx (1/2), s); MS (FAB) ni / z: 773 ((M + H) +). HRMS (ESI +) m / z: C36H40F3N6O8S ((M + H) +) Calculate 値 · 773.2581, found 値: 773.2598. Ethyl acetate (5ml) containing the title compound of the title (diastereomer ratio = about 1: 1; 235mg, 0.333mmol) The solution was cooled at 0 ° C, and 200410948 was added with stirring with hydrogen chloride (4N ethyl acetate solution; 82 μ1, 0.3 3 mmol). The solvent was evaporated under reduced pressure, and the obtained oily residue was dissolved in water (5m 1) at The membrane filters out insoluble matter. The obtained aqueous solution was freeze-dried to obtain the hydrochloride (25 1 mg) of the title compound as a colorless amorphous solid (diastereomeric ratio = about 1: 1).

IR (KBr) vmax 3049, 2979, 2230, 1770, 1687, 1615, 1504, 1275 cm · 1; hNMR (DMSO-d6, 400MHz): 5 125 (3Hx (1/2), d, J = 6Hz), 1.27 (3Hx (1/2), d, J = 6Hz), 1.48 (3Hx (1/2), d, J = 5Hz), 1.51 (3Hx (1/2), d, J = 5Hz), 2.69 ( 6H, s), 2.87-2.95 (1H, m), 3.39-3.95 (5H, m), 4.02-4.13 (4H, m), 5.03 (lHx (1/2), d, J = 4Hz), 5.04 ( lHx (1/2), d, J = 4Hz), 5.23 (lHx (1/2), d, J = 15HZ), 5.26

(lHx (1/2), d, J = 15Hz), 5.45 (lHx (1/2), d, J = 14Hz), 5.47 (lHx (1/2), d, J = 14Hz), 5.89 (1H, d, J = 15, 5Hz), 6.57 (1H, dd, J = 15, 10Hz), 6.68 (lHx (1/2), q, J = 5Hz), 6.70 (lHx (1/2), q, J = 5Hz), 6.82 (1H, d, J = 16Hz), 7.16-7.22 (2H, m), 7.32-7.37 (1H, m), 7.41-7.51 (1H, m), 7.68 (1H, dd , J = 10, 2Hz), 7.84-7.89 (2H, m), 8.06 (lHx (1/2), s), 8.08 (lHx (1/2), s), 8.37 (lHx (1/2), s), 8.48 (lHx (1/2), s), 8.90 (1H, s), 9.85 (1H, s);

MS (FAB) m / z: 773 ((M + H) +). HRMS (ESI +) m / z: C36H4F3N608S ((M + H) +) Calculated 値: 773.2580, Measured 値: 773.2554. C36H4F3N608S · (3/4) HQ · (3/2) H20 Calculate 値: C, 52.27; Η, 5.21; N, 10.16; F, 6.89; Cl, 3.21; S, 3.88. Found 値: C, 52.12; Η, 5.07; N, 10.12; F, 6.70; Cl, 3.48; S, 3.90. Example 2 7 [N-methyl-N-[(4-methyl 1-1-piperidyl) ethenyl] amino] acetic acid 1-[[(111, 2 feet) -2-[[trans-2-[(1 £, 3 £) -4- (4-cyano Phenyl-2-fluorophenyl) -1'3-butane-1-yl] -1'3-yi ^ yen-5-yl] thio] -1- (2'-358-200410948 4-difluorobenzene )-[[1 Η-〗, 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-3 2 8) (27a) [Ν- Methyl [(4-methyl-1-piperidyl) ethenyl] amino] Ethyl acetate Ethyl inosinate hydrochloride (ie methylamine ethyl acetate hydrochloride; 1.0 g, 65 mmol) It was dissolved in a saturated aqueous sodium bicarbonate solution (50 ml) and the free ethyl sarcosinate was extracted with dichloromethane (50 m 1 X 6). The organic layer was combined, washed with saturated brine (50m 1 X 1), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a dichloromethane solution (80m 1) of crude sarcosinate. Stir at room temperature and add (4-methyl-1-piperidyl) acetic acid ((J. Med · Chem ·, 4343, page 1489 (2000); 1.2 g, 78 mmol), 4-(N , N-dimethylamino) P than Udine (l.lg, 91mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.6g, 85mmol) , Anhydrous tetrahydrofuran (10 ml), and anhydrous N, N-dimethylformamide (10 ml), stirred at room temperature for 6 days. Under ice-cooling, an aqueous sodium hydrogen carbonate solution (50 ml) was added to Extract with ethyl acetate (80m 1x3). Combine the organic layers, wash with saturated brine (50m 1 X1), and dry under anhydrous magnesium sulfate to obtain the crude title compound. The crude title compound obtained is cyclically fractionated by HPLC [LC-908; manufactured by Japan Analytical Industries; GPC column JAIGEL-1H (20mm idx600mm) and JAIGEL-2H (20mm idx600mm) used in series; solvent, chloroform] Refined to obtain the title compound (1.45 g, yield 8 7%), light yellow oily substance. IR (liquid film) u max 3474, 2939, 2800, 1749, 1654, 1459, 1202cm · 1; bNMR (CDC13, 500MHz): (51.27 (3Hx (1/2), t J = 7Hz), 1.31 (3Ηχ (1/2), t, J = 7Hz), 2.26 (3Hx (1/2), s), 2.29 (3Hx (1/2), s), 2.22-2.57 (8H , M), 3.00 200410948 (3Hx (1/2), s), 3.15 (1H, s), 3.16 (3Hx (1/2), s), 3.24 (1H, s), 4. · 0 ( 1H, s), 4.18 (1H, q, J = 7Hz), 4.22 (1H, s), 4.24 (1H, q, J = 7Hz); MS (El) m / z: 257 (M +) 〇HRMS (El ) m / z: C] 2H23N303 (M) + Calculated 値 ·· 257.1739, Measured 値: 257.1732. (27b) [N -methyl-N-[(4-methyl-1-piperidinyl) ethenyl ] Amino] acetic acid 1-[[(1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butane Dienyl] -1,3-dioxan-5-yl] thio] -1- (2,, 4-difluorophenyl) -l-[(1H-1,2,4-triazole- 1-yl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound) [N -methyl-N-[(4-methyl-bu Piperazinyl) acetamido] amino] ethyl acetate (83 3 mg, 3.2 mmol) was dissolved in water (10 ml), and carbonic acid (517 mg, 1.6 mmol) was added. After stirring at 70 ° C for 3.5 hours, the aqueous solution was added. freezing Dry. The obtained shaved salt was dissolved in N, N-dimethylformamide (5 m 1) and stirred at 0 ° C. Add 1-chloroethyl carbonate (1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) produced in Example 1 (1 a) ) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -Bu (2,4-difluorophenyl) -1-[(1H-1,2, 4-triazol-1-yl)] methyl] propyl ester (diastereomer ratio = about 1: 1; 700 mg, 1.1 mmol) in N, N-dimethylformamide (5 ml) And 18-crown-6 (910 mg, 3.2 mm). After stirring at room temperature for 3 days, ethyl acetate (150 ml) and brine (50 ml) were added to the reaction solution under ice-cooling. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate (1 × 3). The organic layer was combined, washed with saturated brine (50 m 1 X 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The obtained crude title compound was subjected to HPLC [LC-9 0 8; manufactured by Analytical Industries Japan; GPC column-360- 200410948 JAIGEL-1H (20mm idx600mm) and JAIGEL-2H (20mm id x600mm) were used in series; Solvent, chloroform] was purified to obtain the title object compound (79 mg, yield 20%) as a pale yellow oily substance (diastereomer ratio = about 1: 1). IR (KBr) V max 3430 »2938 ^ 2799 ^ 2230 ^ 1770 ^ 1655 ^ 1504 ^ 1276 cm , 1.36 (3HX (1/2), d, J = 7Hz), 1.53-1.62 (3H, m), 2.20-4.48 (24H, m), 4.97 (lHx (1/2), d, J = 5Hz), 4.98 (lHx (1/2), d, J = 5Hz), 5.28-5.45 (2H, m), 5.85 (lHx (1/2), dd, J2) 5.5Hz), 5.85 (lHx ( 1/2), dd, 15, 5Hz), 6.58 (1H, dd, J = 14, 12Hz), 6.73 (1H, d, J = 16Hz), 6.73 (lHx (1/2), q, J = 6Hz), 6.81 (lHx (1/2), q, J = 6Hz), 6.79-7.00 (3H, m), 7.33 (1H, dd, J = 10, 2Hz), 7.39-7.46 (2H, m) , 7.57 (1H, t, J = 8Hz), 7.92 (lHx (1/4), s), 7.93 (lHx (1/4), s), 7.95 (lHx (1/2), S ), 7.98 (lHx (1/4), s), 7.99 (lHx (1/2), s), 8.17 (lHx (1/4), s); MS (FAB) m / z: 842 ((M + H) +) 〇HRMS (ESI +) m / z: C40H47F3N7O8S ((M + H) +) Calculated 値: 842.3159, Measured 値: 842.3154. An ethyl acetate (5 ml) solution containing the above titled target compound (diastereomer ratio of about 1: 1; 159 mg, 0.19 mmol) was cooled at 0 ° C, and hydrogen chloride (4N ethyl acetate solution was added under stirring). ·, 47 μ 1, 0.1 9 mmol). The solvent was distilled off under reduced pressure, and the obtained oily residue was dissolved in water (5 m 1) at 0 t, and the insoluble matter was removed by membrane filtration. The obtained filtrate was freeze-dried to obtain the title compound hydrochloride (153 mg) as a colorless amorphous solid (diastereomeric ratio = about 1: 1). IR (KBr) vmax 3418, 2936, 2849, 2230, 1769, 1656, 1615, 1504, 1276 cnT1; hNMR (DMSO-d6, 400MHz): (51.24 (3Hx (1/2), d, J = 7Hz), 1.26 (3Hx (1/2), d, J = 7Hz), 1.47-1.56 (3H, m), 2.20-4.40 (24H, m), 5.03 (lHx (1/2), d, J = 4Hz ), -361- 200410948 5.04 (] Hx (] / 2), d, J = 4Hz), 5.23 (ΙΗχ (1/2), d, J = 15Hz), 5.27 (ΙΗχ (1/2), d, J = 15Hz), 5.38-5.55 (] H, m), 5.88 (1H, d, 15, 4Hz), 6.57 (] H, dd, J = 15, 10Hz), 6.67 (lHx (1/2), q , J = 6Hz), 6.70 (lHx (1/2), q, J = 6Hz), 6.82 (] H, d, J2] 5Hz), 7.16-7.22 (2H, m), 7.33-7.38 (1H, m), 7.40-7.55 (1H, m), 7.68 (1H, dd, J = 8.2Hz), 7.84-7.89 (2H, m), 8.06 (lHx (1/2), s), 8.07 (lHx (1 / 2), s), 8,36 (lHx (1/4), s), 8.37 (lHx (1/4), s), 8.49 (lHx (1/4), s), 8.51 (lHx (1 / 4), s), 9.69 (1H, brs); MS (FAB) m / z: 842 ((M + H) +). HRMS (ESI +) m / z: C4〇H47F3N708S ((M + H) + ) Calculated 値: 842.3159, Measured 値: 842.3170. C40H47F3N7O8S -2H20 Calculated 値: C, 52.54; Η, 5.62; N, 10.72; F 6.23; Cl, 3.88; S, 3.51. Found 値: C, 52.30; 30, 5.31; N, 10.61; F, 6.29; Cl, 3.71; S.3.65. Example 2 8 Hydroglutaric acid l -[[(1R, 2R) -2-[[trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1 , 3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl Ester (exemplified compound 1-39) (28a) allyl glutarate 1-[[(1 foot, 211) -2-[[trans-2-[(; ^, 3E) -4- (4-cyano Phenyl-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -b (2,4-difluorophenyl) -1-[ (1 Η-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester propyl glutarate (Tetrahedron Lett., 36 巻, p. 1701 (1 '995); 1.53 g, 8.9 mmol) was dissolved in N, N-dimethylformamide (30 ml), and 18-crown-6 (2.3 8 g, 9 mmol) and carbonate shavings (1.30 g, 4 mmol) were added. Stir at room temperature for 2 hours, and add the dichloroethyl carbonate (1R, 2R) produced in Example 1 (1a) -2-[[Trans- 2-[(IE, 3E) -4- (4--362 -200410948 cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1Η-〗, 2,4-triazole-butyl) methyl] propyl ester (diastereomer ratio of about 2: 1; 2 · 5 2 g, 4 πί m ο 1) , Stir at room temperature for 14 hours. Under ice-cooling, a phosphate buffer solution (60 ml) was added to the reaction solution, and the crude product was extracted with ethyl acetate (50 ml 1x3). The organic layer was combined, washed with water (30 ml x 3), and then with saturated brine (50 ml x 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the residue of the title compound. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate, 6 5: 35-50: 50, V / V, 75 g of silica gel) to obtain a crude title compound (2.35 g in total, content of title compound). = About 1.65 g, yield of the title compound = about 54%, impurities and 4-[(1 E, 3 E)-4-[trans-5-[[(1 R, 2 R) -2- (2, 4-difluorophenyl) _2_hydroxy-bumethyl-3— (1H-1,2,4-triazol-1-yl) propoxy] thio] _:!, 3_dioxane-2- Group] -1,3-butadienyl] -3 -fluorobenzonitrile), a colorless amorphous solid (diastereomer ratio = about 1 ·· 1). It can be used in the next project without refining (2 8 b). (28b) Hydroglutaric acid H 2r) -2-[[trans- 2-[(IE, 3E) "-('cyano" -fluorophenylfluorene-^^ butadienylfluorene-^^ difluorene Alkyl-Hongyl] thio] -1- (2 '4-difluorophenyl) -1-[(1H-1,2,4-triazole-butyl) methyl] propoxy] carbonyloxy] Ethyl ester (title compound of the title) The crude allyl glutarate produced in Example 28 (28a) [[(1R, 2R) -2-[[trans- 2-[(1Ε, π) -4_ (4 -Cyano-2-fluorophenyl) -1,3-butadienyl] -1,% dicropin · 5 • yl] thio] _b (2,4-difluorophenyl) -b [ (1Η-1 '2, triazole- ^ yl) methyl] propoxy] carbonyloxy] ethyl ester (content about 0.84 g, about 111 mm; diastereomeric ratio = about 1: 200410948 1) Dissolve in dichloromethane (20 m 1) and add ice (triphenylphosphine) palladium (62.1 mg, 0.05 mmol) and 5,5 ~ dimethyl-i, 3 -cyclohexanedi under ice cooling. Ketone (75.7mg '0.54 mmol) and stirred at room temperature for 50 minutes under nitrogen. The reaction solution was purified by silica gel column chromatography (ethyl acetate-methanol, 1000: 0-90: 10, V / V, ϊ Evening gum 25g) to obtain the title object compound (577.4mg, Yield: about 72%) light yellow amorphous solid (diastereomer ratio = about i: 1) ° IR (KBr) 2231, 1763, 1615, 1504, 1276, 1141, 1056 cm1; iHNMR (CDC13, 400MHz): δ 1.37 (3H, dd, J = 7, 2Hz), 1.53 (3Hx (1/2), d, J = 5Hz), 1.58 (3Hx (1/2), d, J = 5Hz), 1.95 -2.09 (2H, m), 2.42-2.54 (4H, m), 2.99 (lHx (1/2), tt, J = 11, 5Hz), 3.04 (lHx (1/2), tt, J = 11, 5Hz), 3.46 (lHx (1/2) 't, 11Hz), 3.47 (lHx (1/2), t, 11Hz), 3.51 (lHx (1/2), t, 11Hz), 3.53 (lHx (1 / 2), t, J ^ llz), 3.61 (lHx (1/2), q, J = 7Hz), 3.95 (lHx (1/2), q, J = 7Hz), 4.13 (lHx (1/2 ), Ddd, J = ll, 5, 2Hz), 4.19 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.25 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.30 (lHx (1/2), ddd, J =; U, 5, 2Hz), 4.96 (lHx (1/2) 'd' J = 4Hz), 5.00 (lHx (1/2), d , J = 4Hz), 5.34 (lHx (1/2), d, J = 15Hz), 5.35 (lHx (1/2), dd, J = 15, 3Hz), 5.47 (lHx (1/2), dd , J = 15, 2Hz), 5.48 (lHx (1/2), d, J = 15Hz), 5.85 (lHx (1/2), dd, J = 15 4Hz), 5.86 (lHx (1/2), dd, J = 15, 4Hz), 6.57 (lHx (1/2), dd, J = 15, 11Hz), 6.58 (lHx (1/2), dd, J = 15, 11Hz), 6.73 (1H, d, J = 16Hz), 6.79 (1H, q, J = 5Hz), 6.86-6.97 (3H, m), 7.33 (lH.d, J = 10Hz) , 7.40 (1H, d, J = 7Hz), 7.57 (1H, t, J = 8Hz), 7.81 (lHx (1/2), s), 8Ό1 (lHx (1/2), s), 8.19 (lHx (1/2), s), 8.36 (lHx (1/2), s); MS (FAB) m / z: 745 ((M + H) +). The title compound (diastereomer ratio = about 1: 1; 283.5 mg, 0.38 mmol) prepared in the above was dissolved in tetrahydrofuran (5 ml) 'and sodium carbonate 364-200410948 (2 8 · 8 mg, 0 · A solution of 3 4 mm ο 1) in water (5 m 1) was stirred at room temperature for 5 minutes. After distilling off tetrahydrofuran under reduced pressure, the insoluble matter was removed by filtration through a membrane, and the obtained aqueous solution was freeze-dried to obtain the sodium salt of the title object compound (2 8 6.3 mg, yield 98%) as a colorless amorphous solid (diastereomer). Ratio = about 1: 1). IR (KBr) ^ max2230, 1763, 1576, 1504, 1418, 1276, 1141, 1055cm · 1; 4 NMR (CD3OD, 400MHz): 5 1.30 (3Hx (1/2), dd, J = 7, 2Hz), 1.34 (3Hx (1/2), dd, J = 7, 2Hz), 1.52 (3H, d, J = 5Hz), 1.91 (2Hx (1/2), five wires, J = 8Hz), L91 ( 2Hx (1/2), five lines, J = 8Hz, overlap), 2.22 (2H, q, J = 8Hz), 2.40 (lHx (1/2), t, J = 8Hz), 2.47 (lHx (1 / 2), t, J = 8Hz), 2.95 (lHx (1/2), tt, 11, 5Hz), 2.97 (lHx (1/2), tt, J = ll, 5Hz), 3.48 (lHx (1 / 2), t, J = llHz), 3.48 (lHx (1/2), t, J = 11Hz, overlap), 3.49 (lHx (1/2), t, J = llHz), 3.51 (lHx (1 / 2), t, J = llHz), 3.83

(lHx (1/2), q, J = 7Hz), 3.84 (IHx (1/2), q, J = 7Hz), 4.11 (lHx (1/2), ddd, J = 11, 5, 2Hz) , 4.12 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.25 (1H, ddd, J = 11.5, 2Hz), 5.01 (lHx (1/2), d, J = 4Hz ), 5.02 (lHx (1/2), d, J = 4Hz), 5.45-5.46 (2H, m), 5.87 (lHx (1/2), dd, 16, 11Hz), 5.88 (lHx (1/2 ), Dd, J = 16, 11Hz), 6.59 (1H, dd, J = 16, 11Hz), 6.67 (lHx (1/2), q, J = 5Hz), 6.77 (lHx (1/2), q , J = 5Hz), 6.79 (1H, d, J = 16Hz), 6.99-7.10 (2H, m), 7.10 (1H, dd, J = 16, 11Hz), 7,49-7.54 (3H, m ), 7.78 (1H, t, J = 8Hz), 7.80 (lHx (1/2), s), 7.99 (lHx (1/2), s), 8.29 (lHx (1/2), s) , 8.41 (lHx (1/2), s); MS (FAB) m / z ·· 67 ((sodium salt overall + H) +). Example 29 Hydrocis-1,4-cyclohexanedicarboxylic acid 1 [(1R, 2R) -2-[[trans- 2-[(IE, 3E) -4- (4-cyano-2-fluoro Phenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1 , 2,4--365-200410948 triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound [759) (29a) hydrocis-1,4-cyclohexanedicarboxylic acid Allyl ester Dissolve cis-1 '4-cyclohexanedicarboxylic acid (9.98 g, 58 mm 〇1) in N, N_dimethylformamide (100ml), and add allyl iodide (10.22 g, 60.9 mm) and monocyclohexylamine (11.04 g, 60.9 mmol) at 90. 〇 Stir and stir for 1 hour. Water (200 m 1) and ethyl acetate (1000 m 1) were added at room temperature, and the precipitated solid was filtered through celite, and the solid was washed with ethyl acetate (100 m). The mixture of the mother liquor and the washing solution was partitioned into water and ethyl acetate. The organic layers were combined, washed with water (100 m 1 X 3), and then saturated brine (100 m 1 X 1). The title compound was obtained by drying under anhydrous magnesium sulfate and distilling off the solvent under reduced pressure. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 50:50, V / V, 200 g of silica gel) to obtain the title compound (5.2 g, yield 42%) as a yellow oily substance. IR (CHC13) y orbital 1727, 1706, 1453, 1247, 1170, 1143 cm.1; iHNMR (CDC13, 400MHz): 5 1.68-1.78 (4H, m), L91-2.00 (4H, m), 2.45-2.6 (2H, m), 5.24 (1H, dd, J = 10, 1Hz), 5.33 (1H, dd, J = 17, 1Hz), 5.93 (1H, ddt, J = 17, 10, 5Hz); MS (FAB) m / z: 213 ((M + H) +) 〇 (2 9b) allyl cis-1,4-cyclohexanedicarboxylate 1-[[(1R, 2R) -2-[[trans -2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-diBfalk-5-yl] thio] -1-(2,4-difluorophenyl) -bu [(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester Example 2 9 (2 9 a) Allyl hydrocis-1,4-cyclohexanedicarboxylate (2.06 g, 9.7 mmol) was dissolved in N, N -dimethylformic acid amine (30 ml), Likou-366- 200410948 18-crown-6 (2.64 g, 10 vol) and carbonate shavings (1.42 g, 4.4 mmol) were added. The mixture was stirred at room temperature for 2 hours, and dichloroethyl carbonate (1R, 2R) produced in Example 1 (1a) was added. 2-[[trans- 2-[(1E '3E) -4- (4-cyano -2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -bu (2,4-difluorophenyl) 2,4-tri The azole-butyl) methyl] propyl ester (diastereomeric ratio = about 1: 1; 2.59 g, 4 mmol) was stirred at room temperature for 17 hours. Under ice-cooling, a phosphate buffer solution (60 m 1) was added to the reaction solution, and the resultant was extracted with ethyl acetate (50 m 1 × 3). The organic layer was combined, washed with water (30 ml x 3), and then with saturated brine (50 ml x 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue containing the title compound. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 50: 50-20: 80, V / V, silica gel 75g) to obtain a crude title compound (total amount -2.68 g). , The title compound content = about 1.6 g, the title compound yield = about 59%, impurities and 4-[(IE, 3E) -4- [trans- 5-[[(1R, 2R) -2- ( 2,4-difluorophenyl) -2-hydroxy-bumethyl- 3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1 '3-Yiyuan-2 -Yl] -1,3-butanediyl] -3 -fluorobenzonitrile) is a colorless amorphous solid (diastereomer ratio = about 1 :). It can be used in the next project without purification (29c). (2 9c) hydrocis-1,4-cyclohexanedicarboxylic acid 1-[[(1R, 2R) -2-[[trans-2-[(lE, 3E) -4- (4-cyano-2 -Fluorophenyl) 1,3_butadienyl] _1,3 -anhydrogen-5-yl] thio] -1- (2 '4-difluorophenyl) -1-[(1H-1 , 2 '4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound) The crude hydrogen cis-1, 4-produced in Example 2 9 (2 9 b) Cyclohexanedicarboxylic ene-367-200410948 Propyl 1-[[(1R, 2R) -2-[[ Trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-difluoren | alk-5-yl] sulfur Group] -1- (2,4-monochlorophenyl) -l-[(1H-] '2' 4-difluoren-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (content Approximately 0.84 g, 1.0 mmol) was dissolved in dichloromethane (20 ml). Under ice cooling, tris (triphenylphosphine) palladium (58.7 mg, 0.05 mmol) and 5,5-dimethyl-1 '3 were added. -Cyclohexanedione (70.1 mg, 0.5 mmol), and stirred at room temperature for 80 minutes under nitrogen. The reaction solution was purified by silica gel column chromatography (ethyl acetate-methanol, 100: 0-90: 10, V / V, silicone 20g) to obtain the title object compound (0.53g, yield about 67%) as a colorless amorphous solid (diastereomer ratio = about 1: 1). IR (KBr) vmax2231, 1763, 1615, 1504, 1276, 1140, 1061, 973cm]; hNMR (CDC13, 400MHz): 51 · 36 (3H, dd, J = 7, 2Hz), 1.55 (3Hx (1/2), d, J = 5Hz), 1.56 (3Hx (1/2), d, J = 5Hz), 1.6-1,8 (4H, m), 1.8-2.0 (4H, m), 2.4-2.6 (2H, m), 2.99-3.06 ( 1H, m), 3.48 (lHx (1/2), t, J = llHz), 3.49 (lHx (1/2), t 'J = llHz) 3.49 (lHx (1/2), t, J = llHz, overlapping), 3.50 (lHx (1/2), t, J = llHz), 3.75 (IHx (1/2), q, J = 7Hz), 3.90 (lHx (1/2), q, J = 7Hz), 4.17 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.19 (lHx (l / 2), ddd, J = ll , 2Hz), 4.25-4.30 (lH, m), 4.98 (lH, d, J = 4Hz), 5.36 (IHx (1/2), dd, J = 15, 3Hz), 5.36 (IHx (1/2) , Dd, J = 15, 3Hz, overlap), 5.42 (IHx (1/2), d, J = 15Hz), 5.43 (IHx (1/2) 'd, J = 15Hz), 5.86 (1H, dd, J = 15, 4Hz), 6.59 (1H, dd, J = 15, 11Hz), 6.71 (IHx (1/2), q, J = 5Hz), 6.74 (1H, d, J = 16Hz) , 6.76 (IHx (1/2), q, J = 5Hz), 6.85-6.96 (2H, m), 6.94 (1H, dd, J = 16, 11Hz), 7.34 (lH, dd, J = 10 , 1Hz), 7.41 (lH, dd, J = 8, 1H =), 7.35-7.47 (1H, m), 7.78 (1H, t, J = 8Hz), 7.94 (IHx (1/2), s ), 7.98 (IHx (1/2), s), 8.05 (IHx (1/2), s), 8.12 (IHx (1/2), s)) MS (FAB) m / z: 785 ((M + H) +). -368-200410948 The title compound (diastereomer ratio = about 1: 1; 3 3 3 · 4 mg, 0 · 4 2 mm ο 1) prepared above was dissolved in tetrahydrofuran (5 m 1) and added A solution of sodium bicarbonate (3 3.9 mg, 0.4 m 0 1) in water (5 m 1) was stirred at room temperature for 5 minutes. Tetrahydrofuran was distilled off under reduced pressure, and the insoluble matter was removed by membrane filtration. The obtained aqueous solution was freeze-dried to obtain the sodium salt of the title object compound (138 · 8mg, yield 41%) as a colorless amorphous solid (diastereomeric ratio = About 1: 1). IR (KBr) ymax 2231, 1762, 1614, 1563, 1504, 1417, 1276, 1141, 1059, 973 cm · 1;

4 NMR (CD3OD, 400MHz): 51.30 (3Hx (1/2), dd, J = 7, 2Hz), 1.33 (3Hx (1/2), dd, J = 7, 2Hz), 1.52 (3Hx (1 / 2), d, J = 4Hz), 1.54 (3Hx (1/2), d, J = 4Hz), 1.55-1.7 (4H, m), 1.8-1.9 (2H, m), 1.9- 2.1 (4H, m), 2.95 (lHx (1/2), tt, J = 11,5Hz), 2.97 (lHx (1/2), tt, J = ll, 5Hz), 3.47 (lHx (1/2), t, J = llHz), 3.48 (lHx (1/2), t, J = llHz), 3.49 (lHx (1/2), t, J = llHz), 3.51 (lHx (1/2), t, J = llHz), 3.80 (lHx (1/2), q, J = 7Hz), 3.82 (lHx (1/2), q, J = 7Hz), 4.11 (lHx (1/2), ddd, J = (1, 5, 2 Hz), 4.12 (lHx (1/2), ddd, J = ll, 5, 2 Hz), 4.26 (lHx

(1/2), ddd, J = ll, 5, 2Hz), 4.27 (lHx (1/2), ddd, J = ll, 5, 2Hz), 5.01 (lHx (1/2), d, J = 4Hz), 5.02 (lHx (1/2), d, J = 4Hz), 5.4-5.5. (2H, m), 5.86 (lHx (1/2), dd, J = 16, 11Hz), 5.87 (lHx (1/2), dd, J = 16, HHz), 6.59 (1H, dd, J = 16, 11Hz) '6.67 (lHx (1/2). q, J = 4Hz), 6.78 (lHx (1/2), q, J = 4Hz), 6.79 (1H, d, J = 16Hz), 7.0-7.12 (3H, m), 7.5-7.6 (3H, m), 7.78 (1H, t, J = 8Hz), 7.98 (1H x (1/2), s), 8.04 (lHx (1/2), s), 8.28 (lHx (1/2), s), 8.42 (lHx (1/2), s). Example 3 0 hydrogen trans-1,4-cyclohexanedicarboxylic acid 1-[[(1R, 2R) -2-[[trans- 2-[(IE, 3E) -4- (4-cyano-2 -Fluorophenyl) -1,3-butadienyl] -1,3-difluorenyl-5-yl] thio] -1- (2,4-monochlorophenyl) -1-[(1H -1,2,4--369- 200410948 triazole-butyl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compound 1-7 5 9) (3 0a) hydrogen trans-1,4- Allyl cyclohexanedicarboxylate dissolves trans ·], 4-cyclohexanedicarboxylic acid (9.98 g, 58 mm ο 1) in N, N -dimethylformamide (100 m) 1), add allyl iodide (0.22 g, 60.9 mmol) and dicyclohexylamine (11.04 g, 60.9 mmol), and stir at 90 ° C. for 1 hour. Water (200 ml) and ethyl acetate (100 ml) were added at room temperature, and the precipitated solid was filtered through celite, and the solid matter was washed with ethyl acetate (100 m 1). The mixture of the mother liquor and the washing solution was partitioned into water and ethyl acetate. The organic layer was combined, washed with water (100 ml x 3), and then saturated brine (100 ml x 1), and then dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Removal of the solvent gave the crude title compound. The obtained crude title compound was purified with a silica gel column (hexane: ethyl acetate, 50:50, V / V, 150 g of silica gel) to obtain the title compound (4.24 g, yield 34%) as a yellow solid.

Mp 47-49〇C IR (KBr) 2 &gt; max 1729, 1695, 1323, 1259, 1174 cm · 1; 4NMR (CDC13, 400MHz): (Π.43-1.53 (4H, m), 2.04-2.15 (4H , M), 2.30-2 · 34 (2H, m), 4.58 (2H, d, J = 6Hz), 5.23 (1H, d, J = 10Hz), 5.31 (1H, d, J = 17Hz), 5.91 (1H, ddt, J = 17,10,5Hz), (30b) all-trans-1,4-cyclohexanedicarboxylic acid l-[[(lR, 2R) -2-[[ Trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1'3-butadienyl] -1,3-diseno-5-yl] thio ] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester Example Hydrogen trans-1 '4-cyclohexadicarboxylic acid allyl ester manufactured by 3 0 (30a)-370- 200410948 (2.06 g, 9.7 mmol) dissolved in N, N -dimethylformamide (3 0 m 1 ), 1 8-crown-6 (2.46 g, 10 mm ο 1) and carbon shavings (1.4 2 g, 4.4 mm ο 1) were added. Stir at room temperature for 2 hours, add Example 1 ( 1 a) 1-chloroethyl carbonate (] R, 2R) -2-[[trans- 2-[(] E, 3E) -4- (4-cyano-2-fluorophenyl) -1 , 3 -butadienyl] -1,3 -di Alk-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1H-1,2,4-triazole-butyl) methyl] propyl ester (diastereomer Isomer ratio = about 1: 1; 2.59 g, 4 mmol), and stirred at room temperature for 20 hours. Under ice cooling, a phosphate buffer solution (60 ml) was added to the reaction solution, and the crude product was ethyl acetate (50). m 1 X 3) extraction. Combine the organic layers, wash with water (30 m 1 x 3), then wash with saturated brine (50 ml x 1), dry under anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure to obtain the title compound. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 50: 50-20: 80, V / V; silica gel 75g) to obtain the crude title compound (total = 2.43g). , The title compound content = 1.62g, the title compound yield = 49%, containing impurities 4 · [(IE, 3E) -4- [trans- 5-[[(1R, 2R) -2- (2,4 · 二Fluorophenyl) -2-hydroxy-1-methyl-3- (1,2-1,2,4-triazol-1-yl) propoxy] thio] -1,3-dioxane-2- Group] -1,3-butadienyl] -3-fluorobenzonitrile) a colorless amorphous solid (diastereomer ratio = about 1: 1). It can be used in the next project without refining (30c). (30c) hydrogen trans-1,4-cyclohexanedicarboxylic acid [[(1R, 2R) -2-[[trans-2-[(lE, 3E) -4- (4-cyano-2-fluoro Phenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1 Η- 1,2, I triazole- 丨 -yl) methyl] propoxy] carbonyloxy] ethyl ester The crude trans-1,4-cyclohexanedicarboxylic acid allyl produced in Example 30 (30b) 200410948 Ester 1-[[(1R, 2R) -2-[[trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] (2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl (Content about 1.07g, about] .3mmo]) was dissolved in dichloromethane (25ml), and (triphenylphosphine) palladium (75mg, 0.065mmol) and 5,5-dimethyl- 1,3-Cyclohexanedione (98.1 mg, 0.7 mm ο 1) was stirred at room temperature under nitrogen for 1 hour. The reaction solution was purified by silica gel column chromatography (ethyl acetate-methanol, 1 00: 0-90: 10, V / V, 20 g of silica gel) to obtain the title object compound (0.48 g, yield 47%) as a pale yellow amorphous substance. Solid (diastereomeric ratio = about 1 ·· 1). IR (KBr) vmax 2231, 1763, 1615, 1504, 1276, 1140, 1061, 973 cm-1;

bNMR (CDC13, 400MHz): 51.35 (3H, dd, J = 7, 2Hz), 1.40-1.58 (4H, m), 1.54 (3Hx (1/2), d, J = 5Hz), 1.55 (3Hx (1 / 2), d, J = 5Hz), 2.01-2.17 (4H, m), 2.28-2.40 (2H, m), 2.97 (lHx (1/2), tt, J = 1, 5Hz), 3.03 (lHx (1/2), tt, J = ll, 5Hz), 3.44 (lHx (1/2), t, 11Hz), 3.47 (lHx (1/2), t, 11Hz), 3.49 (lHx (1/2 ), T, J ^ llHz), 3.49 (lHx (1/2), t, J = llHz, overlapping), 3.62 (lHx (1/2), q, J = 7Hz), 3.90 (lHx (1/2 ), Q, J = 7Hz), 4.12 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.19 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.25 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.28 (IHx (1/2), ddd, J = n, 5, 2Hz), 4.95 (lHx (1/2), d, J = 4Hz), 4.98 (lHx (1/2), d, J = 4Hz), 5.36 (lHx (1/2), dd, J = 15, 3Hz), 5.38 (1H, s), 5.46 ( lHx (1/2), d, J = 15Hz), 5.83 (lHx (1/2), dd, J = 16, 4HZ), 5.85 (lHx (1/2), dd, J = 16, 4Hz), 6.56 (IHx (1/2), dd, J = 16, 11Hz), 6.58 (IHx (1/2), dd, J = 16, 11Hz); 6.69 (1H x (1/2), q, J = 5Hz), 6.73 (1H, d, J = 16Hz), 6.75 (IHx (1/2), q, J = 5Hz), 6.84-6.96 (2H, m), 6.91 (1H, dd, J = 16, 11Hz), 7.31 (lHx (1/2), dd, J = 10, 1Hz), 7.33 (lHx (1/2), dd, 10, 1Hz), 7.37-7.42 (2H, m), 7.56 (1H, t, J = 8Hz), 7.92 (1H-372-200410948 x (] / 2), s), 8. 0 (ΙΗχ (1/2), s), 8.08 (IHx (1/2), s), 8.21 (ΙΗχ (1/2), S ). The above-prepared title compound (2 0 · 1 · 7 mg, 0 · 2 6 mmo 1) was dissolved in tetrahydrofuran (5 ml), and a solution of sodium hydrogen carbonate (20.5 mg, 0.25 mmol) in water (5 m 1) was added. Stir for 5 minutes. The tetrahydrofuran was distilled off under reduced pressure, the insoluble matter was removed by membrane filtration, and the obtained aqueous solution was freeze-dried to obtain the sodium salt of the title object compound (178.8 mg, yield 86%) as a colorless amorphous solid (diastereoisomer ratio = about 1: 0. IR (KBr) vmax 2231, 1763, 1560, 1504, 1418, 1276, 1141 cm · 1;

4 NMR (CD3OD, 400MHz): 5 1 · 30 (3Hx (1/2), dd, J = 7, 2Hz), 1.32 (3Hx (1/2), dd, J = 7, 2Hz), 1.37-1.48 (4H, m), 1.52 (3Hx (.1 / 2), d, J = 5Hz), 1.53 (3Hx (1/2), d, J = 5Hz), 1.9-2.1 (6H, m), 2.96 ( lHx (1/2), tt, J = ll, 5Hz), 2.97 (lHx (1/2), tt, 11, 5Hz), 3.46 (lHx (1/2), t, J = llHz), 3.48 ( lHx (1/2), t, J = llHz), 3.48 (lHx (1/2), t, J = llHz, overlapping), 3.50 (lHx (1/2), t, J = llHz), 3. · 78

(lx (1/2), q, J = 7Hz), 3.79 (lHx (1/2), q, J = 7Hz), 4.11 (lHx (1/2), ddd, J = 11, 5, 2Hz), 4.12 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.25 (lHx (1/2), ddd, J = 11, 5, 2Hz), 4.26 (lHx (1/2 ), Ddd, J = ll, 5, 2Hz), 5.01 (1H, d, J = 4Hz),

5.4-5.5 (2H, m), 5.86 (lHx (1/2), dd, J = 16, 4Hz), 5.87 (lHx (1/2), d), J = 16, 4Hz), 6.58 [ 1H, dd, J = 16, 11Hz], 6.65 (lHx (1/2), q, J = 5Hz); 6.75 (lHx (1/2), q, J = 5Hz), 6.79 (1H, d, J = 16Hz), 7.00-7.10 (3H, m), 7.50-7.60 (3H, m), 7.78 (1H, t, J = 8Hz) '7.99 (lHx (1/2), s), 8.05 (lHx (1 / 2), s), 8.30 (lHx (1/2), s), 8.43 (lHx (1/2), s). Example 3 1 4- [4- (2-hydroxyethyl) -bupi Phenyl] -4-oxobutanoic acid l-[[(1R, 2R) -2-[[trans-2 [(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1, 3-butadienyl] -1,3-dioxan-5-yl] thio]-(2,4-difluorophenyl)-[(1H-1,-373-200410948 2,4_tri Azol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-7 3) (3 1 a) 1-[2-[(tertiary butanesilyl) oxy] Ethyl] piperidine Dissolve commercially available 4- (2-hydroxyethyl) piperin (6.512, 5010111111) and triethylamine (10 · lg, 100 mmol) in tetrahydrofuran (100ml), and stir with cooling on ice. Add Tertiary Butyl Chloride (15g, 100mmol)The mixture was stirred under ice-cooling for 15 minutes, and further stirred at room temperature for 2 hours. Under ice-cooling, a solution of potassium carbonate (14 g, 100 mmol) in water (60 ml) and ether were added to separate the layers. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain an oily residue. The obtained oily residue was purified by aluminum column chromatography (toluene: ethyl acetate, 100: 0-8 0: 20, V / V, using aluminum 200 g of activity I) to obtain a crude product of the title compound (7.5 g) Colorless oil. This product contains tertiary butadisilanol, which can be used in the next process without purification (Example 3 1 (3 1 b)). The molar ratio of the target compound and the third succinic acid is about 2: 1 (based on NMR). A part of the mixture was purified by silica gel column chromatography (2-propanol: dimethylamine, 90:10, V / V) to obtain a pure colorless oil. IR (CHC13) ymax2953, 293, 147, 147, 1463, 125 ?, 1101 cm_1;! HNMR (CDC13, 400MHz): 50.058 (6H, s), 0.891 (9H, s), ca.1.6 (1H, b0, ca .2.5 (4H, br), 2,511 (2H, t, J = 6.5Hz), 2.882 (4H, t, J = 5Hz), 3.755 (2H, t, J = 6.5Hz); MS (FAB) m / z: 245 ((M + H) +); HRMS (ESI +) m / z: C12H29N2OSi ((M + H) +) Calculate 値: 245.2049, Measured 値: 245.2043. (31b) 4- [4- [2 -[Third butadisilyl] oxy] ethyl]-374- 200410948 -1 -piperidinyl]-4-oxybutyric acid The crude product produced in Example 3 1 (3 1 a) __ [I [(Third Dimethyl Siloxanyl) Xingji] Ethyl] Pyrene (contains the second dimethyl succinic alcohol impure substance; l.Og '1- [2-[(Third Dimethyl Dimethyl) Alkyl) oxy] ethyl] piperin content of about 3.2mmol) was dissolved in tetrahydrofuran (20ml), succinic anhydride (400mg, 4.0mmol) was added under ice-cooling stirring, and the mixture was stirred at room temperature for 1 hour. Add Triethylamine (101 mg, 1.0 mm ο 1), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel. Purified by column chromatography (ethyl acetate: ethanol, 50 ·· 50, V / V, 10 g of silica gel) to obtain a crude oil (partially cured) of the title compound of interest. Recrystallized from a hexane-ethyl acetate mixed solvent The title compound (980 mg, about 89% yield based on the purity of the starting material) was obtained as a purified, colorless hygroscopic needle-like crystal.

Mp85-90 ° C; IR (KBr) umax 1721, 1650, 1643, 1455, 1256, 1240, 1103 cm · 1; 4NMR (CDC13, 400MHz) · 50.059 (6H, s), 0.890 (9H's), 2.5-2.7 (9H, m), 2.585 (2H, t, J = 6Hz), 3.512 (2H, t-like, J = 5Hz), 3.660 (2H, t-like, J = 5Hz), 3.737 (2H, t, J = 6Hz); MS (FAB) m / z: 345 ((M + H) +); HRMS (ESI +) m / z: C16H33N204Si ((M + H) +) Calculate 値: 345.2210 'Found 値: 345.2202. (31c) 4- [4- [2-[(Third-butyldimethylsilyl) oxy] ethyl] -1-piperidinyl] -4-oxobutanoic acid 1-[[(1R, 2R)- 2-[[trans-2-[(1E, 3E) _4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl ] Thio] -1- (2,4-difluorophenyl)-: 1-[(1HM, 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester- 375-200410948 4-[4-[2-[Third-Butylsilyl] oxy] ethyl] -1-piperidinyl] -4 -oxetane produced in Example 3] (3 1 b) Acid (3), 8 mg, 0.923 m mol), potassium tert-butoxide (78 nig, 0.70 mmol), and N, N-dimethylacetamide (2 m 1) were added to the example] (1 a) Manufactured 1-chloroethyl carbonate (1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3- Butadienyl] -1,3-dioxan-5-yl] thio] 4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl ] N-N-dimethylacetamide (5 m 1) solution of propyl ester (diastereomeric ratio = about 1: 1; 300 mg, 0.6 4 mm ο 1), and the mixture at room temperature Stir for 1 hour, then at 50 ° C for 4 hours, and then at 60 ° C for 3 hours. To the mixture were added an aqueous sodium hydrogen carbonate solution and ethyl acetate to separate the layers. The organic layer was separated, washed with 10% brine (5 times), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a mixture of two diastereomers of the crude title compound (diastereomer ratio = about 1: 1). The obtained residue was purified by silica gel column chromatography (silica gel 5 g) and dissolved in a mixed solvent of ethyl acetate: 2-propanol (96: 4, V / V) to obtain a low-polar diastereomer A (33 mg, yield 7%) colorless gum-like substance. Redissolve in a mixed solvent of ethyl acetate: 2-propanol (96: 6-9: 2: .8, V / V) to obtain low-polar diastereomer A and high-polar diastereomer A mixture of B (29 mg, 7% yield) was a colorless gum-like substance. After re-dissolving in a mixed solvent of ethyl acetate: 2-propanol (90:10, V / V), a highly polar diastereomer B (38 mg, yield 9%) was obtained as a colorless gum. Spectral data of diastereomer A (low polarity): IR (CHC13) U Dirty 2233, 1764, 1643, 1505, 1277, 1258, 1141 cm · 1; NMR (CDC13, 400MHz): 50.055 (6H, s ), 0.887 (9H, s), 1.356 (3H, dd, 200410948 J = 7, 2Hz), 1.552 (3H, d, J = 6Hz), 2.47 (2Η, like tJ = 5Hz), 2.530 (4H, t, J = 6Hz), 2.54-2.80 (4H, m), 3.030 (1H, tt, 11, 5Hz), 3.4-3.5 (2H, m), 3.486 (1H, t, J = 11Hz), 3.498 (1H, t, J =] lHz), 3.59 (2H, like t, J = 5Hz), 3.749 (2Η, t, J = 6Hz), 3.881 (1H, q, J = 7Hz), 4.178 (1H , Ddd, J = 11, 5, 2 Hz), 4.297 (1H, ddd, J = 11, 5, 2 Hz), 4.974 (1H, d, J = 4 Hz), 5.373 (2H, brs), 5.853 (1H, dd , J = 15, 4Hz), 6.579 (1H, dd, J = 15, 11Hz), 6.733 (1H, q, J = 6Hz), 6.734 (1H, d, J = 15Hz), 6.8-7.0 (2H, m ), 6.929 (1H, dd, J = 15, 11Hz), 7.332 (1H, dd, J = 10, 2Hz), 7.398 (1H, dd, J = 8, 2Hz), 7.428 (1H, td, J2 9 , 6Hz), 7.569 (1H, t, J = 8Hz), 7.908 (] H, s), 8.020 (1H, s); MS (FAB) n / z: 957 ((M + H) +); HRMS ( ESI +) m / z: C46H60F3N6O9SSi ((M + H) +) Calculated 値: 957.3864, Measured 値: 957.3892. Spectral data of diastereomer B (high polar animals) z IR (CHC13) V service x 2233, 1767, 1643, 1505, 1277, 1259, 1141 cm · 1; bNMR (CDC13, 400MHz) ·· δθ.051 (6H, s), 0 · 884 (9H, s), 1.360 (3H, dd, J = 7, 2Hz), 1.538 (3H, d, J = 5Hz), 2.463 (2H, br t, J = 6Hz), 2.523 (2H, t, J = 6Hz), 2.538 (2H, brt, J = 6Hz), 2.6-2.8 (4H, m), 3.026 (1H, tt, J = n, 5Hz), 3 43-3 · 53 (2H, m), 3.480 (1H, t, J = llHz), 3.491 (1H, t, J = llHz), 3.579 (1H, t, J = 5Hz), 3.592 (1H, t, J = 5Hz), 3.744 (2H, t, J = 6Hz), 3.828 (1H, q, J = 7Hz), 4 = 69 (IH.ddd, J = ll, 5, 2Hz), 4.280 (1H, ddd, J = 11, 5, 2Hz), 4.971 (1H, d, J = 4Hz), 5.314 (1H, dd, J = 15, 4Hz), 5.444 (1H, d, J = 15Hz), 5.857 (1H, dd, J = 15, 4Hz), 6.585 (1H, dd, J = 15, 11Hz), 6.735 (1H, d, J = 16Hz), 6.811 (1H, q, J = 5Hz), 6.84-6.95 (2H, m), 6.931 (1H, dd, J = 16, 11Hz), 7.331 (1H, dd, J = 10, 2Hz), 7.35-7.45 (1H, m), 7.395 (1H, dd, J = 8, 2 Hz), 7.571 (1H, t J = 8Hz), 7.946 (1H, s), 8.231 (1H, s); MS (FAB) m / z: 957 ((M + H) +);-377-200410948 HRMS (ESI +) m / z ··· C46H6〇F3N609SSi ((M + H) +) Calculated 値: 957.3864 Guest test 値: 957.3874. (31d) 4- [4- (2-Hydroxyethylpiperidyl] _4-oxobutanoic acid u (ir, 2R) -2-[[trans-2-[(IE, 3E) -4- (4- Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -b [(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (the title object compound) 4- [4- [manufactured by Example 31 (31c) 2-[(Third-Butylsilyl) oxy] ethyl] -1-piperidinyl] -4-oxobutanoic acid 1-[[(1R, 2R) -2-[[Trans-2- [ (IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- ( Low-polar diastereomers of 2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester Compound A (30 mg, 0.31 mm ο 1) was dissolved in tetrahydrofuran (1 ml), and tetrabutylammonium fluoride (26 mg, 0.1 mmol), acetic acid (4 mg, 0.07 mmol), and tetrahydrofuran (0.1 lml). After 17 hours, the reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate aqueous solution (2 times), and saturated brine (i times). The organic layer was dried under anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol, 85:15, V / V, 2.5 g of silica gel) to obtain Low-polar diastereomer A of the title object compound (8 mg, 30% yield) was a colorless oil. In the same manner, 1-[[(1 R , 2 R)-2-[[trans-2-[(: ^, 3 £) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3 -Dioxane-5-yl] thio] -bu (2,4-difluorophenyl) -bu [(1H-1,2,4-triazol-1-yl) methyl] propoxy] Carbonyloxy] ethyl = 4- [4- [2-[((Third-butadiylsilyl) oxy] ethyl] -bupizone-378-200410948 based) highly polar diastereomer Isomer B (38mg, 0.040mmol) was dissolved in tetrahydrofuran, treated with tetrabutylammonium fluoride and acetic acid, and purified by silica gel column chromatography (ethyl acetate: methanol, 80:20, V / V, 2.5g of silica gel) A highly polar diastereomer B (6 mg, yield 18%) of the title object compound was obtained as a colorless oil. Diastereomer A ( Low polarity) Spectral data: IR (KBr) 2 &gt; max 2230, 1764, 1645, 1504, 1447 '1418, 1386, 1276, 1141, 1056 cm-1; 4 NMR (CDC13, 400MHz): 5 1.357 (3H, dd , J = 7, 2Hz), 1.556 (3H, d, J = 5Hz), 2.474 (2H, like t, J = 5Hz), 2.525 (2H, like t, J = 5Hz), 2.569 (2H, like t, J = 5 Hz), 2 · 6-2 · 8 (4H, m), 3 · 031 (1H, tt, J = 11, 5Hz), 3.4-3.6 (4H, m), 3 · 5-3 · 7 (4H, m), 3.635 (1H, q, J = 7Hz), 4.171 (1H, ddd, J = ll, 5, 2Hz), 4.300 (1H, ddd, J = 11, 5, 2Hz), 4.976 ( 1H, d, J = 4Hz), 5.376 (2H, brs), 5.854 (1H, dd, J = 16, 4Hz), 6.581 (1H, dd, J = 16, 11Hz), 6.738 (1H, q, J = 5Hz), 6.738 (1H, d, J = 16Hz), 6.8-7.0 (2H, m), 5.929 (1H, dd, J = 16, 11Hz), 7.333 (1H, dd, J = 10, 1Hz), 7.400 (1H, dd, J = 8, 1Hz), 7.429 (1H, td, J = 9, 6Hz), 7.571 (1H, t, J = 8Hz), 7.907 (lH.s) , 8.024 (1H, s); MS (FAB) m / z: 843 ((M + H) +); HRMS (ESI +) m / z ·· C40H46F3N6O9S ((M + H) +) Calculate 値 ·· 843.2999, Found 値: 843.29 86. Diastereomer B (high polarity) spectral data: IR (CHC13) vmax 2233, 1766, 1645, 1505, 1462, 1448, 1383, 1276, 1141, 1056 cm &quot;1;

4 NMR (CDC13, 400MHz): 1.361 (3H, dd, J = 7, 2Hz), 1.540 (3H, d, J = 5Hz), 2.51 (2H, m), 2.60 (4H, br, m), 2.6 -2.8 (4H, m), 3.027 (1H, tt, J = 11, 5Hz), 3.481 (1H, t, J = llHz), 3.490 (1H, t, J = llHz), 3.58 (2H , Brm), 3.66 (4H, m), 3.825 (1H, q, J = 7Hz), 4.170 (1H, ddd, J = 11, 5, 2Hz), 4.280 (1H, ddd, J

φ-379-200410948 = 11.5, 2Hz), 4.972 (1H, d, J = 4Hz), 5.314 〇H, dd, J = 15, 3Hz), 5.449 (1H, d, J = 15Hz), 5.857 (1H, dd, J = 15, 4Hz), 6.585 (1H, dd, J = 15, 11Hz), 6.737 (1H, d, J = 16Hz), 5.889 (] H, q, J = 5Hz), 6.8-7.0 (2H, m), 6.906 (] H, dd, J = 16, 11 Hz), 7.333 (1H, dd, J = 10, 2 Hz), 7.38-7.44 (2H, m), 7.40 (1H, dd, J = 8, 2 Hz), 7.574 (1H, t, J = 8Hz), 7.950 (1H, s), 8.236 (1H, s); MS (FAB) m / z: 843 ((M + H) +); HRMS (ESI +) m / z: C40H46F3N6O9S ((M + H) +) Calculated 値: 843.2999, Measured 値: 8432.991. About 1: 1 mixture of the title object compound diastereomer A and diastereomer B (260 mg in total, 0.3 09 mmol) was dissolved in ethyl acetate (20 ml), and the solution was dropped at -25 ° C under cooling and stirring. Add hydrogen chloride (1N ethyl acetate solution; 0.35 ml, 0.35 mmol). The solvent was distilled off under reduced pressure, and the residue was dried under vacuum to obtain 1 hydrochloride (250 mg) of the title object compound as a pale yellow solid (diastereomeric ratio = about 1: 1). Example 32 (1-Methyl-4-piperidinyl) acetic acid 1-1 [(1 foot, 251) -2-[[trans-2-[(IE, 3E) -4- (4-cyano- 2-fluorophenyl) -1,3-butadienyl] -1,3-diDf alkyl-5-yl] thio] -1- (2,4-difluorophenyl) -1-[( 1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-9) (32a) (l-methyl-4-piperidinyl ) Methyl acetate Dissolve 1-methyl-4-piperidone (4.80 g, 42.4 mmol) and trimethyl phosphonate acetate (13.8 g, 46.7 mmol) in tetrahydrofuran (100 ml). Under ice-cooling and stirring, the third potassium butoxide (5.20 g, 46.4 mmol) was added in small portions 3 times. The reaction mixture was difficult to stir due to the formation of a viscous oil. 1,2-Dimethoxyethane (50 m 1) was added and warmed to 30 ° C and stirred. -380- 200410948 Stir the mixture at 30 ~ 3 5 ° C for 3 hours to obtain a solid precipitated mixture. After cooling, ethyl acetate and water were added to the resulting mixture to separate the layers. The resulting organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily residue. Purified by silica gel column chromatography (ethyl acetate: methanol, 95: 5-80: 20'V / V, silica gel 50g) to obtain the title compound (6.2g, yield 86%) as a colorless oil.

IR (CHC13) vmax2949, 2796, 1711, 1656, 1437, 1385, 1279, 1251, 1169 cnf1;! HNMR (CDC13, 400MHz): 52.295 (3H, S), 2.354 (2H, like t, J = 6Hz), 2.468 (2H, t-like, J = 6Hz), 2.495 (2H, t-like, J = 6Hz), 3.001 (2H, t-like, J = 6Hz), 3.691 (3H, s), 5.657 (1H, brs); MS (El) m / z: 169 (M +), 154, 136, 110. (3 2b) (1-methyl-4-piperidinyl) acetic acid methyl (1-methyl-4-piperidinyl) acetic acid produced in Example 3 2 (3 2a)

Methyl ester (1 · 0 1 g, 6 · 0 mm ο 1) was dissolved in ethanol (15 m 1), 10% fine carbon catalyst (75 mg) was added, and the mixture was stirred under hydrogen (normal pressure) gas and room temperature 2 hour. The resulting reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.98 g, yield 95%) as a colorless oil. IR (CHC13) y leg 2941, 2792, 1732, 1448, 1439, 1279, 1173 cm · 1; bNMR (CDC13, 400MHz): ό 1.319 (2H, like qd 'J = ll, 4Hz), ca.1.71 (2H , Like d, J = ca.lIHz), ca.1.75 (1H, m, overlap), 1.940 (2H, td, J = ll, 2Hz), ca.2.245 (2H, d, J = ca. 7Hz, overlap ), 2.258 (3H, s), 182 (2H, like d, J = ca.llHz), 3.669 (3H, s); MS (El) m / z: 171 (M +), 170, 156, 140 , 112, 96. (3 2 c) (1 -methyl-4-piperidinyl) acetic acid (1-methyl-4-piperidinyl) methyl-381- 200410948 ester (0.1 98 g, 6.0 mmol) was dissolved in water (10 ml), and a carbonic acid planer (97 7 mg, 3.0 mm ο 1) was added under stirring, followed by stirring at room temperature for 9 3 hours. The solvent was distilled off under reduced pressure, toluene and methanol were added to the residue, and the volatile component was distilled off under reduced pressure to obtain the title compound (1.67 g, yield 96%) as a light brown solid. IR (KBr) 2; max 2932, 2778, 1655, 1574, 1402 cm-1; 1H NMR (CD3OD, 400MHz): 51 · 35 (2H, like q, J = ca.llHz), 1.75-1.85 (3H, m), 2.092 (2H, like d, J = 7Hz), 2.19 (2H 'like t, J = ca.llHz), 2.336 (3H, s), 2.940 (2H, like d, J = ca.llHz); MS (FAB +) m / z: 290 ((planed salt overall + H) +); HRMS (ESI +) m / z: C8H14N02 ((non-planed) ·) Calculated 値: 156.1024, measured 値: 156 · 1025 · ( 32d) (l-methyl-4-piperidinyl) acetate ll [(lR, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorobenzene Group) -1,3-butadienyl]

-1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl 1H-1, 2, 4-triazol-1-yl) methyl] propoxy] Carbonyloxy] ethyl ester (the title object compound) (1-methyl-4-piperidinyl) acetic acid (1.16 g, 4.0 mmol) produced in Example 32 (32c), and produced in Example 1 (la) 1-ethyl ethyl carbonate (1R, 2R) -2 _ [[trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1 · (2,4-difluorophenyl) -1-[(1Η-1,2,4-triazol-1-yl) methyl Propyl] propyl ester (diastereomer ratio = about 1: 1; 1.30 g, 2.0 mmol), and a mixture of N, N-dimethylacetamide (22 ml) was stirred at 40 ° C for 8 hours. The mixture was cooled at room temperature, and ethyl acetate and 10% saline were added to separate the layers. The obtained organic layer was separated with 10% saline (3 times), and then saturated-382-200410948 saline (1 time). After washing and drying under anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude title object compound. The obtained crude title compound was purified by silica gel column chromatography (ethyl acetate: methanol, 50: 50-0-0: 100, V / V, silica gel 20g) to obtain the title target compound (480 mg, yield 31). %), Brown amorphous solid (diastereomeric ratio = about 1: 1). IR (KBr) vmax 2230, 1763, 1615, 1504, 1277, 1141, 1060 cm-1; NMR (CDC13, 400MHz): (5 1.25-1.40 (2H, m), 1.357 (3H, like d, J = 7Hz ), 1.535 (3Hx (1/2), d, J = 5Hz), 1.556 (3Hx (1/2), d, J = 5Hz), 1.6--1 · 9 (3H, m), 1.87-2.02 (2H, m), 2.2-2.3 (2Hx (1/2), m, overlap), 2.255 (3H, s), 2.32 (lHx (1/2), dd, J = 15, 7Hz), 2.36 (lHx (1/2), dd, J = 15, 7Hz), 2.7-2.9 (2H, m), 2.998 (1H x (1/2), tt, J-2 11, 5Hz), 3.020 (lHx (1/2 ), Tt, J = ll, 5Hz), 3.471 (lHx (1/2), t, J = llHz), 3.478 (lHx (1/2), t, J = llHz), 3.478 (lHx (1/2 ), T, J = llHz, overlap), 3.500 (ΙΗχ (1/2), t, J = llHz), 3.747 (lHx (1/2), q, J = 7Hz), 3.883 (ΙΗχ (1/2 ), Q, J = 7Hz), 4.15 (lHx (1/2), ddd, J = n, 5, 2Hz), 4.18 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.27 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.28 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.967 (1H, d, J = 4Hz), 5.33 (1H, dd, J = 15, 4Hz), 5.40 (1H, d, J = 15Hz), 5.854 (1H, dd, J = 16, 4Hz), 6.581 (1H, dd, J = 16, 11Hz), 6.678 (lHx (1/2), q, J = 5Hz), 6.735 (1H, d, J = 16Hz), 6.76 (lHx (1/2), q, J = 5Hz), 6.85-6.95 (2H, m), 6.931 (1H, dd, J = 16, 11Hz), 7.335 (1H, dd, J = 10, 2Hz), 7.400 (1H, dd, J = 8, 2Hz), 7.401 (lHx (1/2), td, J = 9, 6Hz), 7.432 (lHx (1/2), td, J = 9, 6Hz), 7.569 (1H, t, J = 8Hz ), 7.940 (lHx (1/2), s), 7.944 (lHx (1/2), s), 7.995 (IHx (1/2), s), 8.021 (lHx (1/2), s); MS (FAB) m / z: 770 ((M + H) +); HRMS (ESI +) m / z: C38H43F3N507S ((M + H) +) Calculated 値: 770.2836, Found 値: 770.2805. 200410948 The title compound (diastereomer ratio = approximately): 1; 4 7 5 mg, 0.6 1 7 mm ο 1) prepared above was dissolved in ethyl acetate (40 m 1) at -3 0 ° C Hydrogen chloride (N solution of ethyl acetate; 0.7 5 m 1, 0.7 5 mm ο 1) was added dropwise with cooling and stirring. The solvent was distilled off under reduced pressure, and the residue was dried under vacuum to obtain 1 hydrochloride salt of the title compound (57 μm, diastereomeric ratio = about J ·· 1) as a yellow-brown solid. Example 3 3 Hydrogen adipate [[(1R, 2R) -2-[[trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3 -Butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triwa -1-yl) methyl] propoxy] carbonyloxy] ethyl ester (exemplified compounds 1-795) (33a) allyl adipate [[(lR, 2R) -2-[[trans-2 -[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1 -(2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl hydrogen adipate Propyl ester (J. Am. Chem. Soc., 78 巻, page 104 (1956); 1.87g, 10mmol) was dissolved in N, N-dimethylformamide (30ml), and 18-crown-6 was added (2.91 g, 11 mmol) and carbonate shavings (1.47 g, 4.5 mmol). After stirring at room temperature for 5 hours, 1-chloroethyl carbonate (1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4 -Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 · yl] thio] -1- (2,4-difluorophenyl)- 1-[(1H-1,2,4-triazol-1-yl) methyl] propyl ester (diastereomer ratio = about 1: 1; 2.52 g, 4 mmol), stirred at room temperature for 15 hours . Under ice-cooling, a phosphate buffer solution (60 m 1) 'was added to the reaction solution to give crude product-384-200410948. The product was extracted with ethyl acetate (50 m 1 x 3). Combine the organic layers, wash with water (30 m 1 x 3) and then with saturated brine (5 Om 1 x 1) and dry under anhydrous magnesium sulfate to evaporate the solvent under reduced pressure to obtain the residue containing the title compound. Thing. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 6 5: 3 5-5 0:50, V / V, silica 7 5 g) to obtain the crude title compound (total amount 2 · 2 · 5 5 g, the content of the title compound = about 1.51 g, the yield of the title compound is about 4 7%, with impurities 4-[(1 E, 3 E)-4-[trans-5-[[(1 R , 2 R)-2 '(2,4-difluorophenyl) -2-hydroxy-1-methyl- 3- (1 ， -1,2,4-tri-D--1-yl) propoxy] Thio] -1,3-dioxan-2-yl] -1,3-butanecanyl] -3 -fluorobenzonitrile), a colorless amorphous solid (diastereomer ratio = about 1: 1 ). It can be used in the next project without refining (3 3 b). (33b) Hydrodipic acid [[(1R '2R) -2-[[trans- 2-[(IE, 3E) —cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) 2 '4-triazol-yl) methyl] propoxy] carbonyloxy] ethyl Ester (title object compound) The crude allyl adipate produced in Example 3 3 (3 3 a) [[(1 R, 2 aniso) -2-[[trans-2-[(1 £, 3 £) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] u, 3-dioxan-5-yl] thio] -1- (2 '4- Difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester (content about 0.80 g, about 1 mmol; diastereomer Isomer ratio = about 1: 1) dissolved in dichloromethane (20 m 1), and under ice cooling, add triphenylphosphine (34: 7mg, 0.03m mol) and 5,5- Dimethyl-1,3-cyclohexanedione (84.1 mg, 0.6 mmol) was stirred at room temperature under nitrogen for 2 hours. The reaction solution was purified by silica gel column chromatography (ethyl acetate · methanol '1 00: 0-95: 5, V / V, 25 g of silica gel) to obtain the title object compound (603.lmg, -385-200410948, yield approximately 76%) light yellow amorphous solid (diastereoisomer ratio = about 1: 1) ° IR (KBr) ζλ brain 223], 1763, 1504, 1276,]] 40;] 057, 973 cm · 1 ; 4 NMR (CDC13, 400MHz): (5) · 36 (3Hx (1/2), dd, J = 7, 2Hz),]. 38 (3Hx (1/2), dd, J = 7, 2Hz) , 1.53 (3Hx (1/2), d, J = 5Hz), 1.56 (3Hx (1/2), d, J = 5Hz), 1.65 -1.8 (4H, m), 2.3-2.5 (4H, m) , 3.02 (lHx (1/2), tt, J = ll, 5Hz), 3.03 (lHx (1/2), tt, J = ll, 5Hz), 3.47 (lHx (1/2), t, J = llHz), 3.48 (lHx (1/2), t, J = llHz), 3.50 (lHx (1/2), t, J = llHz), 3, 51 (lHx (1/2), t, J = llHz), 3.70 (lHx (1/2), q, J = 7Hz), 3.91 (lHx (1/2), q, J = 7Hz), 4.15 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.19 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.27 (lHx (1/2), ddd, J = ll, 5, 2Hz), 4.29 (lHx (1/2), ddd, J = ll, 5, 2 Hz), 4.97 (lHx (1/2) , D, J- = 4Hz), 4.99 (lHx (1/2), d, J = 4Hz), 5.34 (lHx (1/2), dd, J = 15, 3Hz), 5.35 (lHx (1 / 2), d, J = 15Hz), 5.44 (lHx (1/2), dd, J = 15, 3Hz), 5.47 (1H, d, J = 15Hz), 5.86 (1H, dd, J = 15, 11Hz), 6.58 (1H, dd.J = 15, 11Hz), 6.72 (lHx (1/2), q, J = 5Hz), 6.73 (1H, d, J = 16Hz), 6.74 (lHx (1 / 2), q, J = 7Hz), 6.85-6.96 (3H, m), 7.33 (1H, dd, J = 10, 1Hz), 7.39 (1H, d, J = 8Hz), 7.35-7.45 (1H, m), 7.56 (1H, t, J = 8Hz), 7.87 (lHx (1/2), s), 8.01 (lHx (1/2), s), 8.11 (lHx (1/2), s), 8.25 (lHx (1/2), s) o Dissolve the title compound (diastereomer ratio = about 1: 1; 209.1 mg, 0.2 7 mmol) prepared above in tetrahydrofuran (5 ml), and add hydrogen carbonate Water (5 m 1) of sodium (2 2 · 1 mg, 0.2 6 mm ο 1) was stirred at room temperature for 5 minutes. The tetrahydrofuran was distilled off under reduced pressure, the insoluble matter was removed by membrane filtration, and the obtained aqueous solution was freeze-dried to obtain the sodium salt of the title object compound (210 · 2mg, yield 97%) as a colorless amorphous solid (diastereomer ratio 2). About 1: 1). -386- 200410948 DR (KBr) 颜 223223 1176, 1576, 1417,] 276, 1141, 1055, 971cm · 1; NMR (CD30D, 400MHz) · 5 1.30 (3Hx (1/2), dd , J = 7, 2Hz), 1.34 (3Hx (1/2), dd, J = 7, 2Hz) '1.52 (3H'd, J = 7Hz), 1.62-1.71 (4H, m), 2 · 14-2 · 20 (2H, in), 2.36-3.40 (1H, m), 2.42-2.46 (1H, m), 2.95 (lHx (1/2), tt, J2] 1, 5Hz), 2.96 (lHx (1/2), U, J = 11, 5Hz), 3.47 (lHx (1/2), t, J = llHz), 3.48 (lx (1/2), t, J = llHz), 3.49 (lHx (1/2), t, J = llHz), 3.50 (lHx (1/2), t, J = llHz), 3.80 (1H x (1/2), q, J = 7Hz), 3.84 (lHx (1/2), q, J = 7Hz), 4.09-4.14 (1H, m), 4.25 (1H x (1/2), ddd, J-2 11, 5, 2Hz), 4.25 (lHx (1 / 2), ddd, J = 11, 5, 2Hz, overlap), 5.02 (1H, d, J = 4Hz), 5.46 (2H, brs), 5.87 (lHx (1/2), dd, 15, 4Hz), 5.88 (1H x (1/2), dd, J = 15, 4Hz), 6.59 (1H, dd, J = 15, 11Hz), 6.66 (lHx (1/2), q, J = 5Hz), 6.78 (lHx (1/2), q, J = 5Hz), 6.79 (1H, d, J = 16Hz), 7.01-7 · 14 (3H, m), 7.49-7.53 (3H , M), 7.79 ( 1H, td, J = 8, 3Hz), 7.99 (lHx (1/2), s), 8.04 (lHx (1/2), s), 8.29 (lHx (1/2), s), 8.42 (lHx (1/2), s). Example 3 4 2- [N- [8- [l-[[(1R, 2R) -2 · [[trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorobenzene Group) butadienyl] dioxanyl] thio] -l- (2,4-difluorophenyl) -1-[(ih-1,2,4-triazol-1-yl) methyl ] Propoxy] carbonyloxy] ethoxy] oxoctyl] -N_methylamino] ethanesulfonic acid (exemplified compound 1-8) (34a) salt of 2- (methylamino) isobutyl ethanesulfonate The acid salt was dissolved in 2- [N- (third-butoxycarbonyl) -N-methylamino] ethane isosulfonate (5.07 g, 17.2 mm) produced in Example 8 (8a) in acetic acid. Ethyl ester (5 m 1) ′ was added with hydrogen chloride (4N ethyl acetate solution; 15 m 1, about 60 mm ο 1) under ice cooling, and stirred at room temperature for 2 hours. Hexane (20 ml) was added to the mixture, and the precipitated solid was collected by filtration, and washed with hexane-387-200410948. The obtained solid was dried under reduced pressure to obtain the title compound (3.5 1 g, yield 88%) as colorless crystals. bNMiUCDCbdOOMHz): (51.01 (6H, d, J = 7Hz), 2.0-2.1 (1H, m), 2.77 (3Η, s), 3.48 (2H, t, J = 7Hz), 3.69 (2H, t, J = 7 Hz), 4.12 (2H, d, J = 6 Hz); MS (El) m / z: 195 (M +) 〇 (3 4b) 8- [N- [2- (isobutoxysulfonyl) ethyl Group] -N-methylamino] -8-oxooctoate Allyl hydrogen suberate (J. Amer. Chem. Soc., 120 巻, p. 457 (1998); 3.5g, 16.3 mmol) was dissolved in dichloromethane (80 ml), and the hydrochloride salt of 2- (methylamino) isobutyl ethanesulfonate (3.5; ^, 15.11111111), 1-ethyl, prepared in Example 34 (34a) was added. 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.12 g, 16.3 mmol), and 4- (dimethylamino) pyridine (2 · 2 0 g, 18 mm ο 1 ), And stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane, washed with water, and then saturated aqueous sodium bicarbonate solution, and saturated brine. The crude title compound was obtained. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 50: 50-20: 80, V / V, 100g of silica gel) to obtain the title compound (5.24g, yield 88%) as a brown oily substance. IR (CHC13) vmax 2940, 1730, 1643, 1356, 1170, 972, 941 cm-1; NMR (CDC13, 400MHz) ): (50.99 (6H, d, J = 7Hz) '1.34-1.38 (4H, m), 1.61-1.67 (4H, m), 2.00-2.07 (1H, m), 2.28-2.35 (4H, m ), 3.10 (3H, s), 3.39 (2H, t, J = 7Hz), 3.77 (2H, t, J = 7Hz), 4.00 (2H, d ,; = = 7Ηζ), 4.57 (2H, d, J = 6Hz), 5.23 (1H, d, J = 10Hz), 5.31 (1H, dd, J = 17, 2Hz), 5.92 (1H, ddt, J = 17, 10, 6Hz), ( 34c) 8- [N- [2- (Isobutoxysulfonyl) ethyl] -N-methylamino]-388-200410948 -8 -oxooctanoic acid 8- [N produced in Example 34 (34b) -[2- (Isobutoxysulfonyl) ethyl] -N-methylamino] -8-allyl octanoate (5.24 g, 13.4 mmol) dissolved in dichloromethane (50 m 1) and cooled in ice Next, tris (triphenylphosphine) palladium (774.2 mg, 0.67 mmo 1) and 5,5-dimethyl-1,3-cyclohexanedione (1.03 g, 7.4 mm) were added. Stir under nitrogen and room temperature for 1 hour and evaporate the solvent under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate, 50: 50-20: 80, V / V, silica gel 100g) to obtain the title compound (3.38g, yield 72%), yellow Oily substance. IR (CHC13) vmax 2940, 1710, 1642, 1356, 1170, 972, 945 cm · 1; bNMR (CDC13, 400MHz): 50.99 (6H, d, J = 7Hz), 1.37-1.39 (4H, m), 1 61-1 · 67 (4H, m), 1.99-2.07 (1H, m), 2.29-2.37 (4H, m), 3.10 (3H, s), 3.39 (2H, t, J = 7Hz), 3.77 (2H, t, J = 7Hz), 4.00 (2H, d, J = 7Hz). (34d) 8- [N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -8-oxooctanoic acid 1-[[(1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio]- 1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester Example 34 ( 34c) 8- [N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -8-oxooctanoic acid (3.37 g, 9.6 mmol) manufactured in N, N-dimethyl Methylformamide (10 ml), 18-crown-6 (2, 64 g, 10 mmol) and carbonate shavings (1.47 g, 4.5 mmol) were added. After stirring at room temperature for 30 minutes, 1-chloroethyl carbonate (1R, 2R) produced in Example 1 (la) was added. 2-[[Trans-2-[(lE, 3E) -4- (4-cyano 2-fluorophenyl) -1,3-butadienyl]-389-200410948 -1,3-dioxan-5-yl] thio]-1-(2,4-difluorophenyl ) -1-[(1H-1,2,4-triazolyl) methyl] propyl ester (diastereomer ratio = about): 1; 2 · 6 g, 4 mm ο 1), at room temperature Stir for 10 hours and then at 40 ° C for 3.5 hours. Under ice-cooling, a phosphate buffer solution (30 m 1) was added to the reaction solution, and the resultant was extracted with ethyl acetate (30 ml × 3). The organic layer was combined, washed with water (10 ml x 3), and then saturated brine (30 ml x 1), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane · ethyl acetate, 50: 50-20: 80, V / V, silica gel 100 g) to obtain the title compound (615 mg, product Rate 16%), thin brown amorphous solid (diastereoisomer ratio = about 1: 1).

IR (CHC13) X; dirty 2977, 2233, 1764, 1642, 1505, 1277, 1141, 1059, 973 cm · 1;! HNMR (CDC13, 400MHz): 50.98 (6H, d, J = 7Hz), 1.32-1.39 (7H, m), 1.53 (3Hx (1/2), d, J = 5Hz), 1.54 (3Hx (1/2), d, J = 5Hz &gt;, 1.5-1.7 (4H, m), 1.99-2.08 (1H, m), 2.27-2.34 (3H, m), 2.40 (1H, td, J = 7, 5Hz), 2.88 (3Hx (1/2), s), 2.96 (3Hx (1/2), s ), 2.97-3.06 (1H, m), 3.38 (1H, t, J = 7Hz), 3.38 (1H, t, J = 7Hz, overlap), 3.48 (lHx (1/2), t, 11Hz) , 3.49 (lHx (1/2), t, 11Hz), 3.49 (1Hx (1/2), t, J = llHz, overlapping), 3.50 (lHx (1/2), t, J = llHz), 3.76 (1H, t, J = 7Hz), 3.77 (1H, t, J = 7Hz), 3.78-3.85 (lHx (1/2), m), 3.88 (lHx (1/2), q, J = 7Hz ), 3.99 (2H, d, J = 7Hz), 4.13-4.20 (1H, m), 4.26 (lHx (1/2), ddd, J = 11, 5, 2Hz), 4.28 (lHx (] / 2) , Ddd, J = ll, 5, 2Hz), 4.97 (1H, d, J = 4Hz), 5.33 (lHx (1/2), dd, 15, 3Hz), 5.38 (1H, s), 5. · 41 (lHx (1/2), d, J = 15Hz), 5.85 (1H, dd, J = 15, 4Hz), 6.58 (1H, dd, J = 15, 1 1Hz), 6.68 (lHx (1/2), q, J = 5Hz), 6.73 (1H, d, J = 16Hz), 6.77 (lHx (1/2), q, J = 5Hz), 6.85-6.95 ( 2H, m), 7.33 (1H, dd, J 200410948 = 10, 1Hz), 7.40 (1Η, dd, J = 8, 1Hz), 7.40-7.49 (1H, no, 7.55-7.60 (1H, m), 7.93 (lHx (1/2), s), 7.94 (lHx (1/2), s), 8.00 (] Hx (1/2), s), 8.01 (lHx (1/2), s). (34e) 2- [N_ [8_ [[[(1R, 2R) _2 · [[Transfer_2 _ [(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3 -Butadienyl]-〗, 3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole -Bryl) methyl] propoxy] carbonyloxy] ethoxy] -8-oxooctyl] -N-methylamino] ethanesulfonic acid (the title object compound) 8 prepared in Example 34 (34d) -[N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -8-oxooctanoic acid 1-[[(1R, 2R) -2-[[trans-2-[( IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1, 3-1% 1 --5-yl] thio] -1- ( 2 '4-mono ^ phenyl) -l-[(1H-1' 2,4-triazol-1-yl) methyl] propoxy] carbonyloxy]. Ethyl ester (diastereomer 600 mg, 0.62 mmol) was dissolved in acetone (20 ml), sodium iodide (932 ·, 8 mg, 6.2 mmol) was added, and the mixture was stirred at 50 ° C for 8.5 hours. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to Cosmosil 75 C18-PREP (manufactured by Nakaraitesc) reversed-phase column chromatography (methanol: water, 10: 9 0 to 3 0: 70, and Cosmosil 75 C18-PREPP was used at V / V. 25g) purified. It was concentrated and lyophilized to obtain the title object compound (diastereomer ratio = about 1: 1) sodium salt (colorless amorphous solid, 400 mg, yield 7%). IR (KBr) 2; max 2230, 1764, 1637, 1617, 1504, 1275, 1204, 1141, 1054 473 cm · 1; hNMR (CD3OD, 400MHz): 51.30 (3H, dd 'J = 7' 2Hz), 1.32 -1.37 (4H, m), 1.52 (3H, d, J = 5Hz), 1.54-1.68 (4H, m), 2.30-2.38 (2H, m), 2.39-2 · 44 (2H, m), 2.91 (3Hx (1/2), s), 2.93-3.04 (3H, m), 3.08 (3Hx (1/2), s), 3.46 (lHx (1/2), 200410948 t , J =] lHz), 3.48 (IΗχ (1/2, t, J = llHz), 3.48 (IΗχ (1/2), t, J ^ llHz, overlap), 3.51 (lHx (1 / 2), t, J = llHz), 3.70-3.86 (3H, m), 4.12 (1H, ddd, J =) 1, 5, 2Hz), 4.23-4.28 (1H, m), 5.01 (1H, d, J = 4Hz), 5.46 (1H, s), 5.47 (1H, s), 5.87 (1H, dd, J = 15, 5Hz), 6.59 (1H, dd, J2 15, 11Hz), 6.66 &amp; 6.67 (lHx (1/2) all, relative intensity = 1: 1, each q, J = 5Hz), 6.77 (ΙΗχ (1/2), q, J = 5Hz), 7.00-7.15 ( 3H, m), 7.18 (1H, dd, J2 16, 11Hz), 7.49-7.58 (3H, m), 7.76-7.82 (1H, m), 7.80 &amp; 7.81 (1H x (1/2 ) All, relative intensity = 1: 1, each s), 8.04 (lHx (1/2), s), 8 .31 (lHx (1/2), s), 8.43 (lHx (1/2), s). Example 3 5 6- [l-[[(lR, 21〇-2-[[Trans-2- [(1,3 £) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio]- 1- (2,4-difluorophenyl) -1-[(1H-1,2.4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -6 -oxy- 1-hexanesulfonic acid (exemplified compound 1-800) (35a) 6- (isobutoxysulfonyl) hexanoic acid 4-methoxybenzyl ester 6-bromohexanoic acid 4-methoxybenzyl ester (Bioorg. Med. Chem. Lett ·, 7 巻, page 225 (1997); 9.20 g, 29.2 mmol) was dissolved in a mixed solution of oxane-water (1: 1, V / V, 120 m 1), and sodium sulfite was added. (4.05 g, 32.1 mmol) at 1 2 5 t: heating to reflux for 5 hours. The reaction solution was concentrated under reduced pressure to 1/2 volume, and washed with diethyl ether. To the obtained aqueous layer was added tetrabutylammonium hydrogen sulfate (10.9 g, 3 2 · 1 mm 1), and the mixture was stirred at room temperature for 15 hours. The resultant was extracted several times with dichloromethane, and the organic layer was combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude 6- (4-methoxybenzyloxy) -6-oxo-tetrabutylammonium tetrabutylammonium colorless oily substance. -392-200410948 The crude 6- (4-methoxybenzyloxy) -6-oxo-1-hexanesulfonic acid tetrabutylammonium produced above was dissolved in dichloromethane (600m 1), and the solution was added under ice cooling. Gas (4.3 3 g, 14.6 mmol) and N, N-dimethylformamide (0.1 μm), and stirred under nitrogen at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain crude 6- (chlorosulfonyl) hexanoate 4-methoxybenzyl ester. Isobutanol (3.71 g, 50 mm 〇1) was dissolved in pyridine (30 m 1), and the crude 6- (chlorosulfonyl) hexanoic acid 4-formaldehyde produced above was added under ice cooling. The oxybenzyl ester was stirred at room temperature for 1.5 hours. Under ice cooling, a saturated ammonium chloride aqueous solution (100 m 1) was added to the reaction solution, and the crude product was extracted with ethyl acetate. The organic layer was combined, saturated with an aqueous solution of sodium bicarbonate with 1 N hydrochloric acid, and washed with water. Drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure gave the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (hexane · ethyl acetate, 100: 10, 100: 20, 100: 50, V / V, silica gel 120 g) to obtain the title compound (5.6 3 g, yield 5 2%) of a yellow oily substance. IR (CHC13) vmax 2962, 1729, 1613, 1516, 1466, 1356, 1253, 1167, 974 cm_1; WNMR (CDC13, 500MHz): 50.98 (6H, d, J = 8Hz), 1.46 (2H, five lines, J = 8Hz), 1.67 (2H, five-wire, J = 8Hz), 1.85 (2H, five-wire, J = 8Hz), 2.02 (1H, m), 2.35 (2H, t, J = 8Hz) , 3.06 (2H, t, J = 8Hz), 3.81 (3H, s), 3.97 (2H, d, J = 7Hz), 5.05 (2H, s), 6.89 (2H, d, J = 8Hz), 7.29 (2H, d, J = 8Hz); MS (FAB) m / z: 372 (M +). (35b) 6- (isobutoxysulfonyl) hexanoic acid 4-methoxybenzyl produced in Example 35 (35a) = 6- (isobutoxysulfonyl) hexanoate (3.37g, 9.05mm (01) was dissolved in anisole (3.4 g), and trifluoroacetic acid (12 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 40 minutes. -393-200410948 The solvent was distilled off under reduced pressure and azeotroped with toluene 3 times to obtain the crude title compound. The obtained crude title compound was purified by silica gel column chromatography (dichloromethane: ethyl acetate, 100: 10-100: 20, V / V, silica gel 70 g) to obtain the title compound (1.98 g, yield 87%) as colorless. solid. IR (CHC13) vm-like 2965, 1740, 1711, 1357, 1342, 1165, 974, 945 cm · 1; 4 NMR (CDC13, 400MHz): 50.99 (6H, d, J = 6Hz), 1.52 (2H, tt, J = 8, 7Hz), 1.69 (2H, tt, J = 8, 7Hz), 1.90 (2H, tt, J = 8, 7Hz), 2.03 (1H, m), 2.39 (2H, d, J = 7Hz), 3.10 (2H, t, J = 8Hz), 3.98 (2H, d, J = 7Hz); MS (FAB) m / z: 253 ((M + H) +) 〇 (35c ) 6- (isobutoxysulfonyl) hexanoic acid l-[[(lR, 2R) -2-[[trans-2-[(IE, 3E) -4- (4-cyano-2-fluorobenzene Group) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl 1H-1, 2,4-triazole 1-yl) methyl] propoxy] carbonyloxy] ethyl ester 6 &lt; Isobutoxysulfonyl) hexanoic acid (2.14g, 8.50mmol) prepared in Example 3 5 (35b) was dissolved in N, N-dimethylformamide (30 ml), 18-crown-6 (2.26 g, 8.55 mmol) and carbonate shavings (1.38 g, 4.23 mmol) were added. Stir at room temperature for 1 hour, and add the chlorochlorocarbonate (1R, 2R) produced in Example 1 (1 a) -2-[[Trans- 2-[(1E, 3E) -4- (4-cyano -2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -b (2,4-difluorophenyl) · b [( 1H-1,2,4-triazol-1-yl) methyl] propyl ester (diastereomer ratio = about 1: 1; 1.95 g, 3 mmol), and stirred at room temperature for 15 hours.

Under ice cooling, a phosphate buffer solution was added to the reaction solution, and the crude product was extracted with ethyl acetate (50 m 1 X 3). Combine the organic layers, wash with saturated sodium bicarbonate aqueous solution (50 m 1 X 1), water (30 m 1 X 3), and then with saturated brine (50 m 1 X-394-200410948 1). Drying under anhydrous magnesium sulfate and distilling off the solvent under reduced pressure, a residue containing the title compound was obtained. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate, 60: 4 0-50: 50, V / V, silica gel 1 50g) to obtain the crude title compound (total = 2.10g, title Compound content = about 7 98 mg, yield of the title compound = about 31%, containing impurities 4-[(IE, 3E)-4-[trans-5- [[(1R, 2R) -2- (2, 4- Difluorophenyl) -2-hydroxy-1-methyl-3- (1Η-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxane-2- Group] -1,3-butadienyl] -3-fluorobenzonitrile), a colorless amorphous solid (diastereomeric ratio = about 1: 1). It can be used in the next project without refining (3 5 d). (35d) 6-[[[(1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-but Dienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole-1 -Methyl) methyl] propoxy] carbonyloxy] ethoxy] -6-oxo-hexanoic acid (the title object compound) 6- (isobutoxy) produced in Example 3 5 (3 5 c) Sulfonyl) hexanoic acid 1-[[((1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3- Butadienyl] -1,3-Yipinyuan-5-yl] thio] -1- (2,4-difluorophenyl) -bu [(1H-1,2,4-triazole-1 -Methyl) methyl] propoxy] carbonyloxy] ethyl ester diastereomer ratio = about 1: 1; 380 mg, 0.43 9 mmol) dissolved in acetone (10 ml), and sodium trihalide (659 mg , 4.4 mmol) 'was stirred at 45 ° C for 25 hours. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to Cosmosil 75 C18-PREP (manufactured by Nakaraitesc) reverse phase column chromatography (methanol: water, 20 ·· 80-70: 30, V / V, using Cosmosil 75 Cis-PREPP 25g) purified. -395-200410948 Concentrated and lyophilized to obtain the title object compound (diastereomeric ratio = about 1: 1) sodium salt (colorless amorphous solid, 240 mg, yield 66%). IR (KBi ·) pmax 2231, 1764, 1616, 1504, 1418, 1388, 1276, 1258, 1205, 114 and 1050 cm_j;】 H NMR (CD3OD, 400 MHz) ·· 51.30 (3Hx (1/2), dd , J = 7, 2Hz), 1.34 (3Hx (1/2), dd, J2 7, 2Hz), 1.4-1.5 (2H, m), 1.53 (3H, d, J = 5Hz), 1.60-1 / 72 (2H, m), 1.72-1.85 (2H, m, 2.38 (2Hx (1/2), t, J = 7Hz), 2.39-2.46 (2Hx (1/2), m), 2.73-2.82 (2H , M), 2.90-3.03 (1H, m), 3.47 (lHx (1/2), t, J = llHz), 3.486 (1H x (1/2), t 'J = llHz), 3.491 (lHx ( 1/2), t, J = 11HZ), 3.50 (lHx (1/2), t, J = 11Hz), 3.80 (lHx (1/2), q, J = 7Hz), 3.86 (lHx (1 / 2), q, J = 7Hz), 4.12 (1H, ddd, J = 11, 5, 2Hz), 4.26 (1H, ddd, J = 11, 5, 2Hz), 5.02 (1H, d, J = 5Hz) , 5.46 (2Hx (1/2), s), 5.47 (2Hx (1/2), s), 5.87 (lHx (1/2), dd, J = 16, 5Hz), 5.89 (lHx (1 / 2), dd, J = 16, 5Hz), 6.59 (1H, dd, J = 16, 10Hz), 6.68 (lHx (1/2), q, J = 5Hz), 6.78 (lHx (1 / 2), q, J = 5Hz), 6.80 (1H, d, J = 16Hz), 7.00-7.06 (3H, m), 7.45-7.55 (3H, m), 7.80 (lHx ( 1/2), t, J = 8Hz), 7.81 (lHx (1/2), J = 8Hz), 8.00 (lHx (1/2), s), 8.04 (lHx (1/2), s), 8.29 (lHx (1/2), s), 8.42 (lHx (1/2), s); MS (FAB +) m / z: 831 ((sodium salt + H) +); HRMS (LC, ESI +) m / z: C36H38F3N4O10S2Na2 ((sodium salt + Na) +) Calculated 値: 853.1787, Found 値: 853.1796. Example 3 6 5- [l-[[(lR, 2R) -2-[[trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3 -Butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl)-; 1-[(1H-1'2,4-tri Azole-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -5 -oxo-1-pentanesulfonic acid (exemplified compound 1 -796)-396- 200410948 (36a) 5 -bromopentanoic acid 4-methoxybenzyl ester 4-methoxybenzyl alcohol (4.15g, 30.0mmol) was dissolved in dichloromethane (approximately 100ml), and commercially available 5-bromovaleric acid (6.52g, 36.0mmol) was sequentially added under ice-cooling and stirring. ), 4- (N, N-dimethylamino) ratio D (4.76g, 39.0mmol), and ethyl ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (6.90g , 36.0 mm). The mixture was stirred at room temperature for 135 minutes, and an ammonium chloride aqueous solution was added under ice-cooling to stop the reaction, and the resultant was extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid, an aqueous sodium hydrogen carbonate solution, and a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, and the resulting residue was extracted with a vacuum pump to obtain the title compound (7.30 g, yield 81%) as an oil. IR (CHC13) vmax 1730, 1613, 1515, 1253, 1173 cm-1; 4 NMR (CDC13, 400MHz): (5ca.l.77 (2H, like five lines, J = ca / 7Hz), ca.1.88 ( 2H, like five wires, J = ca / 7Hz), 2.37 (2H, t, J = 7Hz), 3.39 (2H, t, J = 7Hz), 3.81 (3H, s), 5.05 (2H, s), 6.89 (2H, d, J = 8Hz), 7.29 (2H, d, J = 8Hz); MS (FAB +) m / z: 300 (C13H1779Br03 M +); HRMS (FAB +) m / z: C13H1779Br03 calculation 之: 300.0361. Measured tritium: 300.0350. (36b) 5- (Isobutoxysulfonyl) valeric acid 4-methoxybenzyl ester 5-Bromopentanoic acid 4-hydroxybenzyl produced in Example 3 6 (3 6 a) The ester (7.30g) was treated according to the method of Example 3 5 (35a) to obtain the title compound (4.27g, yield 49%) as an oil. IR (CHC13) i / max 1730, 1613, 1516 , 1466, 1356, 1252, 1170, 909 cm_1; b NMR (CDC13, 400MHz): 50.974 (5H, d, J = 6Hz), 1.79 (2H, like five wires,] = ca. 7Hz), ca. l.90 (2H, similar to the five wires, J = ea.7Hz), 1.95-2.08 (1H, m), 2.38 (2H, t, J = 7Hz), 3.09 (2H, t, J = 7Hz), 3.81 (3H, s), 3.97 (2H, d, J = 7Hz), 5.05 (2H, s), 6.89 (2H, d, J = 8Hz), 7.28 (2H, d, J = 8Hz);-397-200410948 MS (FAB +) m / z: 358 (M +); HRMS (LC, ESI +) m / z: C17H2606SNa ((M + Na) + ) Calculated 値: 381.1347. Measured 値: 381.1333. (36c) 5- (isobutoxysulfonyl) pentanoic acid Methoxybenzyl ester (4.2 7 g, 11.9 mmol) was treated according to the method of Example 35 (35b) to obtain the title compound (1.86 g, yield 66%). Crystals having a melting point of 5 3 ° C. IR ( CHC13) umax 1703, 1349, 1164, 977 cm_1; 4 NMR (CDC13, 400MHz) · δ θ.987 (6H, d, J = 7Hz), 1.81 (2H, similar to five wires, J = ca.7Hz), 1 · 94 (2H, like five wires, J = ca.7Hz), 2.0-2.1 (1H, m) '2.431 (2H, t, J = 7Hz), 3.124 (2H, t, J = 7Hz), 3.99 (2H , D, J = 7Hz); MS (FAB +) m / z: 239 (M +); HRMS (FAB +, added KI) m / z: C9H1805SK ((M + K) +) calculation 値: 277.0512. Found: 277.0522 0 (36d) 5- (isobutoxysulfonyl) pentanoic acid l-[[(lR, 2R) -2-[[trans-2-[(; ^, 3 £) -4- ( 4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl 1Η · 1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl ester, 5- (isobutoxysulfonyl) pentanyl produced in Example 3 6 (3 6c) Acid (953 mg, 4.0mmo 1) was dissolved in N, N-dimethylformamide (20ml), and 'carbonate shavings (652mg, 2.0mmol) and 18-crown-6 (1.08g, 4.1mm) were added. ), The mixture was stirred at room temperature for 70 minutes. 1-chloroethyl carbonate (1R, 2R) produced in Example 1 (la) was added -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl)] -1,3-butadienyl] -1,3-dicropane 5- 5- 398-200410948 radical] thio] -1- (2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazol-1-yl) methyl] propyl ester (diastereomer ratio = about 1: 1; 1.36 g, 2.1 mmol). The mixture was stirred at room temperature for 17 hours and then at 40 ° C for 3 hours. The mixture was cooled, a phosphate buffer was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue containing the title compound. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 60: 40-50: 50, V / V, 60 g of silica gel) to obtain a crude title compound (total amount = 1.467 g, content of the title compound). = About 582 mg, yield of the title compound = about 34%, containing impurities 4-[(IE, 3E) -4- [trans-5-[[(1R'2R) -2- (2,4-difluorophenyl ) -2-Ethyl-p-methyl-3- (1H-1,2,4-triazol-1-yl) propoxy] thio] -1,3-dioxane-2-yl] -1, 3-butadienyl] -3-fluorobenzonitrile), an amorphous solid (diastereomeric ratio = about 1: 1). It can be used in the next project without refining (3 6 e). (36e) 5- [l-[[(lR, 2R) -2-[[trans-2-[(1E, 3E) -4, (4-cyano-2-fluorophenyl) -1,3-butane Dienyl] -1'dioxane-yl] thio]-[(2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl ] Propoxy] mineoxy] ethoxy] -oxy-1-pentanesulfonic acid (the title object compound) The crude 5- (isobutoxysulfonyl) pentanoic acid 1_ [1 [(1R '2R) -2-[[trans- 2-[(ΐβ' 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butanediyl] · 1,3 -Secondary Institute-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(HI, 2,4-triazol-1-yl) methyl] propoxy] Carbonyloxy] ethyl ester (content about 582mg 'about 0.6684mmo1; -399-200410948 diastereomeric ratio = about]: 1) was dissolved in acetone (1 Om 1), and sodium iodide (1.0 3 g, 6.8 4 mm ο 1), and stirred at 40 ~ 50 ° C for 9.5 hours. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to Cosmosil 75 C] 8-PREP (manufactured by Nakaraitesc) reverse phase column chromatography (methanol: water, 70: 30, V / V, using Cosmosil 7 5 C18-PREPP 25g) purification. After concentration and lyophilization, the title compound (diastereomeric ratio of about 1: 1) sodium salt (colorless amorphous solid, 398 mg, yield 71%) was obtained. IR (KBr) vmax2231, 1763, 1615, 1504, 1418, 1388, 1276, 1258, 1206, 1141, 1050 cm &quot;1; 4 NMR (CD3OD, 400 MHz): (51.30 (3Hx (1/2), dd, J = 7, 2Hz), 1.34 (3Hx (1/2), dd, J = 12Hz), 1.53 (3H, d, J = 5Hz), 1.7-1.9 (4H, m), 2.41 (2Hx (1/2 ), T, J = 7Hz), 2.44-2.50 (2Hx (1/2), m), 2 / 75-2.85 (2H, m), 2.88-3.03 (1H, m), 3.48 (1H, t , J = llHz), 3.49 (lHx (1/2), t, J = llHz), 3.50 (lHx (1/2), t, J = imz), 3.80 (lHx (1/2), q, J = 7Hz), 3.86 (lHx (1/2), q, J = 7Hz), 4.12 (1H, like ddd, J = ca.ll, 5, 2Hz), 4.25 (1H, ddd, J = ll, 5, 2Hz), 5.02 (1H, d, J = 5Hz), 5.46 (2H x (1/2), s), 5.47 (2Hx (1/2), s), 5.87 (lHx (1/2), dd, J = 15, 5Hz), 5.89 (lHx (1/2), dd, J = 15, 5Hz) '6.54-6.63 (2H, m), 6.66 (lHx (1/2), q, J = 5Hz), 6.78 (lHx (1/2), q, J = 5Hz), 6.80 (1H, d, J = 16Hz), 7.0-7.2 (3H, m), 7.45 · 7 · 55 (3H, m) , 7.80 (lHx (1/2), t, J = 8Hz), 7.81 (lHx (1/2), J = 8Hz), 8.00 (lHx (1/2), s), 8.04 (lHx (1 /2) s), 8.31 (lHx (1/2), s), 8.42 (lHx (1/2), s); MS (FAB-) m / z: 793 ((non-sodium portion) ·); HRMS (ESI- ) m / z: C35H36F3N401GS2 ((non-sodium portion) ·) Calculated 値: 793.1825, measured 値: 793.1809 〇 Example 3 7 6-[[(lR, 2R) -2-[[反 -2-[(IE, 3E) -4- (4-cyano-2--400- 200410948 fluorophenyl)-], 3 -butadienyl] _ 丨, 3 _dinosin-5-yl] thio] _ 1 _ (2,4-difluorophenyl) -1-[(ih-1,2,4-triazolyl) methyl] propoxy] carbonyloxymethoxy] -6-oxy-]-hexanesulfonic acid (Exemplified compound 丨 _ 8 丨 2) (37a) 6- (isobutoxysulfonyl) hexanoic acid [(1R, 2RH [[trans-2-[(] E, 3E) -4- (4-cyano _2_ fluorophenyl) -1,3-butanediyl] -1,3 -yipin-5-yl] thio] 2,4-difluorophenyl)-] _ [(iju, 2, 4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl ester 6- (isobutoxysulfonyl) hexanoic acid (462mg, 1.83mmol) prepared in Example 3 5 (35b) was dissolved. To n, N-dimethylformamide (20ml), add carbonate shavings (299mg, 0.92mmol) and 18-crown j (502mg, 1.90mmol) The mixture was stirred at room temperature for 20 minutes, using a commercially available ultra-sound wave washer ultra wave illumination alfalfa 5 minutes. The mixture was recovered from the ultrasonic cleaner, stirred at room temperature, and the chloromethyl carbonate (1R, 2R) manufactured in Example 14 (14a) was added. -2-[[Trans- 2-[(1E, 3E) -4- (4-cyano_2-fluorophenyl) -1 '3-butanyl] -1,3-Yipinyuan-5 -yl] thio] * _; [_ (2, 4-difluoro Phenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propyl ester (1.06 g, 1.50 mmol). After the mixture was stirred at room temperature for 4 hours, a phosphate buffer solution was added under ice-cooling, and the crude product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue containing the title compound. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 50:50, V / V, silica gel 3 5 g) to obtain a crude title substance (total = 1.0 0 g). The content of the title compound = about 920 mg, the yield of the title compound = about 71%, with impurities 4-[(IE, 3E) -4- [trans- 5-[[(lR, 2R) -2- (2 , 4- -401-200410948 difluorophenyl) -2-hydroxy-1-methyl-3 (H-1,2,4-triazol-1-yl) propoxy] thio] -1 , 3-dioxane-2-yl]-], 3-butadienyl] -3 -fluorobenzonitrile and chloromethyl carbonate (1 R, 2 R)-2-[[trans-2-[( 1 E, 3 E)-4-(4-cyano-2-fluorophenyl) -1,3-butadienyl]-〗, 3-dioxane-5 -yl] thio] -1- (2, cardiodifluorophenyl) -1-[(1H-1,2,4-triazole-butyl) methyl] propanecarbonate), an amorphous solid. It can be used in the next project without refining (37b). (37b) 6-[[(lR, 2R) -2-[[trans · 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadiene Group] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2.4-triazol-1-yl) formyl [Propyl]] propoxy] carbonyloxymethoxy] -6-oxo-1-hexanesulfonic acid (the title object compound) The crude 6- (isobutoxysulfonyl) produced in Example 3 7 (3 7 a) Caproic acid [(111, 2 feet) -2-[[trans-2-[(: ^, 3 £) -4- (4-cyano-2-fluorophenyl) -1 '3-butadienyl ] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -bu [(1H-1,2,4-triazol-1-yl) methyl Group] propoxy] methyl carbonyloxy (content about 902 mg, about 1.06 mm ο 1) was dissolved in acetone (10m 1), and sodium iodide (1.36 g, 6 · 8 4 mm ο 1), and the mixture was stirred at 40 ~ 4 5 ° C for 7.7 hours. Add acetone (5 m 1) and stir the mixture at 40 ~ 4 5 ° C for 30 minutes. The reaction solution (1 5.93 g) was purified in an amount of 1/2 (7 · 96 g). The solvent was distilled off under reduced pressure, and the obtained crude product was purified by Cosmosil 75 C18-PREP (manufactured by Nakaraitesc) reverse phase column chromatography (methanol: water, 70: 30, V / V, using Cosmosil 7 5 Ci8-PREPP 25 g). After concentrating and lyophilizing, the title compound sodium salt was obtained (yield 2 87 mg, yield 33%; yield of the total purification process was 57.4 mg, yield 66%). 200410948 IR (KBr) vmax 2231, 1767, 1616, 1504, 1418, 1388, 1275, 1257, 1205, 1] 42,] 048,974 cm ": 4 NMR (CD3OD, 400MHz): ά 1.33 (3H, dd, J = 7, 2Hz), 1.48 (2H, five wires, J = 7Hz), 1.69 (2H, quinl, J = 7Hz), 1.81 (2H, like five wires, J = ca. 7Hz), 2.47 (2H , T, J = 7Hz), 2.80 (2H, like t, J = ca.7Hz), 2,98 (1H, U, J =] l, 5Hz), 3.488 (1H, t, J = llHz), 3.493 (1H, t, J = l] Hz), 3.85 (1H, q, J = 7Hz), 4.12 (1H, ddd, J = 11.5, 2Hz), 4.24 (1H, ddd, J = ll, 5, 2Hz), 5.02 (1H, d, J = 4Hz), 5.47 (2H, br s), 5.79 (2H, s), 5.88 (1H, dd, 15, 4Hz), 6.60 (1H, dd, 16, 11Hz), 6.80 (1H, d, J = 15Hz), 7.0-7.1 (2H, m), 7.11 (1H, dd, J = 15, 11Hz), 7.44-7 · 56 (3H, m), 7.80 (1H, t, J = 8Hz), 8.01 (1H, s), 8.36 (1H, s); MS (FAB-) m / z ·· 793 ((non-sodium portion) _); HRMS (ESI-) m / z: C35H36F3N401GS2 ((non-sodium portion) _) calculated 値: 793.1825, measured 値: 793.1841 〇 Example 3 8 2_ [N_ [8 _ [[(1R, 2R) _2 _ [[Reverse-2 [(ΙΕ '3Ε) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -b (2,4-difluorophenyl) -bu [(1H-1,2,4-triazol-1-yl) methyl] propoxy] mineoxymethoxy] -oxoctyl] -N-formyl Amine] Ethanesulfonic acid (exemplified compounds 1-8 1 8) (3 8 a) 8- [N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -8-oxyl Caprylic acid [(111,21〇-2-[[trans-2-[(", 3 £) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl], 3 _Difluorenyl] thio] -1- (2,4-difluorophenyl) -bu [(11 ^ -1'2,4-triazole-buyl) methyl] propoxy] carbonyloxy The methyl ester produced 8_ [N_ [2_ (isobutoxysulfonyl) -403-2004-10948 ethyl] -N-methylamino] -8-oxooctanoic acid (2 · 3] g produced in Example 34 (34c), 6.5 7 mm ο 1) dissolved in N, N -dimethylformamide (30 m 1), add carbon shavings (.0 7 g, 3 · 2 8 mm ο 1) and 1 8-crown-6 ( 1.75 g, 6.6 m mo]), and the mixture was stirred at room temperature for 50 minutes. Chloromethyl carbonate (1 R, 2R) manufactured in Example 14 (14a) was added. 2-[[trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) ) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[[11 ^ -1, 2,4-triazole-; 1-yl) methyl] propyl ester (1.41 g, 2.00 mmol), and the mixture was stirred at room temperature for 3.5 hours. Extraction and purification were carried out according to the method of Example 34 (34d) to obtain the title compound (1.11 g, yield 58%) as an amorphous solid. IR (film) vmax 2231, 1768, 1645, 1618, 1504, 1418, 1354, 1274, 1259, 1169, 1141, 975 cm · 1:

! H NMR (CDCI3, 400MHz) · 6 0 · 99 (6H, d, J = 7Hz), 1.32-1.44 (7H, m), 1.58-1.76 (4H, m), 2.03 (1H, nine wires, J = 7Hz), 2.30 (2H, t 'J = 7Hz), 2.44 (2H, t, J = 7Hz), 3.03 (1H, tt, J = ll, 5Hz), 3.10 (3H, s), 3.39 ( 2H, t, J = 7Hz), 3.49 (1H, t, J

= llHz), 3.50 (1H, t, J = llHz), 3.77 (2H, t, J = 7Hz), 3.90 (1H, q, J = 7Hz), 4.00 (2H, d, J = 7Hz), 4.18 ( 1H, ddd, J = ll, 5, 2Hz), 4.26 (1H, ddd, J = ll, 5, 2Hz), 4.98 (1H, d, J = 4Hz), 5.38 (1H, dd , J = 15, 2Hz), 5.39 (1H, d, J = 15Hz), 5.77 (2H, brd), 5.86 (1H, dd, J = 16, 4Hz), 6.59 (1H, dd, J = 15, 10Hz), 6.74 (1H, d, J = 16Hz), 6.86-6.96 (2H, m), 6.93 (1H, dd, J = 16, 10Hz), 7.34 (1H, dd, J = 10, 2Hz ), 7.41 (1H, dd, J = 8, 2Hz), 7.43 (1H, td, 10, 8Hz), 7.58 (1H, t, J = 8Hz), 7.93 (1H, s), 7.98 (1H, s); MS (FAB +) m / z: 950 ((M + H) +); HRMS (LC, ESI +) m / z: C44H54F3N50uS2Na ((M + Na) +) Calculate ··· 972.3111, measured · 972.3119. -404-200410948 (38b) 2- [N- [8-[[(1R, 2R) -2-[[trans-2-[(] E, 3E) -4- (4-cyano-2-fluoro Phenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4'difluorophenyl) -1-[(1 Η- 1,2,4-triazolyl) methyl] propoxy] carbonyloxymethoxy] -8-oxoctyl] methylamino] ethanesulfonic acid (the title object compound) Example 3 8 (3 8 a ) Produced 8-[Ν-[2-(isobutoxysulfonyl) ethyl] methylamino] -8-oxooctanoic acid [(1R, 2R) -2-[[trans-2- [(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1-(2,4 -Difluorophenyl) -1-[(1 Η -1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl ester (280 mg, 0.295 mmol) dissolved in acetone (10 ml) Then, sodium iodide (442 mg, 2.95 mmol) was added, and the mixture was stirred at 45 to 50 ° C for 10 hours. After concentration and purification according to the method of Example 34 (34e), the title compound sodium salt (amorphous solid; yield 220mg, yield 81%) was obtained. IR (KBr) vmax 2230, 1767, 1635, 1618, 1504, 1418, 1388, 1257, 1206, 1141, 1050, 975 cnf1: b NMR (CD3OD, 400MHz): δ 1.33 (3H, d, J = 7Hz), 1.31-1.43 (4H, m), 1.54-1.62 (2H, m), 1.62-1.69 (2H, m), 2.33 (2Hx (1/2), t, J = 7Hz), 2.42-2.47 (2Hx (1 / 2) + 2H, m), 2.91 (3Hx (1/2), s), 2.91-3.05 (3H, m), 3.08 (3Hx (1/2), s), 3.48 (1H, t, J = llHz), 3.49 (1H, t, J = llHz), 3.70-3.78 (2H, m), 3.80-3.90 (1H, m), 4.12 (1H, ddd, J = 11, 5, 2Hz), 4 24 (1Η, ddd, J = n, 5) 2Hz), 5.01 (1H, d, J = 4Hz), 5.47 (2H, brs), 5.78 (2H, s), 5.87 (1H, dd , J = 16, 4Hz), 6.59 (1H, dd, J2 15, 10Hz), 6.80 (1H, d, J2 16Hz), 7.00-7.13 (3H, m), 7.50-7.56 (3H, m ), 7.79 (1H, td 'J = 8' 2Hz) '8.01 (1H, s), 8.37 (1H, s); MS (FAB +) m / z: 916 ((sodium salt + H) +) 200410948 HRMS (LC, ESI +) m / z: total sodium salt + H) +)) calculated 値: 916.244], found 値: 916.2463. Example 3 9 [[4-[[(lR, 2R) -2-[[trans-2-[(IE, 3E) -4- (4-cyano-2 -fluorophenyl) -1,3- Butadienyl]-], 3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutyryl] amino] acetic acid (exemplified compounds) -727) (39a) allyl succinate [(1R, 2R)- 2-[[trans-2-[(1E, 3E) -4- (4-truncyl-2-perphenyl) -1 '3-butanyl]-1' 3-monoalkyl-5- []] Thio]-(2,4-difluorophenyl) -bu [(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl Hydroallyl ester (J, Pharm. Sci., 50 记载, page 487 (1961); 1.40g, 8.85mmmml) was dissolved in N, N-dimethylformamide (40ml), and carbonic acid was added. (1.44 g, 4: 43 mmo1) and 18-crown-6 (2.40 g, 8.8 5 mmol). After stirring at room temperature for 1 hour, chloromethyl carbonate (1R, 2R) produced in Example 14 (1 4 a) was added. 2-[[trans- 2-[(1E, 3E) -4 · (4-cyano Phenyl-2-fluorophenyl) -1,3-butadienyl] -1,3-difluorenylfalkyl-5-yl] thio] -b (2,4-difluorophenyl) -1- [(1H-1'2'4-triazol-1-yl) methyl] propyl ester (2.82 g, 4.0 mm 0), and the mixture was stirred at room temperature for 2.3 hours. Extraction and purification were carried out according to the method of Example 6 (6 a) to obtain the crude title compound (total amount = 3.10 g 'content of the title compound = about 2.81 g, yield of the title compound = about 93%, containing Impurities 4-[(1 E, 3 E) one heart [trans_5-[[(1R, 2R) -2- (2, difluorophenyl) -2-hydroxy-1-methyl-3- (1H- 1,2,4-triazol-1-yl) propoxy] thio] -1,3- -406- 200410948 dioxan-2-yl] -1,3-butadienyl] -3- Fluorobenzonitrile and chloromethyl carbonate (] R, 2R) -2 '[[trans- 2-[(] E, 3E) -4- (4-cyano-2-fluorophenyl)-], 3- Butadienyl] -1,3-dioxane-5-yl] thio]-]-(2,4-difluorophenyl)-]-[(1H-1,2,4-triazole- 1-yl) methyl] propyl ester) amorphous solid. It can be used in the next project without refining (39b). ] H NMR (CDC13, 400MHz, selective signal): 5 1.37 (3H, dd, J = 7, 2Hz), 2.65-2.81 (4H, m), 3.04 (lH, tt, J = ll, 5Hz), 3.49 (lH, t, J = llHz), 3.50 (lH, t, J = 11Hz), 3.91 (1Η, q, J = 7Hz), 4.18 (1H, ddd, J = ll, 5, 2Hz), 4.27 (1H , Ddd, J =] 1, 5, 2 Hz), 4.60 (2H, dt, J = 6, 1 Hz), 4.98 (1H, d, J = 4Hz), 5.23 (1H, dd, J = 10 , 1Hz), 5.31 (1H, dd, J = 17, 1Hz), 5.37 (1H, dd, J = 15, 3Hz), 5.40 (1H, d, J = 15Hz), 5.76 (1H, d, J = 6Hz ), 5.81 (1H, d, J = 6Hz), 5.85 (1H, dd, J = 15, 4Hz), 5.91 (1H, ddt, J = 17, 10, 7Hz), 6.58 (1H, dd , J = 15, 10Hz), 6.73 (1H, d, J = 16Hz), 6.85-7.00 (3H, m), 7.33 (1H, dd, J = 10, 1Hz), 7.40 (1H, dd, J = 8, 1Hz), 7.44 (1H, td, J = 8, 2Hz), 7.57 (1H, t, J = 8Hz), 7.94 (1H, s), 8.01 (1H, s); MS (FAB +) m / z: 757 ((M + H) +); HRMS (LC, ESI +) m / z: C36H36F3N409S ((M + H) +) Calculated 値: 757.2155, measured 値: 757.2186. (39b) Hydrosuccinic acid [(1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-fluorenyl-2-p-phenylene) -1,3-butane Alkenyl] -1,3-difluorenylf--5-yl] thio] 4-dichlorophenyl) -1-[(1H-1,2,4-trisordin-1-yl) methyl] Propoxy] carbonyloxymethyl The crude allyl succinate produced in Example 3 9 (3 9 a) [(ir, 2 R) • 2- [[trans-2-[(^, 3 it) -4- (4-cyano-2-_phenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-di Fluorophenyl) -407-200410948 -1-[(] Hl, 2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl (content about 2.8 1 g, about 3.7 1 mm ο 1) dissolved in dichloromethane compound (40 in 1), and under ice cooling, forcefully add (triphenylphosphine) palladium (2 1 5 mg, 0 ·] 8 6 mm ο 1) and 5, 5-dimethyl-1,3-cyclohexanedione (262 mg, 1.86 mmol) was stirred under nitrogen at room temperature for 2.2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-methanol, 100: 0-83: 17, V / V, silica gel 50g) to obtain the crude title compound (total = 1.10g, The content of the title compound = about 937 mg, the yield of the title compound is about 35%, and the impurity is 4- [(IE, 3E) -4- [trans_5_ [[(1 foot, 21〇-2- (2,4 -Difluorophenyl) -2-hydroxy-1-methyl-3-(; ^-1, 2,4-triazole-butyl) propyl] thio] -1,3-disecane-2 -Yl], 3-butadienyl] -3-fluorobenzonitrile and allyl succinate [(1R, 2R) -2-[[反 冬 [(; ^, 3 £) -4- (4 -Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2, 4-difluorophenyl 1H- 1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl) amorphous solid. It can be used in the next project without purification (39c). 4 NMR (CDC13, 400MHz, Selective signal): (51.37 (3H, d, J = 7Hz), 2.5-2.8 (4H, m) 3.05 (1H, tt, J = ll, 5Hz), 3.49 (2H, t, J = llHz) , 3.88 (1Η, q, J = 7Hz), 4.17 (1H, ddd, J = 11, 5, 2Hz), 4.27 (1H, ddd, J = n, 5 2Hz), 4.99 (1H, d, J = 4Hz), 5.36 (1H, d, J = 15, 3Hz), 5.41 (1H, d, J = 15Hz), 5.72 (1H, d, J = 6Hz), 5.85 (1H, d, J = 6Hz), 5.86 (1H, dd, J = 15, 4Hz), 6.57 (1H, dd, J = 15, 11Hz), 6.73 (1H, d, J = 16Hz), 6.84-7.00 (3H, m), 7.33 (1H, d, J = 10Hz), 7.35-7.60 (3H, m), 7.97 (1H's), 8.15 (1H, s); MS (FAB +) m / z: 717 ((M + H) +); HRMS (ESI +) m / z: C33H32F3N409S ((M + H) +) calculation: 717.1842, actual measurement: 717.1860. 200410948 (39c) [[4-[[(( lR, 2R) -2-[[trans- 2-[(lE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -i, 3-di Pinane-5-yl] thio]-]-(2,4-difluorophenyl)-]-[(1 Η-], 2,4-triazol-1-yl) methyl] propoxy ] Carbonoxymethoxy] -4-oxobutanyl] amino] allyl acetate The crude hydrosuccinic acid produced in Example 3 9 (3 9b) [(] R, 2R) -2- [[trans- 2-[(: ^, 3 £) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1 '3-dioxan-5-yl] thio ] -1- (2,4-difluorophenyl) -1-[(1H-1,2 4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl (content about 9 37 mg, about 1; 3 1 mm ο 1) was dissolved in dichloromethane (20 m 1), and Add 1-ethyl-3-(3-dimethylaminepropyl) carbodiimide hydrochloride (251mg, 1.31mmol), 4- (N, N-dimethylamino) pyridine (3 99mg, 3.27mmOl), and allyl glycine hydrochloride (J. Org. Chem. '57, page 6421 (1992)); 238mg, 1.57mmol) Remove the ice bath After naturally returning to room temperature and stirring for 3 minutes, 4- (N, N-dimethylamino) pyridine (200 mg, 1.64 mm) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was stopped by adding ice-cold phosphate buffer. Ethyl acetate was added to separate the layers, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate, 20: 80 to 12: 88, V / V, silica gel 50 g) to obtain the title compound (162 mg, yield 20%) amorphous solid. 4 NMR (CDC13, 400MHz): 51.38 (3H, dd, J = 7, 2Hz), 2.63 (2H, t, J = 7Hz), 2.74-2.88 (2H, in), 3.05 (1H, tt, J = n , 5Hz), 3.49 (1H, t, J = llHz), 3.50 (1H, t, J = ll Hz), 3.95 (1H, q, J = 7Hz), 4.00-4.15 (2H, m), 4.18 (1H , Ddd, J = 11, 5, 200410948 2Hz), 4.27 (1H, ddd, J2 11, 5, 2Hz), 4.64 (2H, brd, J = 5Hz), 4.98 (] Η, d, J = 4Hz) , 5.25 (1H, dd, J = 10, 1Hz), 5.33 (1H, dd, J =] 7, 1Hz), 5.34 (] H, dd, J = 15, 4Hz), 5.43 (1H, d, J = 15Hz), 5.71 (1H, lJ = 6Hz), 5.84 (1H, d, J = 6Hz), 5.86 (] H, dd, J = 15, 4Hz), 5.90 (lH, ddt, J = 17, 10 , 5Hz), 6.59 (lH, dd, J = 15, llHz), 6.74 (1H, d, J = 16Hz), 6.85-6.95 (2H, m), 6.93 (1H, dd, J2) 6, 11Hz), 7.00 (1H, brt, J = 5Hz), 7.33 (1H, dd, J = 10, lHz), 7.39 (lH, dd, J = 8, 1Hz), 7.43 (1H, td, J = 8, 2Hz), 7.57 (1H, t, J = 8Hz), 7.97 (1H, s), 8.10 (1H, s); MS (FAB +) m / z: 814 ((M + H) + ); HRMS (LC, ESI +) m / z: C38H38F3N50k) S ((M + Na) +) calculation 値: 83 6.2189. Found 値 836.2164. (39d) [[4-[[(1R, 2R) -2-[[trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-but Dienyl] -1,3-dioxan-5-yl] thio]] [(2,4-difluorophenyl) -1-[(1H-1,2,4-triazole-1- (Methyl) propoxy] carbonyloxymethoxy] -4-oxobutyryl] amino] acetic acid (the title object compound) [[4-[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1, 3-butadienyl] -1 J 3-, one Y-5-yl] thio] -1- (2,4-dichlorophenyl)-]-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyl Oxymethoxy] -4-oxobutanyl] amino] allyl acetate (448 mg, 0.55 1 mmol) was dissolved in dichloromethane (20m 1), and triphenylphosphine palladium ( 3 1.8 mg, 0.0275 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (38.5 mg, 0.27 5 m mol). The mixture was naturally warmed at room temperature and stirred for 2.5 hours. The reaction solution was concentrated under reduced pressure, and a 0.1 M sodium phosphate-410-200410948 buffer (30 m) was added to the obtained yellow residue, and a commercially available ultrasonic cleaner was used for ultrasonic irradiation to dissolve insoluble matters. The obtained crude product was purified by Cosmosil 75 C18-PREP (manufactured by Nakar aite s c) reverse phase column chromatography (using Co s m o s i] 7 5 C18-PREPP 20 g). U (30 · · 70, V / V) was dissolved and dissolved in acetonitrile-water mixture, and concentrated and lyophilized to obtain the title object compound sodium salt (180 mg, yield 44%). IR (KBr) ymax 2230, 1767, 1614, 1275, 1258, 1142, 986, 975 cnf]; bNMlUCDsOD, 400MHz): (5 1.33 (3H, dd, J = 7, 2Hz), 2.62 (2H, t, J = 7Hz), 2.75 (2H, t, J = 7Hz), 2.98 (1H, U, J = 11, 5Hz), 3.49 (2H, t, J = 11Hz), 3.76 (2H, s), 3 · 85 (1H, q, J = 7Hz), 4.12 (1H, ddd, J = ll, 5, 2Hz), 4.24 (1H, ddd 'J = ll, 5, 2Hz), 5.01 (1H, d , J = 4Hz), 5.45-5 · 49 (2H, m), 5.77 (1H, d, J = 6Hz), 5.80 (1H, d, J = 6Hz), 5.87 (1H, dd, J = 15 , 4Hz), 6.59 (1H, dd, J = 15, 11Hz), 6.79 (1H, d, J = 16Hz), 7.02-7.09 (2H, m), 7.09 (1H, dd, J = 16, 11Hz), 7.49- 7.56 (3H, m), 7.78 (1H, t, J = 8Hz), 8.02 (1H, s), 8.38 (1H, s); MS (FAB +) m / z: 796 ((M + H) +); HRMS (LC, ESI +) m / z: C35H34F3N501 () SNa ((M + H) +) Calculated 値: 796.1876, found 79 796.1877 〇 Example 40 4- [Ν- [2- [1-[[(1R, 2R) -2-[[trans-2-[(ΙΕ, 3Ε) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-disorane-5-yl] thio] -1- (2,4-difluoro Group) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -2-oxoethyl] -N-methylamino ] -4-O-butyric acid (Exemplified compound 1-3 3 4) (40a) N- [4- (allyloxy) -4-oxobutyryl] -N-methylglycinic acid dipropyl succinate (J. Pharm. Sci., 50 巻, page 487 (1961 200410948); 3.17 g, 20 mm ο]) was dissolved in dichloromethane (500 m 〇, and chlorine was added under ice-cooling and stirring. Isobutyl formate (3.00g, 22m-1; l) and N, N-diisopropylethylamine (2.84g, 22mmo: |). The mixture was cooled under ice cooling for 15 minutes, and N-methanamine was added. Acid (3.56 g, 40 mmol) and N, N-diisopropylethylamine (10.3 g, 80 mm). The mixture was naturally warmed at room temperature and stirred for 36 minutes. Ice-cold 2N hydrochloric acid was added to stop the reaction, and the resultant was extracted 3 times with dichloromethane. Combine the organic layers and wash with water and saturated brine in that order. The extract was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 67: 33 ~ 80: 20, V / V, silica gel 75g) to obtain the title compound (1.7 9 g, product Rate 39%) brown oil. IR (CHC13) vmax 1731, 1656, 1411, Π73, 1125 cm-1; bNMR (CDC13, 400MHz) · 52.72 (4H, s), 3.13 (3H, s), 4.16 (2H, s), 4.60 (2H, d, J = 6Hz), 5.23 (1H, d, J = 10Hz), 5.32 (1H, d, J = 17Hz), 5.92 (1H, ddt, 17, 10, 6Hz); MS (FAB +) m / z: 230 ((M + H) +); HRMS (LC, ESI +) m / z: C1 () H15N05Na ((M + Na) +) Calculated 値: 252.0848, found 値: 252.0854. (40b) 4_ [N_ [2_ [l-[[(1R, 2R) [[trans_2 _ [(IE, 3))-4- (4-cyano-2-fluorophenyl) -1,3- Butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -bu [OH · 1,2,4-triazole-buyl ) Methyl] propoxy] carbonyloxy] ethoxy] oxyethyl] methylamino] -4 · -allyloxybutyrate N- [4- (ene) produced in Example 40 (40a) Fouled oxygen) oxybutyryl] -methylglycine (1.77 g, 7.72 nimol) was dissolved in N'N-methyl 200410948 methylformamide (30 m)), and carbon shavings (; ι.丨 7 g, 3.6 mm ο 1) and] 8-crown-6 (2 · 11 g, 7 · 9 8 mm ο 1). After the mixture was stirred at room temperature for 1 hour, 1-chloroethyl carbonate (1R, 2R) produced in Example 1 (1a) was added. 2-[[Trans- 2-[(1Ε, 3Ε) -4- ( 4, cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -] _ [(1H-1,2,4-triazol-1-yl) methyl] propyl ester (diastereomeric ratio = about 1: 1; 1.67 g, 2.57 mmol). The mixture was stirred at room temperature for 1 3 · 7 hours, and a phosphate buffer solution was added under ice-cooling, and the resultant was extracted 3 times with ethyl acetate. The organic layer was washed with water (3 times) and saturated saline water (1 time) in that order. The extract was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 40: 60 to 25: 75, V / V, 65 g of silica gel) to obtain the title compound (1.34 g, yield 49%) amorphous solid (diastereomer ratio of about 1: 1). IR (CHC13) 1 &gt; Yan 2233, 1771, 1656, 1504, 1277, 1140, 1064 cm · 1; 々NMR (CDC13, 400MHz): 51.36 (3H, d, J = 7Hz), 1.54 (3Hx (1 / 2), d, J = 5Hz), 1.56 (3Hx (1/2), d, J = 5Hz), 2.64-2.76 (4H, m), 3.09 (3Hx (1/2), s ), 3.18 (3Hx (1/2), s), 3.00-3.06 (1H, m), 3.49 (1H, t, J = llHz), 3.49 (1H, t, J = llHz), 3.87. (LHx ( 1/2), q, J = 7Hz), 3.88 (lHx (1/2), q, J = 7Hz), 4.06-4.37 (4H, m), 4.57_4 · 60 (2H, m), 4.98 ( 1H, d, J = 4Hz), 5.20-5.44 (4H, m), 5.85 (1H, dd, J 2: 15, 4Hz), 5.92 (1H, ddt, J = 17, 11, 6Hz), 6.58 (1H, dd, J = 15, ΠΗζ), 6.72 (lHx (1/2) 'q, J = 5Hz), 6.73 (1H, d, J = 15Hz), 6.81 (lHx (1/2), q, J = 5Hz ), 6.85-6.97 (3H, m), 7.33 (1H, dd, 10, 1Hz), 7.37-7.45 (2H, m), 7.57 (1H, t, J 8Hz), 7.92 (lHx (1 / 2), s), 7.94 (lHx (1/2), s), 7.94 (lHx (1/2) x (1/2), s), 7.99 (lHx (1/2), s), 8.02 ( lHx (1/2) x (1/2), s); 200410948 MS (FAB +) m / z: 842 ((M + H) +); HRMS (LC, ESI +) m / z: C40H42F3N5 〇] OsNa ((M + Na) +)) Calculated 値: 864.2503, Measured 値: 864.2520. (40c) 4- [N- [2- []-[[(] R, 2R)-2-[[trans- 2-[(1 E, 3E) -4- (4-cyano-2-fluoro Phenyl) -1,3-butadienyl] _1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -Bu [(1H-1,2 , 4-triazole- 丨 _yl) methyl] propoxy] carbonyloxy] ethoxy] -2-oxoethyl] -N -methylamino] -4-oxobutanoic acid (the title object compound) 4- [N- [2_ [h [[(lR, 2R) -2-[[trans-2-[(IE, 3E) -4- (4-cyano-2 -Fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) 2,4-dihydro -1-yl) methyl] propoxy] orexyl] ethoxy] -2-oxoethyl] -N-methylamino] allyl 4-oxobutanoate (diastereomers Ratio = about 1: 1: 1 · 3 3 g, 1 · 5 8 mm ο 1) dissolved in dichloromethane (20ml), and under cooling and stirring, add palladium (triphenylscale) palladium (91.3 mg, 〇. 〇79mmol) and 5,5-dimethyl-1,3-cyclohexanedione (110.7mg, 0.79mmol). The mixture was naturally heated at room temperature and stirred for 50 minutes, and then concentrated under reduced pressure to obtain a residue (1.60 g) containing the title object compound. A part of the residue (0.870 g) was purified. HPLC [LC-908; manufactured by Japan Analytical Industries; GPC column JAIGEL-1H (20 mm id x 600 mm) and JAIGEL-2H (20 mm id x 600mm) are used in series; solvent, chloroform] can be used for purification. The title object compound was obtained (yield: 5 24 mg, yield: 41%; total yield: 1.06 g, yield: 79%) for the refinement. Amorphous solid (diastereomeric ratio = about 1: 1). IR (KBr) vmax2230, 1769, 1655, 1616, 1504, 1276, 1140, 1070cm_1; 200410948

4 NMR (CDC) 3, 400MHz: 5 1.35 (3Hx (1/2), dd, J = 7, 2Hz),] .37 (3Hx (1/2), dd, J = 7, 2Hz) , 1.53 (3Hx (1/2), d, J = 5Hz), 1.60 (3Hx (1/2) d, J = 5Hz), 2.56-2.84 (4H, m), 2.98 () Hx (1/2) , Tt, J = l], 5Hz), 3.02 (IHx (] / 2), tt, J = 5, 2Hz), 3.13 (3Hx (1/2), s), 3.16 (3Hx (1/2), s), 3.46 (] Hx (1/2), t, J =] lHz) '3.47 (1H x (1/2), t, J = llHz), 3.52 〇Hx (1/2), t, J = llHz), 3.55 (lHx (1/2), t, J = llHz), 3.64 (] Hx (1/2), q, J = 7Hz), 3.90 (lHx (1/2), q, J = 7Hz), 3.96 (IHx (1/2), d, J = 18Hz), 4.10 (lHx (1/2), d, 18Hz), 4.31 (lHx (1/2), d, J = 18Hz), 4 48 (1H x (1/2), d, 18Hz), 4.96 (lHx (1/2), d, J = 4Hz), 5.01 (lHx (1/2), d, J = 4 Hz) , 5.29 (lHx (1/2), d, J = 15Hz), 5.33 (lHx (1/2), d, J = 15Hz), 5.49 (lHx (1/2), d, J = 15Hz), 5.51 (lHx (1/2), d, J = 15Hz), 5.86 (1H, dd, J = 15, 4Hz), 6.59 (1H, dd, J = 16, 11Hz), 6.74 (1H, d, J = 16Hz), 6.76 (lHx (1/2), q, J = 5Hz), 5 6.84-6.90 (l Hx (1/2), m), 6.84-6.97 (3H, m), 7.32-7.42 (3H, m), 7.57 (1H, t, J = 8Hz), 7.80 (lHx () / 2), s) , .04 (lHx (1/2), s), 8.14 (lHx (1/2), s), 8.33 (1H x (1/2), s); MS (FAB +) m / z: 802 (( M + H) +). HRMS (LC, ESI +) m / z: C37H39F3N501 () S ((M + H) +) Calculated 値: 802.2369, Measured 値: 802.2363. The above titled target compound (34 mg, 0.4 0 4 mm ο 1; diastereomeric ratio = about 1: 1) was dissolved in tetrahydrofuran (5 m 1), and stirred at room temperature with force. A solution of sodium bicarbonate (33.9 mg, 0.404 mmol) in water (3 ml). The solution was concentrated under reduced pressure to remove tetrahydrofuran, and the resulting aqueous solution was filtered through a membrane and freeze-dried to obtain the title compound sodium salt (diastereomeric ratio of about 1: 1) as an amorphous solid. IR (KBr)} &gt; Planes 2230, 1770, 1615, 1418, 1396, 1276, 1140, 1052, 970 cm · 1; 4 NMR (CD3〇D, 400 MHz): άΐ31 (3Hx 〇 / 2), dd, J = 7, 2Hz), 1.33 (3Hx 200410948 (1/2), dd, 1 = 7, 2Hz), 1.54 (3Hx (1/2), d, J = 5Hz), 1.55 (3Hx (1 / 2), d, J = 5Hz), 2 · 4-2 · 7 (4H, no, 2.9-3Ό5 (1H, m), 3.] 2 (3Hx 〇 / 2), s), 3.17 (3Hx ( 1/2), s), 3.48 (1H, t, J = llHz), 3.5] (1H, t, J = mfe), 3.90 (lHx (1/2), q, J = 7Hz), 3.91 (] Hx (] / 2), q, J = 7Hz), 4.1-4.4 (4H, m), 5.02 (1H, d, J = 4Hz), 5.44 (1H, dd, J = 15, 3Hz), 5.47 (1H , D, J = 15Hz), 5.88 (1H, dd, J = 15, 4Hz), 6.51 (1H, dd, J = 15, 11Hz), 6.72 (lHx (1/2), q, J = 5Hz), 6.79 (1H, d, J =] 6Hz), 6.81 (lHx (1/2), q, J = 5Hz), 7.01-7.10 (2H, m), 7.10 (1H, dd, J = 16, 11Hz), 7.50-7.55 (3H, ni), 7.78 (1H, t, J = 8Hz), 8.04 (lHx (1/2), S), 8.05 (lHx (1/2), s), 8.36 (lHx ( l / 2), s), 8.40 (lHx (1/2), s); MS (FAB +) m / z: 824 ((sodium salt + H) +); HRMS (LC, ESI +) m / z: C37H38F3N 501GSNa ((sodium salt total + H) +) calculated 値: 824.2189, found 値: 824.2177. Example 4 1 [2- [1-[[(1 R ^ 2R) -2-[[反 冬 [(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3 -Butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] propane Oxy] carbonyloxy] ethoxy] -2-oxyethoxy] acetic acid (exemplified compound 1-237) (41a) allyl hydrodiacetate will be commercially available dihydroxyacetic acid (6.70 g, 50 mmol) Dissolved in N, N-dimethylformamide (70m 1) 'and stirred at room temperature, add mono-hexylamine (8.82 g, 52.5mmol) and allyl iodide (9.52 g' 5 2 · 5 mm ο 1). Mix the mixture at 90. (: Stir for 1 hour, cool to room temperature 'Add water (200 m 1) and ethyl acetate (100 m 1) to dissolve insoluble matter. Filter off the insoluble matter, wash with ethyl acetate. Combine the filtrate and The washing solution was sequentially washed with water (3 times) and saturated brine (1 times) -416- 200410948. The extract was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate, 50%). : 50, V / V, silicone 150 g) to obtain the title compound (3.61 g, yield 41%) as a brown oil. IR (CHC13) vmax 1753, 1736, 1251, 1145, 989,940cm'1;] H NMR (CDC13 5 400MHz): 54.28 (2H ^ s) ^ 4.29 (2H ^ s) »4.70 (2H» d ^ J = 6Hz), 5.30 (1H, d, J = 10Hz) , 5.36 (1H, d, J = 17Hz), 5.92 (1H, ddt, J = 17, 10, 6Hz); MS (El) m / z: 175 ((M + H) +). Call for (4 1b) allyl oxydiacetate 1-[[((1R, 2R) -2-[[trans- 2-[(IE'3E) -4- (4-cyano-2-fluorophenyl) -1, 3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] Propoxy] carbonyloxy] ethyl ester will be implemented Example 41 (41a) The allyl oxydiacetate (1.8 6 g '] 0.6 8 mmol) was dissolved in N, N -dimethylformamide (30 ml), and carbonic acid (1.63 g) was added under stirring at room temperature. , 5.0 mmol) and 8-crown-6 (2.91 g '11.10 mmol). After the mixture was stirred at room temperature for 1 hour, dichloroethyl carbonate (1R, 2R) produced in Example 1 (la) was added.-[[Trans- 2- [(1E '3E) -4- (4 -Cyano · 2-fluorophenyl) -13-butadienyl] -1,3-difluoren-5-yl] thio] -1- (2,4-difluorophenyl) -1- [(1′-1,2 ′ 4-triazol-1-yl) methyl] propyl ester (diastereomeric ratio of about 1: 1; 2 · 6 g′4.0 mmol). The mixture was stirred at room temperature for 25 hours, and a phosphate buffer solution was added under ice-cooling, and the resultant was extracted three times with ethyl acetate. The organic layer was washed successively with water (3 times) and saturated saline (1 time). The extract was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (5 END = -417- 200410948 ethyl acetate, 6 7: 3 3, V / V, silicone 70 g) to obtain the crude title compound ( A total of two 3.9 g, the title compound content = about 2.2 2 g, the title compound yield-about 70%, containing impurities 4-[(1 E, 3 E)-4-[trans-5-[[(] R , 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3-(] fluorene-1,2,4-triazol-1-yl) propoxy] sulfur Group] -1,3-dioxan-2-yl] -1,3-butadienyl] -3 -fluorobenzonitrile), amorphous solid (diastereomeric ratio = about 1: 1) ). It can be used in the next project without refining (4 1 c). (41c) [2- [1-[[(1R, 2R) -2-[[trans- 2-[(IE, 3E) -4- (4-cyano-2 -fluorophenyl) -1,3 -Butadienyl] -1'3-dioxane-5-yl] _thio] -1- (2,4-difluorophenyl) -bu [(1H-1,2, cardiac triazole- (Bryl) methyl] propoxy] carbonyloxy] ethoxy] oxyethoxy] acetic acid (the title object compound) The crude allyl oxydiacetate prepared in Example 4 1 (4 1 b) [[(1R, 2R) -2-[[trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1, 3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -l-[(1H-1,2,4-triazole-butyl) methyl] propoxy Group] carbonyloxy] ethyl ester (content about 2.22 g, about 2.82 mmol; diastereoisomeric ratio of spring = about 1: 1) was dissolved in dichloromethane (5 Om 1), and added under ice-cooling and stirring (Triphenylphosphine) palladium (162.9 mg, 0.14 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (196.3 mg,] .4 mmol). The mixture was naturally warmed to room temperature and stirred for 130 minutes. The reaction solution was concentrated under reduced pressure to obtain a residue (3.5 g) containing the title compound. A portion (.93 g) of the residue was purified. HPLC HPLC [LC-908; manufactured by Japan Analytical Industries; GpC column jaIGEL-1H (20 mm id x 600mm) and JAIGEL-2 Η (200 mm idx 6 00mm) are used in series; -418- 200410948 solvent , Chloroform], the title compound was obtained (yield: 325 mg, yield]: 5%; total yield: 1.22 g, yield: 58%): colorless amorphous solid (diastereomer) Structure ratio = about 1: 1). IR (KBr) max 2231, 1769, 1504, 1277,]] 40, 1071, 973 cnf]; 1H NMR (CDC13, 400MHz) · ά 1.37 (3Hx (1/2), dd, J = 7, 2Hz) , 1 · 37 (3Hx (1/2), dd, J 2 7, 2Hz), 1.56 (3Hx (1/2), d, J = 5Hz), 1.60 (3Hx (1/2), d, J = 5Hz), 2.99-3.08 (1H, m), 3.46 (IHx (1/2), t, J = llHz), 3.48 (lHx (1/2), t, J = llHz), 3.51 (] H x ( 1/2), t, J = llHz), 3.52 (lHx (1/2), t, J = llHz), 3.82 (lHx (1/2), q, J = 7Hz), 3.93 (lHx ( 1/2), q, J = 7Hz), 4.15-4.35 (6H, m), 4.98 (lHx (1/2), d, J = 4Hz), 5Ό0 (lHx (1/2), d, J = 4Hz), 5.30 (lHx (1/2), dd, J = 15, 3Hz), 5.34 (lHx (1/2), d, J = 15Hz), 5.46 (lHx (1/2), d, J = 15Hz), 5.47 (lHx (1/2), dd, J = 15, 3Hz), 5.86 (1H, dd, J = 15, 4Hz), 6.59 (1H, dd, J = 15, 11Hz), 6 74 (1H, d, J = 16Hz), 6.85 (lHx (1/2), q, J = 5Hz), 6.85 = 6.93 (2H + lHx (1/2), m), 6.93 (1H, dd, J = 16, 11Hz), 7.33 (1H, d, J = 10Hz), 7.36-7.43 (2H, m), 7.57 (1H, t, J = 8Hz), 7.85 (IHx (1/2) , S), 8.03 (lH x (1/2), s), 8.16 (lHx (1/2), s), 8.27 (lHx (1/2), s); MS (FAB +) m / z: 747 ((M + H) + ); HRMS (ESI-) m / z: C34H33F3N401 () SNa ((M + Na) +) Calculated 値: 769.1767, Measured 値: 769.1753 〇The title object compound (diastereomer ratio than 1: 1; 7 3.9 mg, 0 · 0.999 mm ο 1) dissolved in a small amount of tetrahydrofuran, and an aqueous solution of sodium bicarbonate (8 · 1 mg, 0.9 7 0 mm 0 1) was added at room temperature. The aqueous solution (partial solution) obtained by distilling off tetrahydrofuran using a rotary evaporator was removed by membrane filtration, and the filtrate was freeze-dried 'to obtain the title object sodium salt (5 1 · 3 mg, yield from free residual acid 68%) Colorless amorphous solid. -419- 200410948 IR (KBr) ^ max2230, 1770,] 614,] 4] 8,1276,1140,1053,971 cm-];] H NMR (CD30D, 400MHz): ά 1.3] (3Hx (1 / 2), dd, J = 7, 2Hz), 1.34 (3Hx (1/2), dd, J-2 7, 2Hz),] · 56 (3Η, d, J = 5Hz), 2.94-2.99 (1H, m), 3.48 (lHx (l / 2), t, 3.49 (] Hx (] / 2), t, J = llHz), 3.50 (IHx (1/2), t, J ^ imz), 3.51 ( lHx (] / 2), t, J = llHz), 3.66 (lHx (1/2), q, J = 7Hz), 3.78 (lHx (1/2), q, J = 7HZ), 3.9-4.4 ( 6H, m), 5.02 (lHx (1/2), d, J = 4Hz), 5.03 (lHx (1/2), d, J = 4Hz), 5.47 (2H, s), 5.88 ( 1H, dd, J = 16, 4Hz), 6.59 (1H, dd, J = 16, 11Hz), 6.77 (1Ηχ (1/2), q, J = 5Hz), 6.80 (1H, d, J = 16Hz), 6.84 (lHx (l / 2), q, J = 5Hz), 7.03-7.14 (3H, m), 7.50-7.56 (3H, m), 7.79 (1H, t, J = 8Hz), 8.02 (lHx (1/2), s), 8.05 (lHx (1/2), s), 8.34 (lHx (1/2), s), 8.44 (lHx (1/2), s); MS ( FAB +) m / z: 769 ((M + H) +). Example 42 l- [4-[(lR, 2R) -2-[[Trans-2-[(IE, 3E) -4- (4 -Cyano-2 -fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl Group] propoxy] carbonyloxymethoxy] -4-oxobutanyl] -4-piperidinecarboxylic acid (exemplified compounds 1-4 8 5) (42a) 1-[4- [[(1 R ^ 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl]-], 3-diDfane-5 -Yl] thio]-[(2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy ] -4-oxobutanyl] 4-piperidinecarboxylic acid allyl 4- [4- (allyloxycarbonyl) piperidinyl] -4 -oxobutanoic acid (1 · 1 6 g, 4 · 3 0 mm ο 1) dissolved in N, N -dimethylformamide (15ml), stirred at room temperature, add carbon shavings (65 1.6 mg, 2.0 mmol) -420-200410948 and 1 8-crown-6 (1.] 9 g, 4.5 mm ο 1). After the mixture was stirred at room temperature for 35 minutes, chloromethyl carbonate (1 R, 2r) manufactured in Example] 4 (1 4a) was added. -Cyano-2-fluorophenyl)-], 3-butadienyl] -1,3-dioxan-5-yl] thio] (2,4-difluorophenyl)-[(1H -1 '2' 4 -di-1--1-yl) methyl] propyl ester (i.27 g, 2.00 mmol), and the mixture was stirred at room temperature for 65 minutes. Extraction and purification were carried out according to the method of 7 (7c) to obtain the title compound (1.45 g, yield 84%) as a colorless amorphous solid.

IR (KBr) surface 2230, 1767, 1732, 1645, 1504, 1273, 1258, 1142, 976cm · 1; NMR (CDC13, 400MHz) ·· δ 1.37 (3H, dd, J = 7, 2Ηζ), 1 · 60-1 · 77 (2H, m), 1.89-2.00 (2H, m), 2.58 (1H, tt, J = ll, 4Hz), 2.64-2.87 (5H, m), 3.03 (1H, tt, J = ] 1.5Hz), 3.15 (1H, td, J = 14, 3Hz), 3.49 (1H, t, J = 11Hz), 3.50 (1H, t, J = 11Hz), 3.84-3.93 (2H, m), 4.17 (1H, ddd, J = 11, 5, 2 Hz), 4.27 (1H, ddd, J = 11,

5, 2Hz), 4.38 (1H, dt, J = 14, 4Hz), 4.59 (2H, d, J = 6Hz), 4.98 (1H, d, J = 4Hz), 5.24 (1H, dd, J = 10, 1Hz), 5.31 (1H, dd, J = 17, 1Hz), 5.39 (1H, dd, J = 15, 3Hz), 5.42 (1Η, d, J = 15Hz), 5.74 (1Η, d, J = 6Hz), 5.84 (1H, d, J = 6Hz), 5.83-5.88 (1H, m), 5.91 (1H, ddt, J = 17, 11, 6Hz ), 6.59 (1H, dd, J = 16, 11Hz), 6.74 (1H, d, J = 16Hz), 6.85-6.95 (2H, m), 6.93 (1H, dd, J-2 16, 11Hz), 7.33 ( 1H, dd, J (10, 2Hz), 7.40 (1H, dd, J = 8, 1Hz), 7.44 (1H, td, J = 9, 6Hz), 7.57 (1H, t, J = 8Hz), 7.93 (1H, s), 8.038 (lHx (1/2), s), 8.044 (lHx (1/2), s); MS (FAB +) m / z: 868 ((M + H) +) : HRMS (LC, ESI +) m / z: C42H45F3N50k) S ((M + H) +) Calculated 値: 868.2840, Found 値: 868.2838. (42b) l- [4-[[(lR, 2R) -2-[[trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3- Butadienyl] -1,3-dioxan-5-yl] -421-200410948 thio] -l- (2,4-difluorophenyl) -1 _ [(1H-1 '2' 4- Dioxanyl) Methyl] propoxy] carbonyloxymethoxy] -4_oxobutynyl] -4-piperidinecarboxylic acid (the title object compound) The compound produced in Example 4 2 (4 2 a) [ 4-[[(1 R, 2 R)-2-[[trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butanediyl ] -1,3-dioxane-5 -yl] thio] -1-(2,4-difluorophenyl) -1-[(1 （-1,2,4-triazol-1-yl ) Methyl] propoxy] carbonyloxymethoxy] -4-oxobutyroyl] 4-piperidinecarboxylic acid allyl 7 7 7 mg, 0.9 0 mm ο 1) dissolved in dichloromethane (12ml), Add (triphenylphosphine) palladium (31.0 mg, 0.027 mmol) and 5,5-^-methyl-1'3-¾-hexamidine (63.11 mg '0.4 5 mm ο 1) under ice-cooling and stirring. The mixture was allowed to warm naturally at room temperature and allowed to stand for 1.5 hours. The reaction mixture was directly purified by silica gel column chromatography (ethyl acetate-methanol (90:10) to methanol-ethyl acetate (10:90), V / V, 30 ml of silica gel) to obtain the title object compound (6 0 3 mg, yield 81%) is a colorless amorphous solid. IR (KBr) vmax 2230, 1767, 1644, 1616, 1504, 1418, 1376, 1273, 1142, 986, 975 cm-1 · hNMR (CDC13, 400MHz): 51.37 (3H, dd, J = 7, 2Hz) , 1.61, 1.77 (2H, m), 1.97 (2H, brt, J = 12Hz), 2.55-2.89 (6H, m), 3.03 (1H, tt, J = 11, 5Hz), 3.17 (1H , Td, J = 11, 3Hz), 3.49 (1H, t, J = llHz), 3.50 (1H, t, J = llHz), 3.83-3.91 (2H, m), 4.17 (1H, ddd, J 2: 11 , 5, 2Hz), 4.27 (1H, ddd, J = ll, 5, 2Hz), 4.35-4.38 (1H, m), 4.98 (1H, d, J = 4Hz), 5.36 (1H, d, J = 15Hz ), 5.42 (1H, d, J = 15Hz), 5.73 (1H, d, J = 6Hz), 5.83-5.88 (2H, m), 6.59 (1H, dd, 16, 11Hz), 6.73 (1H, d, J = 16Hz), &amp; 85-6.95 (2H, m), 6.93 (1H, dd, J = 16, 11Hz), 7.33 (1Π, dd, J = 10, 1Hz), 7.40 ( 1H, d, J = 8Hz), 7.44 (1H, td, J = 9, 6Hz), 7.57 (1H, t, J = 8Hz), 7.95 (lHx (1/2), s) '7.96 (lHx (1/2), s), 8.07 (lHx (1/2), s), 8.10 (lHx 200410948 (1/2), s); MS (FAB +) m / z: 828 ((M + H) + ); HRMS (LC, ESI +) nVz: C39H4〇F3N50 丨 () SNa ((M + Na) +) Calculated 値: 850.2345, measured 値: 850.2360. The title compound (266 mg, 0.32 mmol) prepared above was dissolved in tetrahydrofuran (5 m 1), and stirred at room temperature, and sodium bicarbonate (27.0 mg, 0.3 2 mm ο 1) in water (3 m 1) Solution. Tetrahydrofuran was distilled off under reduced pressure using a rotary evaporator, and the obtained aqueous solution was freeze-dried to obtain the sodium salt of the title object compound (28.3 mg, yield of 96% from free carboxylic acid) as a colorless amorphous solid. IR (KBr) vmax 2231, 1767, 1616, 1417, 1274, 1142, 984, 975 cm.1; WNM1UCDsOD, 400MΗζ): δ 1.33 (3H, d, J = 7Hz), 1.5-2.1 (4H, m), 2.69-2 · 78 (5H, m), 2.98 (1H, tt, J = ll, 5Hz), 3.11 (1H, td, J = 14, 3Hz), 3.49 (2H, t, J = llHz ), 3.83-3.96 (2H, m), 4.12 (1H, ddd, J = ll, 5, 2Hz), 4.24 (1H, ddd, J = 11, 5, 2Hz), 4.37 (1H, dt, 14 , 4Hz), 5.01 (1H, d, J 2 5Hz), 5.45-5.47 (3H, m), 5.75_5.82 (2H, m), 5.87 (1H, dd, J = 15, 4Hz), 6.59 ( 1H, dd, J = 15, 11Hz), 6.80 (1H, d, J = 16Hz), 7.01-7.07 (2H, m), 7.10 (1H, dd, J = 16, 11Hz), 7.49-7.58 ( 3H, m), 7.79 (] H, t, J = 8Hz), 8.02 (1H, s), 8.38 (1H, s); MS (FAB) m / z: 850 ((sodium salt + H) +) ; HRMS (LC, ESI +) m / z: C39H40F3N5O10SNa ((sodium salt + H) +) Calculated 値: 850.2345, Measured 値: 850.2 / 2319. Example 43 Hydroglutaric acid [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butane Alkenyl] -1,3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazole-1 -Yl) -423-200410948 methyl] propoxy] carbonyloxymethyl (exemplified compounds 1-4 1 8) (43a) allyl glutarate [(1 R, 2R) -2- [[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl)-; 1,3-butadienyl] -1,3-di-P-phenyl-5-yl] sulfur Phenyl] -1- (2,4 -monophenylene) -l-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl Hydroallyl ester (Tetrahedron Lett., 36 巻, page 1701 (1995); 1.42g, 8.24mmol) was dissolved in N, N-dimethylformamide (20ml), and carbonic acid (1.30g, 4mmol) was added. ) And 18-crown-6 (2.3 8 g, 9 mmol). After stirring at room temperature for 45 minutes, chloromethyl carbonate (1R, 2R) produced in Example 14 (14a) was added. 2-[[Trans- 2-[(1E, 3E) -4- (4-cyano- 2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[( 1H-1,2,4-triazol-yl) methyl] propyl ester (2.54 g, 4.0 mmol), and the mixture was stirred at room temperature for 55 minutes. The title compound (1.19 g, yield 39%) was obtained as a colorless amorphous solid by treatment and purification according to the method of Example 28 (28a). IR (CHC13) vmax 2995, 2233, 1767, 1734, 1504, 1276, 114, 987 cm · 1; bNMR (CDC13, 400MHz): ά 1.37 (3H, dd, J-2 7, 2Hz), 2.01 (2H, t , J = 7Hz), 2.45 (2H, t, J = 7Hz), 2.53 (2H, t, J = 7Hz), 3.03 (1H, tt, J =] l, 5Hz), 3.49 (lH.t, J = llHz), 3.50 (1H, t, J = llHz), 3.90 (1H, q, J = 7Hz), 4.17 (1H, ddd, J = 1, 5, 2Hz), 4.27 (1H, ddd, J = ll, 5, 2Hz), 4.58 (2H, d, J = 6Hz), 4.98 (1H, d, J = 4Hz), 5.23 (1H, d, 11Hz), 5.31 (1H, dd, J = 17, 2Hz), 5.36 (1H, d, J = 15Hz), 5.40 (1H, d, J = 15Hz), 5.77 (2H, s), 5.85 (1H, dd, J = 15, 4Hz), 5.93 (1H, ddt, J2 17, 11, 6Hz), 6.59 (1H, dd, J = 15, 11Hz), 6.74 (1H, d, J = 16Hz), 6.86-6.95 (2H, m), 6.93 (1H, dd, J = 16, 11Hz), 7.33 (1H, dd, 10, 1Hz), 7.39-7.46 (2H, 200410948 m), 7.57 (1Η, t, J = 8Hz), 7.94 (] Η, s), 7.98 (1H, s); MS (FAB +) m / z: 771 ((M + H) +); HRMS (LC, ESI-) m / z: C37H37F4N409SNa ((M + Na ) ·) Calculate 値: 793.213], Measured 値 · 793.2 128. (43b) Hydroglutaric acid [(1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butane Alkenyl] -1,3-difluorenf-alkyl-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole-1 -Methyl) methyl] propoxy] carbonyloxymethyl (the title objective compound) Allyl glutarate [(1R, 2R)] 2-[[Trans-2 -[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1 -(2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl ester (1.17 g, 1.5 2 mm ο 1) dissolved in dichloromethane (2 5 m 1), and under cooling with ice, tris (triphenylphosphine) (87.7mg, 0.076mmol) and 5,5-dimethyl-1,3-cyclo Hexanedione (106.5 mg, 0.76 mmol), and the mixture was stirred under nitrogen at room temperature for 50 minutes. The reaction solution was purified by silica gel column chromatography (ethyl acetate-methanol, 67: 3 3-100: 0, V / V, 30 g of silica gel) to obtain a crude product of the title object compound (about 0.4 g). A methanol-ethyl acetate mixed solvent (10:90, V / V) was used to dissociate to obtain a crude product (61 mg). HPLC [LC-908; manufactured by Japan Analytical Industries; GPC column JAIGEL-1H (20nim idx600mm) and JA IG EL-2 H (2 0mm i. D. X 6 0 0 mm) Continuous use; solvent, chloroform] Refined, the title compound was obtained in pure form (yield: 370 mg and 600 mg of each crude product, yield: 87% in total) as a colorless amorphous solid. 200410948 IR (KBr) 2Λ should be 2231,] 767, 1504, 1418, 1258, 1140, 986, 975 cm]];

! Η NMR (CDC) 3, 400MHz: δ 1.37 (3H, dd, J = 7, 2Hz), 2.05 (2H, five-wire, J = 7Hz), 2.49 (2H, t, J = 7Hz), 2.55 (1H, t, J = 7Hz), 2.56 (1H, t, J = 7Hz), 3.03 (] H, tt ,, 5Hz), 3.49 (1H, t, J = 7Hz), 3.49 (1H, t, J = 7Hz), 3.81 (] H, q, J = 7Hz), 4.17 (1H, ddd, J = ll, 5, 2Hz), 4.28 (1H, ddd, J = ll, 5, 2Hz), 4.98 (1H, d, J = 4Hz), 5.39 (1H, dd, J = 15, 3Hz), 5.45 (1H, d, J = 15Hz), 5.66 (1Η, d, J = 6Hz), 5 85 (1H, dd, J = 16, 4Hz), 5.91 (1H, d, J = 6Hz), 6.58 (1H, dd, J = 16, 11Hz), 6.74 (1H, d, J = 16Hz) , 6.88-6.95 (2H, m), 6.93 (1H, dd, 16, 11Hz), 7.33 (1H, dd, J = 10, 1Hz), 7.39-7.44 (2H, m), 7.57 (1H, t J, 8Hz), 7.96 (1H, s), 8.19 (1H, s); MS (FAB +) m / z: 731 ((M + H) +); HRMS (LC, ESI +) m / z: C34H33F3N409SNa ( (M + Na) +) Calculated tritium: 753.1818, found tritium: 753.1815. The title object compound (306 mg, 0.419 mmol) prepared above was dissolved in tetrahydrofuran (about 5 ml), and a solution of sodium bicarbonate (35.2 mg, 0.419 mmol) in water (5 m 1) was added.

After distilling off tetrahydrofuran using a rotary evaporator under reduced pressure, the insoluble matter was removed by membrane filtration, and the obtained aqueous solution was freeze-dried to obtain the title object compound sodium salt (292 mg, yield from free carboxylic acid 93%) as a colorless amorphous shape. solid. IR (KBi ·) vmax 2230, 1766, 1574, 1417, 1275, 1258, 1141, 986, 975 cm · 1;

4 NMR (CD3OD, 400MHz): 5 1.32 (3H, dd, J = 7, 2Hz), 1.93 (2H, five-wire, J = 7Hz), 2.23 (2H, t, J-2 7Hz), 2.49 (2H, t , J = 7Hz), 2.97 (1H, tt, J- = ll, 5Hz), 3.49 (2H, t, J = llHz), 3.82 (1H, q, J = 7Hz), 4.11 (1H, ddd, J = ll, 5, 2Hz), 4.23 (1H, ddd, J = ll, 5, 2Hz), 5.01 (1H, d, J = 4Hz), 5.47 (2H, s), 5.77 (1H, d, J = 6Hz), 5.79 (1H, d, J = 5 Hz), 5.87 (1H, dd, J = 15Hz), 6.59 (1H, dd, J -426-200410948 = 15, 1) Ηζ), 6.79 (] H, d, J = 16Hz), 7.02-7.07 (2H, m), 7.09 (1H, dd, J =) 5, 11Hz), 7.49-7.55 (3H, m), 7.79 (1H, t , J = 8Hz), 8.0] (1H, s), 8.37 (1H, s); MS (FAB +) m / z: 753 ((sodium salt + H) +); HRMS (LC, ESI +) m / z : C34H33F3N409SNa ((sodium salt total + H) +) Calculated 値 753.1818, Measured 値: 753.1819. The title compound (300 mg, 0.41 mm ο 1) prepared above was dissolved in tetrahydrofuran (about 5 ml), and N-methylglucosamine (80.0 mg, 0.41 mmol) in methanol was added under ice-cooling and stirring. (About 3ml) solution. The solvent was distilled off under reduced pressure to obtain the title object compound, N-methylglucamine salt (38 mg, yield from free carboxylic acid: quantitative) as a pale yellow amorphous solid. DR (KBr) vmax 2230, 1766, 1561, 1504, 1418, 1275, 1258, 114 and 1050cm_1; bNMR (CD3OD, 400MHz): (51.32 (3H, dd, J = 7, 2Hz), 1.93 (2H, Five wires, J = 8Hz), 2.25 (2H, t, J = 8Hz), 2.49 (2H, t, J = 8Hz), 2, 67 (3H, s), 2.97 (1H, tt, J = ll, 5Hz), 3.12 (2H, dd, J = 5, 1Hz), 3.49 (2H, t, J = llHz), 3.6-3.6 (6H, m), 4.01-4.04 (1H, m), 4 · 12 (1H, ddd, J = 11, 5, 2 Hz), 4.23 (1H, ddd, J = 11, 5, 2 Hz), 5.01 (1H, d, J = 5 Hz), 5.47 (2H, s), 5.77 ( 1H, d, J = 7Hz), 5.79 (1H, d, J = 7Hz), 5.87 (1H, dd, J = 15, 5Hz), 6.59 (1H, dd, J = 15, 11Hz) ), 6.79 (1H, d, J = I6Hz), 7.02-7 · 10 (2H, m), 7.10 (1H, dd, J = 16, 11Ηζ), 7.49-7 · 55 (3H, m ), 7/79 (1H, t, J = 8Hz) '8.01 (1H, s), 8.37 (1H, s); MS (FAB) m / z: 731 ((non-N-methylglucosamine moiety + H) +); HRMS (LC, ESI +) m / z: C34H33F3N409SNa ((non-N-methylglucosamine moiety + H) +) Calculated 値: 7 5 3.1 8 18, Measured 値: 7 5 3.1 79 6. Example 4 4 [[4- [(LR, 2R) -2-[[Trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3 -Dioxane-5-yl] thio] 200410948 -l- (2,4-difluorophenyl)-]-[(1Η-1,2.4-triazol-1-yl) methyl] propoxy ] Carbonyloxymethoxy] oxobutyryl] oxy] acetic acid (exemplified compounds)-1 2 2 4) (44a) Hydrosuccinic acid 2- (allyloxy) -2-oxoethyl Esters (described in US Patent Publication No. 2449792; 4 · 83 g, 4 1 · 6 mm ο 1) were dissolved in dichloromethane (70 m 1), and succinic anhydride (3.75 mmol) and 4 were added under ice-cooling and stirring. -(n, N-dimethylamino) pyridine. After the mixture was naturally heated at room temperature and stirred for 100 minutes, the solvent was distilled off under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with 2N hydrochloric acid and saturated brine in that order. The extract was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 50:50, V / V, 100 g of silica gel) to obtain the title compound (6.4 8 g, yield 75%) ) Brown oil. IR (CHC13) ^ niax 1749, 1716, 1161 cm.1;】 HNMR (CDC13, 400MHz): (5 2.72-2.78 (4H, η), 4.67 (2H, d, J = 6Hz), 4.68 (2H , S), 5.28 (1H, dJ = 11Hz), 5.34 (1H, d, J = 18Hz), 5.91 (1H, ddt, 18, 11, 6Hz); MS (FAB) m / z: 217 ((M + H) +). (44b) [[4-[[(lR, 2R) -2-[[trans-2-[(IE, 3E) -4- (4-cyano-2-fluoro Phenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1 , 2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutanyl] oxy] allyl acetate The hydrobutadiene produced in Example 44 (44a) 2- (allyloxy) -2-oxoethyl acid (5.66 g, 26.2 mmol) was dissolved in N, N-dimethylformamide 200410948 (80 m 1), and carbonic acid was added under ice-cooling and stirring. (3 · 9 1 g '1 2 mm 0]) and 1 8 -Crown-6 (7 · 9 3 g' 3 0 mm ο 1) ° Using a towel to sell a super wave cleaner, while irradiating with ultrasonic waves, The mixture was stirred at room temperature] for hours. The mixture was taken out of the ultrasonic cleaner 'stirred at room temperature' and added to the example] 4 (] 4a) chloromethyl carbonate (1R, 2R) [[trans_2 _ [(1Ε '3Ε) -4- (4-cyano-2-fluorophenyl) -1' 3-butanediyl ] -1 '3 --- Alkane-5-yl] thio]]-((2,4-difluorophenyl) 2,4-triazole-butyl) methyl] propyl ester (5.64 g , 8 · 8 8 mm ο 1). The mixture was stirred at room temperature for 3 · 7 hours, and a phosphate buffer solution was added under ice-cooling, and the crude product was extracted with ethyl acetate. The organic layer was washed sequentially with water (3 times) and saturated saline (1 time). The extract was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate '40 ·· 60 ~ 33: 67, V / V 'gelatin gum 175g)' to obtain the crude title compound (total amount = 6. 10 g, title compound content = about 4. 8 8 g 'yield of title compound = about 68%, containing impurities 4-[(1 E, 3 E)-4-[trans- 5- [[ (LR, 2R) -2- (2,4-difluorophenyl) _2_hydroxy-1-methyl-3_ (1H-1 '2,4-trifluoren-1-yl) propoxy] thio ] -1 'group] -1,3-butadienyl] -3-fluorobenzonitrile), an amorphous solid (diastereomeric ratio = about 1: 1). It can be used in the next project without purification (4 4 C) ° (44c) [[4-[[(lR, 2R) winter [[trans- 2- [(1E, 3E) -4- (4-cyano -2-Fluorophenyl) -1,3-butadienyl]-〗, 3_Secondyl] thio] -1- (2, [difluorophenyl) I [(1H-1,2 , 4-tris (1-methyl) -1-methyl) methyl] propoxy] carbonyloxymethoxy] oxobutyryl] oxy] acetic acid (the title object compound) The crude product produced in Example 44 (44b) [[[[[ (1R '2R) —2_ -429- 200410948 [[trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1' 3.butanediyl] -1 , 3-dioxane-5-yl] thio] -1-(2,4-difluorophenyl) -bu [(1H-1,2,4-triazol-1-yl) methyl] propyl Oxy] carbonyloxymethoxy] -4-oxobutylamyl] oxy] allyl acetate (84 3 mg, 1.04 m mol) was dissolved in dichloromethane (50 mm ο 1), and stirred under ice cooling Add (diphenylphosphine) palladium (59.8 mg, 0.052 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (65.6 mg, 0.468 m mol). The mixture was naturally warmed at room temperature and stirred for 2.5 hours. The reaction solution was purified by silica gel column chromatography (methanol: ethyl acetate '1 0 · · 90 ~ 2 0: 80, V / V, silica gel 25 g) to obtain the title object compound (487 mg, yield Rate 61%) colorless amorphous solid. DR (KBr) v-plane 2231, 1767, 1615, 1504, 1419, 1275, 1258, 1142 cm-1; NMR (CDC13, 400MHz): (5 1.32 (3H, dd, J-2 7, 2Hz), 2.78 (4H, s), 2.98 (1H, tt, J = ll, 5Hz), 3.485 (1H, t, J ^ llHz), 3.489 (1H, t, J = llHz), 3.83 (1H, q, J = 7Hz), 4.12 (1H, ddd, J = ll, 5, 2Hz), 4.24 (1H, ddd, J = ll, 5, 2Hz), 5.46 (lH.s), 5.46 (1H, s), 5.01 ( 1H, d, J = 5Hz), 5.47-5.49 (2H, m), 5.78 (1H, d, J = 6Hz), 5.80 (1H, d, J = 6Hz), 5.86 (1H, dd, J = 15, 5Hz), 6.59 (1H, dd, J = 15, 11Hz), 6.79 (1H, d, J = 16Hz), 7.01-7.09 (2H, m), 7.09 (1H, d, J = 16, 11Hz) , 7.49-7.56 (3H, m), 7.78 (1H, t, J 8Hz), 8.03 (1H, s), 8.09 (1H, s); MS (FAB +) m / z: 775 ((M + H) +); HRMS (FAB +) m / z: ((M + H) +) Calculated 値: 775.1897, found 値: 775.1890. The title object compound (159.4 mg, 0.2 mmol) prepared above was dissolved in a small amount of tetrahydrofuran, Add sodium phosphate buffer (pH 6, phosphoric acid concentration 0.1 N; 6 m 1). The solution was distilled off using a rotary evaporator. Then, the resulting suspension was filtered through a filter membrane (0.45 // m) and freeze-dried to obtain the title objective-430-200410948 compound as a colorless solid (180 mg) of sodium salt. BNMR (CD3OD, 400 MHz) : 〇1.32 (3H, dd, J = 7, 2Hz) '2.78 (4H, brs), 2.98 (1H, tt, J-2 11,5Hz), 3.49 (2H, t, J-2 7Hz), 3.84 (1H, q, J = 7Hz), 4 · 12 (1H, ddd, J2, 1b, 5, 2Hz), 4.24 (1H, ddd, J = n, 5, 2Hz), 4.48 (2H, br s), 5.01 (1H, d, J = 5Hz), 5.47 (2H, brs), 5.78 (1H, d, J = 6Hz), 5.80 (1H, d, J = 6Hz), 5.87 (1H, d, J = 16, 5Hz ), 6.59 (1H, dd, J = 16, 11Hz), 6.77 (1H, d, J = 16Hz), 7.01-7.05 (2H, m), 7.09 (1H, dd, J-2 16, 11Hz), 7.49- 7 57 (3H, m), 7.78 (1H, t, J = 8Hz), 8.02 (1H, s), 8.04 (1H, s); MS (FAB +) m / z: 797 ((M + H) +) .

The structural formula of the compound of the above example is γ Example 1

-431-200410948 Example 1

Example 2

F Example 3 9H3

Example 4 432 200410948

ch3 1 3 〇Α〇

Example 5

Example 6

Example 7 200410948

Example 8

Example 9

Example 10-434-200410948

Example 1 1

F

Example 1 2

Sinus Example 1 3 -435-200410948

Example 1 4

Example 1 5

10 Example 1 6

F-436-200410948 Example 1 7

Example 1 8 ch3o

Example 1 9

Example 2 0 200410948

Example 2

Example 2 2

CN Example 2 3 -438-200410948

Example 2 4

Example 2 5

Sinus Example 2 6 -439-200410948

CN Example 2 7 9h3

Example 2 8 CH〇0

Example 2 9 -440-200410948

Example 3 0 CH〇0

Example 3 1

Example 3 2

-441-200410948 Example 3 3 CH〇0

Example 3 4

CH.

Example 3 5

Example 3 6 -442-200410948

Example 3 7

Example · 3 8

Example 3 9 〇 Η

-443-200410948 Example 4 0 CH〇0 CH〇

Example 4 1

Example 4 2

Example 4 3 〇 〇

-444-200410948 Example 44

(Test Example 1) Production confirmation test of active compound Initially, about 1 mg of the test compound was taken in a test tube and about 100 // 1 distilled water was added, and it was visually confirmed that the test compound was dissolved at 10 mg / m 1 or more. The test compound was dissolved in human plasma to an initial concentration of 2 // mo 1/1, and the mixture was cultured at 37 ° C.毎 A small amount of sample is taken from the mixture for a certain period of time, and the residual rate of the initial amount of the test compound and the production rate of the following compound A of the active substance are quantified by HPLC method.

The results of culturing the compound of Example 27 (example number 1-3 2 8; hydrochloride) are shown in Fig. 1. It is known from Fig. 1 that the compound of Example 27 of the compound of the present invention (example number 1-3 2 8) disappeared quickly after the start of the culture, and almost 20 minutes later, it was observed that the compound A was completely converted. Therefore, the compounds of the present invention are water-soluble, and are hydrolyzed in vivo to be converted into compounds having antifungal activity. (Test Example 2) Confirmation test for production of active compounds in liver microsomes -445-200410948 Human liver microsomes (manufactured by GENTEST Corporation; 0.5 mg protein / m 1) were used to dissolve the test compounds in an initial concentration of 1 to 5 / M, the mixture was incubated at 37 ° C.毎 Take a small amount of sample from the mixture for a certain period of time. The residual rate of the initial amount of the test compound and the production rate of the following compound A of the active substance are quantified by HP LC method. Examples 7, 8, 12, 14, 15, 19, 25, 27, 28, 29, 30, 31, 33, 34, 35, 36, 37, 38, 39, 40, 42, 43 and 44 (7) The results of the compound culture are shown in Table 10. Table 10 Production rate of compound A The production rate of compound A (%) after 120 minutes from the start of culture of the test compound, for example, salt! Shape energy 7 1 sodium salt 39., 23 8 1 sodium salt 4 1, 12 12 2 sodium salt 40 , 71 14 1 hydrochloride 7 1,, 13 15 1 hydrochloride 28.. 06 19 1 hydrochloride 6 5., 11 25 1 hydrochloride 3 7.. 93 27 1 hydrochloride 2 8. .49 28 1 sodium salt 6 3, .44 29 1 sodium salt 5 2 .90 3 0 1 sodium salt 56 .60 3 1 1 m rm. Acid salt 42 .45 3 3 1 sodium salt 72 .80 34 1 sodium salt 59 • 30 446-200410948 3 5 1 sodium salt 4 1 • 49 3 6 1 sodium salt 42 .62 3 7 1 sodium salt 56 .40 3 8 1 sodium salt 54.5 50 3 9 1 sodium salt 49 • 60 40 free Acid 36 • 63 42 1 Sodium salt 49 • 80 43 1 (N-methylglucamine) salt 46 • 60 44 1 Sodium salt 6 1. 60 &amp; Table 1 shows the compound of the present invention Example 7, 8 29, 3C &gt;, 31, 33, 34, 35, 36, 37, 38:, 39, 40, 42, disappeared quickly after 120 minutes, and it was observed that almost all of them were converted into compounds ^ A after 120 minutes. ^

The chemical compounds of the present invention are water-soluble and are hydrolyzed in vivo to be converted into compounds having antifungal activity. (g formula test example 3) Test for measuring antifungal activity of compound A The anti-epicyclic activity of the compound being evaluated can be evaluated by measuring the minimum development inhibitory concentrations (MICs) according to the following method.

Determination method of Candida genus: M I C s is determined by a micro liquid dilution method. The test compound was dissolved in dimethylarsine (DMSO). The compound was diluted two-fold with DMS 0, and the final dilution was buffered with 0.1-6.5 μ-3- (morpholinyl) propanesulfonic acid (Μ Ο PS) R ρ Μ 7.0 I 1 6 4 0 medium. The final concentration of D M S 0 is not higher than 1%. The inoculated fungus was suspended in physiological saline and 'RPMI 1 640 culture medium buffered with 0.1-6.5 3-(morpholinyl) propanesulfonic acid (MO PS) to pH 7.0 was prepared to a final concentration of 5.0 × 10. 2 ~ 2 · 5χ103 cells / m 1. In each well of the microplate, the bacterial solution 1 00 0 // 1 was dissolved with the diluted compound -447-200410948 solution 1 0 0 // 1 and mixed 'and cultured at 3 5 ° C for 2 4 to 7 2 hours. The control acupoints containing no compound were used to determine the M I C s of the compound at the time when obvious colonization occurred. MICs are the minimum compound concentrations that cause at least 80% inhibition of colonization compared to the control group. New Cryptococcus method: MIC C s is determined by the micro-liquid dilution method. The test compound was dissolved in dimethylformate (DMSO). Compounds were diluted two-fold with D M S 0, and the final dilution was performed in a yeast nitrogen medium with 0.1-65 M 3- (morpholinyl) propanesulfonic acid (M 0 P S) buffered to pH 7.0. The final concentration of D M S 0 is not higher than 1%. The inoculated fungus was suspended in physiological saline, and a yeast nitrogen medium buffered with ρΗ7.0 with 0 _ 1 6 5 Μ 3-(morpholinyl) propanesulfonic acid (Μ Ο PS) was prepared to a final concentration of 5.0x102 ~ 2.5 χ103 cells / m 1. In each well of the microplate, the bacterial solution 1 00 // 1 and the diluted compound solution 1 00 // 1 were mixed and cultured at 3 5 ° C for 4 8 to 7 2 hours. The control acupoints containing no compound were used to determine the MIC s of the compound at the time when obvious colonization appeared. MICs are the minimum compound concentrations that cause at least 50% inhibition of colonization compared to the control group. The inhibition of colonization was measured using absorbance at a wavelength of 4 8 5 nm. Determination method of Aspergillus: MICs are determined according to the micro liquid dilution method. The test compound was dissolved in dimethyl sulfoxide (DMSO). The compound was diluted two-fold with DM SO. The final dilution was RP Μ Π 6 4 0 medium buffered with ρ Η 7.0 with 3-(morpholinyl) propanesulfonic acid (Μ Ο PS). Execute. The final concentration of D M S 0 is not higher than 1%. The inoculated fungus was suspended in physiological saline, and was prepared with RP Μ I 1 6 4 0 culture medium buffered with 0.1 -65 μM 3- (morpholinyl) propanoic acid (M 0 PS) to ρ Η 7.0. It contains about 1.0 × 10 4 cells / ml. Mix the bacterial solution 1000 // 1 with the diluted compound solution 100 μ 1 in each well of the microplate, and incubate at 30 ° C for 24 to 72 hours. For control acupoints without compounds, the M I C s of the compounds was determined at the time when obvious colonization was exhibited. M I C s 200410948 is the concentration of forging compounds that causes at least 80% inhibition of colonization compared to the control group. The smaller the compound M: IC 化合物, the stronger the antifungal activity. The results of the determination of the antifungal activity of Compound A are shown in Table M. Table II Antifungal activity Test compound_MIC 値 (ug / m 1) _ Canr0 Ca (2) b) CaCDc) Cnd) _A.fe) Compound a__0.25 &lt; 0.002 0.08 0.063 &lt; 0.008 0.031 a ): Ca (l) Candida albicans ATCC 64 5 50. b): C.a. (2) = Candida albicans TIMM 3164. c): C.a. (3) = Candida albicans TIMM 3165.

d): C.n. == Cryptococcus neoform ans TIMM 0 3 6 2. e): A. ". Aspergillus fumigat us SANK 10569. Compound A has excellent antifungal activity in vitro. (Preparation Example 1) Injection 5,000 mg of the compound of Example 1 was dissolved in 2.5 ml of distilled water for injection, and lyophilized by using filter paper for sterilization to obtain a freeze-dried preparation for injection. INDUSTRIAL APPLICABILITY The compound of formula (I) or a pharmacologically acceptable salt thereof in the present invention has high water solubility, and the ester portion can be rapidly cracked in the body to have antifungal activity and high safety, so it can be used as medicine (specifically antifungal Agents) and (particularly injections). [Brief description of the figure] Fig. 1 is a graph of the result of Test Example 1. The horizontal axis is the culture time and the vertical axis is the residual rate (%) of the compound of Example 27 or the production rate (%) of compound A.

Claims (1)

200410948 The scope of the patent application · 1. A compound such as formula (I) or a pharmacologically acceptable salt thereof: L1-G—- A 0) N〆N _Ra ^ —N Ar [where L1 is a C3-C7 cycloalkyl group, Ci-Cs alkylene group or C2-C6 alkenyl group, G is a single bond, a double bond , -0-, -NH-C (= 0)-, -N (CH3) -C (= 0)-, -C (= Ο) -NΗ-, -C (= 0) -N (CH3)- , Carbon group, -〇_C (= 0)-, or -C (= 0) -0-, L2 is a single bond, double bond, C3-C7 cycloalkyl, or 4-7 member heterocyclic group, L3 Is a single bond, double bond, (^-^ alkylene or 02-(: 6alkenyl, A is carboxyl, -oso3h, -oso3h, -so2nh2, -opo3h2, nitrogen-containing heterocyclic group, A nitrogen-containing heterocyclic group substituted with 1 or 2 of the same or different substituents selected from the substituent group α and the substituent group ^, or a formula -NR2R2 '(where R2 is a hydrogen atom, a methyl group, 1- Imineethyl, CrQ alkyl, 1 or 2 substituted C 丨 -C 6 alkyl, C 丨 -C 6 halogenated alkyl, C 6 -C selected from substituent group / 3丨 〇aryl, or C7-C14 aralkyl, R2 'is a hydrogen atom, K6 alkyl, has 1 or 2 substituted C, -C6 alkyl selected from the same or different substituents of the substituent group Θ, C i-C 6 haloalkyl), R 1 is a hydrogen atom or C i-C 6 alkyl, A r is a C6_CiQ square group 'or a C6-C] Q aryl group having the same or different 1 to 3 substituents selected from a halogen atom and a Ci_C6 halide group, -450-200410948 Ra _ organic group (but the following formula (π ) OH Q. "杧 (Η) Ar & compounds have antifungal activity)], &lt; Substituent group α &gt; Formamyl, blimimine ethyl, c 1 -c 6 alkyl, selected from substituted 1 or 2 substituted Cl-C6 alkyl groups with the same or different substituents, _H group, C2-c4 alkyl group, C6-C1G aryl group, C7-Ci4 aromatic group, <substituent group / 3 &gt; N- (C2-C7 alkyl) amino, N- (C &quot; C6 &amp; yl) · N_ (κ7alkyl) amino, aminomethyl Fluorenyl, and amine methyl methoxy. The compound or the pharmacologically acceptable salt thereof according to item 1 of the patent application, wherein A r is benzyl, hydrazone, or is the same or different from a halogen atom and trifluoromethyl. 1 ~ 3 phenyl groups with 1% lower I substituents. For example, the compound or the pharmacologically acceptable salt of Tongweiwei No. 1 applied for patent, 苴 φ Ar is 2,4 ~ 〆, 卞 -fluorophenyl or 2,5- Difluorophenyl. If applying for planning ~ π range item 1 The compound or its pharmacologically acceptable salt is preferably a fluorophenyl group. The compound of the item or its drug Wangliru applies 萆 ~ Scope Gu 1 ~ 4 in any of the scope, 1 ~ 4 Ra, the meaning of #Ra is the following formula fs | W Such as the application for a patent 浐 ^ _ Shouwei 1 ~ 4 Compound or item thereof -451-200410948 Allowable salt, wherein Ra is the following formula, CN CH For example, a compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein Ra is a group of the formula CH3 p 8. A compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4 in the scope of patent application, wherein 1 ^ is the following formula 9. A compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4 in the scope of patent application, wherein Ra is the following formula ^ S0 ^ ch2ch3 1 ο. As in any one of claims 1 to 4 of the scope of patent application A compound or a pharmacologically acceptable salt thereof, wherein Ra is a group of the formula OH. ocf3-452-200410948] 1. As per the patent application __4 Allowable salt, where Ra is the base of the formula below, its pharmacology 12. As described in the item of the scope of the patent of M patent, the compound of s ^ ren 1 or its pharmacologically acceptable salt is allowed to be at t., Where Ra is the following formula (m) R3 R4 Ar2 side R and R are each a hydrogen atom Or Ci-C6 alkyl, Α Γ is phenyl, and there are 1 to 5 substituted phenyls selected from the same or different substituents of substituent group 7, monocyclic heteroaryl, R, R ^^ Group, is there a group of self-substituting groups? ^ Two, 1 to 5 substituted monocyclic heteroaryl groups with the same substituents, naphthyl, 5 substituted zeenyl groups with the same or different substituents in the substituent group r, and bicyclic heteroaryl groups Or 5 substituted fused bicyclic heteroaryl groups with the same ❿ or different substituents selected from Substituent Group 7, E is methylene, · ^ formula, a () nl ~ (where m Is an integer of 0 to 2), E- is C ^ c: 7 cycloalkyl or heterocyclic group, and E3 is a group of formula (Ga):-(Ga) (wherein R5, r6, chi 7 and r8 Each is a hydrogen atom, a K6 alkyl group, or a C1-C6-alkylated group, -453-200410948 P is 0 or 1, q is an integer of 0 to 3, and r and s are each an integer of 0 to 2), or below Group of formula (Gb): (wherein, Al, 3 is a phenylene group, and there are 1 or 2 substituted phenylene groups which are the same or different substituents selected from (fluorine and chlorine atom) substituent groups , Naphthalene Or a 1 or 2 substituted naphthyl group with the same or different substituents from the (fluorine and chlorine atom) substituent group, R9 is a hydrogen atom or a Cl-C6 alkyl group, butylene is a single bond, or C8 alkylene)], &lt; Substituent group T &gt; ^ Atom 'Cycloyl, sulfhydryl, nitro, amine, cyano, cyclyl, c ^ alkyl' has the same or selected from the group consisting of (halogen, cyclo, cyano, and C1-C6 oxygen substituent groups I ~ 5 substituted C1 C, 'c〗 -C6 alkoxy' with different substituents have 1 of the same or different substituents selected from (halogen, hydroxyl, cyano, alkoxy) substituent groups ~ ^ = Of Cl-C6 alkoxy 'Cl-C6 alkanoyl' has a phase selected from (halogen: ~, amino,% substituents of μ-:-oxyl) broad-generation group_ (弋 C 丨 -c6 fluorenyl, c2-c6 alkyl, oxygen atom, via, cyano, and ... oxy) Substituted by one of different substituents of C ... by 2. oxoyl, C2 -C5 is an amino group, and the formulas -C (0) -NR &lt; (and P are crude phases, each of which is a chlorine atom or a C 'group, or-^ lysine forms a 4 to 7 member nitrogen-containing heterocyclic ring -454-200410948 radical 'Formula -S (0) m-R1, where w is an integer from 0 to 2 and is C], C ", the end group is the same as the group selected from (halogen atom and hydroxyl group) substituents Or different substituents:! ~ 5 substituted CpC6 alkyl) groups, formula π 〇) rRl4 (where, from 2 is Integer 0 ~ 2, RM is ^ 6 radical, there are 1 or 1 substituted Cl-C6 alkyl groups which are the same or different from the (halogen atom and hydroxyl) substituent group, the formula-by, &quot; 3-R 3 (Formula # 3 is an integer of 0 ~ 2, and is a phenyl group and a glycan group B 1 C ”. It has one of the same or different substitutions of the Γ substituent group selected from the group of (halogen butyl and hydroxy) substituents. ~ M solid substitution] c6 j: carbyl), the base is D, with the same 不同 π tear group ^ order of the substituent group of the phase J times different substituents; [~ 2 stomach self-replacement other ... The stilbyl group has a selective group (5 of the same or different substituents) ~ azolyl, di-I right, Β Β substituted pyr-i group, there are 1 to 5 from the substituent group., ”Different substitutions are very similar η ~: Three degrees of solid substituents, four miles groups, have a member selected from the substituent group" of: or 1 of different substituents substituted for tetramethyl, c2-c6 ^ its fluorenyl group, c3-c6 cycloalkyl, and C2-c6 alkyl 'C3-C6 far alkyl substituted ^ 6 alkyl &lt; substituent group (5 &gt; c 丨 -C4 alkyl, right, eB ~ c are selected from 5 substituted C, C4 alkyl groups, same or different, Atoms 1 1 0, earth and halogen atoms. Compounds or pharmacologically acceptable salts thereof in the scope of patent application No. 2 in which R is a C "c4 alkyl group, R is a hydrogen atom or Ci-C: 4 alkyl group, A1 is a phenyl group, which is the same or different from the group of substitutions ~ 5 _ π, which is the same or different, and is selected from the group of ... 5 substituted phenyl groups, the i phase of a single 瓖 substituent, θ 4 雑 square group, and is selected from the substitution μ 1 question or different substituents 1 to 1 substituted monocyclic heteroaromatic group r 200410948 E1 is a group of the formula-S (O) n]-(where nl is an integer of 0 to 2), Ε2 Is a group of the following formula (GaA): (where R5A, R6A, and R7ARR8A are each a hydrogen atom, CrCs alkyl, or C 丨 -C 6 haloalkyl, pA is 0 or 1, qA, rA, and sA are each 0 ~ 2 integers). 14. The compound or pharmacologically acceptable salt thereof according to item 12 of the scope of patent application, wherein Ra is the following formula: # E2 is the base of the following formula (GaB):-— (C = C) rg_ {HC-CH} sb— (Ga ^) (where qB is an integer of 0 to 3, and sB is an integer of 0 to 2; However, the sum of qB, rB and sB is 3 or less). 16. If the compound or the pharmacologically acceptable salt thereof according to item 12 of the patent application scope, which is-456-1 5. If the compound or the pharmacologically acceptable salt compound according to item 12 of the patent application scope, 2 E3 is selected from the following groups: 3 E1 is methylene, and in 200410948 Ra is a group of the formula: 1 7 If the compound of the 2nd item in the scope of the patent application or its pharmacologically acceptable salt, R4 is a hydrogen atom, Ar2 is a naphthyl group, and there are the same or different substitutions of the group 7 and the substitution of 5 to 5 "" 1 π group of substituents, condensed bicyclic heteroaryl groups, the same or different substitutions of 1 to 5 substituted condensed groups r # 一, _ 1 L self-substituted aryl hetero hetero E is of the formula- S (〇) E is the following formula (Gac). In the formula, nl is a base of 0 ~ 2),-(C〇W &quot; (RSGC = CR6e) Rna, R, R, R7C: Sr8C Is a hydrogen atom, C ^ -c ~ or C 1 -c 6 halogenated alkyl, 16 alkane, P0 &quot; is 0 or 1, qe '' and SC are each 0 '18 · As in the U of the patent application- Seven compounds or pharmacologically acceptable _, R 2 integer) 1 2 its hydrogen atom, Λ 1 is a phenyl group, and has 潠 from: @ \ 7 "~ 5 substituted groups of the same or not η substituted benzene Group, rien-different substitution_: &gt; or different substitutions] ^ This, or there may be 15 substituted naphthyl groups selected from the substituent group r &gt; 1 substituted group, the same as' 457 ^ 200410948 EE is Methylene, or Is a sulfur atom of the formula (Gb), a group: (Gb) (wherein the Ar3 β ^ substituent group is a naphthyl group, which is the same as the substituent ... a phenyl group, and is the same or not selected from (fluorine and chlorine atoms) Front ^] 1 or 2 substituted phenylene substituted, or a 1 or 2 substituted naphthyl substituted with the same or not selected from the group of (fluorine and chlorine atoms), R9 is a hydrogen atom or C!- C6 alkyl, T is a single bond, or alkylene). 19 · The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 18 in the scope of patent application, wherein R1 is a hydrogen atom or a methyl group. 20. The compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt thereof, wherein R1 is methyl. 2 1. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 20 in the scope of patent application, wherein L1 is CrC6 alkylene or CrC6 alkylene. 22. A compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 20 in the scope of application for a patent, wherein L1 is a C2-C6 eutectic group or _CH == CH ~. 2 3 · The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 20 in the scope of patent application, wherein L1 is 0: 2 alkylene or -CHdiCH-. 24. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 20 of the patent application, wherein L1 is a C 2 alkylene group. 25. A compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 24 in the scope of application for a patent, wherein G is a single bond, -0_, -NH-C (20) ..._ c (20) ~ NH_, -C (= 0) -N (CH3)-, carbonyl 'or -C (di-458-200410948 o)-o-〇2. As in any one of the scope of the patent application] ~ 24 compounds or Its pharmacologically acceptable salt, where G is -NH-C (di0)-, -C (di0) -N (CH3)-, mineral-based, or -C (= 0) -0-. 27. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 24, wherein G is -C (= 0) -NH- or carbonyl. 2 8. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 24 in the scope of patent application, wherein G is -C (= 0) -NH-. 2 9. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 28 in the scope of patent application, wherein L2 is a single bond, a double bond, or a 4- to 7-membered heterocyclic group. 30. The compound according to any one of claims 1 to 28 or a pharmacologically acceptable salt thereof, wherein L2 is a single bond. 31. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 30 in the scope of patent application, wherein L3 is a single bond, a double bond, or Ci-C6 alkylene. 32. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 30 in the scope of patent application, wherein L3 is a single bond, a double bond, -CH2- or -CH2CH2-. 33. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 30, wherein L3 is a single bond, -CH2- or -CH2CH2-. 34. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 30, wherein L3 is -CH2- or -CH2CH2-. 35. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 30 in the scope of patent application, wherein L3 is -CH2-. 3 6. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 35 in the scope of the applied patent, wherein A is a carboxyl group, -SO3H group, -OS03H group, -SO2NH2 group, -0 Ρ Ο 3 Η 2 group, azetidinyl, pyrrolidinyl, piperidinyl, piperin 200410948, morpholinyl, 1 substituted azetidinyl (the substituent: methyl, -SO3H or -OP. 3H2 group), 1 substituted with piperidinyl (this substituent: methyl, -0so3H or-〇〇〇3H2 group), 1 substituted with piperidin [the substituent: methyl The substituent is a 1-substituted c2-c6 alkyl group (the substituent: -S03H group, -0S03H group, -S02NH2 group, -OP03Η2 group or -NMe2 group)] or -NMe2 group. 37. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 35 in the scope of patent application, wherein A is a carboxyl group, -S03H group, -0S03H group, -OP03Η2 group, 1-azetidinyl group, 1 -pyrrole Pyridyl, piperidinyl (i.e. 1-piperidinyl), morpholinyl (i.e. 4-morpholinyl), 1-methyl-3-azetidinyl, 3- (sulfonyloxy) -buazidinyl 3- (sulfofluorenyloxy) -1 -azetidinyl, 1-methyl-4-piperidinyl, 1-methyl-4-piperidinyl, 3- (sulfofluorenyloxy) -1 -piperidine , 3- (phosphonooxy) -piperidinyl, 4-methyl-1-piperidinyl, 4- (2-hydroxyethyl) -1-piperidyl, 4- [2- (sulfo Fluorenyl) ethyl] -1-piperazinyl, 4- [2- (phosphofluorenyloxy) ethyl] -1-piperazinyl or -NMe2 radical. 38. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 35 in the scope of application for a patent, wherein A is a carboxyl group, -S03H group, -0P03Η2 group, 4-methyl-1-piperidyl group or 4 -(2-hydroxyethyl) -1 -piperidinyl. 39. The compound according to any one of claims 1 to 35 or a pharmacologically acceptable salt thereof, wherein A is a carboxyl group, -S03H group or -OP03Η2 group. 40. The compound according to any one of claims 1 to 35 or a pharmacologically acceptable salt thereof, wherein A is a carboxyl group. 41. The compound or pharmacologically acceptable salt thereof according to item 1 of the scope of patent application, wherein Ra is the following formula: -460-200410948 Ar is 2,4-difluorophenyl, and R] is a hydrogen atom or a methyl group. Is C2-C6 alkylene or -CH = CH-, G is -C (= 0) -NH-, -C (= 〇) -N (CH3)-, carbonyl, or -C (20) -0 -, L2 is a single bond, L3 is a single bond, -CH2-or -CH2CH2-, A is a carboxyl group,-S03H group,-oso3h group, -0 ρ Ο 3 Η 2 group, 1-azetidinyl group, 1-pyrrole D Amidyl, piperidinyl, morpholinyl, 1-methyl-3 -azetidinyl, 3- (sulfofluorenyloxy) -1-azetidinyl, 3- (phosphofluorenyloxy) -1-azetidinyl, 1- Methyl-4 -piperidinyl, 1 -methyl-4 -piperidinyl, 3- (sulfonyloxy) -1-piperidinyl, 3- (phosphofluorenyloxy) -1 -piperidinyl , 4-methyl-1 -piperidinyl, 4- (2-hydroxyethyl) -1-piperidinyl, 4- [2- (sulfonyloxy) ethyl] -1-piperidinyl, 4 -[2- (phosphonooxy) ethyl] -1-piperidyl or -NMe2. 42. The compound or pharmacologically acceptable salt thereof according to item 1 of the scope of patent application, wherein Ra is a group of the formula Ar is 2,4-difluorophenyl, R1 is a hydrogen atom or a methyl group, L1 is a C2-C6 alkylene group or -CH = CH-, G is -C (= 0) -NH- or a carbonyl group, and L2 is Single bond, L3 is a single bond, -CH2- or -CH2CH2-, A is a carboxyl group, -S03H group, -0 S Ο 3 fluorenyl group, -Ο Ρ Ο 3 Η 2 group, 1-azetidinyl group, 1-pyrrolidine , Piperidinyl, morpholinyl, 1-methyl-3 -azetidinyl, 3- (sulfofluorenyloxy) -1-azetidinyl, 3- (phosphofluorenyloxy) -1-azetidinyl, 1- Methyl-4--461-200410948 piperidinyl,] -methyl-4 -piperidinyl, 3- (sulfofluorenyloxy) -1 -piperidinyl, 3- (phosphofluorenyloxy) -1 -Piperidinyl, 4-methyl-piperidinyl, 4- (2-hydroxyethyl)-〗-piperidinyl, 4- [2- (sulfofluorenyloxy) ethyl]-]-piperidinyl , 4- [2- (phospho (fluorenoxy) ethyl] -1-piperidyl or -NMe2 group. 43. The compound or pharmacologically acceptable salt thereof according to item 1 of the scope of patent application, wherein Ra is a group of the formula Ar is 2,4-difluorophenyl, R1 is a hydrogen atom or methyl, 1 ^ is C2-C6 alkylene or -CHdiCH-, G is -C (= 0) -NH- or carbonyl, L2 Is a single bond, L3 is a single bond, -CH2- or -CH2CH2-, A is a carboxyl group, -S03H group, -0S03H group, -0P03Η2 group, 1-azetidinyl, 1-pyrrolidinyl, piperidinyl, morpholine , 1-methyl-3 -azetidinyl, 3- (sulfofluorenyloxy) '1-azetidinyl, 3- (phosphofluorenyloxy) -1-azetidinyl, 1-methyl-4-fluorenyl 1'-methyl-4 -Mentinofluorenyl ^ 3- (mineral oxygen group) -1-Membranyl group 5 3-(squamyloxy group) -1-Membranyl group 5 4 -Methyl group -1-veinyl group 4- (2-hydroxyethyl) -1-piperidinyl, 4- [2- (sulfonyloxy) ethyl] -1-piperidyl, 4- [2- (phosphorus (Methoxy) ethyl] -1-piperidyl or -NMe2. 4 4. The compound or pharmacologically acceptable salt thereof according to item 1 of the scope of patent application, wherein Ra is a group of the formula Ar is a 2,4-difluorophenyl group, R1 is a hydrogen atom or a methyl group, L1 is a 02-462-200410948 alkyl group, G is -C (= 0) -NH- or a carbonyl group, L2 is a single bond, and L3 Is a single bond, -CH2-or-CH2CH2-, A is a carboxyl group, -so3h group, -oso3h group, -0 ΡΟ 3 Η 2 group, 1-azetidinyl group, 1-pyrrolidinyl group, piperidinyl group, morpholine , 1-methyl-3 -azetidinyl, 3- (sulfofluorenyloxy) H-butyridinyl, 3- (phosphoryloxy) -1-sulfanylbutanyl 5 methyl-4-carboxamidine Fluorenyl '1-methyl-4-piperidinyl, 3- (sulfofluorenyloxy) -1-piperidinyl, 3- (phosphofluorenyloxy) -1-piperidinyl, 4-methyl- Buperithionyl, 4- (2-hydroxyethyl)-]-piperidinyl, 4- [2- (sulfofluorenyloxy) ethyl] -1-piperidinyl, 4- [2- (phosphonium (Oxy) ethyl] -1-piperidyl or -NMe2. 45. The compound or pharmacologically acceptable salt thereof according to the scope of patent application, wherein Ra is a group of the formula Ar is 2,4-difluorophenyl, R1 is a hydrogen atom or a methyl group, L1 is a C2 alkylene group, G is -C (= 0) -N-- or a carbonyl group, L2 is a single bond, and L3 is -CH2- Or -CH2CH2-, A is a carboxyl group, -S03H group, -OP03Ρ2 group, 4-methyl-1 -piperidinyl group or 4- (2-hydroxyethyl) -1 -piperidinyl group. 4 6. The compound or pharmacologically acceptable salt thereof according to item 1 of the scope of patent application, wherein Ra is a group of the formula Ar is 2,4-difluorophenyl, R1 is a hydrogen atom or a methyl group, L1 is an alkylene group, G is -C (= 0) -NH-, L2 is a single bond, and L3 is -CH2- or 200410948 -CH2CH2-, A is a carboxyl group, a -s03h group, or a -opo3H2 group. 47. The compound or pharmacologically acceptable salt thereof according to item 1 of the scope of patent application, wherein R a is Ar is 2,4-difluorophenyl, R1 is a hydrogen atom or a methyl group, L1 is (: 2 alkylene, G is -C (= 0) -NH-, L2 is a single bond, and L3 is a single bond, A Is carboxyl. 48. Hydroglutaric acid 1-[[(1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-oxo-2-urabenyl) -1 '3- Butanyl group] -1 '3-1-methyl- 5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propoxy] carbonyloxy] ethyl, 1_ [4- [1-[[(1R, 2R) -2-[[trans- 2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-but Dienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -bu [(1H-1,2,4-triazole-1- (Methyl) propoxy] carbonyloxy] ethoxy] -4-oxobutanyl] -4-piperidinecarboxylic acid, [[4- [l-[[(lR, 2R) -2--2-[[ Trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-diseno-5-yl] thio ] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole-butyl) methyl] propoxy] roxy] ethoxy] -4 -Oxobutanoyl] amino] acetic acid, 3-[[4- [b [[(1R, 2R) -2-[[trans- 2-[(IE, 3E) -4-(4-cyano- 2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] -464-200410948 thio]-]-(2,4-difluorophenyl)- ]-[(1 H1,2,4-triazole-: [-yl] methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutanyl] amino] propionic acid, [N- [ 4-[]-[[(] R, 2R) -2-[[Trans- 2-[(1Ε, 3E) -4- (4- Cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1 -[(1H-1,2,4-triazole-butyl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutyryl] -N-methylamino] acetic acid, Φ hydropentyl Diacid [(1R, 2R) -2-[[Trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1 , 3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl, l- [4-[[(lR, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3 -butadiene Group] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazol-1-yl ) Methyl] propoxy] carbonyloxymethoxy] -4-oxobutyryl] -4-piperidinecarboxylic acid, [[4-[[(lR, 2R) -2-[[trans- 2-[( 1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5 -yl] thio]-]-(2 , 4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy Yl] -4-oxobutanyl] amino] acetic acid, 3-[[4-[[(lR, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano- 2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) 4-triazole- 1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutanyl] amino] propanoic acid, [N- [4-[[(lR, 2R) -2-[[trans-2 -[(1Ε, 3E) -4- (4--465-200410948 Minyl-2- ^ benzyl) -1 '3 -Dingyi ^ Chanji] -1' 3-Ichinosekiin-5-ki ] Thio]-1-(2,4-difluorophenyl)-[-((1 Η-1,2,4-triazol-1 -yl) methyl] propoxy] carbonyloxymethoxy ] -4-oxobutanyl] methylamino] acetic acid, 5- [1-[[(1R, 2R) -2-[[trans-2-[(ΙΕ, 3Ε) -4- (4-cyano-2 -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1Η -1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -5 -oxo-1-heptanesulfonic acid, 6- [l-[[(lR, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2- 2-benzyl) -1 '3 -butyrate Yl] -1 '3 -monothiophene-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazole-1- (Methyl) propoxy] carbonyloxy] ethoxy] -6-oxo-1-hexanesulfonic acid, 5-[[((1R, 2R) -2-[[trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] thio]-1- (2,4 -Difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -5-oxo-1-heptanesulfonic acid, 6- [[(lR, 2R) -2-[[Trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -l, 3-butadienyl]- l, 3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) 2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy Group] -6-oxo-1-hexanesulfonic acid, [[4-[[[(1R, ZR) -2-[[trans-2-[(IE, 3E) -4- (4-cyano- 2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutanyl] oxy] acetic acid, -466-200410948 [[4- [[(LR, 2R) -2-[[trans- 2-[(] E, 3E) -4- (cardiocyano-2-fluorophenyl)-], 3 -butadienyl] -3- Dioxane-5 -yl] thio] (2,4-difluorophenyl) -1-[(1 Η -1,2,4-triazol-1 -yl) methyl] propoxy] carbonyl Oxymethoxy] oxobutyryl] oxy] acetic acid or a pharmacologically acceptable salt thereof. 49. [[4- [1-[[(1R, 2R) -2-[[trans-2-[(ΙΕ, 3Ε) -4- (4-cyano-2-fluorophenyl) -1,3 -Butadienyl] -1,3-dioxan-5-yl] thio] -1- (2,4-difluorophenyl) -l-[(1H-1,2,4-triazole -1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutanyl] amino] acetic acid, 3-[[4- [1-[[(1R, 2R) -2- [[Trans-2-[(IE, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxan-5-yl] Thio]-]-(2,4-difluorophenyl) -1-[(119H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy ] -4-oxobutanyl] amino] propanoic acid, [[4-[[(lR, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2- Truncate base) -1 '3 -Ding_ • Chuji] -1 5 3-1 * Huanyuan-5 · yl] thio] -1- (2,4-difluorophenyl) -1- [ (1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutanyl] amino] acetic acid, 3-[[4-[[(lR , 2R) -2-[[trans- 2-[(1Ε, · 3Ε) -4- (4-cyano-2 -fluoro Group) -1,3 -butadienyl] -1,3-dioxane-5 -yl] thio] -1- (2,4-difluorophenyl) -1-[(1Η-1 · 2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutyryl] amino] propionic acid or a pharmacologically acceptable salt thereof. 50. — A medicinal composition containing an active ingredient selected from the group consisting of a tertiary compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 49 of the scope of application for patents -467-200410948. An antifungal agent containing a triazole compound or a pharmacologically acceptable salt thereof selected from any one of items 1 to 49 in the scope of patent application as an active ingredient. 2. A method for preparing a medical composition, using a triazole compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 49 in the scope of patent application. 5 3 · — A method for preparing an antifungal agent, which uses a triazole compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 49 in the scope of patent application. 5 4 · A method of prevention or treatment is to administer an effective amount of a compound as described in any one of claims 1 to 49 in the scope of the patent application to a warm-blooded animal. 5 5 · The method according to claim 5 in the patent application scope, wherein the warm-blooded animal is human. -468-