JP2005263636A - Water soluble triazole medicinal composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine containing a triazole compound or its pharmacologically acceptable salts having an excellent pharmacokinetic property and antifungal activity as the medicine (especially as an antifungal agent). <P>SOLUTION: This medicinal composition contains a triazole compound expressed by general formula (I) [wherein, L<SP>1</SP>is a 1-6C alkylene or the like: G is C(=O)NH, C(C=O)N(CH<SB>3</SB>), carbonyl or the like; L<SP>2</SP>is a single bond or the like; L<SP>3</SP>is a 1-6C alkylene or the like; A is carboxyl, SO<SB>3</SB>H, OSO<SB>3</SB>H, SO<SB>2</SB>NH<SB>2</SB>, OPO<SB>3</SB>H<SB>2</SB>or the like; R<SP>1</SP>is H or a 1-6C alkyl; Ar is a 6-10C aryl or a 6-10C aryl having the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and a 1-6C halogenated alkyl; and R<SP>a</SP>is an organic group] or its pharmaceutically acceptable salt as an active ingredient. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a novel water-soluble triazole compound and a pharmacologically acceptable salt having excellent pharmacokinetics and antifungal activity as a medicine (particularly an injection), and a medicine (particularly, an antifungal agent) containing it as an active ingredient. .

  Conventionally, various triazole compounds are known as agents for treating fungal infections. For example, Patent Literature 1, Patent Literature 2, Patent Literature 3, Patent Literature 4 and Patent Literature 5 describe triazole compounds having a tertiary hydroxyl group. Patent Document 6 describes 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) -2-propanol (fluconazole). Patent Document 7 discloses 3- [4- (4-cyanophenyl) thiazol-2-yl] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazole-1- Yl) -2-butanol (labconazole) is described. In Patent Document 8, 2- (2,5-difluorophenyl) -3- [4- (4-cyanophenyl) thiazol-2-yl] -1- (1H-1,2,4-triazole-1- Yl) -2-butanol (RO0094815) is described. Patent Document 9 discloses 2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1- (1H-1,2,4-triazol-1-yl) -2-butano. -Ru (voriconazole) is described. Patent Document 10 discloses 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl). ) Propyl] -3- [4- (1H-1-tetrazolyl) phenyl] -2-imidazolidinone (TAK-456). In Patent Document 11, 2- (2,4-difluorophenyl) -1- (ethylsulfonyl) -1,1-difluoro-3- (1H-1,2,4-triazol-1-yl) -2- Propanol (SS750) is described. Patent Document 12 discloses (2R, 3R) -2- (2,4-difluorophenyl) -3- [4- [4- [3-oxo-2- (4-trifluoromethoxybenzyl) -2H-1]. , 2,4-Triazol-4-yl] phenyl] -1-piperazinyl] -1- (1H-1,2,4-triazol-1-yl) -2-butanol (Syn-2869) has been described . Patent Document 13 discloses 7-chloro-3-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazole). -1-yl) propyl] quinazolin-4 (3H) -one (UR-9825) is described. Patent Document 14 discloses (2R, 3R) -3-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadiene-1-yl]- 1,3-Dioxane-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol is described . In addition, Patent Document 15, Patent Document 16, Patent Document 17, Patent Document 18, and Patent Document 19 also describe triazole compounds having a tertiary hydroxyl group.

  The dosage form of a fungal infection therapeutic agent varies depending on the type of fungus and the mode of infection. This administration form includes, for example, oral administration and injection administration. Since these administration methods have merits and demerits, it is desirable that the fungal infection therapeutic agent can be administered either orally or by injection. However, the known triazole fungal infection treatment agents shown above have the disadvantage that they are difficult to administer as injections due to low water solubility while having excellent antifungal activity. .

  As a means for improving this low water solubility, it is conceivable to convert a hydroxyl group into an ester group that increases water solubility. However, since the hydroxyl group that these therapeutic agents have in common is a tertiary hydroxyl group, due to its low reactivity, the ester group does not cleave quickly in the body after administration, and the active body does not appear. there were.

  As compounds for solving this inconvenience, Patent Document 20 and Patent Document 21 disclose an acyl carbonate ester derivative having a substituted benzoyl group in the side chain. However, these compounds have not been sufficiently satisfactory as pharmaceuticals (antifungal agents for injection) in terms of physical properties, chemical stability, pharmacokinetics, safety, and ease of synthesis. The compounds of the present invention differ from these compounds in that they have an aliphatic acyl group in the side chain. Patent Document 20 and Patent Document 21 do not disclose or suggest an acyl carbonate having an aliphatic acyl group. As water-soluble triazole derivatives, for example, ester derivatives are described in Patent Document 22, but these compounds are different in structure from the acyl derivatives of the present invention in which the acyl is adjacent to one oxygen atom.

Patent Document 23 discloses a compound obtained by chemically modifying an agrochemical compound with an asylal carbonate group (providing group). However, these compounds differ from the compounds of the present invention in that the active body is an agrochemical compound. The imparting group is a group for imparting physical properties suitable for agricultural chemicals, and is different from the imparting group of the compound of the present invention modified with a group suitable for an antifungal agent for injection. Therefore, the disclosed compounds are used as medicines (injectable antifungal agents) in terms of antifungal activity (especially spectrum and strength), physical properties (especially water solubility and chemical stability), pharmacokinetics, and safety. It is not possible. Patent Document 23 does not disclose or suggest a chemical modification for a medicine (an antifungal agent for injection).
JP-A-8-333350 Japanese Patent Laid-Open No. 11-80135 JP-A-10-279567 JP 2001-342187 A WO02 / 40472 Publication JP-A-62-14766 JP-A-8-53426 WO99 / 45008 publication Japanese Patent No. 2625584 JP-A-9-183769 JP-A-11-240871 WO98 / 31675 gazette WO97 / 05130 Publication EP1083175A2 publication Japanese Patent No. 3050982 WO95 / 25107 WO00 / 27852 WO01 / 66551 WO01 / 79196 WO00 / 30655 publication WO99 / 61017 JP 2002-322176 A WO01 / 56358

  The problem to be solved by the present invention is that it is highly water-soluble, is converted into an active body at a preferred site in the living body, the conversion speed is fast, the organ selectivity for conversion is excellent, the conversion rate is excellent, and the safety is high. It is an object of the present invention to provide a chemically stable triazole compound for injection which is carbonated at a tertiary hydroxyl group.

  In order to solve the above-mentioned problems, the present inventors have intensively studied and proposed and synthesized a carbonate ester compound according to the present invention, and the compound according to the present invention is useful as a medicine (particularly an antifungal agent for injection). As a result, the present invention has been completed.

The present invention relates to (1) the general formula (I)

[Wherein L ¹ represents a C ₃ -C ₇ cycloalkyl group, a C ₁ -C ₆ alkylene group or a C ₂ -C ₆ alkenylene group,
G is a single bond, a double bond, -O-, -NH-C (= O)-, -N (CH ₃ ) -C (= O)-, -C (= O) -NH-, -C ( = O) -N (CH ₃ )-, carbonyl group, -OC (= O)-, or -C (= O) -O-
L ² represents a single bond, a double bond, a C ₃ -C ₇ cycloalkyl group, or a 4- to 7-membered heterocyclic group,
L ³ represents a single bond, a double bond, a C ₁ -C ₆ alkylene group or a C ₂ -C ₆ alkenylene group,
A is selected from a carboxy group, a —SO ₃ H group, a —OSO ₃ H group, a —SO ₂ NH ₂ group, a —OPO ₃ H ₂ group, a nitrogen-containing heterocyclic group, a substituent group α, and a substituent group β. that identical or different substituents 1 or 2 substituted nitrogen-containing heterocyclic group by group, or, ² R ² '(wherein wherein -NR, R ² is a hydrogen atom, an amidino group, 1-iminoethyl group, C ₁ - C ₆ alkyl group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ halogenated alkyl group, C ₆ -C ₁₀ aryl group, which is 1 or 2 substituted with the same or different substituents selected from substituent group β or, C ₇ -C ₁₄ aralkyl group, R 2 ^'is hydrogen, C ₁ -C ₆ alkyl, C ₁ which is 1 or 2 substituted by identical or different substituents selected from substituent group β A —C ₆ alkyl group or a C ₁ -C ₆ halogenated alkyl group).
R ¹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
Ar is a C ₆ -C ₁₀ aryl group, or a C ₆ -C ₁₀ aryl having the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and a C ₁ -C ₆ halogenated alkyl group Group,
R ^a is an organic group (however, the following formula (II)

The compound represented by has antifungal activity. ). ]
Or a pharmacologically acceptable salt thereof as an active ingredient.
<Substituent group α>
Amidino group, 1-iminoethyl group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkyl group substituted with the same or different substituent selected from substituent group β, C ₁ -C ₆ alkyl group, C ₁ -C ₆ halogen Alkyl group, C ₂ -C ₄ alkanoyl group, C ₆ -C ₁₀ aryl group, and C ₇ -C ₁₄ aralkyl group.
<Substituent group β>
Hydroxyl group, mercapto group, cyano group, N- (C ₂ -C ₇ alkanoyl) amino group, N- (C ₁ -C ₆ alkyl) -N- (C ₂ -C ₇ alkanoyl) amino group, carbamoyl group, and Carbamoyloxy group.

In a medicament containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient,
(2) A compound or a pharmacologically acceptable salt thereof, wherein Ar is a phenyl group or a phenyl group substituted with the same or different substituent selected from the group consisting of a halogen atom and a trifluoromethyl group. As an active ingredient,
(3) A pharmaceutical comprising a compound wherein Ar is a 2,4-difluorophenyl group or a 2,5-difluorophenyl group or a pharmacologically acceptable salt thereof as an active ingredient,
(4) A pharmaceutical comprising a compound wherein Ar is a 2,4-difluorophenyl group or a pharmacologically acceptable salt thereof as an active ingredient,
(5) In any one of (1) to (4), R ^a is represented by the following formula:

Is a pharmaceutical comprising a compound represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient,
(6) In any one of (1) to (4), R ^a is represented by the following formula:

Is a pharmaceutical comprising a compound represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient,
(7) In any one of (1) to (4), R ^a is represented by the following formula:

Is a pharmaceutical comprising a compound represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient,
(8) In any one of (1) to (4), R ^a is represented by the following formula:

Is a pharmaceutical comprising a compound represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient,
(9) In any one of (1) to (4), R ^a is represented by the following formula:

Is a pharmaceutical comprising a compound represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient,
(10) In any one of (1) to (4), R ^a is represented by the following formula:

Is a pharmaceutical comprising a compound represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient,
(11) In any one of (1) to (4), R ^a is represented by the following formula:

Is a pharmaceutical comprising a compound represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient,
(12) In any one of (1) to (4), R ^a is represented by the following formula (III):

[Wherein R ³ and R ⁴ independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group,
Ar ² is a phenyl group, a phenyl group substituted by 1 to 5 substituents selected from the same or different substituents selected from substituent group γ, a monocyclic heteroaryl group, and the same or different substituents selected from substituent group γ 1 to 5 substituted monocyclic heteroaryl group, naphthyl group, naphthyl group 1 to 5 substituted with the same or different substituents selected from substituent group γ, condensed bicyclic heteroaryl group, or A fused bicyclic heteroaryl group substituted 1 to 5 with the same or different substituents selected from the substituent group γ,
E ¹ represents a methylene group or a group represented by the formula —S (O) _n1 — (wherein _n1 represents an integer of 0 to 2);
E ² represents a C ₄ -C ₇ cycloalkyl group or a heterocyclyl group,
E ³ represents the formula (Ga)

(Wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ independently represent a hydrogen atom, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ halogenated alkyl group,
p represents 0 or 1,
q represents an integer of 0 to 3,
r and s independently represent an integer of 0 to 2. ) Group represented by
Or the formula (Gb)

(In the formula, Ar ³ is a phenylene group, a phenylene group, a naphthylene group, or a (fluorine atom) substituted with the same or different substituents selected from the substituent group consisting of (fluorine atom and chlorine atom) And a naphthylene group substituted with the same or different substituents selected from the substituent group consisting of
R ⁹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
T represents a single bond or a C ₁ -C ₈ alkylene group. ) Is represented. ]
Is a pharmaceutical comprising a compound represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient,
(13) In (12), R ³ is a C ₁ -C ₄ alkyl group,
R ⁴ is a hydrogen atom or a C ₁ -C ₄ alkyl group,
Ar ² is the same or different phenyl group, phenyl group substituted with 1 to 5 substituents selected from the same or different substituents selected from substituent group γ, monocyclic heteroaryl group, or substituent group γ A monocyclic heteroaryl group substituted with 1 to 5 substituents;
E ¹ is a group represented by the formula —S (O) _n1 — (wherein _n1 represents an integer of 0 to 2);
E ³ is the formula (Ga ^A )

(Wherein R ^5A , R ^6A , R ^7A and R ^{8A each} independently represents a hydrogen atom, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ halogenated alkyl group,
p ^A represents 0 or 1,
q ^A , r ^A and s ^A independently represent an integer of 0 to 2. ) Or a pharmacologically acceptable salt thereof as an active ingredient,
(14) In (12), R ^a is

Is a pharmaceutical comprising a compound represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient,
(15) In (12), E ¹ is a methylene group,
E ²

A group selected from the group consisting of:
E ³ represents the formula (Ga ^B )

(In the formula, q ^B represents an integer of 0 to 3, r ^B and s ^B independently represent an integer of 0 to 2, provided that the sum of q ^B , r ^B and s ^B is 3 or less. .) A pharmaceutical comprising a compound represented by the following formula or a pharmacologically acceptable salt thereof as an active ingredient:
(16) In (12), R ^a is

Is a pharmaceutical comprising a compound represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient,
(17) In (12), R ⁴ is a hydrogen atom,
Ar ² is a naphthyl group, a naphthyl group substituted by 1 to 5 substituents selected from the same or different substituent selected from substituent group γ, a fused bicyclic heteroaryl group, or the same or selected from substituent group γ A fused bicyclic heteroaryl group substituted 1 to 5 with different substituents,
E ¹ is a group represented by the formula —S (O) _n1 — (wherein _n1 represents an integer of 0 to 2);
E ³ represents the formula (Ga ^C )

(Wherein R ^5C , R ^6C , R ^7C , and R ^8C independently represent a hydrogen atom, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ halogenated alkyl group,
p ^C represents 0 or 1,
q ^C , r ^C and s ^C independently represent an integer of 0 to 2. ) Or a pharmacologically acceptable salt thereof as an active ingredient,
(18) In (12), R ⁴ is a hydrogen atom,
Ar ² is 1 to 5 phenyl groups, naphthyl groups, or the same or different substituents selected from the substituent group γ, substituted with the same or different substituents selected from the phenyl group and the substituent group γ To a 5-substituted naphthyl group,
E ¹ is a methylene group or a sulfur atom,
E ³ is the formula (Gb)

(In the formula, Ar ³ is a phenylene group, a phenylene group, a naphthylene group, or a (fluorine atom) substituted with the same or different substituents selected from the substituent group consisting of (fluorine atom and chlorine atom) And a naphthylene group substituted with the same or different substituents selected from the substituent group consisting of
R ⁹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
T represents a single bond or a C ₁ -C ₈ alkylene group. ) Or a pharmacologically acceptable salt thereof as an active ingredient,
<Substituent group γ>
Halogen atom, a hydroxyl group, a mercapto group, a nitro group, an amino group, a cyano group, a carboxy _group, C 1 -C ₆ alkyl, substituted consisting (a halogen atom, a hydroxyl group, a cyano group, _and, C 1 -C ₆ alkoxy group) A C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom, a hydroxyl group, a cyano group, and C ₁ -C ₆ , which are substituted with the same or different substituents selected from the group of groups. C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkanoyl group, (halogen atom, hydroxyl group, cyano group, and ₁ to 5 substituted with the same or different substituents selected from the substituent group consisting of alkoxy groups) A C ₁ -C ₆ alkanoyl group, a C ₂ -C ₆ alkanoyloxy group substituted with the same or different substituents selected from the substituent group consisting of C ₁ -C ₆ alkoxy groups), A C ₂ -C ₆ alkanoyloxy group substituted with the same or different substituents selected from the substituent group consisting of a halogen atom, a hydroxyl group, a cyano group, and a C ₁ -C ₆ alkoxy group), C ₂ -C ₇ alkoxycarbonyl _group, C 2 -C ₅ alkanoylamino group, the formula ^{-C (O) -NR 10 R 11} ( wherein, R ¹⁰ and R ¹¹ are each independently a hydrogen atom or a _C 1 -C ₆ Or an alkyl group, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-membered to 7-membered nitrogen-containing heterocyclic ring). S (O) _μ1- R ¹³ (wherein μ1 represents an integer of 0 to 2, and R ¹³ is selected from a C ₁ -C ₆ alkyl group or a substituent group consisting of (halogen atom and hydroxyl group). that the same or different 1 to 5 substituted C ₁ -C substituents An alkyl group group represented by.), Wherein _{-S (O) μ2 -O-R} 14 ( wherein, .mu.2 is an integer of 0 to 2, R ¹⁴ is _C 1 -C ₆ alkyl group, or A C ₁ -C ₆ alkyl group substituted with 1 to 5 substituents selected from the same or different substituents selected from the substituent group consisting of a halogen atom and a hydroxyl group. S (O) _μ3- R ¹⁵ (wherein μ3 represents an integer of 0 to 2, and R ¹⁵ is selected from a C ₁ -C ₆ alkyl group or a substituent group consisting of (halogen atom and hydroxyl group). A C ₁ -C ₆ alkyl group substituted with 1 to 5 the same or different substituents. And the same or different substituents selected from one or two substituted imidazolyl groups, pyrazolyl groups, or substituent groups δ selected from the same or different substituents selected from substituent group δ. 1 or 2 substituted pyrazolyl group, triazolyl group, 1 selected from the same or different substituent selected from substituent group δ, 1 or 2 substituted triazolyl group, tetrazolyl group, substituent selected from substituent group δ substituted tetrazolyl _group, C 2 -C ₆ alkenyl _group, C 2 -C ₆ alkynyl _group, C 3 -C ₆ cycloalkyl group, _{and, C} 1 -C substituted by C 3 -C ₆ cycloalkyl group ₆ An alkyl group;
<Substituent group δ> A C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkyl group substituted with 1 to 5 identical or different halogen atoms, and a halogen atom.
(19) The pharmaceutical composition according to any one of (1) to (18), wherein R ¹ is a hydrogen atom or a methyl group or a pharmacologically acceptable salt thereof as an active ingredient,
(20) In any one of (1) to (18), a drug containing a compound wherein R ¹ is a methyl group or a pharmacologically acceptable salt thereof as an active ingredient,
(21) The compound according to any one of (1) to (20), wherein L ¹ is a C ₁ -C ₆ alkylene group or a C ₂ -C ₆ alkenylene group, or a pharmacologically acceptable salt thereof as an active ingredient Is a medicine containing,
(22) The compound according to any one of (1) to (20), wherein L ¹ is a C ₂ -C ₆ alkylene group or —CH═CH— or a pharmacologically acceptable salt thereof as an active ingredient A medicine,
(23) A medicament comprising, as an active ingredient, a compound or a pharmacologically acceptable salt thereof wherein L ¹ is a C ₂ alkylene group or —CH═CH— in any one of (1) to (20) ,
(24) In any one of (1) to (20), a pharmaceutical comprising a compound wherein L ¹ is a C ₂ alkylene group or a pharmacologically acceptable salt thereof as an active ingredient,
(25) In any one of (1) to (24), G is a single bond, -O-, -NH-C (= O)-, -C (= O) -NH-, -C (= O) -N (CH ₃ )-, a carbonyl group, or a compound that is -C (= O) -O- or a pharmacologically acceptable salt thereof as a pharmaceutical,
(26) In any one of (1) to (24), G is -C (= O) -NH -, - C (= O) -N (CH 3) -, carbonyl group, or -C ( = O) a drug containing a compound of -O- or a pharmacologically acceptable salt thereof as an active ingredient,
(27) A medicament containing the compound or pharmacologically acceptable salt thereof, wherein G is —C (═O) —NH— or a carbonyl group as an active ingredient in any one of (1) to (24) Yes,
(28) In any one of (1) to (24), a drug containing a compound wherein G is -C (= O) -NH- or a pharmacologically acceptable salt thereof as an active ingredient,
(29) The compound or pharmacologically acceptable salt thereof, wherein L ² is a single bond, a double bond, or a 4- to 7-membered heterocyclic group in any one of (1) to (28) As a medicine containing
(30) In any one of (1) to (28), a pharmaceutical comprising a compound wherein L ² is a single bond or a pharmacologically acceptable salt thereof as an active ingredient,
(31) The compound or pharmacologically acceptable salt thereof, wherein L ³ is a single bond, a double bond, or a C ₁ -C ₆ alkylene group in any one of (1) to (30) Containing medicines,
(32) The compound or a pharmacologically acceptable salt thereof according to any one of (1) to (30), wherein L ³ is a single bond, a double bond, —CH ₂ — or —CH ₂ CH ₂ —. A medicine containing as an active ingredient,
(33) The compound according to any one of (1) to (30), wherein L ³ is a single bond, —CH ₂ — or —CH ₂ CH ₂ — or a pharmacologically acceptable salt thereof as an active ingredient Medicine
(34) A medicament containing the compound or pharmacologically acceptable salt thereof as an active ingredient in any one of (1) to (30), wherein L ³ is —CH ₂ — or —CH ₂ CH ₂ —. Yes,
(35) A drug containing the compound or pharmacologically acceptable salt thereof, wherein L ³ is —CH ₂ — in any one of (1) to (30) as an active ingredient,
(36) In any one of (1) to (35), A is a carboxy group, a —SO ₃ H group, a —OSO ₃ H group, a —SO ₂ NH ₂ group, a —OPO ₃ H ₂ group, or an azetidinyl group. , A pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an azetidinyl group monosubstituted by a substituent (the substituent: a methyl group, an -OSO ₃ H group or an -OPO ₃ H ₂ group), and a monosubstituted by a substituent Piperidinyl group (substituent: methyl group, -OSO ₃ H group or -OPO ₃ H ₂ group), piperazinyl group monosubstituted with a substituent [substituent: methyl group, C monosubstituted with a substituent ₂ -C ₆ alkyl group (substituent: —SO ₃ H group, —OSO ₃ H group, —SO ₂ NH ₂ group, —OPO ₃ H ₂ group or —NMe ₂ group)] or —NMe ₂ group A pharmaceutical comprising a compound or a pharmacologically acceptable salt thereof as an active ingredient,
(37) In any one of (1) to (35), A is a carboxy group, —SO ₃ H group, —OSO ₃ H group, —OPO ₃ H ₂ group, 1-azetidinyl group, 1-pyrrolidinyl group Piperidino group (ie 1-piperidinyl group), morpholino group (ie 4-morpholinyl group), 1-methyl-3-azetidinyl group, 3- (sulfooxy) -1-azetidinyl group, 3- (phosphonooxy) -1-azetidinyl group Group, 1-methyl-4-piperidinyl group, 1-methyl-4-piperidinylidene group, 3- (sulfooxy) -1-piperidinyl group, 3- (phosphonooxy) -1-piperidinyl group, 4-methyl-1-piperazinyl group 4- (2-hydroxyethyl) -1-piperazinyl group, 4- [2- (sulfooxy) ethyl] -1-piperazinyl group, 4- [2- (phosphonooxy) ethyl] -1- A medicine containing Perajiniru a group or -NMe ₂ group compound or a pharmacologically acceptable salt thereof as an active ingredient,
(38) In any one of (1) to (35), A is a carboxy group, a —SO ₃ H group, a —OPO ₃ H ₂ group, a 4-methyl-1-piperazinyl group, or 4- (2-hydroxy). Ethyl) -1-piperazinyl group or a pharmacologically acceptable salt thereof as an active ingredient,
(39) The compound according to any one of (1) to (35), wherein A is a carboxy group, —SO ₃ H group or —OPO ₃ H ₂ group, or a pharmacologically acceptable salt thereof as an active ingredient Medicine
(40) In any one of (1) to (35), a pharmaceutical comprising a compound wherein A is a carboxy group or a pharmacologically acceptable salt thereof as an active ingredient,
(41) R ^a is the following formula

And Ar is a 2,4-difluorophenyl group, R ¹ is a hydrogen atom or a methyl group, L ¹ is a C ₂ -C ₆ alkylene group or —CH═CH—, G is —C (═O) —NH—, —C (═O) —N (CH ₃ ) —, a carbonyl group, or —C (═O) —O—, L ² is a single bond, L ³ is a single bond, —CH ₂ — or —CH ₂ CH ₂ —, and A is a carboxy group, —SO ₃ H group, —OSO ₃ H group, —OPO ₃ H ₂ group, 1-azetidinyl group, 1 -Pyrrolidinyl group, piperidino group, morpholino group, 1-methyl-3-azetidinyl group, 3- (sulfooxy) -1-azetidinyl group, 3- (phosphonooxy) -1-azetidinyl group, 1-methyl-4-piperidinyl group, 1-methyl-4-piperidinylidene group, 3- (sulfooxy) -1-piperidinyl group, 3- (phosphonooxy) -1-piperidinyl group, 4-methyl-1-piperazinyl group Group, 4- (2-hydroxyethyl) -1-piperazinyl group, 4- [2- (sulfooxy) ethyl] -1-piperazinyl group, 4- [2- (phosphonooxy) ethyl] -1-piperazinyl group or -NMe It is a medicament containing a compound that is _two groups or a pharmacologically acceptable salt thereof as an active ingredient,
(42) R ^a is the following formula

And Ar is a 2,4-difluorophenyl group, R ¹ is a hydrogen atom or a methyl group, L ¹ is a C ₂ -C ₆ alkylene group or —CH═CH—, G is —C (═O) —NH— or a carbonyl group, L ² is a single bond, L ³ is a single bond, —CH ₂ — or —CH ₂ CH ₂ —, and A is a carboxy group, -SO ₃ H group, -OSO ₃ H group, -OPO ₃ H ₂ group, 1-azetidinyl, 1-pyrrolidinyl group, piperidino group, morpholino group, 1-methyl-3-azetidinyl group, 3- (sulfooxy) - 1-azetidinyl group, 3- (phosphonooxy) -1-azetidinyl group, 1-methyl-4-piperidinyl group, 1-methyl-4-piperidinylidene group, 3- (sulfooxy) -1-piperidinyl group, 3- (phosphonooxy) -1-piperidinyl group, 4-methyl-1-piperazinyl group, 4- (2-hydroxy group) Ethyl) -1-piperazinyl group, 4- [2- (sulphooxy) ethyl] -1-piperazinyl group, 4- [2- (phosphonooxy) ethyl] -1-compound or a pharmacologically piperazinyl group or -NMe ₂ group A pharmaceutical comprising a top acceptable salt as an active ingredient,
(43) R ^a is the following formula

Ar is a 2,4-difluorophenyl group, R ¹ is a hydrogen atom or a methyl group, L ¹ is a C ₂ alkylene group or —CH═CH—, and G is — C (═O) —NH— or a carbonyl group, L ² is a single bond, L ³ is a single bond, —CH ₂ — or —CH ₂ CH ₂ —, A is a carboxy group, —SO ₃ H group, -OSO ₃ H group, -OPO ₃ H ₂ group, 1-azetidinyl group, 1-pyrrolidinyl group, piperidino group, morpholino group, 1-methyl-3-azetidinyl group, 3- (sulfooxy) -1-azetidinyl Group, 3- (phosphonooxy) -1-azetidinyl group, 1-methyl-4-piperidinyl group, 1-methyl-4-piperidinylidene group, 3- (sulfooxy) -1-piperidinyl group, 3- (phosphonooxy) -1- Piperidinyl group, 4-methyl-1-piperazinyl group, 4- (2-hydroxyethyl) Til) -1-piperazinyl group, 4- [2- (sulfooxy) ethyl] -1-piperazinyl group, 4- [2- (phosphonooxy) ethyl] -1-piperazinyl group or —NMe ₂ group or a pharmacology thereof A pharmaceutical comprising a top acceptable salt as an active ingredient,
(44) R ^a is the following formula

Ar is a 2,4-difluorophenyl group, R ¹ is a hydrogen atom or a methyl group, L ¹ is a C ₂ alkylene group, and G is —C (═O) —. NH— or a carbonyl group, L ² is a single bond, L ³ is a single bond, —CH ₂ — or —CH ₂ CH ₂ —, A is a carboxy group, —SO ₃ H group, —OSO ₃ H group, -OPO ₃ H ₂ group, 1-azetidinyl group, 1-pyrrolidinyl group, piperidino group, morpholino group, 1-methyl-3-azetidinyl group, 3- (sulfooxy) -1-azetidinyl group, 3- (phosphonooxy ) -1-azetidinyl group, 1-methyl-4-piperidinyl group, 1-methyl-4-piperidinylidene group, 3- (sulfooxy) -1-piperidinyl group, 3- (phosphonooxy) -1-piperidinyl group, 4-methyl -1-piperazinyl group, 4- (2-hydroxyethyl)- - piperazinyl, 4- [2- (sulphooxy) ethyl] -1-piperazinyl group, are allowed 4- [2- (phosphonooxy) ethyl] -1-piperazinyl group, or -NMe a ₂ group compound or a pharmacologically A medicine containing salt as an active ingredient,
(45) R ^a is the following formula

Ar is a 2,4-difluorophenyl group, R ¹ is a hydrogen atom or a methyl group, L ¹ is a C ₂ alkylene group, and G is —C (═O) —. NH— or a carbonyl group, L ² is a single bond, L ³ is —CH ₂ — or —CH ₂ CH ₂ —, and A is a carboxy group, —SO ₃ H group, —OPO ₃ H ₂ group , A pharmaceutical comprising a compound that is a 4-methyl-1-piperazinyl group or 4- (2-hydroxyethyl) -1-piperazinyl group or a pharmacologically acceptable salt thereof as an active ingredient,
(46) R ^a is the following formula

Ar is a 2,4-difluorophenyl group, R ¹ is a hydrogen atom or a methyl group, L ¹ is a C ₂ alkylene group, and G is —C (═O) —. Compound which is NH-, L ² is a single bond, L ³ is —CH ₂ — or —CH ₂ CH ₂ —, and A is a carboxy group, —SO ₃ H group or —OPO ₃ H ₂ group Or a medicament containing a pharmacologically acceptable salt thereof as an active ingredient,
(47) R ^a is the following formula

Ar is a 2,4-difluorophenyl group, R ¹ is a hydrogen atom or a methyl group, L ¹ is a C ₂ alkylene group, and G is —C (═O) —. NH-, L ² is a single bond, L ³ is -CH _2- , and A is a pharmacologically acceptable salt or a pharmacologically acceptable salt thereof as a pharmaceutical,
(48) 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 = hydrogen = Glutarate,
1- [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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] Ethoxy] -4-oxobutyryl] -4-piperidinecarboxylic 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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy ] -4-oxobutyryl] amino] acetic acid,
3-[[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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy ] Ethoxy] -4-oxobutyryl] amino] propionic acid,
[N- [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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy ] Ethoxy] -4-oxobutyryl] -N-methylamino] acetic 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-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl = hydrogen = glutarate,
1- [4-[[(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] carbonyloxymethoxy] -4 -Oxobutyryl] -4-piperidinecarboxylic acid,
[[4-[[(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] carbonyloxymethoxy] -4- Oxobutyryl] amino] acetic acid,
3-[[4-[[(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] carbonyloxymethoxy]- 4-oxobutyryl] amino] propionic acid,
[N- [4-[[(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] carbonyloxymethoxy]- 4-oxobutyryl] -N-methylamino] acetic acid,
5- [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] ethoxy]- 5-oxo-1-pentanesulfonic acid,
6- [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] ethoxy]- 6-oxo-1-hexanesulfonic acid,
5-[[(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] carbonyloxymethoxy] -5-oxo- 1-pentanesulfonic acid,
6-[[(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] carbonyloxymethoxy] -6-oxo- 1-hexanesulfonic 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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy ] -4-oxobutyryl] oxy] acetic acid,
[[4-[[(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] carbonyloxymethoxy] -4- Oxobutyryl] oxy] acetic acid or a pharmacologically acceptable salt thereof as an active ingredient,
(49) [[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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyl Oxy] ethoxy] -4-oxobutyryl] amino] acetic acid,
3-[[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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy ] Ethoxy] -4-oxobutyryl] amino] propionic acid,
[[4-[[(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] carbonyloxymethoxy] -4- Oxobutyryl] amino] acetic acid,
3-[[4-[[(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] carbonyloxymethoxy]- 4-oxobutyryl] amino] propionic acid or a pharmacologically acceptable salt thereof as an active ingredient,
(50) An antifungal agent comprising the triazole compound described in any one of (1) to (49) or a pharmacologically acceptable salt thereof as an active ingredient.

The “C ₁ -C ₆ alkyl group” in the above is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl. 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1- A linear or branched alkyl group having 1 to 6 carbon atoms such as dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, and preferably Is a linear or branched alkyl group having 1 to 4 carbon atoms, more preferably methyl.

The “C ₁ -C ₆ halogenated alkyl group” in the above is a group in which 1 to 5 halogen atoms which are the same or different from the “C ₁ -C ₆ alkyl group” are substituted, such as trifluoromethyl, trichloromethyl, and the like. , Difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3 -Chloropropyl, 4-fluorobutyl, 6-iodohexyl, 2,2-dibromoethyl are mentioned, and trifluoromethyl is preferred.

The “C ₆ -C ₁₀ aryl group” in the above is an aromatic hydrocarbon group having 6 to 10 carbon atoms such as phenyl, indenyl and naphthyl, and is preferably a phenyl group.

The “C ₇ -C ₁₄ aralkyl group” in the above is a group in which the “C ₁ -C ₆ alkyl group” is bonded to the “C ₆ -C ₁₀ aryl group”, and examples thereof include benzyl, α-naphthylmethyl, β-naphthylmethyl, indenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthyl Propyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, Benzyl is preferred.

“C ₃ -C ₇ cycloalkyl group” in L ¹ and L ² above, “C ₄ -C ₇ cycloalkyl group” in E ² , “C ₃ -C ₆ cycloalkyl group” in substituent group γ, and substitution The “cycloalkyl group” in the “C ₁ -C ₆ alkyl group substituted with a C ₃ -C ₆ cycloalkyl group” in the group γ is a saturated cyclic hydrocarbon group which may be condensed, and “C Examples of the “ _4- C ₆ cycloalkyl group” include cyclobutyl, cyclopentyl, and cyclohexyl groups, and “C ₄ -C ₇ cycloalkyl group” includes, in addition to these, cycloheptyl group, and “C ₃ — The “C ₇ cycloalkyl group” includes a cyclopropyl group in addition to these. Of the “C ₃ -C ₇ cycloalkyl group” in L ¹ and L ^2, preferred is a C ₄ -C ₆ cycloalkyl group, and more preferred is cyclohexyl.

The “C ₁ -C ₆ alkylene group” in the above is, for example, methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, pentamethylene, A straight-chain or branched alkylene group having 1 to 6 carbon atoms such as hexamethylene, and L ¹ is preferably a straight-chain or branched alkylene group having 2 to 6 carbon atoms; More preferably, it is a linear or branched alkylene group having 2 carbon atoms, and in L ³ , methylene or ethylene is preferred, and methylene is more preferred.

The “C ₁ -C ₈ alkylene group” in the above is, for example, methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, pentamethylene, A straight or branched alkylene group having 1 to 8 carbon atoms, such as hexamethylene, heptamethylene, octamethylene, and preferably a straight chain or branched alkylene group having 2 to 6 carbon atoms. More preferably, it is a straight chain or branched chain alkylene group having 2 carbon atoms, preferably methylene or ethylene, and more preferably methylene.

The “C ₂ -C ₆ alkenylene group” in the above is a linear or branched alkenylene group having 1 to 6 carbon atoms such as vinylene, propenylene, butenylene, hexenylene, and preferably 1 carbon atom. It is thru | or 4 linear or branched alkenylene group, More preferably, it is vinylene.

“C ₂ -C ₄ alkanoyl group” in the substituent group α, “N- (C ₂ -C ₇ alkanoyl) amino group” in the substituent group β, and “N- (C ₁ -C) in the substituent group β. The “alkanoyl group” in “ ₆ alkyl) -N— (C ₂ -C ₇ alkanoyl) amino group” is a linear or branched alkanoyl group, and “C ₂ -C ₄ alkanoyl group” includes, for example, acetyl, Examples thereof include propionyl, butyryl, isobutyryl and pivaloyl groups, and “C ₂ -C ₇ alkanoyl group” includes, in addition to these, valeryl, isovaleryl, hexanoyl and heptanoyl groups. The “C ₂ -C ₇ alkanoyl group” is preferably a linear or branched alkanoyl group having 2 to 4 carbon atoms, and more preferably an acetyl group. Of the “C ₂ -C ₄ alkanoyl group”, an acetyl group is preferred.

  The “halogen atom” in the above is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

  The “4- to 7-membered heterocyclic group” in the above is a 4- to 7-membered heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, for example, furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, Moieties such as imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, pyrrolinyl, imidazolinyl, pyrazolinyl Reduced heterocyclic groups and oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, perhydroazepinyl, piperazinyl, homo And a fully reduced group such as perazinyl, and preferably a 5- to 7-membered heterocyclic group containing at least one nitrogen atom and optionally containing an oxygen atom or a sulfur atom, such as pyrrolyl and azepinyl. , Pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and heterocyclic groups and azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl , Imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, perhydroazepinyl, piperazinyl, homopiperazinyl or a partially reduced group, and more preferably, azetidin Le, morpholinyl, piperidyl, piperazinyl.

  The “nitrogen-containing heterocyclic group” in the above includes at least one nitrogen atom among the “4- to 7-membered heterocyclic group”, and examples of such a group include pyrrolyl, azepinyl, pyrazolyl, imidazolyl, Aromatic heterocyclic groups such as oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, Partial or fully reduced groups such as imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl are preferred, preferably azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl A fully reduced form of groups such as Le, more preferably, 1-azetidinyl, 1-pyrrolidinyl, piperidino (i.e. 1-piperidinyl), morpholino (i.e. 4-morpholinyl).

In the above, “the nitrogen-containing heterocyclic group substituted one or two by the same or different substituents selected from the substituent group α and the substituent group β” is substituted with the substituent group α and the above-mentioned “nitrogen-containing heterocyclic group”. The same or different group selected from group β is a group substituted by 1 or 2 and is preferably azetidinyl monosubstituted by a substituent (the substituent: methyl group, —OSO ₃ H group or —OPO ₃ H ₂ group), piperidinyl monosubstituted with a substituent (substituent: methyl group, —OSO ₃ H group or —OPO ₃ H ₂ group), piperazinyl monosubstituted with a substituent [substituent: methyl Group, C ₂ -C ₆ alkyl group monosubstituted with a substituent (the substituent: —SO ₃ H group, —OSO ₃ H group, —SO ₂ NH ₂ group, —OPO ₃ H ₂ group or —NMe ₂ More preferably 1-methyl-3-azetidinyl, 3- (sulfooxy) -1-azetidinyl, 3- (phosphonooxy)- -Azetidinyl, 1-methyl-4-piperidinyl, 1-methyl-4-piperidinylidene, 3- (sulfooxy) -1-piperidinyl, 3- (phosphonooxy) -1-piperidinyl, 4-methyl-1-piperazinyl, 4- ( 2-hydroxyethyl) -1-piperazinyl, 4- [2- (sulfooxy) ethyl] -1-piperazinyl, 4- [2- (phosphonooxy) ethyl] -1-piperazinyl, and even more preferably 4- Methyl-1-piperazinyl or 4- (2-hydroxyethyl) -1-piperazinyl.

The “N— (C ₂ -C ₇ alkanoyl) amino group” in the above is a group in which one “C ₂ -C ₇ alkanoyl group” is substituted on the amino group, and preferably an acetylamino group.

"N- (C ₁ -C ₆ alkyl) -N- (C ₂ -C ₇ alkanoyl) amino group" described above to the nitrogen atom of the "N- (C ₂ -C ₇ alkanoyl) amino group", "C in the ₁ -C ₆ alkyl "is the one substituted group, preferably an acetyl methylamino group.

  The “monocyclic heteroaryl group” in the above is, for example, furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, A 5- to 7-membered aromatic heterocyclic group containing 1 to 4 sulfur atoms, oxygen atoms and / or nitrogen atoms such as pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, and preferably pyridyl.

  The “fused bicyclic heteroaryl group” in the above is a condensed bicyclic aromatic group having 1 to 3 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. For example, 9-membered polycyclic heteroaryl such as isobenzofuranyl, benzofuranyl, isobenzothiophenyl, benzothiophenyl, indolizinyl, isoindolyl, indolyl, benzoxazolyl, benzothiazolyl; and chromenyl, isoquinolyl, quinolyl, quinazolinyl, etc. 10-membered polycyclic heteroaryl, and quinolyl, benzothiophenyl or indolyl is preferable.

Selected from "is 1 or 2 substituted by identical or different substituents selected from Substituent group β C ₁ -C ₆ alkyl group", a group substituent to the "C ₁ -C ₆ alkyl group" β in the above Are the same or different substituents substituted by 1 or 2, preferably cyanomethyl, 2-cyanoethyl, 2- (acetylamino) ethyl, 2- (N-acetyl-N-methylamino) ethyl, It is carbamoylmethyl, 2-carbamoylethyl or 2- (carbamoyloxy) ethyl, and more preferably 2- (acetylamino) ethyl or carbamoylmethyl.

The “C ₆ -C ₁₀ aryl group having the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and a C ₁ -C ₆ halogenated alkyl group” in the above is the above “C ₆ -C ₁₀ aryl group ”is a group obtained by substituting 1 to 3 of the above“ halogen atom ”or“ C ₁ -C ₆ halogenated alkyl group ”, preferably a phenyl group, or a halogen atom and a trifluoromethyl group A phenyl group having 1 to 3 substituents selected from the group consisting of the same or different substituents, more preferably a 2,4-difluorophenyl group or a 2,5-difluorophenyl group, and even more preferable. Is a 2,4-difluorophenyl group.

  In the above “phenyl group substituted 1 to 5 with the same or different substituent selected from substituent group γ”, 1 to 5 identical or different substituents selected from substituent group γ are substituted on the phenyl group Preferably, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, (trifluoromethyl) phenyl, (trichloromethyl) phenyl, fluoro- (trifluoromethyl) phenyl, (difluoromethoxy) phenyl, (trifluoro Methoxy) phenyl, (2,2,2-trifluoroethoxy) phenyl, (1,1,2,2-tetrafluoroethoxy) phenyl, (2,2,3,3-tetrafluoropropoxy) phenyl, fluoro- ( 2,2,3,3-tetrafluoropropoxy) phenyl, nitrophenyl, full Rho-nitrophenyl, cyanophenyl, cyano-fluorophenyl, chloro-cyanophenyl, (methylthio) phenyl, (methylsulfinyl) phenyl, (methylsulfonyl) phenyl, (trifluoromethylthio) phenyl, (trifluoromethylsulfinyl) Phenyl or (trifluoromethylsulfonyl) phenyl, more preferably 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 4- (trifluoromethyl) phenyl, 4- ( Trichloromethyl) phenyl, 2-fluoro-4- (trifluoromethyl) phenyl, 4- (difluoromethoxy) phenyl, 3- (trifluoromethoxy) phenyl, 4- (trifluoromethoxy) phenyl, 4- (2,2 , 2-Triff Fluoroethoxy) phenyl, 4- (1,1,2,2-tetrafluoroethoxy) phenyl, 4- (2,2,3,3-tetrafluoropropoxy) phenyl, 2-fluoro-4- (2,2,3 , 3-tetrafluoropropoxy) phenyl, 4-nitrophenyl, 2-fluoro-4-nitrophenyl, 4-cyanophenyl, 4-cyano-2-fluorophenyl, 4-cyano-3-fluorophenyl, 2-chloro- 4-cyanophenyl, 4- (methylthio) phenyl, 4- (methylsulfinyl) phenyl, 4- (methylsulfonyl) phenyl, 4- (trifluoromethylthio) phenyl, 4- (trifluoromethylsulfinyl) phenyl, 4 -(Trifluoromethylsulfonyl) phenyl, still more preferably 4-chlorophenyl, 4- Ano-2-fluorophenyl, 4-cyano-3-fluorophenyl, 4- (trifluoromethylthio) phenyl, 4- (trifluoromethylsulfonyl) phenyl, 4- (trifluoromethyl) phenyl, 4- (trifluoromethoxy ) Phenyl, 4- (1,1,2,2-tetrafluoroethoxy) phenyl or 4- (2,2,3,3-tetrafluoropropoxy) phenyl group, particularly preferably 4-cyano-2 -Fluorophenyl.

  The above-mentioned “monocyclic heteroaryl group substituted 1 to 5 with the same or different substituent selected from substituent group γ” is selected from substituent group γ in the above “monocyclic heteroaryl group” 1 to 5 substituents having the same or different substituents, preferably 5-chloro-2-thienyl, 6-chloro-3-pyridyl or 6- (2,2,3,3-tetrafluoropropoxy ) -3-Pyridyl.

  In the above, “a naphthyl group having 1 to 5 substituents selected from the same or different substituents selected from substituent group γ” is substituted with 1 to 5 same or different substituents selected from substituent group γ in the naphthyl group Preferably 6-chloro-2-naphthyl, 6-bromo-2-naphthyl, 6-cyano-2-naphthyl, 6- (trifluoromethyl) -2-naphthyl, 6- (trifluoro Methoxy) -2-naphthyl, 6- (2,2,3,3-tetrafluoropropoxy) -2-naphthyl, 6-[(trifluoromethyl) thio] -2-naphthyl or 6-[(trifluoromethyl) Sulfonyl] -2-naphthyl, more preferably 6-bromo-2-naphthyl or 6- (2,2,3,3-tetrafluoropropoxy) -2-naphthyl.

  The above-mentioned “fused bicyclic heteroaryl group substituted 1 to 5 with the same or different substituent selected from substituent group γ” is selected from substituent group γ in the above “fused bicyclic heteroaryl group” The same or different substituents are substituted groups of 1 to 5, preferably 6-chloro-2-quinolyl, 6- (trifluoromethyl) -2-quinolyl, 6- (trifluoromethoxy)- 2-quinolyl, 6- (2,2,3,3-tetrafluoropropoxy) -2-quinolyl, 7- (trifluoromethyl) -3-isoquinolyl, 5- (trifluoromethyl) benzo [b] furan-2 -Yl, 2- (trifluoromethyl) benzo [b] furan-6-yl, 2-bromobenzo [b] thiophen-6-yl, 5- (trifluoromethyl) benzo [b] thiophen-2-yl, -(Trifluoromethyl) benzo [b] thiophen-6-yl, 5- (methylsulfonyl) benzo [b] thiophen-2-yl, 5- (2,2,3,3-tetrafluoropropoxy) benzo [b ] Thiophen-2-yl, 5-bromo-2-indolyl, 5- (trifluoromethyl) -2-indolyl, 3,5-dichloro-1-methyl-2-indolyl, 6- (trifluoromethyl) benzoxazole -2-yl, 6- (trifluoromethyl) benzothiazol-2-yl, 6- (2,2,3,3-tetrafluoropropoxy) benzothiazol-2-yl, 6- (trifluoromethyl) -1H -Benzimidazol-2-yl or 5-bromo-1H-benzimidazol-2-yl, more preferably 6- (2,2,3,3-tetra Fluoropropoxy) -2-quinolyl, 5- (2,2,3,3-tetrafluoropropoxy) benzo [b] thiophen-2-yl, 3,5-dichloro-1-methyl-2-indolyl or 6- ( 2,2,3,3-tetrafluoropropoxy) benzothiazol-2-yl.

  The “heterocyclyl” in the above is a 4- to 7-membered aliphatic heterocyclic group having at least one nitrogen, oxygen, or sulfur atom, and preferably azetidine, piperidine, 1,3-dioxane, 1,4,5, 6-tetrahydropyrimidine, tetrahydrooxazine or 1,3-dithiane ring, more preferably azetidine, piperidine, 1,3-dioxane, 1,4,5,6-tetrahydropyrimidine, tetrahydrooxazine or 1,3- It is a dithiane ring, still more preferably piperidine or 1,3-dioxane, and particularly preferably 1,3-dioxane.

  In the above, “a phenylene group which is substituted 1 or 2 by the same or different substituent selected from the substituent group consisting of (a fluorine atom and a chlorine atom)” is a substituent consisting of (a fluorine atom and a chlorine atom) on the phenylene group A group substituted with one or two substituents selected from the group, preferably 2-fluoro-1,4-phenylene, 3-fluoro-1,4-phenylene, 2-chloro-1 , 4-phenylene, 3-chloro-1,4-phenylene, 2,6-difluoro-1,4-phenylene or 2,6-dichloro-1,4-phenylene.

  In the above “2,6-difluoro-1,4-phenylene”, the formula (Gb) is represented by the following formula:

It is.

  In the above, “naphthylene group substituted 1 or 2 by the same or different substituents selected from the substituent group consisting of (fluorine atom and chlorine atom)” is a substituent group consisting of (fluorine atom and chlorine atom) on the naphthylene group It is a group substituted by 1 or 2 identical or different substituents selected from the group, and is preferably 1-fluoro-2,6-naphthylene.

  In the above “1-fluoro-2,6-naphthylene”, the formula (Gb) is represented by the following formula:

It is.

In G, L ² and L ³ above, “-single bond-single bond-” and “-single bond-single bond-single bond-” in which two or more “single bonds” are continued represent one single bond.

In the above G, L ² and L ³ , “-double bond-double bond-” and “-double bond-double bond-double bond-” followed by two or more “double bonds” are 1 Represents one double bond.

In the above G, L ² and L ³ , “single bond” and “double bond” are not continued.

The “organic residue” in R ^a is a group containing carbon, and includes the following formula (II) containing R ^a

If the compound represented by these is a compound which has antifungal activity, there will be no limitation in particular.

In the above formula (I), preferred R ^a is

It is.

  In the above formula (I), preferred Ar is a 2,4-difluorophenyl group or a 2,5-difluorophenyl group, and more preferred Ar is a 2,4-difluorophenyl group.

In the above formula (I), preferred R ¹ is a hydrogen atom or a methyl group, and more preferred R ¹ is a methyl group.

In the above formula (I), preferred L ¹ is a C ₁ -C ₆ alkylene group or C ₂ -C ₆ alkenylene group, and more preferred L ¹ is a C ₂ -C ₆ alkylene group or —CH═CH—. And even more preferred L ¹ is a C ₂ alkylene group or —CH═CH—, and the most preferred L ¹ is a C ₂ alkylene group.

In the above formula (I), preferable G is a single bond, —O—, —NH—C (═O) —, —C (═O) —NH—, —C (═O) —N (CH ₃ ). -, A carbonyl group, or -C (= O) -O-, and more preferably G is -C (= O) -NH-, -C (= O) -N (CH ₃ )-, a carbonyl group, Or -C (= O) -O, and even more preferred G is -C (= O) -NH-, a carbonyl group, and the most preferred G is -C (= O) -NH-.

In the above formula (I), preferable L ² is a single bond, a double bond, or a 4- to 7-membered heterocyclic group, and more preferable L ² is a single bond.

In the above formula (I), preferable L ³ is a single bond, a double bond, or a C ₁ -C ₆ alkylene group, and more preferable L ³ is a single bond, a double bond, —CH ₂ — or —CH. ₂ CH ₂ —, even more preferred L ³ is a single bond, —CH ₂ — or —CH ₂ CH ₂ —, and particularly preferred L ³ is —CH ₂ — or —CH ₂ CH ₂ —. The most preferred L ³ is —CH ₂ —.

In the above formula (I), preferable A is carboxy group, —SO ₃ H group, —OSO ₃ H group, —SO ₂ NH ₂ group, —OPO ₃ H ₂ group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl Group, morpholinyl group, azetidinyl group monosubstituted with a substituent (substituent: methyl group, -OSO ₃ H group or -OPO ₃ H ₂ group), piperidinyl group monosubstituted with a substituent (substituent: Methyl group, -OSO ₃ H group or -OPO ₃ H ₂ group), piperazinyl group monosubstituted with a substituent [substituent: methyl group, C ₂ -C ₆ alkyl group monosubstituted with a substituent (this group Substituent: —SO ₃ H group, —OSO ₃ H group, —SO ₂ NH ₂ group, —OPO ₃ H ₂ group or —NMe ₂ group)] or —NMe ₂ group, and more preferable A is a carboxy group , -SO ₃ H group, -OSO ₃ H group, -OPO ₃ H ₂ group, 1-azetidinyl group, 1-pyrrolidinyl group, piperidino group, morpholino group, 1-methyl-3-azetidinyl group, 3- (sulfur Hooxy) -1-azetidinyl group, 3- (phosphonooxy) -1-azetidinyl group, 1-methyl-4-piperidinyl group, 1-methyl-4-piperidinylidene group, 3- (sulfooxy) -1-piperidinyl group, 3- (Phosphonooxy) -1-piperidinyl group, 4-methyl-1-piperazinyl group, 4- (2-hydroxyethyl) -1-piperazinyl group, 4- [2- (sulfooxy) ethyl] -1-piperazinyl group, 4- [2- (phosphonooxy) ethyl] -1-piperazinyl group or —NMe ₂ group, and more preferable A is a carboxy group, —SO ₃ H group, —OPO ₃ H ₂ group, 4-methyl-1-piperazinyl group. a group or 4- (2-hydroxyethyl) -1-piperazinyl group, particularly preferred a is a carboxy group, a -SO ₃ H group or a -OPO ₃ H ₂ group, most preferred a is a carboxy group der .

  “Antifungal activity” means that a therapeutic effect can be expected for fungal infections (mycosis) such as deep mycosis, deep cutaneous mycosis, superficial mycosis, etc. Those skilled in the art can easily discriminate whether or not it has such an effect, for example, according to the following method.

  The applied method is a measurement method (M27-A, M38-P) standardized by the US National Committee for Clinical Laboratory Standards (NCCLS) or the literature (Journal of Clinical Microbiology, Vol. 38, p. 341-344 (2000). )) Measure the MIC (minimum growth inhibitory concentration) for the genus Candida, Aspergillus genus, Cryptococcus neoformans or Trichophyton genus, which is a representative mycosis, according to the measurement method described above, and the concentration is a fixed value set in advance. If it is (preferably 64 μg / mL) or less, a method for determining that it has antifungal activity can be mentioned.

The “pharmacologically acceptable salt” in the compound according to the present invention means an acidic group such as a carboxy group, a —P (═O) (OH) ₂ group and a —SO ₃ H group in the general formula (I), In addition, they are salts generally used in pharmaceutical compounds for basic groups such as triazole group, amino group and piperidyl group.

  Such salts for the acidic groups in general formula (I) include, for example, alkali metal salts such as sodium, potassium and lithium salts; alkaline earth metal salts such as calcium and magnesium salts; aluminum salts, Metal salts such as iron salt, zinc salt, copper salt, nickel salt, cobalt salt; inorganic salt such as ammonium salt; t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, Ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-N-phenethylamine Salt, piperazine salt, tetramethylammonium salt, tris ( Dorokishimechiru) organic amine salts such as aminomethane salts.

  Such salts for basic groups include, for example, hydrohalides such as hydrofluorates, hydrochlorides, hydrobromides, hydroiodides; nitrates, perchlorates, Inorganic acid salts such as sulfate and phosphate; salts of lower alkane sulfonic acids such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; benzene sulfonate and p-toluene sulfonate Aryl sulfonates such as: amino acid salts such as lunitinate, glutamate; and carboxylates such as fumarate, succinate, citrate, tartrate, oxalate, maleate be able to.

  In addition, the compound according to the present invention may be left in the air or recrystallized to absorb moisture and have adsorbed water or become a hydrate. The triazole compound and the pharmacologically acceptable salt according to the present invention each include such a hydrate.

  Furthermore, the compounds according to the present invention may absorb certain other solvents and become solvates. The triazole compound and the pharmacologically acceptable salt according to the present invention each include such a solvate.

The compound of the present invention includes various isomers. For example, since an asymmetric carbon exists in the general formula (I), various stereoisomers based on this exist. In addition, since ^Ra in the general formula (I) may also have an asymmetric carbon or a carbon-carbon double bond, the compound according to the present invention has various stereoisomers. Each of these, or any mixture thereof, is included in the present invention. For such stereoisomers, stereospecific raw material compounds are used, or the compounds according to the present invention are synthesized using asymmetric synthesis or asymmetric induction techniques, or the synthesized compounds according to the present invention are synthesized. If desired, it can be obtained by isolation using a conventional optical resolution method or separation method.

Examples of the compound according to the present invention include the compounds shown in Tables 1 to 9 listed below, but the present invention is not limited to these groups.
In Tables 1 to 9 below, the meanings of the abbreviations are as follows. That is,
Ac represents an acetyl group,
1-Azt represents a 1-azetidinyl group,
3-Azt represents a 3-azetidinyl group,
1,3-Azt represents a 1,3-azetidinediyl group,

3,1-Azt represents a 3,1-azetidinediyl group,

tBu represents a t-butyl group,
Car represents a carbamoyl group,
Hx represents a hexyl group,
cHx represents a cyclohexyl group,
1,4-cHx represents a 1,4-cyclohexylene group,
Et represents an ethyl group,
Me represents a methyl group,
4-Mor represents a 4-morpholinyl group (ie, morpholino group)
Ph represents a phenyl group,
1-Pip represents a 1-piperidyl group (ie, piperidino group),
4-Pip represents a 4-piperidyl group,
1,4-Pip represents a 1,4-piperidinediyl group,

4,1-Pip represents a 4,1-piperidinediyl group,

4,4-Pip represents a 4-piperidinylidene group,

1-Pyrd represents a 1-pyrrolidinyl group,
1-Piz represents a 1-piperazinyl group,
1,4-Piz represents a 1,4-piperazinediyl group,
Pr represents a propyl group,
iPr represents an isopropyl group.
-Represents a single bond, and "-single bond-single bond-" and "-single bond-single bond-single bond-" in which two or more single bonds continued represent one single bond.
= Represents a double bond, and “-double bond-double bond-double bond-” followed by three double bonds represents one double bond.
Single and double bonds do not continue.
(Table 1)

-------------------------------------------------- -----------------
Example R¹   -L¹--G- -L²--L^Three--A
Compound
number
-------------------------------------------------- -----------------
1-1 Me -CH₂-----COOH
1-2 Me -CH₂-----SO_ThreeH
1-3 Me -CH₂-----OSO_ThreeH
1-4 Me -CH₂-----OPO_ThreeH₂
1-5 Me -CH₂----1-Azt
1-6 Me -CH₂----1-Pyrd
1-7 Me -CH₂----1-Pip
1-8 Me -CH₂----4-Pip
1-9 Me -CH₂----1-Me-4-Pip
1-10 Me -CH₂----1- (CH₂CH₂OH) -4-Pip
1-11 Me -CH₂----1-Piz
1-12 Me -CH₂----4-Me-1-Piz
1-13 Me -CH₂----4- (CH₂CH₂OH) -1-Piz
1-14 Me -CH₂----4- (CH₂CH₂NHAc) -1-Piz
1-15 Me -CH₂----4-Mor
1-16 Me -CH₂-----NH₂
1-17 Me -CH₂-----NHMe
1-18 Me -CH₂-----NMe₂
1-19 Me -CH₂--1,4-cHx--NMe₂
1-20 Me -CH₂CH₂-----COOH
1-21 Me -CH₂CH₂-----SO_ThreeH
1-22 Me -CH₂CH₂-----OSO_ThreeH
1-23 Me -CH₂CH₂-----SO₂NH₂
1-24 Me -CH₂CH₂-----OPO_ThreeH₂
1-25 Me -CH₂CH₂----1-Azt
1-26 Me -CH₂CH₂----1-Pyrd
1-27 Me -CH₂CH₂----1-Pip
1-28 Me -CH₂CH₂----4-Pip
1-29 Me -CH₂CH₂----1-Me-4-Pip
1-30 Me -CH₂CH₂----1- (CH₂CH₂OH) -4-Pip
1-31 Me -CH₂CH₂----1-Piz
1-32 Me -CH₂CH₂----4-Me-1-Piz
1-33 Me -CH₂CH₂----4- (CH₂CH₂OH) -1-Piz
1-34 Me -CH₂CH₂----4-Mor
1-35 Me -CH₂CH₂-----NH₂
1-36 Me -CH₂CH₂-----NHMe
1-37 Me -CH₂CH₂-----NMe₂
1-38 Me -CH₂CH₂--1,4-cHx--NMe₂
1-39 Me-(CH₂)_Three-----COOH
1-40 Me-(CH₂)_Three-----SO_ThreeH
1-41 Me-(CH₂)_Three-----OSO_ThreeH
1-42 Me-(CH₂)_Three-----SO₂NH₂
1-43 Me-(CH₂)_Three-----OPO_ThreeH₂
1-44 Me-(CH₂)_Three----1-Azt
1-45 Me-(CH₂)_Three----1-Pyrd
1-46 Me-(CH₂)_Three----1-Pip
1-47 Me-(CH₂)_Three----1-Me-4-Pip
1-48 Me-(CH₂)_Three----1- (CH₂CH₂OH) -4-Pip
1-49 Me-(CH₂)_Three----1-Piz
1-50 Me-(CH₂)_Three----4-Me-1-Piz
1-51 Me-(CH₂)_Three----4- (CH₂CH₂OH) -1-Piz
1-52 Me-(CH₂)_Three----4-Mor
1-53 Me-(CH₂)_Three-----NMe₂
1-54 Me-(CH₂)_Three--1,4-cHx--NMe₂
1-55 Me-(CH₂)_Four----4-Me-1-Piz
1-56 Me-(CH₂)_Four----4- (CH₂CH₂OH) -1-Piz
1-57 Me-(CH₂)_Four----4-Mor
1-58 Me-(CH₂)_Four-----NMe₂
1-59 Me -CH₂CH₂--C (= O)---1-Azt
1-60 Me -CH₂CH₂--C (= O)---3- (OH) -1-Azt
1-61 Me -CH₂CH₂--C (= O)---3- (OCar) -1-Azt
1-62 Me -CH₂CH₂--C (= O)---1-Pyrd
1-63 Me -CH₂CH₂--C (= O)---1-Pip
1-64 Me -CH₂CH₂--C (= O)---4- (OH) -1-Pip
1-65 Me -CH₂CH₂--C (= O)---4-Car-1-Pip
1-66 Me -CH₂CH₂--C (= O)---4- (OCar) -1-Pip
1-67 Me -CH₂CH₂--C (= O)---1-Piz
1-68 Me -CH₂CH₂--C (= O)---4- [C (= NH) NH₂] -1-Piz
1-69 Me -CH₂CH₂--C (= O)---4- [C (= NH) CH_Three] -1-Piz
1-70 Me -CH₂CH₂--C (= O)---4-Me-1-Piz
1-71 Me -CH₂CH₂--C (= O)---2,6-diMe-1-Piz
1-72 Me -CH₂CH₂--C (= O)---3,5-diMe-1-Piz
1-73 Me -CH₂CH₂--C (= O)---4- (CH₂CH₂OH) -1-Piz
1-74 Me -CH₂CH₂--C (= O)---4- (CH₂CH₂NHAc) -1-Piz
1-75 Me -CH₂CH₂--C (= O)---4- (CH₂CH₂NMeAc) -1-Piz
1-76 Me -CH₂CH₂--C (= O)---2,4,6-triMe-1-Piz
1-77 Me -CH₂CH₂--C (= O)---3,4,5-triMe-1-Piz
1-78 Me -CH₂CH₂--C (= O)---4- (CH₂CH₂OH) -2,6-diMe-1-Piz
1-79 Me -CH₂CH₂--C (= O)---4- (CH₂CH₂OH) -3,5-diMe-1-Piz
1-80 Me -CH₂CH₂--C (= O)---4- (CH₂CN) -1-Piz
1-81 Me -CH₂CH₂--C (= O)---4- (CH₂CH₂CN) -1-Piz
1-82 Me -CH₂CH₂--C (= O)---4- (CH₂Car) -1-Piz
1-83 Me -CH₂CH₂--C (= O)---4- (CH₂CH₂OCar) -1-Piz
1-84 Me -CH₂CH₂--C (= O)---4- (CH₂CH₂F) -1-Piz
1-85 Me -CH₂CH₂--C (= O)---4-Car-1-Piz
1-86 Me -CH₂CH₂--C (= O)---4-Mor
1-87 Me -CH₂CH₂--C (= O)-1,4-cHx--NMe₂
1-88 Me -CH₂CH₂--C (= O)-1,3-Azt--COOH
1-89 Me -CH₂CH₂--C (= O)-1,3-Azt--OSO_ThreeH
1-90 Me -CH₂CH₂--C (= O)-1,3-Azt--OPO_ThreeH₂
1-91 Me -CH₂CH₂--C (= O)-1,3-Azt-1-Azt
1-92 Me -CH₂CH₂--C (= O)-1,3-Azt-1-Pyrd
1-93 Me -CH₂CH₂--C (= O)-1,3-Azt-1-Piz
1-94 Me -CH₂CH₂--C (= O)-1,3-Azt-1-Pip
1-95 Me -CH₂CH₂--C (= O)-1,3-Azt-4-Me-1-Piz
1-96 Me -CH₂CH₂--C (= O)-1,3-Azt-4- (CH₂CH₂OH) -1-Piz
1-97 Me -CH₂CH₂--C (= O)-1,3-Azt-4-Mor
1-98 Me -CH₂CH₂--C (= O)-1,3-Azt--NHMe
1-99 Me -CH₂CH₂--C (= O)-1,3-Azt--NMe₂
1-100 Me -CH₂CH₂--C (= O)-1,3-Azt--NMeCH₂CH₂OH
1-101 Me -CH₂CH₂--C (= O)-1,3-Azt--NMeCH₂CH₂CN
1-102 Me -CH₂CH₂--C (= O)-1,3-Azt--NMeCH₂Car
1-103 Me -CH₂CH₂--C (= O)-1,3-Azt--NMeCH₂CH₂Car
1-104 Me -CH₂CH₂--C (= O)-1,3-Azt--NMeCH₂CH₂OCar
1-105 Me -CH₂CH₂--C (= O)-1,3-Azt--N (CH₂CH₂OH)₂
1-106 Me -CH₂CH₂--C (= O)-1,4-Pip--COOH
1-107 Me -CH₂CH₂--C (= O)-1,4-Pip--SO_ThreeH
1-108 Me -CH₂CH₂--C (= O)-1,4-Pip--OSO_ThreeH
1-109 Me -CH₂CH₂--C (= O)-1,4-Pip--OPO_ThreeH₂
1-110 Me -CH₂CH₂--C (= O)-1,4-Pip-1-Azt
1-111 Me -CH₂CH₂--C (= O)-1,4-Pip-1-Pyrd
1-112 Me -CH₂CH₂--C (= O)-1,4-Pip-1-Pip
1-113 Me -CH₂CH₂--C (= O)-1,4-Pip-1-Piz
1-114 Me -CH₂CH₂--C (= O)-1,4-Pip-4-Me-1-Piz
1-115 Me -CH₂CH₂--C (= O)-1,4-Pip-4- (CH₂CH₂OH) -1-Piz
1-116 Me -CH₂CH₂--C (= O)-1,4-Pip-4-Mor
1-117 Me -CH₂CH₂--C (= O)-1,4-Pip--NHMe
1-118 Me -CH₂CH₂--C (= O)-1,4-Pip--NMe₂
1-119 Me -CH₂CH₂--C (= O)-1,4-Pip--NMeCH₂CH₂OH
1-120 Me -CH₂CH₂--C (= O)-1,4-Pip--NMeCH₂CH₂CN
1-121 Me -CH₂CH₂--C (= O)-1,4-Pip--NMeCH₂Car
1-122 Me -CH₂CH₂--C (= O)-1,4-Pip--NMeCH₂CH₂Car
1-123 Me -CH₂CH₂--C (= O)-1,4-Pip--NMeCH₂CH₂OCar
1-124 Me -CH₂CH₂--C (= O)-1,4-Pip--N (CH₂CH₂OH)₂
1-125 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--COOH
1-126 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--SO_ThreeH
1-127 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--OSO_ThreeH
1-128 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--OPO_ThreeH₂
1-129 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂-1-Azt
1-130 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂-1-Pyrd
1-131 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂-1-Pip
1-132 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂-1-Piz
1-133 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂-4-Me-1-Piz
1-134 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂-4- (CH₂CH₂OH) -1-Piz
1-135 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂-4-Mor
1-136 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NH₂
1-137 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NHMe
1-138 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NMe₂
1-139 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NMeCH₂CH₂OH
1-140 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--N (CH₂CH₂OH)₂
1-141 Me -CH₂CH₂--C (= O)-1,4-Piz--SO₂NH₂
1-142 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-1-Azt
1-143 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-1-Pyrd
1-144 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-1-Pip
1-145 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-4-Me-1-Piz
1-146 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-147 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-4-Mor
1-148 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--NHCH₂CH₂OH
1-149 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--NHMe
1-150 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--NMe₂
1-151 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--NMeCH₂CH₂OH
1-152 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--N (CH₂CH₂OH)₂
1-153 Me -CH = CH- -C (= O)---1-Piz
1-154 Me -CH = CH- -C (= O)---4- (C (= NH) NH₂) -1-Piz
1-155 Me -CH = CH- -C (= O)---4- (C (= NH) CH_Three) -1-Piz
1-156 Me -CH = CH- -C (= O)---4-Me-1-Piz
1-157 Me -CH = CH- -C (= O)---2,6-diMe-1-Piz
1-158 Me -CH = CH- -C (= O)---3,5-diMe-1-Piz
1-159 Me -CH = CH- -C (= O)---4- (CH₂CH₂OH) -1-Piz
1-160 Me -CH = CH- -C (= O)---4- (CH₂CH₂CN) -1-Piz
1-161 Me -CH = CH- -C (= O)---4- (CH₂Car) -1-Piz
1-162 Me -CH = CH- -C (= O)---4- (CH₂CH₂OCar) -1-Piz
1-163 Me -CH = CH- -C (= O)---4- (CH₂CH₂F) -1-Piz
1-164 Me -CH = CH- -C (= O)---4-Mor
1-165 Me -CH = CH- -C (= O)-1,3-Azt--COOH
1-166 Me -CH = CH- -C (= O)-1,3-Azt--SO_ThreeH
1-167 Me -CH = CH- -C (= O)-1,3-Azt--OSO_ThreeH
1-168 Me -CH = CH- -C (= O)-1,3-Azt--OPO_ThreeH₂
1-169 Me -CH = CH- -C (= O)-1,3-Azt-1-Azt
1-170 Me -CH = CH- -C (= O)-1,3-Azt-1-Pyrd
1-171 Me -CH = CH- -C (= O)-1,3-Azt-1-Pip
1-172 Me -CH = CH- -C (= O)-1,3-Azt-1-Piz
1-173 Me -CH = CH- -C (= O)-1,3-Azt-4-Me-1-Piz
1-174 Me -CH = CH- -C (= O)-1,3-Azt-4- (CH₂CH₂OH) -1-Piz
1-175 Me -CH = CH- -C (= O)-1,3-Azt-4-Mor
1-176 Me -CH = CH- -C (= O)-1,3-Azt--NHMe
1-177 Me -CH = CH- -C (= O)-1,3-Azt--NMe₂
1-178 Me -CH = CH- -C (= O)-1,3-Azt--NMeCH₂CH₂OH
1-179 Me -CH = CH- -C (= O)-1,3-Azt--NMeCH₂CH₂CN
1-180 Me -CH = CH- -C (= O)-1,3-Azt--NMeCH₂Car
1-181 Me -CH = CH- -C (= O)-1,3-Azt--NMeCH₂CH₂Car
1-182 Me -CH = CH- -C (= O)-1,3-Azt--NMeCH₂CH₂OCar
1-183 Me -CH = CH- -C (= O)-1,3-Azt--N (CH₂CH₂OH)₂
1-184 Me -CH = CH- -C (= O)-1,4-Pip--COOH
1-185 Me -CH = CH- -C (= O)-1,4-Pip--SO_ThreeH
1-186 Me -CH = CH- -C (= O)-1,4-Pip--OSO_ThreeH
1-187 Me -CH = CH- -C (= O)-1,4-Pip--OPO_ThreeH₂
1-188 Me -CH = CH- -C (= O)-1,4-Pip-1-Azt
1-189 Me -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
1-190 Me -CH = CH- -C (= O)-1,4-Pip-1-Pip
1-191 Me -CH = CH- -C (= O)-1,4-Pip-1-Piz
1-192 Me -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
1-193 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH₂CH₂OH) -1-Piz
1-194 Me -CH = CH- -C (= O)-1,4-Pip-4-Mor
1-195 Me -CH = CH- -C (= O)-1,4-Pip--NHMe
1-196 Me -CH = CH- -C (= O)-1,4-Pip--NMe₂
1-197 Me -CH = CH- -C (= O)-1,4-Pip--NMeCH₂CH₂OH
1-198 Me -CH = CH- -C (= O)-1,4-Pip--NMeCH₂CH₂CN
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--NMeCH₂CH₂OCar
1-202 Me -CH = CH- -C (= O)-1,4-Pip--N (CH₂CH₂OH)₂
1-203 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--COOH
1-204 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--OSO_ThreeH
1-205 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--OPO_ThreeH₂
1-206 Me -CH = CH- -C (= O)-1,4-Pip -CH₂-1-Azt
1-207 Me -CH = CH- -C (= O)-1,4-Pip -CH₂-1-Pyrd
1-208 Me -CH = CH- -C (= O)-1,4-Pip -CH₂-1-Pip
1-209 Me -CH = CH- -C (= O)-1,4-Pip -CH₂-4-Me-1-Piz
1-210 Me -CH = CH- -C (= O)-1,4-Pip -CH₂-4- (CH₂CH₂OH) -1-Piz
1-211 Me -CH = CH- -C (= O)-1,4-Pip -CH₂-4-Mor
1-212 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--NH₂
1-213 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--NHMe
1-214 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--NMe₂
1-215 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--NMeCH₂CH₂OH
1-216 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--N (CH₂CH₂OH)₂
1-217 Me -CH₂CH₂--C (= O)-1,4-Piz--SO₂NH₂
1-218 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-1-Azt
1-219 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-1-Pyrd
1-220 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-1-Pip
1-221 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-1-Piz
1-222 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-4-Me-1-Piz
1-223 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-224 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-4-Mor
1-225 Me -CH = CH- -C (= O)---4- (CH₂CH₂NHAc) -1-Piz
1-226 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--NHMe
1-227 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--NMe₂
1-228 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--NMeCH₂CH₂OH
1-229 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--N (CH₂CH₂OH)₂
1-230 Me -CH₂--O---1-Me-3-Azt
1-231 Me -CH₂--O---1- (CH₂CH₂OH) -3-Azt
1-232 Me -CH₂--O---1- (CH₂CH₂NHAc) -3-Azt
1-233 Me -CH₂--O---4-Pip
1-234 Me -CH₂--O---1-Me-4-Pip
1-235 Me -CH₂--O---1- (CH₂CH₂OH) -4-Pip
1-236 Me -CH₂--O---1- (CH₂CH₂NHAc) -4-Pip
1-237 Me -CH₂--O---CH₂--COOH
1-238 Me -CH₂--O---CH₂CH₂--COOH
1-239 Me -CH₂--O---CH₂CH₂--SO_ThreeH
1-240 Me -CH₂--O---CH₂CH₂--OSO_ThreeH
1-241 Me -CH₂--O---CH₂CH₂--SO₂NH₂
1-242 Me -CH₂--O---CH₂CH₂--OPO_ThreeH₂
1-243 Me -CH₂--O---CH₂CH₂-1-Azt
1-244 Me -CH₂--O---CH₂CH₂-1-Pyrd
1-245 Me -CH₂--O---CH₂CH₂-1-Pip
1-246 Me -CH₂--O---CH₂CH₂-1-Piz
1-247 Me -CH₂--O---CH₂CH₂-4-Me-1-Piz
1-248 Me -CH₂--O---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-249 Me -CH₂--O---CH₂CH₂-4-Mor
1-250 Me -CH₂--O---CH₂CH₂--NMe₂
1-251 Me -CH₂--O---CH₂CH₂--NMeCH₂CH₂OH
1-252 Me -CH₂--O---CH₂CH₂--N (CH₂CH₂OH)₂
1-253 Me -CH₂--O- 1,4-cHx--NMe₂
1-254 Me -CH₂--O- 1,4-cHx--NMeCH₂CH₂OH
1-255 Me -CH₂--O- 1,4-cHx--N (CH₂CH₂OH)₂
1-256 Me -CH₂--O- 3,1-Azt--SO₂NH₂
1-257 Me -CH₂--O- 3,1-Azt-3-Azt
1-258 Me -CH₂--O- 3,1-Azt-1-Me-3-Azt
1-259 Me -CH₂--O- 3,1-Azt-1- (CH₂CH₂OH) -3-Azt
1-260 Me -CH₂--O- 3,1-Azt-4-Pip
1-261 Me -CH₂--O- 3,1-Azt-1-Me-4-Pip
1-262 Me -CH₂--O- 3,1-Azt-1- (CH₂CH₂OH) -4-Pip
1-263 Me -CH₂--O- 3,1-Azt -CH₂CH₂-1-Azt
1-264 Me -CH₂--O- 3,1-Azt -CH₂CH₂-1-Pyrd
1-265 Me -CH₂--O- 3,1-Azt -CH₂CH₂-1-Pip
1-266 Me -CH₂--O- 3,1-Azt -CH₂CH₂-1-Piz
1-267 Me -CH₂--O- 3,1-Azt -CH₂CH₂-4-Me-1-Piz
1-268 Me -CH₂--O- 3,1-Azt -CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-269 Me -CH₂--O- 3,1-Azt -CH₂CH₂-4-Mor
1-270 Me -CH₂--O- 3,1-Azt -CH₂CH₂--NHMe
1-271 Me -CH₂--O- 3,1-Azt -CH₂CH₂--NMe₂
1-272 Me -CH₂--O- 3,1-Azt -CH₂CH₂--NMeCH₂CH₂OH
1-273 Me -CH₂--O- 3,1-Azt -CH₂CH₂--N (CH₂CH₂OH)₂
1-274 Me -CH₂--O- 4,1-Pip--SO₂NH₂
1-275 Me -CH₂--O- 4,1-Pip-3-Azt
1-276 Me -CH₂--O- 4,1-Pip-1-Me-3-Azt
1-277 Me -CH₂--O- 4,1-Pip-1- (CH₂CH₂OH) -3-Azt
1-278 Me -CH₂--O- 4,1-Pip-4-Pip
1-279 Me -CH₂--O- 4,1-Pip-1-Me-4-Pip
1-280 Me -CH₂--O- 4,1-Pip-1- (CH₂CH₂OH) -4-Pip
1-281 Me -CH₂--O- 4,1-Pip -CH₂CH₂-1-Azt
1-282 Me -CH₂--O- 4,1-Pip -CH₂CH₂-1-Pyrd
1-283 Me -CH₂--O- 4,1-Pip -CH₂CH₂-1-Pip
1-284 Me -CH₂--O- 4,1-Pip -CH₂CH₂-1-Piz
1-285 Me -CH₂--O- 4,1-Pip -CH₂CH₂-4-Me-1-Piz
1-286 Me -CH₂--O- 4,1-Pip -CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-287 Me -CH₂--O- 4,1-Pip -CH₂CH₂-4-Mor
1-288 Me -CH₂--O- 4,1-Pip -CH₂CH₂--NHMe
1-289 Me -CH₂--O- 4,1-Pip -CH₂CH₂--NMe₂
1-290 Me -CH₂--O- 4,1-Pip -CH₂CH₂--NMeCH₂CH₂OH
1-291 Me -CH₂--O- 4,1-Pip -CH₂CH₂--N (CH₂CH₂OH)₂
1-292 Me -CH₂--NHC (= O)---CH₂--COOH
1-293 Me -CH₂--NHC (= O)---CH₂--SO_ThreeH
1-294 Me -CH₂--NHC (= O)---CH₂--OSO_ThreeH
1-295 Me -CH₂--NHC (= O)---CH₂--OPO_ThreeH₂
1-296 Me -CH₂--NHC (= O)---CH₂-1-Azt
1-297 Me -CH₂--NHC (= O)---CH₂-1-Pyrd
1-298 Me -CH₂--NHC (= O)---CH₂-1-Pip
1-299 Me -CH₂--NHC (= O)---CH₂-4-Me-1-Piz
1-300 Me -CH₂--NHC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
1-301 Me -CH₂--NHC (= O)---CH₂-4-Mor
1-302 Me -CH₂--NHC (= O)---CH₂--NMe₂
1-303 Me -CH₂--NHC (= O)---CH₂--NMeCH₂CH₂OH
1-304 Me -CH₂--NHC (= O)---CH₂--N (CH₂CH₂OH)₂
1-305 Me -CH₂--NHC (= O)---CH₂CH₂--COOH
1-306 Me -CH₂--NHC (= O)---CH₂CH₂--SO_ThreeH
1-307 Me -CH₂--NHC (= O)---CH₂CH₂--OSO_ThreeH
1-308 Me -CH₂--NHC (= O)---CH₂CH₂--OPO_ThreeH₂
1-309 Me -CH₂--NHC (= O)---CH₂CH₂-1-Azt
1-310 Me -CH₂--NHC (= O)---CH₂CH₂-1-Pyrd
1-311 Me -CH₂--NHC (= O)---CH₂CH₂-1-Pip
1-312 Me -CH₂--NHC (= O)---CH₂CH₂-4-Pip
1-313 Me -CH₂--NHC (= O)---CH₂CH₂-1-Me-4-Pip
1-314 Me -CH₂--NHC (= O)---CH₂CH₂-1-Piz
1-315 Me -CH₂--NHC (= O)---CH₂CH₂-4-Me-1-Piz
1-316 Me -CH₂--NHC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-317 Me -CH₂--NHC (= O)---CH₂CH₂-4-Mor
1-318 Me -CH₂--NHC (= O)---CH₂CH₂--NMe₂
1-319 Me -CH₂--NHC (= O)---CH₂CH₂--NMeCH₂CH₂OH
1-320 Me -CH₂--NHC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
1-321 Me -CH₂--NMeC (= O)---CH₂--COOH
1-322 Me -CH₂--NMeC (= O)---CH₂--SO_ThreeH
1-323 Me -CH₂--NMeC (= O)---CH₂--OSO_ThreeH
1-324 Me -CH₂--NMeC (= O)---CH₂--OPO_ThreeH₂
1-325 Me -CH₂--NMeC (= O)---CH₂-1-Azt
1-326 Me -CH₂--NMeC (= O)---CH₂-1-Pyrd
1-327 Me -CH₂--NMeC (= O)---CH₂-1-Pip
1-328 Me -CH₂--NMeC (= O)---CH₂-4-Me-1-Piz
1-329 Me -CH₂--NMeC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
1-330 Me -CH₂--NMeC (= O)---CH₂-4-Mor
1-331 Me -CH₂--NMeC (= O)---CH₂--NMe₂
1-332 Me -CH₂--NMeC (= O)---CH₂--NMeCH₂CH₂OH
1-333 Me -CH₂--NMeC (= O)---CH₂--N (CH₂CH₂OH)₂
1-334 Me -CH₂--NMeC (= O)---CH₂CH₂--COOH
1-335 Me -CH₂--NMeC (= O)---CH₂CH₂--SO_ThreeH
1-336 Me -CH₂--NMeC (= O)---CH₂CH₂--OSO_ThreeH
1-337 Me -CH₂--NMeC (= O)---CH₂CH₂--OPO_ThreeH₂
1-338 Me -CH₂--NMeC (= O)---CH₂CH₂-1-Azt
1-339 Me -CH₂--NMeC (= O)---CH₂CH₂-1-Pyrd
1-340 Me -CH₂--NMeC (= O)---CH₂CH₂-1-Pip
1-341 Me -CH₂--NMeC (= O)---CH₂CH₂-1-Piz
1-342 Me -CH₂--NMeC (= O)---CH₂CH₂-4-Me-1-Piz
1-343 Me -CH₂--NMeC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-344 Me -CH₂--NMeC (= O)---CH₂CH₂-4-Mor
1-345 Me -CH₂--NMeC (= O)---CH₂CH₂--NMe₂
1-346 Me -CH₂--NMeC (= O)---CH₂CH₂--NMeCH₂CH₂OH
1-347 Me -CH₂--NMeC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
1-348 Me -CH₂CH₂--C (= O) NH---CH₂--COOH
1-349 Me -CH₂CH₂--C (= O) NH---CH₂CH₂--COOH
1-350 Me -CH₂CH₂--C (= O) NH---CH₂CH₂--SO_ThreeH
1-351 Me -CH₂CH₂--C (= O) NH---CH₂CH₂--OSO_ThreeH
1-352 Me -CH₂CH₂--C (= O) NH---CH₂CH₂--OPO_ThreeH₂
1-353 Me -CH₂CH₂--C (= O) NH---CH₂CH₂-1-Azt
1-354 Me -CH₂CH₂--C (= O) NH---CH₂CH₂-1-Pyrd
1-355 Me -CH₂CH₂--C (= O) NH---CH₂CH₂-1-Pip
1-356 Me -CH₂CH₂--C (= O) NH---CH₂CH₂-4-Me-1-Piz
1-357 Me -CH₂CH₂--C (= O) NH---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-358 Me -CH₂CH₂--C (= O) NH---CH₂CH₂-4-Mor
1-359 Me -CH₂CH₂--C (= O) NH---CH₂CH₂--NMe₂
1-360 Me -CH₂CH₂--C (= O) NH---CH₂CH₂--NMeCH₂CH₂OH
1-361 Me -CH₂CH₂--C (= O) NH---CH₂CH₂--N (CH₂CH₂OH)₂
1-362 Me -CH₂CH₂--C (= O) NMe---CH₂--COOH
1-363 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂--COOH
1-364 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂--SO_ThreeH
1-365 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂--OSO_ThreeH
1-366 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂--OPO_ThreeH₂
1-367 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂-1-Azt
1-368 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂-1-Pyrd
1-369 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂-1-Pip
1-370 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂-1-Piz
1-371 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂-4-Me-1-Piz
1-372 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-373 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂-4-Mor
1-374 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂--NHMe
1-375 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂--NMe₂
1-376 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂--NMeCH₂CH₂OH
1-377 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂--N (CH₂CH₂OH)₂
1-378 Me -CH = = = = 1-Me-4,4-Pip
1-379 Me -CH = = = = 1- (CH₂CH₂OH) -4,4-Pip
1-380 H -CH₂-----COOH
1-381 H -CH₂-----SO_ThreeH
1-382 H -CH₂-----OSO_ThreeH
1-383 H -CH₂-----OPO_ThreeH₂
1-384 H -CH₂----1-Azt
1-385 H -CH₂----1-Pyrd
1-386 H -CH₂----1-Pip
1-387 H -CH₂----4-Pip
1-388 H -CH₂----1-Me-4-Pip
1-389 H -CH₂----1- (CH₂CH₂OH) -4-Pip
1-390 H -CH₂----1-Piz
1-391 H -CH₂----4-Me-1-Piz
1-392 H -CH₂----4- (CH₂CH₂OH) -1-Piz
1-393 H -CH₂----4- (CH₂CH₂NHAc) -1-Piz
1-394 H -CH₂----4-Mor
1-395 H -CH₂-----NH₂
1-396 H -CH₂-----NHMe
1-397 H -CH₂-----NMe₂
1-398 H -CH₂--1,4-cHx--NMe₂
1-399 H -CH₂CH₂-----COOH
1-400 H -CH₂CH₂-----SO_ThreeH
1-401 H -CH₂CH₂-----OSO_ThreeH
1-402 H -CH₂CH₂-----SO₂NH₂
1-403 H -CH₂CH₂-----OPO_ThreeH₂
1-404 H -CH₂CH₂----1-Azt
1-405 H -CH₂CH₂----1-Pyrd
1-406 H -CH₂CH₂----1-Pip
1-407 H -CH₂CH₂----4-Pip
1-408 H -CH₂CH₂----1-Me-4-Pip
1-409 H -CH₂CH₂----1- (CH₂CH₂OH) -4-Pip
1-410 H -CH₂CH₂----1-Piz
1-411 H -CH₂CH₂----4-Me-1-Piz
1-412 H -CH₂CH₂----4- (CH₂CH₂OH) -1-Piz
1-413 H -CH₂CH₂----4-Mor
1-414 H -CH₂CH₂-----NH₂
1-415 H -CH₂CH₂-----NHMe
1-416 H -CH₂CH₂-----NMe₂
1-417 H -CH₂CH₂--1,4-cHx--NMe₂
1-418 H-(CH₂)_Three-----COOH
1-419 H-(CH₂)_Three-----SO_ThreeH
1-420 H-(CH₂)_Three-----OSO_ThreeH
1-421 H-(CH₂)_Three-----SO₂NH₂
1-422 H-(CH₂)_Three-----OPO_ThreeH₂
1-423 H-(CH₂)_Three----1-Azt
1-424 H-(CH₂)_Three----1-Pyrd
1-425 H-(CH₂)_Three----1-Pip
1-426 H-(CH₂)_Three----1-Me-4-Pip
1-427 H-(CH₂)_Three----1- (CH₂CH₂OH) -4-Pip
1-428 H-(CH₂)_Three----1-Piz
1-429 H-(CH₂)_Three----4-Me-1-Piz
1-430 H-(CH₂)_Three----4- (CH₂CH₂OH) -1-Piz
1-431 H-(CH₂)_Three----4-Mor
1-432 H-(CH₂)_Three-----NMe₂
1-433 H-(CH₂)_Three--1,4-cHx--NMe₂
1-434 H-(CH₂)_Four----4-Me-1-Piz
1-435 H-(CH₂)_Four----4- (CH₂CH₂OH) -1-Piz
1-436 H-(CH₂)_Four----4-Mor
1-437 H-(CH₂)_Four-----NMe₂
1-438 H -CH₂CH₂--C (= O)---1-Azt
1-439 H -CH₂CH₂--C (= O)---3- (OH) -1-Azt
1-440 H -CH₂CH₂--C (= O)---3- (OCar) -1-Azt
1-441 H -CH₂CH₂--C (= O)---1-Pyrd
1-442 H -CH₂CH₂--C (= O)---1-Pip
1-443 H -CH₂CH₂--C (= O)---4- (OH) -1-Pip
1-444 H -CH₂CH₂--C (= O)---4-Car-1-Pip
1-445 H -CH₂CH₂--C (= O)---4- (OCar) -1-Pip
1-446 H -CH₂CH₂--C (= O)---1-Piz
1-447 H -CH₂CH₂--C (= O)---4- (C (= NH) NH₂) -1-Piz
1-448 H -CH₂CH₂--C (= O)---4- (C (= NH) CH_Three) -1-Piz
1-449 H -CH₂CH₂--C (= O)---4-Me-1-Piz
1-450 H -CH₂CH₂--C (= O)---2,6-diMe-1-Piz
1-451 H -CH₂CH₂--C (= O)---3,5-diMe-1-Piz
1-452 H -CH₂CH₂--C (= O)---4- (CH₂CH₂OH) -1-Piz
1-453 H -CH₂CH₂--C (= O)---4- (CH₂CH₂NHAc) -1-Piz
1-454 H -CH₂CH₂--C (= O)---4- (CH₂CH₂NMeAc) -1-Piz
1-455 H -CH₂CH₂--C (= O)---2,4,6-triMe-1-Piz
1-456 H -CH₂CH₂--C (= O)---3,4,5-triMe-1-Piz
1-457 H -CH₂CH₂--C (= O)---4- (CH₂CH₂OH) -2,6-diMe-1-Piz
1-458 H -CH₂CH₂--C (= O)---4- (CH₂CH₂OH) -3,5-diMe-1-Piz
1-459 H -CH₂CH₂--C (= O)---4- (CH₂CN) -1-Piz
1-460 H -CH₂CH₂--C (= O)---4- (CH₂CH₂CN) -1-Piz
1-461 H -CH₂CH₂--C (= O)---4- (CH₂Car) -1-Piz
1-462 H -CH₂CH₂--C (= O)---4- (CH₂CH₂OCar) -1-Piz
1-463 H -CH₂CH₂--C (= O)---4- (CH₂CH₂F) -1-Piz
1-464 H -CH₂CH₂--C (= O)---4-Car-1-Piz
1-465 H -CH₂CH₂--C (= O)---4-Mor
1-466 H -CH₂CH₂--C (= O)-1,4-cHx--NMe₂
1-467 H -CH₂CH₂--C (= O)-1,3-Azt--COOH
1-468 H -CH₂CH₂--C (= O)-1,3-Azt--OSO_ThreeH
1-469 H -CH₂CH₂--C (= O)-1,3-Azt--OPO_ThreeH₂
1-470 H -CH₂CH₂--C (= O)-1,3-Azt-1-Azt
1-471 H -CH₂CH₂--C (= O)-1,3-Azt-1-Pyrd
1-472 H -CH₂CH₂--C (= O)-1,3-Azt-1-Piz
1-473 H -CH₂CH₂--C (= O)-1,3-Azt-1-Pip
1-474 H -CH₂CH₂--C (= O)-1,3-Azt-4-Me-1-Piz
1-475 H -CH₂CH₂--C (= O)-1,3-Azt-4- (CH₂CH₂OH) -1-Piz
1-476 H -CH₂CH₂--C (= O)-1,3-Azt-4-Mor
1-477 H -CH₂CH₂--C (= O)-1,3-Azt--NHMe
1-478 H -CH₂CH₂--C (= O)-1,3-Azt--NMe₂
1-479 H -CH₂CH₂--C (= O)-1,3-Azt--NMeCH₂CH₂OH
1-480 H -CH₂CH₂--C (= O)-1,3-Azt--NMeCH₂CH₂CN
1-481 H -CH₂CH₂--C (= O)-1,3-Azt--NMeCH₂Car
1-482 H -CH₂CH₂--C (= O)-1,3-Azt--NMeCH₂CH₂Car
1-483 H -CH₂CH₂--C (= O)-1,3-Azt--NMeCH₂CH₂OCar
1-484 H -CH₂CH₂--C (= O)-1,3-Azt--N (CH₂CH₂OH)₂
1-485 H -CH₂CH₂--C (= O)-1,4-Pip--COOH
1-486 H -CH₂CH₂--C (= O)-1,4-Pip--SO_ThreeH
1-487 H -CH₂CH₂--C (= O)-1,4-Pip--OSO_ThreeH
1-488 H -CH₂CH₂--C (= O)-1,4-Pip--OPO_ThreeH₂
1-489 H -CH₂CH₂--C (= O)-1,4-Pip-1-Azt
1-490 H -CH₂CH₂--C (= O)-1,4-Pip-1-Pyrd
1-491 H -CH₂CH₂--C (= O)-1,4-Pip-1-Pip
1-492 H -CH₂CH₂--C (= O)-1,4-Pip-1-Piz
1-493 H -CH₂CH₂--C (= O)-1,4-Pip-4-Me-1-Piz
1-494 H -CH₂CH₂--C (= O)-1,4-Pip-4- (CH₂CH₂OH) -1-Piz
1-495 H -CH₂CH₂--C (= O)-1,4-Pip-4-Mor
1-496 H -CH₂CH₂--C (= O)-1,4-Pip--NHMe
1-497 H -CH₂CH₂--C (= O)-1,4-Pip--NMe₂
1-498 H -CH₂CH₂--C (= O)-1,4-Pip--NMeCH₂CH₂OH
1-499 H -CH₂CH₂--C (= O)-1,4-Pip--NMeCH₂CH₂CN
1-500 H -CH₂CH₂--C (= O)-1,4-Pip--NMeCH₂Car
1-501 H -CH₂CH₂--C (= O)-1,4-Pip--NMeCH₂CH₂Car
1-502 H -CH₂CH₂--C (= O)-1,4-Pip--NMeCH₂CH₂OCar
1-503 H -CH₂CH₂--C (= O)-1,4-Pip--N (CH₂CH₂OH)₂
1-504 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--COOH
1-505 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--SO_ThreeH
1-506 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--OSO_ThreeH
1-507 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--OPO_ThreeH₂
1-508 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂-1-Azt
1-509 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂-1-Pyrd
1-510 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂-1-Pip
1-511 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂-1-Piz
1-512 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂-4-Me-1-Piz
1-513 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂-4- (CH₂CH₂OH) -1-Piz
1-514 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂-4-Mor
1-515 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NH₂
1-516 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NHMe
1-517 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NMe₂
1-518 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NMeCH₂CH₂OH
1-519 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--N (CH₂CH₂OH)₂
1-520 H -CH₂CH₂--C (= O)-1,4-Piz--SO₂NH₂
1-521 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-1-Azt
1-522 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-1-Pyrd
1-523 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-1-Pip
1-524 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-4-Me-1-Piz
1-525 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-526 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-4-Mor
1-527 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--NHCH₂CH₂OH
1-528 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--NHMe
1-529 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--NMe₂
1-530 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--NMeCH₂CH₂OH
1-531 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--N (CH₂CH₂OH)₂
1-532 H -CH = CH- -C (= O)---1-Piz
1-533 H -CH = CH- -C (= O)---4- (C (= NH) NH₂) -1-Piz
1-534 H -CH = CH- -C (= O)---4- (C (= NH) CH_Three) -1-Piz
1-535 H -CH = CH- -C (= O)---4-Me-1-Piz
1-536 H -CH = CH- -C (= O)---2,6-diMe-1-Piz
1-537 H -CH = CH- -C (= O)---3,5-diMe-1-Piz
1-538 H -CH = CH- -C (= O)---4- (CH₂CH₂OH) -1-Piz
1-539 H -CH = CH- -C (= O)---4- (CH₂CH₂CN) -1-Piz
1-540 H -CH = CH- -C (= O)---4- (CH₂Car) -1-Piz
1-541 H -CH = CH- -C (= O)---4- (CH₂CH₂OCar) -1-Piz
1-542 H -CH = CH- -C (= O)---4- (CH₂CH₂F) -1-Piz
1-543 H -CH = CH- -C (= O)---4-Mor
1-544 H -CH = CH- -C (= O)-1,3-Azt--COOH
1-545 H -CH = CH- -C (= O)-1,3-Azt--SO_ThreeH
1-546 H -CH = CH- -C (= O)-1,3-Azt--OSO_ThreeH
1-547 H -CH = CH- -C (= O)-1,3-Azt--OPO_ThreeH₂
1-548 H -CH = CH- -C (= O)-1,3-Azt-1-Azt
1-549 H -CH = CH- -C (= O)-1,3-Azt-1-Pyrd
1-550 H -CH = CH- -C (= O)-1,3-Azt-1-Pip
1-551 H -CH = CH- -C (= O)-1,3-Azt-1-Piz
1-552 H -CH = CH- -C (= O)-1,3-Azt-4-Me-1-Piz
1-553 H -CH = CH- -C (= O)-1,3-Azt-4- (CH₂CH₂OH) -1-Piz
1-554 H -CH = CH- -C (= O)-1,3-Azt-4-Mor
1-555 H -CH = CH- -C (= O)-1,3-Azt--NHMe
1-556 H -CH = CH- -C (= O)-1,3-Azt--NMe₂
1-557 H -CH = CH- -C (= O)-1,3-Azt--NMeCH₂CH₂OH
1-558 H -CH = CH- -C (= O)-1,3-Azt--NMeCH₂CH₂CN
1-559 H -CH = CH- -C (= O)-1,3-Azt--NMeCH₂Car
1-560 H -CH = CH- -C (= O)-1,3-Azt--NMeCH₂CH₂Car
1-561 H -CH = CH- -C (= O)-1,3-Azt--NMeCH₂CH₂OCar
1-562 H -CH = CH- -C (= O)-1,3-Azt--N (CH₂CH₂OH)₂
1-563 H -CH = CH- -C (= O)-1,4-Pip--COOH
1-564 H -CH = CH- -C (= O)-1,4-Pip--SO_ThreeH
1-565 H -CH = CH- -C (= O)-1,4-Pip--OSO_ThreeH
1-566 H -CH = CH- -C (= O)-1,4-Pip--OPO_ThreeH₂
1-567 H -CH = CH- -C (= O)-1,4-Pip-1-Azt
1-568 H -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
1-569 H -CH = CH- -C (= O)-1,4-Pip-1-Pip
1-570 H -CH = CH- -C (= O)-1,4-Pip-1-Piz
1-571 H -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
1-572 H -CH = CH- -C (= O)-1,4-Pip-4- (CH₂CH₂OH) -1-Piz
1-573 H -CH = CH- -C (= O)-1,4-Pip-4-Mor
1-574 H -CH = CH- -C (= O)-1,4-Pip--NHMe
1-575 H -CH = CH- -C (= O)-1,4-Pip--NMe₂
1-576 H -CH = CH- -C (= O)-1,4-Pip--NMeCH₂CH₂OH
1-577 H -CH = CH- -C (= O)-1,4-Pip--NMeCH₂CH₂CN
1-578 H -CH = CH- -C (= O)-1,4-Pip--NMeCH₂Car
1-579 H -CH = CH- -C (= O)-1,4-Pip--NMeCH₂CH₂Car
1-580 H -CH = CH- -C (= O)-1,4-Pip--NMeCH₂CH₂OCar
1-581 H -CH = CH- -C (= O)-1,4-Pip--N (CH₂CH₂OH)₂
1-582 H -CH = CH- -C (= O)-1,4-Pip -CH₂--COOH
1-583 H -CH = CH- -C (= O)-1,4-Pip -CH₂--OSO_ThreeH
1-584 H -CH = CH- -C (= O)-1,4-Pip -CH₂--OPO_ThreeH₂
1-585 H -CH = CH- -C (= O)-1,4-Pip -CH₂-1-Azt
1-586 H -CH = CH- -C (= O)-1,4-Pip -CH₂-1-Pyrd
1-587 H -CH = CH- -C (= O)-1,4-Pip -CH₂-1-Pip
1-588 H -CH = CH- -C (= O)-1,4-Pip -CH₂-4-Me-1-Piz
1-589 H -CH = CH- -C (= O)-1,4-Pip -CH₂-4- (CH₂CH₂OH) -1-Piz
1-590 H -CH = CH- -C (= O)-1,4-Pip -CH₂-4-Mor
1-591 H -CH = CH- -C (= O)-1,4-Pip -CH₂--NH₂
1-592 H -CH = CH- -C (= O)-1,4-Pip -CH₂--NHMe
1-593 H -CH = CH- -C (= O)-1,4-Pip -CH₂--NMe₂
1-594 H -CH = CH- -C (= O)-1,4-Pip -CH₂--NMeCH₂CH₂OH
1-595 H -CH = CH- -C (= O)-1,4-Pip -CH₂--N (CH₂CH₂OH)₂
1-596 H -CH₂CH₂--C (= O)-1,4-Piz--SO₂NH₂
1-597 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-1-Azt
1-598 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-1-Pyrd
1-599 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-1-Pip
1-600 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-1-Piz
1-601 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-4-Me-1-Piz
1-602 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-603 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-4-Mor
1-604 H -CH = CH- -C (= O)---4- (CH₂CH₂NHAc) -1-Piz
1-605 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--NHMe
1-606 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--NMe₂
1-607 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--NMeCH₂CH₂OH
1-608 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--N (CH₂CH₂OH)₂
1-609 H -CH₂--O---1-Me-3-Azt
1-610 H -CH₂--O---1- (CH₂CH₂OH) -3-Azt
1-611 H -CH₂--O---1- (CH₂CH₂NHAc) -3-Azt
1-612 H -CH₂--O---4-Pip
1-613 H -CH₂--O---1-Me-4-Pip
1-614 H -CH₂--O---1- (CH₂CH₂OH) -4-Pip
1-615 H -CH₂--O---1- (CH₂CH₂NHAc) -4-Pip
1-616 H -CH₂--O---CH₂--COOH
1-617 H -CH₂--O---CH₂CH₂--COOH
1-618 H -CH₂--O---CH₂CH₂--SO_ThreeH
1-619 H -CH₂--O---CH₂CH₂--OSO_ThreeH
1-620 H -CH₂--O---CH₂CH₂--SO₂NH₂
1-621 H -CH₂--O---CH₂CH₂--OPO_ThreeH₂
1-622 H -CH₂--O---CH₂CH₂-1-Azt
1-623 H -CH₂--O---CH₂CH₂-1-Pyrd
1-624 H -CH₂--O---CH₂CH₂-1-Pip
1-625 H -CH₂--O---CH₂CH₂-1-Piz
1-626 H -CH₂--O---CH₂CH₂-4-Me-1-Piz
1-627 H -CH₂--O---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-628 H -CH₂--O---CH₂CH₂-4-Mor
1-629 H -CH₂--O---CH₂CH₂--NMe₂
1-630 H -CH₂--O---CH₂CH₂--NMeCH₂CH₂OH
1-631 H -CH₂--O---CH₂CH₂--N (CH₂CH₂OH)₂
1-632 H -CH₂--O- 1,4-cHx--NMe₂
1-633 H -CH₂--O- 1,4-cHx--NMeCH₂CH₂OH
1-634 H -CH₂--O- 1,4-cHx--N (CH₂CH₂OH)₂
1-635 H -CH₂--O- 3,1-Azt--SO₂NH₂
1-636 H -CH₂--O- 3,1-Azt-3-Azt
1-637 H -CH₂--O- 3,1-Azt-1-Me-3-Azt
1-638 H -CH₂--O- 3,1-Azt-1- (CH₂CH₂OH) -3-Azt
1-639 H -CH₂--O- 3,1-Azt-4-Pip
1-640 H -CH₂--O- 3,1-Azt-1-Me-4-Pip
1-641 H -CH₂--O- 3,1-Azt-1- (CH₂CH₂OH) -4-Pip
1-642 H -CH₂--O- 3,1-Azt -CH₂CH₂-1-Azt
1-643 H -CH₂--O- 3,1-Azt -CH₂CH₂-1-Pyrd
1-644 H -CH₂--O- 3,1-Azt -CH₂CH₂-1-Pip
1-645 H -CH₂--O- 3,1-Azt -CH₂CH₂-1-Piz
1-646 H -CH₂--O- 3,1-Azt -CH₂CH₂-4-Me-1-Piz
1-647 H -CH₂--O- 3,1-Azt -CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-648 H -CH₂--O- 3,1-Azt -CH₂CH₂-4-Mor
1-649 H -CH₂--O- 3,1-Azt -CH₂CH₂--NHMe
1-650 H -CH₂--O- 3,1-Azt -CH₂CH₂--NMe₂
1-651 H -CH₂--O- 3,1-Azt -CH₂CH₂--NMeCH₂CH₂OH
1-652 H -CH₂--O- 3,1-Azt -CH₂CH₂--N (CH₂CH₂OH)₂
1-653 H -CH₂--O- 4,1-Pip--SO₂NH₂
1-654 H -CH₂--O- 4,1-Pip-3-Azt
1-655 H -CH₂--O- 4,1-Pip-1-Me-3-Azt
1-656 H -CH₂--O- 4,1-Pip-1- (CH₂CH₂OH) -3-Azt
1-657 H -CH₂--O- 4,1-Pip-4-Pip
1-658 H -CH₂--O- 4,1-Pip-1-Me-4-Pip
1-659 H -CH₂--O- 4,1-Pip-1- (CH₂CH₂OH) -4-Pip
1-660 H -CH₂--O- 4,1-Pip -CH₂CH₂-1-Azt
1-661 H -CH₂--O- 4,1-Pip -CH₂CH₂-1-Pyrd
1-662 H -CH₂--O- 4,1-Pip -CH₂CH₂-1-Pip
1-663 H -CH₂--O- 4,1-Pip -CH₂CH₂-1-Piz
1-664 H -CH₂--O- 4,1-Pip -CH₂CH₂-4-Me-1-Piz
1-665 H -CH₂--O- 4,1-Pip -CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-666 H -CH₂--O- 4,1-Pip -CH₂CH₂-4-Mor
1-667 H -CH₂--O- 4,1-Pip -CH₂CH₂--NHMe
1-668 H -CH₂--O- 4,1-Pip -CH₂CH₂--NMe₂
1-669 H -CH₂--O- 4,1-Pip -CH₂CH₂--NMeCH₂CH₂OH
1-670 H -CH₂--O- 4,1-Pip -CH₂CH₂--N (CH₂CH₂OH)₂
1-671 H -CH₂--NHC (= O)---CH₂--COOH
1-672 H -CH₂--NHC (= O)---CH₂--SO_ThreeH
1-673 H -CH₂--NHC (= O)---CH₂--OSO_ThreeH
1-674 H -CH₂--NHC (= O)---CH₂--OPO_ThreeH₂
1-675 H -CH₂--NHC (= O)---CH₂-1-Azt
1-676 H -CH₂--NHC (= O)---CH₂-1-Pyrd
1-677 H -CH₂--NHC (= O)---CH₂-1-Pip
1-678 H -CH₂--NHC (= O)---CH₂-4-Me-1-Piz
1-679 H -CH₂--NHC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
1-680 H -CH₂--NHC (= O)---CH₂-4-Mor
1-681 H -CH₂--NHC (= O)---CH₂--NMe₂
1-682 H -CH₂--NHC (= O)---CH₂--NMeCH₂CH₂OH
1-683 H -CH₂--NHC (= O)---CH₂--N (CH₂CH₂OH)₂
1-684 H -CH₂--NHC (= O)---CH₂CH₂--COOH
1-685 H -CH₂--NHC (= O)---CH₂CH₂--SO_ThreeH
1-686 H -CH₂--NHC (= O)---CH₂CH₂--OSO_ThreeH
1-687 H -CH₂--NHC (= O)---CH₂CH₂--OPO_ThreeH₂
1-688 H -CH₂--NHC (= O)---CH₂CH₂-1-Azt
1-689 H -CH₂--NHC (= O)---CH₂CH₂-1-Pyrd
1-690 H -CH₂--NHC (= O)---CH₂CH₂-1-Pip
1-691 H -CH₂--NHC (= O)---CH₂CH₂-4-Pip
1-692 H -CH₂--NHC (= O)---CH₂CH₂-1-Me-4-Pip
1-693 H -CH₂--NHC (= O)---CH₂CH₂-1-Piz
1-694 H -CH₂--NHC (= O)---CH₂CH₂-4-Me-1-Piz
1-695 H -CH₂--NHC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-696 H -CH₂--NHC (= O)---CH₂CH₂-4-Mor
1-697 H -CH₂--NHC (= O)---CH₂CH₂--NMe₂
1-698 H -CH₂--NHC (= O)---CH₂CH₂--NMeCH₂CH₂OH
1-699 H -CH₂--NHC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
1-700 H -CH₂--NMeC (= O)---CH₂--COOH
1-701 H -CH₂--NMeC (= O)---CH₂--SO_ThreeH
1-702 H -CH₂--NMeC (= O)---CH₂--OSO_ThreeH
1-703 H -CH₂--NMeC (= O)---CH₂--OPO_ThreeH₂
1-704 H -CH₂--NMeC (= O)---CH₂-1-Azt
1-705 H -CH₂--NMeC (= O)---CH₂-1-Pyrd
1-706 H -CH₂--NMeC (= O)---CH₂-1-Pip
1-707 H -CH₂--NMeC (= O)---CH₂-4-Me-1-Piz
1-708 H -CH₂--NMeC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
1-709 H -CH₂--NMeC (= O)---CH₂-4-Mor
1-710 H -CH₂--NMeC (= O)---CH₂--NMe₂
1-711 H -CH₂--NMeC (= O)---CH₂--NMeCH₂CH₂OH
1-712 H -CH₂--NMeC (= O)---CH₂--N (CH₂CH₂OH)₂
1-713 H -CH₂--NMeC (= O)---CH₂CH₂--COOH
1-714 H -CH₂--NMeC (= O)---CH₂CH₂--SO_ThreeH
1-715 H -CH₂--NMeC (= O)---CH₂CH₂--OSO_ThreeH
1-716 H -CH₂--NMeC (= O)---CH₂CH₂--OPO_ThreeH₂
1-717 H -CH₂--NMeC (= O)---CH₂CH₂-1-Azt
1-718 H -CH₂--NMeC (= O)---CH₂CH₂-1-Pyrd
1-719 H -CH₂--NMeC (= O)---CH₂CH₂-1-Pip
1-720 H -CH₂--NMeC (= O)---CH₂CH₂-1-Piz
1-721 H -CH₂--NMeC (= O)---CH₂CH₂-4-Me-1-Piz
1-722 H -CH₂--NMeC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-723 H -CH₂--NMeC (= O)---CH₂CH₂-4-Mor
1-724 H -CH₂--NMeC (= O)---CH₂CH₂--NMe₂
1-725 H -CH₂--NMeC (= O)---CH₂CH₂--NMeCH₂CH₂OH
1-726 H -CH₂--NMeC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
1-727 H -CH₂CH₂--C (= O) NH---CH₂--COOH
1-728 H -CH₂CH₂--C (= O) NH---CH₂CH₂--COOH
1-729 H -CH₂CH₂--C (= O) NH---CH₂CH₂--SO_ThreeH
1-730 H -CH₂CH₂--C (= O) NH---CH₂CH₂--OSO_ThreeH
1-731 H -CH₂CH₂--C (= O) NH---CH₂CH₂--OPO_ThreeH₂
1-732 H -CH₂CH₂--C (= O) NH---CH₂CH₂-1-Azt
1-733 H -CH₂CH₂--C (= O) NH---CH₂CH₂-1-Pyrd
1-734 H -CH₂CH₂--C (= O) NH---CH₂CH₂-1-Pip
1-735 H -CH₂CH₂--C (= O) NH---CH₂CH₂-4-Me-1-Piz
1-736 H -CH₂CH₂--C (= O) NH---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-737 H -CH₂CH₂--C (= O) NH---CH₂CH₂-4-Mor
1-738 H -CH₂CH₂--C (= O) NH---CH₂CH₂--NMe₂
1-739 H -CH₂CH₂--C (= O) NH---CH₂CH₂--NMeCH₂CH₂OH
1-740 H -CH₂CH₂--C (= O) NH---CH₂CH₂--N (CH₂CH₂OH)₂
1-741 H -CH₂CH₂--C (= O) NMe---CH₂--COOH
1-742 H -CH₂CH₂--C (= O) NMe---CH₂CH₂--COOH
1-743 H -CH₂CH₂--C (= O) NMe---CH₂CH₂--SO_ThreeH
1-744 H -CH₂CH₂--C (= O) NMe---CH₂CH₂--OSO_ThreeH
1-745 H -CH₂CH₂--C (= O) NMe---CH₂CH₂--OPO_ThreeH₂
1-746 H -CH₂CH₂--C (= O) NMe---CH₂CH₂-1-Azt
1-747 H -CH₂CH₂--C (= O) NMe---CH₂CH₂-1-Pyrd
1-748 H -CH₂CH₂--C (= O) NMe---CH₂CH₂-1-Pip
1-749 H -CH₂CH₂--C (= O) NMe---CH₂CH₂-1-Piz
1-750 H -CH₂CH₂--C (= O) NMe---CH₂CH₂-4-Me-1-Piz
1-751 H -CH₂CH₂--C (= O) NMe---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-752 H -CH₂CH₂--C (= O) NMe---CH₂CH₂-4-Mor
1-753 H -CH₂CH₂--C (= O) NMe---CH₂CH₂--NHMe
1-754 H -CH₂CH₂--C (= O) NMe---CH₂CH₂--NMe₂
1-755 H -CH₂CH₂--C (= O) NMe---CH₂CH₂--NMeCH₂CH₂OH
1-756 H -CH₂CH₂--C (= O) NMe---CH₂CH₂--N (CH₂CH₂OH)₂
1-757 H -CH = = = = 1-Me-4,4-Pip
1-758 H -CH = = = = 1- (CH₂CH₂OH) -4,4-Pip
1-759 Me 1,4-cHx----COOH
1-760 Me 1,4-cHx----SO_ThreeH
1-761 Me 1,4-cHx----OSO_ThreeH
1-762 Me 1,4-cHx----SO₂NH₂
1-763 Me 1,4-cHx----OPO_ThreeH₂
1-764 Me 1,4-cHx---1-Azt
1-765 Me 1,4-cHx---1-Pyrd
1-766 Me 1,4-cHx---1-Pip
1-767 Me 1,4-cHx---4-Pip
1-768 Me 1,4-cHx---1-Me-4-Pip
1-769 Me 1,4-cHx---1- (CH₂CH₂OH) -4-Pip
1-770 Me 1,4-cHx---1-Piz
1-771 Me 1,4-cHx---4-Me-1-Piz
1-772 Me 1,4-cHx---4- (CH₂CH₂OH) -1-Piz
1-773 Me 1,4-cHx---4-Mor
1-774 Me 1,4-cHx----NH₂
1-775 Me 1,4-cHx----NHMe
1-776 Me 1,4-cHx----NMe₂
1-777 H 1,4-cHx----COOH
1-778 H 1,4-cHx----SO_ThreeH
1-779 H 1,4-cHx----OSO_ThreeH
1-780 H 1,4-cHx----SO₂NH₂
1-781 H 1,4-cHx----OPO_ThreeH₂
1-782 H 1,4-cHx---1-Azt
1-783 H 1,4-cHx---1-Pyrd
1-784 H 1,4-cHx---1-Pip
1-785 H 1,4-cHx---4-Pip
1-786 H 1,4-cHx---1-Me-4-Pip
1-787 H 1,4-cHx---1- (CH₂CH₂OH) -4-Pip
1-788 H 1,4-cHx---1-Piz
1-789 H 1,4-cHx---4-Me-1-Piz
1-790 H 1,4-cHx---4- (CH₂CH₂OH) -1-Piz
1-791 H 1,4-cHx---4-Mor
1-792 H 1,4-cHx----NH₂
1-793 H 1,4-cHx----NHMe
1-794 H 1,4-cHx----NMe₂
1-795 Me-(CH₂)_Four-----COOH
1-796 Me-(CH₂)_Four-----SO_ThreeH
1-797 Me-(CH₂)_Four-----OSO_ThreeH
1-798 Me-(CH₂)_Four-----OPO_ThreeH₂
1-799 Me-(CH₂)_Five-----COOH
1-800 Me-(CH₂)_Five-----SO_ThreeH
1-801 Me-(CH₂)_Five-----OSO_ThreeH
1-802 Me-(CH₂)_Five-----OPO_ThreeH₂
1-803 Me-(CH₂)_Three--C (= O) NMe---CH₂CH₂--SO_ThreeH
1-804 Me-(CH₂)_Four--C (= O) NMe---CH₂CH₂--SO_ThreeH
1-805 Me-(CH₂)_Five--C (= O) NMe---CH₂CH₂--SO_ThreeH
1-806 Me-(CH₂)₆--C (= O) NMe---CH₂CH₂--SO_ThreeH
1-807 H-(CH₂)_Four-----COOH
1-808 H-(CH₂)_Four-----SO_ThreeH
1-809 H-(CH₂)_Four-----OSO_ThreeH
1-810 H-(CH₂)_Four-----OPO_ThreeH₂
1-811 H-(CH₂)_Five-----COOH
1-812 H-(CH₂)_Five-----SO_ThreeH
1-813 H-(CH₂)_Five-----OSO_ThreeH
1-814 H-(CH₂)_Five-----OPO_ThreeH₂
1-815 H-(CH₂)_Three--C (= O) NMe---CH₂CH₂--SO_ThreeH
1-816 H-(CH₂)_Four--C (= O) NMe---CH₂CH₂--SO_ThreeH
1-817 H-(CH₂)_Five--C (= O) NMe---CH₂CH₂--SO_ThreeH
1-818 H-(CH₂)₆--C (= O) NMe---CH₂CH₂--SO_ThreeH
1-819 Me -CH₂--OC (= O)---4-Pip
1-820 Me -CH₂--OC (= O)---1-Me-4-Pip
1-821 Me -CH₂--OC (= O)---CH₂--COOH
1-822 Me -CH₂--OC (= O)---CH₂--SO_ThreeH
1-823 Me -CH₂--OC (= O)---CH₂--OSO_ThreeH
1-824 Me -CH₂--OC (= O)---CH₂--OPO_ThreeH₂
1-825 Me -CH₂--OC (= O)---CH₂-1-Azt
1-826 Me -CH₂--OC (= O)---CH₂-1-Pyrd
1-827 Me -CH₂--OC (= O)---CH₂-1-Pip
1-828 Me -CH₂--OC (= O)---CH₂-4-Pip
1-829 Me -CH₂--OC (= O)---CH₂-1-Me-4-Pip
1-830 Me -CH₂--OC (= O)---CH₂-1-Piz
1-831 Me -CH₂--OC (= O)---CH₂-4-Me-1-Piz
1-832 Me -CH₂--OC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
1-833 Me -CH₂--OC (= O)---CH₂-4-Mor
1-834 Me -CH₂--OC (= O)---CH₂--NMe₂
1-835 Me -CH₂--OC (= O)---CH₂--NMeCH₂CH₂OH
1-836 Me -CH₂--OC (= O)---CH₂--N (CH₂CH₂OH)₂
1-837 Me -CH₂--OC (= O)---CH₂CH₂--COOH
1-838 Me -CH₂--OC (= O)---CH₂CH₂--SO_ThreeH
1-839 Me -CH₂--OC (= O)---CH₂CH₂--OSO_ThreeH
1-840 Me -CH₂--OC (= O)---CH₂CH₂--OPO_ThreeH₂
1-841 Me -CH₂--OC (= O)---CH₂CH₂-1-Azt
1-842 Me -CH₂--OC (= O)---CH₂CH₂-1-Pyrd
1-843 Me -CH₂--OC (= O)---CH₂CH₂-1-Pip
1-844 Me -CH₂--OC (= O)---CH₂CH₂-4-Pip
1-845 Me -CH₂--OC (= O)---CH₂CH₂-1-Me-4-Pip
1-846 Me -CH₂--OC (= O)---CH₂CH₂-1-Piz
1-847 Me -CH₂--OC (= O)---CH₂CH₂-4-Me-1-Piz
1-848 Me -CH₂--OC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-849 Me -CH₂--OC (= O)---CH₂CH₂-4-Mor
1-850 Me -CH₂--OC (= O)---CH₂CH₂--NMe₂
1-851 Me -CH₂--OC (= O)---CH₂CH₂--NMeCH₂CH₂OH
1-852 Me -CH₂--OC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
1-853 Me -CH₂CH₂--OC (= O)---4-Pip
1-854 Me -CH₂CH₂--OC (= O)---1-Me-4-Pip
1-855 Me -CH₂CH₂--OC (= O)---CH₂--COOH
1-856 Me -CH₂CH₂--OC (= O)---CH₂--SO_ThreeH
1-857 Me -CH₂CH₂--OC (= O)---CH₂--OSO_ThreeH
1-858 Me -CH₂CH₂--OC (= O)---CH₂--OPO_ThreeH₂
1-859 Me -CH₂CH₂--OC (= O)---CH₂-1-Azt
1-860 Me -CH₂CH₂--OC (= O)---CH₂-1-Pyrd
1-861 Me -CH₂CH₂--OC (= O)---CH₂-1-Pip
1-862 Me -CH₂CH₂--OC (= O)---CH₂-4-Pip
1-863 Me -CH₂CH₂--OC (= O)---CH₂-1-Me-4-Pip
1-864 Me -CH₂CH₂--OC (= O)---CH₂-1-Piz
1-865 Me -CH₂CH₂--OC (= O)---CH₂-4-Me-1-Piz
1-866 Me -CH₂CH₂--OC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
1-867 Me -CH₂CH₂--OC (= O)---CH₂-4-Mor
1-868 Me -CH₂CH₂--OC (= O)---CH₂--NMe₂
1-869 Me -CH₂CH₂--OC (= O)---CH₂--NMeCH₂CH₂OH
1-870 Me -CH₂CH₂--OC (= O)---CH₂--N (CH₂CH₂OH)₂
1-871 Me -CH₂CH₂--OC (= O)---CH₂CH₂--COOH
1-872 Me -CH₂CH₂--OC (= O)---CH₂CH₂--SO_ThreeH
1-873 Me -CH₂CH₂--OC (= O)---CH₂CH₂--OSO_ThreeH
1-874 Me -CH₂CH₂--OC (= O)---CH₂CH₂--OPO_ThreeH₂
1-875 Me -CH₂CH₂--OC (= O)---CH₂CH₂-1-Azt
1-876 Me -CH₂CH₂--OC (= O)---CH₂CH₂-1-Pyrd
1-877 Me -CH₂CH₂--OC (= O)---CH₂CH₂-1-Pip
1-878 Me -CH₂CH₂--OC (= O)---CH₂CH₂-4-Pip
1-879 Me -CH₂CH₂--OC (= O)---CH₂CH₂-1-Me-4-Pip
1-880 Me -CH₂CH₂--OC (= O)---CH₂CH₂-1-Piz
1-881 Me -CH₂CH₂--OC (= O)---CH₂CH₂-4-Me-1-Piz
1-882 Me -CH₂CH₂--OC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-883 Me -CH₂CH₂--OC (= O)---CH₂CH₂-4-Mor
1-884 Me -CH₂CH₂--OC (= O)---CH₂CH₂--NMe₂
1-885 Me -CH₂CH₂--OC (= O)---CH₂CH₂--NMeCH₂CH₂OH
1-886 Me -CH₂CH₂--OC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
1-887 Me-(CH₂)_Three--OC (= O)---4-Pip
1-888 Me-(CH₂)_Three--OC (= O)---1-Me-4-Pip
1-889 Me-(CH₂)_Three--OC (= O)---CH₂--COOH
1-890 Me-(CH₂)_Three--OC (= O)---CH₂--SO_ThreeH
1-891 Me-(CH₂)_Three--OC (= O)---CH₂--OSO_ThreeH
1-892 Me-(CH₂)_Three--OC (= O)---CH₂--OPO_ThreeH₂
1-893 Me-(CH₂)_Three--OC (= O)---CH₂-1-Azt
1-894 Me-(CH₂)_Three--OC (= O)---CH₂-1-Pyrd
1-895 Me-(CH₂)_Three--OC (= O)---CH₂-1-Pip
1-896 Me-(CH₂)_Three--OC (= O)---CH₂-4-Pip
1-897 Me-(CH₂)_Three--OC (= O)---CH₂-1-Me-4-Pip
1-898 Me-(CH₂)_Three--OC (= O)---CH₂-1-Piz
1-899 Me-(CH₂)_Three--OC (= O)---CH₂-4-Me-1-Piz
1-900 Me-(CH₂)_Three--OC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
1-901 Me-(CH₂)_Three--OC (= O)---CH₂-4-Mor
1-902 Me-(CH₂)_Three--OC (= O)---CH₂--NMe₂
1-903 Me-(CH₂)_Three--OC (= O)---CH₂--NMeCH₂CH₂OH
1-904 Me-(CH₂)_Three--OC (= O)---CH₂--N (CH₂CH₂OH)₂
1-905 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--COOH
1-906 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--SO_ThreeH
1-907 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--OSO_ThreeH
1-908 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--OPO_ThreeH₂
1-909 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Azt
1-910 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Pyrd
1-911 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Pip
1-912 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-4-Pip
1-913 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Me-4-Pip
1-914 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Piz
1-915 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-4-Me-1-Piz
1-916 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-917 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-4-Mor
1-918 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--NMe₂
1-919 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--NMeCH₂CH₂OH
1-920 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
1-921 Me-(CH₂)_Four--OC (= O)---4-Pip
1-922 Me-(CH₂)_Four--OC (= O)---1-Me-4-Pip
1-923 Me-(CH₂)_Four--OC (= O)---CH₂--COOH
1-924 Me-(CH₂)_Four--OC (= O)---CH₂--SO_ThreeH
1-925 Me-(CH₂)_Four--OC (= O)---CH₂--OSO_ThreeH
1-926 Me-(CH₂)_Four--OC (= O)---CH₂--OPO_ThreeH₂
1-927 Me-(CH₂)_Four--OC (= O)---CH₂-1-Azt
1-928 Me-(CH₂)_Four--OC (= O)---CH₂-1-Pyrd
1-929 Me-(CH₂)_Four--OC (= O)---CH₂-1-Pip
1-930 Me-(CH₂)_Four--OC (= O)---CH₂-4-Pip
1-931 Me-(CH₂)_Four--OC (= O)---CH₂-1-Me-4-Pip
1-932 Me-(CH₂)_Four--OC (= O)---CH₂-1-Piz
1-933 Me-(CH₂)_Four--OC (= O)---CH₂-4-Me-1-Piz
1-934 Me-(CH₂)_Four--OC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
1-935 Me-(CH₂)_Four--OC (= O)---CH₂-4-Mor
1-936 Me-(CH₂)_Four--OC (= O)---CH₂--NMe₂
1-937 Me-(CH₂)_Four--OC (= O)---CH₂--NMeCH₂CH₂OH
1-938 Me-(CH₂)_Four--OC (= O)---CH₂--N (CH₂CH₂OH)₂
1-939 Me-(CH₂)_Four--OC (= O)---CH₂CH₂--COOH
1-940 Me-(CH₂)_Four--OC (= O)---CH₂CH₂--SO_ThreeH
1-941 Me-(CH₂)_Four--OC (= O)---CH₂CH₂--OSO_ThreeH
1-942 Me-(CH₂)_Four--OC (= O)---CH₂CH₂--OPO_ThreeH₂
1-943 Me-(CH₂)_Four--OC (= O)---CH₂CH₂-1-Azt
1-944 Me-(CH₂)_Four--OC (= O)---CH₂CH₂-1-Pyrd
1-945 Me-(CH₂)_Four--OC (= O)---CH₂CH₂-1-Pip
1-946 Me-(CH₂)_Four--OC (= O)---CH₂CH₂-4-Pip
1-947 Me-(CH₂)_Four--OC (= O)---CH₂CH₂-1-Me-4-Pip
1-948 Me-(CH₂)_Four--OC (= O)---CH₂CH₂-1-Piz
1-949 Me-(CH₂)_Four--OC (= O)---CH₂CH₂-4-Me-1-Piz
1-950 Me-(CH₂)_Four--OC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-951 Me-(CH₂)_Four--OC (= O)---CH₂CH₂-4-Mor
1-952 Me-(CH₂)_Four--OC (= O)---CH₂CH₂--NMe₂
1-953 Me-(CH₂)_Four--OC (= O)---CH₂CH₂--NMeCH₂CH₂OH
1-954 Me-(CH₂)_Four--OC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
1-955 Me -CH = CH-CH₂--OC (= O)---4-Pip
1-956 Me -CH = CH-CH₂--OC (= O)---1-Me-4-Pip
1-957 Me -CH = CH-CH₂--OC (= O)---CH₂--COOH
1-958 Me -CH = CH-CH₂--OC (= O)---CH₂--SO_ThreeH
1-959 Me -CH = CH-CH₂--OC (= O)---CH₂--OSO_ThreeH
1-960 Me -CH = CH-CH₂--OC (= O)---CH₂--OPO_ThreeH₂
1-961 Me -CH = CH-CH₂--OC (= O)---CH₂-1-Azt
1-962 Me -CH = CH-CH₂--OC (= O)---CH₂-1-Pyrd
1-963 Me -CH = CH-CH₂--OC (= O)---CH₂-1-Pip
1-964 Me -CH = CH-CH₂--OC (= O)---CH₂-4-Pip
1-965 Me -CH = CH-CH₂--OC (= O)---CH₂-1-Me-4-Pip
1-966 Me -CH = CH-CH₂--OC (= O)---CH₂-1-Piz
1-967 Me -CH = CH-CH₂--OC (= O)---CH₂-4-Me-1-Piz
1-968 Me -CH = CH-CH₂--OC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
1-969 Me -CH = CH-CH₂--OC (= O)---CH₂-4-Mor
1-970 Me -CH = CH-CH₂--OC (= O)---CH₂--NMe₂
1-971 Me -CH = CH-CH₂--OC (= O)---CH₂--NMeCH₂CH₂OH
1-972 Me -CH = CH-CH₂--OC (= O)---CH₂--N (CH₂CH₂OH)₂
1-973 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂--COOH
1-974 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂--SO_ThreeH
1-975 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂--OSO_ThreeH
1-976 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂--OPO_ThreeH₂
1-977 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂-1-Azt
1-978 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂-1-Pyrd
1-979 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂-1-Pip
1-980 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂-4-Pip
1-981 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂-1-Me-4-Pip
1-982 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂-1-Piz
1-983 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂-4-Me-1-Piz
1-984 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-985 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂-4-Mor
1-986 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂--NMe₂
1-987 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂--NMeCH₂CH₂OH
1-988 Me -CH = CH-CH₂--OC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
1-989 Me -CH₂CH₂--C (= O) O---4-Pip
1-990 Me -CH₂CH₂--C (= O) O---1-Me-4-Pip
1-991 Me -CH₂CH₂--C (= O) O---CH₂--COOH
1-992 Me -CH₂CH₂--C (= O) O---CH₂-4-Pip
1-993 Me -CH₂CH₂--C (= O) O---CH₂-1-Me-4-Pip
1-994 Me -CH₂CH₂--C (= O) O---CH₂CH₂--COOH
1-995 Me -CH₂CH₂--C (= O) O---CH₂CH₂--SO_ThreeH
1-996 Me -CH₂CH₂--C (= O) O---CH₂CH₂--OSO_ThreeH
1-997 Me -CH₂CH₂--C (= O) O---CH₂CH₂--OPO_ThreeH₂
1-998 Me -CH₂CH₂--C (= O) O---CH₂CH₂-1-Azt
1-999 Me -CH₂CH₂--C (= O) O---CH₂CH₂-1-Pyrd
1-1000 Me -CH₂CH₂--C (= O) O---CH₂CH₂-1-Pip
1-1001 Me -CH₂CH₂--C (= O) O---CH₂CH₂-4-Pip
1-1002 Me -CH₂CH₂--C (= O) O---CH₂CH₂-1-Me-4-Pip
1-1003 Me -CH₂CH₂--C (= O) O---CH₂CH₂-1-Piz
1-1004 Me -CH₂CH₂--C (= O) O---CH₂CH₂-4-Me-1-Piz
1-1005 Me -CH₂CH₂--C (= O) O---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-1006 Me -CH₂CH₂--C (= O) O---CH₂CH₂-4-Mor
1-1007 Me -CH₂CH₂--C (= O) O---CH₂CH₂--NMe₂
1-1008 Me -CH₂CH₂--C (= O) O---CH₂CH₂--NMeCH₂CH₂OH
1-1009 Me -CH₂CH₂--C (= O) O---CH₂CH₂--N (CH₂CH₂OH)₂
1-1010 Me-(CH₂)_Three--C (= O) O---4-Pip
1-1011 Me-(CH₂)_Three--C (= O) O---1-Me-4-Pip
1-1012 Me-(CH₂)_Three--C (= O) O---CH₂--COOH
1-1013 Me-(CH₂)_Three--C (= O) O---CH₂-4-Pip
1-1014 Me-(CH₂)_Three--C (= O) O---CH₂-1-Me-4-Pip
1-1015 Me-(CH₂)_Three--C (= O) O---CH₂CH₂--COOH
1-1016 Me-(CH₂)_Three--C (= O) O---CH₂CH₂--SO_ThreeH
1-1017 Me-(CH₂)_Three--C (= O) O---CH₂CH₂--OSO_ThreeH
1-1018 Me-(CH₂)_Three--C (= O) O---CH₂CH₂--OPO_ThreeH₂
1-1019 Me-(CH₂)_Three--C (= O) O---CH₂CH₂-1-Azt
1-1020 Me-(CH₂)_Three--C (= O) O---CH₂CH₂-1-Pyrd
1-1021 Me-(CH₂)_Three--C (= O) O---CH₂CH₂-1-Pip
1-1022 Me-(CH₂)_Three--C (= O) O---CH₂CH₂-4-Pip
1-1023 Me-(CH₂)_Three--C (= O) O---CH₂CH₂-1-Me-4-Pip
1-1024 Me-(CH₂)_Three--C (= O) O---CH₂CH₂-1-Piz
1-1025 Me-(CH₂)_Three--C (= O) O---CH₂CH₂-4-Me-1-Piz
1-1026 Me-(CH₂)_Three--C (= O) O---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-1027 Me-(CH₂)_Three--C (= O) O---CH₂CH₂-4-Mor
1-1028 Me-(CH₂)_Three--C (= O) O---CH₂CH₂--NMe₂
1-1029 Me-(CH₂)_Three--C (= O) O---CH₂CH₂--NMeCH₂CH₂OH
1-1030 Me-(CH₂)_Three--C (= O) O---CH₂CH₂--N (CH₂CH₂OH)₂
1-1031 Me -CH = CH- -C (= O) O---4-Pip
1-1032 Me -CH = CH- -C (= O) O---1-Me-4-Pip
1-1033 Me -CH = CH- -C (= O) O---CH₂--COOH
1-1034 Me -CH = CH- -C (= O) O---CH₂-4-Pip
1-1035 Me -CH = CH- -C (= O) O---CH₂-1-Me-4-Pip
1-1036 Me -CH = CH- -C (= O) O---CH₂CH₂--COOH
1-1037 Me -CH = CH- -C (= O) O---CH₂CH₂--SO_ThreeH
1-1038 Me -CH = CH- -C (= O) O---CH₂CH₂--OSO_ThreeH
1-1039 Me -CH = CH- -C (= O) O---CH₂CH₂--OPO_ThreeH₂
1-1040 Me -CH = CH- -C (= O) O---CH₂CH₂-1-Azt
1-1041 Me -CH = CH- -C (= O) O---CH₂CH₂-1-Pyrd
1-1042 Me -CH = CH- -C (= O) O---CH₂CH₂-1-Pip
1-1043 Me -CH = CH- -C (= O) O---CH₂CH₂-4-Pip
1-1044 Me -CH = CH- -C (= O) O---CH₂CH₂-1-Me-4-Pip
1-1045 Me -CH = CH- -C (= O) O---CH₂CH₂-1-Piz
1-1046 Me -CH = CH- -C (= O) O---CH₂CH₂-4-Me-1-Piz
1-1047 Me -CH = CH- -C (= O) O---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-1048 Me -CH = CH- -C (= O) O---CH₂CH₂-4-Mor
1-1049 Me -CH = CH- -C (= O) O---CH₂CH₂--NMe₂
1-1050 Me -CH = CH- -C (= O) O---CH₂CH₂--NMeCH₂CH₂OH
1-1051 Me -CH = CH- -C (= O) O---CH₂CH₂--N (CH₂CH₂OH)₂
1-1052 H -CH₂--OC (= O)---4-Pip
1-1053 H -CH₂--OC (= O)---1-Me-4-Pip
1-1054 H -CH₂--OC (= O)---CH₂--COOH
1-1055 H -CH₂--OC (= O)---CH₂--SO_ThreeH
1-1056 H -CH₂--OC (= O)---CH₂--OSO_ThreeH
1-1057 H -CH₂--OC (= O)---CH₂--OPO_ThreeH₂
1-1058 H -CH₂--OC (= O)---CH₂-1-Azt
1-1059 H -CH₂--OC (= O)---CH₂-1-Pyrd
1-1060 H -CH₂--OC (= O)---CH₂-1-Pip
1-1061 H -CH₂--OC (= O)---CH₂-4-Pip
1-1062 H -CH₂--OC (= O)---CH₂-1-Me-4-Pip
1-1063 H -CH₂--OC (= O)---CH₂-1-Piz
1-1064 H -CH₂--OC (= O)---CH₂-4-Me-1-Piz
1-1065 H -CH₂--OC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
1-1066 H -CH₂--OC (= O)---CH₂-4-Mor
1-1067 H -CH₂--OC (= O)---CH₂--NMe₂
1-1068 H -CH₂--OC (= O)---CH₂--NMeCH₂CH₂OH
1-1069 H -CH₂--OC (= O)---CH₂--N (CH₂CH₂OH)₂
1-1070 H -CH₂--OC (= O)---CH₂CH₂--COOH
1-1071 H -CH₂--OC (= O)---CH₂CH₂--SO_ThreeH
1-1072 H -CH₂--OC (= O)---CH₂CH₂--OSO_ThreeH
1-1073 H -CH₂--OC (= O)---CH₂CH₂--OPO_ThreeH₂
1-1074 H -CH₂--OC (= O)---CH₂CH₂-1-Azt
1-1075 H -CH₂--OC (= O)---CH₂CH₂-1-Pyrd
1-1076 H -CH₂--OC (= O)---CH₂CH₂-1-Pip
1-1077 H -CH₂--OC (= O)---CH₂CH₂-4-Pip
1-1078 H -CH₂--OC (= O)---CH₂CH₂-1-Me-4-Pip
1-1079 H -CH₂--OC (= O)---CH₂CH₂-1-Piz
1-1080 H -CH₂--OC (= O)---CH₂CH₂-4-Me-1-Piz
1-1081 H -CH₂--OC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-1082 H -CH₂--OC (= O)---CH₂CH₂-4-Mor
1-1083 H -CH₂--OC (= O)---CH₂CH₂--NMe₂
1-1084 H -CH₂--OC (= O)---CH₂CH₂--NMeCH₂CH₂OH
1-1085 H -CH₂--OC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
1-1086 H -CH₂CH₂--OC (= O)---4-Pip
1-1087 H -CH₂CH₂--OC (= O)---1-Me-4-Pip
1-1088 H -CH₂CH₂--OC (= O)---CH₂--COOH
1-1089 H -CH₂CH₂--OC (= O)---CH₂--SO_ThreeH
1-1090 H -CH₂CH₂--OC (= O)---CH₂--OSO_ThreeH
1-1091 H -CH₂CH₂--OC (= O)---CH₂--OPO_ThreeH₂
1-1092 H -CH₂CH₂--OC (= O)---CH₂-1-Azt
1-1093 H -CH₂CH₂--OC (= O)---CH₂-1-Pyrd
1-1094 H -CH₂CH₂--OC (= O)---CH₂-1-Pip
1-1095 H -CH₂CH₂--OC (= O)---CH₂-4-Pip
1-1096 H -CH₂CH₂--OC (= O)---CH₂-1-Me-4-Pip
1-1097 H -CH₂CH₂--OC (= O)---CH₂-1-Piz
1-1098 H -CH₂CH₂--OC (= O)---CH₂-4-Me-1-Piz
1-1099 H -CH₂CH₂--OC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
1-1100 H -CH₂CH₂--OC (= O)---CH₂-4-Mor
1-1101 H -CH₂CH₂--OC (= O)---CH₂--NMe₂
1-1102 H -CH₂CH₂--OC (= O)---CH₂--NMeCH₂CH₂OH
1-1103 H -CH₂CH₂--OC (= O)---CH₂--N (CH₂CH₂OH)₂
1-1104 H -CH₂CH₂--OC (= O)---CH₂CH₂--COOH
1-1105 H -CH₂CH₂--OC (= O)---CH₂CH₂--SO_ThreeH
1-1106 H -CH₂CH₂--OC (= O)---CH₂CH₂--OSO_ThreeH
1-1107 H -CH₂CH₂--OC (= O)---CH₂CH₂--OPO_ThreeH₂
1-1108 H -CH₂CH₂--OC (= O)---CH₂CH₂-1-Azt
1-1109 H -CH₂CH₂--OC (= O)---CH₂CH₂-1-Pyrd
1-1110 H -CH₂CH₂--OC (= O)---CH₂CH₂-1-Pip
1-1111 H -CH₂CH₂--OC (= O)---CH₂CH₂-4-Pip
1-1112 H -CH₂CH₂--OC (= O)---CH₂CH₂-1-Me-4-Pip
1-1113 H -CH₂CH₂--OC (= O)---CH₂CH₂-1-Piz
1-1114 H -CH₂CH₂--OC (= O)---CH₂CH₂-4-Me-1-Piz
1-1115 H -CH₂CH₂--OC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-1116 H -CH₂CH₂--OC (= O)---CH₂CH₂-4-Mor
1-1117 H -CH₂CH₂--OC (= O)---CH₂CH₂--NMe₂
1-1118 H -CH₂CH₂--OC (= O)---CH₂CH₂--NMeCH₂CH₂OH
1-1119 H -CH₂CH₂--OC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
1-1120 H-(CH₂)_Three--OC (= O)---4-Pip
1-1121 H-(CH₂)_Three--OC (= O)---1-Me-4-Pip
1-1122 H-(CH₂)_Three--OC (= O)---CH₂--COOH
1-1123 H-(CH₂)_Three--OC (= O)---CH₂--SO_ThreeH
1-1124 H-(CH₂)_Three--OC (= O)---CH₂--OSO_ThreeH
1-1125 H-(CH₂)_Three--OC (= O)---CH₂--OPO_ThreeH₂
1-1126 H-(CH₂)_Three--OC (= O)---CH₂-1-Azt
1-1127 H-(CH₂)_Three--OC (= O)---CH₂-1-Pyrd
1-1128 H-(CH₂)_Three--OC (= O)---CH₂-1-Pip
1-1129 H-(CH₂)_Three--OC (= O)---CH₂-4-Pip
1-1130 H-(CH₂)_Three--OC (= O)---CH₂-1-Me-4-Pip
1-1131 H-(CH₂)_Three--OC (= O)---CH₂-1-Piz
1-1132 H-(CH₂)_Three--OC (= O)---CH₂-4-Me-1-Piz
1-1133 H-(CH₂)_Three--OC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
1-1134 H-(CH₂)_Three--OC (= O)---CH₂-4-Mor
1-1135 H-(CH₂)_Three--OC (= O)---CH₂--NMe₂
1-1136 H-(CH₂)_Three--OC (= O)---CH₂--NMeCH₂CH₂OH
1-1137 H-(CH₂)_Three--OC (= O)---CH₂--N (CH₂CH₂OH)₂
1-1138 H-(CH₂)_Three--OC (= O)---CH₂CH₂--COOH
1-1139 H-(CH₂)_Three--OC (= O)---CH₂CH₂--SO_ThreeH
1-1140 H-(CH₂)_Three--OC (= O)---CH₂CH₂--OSO_ThreeH
1-1141 H-(CH₂)_Three--OC (= O)---CH₂CH₂--OPO_ThreeH₂
1-1142 H-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Azt
1-1143 H-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Pyrd
1-1144 H-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Pip
1-1145 H-(CH₂)_Three--OC (= O)---CH₂CH₂-4-Pip
1-1146 H-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Me-4-Pip
1-1147 H-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Piz
1-1148 H-(CH₂)_Three--OC (= O)---CH₂CH₂-4-Me-1-Piz
1-1149 H-(CH₂)_Three--OC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-1150 H-(CH₂)_Three--OC (= O)---CH₂CH₂-4-Mor
1-1151 H-(CH₂)_Three--OC (= O)---CH₂CH₂--NMe₂
1-1152 H-(CH₂)_Three--OC (= O)---CH₂CH₂--NMeCH₂CH₂OH
1-1153 H-(CH₂)_Three--OC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
1-1154 H-(CH₂)_Four--OC (= O)---4-Pip
1-1155 H-(CH₂)_Four--OC (= O)---1-Me-4-Pip
1-1156 H-(CH₂)_Four--OC (= O)---CH₂--COOH
1-1157 H-(CH₂)_Four--OC (= O)---CH₂--SO_ThreeH
1-1158 H-(CH₂)_Four--OC (= O)---CH₂--OSO_ThreeH
1-1159 H-(CH₂)_Four--OC (= O)---CH₂--OPO_ThreeH₂
1-1160 H-(CH₂)_Four--OC (= O)---CH₂-1-Azt
1-1161 H-(CH₂)_Four--OC (= O)---CH₂-1-Pyrd
1-1162 H-(CH₂)_Four--OC (= O)---CH₂-1-Pip
1-1163 H-(CH₂)_Four--OC (= O)---CH₂-4-Pip
1-1164 H-(CH₂)_Four--OC (= O)---CH₂-1-Me-4-Pip
1-1165 H-(CH₂)_Four--OC (= O)---CH₂-1-Piz
1-1166 H-(CH₂)_Four--OC (= O)---CH₂-4-Me-1-Piz
1-1167 H-(CH₂)_Four--OC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
1-1168 H-(CH₂)_Four--OC (= O)---CH₂-4-Mor
1-1169 H-(CH₂)_Four--OC (= O)---CH₂--NMe₂
1-1170 H-(CH₂)_Four--OC (= O)---CH₂--NMeCH₂CH₂OH
1-1171 H-(CH₂)_Four--OC (= O)---CH₂--N (CH₂CH₂OH)₂
1-1172 H-(CH₂)_Four--OC (= O)---CH₂CH₂--COOH
1-1173 H-(CH₂)_Four--OC (= O)---CH₂CH₂--SO_ThreeH
1-1174 H-(CH₂)_Four--OC (= O)---CH₂CH₂--OSO_ThreeH
1-1175 H-(CH₂)_Four--OC (= O)---CH₂CH₂--OPO_ThreeH₂
1-1176 H-(CH₂)_Four--OC (= O)---CH₂CH₂-1-Azt
1-1177 H-(CH₂)_Four--OC (= O)---CH₂CH₂-1-Pyrd
1-1178 H-(CH₂)_Four--OC (= O)---CH₂CH₂-1-Pip
1-1179 H-(CH₂)_Four--OC (= O)---CH₂CH₂-4-Pip
1-1180 H-(CH₂)_Four--OC (= O)---CH₂CH₂-1-Me-4-Pip
1-1181 H-(CH₂)_Four--OC (= O)---CH₂CH₂-1-Piz
1-1182 H-(CH₂)_Four--OC (= O)---CH₂CH₂-4-Me-1-Piz
1-1183 H-(CH₂)_Four--OC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-1184 H-(CH₂)_Four--OC (= O)---CH₂CH₂-4-Mor
1-1185 H-(CH₂)_Four--OC (= O)---CH₂CH₂--NMe₂
1-1186 H-(CH₂)_Four--OC (= O)---CH₂CH₂--NMeCH₂CH₂OH
1-1187 H-(CH₂)_Four--OC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
1-1188 H -CH = CH-CH₂--OC (= O)---4-Pip
1-1189 H -CH = CH-CH₂--OC (= O)---1-Me-4-Pip
1-1190 H -CH = CH-CH₂--OC (= O)---CH₂--COOH
1-1191 H -CH = CH-CH₂--OC (= O)---CH₂--SO_ThreeH
1-1192 H -CH = CH-CH₂--OC (= O)---CH₂--OSO_ThreeH
1-1193 H -CH = CH-CH₂--OC (= O)---CH₂--OPO_ThreeH₂
1-1194 H -CH = CH-CH₂--OC (= O)---CH₂-1-Azt
1-1195 H -CH = CH-CH₂--OC (= O)---CH₂-1-Pyrd
1-1196 H -CH = CH-CH₂--OC (= O)---CH₂-1-Pip
1-1197 H -CH = CH-CH₂--OC (= O)---CH₂-4-Pip
1-1198 H -CH = CH-CH₂--OC (= O)---CH₂-1-Me-4-Pip
1-1199 H -CH = CH-CH₂--OC (= O)---CH₂-1-Piz
1-1200 H -CH = CH-CH₂--OC (= O)---CH₂-4-Me-1-Piz
1-1201 H -CH = CH-CH₂--OC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
1-1202 H -CH = CH-CH₂--OC (= O)---CH₂-4-Mor
1-1203 H -CH = CH-CH₂--OC (= O)---CH₂--NMe₂
1-1204 H -CH = CH-CH₂--OC (= O)---CH₂--NMeCH₂CH₂OH
1-1205 H -CH = CH-CH₂--OC (= O)---CH₂--N (CH₂CH₂OH)₂
1-1206 H -CH = CH-CH₂--OC (= O)---CH₂CH₂--COOH
1-1207 H -CH = CH-CH₂--OC (= O)---CH₂CH₂--SO_ThreeH
1-1208 H -CH = CH-CH₂--OC (= O)---CH₂CH₂--OSO_ThreeH
1-1209 H -CH = CH-CH₂--OC (= O)---CH₂CH₂--OPO_ThreeH₂
1-1210 H -CH = CH-CH₂--OC (= O)---CH₂CH₂-1-Azt
1-1211 H -CH = CH-CH₂--OC (= O)---CH₂CH₂-1-Pyrd
1-1212 H -CH = CH-CH₂--OC (= O)---CH₂CH₂-1-Pip
1-1213 H -CH = CH-CH₂--OC (= O)---CH₂CH₂-4-Pip
1-1214 H -CH = CH-CH₂--OC (= O)---CH₂CH₂-1-Me-4-Pip
1-1215 H -CH = CH-CH₂--OC (= O)---CH₂CH₂-1-Piz
1-1216 H -CH = CH-CH₂--OC (= O)---CH₂CH₂-4-Me-1-Piz
1-1217 H -CH = CH-CH₂--OC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-1218 H -CH = CH-CH₂--OC (= O)---CH₂CH₂-4-Mor
1-1219 H -CH = CH-CH₂--OC (= O)---CH₂CH₂--NMe₂
1-1220 H -CH = CH-CH₂--OC (= O)---CH₂CH₂--NMeCH₂CH₂OH
1-1221 H -CH = CH-CH₂--OC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
1-1222 H -CH₂CH₂--C (= O) O---4-Pip
1-1223 H -CH₂CH₂--C (= O) O---1-Me-4-Pip
1-1224 H -CH₂CH₂--C (= O) O---CH₂--COOH
1-1225 H -CH₂CH₂--C (= O) O---CH₂-4-Pip
1-1226 H -CH₂CH₂--C (= O) O---CH₂-1-Me-4-Pip
1-1227 H -CH₂CH₂--C (= O) O---CH₂CH₂--COOH
1-1228 H -CH₂CH₂--C (= O) O---CH₂CH₂--SO_ThreeH
1-1229 H -CH₂CH₂--C (= O) O---CH₂CH₂--OSO_ThreeH
1-1230 H -CH₂CH₂--C (= O) O---CH₂CH₂--OPO_ThreeH₂
1-1231 H -CH₂CH₂--C (= O) O---CH₂CH₂-1-Azt
1-1232 H -CH₂CH₂--C (= O) O---CH₂CH₂-1-Pyrd
1-1233 H -CH₂CH₂--C (= O) O---CH₂CH₂-1-Pip
1-1234 H -CH₂CH₂--C (= O) O---CH₂CH₂-4-Pip
1-1235 H -CH₂CH₂--C (= O) O---CH₂CH₂-1-Me-4-Pip
1-1236 H -CH₂CH₂--C (= O) O---CH₂CH₂-1-Piz
1-1237 H -CH₂CH₂--C (= O) O---CH₂CH₂-4-Me-1-Piz
1-1238 H -CH₂CH₂--C (= O) O---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-1239 H -CH₂CH₂--C (= O) O---CH₂CH₂-4-Mor
1-1240 H -CH₂CH₂--C (= O) O---CH₂CH₂--NMe₂
1-1241 H -CH₂CH₂--C (= O) O---CH₂CH₂--NMeCH₂CH₂OH
1-1242 H -CH₂CH₂--C (= O) O---CH₂CH₂--N (CH₂CH₂OH)₂
1-1243 H-(CH₂)_Three--C (= O) O---4-Pip
1-1244 H-(CH₂)_Three--C (= O) O---1-Me-4-Pip
1-1245 H-(CH₂)_Three--C (= O) O---CH₂--COOH
1-1246 H-(CH₂)_Three--C (= O) O---CH₂-4-Pip
1-1247 H-(CH₂)_Three--C (= O) O---CH₂-1-Me-4-Pip
1-1248 H-(CH₂)_Three--C (= O) O---CH₂CH₂--COOH
1-1249 H-(CH₂)_Three--C (= O) O---CH₂CH₂--SO_ThreeH
1-1250 H-(CH₂)_Three--C (= O) O---CH₂CH₂--OSO_ThreeH
1-1251 H-(CH₂)_Three--C (= O) O---CH₂CH₂--OPO_ThreeH₂
1-1252 H-(CH₂)_Three--C (= O) O---CH₂CH₂-1-Azt
1-1253 H-(CH₂)_Three--C (= O) O---CH₂CH₂-1-Pyrd
1-1254 H-(CH₂)_Three--C (= O) O---CH₂CH₂-1-Pip
1-1255 H-(CH₂)_Three--C (= O) O---CH₂CH₂-4-Pip
1-1256 H-(CH₂)_Three--C (= O) O---CH₂CH₂-1-Me-4-Pip
1-1257 H-(CH₂)_Three--C (= O) O---CH₂CH₂-1-Piz
1-1258 H-(CH₂)_Three--C (= O) O---CH₂CH₂-4-Me-1-Piz
1-1259 H-(CH₂)_Three--C (= O) O---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-1260 H-(CH₂)_Three--C (= O) O---CH₂CH₂-4-Mor
1-1261 H-(CH₂)_Three--C (= O) O---CH₂CH₂--NMe₂
1-1262 H-(CH₂)_Three--C (= O) O---CH₂CH₂--NMeCH₂CH₂OH
1-1263 H-(CH₂)_Three--C (= O) O---CH₂CH₂--N (CH₂CH₂OH)₂
1-1264 H -CH = CH- -C (= O) O---4-Pip
1-1265 H -CH = CH- -C (= O) O---1-Me-4-Pip
1-1266 H -CH = CH- -C (= O) O---CH₂--COOH
1-1267 H -CH = CH- -C (= O) O---CH₂-4-Pip
1-1268 H -CH = CH- -C (= O) O---CH₂-1-Me-4-Pip
1-1269 H -CH = CH- -C (= O) O---CH₂CH₂--COOH
1-1270 H -CH = CH- -C (= O) O---CH₂CH₂--SO_ThreeH
1-1271 H -CH = CH- -C (= O) O---CH₂CH₂--OSO_ThreeH
1-1272 H -CH = CH- -C (= O) O---CH₂CH₂--OPO_ThreeH₂
1-1273 H -CH = CH- -C (= O) O---CH₂CH₂-1-Azt
1-1274 H -CH = CH- -C (= O) O---CH₂CH₂-1-Pyrd
1-1275 H -CH = CH- -C (= O) O---CH₂CH₂-1-Pip
1-1276 H -CH = CH- -C (= O) O---CH₂CH₂-4-Pip
1-1277 H -CH = CH- -C (= O) O---CH₂CH₂-1-Me-4-Pip
1-1278 H -CH = CH- -C (= O) O---CH₂CH₂-1-Piz
1-1279 H -CH = CH- -C (= O) O---CH₂CH₂-4-Me-1-Piz
1-1280 H -CH = CH- -C (= O) O---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
1-1281 H -CH = CH- -C (= O) O---CH₂CH₂-4-Mor
1-1282 H -CH = CH- -C (= O) O---CH₂CH₂--NMe₂
1-1283 H -CH = CH- -C (= O) O---CH₂CH₂--NMeCH₂CH₂OH
1-1284 H -CH = CH- -C (= O) O---CH₂CH₂--N (CH₂CH₂OH)₂
1-1285 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂CH₂--NHMe
1-1286 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂CH₂--NHMe
-------------------------------------------------- -----------------
(Table 2)

-------------------------------------------------- -----------------
Example R ¹ -L ¹ --G- -L ² --L ³ --A
Compound number
-------------------------------------------------- -----------------
2-1 Me -CH ₂ ----1-Pyrd
2-2 Me -CH ₂ ----1-Pip
2-3 Me -CH ₂ ----1-Me-4-Pip
2-4 Me -CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
2-5 Me -CH ₂ ----4-Me-1-Piz
2-6 Me -CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
2-7 Me -CH ₂ ----4-Mor
2-8 Me -CH ₂ -----NH ₂
2-9 Me -CH ₂ -----NHMe
2-10 Me -CH ₂ -----NMe ₂
2-11 Me -CH ₂ CH ₂ -----COOH
2-12 Me -CH ₂ CH ₂ -----OPO ₃ H ₂
2-13 Me -CH ₂ CH ₂ ----1-Pyrd
2-14 Me -CH ₂ CH ₂ ----1-Pip
2-15 Me -CH ₂ CH ₂ ----1-Me-4-Pip
2-16 Me -CH ₂ CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
2-17 Me -CH ₂ CH ₂ ----4-Me-1-Piz
2-18 Me -CH ₂ CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
2-19 Me -CH ₂ CH ₂ ----4-Mor
2-20 Me -CH ₂ CH ₂ -----NH ₂
2-21 Me -CH ₂ CH ₂ -----NHMe
2-22 Me -CH ₂ CH ₂ -----NMe ₂
2-23 Me-(CH ₂ ) ₃ -----COOH
2-24 Me-(CH ₂ ) ₃ -----OPO ₃ H ₂
2-25 Me -CH ₂ CH ₂ --C (= O)---1-Piz
2-26 Me -CH ₂ CH ₂ --C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
2-27 Me -CH ₂ CH ₂ --C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
2-28 Me -CH ₂ CH ₂ --C (= O)---4-Me-1-Piz
2-29 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
2-30 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
2-31 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ Car) -1-Piz
2-32 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
2-33 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ F) -1-Piz
2-34 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--COOH
2-35 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--OSO ₃ H
2-36 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--OPO ₃ H ₂
2-37 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--COOH
2-38 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--SO ₃ H
2-39 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--OSO ₃ H
2-40 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--OPO ₃ H ₂
2-41 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pyrd
2-42 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pip
2-43 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Me-1-Piz
2-44 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
2-45 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Mor
2-46 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NHMe
2-47 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMe ₂
2-48 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
2-49 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
2-50 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --COOH
2-51 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --SO ₃ H
2-52 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
2-53 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
2-54 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH _2-4 -Mor
2-55 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NH ₂
2-56 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NHMe
2-57 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMe ₂
2-58 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
2-59 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
2-60 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH _{2
2-61 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Azt
_{2-62 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pyrd
_{2-63 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pip
2-64 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Me-1-Piz
2-65 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ -4- (CH ₂ CH ₂ OH) -1-Piz
2-66 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
2-67 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
2-68 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
2-69 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
2-70 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
2-71 Me -CH = CH- -C (= O)---1-Piz
2-72 Me -CH = CH- -C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
2-73 Me -CH = CH- -C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
2-74 Me -CH = CH- -C (= O)---4-Me-1-Piz
2-75 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
2-76 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
2-77 Me -CH = CH- -C (= O)---4- (CH ₂ Car) -1-Piz
2-78 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
2-79 Me -CH = CH- -C (= O)-1,3-Azt--COOH
2-80 Me -CH = CH- -C (= O)-1,3-Azt--OSO ₃ H
2-81 Me -CH = CH- -C (= O)-1,3-Azt--OPO ₃ H ₂
2-82 Me -CH = CH- -C (= O)-1,4-Pip--COOH
2-83 Me -CH = CH- -C (= O)-1,4-Pip--SO ₃ H
2-84 Me -CH = CH- -C (= O)-1,4-Pip--OSO ₃ H
2-85 Me -CH = CH- -C (= O)-1,4-Pip--OPO ₃ H ₂
2-86 Me -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
2-87 Me -CH = CH- -C (= O)-1,4-Pip-1-Pip
2-88 Me -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
2-89 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
2-90 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ NHAc) -1-Piz
2-91 Me -CH = CH- -C (= O)-1,4-Pip-4-Mor
2-92 Me -CH = CH- -C (= O)-1,4-Pip--NHMe
2-93 Me -CH = CH- -C (= O)-1,4-Pip--NMe ₂
2-94 Me -CH = CH- -C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
2-95 Me -CH = CH- -C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
2-96 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --COOH
2-97 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
2-98 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
2-99 Me -CH = CH- -C (= O)-1,4-Pip -CH _2-4 -Mor
2-100 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NH ₂
2-101 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NHMe
2-102 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMe ₂
2-103 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
2-104 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
2-105 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH ₂
2-106 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
2-107 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
2-108 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
2-109 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
2-110 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) _{2
2-111 Me -CH 2 - -NHC (=} O) - - -CH 2 - 4-Me-1-Piz
_{2-112 Me -CH 2 - -NHC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
2-113 Me -CH ₂ --NHC (= O)---CH ₂ --NMe ₂
2-114 Me -CH ₂ --NMeC (= O)---CH _2-4 -Me-1-Piz
_{2-115 Me -CH 2 - -NMeC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
2-116 Me -CH ₂ --NMeC (= O)---CH ₂ --NMe ₂
2-117 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --COOH
2-118 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
2-119 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --NMe ₂
2-120 H -CH ₂ ----1-Pyrd
2-121 H -CH ₂ ----1-Pip
2-122 H -CH ₂ ----1-Me-4-Pip
2-123 H -CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
2-124 H -CH ₂ ----4-Me-1-Piz
2-125 H -CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
2-126 H -CH ₂ ----4-Mor
2-127 H -CH ₂ -----NH ₂
2-128 H -CH ₂ -----NHMe
2-129 H -CH ₂ -----NMe ₂
2-130 H -CH ₂ CH ₂ -----COOH
2-131 H -CH ₂ CH ₂ -----OPO ₃ H ₂
2-132 H -CH ₂ CH ₂ ----1-Pyrd
2-133 H -CH ₂ CH ₂ ----1-Pip
2-134 H -CH ₂ CH ₂ ----1-Me-4-Pip
2-135 H -CH ₂ CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
2-136 H -CH ₂ CH ₂ ----4-Me-1-Piz
2-137 H -CH ₂ CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
2-138 H -CH ₂ CH ₂ ----4-Mor
2-139 H -CH ₂ CH ₂ -----NH ₂
2-140 H -CH ₂ CH ₂ -----NHMe
2-141 H -CH ₂ CH ₂ -----NMe ₂
2-142 H-(CH ₂ ) ₃ -----COOH
2-143 H-(CH ₂ ) ₃ -----OPO ₃ H ₂
2-144 H -CH ₂ CH ₂ --C (= O)---1-Piz
2-145 H -CH ₂ CH ₂ --C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
2-146 H -CH ₂ CH ₂ --C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
2-147 H -CH ₂ CH ₂ --C (= O)---4-Me-1-Piz
2-148 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
2-149 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
2-150 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ Car) -1-Piz
2-151 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
2-152 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ F) -1-Piz
2-153 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--COOH
2-154 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--OSO ₃ H
2-155 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--OPO ₃ H ₂
2-156 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--COOH
2-157 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--SO ₃ H
2-158 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--OSO ₃ H
2-159 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--OPO ₃ H ₂
2-160 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pyrd
2-161 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pip
2-162 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Me-1-Piz
2-163 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
2-164 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Mor
2-165 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NHMe
2-166 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMe ₂
2-167 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
2-168 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
2-169 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --COOH
2-170 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --SO ₃ H
2-171 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
2-172 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
2-173 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH _2-4 -Mor
2-174 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NH ₂
2-175 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NHMe
2-176 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMe ₂
2-177 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
2-178 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
2-179 H -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH _{2
2-180 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Azt
_{2-181 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pyrd
_{2-182 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pip
2-183 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Me-1-Piz
2-184 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ -4- (CH ₂ CH ₂ OH) -1-Piz
2-185 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
2-186 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
2-187 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
2-188 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
2-189 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
2-190 H -CH = CH- -C (= O)---1-Piz
2-191 H -CH = CH- -C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
2-192 H -CH = CH- -C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
2-193 H -CH = CH- -C (= O)---4-Me-1-Piz
2-194 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
2-195 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
2-196 H -CH = CH- -C (= O)---4- (CH ₂ Car) -1-Piz
2-197 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
2-198 H -CH = CH- -C (= O)-1,3-Azt--COOH
2-199 H -CH = CH- -C (= O)-1,3-Azt--OSO ₃ H
2-200 H -CH = CH- -C (= O)-1,3-Azt--OPO ₃ H ₂
2-201 H -CH = CH- -C (= O)-1,4-Pip--COOH
2-202 H -CH = CH- -C (= O)-1,4-Pip--SO ₃ H
2-203 H -CH = CH- -C (= O)-1,4-Pip--OSO ₃ H
2-204 H -CH = CH- -C (= O)-1,4-Pip--OPO ₃ H ₂
2-205 H -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
2-206 H -CH = CH- -C (= O)-1,4-Pip-1-Pip
2-207 H -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
2-208 H -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
2-209 H -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ NHAc) -1-Piz
2-210 H -CH = CH- -C (= O)-1,4-Pip-4-Mor
2-211 H -CH = CH- -C (= O)-1,4-Pip--NHMe
2-212 H -CH = CH- -C (= O)-1,4-Pip--NMe ₂
2-213 H -CH = CH- -C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
2-214 H -CH = CH- -C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
2-215 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --COOH
2-216 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
2-217 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
2-218 H -CH = CH- -C (= O)-1,4-Pip -CH _2-4 -Mor
2-219 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NH ₂
2-220 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NHMe
2-221 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMe ₂
2-222 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
2-223 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
2-224 H -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH ₂
2-225 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
2-226 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
2-227 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
2-228 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
2-229 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) _{2
2-230 H -CH 2 - -NHC (=} O) - - -CH 2 - 4-Me-1-Piz
_{2-231 H -CH 2 - -NHC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
2-232 H -CH ₂ --NHC (= O)---CH ₂ --NMe ₂
2-233 H -CH ₂ --NMeC (= O)---CH _2-4 -Me-1-Piz
_{2-234 H -CH 2 - -NMeC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
2-235 H -CH ₂ --NMeC (= O)---CH ₂ --NMe ₂
2-236 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --COOH
2-237 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
2-238 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --NMe ₂
2-239 Me 1,4-cHx----COOH
2-240 Me 1,4-cHx----OPO ₃ H ₂
2-241 Me 1,4-cHx---1-Pyrd
2-242 Me 1,4-cHx---1-Pip
2-243 Me 1,4-cHx---1-Me-4-Pip
2-244 Me 1,4-cHx---1- (CH ₂ CH ₂ OH) -4-Pip
2-245 Me 1,4-cHx---4-Me-1-Piz
2-246 Me 1,4-cHx---4- (CH ₂ CH ₂ OH) -1-Piz
2-247 Me 1,4-cHx---4-Mor
2-248 Me 1,4-cHx----NH ₂
2-249 Me 1,4-cHx----NHMe
2-250 Me 1,4-cHx----NMe ₂
2-251 H 1,4-cHx----COOH
2-252 H 1,4-cHx----OPO ₃ H ₂
2-253 H 1,4-cHx---1-Pyrd
2-254 H 1,4-cHx---1-Pip
2-255 H 1,4-cHx---1-Me-4-Pip
2-256 H 1,4-cHx---1- (CH ₂ CH ₂ OH) -4-Pip
2-257 H 1,4-cHx---4-Me-1-Piz
2-258 H 1,4-cHx---4- (CH ₂ CH ₂ OH) -1-Piz
2-259 H 1,4-cHx---4-Mor
2-260 H 1,4-cHx----NH ₂
2-261 H 1,4-cHx----NHMe
2-262 H 1,4-cHx----NMe ₂
2-263 Me-(CH ₂ ) ₄ -----COOH
2-264 Me-(CH ₂ ) ₄ -----SO ₃ H
2-265 Me-(CH ₂ ) ₄ -----OSO ₃ H
2-266 Me-(CH ₂ ) ₄ -----OPO ₃ H ₂
2-267 Me-(CH ₂ ) ₅ -----COOH
2-268 Me-(CH ₂ ) ₅ -----SO ₃ H
2-269 Me-(CH ₂ ) ₅ -----OSO ₃ H
2-270 Me-(CH ₂ ) ₅ -----OPO ₃ H ₂
2-271 Me-(CH ₂ ) ₃ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
2-272 Me-(CH ₂ ) ₄ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
2-273 Me-(CH ₂ ) ₅ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
2-274 Me-(CH ₂ ) ₆ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
2-275 H-(CH ₂ ) ₄ -----COOH
2-276 H-(CH ₂ ) ₄ -----SO ₃ H
2-277 H-(CH ₂ ) ₄ -----OSO ₃ H
2-278 H-(CH ₂ ) ₄ -----OPO ₃ H ₂
2-279 H-(CH ₂ ) ₅ -----COOH
2-280 H-(CH ₂ ) ₅ -----SO ₃ H
2-281 H-(CH ₂ ) ₅ -----OSO ₃ H
2-282 H-(CH ₂ ) ₅ -----OPO ₃ H ₂
2-283 H-(CH ₂ ) ₃ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
2-284 H-(CH ₂ ) ₄ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
2-285 H-(CH ₂ ) ₅ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
2-286 H-(CH ₂ ) ₆ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
2-287 Me -CH ₂ CH ₂ --OC (= O)---1-Me-4-Pip
2-288 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --COOH
2-289 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --SO ₃ H
_{2-290 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -OPO 3 H 2
_{2-291 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Azt
_{2-292 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pyrd
_{2-293 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pip
_{2-294 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Me-4-Pip
_{2-295 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Me-1-Piz
_{2-296 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{2-297 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Mor
2-298 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --NMe _{2
2-299 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{2-300 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
2-301 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --COOH
_{2-302 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -SO 3 H
_{2-303 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{2-304 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Azt
_{2-305 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pyrd
_{2-306 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pip
_{2-307 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{2-308 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{2-309 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
2-310 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH _2-4 -Mor
_{2-311 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMe 2
_{2-312 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{2-313 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
2-314 Me-(CH ₂ ) ₃ --OC (= O)---1-Me-4-Pip
2-315 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --COOH
2-316 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --SO ₃ H
_{2-317 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -OPO 3 H 2
_{2-318 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Azt
_{2-319 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pyrd
_{2-320 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pip
_{2-321 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Me-4-Pip
_{2-322 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Me-1-Piz
_{2-323 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{2-324 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Mor
2-325 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --NMe _{2
2-326 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{2-327 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
_{2-328 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -COOH
2-329 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{2-330 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{2-331 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Azt
_{2-332 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pyrd
_{2-333 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pip
_{2-334 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{2-335 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{2-336 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
2-337 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH _2-4 -Mor
_{2-338 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMe 2
_{2-339 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{2-340 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
2-341 Me -CH ₂ CH ₂ --C (= O) O---1-Me-4-Pip
2-342 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ --COOH
_{2-343 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 - 1-Me-4-Pip
2-344 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --COOH
2-345 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --SO ₃ H
_{2-346 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
_{2-347 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Azt
_{2-348 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pyrd
_{2-349 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pip
_{2-350 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
_{2-351 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
_{2-352 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
2-353 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH _2-4 -Mor
_{2-354 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMe 2
_{2-355 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{2-356 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
2-357 Me -CH = CH- -C (= O) O---1-Me-4-Pip
2-358 Me -CH = CH- -C (= O) O---CH ₂ --COOH
2-358 Me -CH = CH- -C (= O) O- - -CH 2 - 1-Me-4-Pip
2-359 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -COOH
2-360 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -SO 3 H
2-361 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
2-362 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Azt
2-363 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pyrd
2-364 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pip
2-365 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
2-366 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
2-367 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
2-368 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Mor
2-369 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMe 2
2-370 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
2-371 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
2-372 H -CH ₂ CH ₂ --OC (= O)---1-Me-4-Pip
2-373 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --COOH
2-374 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --SO ₃ H
_{2-375 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -OPO 3 H 2
_{2-376 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Azt
_{2-377 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pyrd
_{2-378 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pip
_{2-379 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Me-4-Pip
_{2-380 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Me-1-Piz
_{2-381 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{2-382 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Mor
2-383 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --NMe _{2
2-384 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{2-385 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
2-386 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --COOH
2-387 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{2-388 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{2-389 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Azt
_{2-390 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pyrd
_{2-391 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pip
_{2-392 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{2-393 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{2-394 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
2-395 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH _2-4 -Mor
_{2-306 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMe 2
_{2-397 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{2-398 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
2-399 Me-(CH ₂ ) ₃ --OC (= O)---1-Me-4-Pip
2-400 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --COOH
2-401 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --SO ₃ H
_{2-402 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -OPO 3 H 2
_{2-403 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Azt
_{2-404 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pyrd
_{2-405 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pip
_{2-406 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Me-4-Pip
_{2-407 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Me-1-Piz
_{2-408 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{2-409 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Mor
2-410 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --NMe _{2
2-411 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{2-412 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
2-413 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --COOH
2-414 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{2-415 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{2-416 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Azt
_{2-417 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pyrd
_{2-418 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pip
_{2-419 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{2-420 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{2-421 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
2-422 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH _2-4 -Mor
_{2-423 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMe 2
_{2-424 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{2-425 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
2-426 H -CH ₂ CH ₂ --C (= O) O---1-Me-4-Pip
2-427 H -CH ₂ CH ₂ --C (= O) O---CH ₂ --COOH
_{2-428 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 - 1-Me-4-Pip
2-429 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --COOH
2-430 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --SO ₃ H
_{2-431 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
_{2-432 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Azt
_{2-433 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pyrd
_{2-434 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pip
_{2-435 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
_{2-436 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
_{2-437 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
2-438 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH _2-4 -Mor
_{2-439 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMe 2
_{2-440 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{2-441 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
2-442 H -CH = CH- -C (= O) O---1-Me-4-Pip
2-443 H -CH = CH- -C (= O) O---CH ₂ --COOH
2-444 H -CH = CH- -C (= O) O- - -CH 2 - 1-Me-4-Pip
2-445 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -COOH
2-446 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -SO 3 H
2-447 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
2-448 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Azt
2-449 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pyrd
2-450 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pip
2-451 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
2-452 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
2-453 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
2-454 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Mor
2-455 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMe 2
2-456 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
2-457 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
-------------------------------------------------- -----------------
(Table 3)

-------------------------------------------------- -----------------
Example R ¹ -L ¹ --G- -L ² --L ³ --A
Compound number
-------------------------------------------------- -----------------
3-1 Me -CH ₂ ----1-Pyrd
3-2 Me -CH ₂ ----1-Pip
3-3 Me -CH ₂ ----1-Me-4-Pip
3-4 Me -CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
3-5 Me -CH ₂ ----4-Me-1-Piz
3-6 Me -CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
3-7 Me -CH ₂ ----4-Mor
3-8 Me -CH ₂ -----NH ₂
3-9 Me -CH ₂ -----NHMe
3-10 Me -CH ₂ -----NMe ₂
3-11 Me -CH ₂ CH ₂ -----COOH
3-12 Me -CH ₂ CH ₂ -----OPO ₃ H ₂
3-13 Me -CH ₂ CH ₂ ----1-Pyrd
3-14 Me -CH ₂ CH ₂ ----1-Pip
3-15 Me -CH ₂ CH ₂ ----1-Me-4-Pip
3-16 Me -CH ₂ CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
3-17 Me -CH ₂ CH ₂ ----4-Me-1-Piz
3-18 Me -CH ₂ CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
3-19 Me -CH ₂ CH ₂ ----4-Mor
3-20 Me -CH ₂ CH ₂ -----NH ₂
3-21 Me -CH ₂ CH ₂ -----NHMe
3-22 Me -CH ₂ CH ₂ -----NMe ₂
3-23 Me-(CH ₂ ) ₃ -----COOH
3-24 Me-(CH ₂ ) ₃ -----OPO ₃ H ₂
3-25 Me -CH ₂ CH ₂ --C (= O)---1-Piz
3-26 Me -CH ₂ CH ₂ --C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
3-27 Me -CH ₂ CH ₂ --C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
3-28 Me -CH ₂ CH ₂ --C (= O)---4-Me-1-Piz
3-29 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
3-30 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
3-31 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ Car) -1-Piz
3-32 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
3-33 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ F) -1-Piz
3-34 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--COOH
3-35 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--OSO ₃ H
3-36 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--OPO ₃ H ₂
3-37 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--COOH
3-38 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--SO ₃ H
3-39 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--OSO ₃ H
3-40 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--OPO ₃ H ₂
3-41 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pyrd
3-42 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pip
3-43 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Me-1-Piz
3-44 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
3-45 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Mor
3-46 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NHMe
3-47 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMe ₂
3-48 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
3-49 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
3-50 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --COOH
3-51 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --SO ₃ H
3-52 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
3-53 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
3-54 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH _2-4 -Mor
3-55 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NH ₂
3-56 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NHMe
3-57 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMe ₂
3-58 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
3-59 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
3-60 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH _{2
3-61 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Azt
_{3-62 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pyrd
_{3-63 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pip
3-64 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Me-1-Piz
3-65 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ -4- (CH ₂ CH ₂ OH) -1-Piz
3-66 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
3-67 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
3-68 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
3-69 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
3-70 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
3-71 Me -CH = CH- -C (= O)---1-Piz
3-72 Me -CH = CH- -C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
3-73 Me -CH = CH- -C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
3-74 Me -CH = CH- -C (= O)---4-Me-1-Piz
3-75 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
3-76 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
3-77 Me -CH = CH- -C (= O)---4- (CH ₂ Car) -1-Piz
3-78 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
3-79 Me -CH = CH- -C (= O)-1,3-Azt--COOH
3-80 Me -CH = CH- -C (= O)-1,3-Azt--OSO ₃ H
3-81 Me -CH = CH- -C (= O)-1,3-Azt--OPO ₃ H ₂
3-82 Me -CH = CH- -C (= O)-1,4-Pip--COOH
3-83 Me -CH = CH- -C (= O)-1,4-Pip--SO ₃ H
3-84 Me -CH = CH- -C (= O)-1,4-Pip--OSO ₃ H
3-85 Me -CH = CH- -C (= O)-1,4-Pip--OPO ₃ H ₂
3-86 Me -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
3-87 Me -CH = CH- -C (= O)-1,4-Pip-1-Pip
3-88 Me -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
3-89 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
3-90 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ NHAc) -1-Piz
3-91 Me -CH = CH- -C (= O)-1,4-Pip-4-Mor
3-92 Me -CH = CH- -C (= O)-1,4-Pip--NHMe
3-93 Me -CH = CH- -C (= O)-1,4-Pip--NMe ₂
3-94 Me -CH = CH- -C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
3-95 Me -CH = CH- -C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
3-96 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --COOH
3-97 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
3-98 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
3-99 Me -CH = CH- -C (= O)-1,4-Pip -CH _2-4 -Mor
3-100 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NH ₂
3-101 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NHMe
3-102 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMe ₂
3-103 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
3-104 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
3-105 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH ₂
3-106 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
3-107 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
3-108 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
3-109 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
3-110 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) _{2
3-111 Me -CH 2 - -NHC (=} O) - - -CH 2 - 4-Me-1-Piz
_{3-112 Me -CH 2 - -NHC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
3-113 Me -CH ₂ --NHC (= O)---CH ₂ --NMe ₂
3-114 Me -CH ₂ --NMeC (= O)---CH _2-4 -Me-1-Piz
_{3-115 Me -CH 2 - -NMeC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
3-116 Me -CH ₂ --NMeC (= O)---CH ₂ --NMe ₂
3-117 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --COOH
3-118 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
3-119 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --NMe ₂
3-120 H -CH ₂ ----1-Pyrd
3-121 H -CH ₂ ----1-Pip
3-122 H -CH ₂ ----1-Me-4-Pip
3-123 H -CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
3-124 H -CH ₂ ----4-Me-1-Piz
3-125 H -CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
3-126 H -CH ₂ ----4-Mor
3-127 H -CH ₂ -----NH ₂
3-128 H -CH ₂ -----NHMe
3-129 H -CH ₂ -----NMe ₂
3-130 H -CH ₂ CH ₂ -----COOH
3-131 H -CH ₂ CH ₂ -----OPO ₃ H ₂
3-132 H -CH ₂ CH ₂ ----1-Pyrd
3-133 H -CH ₂ CH ₂ ----1-Pip
3-134 H -CH ₂ CH ₂ ----1-Me-4-Pip
3-135 H -CH ₂ CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
3-136 H -CH ₂ CH ₂ ----4-Me-1-Piz
3-137 H -CH ₂ CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
3-138 H -CH ₂ CH ₂ ----4-Mor
3-139 H -CH ₂ CH ₂ -----NH ₂
3-140 H -CH ₂ CH ₂ -----NHMe
3-141 H -CH ₂ CH ₂ -----NMe ₂
3-142 H-(CH ₂ ) ₃ -----COOH
3-143 H-(CH ₂ ) ₃ -----OPO ₃ H ₂
3-144 H -CH ₂ CH ₂ --C (= O)---1-Piz
3-145 H -CH ₂ CH ₂ --C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
3-146 H -CH ₂ CH ₂ --C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
3-147 H -CH ₂ CH ₂ --C (= O)---4-Me-1-Piz
3-148 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
3-149 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
3-150 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ Car) -1-Piz
3-151 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
3-152 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ F) -1-Piz
3-153 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--COOH
3-154 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--OSO ₃ H
3-155 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--OPO ₃ H ₂
3-156 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--COOH
3-157 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--SO ₃ H
3-158 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--OSO ₃ H
3-159 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--OPO ₃ H ₂
3-160 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pyrd
3-161 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pip
3-162 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Me-1-Piz
3-163 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
3-164 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Mor
3-165 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NHMe
3-166 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMe ₂
3-167 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
3-168 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
3-169 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --COOH
3-170 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --SO ₃ H
3-171 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
3-172 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
3-173 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH _2-4 -Mor
3-174 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NH ₂
3-175 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NHMe
3-176 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMe ₂
3-177 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
3-178 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
3-179 H -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH _{2
3-180 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Azt
_{3-181 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pyrd
_{3-182 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pip
3-183 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Me-1-Piz
3-184 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ -4- (CH ₂ CH ₂ OH) -1-Piz
3-185 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
3-186 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
3-187 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
3-188 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
3-189 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
3-190 H -CH = CH- -C (= O)---1-Piz
3-191 H -CH = CH- -C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
3-192 H -CH = CH- -C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
3-193 H -CH = CH- -C (= O)---4-Me-1-Piz
3-194 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
3-195 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
3-196 H -CH = CH- -C (= O)---4- (CH ₂ Car) -1-Piz
3-197 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
3-198 H -CH = CH- -C (= O)-1,3-Azt--COOH
3-199 H -CH = CH- -C (= O)-1,3-Azt--OSO ₃ H
3-200 H -CH = CH- -C (= O)-1,3-Azt--OPO ₃ H ₂
3-201 H -CH = CH- -C (= O)-1,4-Pip--COOH
3-202 H -CH = CH- -C (= O)-1,4-Pip--SO ₃ H
3-203 H -CH = CH- -C (= O)-1,4-Pip--OSO ₃ H
3-204 H -CH = CH- -C (= O)-1,4-Pip--OPO ₃ H ₂
3-205 H -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
3-206 H -CH = CH- -C (= O)-1,4-Pip-1-Pip
3-207 H -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
3-208 H -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
3-209 H -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ NHAc) -1-Piz
3-210 H -CH = CH- -C (= O)-1,4-Pip-4-Mor
3-211 H -CH = CH- -C (= O)-1,4-Pip--NHMe
3-212 H -CH = CH- -C (= O)-1,4-Pip--NMe ₂
3-213 H -CH = CH- -C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
3-214 H -CH = CH- -C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
3-215 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --COOH
3-216 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
3-217 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
3-218 H -CH = CH- -C (= O)-1,4-Pip -CH _2-4 -Mor
3-219 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NH ₂
3-220 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NHMe
3-221 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMe ₂
3-222 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
3-223 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
3-224 H -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH ₂
3-225 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
3-226 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
3-227 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
3-228 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
3-229 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) _{2
3-230 H -CH 2 - -NHC (=} O) - - -CH 2 - 4-Me-1-Piz
_{3-231 H -CH 2 - -NHC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
3-232 H -CH ₂ --NHC (= O)---CH ₂ --NMe ₂
3-233 H -CH ₂ --NMeC (= O)---CH _2-4 -Me-1-Piz
_{3-234 H -CH 2 - -NMeC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
3-235 H -CH ₂ --NMeC (= O)---CH ₂ --NMe ₂
3-236 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --COOH
3-237 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
3-238 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --NMe ₂
3-239 Me 1,4-cHx----COOH
3-240 Me 1,4-cHx----OPO ₃ H ₂
3-241 Me 1,4-cHx---1-Pyrd
3-242 Me 1,4-cHx---1-Pip
3-243 Me 1,4-cHx---1-Me-4-Pip
3-244 Me 1,4-cHx---1- (CH ₂ CH ₂ OH) -4-Pip
3-245 Me 1,4-cHx---4-Me-1-Piz
3-246 Me 1,4-cHx---4- (CH ₂ CH ₂ OH) -1-Piz
3-247 Me 1,4-cHx---4-Mor
3-248 Me 1,4-cHx----NH ₂
3-249 Me 1,4-cHx----NHMe
3-250 Me 1,4-cHx----NMe ₂
3-251 H 1,4-cHx----COOH
3-252 H 1,4-cHx----OPO ₃ H ₂
3-253 H 1,4-cHx---1-Pyrd
3-254 H 1,4-cHx---1-Pip
3-255 H 1,4-cHx---1-Me-4-Pip
3-256 H 1,4-cHx---1- (CH ₂ CH ₂ OH) -4-Pip
3-257 H 1,4-cHx---4-Me-1-Piz
3-258 H 1,4-cHx---4- (CH ₂ CH ₂ OH) -1-Piz
3-259 H 1,4-cHx---4-Mor
3-260 H 1,4-cHx----NH ₂
3-261 H 1,4-cHx----NHMe
3-262 H 1,4-cHx----NMe ₂
3-263 Me-(CH ₂ ) ₄ -----COOH
3-264 Me-(CH ₂ ) ₄ -----SO ₃ H
3-265 Me-(CH ₂ ) ₄ -----OSO ₃ H
3-266 Me-(CH ₂ ) ₄ -----OPO ₃ H ₂
3-267 Me-(CH ₂ ) ₅ -----COOH
3-268 Me-(CH ₂ ) ₅ -----SO ₃ H
3-269 Me-(CH ₂ ) ₅ -----OSO ₃ H
3-270 Me-(CH ₂ ) ₅ -----OPO ₃ H ₂
3-271 Me-(CH ₂ ) ₃ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
3-272 Me-(CH ₂ ) ₄ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
3-273 Me-(CH ₂ ) ₅ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
3-274 Me-(CH ₂ ) ₆ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
3-275 H-(CH ₂ ) ₄ -----COOH
3-276 H-(CH ₂ ) ₄ -----SO ₃ H
3-277 H-(CH ₂ ) ₄ -----OSO ₃ H
3-278 H-(CH ₂ ) ₄ -----OPO ₃ H ₂
3-279 H-(CH ₂ ) ₅ -----COOH
3-280 H-(CH ₂ ) ₅ -----SO ₃ H
3-281 H-(CH ₂ ) ₅ -----OSO ₃ H
3-282 H-(CH ₂ ) ₅ -----OPO ₃ H ₂
3-283 H-(CH ₂ ) ₃ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
3-284 H-(CH ₂ ) ₄ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
3-285 H-(CH ₂ ) ₅ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
3-286 H-(CH ₂ ) ₆ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
3-287 Me -CH ₂ CH ₂ --OC (= O)---1-Me-4-Pip
3-288 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --COOH
3-289 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --SO ₃ H
_{3-290 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -OPO 3 H 2
_{3-291 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Azt
_{3-292 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pyrd
_{3-293 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pip
_{3-294 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Me-4-Pip
_{3-295 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Me-1-Piz
_{3-296 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{3-297 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Mor
3-298 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --NMe _{2
3-299 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{3-300 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
3-301 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --COOH
3-302 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{3-303 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{3-304 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Azt
_{3-305 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pyrd
_{3-306 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pip
_{3-307 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{3-308 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{3-309 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{3-310 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Mor
_{3-311 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMe 2
_{3-312 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{3-313 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
3-314 Me-(CH ₂ ) ₃ --OC (= O)---1-Me-4-Pip
3-315 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --COOH
3-316 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --SO ₃ H
_{3-317 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -OPO 3 H 2
_{3-318 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Azt
_{3-319 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pyrd
_{3-320 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pip
_{3-321 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Me-4-Pip
_{3-322 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Me-1-Piz
_{3-323 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{3-324 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Mor
3-325 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --NMe _{2
3-326 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{3-327 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
_{3-328 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -COOH
3-329 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{3-330 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{3-331 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Azt
_{3-332 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pyrd
_{3-333 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pip
_{3-334 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{3-335 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{3-336 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
3-337 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH _2-4 -Mor
_{3-338 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMe 2
_{3-339 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{3-340 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
3-341 Me -CH ₂ CH ₂ --C (= O) O---1-Me-4-Pip
3-342 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ --COOH
_{3-343 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 - 1-Me-4-Pip
3-344 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --COOH
3-345 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --SO ₃ H
_{3-346 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
_{3-347 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Azt
_{3-348 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pyrd
_{3-349 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pip
_{3-350 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
_{3-351 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
_{3-352 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
3-353 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH _2-4 -Mor
_{3-354 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMe 2
_{3-355 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{3-356 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
3-357 Me -CH = CH- -C (= O) O---1-Me-4-Pip
3-358 Me -CH = CH- -C (= O) O---CH ₂ --COOH
3-358 Me -CH = CH- -C (= O) O- - -CH 2 - 1-Me-4-Pip
3-359 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -COOH
3-360 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -SO 3 H
3-361 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
3-362 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Azt
3-363 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pyrd
3-364 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pip
3-365 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
3-366 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
3-367 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
3-368 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Mor
3-369 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMe 2
3-370 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
3-371 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
3-372 H -CH ₂ CH ₂ --OC (= O)---1-Me-4-Pip
3-373 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --COOH
3-374 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --SO ₃ H
_{3-375 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -OPO 3 H 2
_{3-376 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Azt
_{3-377 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pyrd
_{3-378 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pip
_{3-379 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Me-4-Pip
_{3-380 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Me-1-Piz
_{3-381 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{3-382 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Mor
3-383 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --NMe _{2
3-384 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{3-385 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
3-386 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --COOH
3-387 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{3-388 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{3-389 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Azt
_{3-390 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pyrd
_{3-391 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pip
_{3-392 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{3-393 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{3-394 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
3-395 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH _2-4 -Mor
_{3-306 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMe 2
_{3-397 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{3-398 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
3-399 Me-(CH ₂ ) ₃ --OC (= O)---1-Me-4-Pip
3-400 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --COOH
3-401 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --SO ₃ H
_{3-402 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -OPO 3 H 2
_{3-403 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Azt
_{3-404 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pyrd
_{3-405 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pip
_{3-406 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Me-4-Pip
_{3-407 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Me-1-Piz
_{3-408 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{3-409 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Mor
3-410 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --NMe _{2
3-411 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{3-412 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
3-413 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --COOH
3-414 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{3-415 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{3-416 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Azt
_{3-417 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pyrd
_{3-418 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pip
_{3-419 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{3-420 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{3-421 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
3-422 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH _2-4 -Mor
_{3-423 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMe 2
_{3-424 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{3-425 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
3-426 H -CH ₂ CH ₂ --C (= O) O---1-Me-4-Pip
3-427 H -CH ₂ CH ₂ --C (= O) O---CH ₂ --COOH
_{3-428 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 - 1-Me-4-Pip
3-429 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --COOH
_{3-430 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -SO 3 H
_{3-431 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
_{3-432 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Azt
_{3-433 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pyrd
_{3-434 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pip
_{3-435 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
_{3-436 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
_{3-437 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
3-438 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH _2-4 -Mor
_{3-439 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMe 2
_{3-440 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{3-441 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
3-442 H -CH = CH- -C (= O) O---1-Me-4-Pip
3-443 H -CH = CH- -C (= O) O---CH ₂ --COOH
3-444 H -CH = CH- -C (= O) O- - -CH 2 - 1-Me-4-Pip
3-445 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -COOH
3-446 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -SO 3 H
3-447 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
3-448 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Azt
3-449 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pyrd
3-450 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pip
3-451 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
3-452 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
3-453 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
3-454 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Mor
3-455 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMe 2
3-456 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
3-457 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
-------------------------------------------------- -----------------
(Table 4)

-------------------------------------------------- -----------------
Example R ¹ -L ¹ --G- -L ² --L ³ --A
Compound number
-------------------------------------------------- -----------------
4-1 Me -CH ₂ ----1-Pyrd
4-2 Me -CH ₂ ----1-Pip
4-3 Me -CH ₂ ----1-Me-4-Pip
4-4 Me -CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
4-5 Me -CH ₂ ----4-Me-1-Piz
4-6 Me -CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
4-7 Me -CH ₂ ----4-Mor
4-8 Me -CH ₂ -----NH ₂
4-9 Me -CH ₂ -----NHMe
4-10 Me -CH ₂ -----NMe ₂
4-11 Me -CH ₂ CH ₂ -----COOH
4-12 Me -CH ₂ CH ₂ -----OPO ₃ H ₂
4-13 Me -CH ₂ CH ₂ ----1-Pyrd
4-14 Me -CH ₂ CH ₂ ----1-Pip
4-15 Me -CH ₂ CH ₂ ----1-Me-4-Pip
4-16 Me -CH ₂ CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
4-17 Me -CH ₂ CH ₂ ----4-Me-1-Piz
4-18 Me -CH ₂ CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
4-19 Me -CH ₂ CH ₂ ----4-Mor
4-20 Me -CH ₂ CH ₂ -----NH ₂
4-21 Me -CH ₂ CH ₂ -----NHMe
4-22 Me -CH ₂ CH ₂ -----NMe ₂
4-23 Me-(CH ₂ ) ₃ -----COOH
4-24 Me-(CH ₂ ) ₃ -----OPO ₃ H ₂
4-25 Me -CH ₂ CH ₂ --C (= O)---1-Piz
4-26 Me -CH ₂ CH ₂ --C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
4-27 Me -CH ₂ CH ₂ --C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
4-28 Me -CH ₂ CH ₂ --C (= O)---4-Me-1-Piz
4-29 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
4-30 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
4-31 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ Car) -1-Piz
4-32 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
4-33 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ F) -1-Piz
4-34 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--COOH
4-35 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--OSO ₃ H
4-36 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--OPO ₃ H ₂
4-37 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--COOH
4-38 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--SO ₃ H
4-39 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--OSO ₃ H
4-40 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--OPO ₃ H ₂
4-41 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pyrd
4-42 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pip
4-43 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Me-1-Piz
4-44 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
4-45 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Mor
4-46 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NHMe
4-47 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMe ₂
4-48 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
4-49 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
4-50 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --COOH
4-51 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --SO ₃ H
4-52 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
4-53 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
4-54 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH _2-4 -Mor
4-55 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NH ₂
4-56 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NHMe
4-57 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMe ₂
4-58 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
4-59 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
4-60 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH _{2
4-61 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Azt
_{4-62 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pyrd
_{4-63 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pip
4-64 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Me-1-Piz
_{4-65 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
4-66 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
4-67 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
4-68 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
4-69 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
4-70 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
4-71 Me -CH = CH- -C (= O)---1-Piz
4-72 Me -CH = CH- -C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
4-73 Me -CH = CH- -C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
4-74 Me -CH = CH- -C (= O)---4-Me-1-Piz
4-75 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
4-76 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
4-77 Me -CH = CH- -C (= O)---4- (CH ₂ Car) -1-Piz
4-78 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
4-79 Me -CH = CH- -C (= O)-1,3-Azt--COOH
4-80 Me -CH = CH- -C (= O)-1,3-Azt--OSO ₃ H
4-81 Me -CH = CH- -C (= O)-1,3-Azt--OPO ₃ H ₂
4-82 Me -CH = CH- -C (= O)-1,4-Pip--COOH
4-83 Me -CH = CH- -C (= O)-1,4-Pip--SO ₃ H
4-84 Me -CH = CH- -C (= O)-1,4-Pip--OSO ₃ H
4-85 Me -CH = CH- -C (= O)-1,4-Pip--OPO ₃ H ₂
4-86 Me -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
4-87 Me -CH = CH- -C (= O)-1,4-Pip-1-Pip
4-88 Me -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
4-89 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
4-90 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ NHAc) -1-Piz
4-91 Me -CH = CH- -C (= O)-1,4-Pip-4-Mor
4-92 Me -CH = CH- -C (= O)-1,4-Pip--NHMe
4-93 Me -CH = CH- -C (= O)-1,4-Pip--NMe ₂
4-94 Me -CH = CH- -C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
4-95 Me -CH = CH- -C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
4-96 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --COOH
4-97 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
4-98 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
4-99 Me -CH = CH- -C (= O)-1,4-Pip -CH _2-4 -Mor
4-100 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NH ₂
4-101 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NHMe
4-102 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMe ₂
4-103 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
4-104 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
4-105 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH ₂
4-106 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
4-107 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
4-108 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
4-109 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
4-110 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
4-111 Me -CH ₂ --NHC (= O)---CH _2-4 -Me-1-Piz
_{4-112 Me -CH 2 - -NHC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
4-113 Me -CH ₂ --NHC (= O)---CH ₂ --NMe ₂
4-114 Me -CH ₂ --NMeC (= O)---CH _2-4 -Me-1-Piz
_{4-115 Me -CH 2 - -NMeC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
4-116 Me -CH ₂ --NMeC (= O)---CH ₂ --NMe ₂
4-117 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --COOH
4-118 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
4-119 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --NMe ₂
4-120 H -CH ₂ ----1-Pyrd
4-121 H -CH ₂ ----1-Pip
4-122 H -CH ₂ ----1-Me-4-Pip
4-123 H -CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
4-124 H -CH ₂ ----4-Me-1-Piz
4-125 H -CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
4-126 H -CH ₂ ----4-Mor
4-127 H -CH ₂ -----NH ₂
4-128 H -CH ₂ -----NHMe
4-129 H -CH ₂ -----NMe ₂
4-130 H -CH ₂ CH ₂ -----COOH
4-131 H -CH ₂ CH ₂ -----OPO ₃ H ₂
4-132 H -CH ₂ CH ₂ ----1-Pyrd
4-133 H -CH ₂ CH ₂ ----1-Pip
4-134 H -CH ₂ CH ₂ ----1-Me-4-Pip
4-135 H -CH ₂ CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
4-136 H -CH ₂ CH ₂ ----4-Me-1-Piz
4-137 H -CH ₂ CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
4-138 H -CH ₂ CH ₂ ----4-Mor
4-139 H -CH ₂ CH ₂ -----NH ₂
4-140 H -CH ₂ CH ₂ -----NHMe
4-141 H -CH ₂ CH ₂ -----NMe ₂
4-142 H-(CH ₂ ) ₃ -----COOH
4-143 H-(CH ₂ ) ₃ -----OPO ₃ H ₂
4-144 H -CH ₂ CH ₂ --C (= O)---1-Piz
4-145 H -CH ₂ CH ₂ --C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
4-146 H -CH ₂ CH ₂ --C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
4-147 H -CH ₂ CH ₂ --C (= O)---4-Me-1-Piz
4-148 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
4-149 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
4-150 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ Car) -1-Piz
4-151 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
4-152 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ F) -1-Piz
4-153 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--COOH
4-154 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--OSO ₃ H
4-155 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--OPO ₃ H ₂
4-156 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--COOH
4-157 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--SO ₃ H
4-158 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--OSO ₃ H
4-159 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--OPO ₃ H ₂
4-160 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pyrd
4-161 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pip
4-162 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Me-1-Piz
4-163 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
4-164 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Mor
4-165 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NHMe
4-166 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMe ₂
4-167 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
4-168 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
4-169 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --COOH
4-170 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --SO ₃ H
4-171 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
4-172 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
4-173 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH _2-4 -Mor
4-174 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NH ₂
4-175 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NHMe
4-176 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMe ₂
4-177 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
4-178 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
4-179 H -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH _{2
4-180 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Azt
_{4-181 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pyrd
_{4-182 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pip
4-183 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Me-1-Piz
4-184 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ -4- (CH ₂ CH ₂ OH) -1-Piz
4-185 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
4-186 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
4-187 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
4-188 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
4-189 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
4-190 H -CH = CH- -C (= O)---1-Piz
4-191 H -CH = CH- -C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
4-192 H -CH = CH- -C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
4-193 H -CH = CH- -C (= O)---4-Me-1-Piz
4-194 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
4-195 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
4-196 H -CH = CH- -C (= O)---4- (CH ₂ Car) -1-Piz
4-197 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
4-198 H -CH = CH- -C (= O)-1,3-Azt--COOH
4-199 H -CH = CH- -C (= O)-1,3-Azt--OSO ₃ H
4-200 H -CH = CH- -C (= O)-1,3-Azt--OPO ₃ H ₂
4-201 H -CH = CH- -C (= O)-1,4-Pip--COOH
4-202 H -CH = CH- -C (= O)-1,4-Pip--SO ₃ H
4-203 H -CH = CH- -C (= O)-1,4-Pip--OSO ₃ H
4-204 H -CH = CH- -C (= O)-1,4-Pip--OPO ₃ H ₂
4-205 H -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
4-206 H -CH = CH- -C (= O)-1,4-Pip-1-Pip
4-207 H -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
4-208 H -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
4-209 H -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ NHAc) -1-Piz
4-210 H -CH = CH- -C (= O)-1,4-Pip-4-Mor
4-211 H -CH = CH- -C (= O)-1,4-Pip--NHMe
4-212 H -CH = CH- -C (= O)-1,4-Pip--NMe ₂
4-213 H -CH = CH- -C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
4-214 H -CH = CH- -C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
4-215 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --COOH
4-216 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
4-217 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
4-218 H -CH = CH- -C (= O)-1,4-Pip -CH _2-4 -Mor
4-219 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NH ₂
4-220 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NHMe
4-221 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMe ₂
4-222 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
4-223 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
4-224 H -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH ₂
4-225 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
4-226 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
4-227 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
4-228 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
4-229 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) _{2
4-230 H -CH 2 - -NHC (=} O) - - -CH 2 - 4-Me-1-Piz
_{4-231 H -CH 2 - -NHC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
4-232 H -CH ₂ --NHC (= O)---CH ₂ --NMe ₂
4-233 H -CH ₂ --NMeC (= O)---CH _2-4 -Me-1-Piz
_{4-234 H -CH 2 - -NMeC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
4-235 H -CH ₂ --NMeC (= O)---CH ₂ --NMe ₂
4-236 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --COOH
4-237 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
4-238 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --NMe ₂
4-239 Me 1,4-cHx----COOH
4-240 Me 1,4-cHx----OPO ₃ H ₂
4-241 Me 1,4-cHx---1-Pyrd
4-242 Me 1,4-cHx---1-Pip
4-243 Me 1,4-cHx---1-Me-4-Pip
4-244 Me 1,4-cHx---1- (CH ₂ CH ₂ OH) -4-Pip
4-245 Me 1,4-cHx---4-Me-1-Piz
4-246 Me 1,4-cHx---4- (CH ₂ CH ₂ OH) -1-Piz
4-247 Me 1,4-cHx---4-Mor
4-248 Me 1,4-cHx----NH ₂
4-249 Me 1,4-cHx----NHMe
4-250 Me 1,4-cHx----NMe ₂
4-251 H 1,4-cHx----COOH
4-252 H 1,4-cHx----OPO ₃ H ₂
4-253 H 1,4-cHx---1-Pyrd
4-254 H 1,4-cHx---1-Pip
4-255 H 1,4-cHx---1-Me-4-Pip
4-256 H 1,4-cHx---1- (CH ₂ CH ₂ OH) -4-Pip
4-257 H 1,4-cHx---4-Me-1-Piz
4-258 H 1,4-cHx---4- (CH ₂ CH ₂ OH) -1-Piz
4-259 H 1,4-cHx---4-Mor
4-260 H 1,4-cHx----NH ₂
4-261 H 1,4-cHx----NHMe
4-262 H 1,4-cHx----NMe ₂
4-263 Me-(CH ₂ ) ₄ -----COOH
4-264 Me-(CH ₂ ) ₄ -----SO ₃ H
4-265 Me-(CH ₂ ) ₄ -----OSO ₃ H
4-266 Me-(CH ₂ ) ₄ -----OPO ₃ H ₂
4-267 Me-(CH ₂ ) ₅ -----COOH
4-268 Me-(CH ₂ ) ₅ -----SO ₃ H
4-269 Me-(CH ₂ ) ₅ -----OSO ₃ H
4-270 Me-(CH ₂ ) ₅ -----OPO ₃ H ₂
4-271 Me-(CH ₂ ) ₃ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
4-272 Me-(CH ₂ ) ₄ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
4-273 Me-(CH ₂ ) ₅ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
4-274 Me-(CH ₂ ) ₆ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
4-275 H-(CH ₂ ) ₄ -----COOH
4-276 H-(CH ₂ ) ₄ -----SO ₃ H
4-277 H-(CH ₂ ) ₄ -----OSO ₃ H
4-278 H-(CH ₂ ) ₄ -----OPO ₃ H ₂
4-279 H-(CH ₂ ) ₅ -----COOH
4-280 H-(CH ₂ ) ₅ -----SO ₃ H
4-281 H-(CH ₂ ) ₅ -----OSO ₃ H
4-282 H-(CH ₂ ) ₅ -----OPO ₃ H ₂
4-283 H-(CH ₂ ) ₃ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
4-284 H-(CH ₂ ) ₄ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
4-285 H-(CH ₂ ) ₅ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
4-286 H-(CH ₂ ) ₆ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
4-287 Me -CH ₂ CH ₂ --OC (= O)---1-Me-4-Pip
4-288 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --COOH
4-289 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --SO ₃ H
_{4-290 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -OPO 3 H 2
_{4-291 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Azt
_{4-292 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pyrd
_{4-293 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pip
_{4-294 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Me-4-Pip
_{4-295 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Me-1-Piz
_{4-296 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{4-297 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Mor
4-298 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --NMe _{2
4-299 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{4-300 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
4-301 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --COOH
4-302 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{4-303 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{4-304 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Azt
_{4-305 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pyrd
_{4-306 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pip
_{4-307 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{4-308 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{4-309 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
4-310 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH _2-4 -Mor
_{4-311 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMe 2
_{4-312 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{4-313 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
4-314 Me-(CH ₂ ) ₃ --OC (= O)---1-Me-4-Pip
4-315 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --COOH
4-316 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --SO ₃ H
_{4-317 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -OPO 3 H 2
_{4-318 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Azt
_{4-319 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pyrd
_{4-320 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pip
_{4-321 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Me-4-Pip
_{4-322 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Me-1-Piz
_{4-323 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{4-324 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Mor
4-325 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --NMe _{2
4-326 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{4-327 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
4-328 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --COOH
4-329 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{4-330 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{4-331 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Azt
_{4-332 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pyrd
_{4-333 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pip
_{4-334 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{4-335 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{4-336 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
4-337 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH _2-4 -Mor
_{4-338 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMe 2
_{4-339 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{4-340 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
4-341 Me -CH ₂ CH ₂ --C (= O) O---1-Me-4-Pip
4-342 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ --COOH
_{4-343 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 - 1-Me-4-Pip
4-344 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --COOH
4-345 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --SO ₃ H
_{4-346 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
_{4-347 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Azt
_{4-348 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pyrd
_{4-349 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pip
_{4-350 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
_{4-351 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
_{4-352 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
4-353 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH _2-4 -Mor
_{4-354 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMe 2
_{4-355 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{4-356 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
4-357 Me -CH = CH- -C (= O) O---1-Me-4-Pip
4-358 Me -CH = CH- -C (= O) O---CH ₂ --COOH
4-358 Me -CH = CH- -C (= O) O- - -CH 2 - 1-Me-4-Pip
4-359 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -COOH
4-360 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -SO 3 H
4-361 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
4-362 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Azt
4-363 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pyrd
4-364 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pip
4-365 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
4-366 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
4-367 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
4-368 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Mor
4-369 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMe 2
4-370 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
4-371 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
4-372 H -CH ₂ CH ₂ --OC (= O)---1-Me-4-Pip
4-373 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --COOH
4-374 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --SO ₃ H
_{4-375 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -OPO 3 H 2
_{4-376 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Azt
_{4-377 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pyrd
_{4-378 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pip
_{4-379 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Me-4-Pip
_{4-380 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Me-1-Piz
_{4-381 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{4-382 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Mor
4-383 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --NMe _{2
4-384 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{4-385 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
4-386 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --COOH
4-387 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{4-388 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{4-389 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Azt
_{4-390 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pyrd
_{4-391 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pip
_{4-392 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{4-393 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{4-394 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
4-395 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH _2-4 -Mor
_{4-306 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMe 2
_{4-397 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{4-398 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
4-399 Me-(CH ₂ ) ₃ --OC (= O)---1-Me-4-Pip
4-400 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --COOH
4-401 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --SO ₃ H
_{4-402 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -OPO 3 H 2
_{4-403 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Azt
_{4-404 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pyrd
_{4-405 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pip
_{4-406 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Me-4-Pip
_{4-407 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Me-1-Piz
_{4-408 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{4-409 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Mor
4-410 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --NMe _{2
4-411 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{4-412 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
4-413 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --COOH
4-414 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{4-415 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{4-416 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Azt
_{4-417 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pyrd
_{4-418 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pip
_{4-419 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{4-420 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{4-421 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
4-422 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH _2-4 -Mor
_{4-423 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMe 2
_{4-424 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{4-425 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
4-426 H -CH ₂ CH ₂ --C (= O) O---1-Me-4-Pip
4-427 H -CH ₂ CH ₂ --C (= O) O---CH ₂ --COOH
_{4-428 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 - 1-Me-4-Pip
4-429 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --COOH
4-430 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --SO ₃ H
_{4-431 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
_{4-432 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Azt
_{4-433 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pyrd
_{4-434 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pip
_{4-435 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
_{4-436 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
_{4-437 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
4-438 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH _2-4 -Mor
_{4-439 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMe 2
_{4-440 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{4-441 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
4-442 H -CH = CH- -C (= O) O---1-Me-4-Pip
4-443 H -CH = CH- -C (= O) O---CH ₂ --COOH
4-444 H -CH = CH- -C (= O) O- - -CH 2 - 1-Me-4-Pip
4-445 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -COOH
4-446 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -SO 3 H
4-447 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
4-448 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Azt
4-449 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pyrd
4-450 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pip
4-451 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
4-452 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
4-453 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
4-454 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Mor
4-455 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMe 2
4-456 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
4-457 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
-------------------------------------------------- -----------------
(Table 5)

-------------------------------------------------- -----------------
Example R ¹ -L ¹ --G- -L ² --L ³ --A
Compound number
-------------------------------------------------- -----------------
5-1 Me -CH ₂ ----1-Pyrd
5-2 Me -CH ₂ ----1-Pip
5-3 Me -CH ₂ ----1-Me-4-Pip
5-4 Me -CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
5-5 Me -CH ₂ ----4-Me-1-Piz
5-6 Me -CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
5-7 Me -CH ₂ ----4-Mor
5-8 Me -CH ₂ -----NH ₂
5-9 Me -CH ₂ -----NHMe
5-10 Me -CH ₂ -----NMe ₂
5-11 Me -CH ₂ CH ₂ -----COOH
5-12 Me -CH ₂ CH ₂ -----OPO ₃ H ₂
5-13 Me -CH ₂ CH ₂ ----1-Pyrd
5-14 Me -CH ₂ CH ₂ ----1-Pip
5-15 Me -CH ₂ CH ₂ ----1-Me-4-Pip
5-16 Me -CH ₂ CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
5-17 Me -CH ₂ CH ₂ ----4-Me-1-Piz
5-18 Me -CH ₂ CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
5-19 Me -CH ₂ CH ₂ ----4-Mor
5-20 Me -CH ₂ CH ₂ -----NH ₂
5-21 Me -CH ₂ CH ₂ -----NHMe
5-22 Me -CH ₂ CH ₂ -----NMe ₂
5-23 Me-(CH ₂ ) ₃ -----COOH
5-24 Me-(CH ₂ ) ₃ -----OPO ₃ H ₂
5-25 Me -CH ₂ CH ₂ --C (= O)---1-Piz
5-26 Me -CH ₂ CH ₂ --C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
5-27 Me -CH ₂ CH ₂ --C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
5-28 Me -CH ₂ CH ₂ --C (= O)---4-Me-1-Piz
5-29 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
5-30 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
5-31 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ Car) -1-Piz
5-32 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
5-33 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ F) -1-Piz
5-34 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--COOH
5-35 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--OSO ₃ H
5-36 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--OPO ₃ H ₂
5-37 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--COOH
5-38 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--SO ₃ H
5-39 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--OSO ₃ H
5-40 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--OPO ₃ H ₂
5-41 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pyrd
5-42 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pip
5-43 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Me-1-Piz
5-44 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
5-45 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Mor
5-46 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NHMe
5-47 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMe ₂
5-48 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
5-49 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
5-50 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --COOH
5-51 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --SO ₃ H
5-52 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
5-53 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
5-54 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH _2-4 -Mor
5-55 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NH ₂
5-56 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NHMe
5-57 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMe ₂
5-58 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
5-59 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
5-60 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH _{2
5-61 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Azt
_{5-62 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pyrd
_{5-63 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pip
5-64 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Me-1-Piz
5-65 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ -4- (CH ₂ CH ₂ OH) -1-Piz
5-66 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
5-67 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
5-68 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
5-69 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
5-70 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
5-71 Me -CH = CH- -C (= O)---1-Piz
5-72 Me -CH = CH- -C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
5-73 Me -CH = CH- -C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
5-74 Me -CH = CH- -C (= O)---4-Me-1-Piz
5-75 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
5-76 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
5-77 Me -CH = CH- -C (= O)---4- (CH ₂ Car) -1-Piz
5-78 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
5-79 Me -CH = CH- -C (= O)-1,3-Azt--COOH
5-80 Me -CH = CH- -C (= O)-1,3-Azt--OSO ₃ H
5-81 Me -CH = CH- -C (= O)-1,3-Azt--OPO ₃ H ₂
5-82 Me -CH = CH- -C (= O)-1,4-Pip--COOH
5-83 Me -CH = CH- -C (= O)-1,4-Pip--SO ₃ H
5-84 Me -CH = CH- -C (= O)-1,4-Pip--OSO ₃ H
5-85 Me -CH = CH- -C (= O)-1,4-Pip--OPO ₃ H ₂
5-86 Me -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
5-87 Me -CH = CH- -C (= O)-1,4-Pip-1-Pip
5-88 Me -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
5-89 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
5-90 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ NHAc) -1-Piz
5-91 Me -CH = CH- -C (= O)-1,4-Pip-4-Mor
5-92 Me -CH = CH- -C (= O)-1,4-Pip--NHMe
5-93 Me -CH = CH- -C (= O)-1,4-Pip--NMe ₂
5-94 Me -CH = CH- -C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
5-95 Me -CH = CH- -C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
5-96 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --COOH
5-97 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
5-98 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
5-99 Me -CH = CH- -C (= O)-1,4-Pip -CH _2-4 -Mor
5-100 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NH ₂
5-101 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NHMe
5-102 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMe ₂
5-103 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
5-104 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
5-105 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH ₂
5-106 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
5-107 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
5-108 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
5-109 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
5-110 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
5-111 Me -CH ₂ --NHC (= O)---CH _2-4 -Me-1-Piz
_{5-112 Me -CH 2 - -NHC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
5-113 Me -CH ₂ --NHC (= O)---CH ₂ --NMe ₂
5-114 Me -CH ₂ --NMeC (= O)---CH _2-4 -Me-1-Piz
_{5-115 Me -CH 2 - -NMeC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
5-116 Me -CH ₂ --NMeC (= O)---CH ₂ --NMe ₂
5-117 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --COOH
5-118 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
5-119 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --NMe ₂
5-120 H -CH ₂ ----1-Pyrd
5-121 H -CH ₂ ----1-Pip
5-122 H -CH ₂ ----1-Me-4-Pip
5-123 H -CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
5-124 H -CH ₂ ----4-Me-1-Piz
5-125 H -CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
5-126 H -CH ₂ ----4-Mor
5-127 H -CH ₂ -----NH ₂
5-128 H -CH ₂ -----NHMe
5-129 H -CH ₂ -----NMe ₂
5-130 H -CH ₂ CH ₂ -----COOH
5-131 H -CH ₂ CH ₂ -----OPO ₃ H ₂
5-132 H -CH ₂ CH ₂ ----1-Pyrd
5-133 H -CH ₂ CH ₂ ----1-Pip
5-134 H -CH ₂ CH ₂ ----1-Me-4-Pip
5-135 H -CH ₂ CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
5-136 H -CH ₂ CH ₂ ----4-Me-1-Piz
5-137 H -CH ₂ CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
5-138 H -CH ₂ CH ₂ ----4-Mor
5-139 H -CH ₂ CH ₂ -----NH ₂
5-140 H -CH ₂ CH ₂ -----NHMe
5-141 H -CH ₂ CH ₂ -----NMe ₂
5-142 H-(CH ₂ ) ₃ -----COOH
5-143 H-(CH ₂ ) ₃ -----OPO ₃ H ₂
5-144 H -CH ₂ CH ₂ --C (= O)---1-Piz
5-145 H -CH ₂ CH ₂ --C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
5-146 H -CH ₂ CH ₂ --C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
5-147 H -CH ₂ CH ₂ --C (= O)---4-Me-1-Piz
5-148 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
5-149 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
5-150 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ Car) -1-Piz
5-151 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
5-152 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ F) -1-Piz
5-153 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--COOH
5-154 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--OSO ₃ H
5-155 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--OPO ₃ H ₂
5-156 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--COOH
5-157 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--SO ₃ H
5-158 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--OSO ₃ H
5-159 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--OPO ₃ H ₂
5-160 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pyrd
5-161 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pip
5-162 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Me-1-Piz
5-163 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
5-164 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Mor
5-165 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NHMe
5-166 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMe ₂
5-167 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
5-168 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
5-169 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --COOH
5-170 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --SO ₃ H
5-171 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
5-172 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
5-173 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH _2-4 -Mor
5-174 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NH ₂
5-175 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NHMe
5-176 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMe ₂
5-177 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
5-178 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
5-179 H -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH _{2
5-180 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Azt
_{5-181 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pyrd
_{5-182 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pip
5-183 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Me-1-Piz
5-184 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ -4- (CH ₂ CH ₂ OH) -1-Piz
5-185 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
5-186 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
5-187 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
5-188 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
5-189 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
5-190 H -CH = CH- -C (= O)---1-Piz
5-191 H -CH = CH- -C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
5-192 H -CH = CH- -C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
5-193 H -CH = CH- -C (= O)---4-Me-1-Piz
5-194 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
5-195 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
5-196 H -CH = CH- -C (= O)---4- (CH ₂ Car) -1-Piz
5-197 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
5-198 H -CH = CH- -C (= O)-1,3-Azt--COOH
5-199 H -CH = CH- -C (= O)-1,3-Azt--OSO ₃ H
5-200 H -CH = CH- -C (= O)-1,3-Azt--OPO ₃ H ₂
5-201 H -CH = CH- -C (= O)-1,4-Pip--COOH
5-202 H -CH = CH- -C (= O)-1,4-Pip--SO ₃ H
5-203 H -CH = CH- -C (= O)-1,4-Pip--OSO ₃ H
5-204 H -CH = CH- -C (= O)-1,4-Pip--OPO ₃ H ₂
5-205 H -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
5-206 H -CH = CH- -C (= O)-1,4-Pip-1-Pip
5-207 H -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
5-208 H -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
5-209 H -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ NHAc) -1-Piz
5-210 H -CH = CH- -C (= O)-1,4-Pip-4-Mor
5-211 H -CH = CH- -C (= O)-1,4-Pip--NHMe
5-212 H -CH = CH- -C (= O)-1,4-Pip--NMe ₂
5-213 H -CH = CH- -C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
5-214 H -CH = CH- -C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
5-215 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --COOH
5-216 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
5-217 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
5-218 H -CH = CH- -C (= O)-1,4-Pip -CH _2-4 -Mor
5-219 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NH ₂
5-220 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NHMe
5-221 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMe ₂
5-222 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
5-223 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
5-224 H -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH ₂
5-225 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
5-226 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
5-227 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
5-228 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
5-229 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) _{2
5-230 H -CH 2 - -NHC (=} O) - - -CH 2 - 4-Me-1-Piz
_{5-231 H -CH 2 - -NHC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
5-232 H -CH ₂ --NHC (= O)---CH ₂ --NMe ₂
5-233 H -CH ₂ --NMeC (= O)---CH _2-4 -Me-1-Piz
_{5-234 H -CH 2 - -NMeC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
5-235 H -CH ₂ --NMeC (= O)---CH ₂ --NMe ₂
5-236 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --COOH
5-237 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
5-238 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --NMe ₂
5-239 Me 1,4-cHx----COOH
5-240 Me 1,4-cHx----OPO ₃ H ₂
5-241 Me 1,4-cHx---1-Pyrd
5-242 Me 1,4-cHx---1-Pip
5-243 Me 1,4-cHx---1-Me-4-Pip
5-244 Me 1,4-cHx---1- (CH ₂ CH ₂ OH) -4-Pip
5-245 Me 1,4-cHx---4-Me-1-Piz
5-246 Me 1,4-cHx---4- (CH ₂ CH ₂ OH) -1-Piz
5-247 Me 1,4-cHx---4-Mor
5-248 Me 1,4-cHx----NH ₂
5-249 Me 1,4-cHx----NHMe
5-250 Me 1,4-cHx----NMe ₂
5-251 H 1,4-cHx----COOH
5-252 H 1,4-cHx----OPO ₃ H ₂
5-253 H 1,4-cHx---1-Pyrd
5-254 H 1,4-cHx---1-Pip
5-255 H 1,4-cHx---1-Me-4-Pip
5-256 H 1,4-cHx---1- (CH ₂ CH ₂ OH) -4-Pip
5-257 H 1,4-cHx---4-Me-1-Piz
5-258 H 1,4-cHx---4- (CH ₂ CH ₂ OH) -1-Piz
5-259 H 1,4-cHx---4-Mor
5-260 H 1,4-cHx----NH ₂
5-261 H 1,4-cHx----NHMe
5-262 H 1,4-cHx----NMe ₂
5-263 Me-(CH ₂ ) ₄ -----COOH
5-264 Me-(CH ₂ ) ₄ -----SO ₃ H
5-265 Me-(CH ₂ ) ₄ -----OSO ₃ H
5-266 Me-(CH ₂ ) ₄ -----OPO ₃ H ₂
5-267 Me-(CH ₂ ) ₅ -----COOH
5-268 Me-(CH ₂ ) ₅ -----SO ₃ H
5-269 Me-(CH ₂ ) ₅ -----OSO ₃ H
5-270 Me-(CH ₂ ) ₅ -----OPO ₃ H ₂
5-271 Me-(CH ₂ ) ₃ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
5-272 Me-(CH ₂ ) ₄ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
5-273 Me-(CH ₂ ) ₅ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
5-274 Me-(CH ₂ ) ₆ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
5-275 H-(CH ₂ ) ₄ -----COOH
5-276 H-(CH ₂ ) ₄ -----SO ₃ H
5-277 H-(CH ₂ ) ₄ -----OSO ₃ H
5-278 H-(CH ₂ ) ₄ -----OPO ₃ H ₂
5-279 H-(CH ₂ ) ₅ -----COOH
5-280 H-(CH ₂ ) ₅ -----SO ₃ H
5-281 H-(CH ₂ ) ₅ -----OSO ₃ H
5-282 H-(CH ₂ ) ₅ -----OPO ₃ H ₂
5-283 H-(CH ₂ ) ₃ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
5-284 H-(CH ₂ ) ₄ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
5-285 H-(CH ₂ ) ₅ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
5-286 H-(CH ₂ ) ₆ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
5-287 Me -CH ₂ CH ₂ --OC (= O)---1-Me-4-Pip
5-288 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --COOH
5-289 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --SO ₃ H
_{5-290 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -OPO 3 H 2
_{5-291 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Azt
_{5-292 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pyrd
_{5-293 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pip
_{5-294 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Me-4-Pip
_{5-295 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Me-1-Piz
_{5-296 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{5-297 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Mor
5-298 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --NMe _{2
5-299 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{5-300 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
5-301 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --COOH
5-302 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{5-303 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{5-304 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Azt
_{5-305 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pyrd
_{5-306 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pip
_{5-307 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{5-308 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{5-309 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
5-310 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH _2-4 -Mor
_{5-311 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMe 2
_{5-312 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{5-313 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
5-314 Me-(CH ₂ ) ₃ --OC (= O)---1-Me-4-Pip
5-315 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --COOH
5-316 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --SO ₃ H
5-317 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --OPO ₃ H _{2
5-318 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Azt
_{5-319 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pyrd
_{5-320 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pip
_{5-321 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Me-4-Pip
_{5-322 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Me-1-Piz
_{5-323 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{5-324 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Mor
5-325 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --NMe _{2
5-326 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{5-327 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
5-328 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --COOH
5-329 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{5-330 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{5-331 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Azt
_{5-332 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pyrd
_{5-333 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pip
_{5-334 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{5-335 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{5-336 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
5-337 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH _2-4 -Mor
_{5-338 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMe 2
_{5-339 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{5-340 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
5-341 Me -CH ₂ CH ₂ --C (= O) O---1-Me-4-Pip
5-342 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ --COOH
_{5-343 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 - 1-Me-4-Pip
5-344 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --COOH
5-345 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --SO ₃ H
_{5-346 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
_{5-347 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Azt
_{5-348 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pyrd
_{5-349 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pip
_{5-350 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
_{5-351 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
_{5-352 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
5-353 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH _2-4 -Mor
_{5-354 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMe 2
_{5-355 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{5-356 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
5-357 Me -CH = CH- -C (= O) O---1-Me-4-Pip
5-358 Me -CH = CH- -C (= O) O---CH ₂ --COOH
5-358 Me -CH = CH- -C (= O) O- - -CH 2 - 1-Me-4-Pip
5-359 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -COOH
5-360 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -SO 3 H
5-361 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
5-362 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Azt
5-363 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pyrd
5-364 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pip
5-365 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
5-366 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
5-367 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
5-368 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Mor
5-369 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMe 2
5-370 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
5-371 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
5-372 H -CH ₂ CH ₂ --OC (= O)---1-Me-4-Pip
5-373 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --COOH
5-374 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --SO ₃ H
_{5-375 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -OPO 3 H 2
_{5-376 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Azt
_{5-377 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pyrd
_{5-378 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pip
_{5-379 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Me-4-Pip
_{5-380 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Me-1-Piz
_{5-381 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{5-382 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Mor
5-383 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --NMe _{2
5-384 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{5-385 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
5-386 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --COOH
5-387 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{5-388 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{5-389 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Azt
_{5-390 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pyrd
_{5-391 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pip
_{5-392 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{5-393 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{5-394 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
5-395 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH _2-4 -Mor
_{5-306 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMe 2
_{5-397 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{5-398 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
5-399 Me-(CH ₂ ) ₃ --OC (= O)---1-Me-4-Pip
5-400 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --COOH
5-401 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --SO ₃ H
_{5-402 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -OPO 3 H 2
_{5-403 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Azt
_{5-404 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pyrd
_{5-405 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pip
_{5-406 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Me-4-Pip
_{5-407 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Me-1-Piz
_{5-408 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{5-409 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Mor
5-410 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --NMe _{2
5-411 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{5-412 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
5-413 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --COOH
5-414 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{5-415 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{5-416 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Azt
_{5-417 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pyrd
_{5-418 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pip
_{5-419 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{5-420 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{5-421 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
5-422 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH _2-4 -Mor
_{5-423 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMe 2
_{5-424 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{5-425 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
5-426 H -CH ₂ CH ₂ --C (= O) O---1-Me-4-Pip
5-427 H -CH ₂ CH ₂ --C (= O) O---CH ₂ --COOH
_{5-428 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 - 1-Me-4-Pip
5-429 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --COOH
5-430 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --SO ₃ H
_{5-431 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
_{5-432 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Azt
_{5-433 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pyrd
_{5-434 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pip
_{5-435 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
_{5-436 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
_{5-437 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
5-438 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH _2-4 -Mor
_{5-439 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMe 2
_{5-440 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{5-441 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
5-442 H -CH = CH- -C (= O) O---1-Me-4-Pip
5-443 H -CH = CH- -C (= O) O---CH ₂ --COOH
5-444 H -CH = CH- -C (= O) O- - -CH 2 - 1-Me-4-Pip
5-445 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -COOH
5-446 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -SO 3 H
5-447 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
5-448 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Azt
5-449 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pyrd
5-450 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pip
5-451 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
5-452 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
5-453 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
5-454 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Mor
5-455 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMe 2
5-456 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
5-457 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
-------------------------------------------------- -----------------
(Table 6)

-------------------------------------------------- -----------------
Example R ¹ -L ¹ --G- -L ² --L ³ --A
Compound number
-------------------------------------------------- -----------------
6-1 Me -CH ₂ ----1-Pyrd
6-2 Me -CH ₂ ----1-Pip
6-3 Me -CH ₂ ----1-Me-4-Pip
6-4 Me -CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
6-5 Me -CH ₂ ----4-Me-1-Piz
6-6 Me -CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
6-7 Me -CH ₂ ----4-Mor
6-8 Me -CH ₂ -----NH ₂
6-9 Me -CH ₂ -----NHMe
6-10 Me -CH ₂ -----NMe ₂
6-11 Me -CH ₂ CH ₂ -----COOH
6-12 Me -CH ₂ CH ₂ -----OPO ₃ H ₂
6-13 Me -CH ₂ CH ₂ ----1-Pyrd
6-14 Me -CH ₂ CH ₂ ----1-Pip
6-15 Me -CH ₂ CH ₂ ----1-Me-4-Pip
6-16 Me -CH ₂ CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
6-17 Me -CH ₂ CH ₂ ----4-Me-1-Piz
6-18 Me -CH ₂ CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
6-19 Me -CH ₂ CH ₂ ----4-Mor
6-20 Me -CH ₂ CH ₂ -----NH ₂
6-21 Me -CH ₂ CH ₂ -----NHMe
6-22 Me -CH ₂ CH ₂ -----NMe ₂
6-23 Me-(CH ₂ ) ₃ -----COOH
6-24 Me-(CH ₂ ) ₃ -----OPO ₃ H ₂
6-25 Me -CH ₂ CH ₂ --C (= O)---1-Piz
6-26 Me -CH ₂ CH ₂ --C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
6-27 Me -CH ₂ CH ₂ --C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
6-28 Me -CH ₂ CH ₂ --C (= O)---4-Me-1-Piz
6-29 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
6-30 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
6-31 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ Car) -1-Piz
6-32 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
6-33 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ F) -1-Piz
6-34 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--COOH
6-35 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--OSO ₃ H
6-36 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--OPO ₃ H ₂
6-37 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--COOH
6-38 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--SO ₃ H
6-39 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--OSO ₃ H
6-40 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--OPO ₃ H ₂
6-41 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pyrd
6-42 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pip
6-43 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Me-1-Piz
6-44 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
6-45 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Mor
6-46 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NHMe
6-47 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMe ₂
6-48 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
6-49 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
6-50 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --COOH
6-51 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --SO ₃ H
6-52 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
6-53 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
6-54 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH _2-4 -Mor
6-55 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NH ₂
6-56 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NHMe
6-57 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMe ₂
6-58 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
6-59 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
6-60 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH _{2
6-61 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Azt
_{6-62 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pyrd
_{6-63 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pip
6-64 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Me-1-Piz
6-65 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ -4- (CH ₂ CH ₂ OH) -1-Piz
6-66 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
6-67 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
6-68 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
6-69 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
6-70 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
6-71 Me -CH = CH- -C (= O)---1-Piz
6-72 Me -CH = CH- -C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
6-73 Me -CH = CH- -C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
6-74 Me -CH = CH- -C (= O)---4-Me-1-Piz
6-75 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
6-76 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
6-77 Me -CH = CH- -C (= O)---4- (CH ₂ Car) -1-Piz
6-78 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
6-79 Me -CH = CH- -C (= O)-1,3-Azt--COOH
6-80 Me -CH = CH- -C (= O)-1,3-Azt--OSO ₃ H
6-81 Me -CH = CH- -C (= O)-1,3-Azt--OPO ₃ H ₂
6-82 Me -CH = CH- -C (= O)-1,4-Pip--COOH
6-83 Me -CH = CH- -C (= O)-1,4-Pip--SO ₃ H
6-84 Me -CH = CH- -C (= O)-1,4-Pip--OSO ₃ H
6-85 Me -CH = CH- -C (= O)-1,4-Pip--OPO ₃ H ₂
6-86 Me -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
6-87 Me -CH = CH- -C (= O)-1,4-Pip-1-Pip
6-88 Me -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
6-89 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
6-90 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ NHAc) -1-Piz
6-91 Me -CH = CH- -C (= O)-1,4-Pip-4-Mor
6-92 Me -CH = CH- -C (= O)-1,4-Pip--NHMe
6-93 Me -CH = CH- -C (= O)-1,4-Pip--NMe ₂
6-94 Me -CH = CH- -C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
6-95 Me -CH = CH- -C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
6-96 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --COOH
6-97 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
6-98 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
6-99 Me -CH = CH- -C (= O)-1,4-Pip -CH _2-4 -Mor
6-100 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NH ₂
6-101 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NHMe
6-102 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMe ₂
6-103 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
6-104 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
6-105 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH ₂
6-106 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
6-107 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
6-108 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
6-109 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
6-110 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) _{2
6-111 Me -CH 2 - -NHC (=} O) - - -CH 2 - 4-Me-1-Piz
_{6-112 Me -CH 2 - -NHC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
6-113 Me -CH ₂ --NHC (= O)---CH ₂ --NMe ₂
6-114 Me -CH ₂ --NMeC (= O)---CH _2-4 -Me-1-Piz
_{6-115 Me -CH 2 - -NMeC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
6-116 Me -CH ₂ --NMeC (= O)---CH ₂ --NMe ₂
6-117 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --COOH
6-118 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
6-119 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --NMe ₂
6-120 H -CH ₂ ----1-Pyrd
6-121 H -CH ₂ ----1-Pip
6-122 H -CH ₂ ----1-Me-4-Pip
6-123 H -CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
6-124 H -CH ₂ ----4-Me-1-Piz
6-125 H -CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
6-126 H -CH ₂ ----4-Mor
6-127 H -CH ₂ -----NH ₂
6-128 H -CH ₂ -----NHMe
6-129 H -CH ₂ -----NMe ₂
6-130 H -CH ₂ CH ₂ -----COOH
6-131 H -CH ₂ CH ₂ -----OPO ₃ H ₂
6-132 H -CH ₂ CH ₂ ----1-Pyrd
6-133 H -CH ₂ CH ₂ ----1-Pip
6-134 H -CH ₂ CH ₂ ----1-Me-4-Pip
6-135 H -CH ₂ CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
6-136 H -CH ₂ CH ₂ ----4-Me-1-Piz
6-137 H -CH ₂ CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
6-138 H -CH ₂ CH ₂ ----4-Mor
6-139 H -CH ₂ CH ₂ -----NH ₂
6-140 H -CH ₂ CH ₂ -----NHMe
6-141 H -CH ₂ CH ₂ -----NMe ₂
6-142 H-(CH ₂ ) ₃ -----COOH
6-143 H-(CH ₂ ) ₃ -----OPO ₃ H ₂
6-144 H -CH ₂ CH ₂ --C (= O)---1-Piz
6-145 H -CH ₂ CH ₂ --C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
6-146 H -CH ₂ CH ₂ --C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
6-147 H -CH ₂ CH ₂ --C (= O)---4-Me-1-Piz
6-148 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
6-149 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
6-150 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ Car) -1-Piz
6-151 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
6-152 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ F) -1-Piz
6-153 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--COOH
6-154 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--OSO ₃ H
6-155 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--OPO ₃ H ₂
6-156 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--COOH
6-157 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--SO ₃ H
6-158 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--OSO ₃ H
6-159 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--OPO ₃ H ₂
6-160 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pyrd
6-161 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pip
6-162 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Me-1-Piz
6-163 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
6-164 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Mor
6-165 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NHMe
6-166 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMe ₂
6-167 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
6-168 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
6-169 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --COOH
6-170 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --SO ₃ H
6-171 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
6-172 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
6-173 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH _2-4 -Mor
6-174 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NH ₂
6-175 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NHMe
6-176 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMe ₂
6-177 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
6-178 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
6-179 H -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH _{2
6-180 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Azt
_{6-181 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pyrd
_{6-182 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pip
6-183 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Me-1-Piz
6-184 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ -4- (CH ₂ CH ₂ OH) -1-Piz
6-185 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
6-186 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
6-187 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
6-188 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
6-189 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
6-190 H -CH = CH- -C (= O)---1-Piz
6-191 H -CH = CH- -C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
6-192 H -CH = CH- -C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
6-193 H -CH = CH- -C (= O)---4-Me-1-Piz
6-194 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
6-195 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
6-196 H -CH = CH- -C (= O)---4- (CH ₂ Car) -1-Piz
6-197 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
6-198 H -CH = CH- -C (= O)-1,3-Azt--COOH
6-199 H -CH = CH- -C (= O)-1,3-Azt--OSO ₃ H
6-200 H -CH = CH- -C (= O)-1,3-Azt--OPO ₃ H ₂
6-201 H -CH = CH- -C (= O)-1,4-Pip--COOH
6-202 H -CH = CH- -C (= O)-1,4-Pip--SO ₃ H
6-203 H -CH = CH- -C (= O)-1,4-Pip--OSO ₃ H
6-204 H -CH = CH- -C (= O)-1,4-Pip--OPO ₃ H ₂
6-205 H -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
6-206 H -CH = CH- -C (= O)-1,4-Pip-1-Pip
6-207 H -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
6-208 H -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
6-209 H -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ NHAc) -1-Piz
6-210 H -CH = CH- -C (= O)-1,4-Pip-4-Mor
6-211 H -CH = CH- -C (= O)-1,4-Pip--NHMe
6-212 H -CH = CH- -C (= O)-1,4-Pip--NMe ₂
6-213 H -CH = CH- -C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
6-214 H -CH = CH- -C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
6-215 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --COOH
6-216 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
6-217 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
6-218 H -CH = CH- -C (= O)-1,4-Pip -CH _2-4 -Mor
6-219 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NH ₂
6-220 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NHMe
6-221 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMe ₂
6-222 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
6-223 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
6-224 H -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH ₂
6-225 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
6-226 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
6-227 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
6-228 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
6-229 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
6-230 H -CH ₂ --NHC (= O)---CH _2-4 -Me-1-Piz
_{6-231 H -CH 2 - -NHC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
6-232 H -CH ₂ --NHC (= O)---CH ₂ --NMe ₂
6-233 H -CH ₂ --NMeC (= O)---CH _2-4 -Me-1-Piz
_{6-234 H -CH 2 - -NMeC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
6-235 H -CH ₂ --NMeC (= O)---CH ₂ --NMe ₂
6-236 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --COOH
6-237 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
6-238 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --NMe ₂
6-239 Me 1,4-cHx----COOH
6-240 Me 1,4-cHx----OPO ₃ H ₂
6-241 Me 1,4-cHx---1-Pyrd
6-242 Me 1,4-cHx---1-Pip
6-243 Me 1,4-cHx---1-Me-4-Pip
6-244 Me 1,4-cHx---1- (CH ₂ CH ₂ OH) -4-Pip
6-245 Me 1,4-cHx---4-Me-1-Piz
6-246 Me 1,4-cHx---4- (CH ₂ CH ₂ OH) -1-Piz
6-247 Me 1,4-cHx---4-Mor
6-248 Me 1,4-cHx----NH ₂
6-249 Me 1,4-cHx----NHMe
6-250 Me 1,4-cHx----NMe ₂
6-251 H 1,4-cHx----COOH
6-252 H 1,4-cHx----OPO ₃ H ₂
6-253 H 1,4-cHx---1-Pyrd
6-254 H 1,4-cHx---1-Pip
6-255 H 1,4-cHx---1-Me-4-Pip
6-256 H 1,4-cHx---1- (CH ₂ CH ₂ OH) -4-Pip
6-257 H 1,4-cHx---4-Me-1-Piz
6-258 H 1,4-cHx---4- (CH ₂ CH ₂ OH) -1-Piz
6-259 H 1,4-cHx---4-Mor
6-260 H 1,4-cHx----NH ₂
6-261 H 1,4-cHx----NHMe
6-262 H 1,4-cHx----NMe ₂
6-263 Me-(CH ₂ ) ₄ -----COOH
6-264 Me-(CH ₂ ) ₄ -----SO ₃ H
6-265 Me-(CH ₂ ) ₄ -----OSO ₃ H
6-266 Me-(CH ₂ ) ₄ -----OPO ₃ H ₂
6-267 Me-(CH ₂ ) ₅ -----COOH
6-268 Me-(CH ₂ ) ₅ -----SO ₃ H
6-269 Me-(CH ₂ ) ₅ -----OSO ₃ H
6-270 Me-(CH ₂ ) ₅ -----OPO ₃ H ₂
6-271 Me-(CH ₂ ) ₃ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
6-272 Me-(CH ₂ ) ₄ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
6-273 Me-(CH ₂ ) ₅ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
6-274 Me-(CH ₂ ) ₆ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
6-275 H-(CH ₂ ) ₄ -----COOH
6-276 H-(CH ₂ ) ₄ -----SO ₃ H
6-277 H-(CH ₂ ) ₄ -----OSO ₃ H
6-278 H-(CH ₂ ) ₄ -----OPO ₃ H ₂
6-279 H-(CH ₂ ) ₅ -----COOH
6-280 H-(CH ₂ ) ₅ -----SO ₃ H
6-281 H-(CH ₂ ) ₅ -----OSO ₃ H
6-282 H-(CH ₂ ) ₅ -----OPO ₃ H ₂
6-283 H-(CH ₂ ) ₃ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
6-284 H-(CH ₂ ) ₄ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
6-285 H-(CH ₂ ) ₅ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
6-286 H-(CH ₂ ) ₆ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
6-287 Me -CH ₂ CH ₂ --OC (= O)---1-Me-4-Pip
6-288 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --COOH
6-289 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --SO ₃ H
_{6-290 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -OPO 3 H 2
_{6-291 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Azt
_{6-292 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pyrd
_{6-293 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pip
_{6-294 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Me-4-Pip
_{6-295 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Me-1-Piz
_{6-296 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{6-297 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Mor
6-298 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --NMe _{2
6-299 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{6-300 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
6-301 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --COOH
_{6-302 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -SO 3 H
_{6-303 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{6-304 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Azt
_{6-305 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pyrd
_{6-306 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pip
_{6-307 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{6-308 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{6-309 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
6-310 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH _2-4 -Mor
_{6-311 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMe 2
_{6-312 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{6-313 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
6-314 Me-(CH ₂ ) ₃ --OC (= O)---1-Me-4-Pip
6-315 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --COOH
6-316 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --SO ₃ H
_{6-317 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -OPO 3 H 2
_{6-318 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Azt
_{6-319 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pyrd
_{6-320 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pip
_{6-321 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Me-4-Pip
_{6-322 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Me-1-Piz
_{6-323 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{6-324 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Mor
6-325 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --NMe _{2
6-326 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{6-327 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
6-328 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --COOH
_{6-329 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -SO 3 H
_{6-330 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{6-331 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Azt
_{6-332 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pyrd
_{6-333 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pip
_{6-334 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{6-335 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{6-336 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
6-337 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH _2-4 -Mor
_{6-338 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMe 2
_{6-339 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{6-340 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
6-341 Me -CH ₂ CH ₂ --C (= O) O---1-Me-4-Pip
6-342 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ --COOH
_{6-343 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 - 1-Me-4-Pip
6-344 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --COOH
6-345 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --SO ₃ H
_{6-346 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
_{6-347 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Azt
_{6-348 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pyrd
_{6-349 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pip
_{6-350 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
_{6-351 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
_{6-352 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
6-353 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH _2-4 -Mor
_{6-354 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMe 2
_{6-355 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{6-356 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
6-357 Me -CH = CH- -C (= O) O---1-Me-4-Pip
6-358 Me -CH = CH- -C (= O) O---CH ₂ --COOH
6-358 Me -CH = CH- -C (= O) O- - -CH 2 - 1-Me-4-Pip
6-359 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -COOH
6-360 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -SO 3 H
6-361 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
6-362 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Azt
6-363 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pyrd
6-364 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pip
6-365 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
6-366 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
6-367 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
6-368 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Mor
6-369 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMe 2
6-370 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
6-371 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
6-372 H -CH ₂ CH ₂ --OC (= O)---1-Me-4-Pip
6-373 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --COOH
6-374 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --SO ₃ H
_{6-375 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -OPO 3 H 2
_{6-376 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Azt
_{6-377 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pyrd
_{6-378 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pip
_{6-379 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Me-4-Pip
_{6-380 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Me-1-Piz
_{6-381 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{6-382 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Mor
6-383 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --NMe _{2
6-384 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{6-385 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
6-386 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --COOH
6-387 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{6-388 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{6-389 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Azt
_{6-390 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pyrd
_{6-391 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pip
_{6-392 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{6-393 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{6-394 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
6-395 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH _2-4 -Mor
_{6-306 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMe 2
_{6-397 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{6-398 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
6-399 Me-(CH ₂ ) ₃ --OC (= O)---1-Me-4-Pip
6-400 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --COOH
6-401 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --SO ₃ H
_{6-402 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -OPO 3 H 2
_{6-403 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Azt
_{6-404 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pyrd
_{6-405 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pip
_{6-406 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Me-4-Pip
_{6-407 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Me-1-Piz
_{6-408 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{6-409 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Mor
6-410 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --NMe _{2
6-411 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{6-412 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
6-413 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --COOH
6-414 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{6-415 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{6-416 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Azt
_{6-417 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pyrd
_{6-418 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pip
_{6-419 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{6-420 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{6-421 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
6-422 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH _2-4 -Mor
_{6-423 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMe 2
_{6-424 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{6-425 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
6-426 H -CH ₂ CH ₂ --C (= O) O---1-Me-4-Pip
6-427 H -CH ₂ CH ₂ --C (= O) O---CH ₂ --COOH
_{6-428 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 - 1-Me-4-Pip
6-429 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --COOH
6-430 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --SO ₃ H
_{6-431 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
_{6-432 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Azt
_{6-433 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pyrd
_{6-434 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pip
_{6-435 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
_{6-436 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
_{6-437 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
6-438 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH _2-4 -Mor
_{6-439 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMe 2
_{6-440 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{6-441 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
6-442 H -CH = CH- -C (= O) O---1-Me-4-Pip
6-443 H -CH = CH- -C (= O) O---CH ₂ --COOH
6-444 H -CH = CH- -C (= O) O- - -CH 2 - 1-Me-4-Pip
6-445 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -COOH
6-446 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -SO 3 H
6-447 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
6-448 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Azt
6-449 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pyrd
6-450 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pip
6-451 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
6-452 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
6-453 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
6-454 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Mor
6-455 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMe 2
6-456 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
6-457 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
-------------------------------------------------- -----------------
(Table 7)

-------------------------------------------------- -----------------
Example R ¹ -L ¹ --G- -L ² --L ³ --A
Compound number
-------------------------------------------------- -----------------
7-1 Me -CH ₂ ----1-Pyrd
7-2 Me -CH ₂ ----1-Pip
7-3 Me -CH ₂ ----1-Me-4-Pip
7-4 Me -CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
7-5 Me -CH ₂ ----4-Me-1-Piz
7-6 Me -CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
7-7 Me -CH ₂ ----4-Mor
7-8 Me -CH ₂ -----NH ₂
7-9 Me -CH ₂ -----NHMe
7-10 Me -CH ₂ -----NMe ₂
7-11 Me -CH ₂ CH ₂ -----COOH
7-12 Me -CH ₂ CH ₂ -----OPO ₃ H ₂
7-13 Me -CH ₂ CH ₂ ----1-Pyrd
7-14 Me -CH ₂ CH ₂ ----1-Pip
7-15 Me -CH ₂ CH ₂ ----1-Me-4-Pip
7-16 Me -CH ₂ CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
7-17 Me -CH ₂ CH ₂ ----4-Me-1-Piz
7-18 Me -CH ₂ CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
7-19 Me -CH ₂ CH ₂ ----4-Mor
7-20 Me -CH ₂ CH ₂ -----NH ₂
7-21 Me -CH ₂ CH ₂ -----NHMe
7-22 Me -CH ₂ CH ₂ -----NMe ₂
7-23 Me-(CH ₂ ) ₃ -----COOH
7-24 Me-(CH ₂ ) ₃ -----OPO ₃ H ₂
7-25 Me -CH ₂ CH ₂ --C (= O)---1-Piz
7-26 Me -CH ₂ CH ₂ --C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
7-27 Me -CH ₂ CH ₂ --C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
7-28 Me -CH ₂ CH ₂ --C (= O)---4-Me-1-Piz
7-29 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
7-30 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
7-31 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ Car) -1-Piz
7-32 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
7-33 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ F) -1-Piz
7-34 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--COOH
7-35 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--OSO ₃ H
7-36 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--OPO ₃ H ₂
7-37 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--COOH
7-38 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--SO ₃ H
7-39 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--OSO ₃ H
7-40 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--OPO ₃ H ₂
7-41 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pyrd
7-42 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pip
7-43 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Me-1-Piz
7-44 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
7-45 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Mor
7-46 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NHMe
7-47 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMe ₂
7-48 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
7-49 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
7-50 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --COOH
7-51 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --SO ₃ H
7-52 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
7-53 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
7-54 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH _2-4 -Mor
7-55 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NH ₂
7-56 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NHMe
7-57 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMe ₂
7-58 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
7-59 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
7-60 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH _{2
7-61 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Azt
_{7-62 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pyrd
_{7-63 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pip
7-64 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Me-1-Piz
7-65 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ -4- (CH ₂ CH ₂ OH) -1-Piz
7-66 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
7-67 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
7-68 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
7-69 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
7-70 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
7-71 Me -CH = CH- -C (= O)---1-Piz
7-72 Me -CH = CH- -C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
7-73 Me -CH = CH- -C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
7-74 Me -CH = CH- -C (= O)---4-Me-1-Piz
7-75 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
7-76 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
7-77 Me -CH = CH- -C (= O)---4- (CH ₂ Car) -1-Piz
7-78 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
7-79 Me -CH = CH- -C (= O)-1,3-Azt--COOH
7-80 Me -CH = CH- -C (= O)-1,3-Azt--OSO ₃ H
7-81 Me -CH = CH- -C (= O)-1,3-Azt--OPO ₃ H ₂
7-82 Me -CH = CH- -C (= O)-1,4-Pip--COOH
7-83 Me -CH = CH- -C (= O)-1,4-Pip--SO ₃ H
7-84 Me -CH = CH- -C (= O)-1,4-Pip--OSO ₃ H
7-85 Me -CH = CH- -C (= O)-1,4-Pip--OPO ₃ H ₂
7-86 Me -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
7-87 Me -CH = CH- -C (= O)-1,4-Pip-1-Pip
7-88 Me -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
7-89 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
7-90 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ NHAc) -1-Piz
7-91 Me -CH = CH- -C (= O)-1,4-Pip-4-Mor
7-92 Me -CH = CH- -C (= O)-1,4-Pip--NHMe
7-93 Me -CH = CH- -C (= O)-1,4-Pip--NMe ₂
7-94 Me -CH = CH- -C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
7-95 Me -CH = CH- -C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
7-96 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --COOH
7-97 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
7-98 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
7-99 Me -CH = CH- -C (= O)-1,4-Pip -CH _2-4 -Mor
7-100 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NH ₂
7-101 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NHMe
7-102 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMe ₂
7-103 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
7-104 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
7-105 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH ₂
7-106 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
7-107 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
7-108 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
7-109 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
7-110 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) _{2
7-111 Me -CH 2 - -NHC (=} O) - - -CH 2 - 4-Me-1-Piz
_{7-112 Me -CH 2 - -NHC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
7-113 Me -CH ₂ --NHC (= O)---CH ₂ --NMe ₂
7-114 Me -CH ₂ --NMeC (= O)---CH _2-4 -Me-1-Piz
_{7-115 Me -CH 2 - -NMeC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
7-116 Me -CH ₂ --NMeC (= O)---CH ₂ --NMe ₂
7-117 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --COOH
7-118 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
7-119 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --NMe ₂
7-120 H -CH ₂ ----1-Pyrd
7-121 H -CH ₂ ----1-Pip
7-122 H -CH ₂ ----1-Me-4-Pip
7-123 H -CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
7-124 H -CH ₂ ----4-Me-1-Piz
7-125 H -CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
7-126 H -CH ₂ ----4-Mor
7-127 H -CH ₂ -----NH ₂
7-128 H -CH ₂ -----NHMe
7-129 H -CH ₂ -----NMe ₂
7-130 H -CH ₂ CH ₂ -----COOH
7-131 H -CH ₂ CH ₂ -----OPO ₃ H ₂
7-132 H -CH ₂ CH ₂ ----1-Pyrd
7-133 H -CH ₂ CH ₂ ----1-Pip
7-134 H -CH ₂ CH ₂ ----1-Me-4-Pip
7-135 H -CH ₂ CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
7-136 H -CH ₂ CH ₂ ----4-Me-1-Piz
7-137 H -CH ₂ CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
7-138 H -CH ₂ CH ₂ ----4-Mor
7-139 H -CH ₂ CH ₂ -----NH ₂
7-140 H -CH ₂ CH ₂ -----NHMe
7-141 H -CH ₂ CH ₂ -----NMe ₂
7-142 H-(CH ₂ ) ₃ -----COOH
7-143 H-(CH ₂ ) ₃ -----OPO ₃ H ₂
7-144 H -CH ₂ CH ₂ --C (= O)---1-Piz
7-145 H -CH ₂ CH ₂ --C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
7-146 H -CH ₂ CH ₂ --C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
7-147 H -CH ₂ CH ₂ --C (= O)---4-Me-1-Piz
7-148 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
7-149 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
7-150 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ Car) -1-Piz
7-151 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
7-152 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ F) -1-Piz
7-153 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--COOH
7-154 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--OSO ₃ H
7-155 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--OPO ₃ H ₂
7-156 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--COOH
7-157 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--SO ₃ H
7-158 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--OSO ₃ H
7-159 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--OPO ₃ H ₂
7-160 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pyrd
7-161 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pip
7-162 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Me-1-Piz
7-163 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
7-164 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Mor
7-165 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NHMe
7-166 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMe ₂
7-167 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
7-168 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
7-169 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --COOH
7-170 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --SO ₃ H
7-171 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
7-172 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
7-173 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH _2-4 -Mor
7-174 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NH ₂
7-175 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NHMe
7-176 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMe ₂
7-177 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
7-178 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
7-179 H -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH _{2
7-180 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Azt
_{7-181 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pyrd
_{7-182 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pip
7-183 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Me-1-Piz
7-184 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ -4- (CH ₂ CH ₂ OH) -1-Piz
7-185 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
7-186 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
7-187 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
7-188 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
7-189 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
7-190 H -CH = CH- -C (= O)---1-Piz
7-191 H -CH = CH- -C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
7-192 H -CH = CH- -C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
7-193 H -CH = CH- -C (= O)---4-Me-1-Piz
7-194 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
7-195 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
7-196 H -CH = CH- -C (= O)---4- (CH ₂ Car) -1-Piz
7-197 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
7-198 H -CH = CH- -C (= O)-1,3-Azt--COOH
7-199 H -CH = CH- -C (= O)-1,3-Azt--OSO ₃ H
7-200 H -CH = CH- -C (= O)-1,3-Azt--OPO ₃ H ₂
7-201 H -CH = CH- -C (= O)-1,4-Pip--COOH
7-202 H -CH = CH- -C (= O)-1,4-Pip--SO ₃ H
7-203 H -CH = CH- -C (= O)-1,4-Pip--OSO ₃ H
7-204 H -CH = CH- -C (= O)-1,4-Pip--OPO ₃ H ₂
7-205 H -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
7-206 H -CH = CH- -C (= O)-1,4-Pip-1-Pip
7-207 H -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
7-208 H -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
7-209 H -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ NHAc) -1-Piz
7-210 H -CH = CH- -C (= O)-1,4-Pip-4-Mor
7-211 H -CH = CH- -C (= O)-1,4-Pip--NHMe
7-212 H -CH = CH- -C (= O)-1,4-Pip--NMe ₂
7-213 H -CH = CH- -C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
7-214 H -CH = CH- -C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
7-215 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --COOH
7-216 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
7-217 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
7-218 H -CH = CH- -C (= O)-1,4-Pip -CH _2-4 -Mor
7-219 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NH ₂
7-220 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NHMe
7-221 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMe ₂
7-222 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
7-223 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
7-224 H -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH ₂
7-225 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
7-226 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
7-227 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
7-228 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
7-229 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) _{2
7-230 H -CH 2 - -NHC (=} O) - - -CH 2 - 4-Me-1-Piz
_{7-231 H -CH 2 - -NHC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
7-232 H -CH ₂ --NHC (= O)---CH ₂ --NMe ₂
7-233 H -CH ₂ --NMeC (= O)---CH _2-4 -Me-1-Piz
_{7-234 H -CH 2 - -NMeC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
7-235 H -CH ₂ --NMeC (= O)---CH ₂ --NMe ₂
7-236 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --COOH
7-237 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
7-238 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --NMe ₂
7-239 Me 1,4-cHx----COOH
7-240 Me 1,4-cHx----OPO ₃ H ₂
7-241 Me 1,4-cHx---1-Pyrd
7-242 Me 1,4-cHx---1-Pip
7-243 Me 1,4-cHx---1-Me-4-Pip
7-244 Me 1,4-cHx---1- (CH ₂ CH ₂ OH) -4-Pip
7-245 Me 1,4-cHx---4-Me-1-Piz
7-246 Me 1,4-cHx---4- (CH ₂ CH ₂ OH) -1-Piz
7-247 Me 1,4-cHx---4-Mor
7-248 Me 1,4-cHx----NH ₂
7-249 Me 1,4-cHx----NHMe
7-250 Me 1,4-cHx----NMe ₂
7-251 H 1,4-cHx----COOH
7-252 H 1,4-cHx----OPO ₃ H ₂
7-253 H 1,4-cHx---1-Pyrd
7-254 H 1,4-cHx---1-Pip
7-255 H 1,4-cHx---1-Me-4-Pip
7-256 H 1,4-cHx---1- (CH ₂ CH ₂ OH) -4-Pip
7-257 H 1,4-cHx---4-Me-1-Piz
7-258 H 1,4-cHx---4- (CH ₂ CH ₂ OH) -1-Piz
7-259 H 1,4-cHx---4-Mor
7-260 H 1,4-cHx----NH ₂
7-261 H 1,4-cHx----NHMe
7-262 H 1,4-cHx----NMe ₂
7-263 Me-(CH ₂ ) ₄ -----COOH
7-264 Me-(CH ₂ ) ₄ -----SO ₃ H
7-265 Me-(CH ₂ ) ₄ -----OSO ₃ H
7-266 Me-(CH ₂ ) ₄ -----OPO ₃ H ₂
7-267 Me-(CH ₂ ) ₅ -----COOH
7-268 Me-(CH ₂ ) ₅ -----SO ₃ H
7-269 Me-(CH ₂ ) ₅ -----OSO ₃ H
7-270 Me-(CH ₂ ) ₅ -----OPO ₃ H ₂
7-271 Me-(CH ₂ ) ₃ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
7-272 Me-(CH ₂ ) ₄ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
7-273 Me-(CH ₂ ) ₅ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
7-274 Me-(CH ₂ ) ₆ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
7-275 H-(CH ₂ ) ₄ -----COOH
7-276 H-(CH ₂ ) ₄ -----SO ₃ H
7-277 H-(CH ₂ ) ₄ -----OSO ₃ H
7-278 H-(CH ₂ ) ₄ -----OPO ₃ H ₂
7-279 H-(CH ₂ ) ₅ -----COOH
7-280 H-(CH ₂ ) ₅ -----SO ₃ H
7-281 H-(CH ₂ ) ₅ -----OSO ₃ H
7-282 H-(CH ₂ ) ₅ -----OPO ₃ H ₂
7-283 H-(CH ₂ ) ₃ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
7-284 H-(CH ₂ ) ₄ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
7-285 H-(CH ₂ ) ₅ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
7-286 H-(CH ₂ ) ₆ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
7-287 Me -CH ₂ CH ₂ --OC (= O)---1-Me-4-Pip
7-288 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --COOH
7-289 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --SO ₃ H
_{7-290 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -OPO 3 H 2
_{7-291 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Azt
_{7-292 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pyrd
_{7-293 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pip
_{7-294 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Me-4-Pip
_{7-295 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Me-1-Piz
_{7-296 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{7-297 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Mor
7-298 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --NMe _{2
7-299 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{7-300 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
7-301 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --COOH
7-302 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{7-303 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{7-304 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Azt
_{7-305 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pyrd
_{7-306 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pip
_{7-307 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{7-308 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{7-309 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
7-310 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH _2-4 -Mor
_{7-311 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMe 2
_{7-312 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{7-313 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
7-314 Me-(CH ₂ ) ₃ --OC (= O)---1-Me-4-Pip
7-315 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --COOH
7-316 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --SO ₃ H
_{7-317 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -OPO 3 H 2
_{7-318 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Azt
_{7-319 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pyrd
_{7-320 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pip
_{7-321 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Me-4-Pip
_{7-322 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Me-1-Piz
_{7-323 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{7-324 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Mor
7-325 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --NMe _{2
7-326 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{7-327 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
7-328 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --COOH
7-329 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{7-330 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{7-331 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Azt
_{7-332 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pyrd
_{7-333 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pip
_{7-334 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{7-335 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{7-336 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
7-337 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH _2-4 -Mor
_{7-338 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMe 2
_{7-339 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{7-340 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
7-341 Me -CH ₂ CH ₂ --C (= O) O---1-Me-4-Pip
7-342 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ --COOH
_{7-343 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 - 1-Me-4-Pip
7-344 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --COOH
7-345 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --SO ₃ H
_{7-346 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
_{7-347 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Azt
_{7-348 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pyrd
_{7-349 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pip
_{7-350 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
_{7-351 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
_{7-352 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
7-353 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH _2-4 -Mor
_{7-354 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMe 2
_{7-355 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{7-356 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
7-357 Me -CH = CH- -C (= O) O---1-Me-4-Pip
7-358 Me -CH = CH- -C (= O) O---CH ₂ --COOH
7-358 Me -CH = CH- -C (= O) O- - -CH 2 - 1-Me-4-Pip
7-359 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -COOH
7-360 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -SO 3 H
7-361 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
7-362 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Azt
7-363 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pyrd
7-364 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pip
7-365 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
7-366 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
7-367 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
7-368 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Mor
7-369 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMe 2
7-370 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
7-371 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
7-372 H -CH ₂ CH ₂ --OC (= O)---1-Me-4-Pip
7-373 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --COOH
7-374 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --SO ₃ H
_{7-375 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -OPO 3 H 2
_{7-376 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Azt
_{7-377 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pyrd
_{7-378 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pip
_{7-379 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Me-4-Pip
_{7-380 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Me-1-Piz
_{7-381 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{7-382 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Mor
7-383 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --NMe _{2
7-384 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{7-385 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
7-386 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --COOH
7-387 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{7-388 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{7-389 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Azt
_{7-390 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pyrd
_{7-391 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pip
_{7-392 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{7-393 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{7-394 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
7-395 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH _2-4 -Mor
_{7-306 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMe 2
_{7-397 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{7-398 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
7-399 Me-(CH ₂ ) ₃ --OC (= O)---1-Me-4-Pip
7-400 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --COOH
7-401 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --SO ₃ H
_{7-402 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -OPO 3 H 2
_{7-403 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Azt
_{7-404 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pyrd
_{7-405 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pip
_{7-406 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Me-4-Pip
_{7-407 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Me-1-Piz
_{7-408 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{7-409 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Mor
7-410 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --NMe _{2
7-411 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{7-412 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
7-413 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --COOH
7-414 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{7-415 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{7-416 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Azt
_{7-417 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pyrd
_{7-418 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pip
_{7-419 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{7-420 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{7-421 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
7-422 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH _2-4 -Mor
_{7-423 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMe 2
_{7-424 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{7-425 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
7-426 H -CH ₂ CH ₂ --C (= O) O---1-Me-4-Pip
7-427 H -CH ₂ CH ₂ --C (= O) O---CH ₂ --COOH
_{7-428 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 - 1-Me-4-Pip
7-429 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --COOH
7-430 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --SO ₃ H
_{7-431 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
_{7-432 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Azt
_{7-433 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pyrd
_{7-434 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pip
_{7-435 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
_{7-436 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
_{7-437 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
7-438 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH _2-4 -Mor
_{7-439 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMe 2
_{7-440 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{7-441 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
7-442 H -CH = CH- -C (= O) O---1-Me-4-Pip
7-443 H -CH = CH- -C (= O) O---CH ₂ --COOH
7-444 H -CH = CH- -C (= O) O- - -CH 2 - 1-Me-4-Pip
7-445 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -COOH
7-446 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -SO 3 H
7-447 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
7-448 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Azt
7-449 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pyrd
7-450 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pip
7-451 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
7-452 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
7-453 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
7-454 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Mor
7-455 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMe 2
7-456 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
7-457 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
-------------------------------------------------- -----------------
(Table 8)

-------------------------------------------------- -----------------
Example R ¹ -L ¹ --G- -L ² --L ³ --A
Compound number
-------------------------------------------------- -----------------
8-1 Me -CH ₂ ----1-Pyrd
8-2 Me -CH ₂ ----1-Pip
8-3 Me -CH ₂ ----1-Me-4-Pip
8-4 Me -CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
8-5 Me -CH ₂ ----4-Me-1-Piz
8-6 Me -CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
8-7 Me -CH ₂ ----4-Mor
8-8 Me -CH ₂ -----NH ₂
8-9 Me -CH ₂ -----NHMe
8-10 Me -CH ₂ -----NMe ₂
8-11 Me -CH ₂ CH ₂ -----COOH
8-12 Me -CH ₂ CH ₂ -----OPO ₃ H ₂
8-13 Me -CH ₂ CH ₂ ----1-Pyrd
8-14 Me -CH ₂ CH ₂ ----1-Pip
8-15 Me -CH ₂ CH ₂ ----1-Me-4-Pip
8-16 Me -CH ₂ CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
8-17 Me -CH ₂ CH ₂ ----4-Me-1-Piz
8-18 Me -CH ₂ CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
8-19 Me -CH ₂ CH ₂ ----4-Mor
8-20 Me -CH ₂ CH ₂ -----NH ₂
8-21 Me -CH ₂ CH ₂ -----NHMe
8-22 Me -CH ₂ CH ₂ -----NMe ₂
8-23 Me-(CH ₂ ) ₃ -----COOH
8-24 Me-(CH ₂ ) ₃ -----OPO ₃ H ₂
8-25 Me -CH ₂ CH ₂ --C (= O)---1-Piz
8-26 Me -CH ₂ CH ₂ --C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
8-27 Me -CH ₂ CH ₂ --C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
8-28 Me -CH ₂ CH ₂ --C (= O)---4-Me-1-Piz
8-29 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
8-30 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
8-31 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ Car) -1-Piz
8-32 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
8-33 Me -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ F) -1-Piz
8-34 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--COOH
8-35 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--OSO ₃ H
8-36 Me -CH ₂ CH ₂ --C (= O)-1,3-Azt--OPO ₃ H ₂
8-37 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--COOH
8-38 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--SO ₃ H
8-39 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--OSO ₃ H
8-40 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--OPO ₃ H ₂
8-41 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pyrd
8-42 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pip
8-43 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Me-1-Piz
8-44 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
8-45 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Mor
8-46 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NHMe
8-47 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMe ₂
8-48 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
8-49 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
8-50 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --COOH
8-51 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --SO ₃ H
8-52 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
8-53 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
8-54 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH _2-4 -Mor
8-55 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NH ₂
8-56 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NHMe
8-57 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMe ₂
8-58 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
8-59 Me -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
8-60 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH _{2
8-61 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Azt
_{8-62 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pyrd
_{8-63 Me -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pip
8-64 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Me-1-Piz
8-65 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ -4- (CH ₂ CH ₂ OH) -1-Piz
8-66 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
8-67 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
8-68 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
8-69 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
8-70 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
8-71 Me -CH = CH- -C (= O)---1-Piz
8-72 Me -CH = CH- -C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
8-73 Me -CH = CH- -C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
8-74 Me -CH = CH- -C (= O)---4-Me-1-Piz
8-75 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
8-76 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
8-77 Me -CH = CH- -C (= O)---4- (CH ₂ Car) -1-Piz
8-78 Me -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
8-79 Me -CH = CH- -C (= O)-1,3-Azt--COOH
8-80 Me -CH = CH- -C (= O)-1,3-Azt--OSO ₃ H
8-81 Me -CH = CH- -C (= O)-1,3-Azt--OPO ₃ H ₂
8-82 Me -CH = CH- -C (= O)-1,4-Pip--COOH
8-83 Me -CH = CH- -C (= O)-1,4-Pip--SO ₃ H
8-84 Me -CH = CH- -C (= O)-1,4-Pip--OSO ₃ H
8-85 Me -CH = CH- -C (= O)-1,4-Pip--OPO ₃ H ₂
8-86 Me -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
8-87 Me -CH = CH- -C (= O)-1,4-Pip-1-Pip
8-88 Me -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
8-89 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
8-90 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ NHAc) -1-Piz
8-91 Me -CH = CH- -C (= O)-1,4-Pip-4-Mor
8-92 Me -CH = CH- -C (= O)-1,4-Pip--NHMe
8-93 Me -CH = CH- -C (= O)-1,4-Pip--NMe ₂
8-94 Me -CH = CH- -C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
8-95 Me -CH = CH- -C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
8-96 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --COOH
8-97 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
8-98 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
8-99 Me -CH = CH- -C (= O)-1,4-Pip -CH _2-4 -Mor
8-100 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NH ₂
8-101 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NHMe
8-102 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMe ₂
8-103 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
8-104 Me -CH = CH- -C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
8-105 Me -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH ₂
8-106 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
8-107 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
8-108 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
8-109 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
8-110 Me -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) _{2
8-111 Me -CH 2 - -NHC (=} O) - - -CH 2 - 4-Me-1-Piz
_{8-112 Me -CH 2 - -NHC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
8-113 Me -CH ₂ --NHC (= O)---CH ₂ --NMe ₂
8-114 Me -CH ₂ --NMeC (= O)---CH _2-4 -Me-1-Piz
_{8-115 Me -CH 2 - -NMeC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
8-116 Me -CH ₂ --NMeC (= O)---CH ₂ --NMe ₂
8-117 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --COOH
8-118 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
8-119 Me -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --NMe ₂
8-120 H -CH ₂ ----1-Pyrd
8-121 H -CH ₂ ----1-Pip
8-122 H -CH ₂ ----1-Me-4-Pip
8-123 H -CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
8-124 H -CH ₂ ----4-Me-1-Piz
8-125 H -CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
8-126 H -CH ₂ ----4-Mor
8-127 H -CH ₂ -----NH ₂
8-128 H -CH ₂ -----NHMe
8-129 H -CH ₂ -----NMe ₂
8-130 H -CH ₂ CH ₂ -----COOH
8-131 H -CH ₂ CH ₂ -----OPO ₃ H ₂
8-132 H -CH ₂ CH ₂ ----1-Pyrd
8-133 H -CH ₂ CH ₂ ----1-Pip
8-134 H -CH ₂ CH ₂ ----1-Me-4-Pip
8-135 H -CH ₂ CH ₂ ----1- (CH ₂ CH ₂ OH) -4-Pip
8-136 H -CH ₂ CH ₂ ----4-Me-1-Piz
8-137 H -CH ₂ CH ₂ ----4- (CH ₂ CH ₂ OH) -1-Piz
8-138 H -CH ₂ CH ₂ ----4-Mor
8-139 H -CH ₂ CH ₂ -----NH ₂
8-140 H -CH ₂ CH ₂ -----NHMe
8-141 H -CH ₂ CH ₂ -----NMe ₂
8-142 H-(CH ₂ ) ₃ -----COOH
8-143 H-(CH ₂ ) ₃ -----OPO ₃ H ₂
8-144 H -CH ₂ CH ₂ --C (= O)---1-Piz
8-145 H -CH ₂ CH ₂ --C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
8-146 H -CH ₂ CH ₂ --C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
8-147 H -CH ₂ CH ₂ --C (= O)---4-Me-1-Piz
8-148 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
8-149 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
8-150 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ Car) -1-Piz
8-151 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
8-152 H -CH ₂ CH ₂ --C (= O)---4- (CH ₂ CH ₂ F) -1-Piz
8-153 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--COOH
8-154 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--OSO ₃ H
8-155 H -CH ₂ CH ₂ --C (= O)-1,3-Azt--OPO ₃ H ₂
8-156 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--COOH
8-157 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--SO ₃ H
8-158 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--OSO ₃ H
8-159 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--OPO ₃ H ₂
8-160 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pyrd
8-161 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-1-Pip
8-162 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Me-1-Piz
8-163 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
8-164 H -CH ₂ CH ₂ --C (= O)-1,4-Pip-4-Mor
8-165 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NHMe
8-166 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMe ₂
8-167 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
8-168 H -CH ₂ CH ₂ --C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
8-169 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --COOH
8-170 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --SO ₃ H
8-171 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
8-172 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
8-173 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH _2-4 -Mor
8-174 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NH ₂
8-175 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NHMe
8-176 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMe ₂
8-177 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
8-178 H -CH ₂ CH ₂ --C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
8-179 H -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH _{2
8-180 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Azt
_{8-181 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pyrd
_{8-182 H -CH 2 CH 2 - -C} (= O) - 1,4-Piz -CH 2 CH 2 - 1-Pip
8-183 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Me-1-Piz
8-184 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ -4- (CH ₂ CH ₂ OH) -1-Piz
8-185 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
8-186 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
8-187 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
8-188 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
8-189 H -CH ₂ CH ₂ --C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) ₂
8-190 H -CH = CH- -C (= O)---1-Piz
8-191 H -CH = CH- -C (= O)---4- (C (= NH) NH ₂ ) -1-Piz
8-192 H -CH = CH- -C (= O)---4- (C (= NH) CH ₃ ) -1-Piz
8-193 H -CH = CH- -C (= O)---4-Me-1-Piz
8-194 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OH) -1-Piz
8-195 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ NHAc) -1-Piz
8-196 H -CH = CH- -C (= O)---4- (CH ₂ Car) -1-Piz
8-197 H -CH = CH- -C (= O)---4- (CH ₂ CH ₂ OCar) -1-Piz
8-198 H -CH = CH- -C (= O)-1,3-Azt--COOH
8-199 H -CH = CH- -C (= O)-1,3-Azt--OSO ₃ H
8-200 H -CH = CH- -C (= O)-1,3-Azt--OPO ₃ H ₂
8-201 H -CH = CH- -C (= O)-1,4-Pip--COOH
8-202 H -CH = CH- -C (= O)-1,4-Pip--SO ₃ H
8-203 H -CH = CH- -C (= O)-1,4-Pip--OSO ₃ H
8-204 H -CH = CH- -C (= O)-1,4-Pip--OPO ₃ H ₂
8-205 H -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
8-206 H -CH = CH- -C (= O)-1,4-Pip-1-Pip
8-207 H -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
8-208 H -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ OH) -1-Piz
8-209 H -CH = CH- -C (= O)-1,4-Pip-4- (CH ₂ CH ₂ NHAc) -1-Piz
8-210 H -CH = CH- -C (= O)-1,4-Pip-4-Mor
8-211 H -CH = CH- -C (= O)-1,4-Pip--NHMe
8-212 H -CH = CH- -C (= O)-1,4-Pip--NMe ₂
8-213 H -CH = CH- -C (= O)-1,4-Pip--NMeCH ₂ CH ₂ OH
8-214 H -CH = CH- -C (= O)-1,4-Pip--N (CH ₂ CH ₂ OH) ₂
8-215 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --COOH
8-216 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OSO ₃ H
8-217 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --OPO ₃ H ₂
8-218 H -CH = CH- -C (= O)-1,4-Pip -CH _2-4 -Mor
8-219 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NH ₂
8-220 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NHMe
8-221 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMe ₂
8-222 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --NMeCH ₂ CH ₂ OH
8-223 H -CH = CH- -C (= O)-1,4-Pip -CH ₂ --N (CH ₂ CH ₂ OH) ₂
8-224 H -CH ₂ CH ₂ --C (= O)-1,4-Piz--SO ₂ NH ₂
8-225 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH _2-4 -Mor
8-226 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NHMe
8-227 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMe ₂
8-228 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --NMeCH ₂ CH ₂ OH
8-229 H -CH = CH- -C (= O)-1,4-Piz -CH ₂ CH ₂ --N (CH ₂ CH ₂ OH) _{2
8-230 H -CH 2 - -NHC (=} O) - - -CH 2 - 4-Me-1-Piz
_{8-231 H -CH 2 - -NHC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
8-232 H -CH ₂ --NHC (= O)---CH ₂ --NMe ₂
8-233 H -CH ₂ --NMeC (= O)---CH _2-4 -Me-1-Piz
_{8-234 H -CH 2 - -NMeC (=} O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
8-235 H -CH ₂ --NMeC (= O)---CH ₂ --NMe ₂
8-236 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --COOH
8-237 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
8-238 H -CH ₂ CH ₂ --C (= O) NMe---CH ₂ CH ₂ --NMe ₂
8-239 Me 1,4-cHx----COOH
8-240 Me 1,4-cHx----OPO ₃ H ₂
8-241 Me 1,4-cHx---1-Pyrd
8-242 Me 1,4-cHx---1-Pip
8-243 Me 1,4-cHx---1-Me-4-Pip
8-244 Me 1,4-cHx---1- (CH ₂ CH ₂ OH) -4-Pip
8-245 Me 1,4-cHx---4-Me-1-Piz
8-246 Me 1,4-cHx---4- (CH ₂ CH ₂ OH) -1-Piz
8-247 Me 1,4-cHx---4-Mor
8-248 Me 1,4-cHx----NH ₂
8-249 Me 1,4-cHx----NHMe
8-250 Me 1,4-cHx----NMe ₂
8-251 H 1,4-cHx----COOH
8-252 H 1,4-cHx----OPO ₃ H ₂
8-253 H 1,4-cHx---1-Pyrd
8-254 H 1,4-cHx---1-Pip
8-255 H 1,4-cHx---1-Me-4-Pip
8-256 H 1,4-cHx---1- (CH ₂ CH ₂ OH) -4-Pip
8-257 H 1,4-cHx---4-Me-1-Piz
8-258 H 1,4-cHx---4- (CH ₂ CH ₂ OH) -1-Piz
8-259 H 1,4-cHx---4-Mor
8-260 H 1,4-cHx----NH ₂
8-261 H 1,4-cHx----NHMe
8-262 H 1,4-cHx----NMe ₂
8-263 Me-(CH ₂ ) ₄ -----COOH
8-264 Me-(CH ₂ ) ₄ -----SO ₃ H
8-265 Me-(CH ₂ ) ₄ -----OSO ₃ H
8-266 Me-(CH ₂ ) ₄ -----OPO ₃ H ₂
8-267 Me-(CH ₂ ) ₅ -----COOH
8-268 Me-(CH ₂ ) ₅ -----SO ₃ H
8-269 Me-(CH ₂ ) ₅ -----OSO ₃ H
8-270 Me-(CH ₂ ) ₅ -----OPO ₃ H ₂
8-271 Me-(CH ₂ ) ₃ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
8-272 Me-(CH ₂ ) ₄ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
8-273 Me-(CH ₂ ) ₅ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
8-274 Me-(CH ₂ ) ₆ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
8-275 H-(CH ₂ ) ₄ -----COOH
8-276 H-(CH ₂ ) ₄ -----SO ₃ H
8-277 H-(CH ₂ ) ₄ -----OSO ₃ H
8-278 H-(CH ₂ ) ₄ -----OPO ₃ H ₂
8-279 H-(CH ₂ ) ₅ -----COOH
8-280 H-(CH ₂ ) ₅ -----SO ₃ H
8-281 H-(CH ₂ ) ₅ -----OSO ₃ H
8-282 H-(CH ₂ ) ₅ -----OPO ₃ H ₂
8-283 H-(CH ₂ ) ₃ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
8-284 H-(CH ₂ ) ₄ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
8-285 H-(CH ₂ ) ₅ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
8-286 H-(CH ₂ ) ₆ --C (= O) NMe---CH ₂ CH ₂ --SO ₃ H
8-287 Me -CH ₂ CH ₂ --OC (= O)---1-Me-4-Pip
8-288 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --COOH
8-289 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --SO ₃ H
_{8-290 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -OPO 3 H 2
_{8-291 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Azt
_{8-292 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pyrd
_{8-293 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pip
_{8-294 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Me-4-Pip
_{8-295 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Me-1-Piz
_{8-296 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{8-297 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Mor
8-298 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ --NMe _{2
8-299 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{8-300 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
8-301 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --COOH
8-302 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{8-303 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{8-304 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Azt
_{8-305 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pyrd
_{8-306 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pip
_{8-307 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{8-308 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{8-309 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
8-310 Me -CH ₂ CH ₂ --OC (= O)---CH ₂ CH _2-4 -Mor
_{8-311 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMe 2
_{8-312 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{8-313 Me -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
8-314 Me-(CH ₂ ) ₃ --OC (= O)---1-Me-4-Pip
8-315 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --COOH
8-316 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --SO ₃ H
_{8-317 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -OPO 3 H 2
_{8-318 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Azt
_{8-319 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pyrd
_{8-320 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pip
_{8-321 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Me-4-Pip
_{8-322 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Me-1-Piz
_{8-323 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{8-324 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Mor
8-325 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --NMe _{2
8-326 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{8-327 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
8-328 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --COOH
8-329 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{8-330 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{8-331 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Azt
_{8-332 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pyrd
_{8-333 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pip
_{8-334 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{8-335 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{8-336 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
8-337 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH _2-4 -Mor
_{8-338 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMe 2
_{8-339 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{8-340 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
8-341 Me -CH ₂ CH ₂ --C (= O) O---1-Me-4-Pip
8-342 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ --COOH
_{8-343 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 - 1-Me-4-Pip
8-344 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --COOH
8-345 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --SO ₃ H
_{8-346 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
_{8-347 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Azt
_{8-348 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pyrd
_{8-349 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pip
_{8-350 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
_{8-351 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
_{8-352 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
8-353 Me -CH ₂ CH ₂ --C (= O) O---CH ₂ CH _2-4 -Mor
_{8-354 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMe 2
_{8-355 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{8-356 Me -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
8-357 Me -CH = CH- -C (= O) O---1-Me-4-Pip
8-358 Me -CH = CH- -C (= O) O---CH ₂ --COOH
8-358 Me -CH = CH- -C (= O) O- - -CH 2 - 1-Me-4-Pip
8-359 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -COOH
8-360 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -SO 3 H
8-361 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
8-362 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Azt
8-363 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pyrd
8-364 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pip
8-365 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
8-366 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
8-367 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
8-368 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Mor
8-369 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMe 2
8-370 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
8-371 Me -CH = CH- -C (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
8-372 H -CH ₂ CH ₂ --OC (= O)---1-Me-4-Pip
8-373 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --COOH
8-374 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --SO ₃ H
_{8-375 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -OPO 3 H 2
_{8-376 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Azt
_{8-377 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pyrd
_{8-378 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Pip
_{8-379 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 1-Me-4-Pip
_{8-380 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Me-1-Piz
_{8-381 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{8-382 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - 4-Mor
8-383 H -CH ₂ CH ₂ --OC (= O)---CH ₂ --NMe _{2
8-384 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{8-385 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
8-386 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --COOH
8-387 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{8-388 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{8-389 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Azt
_{8-390 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pyrd
_{8-391 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Pip
_{8-392 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{8-393 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{8-394 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
8-395 H -CH ₂ CH ₂ --OC (= O)---CH ₂ CH _2-4 -Mor
_{8-306 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMe 2
_{8-397 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{8-398 H -CH 2 CH 2 - -OC} (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
8-399 Me-(CH ₂ ) ₃ --OC (= O)---1-Me-4-Pip
8-400 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --COOH
8-401 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --SO ₃ H
8-402 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --OPO ₃ H _{2
8-403 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Azt
_{8-404 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pyrd
_{8-405 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Pip
_{8-406 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 1-Me-4-Pip
_{8-407 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Me-1-Piz
_{8-408 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
_{8-409 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - 4-Mor
8-410 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ --NMe _{2
8-411 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -NMeCH 2 CH 2 OH
_{8-412 Me - (CH 2) 3} - -OC (= O) - - -CH 2 - -N (CH 2 CH 2 OH) 2
8-413 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --COOH
8-414 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH ₂ --SO ₃ H
_{8-415 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -OPO 3 H 2
_{8-416 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Azt
_{8-417 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pyrd
_{8-418 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Pip
_{8-419 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 1-Me-4-Pip
_{8-420 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4-Me-1-Piz
_{8-421 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
8-422 Me-(CH ₂ ) ₃ --OC (= O)---CH ₂ CH _2-4 -Mor
_{8-423 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMe 2
_{8-424 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{8-425 Me - (CH 2) 3} - -OC (= O) - - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
8-426 H -CH ₂ CH ₂ --C (= O) O---1-Me-4-Pip
8-427 H -CH ₂ CH ₂ --C (= O) O---CH ₂ --COOH
_{8-428 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 - 1-Me-4-Pip
8-429 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --COOH
8-430 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH ₂ --SO ₃ H
_{8-431 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
_{8-432 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Azt
_{8-433 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pyrd
_{8-434 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Pip
_{8-435 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
_{8-436 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
_{8-437 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
8-438 H -CH ₂ CH ₂ --C (= O) O---CH ₂ CH _2-4 -Mor
_{8-439 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMe 2
_{8-440 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
_{8-441 H -CH 2 CH 2 - -C} (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
8-442 H -CH = CH- -C (= O) O---1-Me-4-Pip
8-443 H -CH = CH- -C (= O) O---CH ₂ --COOH
8-444 H -CH = CH- -C (= O) O- - -CH 2 - 1-Me-4-Pip
8-445 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -COOH
8-446 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -SO 3 H
8-447 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -OPO 3 H 2
8-448 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Azt
8-449 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pyrd
8-450 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Pip
8-451 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 1-Me-4-Pip
8-452 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Me-1-Piz
8-453 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4- (CH 2 CH 2 OH) -1-Piz
8-454 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - 4-Mor
8-455 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMe 2
8-456 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -NMeCH 2 CH 2 OH
8-457 H -CH = CH- -C (= O) O- - -CH 2 CH 2 - -N (CH 2 CH 2 OH) 2
-------------------------------------------------- -----------------
(Table 9)

-------------------------------------------------- -----------------
Example R¹   -L¹--G- -L²--L^Three--A
Compound
number
-------------------------------------------------- -----------------
9-1 Me -CH₂----1-Pyrd
9-2 Me -CH₂----1-Pip
9-3 Me -CH₂----1-Me-4-Pip
9-4 Me -CH₂----1- (CH₂CH₂OH) -4-Pip
9-5 Me -CH₂----4-Me-1-Piz
9-6 Me -CH₂----4- (CH₂CH₂OH) -1-Piz
9-7 Me -CH₂----4-Mor
9-8 Me -CH₂-----NH₂
9-9 Me -CH₂-----NHMe
9-10 Me -CH₂-----NMe₂
9-11 Me -CH₂CH₂-----COOH
9-12 Me -CH₂CH₂-----OPO_ThreeH₂
9-13 Me -CH₂CH₂----1-Pyrd
9-14 Me -CH₂CH₂----1-Pip
9-15 Me -CH₂CH₂----1-Me-4-Pip
9-16 Me -CH₂CH₂----1- (CH₂CH₂OH) -4-Pip
9-17 Me -CH₂CH₂----4-Me-1-Piz
9-18 Me -CH₂CH₂----4- (CH₂CH₂OH) -1-Piz
9-19 Me -CH₂CH₂----4-Mor
9-20 Me -CH₂CH₂-----NH₂
9-21 Me -CH₂CH₂-----NHMe
9-22 Me -CH₂CH₂-----NMe₂
9-23 Me-(CH₂)_Three-----COOH
9-24 Me-(CH₂)_Three-----OPO_ThreeH₂
9-25 Me -CH₂CH₂--C (= O)---1-Piz
9-26 Me -CH₂CH₂--C (= O)---4- (C (= NH) NH₂) -1-Piz
9-27 Me -CH₂CH₂--C (= O)---4- (C (= NH) CH_Three) -1-Piz
9-28 Me -CH₂CH₂--C (= O)---4-Me-1-Piz
9-29 Me -CH₂CH₂--C (= O)---4- (CH₂CH₂OH) -1-Piz
9-30 Me -CH₂CH₂--C (= O)---4- (CH₂CH₂NHAc) -1-Piz
9-31 Me -CH₂CH₂--C (= O)---4- (CH₂Car) -1-Piz
9-32 Me -CH₂CH₂--C (= O)---4- (CH₂CH₂OCar) -1-Piz
9-33 Me -CH₂CH₂--C (= O)---4- (CH₂CH₂F) -1-Piz
9-34 Me -CH₂CH₂--C (= O)-1,3-Azt--COOH
9-35 Me -CH₂CH₂--C (= O)-1,3-Azt--OSO_ThreeH
9-36 Me -CH₂CH₂--C (= O)-1,3-Azt--OPO_ThreeH₂
9-37 Me -CH₂CH₂--C (= O)-1,4-Pip--COOH
9-38 Me -CH₂CH₂--C (= O)-1,4-Pip--SO_ThreeH
9-39 Me -CH₂CH₂--C (= O)-1,4-Pip--OSO_ThreeH
9-40 Me -CH₂CH₂--C (= O)-1,4-Pip--OPO_ThreeH₂
9-41 Me -CH₂CH₂--C (= O)-1,4-Pip-1-Pyrd
9-42 Me -CH₂CH₂--C (= O)-1,4-Pip-1-Pip
9-43 Me -CH₂CH₂--C (= O)-1,4-Pip-4-Me-1-Piz
9-44 Me -CH₂CH₂--C (= O)-1,4-Pip-4- (CH₂CH₂OH) -1-Piz
9-45 Me -CH₂CH₂--C (= O)-1,4-Pip-4-Mor
9-46 Me -CH₂CH₂--C (= O)-1,4-Pip--NHMe
9-47 Me -CH₂CH₂--C (= O)-1,4-Pip--NMe₂
9-48 Me -CH₂CH₂--C (= O)-1,4-Pip--NMeCH₂CH₂OH
9-49 Me -CH₂CH₂--C (= O)-1,4-Pip--N (CH₂CH₂OH)₂
9-50 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--COOH
9-51 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--SO_ThreeH
9-52 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--OSO_ThreeH
9-53 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--OPO_ThreeH₂
9-54 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂-4-Mor
9-55 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NH₂
9-56 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NHMe
9-57 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NMe₂
9-58 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NMeCH₂CH₂OH
9-59 Me -CH₂CH₂--C (= O)-1,4-Pip -CH₂--N (CH₂CH₂OH)₂
9-60 Me -CH₂CH₂--C (= O)-1,4-Piz--SO₂NH₂
9-61 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-1-Azt
9-62 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-1-Pyrd
9-63 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-1-Pip
9-64 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-4-Me-1-Piz
9-65 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
9-66 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-4-Mor
9-67 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--NHMe
9-68 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--NMe₂
9-69 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--NMeCH₂CH₂OH
9-70 Me -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--N (CH₂CH₂OH)₂
9-71 Me -CH = CH- -C (= O)---1-Piz
9-72 Me -CH = CH- -C (= O)---4- (C (= NH) NH₂) -1-Piz
9-73 Me -CH = CH- -C (= O)---4- (C (= NH) CH_Three) -1-Piz
9-74 Me -CH = CH- -C (= O)---4-Me-1-Piz
9-75 Me -CH = CH- -C (= O)---4- (CH₂CH₂OH) -1-Piz
9-76 Me -CH = CH- -C (= O)---4- (CH₂CH₂NHAc) -1-Piz
9-77 Me -CH = CH- -C (= O)---4- (CH₂Car) -1-Piz
9-78 Me -CH = CH- -C (= O)---4- (CH₂CH₂OCar) -1-Piz
9-79 Me -CH = CH- -C (= O)-1,3-Azt--COOH
9-80 Me -CH = CH- -C (= O)-1,3-Azt--OSO_ThreeH
9-81 Me -CH = CH- -C (= O)-1,3-Azt--OPO_ThreeH₂
9-82 Me -CH = CH- -C (= O)-1,4-Pip--COOH
9-83 Me -CH = CH- -C (= O)-1,4-Pip--SO_ThreeH
9-84 Me -CH = CH- -C (= O)-1,4-Pip--OSO_ThreeH
9-85 Me -CH = CH- -C (= O)-1,4-Pip--OPO_ThreeH₂
9-86 Me -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
9-87 Me -CH = CH- -C (= O)-1,4-Pip-1-Pip
9-88 Me -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
9-89 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH₂CH₂OH) -1-Piz
9-90 Me -CH = CH- -C (= O)-1,4-Pip-4- (CH₂CH₂NHAc) -1-Piz
9-91 Me -CH = CH- -C (= O)-1,4-Pip-4-Mor
9-92 Me -CH = CH- -C (= O)-1,4-Pip--NHMe
9-93 Me -CH = CH- -C (= O)-1,4-Pip--NMe₂
9-94 Me -CH = CH- -C (= O)-1,4-Pip--NMeCH₂CH₂OH
9-95 Me -CH = CH- -C (= O)-1,4-Pip--N (CH₂CH₂OH)₂
9-96 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--COOH
9-97 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--OSO_ThreeH
9-98 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--OPO_ThreeH₂
9-99 Me -CH = CH- -C (= O)-1,4-Pip -CH₂-4-Mor
9-100 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--NH₂
9-101 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--NHMe
9-102 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--NMe₂
9-103 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--NMeCH₂CH₂OH
9-104 Me -CH = CH- -C (= O)-1,4-Pip -CH₂--N (CH₂CH₂OH)₂
9-105 Me -CH₂CH₂--C (= O)-1,4-Piz--SO₂NH₂
9-106 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-4-Mor
9-107 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--NHMe
9-108 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--NMe₂
9-109 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--NMeCH₂CH₂OH
9-110 Me -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--N (CH₂CH₂OH)₂
9-111 Me -CH₂--NHC (= O)---CH₂-4-Me-1-Piz
9-112 Me -CH₂--NHC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
9-113 Me -CH₂--NHC (= O)---CH₂--NMe₂
9-114 Me -CH₂--NMeC (= O)---CH₂-4-Me-1-Piz
9-115 Me -CH₂--NMeC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
9-116 Me -CH₂--NMeC (= O)---CH₂--NMe₂
9-117 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂--COOH
9-118 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂--SO_ThreeH
9-119 Me -CH₂CH₂--C (= O) NMe---CH₂CH₂--NMe₂
9-120 H -CH₂----1-Pyrd
9-121 H -CH₂----1-Pip
9-122 H -CH₂----1-Me-4-Pip
9-123 H -CH₂----1- (CH₂CH₂OH) -4-Pip
9-124 H -CH₂----4-Me-1-Piz
9-125 H -CH₂----4- (CH₂CH₂OH) -1-Piz
9-126 H -CH₂----4-Mor
9-127 H -CH₂-----NH₂
9-128 H -CH₂-----NHMe
9-129 H -CH₂-----NMe₂
9-130 H -CH₂CH₂-----COOH
9-131 H -CH₂CH₂-----OPO_ThreeH₂
9-132 H -CH₂CH₂----1-Pyrd
9-133 H -CH₂CH₂----1-Pip
9-134 H -CH₂CH₂----1-Me-4-Pip
9-135 H -CH₂CH₂----1- (CH₂CH₂OH) -4-Pip
9-136 H -CH₂CH₂----4-Me-1-Piz
9-137 H -CH₂CH₂----4- (CH₂CH₂OH) -1-Piz
9-138 H -CH₂CH₂----4-Mor
9-139 H -CH₂CH₂-----NH₂
9-140 H -CH₂CH₂-----NHMe
9-141 H -CH₂CH₂-----NMe₂
9-142 H-(CH₂)_Three-----COOH
9-143 H-(CH₂)_Three-----OPO_ThreeH₂
9-144 H -CH₂CH₂--C (= O)---1-Piz
9-145 H -CH₂CH₂--C (= O)---4- (C (= NH) NH₂) -1-Piz
9-146 H -CH₂CH₂--C (= O)---4- (C (= NH) CH_Three) -1-Piz
9-147 H -CH₂CH₂--C (= O)---4-Me-1-Piz
9-148 H -CH₂CH₂--C (= O)---4- (CH₂CH₂OH) -1-Piz
9-149 H -CH₂CH₂--C (= O)---4- (CH₂CH₂NHAc) -1-Piz
9-150 H -CH₂CH₂--C (= O)---4- (CH₂Car) -1-Piz
9-151 H -CH₂CH₂--C (= O)---4- (CH₂CH₂OCar) -1-Piz
9-152 H -CH₂CH₂--C (= O)---4- (CH₂CH₂F) -1-Piz
9-153 H -CH₂CH₂--C (= O)-1,3-Azt--COOH
9-154 H -CH₂CH₂--C (= O)-1,3-Azt--OSO_ThreeH
9-155 H -CH₂CH₂--C (= O)-1,3-Azt--OPO_ThreeH₂
9-156 H -CH₂CH₂--C (= O)-1,4-Pip--COOH
9-157 H -CH₂CH₂--C (= O)-1,4-Pip--SO_ThreeH
9-158 H -CH₂CH₂--C (= O)-1,4-Pip--OSO_ThreeH
9-159 H -CH₂CH₂--C (= O)-1,4-Pip--OPO_ThreeH₂
9-160 H -CH₂CH₂--C (= O)-1,4-Pip-1-Pyrd
9-161 H -CH₂CH₂--C (= O)-1,4-Pip-1-Pip
9-162 H -CH₂CH₂--C (= O)-1,4-Pip-4-Me-1-Piz
9-163 H -CH₂CH₂--C (= O)-1,4-Pip-4- (CH₂CH₂OH) -1-Piz
9-164 H -CH₂CH₂--C (= O)-1,4-Pip-4-Mor
9-165 H -CH₂CH₂--C (= O)-1,4-Pip--NHMe
9-166 H -CH₂CH₂--C (= O)-1,4-Pip--NMe₂
9-167 H -CH₂CH₂--C (= O)-1,4-Pip--NMeCH₂CH₂OH
9-168 H -CH₂CH₂--C (= O)-1,4-Pip--N (CH₂CH₂OH)₂
9-169 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--COOH
9-170 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--SO_ThreeH
9-171 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--OSO_ThreeH
9-172 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--OPO_ThreeH₂
9-173 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂-4-Mor
9-174 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NH₂
9-175 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NHMe
9-176 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NMe₂
9-177 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--NMeCH₂CH₂OH
9-178 H -CH₂CH₂--C (= O)-1,4-Pip -CH₂--N (CH₂CH₂OH)₂
9-179 H -CH₂CH₂--C (= O)-1,4-Piz--SO₂NH₂
9-180 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-1-Azt
9-181 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-1-Pyrd
9-182 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-1-Pip
9-183 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-4-Me-1-Piz
9-184 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
9-185 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂-4-Mor
9-186 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--NHMe
9-187 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--NMe₂
9-188 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--NMeCH₂CH₂OH
9-189 H -CH₂CH₂--C (= O)-1,4-Piz -CH₂CH₂--N (CH₂CH₂OH)₂
9-190 H -CH = CH- -C (= O)---1-Piz
9-191 H -CH = CH- -C (= O)---4- (C (= NH) NH₂) -1-Piz
9-192 H -CH = CH- -C (= O)---4- (C (= NH) CH_Three) -1-Piz
9-193 H -CH = CH- -C (= O)---4-Me-1-Piz
9-194 H -CH = CH- -C (= O)---4- (CH₂CH₂OH) -1-Piz
9-195 H -CH = CH- -C (= O)---4- (CH₂CH₂NHAc) -1-Piz
9-196 H -CH = CH- -C (= O)---4- (CH₂Car) -1-Piz
9-197 H -CH = CH- -C (= O)---4- (CH₂CH₂OCar) -1-Piz
9-198 H -CH = CH- -C (= O)-1,3-Azt--COOH
9-199 H -CH = CH- -C (= O)-1,3-Azt--OSO_ThreeH
9-200 H -CH = CH- -C (= O)-1,3-Azt--OPO_ThreeH₂
9-201 H -CH = CH- -C (= O)-1,4-Pip--COOH
9-202 H -CH = CH- -C (= O)-1,4-Pip--SO_ThreeH
9-203 H -CH = CH- -C (= O)-1,4-Pip--OSO_ThreeH
9-204 H -CH = CH- -C (= O)-1,4-Pip--OPO_ThreeH₂
9-205 H -CH = CH- -C (= O)-1,4-Pip-1-Pyrd
9-206 H -CH = CH- -C (= O)-1,4-Pip-1-Pip
9-207 H -CH = CH- -C (= O)-1,4-Pip-4-Me-1-Piz
9-208 H -CH = CH- -C (= O)-1,4-Pip-4- (CH₂CH₂OH) -1-Piz
9-209 H -CH = CH- -C (= O)-1,4-Pip-4- (CH₂CH₂NHAc) -1-Piz
9-210 H -CH = CH- -C (= O)-1,4-Pip-4-Mor
9-211 H -CH = CH- -C (= O)-1,4-Pip--NHMe
9-212 H -CH = CH- -C (= O)-1,4-Pip--NMe₂
9-213 H -CH = CH- -C (= O)-1,4-Pip--NMeCH₂CH₂OH
9-214 H -CH = CH- -C (= O)-1,4-Pip--N (CH₂CH₂OH)₂
9-215 H -CH = CH- -C (= O)-1,4-Pip -CH₂--COOH
9-216 H -CH = CH- -C (= O)-1,4-Pip -CH₂--OSO_ThreeH
9-217 H -CH = CH- -C (= O)-1,4-Pip -CH₂--OPO_ThreeH₂
9-218 H -CH = CH- -C (= O)-1,4-Pip -CH₂-4-Mor
9-219 H -CH = CH- -C (= O)-1,4-Pip -CH₂--NH₂
9-220 H -CH = CH- -C (= O)-1,4-Pip -CH₂--NHMe
9-221 H -CH = CH- -C (= O)-1,4-Pip -CH₂--NMe₂
9-222 H -CH = CH- -C (= O)-1,4-Pip -CH₂--NMeCH₂CH₂OH
9-223 H -CH = CH- -C (= O)-1,4-Pip -CH₂--N (CH₂CH₂OH)₂
9-224 H -CH₂CH₂--C (= O)-1,4-Piz--SO₂NH₂
9-225 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂-4-Mor
9-226 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--NHMe
9-227 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--NMe₂
9-228 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--NMeCH₂CH₂OH
9-229 H -CH = CH- -C (= O)-1,4-Piz -CH₂CH₂--N (CH₂CH₂OH)₂
9-230 H -CH₂--NHC (= O)---CH₂-4-Me-1-Piz
9-231 H -CH₂--NHC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
9-232 H -CH₂--NHC (= O)---CH₂--NMe₂
9-233 H -CH₂--NMeC (= O)---CH₂-4-Me-1-Piz
9-234 H -CH₂--NMeC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
9-235 H -CH₂--NMeC (= O)---CH₂--NMe₂
9-236 H -CH₂CH₂--C (= O) NMe---CH₂CH₂--COOH
9-237 H -CH₂CH₂--C (= O) NMe---CH₂CH₂--SO_ThreeH
9-238 H -CH₂CH₂--C (= O) NMe---CH₂CH₂--NMe₂
9-239 Me 1,4-cHx----COOH
9-240 Me 1,4-cHx----OPO_ThreeH₂
9-241 Me 1,4-cHx---1-Pyrd
9-242 Me 1,4-cHx---1-Pip
9-243 Me 1,4-cHx---1-Me-4-Pip
9-244 Me 1,4-cHx---1- (CH₂CH₂OH) -4-Pip
9-245 Me 1,4-cHx---4-Me-1-Piz
9-246 Me 1,4-cHx---4- (CH₂CH₂OH) -1-Piz
9-247 Me 1,4-cHx---4-Mor
9-248 Me 1,4-cHx----NH₂
9-249 Me 1,4-cHx----NHMe
9-250 Me 1,4-cHx----NMe₂
9-251 H 1,4-cHx----COOH
9-252 H 1,4-cHx----OPO_ThreeH₂
9-253 H 1,4-cHx---1-Pyrd
9-254 H 1,4-cHx---1-Pip
9-255 H 1,4-cHx---1-Me-4-Pip
9-256 H 1,4-cHx---1- (CH₂CH₂OH) -4-Pip
9-257 H 1,4-cHx---4-Me-1-Piz
9-258 H 1,4-cHx---4- (CH₂CH₂OH) -1-Piz
9-259 H 1,4-cHx---4-Mor
9-260 H 1,4-cHx----NH₂
9-261 H 1,4-cHx----NHMe
9-262 H 1,4-cHx----NMe₂
9-263 Me-(CH₂)_Four-----COOH
9-264 Me-(CH₂)_Four-----SO_ThreeH
9-265 Me-(CH₂)_Four-----OSO_ThreeH
9-266 Me-(CH₂)_Four-----OPO_ThreeH₂
9-267 Me-(CH₂)_Five-----COOH
9-268 Me-(CH₂)_Five-----SO_ThreeH
9-269 Me-(CH₂)_Five-----OSO_ThreeH
9-270 Me-(CH₂)_Five-----OPO_ThreeH₂
9-271 Me-(CH₂)_Three--C (= O) NMe---CH₂CH₂--SO_ThreeH
9-272 Me-(CH₂)_Four--C (= O) NMe---CH₂CH₂--SO_ThreeH
9-273 Me-(CH₂)_Five--C (= O) NMe---CH₂CH₂--SO_ThreeH
9-274 Me-(CH₂)₆--C (= O) NMe---CH₂CH₂--SO_ThreeH
9-275 H-(CH₂)_Four-----COOH
9-276 H-(CH₂)_Four-----SO_ThreeH
9-277 H-(CH₂)_Four-----OSO_ThreeH
9-278 H-(CH₂)_Four-----OPO_ThreeH₂
9-279 H-(CH₂)_Five-----COOH
9-280 H-(CH₂)_Five-----SO_ThreeH
9-281 H-(CH₂)_Five-----OSO_ThreeH
9-282 H-(CH₂)_Five-----OPO_ThreeH₂
9-283 H-(CH₂)_Three--C (= O) NMe---CH₂CH₂--SO_ThreeH
9-284 H-(CH₂)_Four--C (= O) NMe---CH₂CH₂--SO_ThreeH
9-285 H-(CH₂)_Five--C (= O) NMe---CH₂CH₂--SO_ThreeH
9-286 H-(CH₂)₆--C (= O) NMe---CH₂CH₂--SO_ThreeH
9-287 Me -CH₂CH₂--OC (= O)---1-Me-4-Pip
9-288 Me -CH₂CH₂--OC (= O)---CH₂--COOH
9-289 Me -CH₂CH₂--OC (= O)---CH₂--SO_ThreeH
9-290 Me -CH₂CH₂--OC (= O)---CH₂--OPO_ThreeH₂
9-291 Me -CH₂CH₂--OC (= O)---CH₂-1-Azt
9-292 Me -CH₂CH₂--OC (= O)---CH₂-1-Pyrd
9-293 Me -CH₂CH₂--OC (= O)---CH₂-1-Pip
9-294 Me -CH₂CH₂--OC (= O)---CH₂-1-Me-4-Pip
9-295 Me -CH₂CH₂--OC (= O)---CH₂-4-Me-1-Piz
9-296 Me -CH₂CH₂--OC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
9-297 Me -CH₂CH₂--OC (= O)---CH₂-4-Mor
9-298 Me -CH₂CH₂--OC (= O)---CH₂--NMe₂
9-299 Me -CH₂CH₂--OC (= O)---CH₂--NMeCH₂CH₂OH
9-300 Me -CH₂CH₂--OC (= O)---CH₂--N (CH₂CH₂OH)₂
9-301 Me -CH₂CH₂--OC (= O)---CH₂CH₂--COOH
9-302 Me -CH₂CH₂--OC (= O)---CH₂CH₂--SO_ThreeH
9-303 Me -CH₂CH₂--OC (= O)---CH₂CH₂--OPO_ThreeH₂
9-304 Me -CH₂CH₂--OC (= O)---CH₂CH₂-1-Azt
9-305 Me -CH₂CH₂--OC (= O)---CH₂CH₂-1-Pyrd
9-306 Me -CH₂CH₂--OC (= O)---CH₂CH₂-1-Pip
9-307 Me -CH₂CH₂--OC (= O)---CH₂CH₂-1-Me-4-Pip
9-308 Me -CH₂CH₂--OC (= O)---CH₂CH₂-4-Me-1-Piz
9-309 Me -CH₂CH₂--OC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
9-310 Me -CH₂CH₂--OC (= O)---CH₂CH₂-4-Mor
9-311 Me -CH₂CH₂--OC (= O)---CH₂CH₂--NMe₂
9-312 Me -CH₂CH₂--OC (= O)---CH₂CH₂--NMeCH₂CH₂OH
9-313 Me -CH₂CH₂--OC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
9-314 Me-(CH₂)_Three--OC (= O)---1-Me-4-Pip
9-315 Me-(CH₂)_Three--OC (= O)---CH₂--COOH
9-316 Me-(CH₂)_Three--OC (= O)---CH₂--SO_ThreeH
9-317 Me-(CH₂)_Three--OC (= O)---CH₂--OPO_ThreeH₂
9-318 Me-(CH₂)_Three--OC (= O)---CH₂-1-Azt
9-319 Me-(CH₂)_Three--OC (= O)---CH₂-1-Pyrd
9-320 Me-(CH₂)_Three--OC (= O)---CH₂-1-Pip
9-321 Me-(CH₂)_Three--OC (= O)---CH₂-1-Me-4-Pip
9-322 Me-(CH₂)_Three--OC (= O)---CH₂-4-Me-1-Piz
9-323 Me-(CH₂)_Three--OC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
9-324 Me-(CH₂)_Three--OC (= O)---CH₂-4-Mor
9-325 Me-(CH₂)_Three--OC (= O)---CH₂--NMe₂
9-326 Me-(CH₂)_Three--OC (= O)---CH₂--NMeCH₂CH₂OH
9-327 Me-(CH₂)_Three--OC (= O)---CH₂--N (CH₂CH₂OH)₂
9-328 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--COOH
9-329 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--SO_ThreeH
9-330 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--OPO_ThreeH₂
9-331 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Azt
9-332 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Pyrd
9-333 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Pip
9-334 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Me-4-Pip
9-335 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-4-Me-1-Piz
9-336 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
9-337 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-4-Mor
9-338 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--NMe₂
9-339 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--NMeCH₂CH₂OH
9-340 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
9-341 Me -CH₂CH₂--C (= O) O---1-Me-4-Pip
9-342 Me -CH₂CH₂--C (= O) O---CH₂--COOH
9-343 Me -CH₂CH₂--C (= O) O---CH₂-1-Me-4-Pip
9-344 Me -CH₂CH₂--C (= O) O---CH₂CH₂--COOH
9-345 Me -CH₂CH₂--C (= O) O---CH₂CH₂--SO_ThreeH
9-346 Me -CH₂CH₂--C (= O) O---CH₂CH₂--OPO_ThreeH₂
9-347 Me -CH₂CH₂--C (= O) O---CH₂CH₂-1-Azt
9-348 Me -CH₂CH₂--C (= O) O---CH₂CH₂-1-Pyrd
9-349 Me -CH₂CH₂--C (= O) O---CH₂CH₂-1-Pip
9-350 Me -CH₂CH₂--C (= O) O---CH₂CH₂-1-Me-4-Pip
9-351 Me -CH₂CH₂--C (= O) O---CH₂CH₂-4-Me-1-Piz
9-352 Me -CH₂CH₂--C (= O) O---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
9-353 Me -CH₂CH₂--C (= O) O---CH₂CH₂-4-Mor
9-354 Me -CH₂CH₂--C (= O) O---CH₂CH₂--NMe₂
9-355 Me -CH₂CH₂--C (= O) O---CH₂CH₂--NMeCH₂CH₂OH
9-356 Me -CH₂CH₂--C (= O) O---CH₂CH₂--N (CH₂CH₂OH)₂
9-357 Me -CH = CH- -C (= O) O---1-Me-4-Pip
9-358 Me -CH = CH- -C (= O) O---CH₂--COOH
9-358 Me -CH = CH- -C (= O) O---CH₂-1-Me-4-Pip
9-359 Me -CH = CH- -C (= O) O---CH₂CH₂--COOH
9-360 Me -CH = CH- -C (= O) O---CH₂CH₂--SO_ThreeH
9-361 Me -CH = CH- -C (= O) O---CH₂CH₂--OPO_ThreeH₂
9-362 Me -CH = CH- -C (= O) O---CH₂CH₂-1-Azt
9-363 Me -CH = CH- -C (= O) O---CH₂CH₂-1-Pyrd
9-364 Me -CH = CH- -C (= O) O---CH₂CH₂-1-Pip
9-365 Me -CH = CH- -C (= O) O---CH₂CH₂-1-Me-4-Pip
9-366 Me -CH = CH- -C (= O) O---CH₂CH₂-4-Me-1-Piz
9-367 Me -CH = CH- -C (= O) O---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
9-368 Me -CH = CH- -C (= O) O---CH₂CH₂-4-Mor
9-369 Me -CH = CH- -C (= O) O---CH₂CH₂--NMe₂
9-370 Me -CH = CH- -C (= O) O---CH₂CH₂--NMeCH₂CH₂OH
9-371 Me -CH = CH- -C (= O) O---CH₂CH₂--N (CH₂CH₂OH)₂
9-372 H -CH₂CH₂--OC (= O)---1-Me-4-Pip
9-373 H -CH₂CH₂--OC (= O)---CH₂--COOH
9-374 H -CH₂CH₂--OC (= O)---CH₂--SO_ThreeH
9-375 H -CH₂CH₂--OC (= O)---CH₂--OPO_ThreeH₂
9-376 H -CH₂CH₂--OC (= O)---CH₂-1-Azt
9-377 H -CH₂CH₂--OC (= O)---CH₂-1-Pyrd
9-378 H -CH₂CH₂--OC (= O)---CH₂-1-Pip
9-379 H -CH₂CH₂--OC (= O)---CH₂-1-Me-4-Pip
9-380 H -CH₂CH₂--OC (= O)---CH₂-4-Me-1-Piz
9-381 H -CH₂CH₂--OC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
9-382 H -CH₂CH₂--OC (= O)---CH₂-4-Mor
9-383 H -CH₂CH₂--OC (= O)---CH₂--NMe₂
9-384 H -CH₂CH₂--OC (= O)---CH₂--NMeCH₂CH₂OH
9-385 H -CH₂CH₂--OC (= O)---CH₂--N (CH₂CH₂OH)₂
9-386 H -CH₂CH₂--OC (= O)---CH₂CH₂--COOH
9-387 H -CH₂CH₂--OC (= O)---CH₂CH₂--SO_ThreeH
9-388 H -CH₂CH₂--OC (= O)---CH₂CH₂--OPO_ThreeH₂
9-389 H -CH₂CH₂--OC (= O)---CH₂CH₂-1-Azt
9-390 H -CH₂CH₂--OC (= O)---CH₂CH₂-1-Pyrd
9-391 H -CH₂CH₂--OC (= O)---CH₂CH₂-1-Pip
9-392 H -CH₂CH₂--OC (= O)---CH₂CH₂-1-Me-4-Pip
9-393 H -CH₂CH₂--OC (= O)---CH₂CH₂-4-Me-1-Piz
9-394 H -CH₂CH₂--OC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
9-395 H -CH₂CH₂--OC (= O)---CH₂CH₂-4-Mor
9-306 H -CH₂CH₂--OC (= O)---CH₂CH₂--NMe₂
9-397 H -CH₂CH₂--OC (= O)---CH₂CH₂--NMeCH₂CH₂OH
9-398 H -CH₂CH₂--OC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
9-399 Me-(CH₂)_Three--OC (= O)---1-Me-4-Pip
9-400 Me-(CH₂)_Three--OC (= O)---CH₂--COOH
9-401 Me-(CH₂)_Three--OC (= O)---CH₂--SO_ThreeH
9-402 Me-(CH₂)_Three--OC (= O)---CH₂--OPO_ThreeH₂
9-403 Me-(CH₂)_Three--OC (= O)---CH₂-1-Azt
9-404 Me-(CH₂)_Three--OC (= O)---CH₂-1-Pyrd
9-405 Me-(CH₂)_Three--OC (= O)---CH₂-1-Pip
9-406 Me-(CH₂)_Three--OC (= O)---CH₂-1-Me-4-Pip
9-407 Me-(CH₂)_Three--OC (= O)---CH₂-4-Me-1-Piz
9-408 Me-(CH₂)_Three--OC (= O)---CH₂-4- (CH₂CH₂OH) -1-Piz
9-409 Me-(CH₂)_Three--OC (= O)---CH₂-4-Mor
9-410 Me-(CH₂)_Three--OC (= O)---CH₂--NMe₂
9-411 Me-(CH₂)_Three--OC (= O)---CH₂--NMeCH₂CH₂OH
9-412 Me-(CH₂)_Three--OC (= O)---CH₂--N (CH₂CH₂OH)₂
9-413 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--COOH
9-414 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--SO_ThreeH
9-415 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--OPO_ThreeH₂
9-416 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Azt
9-417 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Pyrd
9-418 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Pip
9-419 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-1-Me-4-Pip
9-420 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-4-Me-1-Piz
9-421 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
9-422 Me-(CH₂)_Three--OC (= O)---CH₂CH₂-4-Mor
9-423 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--NMe₂
9-424 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--NMeCH₂CH₂OH
9-425 Me-(CH₂)_Three--OC (= O)---CH₂CH₂--N (CH₂CH₂OH)₂
9-426 H -CH₂CH₂--C (= O) O---1-Me-4-Pip
9-427 H -CH₂CH₂--C (= O) O---CH₂--COOH
9-428 H -CH₂CH₂--C (= O) O---CH₂-1-Me-4-Pip
9-429 H -CH₂CH₂--C (= O) O---CH₂CH₂--COOH
9-430 H -CH₂CH₂--C (= O) O---CH₂CH₂--SO_ThreeH
9-431 H -CH₂CH₂--C (= O) O---CH₂CH₂--OPO_ThreeH₂
9-432 H -CH₂CH₂--C (= O) O---CH₂CH₂-1-Azt
9-433 H -CH₂CH₂--C (= O) O---CH₂CH₂-1-Pyrd
9-434 H -CH₂CH₂--C (= O) O---CH₂CH₂-1-Pip
9-435 H -CH₂CH₂--C (= O) O---CH₂CH₂-1-Me-4-Pip
9-436 H -CH₂CH₂--C (= O) O---CH₂CH₂-4-Me-1-Piz
9-437 H -CH₂CH₂--C (= O) O---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
9-438 H -CH₂CH₂--C (= O) O---CH₂CH₂-4-Mor
9-439 H -CH₂CH₂--C (= O) O---CH₂CH₂--NMe₂
9-440 H -CH₂CH₂--C (= O) O---CH₂CH₂--NMeCH₂CH₂OH
9-441 H -CH₂CH₂--C (= O) 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--COOH
9-444 H -CH = CH- -C (= O) O---CH₂-1-Me-4-Pip
9-445 H -CH = CH- -C (= O) O---CH₂CH₂--COOH
9-446 H -CH = CH- -C (= O) O---CH₂CH₂--SO_ThreeH
9-447 H -CH = CH- -C (= O) O---CH₂CH₂--OPO_ThreeH₂
9-448 H -CH = CH- -C (= O) O---CH₂CH₂-1-Azt
9-449 H -CH = CH- -C (= O) O---CH₂CH₂-1-Pyrd
9-450 H -CH = CH- -C (= O) O---CH₂CH₂-1-Pip
9-451 H -CH = CH- -C (= O) O---CH₂CH₂-1-Me-4-Pip
9-452 H -CH = CH- -C (= O) O---CH₂CH₂-4-Me-1-Piz
9-453 H -CH = CH- -C (= O) O---CH₂CH₂-4- (CH₂CH₂OH) -1-Piz
9-454 H -CH = CH- -C (= O) O---CH₂CH₂-4-Mor
9-455 H -CH = CH- -C (= O) O---CH₂CH₂--NMe₂
9-456 H -CH = CH- -C (= O) O---CH₂CH₂--NMeCH₂CH₂OH
9-457 H -CH = CH- -C (= O) O---CH₂CH₂--N (CH₂CH₂OH)₂
-------------------------------------------------- -----------------
  Among the above exemplified compounds, preferred compounds are compound numbers 1-9, 1-20, 1-21, 1-24, 1-32, 1-33, 1-39, 1-47, 1-59, 1 -62, 1-63, 1-64, 1-67, 1-65, 1-70, 1-71, 1-72, 1-73, 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, 1-97, 1-99, 1-106, 1 -107, 1-108, 1-109, 1-110, 1-111, 1-112, 1-114, 1-115, 1-116, 1-117, 1-118, 1-125, 1-126 , 1-127, 1-128, 1-129, 1-130, 1-131, 1-132, 1-133, 1-134, 1-135, 1-136, 1-137, 1-138, 1 -139, 1-140, 1-142, 1-143, 1-144, 1-145, 1-146, 1-147, 1-150, 1-156, 1-159, 1-164, 1-165 1-166, 1-168, 1-169, 1-170, 1-171, 1-173, 1-174, 1-175, 1-177, 1-184, 1-185, 1-187, 1 -188, 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, 1-220, 1-222, 1-223, 1-224, 1-227, 1-237, 1 -238,1-292,1-293,1-295,1-302,1-305,1-321,1-328,1-334,1-348,1-349,1-350 , 1-351, 1-352, 1-353, 1-354, 1-355, 1-356, 1-357, 1-358, 1-359, 1-360, 1-361, 1-362, 1 -363, 1-364, 1-365, 1-366, 1-367, 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, 1-426, 1-438, 1-441, 1-442, 1-443, 1 -444, 1-446, 1-449, 1-450, 1-451, 1-452, 1-453, 1-459, 1-461, 1-462, 1-465, 1-467, 1-468 , 1-469, 1-470, 1-471, 1-473, 1-474, 1-475, 1-476, 1-478, 1-485, 1-486, 1-487, 1-488, 1 -489, 1-490, 1-491, 1-493, 1-494, 1-495, 1-496, 1-497, 1-504, 1-505, 1-506, 1-507, 1-508 , 1-509, 1-510, 1-511, 1-512, 1-513, 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, 1-535, 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, 1-571, 1-572, 1-573, 1 -575, 1-582, 1-583, 1-584, 1-585, 1-586, 1-587, 1-588, 1-589, 1-590, 1-593, 1-597, 1-598 , 1-599, 1-601, 1-602, 1-603, 1-606, 1-616, 1-617, 1-671, 1-672, 1-674, 1-681, 1-684, 1 -700, 1-707, 1-713, 1-727, 1-728, 1-729, 1-730, 1-731, 1-732, 1-733, 1-734, 1-735, 1-736 , 1-737, 1-738, 1-739, 1-740, 1-741, 1-742, 1-743, 1-744, 1-745, 1-746, 1-747, 1-748, 1 -749, 1-750, 1-751, 1-752, 1-754, 1-757, 1-759, 1-777, 1-795, 1-796, 1-797, 1-799, 1-800 , 1-806, 1-807, 1-808, 1-811, 1-812, 1-818, 1-821, 1-855, 1-856, 1-857, 1-859, 1-860, 1 -861, 1-865, 1-866, 1-867, 1-868, 1-871, 1-872, 1-881, 1-882, 1-889, 1-890, 1-892, 1-905 , 1-923, 1-924, 1-926, 1-939, 1-957, 1-990, 1-991, 1-992, 1-993, 1-994, 1-995, 1-996, 1 -997, 1-998, 1-999, 1-1000, 1-1001, 1-1002, 1-1003, 1-1004, 1-1005, 1-1006, 1-1007, 1-1012, 1-1014 , 1-1015, 1-1016, 1-1018, 1-1025, 1-1026, 1-1033, 1-1034, 1-1035, 1-1036, 1-1037, 1-1038, 1-1039, 1 -1040, 1-1041, 1-1042, 1-1046, 1-1047, 1-1048, 1-1049, 1-1054, 1-1088 1-1089, 1-1090, 1-1092, 1-1093, 1-1094, 1-1098, 1-1099, 1-1100, 1-1101, 1-1104, 1-1105, 1-1114, 1- 1115, 1-1122, 1-1123, 1-1125, 1-1138, 1-1156, 1-1157, 1-1159, 1-1172, 1-1190, 1-1223, 1-1224, 1-1225, 1-1226, 1-1227, 1-1228, 1-1229, 1-1230, 1-1231, 1-1232, 1-1233, 1-1234, 1-1235, 1-1236, 1-1237, 1- 1238, 1-1239, 1-1240, 1-1245, 1-1247, 1-1248, 1-1249, 1-1251, 1-1258, 1-1259, 1-1266, 1-1267, 1-1268, 1-1269, 1-1270, 1-1271, 1-1272, 1-1273, 1-1274, 1-1275, 1-1279, 1-1280, 1-1281, 1-1282, 1-1285 or 1- 1286 compounds,
  More preferably, compound numbers 1-9, 1-20, 1-21, 1-24, 1-39, 1-47, 1-59, 1-62, 1-63, 1-70, 1-73 , 1-74, 1-82, 1-83, 1-86, 1-88, 1-91, 1-92, 1-94, 1-95, 1-96, 1-97, 1-99, 1 -106, 1-107, 1-109, 1-110, 1-111, 1-112, 1-114, 1-115, 1-116, 1-118, 1-125, 1-126, 1-127 , 1-128, 1-129, 1-130, 1-131, 1-132, 1-133, 1-134, 1-135, 1-138, 1-142, 1-143, 1-144, 1 -145, 1-146, 1-147, 1-150, 1-156, 1-159, 1-165, 1-166, 1-168, 1-169, 1-170, 1-171, 1-175 1-177, 1-184, 1-185, 1-187, 1-188, 1-189, 1-190, 1-194, 1-196, 1-203, 1-204, 1-205, 1 -206, 1-207, 1-208, 1-209, 1-210, 1-211, 1-214, 1-222, 1-223, 1-237, 1-292, 1-302, 1-328 , 1-334, 1-348, 1-349, 1-350, 1-351, 1-352, 1-353, 1-354, 1-355, 1-356, 1-357, 1-358, 1 -359,1-360,1-361,1-362,1-363,1-364,1-365,1-366,1-367,1-368,1-369,1-371,1-372 , 1-373, 1-375, 1-378, 1-388, 1-399, 1-400, 1-403, 1-418, 1-426, 1-438, 1-441, 1-442, 1 -44 9, 1-452, 1-453, 1-461, 1-462, 1-465, 1-467, 1-470, 1-471, 1-473, 1-474, 1-475, 1-476, 1-478, 1-485, 1-486, 1-488, 1-489, 1-490, 1-491, 1-493, 1-494, 1-495, 1-497, 1-504, 1- 505, 1-506, 1-507, 1-508, 1-509, 1-510, 1-511, 1-512, 1-513, 1-514, 1-517, 1-521, 1-522, 1-523, 1-524, 1-525, 1-526, 1-529, 1-535, 1-538, 1-544, 1-545, 1-547, 1-554, 1-556, 1- 563, 1-564, 1-566, 1-573, 1-575, 1-582, 1-583, 1-584, 1-585, 1-585, 1-586, 1-587, 1-588, 1-589, 1-590, 1-593, 1-601, 1-602, 1-616, 1-671, 1-681, 1-707, 1-713, 1-727, 1-728, 1-729, 1- 730, 1-731, 1-732, 1-733, 1-734, 1-735, 1-736, 1-737, 1-738, 1-739, 1-740, 1-741, 1-742, 1-743, 1-744, 1-745, 1-746, 1-747, 1-748, 1-750, 1-751, 1-752, 1-754, 1-757, 1-759, 1- 777, 1-795, 1-796, 1-800, 1-806, 1-807, 1-808, 1-812, 1-818, 1-855, 1-856, 1-858, 1-865, 1-866, 1-871, 1-872, 1-889, 1-923, 1-991, 1-992, 1-993, 1-994, 1-995, 1-996, 1-997, 1- 99 8, 1-999, 1-1000, 1-1004, 1-1005, 1-1006, 1-1007, 1-1012, 1-1015, 1-1016, 1-1018, 1-1033, 1-1035, 1-1036, 1-1037, 1-1039, 1-1046, 1-1047, 1-1088, 1-1089, 1-1091, 1-1098, 1-1099, 1-1104, 1-1105, 1- 1122, 1-1156, 1-1224, 1-1225, 1-1226, 1-1227, 1-1228, 1-1229, 1-1230, 1-1231, 1-1232, 1-1233, 1-1237, 1-1238, 1-1239, 1-1240, 1-1245, 1-1248, 1-1249, 1-1251, 1-1266, 1-1268, 1-1269, 1-1270, 1-1272, 1- 1279 or 1-1280 compound,
  Even more preferably,
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 = (1-methyl-4-piperidyl) acetate (Exemplary Compound No. 1-9) ,
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 = hydrogen = succinate (Exemplified Compound No. 1-20),
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 = hydrogen = glutarate (Exemplary Compound No. 1-39),
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 = 4- (4-methyl-1-piperazinyl) -4-oxobutyrate ( Exemplified Compound No. 1-70),
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 = 4- [4- (2-hydroxyethyl) -1-piperazinyl] -4 -Oxobutyrate (Exemplified Compound No. 1-73),
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] -3-azetidinecarboxylic acid (Exemplary compound number 1-88),
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 = 4- [3- (1-azetidinyl) -1-azetidinyl] -4- Oxobutyrate (Exemplified Compound No. 1-91),
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 = 4-oxo-4- [3- (1-pyrrolidinyl) -1-azetidinyl ] Butyrate (Exemplified Compound No. 1-92),
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 = 4-oxo-4- (3-piperidino-1-azetidinyl) butyrate (exemplified) Compound No. 1-94),
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 = 4- (3-morpholino-1-azetidinyl) -4-oxobutyrate ( Exemplified Compound No. 1-97),
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 = 4- [3- (dimethylamino) -1-azetidinyl] -4-oxo Butyrate (Exemplified Compound No. 1-99),
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-piperidinecarboxylic acid ( Exemplified Compound No. 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 No. 1-107),
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-piperidyl = dihydrogen = Phosphate (Exemplified Compound No. 1-109),
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 = 4- [4- (1-azetidinyl) piperidino] -4-oxobutyrate (Exemplary compound number 1-110),
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 = 4-oxo-4- [4- (1-pyrrolidinyl) piperidino] butyrate ( Exemplified compound number 1-111),
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 = 4-oxo-4- (4-piperidinopiperidino) butyrate ( Exemplified Compound No. 1-112),
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 = 4- (4-morpholinopiperidino) -4-oxobutyrate (exemplified) Compound No. 1-116),
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 = 4- [4- (dimethylamino) piperidino] -4-oxobutyrate ( Exemplified Compound No. 1-118),
[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-piperidyl] acetic acid (Exemplary compound number 1-125),
[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-piperidyl] methane Sulfonic acid (Exemplary Compound No. 1-126),
[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-piperidyl] methyl = Hydrogen = sulfate (Exemplified Compound No. 1-127),
[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-piperidyl] methyl = Dihydrogen = phosphate (Exemplified Compound No. 1-128),
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-oxo-2-butenoyl] -3- Azetidinecarboxylic acid (Exemplified Compound No. 1-165),
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 = 4- [3- (1-azetidinyl) -1-azetidinyl] -4- Oxo-2-butenoate (Exemplary Compound 1-169),
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 = 4-oxo-4- [3- (1-pyrrolidinyl) -1-azetidinyl ] -2-butenoate (Exemplary Compound 1-170),
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 = 4-oxo-4- (3-piperidino-1-azetidinyl) -2- Butenoate (Exemplary Compound 1-171),
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 = 4- (3-morpholino-1-azetidinyl) -4-oxo-2- Butenoate (Exemplary Compound 1-175),
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 = 4- [3- (dimethylamino) -1-azetidinyl] -4-oxo -2-butenoate (Exemplary Compound 1-177),
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-oxo-2-butenoyl] -4- Piperidinecarboxylic acid (Exemplified Compound No. 1-184),
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 = 4- [4- (1-azetidinyl) piperidino] -4-oxo-2 -Butenoate (Exemplary Compound 1-188),
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 = 4-oxo-4- [4- (1-pyrrolidinyl) piperidino] -2 -Butenoate (Exemplary Compound 1-189),
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 = 4-oxo-4- (4-piperidinopiperidino) -2 -Butenoate (Exemplary Compound 1-190),
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 = 4- (4-morpholinopiperidino) -4-oxo-2-butenoate (Exemplary compound 1-194),
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 = 4- [4- (dimethylamino) piperidino] -4-oxo-2- Butenoate (Exemplary Compound 1-196),
[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-oxo-2-butenoyl] -4 -Piperidyl] acetic acid (Exemplary Compound 1-203),
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-oxo-2-butenoyl] -4- Piperidyl = hydrogen = sulfate (Exemplary Compound 1-204),
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-oxo-2-butenoyl] -4- Piperidyl-dihydrogen-phosphate (Exemplary Compound 1-205),
[N- [2- [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] -2-oxoethyl] -N-methylamino] -4-oxobutyric acid (Exemplified Compound No. 1-334),
[[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] amino] acetic acid (Exemplary Compound 1- 348),
3-[[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] amino] propionic acid (illustrated Compound 1-349),
2-[[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] amino] ethanesulfonic acid ( Exemplified Compound 1-350),
2-[[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] amino] ethyl = hydrogen = Sulfate (Exemplary Compound 1-351),
2-[[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] amino] ethyl = dihydrogen = Phosphate (Exemplary Compound 1-352),
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 = 4-[[2- (1-azetidinyl) ethyl] amino] -4- Oxobutyrate (Exemplary Compound 1-353),
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 = 4-oxo-4-[[2- (1-pyrrolidinyl) ethyl] amino ] Butyrate (Exemplary Compound 1-354),
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 = 4-oxo-4-[(2-piperidinoethyl) amino] butyrate (exemplary compound 1-355),
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 = 4-[[2- (4-methyl-1-piperazinyl) ethyl] amino ] -4-oxobutyrate (Exemplary Compound 1-356),
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 = 4-[[2- [4- (2-hydroxyethyl) -1- Piperazinyl] ethyl] amino] -4-oxobutyrate (Exemplary Compound 1-357),
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 = 4-[(2-morpholinoethyl) amino] -4-oxobutyrate ( Exemplified compounds 1-358),
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 = 4-[[2- (dimethylamino) ethyl] amino] -4-oxo Butyrate (Exemplary Compound 1-359),
[N- [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] -N-methylamino] Acetic acid (Exemplary Compound 1-362),
3- [N- [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] -N-methyl Amino] propionic acid (Exemplary Compound 1-363),
2- [N- [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] -N-methyl Amino] ethanesulfonic acid (Exemplary Compound 1-364),
2- [N- [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] -N-methyl Amino] ethyl dihydrogen = phosphate (Exemplary Compound 1-366),
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 = (1-methyl-4-piperidinylidene) acetate (Exemplary Compound 1-378),
[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 = (1-methyl-4-piperidyl) acetate (Exemplified Compound No. 1-388),
[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 = hydrogen = succinate (Exemplified Compound No. 1-399),
[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 = hydrogen = glutarate (Exemplary Compound No. 1-418),
[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 = 4- (4-methyl-1-piperazinyl) -4-oxobutyrate (Exemplary Compound No. 1) -449),
[[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 = 4- [4- (2-hydroxyethyl) -1-piperazinyl] -4-oxobutyrate (exemplary compound Number 1-452),
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] carbonyloxymethoxy] -4-oxobutyryl] -3-azetidinecarboxylic acid ( Exemplified compound numbers 1-467),
[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 = 4- [3- (1-azetidinyl) -1-azetidinyl] -4-oxobutyrate ( Exemplified compound numbers 1-470),
[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 = 4-oxo-4- [3- (1-pyrrolidinyl) -1-azetidinyl] butyrate (exemplified) Compound No. 1-471),
[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] carbonyloxytyl-4-oxo-4- (3-piperidino-1-azetidinyl) butyrate (Exemplified Compound No. 1- 473),
[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 = 4- (3-morpholino-1-azetidinyl) -4-oxobutyrate (Exemplary Compound No. 1) -476),
[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 = 4- [3- (dimethylamino) -1-azetidinyl] -4-oxobutyrate (exemplified) Compound No. 1-478),
1- [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-oxobutyryl] -4-piperidinecarboxylic acid (Exemplary Compound No. 1) -485),
1- [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-oxobutyryl] -4-piperidinesulfonic acid (Exemplary Compound No. 1 -486),
1- [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-oxobutyryl] -4-piperidyl = dihydrogen = phosphate (exemplary compound Number 1-488),
[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 = 4- [4- (1-azetidinyl) piperidino] -4-oxobutyrate (exemplary compound number) 1-489),
[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 = 4-oxo-4- [4- (1-pyrrolidinyl) piperidino] butyrate (Exemplary Compound No. 1) -490),
[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 = 4-oxo-4- (4-piperidinopiperidino) butyrate (Exemplary Compound No. 1) -491),
[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 = 4- (4-morpholinopiperidino) -4-oxobutyrate (Exemplary Compound No. 1- 495),
[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 = 4- [4- (dimethylamino) piperidino] -4-oxobutyrate (Exemplary Compound No. 1) -497),
[1- [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-oxobutyryl] -4-piperidyl] acetic acid (Exemplary Compound No. 1-504),
[1- [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-oxobutyryl] -4-piperidyl] methanesulfonic acid (illustrated Compound No. 1-505),
[1- [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-oxobutyryl] -4-piperidyl] methyl = hydrogen = sulfate (Exemplary compound number 1-506),
[1- [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-oxobutyryl] -4-piperidyl] methyl = dihydrogen = phosphate (Exemplary compound number 1-507),
1- [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-butenoyl] -3-azetidinecarboxylic acid (Exemplary compound number 1-544),
[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 = 4- [3- (1-azetidinyl) -1-azetidinyl] -4-oxo-2- Butenoate (Exemplary Compound 1-548),
[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 = 4-oxo-4- [3- (1-pyrrolidinyl) -1-azetidinyl] -2- Butenoate (Exemplary Compound 1-549),
[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 = 4-oxo-4- (3-piperidino-1-azetidinyl) -2-butenoate (Exemplary Compound) 1-550),
[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 = 4- (3-morpholino-1-azetidinyl) -4-oxo-2-butenoate (Exemplary Compound) 1-554),
[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 = 4- [3- (dimethylamino) -1-azetidinyl] -4-oxo-2-butenoate (Exemplary Compound 1-556),
1- [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-butenoyl] -4-piperidinecarboxylic acid ( Exemplified compound number 1-563),
[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 = 4- [4- (1-azetidinyl) piperidino] -4-oxo-2-butenoate (exemplified) Compound 1-567),
[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 = oxo-4- [4- (1-pyrrolidinyl) piperidino] -2-butenoate (exemplified) Compound 1-568),
[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 = 4-oxo-4- (4-piperidinopiperidino) -2-butenoate (exemplified) Compound 1-569),
[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 = 4- (4-morpholinopiperidino) -4-oxo-2-butenoate (Exemplary Compound 1) -573),
[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 = 4- [4- (dimethylamino) piperidino] -4-oxo-2-butenoate (Exemplary Compound) 1-575),
[1- [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-butenoyl] -4-piperidyl] acetic acid (Exemplary Compound 1-582),
1- [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-butenoyl] -4-piperidyl = hydrogen = Sulfate (Exemplary Compound 1-583),
1- [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-butenoyl] -4-piperidyl = dihydrogen = Phosphate (Exemplary Compound 1-584),
[N- [2-[[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] -2-oxoethyl] -N-methylamino] -4-oxo Butyric acid (Exemplified Compound No. 1-713),
[[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-oxobutyryl] amino] acetic acid (Exemplary Compound 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] propoxy] carbonyloxymethoxy] -4-oxobutyryl] amino] propionic acid (Exemplary Compound 1-728) ),
2-[[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-oxobutyryl] amino] ethanesulfonic acid (Exemplary Compound 1- 729),
2-[[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-oxobutyryl] amino] ethyl = hydrogen = sulfate (Exemplary Compound 1-730),
2-[[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-oxobutyryl] amino] ethyl = dihydrogen = phosphate (Exemplary Compound 1-731),
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 = 4-[[2- (1-azetidinyl) ethyl] amino] -4- Oxobutyrate (Exemplary Compound 1-732),
[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 = 4-oxo-4-[[2- (1-pyrrolidinyl) ethyl] amino] butyrate (exemplified) Compound 1-733),
[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 = 4-oxo-4-[(2-piperidinoethyl) amino] butyrate (Exemplary Compound 1-734) ,
[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 = 4-[[2- (4-methyl-1-piperazinyl) ethyl] amino] -4- Oxobutyrate (Exemplary Compound 1-735),
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 = 4-[[2- [4- (2-hydroxyethyl) -1- Piperazinyl] ethyl] amino] -4-oxobutyrate (Exemplified Compound 1-736),
[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 = 4-[(2-morpholinoethyl) amino] -4-oxobutyrate (Exemplary Compound 1- 737),
[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 = 4-[[2- (dimethylamino) ethyl] amino] -4-oxobutyrate (exemplified) Compound 1-738),
[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-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutyryl] -N-methylamino] acetic acid (exemplary 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-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutyryl] -N-methylamino] propionic acid (Exemplary Compound 1-742),
2- [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-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutyryl] -N-methylamino] ethanesulfone Acid (Exemplary Compound 1-743),
2- [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-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutyryl] -N-methylamino] ethyl = Dihydrogen phosphate (Exemplified Compound 1-745),
[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 = (1-methyl-4-piperidinylidene) acetate (Exemplary Compound 1-757),
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 = hydrogen = 1,4-dichlorohexanedicarboxylate (Exemplary Compound 1-759) ,
[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 = hydrogen = 1,4-dichlorohexanedicarboxylate (Exemplary Compound 1-777),
5- [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] -5-oxo-1-pentanesulfonic acid (Exemplary Compound 1- 796),
6- [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] -6-oxo-1-hexanesulfonic acid (Exemplary Compound 1- 800),
2- [N- [8- [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] -8-oxooctanoyl] -N -Methylamino] ethanesulfonic acid (Exemplary Compound 1-806),
5-[[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] -5-oxo-1-pentanesulfonic acid (Exemplary Compound 1-808),
6-[[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] -6-oxo-1-hexanesulfonic acid (Exemplary Compound 1-812),
2- [N- [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-oxooctanoyl] -N-methylamino] Ethanesulfonic acid (Exemplary Compound 1-818),
3- [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] -3-oxopropyl = hydrogen = malonate (Exemplary Compound 1-855) ),
2- [3- [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] -3-oxopropoxy] -2-oxoethanesulfone Acid (Exemplary Compound 1-856),
2- [3- [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] -3-oxopropoxy] -2-oxoethyl = dihydrogen = Phosphate (Exemplary Compound 1-858),
3- [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] -3-oxopropyl = hydrogen = succinate (Exemplary Compound 1-871 ),
[[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] oxy] acetic acid (Exemplary Compound 1- 991),
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 = (4-methyl-1-piperazinyl) methyl = succinate (Exemplary Compound 1-993) ),
3-[[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] oxy] propionic acid (exemplified) Compound 1-994),
2-[[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] oxy] ethanesulfonic acid ( Exemplified compounds 1-995),
2-[[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] oxy] ethyl = dihydrogen = Phosphate (Exemplary Compound 1-997),
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-methyl-1-piperazinyl) ethyl succinate (Exemplary Compound 1 -1004),
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-piperazinyl] ethyl = Succinate (Exemplified Compound 1-1005),
[[5- [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] -5-oxopentanoyl] oxy] acetic acid (exemplary compound 1-1012),
3-[[5- [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] -5-oxopentanoyl] oxy] propionic acid (Exemplary Compound 1-1015),
[[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-oxo-2-butenoyl] oxy] acetic acid ( Exemplified Compound 1-1033),
3-[[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-oxo-2-butenoyl] oxy] Propionic acid (Exemplary Compound 1-1036),
2-[[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-oxo-2-butenoyl] oxy] Ethanesulfonic acid (Exemplary Compound 1-1037),
2-[[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-oxo-2-butenoyl] oxy] Ethyl dihydrogen phosphate (Exemplified Compound 1-1039),
3-[[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] -3-oxopropyl = hydrogen = malonate (Exemplary Compound 1-1088),
2- [3-[[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] -3-oxopropoxy] -2-oxoethanesulfonic acid (exemplary compound 1-1089),
2- [3-[[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] -3-oxopropoxy] -2-oxoethyl = dihydrogen = phosphate Compound 1-1091),
3-[[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] -3-oxopropyl = hydrogen = succinate (Exemplary Compound 1-1104),
[[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-oxobutyryl] oxy] acetic acid (Exemplary Compound 1-1224),
[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 = (4-methyl-1-piperazinyl) methyl = succinate (Exemplary Compound 1-1226),
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-oxobutyryl] oxy] propionic acid (Exemplary Compound 1-1227) ),
2-[[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-oxobutyryl] oxy] ethanesulfonic acid (Exemplary Compound 1- 1228),
2-[[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-oxobutyryl] oxy] ethyl = dihydrogen = phosphate (exemplary compound 1-1230),
[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 = 2- (4-methyl-1-piperazinyl) ethyl succinate (Exemplary Compound 1-1237),
[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 = 2- [4- (2-hydroxyethyl) -1-piperazinyl] ethyl succinate (Exemplary Compound) 1-1238),
[[5-[[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] -5-oxopentanoyl] oxy] acetic acid (Exemplary Compound 1-1245) ,
3-[[5-[[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] -5-oxopentanoyl] oxy] propionic acid (Exemplary Compound 1 -1248),
[[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-butenoyl] oxy] acetic acid (Exemplary Compound 1- 1266),
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-butenoyl] oxy] propionic acid (illustrated Compound 1-1269),
2-[[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-butenoyl] oxy] ethanesulfonic acid ( Exemplified Compound 1-1270) or
2-[[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-butenoyl] oxy] ethyl = dihydrogen = Phosphate (Exemplary Compound 1-1272).

Among these, more preferable compounds are compound numbers 1-39, 1-88, 1-106, 1-125, 1-126, 1-128, 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, 1-731, 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, 1-855, 1-991, 1-994, 1-995, 1-997, 1-1012, 1-1033, 1-1036 1-1088, 1-1224, 1-1227, 1-1228, 1-1230, 1-1245, 1-1266 or 1-1269,
More preferably, the compound numbers 1-39, 1-106, 1-125, 1-126, 1-128, 1-203, 1-348, 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, 1-1033, 1-1224 , 1-1227 or 1-1266,
Even more preferably, compound numbers 1-39, 1-106, 1-348, 1-349, 1-350, 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 or 1-1224 compound,
Most preferred is a compound of Compound No. 1-348, 1-349, 1-727 or 1-728.

  The compound of the present invention can be obtained by Method A shown below.

In the above, R ¹ , R ^a , A, Ar, L ^{1 to} L ³ and G are as defined above.
(Method A)
(Process A-1)
This step is a known compound or a compound (IV) which is known or can be easily obtained in the same manner as in the known method after the compound (II) which is easily obtained in the same manner as in the known method is alkoxideated with a base. ) To obtain compound (V).

  Among the compounds shown above, known methods for producing compound (II) and compound (IV) are as follows.

Compounds (II) are known, or it is easily obtained by a known manner similar to compound, as such methods, for example, R ^a is the formula

In the case of the group represented by the method, the method described in JP-A-62-14766, R ^a is

In the case where the group is represented by the method described in JP-A-8-53426 or WO 99/45008, R ^a is

When the group is represented by the method described in Japanese Patent No. 265584, R ^a

A group represented by the method described in JP-A-9-183769, R ^a is represented by the following formula:

A group represented by the method described in JP-A-11-240871, R ^a is represented by the following formula

In the case where it is a group represented by the method described in WO98 / 31675, ^Ra is represented by the following formula:

In the case where R ^a is a group represented by the general formula (III), JP-A-8-333350, 10-279567, JP-A-11-80135, EP1083175A2, or JP-A-2001-342187, particularly R ³ is a C ₁ -C ₄ alkyl group,
R ⁴ is a hydrogen atom or a C ₁ -C ₄ alkyl group,
Ar ² is a phenyl group, a phenyl group substituted by 1 to 5 substituents selected from the same or different substituent selected from substituent group γ, or the same or different 1 to 5 substituents selected from substituent group γ A monocyclic heteroaryl group which may have
E ¹ is a group represented by the formula —S (O) _n1 — (wherein _n1 represents an integer of 0 to 2);
E ³ is the formula (Ga ^A )

(Wherein R ^5A , R ^6A , R ^7A and R ^8A independently represent a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ halogenated alkyl group,
p ^A represents 0 or 1,
q ^A , r ^A and s ^A independently represent an integer of 0 to 2. ), The method described in JP-A-8-333350, R ^a is represented by the following formula:

And the method described in EP1083175A2 publication, E ¹ is a methylene group,
E ²

A group selected from the group consisting of:
E ³ represents the formula (Ga ^B )

(In the formula, q ^B represents an integer of 0 to 3, r ^B and s ^B independently represent an integer of 0 to 2, provided that the sum of q ^B , r ^B and s ^B is 3 or less. In the case of a group represented by the formula (1))),
R ³ is a hydrogen atom,
Ar ² is a naphthyl group, a naphthyl group substituted by 1 to 5 substituents selected from the same or different substituent selected from substituent group γ, a fused bicyclic heteroaryl group, or the same or selected from substituent group γ A fused bicyclic heteroaryl group substituted 1 to 5 with different substituents,
E ¹ is a group represented by the formula —S (O) _n1 — (wherein _n1 represents an integer of 0 to 2);
E ³ represents the formula (Ga ^C )

(Wherein R ^5C , R ^6C , R ^7C and R ^{8C each} independently represent a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ halogenated alkyl group,
p ^C represents 0 or 1,
q ^C , r ^C and s ^C independently represent an integer of 0 to 2. In the case of a group represented by
R ⁴ is a hydrogen atom,
Ar ² is 1 to 5 phenyl groups, naphthyl groups, or the same or different substituents selected from the substituent group γ, substituted with the same or different substituents selected from the phenyl group and the substituent group γ To a 5-substituted naphthyl group,
E ¹ is a methylene group or a sulfur atom,
E ³ is the formula (Gb)

(In the formula, Ar ³ represents a phenylene group, a phenylene group, a naphthylene group, or a (fluorine atom) that is substituted with the same or different substituents selected from the substituent group consisting of (fluorine atom and chlorine atom). And a naphthylene group that is 1 or 2 substituted with the same or different substituents selected from the substituent group consisting of
R ⁹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
T represents a single bond or a C ₁ -C ₈ alkylene group. ), The method described in JP-A-2001-342187, other patents 3050982, WO95 / 25107, WO00 / 27852, WO01 / 66551, Or the method described in WO01 / 79196 gazette can be mentioned.

  Compound (IV) is described in the literature (Tetrahedron Lett., 30, 2033 (1989), Synthesis, 1159 (1990), J. Chem. Phys., 21, 1049 (1953), J. Mol. Struct., 198, 239 ( 1989))) and can be easily obtained.

  Examples of the solvent used include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; diethyl ether, diisopropyl ether, tetrahydrofuran , Dioxane, dimethoxyethane, ethers such as diethylene glycol dimethyl ether; nitriles such as acetonitrile, isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2- Examples include amides such as pyrrolidone and hexamethylphosphorotriamide, preferably ethers or amides, and more preferably dimethoxyethane, tetrahydrofuran or N, N-dimethylformamide.

  Examples of the base used include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium methoxide; butyllithium, Organic metal bases such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide can be exemplified, and alkali metal hydrides are preferable, and sodium hydride or potassium hydride is more preferable. If necessary, ultrasonic irradiation may be performed for the purpose of allowing the alkoxidation to proceed completely after adding a base.

  While the reaction temperature varies depending on the starting compound and the reaction reagent, it is carried out at −50 ° C. to 50 ° C., preferably 0 ° C. to 25 ° C.

  The reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 4 hours, preferably 30 minutes to 1 hour.

  After completion of the reaction, the target compound of this reaction is, for example, a saturated aqueous sodium hydrogen carbonate solution is added, an immiscible organic solvent such as ethyl acetate is added, and the organic layer is washed with water and a saturated aqueous sodium hydrogen carbonate solution. The organic layer containing the compound is separated, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off.

If necessary, the obtained compound can be further purified by conventional methods such as recrystallization, reprecipitation, silica gel column chromatography and the like.
(Process A-2)
In this step, the compound (V) obtained in the step A-1 is subjected to halogen exchange if necessary (A-2a), and then known or in the same manner as in the known method or the method B described later It is a step (A-2b) in which compound (I) is obtained by reacting with compound (VI) easily obtained according to methods D to D.
(A-2a)
Examples of the solvent used include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; ethyl formate, ethyl acetate, propyl acetate, acetic acid Esters such as butyl and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, and cyclohexanone Ketones; Nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotri There may be mentioned amides such as bromide, preferably aromatic hydrocarbons, and amides or nitriles, more preferably toluene, N, N-dimethylformamide or acetonitrile. If necessary, a small amount of crown ether (preferably 18-crown-6) may be added.

  Examples of the reagent used include alkali metal iodides such as sodium iodide, potassium iodide, rubidium iodide, and cesium iodide; and tetraalkylammonium iodides such as tetrabutylammonium iodide. Are alkali metal iodides, more preferably sodium iodide.

  While the reaction temperature varies depending on the raw material compound and the reaction reagent, it is carried out at 50 ° C. to 120 ° C., preferably 80 ° C. to 120 ° C.

  The reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of the solvent used, but is usually 1 hour to 48 hours, preferably 3 hours to 24 hours.

  After completion of the reaction, the target compound of this reaction is, for example, concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, separating the organic layer containing the target compound, anhydrous magnesium sulfate, etc. After drying, the solvent is distilled off.

If necessary, the obtained compound can be further purified by conventional methods such as recrystallization, reprecipitation, silica gel column chromatography and the like.
(A-2b)
Examples of the solvent used include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; ethyl formate, ethyl acetate, propyl acetate, acetic acid Esters such as butyl and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, and cyclohexanone Ketones; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, Kisa can be mentioned amides such as methyl triamide, preferably an ether or an amide, more preferably tetrahydrofuran, N, is N- dimethylformamide or N, N- dimethylacetamide. If necessary, a small amount of crown ethers (preferably 18-crown-6) may be added.

  Examples of the base used include alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate and cesium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; hydrogenation Alkali metal hydrides such as lithium, sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide; alkali such as barium hydroxide An earth metal hydroxide can be mentioned, and a base using cesium is preferable, and cesium carbonate is more preferable.

  In this reaction, compound (VI) is used as a carboxylate using a base, and such a salt can be prepared by a method of preparing in situ before the reaction or a base and compound (VI). Can be mentioned in an alcohol such as water or ethanol, and then the solvent is distilled off. The former is preferred.

  While the reaction temperature varies depending on the raw material compound and the reaction reagent, it is carried out at 25 ° C. to 80 ° C., preferably 25 ° C. to 40 ° C.

  The reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 1 hour to 48 hours, preferably 1 hour to 24 hours.

  After completion of the reaction, the target compound of this reaction is, for example, concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, separating the organic layer containing the target compound, anhydrous magnesium sulfate, etc. After drying, the solvent is distilled off.

  If necessary, the obtained compound can be further purified by conventional methods such as recrystallization, reprecipitation, silica gel column chromatography and the like.

  In addition, after the completion of the above reaction, a deprotection reaction or functional group conversion may be appropriately performed for the purpose of obtaining a desired compound. Theodora W. Greene, Peter GMWuts, 1999, A Wiley-Interscience Publication)). In addition, the conversion of a hydroxyl group into a phosphate ester is performed, for example, using bis (allyloxy) (diisopropylamino) phosphine in the presence of a base such as tetrazole and in an inert solvent such as dichloromethane under ice cooling.

  The compound (VI) used in the above-mentioned method A is known or can be easily obtained according to a known method. For example, it can be obtained according to the following methods B to D.

In the above, A, L ^{1 to} L ³ and G are as defined above, Pg represents a protecting group for a carboxy group, and Lv represents a leaving group.

  The protecting group for the carboxy group in Pg is not particularly limited as long as it can stably protect the carboxy group during the reaction, and specifically, hydrogenolysis, hydrolysis, electrolysis and photolysis. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl Hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2- “Alkyl groups” such as dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl; 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-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, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3- Butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl- 3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3 “Alkenyl groups” such as hexenyl, 4-hexenyl, 5-hexenyl; 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, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1- “Alkynyl groups” such as methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl “Aliphatic acyl”-“lower alkyl” such as acetylmethyl; benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, 6-phenylhexyl, α- A lower alkyl group substituted with 1 to 3 aryl groups such as naphthyldiphenylmethyl, 9-anthrylmethyl, and 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5 -Trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis ( 2-Nitrophenyl) methyl, piperonyl, 4-methoxycarbonyl Lower alkyl groups substituted with 1 to 3 aryl groups in which the aryl ring is substituted with a lower alkyl group such as benzyl, a lower alkoxy group, a nitro group, a halogen atom, a cyano group, or an alkoxycarbonyl group, etc. "Aralkyl group" of: trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyl di-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropyl Mention may be made of “silyl groups” such as silyl.

  The leaving group in Lv is not particularly limited as long as it is a functional group capable of leaving in a condensation reaction. Examples of such a group include a hydroxyl group; the above-mentioned “halogen atom”; methanesulfonyloxy or ethanesulfonyl. A “lower alkylsulfonyloxy group” such as oxy; a “halogen-substituted lower alkylsulfonyloxy group” such as trifluoromethanesulfonyloxy; an arylsulfonyloxy group such as benzenesulfonyloxy; a lower group such as p-toluenesulfonyloxy Examples thereof include “aromatic sulfonyloxy groups” such as alkylated arylsulfonyloxy groups and halogen-substituted arylsulfonyloxy groups such as parachlorobezensulfonyloxy.

(Method B)
In this step, compound (VII) which is publicly known or easily obtained in the same manner as in known methods is condensed with compound (VIII) which is known or easily obtained in the same manner as in known methods (B -1a) and further deprotecting the protecting group of the carboxy group (B-1b) to obtain compound (VI) (G = carbonyl group).
(B-1a)
This step is not particularly limited as long as it is a commonly performed condensation method, but for example, (i) a reaction in the presence of a condensing agent and (ii) a reaction in the absence of a condensing agent.
(i) Reaction in the Presence of Condensing Agent This reaction is carried out by first reacting compound (VIII) with a condensing agent and then adding compound (VII).

  Examples of the solvent used include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as ether and tetrahydrofuran; amides such as dimethylformamide and dimethylacetamide; and nitriles such as acetonitrile. I can give you.

  Examples of the condensing agent used include N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide; and dipyridyl disulfide. The active esterification reaction is suitably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine.

  The reaction temperature is −10 ° C. to 100 ° C. in the reaction with the condensing agent and is around room temperature in the subsequent reaction, and the time required for the reaction is 30 minutes to 80 hours in both reactions.

  After completion of the reaction, the target compound of this reaction is, for example, concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, separating the organic layer containing the target compound, anhydrous magnesium sulfate, etc. After drying, the solvent is distilled off.

If necessary, the obtained compound can be further purified by conventional methods such as recrystallization, reprecipitation, silica gel column chromatography and the like.
(ii) Reaction in the absence of condensing agent Examples of the solvent used include ethers such as ether and tetrahydrofuran; amides such as dimethylformamide and dimethylacetamide; and nitriles such as acetonitrile. it can.

  The reaction is preferably carried out in the presence of an organic amine such as triethylamine or N-methylmorpholine, the reaction temperature is −10 ° C. to 50 ° C., and the time required for the reaction is 30 minutes to 20 hours. .

  After completion of the reaction, the target compound of this reaction is, for example, concentrating the reaction mixture, adding an immiscible organic solvent such as water and ethyl acetate, washing with water, separating the organic layer containing the target compound, anhydrous magnesium sulfate, etc. After drying, the solvent is distilled off.

If necessary, the obtained compound can be further purified by conventional methods such as recrystallization, reprecipitation, silica gel column chromatography and the like.
(B-1b)
When a lower alkyl group or an aryl group is used as a protecting group for a carboxy group, it can be removed by treatment with an acid or a base.

  As the acid, hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid are used, and the base is not particularly limited as long as it does not affect other parts of the compound, but preferably sodium carbonate, potassium carbonate An alkali metal carbonate such as cesium carbonate; an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or a concentrated ammonia-methanol solution is used.

  When a base is used, it may be performed under the same conditions as (A-2b). In this case, the product of this reaction is subjected to the reaction without being purified (A-2b).

  The solvent to be used is not particularly limited as long as it is used for a normal hydrolysis reaction and does not inhibit the reaction, such as water or methanol, ethanol, n-propanol. A mixed solvent of an organic solvent such as alcohols or ethers such as tetrahydrofuran and dioxane and water is preferable.

  The reaction temperature and reaction time vary depending on the starting material, the solvent, the reagent used, and the like, and are not particularly limited, but are usually 0 to 150 ° C. for 1 to 10 hours in order to suppress side reactions.

  When the protecting group of the carboxy group is an alkoxyarylmethyl group such as p-methoxybenzyl group or a di- or triaryl-substituted methyl group such as diphenylmethyl or trityl, it is usually treated with an acid in a solvent. Removed.

  The solvent used is preferably an aromatic hydrocarbon such as anisole, and the acid used is a fluorinated organic acid such as trifluoroacetic acid.

  While the reaction temperature and reaction time vary depending on the starting materials, solvent, acid used and the like, the reaction is usually carried out at room temperature for 30 minutes to 10 hours.

  When the protecting group for the carboxy group is an aralkyl group or a halogeno lower alkyl group, it is usually removed by reduction in a solvent.

  As the reduction method, when the protecting group of the carboxy group is a halogeno lower alkyl group, a method by chemical reduction such as zinc-acetic acid is preferable, and when it is an aralkyl group, palladium carbon, platinum Such a catalyst is used for the catalytic reduction method, or an alkali metal sulfide such as potassium sulfide or sodium sulfide is used for the chemical reduction method.

  The solvent to be used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; Such fatty acids or mixed solvents of these organic solvents and water are preferred.

  While the reaction temperature and reaction time vary depending on the starting materials, solvent, reduction method and the like, the reaction is usually carried out at 0 ° C. to room temperature for 5 minutes to 12 hours.

  When the protecting group for the carboxy group is an alkoxymethyl group, it is usually removed by treatment with an acid in a solvent.

  The acid used is not particularly limited as long as it is usually used as a Bronsted acid, but preferably an inorganic acid such as hydrochloric acid or sulfuric acid; or an organic acid such as acetic acid or paratoluenesulfonic acid. is there.

  The solvent to be used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; or these A mixed solvent of an organic solvent and water is preferable.

  While the reaction temperature and reaction time vary depending on the starting material, solvent and type of acid used, etc., the reaction is usually carried out at 0 ° C. to 50 ° C. for 10 minutes to 18 hours.

  When the protecting group of the carboxy group is an optionally substituted 2-propenyl group such as a 2-propenyl group or 2-butenyl group, it is usually treated with a noble metal complex and a nucleophilic (reducing) agent in a solvent. Is removed.

  The solvent to be used is not particularly limited as long as it does not participate in this reaction, but hydrocarbons such as toluene; ethers such as tetrahydrofuran; halogenated hydrocarbons such as dichloromethane are preferable. .

  Examples of the noble metal complex used include palladium complexes such as tetrakis (triphenylphosphine) palladium and dichlorobis (triphenylphosphine) palladium. The amount of noble metal complex used is usually 0.001 to 0.1 molar equivalents relative to the starting material.

  Examples of the nucleophilic (reducing) agent used include amines such as pyrrolidine; carboxylates such as potassium 2-ethylhexanoate; tin hydrides such as tributyltin hydride; and formic acid or a salt thereof. It is done.

  While the reaction temperature and reaction time vary depending on the starting material, solvent, noble metal complex, type of nucleophilic (reducing) agent and the like, the reaction is usually carried out at 0 to 50 ° C. for 10 minutes to 5 hours.

  In addition, amidation can also be carried out by removing the protecting group of the carboxy group by ammonia treatment according to a conventional method.

  If desired, the carboxylic acid produced above is dissolved in a mixed solvent of water and an organic solvent immiscible with water such as ethyl acetate according to a conventional method, and an alkali metal carbonate such as an aqueous sodium hydrogen carbonate solution or an aqueous potassium carbonate solution is dissolved. An alkyl metal salt can be produced by adding a salt or bicarbonate aqueous solution at 0 ° C. to room temperature, and then catching the deposited precipitate at about pH 7.

(C method)
In this step, compound (IX) which is publicly known or easily obtained in the same manner as in the known method is condensed with compound (VIII) which is known or easily obtained in the same manner as in the known method (C -1a), and further deprotecting the protecting group of the carboxy group (C-1b) to obtain the amide compound (VI) (G = —C (═O) NH—). If an alcohol compound represented by the formula HO-L ² -L ³ -A is used instead of the raw material compound (IX), an ester compound (VI) (G = -C (= O) O-) is obtained. .
(C-1a)
This step is not particularly limited as long as it is a usual condensation method.For example, as in step (B-1a) above, (i) a reaction in the presence of a condensing agent and (ii) a reaction in the absence of a condensing agent. Done.
(C-1b)
This step is not particularly limited as long as it is a commonly performed deprotection method of a carboxy group. For example, this step is performed in the same manner as the above step (B-1b). That is, when a lower alkyl group or an aryl group is used as a protecting group, the protecting group can be removed by treatment with an acid or a base. When an alkoxyarylmethyl group such as p-methoxybenzyl group or a di- or triaryl-substituted methyl group such as diphenylmethyl or trityl is used as a protecting group, the protecting group is usually treated with an acid in a solvent. To be removed. When an aralkyl group or a halogeno lower alkyl group is used as a protecting group, the protecting group is usually removed by reduction in a solvent. When an alkoxymethyl group is used as a protecting group, the protecting group is usually removed by treatment with an acid in a solvent. When a 2-propenyl group which may be substituted, such as a 2-propenyl group or 2-butenyl group, is used as the protective group, the protective group is usually a noble metal complex and a nucleophilic ( It is removed by treatment with a reducing agent.

  In addition, amidation can also be carried out by removing the protecting group of the carboxy group by ammonia treatment according to a conventional method.

  If desired, the carboxylic acid produced above is dissolved in a mixed solvent of water and an organic solvent immiscible with water such as ethyl acetate according to a conventional method, and an alkali metal carbonate such as an aqueous sodium hydrogen carbonate solution or an aqueous potassium carbonate solution is dissolved. An alkyl metal salt can be produced by adding a salt or bicarbonate aqueous solution at 0 ° C. to room temperature, and then catching the deposited precipitate at about pH 7.

(D method)
In this step, compound (X) which is publicly known or easily obtained in the same manner as in the known method is condensed with compound (VIII) which is known or easily obtained in the same manner as in the known method (D -1a), and further deprotecting the protecting group of the carboxy group (D-1b) to obtain the amide compound (VI) (G = —NHC (═O) —). If an alcohol compound represented by the formula PgO-C (= O) -L ¹ -OH is used instead of the raw material compound (X), the ester compound (VI) (G = -OC (= O)-) can get.
(D-1a)
This step is not particularly limited as long as it is a usual condensation method.For example, as in step (B-1a) above, (i) a reaction in the presence of a condensing agent and (ii) a reaction in the absence of a condensing agent. Done.
(D-1b)
This step is not particularly limited as long as it is a commonly performed deprotection method of a carboxy group. For example, this step is performed in the same manner as the above step (B-1b).

  The compound (I) of the present invention or a pharmacologically acceptable salt thereof exhibits antifungal activity in vivo. In addition, the compound (I) of the present invention is excellent in pharmacokinetics such as absorption, distribution in the body and blood half-life, and has low toxicity to organs such as kidney and liver. Therefore, the compound (I) of the present invention is useful, for example, as a medicament, and particularly useful as a medicament for treating or preventing fungal infections.

  When the compound of the present invention is used as a prophylactic or therapeutic agent for the above-mentioned diseases, the compound having the above general formula (I) or a pharmacologically acceptable salt thereof may be used as such or as appropriate pharmacology. Orally mixed with excipients, diluents, etc., orally by tablets, capsules, granules, powders or syrups, or injections, drops, suppositories, patches, or It can be administered parenterally by external preparations and the like. Among these dosage forms, particularly preferred are dosage forms that are solutions such as injections and drops.

  The triazole compound or pharmacologically acceptable salt according to the present invention has high water solubility and is administered as a medicine (especially an injection) and rapidly cleaved in vivo, so that Candida, Aspergillus, Cryptococcus , Mucor, Histoplasma, Blastmyces, Coccidioides, Paracoccidioides, Trichofeton, Epidermofeton, Microsporum, Malassezia, Pseudorescherlia, Sporothrix, Linospodium , Fonsecaea, Wanghiera, Fialophora, Exophia, Cladosporium, Alternaria, Aureobasidium, Caetium, Curbularia, Drexella, Mycocentrospora, Foma, Hendersonula, Scutarius Genus, Corynespora, Leptosferia, Majurella, Neotestusina, Sedospolium, Pyrenocateta, Geotricum, Trichosporon, Chrysosporium, Coprinus, Schizophyllum, Pneumocystis, Conidiobolus, Basidiobolus, Pepsi It has an excellent antifungal activity against fungi such as Penicillium, Acremonium, Fusarium, Skoplaropsis, Saccharomyces, Cephalosporum, Roboa, Rhizopus, Rhizomucor, Absidia and the like.

  The amount used varies depending on the symptoms of patients (warm-blooded animals, particularly humans), age, administration method (intravenous administration, intramuscular injection, subcutaneous injection, etc.), etc., but in the case of intravenous administration, once A lower limit of 0.002 mg / kg body weight (preferably 0.01 mg / kg body weight) and an upper limit of 10 mg / kg body weight (preferably 8 mg / kg body weight) for adults 1 to 6 times per day depending on symptoms Is desirable.

  The compound having the general formula (I) according to the present invention or a pharmacologically acceptable salt thereof has high water solubility, and the ester moiety is rapidly cleaved in vivo to show antifungal activity and is safe. It is useful as a medicine (particularly an antifungal agent) (particularly as an injection).

  Examples, Reference Examples, Test Examples and Formulation Examples are shown below to explain the present invention in more detail, but the scope of the present invention is not limited to these.

Example 1 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 = 4-oxo-4- [4- (1-pyrrolidinyl) piperidino] butyrate (Exemplary Compound 1-111)
(1a) 1-chloroethyl = (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 carbonate potassium hydride (30 % Mineral oil dispersion; 0.50 g, 3.8 mmol) was suspended in tetrahydrofuran (18 mL), and under ice cooling, 4-[(1E, 3E) -4- [trans-5-[[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxane-2- IL] -1,3-Butadieni ] -3-fluorobenzonitrile (European Patent Publication No. EP1083175A2 (published: according to 2001); 1.09 g, 2.0 mmol) was added and stirred for 1 hour at 0 ° C.. At the same temperature, chloroformate (1-chloroethyl) (429 mg, 3.0 mmol) was added to the mixture, and the mixture was further stirred for 10 minutes.

  Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 80: 20-20: 80, V / V, silica gel 10 g) to give the title compound (1.22 g, yield 94). %) As a colorless amorphous solid (diastereomeric ratio = approximately 1: 1).

IR (CHCl ₃ ) ν _max 2233, 1766, 1616, 1505, 1277, 1256, 1140 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.25 (3H × (1/2), d, J = 7 Hz), 1.27 (3H × (1/2), d, J = 7 Hz), 1.86 ( 3H × (1/2), d, J = 6 Hz), 1.87 (3H × (1/2), d, J = 6 Hz), 2.98-3.09 (1H, m), 3.49 (1H × (1 / 2), t, J = 11 Hz), 3.50 (1H × (1/2), t, J = 11 Hz), 3.52 (1H × (1/2), t, J = 11 Hz), 3.53 (1H × (1/2), t, J = 11 Hz), 3.88 (1H × (1/2), q, J = 7 Hz), 3.93 (1H × (1/2), q, J = 7 Hz) , 4.18 (1H, ddd, J = 11, 5, 2 Hz), 4.28 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.30 (1H × (1/2), ddd , J = 11, 5, 2 Hz), 4.98 (1H × (1/2), d, J = 4 Hz), 4.99 (1H × (1/2), d, J = 4 Hz), 5.39 (2H , br s), 5.86 (1H, dd, J = 16, 4 Hz), 6.37 (1H × (1/2), q-like, J = 6 Hz), 6.38 (1H × (1/2), q -like, J = 6 Hz), 6.59 (1H, dd, J = 16, 11 Hz), 6.75 (1H, d, J = 16 Hz), 6.85-6.95 (2H, m), 6.93 (1H, d, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.40 (1H, d, J = 8 Hz), 7.4-7.5 (1H, m), 7.57 (1H, t, J = 8 Hz), 7.94 (1H, s), 7.98 (1H × (1/2), s), 8.02 (1H × (1/2), s);
MS (FAB) m / z: 649 ((M + H) ⁺ ).
(1b) 4-oxo-4- [4- (1-pyrrolidinyl) piperidino] butyric acid 4- (1-pyrrolidinyl) piperidine (1.17 g, 7.21 mmol) was dissolved in dichloromethane (10 mL), and anhydrous succinate was added thereto. Acid (0.72 g, 7.21 mmol) was added and stirred at room temperature for 4 and a half hours.

  The solvent of the reaction solution was distilled off under reduced pressure to obtain a crude title compound (1.91 g, quantitative yield) as a yellow amorphous solid.

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.20 (1H, br q, J = 13 Hz), 1.34 (1H, br q, J = 13 Hz), 1.64-1.71 (4H, m), 1.72 (2H , br t, J = 13 Hz), 2.18-2.25 (1H, m), 2,38-2.43 (2H, m), 2.47-2.54 (6H, m), 2.72 (1H, td, J = 13, 3 Hz), 3.05 (1H, br t, J = 13 Hz), 3.79 (1H, br d, J = 13 Hz), 4.15 (1H, br d, J = 13 Hz);
MS (EI) m / z: 254 (M ⁺ ).
(1c) 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 = 4 -Oxo-4- [4- (1-pyrrolidinyl) piperidino] butyrate (title target compound)
4-oxo-4- [4- (1-pyrrolidinyl) piperidino] butyric acid (763 mg, 3 mmol) prepared in Example 1 (1b) was dissolved in N, N-dimethylformamide (10 mL), and 18- Crown-6 (793 mg, 3 mmol) and cesium carbonate (456 mg, 1.4 mmol) were added. After stirring for 1 hour and a half at room temperature, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-) prepared in (1a) of Example 1 was used. 2-Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole -1-yl) methyl] propyl carbonate (diastereomer ratio = about 1: 1; 650 mg, 1 mmol) was added and stirred at room temperature for 40 hours.

  Under ice cooling, a phosphate buffer was added to the reaction solution, and the product was extracted three times with ethyl acetate. The obtained organic layers were combined, washed with water (20 mL × 3), then saturated brine (30 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound. Obtained.

  The obtained crude title compound was recycled by preparative HPLC [LC-908; manufactured by Nihon Analytical Industry; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) in series. Used in conjunction; solvent, chloroform] to give the title object compound (356.1 mg, yield 41%) as a pale yellow, amorphous solid (diastereomer ratio = approximately 1: 1).

IR (CHCl ₃ ) ν _max 2233, 1765, 1641, 1505, 1276, 1141, 1055 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, dd, J = 7, 2 Hz), 1.54 (3H × (1/2), d-like, J = ca.5 Hz), 1.55 ( 3H × (1/2), d-like, J = ca.5 Hz), 1.5-1.9 (8H, m), 2.5-2.75 (10H, m), 2.99-3.13 (2H, m), 3.48 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz, overlapped), 3.50 (1H × (1/2), t, J = 11 Hz), 3.79-3.92 (2H, m), 4.18 (1H, ddd, J = 11, 5, 2 Hz), 4.44-4.54 ( 1H, m), 4.97 (1H × (1/2), d, J = 4 Hz), 4.98 (1H × (1/2), d, J = 4 Hz), 5.34 (1H × (1/2) , br d, J = 15 Hz), 5.37 (1H, s), 5.45 (1H × (1/2), dd, J = 15, 5 Hz), 5.86 (1H, dd, J = 15, 4 Hz) , 6.58 (1H, dd, J = 15, 11 Hz), 6.74 (1H, d, J = 16 Hz), 6.72-6.76 (1H × (1/2), m), 6.81 (1H × (1/2 ), q, J = 5 Hz), 6.84-6.95 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.40 (1H , dd, J = 8, 1 Hz), 7.43 (1H, td, J = 9, 6 Hz), 7.57 (1H, t, J = 8 Hz), 7.91 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 (1H × (1/2), d-like), 8.19 & 8.24 (1H × (1/2) in total, relative intensity = 1: 1 each s );
MS (FAB) m / z: 867 ((M + H) ⁺ ).
The title object compound prepared above (diastereomer ratio = about 1: 1; 333.1 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), and hydrogen chloride (4N ethyl acetate solution; 96.1 μL, 0.38 mmol) was added, and the mixture was stirred at the same temperature for 5 minutes.

  The solvent was distilled off under reduced pressure to obtain the monohydrochloride (339.6 mg, yield 98%) of the title target compound as a pale yellow amorphous solid (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 2230, 1765, 1648, 1504, 1275, 1141, 1056, 973 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.25 (3H × (1/2), dd, J = 7, 2 Hz), 1.27 (3H × (1/2), dd, J = 7, 2 Hz), 1.45 (3H × (1/2), d, J = 5 Hz), 1.49 (3H × (1/2), d, J = 5 Hz), 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 (1H × (1/2), t, J = 11 Hz), 3.44 (1H × (1/2), t, J = 11 Hz), 3.44 (1H × (1/2), t, J = 11 Hz, overlapped), 3.46 (1H × (1/2) , t, J = 11 Hz), 3.56 (1H × (1/2), q, J = 7 Hz), 3.74 (1H × (1/2), br q, J = 7 Hz), 3.96-4.06 ( 2H, m), 4.08-4.14 (1H, m), 4.4-4.5 (1H, m), 5.03 (1H × (1/2), d, J = 4 Hz), 5.04 (1H × (1/2) , d, J = 4 Hz), 5.24 (1H × (1/2), d, J-16 Hz), 5.28 (1H × (1/2), d, J = 16 Hz), 5.43 (1H × ( 1/2), d, J = 14 Hz), 5.46 (1H × (1/2), d, J = 14 Hz), 5.88 (1H × (1/2), dd, J = 16, 4 Hz) , 5.89 (1H × (1/2), dd, J = 16, 4 Hz), 6.55-6.62 (1H × (1/2), m), 6.57 (1H, dd, J = 16, 11 Hz), 6.68 (1H × (1/2), q, J = 5 Hz), 6.83 (1H, d, J = 16 Hz), 7.15-7.20 (1H, m), 7.19 (1H, dd, J = 16, 11 Hz), 7.31-7.38 (1H, m), 7.42-7.51 (1H, m), 7.68 (1H, dd, J = 8, 2 Hz), 7.85 (1H, dd, J = 10, 2 Hz), 7.87 (1H, t, J = 8 Hz), 8.06 (1H × (1/2), s), 8.06 (1H × (1/2), s, overlapped), 8.36 (1H × (1/2), d-like), 8.48 (1H × (1/2), s);
MS (FAB) m / z: 867 ((non-hydrochloric acid part + H) ⁺ ).
Example 2 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 = 4-oxo-4- (4-piperidinopiperidino) butyrate (Exemplary Compound 1-112)
(2a) 4-Oxo-4- (4-piperidinopiperidino) butyric acid 4-Piperidinopiperidine (3.70 g, 22.0 mmol) was dissolved in dichloromethane (10 mL), and succinic anhydride ( 2.16 g, 21.6 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours.

  The solvent of the reaction solution was distilled off under reduced pressure to obtain a crude title compound (5.88 g, quantitative yield) as a light brown amorphous solid.

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.20 (1H, qd, J = 12, 3 Hz), 1.32-1.41 (3H, m), 1.41-1.50 (4H, m), 1.72 (2H, br t , J = 13 Hz), 2.37-2.53 (9H, m), 2.94 (1H, br t, J = 13 Hz), 3.88 (1H, dd, J = 13, 2 Hz), 4.37 (1H br d, J = 13 Hz);
MS (EI) m / z: 254 (M ⁺ ).
(2b) 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 = 4 -Oxo-4- (4-piperidinopiperidino) butyrate (title target compound)
4-oxo-4- (4-piperidinopiperidino) butyric acid (805 mg, 3 mmol) prepared in Example 2 (2a) was dissolved in N, N-dimethylformamide (10 mL), and 18- Crown-6 (793 mg, 3 mmol) and cesium carbonate (456 mg, 1.4 mmol) were added. After stirring for 1 hour and a half at room temperature, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-] produced in Example 1 (1a)] was prepared. 2-Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole -1-yl) methyl] propyl carbonate (diastereomer ratio = about 1: 1; 650 mg, 1 mmol) was added and stirred at room temperature for 20 hours.

  Under ice cooling, a phosphate buffer was added to the reaction solution, and the product was extracted three times with ethyl acetate. The obtained organic layers were combined, washed with water (20 mL × 3), then saturated brine (30 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound. Obtained.

  The obtained crude title compound was recycled by preparative HPLC [LC-908; manufactured by Nihon Analytical Industry; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) in series. Used in connection; solvent, chloroform] to give the title object compound (330.6 mg, yield 38%) as a pale yellow amorphous solid (diastereomer ratio = about 1: 1).

IR (CHCl ₃ ) ν _max 2233, 1765, 1640, 1505, 1276, 1141, 1055, 974 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, dd, J = 7, 2 Hz), 1.54 (3H × (1/2), d, J = 5 Hz), 1.55 (3H × (1 / 2), d, J = 5 Hz), 1.4-1.7 (10H, m), 2.45-2.75 (10H, m), 2.97-3.06 (2H, m), 3.45 (1H × (1/2), t , J = 11 Hz), 3.46 (1H × (1/2), t, J = 11 Hz), 3.46 (1H × (1/2), t, J = 11 Hz, overlapped), 3.47 (1 × ( 1/2), t, J = 11 Hz), 3.9-4.0 (2H, m), 4.15-4.21 (1H, m), 4.26-4.33 (1H, m), 4.60 (1H, br d, J = 14 Hz), 4.98 (1H, d, J = 4 Hz), 5.32 (1H × (1/2), d, J = 15 Hz), 5.37 (1H, s), 5.45 (1H × (1/2), dd, J = 15,3 Hz), 5.86 (1H, dd, J = 16, 4 Hz), 6.58 (1H, dd, J = 16, 11 Hz), 6.74 (1H × (1/2), qd, J = 5, 2 Hz), 6.74 (1H, d, J = 16 Hz, overlapped), 6,81 (1H × (1/2), q, J = 5 Hz), 6.84-6.94 (2H, m) , 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.40 (1H, dd, J = 8, 1 Hz), 7.38-7.46 (1H, m ), 7.57 (1H, t, J = 8 Hz), 7.91 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 (1H × (1/2), s), 8.21 & 8.25 (1H × (1/2) in total, relative intensity = 1: 1, each s);
MS (FAB) m / z: 881 ((M + H) ⁺ ).
The title object compound prepared above (diastereomer ratio = about 1: 1; 321.4 mg, 0.36 mmol) was dissolved in dichloromethane (10 mL), and the solution was added with hydrogen chloride (4N ethyl acetate solution; 87 μL, 0.35 mmol) was added, and the mixture was stirred at the same temperature for 5 minutes.

  The solvent was distilled off under reduced pressure to obtain the monohydrochloride (322.2 mg, yield 96%) of the title target compound as a pale yellow, amorphous solid (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 2230, 1765, 1504, 1275, 1141, 1060, 973 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.25 (3H × (1/2), dd, J = 7, 2 Hz), 1.27 (3H × (1/2), dd, J = 7, 2 Hz), 1.3-1.8 (10H, m), 1.45 (3H × (1/2), d, J = 5 Hz), 1.48 (3H × (1/2), d, J = 5 Hz), 2.3 -2.7 (8H, m), 2.85-3.05 (4H, m), 3.41 (1H × (1/2), t, J = 11 Hz), 3.43 (1H × (1/2), t, J = 13 Hz), 3.44 (1H × (1/2), t, J = 11 Hz), 3.46 (1H × (1/2), t, J = 11 Hz), 3.57 (1H × (1/2), q , J = 7 Hz), 3.72-3.76 (1H × (1/2), m), 4.02-4.07 (2H, m), 4.08-4.13 (1H, m), 4.4-4.5 (1H, m), 5.03 (1H × (1/2), d, J = 4 Hz), 5.04 (1H × (1/2), d, J = 4 Hz), 5.24 (1H × (1/2), d, J = 15 Hz), 5.28 (1H × (1/2), d, J = 15 Hz), 5.43 (1H × (1/2), d, J = 13 Hz), 5.46 (1H × (1/2), d , J = 13 Hz), 5.88 (1H × (1/2), dd, J = 16, 4 Hz), 5.89 (1H × (1/2), dd, J = 16, 4 Hz), 6.57 (1H × (1/2), dd, J = 16, 11 Hz), 6.58 (1H × (1/2), dd, J = 16, 11 Hz), 6.56-6.64 (1H × (1/2), m ), 6.68 (1H × (1/2), q, J = 5 Hz), 6.82 (1H, d, J = 16 Hz), 7.12-7.20 (1H, m), 7.19 (1H, dd, J = 16 , 11 Hz), 7.31-7.37 (1H, m), 7.42-7.51 (1H, m), 7.68 (1H, dd, J = 8, 1 Hz), 7.85 (1H, dd, J = 11, 1 Hz) , 7.87 (1H, t, J = 8 Hz), 8.06 ( 1H × (1/2), s), 8.06 (1H × (1/2), s, overlapped), 8.35 & 8.36 (1H × (1/2) in total, relative intensity = 1: 1, each s) , 8.48 (1H × (1/2), s);
MS (FAB) m / z: 881 ((non-hydrochloric acid part + H) ⁺ ).
Example 3 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 = 4- [4- (Dimethylamino) piperidino] -4-oxobutyrate (Exemplary Compound 1-118)
(3a) 4- (dimethylamino) -1- (tert-butoxycarbonyl) piperidine 1- (tert-butoxycarbonyl) -4-piperidinone (J. Med. Chem., 35, 4118 (1992) 6.33 g, 32 mmol) was dissolved in ethanol (100 mL), dimethylamine hydrochloride (12.95 g, 159 mmol) and molecular sieves 3A (5 g) were added, and the mixture was stirred at room temperature for 1.5 hours. Thereto was added sodium cyanoborohydride (2.07 g, 33 mmol), and the mixture was further stirred at room temperature for 1 hour.

  The insoluble material was filtered through Celite at room temperature, and the solid was washed with ethanol. The filtrate and washings were combined and concentrated under reduced pressure, and the resulting residue was partitioned between water and ether. The obtained organic layers were combined, washed with water and then with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (methanol: ethyl acetate, 10: 90-50: 50, V / V, silica gel 60 g) to give the title compound (2.38 g, yield 32). %) As a colorless oil.

IR (CHCl ₃ ) ν _max 1682, 1428, 1367, 1247, 1161 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.37 (2H, qd, J = 12, 4 Hz), 1.46 (9H, s), 1.79 (2H, d, J = 12 Hz), 2.2-2.3 (1H , m), 2.28 (6H, s), 2.71 (2H, br t, J = 12 Hz), 4.08-4.18 (2H, br);
MS (FAB) m / z: 229 ((M + H) ⁺ ).
(3b) Ethyl = 4- [4- (dimethylamino) piperidino] -4-oxobutyrate 4- (dimethylamino) -1- (tert-butoxycarbonyl) piperidine (1) prepared in (3a) of Example 3 .553 g, 6.8 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added under ice cooling. The mixture was stirred at room temperature for 15 minutes, and then the solvent was distilled off under reduced pressure. Further, toluene was added and the solvent was distilled off twice to obtain crude 4- (dimethylamino) piperidine as trifluoroacetate salt. Got as.

  The crude trifluoroacetate salt of 4- (dimethylamino) piperidine prepared above was dissolved in dichloromethane (20 mL), and triethylamine (3.44 g, 34 mmol) and ethyl 4-chloro-4-oxobutyrate were cooled with ice. Lat (1.119 g, 6.8 mmol) was added and stirred at room temperature for 2.5 hours.

  Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the product was extracted with dichloromethane, and the resulting organic layers were combined and washed with saturated brine, and the solvent was evaporated under reduced pressure to give the crude title compound. .

  The resulting crude title compound was purified using silica gel column chromatography (methanol: ethyl acetate, 10: 90-20: 80, V / V, silica gel 50 g) to give the title compound (1.01 g, yield 58%). ) Was obtained as a colorless oil.

IR (CHCl ₃ ) ν _max 1727, 1647, 1455, 1377, 1180, 1153 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.27 (3H, t, J = 7 Hz), 1.45 (1H, qd, J = 12, 4 Hz), 1.54 (1H, qd, J = 12, 4 Hz ), 1.92 (1H, br d, J = 13 Hz), 2.01 (1H, br d, J = 12 Hz), 2.48 (6H, s), 2.56-2.69 (6H, m), 3.06 (1H, br t , J = 12 Hz), 4.00 (1H, br d, J = 13 Hz), 4.15 (2H, q, J = 7 Hz), 4.71 (1H, br d, J = 13 Hz);
MS (EI) m / z: 256 (M ⁺ ).
(3c) 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 = 4 -[4- (Dimethylamino) piperidino] -4-oxobutyrate (title target compound)
Ethyl 4- [4- (dimethylamino) piperidino] -4-oxobutyrate (1.01 g, 3.94 mmol) prepared in (3b) of Example 3 was suspended in water (35 mL) and cesium carbonate was added. (609.8 mg, 1.87 mmol) was added, and the mixture was stirred at 70 ° C. for 8 hours. The solvent was distilled off under reduced pressure, and crude cesium = 4- [4- (dimethylamino) piperidino] -4-oxobutyrate was added. Obtained.

  Crude cesium = 4- [4- (dimethylamino) piperidino] -4-oxobutyrate obtained above was dissolved in N, N-dimethylformamide (30 mL) and prepared in Example 1 (1a) 1 -Chloroethyl = (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 carbonate (diastereomeric ratio = about 1: 1; 1.12 g, 1.73 mmol) was added, and the mixture was stirred at 40 ° C. for 20 hours.

  Under ice cooling, a phosphate buffer was added to the reaction solution, and the product was extracted three times with ethyl acetate. The obtained organic layers were combined, washed with water (30 mL × 3) and then with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound. Obtained.

  The resulting crude title compound was purified using silica gel column chromatography (methanol: ethyl acetate, 5: 95-20: 80, V / V, silica gel 25 g) to give the title object compound (581.1 mg, yield 36). %) Was obtained as a brown, amorphous solid (diastereomeric ratio = about 1: 1).

IR (KBr) ν _max 2230, 1765, 1720, 1644, 1504, 1275, 1142, 1058 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, dd, J = 7, 2 Hz), 1.30-1.49 (2H, m), 1.54 (3H × (1/2), d, J = 5 Hz), 1.55 (3H × (1/2), d, J = 5 Hz), 1.81-1.90 (2H, m), 2.28 (6H × (1/2), s), 2.28 (6H × (1 / 2), s, overlapped), 2.54-2.77 (6H, m), 2.98-3.19 (2H, m), 3.48 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1 / 2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz, overlapped), 3.50 (1H × (1/2), t, J = 11 Hz), 3.80-3.97 (2H, m), 4.14 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.17 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.25-4.33 (1H, m), 4.57 (1H, br d, J = 13 Hz), 4.98 (1H, d, J = 4 Hz), 5.32 (1H × (1/2), d, J = 15 Hz), 5.37 (1H, s), 5.45 (1H × (1/2), dd, J = 15, 4 Hz), 5.85 (1H, dd, J = 16, 4 Hz), 6.58 (1H, dd, J = 16, 11 Hz), 6.73 (1H × (1/2), qd, J = 5, 2 Hz), 6.74 (1H, d, J = 16 Hz), 6.81 (1H × (1/2 ), q, J = 5 Hz), 6.84-6.95 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.40 (1H , dd, J = 8, 1 Hz), 7.43 (1H, td, J = 9, 6 Hz), 7.57 (1H, t, J = 8 Hz), 7.91 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 & 8.03 (1H × (1/2) in total, relative intensity = 1 : 1, each s), 8.21 & 8.26 (1H × (1/2) in total, relative intensity = 1: 1, each s);
MS (FAB) m / z: 841 ((M + H) ⁺ ).
The title object compound prepared above (diastereomer ratio = about 1: 1; 470 mg, 0.56 mmol) was dissolved in dichloromethane (10 mL), and the mixture was added with hydrogen chloride (4N ethyl acetate solution; 140 μL, under ice cooling) 0.56 mmol) was added, and the mixture was stirred at the same temperature for 5 minutes.

  The solvent was distilled off under reduced pressure to obtain the monohydrochloride (466 mg, yield 95%) of the title object compound as a pale yellow, amorphous solid (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 2230, 1765, 1646, 1504, 1275, 1142, 1055 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.24 (3H × (1/2), dd, J = 7, 2 Hz), 1.27 (3H × (1/2), dd, J = 7, 2 Hz), 1.2-1.36 (2H, m), 1.45 (3H × (1/2), d, J = 5 Hz), 1.48 (3H × (1/2), d, J = 5 Hz), 1.84 -2.00 (2H, m), 2.5-2.7 (5H, m), 2.90 (1H × (1/2), tt, J = 11, 5 Hz), 2.91 (1H × (1/2), tt, J = 11, 5 Hz), 3.00 (2H, br t, J = 12 Hz), 3.26-3.35 (2H, m), 3.41 (1H × (1/2), t, J = 11 Hz), 3.42 (1H × (1/2), t, J = 11 Hz), 3.44 (1H × (1/2), t, J = 11 Hz), 3.44 (1H × (1/2), t, J = 11, overlapped ), 3.57 (1H × (1/2), q, J = 7 Hz), 3.72-3.78 (1H × (1/2), m), 3.95-4.06 (2H, m), 4.07-4.14 (1H, m), 4.43 (1H, br d, J = 12 Hz), 5.03 (1H × (1/2), d, J = 4 Hz), 5.04 (1H × (1/2), d, J = 4 Hz ), 5.24 (1H × (1/2), d, J = 15 Hz), 5.28 (1H × (1/2), d, J = 15 Hz), 5.44 (1H × (1/2), d, J = 15 Hz), 5.46 (1H × (1/2), d, J = 15 Hz), 5.88 (1H × (1/2), dd, J = 16, 4 Hz), 5.89 (1H × (1 / 2), dd, J = 16, 4 Hz), 6.57 (1H, dd, J = 16, 11 Hz), 6.56-6.63 (1H × (1/2), m), 6.68 (1H × (1 / 2), q, J = 5 Hz), 6.82 (1H, d, J = 16 Hz), 7.14-7.20 (1H, m), 7.19 (1H, dd, J = 16, 11 Hz), 7.31-7.37 ( 1H, m), 7.42-7.51 ( 1H, m), 7.68 (1H, dd, J = 8, 1 Hz), 7.85 (1H, dd, J = 10, 1 Hz), 7.87 (1H, t, J = 8 Hz), 8.06 (1H, s ), 8.35 & 8.37 (1H × (1/2) in total, relative intensity = 1: 1, each s), 8.48 (1H × (1/2), s);
MS (FAB) m / z: 841 ((non-hydrochloric acid part + H) ⁺ )
Example 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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethyl = 4- [4- (Methylamino) piperidino] -4-oxobutyrate (Exemplary Compound 1-117)
(4a) 4- [N- (allyloxycarbonyl) -N-methylamino] -1- (tert-butoxycarbonyl) piperidine 1- (tert-butoxycarbonyl) -4- (methylamino) piperidine (J. Med. Chem., 42, 693 (1999); 9.0 g, 42 mmol) was dissolved in water (100 mL) and allyl chloroformate (5.46 g, 45.3 mmol), and 4- (Dimethylamino) pyridine (5.54 g, 45.3 mmol) was added and stirred at room temperature for 30 minutes.

  Under ice-cooling, saturated aqueous sodium hydrogen carbonate solution was added, and the product was extracted with ethyl acetate (80 mL × 3). The obtained organic layers were combined, washed with water and then 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 resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 80: 20-50: 50, V / V, silica gel 50 g) to give the title compound (7.3 g, yield 58). %) As a colorless oil.

IR (CHCl ₃ ) ν _max 1683, 1428, 1317, 1156, 1013 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 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 = 5 Hz), 5.21 (1H, dd, J = 10, 1 Hz), 5.30 (1H, d, J = 17 Hz), 5.95 (1H, ddt, J = 17 , 10, 5 Hz);
MS (FAB) m / z: 299 ((M + H) ⁺ ).
(4b) 4- [N- (allyloxycarbonyl) -N-methylamino] piperidine 4- [N- (allyloxycarbonyl) -N-methylamino] -1- (prepared in (4a) of Example 4 tert-Butoxycarbonyl) piperidine (2.6 g, 8.7 mmol) is dissolved in ethyl acetate (5 mL), hydrogen chloride (4N ethyl acetate solution; 10 mL) is added at 0 ° C., and the mixture is stirred at room temperature for 30 minutes. Stir.

  The solution obtained by diluting the mixture with water was washed twice with ethyl acetate, sodium hydrogen carbonate was added, and the product was extracted with ethyl acetate. The obtained organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.91 g, yield 53%) as a pale brown oily substance. Got as.

IR (CHCl ₃ ) ν _max 1686, 1451, 1410, 1319, 1165 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ1.59-1.72 (4H, m), 2.6-2.8 (1H, br), 2.69 (2H, br t, J = 12 Hz), 2.82 (3H, s) , 3.14 (2H, br d, J = 12 Hz), 4.60 (2H, d, J = 5 Hz), 5.21 (1H, d, J = 11 Hz), 5.30 (1H, d, J = 17 Hz), 5.96 (1H, ddt, J = 17, 11 5 Hz);
MS (EI) m / z: 198 (M ⁺ ).
(4c) 4- [4- [N- (allyloxycarbonyl) -N-methylamino] piperidino] -4-oxobutyric acid 4- [N- (allyloxycarbonyl)-prepared in (4b) of Example 4 N-methylamino] piperidine (0.90 g, 4.59 mmol) was dissolved in dichloromethane (15 mL), succinic anhydride (450.3 mg, 4.5 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. did.

  The residue obtained by distilling off the solvent under reduced pressure was diluted with aqueous sodium hydrogen carbonate solution, this aqueous solution was washed twice with ethyl acetate, then 2N hydrochloric acid was added, and the product was extracted with ethyl acetate. The obtained organic layers were combined, washed with saturated brine, and the solvent was evaporated under reduced pressure to give the crude title compound (1.33 g, yield 96%) as a colorless solid.

Mp 85-87 ℃
IR (CHCl ₃ ) ν _max 1713, 1691, 1645, 1452, 1317, 1157, 1011 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.6-1.7 (2H, m), 1.7-1.82 (2H, m), 2.6-2.8 (5H, m), 2.79 (3H, s), 3.13 (2H, br t, J = 13 Hz), 3.95 (1H, br d, J = 14 Hz), 4.61 (2H, d, J = 5 Hz), 4.74 (1H, br d, J = 11 Hz), 5.22 (1H , d, J = 10 Hz), 5.30 (1H, d, J = 17 Hz), 5.95 (1H, ddt, J = 17, 10, 5 Hz);
MS (FAB) m / z: 299 ((M + H) ⁺ ).
(4d) 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 = 4 -[4- [N- (allyloxycarbonyl) -N-methylamino] piperidino] -4-oxobutyrate 4- [4- [N- (allyloxycarbonyl)-prepared in (4c) of Example 4 N-methylamino] piperidino] -4-oxobutyric acid (1.32 g, 4.4 mmol) was dissolved in N, N-dimethylformamide (10 mL) and 18-crown-6 (0.79 g, 3 mmol) and Carbonate Um (0.46 g, 1.5 mmol) was added. After stirring at room temperature for 2 hours, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2] prepared in Example 1 (1a)] was prepared. -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propyl carbonate (diastereomer ratio = approximately 1: 1; 0.65 g, 1 mmol) was added and stirred at room temperature for 40 hours.

  Under ice cooling, a phosphate buffer was added to the reaction solution, and the product was extracted three times with ethyl acetate. The obtained organic layers were combined, washed with water (20 mL × 3), then saturated brine (30 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound. Obtained.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 25: 75-10: 90, V / V, silica gel 25 g) to give the title compound (0.56 g, 44% yield). ) Was obtained as a colorless, amorphous solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2230, 1765, 1700, 1644, 1504, 1275, 1143 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, dd, J = 7, 2 Hz), 1.54 (3H × (1/2), d, J = 5 Hz), 1.56 (3H × (1 / 2), d, J = 5 Hz), 1.5-1.8 (4H, m), 2.54-2.76 (5H, m), 2.77 (3H, s), 3.10-3.15 (3H, m), 3.48 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz, overlapped ), 3.50 (1H × (1/2), t, J = 11 Hz), 3.83 (1H × (1/2), q, J = 7 Hz), 3.88 (1H × (1/2), q, J = 7 Hz), 3.91-4.04 (1H, m), 4.15-4.20 (1H, m), 4.28 (1H × (1/2), ddd, J = 11, 5, 2Hz), 4.29 (1H × ( 1/2), ddd, J = 11, 5, 2 Hz), 4.60 (2H, d, J = 5 Hz), 4.70 (1H, br d, J = 13 Hz), 4.98 (1H, d, J = 4 Hz), 5.22 (1H, d, J = 10 Hz), 5.30 (1H, br d, J = 17 Hz), 5.31 (1H × (1/2), dd, J = 15, 4 Hz), 5.37 (1H, s), 5.45 (1H × (1/2), d, J = 15 Hz), 5.85 (1H, dd, J = 16, 4 Hz), 5.95 (1H, ddt, J = 17, 11, 5 Hz), 6.58 (1H × (1/2), dd, J = 16, 11 Hz), 6.58 (1H × (1/2), dd, J = 16, 11 Hz, overlapped), 6.74 (1H × (1/2), q, J = 6 Hz), 6.74 (1H, d, J = 16 Hz, overlapped), 6.81 (1H × (1/2), q, J = 6 Hz), 6.85-6.95 ( 2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.40 (1H, dd, J = 7, 1 Hz), 7.38-7.46 (1H, m), 7.57 (1H, t, J = 8 Hz), 7.90 (1H × (1/2), s), 7.95 (1H × (1 / 2), s), 8.02 (1H × (1/2), s), 8.24 & 8.25 (1H × (1/2) in total, relative intensity = 1: 1, each s);
MS (FAB) m / z: 939 ((M + H) ⁺ ).
(4e) 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 = 4 -[4- (Methylamino) piperidino] -4-oxobutyrate (title target compound)
1-[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1, prepared in (4d) of Example 4] 3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy ] Carbonyloxy] ethyl = 4- [4- [N- (allyloxycarbonyl) -N-methylamino] piperidino] -4-oxobutyrate (diastereomeric ratio = approximately 1: 1; 0.55 g,. 60 mmol) was dissolved in dichloromethane (15 mL), and bis (triphenylphosphine) dichloropalladium (21.2 mg, 0.03 mmol) and tributyltin hydride (175.7 mg, 0.79 m) were cooled with ice. ol) was added, under a nitrogen atmosphere and stirred at room temperature for 20 minutes.

  The reaction mixture was subjected to silica gel chromatography (ethyl acetate-methanol, 100: 0-75: 25, V / V, silica gel 20 g) to give the title object compound (297.2 mg, yield 60%) as a pale yellow amorphous substance. As a solid (diastereomeric ratio = about 1: 1).

IR (KBr) ν _max 2230, 1765, 1643, 1504, 1275, 1141 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.16-1.30 (2H, m), 1.36 (3H, dd, J = 7, 2 Hz), 1.54 (3H × (1/2), d, J = 6 Hz), 1.55 (3H × (1/2), d, J = 6 Hz), 1.86-1.97 (2H, m), 2.44 (3H, s), 2.6-2.8 (6H, m), 3.0-3.15 ( 2H, m), 3.49 (1H × (1/2), t, J = 11 Hz), 3.50 (1H × (1/2), t, J = 11 Hz), 3.50 (1H × (1/2) , t, J = 11 Hz, overlapped), 3.51 (1H × (1/2), t, J = 11 Hz), 3.82-3.91 (2H, m), 4.18 (1H, ddd, J = 11, 5, 2 Hz), 4.28 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.30 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.41 (1H , br d, J = 13 Hz), 4.97 (1H, d, J = 4 Hz), 5.32 (1H × (1/2), d, J = 15 Hz), 5.37 (1H, s), 5.43 (1H × (1/2), dd, J = 15, 4 Hz), 5.85 (1H, dd, J = 16, 4 Hz), 6.58 (1H, dd, J = 16, 11 Hz), 6.73 (1H × ( 1/2), q, J = 5 Hz), 6.74 (1H, d, J = 16 Hz), 6.80 (1H × (1/2), q, J = 5 Hz), 6.84-6.92 (2H, m ), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.40 (1H, dd, J = 8, 1 Hz), 7.37-7.44 (1H, m), 7.57 (1H, t, J = 8 Hz), 7.91 (1H × (1/2), s), 7.95 (1H × (1/2), d-like), 8.02 (1H × (1 / 2), s), 8.21 & 8.25 (1H × (1/2) in total, relative intensity = 1: 1, each s);
MS (FAB) m / z 827 (M + 1) ⁺ .
The title target compound prepared above (diastereomer ratio = about 1: 1; 288.2 mg, 0.35 mmol) was dissolved in dichloromethane (5 mL), and the mixture was added with hydrogen chloride (4N ethyl acetate solution; 87 μL, 0.35 mmol) was added, and the mixture was stirred at the same temperature for 5 minutes.

  The solvent was distilled off under reduced pressure to obtain the monohydrochloride (290 mg, yield 96%) of the title target compound as a pale yellow, amorphous solid (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 2231, 1765, 1646, 1616, 1504, 1275, 1141, 1055, 974 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, dd, J = 7, 2 Hz), 1.54 (3H × (1/2), d, J = 5 Hz), 1.57 (3H × (1 / 2), d, J = 5 Hz), 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 (1H × (1/2), t, J = 11 Hz), 3.50 (1H × (1/2), t, J = 11 Hz), 3.51 (1H × (1/2) , t, J = 11 Hz), 3.51 (1H × (1/2), t, J = 11 Hz, overlapped), 3.8-3.9 (1H × (1/2), m), 3.89 (1H × (1 / 2), q, J = 7 Hz), 3.95-4.05 (1H, m), 4.18 (1H, ddd, J = 11, 5, 2 Hz), 4.25-4.35 (1H, m), 4.63 (1H, br d, J = 13 Hz), 4.98 (1H × (1/2), d, J = 4 Hz), 4.99 (1H × (1/2), d, J = 4 Hz), 5.3-5.4 (2H , m), 5.85 (1H, dd, J = 16, 4 Hz), 6.58 (1H, dd, J = 16, 11 Hz), 6.71-6.79 (1H, m), 6.75 (1H, d, J = 10 Hz), 6.84-6.94 (2H, m), 6.94 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.40 (1H, dd, J = 8, 1 Hz), 7.37-7.43 (1H, m), 7.57 (1H, t, J = 8 Hz), 7.92 (1H × (1/2), s), 7.95 (1H × (1/2), d- like), 8.02 (1H × (1/2), s), 8.21 & 8.26 (1H × (1/2) in total, relative intensity = 1: 1, each s);
MS (FAB) m / z: 827 ((M + H) ⁺ ).
Example 5 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 = 4- [4- [2- (Methylamino) ethyl] piperidino] -4-oxobutyrate (Exemplary Compound 1-1285)
(5a) 1- (tert-butoxycarbonyl) -4- [2- (mesyloxy) ethyl] piperidine 1- (tert-butoxycarbonyl) -4- (2-hydroxyethyl) piperidine (6.14 g, 26.8 mmol) Was dissolved in dichloromethane (80 mL), and thereto was added triethylamine (2.71 g, 26.8 mmol), 4- (dimethylamino) pyridine (327.4 mg, 2.68 mmol), and methanesulfonyl chloride (3) under ice-cooling. .37 g, 29.5 mmol) was added, and the mixture was stirred at the same temperature for 1 hour.

  The reaction solution was diluted with dichloromethane, and the organic layer was washed with a saturated aqueous ammonium chloride solution and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 50:50, V / V, silica gel 150 g) to give the title compound (6.80 g, yield 83%) as colorless. As a solid.

Mp 80-82 ° C;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.12-1.16 (2H, m), 1.56 (9H, s), 1.61-1.73 (5H, m), 2.70 (2H, br t, J = 12 Hz), 3.01 (3H, s), 4.05-4.15 (2H, br), 4.29 (2H, t, J = 6 Hz).
(5b) 1- (tert-Butoxycarbonyl) -4- [2- [N- (allyloxycarbonyl) -N-methylamino] ethyl] piperidine N- (allyloxycarbonyl) methylamine (Angew. Chem., 93) Vol. 115 (1981); 1.266 g, 11 mmol) is dissolved in N, N-dimethylformamide (30 mL) and sodium hydride (55% mineral oil dispersion; 0.48 g, 11 mmol) is added, Stir at room temperature for 1 hour. Thereto was added 1- (tert-butoxycarbonyl) -4- [2- (mesyloxy) ethyl] piperidine (3.07 g, 10 mmol) prepared in (5a) of Example 5, and the mixture was stirred at 70 ° C. for 1 hour. .

  Water was added to the reaction solution at room temperature, and the product was washed with ethyl acetate. The obtained organic layers were combined, washed three times with water and then once with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 67:33, V / V, silica gel 75 g) to give the title compound (3.19 g, yield 98%) as colorless. As an oil.

IR (CHCl ₃ ) ν _max 1686, 1428, 1279, 1248, 1158 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.12 (2H, qd, J = 12, 4 Hz), 1.45 (9H, s), 1.35-1.7 (5H, m), 2.67 (2H, br t, J = 12 Hz), 2.90 (3H, s), 3.31 (2H, br t, J = 7 Hz), 4.03-4.11 (2H, br), 4.58 (2H, d, J = 5 Hz), 5.20 (1H, dd, J = 10, 1 Hz), 5.29 (1H, dd, J = 17, 2 Hz), 5.93 (1H, ddt, J = 17, 11, 5 Hz);
MS (FAB) m / z: 327 ((M + H) ⁺ ).
(5c) 4- [2- [N- (allyloxycarbonyl) -N-methylamino] ethyl] piperidine 1- (tert-butoxycarbonyl) -4- [2- [prepared in (5b) of Example 5 N- (allyloxycarbonyl) -N-methylamino] ethyl] piperidine (3.15 g, 9.1 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added thereto under ice-cooling. For one and a half hours.

  The reaction solution was concentrated under reduced pressure, and water (30 mL) was added to the resulting residue. Sodium bicarbonate was added to this aqueous solution, and the product was extracted with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the crude title compound (2.71 g, collected). Was obtained as a light brown oil.

IR (CHCl ₃ ) ν _max 1686, 1406, 1248, 1180, 1141 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.45-1.53 (5H, br), 1.83-1.97 (2H, br), 2.75-2.85 (2H, br), 2.90 (3H, s), 3.33 (4H, d, J = 12 Hz), 4.58 (2H, d, J = 6 Hz), 5.21 (1H, d, J = 10 Hz), 5.30 (1H, d, J = 17 Hz), 5.89-5.97 (1H, m);
MS (EI) m / z: 226 (M ⁺ ).
(5d) 4- [2- [N- (allyloxycarbonyl) -N-methylamino] ethyl] piperidino-4-oxobutyric acid 4- [2- [N- (allyl) prepared in (5c) of Example 5 Oxycarbonyl) -N-methylamino] ethyl] piperidine (1.245 g, 5.5 mmol) was dissolved in dichloromethane (25 mL), succinic anhydride (500.4 mg, 5 mmol) was added, and the mixture was stirred at room temperature for 2 hr.

  Under reduced pressure, the solvent was distilled off, and an aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the aqueous solution was washed with ethyl acetate. 2N hydrochloric acid was added to this aqueous solution, and the product was extracted with ethyl acetate. The obtained organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The title compound (0.84 g, 47% yield) was obtained as a light brown oil.

IR (CHCl ₃ ) ν _max 1691, 1645, 1600, 1452, 1317, 1157, 1011 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.13-1.23 (2H, m), 1.45-1.55 (3H, br), 1.7-1.9 (2H, br), 2.61 (1H, br t, J = 13 Hz ), 2.71 (4H, s), 2.91 (3H, s), 3.04 (1H, br t, J = 13 Hz), 3.33 (2H, br t, J = 7 Hz), 3.85 (1H, br d, J = 13 Hz), 4.56-4.61 (1H, br), 4.59 (2H, d, J = 6 Hz), 5.22 (1H, d, J = 10 Hz), 5.30 (1H, d, J = 16 Hz), 5.90-5.97 (1H, m);
MS (FAB) m / z: 299 ((M + H) ⁺ ).
(5e) 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 = 4 -[4- [2- [N- (allyloxycarbonyl) -N-methylamino] ethyl] piperidino] -4-oxobutyrate 4- [2- [N- () prepared in (5d) of Example 5 Allyloxycarbonyl) -N-methylamino] ethyl] piperidino-4-oxobutyric acid (913 mg, 2.80 mmol) is dissolved in N, N-dimethylacetamide (15 mL) and potassium = tert-butoxide (282. 5 mg, 2.52 mmol) was added, and the mixture was stirred at the same temperature for 2 hours. There, 1-chloroethyl produced in (1a) of Example 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] propyl carbonate (diastereomer ratio = about 1: 1; 1.01 g, 1.4 mmol) was added and stirred at 50 ° C. for 22 hours.

  Under ice cooling, a phosphate buffer was added to the reaction solution, and the product was extracted three times with ethyl acetate. The obtained organic layers were combined, washed with water (30 mL × 3) and then with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound. Obtained.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 25: 75-10: 90, V / V, silica gel 25 g) to give the title compound (0.56 g, yield 38%). ) Was obtained as a colorless, amorphous solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2230, 1765, 1699, 1644, 1504, 1275, 1143, 1056, 973 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.06-1.20 (2H, m), 1.36 (3H, d, J = 7 Hz), 1.4-1.6 (3H, m), 1.54 (3H × (1/2 ), d, J = 5 Hz), 1.55 (3H × (1/2), d, J = 5 Hz), 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 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t , J = 11 Hz), 3.50 (1H × (1/2), t, J = 11 Hz), 3.52 (1H × (1/2), t, J = 11 Hz), 3.8-3.92 (2H, m ), 4.15-4.21 (1H, m), 4.27 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.30 (1H × (1/2), ddd, J = 11, 5 , 2 Hz), 4.52-4.58 (1H, br), 4.58 (2H, dd, J = 5, 1 Hz), 4.98 (1H, d, J = 4 Hz), 5.20 (1H, d, J = 10 Hz ), 5.29 (1H, d, J = 17 Hz), 5.32 (1H × (1/2), d, J = 15 Hz), 5.38 (1H, s), 5.45 (1H × (1/2), dd , J = 15, 3 Hz), 5.86 (1H, dd, J = 15, 4 Hz), 5.90-5.94 (1H, m), 6.58 (1H, dd, J = 15, 11 Hz), 6.73 (1H × (1/2), qd, J = 5, 1 Hz), 6.74 (1H, d, J = 16 Hz), 6.81 (1H × (1/2), q, J = 5 Hz), 6.85-6.94 ( 2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.36 (1H, dd, J = 10, 1 Hz), 7.40 (1H, dd, J = 8, 1 Hz), 7.43 (1H , td, J = 9, 6 Hz), 7.57 (1H, t, J = 8 Hz), 7.91 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 (1H × (1/2), s), 8.22 and 8.55 (1H × (1/2) in total, relative intensity = 1: 1, each s);
MS (FAB) m / z: 939 ((M + H) ⁺ ).
(5f) 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 = 4 -[4- [2- (Methylamino) ethyl] piperidino] -4-oxobutyrate (title target compound)
1-[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1, prepared in (5e) of Example 5]. 3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy ] Carbonyloxy] ethyl = 4- [4- [2- [2- [N- (allyloxycarbonyl) -N-methylamino] ethyl] piperidino] -4-oxobutyrate (diastereomeric ratio = approximately 1: 1; .3 mg, 0.59 mmol) was dissolved in dichloromethane (10 mL), and under ice cooling, tetrakis (triphenylphosphine) palladium (34.3 mg, 0.03 mmol) and 5,5-dimethyl-1,3-cyclo Kisanjion (124.7mg, 0.89mmol) was added, under a nitrogen atmosphere and stirred at room temperature for 2 hours.

  The reaction mixture was subjected to silica gel chromatography (ethyl acetate-methanol, 100: 0-75: 25, V / V, silica gel 20 g) to give the title object compound (327.9 mg, yield 65%) as a pale yellow amorphous substance. As a solid (diastereomeric ratio = about 1: 1).

IR (KBr) ν _max 2230, 1765, 1642, 1504, 1275, 1141, 1054, 972 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.15-1.2 (2H, m), 1.36 (3H, dd, J = 7, 2 Hz), 1.4-1.5 (2H, m), 1.54 (3H × (1 / 2), d, J = 5 Hz), 1.55 (3H × (1/2), d, J = 5 Hz), 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 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2) , t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz, overlapped), 3.50 (1H × (1/2), t, J = 11 Hz), 3.81-3.92 (2H, m), 4.14-4.21 (1H, m), 4.28 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.30 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.54 (1H, br d, J = 13 Hz), 4.97 (1H, d, J = 4 Hz), 5.31 (1H × (1/2), d, J = 15 Hz ), 5.37 (1H, s), 5.44 (1H × (1/2), dd, J = 15, 4 Hz), 5.85 (1H, dd, J = 16, 4 Hz), 6.58 (1H, dd, J = 16, 11Hz), 6.73 (1H × (1/2), m), 6.74 (1H, d, J = 16 Hz), 6.81 (1H × (1/2), q, J = 5 Hz), 6.85 -6.95 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.40 (1H, dd, J = 8, 1 Hz), 7.43 (1H, dd, J = 8, 1 Hz), 7.57 (1H, t, J = 8 Hz), 7.91 (1H × (1/2), s). 7.94 (1H × (1/2), s ), 8.02 (1H × (1/2), s), 8.21 & 8.25 (1H × (1/2) in total, relative intensity = 1: 1, eac h s);
MS (FAB) m / z: 855 ((M + H) ⁺ ).
The title target compound prepared above (diastereomer ratio = about 1: 1; 310 mg, 0.33 mmol) was dissolved in dichloromethane (5 mL), and hydrogen chloride (4N ethyl acetate solution; 82 μL, 0.33 mmol) was added and stirred at the same temperature for 5 minutes.

  The oily residue obtained by distilling off the solvent under reduced pressure was dissolved in water (5 mL) at 0 ° C., the insoluble matter was filtered off through a membrane filter, and the aqueous solution obtained was lyophilized to give the title compound. Was obtained as a pale yellow, amorphous solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2230, 1765, 1640, 1504, 1275, 1142, 972 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.05-1.15 (2H, m), 1.31 (3H × (1/2), dd, J = 7, 2 Hz), 1.33 (3H × (1/2) , dd, J = 7, 2 Hz), 1.52 (3H × (1/2), d, J = 5 Hz), 1.53 (3H × (1/2), d, J = 5 Hz), 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 = 13 Hz), 3.48 (1H × (1/2), t, J = 11 Hz), 3.48 (1H × (1/2), t, J = 11 Hz, overlapped), 3.49 (1H × (1/2) , t, J = 11 Hz), 3.51 (1H × (1/2), t, J = 11 Hz), 3.81 (1H × (1/2), q, J = 7 Hz), 3.87 (1H × ( 1/2), q, J = 7 Hz), 3.96-4.04 (1H, m), 4.11 (1H, ddd, J = 11, 5, 2 Hz), 4.26 (1H, ddd, J = 11, 5, 2 Hz), 4.48 (1H, br d, J = 13 Hz), 5.01 (1H, d, J = 4 Hz), 5.43 (1H × (1/2), d, J = 15 Hz), 5.45 (1H , s), 5.50 (1H × (1/2), dd, J = 15, 3 Hz), 5.87 (1H, dd, J = 16,11 Hz), 6.59 (1H, dd, J = 16, 11 Hz ), 6.69 (1H × (1/2), q, J = 5 Hz), 6.75-6.80 (1H × (1/2), m), 6.80 (1H, d, J = 16 Hz), 7.02-7.10 (2H, m), 7.10 (1H, dd, J = 16, 11 Hz), 7.50-7.55 (3H, m), 7.78 (1H, t, J = 8 Hz), 8.03 (1H × (1/2) , s), 8.04 (1H × (1/2), s), 8.39 & 8.41 (1H × (1/2) in total, relative intensity = 1 : 1, each s), 8.42 (1H × (1/2), s);
MS (FAB) m / z: 855 ((non-hydrochloric acid part + H) ⁺ ).
Example 6 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 = Hydrogen = Succinate (Exemplary Compound 1-20)
(6a) Allyl = 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 = Succinate Allyl hydrogen succinate (described in J. Pharm. Sci., 50, 487 (1961); 1.12 g, 7.1 mmol) dissolved in N, N-dimethylformamide (30 mL) 18-Crown-6 (1.88 g, 7.1 mmol) and cesium carbonate (1.10 g, 3.4 mmol) were added. After stirring for 3 hours at room temperature, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2] prepared in Example 1 (1a)]. -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propyl carbonate (diastereomer ratio = approximately 1: 1; 1.95 g, 3 mmol) was added and stirred 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 × 3). The obtained organic layers were combined, washed with water (30 mL × 3) and then with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to leave a residue containing the title compound. I got a thing.

The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate, 50: 50-20: 80, V / V, silica gel 75 g) to obtain the crude title compound (total = 2.4 g, title compound). Content = about 1.68 g, yield of the title compound = about 72%, 4-[(1E, 3E) -4- [trans-5-[[(1R, 2R) -2- (2,4 -Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl] -1,3- (Butadienyl) -3-fluorobenzonitrile) was obtained as a colorless, amorphous solid (diastereomeric ratio = approximately 1: 1). This product was used in the next step (6b) without further purification.
(6b) 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 = hydrogen = Succinate (titled compound)
The crude allyl prepared in Example 6 (6a) = 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 succinate (content about 0.69 g, about 0.9 mmol; diastereomeric ratio = about 1: 1) was dissolved in dichloromethane (20 mL) and tetrakis (triphenyl) was cooled with ice. Phosphine) palladium (52 mg, 0.045 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (63.1 mg, 0.45 mmol) are added and 50 minutes at room temperature under nitrogen atmosphere. It was 拌.

  The reaction mixture was subjected to silica gel chromatography (ethyl acetate-methanol, 100: 0-90: 10, V / V, silica gel 20 g) to give the title object compound (468.2 mg, yield about 72%) as a pale yellow, amorphous product. As a solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2231, 1765, 1615, 1504, 1418, 1277, 1141 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.35 (3H, dd, J = 7, 2 Hz), 1.53 (3H × (1/2), d, J = 5 Hz), 1.57 (3H × (1 / 2), d, J = 5 Hz), 2.64-2.78 (4H, m), 3.47 (1H × (1/2), t, J = 11 Hz), 3.13 (1H × (1/2), tt , J = 11, 5 Hz), 3.02 (1H × (1/2), tt, J = 11, 5 Hz), 3.47 (1H × (1/2), t, J = 11 Hz), 3.47 (1H × (1/2), t, J = 11 Hz, overlapped), 3.52 (1H × (1/2), t, J = 11 Hz), 3.53 (1H × (1/2), t, J = 11 Hz), 3.66 (1H × (1/2), q, J = 7 Hz), 3.94 (1H × (1/2), t, J = 7 Hz), 4.14-4.17 (1H × (1/2) , m), 4.19 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.26 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.34 ( 1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.97 (1H × (1/2), d, J = 4 Hz), 5.02 (1H × (1/2), d, J = 4 Hz), 5.31 (1H × (1/2), dd, J = 15, 2 Hz), 5.35 (1H × (1/2), d, J = 15 Hz), 5.43 (1H × (1 / 2), dd, J = 15, 2 Hz), 5.44 (1H × (1/2), d, J = 15 Hz), 5.86 (1H, dd, J = 16, 4 Hz), 6.59 (1H, dd, J = 16, 11 Hz), 6.74 (1H, d, J = 16 Hz), 6.80 (1H × (1/2), q, J = 4 Hz), 6.81 (1H × (1/2), q, J = 4 Hz), 6.84-6.96 (2H, m), 6.93 (1H, dd, = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.33-7.43 (1H, m), 7.40 (1H, d, J = 8 Hz), 7.5 7 (1H × (1/2), s), 7.83 (1H × (1/2), s), 8.00 (1H × (1/2), s), 8.10 (1H × (1/2), s ), 8.31 (1H × (1/2), s);
MS (FAB) m / z: 731 ((M + 1) ⁺ ).
Example 7 1- [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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] Propoxy] carbonyloxy] ethoxy] -4-oxobutyryl] -4-piperidinecarboxylic acid (Exemplary Compound 1-106)
(7a) Allyl = 1- (tert-butoxycarbonyl) -4-piperidinecarboxylate 1- (tert-butoxycarbonyl) -4-piperidinecarboxylic acid (Bioorg. Med. Chem. Lett., 10, 79 (2000) 6.92 g, 30.18 mmol) was dissolved in N, N-dimethylformamide (60 mL), into which dicyclohexylamine (6.57 g, 36.22 mmol) and allyl iodide (6.08 g, 36.22 mmol) was added and the mixture was stirred at 90 ° C. for 1 hour under a nitrogen atmosphere.

  Water (100 mL) was added at room temperature, the precipitated solid was filtered through Celite, and the solid was washed with ethyl acetate (100 mL). The mixture of mother liquor and washing solution was partitioned into water-ethyl acetate, and the obtained organic layers were combined and washed with water (100 mL × 3) and then with saturated brine (100 mL × 1), and then dried over anhydrous magnesium sulfate, The solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 25:75, V / V, silica gel 150 g) to give the title compound (7.42 g, yield 91%) as yellow. As an oil.

IR (CHCl ₃ ) ν _max 1730, 1685, 1427, 1367, 1165, 1127, 1039 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.46 (9H, s), 1.61 (1H, dd, J = 11, 4 Hz), 1.67 (1H, dd, J = 11, 4 Hz), 1.89 (2H , d, J = 11 Hz), 2.48 (1H, tt, J = 11, 4 Hz), 2.84 (2H, t, J = 11 Hz), 4.01-4.10 (2H, br s), 4.59 (2H, d , J = 6 Hz), 5.24 (1H, d, J = 12 Hz), 5.31 (1H, dd, J = 17, 2 Hz), 5.91 (1H, ddt, J = 17, 12, 6 Hz);
MS (FAB) m / z: 270 ((M + H) ⁺ ).
(7b) Hydrochloride of allyl = 4-piperidinecarboxylate Allyl = 1- (tert-butoxycarbonyl) -4-piperidinecarboxylate (4.05 g, 15.0 mmol) prepared in (7a) of Example 7 was converted to acetic acid. It melt | dissolved in ethyl (3 mL) and hydrogen chloride (4N ethyl acetate solution; 15 mL, about 60 mmol) was added under 0 degreeC. After stirring the mixture at room temperature for 20 minutes, the solvent was distilled off under reduced pressure, and the resulting solid was washed with diethyl ether (30 mL) to give the title compound (2.25 g, yield 73%) as a colorless solid. Obtained.

Mp 125-127 ℃
IR (KBr) ν _max 2962, 2806, 1720, 1582, 1284, 1247 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.72 (1H, dd, J = 11, 4 Hz), 1.79 (1H, dd, J = 11, 4 Hz), 2.00 (2H, d, J = 11 Hz), 2.73 (1H, tt, J = 11, 4 Hz), 2.91 (2H, td, J = 12, 2 Hz), 3.23 (2H, d, J = 12 Hz), 4.58 (2H, d, J = 6 Hz), 5.23 (1H, d, J = 10 Hz), 5.30 (1H, d, J = 17 Hz), 5.93 (1H, ddt, J = 17, 10, 6 Hz);
MS (EI) m / z: 169 (M ⁺ ).
(7c) 4- [4- (Allyloxycarbonyl) piperidino] -4-oxobutyric acid Hydrochloride of allyl = piperidine-4-carboxylate prepared in (7b) of Example 7 (2.24 g, 10.89 mmol) Was dissolved in dichloromethane (25 mL), succinic anhydride (1.90 g, 10.89 mmol) and N, N-diisopropylethylamine (1.41 g, 10.89 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. .

  Water (30 mL) was added and the product was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with 2N hydrochloric acid, water and then saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound (2.87 g, yield 98%). ) Was obtained as a pale yellow oil.

IR (KBr) ν _max 1731, 1637, 1598, 1450, 1270, 1250, 1175, 1038 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.65-1.80 (2H, m), 1.99 (2H, m), 2.62 (1H, m), 2.71 (4H, m), 2.91 (1H, t, J = 12 Hz), 3.19 (1H, t, J = 12 Hz), 3.86 (1H, br d, J = 13 Hz), 4.40 (1H, d, J = 14 Hz), 4.63 (2H, d, J = 5 Hz), 5.27 (1H, d, J = 10 Hz), 5.34 (1H, d, J = 17 Hz), 5.93 (1H, ddt, J = 17, 10, 5 Hz);
MS (FAB) m / z: 270 ((M + H) ⁺ ).
(7d) Allyl = 1- [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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] Propoxy] carbonyloxy] ethoxy] -4-oxobutyryl] -4-piperidinecarboxylate 4- [4- (allyloxycarbonyl) piperidino] -4-oxobutyric acid (2.60 g, prepared in (7c) of Example 7 4.0 mmol) was dissolved in N, N-dimethylformamide (20 mL), and 18-crown-6 (2.80 g, 10.58 mmol) and cesium carbonate (1.63 g, 5.0 mmol) were added thereto. Yeah. After stirring at room temperature for 2 hours, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2] prepared in Example 1 (1a)] was prepared. -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propyl carbonate (diastereomer ratio = approximately 1: 1; 2.6 g, 4 mmol) was added and stirred at room temperature for 18 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 × 3). The obtained organic layers were combined, washed with water (30 mL × 3) and then with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound. Obtained.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 60: 40-0: 100, V / V, silica gel 75 g) to give the title compound (2.18 g, 62% yield). ) Was obtained as a colorless, amorphous solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2233, 1765, 1732, 1643, 1505, 1276, 1141, 1055 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, d, J = 7 Hz), 1.54 (3H × (1/2), d, J = 6 Hz), 1.55 (3H × (1/2 ), d, J = 6 Hz), 1.63-1.74 (1H, m), 1.91-1.98 (2H, m), 2.54-2.88 (7H, m), 3.00-3.06 (1H, m), 3.10-3.16 ( 1H, m), 3.45 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, 11 Hz), 3.49 (1H × (1/2), t , 11 Hz), 3.50 (1H × (1/2), t, J = 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, m), 4.59 (2H, br d, J = 5 Hz), 4.97 (1H, d, J = 4 Hz), 5.24 (1H, br d, J = 10 Hz), 5.31 (1H , br d, J = 17 Hz), 5.30-5.42 (2H, m), 5.85 (1H, dd, J = 16, 4 Hz), 5.90 (1H, ddt, J = 16, 11, 5 Hz), 6.58 (1H, dd, J = 16, 11 Hz), 6.73 (1H, d, J = 16 Hz), 6.74 (1H × (1/2), q, J = 5 Hz), 6.81 (1H × (1 / 2), q, J = 5 Hz), 6.83-6.93 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, d, J = 10 Hz), 7.39-7.44 ( 2H, m), 7.57 (1H, t, J = 8 Hz), 7.91 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 (1H × (1 / 2), s), 8.20 & 8.24 (1H × (1/2) in total, relative intensity = 1: 1, each s);
MS (FAB) m / z: 882 ((M + H) ⁺ ).
(7e) 1- [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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] Carbonyloxy] ethoxy] -4-oxobutyryl] -4-piperidinecarboxylic acid (titled compound)
Allyl prepared in Example 7 (7d) = 1- [3- [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-triazole -1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutyryl] -4-piperidinecarboxylate (diastereomeric ratio = approximately 1: 1; 526.1 mg, 0.60 mmol) in dichloromethane (15 mL). Dissolve and under ice cooling, tetrakis (triphenylphosphine) palladium (34.5 mg, 0.0298 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (42.1 mg, .30Mmol) was added, under a nitrogen atmosphere and stirred at room temperature for 40 minutes.

  The reaction mixture was subjected to silica gel chromatography (ethyl acetate-methanol, 100: 0-80: 20, V / V, silica gel 20 g), and the title compound (489.9 mg, 98% yield) was obtained as a pale yellow amorphous product. Obtained as a solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2934, 2230, 1765, 1644, 1615, 1504, 1275, 1141, 1055, 973 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, dd, J = 7, 2 Hz), 1.54 (3H × (1/2), d, J = 5 Hz), 1.55 (3H × (1 / 2), d, J = 5 Hz), 1.60-1.78 (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 = 11, 5 Hz), 3.15 (1H, td, J = 11, 3 Hz), 3.48 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1 / 2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz), 3.50 (1H × (1/2), 3.79-3.86 (1H, m), 3.86 (1H × (1/2), q. J = 7 Hz), 3.88 (1H × (1/2), q, J = 7 Hz), 4.18 (1H, ddd, J = 11, 5, 2 Hz) , 4.25-4.27 (2H, m), 4.98 (1H, d, J = 4 Hz), 5.38 (2H, br s), 5.85 (1H, dd, J = 15, 4 Hz), 6.58 (1H, dd, J = 15, 11 Hz), 6.73 (1H, d, J = 16 Hz), 6.74 (1H × (1/2), q, J = 5 Hz), 6.80 (1H × (1/2), q, J = 5 Hz), 6.85-6.95 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.39-7.44 (2H, m ), 7.57 (1H, t, J = 8 Hz), 7.92 (1H × (1/2), s), 7.98 (1H × (1/2), s), 8.06 & 8.07 (1H × (1/2 ) in total, relative intensity = 1: 1, each s), 8.32 (1H, s);
MS (FAB) m / z: 842 ((M + H) ⁺ ).
The title compound prepared above (diastereomeric ratio = about 1: 1; 366.8 mg, 0.436 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydrogen carbonate (34.7 mg, 0.414 mmol) in water (5 mL) solution was added and stirred at room temperature for 5 minutes.

  Tetrahydrofuran was distilled off under reduced pressure, and the insoluble material was removed by filtration through a membrane filter. The resulting aqueous solution was lyophilized, and the sodium salt (340.1 mg, 90% yield) of the title compound was obtained as a colorless, amorphous substance. Obtained as a solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2230, 1764, 1636, 1616, 1576, 1504, 1417, 1276, 1142, 1055, 973 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.33 (3H, dd, J = 7, 2 Hz), 1.45 (3H × (1/2), d, J = 5 Hz), 1.48 (3H × (1/2), d, J = 5 Hz), 1.60-1.73 (2H, m), 1.93-1.99 (1H, m), 2.52-2.60 (4H, m), 2.70-2.79 (1H, m), 2.86-2.96 (1H, m), 3.02 (1H, br t, J = 13 Hz), 3.41 (1H × (1/2), t, J = 13 Hz), 3.41 (1H × (1/2), t, J = 11 Hz), 3.44 (1H × (1/2), t, J = 11 Hz), 3.44 (1H × (1/2), t, J = 11 Hz), 3.46 (1H × (1 / 2), t, J = 11 Hz), 3.46 (1H × (1/2), t, J = 11 Hz), 3.57 (1H × (1/2), q, J = 7 Hz), 3.65- 3.75 (1H, m), 3.98 (1H × (1/2), q, J = 7 Hz), 3.96-4.08 (2H, m), 4.11 (1H, ddd, J = 11, 5, 2 Hz), 5.03 (1H × (1/2), d, J = 4 Hz), 5.04 (1H × (1/2), d, J = 4 Hz), 5.28 (1H × (1/2), d, J = 15 Hz), 5.31 (1H × (1/2), d, J = 15 Hz), 5.43 (1H × (1/2), d, J = 10 Hz), 5.46 (1H × (1/2), d, J = 10 Hz), 5.88 (1H × (1/2), dd, J = 15, 4 Hz), 5.89 (1H × (1/2), dd, J = 15, 4 Hz), 6.57 ( 1H × (1/2), dd, J = 16, 11 Hz), 6.58 (1H × (1/2), dd, J = 16, 11 Hz), 6.66 (1H × (1/2), q, J = 6 Hz), 6.68 (1H × (1/2), q, J = 6 Hz), 6.82 (1H, d, J = 16 Hz), 7.19 (1H, dd, J = 16, 11 Hz), 7.15-7.21 (1H, m), 7.30-7.36 (1 H, m), 7.41-7.48 (1H, m), 7.67 (1H, dd, J = 8, 1 Hz), 7.84 (1H, dd, J = 10, 1 Hz), 7.88 (1H, td, J = 8, 2 Hz), 8.04 (1H × (1/2), s), 8.05 (1H × (1/2), s), 8.35 & 8.36 (1H × (1/2) in total, relative intensity = 1 : 1, each s), 8.47 (1H × (1/2), s);
MS (FAB) m / z: 864 ((M + H) ⁺ ).
Example 8 2- [N- [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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) ) Methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutyryl] -N-methylamino] ethanesulfonic acid (Exemplary Compound 1-364)
(8a) Isobutyl = 2- [N- (tert-butoxycarbonyl) -N-methylamino] ethanesulfonate N-methyltaurine (4.18 g, 30 mmol) was dissolved in water (20 mL), and tetrahydroxylated to it. Butylammonium (40 weight percent aqueous solution; 21.41 g, 33 mmol) was added followed by di-tert-butyl dicarbonate (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 obtained organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude tetrabutylammonium = 2- [N- (tert-butoxycarbonyl) -N-methylamino] ethanesulfonate as a colorless oily substance.

  The crude tetrabutylammonium = 2- [N- (tert-butoxycarbonyl) -N-methylamino] ethanesulfonate prepared above was dissolved in dichloromethane (80 mL) and triphosgene (4.60 g, 15 0.5 mmol) and N, N-dimethylformamide (0.1 mL) were added, and the mixture was stirred at the same temperature for 1 hour under a nitrogen atmosphere.

  The solvent of the reaction solution was distilled off under reduced pressure to obtain crude 2- [N- (tert-butoxycarbonyl) -N-methylamino] ethanesulfonyl chloride.

  Isobutyl alcohol (3.71 g, 50 mmol) was dissolved in pyridine (50 mL), and the crude 2- [N- (tert-butoxycarbonyl) -N-methylamino] ethanesulfonyl chloride prepared above was cooled under ice cooling. The mixture was further stirred at room temperature for 1 hour.

  Under ice cooling, a phosphate buffer solution (100 mL) was added to the reaction solution, and the crude product was extracted with dichloromethane. The obtained organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 100: 20, V / V, silica gel 75 g) to give the title compound (6.33 g, 71% yield) as colorless. Obtained as an oil.

IR (CHCl ₃ ) ν _max 1688, 1479, 1394, 1368, 1168 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.99 (6H, d, J = 7 Hz), 1.47 (9H, s), 2.01 (1H, m), 2.93 (2H, s), 3.25-3.40 (2H , m), 3.67 (2H, t, J = 7 Hz), 4.00 (2H, d, J = 7 Hz);
MS (FAB) m / z: 296 ((M + H) ⁺ ).
(8b) Isobutyl = 2- (methylamino) ethanesulfonate Isobutyl = 2- [N- (tert-butoxycarbonyl) -N-methylamino] ethanesulfonate prepared in (8a) of Example 8 (3.0 g) 10.2 mmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (5 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour.

  The solvent of the reaction solution was distilled off under reduced pressure, water (20 mL) was added to the resulting oily residue, and this aqueous solution was washed with ethyl acetate. A saturated aqueous sodium hydrogen carbonate solution was added to the aqueous solution, and the product was extracted with dichloromethane (30 mL × 4). The organic layers were combined, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the crude title compound (396.0 mg, yield 20%) as a yellow oil.

IR (CHCl ₃ ) ν _max 1688, 1479, 1394, 1368, 1168 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.99 (6H, d, J = 7 Hz), 2.04 (1H, m), 2.47 (3H, s), 3.09 (2H, t, J = 6 Hz), 3.30 (2H, t, J = 6 Hz), 4.01 (2H, d, J = 6 Hz);
MS (FAB) m / z: 196 ((M + H) ⁺ ).
(8c) 4- [N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -4-oxobutyric acid Isobutyl = 2- (methylamino) ethanesulfonate prepared in (8b) of Example 8 (396 mg, 2.03 mmol) was dissolved in dichloromethane (10 mL), succinic anhydride (202.9 mg, 2.03 mmol) was added thereto, and the mixture was stirred at room temperature for 2.5 hours.

  The solvent of the reaction solution was distilled off under reduced pressure to obtain crude 4- [N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -4-oxobutyric acid (620.6 mg, quantitative yield). ) Was obtained as a yellow oil.

IR (CHCl ₃ ) ν _max 1748, 1715, 1650, 1356, 1171 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.99 (6H, d, J = 7 Hz), 1.99-2.07 (1H, m), 2.61-2.73 (4H, m), 3.14 (3H, s), 3.39 (2H, t, J = 7 Hz), 3.87 (2H, t, J = 7 Hz), 4.00 (2H, d, J = 7 Hz);
MS (FAB) m / z: 296 ((M + H) ⁺ ).
(8d) 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 = 4 -[N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -4-oxobutyrate 4- [N- [2- (isobutoxysulfonyl) ethyl prepared in (8c) of Example 8 ] -N-methylamino] -4-oxobutyric acid (620 mg, 2 mmol) was dissolved in N, N-dimethylformamide (10 mL), and 18-crown-6 (528.6 mg, 2 mmol) and cesium carbonate (2 93.2 mg, 0.9 mmol) was added. After stirring at room temperature for 30 minutes, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2] prepared in Example 1 (1a)] -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propyl = carbonate (diastereomer ratio = about 1: 1; 806.3 mg, 1.2 mmol) was added and further stirred at room temperature for 21 hours.

  Under ice cooling, a phosphate buffer solution (30 mL) was added to the reaction solution, and the product was extracted with ethyl acetate (30 mL × 3). The obtained organic layers were combined, washed with water (10 mL × 3), then saturated brine (30 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound. Obtained.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 50: 100-0: 100, V / V, silica gel 25 g) to give the title compound (396.3 mg, 35% yield). ) Was obtained as a colorless, amorphous solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 1765, 1652, 1616, 1504, 1418, 1275, 1142 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.96 (6H × (1/2), d, J = 6 Hz), 0.97 (6H × (1/2), d, J = 6 Hz), 1.36 ( 3H, dd, J = 7, 2 Hz), 1.54 (3H, dd, J = 6 Hz), 1.99-2.04 (1H, m), 2.6-2.8 (4H, m), 2.98-3.08 (1H, m) , 3.13 (3H × (1/2), s), 3.15 (3H × (1/2), s), 3.33-3.39 (2H, m), 3.45-3.53 (2H, m), 3.77 (2H, t , J = 7 Hz), 3.76-3.90 (1H, m), 3.96 (2H × (1/2), d, J = 7 Hz), 3.98 (2H × (1/2), d, J = 7 Hz ), 4.17 (1H, ddd, J = 11, 5, 2 Hz), 4.28 (1H, ddd, J = 11,5, 2 Hz), 5.97 (1H × (1/2), d, J = 4 Hz ), 4.98 (1H × (1/2), d, J = 4 Hz), 5.29-5.46 (2H, m), 5.86 (1H, dd, J = 16, 4 Hz), 6.58 (1H, dd, J = 16, 11 Hz), 6.72-6.76 (1H × (1/2), m), 6.74 (1H, d, J = 16 Hz), 6.80 (1H × (1/2), q, J = 5 Hz ), 6.84-6.93 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, tt, J = 10, 1 Hz), 7.38-7.43 (1H, m), 7.40 ( 1H, dd, J = 8, 1 Hz), 7.57 (1H, t, J = 8 Hz), 7.90 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 (1H × (1/2), s), 8.20 (1H × (1/2), s);
MS (FAB) m / z: 908 ((M + H) ⁺ ).
(8e) 2- [N- [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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl ] Propoxy] carbonyloxy] ethoxy] -4-oxobutyryl] -N-methylamino] ethanesulfonic acid (title target compound)
1-[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1, prepared in (8d) of Example 8] 3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy ] Carbonyloxy] ethyl = 4- [N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -4-oxobutyrate (diastereomer ratio = approximately 1: 1; 396 mg, 0.43 mmol) Was dissolved in acetone (10 mL), sodium iodide (643.8 mg, 4.3 mmol) was added, and the mixture was stirred at 40 ° C. for 5 hours.

The solvent of the reaction solution was distilled off under reduced pressure, and the resulting crude product was subjected to reverse phase column chromatography (methanol: water, 20: 80-60: 40) using Cosmosil 75 C ₁₈ -PREP (manufactured by Nacalai Tesque). , V / V, using 25 g of Cosmosil 75 C ₁₈ -PREP). The eluates were combined and concentrated, and then lyophilized to give the title object compound (diastereomer ratio = about 1: 1) as a sodium salt (colorless amorphous solid, 211.7 mg, yield 56%).

IR (KBr) ν _max 2230, 1764, 1641, 1504, 1418, 1275, 1258, 1207, 1142 cm ^-1 ;
¹ H NMR (DMSO, 400 MHz): δ 1.24 (3H × (1/2), dd, J = 7, 2 Hz), 1.27 (3H × (1/2), dd, J = 7, 3 Hz) , 1.45 (3H × (1/2), d, J = 5 Hz), 1.48 (3H × (1/2), d, J = 5 Hz), 2.48-2.71 (6H, m), 2.88-2.97 ( 1H, m), 2,76 (3H × (1/2), s), 2.94 (3H × (1/2), s), 3.36-3.60 (4H, m), 3.55-3.60 (1H × (1 / 2), m), 3.74-3.78 (1H × (1/2), m), 4.01-4.08 (1H, m), 4.11 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 5.04 (1H, d, J = 4 Hz), 5.25 (1H × (1/2), d, J = 15 Hz), 5.29 (1H × (1/2), d, J = 15 Hz) , 5.42 (1H × (1/2), d, J = 13 Hz), 5.46 (1H × (1/2), d, J = 13 Hz), 5.88 (1H × (1/2), dd, J = 16, 5 Hz), 5.90 (1H × (1/2), dd, J = 16, 5 Hz), 6.58-6.63 (1H × (1/2), m), 6.57 (1H × (1/2 ), dd, J = 16, 11 Hz), 6.58 (1H × (1/2), dd, J = 16, 11 Hz), 6.68 (1H × (1/2), qd, J = 5, 1 Hz ), 6.82 (1H, d, J = 16 Hz), 7.13-7.23 (1H, m), 7.18 (1H, dd, J = 16, 11 Hz), 7.29-7.37 (1H, m), 7.41-7.51 ( 1H, m), 7.67 (1H, d, J = 8 Hz), 7.84 (1H, dd, J = 10, 1 Hz), 7.88 (1H, td, J = 8, 3 Hz), 8.04 (1H × ( 1/2), s), 8.05 & 8.06 (1H × (1/2) in total, relative intensity = 1: 1, each s), 8.34 and 8.35 (1H × (1/2) in tota l, relative intensity = 1: 1, each s), 8.48 (1H × (1/2), s);
MS (FAB) m / z: 874 ((M + H) ⁺ ).
Example 9 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 = 4- (cis-2,6-dimethyl-1-piperazinyl) -4-oxobutyrate (Exemplary Compound 1-71)
(9a) cis-1- (allyloxycarbonyl) -3,5-dimethylpiperazine cis-2,6-dimethylpiperazine (3.43 g, 30 mmol) is dissolved in water (50 mL), and carbonated therein under ice cooling. Sodium (3.18 g, 30 mmol) and allyl chloroformate (3.62 g, 30 mmol) were added, and the mixture was stirred at room temperature for 2.5 hours.

  Under ice-cooling, 2N hydrochloric acid (30 mL) was added to the reaction mixture, and the aqueous layer was washed once with ethyl acetate. Saturated aqueous sodium hydrogen carbonate solution was added to the aqueous layer, and the mixture was extracted 4 times with dichloromethane. The organic layers were combined, washed with water and then saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.23 g, yield 37%) as a colorless oil. Obtained.

IR (CHCl ₃ ) ν _max 1686, 1456, 1262, 1144, 1125 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.07 (6H, d, J = 6 Hz), 2.35-3.43 (2H, br), 2.78-2.83 (2H, m), 3.9-4.1 (2H, br) , 4.60 (2H, d, J = 6 Hz), 5.21 (1H, d, J = 10 Hz), 5.30 (1H, br d, J = 17 Hz), 5.95 (1H, ddt, J = 17, 10, 6 Hz);
MS (EI) m / z: 198 (M ⁺ ).
(9b) 4- [cis-4- (allyloxycarbonyl) -2,6-dimethyl-1-piperazinyl] -4-oxobutyric acid cis-1- (allyloxycarbonyl) prepared in (9a) of Example 9 −3,5-dimethylpiperazine (2.12 g, 10.7 mmol) was dissolved in acetonitrile (30 mL), succinic anhydride (1.07 g, 10.7 mmol) was added under ice cooling, and the mixture was stirred at 50 ° C. for 15 hours. .

  2N hydrochloric acid was added to the reaction solution at room temperature, and the product was extracted with dichloromethane. The organic layers were combined, washed with water and then saturated brine, and the solvent was evaporated under reduced pressure to give the title compound (2.54 g, yield 80%) as a pale yellow oil.

IR (liquid film) ν _max 1785, 1734, 1704, 1645, 1436, 1148 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.3-1.4 (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, 1 Hz), 5.32 (1H, dd, J = 17, 2 Hz), 5.95 (1H, ddt, J = 17, 11, 6 Hz);
MS (EI) m / z: 298 (M ⁺ ).
(9c) 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 = 4 -[Cis-4- (allyloxycarbonyl) -2,6-dimethyl-1-piperazinyl] -4-oxobutyrate 4- [cis-4- (allyloxycarbonyl) prepared in (9b) of Example 9 -2,6-dimethyl-1-piperazinyl] -4-oxobutyric acid (1.51 g, 5.1 mmol) was dissolved in N, N-dimethylformamide (20 mL), and 18-crown-6 (1.34 g) was dissolved therein. 5.1 mmo ) And cesium carbonate (785.2mg, 2.41mmol) was added. After stirring at room temperature for 1 hour, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2] prepared in Example 1 (1a)] was prepared. -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propyl carbonate (diastereomeric ratio = about 1: 1; 1.31 g, 1.91 mmol) was added and stirred at room temperature for 11 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 × 3). The obtained organic layers were combined, washed with water (30 mL × 3) and then with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound. Obtained.

  The obtained crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 60: 40-0: 100, V / V, silica gel 60 g) to give the title compound (1.09 g, yield 59%). ) Was obtained as a colorless, amorphous solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2230, 1765, 1703, 1644, 1504, 1419, 1275, 1145, 1057 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.1-1.2 (6H, m), 1.23 (3H, dd, J = 7, 2 Hz), 1.55 (3H × (1/2), d, J = 6 Hz), 1.56 (3H × (1/2), d, J = 6 Hz), 2.6-2.8 (4H, m), 2.9-3.1 (3H, m), 3.48 (1H × (1/2), t , J = 11 Hz), 3.50 (1H × (1/2), t, J = 11 Hz), 3.50 (1H × (1/2), t, J = 11 Hz, overlapped), 3.51 (1H × ( 1/2), t, J = 11 Hz), 3.80-3.85 (1H × (1/2), br), 3.89 (1H × (1/2), q, J = 7 Hz), 3.95-4.10 ( 3H, br), 4.18 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.19 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.26 -4.32 (1H, m), 4.6 (3H, br s), 4.97 (1H × (1/2), d, J = 4 Hz), 4.98 (1H × (1/2), d, J = 4 Hz ), 5.23 (1H, br d, J = 11 Hz), 5.32 (1H, br d, J = 17 Hz), 5.32 (1H × (1/2), d, J = 15 Hz, overlapped), 5.38 ( 1H, s), 5.45 (1H × (1/2), d, J = 15 Hz), 5.95 (1H × (1/2), ddt, J = 17, 11, 5 Hz), 6.59 (1H, dd , J = 15, 11 Hz), 6.74 (1H × (1/2), q, J = 6 Hz), 6.74 (1H, d, J = 16 Hz, overlapped), 6.82 (1H × (1/2) , q, J = 6 Hz), 6.85-6.96 (2H, m), 6.94 (1H, dd, J = 16, 11 Hz), 7.34 (1H, dd, J = 10, 2 Hz), 7.40 (1H, dd, J = 8, 2 Hz), 7.38-7.46 (1H, m), 7.58 (1H, t, J = 8 Hz), 7.91 (1H × (1/2), s) , 7.95 (1H × (1/2), s), 8.03 (1H × (1/2), s), 8.23 (1H × (1/2), s);
MS (FAB) m / z: 911 ((M + H) ⁺ ).
(9d) 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 = 4 -(Cis-2,6-dimethyl-1-piperazinyl) -4-oxobutyrate (title target compound)
1-[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1, prepared in (9c) of Example 9] 3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy ] Carbonyloxy] ethyl = 4- [cis-4- (allyloxycarbonyl) -2,6-dimethyl-1-piperazinyl] -4-oxobutyrate (diastereomer ratio = approximately 1: 1; 443.6 mg, 0.49 mmol) was dissolved in dichloromethane (10 mL), and under ice cooling, tetrakis (triphenylphosphine) palladium (28.1 mg, 0.024 mmol) and 5,5-dimethyl-1,3-cyclohexane were obtained. Dione (81.9 mg, 0.58 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour under a nitrogen atmosphere.

  The reaction solution was subjected to silica gel column chromatography (ethyl acetate: methanol, 100: 0-80: 20, V / V, silica gel 20 g), and the title compound (255.8 mg, yield 64%) was pale yellow and amorphous. As a solid (diastereomeric ratio = about 1: 1).

IR (KBr) ν _max 2230, 1765, 1634, 1504, 1419, 1276, 1141, 1061, 973 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.3-1.4 (6H, br), 1.36 (3H, d, J = 7 Hz), 1.54 (3H × (1/2), d, J = 5 Hz) , 1.55 (3H × (1/2), d, J = 5 Hz), 2.6-2.9 (8H, m), 3.02 (1H × (1/2), tt, J = 11, 5 Hz), 3.03 ( 1H × (1/2), tt, J = 11, 5 Hz), 3.49 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz, overlapped), 3.49 (1H × (1/2), t, J = 11 Hz, overlapped), 3.50 (1H × (1/2), t, J = 11 Hz), 3.81 (1H × (1 / 2), q, J = 7 Hz), 3.88 (1H × (1/2), q, J = 7 Hz), 3.8-4.0 (1H, br), 4.17 (1H × (1/2), ddd , J = 11, 5, 2 Hz), 4.18 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.28 (1H × (1/2), ddd, J = 11, 5 , 2 Hz), 4.30 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.4-4.5 (1H, br), 4.98 (1H, d, J = 4 Hz), 5.32 ( 1H × (1/2), dd, J = 15, 3 Hz), 5.38 (1H, s), 5.44 (1H × (1/2), d, J = 15 Hz), 5.86 (1H, dd, J = 15, 4 Hz), 6.58 (1H, dd, J = 15, 11 Hz), 6.73 (1H × (1/2), q, J = 5 Hz), 6.73 (1H, d, J = 16 Hz) , 6.82 (1H × (1/2), q, J = 5 Hz), 6.84-6.93 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.39 (1H, dd, J = 8, 1 Hz), 7.38-7.46 (1H, m), 7.57 (1H, t, J = 8 Hz), 7.91 (1H × (1/2) , s), 7.94 (1H × (1/2), s), 8.02 (1H × (1/2), s), 8.21 (1H × (1/2), s);
MS (FAB) m / z: 827 ((M + H) ⁺ ).
The title object compound prepared above (diastereomer ratio = about 1: 1; 250.0 mg, 0.30 mmol) was dissolved in dichloromethane (5 mL), and the solution was added with hydrogen chloride (4N ethyl acetate solution; (75.7 μL, 0.30 mmol) was added, and the mixture was stirred at the same temperature for 5 minutes.

  The solvent was distilled off under reduced pressure to obtain the hydrochloride of the title object compound (262.2 mg, quantitative yield) as a pale yellow amorphous solid (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 2230, 1765, 1504, 1419, 1276, 1141, 1066, 973 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 Mz): δ 1.2-1.4 (6H, m), 1.25 (3H × (1/2), dd, J = 7, 2 Hz), 1.27 (3H × (1 / 2), dd, J = 7, 2 Hz), 1.45 (3H × (1/2), d, J = 5 Hz), 1.48 (3H × (1/2), d J = 5 Hz), 2.5- 2.7 (6H, m), 2.85-2.95 (3H, m), 3.05 (1H, br d, J = 13 Hz), 3.42 (1H × (1/2), t, J = 11 Hz), 3.43 (1H × (1/2), t, J = 11 Hz), 3.44 (1H × (1/2), t, J = 11 Hz), 3.46 (1H × (1/2), t, J = 11 Hz), 3.57 (1H × (1/2), q, J = 7 Hz), 3.64 (1H × (1/2), q, J = 7 Hz), 4.03-4.08 (1H, m), 4.10-4.15 (1H , m), 5.03 (1H × (1/2), d, J = 5 Hz), 5.04 (1H × (1/2), d, J = 5 Hz), 5.22 (1H × (1/2), d, J = 15 Hz), 5.28 (1H × (1/2), d, J = 15 Hz), 5.43 (1H × (1/2), d, J = 13 Hz), 5.46 (1H × (1 / 2), d, J = 13 Hz), 5.88 (1H × (1/2), dd, J = 16, 5 Hz), 5.89 (1H × (1/2), dd, J = 16, 5 Hz ), 6.58-6.62 (1H × (1/2), m), 6.57 (1H × (1/2), dd, J = 16, 11 Hz), 6.59 (1H × (1/2), dd, J = 16, 11 Hz), 6.68 (1H × (1/2), q, J = 5 Hz), 6.82 (1H, d, J = 16 Hz), 7.12-7.20 (1H, m), 7.19 (1H, dd, J = 16, 11 Hz), 7.30-7.37 (1H, m), 7.41-7.50 (1H, m), 7.68 (1H, dd, J = 8, 1 Hz), 7.85 (1H, dd, J = 11, 1 Hz), 7.87 (1H, t, J = 8 Hz) , 8.05 (1H, s), 8.35 (1H × (1/2), s), 8.48 (1H × (1/2), s);
MS (FAB) m / z: 827 ((non-hydrochloric acid part + H) ⁺ ).
Example 10 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 = 4- (cis-3,5-dimethyl-1-piperazinyl) -4-oxobutyrate (Exemplary Compound 1-72)
(10a) cis-1- (allyloxycarbonyl) -4- (tert-butoxycarbonyl) -2,6-dimethylpiperazine cis-1- (tert-butoxycarbonyl) -3,5-dimethylpiperazine (Helv. Chim. Acta., 73, 839 (1990); 3.76 g, 17.55 mmol) are suspended in water (50 mL), and thereto are added sodium carbonate (2.20 g, 20 mmol) and chloroform under ice-cooling. Allyl acid (2.41 g, 20 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours.

  Under ice cooling, water was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layers were combined, washed with water and then with saturated brine, 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 using silica gel column chromatography (hexane: ethyl acetate, 1: 5-1: 2, V / V, silica gel 75 g) to give the title compound (4.74 g, yield 91). %) As a colorless oil.

IR (CHCl ₃ ) ν _max 1686, 1430, 1408, 1150, 1112 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.24 (6H, d, J = 7 Hz), 1.58 (9H, s), 2.90-3.08 (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, 2 Hz), 5.21 (1H, dd, J = 11, 2 Hz), 5.30 (1H, dd , J = 17, 2 Hz), 5.94 (1H, ddt, J = 17, 11, 5 Hz);
MS (FAB) m / z: 299 ((M + H) ⁺ ).
(10b) cis-1- (allyloxycarbonyl) -2,6-dimethylpiperazine cis-1- (allyloxycarbonyl) -4- (tert-butoxycarbonyl) -2 produced in (10a) of Example 10 6-Dimethylpiperazine (4.72 g, 15.8 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (15 mL) was added thereto under ice cooling, and the mixture was stirred at room temperature for 30 minutes.

  The solvent was distilled off under reduced pressure, toluene was added to the obtained oily residue, and the solvent was distilled off under reduced pressure to remove volatile components as azeotropically as possible (three times). A sodium bicarbonate aqueous solution was added to the residue under ice cooling. The product was extracted with dichloromethane, and the resulting organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.04 g, yield 97%). Was obtained as a colorless oil.

IR (CHCl ₃ ) ν _max 1684, 1409, 1316, 1106 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.29 (6H, d, J = 7 Hz), 2.81 (2H, d, J = 12 Hz), 2.87 (2H, dd, J = 12, 4 Hz), 4.11 (2H, qd, J = 7, 4 Hz), 4.61 (2H, d, J = 5 Hz), 5.20 (1H, d, J = 11 Hz), 5.30 (1H, d, J = 17 Hz), 5.95 (1H, ddt, J = 17, 11, 5 Hz);
MS (FAB) m / z: 199 ((M + H) ⁺ ).
(10c) 4- [cis-4- (allyloxycarbonyl) -3,5-dimethyl-1-piperazinyl] -4-oxobutyric acid cis-1- (allyloxycarbonyl) obtained in (10b) of Example 10 ) -2,6-dimethylpiperazine (3.02 g, 15.23 mmol) was dissolved in dichloromethane (30 mL), succinic anhydride (1.45 g, 14.47 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. did. The solvent was distilled off under reduced pressure to obtain the title compound (4.53 g, quantitative yield) as a colorless amorphous solid.

IR (CHCl ₃ ) ν _max 1692, 1649, 1408, 1336, 1309, 1103, 1093 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.21 (3H, d, J = 7 Hz), 1.30 (3H, d, J = 7 Hz), 2.65-2.81 (4H, m), 2.85 (1H, dd , J = 13, 5 Hz), 3.34 (1H, dd, J = 13, 5 Hz), 3.68 (1H, d, J = 13 Hz), 4.28-4.34 (2H, m), 4.44 (1H, d, J = 13 Hz), 4.63 (2H, d, J = 15 Hz), 5.23 (1H, dd, J = 10, 1 Hz), 5.31 (1H, dd, J = 17, 2 Hz), 5.94 (1H, ddt, J = 17, 10, 5 Hz);
MS (FAB) m / z: 299 ((M + H) ⁺ ).
(10d) 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 = 4 -[Cis-4- (allyloxycarbonyl) -3,5-dimethyl-1-piperazinyl] -4-oxobutyrate 4- [cis-4- (allyloxycarbonyl) prepared in (10c) of Example 10 −3,5-dimethyl-1-piperazinyl] -4-oxobutyric acid (1.28 g, 4.3 mmol) was dissolved in N, N-dimethylformamide (15 mL), and 18-crown-6 (1.13 g) was dissolved therein. 4.3 mmol) and cesium carbonate (628.8 mg, 1.93 mmol) were added. After stirring at 40 ° C. for 1 hour, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-) prepared in (1a) of Example 1 was used. 2-Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole -1-yl) methyl] propyl carbonate (diastereomer ratio = about 1: 1; 1.11 g, 1.72 mmol) was added and stirred at room temperature for 11 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 × 3). The obtained organic layers were combined, washed with water (30 mL × 3) and then with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound. Obtained.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 60: 40-20: 80, V / V, silica gel 25 g) to give the title compound (907.3 mg, yield 65%). ) Was obtained as a colorless, amorphous solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2230, 1765, 1695, 1651, 1504, 1275, 1061 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.17-1.21 (3H, m), 1.28-1.31 (3H, m), 1.36 (3H, dd, J = 7, 2 Hz), 1.54 (3H × (1 / 2), d, J = 6 Hz), 1.56 (3H × (1/2), d, J = 6 Hz), 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 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz ), 3.50 (1H × (1/2), t, J = 11 Hz), 3.68 (1H × (1/2), d, J = 14 Hz), 3.72-3.78 (1H × (1/2), m), 3.78-3.85 (1H × (1/2), m), 3.88 (1H × (1/2), q, J = 7 Hz), 4.17 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.18 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.25-4.31 (3H, m), 4.40 (1H, d, J = 13 Hz) , 4.62 (2H, br d, J = 6 Hz), 4.97 (1H × (1/2), d, J = 4 Hz), 4.98 (1H × (1/2), d, J = 4 Hz), 5.22 (1H, br d, J = 10 Hz), 5.30 (1H, br d, J = 17 Hz), 5.29-5.33 (1H × (1/2), m), 5.37 (1H, s), 5.43 ( 1H × (1/2), d, J = 15 Hz), 5.85 (1H, dd, J = 16, 4 Hz), 5.94 (1H, ddt, J = 17, 10, 5 Hz), 6.58 (1H, dd, J = 16, 11 Hz), 6.73 (1H, d, J = 16 Hz), 6.72-6.75 (1H × (1/2), m), 6.82 (1H × (1/2), q, J = 5 Hz), 6.85-6.94 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 8, 1 Hz), 7.40 (1H, dd, J = 8, 1 Hz), 7.43 (1H, td, J = 9, 6 Hz), 7.57 (1H, t, J = 8 Hz), 7.90 (1H, s), 7.94 (1H × (1/2) , s), 8.20 (1H × (1/2), s);
MS (FAB) m / z: 911 ((M + H) ⁺ ).
(10e) 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 = 4 -(Cis-3,5-dimethyl-1-piperazinyl) -4-oxobutyrate (title target compound)
1-[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1, prepared in (10d) of Example 10]. 3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy ] Carbonyloxy] ethyl = 4- [cis-4- (allyloxycarbonyl) -3,5-dimethyl-1-piperazinyl] -4-oxobutyrate (diastereomer ratio = approximately 1: 1; 0.88 g, 1.15 mmol) was dissolved in dichloromethane (20 mL), and under ice cooling, tetrakis (triphenylphosphine) palladium (66.4 mg, 0.058 mmol) and 5,5-dimethyl-1,3-cyclohexa Dione (129.3mg, 0.922mmol) was added, under a nitrogen atmosphere and stirred 45 minutes at 0 ° C..

  The reaction solution was subjected to silica gel column chromatography (ethyl acetate: methanol, 100: 0-80: 20, V / V, silica gel 15 g), and the title compound (761.9 mg, yield 95%) was pale brown and amorphous. As a solid (diastereomeric ratio = about 1: 1).

IR (KBr) ν _max 2230, 1765, 1644, 1504, 1275, 1142, 1067, 973 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.04-1.07 (3H, m). 1.09 (3H, d, J = 6 Hz), 1.36 (3H, d, J = 7 Hz), 1.54 (3H × ( 1/2), d, J = 6 Hz), 1.55 (3H × (1/2), d, J = 6 Hz), 2.6-2.8 (6H, m), 3.03 (1H × (1/2), tt, J = 11, 5 Hz), 3.03 (1H × (1/2), tt, J = 11, 5 Hz, overlapped), 3.47 (1H × (1/2), t, J = 11 Hz), 3.48 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz), 3.50 (1H × (1/2), t, J = 11 Hz), 3.67 (1H × (1/2), br d, J = 13 Hz), 3.74 (1H × (1/2), br d, J = 13 Hz), 3.82 (1H × (1/2 ), q-like, J = ca.7 Hz), 3.88 (1H × (1/2), q, J = 7 Hz), 4.16 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.18 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.28 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.30 ( 1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.45 (1H, br d, J = 13 Hz), 4.97 (1H, br s), 5.32 (1H × (1/2) , dd, J = 15, 3 Hz), 5.37 (1H, s), 5.44 (1H × (1/2), d, J = 15 Hz), 5.85 (1H, dd, J = 16, 4 Hz), 6.58 (1H, dd, J = 16, 11 Hz), 6.73 (1H, d, J = 16 Hz), 6.74 (1H × (1/2), q-like, J = ca.5 Hz), 6.82 ( 1H × (1/2), q-like, J = ca.5 Hz), 6.84-6.95 (1H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7 .38-7.44 (1H, m), 7.40 (1H, dd, J = 8, 1 Hz), 7.57 (1H, t, J = 8 Hz), 7.91 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 (1H × (1/2), d-like), 8.22 (1H × (1/2), s);
MS (FAB) m / z: 827 ((M + H) ⁺ ).
The title target compound prepared above (diastereomer ratio = about 1: 1; 407.0 mg, 0.49 mmol) was dissolved in dichloromethane (5 mL), and the solution was added with hydrogen chloride (4N ethyl acetate solution; 123 μL, 0.49 mmol) was added, and the mixture was stirred at the same temperature for 5 minutes.

  The solvent was distilled off under reduced pressure to obtain the hydrochloride salt of the title object compound (417.7 mg, yield 98%) as a pale yellow amorphous solid (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 1765, 1655, 1504, 1275, 1141, 1648, 973 cm ^-1 ;
¹ H NMR (DMSO ₆ , 400 MHz): δ 1.1-1.2 (6H, br), 1.25 (3H × (1/2), dd, J = 7, 2 Hz), 1,27 (3H × (1 / 2), dd, J = 7, 2 Hz), 1.46 (3H × (1/2), d, J = 5 Hz), 1.48 (3H × (1/2), d, J = 5 Hz), 2.3 -3.0 (8H, m), 3.0-3.1 (1H, m), 3.42 (1H × (1/2), t, J = 11 Hz), 3.44 (1H × (1/2), t, J = 11 Hz), 3.44 (1H × (1/2), t, J = 11 Hz, overlapped), 3.47 (1H × (1/2), t, J = 11 Hz), 3.58 (1H × (1/2) , q, J = 7 Hz), 3.71-3.74 (1H × (1/2), m), 3.94-3.98 (1H, m), 4.04-4.07 (1H, m), 4.10-4.13 (1H, m) , 4.37-4.40 (1H, m), 5.03 (1H × (1/2), d, J = 4 Hz), 5.04 (1H × (1/2), d, J = 4 Hz), 5.24 (1H × (1/2), d, J = 16 Hz), 5.28 (1H × (1/2), d, J = 16 Hz), 5.43 (1H × (1/2), d, J = 12 Hz), 5.46 (1H × (1/2), d, J = 12 Hz), 5.88 (1H × (1/2), dd, J = 15, 4 Hz), 5.89 (1H × (1/2), dd, J = 15, 4 Hz), 6.57 (1H × (1/2), dd, J = 15, 11 Hz), 6.58 (1H × (1/2), dd, J = 15, 11 Hz), 6.62 ( 1H × (1/2), q, J = 5 Hz), 6.68 (1H × (1/2), q, J = 5 Hz), 6.82 (1H, d, J = 16 Hz), 7.11-7.21 ( 1H, m), 7.18 (1H × (1/2), dd, J = 16, 11 Hz), 7.19 (1H × (1/2), dd, J = 16, 11 Hz), 7.30-7.37 (1H , m), 7.41-7.51 (1H, m), 7.68 (1 H, dd, J = 8, 1 Hz), 7.84 (1H, dd, J = 10, 1 Hz), 7.87 (1H, t, J = 8 Hz), 8.05 (1H × (1/2), s) , 8.06 (1H × (1/2), s), 8.35 (1H × (1/2), d-like), 8.46 & 8.47 (1H × (1/2) in total, relative intensity = 1: 1, each s);
MS (FAB) m / z: 827 ((non-hydrochloric acid part + H) ⁺ ).
Example 11 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 = 4- (4-Hydroxypiperidino) -4-oxobutyrate (Exemplary Compound 1-64)
(11a) 4- (4-Hydroxypiperidino) -4-oxobutyric acid 4-Hydroxypiperidine (3.03 g, 30 mmol) was suspended in dichloromethane (10 mL), and succinic anhydride (3.00 g, 30 mmol) was suspended therein. ) And stirred at room temperature for 3 hours.

  The solvent of the reaction solution was distilled off under reduced pressure to obtain a crude title compound (3.11 g, yield 52%) as a colorless solid.

Mp 105-112 ℃
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.52-1.62 (2H, m), 1.87-1.95 (2H, m), 2.72 (4H, s), 3.72-3.79 (2H, m), 3.95-4.08 ( 3H, m);
MS (EI) m / z: 201 (M ⁺ ).
(11b) 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 = 4 -(4-Hydroxypiperidino) -4-oxobutyrate (title target compound)
4- (4-Hydroxypiperidino) -4-oxobutyric acid (603.6 mg, 3 mmol) prepared in Example 11 (11a) was dissolved in N, N-dimethylformamide (10 mL) and 18- Crown-6 (793 mg, 3 mmol) and cesium carbonate (456 mg, 1.4 mmol) were added. After stirring at room temperature for 1 hour, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2) prepared in (1a) of Example 1 was used. -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propyl carbonate (diastereomer ratio = approximately 1: 1; 778 mg, 1.2 mmol) was added and stirred at room temperature for 7 hours.

  Under ice cooling, water was added to the reaction solution, and the product was extracted three times with ethyl acetate. The obtained organic layers were combined, washed with water (20 mL × 3), then saturated brine (30 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound. Obtained.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 25: 75-0: 100, V / V, silica gel 25 g) to give the title object compound (619 mg, 60% yield). Was obtained as a colorless, amorphous solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2230, 1765, 1641, 1504, 1275, 1141, 1068, 973 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, dd, J = 7, 2 Hz), 1.4-1.6 (2H, m), 1.54 (3H × (1/2), dd, J = 6 , 3 Hz), 1.56 (3H × (1/2), d, J = 6 Hz), 1.82-1.98 (2H, m), 2.6-2.8 (4H, m), 3.0-3.08 (1H, m), 3.12-3.24 (2H, m), 3.48 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz), 3.49 (1H, t , J = 11 Hz, overlapped), 3.51 (1H × (1/2), t, J = 11 Hz), 3.72-3.75 (1H × (1/2), m), 3.76-3.85 (1H, m) , 3.88 (1H × (1/2), q, J = 7 Hz), 3.89-3.94 (1H, m), 4.03-4.12 (1H, m), 4.15 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.18 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.25-4.30 (1H × (1/2), m), 4.30 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.97 (1H × (1/2), d, J = 4 Hz), 4.98 (1H × (1/2), d, J = 4 Hz), 5.32 (1H × (1/2), br d, J = 15 Hz), 5.38 (1H, s), 5.46 (1H × (1/2), ddd, J = 15, 6 Hz), 5.85 (1H, dd, J = 15, 4 Hz), 6.58 (1H, dd, J = 15, 11 Hz), 6.73 (1H × (1/2), q, J = 6 Hz), 6.74 (1H, d, J = 16 Hz), 6.80 (1H × (1/2), q, J = 6 Hz), 6.84-6.95 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.40 (1H, dd, J = 8, 1 Hz), 7.37-7.45 (1H, m), 7.57 (1H, t, J = 8 Hz ), 7.90 (1H × (1/2), s), 7.95 & 7.96 (1H × (1/2) in total, relative intensity = 1: 1, each s), 8.02 & 8.03 (1H × (1/2 ) in total, relative intensity = 1: 1, each s), 8.21 & 8.04 (1H × (1/2) in total, relative intensity = 1: 1, each s);
MS (FAB) m / z: 814 ((M + H) ⁺ ).
Example 12 1- [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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] Propoxy] carbonyloxy] ethoxy] -4-oxobutyryl] -4-piperidyl = dihydrogen = phosphate (Exemplary Compound 1-109)
(12a) diallyl = 1- [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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] Propoxy] carbonyloxy] ethoxy] -4-oxobutyryl] -4-piperidyl phosphate 1-[[(1R, 2R) -2-[[trans-2-[(1E, prepared in Example 11)] 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-1-y ) Methyl] propoxy] carbonyloxy] ethyl = 4- (4-hydroxypiperidino) -4-oxobutyrate (diastereomeric ratio = approximately 1: 1; 615 mg, 0.76 mmol) is dissolved in dichloromethane and ice Under cooling, tetrazole (133.1 mg, 1.9 mmol), bis (allyloxy) (diisopropylamino) phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 278.1 mg, 1.13 mmol) were added. And stirred at room temperature for 1 hour.

  Tert-butyl hydroperoxide (0.3 mL) was added to the reaction solution, and the mixture was further stirred for 20 minutes, and then an aqueous sodium hydrogen carbonate solution, an aqueous sodium thiosulfate solution, and dichloromethane were added, and the mixture was partitioned between water and the organic layer. The organic layers were combined, washed with saturated brine, and then washed with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (methanol: ethyl acetate, 0: 100-5: 95, V / V, silica gel 30 g) to give the title compound (590 mg, yield 80%). And was obtained as a colorless amorphous solid (diastereomeric ratio = about 1: 1).

IR (KBr) ν _max 2230, 1765, 1647, 1504, 1275, 1142, 1054, 1018 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, d, J = 7 Hz), 1.54 (3H × (1/2), d, J = 6 Hz), 1.55 (3H × (1/2 ), d, J = 6 Hz), 1.7-2.0 (4H, m), 2.59-2.77 (4H, m), 3.03 (1H × (1/2), tt, J = 11, 5 Hz), 3.03 ( 1H × (1/2), tt, J = 11, 5 Hz), 3.48 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz, overlapped), 3.50 (1H × (1/2), t, J = 11 Hz), 3.34-3.59 (2H, m) , 3.62-3.77 (2H, m), 3.77-3.85 (1H × (1/2), m), 3.86 (1H × (1/2), q, J = 6 Hz), 4.15-4.20 (1H, m ), 4.25-4.32 (1H, m), 4.54 (4H, t, J = 6 Hz), 4.61-4.67 (1H, m), 4.97 (1H × (1/2), d, J = 4 Hz), 4.98 (1H × (1/2), d, J = 4 Hz), 5.27-5.50 (2H, m), 5.26 (2H, d, J = 10 Hz), 5.37 (2H, d, J = 17 Hz) , 5.85 (1H, dd, J = 15, 4 Hz), 5.94 (2H, ddt, J = 17, 11, 6 Hz), 6.58 (1H, dd, J = 16, 11 Hz), 6.74 (1H × ( 1/2), q, J = 5 Hz), 6.74 (1H, d, J = 16 Hz), 6.81 (1H × (1/2), q, J = 5 Hz), 6.85-6.95 (2H, m ), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.40 (1H, dd, J = 10, 1 Hz), 7.43 (1H, td, J = 9, 6 Hz), 7.57 (1H, t, J = 8 Hz), 7.90 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 (1H × (1/2), s), 8.22 & 8.24 (1H × (1/2) in total, relative intensity = 1: 1, each s);
MS (FAB) m / z: 973 ((M + H) ⁺ ).
(12b) 1- [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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] Carbonyloxy] ethoxy] -4-oxobutyryl] -4-piperidyl = dihydrogen = phosphate (titled compound)
Diallyl prepared in Example 12 (12a) = 1- [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-difluorophenyl) -1-[(1H-1,2,4-triazole -1-yl) methyl] propoxy] carbonyloxy] ethoxy] -4-oxobutyryl] -4-piperidyl phosphate (diastereomer ratio = approximately 1: 1; 576.7 mg, 0.59 mmol) in dichloromethane (10 mL). Dissolve and add bis (triphenylphosphine) dichloropalladium (20.8 mg, 0.03 mmol) and tributyltin hydride (343.5 mg, 1.19 mmol) at room temperature. And the mixture was stirred for 1 hour.

  The reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned between aqueous sodium bicarbonate and hexane. The obtained aqueous layers were combined, and the solvent was distilled off under reduced pressure to obtain a crude title compound.

The obtained crude title compound was subjected to reverse phase column chromatography (acetonitrile: water, 20: 80-30: 70, V / V, Cosmosil 75 C _18- using Cosmosil 75 C ₁₈ -PREP (manufactured by Nacalai Tesque). Purified using 25 g of PREP). The eluates were combined and concentrated and then lyophilized to obtain the title compound (diastereomer ratio = about 1: 1) as a sodium salt (colorless amorphous solid, 147.5 mg, yield 26%).

IR (KBr) ν _max 2231, 1764, 1636, 1504, 1418, 1276, 1141, 977 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.32 (3H × (1/2), dd, J = 7, 2 Hz), 1.33 (3H × (1/2), dd, J = 7, 2 Hz ), 1.52 (3H × (1/2), d, J = 5 Hz), 1.53 (3H × (1/2), d, J = 5 Hz), 1.63-1.70 (1H, m), 1.73-1.80 (1H, m), 1.83-1.90 (1H, m), 1.92-1.98 (1H, m), 2.6-2.8 (4H, m), 2.98 (1H, tt, J = 11, 5 Hz), 3.35-3.45 (2H, m), 3.51 (1H, t, J = 11 Hz), 3.52 (1H, t, J = 11 Hz), 3.75-3.86 (3H, m), 4.12 (1H, ddd, J = 11, 5 , 2 Hz), 4.24-4.30 (1H, m), 4.31-4.38 (1H, m), 5.01 (1H, d, J = 4 Hz), 5.45 (2H, br s), 5.86 (1H, dd, J = 15, 4 Hz), 6.58 (1H, dd, J = 15, 11 Hz), 6.68 (1H × (1/2), q, J = 5 Hz), 6.78-7.82 (1H × (1/2) , m), 6.79 (1H, d, J = 16 Hz), 7.01-7.10 (2H, m), 7.09 (1H, dd, J = 16, 11 Hz), 7.49-7.56 (3H, m), 7.78 ( 1H, t, J = 8 Hz), 8.02 (1H × (1/2), s), 8.03 (1H × (1/2), s), 8.37 & 8.38 (1H × (1/2) in total, relative intensity = 1: 1, each s), 8.42 (1H × (1/2), s);
MS (FAB) m / z: 938 ((total disodium salt + H) ⁺ ).
Example 13 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 = 4- [4- (Aminomethyl) piperidino] -4-oxobutyrate (Exemplary Compound 1-136)
(13a) 4- (allyloxycarbonylaminomethyl) -1- (tert-butoxycarbonyl) piperidine 4- (aminomethyl) -1- (tert-butoxycarbonyl) piperidine (J. Med. Chem., 39, 487) Page (1996); 5.61 g, 26.2 mmol) suspended in water (80 mL), to which sodium carbonate (3.05 g, 28.8 mmol) and allyl chloroformate (3.47 g, 28 .8 mmol) was added and stirred at room temperature for 15 hours.

  At room temperature, ethyl acetate was added to extract the product (80 mL × 3). The obtained organic layers were combined, washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To give the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 80: 20-1: 1, V / V, silica gel 100 g) to give the title compound (5.10 g, yield 65). %) As a colorless oil.

IR (CHCl ₃ ) ν _max 1720, 1682, 1515, 1427, 1171, 1147 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.11 (2H, qd, J = 12, 4 Hz), 1.45 (9H, s), 1.6-1.7 (1H, m), 1.67 (2H, br d, J = 12 Hz), 2.68 (2H, br t, J = 12 Hz), 3.08 (2H, br t, J = 5 Hz), 4.05-4.15 (2H, br), 4.56 (2H, d, J = 5 Hz ), 4.76-4.82 (1H, br), 5.22 (1H, d, J = 10 Hz), 5.30 (1H, dd, J = 17, 1 Hz), 5.92 (1H, ddt, J = 17, 11, 5 Hz);
MS (FAB) m / z: 299 ((M + H) ⁺ ).
(13b) 4- (allyloxycarbonylaminomethyl) piperidine 4- (allyloxycarbonylaminomethyl) -1- (tert-butoxycarbonyl) piperidine (5.1 g, 17.1 mmol) prepared in (13a) of Example 13 ) Was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (10 mL) was added at 0 ° C. After stirring the mixture at room temperature for 15 minutes, the solvent was distilled off under reduced pressure, and further, toluene was added and the solvent was distilled off twice to obtain an oily residue.

  The obtained oily residue was dissolved in water, sodium hydroxide (3 g) was added, the product was extracted with dichloromethane, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give a crude product. Of the title compound (3.03 g, 89% yield) was obtained as a colorless oil.

IR (CHCl ₃ ) ν _max 1720, 1680, 1515, 1246, 1185, 1142 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.13 (2H, qd, J = 12, 4 Hz), 1.55-1.64 (3H, m), 2.58 (2H, td, J = 12, 3 Hz), 3.05 -3.10 (4H, m), 4.56 (2H, d, J = 5 Hz), 4.75-4.85 (1H, br), 5.21
(1H, dd, J = 10, 1 Hz), 5.30 (1H, dd, J = 17, 2 Hz), 5.92 (1H, ddt, J = 17, 11, 5 Hz);
MS (EI) m / z: 198 (M ⁺ ).
(13c) 4- [4- (Allyloxycarbonylaminomethyl) piperidino] -4-oxobutyric acid 4- (Allyloxycarbonylaminomethyl) piperidine (3.03 g, 15.2 mmol) prepared in (13b) of Example 13 ) Was dissolved in dichloromethane (15 mL), succinic anhydride (1.33 g, 13.2 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours.

  The solvent was distilled off under reduced pressure to obtain the crude title compound (4.30 g, yield 98%) as a colorless oil.

IR (CHCl ₃ ) ν _max 1790, 1718, 1634, 1596, 1515, 1449 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.11-1.22 (2H, m), 1.78 (2H, br t, J = 13 Hz), 1.78 (1H, m, overlapped), 2.61 (1H, br t, J = 13 Hz), 2.64-2.71 (4H, m), 3.01-3.15 (3H, m), 3.88 (1H, br d, J = 13 Hz), 4.56 (2H, d, J = 5 Hz), 4.63 (1H, br d, J = 13 Hz), 4.82-4.87 (1H, br s), 5.22 (1H, d, J = 10 Hz), 5.31 (1H, dd, J = 17, 2 Hz), 5.92 ( 1H, ddt, J = 17, 11, 5 Hz);
MS (FAB) m / z: 299 ((M + H) ⁺ ).
(13d) 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 = 4 -[4- (Allyloxycarbonylaminomethyl) piperidino] -4-oxobutyrate 4- [4- (Allyloxycarbonylaminomethyl) piperidino] -4-oxobutyric acid (1) prepared in (13c) of Example 13 .50 g, 5.0 mmol) is dissolved in N, N-dimethylformamide (20 mL) to which 18-crown-6 (1.66 g, 6.3 mmol) and cesium carbonate (0.74 g, 2.3 mmol) was added. After stirring at room temperature for 2 hours, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2] prepared in Example 1 (1a)] was prepared. -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propyl carbonate (diastereomer ratio = approximately 1: 1; 1.3 g, 1.8 mmol) was added and stirred at room temperature for 13 hours.

  Under ice cooling, a phosphate buffer was added to the reaction solution, and the product was extracted three times with ethyl acetate. The obtained organic layers were combined, washed with water (30 mL × 3) and then with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound. Obtained.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 60: 40-60: 10, V / V, silica gel 30 g) to give the title compound (1.12 g, 68% yield). ) Was obtained as a colorless, amorphous solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2230, 1765, 1720, 1643, 1504, 1275, 1257, 1141 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.10-1.20 (2H, m), 1.36 (3H, dd, J = 7, 2 Hz), 1.54 (3H × (1/2), d, J = 6 Hz), 1.55 (3H × (1/2), d, J = 6 Hz), 1.66-1.78 (3H, m), 2.49-2.75 (6H, m), 2.96-3.13 (4H, m), 3.49 ( 1H × (1/2), t, J = 11 Hz), 3.50 (1H × (1/2), t, J = 11 Hz), 3.50 (1H × (1/2), t, J = 11 Hz , overlapped), 3.52 (1H × (1/2), t, J = 11 Hz), 3.79-3.94 (2H, m), 4.13-4.19 (1H, m), 4.24-4.32 (1H, m), 4.54 (2H, br d, J = 5 Hz), 4.57-4.61 (1H, m), 4.79-4.84 (1H, m), 4.98 (1H, d, J = 4 Hz), 5.22 (1H, dd, J = 10, 2 Hz), 5.35 (1H, dd, J = 17, 2 Hz), 5.25-5.47 (2H, m), 5.85 (1H dd, J = 16, 5 Hz), 5.88-5.94 (1H, m) , 6.58 (1H × (1/2), dd, J = 16, 11 Hz), 6.58 (1H × (1/2), dd, J = 16, 11 Hz, overlapped), 6.73 (1H × (1 / 2), q, J = 5 Hz), 6.73 (1H, d, J = 16 Hz), 6.80 (1H × (1/2), q, J = 5 Hz), 6.84-6.95 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.40-7.46 (1H, m), 7.40 (1H, dd, J = 8, 1 Hz) , 7.57 (1H, t, J = 8 Hz), 7.91 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 (1H × (1/2), s ), 8.22 (1H × (1/2), s);
MS (FAB) m / z: 911 ((M + H) ⁺ ).
(13e) 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 = 4 -[4- (Aminomethyl) piperidino] -4-oxobutyrate (title target compound)
1-[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1, prepared in (13d) of Example 13]. 3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy ] Carbonyloxy] ethyl = 4- [4- (allyloxycarbonylaminomethyl) piperidino] -4-oxobutyrate (diastereomeric ratio = approximately 1: 1; 1.10 g, 1.21 mmol) in dichloromethane (15 mL) In an ice bath, tetrakis (triphenylphosphine) palladium (69.8 mg, 0.06 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (118.7 m) were dissolved. , 0.85 mmol) was added, under a nitrogen atmosphere and stirred at room temperature for 40 minutes.

  The reaction mixture was subjected to silica gel chromatography (ethyl acetate-methanol, 100: 0-40: 60, V / V, silica gel 30 g) to give the title object compound (777.2 mg, yield 78%) as a pale yellow amorphous product. As a solid (diastereomeric ratio = about 1: 1).

IR (KBr) ν _max 2230, 1765, 1641, 1617, 1503, 1275, 1141 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.08-1.20 (3H, m), 1.36 (3H, d, J = 7 Hz), 1.53 (3H × (1/2), d, J = 5 Hz) , 1.55 (3H × (1/2), d, J = 5 Hz), 1.67-1.82 (2H, m), 2.49-3.07 (7H, m), 3.48 (1H × (1/2), t, J = 7 Hz), 3.49 (1H × (1/2), t, J = 7 Hz), 3.49 (1H × (1/2), t, J = 7 Hz, overlapped), 3.50 (1H × (1 / 2), t, J = 11 Hz), 3.80-3.92 (2H, m), 4.15-4.20 (1H, m), 4.28 (1H × (1/2), ddd, J = 11, 5, 2Hz), 4.30 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.25-4.33 (1H, m), 4.59 (1H, br d, J = 13 Hz), 4.98 (1H, d, J = 4 Hz), 5.32 (1H × (1/2), d, J = 15 Hz), 5.38 (1H, s), 5.44 (1H × (1/2), dd, J = 15, 4 Hz) , 5.86 (1H, dd, J = 16, 4 Hz), 6.58 (1H, dd, J = 16, 11 Hz), 6.72-6.77 (1H × (1/2), m), 6.73 (1H, d, J = 16 Hz), 6.81 (1H × (1/2), q, J = 4 Hz). 6.82-6.94 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.40 (1H , dd, J = 7, 1 Hz), 7.41-7.52 (2H, m), 7.57 (1H, t, J = 8 Hz), 7.91 (1H × (1/2), s), 7.95 (1H × ( 1/2), s), 8.02 (1H × (1/2), s), 8.21 & 8.24 (1H × (1/2) in total, relative intensity = 1: 1, each s);
MS (FAB) m / z 827 (M + 1) ⁺ .
Example 14 [[(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] methyl = 4 -(4-Methyl-1-piperazinyl) -4-oxobutyrate (Exemplary Compound 1-449)
(14a) Chloromethyl = (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 carbonate carbonate potassium hydride (30% Mineral oil dispersion (0.50 g, 3.8 mmol) was suspended in tetrahydrofuran (18 mL), and under ice cooling, 4-[(1E, 3E) -4- [trans-5-[[(1R, 2R)- 2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl ] -1,3-butadienyl 3-fluorobenzonitrile (European Patent Publication No. EP1083175A2 (published: according to 2001); 1.09 g, 2.0 mmol) was added and stirred for 1 hour at 0 ° C.. At the same temperature, chloromethyl chloroformate (387 mg, 3.0 mmol) was added to the mixture, and the mixture was further stirred for 15 minutes.

  Under ice-cooling, phosphate buffer (10 mL) was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 90: 10-40: 60, V / V, silica gel 10 g) to give the title compound (1.11 g, yield 87). %) As a colorless, amorphous solid.

IR (CHCl ₃ ) ν _max 2233, 1769, 1732, 1617, 1504, 1277, 1257, 1140 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.37 (3H, dd, J = 7, 2 Hz), 3.04 (1H, tt, J = 11, 5 Hz), 3.49 (1H, t, J = 11 Hz ), 3.51 (1H, t, J = 11 Hz), 3.92 (1H, q, J = 7 Hz), 4.18 (1H, ddd, J = 11, 5, 2 Hz), 4.29 (1H, ddd, J = 11, 5, 2 Hz), 4.98 (1H, d, J = 4 Hz), 5.36 (1H, dd, J = 15, 2 Hz), 5.42 (1H, d, J = 15 Hz), 5.69 (1H, d, J = 6 Hz), 5.76 (1H, d, J = 6 Hz), 5.86 (1H, dd, J = 15, 4 Hz), 6.59 (1H, dd, J = 15, 11 Hz), 6.74 ( 1H, d, J = 16 Hz), 6.87-6.97 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 2 Hz), 7.40 (1H , dd, J = 8, 2 Hz), 7.43 (1H, td, J = 8, 6 Hz), 7.57 (1H, t, J = 8 Hz), 7.96 (1H, s), 8.00 (1H, s) ;
MS (FAB) m / z: 635 ((M + H) ⁺ ).
(14b) [[(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] methyl = 4- ( 4-methyl-1-piperazinyl) -4-oxobutyrate (title target compound)
4- (4-Methyl-1-piperazinyl) -4-oxobutyric acid (described in Bioorg. Med. Chem., 8, 2693 (2000); 600.7 mg, 3 mmol) was converted to N, N-dimethylformamide ( 10 mL), cesium carbonate (456.1 mg, 1.4 mmol) and 18-crown-6 (793.0 mg, 3 mmol) were added, and the mixture was stirred at room temperature for 1 hour. To the mixture was prepared chloromethyl (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1] prepared in Example 14 (14a). , 3-Butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] Propyl carbonate (952.5 mg, 1.5 mmol) was added and further stirred at room temperature for 2.5 hours.

  Under ice cooling, phosphate buffer (20 mL) was added, and the product was extracted with ethyl acetate (30 mL × 3). The obtained organic layers were combined, washed with water (20 mL × 3) and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (ethyl acetate: methanol, 100: 0-90: 10, V / V, silica gel 20 g) to give the title compound (1009.7 mg, yield). 84%) as a colorless amorphous solid.

IR (KBr) ν _max 2230, 1767, 1645, 1504, 1258, 1142 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.37 (3H, dd, J = 7, 2 Hz), 2.30 (3H, s), 2.36 (2H, t, J = 5 Hz), 2.41 (2H, t , J = 5 Hz), 2.68 (1H, t, J = 7 Hz), 2.70 (1H, t, J = 7 Hz), 2.79 (1H, t, J = 7 Hz), 2.80 (1H, t, J = 7 Hz), 3.03 (1H, tt, J = 11, 5 Hz), 3.47-3.53 (2H, br), 3.49 (1H, t, J = 11 Hz), 3.50 (1H, t, J = 11 Hz ), 3.62 (2H, br t, J = 5 Hz), 3.90 (1H, q, J = 7 Hz), 4.17 (1H, ddd, J = 11, 5, 2 Hz), 4.27 (1H, ddd, J = 11, 5, 2 Hz), 4.98 (1H, d, J = 4 Hz), 5.35 (1H, dd, J = 15, 3 Hz), 5.42 (1H, d, J = 15 Hz), 5,74 (1H, d, J = 6 Hz), 5.84 (1H, d, J = 4 Hz), 5.86 (1H, dd, J = 11, 4 Hz), 6.59 (1H, dd, J = 16, 11 Hz) , 6.74 (1H, d, J = 16 Hz), 6.85-6.96 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.40 (1H, dd, J = 8, 1 Hz), 7.44 (1H, td, J = 9, 6 Hz), 7.57 (1H, t, J = 8 Hz), 7.93 (1H, s), 8.04 (1H , s);
MS (FAB) m / z: 799 ((M + H) ⁺ ).
[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3 prepared above] -Dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] methyl = 4- (4-Methyl-1-piperazinyl) -4-oxobutyrate (300.1 mg, 0.375 mmol) was dissolved in dichloromethane (5 mL), and thereto was added hydrogen chloride (4N ethyl acetate solution; 5 μL, 0.374 mmol) was added, and the mixture was stirred at the same temperature for 5 minutes.

  The solvent was distilled off under reduced pressure to obtain the monohydrochloride salt of the title object compound (311 mg, yield 99%) as a pale yellow amorphous solid.

IR (KBr) ν _max 2230, 1767, 1653, 1504, 1418, 1142, 1976 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.26 (3H, d, J = 7, 2 Hz), 2.5-2.7 (9H, m), 2.8-3.1 (4H, br), 2.92 (1H, tt, J = 11, 5 Hz), 3.43 (1H, t, J = 11 Hz), 3.43 (1H, t, J = 11 Hz), 3.5-3.7 (2H, br), 3.63 (1H, q, J = 7 Hz), 4.03-4.10 (2H, m), 5.03 (1H, d, J = 5 Hz), 5.28 (1H, d, J = 15 Hz), 5.47 (1H, d, J = 15 Hz), 5.71 ( 1H, d, J = 7 Hz), 5.73 (1H, d, J = 7 Hz), 5.88 (1H, dd, J = 16, 11 Hz), 6.57 (1H, dd, J = 16, 11 Hz), 6.82 (1H, d, J = 16 Hz), 7.15-7.22 (1H, m), 7.19 (1H, dd, J = 16, 11 Hz), 7.32-7.38 (1H, m), 7.49 (1H, td, J = 9, 6 Hz), 7.68 (1H, dd, J = 8, 1 Hz), 7.85 (1H, dd, J = 11, 1 Hz), 7.87 (1H, t, J = 8 Hz), 8.06 ( 1H, s), 8.44 (1H, s);
MS (FAB) m / z: 799 ((non-hydrochloric acid part + H) ⁺ ).
Example 15 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 = (4-Methyl-1-piperazinyl) acetate (Exemplary Compound 1-9)
(4-Methyl-1-piperazinyl) acetic acid (described in J. Med. Chem., 43, 1489 (2000); 2.5 g, 15.8 mmol) was dissolved in water (30 mL) and stirred at 0 ° C. . Cesium carbonate (2.57 g, 7.9 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. Water was distilled off under reduced pressure to obtain crude cesium = (4-methyl-1-piperazinyl) acetate (4.49 g, yield 98%) as a pale yellow solid.

  Cesium = (4-methyl-1-piperazinyl) acetate (670 mg, 2.3 mmol) prepared above was dissolved in N, N-dimethylformamide (5 mL), to which 1 prepared in Example 1 (1a) was dissolved. -Chloroethyl = (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 carbonate (diastereomeric ratio = about 1: 1; 500 mg, 0.77 mmol) in N, N-dimethylformamide (3 mL) and 18-crown-6 (611 mg, 2.3 mmol) were added. After the reaction solution was stirred at room temperature for 12 hours, ethyl acetate (150 mL) and brine (50 mL) were added under ice cooling. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 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 recycled by preparative HPLC [LC-908; manufactured by Nihon Analytical Industry; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) in series. Used in connection; solvent, chloroform] to give the title object compound (161 mg, yield 28%) as a pale-yellow oil (diastereomer ratio = about 1: 1).

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.34 (3H × (1/2), d, J = 7 Hz), 1.36 (3H × (1/2), d, J = 7 Hz), 1.55 ( 3H × (1/2), d, J = 5 Hz), 1.57 (3H × (1/2), d, J = 6 Hz), 2.29 (3H, s), 2.48 (4H, br s), 2.61 (4H, br s), 2.99-3.19 (1H, m), 3.26 (1H, s), 3.30 (1H × (1/2), s), 3.34 (1H × (1/2), s), 3.48 (1H, t, J = 13 Hz), 3.50 (1H, t, J = 12 Hz), 3.80 (1H × (1/2), q, J = 7 Hz), 3.87 (1H × (1/2) , q, J = 8 Hz), 4.14-4.20 (1H, m), 4.25-4.28 (1H, m), 4.96 (1H × (1/2), d, J = 4 Hz), 4.97 (1H × ( 1/2), d, J = 4 Hz), 5.31-5.42 (2H, m), 5.85 (1H, dd, J = 15, 4 Hz), 6.54-6.62 (1H, m), 6.68-6.81 (2H , m), 6.85-7.06 (3H, m), 7.33 (1H, dd, J = 10, 2 Hz), 7.38-7.47 (2H, m), 7.57 (1H, t, J = 8 Hz), 7.93 ( 1H × (1/2), s), 7.94 (1H × (1/2), s), 7.99 (1H × (1/2), s), 8.05 (1H × (1/2), s);
MS (FAB) m / z: 771 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₃₇ H ₄₂ F ₃ N ₆ O ₇ S ((M + H) ⁺ ): 771.2788. Found: 771.2761.
A solution of the title compound prepared above (diastereomer ratio = approximately 1: 1; 148 mg, 0.20 mmol) in ethyl acetate (4 mL) was cooled to 0 ° C. and stirred into hydrogen chloride (4 N Ethyl acetate solution; 50 μL, 0.20 mmol) was added. The oily residue obtained by evaporating the solvent under reduced pressure was dissolved in water (10 mL) at 0 ° C., the insoluble matter was filtered off through a membrane filter, and the aqueous solution obtained was lyophilized to give the title target compound. Was obtained as a pale yellow, amorphous solid (diastereomer ratio = approximately 1: 1).

¹ H NMR (DMSO-d ₆ , 500 MHz): δ 1.24 (3H × (1/2), d, J = 7 Hz), 1.26 (3H × (1/2), d, J = 7 Hz), 1.48 (3H × (1/2), d, J = 5 Hz), 1.51 (3H × (1/2), d, J = 5 Hz), 2.36-3.51 (16H, m), 3.56 (1H × ( 1/2), q, J = 7 Hz), 3.67 (1H × (1/2), q, J = 7 Hz), 4.04-4.12 (2H, m), 5.02 (1H × (1/2), d, J = 5 Hz), 5.03 (1H × (1/2), d, J = 5 Hz), 5.23 (1H × (1/2), d, J = 15 Hz), 5.27 (1H × (1 / 2), d, J = 15 Hz), 5.44 (1H × (1/2), d, J = 15 Hz), 5.47 (1H × (1/2), d, J = 15 Hz), 5.89 ( 1H, dd, J = 16, 5 Hz), 6.56 (1H, dd, J = 15, 13 Hz), 6.66 (1H × (1/2), q, J = 6 Hz), 6.72 (1H × (1 / 2), q, J = 6 Hz), 6.82 (1H, d, J = 16 Hz), 7.16-7.22 (2H, m), 7.35 (1H, t, J = 11 Hz), 7.42-7.50 (1H , m), 7.68 (1H, d, J = 8 Hz), 7.84-7.89 (2H, m), 8.06 (1H × (1/2), s), 8.34 (1H × (1/2), s) , 8.49 (1H × (1/2), s), 9.58 (1H × (1/2), s);
MS (FAB) m / z: 771 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₃₇ H ₄₂ F ₃ N ₆ O ₇ S ((M + H) ⁺ ): 771.2788. Found: 771.2797.
Example 16 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 = 4- (4-Methyl-1-piperazinyl) butyrate (Exemplary Compound 1-47)
4- (4-Methyl-1-piperazinyl) butyric acid (described in J. Med. Chem., 43, 1489 (2000); 502 mg, 2.7 mmol) dissolved in N, N-dimethylformamide (5 mL) Then, cesium carbonate (436 mg, 1.3 mmol) and 18-crown-6 (714 mg, 2.7 mmol) were added thereto. After the reaction solution was cooled to 0 ° C., 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano) produced in (1a) of Example 1] was prepared. -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 carbonate (diastereomer ratio = about 1: 1; 700 mg, 1.1 mmol) was added and stirred at room temperature for 24 hours. Under ice-cooling, ethyl acetate (150 mL) and brine (50 mL) were added to the reaction solution. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 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 recycled by preparative HPLC [LC-908; manufactured by Japan Analytical Industry; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) in series Used in connection; solvent, chloroform] to give the title object compound (233 mg, yield 27%) as a pale-yellow oil (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 3428, 2938, 2797, 2230, 1763, 1615, 1504, 1277 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H × (1/2), d, J = 7 Hz), 1.36 (3H × (1/2), d, J = 7 Hz), 1.54 ( 3H × (1/2), d, J = 5 Hz), 1.54 (3H × (1/2), d, J = 5 Hz), 1.76-1.89 (2H, m), 2.26 (3H × (1 / 2), s), 2.27 (3H × (1/2), s), 2.33-2.50 (12H, m), 2.98-3.05 (1H, m), 3.48 (1H, t, J = 11 Hz), 3.50 (1H, t, J = 11 Hz), 3.77 (1H × (1/2), q, J = 7 Hz), 3.88 (1H × (1/2), q, J = 7 Hz), 4.10-4.20 (1H, m), 4.25-4.29 (1H, m), 4.97 (1H, d, J = 5 Hz), 5.30-5.45 (2H, m), 5.85 (1H, dd, J = 15, 4 Hz), 6.58 (1H, dd, J = 15, 11 Hz), 6.66-6.80 (2H, m), 6.85-7.00 (3H, m), 7.33 (1H, dd, J = 10, 2 Hz), 7.38-7.47 ( 2H, m), 7.52-7.59 (1H, m), 7.93 (1H, s), 7.99 (1H × (1/2), s), 8.03 (1H × (1/2), s);
MS (FAB) m / z: 799 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₃₉ H ₄₅ F ₃ N ₆ O ₇ SNa ((M + Na) ⁺ ): 821.2920. Found: 821.2896.
A solution of the title compound prepared above (diastereomer ratio = about 1: 1; 230 mg, 0.29 mmol) in ethyl acetate (4 mL) was cooled to 0 ° C. and stirred into hydrogen chloride (4 N). (Ethyl acetate solution; 72 μL, 0.20 mmol) was added, and the solvent was distilled off under reduced pressure. The obtained aqueous solution was lyophilized to obtain 234 mg of hydrochloride of the title target compound as a colorless amorphous solid (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 3412, 2939, 2797, 2230, 1764, 1615, 1504, 1276 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz): δ 1.24 (3H × (1/2), d, J = 7 Hz), 1.26 (3H × (1/2), d, J = 7 Hz), 1.47 (3H × (1/2), d, J = 5 Hz), 1.48 (3H × (1/2), d, J = 5 Hz), 1.67-1.72 (2H, m), 2.32-3.51 (18H , m), 3.56 (1H × (1/2), q, J = 7 Hz), 3.70 (1H × (1/2), q, J = 7 Hz), 4.04-4.12 (2H, m), 5.02 (1H × (1/2), d, J = 4 Hz), 5.04 (1H × (1/2), d, J = 4 Hz), 5.24 (1H × (1/2), d, J = 15 Hz), 5.27 (1H × (1/2), d, J = 15 Hz), 5.43 (1H × (1/2), d, J = 14 Hz), 5.46 (1H × (1/2), d , J = 14 Hz), 5.87 (1H × (1/2), dd, J = 15, 4 Hz), 5.88 (1H × (1/2), dd, J = 15, 4 Hz), 6.54-6.64 (1H, m), 6.62 (1H × (1/2), q, J = 5 Hz), 6.70 (1H × (1/2), q, J = 5 Hz), 6.81 (1H, d, J = 17 Hz), 7.16-7.21 (2H, m), 7.31-7.34 (1H, m), 7.42-7.49 (1H, m), 7.67 (1H, d, J = 8 Hz), 7.84-7.88 (2H, m ), 8.04 (1H × (1/2), s), 8.06 (1H × (1/2), s), 8.30 (1H × (1/2), s), 8.48 (1H × (1/2) , s);
MS (FAB) m / z: 799 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₃₉ H ₄₆ F ₃ N ₆ O ₇ S ((M + H) ⁺ ): 799.3101. Found: 799.3102.
Anal.calcd for C ₃₉ H ₄₅ F ₃ N ₆ O ₇ S ・ (1/2) HCl ・ H ₂ O: C, 56.09; H, 5.73; N, 10.06; F, 6.82; Cl, 2.12; S, 3.84 Found: C, 55.79; H, 5.51; N, 9.95; F, 6.74; Cl, 2.05; S, 3.84.
Example 17 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 = 4- (4-carbamoylpiperidino) -4-oxobutyrate (Exemplary Compound 1-65)
Succinic anhydride (3.0 g, 30 mmol) was dissolved in a mixed solvent of anhydrous tetrahydrofuran (50 mL) and N, N-dimethylformamide (15 mL) and stirred at room temperature. A solution of isonipecotamide (3.9 g, 30 mmol) in anhydrous tetrahydrofuran (50 mL) was added thereto, and the mixture was stirred at room temperature for 24 hours. The precipitate in the reaction solution was collected by filtration to obtain crude 4- (4-carbamoylpiperidino) -4-oxobutyric acid (6.4 g, yield 94%) as a colorless solid.

  The obtained 4- (4-carbamoylpiperidino) -4-oxobutyric acid (972 mg, 2.3 mmol) was dissolved in N, N-dimethylformamide (20 mL), into which cesium carbonate (565 mg, 1.7 mmol) was dissolved. And 18-crown-6 (918 mg, 3.5 mmol) were added. After the reaction solution was cooled to 0 ° C., 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano) produced in (1a) of Example 1] was prepared. -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 carbonate (diastereomer ratio = about 1: 1; 750 mg, 1.2 mmol) was added and stirred at room temperature for 3 days. Under ice-cooling, ethyl acetate (150 mL) and brine (50 mL) were added to the reaction solution. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 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 recycled by preparative HPLC [LC-908; manufactured by Nihon Analytical Industry; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) in series. Used in connection; solvent, chloroform] to give the title object compound (423 mg, yield 47%) as a colorless oil (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 3439, 3354, 2938, 2856, 2230, 1765, 1679, 1640, 1617, 1504, 1276 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H × (1/2), d, J = 6 Hz), 1.36 (3H × (1/2), d, J = 6 Hz), 1.54 ( 3H × (1/2), d, J = 5 Hz), 1.55 (3H × (1/2), d, J = 5 Hz), 1.58-1.77 (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 = 11 Hz), 3.50 (1H, t, J = 11 Hz), 3.79-4.00 (2H, m), 4.10-4.19 (1H, m), 4.22-4.29 (1H × (1/2), m), 4.46-4.60 (1H × (1/2), m), 4.98 (1H, d, J = 3 Hz), 5.26-5.48 (3H, m), 5.85 (1H, dd, J = 15, 4 Hz), 6.58 (1H, dd , J = 15, 11 Hz), 6.74 (1H, d, J = 16 Hz), 6.72-6.81 (1H, m), 6.84-7.00 (3H, m), 7.33 (1H, dd, J = 10, 2 Hz), 7.38-7.46 (2H, m), 7.57 (1H, t, J = 7 Hz), 7.90 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 (1H × (1/2), d-like), 8.20 & 8.24 (1H × (1/2) in total, relative intensity = 1: 1, each s);
MS (FAB) m / z: 841 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₄₀ H ₄₄ F ₃ N ₆ O ₉ S ((M + H) ⁺ ): 841.2843. Found: 841.2835.
Example 18 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 = (1-Methyl-4-piperidinylidene) acetate (Exemplary Compound 1-378)
(18a) tert-butyl = (1-methyl-4-piperidinylidene) acetate 1-methyl-4-piperidone (4.20 g, 37.1 mmol) and tert-butyl = diethylphosphonoacetate (10.3 g, 40. 8 mmol) was dissolved in tetrahydrofuran (150 mL), and potassium tert-butoxide (4.57 g, 40.8 mmol) was added to the solution while stirring under ice-cooling. The mixture was stirred at room temperature for 1 hour and then stirred at 35 to 45 ° C. for 1 hour to obtain a slurry mixture.

  After cooling, the resulting mixture was separated by adding ethyl acetate and water, and the resulting organic layer was separated, washed with water and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (ethyl acetate: methanol, 100: 0-80: 20, V / V, silica gel 50 g) to give the title compound (6.9 g, yield 88). %) As a colorless oil.

IR (CHCl ₃ ) ν _max 2945, 2796, 1702, 1651, 1387, 1368, 1279, 1252, 1156, 1138 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.475 (9H, s), 2.290 (3H, s), 2.317 (2H, td, J = 6, 1 Hz), 2.462 (2H, t-like, J = 6 Hz), 2.477 (2H, t-like, J = 6 Hz), 2.968 (2H, t, J = 6 Hz), 5.578 (1H, s);
MS (EI) m / z: 211 (M ⁺ ), 154, 110, 44;
HRMS (EI) m / z calcd for C ₁₂ H ₂₁ NO ₂ (M ⁺ ): 211.1573. Found: 211.1582.
(18b) Hydrochloride of (1-methyl-4-piperidinylidene) acetic acid tert-butyl = (1-methyl-4-piperidinylidene) acetate (1.0 g, 4.7 mmol) prepared in (18a) of Example 18 Hydrogen chloride (4N ethyl acetate solution; 6 mL, 24 mmol) was added to the mixture while being dissolved in ethyl acetate (6 mL) and stirring, and the mixture was stirred at room temperature for 2 hours. Subsequently, ethyl acetate (6 mL) and hydrogen chloride (4N ethyl acetate solution; 6 mL, 24 mmol) were added, and the whole was stirred at 40 to 50 ° C. for 7 hours.

  Volatile components were distilled off under reduced pressure, and the residue was sucked well with a vacuum pump. Ethyl acetate was added to the obtained solid, and volatile components were distilled off again under reduced pressure to obtain the crude title hydrochloride.

  The obtained crude hydrochloride was recrystallized from an ethyl acetate-methanol mixed solvent to obtain pure hydrochloride (730 mg, 81% yield) as colorless needle crystals.

Mp begins to sublime gradually from around 185 ° C and melts around 195 ° C;
IR (KBr) ν _max 2721, 1721, 1714, 1659, 1206, 1144 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 2.628 (2H, t, J = 6 Hz), 2.902 (3H, s), 3.2-3.4 (6H, m), 5.888 (1H, s);
MS (EI) m / z: 155 ((non-hydrochloric acid part) ⁺ );
HRMS (EI) m / z calcd for C ₈ H ₁₃ NO ₂ ((Non-hydrochloric acid part) ⁺ ): 155.0947. Found: 155.0945.
Anal.calcd for C ₈ H ₁₃ NO ₂ HCl: C, 50.14; H, 7.36; N, 7.31; Cl, 18.50. Found: C, 49.81; H, 7.48; N, 7.24; Cl, 18.73.
(18c) 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 = ( 1-methyl-4-piperidinylidene) acetate (titled compound)
The hydrochloride salt of (1-methyl-4-piperidinylidene) acetic acid prepared in Example 18 (18b) (575 mg, 3.0 mmol) was dissolved in methanol (12 mL), and cesium carbonate (977 mg, 3.0 mmol) was added. And stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and the residue was sucked well with a vacuum pump to obtain crude cesium = (1-methyl-4-piperidinylidene) acetate as a solid containing cesium chloride.

  The obtained crude cesium = (1-methyl-4-piperidinylidene) acetate (total amount), 1-chloroethyl produced in Example 1 (1a) = (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 carbonate (diastereomeric ratio = about 1: 1; 1.30 g, 2.0 mmol), and N, N-dimethylacetamide (20 mL) was stirred at room temperature for 94 hours.

  To the reaction mixture are added ethyl acetate and 10% brine, and the mixture is separated. The resulting organic layer is separated, washed 5 times with 10% brine, then once with saturated brine, and dried over anhydrous sodium sulfate. did. The solvent was distilled off under reduced pressure to obtain a crude title compound as a mixture of two diastereomers (diastereomer ratio = about 1: 1).

  The obtained mixture was subjected to silica gel column chromatography (silica gel 33 g) and eluted with a mixed solvent of ethyl acetate: methanol (94: 6-90: 10, V / V) to give a low-polar dia of the title target compound. Stereomer A (205 mg, 13% yield) was obtained as a pale yellow amorphous solid. Next, eluting with a mixed solvent of ethyl acetate: methanol (88:12, V / V), a mixture of the diastereomer A having a low polarity and the diastereomer B having a high polarity (50 mg, yield 3) %) As a pale yellow amorphous solid. Further, eluting with a mixed solvent of ethyl acetate: methanol (84: 16-80: 20, V / V), the highly polar diastereomer B (90 mg, 6% yield) of the title target compound was obtained as a pale yellow amorphous Obtained as a solid.

Spectral data for diastereomer A (low polarity):
IR (CHCl ₃ ) ν _max 2233, 1759, 1732, 1649, 1616, 1505, 1388, 1277, 1139 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.361 (3H, dd, J = 7, 2 Hz), 1.553 (3H, d, J = 5 Hz), 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 = 11 Hz), 3.892 (1H, q, J = 7 Hz), 4.180 (1H, ddd, J = 11, 5, 2 Hz), 4.285 (1H, ddd, J = 11, 5, 2 Hz), 4.968 (1H, d, J = 5 Hz), 5.37 (1H, dd, J = 16, 3 Hz), 5.40 (1H, d, J = 16 Hz), 5.644 (1H, s), 5.855 (1H, dd, J = 16, 5 Hz), 6.582 (1H, dd, J = 16, 11 Hz) , 6.74 (1H, d, J = 16 Hz), 6.753 (1H, q, J = 5 Hz), 6.8-7.0 (2H, m), 6.92 (1H, dd, J = 16, 11 Hz), 7.334 ( 1H, dd, J = 10, 1 Hz), 7.400 (1H, dd, J = 8, 1 Hz), 7.445 (1H, td, J = 8, 6 Hz), 7.569 (1H, t, J = 8 Hz ), 7.916 (1H, s), 8.018 (1H, s);
MS (FAB) m / z: 768 ((M + H) ⁺ );
HRMS (ESI +) m / z: calcd for C ₃₈ H ₄₁ F ₃ N ₅ O ₇ SSi ((M + H) ⁺ ): 768.2679. Found: 768.2675.
Spectral data of diastereomer B (high polarity):
IR (CHCl ₃ ) ν _max 2233, 1760, 1731, 1649, 1616, 1505, 1388, 1277, 1140 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.367 (3H, dd, J = 7, 2 Hz), 1.554 (3H, d, J = 5 Hz), 2.3-2.6 (6H, m), 2.9-3.1 (3H, m), 3.474 (1H, t, J = 11 Hz), 3.496 (1H, t, J = 11 Hz), 3.771 (1H, q, J = 7 Hz), 4.16 (1H, ddd, J = 11, 5, 2 Hz), 4.277 (1H, ddd, J = 11, 5, 2 Hz), 4.965 (1H, d, J = 4 Hz), 5.37 (1H, dd, J = 16, 3 Hz), 5.41 (1H, d, J = 16 Hz), 5.728 (1H, s), 5.854 (1H, dd, J = 15, 4 Hz), 6.583 (1H, dd, J = 15, 10 Hz), 6.723 (1H , d, J = 16 Hz), 6.805 (1H, q, J = 5 Hz), 6.85-7.0 (3H, m), 7.332 (1H, dd, J = 10, 2 Hz), 7.399 (1H, dd, J = 8, 2 Hz), 7.39-7.44 (1H, m), 7.567 (1H, t, J = 8 Hz), 7.940 (1H, s), 8.038 (1H, s);
MS (FAB) m / z: 768 ((M + H) ⁺ );
HRMS (ESI +) m / z: calcd for C ₃₈ H ₄₁ F ₃ N ₅ O ₇ SSi ((M + H) ⁺ ): 768.2679. Found: 768.2687.
About 1: 1 mixture of diastereomer A and diastereomer B (total amount: 345 mg, 0.445 mmol) of the title object compound was dissolved in ethyl acetate (40 mL), cooled to −40 ° C. and stirred. Hydrogen chloride (1N ethyl acetate solution; 0.6 ml, 0.6 mmol) was added dropwise. The solvent was distilled off under reduced pressure, the residue was dissolved in water (20 mL) and filtered, and the filtrate was lyophilized to give the monohydrochloride (320 mg) of the title object compound as a pale yellow solid (diastereomer ratio = About 1: 1).

Example 19 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 = 4- (4-Methyl-1-piperazinyl) -4-oxobutyrate (Exemplary Compound 1-70)
4- (4-Methyl-1-piperazinyl) -4-oxobutyric acid (described in Bioorg. Med. Chem. Lett., 8, pp. 2877 (1998); 925 mg, 4.6 mmol) in water (5 mL) After dissolution, cesium carbonate (753 mg, 2.3 mmol) was added thereto, and the resulting aqueous solution was lyophilized to obtain a cesium salt of 4- (4-methyl-1-piperazinyl) -4-oxobutyric acid. The obtained cesium salt (total amount) was dissolved in N, N-dimethylformamide (7 mL), and 1-chloroethyl = (1R, 2R) -2-[[trans- 2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluoro Phenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propyl carbonate (diastereomeric ratio = about 1: 1; 1.0 g, 1.5 mmol) and 18-crown- 6 (1.2 g, 4.6 mmol) was added. After stirring at room temperature for 15 hours, ethyl acetate (150 mL) and brine (50 mL) were added to the reaction mixture under ice cooling. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 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 recycled by preparative HPLC [LC-908; manufactured by Japan Analytical Industry; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) in series. Used in connection; solvent, chloroform] to give the title object compound (320 mg, yield 26%) as a pale-brown oil (diastereomer ratio = approximately 1: 1).

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H × (1/2), d, J = 7 Hz), 1.36 (3H × (1/2), d, J = 7 Hz), 1.54 ( 3H × (1/2), d, J = 5 Hz), 1.55 (3H × (1/2), d, J = 5 Hz), 2.29 (3H × (1/2), s), 2.30 (3H × (1/2), s), 2.33-2.41 (4H, m), 2.56-2.75 (4H, m), 3.00-3.06 (1H, m), 3.45-3.53 (4H, m), 3.60-3.64 ( 2H, m), 3.83 (1H × (1/2), q, J = 7 Hz), 3.88 (1H × (1/2), q, J = 7 Hz), 4.15-4.20 (1H, m), 4.26-4.32 (1H, m), 4.97 (1H, d, J = 3 Hz), 5.29-5.46 (2H, m), 5.85 (1H, dd, J = 15, 4 Hz), 6.58 (1H, dd, J = 15, 11 Hz), 6.73 (1H, d, J = 16 Hz), 6.73 (1H × (1/2), q, J = 5 Hz), 6.81 (1H × (1/2), q, J = 5 Hz), 6.84-6.96 (3H, m), 7.33 (1H, dd, J = 10, 2 Hz), 7.38-7.46 (2H, m), 7.57 (1H × (1/2), t, J = 8 Hz), 7.58 (1H × (1/2), t, J = 8 Hz), 7.91 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 (1H × (1/2), s), 8.23 (1H × (1/2), s);
MS (FAB) m / z: 813 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₃₉ H ₄₄ F ₃ N ₆ O ₈ S ((M + H) ⁺ ): 813.2894. Found: 813.2886.
A solution of the title compound prepared above (diastereomeric ratio = about 1: 1; 320 mg, 0.39 mmol) in ethyl acetate (10 mL) was cooled to 0 ° C. and stirred into hydrogen chloride (4 N). (Ethyl acetate solution; 98 μL, 0.39 mmol) was added, and the solvent was distilled off under reduced pressure. The obtained aqueous solution was lyophilized to obtain 319 mg of the hydrochloride salt of the title compound as a pale yellow amorphous solid (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 3437, 2938, 2230, 1765, 1651, 1616, 1504, 1276 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz): δ 1.24 (3H × (1/2), d, J = 8 Hz), 1.26 (3H × (1/2), d, J = 8 Hz), 1.46 (3H × (1/2), d, J = 6 Hz), 1.47 (3H × (1/2), d, J = 6 Hz), 2.36-3.60 (18H, m), 3.57 (1H × ( 1/2), q, J = 7 Hz), 3.73 (1H × (1/2), q, J = 7 Hz), 4.04-4.12 (2H, m), 5.03 (1H × (1/2), d, J = 5 Hz), 5.04 (1H × (1/2), d, J = 5 Hz), 5.24 (1H × (1/2), d, J = 15 Hz), 5.27 (1H × (1 / 2), d, J = 15 Hz), 5.43 (1H × (1/2), d, J = 15 Hz), 5.45 (1H × (1/2), d, J = 15 Hz), 5.88 ( 1H × (1/2), dd, J = 15, 4 Hz), 5.89 (1H × (1/2), dd, J = 15, 4 Hz), 6.54-6.63 (1H, m), 6.62 (1H × (1/2), q, J = 5 Hz), 6.68 (1H × (1/2), q, J = 5 Hz), 6.82 (1H, d, J = 15 Hz), 7.14-7.21 (2H , m), 7.31-7.36 (1H, m), 7.42-7.50 (1H, m), 7.68 (1H, d, J = 8 Hz), 7.84-7.89 (2H, m), 8.05 (1H × (1 / 2), s), 8.06 (1H × (1/2), s), 8.35 (1H × (1/2), s), 8.47 (1H × (1/2), s), 10.09 (1H, br s);
MS (FAB) m / z: 813 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₃₉ H ₄₃ F ₃ N ₆ O ₈ SNa ((M + Na) ⁺ ): 835.2713. Found: 835.2711.
Anal.calcd for C ₃₉ H ₄₃ F ₃ N ₆ O ₈ S ・ (2/3) HCl ・ (9/4) H ₂ O: C, 53.37; H, 5.53; N, 9.58; Cl, 2.69; F, 6.49; S, 3.65. Found: C, 53.15; H, 5.30; N, 9.39; Cl, 2.81; F, 6.47; S, 3.59.
Example 20 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 = 4- [4- (2-Acetamidoethyl) -1-piperazinyl] -4-oxobutyrate (Exemplary Compound 1-74)
(20a) 1- (Benzyloxycarbonyl) -4- [2- (benzyloxycarbonylamino) ethyl] piperazine 1- (2-Aminoethyl) piperazine (4.0 g, 31 mmol) was dissolved in water (60 mL), Stir at room temperature. Sodium carbonate (7.8 g, 74 mmol) and benzyl chloroformate (30% toluene solution; 43 mL, 68 mmol) were added thereto, and the mixture was stirred at room temperature for 12 hours. Hydrochloric acid was added until the reaction was pH = 10 and the product was extracted with ethyl acetate (80 mL × 4). The organic layers were combined, washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 50:50, V / V) to give the title compound (2.1 g, 17% yield) as a colorless oily substance. Got as.

IR (liquid film) ν _max 3342, 2946, 1703, 1530, 1455, 1432, 1241 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.40 (4H, br s), 2.48 (2H, t, J = 6 Hz), 3.30 (2H, br t, J = 6 Hz), 3.48-3.50 (4H , m), 5.10 (2H, s), 5.13 (2H, s), 5.21 (1H, br s), 7.29-7.52 (10H, m);
MS (FAB) m / z: 398 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₂₂ H ₂₈ N ₃ O ₄ ((M + H) ⁺ ): 398.2080. Found: 398.2069.
(20b) 1- [2- [N-acetyl-N- (benzyloxycarbonyl) amino] ethyl] -4- (benzyloxycarbonyl) piperazine 1- (benzyloxycarbonyl) prepared in (20a) of Example 20 -4- [2- (Benzyloxycarbonylamino) ethyl] piperazine (1.9 g, 4.8 mmol) was dissolved in N, N-dimethylformamide (15 mL) and stirred at 0 ° C. Thereto was added a suspension of sodium hydride (55% mineral oil dispersion; 231 mg, 5.3 mmol) in N, N-dimethylformamide (15 mL), and the mixture was stirred at room temperature for 1 hour. After cooling to −78 ° C., a solution of acetyl chloride (0.82 mL, 11.6 mmol) in N, N-dimethylformamide (10 mL) was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was cooled to 0 ° C., aqueous sodium hydrogen carbonate solution (50 mL) was added, and the mixture was extracted with ethyl acetate (80 mL × 4). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 60:40, V / V) to give the title compound (1.0 g, 48% yield) as a yellow oily substance. Got as.

IR (liquid film) ν _max 2949, 2813, 1738, 1703, 1431, 1346 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz): δ 2.36 (4H, s), 2.45 (2H, t, J = 7 Hz), 2.49 (3H, s), 3.39-3.40 (4H, m), 3.86 (2H , t, J = 7 Hz), 5.12 (2H, s), 5.22 (2H, s), 7.30-7.42 (10H, m);
MS (FAB) m / z: 440 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₂₄ H ₃₀ N ₃ O ₅ ((M + H) ⁺ ): 440.2186. Found: 440.2190.
(20c) 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 = 4 -[4- (2-acetamidoethyl) -1-piperazinyl] -4-oxobutyrate (title target compound)
1- [2- [N-acetyl-N- (benzyloxycarbonyl) amino] ethyl] -4- (benzyloxycarbonyl) piperazine (1.0 g, 2.3 mmol) prepared in Example 20 (20b) was used. Dissolve in ethanol (25 mL), add palladium hydroxide on carbon catalyst (20%; 300 mg), and stir at room temperature under hydrogen (normal pressure) for 6 hours. The reaction mixture was filtered through celite, and the solid was washed with dichloromethane (50 mL). The solvent was distilled off under reduced pressure to obtain crude 1- (2-acetamidoethyl) piperazine.

  This was dissolved in N, N-dimethylformamide (8 mL) and stirred at 0 ° C. Thereto was added a solution of succinic anhydride (228 mg, 2.3 mmol) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off from the reaction solution under reduced pressure to obtain crude 4- [4- (2-acetamidoethyl) -1-piperazinyl] -4-oxobutyric acid.

  This was dissolved in N, N-dimethylformamide (12 mL) and stirred at 0 ° C. Cesium carbonate (348 mg, 1.1 mmol) and 18-crown-6 (565 mg, 2.1 mmol) were added thereto, and 1-chloroethyl = (1R, 2R)-produced in Example 1 (1a) at room temperature. 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 carbonate (diastereomer ratio = approximately 1: 1; 770 mg, 1.2 mmol) added. 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 separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 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 recycled by preparative HPLC [LC-908; manufactured by Nihon Analytical Industry; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) in series. Used in connection; solvent, chloroform] to give the title object compound (338 mg, yield 32%) as a pale-yellow oil (diastereomer ratio = about 1: 1).

IR (liquid film) ν _max 3327, 3002, 2232, 1765, 1645, 1505, 1276 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H × (1/2), d, J = 7 Hz), 1.36 (3H × (1/2), d, J = 7 Hz), 1.54 ( 3H × (1/2), d, J = 6 Hz), 1.55 (3H × (1/2), d, J = 6 Hz), 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 = 11 Hz), 3.49 ( 1H, t, J = 11 Hz), 3.45-3.53 (2H, m), 3.61-3.69 (2H, m), 3.83 (1H × (1/2), q, J = 7 Hz), 3.88 (1H × (1/2), q, J = 7 Hz), 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, 5 Hz), 5.88 (1H, br s), 6.59 (1H, dd, J = 15, 10 Hz), 6.74 (1H, d, J = 15 Hz), 6.74 (1H × (1/2), q, J = 7 Hz), 6.81 (1H × (1/2), q, J = 7 Hz), 6.83-7.00 (3H, m), 7.33 (1H, dd, J = 11, 2 Hz), 7.37-7.44 (2H, m), 7.57 (1H, t, J = 7 Hz), 7.91 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 (1H × (1/2), s), 8.25 (1H × (1/2), s);
MS (FAB) m / z: 884 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₄₂ H ₄₉ F ₃ N ₇ O ₉ S ((M + H) ⁺ ): 884.3265. Found: 884.3281.
A solution of the title object compound obtained above (diastereomer ratio = about 1: 1; 328 mg, 0.37 mmol) in ethyl acetate (8 mL) was cooled to 0 ° C. and stirred into hydrogen chloride (4 N (Ethyl acetate solution; 93 μL, 0.37 mmol) was added, and the solvent was distilled off under reduced pressure. The obtained aqueous solution was lyophilized to obtain 332 mg of the hydrochloride of the title object compound as a colorless amorphous solid (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 3284, 2936, 2230, 1765, 1655, 1616, 1504, 1276 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.24 (3H × (1/2), d, J = 7 Hz), 1.26 (3H × (1/2), d, J = 7 Hz), 1.45 (3H × (1/2), d, J = 5 Hz), 1.48 (3H × (1/2), d, J = 5 Hz), 1.84 (3H, br s), 2.33-3.64 (19H, m), 3.57 (1H × (1/2), q, J = 7 Hz), 3.76 (1H × (1/2), q, J = 7 Hz), 3.93-4.10 (2H, m), 5.03 ( 1H × (1/2), d, J = 5 Hz), 5.04 (1H × (1/2), d, J = 5 Hz), 5.24 (1H × (1/2), d, J = 16 Hz ), 5.28 (1H × (1/2), d, J = 16 Hz), 5.43 (1H × (1/2), d, J = 13 Hz), 5.46 (1H × (1/2), d, J = 16 Hz), 5.87 (1H, dd, J = 15, 4 Hz), 6.56 (1H, dd, J = 15, 11 Hz), 6.60 (1H × (1/2), q, J = 6 Hz ), 6.66 (1H × (1/2), q, J = 6 Hz), 6.82 (1H, d, J = 16 Hz), 7.16-7.22 (2H, m), 7.29-7.35 (1H, m), 7.41-7.51 (1H, m), 7.67 (1H, d, J = 8 Hz), 7.84-7.89 (2H, m), 8.06 (1H × (1/2), s), 8.06 (1H × (1 / 2), s), 8.18 (1H, br s), 8.35 (1H × (1/2), s), 8.47 (1H × (1/2), s), 9.54 (1H, br s);
MS (FAB) m / z: 884 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₄₂ H ₄₉ F ₃ N ₇ O ₉ S ((M + H) ⁺ ): 884.3264. Found: 884.3279.
Anal.calcd for C ₄₂ H ₄₈ F ₃ N ₇ O ₉ S ・ (2/3) HCl ・ 2H ₂ O: C, 53.42; H, 5.62; N, 10.38; F, 6.04; Cl, 2.50; S, 3.40 Found: C, 53.50; H, 5.47; N, 10.29; F, 6.04; Cl, 2.20; S, 3.37.
Example 21 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 = 4- [4- (Cyanomethyl) -1-piperazinyl] -4-oxobutyrate (Exemplary Compound 1-80)
(21a) [4- (Benzyloxycarbonyl) -1-piperazinyl] acetonitrile 1- (Benzyloxycarbonyl) piperazine (4.0 g, 18 mmol) was dissolved in N, N-dimethylformamide (20 mL) and stirred at 0 ° C. . Triethylamine (3.8 mL, 27 mmol), sodium iodide (1.4 g, 9.1 mmol) and bromoacetonitrile (1.5 mL, 22 mmol) were added thereto, and the mixture was stirred at room temperature for 4 hours. Under ice-cooling, ethyl acetate (150 mL) and brine (50 mL) were added to the reaction solution. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 33:67, V / V) to give the title compound (4.4 g, yield 92%) as a colorless solid. Obtained.

IR (liquid film) ν _max 2943, 2824, 1700, 1430, 1242 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.56 (4H, br s), 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 (EI) m / z: calcd for C ₁₄ H ₁₇ N ₃ O ₂ (M ⁺ ): 259.1321. Found: 259.1324.
(21b) 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 = 4 -[4- (Cyanomethyl) -1-piperazinyl] -4-oxobutyrate (title target compound)
[4- (Benzyloxycarbonyl) -1-piperazinyl] acetonitrile (856 mg, 3.3 mmol) prepared in (21a) of Example 21 was dissolved in ethanol (25 mL), and palladium hydroxide on carbon catalyst (20% 200 mg), and stirred at room temperature under hydrogen (normal pressure) for 8 hours. The reaction mixture was filtered through celite, and the solid was washed with dichloromethane (50 mL). The solvent was distilled off under reduced pressure to obtain crude 1- (cyanomethyl) piperazine.

  This was dissolved in N, N-dimethylformamide (10 mL) and stirred at 0 ° C. Thereto was added a solution of succinic anhydride (324 mg, 3.2 mmol) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 16 hours. Under reduced pressure, the solvent was distilled off to obtain crude 4- [4- (cyanomethyl) -1-piperazinyl] -4-oxobutyric acid.

  This was dissolved in N, N-dimethylformamide (15 mL) and stirred at 0 ° C. Cesium carbonate (492 mg, 1.5 mmol) and 18-crown-6 (799 mg, 3.0 mmol) were added thereto, and 1-chloroethyl produced in Example 1 (1a) at room temperature = (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 carbonate (diastereomer ratio = approximately 1: 1; 700 mg, 1.1 mmol) added. After stirring at room temperature for 1 day, ethyl acetate (150 mL) and brine (50 mL) were added to the reaction solution under ice cooling. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. Recycle preparative HPLC [LC-908; manufactured by Japan Analytical Industries, Ltd .; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) were connected in series. The title compound (366 mg, yield 41%) was obtained as a colorless oil (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 3429, 2938, 2230, 1765, 1649, 1504, 1275 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H × (1/2), d, J = 7 Hz), 1.36 (3H × (1/2), d, J = 7 Hz), 1.54 ( 3H × (1/2), d, J = 5 Hz), 1.55 (3H × (1/2), d, J = 5 Hz), 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 (1H, t, J = 11 Hz), 3.49 (1H, t, J = 11 Hz), 3.45-3.58 (4H, m), 3.53 (1H, s), 3.54 (1H, s), 3.82 (1H × (1/2), q, J = 7 Hz), 3.88 (1H × (1/2), q, J = 7 Hz), 4.15-4.19 (1H, m), 4.26-4.31 (1H, m), 4.97 (1H × (1/2), d, J = 3 Hz), 4.98 (1H × (1/2), d , J = 3 Hz), 5.29-5.47 (2H, m), 5.85 (1H, dd, J = 15, 4 Hz), 6.58 (1H, dd, J = 15, 11 Hz), 6.73 (1H, d, J = 16 Hz), 6.74 (1H × (1/2), q, J = 5 Hz), 6.81 (1H × (1/2), q, J = 5 Hz), 6.84-7.00 (3H, m) , 7.33 (1H, dd, J = 10, 2 Hz), 7.39-7.46 (2H, m), 7.57 (1H, t, J = 8 Hz), 7.91 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 (1H × (1/2), s), 8.23 (1H × (1/2), s);
MS (FAB) m / z: 838 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₄₀ H ₄₂ F ₃ N ₇ O ₈ SNa ((M + Na) ⁺ ): 860.2666. Found: 860.2681.
Example 22 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 = 4- [4- (2-Amino-2-oxoethyl) -1-piperazinyl] -4-oxobutyrate (Exemplary Compound 1-82)
(22a) 2- [4- (Benzyloxycarbonyl) -1-piperazinyl] acetamide 1- (Benzyloxycarbonyl) piperazine (4.0 g, 18 mmol) was dissolved in N, N-dimethylformamide (25 mL) and treated at 0 ° C. Stir with. Triethylamine (3.8 mL, 27 mmol), sodium iodide (1.4 g, 9.1 mmol) and 2-bromoacetamide (3.0 g, 22 mmol) were added thereto, and the mixture was stirred at room temperature for 2 days. Ethyl acetate (150 mL) and brine (50 mL) were added to the reaction solution. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The resulting crude title compound was purified using silica gel column chromatography (ethyl acetate: methanol, 95: 5, V / V) to give the title compound (4.6 g, 91% yield) as a pale yellow solid. Obtained.

IR (KBr) ν _max 3354, 3170, 1694, 1655, 1433, 1241 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.53 (4H, s), 3.03 (2H, s), 3.53-3.56 (4H, m), 5.14 (2H, s), 5.43 (1H, br s), 6.94 (1H, br s), 7.31-7.52 (5H, m);
MS (FAB) m / z: 278 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₁₄ H ₂₀ N ₃ O ₃ ((M + H) ⁺ ): 278.1505. Found: 278.1501.
Anal.calcd for C ₁₄ H ₁₉ N ₃ O ₃ : C, 60.63; H, 6.91; N, 15.15.Found: C, 60.53; H, 6.74; N, 15.18.
(22b) 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 = 4 -[4- (2-Amino-2-oxoethyl) -1-piperazinyl] -4-oxobutyrate (title target compound)
2- [4- (Benzyloxycarbonyl) -1-piperazinyl] acetamide (915 mg, 3.3 mmol) prepared in (22a) of Example 22 was dissolved in ethanol (30 mL), and palladium hydroxide on carbon catalyst ( 20%; 200 mg) was added, and the mixture was stirred at room temperature under hydrogen (normal pressure) for 2 hours. The reaction mixture was filtered through celite, and the solid was washed with dichloromethane (50 mL). The solvent was distilled off under reduced pressure to obtain crude 2- (1-piperazinyl) acetamide.

  This was dissolved in N, N-dimethylformamide (10 mL) and stirred at 0 ° C. Thereto was added a solution of succinic anhydride (327 mg, 3.3 mmol) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 1 day. The solvent was distilled off from the reaction solution under reduced pressure to obtain crude 4- [4- (2-amino-2-oxoethyl) -1-piperazinyl] -4-oxobutyric acid.

  This was dissolved in N, N-dimethylformamide (15 mL) and stirred at 0 ° C. Thereto, cesium carbonate (502 mg, 1.5 mmol) and 18-crown-6 (815 mg, 3.0 mmol) were added, and 1-chloroethyl = (1R, 2R)-produced in Example 1 (1a) at room temperature. 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 carbonate (diastereomer ratio = approximately 1: 1; 714 mg, 1.1 mmol) added. After stirring at room temperature for 4 days, ethyl acetate (150 mL) and brine (50 mL) were added to the reaction solution under ice cooling. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 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 recycled by preparative HPLC [LC-908; manufactured by Nihon Analytical Industry; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) in series. Used in connection; solvent, chloroform] to give the title object compound (279 mg, yield 30%) as a colorless oil (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 3446, 2939, 2853, 2230, 1765, 1687, 1647, 1504, 1276 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H × (1/2), d, J = 7 Hz), 1.36 (3H × (1/2), d, J = 7 Hz), 1.54 ( 3H × (1/2), d, J = 5 Hz), 1.55 (3H × (1/2), d, J = 5 Hz), 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 = 11 Hz), 3.49 (1H, t, J = 11 Hz), 3.45-3.57 (2H, m), 3.63 (2H, br s), 3.82 (1H × (1/2), q, J = 7 Hz), 3.88 (1H × (1/2), q, J = 7 Hz), 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 = 16, 4 Hz), 6.59 (1H, dd, J = 16, 10 Hz), 6.74 (1H, d, J = 16 Hz), 6.74 (1H × (1/2), q, J = 5 Hz), 6.81 (1H × (1/2), q, J = 5 Hz), 6.83-7.00 (4H, m), 7.33 (1H, dd, J = 10, 2 Hz), 7.37-7.46 (2H, m), 7.57 (1H , t, J = 8 Hz), 7.90 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 (1H × (1/2), s), 8.24 ( 1H × (1/2), s);
MS (FAB) m / z: 856 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₄₀ H ₄₅ F ₃ N ₇ O ₉ S ((M + H) ⁺ ): 856.2951. Found: 856.2975.
A solution of the title compound prepared above (diastereomer ratio = approximately 1: 1; 137 mg, 0.16 mmol) in ethanol (5 mL) was cooled to 0 ° C. and stirred while L-ascorbic acid (28 mg 0.16 mmol), and the solvent was distilled off under reduced pressure. The oily residue obtained was dissolved in water (10 mL) at 0 ° C., and the insoluble material was filtered off with a membrane filter to obtain an aqueous solution obtained. Lyophilization gave the title target compound ascorbate (172 mg) as a colorless, amorphous solid (diastereomer ratio = approximately 1: 1).

IR (KBr) ν _max 3371, 2230, 1763, 1686, 1646, 1616, 1504, 1277 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.24 (3H × (1/2), d, J = 7 Hz), 1.26 (3H × (1/2), d, J = 7 Hz), 1.45 (3H × (1/2), d, J = 5 Hz), 1.48 (3H × (1/2), d, J = 5 Hz), 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 (25H × (1/2), m), 3.56 (1H × (1/2), q, J = 8 Hz), 3.70-3.76 (1H, m), 4.03-4.10 (1H, m), 4.10-4.18 (1H, m), 4.69 (1H × (1/2 ), s), 4.70 (1H × (1/2), s), 4.85 (1H, br s), 5.02 (1H × (1/2), d, J = 5 Hz), 5.03 (1H × (1 / 2), d, J = 5 Hz), 5.25 (1H × (1/2), d, J = 15 Hz), 5.28 (1H × (1/2), d, J = 15 Hz), 5.43 ( 1H × (1/2), d, J = 15 Hz), 5.45 (1H × (1/2), d, J = 15 Hz), 5.88 (1H × (1/2), dd, J = 15, 4 Hz), 5.88 (1H × (1/2), dd, J = 15, 4 Hz), 6.53-6.66 (1H, m), 6.61 (1H × (1/2), q, J = 5 Hz) , 6.67 (1H × (1/2), q, J = 5 Hz), 6.82 (1H, d, J = 16 Hz), 7.13-7.24 (3H, m), 7.34-7.41 (1H, m), 7.43 -7.48 (1H, m), 7.67 (1H, d, J = 8 Hz), 7.83-7.89 (2H, m), 8.05 (1H × (1/2), s), 8.06 (1H × (1/2 ), s), 8.35 (1H × (1/2), s), 8.47 (1H × (1/2), s);
MS (FAB) m / z: 856 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₄₀ H ₄₅ F ₃ N ₇ O ₉ S ((M + H) ⁺ ): 856.2951. Found: 856.2953.
Anal.calcd for C ₄₀ H ₄₄ F ₃ N ₇ O ₉ S ・ C ₆ H ₈ O ₆・ (5/3) H ₂ O: C, 52.02; H, 5.25; N, 9.23; F, 5.37; S, 3.02. Found: C, 51.84; H, 5.16; N, 9.07; F, 5.26; S, 2.96.
Example 23 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 = 4- [4-[(2- (carbamoyloxy) ethyl] -1-piperazinyl] -4-oxobutyrate (Exemplary Compound 1-83)
(23a) 1- (benzyloxycarbonyl) -4- [2- (benzyloxycarbonyloxy) ethyl] piperazine 1- (2-hydroxyethyl) piperazine (4.0 g, 31 mmol) was dissolved in water (60 mL), Stir at room temperature. Sodium carbonate (7.8 g, 74 mmol) and benzyl chloroformate (30% toluene solution; 43 mL, 68 mmol) were added thereto, and the mixture was stirred at room temperature for 12 hours. Hydrochloric acid was added until the reaction solution reached pH = 10 and extracted with ethyl acetate (80 mL × 4). The organic layers were combined, washed with water and saturated brine, 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 using silica gel column chromatography (hexane: ethyl acetate, 66:33, V / V) to give the title compound (7.8 g, yield 63%) as a pale yellow oil. Obtained as material.

IR (liquid film) ν _max 2950, 1746, 1702, 1456, 1431, 1242 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.45 (4H, s), 2.66 (2H, t, J = 6 Hz), 3.46-3.49 (4H, m), 4.26 (2H, t, J = 6 Hz ), 5.13 (2H, s), 5.16 (2H, s), 7.31-7.39 (10H, m);
MS (FAB) m / z: 399 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₂₂ H ₂₇ N ₂ O ₅ ((M + H) ⁺ ): 399.1920. Found: 399.1906.
(23b) 1- (benzyloxycarbonyl) -4- (2-hydroxyethyl) piperazine 1- (benzyloxycarbonyl) -4- [2- (benzyloxycarbonyloxy) ethyl prepared in (23a) of Example 23 Piperazine (7.8 g, 20 mmol) was dissolved in ethanol (80 mL) and stirred at room temperature. Potassium hydroxide (2N aqueous solution; 2.0 mL, 3.9 mmol) was added thereto and stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 ° C., aqueous ammonium chloride solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 4). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound. The resulting crude title compound was purified using silica gel column chromatography (ethyl acetate) to obtain the title compound (4.1 g, yield 74%) as a colorless oily substance.

IR (liquid film) ν _max 3449, 2944, 2816, 1702, 1433, 1241 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.48 (4H, s), 2.56 (2H, t, J = 5 Hz), 3.52-3.54 (4H, m), 3.63 (2H, t, J = 5 Hz) ), 5.14 (2H, s), 7.30-7.39 (5H, m);
MS (FAB) m / z: 265 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₁₄ H ₂₁ N ₂ O ₃ ((M + H) ⁺ ): 265.1552. Found: 265.1563.
(23c) 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 = 4 -[4-[(2- (carbamoyloxy) ethyl] -1-piperazinyl] -4-oxobutyrate (title target compound)
1- (benzyloxycarbonyl) -4- (2-hydroxyethyl) piperazine (2.4 g, 8.4 mmol) prepared in (23b) of Example 23 was dissolved in anhydrous dichloromethane (40 mL) and stirred at 0 ° C. . Trichloroacetyl isocyanate (1.75 g, 9.3 mmol) was added thereto and stirred at room temperature for 1 hour. After the reaction solution was supported on alumina for 2 hours, the reaction solution was filtered through Celite, and the solid was washed with ethyl acetate (100 mL). The filtrate and washings were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give crude 1- (benzyloxycarbonyl) -4- [2- (carbamoyloxy). Ethyl] piperazine (2.1 g, 80% yield) was obtained as a colorless oil.

  The obtained 1- (benzyloxycarbonyl) -4- [2- (carbamoyloxy) ethyl] piperazine (1.0 g, 3.3 mmol) was dissolved in a mixed solvent of ethanol (20 mL) and ethyl acetate (20 mL). The palladium hydroxide carbon catalyst (20%; 250 mg) was added there, and it stirred at room temperature under hydrogen (normal pressure) for 6 hours. The reaction mixture was filtered through celite, and the solid was washed with dichloromethane (50 mL). The solvent was distilled off under reduced pressure to obtain crude 1- [2- (carbamoyloxy) ethyl] piperazine.

  This was dissolved in N, N-dimethylformamide (8 mL) and stirred at 0 ° C. Thereto was added a solution of succinic anhydride (327 mg, 3.3 mmol) in N, N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 12 hours. Under reduced pressure, the solvent was distilled off to obtain crude 4-[(2- (carbamoyloxy) ethyl] -1-piperazinyl] -4-oxobutyric acid.

  This was dissolved in N, N-dimethylformamide (15 mL) and stirred at 0 ° C. Cesium carbonate (502 mg, 1.5 mmol) and 18-crown-6 (815 mg, 3.1 mmol) were added thereto, and 1-chloroethyl produced in Example 1 (1a) at room temperature = (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 carbonate (diastereomer ratio = approximately 1: 1; 714 mg, 1.1 mmol) added. After stirring at room temperature for 1 day, ethyl acetate (150 mL) and brine (50 mL) were added to the reaction solution under ice cooling. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 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 recycled by preparative HPLC [LC-908; manufactured by Nihon Analytical Industry; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) in series. Used in connection; solvent, chloroform] to give the title object compound (460 mg, yield 47%) as a pale-yellow oil (diastereomer ratio = about 1: 1).

IR (liquid film) ν _max 3358, 3008, 2232, 1764, 1726, 1643, 1617, 1505, 1276 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H × (1/2), d, J = 7 Hz), 1.36 (3H × (1/2), d, J = 7 Hz), 1.54 ( 3H × (1/2), d, J = 5 Hz), 1.55 (3H × (1/2), d, J = 5 Hz), 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 = 11 Hz), 3.49 (1H, t, J = 11 Hz), 3.45-3.53 (2H, m) , 3.60-3.62 (2H, m), 3.82 (1H × (1/2), q, J = 7 Hz), 3.88 (1H × (1/2), q, J = 7 Hz), 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, 4 Hz ), 6.57 (1H, dd, J = 15, 10 Hz), 6.73 (1H, d, J = 15 Hz), 6.73 (1H × (1/2), q, J = 5 Hz), 6.81 (1H × (1/2), q, J = 5 Hz), 6.85-7.00 (4H, m), 7.33 (1H, dd, J = 10, 2 Hz), 7.39-7.46 (2H, m), 7.57 (1H, t, J = 8 Hz), 7.91 (1H × (1/2), s), 7.95 (1H × (1/2), s), 8.02 (1H × (1/2), s), 8.23 (1H × (1/2), s);
MS (FAB) m / z: 886 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₄₁ H ₄₇ F ₃ N ₇ O ₁₀ S ((M + H) ⁺ ): 886.3057. Found: 886.3055.
A solution of the title compound prepared above (diastereomer ratio = approximately 1: 1; 444 mg, 0.50 mmol) in ethyl acetate (12 mL) was cooled to 0 ° C. and stirred into hydrogen chloride (4 N Ethyl acetate solution; 125 μL, 0.50 mmol) was added, and the solvent was distilled off under reduced pressure. The oily residue obtained was dissolved in water (12 mL) at 0 ° C., and the insoluble material was filtered off with a membrane filter. The obtained aqueous solution was lyophilized to give the hydrochloride of the title object compound (443 mg) as a colorless amorphous solid (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 3428, 2938, 2231, 1764, 1732, 1648, 1616, 1504, 1276 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.24 (3H × (1/2), d, J = 8 Hz), 1.26 (3H × (1/2), d, J = 8 Hz), 1.45 (3H × (1/2), d, J = 5 Hz), 1.48 (3H × (1/2), d, J = 5 Hz), 2.20-2.80 (10H, m), 2.80-3.62 (7H , m), 3.57 (1H × (1/2), q, J = 7 Hz), 3.63-3.80 (1H × (1/2), m), 3.80-4.50 (5H, m), 5.03 (1H × (1/2), d, J = 5 Hz), 5.04 (1H × (1/2), d, J = 5 Hz), 5.24 (1H × (1/2), d, J = 15 Hz), 5.27 (1H × (1/2), d, J = 15 Hz), 5.43 (1H × (1/2), d, J = 14 Hz), 5.46 (1H × (1/2), d, J = 14 Hz), 5.88 (1H × (1/2), dd, J = 14, 4 Hz), 5.88 (1H × (1/2), dd, J = 14, 4 Hz), 6.30-6.70 (3H, m), 6.82 (1H, d, J = 16 Hz), 7.15-7.22 (2H, m), 7.30-7.41 (1H, m), 7.43-7.51 (1H, m), 7.67 (1H, dd, J = 8, 2 Hz), 7.83-7.89 (2H, m), 8.05 (1H × (1/2), s), 8.06 (1H × (1/2), s), 8.35 (1H × (1/2) , s), 8.47 (1H × (1/2), s);
MS (FAB) m / z: 886 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₄₁ H ₄₇ F ₃ N ₇ O ₁₀ S ((M + H) ⁺ ): 886.3057. Found: 886.3054.
Example 24 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 = 4- [4- [2- (Dimethylamino) ethyl] -1-piperazinyl] -4-oxobutyrate (Exemplary Compound 1-150)
(24a) 1- (Benzyloxycarbonyl) -4- [2- (dimethylamino) ethyl] piperazine 1- (Benzyloxycarbonyl) piperazine (4.0 g, 18 mmol) is dissolved in N, N-dimethylformamide (20 mL). And stirred at 0 ° C. There, N, N-dimethylformamide of triethylamine (6.3 mL, 46 mmol), sodium iodide (1.4 g, 9.1 mmol), and 2- (dimethylamino) ethyl chloride hydrochloride (3.15 g, 22 mmol) (5 mL) suspension was added, and the mixture was stirred at 65 ° C. for 5 hours, and then ethyl acetate (150 mL) and brine (50 mL) were added to the reaction mixture under ice cooling. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 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 using silica gel column chromatography (hexane: ethyl acetate, 50:50, V / V) to give the title compound (2.3 g, yield 44%) as a yellow oily substance. Got as.

IR (liquid film) ν _max 2945, 2817, 1703, 1429, 1241 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.24 (6H, s), 2.40-2.50 (4H, m), 2.48 (2H, t, J = 5 Hz), 3.48 (2H, t, J = 5 Hz ), 3.51-3.54 (4H, m), 5.13 (2H, s), 7.30-7.36 (5H, m);
MS (EI) m / z: 291 (M ⁺ ).
HRMS (EI) m / z: calcd for C ₁₆ H ₂₅ N ₃ O ₂ (M ⁺ ): 291.1947. Found: 291.1948.
(24b) 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 = 4 -[4- [2- (Dimethylamino) ethyl] -1-piperazinyl] -4-oxobutyrate (title target compound)
1- (Benzyloxycarbonyl) -4- [2- (dimethylamino) ethyl] piperazine (962 mg, 3.3 mmol) prepared in (24a) of Example 24 was dissolved in ethanol (20 mL) and hydroxylated therein. Palladium carbon catalyst (20%; 200 mg) was added and stirred at room temperature for 1 day under hydrogen. The reaction mixture was filtered through celite, and the solid was washed with dichloromethane (50 mL). The solvent was distilled off under reduced pressure to obtain crude 1- [2- (dimethylaminoethyl] piperazine.

  This was dissolved in N, N-dimethylformamide (10 mL) and stirred at 0 ° C. To this was added a solution of succinic anhydride (324 mg, 3.2 mmol) in N, N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 3 days. The solvent was distilled off from the reaction solution under reduced pressure to obtain crude 4- [4- [2- (dimethylamino) ethyl] -1-piperazinyl] -4-oxobutyric acid.

  This was dissolved in N, N-dimethylformamide (15 mL) and stirred at 0 ° C. Cesium carbonate (492 mg, 1.5 mmol) and 18-crown-6 (799 mg, 3.0 mmol) were added thereto, and 1-chloroethyl produced in Example 1 (1a) at room temperature = (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 carbonate (diastereomer ratio = approximately 1: 1; 700 mg, 1.1 mmol) added. After stirring at room temperature for 2 days, ethyl acetate (150 mL) and brine (50 mL) were added to the reaction mixture under ice cooling. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 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 recycled by preparative HPLC [LC-908; manufactured by Nihon Analytical Industry; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) in series. Used in connection; solvent, chloroform] to give the title object compound (235 mg, yield 25%) as a yellow oil (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 3421, 2940, 2230, 1765, 1646, 1504, 1276 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H × (1/2), d, J = 7 Hz), 1.36 (3H × (1/2), d, J = 7 Hz), 1.54 ( 3H × (1/2), d, J = 5 Hz), 1.55 (3H × (1/2), d, J = 5 Hz), 2.26 (3H, s), 2.26 (3H, s), 2.41- 2.51 (6H, m), 2.51-2.77 (4H, m), 3.00-3.07 (1H, m), 3.35-3.66 (8H, m), 3.82 (1H × (1/2), q, J = 7 Hz ), 3.88 (1H × (1/2), q, J = 7 Hz), 4.13-4.20 (1H, m), 4.26-4.32 (1H, m), 4.97 (1H, d, J = 4 Hz), 5.29-5.46 (2H, m), 5.85 (1H, dd, J = 15, 4 Hz), 6.57 (1H, dd, J = 15, 11 Hz), 6.73 (1H, d, J = 15 Hz), 6.73 (1H × (1/2), q, J = 5 Hz), 6.81 (1H × (1/2), q, J = 5 Hz), 6.84-7.00 (3H, m), 7.33 (1H, dd, J = 10, 2 Hz), 7.39-7.46 (2H, m), 7.57 (1H, t, J = 8 Hz), 7.91 (1H × (1/2), s), 7.95 (1H × (1/2 ), s), 8.02 (1H × (1/2), s), 8.23 (1H × (1/2), s);
MS (FAB) m / z: 870 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₄₂ H ₅₁ F ₃ N ₇ O ₈ S ((M + H) ⁺ ): 870.3472. Found: 870.3500.
A solution of the title object compound obtained above (diastereomer ratio = about 1: 1; 197 mg, 0.23 mmol) in ethyl acetate (5 mL) was cooled to 0 ° C. and stirred into hydrogen chloride (4 Normal ethyl acetate solution; 56.5 μL, 0.23 mmol) was added, and the solvent was distilled off under reduced pressure. The oily residue obtained was dissolved in water (5 mL) at 0 ° C., and the insoluble material was filtered through a membrane filter. The aqueous solution obtained after lyophilization was freeze-dried to obtain the hydrochloride (198 mg) of the title object compound as a pale yellow amorphous solid (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 3425, 2938, 2230, 1765, 1644, 1504, 1276 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.24 (3H × (1/2), d, J = 7 Hz), 1.27 (3H × (1/2), d, J = 7 Hz), 1.45 (3H × (1/2), d, J = 5 Hz), 1.47 (3H × (1/2), d, J = 5 Hz), 2.34-3.58 (25H, m), 3.56 (1H × ( 1/2), q, J = 7 Hz), 3.74 (1H × (1/2), q, J = 7 Hz), 4.04-4.12 (2H, m), 5.02 (1H × (1/2), d, J = 5 Hz), 5.03 (1H × (1/2), d, J = 5 Hz), 5.24 (1H × (1/2), d, J = 16 Hz), 5.28 (1H × (1 / 2), d, J = 16 Hz), 5.42 (1H × (1/2), d, J = 14 Hz), 5.45 (1H × (1/2), d, J = 14 Hz), 5.88 ( 1H × (1/2), dd, J = 15, 4 Hz), 5.88 (1H × (1/2), dd, J = 15, 4 Hz), 6.53-6.67 (1H, m), 6.61 (1H × (1/2), q, J = 5 Hz), 6.67 (1H × (1/2), q, J = 5 Hz), 6.82 (1H, d, J = 16 Hz), 7.13-7.22 (2H , m), 7.30-7.35 (1H, m), 7.41-7.48 (1H, m), 7.67 (1H, d, J = 7 Hz), 7.84-7.89 (2H, m), 8.05 (1H × (1 / 2), s), 8.06 (1H × (1/2), s), 8.36 (1H × (1/2), s), 8.48 (1H × (1/2), s);
MS (FAB) m / z: 870 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₄₂ H ₅₁ F ₃ N ₇ O ₈ S ((M + H) ⁺ ): 870.3472. Found: 870.3448.
Example 25 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 = 4- (4-Methyl-1-piperazinyl) -4-oxocrotonate (Exemplary Compound 1-156)
(25a) Ethyl = 4- (4-methyl-1-piperazinyl) -4-oxocrotonate Ethyl hydrogen fumarate (4.0 g, 28 mmol) was dissolved in anhydrous dichloromethane (20 mL) and stirred at 0 ° C. To this were added oxalyl dichloride (3.6 mL, 42 mmol) and N, N-dimethylformamide (2 drops), and the mixture was stirred at 35 ° C. for 15 minutes. Chloro-4-oxocrotonate was obtained.

  This was dissolved in anhydrous dichloromethane (20 mL) and stirred at 0 ° C. 1-methylpiperazine (3.3 g, 33 mmol) was added thereto, 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 mixture, and the mixture was extracted with ethyl acetate (50 mL × 5). The obtained organic layers were combined, washed with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound (5.47 g, yield 87%). ) Was obtained as an orange oil.

IR (KBr) ν _max 2939, 2793, 1722, 1653, 1628, 1442, 1295 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.32 (3H, t, J = 7 Hz), 2.32 (3H, s), 2.41-2.44 (4H, m), 3.60 (2H, t, J = 5 Hz ), 3.72 (2H, t, J = 5 Hz), 4.25 (2H, q, J = 7 Hz), 6.76 (1H, d, J = 15 Hz), 7.38 (1H, d, J = 15 Hz);
MS (EI) m / z: 226 (M ⁺ ).
HRMS (EI) m / z: calcd for C ₁₁ H ₁₈ N ₂ O ₃ (M ⁺ ): 226.1317. Found: 226.1323.
(25b) 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 = 4 -(4-Methyl-1-piperazinyl) -4-oxocrotonate (titled compound)
Ethyl 4- (4-methyl-1-piperazinyl) -4-oxocrotonate (733 mg, 3.2 mmol) prepared in Example 25 (25a) was dissolved in water (10 mL), and cesium carbonate ( (517 mg, 1.6 mmol) was added, and the mixture was stirred at 70 ° C. for 7 hours, and then the aqueous solution was lyophilized. The obtained cesium salt was dissolved in N, N-dimethylformamide (5 mL) and stirred at 0 ° C. Thereto, 1-chloroethyl produced in (1a) of Example 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 ] Propyl carbonate (diastereomeric ratio = about 1: 1; 700 mg, 1.1 mmol) and 18-crown-6 (910 mg, 3.2 mmol) were added. After stirring at room temperature for 2 days, ethyl acetate (150 mL) and brine (50 mL) were added to the reaction mixture under ice cooling. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 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 recycled by preparative HPLC [LC-908; manufactured by Nihon Analytical Industries; Used in connection; solvent, chloroform] to give the title object compound (622 mg, yield 71%) as a colorless oil (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 2940, 2849, 2796, 2230, 1763, 1620, 1504, 1279 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.35 (3H × (1/2), d, J = 8 Hz), 1.36 (3H × (1/2), d, J = 8 Hz), 1.60 ( 3H × (1/2), d, J = 6 Hz), 1.60 (3H × (1/2), d, J = 6 Hz), 2.32 (3H, s), 2.42-2.48 (4H, m), 2.98-3.07 (1H, m), 3.49 (1H, t, J = 11 Hz), 3.50 (1H, t, J = 11 Hz), 3.52-3.60 (2H, m), 3.66-3.73 (2H, m) , 3.87 (1H, q, J = 7 Hz), 4.18 (1H, ddd, J = 11, 5, 2 Hz), 4.27 (1H, ddd, J = 11, 5, 2 Hz), 4.97 (1H, d , J = 4 Hz), 5.35 (1H, d, J = 15 Hz), 5.38 (1H, d, J = 15 Hz), 5.85 (1H, dd, J = 15, 4 Hz), 6.58 (1H, dd , J = 15, 11 Hz), 6.74 (1H, d, J = 16 Hz), 6.75 (1H, d, J = 15 Hz), 6.80 (1H, q, J = 5 Hz), 6.82-6.96 (3H , m), 7.33 (1H, dd, J = 10, 2 Hz), 7.39-7.44 (2H, m), 7.42 (1H, d, J = 15 Hz), 7.57 (1H, t, J = 8 Hz) , 7.92 (1H, s), 8.00 (1H, s);
MS (FAB) m / z: 811 (M + H) ⁺ .
HRMS (ESI +) m / z: calcd for C ₃₉ H ₄₂ F ₃ N ₆ O ₈ S ((M + H) ⁺ ): 811.2737. Found: 811.2754.
A solution of the title object compound (diastereomer ratio = approximately 1: 1; 611 mg, 0.75 mmol) in ethyl acetate (15 mL) is cooled to 0 ° C. and stirred into hydrogen chloride (4N ethyl acetate solution; 188 μL, 0.75 mmol) was added, and the solvent was distilled off under reduced pressure. The oily residue obtained was dissolved in water (25 mL) at 0 ° C., and the insoluble material was filtered off through a membrane filter. Was lyophilized to give the hydrochloride salt of the title object compound (595 mg) as a pale yellow, amorphous solid (diastereomer ratio = approximately 1: 1).

IR (KBr) ν _max 3434, 2940, 2230, 1763, 1656, 1617, 1504, 1276 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.25 (3H × (1/2), d, J = 7 Hz), 1.26 (3H × (1/2), d, J = 7 Hz), 1.54 (3H × (1/2), d, J = 5 Hz), 1.56 (3H × (1/2), d, J = 5 Hz), 2.33-3.57 (14H, m), 3.56 (1H × ( 1/2), q, J = 7 Hz), 3.72 (1H × (1/2), q, J = 7 Hz), 4.02-4.14 (2H, m), 5.01 (1H × (1/2), d, J = 5 Hz), 5.04 (1H × (1/2), d, J = 5 Hz), 5.23 (1H × (1/2), d, J = 16 Hz), 5.28 (1H × (1 / 2), d, J = 16 Hz), 5.43 (1H × (1/2), d, J = 16 Hz), 5.47 (1H × (1/2), d, J = 16 Hz), 5.88 ( 1H × (1/2), dd, J = 15, 5 Hz), 5.88 (1H × (1/2), dd, J = 15, 5 Hz), 6.55 (1H, dd, J = 15, 10 Hz ), 6.59 (1H × (1/2), d, J = 15 Hz), 6.63 (1H × (1/2), d, J = 15 Hz), 6.74 (1H × (1/2), q, J = 5 Hz), 6.79 (1H × (1/2), q, J = 5 Hz), 6.82 (1H, d, J = 17 Hz), 7.15-7.22 (2H, m), 7.29-7.35 (1H , m), 7.38-7.51 (1H, m), 7.56 (1H × (1/2), d, J = 15 Hz), 7.59 (1H × (1/2), d, J = 15 Hz), 7.68 (1H, dd, J = 8, 2 Hz), 7.84-7.89 (2H, m), 8.05 (1H × (1/2), s), 8.06 (1H × (1/2), s), 8.31 ( 1H × (1/2), s), 8.49 (1H × (1/2), s);
MS (FAB) m / z: 811 (M + H) ⁺ .
HRMS (ESI +) m / z: calcd for C ₃₉ H ₄₂ F ₃ N ₆ O ₈ S ((M + H) ⁺ ): 811.2736. Found: 811.2776.
Anal.calcd for C ₃₉ H ₄₁ F ₃ N ₆ O ₈ S ・ (4/5) HCl ・ 2H ₂ O: C, 53.47; H, 5.27; N, 9.59; F, 6.51; Cl, 3.24; S, 3.66 Found: C, 53.61; H, 5.15; N, 9.62; F, 6.51; Cl, 3.28; S, 3.67.
Example 26 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 = [[(Dimethylamino) acetyl] amino] acetate (Exemplary Compound 1-302)
(26a) Ethyl = [[((dimethylamino) acetyl] amino] acetate N, N-dimethylglycine (2.2 g, 22 mmol) was dissolved in anhydrous dichloromethane (50 mL) and stirred at 0 ° C. Thereto, oxalyl dichloride (5.7 g, 45 mmol) and N, N-dimethylformamide (25 mL) were added, and the mixture was stirred at room temperature for 30 minutes. Chloride was obtained.

  This was dissolved in anhydrous tetrahydrofuran (25 mL) and stirred at 0 ° C. Thereto were added a suspension of triethylamine (6.2 mL, 45 mmol) and glycine ethyl ester hydrochloride (2.5 g, 18 mmol) in N, N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 12 hours. Under ice-cooling, aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (70 mL × 5). The obtained organic layers were combined, washed with saturated brine (50 mL × 1), and dried over anhydrous magnesium sulfate to obtain the crude title compound. The resulting crude title compound was purified using silica gel column chromatography (ethyl acetate) to obtain the title compound (884 mg, 26% yield) as a brown oily substance.

IR (liquid film) ν _max 3367, 2982, 2947, 2782, 1751, 1675, 1524, 1200 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.29 (3H, t, J = 7 Hz), 2.33 (6H, s), 3.00 (2H, s), 4.07 (2H, d, J = 6 Hz), 4.21 (2H, q, J = 7 Hz), 7.61 (1H, br s);
MS (EI) m / z: 188 (M ⁺ ).
HRMS (EI) m / z: calcd for C ₈ H ₁₆ N ₂ O ₃ (M ⁺ ): 188.1161. Found: 188.1160.
(26b) 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 = [ [(Dimethylamino) acetyl] amino] acetate (titled compound)
Ethyl = [[(dimethylamino) acetyl] amino] acetate (508 mg, 2.7 mmol) prepared in Example 26 (26a) was dissolved in water (10 mL), and cesium hydroxide (50% (W / W) was added thereto. W) Aqueous solution; 795 mg, 2.7 mmol) was added and stirred at 70 ° C. for 2 hours, and then the aqueous solution was lyophilized. The obtained cesium salt was dissolved in N, N-dimethylformamide (5 mL) and stirred at 0 ° C. Thereto, 1-chloroethyl produced in (1a) of Example 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 ] Propyl carbonate (diastereomeric ratio = about 1: 1; 700 mg, 1.1 mmol) and 18-crown-6 (715 mg, 2.7 mmol) were added. After stirring at room temperature for 1 day, ethyl acetate (150 mL) and brine (50 mL) were added to the reaction solution under ice cooling. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 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 recycled by preparative HPLC [LC-908; manufactured by Nihon Analytical Industries; Used in connection; solvent, chloroform] to give the title object compound (294 mg, yield 38%) as a pale-yellow oil (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 3371, 2851, 2230, 1770, 1681, 1505, 1275 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz): δ 1.36 (3H × (1/2), d, J = 7 Hz), 1.36 (3H × (1/2), d, J = 7 Hz), 1.55 ( 3H × (1/2), d, J = 6 Hz), 1.57 (3H × (1/2), d, J = 6 Hz), 2.34 (3H, s), 2.34 (3H, s), 3.02 ( 2H, s), 2.98-3.07 (1H, m), 3.49 (1H, t, J = 11 Hz), 3.49 (1H, t, J = 11 Hz), 3.87 (1H × (1/2), q, J = 7 Hz), 3.89-4.00 (1H × (1/2), m), 4.16-4.22 (3H, m), 4.24-4.29 (1H, m), 4.98 (1H, d, J = 4 Hz) , 5.30-5.42 (2H, m), 5.86 (1H × (1/2), dd, J = 15, 4 Hz), 5.86 (1H × (1/2), dd, J = 15, 4 Hz), 6.58 (1H, dd, J = 15, 10 Hz), 6.74 (1H, d, J = 15 Hz), 6.74 (1H × (1/2), q, J = 6 Hz), 6.85 (1H × (1 / 2), q, J = 6 Hz), 6.83-6.95 (3H, m), 7.33 (1H, d, J = 10 Hz), 7.39-7.47 (2H, m), 7.57 (1H, t, J = 8 Hz), 7.63 (1H × (1/2), br s), 7.78 (1H × (1/2), br s), 7.94 (1H, s), 7.98 (1H × (1/2), s ), 8.08 (1H × (1/2), s);
MS (FAB) m / z: 773 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₃₆ H ₄₀ F ₃ N ₆ O ₈ S ((M + H) ⁺ ): 773.2581. Found: 773.2598.
A solution of the title compound obtained above (diastereomer ratio = about 1: 1; 235 mg, 0.33 mmol) in ethyl acetate (5 mL) was cooled to 0 ° C. and stirred into hydrogen chloride (4 Normal ethyl acetate solution; 82 μL, 0.33 mmol) was added. The oily residue obtained by evaporating the solvent under reduced pressure was dissolved in water (5 mL) at 0 ° C., and the insoluble material was removed by filtration through a membrane filter. The obtained aqueous solution was lyophilized to give the hydrochloride of the title compound (251 mg) as a colorless amorphous solid (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 3049, 2979, 2230, 1770, 1687, 1615, 1504, 1275 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.25 (3H × (1/2), d, J = 6 Hz), 1.27 (3H × (1/2), d, J = 6 Hz), 1.48 (3H × (1/2), d, J = 5 Hz), 1.51 (3H × (1/2), d, J = 5 Hz), 2.69 (6H, s), 2.87-2.95 (1H, m ), 3.39-3.95 (5H, m), 4.02-4.13 (4H, m), 5.03 (1H × (1/2), d, J = 4 Hz), 5.04 (1H × (1/2), d, J = 4 Hz), 5.23 (1H × (1/2), d, J = 15 Hz), 5.26 (1H × (1/2), d, J = 15 Hz), 5.45 (1H × (1/2 ), d, J = 14 Hz), 5.47 (1H × (1/2), d, J = 14 Hz), 5.89 (1H, d, J = 15, 5 Hz), 6.57 (1H, dd, J = 15, 10 Hz), 6.68 (1H × (1/2), q, J = 5 Hz), 6.70 (1H × (1/2), q, J = 5 Hz), 6.82 (1H, d, J = 16 Hz), 7.16-7.22 (2H, m), 7.32-7.37 (1H, m), 7.41-7.51 (1H, m), 7.68 (1H, dd, J = 10, 2 Hz), 7.84-7.89 (2H , m), 8.06 (1H × (1/2), s), 8.08 (1H × (1/2), s), 8.37 (1H × (1/2), s), 8.48 (1H × (1 / 2), s), 8.90 (1H, s), 9.85 (1H, s);
MS (FAB) m / z: 773 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₃₆ H ₄₀ F ₃ N ₆ O ₈ S ((M + H) ⁺ ): 773.2580. Found: 773.2554.
Anal.calcd for C ₃₆ H ₃₉ F ₃ N ₆ O ₈ S ・ (3/4) HCl ・ (3/2) H ₂ O: C, 52.27; H, 5.21; N, 10.16; F, 6.89; Cl, 3.21; S, 3.88. Found: C, 52.12; H, 5.07; N, 10.12; F, 6.70; Cl, 3.48; S, 3.90.
Example 27 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 = [N-methyl-N-[(4-methyl-1-piperazinyl) acetyl] amino] acetate (Exemplary Compound 1-328)
(27a) Ethyl = [N-methyl-N-[(4-methyl-1-piperazinyl) acetyl] amino] acetate ethyl = sarcosinate hydrochloride (ie, ethyl = methylaminoacetate hydrochloride; 1.0 g, 65 mmol) Was dissolved in saturated aqueous sodium hydrogen carbonate solution (50 mL), and the free ethyl sarcosinate was extracted with dichloromethane (50 mL × 6). The obtained organic layers were combined, washed with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude ethyl sarcosinate dichloromethane solution (80 mL).

  This was stirred at room temperature, and (4-methyl-1-piperazinyl) acetic acid (described in (J. Med. Chem., 43, 1489 (2000); 1.2 g, 78 mmol), 4- (N, N-dimethylamino) pyridine (1.1 g, 91 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.6 g, 85 mmol), anhydrous tetrahydrofuran (10 mL), and anhydrous N , N-dimethylformamide (10 mL) was added, and the mixture was stirred at room temperature for 6 days under ice-cooling, aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic layers were combined, washed with saturated brine (50 mL × 1), and dried over anhydrous magnesium sulfate to obtain the crude title compound. Recycle preparative HPLC [LC-908; manufactured by Japan Analytical Industries; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) are used in series; solvent , Chloroform] to give the title compound (1.45 g, yield 87%) as a pale yellow oil.

IR (liquid film) ν _max 3474, 2939, 2800, 1749, 1654, 1459, 1202cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz): δ 1.27 (3H × (1/2), t, J = 7 Hz), 1.31 (3H × (1/2), t, J = 7 Hz), 2.26 ( 3H × (1/2), s), 2.29 (3H × (1/2), s), 2.22-2.57 (8H, m), 3.00 (3H × (1/2), s), 3.15 (1H, s), 3.16 (3H × (1/2), s), 3.24 (1H, s), 4.10 (1H, s), 4.18 (1H, q, J = 7 Hz), 4.22 (1H, s), 4.24 (1H, q, J = 7 Hz);
MS (EI) m / z: 257 (M ⁺ ).
HRMS (EI) m / z: calcd for C ₁₂ H ₂₃ N ₃ O ₃ (M ⁺ ): 257.1739. Found: 257.1732.
(27b) 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 = [ N-methyl-N-[(4-methyl-1-piperazinyl) acetyl] amino] acetate (titled compound)
Ethyl = [N-methyl-N-[(4-methyl-1-piperazinyl) acetyl] amino] acetate (833 mg, 3.2 mmol) prepared in Example 27 (27a) was dissolved in water (10 mL), Cesium carbonate (517 mg, 1.6 mmol) was added thereto and stirred at 70 ° C. for 3.5 hours, and then the aqueous solution was lyophilized. The obtained cesium salt was dissolved in N, N-dimethylformamide (5 mL) and stirred at 0 ° C. Thereto, 1-chloroethyl produced in (1a) of Example 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 ] A solution of propyl carbonate (diastereomer ratio = about 1: 1; 700 mg, 1.1 mmol) in N, N-dimethylformamide (5 mL) and 18-crown-6 (910 mg, 3.2 mmol) were added. After stirring at room temperature for 3 days, ethyl acetate (150 mL) and brine (50 mL) were added to the reaction mixture under ice cooling. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 3). The obtained organic layers were combined, washed with saturated brine (50 mL × 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 recycled by preparative HPLC [LC-908; manufactured by Japan Analytical Industry; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) in series. Used in connection; solvent, chloroform] to give the title object compound (179 mg, yield 20%) as a pale-yellow oil (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 3430, 2938, 2799, 2230, 1770, 1655, 1504, 1276 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.35 (3H × (1/2), d, J = 7 Hz), 1.36 (3H × (1/2), d, J = 7 Hz), 1.53- 1.62 (3H, m), 2.20-4.48 (24H, m), 4.97 (1H × (1/2), d, J = 5 Hz), 4.98 (1H × (1/2), d, J = 5 Hz ), 5.28-5.45 (2H, m), 5.85 (1H × (1/2), dd, J = 15, 5 Hz), 5.85 (1H × (1/2), dd, J = 15, 5 Hz) , 6.58 (1H, dd, J = 14, 12 Hz), 6.73 (1H, d, J = 16 Hz), 6.73 (1H × (1/2), q, J = 6 Hz), 6.81 (1H × ( 1/2), q, J = 6 Hz), 6.79-7.00 (3H, m), 7.33 (1H, dd, J = 10, 2 Hz), 7.39-7.46 (2H, m), 7.57 (1H, t , J = 8 Hz), 7.92 (1H × (1/4), s), 7.93 (1H × (1/4), s), 7.95 (1H × (1/2), s), 7.98 (1H × (1/4), s), 7.99 (1H × (1/2), s), 8.17 (1H × (1/4), s);
MS (FAB) m / z: 842 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₄₀ H ₄₇ F ₃ N ₇ O ₈ S ((M + H) ⁺ ): 842.3159. Found: 842.3154.
A solution of the title object compound obtained above (diastereomeric ratio = about 1: 1; 159 mg, 0.19 mmol) in ethyl acetate (5 mL) was cooled to 0 ° C. and stirred into hydrogen chloride (4 N Ethyl acetate solution; 47 μL, 0.19 mmol) was added. The oily residue obtained by evaporating the solvent under reduced pressure was dissolved in water (5 mL) at 0 ° C., and the insoluble material was removed by filtration through a membrane filter. The obtained filtrate was lyophilized to give the hydrochloride of the title object compound (153 mg) as a colorless amorphous solid (diastereomer ratio = about 1: 1).

IR (KBr) ν _max 3418, 2936, 2849, 2230, 1769, 1656, 1615, 1504, 1276 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.24 (3H × (1/2), d, J = 7 Hz), 1.26 (3H × (1/2), d, J = 7 Hz), 1.47-1.56 (3H, m), 2.20-4.40 (24H, m), 5.03 (1H × (1/2), d, J = 4 Hz), 5.04 (1H × (1/2), d, J = 4 Hz), 5.23 (1H × (1/2), d, J = 15 Hz), 5.27 (1H × (1/2), d, J = 15 Hz), 5.38-5.55 (1H, m), 5.88 (1H, d, J = 15, 4 Hz), 6.57 (1H, dd, J = 15, 10 Hz), 6.67 (1H × (1/2), q, J = 6 Hz), 6.70 (1H × ( 1/2), q, J = 6 Hz), 6.82 (1H, d, J = 15 Hz), 7.16-7.22 (2H, m), 7.33-7.38 (1H, m), 7.40-7.55 (1H, m ), 7.68 (1H, dd, J = 8, 2 Hz), 7.84-7.89 (2H, m), 8.06 (1H × (1/2), s), 8.07 (1H × (1/2), s) , 8.36 (1H × (1/4), s), 8.37 (1H × (1/4), s), 8.49 (1H × (1/4), s), 8.51 (1H × (1/4), s), 9.69 (1H, br s);
MS (FAB) m / z: 842 ((M + H) ⁺ ).
HRMS (ESI +) m / z: calcd for C ₄₀ H ₄₇ F ₃ N ₇ O ₈ S ((M + H) ⁺ ): 842.3159. Found: 842.3170.
Anal.calcd for C ₄₀ H ₄₆ F ₃ N ₇ O ₈ S ・ HCl ・ 2H ₂ O: C, 52.54; H, 5.62; N, 10.72; F, 6.23; Cl, 3.88; S, 3.51. Found: C, 52.30; H, 5.31; N, 10.61; F, 6.29; Cl, 3.71; S, 3.65.
Example 28 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 = Hydrogen = Glutarate (Exemplary Compound 1-39)
(28a) Allyl = 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 = Glutarate allyl hydrogen glutarate (described in Tetrahedron Lett., 36, 1701 (1995); 1.53 g, 8.9 mmol) was dissolved in N, N-dimethylformamide (30 mL) and 18-crown was added thereto -6 (2.38 g, 9 mmol) and cesium carbonate (1.30 g, 4 mmol) were added. After stirring at room temperature for 2 hours, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2] prepared in Example 1 (1a)] was prepared. -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propyl carbonate (diastereomer ratio = about 1: 1; 2.52 g, 4 mmol) was added and stirred 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 × 3). The obtained organic layers were combined, washed with water (30 mL × 3) and then with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to leave a residue containing the title compound. I got a thing.

The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate, 65: 35-50: 50, V / V, silica gel 75 g) to obtain the crude title compound (total amount = 2.35 g, title compound). Content = about 1.65 g, yield of the title compound = about 54%, 4-[(1E, 3E) -4- [trans-5-[[(1R, 2R) -2- (2,4 -Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl] -1,3- (Butadienyl) -3-fluorobenzonitrile) was obtained as a colorless, amorphous solid (diastereomeric ratio = approximately 1: 1). This product was used in the next step (28b) without further purification.
(28b) 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 = hydrogen = Glutarate (titled compound)
The crude allyl prepared in Example 28 (28a) = 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 glutarate (content about 0.84 g, about 1.1 mmol; diastereomeric ratio = about 1: 1) was dissolved in dichloromethane (20 mL) and tetrakis (triphenyl) under ice cooling. Phosphine) palladium (62.1 mg, 0.05 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (75.7 mg, 0.54 mmol) were added, and 5 at room temperature under nitrogen atmosphere. Minutes and the mixture was stirred.

  The reaction mixture was subjected to silica gel chromatography (ethyl acetate-methanol, 100: 0-90: 10, V / V, silica gel 25 g) to give the title object compound (577.4 mg, yield about 72%) as a pale yellow, amorphous product. As a solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2231, 1763, 1615, 1504, 1276, 1141, 1056 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.37 (3H, dd, J = 7, 2 Hz), 1.53 (3H × (1/2), d, J = 5 Hz), 1.58 (3H × (1 / 2), d, J = 5 Hz), 1.95-2.09 (2H, m), 2.42-2.54 (4H, m), 2.99 (1H × (1/2), tt, J = 11, 5 Hz), 3.04 (1H × (1/2), tt, J = 11, 5 Hz), 3.46 (1H × (1/2), t, J = 11 Hz), 3.47 (1H × (1/2), t, J = 11 Hz), 3.51 (1H × (1/2), t, J = 11 Hz), 3.53 (1H × (1/2), t, J = 11 Hz), 3.61 (1H × (1/2 ), q, J = 7 Hz), 3.95 (1H × (1/2), q, J = 7 Hz), 4.13 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.19 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.25 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.30 (1H × (1 / 2), ddd, J = 11, 5, 2 Hz), 4.96 (1H × (1/2), d, J = 4 Hz), 5.00 (1H × (1/2), d, J = 4 Hz ), 5.34 (1H × (1/2), d, J = 15 Hz), 5.35 (1H × (1/2), dd, J = 15, 3 Hz), 5.47 (1H × (1/2), dd, J = 15, 2 Hz), 5.48 (1H × (1/2), d, J = 15 Hz), 5.85 (1H × (1/2), dd, J = 15, 4 Hz), 5.86 ( 1H × (1/2), dd, J = 15, 4 Hz), 6.57 (1H × (1/2), dd, J = 15, 11 Hz), 6.58 (1H × (1/2), dd, J = 15, 11 Hz), 6.73 (1H, d, J = 16 Hz), 6.79 (1H, q, J = 5 Hz), 6.86-6.97 (3H, m), 7.33 (1H, d, J = 10 Hz), 7.40 (1H, d, J = 7 Hz), 7.57 (1H, t, J = 8 Hz), 7.81 (1H × (1/2), s), 8.01 (1H × (1/2), s), 8.19 (1H × (1/2), s), 8.36 (1H × (1/2 ), s);
MS (FAB) m / z: 745 ((M + H) ⁺ ).
The title compound prepared above (diastereomer ratio = approximately 1: 1; 283.5 mg, 0.38 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydrogen carbonate (28.8 mg, 0.34 mmol) was dissolved therein. Water (5 mL) solution was added and stirred at room temperature for 5 minutes.

  Tetrahydrofuran was distilled off under reduced pressure, and the insoluble material was removed by filtration through a membrane filter. The resulting aqueous solution was lyophilized, and the sodium salt of the title compound (286.3 mg, 98% yield) was obtained as a colorless, amorphous substance. Obtained as a solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2230, 1763, 1576, 1504, 1418, 1276, 1141, 1055 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.30 (3H × (1/2), dd, J = 7, 2 Hz), 1.34 (3H × (1/2), dd, J = 7, 2 Hz), 1.52 (3H, d, J = 5 Hz), 1.91 (2H × (1/2), quint, J = 8 Hz), 1.91 (2H × (1/2), quint, J = 8 Hz, overlapped), 2.22 (2H, q, J = 8 Hz), 2.40 (1H × (1/2), t, J = 8 Hz), 2.47 (1H × (1/2), t, J = 8 Hz) , 2.95 (1H × (1/2), tt, J = 11, 5 Hz), 2.97 (1H × (1/2), tt, J = 11, 5 Hz), 3.48 (1H × (1/2) , t, J = 11 Hz), 3.48 (1H × (1/2), t, J = 11 Hz, overlapped), 3.49 (1H × (1/2), t, J = 11 Hz), 3.51 (1H × (1/2), t, J = 11 Hz), 3.83 (1H × (1/2), q, J = 7 Hz), 3.84 (1H × (1/2), q, J = 7 Hz) , 4.11 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.12 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.25 (1H, ddd , J = 11, 5, 2 Hz), 5.01 (1H × (1/2), d, J = 4 Hz), 5.02 (1H × (1/2), d, J = 4 Hz), 5.45-5.46 (2H, m), 5.87 (1H × (1/2), dd, J = 16, 11 Hz), 5.88 (1H × (1/2), dd, J = 16, 11 Hz), 6.59 (1H, dd, J = 16, 11 Hz), 6.67 (1H × (1/2), q, J = 5 Hz), 6.77 (1H × (1/2), q, J = 5 Hz), 6.79 (1H, d, J = 16 Hz), 6.99-7.10 (2H, m), 7.10 (1H, dd, J = 16, 11 Hz), 7.49-7.54 (3H, m), 7.78 (1H, t, J = 8 Hz ), 7.80 (1H × (1/2) , s), 7.99 (1H × (1/2), s), 8.29 (1H × (1/2), s), 8.41 (1H × (1/2), s);
MS (FAB) m / z: 767 ((total sodium salt + H) ⁺ ).
Example 29 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 = Hydrogen = cis-1,4-cyclohexanedicarboxylate (Exemplary Compound 1-759)
(29a) Allyl = hydrogen = cis-1,4-cyclohexanedicarboxylate cis-1,4-cyclohexanedicarboxylic acid (9.98 g, 58 mmol) was dissolved in N, N-dimethylformamide (100 mL), to which Allyl chloride (10.22 g, 60.9 mmol) and dicyclohexylamine (11.04 g, 60.9 mmol) were added, and the mixture was stirred at 90 ° C. for 1 hour.

  Water (200 mL) and ethyl acetate (100 mL) were added at room temperature, the precipitated solid was filtered through Celite, and the solid was washed with ethyl acetate (100 mL). The mixture of mother liquor and washing solution was partitioned between water and ethyl acetate, and the resulting organic layers were combined and washed with water (100 mL × 3), then with saturated brine (100 mL × 1), and then dried over anhydrous magnesium sulfate, The solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 50:50, V / V, silica gel 200 g) to give the title compound (5.2 g, yield 42%) as yellow. As an oil.

IR (CHCl ₃ ) ν _max 1727, 1706, 1453, 1247, 1170, 1143 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.68-1.78 (4H, m), 1.91-2.00 (4H, m), 2.45-2.6 (2H, m), 5.24 (1H, dd, J = 10, 1 Hz), 5.33 (1H, dd, J = 17, 1 Hz), 5.93 (1H, ddt, J = 17, 10, 5 Hz);
MS (FAB) m / z: 213 ((M + H) ⁺ ).
(29b) allyl = 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 = Cis-1,4-cyclohexanedicarboxylate Allyl = hydrogen = cis-1,4-cyclohexanedicarboxylate (2.06 g, 9.7 mmol) prepared in (29a) of Example 29 was converted to N, N-dimethyl. Dissolved in formamide (30 mL), 18-crown-6 (2.64 g, 10 mmol) and cesium carbonate (1.42 g, 4.4 mmol) were added thereto. After stirring at room temperature for 2 hours, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2] prepared in Example 1 (1a)] was prepared. -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propyl carbonate (diastereomer ratio = approximately 1: 1; 2.59 g, 4 mmol) was added and stirred at room temperature for 17 hours.

  Under ice-cooling, phosphate buffer (60 mL) was added to the reaction mixture, and the product was extracted with ethyl acetate (50 mL × 3). The obtained organic layers were combined, washed with water (30 mL × 3) and then with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to leave a residue containing the title compound. I got a thing.

The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate, 50: 50-20: 80, V / V, silica gel 75 g) to obtain the crude title compound (total amount = 2.68 g, title). Compound content = about 1.68 g, yield of the title compound = about 59%, 4-[(1E, 3E) -4- [trans-5-[[(1R, 2R) -2- (2, 4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl] -1,3 -Butadienyl] -3-fluorobenzonitrile) was obtained as a colorless, amorphous solid (diastereomeric ratio = approximately 1: 1). This product was used in the next step (29c) without further purification.
(29c) 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 = hydrogen = Cis-1,4-cyclohexanedicarboxylate (titled compound)
Crude allyl prepared in Example 29 (29b) = 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 cis-1,4-cyclohexanedicarboxylate (content about 0.84 g, 1.0 mmol) was dissolved in dichloromethane (20 mL) and tetrakis (triphenylphosphine) was cooled with ice. Add palladium (58.7 mg, 0.05 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (70.1 mg, 0.5 mmol) and add 8 at room temperature under nitrogen atmosphere. Minutes and the mixture was stirred.

  The reaction mixture was subjected to silica gel chromatography (ethyl acetate-methanol, 100: 0-90: 10, V / V, silica gel 20 g) to give the title object compound (0.53 g, yield about 67%) as a colorless amorphous product. As a solid (diastereomeric ratio = about 1: 1).

IR (KBr) ν _max 2231, 1763, 1615, 1504, 1276, 1140, 1061, 973 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, dd, J = 7, 2 Hz), 1.55 (3H × (1/2), d, J = 5 Hz), 1.56 (3H × (1 / 2), d, J = 5 Hz), 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 ( 1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz , overlapped), 3.50 (1H × (1/2), t, J = 11 Hz), 3.75 (1H × (1/2), q, J = 7 Hz), 3.90 (1H × (1/2), q, J = 7 Hz), 4.17 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.19 (1H × (1/2), ddd, J = 11,, 2 Hz) , 4.25-4.30 (1H, m). 4.98 (1H, d, J = 4 Hz), 5.36 (1H × (1/2), dd, J = 15, 3 Hz), 5.36 (1H × (1/2 ), dd, J = 15, 3 Hz, overlapped), 5.42 (1H × (1/2), d, J = 15 Hz), 5.43 (1H × (1/2), d, J = 15 Hz), 5.86 (1H, dd, J = 15, 4 Hz), 6.59 (1H, dd, J = 15, 11 Hz), 6.71 (1H × (1/2), q, J = 5 Hz), 6.74 (1H, d, J = 16 Hz), 6.76 (1H × (1/2), q, J = 5 Hz), 6.85-6.96 (2H, m), 6.94 (1H, dd, J = 16, 11 Hz), 7.34 (1H, dd, J = 10, 1 Hz), 7.41 (1H, dd, J = 8, 1 Hz), 7.35-7.47 (1H, m), 7.78 (1H, t, J = 8 Hz), 7.94 ( 1H × (1/2), s), 7.98 (1H × (1/2), s), 8.05 (1H × (1/2), s), 8.12 (1H × (1/2), s).
MS (FAB) m / z: 785 ((M + H) ⁺ )
The title compound prepared above (diastereomer ratio = about 1: 1; 333.4 mg, 0.42 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydrogen carbonate (33.9 mg, 0.40 mmol) was dissolved therein. Water (5 mL) solution was added and stirred at room temperature for 5 minutes.

  Tetrahydrofuran was distilled off under reduced pressure, and the insoluble material was removed by filtration through a membrane filter. The aqueous solution obtained was lyophilized, and the sodium salt of the title object compound (138.8 mg, yield 41%) was colorless and amorphous. Obtained as a solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2231, 1762, 1614, 1563, 1504, 1417, 1276, 1141, 1059, 973 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.30 (3H × (1/2), dd, J = 7, 2 Hz), 1.33 (3H × (1/2), dd, J = 7, 2 Hz), 1.52 (3H × (1/2), d, J = 4 Hz), 1.54 (3H × (1/2), d, J = 4 Hz), 1.55-1.7 (4H, m), 1.8- 1.9 (2H, m), 1.9-2.1 (4H, m), 2.95 (1H × (1/2), tt, J = 11, 5 Hz), 2.97 (1H × (1/2), tt, J = 11, 5 Hz), 3.47 (1H × (1/2), t, J = 11 Hz), 3.48 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2 ), t, J = 11 Hz), 3.51 (1H × (1/2), t, J = 11 Hz), 3.80 (1H × (1/2), q, J = 7 Hz), 3.82 (1H × (1/2), q, J = 7 Hz), 4.11 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.12 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.26 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.27 (1H × (1/2), ddd, J = 11, 5, 2 Hz ), 5.01 (1H × (1/2), d, J = 4 Hz), 5.02 (1H × (1/2), d, J = 4 Hz), 5.4-5.5. (2H, m), 5.86 ( 1H × (1/2), dd, J = 16, 11 Hz), 5.87 (1H × (1/2), dd, J = 16, 11 Hz), 6.59 (1H, dd, J = 16, 11 Hz ), 6.67 (1H × (1/2), q, J = 4 Hz), 6.78 (1H × (1/2), q, J = 4 Hz), 6.79 (1H, d, J = 16 Hz), 7.0-7.12 (3H, m), 7.5-7.6 (3H, m), 7.78 (1H, t, J = 8 Hz), 7.98 (1H × (1/2), s), 8.04 (1H × (1 / 2), s), 8.28 (1H × (1/2), s), 8.42 (1H × (1/2), s).
Example 30 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 = Hydrogen = trans-1,4-cyclohexanedicarboxylate (Exemplary Compound 1-759)
(30a) Allyl = hydrogen = trans-1,4-cyclohexanedicarboxylate Trans-1,4-cyclohexanedicarboxylic acid (9.98 g, 58 mmol) is dissolved in N, N-dimethylformamide (100 mL), and iodine is added thereto. Allyl chloride (10.22 g, 60.9 mmol) and dicyclohexylamine (11.04 g, 60.9 mmol) were added, and the mixture was stirred at 90 degrees for 1 hour.

  Water (200 mL) and ethyl acetate (100 mL) were added at room temperature, the precipitated solid was filtered through celite, and the solid was washed with ethyl acetate (100 mL). The mixture of mother liquor and washing solution was partitioned between water and ethyl acetate, and the resulting organic layers were combined and washed with water (100 mL × 3), then with saturated brine (100 mL × 1), and then dried over anhydrous magnesium sulfate, The solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 50:50, V / V, silica gel 150 g) to give the title compound (4.24 g, yield 34%) as yellow. As a solid.

Mp 47-49 ° C
IR (KBr) ν _max 1729, 1695, 1323, 1259, 1174 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.43-1.53 (4H, m), 2.04-2.15 (4H, m), 2.30-2.34 (2H, m), 4.58 (2H, d, J = 6 Hz) , 5.23 (1H, d, J = 10 Hz), 5.31 (1H, d, J = 17 Hz), 5.91 (1H, ddt, J = 17, 10, 6 Hz).
(30b) Allyl = 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 = Trans-1,4-cyclohexanedicarboxylate allyl hydrogen prepared in Example 30 (30a) = trans-1,4-cyclohexanedicarboxylate (2.06 g, 9.7 mmol) was converted to N, N-dimethyl Dissolved in formamide (30 mL), 18-crown-6 (2.64 g, 10 mmol) and cesium carbonate (1.42 g, 4.4 mmol) were added thereto. After stirring at room temperature for 2 hours, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2] prepared in Example 1 (1a)] was prepared. -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propyl carbonate (diastereomer ratio = approximately 1: 1; 2.59 g, 4 mmol) was added 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 extracted with ethyl acetate (50 mL × 3). The obtained organic layers were combined, washed with water (30 mL × 3) and then with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to leave a residue containing the title compound. I got a thing.

The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate, 50: 50-20: 80, V / V, silica gel 75 g) to obtain the crude title compound (total amount: 2.43 g, title). Compound content = 1.62 g, yield of the title compound = 49%, 4-[(1E, 3E) -4- [trans-5-[[(1R, 2R) -2- (2,4- Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl] -1,3-butadienyl ] -3-fluorobenzonitrile) was obtained as a colorless, amorphous solid (diastereomer ratio = approximately 1: 1). This product was used in the next step (30c) without further purification.
(30c) 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 = hydrogen = Trans-1,4-cyclohexanedicarboxylate Crude allyl prepared in Example 30 (30b) = 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-triazole-1- Yl) methyl] propoxy] carbonyloxy] ethyl = trans-1,4-cyclohexanedicarboxylate (content about 1.07 g, about 1.3 mmol) was dissolved in dichloromethane (25 mL), and tetrakis (triphenyl) was cooled with ice. Phosphine) palladium (75 mg, 0.065 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (98.1 mg, 0.7 mmol) were added, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere.

  The reaction mixture was subjected to silica gel chromatography (ethyl acetate-methanol, 100: 0-90: 10, V / V, silica gel 20 g) to give the title object compound (0.48 g, yield 47%) as a pale yellow amorphous substance. As a solid (diastereomeric ratio = about 1: 1).

IR (KBr) ν _max 2231, 1763, 1615, 1504, 1276, 1140, 1061, 973 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.35 (3H, dd, J = 7, 2 Hz), 1.40-1.58 (4H, m), 1.54 (3H × (1/2), d, J = 5 Hz), 1.55 (3H × (1/2), d, J = 5 Hz), 2.01-2.17 (4H, m), 2.28-2.40 (2H, m), 2.97 (1H × (1/2), tt , J = 1, 5 Hz), 3.03 (1H × (1/2), tt, J = 11, 5 Hz), 3.44 (1H × (1/2), t, J = 11 Hz), 3.47 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz, overlapped), 3.62 (1H × (1/2), q, J = 7 Hz), 3.90 (1H × (1/2), q, J = 7 Hz), 4.12 (1H × (1/2), ddd , J = 11, 5, 2 Hz), 4.19 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.25 (1H × (1/2), ddd, J = 11, 5 , 2 Hz), 4.28 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.95 (1H × (1/2), d, J = 4 Hz), 4.98 (1H × ( 1/2), d, J = 4 Hz), 5.36 (1H × (1/2), dd, J = 15, 3 Hz), 5.38 (1H, s), 5.46 (1H × (1/2), d, J = 15 Hz), 5.83 (1H × (1/2), dd, J = 16, 4 Hz), 5.85 (1H × (1/2), dd, J = 16, 4 Hz), 6.56 ( 1H × (1/2), dd, J = 16, 11 Hz), 6.58 (1H × (1/2), dd, J = 16, 11 Hz), 6.69 (1H × (1/2), q, J = 5 Hz), 6.73 (1H, d, J = 16 Hz), 6.75 (1H × (1/2), q, J = 5 Hz), 6.84-6.96 (2H, m), 6.91 (1H, dd , J = 16, 11 Hz), 7.31 (1H × (1/2), dd , J = 10, 1 Hz), 7.33 (1H × (1/2), dd, J = 10, 1 Hz), 7.37-7.42 (2H, m), 7.56 (1H, t, J = 8 Hz), 7.92 (1H × (1/2), s), 8.0 (1H × (1/2), s), 8.08 (1H × (1/2), s), 8.21 (1H × (1/2), s ).
The title compound prepared above (201.7 mg, 0.26 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of sodium hydrogen carbonate (20.5 mg, 0.25 mmol) in water (5 mL) was added thereto at room temperature. Stir for 5 minutes.

  Tetrahydrofuran was distilled off under reduced pressure, and the insoluble material was removed by filtration through a membrane filter. The aqueous solution obtained was lyophilized, and the sodium salt of the title object compound (178.8 mg, yield 86%) was colorless and amorphous Obtained as a solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2231, 1763, 1560, 1504, 1418, 1276, 1141 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.30 (3H × (1/2), dd, J = 7, 2 Hz), 1.32 (3H × (1/2), dd, J = 7, 2 Hz), 1.37-1.48 (4H, m), 1.52 (3H × (1/2), d, J = 5 Hz), 1.53 (3H × (1/2), d, J = 5 Hz), 1.9- 2.1 (6H, m), 2.96 (1H × (1/2), tt, J = 11, 5 Hz), 2.97 (1H × (1/2), tt, J = 11, 5 Hz), 3.46 (1H × (1/2), t, J = 11 Hz), 3.48 (1H × (1/2), t, J = 11 Hz), 3.48 (1H × (1/2), t, J = 11 Hz, overlapped), 3.50 (1H × (1/2), t, J = 11 Hz), 3.78 (1 × (1/2), q, J = 7 Hz), 3.79 (1H × (1/2), q , J = 7 Hz), 4.11 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.12 (1H × (1/2), ddd, J = 11, 5, 2 Hz) , 4.25 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.26 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 5.01 (1H, d , J = 4 Hz), 5.4-5.5 (2H, m), 5.86 (1H × (1/2), dd, J = 16, 4 Hz), 5.87 (1H × (1/2), dd, J = 16, 4 Hz), 6.58 (1H, dd, J = 16, 11 Hz), 6.65 (1H × (1/2), q, J = 5 Hz), 6.75 (1H × (1/2), q, J = 5 Hz), 6.79 (1H, d, J = 16 Hz), 7.00-7.10 (3H, m), 7.50-7.60 (3H, m), 7.78 (1H, t, J = 8 Hz), 7.99 ( 1H × (1/2), s), 8.05 (1H × (1/2), s), 8.30 (1H × (1/2), s), 8.43 (1H × (1/2), s).
Example 31 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 = 4- [4- (2-hydroxyethyl) -1-piperazinyl] -4-oxobutyrate (Exemplary Compound 1-73)
(31a) 1- [2-[(tert-Butyldimethylsilyl) oxy] ethyl] piperazine Commercially available 4- (2-hydroxyethyl) piperazine (6.51 g, 50 mmol) and triethylamine (10.1 g, 100 mmol) were dissolved in tetrahydrofuran. Tert-Butylchlorodimethylsilane (15 g, 100 mmol) was added to the solution dissolved in (100 mL) and stirred under ice-cooling. The mixture was stirred for 15 minutes under ice-cooling, 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 diethyl ether were added to separate the layers. The obtained organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain an oily residue.

  The resulting oily residue was purified using alumina column chromatography (toluene: ethyl acetate, 100: 0-80: 20, V / V, 200 g of activity I alumina). The product (7.5 g) was obtained as a colorless oil. This product contained tert-butyldimethylsilanol and was used in the next step (Example 31 (31b)) without further purification. The molar ratio of the target compound to tert-butyldimethylsilanol was about 2: 1 (determined by the integral ratio of NMR). The pure product was obtained as a colorless oil by purifying a part of the mixture using silica gel column chromatography (2-propanol: diethylamine, 90:10, V / V).

IR (CHCl ₃ ) ν _max 2953, 2931, 1471, 1463, 1257, 1101 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.058 (6H, s), 0.891 (9H, s), ca.1.6 (1H, br), ca.2.5 (4H, br), 2,511 (2H, t, J = 6.5 Hz), 2.882 (4H, t, J = 5 Hz), 3.755 (2H, t, J = 6.5 Hz);
MS (FAB) m / z: 245 ((M + H) ⁺ );
HRMS (ESI +) m / z: calcd for C ₁₂ H ₂₉ N ₂ OSi ((M + H) ⁺ ): 245.2049. Found: 245.2043.
(31b) 4- [4- [2-[(tert-Butyldimethylsilyl) oxy] ethyl] -1-piperazinyl] -4-oxobutyric acid Crude 1- [2-produced in (31a) of Example 31 [(Tert-Butyldimethylsilyl) oxy] ethyl] piperazine (containing tert-butyldimethylsilanol as impurities; 1.0 g, 1- [2-[(tert-butyldimethylsilyl) oxy] ethyl] piperazine content = about 3.2 mmol) was dissolved in tetrahydrofuran (20 mL), and succinic anhydride (400 mg, 4.0 mmol) was added to the solution while stirring under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Thereto was added triethylamine (101 mg, 1.0 mmol), and the mixture was further stirred at room temperature for 1 hour.

  The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (ethyl acetate: ethanol, 50:50, V / V, 10 g of silica gel) to give the crude title compound as an oil (one (Partially solidified). It was recrystallized from a mixed solvent of hexane-ethyl acetate to obtain a pure title object compound (980 mg, a yield of about 89% considering the purity of the raw material) as colorless and hygroscopic needle-like crystals.

Mp 85-90 ° C;
IR (KBr) ν _max 1721, 1650, 1643, 1455, 1256, 1240, 1103 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.059 (6H, s), 0.890 (9H, s), 2.5-2.7 (9H, m), 2.585 (2H, t, J = 6 Hz), 3.512 (2H , t-like, J = 5 Hz), 3.660 (2H, t-like, J = 5 Hz), 3.773 (2H, t, J = 6 Hz);
MS (FAB) m / z: 345 ((M + H) ⁺ );
HRMS (ESI +) m / z: calcd for C ₁₆ H ₃₃ N ₂ O ₄ Si ((M + H) ⁺ ): 345.2210. Found: 345.2202.
(31c) 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 = 4 -[4- [2-[(tert-Butyldimethylsilyl) oxy] ethyl] -1-piperazinyl] -4-oxobutyrate 4- [4- [2-[(prepared in (31b) of Example 31] tert-butyldimethylsilyl) oxy] ethyl] -1-piperazinyl] -4-oxobutyric acid (318 mg, 0.923 mmol), potassium tert-butoxide (78 mg, 0.70 mmol), and N, N- Into a mixture of dimethylacetamide (2 mL) 1-chloroethyl prepared in Example 1 (1a) = (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 carbonate (diastereomer ratio = approximately 1: 1; 300 mg, 0.64 mmol) in N, N-dimethylacetamide (5 mL) is added and the mixture is stirred at room temperature for 1 hour. Then, the mixture was stirred at 50 ° C. for 4 hours and further at 60 ° C. for 3 hours.

  An aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the mixture for liquid separation, and the resulting organic layer was separated, washed 5 times with 10% brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the crude title compound as a mixture of two diastereomers (diastereomeric ratio = about 1: 1).

  The obtained mixture was subjected to silica gel column chromatography (silica gel 5 g) and eluted with an ethyl acetate: 2-propanol mixed solvent (96: 4, V / V) to give a diastereomer A having low polarity (33 mg, (Yield 7%) was obtained as a colorless gum. Next, eluting with a mixed solvent of ethyl acetate: 2-propanol (96: 6-92: 8, V / V) to obtain a mixture of low-polar diastereomer A and high-polar diastereomer B (29 mg, yield) 7%) was obtained as a colorless gum. Furthermore, elution was performed with an ethyl acetate: 2-propanol mixed solvent (90:10, V / V) to obtain a highly polar diastereomer B (38 mg, 9% yield) as a colorless gum.

Spectral data for diastereomer A (low polarity):
IR (CHCl ₃ ) ν _max 2233, 1764, 1643, 1505, 1277, 1258, 1141 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.055 (6H, s), 0.887 (9H, s), 1.356 (3H, dd, J = 7, 2 Hz), 1.552 (3H, d, J = 6 Hz ), 2.47 (2H, t-like, J = 5 Hz), 2.530 (4H, t, J = 6 Hz), 2.54-2.80 (4H, m), 3.030 (1H, tt, J = 11, 5 Hz) , 3.4-3.5 (2H, m), 3.486 (1H, t, J = 11 Hz), 3.498 (1H, t, J = 11 Hz), 3.59 (2H, t-like, J = 5 Hz), 3.749 ( 2H, t, J = 6 Hz), 3.881 (1H, q, J = 7 Hz), 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, br s), 5.853 (1H, dd, J = 15, 4 Hz), 6.579 (1H, dd, J = 15, 11 Hz ), 6.733 (1H, q, J = 6 Hz), 6.734 (1H, d, J = 15 Hz), 6.8-7.0 (2H, m), 6.929 (1H, dd, J = 15, 11 Hz), 7.332 (1H, dd, J = 10, 2 Hz), 7.398 (1H, dd, J = 8, 2 Hz), 7.428 (1H, td, J = 9, 6 Hz), 7.569 (1H, t, J = 8 Hz), 7.908 (1H, s), 8.020 (1H, s);
MS (FAB) m / z: 957 ((M + H) ⁺ );
HRMS (ESI +) m / z: calcd for C ₄₆ H ₆₀ F ₃ N ₆ O ₉ SSi ((M + H) ⁺ ): 957.3864. Found: 957.3892.
Spectral data of diastereomer B (high polarity):
IR (CHCl ₃ ) ν _max 2233, 1767, 1643, 1505, 1277, 1259, 1141 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.051 (6H, s), 0.884 (9H, s), 1.360 (3H, dd, J = 7, 2 Hz), 1.538 (3H, d, J = 5 Hz ), 2.463 (2H, br t, J = 6 Hz), 2.523 (2H, t, J = 6 Hz), 2.538 (2H, br t, J = 6 Hz), 2.6-2.8 (4H, m), 3.026 (1H, tt, J = 11, 5 Hz), 3.43-3.53 (2H, m), 3.480 (1H, t, J = 11 Hz), 3.491 (1H, t, J = 11 Hz), 3.579 (1H, t, J = 5 Hz), 3.592 (1H, t, J = 5 Hz), 3.744 (2H, t, J = 6 Hz), 3.828 (1H, q, J = 7 Hz), 4.169 (1H, ddd, J = 11, 5, 2 Hz), 4.280 (1H, ddd, J = 11, 5, 2 Hz), 4.971 (1H, d, J = 4 Hz), 5.314 (1H, dd, J = 15, 4 Hz ), 5.444 (1H, d, J = 15 Hz), 5.857 (1H, dd, J = 15, 4 Hz), 6.585 (1H, dd, J = 15, 11 Hz), 6.735 (1H, d, J = 16 Hz), 6.811 (1H, q, J = 5 Hz), 6.84-6.95 (2H, m), 6.931 (1H, dd, J = 16, 11 Hz), 7.331 (1H, dd, J = 10, 2 Hz), 7.35-7.45 (1H, m), 7.395 (1H, dd, J = 8, 2 Hz), 7.571 (1H, t, J = 8 Hz), 7.946 (1H, s), 8.231 (1H, s );
MS (FAB) m / z: 957 ((M + H) ⁺ );
HRMS (ESI +) m / z: calcd for C ₄₆ H ₆₀ F ₃ N ₆ O ₉ SSi ((M + H) ⁺ ): 957.3864. Found: 957.3874.
(31d) 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 = 4 -[4- (2-hydroxyethyl) -1-piperazinyl] -4-oxobutyrate (title target compound)
1-[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1, prepared in (31c) of Example 31, 3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy ] Carbonyloxy] ethyl = 4- [4- [2-[(tert-butyldimethylsilyl) oxy] ethyl] -1-piperazinyl] -4-oxobutyrate Low polarity diastereomer A (30 mg,. 031 mmol) in tetrahydrofuran (1 mL) to which tetrabutylammonium fluoride (26 mg, 0.1 mmol), acetic acid (4 mg, 0.07 mmol), and tetrahydro It was added a mixture of run (0.1 mL).

  After 17 hours, the reaction mixture was diluted with ethyl acetate and washed successively with aqueous sodium hydrogen carbonate solution twice and saturated brine once. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: methanol, 85:15, V / V, silica gel 2.5 g). To obtain the low-polar diastereomer A (8 mg, 30% yield) of the title compound as a colorless oil.

  Similarly, 1-[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl)] prepared in (31c) of Example 31. -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 = 4- [4- [2-[(tert-butyldimethylsilyl) oxy] ethyl] -1-piperazinyl] -4-oxobutyrate highly polar diastereomer B (38 mg , 0.040 mmol) in tetrahydrofuran with tetrabutylammonium fluoride and acetic acid, and silica gel column chromatography (ethyl acetate: methanol, 80:20, V / V). Purification using silica gel 2.5 g), to give more polar diastereomer B (6 mg of the title target compound, 18% yield) as a colorless oil.

Spectral data for diastereomer A (low polarity):
IR (KBr) ν _max 2230, 1764, 1645, 1504, 1447, 1418, 1386, 1276, 1141, 1056 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.357 (3H, dd, J = 7, 2 Hz), 1.556 (3H, d, J = 5 Hz), 2.474 (2H, t-like, J = 5 Hz ), 2.525 (2H, t-like, J = 5 Hz), 2.569 (2H, t-like, J = 5 Hz), 2.6-2.8 (4H, m), 3.031 (1H, tt, J = 11, 5 Hz), 3.4-3.6 (4H, m), 3.5-3.7 (4H, m), 3.635 (1H, q, J = 7 Hz), 4.171 (1H, ddd, J = 11, 5, 2 Hz), 4.300 (1H, ddd, J = 11, 5, 2 Hz), 4.976 (1H, d, J = 4 Hz), 5.376 (2H, br s), 5.854 (1H, dd, J = 16, 4 Hz), 6.581 (1H, dd, J = 16, 11 Hz), 6.738 (1H, q, J = 5 Hz), 6.738 (1H, d, J = 16 Hz), 6.8-7.0 (2H, m), 6.929 (1H, dd, J = 16, 11 Hz), 7.333 (1H, dd, J = 10, 1 Hz), 7.400 (1H, dd, J = 8, 1 Hz), 7.429 (1H, td, J = 9, 6 Hz ), 7.571 (1H, t, J = 8 Hz), 7.907 (1H, s), 8.024 (1H, s);
MS (FAB) m / z: 843 ((M + H) ⁺ );
HRMS (ESI +) m / z: calcd for C ₄₀ H ₄₆ F ₃ N ₆ O ₉ S ((M + H) ⁺ ): 843.2999. Found: 843.2986.
Spectral data of diastereomer B (high polarity):
IR (CHCl ₃ ) ν _max 2233, 1766, 1645, 1505, 1462, 1448, 1383, 1276, 1141, 1056 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.361 (3H, dd, J = 7, 2 Hz), 1.540 (3H, d, J = 5 Hz), 2.51 (2H, m), 2.60 (4H, br , m), 2.6-2.8 (4H, m), 3.027 (1H, tt, J = 11, 5 Hz), 3.481 (1H, t, J = 11 Hz), 3.490 (1H, t, J = 11 Hz) , 3.58 (2H, br m), 3.66 (4H, m), 3.825 (1H, q, J = 7 Hz), 4.170 (1H, ddd, J = 11, 5, 2 Hz), 4.280 (1H, ddd, J = 11, 5, 2 Hz), 4.972 (1H, d, J = 4 Hz), 5.314 (1H, dd, J = 15, 3 Hz), 5.449 (1H, d, J = 15 Hz), 5.857 ( 1H, dd, J = 15, 4 Hz), 6.585 (1H, dd, J = 15, 11 Hz), 6.737 (1H, d, J = 16 Hz), 5.889 (1H, q, J = 5 Hz), 6.8-7.0 (2H, m), 6.906 (1H, 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 = 8 Hz), 7.950 (1H, s), 8.236 (1H, s);
MS (FAB) m / z: 843 ((M + H) ⁺ );
HRMS (ESI +) m / z: calcd for C ₄₀ H ₄₆ F ₃ N ₆ O ₉ S ((M + H) ⁺ ): 843.2999. Found: 843.2991.
An approximately 1: 1 mixture of diastereomer A and diastereomer B of the title target compound (total amount 260 mg, 0.309 mmol) was dissolved in ethyl acetate (20 mL), cooled to −25 ° C., and stirred. Hydrogen chloride (1N ethyl acetate solution; 0.35 mL, 0.35 mmol) was added dropwise therein. The solvent was distilled off under reduced pressure, and the residue was dried in vacuo to obtain the monohydrochloride (250 mg) of the title object compound as a pale yellow solid (diastereomer ratio = about 1: 1).

Example 32 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 = (1-Methyl-4-piperidyl) acetate (Exemplary Compound 1-9)
(32a) Methyl = (1-methyl-4-piperidinylidene) acetate 1-methyl-4-piperidone (4.80 g, 42.4 mmol) and trimethyl = phosphonoacetate (13.8 g, 46.7 mmol) were added to tetrahydrofuran ( (100 mL), and potassium tert-butoxide (5.20 g, 46.4 mmol) was added in portions over 3 minutes while stirring under ice-cooling. The reaction mixture produced a viscous oil that was difficult to stir, but 1,2-dimethoxyethane (50 mL) was added to it and warmed to 30 ° C. so that it could be stirred. The mixture was further stirred at 30 to 35 ° C. for 3 hours to obtain a mixture containing a solid precipitate.

  After cooling, ethyl acetate and water were added to the obtained mixture for liquid separation, and the obtained 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.

  It was purified using silica gel column chromatography (ethyl acetate: methanol, 95: 5-80: 20, V / V, silica gel 50 g) to give the title compound (6.2 g, yield 86%) as a colorless oil. Obtained as a thing.

IR (CHCl ₃ ) ν _max 2949, 2796, 1711, 1656, 1437, 1385, 1279, 1251, 1169 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.295 (3H, s), 2.354 (2H, t-like, J = 6 Hz), 2.468 (2H, t-like, J = 6 Hz), 2.495 (2H , t-like, J = 6 Hz), 3.001 (2H, t-like, J = 6 Hz), 3.691 (3H, s), 5.657 (1H, br s);
MS (EI) m / z: 169 (M ⁺ ), 154, 136, 110.
(32b) Methyl = (1-methyl-4-piperidyl) acetate Methyl = (1-methyl-4-piperidinylidene) acetate (1.01 g, 6.0 mmol) prepared in (32a) of Example 32 was added to ethanol (15 mL). 10% palladium on carbon catalyst (75 mg) was added, and the mixture was stirred at room temperature for 2 hours under an atmosphere of hydrogen (normal pressure).

  The resulting reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.98 g, yield 95%) as a colorless oil.

IR (CHCl ₃ ) ν _max 2941, 2792, 1732, 1448, 1439, 1279, 1173 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.319 (2H, qd-like, J = 11, 4 Hz), ca.1.71 (2H, d-like, J = ca.11 Hz), ca.1.75 ( 1H, m, overlapped), 1.940 (2H, td, J = 11, 2 Hz), ca.2.24 (2H, d, J = ca.7 Hz, overlapped), 2.258 (3H, s), 2.82 (2H, d-like, J = ca.11 Hz), 3.669 (3H, s);
MS (EI) m / z: 171 (M ⁺ ), 170, 156, 140, 112, 96.
(32c) Cesium = (1-methyl-4-piperidyl) acetate Methyl = (1-methyl-4-piperidyl) acetate (0.98 g, 6.0 mmol) prepared in (32b) of Example 32 was added to water (10 mL). ), And cesium carbonate (977 mg, 3.0 mmol) was added thereto, and the mixture was stirred at room temperature for 93 hours.

  The solvent was distilled off under reduced pressure, toluene and methanol were added to the residue, and volatile components were removed again under reduced pressure to obtain the title compound (1.67 g, yield 96%) as a light brown solid.

IR (KBr) ν _max 2932, 2778, 1655, 1574, 1402 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.35 (2H, q-like, J = ca.11 Hz), 1.75-1.85 (3H, m), 2.092 (2H, d-like, J = 7 Hz ), 2.19 (2H, t-like, J = ca.11 Hz), 2.336 (3H, s), 2.940 (2H, d-like, J = ca.11 Hz);
MS (FAB +) m / z: 290 ((total cesium salt + H) ⁺ );
HRMS (FAB-) m / z calcd for C ₈ H ₁₄ NO ₂ ((Non-cesium part) ^- ): 156.1024. Found: 156.1025.
(32d) 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 = ( 1-methyl-4-piperidyl) acetate (title target compound)
Cesium = (1-methyl-4-piperidyl) acetate prepared in Example 32 (32c) (1.16 g, 4.0 mmol), 1-chloroethyl prepared in Example 1 (1a) = (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 carbonate (diastereomeric ratio = approximately 1: 1; 1.30 g, 2 0.0 mmol) and N, N-dimethylacetamide (22 mL) were stirred at 40 ° C. for 8 hours.

  The mixture was cooled to room temperature, and ethyl acetate and 10% brine were added for liquid separation, and the resulting organic layer was separated, washed 3 times with 10% brine, then once with saturated brine, and dried. The extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude title compound.

  The obtained crude title target compound was purified by silica gel column chromatography (ethyl acetate: methanol, 50: 50-0: 100, V / V, silica gel 20 g) to give the title target compound (480 mg, yield 31). %) Was obtained as a brown, amorphous solid (diastereomeric ratio = about 1: 1).

IR (KBr) ν _max 2230, 1763, 1615, 1504, 1277, 1141, 1060 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.25-1.40 (2H, m), 1.357 (3H, d-like, J = 7 Hz), 1.535 (3H × (1/2), d, J = 5 Hz), 1.556 (3H × (1/2), d, J = 5 Hz), 1.6-1.9 (3H, m), 1.87-2.02 (2H, m), 2.2-2.3 (2H × (1/2) , m, overlapped), 2.255 (3H, s), 2.32 (1H × (1/2), dd, J = 15, 7 Hz), 2.36 (1H × (1/2), dd, J = 15, 7 Hz), 2.7-2.9 (2H, m), 2.998 (1H × (1/2), tt, J = 11, 5 Hz), 3.020 (1H × (1/2), tt, J = 11, 5 Hz ), 3.471 (1H × (1/2), t, J = 11 Hz), 3.478 (1H × (1/2), t, J = 11 Hz), 3.478 (1H × (1/2), t, J = 11 Hz, overlapped), 3.500 (1H × (1/2), t, J = 11 Hz), 3.747 (1H × (1/2), q, J = 7 Hz), 3.883 (1H × (1 / 2), q, J = 7 Hz), 4.15 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.18 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.27 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.28 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.967 (1H, d, J = 4 Hz), 5.33 (1H, dd, J = 15, 4 Hz), 5.40 (1H, d, J = 15 Hz), 5.854 (1H, dd, J = 16, 4 Hz) ), 6.581 (1H, dd, J = 16, 11 Hz), 6.678 (1H × (1/2), q, J = 5 Hz), 6.735 (1H, d, J = 16 Hz), 6.76 (1H × (1/2), q, J = 5 Hz), 6.85-6.95 (2H, m), 6.931 (1H, dd, J = 16, 11 Hz), 7.335 (1H, dd, J = 10, 2 Hz), 7.400 (1H, dd, J = 8, 2 Hz), 7.401 (1H × (1/2), td, J = 9, 6 Hz), 7.432 (1H × (1 / 2), td, J = 9, 6 Hz), 7.569 (1H, t, J = 8 Hz), 7.940 (1H × (1/2), s), 7.944 (1H × (1/2), s ), 7.995 (1H × (1/2), s), 8.021 (1H × (1/2), s);
MS (FAB) m / z: 770 ((M + H) ⁺ );
HRMS (ESI +) m / z: calcd for C ₃₈ H ₄₃ F ₃ N ₅ O ₇ S ((M + H) ⁺ ): 770.2836. Found: 770.2805.
The title compound prepared above (diastereomeric ratio = approximately 1: 1; 475 mg, 0.617 mmol) is dissolved in ethyl acetate (40 ml), cooled to −30 ° C. and stirred into hydrogen chloride. (1N ethyl acetate solution; 0.75 ml, 0.75 mmol) was added dropwise. The solvent was distilled off under reduced pressure, and the residue was dried in vacuo to obtain the monohydrochloride (570 mg, diastereomeric ratio = about 1: 1) of the title object compound as a tan solid.

Example 33 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 = Hydrogen = Adipate (Exemplary Compound 1-795)
(33a) allyl = 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 = Adipate Allyl hydrogen adipate (described in J. Am. Chem. Soc., 78, 104 (1956); 1.87 g, 10 mmol) dissolved in N, N-dimethylformamide (30 mL) 18-Crown-6 (2.91 g, 11 mmol) and cesium carbonate (1.47 g, 4.5 mmol) were added. After stirring for 5 hours at room temperature, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2) prepared in (1a) of Example 1]. -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propyl carbonate (diastereomeric ratio = approximately 1: 1; 2.52 g, 4 mmol) was added and stirred at room temperature for 15 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 × 3). The obtained organic layers were combined, washed with water (30 mL × 3) and then with saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to leave a residue containing the title compound. I got a thing.

The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate, 65: 35-50: 50, V / V, silica gel 75 g) to obtain the crude title compound (total amount = 2.55 g, title compound). Content = about 1.51 g, yield of the title compound = about 47%, 4-[(1E, 3E) -4- [trans-5-[[(1R, 2R) -2- (2,4 -Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl] -1,3- (Butadienyl) -3-fluorobenzonitrile) was obtained as a colorless, amorphous solid (diastereomeric ratio = approximately 1: 1). This product was used in the next step (33b) without further purification.
(33b) 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 = hydrogen = Adipate (titled compound)
The crude allyl prepared in Example 33 (33a) = 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 = adipate (content about 0.80 g, about 1 mmol; diastereomeric ratio = about 1: 1) was dissolved in dichloromethane (20 mL) and tetrakis (triphenylphosphine) under ice cooling. Palladium (34.7 mg, 0.03 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (84.1 mg, 0.6 mmol) were added, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. It was.

  The reaction mixture was subjected to silica gel chromatography (ethyl acetate-methanol, 100: 0-95: 5, V / V, silica gel 25 g) to give the title object compound (603.1 mg, about 76% yield) as a pale yellow and amorphous product. As a solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2231, 1763, 1504, 1276, 1140, 1057, 973 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H × (1/2), dd, J = 7, 2 Hz), 1.38 (3H × (1/2), dd, J = 7, 2 Hz ), 1.53 (3H × (1/2), d, J = 5 Hz), 1.56 (3H × (1/2), d, J = 5 Hz), 1.65-1.8 (4H, m), 2.3-2.5 (4H, m), 3.02 (1H × (1/2), tt, J = 11, 5 Hz), 3.03 (1H × (1/2), tt, J = 11, 5 Hz), 3.47 (1H × (1/2), t, J = 11 Hz), 3.48 (1H × (1/2), t, J = 11 Hz), 3.50 (1H × (1/2), t, J = 11 Hz), 3.51 (1H × (1/2), t, J = 11 Hz), 3.70 (1H × (1/2), q, J = 7 Hz), 3.91 (1H × (1/2), q, J = 7 Hz), 4.15 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.19 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.27 ( 1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.29 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.97 (1H × (1/2 ), d, J = 4 Hz), 4.99 (1H × (1/2), d, J = 4 Hz), 5.34 (1H × (1/2), dd, J = 15, 3 Hz), 5.35 ( 1H × (1/2), d, J = 15 Hz), 5.44 (1H × (1/2), dd, J = 15, 3 Hz), 5.47 (1H, d, J = 15 Hz), 5.86 ( 1H, dd, J = 15, 11 Hz), 6.58 (1H, dd, J = 15, 11 Hz), 6.72 (1H × (1/2), q, J = 5 Hz), 6.73 (1H, d, J = 16 Hz), 6.74 (1H × (1/2), q, J = 7 Hz), 6.85-6.96 (3H, m), 7.33 (1H, dd, J = 10, 1 Hz), 7.39 (1H , d, J = 8 Hz), 7.35-7.45 (1H, m), 7.56 (1H, t, J = 8 Hz), 7.87 (1H × (1/2), s), 8.01 (1H × (1/2), s), 8.11 (1H × (1/2), s), 8.25 (1H × (1/2), s).
The title compound prepared above (diastereomer ratio = about 1: 1; 209.1 mg, 0.27 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium bicarbonate (22.1 mg, 0.26 mmol) was dissolved therein. Water (5 mL) solution was added and stirred at room temperature for 5 minutes.

  Tetrahydrofuran was distilled off under reduced pressure, and the insoluble material was removed by filtration through a membrane filter. The resulting aqueous solution was lyophilized, and the sodium salt (210.2 mg, 97% yield) of the title compound was obtained as a colorless, amorphous substance. Obtained as a solid (diastereomeric ratio = approximately 1: 1).

IR (KBr) ν _max 2231, 1763, 1576, 1417, 1276, 1141, 1055, 971 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.30 (3H × (1/2), dd, J = 7, 2 Hz), 1.34 (3H × (1/2), dd, J = 7, 2 Hz), 1.52 (3H, d, J = 7 Hz), 1.62-1.71 (4H, m), 2.14-2.20 (2H, m), 2.36-3.40 (1H, m), 2.42-2.46 (1H, m) , 2.95 (1H × (1/2), tt, J = 11, 5 Hz), 2.96 (1H × (1/2), tt, J = 11, 5 Hz), 3.47 (1H × (1/2) , t, J = 11 Hz), 3.48 (1 × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz), 3.50 (1H × ( 1/2), t, J = 11 Hz), 3.80 (1H × (1/2), q, J = 7 Hz), 3.84 (1H × (1/2), q, J = 7 Hz), 4.09 -4.14 (1H, m), 4.25 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.25 (1H × (1/2), ddd, J = 11, 5, 2 Hz , overlapped), 5.02 (1H, d, J = 4 Hz), 5.46 (2H, br s), 5.87 (1H × (1/2), dd, J = 15, 4 Hz), 5.88 (1H × (1 / 2), dd, J = 15, 4 Hz), 6.59 (1H, dd, J = 15, 11 Hz), 6.66 (1H × (1/2), q, J = 5 Hz), 6.78 (1H × (1/2), q, J = 5 Hz), 6.79 (1H, d, J = 16 Hz), 7.01-7.14 (3H, m), 7.49-7.53 (3H, m), 7.79 (1H, td, J = 8, 3 Hz), 7.99 (1H × (1/2), s), 8.04 (1H × (1/2), s), 8.29 (1H × (1/2), s), 8.42 (1H × (1/2), s).
Example 34 2- [N- [8- [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] ethoxy] -8-oxooctanoyl] -N-methylamino] ethanesulfonic acid (Exemplary Compound 1-806)
(34a) Hydrochloride of isobutyl = 2- (methylamino) ethanesulfonate Isobutyl = 2- [N- (tert-butoxycarbonyl) -N-methylamino] ethanesulfonate prepared in (8a) of Example 8 5.07 g, 17.2 mmol) was dissolved in ethyl acetate (5 mL), hydrogen chloride (4N ethyl acetate solution; 15 mL, about 60 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr.

  Hexane (20 mL) was added to the mixture, and the precipitated solid was collected by filtration and washed with hexane. The obtained solid was dried under reduced pressure to obtain the title compound (3.51 g, yield 88%) as colorless crystals.

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.01 (6H, d, J = 7 Hz), 2.0-2.1 (1H, m), 2.77 (3H, s), 3.48 (2H, t, J = 7 Hz ), 3.69 (2H, t, J = 7 Hz), 4.12 (2H, d, J = 6 Hz);
MS (EI) m / z: 195 (M ⁺ ).
(34b) Allyl = 8- [N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -8-oxooctanoate Allyl hydrogen suberate (J. Amer. Chem. Soc., 120 volumes, 457 (1998); 3.5 g, 16.3 mmol) dissolved in dichloromethane (80 mL) and the hydrochloride of isobutyl = 2- (methylamino) ethanesulfonate prepared in Example 34 (34a) (3.51 g, 15.1 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.12 g, 16.3 mmol), and 4- (dimethylamino) pyridine (2.20 g, 18 mmol) ) And stirred at room temperature for 1 hour.

  The mixture was diluted with dichloromethane and washed with water, then saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 50: 50-20: 80, V / V, silica gel 100 g) to give the title compound (5.24 g, yield 88%). ) Was obtained as a brown oil.

IR (CHCl ₃ ) ν _max 2940, 1730, 1643, 1356, 1170, 972, 941 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.99 (6H, d, J = 7 Hz), 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 = 7 Hz), 3.77 (2H, t, J = 7 Hz), 4.00 (2H, d, J = 7 Hz), 4.57 (2H, d, J = 6 Hz), 5.23 (1H, d, J = 10 Hz), 5.31 (1H, dd, J = 17, 2 Hz), 5.92 (1H, ddt, J = 17 , 10, 6 Hz).
(34c) 8- [N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -8-oxooctanoic acid Allyl prepared in (34b) of Example 34 = 8- [N- [2- (Isobutoxysulfonyl) ethyl] -N-methylamino] -8-oxooctanoate (5.24 g, 13.4 mmol) was dissolved in dichloromethane (50 mL), and tetrakis (triphenylphosphine) palladium ( 774.2 mg, 0.67 mmol) and 5,5-dimethyl-1,3-cyclohexynesandione (1.03 g, 7.4 mmol) were added. After stirring for 1 hour at room temperature under a nitrogen atmosphere, the solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 50: 50-20: 80, V / V, silica gel 100 g) to give the title compound (3.38 g, 72% yield). ) Was obtained as a yellow oil.

IR (CHCl ₃ ) ν _max 2940, 1710, 1642, 1356, 1170, 972, 945 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.99 (6H, d, J = 7 Hz), 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 = 7 Hz), 3.77 (2H, t, J = 7 Hz), 4.00 (2H, d, J = 7 Hz).
(34d) 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 = 8 -[N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -8-oxooctanoate 8- [N- [2- (isobutoxysulfonyl) prepared in (34c) of Example 34 Ethyl] -N-methylamino] -8-oxooctanoic acid (3.37 g, 9.6 mmol) was dissolved in N, N-dimethylformamide (10 mL), and 18-crown-6 (2,64 g, 10 mmol) was dissolved therein. And And cesium carbonate (1.47 g, 4.5 mmol) was added. After stirring at room temperature for 30 minutes, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2] prepared in (1a) of Example 1] was prepared. -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propyl carbonate (diastereomer ratio = approximately 1: 1; 2.6 g, 4 mmol) was added, and the mixture was further stirred at room temperature for 10 hours and then at 40 ° C. for 3 hours and a half.

  Under ice cooling, a phosphate buffer solution (30 mL) was added to the reaction solution, and the product was extracted with ethyl acetate (30 mL × 3). The obtained organic layers were combined, washed with water (10 mL × 3), then saturated brine (30 mL × 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound. Obtained.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 50: 50-20: 80, V / V, silica gel 100 g) to give the title compound (615 mg, yield 16%). , Obtained as a light brown, amorphous solid (diastereomeric ratio = approximately 1: 1).

IR (CHCl ₃ ) ν _max 2977, 2233, 1764, 1642, 1505, 1277, 1141, 1059, 973 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.98 (6H, d, J = 7 Hz), 1.32-1.39 (7H, m), 1.53 (3H × (1/2), d, J = 5 Hz) , 1.54 (3H × (1/2), d, J = 5 Hz), 1.5-1.7 (4H, m), 1.99-2.08 (1H, m), 2.27-2.34 (3H, m), 2.40 (1H, td, J = 7, 5 Hz), 2.88 (3H × (1/2), s), 2.96 (3H × (1/2), s), 2.97-3.06 (1H, m), 3.38 (1H, t , J = 7 Hz), 3.38 (1H, t, J = 7 Hz, overlapped), 3.48 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2), t , J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz, overlapped), 3.50 (1H × (1/2), t, J = 11 Hz), 3.76 (1H, t , J = 7 Hz), 3.77 (1H, t, J = 7 Hz), 3.78-3.85 (1H × (1/2), m), 3.88 (1H × (1/2), q, J = 7 Hz ), 3.99 (2H, d, J = 7 Hz), 4.13-4.20 (1H, m), 4.26 (1H × (1/2), ddd, J = 11, 5, 2 Hz), 4.28 (1H × ( 1/2), ddd, J = 11, 5, 2 Hz), 4.97 (1H, d, J = 4 Hz), 5.33 (1H × (1/2), dd, J = 15, 3 Hz), 5.38 (1H, s), 5.41 (1H × (1/2), d, J = 15 Hz), 5.85 (1H, dd, J = 15, 4 Hz), 6.58 (1H, dd, J = 15, 11 Hz ), 6.68 (1H × (1/2), q, J = 5 Hz), 6.73 (1H, d, J = 16 Hz), 6.77 (1H × (1/2), q, J = 5 Hz), 6.85-6.95 (2H, m), 7.33 (1H, dd, J = 10, 1 Hz), 7.40 (1H, dd, J = 8, 1 Hz), 7.40-7.49 (1H, m) , 7.55-7.60 (1H, m), 7.93 (1H × (1/2), s), 7.94 (1H × (1/2), s), 8.00 (1H × (1/2), s), 8.01 (1H × (1/2), s).
(34e) 2- [N- [8- [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] ethoxy] -8-oxooctanoyl] -N-methylamino] ethanesulfonic acid (title target compound)
1-[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1, prepared in (34d) of Example 34, 3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy ] Carbonyloxy] ethyl = 8- [N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -8-oxooctanoate (diastereomeric ratio = about 1: 1; 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 and a half hours.

The solvent of the reaction solution was distilled off under reduced pressure, and the resulting crude product was subjected to reverse phase column chromatography (acetonitrile: water, 10: 90-30: 70) using Cosmosil 75 C ₁₈ -PREP (manufactured by Nacalai Tesque). , V / V, using 60 g of Cosmosil 75 C ₁₈ -PREP). The eluates were combined and concentrated, and then lyophilized to give the title object compound (diastereomer ratio = about 1: 1) as a sodium salt (colorless amorphous solid, 400 mg, yield 70%).

IR (KBr) ν _max 2230, 1764, 1637, 1617, 1504, 1275, 1204, 1141, 1054, 973 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.30 (3H, dd, J = 7, 2 Hz), 1.32-1.37 (4H, m), 1.52 (3H, d, J = 5 Hz), 1.54- 1.68 (4H, m), 2.30-2.38 (2H, m), 2.39-2.44 (2H, m), 2.91 (3H × (1/2), s), 2.93-3.04 (3H, m), 3.08 (3H × (1/2), s), 3.46 (1H × (1/2), t, J = 11 Hz), 3.48 (1H × (1/2, t, J = 11 Hz), 3.48 (1H × ( 1/2), t, J = 11 Hz, overlapped), 3.51 (1H × (1/2), t, J = 11 Hz), 3.70-3.86 (3H, m), 4.12 (1H, ddd, J = 11, 5, 2 Hz), 4.23-4.28 (1H, m), 5.01 (1H, d, J = 4 Hz), 5.46 (1H, s), 5.47 (1H, s), 5.87 (1H, dd, J = 15, 5 Hz), 6.59 (1H, dd, J = 15, 11 Hz), 6.66 & 6.67 (1H × (1/2) in total, relative intensity = 1: 1, each q, J = 5 Hz) , 6.77 (1H × (1/2), q, J = 5 Hz), 7.00-7.15 (3H, m), 7.18 (1H, dd, J = 16, 11 Hz), 7.49-7.58 (3H, m) , 7.76-7.82 (1H, m), 7.80 & 7.81 (1H × (1/2) in total, relative intensity = 1: 1, each s), 8.04 (1H × (1/2), s), 8.31 ( 1H × (1/2), s), 8.43 (1H × (1/2), s).
Example 35 6- [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] carbonyl Oxy] ethoxy] -6-oxo-1-hexanesulfonic acid (Exemplary Compound 1-800)
(35a) 4-methoxybenzyl = 6- (isobutoxysulfonyl) hexanoate 4-methoxybenzyl = 6-bromohexanoate (Bioorg. Med. Chem. Lett., 7, 225 (1997) 9.20 g, 29.2 mmol) was suspended in a dioxane-water mixed solvent (1: 1, V / V, 120 mL), and sodium sulfite (4.05 g, 32.1 mmol) was added thereto, and 5 ° C. at 125 ° C. Heated to reflux for hours.

  Under reduced pressure, the reaction solution was concentrated to half volume, washed with diethyl ether, tetrabutylammonium hydrogen sulfate (10.9 g, 32.1 mmol) was added to the resulting aqueous layer, and the mixture was stirred at room temperature for 1 hour.

  The product was extracted several times with dichloromethane, and the resulting organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude tetrabutylammonium = 6- (4-methoxybenzyloxy) -6-oxo-1-hexanesulfonate as a colorless oily substance.

  Crude tetrabutylammonium 6- (4-methoxybenzyloxy) -6-oxo-1-hexanesulfonate prepared above was dissolved in dichloromethane (60 mL), and triphosgene (4.33 g, 14. 6 mmol) and N, N-dimethylformamide (0.1 mL) were added, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere.

  The solvent of the reaction solution was distilled off under reduced pressure to obtain crude 4-methoxybenzyl = 6- (chlorosulfonyl) hexanoate.

  Isobutyl alcohol (3.71 g, 50 mmol) was dissolved in pyridine (30 mL), and the crude 4-methoxybenzyl = 6- (chlorosulfonyl) hexanoate prepared above was added under ice-cooling, and 1.5 mL at room temperature was added. Stir for hours.

  Under ice-cooling, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The obtained organic layers were combined and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and then water. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (hexane: ethyl acetate, 100: 10, 100: 20, 100: 50, V / V, silica gel 120 g) to give the title compound (5.63 g, Yield 52%) was obtained as a yellow oil.

IR (CHCl ₃ ) ν _max 2962, 1729, 1613, 1516, 1466, 1356, 1253, 1167, 974 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz): δ 0.98 (6H, d, J = 8 Hz), 1.46 (2H, quint, J = 8 Hz), 1.67 (2H, quint., J = 8 Hz), 1.85 (2H, quint, J = 8 Hz), 2.02 (1H, m), 2.35 (2H, t, J = 8 Hz), 3.06 (2H, t, J = 8 Hz), 3.81 (3H, s), 3.97 (2H, d, J = 7 Hz), 5.05 (2H, s), 6.89 (2H, d, J = 8 Hz), 7.29 (2H, d, J = 8 Hz);
MS (FAB) m / z: 372 (M ⁺ ).
(35b) 6- (Isobutoxysulfonyl) hexanoic acid 4-methoxybenzyl = 6- (isobutoxysulfonyl) hexanoate (3.37 g, 9.05 mmol) prepared in (35a) of Example 35 was converted to anisole (3 4 g), trifluoroacetic acid (12 mL) was added under ice cooling, and the mixture was stirred at room temperature for 40 minutes.

  The solvent of the reaction solution was distilled off under reduced pressure, and azeotroped with toluene three times to obtain the crude title compound.

  The resulting crude title compound was purified using silica gel column chromatography (dichloromethane: ethyl acetate, 100: 10-100: 20, V / V, silica gel 70 g) to give the title compound (1.98 g, yield 87%). ) Was obtained as a colorless solid.

IR (CHCl ₃ ) ν _max 2965, 1740, 1711, 1357, 1342, 1165, 974, 945 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.99 (6H, d, J = 6 Hz), 1.52 (2H, tt, J = 8, 7 Hz), 1.69 (2H, tt, J = 8, 7 Hz) ), 1.90 (2H, tt, J = 8, 7 Hz), 2.03 (1H, m), 2.39 (2H, d, J = 7 Hz), 3.10 (2H, t, J = 8 Hz), 3.98 (2H , d, J = 7 Hz);
MS (FAB) m / z: 253 ((M + H) ⁺ ).
(35c) 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 = 6 -(Isobutoxysulfonyl) hexanoate 6- (Isobutoxysulfonyl) hexanoic acid (2.14 g, 8.50 mmol) prepared in (35b) of Example 35 was dissolved in N, N-dimethylformamide (30 mL). 18-crown-6 (2.26 g, 8.55 mmol) and cesium carbonate (1.38 g, 4.23 mmol) were added thereto. After stirring at room temperature for 1 hour, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2] prepared in Example 1 (1a)] was prepared. -Fluorophenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole- 1-yl) methyl] propyl carbonate (diastereomer ratio = approximately 1: 1; 1.95 g, 3 mmol) was added and stirred at room temperature for 15 hours.

  Under ice cooling, a phosphate buffer was added to the reaction solution, and the crude product was extracted with ethyl acetate (50 mL × 3). The obtained organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (50 mL × 1), water (30 mL × 3), then saturated brine (50 mL × 1), dried over anhydrous magnesium sulfate, To give 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, silica gel 150 g) to obtain the crude title compound (total amount = 2.10 g, title compound). Content = about 798 mg, yield of the title compound = about 31%, 4-[(1E, 3E) -4- [trans-5-[[(1R, 2R) -2- (2,4-difluoro] as an impurity) Phenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl] -1,3-butadienyl] -3-fluorobenzonitrile) was obtained as a colorless, amorphous solid (diastereomeric ratio = about 1: 1). This product was used in the next step (35d) without further purification.
(35d) 6- [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] Ethoxy] -6-oxo-1-hexanesulfonic acid (title target compound)
1-[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1, prepared in (35c) of Example 35, 3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy Carbonyloxy] ethyl = 6- (isobutoxysulfonyl) hexanoate (diastereomer ratio = about 1: 1; 380 mg, 0.439 mmol) was dissolved in acetone (10 mL) and sodium iodide (659 mg, 4. 4 mmol) was added and the mixture was stirred at 45 ° C. for 25 hours.

The solvent of the reaction solution was distilled off under reduced pressure, and the resulting crude product was subjected to reverse phase column chromatography (methanol: water, 20: 80-70: 30) using Cosmosil 75 C ₁₈ -PREP (manufactured by Nacalai Tesque). , V / V, using 75 g of Cosmosil 75 C ₁₈ -PREP). The eluates were combined and concentrated, and then lyophilized to give the title object compound (diastereomer ratio = about 1: 1) as a sodium salt (colorless amorphous solid, 240 mg, 66% yield).

IR (KBr) ν _max 2231, 1764, 1616, 1504, 1418, 1388, 1276, 1258, 1205, 1141, 1050 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.30 (3H × (1/2), dd, J = 7, 2 Hz), 1.34 (3H × (1/2), dd, J = 7, 2 Hz), 1.4-1.5 (2H, m), 1.53 (3H, d, J = 5 Hz), 1.60-1.72 (2H, m), 1.72-1.85 (2H, m), 2.38 (2H × (1/2 ), t, J = 7 Hz), 2.39-2.46 (2H × (1/2), m), 2.73-2.82 (2H, m), 2.90-3.03 (1H, m), 3.47 (1H × (1 / 2), t, J = 11 Hz), 3.486 (1H × (1/2), t, J = 11 Hz), 3.491 (1H × (1/2), t, J = 11 Hz), 3.50 (1H × (1/2), t, J = 11 Hz), 3.80 (1H × (1/2), q, J = 7 Hz), 3.86 (1H × (1/2), q, J = 7 Hz) , 4.12 (1H, ddd, J = 11, 5, 2 Hz), 4.26 (1H, ddd, J = 11, 5, 2 Hz), 5.02 (1H, d, J = 5 Hz), 5.46 (2H × ( 1/2), s), 5.47 (2H × (1/2), s), 5.87 (1H × (1/2), dd, J = 16, 5 Hz), 5.89 (1H × (1/2) , dd, J = 16, 5 Hz), 6.59 (1H, dd, J = 16, 10 Hz), 6.68 (1H × (1/2), q, J = 5 Hz), 6.78 (1H × (1 / 2), q, J = 5 Hz), 6.80 (1H, d, J = 16 Hz), 7.00-7.06 (3H, m), 7.45-7.55 (3H, m), 7.80 (1H × (1/2) , t, J = 8 Hz), 7.81 (1H × (1/2), J = 8 Hz), 8.00 (1H × (1/2), s), 8.04 (1H × (1/2), s) , 8.29 (1H × (1/2), s), 8.42 (1H × (1/2), s);
MS (FAB +) m / z: 831 ((sodium salt + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₃₆ H ₃₈ F ₃ N ₄ O ₁₀ S ₂ Na ₂ ((sodium salt + Na) ⁺ ): 853.1787. Found: 853.1796.
Example 36 5- [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] carbonyl Oxy] ethoxy] -5-oxo-1-pentanesulfonic acid (Exemplary Compound 1-796)
(36a) 4-Methoxybenzyl = 5-bromopentanoate 4-Methoxybenzyl alcohol (4.15 g, 30.0 mmol) was dissolved in dichloromethane (about 100 ml) and stirred under ice-cooling. -Bromovaleric acid (6.52 g, 36.0 mmol), 4- (N, N-dimethylamino) pyridine (4.76 g, 39.0 mmol), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Hydrochloride (6.90 g, 36.0 mmol) was added in order. The mixture was stirred at room temperature for 135 minutes, cooled on ice, quenched with aqueous ammonium chloride solution, and the product was extracted with ethyl acetate. The organic layer was washed successively with 2N hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure, and the obtained residue was sucked with a vacuum pump to give the title compound (7.30 g, yield 81%) as an oil.

IR (CHCl ₃ ) ν _max 1730, 1613, 1515, 1253, 1173 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ ca. 1.77 (2H, quint-like, J = ca. 7 Hz), ca. 1.88 (2H, quint-like, J = ca. 7 Hz), 2.37 ( 2H, t, J = 7 Hz), 3.39 (2H, t, J = 7 Hz), 3.81 (3H, s), 5.05 (2H, s), 6.89 (2H, d, J = 8 Hz), 7.29 ( 2H, d, J = 8 Hz);
MS (FAB +) m / z: 300 (M ⁺ for C ₁₃ H ₁₇ ⁷⁹ BrO ₃ );
HRMS (FAB +) m / z: calcd for C ₁₃ H ₁₇ ⁷⁹ BrO ₃ (M ⁺ ): 300.0361. Found: 300.0350.
(36b) 4-methoxybenzyl = 5- (isobutoxysulfonyl) pentanoate 4-methoxybenzyl = 5-bromopentanoate (7.30 g) prepared in (36a) of Example 36 The title compound (4.27 g, yield 49%) was obtained as an oil by treatment in a manner similar to that described for (35a).

IR (CHCl ₃ ) ν _max 1730, 1613, 1516, 1466, 1356, 1252, 1170, 909 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.974 (6H, d, J = 6 Hz), 1.79 (2H, quint-like, J = ca. 7 Hz), ca. 1.90 (2H, quint-like, J = ca. 7 Hz), 1.95-2.08 (1H, m), 2.38 (2H, t, J = 7 Hz), 3.09 (2H, t, J = 7 Hz), 3.81 (3H, s), 3.97 ( 2H, d, J = 7 Hz), 5.05 (2H, s), 6.89 (2H, d, J = 8 Hz), 7.28 (2H, d, J = 8 Hz);
MS (FAB +) m / z: 358 (M ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₁₇ H ₂₆ O ₆ SNa ((M + Na) ⁺ ): 381.1347. Found: 381.1333.
(36c) 5- (Isobutoxysulfonyl) pentanoic acid 4-methoxybenzyl = 5- (isobutoxysulfonyl) pentanoate (4.27 g, 11.9 mmol) prepared in (36b) of Example 36 The title compound (1.86 g, yield 66%) was obtained as crystals having a melting point of 53 ° C. by a method similar to the method described in 35 (35b).

IR (KBr) ν _max 1703, 1349, 1164, 977 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.987 (6H, d, J = 7 Hz), 1.81 (2H, quint-like, J = ca. 7 Hz), 1.94 (2H, quint-like, J = ca. 7 Hz), 2.0-2.1 (1H, m), 2.431 (2H, t, J = 7 Hz), 3.124 (2H, t, J = 7 Hz), 3.99 (2H, d, J = 7 Hz) ;
MS (FAB +) m / z: 239 (M ⁺ );
HRMS (FAB +, KI addition) m / z: calcd for C ₉ H ₁₈ O ₅ SK ((M + K) ⁺ ): 277.0512. Found: 277.0522.
(36d) 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 = 5 -(Isobutoxysulfonyl) pentanoate 5- (isobutoxysulfonyl) pentanoic acid (953 mg, 4.0 mmol) prepared in (36c) of Example 36 was dissolved in N, N-dimethylformamide (20 ml) to give cesium carbonate. (652 mg, 2.0 mmol) and 18-crown-6 (1.08 g, 4.1 mmol) were added and the mixture was stirred at room temperature for 70 minutes. There, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl)-] produced in Example 1 (1a) was prepared. 1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl ] Propyl carbonate (diastereomeric ratio = about 1: 1; 1.36 g, 2.1 mmol) was added. The mixture was stirred at room temperature for 17 hours and then at 40 ° C. for 3 hours. The mixture was ice-cooled, phosphate buffer was added, and the crude product was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a residue containing the title compound.

The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate, 60: 40-50: 50, V / V, silica gel 60 g) to obtain the crude title compound (total amount = 1.467 g, title compound). Content = about 582 mg, yield of the title compound = about 34%, 4-[(1E, 3E) -4- [trans-5-[[(1R, 2R) -2- (2,4-difluoro] as impurities Phenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl] -1,3-butadienyl] -3-fluorobenzonitrile) was obtained as an amorphous solid (diastereomeric ratio = about 1: 1). This product was used in the next step (36e) without further purification.
(36e) 5- [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] Ethoxy] -5-oxo-1-pentanesulfonic acid (title target compound)
The crude 1-[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl)-] prepared in (36d) of Example 36. 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 = 5- (isobutoxysulfonyl) pentanoate (content about 582 mg, about 0.684 mmol; diastereomeric ratio = about 1: 1) was dissolved in acetone (10 ml) and sodium iodide was added. (1.03 g, 6.84 mmol) was added and stirred at 40-50 ° C. for 9.5 hours.

The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to reverse phase column chromatography (methanol: water, 70:30, V / V, Cosmosil 75) using Cosmosil 75 C ₁₈ -PREP (manufactured by Nacalai Tesque). C ₁₈ -PREP 38 g was used). The eluates were combined and concentrated, and then lyophilized to give the title object compound (diastereomer ratio = about 1: 1) as a sodium salt (colorless amorphous solid, 398 mg, yield 71%).

IR (KBr) ν _max 2231, 1763, 1615, 1504, 1418, 1388, 1276, 1258, 1206, 1141, 1050 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.30 (3H × (1/2), dd, J = 7, 2 Hz), 1.34 (3H × (1/2), dd, J = 7, 2 Hz), 1.53 (3H, d, J = 5 Hz), 1.7-1.9 (4H, m), 2.41 (2H × (1/2), t, J = 7 Hz), 2.44-2.50 (2H × (1 / 2), m), 2.75-2.85 (2H, m), 2.88-3.03 (1H, m), 3.48 (1H, t, J = 11 Hz), 3.49 (1H × (1/2), t, J = 11 Hz), 3.50 (1H × (1/2), t, J = 11 Hz), 3.80 (1H × (1/2), q, J = 7 Hz), 3.86 (1H × (1/2) , q, J = 7 Hz), 4.12 (1H, ddd-like, J = ca. 11, 5, 2 Hz), 4.25 (1H, ddd, J = 11, 5, 2 Hz), 5.02 (1H, d , J = 5 Hz), 5.46 (2H × (1/2), s), 5.47 (2H × (1/2), s), 5.87 (1H × (1/2), dd, J = 15, 5 Hz), 5.89 (1H × (1/2), dd, J = 15, 5 Hz), 6.54-6.63 (2H, m), 6.66 (1H × (1/2), q, J = 5 Hz), 6.78 (1H × (1/2), q, J = 5 Hz), 6.80 (1H, d, J = 16 Hz), 7.0-7.2 (3H, m), 7.45-7.55 (3H, m), 7.80 ( 1H × (1/2), t, J = 8 Hz), 7.81 (1H × (1/2), J = 8 Hz), 8.00 (1H × (1/2), s), 8.04 (1H × ( 1/2), s), 8.31 (1H × (1/2), s), 8.42 (1H × (1/2), s);
MS (FAB-) m / z: 793 ((non-sodium part) ^- );
HRMS (ESI-) m / z: calcd for C ₃₅ H ₃₆ F ₃ N ₄ O ₁₀ S ₂ ((Non-sodium part) ^- ): 793.1825. Found: 793.1809.
Example 37 6-[[(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] carbonyloxymethoxy] -6-oxo-1-hexanesulfonic acid (Exemplary Compound 1-812)
(37a) [(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] carbonyloxymethyl = 6- (isobutoxy Sulfonyl) hexanoate 6- (Isobutoxysulfonyl) hexanoic acid (462 mg, 1.83 mmol) prepared in Example 35 (35b) was dissolved in N, N-dimethylformamide (20 ml) and cesium carbonate (299 mg, 0 .92 mmol) and 18-crown-6 (502 mg, 1.90 mmol) were added and the mixture was stirred at room temperature for 20 minutes before using a commercially available ultrasonic cleaner. Ultrasound was irradiated for 5 minutes. The mixture was removed from the ultrasonic cleaner and stirred there at room temperature, where chloromethyl prepared in Example 14 (14a) = (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 carbonate (1.06 g, 1.50 mmol) was added. The mixture was stirred at room temperature for 4 hours, then ice-cooled, phosphate buffer was added, and the crude product was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a residue containing the title compound.

The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate, 50:50, V / V, silica gel 35 g) to obtain crude title compound (total amount = 1.01 g, content of title compound = about). 902 mg, yield of the title compound = about 71%, 4-[(1E, 3E) -4- [trans-5-[[(1R, 2R) -2- (2,4-difluorophenyl) -2] as an impurity -Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl] -1,3-butadienyl] -3-fluoro Benzonitrile and chloromethyl = (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-[(including 1H-1,2,4-triazol-1-yl) methyl] propyl carbonate) as an amorphous solid Got as. This product was used in the next step (37b) without further purification.
(37b) 6-[[(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] carbonyloxymethoxy] -6 -Oxo-1-hexanesulfonic acid (title target compound)
The crude [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3] prepared in Example 37 (37a). -Butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] Carbonyloxymethyl = 6- (isobutoxysulfonyl) hexanoate (content about 902 mg, about 1.06 mmol) is dissolved in acetone (10 ml), sodium iodide (1.36 g, 6.84 mmol) is added and the mixture is added. The mixture was stirred at 40 to 45 ° C. for 7.7 hours. Acetone (5 ml) was added thereto, and the mixture was further stirred at 40 to 45 ° C. for 30 minutes. Only one half (7.96 g) of this reaction solution (15.93 g) was advanced to purification.

The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to reverse phase column chromatography (methanol: water, 70:30, V / V, Cosmosil 75 C) using Cosmosil 75 C ₁₈ -PREP (manufactured by Nacalai Tesque). _18- PREP 50g was used). The eluates were combined and concentrated and then lyophilized to obtain the title compound as a sodium salt (yield 287 mg, yield 33%; yield 574 mg, yield 66% that would have been obtained when the total amount was purified). .

IR (KBr) ν _max 2231, 1767, 1616, 1504, 1418, 1388, 1275, 1257, 1205, 1142, 1048, 974 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.33 (3H, dd, J = 7, 2 Hz), 1.48 (2H, quint, J = 7 Hz), 1.69 (2H, quint, J = 7 Hz) , 1.81 (2H, quint-like, J = ca. 7 Hz), 2.47 (2H, t, J = 7 Hz), 2.80 (2H, t-like, J = ca. 7 Hz), 2,98 (1H , tt, J = 11, 5 Hz), 3.488 (1H, t, J = 11 Hz), 3.493 (1H, t, J = 11 Hz), 3.85 (1H, q, J = 7 Hz), 4.12 (1H , ddd, J = 11, 5, 2 Hz), 4.24 (1H, ddd, J = 11, 5, 2 Hz), 5.02 (1H, d, J = 4 Hz), 5.47 (2H, br s), 5.79 (2H, s), 5.88 (1H, dd, J = 15, 4 Hz), 6.60 (1H, dd, J = 16, 11 Hz), 6.80 (1H, d, J = 15 Hz), 7.0-7.1 ( 2H, m), 7.11 (1H, dd, J = 15, 11 Hz), 7.44-7.56 (3H, m), 7.80 (1H, t, J = 8 Hz), 8.01 (1H, s), 8.36 (1H , s);
MS (FAB-) m / z: 793 ((non-sodium part) ^- );
HRMS (ESI-) m / z: calcd for C ₃₅ H ₃₆ F ₃ N ₄ O ₁₀ S ₂ ((Non-sodium part) ^- ): 793.1825. Found: 793.1841.
Example 38 2- [N- [8-[[(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] carbonyloxymethoxy] -8-oxooctanoyl] -N-methylamino] ethanesulfonic acid (Exemplary Compound 1-818)
(38a) [(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] carbonyloxymethyl = 8- [N- [2- (Isobutoxysulfonyl) ethyl] -N-methylamino] -8-oxooctanoate 8- [N- [2- (isobutoxysulfonyl) ethyl] -N prepared in (34c) of Example 34 -Methylamino] -8-oxooctanoic acid (2.31 g, 6.57 mmol) was dissolved in N, N-dimethylformamide (30 ml), cesium carbonate (1.07 g, 3.28 mmol) and 18-clau -6 (1.75 g, 6.6 mmol) was added and the mixture was stirred at room temperature for 50 minutes. Thereto, chloromethyl produced in (14a) of Example 14 = (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 carbonate (1.41 g, 2.00 mmol) was added and the mixture was stirred at room temperature for 3.5 hours. Thereafter, extraction and purification were conducted in the same manner as in the procedure described in (34d) of Example 34 to obtain the title compound (1.11 g, yield 58%) as an amorphous solid.

IR (thin film) ν _max 2231, 1768, 1645, 1618, 1504, 1418, 1354, 1274, 1259, 1169, 1141, 975 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.99 (6H, d, J = 7 Hz), 1.32-1.44 (7H, m), 1.58-1.76 (4H, m), 2.03 (1H, nonet, J = 7 Hz), 2.30 (2H, t, J = 7 Hz), 2.44 (2H, t, J = 7 Hz), 3.03 (1H, tt, J = 11, 5 Hz), 3.10 (3H, s), 3.39 (2H, t, J = 7 Hz), 3.49 (1H, t, J = 11 Hz), 3.50 (1H, t, J = 11 Hz), 3.77 (2H, t, J = 7 Hz), 3.90 (1H , q, J = 7 Hz), 4.00 (2H, d, J = 7 Hz), 4.18 (1H, ddd, J = 11, 5, 2 Hz), 4.26 (1H, ddd, J = 11, 5, 2 Hz), 4.98 (1H, d, J = 4 Hz), 5.38 (1H, dd, J = 15, 2 Hz), 5.39 (1H, d, J = 15 Hz), 5.77 (2H, br d), 5.86 (1H, dd, J = 16, 4 Hz), 6.59 (1H, dd, J = 15, 10 Hz), 6.74 (1H, d, J = 16 Hz), 6.86-6.96 (2H, m), 6.93 ( 1H, dd, J = 16, 10 Hz), 7.34 (1H, dd, J = 10, 2 Hz), 7.41 (1H, dd, J = 8, 2 Hz), 7.43 (1H, td, J = 10, 8 Hz), 7.58 (1H, t, J = 8 Hz), 7.93 (1H, s), 7.98 (1H, s);
MS (FAB +) m / z: 950 ((M + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₄₄ H ₅₄ F ₃ N ₅ O ₁₁ S ₂ Na ((M + Na) ⁺ ): 972.3111. Found: 972.3119.
(38b) 2- [N- [8-[[(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] Carbonyloxymethoxy] -8-oxooctanoyl] -N-methylamino] ethanesulfonic acid (title target compound)
[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3-butadienyl] prepared in (38a) of Example 38 ] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy Methyl = 8- [N- [2- (isobutoxysulfonyl) ethyl] -N-methylamino] -8-oxooctanoate (280 mg, 0.295 mmol) was dissolved in acetone (10 ml) and sodium iodide ( 442 mg, 2.95 mmol) was added and the mixture was stirred at 45-50 ° C. for 10 hours. Thereafter, concentration and purification were carried out in the same manner as in the procedure described in Example 34 (34e) to obtain the title object compound as a sodium salt (amorphous solid; yield 220 mg, yield 81%).

IR (KBr) ν _max 2230, 1767, 1635, 1618, 1504, 1418, 1388, 1257, 1206, 1141, 1050, 975 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.33 (3H, d, J = 7 Hz), 1.31-1.43 (4H, m), 1.54-1.62 (2H, m), 1.62-1.69 (2H, m ), 2.33 (2H × (1/2), t, J = 7 Hz), 2.42-2.47 (2H × (1/2) + 2H, m), 2.91 (3H × (1/2), s), 2.91-3.05 (3H, m), 3.08 (3H × (1/2), s), 3.48 (1H, t, J = 11 Hz), 3.49 (1H, t, J = 11 Hz), 3.70-3.78 ( 2H, m), 3.80-3.90 (1H, m), 4.12 (1H, ddd, J = 11, 5, 2 Hz), 4.24 (1H, ddd, J = 11, 5, 2 Hz), 5.01 (1H, d, J = 4 Hz), 5.47 (2H, br s), 5.78 (2H, s), 5.87 (1H, dd, J = 16, 4 Hz), 6.59 (1H, dd, J = 15, 10 Hz) , 6.80 (1H, d, J = 16 Hz), 7.00-7.13 (3H, m), 7.50-7.56 (3H, m), 7.79 (1H, td, J = 8, 2 Hz), 8.01 (1H, s ), 8.37 (1H, s);
MS (FAB +) m / z: 916 ((total sodium salt + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₄₀ H ₄₆ F ₃ N ₅ O ₁₁ S ₂ Na ((total sodium salt + H) ⁺ ): 916.2441. Found: 916.2463.
Example 39 [[4-[[(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 Methoxy] -4-oxobutyryl] amino] acetic acid (Exemplified Compound 1-727)
(39a) Allyl = [(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] carbonyloxymethyl succinate succinate Allyl hydrogen (described in J. Pharm. Sci., 50, 487 (1961); 1.40 g, 8.85 mmol) was dissolved in N, N-dimethylformamide (40 mL), and cesium carbonate (1 .44 g, 4.43 mmol) and 18-crown-6 (2.40 g, 8.85 mmol) were added. After stirring at room temperature for 1 hour, the chloromethyl prepared in Example 14 (14a) = (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-triazole-1 -Yl) methyl] propyl carbonate (2.82 g, 4.00 mmol) was added and the mixture was stirred at room temperature for 2.3 hours. Thereafter, extraction and purification were conducted in the same manner as in Example 6 (6a), and the crude title compound (total amount = 3.10 g, content of title compound = about 2.81 g, yield of title compound = about 93) %, 4-[(1E, 3E) -4- [trans-5-[[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- ( 1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl] -1,3-butadienyl] -3-fluorobenzonitrile and chloromethyl = (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- To give including) a 1,2,4-triazol-1-yl) methyl] propyl = carbonate as an amorphous solid. This product was used in the next step (39b) without further purification.

¹ H NMR (CDCl ₃ , 400 MHz, selected signals): δ 1.37 (3H, dd, J = 7, 2 Hz), 2.65-2.81 (4H, m), 3.04 (1H, tt, J = 11, 5 Hz ), 3.49 (1H, t, J = 11 Hz), 3.50 (1H, t, J = 11 Hz), 3.91 (1H, q, J = 7 Hz), 4.18 (1H, ddd, J = 11, 5, 2 Hz), 4.27 (1H, ddd, J = 11, 5, 2 Hz), 4.60 (2H, dt, J = 6, 1 Hz), 4.98 (1H, d, J = 4 Hz), 5.23 (1H, dd, J = 10, 1 Hz), 5.31 (1H, dd, J = 17, 1 Hz), 5.37 (1H, dd, J = 15, 3 Hz), 5.40 (1H, d, J = 15 Hz), 5.76 (1H, d, J = 6 Hz), 5.81 (1H, d, J = 6 Hz), 5.85 (1H, dd, J = 15, 4 Hz), 5.91 (1H, ddt, J = 17, 10, 7 Hz), 6.58 (1H, dd, J = 15, 10 Hz), 6.73 (1H, d, J = 16 Hz), 6.85-7.00 (3H, m), 7.33 (1H, dd, J = 10, 1 Hz), 7.40 (1H, dd, J = 8, 1 Hz), 7.44 (1H, td, J = 8, 2 Hz), 7.57 (1H, t, J = 8 Hz), 7.94 (1H, s), 8.01 (1H, s);
MS (FAB +) m / z: 757 ((M + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₃₆ H ₃₆ F ₃ N ₄ O ₉ S ((M + H) ⁺ ): 757.2155. Found: 757.2186.
(39b) [(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] carbonyloxymethyl = hydrogen = succinate The crude allyl prepared in 39 (39a) = [(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] Carbonyloxymethyl Cuxinate (content about 2.81 g, about 3.71 mmol) was dissolved in dichloromethane (40 mL), and tetrakis (triphenylphosphine) palladium (215 mg, 0.186 mmol) and 5,5-dimethyl-1,3 were added under ice cooling. -Cyclohexanedione (262 mg, 1.86 mmol) was added, and the mixture was stirred at room temperature for 2.2 hours under a nitrogen atmosphere.

  The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate-methanol, 100: 0-83: 17, V / V, 50 g of silica gel) to give the crude title compound (total amount = 1.10 g). The content of the title compound = about 937 mg, the yield of the title compound = about 35%, and 4-[(1E, 3E) -4- [trans-5-[[(1R, 2R) -2- (2, 4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl] -1,3 -Butadienyl] -3-fluorobenzonitrile and allyl = [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluorophenyl) -1,3 -Butadienyl]- , 3-Dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl succinate Was obtained as an amorphous solid. This product was used in the next step (39c) without further purification.

¹ H NMR (CDCl ₃ , 400 MHz, selected signals): δ 1.37 (3H, d, J = 7 Hz), 2.5-2.8 (4H, m), 3.05 (1H, tt, J = 11, 5 Hz), 3.49 (2H, t, J = 11 Hz), 3.88 (1H, q, J = 7 Hz), 4.17 (1H, ddd, J = 11, 5, 2 Hz), 4.27 (1H, ddd, J = 11, 5, 2 Hz), 4.99 (1H, d, J = 4 Hz), 5.36 (1H, dd, J = 15, 3 Hz), 5.41 (1H, d, J = 15 Hz), 5.72 (1H, d, J = 6 Hz), 5.85 (1H, d, J = 6 Hz), 5.86 (1H, dd, J = 15, 4 Hz), 6.57 (1H, dd, J = 15, 11 Hz), 6.73 (1H, d, J = 16 Hz), 6.84-7.00 (3H, m), 7.33 (1H, d, J = 10 Hz), 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: calcd for C ₃₃ H ₃₂ F ₃ N ₄ O ₉ S ((M + H) ⁺ ): 717.1842. Found: 717.1860.
(39c) Allyl = [[4-[[(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 Methoxy] -4-oxobutyryl] amino] acetate Crude [(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano] prepared in (39b) of Example 39. -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 = hydrogen = succinate (content: about 937 mg, about 1.31 mmol) was dissolved in dichloromethane (20 ml), and the mixture was stirred with ice-cooling while stirring with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 251 mg, 1.31 mmol), 4- (N, N-dimethylamino) pyridine (399 mg, 3.27 mmol), and glycine allyl ester hydrochloride (J. Org. Chem., 57, 6421 (1992)). Description; 238 mg, 1.57 mmol) was added thereto. The ice bath was removed, and the mixture was stirred for 30 minutes while allowing the mixture to naturally warm to room temperature, and then 4- (N, N-dimethylamino) pyridine (200 mg, 1.64 mmol) was added. The mixture was further stirred at room temperature for 1 hour, then ice-cooled, and the reaction was stopped by adding a phosphate buffer. Ethyl acetate was added for liquid separation, and the collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.

  The solvent was distilled off under reduced pressure, and the resulting crude product was purified using silica gel column chromatography (hexane: ethyl acetate, 20: 80-12: 88, V / V, 50 g of silica gel) to give the title compound (162 mg Yield 20%) as an amorphous solid.

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.38 (3H, dd, J = 7, 2 Hz), 2.63 (2H, t, J = 7 Hz), 2.74-2.88 (2H, m), 3.05 (1H , tt, J = 11, 5 Hz), 3.49 (1H, t, J = 11 Hz), 3.50 (1H, t, J = 11 Hz), 3.95 (1H, q, J = 7 Hz), 4.00-4.15 (2H, m), 4.18 (1H, ddd, J = 11, 5, 2 Hz), 4.27 (1H, ddd, J = 11, 5, 2 Hz), 4.64 (2H, br d, J = 5 Hz) , 4.98 (1H, d, J = 4 Hz), 5.25 (1H, dd, J = 10, 1 Hz), 5.33 (1H, dd, J = 17, 1 Hz), 5.34 (1H, dd, J = 15 , 4 Hz), 5.43 (1H, d, J = 15 Hz), 5.71 (1H, d, J = 6 Hz), 5.84 (1H, d, J = 6 Hz), 5.86 (1H, dd, J = 15 , 4 Hz), 5.90 (1H, ddt, J = 17, 10, 5 Hz), 6.59 (1H, dd, J = 15, 11 Hz), 6.74 (1H, d, J = 16 Hz), 6.85-6.95 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.00 (1H, br t, J = 5 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.39 (1H , dd, J = 8, 1 Hz), 7.43 (1H, td, J = 8, 2 Hz), 7.57 (1H, t, J = 8 Hz), 7.97 (1H, s), 8.10 (1H, s) ;
MS (FAB +) m / z: 814 ((M + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₃₈ H ₃₈ F ₃ N ₅ O ₁₀ S ((M + Na) ⁺ ): 836.2189. Found: 836.2164.
(39d) [[4-[[(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] carbonyloxymethoxy] -4-Oxobutyryl] amino] acetic acid (title target compound)
Allyl prepared in (39c) of Example 39 = [[4-[[(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] carbonyloxymethoxy] -4-oxobutyryl] amino] acetate (448 mg, 0.551 mmol) was dissolved in dichloromethane (20 ml) and stirred under ice-cooling while adding tetrakis (triphenylphosphine) palladium ( 31.8 mg, 0.0275 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (38.5 mg, 0.275 mmol) were added. The mixture was stirred for 2.5 hours while naturally warming to room temperature.

Concentrate the reaction solution under reduced pressure, add 0.1 M sodium phosphate buffer (30 ml) to the resulting yellow residue, irradiate the mixture with a commercially available ultrasonic cleaner to remove insoluble matter. Mostly dissolved. The resulting was purified by a substantially uniform solution Cosmosil 75 C ₁₈ -PREP reverse phase column chromatography using (Nacalai Tesque) (Cosmosil 75 C ₁₈ -PREP20g used). The eluates eluted with an acetonitrile-water mixed solvent (30:70, V / V) were combined, concentrated and lyophilized to obtain the title compound as a sodium salt (180 mg, yield 44%).

IR (KBr) ν _max 2230, 1767, 1614, 1275, 1258, 1142, 986, 975 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.33 (3H, dd, J = 7, 2 Hz), 2.62 (2H, t, J = 7 Hz), 2.75 (2H, t, J = 7 Hz) , 2.98 (1H, tt, J = 11, 5 Hz), 3.49 (2H, t, J = 11 Hz), 3.76 (2H, s), 3.85 (1H, q, J = 7 Hz), 4.12 (1H, ddd, J = 11, 5, 2 Hz), 4.24 (1H, ddd, J = 11, 5, 2 Hz), 5.01 (1H, d, J = 4 Hz), 5.45-5.49 (2H, m), 5.77 (1H, d, J = 6 Hz), 5.80 (1H, d, J = 6 Hz), 5.87 (1H, dd, J = 15, 4 Hz), 6.59 (1H, dd, J = 15, 11 Hz) , 6.79 (1H, d, J = 16 Hz), 7.02-7.09 (2H, m), 7.09 (1H, dd, J = 16, 11 Hz), 7.49-7.56 (3H, m), 7.78 (1H, t , J = 8 Hz), 8.02 (1H, s), 8.38 (1H, s);
MS (FAB +) m / z: 796 ((M + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₃₅ H ₃₄ F ₃ N ₅ O ₁₀ SNa ((M + H) ⁺ ): 796.1876. Found: 796.1877.
Example 40 4- [N- [2- [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] ethoxy] -2-oxoethyl] -N-methylamino] -4-oxobutyric acid (Exemplary Compound 1-334)
(40a) N- [4- (allyloxy) -4-oxobutyryl] -N-methylglycine allyl hydrogen succinate (described in J. Pharm. Sci., 50, 487 (1961)); 3.17 g, 20 mmol ) Was dissolved in dichloromethane (50 ml), and isobutyl chloroformate (3.00 g, 22 mmol) and N, N-diisopropylethylamine (2.84 g, 22 mmol) were added to the solution while stirring under ice cooling. After the mixture was stirred for 15 minutes under ice cooling, N-methylglycine (3.56 g, 40 mmol) and N, N-diisopropylethylamine (10.3 g, 80 mmol) were added. The mixture was stirred for 36 minutes while allowing the temperature to rise naturally, then ice-cooled, 2N hydrochloric acid was added to stop the reaction, and the product was extracted three times with dichloromethane. The organic layers were combined and washed sequentially with water and saturated brine.

  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 75 g) to give the title compound (1 .79 g, 39% yield) was obtained as a brown oil.

IR (CHCl ₃ ) ν _max 1731, 1656, 1411, 1173, 1125 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.72 (4H, s), 3.13 (3H, s), 4.16 (2H, s), 4.60 (2H, d, J = 6 Hz), 5.23 (1H, d , J = 10 Hz), 5.32 (1H, d, J = 17 Hz), 5.92 (1H, ddt, J = 17, 10, 6 Hz);
MS (FAB +) m / z: 230 ((M + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₁₀ H ₁₅ NO ₅ Na ((M + Na) +): 252.0848. Found: 252.0854.
(40b) Allyl = 4- [N- [2- [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] ethoxy] -2-oxoethyl] -N-methylamino] -4-oxobutyrate N- [4- (allyloxy) -4-oxobutyryl] prepared in (40a) of Example 40] -N-methylglycine (1.77 g, 7.72 mmol) was dissolved in N, N-dimethylformamide (30 ml), and stirred at room temperature, cesium carbonate (1.17 g, 3.6 mmol) and 18-claw were added thereto. -6 (2.11g, 7.98mmol) was added. After the mixture was stirred at room temperature for 1 hour, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4) prepared in (1a) of Example 1] was obtained. -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 carbonate (diastereomeric ratio = about 1: 1; 1.67 g, 2.57 mmol) was added. After the mixture was stirred at room temperature for 13.7 hours, a phosphate buffer was added under ice cooling, and the crude product was extracted three times with ethyl acetate. The organic layer was washed with water three times and then with saturated saline once.

  The extract was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate, 40:60 to 25:75, V / V, silica gel 65 g) to give the title compound (1 .34 g, 49% yield) was obtained as an amorphous solid (diastereomeric ratio = approximately 1: 1).

IR (CHCl ₃ ) ν _max 2233, 1771, 1656, 1504, 1277, 1140, 1064 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, d, J = 7 Hz), 1.54 (3H × (1/2), d, J = 5 Hz), 1.56 (3H × (1/2 ), d, J = 5 Hz), 2.64-2.76 (4H, m), 3.09 (3H × (1/2), s), 3.18 (3H × (1/2), s), 3.00-3.06 (1H , m), 3.49 (1H, t, J = 11 Hz), 3.49 (1H, t, J = 11 Hz), 3.87 (1H × (1/2), q, J = 7 Hz), 3.88 (1H × (1/2), q, J = 7 Hz), 4.06-4.37 (4H, m), 4.57-4.60 (2H, m), 4.98 (1H, d, J = 4 Hz), 5.20-5.44 (4H, m), 5.85 (1H, dd, J = 15, 4 Hz), 5.92 (1H, ddt, J = 17, 11, 6 Hz), 6.58 (1H, dd, J = 15, 11 Hz), 6.72 (1H × (1/2), q, J = 5 Hz), 6.73 (1H, d, J = 15 Hz), 6.81 (1H × (1/2), q, J = 5 Hz), 6.85-6.97 (3H , m), 7.33 (1H, dd, J = 10, 1 Hz), 7.37-7.45 (2H, m), 7.57 (1H, t, J = 8 Hz), 7.92 (1H × (1/2), s ), 7.94 (1H × (1/2), s), 7.94 (1H × (1/2) × (1/2), s), 7.99 (1H × (1/2), s), 8.02 (1H × (1/2) × (1/2), s);
MS (FAB +) m / z: 842 ((M + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₄₀ H ₄₂ F ₃ N ₅ O ₁₀ SNa ((M + Na) ⁺ ): 864.2503. Found: 864.2520.
(40c) 4- [N- [2- [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] ethoxy] -2-oxoethyl] -N-methylamino] -4-oxobutyric acid (title target compound)
Allyl prepared in (40b) of Example 40 = 4- [N- [2- [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] ethoxy] -2-oxoethyl] -N-methylamino] -4-oxobutyrate (diastereomeric ratio = approximately 1: 1; 1.33 g, 1 .58 mmol) was dissolved in dichloromethane (20 ml) and stirred under ice cooling while tetrakis (triphenylphosphine) palladium (91.3 mg, 0.079 mmol) and 5,5-dimethyl-1,3-cyclohexane were mixed. Dione (110.7 mg, 0.79 mmol) was added. The mixture was stirred for 50 minutes while allowing the mixture to naturally warm to room temperature, and then concentrated under reduced pressure to obtain a residue (1.670 g) containing the title object compound.

  Only a portion (0.870 g) of this residue was advanced to purification. Recycle preparative HPLC [LC-908; manufactured by Japan Analytical Industry; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) connected in series; solvent, chloroform; 7 cycles] to give the title compound (yield 524 mg, yield 41%; yield 1.006 g, yield 79% that would have been obtained when the whole amount was purified) as an amorphous solid (diastereo Mer ratio = about 1: 1).

IR (KBr) ν _max 2230, 1769, 1655, 1616, 1504, 1276, 1140, 1070 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.35 (3H × (1/2), dd, J = 7, 2 Hz), 1.37 (3H × (1/2), dd, J = 7, 2 Hz ), 1.53 (3H × (1/2), d, J = 5 Hz), 1.60 (3H × (1/2) d, J = 5 Hz), 2.56-2.84 (4H, m), 2.98 (1H × (1/2), tt, J = 11, 5 Hz), 3.02 (1H × (1/2), tt, J = 5, 2 Hz), 3.13 (3H × (1/2), s), 3.16 (3H × (1/2), s), 3.46 (1H × (1/2), t, J = 11 Hz), 3.47 (1H × (1/2), t, J = 11 Hz), 3.52 ( 1H × (1/2), t, J = 11 Hz), 3.55 (1H × (1/2), t, J = 11 Hz), 3.64 (1H × (1/2), q, J = 7 Hz ), 3.90 (1H × (1/2), q, J = 7 Hz), 3.96 (1H × (1/2), d, J = 18 Hz), 4.10 (1H × (1/2), d, J = 18 Hz), 4.31 (1H × (1/2), d, J = 18 Hz), 4.48 (1H × (1/2), d, J = 18 Hz), 4.96 (1H × (1/2 ), d, J = 4 Hz), 5.01 (1H × (1/2), d, J = 4 Hz), 5.29 (1H × (1/2), d, J = 15 Hz), 5.33 (1H × (1/2), d, J = 15 Hz), 5.49 (1H × (1/2), d, J = 15 Hz), 5.51 (1H × (1/2), d, J = 15 Hz), 5.86 (1H, dd, J = 15, 4 Hz), 6.59 (1H, dd, J = 16, 11 Hz), 6.74 (1H, d, J = 16 Hz), 6.76 (1H × (1/2), q, J = 5 Hz), 6.84-6.90 (1H × (1/2), m), 6.84-6.97 (3H, m), 7.32-7.42 (3H, m), 7.57 (1H, t, J = 8 Hz), 7.80 (1H × (1/2), s), 8.04 (1H × (1/2), s), 8.14 (1H × (1/2), s), 8.33 (1H × (1/2), s);
MS (FAB +) m / z: 802 ((M + H) ⁺ ).
HRMS (LC, ESI +) m / z: calcd for C ₃₇ H ₃₉ F ₃ N ₅ O ₁₀ S ((M + H) ⁺ ): 802.2369. Found: 802.2363.
The title compound prepared above (324 mg, 0.404 mmol; diastereomeric ratio = approximately 1: 1) was dissolved in tetrahydrofuran (5 ml) and stirred at room temperature into sodium bicarbonate (33.9 mg, 0.404 mmol) in water (3 ml) was added. The solution was concentrated under reduced pressure to remove tetrahydrofuran as much as possible, and the resulting aqueous solution was filtered through a membrane filter and lyophilized to give the sodium salt of the title compound (diastereomer ratio = about 1: 1) as an amorphous solid. Got as.

IR (KBr) ν _max 2230, 1770, 1615, 1418, 1396, 1276, 1140, 1052, 970 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.31 (3H × (1/2), dd, J = 7, 2 Hz), 1.33 (3H × (1/2), dd, J = 7, 2 Hz), 1.54 (3H × (1/2), d, J = 5 Hz), 1.55 (3H × (1/2), d, J = 5 Hz), 2.4-2.7 (4H, m), 2.9- 3.05 (1H, m), 3.12 (3H × (1/2), s), 3.17 (3H × (1/2), s), 3.48 (1H, t, J = 11 Hz), 3.51 (1H, t , J = 11 Hz), 3.90 (1H × (1/2), q, J = 7 Hz), 3.91 (1H × (1/2), q, J = 7 Hz), 4.1-4.4 (4H, m ), 5.02 (1H, d, J = 4 Hz), 5.44 (1H, dd, J = 15, 3 Hz), 5.47 (1H, d, J = 15 Hz), 5.88 (1H, dd, J = 15, 4 Hz), 6.51 (1H, dd, J = 15, 11 Hz), 6.72 (1H × (1/2), q, J = 5 Hz), 6.79 (1H, d, J = 16 Hz), 6.81 ( 1H × (1/2), q, J = 5 Hz), 7.01-7.10 (2H, m), 7.10 (1H, dd, J = 16, 11 Hz), 7.50-7.55 (3H, m), 7.78 ( 1H, t, J = 8 Hz), 8.04 (1H × (1/2), s), 8.05 (1H × (1/2), s), 8.36 (1H × (1/2), s), 8.40 (1H × (1/2), s);
MS (FAB +) m / z: 824 ((total sodium salt + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₃₇ H ₃₈ F ₃ N ₅ O ₁₀ SNa ((total sodium salt + H) ⁺ ): 824.2189. Found: 824.2177.
Example 41 [2- [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] ethoxy] -2-oxoethoxy] acetic acid (Exemplary Compound 1-237)
(41a) Allyl = hydrogen = oxydiacetate Commercially available diglycolic acid (6.70 g, 50 mmol) was dissolved in N, N-dimethylformamide (70 ml) and stirred at room temperature while dicyclohexylamine (8. 82 g, 52.5 mmol) and allyl iodide (9.52 g, 52.5 mmol) were added. The mixture was stirred at 90 ° C. for 1 hour, then cooled to room temperature, and water (200 ml) and ethyl acetate (100 ml) were added to dissolve insoluble matters as much as possible. The insoluble material was removed by filtration and washed with ethyl acetate. The filtrate and the washing solution were combined and washed with water three times and with saturated saline once.

  The extract was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate, 50:50, V / V, silica gel 150 g) to give the title compound (3.61 g, yield). 41%) as a brown oil.

IR (CHCl ₃ ) ν _max 1753, 1736, 1251, 1145, 989, 940 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.28 (2H, s), 4.29 (2H, s), 4.70 (2H, d, J = 6 Hz), 5.30 (1H, d, J = 10 Hz), 5.36 (1H, d, J = 17 Hz), 5.92 (1H, ddt, J = 17, 10, 6 Hz);
MS (EI) m / z: 175 ((M + H) ⁺ ).
(41b) allyl = 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 = Oxydiacetate Allyl = Hydrogen = Oxydiacetate (1.86 g, 10.68 mmol) prepared in (41a) of Example 41 was dissolved in N, N-dimethylformamide (30 ml) and stirred at room temperature. Cesium carbonate (1.63 g, 5.0 mmol) and 18-crown-6 (2.91 g, 11.0 mmol) were added. After the mixture was stirred at room temperature for 1 hour, 1-chloroethyl = (1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4) prepared in (1a) of Example 1] was used. -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 carbonate (diastereomeric ratio = about 1: 1; 2.6 g, 4.0 mmol) was added. The mixture was stirred at room temperature for 25 hours, then ice-cooled, phosphate buffer was added, and the product was extracted with ethyl acetate. The organic layer was washed with water three times and then with saturated saline once.

The extract was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate, 67:33, V / V, silica gel 70 g) to give the crude title compound (total amount = 3). .9 g, content of the title compound = about 2.22 g, yield of the title compound = about 70%, 4-[(1E, 3E) -4- [trans-5-[[(1R, 2R) -2 as impurities] -(2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl] -1,3-butadienyl] -3-fluorobenzonitrile) was obtained as an amorphous solid (diastereomeric ratio = approximately 1: 1). This product was used in the next step (41c) without further purification.
(41c) [2- [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 ] Ethoxy] -2-oxoethoxy] acetic acid (titled compound)
Crude allyl prepared in Example 41 (41b) = 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 oxydiacetate (content about 2.22 g, about 2.82 mmol; diastereomeric ratio = 1: 1) was dissolved in dichloromethane (50 ml) and stirred under ice cooling. To the solution, tetrakis (triphenylphosphine) palladium (162.9 mg, 0.14 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (196.3 mg, 1.4 mmol) were added. It was. The mixture was stirred for 130 minutes while naturally warming to room temperature.
The reaction solution was concentrated under reduced pressure to obtain a residue (3.5 g) containing the title target compound.

  Only a portion (0.93 g) of this residue was advanced to purification. Recycle preparative HPLC [LC-908; manufactured by Japan Analytical Industry; GPC column JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm) connected in series; solvent, chloroform; 6 cycles] to give the title target compound (yield 325 mg, yield 15%; yield 1.223 g, yield 58% that would have been obtained when the whole amount was purified) as a colorless amorphous solid ( Diastereomer ratio = approximately 1: 1).

IR (KBr) ν _max 2231, 1769, 1504, 1277, 1140, 1071, 973 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.37 (3H × (1/2), dd, J = 7, 2 Hz), 1.37 (3H × (1/2), dd, J = 7, 2 Hz ), 1.56 (3H × (1/2), d, J = 5 Hz), 1.60 (3H × (1/2), d, J = 5 Hz), 2.99-3.08 (1H, m), 3.46 (1H × (1/2), t, J = 11 Hz), 3.48 (1H × (1/2), t, J = 11 Hz), 3.51 (1H × (1/2), t, J = 11 Hz) , 3.52 (1H × (1/2), t, J = 11 Hz), 3.82 (1H × (1/2), q, J = 7 Hz), 3.93 (1H × (1/2), q, J = 7 Hz), 4.15-4.35 (6H, m), 4.98 (1H × (1/2), d, J = 4 Hz), 5.00 (1H × (1/2), d, J = 4 Hz), 5.30 (1H × (1/2), dd, J = 15, 3 Hz), 5.34 (1H × (1/2), d, J = 15 Hz), 5.46 (1H × (1/2), d, J = 15 Hz), 5.47 (1H × (1/2), dd, J = 15, 3 Hz), 5.86 (1H, dd, J = 15, 4 Hz), 6.59 (1H, dd, J = 15, 11 Hz), 6.74 (1H, d, J = 16 Hz), 6.85 (1H × (1/2), q, J = 5 Hz), 6.85-6.93 (2H + 1H × (1/2), m) , 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, d, J = 10 Hz), 7.36-7.43 (2H, m), 7.57 (1H, t, J = 8 Hz), 7.85 ( 1H × (1/2), s), 8.03 (1H × (1/2), s), 8.16 (1H × (1/2), s), 8.27 (1H × (1/2), s);
MS (FAB +) m / z: 747 ((M + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₃₄ H ₃₃ F ₃ N ₄ O ₁₀ SNa ((M + Na) +): 769.1767. Found: 769.1753.
The title compound prepared above (diastereomer ratio = approximately 1: 1; 73.9 mg, 0.0990 mmol) is dissolved in a small amount of tetrahydrofuran, and an aqueous solution of sodium hydrogen carbonate (8.1 mg, 0.970 mmol) is brought to room temperature. Added. Tetrahydrofuran was distilled off using a rotary evaporator, the resulting aqueous solution (partially suspended) was filtered through a membrane filter, the filtrate was freeze-dried, and the sodium salt (51.3 mg, free carboxylic acid) of the title product was obtained. Yield 68%) as a colorless amorphous solid.

IR (KBr) ν _max 2230, 1770, 1614, 1418, 1276, 1140, 1053, 971 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.31 (3H × (1/2), dd, J = 7, 2 Hz), 1.34 (3H × (1/2), dd, J = 7, 2 Hz), 1.56 (3H, d, J = 5 Hz), 2.94-2.99 (1H, m), 3.48 (1H × (1/2), t, J = 11 Hz), 3.49 (1H × (1/2 ), t, J = 11 Hz), 3.50 (1H × (1/2), t, J = 11 Hz), 3.51 (1H × (1/2), t, J = 11 Hz), 3.66 (1H × (1/2), q, J = 7 Hz), 3.78 (1H × (1/2), q, J = 7 Hz), 3.9-4.4 (6H, m), 5.02 (1H × (1/2) , d, J = 4 Hz), 5.03 (1H × (1/2), d, J = 4 Hz), 5.47 (2H, s), 5.88 (1H, dd, J = 16, 4 Hz), 6.59 ( 1H, dd, J = 16, 11 Hz), 6.77 (1H × (1/2), q, J = 5 Hz), 6.80 (1H, d, J = 16 Hz), 6.84 (1H × (1/2 ), q, J = 5 Hz), 7.03-7.14 (3H, m), 7.50-7.56 (3H, m), 7.79 (1H, t, J = 8 Hz), 8.02 (1H × (1/2), s), 8.05 (1H × (1/2), s), 8.34 (1H × (1/2), s), 8.44 (1H × (1/2), s);
MS (FAB +) m / z: 769 ((M + H) ⁺ ).
Example 42 1- [4-[[(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] carbonyl Oxymethoxy] -4-oxobutyryl] -4-piperidinecarboxylic acid (Exemplary Compound 1-485)
(42a) Allyl = 1- [4-[[(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] carbonyl Oxymethoxy] -4-oxobutyryl] -4-piperidinecarboxylate 4- [4- (allyloxycarbonyl) piperidino] -4-oxobutyric acid (1.16 g, 4.30 mmol) prepared in Example 7 (7c) Was dissolved in N, N-dimethylformamide (15 ml) and stirred at room temperature into cesium carbonate (651.6 mg, 2.0 mmol) and 18-crown-6 (1.19 g, 4.5). mmol) was added. After the mixture was stirred at room temperature for 35 minutes, the chloromethyl prepared in Example 14 (14a) = (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 carbonate (1.27 g, 2.00 mmol) was added and the mixture was stirred at room temperature for 65 minutes. Thereafter, extraction and purification were carried out in the same manner as in the procedure described in (7c) of Example 7 to obtain the title compound (1.45 g, yield 84%) as a colorless amorphous solid.

IR (KBr) ν _max 2230, 1767, 1732, 1645, 1504, 1273, 1258, 1142, 976 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.37 (3H, dd, J = 7, 2 Hz), 1.60-1.77 (2H, m), 1.89-2.00 (2H, m), 2.58 (1H, tt, J = 11, 4 Hz), 2.64-2.87 (5H, m), 3.03 (1H, tt, J = 11, 5 Hz), 3.15 (1H, td, J = 14, 3 Hz), 3.49 (1H, t , J = 11 Hz), 3.50 (1H, t, J = 11 Hz), 3.84-3.93 (2H, m), 4.17 (1H, ddd, J = 11, 5, 2 Hz), 4.27 (1H, ddd, J = 11, 5, 2 Hz), 4.38 (1H, dt, J = 14, 4 Hz), 4.59 (2H, d, J = 6 Hz), 4.98 (1H, d, J = 4 Hz), 5.24 ( 1H, dd, J = 10, 1 Hz), 5.31 (1H, dd, J = 17, 1 Hz), 5.39 (1H, dd, J = 15, 3 Hz), 5.42 (1H, d, J = 15 Hz ), 5.74 (1H, d, J = 6 Hz), 5.84 (1H, d, J = 6 Hz), 5.83-5.88 (1H, m), 5.91 (1H, ddt, J = 17, 11, 6 Hz) , 6.59 (1H, dd, J = 16, 11 Hz), 6.74 (1H, d, J = 16 Hz), 6.85-6.95 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 2 Hz), 7.40 (1H, dd, J = 8, 1 Hz), 7.44 (1H, td, J = 9, 6 Hz), 7.57 (1H, t, J = 8 Hz), 7.93 (1H, s), 8.038 (1H × (1/2), s), 8.044 (1H × (1/2), s);
MS (FAB +) m / z: 868 ((M + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₄₂ H ₄₅ F ₃ N ₅ O ₁₀ S ((M + H) +): 868.2840. Found: 868.2838.
(42b) 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-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethoxy ] -4-Oxobutyryl] -4-piperidinecarboxylic acid (titled compound)
Allyl prepared in Example 42, (42a) = 1- [4-[[(1R, 2R) -2-[[trans-2-[(1E, 3E) -4- (4-cyano-2-fluoro] Phenyl) -1,3-butadienyl] -1,3-dioxane-5-yl] thio] -1- (2,4-difluorophenyl) -1-[(1H-1,2,4-triazole-1- Yl) methyl] propoxy] carbonyloxymethoxy] -4-oxobutyryl] -4-piperidinecarboxylate (777 mg, 0.90 mmol) in dichloromethane (12 ml) and stirred under ice-cooling, tetrakis (triphenyl Phosphine) palladium (31.0 mg, 0.027 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (63.1 mg, 0.45 mmol). I was painting. The mixture was stirred for 1.5 hours while naturally warming to room temperature.

  The reaction mixture was directly subjected to silica gel column chromatography (ethyl acetate-methanol (90:10) to methanol-ethyl acetate (10:90), V / V, silica gel 30 ml) to give the title object compound (603 mg, yield 81). %) As a colorless amorphous solid.

IR (KBr) ν _max 2230, 1767, 1644, 1616, 1504, 1418, 1376, 1273, 1142, 986, 975 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.37 (3H, dd, J = 7, 2 Hz), 1.61-1.77 (2H, m), 1.97 (2H, br t, J = 12 Hz), 2.55- 2.89 (6H, m), 3.03 (1H, tt, J = 11, 5 Hz), 3.17 (1H, td, J = 11, 3 Hz), 3.49 (1H, t, J = 11 Hz), 3.50 (1H , t, J = 11 Hz), 3.83-3.91 (2H, m), 4.17 (1H, ddd, J = 11, 5, 2 Hz), 4.27 (1H, ddd, J = 11, 5, 2 Hz), 4.35-4.38 (1H, m), 4.98 (1H, d, J = 4 Hz), 5.36 (1H, d, J = 15 Hz), 5.42 (1H, d, J = 15 Hz), 5.73 (1H, d , J = 6 Hz), 5.83-5.88 (2H, m), 6.59 (1H, dd, J = 16, 11 Hz), 6.73 (1H, d, J = 16 Hz), 6.85-6.95 (2H, m) , 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.40 (1H, d, J = 8 Hz), 7.44 (1H, td, J = 9 , 6 Hz), 7.57 (1H, t, J = 8 Hz), 7.95 (1H × (1/2), s), 7.96 (1H × (1/2), s), 8.07 (1H × (1 / 2), s), 8.10 (1H × (1/2), s);
MS (FAB +) m / z: 828 ((M + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₃₉ H ₄₀ F ₃ N ₅ O ₁₀ SNa ((M + Na) +): 850.2345. Found: 850.2360.
Dissolve the title compound prepared above (266 mg, 0.32 mmol) in tetrahydrofuran (5 ml) and stir at room temperature with sodium bicarbonate (27.0 mg, 0.32 mmol) in water (3 ml) Was added. Under reduced pressure, tetrahydrofuran was removed as much as possible with a rotary evaporator, and the obtained aqueous solution was lyophilized to obtain the sodium salt of the title object compound (283 mg, yield from free carboxylic acid 96%) as a colorless amorphous solid. It was.

IR (KBr) ν _max 2231, 1767, 1616, 1417, 1274, 1142, 984, 975 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.33 (3H, d, J = 7 Hz), 1.5-2.1 (4H, m), 2.69-2.78 (5H, m), 2.98 (1H, tt, J = 11, 5 Hz), 3.11 (1H, td, J = 14, 3 Hz), 3.49 (2H, t, J = 11 Hz), 3.83-3.96 (2H, m), 4.12 (1H, ddd, J = 11, 5, 2 Hz), 4.24 (1H, ddd, J = 11, 5, 2 Hz), 4.37 (1H, dt, J = 14, 4 Hz), 5.01 (1H, d, J = 5 Hz), 5.45-5.47 (3H, m), 5.75-5.82 (2H, m), 5.87 (1H, dd, J = 15, 4 Hz), 6.59 (1H, dd, J = 15, 11 Hz), 6.80 (1H, d, J = 16 Hz), 7.01-7.07 (2H, m), 7.10 (1H, dd, J = 16, 11 Hz), 7.49-7.58 (3H, m), 7.79 (1H, t, J = 8 Hz ), 8.02 (1H, s), 8.38 (1H, s);
MS (FAB) m / z: 850 ((total sodium salt + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₃₉ H ₄₀ F ₃ N ₅ O ₁₀ SNa ((total sodium salt + H) ⁺ ): 850.2345. Found: 850.2319.
Example 43 [(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] carbonyloxymethyl = hydrogen = glutarate (Exemplary Compound 1-418)
(43a) Allyl = [(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] carbonyloxymethyl glutarate glutaric acid Allyl hydrogen (described in Tetrahedron Lett., 36, 1701 (1995); 1.42 g, 8.24 mmol) was dissolved in N, N-dimethylformamide (20 mL), and cesium carbonate (1.30 g, 4 mmol) and 18-crown-6 (2.38 g, 9 mmol) were added. After stirring at room temperature for 45 minutes, the chloromethyl prepared in Example 14 (14a) = (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-triazole-1 -Yl) methyl] propyl carbonate (2.54 g, 4.0 mmol) was added and the mixture was stirred at room temperature for 55 min.

  Thereafter, the product was treated and purified in the same manner as described in Example 28, (28a), and the title compound (1.19 g, yield 39%) was obtained as a colorless amorphous solid.

IR (CHCl ₃ ) ν _max 2995, 2233, 1767, 1734, 1504, 1276, 1141, 987 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.37 (3H, dd, J = 7, 2 Hz), 2.01 (2H, t, J = 7 Hz), 2.45 (2H, t, J = 7 Hz), 2.53 (2H, t, J = 7 Hz), 3.03 (1H, tt, J = 11, 5 Hz), 3.49 (1H, t, J = 11 Hz), 3.50 (1H, t, J = 11 Hz), 3.90 (1H, q, J = 7 Hz), 4.17 (1H, ddd, J = 11, 5, 2 Hz), 4.27 (1H, ddd, J = 11, 5, 2 Hz), 4.58 (2H, d, J = 6 Hz), 4.98 (1H, d, J = 4 Hz), 5.23 (1H, d, J = 11 Hz), 5.31 (1H, dd, J = 17, 2 Hz), 5.36 (1H, d, J = 15 Hz), 5.40 (1H, d, J = 15 Hz), 5.77 (2H, s), 5.85 (1H, dd, J = 15, 4 Hz), 5.93 (1H, ddt, J = 17, 11 , 6 Hz), 6.59 (1H, dd, J = 15, 11 Hz), 6.74 (1H, d, J = 16 Hz), 6.86-6.95 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.39-7.46 (2H, m), 7.57 (1H, t, J = 8 Hz), 7.94 (1H, s), 7.98 (1H, s);
MS (FAB +) m / z: 771 ((M + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₃₇ H ₃₇ F ₄ N ₄ O ₉ SNa ((M + Na) ⁺ ): 793.2131. Found: 793.2128.
(43b) [(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] carbonyloxymethyl = hydrogen = glutarate (title Target compound)
Allyl prepared in (28a) of Example 28 = [(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] Carbonyloxymethyl glutarate (1.17 g, 1.52 mmol) was dissolved in dichloromethane (25 mL), and tetrakis (triphenylphosphine) palladium (87.7 mg, 0.076 mmol) and 5,5-dimethyl- were dissolved under ice cooling. 1,3-Cyclohexanedione (106.5 mg, 0.76 mmol) was added and the mixture was stirred at room temperature for 50 minutes under a nitrogen atmosphere.

  The reaction mixture was subjected to silica gel chromatography (ethyl acetate-methanol, 67: 33-100: 0, V / V, 30 g of silica gel) to give a crude product (about 0.4 g) of the title object compound. Further elution with a methanol-ethyl acetate mixed solvent (10:90, V / V) gave a further crude product (610 mg).

  Each of the crude products obtained above was subjected to recycle preparative HPLC [LC-908; manufactured by Japan Analytical Industry; GPC columns JAIGEL-1H (20 mm.d. × 600 mm) and JAIGEL-2H (20 mm.d. × 600 mm). Used in series; solvent, chloroform] to give pure title compound (yield: 370 mg and 600 mg from each crude product, total yield: 87%) as a colorless amorphous solid. It was.

IR (KBr) ν _max 2231, 1767, 1504, 1418, 1258, 1140, 986, 975 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.37 (3H, dd, J = 7, 2 Hz), 2.05 (2H, quint, J = 7 Hz), 2.49 (2H, t, J = 7 Hz), 2.55 (1H, t, J = 7 Hz), 2.56 (1H, t, J = 7 Hz), 3.03 (1H, tt, J = 11, 5 Hz), 3.49 (1H, t, J = 7 Hz), 3.49 (1H, t, J = 7 Hz), 3.81 (1H, q, J = 7 Hz), 4.17 (1H, ddd, J = 11, 5, 2 Hz), 4.28 (1H, ddd, J = 11, 5, 2 Hz), 4.98 (1H, d, J = 4 Hz), 5.39 (1H, dd, J = 15, 3 Hz), 5.45 (1H, d, J = 15 Hz), 5.66 (1H, d, J = 6 Hz), 5.85 (1H, dd, J = 16, 4 Hz), 5.91 (1H, d, J = 6 Hz), 6.58 (1H, dd, J = 16, 11 Hz), 6.74 (1H, d, J = 16 Hz), 6.88-6.95 (2H, m), 6.93 (1H, dd, J = 16, 11 Hz), 7.33 (1H, dd, J = 10, 1 Hz), 7.39-7.44 (2H , m), 7.57 (1H, t, J = 8 Hz), 7.96 (1H, s), 8.19 (1H, s);
MS (FAB +) m / z: 731 ((M + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₃₄ H ₃₃ F ₃ N ₄ O ₉ SNa ((M + Na) +): 753.1818. Found: 753.1815.
The title target compound prepared above (306 mg, 0.419 mmol) was dissolved in tetrahydrofuran (about 5 ml), and a solution of sodium hydrogen carbonate (35.2 mg, 0.419 mmol) in water (5 ml) was added thereto.

  Tetrahydrofuran was distilled off as much as possible with a rotary evaporator under reduced pressure, and then the aqueous solution obtained by filtering insolubles through a membrane filter was lyophilized to give the sodium salt of the title compound (292 mg, yield from free carboxylic acid). 93%) was obtained as a colorless, amorphous solid.

IR (KBr) ν _max 2230, 1766, 1574, 1417, 1275, 1258, 1141, 986, 975 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.32 (3H, dd, J = 7, 2 Hz), 1.93 (2H, quint, J = 7 Hz), 2.23 (2H, t, J = 7 Hz) , 2.49 (2H, t, J = 7 Hz), 2.97 (1H, tt, J = 11, 5 Hz), 3.49 (2H, t, J = 11 Hz), 3.82 (1H, q, J = 7 Hz) , 4.11 (1H, ddd, J = 11, 5, 2 Hz), 4.23 (1H, ddd, J = 11, 5, 2 Hz), 5.01 (1H, d, J = 4 Hz), 5.47 (2H, s ), 5.77 (1H, d, J = 6 Hz), 5.79 (1H, d, J = 6 Hz), 5.87 (1H, dd, J = 15 Hz), 6.59 (1H, dd, J = 15, 11 Hz) ), 6.79 (1H, d, J = 16 Hz), 7.02-7.07 (2H, m), 7.09 (1H, dd, J = 15, 11 Hz), 7.49-7.55 (3H, m), 7.79 (1H, t, J = 8 Hz), 8.01 (1H, s), 8.37 (1H, s);
MS (FAB +) m / z: 753 ((total sodium salt + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₃₄ H ₃₃ F ₃ N ₄ O ₉ SNa ((total sodium salt + H) ⁺ ): 753.1818. Found: 753.1819.
The title compound (300 mg, 0.41 mmol) prepared above was dissolved in tetrahydrofuran (about 5 ml) and stirred under ice-cooling, and N-methylglucamine (80.0 mg, 0.41 mmol) was added. Of methanol (about 3 ml) was added. The solvent was distilled off under reduced pressure to obtain N-methylglucanonium salt of the title object compound (378 mg, yield from free carboxylic acid: quantitative) as a pale yellow amorphous solid.

IR (KBr) ν _max 2230, 1766, 1561, 1504, 1418, 1275, 1258, 1141, 1050 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.32 (3H, dd, J = 7, 2 Hz), 1.93 (2H, quint, J = 8 Hz), 2.25 (2H, t, J = 8 Hz) , 2.49 (2H, t, J = 8 Hz), 2,67 (3H, s), 2.97 (1H, tt, J = 11, 5 Hz), 3.12 (2H, dd, J = 5, 1 Hz), 3.49 (2H, t, J = 11 Hz), 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 = 7 Hz), 5.79 (1H, d, J = 7 Hz), 5.87 (1H, dd, J = 15, 5 Hz), 6.59 (1H, dd, J = 15, 11 Hz), 6.79 (1H, d, J = 16 Hz), 7.02-7.10 (2H , m), 7.10 (1H, dd, J = 16, 11 Hz), 7.49-7.55 (3H, m), 7.79 (1H, t, J = 8 Hz), 8.01 (1H, s), 8.37 (1H, s);
MS (FAB) m / z: 731 ((non-N-methylglucamine moiety + H) ⁺ );
HRMS (LC, ESI +) m / z: calcd for C ₃₄ H ₃₃ F ₃ N ₄ O ₉ SNa ((non-N-methylglucamine moiety + H) ⁺ ): 753.1818. Found: 753.1796.
Example 44 [[4-[[(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 Methoxy] -4-oxobutyryl] oxy] acetic acid (Exemplary Compound 1-1224)
(44a) 2- (allyloxy) -2-oxoethyl = hydrogen = succinate Allyl glycolate (described in US Pat. No. 2,464,992; 4.83 g, 41.6 mmol) was dissolved in dichloromethane (70 ml) and stirred under ice-cooling. To this was added succinic anhydride (3.75 mmol) and 4- (N, N-dimethylamino) pyridine. The mixture was stirred for 100 minutes while allowing the mixture to naturally warm to room temperature, and then the solvent was distilled off under reduced pressure. The obtained residue was diluted with ethyl acetate and washed successively with 2N hydrochloric acid and saturated brine.

  The extract was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate, 50:50, V / V, silica gel 100 g) to give the title compound (6.48 g, yield). 75%) was obtained as a brown oil.

IR (CHCl ₃ ) ν _max 1749, 1716, 1161 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.72-2.78 (4H, m), 4.67 (2H, d, J = 6 Hz), 4.68 (2H, s), 5.28 (1H, d J = 11 Hz) , 5.34 (1H, d, J = 18 Hz), 5.91 (1H, ddt, J = 18, 11, 6 Hz);
MS (FAB) m / z: 217 ((M + H) ⁺ ).
(44b) Allyl = [[4-[[(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 Methoxy] -4-oxobutyryl] oxy] acetate 2- (allyloxy) -2-oxoethyl hydrogen succinate (5.66 g, 26.2 mmol) prepared in (44a) of Example 44 was converted to N, N-dimethylformamide ( 80 ml), and cesium carbonate (3.91 g, 12 mmol) and 18-crown-6 (7.93 g, 30 mmol) were added to the solution while stirring under ice cooling. The mixture was stirred at room temperature for 1 hour while appropriately irradiating the mixture with ultrasonic waves using a commercially available ultrasonic cleaner. The mixture was removed from the ultrasonic cleaner and stirred there at room temperature, where chloromethyl prepared in Example 14 (14a) = (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 carbonate (5.64 g, 8.88 mmol) was added. The mixture was stirred at room temperature for 3.7 hours, then ice-cooled, phosphate buffer was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with water three times and with saturated brine once.
The extract was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate, 40:60 to 33:67, V / V, silica gel 175 g) to give the crude title compound. (Total amount = 6.10 g, content of title compound = about 4.88 g, yield of title compound = about 68%, 4-[(1E, 3E) -4- [trans-5-[[(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxane- 2-yl] -1,3-butadienyl] -3-fluorobenzonitrile) was obtained as an amorphous solid (diastereomeric ratio = approximately 1: 1). This product was used in the next step (44c) without further purification.
(44c) [[4-[[(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] carbonyloxymethoxy] -4-Oxobutyryl] oxy] acetic acid (title target compound)
The crude allyl prepared in Example 44, (44b) = [[4-[[(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-triazole-1 -Il) methyl] propoxy] carbonyloxymethoxy] -4-oxobutyryl] oxy] acetate (843 mg, 1.04 mmol) was dissolved in dichloromethane (50 mmol), and tetrakis (triphenylphosphine) was added while stirring under ice-cooling. ) Palladium (59.8 mg, 0.052 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (65.6 mg, 0.468 mmol) were added. The mixture was stirred for 2.5 hours while naturally warming to room temperature.

  The reaction mixture was subjected to silica gel column chromatography (methanol: ethyl acetate, 10:90 to 20:80, V / V, silica gel 25 g) to give the title object compound (487 mg, 61% yield) in a colorless and amorphous state. Obtained as a solid.

IR (KBr) ν _max 2231, 1767, 1615, 1504, 1419, 1275, 1258, 1142 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.32 (3H, dd, J = 7, 2 Hz), 2.78 (4H, s), 2.98 (1H, tt, J = 11, 5 Hz), 3.485 (1H , t, J = 11 Hz), 3.489 (1H, t, J = 11 Hz), 3.83 (1H, q, J = 7 Hz), 4.12 (1H, ddd, J = 11, 5, 2 Hz), 4.24 (1H, ddd, J = 11, 5, 2 Hz), 5.46 (1H, s), 5.46 (1H, s), 5.01 (1H, d, J = 5 Hz), 5.47-5.49 (2H, m), 5.78 (1H, d, J = 6 Hz), 5.80 (1H, d, J = 6 Hz), 5.86 (1H, dd, J = 15, 5 Hz), 6.59 (1H, dd, J = 15, 11 Hz ), 6.79 (1H, d, J = 16 Hz), 7.01-7.09 (2H, m), 7.09 (1H, d, J = 16, 11 Hz), 7.49-7.56 (3H, m), 7.78 (1H, t, J = 8 Hz), 8.03 (1H, s), 8.09 (1H, s);
MS (FAB +) m / z: 775 ((M + H) ⁺ );
HRMS (FAB +) m / z calcd for C ₃₅ H ₃₄ F ₃ N ₄ O ₁₁ S ((M + H) ⁺ ): 775.1897. Found: 775.1890.
The title object compound prepared above (159.4 mg, 0.2 mmol) was dissolved in a small amount of tetrahydrofuran, and sodium phosphate buffer (pH 6, phosphoric acid concentration 0.1 N; 6 ml) was added. The solution was passed through a rotary evaporator to remove the tetrahydrofuran, and the resulting suspension was filtered through a membrane filter (0.45 μm) and freeze-dried to obtain a colorless solid (180 mg) containing the sodium salt of the title compound. .

¹ H NMR (CD ₃ OD, 400 MHz): δ 1.32 (3H, dd, J = 7, 2 Hz), 2.78 (4H, br s), 2.98 (1H, tt, J = 11, 5 Hz), 3.49 (2H, t, J = 7 Hz), 3.84 (1H, q, J = 7 Hz), 4.12 (1H, ddd, J = 11, 5, 2 Hz), 4.24 (1H, ddd, J = 11, 5 , 2 Hz), 4.48 (2H, br s), 5.01 (1H, d, J = 5 Hz), 5.47 (2H, br s), 5.78 (1H, d, J = 6 Hz), 5.80 (1H, d , J = 6 Hz), 5.87 (1H, dd, J = 16, 5 Hz), 6.59 (1H, dd, J = 16, 11 Hz), 6.77 (1H, d, J = 16 Hz), 7.01-7.05 (2H, m), 7.09 (1H, dd, J = 16, 11 Hz), 7.49-7.57 (3H, m), 7.78 (1H, t, J = 8 Hz), 8.02 (1H, s), 8.04 ( 1H, s);
MS (FAB +) m / z: 797 ((M + H) ⁺ ).
The structural formulas of the above-described example compounds are as follows.

(Test Example 1) Active compound production confirmation test First, about 1 mg of a test compound was placed in a test tube, about 100 μL of distilled water was added, and it was visually confirmed that the test compound was dissolved by 10 mg / mL or more.

  The test compound was dissolved in human plasma to an initial concentration of 2 μmol / L, and the mixture was incubated at 37 ° C. A small amount of sample was taken from the mixture at regular intervals, and the residual rate of the test compound relative to the initial amount of the test compound and the production rate of the following active compound A were determined by HPLC.

  The result of incubating the compound of Example 27 (Ex. No. 1-328; hydrochloride) is shown in FIG.

As is clear from FIG. 1, the compound of Example 27 (exemplary number 1-328) which is a compound of the present invention disappears rapidly after the start of incubation, and almost all of it is converted to Compound A after 120 minutes. It was observed that Therefore, it was clarified that the compound of the present invention is water-soluble and is hydrolyzed in vivo to be converted into a compound exhibiting antifungal activity.
(Test Example 2) Production confirmation test of active compound in liver microsomes Test compound was dissolved in human liver microsome (GENTEST Corporation; 0.5 mg protein / ml) to an initial concentration of 1 to 5 μM, and the mixture was incubated at 37 ° C. did. A small amount of sample was taken from the mixture at regular intervals, and the residual rate of the test compound relative to the initial amount of the test compound and the production rate of compound A as the active substance were quantified by the HPLC method.

The compounds of 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 are prepared. The results of incubation are shown in Table 10.
(Table 10) Formation rate of Compound A ――――――――――――――――――――――――――――――――――――――
Test compound 120 minutes after the start of incubation ――――――――――――――――― Compound A production rate Example number Salt form (%)
―――――――――――――――――――――――――――――――――――――
7 Monosodium salt 39.23
8 Sodium salt 41.12
12 disodium salt 40.71
14 1 Hydrochloride 71.13
15 Monohydrochloride 28.06
19 1 Hydrochloride 65.11
25 monohydrochloride 37.93
27 1 Hydrochloride 28.49
28 monosodium salt 63.44
29 Monosodium salt 52.90
30 monosodium salt 56.60
31 1 hydrochloride 42.45
33 Monosodium salt 72.80
34 Monosodium salt 59.30
35 Monosodium salt 41.49
36 monosodium salt 42.62
37 monosodium salt 56.40
38 monosodium salt 54.50
39 monosodium salt 49.60
40 Free acid 36.63
42 monosodium salt 49.80
43 1 (N-methylglucaminium) salt 46.60
44 monosodium salt 61.60
―――――――――――――――――――――――――――――――――――――
As is apparent from Table 10, Examples 7, 8, 12, 14, 15, 19, 25, 27, 28, 29, 30, 31, 33, 34, 35, 36, 37 which are compounds of the present invention. 38, 39, 40, 42, 43 and 44 were observed to produce Compound A 120 minutes after the start of incubation. Therefore, it was revealed that the compound of the present invention is converted into a compound that is hydrolyzed in vivo and exhibits antifungal activity.
Test Example 3 Antifungal Activity Measurement Test of Compound A The antifungal activity of the test compound was evaluated by the minimum growth inhibitory concentration (MICs) measured by the following method.

Measurement method for Candida: MICs were measured by the micro liquid dilution method. The test compound was dissolved in dimethyl sulfoxide (DMSO). Two-fold serial dilutions of compounds were made in DMSO, and final dilutions were made in RPMI 1640 medium buffered to pH 7.0 with 0.165 M 3- (morpholino) propanesulfonic acid (MOPS). The final concentration of DMSO did not exceed 1%. The inoculated fungus is suspended in physiological saline and buffered to pH 7.0 with 0.165 M 3- (morpholino) propanesulfonic acid (MOPS) to a final volume of 5.0 x 10 ^{2 to} 2.5 x 10 ³ cells / ml. Prepared in RPMI 1640 medium. In each well of the microplate, 100 μl of the bacterial solution and 100 μl of the diluted compound solution were mixed and cultured at 35 ° C. for 24 to 72 hours. Compound MICs were measured when clear growth was observed in control wells without compound. MICs were the minimum compound concentration that produced at least 80% growth inhibition compared to the control.

Measurement method for Cryptococcus neoformans: MICs were measured by the micro liquid dilution method. The test compound was dissolved in DMSO. 2-fold serial dilution of each compound was performed in DMSO, and final dilution was performed in yeast nitrogen base medium buffered to pH 7.0 with 0.165 M MOPS. The final concentration of DMSO did not exceed 1%. The inoculated fungus was suspended in physiological saline and prepared in yeast nitrogen base medium buffered to pH 7.0 with 0.165 M MOPS so that the final concentration was 5.0 × 10 ^{3 to} 2.5 × 10 ⁴ cells / ml. In each well of the microplate, 100 μl of the bacterial solution and 100 μl of the diluted compound solution were mixed and cultured at 35 ° C. for 48 to 72 hours. Compound MICs were measured when clear growth was observed in control wells without compound. MICs were the minimum compound concentration that produced at least 50% growth inhibition compared to the control. For measurement of growth inhibition, absorbance at a wavelength of 485 nm was used.

Measurement method for Aspergillus: MICs were measured by the micro liquid dilution method. The test compound was dissolved in DMSO. Two-fold serial dilutions of each compound were made in DMSO, and final dilutions were made in RPMI1640 medium buffered to pH 7.0 with 0.165 M MOPS. The final concentration of DMSO did not exceed 1%. The inoculated fungus was suspended in physiological saline and prepared in RPMI1640 medium buffered to pH 7.0 with 0.165 M MOPS to a final concentration of about 1.0 × 10 ⁴ cells / ml. In each well of the microplate, 100 μl of the bacterial solution and 100 μl of the diluted compound solution were mixed and cultured at 30 ° C. for 24 to 72 hours. Compound MICs were measured when clear growth was observed in control wells without compound. MICs were the minimum compound concentration that produced at least 80% growth inhibition compared to the control.

  The smaller the MIC value of the compound, the stronger the antifungal activity.

The antifungal activity measurement results for Compound A are shown in Table 11.
Table 11: Antifungal activity

Test compound MIC value (μg / ml)

Ca (1) ^a) Ca (2) ^b) Ca (3) ^c) Cn ^d) Af ^e)

Compound A 0.25 <= 0.008 0.063 <= 0.008 0.031

a): Ca (1) = Candida albicans ATCC 64550.
b): Ca (2) = Candida albicans TIMM 3164.
c): Ca (3) = Candida albicans TIMM 3165.
d): Cn = Cryptococcus neoformans TIMM 0362.
e): Af = Aspergillus fumigatus SANK 10569.
Compound A showed excellent in vitro antifungal activity.

(Formulation Example 1) Injection The compound of Example 1 (500 mg) is dissolved in 25 ml of distilled water for injection, passed through a sterilizing filter, and then freeze-dried to obtain a freeze-dried preparation for injection.

It is a graph which shows the result of Test Example 1, a horizontal axis shows incubation time, and a vertical axis | shaft shows the residual rate (%) of the compound of Example 27, or the production rate (%) of compound A.

Claims (50)

Formula (I)

[Wherein L ¹ represents a C ₃ -C ₇ cycloalkyl group, a C ₁ -C ₆ alkylene group or a C ₂ -C ₆ alkenylene group,
G is a single bond, a double bond, -O-, -NH-C (= O)-, -N (CH ₃ ) -C (= O)-, -C (= O) -NH-, -C ( = O) -N (CH ₃ )-, carbonyl group, -OC (= O)-, or -C (= O) -O-
L ² represents a single bond, a double bond, a C ₃ -C ₇ cycloalkyl group, or a 4- to 7-membered heterocyclic group,
L ³ represents a single bond, a double bond, a C ₁ -C ₆ alkylene group or a C ₂ -C ₆ alkenylene group,
A is selected from a carboxy group, a —SO ₃ H group, a —OSO ₃ H group, a —SO ₂ NH ₂ group, a —OPO ₃ H ₂ group, a nitrogen-containing heterocyclic group, a substituent group α, and a substituent group β. that identical or different substituents 1 or 2 substituted nitrogen-containing heterocyclic group by group, or, ² R ² '(wherein wherein -NR, R ² is a hydrogen atom, an amidino group, 1-iminoethyl group, C ₁ - C ₆ alkyl group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ halogenated alkyl group, C ₆ -C ₁₀ aryl group, which is 1 or 2 substituted with the same or different substituents selected from substituent group β or, C ₇ -C ₁₄ aralkyl group, R 2 ^'is hydrogen, C ₁ -C ₆ alkyl, C ₁ which is 1 or 2 substituted by identical or different substituents selected from substituent group β A —C ₆ alkyl group or a C ₁ -C ₆ halogenated alkyl group).
R ¹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
Ar is a C ₆ -C ₁₀ aryl group, or a C ₆ -C ₁₀ aryl having the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and a C ₁ -C ₆ halogenated alkyl group Group,
R ^a is an organic group (however, the following formula (II)

The compound represented by has antifungal activity. ). ]
Or a pharmacologically acceptable salt thereof as an active ingredient.
<Substituent group α>
Amidino group, 1-iminoethyl group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkyl group substituted with the same or different substituent selected from substituent group β, C ₁ -C ₆ alkyl group, C ₁ -C ₆ halogen Alkyl group, C ₂ -C ₄ alkanoyl group, C ₆ -C ₁₀ aryl group, and C ₇ -C ₁₄ aralkyl group.
<Substituent group β>
Hydroxyl group, mercapto group, cyano group, N- (C ₂ -C ₇ alkanoyl) amino group, N- (C ₁ -C ₆ alkyl) -N- (C ₂ -C ₇ alkanoyl) amino group, carbamoyl group, and Carbamoyloxy group. 2. The compound or pharmacologically acceptable compound thereof, wherein Ar is a phenyl group or a phenyl group having 1 to 3 substituents selected from the group consisting of a halogen atom and a trifluoromethyl group, the same or different substituents. A medicine containing salt as an active ingredient. The pharmaceutical which contains the compound whose Ar is 2,4-difluorophenyl group or 2,5-difluorophenyl group in Claim 1, or its pharmacologically acceptable salt as an active ingredient. A medicament comprising, as an active ingredient, a compound according to claim 1, wherein Ar is a 2,4-difluorophenyl group, or a pharmacologically acceptable salt thereof. In any one of Claims 1 thru | or 4, ^Ra is following Formula

Or a pharmacologically acceptable salt thereof as an active ingredient. In any one of Claims 1 thru | or 4, ^Ra is following Formula

Or a pharmacologically acceptable salt thereof as an active ingredient. In any one of Claims 1 thru | or 4, ^Ra is following Formula

Or a pharmacologically acceptable salt thereof as an active ingredient. In any one of Claims 1 thru | or 4, ^Ra is following Formula

Or a pharmacologically acceptable salt thereof as an active ingredient. In any one of Claims 1 thru | or 4, ^Ra is following Formula

Or a pharmacologically acceptable salt thereof as an active ingredient. In any one of Claims 1 thru | or 4, ^Ra is following Formula

Or a pharmacologically acceptable salt thereof as an active ingredient. In any one of Claims 1 thru | or 4, ^Ra is following Formula

Or a pharmacologically acceptable salt thereof as an active ingredient. In any one of Claims 1 thru | or 4, R ^a is following Formula (III)

[Wherein R ³ and R ⁴ independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group,
Ar ² is a phenyl group, a phenyl group substituted by 1 to 5 substituents selected from the same or different substituents selected from substituent group γ, a monocyclic heteroaryl group, and the same or different substituents selected from substituent group γ 1 to 5 substituted monocyclic heteroaryl group, naphthyl group, naphthyl group 1 to 5 substituted with the same or different substituents selected from substituent group γ, condensed bicyclic heteroaryl group, or A fused bicyclic heteroaryl group substituted 1 to 5 with the same or different substituents selected from the substituent group γ,
E ¹ represents a methylene group or a group represented by the formula —S (O) _n1 — (wherein _n1 represents an integer of 0 to 2);
E ² represents a C ₄ -C ₇ cycloalkyl group or a heterocyclyl group,
E ³ represents the formula (Ga)

(Wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ independently represent a hydrogen atom, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ halogenated alkyl group,
p represents 0 or 1,
q represents an integer of 0 to 3,
r and s independently represent an integer of 0 to 2. ) Group represented by
Or the formula (Gb)

(In the formula, Ar ³ is a phenylene group, a phenylene group, a naphthylene group, or a (fluorine atom) substituted with the same or different substituents selected from the substituent group consisting of (fluorine atom and chlorine atom) And a naphthylene group substituted with the same or different substituents selected from the substituent group consisting of
R ⁹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
T represents a single bond or a C ₁ -C ₈ alkylene group. ) Is represented. ]
Or a pharmacologically acceptable salt thereof as an active ingredient.
<Substituent group γ>
Halogen atom, a hydroxyl group, a mercapto group, a nitro group, an amino group, a cyano group, a carboxy _group, C 1 -C ₆ alkyl, substituted consisting (a halogen atom, a hydroxyl group, a cyano group, _and, C 1 -C ₆ alkoxy group) A C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom, a hydroxyl group, a cyano group, and C ₁ -C ₆ , which are substituted with the same or different substituents selected from the group of groups. C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkanoyl group, (halogen atom, hydroxyl group, cyano group, and ₁ to 5 substituted with the same or different substituents selected from the substituent group consisting of alkoxy groups) A C ₁ -C ₆ alkanoyl group, a C ₂ -C ₆ alkanoyloxy group substituted with the same or different substituents selected from the substituent group consisting of C ₁ -C ₆ alkoxy groups), A C ₂ -C ₆ alkanoyloxy group substituted with the same or different substituents selected from the substituent group consisting of a halogen atom, a hydroxyl group, a cyano group, and a C ₁ -C ₆ alkoxy group), C ₂ -C ₇ alkoxycarbonyl _group, C 2 -C ₅ alkanoylamino group, the formula ^{-C (O) -NR 10 R 11} ( wherein, R ¹⁰ and R ¹¹ are each independently a hydrogen atom or a _C 1 -C ₆ Or an alkyl group, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-membered to 7-membered nitrogen-containing heterocyclic ring). S (O) _μ1- R ¹³ (wherein μ1 represents an integer of 0 to 2, and R ¹³ is selected from a C ₁ -C ₆ alkyl group or a substituent group consisting of (halogen atom and hydroxyl group). that the same or different 1 to 5 substituted C ₁ -C substituents An alkyl group group represented by.), Wherein _{-S (O) μ2 -O-R} 14 ( wherein, .mu.2 is an integer of 0 to 2, R ¹⁴ is _C 1 -C ₆ alkyl group, or A C ₁ -C ₆ alkyl group substituted with 1 to 5 substituents selected from the same or different substituents selected from the substituent group consisting of a halogen atom and a hydroxyl group. S (O) _μ3- R ¹⁵ (wherein μ3 represents an integer of 0 to 2, and R ¹⁵ is selected from a C ₁ -C ₆ alkyl group or a substituent group consisting of (halogen atom and hydroxyl group). A C ₁ -C ₆ alkyl group substituted with 1 to 5 the same or different substituents. And the same or different substituents selected from one or two substituted imidazolyl groups, pyrazolyl groups, or substituent groups δ selected from the same or different substituents selected from substituent group δ. 1 or 2 substituted pyrazolyl group, triazolyl group, 1 selected from the same or different substituent selected from substituent group δ, 1 or 2 substituted triazolyl group, tetrazolyl group, substituent selected from substituent group δ substituted tetrazolyl _group, C 2 -C ₆ alkenyl _group, C 2 -C ₆ alkynyl _group, C 3 -C ₆ cycloalkyl group, _{and, C} 1 -C substituted by C 3 -C ₆ cycloalkyl group ₆ An alkyl group;
<Substituent group δ> A C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkyl group substituted with 1 to 5 identical or different halogen atoms, and a halogen atom. According to claim 12, R ³ is _C 1 -C ₄ alkyl group,
R ⁴ is a hydrogen atom or a C ₁ -C ₄ alkyl group,
Ar ² is the same or different phenyl group, phenyl group substituted with 1 to 5 substituents selected from the same or different substituents selected from substituent group γ, monocyclic heteroaryl group, or substituent group γ A monocyclic heteroaryl group substituted with 1 to 5 substituents;
E ¹ is a group represented by the formula —S (O) _n1 — (wherein _n1 represents an integer of 0 to 2);
E ³ is the formula (Ga ^A )

(Wherein R ^5A , R ^6A , R ^7A and R ^{8A each} independently represents a hydrogen atom, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ halogenated alkyl group,
p ^A represents 0 or 1,
q ^A , r ^A and s ^A independently represent an integer of 0 to 2. ) Or a pharmacologically acceptable salt thereof as an active ingredient. In claim 12, R ^a is:

Or a pharmacologically acceptable salt thereof as an active ingredient. In Claim 12, E ¹ is a methylene group,
E ²

A group selected from the group consisting of:
E ³ represents the formula (Ga ^B )

(In the formula, q ^B represents an integer of 0 to 3, r ^B and s ^B independently represent an integer of 0 to 2, provided that the sum of q ^B , r ^B and s ^B is 3 or less. .) A pharmaceutical comprising a compound represented by the above formula) or a pharmacologically acceptable salt thereof as an active ingredient. In claim 12, R ^a is:

Or a pharmacologically acceptable salt thereof as an active ingredient. In claim 12, R ⁴ is a hydrogen atom,
Ar ² is a naphthyl group, a naphthyl group substituted by 1 to 5 substituents selected from the same or different substituent selected from substituent group γ, a fused bicyclic heteroaryl group, or the same or selected from substituent group γ A fused bicyclic heteroaryl group substituted 1 to 5 with different substituents,
E ¹ is a group represented by the formula —S (O) _n1 — (wherein _n1 represents an integer of 0 to 2);
E ³ represents the formula (Ga ^C )

(Wherein R ^5C , R ^6C , R ^7C , and R ^8C independently represent a hydrogen atom, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ halogenated alkyl group,
p ^C represents 0 or 1,
q ^C , r ^C and s ^C independently represent an integer of 0 to 2. ) Or a pharmacologically acceptable salt thereof as an active ingredient. In claim 12, R ⁴ is a hydrogen atom,
Ar ² is 1 to 5 phenyl groups, naphthyl groups, or the same or different substituents selected from the substituent group γ, substituted with the same or different substituents selected from the phenyl group and the substituent group γ To a 5-substituted naphthyl group,
E ¹ is a methylene group or a sulfur atom,
E ³ is the formula (Gb)

(In the formula, Ar ³ is a phenylene group, a phenylene group, a naphthylene group, or a (fluorine atom) substituted with the same or different substituents selected from the substituent group consisting of (fluorine atom and chlorine atom) And a naphthylene group substituted with the same or different substituents selected from the substituent group consisting of
R ⁹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
T represents a single bond or a C ₁ -C ₈ alkylene group. ) Or a pharmacologically acceptable salt thereof as an active ingredient. 19. A pharmaceutical comprising as an active ingredient a compound or a pharmacologically acceptable salt thereof in which R ¹ is a hydrogen atom or a methyl group in any one of claims 1 to 18. A medicament comprising, as an active ingredient, a compound according to any one of claims 1 to 18, wherein R ¹ is a methyl group, or a pharmacologically acceptable salt thereof. 21. A medicament comprising, as an active ingredient, a compound or a pharmacologically acceptable salt thereof in which L ¹ is a C ₁ -C ₆ alkylene group or C ₂ -C ₆ alkenylene group in any one of claims 1 to 20. 21. A pharmaceutical comprising the compound or pharmacologically acceptable salt thereof, wherein L ¹ is a C ₂ -C ₆ alkylene group or —CH═CH— in any one of claims 1 to 20 as an active ingredient. 21. A medicament comprising, as an active ingredient, a compound or a pharmacologically acceptable salt thereof wherein L ¹ is a C ₂ alkylene group or —CH═CH— in any one of claims 1 to 20. 21. A medicament comprising as an active ingredient a compound or a pharmacologically acceptable salt thereof, wherein L ¹ is a C ₂ alkylene group in any one of claims 1 to 20. 25. In any one of claims 1 to 24, G is a single bond, -O-, -NH-C (= O)-, -C (= O) -NH-, -C (= O) -N (CH ₃ ) A medicament containing, as an active ingredient, a compound which is-, a carbonyl group, or -C (= O) -O- or a pharmacologically acceptable salt thereof. 25. In any one of claims 1 to 24, G is —C (═O) —NH—, —C (═O) —N (CH ₃ ) —, a carbonyl group, or —C (═O) —O—. Or a pharmacologically acceptable salt thereof as an active ingredient. 25. A medicament comprising, as an active ingredient, a compound or a pharmacologically acceptable salt thereof in which G is —C (═O) —NH— or a carbonyl group in any one of claims 1 to 24. 25. A pharmaceutical comprising the compound according to any one of claims 1 to 24 or a pharmacologically acceptable salt thereof as an active ingredient, wherein G is -C (= O) -NH-. 29. A pharmaceutical comprising as an active ingredient a compound or a pharmacologically acceptable salt thereof, wherein L ² is a single bond, a double bond, or a 4- to 7-membered heterocyclic group according to any one of claims 1 to 28. Medicament according to any one of claims 1 to 28 L ² contains a compound or active ingredient a pharmacologically acceptable salt thereof is a single bond. 31. A medicament comprising, as an active ingredient, a compound or a pharmacologically acceptable salt thereof, wherein L ³ is a single bond, a double bond, or a C ₁ -C ₆ alkylene group in any one of claims 1 to 30. 31. A pharmaceutical comprising as an active ingredient a compound or a pharmacologically acceptable salt thereof wherein L ³ is a single bond, double bond, —CH ₂ — or —CH ₂ CH ₂ — in any one of claims 1 to 30 . 31. A medicament comprising the compound or pharmacologically acceptable salt thereof, wherein L ³ is a single bond, —CH ₂ — or —CH ₂ CH ₂ — in any one of claims 1 to 30 as an active ingredient. 31. A pharmaceutical comprising as an active ingredient a compound or a pharmacologically acceptable salt thereof wherein L ³ is —CH ₂ — or —CH ₂ CH ₂ — in any one of claims 1 to 30. 31. A medicament comprising as an active ingredient a compound or a pharmacologically acceptable salt thereof, wherein L ³ is —CH ₂ — in any one of claims 1 to 30. A carboxy group in any one of claims 1 to 35, -SO ₃ H group, -OSO ₃ H group, -SO ₂ NH ₂ group, -OPO ₃ H ₂ group, azetidinyl group, pyrrolidinyl group, piperidinyl group , A piperazinyl group, a morpholinyl group, an azetidinyl group monosubstituted with a substituent (the substituent: a methyl group, an -OSO ₃ H group or an -OPO ₃ H ₂ group), a piperidinyl group monosubstituted with a substituent (the substitution Group: methyl group, -OSO ₃ H group or -OPO ₃ H ₂ group), piperazinyl group substituted by one substituent [the substituent: methyl group, C ₂ -C ₆ alkyl group substituted by one substituent (Substituents: —SO ₃ H group, —OSO ₃ H group, —SO ₂ NH ₂ group, —OPO ₃ H ₂ group or —NMe ₂ group)] or a compound that is —NMe ₂ group or a pharmacologically acceptable salt thereof The pharmaceutical which contains the salt made as an active ingredient. A carboxy group in any one of claims 1 to 35, -SO ₃ H group, -OSO ₃ H group, -OPO ₃ H ₂ group, 1-azetidinyl, 1-pyrrolidinyl group, piperidino group (i.e. 1 -Piperidinyl group), morpholino group (ie 4-morpholinyl group), 1-methyl-3-azetidinyl group, 3- (sulfooxy) -1-azetidinyl group, 3- (phosphonooxy) -1-azetidinyl group, 1-methyl- 4-piperidinyl group, 1-methyl-4-piperidinylidene group, 3- (sulfooxy) -1-piperidinyl group, 3- (phosphonooxy) -1-piperidinyl group, 4-methyl-1-piperazinyl group, 4- (2- Hydroxyethyl) -1-piperazinyl group, 4- [2- (sulfooxy) ethyl] -1-piperazinyl group, 4- [2- (phosphonooxy) ethyl] -1-piperazinyl group Pharmaceutical comprising as an active ingredient acceptable salt compound or a pharmacologically a ₂ group -NMe is. A carboxy group in any one of claims 1 to 35, -SO ₃ H group, -OPO ₃ H ₂ group, 4-methyl-1-piperazinyl or 4- (2-hydroxyethyl) -1-piperazinyl The pharmaceutical which contains the compound which is group, or its pharmacologically acceptable salt as an active ingredient. 36. A pharmaceutical comprising the compound or pharmacologically acceptable salt thereof, wherein A is a carboxy group, —SO ₃ H group or —OPO ₃ H ₂ group according to any one of claims 1 to 35 as an active ingredient. 36. A medicament comprising the compound according to any one of claims 1 to 35, wherein A is a carboxy group, or a pharmacologically acceptable salt thereof as an active ingredient. In claim 1, R ^a is:

And Ar is a 2,4-difluorophenyl group, R ¹ is a hydrogen atom or a methyl group, L ¹ is a C ₂ -C ₆ alkylene group or —CH═CH—, G is —C (═O) —NH—, —C (═O) —N (CH ₃ ) —, a carbonyl group, or —C (═O) —O—, L ² is a single bond, L ³ is a single bond, —CH ₂ — or —CH ₂ CH ₂ —, and A is a carboxy group, —SO ₃ H group, —OSO ₃ H group, —OPO ₃ H ₂ group, 1-azetidinyl group, 1 -Pyrrolidinyl group, piperidino group, morpholino group, 1-methyl-3-azetidinyl group, 3- (sulfooxy) -1-azetidinyl group, 3- (phosphonooxy) -1-azetidinyl group, 1-methyl-4-piperidinyl group, 1-methyl-4-piperidinylidene group, 3- (sulfooxy) -1-piperidinyl group, 3- (phosphonooxy) -1-piperidinyl group, 4-methyl-1-piperazinyl group Group, 4- (2-hydroxyethyl) -1-piperazinyl group, 4- [2- (sulfooxy) ethyl] -1-piperazinyl group, 4- [2- (phosphonooxy) ethyl] -1-piperazinyl group or -NMe A medicament comprising as an active ingredient a compound that is _two groups or a pharmacologically acceptable salt thereof. In claim 1, R ^a is:

And Ar is a 2,4-difluorophenyl group, R ¹ is a hydrogen atom or a methyl group, L ¹ is a C ₂ -C ₆ alkylene group or —CH═CH—, G is —C (═O) —NH— or a carbonyl group, L ² is a single bond, L ³ is a single bond, —CH ₂ — or —CH ₂ CH ₂ —, and A is a carboxy group, -SO ₃ H group, -OSO ₃ H group, -OPO ₃ H ₂ group, 1-azetidinyl, 1-pyrrolidinyl group, piperidino group, morpholino group, 1-methyl-3-azetidinyl group, 3- (sulfooxy) - 1-azetidinyl group, 3- (phosphonooxy) -1-azetidinyl group, 1-methyl-4-piperidinyl group, 1-methyl-4-piperidinylidene group, 3- (sulfooxy) -1-piperidinyl group, 3- (phosphonooxy) -1-piperidinyl group, 4-methyl-1-piperazinyl group, 4- (2-hydroxy group) Ethyl) -1-piperazinyl group, 4- [2- (sulphooxy) ethyl] -1-piperazinyl group, 4- [2- (phosphonooxy) ethyl] -1-compound or a pharmacologically piperazinyl group or -NMe ₂ group A pharmaceutical comprising a top acceptable salt as an active ingredient. In claim 1, R ^a is:

Ar is a 2,4-difluorophenyl group, R ¹ is a hydrogen atom or a methyl group, L ¹ is a C ₂ alkylene group or —CH═CH—, and G is — C (═O) —NH— or a carbonyl group, L ² is a single bond, L ³ is a single bond, —CH ₂ — or —CH ₂ CH ₂ —, A is a carboxy group, —SO ₃ H group, -OSO ₃ H group, -OPO ₃ H ₂ group, 1-azetidinyl group, 1-pyrrolidinyl group, piperidino group, morpholino group, 1-methyl-3-azetidinyl group, 3- (sulfooxy) -1-azetidinyl Group, 3- (phosphonooxy) -1-azetidinyl group, 1-methyl-4-piperidinyl group, 1-methyl-4-piperidinylidene group, 3- (sulfooxy) -1-piperidinyl group, 3- (phosphonooxy) -1- Piperidinyl group, 4-methyl-1-piperazinyl group, 4- (2-hydroxyethyl) Til) -1-piperazinyl group, 4- [2- (sulfooxy) ethyl] -1-piperazinyl group, 4- [2- (phosphonooxy) ethyl] -1-piperazinyl group or —NMe ₂ group or a pharmacology thereof A pharmaceutical comprising a top acceptable salt as an active ingredient. In claim 1, R ^a is:

Ar is a 2,4-difluorophenyl group, R ¹ is a hydrogen atom or a methyl group, L ¹ is a C ₂ alkylene group, and G is —C (═O) —. NH— or a carbonyl group, L ² is a single bond, L ³ is a single bond, —CH ₂ — or —CH ₂ CH ₂ —, A is a carboxy group, —SO ₃ H group, —OSO ₃ H group, -OPO ₃ H ₂ group, 1-azetidinyl group, 1-pyrrolidinyl group, piperidino group, morpholino group, 1-methyl-3-azetidinyl group, 3- (sulfooxy) -1-azetidinyl group, 3- (phosphonooxy ) -1-azetidinyl group, 1-methyl-4-piperidinyl group, 1-methyl-4-piperidinylidene group, 3- (sulfooxy) -1-piperidinyl group, 3- (phosphonooxy) -1-piperidinyl group, 4-methyl -1-piperazinyl group, 4- (2-hydroxyethyl)- - piperazinyl, 4- [2- (sulphooxy) ethyl] -1-piperazinyl group, are allowed 4- [2- (phosphonooxy) ethyl] -1-piperazinyl group, or -NMe a ₂ group compound or a pharmacologically A medicine containing salt as an active ingredient. In claim 1, R ^a is:

Ar is a 2,4-difluorophenyl group, R ¹ is a hydrogen atom or a methyl group, L ¹ is a C ₂ alkylene group, and G is —C (═O) —. NH— or a carbonyl group, L ² is a single bond, L ³ is —CH ₂ — or —CH ₂ CH ₂ —, and A is a carboxy group, —SO ₃ H group, —OPO ₃ H ₂ group Or a 4-methyl-1-piperazinyl group or a 4- (2-hydroxyethyl) -1-piperazinyl group or a pharmacologically acceptable salt thereof as an active ingredient. In claim 1, R ^a is:

Ar is a 2,4-difluorophenyl group, R ¹ is a hydrogen atom or a methyl group, L ¹ is a C ₂ alkylene group, and G is —C (═O) —. Compound which is NH-, L ² is a single bond, L ³ is —CH ₂ — or —CH ₂ CH ₂ —, and A is a carboxy group, —SO ₃ H group or —OPO ₃ H ₂ group Or the pharmaceutical which contains the salt accept | permitted pharmacologically as an active ingredient. In claim 1, R ^a is:

Ar is a 2,4-difluorophenyl group, R ¹ is a hydrogen atom or a methyl group, L ¹ is a C ₂ alkylene group, and G is —C (═O) —. A pharmaceutical comprising NH-, L ² is a single bond, L ³ is -CH _2- , and A is a carboxy group or a pharmacologically acceptable salt thereof as an active ingredient. 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 = hydrogen = glutarate,
1- [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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] Ethoxy] -4-oxobutyryl] -4-piperidinecarboxylic 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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy ] -4-oxobutyryl] amino] acetic acid,
3-[[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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy ] Ethoxy] -4-oxobutyryl] amino] propionic acid,
[N- [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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy ] Ethoxy] -4-oxobutyryl] -N-methylamino] acetic 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-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxymethyl = hydrogen = glutarate,
1- [4-[[(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] carbonyloxymethoxy] -4 -Oxobutyryl] -4-piperidinecarboxylic acid,
[[4-[[(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] carbonyloxymethoxy] -4- Oxobutyryl] amino] acetic acid,
3-[[4-[[(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] carbonyloxymethoxy]- 4-oxobutyryl] amino] propionic acid,
[N- [4-[[(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] carbonyloxymethoxy]- 4-oxobutyryl] -N-methylamino] acetic acid,
5- [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] ethoxy]- 5-oxo-1-pentanesulfonic acid,
6- [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] ethoxy]- 6-oxo-1-hexanesulfonic acid,
5-[[(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] carbonyloxymethoxy] -5-oxo- 1-pentanesulfonic acid,
6-[[(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] carbonyloxymethoxy] -6-oxo- 1-hexanesulfonic 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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy ] -4-oxobutyryl] oxy] acetic acid,
[[4-[[(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] carbonyloxymethoxy] -4- Oxobutyryl] oxy] acetic acid or a pharmacologically acceptable salt thereof as an active ingredient. [[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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy] ethoxy ] -4-oxobutyryl] amino] acetic acid,
3-[[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-difluorophenyl) -1-[(1H-1,2,4-triazol-1-yl) methyl] propoxy] carbonyloxy ] Ethoxy] -4-oxobutyryl] amino] propionic acid,
[[4-[[(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] carbonyloxymethoxy] -4- Oxobutyryl] amino] acetic acid,
3-[[4-[[(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] carbonyloxymethoxy]- 4-oxobutyryl] amino] propionic acid or a pharmacologically acceptable salt thereof as an active ingredient. 50. An antifungal agent comprising the triazole compound according to any one of claims 1 to 49 or a pharmacologically acceptable salt thereof as an active ingredient.

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