JP2008260760A - Pharmaceutical composition containing substituted cycloalkene derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition excellent in prevention and/or therapy of diseases such as septicemia, a compound able to be used for the same and a method for producing the same. <P>SOLUTION: The pharmaceutical composition contains a compound expressed by general formula (I) [wherein X and Y express each a group or the like forming the ring A together with carbon atoms of the ring B to which they are bonded; l and m independently express each an integer of 0-3, and l+m is 1-3; R<SP>1</SP>expresses an aliphatic hydrocarbon group which may be substituted with a group selected from a substitution group β and a substitution group γ; n expresses an integer of 0-3; R<SP>2</SP>expresses H or the like; R<SP>3</SP>is a phenyl group or the like which may be substituted with a group selected from a substitution group ε; R<SP>5</SP>expresses a 1-6C alkyl group or the like, however, when R<SP>3</SP>expresses the phenyl group which may be substituted with the group selected from the substitution group ε, X and Y express each the group forming the ring A together with carbon atoms of the ring B to which they are bonded] or a pharmaceutically acceptable salt of the same as an active ingredient. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

The present invention suppresses intracellular signal transduction or cell activation in various cells such as monocytes, macrophages, vascular endothelial cells and the production of inflammatory mediators such as TNF-α caused by endotoxin. A pharmaceutical composition containing a novel compound having an active ingredient, a method for producing the novel compound, and a prophylactic and / or therapeutic agent for various diseases such as sepsis (septic shock, disseminated intravascular coagulation syndrome, multiple organ failure, etc.) It relates to the use of the pharmaceutical composition as.

Sepsis is a systemic inflammatory response syndrome (SIRS) caused by an excessive inflammatory response in the body to bacterial infection.
ndrome), and is a disease that causes death when accompanied by shock or organ damage. Although there are few effective drugs for sepsis to date, it is considered a disease that is difficult to prevent and treat. However, because of the high fatality rate and the large number of patients, the development of such drugs is extremely important. (For example, refer nonpatent literature 1).

Endotoxin (lipopolysaccharide: LPS), a membrane component of bacteria, is a monocyte,
Acts on cells such as macrophages and vascular endothelial cells, causes overproduction of various inflammatory mediators such as TNF-α, etc. In addition to systemic inflammatory reactions, rapid blood pressure drop, abnormal blood coagulation, circulatory disturbance, etc. Induces and exhibits sepsis (see, for example, Non-Patent Document 2). Lipid A corresponding to lipopolysaccharide and its partial structure undergoes binding to CD14,
TLR4 (Toll-like receptor 4), a functional receptor on the cell surface
By activating intracellular signal transduction via ss (see, for example, Non-Patent Document 3), various cellular responses typified by inflammatory mediator production are initiated. Therefore, substances that suppress various cellular responses typified by endotoxin-induced intracellular signal transduction or cell activation and the overproduction of inflammatory mediators such as TNF-α are effective prevention of sepsis. It is considered that the drug can be a therapeutic drug (see, for example, Non-Patent Document 3, Non-Patent Document 4, Patent Document 1, and Patent Document 2).

Various cell responses such as intracellular signal transduction or cell activation caused by endotoxin and overproduction of inflammatory mediators such as TNF-α are caused by ischemic brain injury, arteriosclerosis, coronary artery in addition to the above-mentioned sepsis. Poor prognosis after plastic surgery, heart failure,
Diabetes, diabetic complications, arthritis, osteoporosis, osteopenia, autoimmune disease, tissue damage and rejection after organ transplantation, bacterial infection, viral infection, gastritis, pancreatitis, nephritis, pneumonia, hepatitis,
It causes the onset and progress of various diseases such as leukemia (for example, Non-Patent Document 5 and Patent Document 3).

For this reason, substances having an action to suppress various cellular responses such as intracellular signal transduction or cell activation caused by endotoxin and overproduction of inflammatory mediators such as TNF-α caused by them are effective against these various diseases. On the other hand, it is considered useful as a preventive and / or therapeutic agent, and development of an excellent therapeutic agent is desired.
Iqbal et al. , Expert Opin. Emerging Drugs, Volume 7, Section 111, 2002 Hawkins et al. , Current Topics in Medicinal Chemistry, Volume 4, p. 1147, 2004. Butler, Nature, 430, 257-263, 2004. Kakutani et al. , Inflammation Research, 48, 461, 1999. Donald N.M. Cook et al. , Nature Immunology, Vol. 5, 975-979, 2004. JP 2000-178246 A JP 2004-2370 A International Publication No. 00/41698 pamphlet

The present inventors have various intracellular signal transduction or cell activation of monocytes, macrophages, vascular endothelial cells and the like caused by endotoxin and TNF-
As a result of diligent research on the pharmacological activity of various substituted cycloalkene derivatives with the aim of developing compounds that have the effect of suppressing various cellular responses such as the production of inflammatory mediators such as α, substitution with a unique structure Cycloalkene derivatives have excellent suppressive action on intracellular responses such as intracellular signal transduction or cell activation caused by endotoxin and inflammatory mediator production resulting from them, and intracellular signal transduction caused by endotoxin or The present inventors have found that the present invention is useful as an active ingredient of prophylactic and / or therapeutic agents for various diseases such as sepsis related to cell activation and various cell responses resulting therefrom, and have completed the present invention.

The present invention relates to a substituted cycloalkene derivative having an action of suppressing cellular responses such as intracellular signal transduction or cell activation caused by endotoxin and overproduction of inflammatory mediators such as TNF-α caused by them, or pharmacologically thereof Pharmaceutical composition containing an acceptable salt as an active ingredient, use of the above-mentioned substituted cycloalkene derivative or a pharmacologically acceptable salt thereof as an active ingredient, substituted cycloalkene derivative or a pharmacologically acceptable salt thereof Provide a method of making salt.

That is, the present invention
(1) General formula (I)

{Where,
X and Y represent a group that forms ring A together with the carbon atom of ring B to which they are bonded, or X and Y together represent a substituent of ring B, or X And Y each represents a hydrogen atom.

1) When X and Y represent a group that together with the carbon atom of ring B forms ring A:
Ring A is
3- to 7-membered heterocyclyl ring [wherein X and Y are each independently a carbon atom, a group having the formula NR, wherein R is a hydrogen atom or a group selected from substituent group α. Or a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, or a C ₁ -C ₆ alkanoyl group), an oxygen atom, a sulfur atom, a formula SO
Any one selected from a group having the formula and a group having the formula SO ₂ ,
The heterocyclyl ring may contain an unsaturated bond,
A 3- to 7-membered heterocyclyl ring or a 3- to 7-membered cycloalkyl ring may form a condensed ring or a spiro ring,
Ring A includes a condensed ring and a spiro ring, an oxo group, a thioxo group, a substituent group α, a cyclopropyl C ₁ -C ₆ alkyl group,
A C ₁ -C ₆ alkyl group optionally substituted with a group selected from 1 to 5 substituent groups α,
A C ₂ -C ₆ alkenyl group optionally substituted with a group selected from 1 to 5 substituent groups α, and a group selected from 1 to 5 substituent groups α. And may be substituted with the same or different 1 to 4 groups selected from the group consisting of C ₂ -C ₆ alkynyl groups. ]
Or

3- to 7-membered cycloalkyl ring (the cycloalkyl ring may contain an unsaturated bond,
A 3- to 7-membered heterocyclyl ring or a 3- to 7-membered cycloalkyl ring may form a condensed ring or a spiro ring,
Ring A includes a condensed ring and a spiro ring, a substituent group α, a cyclopropyl C ₁ -C ₆ alkyl group,
A C ₁ -C ₆ alkyl group optionally substituted with a group selected from 1 to 5 substituent groups α,
A C ₂ -C ₆ alkenyl group optionally substituted with a group selected from 1 to 5 substituent groups α, and
Substituted with 1 to 4 identical or different groups selected from the group consisting of C ₂ -C ₆ alkynyl groups optionally substituted with a group selected from 1 to 5 substituent groups α. May be. ).

2) When X and Y together represent a substituent of ring B:
X and Y each represents an oxo group or a thioxo group.

l and m each independently represent an integer of 0 to 3,
l + m is 1 to 3.

R ¹ is
An aliphatic hydrocarbon group which may be substituted with a group selected from substituent group β and substituent group γ (the aliphatic hydrocarbon group is a C ₁ -C ₂₀ alkyl group, C ₃ -C ₁₀ cycloalkyl group) Group, C ₄ -C _1
2 cycloalkylalkyl group, a C ₃ -C ₆ alkenyl or C ₃ -C ₆ alkynyl group.
),
A phenyl group optionally substituted with a group selected from substituent group δ,
A group having the formula OR ⁴ (wherein R ⁴ represents a hydrogen atom or an aliphatic hydrocarbon group which may be substituted with a group selected from the substituent group β and the substituent group γ. Group hydrocarbon group is
The meaning is the same as above. ) Or a halogen atom.

n represents an integer of 0 to 3.

R ² is a hydrogen atom,
A C ₁ -C ₆ alkyl group optionally substituted with a group selected from substituent group β,
A C ₂ -C ₆ alkenyl group optionally substituted with a group selected from substituent group β, or a C ₂ -C ₆ alkynyl group optionally substituted with a group selected from substituent group β .

R ³ is
A phenyl group optionally substituted with a group selected from substituent group ε, or a 5- to 6-membered heteroaryl group optionally substituted with a group selected from substituent group ε (the heteroaryl group is 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom).

R ⁵ represents a hydrogen atom,
A C ₁ -C ₆ alkyl group optionally substituted with a group selected from substituent group β,
A C ₂ -C ₆ alkenyl group optionally substituted with a group selected from substituent group β, or a C ₂ -C ₆ alkynyl group optionally substituted with a group selected from substituent group β .

However, when R ³ is a phenyl group which may be substituted with a group selected from the substituent group ε, X and Y represent the above (1) or (2).

Substituent group α is
Hydroxy group, a halogen atom, C ₁ -C ₆ alkoxy group, a halogeno C ₁ -C ₆ alkoxy group, a carboxy group, C ₁ -C ₆ alkoxy - carbonyl group;
Optionally substituted by a group selected from a carbonyl group - C ₁ -C ₆ alkyl _group, C 2 -C ₆ alkenyl _group, C 2 -C ₆ alkynyl group, C ₁ -C ₆ alkanoyl group or a _C 2 -C ₆ alkenyl An optional carbamoyl group;
And a group having the formula NR ⁶ R ⁷ .

R ⁶ and R ⁷ are each independently a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a C ₁ -C ₆ alkanoyl group, or C _2. -C ₆ alkenyl-
Represents a carbonyl group, or together with the nitrogen atom to which R ⁶ and R ⁷ are attached,
Forms a heterocyclyl group;

Substituent group β is
Oxo group, hydroxy group, cyclopropyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, a nitro group, a halogen atom, a cyano group, a carboxy group, C ₁ -C ₁₀ alkoxy - carbonyl group, C ₁ -C ₆ alkanoyl _group, C 2 -C ₄ alkenyl - carbonyl group, C ₂ -C ₆
Alkanoyloxy groups, C ₂ -C ₄ alkenyl - carbonyl group;
C ₁ -C ₄ alkyl group, a phenyl group, C ₁ -C ₇ acyl group and C ₁ -C ₄ alkoxy - carbamoyl group optionally substituted by a group selected from a phenyl group;
C ₁ -C ₄ alkyl group or an optionally substituted thiocarbamoyl group in a phenyl group,
C ₁ -C ₄ alkyl group or an optionally substituted carbamoyloxy group with a phenyl group,
C ₁ -C ₆ alkanoylamino group, C ₁ -C ₁₀ alkoxy-carboxamide group, C ₁ -C ₁₀ alkoxy-carbonyloxy group, and ureido group optionally substituted by C ₁ -C ₄ alkyl group or phenyl group Indicates.

Substituent group γ is
Heterocyclic group, C ₃ -C ₁₀ cycloalkyl group, C ₆ -C ₁₀ aryloxy group, C ₇ -C ₁₉
Aralkyloxy group, a heterocyclic oxy group, C ₃ -C ₁₀ cycloalkyl thio groups, C ₆ -C ₁₀ arylthio group, C ₇ -C ₁₉ aralkylthio group, a heterocyclic thio group, a heterocyclic sulfinyl group, heterocyclic sulfonyl group, C ₃ -C ₆ cycloalkyloxy - carbonyl group, C ₆ -C ₁₀ aryloxy - carbonyl group, C ₇ -C ₁₉ aralkyloxy - carbonyl group, a heterocyclic oxycarbonyl group, C ₆ -C ₁₀ aryl - carbonyl group, C ₆ -C ₁₀ aryl - carbonyl group,
C ₆ -C ₁₀ aryl - carbonyl amino group, C ₆ -C ₁₀ aryloxy - carboxamide group, C ₇ -C ₁₉ aralkyloxy - carboxamide group, C ₆ -C ₁₀ aryloxy - carbonyl group, C ₇ -C ₁₉ aralkyloxy - carbonyl group, C ₃ -C ₁₀ cycloalkyl-oxy - carbonyl group, and show the optionally substituted C ₆ -C ₁₀ aryl group with a group selected from the substituent group beta.

Substituent group δ is
Hydroxy group, nitro group, cyano group, halogen atom, C ₁ -C ₆ alkyl, halogeno C ₁
-C ₆ alkyl group, C ₁ -C ₆ alkoxy group, a halogeno C ₁ -C ₆ alkoxy group, a carboxy group, C ₁ -C ₆ alkanoyl group, C ₁ -C ₆ alkoxy - carbonyl group, C ₁ -C ₆ alkanoyl amino group, C ₁ -C ₆ alkylthio group, a carbamoyl group, C ₁ -C ₆ alkyl - carbamoyl group, C ₁ -C ₆ alkoxy - carbonyl C ₁ -C ₆ alkyl - carbamoyl group, 1,3-diacylguanidino C ₁ -C ₆ alkyl group, a group having the formula ^NR 6 ^{R 7 (R 6} and ^{R 7} have the same meanings as ^{R 6} and ^{R 7} in the substituent group alpha.), C ₃ -C ₆ cycloalkyl group, C ₆ -C ₁₀
An aryl group and a 5-membered heteroaryl group are shown.

Substituent group ε is
Hydroxy group, nitro group, cyano group, halogen atom, C ₁ -C ₁₄ alkyl group, cyclopropyl C ₁ -C ₁₄ alkyl group, halogeno C ₁ -C ₁₄ alkyl group, C ₁ -C ₁₄ alkoxy group, a halogeno C ₁ -C ₁₄ alkoxy group, a carboxy group, C ₁ -C ₁₄ alkanoyl groups, C ₁ -C ₁₄ alkoxy - carbonyl group, C ₁ -C ₁₄ alkanoylamino group, C ₁ -C ₁₄ alkylthio group,
Carbamoyl group, C ₁ -C ₁₄ alkyl-carbamoyl group, C ₁ -C ₁₄ alkoxy-carbonyl C ₁ -C ₁₄ alkyl-carbamoyl group, 1,3-diacylguanidino C ₁ -C ₁₄ alkyl group, formula NR ⁶ R ⁷ groups having ^{(R 6} and ^{R 7} are the same meaning as ^{R 6} and ^{R 7} in the substituent group α.), C ₃ -C ₆ cycloalkyl group, C ₆ -C ₁₀ aryl group and 5-membered heteroaryl group Indicates. }
Or a pharmacologically acceptable salt thereof as an active ingredient,
(2) In the above (1), l is 0 and m is an integer of 1 to 3,
(3) In the above (1), l is 0 and m is 2,
(4) In any one item selected from (1) to (3) above,
X and Y together with the carbon atom of ring B form ring A, where ring A is

3- to 7-membered heterocyclyl ring [wherein X and Y are each independently a carbon atom, a group having the formula NR, wherein R is a hydrogen atom or a group selected from substituent group α. C ₁
-C ₆ alkyl _group, C 2 -C ₆ alkenyl _group, C 2 -C ₆ alkynyl group, or, _{C 1}
—C ₆ alkanoyl group. ), An oxygen atom, a sulfur atom, a group having the formula SO and the formula SO ₂
Any one selected from the group having
The heterocyclyl ring is a 5- to 6-membered heterocyclyl ring (the heterocyclyl ring contains 1 to 2 oxygen atoms and / or nitrogen atoms as heteroatoms) or a 5- to 6-membered cycloalkyl ring and a condensed or spiro ring. May form a ring,
Ring A is substituted with a group selected from an oxo group, a thioxo group, a substituent group α, a cyclopropyl C ₁ -C ₆ alkyl group, and 1 to 5 substituent groups α, including a condensed ring and a spiro ring. Optionally substituted by 1 to 4 groups identical or different selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl groups. ]

Or

3- to 7-membered saturated cycloalkyl ring (the 3- to 7-membered saturated cycloalkyl ring is a hydroxy group, a hydroxymethyl group, 1, 2,
-Substituted by 1 to 2 groups selected from the group consisting of a dihydroxyethyl group, a 1,2,3-trihydroxypropyl group, a 1,2,3,4-tetrahydroxybutyl group, and an acetylamino group It may be. )
A pharmaceutical composition,
(5) In any one item selected from (1) to (3) above,
X and Y represent a group that together with the carbon atom of ring B forms ring A,

A 3- to 7-membered heterocyclyl ring [wherein X and Y are each independently selected from a carbon atom, an oxygen atom, a sulfur atom, a group having the formula SO, and a group having the formula SO ₂ ; Show
The heterocyclyl ring is a 5- to 6-membered heterocyclyl ring (the heterocyclyl ring contains 1 to 2 oxygen atoms and / or nitrogen atoms as heteroatoms) or a 5- to 6-membered cycloalkyl ring and a condensed or spiro ring. May form a ring,
Ring A is a C ₁ -C ₆ alkyl optionally substituted with a group selected from an oxo group, a thioxo group, a substituent group α, and 1 to 4 substituent groups α, including a condensed ring and a spiro ring. It may be substituted with 1 to 4 groups which are the same or different and are selected from the group consisting of groups. ]

Or

3- to 5-membered saturated cycloalkyl ring (the 3- to 5-membered saturated cycloalkyl ring is a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-trihydroxypropyl group, 1,2,3,4 -It may be substituted by one or two groups selected from the group consisting of a tetrahydroxybutyl group and an acetylamino group.
A pharmaceutical composition,
(6) In any one item selected from (1) to (3) above,
X and Y represent a group that together with the carbon atom of ring B forms ring A,

A 3- to 7-membered heterocyclyl ring [the 3- to 7-membered heterocyclyl ring is
Oxirane, oxolane, tetrahydrofuran, tetrahydropyran,
1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane,
1,3-dithiolane, 1,3-dithiane,
1,1,3,3-tetraoxo-1,3-dithiolane,
1,3-oxathiolane, 1,3-oxathiane, or 1,3-oxathiepan,
These heterocyclyl rings are 5- to 6-membered heterocyclyl rings (the 5- to 6-membered heterocyclyl ring is tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine or 1,
3-dioxane. ) Or a cyclohexyl ring and a condensed or spiro ring may be formed,
Ring A includes a condensed ring and a spiro ring, an oxo group, a thioxo group, a substituent group α (the substituent group α
Represents a hydroxy group and a group having the formula NR ⁶ R ⁷ . R ⁶ and R ⁷ each independently represent a hydrogen atom or a C ₁ -C ₆ alkanoyl group. ), Methyl group, ethyl group and 1 to 4
1 to 2 selected from the group consisting of C ₁ -C ₆ alkyl groups substituted with ₁ hydroxy group
It may be substituted with groups. ],

Or

Cyclopropyl or cyclopentyl (the cyclopropyl or cyclopentyl is composed of a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-trihydroxypropyl group, and a 1,2,3,4-tetrahydroxybutyl group) It may be substituted with 1 to 2 groups selected from the group consisting of
A pharmaceutical composition,
(7) In any one item selected from (1) to (3) above,
X and Y represent a group that together with the carbon atom of ring B forms ring A,

3-6 membered heterocyclyl ring {wherein the heterocyclyl ring is
Oxirane, tetrahydrofuran,
1,3-dioxolane, 1,3-dioxane,
1,3-dithiolane, 1,3-dithiane,
1,3-oxathiolane or 1,3-oxathiane,
These heterocyclyl rings may form a condensed ring or a spiro ring with 5- to 6-membered heterocyclyl ring (the 5- to 6-membered heterocyclyl ring is tetrahydrofuran, tetrahydropyran or 1,3-dioxane) or cyclohexyl. Often,
Ring A includes a condensed ring and a spiro ring, and includes a substituent group α [the substituent group α is a hydroxy group and a group having the formula NR ⁶ R ⁷ (R ⁶ and R ⁷ are independently of each other; Represents a hydrogen atom or an acetyl group. ], A methyl group, an ethyl group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-trihydroxypropyl group, and a 1,2,3,4-tetrahydroxybutyl group. May be substituted by 1 to 2 groups. }
A pharmaceutical composition,
(8) In any one item selected from (1) to (7) above,
n is 0 or 1;
R ¹ is a hydroxy group, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group,
(9) In any one item selected from (1) to (7) above,
n is 0 or 1;
R ¹ is a pharmaceutical composition which is a fluorine atom or a methyl group,
(10) In any one item selected from the above (1) to (7),
a pharmaceutical composition wherein n is 0,
(11) In any one item selected from the above (1) to (10),
A pharmaceutical composition wherein R ² is a C ₁ -C ₆ alkyl group;
(12) In any one item selected from (1) to (10) above,
A pharmaceutical composition wherein R ² is a C ₁ -C ₄ alkyl group;
(13) In any one item selected from (1) to (10) above,
A pharmaceutical composition wherein R ² is an ethyl group,
(14) In any one item selected from (1) to (13) above,
R ³ is
A phenyl group optionally substituted with a group selected from the substituent group ε, or
A pyrrolyl group optionally substituted with a group selected from the substituent group ε,
A pharmaceutical composition wherein the substituent group ε is a halogen atom, a C ₁ -C ₁₄ alkyl group and a halogeno C ₁ -C ₁₄ alkyl group;
(15) In any one item selected from (1) to (13) above,
R ³ is
A phenyl group optionally substituted with a group selected from the substituent group ε, or
A pyrrolyl group optionally substituted with a group selected from the substituent group ε,
Substituent group ε is a fluorine atom, chlorine atom, bromine atom, C ₃ -C ₈ alkyl group and halogeno C
Pharmaceutical compositions which are ₄ -C ₈ alkyl group,
(16) In any one item selected from (1) to (13) above,
R ³ is
A phenyl group which may be substituted with a group selected from the substituent group ε,
A pharmaceutical composition wherein the substituent group ε is a fluorine atom, a chlorine atom and a C ₃ -C ₈ alkyl group;
(17) In any one item selected from (1) to (16) above,
A pharmaceutical composition wherein R ⁵ is a hydrogen atom or a C ₁ -C ₆ alkyl group;
(18) In any one item selected from (1) to (16) above,
A pharmaceutical composition wherein R ⁵ is a hydrogen atom or a methyl group;
(19) In any one item selected from (1) to (16) above,
A pharmaceutical composition wherein R ⁵ is a hydrogen atom;
(20) A pharmaceutical composition comprising as an active ingredient a compound of the following group selected from the above (1) or a pharmacologically acceptable salt thereof:
Ethyl 8- [N- (2-chlorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate;
Ethyl 8- [N- (2-chlorophenyl) sulfamoyl] -2,3-bis (1,2
-Dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (2,4-difluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate;
Ethyl 8- [N- (2,4-difluorophenyl) sulfamoyl] -2,3-bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-
7-carboxylate,
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2-hydroxymethyl-1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate;
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3
-Bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-
Carboxylate,
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3
-Bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-
Ene-7-carboxylate,
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2- (
1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7
-Carboxylates,
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2- (
1,2,3-trihydroxypropyl) -1,4-dioxaspiro [4.5] dec-6-
Ene-7-carboxylate,
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2- (
1,2,3,4-tetrahydroxybutyl) -1,4-dioxaspiro [4.5] deca-
6-ene-7-carboxylate,
Ethyl 2,3-bis (acetylaminomethyl) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-
7-carboxylate,
Ethyl 9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-hydroxy-1,5-dioxaspiro [5.5] undec-7-ene-8-carboxylate,
Ethyl 3-acetylamino-9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,5-dioxaspiro [5.5] undec-7-ene-8-carboxylate;
Ethyl 9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3, 3
-Bis (hydroxymethyl) -1,5-dioxaspiro [5.5] undec-7-ene-
8-carboxylate,
Ethyl 8- [N- (2-butyl-4-fluorophenyl) sulfamoyl] -2,3
-Bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-
Carboxylate,
Ethyl 8- [N- (2-butyl-4-fluorophenyl) sulfamoyl] -2,3
-Bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-
Ene-7-carboxylate,
Ethyl 8- [N- (2-hexylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (2-hexylphenyl) sulfamoyl] -2,3-bis (1,
2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (4-fluoro-2-hexylphenyl) sulfamoyl] -2,
3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7
-Carboxylates,
Ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N- (4-fluoro-
2-hexylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate,
Ethyl 8- [N- (2-heptylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (2-heptylphenyl) sulfamoyl] -2,3-bis (1,
2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (4-fluoro-2-heptylphenyl) sulfamoyl] -2,
3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7
-Carboxylates,
Ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N- (4-fluoro-
2-Heptylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate,
Ethyl 8- [N- (2-bromophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (2-bromophenyl) sulfamoyl] -2,3-bis (1,2
-Dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (2-chloro-6-methylphenyl) sulfamoyl] -2, 3-
Bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (2-chloro-6-methylphenyl) sulfamoyl] -2, 3-
Bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -2,3
-Bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-
Carboxylate,
Ethyl 8- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -2,3
-Bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-
Ene-7-carboxylate,
Ethyl 2,3-bis (hydroxymethyl) -8- [N- (2-pentylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N- (2-pentylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (4-fluoro-2-pentylphenyl) sulfamoyl] -2,
3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7
-Carboxylates,
Ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N- (4-fluoro-
2-pentylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate,
Ethyl 8- [N- (4-fluoro-2-octylphenyl) sulfamoyl] -2,
3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7
-Carboxylates,
Ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N- (4-fluoro-
2-octylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate,
Ethyl 8- [N- (4-fluoro-2-propylphenyl) sulfamoyl] -2,
3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7
-Carboxylates,
Ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N- (4-fluoro-
2-propylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate,
And ethyl 8- [N- (2-chloro-4-fluorophenyl) -N-methylsulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate,
(21) The pharmaceutical composition according to any one of (1) to (20), which is used for suppressing intracellular signal transduction or cell activation caused by endotoxin,
(22) Said (1) thru | or (20) used in order to suppress the production of the inflammatory mediator resulting from intracellular signal transduction or cell activation caused by endotoxin
A pharmaceutical composition according to any one of
(23) The above (1) to (20), which is used for suppressing production of inflammatory mediators resulting from intracellular signal transduction or cell activation caused by endotoxin.
A pharmaceutical composition according to any one of
(24) The pharmaceutical composition according to any one of (1) to (20) above, which is used as a preventive and / or therapeutic agent for a disease mediated by an inflammatory mediator whose production is caused by endotoxin,
(25) The above (1) to (20), which is used as a preventive and / or therapeutic agent for a disease mediated by an inflammatory mediator produced due to intracellular signal transduction or cell activation caused by endotoxin. The pharmaceutical composition according to any one of the above,
(26) The pharmaceutical composition according to any one of (1) to (20) above, which is used as an agent for preventing and / or treating sepsis,
And (i) intracellular signal transduction caused by endotoxin, comprising administering the pharmaceutical composition according to any one of (1) to (20) to a warm-blooded animal (preferably a human). And a method for suppressing the overproduction of inflammatory mediators such as TNF-α resulting therefrom, and (ii) prevention of diseases mediated by such intracellular signal transduction and inflammatory mediators produced thereby and / or A method of treatment is provided.

The substituted cycloalkene derivatives having the general formula (I) of the present invention can be used for intracellular signal transduction or cell activation caused by endotoxin and TNF-α resulting therefrom.
Ischemic brain injury which is excellent in the action to suppress overproduction of inflammatory mediators such as, and is mediated by pharmaceutical compositions, in particular, intracellular signaling or cell activation and inflammatory mediators resulting therefrom , Arteriosclerosis, poor prognosis after coronary angioplasty, heart failure, diabetes, diabetic complications, arthritis, osteoporosis, osteopenia, sepsis, autoimmune disease, tissue damage and rejection after organ transplantation, bacterial infection, virus Infection, gastritis, pancreatitis, nephritis,
It is useful as a preventive and / or therapeutic agent for pneumonia, hepatitis, leukemia and the like.

The “halogen atom” in the definition of R ¹ , substituent group α, substituent group β, substituent group δ, and substituent group ε is, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

R ¹ is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The substituent group ε is preferably a fluorine atom, a chlorine atom or a bromine atom, and more preferably a fluorine atom or a chlorine atom.

NR group which can be contained in ring A, substituent of ring A, R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , substituent group β, substituent group δ, substituent group ε "Is a linear or branched alkyl group.

“C ₁ -C ₆ alkyl group” of “C ₁ -C ₆ alkyl group optionally substituted with a group selected from substituent group α” in the definition of NR group that may be contained in ring A; ring A is selected from "1 to group 5 substituents α in the definition of the substituents of ring a;" C ₁ -C ₆ alkyl group "of the" cyclopropyl C ₁ -C ₆ alkyl group "in the definition of substituents C _1- which may be substituted with a group
“C ₁ -C ₆ alkyl group” of “C ₆ alkyl group”; “substituent group β in the definition of R ² and R ⁵
"C ₁ -C ₆ alkyl group" is as good C ₁ -C ₆ alkyl group optionally substituted with a group "chosen from;" C ₁ -C in Substituent group [delta], the definition of R ⁶ and R ⁷ ₆ The “alkyl group” is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-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-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2
, 3-dimethylbutyl, 2-ethylbutyl group and the like.

Among the “C ₁ -C ₆ alkyl groups”, the NR group that may be contained in ring A is preferably methyl.

The substituents on the ring A, preferably a C ₁ -C ₄ alkyl group.

R ² is preferably a C ₁ -C ₄ alkyl group, and more preferably ethyl.

R ⁵ is preferably methyl.

R ⁶ and R ⁷ are preferably methyl.

The substituent group δ is preferably a C ₁ -C ₄ alkyl group.

"C ₁ -C ₁₄ alkyl group" in the definition of Substituent group epsilon, C ₁ -C ₁₄ alkyl group "cyclopropyl C ₁ -C ₁₄ alkyl group", for example, the "C ₁ -C ₆ alkyl group" , Octyl,
Nonyl, decyl, dodecyl, tetradecyl and the like.

In the “C ₁ -C ₁₄ alkyl group” in the definition of the substituent group ε, preferably, C ₃ -C ₈
It is an alkyl group.

The “C ₁ -C ₂₀ alkyl group” in the definition of R ¹ is, for example, the above “C ₁ -C ₁₄ alkyl group”, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl and the like. Preferably a C ₁ -C ₆ alkyl group, more preferably a methyl group.

The NR group that can be contained in ring A, the substituent of ring A, R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , the “alkenyl group” in the definition of substituent group α is linear or branched alkenyl It is a group.

The “C ₃ -C ₆ alkenyl group” in the definition of R ¹ is, for example, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 2-
Butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl- 3-butenyl, 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, 2-
Hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, preferably C ₃
-C is a ₄ alkenyl group.

“C ₂ -C ₆ alkenyl group” of C ₂ -C ₆ alkenyl group “optionally substituted with a group selected from substituent group α” in the definition of NR group that may be contained in ring A; “C ₂ -C ₆ alkenyl group” of “C ₂ -C ₆ alkenyl group optionally substituted with a group selected from 1 to 5 substituent groups α” in the definition of substituent; R ² and R “C ₂ -C ₆ alkenyl group” of “C ₂ -C ₆ alkenyl group optionally substituted with a group selected from substituent group β” in definition ⁵ ; “C ₂ in definition of R ⁶ and R ⁷ ” _“2- C ₆ alkenyl group” means, for example, vinyl, the above “
C ₃ -C ₆ alkenyl group ”, preferably C ₃ -C ₄ alkenyl group.

“Alkynyl group” in the definition of NR group, ring A substituent, R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , substituent group α, which can be contained in ring A, is linear or branched alkynyl. It is a group.

The “C ₃ -C ₆ alkynyl group” in the definition of R ¹ is, for example, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-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, 3-pentynyl, 1
-Methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4
- hexynyl, a 5-hexynyl, preferably a C ₃ -C ₄ alkynyl group.

“C ₂ -C ₆ alkynyl group” of C ₂ -C ₆ alkynyl group “optionally substituted with a group selected from substituent group α” in the definition of NR group that may be contained in ring A; “C ₂ -C ₆ alkynyl group” of “C ₂ -C ₆ alkynyl group optionally substituted with a group selected from 1 to 5 substituent groups α” in the definition of substituent; R ² and R “C ₂ -C ₆ alkynyl group” of “C ₂ -C ₆ alkynyl group optionally substituted with a group selected from substituent group β” in definition ⁵ ; “C ₂ in definition of R ⁶ and R ⁷ ” _{The “2-} C ₆ alkynyl group” is, for example, ethynyl, the above-mentioned “C ₃ -C ₆ alkynyl group”, preferably a C ₃ -C ₄ alkynyl group.

The “C ₃ -C ₆ cycloalkyl group” in the definition of the substituent group δ and the substituent group ε is, for example, cyclopropyl, cyclopentyl, cyclohexyl.

The “3- to 7-membered cycloalkyl ring” in the definition of ring A may contain an unsaturated bond, and examples of such a ring include cyclopropane, cyclobutane, cyclopentane,
Cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptadiene.

The “3- to 7-membered cycloalkyl ring” may form a condensed or spiro ring with a 3- to 7-membered heterocyclyl ring or a 3- to 7-membered cycloalkyl ring. 2-oxa-bicyclo [4,3,0] nonane-8-ylidene, 3-oxa-bicyclo [3,3,0] heptane-7-ylidene, 2,4-dioxa-spiro [6.6
] Undecan-8-ylidene, bicyclo [4,3,0] nonane-7-ylidene, spiro [
6.6] undecane-8-ylidene and the like.

The “3- to 7-membered cycloalkyl ring” may be substituted with an oxo group or a thioxo group without forming a condensed ring or a spiro ring.

The “cycloalkyl ring” includes a cycloalkyl ring, a condensed ring fused to the cycloalkyl ring, or a spiro ring spiro-bonded to the cycloalkyl ring, the substituent group α, cyclopropyl C ₁ —
C ₆ alkyl group, C _1- which may be substituted with a group selected from 1 to 5 substituent groups α
C ₆ -alkyl group, C _2- optionally substituted with a group selected from 1 to 5 substituent groups α
C ₆ alkenyl group, and is selected from the group consisting of 1 to 5 substituents which may be substituted with a group selected from substituent group α C ₂ -C ₆ alkynyl group, the same or different 1 to 4 (Preferably 1 to 2) groups may be substituted.

Examples of suitable rings include 3-hydroxycyclopentane, 4-hydroxycyclohexane,
3-hydroxymethylcyclopentane, 3,4-dihydroxymethylcyclopentane, 4
-Hydroxymethylcyclohexane, 4,4-dihydroxymethylcyclohexane,
3- (1,2-dihydroxyethyl) cyclopentane, 4- (1,2-dihydroxyethyl) cyclohexane, 3,4-bis (1,2-dihydroxyethyl) cyclopentane, 4
, 4-bis (1,2-dihydroxyethyl) cyclohexane,
3- (1,2,3-trihydroxypropyl) cyclopentane, 4- (1,2,3-trihydroxypropyl) cyclohexane,
3- (1,2,3,4-tetrahydroxybutyl) cyclopentane, 4- (1,2,3,
4-tetrahydroxybutyl) cyclohexane,
3-ethoxycarbonylcyclopentane, 4-ethoxycarbonylcyclohexane, 4,
4-diethoxycarbonylcyclohexane,
3-carbamoylcyclopentane, 4-carbamoylcyclohexane,
3-acetylaminocyclopentane, 4-acetylaminocyclohexane,
3,4-diacetylaminomethylcyclopentane,
2,3,4,5-tetrahydroxybicyclo [4,3,0] nonane (bonding position with ring B is at position 8),
3-oxa-bicyclo [3,3,0] octane (bonding position with ring B is position 7),
2,4-dihydroxymethyl-3-oxa-bicyclo [3,3,0] octane (bonding position with ring B is position 7),
2,4-dioxaspiro [5.5] undecane (bonding position with ring B is position 9)
A ring such as

Among the above, the “cycloalkyl ring” in the definition of ring A is preferably a hydroxy group comprising a hydroxy group, a -trihydroxypropyl group, a 1,2,3,4-tetrahydroxybutyl group, and an acetylamino group. Methyl group, 1,2-dihydroxyethyl group, 1,2,
A 3- to 7-membered saturated cycloalkyl ring optionally substituted by 1 to 2 groups selected from Group 3, more preferably a hydroxymethyl group, 1,2-dihydroxyethyl group, 1, Optionally substituted by 1 to 2 groups selected from the group consisting of 2,3-trihydroxypropyl group, 1,2,3,4-tetrahydroxybutyl group and acetylamino group A 5-membered saturated cycloalkyl ring, particularly preferably a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-trihydroxypropyl group, and 1,
Cyclopropyl or cyclopentyl which may be substituted by 1 to 2 groups selected from the group consisting of 2,3,4-tetrahydroxybutyl groups.

The “C ₃ -C ₁₀ cycloalkyl group” in the definition of R ¹ is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclocycleheptyl, cyclooctyl.

The “C ₄ -C ₁₂ cycloalkylalkyl group” in the definition of R ¹ is, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, and preferably a C ₄ -C ₈ cycloalkylalkyl group. More preferably a C ₄ -C ₇ cycloalkylalkyl group.

The “3- to 7-membered heterocyclyl ring” in the definition of ring A is a group in which X and Y contained in the ring each independently have a carbon atom or a formula NR (R represents a hydrogen atom or a substituent group α. A C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C _2- group, which may be substituted with a selected group.
C ₆ alkynyl group, or a C ₁ -C ₆ alkylcarbonyl group. ), An oxygen atom, a sulfur atom, one any one selected from the group having the group and the formula SO ₂ having the formula SO, preferably a carbon atom, an oxygen atom, a sulfur atom, group and the formula having the formula SO Any one selected from the group having SO ₂ is shown. The 3- to 7-membered heterocyclyl ring may contain an unsaturated bond.

Such rings include, for example, heterocyclyl rings containing nitrogen atoms such as aziridine, azetidine, pyrrolidine, pyrroline, piperidine, imidazolidine; oxirane,
Oxetane, tetrahydrofuran, oxolene, tetrahydropyran, dihydropyran,
Heterocyclyl rings containing oxygen atoms, such as oxepane, 1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane; thiirane, thietane, thiolane, thiolene, thiane, thiepan, 1,3-dithiolane, 1, 3-dithiane, 1,3-dithiepan, 1,3
-Dioxo-1,3-dithiolane, 1,3-dioxo-1,3-dithiane, 1,1,3
A heterocyclyl ring containing a sulfur atom such as 3-tetraoxo-1,3-dithiolane, 1,1,3,3-tetraoxo-1,3-dithiane, a group having the formula SO or a group having the formula SO ₂ ; , 3-oxathiolane, 1,3-oxathiane, heterocyclyl rings containing oxygen and sulfur atoms such as 1,3-oxathiepane; 1,3-oxapyrrolidine, 1
, Heterocyclyl rings containing nitrogen and oxygen atoms, such as 3-oxapyrroline;
And heterocyclyl rings containing nitrogen and sulfur atoms such as 3-thiapyrrolidine and 1,3-thiapyrroline.

Preferably, oxirane, tetrahydrofuran, tetrahydropyran, 1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane, 1,3-dithiolane, 1,3-dithiane, 1,1,3,3-tetraoxo -1,3-dithiolane, 1,3-oxathiolane,
1,3-oxathiane or 1,3-oxathiepan.

More preferably, oxirane, tetrahydrofuran, 1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3-dithiane, 1,3-oxathiolane, 1,3-
Oxathian.

More preferred are oxirane, 1,3-dioxolane, 1,3-dioxane, and 1,3-oxathiolane.

The “3- to 7-membered heterocyclyl ring” may form a condensed or spiro ring with a 3- to 7-membered heterocyclyl ring or a 3- to 7-membered cycloalkyl ring, and preferably a 5- to 6-membered heterocyclyl ring ( The heterocyclyl ring contains 1 to 2 oxygen atoms and / or nitrogen atoms as heteroatoms.) Or may form a condensed or spiro ring with a 5- to 6-membered cycloalkyl ring, and more preferably May form a condensed ring or a spiro ring with tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, 1,3-dioxane or a cyclohexyl ring.

Such heterocyclyl rings are for example 2,4-dioxa-bicyclo [3,3,0].
Octane (bonding position with ring B is the 3rd position), 2,4,7-trioxa-bicyclo [3,
3,0] octane (position of bonding with ring B is position 3), 7,9-dioxa-bicyclo [4
, 3,0] nonane (bonding position with ring B is at position 8), 7-aza-2,4-dioxa-bicyclo [3,3,0] octane (bonding position with ring B is at position 3) 2), 4, 4, 8, 10-
Tetraoxaspiro [5.5] undecane (the binding position with ring B is the 3-position) and the like.
The bonding positions of these rings and ring B are the same as the positions described here.

The “3- to 7-membered heterocyclyl ring” may be substituted with an oxo group or a thioxo group without forming a condensed ring or a spiro ring.

The “heterocyclyl ring” is a heterocyclyl ring, a condensed ring fused to a heterocyclyl ring, or 1 to 4 spiro rings each having the same or different spiro bond to a heterocyclyl ring (
Preferably, it may be substituted with 1 to 2 substituents.

The substituent is an oxo group, a thioxo group, a substituent group α, a cyclopropyl C ₁ -C ₆ alkyl group, or a C ₁ — optionally substituted with a group selected from 1 to 5 substituent groups α. A C ₆ alkyl group, a C ₂ -C ₆ alkenyl group optionally substituted with a group selected from 1 to 5 substituent groups α, and a group selected from 1 to 5 substituent groups α A group selected from the group consisting of a C ₂ -C ₆ alkynyl group optionally substituted by

The substituent is preferably an oxo group, a thioxo group, a substituent group α, cyclopropyl C ₁ -C _6.
C _1- which may be substituted with an alkyl group and a group selected from 1 to 5 substituent groups α
It is a group selected from the group consisting of C ₆ alkyl groups.

More preferably, it may be substituted with a group selected from an oxo group, a thioxo group, a substituent group α and 1 to 4 substituent groups α, and may be substituted C ₁ -C ₆ alkyl. A group selected from the group consisting of groups.

More preferably, an oxo group, a thioxo group, a substituent group α (the substituent group α is a hydroxy group and a group having the formula NR ⁶ R ^7. R ⁶ and R ⁷ are each independently a hydrogen atom. Atom or C ₁
—C _{6 represents} an alkylcarbonyl group. ), 1 to 2 groups selected from the group consisting of a methyl group, an ethyl group, and a C ₁ -C ₆ alkyl group substituted with 1 to 4 hydroxy groups.

Even more preferably, the substituent group α [the substituent group α is a hydroxy group and a group represented by the formula NR ⁶ R ⁷
(R ⁶ and R ⁷ each independently represents a hydrogen atom or a methylcarbonyl group). A methyl group, an ethyl group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-trihydroxypropyl group, and a 1,2,3,4-tetrahydroxybutyl group. 1 to 2 groups.

For example,
Oxirane, oxolane, tetrahydrofuran (common name; oxolane in IUPAC nomenclature), tetrahydropyran (common name. Oxane in IUPAC nomenclature), 1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane, 1,3 -Dithiolane, 1,3-dithiane, 1,3-oxathiolane, 1,3-oxathiane, 1,3-oxathiepane, tetrahydrooxazole, tetrahydro-1,3-oxazine, tetrahydrothiazole, tetrahydro-1,3-thiazine, 1 , 1,3,3-tetraoxo-1,3-dithiane, 2,4,7-trioxa-bicyclo [3,3,0] octane, 2,4-dithia-7-oxa-bicyclo [3,3,0 ] Octane, 2-thia-4,7-dioxa-bicyclo [3,
3,0] octane, 2,4,8,10-tetraoxaspiro [5.5] undecane, 2,
4-dithia-8,10-dioxaspiro [5.5] undecane, 2-thia-4,8,10
-Trioxaspiro [5.5] undecane,
2-hydroxytetrahydrofuran, 4-hydroxy-1,3-dioxolane, 4,5-
Dihydroxy-1,3-dioxolane, 5-hydroxy-1,3-dioxane, 5,5-
Dihydroxy-1,3-dioxane, 4-hydroxy-1,3-dithiolane, 4,5-dihydroxy-1,3-dithiolane, 5-hydroxy-1,3-dithiane, 5,5-dihydroxy-1,3- Dithian, 4-hydroxy-1,1,3,3-tetraoxo-1,3-
Dithiolane, 4,5-dihydroxy-1,1,3,3-tetraoxo-1,3-dithiolane, 4-hydroxy-1,3-oxathiolane, 5-hydroxy-1,3-oxathiane, 5,5-dihydroxy- 1,3-oxathiane, 6,8-dihydroxy-2,4-dioxa-bicyclo [3,3,0] octane, 6,8-dihydroxy-2,4,7-trioxa-bicyclo [3,3,0] Octane, 2,3,4,5-tetrahydroxy-7,9-dioxa-bicyclo [4,3,0] nonane, 6,8-dihydroxy-7-aza-2,4-dioxa-bicyclo [3,3 , 0] octane, 9-hydroxy-2,4,8,10-tetraoxaspiro [5.5] undecane, 2,3,4,5-tetrahydro-7,9-dithia-
Bicyclo [4,3,0] nonane, 2,3,4,5-tetrahydro-7-thia-9-oxa
Bicyclo [4,3,0] nonane,
2-carboxytetrahydrofuran, 4-carboxy-1,3-dioxolane, 5-carboxy-1,3-dioxane, 4-carboxy-1,3-dithiolane, 5-carboxy-
1,3-dithiane, 4-carboxy-1,1,3,3-tetraoxo-1,3-dithiolane, 4-carboxy-1,3-oxathiolane, 5-carboxy-1,3-oxathiane,
2-methoxycarbonyltetrahydrofuran, 4-methoxycarbonyl-1,3-dioxolane, 5-methoxycarbonyl-1,3-dioxane, 5,5-dimethoxycarbonyl-1,3-dioxane, 4-methoxycarbonyl-1,3 -Dithiolane, 5-methoxycarbonyl-1,3-dithiane, 5,5-dimethoxycarbonyl-1,3-dithiane, 4
-Methoxycarbonyl-1,1,3,3-tetraoxo-1,3-dithiolane, 4-methoxycarbonyl-1,3-oxathiolane, 5-methoxycarbonyl-1,3-oxathiane, 5,5-dimethoxycarbonyl-1 , 3-oxathiane, 6,8-dimethoxycarbonyl-2,4-dioxa-bicyclo [3,3,0] octane, 6,8-dimethoxycarbonyl-2,4,7-trioxa-bicyclo [3,3,0 ] Octane, 6,8-dimethoxycarbonyl-7-aza-2,4-dioxa-bicyclo [3,3,0] octane, 8-methoxycarbonyl-2,4,7,9-tetraoxaspiro [5.5 ] Undecane,
2-ethoxycarbonyltetrahydrofuran, 4-ethoxycarbonyl-1,3-dioxolane, 5-ethoxycarbonyl-1,3-dioxane, 5,5-diethoxycarbonyl-1,3-dioxane, 4-ethoxycarbonylsilane-1, 3-dithiolane, 5-ethoxycarbonyl-1,3-dithiane, 5,5-diethoxycarbonyl-1,3-dithiane, 4
-Ethoxycarbonyl-1,1,3,3-tetraoxo-1,3-dithiolane, 4-ethoxycarbonyl-1,3-oxathiolane, 5-ethoxycarbonyl-1,3-oxathiane, 5,5-diethoxycarbonyl- 1,3-oxathiane, 6,8-diethoxycarbonyl-2,4-dioxa-bicyclo [3,3,0] octane, 6,8-diethoxycarbonyl-2,4,7-trioxa-bicyclo [3, 3,0] octane, 6,8-diethoxycarbonyl-7-aza-2,4-dioxa-bicyclo [3,3,0] octane, 8-ethoxycarbonyl-2,4,7,9-tetraoxaspiro [5.5] Undecane,
2-aminotetrahydrofuran, 4-amino-1,3-dioxolane, 4,5-diamino-1,3-dioxolane, 5-amino-1,3-dioxane, 4-amino-1,3-dithiolane, 4,5 -Diamino-1,3-dithiolane, 5-amino-1,3-dithiane, 4-
Amino-1,1,3,3-tetraoxo-1,3-dithiolane, 4-amino-1,3-oxathiolane, 5-amino-1,3-oxathiane,
2-acetylaminotetrahydrofuran, 4-acetylamino-1,3-dioxolane,
4,5-bis (acetylamino) -1,3-dioxolane, 5-acetylamino-1,3
-Dioxane, 4-acetylamino-1,3-dithiolane, 4,5-bis (acetylamino) -1,3-dithiolane, 5-acetylamino-1,3-dithiane, 4-acetylamino-1,1, 3,3-tetraoxo-1,3-dithiolane, 4-acetylamino-1,3
-Oxathiolane, 5-acetylamino-1,3-oxathiane, 6,8-diacetylamino-2,4-dioxa-bicyclo [3,3,0] octane, 6,8-diacetylamino-2,4,7- Trioxa-bicyclo [3,3,0] octane, 6,8-diacetylamino-7-aza-2,4-dioxa-bicyclo [3,3,0] octane, 8-acetylamino-2,4,7, 9-tetraoxaspiro [5.5] undecane,
2-methyltetrahydrofuran, 4-methyl-1,3-dioxolane, 4,5-dimethyl-1,3-dioxolane, 5-methyl-1,3-dioxane, 4-methyl-1,3-dithiolane, 4,5 -Dimethyl-1,3-dithiolane, 5-methyl-1,3-dithiane, 4-
Methyl-1,1,3,3-tetraoxo-1,3-dithiolane, 4-methyl-1,3-oxathiolane, 5-methyl-1,3-oxathiane,
5,5-dimethyl-1,3-dioxane, 5,5-dimethyl-1,3-dithiane, 5,5
-Dimethyl-1,3-oxathiane,
2-ethyltetrahydrofuran, 4-ethyl-1,3-dioxolane, 4,5-diethyl-1,3-dioxolane, 5-ethyl-1,3-dioxane, 4-ethyl-1,3-dithiolane, 4,5 -Diethyl-1,3-dithiolane, 5-ethyl-1,3-dithiane, 4-
Ethyl-1,1,3,3-tetraoxo-1,3-dithiolane, 4-ethyl-1,3-oxathiolane, 5-ethyl-1,3-oxathiane,
2-hydroxymethyltetrahydrofuran, 4-hydroxymethyl-1,3-dioxolane, 5-hydroxymethyl-1,3-dioxane, 5,5-dihydroxymethyl-1,3
-Dioxane, 4-hydroxymethyl-1,3-dithiolane, 5-hydroxymethyl-1
, 3-dithiane, 5,5-dihydroxymethyl-1,3-dithiane, 4-hydroxymethyl-1,1,3,3-tetraoxo-1,3-dithiolane, 4-hydroxymethyl-1,
3-oxathiolane, 5-hydroxymethyl-1,3-oxathiane, 5,5-dihydroxymethyl-1,3-oxathiane,
4,5-dihydroxymethyl-1,3-dioxolane, 4,5-dihydroxymethyl-1
, 3-dithiolane, 4,5-dihydroxymethyl-1,3-oxathiolane,
5,5-dihydroxymethyl-1,3-dioxane, 5,5-dihydroxymethyl-1,
3-dithiane, 5,5-dihydroxymethyl-1,3-oxathiane, 6,8-dihydroxymethyl-2,4,7-trioxa-bicyclo [3,3,0] octane, 6,8-dihydroxymethyl-2 , 4-dithia-7-oxa-bicyclo [3,3,0] octane, 6,8-
Dihydroxymethyl-2-thia-4,7-dioxa-bicyclo [3,3,0] octane, 6
-Oxo-8-hydroxymethyl-2,4,7-trioxa-bicyclo [3,3,0] octane,
2- (1,2-dihydroxyethyl) tetrahydrofuran, 4- (1,2-dihydroxyethyl) -1,3-dioxolane, 5- (1,2-dihydroxyethyl) -1,3-dioxane, 5,5- Bis (1,2-dihydroxyethyl) -1,3-dioxane, 4- (1
, 2-dihydroxyethyl) -1,3-dithiolane, 5- (1,2-dihydroxyethyl) -1,3-dithiane, 5,5-bis (1,2-dihydroxyethyl) -1,3-dithiane, 4- (1,2-dihydroxyethyl) -1,1,3,3-tetraoxo-1,3-dithiolane, 4- (1,2-dihydroxyethyl) -1,3-oxathiolane, 5- (1,
2-dihydroxyethyl) -1,3-oxathiane, 5,5-bis (1,2-dihydroxyethyl) -1,3-oxathiane,
4,5-bis (1,2-dihydroxyethyl) -1,3-dioxolane, 4,5-bis (
1,2-dihydroxyethyl) -1,3-dithiolane, 4,5-bis (1,2-dihydroxyethyl) -1,3-oxathiolane,
4,5-bis (1-hydroxyethyl) -1,3-dioxolane, 4,5-bis (1-hydroxypropyl) -1,3-dioxolane,
2- (1,2,3-trihydroxypropyl) tetrahydrofuran, 4- (1,2,3-
Trihydroxypropyl) -1,3-dioxolane, 5- (1,2,3-trihydroxypropyl) -1,3-dioxane, 5,5-bis (1,2,3-trihydroxypropyl) -1, 3-dioxane, 4- (1,2,3-trihydroxypropyl) -1,3-dithiolane, 5- (1,2,3-trihydroxypropyl) -1,3-dithiane, 5,5-bis ( 1,2,3-trihydroxypropyl) -1,3-dithiane, 4- (1,2,3-trihydroxypropyl) -1,1,3,3-tetraoxo-1,3-dithiolane, 4- (
1,2,3-trihydroxypropyl) -1,3-oxathiolane, 5- (1,2-dihydroxyethyl) -1,3-oxathiane, 5,5-bis (1,2,3-trihydroxypropyl) -1,3-oxathiane,
2- (1,2,3,4-tetrahydroxybutyl) otetrahydrofuran, 4- (1,2
, 3,4-tetrahydroxybutyl) -1,3-dioxolane, 5- (1,2,3,4-
Tetrahydroxybutyl) -1,3-dioxane, 5,5-bis (1,2,3,4-tetrahydroxybutyl) -1,3-dioxane, 4- (1,2,3,4-tetrahydroxybutyl) ) -1,3-dithiolane, 5- (1,2,3,4-tetrahydroxybutyl) -1
, 3-Dithiane, 5,5-bis (1,2,3,4-tetrahydroxybutyl) -1,3-
Dithiane, 4- (1,2,3,4-tetrahydroxybutyl) -1,1,3,3-tetraoxo-1,3-dithiolane, 4- (1,2,3,4-tetrahydroxybutyl)- 1,
3-oxathiolane, 5- (1,2,3,4-tetrahydroxybutyl) -1,3-oxathiane, 5,5-bis (1,2,3,4-tetrahydroxybutyl) -1,3-oxathiane ,
2-acetylaminomethyltetrahydrofuran, 4-acetylaminomethyl-1,3-dioxolane, 4,5-diacetylaminomethyl-1,3-dioxolane, 5-acetylaminomethyl-1,3-dioxane, 4-acetylaminomethyl -1,3-dithiolane, 4
, 5-Diacetylaminomethyl-1,3-dithiolane, 5-acetylaminomethyl-1,
3-dithiane, 4-acetylaminomethyl-1,1,3,3-tetraoxo-1,3-dithiolane, 4-acetylaminomethyl-1,3-oxathiolane, 5-acetylaminomethyl-1,3-oxathiane,
4,5-diacetylaminomethyl-1,3-dioxolane, 4,5-diacetylaminomethyl-1,3-dithiolane, 4,5-diacetylaminomethyl-1,3-oxathiolane,
2-vinyltetrahydrofuran, 4-vinyl-1,3-dioxolane, 4,5-divinyl-1,3-dioxolane, 5-vinyl-1,3-dioxane, 4-vinyl-1,3-dithiolane, 4,5 -Divinyl-1,3-dithiolane, 5-vinyl-1,3-dithiane, 4-
Vinyl-1,1,3,3-tetraoxo-1,3-dithiolane, 4-vinyl-1,3-oxathiolane, 5-vinyl-1,3-oxathiane,
2-propenyltetrahydrofuran, 4-propenyl-1,3-dioxolane, 4,5-
Dipropenyl-1,3-dioxolane, 5-propenyl-1,3-dioxane, 4-propenyl-1,3-dithiolane, 4,5-dipropenyl-1,3-dithiolane, 5-propenyl-1,3-dithiane, 4-propenyl-1,1,3,3-tetraoxo-1,3-dithiolane, 4-propenyl-1,3-oxathiolane, 5-propenyl-1,3-oxathiane,
2-propynyltetrahydrofuran, 4-propynyl-1,3-dioxolane, 4,5-
Dipropynyl-1,3-dioxolane, 5-propynyl-1,3-dioxane, 4-propynyl-1,3-dithiolane, 4,5-dipropynyl-1,3-dithiolane, 5-propynyl-1,3-dithiane, Examples include 4-propynyl-1,1,3,3-tetraoxo-1,3-dithiolane, 4-propynyl-1,3-oxathiolane, and 5-propynyl-1,3-oxathiane.

In the definition of substituent group γ, “C ₆ optionally substituted with a group selected from substituent group β
-C ₁₀ "C ₆ -C ₁₀ aryl group of the aryl group", "; Substituent Group [delta]," C ₆ -C ₁₀ aryl group in the definition of Substituent group ε ", for example, phenyl, naphthyl.

In the “C ₆ -C ₁₀ aryl group optionally substituted with a group selected from substituent group β”, the “C ₆ -C ₁₀ aryl group” means that the substitutable site is selected from substituent group β The number of substituents is not limited to one, and there may be a plurality (2 to 4) of the same or different.

The “5- to 6-membered heteroaryl group” in the definition of R ³ contains 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Such heteroaryl includes, for example, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, preferably furyl, thienyl, pyrrolyl, pyridyl or Pyrimidinyl, more preferably pyrrolyl.

The “5-membered heteroaryl group” in the definition of the substituent group δ and the substituent group ε is, for example, 1, 2
, 3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, thienyl, furyl.

Examples of the “halogeno C ₁ -C ₆ alkyl group” in the definition of the substituent group δ are trifluoromethyl and trifluoroethyl.

Examples of the “halogeno C ₁ -C ₁₄ alkyl group” in the definition of the substituent group ε include, for example, the above-mentioned “halogeno C ₁ -C ₆ alkyl group”, 4,4,4-trifluorobutyl, 5,5,5, -Trifluoropentyl, 6,6,6-trifluorohexyl, 7,7,7-trifluoroheptyl, 8,8,8-trifluorooctyl, preferably a halogeno C ₄ -C ₈ alkyl group is there.

“C ₁ -C ₆ alkoxy group” in the definition of substituent group α, substituent group β, and substituent group δ is:
A group in which an oxygen atom is bonded to the “C ₁ -C ₆ alkyl group”, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methyl Butoxy, 1-ethylpropoxy, 2-ethylpropoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1 , 1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, preferably a C ₁ -C ₄ alkoxy group, more preferably C ₁ -C _{2 is an} alkoxy group.

The "C ₁ -C ₁₄ alkoxy group" in the definition of Substituent group epsilon, represents "C ₁ -C ₁₄ alkyl group" in the group having an oxygen atom attached thereto described above, for example, the aforementioned "C ₁ -C ₆ alkoxy group ", octyloxy, nonyloxy, decyloxy, dodecyloxy, a tetradecyloxy like, preferably a C ₁ -C ₁₀ alkoxy group, more preferably a C ₄ -C ₈ alkoxy group.

The “halogeno C ₁ -C ₆ alkoxy group” in the definition of the substituent group α and the substituent group δ is one or two or more hydrogen atoms of the above “C ₁ -C ₆ alkyl group”. A group substituted by “atom” is shown. A halogeno C ₁ -C ₄ alkoxy group is preferable, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy is more preferable, and trifluoromethoxy is more preferable.

The “halogeno C ₁ -C ₁₄ alkoxy group” in the definition of the substituent group ε is the above “C ₁ -C _14”.
1 or 2 or more hydrogen atoms of the “alkyl group” are groups substituted by the aforementioned “halogen atom”, preferably a halogeno C ₁ -C ₁₀ alkoxy group, more preferably a halogeno C ₄ -C ₈ alkoxy group, and more preferably, 4,4,4-trifluorobutoxy,
5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy,
7,7,7-trifluoroheptyloxy, 8,8,8-trifluorooctyloxy.

As the “C ₃ -C ₁₀ cycloalkyloxy group” in the definition of the substituent group γ, for example,
Cyclopropyloxy, cyclohexyloxy and the like.

Examples of the “C ₆ -C ₁₀ aryloxy group” in the definition of the substituent group γ include phenoxy and naphthyloxy.

Examples of the “C ₇ -C ₁₉ aralkyloxy group” in the definition of the substituent group γ include benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, benzhydryloxy, and 1-naphthylmethyloxy.

The “C ₁ -C ₆ alkylthio group” in the definition of the substituent group β and the substituent group δ is the above-mentioned “
C ₁ -C ₆ alkyl group "in a group which has a sulfur atom bonded, sulfur atom may be oxidized. Preferably a C ₁ -C ₄ alkylthio groups, for example, methylthio, ethylthio, n- propylthio, n- butylthio, methylsulfinyl, methylsulfonyl.

"C ₁ -C ₁₄ alkylthio group" in the definition of Substituent group ε may be a sulfur atom which alkyl group is attached has been oxidated, for example, "C ₁ -C ₆ alkylthio group" described above, n
-Heptylthio, 3-methylhexylthio, n-octylthio, 2,4-dimethylhexylthio, n-octylthio, 2,3,6-trimethylheptylthio, preferably C
A ₁ -C ₁₀ alkylthio group, more preferably a C ₄ -C ₈ alkylthio group.

The “C ₃ -C ₁₀ cycloalkylthio group” in the definition of the substituent group γ may have a sulfur atom oxidized, and examples thereof include cyclopropylthio, cyclohexylthio, cyclopentylsulfinyl, and cyclohexylsulfonyl.

The “C ₆ -C ₁₀ arylthio group” in the definition of the substituent group γ may be a group in which a sulfur atom may be oxidized, for example, phenylthio, naphthylthio, phenylsulfinyl, phenylsulfonyl.

The “C ₇ -C ₁₉ aralkylthio group” in the definition of the substituent group γ may have a sulfur atom oxidized, such as benzylthio, phenylethylthio, benzhydrylthio,
Benzylsulfinyl, benzylsulfonyl.

“C ₁ -C ₆ alkanoyl group” in the definition of R ⁶ , R ⁷ , substituent group β, and substituent group δ is:
Hydrogen atom or a C ₁ -C ₅ alkyl group represents a group attached to a carbonyl group, e.g., formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl.

"C ₁ -C ₁₄ alkanoyl group" in the definition of Substituent group ε is, for example, the aforementioned "C ₁ -C
₆ alkanoyl groups ", octanoyl, decanoyl, dodecanoyl, tetradecanoyl.

The “C ₂ -C ₄ alkenyl-carbonyl group” in the definition of the substituent group β is, for example, acryloyl or crotonoyl.

The “C ₂ -C ₆ alkenyl-carbonyl group” in the definition of R ⁶ and R ⁷ is, for example, the above-mentioned “
C ₂ -C ₄ alkenyl-carbonyl group ”, 1,3-butadienylcarbonyl, 3-methyl-
2-Butenylcarbonyl.

As the “C ₆ -C ₁₀ aryl-carbonyl group” in the definition of the substituent group γ, for example,
Benzoyl, naphthoyl and phenylacetyl.

“C ₁ -C ₆ alkoxy-carbonyl group” in the definition of substituent group α and substituent group δ is:
The above-mentioned “C ₁ -C ₆ alkoxy group” represents a group bonded to a carbonyl group. For example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxy Carbonyl and the like.

Examples of the “C ₁ -C ₁₀ alkoxy-carbonyl group” in the definition of the substituent group β include the above-mentioned “C ₁ -C ₆ alkoxycarbonyl group”, heptyloxy, octyloxy, nonyloxy and decyloxy.

Examples of the “C ₁ -C ₁₄ alkoxy-carbonyl group” in the definition of the substituent group ε include the above-mentioned “C ₁ -C ₁₀ alkoxy-carbonyl group”, dodecyloxycarbonyl, and tetradecyloxycarbonyl, is, C ₁ -C ₁₀ alkoxy - carbonyl group, and more preferably, C ₄ -C ₈ alkoxy - carbonyl group.

As the “C ₃ -C ₆ cycloalkyloxycarbonyl group” in the definition of substituent group γ,
For example, cyclopropyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, norbornyloxycarbonyl.

Examples of the “C ₆ -C ₁₀ aryloxy-carbonyl group” in the definition of the substituent group γ include phenoxycarbonyl and naphthyloxycarbonyl.

As the “C ₇ -C ₁₉ aralkyloxy-carbonyl group” in the definition of substituent group γ,
For example, benzyloxycarbonyl, benzhydryloxycarbonyl, 2-phenethyloxycarbonyl.

The “C ₂ -C ₆ alkanoyloxy group” in the definition of the substituent group β represents a group in which a C ₂ -C ₆ alkanoyl group is bonded to an oxygen atom. is there.

As the “C ₁ -C ₁₀ alkoxy-carbonyloxy group” in the definition of substituent group β,
For example, methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, isopropoxycarbonyloxy, n-butoxycarbonyloxy, tert-
Butoxycarbonyloxy, n-pentyloxycarbonyloxy, n-hexyloxycarbonyloxy.

Examples of the “C ₆ -C ₁₀ aryl-carbonyloxy group” in the definition of the substituent group γ include benzoyloxy, naphthoyloxy, and phenylacetoxy.

“C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ group” in the definition of substituent group α
The “carbamoyl group optionally substituted with a group selected from an alkynyl group, a C ₁ -C ₆ alkanoyl group or a C ₂ -C ₆ alkenyl-carbonyl group” means C ₁ -C ₆ such as methyl, ethyl, propyl and the like. alkyl group, vinyl, allyl, _C 2 -C ₆ alkenyl group isopropenyl, etc.,
C ₂ -C ₆ alkynyl group ethynyl etc., C ₁ -C ₆ alkanoyl group such Aseniru, and, C ₂ -C ₆ alkenyl acryloyl etc. - is substituted by 1 to 2 substituents selected from the group Which may be a carbamoyl group or a cyclic aminocarbonyl group, preferably, specifically, 1 to 2 groups selected from, for example, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkanoyl group A carbamoyl group or a cyclic aminocarbonyl group which may be substituted with a substituent, more preferably a carbamoyl group or a cyclic aminocarbonyl group substituted with _{1 to 2} C ₁ -C ₂ alkanoyl groups. . Specifically, carbamoyl, N-
Methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-
Diethylcarbamoyl and N-acetylcarbamoyl are preferable, and N-acetylcarbamoyl is preferable.

“Carbamoyl group optionally substituted with a group selected from a C ₁ -C ₄ alkyl group, a phenyl group, a C ₁ -C ₇ acyl group and a C ₁ -C ₄ alkoxyphenyl group” in the definition of the substituent group β Is selected from C ₁ -C ₄ alkyl groups such as methyl and ethyl, phenyl groups, C ₁ -C ₇ acyl groups such as acetyl, propionyl and benzoyl, and C ₁ -C ₄ alkoxyphenyl groups such as methoxyphenyl A carbamoyl group or a cyclic aminocarbonyl group which may be substituted by 1 to 2 substituents, specifically, for example, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N, N- Dimethylcarbamoyl, N, N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N- ( p-methoxyphenyl) carbamoyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, 1-piperazinylcarbonyl, morpholinocarbonyl.

The “thiocarbamoyl group optionally substituted with a C ₁ -C ₄ alkyl group or a phenyl group” in the definition of the substituent group β is selected from a C ₁ -C ₄ alkyl group such as methyl and ethyl, and a phenyl group. A thiocarbamoyl group optionally substituted by 1 to 2 substituents, specifically, for example, thiocarbamoyl, N-methylthiocarbamoyl, N-phenylthiocarbamoyl.

The “carbamoyloxy group optionally substituted with a C ₁ -C ₄ alkyl group or phenyl group” in the definition of the substituent group β is selected from a C ₁ -C ₄ alkyl group such as methyl and ethyl, and a phenyl group. A carbamoyloxy group optionally substituted by 1 to 2 substituents,
Specific examples include carbamoyloxy, N-methylcarbamoyloxy, N, N-dimethylcarbamoyloxy, N-ethylcarbamoyloxy, and N-phenylcarbamoyloxy.

The “group having the formula NR ⁶ R ⁷ ” in the definition of the substituent group α, the substituent group δ, and the substituent group ε is R
⁶ and R ⁷ are each independently a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a C ₁ -C ₆ alkanoyl group, or a C _2- C _{6 represents an} alkenyl-carbonyl group, or together with the nitrogen atom to which R ⁶ and R ⁷ are attached, forms a heterocyclyl group. Preferably, R ⁶ and R ⁷ are a hydrogen atom, a C ₁ -C ₆ alkyl group or C
₁ -C ₆ alkanoyl group, and more preferably, R ⁶ and R ⁷ are a hydrogen atom, C _1-
A group that is a C ₄ alkyl group or a C ₁ -C ₄ alkanoyl group, and more preferably R ⁶ and R ^6.
7 is a hydrogen atom or a C ₁ -C ₂ alkanoyl group. Specifically, amino, methylamino,
Ethylamino, dimethylamino, diethylamino and acetylamino are preferred, and acetylamino is preferred.

As the “C ₁ -C ₆ alkanoylamino group” in the definition of substituent group β and substituent group δ,
For example, acetamide, propionamide, butyroamide, valeroamide, pivalamide.

Examples of the “C ₁ -C ₁₄ alkanoylamino group” in the definition of the substituent group ε include the above-mentioned “C ₁ -C ₆ alkanoylamino group”, octanoylamino, decanoylamino, dodecanoylamino, tetradecanoyl, and the like. Amino.

Examples of the “C ₁ -C ₁₀ alkoxy-carboxamide group” in the definition of the substituent group β include methoxycarboxamide, ethoxycarboxamide, and tert-butoxycarboxamide.

Examples of the “C ₁ -C ₄ alkyl group or ureido group optionally substituted with a phenyl group” in the definition of the substituent group β include, for example, a C ₁ -C ₄ alkyl group such as a methyl group, an ethyl group, and a phenyl group. A ureido group optionally substituted with 1 to 3 (preferably 1 to 2) selected substituents such as ureido, 1-methylureido, 3-methylureido, 3, 3
-Dimethylureido, 1,3-dimethylureido, 3-phenylureido.

Examples of the “C ₆ -C ₁₀ aryl-carbonylamino group” in the definition of the substituent group γ include benzamide, naphthamide, and phthalimide.

The “C ₆ -C ₁₀ aryloxy-carboxamide group” in the definition of the substituent group γ is, for example, phenoxycarboxamide.

Examples of the “C ₇ -C ₁₉ aralkyloxy-carboxamide group” in the definition of the substituent group γ include benzyloxycarboxamide and benzhydryloxycarboxamide.

“C ₃ -C ₁₀ cycloalkyloxy-carbonyloxy group” in the definition of substituent group γ
Examples thereof include cyclopropyloxycarbonyloxy and cyclohexyloxycarbonyloxy.

Examples of the “C ₆ -C ₁₀ aryloxy-carbonyloxy group” in the definition of the substituent group γ include phenoxycarbonyloxy and naphthyloxycarbonyloxy.

Examples of the “C ₇ -C ₁₉ aralkyloxy-carbonyloxy group” in the definition of the substituent group γ include benzyloxycarbonyloxy, 1-phenylethyloxycarbonyloxy, 2-phenylethyloxycarbonyloxy, benzhydryloxy, and the like. Carbonyloxy.

“Heterocyclic group” in the definition of substituent group γ; “heterocyclic oxy group”, “heterocyclic thio group”, “
"Heterocyclic sulfinyl group", "heterocyclic sulfonyl group", "heterocyclic oxycarbonyl group"
The “heterocyclic group” is a 5- to 8-membered ring containing 1 to several (preferably 1 to 4) heteroatoms such as nitrogen atom (which may be oxidized), oxygen atom and sulfur atom (preferably 1 to 4) (preferably 5 to 6
Member) or a condensed ring group thereof. Examples of such “heterocyclic groups” include, for example,
Pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, 1,2,3
-Oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, Pyrazinyl, indolyl, pyranyl, thiopyranyl, dioxonyl, dioxolyl, quinolyl, pyrido [2,3-d] pyrimidyl, 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2 , 7-naphthyridyl group, thieno [2,3-d] pyridyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl.

These heterocyclic groups are represented by 1 to 3 substituents selected from C ₁ -C ₄ alkyl groups such as methyl and ethyl, hydroxy groups, oxo groups, C ₁ -C ₄ alkoxy groups such as methoxy and ethoxy, and the like. It may be substituted at a substitutable site.

As the “C ₁ -C ₆ alkyl-carbamoyl group” in the definition of the substituent group δ, for example,
Methylcarbamoyl, dimethylcarbamoyl, propylcarbamoyl.

Examples of the “C ₁ -C ₁₄ alkyl-carbamoyl group” in the definition of the substituent group ε include the above-mentioned “C ₁ -C ₆ alkyl-carbamoyl group”, octylcarbamoyl, decylcarbamoyl, dodecylcarbamoyl, tetradecylcarbamoyl, and the like. Yes, preferably C ₁ -C _1
0 alkyl - a carbamoyl group, more preferably, C ₄ -C ₈ alkyl - carbamoyl group.

Examples of the “C ₁ -C ₆ alkoxy-carbonyl C ₁ -C ₆ alkyl-carbamoyl group” in the definition of the substituent group δ include butoxycarbonylmethylcarbamoyl and ethoxycarbonylmethylcarbamoyl.

Examples of the “C ₁ -C ₁₄ alkoxy-carbonyl C ₁ -C ₁₄ alkyl-carbamoyl group” in the definition of the substituent group ε include the above-mentioned “C ₁ -C ₆ alkoxy-carbonyl C ₁ -C ₆ alkyl-carbamoyl groups”. Group ", octyloxycarbonylmethylcarbamoyl,
Preferred is a C ₁ -C ₁₀ alkoxy-carbonyl C ₁ -C ₁₀ alkyl-carbamoyl group, and more preferred is a C ₄ -C ₈ alkoxy-carbonyl C ₄ -C ₈ alkyl-carbamoyl group.

Examples of the “1,3-diacylguanidino C ₁ -C ₆ alkyl group” in the definition of the substituent group δ are 1,3-diacetylguanidinomethyl and 1,3-bis-tert-butoxycarbonylguanidinomethyl.

Examples of the “1,3-diacylguanidino C ₁ -C ₁₄ alkyl group” in the definition of the substituent group ε include, for example, the above-mentioned “1,3-diacylguanidino C ₁ -C ₆ alkyl group”, 1,3-diacetyl Guanidinooctyl, 1,3-bis-tert-butoxycarbonylguanidinooctyl, preferably 1,3-diacylguanidino C ₁ -C ₁₀ alkyl group, more preferably 1,3-diacylguanidino C it is ₄ -C ₈ alkyl group.

X and Y represent a group that forms ring A together with the carbon atom of ring B to which they are bonded, each represents a hydrogen atom, or X and Y are combined to form a ring B A substituent (which is an oxo group or a thioxo group) preferably represents a group that together with the carbon atom of ring B to which they are attached to form ring A, Whether it represents a hydrogen atom.

In a preferred example, when X and Y represent a group that together with the carbon atom of ring B forms ring A, ring A is a 3-7 membered heterocyclyl ring or a 3-7 membered saturated cycloalkyl. It is a ring.

In the heterocyclyl ring, X and Y contained in the ring are each independently a carbon atom or a group having the formula NR (wherein R is a hydrogen atom or a group selected from the substituent group α). C ₁ −
C ₆ alkyl group, optionally substituted with a group selected from the substituent group alpha C ₂ -C ₆ alkenyl group, which may be C ₂ -C substituent groups selected from substituent group alpha ₆ An alkynyl group or a C ₁ -C ₆ alkanoyl group optionally substituted with a group selected from substituent group α is shown. ), An oxygen atom, a sulfur atom, one any one selected from the group having the group and the formula SO ₂ having the formula SO,
5- to 6-membered heterocyclyl ring (the heterocyclyl ring contains 1 to 2 oxygen atoms and / or nitrogen atoms as heteroatoms) or a 5- to 6-membered cycloalkyl ring to form a condensed or spiro ring You can,
Any of the heterocyclyl ring, the condensed ring fused to the heterocyclyl ring or the spiro ring that is spiro-bonded is an oxo group, a thioxo group, a substituent group α, cyclopropyl C ₁ -C _6.
C _1- which may be substituted with an alkyl group and a group selected from 1 to 5 substituent groups α
It may be substituted with 1 to 4 identical or different groups selected from the group consisting of C ₆ alkyl groups.

The 3- to 7-membered saturated cycloalkyl ring is a hydroxy group, a hydroxymethyl group, 1,2-
Substituted with one or two groups selected from the group consisting of a dihydroxyethyl group, a 1,2,3-trihydroxypropyl group, a 1,2,3,4-tetrahydroxybutyl group, and an acetylamino group. May be.

Ring A is more preferably a 3- to 7-membered heterocyclyl ring or a 3- to 5-membered cycloalkyl ring.

The heterocyclyl ring is more preferable examples of ring A, X and Y included in the ring are each independently, a carbon atom, an oxygen atom, a sulfur atom, a group having a group and the formula SO ₂ having the formula SO Indicates one of the choices,
5- to 6-membered heterocyclyl ring (the heterocyclyl ring contains 1 to 2 oxygen atoms and / or nitrogen atoms as heteroatoms) or a 5- to 6-membered cycloalkyl ring to form a condensed or spiro ring You can,
Any of the heterocyclyl ring, the condensed ring fused to the heterocyclyl ring or the spiro ring that is spiro-bonded is selected from an oxo group, a thioxo group, a substituent group α, and 1 to 4 substituent groups α. And optionally substituted with 1 to 4 groups which are the same or different and are selected from the group consisting of C ₁ -C ₆ alkyl groups optionally substituted.

The 3- to 5-membered cycloalkyl ring includes a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-trihydroxypropyl group, a 1,2,3,4-tetrahydroxybutyl group, and an acetylamino group. It may be substituted by 1 to 2 groups selected from the group consisting of groups.

Ring A is more preferably the following heterocyclyl ring, or the following cyclopropyl or cyclopentyl.

Such heterocyclyl rings are, for example,
Oxirane, tetrahydrofuran, tetrahydropyran,
1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane,
1,3-dithiolane, 1,3-dithiane,
1,1,3,3-tetraoxo-1,3-dithiolane,
1,3-oxathiolane, 1,3-oxathiane or 1,3-oxathiepan,
These heterocyclyl rings form a condensed or spiro ring with a 5- to 6-membered heterocyclyl ring (the heterocyclyl ring is tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine or 1,3-dioxane) or a cyclohexyl ring. Well,
Any of a heterocyclyl ring, a condensed ring fused with the heterocyclyl ring, or a spiro-bonded spiro ring may be an oxo group, a thioxo group, a substituent group α (the substituent group α is a hydroxy group, ⁶ represents a group having R ^7. R ⁶ and R ⁷ each independently represent a hydrogen atom or a C ₁ -C ₆ alkanoyl group.), A methyl group, an ethyl group, and 1 to 4 hydroxy groups It may be substituted with 1 to 2 groups selected from the group consisting of substituted C ₁ -C ₆ alkyl groups.

The cyclopropyl or cyclopentyl includes a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-trihydroxypropyl group, and 1,2,3,4-
Cyclopropyl or cyclopentyl which may be substituted by 1 to 2 groups selected from the group consisting of tetrahydroxybutyl groups.

Ring A is more preferably, for example,
Oxirane, tetrahydrofuran, 1,3-dioxolane, 1,3-dioxane, 1,3
-Dithiolane, 1,3-dithiane, 1,3-oxathiolane or 1,3-oxathiane, and these heterocyclyl rings are 5- to 6-membered heterocyclyl rings (the heterocyclyl ring is tetrahydrofuran, tetrahydropyran or 1,3- Dioxane) or may form a condensed ring or a spiro ring with cyclohexyl,
Any ring of a heterocyclyl ring, a condensed ring condensed with the heterocyclyl ring, or a spiro ring having a spiro bond may be substituted with a substituent group α [the substituent group α is a hydroxy group, and a group represented by the formula NR ⁶ R
⁷ (R ⁶ and R ⁷ are each independently a hydrogen atom or an acetyl group). ], Methyl group, ethyl group, hydroxymethyl group, 1,2-dihydroxyethyl group,
It may be substituted with 1 or 2 groups selected from the group consisting of 1,2,3-trihydroxypropyl group and 1,2,3,4-tetrahydroxybutyl group.

Ring A is particularly preferably
Oxirane, 1,3-dioxolane, 1,3-dioxane, or 1,3-oxathiolane, and these heterocyclyl rings are 5- to 6-membered heterocyclyl rings (the heterocyclyl ring is tetrahydrofuran, tetrahydropyran or 1,3 -Dioxane) or may form a condensed ring or a spiro ring with cyclohexyl,
Any ring of a heterocyclyl ring, a condensed ring condensed with the heterocyclyl ring, or a spiro ring having a spiro bond is substituted with a substituent group α [the substituent group α is a hydroxy group, and a group represented by the formula NR ⁶ R
⁷ (R ⁶ and R ⁷ are each independently a hydrogen atom or an acetyl group). ], Methyl group, hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3
-It may be substituted with 1 to 2 groups selected from a trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group.

As a preferable specific example of ring A,
Cyclopropyl, 1-hydroxymethylcyclopropyl, 1,2-dihydroxymethylcyclopropyl, cyclopentyl, 2-hydroxymethylcyclopentyl, 2,3-dihydroxymethylcyclopentyl, 2,3-bis (1,2-dihydroxyethyl) cyclopentyl, 2- (1,2-dihydroxyethyl) cyclopentyl, 2- (1,2,3-trihydroxypropyl) cyclopentyl, 2- (1,2,3,4-tetrahydroxybutyl)
Cyclopentyl,
Oxirane, tetrahydrofuran, tetrahydropyran, 1,3-dioxolane, 1,3
-Dioxane, 1,3-oxathiolane, 4-hydroxymethyl-1,3-dioxolane, 4,5-dihydroxymethyl-1,3-dioxolane, 4,5-bis (1,2-dihydroxyethyl) -1,3 -Dioxolane, 4- (1,2-dihydroxyethyl) -1,3
-Dioxolane, 4- (1,2,3-trihydroxypropyl) -1,3-dioxolane, 4- (1,2,3,4-tetrahydroxybutyl) -1,3-dioxolane, 4,5-
Diacetylaminomethyl-1,3-dioxolane, 5-hydroxy-1,3-dioxane, 5,5-dihydroxymethyl-1,3-dioxane, 5-acetylamino-1,3-dioxane, 5,5-diethoxy Carbonyl-1,3-dioxane, 2,4,7,9-tetraoxaspiro [5.5] undecane,
More preferred specific examples include 4-hydroxymethyl-1,3-dioxolane, 4,5-dihydroxymethyl-1,3-dioxolane, 4,5-bis (1,2-dihydroxyethyl) -1,3- Dioxolane, 4- (1,2-dihydroxyethyl) -1,3-dioxolane, 4- (1,2,3-trihydroxypropyl) -1,3-dioxolane, 4- (1,
2,3,4-tetrahydroxybutyl) -1,3-dioxolane, 4,5-diacetylaminomethyl-1,3-dioxolane, 5-hydroxy-1,3-dioxane, 5-acetylamino-1,3- Dioxane, 5,5-dihydroxymethyl-1,3-dioxane.

Ring B is a 5- to 7-membered cycloalkene group. At this time, l and m, which are parameters for determining the number of members in ring B, each independently take an integer of 0 to 3, and l + m is 1 to 3. l + m
1 to 3 indicates that ring B is 5 to 7 members. Preferably, l is 0 and m is 1.
An integer from 3 to 3. More preferably, it is a cyclohexylinyl group in which l is 0 and m is 1.

Among the groups defined as R ¹ , a hydroxy group, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group is preferable, and a hydroxy group, a fluorine atom,
A chlorine atom, a methyl group, an ethyl group, a propyl group, a methoxy group or an ethoxy group, more preferably a fluorine atom or a methyl group.

The number n of substitutions for ring B of R ¹ is 0 to 3, but is preferably 0 or 1. More preferably, n is 0.

Among the groups defined as R ² , a C ₁ -C ₆ alkyl group which may be substituted with a group selected from substituent group β is more preferable, and C ₁ -C ₆ is more preferable. alkyl group, more preferably a C ₁ -C ₄ alkyl group, particularly preferably an ethyl group.

Of the groups defined as R ³ , the “5- to 6-membered heteroaryl group” in the “5- to 6-membered heteroaryl group optionally substituted with a group selected from substituent group ε” is particularly preferably Is
It is a pyrrolyl group. That is, preferably R ^3, phenyl group or substituted with a group selected from the substituent group ε is pyrrolyl group. Preferably, a halogen atom, C ₁ -C _1
4 alkyl group and a halogeno C ₁ -C ₁₄ phenyl group or optionally substituted with a group selected from alkyl groups are pyrrolyl group, more preferably, fluorine atom, chlorine atom, C ₁ -C ₁₀ alkyl group A phenyl group or a pyrrolyl group optionally substituted with a group selected from a halogeno C ₁ -C ₁₀ alkyl group and a cyclopropyl C ₁ -C ₁₀ alkyl group, and more preferably a fluorine atom, a chlorine atom, a bromine atom, a phenyl group or substituted by a group selected from C ₃ -C ₈ alkyl group and a halogeno C ₄ -C ₈ alkyl groups are pyrrolyl group, more preferably more, fluorine atom, chlorine atom and C ₃ -C ₈ optionally substituted by a group selected from alkyl groups are also phenyl group.

  Further, when the substituent is substituted, the substitution positions are preferably the 2nd and 4th positions.

R ³ is, for example,
Phenyl group, a halogenophenyl group, C ₁ -C ₁₄ alkylphenyl group, cyclopropyl C ₁ -
C ₁₄ alkylphenyl group, C ₁ -C ₁₄ alkoxyphenyl group, C ₁ -C ₁₄ alkoxycarbonyl phenyl group, carboxyphenyl group, nitrophenyl group, cyanophenyl group, halogeno C ₁ -C ₁₄ alkylphenyl group, a halogeno C ₁ -C ₁₄ alkoxyphenyl group, C ₁ -C _1
4 alkanoyl phenyl group, a phenyl group substituted by 5-membered heteroaryl group, C ₁ -C ₁₄ alkoxy - carbonyl -C ₁ -C ₁₄ alkyl - carbamoyl phenyl group, 1,3-diacylguanidino -C ₁ -C ₁₄ alkyl phenyl, halogen and C ₁ -C ₁₄ alkyl-substituted phenyl group, halogen and C ₁ -C ₁₄ alkoxy phenyl group substituted with a carbonyl, phenyl group substituted with a halogen and cyano, halogen and 5-membered heteroaryl substituted phenyl, halogen and C ₁ -C ₁₄ alkoxy - carbonyl -C ₁ -
C ₁₄ alkyl - phenyl group substituted with carbamoyl,
Pyrrolyl group, Harogenopiroriru group, C ₁ -C ₁₄ alkyl pyrrolyl group, cyclopropyl C ₁ -
C ₁₄ alkyl pyrrolyl group, C ₁ -C ₁₄ alkoxy pyrrolyl group, C ₁ -C ₁₄ alkoxycarbonyl pyrrolyl group, a carboxyl pyrrolyl group, Nitoropiroriru group, Shianopiroriru group, halogeno C ₁ -C ₁₄ alkyl pyrrolyl group, Halogeno C ₁ -C ₁₄ alkoxypyrrolyl group, C ₁ -C _1
4 alkanoylamino pyrrolyl group, substituted pyrrolyl group in 5-membered heteroaryl group, C ₁ -C ₁₄ alkoxy - carbonyl -C ₁ -C ₁₄ alkyl - carbamoyl pyrrolyl group, 1, 3-di-acyl guanidino -C ₁ - C ₁₄ alkyl pyrrolyl group, halogen and C ₁ -C ₁₄ alkyl substituted pyrrolyl group, halogen and C ₁ -C ₁₄ alkoxy-substituted pyrrolyl group carbonyl, halogen and cyano-substituted pyrrolyl group, a halogen and A pyrrolyl group substituted with a 5-membered heteroaryl group, halogen and C ₁ -C ₁₄ alkoxy-carbonyl-C _1-
A pyrrolyl group substituted with a C ₁₄ alkyl-carbamoyl, and the like.

Among them, preferred specific examples are:
Phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-iodophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-
Chlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-difluorophenyl, 2,5-
Dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,4-
Difluorophenyl, 3,4-dichlorophenyl, 3,5-difluorophenyl, 3,5
-Dichlorophenyl, 2,4-dibromophenyl, 2,6-dibromophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 2-bromo-4- Fluorophenyl, 3-chloro-4-fluorophenyl, 2-bromo-4-chlorophenyl, 5-chloro-2-fluorophenyl, 4-bromo-
2-chlorophenyl, 2-chloro-6-fluorophenyl, 2,4-dimethoxyphenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6
-Trifluorophenyl, 2-chloro-4,6-difluorophenyl, 2,6-dichloro-4-fluorophenyl, 2-bromo-6-chloro-4-fluorophenyl, 2-methylphenyl, 2-ethylphenyl, 2- (n-propyl) phenyl, 2- (n-butyl) phenyl, 2- (n-pentyl) phenyl, 2- (n-hexyl) phenyl, 2- (n-heptyl) phenyl, 2- (n- Octyl) phenyl, 2- (n-nonyl) phenyl, 2-
(N-decyl) phenyl, 2- (n-undecyl) phenyl, 2- (n-dodecyl) phenyl, 2- (n-tridecyl) phenyl, 2- (n-tetradecyl) phenyl, 2-ethynylphenyl, 2- Isopropylphenyl, 2-t-butylphenyl, 2-sec-butylphenyl,
2-methoxyphenyl, 2-ethoxyphenyl, 2-difluoromethoxyphenyl, 2-
Methylsulfanylphenyl, 2-acetylphenyl, 2-benzylphenyl, 2- (morpholin-4-yl) phenyl, 2- [2- (pyridin-4-yl) ethyl] phenyl, 2
-[2- (t-butoxycarbonylamino) ethyl] phenyl, 2-aminophenyl, 2,
6-diisopropylphenyl, 2-chloro-4-methylphenyl, 4-fluoro-3-trifluoromethylphenyl, 4-fluoro-3-methoxyphenyl, 4-chloro-2-methoxycarbonylphenyl, 2-fluoro-4- Methoxyphenyl, 4-chloro-2-methylphenyl, 2-fluoro-4-methylphenyl, 2-fluoro-5-methylphenyl, 2-chloro-4-methylphenyl, 2-chloro-6-methylphenyl, 4- t-butyl-2-chlorophenyl, 2-bromo-4-isopropylphenyl, 4-chloro-2-methoxy-5-methylphenyl, 4-fluoro-2-methylphenyl, 2-ethyl-4-fluorophenyl, 4- Fluoro-2- (n-propyl) phenyl, 2- (n-butyl) -4
-Fluorophenyl, 4-fluoro-2- (n-pentyl) phenyl, 4-fluoro-2
-(N-hexyl) phenyl, 4-fluoro-2- (n-heptyl) phenyl, 4-fluoro-2- (n-octyl) phenyl, 4-fluoro-2- (n-nonyl) phenyl, 2
-(N-decyl) -4-fluorophenyl, 4-fluoro-2- (n-undecyl) phenyl, 2- (n-dodecyl) -4-fluorophenyl, 4-fluoro-2- (n-tridecyl) phenyl 4-fluoro-2- (n-tetradecyl) phenyl, 2-trifluoromethylphenyl, 2- (2,2,2-trifluoroethyl) phenyl, 2- (3,3,3
-Trifluoropropyl) phenyl, 2- (4,4,4-trifluorobutyl) phenyl, 2- (5,5,5-trifluoropentyl) phenyl, 2- (6,6,6-trifluorohexyl) Phenyl, 2- (7,7,7-trifluoroheptyl) phenyl, 2- (8
, 8,8-trifluorooctyl) phenyl, 2- (9,9,9-trifluorononyl)
Phenyl, 2- (10,10,10-trifluorodecyl) phenyl, 2-cyclopropylethylphenyl, 2- [3-cyclopropyl- (n-propyl)] phenyl, 2- [4
-Cyclopropyl- (n-butyl)] phenyl, 2- [5-cyclopropyl- (n-pentyl)] phenyl, 2- [6-cyclopropyl- (n-hexyl)] phenyl, 2- [7
-Cyclopropyl- (n-heptyl)] phenyl, 2- [8-cyclopropyl- (n-octyl)] phenyl, pyrrolyl, 2-fluoropyrrolyl, 2-chloropyrrolyl, 2-bromopyrrolyl, 2,5-difluoropyrrole 2,5-dichloropyrrolyl, 2,5-dibromopyrrolyl, 2-chloro-5-fluoropyrrolyl, 2-methylpyrrolyl, 2-ethylpyrrolyl, 2- (n-propyl) pyrrolyl, 2- (n- Butyl) pyrrolyl, 2- (n-pentyl) pyrrolyl, 2- (n-hexyl) pyrrolyl, 2- (n-heptyl) pyrrolyl, 2- (
n-octyl) pyrrolyl, 2- (n-nonyl) pyrrolyl, 2- (n-decyl) pyrrolyl,
And
More preferably,
2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-iodophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2
-Chloro-4-fluorophenyl, 2-bromo-4-fluorophenyl, 3-chloro-4
-Fluorophenyl, 2-bromo-4-chlorophenyl, 2,4-dimethoxyphenyl,
2-chloro-4,6-difluorophenyl, 2,6-dichloro-4-fluorophenyl,
2-bromo-6-chloro-4-fluorophenyl, 2-methylphenyl, 2-ethylphenyl, 2- (n-propyl) phenyl, 2- (n-butyl) phenyl, 2- (n-pentyl) phenyl, 2- (n-hexyl) phenyl, 2- (n-heptyl) phenyl, 2- (
n-octyl) phenyl, 2- (n-nonyl) phenyl, 2- (n-decyl) phenyl,
2-ethynylphenyl, 2-sec-butylphenyl, 2-methoxyphenyl, 2-methylsulfanylphenyl, 2-benzylphenyl, 2- [2- (t-butoxycarbonylamino) ethyl] phenyl, 4-chloro-2- Methylphenyl, 2-fluoro-5-methylphenyl, 2-chloro-4-methylphenyl, 2-chloro-6-methylphenyl, 4-chloro-2-methoxy-5-methylphenyl, 4-fluoro-2-methyl Phenyl, 2-ethyl-4-fluorophenyl, 4-fluoro-2- (n-propyl) phenyl, 2- (n
-Butyl) -4-fluorophenyl, 4-fluoro-2- (n-pentyl) phenyl, 4
-Fluoro-2- (n-hexyl) phenyl, 4-fluoro-2- (n-heptyl) phenyl, 4-fluoro-2- (n-octyl) phenyl, 4-fluoro-2- (n-nonyl) phenyl 2- (n-decyl) -4-fluorophenyl, 2- (n-butyl) pyrrolyl, 2- (n-pentyl) pyrrolyl, 2- (n-hexyl) pyrrolyl, 2- (n-heptyl) pyrrolyl, 2- (n-octyl) pyrrolyl,
And
More preferably,
2-chlorophenyl, 2-bromophenyl, 2,4-difluorophenyl, 2-chloro-
4-fluorophenyl, 2-bromo-4-fluorophenyl, 2- (n-pentyl) phenyl, 2- (n-hexyl) phenyl, 2- (n-heptyl) phenyl, 2-chloro-6
-Methylphenyl, 4-fluoro-2- (n-propyl) phenyl, 2- (n-butyl)
-4-fluorophenyl, 4-fluoro-2- (n-pentyl) phenyl, 4-fluoro-2- (n-hexyl) phenyl, 4-fluoro-2- (n-heptyl) phenyl, 4-
Fluoro-2- (n-octyl) phenyl.

“Pharmaceutically acceptable salt thereof” means that a compound having the general formula (I) of the present invention has a basic group such as an amino group by reacting with an acid or a carboxyl group. If it has an acidic group, it can be made into a salt by reacting with a base.
The salt is shown.

Salts based on basic groups are preferably inorganic such as hydrohalides such as hydrochlorides, hydrobromides, hydroiodides, nitrates, perchlorates, sulfates, phosphates, etc. Acid salts; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, arylsulfonates such as benzenesulfonate, p-toluenesulfonate, acetates, Malate, fumarate, succinate, citrate, ascorbate,
Organic acid salts such as tartrate, succinate and maleate; or amino acid salts such as glycine, lysine, arginine, ornithine, glutamate and aspartate.

On the other hand, the salt based on an acidic group is preferably a metal such as an alkali metal salt such as sodium salt, potassium salt or lithium salt, an alkaline earth metal salt such as calcium salt or magnesium salt, an aluminum salt or an iron salt. 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-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt Amine salts such as organic salts; or amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, aspartates.

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an asymmetric carbon atom in the molecule, and R and S stereoisomers exist. Any pharmaceutical composition containing each or any proportion thereof as an active ingredient is included in the present invention. For such stereoisomers, for example, compound (I) is synthesized using an optically resolved starting material compound, or the synthesized compound (I) is optically resolved using an ordinary optical resolution or separation method as desired. be able to.

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has optical isomers, and each of the optical isomers and a mixture of the optical isomers are used as active ingredients. Any of these are included in the present invention.

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof absorbs moisture by being left in the air or recrystallized, so that adsorbed water is attached, and hydrates are formed. A pharmaceutical composition containing such a compound containing water and a salt as an active ingredient is also included in the present invention.

Among the compounds contained as active ingredients in the pharmaceutical composition of the present invention, examples of the representative compounds include the compounds described in the following Tables 1 to 3, and the present invention includes these compounds as active ingredients. It is not limited to the pharmaceutical composition contained as.

Abbreviations in the table, “Ring 1” to “Ring 18” are as follows.
Ac: Acetyl Boc: Butoxycarbonyl Bn: benzyl nBu: n-butyl sBu: sec-butyl tBu: tert-butyl cBu: cyclobutylidene nDec: n-decane Flu: fluoren-1-yl cPent: cyclopentylidene cPr: cyclo Propylidene cPrl: cyclopropyl cHept: cycloheptylidene cHex: cyclohexylidene dioxa: 1,3-dioxan-2-ylidene diox: 1,3-dioxepane-2-ylidene dioxo: 1,3-dioxolan-2-ylidene dithia: 1,3-dithian-2-ylidene dithio: 1,3-dithiolane-2-ylidene Et: ethyl HB: 1,2,3,4-tetrahydroxybutyl HE: 1,2-dihydroxyethyl nHept : N-heptyl nHex: n-hexyl HM: hydroxymethyl HP: 1,2,3-trihydroxypropyl Me: methyl Mor: morpholino nNon: n-nonane O =: oxo nOct: n-octyl nPent: n-pentyl Ph : Phenyl nPr: n-propyl Pyr: pyrrolyl Pyrd: pyridyl S =: thioxooxa: 2-oxanilidene oxathia: 1,3-oxathian-2-ylidene oxathio: 1,3-oxathiolane-2-ylidene ox: 2-oxetanilidene oxi : 2-oxiranylidene oxo: 2-oxolanylidene ozl: tetrahydrooxazole-2-ylidene ozn: tetrahydro-1,3-oxazine-2-ylidene tzl: tetrahydrothiazol-2-ylidene tzn Tetrahydro-1,3-thiazin-2-ylidene

In the table, “di” means two identical substituents, and “tri” means three identical substituents.

  The bonding position between ring 1 to ring 21 and ring B is the position of the black dot at the right end of the chemical structural formula.

The substituents indicated by abbreviations as X and Y in Table 1 are illustrated below.

(Table 1)
――――――――――――――――――――――――――――
Compound X, Y R^Three
Number
――――――――――――――――――――――――――――
1-1 O = Ph
1-2 S = Ph
1-3 cPr Ph
1-4 cBu Ph
1-5 cPent Ph
1-6 cHex Ph
1-7 cHept Ph
1-8 oxi Ph
1-9 oxe Ph
1-10 oxo Ph
1-11 oxa Ph
1-12 dioxo Ph
1-13 dioxa Ph
1-14 dioxe Ph
1-15 dithio Ph
1-16 dithia Ph
1-17 Ring 1 Ph
1-18 Ring 2 Ph
1-19 oxathio Ph
1-20 oxathia Ph
1-21 ozl Ph
1-22 ozn Ph
1-23 tzl Ph
1-24 tzn Ph
1-25 3-HM-cPent Ph
1-26 4-HM-dioxo Ph
1-27 4-HM-dithio Ph
1-28 4-HM-oxathio Ph
1-29 3,4-diHM-cPent Ph
1-30 4,5-diHM-dioxo Ph
1-31 4,5-diHM-dithio Ph
1-32 4,5-diHM-oxathio Ph
1-33 3,4-diHE-cPent Ph
1-34 4,5-diHE-dioxo Ph
1-35 4,5-diHE-dithio Ph
1-36 4,5-diHE-oxathio Ph
1-37 3-HE-cPent Ph
1-38 4-HE-dioxo Ph
1-39 4-HE-dithio Ph
1-40 4-HE-oxathio Ph
1-41 3-HP-cPent Ph
1-42 4-HP-dioxo Ph
1-43 4-HP-dithio Ph
1-44 4-HP-oxathio Ph
1-45 3-HB-cPent Ph
1-46 4-HB-dioxo Ph
1-47 4-HB-dithio Ph
1-48 4-HB-oxathio Ph
1-49 Ring 3 Ph
1-50 Ring 4 Ph
1-51 Ring 5 Ph
1-52 Ring 6 Ph
1-53 Ring 7 Ph
1-54 Ring 8 Ph
1-55 Ring 9 Ph
1-56 Ring 10 Ph
1-57 3,4-diCH₂NHAc-cPent Ph
1-58 4,5-diCH₂NHAc-dioxo Ph
1-59 4,5-diCH₂NHAc-dithio Ph
1-60 4,5-diCH₂NHAc-oxathio Ph
1-61 Ring 11 Ph
1-62 Ring 12 Ph
1-63 Ring 13 Ph
1-64 Ring 14 Ph
1-65 4-OH-cHex Ph
1-66 5-OH-dioxa Ph
1-67 5-OH-dithia Ph
1-68 5-OH-oxathia Ph
1-69 4-NHAc-cHex Ph
1-70 5-NHAc-dioxa Ph
1-71 5-NHAc-dithia Ph
1-72 5-NHAc-oxathia Ph
1-73 4,4-diMe-cHex Ph
1-74 5,5-diMe-dioxa Ph
1-75 5,5-diMe-dithia Ph
1-76 5,5-diMe-oxathia Ph
1-77 4,4-diHM-cHex Ph
1-78 5,5-diHM-dioxa Ph
1-79 5,5-diHM-dithia Ph
1-80 5,5-diHM-oxathia Ph
1-81 Ring 15 Ph
1-82 Ring 16 Ph
1-83 Ring 17 Ph
1-84 Ring 18 Ph
1-85 4,4-diCO₂Et-cHex Ph
1-86 5,5-diCO₂Et-dioxa Ph
1-87 5,5-diCO₂Et-dithia Ph
1-88 5,5-diCO₂Et-oxathia Ph
1-89 O = 4-F-Ph
1-90 S = 4-F-Ph
1-91 cPr 4-F-Ph
1-92 cBu 4-F-Ph
1-93 cPent 4-F-Ph
1-94 cHex 4-F-Ph
1-95 cHept 4-F-Ph
1-96 oxi 4-F-Ph
1-97 oxe 4-F-Ph
1-98 oxo 4-F-Ph
1-99 oxa 4-F-Ph
1-100 dioxo 4-F-Ph
1-101 dioxa 4-F-Ph
1-102 dioxe 4-F-Ph
1-103 dithio 4-F-Ph
1-104 dithia 4-F-Ph
1-105 Ring 1 4-F-Ph
1-106 Ring 2 4-F-Ph
1-107 oxathio 4-F-Ph
1-108 oxathia 4-F-Ph
1-109 ozl 4-F-Ph
1-110 ozn 4-F-Ph
1-111 tzl 4-F-Ph
1-112 tzn 4-F-Ph
1-113 3-HM-cPent 4-F-Ph
1-114 4-HM-dioxo 4-F-Ph
1-115 4-HM-dithio 4-F-Ph
1-116 4-HM-oxathio 4-F-Ph
1-117 3,4-diHM-cPent 4-F-Ph
1-118 4,5-diHM-dioxo 4-F-Ph
1-119 4,5-diHM-dithio 4-F-Ph
1-120 4,5-diHM-oxathio 4-F-Ph
1-121 3,4-diHE-cPent 4-F-Ph
1-122 4,5-diHE-dioxo 4-F-Ph
1-123 4,5-diHE-dithio 4-F-Ph
1-124 4,5-diHE-oxathio 4-F-Ph
1-125 3-HE-cPent 4-F-Ph
1-126 4-HE-dioxo 4-F-Ph
1-127 4-HE-dithio 4-F-Ph
1-128 4-HE-oxathio 4-F-Ph
1-129 3-HP-cPent 4-F-Ph
1-130 4-HP-dioxo 4-F-Ph
1-131 4-HP-dithio 4-F-Ph
1-132 4-HP-oxathio 4-F-Ph
1-133 3-HB-cPent 4-F-Ph
1-134 4-HB-dioxo 4-F-Ph
1-135 4-HB-dithio 4-F-Ph
1-136 4-HB-oxathio 4-F-Ph
1-137 Ring 3 4-F-Ph
1-138 Ring 4 4-F-Ph
1-139 Ring 5 4-F-Ph
1-140 Ring 6 4-F-Ph
1-141 Ring 7 4-F-Ph
1-142 Ring 8 4-F-Ph
1-143 Ring 9 4-F-Ph
1-144 Ring 10 4-F-Ph
1-145 3,4-diCH₂NHAc-cPent 4-F-Ph
1-146 4,5-diCH₂NHAc-dioxo 4-F-Ph
1-147 4,5-diCH₂NHAc-dithio 4-F-Ph
1-148 4,5-diCH₂NHAc-oxathio 4-F-Ph
1-149 Ring 11 4-F-Ph
1-150 Ring 12 4-F-Ph
1-151 Ring 13 4-F-Ph
1-152 Ring 14 4-F-Ph
1-153 4-OH-cHex 4-F-Ph
1-154 5-OH-dioxa 4-F-Ph
1-155 5-OH-dithia 4-F-Ph
1-156 5-OH-oxathia 4-F-Ph
1-157 4-NHAc-cHex 4-F-Ph
1-158 5-NHAc-dioxa 4-F-Ph
1-159 5-NHAc-dithia 4-F-Ph
1-160 5-NHAc-oxathia 4-F-Ph
1-161 4,4-diMe-cHex 4-F-Ph
1-162 5,5-diMe-dioxa 4-F-Ph
1-163 5,5-diMe-dithia 4-F-Ph
1-164 5,5-diMe-oxathia 4-F-Ph
1-165 4,4-diHM-cHex 4-F-Ph
1-166 5,5-diHM-dioxa 4-F-Ph
1-167 5,5-diHM-dithia 4-F-Ph
1-168 5,5-diHM-oxathia 4-F-Ph
1-169 Ring 15 4-F-Ph
1-170 ring 16 4-F-Ph
1-171 ring 17 4-F-Ph
1-172 ring 18 4-F-Ph
1-173 4,4-diCO₂Et-cHex 4-F-Ph
1-174 5,5-diCO₂Et-dioxa 4-F-Ph
1-175 5,5-diCO₂Et-dithia 4-F-Ph
1-176 5,5-diCO₂Et-oxathia 4-F-Ph
1-177 O = 2-Cl-Ph
1-178 S = 2-Cl-Ph
1-179 cPr 2-Cl-Ph
1-180 cBu 2-Cl-Ph
1-181 cPent 2-Cl-Ph
1-182 cHex 2-Cl-Ph
1-183 cHept 2-Cl-Ph
1-184 oxi 2-Cl-Ph
1-185 oxe 2-Cl-Ph
1-186 oxo 2-Cl-Ph
1-187 oxa 2-Cl-Ph
1-188 dioxo 2-Cl-Ph
1-189 dioxa 2-Cl-Ph
1-190 dioxe 2-Cl-Ph
1-191 dithio 2-Cl-Ph
1-192 dithia 2-Cl-Ph
1-193 Ring 1 2-Cl-Ph
1-194 Ring 2 2-Cl-Ph
1-195 oxathio 2-Cl-Ph
1-196 oxathia 2-Cl-Ph
1-197 ozl 2-Cl-Ph
1-198 ozn 2-Cl-Ph
1-199 tzl 2-Cl-Ph
1-200 tzn 2-Cl-Ph
1-201 3-HM-cPent 2-Cl-Ph
1-202 4-HM-dioxo 2-Cl-Ph
1-203 4-HM-dithio 2-Cl-Ph
1-204 4-HM-oxathio 2-Cl-Ph
1-205 3,4-diHM-cPent 2-Cl-Ph
1-206 4,5-diHM-dioxo 2-Cl-Ph
1-207 4,5-diHM-dithio 2-Cl-Ph
1-208 4,5-diHM-oxathio 2-Cl-Ph
1-209 3,4-diHE-cPent 2-Cl-Ph
1-210 4,5-diHE-dioxo 2-Cl-Ph
1-211 4,5-diHE-dithio 2-Cl-Ph
1-212 4,5-diHE-oxathio 2-Cl-Ph
1-213 3-HE-cPent 2-Cl-Ph
1-214 4-HE-dioxo 2-Cl-Ph
1-215 4-HE-dithio 2-Cl-Ph
1-216 4-HE-oxathio 2-Cl-Ph
1-217 3-HP-cPent 2-Cl-Ph
1-218 4-HP-dioxo 2-Cl-Ph
1-219 4-HP-dithio 2-Cl-Ph
1-220 4-HP-oxathio 2-Cl-Ph
1-221 3-HB-cPent 2-Cl-Ph
1-222 4-HB-dioxo 2-Cl-Ph
1-223 4-HB-dithio 2-Cl-Ph
1-224 4-HB-oxathio 2-Cl-Ph
1-225 Ring 3 2-Cl-Ph
1-226 Ring 4 2-Cl-Ph
1-227 Ring 5 2-Cl-Ph
1-228 Ring 6 2-Cl-Ph
1-229 Ring 7 2-Cl-Ph
1-230 Ring 8 2-Cl-Ph
1-231 Ring 9 2-Cl-Ph
1-232 ring 10 2-Cl-Ph
1-233 3,4-diCH₂NHAc-cPent 2-Cl-Ph
1-234 4,5-diCH₂NHAc-dioxo 2-Cl-Ph
1-235 4,5-diCH₂NHAc-dithio 2-Cl-Ph
1-236 4,5-diCH₂NHAc-oxathio 2-Cl-Ph
1-237 Ring 11 2-Cl-Ph
1-238 Ring 12 2-Cl-Ph
1-239 Ring 13 2-Cl-Ph
1-240 Ring 14 2-Cl-Ph
1-241 4-OH-cHex 2-Cl-Ph
1-242 5-OH-dioxa 2-Cl-Ph
1-243 5-OH-dithia 2-Cl-Ph
1-244 5-OH-oxathia 2-Cl-Ph
1-245 4-NHAc-cHex 2-Cl-Ph
1-246 5-NHAc-dioxa 2-Cl-Ph
1-247 5-NHAc-dithia 2-Cl-Ph
1-248 5-NHAc-oxathia 2-Cl-Ph
1-249 4,4-diMe-cHex 2-Cl-Ph
1-250 5,5-diMe-dioxa 2-Cl-Ph
1-251 5,5-diMe-dithia 2-Cl-Ph
1-252 5,5-diMe-oxathia 2-Cl-Ph
1-253 4,4-diHM-cHex 2-Cl-Ph
1-254 5,5-diHM-dioxa 2-Cl-Ph
1-255 5,5-diHM-dithia 2-Cl-Ph
1-256 5,5-diHM-oxathia 2-Cl-Ph
1-257 Ring 15 2-Cl-Ph
1-258 Ring 16 2-Cl-Ph
1-259 Ring 17 2-Cl-Ph
1-260 ring 18 2-Cl-Ph
1-261 4,4-diCO₂Et-cHex 2-Cl-Ph
1-262 5,5-diCO₂Et-dioxa 2-Cl-Ph
1-263 5,5-diCO₂Et-dithia 2-Cl-Ph
1-264 5,5-diCO₂Et-oxathia 2-Cl-Ph
1-265 O = 2,4-diF-Ph
1-266 S = 2,4-diF-Ph
1-267 cPr 2,4-diF-Ph
1-268 cBu 2,4-diF-Ph
1-269 cPent 2,4-diF-Ph
1-270 cHex 2,4-diF-Ph
1-271 cHept 2,4-diF-Ph
1-272 oxi 2,4-diF-Ph
1-273 oxe 2,4-diF-Ph
1-274 oxo 2,4-diF-Ph
1-275 oxa 2,4-diF-Ph
1-276 dioxo 2,4-diF-Ph
1-277 dioxa 2,4-diF-Ph
1-278 dioxe 2,4-diF-Ph
1-279 dithio 2,4-diF-Ph
1-280 dithia 2,4-diF-Ph
1-281 Ring 1 2,4-diF-Ph
1-282 Ring 2 2,4-diF-Ph
1-283 oxathio 2,4-diF-Ph
1-284 oxathia 2,4-diF-Ph
1-285 ozl 2,4-diF-Ph
1-286 ozn 2,4-diF-Ph
1-287 tzl 2,4-diF-Ph
1-288 tzn 2,4-diF-Ph
1-289 3-HM-cPent 2,4-diF-Ph
1-290 4-HM-dioxo 2,4-diF-Ph
1-291 4-HM-dithio 2,4-diF-Ph
1-292 4-HM-oxathio 2,4-diF-Ph
1-293 3,4-diHM-cPent 2,4-diF-Ph
1-294 4,5-diHM-dioxo 2,4-diF-Ph
1-295 4,5-diHM-dithio 2,4-diF-Ph
1-296 4,5-diHM-oxathio 2,4-diF-Ph
1-297 3,4-diHE-cPent 2,4-diF-Ph
1-298 4,5-diHE-dioxo 2,4-diF-Ph
1-299 4,5-diHE-dithio 2,4-diF-Ph
1-300 4,5-diHE-oxathio 2,4-diF-Ph
1-301 3-HE-cPent 2,4-diF-Ph
1-302 4-HE-dioxo 2,4-diF-Ph
1-303 4-HE-dithio 2,4-diF-Ph
1-304 4-HE-oxathio 2,4-diF-Ph
1-305 3-HP-cPent 2,4-diF-Ph
1-306 4-HP-dioxo 2,4-diF-Ph
1-307 4-HP-dithio 2,4-diF-Ph
1-308 4-HP-oxathio 2,4-diF-Ph
1-309 3-HB-cPent 2,4-diF-Ph
1-310 4-HB-dioxo 2,4-diF-Ph
1-311 4-HB-dithio 2,4-diF-Ph
1-312 4-HB-oxathio 2,4-diF-Ph
1-313 Ring 3 2,4-diF-Ph
1-314 Ring 4 2,4-diF-Ph
1-315 Ring 5 2,4-diF-Ph
1-316 Ring 6 2,4-diF-Ph
1-317 Ring 7 2,4-diF-Ph
1-318 ring 8 2,4-diF-Ph
1-319 Ring 9 2,4-diF-Ph
1-320 ring 10 2,4-diF-Ph
1-321 3,4-diCH₂NHAc-cPent 2,4-diF-Ph
1-322 4,5-diCH₂NHAc-dioxo 2,4-diF-Ph
1-323 4,5-diCH₂NHAc-dithio 2,4-diF-Ph
1-324 4,5-diCH₂NHAc-oxathio 2,4-diF-Ph
1-325 ring 11 2,4-diF-Ph
1-326 Ring 12 2,4-diF-Ph
1-327 Ring 13 2,4-diF-Ph
1-328 ring 14 2,4-diF-Ph
1-329 4-OH-cHex 2,4-diF-Ph
1-330 5-OH-dioxa 2,4-diF-Ph
1-331 5-OH-dithia 2,4-diF-Ph
1-332 5-OH-oxathia 2,4-diF-Ph
1-333 4-NHAc-cHex 2,4-diF-Ph
1-334 5-NHAc-dioxa 2,4-diF-Ph
1-335 5-NHAc-dithia 2,4-diF-Ph
1-336 5-NHAc-oxathia 2,4-diF-Ph
1-337 4,4-diMe-cHex 2,4-diF-Ph
1-338 5,5-diMe-dioxa 2,4-diF-Ph
1-339 5,5-diMe-dithia 2,4-diF-Ph
1-340 5,5-diMe-oxathia 2,4-diF-Ph
1-341 4,4-diHM-cHex 2,4-diF-Ph
1-342 5,5-diHM-dioxa 2,4-diF-Ph
1-343 5,5-diHM-dithia 2,4-diF-Ph
1-344 5,5-diHM-oxathia 2,4-diF-Ph
1-345 Ring 15 2,4-diF-Ph
1-346 Ring 16 2,4-diF-Ph
1-347 ring 17 2,4-diF-Ph
1-348 ring 18 2,4-diF-Ph
1-349 4,4-diCO₂Et-cHex 2,4-diF-Ph
1-350 5,5-diCO₂Et-dioxa 2,4-diF-Ph
1-351 5,5-diCO₂Et-dithia 2,4-diF-Ph
1-352 5,5-diCO₂Et-oxathia 2,4-diF-Ph
1-353 O = 2-Cl-4-F-Ph
1-354 S = 2-Cl-4-F-Ph
1-355 cPr 2-Cl-4-F-Ph
1-356 cBu 2-Cl-4-F-Ph
1-357 cPent 2-Cl-4-F-Ph
1-358 cHex 2-Cl-4-F-Ph
1-359 cHept 2-Cl-4-F-Ph
1-360 oxi 2-Cl-4-F-Ph
1-361 oxe 2-Cl-4-F-Ph
1-362 oxo 2-Cl-4-F-Ph
1-363 oxa 2-Cl-4-F-Ph
1-364 dioxo 2-Cl-4-F-Ph
1-365 dioxa 2-Cl-4-F-Ph
1-366 dioxe 2-Cl-4-F-Ph
1-367 dithio 2-Cl-4-F-Ph
1-368 dithia 2-Cl-4-F-Ph
1-369 Ring 1 2-Cl-4-F-Ph
1-370 Ring 2 2-Cl-4-F-Ph
1-371 oxathio 2-Cl-4-F-Ph
1-372 oxathia 2-Cl-4-F-Ph
1-373 ozl 2-Cl-4-F-Ph
1-374 ozn 2-Cl-4-F-Ph
1-375 tzl 2-Cl-4-F-Ph
1-376 tzn 2-Cl-4-F-Ph
1-377 3-HM-cPent 2-Cl-4-F-Ph
1-378 4-HM-dioxo 2-Cl-4-F-Ph
1-379 4-HM-dithio 2-Cl-4-F-Ph
1-380 4-HM-oxathio 2-Cl-4-F-Ph
1-381 3,4-diHM-cPent 2-Cl-4-F-Ph
1-382 4,5-diHM-dioxo 2-Cl-4-F-Ph
1-383 4,5-diHM-dithio 2-Cl-4-F-Ph
1-384 4,5-diHM-oxathio 2-Cl-4-F-Ph
1-385 3,4-diHE-cPent 2-Cl-4-F-Ph
1-386 4,5-diHE-dioxo 2-Cl-4-F-Ph
1-387 4,5-diHE-dithio 2-Cl-4-F-Ph
1-388 4,5-diHE-oxathio 2-Cl-4-F-Ph
1-389 3-HE-cPent 2-Cl-4-F-Ph
1-390 4-HE-dioxo 2-Cl-4-F-Ph
1-391 4-HE-dithio 2-Cl-4-F-Ph
1-392 4-HE-oxathio 2-Cl-4-F-Ph
1-393 3-HP-cPent 2-Cl-4-F-Ph
1-394 4-HP-dioxo 2-Cl-4-F-Ph
1-395 4-HP-dithio 2-Cl-4-F-Ph
1-396 4-HP-oxathio 2-Cl-4-F-Ph
1-397 3-HB-cPent 2-Cl-4-F-Ph
1-398 4-HB-dioxo 2-Cl-4-F-Ph
1-399 4-HB-dithio 2-Cl-4-F-Ph
1-400 4-HB-oxathio 2-Cl-4-F-Ph
1-401 Ring 3 2-Cl-4-F-Ph
1-402 Ring 4 2-Cl-4-F-Ph
1-403 Ring 5 2-Cl-4-F-Ph
1-404 Ring 6 2-Cl-4-F-Ph
1-405 Ring 7 2-Cl-4-F-Ph
1-406 Ring 8 2-Cl-4-F-Ph
1-407 Ring 9 2-Cl-4-F-Ph
1-408 Ring 10 2-Cl-4-F-Ph
1-409 3,4-diCH₂NHAc-cPent 2-Cl-4-F-Ph
1-410 4,5-diCH₂NHAc-dioxo 2-Cl-4-F-Ph
1-411 4,5-diCH₂NHAc-dithio 2-Cl-4-F-Ph
1-412 4,5-diCH₂NHAc-oxathio 2-Cl-4-F-Ph
1-413 Ring 11 2-Cl-4-F-Ph
1-414 Ring 12 2-Cl-4-F-Ph
1-415 Ring 13 2-Cl-4-F-Ph
1-416 Ring 14 2-Cl-4-F-Ph
1-417 4-OH-cHex 2-Cl-4-F-Ph
1-418 5-OH-dioxa 2-Cl-4-F-Ph
1-419 5-OH-dithia 2-Cl-4-F-Ph
1-420 5-OH-oxathia 2-Cl-4-F-Ph
1-421 4-NHAc-cHex 2-Cl-4-F-Ph
1-422 5-NHAc-dioxa 2-Cl-4-F-Ph
1-423 5-NHAc-dithia 2-Cl-4-F-Ph
1-424 5-NHAc-oxathia 2-Cl-4-F-Ph
1-425 4,4-diMe-cHex 2-Cl-4-F-Ph
1-426 5,5-diMe-dioxa 2-Cl-4-F-Ph
1-427 5,5-diMe-dithia 2-Cl-4-F-Ph
1-428 5,5-diMe-oxathia 2-Cl-4-F-Ph
1-429 4,4-diHM-cHex 2-Cl-4-F-Ph
1-430 5,5-diHM-dioxa 2-Cl-4-F-Ph
1-431 5,5-diHM-dithia 2-Cl-4-F-Ph
1-432 5,5-diHM-oxathia 2-Cl-4-F-Ph
1-433 Ring 15 2-Cl-4-F-Ph
1-434 Ring 16 2-Cl-4-F-Ph
1-435 Ring 17 2-Cl-4-F-Ph
1-436 ring 18 2-Cl-4-F-Ph
1-437 4,4-diCO₂Et-cHex 2-Cl-4-F-Ph
1-438 5,5-diCO₂Et-dioxa 2-Cl-4-F-Ph
1-439 5,5-diCO₂Et-dithia 2-Cl-4-F-Ph
1-440 5,5-diCO₂Et-oxathia 2-Cl-4-F-Ph
1-441 O = 2-Cl-4-Me-Ph
1-442 S = 2-Cl-4-Me-Ph
1-443 cPr 2-Cl-4-Me-Ph
1-444 cBu 2-Cl-4-Me-Ph
1-445 cPent 2-Cl-4-Me-Ph
1-446 cHex 2-Cl-4-Me-Ph
1-447 cHept 2-Cl-4-Me-Ph
1-448 oxi 2-Cl-4-Me-Ph
1-449 oxe 2-Cl-4-Me-Ph
1-450 oxo 2-Cl-4-Me-Ph
1-451 oxa 2-Cl-4-Me-Ph
1-452 dioxo 2-Cl-4-Me-Ph
1-453 dioxa 2-Cl-4-Me-Ph
1-454 dioxe 2-Cl-4-Me-Ph
1-455 dithio 2-Cl-4-Me-Ph
1-456 dithia 2-Cl-4-Me-Ph
1-457 Ring 1 2-Cl-4-Me-Ph
1-458 Ring 2 2-Cl-4-Me-Ph
1-459 oxathio 2-Cl-4-Me-Ph
1-460 oxathia 2-Cl-4-Me-Ph
1-461 ozl 2-Cl-4-Me-Ph
1-462 ozn 2-Cl-4-Me-Ph
1-463 tzl 2-Cl-4-Me-Ph
1-464 tzn 2-Cl-4-Me-Ph
1-465 3-HM-cPent 2-Cl-4-Me-Ph
1-466 4-HM-dioxo 2-Cl-4-Me-Ph
1-467 4-HM-dithio 2-Cl-4-Me-Ph
1-468 4-HM-oxathio 2-Cl-4-Me-Ph
1-469 3,4-diHM-cPent 2-Cl-4-Me-Ph
1-470 4,5-diHM-dioxo 2-Cl-4-Me-Ph
1-471 4,5-diHM-dithio 2-Cl-4-Me-Ph
1-472 4,5-diHM-oxathio 2-Cl-4-Me-Ph
1-473 3,4-diHE-cPent 2-Cl-4-Me-Ph
1-474 4,5-diHE-dioxo 2-Cl-4-Me-Ph
1-475 4,5-diHE-dithio 2-Cl-4-Me-Ph
1-476 4,5-diHE-oxathio 2-Cl-4-Me-Ph
1-477 3-HE-cPent 2-Cl-4-Me-Ph
1-478 4-HE-dioxo 2-Cl-4-Me-Ph
1-479 4-HE-dithio 2-Cl-4-Me-Ph
1-480 4-HE-oxathio 2-Cl-4-Me-Ph
1-481 3-HP-cPent 2-Cl-4-Me-Ph
1-482 4-HP-dioxo 2-Cl-4-Me-Ph
1-483 4-HP-dithio 2-Cl-4-Me-Ph
1-484 4-HP-oxathio 2-Cl-4-Me-Ph
1-485 3-HB-cPent 2-Cl-4-Me-Ph
1-486 4-HB-dioxo 2-Cl-4-Me-Ph
1-487 4-HB-dithio 2-Cl-4-Me-Ph
1-488 4-HB-oxathio 2-Cl-4-Me-Ph
1-489 Ring 3 2-Cl-4-Me-Ph
1-490 Ring 4 2-Cl-4-Me-Ph
1-491 Ring 5 2-Cl-4-Me-Ph
1-492 Ring 6 2-Cl-4-Me-Ph
1-493 Ring 7 2-Cl-4-Me-Ph
1-494 Ring 8 2-Cl-4-Me-Ph
1-495 Ring 9 2-Cl-4-Me-Ph
1-496 Ring 10 2-Cl-4-Me-Ph
1-497 3,4-diCH₂NHAc-cPent 2-Cl-4-Me-Ph
1-498 4,5-diCH₂NHAc-dioxo 2-Cl-4-Me-Ph
1-499 4,5-diCH₂NHAc-dithio 2-Cl-4-Me-Ph
1-500 4,5-diCH₂NHAc-oxathio 2-Cl-4-Me-Ph
1-501 Ring 11 2-Cl-4-Me-Ph
1-502 Ring 12 2-Cl-4-Me-Ph
1-503 Ring 13 2-Cl-4-Me-Ph
1-504 Ring 14 2-Cl-4-Me-Ph
1-505 4-OH-cHex 2-Cl-4-Me-Ph
1-506 5-OH-dioxa 2-Cl-4-Me-Ph
1-507 5-OH-dithia 2-Cl-4-Me-Ph
1-508 5-OH-oxathia 2-Cl-4-Me-Ph
1-509 4-NHAc-cHex 2-Cl-4-Me-Ph
1-510 5-NHAc-dioxa 2-Cl-4-Me-Ph
1-511 5-NHAc-dithia 2-Cl-4-Me-Ph
1-512 5-NHAc-oxathia 2-Cl-4-Me-Ph
1-513 4,4-diMe-cHex 2-Cl-4-Me-Ph
1-514 5,5-diMe-dioxa 2-Cl-4-Me-Ph
1-515 5,5-diMe-dithia 2-Cl-4-Me-Ph
1-516 5,5-diMe-oxathia 2-Cl-4-Me-Ph
1-517 4,4-diHM-cHex 2-Cl-4-Me-Ph
1-518 5,5-diHM-dioxa 2-Cl-4-Me-Ph
1-519 5,5-diHM-dithia 2-Cl-4-Me-Ph
1-520 5,5-diHM-oxathia 2-Cl-4-Me-Ph
1-521 Ring 15 2-Cl-4-Me-Ph
1-522 Ring 16 2-Cl-4-Me-Ph
1-523 Ring 17 2-Cl-4-Me-Ph
1-524 Ring 18 2-Cl-4-Me-Ph
1-525 4,4-diCO₂Et-cHex 2-Cl-4-Me-Ph
1-526 5,5-diCO₂Et-dioxa 2-Cl-4-Me-Ph
1-527 5,5-diCO₂Et-dithia 2-Cl-4-Me-Ph
1-528 5,5-diCO₂Et-oxathia 2-Cl-4-Me-Ph
1-529 O = 2-nBu-Ph
1-530 S = 2-nBu-Ph
1-531 cPr 2-nBu-Ph
1-532 cBu 2-nBu-Ph
1-533 cPent 2-nBu-Ph
1-534 cHex 2-nBu-Ph
1-535 cHept 2-nBu-Ph
1-536 oxi 2-nBu-Ph
1-537 oxe 2-nBu-Ph
1-538 oxo 2-nBu-Ph
1-539 oxa 2-nBu-Ph
1-540 dioxo 2-nBu-Ph
1-541 dioxa 2-nBu-Ph
1-542 dioxe 2-nBu-Ph
1-543 dithio 2-nBu-Ph
1-544 dithia 2-nBu-Ph
1-545 Ring 1 2-nBu-Ph
1-546 Ring 2 2-nBu-Ph
1-547 oxathio 2-nBu-Ph
1-548 oxathia 2-nBu-Ph
1-549 ozl 2-nBu-Ph
1-550 ozn 2-nBu-Ph
1-551 tzl 2-nBu-Ph
1-552 tzn 2-nBu-Ph
1-553 3-HM-cPent 2-nBu-Ph
1-554 4-HM-dioxo 2-nBu-Ph
1-555 4-HM-dithio 2-nBu-Ph
1-556 4-HM-oxathio 2-nBu-Ph
1-557 3,4-diHM-cPent 2-nBu-Ph
1-558 4,5-diHM-dioxo 2-nBu-Ph
1-559 4,5-diHM-dithio 2-nBu-Ph
1-560 4,5-diHM-oxathio 2-nBu-Ph
1-561 3,4-diHE-cPent 2-nBu-Ph
1-562 4,5-diHE-dioxo 2-nBu-Ph
1-563 4,5-diHE-dithio 2-nBu-Ph
1-564 4,5-diHE-oxathio 2-nBu-Ph
1-565 3-HE-cPent 2-nBu-Ph
1-566 4-HE-dioxo 2-nBu-Ph
1-567 4-HE-dithio 2-nBu-Ph
1-568 4-HE-oxathio 2-nBu-Ph
1-569 3-HP-cPent 2-nBu-Ph
1-570 4-HP-dioxo 2-nBu-Ph
1-571 4-HP-dithio 2-nBu-Ph
1-572 4-HP-oxathio 2-nBu-Ph
1-573 3-HB-cPent 2-nBu-Ph
1-574 4-HB-dioxo 2-nBu-Ph
1-575 4-HB-dithio 2-nBu-Ph
1-576 4-HB-oxathio 2-nBu-Ph
1-577 Ring 3 2-nBu-Ph
1-578 Ring 4 2-nBu-Ph
1-579 Ring 5 2-nBu-Ph
1-580 Ring 6 2-nBu-Ph
1-581 Ring 7 2-nBu-Ph
1-582 Ring 8 2-nBu-Ph
1-583 Ring 9 2-nBu-Ph
1-584 Ring 10 2-nBu-Ph
1-585 3,4-diCH₂NHAc-cPent 2-nBu-Ph
1-586 4,5-diCH₂NHAc-dioxo 2-nBu-Ph
1-587 4,5-diCH₂NHAc-dithio 2-nBu-Ph
1-588 4,5-diCH₂NHAc-oxathio 2-nBu-Ph
1-589 Ring 11 2-nBu-Ph
1-590 Ring 12 2-nBu-Ph
1-591 Ring 13 2-nBu-Ph
1-592 Ring 14 2-nBu-Ph
1-593 4-OH-cHex 2-nBu-Ph
1-594 5-OH-dioxa 2-nBu-Ph
1-595 5-OH-dithia 2-nBu-Ph
1-596 5-OH-oxathia 2-nBu-Ph
1-597 4-NHAc-cHex 2-nBu-Ph
1-598 5-NHAc-dioxa 2-nBu-Ph
1-599 5-NHAc-dithia 2-nBu-Ph
1-600 5-NHAc-oxathia 2-nBu-Ph
1-601 4,4-diMe-cHex 2-nBu-Ph
1-602 5,5-diMe-dioxa 2-nBu-Ph
1-603 5,5-diMe-dithia 2-nBu-Ph
1-604 5,5-diMe-oxathia 2-nBu-Ph
1-605 4,4-diHM-cHex 2-nBu-Ph
1-606 5,5-diHM-dioxa 2-nBu-Ph
1-607 5,5-diHM-dithia 2-nBu-Ph
1-608 5,5-diHM-oxathia 2-nBu-Ph
1-609 Ring 15 2-nBu-Ph
1-610 Ring 16 2-nBu-Ph
1-611 Ring 17 2-nBu-Ph
1-612 Ring 18 2-nBu-Ph
1-613 4,4-diCO₂Et-cHex 2-nBu-Ph
1-614 5,5-diCO₂Et-dioxa 2-nBu-Ph
1-615 5,5-diCO₂Et-dithia 2-nBu-Ph
1-616 5,5-diCO₂Et-oxathia 2-nBu-Ph
1-617 O = 2-nBu-4-F-Ph
1-618 S = 2-nBu-4-F-Ph
1-619 cPr 2-nBu-4-F-Ph
1-620 cBu 2-nBu-4-F-Ph
1-621 cPent 2-nBu-4-F-Ph
1-622 cHex 2-nBu-4-F-Ph
1-623 cHept 2-nBu-4-F-Ph
1-624 oxi 2-nBu-4-F-Ph
1-625 oxe 2-nBu-4-F-Ph
1-626 oxo 2-nBu-4-F-Ph
1-627 oxa 2-nBu-4-F-Ph
1-628 dioxo 2-nBu-4-F-Ph
1-629 dioxa 2-nBu-4-F-Ph
1-630 dioxe 2-nBu-4-F-Ph
1-631 dithio 2-nBu-4-F-Ph
1-632 dithia 2-nBu-4-F-Ph
1-633 Ring 1 2-nBu-4-F-Ph
1-634 Ring 2 2-nBu-4-F-Ph
1-635 oxathio 2-nBu-4-F-Ph
1-636 oxathia 2-nBu-4-F-Ph
1-637 ozl 2-nBu-4-F-Ph
1-638 ozn 2-nBu-4-F-Ph
1-639 tzl 2-nBu-4-F-Ph
1-640 tzn 2-nBu-4-F-Ph
1-641 3-HM-cPent 2-nBu-4-F-Ph
1-642 4-HM-dioxo 2-nBu-4-F-Ph
1-643 4-HM-dithio 2-nBu-4-F-Ph
1-644 4-HM-oxathio 2-nBu-4-F-Ph
1-645 3,4-diHM-cPent 2-nBu-4-F-Ph
1-646 4,5-diHM-dioxo 2-nBu-4-F-Ph
1-647 4,5-diHM-dithio 2-nBu-4-F-Ph
1-648 4,5-diHM-oxathio 2-nBu-4-F-Ph
1-649 3,4-diHE-cPent 2-nBu-4-F-Ph
1-650 4,5-diHE-dioxo 2-nBu-4-F-Ph
1-651 4,5-diHE-dithio 2-nBu-4-F-Ph
1-652 4,5-diHE-oxathio 2-nBu-4-F-Ph
1-653 3-HE-cPent 2-nBu-4-F-Ph
1-654 4-HE-dioxo 2-nBu-4-F-Ph
1-655 4-HE-dithio 2-nBu-4-F-Ph
1-656 4-HE-oxathio 2-nBu-4-F-Ph
1-657 3-HP-cPent 2-nBu-4-F-Ph
1-658 4-HP-dioxo 2-nBu-4-F-Ph
1-659 4-HP-dithio 2-nBu-4-F-Ph
1-660 4-HP-oxathio 2-nBu-4-F-Ph
1-661 3-HB-cPent 2-nBu-4-F-Ph
1-662 4-HB-dioxo 2-nBu-4-F-Ph
1-663 4-HB-dithio 2-nBu-4-F-Ph
1-664 4-HB-oxathio 2-nBu-4-F-Ph
1-665 Ring 3 2-nBu-4-F-Ph
1-666 Ring 4 2-nBu-4-F-Ph
1-667 Ring 5 2-nBu-4-F-Ph
1-668 Ring 6 2-nBu-4-F-Ph
1-669 Ring 7 2-nBu-4-F-Ph
1-670 Ring 8 2-nBu-4-F-Ph
1-671 Ring 9 2-nBu-4-F-Ph
1-672 Ring 10 2-nBu-4-F-Ph
1-673 3,4-diCH₂NHAc-cPent 2-nBu-4-F-Ph
1-674 4,5-diCH₂NHAc-dioxo 2-nBu-4-F-Ph
1-675 4,5-diCH₂NHAc-dithio 2-nBu-4-F-Ph
1-676 4,5-diCH₂NHAc-oxathio 2-nBu-4-F-Ph
1-677 Ring 11 2-nBu-4-F-Ph
1-678 Ring 12 2-nBu-4-F-Ph
1-679 Ring 13 2-nBu-4-F-Ph
1-680 Ring 14 2-nBu-4-F-Ph
1-681 4-OH-cHex 2-nBu-4-F-Ph
1-682 5-OH-dioxa 2-nBu-4-F-Ph
1-683 5-OH-dithia 2-nBu-4-F-Ph
1-684 5-OH-oxathia 2-nBu-4-F-Ph
1-685 4-NHAc-cHex 2-nBu-4-F-Ph
1-686 5-NHAc-dioxa 2-nBu-4-F-Ph
1-687 5-NHAc-dithia 2-nBu-4-F-Ph
1-688 5-NHAc-oxathia 2-nBu-4-F-Ph
1-689 4,4-diMe-cHex 2-nBu-4-F-Ph
1-690 5,5-diMe-dioxa 2-nBu-4-F-Ph
1-691 5,5-diMe-dithia 2-nBu-4-F-Ph
1-692 5,5-diMe-oxathia 2-nBu-4-F-Ph
1-693 4,4-diHM-cHex 2-nBu-4-F-Ph
1-694 5,5-diHM-dioxa 2-nBu-4-F-Ph
1-695 5,5-diHM-dithia 2-nBu-4-F-Ph
1-696 5,5-diHM-oxathia 2-nBu-4-F-Ph
1-697 Ring 15 2-nBu-4-F-Ph
1-698 Ring 16 2-nBu-4-F-Ph
1-699 Ring 17 2-nBu-4-F-Ph
1-700 ring 18 2-nBu-4-F-Ph
1-701 4,4-diCO₂Et-cHex 2-nBu-4-F-Ph
1-702 5,5-diCO₂Et-dioxa 2-nBu-4-F-Ph
1-703 5,5-diCO₂Et-dithia 2-nBu-4-F-Ph
1-704 5,5-diCO₂Et-oxathia 2-nBu-4-F-Ph
1-705 O = 2-nHex-Ph
1-706 S = 2-nHex-Ph
1-707 cPr 2-nHex-Ph
1-708 cBu 2-nHex-Ph
1-709 cPent 2-nHex-Ph
1-710 cHex 2-nHex-Ph
1-711 cHept 2-nHex-Ph
1-712 oxi 2-nHex-Ph
1-713 oxe 2-nHex-Ph
1-714 oxo 2-nHex-Ph
1-715 oxa 2-nHex-Ph
1-716 dioxo 2-nHex-Ph
1-717 dioxa 2-nHex-Ph
1-718 dioxe 2-nHex-Ph
1-719 dithio 2-nHex-Ph
1-720 dithia 2-nHex-Ph
1-721 Ring 1 2-nHex-Ph
1-722 Ring 2 2-nHex-Ph
1-723 oxathio 2-nHex-Ph
1-724 oxathia 2-nHex-Ph
1-725 ozl 2-nHex-Ph
1-726 ozn 2-nHex-Ph
1-727 tzl 2-nHex-Ph
1-728 tzn 2-nHex-Ph
1-729 3-HM-cPent 2-nHex-Ph
1-730 4-HM-dioxo 2-nHex-Ph
1-731 4-HM-dithio 2-nHex-Ph
1-732 4-HM-oxathio 2-nHex-Ph
1-733 3,4-diHM-cPent 2-nHex-Ph
1-734 4,5-diHM-dioxo 2-nHex-Ph
1-735 4,5-diHM-dithio 2-nHex-Ph
1-736 4,5-diHM-oxathio 2-nHex-Ph
1-737 3,4-diHE-cPent 2-nHex-Ph
1-738 4,5-diHE-dioxo 2-nHex-Ph
1-739 4,5-diHE-dithio 2-nHex-Ph
1-740 4,5-diHE-oxathio 2-nHex-Ph
1-741 3-HE-cPent 2-nHex-Ph
1-742 4-HE-dioxo 2-nHex-Ph
1-743 4-HE-dithio 2-nHex-Ph
1-744 4-HE-oxathio 2-nHex-Ph
1-745 3-HP-cPent 2-nHex-Ph
1-746 4-HP-dioxo 2-nHex-Ph
1-747 4-HP-dithio 2-nHex-Ph
1-748 4-HP-oxathio 2-nHex-Ph
1-749 3-HB-cPent 2-nHex-Ph
1-750 4-HB-dioxo 2-nHex-Ph
1-751 4-HB-dithio 2-nHex-Ph
1-752 4-HB-oxathio 2-nHex-Ph
1-753 Ring 3 2-nHex-Ph
1-754 Ring 4 2-nHex-Ph
1-755 Ring 5 2-nHex-Ph
1-756 Ring 6 2-nHex-Ph
1-757 Ring 7 2-nHex-Ph
1-758 Ring 8 2-nHex-Ph
1-759 Ring 9 2-nHex-Ph
1-760 Ring 10 2-nHex-Ph
1-761 3,4-diCH₂NHAc-cPent 2-nHex-Ph
1-762 4,5-diCH₂NHAc-dioxo 2-nHex-Ph
1-763 4,5-diCH₂NHAc-dithio 2-nHex-Ph
1-764 4,5-diCH₂NHAc-oxathio 2-nHex-Ph
1-765 Ring 11 2-nHex-Ph
1-766 Ring 12 2-nHex-Ph
1-767 Ring 13 2-nHex-Ph
1-768 Ring 14 2-nHex-Ph
1-769 4-OH-cHex 2-nHex-Ph
1-770 5-OH-dioxa 2-nHex-Ph
1-771 5-OH-dithia 2-nHex-Ph
1-772 5-OH-oxathia 2-nHex-Ph
1-773 4-NHAc-cHex 2-nHex-Ph
1-774 5-NHAc-dioxa 2-nHex-Ph
1-775 5-NHAc-dithia 2-nHex-Ph
1-776 5-NHAc-oxathia 2-nHex-Ph
1-777 4,4-diMe-cHex 2-nHex-Ph
1-778 5,5-diMe-dioxa 2-nHex-Ph
1-779 5,5-diMe-dithia 2-nHex-Ph
1-780 5,5-diMe-oxathia 2-nHex-Ph
1-781 4,4-diHM-cHex 2-nHex-Ph
1-782 5,5-diHM-dioxa 2-nHex-Ph
1-783 5,5-diHM-dithia 2-nHex-Ph
1-784 5,5-diHM-oxathia 2-nHex-Ph
1-785 Ring 15 2-nHex-Ph
1-786 Ring 16 2-nHex-Ph
1-787 Ring 17 2-nHex-Ph
1-788 Ring 18 2-nHex-Ph
1-789 4,4-diCO₂Et-cHex 2-nHex-Ph
1-790 5,5-diCO₂Et-dioxa 2-nHex-Ph
1-791 5,5-diCO₂Et-dithia 2-nHex-Ph
1-792 5,5-diCO₂Et-oxathia 2-nHex-Ph
1-793 O = 4-F-2-nHex-Ph
1-794 S = 4-F-2-nHex-Ph
1-795 cPr 4-F-2-nHex-Ph
1-796 cBu 4-F-2-nHex-Ph
1-797 cPent 4-F-2-nHex-Ph
1-798 cHex 4-F-2-nHex-Ph
1-799 cHept 4-F-2-nHex-Ph
1-800 oxi 4-F-2-nHex-Ph
1-801 oxe 4-F-2-nHex-Ph
1-802 oxo 4-F-2-nHex-Ph
1-803 oxa 4-F-2-nHex-Ph
1-804 dioxo 4-F-2-nHex-Ph
1-805 dioxa 4-F-2-nHex-Ph
1-806 dioxe 4-F-2-nHex-Ph
1-807 dithio 4-F-2-nHex-Ph
1-808 dithia 4-F-2-nHex-Ph
1-809 Ring 1 4-F-2-nHex-Ph
1-810 Ring 2 4-F-2-nHex-Ph
1-811 oxathio 4-F-2-nHex-Ph
1-812 oxathia 4-F-2-nHex-Ph
1-813 ozl 4-F-2-nHex-Ph
1-814 ozn 4-F-2-nHex-Ph
1-815 tzl 4-F-2-nHex-Ph
1-816 tzn 4-F-2-nHex-Ph
1-817 3-HM-cPent 4-F-2-nHex-Ph
1-818 4-HM-dioxo 4-F-2-nHex-Ph
1-819 4-HM-dithio 4-F-2-nHex-Ph
1-820 4-HM-oxathio 4-F-2-nHex-Ph
1-821 3,4-diHM-cPent 4-F-2-nHex-Ph
1-822 4,5-diHM-dioxo 4-F-2-nHex-Ph
1-823 4,5-diHM-dithio 4-F-2-nHex-Ph
1-824 4,5-diHM-oxathio 4-F-2-nHex-Ph
1-825 3,4-diHE-cPent 4-F-2-nHex-Ph
1-826 4,5-diHE-dioxo 4-F-2-nHex-Ph
1-827 4,5-diHE-dithio 4-F-2-nHex-Ph
1-828 4,5-diHE-oxathio 4-F-2-nHex-Ph
1-829 3-HE-cPent 4-F-2-nHex-Ph
1-830 4-HE-dioxo 4-F-2-nHex-Ph
1-831 4-HE-dithio 4-F-2-nHex-Ph
1-832 4-HE-oxathio 4-F-2-nHex-Ph
1-833 3-HP-cPent 4-F-2-nHex-Ph
1-834 4-HP-dioxo 4-F-2-nHex-Ph
1-835 4-HP-dithio 4-F-2-nHex-Ph
1-836 4-HP-oxathio 4-F-2-nHex-Ph
1-837 3-HB-cPent 4-F-2-nHex-Ph
1-838 4-HB-dioxo 4-F-2-nHex-Ph
1-839 4-HB-dithio 4-F-2-nHex-Ph
1-840 4-HB-oxathio 4-F-2-nHex-Ph
1-841 Ring 3 4-F-2-nHex-Ph
1-842 Ring 4 4-F-2-nHex-Ph
1-843 Ring 5 4-F-2-nHex-Ph
1-844 Ring 6 4-F-2-nHex-Ph
1-845 Ring 7 4-F-2-nHex-Ph
1-846 Ring 8 4-F-2-nHex-Ph
1-847 Ring 9 4-F-2-nHex-Ph
1-848 Ring 10 4-F-2-nHex-Ph
1-849 3,4-diCH₂NHAc-cPent 4-F-2-nHex-Ph
1-850 4,5-diCH₂NHAc-dioxo 4-F-2-nHex-Ph
1-851 4,5-diCH₂NHAc-dithio 4-F-2-nHex-Ph
1-852 4,5-diCH₂NHAc-oxathio 4-F-2-nHex-Ph
1-853 Ring 11 4-F-2-nHex-Ph
1-854 Ring 12 4-F-2-nHex-Ph
1-855 Ring 13 4-F-2-nHex-Ph
1-856 Ring 14 4-F-2-nHex-Ph
1-857 4-OH-cHex 4-F-2-nHex-Ph
1-858 5-OH-dioxa 4-F-2-nHex-Ph
1-859 5-OH-dithia 4-F-2-nHex-Ph
1-860 5-OH-oxathia 4-F-2-nHex-Ph
1-861 4-NHAc-cHex 4-F-2-nHex-Ph
1-862 5-NHAc-dioxa 4-F-2-nHex-Ph
1-863 5-NHAc-dithia 4-F-2-nHex-Ph
1-864 5-NHAc-oxathia 4-F-2-nHex-Ph
1-865 4,4-diMe-cHex 4-F-2-nHex-Ph
1-866 5,5-diMe-dioxa 4-F-2-nHex-Ph
1-867 5,5-diMe-dithia 4-F-2-nHex-Ph
1-868 5,5-diMe-oxathia 4-F-2-nHex-Ph
1-869 4,4-diHM-cHex 4-F-2-nHex-Ph
1-870 5,5-diHM-dioxa 4-F-2-nHex-Ph
1-871 5,5-diHM-dithia 4-F-2-nHex-Ph
1-872 5,5-diHM-oxathia 4-F-2-nHex-Ph
1-873 Ring 15 4-F-2-nHex-Ph
1-874 Ring 16 4-F-2-nHex-Ph
1-875 Ring 17 4-F-2-nHex-Ph
1-876 Ring 18 4-F-2-nHex-Ph
1-877 4,4-diCO₂Et-cHex 4-F-2-nHex-Ph
1-878 5,5-diCO₂Et-dioxa 4-F-2-nHex-Ph
1-879 5,5-diCO₂Et-dithia 4-F-2-nHex-Ph
1-880 5,5-diCO₂Et-oxathia 4-F-2-nHex-Ph
1-881 O = 2-nHept-Ph
1-882 S = 2-nHept-Ph
1-883 cPr 2-nHept-Ph
1-884 cBu 2-nHept-Ph
1-885 cPent 2-nHept-Ph
1-886 cHex 2-nHept-Ph
1-887 cHept 2-nHept-Ph
1-888 oxi 2-nHept-Ph
1-889 oxe 2-nHept-Ph
1-890 oxo 2-nHept-Ph
1-891 oxa 2-nHept-Ph
1-892 dioxo 2-nHept-Ph
1-893 dioxa 2-nHept-Ph
1-894 dioxe 2-nHept-Ph
1-895 dithio 2-nHept-Ph
1-896 dithia 2-nHept-Ph
1-897 Ring 1 2-nHept-Ph
1-898 Ring 2 2-nHept-Ph
1-899 oxathio 2-nHept-Ph
1-900 oxathia 2-nHept-Ph
1-901 ozl 2-nHept-Ph
1-902 ozn 2-nHept-Ph
1-903 tzl 2-nHept-Ph
1-904 tzn 2-nHept-Ph
1-905 3-HM-cPent 2-nHept-Ph
1-906 4-HM-dioxo 2-nHept-Ph
1-907 4-HM-dithio 2-nHept-Ph
1-908 4-HM-oxathio 2-nHept-Ph
1-909 3,4-diHM-cPent 2-nHept-Ph
1-910 4,5-diHM-dioxo 2-nHept-Ph
1-911 4,5-diHM-dithio 2-nHept-Ph
1-912 4,5-diHM-oxathio 2-nHept-Ph
1-913 3,4-diHE-cPent 2-nHept-Ph
1-914 4,5-diHE-dioxo 2-nHept-Ph
1-915 4,5-diHE-dithio 2-nHept-Ph
1-916 4,5-diHE-oxathio 2-nHept-Ph
1-917 3-HE-cPent 2-nHept-Ph
1-918 4-HE-dioxo 2-nHept-Ph
1-919 4-HE-dithio 2-nHept-Ph
1-920 4-HE-oxathio 2-nHept-Ph
1-921 3-HP-cPent 2-nHept-Ph
1-922 4-HP-dioxo 2-nHept-Ph
1-923 4-HP-dithio 2-nHept-Ph
1-924 4-HP-oxathio 2-nHept-Ph
1-925 3-HB-cPent 2-nHept-Ph
1-926 4-HB-dioxo 2-nHept-Ph
1-927 4-HB-dithio 2-nHept-Ph
1-928 4-HB-oxathio 2-nHept-Ph
1-929 Ring 3 2-nHept-Ph
1-930 Ring 4 2-nHept-Ph
1-931 Ring 5 2-nHept-Ph
1-932 Ring 6 2-nHept-Ph
1-933 Ring 7 2-nHept-Ph
1-934 Ring 8 2-nHept-Ph
1-935 Ring 9 2-nHept-Ph
1-936 Ring 10 2-nHept-Ph
1-937 3,4-diCH₂NHAc-cPent 2-nHept-Ph
1-938 4,5-diCH₂NHAc-dioxo 2-nHept-Ph
1-939 4,5-diCH₂NHAc-dithio 2-nHept-Ph
1-940 4,5-diCH₂NHAc-oxathi 2-nHept-Ph
1-941 Ring 11 2-nHept-Ph
1-942 Ring 12 2-nHept-Ph
1-943 Ring 13 2-nHept-Ph
1-944 Ring 14 2-nHept-Ph
1-945 4-OH-cHex 2-nHept-Ph
1-946 5-OH-dioxa 2-nHept-Ph
1-947 5-OH-dithia 2-nHept-Ph
1-948 5-OH-oxathia 2-nHept-Ph
1-949 4-NHAc-cHex 2-nHept-Ph
1-950 5-NHAc-dioxa 2-nHept-Ph
1-951 5-NHAc-dithia 2-nHept-Ph
1-952 5-NHAc-oxathia 2-nHept-Ph
1-953 4,4-diMe-cHex 2-nHept-Ph
1-954 5,5-diMe-dioxa 2-nHept-Ph
1-955 5,5-diMe-dithia 2-nHept-Ph
1-956 5,5-diMe-oxathia 2-nHept-Ph
1-957 4,4-diHM-cHex 2-nHept-Ph
1-958 5,5-diHM-dioxa 2-nHept-Ph
1-959 5,5-diHM-dithia 2-nHept-Ph
1-960 5,5-diHM-oxathia 2-nHept-Ph
1-961 Ring 15 2-nHept-Ph
1-962 Ring 16 2-nHept-Ph
1-963 Ring 17 2-nHept-Ph
1-964 Ring 18 2-nHept-Ph
1-965 4,4-diCO₂Et-cHex 2-nHept-Ph
1-966 5,5-diCO₂Et-dioxa 2-nHept-Ph
1-967 5,5-diCO₂Et-dithia 2-nHept-Ph
1-968 5,5-diCO₂Et-oxathia 2-nHept-Ph
1-969 O = 4-F-2-nHept-Ph
1-970 S = 4-F-2-nHept-Ph
1-971 cPr 4-F-2-nHept-Ph
1-972 cBu 4-F-2-nHept-Ph
1-973 cPent 4-F-2-nHept-Ph
1-974 cHex 4-F-2-nHept-Ph
1-975 cHept 4-F-2-nHept-Ph
1-976 oxi 4-F-2-nHept-Ph
1-977 oxe 4-F-2-nHept-Ph
1-978 oxo 4-F-2-nHept-Ph
1-979 oxa 4-F-2-nHept-Ph
1-980 dioxo 4-F-2-nHept-Ph
1-981 dioxa 4-F-2-nHept-Ph
1-982 dioxe 4-F-2-nHept-Ph
1-983 dithio 4-F-2-nHept-Ph
1-984 dithia 4-F-2-nHept-Ph
1-985 Ring 1 4-F-2-nHept-Ph
1-986 Ring 2 4-F-2-nHept-Ph
1-987 oxathio 4-F-2-nHept-Ph
1-988 oxathia 4-F-2-nHept-Ph
1-989 ozl 4-F-2-nHept-Ph
1-990 ozn 4-F-2-nHept-Ph
1-991 tzl 4-F-2-nHept-Ph
1-992 tzn 4-F-2-nHept-Ph
1-993 3-HM-cPent 4-F-2-nHept-Ph
1-994 4-HM-dioxo 4-F-2-nHept-Ph
1-995 4-HM-dithio 4-F-2-nHept-Ph
1-996 4-HM-oxathio 4-F-2-nHept-Ph
1-997 3,4-diHM-cPent 4-F-2-nHept-Ph
1-998 4,5-diHM-dioxo 4-F-2-nHept-Ph
1-999 4,5-diHM-dithio 4-F-2-nHept-Ph
1-1000 4,5-diHM-oxathio 4-F-2-nHept-Ph
1-1001 3,4-diHE-cPent 4-F-2-nHept-Ph
1-1002 4,5-diHE-dioxo 4-F-2-nHept-Ph
1-1003 4,5-diHE-dithio 4-F-2-nHept-Ph
1-1004 4,5-diHE-oxathio 4-F-2-nHept-Ph
1-1005 3-HE-cPent 4-F-2-nHept-Ph
1-1006 4-HE-dioxo 4-F-2-nHept-Ph
1-1007 4-HE-dithio 4-F-2-nHept-Ph
1-1008 4-HE-oxathio 4-F-2-nHept-Ph
1-1009 3-HP-cPent 4-F-2-nHept-Ph
1-1010 4-HP-dioxo 4-F-2-nHept-Ph
1-1011 4-HP-dithio 4-F-2-nHept-Ph
1-1012 4-HP-oxathio 4-F-2-nHept-Ph
1-1013 3-HB-cPent 4-F-2-nHept-Ph
1-1014 4-HB-dioxo 4-F-2-nHept-Ph
1-1015 4-HB-dithio 4-F-2-nHept-Ph
1-1016 4-HB-oxathio 4-F-2-nHept-Ph
1-1017 Ring 3 4-F-2-nHept-Ph
1-1018 Ring 4 4-F-2-nHept-Ph
1-1019 Ring 5 4-F-2-nHept-Ph
1-1020 Ring 6 4-F-2-nHept-Ph
1-1021 Ring 7 4-F-2-nHept-Ph
1-1022 Ring 8 4-F-2-nHept-Ph
1-1023 Ring 9 4-F-2-nHept-Ph
1-1024 Ring 10 4-F-2-nHept-Ph
1-1025 3,4-diCH₂NHAc-cPent 4-F-2-nHept-Ph
1-1026 4,5-diCH₂NHAc-dioxo 4-F-2-nHept-Ph
1-1027 4,5-diCH₂NHAc-dithio 4-F-2-nHept-Ph
1-1028 4,5-diCH₂NHAc-oxathio 4-F-2-nHept-Ph
1-1029 Ring 11 4-F-2-nHept-Ph
1-1030 Ring 12 4-F-2-nHept-Ph
1-1031 Ring 13 4-F-2-nHept-Ph
1-1032 ring 14 4-F-2-nHept-Ph
1-1033 4-OH-cHex 4-F-2-nHept-Ph
1-1034 5-OH-dioxa 4-F-2-nHept-Ph
1-1035 5-OH-dithia 4-F-2-nHept-Ph
1-1036 5-OH-oxathia 4-F-2-nHept-Ph
1-1037 4-NHAc-cHex 4-F-2-nHept-Ph
1-1038 5-NHAc-dioxa 4-F-2-nHept-Ph
1-1039 5-NHAc-dithia 4-F-2-nHept-Ph
1-1040 5-NHAc-oxathia 4-F-2-nHept-Ph
1-1041 4,4-diMe-cHex 4-F-2-nHept-Ph
1-1042 5,5-diMe-dioxa 4-F-2-nHept-Ph
1-1043 5,5-diMe-dithia 4-F-2-nHept-Ph
1-1044 5,5-diMe-oxathia 4-F-2-nHept-Ph
1-1045 4,4-diHM-cHex 4-F-2-nHept-Ph
1-1046 5,5-diHM-dioxa 4-F-2-nHept-Ph
1-1047 5,5-diHM-dithia 4-F-2-nHept-Ph
1-1048 5,5-diHM-oxathia 4-F-2-nHept-Ph
1-1049 Ring 15 4-F-2-nHept-Ph
1-1050 Ring 16 4-F-2-nHept-Ph
1-1051 Ring 17 4-F-2-nHept-Ph
1-1052 Ring 18 4-F-2-nHept-Ph
1-1053 4,4-diCO₂Et-cHex 4-F-2-nHept-Ph
1-1054 5,5-diCO₂Et-dioxa 4-F-2-nHept-Ph
1-1055 5,5-diCO₂Et-dithia 4-F-2-nHept-Ph
1-1056 5,5-diCO₂Et-oxathia 4-F-2-nHept-Ph
1-1057 H, H Pyr
1-1058 O = Pyr
1-1059 S = Pyr
1-1060 cPent Pyr
1-1061 cHex Pyr
1-1062 dioxo Pyr
1-1063 dioxa Pyr
1-1064 dithio Pyr
1-1065 dithia Pyr
1-1066 oxathio Pyr
1-1067 oxathia Pyr
1-1068 4-HM-dioxo Pyr
1-1069 4,5-diHM-dioxo Pyr
1-1070 4,5-diHE-dioxo Pyr
1-1071 5-OH-dioxa Pyr
1-1072 5-NHAc-dioxa Pyr
1-1073 5,5-diHM-dioxa Pyr
1-1074 H, H 2-F-Pyr
1-1075 O = 2-F-Pyr
1-1076 S = 2-F-Pyr
1-1077 cPent 2-F-Pyr
1-1078 cHex 2-F-Pyr
1-1079 dioxo 2-F-Pyr
1-1080 dioxa 2-F-Pyr
1-1081 dithio 2-F-Pyr
1-1082 dithia 2-F-Pyr
1-1083 oxathio 2-F-Pyr
1-1084 oxathia 2-F-Pyr
1-1085 4-HM-dioxo 2-F-Pyr
1-1086 4,5-diHM-dioxo 2-F-Pyr
1-1087 4,5-diHE-dioxo 2-F-Pyr
1-1088 5-OH-dioxa 2-F-Pyr
1-1089 5-NHAc-dioxa 2-F-Pyr
1-1090 5,5-diHM-dioxa 2-F-Pyr
1-1091 H, H 2-Cl-Pyr
1-1092 O = 2-Cl-Pyr
1-1093 S = 2-Cl-Pyr
1-1094 cPent 2-Cl-Pyr
1-1095 cHex 2-Cl-Pyr
1-1096 dioxo 2-Cl-Pyr
1-1097 dioxa 2-Cl-Pyr
1-1098 dithio 2-Cl-Pyr
1-1099 dithia 2-Cl-Pyr
1-1100 oxathio 2-Cl-Pyr
1-1101 oxathia 2-Cl-Pyr
1-1102 4-HM-dioxo 2-Cl-Pyr
1-1103 4,5-diHM-dioxo 2-Cl-Pyr
1-1104 4,5-diHE-dioxo 2-Cl-Pyr
1-1105 5-OH-dioxa 2-Cl-Pyr
1-1106 5-NHAc-dioxa 2-Cl-Pyr
1-1107 5,5-diHM-dioxa 2-Cl-Pyr
1-1108 H, H 2-Br-Pyr
1-1109 O = 2-Br-Pyr
1-1110 S = 2-Br-Pyr
1-1111 cPent 2-Br-Pyr
1-1112 cHex 2-Br-Pyr
1-1113 dioxo 2-Br-Pyr
1-1114 dioxa 2-Br-Pyr
1-1115 dithio 2-Br-Pyr
1-1116 dithia 2-Br-Pyr
1-1117 oxathio 2-Br-Pyr
1-1118 oxathia 2-Br-Pyr
1-1119 4-HM-dioxo 2-Br-Pyr
1-1120 4,5-diHM-dioxo 2-Br-Pyr
1-1121 4,5-diHE-dioxo 2-Br-Pyr
1-1122 5-OH-dioxa 2-Br-Pyr
1-1123 5-NHAc-dioxa 2-Br-Pyr
1-1124 5,5-diHM-dioxa 2-Br-Pyr
1-1125 H, H 2,5-diF-Pyr
1-1126 O = 2,5-diF-Pyr
1-1127 S = 2,5-diF-Pyr
1-1128 cPent 2,5-diF-Pyr
1-1129 cHex 2,5-diF-Pyr
1-1130 dioxo 2,5-diF-Pyr
1-1131 dioxa 2,5-diF-Pyr
1-1132 dithio 2,5-diF-Pyr
1-1133 dithia 2,5-diF-Pyr
1-1134 oxathio 2,5-diF-Pyr
1-1135 oxathia 2,5-diF-Pyr
1-1136 4-HM-dioxo 2,5-diF-Pyr
1-1137 4,5-diHM-dioxo 2,5-diF-Pyr
1-1138 4,5-diHE-dioxo 2,5-diF-Pyr
1-1139 5-OH-dioxa 2,5-diF-Pyr
1-1140 5-NHAc-dioxa 2,5-diF-Pyr
1-1141 5,5-diHM-dioxa 2,5-diF-Pyr
1-1142 H, H 2,5-diCl-Pyr
1-1143 O = 2,5-diCl-Pyr
1-1144 S = 2,5-diCl-Pyr
1-1145 cPent 2,5-diCl-Pyr
1-1146 cHex 2,5-diCl-Pyr
1-1147 dioxo 2,5-diCl-Pyr
1-1148 dioxa 2,5-diCl-Pyr
1-1149 dithio 2,5-diCl-Pyr
1-1150 dithia 2,5-diCl-Pyr
1-1151 oxathio 2,5-diCl-Pyr
1-1152 oxathia 2,5-diCl-Pyr
1-1153 4-HM-dioxo 2,5-diCl-Pyr
1-1154 4,5-diHM-dioxo 2,5-diCl-Pyr
1-1155 4,5-diHE-dioxo 2,5-diCl-Pyr
1-1156 5-OH-dioxa 2,5-diCl-Pyr
1-1157 5-NHAc-dioxa 2,5-diCl-Pyr
1-1158 5,5-diHM-dioxa 2,5-diCl-Pyr
1-1159 H, H 2,5-diBr-Pyr
1-1160 O = 2,5-diBr-Pyr
1-1161 S = 2,5-diBr-Pyr
1-1162 cPent 2,5-diBr-Pyr
1-1163 cHex 2,5-diBr-Pyr
1-1164 dioxo 2,5-diBr-Pyr
1-1165 dioxa 2,5-diBr-Pyr
1-1166 dithio 2,5-diBr-Pyr
1-1167 dithia 2,5-diBr-Pyr
1-1168 oxathio 2,5-diBr-Pyr
1-1169 oxathia 2,5-diBr-Pyr
1-1170 4-HM-dioxo 2,5-diBr-Pyr
1-1171 4,5-diHM-dioxo 2,5-diBr-Pyr
1-1172 4,5-diHE-dioxo 2,5-diBr-Pyr
1-1173 5-OH-dioxa 2,5-diBr-Pyr
1-1174 5-NHAc-dioxa 2,5-diBr-Pyr
1-1175 5,5-diHM-dioxa 2,5-diBr-Pyr
1-1176 H, H 2-Me-Pyr
1-1177 O = 2-Me-Pyr
1-1178 S = 2-Me-Pyr
1-1179 cPent 2-Me-Pyr
1-1180 cHex 2-Me-Pyr
1-1181 dioxo 2-Me-Pyr
1-1182 dioxa 2-Me-Pyr
1-1183 dithio 2-Me-Pyr
1-1184 dithia 2-Me-Pyr
1-1185 oxathio 2-Me-Pyr
1-1186 oxathia 2-Me-Pyr
1-1187 4-HM-dioxo 2-Me-Pyr
1-1188 4,5-diHM-dioxo 2-Me-Pyr
1-1189 4,5-diHE-dioxo 2-Me-Pyr
1-1190 5-OH-dioxa 2-Me-Pyr
1-1191 5-NHAc-dioxa 2-Me-Pyr
1-1192 5,5-diHM-dioxa 2-Me-Pyr
1-1193 H, H 2-Et-Pyr
1-1194 O = 2-Et-Pyr
1-1195 S = 2-Et-Pyr
1-1196 cPent 2-Et-Pyr
1-1197 cHex 2-Et-Pyr
1-1198 dioxo 2-Et-Pyr
1-1199 dioxa 2-Et-Pyr
1-1200 dithio 2-Et-Pyr
1-1201 dithia 2-Et-Pyr
1-1202 oxathio 2-Et-Pyr
1-1203 oxathia 2-Et-Pyr
1-1204 4-HM-dioxo 2-Et-Pyr
1-1205 4,5-diHM-dioxo 2-Et-Pyr
1-1206 4,5-diHE-dioxo 2-Et-Pyr
1-1207 5-OH-dioxa 2-Et-Pyr
1-1208 5-NHAc-dioxa 2-Et-Pyr
1-1209 5,5-diHM-dioxa 2-Et-Pyr
1-1210 H, H 2-nPr-Pyr
1-1211 O = 2-nPr-Pyr
1-1212 S = 2-nPr-Pyr
1-1213 cPent 2-nPr-Pyr
1-1214 cHex 2-nPr-Pyr
1-1215 dioxo 2-nPr-Pyr
1-1216 dioxa 2-nPr-Pyr
1-1217 dithio 2-nPr-Pyr
1-1218 dithia 2-nPr-Pyr
1-1219 oxathio 2-nPr-Pyr
1-1220 oxathia 2-nPr-Pyr
1-1221 4-HM-dioxo 2-nPr-Pyr
1-1222 4,5-diHM-dioxo 2-nPr-Pyr
1-1223 4,5-diHE-dioxo 2-nPr-Pyr
1-1224 5-OH-dioxa 2-nPr-Pyr
1-1225 5-NHAc-dioxa 2-nPr-Pyr
1-1226 5,5-diHM-dioxa 2-nPr-Pyr
1-1227 H, H 2-nBu-Pyr
1-1228 O = 2-nBu-Pyr
1-1229 S = 2-nBu-Pyr
1-1230 cPent 2-nBu-Pyr
1-1231 cHex 2-nBu-Pyr
1-1232 dioxo 2-nBu-Pyr
1-1233 dioxa 2-nBu-Pyr
1-1234 dithio 2-nBu-Pyr
1-1235 dithia 2-nBu-Pyr
1-1236 oxathio 2-nBu-Pyr
1-1237 oxathia 2-nBu-Pyr
1-1238 4-HM-dioxo 2-nBu-Pyr
1-1239 4,5-diHM-dioxo 2-nBu-Pyr
1-1240 4,5-diHE-dioxo 2-nBu-Pyr
1-1241 5-OH-dioxa 2-nBu-Pyr
1-1242 5-NHAc-dioxa 2-nBu-Pyr
1-1243 5,5-diHM-dioxa 2-nBu-Pyr
1-1244 H, H 2-nPent-Pyr
1-1245 O = 2-nPent-Pyr
1-1246 S = 2-nPent-Pyr
1-1247 cPent 2-nPent-Pyr
1-1248 cHex 2-nPent-Pyr
1-1249 dioxo 2-nPent-Pyr
1-1250 dioxa 2-nPent-Pyr
1-1251 dithio 2-nPent-Pyr
1-1252 dithia 2-nPent-Pyr
1-1253 oxathio 2-nPent-Pyr
1-1254 oxathia 2-nPent-Pyr
1-1255 4-HM-dioxo 2-nPent-Pyr
1-1256 4,5-diHM-dioxo 2-nPent-Pyr
1-1257 4,5-diHE-dioxo 2-nPent-Pyr
1-1258 5-OH-dioxa 2-nPent-Pyr
1-1259 5-NHAc-dioxa 2-nPent-Pyr
1-1260 5,5-diHM-dioxa 2-nPent-Pyr
1-1261 H, H 2-nHex-Pyr
1-1262 O = 2-nHex-Pyr
1-1263 S = 2-nHex-Pyr
1-1264 cPent 2-nHex-Pyr
1-1265 cHex 2-nHex-Pyr
1-1266 dioxo 2-nHex-Pyr
1-1267 dioxa 2-nHex-Pyr
1-1268 dithio 2-nHex-Pyr
1-1269 dithia 2-nHex-Pyr
1-1270 oxathio 2-nHex-Pyr
1-1271 oxathia 2-nHex-Pyr
1-1272 4-HM-dioxo 2-nHex-Pyr
1-1273 4,5-diHM-dioxo 2-nHex-Pyr
1-1274 4,5-diHE-dioxo 2-nHex-Pyr
1-1275 5-OH-dioxa 2-nHex-Pyr
1-1276 5-NHAc-dioxa 2-nHex-Pyr
1-1277 5,5-diHM-dioxa 2-nHex-Pyr
1-1278 H, H 2-nHept-Pyr
1-1279 O = 2-nHept-Pyr
1-1280 S = 2-nHept-Pyr
1-1281 cPent 2-nHept-Pyr
1-1282 cHex 2-nHept-Pyr
1-1283 dioxo 2-nHept-Pyr
1-1284 dioxa 2-nHept-Pyr
1-1285 dithio 2-nHept-Pyr
1-1286 dithia 2-nHept-Pyr
1-1287 oxathio 2-nHept-Pyr
1-1288 oxathia 2-nHept-Pyr
1-1289 4-HM-dioxo 2-nHept-Pyr
1-1290 4,5-diHM-dioxo 2-nHept-Pyr
1-1291 4,5-diHE-dioxo 2-nHept-Pyr
1-1292 5-OH-dioxa 2-nHept-Pyr
1-1293 5-NHAc-dioxa 2-nHept-Pyr
1-1294 5,5-diHM-dioxa 2-nHept-Pyr
1-1295 H, H 2-nOct-Pyr
1-1296 O = 2-nOct-Pyr
1-1297 S = 2-nOct-Pyr
1-1298 cPent 2-nOct-Pyr
1-1299 cHex 2-nOct-Pyr
1-1300 dioxo 2-nOct-Pyr
1-1301 dioxa 2-nOct-Pyr
1-1302 dithio 2-nOct-Pyr
1-1303 dithia 2-nOct-Pyr
1-1304 oxathio 2-nOct-Pyr
1-1305 oxathia 2-nOct-Pyr
1-1306 4-HM-dioxo 2-nOct-Pyr
1-1307 4,5-diHM-dioxo 2-nOct-Pyr
1-1308 4,5-diHE-dioxo 2-nOct-Pyr
1-1309 5-OH-dioxa 2-nOct-Pyr
1-1310 5-NHAc-dioxa 2-nOct-Pyr
1-1311 5,5-diHM-dioxa 2-nOct-Pyr
1-1312 H, H 2-cPrl-Pyr
1-1313 O = 2-cPrl-Pyr
1-1314 S = 2-cPrl-Pyr
1-1315 cPent 2-cPrl-Pyr
1-1316 cHex 2-cPrl-Pyr
1-1317 dioxo 2-cPrl-Pyr
1-1318 dioxa 2-cPrl-Pyr
1-1319 dithio 2-cPrl-Pyr
1-1320 dithia 2-cPrl-Pyr
1-1321 oxathio 2-cPrl-Pyr
1-1322 oxathia 2-cPrl-Pyr
1-1323 4-HM-dioxo 2-cPrl-Pyr
1-1324 4,5-diHM-dioxo 2-cPrl-Pyr
1-1325 4,5-diHE-dioxo 2-cPrl-Pyr
1-1326 5-OH-dioxa 2-cPrl-Pyr
1-1327 5-NHAc-dioxa 2-cPrl-Pyr
1-1328 5,5-diHM-dioxa 2-cPrl-Pyr
1-1329 H, H 2-Ph-Pyr
1-1330 O = 2-Ph-Pyr
1-1331 S = 2-Ph-Pyr
1-1332 cPent 2-Ph-Pyr
1-1333 cHex 2-Ph-Pyr
1-1334 dioxo 2-Ph-Pyr
1-1335 dioxa 2-Ph-Pyr
1-1336 dithio 2-Ph-Pyr
1-1337 dithia 2-Ph-Pyr
1-1338 oxathio 2-Ph-Pyr
1-1339 oxathia 2-Ph-Pyr
1-1340 4-HM-dioxo 2-Ph-Pyr
1-1341 4,5-diHM-dioxo 2-Ph-Pyr
1-1342 4,5-diHE-dioxo 2-Ph-Pyr
1-1343 5-OH-dioxa 2-Ph-Pyr
1-1344 5-NHAc-dioxa 2-Ph-Pyr
1-1345 5,5-diHM-dioxa 2-Ph-Pyr
1-1346 H, H 2,5-diMe-Pyr
1-1347 O = 2,5-diMe-Pyr
1-1348 S = 2,5-diMe-Pyr
1-1349 cPent 2,5-diMe-Pyr
1-1350 cHex 2,5-diMe-Pyr
1-1351 dioxo 2,5-diMe-Pyr
1-1352 dioxa 2,5-diMe-Pyr
1-1353 dithio 2,5-diMe-Pyr
1-1354 dithia 2,5-diMe-Pyr
1-1355 oxathio 2,5-diMe-Pyr
1-1356 oxathia 2,5-diMe-Pyr
1-1357 4-HM-dioxo 2,5-diMe-Pyr
1-1358 4,5-diHM-dioxo 2,5-diMe-Pyr
1-1359 4,5-diHE-dioxo 2,5-diMe-Pyr
1-1360 5-OH-dioxa 2,5-diMe-Pyr
1-1361 5-NHAc-dioxa 2,5-diMe-Pyr
1-1362 5,5-diHM-dioxa 2,5-diMe-Pyr
1-1363 O = 2-Br-Ph
1-1364 S = 2-Br-Ph
1-1365 cPr 2-Br-Ph
1-1366 cBu 2-Br-Ph
1-1367 cPent 2-Br-Ph
1-1368 cHex 2-Br-Ph
1-1369 cHept 2-Br-Ph
1-1370 oxi 2-Br-Ph
1-1371 oxe 2-Br-Ph
1-1372 oxo 2-Br-Ph
1-1373 oxa 2-Br-Ph
1-1374 dioxo 2-Br-Ph
1-1375 dioxa 2-Br-Ph
1-1376 dioxe 2-Br-Ph
1-1377 dithio 2-Br-Ph
1-1378 dithia 2-Br-Ph
1-1379 Ring 1 2-Br-Ph
1-1380 Ring 2 2-Br-Ph
1-1381 oxathio 2-Br-Ph
1-1382 oxathia 2-Br-Ph
1-1383 ozl 2-Br-Ph
1-1384 ozn 2-Br-Ph
1-1385 tzl 2-Br-Ph
1-1386 tzn 2-Br-Ph
1-1387 3-HM-cPent 2-Br-Ph
1-1388 4-HM-dioxo 2-Br-Ph
1-1389 4-HM-dithio 2-Br-Ph
1-1390 4-HM-oxathio 2-Br-Ph
1-1391 3,4-diHM-cPent 2-Br-Ph
1-1392 4,5-diHM-dioxo 2-Br-Ph
1-1393 4,5-diHM-dithio 2-Br-Ph
1-1394 4,5-diHM-oxathio 2-Br-Ph
1-1395 3,4-diHE-cPent 2-Br-Ph
1-1396 4,5-diHE-dioxo 2-Br-Ph
1-1397 4,5-diHE-dithio 2-Br-Ph
1-1398 4,5-diHE-oxathio 2-Br-Ph
1-1399 3-HE-cPent 2-Br-Ph
1-1400 4-HE-dioxo 2-Br-Ph
1-1401 4-HE-dithio 2-Br-Ph
1-1402 4-HE-oxathio 2-Br-Ph
1-1403 3-HP-cPent 2-Br-Ph
1-1404 4-HP-dioxo 2-Br-Ph
1-1405 4-HP-dithio 2-Br-Ph
1-1406 4-HP-oxathio 2-Br-Ph
1-1407 3-HB-cPent 2-Br-Ph
1-1408 4-HB-dioxo 2-Br-Ph
1-1409 4-HB-dithio 2-Br-Ph
1-1410 4-HB-oxathio 2-Br-Ph
1-1411 Ring 3 2-Br-Ph
1-1412 Ring 4 2-Br-Ph
1-1413 Ring 5 2-Br-Ph
1-1414 Ring 6 2-Br-Ph
1-1415 Ring 7 2-Br-Ph
1-1416 Ring 8 2-Br-Ph
1-1417 Ring 9 2-Br-Ph
1-1418 Ring 10 2-Br-Ph
1-1419 3,4-diCH₂NHAc-cPent 2-Br-Ph
1-1420 4,5-diCH₂NHAc-dioxo 2-Br-Ph
1-1421 4,5-diCH₂NHAc-dithio 2-Br-Ph
1-1422 4,5-diCH₂NHAc-oxathio 2-Br-Ph
1-1423 ring 11 2-Br-Ph
1-1424 Ring 12 2-Br-Ph
1-1425 Ring 13 2-Br-Ph
1-1426 Ring 14 2-Br-Ph
1-1427 4-OH-cHex 2-Br-Ph
1-1428 5-OH-dioxa 2-Br-Ph
1-1429 5-OH-dithia 2-Br-Ph
1-1430 5-OH-oxathia 2-Br-Ph
1-1431 4-NHAc-cHex 2-Br-Ph
1-1432 5-NHAc-dioxa 2-Br-Ph
1-1433 5-NHAc-dithia 2-Br-Ph
1-1434 5-NHAc-oxathia 2-Br-Ph
1-1435 4,4-diMe-cHex 2-Br-Ph
1-1436 5,5-diMe-dioxa 2-Br-Ph
1-1437 5,5-diMe-dithia 2-Br-Ph
1-1438 5,5-diMe-oxathia 2-Br-Ph
1-1439 4,4-diHM-cHex 2-Br-Ph
1-1440 5,5-diHM-dioxa 2-Br-Ph
1-1441 5,5-diHM-dithia 2-Br-Ph
1-1442 5,5-diHM-oxathia 2-Br-Ph
1-1443 Ring 15 2-Br-Ph
1-1444 Ring 16 2-Br-Ph
1-1445 Ring 17 2-Br-Ph
1-1446 Ring 18 2-Br-Ph
1-1447 4,4-diCO₂Et-cHex 2-Br-Ph
1-1448 5,5-diCO₂Et-dioxa 2-Br-Ph
1-1449 5,5-diCO₂Et-dithia 2-Br-Ph
1-1450 5,5-diCO₂Et-oxathia 2-Br-Ph
1-1451 O = 2-Cl-6-Me-Ph
1-1452 S = 2-Cl-6-Me-Ph
1-1453 cPr 2-Cl-6-Me-Ph
1-1454 cBu 2-Cl-6-Me-Ph
1-1455 cPent 2-Cl-6-Me-Ph
1-1456 cHex 2-Cl-6-Me-Ph
1-1457 cHept 2-Cl-6-Me-Ph
1-1458 oxi 2-Cl-6-Me-Ph
1-1459 oxe 2-Cl-6-Me-Ph
1-1460 oxo 2-Cl-6-Me-Ph
1-1461 oxa 2-Cl-6-Me-Ph
1-1462 dioxo 2-Cl-6-Me-Ph
1-1463 dioxa 2-Cl-6-Me-Ph
1-1464 dioxe 2-Cl-6-Me-Ph
1-1465 dithio 2-Cl-6-Me-Ph
1-1466 dithia 2-Cl-6-Me-Ph
1-1467 Ring 1 2-Cl-6-Me-Ph
1-1468 Ring 2 2-Cl-6-Me-Ph
1-1469 oxathio 2-Cl-6-Me-Ph
1-1470 oxathia 2-Cl-6-Me-Ph
1-1471 ozl 2-Cl-6-Me-Ph
1-1472 ozn 2-Cl-6-Me-Ph
1-1473 tzl 2-Cl-6-Me-Ph
1-1474 tzn 2-Cl-6-Me-Ph
1-1475 3-HM-cPent 2-Cl-6-Me-Ph
1-1476 4-HM-dioxo 2-Cl-6-Me-Ph
1-1477 4-HM-dithio 2-Cl-6-Me-Ph
1-1478 4-HM-oxathio 2-Cl-6-Me-Ph
1-1479 3,4-diHM-cPent 2-Cl-6-Me-Ph
1-1480 4,5-diHM-dioxo 2-Cl-6-Me-Ph
1-1481 4,5-diHM-dithio 2-Cl-6-Me-Ph
1-1482 4,5-diHM-oxathio 2-Cl-6-Me-Ph
1-1483 3,4-diHE-cPent 2-Cl-6-Me-Ph
1-1484 4,5-diHE-dioxo 2-Cl-6-Me-Ph
1-1485 4,5-diHE-dithio 2-Cl-6-Me-Ph
1-1486 4,5-diHE-oxathio 2-Cl-6-Me-Ph
1-1487 3-HE-cPent 2-Cl-6-Me-Ph
1-1488 4-HE-dioxo 2-Cl-6-Me-Ph
1-1489 4-HE-dithio 2-Cl-6-Me-Ph
1-1490 4-HE-oxathio 2-Cl-6-Me-Ph
1-1491 3-HP-cPent 2-Cl-6-Me-Ph
1-1492 4-HP-dioxo 2-Cl-6-Me-Ph
1-1493 4-HP-dithio 2-Cl-6-Me-Ph
1-1494 4-HP-oxathio 2-Cl-6-Me-Ph
1-1495 3-HB-cPent 2-Cl-6-Me-Ph
1-1496 4-HB-dioxo 2-Cl-6-Me-Ph
1-1497 4-HB-dithio 2-Cl-6-Me-Ph
1-1498 4-HB-oxathio 2-Cl-6-Me-Ph
1-1499 Ring 3 2-Cl-6-Me-Ph
1-1500 Ring 4 2-Cl-6-Me-Ph
1-1501 Ring 5 2-Cl-6-Me-Ph
1-1502 Ring 6 2-Cl-6-Me-Ph
1-1503 Ring 7 2-Cl-6-Me-Ph
1-1504 Ring 8 2-Cl-6-Me-Ph
1-1505 Ring 9 2-Cl-6-Me-Ph
1-1506 Ring 10 2-Cl-6-Me-Ph
1-1507 3,4-diCH₂NHAc-cPent 2-Cl-6-Me-Ph
1-1508 4,5-diCH₂NHAc-dioxo 2-Cl-6-Me-Ph
1-1509 4,5-diCH₂NHAc-dithio 2-Cl-6-Me-Ph
1-1510 4,5-diCH₂NHAc-oxathio 2-Cl-6-Me-Ph
1-1511 Ring 11 2-Cl-6-Me-Ph
1-1512 Ring 12 2-Cl-6-Me-Ph
1-1513 Ring 13 2-Cl-6-Me-Ph
1-1514 Ring 14 2-Cl-6-Me-Ph
1-1515 4-OH-cHex 2-Cl-6-Me-Ph
1-1516 5-OH-dioxa 2-Cl-6-Me-Ph
1-1517 5-OH-dithia 2-Cl-6-Me-Ph
1-1518 5-OH-oxathia 2-Cl-6-Me-Ph
1-1519 4-NHAc-cHex 2-Cl-6-Me-Ph
1-1520 5-NHAc-dioxa 2-Cl-6-Me-Ph
1-1521 5-NHAc-dithia 2-Cl-6-Me-Ph
1-1522 5-NHAc-oxathia 2-Cl-6-Me-Ph
1-1523 4,4-diMe-cHex 2-Cl-6-Me-Ph
1-1524 5,5-diMe-dioxa 2-Cl-6-Me-Ph
1-1525 5,5-diMe-dithia 2-Cl-6-Me-Ph
1-1526 5,5-diMe-oxathia 2-Cl-6-Me-Ph
1-1527 4,4-diHM-cHex 2-Cl-6-Me-Ph
1-1528 5,5-diHM-dioxa 2-Cl-6-Me-Ph
1-1529 5,5-diHM-dithia 2-Cl-6-Me-Ph
1-1530 5,5-diHM-oxathia 2-Cl-6-Me-Ph
1-1531 Ring 15 2-Cl-6-Me-Ph
1-1532 Ring 16 2-Cl-6-Me-Ph
1-1533 Ring 17 2-Cl-6-Me-Ph
1-1534 Ring 18 2-Cl-6-Me-Ph
1-1535 4,4-diCO₂Et-cHex 2-Cl-6-Me-Ph
1-1536 5,5-diCO₂Et-dioxa 2-Cl-6-Me-Ph
1-1537 5,5-diCO₂Et-dithia 2-Cl-6-Me-Ph
1-1538 5,5-diCO₂Et-oxathia 2-Cl-6-Me-Ph
1-1539 O = 2-Br-4-F-Ph
1-1540 S = 2-Br-4-F-Ph
1-1541 cPr 2-Br-4-F-Ph
1-1542 cBu 2-Br-4-F-Ph
1-1543 cPent 2-Br-4-F-Ph
1-1544 cHex 2-Br-4-F-Ph
1-1545 cHept 2-Br-4-F-Ph
1-1546 oxi 2-Br-4-F-Ph
1-1547 oxe 2-Br-4-F-Ph
1-1548 oxo 2-Br-4-F-Ph
1-1549 oxa 2-Br-4-F-Ph
1-1550 dioxo 2-Br-4-F-Ph
1-1551 dioxa 2-Br-4-F-Ph
1-1552 dioxe 2-Br-4-F-Ph
1-1553 dithio 2-Br-4-F-Ph
1-1554 dithia 2-Br-4-F-Ph
1-1555 Ring 1 2-Br-4-F-Ph
1-1556 Ring 2 2-Br-4-F-Ph
1-1557 oxathio 2-Br-4-F-Ph
1-1558 oxathia 2-Br-4-F-Ph
1-1559 ozl 2-Br-4-F-Ph
1-1560 ozn 2-Br-4-F-Ph
1-1561 tzl 2-Br-4-F-Ph
1-1562 tzn 2-Br-4-F-Ph
1-1563 3-HM-cPent 2-Br-4-F-Ph
1-1564 4-HM-dioxo 2-Br-4-F-Ph
1-1565 4-HM-dithio 2-Br-4-F-Ph
1-1566 4-HM-oxathio 2-Br-4-F-Ph
1-1567 3,4-diHM-cPent 2-Br-4-F-Ph
1-1568 4,5-diHM-dioxo 2-Br-4-F-Ph
1-1569 4,5-diHM-dithio 2-Br-4-F-Ph
1-1570 4,5-diHM-oxathio 2-Br-4-F-Ph
1-1571 3,4-diHE-cPent 2-Br-4-F-Ph
1-1572 4,5-diHE-dioxo 2-Br-4-F-Ph
1-1573 4,5-diHE-dithio 2-Br-4-F-Ph
1-1574 4,5-diHE-oxathio 2-Br-4-F-Ph
1-1575 3-HE-cPent 2-Br-4-F-Ph
1-1576 4-HE-dioxo 2-Br-4-F-Ph
1-1577 4-HE-dithio 2-Br-4-F-Ph
1-1578 4-HE-oxathio 2-Br-4-F-Ph
1-1579 3-HP-cPent 2-Br-4-F-Ph
1-1580 4-HP-dioxo 2-Br-4-F-Ph
1-1581 4-HP-dithio 2-Br-4-F-Ph
1-1582 4-HP-oxathio 2-Br-4-F-Ph
1-1583 3-HB-cPent 2-Br-4-F-Ph
1-1584 4-HB-dioxo 2-Br-4-F-Ph
1-1585 4-HB-dithio 2-Br-4-F-Ph
1-1586 4-HB-oxathio 2-Br-4-F-Ph
1-1587 Ring 3 2-Br-4-F-Ph
1-1588 Ring 4 2-Br-4-F-Ph
1-1589 Ring 5 2-Br-4-F-Ph
1-1590 Ring 6 2-Br-4-F-Ph
1-1591 Ring 7 2-Br-4-F-Ph
1-1592 Ring 8 2-Br-4-F-Ph
1-1593 Ring 9 2-Br-4-F-Ph
1-1594 Ring 10 2-Br-4-F-Ph
1-1595 3,4-diCH₂NHAc-cPent 2-Br-4-F-Ph
1-1596 4,5-diCH₂NHAc-dioxo 2-Br-4-F-Ph
1-1597 4,5-diCH₂NHAc-dithio 2-Br-4-F-Ph
1-1598 4,5-diCH₂NHAc-oxathio 2-Br-4-F-Ph
1-1599 Ring 11 2-Br-4-F-Ph
1-1600 Ring 12 2-Br-4-F-Ph
1-1601 Ring 13 2-Br-4-F-Ph
1-1602 Ring 14 2-Br-4-F-Ph
1-1603 4-OH-cHex 2-Br-4-F-Ph
1-1604 5-OH-dioxa 2-Br-4-F-Ph
1-1605 5-OH-dithia 2-Br-4-F-Ph
1-1606 5-OH-oxathia 2-Br-4-F-Ph
1-1607 4-NHAc-cHex 2-Br-4-F-Ph
1-1608 5-NHAc-dioxa 2-Br-4-F-Ph
1-1609 5-NHAc-dithia 2-Br-4-F-Ph
1-1610 5-NHAc-oxathia 2-Br-4-F-Ph
1-1611 4,4-diMe-cHex 2-Br-4-F-Ph
1-1612 5,5-diMe-dioxa 2-Br-4-F-Ph
1-1613 5,5-diMe-dithia 2-Br-4-F-Ph
1-1614 5,5-diMe-oxathia 2-Br-4-F-Ph
1-1615 4,4-diHM-cHex 2-Br-4-F-Ph
1-1616 5,5-diHM-dioxa 2-Br-4-F-Ph
1-1617 5,5-diHM-dithia 2-Br-4-F-Ph
1-1618 5,5-diHM-oxathia 2-Br-4-F-Ph
1-1619 Ring 15 2-Br-4-F-Ph
1-1620 Ring 16 2-Br-4-F-Ph
1-1621 Ring 17 2-Br-4-F-Ph
1-1622 Ring 18 2-Br-4-F-Ph
1-1623 4,4-diCO₂Et-cHex 2-Br-4-F-Ph
1-1624 5,5-diCO₂Et-dioxa 2-Br-4-F-Ph
1-1625 5,5-diCO₂Et-dithia 2-Br-4-F-Ph
1-1626 5,5-diCO₂Et-oxathia 2-Br-4-F-Ph
1-1627 O = 2-nPent-Ph
1-1628 S = 2-nPent-Ph
1-1629 cPr 2-nPent-Ph
1-1630 cBu 2-nPent-Ph
1-1631 cPent 2-nPent-Ph
1-1632 cHex 2-nPent-Ph
1-1633 cHept 2-nPent-Ph
1-1634 oxi 2-nPent-Ph
1-1635 oxe 2-nPent-Ph
1-1636 oxo 2-nPent-Ph
1-1637 oxa 2-nPent-Ph
1-1638 dioxo 2-nPent-Ph
1-1639 dioxa 2-nPent-Ph
1-1640 dioxe 2-nPent-Ph
1-1641 dithio 2-nPent-Ph
1-1642 dithia 2-nPent-Ph
1-1643 Ring 1 2-nPent-Ph
1-1644 Ring 2 2-nPent-Ph
1-1645 oxathio 2-nPent-Ph
1-1646 oxathia 2-nPent-Ph
1-1647 ozl 2-nPent-Ph
1-1648 ozn 2-nPent-Ph
1-1649 tzl 2-nPent-Ph
1-1650 tzn 2-nPent-Ph
1-1651 3-HM-cPent 2-nPent-Ph
1-1652 4-HM-dioxo 2-nPent-Ph
1-1653 4-HM-dithio 2-nPent-Ph
1-1654 4-HM-oxathio 2-nPent-Ph
1-1655 3,4-diHM-cPent 2-nPent-Ph
1-1656 4,5-diHM-dioxo 2-nPent-Ph
1-1657 4,5-diHM-dithio 2-nPent-Ph
1-1658 4,5-diHM-oxathio 2-nPent-Ph
1-1659 3,4-diHE-cPent 2-nPent-Ph
1-1660 4,5-diHE-dioxo 2-nPent-Ph
1-1661 4,5-diHE-dithio 2-nPent-Ph
1-1662 4,5-diHE-oxathio 2-nPent-Ph
1-1663 3-HE-cPent 2-nPent-Ph
1-1664 4-HE-dioxo 2-nPent-Ph
1-1665 4-HE-dithio 2-nPent-Ph
1-1666 4-HE-oxathio 2-nPent-Ph
1-1667 3-HP-cPent 2-nPent-Ph
1-1668 4-HP-dioxo 2-nPent-Ph
1-1669 4-HP-dithio 2-nPent-Ph
1-1670 4-HP-oxathio 2-nPent-Ph
1-1671 3-HB-cPent 2-nPent-Ph
1-1672 4-HB-dioxo 2-nPent-Ph
1-1673 4-HB-dithio 2-nPent-Ph
1-1674 4-HB-oxathio 2-nPent-Ph
1-1675 Ring 3 2-nPent-Ph
1-1676 Ring 4 2-nPent-Ph
1-1677 Ring 5 2-nPent-Ph
1-1678 Ring 6 2-nPent-Ph
1-1679 Ring 7 2-nPent-Ph
1-1680 Ring 8 2-nPent-Ph
1-1681 Ring 9 2-nPent-Ph
1-1682 ring 10 2-nPent-Ph
1-1683 3,4-diCH₂NHAc-cPent 2-nPent-Ph
1-1684 4,5-diCH₂NHAc-dioxo 2-nPent-Ph
1-1685 4,5-diCH₂NHAc-dithio 2-nPent-Ph
1-1686 4,5-diCH₂NHAc-oxathio 2-nPent-Ph
1-1687 Ring 11 2-nPent-Ph
1-1688 Ring 12 2-nPent-Ph
1-1689 Ring 13 2-nPent-Ph
1-1690 Ring 14 2-nPent-Ph
1-1691 4-OH-cHex 2-nPent-Ph
1-1692 5-OH-dioxa 2-nPent-Ph
1-1693 5-OH-dithia 2-nPent-Ph
1-1694 5-OH-oxathia 2-nPent-Ph
1-1695 4-NHAc-cHex 2-nPent-Ph
1-1696 5-NHAc-dioxa 2-nPent-Ph
1-1697 5-NHAc-dithia 2-nPent-Ph
1-1698 5-NHAc-oxathia 2-nPent-Ph
1-1699 4,4-diMe-cHex 2-nPent-Ph
1-1700 5,5-diMe-dioxa 2-nPent-Ph
1-1701 5,5-diMe-dithia 2-nPent-Ph
1-1702 5,5-diMe-oxathia 2-nPent-Ph
1-1703 4,4-diHM-cHex 2-nPent-Ph
1-1704 5,5-diHM-dioxa 2-nPent-Ph
1-1705 5,5-diHM-dithia 2-nPent-Ph
1-1706 5,5-diHM-oxathia 2-nPent-Ph
1-1707 Ring 15 2-nPent-Ph
1-1708 Ring 16 2-nPent-Ph
1-1709 Ring 17 2-nPent-Ph
1-1710 Ring 18 2-nPent-Ph
1-1711 4,4-diCO₂Et-cHex 2-nPent-Ph
1-1712 5,5-diCO₂Et-dioxa 2-nPent-Ph
1-1713 5,5-diCO₂Et-dithia 2-nPent-Ph
1-1714 5,5-diCO₂Et-oxathia 2-nPent-Ph
1-1715 O = 4-F-2-nPent-Ph
1-1716 S = 4-F-2-nPent-Ph
1-1717 cPr 4-F-2-nPent-Ph
1-1718 cBu 4-F-2-nPent-Ph
1-1719 cPent 4-F-2-nPent-Ph
1-1720 cHex 4-F-2-nPent-Ph
1-1721 cHept 4-F-2-nPent-Ph
1-1722 oxi 4-F-2-nPent-Ph
1-1723 oxe 4-F-2-nPent-Ph
1-1724 oxo 4-F-2-nPent-Ph
1-1725 oxa 4-F-2-nPent-Ph
1-1726 dioxo 4-F-2-nPent-Ph
1-1727 dioxa 4-F-2-nPent-Ph
1-1728 dioxe 4-F-2-nPent-Ph
1-1729 dithio 4-F-2-nPent-Ph
1-1730 dithia 4-F-2-nPent-Ph
1-1731 Ring 1 4-F-2-nPent-Ph
1-1732 Ring 2 4-F-2-nPent-Ph
1-1733 oxathio 4-F-2-nPent-Ph
1-1734 oxathia 4-F-2-nPent-Ph
1-1735 ozl 4-F-2-nPent-Ph
1-1736 ozn 4-F-2-nPent-Ph
1-1737 tzl 4-F-2-nPent-Ph
1-1738 tzn 4-F-2-nPent-Ph
1-1739 3-HM-cPent 4-F-2-nPent-Ph
1-1740 4-HM-dioxo 4-F-2-nPent-Ph
1-1741 4-HM-dithio 4-F-2-nPent-Ph
1-1742 4-HM-oxathio 4-F-2-nPent-Ph
1-1743 3,4-diHM-cPent 4-F-2-nPent-Ph
1-1744 4,5-diHM-dioxo 4-F-2-nPent-Ph
1-1745 4,5-diHM-dithio 4-F-2-nPent-Ph
1-1746 4,5-diHM-oxathio 4-F-2-nPent-Ph
1-1747 3,4-diHE-cPent 4-F-2-nPent-Ph
1-1748 4,5-diHE-dioxo 4-F-2-nPent-Ph
1-1749 4,5-diHE-dithio 4-F-2-nPent-Ph
1-1750 4,5-diHE-oxathio 4-F-2-nPent-Ph
1-1751 3-HE-cPent 4-F-2-nPent-Ph
1-1752 4-HE-dioxo 4-F-2-nPent-Ph
1-1753 4-HE-dithio 4-F-2-nPent-Ph
1-1754 4-HE-oxathio 4-F-2-nPent-Ph
1-1755 3-HP-cPent 4-F-2-nPent-Ph
1-1756 4-HP-dioxo 4-F-2-nPent-Ph
1-1757 4-HP-dithio 4-F-2-nPent-Ph
1-1758 4-HP-oxathio 4-F-2-nPent-Ph
1-1759 3-HB-cPent 4-F-2-nPent-Ph
1-1760 4-HB-dioxo 4-F-2-nPent-Ph
1-1761 4-HB-dithio 4-F-2-nPent-Ph
1-1762 4-HB-oxathio 4-F-2-nPent-Ph
1-1763 Ring 3 4-F-2-nPent-Ph
1-1764 Ring 4 4-F-2-nPent-Ph
1-1765 Ring 5 4-F-2-nPent-Ph
1-1766 Ring 6 4-F-2-nPent-Ph
1-1767 Ring 7 4-F-2-nPent-Ph
1-1768 Ring 8 4-F-2-nPent-Ph
1-1769 Ring 9 4-F-2-nPent-Ph
1-1770 Ring 10 4-F-2-nPent-Ph
1-1771 3,4-diCH₂NHAc-cPent 4-F-2-nPent-Ph
1-1772 4,5-diCH₂NHAc-dioxo 4-F-2-nPent-Ph
1-1773 4,5-diCH₂NHAc-dithio 4-F-2-nPent-Ph
1-1774 4,5-diCH₂NHAc-oxathio 4-F-2-nPent-Ph
1-1775 Ring 11 4-F-2-nPent-Ph
1-1776 Ring 12 4-F-2-nPent-Ph
1-1777 Ring 13 4-F-2-nPent-Ph
1-1778 Ring 14 4-F-2-nPent-Ph
1-1779 4-OH-cHex 4-F-2-nPent-Ph
1-1780 5-OH-dioxa 4-F-2-nPent-Ph
1-1781 5-OH-dithia 4-F-2-nPent-Ph
1-1782 5-OH-oxathia 4-F-2-nPent-Ph
1-1783 4-NHAc-cHex 4-F-2-nPent-Ph
1-1784 5-NHAc-dioxa 4-F-2-nPent-Ph
1-1785 5-NHAc-dithia 4-F-2-nPent-Ph
1-1786 5-NHAc-oxathia 4-F-2-nPent-Ph
1-1787 4,4-diMe-cHex 4-F-2-nPent-Ph
1-1788 5,5-diMe-dioxa 4-F-2-nPent-Ph
1-1789 5,5-diMe-dithia 4-F-2-nPent-Ph
1-1790 5,5-diMe-oxathia 4-F-2-nPent-Ph
1-1791 4,4-diHM-cHex 4-F-2-nPent-Ph
1-1792 5,5-diHM-dioxa 4-F-2-nPent-Ph
1-1793 5,5-diHM-dithia 4-F-2-nPent-Ph
1-1794 5,5-diHM-oxathia 4-F-2-nPent-Ph
1-1795 Ring 15 4-F-2-nPent-Ph
1-1796 Ring 16 4-F-2-nPent-Ph
1-1797 Ring 17 4-F-2-nPent-Ph
1-1798 ring 18 4-F-2-nPent-Ph
1-1799 4,4-diCO₂Et-cHex 4-F-2-nPent-Ph
1-1800 5,5-diCO₂Et-dioxa 4-F-2-nPent-Ph
1-1801 5,5-diCO₂Et-dithia 4-F-2-nPent-Ph
1-1802 5,5-diCO₂Et-oxathia 4-F-2-nPent-Ph
1-1803 O = 2-nOct-Ph
1-1804 S = 2-nOct-Ph
1-1805 cPr 2-nOct-Ph
1-1806 cBu 2-nOct-Ph
1-1807 cPent 2-nOct-Ph
1-1808 cHex 2-nOct-Ph
1-1809 cHept 2-nOct-Ph
1-1810 oxi 2-nOct-Ph
1-1811 oxe 2-nOct-Ph
1-1812 oxo 2-nOct-Ph
1-1813 oxa 2-nOct-Ph
1-1814 dioxo 2-nOct-Ph
1-1815 dioxa 2-nOct-Ph
1-1816 dioxe 2-nOct-Ph
1-1817 dithio 2-nOct-Ph
1-1818 dithia 2-nOct-Ph
1-1819 Ring 1 2-nOct-Ph
1-1820 Ring 2 2-nOct-Ph
1-1821 oxathio 2-nOct-Ph
1-1822 oxathia 2-nOct-Ph
1-1823 ozl 2-nOct-Ph
1-1824 ozn 2-nOct-Ph
1-1825 tzl 2-nOct-Ph
1-1826 tzn 2-nOct-Ph
1-1827 3-HM-cPent 2-nOct-Ph
1-1828 4-HM-dioxo 2-nOct-Ph
1-1829 4-HM-dithio 2-nOct-Ph
1-1830 4-HM-oxathio 2-nOct-Ph
1-1831 3,4-diHM-cPent 2-nOct-Ph
1-1832 4,5-diHM-dioxo 2-nOct-Ph
1-1833 4,5-diHM-dithio 2-nOct-Ph
1-1834 4,5-diHM-oxathio 2-nOct-Ph
1-1835 3,4-diHE-cPent 2-nOct-Ph
1-1836 4,5-diHE-dioxo 2-nOct-Ph
1-1837 4,5-diHE-dithio 2-nOct-Ph
1-1838 4,5-diHE-oxathio 2-nOct-Ph
1-1839 3-HE-cPent 2-nOct-Ph
1-1840 4-HE-dioxo 2-nOct-Ph
1-1841 4-HE-dithio 2-nOct-Ph
1-1842 4-HE-oxathio 2-nOct-Ph
1-1843 3-HP-cPent 2-nOct-Ph
1-1844 4-HP-dioxo 2-nOct-Ph
1-1845 4-HP-dithio 2-nOct-Ph
1-1846 4-HP-oxathio 2-nOct-Ph
1-1847 3-HB-cPent 2-nOct-Ph
1-1848 4-HB-dioxo 2-nOct-Ph
1-1849 4-HB-dithio 2-nOct-Ph
1-1850 4-HB-oxathio 2-nOct-Ph
1-1851 Ring 3 2-nOct-Ph
1-1852 Ring 4 2-nOct-Ph
1-1853 Ring 5 2-nOct-Ph
1-1854 Ring 6 2-nOct-Ph
1-1855 Ring 7 2-nOct-Ph
1-1856 Ring 8 2-nOct-Ph
1-1857 Ring 9 2-nOct-Ph
1-1858 Ring 10 2-nOct-Ph
1-1859 3,4-diCH₂NHAc-cPent 2-nOct-Ph
1-1860 4,5-diCH₂NHAc-dioxo 2-nOct-Ph
1-1861 4,5-diCH₂NHAc-dithio 2-nOct-Ph
1-1862 4,5-diCH₂NHAc-oxathio 2-nOct-Ph
1-1863 ring 11 2-nOct-Ph
1-1864 Ring 12 2-nOct-Ph
1-1865 Ring 13 2-nOct-Ph
1-1866 Ring 14 2-nOct-Ph
1-1867 4-OH-cHex 2-nOct-Ph
1-1868 5-OH-dioxa 2-nOct-Ph
1-1869 5-OH-dithia 2-nOct-Ph
1-1870 5-OH-oxathia 2-nOct-Ph
1-1871 4-NHAc-cHex 2-nOct-Ph
1-1872 5-NHAc-dioxa 2-nOct-Ph
1-1873 5-NHAc-dithia 2-nOct-Ph
1-1874 5-NHAc-oxathia 2-nOct-Ph
1-1875 4,4-diMe-cHex 2-nOct-Ph
1-1876 5,5-diMe-dioxa 2-nOct-Ph
1-1877 5,5-diMe-dithia 2-nOct-Ph
1-1878 5,5-diMe-oxathia 2-nOct-Ph
1-1879 4,4-diHM-cHex 2-nOct-Ph
1-1880 5,5-diHM-dioxa 2-nOct-Ph
1-1881 5,5-diHM-dithia 2-nOct-Ph
1-1882 5,5-diHM-oxathia 2-nOct-Ph
1-1883 Ring 15 2-nOct-Ph
1-1884 Ring 16 2-nOct-Ph
1-1885 Ring 17 2-nOct-Ph
1-1886 ring 18 2-nOct-Ph
1-1887 4,4-diCO₂Et-cHex 2-nOct-Ph
1-1888 5,5-diCO₂Et-dioxa 2-nOct-Ph
1-1889 5,5-diCO₂Et-dithia 2-nOct-Ph
1-1890 5,5-diCO₂Et-oxathia 2-nOct-Ph
1-1891 O = 4-F-2-nOct-Ph
1-1892 S = 4-F-2-nOct-Ph
1-1893 cPr 4-F-2-nOct-Ph
1-1894 cBu 4-F-2-nOct-Ph
1-1895 cPent 4-F-2-nOct-Ph
1-1896 cHex 4-F-2-nOct-Ph
1-1897 cHept 4-F-2-nOct-Ph
1-1898 oxi 4-F-2-nOct-Ph
1-1899 oxe 4-F-2-nOct-Ph
1-1900 oxo 4-F-2-nOct-Ph
1-1901 oxa 4-F-2-nOct-Ph
1-1902 dioxo 4-F-2-nOct-Ph
1-1903 dioxa 4-F-2-nOct-Ph
1-1904 dioxe 4-F-2-nOct-Ph
1-1905 dithio 4-F-2-nOct-Ph
1-1906 dithia 4-F-2-nOct-Ph
1-1907 Ring 1 4-F-2-nOct-Ph
1-1908 Ring 2 4-F-2-nOct-Ph
1-1909 oxathio 4-F-2-nOct-Ph
1-1910 oxathia 4-F-2-nOct-Ph
1-1911 ozl 4-F-2-nOct-Ph
1-1912 ozn 4-F-2-nOct-Ph
1-1913 tzl 4-F-2-nOct-Ph
1-1914 tzn 4-F-2-nOct-Ph
1-1915 3-HM-cPent 4-F-2-nOct-Ph
1-1916 4-HM-dioxo 4-F-2-nOct-Ph
1-1917 4-HM-dithio 4-F-2-nOct-Ph
1-1918 4-HM-oxathio 4-F-2-nOct-Ph
1-1919 3,4-diHM-cPent 4-F-2-nOct-Ph
1-1920 4,5-diHM-dioxo 4-F-2-nOct-Ph
1-1921 4,5-diHM-dithio 4-F-2-nOct-Ph
1-1922 4,5-diHM-oxathio 4-F-2-nOct-Ph
1-1923 3,4-diHE-cPent 4-F-2-nOct-Ph
1-1924 4,5-diHE-dioxo 4-F-2-nOct-Ph
1-1925 4,5-diHE-dithio 4-F-2-nOct-Ph
1-1926 4,5-diHE-oxathio 4-F-2-nOct-Ph
1-1927 3-HE-cPent 4-F-2-nOct-Ph
1-1928 4-HE-dioxo 4-F-2-nOct-Ph
1-1929 4-HE-dithio 4-F-2-nOct-Ph
1-1930 4-HE-oxathio 4-F-2-nOct-Ph
1-1931 3-HP-cPent 4-F-2-nOct-Ph
1-1932 4-HP-dioxo 4-F-2-nOct-Ph
1-1933 4-HP-dithio 4-F-2-nOct-Ph
1-1934 4-HP-oxathio 4-F-2-nOct-Ph
1-1935 3-HB-cPent 4-F-2-nOct-Ph
1-1936 4-HB-dioxo 4-F-2-nOct-Ph
1-1937 4-HB-dithio 4-F-2-nOct-Ph
1-1938 4-HB-oxathio 4-F-2-nOct-Ph
1-1939 Ring 3 4-F-2-nOct-Ph
1-1940 Ring 4 4-F-2-nOct-Ph
1-1941 Ring 5 4-F-2-nOct-Ph
1-1942 Ring 6 4-F-2-nOct-Ph
1-1943 Ring 7 4-F-2-nOct-Ph
1-1944 Ring 8 4-F-2-nOct-Ph
1-1945 Ring 9 4-F-2-nOct-Ph
1-1946 Ring 10 4-F-2-nOct-Ph
1-1947 3,4-diCH₂NHAc-cPent 4-F-2-nOct-Ph
1-1948 4,5-diCH₂NHAc-dioxo 4-F-2-nOct-Ph
1-1949 4,5-diCH₂NHAc-dithio 4-F-2-nOct-Ph
1-1950 4,5-diCH₂NHAc-oxathio 4-F-2-nOct-Ph
1-1951 Ring 11 4-F-2-nOct-Ph
1-1952 Ring 12 4-F-2-nOct-Ph
1-1953 Ring 13 4-F-2-nOct-Ph
1-1954 Ring 14 4-F-2-nOct-Ph
1-1955 4-OH-cHex 4-F-2-nOct-Ph
1-1956 5-OH-dioxa 4-F-2-nOct-Ph
1-1957 5-OH-dithia 4-F-2-nOct-Ph
1-1958 5-OH-oxathia 4-F-2-nOct-Ph
1-1959 4-NHAc-cHex 4-F-2-nOct-Ph
1-1960 5-NHAc-dioxa 4-F-2-nOct-Ph
1-1961 5-NHAc-dithia 4-F-2-nOct-Ph
1-1962 5-NHAc-oxathia 4-F-2-nOct-Ph
1-1963 4,4-diMe-cHex 4-F-2-nOct-Ph
1-1964 5,5-diMe-dioxa 4-F-2-nOct-Ph
1-1965 5,5-diMe-dithia 4-F-2-nOct-Ph
1-1966 5,5-diMe-oxathia 4-F-2-nOct-Ph
1-1967 4,4-diHM-cHex 4-F-2-nOct-Ph
1-1968 5,5-diHM-dioxa 4-F-2-nOct-Ph
1-1969 5,5-diHM-dithia 4-F-2-nOct-Ph
1-1970 5,5-diHM-oxathia 4-F-2-nOct-Ph
1-1971 Ring 15 4-F-2-nOct-Ph
1-1972 Ring 16 4-F-2-nOct-Ph
1-1973 Ring 17 4-F-2-nOct-Ph
1-1974 Ring 18 4-F-2-nOct-Ph
1-1975 4,4-diCO₂Et-cHex 4-F-2-nOct-Ph
1-1976 5,5-diCO₂Et-dioxa 4-F-2-nOct-Ph
1-1977 5,5-diCO₂Et-dithia 4-F-2-nOct-Ph
1-1978 O = 2-nPr-Ph
1-1979 S = 2-nPr-Ph
1-1980 cPr 2-nPr-Ph
1-1981 cBu 2-nPr-Ph
1-1982 cPent 2-nPr-Ph
1-1983 cHex 2-nPr-Ph
1-1984 cHept 2-nPr-Ph
1-1985 oxi 2-nPr-Ph
1-1986 oxe 2-nPr-Ph
1-1987 oxo 2-nPr-Ph
1-1988 oxa 2-nPr-Ph
1-1989 dioxo 2-nPr-Ph
1-1990 dioxa 2-nPr-Ph
1-1991 dioxe 2-nPr-Ph
1-1992 dithio 2-nPr-Ph
1-1993 dithia 2-nPr-Ph
1-1994 Ring 1 2-nPr-Ph
1-1995 Ring 2 2-nPr-Ph
1-1996 oxathio 2-nPr-Ph
1-1997 oxathia 2-nPr-Ph
1-1998 ozl 2-nPr-Ph
1-1999 ozn 2-nPr-Ph
1-2000 tzl 2-nPr-Ph
1-2001 tzn 2-nPr-Ph
1-2002 3-HM-cPent 2-nPr-Ph
1-2003 4-HM-dioxo 2-nPr-Ph
1-2004 4-HM-dithio 2-nPr-Ph
1-2005 4-HM-oxathio 2-nPr-Ph
1-2006 3,4-diHM-cPent 2-nPr-Ph
1-2007 4,5-diHM-dioxo 2-nPr-Ph
1-2008 4,5-diHM-dithio 2-nPr-Ph
1-2009 4,5-diHM-oxathio 2-nPr-Ph
1-2010 3,4-diHE-cPent 2-nPr-Ph
1-2011 4,5-diHE-dioxo 2-nPr-Ph
1-2012 4,5-diHE-dithio 2-nPr-Ph
1-2013 4,5-diHE-oxathio 2-nPr-Ph
1-2014 3-HE-cPent 2-nPr-Ph
1-2015 4-HE-dioxo 2-nPr-Ph
1-2016 4-HE-dithio 2-nPr-Ph
1-2017 4-HE-oxathio 2-nPr-Ph
1-2018 3-HP-cPent 2-nPr-Ph
1-2019 4-HP-dioxo 2-nPr-Ph
1-2020 4-HP-dithio 2-nPr-Ph
1-2021 4-HP-oxathio 2-nPr-Ph
1-2022 3-HB-cPent 2-nPr-Ph
1-2023 4-HB-dioxo 2-nPr-Ph
1-2024 4-HB-dithio 2-nPr-Ph
1-2025 4-HB-oxathio 2-nPr-Ph
1-2026 Ring 3 2-nPr-Ph
1-2027 Ring 4 2-nPr-Ph
1-2028 Ring 5 2-nPr-Ph
1-2029 Ring 6 2-nPr-Ph
1-2030 Ring 7 2-nPr-Ph
1-2031 Ring 8 2-nPr-Ph
1-2032 Ring 9 2-nPr-Ph
1-2033 Ring 10 2-nPr-Ph
1-2034 3,4-diCH₂NHAc-cPent 2-nPr-Ph
1-2035 4,5-diCH₂NHAc-dioxo 2-nPr-Ph
1-2036 4,5-diCH₂NHAc-dithio 2-nPr-Ph
1-2037 4,5-diCH₂NHAc-oxathio 2-nPr-Ph
1-2038 Ring 11 2-nPr-Ph
1-2039 Ring 12 2-nPr-Ph
1-2040 Ring 13 2-nPr-Ph
1-2041 Ring 14 2-nPr-Ph
1-2042 4-OH-cHex 2-nPr-Ph
1-2043 5-OH-dioxa 2-nPr-Ph
1-2044 5-OH-dithia 2-nPr-Ph
1-2045 5-OH-oxathia 2-nPr-Ph
1-2046 4-NHAc-cHex 2-nPr-Ph
1-2047 5-NHAc-dioxa 2-nPr-Ph
1-2048 5-NHAc-dithia 2-nPr-Ph
1-2049 5-NHAc-oxathia 2-nPr-Ph
1-2050 4,4-diMe-cHex 2-nPr-Ph
1-2051 5,5-diMe-dioxa 2-nPr-Ph
1-2052 5,5-diMe-dithia 2-nPr-Ph
1-2053 5,5-diMe-oxathia 2-nPr-Ph
1-2054 4,4-diHM-cHex 2-nPr-Ph
1-2055 5,5-diHM-dioxa 2-nPr-Ph
1-2056 5,5-diHM-dithia 2-nPr-Ph
1-2057 5,5-diHM-oxathia 2-nPr-Ph
1-2058 Ring 15 2-nPr-Ph
1-2059 Ring 16 2-nPr-Ph
1-2060 Ring 17 2-nPr-Ph
1-2061 Ring 18 2-nPr-Ph
1-2062 4,4-diCO₂Et-cHex 2-nPr-Ph
1-2063 5,5-diCO₂Et-dioxa 2-nPr-Ph
1-2064 5,5-diCO₂Et-dithia 2-nPr-Ph
1-2065 5,5-diCO₂Et-oxathia 2-nPr-Ph
1-2066 O = 4-F-2-nPr-Ph
1-2067 S = 4-F-2-nPr-Ph
1-2068 cPr 4-F-2-nPr-Ph
1-2069 cBu 4-F-2-nPr-Ph
1-2070 cPent 4-F-2-nPr-Ph
1-2071 cHex 4-F-2-nPr-Ph
1-2072 cHept 4-F-2-nPr-Ph
1-2073 oxi 4-F-2-nPr-Ph
1-2074 oxe 4-F-2-nPr-Ph
1-2075 oxo 4-F-2-nPr-Ph
1-2076 oxa 4-F-2-nPr-Ph
1-2077 dioxo 4-F-2-nPr-Ph
1-2078 dioxa 4-F-2-nPr-Ph
1-2079 dioxe 4-F-2-nPr-Ph
1-2080 dithio 4-F-2-nPr-Ph
1-2081 dithia 4-F-2-nPr-Ph
1-2082 Ring 1 4-F-2-nPr-Ph
1-2083 Ring 2 4-F-2-nPr-Ph
1-2084 oxathio 4-F-2-nPr-Ph
1-2085 oxathia 4-F-2-nPr-Ph
1-2086 ozl 4-F-2-nPr-Ph
1-2087 ozn 4-F-2-nPr-Ph
1-2088 tzl 4-F-2-nPr-Ph
1-2089 tzn 4-F-2-nPr-Ph
1-2090 3-HM-cPent 4-F-2-nPr-Ph
1-2091 4-HM-dioxo 4-F-2-nPr-Ph
1-2092 4-HM-dithio 4-F-2-nPr-Ph
1-2093 4-HM-oxathio 4-F-2-nPr-Ph
1-2094 3,4-diHM-cPent 4-F-2-nPr-Ph
1-2095 4,5-diHM-dioxo 4-F-2-nPr-Ph
1-2096 4,5-diHM-dithio 4-F-2-nPr-Ph
1-2097 4,5-diHM-oxathio 4-F-2-nPr-Ph
1-2098 3,4-diHE-cPent 4-F-2-nPr-Ph
1-2099 4,5-diHE-dioxo 4-F-2-nPr-Ph
1-2100 4,5-diHE-dithio 4-F-2-nPr-Ph
1-2101 4,5-diHE-oxathio 4-F-2-nPr-Ph
1-2102 3-HE-cPent 4-F-2-nPr-Ph
1-2103 4-HE-dioxo 4-F-2-nPr-Ph
1-2104 4-HE-dithio 4-F-2-nPr-Ph
1-2105 4-HE-oxathio 4-F-2-nPr-Ph
1-2106 3-HP-cPent 4-F-2-nPr-Ph
1-2107 4-HP-dioxo 4-F-2-nPr-Ph
1-2108 4-HP-dithio 4-F-2-nPr-Ph
1-2109 4-HP-oxathio 4-F-2-nPr-Ph
1-2110 3-HB-cPent 4-F-2-nPr-Ph
1-2111 4-HB-dioxo 4-F-2-nPr-Ph
1-2112 4-HB-dithio 4-F-2-nPr-Ph
1-2113 4-HB-oxathio 4-F-2-nPr-Ph
1-2114 Ring 3 4-F-2-nPr-Ph
1-2115 Ring 4 4-F-2-nPr-Ph
1-2116 Ring 5 4-F-2-nPr-Ph
1-2117 Ring 6 4-F-2-nPr-Ph
1-2118 ring 7 4-F-2-nPr-Ph
1-2119 Ring 8 4-F-2-nPr-Ph
1-2120 Ring 9 4-F-2-nPr-Ph
1-2121 ring 10 4-F-2-nPr-Ph
1-2122 3,4-diCH₂NHAc-cPent 4-F-2-nPr-Ph
1-2123 4,5-diCH₂NHAc-dioxo 4-F-2-nPr-Ph
1-2124 4,5-diCH₂NHAc-dithio 4-F-2-nPr-Ph
1-2125 4,5-diCH₂NHAc-oxathio 4-F-2-nPr-Ph
1-2126 Ring 11 4-F-2-nPr-Ph
1-2127 Ring 12 4-F-2-nPr-Ph
1-2128 Ring 13 4-F-2-nPr-Ph
1-2129 ring 14 4-F-2-nPr-Ph
1-2130 4-OH-cHex 4-F-2-nPr-Ph
1-2131 5-OH-dioxa 4-F-2-nPr-Ph
1-2132 5-OH-dithia 4-F-2-nPr-Ph
1-2133 5-OH-oxathia 4-F-2-nPr-Ph
1-2134 4-NHAc-cHex 4-F-2-nPr-Ph
1-2135 5-NHAc-dioxa 4-F-2-nPr-Ph
1-2136 5-NHAc-dithia 4-F-2-nPr-Ph
1-2137 5-NHAc-oxathia 4-F-2-nPr-Ph
1-2138 4,4-diMe-cHex 4-F-2-nPr-Ph
1-2139 5,5-diMe-dioxa 4-F-2-nPr-Ph
1-2140 5,5-diMe-dithia 4-F-2-nPr-Ph
1-2141 5,5-diMe-oxathia 4-F-2-nPr-Ph
1-2142 4,4-diHM-cHex 4-F-2-nPr-Ph
1-2143 5,5-diHM-dioxa 4-F-2-nPr-Ph
1-2144 5,5-diHM-dithia 4-F-2-nPr-Ph
1-2145 5,5-diHM-oxathia 4-F-2-nPr-Ph
1-2146 Ring 15 4-F-2-nPr-Ph
1-2147 Ring 16 4-F-2-nPr-Ph
1-2148 Ring 17 4-F-2-nPr-Ph
1-2149 Ring 18 4-F-2-nPr-Ph
1-2150 4,4-diCO₂Et-cHex 4-F-2-nPr-Ph
1-2151 5,5-diCO₂Et-dioxa 4-F-2-nPr-Ph
1-2152 5,5-diCO₂Et-dithia 4-F-2-nPr-Ph
1-2153 5,5-diCO₂Et-oxathia 4-F-2-nPr-Ph
1-2154 Ring 19 2-Cl-Ph
1-2155 Ring 20 2-Cl-Ph
1-2156 Ring 21 2-Cl-Ph
1-2157 Ring 19 2-Br-Ph
1-2158 Ring 20 2-Br-Ph
1-2159 Ring 21 2-Br-Ph
1-2160 Ring 19 2-Cl-6-Me-Ph
1-2161 Ring 20 2-Cl-6-Me-Ph
1-2162 Ring 21 2-Cl-6-Me-Ph
1-2163 Ring 19 2-Cl-4-F-Ph
1-2164 Ring 20 2-Cl-4-F-Ph
1-2165 Ring 21 2-Cl-4-F-Ph
1-2166 ring 19 2,4-diF
1-2167 Ring 20 2,4-diF
1-2168 Ring 21 2,4-diF
1-2169 Ring 19 2-Br-4-F-Ph
1-2170 Ring 20 2-Br-4-F-Ph
1-2171 Ring 21 2-Br-4-F-Ph
1-2172 Ring 19 2-nBu-4-F-Ph
1-2173 ring 20 2-nBu-4-F-Ph
1-2174 Ring 21 2-nBu-4-F-Ph
1-2175 Ring 19 2-nPent-Ph
1-2176 Ring 20 2-nPent-Ph
1-2177 Ring 21 2-nPent-Ph
1-2178 Ring 19 4-F-2-nPent-Ph
1-2179 ring 20 4-F-2-nPent-Ph
1-2180 Ring 21 4-F-2-nPent-Ph
1-2181 Ring 19 2-nHex-Ph
1-2182 Ring 20 2-nHex-Ph
1-2183 Ring 21 2-nHex-Ph
1-2184 ring 19 4-F-2-nHex-Ph
1-2185 ring 20 4-F-2-nHex-Ph
1-2186 Ring 21 4-F-2-nHex-Ph
1-2187 Ring 19 2-nHept-Ph
1-2188 ring 20 2-nHept-Ph
1-2189 ring 21 2-nHept-Ph
1-2190 ring 19 4-F-2-nHept-Ph
1-2191 Ring 20 4-F-2-nHept-Ph
1-2192 Ring 21 4-F-2-nHept-Ph
1-2193 Ring 19 2-nOct-Ph
1-2194 ring 20 2-nOct-Ph
1-2195 Ring 21 2-nOct-Ph
1-2196 Ring 19 4-F-2-nOct-Ph
1-2197 ring 20 4-F-2-nOct-Ph
1-2198 Ring 21 4-F-2-nOct-Ph
1-2199 Ring 19 Ph
1-2200 ring 20 Ph
1-2201 Ring 21 Ph
1-2202 Ring 19 4-F-Ph
1-2203 ring 20 4-F-Ph
1-2204 Ring 21 4-F-Ph
1-2205 Ring 19 2-Cl-4-Me-Ph
1-2206 Ring 20 2-Cl-4-Me-Ph
1-2207 Ring 21 2-Cl-4-Me-Ph
1-2208 Ring 19 2-nBu-Ph
1-2209 Ring 20 2-nBu-Ph
1-2210 Ring 21 2-nBu-Ph
1-2211 ring 19 2-nPr-Ph
1-2212 ring 20 2-nPr-Ph
1-2213 Ring 21 2-nPr-Ph
1-2214 Ring 19 4-F-2-nPr-Ph
1-2215 Ring 20 4-F-2-nPr-Ph
1-2216 Ring 21 4-F-2-nPr-Ph
1-2217 dioxo 2-F-Ph
1-2218 4-HM-dioxo 2-F-Ph
1-2219 4,5-diHM-dioxo 2-F-Ph
1-2220 4,5-diHE-dioxo 2-F-Ph
1-2221 Ring 19 2-F-Ph
1-2222 ring 20 2-F-Ph
1-2223 Ring 21 2-F-Ph
1-2224 dioxo 2-I-Ph
1-2225 4-HM-dioxo 2-I-Ph
1-2226 4,5-diHM-dioxo 2-I-Ph
1-2227 4,5-diHE-dioxo 2-I-Ph
1-2228 Ring 19 2-I-Ph
1-2229 Ring 20 2-I-Ph
1-2230 Ring 21 2-I-Ph
1-2231 dioxo 4-Cl-Ph
1-2232 4-HM-dioxo 4-Cl-Ph
1-2233 4,5-diHM-dioxo 4-Cl-Ph
1-2234 4,5-diHE-dioxo 4-Cl-Ph
1-2235 Ring 19 4-Cl-Ph
1-2236 ring 20 4-Cl-Ph
1-2237 Ring 21 4-Cl-Ph
1-2238 dioxo 2-Me-Ph
1-2239 4-HM-dioxo 2-Me-Ph
1-2240 4,5-diHM-dioxo 2-Me-Ph
1-2241 4,5-diHE-dioxo 2-Me-Ph
1-2242 Ring 19 2-Me-Ph
1-2243 ring 20 2-Me-Ph
1-2244 Ring 21 2-Me-Ph
1-2245 dioxo 2-Et-Ph
1-2246 4-HM-dioxo 2-Et-Ph
1-2247 4,5-diHM-dioxo 2-Et-Ph
1-2248 4,5-diHE-dioxo 2-Et-Ph
1-2249 Ring 19 2-Et-Ph
1-2250 Ring 20 2-Et-Ph
1-2251 Ring 21 2-Et-Ph
1-2252 dioxo 2-C≡CH-Ph
1-2253 4-HM-dioxo 2-C≡CH-Ph
1-2254 4,5-diHM-dioxo 2-C≡CH-Ph
1-2255 4,5-diHE-dioxo 2-C≡CH-Ph
1-2256 Ring 19 2-C≡CH-Ph
1-2257 Ring 20 2-C≡CH-Ph
1-2258 Ring 21 2-C≡CH-Ph
1-2259 dioxo 2-iPr-Ph
1-2260 4-HM-dioxo 2-iPr-Ph
1-2261 4,5-diHM-dioxo 2-iPr-Ph
1-2262 4,5-diHE-dioxo 2-iPr-Ph
1-2263 Ring 19 2-iPr-Ph
1-2264 Ring 20 2-iPr-Ph
1-2265 Ring 21 2-iPr-Ph
1-2266 dioxo 2-tBu-Ph
1-2267 4-HM-dioxo 2-tBu-Ph
1-2268 4,5-diHM-dioxo 2-tBu-Ph
1-2269 4,5-diHE-dioxo 2-tBu-Ph
1-2270 ring 19 2-tBu-Ph
1-2271 Ring 20 2-tBu-Ph
1-2272 Ring 21 2-tBu-Ph
1-2273 dioxo 2-sBu-Ph
1-2274 4-HM-dioxo 2-sBu-Ph
1-2275 4,5-diHM-dioxo 2-sBu-Ph
1-2276 4,5-diHE-dioxo 2-sBu-Ph
1-2277 Ring 19 2-sBu-Ph
1-2278 Ring 20 2-sBu-Ph
1-2279 Ring 21 2-sBu-Ph
1-2280 dioxo 2-OMe-Ph
1-2281 4-HM-dioxo 2-OMe-Ph
1-2282 4,5-diHM-dioxo 2-OMe-Ph
1-2283 4,5-diHE-dioxo 2-OMe-Ph
1-2284 Ring 19 2-OMe-Ph
1-2285 Ring 20 2-OMe-Ph
1-2286 Ring 21 2-OMe-Ph
1-2287 dioxo 2-OEt-Ph
1-2288 4-HM-dioxo 2-OEt-Ph
1-2289 4,5-diHM-dioxo 2-OEt-Ph
1-2290 4,5-diHE-dioxo 2-OEt-Ph
1-2291 Ring 19 2-OEt-Ph
1-2292 Ring 20 2-OEt-Ph
1-2293 Ring 21 2-OEt-Ph
1-2294 dioxo 2-OCHF₂-Ph
1-2295 4-HM-dioxo 2-OCHF₂-Ph
1-2296 4,5-diHM-dioxo 2-OCHF₂-Ph
1-2297 4,5-diHE-dioxo 2-OCHF₂-Ph
1-2298 Ring 19 2-OCHF₂-Ph
1-2299 Ring 20 2-OCHF₂-Ph
1-2300 Ring 21 2-OCHF₂-Ph
1-2301 dioxo 2-SMe-Ph
1-2302 4-HM-dioxo 2-SMe-Ph
1-2303 4,5-diHM-dioxo 2-SMe-Ph
1-2304 4,5-diHE-dioxo 2-SMe-Ph
1-2305 Ring 19 2-SMe-Ph
1-2306 Ring 20 2-SMe-Ph
1-2307 Ring 21 2-SMe-Ph
1-2308 dioxo 2-Ac-Ph
1-2309 4-HM-dioxo 2-Ac-Ph
1-2310 4,5-diHM-dioxo 2-Ac-Ph
1-2311 4,5-diHE-dioxo 2-Ac-Ph
1-2312 Ring 19 2-Ac-Ph
1-2313 Ring 20 2-Ac-Ph
1-2314 Ring 21 2-Ac-Ph
1-2315 dioxo 2-Bn-Ph
1-2316 4-HM-dioxo 2-Bn-Ph
1-2317 4,5-diHM-dioxo 2-Bn-Ph
1-2318 4,5-diHE-dioxo 2-Bn-Ph
1-2319 Ring 19 2-Bn-Ph
1-2320 Ring 20 2-Bn-Ph
1-2321 Ring 21 2-Bn-Ph
1-2322 dioxo 2-Mor-Ph
1-2323 4-HM-dioxo 2-Mor-Ph
1-2324 4,5-diHM-dioxo 2-Mor-Ph
1-2325 4,5-diHE-dioxo 2-Mor-Ph
1-2326 Ring 19 2-Mor-Ph
1-2327 Ring 20 2-Mor-Ph
1-2328 Ring 21 2-Mor-Ph
1-2329 dioxo Flu
1-2330 4-HM-dioxo Flu
1-2331 4,5-diHM-dioxo Flu
1-2332 4,5-diHE-dioxo Flu
1-2333 Ring 19 Flu
1-2334 Ring 20 Flu
1-2335 Ring 21 Flu
1-2336 dioxo 2-CH₂CH₂Pyrd-Ph
1-2337 4-HM-dioxo 2-CH₂CH₂Pyrd-Ph
1-2338 4,5-diHM-dioxo 2-CH₂CH₂Pyrd-Ph
1-2339 4,5-diHE-dioxo 2-CH₂CH₂Pyrd-Ph
1-2340 Ring 19 2-CH₂CH₂Pyrd-Ph
1-2341 Ring 20 2-CH₂CH₂Pyrd-Ph
1-2342 ring 21 2-CH₂CH₂Pyrd-Ph
1-2343 dioxo 2-CH₂CH₂NHBoc-Ph
1-2344 4-HM-dioxo 2-CH₂CH₂NHBoc-Ph
1-2345 4,5-diHM-dioxo 2-CH₂CH₂NHBoc-Ph
1-2346 4,5-diHE-dioxo 2-CH₂CH₂NHBoc-Ph
1-2347 Ring 19 2-CH₂CH₂NHBoc-Ph
1-2348 Ring 20 2-CH₂CH₂NHBoc-Ph
1-2349 Ring 21 2-CH₂CH₂NHBoc-Ph
1-2350 dioxo 2-NH₂-Ph
1-2351 4-HM-dioxo 2-NH₂-Ph
1-2352 4,5-diHM-dioxo 2-NH₂-Ph
1-2353 4,5-diHE-dioxo 2-NH₂-Ph
1-2354 ring 19 2-NH₂-Ph
1-2355 ring 20 2-NH₂-Ph
1-2356 Ring 21 2-NH₂-Ph
1-2357 dioxo 4-F-2-Me-Ph
1-2358 4-HM-dioxo 4-F-2-Me-Ph
1-2359 4,5-diHM-dioxo 4-F-2-Me-Ph
1-2360 4,5-diHE-dioxo 4-F-2-Me-Ph
1-2361 Ring 19 4-F-2-Me-Ph
1-2362 ring 20 4-F-2-Me-Ph
1-2363 Ring 21 4-F-2-Me-Ph
1-2364 dioxo 3-Cl-4-F-Ph
1-2365 4-HM-dioxo 3-Cl-4-F-Ph
1-2366 4,5-diHM-dioxo 3-Cl-4-F-Ph
1-2367 4,5-diHE-dioxo 3-Cl-4-F-Ph
1-2368 ring 19 3-Cl-4-F-Ph
1-2369 Ring 20 3-Cl-4-F-Ph
1-2370 Ring 21 3-Cl-4-F-Ph
1-2371 dioxo 4-F-3-CF_Three-Ph
1-2372 4-HM-dioxo 4-F-3-CF_Three-Ph
1-2373 4,5-diHM-dioxo 4-F-3-CF_Three-Ph
1-2374 4,5-diHE-dioxo 4-F-3-CF_Three-Ph
1-2375 Ring 19 4-F-3-CF_Three-Ph
1-2376 ring 20 4-F-3-CF_Three-Ph
1-2377 Ring 21 4-F-3-CF_Three-Ph
1-2378 dioxo 4-F-3-OMe-Ph
1-2379 4-HM-dioxo 4-F-3-OMe-Ph
1-2380 4,5-diHM-dioxo 4-F-3-OMe-Ph
1-2381 4,5-diHE-dioxo 4-F-3-OMe-Ph
1-2382 Ring 19 4-F-3-OMe-Ph
1-2383 ring 20 4-F-3-OMe-Ph
1-2384 ring 21 4-F-3-OMe-Ph
1-2385 dioxo 3,4-diF-Ph
1-2386 4-HM-dioxo 3,4-diF-Ph
1-2387 4,5-diHM-dioxo 3,4-diF-Ph
1-2388 4,5-diHE-dioxo 3,4-diF-Ph
1-2389 ring 19 3,4-diF-Ph
1-2390 ring 20 3,4-diF-Ph
1-2391 ring 21 3,4-diF-Ph
1-2392 dioxo 2,4-diOMe-Ph
1-2393 4-HM-dioxo 2,4-diOMe-Ph
1-2394 4,5-diHM-dioxo 2,4-diOMe-Ph
1-2395 4,5-diHE-dioxo 2,4-diOMe-Ph
1-2396 ring 19 2,4-diOMe-Ph
1-2397 Ring 20 2,4-diOMe-Ph
1-2398 ring 21 2,4-diOMe-Ph
1-2399 dioxo 4-Cl-2-F-Ph
1-2400 4-HM-dioxo 4-Cl-2-F-Ph
1-2401 4,5-diHM-dioxo 4-Cl-2-F-Ph
1-2402 4,5-diHE-dioxo 4-Cl-2-F-Ph
1-2403 Ring 19 4-Cl-2-F-Ph
1-2404 ring 20 4-Cl-2-F-Ph
1-2405 Ring 21 4-Cl-2-F-Ph
1-2406 dioxo 2-Br-4-Cl-Ph
1-2407 4-HM-dioxo 2-Br-4-Cl-Ph
1-2408 4,5-diHM-dioxo 2-Br-4-Cl-Ph
1-2409 4,5-diHE-dioxo 2-Br-4-Cl-Ph
1-2410 Ring 19 2-Br-4-Cl-Ph
1-2411 ring 20 2-Br-4-Cl-Ph
1-2412 Ring 21 2-Br-4-Cl-Ph
1-2413 dioxo 4-Cl-2-Me-Ph
1-2414 4-HM-dioxo 4-Cl-2-Me-Ph
1-2415 4,5-diHM-dioxo 4-Cl-2-Me-Ph
1-2416 4,5-diHE-dioxo 4-Cl-2-Me-Ph
1-2417 Ring 19 4-Cl-2-Me-Ph
1-2418 ring 20 4-Cl-2-Me-Ph
1-2419 Ring 21 4-Cl-2-Me-Ph
1-2420 dioxo 4-Cl-2-CO₂Me-Ph
1-2421 4-HM-dioxo 4-Cl-2-CO₂Me-Ph
1-2422 4,5-diHM-dioxo 4-Cl-2-CO₂Me-Ph
1-2423 4,5-diHE-dioxo 4-Cl-2-CO₂Me-Ph
1-2424 Ring 19 4-Cl-2-CO₂Me-Ph
1-2425 ring 20 4-Cl-2-CO₂Me-Ph
1-2426 ring 21 4-Cl-2-CO₂Me-Ph
1-2427 dioxo 3,4-diCl-Ph
1-2428 4-HM-dioxo 3,4-diCl-Ph
1-2429 4,5-diHM-dioxo 3,4-diCl-Ph
1-2430 4,5-diHE-dioxo 3,4-diCl-Ph
1-2431 ring 19 3,4-diCl-Ph
1-2432 ring 20 3,4-diCl-Ph
1-2433 ring 21 3,4-diCl-Ph
1-2434 dioxo 2,5-diF-Ph
1-2435 4-HM-dioxo 2,5-diF-Ph
1-2436 4,5-diHM-dioxo 2,5-diF-Ph
1-2437 4,5-diHE-dioxo 2,5-diF-Ph
1-2438 ring 19 2,5-diF-Ph
1-2439 ring 20 2,5-diF-Ph
1-2440 Ring 21 2,5-diF-Ph
1-2441 dioxo 2,6-diF-Ph
1-2442 4-HM-dioxo 2,6-diF-Ph
1-2443 4,5-diHM-dioxo 2,6-diF-Ph
1-2444 4,5-diHE-dioxo 2,6-diF-Ph
1-2445 Ring 19 2,6-diF-Ph
1-2446 ring 20 2,6-diF-Ph
1-2447 Ring 21 2,6-diF-Ph
1-2448 dioxo 2-F-4-Me-Ph
1-2449 4-HM-dioxo 2-F-4-Me-Ph
1-2450 4,5-diHM-dioxo 2-F-4-Me-Ph
1-2451 4,5-diHE-dioxo 2-F-4-Me-Ph
1-2452 Ring 19 2-F-4-Me-Ph
1-2453 Ring 20 2-F-4-Me-Ph
1-2454 Ring 21 2-F-4-Me-Ph
1-2455 dioxo 2-F-5-Me-Ph
1-2456 4-HM-dioxo 2-F-5-Me-Ph
1-2457 4,5-diHM-dioxo 2-F-5-Me-Ph
1-2458 4,5-diHE-dioxo 2-F-5-Me-Ph
1-2459 Ring 19 2-F-5-Me-Ph
1-2460 Ring 20 2-F-5-Me-Ph
1-2461 Ring 21 2-F-5-Me-Ph
1-2462 dioxo 2-F-4-OMe-Ph
1-2463 4-HM-dioxo 2-F-4-OMe-Ph
1-2464 4,5-diHM-dioxo 2-F-4-OMe-Ph
1-2465 4,5-diHE-dioxo 2-F-4-OMe-Ph
1-2466 Ring 19 2-F-4-OMe-Ph
1-2467 Ring 20 2-F-4-OMe-Ph
1-2468 Ring 21 2-F-4-OMe-Ph
1-2469 dioxo 5-Cl-2-F-Ph
1-2470 4-HM-dioxo 5-Cl-2-F-Ph
1-2471 4,5-diHM-dioxo 5-Cl-2-F-Ph
1-2472 4,5-diHE-dioxo 5-Cl-2-F-Ph
1-2473 Ring 19 5-Cl-2-F-Ph
1-2474 Ring 20 5-Cl-2-F-Ph
1-2475 Ring 21 5-Cl-2-F-Ph
1-2476 dioxo 2,3,4-triF-Ph
1-2477 4-HM-dioxo 2,3,4-triF-Ph
1-2478 4,5-diHM-dioxo 2,3,4-triF-Ph
1-2479 4,5-diHE-dioxo 2,3,4-triF-Ph
1-2480 Ring 19 2,3,4-triF-Ph
1-2481 ring 20 2,3,4-triF-Ph
1-2482 Ring 21 2,3,4-triF-Ph
1-2483 dioxo 2,4,5-triF-Ph
1-2484 4-HM-dioxo 2,4,5-triF-Ph
1-2485 4,5-diHM-dioxo 2,4,5-triF-Ph
1-2486 4,5-diHE-dioxo 2,4,5-triF-Ph
1-2487 ring 19 2,4,5-triF-Ph
1-2488 ring 20 2,4,5-triF-Ph
1-2489 Ring 21 2,4,5-triF-Ph
1-2490 dioxo 2,4,6-triF-Ph
1-2491 4-HM-dioxo 2,4,6-triF-Ph
1-2492 4,5-diHM-dioxo 2,4,6-triF-Ph
1-2493 4,5-diHE-dioxo 2,4,6-triF-Ph
1-2494 ring 19 2,4,6-triF-Ph
1-2495 ring 20 2,4,6-triF-Ph
1-2496 Ring 21 2,4,6-triF-Ph
1-2497 dioxo 2,4-diCl-Ph
1-2498 4-HM-dioxo 2,4-diCl-Ph
1-2499 4,5-diHM-dioxo 2,4-diCl-Ph
1-2500 4,5-diHE-dioxo 2,4-diCl-Ph
1-2501 Ring 19 2,4-diCl-Ph
1-2502 ring 20 2,4-diCl-Ph
1-2503 ring 21 2,4-diCl-Ph
1-2504 dioxo 4-Br-2-Cl-Ph
1-2505 4-HM-dioxo 4-Br-2-Cl-Ph
1-2506 4,5-diHM-dioxo 4-Br-2-Cl-Ph
1-2507 4,5-diHE-dioxo 4-Br-2-Cl-Ph
1-2508 Ring 19 4-Br-2-Cl-Ph
1-2509 ring 20 4-Br-2-Cl-Ph
1-2510 Ring 21 4-Br-2-Cl-Ph
1-2511 dioxo 4-tBu-2-Cl-Ph
1-2512 4-HM-dioxo 4-tBu-2-Cl-Ph
1-2513 4,5-diHM-dioxo 4-tBu-2-Cl-Ph
1-2514 4,5-diHE-dioxo 4-tBu-2-Cl-Ph
1-2515 Ring 19 4-tBu-2-Cl-Ph
1-2516 Ring 20 4-tBu-2-Cl-Ph
1-2517 Ring 21 4-tBu-2-Cl-Ph
1-2518 dioxo 2-Cl-6-F-Ph
1-2519 4-HM-dioxo 2-Cl-6-F-Ph
1-2520 4,5-diHM-dioxo 2-Cl-6-F-Ph
1-2521 4,5-diHE-dioxo 2-Cl-6-F-Ph
1-2522 Ring 19 2-Cl-6-F-Ph
1-2523 Ring 20 2-Cl-6-F-Ph
1-2524 Ring 21 2-Cl-6-F-Ph
1-2525 dioxo 2,6-diCl-Ph
1-2526 4-HM-dioxo 2,6-diCl-Ph
1-2527 4,5-diHM-dioxo 2,6-diCl-Ph
1-2528 4,5-diHE-dioxo 2,6-diCl-Ph
1-2529 Ring 19 2,6-diCl-Ph
1-2530 Ring 20 2,6-diCl-Ph
1-2531 Ring 21 2,6-diCl-Ph
1-2532 dioxo 2,3-diCl-Ph
1-2533 4-HM-dioxo 2,3-diCl-Ph
1-2534 4,5-diHM-dioxo 2,3-diCl-Ph
1-2535 4,5-diHE-dioxo 2,3-diCl-Ph
1-2536 ring 19 2,3-diCl-Ph
1-2537 ring 20 2,3-diCl-Ph
1-2538 Ring 21 2,3-diCl-Ph
1-2539 dioxo 2,5-diCl-Ph
1-2540 4-HM-dioxo 2,5-diCl-Ph
1-2541 4,5-diHM-dioxo 2,5-diCl-Ph
1-2542 4,5-diHE-dioxo 2,5-diCl-Ph
1-2543 ring 19 2,5-diCl-Ph
1-2544 Ring 20 2,5-diCl-Ph
1-2545 Ring 21 2,5-diCl-Ph
1-2546 dioxo 2-Cl-4,6-diF-Ph
1-2547 4-HM-dioxo 2-Cl-4,6-diF-Ph
1-2548 4,5-diHM-dioxo 2-Cl-4,6-diF-Ph
1-2549 4,5-diHE-dioxo 2-Cl-4,6-diF-Ph
1-2550 Ring 19 2-Cl-4,6-diF-Ph
1-2551 Ring 20 2-Cl-4,6-diF-Ph
1-2552 Ring 21 2-Cl-4,6-diF-Ph
1-2553 dioxo 2,6-diCl-4-F-Ph
1-2554 4-HM-dioxo 2,6-diCl-4-F-Ph
1-2555 4,5-diHM-dioxo 2,6-diCl-4-F-Ph
1-2556 4,5-diHE-dioxo 2,6-diCl-4-F-Ph
1-2557 Ring 19 2,6-diCl-4-F-Ph
1-2558 ring 20 2,6-diCl-4-F-Ph
1-2559 ring 21 2,6-diCl-4-F-Ph
1-2560 dioxo 2-Br-6-Cl-4-F-Ph
1-2561 4-HM-dioxo 2-Br-6-Cl-4-F-Ph
1-2562 4,5-diHM-dioxo 2-Br-6-Cl-4-F-Ph
1-2563 4,5-diHE-dioxo 2-Br-6-Cl-4-F-Ph
1-2564 ring 19 2-Br-6-Cl-4-F-Ph
1-2565 ring 20 2-Br-6-Cl-4-F-Ph
1-2566 Ring 21 2-Br-6-Cl-4-F-Ph
1-2567 dioxo 4-Cl-2-OMe-5-Me-Ph
1-2568 4-HM-dioxo 4-Cl-2-OMe-5-Me-Ph
1-2569 4,5-diHM-dioxo 4-Cl-2-OMe-5-Me-Ph
1-2570 4,5-diHE-dioxo 4-Cl-2-OMe-5-Me-Ph
1-2571 Ring 19 4-Cl-2-OMe-5-Me-Ph
1-2572 Ring 20 4-Cl-2-OMe-5-Me-Ph
1-2573 Ring 21 4-Cl-2-OMe-5-Me-Ph
1-2574 dioxo 2,4-diBr-Ph
1-2575 4-HM-dioxo 2,4-diBr-Ph
1-2576 4,5-diHM-dioxo 2,4-diBr-Ph
1-2577 4,5-diHE-dioxo 2,4-diBr-Ph
1-2578 Ring 19 2,4-diBr-Ph
1-2579 ring 20 2,4-diBr-Ph
1-2580 ring 21 2,4-diBr-Ph
1-2581 dioxo 2,6-diBr-Ph
1-2582 4-HM-dioxo 2,6-diBr-Ph
1-2583 4,5-diHM-dioxo 2,6-diBr-Ph
1-2584 4,5-diHE-dioxo 2,6-diBr-Ph
1-2585 ring 19 2,6-diBr-Ph
1-2586 ring 20 2,6-diBr-Ph
1-2587 Ring 21 2,6-diBr-Ph
1-2588 dioxo 2-Br-4-iPr-Ph
1-2589 4-HM-dioxo 2-Br-4-iPr-Ph
1-2590 4,5-diHM-dioxo 2-Br-4-iPr-Ph
1-2591 4,5-diHE-dioxo 2-Br-4-iPr-Ph
1-2592 Ring 19 2-Br-4-iPr-Ph
1-2593 Ring 20 2-Br-4-iPr-Ph
1-2594 Ring 21 2-Br-4-iPr-Ph
1-2595 dioxo 2-nNon-Ph
1-2596 4-HM-dioxo 2-nNon-Ph
1-2597 4,5-diHM-dioxo 2-nNon-Ph
1-2598 4,5-diHE-dioxo 2-nNon-Ph
1-2599 Ring 19 2-nNon-Ph
1-2600 ring 20 2-nNon-Ph
1-2601 Ring 21 2-nNon-Ph
1-2602 dioxo 4-F-2-nNon-Ph
1-2603 4-HM-dioxo 4-F-2-nNon-Ph
1-2604 4,5-diHM-dioxo 4-F-2-nNon-Ph
1-2605 4,5-diHE-dioxo 4-F-2-nNon-Ph
1-2606 Ring 19 4-F-2-nNon-Ph
1-2607 ring 20 4-F-2-nNon-Ph
1-2608 Ring 21 4-F-2-nNon-Ph
1-2609 dioxo 2-nDec-Ph
1-2610 4-HM-dioxo 2-nDec-Ph
1-2611 4,5-diHM-dioxo 2-nDec-Ph
1-2612 4,5-diHE-dioxo 2-nDec-Ph
1-2613 Ring 19 2-nDec-Ph
1-2614 Ring 20 2-nDec-Ph
1-2615 Ring 21 2-nDec-Ph
1-2616 dioxo 4-F-2-nDec-Ph
1-2617 4-HM-dioxo 4-F-2-nDec-Ph
1-2618 4,5-diHM-dioxo 4-F-2-nDec-Ph
1-2619 4,5-diHE-dioxo 4-F-2-nDec-Ph
1-2620 Ring 19 4-F-2-nDec-Ph
1-2621 Ring 20 4-F-2-nDec-Ph
1-2622 Ring 21 4-F-2-nDec-Ph
1-2623 dioxo 2-Et-4-F-Ph
1-2624 4-HM-dioxo 2-Et-4-F-Ph
1-2625 4,5-diHM-dioxo 2-Et-4-F-Ph
1-2626 4,5-diHE-dioxo 2-Et-4-F-Ph
1-2627 Ring 19 2-Et-4-F-Ph
1-2628 Ring 20 2-Et-4-F-Ph
1-2629 Ring 21 2-Et-4-F-Ph
―――――――――――――――――――――――――――――

(Table 2)
――――――――――――――――――――――――
Compound X, YR ³
No .――――――――――――――――――――――――
2-1 dioxo 2-Cl-Ph
2-2 4-HM-dioxo 2-Cl-Ph
2-3 4,5-diHM-dioxo 2-Cl-Ph
2-4 4,5-diHE-dioxo 2-Cl-Ph
2-5 dioxo 2-Br-Ph
2-6 4-HM-dioxo 2-Br-Ph
2-7 4,5-diHM-dioxo 2-Br-Ph
2-8 4,5-diHE-dioxo 2-Br-Ph
2-9 dioxo 2-Cl-6-Me-Ph
2-10 4-HM-dioxo 2-Cl-6-Me-Ph
2-11 4,5-diHM-dioxo 2-Cl-6-Me-Ph
2-12 4,5-diHE-dioxo 2-Cl-6-Me-Ph
2-13 dioxo 2-Cl-4-F-Ph
2-14 4-HM-dioxo 2-Cl-4-F-Ph
2-15 4,5-diHM-dioxo 2-Cl-4-F-Ph
2-16 4,5-diHE-dioxo 2-Cl-4-F-Ph
2-17 dioxo 2,4-diF
2-18 4-HM-dioxo 2,4-diF
2-19 4,5-diHM-dioxo 2,4-diF
2-20 4,5-diHE-dioxo 2,4-diF
2-21 dioxo 2-Br-4-F-Ph
2-22 4-HM-dioxo 2-Br-4-F-Ph
2-23 4,5-diHM-dioxo 2-Br-4-F-Ph
2-24 4,5-diHE-dioxo 2-Br-4-F-Ph
2-25 dioxo 2-nBu-4-F-Ph
2-26 4-HM-dioxo 2-nBu-4-F-Ph
2-27 4,5-diHM-dioxo 2-nBu-4-F-Ph
2-28 4,5-diHE-dioxo 2-nBu-4-F-Ph
2-29 dioxo 2-nPent-Ph
2-30 4-HM-dioxo 2-nPent-Ph
2-31 4,5-diHM-dioxo 2-nPent-Ph
2-32 4,5-diHE-dioxo 2-nPent-Ph
2-33 dioxo 4-F-2-nPent-Ph
2-34 4-HM-dioxo 4-F-2-nPent-Ph
2-35 4,5-diHM-dioxo 4-F-2-nPent-Ph
2-36 4,5-diHE-dioxo 4-F-2-nPent-Ph
2-37 dioxo 2-nHex-Ph
2-38 4-HM-dioxo 2-nHex-Ph
2-39 4,5-diHM-dioxo 2-nHex-Ph
2-40 4,5-diHE-dioxo 2-nHex-Ph
2-41 dioxo 4-F-2-nHex-Ph
2-42 4-HM-dioxo 4-F-2-nHex-Ph
2-43 4,5-diHM-dioxo 4-F-2-nHex-Ph
2-44 4,5-diHE-dioxo 4-F-2-nHex-Ph
2-45 dioxo 2-nHept-Ph
2-46 4-HM-dioxo 2-nHept-Ph
2-47 4,5-diHM-dioxo 2-nHept-Ph
2-48 4,5-diHE-dioxo 2-nHept-Ph
2-49 dioxo 4-F-2-nHept-Ph
2-50 4-HM-dioxo 4-F-2-nHept-Ph
2-51 4,5-diHM-dioxo 4-F-2-nHept-Ph
2-52 4,5-diHE-dioxo 4-F-2-nHept-Ph
2-53 dioxo 2-nOct-Ph
2-54 4-HM-dioxo 2-nOct-Ph
2-55 4,5-diHM-dioxo 2-nOct-Ph
2-56 4,5-diHE-dioxo 2-nOct-Ph
2-57 dioxo 4-F-2-nOct-Ph
2-58 4-HM-dioxo 4-F-2-nOct-Ph
2-59 4,5-diHM-dioxo 4-F-2-nOct-Ph
2-60 4,5-diHE-dioxo 4-F-2-nOct-Ph
2-61 dioxo Ph
2-62 4-HM-dioxo Ph
2-63 4,5-diHM-dioxo Ph
2-64 4,5-diHE-dioxo Ph
2-65 dioxo 4-F-Ph
2-66 4-HM-dioxo 4-F-Ph
2-67 4,5-diHM-dioxo 4-F-Ph
2-68 4,5-diHE-dioxo 4-F-Ph
2-69 dioxo 2-Cl-4-Me-Ph
2-70 4-HM-dioxo 2-Cl-4-Me-Ph
2-71 4,5-diHM-dioxo 2-Cl-4-Me-Ph
2-72 4,5-diHE-dioxo 2-Cl-4-Me-Ph
2-73 dioxo 2-nBu-Ph
2-74 4-HM-dioxo 2-nBu-Ph
2-75 4,5-diHM-dioxo 2-nBu-Ph
2-76 4,5-diHE-dioxo 2-nBu-Ph
2-77 dioxo 2-nPr-Ph
2-78 4-HM-dioxo 2-nPr-Ph
2-79 4,5-diHM-dioxo 2-nPr-Ph
2-80 4,5-diHE-dioxo 2-nPr-Ph
2-81 dioxo 4-F-2-nPr-Ph
2-82 4-HM-dioxo 4-F-2-nPr-Ph
2-83 4,5-diHM-dioxo 4-F-2-nPr-Ph
2-84 4,5-diHE-dioxo 4-F-2-nPr-Ph
――――――――――――――――――――――――.

(Table 3)
―――――――――――――――――――――――――――――――――――
Compound X, YR ² R ³
No .――――――――――――――――――――――――――――――――――――
3-1 dioxo Me 2-Cl-Ph
3-2 4-HM-dioxo Me 2-Cl-Ph
3-3 4,5-diHM-dioxo Me 2-Cl-Ph
3-4 4,5-diHE-dioxo Me 2-Cl-Ph
3-5 dioxo nPr 2-Cl-Ph
3-6 4-HM-dioxo nPr 2-Cl-Ph
3-7 4,5-diHM-dioxo nPr 2-Cl-Ph
3-8 4,5-diHE-dioxo nPr 2-Cl-Ph
3-9 dioxo nBu 2-Cl-Ph
3-10 4-HM-dioxo nBu 2-Cl-Ph
3-11 4,5-diHM-dioxo nBu 2-Cl-Ph
3-12 4,5-diHE-dioxo nBu 2-Cl-Ph
3-13 dioxo iPr 2-Cl-Ph
3-14 4-HM-dioxo iPr 2-Cl-Ph
3-15 4,5-diHM-dioxo iPr 2-Cl-Ph
3-16 4,5-diHE-dioxo iPr 2-Cl-Ph
3-17 dioxo tBu 2-Cl-Ph
3-18 4-HM-dioxo tBu 2-Cl-Ph
3-19 4,5-diHM-dioxo tBu 2-Cl-Ph
3-20 4,5-diHE-dioxo tBu 2-Cl-Ph
3-21 dioxo CH ₂ OAc 2-Cl-Ph
3-22 4-HM-dioxo CH ₂ OAc 2-Cl-Ph
3-23 4,5-diHM-dioxo CH ₂ OAc 2-Cl-Ph
3-24 4,5-diHE-dioxo CH ₂ OAc 2-Cl-Ph
3-25 dioxo Me 2-Br-Ph
3-26 4-HM-dioxo Me 2-Br-Ph
3-27 4,5-diHM-dioxo Me 2-Br-Ph
3-28 4,5-diHE-dioxo Me 2-Br-Ph
3-29 dioxo nPr 2-Br-Ph
3-30 4-HM-dioxo nPr 2-Br-Ph
3-31 4,5-diHM-dioxo nPr 2-Br-Ph
3-32 4,5-diHE-dioxo nPr 2-Br-Ph
3-33 dioxo nBu 2-Br-Ph
3-34 4-HM-dioxo nBu 2-Br-Ph
3-35 4,5-diHM-dioxo nBu 2-Br-Ph
3-36 4,5-diHE-dioxo nBu 2-Br-Ph
3-37 dioxo iPr 2-Br-Ph
3-38 4-HM-dioxo iPr 2-Br-Ph
3-39 4,5-diHM-dioxo iPr 2-Br-Ph
3-40 4,5-diHE-dioxo iPr 2-Br-Ph
3-41 dioxo tBu 2-Br-Ph
3-42 4-HM-dioxo tBu 2-Br-Ph
3-43 4,5-diHM-dioxo tBu 2-Br-Ph
3-44 4,5-diHE-dioxo tBu 2-Br-Ph
3-45 dioxo CH ₂ OAc 2-Br-Ph
3-46 4-HM-dioxo CH ₂ OAc 2-Br-Ph
3-47 4,5-diHM-dioxo CH ₂ OAc 2-Br-Ph
3-48 4,5-diHE-dioxo CH ₂ OAc 2-Br-Ph
3-49 dioxo Me 2-Cl-6-Me-Ph
3-50 4-HM-dioxo Me 2-Cl-6-Me-Ph
3-51 4,5-diHM-dioxo Me 2-Cl-6-Me-Ph
3-52 4,5-diHE-dioxo Me 2-Cl-6-Me-Ph
3-53 dioxo nPr 2-Cl-6-Me-Ph
3-54 4-HM-dioxo nPr 2-Cl-6-Me-Ph
3-55 4,5-diHM-dioxo nPr 2-Cl-6-Me-Ph
3-56 4,5-diHE-dioxo nPr 2-Cl-6-Me-Ph
3-57 dioxo nBu 2-Cl-6-Me-Ph
3-58 4-HM-dioxo nBu 2-Cl-6-Me-Ph
3-59 4,5-diHM-dioxo nBu 2-Cl-6-Me-Ph
3-60 4,5-diHE-dioxo nBu 2-Cl-6-Me-Ph
3-61 dioxo iPr 2-Cl-6-Me-Ph
3-62 4-HM-dioxo iPr 2-Cl-6-Me-Ph
3-63 4,5-diHM-dioxo iPr 2-Cl-6-Me-Ph
3-64 4,5-diHE-dioxo iPr 2-Cl-6-Me-Ph
3-65 dioxo tBu 2-Cl-6-Me-Ph
3-66 4-HM-dioxo tBu 2-Cl-6-Me-Ph
3-67 4,5-diHM-dioxo tBu 2-Cl-6-Me-Ph
3-68 4,5-diHE-dioxo tBu 2-Cl-6-Me-Ph
3-69 dioxo CH ₂ OAc 2-Cl-6-Me-Ph
3-70 4-HM-dioxo CH ₂ OAc 2-Cl-6-Me-Ph
3-71 4,5-diHM-dioxo CH ₂ OAc 2-Cl-6-Me-Ph
3-72 4,5-diHE-dioxo CH ₂ OAc 2-Cl-6-Me-Ph
3-73 dioxo Me 2-Cl-4-F-Ph
3-74 4-HM-dioxo Me 2-Cl-4-F-Ph
3-75 4,5-diHM-dioxo Me 2-Cl-4-F-Ph
3-76 4,5-diHE-dioxo Me 2-Cl-4-F-Ph
3-77 dioxo nPr 2-Cl-4-F-Ph
3-78 4-HM-dioxo nPr 2-Cl-4-F-Ph
3-79 4,5-diHM-dioxo nPr 2-Cl-4-F-Ph
3-80 4,5-diHE-dioxo nPr 2-Cl-4-F-Ph
3-81 dioxo nBu 2-Cl-4-F-Ph
3-82 4-HM-dioxo nBu 2-Cl-4-F-Ph
3-83 4,5-diHM-dioxo nBu 2-Cl-4-F-Ph
3-84 4,5-diHE-dioxo nBu 2-Cl-4-F-Ph
3-85 dioxo iPr 2-Cl-4-F-Ph
3-86 4-HM-dioxo iPr 2-Cl-4-F-Ph
3-87 4,5-diHM-dioxo iPr 2-Cl-4-F-Ph
3-88 4,5-diHE-dioxo iPr 2-Cl-4-F-Ph
3-89 dioxo tBu 2-Cl-4-F-Ph
3-90 4-HM-dioxo tBu 2-Cl-4-F-Ph
3-91 4,5-diHM-dioxo tBu 2-Cl-4-F-Ph
3-92 4,5-diHE-dioxo tBu 2-Cl-4-F-Ph
3-93 dioxo CH ₂ OAc 2-Cl-4-F-Ph
3-94 4-HM-dioxo CH ₂ OAc 2-Cl-4-F-Ph
3-95 4,5-diHM-dioxo CH ₂ OAc 2-Cl-4-F-Ph
3-96 4,5-diHE-dioxo CH ₂ OAc 2-Cl-4-F-Ph
3-97 dioxo Me 2,4-diF-Ph
3-98 4-HM-dioxo Me 2,4-diF-Ph
3-99 4,5-diHM-dioxo Me 2,4-diF-Ph
3-100 4,5-diHE-dioxo Me 2,4-diF-Ph
3-101 dioxo nPr 2,4-diF-Ph
3-102 4-HM-dioxo nPr 2,4-diF-Ph
3-103 4,5-diHM-dioxo nPr 2,4-diF-Ph
3-104 4,5-diHE-dioxo nPr 2,4-diF-Ph
3-105 dioxo nBu 2,4-diF-Ph
3-106 4-HM-dioxo nBu 2,4-diF-Ph
3-107 4,5-diHM-dioxo nBu 2,4-diF-Ph
3-108 4,5-diHE-dioxo nBu 2,4-diF-Ph
3-109 dioxo iPr 2,4-diF-Ph
3-110 4-HM-dioxo iPr 2,4-diF-Ph
3-111 4,5-diHM-dioxo iPr 2,4-diF-Ph
3-112 4,5-diHE-dioxo iPr 2,4-diF-Ph
3-113 dioxo tBu 2,4-diF-Ph
3-114 4-HM-dioxo tBu 2,4-diF-Ph
3-115 4,5-diHM-dioxo tBu 2,4-diF-Ph
3-116 4,5-diHE-dioxo tBu 2,4-diF-Ph
3-117 dioxo CH ₂ OAc 2,4-diF-Ph
3-118 4-HM-dioxo CH ₂ OAc 2,4-diF-Ph
3-119 4,5-diHM-dioxo CH ₂ OAc 2,4-diF-Ph
3-120 4,5-diHE-dioxo CH ₂ OAc 2,4-diF-Ph
3-121 dioxo Me 2-Br-4-F-Ph
3-122 4-HM-dioxo Me 2-Br-4-F-Ph
3-123 4,5-diHM-dioxo Me 2-Br-4-F-Ph
3-124 4,5-diHE-dioxo Me 2-Br-4-F-Ph
3-125 dioxo nPr 2-Br-4-F-Ph
3-126 4-HM-dioxo nPr 2-Br-4-F-Ph
3-127 4,5-diHM-dioxo nPr 2-Br-4-F-Ph
3-128 4,5-diHE-dioxo nPr 2-Br-4-F-Ph
3-129 dioxo nBu 2-Br-4-F-Ph
3-130 4-HM-dioxo nBu 2-Br-4-F-Ph
3-131 4,5-diHM-dioxo nBu 2-Br-4-F-Ph
3-132 4,5-diHE-dioxo nBu 2-Br-4-F-Ph
3-133 dioxo iPr 2-Br-4-F-Ph
3-134 4-HM-dioxo iPr 2-Br-4-F-Ph
3-135 4,5-diHM-dioxo iPr 2-Br-4-F-Ph
3-136 4,5-diHE-dioxo iPr 2-Br-4-F-Ph
3-137 dioxo tBu 2-Br-4-F-Ph
3-138 4-HM-dioxo tBu 2-Br-4-F-Ph
3-139 4,5-diHM-dioxo tBu 2-Br-4-F-Ph
3-140 4,5-diHE-dioxo tBu 2-Br-4-F-Ph
3-141 dioxo CH ₂ OAc 2-Br-4-F-Ph
3-142 4-HM-dioxo CH ₂ OAc 2-Br-4-F-Ph
3-143 4,5-diHM-dioxo CH ₂ OAc 2-Br-4-F-Ph
3-144 4,5-diHE-dioxo CH ₂ OAc 2-Br-4-F-Ph
3-145 dioxo Me 2-nBu-4-F-Ph
3-146 4-HM-dioxo Me 2-nBu-4-F-Ph
3-147 4,5-diHM-dioxo Me 2-nBu-4-F-Ph
3-148 4,5-diHE-dioxo Me 2-nBu-4-F-Ph
3-149 dioxo nPr 2-nBu-4-F-Ph
3-150 4-HM-dioxo nPr 2-nBu-4-F-Ph
3-151 4,5-diHM-dioxo nPr 2-nBu-4-F-Ph
3-152 4,5-diHE-dioxo nPr 2-nBu-4-F-Ph
3-153 dioxo nBu 2-nBu-4-F-Ph
3-154 4-HM-dioxo nBu 2-nBu-4-F-Ph
3-155 4,5-diHM-dioxo nBu 2-nBu-4-F-Ph
3-156 4,5-diHE-dioxo nBu 2-nBu-4-F-Ph
3-157 dioxo iPr 2-nBu-4-F-Ph
3-158 4-HM-dioxo iPr 2-nBu-4-F-Ph
3-159 4,5-diHM-dioxo iPr 2-nBu-4-F-Ph
3-160 4,5-diHE-dioxo iPr 2-nBu-4-F-Ph
3-161 dioxo tBu 2-nBu-4-F-Ph
3-162 4-HM-dioxo tBu 2-nBu-4-F-Ph
3-163 4,5-diHM-dioxo tBu 2-nBu-4-F-Ph
3-164 4,5-diHE-dioxo tBu 2-nBu-4-F-Ph
3-165 dioxo CH ₂ OAc 2-nBu-4-F-Ph
3-166 4-HM-dioxo CH ₂ OAc 2-nBu-4-F-Ph
3-167 4,5-diHM-dioxo CH ₂ OAc 2-nBu-4-F-Ph
3-168 4,5-diHE-dioxo CH ₂ OAc 2-nBu-4-F-Ph
3-169 dioxo Me 2-nPent-Ph
3-170 4-HM-dioxo Me 2-nPent-Ph
3-171 4,5-diHM-dioxo Me 2-nPent-Ph
3-172 4,5-diHE-dioxo Me 2-nPent-Ph
3-173 dioxo nPr 2-nPent-Ph
3-174 4-HM-dioxo nPr 2-nPent-Ph
3-175 4,5-diHM-dioxo nPr 2-nPent-Ph
3-176 4,5-diHE-dioxo nPr 2-nPent-Ph
3-177 dioxo nBu 2-nPent-Ph
3-178 4-HM-dioxo nBu 2-nPent-Ph
3-179 4,5-diHM-dioxo nBu 2-nPent-Ph
3-180 4,5-diHE-dioxo nBu 2-nPent-Ph
3-181 dioxo iPr 2-nPent-Ph
3-182 4-HM-dioxo iPr 2-nPent-Ph
3-183 4,5-diHM-dioxo iPr 2-nPent-Ph
3-184 4,5-diHE-dioxo iPr 2-nPent-Ph
3-185 dioxo tBu 2-nPent-Ph
3-186 4-HM-dioxo tBu 2-nPent-Ph
3-187 4,5-diHM-dioxo tBu 2-nPent-Ph
3-188 4,5-diHE-dioxo tBu 2-nPent-Ph
3-189 dioxo CH ₂ OAc 2-nPent-Ph
3-190 4-HM-dioxo CH ₂ OAc 2-nPent-Ph
3-191 4,5-diHM-dioxo CH ₂ OAc 2-nPent-Ph
3-192 4,5-diHE-dioxo CH ₂ OAc 2-nPent-Ph
3-193 dioxo Me 4-F-2-nPent-Ph
3-194 4-HM-dioxo Me 4-F-2-nPent-Ph
3-195 4,5-diHM-dioxo Me 4-F-2-nPent-Ph
3-196 4,5-diHE-dioxo Me 4-F-2-nPent-Ph
3-197 dioxo nPr 4-F-2-nPent-Ph
3-198 4-HM-dioxo nPr 4-F-2-nPent-Ph
3-199 4,5-diHM-dioxo nPr 4-F-2-nPent-Ph
3-200 4,5-diHE-dioxo nPr 4-F-2-nPent-Ph
3-201 dioxo nBu 4-F-2-nPent-Ph
3-202 4-HM-dioxo nBu 4-F-2-nPent-Ph
3-203 4,5-diHM-dioxo nBu 4-F-2-nPent-Ph
3-204 4,5-diHE-dioxo nBu 4-F-2-nPent-Ph
3-205 dioxo iPr 4-F-2-nPent-Ph
3-206 4-HM-dioxo iPr 4-F-2-nPent-Ph
3-207 4,5-diHM-dioxo iPr 4-F-2-nPent-Ph
3-208 4,5-diHE-dioxo iPr 4-F-2-nPent-Ph
3-209 dioxo tBu 4-F-2-nPent-Ph
3-210 4-HM-dioxo tBu 4-F-2-nPent-Ph
3-211 4,5-diHM-dioxo tBu 4-F-2-nPent-Ph
3-212 4,5-diHE-dioxo tBu 4-F-2-nPent-Ph
3-213 dioxo CH ₂ OAc 4-F-2-nPent-Ph
3-214 4-HM-dioxo CH ₂ OAc 4-F-2-nPent-Ph
3-215 4,5-diHM-dioxo CH ₂ OAc 4-F-2-nPent-Ph
3-216 4,5-diHE-dioxo CH ₂ OAc 4-F-2-nPent-Ph
3-217 dioxo Me 2-nHex-Ph
3-218 4-HM-dioxo Me 2-nHex-Ph
3-219 4,5-diHM-dioxo Me 2-nHex-Ph
3-220 4,5-diHE-dioxo Me 2-nHex-Ph
3-221 dioxo nPr 2-nHex-Ph
3-222 4-HM-dioxo nPr 2-nHex-Ph
3-223 4,5-diHM-dioxo nPr 2-nHex-Ph
3-224 4,5-diHE-dioxo nPr 2-nHex-Ph
3-225 dioxo nBu 2-nHex-Ph
3-226 4-HM-dioxo nBu 2-nHex-Ph
3-227 4,5-diHM-dioxo nBu 2-nHex-Ph
3-228 4,5-diHE-dioxo nBu 2-nHex-Ph
3-229 dioxo iPr 2-nHex-Ph
3-230 4-HM-dioxo iPr 2-nHex-Ph
3-231 4,5-diHM-dioxo iPr 2-nHex-Ph
3-232 4,5-diHE-dioxo iPr 2-nHex-Ph
3-233 dioxo tBu 2-nHex-Ph
3-234 4-HM-dioxo tBu 2-nHex-Ph
3-235 4,5-diHM-dioxo tBu 2-nHex-Ph
3-236 4,5-diHE-dioxo tBu 2-nHex-Ph
3-237 dioxo CH ₂ OAc 2-nHex-Ph
3-238 4-HM-dioxo CH ₂ OAc 2-nHex-Ph
3-239 4,5-diHM-dioxo CH ₂ OAc 2-nHex-Ph
3-240 4,5-diHE-dioxo CH ₂ OAc 2-nHex-Ph
3-241 dioxo Me 4-F-nHex-Ph
3-242 4-HM-dioxo Me 4-F-nHex-Ph
3-243 4,5-diHM-dioxo Me 4-F-nHex-Ph
3-244 4,5-diHE-dioxo Me 4-F-nHex-Ph
3-245 dioxo nPr 4-F-nHex-Ph
3-246 4-HM-dioxo nPr 4-F-nHex-Ph
3-247 4,5-diHM-dioxo nPr 4-F-nHex-Ph
3-248 4,5-diHE-dioxo nPr 4-F-nHex-Ph
3-249 dioxo nBu 4-F-nHex-Ph
3-250 4-HM-dioxo nBu 4-F-nHex-Ph
3-251 4,5-diHM-dioxo nBu 4-F-nHex-Ph
3-252 4,5-diHE-dioxo nBu 4-F-nHex-Ph
3-253 dioxo iPr 4-F-nHex-Ph
3-254 4-HM-dioxo iPr 4-F-nHex-Ph
3-255 4,5-diHM-dioxo iPr 4-F-nHex-Ph
3-256 4,5-diHE-dioxo iPr 4-F-nHex-Ph
3-257 dioxo tBu 4-F-nHex-Ph
3-258 4-HM-dioxo tBu 4-F-nHex-Ph
3-259 4,5-diHM-dioxo tBu 4-F-nHex-Ph
3-260 4,5-diHE-dioxo tBu 4-F-nHex-Ph
3-261 dioxo CH ₂ OAc 4-F-nHex-Ph
3-262 4-HM-dioxo CH ₂ OAc 4-F-nHex-Ph
3-263 4,5-diHM-dioxo CH ₂ OAc 4-F-nHex-Ph
3-264 4,5-diHE-dioxo CH ₂ OAc 4-F-nHex-Ph
3-265 dioxo Me 2-nHept-Ph
3-266 4-HM-dioxo Me 2-nHept-Ph
3-267 4,5-diHM-dioxo Me 2-nHept-Ph
3-268 4,5-diHE-dioxo Me 2-nHept-Ph
3-269 dioxo nPr 2-nHept-Ph
3-270 4-HM-dioxo nPr 2-nHept-Ph
3-271 4,5-diHM-dioxo nPr 2-nHept-Ph
3-272 4,5-diHE-dioxo nPr 2-nHept-Ph
3-273 dioxo nBu 2-nHept-Ph
3-274 4-HM-dioxo nBu 2-nHept-Ph
3-275 4,5-diHM-dioxo nBu 2-nHept-Ph
3-276 4,5-diHE-dioxo nBu 2-nHept-Ph
3-277 dioxo iPr 2-nHept-Ph
3-278 4-HM-dioxo iPr 2-nHept-Ph
3-279 4,5-diHM-dioxo iPr 2-nHept-Ph
3-280 4,5-diHE-dioxo iPr 2-nHept-Ph
3-281 dioxo tBu 2-nHept-Ph
3-282 4-HM-dioxo tBu 2-nHept-Ph
3-283 4,5-diHM-dioxo tBu 2-nHept-Ph
3-284 4,5-diHE-dioxo tBu 2-nHept-Ph
3-285 dioxo CH ₂ OAc 2-nHept-Ph
3-286 4-HM-dioxo CH ₂ OAc 2-nHept-Ph
3-287 4,5-diHM-dioxo CH ₂ OAc 2-nHept-Ph
3-288 4,5-diHE-dioxo CH ₂ OAc 2-nHept-Ph
3-289 dioxo Me 4-F-2-nHept-Ph
3-290 4-HM-dioxo Me 4-F-2-nHept-Ph
3-291 4,5-diHM-dioxo Me 4-F-2-nHept-Ph
3-292 4,5-diHE-dioxo Me 4-F-2-nHept-Ph
3-293 dioxo nPr 4-F-2-nHept-Ph
3-294 4-HM-dioxo nPr 4-F-2-nHept-Ph
3-295 4,5-diHM-dioxo nPr 4-F-2-nHept-Ph
3-296 4,5-diHE-dioxo nPr 4-F-2-nHept-Ph
3-297 dioxo nBu 4-F-2-nHept-Ph
3-298 4-HM-dioxo nBu 4-F-2-nHept-Ph
3-299 4,5-diHM-dioxo nBu 4-F-2-nHept-Ph
3-300 4,5-diHE-dioxo nBu 4-F-2-nHept-Ph
3-301 dioxo iPr 4-F-2-nHept-Ph
3-302 4-HM-dioxo iPr 4-F-2-nHept-Ph
3-303 4,5-diHM-dioxo iPr 4-F-2-nHept-Ph
3-304 4,5-diHE-dioxo iPr 4-F-2-nHept-Ph
3-305 dioxo tBu 4-F-2-nHept-Ph
3-306 4-HM-dioxo tBu 4-F-2-nHept-Ph
3-307 4,5-diHM-dioxo tBu 4-F-2-nHept-Ph
3-308 4,5-diHE-dioxo tBu 4-F-2-nHept-Ph
3-309 dioxo CH ₂ OAc 4-F-2-nHept-Ph
3-310 4-HM-dioxo CH ₂ OAc 4-F-2-nHept-Ph
3-311 4,5-diHM-dioxo CH ₂ OAc 4-F-2-nHept-Ph
3-312 4,5-diHE-dioxo CH ₂ OAc 4-F-2-nHept-Ph
3-313 dioxo Me 2-nOct-Ph
3-314 4-HM-dioxo Me 2-nOct-Ph
3-315 4,5-diHM-dioxo Me 2-nOct-Ph
3-316 4,5-diHE-dioxo Me 2-nOct-Ph
3-317 dioxo nPr 2-nOct-Ph
3-318 4-HM-dioxo nPr 2-nOct-Ph
3-319 4,5-diHM-dioxo nPr 2-nOct-Ph
3-320 4,5-diHE-dioxo nPr 2-nOct-Ph
3-321 dioxo nBu 2-nOct-Ph
3-322 4-HM-dioxo nBu 2-nOct-Ph
3-323 4,5-diHM-dioxo nBu 2-nOct-Ph
3-324 4,5-diHE-dioxo nBu 2-nOct-Ph
3-325 dioxo iPr 2-nOct-Ph
3-326 4-HM-dioxo iPr 2-nOct-Ph
3-327 4,5-diHM-dioxo iPr 2-nOct-Ph
3-328 4,5-diHE-dioxo iPr 2-nOct-Ph
3-329 dioxo tBu 2-nOct-Ph
3-330 4-HM-dioxo tBu 2-nOct-Ph
3-331 4,5-diHM-dioxo tBu 2-nOct-Ph
3-332 4,5-diHE-dioxo tBu 2-nOct-Ph
3-333 dioxo CH ₂ OAc 2-nOct-Ph
3-334 4-HM-dioxo CH ₂ OAc 2-nOct-Ph
3-335 4,5-diHM-dioxo CH ₂ OAc 2-nOct-Ph
3-336 4,5-diHE-dioxo CH ₂ OAc 2-nOct-Ph
3-337 dioxo Me 4-F-2-nOct-Ph
3-338 4-HM-dioxo Me 4-F-2-nOct-Ph
3-339 4,5-diHM-dioxo Me 4-F-2-nOct-Ph
3-340 4,5-diHE-dioxo Me 4-F-2-nOct-Ph
3-341 dioxo nPr 4-F-2-nOct-Ph
3-342 4-HM-dioxo nPr 4-F-2-nOct-Ph
3-343 4,5-diHM-dioxo nPr 4-F-2-nOct-Ph
3-344 4,5-diHE-dioxo nPr 4-F-2-nOct-Ph
3-345 dioxo nBu 4-F-2-nOct-Ph
3-346 4-HM-dioxo nBu 4-F-2-nOct-Ph
3-347 4,5-diHM-dioxo nBu 4-F-2-nOct-Ph
3-348 4,5-diHE-dioxo nBu 4-F-2-nOct-Ph
3-349 dioxo iPr 4-F-2-nOct-Ph
3-350 4-HM-dioxo iPr 4-F-2-nOct-Ph
3-351 4,5-diHM-dioxo iPr 4-F-2-nOct-Ph
3-352 4,5-diHE-dioxo iPr 4-F-2-nOct-Ph
3-353 dioxo tBu 4-F-2-nOct-Ph
3-354 4-HM-dioxo tBu 4-F-2-nOct-Ph
3-355 4,5-diHM-dioxo tBu 4-F-2-nOct-Ph
3-356 4,5-diHE-dioxo tBu 4-F-2-nOct-Ph
3-357 dioxo CH ₂ OAc 4-F-2-nOct-Ph
3-358 4-HM-dioxo CH ₂ OAc 4-F-2-nOct-Ph
3-359 4,5-diHM-dioxo CH ₂ OAc 4-F-2-nOct-Ph
3-360 4,5-diHE-dioxo CH ₂ OAc 4-F-2-nOct-Ph
3-361 dioxo Me Ph
3-362 4-HM-dioxo Me Ph
3-363 4,5-diHM-dioxo Me Ph
3-364 4,5-diHE-dioxo Me Ph
3-365 dioxo nPr Ph
3-366 4-HM-dioxo nPr Ph
3-367 4,5-diHM-dioxo nPr Ph
3-368 4,5-diHE-dioxo nPr Ph
3-369 dioxo nBu Ph
3-370 4-HM-dioxo nBu Ph
3-371 4,5-diHM-dioxo nBu Ph
3-372 4,5-diHE-dioxo nBu Ph
3-373 dioxo iPr Ph
3-374 4-HM-dioxo iPr Ph
3-375 4,5-diHM-dioxo iPr Ph
3-376 4,5-diHE-dioxo iPr Ph
3-377 dioxo tBu Ph
3-378 4-HM-dioxo tBu Ph
3-379 4,5-diHM-dioxo tBu Ph
3-380 4,5-diHE-dioxo tBu Ph
3-381 dioxo CH ₂ OAc Ph
3-382 4-HM-dioxo CH ₂ OAc Ph
3-383 4,5-diHM-dioxo CH ₂ OAc Ph
3-384 4,5-diHE-dioxo CH ₂ OAc Ph
3-385 dioxo Me 4-F-Ph
3-386 4-HM-dioxo Me 4-F-Ph
3-387 4,5-diHM-dioxo Me 4-F-Ph
3-388 4,5-diHE-dioxo Me 4-F-Ph
3-389 dioxo nPr 4-F-Ph
3-390 4-HM-dioxo nPr 4-F-Ph
3-391 4,5-diHM-dioxo nPr 4-F-Ph
3-392 4,5-diHE-dioxo nPr 4-F-Ph
3-393 dioxo nBu 4-F-Ph
3-394 4-HM-dioxo nBu 4-F-Ph
3-395 4,5-diHM-dioxo nBu 4-F-Ph
3-396 4,5-diHE-dioxo nBu 4-F-Ph
3-397 dioxo iPr 4-F-Ph
3-398 4-HM-dioxo iPr 4-F-Ph
3-399 4,5-diHM-dioxo iPr 4-F-Ph
3-400 4,5-diHE-dioxo iPr 4-F-Ph
3-401 dioxo tBu 4-F-Ph
3-402 4-HM-dioxo tBu 4-F-Ph
3-403 4,5-diHM-dioxo tBu 4-F-Ph
3-404 4,5-diHE-dioxo tBu 4-F-Ph
3-405 dioxo CH ₂ OAc 4-F-Ph
3-406 4-HM-dioxo CH ₂ OAc 4-F-Ph
3-407 4,5-diHM-dioxo CH ₂ OAc 4-F-Ph
3-408 4,5-diHE-dioxo CH ₂ OAc 4-F-Ph
3-409 dioxo Me 2-Cl-4-Me-Ph
3-410 4-HM-dioxo Me 2-Cl-4-Me-Ph
3-411 4,5-diHM-dioxo Me 2-Cl-4-Me-Ph
3-412 4,5-diHE-dioxo Me 2-Cl-4-Me-Ph
3-413 dioxo nPr 2-Cl-4-Me-Ph
3-414 4-HM-dioxo nPr 2-Cl-4-Me-Ph
3-415 4,5-diHM-dioxo nPr 2-Cl-4-Me-Ph
3-416 4,5-diHE-dioxo nPr 2-Cl-4-Me-Ph
3-417 dioxo nBu 2-Cl-4-Me-Ph
3-418 4-HM-dioxo nBu 2-Cl-4-Me-Ph
3-419 4,5-diHM-dioxo nBu 2-Cl-4-Me-Ph
3-420 4,5-diHE-dioxo nBu 2-Cl-4-Me-Ph
3-421 dioxo iPr 2-Cl-4-Me-Ph
3-422 4-HM-dioxo iPr 2-Cl-4-Me-Ph
3-423 4,5-diHM-dioxo iPr 2-Cl-4-Me-Ph
3-424 4,5-diHE-dioxo iPr 2-Cl-4-Me-Ph
3-425 dioxo tBu 2-Cl-4-Me-Ph
3-426 4-HM-dioxo tBu 2-Cl-4-Me-Ph
3-427 4,5-diHM-dioxo tBu 2-Cl-4-Me-Ph
3-428 4,5-diHE-dioxo tBu 2-Cl-4-Me-Ph
3-429 dioxo CH ₂ OAc 2-Cl-4-Me-Ph
3-430 4-HM-dioxo CH ₂ OAc 2-Cl-4-Me-Ph
3-431 4,5-diHM-dioxo CH ₂ OAc 2-Cl-4-Me-Ph
3-432 4,5-diHE-dioxo CH ₂ OAc 2-Cl-4-Me-Ph
3-433 dioxo Me 2-nBu-Ph
3-434 4-HM-dioxo Me 2-nBu-Ph
3-435 4,5-diHM-dioxo Me 2-nBu-Ph
3-436 4,5-diHE-dioxo Me 2-nBu-Ph
3-437 dioxo nPr 2-nBu-Ph
3-438 4-HM-dioxo nPr 2-nBu-Ph
3-439 4,5-diHM-dioxo nPr 2-nBu-Ph
3-440 4,5-diHE-dioxo nPr 2-nBu-Ph
3-441 dioxo nBu 2-nBu-Ph
3-442 4-HM-dioxo nBu 2-nBu-Ph
3-443 4,5-diHM-dioxo nBu 2-nBu-Ph
3-444 4,5-diHE-dioxo nBu 2-nBu-Ph
3-445 dioxo iPr 2-nBu-Ph
3-446 4-HM-dioxo iPr 2-nBu-Ph
3-447 4,5-diHM-dioxo iPr 2-nBu-Ph
3-448 4,5-diHE-dioxo iPr 2-nBu-Ph
3-449 dioxo tBu 2-nBu-Ph
3-450 4-HM-dioxo tBu 2-nBu-Ph
3-451 4,5-diHM-dioxo tBu 2-nBu-Ph
3-452 4,5-diHE-dioxo tBu 2-nBu-Ph
3-453 dioxo CH ₂ OAc 2-nBu-Ph
3-454 4-HM-dioxo CH ₂ OAc 2-nBu-Ph
3-455 4,5-diHM-dioxo CH ₂ OAc 2-nBu-Ph
3-456 4,5-diHE-dioxo CH ₂ OAc 2-nBu-Ph
3-457 dioxo Me 2-nPr-Ph
3-458 4-HM-dioxo Me 2-nPr-Ph
3-459 4,5-diHM-dioxo Me 2-nPr-Ph
3-460 4,5-diHE-dioxo Me 2-nPr-Ph
3-461 dioxo nPr 2-nPr-Ph
3-462 4-HM-dioxo nPr 2-nPr-Ph
3-463 4,5-diHM-dioxo nPr 2-nPr-Ph
3-464 4,5-diHE-dioxo nPr 2-nPr-Ph
3-465 dioxo nBu 2-nPr-Ph
3-466 4-HM-dioxo nBu 2-nPr-Ph
3-467 4,5-diHM-dioxo nBu 2-nPr-Ph
3-468 4,5-diHE-dioxo nBu 2-nPr-Ph
3-469 dioxo iPr 2-nPr-Ph
3-470 4-HM-dioxo iPr 2-nPr-Ph
3-471 4,5-diHM-dioxo iPr 2-nPr-Ph
3-472 4,5-diHE-dioxo iPr 2-nPr-Ph
3-473 dioxo tBu 2-nPr-Ph
3-474 4-HM-dioxo tBu 2-nPr-Ph
3-475 4,5-diHM-dioxo tBu 2-nPr-Ph
3-476 4,5-diHE-dioxo tBu 2-nPr-Ph
3-477 dioxo CH ₂ OAc 2-nPr-Ph
3-478 4-HM-dioxo CH ₂ OAc 2-nPr-Ph
3-479 4,5-diHM-dioxo CH ₂ OAc 2-nPr-Ph
3-480 4,5-diHE-dioxo CH ₂ OAc 2-nPr-Ph
3-481 dioxo Me 4-F-2-nPr-Ph
3-482 4-HM-dioxo Me 4-F-2-nPr-Ph
3-483 4,5-diHM-dioxo Me 4-F-2-nPr-Ph
3-484 4,5-diHE-dioxo Me 4-F-2-nPr-Ph
3-485 dioxo nPr 4-F-2-nPr-Ph
3-486 4-HM-dioxo nPr 4-F-2-nPr-Ph
3-487 4,5-diHM-dioxo nPr 4-F-2-nPr-Ph
3-488 4,5-diHE-dioxo nPr 4-F-2-nPr-Ph
3-489 dioxo nBu 4-F-2-nPr-Ph
3-490 4-HM-dioxo nBu 4-F-2-nPr-Ph
3-491 4,5-diHM-dioxo nBu 4-F-2-nPr-Ph
3-492 4,5-diHE-dioxo nBu 4-F-2-nPr-Ph
3-493 dioxo iPr 4-F-2-nPr-Ph
3-494 4-HM-dioxo iPr 4-F-2-nPr-Ph
3-495 4,5-diHM-dioxo iPr 4-F-2-nPr-Ph
3-496 4,5-diHE-dioxo iPr 4-F-2-nPr-Ph
3-497 dioxo tBu 4-F-2-nPr-Ph
3-498 4-HM-dioxo tBu 4-F-2-nPr-Ph
3-499 4,5-diHM-dioxo tBu 4-F-2-nPr-Ph
3-500 4,5-diHE-dioxo tBu 4-F-2-nPr-Ph
3-501 dioxo CH ₂ OAc 4-F-2-nPr-Ph
3-502 4-HM-dioxo CH ₂ OAc 4-F-2-nPr-Ph
3-503 4,5-diHM-dioxo CH ₂ OAc 4-F-2-nPr-Ph
3-504 4,5-diHE-dioxo CH ₂ OAc 4-F-2-nPr-Ph
―――――――――――――――――――――――――――――――――――.

Among the compounds having the general formula (I) of the present invention, suitable compounds include exemplified compound numbers.
: 1-12, 1-13, 1-19, 1-20, 1-26, 1-28, 1-30, 1-32
, 1-34, 1-36, 1-38, 1-40, 1-42, 1-44, 1-46, 1-48
1-50, 1-54, 1-58, 1-60, 1-62, 1-66, 1-68, 1-70
1-72, 1-74, 1-78, 1-80, 1-82, 1-86, 1-100, 1-1
01, 1-107, 1-108, 1-114, 1-116, 1-118, 1-120, 1
-122, 1-124, 1-126, 1-128, 1-130, 1-132, 1-134
1-136, 1-138, 1-142, 1-146, 1-148, 1-150, 1-1
54, 1-156, 1-158, 1-160, 1-162, 1-166, 1-168, 1
-170, 1-174, 1-188, 1-189, 1-195, 1-196, 1-202
, 1-24, 1-206, 1-208, 1-210, 1-212, 1-214, 1-2
16, 1-218, 1-220, 1-222, 1-224, 1-226, 1-230, 1
-234, 1-236, 1-238, 1-242, 1-244, 1-246, 1-248
, 1-250, 1-254, 1-256, 1-258, 1-262, 1-276, 1-2
77, 1-283, 1-284, 1-290, 1-292, 1-294, 1-296, 1
-298, 1-300, 1-302, 1-304, 1-306, 1-308, 1-310
1-312, 1-314, 1-318, 1-322, 1-324, 1-326, 1-3
30, 1-332, 1-334, 1-336, 1-338, 1-342, 1-344, 1
-346, 1-350, 1-353, 1-355, 1-360 to 1-369, 1-37
1, 1-372, 1-378, 1-380, 1-382, 1-384, 1-386, 1-
388, 1-390, 1-392, 1-394, 1-396, 1-398, 1-400,
1-402, 1-406, 1-410, 1-412, 1-414, 1-418, 1-42
0, 1-422, 1-424, 1-426, 1-430, 1-432, 1-434, 1-
438, 1-452, 1-453, 1-459, 1-460, 1-466, 1-468,
1-470, 1-472, 1-474, 1-476, 1-478, 1-480, 1-48
2, 1-484, 1-486, 1-488, 1-490, 1-494, 1-498, 1-
500, 1-502, 1-506, 1-508, 1-510, 1-512, 1-514,
1-518, 1-520, 1-522, 1-526, 1-540, 1-541, 1-54
7, 1-548, 1-554, 1-556, 1-558, 1-560, 1-562, 1-
564, 1-566, 1-568, 1-570, 1-572, 1-574, 1-576,
1-578, 1-582, 1-586, 1-588, 1-590, 1-594, 1-59
6, 1-598, 1-600, 1-602, 1-604, 1-606, 1-608, 1-
610, 1-614, 1-628, 1-629, 1-635, 1-636, 1-642,
1-644, 1-646, 1-648, 1-650, 1-652, 1-654, 1-65
6, 1-658, 1-660, 1-662, 1-664, 1-666, 1-670, 1-
674, 1-676, 1-678, 1-682, 1-684, 1-686, 1-688,
1-690, 1-694, 1-696, 1-698, 1-702, 1-712 to 1-7
20, 1-723, 1-724, 1-730, 1-732, 1-734, 1-736, 1
-738, 1-740, 1-742, 1-744, 1-746, 1-748, 1-750
1-752, 1-754, 1-758, 1-762, 1-764, 1-766, 1-7
70, 1-772, 1-774, 1-776, 1-778, 1-782, 1-784, 1
-786, 1-790, 1-804, 1-805, 1-811, 1-812, 1-818
1-820, 1-822, 1-824, 1-826, 1-828, 1-830, 1-8
32, 1-834, 1-836, 1-838, 1-840, 1-842, 1-846, 1
-850, 1-852, 1-854, 1-858, 1-860, 1-862, 1-864
1-866, 1-870, 1-872, 1-874, 1-878, 1-888 to 1-
896, 1-899, 1-900, 1-906, 1-908, 1-910, 1-912,
1-914, 1-916, 1-918, 1-920, 1-922, 1-924, 1-92
6, 1-928, 1-930, 1-934, 1-938, 1-940, 1-942, 1-
946, 1-948, 1-950, 1-952, 1-954, 1-958, 1-960,
1-962, 1-966, 1-980, 1-981, 1-987, 1-988, 1-99
4, 1-996, 1-998, 1-1000, 1-1002, 1-1004, 1-100
6, 1-1008, 1-1010, 1-1012, 1-1014, 1-1016, 1-1
018, 1-1022, 1-1026, 1-1028, 1-1030, 1-1034, 1
-1036, 1-1038, 1-1040, 1-1042, 1-1046, 1-1048
1-1050, 1-1054, 1-1057, 1-1062, 1-1063, 1-10
66, 1-1067 to 1-1070, 1-1074, 1-1079, 1-1080, 1
-1083, 1-1085 to 1-1087, 1-1091, 1-1096, 1-109
7, 1-1100, 1-1102 to 1-1104, 1-1108, 1-1113, 1-
1114, 1-1117, 1-1119 to 1-1121, 1-1125, 1-1130
1-1131, 1-1134, 1-1136 to 1-1138, 1-1142, 1-1
147, 1-1148, 1-1115, 1-1153 to 1-1155, 1-1159,
1-1164, 1-1165, 1-1168, 1-1170 to 1-1172, 1-11
76, 1-1811, 1-182, 1-1185, 1-1187 to 1-1189, 1
-1193, 1-1198, 1-1199, 1-1202, 1-1204 to 1-120
6, 1-1210, 1-1215, 1-1216, 1-1219, 1-1221 to 1-
1223, 1-1227, 1-1232, 1-1233, 1-1236, 1-1238
To 1-1240, 1-1244, 1-1249, 1-1250, 1-1253, 1-12
55 to 1-1257, 1-12611, 1-1266, 1-1267, 1-1270, 1
-1272 to 1-1274, 1-1278, 1-1283, 1-1284, 1-128
7, 1-1289 to 1-1291, 1-1295, 1-1300, 1-1301, 1-
1304, 1-1306 to 1-1308, 1-11312, 1-1317, 1-1318
1-11321, 1-1323 to 1-1325, 1-1329, 1-1334, 1-1
335, 1-1337, 1-1340 to 1-1342, 1-1346, 1-1351,
1-1352, 1-1355, 1-1357 to 1-1359, 1-1374, 1-13
75, 1-11381, 1-1382, 1-1388, 1-1390, 1-1392, 1-
1394, 1-1396, 1-1398, 1-1400, 1-1402, 1-1404,
1-1406, 1-1408, 1-1410, 1-1414, 1-1416, 1-142
0, 1-1422, 1-1428, 1-1430, 1-1432, 1-1434, 1-1
436, 1-1440, 1-1442, 1-1444, 1-1448, 1-1462, 1
-1463, 1-1469, 1-1470, 1-1476, 1-1478, 1-1480
1-1482, 1-1484, 1-1486, 1-1488, 1-1490, 1-14
92, 1-1494, 1-1495, 1-1498, 1-1500, 1-1504, 1-
1508, 1-1510, 1-1516, 1-1518, 1-1520, 1-1522,
1-1524, 1-1528, 1-1530, 1-1532, 1-1536, 1-155
0, 1-1551, 1-1557, 1-1558, 1-1564, 1-1565, 1-1
568, 1-1570, 1-1572, 1-1574, 1-1576, 1-1578, 1
-1580, 1-1582, 1-1584, 1-1586, 1-1588, 1-1582
, 1-1596, 1-1598, 1-1604, 1-1606, 1-1608, 1-16
10, 1-1612, 1-1616, 1-1618, 1-1620, 1-1624, 1-
1638, 1-1639, 1-1645, 1-1646, 1-1652, 1-1654,
1-1656, 1-1658, 1-1660, 1-162, 1-1664, 1-166
6, 1-1668, 1-1670, 1-1672, 1-1647, 1-1676, 1-1
680, 1-1684, 1-1686, 1-1692, 1-1694, 1-1696, 1
-1698, 1-1700, 1-1704, 1-1706, 1-1708, 1-1712
1-1726, 1-1727, 1-1733, 1-1734, 1-1740, 1-17
42, 1-1744, 1-1746, 1-1748, 1-1750, 1-1752, 1-
1754, 1-1756, 1-1758, 1-1760, 1-1762, 1-176,
1-1768, 1-1772, 1-1774, 1-1780, 1-1782, 1-178
4, 1-1786, 1-1788, 1-17902, 1-1794, 1-1996, 1-1
800, 1-1818, 1-1815, 1-1821, 1-1822, 1-1828, 1
-1830, 1-1832, 1-1834, 1-1836, 1-1838, 1-1840
1-1842, 1-1844, 1-1848, 1-1848, 1-1850, 1-18
52, 1-1856, 1-1860, 1-1862, 1-1868, 1-1870, 1-
1872, 1-1874, 1-1876, 1-1880, 1-1882, 1-1884,
1-1888, 1-1902, 1-1903, 1-1909, 1-1910, 1-191
6, 1-1918, 1-1920, 1-1922, 1-1924, 1-1926, 1-1
928, 1-1930, 1-1932, 1-1934, 1-1936, 1-1938, 1
-1940, 1-1944, 1-1948, 1-1950, 1-1958, 1-1958
1-1960, 1-1962, 1-1964, 1-1968, 1-1970, 1-19
72, 1-1976, 1-1989, 1-1990, 1-1996, 1-1997, 1-
2003, 1-2005, 1-2007, 1-2009, 1-2011, 1-2013,
1-2015, 1-2017, 1-2019, 1-2021, 1-2023, 1-202
5, 1-2027, 1-2031, 1-2035, 1-2037, 1-2043, 1-2
045, 1-2047, 1-2049, 1-2051, 1-2055, 1-2057, 1
-2059, 1-2063, 1-2077, 1-2078, 1-2084, 1-2085
1-2091, 1-2093, 1-2095, 1-2097, 1-2099, 1-21
01, 1-2103, 1-2105, 1-2107, 1-2109, 1-2111, 1-
2113, 1-2115, 1-2119, 1-2123, 1-2125, 1-2131,
1-2133, 1-2135, 1-2137, 1-2139, 1-2143, 1-214
5, 1-2147, 1-2151, 1-2154, 1-2157, 1-2160, 1-2
163, 1-2166, 1-2169, 1-2172, 1-2175, 1-2178, 1
-2181, 1-2184, 1-2187, 1-2190, 1-2193, 1-2196
, 1-2199, 1-2202, 1-2205, 1-2208, 1-2211, 1-22
14, 1-2217 to 1-2221, 1-2224 to 1-2228, 1-2231
To 1-2235, 1-2238 to 1-2242, 1-2245 to 1-2249, 1-
2252 to 1-2256, 1-2259 to 1-2263, 1-2266 to 1-22
70, 1-2273 to 1-2277, 1-2280 to 1-2284, 1-2287
To




1-2291, 1-2294 to 1-2298, 1-2301 to 1-2305, 1-2
308 to 1-2312, 1-2315 to 1-2319, 1-2322 to 1-232
6, 1-2329 to 1-2333, 1-2336 to 1-2340, 1-2343 to
1-2347, 1-2350 to 1-2354, 1-2357 to 1-2361, 1-2
364 to 1-2368, 1-2371 to 1-2375, 1-2378 to 1-238
2, 1-2385 to 1-2389, 1-2392 to 1-2396, 1-2399 to
1-2403, 1-2406 to 1-2410, 1-2413 to 1-2417, 1-2
420 to 1-2424, 1-2427 to 1-2243, 1-2434 to 1-243
8, 1-2441 to 1-2445, 1-2448 to 1-2245, 1-2455 to
1-259, 1-2462 to 1-2466, 1-2469 to 1-2473, 1-2
476 to 1-2480, 1-2483 to 1-2487, 1-2490 to 1-249
4, 1-2497 to 1-2501, 1-2504 to 1-2508, 1-2511 to
1-2525, 1-2518 to 1-2522, 1-2525 to 1-2529, 1-2
532 to 1-2536, 1-2539 to 1-2543, 1-2546 to 1-255
0, 1-2553 to 1-2557, 1-2560 to 1-2564, 1-2567 to
1-2571, 1-2574 to 1-2578, 1-2588 to 1-2585, 1-2
588 to 1-2592, 1-2595 to 1-2599, 1-2602 to 1-260
6, 1-2609 to 1-2613, 1-2616 to 1-2620, 1-2623 to
1-2627,
2-3, 2-4, 2-7, 2-8, 2-11, 2-12, 2-15, 2-16, 2-19
2-20, 2-23, 2-24, 2-27, 2-28, 2-31, 2-32, 2-35
2-36, 2-39, 2-40, 2-43, 2-44, 2-47, 2-48, 2-51
2-52, 2-59, 2-60, 2-83, 2-84,
3-3, 3-4, 3-7, 3-8, 3-11, 3-12, 3-15, 3-16, 3-27
, 3-28, 3-31, 3-32, 3-35, 3-36, 3-39, 3-40, 3-51
3-52, 3-55, 3-56, 3-59, 3-60, 3-63, 3-64, 3-75
, 3-76, 3-79, 3-80, 3-83, 3-84, 3-87, 3-88, 3-99
3-100, 3-103, 3-104, 3-107, 3-108, 3-111, 3-1.
12, 3-123, 3-124, 3-127, 3-128, 3-131, 3-132, 3
-135, 3-136, 3-147, 3-148, 3-151, 3-152, 3-155
3-156, 3-159, 3-160, 3-171, 3-172, 3-175, 3-1.
76, 3-179, 3-180, 3-183, 3-184, 3-195, 3-196, 3
-199, 3-200, 3-203, 3-204, 3-207, 3-208, 3-219
3-220, 3-223, 3-224, 3-227, 3-228, 3-231, 3-2
32, 3-243, 3-244, 3-247, 3-248, 3-251, 3-252, 3
-255, 3-256, 3-267, 3-268, 3-271, 3-272, 3-275
3-276, 3-279, 3-280, 3-291, 3-292, 3-295, 3-2
96, 3-299, 3-300, 3-303, 3-304, 3-339, 3-340, 3
-343, 3-344, 3-347, 3-348, 3-351, 3-352, 3-483
3-484, 3-487, 3-488, 3-491, 3-492, 3-495, 3-4
96,
Can mention
More preferably, exemplary compound numbers: 1-12, 1-26, 1-30, 1-34, 1-38,
1-42, 1-46, 1-58, 1-66, 1-70, 1-78, 1-100, 1-11
4, 1-118, 1-122, 1-126, 1-130, 1-134, 1-146, 1-
154, 1-158, 1-166, 1-188, 1-202, 1-206, 1-210,
1-214, 1-218, 1-222, 1-234, 1-242, 1-246, 1-25
4, 1-276, 1-290, 1-294, 1-298, 1-302, 1-306, 1-
310, 1-322, 1-330, 1-334, 1-342, 1-364, 1-378,
1-382, 1-386, 1-390, 1-394, 1-398, 1-410, 1-41
8, 1-422, 1-430, 1-452, 1-466, 1-470, 1-474, 1-
478, 1-482, 1-486, 1-498, 1-506, 1-510, 1-518,
1-540, 1-554, 1-558, 1-562, 1-566, 1-570, 1-57
4, 1-586, 1-594, 1-598, 1-604, 1-606, 1-628, 1-
642, 1-646, 1-650, 1-654, 1-658, 1-662, 1-674,
1-682, 1-686, 1-694, 1-716, 1-730, 1-734, 1-73
8, 1-742, 1-746, 1-750, 1-762, 1-770, 1-774, 1-
782, 1-804, 1-818, 1-822, 1-826, 1-830, 1-834,
1-838, 1-850, 1-858, 1-862, 1-870, 1-892, 1-90
6, 1-910, 1-914, 1-918, 1-922, 1-926, 1-938, 1-
946, 1-950, 1-958, 1-980, 1-994, 1-998, 1-1002
1-1006, 1-1010, 1-1014, 1-1026, 1-1034, 1-10
38, 1-1046, 1-1227, 1-1232, 1-1239, 1-1240, 1-
1244, 1-1249, 1-1256, 1-1257, 1-12611, 1-1266,
1-1273, 1-1274, 1-1278, 1-1283, 1-1290, 1-129
1, 1-1295, 1-1300, 1-1307, 1-1308, 1-1374, 1-1
388, 1-1392, 1-1396, 1-1400, 1-1404, 1-1408, 1
-1420, 1-1428, 1-1432, 1-1440, 1-1462, 1-1476
1-1480, 1-1484, 1-1488, 1-1492, 1-1696, 1-15
08, 1-1516, 1-1520, 1-1528, 1-1550, 1-1564, 1-
1568, 1-1572, 1-1576, 1-1580, 1-1584, 1-1596,
1-1604, 1-1608, 1-1616, 1-1638, 1-1651, 1-165
6, 1-1660, 1-1664, 1-1668, 1-1672, 1-1684, 1-1
692, 1-1696, 1-1704, 1-1726, 1-1740, 1-1744, 1
-1748, 1-1752, 1-1756, 1-1760, 1-1772, 1-1780
1-1784, 1-17902, 1-1814, 1-1828, 1-1832, 1-18
36, 1-1840, 1-1844, 1-1848, 1-1860, 1-1868, 1-
1872, 1-1880, 1-1902, 1-1916, 1-1920, 1-1924,
1-1-1928, 1-1932, 1-1936, 1-1948, 1-1958, 1-196
0, 1-1968, 1-1989, 1-2003, 1-2007, 1-2011, 1-2
015, 1-2019, 1-2023, 1-2035, 1-2043, 1-2047, 1
-2055, 1-2077, 1-2091, 1-2095, 1-2099, 1-2103
1-2107, 1-2111, 1-2123, 1-2131, 1-2135, 1-21
43, 1-2219, 1-2220, 1-2226, 1-2227, 1-2233, 1-
2234, 1-2240, 1-2241, 1-2247, 1-2248, 1-2254,
1-2255, 1-2261, 1-2226, 1-2268, 1-2269, 1-227
5, 1-2276, 1-2282, 1-2283, 1-2289, 1-2290, 1-2
296, 1-2297, 1-2303, 1-2304, 1-2310, 1-2231, 1
-2317, 1-2318, 1-2324, 1-2325, 1-2233, 1-2332
1-2338, 1-2339, 1-2345, 1-2346, 1-2352, 1-23
53, 1-2359, 1-2360, 1-2366, 1-2367, 1-2373, 1-
2374, 1-2380, 1-22381, 1-2387, 1-2388, 1-2394,
1-2395, 1-2401, 1-2402, 1-2408, 1-2409, 1-241
5, 1-2416, 1-2422, 1-2423, 1-2429, 1-2430, 1-2
436, 1-2437, 1-2443, 1-2444, 1-2450, 1-2451, 1
-2457, 1-2458, 1-2464, 1-2465, 1-2471, 1-2472
1-2478, 1-2479, 1-2485, 1-2486, 1-2492, 1-24
93, 1-2499, 1-2500, 1-2506, 1-2507, 1-2513, 1-
2514, 1-2520, 1-2521, 1-2527, 1-2528, 1-2534,
1-2535, 1-2541, 1-2542, 1-2548, 1-2549, 1-255
5, 1-2556, 1-2562, 1-2563, 1-2569, 1-2570, 1-2
576, 1-2577, 1-2583, 1-2588, 1-2590, 1-2591, 1
-2597, 1-2598, 1-2604, 1-2605, 1-2611, 1-2612
, 1-2618, 1-2619, 1-2625, 1-2626,
2-3, 2-7, 2-11, 2-15, 2-19, 2-23, 2-27, 2-31, 2-
35, 2-39, 2-43, 2-47, 2-51, 2-59, 2-83,
3-7, 3-31, 3-55, 3-79, 3-103, 3-127, 3-151, 3-1
75, 3-199, 3-223, 3-247, 3-271, 3-295, 3-343, 3
-487,
Can mention
More preferably,
Illustrative compound number 1-206: ethyl 8- [N- (2-chlorophenyl) sulfamoy
L] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
Ene-7-carboxylate,
Exemplified Compound No. 1-210: Ethyl 8- [N- (2-chlorophenyl) sulfamoy
L] -2,3-bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5]
Deca-6-ene-7-carboxylate,
Illustrative compound number 1-294: ethyl 8- [N- (2,4-difluorophenyl) sulfur
Famoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] de
Car-6-ene-7-carboxylate,
Exemplified Compound No. 1-298: Ethyl 8- [N- (2,4-difluorophenyl) sulfur
Famoyl] -2,3-bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [
4.5] Deca-6-ene-7-carboxylate,
Illustrative compound number 1-378: ethyl 8- [N- (2-chloro-4-fluorophenyl)
) Sulfamoyl] -2-hydroxymethyl-1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate,
Illustrative compound number 1-382: ethyl 8- [N- (2-chloro-4-fluorophenyl)
) Sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.
5] Deca-6-ene-7-carboxylate,
Exemplified compound number 1-386: ethyl 8- [N- (2-chloro-4-fluorophenyl)
) Sulfamoyl] -2,3-bis (1,2-dihydroxyethyl) -1,4-dioxa
Spiro [4.5] dec-6-ene-7-carboxylate,
Exemplified compound number 1-390: ethyl 8- [N- (2-chloro-4-fluorophenyl)
) Sulfamoyl] -2- (1,2-dihydroxyethyl) -1,4-dioxaspiro [4
. 5] Deca-6-ene-7-carboxylate,
Exemplified compound number 1-394: ethyl 8- [N- (2-chloro-4-fluorophenyl)
) Sulfamoyl] -2- (1,2,3-trihydroxypropyl) -1,4-dioxa
Spiro [4.5] dec-6-ene-7-carboxylate,
Exemplified compound number 1-398: ethyl 8- [N- (2-chloro-4-fluorophenyl)
) Sulfamoyl] -2- (1,2,3,4-tetrahydroxybutyl) -1,4-dio
Oxaspiro [4.5] dec-6-ene-7-carboxylate,
Exemplified Compound No. 1-410: Ethyl 2,3-bis (acetylaminomethyl) -8- [
N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Deca-6-ene-7-carboxylate,
Exemplified Compound No. 1-418: Ethyl 9- [N- (2-chloro-4-fluorophenyl)
Sulfamoyl] -3-hydroxy-1,5-dioxaspiro [5.5] undec-7-
Ene-8-carboxylate,
Illustrative compound number 1-422: ethyl 3-acetylamino-9- [N- (2-chloro-
4-Fluorophenyl) sulfamoyl] -1,5-dioxaspiro [5.5] undeca-
7-ene-8-carboxylate,
Exemplified Compound No. 1-430: Ethyl 9- [N- (2-chloro-4-fluorophenyl)
) Sulfamoyl] -3,3-bis (hydroxymethyl) -1,5-dioxaspiro [5.
5] undec-7-ene-8-carboxylate,
Exemplified compound number 1-646: ethyl 8- [N- (2-butyl-4-fluorophenyl)
) Sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.
5] Deca-6-ene-7-carboxylate,
Illustrative compound number 1-650: ethyl 8- [N- (2-butyl-4-fluorophenyl)
) Sulfamoyl] -2,3-bis (1,2-dihydroxyethyl) -1,4-dioxa
Spiro [4.5] dec-6-ene-7-carboxylate,
Exemplified Compound No. 1-734: Ethyl 8- [N- (2-hexylphenyl) sulfamo
Yl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6
-Ene-7-carboxylate,
Illustrative compound number 1-738: ethyl 8- [N- (2-hexylphenyl) sulfamo
Yl] -2,3-bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5
Deca-6-ene-7-carboxylate,
Illustrative compound number 1-822: ethyl 8- [N- (4-fluoro-2-hexylpheny
L) Sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4
. 5] Deca-6-ene-7-carboxylate,
Illustrative compound number 1-826: ethyl 2,3-bis (1,2-dihydroxyethyl)-
8- [N- (4-Fluoro-2-hexylphenyl) sulfamoyl] -1,4-dioxa
Spiro [4.5] dec-6-ene-7-carboxylate,
Exemplified Compound No. 1-910: Ethyl 8- [N- (2-heptylphenyl) sulfamo
Yl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6
-Ene-7-carboxylate,
Illustrative compound number 1-914: ethyl 8- [N- (2-heptylphenyl) sulfamo
Yl] -2,3-bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5
Deca-6-ene-7-carboxylate,
Illustrative compound number 1-998: ethyl 8- [N- (4-fluoro-2-heptylpheny
L) Sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4
. 5] Deca-6-ene-7-carboxylate,
Exemplified Compound No. 1-1002: Ethyl 2,3-bis (1,2-dihydroxyethyl)
-8- [N- (4-fluoro-2-heptylphenyl) sulfamoyl] -1,4-dioxy
Saspiro [4.5] dec-6-ene-7-carboxylate,
Exemplified Compound No. 1-1392: Ethyl 8- [N- (2-bromophenyl) sulfamo
Yl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6
-Ene-7-carboxylate,
Exemplified Compound No. 1-1396: Ethyl 8- [N- (2-bromophenyl) sulfamo
Yl] -2,3-bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5
Deca-6-ene-7-carboxylate,
Exemplified Compound No. 1-1480: Ethyl 8- [N- (2-chloro-6-methylphenyl)
) Sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.
5] Deca-6-ene-7-carboxylate,
Exemplified Compound No. 1-1484: Ethyl 8- [N- (2-chloro-6-methylphenyl)
) Sulfamoyl] -2,3-bis (1,2-dihydroxyethyl) -1,4-dioxa
Spiro [4.5] dec-6-ene-7-carboxylate,
Exemplified Compound No. 1-1568: Ethyl 8- [N- (2-bromo-4-fluoropheny
L) Sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4
. 5] Deca-6-ene-7-carboxylate,
Exemplified Compound No. 1-1572: Ethyl 8- [N- (2-bromo-4-fluoropheny
Sulfamoyl] -2,3-bis (1,2-dihydroxyethyl) -1,4-dioxy
Saspiro [4.5] dec-6-ene-7-carboxylate,
Exemplified Compound No. 1-1656: Ethyl 2,3-bis (hydroxymethyl) -8- [N
-(2-pentylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] deca-
6-ene-7-carboxylate,
Exemplified Compound No. 1-1660: Ethyl 2,3-bis (1,2-dihydroxyethyl)
-8- [N- (2-pentylphenyl) sulfamoyl] -1,4-dioxaspiro [4.
5] Deca-6-ene-7-carboxylate,
Exemplified Compound No. 1-1744: Ethyl 8- [N- (4-fluoro-2-pentylphene)
Nyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [
4.5] Deca-6-ene-7-carboxylate,
Exemplified Compound No. 1-1748: Ethyl 2,3-bis (1,2-dihydroxyethyl)
-8- [N- (4-Fluoro-2-pentylphenyl) sulfamoyl] -1,4-dioxy
Saspiro [4.5] dec-6-ene-7-carboxylate,
Exemplified Compound No. 1-1920: ethyl 8- [N- (4-fluoro-2-octyl fe
Nyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [
4.5] Deca-6-ene-7-carboxylate,
Exemplified Compound No. 1-1924: Ethyl 2,3-bis (1,2-dihydroxyethyl)
-8- [N- (4-fluoro-2-octylphenyl) sulfamoyl] -1,4-dioxy
Saspiro [4.5] dec-6-ene-7-carboxylate,
Exemplary compound number 1-2095: ethyl 8- [N- (4-fluoro-2-propylphenol
Nyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [
4.5] Deca-6-ene-7-carboxylate,
Exemplified Compound No. 1-2099: Ethyl 2,3-bis (1,2-dihydroxyethyl)
-8- [N- (4-fluoro-2-propylphenyl) sulfamoyl] -1,4-dioxy
Saspiro [4.5] dec-6-ene-7-carboxylate,
as well as
Exemplary compound number 2-15: ethyl 8- [N- (2-chloro-4-fluorophenyl)
-N-methylsulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxa
Spiro [4.5] dec-6-ene-7-carboxylate
Can be mentioned.

The compound having the general formula (I) of the present invention can be easily produced according to the following methods A to C.

Method A is a method for producing a compound having the general formula (I) by introducing a cyclic ketal in the first stage of production.

Method B is a method for producing a compound having the general formula (I) by introducing a cyclic ketal at the final stage of production.

Method C is a method for producing a compound having the general formula (I) by introducing R ⁵ at the final stage of production.

In the above methods A to C, ring A, ring B, X, Y, R ¹ , R ² , R ³ , R ⁵ , m and n
Represents the same meaning as described above, L represents a leaving group, and Z represents a protecting group.

In the reaction of Method A to Method C, when the compound serving as a reaction substrate has a group that inhibits the desired reaction such as an amino group, a hydroxy group and / or a carboxyl group, these groups are protected as necessary. It may be protected by a group. The protecting group for the group that inhibits the target reaction is not particularly limited as long as it is a protecting group that is usually used for allowing the reaction to proceed. For example, Protective Groups in Organic Synthesis, No. 3 Edition, T
. W. Green & P. G. M.M. Watts, John Wiley & Sons, Inc. [Protective Groups in Organic Synthesis, 3rd edition, TWGreene & PGMWu
ts; John Wiley & Sons, Inc.].

The amino protecting group is not particularly limited as long as it is a group generally used as an amino protecting group, but is preferably formyl, the aforementioned C ₁ -C ₆ alkylcarbonyl group; A C ₁ -C ₆ alkoxycarbonyl group described above; a C ₁ -C ₆ alkanoyl group substituted with the above halogen; benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, α-naphthylmethyl, Examples thereof include aralkyl groups such as β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl and 9-anthrylmethyl; the aforementioned aralkyloxycarbonyl groups and the like.

The protecting group for hydroxy group is a group generally used as a protecting group for hydroxy group,
Although there is no particular limitation, it can be used, but preferably C ₁ -C ₆ such as formyl and acetyl.
Examples thereof include arylcarbonyls such as an alkylcarbonyl group and benzoyl group; alkoxylated alkoxymethyls such as 2-methoxyethoxymethyl.

Protecting group of a carboxyl group, if generally a group used as a protecting group of carboxyl group, although specifically limited may be used without, preferably, C ₁ -C ₆ alkyl described above; benzyl, phenethyl, Mention may be made of aralkyl groups such as phenylpropyl.

Moreover, you may remove the protecting group of the group which inhibits these target reactions suitably as needed. The desired reaction, removal of these protecting groups, can be performed using conventional methods used in the field of synthetic organic chemistry (see, eg, Protective Groups in Organic Synthesis, 3rd Edition, TW. Green and PGM M. Watts, the method described in John Wiley & Sons Inc.).

<Method A>
In the first step of Method A, the ketone compound (1) is reacted with the compound (2) in an inert solvent in the presence of an acid.
) Or a compound (3) in which a trimethylsilyl group (described as TMS in the above formula) is substituted at the end of the compound (2) to produce a cyclic ketal compound (4).

This step can employ a cyclic ketalization reaction (protection) of ketones commonly used in organic synthesis, such as Protective Groups in Organic Synthesis (T. W. Greene, PG Wuts, Protective). Groups in Organic Synthesis. Third E
dition, 1999, Chapter 4, pp. 293-368, John Wiley & Sons, Inc.) or the like.

The cyclic ketal compound (4) can also be produced by the following method (Method A, 1 ′ step).

Method A 1 'step comprises dimethyl ketal compound (5) in an inert solvent in the presence of an acid,
This is a step for producing a cyclic ketal compound (4) by reacting with the compound (2) or the compound (3). This reaction can be carried out according to the same method as in the first step or a method analogous thereto.

In the second step of Method A, the cyclic ketal compound (4) obtained in the first step or the first 'step is converted to D.
This is a step for producing a ketoester compound (7) by subjecting it to an ieckmann reaction.

This step can employ a Dieckmann reaction, which is generally used in organic synthesis, for example, Chemical Pharm. Bull.
29, pages 3238-3248 (1981), etc., or a method analogous thereto.

The ketoester compound (7) can also be produced by the following method (Method A, second step).

Method A 2 ′ step is a step for producing a ketoester compound (7) by reacting the ketone compound (6) with a dialkyl carbonate in the presence of a base in an inert solvent.

In this step, an ester group introduction reaction generally used in organic synthesis can be employed. For example, Canadian Journal of Chemistry, Volume 70, pages 1406-1426 (1992) ) Or a method analogous thereto.

In the third step of Method A, the ketoester compound (7) obtained in the second step or the second ′ step is used.
This is a step for producing a compound (8) having a leaving group L by enolization in an inert solvent in the presence of a base.

This process is performed, for example, by Journal of American Chemical Society (J. Am. C
hem. Soc.), Volume 120, pages 3664-3670 (1998) or a method analogous thereto.

The “leaving group” in the definition of L usually indicates a group leaving as a nucleophilic residue, for example,
Halogen atoms such as fluorine, chlorine, bromine and iodine; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; halogeno lower alkanesulfonyl such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy An oxy group; an arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy, and p-nitrobenzenesulfonyloxy. A halogeno lower alkanesulfonyloxy group is preferable, and a trifluoromethanesulfonyloxy group is particularly preferable.

The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene, xylene; dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether
Ethers such as ter, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; formamide, N, N-dimethylformamide, N,
Amides such as N-dimethylacetamide, N-methyl-2-pyrrolidinone and hexamethylphosphorotriamide; Sulfoxides such as dimethyl sulfoxide and sulfolane;
Alternatively, a mixed solvent of these can be used, preferably halogenated hydrocarbons, and more preferably dichloromethane.

Examples of the base used include alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; lithium hydride and hydrogen Alkali metal hydrides such as sodium fluoride and potassium hydride; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxy Alkali metal alkoxides such as potassium, potassium t-butoxide, lithium methoxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N
-Methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline,
N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.
3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (
DABCO), and organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably alkali metal hydrides or organic bases, More preferred is sodium hydride or diisopropylethylamine.

While the reaction temperature varies depending on the raw material compound and the reaction reagent, it is carried out at −100 ° C. to 100 ° C., preferably −78 ° C. to 50 ° 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 minute to 48 hours, preferably 5 minutes to 12 hours.

In the fourth step of Method A, the compound (8) having the leaving group L obtained in the third step is reacted with the thiol compound (9) in the presence of a base in an inert solvent to produce the compound (10). It is a process to do.

The “protecting group” for the sulfanyl group in the definition of Z is not particularly limited as long as it is a protecting group for a sulfanyl group generally used in organic synthesis. For example, an alkanoyl group such as formyl, acetyl, propionyl, butyryl, An arylcarbonyl group such as benzoyl, α-naphthoyl, β-naphthoyl, pyridoyl, thienoyl, furoyl and the like, preferably a group that forms a pharmacologically acceptable ester, and more preferably An acetyl group.

The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene, xylene; dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether
Ethers such as ter, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; formamide, N, N-dimethylformamide, N,
An aprotic polar solvent such as N-dimethylacetamide or dimethyl sulfoxide; or a mixed solvent thereof can be mentioned, and is preferably an aprotic polar solvent, more preferably N, N-dimethyl. Formamide.

Examples of the base used include alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; lithium hydride and hydrogen Alkali metal hydrides such as sodium fluoride and potassium hydride; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxy Alkali metal alkoxides such as potassium, potassium t-butoxide, lithium methoxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N
-Methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline,
N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.
3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (
DABCO), and organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably alkali metal hydrides, and more preferably Sodium hydride or potassium hydride.

While the reaction temperature varies depending on the raw material compound and the reaction reagent, it is carried out at -78 ° C to 100 ° C, preferably -20 ° C to 50 ° 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 minute to 120 hours, preferably 10 minutes to 72 hours.

Method A Step 5 is a step for producing compound (11) by deprotecting the protecting group of the sulfanyl group of compound (10) obtained in Step 4 in an inert solvent.

This step is a deprotection step of a protecting group for a sulfanyl group that is generally used in organic synthesis. For example, the above-mentioned Protective Groups in Organic Synthesis [Pr
otective Groups in Organic Synthesis, 3rd edition, TWGreene &PGMWuts; John
The method described in Wiley & Sons, Inc.] or a method analogous thereto is used, but the deprotection can be preferably performed in an inert solvent in the presence of a base.

The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene, xylene; dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether
Ethers such as ter, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol Alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, alcohols such as 2-methoxyethanol; formamide, N, N-dimethylformamide, N
, N-dimethylacetamide, N-methyl-2-pyrrolidinone, amides such as hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane; or a mixed solvent thereof. , Alcohols, and more preferably methanol or ethanol.

Examples of the base used include alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; sodium methoxide, sodium Alkali metal alkoxides such as ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium methoxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methyl Piperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N
, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3. 0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (D
Organic bases such as BU), preferably alkali metal carbonates,
More preferred is potassium carbonate.

While the reaction temperature varies depending on the raw material compound and the reaction reagent, it is carried out at -78 ° C to 100 ° C, preferably -20 ° C to 50 ° C.

While the reaction time varies depending on the reaction temperature, raw material compound, reaction reagent or the type of solvent used, it is generally 1 minute to 24 hours, preferably 5 minutes to 5 hours.

In the sixth step of Method A, the thiol group of the compound (11) obtained in the fifth step is placed in an inert solvent.
In this step, the compound (12) is produced by chlorosulfonylation.

This process is performed, for example, by Journal of Organic Chemistry (J. Org. Chem.
), Vol. 16, pp. 621-625 (1951), or a method analogous thereto.

The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene, xylene; dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride and dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol Alcohols such as -ol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, 2-methoxyethanol;
Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; formic acid, acetic acid, propionic acid, Carboxylic acids such as trifluoroacetic acid; water or a mixed solvent thereof can be mentioned, preferably a mixed solvent of carboxylic acids and water or a mixed solvent of nitriles and water, more preferably , A mixed solvent of acetic acid and water or a mixed solvent of acetonitrile and water.

While the reaction temperature varies depending on the raw material compound and the reaction reagent, it is carried out at -78 ° C to 100 ° C, preferably -20 ° C to 50 ° 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 minute to 12 hours, preferably 5 minutes to 1 hour.

In Method A, Step 7, the compound (12) obtained in Step 6 is reacted with an amine compound (13) in an inert solvent in the presence or absence of a base to give the general formula (I). It is the process of manufacturing the compound which has.

The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene, xylene; dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride and dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; N
Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; or a mixed solvent thereof Preferred are esters, and more preferred is ethyl acetate.

Examples of the base used include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N -Methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N,
N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0 Nona-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DB)
Organic bases such as U) can be mentioned, organic bases are preferred, and triethylamine is more preferred.

While the reaction temperature varies depending on the raw material compound and the reaction reagent, it is carried out at -78 ° C to 100 ° C, preferably -20 ° C to 50 ° 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 minute to 120 hours, preferably 10 minutes to 48 hours.

<Method B>
The eighth step of Method B is a step of producing a ketone compound (15) by hydrolyzing the cyclic ketal compound (14) obtained by Method A in the presence of an acid in an inert solvent.

This step can employ a deprotection reaction of a cyclic ketal compound generally used in organic synthesis. For example, the above-mentioned Protective Groups in Organic Synthesis [T. W. Greene, PG Wuts, Protective Groups in Organic Synthesis. Third
Edition, 1999, Chapter 4, pages 293-368, John Wiley & Sons, Inc.] or a method analogous thereto.

The ninth step of Method B is a step of producing the dimethyl ketal compound (16) from the ketone compound (15) obtained in the eighth step in the presence of an acid in an inert solvent.

This process is a dimethyl ketalization reaction (protection) of ketones commonly used in organic synthesis.
For example, the above-mentioned Protective Groups in Organic Synthesis [T. W. Greene, PG Wuts, Protective Groups in Organic Synthesis]
Third Edition, 1999, Chapter 4, pages 293-368, John Wiley & Sons, Inc.] or a method analogous thereto.

In Method B, Step 10, the ketone compound (15) obtained in Step 8 is reacted with compound (2) or compound (3) in the presence of an acid in an inert solvent to give a compound of the general formula (I Is a step of producing a compound having.

  In addition, this reaction can be performed according to the method similar to a 1st process.

In Method B, Step 10 ′, the dimethyl ketal compound (16) obtained in Step 9 is reacted with compound (2) or compound (3) in the presence of an acid in an inert solvent to give a general formula This is a process for producing a compound having (I).

  In addition, this reaction can be performed according to the method similar to 1 'process.

<Method C>
Step 11 of Method C comprises the presence of a base in an inert solvent when R ⁵ is a hydrogen atom in the cyclic ketal compound (14) obtained by Method A or the compound having the general formula (I) obtained by Method B. Under the general formula (I) substituted with the desired R ⁵ by reaction with R ⁵ -L (17)
Is a step of producing a compound having.

R ⁵ and L are as defined above, and the “leaving group” in the definition of L usually represents a group leaving as a nucleophilic residue, for example, fluorine atom, chlorine atom, bromine atom, iodine Halogen atoms such as atoms; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; halogeno lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; benzenesulfonyloxy and p-toluene Examples thereof include arylsulfonyloxy groups such as sulfonyloxy and p-nitrobenzenesulfonyloxy. Preferred is a halogen atom,
Particularly preferred is an iodine atom.

The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; diethyl Ethers such as ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic polar solvents such as dimethylformamide, dimethylacetamide and dimethylsulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; benzene Aromatic hydrocarbons such as toluene, xylene; aliphatic hydrocarbons such as pentane, hexane, heptane, and preferably ethers, ketones or aprotic polar solvents, Preferably Tetrahydrofuran, acetone or dimethylformamide is used.

Examples of the base used include alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; sodium methoxide, sodium Alkali metal alkoxides such as ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium methoxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methyl Piperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N
, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3. 0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (D
Organic bases such as BU), preferably alkali metal carbonates,
More preferred is potassium carbonate.

While the reaction temperature varies depending on the raw material compound and the reaction reagent, it is carried out at -78 ° C to 150 ° C, preferably -20 ° C to 100 ° 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 minute to 24 hours, preferably 10 minutes to 5 hours.

  After completion of each of the above reactions, the target compound is collected from the reaction mixture according to a conventional method.

For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, and then the reaction solution is extracted with an organic solvent immiscible with water such as ethyl acetate, washed with water, etc. The organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off.

If necessary, the obtained target compound can be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel-type florisil. Adsorption column chromatography using a simple carrier; such as Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical) A method using a synthetic adsorbent such as partition column chromatography using a simple carrier, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel (preferably high-speed Liquid chromatography)) and combined elution with an appropriate eluent. Separation Te, can be purified.

Raw material compounds (1), (2), (3), (5), (6) of the above-described production method disclosed in the present invention
), (9), (13), (17), etc. are known or easily produced according to known methods.

The pharmaceutical composition containing the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is an intracellular substance in various cells such as monocytes, macrophages and vascular endothelial cells caused by endotoxin. Intracellular signals caused by drugs, particularly endotoxins, have excellent suppressive action against various cellular responses such as signal transduction or cell activation and the overproduction of inflammatory mediators such as TNF-α resulting therefrom. Transmission or cell activation and the various cellular responses resulting from them (eg TNF
It is effective as a prophylactic and / or therapeutic drug for various diseases associated with (overproduction of inflammatory mediators such as -α). Such pharmaceutical compositions include, for example, ischemic brain damage, arteriosclerosis, poor prognosis after coronary angioplasty, heart failure, diabetes, diabetic complications, arthritis, osteoporosis, osteopenia, sepsis, autoimmune diseases, Examples include preventive and / or therapeutic agents for tissue damage and rejection after organ transplantation, bacterial infections, viral infections, gastritis, pancreatitis, nephritis, pneumonia, hepatitis, leukemia.

When the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is used as a therapeutic and / or prophylactic agent for the above-mentioned diseases, the compound itself or appropriate pharmacologically acceptable Injections for oral or intraperitoneal administration, subcutaneous administration, intramuscular administration, or intravenous administration in tablets, capsules, granules, powders, syrups, etc. It can be administered parenterally, such as with suppositories.

These formulations include excipients (eg sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; Gum arabic; dextran; organic excipients such as pullulan; and light anhydrous silicic acid, synthetic aluminum silicate,
Examples include inorganic excipients such as silicate derivatives such as calcium silicate and magnesium aluminate metasilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. it can. ), Lubricants (eg, stearic acid metal salts such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as beeswax and gay wax; boric acid; adipic acid; sodium sulfate, etc. Glycol; fumaric acid; sodium benzoate; DL leucine; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic anhydride,
Examples thereof include silicic acids such as silicic acid hydrate; and the above starch derivatives. ), Binder (
For example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the same compound as the excipient can be mentioned. ), Disintegrants (eg, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally crosslinked sodium carboxymethylcellulose; chemically modified such as carboxymethylstarch, sodium carboxymethylstarch, crosslinked polyvinylpyrrolidone Starch, celluloses, etc.), emulsifiers (eg, colloidal clays such as bentonite and bee gum; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; sodium lauryl sulfate and calcium stearate Anionic surfactants; cationic surfactants such as benzalkonium chloride; and polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fats Non-ionic surfactants such as acid esters and sucrose fatty acid esters), stabilizers (paraoxybenzoates such as methylparaben and propylparaben; chlorobutanol, benzyl alcohol, phenylethyl alcohol, etc.) Alcohols; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.), Flavoring agents (for example, commonly used sweeteners, acidity And additives such as diluents, etc., and can be produced by a known method.

The amount used varies depending on symptoms, age, etc., but the lower limit of 0.0 per day as the compound of the present invention.
1 mg / kg (preferably 0.10 mg / kg), upper limit 1000 mg / kg (preferably
100 mg / kg) is preferably administered orally or parenterally to adults from once to several times a day depending on the symptoms.

Examples, Formulation Examples and Test Examples are shown below, and the compounds contained as active ingredients in the pharmaceutical composition of the present invention will be described in more detail. However, the scope of the present invention is not limited to these.

Example 1
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
364)

(1a) Ethyl 8-acetylsulfanyl-1,4-dioxaspiro [4.5] deca
7-ene-7-carboxylate
Ethyl 8-trifluoromethanesulfonyloxy-1,4-dioxaspiro [4.5]
Dec-7-ene-7-carboxylate [Tetrahedron Letter, 39, 6139-6142 (19
98) is dissolved in 200 ml of dimethylformamide, and 9.50 g (83.1) of potassium thioacetate is stirred under ice-cooling.
mmol) was added and stirred at room temperature for 91 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 17: 3) to obtain 7.15 g of the title compound as a light brown oil (yield 45%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.20 (2H, q, 7Hz), 4.04-3.96 (4H, m), 2.73-2.66 (4H, m), 2.34 (3H, s),
1.87 (2H, t, J = 6Hz), 1.28 (3H, t, J = 7Hz).

(1b) Ethyl 8-mercapto-1,4-dioxaspiro [4.5] dec-7-ene-
Ethyl 8-acetylsulfanyl-1,4-dioxaspiro obtained from 7-carboxylate (1a) [4.5]
Deca-7-ene-7-carboxylate (7.14 g, 24.9 mmol) was added to methanol 1
It melt | dissolved in 45 ml, 2.58 g (18.7 mmol) of potassium carbonate was added under ice-cooling stirring, and it stirred at the same temperature for 1 hour, and also at room temperature for 1 hour. 1N Hydrochloric acid was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 9: 1) to obtain 5.63 g of the title compound as a pale yellow oil (yield 92%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.32 (1H, s), 4.21 (2H, q, 7Hz), 4.04-3.95 (4H, m), 2.72-2.67 (2H, m),
2.59-2.57 (2H, m), 1.82 (2H, t, J = 7Hz), 1.30 (3H, t, J = 7Hz).

(1c) Ethyl 8-chlorosulfonyl-1,4-dioxaspiro [4.5] dec-7-
Ethyl 8-mercapto-1, 4 obtained in (1b) was stirred into a saturated solution prepared by blowing chlorine gas into 80 ml of a mixture of ene-7-carboxylate acetonitrile-water (1: 1) for 20 minutes under ice cooling. -Dioxaspiro [4.5] dec-7-ene-7-carboxylate 5.00 g (20.5 mmol)
10 ml of acetonitrile solution was added, and chlorine gas was further blown in at the same temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 2: 1) to give 5.83 g of the title compound as a colorless oil (yield 92
%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.30 (2H, q, 7Hz), 4.05-3.98 (4H, m), 2.91-2.86 (2H, m),
2.71-2.69 (2H, m), 1.93 (2H, t, J = 7Hz), 1.34 (3H, t, J = 7Hz).

(1d) Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl]-
1,4-Dioxaspiro [4.5] dec-6-ene-7-carboxylate To 5 ml of an ethyl acetate solution of 197 mg (1.35 mmol) of 2-chloro-4-fluoroaniline and 0.20 ml (1.42 mmol) of triethylamine (1c)
3 ml of an ethyl acetate solution of 400 mg (1.29 mmol) of ethyl 8-chlorosulfonyl-1,4-dioxaspiro [4.5] dec-7-ene-7-carboxylate obtained in 1) was added dropwise and stirred at room temperature for 48 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 3: 1), and the resulting solid was washed with a mixed solvent of hexane-isopropyl ether (1: 1) to give 325 mg of the title compound.
Was obtained as a white powder (yield 60%).
Melting point 117-119 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.67 (1H, dd, J = 9Hz, 5Hz), 7.16 (1H, dd, J = 8Hz, 3Hz), 7.05-6.98 (2H, m),
6.83 (1H, s), 4.43-4.41 (1H, m), 4.26-4.01 (5H, m), 3.95-3.88 (1H, m),
2.56-2.45 (2H, m), 2.24-2.11 (1H, m), 1.88-1.80 (1H, m), 1.27 (3H, t, J = 7Hz).

(Example 2)
Ethyl 8- (N-phenylsulfamoyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-12)

According to the method described in Example (1d) using aniline instead of 2-chloro-4-fluoroaniline, the title compound was obtained as an amorphous substance (yield 81%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.37-7.31 (4H, m), 7.21-7.15 (1H, m), 6.95 (1H, s), 6.85-6.87 (1H, m),
4.30-4.20 (3H, m), 4.13-4.01 (3H, m), 3.94-3.88 (1H, m), 2.48-2.41 (1H, m),
2.31 (1H,, td, J = 14Hz, 3Hz), 2.10-2.00 (1H, m), 1.86-1.80 (1H, m), 1.31 (3H, t,
J = 7Hz).

(Example 3)
Ethyl 8- [N- (2-butylphenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Deca-6-ene-7-carboxylate (Exemplified Compound No. 1-540)

Example (1) using 2-butylaniline instead of 2-chloro-4-fluoroaniline
According to the method described in d), the title compound was obtained as a colorless oil (yield 56%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.55-7.52 (1H, m), 7.22-7.17 (2H, m), 7.13-7.08 (1H, m), 6.85-6.84 (1H, m),
6.63 (1H, s), 4.47-4.44 (1H, m), 4.25-4.02 (5H, m), 3.95-3.89 (1H, m),
2.71-2.62 (2H, m), 2.54-2.38 (2H, m), 2.19-2.09 (1H, m), 1.86-1.81 (1H, m),
1.62-1.53 (2H, m), 1.45-1.34 (2H, m), 1.26 (3H, t, J = 7Hz), 0.95 (3H, t, J = 7Hz).

Example 4
Ethyl 8- [N- (2-hexylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-716)

Example using 2-hexylaniline instead of 2-chloro-4-fluoroaniline (
The title compound was obtained as a pale yellow oil according to the method described in 1d) (yield 82%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.55-7.52 (1H, m), 7.22-7.17 (2H, m), 7.13-7.08 (1H, m), 6.85-6.84 (1H, m),
6.63 (1H, s), 4.47-4.44 (1H, m), 4.25-4.02 (5H, m), 3.95-3.89 (1H, m),
2.70-2.61 (2H, m), 2.54-2.38 (2H, m), 2.19-2.09 (1H, m), 1.86-1.81 (1H, m),
1.64-1.54 (2H, m), 1.41-1.24 (6H, m), 1.26 (3H, t, J = 7Hz), 0.91-0.85 (3H, m).

(Example 5)
Ethyl 8- [N- (2-heptylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-892)

Example using 2-heptylaniline instead of 2-chloro-4-fluoroaniline (
The title compound was obtained as a pale yellow oil according to the method described in 1d) (yield 87%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.55-7.52 (1H, m), 7.22-7.17 (2H, m), 7.13-7.08 (1H, m), 6.85-6.84 (1H, m),
6.63 (1H, s), 4.47-4.44 (1H, m), 4.25-4.02 (5H, m), 3.95-3.89 (1H, m),
2.69-2.61 (2H, m), 2.54-2.38 (2H, m), 2.19-2.09 (1H, m), 1.86-1.81 (1H, m),
1.64-1.54 (2H, m), 1.42-1.23 (8H, m), 1.26 (3H, t, J = 7Hz), 0.88 (3H, t, J = 7Hz).

(Example 6)
Ethyl 8- [N- (1H-pyrrol-1-yl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-1062)

The title compound was obtained as a white powder according to the method described in Example (1d) using 1H-pyrrol-1-ylamine instead of 2-chloro-4-fluoroaniline (yield 33).
%).

Melting point 115-117 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
8.05 (1H, s), 6.99 (2H, t, J = 2Hz), 6.94 (1H, s), 6.17 (2H, t, J = 2Hz),
4.55-4.51 (1H, m), 4.30 (2H, q, J = 7Hz), 4.14-4.03 (3H, m), 3.98-3.89 (1H, m),
2.51-2.44 (1H, m), 2.26-2.05 (2H, m), 1.89-1.83 (1H, m), 1.35 (3H, t, J = 7Hz).

(Example 7)
Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-oxo-1-cyclohexene-1-carboxylate (Exemplary Compound No. 1-353)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate 2.55 obtained in Example 1
100 ml of a mixture of 1N hydrochloric acid-tetrahydrofuran (1: 1) to g (6.07 mmol)
And stirred at room temperature for 64 hours. Tetrahydrofuran was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 4: 1) to obtain 2.19 g of the title compound as a light brown powder (yield 96%).
Melting point 128-130 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.69 (1H, dd, J = 9Hz, 5Hz), 7.20 (1H, dd, J = 8Hz, 3Hz), 7.09-7.03 (1H, m),
6.91 (2H, s), 4.68 (1H, dd, J = 5Hz, 2Hz), 4.28-4.18 (2H, m), 3.21-3.09 (1H, m),
2.80-2.72 (1H, m), 2.57-2.49 (1H, m), 2.44-2.31 (1H, m), 1.28 (3H, t, J = 7Hz).

(Example 8)
Ethyl 9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,5-
Dioxaspiro [5.5] undec-7-ene-8-carboxylate (Exemplified Compound No. 1-365)

Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-oxo-1-cyclohexene-1-carboxylate 100 mg (0.27 m) obtained in Example 7
mol) was dissolved in 2 ml of toluene, and 0.04 ml (0.5%) of propane-1,3-diol was dissolved.
4 mmol) and 68 mg (0.27 mmol) of pyridinium p-toluenesulfonate were added and heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 2
1), and the resulting solid was washed with hexane to obtain 60 mg of the title compound as a white powder (yield 51%).
Melting point 120-121 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.65 (1H, dd, J = 9Hz, 5Hz), 7.36 (1H, s), 7.14 (1H, dd, J = 8Hz, 3Hz),
7.01 (1H, dd, J = 7Hz, 2Hz), 6.98 (1H, s), 4.45-4.39 (1H, m), 4.27-4.12 (2H, m),
4.11-3.84 (4H, m), 2.46-2.06 (4H, m), 1.92-1.67 (2H, m), 1.28 (3H, t, J = 7Hz).

Example 9
Ethyl 9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3, 3-
Dimethyl-1,5-dioxaspiro [5.5] undec-7-ene-8-carboxylate (Exemplified Compound No. 1-426)

According to the method described in Example 8 using 2,2-dimethylpropane-1,3-diol instead of propane-1,3-diol, the title compound was obtained as a pale brown oil (yield) 64%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.64 (1H, dd, J = 9Hz, 5Hz), 7.31 (1H, s), 7.13 (1H, dd, J = 8Hz, 3Hz),
7.04-6.94 (2H, m), 4.45-4.39 (1H, m), 4.27-4.12 (2H, m), 3.69-3.46 (4H, m),
2.42-2.11 (4H, m), 1.28 (3H, t, J = 7Hz), 1.03 (3H, s), 0.97 (3H, s).

(Example 10)
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-
Dithiaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-3
67)

Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-oxo-1-cyclohexene-1-carboxylate 100 mg (0.27 m) obtained in Example 7
mol) was dissolved in 1 ml of dichloromethane, and ethane-1,2-dithiol 0 was stirred with ice-cooling.
. 034 ml (0.405 mmol) and boron trifluoride diethyl ether complex 0.02
5 ml (0.203 mmol) was added and stirred at room temperature for 1 hour. A 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was washed with diethyl ether and then with hexane to obtain 325 mg of the title compound as a white powder (yield 76%).
Melting point 160-161 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.65 (1H, dd, J = 9Hz, 5Hz), 7.14 (1H, dd, J = 8Hz, 3Hz), 7.10 (1H, s),
7.04-6.96 (2H, m), 4.40 (1H, d, J = 5Hz), 4.25-4.10 (2H, m), 3.52-3.26 (4H, m),
2.82-2.72 (1H, m), 2.58-2.50 (1H, m), 2.33-2.24 (1H, m), 2.11-1.99 (1H, m),
1.27 (3H, t, J = 7Hz).

(Example 11)
Ethyl 9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,5-
Dithiaspiro [5.5] undec-7-ene-8-carboxylate (Exemplary Compound No. 1
-368)

According to the method described in Example 10 using propane-1,3-dithiol instead of ethane-1,2-dithiol, the title compound was obtained as an amorphous substance (yield 72%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.65 (1H, dd, J = 9Hz, 5Hz), 7.40 (1H, s), 7.14 (1H, dd, J = 8Hz, 3Hz),
7.03-6.96 (1H, m), 6.94 (1H, s), 4.51 (1H, d, J = 5Hz), 4.24-4.11 (2H, m),
3.17-3.07 (1H, m), 2.98-2.77 (3H, m), 2.61-2.51 (1H, m), 2.47-2.38 (1H, m),
2.36-2.27 (1H, m), 2.25-2.13 (1H, m), 2.12-1.95 (2H, m), 1.27 (3H, t, J = 7Hz).

(Example 12)
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-oxa-4-thiaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-371)

The title compound was obtained as a white powder according to the method described in Example 10 using 2-mercaptoethal instead of ethane-1 and 2-dithiol (yield 61%).
Melting point 133-134 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.65 (1H, dd, J = 9Hz, 5Hz), 7.14 (1H, dd, J = 8Hz, 3Hz), 7.06 (0.4H, s),
7.04-6.96 (2.6H, m), 4.46 (0.4H, dd, J = 5Hz, 3Hz), 4.39-4.01 (4.6H, m),
3.23-3.06 (2H, m), 2.77-2.51 (1.6H, m), 2.45-2.36 (0.4H, m), 2.20-2.00 (2H, m),
1.27 (3H, t, J = 7Hz).

(Example 13)
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,1,
4,4-tetraoxo-1λ ⁶ , 4λ ⁶ -dithiaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-369)

80 mg of ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dithiaspiro [4.5] dec-6-ene-7-carboxylate obtained in Example 10
(0.18 mmol) was dissolved in 2 ml of dichloromethane, and 91 mg (1.08 mmol) of sodium hydrogen carbonate was added with stirring under ice cooling.
g (0.90 mmol) was added in small portions and stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane: ethyl acetate = 1: 1) to obtain 42 mg of the title compound as a white powder (yield 45%).
Melting point 88-90 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.65 (1H, dd, J = 9Hz, 5Hz), 7.15 (1H, dd, J = 8Hz, 3Hz), 7.06-6.98 (2H, m),
6.92 (1H, s), 4.57 (1H, d, J = 5Hz), 4.26-4.16 (2H, m), 3.79-3.60 (4H, m),
3.14-2.98 (1H, m), 2.69-2.60 (1H, m), 2.45-2.36 (1H, m), 2.29-2.16 (1H, m),
1.28 (3H, t, J = 7Hz).

(Example 14)
Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-oxaspiro [2.5] oct-4-ene-5-carboxylate (Exemplified Compound No. 1-36)
0)

50 mg (0.133 m) of ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7
mol) and 0.01 ml (0.146 mmol) of dibromomethane are dissolved in 1 ml of tetrahydrofuran, and at −78 ° C., an n-butyllithium / hexane solution (1.58 M) 0.18 is dissolved.
After adding ml (0.279 mmol) dropwise, the mixture was stirred at room temperature for 4 hours. The reaction mixture was ice-cooled, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (solvent;
(Hexane: ethyl acetate = 2: 1) to give 7 mg of the title compound as a yellow oil (yield 14%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.68 (1H, dd, J = 9Hz, 5Hz), 7.15 (1H, dd, J = 8Hz, 3Hz), 7.07-6.91 (2H, m),
6.60 (1H, s), 4.50 (1H, d, J = 4Hz), 4.27-4.06 (2H, m), 2.98-2.92 (1H, m),
2.91-2.88 (1H, m), 2.83-2.70 (1H, m), 2.68-2.59 (1H, m), 2.21-2.07 (2H, m),
1.25 (3H, t, J = 7Hz).

(Example 15)
Ethyl (2S) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl]-
2-Hydroxymethyl-1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-378)

Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-oxo-1-cyclohexene-1-carboxylate 100 mg (0.27 m) obtained in Example 7
mol) and (R) -2,3-dihydroxypropyl benzoate 69 mg (0.35
mmol) was dissolved in 2 ml of dichloromethane, and 0.19 ml (1.05 mmol) of isopropoxytrimethylsilane and 2 ml (0.014 mmol) of trimethylsilyl trifluoromethanesulfonate were sequentially added with stirring under ice cooling and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate =
1: 1) to ethyl (2R) -2-benzoyloxymethyl-8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] deca- Obtained 121 mg of 6-ene-7-carboxylate as a pale yellow oil (yield 81%).
.

Subsequently, 121 mg (0.22 mmol) of this product was added to methanol-tetrahydrofuran (
1) 1) aqueous solution with 1N sodium hydroxide solution
(0.50 mmol) was added and stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 1: 1) to obtain 41 mg of the title compound as an amorphous substance (yield 41%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.64 (1H, dd, J = 9Hz, 5Hz), 7.14 (1H, dd, J = 8Hz, 3Hz), 7.06-6.97 (2H, m),
6.89 (0.25H, s), 6.86 (0.25H, s), 6.80 (0.25H, s), 6.78 (0.25H, s),
4.43-4.31 (1.75H, m), 4.26-4.02 (3.25H, m), 3.95-3.87 (0.75H, m),
3.85-3.77 (1H, m), 3.75-3.69 (0.25H, m), 3.68-3.59 (1H, m),
2.65-2.38 (2H, m), 2.25-2.11 (1H, m), 2.11-2.05 (0.25H, m),
2.03-1.97 (0.25H, m), 1.94-1.81 (1.5H, m), 1.26 (3H, t, J = 7Hz).

(Example 16)
Ethyl (2R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl]-
2-Hydroxymethyl-1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-378)

(16a) Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl]
-3,3-Dimethoxy-1-cyclohexene-1-carboxylate Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-oxo-1-cyclohexene-1- obtained in Example 7 Carboxylate 6.1 g (16.2 mm
ol) is dissolved in 120 ml of methanol, and 4.1 g (16.2 mmol) of pyridinium p-toluenesulfonate and 8.86 ml (81.0 mmol) of trimethoxymethane are stirred under ice-cooling.
l) was sequentially added and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 2: 1) to give the title compound 6.
0 g was obtained as a white powder (88% yield).
Melting point 97-98 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.65 (1H, dd, J = 9Hz, 5Hz), 7.14 (1H, dd, J = 8Hz, 3Hz), 7.07-6.97 (3H, m),
4.41 (1H, d, J = 4Hz), 4.28-4.12 (2H, m), 3.29 (3H, s), 3.23 (3H, s),
2.47-2.38 (1H, m), 2.31-2.21 (1H, m), 2.18-2.06 (1H, m), 2.01-1.93 (1H, m),
1.28 (3H, t, J = 7Hz).

(16b) Ethyl (2R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2-hydroxymethyl-1,4-dioxaspiro [4.5] dec-6-ene-
7-carboxylate Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethoxy-1-cyclohexene-1-carboxylate 342 mg obtained from (16a) (
0.81 mmol) and (S) -2,3-dihydroxypropyl benzoate 206m
g (1.05 mmol) was dissolved in 7 ml of dichloromethane, and 0.56 ml (3.15 mmol) of isopropoxytrimethylsilane and 7 ml (0.041 mmol) of trimethylsilyl trifluoromethanesulfonate were successively added with stirring under ice cooling for 1 hour at the same temperature. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:
Ethyl acetate = 1: 1) and ethyl (2S) -2-benzoyloxymethyl-8- [
N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] 410 mg of deca-6-ene-7-carboxylate was obtained as a colorless oil (yield 91%).

Next, 410 mg (0.74 mmol) of this product was added to methanol-tetrahydrofuran (
1: 1) and 3 ml of 1N aqueous sodium hydroxide solution (3.0 mmol)
l) was added and stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 1: 1) to give the title compound 2
93 mg was obtained as amorphous (88% yield).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.64 (1H, dd, J = 9Hz, 5Hz), 7.14 (1H, dd, J = 8Hz, 3Hz), 7.04-6.95 (2H, m),
6.89 (0.42H, s), 6.86 (0.02H, s), 6.80 (0.02H, s), 6.78 (0.42H, s),
4.43-4.31 (1.5H, m), 4.26-4.02 (2.5H, m), 3.96-3.89 (1H, m),
3.83-3.77 (0.5H, m), 3.75-3.69 (0.5H, m), 3.68-3.59 (1H, m),
2.65-2.41 (2H, m), 2.25-2.10 (1H, m), 1.93-1.82 (1H, m),
1.77-1.67 (0.5H, br. S), 1.58 (0.5H, br. S), 1.26 (3H, t, J = 7Hz).

(Example 17)
Ethyl (2R, 3R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate (Exemplified Compound No. 1-382)

In accordance with the method described in Example (16b) using 1,4-di-O-benzoyl-D-threitol instead of (S) -2,3-dihydroxypropyl benzoate, the title compound was converted to amorphous. Obtained (44% yield).
<Alternative method>
(17a) Ethyl (2R, 3R) -2,3-bis (benzoyloxymethyl) -8-
[N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Deca-6-ene-7-carboxylate 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D obtained in Reference Example 18
-1.46 g (3.08 mmol) of threitol was suspended in 2 ml of acetonitrile, and 0.04 ml (0.24 m) of trimethylsilyl trifluoromethanesulfonate was stirred with ice cooling.
mol), ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a), 1.00 g (2. 37 ml) of acetonitrile solution was added sequentially, and 1 at the same temperature.
Stir for hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 2: 1) to give 1.50 g of the title compound as a pale yellow powder (yield 92%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
8.10-8.04 (4H, m), 7.68-7.57 (3H, m), 7.49-7.44 (4H, m), 7.16 (1H, dt, J = 8.0Hz, 2.6H
z), 7.05-7.00 (2H, m), 6.87 (1H, d, J = 14.0Hz), 4.66-4.07 (9H, m), 2.63-2.44 (2H, m),
2.25-2.19 (1H, m), 1.94 (1H, t, J = 15.2Hz), 1.19 (3H, t, J = 7.0Hz).

(17b) Ethyl (2R, 3R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5]
Ethyl (2R, 3R) -2,3-bis (benzoyloxymethyl)-obtained from Deca-6-ene-7-carboxylate (17a)
8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (1.50 g, 2.18 mmol) was dissolved in methanol-tetrahydrofuran. (4: 1) is dissolved in 10 ml of a mixed solution and stirred under ice-cooling.
N aqueous solution of sodium hydroxide (10 ml, 10.0 mmol) was added and stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 1: 1) to obtain 900 mg of the title compound as a white amorphous (yield 86%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.69-7.64 (1H, m), 7.16 (1H, dd, J = 8Hz, 3Hz), 7.05-6.99 (2H, m),
6.91-6.90 (0.5H, m), 6.85-6.84 (0.5H, m), 4.43-4.41 (1H, m), 4.27-4.09 (3.5H, m)
,
4.05-4.01 (0.5H, m), 3.93-3.81 (2H, m), 3.75-3.69 (2H, m), 2.59-2.45 (2H, m),
2.23-1.50 (4H, m), 1.29-1.24 (3H, m).

(Example 18)
Ethyl (2S, 3S) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate (Exemplified Compound No. 1-382)

According to the method described in Example (16b) using 1,4-di-O-benzoyl-L-threitol instead of (S) -2,3-dihydroxypropyl benzoate, Obtained (yield 34%).
<Alternative method>
1,4-di-O-benzoyl-2,3-di-O obtained in Reference Example 19 instead of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol According to the method described in Example 17 (alternate method) using trimethylsilyl-L-threitol, the title compound was obtained as an amorphous substance (yield 73%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.69-7.64 (1H, m), 7.16 (1H, dd, J = 8Hz, 3Hz), 7.05-6.99 (2H, m),
6.91-6.90 (0.5H, m), 6.85-6.84 (0.5H, m), 4.43-4.41 (1H, m),
4.27-4.09 (3.5H, m), 4.05-4.01 (0.5H, m), 3.93-3.81 (2H, m),
3.75-3.69 (2H, m), 2.59-2.45 (2H, m), 2.23-1.50 (4H, m), 1.29-1.24 (3H, m).

(Example 19)
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -meso-2
3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7
-Carboxylate (Exemplary Compound No. 1-382)

Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethoxy-1-cyclohexene-1-carboxylate 200 obtained in Example (16a)
mg (0.47 mmol) and 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-meso-erythritol 290 mg (0.61 mmol) obtained in Reference Example 1 were dissolved in 4 ml of dichloromethane. Under cold stirring, 4 ml (0.024 mmol) of trimethylsilyl trifluoromethanesulfonate was added and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 2:
1), ethyl meso-2,3-bis [(benzoyloxy) methyl] -8- [N- (
2-Chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5
] 171 mg of deca-6-ene-7-carboxylate was obtained as an amorphous substance (yield 5
3%).

Next, 170 mg (0.25 mmol) of this product was added to methanol-tetrahydrofuran (
1: 1) and 3 ml of 1N aqueous sodium hydroxide solution with stirring under ice-cooling (3: 1)
3.0 mmol) was added and stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 1: 3),
105 mg of the title compound was obtained as an amorphous substance (yield 89%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.64 (1H, dd, J = 9Hz, 5Hz), 7.15 (1H, dd, J = 8Hz, 3Hz), 7.04-6.95 (2H, m),
6.93 (0.4H, s), 6.72 (0.6H, s), 4.49-4.33 (2.4H, m), 4.32-4.26 (0.6H, m),
4.25-4.07 (2H, m), 3.93-3.70 (4H, m), 2.69-2.58 (0.4H, m), 2.58-2.35 (3.6H, m),
2.24-2.09 (1H, m), 1.99-1.91 (0.6H, m), 1.90-1.83 (0.4H, m), 1.27 (3H, t, J = 7Hz)
.

(Example 20)
Ethyl (2R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl]-
2-((1R) -1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-390)

Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethoxy-1-cyclohexene-1-carboxylate 300 obtained in Example (16a)
mg (0.71 mmol) and (4R, 5R) -2,2-dimethyl-4,5-bis [(trimethylsilyl) oxy] methyl [1.3] dioxolane (436 mg, 1.42 mmol) were dissolved in dichloromethane (12 ml), Under ice-cooling and stirring, 26 ml (0.142 mmol) of trimethylsilyl trifluoromethanesulfonate was added and stirred at room temperature for 90 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 4: 1) to give ethyl (2R) -8- [N-
(2-Chloro-4-fluorophenyl) sulfamoyl] -2-((4R) -2,2-dimethyl [1.3] dioxolan-4-yl) -1,4-dioxaspiro [4.5] dec-6 -90 mg of ene-7-carboxylate was obtained as amorphous (yield 24%).

Next, 85 ml (0.163 mmol) of this product and 4 ml of a mixture of acetic acid and water (1: 1)
And stirred overnight at room temperature. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate only) to obtain 46 mg of the title compound as an amorphous substance (yield 59%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.69-7.64 (1H, m), 7.19-7.15 (1H, m), 7.06-6.98 (2H, m), 6.89-6.80 (1H, m),
4.43-4.41 (1H, m), 4.38-4.08 (4H, m), 4.03-3.95 (0.7H, m), 3.86 (0.3H, t, J = 8Hz)
,
3.77-3.63 (3H, m), 2.67-2.37 (3H, m), 2.22-1.84 (3H, m), 1.30-1.25 (3H, m).

(Example 21)
Ethyl (2R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl]
-2-((2R) -1,2,3-trihydroxypropyl) -1,4-dioxaspiro [4
. 5] Deca-6-ene-7-carboxylate (Exemplified Compound No. 1-394)

547 mg (1.07 mmol) of 1,3,4,5,7-penta-O-trimethylsilyl-D-arabitol obtained in Reference Example 2 was dissolved in 3 ml of nitromethane, and 13 ml of trimethylsilyl trifluoromethanesulfonate (0 ml) was stirred under ice cooling. .007 mmol), then ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethoxy-1-cyclohexene-1-carboxylate 300 mg obtained in Example (16a)
(0.71 mmol) was added and stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate only) to obtain 151 mg of the title compound as an amorphous substance (yield 42%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.66 (1H, dd, J = 9Hz, 5Hz), 7.19-7.15 (1H, m), 7.10-6.99 (2H, m),
6.86 (0.5H, s), 6.82-6.80 (0.5H, m), 4.42-4.39 (1H, m), 4.28-3.65 (9H, m),
3.20-1.40 (3H, br), 2.57-2.43 (2H, m), 2.23-2.09 (1H, m), 1.92-1.82 (1H, m),
1.29-1.25 (3H, m).

(Example 22)
Ethyl (2R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl]
-2-((1S, 2R, 3R) -1,2,3,4-tetrahydroxybutyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1 -3
98)

Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethoxy-1-cyclohexene-1-carboxylate 200 obtained in Example (16a)
mg (0.47 mmol) and 1,434,3,4,5,6-hexa-O-trimethylsilyl-D-mannitol (434 mg, 0.71 mmol) were dissolved in 4 ml of dichloromethane,
Under ice-cooling, 0.12 ml (0.47 mmol) of isopropoxytrimethylsilane and 4 ml (0.024 mmol) of trimethylsilyl trifluoromethanesulfonate were sequentially added and stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; dichloromethane: methanol = 10: 1) to obtain 130 mg of the title compound as amorphous (yield 51%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.62 (1H, dd, J = 9Hz, 5Hz), 7.22-7.12 (2H, m), 7.04-6.96 (1H, m),
6.88-6.84 (0.2H, m), 6.80-6.77 (0.4H, m), 6.76 (0.4H, s), 4.41-4.31 (1H, m),
4.25-4.03 (4H, m), 3.98-3.63 (6H, m), 2.54-2.41 (2H, m), 2.22-2.08 (1H, m),
1.92-1.81 (1H, m), 1.26 (3H, t, J = 7Hz).

(Example 23)
Ethyl (2R, 3R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis ((1R) -1,2-dihydroxyethyl) -1,4-dioxaspiro [4 .5] Deca-6-ene-7-carboxylate (Exemplified Compound No. 1-386)

1,6-Di-O-benzoyl-2, 3, 4, 5-, obtained in Reference Example 3 instead of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-meso-erythritol Tetra-O-
The title compound was obtained as a white powder according to the method described in Example 19 using trimethylsilyl-D-mannitol (yield 11%).
Melting point 55-56 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.65 (1H, dd, J = 9Hz, 5Hz), 7.20-7.13 (2H, m), 7.06-7.00 (1H, m), 6.80 (0.5H, s),

6.78 (0.5H, s), 4.38 (1H, d, J = 5Hz), 4.26-4.00 (5H, m), 3.98-3.88 (1.5H, m),
3.87-3.65 (5.5H, m), 2.78-2.56 (2H, m), 2.55-2.40 (2H, m), 2.23-2.09 (1H, m),
1.92-1.80 (1H, m), 1.26 (3H, t, J = 7Hz).

(Example 24)
Ethyl 9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-hydroxy-1,5-dioxaspiro [5.5] undec-7-ene-8-carboxylate
(Exemplary compound number 1-418)

Instead of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-meso-erythritol, 2-trimethylsilyloxy-1-trimethylsilyloxymethylethyl adamantane-1-carboxylate obtained in Reference Example 4 was used. The title compound was obtained as an amorphous product according to the method described in Example 19 (yield 17%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.69-7.64 (1H, m), 7.52-7.51 (0.5H, m), 7.18-7.15 (1H, m), 7.08-6.99 (2.5H, m),
4.45-4.42 (1H, m), 4.31-4.05 (4H, m), 3.88-3.74 (2H, m), 3.72-3.63 (1H, m),
2.78-2.52 (1H, br), 2.48-1.97 (4H, m), 1.31-1.26 (3H, m).

(Example 25)
Ethyl 12- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2, 4
, 8,5-tetraoxadispiro [5.2.5.2] hexadeca-10-ene-11-carboxylate (Exemplified Compound No. 1-434)

Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-oxo-1-cyclohexene-1-carboxylate 100 mg (0.266) obtained in Example 7
mmol) and 5,5-bis [(trimethylsilyl) oxy] methyl [1.3] dioxane 1
56 mg (0.532 mmol) was dissolved in 2 ml of dichloromethane, 10 ml (0.053 mmol) of trimethylsilyl trifluoromethanesulfonate was added at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes and further at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 2: 1), and the obtained solid was washed with isopropyl ether to obtain 49 mg of the title compound as a white powder (yield 52%). ).
Melting point: 156-157 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.66 (1H, dd, J = 9Hz, 5Hz), 7.17 (1H, dd, J = 8Hz, 3Hz), 7.05-6.98 (2H, m),
4.83 (1H, d, J = 6Hz), 4.78 (1H, d, J = 6Hz), 4.44-4.42 (1H, m), 4.29-4.14 (2H, m),
3.87-3.70 (8H, m), 2.44-2.38 (1H, m), 2.32-2.24 (1H, m), 2.18-2.08 (2H, m),
1.28 (3H, t, J = 7Hz).

(Example 26)
Ethyl 3-acetylamino-9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,5-dioxaspiro [5.5] undec-7-ene-8-carboxylate (Exemplary Compound No. 1- 422)

Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethoxy-1-cyclohexene-1-carboxylate 500 obtained in Example (16a)
mg (1.19 mmol) and 205 mg (1.54 mmol) of N- (2-hydroxy-1-hydroxymethylethyl) acetamide were dissolved in 20 ml of dichloromethane, and stirred with ice cooling, 0.84 ml (4.74 mmol) of isopropoxytrimethylsilane. ) And 43 ml (0.24 mmol) of trimethylsilyl trifluoromethanesulfonate were sequentially added, and the mixture was stirred at the same temperature for 30 minutes and further at room temperature for 66 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate: methanol = 39: 1) to obtain 288 mg of the title compound as amorphous (yield: 50
%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.66 (1H, dd, J = 9Hz, 5Hz), 7.62-7.60 (0.5H, m), 7.17 (1H, dd, J = 8Hz, 3Hz),
7.05-6.99 (2H, m), 6.93-6.91 (0.5H, m), 6.35 (1H, br.d, J = 8Hz),
4.46-4.42 (1H, m), 4.35-4.11 (4H, m), 4.03-3.95 (1H, m), 3.82-3.70 (2H, m),
2.60-2.55 (0.5H, m), 2.48-2.01 (3H, m), 2.06 (3H, s), 1.95-1.90 (0.5H, m),
1.30 (3H, t, J = 7Hz).

(Example 27)
Ethyl 9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3, 3-
Bis (hydroxymethyl) -1,5-dioxaspiro [5.5] undec-7-ene-8-
Carboxylate (Exemplified Compound No. 1-430)

Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethoxy-1-cyclohexene-1-carboxylate 500 obtained in Example (16a)
mg (1.19 mmol) and 1.0 g (2.38 mmol) of 1,3-bis [(trimethylsilyl) oxy] -2,2-bis [(trimethylsilyl) oxy] methylpropane were dissolved in 10 ml of dichloromethane and stirred on ice. Then, 10 ml (0.06 mmol) of trimethylsilyl trifluoromethanesulfonate was added and stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate only),
The title compound (510 mg) was obtained as an amorphous substance (yield 87%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.66 (1H, dd, J = 9Hz, 5Hz), 7.28 (1H, s), 7.17 (1H, dd, J = 8Hz, 3Hz), 7.11 (1H, s)
,
7.07-6.98 (1H, m), 4.42 (1H, d, J = 4Hz), 4.30-4.10 (2H, m), 3.92-3.68 (8H, m),
2.54-2.36 (3H, m), 2.34-2.23 (1H, m), 2.21-2.07 (2H, m), 1.28 (3H, t, J = 7Hz).

(Example 28)
Triethyl 9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,
5-Dioxaspiro [5.5] undec-7-ene-3,3,8-tricarboxylate
(Exemplary compound number 1-438)

Instead of 1,3-bis [(trimethylsilyl) oxy] -2,2-bis [(trimethylsilyl) oxy] methylpropane, diethyl 2,2-bis [(trimethylsilyl) oxy] methylmalonate obtained in Reference Example 5 was used. The title compound was obtained as an amorphous product according to the method described in Example 27 (yield 42%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.65 (1H, dd, J = 9Hz, 5Hz), 7.23-7.21 (1H, m), 7.16 (1H, dd, J = 8Hz, 3Hz),
7.04-6.99 (1H, m), 6.97 (1H, s), 4.43-4.36 (3H, m), 4.31-4.13 (8H, m),
2.44-2.37 (1H, m), 2.33-2.25 (1H, m), 2.19-2.06 (2H, m), 1.283 (3H, t, J = 7Hz),
1.280 (6H, t, J = 7Hz).

(Example 29)
Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] spiro [2.
5] Oct-4-ene-5-carboxylate (Exemplified Compound No. 1-355)

(29a) Ethyl 3- [1- (2-ethoxycarbonylethyl) cyclopropyl] propionate 1.0 M diethylzinc / hexane solution (24.5 ml, 24.5 mmol) was added to dichloromethane (30 ml). 1.89 ml of fluoroacetic acid (24.5 ml
mmol) in dichloromethane was added. After stirring for 20 minutes at the same temperature, 10 ml of a dichloromethane solution of 1.97 ml (24.5 mmol) of diiodomethane was added and stirred for 20 minutes. Further, diethyl 4-methyleneheptanedicarboxylate (JACS 107, 13
, 3981-3997 (1985)) 10 ml of a solution of 1.40 g (6.13 mmol) in dichloromethane was added. After stirring at room temperature for 6 hours, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 5: 1),
1.48 g of the title compound was obtained as a brown oil (yield 99%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.10 (2H, q, J = 7Hz), 3.37-2.31 (4H, m), 1.60-1.53 (4H, m),
1.25 (6H, t, J = 7Hz), 0.31 (4H, s).

(29b) Ethyl 6-hydroxyspiro [2.5] oct-5-ene-5-carboxylate 1.46 g of ethyl 3- [1- (2-ethoxycarbonylethyl) cyclopropyl] propionate obtained in (29a) ( 6.03 mmol) was dissolved in 60 ml of tetrahydrofuran, 1.35 g (12.1 mmol) of potassium t-butoxide was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was ice-cooled, 1N hydrochloric acid was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate.
The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate only) to give 1.05 g of the title compound.
Was obtained as a yellow oil (yield 89%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
12.23 (0.7H, s), 4.26-4.09 (2H, m), 3.50 (0.3H, dd, J = 10Hz, 6Hz),
2.57-2.42 (0.7H, m), 2.36 (2H, t, J = 6Hz), 2.03-1.94 (0.3H, m),
1.66-1.52 (1H, m), 1.48 (2H, t, J = 6Hz), 1.28 (3H, J = 7Hz), 0.60-0.30 (4H, m).

(29c) ethyl 6-trifluoromethanesulfonyloxyspiro [2.5] octa-
Ethylethyl 6-hydroxyspiro [2.5] oct-5-ene-5 obtained from 5-ene-5-carboxylate (29b)
-Carboxylate (1.05 g, 5.35 mmol) was dissolved in dichloromethane (30 ml), and stirred at -78 ° C, diisopropylethylamine (0.99 ml, 5.89 mmol),
1.40 ml (8.03 mmol) of trifluoromethanesulfonic anhydride was sequentially added, stirred at the same temperature for 3 hours, and then warmed to room temperature. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate only),
This gave 1.56 g of the title compound as a brown oil (yield 89%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.26 (2H, q, J = 7Hz), 2.57-2.46 (2H, m), 2.35-2.29 (2H, m),
1.60-1.53 (2H, m), 1.32 (3H, t, J = 7Hz), 0.49-0.40 (4H, m).

(29d) Ethyl 6-mercaptospiro [2.5] oct-5-ene-5-carboxylate ethyl 8-trifluoromethanesulfonyloxy-1,4-dioxaspiro [4.5]
Example (1a) using ethyl 6-trifluoromethanesulfonyloxyspiro [2.5] oct-5-ene-5-carboxylate obtained in (29c) instead of deca-7-ene-7-carboxylate In accordance with the method described in 1), ethyl 6-acetylsulfanylspiro [2.5] oct-5-ene-5-carboxylate was obtained as a pale yellow oil (yield 5
8%).

Next, 700 mg (2.75 mmol) of this was dissolved in 14 ml of ethanol, and 2.75 ml (11 mmol) of 4N hydrogen chloride / dioxane solution was added with stirring under ice-cooling.
Stir for hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 10: 1) to give 300 mg of the title compound as a pale yellow oil (yield 51%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.19 (2H, q, J = 7Hz), 4.12 (1H, s), 2.57 (2H, t, J = 6Hz), 2.22-2.18 (2H, m),
1.46 (2H, t, J = 6Hz), 1.29 (3H, t, J = 7Hz), 0.40-0.33 (4H, m).

(29e) Ethyl 6- (chlorosulfonyl) spiro [2.5] oct-5-ene-5
Carboxylate sodium peroxoborate tetrahydrate 651 mg (4.23 mmol) and acetic acid 7 ml
And heated to 50 ° C., and ethyl 6-mercaptospiro [2.
5] 3 ml of acetic acid solution of 300 mg (1.41 mmol) of octa-5-ene-5-carboxylate was added and stirred at the same temperature for 2 hours and further at 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue was added 5 ml of thionyl chloride, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled again to room temperature and concentrated under reduced pressure. Ice water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 5: 1) to give the title compound 195
mg was obtained as a colorless oil (yield 50%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.28 (2H, q, J = 7Hz), 2.77-2.69 (2H, m), 2.43-2.38 (2H, m),
1.62 (2H, t, J = 6Hz), 1.33 (3H, t, J = 7Hz), 0.52-0.46 (4H, m).

(29f) Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl]
Spiro [2.5] oct-4-ene-5-carboxylate ethyl 8-chlorosulfonyl-1,4-dioxaspiro [4.5] dec-7-ene-7
According to the method described in Example (1d) using ethyl 6- (chlorosulfonyl) spiro [2.5] oct-5-ene-5-carboxylate obtained in (29e) instead of -carboxylate The title compound was obtained as a white powder (yield 17%).
Melting point 125-126 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.69 (1H, dd, J = 9Hz, 5Hz), 7.13 (1H, dd, J = 8Hz, 3Hz), 7.03-6.96 (2H, m),
6.58 (1H, s), 4.53 (1H, d, J = 5Hz), 4.20-4.04 (2H, m), 2.62-2.50 (2H, m),
1.98-1.85 (1H, m), 1.23 (3H, t, J = 7Hz), 1.22-1.13 (1H, m), 1.09-0.99 (2H, m),
0.93-0.80 (2H, m).

(Example 30)
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-oxaspiro [4.5] dec-6-ene-7-carboxylate (low polarity diastereomer),
(Highly polar diastereomer) (Exemplary Compound No. 1-362)

(30a) 7- (1,3-Dioxane-2-yl) -5- [2- (1,3-dioxan-2-yl) ethyl] heptane-1,5-diol γ-butyrolactone (430 mg, 5 mmol) It melt | dissolved in 10 ml of tetrahydrofuran, 22 ml (11 mmol) of 0.5M (1,3-dioxan-2-ylethyl) magnesium bromide / tetrahydrofuran solutions were added under ice-cooling stirring, and it stirred at 50 degreeC for 3 hours. The reaction mixture was ice-cooled, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate: ethanol = 10: 1) to obtain 880 mg of the title compound as a colorless oil (yield 55%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.51 (2H, t, J = 5Hz), 4.08 (4H, dd, J = 10Hz, 4Hz), 3.79-3.70 (4H, m), 3.61 (2H, t,
J = 6Hz),
2.13-2.00 (2H, m), 1.68-1.56 (12H, m), 1.55-1.49 (2H, m), 1.37-1.29 (2H, m).

(30b) 2- (2- {2- [2- (1,3-Dioxane-2-yl) ethyl] tetrahydrofuran-2-yl} ethyl) -1,3-dioxane (30a) 7- ( 1,3-dioxan-2-yl) -5- [2- (1,3-dioxan-2-yl) ethyl] heptane-1,5-diol 2.60 g (8.17 mmol)
) Is dissolved in 45 ml of pyridine and p-toluenesulfonyl chloride 1.64 is stirred under ice-cooling.
15 ml of a pyridine solution of g (8.58 mmol) was added, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 3 hours.
Stir for hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 1: 1) to obtain 1.31 g of the title compound as a colorless oil (yield 53%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.50 (2H, t, J = 5Hz), 4.09 (2H, dd, J = 11Hz, 5Hz), 3.83-3.68 (6H, m), 2.15-1.99 (2
H, m),
1.92-1.82 (2H, m), 1.73-1.48 (12H, m), 1.38-1.29 (2H, m).

(30c)
Ethyl 3- [2- (2-ethoxycarbonylethyl) tetrahydrofuran-2-yl]
2- (2- {2- [2- (1,3-Dioxane-2-yl) ethyl] tetrahydrofuran-2-yl} ethyl) -1,3-dioxane 1.31 g (4) obtained from propionate (30b) .36mm
ol) is dissolved in 15 ml of acetone, and 16.3 ml (43.
6 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was ice-cooled, isopropyl alcohol was added to stop the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 15 ml of ethanol, 0.76 ml (10.5 mmol) of thionyl chloride was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 1).
1) to give 610 mg of the title compound as a yellow oil (yield 51%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.13 (4H, q, J = 7Hz), 3.78 (2H, t, J = 7Hz), 2.37-2.31 (4H, m), 1.95-1.87 (2H, m),
1.86-1.79 (4H, m), 1.71 (2H, t, J = 7Hz), 1.26 (6H, t, J = 7Hz).

(30d) Ethyl 3- [2- (2-ethoxycarbonylethyl) tetrahydrofuran-2-yl] propionate (610 mg) obtained from ethyl 8-oxo-1-oxaspiro [4.5] decane-7-carboxylate (30c) 2.24 mmol) was dissolved in 18 ml of tetrahydrofuran, 503 mg (4.48 mmol) of potassium t-butoxide was added, and the mixture was heated to reflux for 1 hour. The reaction mixture was ice-cooled, 1N hydrochloric acid was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 2: 1),
340 mg of the title compound was obtained as a colorless oil (yield 67%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
12.24 (1H, s), 4.26-4.12 (2H, m), 3.96-3.79 (2H, m), 2.63-2.47 (1H, m),
2.43-2.12 (3H, m), 2.05-1.86 (2H, m), 1.86-1.60 (4H, m), 1.30 (3H, t, J = 7Hz).

(30e) Ethyl 8-trifluoromethanesulfonyloxy-1-oxaspiro [4
. 5] Deca-7-ene-7-carboxylate Ethyl 8-oxo-1-oxaspiro obtained in (29d) under stirring with ice-cooling in a suspension of 72% (1.65 mmol) of 55% sodium hydride / 3 ml of dichloromethane [4.5] decane-7-carboxylate 340 mg (1.50 mmol) in dichloromethane 4 ml
And stirred at the same temperature for 1 hour. Next, the reaction solution was cooled to −78 ° C., 0.28 ml (1.65 mmol) of trifluoromethanesulfonic anhydride was added, and the mixture was stirred at the same temperature for 1 hour and then warmed to room temperature. Ice water was added to the reaction solution to stop the reaction, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate only) to obtain 480 mg of the title compound as a pale yellow oil (yield 89%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.26 (2H, q, J = 7Hz), 3.92-3.81 (2H, m), 2.74-2.63 (1H, m), 2.62-2.48 (2H, m),
2.45-2.34 (1H, m), 2.04-1.68 (6H, m), 1.32 (3H, t, J = 7Hz).

(30f) Ethyl 8-acetylthio-1-oxaspiro [4.5] dec-7-ene-7
-Carboxylate ethyl 8-trifluoromethanesulfonyloxy-1,4-dioxaspiro [4.5]
Example using ethyl 8-trifluoromethanesulfonyloxy-1-oxaspiro [4.5] dec-7-ene-7-carboxylate obtained in (30e) instead of deca-7-ene-7-carboxylate The title compound was obtained as a yellow oil according to the method described in (1a) (yield 32%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.18 (2H, q, J = 7Hz), 3.91-3.83 (2H, m), 2.65-2.60 (1H, m), 2.60-2.51 (2H, m),
2.40-2.35 (1H, m), 2.32 (2.6H, s), 2.29 (0.4H, s), 2.00-1.93 (2H, m),
1.87-1.67 (4H, m), 1.28 (3H, t, J = 7Hz).

(30 g) Ethyl 8-mercapto-1-oxaspiro [4.5] dec-7-ene-7-
120 mg (0.42 mmol) of ethyl 8-acetylthio-1-oxaspiro [4.5] dec-7-ene-7-carboxylate obtained from carboxylate (30f) was dissolved in 3 ml of ethanol, and 4N hydrogen chloride / dioxane solution was obtained. 1 ml (4 mmol) was added and stirred at room temperature for 4 hours.
The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 3: 1) to give 100 mg of the title compound as a pale yellow oil (yield 98%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.24-4.16 (2H, m), 4.12 (1H, s), 3.91-3.80 (2H, m), 2.84-2.71 (1H, m),
2.52-2.34 (3H, m), 2.01-1.90 (2H, m), 1.82-1.58 (4H, m), 1.23 (3H, t, J = 7Hz).

(30h) Ethyl 8-chlorocapto-1-oxaspiro [4.5] deca-7- obtained from ethyl 8-chlorosulfonyl-1-oxaspiro [4.5] dec-7-ene-7-carboxylate (30f) 100 mg (0.41 mmol) of ene-7-carboxylate was dissolved in 4 ml of a mixed solution of acetic acid and water (acetic acid: water = 1: 1), and chlorine gas was blown for 15 minutes under ice-cooling and stirring. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 3: 1) to give 108 mg of the title compound as a colorless oil (yield 85
%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.28 (2H, q, J = 7Hz), 3.88 (2H, t, J = 7Hz), 2.92-2.81 (1H, m),
2.77-2.66 (1H, m), 1.58 (2H, m), 2.06-1.89 (3H, m), 1.80 (2H, t, 7Hz),
1.77-1.67 (1H, m), 1.34 (3H, t, J = 7Hz).

(30i) Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl]
-1-oxaspiro [4.5] dec-6-ene-7-carboxylate (low polar diastereomer), (high polar diastereomer)
To 1 ml of an ethyl acetate solution of 57 mg (0.39 mmol) of 2-chloro-4-fluoroaniline and 0.05 ml (0.39 mmol) of triethylamine, with stirring under ice-cooling, (29 h
8-chlorosulfonyl-1-oxaspiro [4.5] dec-7-ene-7
-2 ml of an ethyl acetate solution of 108 mg (0.35 mmol) of carboxylate was added dropwise,
Stir overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane: ethyl acetate = 3: 1) to obtain 12 mg of the low-polar diastereomer of the title compound as a white powder and 20 mg of the high-polar diastereomer as an amorphous substance ( Yield 8%, 14%).
(Low polarity diastereomer)
Melting point 112-114 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.65 (1H, dd, J = 9Hz, 5Hz), 7.14 (1H, dd, J = 8Hz, 3Hz), 7.04-6.97 (1H, m),
6.95 (1H, s), 6.90 (1H, s), 4.45 (1H, dd, J = 6Hz, 2Hz), 4.22-4.10 (2H, m),
3.96-3.88 (1H, m), 3.86-3.79 (1H, m), 2.41-2.33 (1H, m), 2.29-2.18 (1H, m),
2.13-2.01 (4H, m), 1.94-1.79 (2H, m), 1.25 (3H, t, J = 7Hz).
(Highly polar diastereomer)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.66 (1H, dd, J = 9Hz, 5Hz), 7.13 (1H, dd, J = 8Hz, 3Hz), 7.04-6.96 (2H, m),
6.95 (1H, s), 4.36 (1H, d, J = 5Hz), 4.22-4.10 (2H, m), 4.03-3.96 (1H, m),
3.93-3.85 (1H, m), 2.56-2.48 (1H, m), 2.40-2.29 (1H, m), 2.06-1.63 (6H, m),
1.26 (3H, t, J = 7Hz).

(Example 31)
Ethyl 6- [N- (1H-pyrrol-1-yl) sulfamoyl] -1-cyclohexene-1-carboxylate (Exemplified Compound No. 1-1057)

Ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxyl was added to 60 ml of an ethyl acetate solution of 1.0 g (12.18 mmol) of 1H-pyrrol-1-ylamine and 1.8 ml (13.40 mmol) of triethylamine under ice-cooling and stirring. Lat (JP 2000-
(Compound described in 178246) 12 ml of an ethyl acetate solution of 3.6 g (12.18 mmol) was added dropwise and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 3: 1), and the obtained solid was washed with isopropyl ether to obtain 1.9 g of the title compound as a white powder (yield) 52%).
Melting point 85-86 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
8.15 (1H, s), 7.44-7.42 (1H, m), 7.02 (2H, t, J = 2Hz), 6.17 (2H, t, J = 2Hz),
4.57-4.56 (1H, m), 4.29 (2H, q, J = 7Hz), 2.52-2.46 (2H, m), 2.32-2.23 (1H, m),
1.93-1.66 (3H, m), 1.34 (3H, t, J = 7Hz).

(Example 32)
Ethyl 6- [N- (2-methyl-1H-pyrrol-1-yl) sulfamoyl] -1-
Cyclohexene-1-carboxylate (Exemplified Compound No. 1-1176)

The title compound was obtained as a white powder according to the method described in Example 31 using 2-methyl-1H-pyrrol-1-ylamine instead of 1H-pyrrol-1-ylamine (yield 32%). .
Melting point 100 ~ 101 ℃
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.95 (1H, s), 7.43-7.39 (1H, m), 7.03-6.99 (1H, m), 6.07 (1H, t, J = 4Hz),
5.88-5.84 (1H, m), 4.60-4.55 (1H, m), 4.26 (2H, q, J = 7Hz), 2.56-2.43 (2H, m),
2.34-2.20 (1H, m), 2.29 (3H, s), 1.95-1.66 (3H, m), 1.33 (3H, t, J = 7Hz).

(Example 33)
Ethyl 6- [N- (2-ethyl-1H-pyrrol-1-yl) sulfamoyl] -1-
Cyclohexene-1-carboxylate (Exemplified Compound No. 1-1193)

The title compound was obtained as a white powder according to the method described in Example 31 using 2-ethyl-1H-pyrrol-1-ylamine instead of 1H-pyrrol-1-ylamine (yield 51%). .
Melting point 77-78 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.97 (1H, s), 7.46-7.41 (1H, m), 7.04-7.01 (1H, m), 6.13 (1H, t, J = 4Hz),
5.92-5.87 (1H, m), 4.62-4.57 (1H, m), 4.28 (2H, q, J = 7Hz), 2.79-2.64 (2H, m),
2.58-2.42 (2H, m), 2.35-2.21 (1H, m), 1.95-1.65 (3H, m), 1.33 (3H, t, J = 7Hz),
1.24 (3H, t, J = 8Hz).

(Example 34)
Ethyl 6- [N- (2-propyl-1H-pyrrol-1-yl) sulfamoyl] -1
-Cyclohexene-1-carboxylate (Exemplified Compound No. 1-1210)

According to the method described in Example 31 using 2-propyl-1H-pyrrol-1-ylamine instead of 1H-pyrrol-1-ylamine, the title compound was obtained as a white powder (yield 31%). .
Melting point 66-68 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.97 (1H, s), 7.46-7.41 (1H, m), 7.04-7.01 (1H, m), 6.12 (1H, t, J = 3Hz),
5.92-5.87 (1H, m), 4.62-4.57 (1H, m), 4.27 (2H, q, J = 7Hz), 2.73-2.62 (2H, m),
2.57-2.43 (2H, m), 2.34-2.21 (1H, m), 1.95-1.63 (5H, m), 1.33 (3H, t, J = 7Hz),
0.99 (3H, t, J = 7Hz).

(Example 35)
Ethyl 6- [N- (2-butyl-1H-pyrrol-1-yl) sulfamoyl] -1-
Cyclohexene-1-carboxylate (Exemplified Compound No. 1-1227)

According to the method described in Example 31 using 2-butyl-1H-pyrrol-1-ylamine instead of 1H-pyrrol-1-ylamine, the title compound was obtained as a white powder (yield 26%). .
Melting point 49-50 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.94 (1H, s), 7.43-7.39 (1H, m), 7.01-6.98 (1H, m), 6.11-6.08 (1H, m),
5.89-5.85 (1H, m), 4.60-4.55 (1H, m), 4.26 (2H, q, J = 7Hz), 2.71-2.65 (2H, m),
2.56-2.43 (2H, m), 2.33-2.20 (1H, m), 1.94-1.57 (5H, m), 1.45-1.35 (2H, m),
1.32 (3H, t, J = 7Hz), 0.93 (3H, t, J = 7Hz).

(Example 36)
Ethyl 6- [N- (2-pentyl-1H-pyrrol-1-yl) sulfamoyl] −
1-cyclohexene-1-carboxylate (Exemplified Compound No. 1-1244)

The title compound was obtained as a white powder in accordance with the method described in Example 31 using 2-pentyl-1H-pyrrol-1-ylamine obtained in Reference Example 6 instead of 1H-pyrrol-1-ylamine. (Yield 33%).
Melting point 60-61 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.96 (1H, s), 7.46-7.41 (1H, m), 7.04-7.00 (1H, m), 6.12 (1H, t, J = 3Hz),
5.92-5.86 (1H, m), 4.62-4.56 (1H, m), 4.28 (2H, q, J = 7Hz), 2.72-2.65 (2H, m),
2.57-2.44 (2H, m), 2.34-2.21 (1H, m), 1.95-1.59 (5H, m), 1.42-1.29 (4H, m),
1.34 (3H, t, J = 7Hz), 0.89 (3H, t, J = 7Hz).

(Example 37)
Ethyl 6- [N- (2-hexyl-1H-pyrrol-1-yl) sulfamoyl] -1
-Cyclohexene-1-carboxylate (Exemplified Compound No. 1-1261)

Using the 2-hexyl-1H-pyrrol-1-ylamine obtained in Reference Example 7 in place of 1H-pyrrol-1-ylamine, the title compound was obtained as a yellow oil according to the method described in Example 31. (Yield 46%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.93 (1H, s), 7.43-7.39 (1H, m), 7.01-6.98 (1H, m), 6.12-6.08 (1H, m),
5.89-5.85 (1H, m), 4.60-4.55 (1H, m), 4.27 (2H, q, J = 'Hz),
2.71-2.64 (2H, m), 2.56-2.43 (2H, m), 2.33-2.21 (1H, m), 1.91-1.58 (5H, m),
1.42-1.27 (6H, m), 1.33 (3H, t, J = 7Hz), 0.88 (3H, t, J = 7Hz).

(Example 38)
Ethyl 6- [N- (2-heptyl-1H-pyrrol-1-yl) sulfamoyl] -1
-Cyclohexene-1-carboxylate (Exemplified Compound No. 1-1278)

The title compound was obtained as a colorless oil according to the method described in Example 31 using 2-heptyl-1H-pyrrol-1-ylamine obtained in Reference Example 8 instead of 1H-pyrrol-1-ylamine according to the method described in Example 31. (Yield 13%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.97 (1H, s), 7.46-7.41 (1H, m), 7.04-7.01 (1H, m), 6.11 (1H, t, J = 3Hz),
5.96-5.86 (1H, m), 4.62-4.56 (1H, m), 4.28 (2H, q, J = 7Hz), 2.72-2.62 (2H, m),
2.58-2.43 (2H, m), 2.35-2.21 (1H, m), 1.94-1.59 (5H, m), 1.41-1.22 (8H, m),
1.33 (3H, t, J = 7Hz), 0.88 (3H, t, J = 7Hz).

(Example 39)
Ethyl 6- [N- (2-octyl-1H-pyrrol-1-yl) sulfamoyl] -1
-Cyclohexene-1-carboxylate (Exemplified Compound No. 1-1295)

According to the method described in Example 31 using 2-octyl-1H-pyrrol-1-ylamine obtained in Reference Example 8 instead of 1H-pyrrol-1-ylamine, the title compound was obtained as a pale yellow oil. Obtained (yield 18%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.96 (1H, s), 7.46-7.41 (1H, m), 7.04-7.00 (1H, m), 6.11 (1H, t, J = 4Hz),
5.91-5.86 (1H, m), 4.61-4.57 (1H, m), 4.28 (2H, q, J = 7Hz), 2.71-2.64 (2H, m),
2.57-2.44 (2H, m), 2.34-2.20 (1H, m), 1.95-1.58 (5H, m), 1.42-1.19 (10H, m),
1.33 (3H, t, J = 7Hz), 0.88 (3H, t, J = 7Hz).

(Example 40)
Ethyl 6- [N- (2-cyclopropyl-1H-pyrrol-1-yl) sulfamoyl]
-1-Cyclohexene-1-carboxylate (Exemplified Compound No. 1-1312)

2-cyclopropyl-1H obtained in Reference Example 10 instead of 1H-pyrrol-1-ylamine
-The title compound was obtained as a slightly pink powder according to the method described in Example 31 using pyrrol-1-ylamine (yield 42%).
Melting point 95-96 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.87 (1H, s), 7.41-7.37 (1H, m), 6.98-6.95 (1H, m), 6.05-6.02 (1H, m),
5.69-5.66 (1H, m), 4.66-4.61 (1H, m), 4.25 (2H, q, J = 7Hz), 2.60-2.43 (2H, m),
2.34-2.20 (1H, m), 2.05-1.87 (2H, m), 1.82-1.68 (2H, m), 1.31 (3H, t, J = 7Hz),
0.94-0.82 (2H, m), 0.73-0.65 (1H, m), 0.59-0.51 (1H, m).

(Example 41)
Ethyl 6- [N- (2-phenyl-1H-pyrrol-1-yl) sulfamoyl] -1
-Cyclohexene-1-carboxylate (Exemplified Compound No. 1-1329)

According to the method described in Example 31 using 2-phenyl-1H-pyrrol-1-ylamine instead of 1H-pyrrol-1-ylamine, the title compound was obtained as a pale yellow powder (
Yield 21%).
Melting point 160-161 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.99 (1H, s), 7.57 (2H, d, J = 8Hz), 7.39 (2H, t, J = 8Hz), 7.33-7.27 (2H, m),
7.14-7.11 (1H, m), 6.32-6.28 (1H, m), 6.25 (1H, t, J = 4Hz), 4.22 (2H, q, J = 7Hz),
4.18-4.14 (1H, m), 2.44-2.32 (1H, m), 2.24-2.07 (2H, m), 1.91-1.75 (1H, m),
1.67-1.51 (1H, m), 1.40-1.29 (1H, m), 1.28 (3H, t, J = 7Hz).

(Example 42)
Ethyl 6- [N- (2,5-dimethyl-1H-pyrrol-1-yl) sulfamoyl]-
1-cyclohexene-1-carboxylate (Exemplified Compound No. 1-1346)

The title compound was obtained as a white powder according to the method described in Example 31 using 2,5-dimethyl-1H-pyrrol-1-ylamine instead of 1H-pyrrol-1-ylamine (yield 29). %).
Melting point 96-97 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.88 (1H, s), 7.40-7.35 (1H, m), 5.75 (2H, s), 4.58-4.52 (1H, m), 4.24 (2H, q, 7
Hz),
2.69-2.61 (1H, m), 2.53-2.42 (1H, m), 2.33-2.19 (1H, m), 2.26 (6H, s),
2.02-1.91 (1H, m), 1.86-1.73 (2H, m), 1.30 (3H, t, J = 7Hz).

(Example 43)
Ethyl 6- [N- (2-chloro-1H-pyrrol-1-yl) sulfamoyl] -1-
Cyclohexene-1-carboxylate (Exemplified Compound No. 1-1091)

Ethyl 6- [N- (1H-pyrrol-1-yl) sulfamoyl] obtained in Example 31 −
1-Cyclohexene-1-carboxylate (150 mg, 0.503 mmol) was dissolved in tetrahydrofuran (3 ml), and the mixture was stirred under ice cooling with 70 mg (0.5 mg) of N-chlorosuccinimide.
28 mmol) was added and stirred overnight at room temperature. Add water to the reaction mixture and extract with ethyl acetate.
The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane: ethyl acetate = 2: 1), and the obtained solid was washed with isopropyl ether to obtain 50 mg of the title compound as a white powder (
Yield 30%).
Melting point 60-61 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.91 (1H, s), 7.43-7.37 (1H, m), 7.04 (1H, dd, J = 4Hz, 2Hz),
6.14 (1H, t, J = 4Hz), 6.10 (1H, dd, J = 4Hz, 2Hz), 4.65-4.61 (1H, m),
4.26 (2H, q, J = 7Hz), 2.61-2.44 (2H, m), 2.33-2.21 (1H, m),
2.05-1.90 (1H, m), 1.83-1.71 (2H, m), 1.30 (3H, t, J = 7Hz).

(Example 44)
Ethyl 6- [N- (2-bromo-1H-pyrrol-1-yl) sulfamoyl] -1-
Cyclohexene-1-carboxylate (Exemplified Compound No. 1-1108)

The title compound was obtained as a white powder according to the method described in Example 43 using N-bromosuccinimide instead of N-chlorosuccinimide (yield 50%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.85 (1H, s), 7.42-7.38 (1H, m), 7.15 (1H, dd, J = 4Hz, 2Hz), 6.22-6.17 (2H, m),
4.67-4.62 (1H, m), 4.25 (2H, q, J = 7Hz), 2.60-2.44 (2H, m), 2.33-2.20 (1H, m),
2.05-1.92 (1H, m), 1.83-1.70 (2H, m), 1.30 (3H, t, J = 7Hz).

(Example 45)
Ethyl 6- [N- (2,5-dichloro-1H-pyrrol-1-yl) sulfamoyl]
-1-cyclohexene-1-carboxylate (Exemplified Compound No. 1-1142)

N-chlorosuccinimide obtained in Example 31 in ethyl 6- [N- (1H-pyrrole-1
-Yl) sulfamoyl] -2.1 for 1-cyclohexene-1-carboxylate
Using the equivalent amount, the title compound was obtained as a pale yellow oil according to the method described in Example 42 (yield 25%).
Melting point 144-145 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
8.08 (1H, s), 7.39-7.33 (1H, m), 6.07 (2H, s), 4.89-4.83 (1H, m), 4.24 (2H, q, J =
7Hz),
2.67-2.58 (1H, m), 2.52-2.42 (1H, m), 2.31-2.19 (1H, m), 2.03-1.88 (1H, m),
1.87-1.72 (2H, m), 1.29 (3H, t, J = 7Hz).

(Example 46)
Ethyl 6- [N- (2,5-dibromo-1H-pyrrol-1-yl) sulfamoyl]
-1-Cyclohexene-1-carboxylate (Exemplified Compound No. 1-1159)

N-bromosuccinimide obtained in Example 31 in ethyl 6- [N- (1H-pyrrole-1
-Yl) sulfamoyl] -2.1 for 1-cyclohexene-1-carboxylate
Using the equivalent amount, the title compound was obtained as a white powder according to the method described in Example 44 (
Yield 3%).
Melting point 123-124 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
8.05 (1H, s), 7.40-7.35 (1H, m), 6.24 (2H, s), 5.02-4.95 (1H, m), 4.25 (2H, q, J
= 7Hz),
2.69-2.60 (1H, m), 2.53-2.42 (1H, m), 2.33-2.19 (1H, m), 2.02-1.90 (1H, m),
1.87-1.72 (2H, m), 1.29 (3H, t, J = 7Hz).

(Example 47)
t-butyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,
4-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 3-89)

(47a) 8- [N- (2-Chloro-4-fluorophenyl) sulfamoyl] -1,4
-Dioxaspiro [4.5] dec-6-ene-7-carboxylic acid Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4. 5] 1.8 g of deca-6-ene-7-carboxylate
(4.29 mmol) was dissolved in 60 ml of a water-tetrahydrofuran (1: 1) mixture,
900 mg (21.45 mmol) of lithium hydroxide was added and stirred at 50 ° C. for 7 hours. The reaction mixture was ice-cooled, 1N hydrochloric acid was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to obtain 1.43 g of the title compound as a light brown powder (yield 85%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.68 (1H, dd, J = 9Hz, 5Hz), 7.16 (1H, dd, J = 8Hz, 3Hz), 7.04-6.93 (3H, m),
4.36 (1H, d, J = 5Hz), 4.16-4.02 (3H, m), 3.97-3.88 (1H, m), 2.57-2.45 (3H, m),
2.25-2.13 (1H, m), 1.90-1.82 (1H, m).

(47b) t-butyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (47a) 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl]-
1,4-Dioxaspiro [4.5] dec-6-ene-7-carboxylic acid 100 mg (0.26
mmol) was dissolved in 2 ml of toluene, 1 ml of N, N-dimethylformamide di-t-butyl acetal was added, and the mixture was stirred at 100 ° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; dichloromethane: methanol = 1: 50) to give 52 mg of the title compound as a white amorphous (yield 45
%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.64 (1H, dd, J = 9Hz, 5Hz), 7.15 (1H, dd, J = 8Hz, 3Hz), 7.05-6.98 (2H, m),
6.71 (1H, s), 4.42-4.38 (1H, m), 4.13-4.01 (3H, m), 3.95-3.88 (1H, m),
2.51-2.40 (2H, m), 2.21-2.10 (1H, m), 1.86-1.79 (1H, m), 1.46 (9H, s).

The compounds of Examples 48 to 51 were synthesized according to the method described in Example (47b) using various corresponding acetals instead of N, N-dimethylformamide di-t-butyl acetal.

(Example 48)
Methyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 3-
73)

White powder (yield 50%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.67 (1H, dd, J = 9Hz, 5Hz), 7.16 (1H, dd, J = 8Hz, 3Hz), 7.06-6.99 (1H, m),
6.98 (1H, s), 6.84 (1H, s), 4.43-4.38 (1H, m), 4.15-3.99 (3H, m), 3.95-3.88 (1H,
m),
3.73 (3H, s), 2.56-2.43 (2H, m), 2.24-2.12 (1H, m), 1.88-1.79 (1H, m).

(Example 49)
Propyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4
-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 3
-77)

White amorphous (18% yield)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.67 (1H, dd, J = 9Hz, 5Hz), 7.16 (1H, dd, J = 8Hz, 3Hz), 7.05-6.97 (2H, m),
6.81 (1H, s), 4.42 (1H, d, J = 5Hz), 4.16-3.99 (5H, m), 3.95-3.88 (1H, m),
2.55-2.44 (2H, m), 2.24-2.11 (1H, m), 1.88-1.81 (1H, m), 1.71-1.60 (2H, m),
0.94 (3H, t, J = 7Hz).

(Example 50)
Butyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 3-
81)

White powder (yield 26%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.66 (1H, dd, J = 9Hz, 5Hz), 7.16 (1H, dd, J = 8Hz, 3Hz), 7.05-6.96 (2H, m),
6.80 (1H, s), 4.42 (1H, d, J = 5Hz), 4.20-4.00 (5H, m), 3.95-3.87 (1H, m),
2.55-2.44 (2H, m), 2.24-2.11 (1H, m), 1.88-1.80 (1H, m), 1.66-1.57 (2H, m),
1.43-1.32 (2H, m), 0.93 (3H, t, J = 7Hz).

(Example 51)
Isopropyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1
4-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 3-85)

White powder (yield 21%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.66 (1H, dd, J = 9Hz, 5Hz), 7.16 (1H, dd, J = 8Hz, 3Hz), 7.06-6.98 (2H, m),
6.78 (1H, s), 5.11-4.99 (1H, m), 4.42 (1H, d, J = 5Hz), 4.15-3.99 (3H, m),
3.95-3.88 (1H, m), 2.55-2.43 (2H, m), 2.24-2.11 (1H, m), 1.99-1.79 (1H, m),
1.26 (3H, d, J = 2Hz), 1.24 (3H, d, J = 2Hz).

(Example 52)
Acetoxymethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl]-
1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 3-93)

1-g of 2- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylic acid obtained in Example (47a) (2. 55
mmol) is dissolved in 20 ml of acetonitrile, and 0.50 ml of bromomethyl acetate is dissolved.
(5.10 mmol), 499 mg (1.53 mmol) of cesium carbonate and 471 mg (1.28 mmol) of tetrabutylammonium iodide were sequentially added and stirred at room temperature for 1 hour.
0.1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; dichloromethane: methanol = 49: 1) to obtain 833 mg of the title compound as an amorphous substance (yield 70%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.67 (1H, dd, J = 9Hz, 5Hz), 7.18 (1H, dd, J = 8Hz, 3Hz), 7.08-7.02 (1H, m),
7.01 (1H, s), 6.92 (1H, s), 5.80 (2H, s), 4.41 (1H, dd, J = 6Hz, 2Hz),
4.15-4.01 (3H, m), 3.94-3.88 (1H, m), 2.48 (1H, td, J = 14Hz, 4Hz), 2.44-2.37 (1H,
m),
2.22-2.14 (1H, m), 2.12 (3H, s), 1.85-1.79 (1H, m).

The compounds of Examples 53 to 121 were synthesized according to the method described in Example (1d) using various corresponding anilines instead of 2-chloro-4-fluoroaniline.

(Example 53)
Ethyl 8- [N- (2-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2217)

Oil (61% yield)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.67-7.62 (1H, m), 7.17-7.09 (3H, m), 6.96 (1H, d, J = 3Hz), 6.83 (1H, t, J = 1Hz),
4.43-4.40 (1H, m), 4.24-4.01 (5H, m), 3.95-3.89 (1H, m), 2.55-2.41 (2H, m),
2.21-2.10 (1H, m), 1.89-1.81 (1H, m), 1.27 (3H, t, J = 7Hz).

(Example 54)
Ethyl 8- [N- (2-chlorophenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Deca-6-ene-7-carboxylate (Exemplified Compound No. 1-188)

Light brown powder (69% yield)
Melting point 157-160 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.70 (1H, dd, J = 8Hz, 1Hz), 7.39 (1H, dd, J = 8Hz, 2Hz), 7.31-7.26 (1H, m),
7.10-7.05 (2H, m), 6.83 (1H, t, J = 1Hz), 4.49-4.46 (1H, m), 4.24-4.02 (5H, m),
3.95-3.89 (1H, m), 2.60-2.48 (2H, m), 2.24-2.13 (1H, m), 1.88-1.81 (1H, m),
1.24 (3H, t, J = 7Hz).

(Example 55)
Ethyl 8- [N- (2-bromophenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Deca-6-ene-7-carboxylate (Exemplified Compound No. 1-1374)

Oil (yield 59%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.70 (1H, dd, J = 8Hz, 1Hz), 7.55 (1H, dd, J = 8Hz, 2Hz), 7.36-7.30 (1H, m),
7.04-6.98 (2H, m), 6.83 (1H, t, J = 1Hz), 4.50-4.47 (1H, m), 4.23-4.01 (5H, m),
3.95-3.88 (1H, m), 2.62-2.49 (2H, m), 2.24-2.13 (1H, m), 1.88-1.81 (1H, m),
1.24 (3H, t, J = 7Hz).

(Example 56)
Ethyl 8- [N- (2-iodophenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Deca-6-ene-7-carboxylate (Exemplified Compound No. 1-2224)

Amorphous (53% yield)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.79 (1H, dd, J = 8Hz, 1Hz), 7.67 (1H, dd, J = 8Hz, 1Hz), 7.38-7.33 (1H, m),
6.88-6.82 (3H, m), 4.49 (1H, d, J = 5Hz), 4.24-4.01 (5H, m), 3.95-3.88 (1H, m),
2.63-2.49 (2H, m), 2.24-2.13 (1H, m), 1.88-1.81 (1H, m), 1.24 (3H, t, J = 7Hz).

(Example 57)
Ethyl 8- [N- (4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-100)

White powder (87% yield)
Melting point 141-146 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.38-7.33 (2H, m), 7.07-7.01 (3H, m), 6.87 (1H, t, J = 1Hz), 4.30-4.21 (3H, m),
4.14-4.01 (3H, m), 3.95-3.89 (1H, m), 2.45-2.38 (1H, m), 2.27 (1H, td, J = 14Hz, 3
Hz),
2.09-1.99 (1H, m), 1.87-1.80 (1H, m), 1.33 (3H, t, J = 7Hz).

(Example 58)
Ethyl 8- [N- (4-chlorophenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Deca-6-ene-7-carboxylate (Exemplified Compound No. 1-2231)

White powder (yield 81%)
Melting point 153-156 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.31 (4H, s), 7.03 (1H, s), 6.87 (1H, t, J = 1Hz), 4.29-4.19 (3H, m),
4.14-4.02 (3H, m), 3.95-3.89 (1H, m), 2.47-2.40 (1H, m), 2.27 (1H, td, J = 14Hz, 3
Hz),
2.10-2.00 (1H, m), 1.88-1.81 (1H, m), 1.32 (3H, t, J = 7Hz).

(Example 59)
Ethyl 8- [N- (2-methylphenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Deca-6-ene-7-carboxylate (Exemplified Compound No. 1-2238)

White powder (75% yield)
Melting point 101-104 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.56-7.53 (1H, m), 7.23-7.18 (2H, m), 7.11-7.06 (1H, m), 6.85 (1H, t, J = 1Hz),
6.62 (1H, s), 4.44 (1H, dd, J = 6Hz, 2Hz), 4.25-4.01 (5H, m), 3.95-3.89 (1H, m),
2.55-2.48 (1H, m), 2.42 (1H, td, J = 14Hz, 4Hz), 2.34 (3H, s), 2.19-2.09 (1H, m),
1.88-1.81 (1H, m), 1.26 (3H, t, J = 7Hz).

(Example 60)
Ethyl 8- [N- (2-ethylphenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Deca-6-ene-7-carboxylate (Exemplified Compound No. 1-2245)

White powder (66% yield)
Melting point 83-87 ° C
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.54 (1H, dd, J = 8Hz, 1Hz), 7.25-7.19 (2H, m), 7.14 (1H, td, J = 7Hz, 1Hz),
6.85 (1H, s), 6.63 (1H, s), 4.47 (1H, dd, J = 6Hz, 2Hz), 4.25-4.02 (5H, m),
2.75-2.66 (2H, m), 2.54-2.48 (1H, m), 2.43 (1H, td, J = 14Hz, 4Hz),
2.19-2.11 (1H, m), 1.87-1.81 (1H, m), 1.28-1.23 (6H, m).

(Example 61)
Ethyl 8- [N- (2-propylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-1989)

Oil (53% yield)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.55-7.52 (1H, m), 7.23-7.18 (2H, m), 7.14-7.09 (1H, m), 6.85 (1H, t, J = 1Hz),
6.64 (1H, s), 4.48-4.44 (1H, m), 4.24-4.02 (5H, m), 3.95-3.89 (1H, m),
2.67-2.62 (2H, m), 2.54-2.39 (2H, m), 2.20-2.10 (1H, m), 1.87-1.81 (1H, m),
1.69-1.58 (2H, m), 1.26 (3H, t, J = 7Hz), 0.99 (3H, t, J = 7Hz).

(Example 62)
Ethyl 8- [N- (2-ethynylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2225)

Oil (Yield 19%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.66 (1H, dd, J = 8Hz, 1Hz), 7.47 (1H, dd, J = 8Hz, 2Hz), 7.37 (1H, td, J = 8Hz, 2Hz),

7.21 (1H, s), 7.07 (1H, td, J = 8Hz, 1Hz), 6.82 (1H, t, J = 1Hz), 4.52-4.49 (1H, m),

4.22-4.01 (5H, m), 3.95-3.88 (1H, m), 3.49 (1H, s), 2.65-2.50 (2H, m),
2.24-2.13 (1H, m), 1.88-1.81 (1H, m), 1.22 (3H, t, J = 7Hz).

(Example 63)
Ethyl 8- [N- (2-isopropylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2259)
)

Light brown powder (yield 65%)
Melting point 115-118 ° C
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.53-7.49 (1H, m), 7.34-7.30 (1H, m), 7.23-7.17 (2H, m), 6.86 (1H, s),
6.69 (1H, s), 4.47 (1H, dd, J = 6Hz, 2Hz), 4.27-4.02 (5H, m), 3.95-3.89 (1H, m),
3.33-3.24 (1H, m), 2.53-2.47 (1H, m), 2.42 (1H, td, J = 14Hz, 3Hz),
2.18-2.10 (1H, m), 1.86-1.81 (1H, m), 1.29-1.21 (9H, m).

(Example 64)
Ethyl 8- [N- (2-t-butylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2266)

White powder (yield 53%)
Melting point 117-120 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.45 (1H, dd, J = 8Hz, 1Hz), 7.38 (1H, dd, J = 8Hz, 2Hz), 7.23 (1H, td, J = 8Hz, 2Hz),

7.12-7.07 (1H, m), 6.86 (1H, t, J = 1Hz), 6.64 (1H, s), 4.64-4.61 (1H, m),
4.24-4.03 (5H, m), 3.97-3.90 (1H, m), 2.65-2.53 (2H, m), 2.28-2.18 (1H, m),
1.90-1.83 (1H, m), 1.45 (9H, s), 1.23 (3H, t, J = 7Hz).

(Example 65)
Ethyl 8- [N- (2-sec-butylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2273)

Oil (yield 71%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.54-7.49 (1H, m), 7.29-7.16 (3H, m), 6.86 (1H, dt, J = 5Hz, 1Hz), 6.68 (1H, d, J =
10Hz),
4.47-4.44 (1H, m), 4.27-4.02 (5H, m), 3.95-3.89 (1H, m), 3.12-2.95 (1H, m),
2.53-2.35 (2H, m), 2.19-2.07 (1H, m), 1.86-1.80 (1H, m), 1.70-1.55 (2H, m),
1.31-1.19 (6H, m), 0.91-0.80 (3H, m).

Example 66
Ethyl 8- [N- (2-methoxyphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2280)

White powder (yield 70%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.57 (1H, dd, J = 8Hz, 2Hz), 7.11-7.05 (2H, m), 6.96 (1H, td, J = 8Hz, 1Hz),
6.89 (1H, dd, J = 8Hz, 1Hz), 6.79 (1H, t, J = 1Hz), 4.44 (1H, d, J = 4Hz),
4.21-4.00 (5H, m), 3.94-3.84 (4H, m), 2.58 (1H, td, J = 14Hz, 4Hz),
2.50-2.43 (1H, m), 2.18-2.08 (1H, m), 1.84-1.77 (1H, m), 1.23 (3H, t, J = 7Hz).

(Example 67)
Ethyl 8- [N- (2-ethoxyphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2287)

White powder (yield 60%)
Melting point: 129-134 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.58 (1H, dd, J = 8Hz, 2Hz), 7.12 (1H, s), 7.06 (1H, td, J = 8Hz, 2Hz),
6.95 (1H, td, J = 8Hz, 2Hz), 6.87 (1H, dd, J = 8Hz, 1Hz), 6.79 (1H, t, J = 1Hz),
4.45-4.42 (1H, m), 4.20-4.00 (7H, m), 3.94-3.87 (1H, m),
2.57 (1H, td, J = 14Hz, 4Hz), 2.50-2.44 (1H, m), 2.18-2.08 (1H, m),
1.85-1.78 (1H, m), 1.45 (3H, t, J = 7Hz), 1.23 (3H, t, J = 7Hz).

(Example 68)
Ethyl 8- [N- (2-difluoromethoxyphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-2
294)

White powder (yield 48%)
Melting point 85-88 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.69 (1H, dd, J = 8Hz, 2Hz), 7.25-7.08 (4H, m), 6.84 (1H, s), 6.57 (1H, dd, J = 74Hz
, 73Hz), 4.44-4.41 (1H, m), 4.21-4.02 (5H, m), 3.95-3.89 (1H, m), 2.57-2.44 (2H,
m), 2.21-2.10 (1H, m), 1.90-1.82 (1H, m), 1.26 (3H, t, J = 7Hz).

(Example 69)
Ethyl 8- [N- (2-methylsulfanylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-2
301)

White powder (yield 56%)
Melting point 93-95 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.70 (1H, s), 7.63 (1H, dd, J = 8Hz, 1Hz), 7.51 (1H, dd, J = 8Hz, 2Hz),
7.33-7.28 (1H, m), 7.08 (1H, td, J = 8Hz, 1Hz), 6.82 (1H, q, J = 1Hz),
4.50 (1H, d, J = 4Hz), 4.21-4.01 (5H, m), 3.95-3.88 (1H, m), 2.65-2.50 (2H, m),
2.38 (3H, s), 2.23-2.12 (1H, m), 1.88-1.81 (1H, m), 1.25-1.21 (3H, m).

(Example 70)
Ethyl 8- [N- (2-acetylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-2308)

Oil (25% yield)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
11.46 (1H, s), 7.91 (1H, dd, J = 8Hz, 1Hz), 7.85 (1H, dd, J = 8Hz, 1Hz),
7.59-7.54 (1H, m), 7.15-7.10 (1H, m), 6.80 (1H, t, J = 1Hz), 4.50-4.47 (1H, m),
4.16-4.00 (5H, m), 3.94-3.88 (1H, m), 2.68-2.59 (4H, m), 2.56-2.49 (1H, m),
2.20-2.09 (1H, m), 1.87-1.80 (1H, m), 1.25 (3H, t, J = 7Hz).

(Example 71)
Ethyl 8- [N- (2-benzylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2315)

White powder (yield 73%)
Melting point 127-129 ° C
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.58 (1H, dd, J = 8Hz, 1Hz), 7.32-7.13 (8H, m), 6.80 (1H, s), 6.50 (1H, s),
4.36 (1H, dd, J = 6Hz, 2Hz), 4.23-4.00 (7H, m), 3.93-3.87 (1H, m),
2.36 (1H, td, J = 14Hz, 4Hz), 2.19-2.13 (1H, m), 2.03-1.94 (1H, m),
1.76-1.70 (1H, m), 1.26 (3H, t, J = 7Hz).

(Example 72)
Ethyl 8- {N- [2- (morpholin-4-yl) phenyl] sulfamoyl} -1,
4-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2322)

White powder (yield 71%)
Melting point 118-121 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
8.10 (1H, s), 7.58 (1H, dd, J = 8Hz, 2Hz), 7.23 (1H, dd, J = 8Hz, 2Hz),
7.20-7.15 (1H, m), 7.07 (1H, td, J = 8Hz, 2Hz), 6.82 (1H, t, 1Hz), 4.47-4.44 (1H,
m),
4.15-4.00 (5H, m), 3.95-3.85 (5H, m), 2.92-2.83 (4H, m), 2.59-2.50 (2H, m),
2.24-2.12 (1H, m), 1.90-1.82 (1H, m), 1.23 (3H, t, J = 7Hz).

(Example 73)
Ethyl 8- [N- (9H-fluoren-1-yl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2329)
)

Light brown powder (yield 60%)
Melting point: 156-160 ° C
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.78 (1H, d, J = 7Hz), 7.62 (1H, d, J = 8Hz), 7.58 (1H, d, J = 7Hz), 7.54 (1H, d, J = 8H
z),
7.42-7.37 (2H, m), 7.34 (1H, td, J = 7Hz, 1Hz), 6.92 (1H, s), 6.86 (1H, s),
4.45 (1H, dd, J = 6Hz, 2Hz), 4.22-4.00 (5H, m), 3.96 (2H, s), 3.94-3.89 (1H, m),
2.56-2.50 (1H, m), 2.37 (1H, td, J = 14Hz, 3Hz), 2.17-2.08 (1H, m), 1.88-1.82 (1H,
m),
1.26 (3H, t, J = 7Hz).

(Example 74)
Ethyl 8- (N- {2- [2- (pyridin-4-yl) ethyl] phenyl} sulfamoyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary compound number) 1-2336)

White powder (yield 26%)
Melting point 77-80 ° C
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
8.50-8.47 (2H, m), 7.54-7.52 (1H, m), 7.26-7.22 (1H, m), 7.19-7.13 (4H, m),
6.89 (1H, t, J = 1Hz), 6.80 (1H, s), 4.43 (1H, dd, J = 6Hz, 3Hz), 4.25-4.18 (2H, m),

4.14-4.03 (3H, m), 3.96-3.90 (1H, m), 3.15-3.00 (2H, m), 2.99-2.89 (2H, m),
2.54-2.48 (1H, m), 2.33 (1H, td, J = 14Hz, 3Hz), 2.17-2.09 (1H, m), 1.88-1.82 (1H,
m),
1.29 (3H, t, J = 7Hz).

(Example 75)
Ethyl 8- (N- {2- [2- (t-butoxycarbonylamino) ethyl] phenyl} sulfamoyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-2343)

Amorphous (65% yield)
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
8.00 (1H, s), 7.62 (1H, d, J = 8Hz), 7.24 (1H, td, J = 8Hz, 2Hz), 7.17 (1H, d, J = 7Hz
),
7.10 (1H, t, J = 7Hz), 6.83 (1H, s), 4.90 (1H, brs), 4.46 (1H, d, J = 5Hz),
4.23-4.01 (5H, m), 3.94-3.88 (1H, m), 3.27 (2H, q, J = 7Hz), 2.96-2.83 (2H, m),
2.59-2.52 (2H, m), 2.18-2.09 (1H, m), 1.83-1.78 (1H, m), 1.48-1.41 (9H, m),
1.27 (3H, t, J = 7Hz).

(Example 76)
Ethyl 8- [N- (2-aminophenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Deca-6-ene-7-carboxylate (Exemplified Compound No. 1-2350)

Oil (13% yield)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.39 (1H, dd, J = 8Hz, 2Hz), 7.11-7.06 (1H, m), 6.89 (1H, t, J = 1Hz),
6.79-6.73 (2H, m), 4.46 (1H, dd, J = 6Hz, 3Hz), 4.31-3.86 (3H, m), 4.28 (2H, q, J =
7Hz),
4.11-4.02 (3H, m), 3.95-3.89 (1H, m), 2.48-2.41 (1H, m), 2.24 (1H, td, J = 14Hz, 3
Hz),
2.13-2.03 (1H, m), 1.86-1.79 (1H, m), 1.32 (3H, t, J = 7Hz).

(Example 77)
Ethyl 8- [N- (2,4-difluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-276)
)

White powder (74% yield)
Melting point 128-131 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.64-7.57 (1H, m), 6.97 (1H, brs), 6.93-6.86 (2H, m), 6.84 (1H, t, J = 1Hz),
4.36 (1H, dd, J = 6Hz, 2Hz), 4.28-4.02 (5H, m), 3.95-3.90 (1H, m), 2.53-2.46 (1H,
m),
2.40 (1H, td, J = 14Hz, 4Hz), 2.21-2.10 (1H, m), 1.88-1.81 (1H, m), 1.29 (3H, t, J
= 7Hz).

(Example 78)
Ethyl 8- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
1550)

Pale yellow powder (48% yield)
Melting point: 106-111 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.68 (1H, dd, J = 9Hz, 5Hz), 7.32 (1H, dd, J = 8Hz, 3Hz), 7.10-7.04 (1H, m),
6.94 (1H, s), 6.82 (1H, t, J = 1Hz), 4.46-4.43 (1H, m), 4.26-4.01 (5H, m),
3.95-3.89 (1H, m), 2.57-2.47 (2H, m), 2.24-2.13 (1H, m), 1.87-1.81 (1H, m),
1.26 (3H, t, J = 7Hz).

(Example 79)
Ethyl 8- [N- (4-fluoro-2-methylphenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
2357)

White powder (yield 79%)
Melting point 103-105 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, dd, J = 9Hz, 5Hz), 6.96-6.85 (3H, m), 6.64 (1H, brs),
4.39 (1H, dd, J = 6Hz, 3Hz), 4.27-4.18 (2H, m), 4.14-4.02 (3H, m), 3.96-3.89 (1H,
m), 2.52-2.45 (1H, m), 2.40-2.31 (4H, m), 2.18-2.08 (1H, m), 1.87-1.80 (1H, m),
1.29 (3H, t, J = 7Hz).

(Example 80)
Ethyl 8- [N- (3-chloro-4-fluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
2364)

Light brown powder (81% yield)
Melting point 111-118 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.47 (1H, dd, J = 6Hz, 3Hz), 7.29-7.25 (1H, m), 7.15-7.09 (2H, m), 6.88 (1H, s),
4.28 (2H, q, J = 7Hz), 4.21-4.18 (1H, m), 4.14-4.02 (3H, m), 3.96-3.89 (1H, m),
2.49-2.41 (1H, m), 2.25 (1H, td, J = 14Hz, 3Hz), 2.12-2.01 (1H, m),
1.89-1.82 (1H, m), 1.34 (3H, t, J = 7Hz).

(Example 81)
Ethyl 8- [N- (4-fluoro-3-trifluoromethylphenyl) sulfamoyl
] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2237)

White powder (yield 78%)
Melting point 109-111 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.64-7.57 (2H, m), 7.27-7.17 (2H, m), 6.89 (1H, s), 4.28 (2H, q, J = 7Hz),
4.19-4.16 (1H, m), 4.14-4.03 (3H, m), 3.96-3.89 (1H, m), 2.49-2.42 (1H, m),
2.26 (1H, td, J = 14Hz, 3Hz), 2.13-2.03 (1H, m), 1.89-1.83 (1H, m), 1.34 (3H, t, J
= 7Hz).

(Example 82)
Ethyl 8- [N- (4-fluoro-3-methoxyphenyl) sulfamoyl] -1,4
-Dioxaspiro [4.5 Dec-6-ene-7-carboxylate (Exemplary Compound No. 1
-2378)

Oil (yield 72%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.09 (1H, dd, J = 7Hz, 2Hz), 7.03 (1H, dd, J = 11Hz, 9Hz), 6.96 (1H, brs),
6.88-6.83 (2H, m), 4.30-4.23 (3H, m), 4.14-4.02 (3H, m), 3.95-3.89 (4H, m),
2.46-2.38 (1H, m), 2.27 (1H, td, J = 14Hz, 3Hz), 2.10-2.00 (1H, m), 1.88-1.81 (1H,
m),
1.33 (3H, t, J = 7Hz).

(Example 83)
Ethyl 8- [N- (3,4-difluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-238
5)

Light brown powder (94% yield)
Melting point 118-121 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.33-7.26 (1H, m), 7.18-7.06 (3H, m), 6.89 (1H, s), 4.28 (2H, q, J = 7Hz),
4.19 (1H, dd, J = 5Hz, 3Hz), 4.14-4.02 (3H, m), 3.96-3.89 (1H, m), 2.48-2.41 (1H,
m),
2.25 (1H, td, J = 14Hz, 3Hz), 2.11-2.01 (1H, m), 1.89-1.82 (1H, m), 1.34 (3H, t, J
= 7Hz).

(Example 84)
Ethyl 8- [N- (2,4-dimethoxyphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-239
2)

White powder (yield 49%)
Melting point 118-121 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.47-7.45 (1H, m), 6.78 (2H, d, J = 9.8Hz), 6.50-6.47 (2H, m), 4.38 (1H, d, J = 4.7Hz),
4.21-3.80 (12H, m), 2.54 (1H, dt, J = 14.2Hz, 7.2Hz), 2.45-2.38 (1H, m), 2.14-2.08 (1H
, m), 1.81-1.76 (1H, m), 1.25 (3H, t, J = 7.0 Hz).

(Example 85)
Ethyl 8- [N- (2-butyl-4-fluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
628)

Brown oil (yield 82%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, dd, J = 9Hz, 5Hz), 6.94 (1H, dd, J = 10Hz, 3Hz), 6.92-6.86 (2H, m),
6.60 (1H, s), 4.41 (1H, dd, J = 6Hz, 2Hz), 4.28-4.18 (2H, m), 4.14-4.02 (3H, m),
3.96-3.89 (1H, m), 2.75-2.63 (2H, m), 2.52-2.45 (1H, m),
2.37 (1H, dt, J = 14Hz, 3Hz), 2.18-2.08 (1H, m), 1.87-1.80 (1H, m),
1.63-1.52 (2H, m), 1.44-1.35 (2H, m), 1.29 (3H, t, J = 7Hz), 0.95 (3H, t, J = 8Hz).

(Example 86)
Ethyl 8- [N- (4-fluoro-2-pentylphenyl) sulfamoyl] -1,4
-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1
-1726)

Brown oil (yield 78%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, dd, J = 9Hz, 5Hz), 6.94 (1H, dd, J = 10Hz, 3Hz), 6.92-6.85 (2H, m),
6.61 (1H, s), 4.40 (1H, dd, J = 6Hz, 2Hz), 4.27-4.18 (2H, m), 4.14-4.02 (3H, m),
3.95-3.90 (1H, m), 2.76-2.61 (2H, m), 2.52-2.45 (1H, m),
2.37 (1H, dt, J = 14Hz, 3Hz), 2.18-2.09 (1H, m), 1.87-1.81 (1H, m),
1.65-1.52 (2H, m), 1.39-1.32 (4H, m), 1.30 (3H, t, J = 7Hz), 0.90 (3H, t, J = 7Hz).

(Example 87)
Ethyl 8- [N- (4-fluoro-2-hexylphenyl) sulfamoyl] -1,4
-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1
-804)

Light brown oil (yield 58%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, dd, J = 9Hz, 5Hz), 6.96-6.85 (3H, m), 6.61 (1H, s), 4.40 (1H, dd, J = 6Hz,
2Hz), 4.28-4.18 (2H, m), 4.14-4.02 (3H, m), 3.95-3.89 (1H, m), 2.76-2.61 (2H, m
), 2.52-2.45 (1H, m), 2.37 (1H, td, J = 14Hz, 3Hz), 2.18-2.08 (1H, m), 1.87-1.81 (
1H, m), 1.63-1.52 (2H, m), 1.42-1.25 (9H, m), 0.91-0.85 (3H, m).

(Example 88)
Ethyl 8- [N- (4-fluoro-2-heptylphenyl) sulfamoyl] -1,4
-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1
-980)

Pale yellow oil (yield 85%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, dd, J = 9Hz, 5Hz), 6.96-6.87 (3H, m), 6.63 (1H, s), 4.41 (1H, dd, J = 6Hz, 2Hz
), 4.27-4.19 (2H, m), 4.14-3.91 (4H, m), 2.76-2.62 (2H, m), 2.52-2.46 (1H, m), 2.37 (
1H, dt, J = 14Hz, 3Hz), 2.18-2.09 (1H, m), 1.84 (1H, dt, J = 13Hz, 4Hz), 1.62-1.55 (2H,
m), 1.40-1.24 (11H, m), 0.88 (3H, t, J = 7Hz).

Example 89
Ethyl 8- [N- (4-fluoro-2-octylphenyl) sulfamoyl] -1,4
-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1
-1902)

Pale yellow oil (yield 72%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, dd, J = 9Hz, 5Hz), 6.96-6.87 (3H, m), 6.62 (1H, s), 4.40 (1H, dd, J = 6Hz, 2Hz
), 4.27-4.19 (2H, m), 4.15-3.90 (4H, m), 2.74-2.62 (2H, m), 2.52-2.46 (1H, m), 2.37 (
1H, dt, J = 14Hz, 3Hz), 2.18-2.10 (1H, m), 1.86-1.81 (1H, m), 1.63-1.53 (2H, m), 1.40
-1.24 (13H, m), 0.88 (3H, t, J = 7Hz).

(Example 90)
Ethyl 8- [N- (4-fluoro-2-nonylphenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
2602)

Pale orange oil (82% yield)
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, dd, J = 9Hz, 5Hz), 6.94 (1H, dd, J = 9Hz, 3Hz), 6.92-6.85 (2H, m),
6.62 (1H, s), 4.40 (1H, dd, J = 6Hz, 2Hz), 4.28-4.17 (2H, m), 4.15-4.03 (3H, m),
3.95-3.90 (1H, m), 2.75-2.62 (2H, m), 2.52-2.45 (1H, m), 2.37 (1H, td, J = 14Hz, 3
Hz),
2.18-2.09 (1H, m), 1.86-1.81 (1H, m), 1.63-1.53 (2H, m), 1.39-1.22 (15H, m),
0.88 (3H, t, J = 7Hz).

(Example 91)
Ethyl 8- [N- (2-decyl-4-fluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
2616)

Pale yellow oil (yield 83%)
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, dd, J = 9Hz, 5Hz), 6.94 (1H, dd, J = 9Hz, 3Hz), 6.92-6.85 (2H, m),
6.62 (1H, s), 4.40 (1H, dd, J = 5Hz, 3Hz), 4.28-4.17 (2H, m), 4.15-4.03 (3H, m),
3.95-3.90 (1H, m), 2.75-2.62 (2H, m), 2.51-2.45 (1H, m), 2.37 (1H, td, J = 14Hz, 3
Hz),
2.18-2.09 (1H, m), 1.86-1.81 (1H, m), 1.63-1.53 (2H, m), 1.39-1.22 (17H, m),
0.88 (3H, t, J = 7Hz).

(Example 92)
Ethyl 8- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
2399)

White powder (yield 65%)
Melting point 130-133 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.62-7.56 (1H, m), 7.18-7.11 (2H, m), 7.02 (1H, s), 6.84 (1H, t, J = 1Hz),
4.37 (1H, dd, J = 6Hz, 2Hz), 4.25-4.02 (5H, m), 3.96-3.89 (1H, m), 2.55-2.48 (1H,
m),
2.42 (1H, td, J = 14Hz, 4Hz), 2.21-2.11 (1H, m), 1.88-1.82 (1H, m), 1.29 (3H, t, J
= 7Hz).

(Example 93)
Ethyl 8- [N- (2-bromo-4-chlorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-2
406)

Light brown powder (51% yield)
Melting point 100-110 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.64 (1H, d, J = 9Hz), 7.56 (1H, d, J = 3Hz), 7.31 (1H, dd, J = 9Hz, 3Hz), 7.02 (1H, s
),
6.83 (1H, t, J = 1Hz), 4.47-4.43 (1H, m), 4.23-4.02 (5H, m), 3.95-3.89 (1H, m),
2.58-2.48 (2H, m), 2.24-2.14 (1H, m), 1.89-1.82 (1H, m), 1.26 (3H, t, J = 7Hz).

(Example 94)
Ethyl 8- [N- (4-chloro-2-methylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-2
413)

White powder (74% yield)
Melting point: 123-126 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, d, J = 9Hz), 4.21-4.15 (2H, m), 6.86 (1H, t, J = 1Hz), 6.65 (1H, s),
4.38 (1H, dd, J = 6Hz, 3Hz), 4.24-4.15 (2H, m), 4.14-4.02 (3H, m),
3.96-3.89 (1H, m), 2.54-2.47 (1H, m), 2.41-2.32 (4H, m), 2.19-2.09 (1H, m),
1.88-1.82 (1H, m), 1.29 (3H, t, J = 7Hz).

(Example 95)
Ethyl 8- [N- (4-chloro-2-methoxycarbonylphenyl) sulfamoyl]
-1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2420)

White powder (yield 46%)
Melting point 131-134 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
10.48 (1H, s), 8.00 (1H, d, J = 3Hz), 7.79 (1H, d, J = 9Hz), 7.50 (1H, dd, J = 9Hz, 3H
z),
6.80 (1H, t, J = 1Hz), 4.47 (1H, dd, J = 6Hz, 2Hz), 4.14-4.01 (5H, m),
3.95-3.88 (4H, m), 2.66-2.50 (2H, m), 2.22-2.11 (1H, m), 1.88-1.81 (1H, m),
1.25 (3H, t, J = 7Hz).

Example 96
Ethyl 8- [N- (3,4-dichlorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2427)
)

White powder (66% yield)
Melting point: 163-164 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, d, J = 2Hz), 7.41 (1H, d, J = 9Hz), 7.23 (1H, dd, J = 9Hz, 3Hz), 7.16 (1H, s
),
6.88 (1H, t, J = 1Hz), 4.27 (2H, q, J = 7Hz), 4.21 (1H, q, J = 3Hz), 4.14-4.02 (3H, m)
,
3.96-3.88 (1H, m), 2.50-2.43 (1H, m), 2.27 (1H, td, J = 14Hz, 3Hz), 2.13-2.03 (1H,
m),
1.89-1.82 (1H, m), 1.33 (3H, t, J = 7Hz).

(Example 97)
Ethyl 8- [N- (2,5-difluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-243
4)

Light brown powder (61% yield)
Melting point 125-128 ° C
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.45-7.41 (1H, m), 7.09-7.00 (2H, m), 6.86 (1H, s), 6.80-6.74 (1H, m),
4.41 (1H, dd, J = 6Hz, 2Hz), 4.26-4.02 (5H, m), 3.95-3.90 (1H, m), 2.58-2.52 (1H,
m),
2.44 (1H, td, J = 14Hz, 3Hz), 2.23-2.14 (1H, m), 1.89-1.84 (1H, m), 1.28 (3H, t, J
= 7Hz).

(Example 98)
Ethyl 8- [N- (2,6-difluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-244)
1)

White powder (yield 56%)
Melting point: 129-131 ° C
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.25-7.18 (1H, m), 7.01-6.95 (2H, m), 6.89-6.87 (2H, m), 4.64 (1H, dd, J = 5Hz, 2H
z),
4.31-4.21 (2H, m), 4.15-4.03 (3H, m), 3.96-3.91 (1H, m), 2.63-2.57 (1H, m),
2.36 (1H, td, J = 14Hz, 3Hz), 2.26-2.17 (1H, m), 1.87-1.82 (1H, m), 1.29 (3H, t, J
= 7Hz).

Example 99
Ethyl 8- [N- (2-fluoro-4-methylphenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
2448)

White powder (yield 69%)
Melting point 136-138 ° C
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, t, J = 9Hz), 6.95-6.92 (2H, m), 6.86 (1H, d, J = 2Hz), 6.83 (1H, s),
4.40-4.37 (1H, m), 4.26-4.15 (2H, m), 4.13-4.01 (3H, m), 3.94-3.89 (1H, m),
2.51-2.40 (2H, m), 2.32 (3H, s), 2.18-2.09 (1H, m), 1.86-1.81 (1H, m),
1.27 (3H, t, J = 7Hz).

(Example 100)
Ethyl 8- [N- (2-fluoro-5-methylphenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
2455)

Oil (yield 63%)
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.43 (1H, dd, J = 8Hz, 2Hz), 6.98 (1H, dd, J = 10Hz, 8Hz), 6.91-6.87 (2H, m),
6.83 (1H, t, J = 1Hz), 4.42 (1H, dd, J = 6Hz, 2Hz), 4.26-4.02 (5H, m),
3.95-3.89 (1H, m), 2.54-2.42 (2H, m), 2.20-2.12 (1H, m), 1.87-1.82 (1H, m),
1.27 (3H, t, J = 7Hz).

(Example 101)
Ethyl 8- [N- (2-fluoro-4-methoxyphenyl) sulfamoyl] -1,4
-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1
-2462)

Light brown powder (57% yield)
Melting point 167-169 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.50 (1H, t, J = 9Hz), 6.82 (1H, t, J = 1Hz), 6.79 (1H, brs), 6.71-6.67 (2H, m),
4.38-4.35 (1H, m), 4.28-4.19 (2H, m), 4.14-4.01 (3H, m), 3.95-3.88 (1H, m),
3.79 (3H, s), 2.49-2.36 (2H, m), 2.18-2.08 (1H, m), 1.86-1.79 (1H, m),
1.29 (3H, t, J = 7Hz).

(Example 102)
Ethyl 8- [N- (5-chloro-2-fluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
2469)

White powder (55% yield)
Melting point 88-90 ° C
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.68-7.65 (1H, m), 7.07-7.01 (3H, m), 6.86 (1H, s), 4.40 (1H, dd, J = 6Hz, 2Hz),
4.27-4.15 (2H, m), 4.14-4.03 (3H, m), 3.96-3.90 (1H, m), 2.58-2.52 (1H, m),
2.43 (1H, td, J = 14Hz, 3Hz), 2.23-2.15 (1H, m), 1.89-1.84 (1H, m), 1.29 (3H, t, J
= 7Hz).

(Example 103)
Ethyl 8- [N- (2,3,4-trifluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
2476)

White powder (yield 71%)
Melting point: 149-152 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.41-7.34 (1H, m), 7.14 (1H, brs), 7.02-6.93 (1H, m), 6.85 (1H, t, J = 1Hz),
4.36 (1H, dd, J = 6Hz, 2Hz), 4.28-4.20 (2H, m), 4.14-4.02 (3H, m),
3.96-3.90 (1H, m), 2.55-2.46 (1H, m), 2.38 (1H, td, J = 14Hz, 4Hz),
2.22-2.12 (1H, m), 1.89-1.82 (1H, m), 1.31 (3H, t, J = 7Hz).

(Example 104)
Ethyl 8- [N- (2,4,5-trifluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
2483)

White powder (yield 72%)
Melting point 104-107 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.60-7.52 (1H, m), 7.05-6.97 (2H, m), 6.86 (1H, t, J = 1Hz), 4.35 (1H, dd, J = 6Hz,
2Hz),
4.28-4.19 (2H, m), 4.15-4.02 (3H, m), 3.96-3.90 (1H, m), 2.56-2.49 (1H, m),
2.38 (1H, td, J = 14Hz, 4Hz), 2.23-2.12 (1H, m), 1.90-1.83 (1H, m), 1.30 (3H, t, J
= 7Hz).

(Example 105)
Ethyl 8- [N- (2,4,6-trifluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
2490)

White powder (yield 61%)
Melting point 131-133 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
6.91 (1H, s), 6.88 (1H, t, J = 1Hz), 6.80-6.72 (2H, m), 4.55 (1H, dd, J = 6Hz, 3Hz),

4.31-4.23 (2H, m), 4.14-4.03 (3H, m), 3.96-3.90 (1H, m), 2.62-2.55 (1H, m),
2.32 (1H, td, J = 14Hz, 3Hz), 2.25-2.15 (1H, m), 1.88-1.81 (1H, m), 1.31 (3H, t, J
= 7Hz).

(Example 106)
Ethyl 8- [N- (2,4-dichlorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2497)
)

Light brown powder (yield 67%)
Melting point 109-111 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.65 (1H, d, J = 9Hz), 7.41 (1H, d, J = 2Hz), 7.28-7.24 (1H, m), 7.07 (1H, s),
6.83 (1H, s), 4.46-4.42 (1H, m), 4.24-4.02 (5H, m), 3.98-3.89 (1H, m),
2.56-2.46 (2H, m), 2.24-2.13 (1H, m), 1.89-1.82 (1H, m), 1.26 (3H, t, J = 7Hz).

(Example 107)
Ethyl 8- [N- (4-bromo-2-chlorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-2
504)

White powder (74% yield)
Melting point 102-107 ° C
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.59 (1H, d, J = 9Hz), 7.55 (1H, d, J = 2Hz), 7.40 (1H, dd, J = 9Hz, 2Hz), 7.08 (1H, s
), 6.83 (1H, s), 4.44 (1H, d, J = 5Hz), 4.23-4.02 (5H, m), 3.95-3.89 (1H, m),
2.55-2.47 (2H, m), 2.23-2.14 (1H, m), 1.89-1.83 (1H, m), 1.26 (3H, t, J = 7Hz).

(Example 108)
Ethyl 8- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-4
52)

Light brown powder (69% yield)
Melting point 130-135 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.57 (1H, d, J = 9Hz), 7.20 (1H, d, J = 2Hz), 7.10-7.06 (1H, m), 6.97 (1H, s),
6.81 (1H, d, J = 1Hz), 4.44 (1H, d, J = 5Hz), 4.25-4.00 (5H, m), 3.95-3.87 (1H, m),
2.59-2.45 (2H, m), 2.31 (3H, s), 2.22-2.10 (1H, m), 1.87-1.79 (1H, m),
1.25 (3H, t, J = 7Hz).

(Example 109)
Ethyl 8- [N- (4-tert-butyl-2-chlorophenyl) sulfamoyl] -1,4
-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1
-2511)

Amorphous (49% yield)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.61 (1H, d, J = 9Hz), 7.38 (1H, d, J = 2Hz), 7.29 (1H, dd, J = 9Hz, 2Hz),
7.00 (1H, s), 6.82 (1H, s), 4.46 (1H, d, J = 4Hz), 4.23-4.01 (5H, m),
3.95-3.88 (1H, m), 2.59-2.47 (2H, m), 2.23-2.12 (1H, m), 1.87-1.80 (1H, m),
1.29 (9H, s), 1.25-1.21 (3H, m).

(Example 110)
Ethyl 8- [N- (2-chloro-6-fluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-
2518)

Amorphous (62% yield)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.27-7.24 (1H, m), 7.21-7.15 (1H, m), 7.12-7.06 (1H, m), 6.98 (1H, s),
6.86 (1H, s), 4.77-4.74 (1H, m), 4.30-4.21 (2H, m), 4.15-4.03 (3H, m),
3.96-3.90 (1H, m), 2.67-2.60 (1H, m), 2.38 (1H, td, J = 14Hz, 3Hz),
2.28-2.17 (1H, m), 1.88-1.81 (1H, m), 1.29 (3H, t, J = 7Hz).

(Example 111)
Ethyl 8- [N- (2,6-dichlorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2525)
)

Amorphous (24% yield)
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.39 (1H, s), 7.38 (1H, s), 7.27 (1H, s), 7.17 (1H, t, J = 8Hz),
6.87 (1H, s), 4.88 (1H, dd, J = 5Hz, 3Hz), 4.29 (2H, q, J = 7Hz), 4.15-4.03 (3H, m),

3.96-3.91 (1H, m), 2.68-2.62 (1H, m), 2.31 (1H, td, J = 14Hz, 3Hz),
2.26-2.18 (1H, m), 1.88-1.82 (1H, m), 1.31 (3H, t, J = 7Hz).

(Example 112)
Ethyl 8- [N- (2-chloro-6-methylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-1
462)

Amorphous (55% yield)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.29-7.23 (1H, m), 7.20-7.09 (3H, m), 6.84 (1H, t, J = 1Hz), 4.80-4.77 (1H, m),
4.30-4.20 (2H, m), 4.13-4.00 (3H, m), 3.95-3.89 (1H, m), 2.58-2.46 (4H, m),
2.33 (1H, td, J = 14Hz, 3Hz), 2.25-2.14 (1H, m), 1.85-1.78 (1H, m), 1.28 (3H, t, J
= 7Hz).

(Example 113)
Ethyl 8- [N- (2,3-dichlorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2532)
)

Amorphous (yield 70%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.66-7.61 (1H, m), 7.26-7.19 (3H, m), 6.83 (1H, s), 4.46 (1H, d, J = 5Hz),
4.22-4.01 (5H, m), 3.95-3.89 (1H, m), 2.57-2.48 (2H, m), 2.25-2.14 (1H, m),
1.89-1.82 (1H, m), 1.25 (3H, t, J = 7Hz).

(Example 114)
Ethyl 8- [N- (2,5-dichlorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2539)
)

White powder (yield 78%)
Melting point 120-124 ° C
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.72 (1H, d, J = 2Hz), 7.31 (1H, d, J = 9Hz), 7.11 (1H, s), 7.05 (1H, dd, J = 9Hz, 2Hz
),
6.86 (1H, s), 4.46 (1H, dd, J = 6Hz, 2Hz), 4.25-4.03 (5H, m), 3.95-3.90 (1H, m),
2.58-2.48 (2H, m), 2.26-2.17 (1H, m), 1.90-1.84 (1H, m), 1.26 (3H, t, J = 7Hz).

(Example 115)
Ethyl 8- [N- (2-chloro-4,6-difluorophenyl) sulfamoyl] -1
4-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2546)

Oil (yield 29%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.07-7.03 (1H, m), 6.99 (1H, s), 6.91-6.83 (2H, m), 4.67 (1H, dd, J = 5Hz, 3Hz),
4.31-4.23 (2H, m), 4.14-4.03 (3H, m), 3.97-3.90 (1H, m), 2.65-2.57 (1H, m),
2.34 (1H, td, J = 14Hz, 3Hz), 2.27-2.17 (1H, m), 1.88-1.81 (1H, m), 1.31 (3H, t, J
= 7Hz).

(Example 116)
Ethyl 8- [N- (2,6-dichloro-4-fluorophenyl) sulfamoyl] -1
4-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2553)

Amorphous (39% yield)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.22 (1H, s), 7.17 (2H, d, J = 7Hz), 6.88 (1H, t, J = 1Hz), 4.84-4.81 (1H, m),
4.29 (2H, q, J = 7Hz), 4.14-4.03 (3H, m), 3.97-3.90 (1H, m), 2.67-2.60 (1H, m),
2.34-2.17 (2H, m), 1.88-1.81 (1H, m), 1.33 (3H, t, J = 7Hz).

(Example 117)
Ethyl 8- [N- (2-bromo-6-chloro-4-fluorophenyl) sulfamoyl
] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2560)

Amorphous (yield 46%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.35 (1H, dd, J = 7.5Hz, 2.8Hz), 7.24-7.21 (2H, m), 7.24 (1H, s), 4.90 (1H, d, J = 5.1Hz
), 4.30 (2H, q, J = 7.2Hz), 4.14-3.92 (4H, m), 2.67-2.62 (1H, m), 2.33-2.18 (2H, m), 1
.88-1.84 (1H, m), 1.33 (3H, t, J = 6.6 Hz).

(Example 118)
Ethyl 8- [N- (4-chloro-2-methoxy-5-methylphenyl) sulfamoyl
] -1,4-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2567)

White powder (yield 54%)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.43 (1H, s), 6.96 (1H, s), 6.87 (1H, s), 6.78 (1H, t, J = 1Hz),
4.41 (1H, dd, J = 6Hz, 2Hz), 4.20-4.00 (5H, m), 3.94-3.88 (1H, m), 3.85 (3H, s),
2.58-2.43 (2H, m), 2.31 (3H, s), 2.20-2.08 (1H, m), 1.85-1.78 (1H, m),
1.25 (3H, t, J = 7Hz).

(Example 119)
Ethyl 8- [N- (2,4-dibromophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-2574)
)

Oil (yield 56%)
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.70 (1H, d, J = 2Hz), 7.59 (1H, d, J = 9Hz), 7.44 (1H, dd, J = 9Hz, 2Hz), 7.02 (1H, s
),
6.83 (1H, s), 4.47-4.44 (1H, m), 4.23-4.02 (5H, m), 3.95-3.90 (1H, m),
2.57-2.49 (2H, m), 2.23-2.15 (1H, m), 1.88-1.83 (1H, m), 1.26 (3H, t, J = 7Hz).

(Example 120)
Ethyl 8- [N- (2,6-dibromophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2581)
)

Amorphous (41% yield)
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.61 (2H, d, J = 8Hz), 7.26 (1H, brs), 7.02 (1H, t, J = 8Hz), 6.88 (1H, s),
5.02-5.00 (1H, m), 4.29 (2H, q, J = 7Hz), 4.15-3.91 (4H, m), 2.70-2.64 (1H, m),
2.33-2.19 (2H, m), 1.87-1.83 (1H, m), 1.32 (3H, t, J = 7Hz).

(Example 121)
Ethyl 8- [N- (2-bromo-4-isopropylphenyl) sulfamoyl] -1,
4-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2588)

White powder (51% yield)
Melting point 130-134 ° C
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.60 (1H, d, J = 8Hz), 7.40 (1H, d, J = 2Hz), 7.18 (1H, dd, J = 8Hz, 2Hz), 6.94 (1H, s
),
6.82 (1H, s), 4.48-4.46 (1H, m), 4.24-4.01 (5H, m), 3.94-3.88 (1H, m),
2.89-2.83 (1H, m), 2.60-2.47 (2H, m), 2.22-2.13 (1H, m), 1.86-1.81 (1H, m),
1.25-1.21 (9H, m).

(Example 122)
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-364)

The ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate obtained in Example 1 was subjected to high performance liquid chromatography. (Column: CHIRALPAK AD-H, size: 2 cm inside diameter,
Separation and purification of two optical isomers by attaching to 25 cm in length, solvent; hexane: 2-propanol, and obtaining each of low-polarity compound (first peak) and high-polarity compound (second peak) as white powder It was. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purity was> 99% ee, respectively.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: hexane: 2-propanol = 1: 1
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 6.1 minutes
High polarity compound (second peak): 10.5 min (low polarity compound, first peak)
Melting point 116-117 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.68 (1H, dd, J = 9.2Hz, 5.3Hz), 7.17 (1H, dd, J = 7.8Hz, 2.7Hz), 7.05-7.00 (2H, m), 6.
83 (1H, s), 4.43 (1H, d, J = 5.4Hz), 4.26-3.90 (6H, m), 2.55-2.47 (2H, m), 4.15-2.47 (1
H, m), 4.02-2.13 (1H, m), 1.27 (3H, t, J = 7.0 Hz).
(High polarity compound, second peak)
Melting point 116-117 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.68 (1H, dd, J = 9.0Hz, 5.5Hz), 7.17 (1H, dd, J = 8.0Hz, 2.9Hz), 7.06-7.00 (2H, m), 6.
84 (1H, s), 4.43 (1H, d, J = 5.4Hz), 4.26-3.90 (6H, m), 2.55-2.47 (2H, m), 1.13-2.23 (1
H, m), 1.87-1.83 (1H, m), 1.27 (3H, t, J = 6.6 Hz).

(Example 123)
Ethyl 9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-
Dioxaspiro [4.5] dec-7-ene-8-carboxylate

(123a) ethyl 7-trifluoromethanesulfonyloxy-1,4-dioxaspiro [4.5] dec-7-ene-8-carboxylate ethyl 8-oxo-1-oxaspiro [4.5] decane-7-carboxylate In place of ethyl 7-oxo-1,4-dioxaspiro [4.5] decane-8-carboxylate [compound described as compound 292c in US Patent US2004 / 259914 A1]
According to the method described in Example (30e), the title compound was obtained as a white powder (
Yield 96%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.28 (2H, q, J = 7Hz), 4.04-3.96 (4H, m), 2.65-2.61 (4H, m), 1.82-1.78 (2H, m), 1.
32 (3H, t, J = 7Hz).

(123b) Ethyl 7-acetylsulfanyl-1,4-dioxaspiro [4.5] dec-7-ene-8-carboxylate ethyl 8-trifluoromethanesulfonyloxy-1,4-dioxaspiro [4.5]
Ethyl 7-trifluoromethanesulfonyloxy-1,4-dioxaspiro [4.5] dec-7-ene-8 obtained in (123a) instead of deca-7-ene-7-carboxylate
-The title compound was obtained as a light brown oily substance according to the method described in Example (1a) using carboxylate (yield 83%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.21 (2H, q, 7Hz), 4.04-3.96 (4H, m), 2.72-2.65 (4H, m), 2.32 (3H, s),
1.85 (2H, t, J = 7Hz), 1.29 (3H, t, J = 7Hz).

(123c) Ethyl 7-mercapto-1,4-dioxaspiro [4.5] dec-7-ene-8-carboxylate ethyl 8-acetylsulfanyl-1,4-dioxaspiro [4.5] dec-7-ene- The ethyl 7-acetylsulfanyl-1,4-dioxaspiro [4.5] dec-7-ene-8-carboxylate obtained in (123b) instead of 7-carboxylate was used as described in Example (1b). According to the method, the title compound was obtained as a light brown powder (yield 85%
).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.22 (2H, q, 7Hz), 4.20 (1H, s), 4.02-3.95 (4H, m), 2.69-2.66 (2H, m),
2.61-2.56 (2H, m), 1.82-1.78 (2H, m), 1.30 (3H, t, J = 7Hz).

(123d) Ethyl 7-chlorosulfonyl-1,4-dioxaspiro [4.5] deca-
7-ene-8-carboxylate ethyl 8-mercapto-1,4-dioxaspiro [4.5] ethyl 7-mercapto-1,4 obtained in (123c) instead of deca-7-ene-7-carboxylate, 4 -The title compound was obtained as a colorless oil according to the method described in Example (1c) using dioxaspiro [4.5] dec-7-ene-8-carboxylate (yield 62%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.31 (2H, q, 7Hz), 4.09-4.00 (4H, m), 2.82-2.73 (4H, m), 1.86 (2H, t, J = 7Hz),
1.35 (3H, t, J = 7Hz).

(123e) Ethyl 9- [N- (2-chloro-4-fluorophenyl) sulfamoyl]
-1,4-dioxaspiro [4.5] dec-7-ene-8-carboxylate ethyl 8-chlorosulfonyl-1,4-dioxaspiro [4.5] dec-7-ene-7
Ethyl 7-chlorosulfonyl-1, obtained in (123d) instead of carboxylate,
Example 4 using 4-dioxaspiro [4.5] dec-7-ene-8-carboxylate
According to the method described in d), the title compound was obtained as a white powder (yield 61%).
Melting point 120-122 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.81 (1H, s), 7.66 (1H, dd, J = 9Hz, 5Hz), 7.14-7.10 (2H, m), 6.98-6.92 (1H, m), 4
.71-4.67 (1H, m), 4.22-3.96 (6H, m), 2.75-2.56 (3H, m), 2.08-2.02 (1H, m),
1.24 (3H, t, J = 7Hz).

(Example 124)
Ethyl 2-bromoethyl-8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate

Example 1 (17a) using 1-bromo-2,3-bis [(trimethylsilyl) oxy] propane instead of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol ) To give the title compound as a white amorphous (yield 100%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.67 (1H, dd, J = 9.2 and 5.3Hz), 7.17 (1H, dd, J = 7.8 and 2.8Hz), 7.05-6.99 (2H, m),
6.86-6.77 (1H, m), 4.53-3.84 (6H, m), 3.53-3.31 (2H, m), 2.66-2.41 (2H, m), 2.24-2.1
2 (1H, m), 1.89-1.86 (1H, m), 1.28-1.24 (3H, m).

(Example 125)
Ethyl (2S) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl]-
2-Methoxycarbonylmethyl-1,4-dioxaspiro [4.5] dec-6-ene-7-
Carboxylate

Methyl (S) -3,4-bis [(trimethylsilyl) oxy] obtained in Reference Example 20 instead of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol
The title compound was obtained as a colorless oil according to the method described in Example (17a) using butyrate (yield 96%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.67 (1H, dd, J = 9.0Hz, 5.4Hz), 7.16 (1H, dd, J = 7.9Hz, 2.8Hz), 7.05-6.98 (2H, m), 6.
88-6.76 (1H, m), 4.63-4.58 (1H, m), 4.47-4.41 (1H, m), 4.32-4.10 (3H, m), 3.84-3.59 (
4H, m), 2.85-2.39 (4H, m), 2.21-2.16 (1H, m), 1.89-1.80 (1H, m), 1.29-1.24 (3H, m).

(Example 126)
Ethyl 3- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -7, 12
-Dioxaspiro [5.6] dodec-1-ene-2-carboxylate (Exemplified Compound No. 1-366)

34 mg (0.61 mmol) of 1,4-butanediol was dissolved in 5 ml of dichloromethane. Under ice-cooling and stirring, 0.32 ml (1.83 mmol) of isopropoxytrimethylsilane,
Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethoxy-1-cyclohexene-1-carboxylate 200m obtained in Example (16a)
g (0.47 mmol) and trimethylsilyl trifluoromethanesulfonate 4 ml
(0.024 mmol) was sequentially added and stirred at the same temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 3: 1), and the obtained solid was washed with hexane to obtain 6 mg of the title compound as a white powder (yield 3%). .
Melting point 142-144 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.68 (1H, dd, J = 9Hz, 5Hz), 7.16 (1H, dd, J = 8Hz, 3Hz),
7.04 (1H, s), 7.03-6.98 (2H, m), 4.44-4.40 (1H, m), 4.27-4.11 (2H, m),
3.91-3.62 (4H, m), 2.46-2.38 (1H, m), 2.31-2.21 (1H, m), 2.17-1.94 (2H, m),
1.71-1.58 (4H, m), 1.27 (3H, t, J = 7Hz).

(Example 127)
Ethyl 4- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3a ′, 4
'
6 ′, 6a′-tetrahydrospiro [cyclohex-2-ene-1,2′-furo [3.4
-D] [1.3] dioxole] -3-carboxylate (Exemplified Compound No. 1-402)

Using 1,4-anhydro-2,3-di-O-trimethylsilyl-meso-erythritol obtained in Reference Example 21 instead of 1,3,4,5,7-penta-O-trimethylsilyl-D-arabitol According to the method described in Example 21, the title compound was obtained as a white powder (
Yield 56%).
Melting point 227-228 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ + CD ₃ OD) δ ppm:
7.61 (1H, dd, J = 9Hz, 5Hz), 7.17 (1H, dd, J = 8Hz, 3Hz), 7.07-6.97 (1H, m),
6.91 (1H, s), 4.93 (1H, dd, J = 6Hz, 4Hz), 4.81 (1H, dd, J = 6Hz, 4Hz), 4.39 (1H, d,
J = 5Hz),
4.26-4.05 (3H, m), 4.01 (1H, d, J = 11Hz), 3.51-3.41 (2H, m), 2.54-2.34 (2H, m),
2.20-2.07 (1H, m), 1.90-1.79 (1H, m), 1.25 (3H, t, J = 7Hz).

(Example 128)
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,2,
3,3-tetramethyl-1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate

Example using 2,3-dimethyl-2,3-bis [(trimethylsilyl) oxy] butane instead of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol The title compound was obtained as a pale yellow oil according to the method described in (17a) (yield 10%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.66 (1H, dd, J = 8.8Hz, 5.6Hz), 7.16 (1H, dd, J = 7.8Hz, 2.7Hz), 7.04-7.03 (1H, m), 6.
89 (1H, s), 4.37 (1H, d, J = 4.0Hz), 4.25-4.10 (2H, m), 2.51-2.43 (2H, m), 2.24-2.14 (1
H, m), 1.94-1.89 (1H, m), 1.31-1.23 (15H, m).

(Example 129)
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,2,
3-Triethyl-1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate

Instead of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol, 3-ethyl-3,4-bis [(trimethylsilyl) oxy] hexane obtained in Reference Example 22 was used. The title compound was obtained as a white powder according to the method described in Example (17a) (yield 88%).
Melting point 124-126 ° C
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.69-7.66 (1H, m), 7.17-7.15 (1H, m), 7.04-7.00 (2H, m), 6.88-6.69 (1H, m), 4.40-4.3
9 (1H, m), 4.28-4.10 (2H, m), 3.90-3.68 (1H, m), 2.54-2.31 (2H, m), 2.25-2.12 (1H, m)
, 1.85-1.37 (7H, m), 1.29-1.24 (3H, m), 1.08-0.84 (9H, m).

(Example 130)
Ethyl (3R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl]-
2,2,3-triphenyl-1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate

(R) -1,2-bis [(trimethylsilyl) oxy] -1 obtained in Reference Example 23 instead of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol 1
The title compound was obtained as a colorless oil according to the method described in Example (17a) using 2-triphenylethane (yield 30%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.22-6.91 (20H, m), 5.99-5.76 (1H, m), 4.54-4.32 (1H, m), 4.34-4.08 (2H, m), 2.87-1.
97 (4H, m), 1.36-1.14 (3H, m).

(Example 131)
Ethyl (2R, 3R) -8- [N- (2-chlorophenyl) sulfamoyl] -2,3-
Bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-206)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 54 -[N- (2-chlorophenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Examples 7, (16a) and 17 (deca-6-ene-7-carboxylate were used.
The title compound was obtained as an amorphous product (yield 31%) according to the method described in Alternative Method).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.71-7.67 (1H, m), 7.41-7.38 (1H, m), 7.32-7.26 (1H, m), 7.14-7.06 (2H, m),
6.90 (0.5H, t, J = 1Hz), 6.84 (0.5H, t, J = 1Hz), 4.47 (1H, dd, J = 6Hz, 2Hz),
4.26-4.07 (3.5H, m), 4.05-4.00 (0.5H, m), 3.94-3.80 (2H, m), 3.77-3.67 (2H, m),
2.64-2.47 (2H, m), 2.27-1.87 (4H, m), 1.27-1.22 (3H, m).

(Example 132)
Ethyl (2R, 3R) -8- [N- (2-bromophenyl) sulfamoyl] -2, 3-
Bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-1392)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 55 -[N- (2-bromophenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Examples 7, (16a) and 17 (deca-6-ene-7-carboxylate were used.
The title compound was obtained as an amorphous product (yield 28%) according to the method described in “Alternative method”.
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.71-7.67 (1H, m), 7.56 (1H, d, J = 8Hz), 7.35-7.31 (1H, m), 7.07-6.98 (2H, m),
6.90 (0.5H, s), 6.84 (0.5H, s), 4.48 (1H, d, J = 5Hz), 4.25-4.08 (3.5H, m),
4.06-4.01 (0.5H, m), 3.94-3.80 (2H, m), 3.76-3.68 (2H, m), 2.65-2.48 (2H, m),
2.23-1.87 (4H, m), 1.27-1.22 (3H, m).

(Example 133)
Ethyl (2R, 3R) -2,3-bis (hydroxymethyl) -8- [N- (2-iodophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxy LATE (Exemplified Compound No. 1-2226)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 56 -[N- (2-iodophenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Examples 7, (16a) and 17 (deca-6-ene-7-carboxylate were used.
The title compound was obtained as an amorphous product (yield% 26) according to the method described in “Alternative method”.
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.80 (1H, d, J = 8Hz), 7.68-7.63 (1H, m), 7.38-7.33 (1H, m), 6.90-6.83 (3H, m),
4.50-4.46 (1H, m), 4.27-4.09 (3.5H, m), 4.06-4.02 (0.5H, m), 3.94-3.80 (2H, m),
3.77-3.68 (2H, m), 3.53 (1H, brs), 2.66-2.56 (1H, m), 2.55-2.49 (1H, m),
2.24-2.14 (1H, m), 2.00-1.85 (2H, m), 1.27-1.23 (3H, m).

(Example 134)
Ethyl (2R, 3R) -8- [N- (2-hexylphenyl) sulfamoyl] -2,3
-Bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-734)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 4 -[N- (2-hexylphenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Examples 7, (16a) and 17 (deca-6-ene-7-carboxylate were used.
The title compound was obtained as a colorless oil according to the method described in (Alternative method) (yield 28%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.54-7.50 (1H, m), 7.23-7.17 (2H, m), 7.15-7.09 (1H, m), 6.94-6.91 (0.5H, m), 6.
88-6.85 (0.5H, m), 6.70 (0.5H, s), 6.65 (0.5H, s), 4.48-4.43 (1H, m), 4.28-4.08
(3.5H, m), 4.06-4.00 (0.5H, m), 3.93-3.80 (2H, m), 3.76-3.68 (2H, m), 2.70-2.61
(2H, m), 2.55-2.41 (2H, m), 2.21-2.07 (1H, m), 1.96-1.75 (3H, m), 1.64-1.52 (2H,
m), 1.42-1.23 (9H, m), 0.91-0.85 (3H, m).

(Example 135)
Ethyl (2R, 3R) -8- [N- (2-heptylphenyl) sulfamoyl] -2,3
-Bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-910)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] ethyl-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 5 -[N- (2-heptylphenyl) sulfamoyl] -1,4-dioxaspiro [
4.5] Examples 7, (16a) and 17 (deca-6-ene-7-carboxylate were used.
The title compound was obtained as a colorless oil according to the method described in “Alternative method” (yield 33%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.54-7.50 (1H, m), 7.23-7.18 (2H, m), 7.14-7.09 (1H, m), 6.94-6.91 (0.5H, m), 6.
88-6.85 (0.5H, m), 6.70 (0.5H, s), 6.65 (0.5H, s), 4.47-4.43 (1H, m), 4.28-4.08
(3.5H, m), 4.06-4.00 (0.5H, m), 3.93-3.80 (2H, m), 3.76-3.68 (2H, m), 2.70-2.61
(2H, m), 2.54-2.41 (2H, m), 2.20-2.08 (1H, m), 1.96-1.74 (3H, m), 1.64-1.53 (2H,
m), 1.41-1.22 (11H, m), 0.88 (3H, t, J = 7Hz).

(Example 136)
Ethyl (2R, 3R) -8- [N- (2-chloro-4-methylphenyl) sulfamoyl
] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-470)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 108 -[N- (2-chloro-4-methylphenyl) sulfamoyl] -1,4-
Example 7, (1) using dioxaspiro [4.5] dec-6-ene-7-carboxylate
According to the method described in 6a) and 17 (alternative method), the title compound was obtained as amorphous (yield 50%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.56 (1H, dd, J = 8Hz, 2Hz), 7.23-7.21 (1H, m), 7.11-7.07 (1H, m), 7.01 (1H, brs),

6.90 (0.5H, t, J = 1Hz), 6.84-6.82 (0.5H, m), 4.44 (1H, dd, J = 6Hz, 2Hz),
4.27-4.08 (3.5H, m), 4.05-4.00 (0.5H, m), 3.93-3.80 (2H, m), 3.77-3.68 (2H, m),
2.63-2.44 (2H, m), 2.31 (3H, s), 2.22-1.62 (4H, m), 1.29-1.23 (3H, m).

(Example 137)
Ethyl (2R, 3R) -8- [N- (2,4-dichlorophenyl) sulfamoyl] -2
3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7
-Carboxylate (Exemplified Compound No. 1-2499)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] ethyl-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 106 Example 7, (16a) with-[N- (2,4-dichlorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate
And 17 (alternative method), the title compound was obtained as an amorphous substance (yield 22%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.64 (1H, dd, J = 9Hz, 2Hz), 7.41 (1H, d, J = 2Hz), 7.28-7.25 (1H, m), 7.07 (1H, brs
),
6.91 (0.5H, t, J = 1Hz), 6.85 (0.5H, t, J = 1Hz), 4.43 (1H, dd, J = 6Hz, 2Hz),
4.26-4.09 (3.5H, m), 4.07-4.02 (0.5H, m), 3.94-3.81 (2H, m), 3.77-3.68 (2H, m),
2.60-2.47 (2H, m), 2.24-1.85 (4H, m), 1.29-1.24 (3H, m).

(Example 138)
Ethyl (2R, 3R) -8- [N- (2-bromo-4-chlorophenyl) sulfamoyl
] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-2408)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 93 Example 7, (16) using-[N- (2-bromo-4-chlorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate
According to the method described in a) and 17 (alternative method), the title compound was obtained as amorphous (
Yield 10%).
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.64 (1H, dd, J = 9Hz, 3Hz), 7.57 (1H, d, J = 2Hz), 7.31 (1H, dd, J = 9Hz, 2Hz),
7.01 (1H, brs), 6.91 (0.5H, s), 6.85 (0.5H, s), 4.45 (1H, d, J = 4Hz),
4.26-4.10 (3.5H, m), 4.06-4.02 (0.5H, m), 3.94-3.82 (2H, m), 3.77-3.69 (2H, m),
2.61-2.48 (2H, m), 2.24-2.15 (1H, m), 2.02-1.85 (3H, m), 1.29-1.24 (3H, m).

(Example 139)
Ethyl (2R, 3R) -8- [N- (2-chloro-6-methylphenyl) sulfamoyl
] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-1480)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 112 -[N- (2-chloro-6-methylphenyl) sulfamoyl] -1,4-
Example 7, (1) using dioxaspiro [4.5] dec-6-ene-7-carboxylate
According to the method described in 6a) and 17 (alternative method), the title compound was obtained as amorphous (yield 45%).
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.28 (1H, dd, J = 8Hz, 1Hz), 7.23-7.07 (3H, m), 6.93-6.91 (0.5H, m),
6.86-6.85 (0.5H, m), 4.80-4.76 (1H, m), 4.30-4.17 (3H, m), 4.11-4.07 (0.5H, m),
4.04-4.00 (0.5H, m), 3.92-3.81 (2H, m), 3.75-3.69 (2H, m), 2.59-2.48 (3H, m),
2.42-2.33 (1H, m), 2.26-2.15 (1H, m), 2.07 (1H, brs), 1.94-1.85 (1H, m),
1.63 (1H, brs), 1.29-1.24 (3H, m).

(Example 140)
Ethyl (2R, 3R) -8- [N- (3-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate (Exemplified Compound No. 1-2366)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 80 -[N- (3-Chloro-4-fluorophenyl) sulfamoyl] -1,4-
Example 7, (1) using dioxaspiro [4.5] dec-6-ene-7-carboxylate
According to the method described in 6a) and 17 (alternative method), the title compound was obtained as an amorphous substance (yield 47%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.47 (1H, dd, J = 6Hz, 3Hz), 7.29-7.25 (1H, m), 7.17-7.06 (2H, m), 6.97 (0.5H, t,
J = 1Hz),
6.93-6.92 (0.5H, m), 4.33-4.09 (4.5H, m), 4.06-4.02 (0.5H, m), 3.94-3.82 (2H, m)
,
3.77-3.68 (2H, m), 2.48-2.40 (1H, m), 2.34-2.24 (1H, m), 2.12-2.01 (2H, m),
1.97-1.89 (2H, m), 1.35 (3H, t, J = 7Hz).

(Example 141)
Ethyl (2R, 3R) -8- [N- (2-chloro-4,6-difluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6 -Ene-7-carboxylate (Exemplified Compound No. 1-2548)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 115 -[N- (2-chloro-4,6-difluorophenyl) sulfamoyl]-
According to the method described in Example 7, (16a) and 17 (alternative method) using 1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate, the title compound was converted to amorphous. Obtained (yield 35%).
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.07-6.85 (4H, m), 4.67 (1H, dd, J = 10Hz, 6Hz), 4.32-4.19 (3H, m), 4.14-4.02 (1H,
m),
3.93-3.82 (2H, m), 3.76-3.70 (2H, m), 2.66-2.55 (1H, m), 2.43-2.34 (1H, m),
2.28-2.17 (1H, m), 2.06-1.88 (3H, m), 1.33-1.29 (3H, m).

(Example 142)
Ethyl (2R, 3R) -8- [N- (2,6-dichloro-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6 -Ene-7-carboxylate (Exemplified Compound No. 1-2555)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 116 -[N- (2,6-dichloro-4-fluorophenyl) sulfamoyl]-
According to the method described in Example 7, (16a) and 17 (alternative method) using 1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate, the title compound was converted to amorphous. Obtained (yield 25%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.26-7.05 (3H, m), 6.97-6.95 (0.5H, m), 6.90-6.89 (0.5H, m), 4.85-4.80 (1H, m),
4.33-4.19 (3H, m), 4.13-4.08 (0.5H, m), 4.06-4.02 (0.5H, m), 3.93-3.82 (2H, m),
3.76-3.70 (2H, m), 2.72-2.56 (1H, m), 2.39-2.20 (2H, m), 2.05-1.59 (3H, m),
1.35-1.30 (3H, m).

(Example 143)
Ethyl (2R, 3R) -8- [N- (2-bromo-6-chloro-4-fluorophenyl)
Sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5
] Deca-6-ene-7-carboxylate (Exemplified Compound No. 1-2562)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 117 Example 7 (16a) using-[N- (2-bromo-6-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate ) And 17 (alternative method), the title compound was obtained as an amorphous substance (yield 29%).
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.36-7.31 (1H, m), 7.23-7.19 (1H, m), 7.16 (1H, brs), 6.95 (0.5H, s),
6.90-6.88 (0.5H, m), 4.91-4.85 (1H, m), 4.33-4.17 (3H, m), 4.15-4.00 (1H, m),
3.94-3.80 (2H, m), 3.76-3.70 (2H, m), 3.55 (1H, brs), 2.70-2.57 (1H, m),
2.38-2.16 (2H, m), 1.96-1.87 (2H, m), 1.35-1.30 (3H, m).

(Example 144)
Ethyl (2R, 3R) -8- [N- (2,4-difluorophenyl) sulfamoyl]-
2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-
7-Carboxylate (Exemplified Compound No. 1-294)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 77 Example 7, (16a) using-[N- (2,4-difluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate
And 17 (alternative method), the title compound was obtained as an amorphous product (yield 35%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.63-7.56 (1H, m), 7.07 (1H, brs), 6.94-6.85 (3H, m), 4.38-4.34 (1H, m),
4.30-4.08 (3.5H, m), 4.06-4.00 (0.5H, m), 3.93-3.81 (2H, m), 3.78-3.68 (2H, m),
2.53-2.40 (2H, m), 2.38-1.87 (4H, m), 1.31-1.27 (3H, m).

(Example 145)
Ethyl (2S, 3S) -8- [N- (2,4-difluorophenyl) sulfamoyl]
-2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1-294)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 77 Example 7, (16a) using-[N- (2,4-difluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate
And 18 (another method), the title compound was obtained as an amorphous product (yield 58%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.62-7.57 (1H, m), 6.93-6.86 (3H, m), 4.37-4.34 (1H, m), 4.29-4.18 (3H, m),
4.13-4.09 (0.5H, m), 4.06-4.01 (0.5H, m), 3.94-3.82 (2H, m), 3.76-3.69 (2H, m),
2.53-2.39 (2H, m), 2.21-1.50 (4H, m), 1.32-1.27 (3H, m).

(Example 146)
Ethyl (2R, 3R) -8- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate (Exemplified Compound No. 1-1568)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 78 -[N- (2-bromo-4-fluorophenyl) sulfamoyl] -1,4-
Example 7, (1) using dioxaspiro [4.5] dec-6-ene-7-carboxylate
According to the method described in 6a) and 17 (alternative method), the title compound was obtained as an amorphous substance (yield 33%).
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.69-7.64 (1H, m), 7.33 (1H, dd, J = 7Hz, 3Hz), 7.10-7.05 (1H, m), 6.93 (1H, brs),

6.93 (0.5H, s), 6.84 (0.5H, s), 4.44 (1H, d, J = 4Hz), 4.27-4.09 (3.5H, m),
4.06-4.01 (0.5H, m), 3.94-3.80 (2H, m), 3.77-3.68 (2H, m), 3.54 (1H, brs),
2.61-2.46 (2H, m), 2.23-2.14 (1H, m), 2.02-1.85 (2H, m), 1.29-1.24 (3H, m).

(Example 147)
Ethyl (2S, 3S) -8- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate (Exemplified Compound No. 1-1568)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 78 -[N- (2-bromo-4-fluorophenyl) sulfamoyl] -1,4-
Example 7, (1) using dioxaspiro [4.5] dec-6-ene-7-carboxylate
According to the method described in 6a) and 18 (alternative method), the title compound was obtained as white amorphous (yield 49%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.69-7.65 (1H, m), 7.33 (1H, dd, J = 8Hz, 3Hz), 7.10-7.06 (1H, m), 6.99 (1H, brs), 6.9
1 (0.5H, s), 6.83 (0.5H, s), 4.44 (1H, d, J = 4Hz), 4.24-3.73 (8H, m), 2.61-2.48 (2H, m
), 2.61-2.48 (1H, m), 1.96-1.87 (1H, m), 1.26 (3H, t, J = 6Hz).

(Example 148)
Ethyl (2R, 3R) -8- [N- (2-butyl-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate (Exemplified Compound No. 1-646)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 85 -[N- (2-butyl-4-fluorophenyl) sulfamoyl] -1,4-
Example 7, (1) using dioxaspiro [4.5] dec-6-ene-7-carboxylate
According to the method described in 6a) and 17 (alternative method), the title compound was obtained as a pale red amorphous (yield 40%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.51-7.45 (1H, m), 6.97-6.85 (3H, m), 6.65 (0.5H, s), 6.59 (0.5H, s),
4.43-4.36 (1H, m), 4.29-4.16 (3H, m), 4.13-4.08 (0.5H, m),
4.07-4.01 (0.5H, m), 3.95-3.80 (2H, m), 3.77-3.68 (2H, m), 2.78-2.62 (2H, m),
2.53-2.35 (2H, m), 2.19-1.84 (4H, m), 1.65-1.49 (2H, m), 1.44-1.35 (2H, m),
1.33-1.27 (3H, m), 0.95 (3H, t, J = 7Hz).

(Example 149)
Ethyl (2S, 3S) -8- [N- (2-butyl-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate (Exemplified Compound No. 1-646)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 85 -[N- (2-butyl-4-fluorophenyl) sulfamoyl] -1,4-
Example 7, (1) using dioxaspiro [4.5] dec-6-ene-7-carboxylate
According to the method described in 6a) and 18 (alternative method), the title compound was obtained as a pale red amorphous (yield 14%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.50-7.44 (1H, m), 6.98-6.86 (3H, m), 6.73 (0.4H, s), 6.68 (0.6H, s),
4.43-4.37 (1H, m), 4.26-4.16 (3H, m), 4.11-4.07 (0.4H, m), 4.05-3.99 (0.6H, m),
3.90-3.80 (2H, m), 3.78-3.68 (2H, m), 2.77-2.62 (2H, m), 2.53-2.23 (3H, m),
2.20-2.07 (2H, m), 1.96-1.86 (1H, m), 1.63-1.53 (2H, m), 1.44-1.34 (2H, m),
1.32-1.26 (3H, m), 0.95 (3H, t, J = 7Hz).

(Example 150)
Ethyl (2R, 3R) -8- [N- (4-fluoro-2-pentylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate (Exemplified Compound No. 1-1744)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 86 -[N- (4-Fluoro-2-pentylphenyl) sulfamoyl] -1,4
Example 7 using dioxaspiro [4.5] dec-6-ene-7-carboxylate, (
According to the method described in 16a) and 17 (alternative method), the title compound was obtained as a pale red amorphous (33% yield).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.50-7.43 (1H, m), 6.97-6.85 (3H, m), 6.67 (0.5H, s), 6.61 (0.5H, s),
4.42-4.37 (1H, m), 4.30-4.17 (3H, m), 4.12-4.08 (0.5H, m), 4.05-4.01 (0.5H, m),
3.93-3.82 (2H, m), 3.76-3.68 (2H, m), 2.77-2.61 (2H, m), 2.53-2.35 (2H, m),
2.19-1.80 (4H, m), 1.66-1.50 (2H, m), 1.40-1.22 (7H, m), 0.95-0.87 (3H, m).

(Example 151)
Ethyl (2S, 3S) -8- [N- (4-fluoro-2-pentylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-
6-ene-7-carboxylate (Exemplified Compound No. 1-1744)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 86 -[N- (4-Fluoro-2-pentylphenyl) sulfamoyl] -1,4
Example 7 using dioxaspiro [4.5] dec-6-ene-7-carboxylate, (
According to the method described in 16a) and 18 (alternative method), the title compound was obtained as a pale red amorphous (yield 30%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.50-7.42 (1H, m), 6.97-6.84 (3H, m), 6.77 (0.5H, s), 6.72 (0.5H, s),
4.42-4.36 (1H, m), 4.30-4.14 (3H, m), 4.12-4.05 (0.5H, m), 4.04-3.98 (0.5H, m),
3.91-3.77 (2H, m), 3.76-3.67 (2H, m), 2.76-2.59 (2H, m), 2.53-2.20 (4H, m),
2.20-2.06 (1H, m), 1.97-1.84 (1H, m), 1.66-1.52 (2H, m), 1.41-1.22 (7H, m),
0.95-0.88 (3H, m).

(Example 152)
Ethyl (2R, 3R) -8- [N- (4-fluoro-2-hexylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate (Exemplified Compound No. 1-822)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 87 -[N- (4-fluoro-2-hexylphenyl) sulfamoyl] -1,4
Example 7 using dioxaspiro [4.5] dec-6-ene-7-carboxylate, (
According to the method described in 16a) and 17 (alternative method), the title compound was obtained as an amorphous substance (yield 54%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.50-7.45 (1H, m), 6.96-6.86 (3H, m), 6.67 (0.5H, s), 6.61 (0.5H, s),
4.41-4.37 (1H, m), 4.30-4.16 (3H, m), 4.13-4.08 (0.5H, m), 4.06-4.01 (0.5H, m),
3.93-3.81 (2H, m), 3.76-3.69 (2H, m), 2.76-2.61 (2H, m), 2.52-2.36 (2H, m),
2.20-1.50 (6H, m), 1.41-1.26 (9H, m), 0.91-0.86 (3H, m).

(Example 153)
Ethyl (2S, 3S) -8- [N- (4-fluoro-2-hexylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-
6-ene-7-carboxylate (Exemplified Compound No. 1-822)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 87 -[N- (4-fluoro-2-hexylphenyl) sulfamoyl] -1,4
Example 7 using dioxaspiro [4.5] dec-6-ene-7-carboxylate, (
According to the method described in 16a) and 18 (alternative method), the title compound was obtained as an amorphous substance (yield 54%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.50-7.44 (1H, m), 6.96-6.86 (3H, m), 6.70-6.67 (0.5H, m), 6.64-6.61 (0.5H, m),
4.41-4.37 (1H, m), 4.29-4.15 (3H, m), 4.12-4.07 (0.5H, m), 4.05-4.00 (0.5H, m),
3.93-3.80 (2H, m), 3.76-3.68 (2H, m), 2.76-2.61 (2H, m), 2.52-2.35 (2H, m),
2.31-1.51 (6H, m), 1.40-1.26 (9H, m), 0.91-0.86 (3H, m).

(Example 154)
Ethyl (2R, 3R) -8- [N- (4-fluoro-2-heptylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate (Exemplified Compound No. 1-998)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 88 -[N- (4-Fluoro-2-heptylphenyl) sulfamoyl] -1,4
Example 7 using dioxaspiro [4.5] dec-6-ene-7-carboxylate, (
According to the method described in 16a) and 17 (alternative method), the title compound was obtained as an amorphous substance (yield 41%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, m), 6.96-6.87 (3H, m), 6.68 (0.5H, s), 6.61 (0.5H, s), 4.41-4.40 (1H, m), 4
.30-3.71 (8H, m), 2.72-2.65 (2H, m), 2.48-2.39 (2H, m), 2.14-2.10 (2H, m), 1.95-1.87
(2H, m), 1.37-1.22 (11H, m), 0.88 (3H, t, J = 7Hz).

(Example 155)
Ethyl (2S, 3S) -8- [N- (4-fluoro-2-heptylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-
6-ene-7-carboxylate (Exemplified Compound No. 1-998)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 88 -[N- (4-Fluoro-2-heptylphenyl) sulfamoyl] -1,4
Example 7 using dioxaspiro [4.5] dec-6-ene-7-carboxylate, (
According to the method described in 16a) and 18 (alternative method), the title compound was obtained as a white amorphous (yield 70%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.50, 7.48 (1H, m), 6.97-6.88 (3H, m), 6.70 (0.5H, s), 6.70 (0.5H, s), 4.41-4.39 (1H,
m), 4.28-3.71 (8H, m), 2.75-2.63 (2H, m), 2.51-2.37 (2H, m), 2.19-2.10 (2H, m), 1.9
5-1.88 (2H, m), 1.35-1.23 (11H, m), 0.88 (3H, t, J = 7Hz).

(Example 156)
Ethyl (2R, 3R) -8- [N- (4-fluoro-2-octylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate (Exemplified Compound No. 1-1920)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 89 -[N- (4-Fluoro-2-octylphenyl) sulfamoyl] -1,4
Example 7 using dioxaspiro [4.5] dec-6-ene-7-carboxylate, (
According to the method described in 16a) and 17 (alternative method), the title compound was obtained as an amorphous substance (yield 47%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.51-7.47 (1H, m), 6.97-6.88 (3H, m), 6.71 (0.5H, s), 6.64 (0.5H, s), 4.41-4.39 (1H,
m), 4.28-3.72 (8H, m), 2.76-2.62 (2H, m), 2.51-2.37 (2H, m), 2.18-1.89 (4H, m), 1.37
-1.27 (13H, m), 0.88 (3H, t, J = 7Hz).

(Example 157)
Ethyl (2S, 3S) -8- [N- (4-fluoro-2-octylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-
6-ene-7-carboxylate (Exemplified Compound No. 1-1920)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 89 -[N- (4-Fluoro-2-octylphenyl) sulfamoyl] -1,4
Example 7 using dioxaspiro [4.5] dec-6-ene-7-carboxylate, (
According to the method described in 16a) and 18 (alternative method), the title compound was obtained as an amorphous substance (yield 51%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, dd, J = 9Hz, 5Hz), 6.97-6.88 (3H, m), 6.69 (0.5H, s), 6.63 (0.5H, s), 4.41-4
.39 (1H, m), 4.31-3.70 (8H, m), 2.72-2.66 (2H, m), 2.52-2.37 (2H, m), 2.19-1.88 (4H,
m), 1.37-1.27 (13H, m), 0.88 (3H, t, J = 7Hz).

(Example 158)
Ethyl (2R, 3R) -8- [N- (4-fluoro-2-nonylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate (Exemplified Compound No. 1-2604)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 90 -[N- (4-Fluoro-2-nonylphenyl) sulfamoyl] -1,4-
Example 7, (1) using dioxaspiro [4.5] dec-6-ene-7-carboxylate
According to the method described in 6a) and 17 (alternative method), the title compound was obtained as an amorphous substance (yield 48%). This compound could be separated into two optical isomers under the following HPLC conditions.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 7: 3
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 4.43 minutes
High polarity compound (second peak): 4.73 minutes
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.50-7.45 (1H, m), 6.97-6.86 (3H, m), 6.66 (0.5H, s), 6.60 (0.5H, s),
4.42-4.37 (1H, m), 4.28-4.18 (3H, m), 4.13-4.08 (0.5H, m), 4.06-4.01 (0.5H, m),
3.95-3.81 (2H, m), 3.76-3.69 (2H, m), 2.77-2.61 (2H, m), 2.53-2.35 (2H, m),
2.19-1.99 (2H, m), 1.96-1.86 (2H, m), 1.64-1.52 (2H, m), 1.40-1.18 (15H, m),
0.91-0.85 (3H, m).

(Example 159)
Ethyl (2S, 3S) -8- [N- (4-fluoro-2-nonylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6
-Ene-7-carboxylate (Exemplified Compound No. 1-2604)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 90 -[N- (4-Fluoro-2-nonylphenyl) sulfamoyl] -1,4-
Example 7, (1) using dioxaspiro [4.5] dec-6-ene-7-carboxylate
According to the method described in 6a) and 18 (alternative method), the title compound was obtained as an amorphous substance (yield 54%). This compound could be separated into two optical isomers under the following HPLC conditions.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 4: 1
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 6.7 minutes
High polarity compound (second peak): 10.1 min
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.50-7.45 (1H, m), 6.97-6.86 (3H, m), 6.71 (0.5H, s), 6.65 (0.5H, s),
4.42-4.37 (1H, m), 4.30-4.16 (3H, m), 4.13-4.08 (0.5H, m), 4.05-4.00 (0.5H, m),
3.93-3.80 (2H, m), 3.77-3.69 (2H, m), 2.76-2.61 (2H, m), 2.52-2.01 (5H, m),
1.95-1.86 (1H, m), 1.64-1.52 (2H, m), 1.41-1.22 (15H, m), 0.88 (3H, t, J = 7Hz).

(Example 160)
Ethyl (2R, 3R) -8- [N- (2-decyl-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate (Exemplified Compound No. 1-2618)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 91 -[N- (2-decyl-4-fluorophenyl) sulfamoyl] -1,4-
Example 7, (1) using dioxaspiro [4.5] dec-6-ene-7-carboxylate
According to the method described in 6a) and 17 (alternative method), the title compound was obtained as amorphous (yield 35%). This compound could be separated into two optical isomers under the following HPLC conditions.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 7: 3
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 4.30 minutes
High polarity compound (second peak): 4.55 min
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.51-7.45 (1H, m), 6.97-6.86 (3H, m), 6.67 (0.5H, s), 6.61 (0.5H, s),
4.42-4.36 (1H, m), 4.30-4.17 (3H, m), 4.13-4.08 (0.5H, m), 4.06-4.01 (0.5H, m),
3.94-3.80 (2H, m), 3.76-3.69 (2H, m), 2.76-2.61 (2H, m), 2.53-2.35 (2H, m),
2.19-2.00 (2H, m), 1.99-1.86 (2H, m), 1.65-1.51 (2H, m), 1.40-1.18 (17H, m),
0.91-0.85 (3H, m).

(Example 161)
Ethyl (2S, 3S) -8- [N- (2-decyl-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6
-Ene-7-carboxylate (Exemplified Compound No. 1-2618)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 91 -[N- (2-decyl-4-fluorophenyl) sulfamoyl] -1,4-
Example 7, (1) using dioxaspiro [4.5] dec-6-ene-7-carboxylate
According to the method described in 6a) and 18 (alternative method), the title compound was obtained as an amorphous substance (yield 56%). This compound could be separated into two optical isomers under the following HPLC conditions.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 4: 1
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 6.4 minutes
High polarity compound (second peak): 9.1 min
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.50-7.45 (1H, m), 6.97-6.87 (3H, m), 6.70 (0.5H, s), 6.64 (0.5H, s),
4.42-4.38 (1H, m), 4.30-4.17 (3H, m), 4.12-4.08 (0.5H, m), 4.05-4.01 (0.5H, m),
3.93-3.81 (2H, m), 3.78-3.69 (2H, m), 2.76-2.62 (2H, m), 2.52-2.37 (2H, m),
2.33-2.09 (2H, m), 2.06-1.87 (2H, m), 1.63-1.52 (2H, m), 1.40-1.22 (17H, m),
0.88 (3H, t, J = 7Hz).

(Example 162)
Ethyl (2R, 3R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-382)

Ethyl (2R, 3R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4] obtained in Example 17
. 5] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column;
CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:
2-Propanol) was used to separate and purify the two optical isomers to obtain a low-polarity compound (first peak) and a high-polarity compound (second peak) as white amorphous. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purity was>
It was 99% ee.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 4: 1
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: low polarity compound (first peak): 12.0 minutes
High polarity compound (second peak): 16.5 minutes (low polarity compound, first peak)
Optical rotation [α] _D +86.7 (c = 2.0, MeOH)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.67 (1H, dd, J = 9Hz, 5Hz), 7.17 (1H, dd, J = 8Hz, 3Hz), 7.07-6.98 (2H, m),
6.91 (1H, s), 4.42 (1H, dd, J = 6Hz, 2Hz), 4.28-4.08 (4H, m),
3.91 (1H, dd, J = 12Hz, 4Hz), 3.84 (1H, dd, J = 12Hz, 4HZ), 3.77-3.68 (2H, m),
2.60-2.43 (2H, m), 2.26-2.11 (1H, m), 1.99-1.87 (1H, m), 1.58 (2H, bs),
1.27 (3H, t, J = 7Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.66 (1H, dd, J = 9Hz, 5Hz), 7.17 (1H, dd, J = 8Hz, 3Hz), 7.07-6.98 (2H, m),
6.84 (1H, s), 4.42 (1H, d, J = 5Hz), 4.28-4.08 (3H, m), 4.07-4.01 (1H, m),
3.93-3.82 (2H, m), 3.77-3.68 (2H, m), 2.61-2.46 (2H, m), 2.24-2.11 (1H, m),
1.95-1.87 (1H, m), 1.57 (2H, bs), 1.27 (3H, t, J = 7Hz).

(Example 163)
Ethyl (2S, 3S) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-382)

Ethyl (2S, 3S) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4] obtained in Example 18
. 5] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column;
CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane:
2-Propanol) was used to separate and purify the two optical isomers to obtain a low-polarity compound (first peak) and a high-polarity compound (second peak) as white amorphous. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purity was>
It was 99% ee.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 4: 1
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: low polarity compound (first peak): 11.4 minutes
High polarity compound (second peak): 27.4 minutes (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.66 (1H, dd, J = 9Hz, 5Hz), 7.17 (1H, dd, J = 8Hz, 3Hz), 7.06-7.00 (1H, m),
6.98 (1H, s), 6.84 (1H, s), 4.42 (1H, d, J = 5Hz), 4.27-4.09 (3H, m),
4.07-4.00 (1H, m), 3.93-3.83 (2H, m), 3.76-3.68 (2H, m), 2.60-2.47 (2H, m),
2.24-2.12 (1H, m), 1.95-1.60 (3H, m), 1.27 (3H, t, J = 7Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.67 (1H, dd, J = 9Hz, 5Hz), 7.17 (1H, dd, J = 8Hz, 3Hz), 7.06-6.99 (2H, m),
6.90 (1H, s), 4.44-4.41 (1H, m), 4.27-4.09 (4H, m), 3.91 (1H, dd, J = 12Hz, 4Hz),
3.84 (1H, dd, J = 12Hz, 4HZ), 3.77-3.68 (2H, m), 2.60-2.45 (2H, m), 2.24-2.12 (1H,
m),
2.00-1.65 (3H, m), 1.27 (3H, t, J = 7Hz).

(Example 164)
Ethyl (2R, 3R) -8- [N- (2,4-difluorophenyl) sulfamoyl]-
2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-
7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak)
(Exemplary compound number 1-294)

Ethyl (2R, 3R) -8- [N- (2,4-difluorophenyl) obtained in Example 144
Sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5
] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CH
IRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane: 2-
(Propanol) was used to separate and purify the two optical isomers, and the low polar compound (first peak) and the high polar compound (second peak) were obtained as amorphous. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purities were> 99% e, respectively.
e.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 4: 1
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 13.7 minutes
High polarity compound (second peak): 15.9 minutes (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.62-7.57 (1H, m), 6.93-6.87 (3H, m), 4.36 (1H, q, J = 3Hz), 4.28-4.18 (3H, m),
4.15-4.09 (1H, m), 3.91 (1H, dd, J = 12Hz, 4Hz), 3.84 (1H, dd, J = 12Hz, 4Hz),
3.75-3.70 (2H, m), 2.51-2.40 (2H, m), 2.20-2.12 (1H, m), 1.96-1.90 (1H, m),
1.61 (2H, brs), 1.29 (3H, t, J = 7Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.62-7.57 (1H, m), 6.97 (1H, brs), 6.93-6.86 (3H, m), 4.37-4.35 (1H, m),
4.29-4.17 (3H, m), 4.06-4.02 (1H, m), 3.91-3.84 (2H, m), 3.76-3.69 (2H, m),
2.53-2.41 (2H, m), 2.20-2.11 (1H, m), 2.05 (1H, brs), 1.94-1.88 (2H, m),
1.29 (3H, t, J = 7Hz).

(Example 165)
Ethyl (2S, 3S) -8- [N- (2,4-difluorophenyl) sulfamoyl]-
2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-
7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak)
(Exemplary compound number 1-294)

Ethyl (2S, 3S) -8- [N- (2,4-difluorophenyl) obtained in Example 145
Sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5
] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CH
IRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane: 2-
(Propanol) was used to separate and purify the two optical isomers, and the low polar compound (first peak) and the high polar compound (second peak) were obtained as amorphous. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purities were> 99% e, respectively.
e.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 7: 3
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 6.9 minutes
High polarity compound (second peak): 10.7 min (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.62-7.57 (1H, m), 6.93-6.86 (3H, m), 4.36 (1H, d, J = 4Hz), 4.29-4.18 (3H, m),
4.06-4.01 (1H, m), 3.91-3.84 (2H, m), 3.75-3.70 (2H, m),
2.52-2.42 (2H, m), 2.19-1.50 (4H, m), 1.29 (3H, t, J = 7Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.62-7.57 (1H, m), 6.93-6.87 (3H, m), 4.36 (1H, dd, J = 6Hz, 3Hz), 4.29-4.18 (3H,
m),
4.13-4.09 (1H, m), 3.91 (1H, dd, J = 12Hz, 4Hz), 3.84 (1H, dd, J = 12Hz, 4Hz),
3.75-3.70 (2H, m), 2.51-2.40 (2H, m), 2.20-1.50 (4H, m), 1.29 (3H, t, J = 7Hz).

(Example 166)
Ethyl (2R, 3R) -8- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-1568)

Ethyl (2R, 3R) -8- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro obtained in Example 146 [
4.5] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size: ID 2 cm, length 25 cm, solvent: hexane: 2-propanol). The optical isomers were separated and purified to obtain a low polar compound (first peak) and a high polar compound (second peak) as amorphous. Obtained 2
As a result of HPLC analysis of the optical isomers of the species under the following conditions, their optical purity was> 9 respectively.
It was 9% ee.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 7: 3
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 6.8 minutes
High polarity compound (second peak): 8.8 minutes (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.68 (1H, dd, J = 9.2Hz, 5.2Hz), 7.34 (1H, dd, J = 7.6Hz, 2.9Hz), 7.11-7.06 (1H, m), 6.
91 (1H, s), 4.44 (1H, dd, J = 5.8Hz, 2.0Hz), 4.28-4.10 (4H, m), 3.93-3.70 (4H, m), 2.6
0-2.47 (2H, m), 2.24-2.14 (1H, m), 1.97-1.92 (1H, m), 1.27 (3H, t, J = 7.0Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.67 (1H, dd, J = 9.2Hz, 5.3Hz), 7.34 (1H, dd, J = 7.6Hz, 2.9Hz), 7.11-7.06 (1H, m), 6.
85 (1H, s), 4.44 (1H, d, J = 5.0Hz), 4.27-4.02 (4H, m), 3.92-3.84 (2H, m), 3.76-3.70 (2
H, m), 2.61-2.48 (2H, m), 2.23-2.15 (1H, m), 1.92-1.88 (1H, m), 1.27 (3H, t, J = 7.2Hz
).

(Example 167)
Ethyl (2S, 3S) -8- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-1568)

Ethyl (2S, 3S) -8- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro obtained in Example 147 [
4.5] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size: ID 2 cm, length 25 cm, solvent: hexane: 2-propanol). The optical isomers were separated and purified to obtain a low polar compound (first peak) and a high polar compound (second peak) as amorphous. Obtained 2
As a result of HPLC analysis of the optical isomers of the species under the following conditions, their optical purity was> 9 respectively.
It was 9% ee.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 7: 3
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 6.7 minutes
High polarity compound (second peak): 13.2 minutes (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.67 (1H, dd, J = 9Hz, 5Hz), 7.33 (1H, dd, J = 8Hz, 3Hz), 7.10-7.06 (1H, m), 6.84 (1H, s
), 4.44 (1H, d, J = 5Hz), 4.24-3.70 (8H, m), 2.61-2.48 (2H, m), 2.24-1.87 (2H, m), 1.2
6 (3H, t, J = 7Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.67 (1H, dd, J = 9Hz, 5Hz), 7.33 (1H, dd, J = 8Hz, 3Hz), 7.10-7.05 (1H, m), 6.91 (1H, s
), 4.44 (1H, d, J = 6Hz), 4.27-3.69 (8H, m), 2.59-2.48 (2H, m), 2.23-1.91 (2H, m), 1.2
6 (3H, t, J = 7Hz).

(Example 168)
Ethyl (2R, 3R) -8- [N- (2-butyl-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-646)

Ethyl (2R, 3R) -8- [N- (2-butyl-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro obtained in Example 148 [
4.5] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size: ID 2 cm, length 25 cm, solvent: hexane: 2-propanol). Were separated and purified to obtain a low-polarity compound (first peak) as a pale red amorphous substance and a high-polarity compound (second peak) as a white powder. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purity was> 99% ee, respectively.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 7: 3
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 5.02 minutes
High polarity compound (second peak): 5.24 minutes (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, dd, J = 9Hz, 5Hz), 6.98-6.93 (2H, m), 6.90 (1H, dt, J = 8Hz, 3Hz),
6.67 (1H, s), 4.40 (1H, dd, J = 6Hz, 3Hz), 4.29-4.19 (3H, m), 4.13-4.08 (1H, m),
3.92 (1H, dd, J = 12Hz, 4Hz), 3.85 (1H, dd, 12Hz, 4Hz), 3.76-3.69 (2H, m),
2.78-2.62 (2H, m), 2.53-2.35 (2H, m), 2.19-1.80 (4H, m), 1.65-1.49 (2H, m),
1.44-1.34 (2H, m), 1.31 (3H, t, J = 7Hz), 0.95 (3H, t, J = 7Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.48 (1H, dd, J = 9Hz, 5Hz), 6.95 (1H, dd, J = 9Hz, 3Hz,), 6.93-6.86 (2H, m), 6.62 (
1H, s), 4.41 (1H, d, J = 4Hz), 4.28-4.17 (3H, m), 4.05-4.01 (1H, m),
3.91-3.83 (2H, m), 3.77-3.69 (2H, m), 2.77-2.62 (2H, m), 2.53-2.35 (2H, m),
2.18-1.76 (4H, m), 1.65-1.50 (2H, m), 1.44-1.35 (2H, m), 1.30 (3H, t, J = 7Hz),
0.95 (3H, t, J = 7Hz).

(Example 169)
Ethyl (2S, 3S) -8- [N- (2-butyl-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-646)

Ethyl (2S, 3S) -8- [N- (2-butyl-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro obtained in Example 149 [
4.5] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size: ID 2 cm, length 25 cm, solvent: hexane: 2-propanol). Were separated and purified to obtain a low polarity compound (first peak) as a white powder and a high polarity compound (second peak) as a pale red amorphous. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purity was> 99% ee, respectively.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 7: 3
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 5.08 minutes
High polarity compound (second peak): 6.58 minutes (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.47 (1H, dd, J = 9Hz, 5Hz), 6.95 (1H, dd, J = 9Hz, 3Hz,), 6.93-6.86 (2H, m), 6.61 (
1H, s), 4.41 (1H, d, J = 4Hz), 4.26-4.16 (3H, m), 4.05-3.99 (1H, m),
3.90-3.80 (2H, m), 3.78-3.68 (2H, m), 2.77-2.62 (2H, m), 2.53-2.39 (2H, m),
2.33-2.05 (2H, m), 1.96-1.86 (1H, m), 1.80-1.65 (1H, m), 1.63-1.52 (2H, m),
1.44-1.35 (2H, m), 1.29 (3H, t, J = 7Hz), 0.95 (3H, t, J = 7Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.48 (1H, dd, J = 9Hz, 5Hz), 6.99-6.86 (3H, m), 6.70 (1H, s),
4.40 (1H, dd, J = 6Hz, 3Hz), 4.29-4.17 (3H, m), 4.13-4.07 (1H, m),
3.90 (1H, dd, J = 12Hz, 4Hz), 3.84 (1H, dd, 12Hz, 4Hz), 3.76-3.69 (2H, m),
2.77-2.62 (2H, m), 2.53-2.23 (3H, m), 2.20-2.00 (2H, m), 1.96-1.86 (1H, m),
1.63-1.52 (2H, m), 1.44-1.34 (2H, m), 1.30 (3H, t, J = 7Hz), 0.95 (3H, t, J = 7Hz).

(Example 170)
Ethyl (2R, 3R) -8- [N- (4-fluoro-2-pentylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-1744)

Ethyl (2R, 3R) -8- [N- (4-fluoro-2-pentylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] obtained in Example 150 ] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size: 2 cm inner diameter, length 25 cm, solvent: hexane: 2-propanol) to give two optical isomerisms The body was separated and purified to obtain a low polar compound (first peak) as a light red amorphous substance and a high polar compound (second peak) as a white powder. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purity was> 99% ee, respectively.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 7: 3
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 4.83 minutes
High polarity compound (second peak): 5.01 min (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.48 (1H, dd, J = 9Hz, 5Hz), 6.97-6.92 (2H, m), 6.90 (1H, dt, J = 8Hz, 3Hz),
6.66 (1H, s), 4.40 (1H, dd, J = 6Hz, 3Hz), 4.28-4.18 (3H, m), 4.14-4.07 (1H, m),
3.92 (1H, dd, J = 12Hz, 4Hz), 3.85 (1H, dd, 12Hz, 4Hz), 3.76-3.69 (2H, m),
2.76-2.61 (2H, m), 2.50-2.35 (2H, m), 2.19-2.08 (1H, m), 1.97-1.87 (1H, m),
1.81-1.49 (4H, m), 1.40-1.32 (4H, m), 1.30 (3H, t, J = 7Hz), 0.90 (3H, t, J = 7Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.48 (1H, dd, J = 9Hz, 5Hz), 6.95 (1H, dd, J = 9Hz, 3Hz), 6.93-6.86 (2H, m),
6.60 (1H, s), 4.41 (1H, d, J = 5Hz), 4.29-4.17 (3H, m), 4.07-4.01 (1H, m),
3.93-3.84 (2H, m), 3.76-3.69 (2H, m), 2.76-2.61 (2H, m), 2.54-2.36 (2H, m),
2.19-2.07 (1H, m), 2.06-1.70 (3H, m), 1.66-1.50 (2H, m), 1.40-1.32 (4H, m),
1.30 (3H, t, J = 7Hz), 0.90 (3H, t, J = 7Hz).

(Example 171)
Ethyl (2S, 3S) -8- [N- (4-fluoro-2-pentylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-1744)

Ethyl (2S, 3S) -8- [N- (4-fluoro-2-pentylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] obtained in Example 151 ] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size: 2 cm inner diameter, length 25 cm, solvent: hexane: 2-propanol) to give two optical isomerisms The body was separated and purified to obtain a low polarity compound (first peak) as a white powder and a high polarity compound (second peak) as a pale red amorphous. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purity was> 99% ee, respectively.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 7: 3
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 4.90 minutes
High polarity compound (second peak): 6.18 min (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.48 (1H, dd, J = 9Hz, 5Hz), 6.97-6.85 (3H, m), 6.59 (1H, s),
4.40 (1H, d, J = 5Hz), 4.29-4.17 (3H, m), 4.06-4.00 (1H, m), 3.91-3.83 (2H, m),
3.76-3.69 (2H, m), 2.76-2.59 (2H, m), 2.53-2.36 (2H, m), 2.20-2.06 (1H, m),
1.94-1.85 (1H, m), 1.80-1.50 (4H, m), 1.41-1.22 (7H, m), 0.91 (3H, t, J = 7Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.47 (1H, dd, J = 9Hz, 5Hz), 6.97-6.92 (2H, m), 6.89 (1H, dt, J = 8Hz, 3Hz),
6.73 (1H, s), 4.40 (1H, dd, J = 6Hz, 3Hz), 4.28-4.17 (3H, m), 4.12-4.05 (1H, m),
3.89 (1H, dd, J = 12Hz, 4Hz), 3.82 (1H, dd, 12Hz, 4Hz), 3.76-3.69 (2H, m),
2.76-2.61 (2H, m), 2.51-2.35 (2H, m), 2.26-2.01 (2H, m), 1.97-1.68 (2H, m),
1.66-1.54 (2H, m), 1.41-1.31 (4H, m), 1.29 (3H, t, J = 7Hz), 0.90 (3H, t, J = 7Hz).

(Example 172)
Ethyl (2R, 3R) -8- [N- (4-fluoro-2-hexylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-822)

Ethyl (2R, 3R) -8- [N- (4-fluoro-2-hexylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro obtained in Example 152 [4.5 ] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size: 2 cm inner diameter, length 25 cm, solvent: hexane: 2-propanol) to give two optical isomerisms The body was separated and purified to obtain a low polar compound (first peak) and a high polar compound (second peak) as amorphous. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purity was>
It was 99% ee.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 9: 1
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 25.2 minutes
High polarity compound (second peak): 29.3 minutes (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.48 (1H, dd, J = 9Hz, 5Hz), 6.97-6.87 (3H, m), 6.66 (1H, s), 4.41-4.37 (1H, m),
4.29-4.19 (3H, m), 4.13-4.09 (1H, m), 3.95-3.88 (1H, m), 3.87-3.81 (1H, m),
3.77-3.69 (2H, m), 2.77-2.62 (2H, m), 2.51-2.36 (2H, m), 2.19-2.09 (2H, m),
1.95-1.89 (2H, m), 1.63-1.52 (2H, m), 1.40-1.28 (9H, m), 0.91-0.86 (3H, m).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.47 (1H, dd, J = 9Hz, 5Hz), 6.96-6.86 (3H, m), 6.63 (1H, s), 4.42-4.39 (1H, m),
4.30-4.16 (3H, m), 4.06-4.01 (1H, m), 3.91-3.83 (2H, m), 3.77-3.69 (2H, m),
2.76-2.61 (2H, m), 2.53-2.37 (2H, m), 2.18-2.08 (2H, m), 2.03-1.98 (1H, m),
1.93-1.86 (1H, m), 1.63-1.52 (2H, m), 1.41-1.26 (9H, m), 0.91-0.86 (3H, m).

(Example 173)
Ethyl (2S, 3S) -8- [N- (4-fluoro-2-hexylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6
-Ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-822)

Ethyl (2S, 3S) -8- [N- (4-fluoro-2-hexylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] obtained in Example 153 ] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size: 2 cm in inner diameter, 25 cm in length, solvent: hexane: 2-propanol) to give two kinds of optical isomerism The body was separated and purified to obtain a low polar compound (first peak) and a high polar compound (second peak) as amorphous. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purity was>
It was 99% ee.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 4: 1
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 7.6 minutes
High polarity compound (second peak): 10.6 minutes (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.48 (1H, dd, J = 9Hz, 5Hz), 6.95 (1H, dd, J = 9Hz, 3Hz), 6.92-6.87 (2H, m),
6.61 (1H, s), 4.40 (1H, d, J = 4Hz), 4.29-4.17 (3H, m), 4.06-4.02 (1H, m),
3.91-3.84 (2H, m), 3.76-3.70 (2H, m), 2.75-2.62 (2H, m), 2.52-2.46 (1H, m),
2.42 (1H, td, J = 14Hz, 3Hz), 2.17-2.09 (1H, m), 2.05 (1H, dd, J = 8Hz, 5Hz),
1.96-1.87 (2H, m), 1.64-1.53 (2H, m), 1.40-1.27 (9H, m), 0.91-0.87 (3H, m).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
7.48 (1H, dd, J = 9Hz, 5Hz), 6.96-6.93 (2H, m), 6.90 (1H, td, J = 8Hz, 3Hz),
6.67 (1H, m), 4.39 (1H, dd, J = 6Hz, 4Hz), 4.30-4.19 (3H, m), 4.13-4.09 (1H, m),
3.91 (1H, dt, J = 12Hz, 4Hz), 3.84 (1H, dt, J = 12Hz, 4Hz), 3.76-3.69 (2H, m),
2.76-2.63 (2H, m), 2.50-2.44 (1H, m), 2.40 (1H, td, J = 13Hz, 3Hz), 2.18-2.10 (2H,
m),
1.95-1.89 (2H, m), 1.63-1.53 (2H, m), 1.40-1.28 (9H, m), 0.91-0.87 (3H, m).

(Example 174)
Ethyl (2R, 3R) -8- [N- (4-fluoro-2-heptylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-998)

Ethyl (2R, 3R) -8- [N- (4-fluoro-2-heptylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] obtained in Example 154 ] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size: 2 cm in inner diameter, 25 cm in length, solvent: hexane: 2-propanol) to give two kinds of optical isomerism The body was separated and purified to obtain each of a low polarity compound (first peak) and a high polarity compound (second peak) as white amorphous. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purity was> 99% ee, respectively.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 9: 1
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 23.9 minutes
High polarity compound (second peak): 27.4 minutes (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.48 (1H, dd, J = 8Hz, 5Hz), 6.96-6.88 (3H, m), 6.67 (1H, s), 4.40-4.38 (1H, m), 4.27-
3.69 (8H, m), 2.72-2.62 (2H, m), 2.49-1.89 (6H, m), 1.34-1.25 (11H, m), 0.88 (3H, t,
J = 7Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.47 (1H, dd, J = 9Hz, 5Hz), 6.96-6.87 (3H, m), 6.64 (1H, brs), 4.40 (1H, d, J = 4Hz), 4
.29-3.71 (8H, m), 2.75-2.61 (2H, m), 2.51-2.37 (2H, m), 2.17-1.86 (4H, m), 1.42-1.22
(11H, m), 0.88 (3H, t, J = 7Hz).

(Example 175)
Ethyl (2S, 3S) -8- [N- (4-fluoro-2-heptylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-998)

Ethyl (2S, 3S) -8- [N- (4-fluoro-2-heptylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] obtained in Example 155 ] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size: 2 cm in inner diameter, 25 cm in length, solvent: hexane: 2-propanol) to give two kinds of optical isomerism The body was separated and purified to obtain a low polarity compound (first peak) as a white powder and a high polarity compound (second peak) as a white amorphous. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purity was> 99% ee, respectively.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 7: 3
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 4.8 minutes
High polarity compound (second peak): 6.3 minutes (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.48 (1H, dd, J = 9Hz, 5Hz), 6.97-6.88 (3H, m), 6.64 (1H, s), 4.41 (1H, d, J = 4Hz), 4.2
7-3.72 (8H, m), 2.75-2.62 (2H, m), 2.51-2.38 (2H, m), 2.18-1.38 (4H, m), 1.38-1.28 (1
1H, m), 0.88 (3H, t, J = 7Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, dd, J = 9Hz, 5Hz), 6.97-6.88 (3H, m), 6.69 (1H, s), 4.41-4.39 (1H, m), 4.29-
3.71 (8H, m), 2.77-2.62 (2H, m), 2.49-1.90 (6H, m), 1.38-1.29 (11H, m), 0.89 (3H, t,
J = 7Hz).

(Example 176)
Ethyl (2R, 3R) -8- [N- (4-fluoro-2-octylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-1920)

Ethyl (2R, 3R) -8- [N- (4-fluoro-2-octylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] obtained in Example 156 ] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size: 2 cm inner diameter, length 25 cm, solvent: hexane: 2-propanol) to give two optical isomerisms The body was separated and purified to obtain each of a low polarity compound (first peak) and a high polarity compound (second peak) as white amorphous. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purity was> 99% ee, respectively.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 9: 1
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 22.9 minutes
High polarity compound (second peak): 25.8 minutes (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.48 (1H, dd, J = 9Hz, 5Hz), 6.96-6.88 (3H, m), 6.68 (1H, s), 6.68-4.40 (1H, m), 4.28-
3.70 (8H, m), 4.28-3.70 (2H, m), 2.52-1.89 (6H, m), 1.36-1.19 (13H, m), 0.88 (3H, t,
J = 7Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.46 (1H, dd, J = 9Hz, 5Hz), 6.95-6.87 (3H, m), 4.40 (1H, d, J = 5Hz), 4.28-3.71 (8H, m)
2.73-2.60 (2H, m), 2.50-1.87 (6H, m), 1.31-1.25 (13H, m), 0.89 (3H, t, J = 7Hz).

(Example 177)
Ethyl (2S, 3S) -8- [N- (4-fluoro-2-octylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6
-Ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-1920)

Ethyl (2S, 3S) -8- [N- (4-fluoro-2-octylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] obtained in Example 157 ] Deca-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size: 2 cm inner diameter, length 25 cm, solvent: hexane: 2-propanol) to give two optical isomerisms The product was separated and purified to obtain a low polarity compound (first peak) as a white powder and a high polarity compound (second peak) as a colorless oil. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purity was> 99% ee, respectively.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 7: 3
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 4.7 minutes
High polarity compound (second peak): 6.1 minutes (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.48 (1H, dd, J = 9Hz, 5Hz), 6.97-6.88 (3H, m), 6.63 (1H, s), 4.41 (1H, d, J = 5Hz), 4.2
8-3.71 (8H, m), 2.75-2.62 (2H, m), 2.51-1.88 (6H, m), 1.38-1.27 (13H, m), 0.88 (3H, t
, J = 7Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, dd, J = 9Hz, 6Hz), 6.97-6.88 (3H, m), 6.97-6.88 (1H, m), 4.41-4.38 (1H, m),
4.31-3.71 (8H, m), 2.77-2.63 (2H, m), 2.50-1.90 (6H, m), 2.50-1.90 (13H, m), 0.88 (3H
, t, J = 7Hz).

(Example 178)
Ethyl (2R, 3R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis (methoxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene -7-carboxylate

1,4-di-O-methyl-2,3-di-O-trimethylsilyl-D-tray instead of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol The title compound was obtained as a colorless oil according to the method described in Example (17a) using Toll (yield 89%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.68-7.64 (1H, m), 7.16 (1H, dd, J = 8.1Hz, 3.0Hz), 7.17-7.16 (3H, m), 4.39 (1H, d, J =
3.5Hz), 4.24-3.98 (4H, m), 3.43-3.42 (4H, m), 3.43 (1.5H, s), 3.42 (1.5H, s), 3.39 (1
.5H, s), 3.38 (1.5H, s), 2.57-2.45 (2H, m), 2.57-2.45 (1H, m), 1.96-1.86 (1H, m), 1.
27 (3H, dt, J = 6.9Hz, 2.1Hz).

(Example 179)
Ethyl (2S, 3S) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis (methoxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene -7-carboxylate

1,4-di-O-methyl-2,3-di-O-trimethylsilyl-L-tray instead of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol The title compound was obtained as a colorless oil according to the method described in Example (17a) using Toll (yield 91%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.68-7.64 (1H, m), 7.16 (1H, dd, J = 7.8 and 2.4Hz), 7.04-7.00 (2H, m), 6.89 (1H, s),
4.40-4.39 (1H, m), 4.23-3.97 (4H, m), 3.62-3.47 (4H, m), 3.43 (1.5H, s), 3.41 (1.5H,
s), 3.39 (1.5H, s), 3.38 (1.5H, s), 2.58-2.45 (2H, m), 2.26-2.16 (1H, m), 1.96-1.86 (
1H, m), 1.26 (3H, dt, J = 7.0 and 3.5Hz).

(Example 180)
Ethyl (2S, 3S) -2,3-bis (benzyloxymethyl) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] deca-
6-ene-7-carboxylate

1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol instead of 1,4-di-O-benzyl-2,3-di-O-trimethylsilyl-L-tray The title compound was obtained as a colorless oil according to the method described in Example (17a) using Toll (yield 94%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.69-7.64 (1H, m), 7.37-7.26 (10H, m), 7.16 (1H, dd, J = 7.8Hz, 2.8Hz), 7.04-6.90 (3H,
m), 4.64-4.51 (4H, m), 4.40 (1H, t, J = 4.5Hz), 4.30-4.05 (4H, m), 3.68-3.57 (4H, m),
2.58-2.45 (2H, m), 2.25-2.17 (1H, m), 1.96-1.86 (1H, m), 1.21 (3H, dt, J = 7.0Hz, 3.5
Hz).

(Example 181)
Ethyl (2R, 3R) -2,3-bis (acetoxymethyl) -8- [N- (2-chloro-
4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate

1,4-di-O-acetyl-2,3-di-O obtained in Reference Example 24 instead of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol The title compound was obtained as a white amorphous according to the method described in Example (17a) using trimethylsilyl-D-threitol (yield 50%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.67 (1H, dd, J = 9.2Hz, 5.3Hz), 7.17 (1H, dd, J = 7.9Hz, 2.8Hz), 7.05-7.00 (2H, m), 6.
90-6.76 (1H, m), 4.41 (1H, d, J = 4.7Hz), 4.37-4.37 (8H, m), 2.60-2.46 (2H, m), 2.23-2
.04 (8H, m), 1.26 (3H, t, J = 7.0Hz).

(Example 182)
Ethyl (2S, 3S) -2,3-bis (acetylaminomethyl) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] deca-
6-ene-7-carboxylate (Exemplified Compound No. 1-410)

N- (4-acetylamino-2R, 3R-dihydroxybutyl) acetamide 218 mg (1
. 07 mmol) and 0.57 ml (3.20 mmol) of isopropoxytrimethylsilane
) Is dissolved in 3 ml of nitromethane, and 13 ml (0.071 mmol) of trimethylsilyl trifluoromethanesulfonate and ethyl 6- [N obtained in Example (16a) are stirred under ice cooling.
-(2-Chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethoxy-1-
Cyclohexene-1-carboxylate (300 mg, 0.711 mmol) was sequentially added, and the mixture was stirred at the same temperature for 3 hours and further at room temperature for 116 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate: methanol = 9: 1) to give 203 mg of the title compound as an amorphous substance (yield 51%
).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.68-7.63 (1H, m), 7.20-7.15 (1H, m), 7.08-7.00 (2H, m), 6.78-6.73 (1H, m), 6.46-6.38
(1H, m), 6.34-6.26 (1H, m), 4.42-4.39 (1H, m), 4.29-4.14 (2H, m), 3.96-3.85 (1.5H, m
), 3.75-3.69 (0.5H, m), 3.61-3.42 (4H, m), 2.55-2.43 (2H, m), 2.21-2.01 (7H, m), 1.9
0-1.78 (1H, m), 1.31-1.25 (3H, m).

(Example 183)
Ethyl (2R, 3R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis ((R) -1-hydroxyethyl) -1,4-dioxaspiro [4.5 ]
Deca-6-ene-7-carboxylate (Exemplified Compound No. 1-2163)

(1R, 2R, 3R, 4R) -4-benzoyloxy-1- obtained in Reference Example 25 instead of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol Example 1 using methyl-2,3-bis [(trimethylsilyl) oxy] pentyl benzoate
According to the method described in 7 (Alternative method), the title compound was obtained as a white amorphous (yield 3
3%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.66 (1H, dd, J = 9.0 and 5.0Hz), 7.17 (1H, dd, J = 7.8 and 2.7Hz), 7.09 (1H, d, J = 9.0H
z), 7.05-7.00 (1H, m), 6.80 (0.5H, s), 6.76 (0.5H, s), 4.39 (1H, d, J = 5.4Hz), 4.27-4
.09 (2H, m), 3.88-3.56 (4H, m), 2.50-2.42 (2H, m), 2.19-2.11 (1H, m), 1.85-1.79 (1H,
m), 1.33 (3H, t, J = 5.3 Hz), 1.27 (6H, t, J = 7.0 Hz).

(Example 184)
Ethyl (2R, 3R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis ((R) -1-hydroxypropyl) -1,4-dioxaspiro [4.
5] Deca-6-ene-7-carboxylate (Exemplified Compound No. 1-2164)

(1R, 2R, 3R, 4R) -4-benzoyloxy-1- obtained in Reference Example 26 instead of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol Example 1 using ethyl-2,3-bis [(trimethylsilyl) oxy] hexyl benzoate
According to the method described in 7 (Alternative method), the title compound was obtained as a white amorphous (yield 2
1%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.68 (1H, dd, J = 9.2Hz, 5.2Hz), 7.18 (1H, dd, J = 7.4Hz, 2.4Hz), 7.06-7.01 (2H, m), 6.
81 (0.5H, s), 6.78 (0.5H, s), 4.40 (1H, d, J = 5.1Hz), 4.29-4.12 (2H, m), 3.88-3.55 (4H
, m), 3.03 (1H, brs), 2.92 (1H, brs), 2.51-2.41 (2H, m), 2.21-2.13 (2H, m), 1.90-1.7
3 (1H, m), 1.55-1.43 (3H, m), 1.29 (3H, t, J = 7.2 Hz), 1.05-0.97 (6H, m).

(Example 185)
Ethyl (3a′R, 6a′R, 6′R) -4- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -6′-hydroxymethyl-4′-oxo-3a ′, 4 ′, 6 ', 6a
'-Tetrahydrospiro [cyclohex-2-ene-1,2'-furo [3.4-d] [1.3
] Dioxole] -3-carboxylate (Exemplified Compound No. 1-2165)

Instead of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol, (3R, 4R, 5R) -3,4-bis [(trimethylsilyl) oxy] -5- [ The title compound was obtained as a white amorphous according to the method described in Example (17a) using (trimethylsilyl) oxy] methyldihydrofuran-2-one (yield 25%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.69-7.64 (1H, m), 7.20-7.16 (1H, m), 7.06-6.96 (2H, m), 6.82-6.68 (1H, m), 5.04-4.6
2 (3H, m), 4.44-4.40 (1H, m), 4.26-4.14 (2H, m), 4.05-3.98 (1H, m), 3.90-3.81 (1H, m)
, 2.74-2.46 (2H, m), 2.24-2.12 (1H, m), 1.97-1.83 (2H, m), 1.30-1.26 (3H, m).

(Example 186)
Ethyl (2R, 3R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis ((1R) -1,2-dihydroxyethyl) -1,4-dioxaspiro
[4.5] Dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplary Compound No. 1-386)

Ethyl (2R, 3R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis ((1R) -1,2-dihydroxyethyl) -1 obtained in Example 23 4
-Dioxaspiro [4.5] dec-6-ene-7-carboxylate was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size: ID 2 cm, length 25 cm
, Solvent: hexane: 2-propanol), and the two optical isomers were separated and purified to obtain a low polar compound (first peak) and a high polar compound (second peak) as white amorphous. As a result of HPLC analysis of the obtained two optical isomers under the following conditions, their optical purity was> 99% ee, respectively.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 7: 3
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 7.3 minutes
High polarity compound (second peak): 9.9 minutes (low polarity compound, first peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.65 (1H, dd, J = 9Hz, 5Hz), 7.21 (1H, bs), 7.17 (1H, dd, J = 8Hz, 3Hz),
7.06-6.99 (1H, m), 6.80 (1H, s), 4.38 (1H, d, J = 5Hz), 4.27-4.12 (4H, m),
4.08 (2H, d, J = 7Hz), 3.95-3.88 (1H, m), 3.87-3.64 (5H, m), 2.98-2.68 (2H, m),
2.54-2.42 (2H, m), 2.22-2.08 (1H, m), 1.91-1.82 (1H, m), 1.25 (3H, t, J = 7Hz).
(High polarity compound, second peak)
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.63 (1H, dd, J = 9Hz, 5Hz), 7.15 (1H, bs), 7.12 (1H, dd, J = 8Hz, 3Hz),
7.05-6.97 (1H, m), 6.76 (1H, s), 4.37 (1H, d, J = 6Hz), 4.27-4.01 (5H, m),
3.97-3.86 (2H, m), 3.85-3.45 (5H, m), 2.77-2.57 (2H, m), 2.52-2.41 (2H, m),
2.21-2.08 (1H, m), 1.89-1.80 (1H, m), 1.26 (3H, t, J = 7Hz).

(Example 187)
Ethyl- (2R, 3R) -8- [N- (2-chloro-4-fluorophenyl) -N-methylsulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4. 5
] Deca-6-ene-7-carboxylate (Exemplified Compound No. 2-15)

Ethyl (2R, 3R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4] obtained in Example 17
. 5] 235 mg (0.49 mmol) of deca-6-ene-7-carboxylate was dissolved in 1.5 ml of acetone, 84 mg (0.59 mmol) of methyl iodide, 138 potassium carbonate
mg (1.00 mmol) was sequentially added and stirred at 50 ° C. for 3 hours. After filtering the reaction solution,
The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 1: 3) to give 175 mg of the title compound as a white amorphous (yield 73%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.57 (1H, brs), 7.22 (1H, dd, J = 8Hz, 3Hz), 7.05-7.00 (1H, m), 6.87 (0.5H, s), 6.79 (0
.5H, s), 4.58 (1H, brs), 4.28-3.73 (8H, m), 3.25 (3H, s), 2.60-1.80 (6H, m), 1.26 (3H
, t, J = 7Hz).

(Example 188)
Ethyl 8- [N- (4-fluoro-2-propylphenyl) sulfamoyl] -1,4
-Dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplary Compound No. 1
-2077)

According to the method described in Example (1d) using 4-fluoro-2-propylphenylamine obtained in Reference Example 27 instead of 2-chloro-4-fluoroaniline, the title compound was obtained as an oil. (Yield 84%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
8.09-8.07 (4H, m), 7.59-7.55 (2H, m), 7.47-7.43 (4H, m), 7.47-7.43 (2H, m), 3.96 (2H,
s), 2.00-1.79 (4H, m), 1.02 (6H, t, J = 7 Hz), 0.07 (18H, s).

(Example 189)
Ethyl (2S, 3S) -8- [N- (4-fluoro-2-propylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6
-Ene-7-carboxylate (Exemplified Compound No. 1-2095)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 188 instead of -[N- (4-fluoro-2-propylphenyl) sulfamoyl] -1,
Example 7, using 4-dioxaspiro [4.5] dec-6-ene-7-carboxylate
The title compound was obtained as a white amorphous according to the method described in (16a) and 18 (alternative method) (yield 38%). This compound could be separated into two optical isomers under the following HPLC conditions.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 4: 1
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: Low polarity compound (first peak): 9.6 minutes
High polarity compound (second peak): 14.1 min
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.51-7.47 (1H, m), 6.97-6.88 (3H, m), 6.70 (0.5H, s), 6.64 (0.5H, s), 4.42-4.39 (1H,
m), 4.28-3.72 (8H, m), 2.75-2.61 (2H, m), 2.52-2.37 (2H, m), 2.19-1.87 (4H, m), 1.68
-1.57 (2H, m), 1.32-1.28 (3H, m), 0.99 (3H, t, J = 8Hz).

(Example 190)
Ethyl (2R, 3R) -2,3-bis ((1R) -1,2-dihydroxyethyl) -8
-[N- (4-Fluoro-2-pentylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified Compound No. 1-1748)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate instead of ethyl 8 obtained in Example 86 -[N- (4-Fluoro-2-pentylphenyl) sulfamoyl] -1,4
Example 7 using dioxaspiro [4.5] dec-6-ene-7-carboxylate, (
The title compound was obtained as a white powder according to the methods described in 16a) and 23 (yield 33
%). This compound could be separated into two optical isomers under the following HPLC conditions.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 7: 3
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: low polarity compound (first peak): 5.29 minutes
High polarity compound (second peak): 5.82 min
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49-7.44 (1H, m), 6.97-6.86 (2H, m), 6.84 (0.5H, m), 6.82 (0.5H, m),
6.73 (0.5H, s), 6.69 (0.5H, s), 4.41-4.36 (1H, m), 4.27-4.17 (2H, m),
4.12-4.01 (1.5H, m), 3.97-3.88 (1.5H, m), 3.88-3.67 (5H, m),
2.77-2.60 (2H, m), 2.50-2.30 (2H, m), 2.20-1.40 (8H, m), 1.39-1.25 (7H, m),
0.93-0.86 (3H, m).

(Example 191)
Ethyl (2S, 3S) -8- [N- (4-fluoro-2-methylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-
En-7-carboxylate (Exemplified Compound No. 1-2359)

Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate The ethyl 8 obtained in Example 79 -[N- (4-Fluoro-2-methylphenyl) sulfamoyl] -1,4-
Example 7, (1) using dioxaspiro [4.5] dec-6-ene-7-carboxylate
According to the method described in 6a) and 18 (alternative method), the title compound was obtained as an amorphous substance (yield 49%). This compound could be separated into two optical isomers under the following HPLC conditions.
HPLC conditions Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)
(Inner diameter 0.46cm, length 25cm)
Mobile phase: Hexane: 2-propanol = 4: 1
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection: 254 nm (UV)
Retention time: low polarity compound (first peak): 13.5 minutes
High polarity compound (second peak): 19.6 minutes
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.49 (1H, dd, J = 8.8Hz, 5.3Hz), 6.96-6.88 (3H, m), 6.70 (0.5H, brs), 6.64 (0.5H, brs)
, 4.40-4.37 (1H, m), 4.28-3.70 (8H, m), 2.51-2.32 (5H, m), 2.21-1.87 (2H, m), 1.31-1
.27 (3H, m).
(Reference Example 1)
1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-meso-erythritol 1,4-di-O-benzoyl-meso-erythritol (J. Am. Chem. Soc., 82, 2585 ( 1960)
300 mg (0.90 mmol), triethylamine 0.28 ml (1
. 98 mmol) and 11 mg (0.09 mmol) of 4-dimethylaminopyridine were dissolved in 6 ml of dichloromethane, and 0.24 ml (0.14 ml) of trimethylsilyl chloride was stirred with ice cooling.
1.89 mmol) was added and stirred at the same temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate.
Concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate only) to obtain 418 mg of the title compound as a white powder (yield 98%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
8.04 (4H, d, J = 7Hz), 7.55 (2H, t, J = 7Hz), 7.43 (4H, t, J = 7Hz),
4.53 (2H, dd, J = 12Hz, J = 3Hz), 4.36 (2H, dd, J = 12Hz, 5Hz), 4.13-4.08 (2H, m)
0.13 (18H, s).

(Reference Example 2)
1, 3, 4, 5, 7-penta-O-trimethylsilyl-D-arabitol According to the method described in Reference Example 1 using D-arabitol instead of 1,4-di-O-benzoyl-meso-erythritol To give the title compound as a colorless oil (yield 26%).
.
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
3.84-3.80 (1H, m), 3.76-3.68 (3H, m), 3.63-3.54 (2H, m),
3.49 (1H, dd, J = 10Hz, J = 7Hz), 0.14-0.09 (45H, m).

(Reference Example 3)
1,6-di-O-benzoyl-2,3,4,5-tetra-O-trimethylsilyl-D-mannitol 1,6-di-O instead of 1,4-di-O-benzoyl-meso-erythritol According to the method described in Reference Example 1 using -benzoyl-D-mannitol, the title compound was obtained as a pale brown oil (yield 98%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
8.05 (4H, d, J = 7Hz), 7.55 (2H, t, J = 7Hz), 7.43 (4H, t, J = 7Hz),
4.59 (2H, dd, J = 12Hz, 2Hz), 4.38-4.31 (2H, m), 4.24-4.20 (2H, m),
3.83 (2H, br.s), 0.17 (18H, s), 0.11 (18H, s).

(Reference Example 4)
2-trimethylsilyloxy-1-trimethylsilyloxymethylethyl adamantane-1-carboxylate (4a) 2-phenyl [1.3] dioxan-5-yl adamantane-1-carboxylate 2-phenyl [1.3] dioxan-5 -1.00 g (5.55 mmol) of all, 1.16 ml (8.32 mmol) of triethylamine and 68 m of 4-dimethylaminopyridine
g (0.56 mmol) was dissolved in 20 ml of dichloromethane, and 1.28 g (6.10 mmol) of 1-adamantanecarbonyl chloride was added with stirring under ice cooling, followed by stirring at the same temperature for 30 minutes and further at room temperature for 15 hours. Dichloromethane was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:
Ethyl acetate = 9: 1) gave 1.52 g of the title compound as a pale yellow powder (yield 80%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.52-7.48 (2H, m), 7.42-7.33 (3H, m), 5.54 (1H, s), 4.68-4.66 (1H, m),
4.26-4.22 (2H, m), 4.18-4.13 (2H, m), 2.07-2.01 (3H, m), 2.01-1.97 (6H, m),
1.77-1.69 (6H, m).

(4b) 2-hydroxy-1-hydroxymethylethyl adamantane-1-carboxylate 400 mg (1.17 mmol) of 2-phenyl [1.3] dioxan-5-yl adamantane-1-carboxylate obtained in (4a) Dissolve in 8 ml of ethyl acetate and add 20
400 mg of% palladium hydroxide-carbon (containing 50% water) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to obtain 294 mg of the title compound as a white powder (yield 99%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.90-4.85 (1H, m), 3.84-3.76 (4H, m), 2.16-2.00 (5H, m),
1.94-1.87 (6H, m), 1.78-1.67 (6H, m).

(4c) 2-Trimethylsilyloxy-1-trimethylsilyloxymethylethyl adamantane-1-carboxylate 2-hydroxy-1-hydroxymethyl obtained in (4b) instead of 1,4-di-O-benzoyl-meso-erythritol The title compound was obtained as a colorless oil according to the method described in Reference Example 1 using ethyl adamantane-1-carboxylate (yield 70%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.85-4.79 (1H, m), 3.72-3.61 (4H, m), 2.04-1.97 (3H, m),
1.92-1.83 (6H, m), 1.76-1.65 (6H, m), 0.11 (18H, s).

(Reference Example 5)
Diethyl 2,2-bis [(trimethylsilyl) oxy] methyl malonate Described in Reference Example 1 using diethyl 2,2-bis (hydroxymethyl) malonate instead of 1,4-di-O-benzoyl-meso-erythritol According to the above method, the title compound was obtained as a colorless oil (yield 75%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.17 (4H, q, J = 7Hz), 4.04 (4H, s), 1.23 (6H, t, J = 7Hz), 0.07 (18H, s).

(Reference Example 6)
2-Pentyl-1H-pyrrol-1-ylamine (6a) (2E) -4-oxo-2-nonenal 2-Pentylfuran 2.0 g (14.47 mmol) was dissolved in 60 ml of dichloromethane and stirred under ice-cooling. 3.84 g (14.47 mmol) of% m-chloroperbenzoic acid was added in small portions and stirred at the same temperature for 1 hour. A saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1.62 g of the title compound as a yellow oil (yield 73%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
10.23 (1H, d, J = 7Hz), 6.95 (1H, d, J = 12Hz), 6.18 (1H, dd, J = 12Hz, 7Hz),
2.26 (2H, t, J = 7Hz), 1.73-1.61 (2H, m), 1.40-1.26 (4H, m), 0.91 (3H, t, J = 6Hz).

(6b) 4-Oxononanal (2E) -4-oxo-2-nonenal obtained in (6a) 1.62 g (10.5 mmol)
) Was dissolved in 30 ml of ethyl acetate, and 10% palladium-carbon (containing 50% water) 160 was added thereto.
mg was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to obtain 1.50 g of the title compound as a pale yellow oil (yield 91%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
9.81 (1H, s), 2.81-2.67 (4H, m), 2.47 (2H, t, J = 7HZ), 1.67-1.53 (2H, m),
1.38-1.21 (4H, m), 0.89 (3H, t, J = 7Hz).

(6c) Benzyl 2-pentyl-1H-pyrrol-1-ylcarbamate 1.50 g (9.60 mmol) of 4-oxononanal obtained in (6b) was added to ethanol-
Dissolve in 45 ml of a mixture of acetic acid (2: 1) and add benzyl hydrazinecarboxylate
60 g (9.60 mmol) was added and stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 2: 1) to give 2.12 g of the title compound as a yellow oil (yield 77%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.36 (5H, bs), 7.21 (1H, ds), 6.63-6.59 (1H, m), 6.07 (1H, t, J = 4Hz),
5.89-5.84 (1H, m), 5.22 (2H, ds), 2.46-2.36 (2H, m), 1.63-1.49 (2H, m),
1.37-1.22 (4H, m), 0.88 (3H, t, J = 7Hz).

(6d) 2-pentyl-1H-pyrrol-1-amine benzyl 2-pentyl-1H-pyrrol-1-ylcarbamate obtained in (6c)
0 g (3.49 mmol) was dissolved in 20 ml of ethanol, 100 mg of 10% palladium-carbon (containing 50% water) was added thereto, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane:
(Ethyl acetate = 2: 1) to give 430 mg of the title compound as a yellow oil (yield 81%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
6.68 (1H, m), 5.97 (1H, t, J = 3Hz), 5.82-5.77 (1H, m), 4.52 (2H, s), 2.58 (2H, t,
J = 8Hz),
1.69-1.57 (2H, m), 1.44-1.31 (4H, m), 0.91 (3H, t, J = 7Hz).

Reference Example 7 2-hexyl-1H-pyrrol-1-ylamine 2-hexylfuran instead of 2-pentylfuran In accordance with the method described in Reference Example 6 and the title compound as a yellow oil Obtained (yield 29%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
6.67-6.63 (1H, m), 5.99-5.94 (1H, m), 5.81-5.77 (1H, m), 4.52 (2H, br.s),
2.62-2.55 (2H, m), 1.67-1.56 (2H, m), 1.44-1.21 (6H, m), 0.89 (3H, t, J = 7Hz).

(Reference Example 8)
2-Heptyl-1H-pyrrol-1-ylamine The title compound was obtained as a pale yellow solid according to the method described in Reference Example 6 using 2-heptylfuran as a starting material instead of 2-pentylfuran (yield) 59%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
6.67-6.63 (1H, m), 5.99-5.94 (1H, m), 5.81-5.77 (1H, m), 4.52 (2H, br.s),
2.62-2.55 (2H, m), 1.67-1.53 (2H, m), 1.44-1.21 (8H, m), 0.89 (3H, t, J = 7Hz).

(Reference Example 9)
2-Octyl-1H-pyrrol-1-ylamine 2-octylfuran was used instead of 2-pentylfuran as a starting material, and the title compound was obtained as a yellow oil according to the method described in Reference Example 6 (yield) 11%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
6.65-6.61 (1H, m), 5.97-5.93 (1H, m), 5.78-5.75 (1H, m), 4.51 (2H, br.s),
2.60-2.55 (2H, m), 1.66-1.54 (2H, m), 1.42-1.21 (10H, m), 0.88 (3H, t, J = 7Hz).

(Reference Example 10)
2-Cyclopropyl-1H-pyrrol-1-ylamine (10a) 4-cyclopropyl-4-oxobutanal 230 mg (1.79 mmol) 1-cyclopropyl-4-hydroxy-1-butanone
Is dissolved in dichloromethane (7 ml), and stirred with ice cooling, pyridinium chlorochromate (580 mg).
(2.69 mmol) was added and stirred at room temperature for 1 hour. Diethyl ether was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; diethyl ether only) to obtain 176 mg of the title compound as a pale yellow oil (yield 78%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
9.78 (1H, s), 2.91 (2H, t, J = 7Hz), 2.78-2.71 (2H, m), 2.01-1.93 (1H, m),
1.08-1.01 (2H, m), 0.96-0.88 (2H, m).

(10b) 2-cyclopropyl-1H-pyrrol-1-ylamine 4-cyclopropyl-4-oxobutanal obtained in (10a) instead of 4-oxononanal was used as reference examples (6c) and (6d). According to the method described, the title compound was obtained as a pale yellow oil (yield 45%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
6.70-6.64 (1H, m), 5.94-5.88 (1H, m), 5.71-5.64 (1H, m), 4.69 (2H, br.s),
1.83-1.72 (1H, m), 0.91-0.83 (2H, m), 0.64-0.57 (2H, m).

(Reference Example 11)
4-fluoro-2-heptylphenylamine (11a) 4-fluoro-2- (hept-1-enyl) -1-nitrobenzenehexyltriphenylphosphonium bromide (3.0 g, 7.0 mmol) was suspended in 30 ml of tetrahydrofuran; N-Butyllithium / hexane solution (1.56M at 10 ° C.
) 4.5 ml (7.0 mmol) was added dropwise. After stirring for 10 minutes at the same temperature, 846 mg (5.0 mmol) of 4-fluoro-2-nitrobenzaldehyde was added, and the mixture was further stirred for 1 hour. A 1N aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 19: 1) to obtain 917 mg of the title compound as a pale yellow oil (yield 77%).
).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
8.09 (1.7H, dd, J = 9Hz, 5Hz), 7.97 (1H, dd, J = 9Hz, 5Hz), 7.26-6.99 (5.4H, m), 6.89 (1
H, d, J = 16Hz), 6.69 (1.7H, d, J = 11Hz), 6.26 (1H, dt, J = 16Hz, 7Hz), 5.87 (1.7H, dt,
J = 12Hz, 8Hz), 2.28 (2H, q, J = 7Hz), 2.10 (3.4H, q, J = 7Hz), 1.52-1.23 (16.2H, m), 0.9
1 (3H, m), 0.86 (5.1H, m).

(11b) 4-Fluoro-2- (hept-1-enyl) -1-nitrobenzene 9 obtained from 4-fluoro-2-heptylphenylamine (11a)
10 mg (3.8 mmol) was dissolved in 5 ml of ethanol, 100 mg of 10% palladium-carbon (containing 50% water) was added thereto, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane:
Ethyl acetate = 9: 1) afforded 730 mg of the title compound as a pale yellow oil (91% yield).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
6.80-6.71 (2H, m), 6.61 (1H, dd, J = 9Hz, 5Hz), 3.47 (2H, brs), 2.45 (2H, t, J = 7Hz), 1
.64-1.58 (2H, m), 1.42-1.24 (8H, m), 0.89 (3H, t, J = 6Hz).

(Reference Example 12)
According to the method described in Reference Example 11 using propyltriphenylphosphonium bromide instead of 2-butyl-4-fluorophenylamine hexyltriphenylphosphonium bromide, the title compound was obtained as a brown oil (yield 78 %).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
6.80-6.69 (2H, m), 6.60 (1H, dd ,, J = 9Hz, 5Hz), 3.51 (2H, bs),
2.46 (2H, t, J = 8Hz), 1.63-1.56 (2H, m), 1.45-1.37 (2H, m), 0.96 (3H, t, J = 7Hz).

(Reference Example 13)
The title compound was obtained as a yellow oil according to the method described in Reference Example 11 using butyltriphenylphosphonium bromide instead of 4-fluoro-2-pentylphenylamine hexyltriphenylphosphonium bromide (yield 78 %).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
6.80-6.69 (2H, m), 6.60 (1H, dd ,, J = 9Hz, 5Hz), 3.50 (2H, bs),
2.45 (2H, t, J = 8Hz), 1.64-1.58 (2H, m), 1.45-1.36 (4H, m), 0.91 (3H, t, J = 7Hz).

(Reference Example 14)
4-Fluoro-2-hexylphenylamine By using pentyltriphenylphosphonium bromide instead of hexyltriphenylphosphonium bromide, the title compound was obtained as a pale brown oil according to the method described in Reference Example 11 (yield) 63%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
6.81-6.71 (2H, m), 6.66 (1H, dd, J = 9Hz, 5Hz), 4.19 (2H, brs), 2.48 (2H, t, J = 8Hz), 1
.65-1.57 (2H, m), 1.43-1.25 (6H, m), 0.92-0.85 (3H, m).

(Reference Example 15)
The title compound was obtained as a pale yellow oil according to the method described in Reference Example 11 using heptyltriphenylphosphonium bromide instead of 4-fluoro-2-octylphenylamine hexyltriphenylphosphonium bromide (yield) 65%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
6.80-6.71 (2H, m), 6.61 (1H, dd, J = 9Hz, 5Hz), 2.45 (2H, t, J = 7Hz), 1.64-1.56 (2H, m)
, 1.38-1.22 (10H, m), 0.88 (3H, t, J = 7Hz).

(Reference Example 16)
According to the method described in Reference Example 11 using octyltriphenylphosphonium bromide instead of 4-fluoro-2-nonylphenylamine hexyltriphenylphosphonium bromide, the title compound was obtained as a pale brown oil (yield) 97%).
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
6.77 (1H, dd, J = 10Hz, 3Hz), 6.72 (1H, td, J = 8Hz, 3Hz), 6.59 (1H, dd, J = 9Hz, 5Hz)
,
3.46 (2H, brs), 2.45 (2H, t, J = 8Hz), 1.64-1.56 (2H, m), 1.44-1.21 (12H, m),
0.88 (3H, t, J = 7Hz).

(Reference Example 17)
According to the method described in Reference Example 11 using nonyltriphenylphosphonium bromide instead of 2-decyl-4-fluorophenylamine hexyltriphenylphosphonium bromide, the title compound was obtained as a pale brown oil (yield) 67%).
¹ H-nuclear magnetic resonance spectrum (500 MHz, CDCl ₃ ) δ ppm:
6.77 (1H, dd, J = 10Hz, 3Hz), 6.73 (1H, dd, J = 8Hz, 3Hz), 6.60 (1H, dd, J = 9Hz, 5Hz)
,
3.47 (2H, brs), 2.45 (2H, t, J = 8Hz), 1.64-1.56 (2H, m), 1.43-1.21 (14H, m),
0.88 (3H, t, J = 7Hz).

(Reference Example 18)
1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol 17.48 g (52.9 mmol) of 1,4-di-O-benzoyl-D-threitol and imidazole 8 g (159 mmol) was dissolved in 250 ml of dichloromethane, and 12.6 g (116 mmol) of chlorotrimethylsilane was added with stirring under ice cooling, followed by stirring at room temperature for 1 hour. The reaction solution was directly subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 20: 1 to 5: 1) to obtain 24.59 g of the title compound as a white powder (yield 98%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
8.04 (4H, dd, J = 8Hz, J = 1Hz), 7.57-7.52 (2H, m), 7.46-7.40 (4H, m), 4.50 (2H, dd,
J = 11Hz, J = 4Hz), 4.48-4.33 (2H, m), 4.13-4.08 (2H, m), 0.14 (18H, s).

(Reference Example 19)
1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-L-threitol 1,4-di-O-benzoyl instead of 1,4-di-O-benzoyl-D-threitol The title compound was obtained as a white powder according to the method described in Reference Example 18 using -L-threitol (yield 98%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
8.04 (4H, dd, J = 8Hz, J = 1Hz), 7.57-7.52 (2H, m), 7.46-7.40 (4H, m), 4.50 (2H, dd,
J = 11Hz, J = 4Hz), 4.48-4.33 (2H, m), 4.13-4.08 (2H, m), 0.14 (18H, s).

(Reference Example 20)
Methyl (S) -3,4-bis [(trimethylsilyl) oxy] butyrate Reference using methyl (S) -3,4-dihydroxybutyrate instead of 1,4-di-O-benzoyl-D-threitol The title compound was obtained as an oil according to the method described in Example 18 (yield 62%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.18-4.12 (1H, m), 3.67 (3H, s), 3.52 (1H, dd, J = 10Hz, 6Hz), 3.40 (1H, dd, J = 10Hz, 6
Hz), 2.59 (1H, dd, J = 15Hz, 5Hz), 2.37 (1H, dd, J = 15Hz, 7Hz), 0.10 (18H, s).

(Reference Example 21)
1,4-Anhydro-2,3-di-O-trimethylsilyl-meso-erythritol Described in Reference Example 1 using 1,4-anhydroerythritol instead of 1,4-di-O-benzoyl-meso-erythritol According to the above method, the title compound was obtained as a colorless oil (yield 21%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.15-4.10 (2H, m), 3.92-3.85 (2H, m), 3.68-3.62 (2H, m), 0.14 (18H, s).

(Reference Example 22)
3-ethyl-3,4-bis [(trimethylsilyl) oxy] hexane (22a) 3-ethylhexane-3,4-diol 590 mg (5.0 mmol) of dimethyl oxalate was dissolved in 20 ml of tetrahydrofuran, and the mixture was stirred under ice-cooling. 1.0M ethylmagnesium bromide / tetrahydrofuran solution 2
2 ml (22 mmol) was added and stirred at the same temperature for 2 hours. 1N Hydrochloric acid was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. After washing the organic layer with water and drying over anhydrous magnesium sulfate,
Concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 3: 1) to obtain 276 mg of the title compound as an oil (yield 38%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
3.45-3.41 (1H, m), 1.87 (1H, d, J = 6Hz), 1.75 (1H, s), 1.70-1.31 (6H, m), 1.04 (3H, t,
J = 7Hz), 0.89 (3H, t, J = 8Hz), 0.89 (3H, t, J = 8Hz).

(22b) 3-ethyl-3,4-bis [(trimethylsilyl) oxy] hexane (22a) 3-ethylhexane-3,4-diol 270 mg (1.85 mmol)
l) was dissolved in 5 ml of pyridine, and 1,1,1,3,3,3-hexamethylsilazane 597 mg (3.7 mmol) and chlorotrimethylsilane 1.20 g (11 mmol) were stirred under ice cooling.
l) was added successively, and the mixture was stirred at the same temperature for 2 hours and further at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 9: 1) to obtain 469 mg of the title compound as an oil (yield 88%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
3.38 (1H, dd, J = 9.0Hz, 3.0Hz), 1.68-1.33 (6H, m), 0.90 (3H, t, J = 6.0Hz), 0.92-0.90 (
6H, m), 0.11-0.08 (18H, m).

(Reference Example 23)
Instead of (R) -1,2-bis [(trimethylsilyl) oxy] -1,1,2-triphenylethane 1,4-di-O-benzoyl-D-threitol, (R) -1,1, The title compound was obtained as a powder using 2-triphenyl-1,2-ethanediol according to the method described in Reference Example 18 (yield 99%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
7.28-7.18 (15H, m), 5.51 (1H, s), -0.05 (9H, s), -0.16 (9H, s).

(Reference Example 24)
1,4-di-O-acetyl-2,3-di-O-trimethylsilyl-D-threitol 1,4-di-O-acetyl instead of 1,4-di-O-benzoyl-D-threitol −D
-The title compound was obtained as an oily substance according to the method described in Reference Example 18 using threitol (yield 96%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
4.20 (2H, dd, J = 11Hz, 4Hz), 4.01 (2H, dd, J = 11Hz, 7Hz), 3.88-3.84 (2H, m), 2.06 (6H,
s), 0.13 (18H, s).

(Reference Example 25)
(1R, 2R, 3R, 4R) -4-benzoyloxy-1-methyl-2,3-bis [(trimethylsilyl) oxy] pentyl benzoate instead of 1,4-di-O-benzoyl-D-threitol ( 1R, 2S, 3S, 4R) -4
-The title compound was obtained as an oil according to the method described in Reference Example 18 using benzoyloxy-2,3-dihydroxy-1-methylpentyl benzoate (yield 86%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
8.06-8.04 (4H, m), 7.57-7.54 (2H, m), 7.46-7.42 (4H, m), 5.31-5.25 (2H, m), 3.98-3.9
7 (2H, m), 1.41 (6H, d, J = 6Hz), 0.12 (18H, s).

(Reference Example 26)
(1R, 2R, 3R, 4R) -4-benzoyloxy-1-ethyl-2,3-bis [(trimethylsilyl) oxy] hexyl benzoate instead of 1,4-di-O-benzoyl-D-threitol ( 1R, 2S, 3S, 4R) -4
-The title compound was obtained as an oily substance according to the method described in Reference Example 18 using benzoyloxy-1-ethyl-2,3-dihydroxyhexyl benzoate (yield 82%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
8.09-8.07 (4H, m), 7.59-7.55 (2H, m), 7.47-7.43 (4H, m), 7.47-7.43 (2H, m), 3.96 (2H,
s), 2.00-1.79 (4H, m), 1.02 (6H, t, J = 7 Hz), 0.07 (18H, s).

(Reference Example 27)
According to the method described in Reference Example 11 using ethyltriphenylphosphonium bromide instead of 4-fluoro-2-propylphenylamine hexyltriphenylphosphonium bromide, the title compound was obtained as a pale yellow oil (yield) 17%).
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
6.80-6.59 (3H, m), 3.48 (2H, brs), 2.45 (2H, t, J = 7Hz), 1.70-1.58 (2H, m), 1.01 (3H,
t, J = 8Hz).

<Formulation example>
(Formulation Example 1) Injection 1.5% by weight of the compound of Example 162 was stirred in 10% by volume of propylene glycol, then adjusted to a constant volume with water for injection, and then sterilized to give an injection. .

(Formulation Example 2) Injection 1.5% by weight of the compound of Example 163 is stirred in 10% by volume of propylene glycol, adjusted to a constant volume with water for injection, and then sterilized to give an injection. .

Formulation Example 3 Injection Injection of 1.5% by weight of the compound of Example 166 in 10% by volume lactose or mannitol, then adjusted to a constant volume with water for injection, then filled into a vial, Injectable by freeze-drying.

(Formulation Example 4) Injection 1.5% by weight of the compound of Example 167 is stirred in 10% by volume of propylene glycol, adjusted to a constant volume with water for injection, and then sterilized to give an injection. .

Formulation Example 5 Powder A powder is obtained by mixing 5 g of the compound of Example 169, 895 g of lactose and 100 g of corn starch with a blender.

(Formulation Example 6) Granules After mixing 5 g of the compound of Example 171, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of a 10% hydroxypropylcellulose aqueous solution is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.

(Formulation Example 7) Capsules After mixing 5 g of the compound of Example 173, 115 g of lactose, 58 g of corn starch and 2 g of magnesium stearate using a V-type mixer, No. 3 capsules are filled 180 mg each to obtain a capsule. .

(Formulation Example 8) Tablet 5 g of the compound of Example 190, lactose 90 g, corn starch 34 g, crystalline cellulose 20 g and magnesium stearate 1 g are mixed with a blender and then tableted to obtain a tablet.

<Test example>
(Test Example 1) Inhibitory effect on TNF-α production of cells by endotoxin stimulation (in
vitro)
The inhibition rate of the compound of the present invention against TNF-α production when endotoxin stimulation was performed on the human monocyte cell line U937 was measured. That is, 12-O-tetradecanoylphorbol 13-acetate was added to an RPMI1640 medium containing 10% (volume%) of inactivated neonatal calf serum to a final concentration of 30 ng / ml. U937 cells were suspended in the medium, seeded in a 96-well culture plate (Sumilon) so that the number / volume of cells per well was 2 × 10 ⁴ cells / 0.1 ml, and 5% CO at 37 ° C. _{2. The} cells were cultured for 3 days in a 100% humidity carbon dioxide incubator. After completion of the culture, the culture supernatant was removed. Various concentrations of the compound of the present invention were added to each well, and lipopolysaccharide (LPS) (E. coli 0111: B4, Sigma) was added to a final concentration of 30 ng / ml. After culturing the culture plate again in a carbon dioxide incubator for 4.5 hours, the culture supernatant was recovered. The TNF-α concentration in the culture supernatant was measured as a time-resolved fluorescence with Discovery (Packard) using a 384 half-hole black plate (Gliner) and an HTRF quantification kit manufactured by Sis Bio International. From the measured value (X) in the absence of LPS, the measured value (Y) in the absence of the compound of the present invention, and the measured value (Z) in the presence of the compound of the present invention, the following calculation formula [I] was used. Thus, the inhibition rate of TNF-α production was determined.
(Equation 1)
TNF-α production inhibition rate (%) = {1− (Z−X) / (Y−X)} × 100 [I]
(Table 4)
<TNF-α production inhibitory effect (in vitro)>
Test compound TNF-α production inhibition rate [%]
(Test compound concentration 100 nM)
Low Polarity Compound of Example 162 87
Low Polarity Compound of Example 163 96
Low Polarity Compound of Example 166 100
Low Polarity Compound of Example 167 98
Low Polarity Compound of Example 168 109
Low Polarity Compound of Example 169 104
Low Polarity Compound of Example 170 95
Low Polarity Compound of Example 171 102
Low Polarity Compound of Example 172 100
Low Polarity Compound of Example 173 105
In this test, the compound of the present invention showed an excellent inhibitory effect on TNF-α production of cells by endotoxin stimulation.

(Test Example 2) Inhibitory effect on increase in blood TNF-α concentration (in vivo)
The inhibitory effect of the compound of the present invention on the increase in blood TNF-α concentration was examined. Blood TNF-
The α concentration increase test was performed in Journal of Leukocyte Biology, 47th.
The method was carried out in accordance with the method of Parant et al. Described in Vol., Item 164 (1990).

For the test, male Sprague Dawley rats (8-9 weeks old) were used as 3-4 animals per group.

1 mg of muramyl dipeptide (1 mg / ml) dissolved in physiological saline 4 hours before LPS administration
It was administered from the tail vein at a rate of ml / kg. Anesthetized with pentobarbital (40 mg / kg) 0.5 hours before LPS administration, the compound of the present invention dissolved in 5% dimethylacetamide / 95% polyethylene glycol 400 solution was administered at a rate of 1 ml / kg from the right femoral vein. . In the control group, 5% dimethylacetamide / 95% polyethylene glycol 400 solution was administered at a rate of 1 ml / kg. 1 ml of LPS (3 μg / ml) dissolved in physiological saline
/ Kg was administered from the left femoral vein. 3.8% as an anticoagulant 2 hours after LPS administration
(W / v) Blood was collected using a sodium citrate solution and centrifuged (10,000 g, 5 minutes, 4 minutes
Plasma was separated by Plasma TNF-α concentration was measured using a TNF-α quantification kit (Biosource International). Blood TNF-α concentration in the control group (X)
From the blood TNF-α concentration (Y) of the group administered with the compound of the present invention, the TNF-α production inhibition rate was determined using the following calculation formula [II].
(Equation 2)
TNF-α production inhibition rate (%) = {1-Y / X} × 100 [II]
(Table 5)
<TNF-α production inhibitory effect (in vivo)>
Test compound TNF-α production inhibition rate [%]
(Test compound concentration 0.3 mg / kg)
Low polarity compound of example 162 97
Low Polarity Compound of Example 163 100
Low Polarity Compound of Example 166 95
Low Polarity Compound of Example 167 97
Low Polarity Compound of Example 169 92
Low Polarity Compound of Example 170 95
Low Polarity Compound of Example 172 97
Low Polarity Compound of Example 173 97
Low Polarity Compound of Example 196 68
In this test, the compound of the present invention showed an excellent inhibitory effect on the increase in blood TNF-α concentration.

Claims (26)

Formula (I)


{Where,
X and Y represent a group that forms ring A together with the carbon atom of ring B to which they are bonded, or X and Y together represent a substituent of ring B, or X And Y each represents a hydrogen atom.

(1) When X and Y represent a group that forms a ring A together with a carbon atom of the ring B:
Ring A is
3- to 7-membered heterocyclyl ring [wherein X and Y are each independently a carbon atom, a group having the formula NR, wherein R is a hydrogen atom or a group selected from substituent group α. C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆
Alkynyl group, or _a C 1 -C ₆ alkanoyl group. ), Oxygen atom, sulfur atom,
Indicates any one selected from the group having the group and the formula SO ₂ having the formula SO,
The heterocyclyl ring may contain an unsaturated bond,
A 3- to 7-membered heterocyclyl ring or a 3- to 7-membered cycloalkyl ring may form a condensed ring or a spiro ring,
Ring A includes condensed ring and spiro ring, oxo group, thioxo group, substituent group α, cyclopropyl C
₁ -C ₆ alkyl group,
A C ₁ -C ₆ alkyl group optionally substituted with a group selected from 1 to 5 substituent groups α,
A C ₂ -C ₆ alkenyl group optionally substituted with a group selected from 1 to 5 substituent groups α, and a group selected from 1 to 5 substituent groups α. good _C 2 -C be
_It may be substituted by the same or different 1 to 4 groups selected from the group consisting of ₆ alkynyl groups. ]
Or

3- to 7-membered cycloalkyl ring (the cycloalkyl ring may contain an unsaturated bond,
A 3- to 7-membered heterocyclyl ring or a 3- to 7-membered cycloalkyl ring may form a condensed ring or a spiro ring,
Ring A includes a condensed ring and a spiro ring, a substituent group α, a cyclopropyl C ₁ -C ₆ alkyl group,
A C ₁ -C ₆ alkyl group optionally substituted with a group selected from 1 to 5 substituent groups α,
A C ₂ -C ₆ alkenyl group optionally substituted with a group selected from 1 to 5 substituent groups α, and
1 to 5 substituents selected from the group consisting of C ₂ -C ₆ alkynyl groups which may be substituted with a group selected from a substituent group α and substituted with 1 to 4 groups which are the same or different. May be. ).

(2) When X and Y together represent a substituent of ring B:
X and Y each represents an oxo group or a thioxo group.

l and m each independently represent an integer of 0 to 3,
l + m is 1 to 3.

R ¹ is
An aliphatic hydrocarbon group which may be substituted with a group selected from substituent group β and substituent group γ (the aliphatic hydrocarbon group is a C ₁ -C ₂₀ alkyl group, C ₃ -C ₁₀ cycloalkyl group) Group, C
₄ -C ₁₂ cycloalkylalkyl _group, C 3 -C ₆ alkenyl or _C 3 -C ₆ alkynyl group),
A phenyl group optionally substituted with a group selected from substituent group δ,
A group having the formula OR ⁴ (wherein R ⁴ represents a hydrogen atom or an aliphatic hydrocarbon group which may be substituted with a group selected from the substituent group β and the substituent group γ. Group hydrocarbon group is
The meaning is the same as above. ) Or a halogen atom.

n represents an integer of 0 to 3.

R ² is a hydrogen atom,
A C ₁ -C ₆ alkyl group optionally substituted with a group selected from substituent group β,
A C ₂ -C ₆ alkenyl group which may be substituted with a group selected from substituent group β, or a C ₂ -C ₆ alkynyl group which may be substituted with a group selected from substituent group β .

R ³ is
A phenyl group optionally substituted with a group selected from substituent group ε, or a 5- to 6-membered heteroaryl group optionally substituted with a group selected from substituent group ε (the heteroaryl group is 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom).

R ⁵ represents a hydrogen atom,
A C ₁ -C ₆ alkyl group optionally substituted with a group selected from substituent group β,
A C ₂ -C ₆ alkenyl group which may be substituted with a group selected from substituent group β, or a C ₂ -C ₆ alkynyl group which may be substituted with a group selected from substituent group β .

However, when R ³ is a phenyl group which may be substituted with a group selected from the substituent group ε, X and Y represent the above (1) or (2).

Substituent group α is
Hydroxy group, a halogen _atom, C 1 -C ₆ alkoxy group, a halogeno _C 1 -C ₆ alkoxy group, a carboxy _group, C 1 -C ₆ alkoxy - carbonyl group;
C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₁ -C
_A carbamoyl group optionally substituted with a group selected from a ₆ alkanoyl group or a C ₂ -C ₆ alkenyl-carbonyl group;
And a group having the formula NR ⁶ R ⁷ .
R ⁶ and R ⁷ are each independently a hydrogen atom, C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₁ -C ₆ alkanoyl group, or C ₂ -C ₆ alkenyl - or shows a carbonyl group, or, together with the nitrogen atom to which R ⁶ and R ⁷ are attached form a heterocyclyl group.

Substituent group β is
Oxo group, hydroxy group, cyclopropyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, nitro group, halogen atom, cyano group, carboxy group, C ₁ -C ₁₀ alkoxy-carbonyl group, C ₁ -C ₆ alkanoyl _group, C 2 -C ₄ alkenyl - carbonyl group,
C ₂ -C ₆ alkanoyloxy _group, C 2 -C ₄ alkenyl - carbonyl group;
A carbamoyl group optionally substituted with a group selected from a C ₁ -C ₄ alkyl group, a phenyl group, a C ₁ -C ₇ acyl group and a C ₁ -C ₄ alkoxy-phenyl group;
C ₁ -C ₄ alkyl group or an optionally substituted thiocarbamoyl group in a phenyl group,
C ₁ -C ₄ alkyl group or an optionally substituted carbamoyloxy group with a phenyl group,
C ₁ -C ₆ alkanoylamino group, C ₁ -C ₁₀ alkoxy-carboxamide group, C _1-
C ₁₀ alkoxy - shows a carbonyl group, and C ₁ -C ₄ alkyl group or a phenyl ureido group optionally substituted with a group.

Substituent group γ is
Heterocyclic _group, C 3 _{-C 10} cycloalkyl oxy _groups, C 6 _{-C 10} aryloxy groups, C
₇ -C ₁₉ aralkyloxy group, a heterocyclic oxy _group, C 3 _{-C 10} cycloalkyl-thio group,
C ₆ -C ₁₀ arylthio _group, C 7 _{-C 19} aralkylthio group, heterocyclic thio groups, heterocyclic sulfinyl groups, heterocyclic sulfonyl _group, C 3 -C ₆ cycloalkyl alkyloxy - group,
C ₆ -C ₁₀ aryloxy - carbonyl _group, C 7 _{-C 19} aralkyloxy - carbonyl group, a heterocyclic oxycarbonyl _group, C 6 _{-C 10} aryl - carbonyl _group, C 6 _{-C 10}
Aryl - carbonyl _group, C 6 _{-C 10} aryl - carbonyl amino _group, C 6 -C
₁₀ aryloxy-carboxamide group, C ₇ -C ₁₉ aralkyloxy-carboxamide group, C ₆ -C ₁₀ aryloxy-carbonyloxy group, C ₇ -C ₁₉ aralkyloxy-carbonyloxy group, C ₃ -C ₁₀ cycloalkyloxy -A carbonyloxy group and a C ₆ -C ₁₀ aryl group which may be substituted with a group selected from the substituent group β.

Substituent group δ is
Hydroxy group, nitro group, cyano group, halogen _atom, C 1 -C ₆ alkyl, halogeno C
₁ -C ₆ alkyl _group, C 1 -C ₆ alkoxy group, a halogeno _C 1 -C ₆ alkoxy group, a carboxy _group, C 1 -C ₆ alkanoyl _group, C 1 -C ₆ alkoxy - carbonyl _groups, C 1 -C
₆ alkanoylamino group, C ₁ -C ₆ alkylthio group, carbamoyl group, C ₁ -C ₆ alkyl-carbamoyl group, C ₁ -C ₆ alkoxy-carbonyl C ₁ -C ₆ alkyl-carbamoyl group, 1,3-diacylguanidino C ₁ -C ₆ alkyl group, the formula ^NR 6 group having ^{R 7 (R 6} and ^{R 7} have the same meanings as ^{R 6} and ^{R 7} in group substituents _α.), C 3 -C ₆ cycloalkyl group, It shows the C ₆ -C ₁₀ aryl group and 5-membered heteroaryl group.

Substituent group ε is
Hydroxy group, nitro group, cyano group, halogen _atom, C 1 _{-C 14} alkyl group, cyclopropyl _C 1 _{-C 14} alkyl group, halogeno _C 1 _{-C 14} alkyl _group, C 1 _{-C 14} alkoxy group, a halogeno _{C 1} -C ₁₄ alkoxy group, a carboxy _group, C 1 _{-C 14} alkanoyl _groups, C 1 _{-C 14} alkoxy - carbonyl _group, C 1 _{-C 14} alkanoylamino group, _{C 1}
-C ₁₄ alkylthio group, a carbamoyl _groups, C 1 _{-C 14} alkyl - carbamoyl groups, C
_1- C ₁₄ alkoxy-carbonyl C ₁ -C ₁₄ alkyl-carbamoyl group, 1,3-diacylguanidino C ₁ -C ₁₄ alkyl group, a group having the formula NR ⁶ R ⁷ (R ⁶ and R ⁷ are
It has the same meaning as R ⁶ and R ⁷ in the substituent group α. ), C ₃ -C ₆ cycloalkyl group, C ₆
—C _{10 represents an} aryl group and a 5-membered heteroaryl group. }
Or a pharmacologically acceptable salt thereof as an active ingredient.   The pharmaceutical composition according to claim 1, wherein l is 0 and m is an integer of 1 to 3.   The pharmaceutical composition according to claim 1, wherein l is 0 and m is 2. In any one selected from Claim 1 thru | or Claim 3,
X and Y together with the carbon atom of ring B form ring A, where ring A is

3- to 7-membered heterocyclyl ring [wherein X and Y are each independently a carbon atom, a group having the formula NR, wherein R is a hydrogen atom or a group selected from substituent group α. C ₁
-C ₆ alkyl _group, C 2 -C ₆ alkenyl _group, C 2 -C ₆ alkynyl group, or, _{C 1}
—C ₆ alkanoyl group. ), An oxygen atom, a sulfur atom, a group having the formula SO and the formula SO ₂
Any one selected from the group having
The heterocyclyl ring is a 5- to 6-membered heterocyclyl ring (the heterocyclyl ring contains 1 to 2 oxygen atoms and / or nitrogen atoms as heteroatoms) or a 5- to 6-membered cycloalkyl ring and a condensed or spiro ring. May form a ring,
Ring A is substituted with a group selected from an oxo group, a thioxo group, a substituent group α, a cyclopropyl C ₁ -C ₆ alkyl group, and 1 to 5 substituent groups α, including a condensed ring and a spiro ring. Optionally substituted by 1 to 4 groups identical or different selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl groups. ]

Or

3- to 7-membered saturated cycloalkyl ring (the 3- to 7-membered saturated cycloalkyl ring is a hydroxy group, a hydroxymethyl group, 1, 2,
-Substituted by 1 to 2 groups selected from the group consisting of a dihydroxyethyl group, a 1,2,3-trihydroxypropyl group, a 1,2,3,4-tetrahydroxybutyl group, and an acetylamino group It may be. )
A pharmaceutical composition. In any one selected from Claim 1 thru | or Claim 3,
X and Y represent a group that together with the carbon atom of ring B forms ring A,

A 3- to 7-membered heterocyclyl ring [wherein X and Y are each independently selected from a carbon atom, an oxygen atom, a sulfur atom, a group having the formula SO, and a group having the formula SO ₂ ; Show
The heterocyclyl ring is a 5- to 6-membered heterocyclyl ring (the heterocyclyl ring contains 1 to 2 oxygen atoms and / or nitrogen atoms as heteroatoms) or a 5- to 6-membered cycloalkyl ring and a condensed or spiro ring. May form a ring,
Ring A is a C ₁ -C ₆ alkyl optionally substituted with a group selected from an oxo group, a thioxo group, a substituent group α, and 1 to 4 substituent groups α, including a condensed ring and a spiro ring. It may be substituted with 1 to 4 groups which are the same or different and are selected from the group consisting of groups. ]

Or

3- to 5-membered saturated cycloalkyl ring (the 3- to 5-membered saturated cycloalkyl ring is a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-trihydroxypropyl group, 1,2,3,4 -It may be substituted by one or two groups selected from the group consisting of a tetrahydroxybutyl group and an acetylamino group.
A pharmaceutical composition. In any one selected from Claim 1 thru | or Claim 3,
X and Y represent a group that together with the carbon atom of ring B forms ring A,

A 3- to 7-membered heterocyclyl ring [the 3- to 7-membered heterocyclyl ring is
Oxirane, oxolane, tetrahydrofuran, tetrahydropyran,
1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane,
1,3-dithiolane, 1,3-dithiane,
1,1,3,3-tetraoxo-1,3-dithiolane,
1,3-oxathiolane, 1,3-oxathiane, or 1,3-oxathiepan,
These heterocyclyl rings are 5- to 6-membered heterocyclyl rings (the 5- to 6-membered heterocyclyl ring is tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine or 1,
3-dioxane. ) Or a cyclohexyl ring and a condensed or spiro ring may be formed,
Ring A includes a condensed ring and a spiro ring, an oxo group, a thioxo group, a substituent group α (the substituent group α
Represents a hydroxy group and a group having the formula NR ⁶ R ⁷ . R ⁶ and R ⁷ each independently represent a hydrogen atom or a C ₁ -C ₆ alkanoyl group. ), Methyl group, ethyl group and 1 to 4
1 to 2 selected from the group consisting of C ₁ -C ₆ alkyl groups substituted with ₁ hydroxy group
It may be substituted with groups. ],

Or

Cyclopropyl or cyclopentyl (the cyclopropyl or cyclopentyl is composed of a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-trihydroxypropyl group, and a 1,2,3,4-tetrahydroxybutyl group) It may be substituted with 1 to 2 groups selected from the group consisting of
A pharmaceutical composition. In any one selected from Claim 1 thru | or Claim 3,
X and Y represent a group that together with the carbon atom of ring B forms ring A,

3-6 membered heterocyclyl ring {wherein the heterocyclyl ring is
Oxirane, tetrahydrofuran,
1,3-dioxolane, 1,3-dioxane,
1,3-dithiolane, 1,3-dithiane,
1,3-oxathiolane or 1,3-oxathiane,
These heterocyclyl rings may form a condensed ring or a spiro ring with 5- to 6-membered heterocyclyl ring (the 5- to 6-membered heterocyclyl ring is tetrahydrofuran, tetrahydropyran or 1,3-dioxane) or cyclohexyl. Often,
Ring A includes a condensed ring and a spiro ring, and includes a substituent group α [the substituent group α is a hydroxy group and a group having the formula NR ⁶ R ⁷ (R ⁶ and R ⁷ are independently of each other; Represents a hydrogen atom or an acetyl group. ], A methyl group, an ethyl group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-trihydroxypropyl group, and a 1,2,3,4-tetrahydroxybutyl group. May be substituted by 1 to 2 groups. }
A pharmaceutical composition. In any one selected from Claim 1 thru | or Claim 7,
n is 0 or 1;
A pharmaceutical composition wherein R ¹ is a hydroxy group, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group. In any one selected from Claim 1 thru | or Claim 7,
n is 0 or 1;
A pharmaceutical composition wherein R ¹ is a fluorine atom or a methyl group. In any one selected from Claim 1 thru | or Claim 7,
A pharmaceutical composition wherein n is 0. In any one selected from Claim 1 thru | or Claim 10,
A pharmaceutical composition wherein R ² is a C ₁ -C ₆ alkyl group. In any one selected from Claim 1 thru | or Claim 10,
A pharmaceutical composition wherein R ² is a C ₁ -C ₄ alkyl group. In any one selected from Claim 1 thru | or Claim 10,
A pharmaceutical composition wherein R ² is an ethyl group. In any one selected from Claim 1 thru | or Claim 13,
R ³ is
A phenyl group optionally substituted with a group selected from the substituent group ε, or
A pyrrolyl group optionally substituted with a group selected from the substituent group ε,
A pharmaceutical composition, wherein the substituent group ε is a halogen atom, a C ₁ -C ₁₄ alkyl group and a halogeno C ₁ -C ₁₄ alkyl group. In any one selected from Claim 1 thru | or Claim 13,
R ³ is
A phenyl group optionally substituted with a group selected from the substituent group ε, or
A pyrrolyl group optionally substituted with a group selected from the substituent group ε,
Substituent group ε is a fluorine atom, a chlorine atom, a bromine _atom, C 3 -C ₈ alkyl group and a halogeno _C 4 -C ₈ pharmaceutical composition is an alkyl group. In any one selected from Claim 1 thru | or Claim 13,
R ³ is
A phenyl group which may be substituted with a group selected from the substituent group ε,
Substituent group ε is a fluorine atom, a pharmaceutical composition is a chlorine atom and a C ₃ -C ₈ alkyl group. In any one selected from Claim 1 thru | or Claim 16,
A pharmaceutical composition, wherein R ⁵ is a hydrogen atom or a C ₁ -C ₆ alkyl group. In any one selected from Claim 1 thru | or 16,
A pharmaceutical composition, wherein R ⁵ is a hydrogen atom or a methyl group. In any one selected from Claim 1 thru | or 16,
A pharmaceutical composition, wherein R ⁵ is a hydrogen atom. A pharmaceutical composition comprising as an active ingredient a compound of the following group selected from claim 1 or a pharmacologically acceptable salt thereof:
Ethyl 8- [N- (2-chlorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate;
Ethyl 8- [N- (2-chlorophenyl) sulfamoyl] -2,3-bis (1,2
-Dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (2,4-difluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate;
Ethyl 8- [N- (2,4-difluorophenyl) sulfamoyl] -2,3-bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-
7-carboxylate,
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2-hydroxymethyl-1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate;
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3
-Bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-
Carboxylate,
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3
-Bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-
Ene-7-carboxylate,
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2- (
1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7
-Carboxylates,
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2- (
1,2,3-trihydroxypropyl) -1,4-dioxaspiro [4.5] dec-6-
Ene-7-carboxylate,
Ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2- (
1,2,3,4-tetrahydroxybutyl) -1,4-dioxaspiro [4.5] deca-
6-ene-7-carboxylate,
Ethyl 2,3-bis (acetylaminomethyl) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-
7-carboxylate,
Ethyl 9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-hydroxy-1,5-dioxaspiro [5.5] undec-7-ene-8-carboxylate,
Ethyl 3-acetylamino-9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,5-dioxaspiro [5.5] undec-7-ene-8-carboxylate;
Ethyl 9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3, 3
-Bis (hydroxymethyl) -1,5-dioxaspiro [5.5] undec-7-ene-
8-carboxylate,
Ethyl 8- [N- (2-butyl-4-fluorophenyl) sulfamoyl] -2,3
-Bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-
Carboxylate,
Ethyl 8- [N- (2-butyl-4-fluorophenyl) sulfamoyl] -2,3
-Bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-
Ene-7-carboxylate,
Ethyl 8- [N- (2-hexylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (2-hexylphenyl) sulfamoyl] -2,3-bis (1,
2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (4-fluoro-2-hexylphenyl) sulfamoyl] -2,
3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7
-Carboxylates,
Ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N- (4-fluoro-
2-hexylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate,
Ethyl 8- [N- (2-heptylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (2-heptylphenyl) sulfamoyl] -2,3-bis (1,
2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (4-fluoro-2-heptylphenyl) sulfamoyl] -2,
3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7
-Carboxylates,
Ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N- (4-fluoro-
2-Heptylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate,
Ethyl 8- [N- (2-bromophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (2-bromophenyl) sulfamoyl] -2,3-bis (1,2
-Dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (2-chloro-6-methylphenyl) sulfamoyl] -2, 3-
Bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (2-chloro-6-methylphenyl) sulfamoyl] -2, 3-
Bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -2,3
-Bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7-
Carboxylate,
Ethyl 8- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -2,3
-Bis (1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5] dec-6-
Ene-7-carboxylate,
Ethyl 2,3-bis (hydroxymethyl) -8- [N- (2-pentylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N- (2-pentylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate,
Ethyl 8- [N- (4-fluoro-2-pentylphenyl) sulfamoyl] -2,
3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7
-Carboxylates,
Ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N- (4-fluoro-
2-pentylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate,
Ethyl 8- [N- (4-fluoro-2-octylphenyl) sulfamoyl] -2,
3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7
-Carboxylates,
Ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N- (4-fluoro-
2-octylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate,
Ethyl 8- [N- (4-fluoro-2-propylphenyl) sulfamoyl] -2,
3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-6-ene-7
-Carboxylates,
Ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N- (4-fluoro-
2-propylphenyl) sulfamoyl] -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate,
And ethyl 8- [N- (2-chloro-4-fluorophenyl) -N-methylsulfamoyl] -2,3-bis (hydroxymethyl) -1,4-dioxaspiro [4.5] deca-6
-Ene-7-carboxylate. The pharmaceutical composition according to any one of claims 1 to 20, which is used to suppress intracellular signal transduction or cell activation caused by endotoxin. The pharmaceutical composition according to any one of claims 1 to 20, which is used for suppressing production of inflammatory mediators resulting from intracellular signal transduction or cell activation caused by endotoxin. 21. A pharmaceutical composition according to any one of claims 1 to 20, which is used as a preventive or therapeutic agent for a disease caused by intracellular signal transduction or cell activation caused by endotoxin. The pharmaceutical composition according to any one of claims 1 to 20, which is used as a preventive and / or therapeutic agent for a disease mediated by an inflammatory mediator whose production is caused by endotoxin. 21. Any one of claims 1 to 20, which is used as a preventive and / or therapeutic agent for a disease mediated by an inflammatory mediator produced due to intracellular signal transduction or cell activation caused by endotoxin. The pharmaceutical composition described in 1. The pharmaceutical composition according to any one of claims 1 to 20, which is used as an agent for preventing and / or treating sepsis.