JP2010202575A - Heterocyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a preventive or therapeutic agent for diabetes exhibiting an excellent hypoglycemic action while hardly causing side effects such as body weight increase and the like. <P>SOLUTION: The preventive-therapeutic agent for diabetes includes a compound represented by the formula or a salt thereof, or a prodrug thereof. The symbols in the formula are specifically defined. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a heterocyclic compound useful as a therapeutic agent for diabetes.

(Background of the Invention)
As the heterocyclic compounds, compounds described in the following documents are known.
(1) Patent Document 1 (International Publication No. 99/47497) describes a formula as a therapeutic agent for pain, diabetic retinopathy and the like:

Wherein HET is a 5-12 membered monocyclic or bicyclic aromatic ring;
A represents O, S (O) _n or the like;
X is a 5- to 10-membered monocyclic or bicyclic aryl group or heteroaryl group having 1 to 3 heteroatoms selected from O, S (O) _n and N (O) _m (these May be substituted with a lower alkyl group or the like);
n is 0, 1 or 2;
m is 0 or 1;
Y _{is, O, S (O) n} , NR 17, ^bond, -CR ¹⁸ = ^CR 18 -; the
B represents — (C (R ¹⁸ ) ₂ ) _p —Y— (C (R ¹⁸ ) ₂ ) _q — [p and q independently represent 0 to 3 (Y is O, S (O) _n , ^{NR 17} or ^{-CR 18} = ^CR 18 - for a p + q = 0~6, if Y is a bond, is p + q = 1~6)];
Z represents OH or NHSO ₂ R ¹⁹ ;
R ¹ , R ² and R ³ independently represent a hydrogen atom, halogen, lower alkyl or the like;
R ¹⁷ independently represents H, lower alkyl or Bn;
R ¹⁸ is independently H, F or lower alkyl;
R ¹⁹ represents lower alkyl, lower alkenyl, lower alkynyl or the like]
The compound represented by these is described.

(2) Patent Document 2 (U.S. Pat. No. 5,776,970) describes the formula:

[Wherein R ¹ is C ₅ -C ₂₀ alkyl, C ₅ -C ₂₀ alkenyl, C ₅ -C ₂₀ acyl carboxylate, C ₃ -C ₈ alkoxycarbonyl, C ₅ -C ₈ cycloalkoxycarbonyl or chloro-substituted. Optionally benzyloxycarbonyl;
R ² represents —COOH, —SO ₃ H or —PO ₃ H;
R ³ is H, phenylthio or pyridylthio, which may be substituted with 1 or 2 nitro groups;
n represents 1 to 3. ]
The compound represented by these is described.

(3) Patent Document 3 (International Publication No. 2006/057448) describes a formula:

[In the formula, Ar represents an optionally substituted aromatic ring;
Xa, Xc, Ya, Yc, Z 1 and ^{Z 2} are independently a bond, an oxygen atom, a sulfur atom, a -CO like;
Xb and Yb independently represent a bond or a divalent hydrocarbon group having 1 to 20 carbon atoms;
R ¹ represents an optionally substituted hydrocarbon group;
Ring A represents an optionally substituted aromatic ring (provided that the ring is not benzimidazole);
n is an integer from 1 to 8;
Ring B represents an optionally substituted aromatic ring (provided that the ring is not oxazole);
W represents a divalent saturated hydrocarbon group having 1 to 20 carbon atoms;
R ² represents —OR ⁸ (R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group) or —NR ⁹ R ¹⁰ (R ⁹ and R ¹⁰ are independently a hydrogen atom, substituted) Represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an acyl group, or R ⁹ and R ¹⁰ are bonded to each other and optionally substituted together with the adjacent nitrogen atom Forming a ring);
Provided that Xa, Xb and Xc are not all bonds.
Z ¹ and Z ² are not all bonds or oxygen atoms;
When Ring A is a benzene ring, Xc and Yc are not able to bind to the carbon atom adjacent the benzene ring and, Z ² is not a sulfur atom. ]
The compound represented by these is described.

(4) In Patent Document 4 (International Publication No. 2007/018314), as a therapeutic agent for diabetes and the like, the formula:

[Wherein ring A represents an optionally substituted aromatic ring;
Ar represents an optionally substituted monocyclic ring;
R ¹ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
X is a spacer having 1 to 2 atoms in the main chain;
Y represents a bond or a spacer having 1 to 2 atoms in the main chain;
W represents an optionally substituted divalent hydrocarbon group having 1 to 20 carbon atoms;
Z represents —CONR ^a SO ₂ —, —SO ₂ NR ^a CO—, —SO ₂ NR ^a COO—, —NR ^a SO ₂ —, —OCONR ^a SO ₂ —, —OCONR ^a SO ₂ NR ^c —, — ^{OCONR c -, - NR a CONR} b SO 2 -, - NR a SO 2 NR b COO- or _{^{-CONR a SO 2 NR c - (}} R a and ^{R b} are each independently a hydrogen atom, optionally substituted An optionally protecting hydrocarbon group or amino group, R ^c represents a hydrogen atom, an optionally substituted hydrocarbon group or amino group protecting group, or R ^c and R ² are adjacent to each other; Together with the nitrogen atom to form an optionally substituted nitrogen-containing heterocycle). ]
The compound represented by these is described.

(5) In Patent Document 5 (International Publication No. 2007/013694), as a therapeutic agent for diabetes and the like, the formula:

[In the formula, A represents an optionally substituted cyclic group;
B represents a bond or a spacer having 1 to 10 main chain atoms;
D represents O or NR ⁵ (wherein R ⁵ represents a hydrogen atom or a substituent);
X represents an optionally substituted aromatic ring;
E represents CO, C (OR ⁶ ) R ⁷ or C═NR ⁸ (wherein R ⁶ , R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a substituent);
G represents an optionally substituted divalent C _1-6 hydrocarbon group;
R is —OR ⁹ (wherein R ⁹ represents a hydrogen atom or an optionally substituted hydrocarbon group) or —NR ¹⁰ R ¹¹ (wherein R ¹⁰ and R ¹¹ are the same or different; Each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R ¹⁰ and R ¹¹ together with the adjacent nitrogen atom form an optionally substituted heterocycle And R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a substituent. ]
The compound represented by these is described.

(6) Patent Document 6 (International Publication No. 2008/093639) discloses a formula:

[Wherein, A represents an optionally substituted benzene ring;
R ¹ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
R ² represents a hydrogen atom or a substituent (excluding an optionally substituted diazenyl group);
R ³ represents a hydrogen atom or a substituent,
Or R ² and R ³ may be joined together to form an optionally substituted monocyclic ring;
X represents O, NR ⁴ (R ⁴ represents a hydrogen atom or a C _1-6 alkyl group), S, SO, S (O) ₂ or CH ₂ ;
Y represents a bond, O, NR ⁵ (R ⁵ represents a hydrogen atom or a C _1-6 alkyl group), S, SO or S (O) ₂ ;
Z represents a bond or a divalent hydrocarbon group having 1 to 9 main chain atoms which may be substituted;
W represents —C (═O) Q (Q represents an optionally substituted hydroxy group or an optionally substituted amino group), or a 5- or 6-membered heterocyclic group having NH (the heterocycle The ring group may have a substituent. ]
The compound represented by these is described.

(7) Patent Document 7 (International Publication No. 2008/099794) discloses a formula:

[Wherein ring A and ring B independently represent an optionally substituted 5-7-membered monocycle;
Ring D ′ represents an optionally substituted 5-membered monocyclic aromatic heterocycle;
Y ′ represents N or C;
X is a spacer having 1 to 4 atoms in the main chain;
W represents —CONR ^1a S (O) _m R ² , —CONR ^1a S (O) _m OR ² , —CONR ^1a CONR ^1c R ² , —CONR ^1a S (O) _m NR ^1c R ² , —NR ^1b CONR ^1a S (O) _m R ² , —NR ^1b S (O) _m NR ^1a CO _n R ² , —S (O) _m NR ^1a CO _n R ² , —S (O) _m NR ^1a CONR ^1c R ² , -OCONR ^1a S (O) _m R ² , -OCONR ^1a S (O) _m NR ^1c R ² , -ONR ^1a CO _n R ² , -OCONR ^1c R ² , or -ONR ^1a CONR ^1c R ² (R ^1a and R ^1b independently represents a hydrogen atom or a C _1-6 alkyl group; R ^1c represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group; R ² represents a hydrogen atom, substituted An optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; and m and n independently represent an integer of 1 or 2. ]
The compound represented by these is described.

The following compounds are registered in the chemical abstract.
Registration number: 478049-49-9

International Publication No. 99/47497 US Pat. No. 5,776,970 International Publication No. 2006/057448 International Publication No. 2007/018314 International Publication No. 2007/013694 International Publication No. 2008/093639 International Publication No. 2008/099794

  Development of a preventive or therapeutic agent for diabetes having an excellent blood glucose lowering effect and few side effects such as weight gain is desired.

  The present inventors have found that a compound represented by the following formula (I) has an excellent hypoglycemic action and is useful for the prevention or treatment of diabetes, and as a result of further investigations, It came to be completed.

That is, the present invention
[1] Formula (I)

[Where:
A is the formula

(Where
R ^6a and R ^6b are independently of the formula —CO—OR ^A1 ,
-CO-NR ^A2 R ^B2 ,
-SOR ^A1 ,
—SO ₂ R ^A1 ,
-SO ₃ R ^A1 ,
—SO ₂ NR ^A2 R ^B2 , or —PO ₃ R ^A1 R ^B1
(Wherein, R ^A1 and R ^B1 are independently a hydrogen atom, a an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,; R ^A2 and R ^B2 are, independently A hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or R ^A2 and R ^B2 are substituted together with the adjacent nitrogen atom; Or a nitrogen-containing heterocycle may be formed.)
Or a 5- to 7-membered heterocyclic group which may be substituted;
R ^4a , R ^5a , R ^4b and R ^5b are
(1) Independently, (a) a hydrogen atom, (b) a halogen atom, (c) an optionally substituted C _1-6 alkyl group, (d) an optionally substituted C _1-6 alkoxy group (E) represents an optionally substituted 5- or 6-membered ring group, (f) a cyano group, or (g) an optionally amidated carboxy group, or
(2) R ^4a and R ^5a are combined with adjacent carbon atoms to form a benzene ring or a pyridine ring (the benzene ring and the pyridine ring are (a) a halogen atom, (b) an optionally substituted C ₁ 1 to 3 substituents selected from a _-6 alkyl group, (c) an optionally substituted C _1-6 alkoxy group, (d) a cyano group, and (e) an optionally amidated carboxy group Or (3) R ^4b and R ^5b together with adjacent carbon atoms can be combined with a benzene ring or a pyridine ring (the benzene ring and the pyridine ring are (A) a halogen atom, (b) an optionally substituted C _1-6 alkyl group, (c) an optionally substituted C _1-6 alkoxy group, (d) a cyano group, and (e) an amide May be . It 1 selected from carboxy group in 3 substituents may be substituted, respectively) may be formed;
R ⁷ represents a hydrogen atom, an optionally halogenated C _1-6 alkyl group, or an optionally halogenated C _3-10 cycloalkyl group; and L ^1a and L ^1b are independently (A) a halogen atom, (b) a hydroxy group, and (c) a substituent selected from a C _1-6 alkyl group, a C _1-6 alkyl-carbonyl group, and a C _1-6 alkoxy-carbonyl group. A spacer having 1 to 5 atoms in the main chain consisting of carbon atoms, which may be substituted with 1 to 3 substituents selected from an optionally substituted amino group. )
A group represented by:
X represents N or CH;
R ¹ and ^{R 2} are independently (1) hydrogen atom, (2) a halogen atom, (3) optionally substituted _{C 1-6} alkyl group, (4) optionally substituted _{C 1 -6} alkoxy group, (5) optionally halogenated _{C 3-10} cycloalkyl group, (6) halogenated which may be _{C 3-10} cycloalkyloxy group, it has been (7) halogenated And may represent a C _6-14 aryl group, or (8) a cyano group; and R ³ represents a hydrogen atom, a halogen atom, or an optionally halogenated C _1-6 alkyl group.
However,
(I) when any one of R ¹ , R ² and R ³ is a hydrogen atom, the other two are not hydrogen atoms; and (ii) R ¹ is of the formula —COO—R ^C1 (wherein R ^C1 is _{C 1-6} alkyl radical, and the formula ^{-COO-R C2} (formula substituted in.) of a hydrogen atom or an optionally substituted _{C 1-6} alkyl ^{group, R C2} is hydrogen It is not a C _1-6 alkoxy group substituted by an atom or an optionally substituted C _1-6 alkyl group. ]
Or a salt thereof (hereinafter abbreviated as compound (I));
[2] R ¹ is a hydrogen atom, a halogen atom, an optionally halogenated C _1-6 alkyl group, or an optionally halogenated C _1-6 alkoxy group;
R ² is a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group; and R ³ is a halogen atom, or C _1-6 alkyl The group,
The compound according to the above [1];
[3] A is the formula

(In the formula, each symbol has the same meaning as described in [1] above.)
The compound of the above-mentioned [1], which is a group represented by:
[4] A compound according to [1] above, wherein R ^6a and R ^6b are independently of the formula —CO—OR ^A1 (wherein R ^A1 has the same meaning as described in [1] above);
[5] R ^4a and R ^5a , or R ^4b and R ^5b , together with adjacent carbon atoms, form a benzene ring (the benzene ring is (a) a halogen atom, (b) an optionally substituted C _{A 1-6} alkyl group, (c) an optionally substituted C _1-6 alkoxy group, and (d) an optionally substituted 1 to 3 substituents selected from a cyano group). And a compound according to the above [1];
[6] L ^1a and L ^1b are each independently an amino group which may be mono- or di-substituted with (a) a halogen atom, (b) a hydroxy group, and (c) a C _1-6 alkoxy-carbonyl group. The compound of the above-mentioned [1], which is a C _2-4 alkylene group or a C _2-4 alkenylene group each optionally substituted by 1 to 3 substituents selected from:
[7] A is the formula

(Where
R ^6a is a formula —CO—OR ^A1 (wherein R ^A1 is as defined above in [1]);
R ^4a and R ^5a are combined with adjacent carbon atoms to form a benzene ring (the benzene ring is (a) a halogen atom, (b) an optionally substituted C _1-6 alkyl group, (c) substituted) A C _1-6 alkoxy group which may be substituted, and (d) optionally substituted by 1 to 3 substituents selected from a cyano group; and L ^1a is (a) a halogen Optionally substituted with 1 to 3 substituents selected from an atom, (b) a hydroxy group, and (c) an amino group optionally mono- or di-substituted with a C _1-6 alkoxy-carbonyl group. , A C _2-4 alkylene group or a C _2-4 alkenylene group. )
A group represented by:
X is N or CH;
R ¹ is a hydrogen atom, a halogen atom, an optionally halogenated C _1-6 alkyl group, or an optionally halogenated C _1-6 alkoxy group;
R ² is a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group; and R ³ is a halogen atom, or C _1-6 alkyl The compound of the above-mentioned [1], which is a group;
[8] A prodrug of the compound according to [1] above;
[9] A medicament comprising the compound according to [1] above or a prodrug thereof;
[10] The medicament according to [9] above, which is an insulin resistance improving agent;
[11] The medicament according to [9] above, which is a preventive or therapeutic agent for diabetes;
[12] A method for preventing or treating diabetes in a mammal, which comprises administering an effective amount of the compound according to [1] above or a prodrug thereof to the mammal;
[13] Use of the compound of the above-mentioned [1] or a prodrug thereof for producing a preventive or therapeutic agent for diabetes;
Etc.

  The present invention provides a preventive or therapeutic agent for diabetes that has an excellent blood glucose lowering effect and has few side effects such as weight gain.

Detailed Description of the Invention
Hereinafter, the definition of each symbol in formula (I) will be described in detail.
The “halogen atom” in the present specification means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom unless otherwise specified.
The “C _1-6 alkyl group” in the present specification is, unless otherwise specified, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethyl. It means propyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
The “C _1-6 alkoxy group” in the present specification means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, unless otherwise specified.
The “C _1-6 alkyl-carbonyl group” in the present specification means acetyl, propanoyl, butanoyl, isobutanoyl, sec-butanoyl, tert-butanoyl, pentanoyl, isopentanoyl, hexanoyl and the like, unless otherwise specified. .
Unless otherwise specified, the “C _1-6 alkoxy-carbonyl group” in the present specification includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like. means.

R ^6a and R ^6b are independently of the formula —CO—OR ^A1 ,
-CO-NR ^A2 R ^B2 ,
-SOR ^A1 ,
—SO ₂ R ^A1 ,
-SO ₃ R ^A1 ,
—SO ₂ NR ^A2 R ^B2 , or —PO ₃ R ^A1 R ^B1
(Wherein, R ^A1 and R ^B1 are independently a hydrogen atom, a an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,; R ^A2 and R ^B2 are, independently A hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or R ^A2 and R ^B2 are substituted together with the adjacent nitrogen atom; Or a nitrogen-containing heterocycle may be formed.)
Or a 5- to 7-membered heterocyclic group which may be substituted.

Examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ^A1 or R ^B1 include a C _1-10 alkyl group, a C _2-10 alkenyl group, and a C _2-10 alkynyl group. C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _4-10 cycloalkadienyl group, C _6-14 aryl group, C _7-13 aralkyl group, C _8-13 arylalkenyl group, etc. Can be mentioned.

Here, as the C _1-10 alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1 , 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like. Of these, a C _1-6 alkyl group is preferable.

Examples of the C _2-10 alkenyl group include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1 -Pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like can be mentioned. Of these, a C _2-6 alkenyl group is preferable.

Examples of the C _2-10 alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -Hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like. Among _{them, C 2-6} alkynyl group are preferred.

Examples of the C _3-10 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Of these, a C _3-6 cycloalkyl group is preferable.

Examples of the C _3-10 cycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. Of these, a C _3-6 cycloalkenyl group is preferable.

The C _4-10 cycloalkadienyl group, for example, 2,4-cyclopentadiene-1-yl, and 2,4-cyclohexadiene-1-yl, 2,5-cyclohexadiene-1-yl and the like . Of these, a C _4-6 cycloalkadienyl group is preferable.

The above C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group and C _4-10 cycloalkadienyl group may each be condensed with a benzene ring to form a condensed ring group. Examples of the fused ring group include indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl and the like.

In addition, the C _3-10 cycloalkyl group, the C _3-10 cycloalkenyl group, and the C _4-10 cycloalkadienyl group may be a C _7-10 bridged hydrocarbon group. Examples of the C _7-10 bridged hydrocarbon group include bicyclo [2.2.1] heptyl (norbornyl), bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3. 2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, adamantyl and the like.

Further, the above C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group and C _4-10 cycloalkadienyl group are respectively C _3-10 cycloalkane, C _3-10 cycloalkene or C _4-10. A cycloalkadiene and a spiro ring group may be formed. Here, as C _3-10 cycloalkane, C _3-10 cycloalkene and C _4-10 cycloalkadiene, the above C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group and C _4-10 cyclo Examples include rings corresponding to alkadienyl groups. Examples of such a spiro ring group include spiro [4.5] decan-8-yl.

Examples of the C _6-14 aryl group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. Of these, a C _6-12 aryl group is preferable.

Examples of the C _7-13 aralkyl group include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like.

Examples of the C _8-13 arylalkenyl group include styryl and the like.

The C _1-10 alkyl group, C _2-10 alkenyl group and C _2-10 alkynyl group exemplified as the “hydrocarbon group” may have 1 to 3 substituents at substitutable positions. .

As such a substituent, for example,
(1) a C _3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl);
(2) (a) a C _1-6 alkyl group _optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and
(d) a C _6-14 aryl group (eg, phenyl, naphthyl) _optionally substituted with 1 to 3 substituents selected from halogen atoms;
(3) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and
(d) an aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from halogen atoms (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl) ;
(4) (a) 1 to 3 substituents which may be C _1-6 alkyl group by a halogen atom,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms,
(d) a halogen atom, and
(e) a non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl) optionally substituted with 1 to 3 substituents selected from oxo groups;
(5) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a C _1-6 alkyl-carbonyl group _optionally substituted by 1 to 3 halogen atoms,
(c) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms,
(d) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 halogen atoms,
(e) a carbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and
(f) Aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl)
An amino group which may be mono- or di-substituted with a substituent selected from:
(6) a C _1-6 alkyl-carbonyl group which may be substituted with 1 to 3 halogen atoms;
(7) (a) a halogen atom,
(b) a C _1-6 alkoxy group,
(c) a C _6-14 aryl group (eg, phenyl), and
(d) Heterocyclic group (eg, tetrahydrofuryl)
A C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 substituents selected from:
(8) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl) optionally substituted with 1 to 3 halogen atoms;
(9) a carbamoyl group which may be mono- or di-substituted with a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms;
(10) a thiocarbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;
(11) 1 to 3 mono- or di-optionally substituted sulfamoyl group substituted with also a C _1-6 alkyl group by a halogen atom;
(12) a carboxy group;
(13) a hydroxy group;
(14) (a) a halogen atom,
(b) a carboxy group,
(c) a C _1-6 alkoxy group,
(d) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 C _6-14 aryl groups (eg, phenyl),
(e) an amino group which may be mono- or di-substituted with a substituent selected from a C _1-6 alkyl group and a C _1-6 alkoxy-carbonyl group,
(f) a heterocyclic group (eg, tetrahydrofuryl), and
(g) a C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group;
(15) a C _2-6 alkenyloxy group (eg, ethenyloxy) optionally substituted by 1 to 3 halogen atoms;
(16) C _7-13 aralkyloxy group (eg, benzyloxy);
(17) C _6-14 aryloxy group (eg, phenyloxy, naphthyloxy);
(18) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy, tert-butylcarbonyloxy);
(19) (a) a halogen atom, and
(b) a C _6-14 aryl-carbonyl group _optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms (eg, Benzoyl);
(20) A non-aromatic heterocyclic carbonyl group optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms (eg, Pyrrolidinylcarbonyl, morpholinylcarbonyl);
(21) mercapto group;
(22) (a) a halogen atom, and
(b) C _1-6 alkoxy - one to three optionally substituted with a substituent C _1-6 alkylthio group selected from a carbonyl group (e.g., methylthio, ethylthio);
_{(23) C 7-13} aralkylthio group (e.g., benzylthio);
(24) C _6-14 arylthio group (eg, phenylthio, naphthylthio);
(25) a cyano group;
(26) a nitro group;
(27) a halogen atom;
(28) C _1-3 alkylenedioxy group;
(29) C _1-3 alkyleneoxy group (eg, methyleneoxy, ethyleneoxy);
(30) an aromatic heterocyclic carbonyl group (eg, pyrazolyl) optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms Carbonyl, pyrazinylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl, thiazolylcarbonyl);
(31) (a) a halogen atom (eg, a fluorine atom), and
(b) C _1-6 alkoxy group (eg, methoxy)
1 selected from to three optionally substituted with a substituent C _3-10 cycloalkoxy kill group (e.g., cyclopropyloxy, cyclopentyloxy)
Etc. When there are two or more substituents, each substituent may be the same or different.

In addition, the C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _4-10 cycloalkadienyl group, C _6-14 aryl group, C _7-13 aralkyl group exemplified as the “hydrocarbon group”. And the C _8-13 arylalkenyl group _optionally has 1 to 3 substituents at substitutable positions.

As such a substituent, for example,
(1) groups exemplified as substituents in the aforementioned C _1-10 alkyl group and the like;
(2) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C _1-6 alkoxy-carbonyl group,
(e) a C _1-6 alkoxy group, and
(f) a C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C _1-6 alkyl group;
(3) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C _1-6 alkoxy-carbonyl group,
(e) a C _1-6 alkoxy group, and
(f) a C _2-6 alkenyl group optionally substituted with 1 to 3 substituents selected from an amino group which may be mono- or di-substituted with a C _1-6 alkyl group (eg, ethenyl, 1 -Propenyl);
(4) (a) 1 to 3 substituents which may be C _1-6 alkyl group by a halogen atom,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group, and
(d) a C _7-13 aralkyl group (eg, benzyl) _optionally substituted with 1 to 3 substituents selected from a halogen atom;
Etc. When there are two or more substituents, each substituent may be the same or different.

^Examples of the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R ^A1 or R ^B1 include an aromatic heterocyclic group and a non-aromatic heterocyclic group.

  Here, as the aromatic heterocyclic group, for example, a 5- to 7-membered monocyclic aromatic containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom Aromatic heterocyclic group and condensed aromatic heterocyclic group. Examples of the condensed aromatic heterocyclic group include a ring corresponding to the 5- to 7-membered monocyclic aromatic heterocyclic group and a 5- or 6-membered aromatic heterocyclic ring containing 1 to 2 nitrogen atoms. (Eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine) From a ring in which 1 or 2 selected from a 5-membered aromatic heterocycle containing one sulfur atom (eg, thiophene) and a benzene ring is condensed Examples include groups to be derived.

As preferable examples of the aromatic heterocyclic group,
Furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl) 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (Eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5 -Thiazolyl), isothiazolyl (eg, 4-isothiazolyl), oxazolyl (eg, 2-oxazolyl, 4 Oxazolyl, 5-oxazolyl), isoxazolyl (eg, 3-isoxazolyl), oxadiazolyl (eg, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (Eg, 1,3,4-thiadiazol-2-yl), triazolyl (eg, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3- Triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl), triazinyl ( Examples, monocyclic aromatic heterocyclic groups such as 1,2,4-triazin-1-yl, 1,2,4-triazin-3-yl, 1,3,5-triazin-1-yl);
Quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (eg, 3-isoquinolyl), quinazolyl (eg, 2-quinazolyl, 4-quinazolyl), quinoxalyl (eg, 2-quinoxalyl) 6-quinoxalyl), benzofuranyl (eg, 2-benzofuranyl, 3-benzofuranyl), benzothiophenyl (eg, 2-benzothiophenyl, 3-benzothiophenyl), benzoxazolyl (eg, 2-benzoxazolyl) ), Benzisoxazolyl (eg, 7-benzisoxazolyl), benzothiazolyl (eg, 2-benzothiazolyl), benzimidazolyl (eg, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazole) -5-yl), benzotriazolyl (eg, 1H-1,2,3-be Zotriazol-5-yl), indolyl (eg, indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), indazolyl (eg, 1H-indazol-3-yl), Pyrrolopyrazinyl (eg, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyrazin-6-yl), imidazopyridinyl (eg, 1H-imidazo [4, 5-b] pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl, 2H-imidazo [1,2-a] pyridin-3-yl), imidazopyrazinyl (eg, 1H-imidazo [4,5-b] pyrazin-2-yl), pyrazolopyridinyl (eg, 1H-pyrazolo [4,3-c] pyridin-3-yl), pyrazolothienyl (eg, 2H-pyrazolo [ 3,4- ] Thiophen-2-yl) pyrazolo triazinyl (e.g., pyrazolo [5,1-c] [1,2,4] triazin-3-yl) fused aromatic heterocyclic groups such as;
Etc.

  Non-aromatic heterocyclic group contains, for example, 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms (the sulfur atoms may be oxidized) and nitrogen atoms in addition to carbon atoms as ring constituent atoms 5 to 7-membered monocyclic non-aromatic heterocyclic group and condensed non-aromatic heterocyclic group. Examples of the condensed non-aromatic heterocyclic group include a ring corresponding to the 5- to 7-membered monocyclic non-aromatic heterocyclic group, and a 5- or 6-membered aromatic containing 1 to 2 nitrogen atoms. Or selected from non-aromatic heterocycles (eg pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), 5-membered aromatic or non-aromatic heterocycles containing one sulfur atom (eg thiophene) and benzene rings And a group derived from a ring in which 1 to 2 are fused, a group obtained by partial saturation of the group, and the like.

As a suitable example of a non-aromatic heterocyclic group,
Tetrahydrofuryl (eg, 2-tetrahydrofuryl), pyrrolidinyl (eg, 1-pyrrolidinyl), 1,1-dioxidetetrahydrothienyl (eg, 1,1-dioxidetetrahydro-3-thienyl), piperidinyl (eg, piperidino) , Morpholinyl (eg, morpholino), thiomorpholinyl (eg, thiomorpholino), 1,1-dioxidethiomorpholinyl (eg, 1,1-dioxidethiomorpholino), piperazinyl (eg, 1-piperazinyl), hexamethylene Iminyl (eg, hexamethyleneimin-1-yl), oxazolinyl (eg, 2,5-dihydrooxazol-3-yl, 3,4-dihydrooxazol-3-yl), thiazolinyl (eg, 2,5-dihydro) Thiazol-3-yl, 3,4-dihydrothiazol-3-yl), imidazo Nil (eg, 2-imidazolin-3-yl), oxazolidinyl (eg, oxazolidine-3-yl), thiazolidinyl (eg, thiazolidin-3-yl, thiazolidin-5-yl), imidazolidinyl (eg, imidazolidin-3-yl) Yl), dioxolyl (eg, 1,3-dioxol-4-yl), dioxolanyl (eg, 1,3-dioxolan-4-yl), dihydrooxadiazolyl (eg, 4,5-dihydro-1,2, 4-oxadiazol-3-yl), thioxooxazolidinyl (eg, 2-thioxo-1,3-oxazolidine-5-yl), tetrahydropyranyl (eg, 4-tetrahydropyranyl), tetrahydrothio Pyranyl (eg, 4-tetrahydrothiopyranyl), 1,1-dioxide tetrahydrothiopyranyl (eg, 1,1-dioxy) Dotetrahydrothiopyran-4-yl), pyrazolidinyl (eg, pyrazolidin-1-yl), oxotetrahydropyridazinyl (eg, 3-oxo-2,3,4,5-tetrahydropyridazin-4-yl), etc. A monocyclic non-aromatic heterocyclic group of
Dihydroisoindolyl (eg, 1,3-dihydro-2H-isoindol-2-yl), dihydrobenzofuranyl (eg, 2,3-dihydro-1-benzofuran-5-yl), dihydrobenzodioxinyl (Eg, 2,3-dihydro-1,4-benzodioxin-2-yl), dihydrobenzodioxepinyl (eg, 3,4-dihydro-2H-1,5-benzodioxepin-2-yl) ), Tetrahydrobenzofuranyl (eg, 4,5,6,7-tetrahydro-1-benzofuran-3-yl), tetrahydrobenzothiazolyl (eg, 4,5,6,7-tetrahydro-1-benzothiazole) -2-yl), tetrahydrobenzoxazolyl (eg, 4,5,6,7-tetrahydro-1-benzoxazol-2-yl), chromenyl (eg, 4H-chromene- -Yl, 2H-chromen-3-yl), dihydroquinolinyl (eg, 1,2-dihydroquinolin-2-yl), tetrahydroquinolinyl (eg, 1,2,3,4-tetrahydroquinoline-2) -Yl), dihydroisoquinolinyl (eg, 1,2-dihydroisoquinolin-2-yl), tetrahydroisoquinolinyl (eg, 1,2,3,4-tetrahydroisoquinolin-4-yl, 1,2 , 3,4-tetrahydroisoquinolin-2-yl), dihydrophthalazinyl (eg, 1,4-dihydrophthalazin-4-yl), tetrahydroindazolyl (eg, 4,5,6,7-tetrahydro- 2H-indazol-2-yl), tetrahydroquinazolinyl (eg, 5,6,7,8-tetrahydroquinazolin-6-yl), tetrahydrothiazolopyridinyl (eg, 4, , 6,7-tetrahydrothiazolo [5.4-c] pyridin-6-yl), tetrahydroimidazopyridinyl (eg, 1,2,3,4-tetrahydroimidazo [4.5-c] pyridine-2) -Yl), tetrahydropyrazolopyridinyl (eg, 1,2,3,4-tetrahydropyrazolo [3.4-c] pyridin-2-yl), tetrahydrotriazolopyrazinyl (eg, 1,2) , 3,4-tetrahydrotriazolo [4.3-a] pyrazin-2-yl), tetrahydroimidazopyrazinyl (eg, 1,2,3,4-tetrahydroimidazo [1.2-a] pyrazine-2 -Yl, 1,2,3,4-tetrahydroimidazo [3.4-a] pyrazin-2-yl), tetrahydropyridopyrimidinyl (eg, 5,6,7,8-tetrahydropyrido [5.4- c] Pyrimidine Condensed non-aromatic heterocyclic groups such as -6-yl);
Is mentioned.

The “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R ^A1 or R ^B1 may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include the C _3-10 cycloalkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ^A1 or R ^B1. Examples of the substituent which may be used are the same. When the “heterocyclic group” is a “non-aromatic heterocyclic group”, an oxo group is further included as a substituent. When there are two or more substituents, each substituent may be the same or different.

R ^A1 and R ^B1 are preferably independently a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted 5- or 6-membered heterocyclic group, and more preferably Independently represents a hydrogen atom, a C _1-6 alkyl group (preferably methyl, ethyl, tert-butyl), or a 5- or 6-membered heterocyclic group (preferably a 5- or 6-membered aromatic heterocyclic ring). Group (preferably triazolyl, tetrazolyl)).

As "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" represented by R ^A2 or R ^B2, may be "optionally substituted represented by R ^A1 or R ^B1 carbide Examples thereof include the same as “hydrogen group” and “optionally substituted heterocyclic group”.

Examples of the “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” that R ^A2 and R ^B2 may form together with the adjacent nitrogen atom include a carbon atom as a ring-constituting atom. In addition, a 5- to 7-membered nitrogen-containing heterocycle containing at least one nitrogen atom and further containing 1 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom is mentioned. Preferable examples of the “nitrogen-containing heterocycle” include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine and the like.

The “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” that R ^A2 and R ^B2 may form together with the adjacent nitrogen atom is 1 to 3 at substitutable positions. It may have a substituent. Examples of such a substituent include those similar to the substituent that the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R ^A1 or R ^B1 may have. It is done. When there are two or more substituents, each substituent may be the same or different.

R ^A2 and R ^B2 are preferably independently a hydrogen atom or an optionally substituted hydrocarbon group, more preferably independently a hydrogen atom or an optionally substituted C _{1. A -6} alkyl group, particularly preferably independently
(1) a hydrogen atom; or
(2) a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group, a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl) and a carboxy group (Preferably methyl, ethyl);
It is.

The “5- to 7-membered heterocyclic group” of the “optionally substituted 5- to 7-membered heterocyclic group” represented by R ^6a or R ^6b is the “substituted or substituted” represented by R ^A1 or R ^B1. Examples of the “aromatic heterocyclic group” and “non-aromatic heterocyclic group” exemplified as the “heterocyclic group” in the “good heterocyclic group” include 5- to 7-membered ones. In addition, when the “5- to 7-membered heterocyclic group” contains a sulfur atom as a ring constituent atom, the sulfur atom may be oxidized.

  The “5- to 7-membered heterocyclic group” is preferably a 5- or 6-membered heterocyclic group, more preferably pyridyl, furyl, thiazolyl, pyrazolyl, tetrazolyl, dioxolanyl, oxadiazolinyl, oxadiazolidinyl. , Thiadiazolidinyl, imidazolidinyl, thiazolidinyl and the like.

The “5- to 7-membered heterocyclic group” in the “optionally substituted 5- to 7-membered heterocyclic group” represented by R ^6a or R ^6b has 1 to 3 substituents at substitutable positions. It may be. Examples of such a substituent include those similar to the substituent that the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R ^A1 or R ^B1 may have. It is done. When there are two or more substituents, each substituent may be the same or different.

Preferred substituents include
(1) a carboxy group;
(2) a C _1-6 alkyl group (preferably methyl, ethyl);
(3) C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl);
(4) an oxo group;
Etc.

The “optionally substituted 5- to 7-membered heterocyclic group” represented by R ^6a or R ^6b is preferably
(1) a carboxy group;
(2) a C _1-6 alkyl group (preferably methyl, ethyl);
(3) C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl);
(4) an oxo group;
5- or 6-membered heterocyclic group (preferably pyridyl, furyl, thiazolyl, pyrazolyl, tetrazolyl, dioxolanyl, oxadiazolinyl, oxadiazolidinyl optionally substituted with 1 to 3 substituents selected from , Thiadiazolidinyl, imidazolidinyl, thiazolidinyl).

R ^6a and R ^6b are preferably independently of the formula —CO—OR ^A1 ,
-CO-NR ^A2 R ^B2 ,
-SOR ^A1 ,
—SO ₂ R ^A1 ,
-SO ₃ R ^A1 ,
—SO ₂ NR ^A2 R ^B2 , or —PO ₃ R ^A1 R ^B1
(Where
R ^A1 and R ^B1 independently represent a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted 5- or 6-membered heterocyclic group (preferably independently A hydrogen atom, a C _1-6 alkyl group (preferably methyl, ethyl, tert-butyl), or a 5- or 6-membered heterocyclic group (preferably a 5- or 6-membered aromatic heterocyclic group (preferably triazolyl) , Tetrazolyl))); and R ^A2 and R ^B2 are independently a hydrogen atom or an optionally substituted hydrocarbon group (preferably independently a hydrogen atom or Good C _1-6 alkyl groups, more preferably independently,
(1) a hydrogen atom; or
(2) a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group, a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl) and a carboxy group (Preferably methyl, ethyl)). );
Or a group represented by
(1) a carboxy group;
(2) a C _1-6 alkyl group (preferably methyl, ethyl);
(3) a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl); and
(4) an oxo group;
A 5- or 6-membered heterocyclic group (preferably pyridyl, furyl, thiazolyl, pyrazolyl, tetrazolyl, dioxolanyl, oxadiazolinyl, oxadiazolidinyl, optionally substituted by 1 to 3 substituents selected from Thiadiazolidinyl, imidazolidinyl, thiazolidinyl).

In another preferred embodiment, R ^6a and R ^6b are preferably independently of the formula —CO—OR ^A1 (wherein R ^A1 is as defined above in [1]).

In this embodiment, R ^6a and R ^6b are more preferably independently
Formula -CO-OR ^A1
(Wherein R ^A1 is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted 5- or 6-membered heterocyclic group (preferably independently a hydrogen atom, A C _1-6 alkyl group (preferably methyl, ethyl, tert-butyl), or a 5- or 6-membered heterocyclic group (preferably a 5- or 6-membered aromatic heterocyclic group (preferably triazolyl, tetrazolyl)) )).)
It is group represented by these.

R ^4a , R ^5a , R ^4b and R ^5b are
(1) Independently, (a) a hydrogen atom, (b) a halogen atom, (c) an optionally substituted C _1-6 alkyl group, (d) an optionally substituted C _1-6 alkoxy group (E) represents an optionally substituted 5- or 6-membered ring group, (f) a cyano group, or (g) an optionally amidated carboxy group, or
(2) R ^4a and R ^5a are combined with adjacent carbon atoms to form a benzene ring or a pyridine ring (the benzene ring and the pyridine ring are (a) a halogen atom, (b) an optionally substituted C ₁ 1 to 3 substituents selected from a _-6 alkyl group, (c) an optionally substituted C _1-6 alkoxy group, (d) a cyano group, and (e) an optionally amidated carboxy group Or (3) R ^4b and R ^5b together with adjacent carbon atoms can be combined with a benzene ring or a pyridine ring (the benzene ring and the pyridine ring are (A) a halogen atom, (b) an optionally substituted C _1-6 alkyl group, (c) an optionally substituted C _1-6 alkoxy group, (d) a cyano group, and (e) an amide May be It 1 selected from carboxyl group with 1-3 substituents may be substituted, respectively.) May be formed.

R ^{4a, R 5a,} _{"C 1-6} alkyl group" in the "optionally substituted _{C 1-6} alkyl group" represented by ^{R 4b} or ^{R 5b} are substituents of 1 to 3 at substitutable positions It may have a group. Examples of such a substituent are the same as the substituents that the C _1-10 alkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” may have. Things. When there are two or more substituents, each substituent may be the same or different.

The “C _1-6 alkoxy group” in the “optionally substituted C _1-6 alkoxy group” represented by R ^4a , R ^5a , R ^4b or R ^5b has 1 to 3 substitutions at substitutable positions. It may have a group. Examples of such a substituent are the same as the substituents that the C _1-10 alkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” may have. Things. When there are two or more substituents, each substituent may be the same or different.

As the “5- or 6-membered cyclic group” in the “optionally substituted 5- or 6-membered cyclic group” represented by R ^4a , R ^5a , R ^4b or R ^5b , a 5- or 6-membered cyclic hydrocarbon group and A 5- or 6-membered heterocyclic group may be mentioned.

Here, examples of the 5- or 6-membered cyclic hydrocarbon group include a C _5-6 cycloalkyl group, a C _5-6 cycloalkenyl group, a C _5-6 cycloalkadienyl group, and a phenyl group. As these C _5-6 cycloalkyl group, C _5-6 cycloalkenyl group and C _5-6 cycloalkadienyl group, in the “optionally substituted hydrocarbon group” represented by R ^A1 or R ^B1 Examples of the C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, and C _4-10 cycloalkadienyl group exemplified as the “hydrocarbon group” include 5- or 6-membered ones.

Examples of the 5- or 6-membered heterocyclic group include an aromatic heterocyclic group and a non-aromatic heterocyclic group exemplified as the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R ^A1 or R ^B1. Among the groups, mention may be made of 5 or 6 members.

The “5- or 6-membered cyclic group” in the “optionally substituted 5- or 6-membered cyclic group” represented by R ^4a , R ^5a , R ^4b or R ^5b is 1 to 3 substitutions at substitutable positions. It may have a group. Examples of such a substituent include those similar to the substituent that the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R ^A1 or R ^B1 may have. It is done. When there are two or more substituents, each substituent may be the same or different.

The “optionally amidated carboxy group” represented by R ^4a , R ^5a , R ^4b or R ^5b includes, for example, the formula —CO—NR ^A3 R ^B3 (wherein R ^A3 And R ^B3 independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or R ^A3 and R ^B3 together with an adjacent nitrogen atom And may form a nitrogen-containing heterocyclic ring which may be substituted.) And the like.

Examples of the “optionally substituted hydrocarbon group” for R ^A3 or R ^B3 include the same as the “optionally substituted hydrocarbon group” for R ^A1 or R ^B1 .

^Examples of the “optionally substituted heterocyclic group” for R ^A3 or R ^B3 include the same as the “optionally substituted heterocyclic group” for R ^A1 or R ^B1 .

The “optionally substituted nitrogen-containing heterocycle” that R ^A3 and R ^B3 may form together with the adjacent nitrogen atom includes R ^A2 and R ^B2 together with the adjacent nitrogen atom. Examples thereof may include the same “optionally substituted nitrogen-containing heterocycle” that may be formed.

R ^4a and R ^5a , or R ^4b and R ^5b , which may be formed together with adjacent carbon atoms, is a substituent of “benzene ring or pyridine ring” “optionally substituted C _1-6 the alkyl group "and" optionally substituted _{C 1-6} alkoxy group ^{", R 4a, R 5a, R} 4b or" optionally substituted _{C 1-6} alkyl group represented by ^{R 5b} "and Examples thereof include those similar to the “optionally substituted C _1-6 alkoxy group”.

“Optionally amidated carboxy group” which is a substituent of “benzene ring or pyridine ring” which R ^4a and R ^5a , or R ^4b and R ^5b may form together with adjacent carbon atoms ^Examples thereof include those similar to the “optionally amidated carboxy group” represented by R ^4a , R ^5a , R ^4b or R ^5b .

R ^4a and R ^5a are preferably independently a hydrogen atom, a halogen atom (preferably a chlorine atom or a bromine atom), an optionally substituted C _1-6 alkyl group (preferably methyl), or An optionally substituted 5- or 6-membered ring group (preferably an aromatic ring group (preferably phenyl)), more preferably independently a hydrogen atom, a halogen atom (preferably a chlorine atom, bromine) Atom), a C _1-6 alkyl group (preferably methyl), or a 5- or 6-membered ring group (preferably an aromatic ring group (preferably phenyl)).

Alternatively, preferably R ^4a and R ^5a together with adjacent carbon atoms are (a) a halogen atom (preferably a fluorine atom, a chlorine atom), (b) 1 to 3 halogen atoms (preferably Is a C _1-6 alkyl group (preferably methyl) optionally substituted with a fluorine atom), (c) is substituted with 1 to 3 C _1-6 alkoxy groups (preferably methoxy) A C _1-6 alkoxy group (preferably methoxy, ethoxy), (d) a cyano group, and (e) an amidated carboxy group [preferably a formula —CO—NR ^A3 R ^B3 (formula ^{among, R A3} and ^{R B3} are preferably independently (preferably, ethyl) hydrogen atom or a _{C 1-6} alkyl group or a, ^{or, R A3} and ^{R B3} are the adjacent nitrogen atom one To form a 5- or 6-membered nitrogen-containing heterocyclic ring (preferably, morpholine)]], and a benzene ring or a pyridine ring each optionally substituted with 1 to 3 substituents May be.

In another preferred embodiment, preferably R ^4a and R ^5a are combined with adjacent carbon atoms to form (a) a halogen atom, (b) an optionally substituted C _1-6 alkyl group, (c And a benzene ring which may be substituted with 1 to 3 substituents selected from (C) an optionally substituted C _1-6 alkoxy group and (d) a cyano group.

In this preferred embodiment, more preferably, R ^4a and R ^5a together with the adjacent carbon atom are (a) a halogen atom (preferably a fluorine atom or a chlorine atom), (b) 1 to 3 A C _1-6 alkyl group (preferably methyl) optionally substituted with a halogen atom (preferably a fluorine atom), (c) 1 to 3 C _1-6 alkoxy groups (preferably methoxy) An optionally substituted C _1-6 alkoxy group (preferably methoxy, ethoxy) and (d) a benzene ring optionally substituted with 1 to 3 substituents selected from a cyano group are formed.

R ^4b and R ^5b are preferably independently a hydrogen atom, a halogen atom (preferably a chlorine atom or a bromine atom), an optionally substituted C _1-6 alkyl group (preferably methyl), or An optionally substituted 5- or 6-membered ring group (preferably an aromatic ring group (preferably phenyl)), more preferably independently a hydrogen atom, a halogen atom (preferably a chlorine atom, bromine) Atom), a C _1-6 alkyl group (preferably methyl), or a 5- or 6-membered ring group (preferably an aromatic ring group (preferably phenyl)).

Alternatively, preferably, R ^4b and R ^5b are combined with an adjacent carbon atom to form (a) a halogen atom (preferably a fluorine atom or a chlorine atom), (b) 1 to 3 halogen atoms (preferably Is a C _1-6 alkyl group (preferably methyl) optionally substituted with a fluorine atom), (c) is substituted with 1 to 3 C _1-6 alkoxy groups (preferably methoxy) A C _1-6 alkoxy group (preferably methoxy, ethoxy), (d) a cyano group, and (e) an amidated carboxy group [preferably a formula —CO—NR ^A3 R ^B3 (formula ^{among, R A3} and ^{R B3} are preferably independently (preferably, ethyl) hydrogen atom or a _{C 1-6} alkyl group or a, ^{or, R A3} and ^{R B3} are the adjacent nitrogen atom one To form a 5- or 6-membered nitrogen-containing heterocyclic ring (preferably, morpholine)]], and a benzene ring or a pyridine ring each optionally substituted with 1 to 3 substituents May be.

In another preferred embodiment, preferably R ^4b and R ^5b are combined with an adjacent carbon atom to form (a) a halogen atom, (b) an optionally substituted C _1-6 alkyl group, (c And a benzene ring which may be substituted with 1 to 3 substituents selected from (C) an optionally substituted C _1-6 alkoxy group and (d) a cyano group.

In the preferred embodiment, more preferably, R ^4b and R ^5b , together with adjacent carbon atoms, are (a) a halogen atom (preferably a fluorine atom or a chlorine atom), (b) 1 to 3 A C _1-6 alkyl group (preferably methyl) optionally substituted with a halogen atom (preferably a fluorine atom), (c) 1 to 3 C _1-6 alkoxy groups (preferably methoxy) An optionally substituted C _1-6 alkoxy group (preferably methoxy, ethoxy) and (d) a benzene ring optionally substituted with 1 to 3 substituents selected from a cyano group are formed.

R ⁷ represents a hydrogen atom, an optionally halogenated C _1-6 alkyl group, or an optionally halogenated C _3-10 cycloalkyl group.

"Optionally halogenated C _1-6 alkyl group" represented by R ^7, 1 to 5 (preferably 1 to 3) C _1-6 alkyl optionally substituted by halogen atom Group, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2- Examples include chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl and the like.

"Optionally halogenated and C _3-10 cycloalkyl group" represented by R ⁷ is 1 to 5 (preferably 1 to 3) optionally C _3-10 optionally substituted with a halogen atom It means a cycloalkyl group, and examples thereof include fluorocyclopropyl, 2-fluorocyclobutyl, 2-fluorocyclopentyl, 2-fluorocyclohexyl, 2-fluorocycloheptyl, 2-fluorocyclooctyl and the like.

R ⁷ is preferably an optionally halogenated C _1-6 alkyl group, more preferably a C _1-6 alkyl group (preferably methyl), and still more preferably methyl.

L ^1a and L ^1b independently represent (a) a halogen atom, (b) a hydroxy group, and (c) a C _1-6 alkyl group, a C _1-6 alkyl-carbonyl group, and a C _1-6 alkoxy-carbonyl. 1 to 5 atoms of the main chain consisting of carbon atoms which may be substituted with 1 to 3 substituents selected from amino groups which may be mono- or di-substituted with substituents selected from the group Indicates a spacer.

“From (a) a halogen atom, (b) a hydroxy group, and (c) a C _1-6 alkyl group, a C _1-6 alkyl-carbonyl group, and a C _1-6 alkoxy-carbonyl group represented by L ^1a or L ^1b A spacer having 1 to 5 atoms in the main chain consisting of carbon atoms, which may be substituted with 1 to 3 substituents selected from amino groups which may be mono- or di-substituted with selected substituents " The “main chain” of the “spacer having 1 to 5 atoms in the main chain consisting of carbon atoms” is a straight chain connecting the imidazole ring and the group R ^6a , or the pyrrole ring and the group R ^6b , The “number of atoms in the main chain” is counted so that the atoms in the main chain are minimized. As long as the main chain consists of 1 to 5 atoms, the number of atoms of the entire spacer is not particularly limited, and may be 5 or more. The “main chain” consists of 1 to 5 carbon atoms, which may be substituted with oxo groups, and may be saturated or unsaturated.

Examples of the “spacer having 1 to 5 carbon atoms in the main chain” include, for example, C _1-5 alkylene group, C _2-5 alkenylene group, C _2-5 alkynylene group, C _3-6 cycloalkylene. Group, C _6-10 arylene group, -X ^1a -X ^2a- (wherein, X ^1a and X ^2a are independently a linear C _1-3 alkylene group, a C _3-6 cycloalkylene group or C _{6 -10 represents an} arylene group).

As a specific example of “a spacer having 1 to 5 atoms in the main chain of carbon atoms”,
(1) C _1-5 alkylene group (eg, —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —, — _{CH (CH 3) -, -} CH (C 2 H 5) -, - CH (C 3 H 7) -, - CH (i-C 3 H 7) -, - CH (CH 3) -CH 2 -, _{-CH 2 CH (CH 3) -} , - CH (CH 3) (CH 2) 2 -, - (CH 2) 2 CH (CH 3) -, - CH 2 -CH (CH 3) -CH 2 -, _{-C (CH 3) 2 -,} - (CH (CH 3)) 2 -, - CH (CH 3) -CH (CH 3) -, - CH 2 -C (CH 3) 2 -);
(2) C _2-4 alkenylene group (eg, —CH═CH—, —CH═CH—CH ₂ —, —CH ₂ —CH═CH—, —C (CH ₃ ) ₂ —CH═CH—, — _{CH 2 -CH = CH-CH 2} -, - CH 2 -CH 2 -CH = CH -, - CH = CH-CH = CH -, - C (CH 3) = CH -, - CH = C (CH 3 _{) -, - CH = C (} C 2 H 5) -);
(3) C _2-4 alkynylene group (eg, —C≡C—, —CH ₂ —C≡C—, —CH ₂ —C≡C—CH ₂ —);
(4) C _3-6 cycloalkylene group (eg, 1,2-cyclopropylene, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene);
(5) C _6-10 arylene group (eg, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene);
(6) -X ^1a -X ^2a- (wherein, X ^1a and X ^2a are each independently a linear C _1-3 alkylene group or a C _3-6 cycloalkylene group (eg, 1,2-cyclopropylene) ) Or a C _6-10 arylene group (eg, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene));
Etc.

The "having 1 to the main chain of atoms consisting of carbon atoms five spacer", _{preferably, C 1-5} alkylene _{group, C 2-5} alkenylene group or ^-X 1a ^{-X 2a} - (wherein each symbol Is as defined above.

L ^1a and L ^1b are preferably independently
(A) a halogen atom (preferably a fluorine atom),
A substitution selected from (b) a hydroxy group, and (c) a C _1-6 alkyl-carbonyl group (preferably acetyl), and a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, tert-butoxycarbonyl) Each optionally substituted with 1 to 3 substituents selected from amino groups that may be mono- or di-substituted with groups,
(1) C _1-5 alkylene group (preferably —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —, _{- (CH 2) 2 CH (} CH 3) -, - CH 2 -C (CH 3) 2 -);
(2) C _2-5 alkenylene group (preferably —CH═CH—); or (3) —X ^1a —X ^2a — (wherein each symbol is as defined above);
It is.

L ^1a and L ^1b are more preferably independently
(A) a halogen atom (preferably a fluorine atom),
1 to 3 selected from (b) a hydroxy group, and (c) an amino group which may be mono- or di-substituted with a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, tert-butoxycarbonyl) Each may be substituted with a substituent,
(1) C _2-4 alkylene group (preferably — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₂ CH (CH ₃ ) —, _{-CH 2 -C (CH 3) 2} -); or _{(2) C 2-4} alkenylene group (preferably, -CH = CH-);
It is.

  A is preferably of the formula

(Where
R ^6a and ^{R 6b} are independently formula ^{-CO-OR A1,}
-CO-NR ^A2 R ^B2 ,
-SOR ^A1 ,
—SO ₂ R ^A1 ,
-SO ₃ R ^A1 ,
—SO ₂ NR ^A2 R ^B2 , or —PO ₃ R ^A1 R ^B1
(Where
R ^A1 and R ^B1 independently represent a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted 5- or 6-membered heterocyclic group (preferably independently A hydrogen atom, a C _1-6 alkyl group (preferably methyl, ethyl, tert-butyl), or a 5- or 6-membered heterocyclic group (preferably a 5- or 6-membered aromatic heterocyclic group (preferably triazolyl) , Tetrazolyl))); and R ^A2 and R ^B2 are independently a hydrogen atom or an optionally substituted hydrocarbon group (preferably independently a hydrogen atom or Good C _1-6 alkyl groups, more preferably independently,
(1) a hydrogen atom; or
(2) a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group, a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl) and a carboxy group (Preferably methyl, ethyl)). );
Or a group represented by
(1) a carboxy group;
(2) a C _1-6 alkyl group (preferably methyl, ethyl);
(3) a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl); and
(4) an oxo group;
A 5- or 6-membered heterocyclic group (preferably pyridyl, furyl, thiazolyl, pyrazolyl, tetrazolyl, dioxolanyl, oxadiazolinyl, oxadiazolidinyl, optionally substituted by 1 to 3 substituents selected from Thiadiazolidinyl, imidazolidinyl, thiazolidinyl);
R ^4a , R ^5a , R ^4b and R ^5b are
(1) Independently, a hydrogen atom, a halogen atom (preferably a chlorine atom, a bromine atom), an optionally substituted C _1-6 alkyl group (preferably methyl), or an optionally substituted 5 Or a 6-membered ring group (preferably an aromatic ring group (preferably phenyl))
(Preferably independently a hydrogen atom, a halogen atom (preferably a chlorine atom, a bromine atom), a C _1-6 alkyl group (preferably methyl), or a 5- or 6-membered ring group (preferably an aromatic ring) Group (preferably phenyl))), or
(2) R ^4a and R ^5a together with the adjacent carbon atom are (a) a halogen atom (preferably a fluorine atom or a chlorine atom), (b) 1 to 3 halogen atoms (preferably A C _1-6 alkyl group (preferably methyl) optionally substituted with a fluorine atom), (c) optionally substituted with 1 to 3 C _1-6 alkoxy groups (preferably methoxy) A C _1-6 alkoxy group (preferably methoxy, ethoxy), (d) a cyano group, and (e) an amidated carboxy group [preferably the formula —CO—NR ^A3 R ^B3 (wherein R ^A3 and R ^B3 are independently a hydrogen atom or a C _1-6 alkyl group (preferably ethyl), or R ^A3 and R ^B3 together with the adjacent nitrogen atom are 5 or 6 Nitrogen inclusion (Preferably morpholine) heterocycle to form a 1 selected from.)] To three substituents may be substituted respectively, may form a benzene ring or a pyridine ring, or (3,) R ^4b and R ^5b together with adjacent carbon atoms are (a) a halogen atom (preferably a fluorine atom, a chlorine atom), (b) 1 to 3 halogen atoms (preferably a fluorine atom) optionally substituted _{C 1-6} alkyl group (preferably, methyl), optionally substituted with (c) 1 to 3 _{C 1-6} alkoxy groups (preferably methoxy) _{C 1-6} an alkoxy group (preferably, methoxy, ethoxy), (d) cyano group, and (e) amidation which may be carboxy group [preferably, the formula ^-CO-NR A3 ^{R B3 (wherein, R A3} and R ^B3 is independently a hydrogen atom or a C _1-6 alkyl group (preferably ethyl), or R ^A3 and R ^B3 together with the adjacent nitrogen atom are 5- or 6-membered nitrogen-containing A heterocyclic ring (preferably morpholine))] may be substituted with 1 to 3 substituents each selected from the above, may form a benzene ring or a pyridine ring;
R ⁷ is an optionally halogenated C _1-6 alkyl group (preferably a C _1-6 alkyl group (preferably methyl); more preferably methyl); and L ^1a and L ^1b
(A) a halogen atom (preferably a fluorine atom),
A substitution selected from (b) a hydroxy group, and (c) a C _1-6 alkyl-carbonyl group (preferably acetyl), and a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, tert-butoxycarbonyl) Each optionally substituted with 1 to 3 substituents selected from amino groups that may be mono- or di-substituted with groups,
(1) C _1-5 alkylene group (preferably —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —, _{- (CH 2) 2 CH (} CH 3) -, - CH 2 -C (CH 3) 2 -);
(2) C _2-5 alkenylene group (preferably —CH═CH—); or (3) —X ^1a —X ^2a — (wherein each symbol is as defined above);
It is. )
It is group represented by these.

  In another preferred embodiment, A is more preferably of the formula

(In the formula, each symbol has the same meaning as described in [1] above.)
It is group represented by these.

  In this embodiment, A is more preferably a formula

(Where
R ^6a is of the formula —CO—OR ^A1 ,
-CO-NR ^A2 R ^B2 ,
-SOR ^A1 ,
—SO ₂ R ^A1 ,
-SO ₃ R ^A1 ,
—SO ₂ NR ^A2 R ^B2 , or —PO ₃ R ^A1 R ^B1
(Where
R ^A1 and R ^B1 independently represent a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted 5- or 6-membered heterocyclic group (preferably independently A hydrogen atom, a C _1-6 alkyl group (preferably methyl, ethyl, tert-butyl), or a 5- or 6-membered heterocyclic group (preferably a 5- or 6-membered aromatic heterocyclic group (preferably triazolyl) , Tetrazolyl))); and R ^A2 and R ^B2 are independently a hydrogen atom or an optionally substituted hydrocarbon group (preferably independently a hydrogen atom or Good C _1-6 alkyl groups, more preferably independently,
(1) a hydrogen atom; or
(2) a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group, a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl) and a carboxy group (Preferably methyl, ethyl)). );
Or a group represented by
(1) a carboxy group;
(2) a C _1-6 alkyl group (preferably methyl, ethyl);
(3) a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl); and
(4) an oxo group;
A 5- or 6-membered heterocyclic group (preferably pyridyl, furyl, thiazolyl, pyrazolyl, tetrazolyl, dioxolanyl, oxadiazolinyl, oxadiazolidinyl, optionally substituted by 1 to 3 substituents selected from Thiadiazolidinyl, imidazolidinyl, thiazolidinyl);
R ^4a and R ^5a are independently a hydrogen atom, a halogen atom (preferably a chlorine atom or a bromine atom), an optionally substituted C _1-6 alkyl group (preferably methyl), or a substituted atom 5- or 6-membered ring group (preferably an aromatic ring group (preferably phenyl))
(Preferably independently a hydrogen atom, a halogen atom (preferably a chlorine atom, a bromine atom), a C _1-6 alkyl group (preferably methyl), or a 5- or 6-membered ring group (preferably an aromatic ring) A group (preferably phenyl))), or R ^4a and R ^5a together with adjacent carbon atoms, (a) a halogen atom (preferably a fluorine atom, a chlorine atom), (b) A C _1-6 alkyl group (preferably methyl) optionally substituted with 1 to 3 halogen atoms (preferably a fluorine atom), (c) 1 to 3 C _1-6 alkoxy groups (preferably It is, is a C _1-6 alkoxy group (preferably substituted with methoxy), methoxy, ethoxy), (d) cyano group, and (e) amidation which may be a carboxyl group [preferably, During ^-CO-NR A3 ^{R B3 (wherein, R A3} and ^{R B3} are, independently, a hydrogen atom or a _{C 1-6} alkyl group (preferably, ethyl) is either, ^{or, R A3} and ^{R B3} are neighboring Together with the nitrogen atom to form a 5- or 6-membered nitrogen-containing heterocycle (preferably morpholine))], a benzene ring each optionally substituted by 1 to 3 substituents Or may form a pyridine ring; and L ^1a is
(A) a halogen atom (preferably a fluorine atom),
A substitution selected from (b) a hydroxy group, and (c) a C _1-6 alkyl-carbonyl group (preferably acetyl), and a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, tert-butoxycarbonyl) Each optionally substituted with 1 to 3 substituents selected from amino groups that may be mono- or di-substituted with groups,
(1) C _1-5 alkylene group (preferably —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —, _{- (CH 2) 2 CH (} CH 3) -, - CH 2 -C (CH 3) 2 -);
(2) C _2-5 alkenylene group (preferably —CH═CH—); or (3) —X ^1a —X ^2a — (wherein each symbol is as defined above);
It is. )
It is group represented by these.

  In yet another preferred embodiment, A is more preferably a formula

(Where
R ^6a is a formula —CO—OR ^A1 (wherein R ^A1 is as defined above in [1]);
R ^4a and R ^5a together with the adjacent carbon atom are (a) a halogen atom, (b) an optionally substituted C _1-6 alkyl group, and (c) an optionally substituted C _{1. A} benzene ring optionally substituted with 1 to 3 substituents selected from a _-6 alkoxy group and (d) a cyano group; and L ^1a is
(A) a halogen atom (preferably a fluorine atom),
1 to 3 selected from (b) a hydroxy group, and (c) an amino group which may be mono- or di-substituted with a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, tert-butoxycarbonyl) Each may be substituted with a substituent,
(1) C _2-4 alkylene group (preferably — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₂ CH (CH ₃ ) —, _{-CH 2 -C (CH 3) 2} -); or _{(2) C 2-4} alkenylene group (preferably, -CH = CH-);
It is. )
It is group represented by these.

  In this embodiment, A is more preferably a formula

(Where
R ^6a is of the formula —CO—OR ^A1
(Wherein R ^A1 is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted 5- or 6-membered heterocyclic group (preferably independently a hydrogen atom, A C _1-6 alkyl group (preferably methyl, ethyl, tert-butyl), or a 5- or 6-membered heterocyclic group (preferably a 5- or 6-membered aromatic heterocyclic group (preferably triazolyl, tetrazolyl)) )).)
A group represented by:
R ^4a and ^{R 5a} together with the adjacent carbon atoms, (a) a halogen atom (preferably, fluorine atom, chlorine atom), (b) 1 to 3 halogen atoms (preferably, fluorine atoms) in an optionally substituted _{C 1-6} alkyl group (preferably, methyl), (c) 1 to 3 _{C 1-6} alkoxy group (preferably, methoxy) which may be substituted by _{C 1-} Forming a benzene ring optionally substituted with 1 to 3 substituents selected from ₆ alkoxy groups (preferably methoxy, ethoxy), and (d) cyano groups; and L ^1a is
(A) a halogen atom (preferably a fluorine atom),
1 to 3 selected from (b) a hydroxy group, and (c) an amino group which may be mono- or di-substituted with a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, tert-butoxycarbonyl) Each may be substituted with a substituent,
(1) C _2-4 alkylene group (preferably — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₂ CH (CH ₃ ) —, _{-CH 2 -C (CH 3) 2} -); or _{(2) C 2-4} alkenylene group (preferably, -CH = CH-);
It is. )
It is group represented by these.

X represents N or CH.
X is preferably N.

R ¹ and R ² are independently (1) a hydrogen atom, (2) a halogen atom, (3) an optionally substituted C _1-6 alkyl group, and (4) an optionally substituted C _{1. -6} alkoxy group, (5) optionally halogenated _{C 3-10} cycloalkyl group, (6) halogenated which may be _{C 3-10} cycloalkyloxy group, it has been (7) halogenated Or a C _6-14 aryl group, or (8) a cyano group.

Examples of the “optionally substituted C _1-6 alkyl group” and the “optionally substituted C _1-6 alkoxy group” represented by R ¹ or R ² include R ^4a , R ^5a , R ^4b or R ^Examples thereof include the same as the “optionally substituted C _1-6 alkyl group” and the “optionally substituted C _1-6 alkoxy group” represented by ^5b .

As "optionally halogenated and C _3-10 cycloalkyl group" represented by R ¹ or R ^2, similar to the "optionally halogenated and C _3-10 cycloalkyl group" represented by R ⁷ Can be mentioned.

The “optionally halogenated C _3-10 cycloalkyloxy group” represented by R ¹ or R ² may be substituted with 1 to 5 (preferably 1 to 3) halogen atoms. C _3-10 cycloalkyloxy group means, for example, fluorocyclopropyloxy, 2-fluorocyclobutyloxy, 2-fluorocyclopentyloxy, 2-fluorocyclohexyloxy, 2-fluorocycloheptyloxy, 2-fluorocyclooctyl Examples include oxy.

R ¹ or R ² in the "optionally halogenated C _6-14 aryl group" represented has 1 to 5 (preferably 1 to 3) which may be substituted with halogen atoms C _{6 -14} aryl group, for example, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,5-difluorophenyl, 2,4, Examples include 6-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-tridichlorophenyl, and the like.

R ¹ and R ² are preferably independently (1) a hydrogen atom, (2) a halogen atom (preferably a chlorine atom or a bromine atom), (3) an optionally substituted C _1-6 alkyl. group (preferably, an optionally halogenated C _1-6 alkyl group), or (4) an optionally substituted C _1-6 alkoxy group (preferably, an optionally halogenated C _{1- 6} alkoxy groups).

R ¹ is preferably a hydrogen atom, a halogen atom (preferably a chlorine atom), an optionally halogenated C _1-6 alkyl group, or an optionally halogenated C _1-6 alkoxy group. More preferably, they are a hydrogen atom or a halogen atom (preferably a chlorine atom).

R ² is preferably a hydrogen atom, a halogen atom (preferably a chlorine atom or a bromine atom), or an optionally substituted C _1-6 alkyl group (preferably methyl), more preferably a hydrogen atom. An atom, a halogen atom (preferably a chlorine atom, a bromine atom) or an optionally halogenated C _1-6 alkyl group (preferably trifluoromethyl), more preferably a hydrogen atom, a halogen atom ( Preferably, they are a chlorine atom, a bromine atom), or a halogenated C _1-6 alkyl group (preferably trifluoromethyl).

In another preferred embodiment, R ² is preferably a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group.

In this embodiment, more preferably, a halogen atom (preferably a chlorine atom or a bromine atom), an optionally halogenated C _1-6 alkyl group (preferably trifluoromethyl), or an optionally halogenated atom A good C _1-6 alkoxy group.

R ³ represents a hydrogen atom, a halogen atom or an optionally halogenated C _1-6 alkyl group.

Examples of the “optionally halogenated C _1-6 alkyl group” for R ³ include those similar to the “ _optionally halogenated C _1-6 alkyl group” for R ^7. .

R ³ is preferably a hydrogen atom, a halogen atom (preferably a fluorine atom or a chlorine atom), or a C _1-6 alkyl group (preferably methyl), more preferably a halogen atom (preferably a fluorine atom). An atom, a chlorine atom), or a C _1-6 alkyl group (preferably methyl).

In formula (I):
(I) when any one of R ¹ , R ² and R ³ is a hydrogen atom, the other two are not hydrogen atoms; and (ii) R ¹ is of the formula —COO—R ^C1 (wherein R ^C1 is _{C 1-6} alkyl radical, and the formula ^{-COO-R C2} (formula substituted in.) of a hydrogen atom or an optionally substituted _{C 1-6} alkyl ^{group, R C2} is hydrogen It is not a C _1-6 alkoxy group substituted by an atom or an optionally substituted C _1-6 alkyl group.

Preferable examples of compound (I) include the following compounds or salts thereof.
[Compound A]
Formula (I)

[Where:
A is the formula

(Where
R ^6a is a formula —CO—OR ^A1 (wherein R ^A1 is as defined above in [1]);
R ^4a and R ^5a are combined with adjacent carbon atoms to form a benzene ring (the benzene ring is (a) a halogen atom, (b) an optionally substituted C _1-6 alkyl group, (c) substituted) A C _1-6 alkoxy group which may be substituted, and (d) optionally substituted by 1 to 3 substituents selected from a cyano group; and L ^1a is (a) a halogen Optionally substituted with 1 to 3 substituents selected from an atom, (b) a hydroxy group, and (c) an amino group optionally mono- or di-substituted with a C _1-6 alkoxy-carbonyl group. , A C _2-4 alkylene group or a C _2-4 alkenylene group. )
A group represented by:
X is N or CH;
R ¹ is a hydrogen atom, a halogen atom, an optionally halogenated C _1-6 alkyl group, or an optionally halogenated C _1-6 alkoxy group;
R ² is a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group; and R ³ is a halogen atom, or C _1-6 alkyl It is a group. ]
Or a salt thereof.

[Compound B]
Formula (I)

[Where:
A is the formula

(Where
R ^6a and ^{R 6b} are independently formula ^{-CO-OR A1,}
-CO-NR ^A2 R ^B2 ,
-SOR ^A1 ,
—SO ₂ R ^A1 ,
-SO ₃ R ^A1 ,
—SO ₂ NR ^A2 R ^B2 , or —PO ₃ R ^A1 R ^B1
(Where
R ^A1 and R ^B1 independently represent a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted 5- or 6-membered heterocyclic group (preferably independently A hydrogen atom, a C _1-6 alkyl group (preferably methyl, ethyl, tert-butyl), or a 5- or 6-membered heterocyclic group (preferably a 5- or 6-membered aromatic heterocyclic group (preferably triazolyl) , Tetrazolyl))); and R ^A2 and R ^B2 are independently a hydrogen atom or an optionally substituted hydrocarbon group (preferably independently a hydrogen atom or Good C _1-6 alkyl groups, more preferably independently,
(1) a hydrogen atom; or
(2) a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group, a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl) and a carboxy group (Preferably methyl, ethyl)). );
Or a group represented by
(1) a carboxy group;
(2) a C _1-6 alkyl group (preferably methyl, ethyl);
(3) a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl); and
(4) an oxo group;
A 5- or 6-membered heterocyclic group (preferably pyridyl, furyl, thiazolyl, pyrazolyl, tetrazolyl, dioxolanyl, oxadiazolinyl, oxadiazolidinyl, optionally substituted by 1 to 3 substituents selected from Thiadiazolidinyl, imidazolidinyl, thiazolidinyl);
R ^4a , R ^5a , R ^4b and R ^5b are
(1) Independently, a hydrogen atom, a halogen atom (preferably a chlorine atom, a bromine atom), an optionally substituted C _1-6 alkyl group (preferably methyl), or an optionally substituted 5 Or a 6-membered ring group (preferably an aromatic ring group (preferably phenyl))
(Preferably independently a hydrogen atom, a halogen atom (preferably a chlorine atom, a bromine atom), a C _1-6 alkyl group (preferably methyl), or a 5- or 6-membered ring group (preferably an aromatic ring) Group (preferably phenyl))), or
(2) R ^4a and R ^5a together with the adjacent carbon atom are (a) a halogen atom (preferably a fluorine atom or a chlorine atom), (b) 1 to 3 halogen atoms (preferably A C _1-6 alkyl group (preferably methyl) optionally substituted with a fluorine atom), (c) optionally substituted with 1 to 3 C _1-6 alkoxy groups (preferably methoxy) A C _1-6 alkoxy group (preferably methoxy, ethoxy), (d) a cyano group, and (e) an amidated carboxy group [preferably the formula —CO—NR ^A3 R ^B3 (wherein R ^A3 and R ^B3 are independently a hydrogen atom or a C _1-6 alkyl group (preferably ethyl), or R ^A3 and R ^B3 together with the adjacent nitrogen atom are 5 or 6 Nitrogen inclusion (Preferably morpholine) heterocycle to form a 1 selected from.)] To three substituents may be substituted respectively, may form a benzene ring or a pyridine ring, or (3,) R ^4b and R ^5b together with adjacent carbon atoms are (a) a halogen atom (preferably a fluorine atom, a chlorine atom), (b) 1 to 3 halogen atoms (preferably a fluorine atom) optionally substituted _{C 1-6} alkyl group (preferably, methyl), optionally substituted with (c) 1 to 3 _{C 1-6} alkoxy groups (preferably methoxy) _{C 1-6} an alkoxy group (preferably, methoxy, ethoxy), (d) cyano group, and (e) amidation which may be carboxy group [preferably, the formula ^-CO-NR A3 ^{R B3 (wherein, R A3} and R ^B3 is independently a hydrogen atom or a C _1-6 alkyl group (preferably ethyl), or R ^A3 and R ^B3 together with the adjacent nitrogen atom are 5- or 6-membered nitrogen-containing A heterocyclic ring (preferably morpholine))] may be substituted with 1 to 3 substituents each selected from the above, may form a benzene ring or a pyridine ring;
R ⁷ is an optionally halogenated C _1-6 alkyl group (preferably a C _1-6 alkyl group (preferably methyl); more preferably methyl); and L ^1a and L ^1b
(A) a halogen atom (preferably a fluorine atom),
A substitution selected from (b) a hydroxy group, and (c) a C _1-6 alkyl-carbonyl group (preferably acetyl), and a C _1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, tert-butoxycarbonyl) Each optionally substituted with 1 to 3 substituents selected from amino groups that may be mono- or di-substituted with groups,
(1) C _1-5 alkylene group (preferably —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —, _{- (CH 2) 2 CH (} CH 3) -, - CH 2 -C (CH 3) 2 -);
(2) C _2-5 alkenylene group (preferably —CH═CH—); or (3) —X ^1a —X ^2a — (wherein each symbol is as defined above);
It is. )
A group represented by:
X is N or CH;
R ¹ and R ² are independently (1) a hydrogen atom, (2) a halogen atom (preferably a chlorine atom, a bromine atom), (3) an optionally substituted C _1-6 alkyl group (preferably Is an optionally halogenated C _1-6 alkyl group), or (4) an optionally substituted C _1-6 alkoxy group (preferably an optionally halogenated C _1-6 alkoxy group). And R ³ is a hydrogen atom, a halogen atom (preferably a fluorine atom or a chlorine atom), or a C _1-6 alkyl group (preferably methyl).
However,
(I) when any one of R ¹ , R ² and R ³ is a hydrogen atom, the other two are not hydrogen atoms; and (ii) R ¹ is of the formula —COO—R ^C1 (wherein R ^C1 is _{C 1-6} alkyl radical, and the formula ^{-COO-R C2} (formula substituted in.) of a hydrogen atom or an optionally substituted _{C 1-6} alkyl ^{group, R C2} is hydrogen It is not a C _1-6 alkoxy group substituted by an atom or an optionally substituted C _1-6 alkyl group. ]
Or a salt thereof.

  The salt of the compound represented by the formula (I) is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid. And salts with basic or acidic amino acids.

  Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt and ammonium salt.

  Preferable examples of the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, And salts with dicyclohexylamine, N, N-dibenzylethylenediamine and the like.

  Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

  Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid And salts with p-toluenesulfonic acid and the like.

Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

  A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. A compound that changes to compound (I) by hydrolysis or the like due to gastric acid or the like. Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, tetrahydropyranylation, pyrrolidylmethylation, pivaloyloxymethylation or tert-butylation Compound); a compound wherein the hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated (eg, hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinyl , Fumarylation, alanylation, dimethylaminomethylcarbonylation or tetrahydation Compound obtained by esterifying or amidating the carboxy group of compound (I) (eg, carboxy group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl) Esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl Esterified or methylamidated compounds) and the like. These compounds can be produced from compound (I) by a method known per se.

  In addition, prodrugs of Compound (I) can be obtained under the physiological conditions as described in Hirokawa Shoten 1990, “Development of Pharmaceuticals”, Volume 7, Molecular Design, pages 163 to 198. It may change to.

  Compound (I) may be a crystal, and the crystal form of the crystal may be single or plural. Crystals can be produced using a crystallization method known per se.

  The crystals of compound (I) are excellent in physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), drug efficacy), pharmaceuticals As extremely useful.

Compound (I) may be a solvate (eg, hydrate) or non-solvate (eg, non-hydrate), and these are all encompassed in compound (I). The
A compound labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I) or the like is also encompassed in the compound (I).
Further, a deuterium converter obtained by converting ¹ H into ² H (D) is also encompassed in compound (I).

  Compound (I) or a prodrug thereof (hereinafter sometimes simply referred to as the compound of the present invention) is toxic (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity) ) Is low, as it is, or mixed with a pharmacologically acceptable carrier or the like to prepare a pharmaceutical composition, so that mammals (eg, human, mouse, rat, rabbit, dog, cat, cow, horse, pig) , Monkeys) can be used as a prophylactic / therapeutic agent for various diseases described later or an insulin resistance improving agent.

  Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.

  Preferable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Anhydrous silicic acid, synthetic aluminum silicate, magnesium magnesium metasilicate, etc. are mentioned.

Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Preferable examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples thereof include propylmethylcellulose and polyvinylpyrrolidone.

  Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low substituted hydroxypropyl cellulose and the like.

Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Etc.

  Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; for example, polyvinyl alcohol, Examples include hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.

Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
Preferable examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, citrate and the like.
Preferable examples of the soothing agent include benzyl alcohol.

Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Preferable examples of the antioxidant include sulfite and ascorbate.
Preferred examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (E.g., aluminum salt of the water-soluble edible tar dye), natural dyes (e.g., [beta] -carotene, chlorophyll, bengara) and the like.
Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.

Examples of the dosage form of the pharmaceutical composition include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, and lozenges. Oral preparations such as syrup, emulsion, suspension, film (eg, orally disintegrating film); and injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, Intravenous preparations, external preparations (eg, transdermal preparations, ointments), suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops Oral preparations are mentioned. These can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration).
These preparations may be controlled-release preparations (eg, sustained-release microcapsules) such as immediate-release preparations or sustained-release preparations.

The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.

The compound of the present invention has a blood glucose lowering action, a blood lipid lowering action, an insulin resistance improving action, an insulin sensitivity enhancing action and a peroxisome proliferator-responsive receptor (hereinafter sometimes abbreviated as PPAR) γ (GenBank Accession No. L40904) Has agonist (activation) action. Here, PPARγ is a retinoid X receptor (hereinafter sometimes abbreviated as RXR) α (GenBank Accession No. X52773), RXRβ (GenBank Accession No. M84820) or RXRγ (GenBank Accession No. U38480). A heterodimeric receptor may be formed.
The compound of the present invention has a selective partial agonist (partial agonist) action particularly on PPARγ.
It has been reported that selective partial agonists for PPARγ do not have side effects such as weight gain, adipocyte accumulation, cardiac hypertrophy, etc., compared to full agonists (eg, thiazolidinedione compounds) for PPARγ (molecular endoclinology ( Molecular Endocrinology), Vol. 17, No. 4, pp. 662, 2003), the compounds of the present invention are not accompanied by side effects such as weight gain, adipocyte accumulation, cardiac hypertrophy, etc., compared with full agonists for PPARγ. It is useful as a hypoglycemic agent.
The compound of the present invention is, for example, a prophylactic / therapeutic agent for diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, obesity type diabetes); hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, high LDL) Preventive / therapeutic agent for cholesterolemia, low HDL choleslerolemia, postprandial hyperlipidemia); Insulin resistance improving agent; Insulin sensitivity enhancer; IGT (Impaired Glucose Tolerance) prevention / treatment An agent; and a transition inhibitor from impaired glucose tolerance to diabetes.

As for the criteria for determining diabetes, a new criterion has been reported by the Japan Diabetes Society.
According to this report, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher. This is a state in which the blood glucose level (glucose concentration in venous plasma) is at least 200 mg / dl as needed. In addition, the above-mentioned diabetes does not apply, and “fasting blood glucose level (glucose concentration in venous plasma) is less than 110 mg / dl or 75 g oral glucose tolerance test (75 gOGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / dl. A state that is not “a state indicating less than dl” (normal type) is referred to as a “boundary type”.

In addition, new criteria for diabetes have been reported by ADA (American Diabetes Association) and WHO.
According to these reports, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more, or a 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) of 200 mg / dl or more. It is the state which shows.

  Further, according to the above reports of ADA and WHO, impaired glucose tolerance is a state in which the 2-hour value of 75 g oral glucose tolerance test (glucose concentration in venous plasma) is 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the state where the fasting blood glucose level (glucose concentration in venous plasma) is 100 mg / dl or more and less than 126 mg / dl is called IFG (Impaired Fasting Glucose). On the other hand, WHO calls this IFG (Impaired Fasting Glucose) an IFG (Impaired Fasting Glycaemia) with a fasting blood glucose level (glucose concentration in venous plasma) of 110 mg / dl or more and less than 126 mg / dl.

  The compound of the present invention is also used as a prophylactic / therapeutic agent for diabetes, borderline type, glucose intolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycaemia) determined by the above-mentioned new criteria. Furthermore, the compound of the present invention can also prevent progression from borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycaemia) to diabetes.

  The compound of the present invention can be used, for example, for diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infection (eg, respiratory infection, Urinary tract infection, digestive tract infection, skin soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorder, peripheral blood circulation disorder], obesity, osteoporosis, cachexia ( Examples: Cancer cachexia, tuberculosis cachex, diabetic cachexia, blood disease cachexia, endocrine disease cachexia, infectious cachexia or cachexia due to acquired immune deficiency syndrome), fatty liver, hypertension , Polycystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephropathy, end-stage renal disease), muscular dystrophy, myocardial infarction, angina, cerebrovascular Disorder (eg, cerebral infarction, stroke), insulin Anti-Syndrome, Syndrome X, Metabolic Syndrome (highly triglyceride (TG) emia, low HDL cholesterol (HDL-C) emia, hypertension, abdominal obesity and glucose intolerance) Insulinemia, sensory disturbance in hyperinsulinemia, tumor (eg, leukemia, breast cancer, prostate cancer, skin cancer), irritable bowel syndrome, acute or chronic diarrhea, inflammatory disease (eg, arteriosclerosis (eg, atherosclerosis) Atherosclerosis), rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout, post-traumatic inflammation, swelling, neuralgia, sore throat, cystitis, hepatitis (including non-alcoholic steatohepatitis) ), Pneumonia, pancreatitis, inflammatory bowel disease, ulcerative colitis, chronic obstructive pulmonary disease (COPD)), visceral obesity syndrome, foot ulcer, sepsis, psoriasis, etc. It can also be used to.

  The compound of the present invention can also be used to improve symptoms such as abdominal pain, nausea, vomiting, and upper abdominal discomfort associated with peptic ulcer, acute or chronic gastritis, biliary dyskinesia, cholecystitis and the like.

  The compound of the present invention is also used as a prophylactic / therapeutic agent for inflammatory diseases involving TNF-α. Here, an inflammatory disease involving TNF-α is an inflammatory disease that develops due to the presence of TNF-α and can be treated through a TNF-α inhibitory effect. Examples of such inflammatory diseases include diabetic complications (eg, retinopathy, nephropathy, neuropathy, macrovascular disorders), rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout, surgery -Post-traumatic inflammation, swelling, neuralgia, sore throat, cystitis, hepatitis, pneumonia, gastric mucosal damage (including gastric mucosal damage caused by aspirin), etc.

  The compound of the present invention has an apoptosis-inhibiting action, and is also used as a prophylactic / therapeutic agent for diseases involving the promotion of apoptosis. Here, diseases associated with the promotion of apoptosis include, for example, viral diseases (eg, AIDS, fulminant hepatitis), neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa). Cerebellar degeneration), spinal dysplasia disease (eg, aplastic anemia), ischemic disease (eg, myocardial infarction, stroke), liver disease (eg, alcoholic hepatitis, hepatitis B, hepatitis C), joint disease (Eg, osteoarthritis), atherosclerosis and the like.

The compound of the present invention reduces visceral fat, suppresses visceral fat accumulation, improves glucose metabolism, improves lipid metabolism, improves insulin resistance, suppresses oxidized LDL production, improves lipoprotein metabolism, improves coronary metabolism, prevents cardiovascular complications It is also used for treatment, prevention and treatment of heart failure complications, blood remnant reduction, anovulation prevention and treatment, hirsutism prevention and treatment, hyperandrogenemia prevention and treatment, etc.
The compound of the present invention is also used for secondary prevention and suppression of progression of the various diseases described above (eg, cardiovascular events such as myocardial infarction).

  The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc. For example, when orally administered to an adult diabetic patient, it is usually about 0.005 to 50 mg / kg body weight as a single dose. The dose is preferably 0.01 to 2 mg / kg body weight, more preferably 0.025 to 0.5 mg / kg body weight, and it is desirable to administer this amount once to three times a day.

  The compound of the present invention comprises a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an anti-obesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, an antithrombotic agent, a therapeutic agent for osteoporosis, It can be used in combination with drugs (hereinafter abbreviated as concomitant drugs) such as dementia drugs, erectile dysfunction-improving drugs, urinary incontinence / frequent urination drugs, and dysuria drugs. These concomitant drugs may be low molecular weight compounds, or may be macromolecular proteins, polypeptides, antibodies, nucleic acids (including antisense nucleic acids, siRNA, shRNA), or vaccines. .

The administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference.
Examples of dosage forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) 2 obtained by separately formulating the compound of the present invention and the concomitant drug. Simultaneous administration by the same route of administration of the seed preparations, (3) administration of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug at different times in the same route of administration, (4) Simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes, (5) Two preparations obtained by separately formulating the compound of the present invention and a concomitant drug And the like (eg, administration in the order of the compound of the present invention and the concomitant drug, or administration in the reverse order).

  The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

The therapeutic agent for diabetes includes insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin Fragment or derivative (eg, INS-1), oral insulin preparation), insulin resistance improving agent (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate), Tesaglitazar, Ragaglitazar, Muraglitazar, Edaglitazone, Metaglidasen, Naveglitazar, AMG-131, THR-0921, TAK-379 E.g. voglibose, acarbose, Miglitol, emiglitate), biguanide (eg, metformin, buformin or salts thereof (eg, hydrochloride, fumarate, succinate)), insulin secretagogue [sulfonylsulfonyl (eg, tolbutamide, glibenclamide, gliclazide, chlor) Propamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybsol), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate], dipeptidyl peptidase IV inhibitor (eg, alogliptin or its salt ( Preferably, benzoate), vildagliptin, sitagliptin, saxagliptin, T-6666, TS-021), β3 agonist (eg, AJ-9677), GPR40 agonist, GLP- Receptor agonist [e.g., GLP-1, GLP-1MR agent, NN-2211, AC-2993 (exendin-4), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH 2, CJC -1131], amylin agonist (eg, pramlintide), phosphotyrosine phosphatase inhibitor (eg, sodium vanadate), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist), SGLUT (Sodium-glucose cotransporter) inhibitors (eg, T-1095), 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498), adiponectin or agonists thereof, IKK inhibitors (eg, AS-2868), leptin resistance Improver, somatostatin receptor agonist, glucokinase activator (eg, Ro-28-1675), GIP (Glucose-dependent insulinotropic peptide), glucose-dependent insulin secretagogue (eg, TAK-875) It is below.

  Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minarerestat, fidarestat, CT-112, ranirestat (AS-3201)), neurotrophic factor and its Increaser (eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (eg, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl)- 5- [3- (2-methylphenoxy) propyl] oxazole), TAK-583), PKC inhibitors (eg, ruboxistaurin mesylate), AGE inhibitors (eg, ALT946, pimagedin, N- Phenacyl thiazolium bromide (ALT766), EXO-226, Pyridorin, pyridoxamine), active oxygen scavenger (eg, thioctic acid), cerebral vasodilator (eg, thiaprid, mexiletine), somatostatin receptor agonist (eg, BIM23190), apoptosis signal regulating kinase-1 ( ASK-1) inhibitors and the like.

  As a therapeutic agent for hyperlipidemia, an HMG-CoA reductase inhibitor (eg, cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, rosuvastatin, pitavastatin or a salt thereof (eg, sodium salt, calcium salt) )), Squalene synthase inhibitors (eg, lapaquistat or a salt thereof (preferably acetate)), fibrate compounds (eg, bezafibrate, clofibrate, simfibrate, clinofibrate), ACAT inhibitors (eg , Avasimibe, Eflucimibe, anion exchange resin (eg, cholestyramine), probucol, nicotinic acid drugs (eg, nicomol, niceritrol), ethyl icosapentate, plant Sterols (e.g., soysterol (Soysterol), gamma oryzanol (γ-oryzanol)), and the like.

  Antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril), angiotensin II antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan, olmesartan medoxomil, tasosartan, 1-[[ 2 ′-(2,5-Dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-1H-benzimidazole-7- Carboxylic acid, TAK-491), calcium channel blocker (eg, manidipine, nifedipine, nicardipine, amlodipine, efonidipine), potassium channel opener (eg, levcromakalim, L-27152, AL0671, NIP-121), clos Jin, and the like.

  Anti-obesity agents include, for example, central anti-obesity drugs (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonist Drugs (eg, SB-568849; SNAP-7941; compounds described in WO01 / 82925 and WO01 / 87834); neuropeptide Y antagonists (eg, CP-422935); cannabinoid receptor antagonists (eg, SR-141716, SR-147778); ghrelin antagonist; 11β-hydroxysteroid dehydrogenase inhibitor (eg, BVT-3498)), pancreatic lipase inhibitor (eg, orlistat, cetilistat (ATL-962)), β3 agonist ( Example , AJ-9777), peptidic appetite suppressant (eg, leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonist (eg, lynchtrypto, FPL-15849), antifeedant (eg, P- 57).

  Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide. , Methiclotiazide), anti-aldosterone preparations (eg, spironolactone, triamterene), carbonic anhydrase inhibitors (eg, acetazolamide), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide), azosemide, isosorbide, ethacrynic acid, Piretanide, bumetanide, furosemide and the like can be mentioned.

  Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide), antimetabolites (eg, methotrexate, 5-fluorouracil and derivatives thereof), anticancer antibiotics (eg, mitomycin, adriamycin). Plant-derived anticancer agents (eg, vincristine, vindesine, taxol), cisplatin, carboplatin, etoposide and the like. Of these, 5-fluorouracil derivatives such as flurtulon or neofluturon are preferable.

  Examples of immunotherapeutic agents include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin), and cytokines obtained by genetic engineering techniques (eg, , Interferon, interleukin (IL)), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin) and the like, and interleukins such as IL-1, IL-2 and IL-12 are particularly preferable.

  Antithrombotic agents include, for example, heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drugs (eg, argatroban, dabigatran) ), Thrombolytic agents (eg, urokinase, tisokinase, alteplase, nateplase, monteplase, pamitepase), platelet aggregation inhibitors (eg, ticlopidine hydrochloride) hydrochloride), cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride, prasugrel, E5555, SHC530348), FXa inhibitors (eg, TAK-442, rivaroxaban) ), Apixaban apixaban), DU-156, YM150) and the like.

  Examples of osteoporosis therapeutic agents include alfacalcidol, calcitriol, elcatonin, salmon calcitonin salmon, estriol, ipriflavone, risedronate disodium (risedronate) disodium), pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and the like.

Examples of the anti-dementia agent include tacrine, donepezil, rivastigmine, galanthamine and the like.
Examples of the erectile dysfunction ameliorating agent include apomorphine, sildenafil citrate, and the like.
Examples of the urinary incontinence / frequent urination therapeutic agent include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.
Examples of the dysuria therapeutic agent include acetylcholinesterase inhibitors (eg, distigmine).

  Concomitant drugs include drugs that have been shown to improve cachexia in animal models and clinically, ie cyclooxygenase inhibitors (eg, indomethacin), progesterone derivatives (eg, megesterol acetate), carbohydrate steroids (eg, Dexamethasone), metoclopramide drugs, tetrahydrocannabinol drugs, fat metabolism improvers (eg, eicosapentaenoic acid), growth hormone, IGF-1, or factors that induce cachexia TNF-α, LIF, IL -6, antibodies against Oncostatin M and the like are also included.

  Furthermore, as a concomitant drug, nerve regeneration promoting drugs (eg, Y-128, VX-853, prosaptide), antidepressants (eg, desipramine, amitriptyline, imipramine), antiepileptic drugs (eg, lamotrigine), antiarrhythmic drugs (Eg, mexiletine), acetylcholine receptor ligand (eg, ABT-594), endothelin receptor antagonist (eg, ABT-627), monoamine uptake inhibitor (eg, tramadol), narcotic analgesic (eg, morphine) GABA receptor agonist (eg, gabapentin), α2 receptor agonist (eg, clonidine), local analgesic (eg, capsaicin), anxiolytic (eg, benzodiazepine), dopamine agonist (eg, apomorphine), Midazolam, ketoconazole, etc. are also mentioned.

The concomitant drug is preferably an insulin preparation, an insulin resistance improving agent, an α-glucosidase inhibitor, a biguanide agent, an insulin secretagogue (preferably a sulfonylurea agent) and the like.
Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.

  When the compound of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the opposite effect of these agents. In particular, the insulin resistance improving agent, insulin secretagogue and biguanide can be reduced from the usual dose. Thus, the adverse effects that would be caused by these agents can be safely prevented. In addition, the dosage of diabetic complication therapeutics, hyperlipidemia therapeutics, antihypertensives can be reduced, and the adverse effects that would be caused by these agents can be effectively prevented.

Hereafter, the manufacturing method of this invention compound is demonstrated.
Compound (I) can be produced by a method known per se, for example, the following A1 method to AG method or a method analogous thereto. In each of the following production methods, the raw material compound may be used as a salt, and as such a salt, those exemplified as the salt of the compound represented by the formula (I) are used.

  Compound (I) is produced, for example, by the following method A1 or A2.

[Method A1]

[Wherein Y ¹ represents a leaving group, and other symbols are as defined above. ]
Here, examples of the “leaving group” represented by Y ¹ include a halogen atom, —OSO ₂ R ⁸ (wherein R ⁸ is a C _1-4 alkyl group which may be halogenated, or 1 to 3). And a C _6-10 aryl group _optionally substituted with a C _1-4 alkyl group).
Examples of the “optionally halogenated C _1-4 alkyl group” represented by R ⁸ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl and the like. Of these, methyl and trifluoromethyl are preferred.
The “C _1-4 alkyl group” in the “C _6-10 aryl group _optionally substituted with 1 to 3 C _1-4 alkyl groups” represented by R ⁸ is, for example, methyl, ethyl, propyl, Examples include isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and methyl is preferable.
As _{"C 6-10} aryl group" of the "one to three _{C 1-4} alkyl optionally _{C 6-10} aryl group which may be substituted with a group" represented by R ^8, mentioned for example phenyl, naphthyl and Of these, phenyl is preferred.
Y ¹ is preferably a halogen atom, trifluoromethanesulfonyloxy or the like.
In this method, compound (I) can be produced by reacting compound (II) with compound (III). This reaction is usually performed in the presence of a base in a solvent that does not adversely influence the reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide Etc.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; ketones such as acetone and 2-butanone; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and isopropyl acetate; N, N-dimethylformamide; Examples thereof include amides such as N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
In this method, the reaction may be carried out in the presence of an organometallic catalyst and a phosphorus ligand. In that case, a reaction known per se, for example, Journal of the American Chemical Society, Vol. 128, 2180 Page (2006) or a method analogous thereto.
Examples of the organometallic catalyst include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), and the like. It is done.
Examples of the phosphorus ligand include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), tris (2-methylphenyl) phosphine, and 1,1′-bis (diphenylphosphino). ) Ferrocene, (2-biphenyl) dicyclohexylphosphine (XPhos), 1,2,3,4,5-pentaphenyl-1 ′-(ditert-butylphosphino) ferrocene (Q-Phos), (R) -1 -[(1S) -2- (diphenylphosphino) ferrocenyl] ethylditert-butylphosphine, (S) -1-[(1R) -2- (diphenylphosphino) ferrocenyl] ethylditert-butylphosphine, 5- ( Di-tert-butyl-phosphino) -1 ′, 3 ′, 5′-triphenyl-1′H- [1,4 ′] bipyrazole, (4- (N, N-dimethyl) Arylamino) phenyl) di -tert- butylphosphine.
The amount of compound (III) to be used is generally 0.1 to 20 mol, preferably 0.5 to 2 mol, per 1 mol of compound (II).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (II).
The usage-amount of an organometallic catalyst is 0.001-1 mol normally with respect to 1 mol of compound (II), Preferably it is 0.01-0.5 mol.
The usage-amount of a phosphorus ligand is 0.001-1 mol normally with respect to 1 mol of compounds (II), Preferably it is 0.01-0.5 mol.
The reaction temperature is generally −30 to 180 ° C., preferably −10 to 150 ° C.
The reaction time is usually 0.5 to 100 hours.
In addition, compound (II) used as a raw material compound by this method can be manufactured in accordance with the O method mentioned later, T1 method, or the method according to these, for example. Compound (III) can be produced according to a method known per se.

[Method A2]

[Wherein Y ² represents a leaving group, and other symbols are as defined above. ]
Examples of the “leaving group” represented by Y ² include the same “leaving group” represented by Y ¹ . Of these, a halogen atom, trifluoromethanesulfonyloxy and the like are preferable.
In this method, compound (I) can be produced by reacting compound (IV) with compound (V). This reaction is carried out in the same manner as described in the aforementioned method A1.
In addition, compound (IV) used as a raw material compound by this method can be manufactured in accordance with the Q1 method, Q2 method mentioned later, or the method according to these, for example. Compound (V) can be produced according to a method known per se.

  In formula (I), A is

The compound (I-1) is, for example, produced by the following method B.
[Method B]

[Wherein Y ³ represents a leaving group, and other symbols are as defined above. ]
Here, examples of the “leaving group” represented by Y ³ include the same “leaving group” represented by Y ¹ or Y ² . Of these, a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy and the like are preferable.
In this method, compound (I-1) can be produced by reacting compound (VI) with compound (VII). This reaction is usually performed in the presence of a base in a solvent that does not adversely influence the reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide Etc.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; ketones such as acetone and 2-butanone; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and isopropyl acetate; N, N-dimethylformamide; Examples thereof include amides such as N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The amount of compound (VII) to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (VI).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (VI).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.
In addition, the compound (VI) used as a raw material compound by this method can be manufactured according to the R1 method, R2 method, Z method mentioned later, or the method according to these, for example. Compound (VII) can be produced according to the AB method described later, a method analogous thereto, or a method known per se.

In the formula (I), a compound (I-2) wherein R ^6a or R ^6b is —CO—OR ⁹ , a compound (I-3) which is —CO—OH, and a compound which is —CO—NR ^A2 R ^B2 (I-4) can be produced, for example, by the following method C.
[Method C]

[Wherein R ⁹ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
B is

And other symbols are as defined above. ]
Here, above-mentioned "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" represented by R ^9, even if the are "substituted represented by R ^A1 or R ^B1 Examples thereof include the same as “good hydrocarbon group” and “optionally substituted heterocyclic group”. R ⁹ is preferably a C _1-6 alkyl group, more preferably methyl, ethyl, tert-butyl or the like.
In this method, compound (I-4) can be produced by reacting compound (I-3) with compound (I-3) from compound (I-2).

[Step 1]
In this step, compound (I-3) can be produced by subjecting compound (I-2) to hydrolysis or dealkylation.
The hydrolysis reaction of compound (I-2) (for example, when R ⁹ is methyl or ethyl) is carried out in a water-containing solvent in the presence of an acid or a base according to a conventional method.
Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; organic acids such as acetic acid.
Examples of the base include alkali metal carbonates such as potassium carbonate and sodium carbonate; alkali metal C _1-6 alkoxides such as sodium methoxide; alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide; potassium trimethyl Examples include silanol alkali metal salts such as silanolates.
The amount of acid or base used is usually an excess amount relative to compound (I-2). Preferably, the amount of acid used is 2 to 50 mol per 1 mol of compound (I-2), and the amount of base used is 1 to 5 mol per 1 mol of compound (I-2).
Examples of the hydrous solvent include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, dioxane and diethyl ether; a mixed solvent of one or more solvents selected from dimethyl sulfoxide, acetone and the like.
The reaction temperature is usually -20 to 150 ° C, preferably -10 to 100 ° C.
The reaction time is usually 0.1 to 20 hours.

The dealkylation reaction of compound (I-2) (for example, when R ⁹ is tert-butyl) is performed according to a conventional method in the presence of an acid in a solvent that does not adversely influence the reaction.
Examples of acids include inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; organic acids such as trifluoroacetic acid; and Lewis acids such as trimethylsilyl trifluoromethanesulfonate, borane trichloride, borane tribromide, and trimethylsilyl trifluoromethanesulfonate. Etc.
The amount of the acid to be used is generally an excess amount, preferably 2 to 50 mol, relative to 1 mol of compound (I-2).
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene, xylene, and pentamethylbenzene; aromatic ethers such as anisole; aromatic thioethers such as thioanisole; tetrahydrofuran, dioxane, Ethers such as diethyl ether; Ketones such as acetone and 2-butanone; Halogenated hydrocarbons such as chloroform and dichloromethane; Nitriles such as acetonitrile and propionitrile; Esters such as ethyl acetate and isopropyl acetate; N, Examples include amides such as N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is usually -20 to 150 ° C, preferably -10 to 100 ° C.
The reaction time is usually 0.1 to 20 hours.

[Step 2]
This step is performed by a method known per se, for example, a method of directly condensing compound (I-3) and compound (VIII), or a method of reacting a reactive derivative of compound (I-3) with compound (VIII). Compound (I-4) can be produced.
Here, as the reactive derivative of compound (I-3), for example, acid anhydride, acid halide (for example, acid chloride, acid bromide), imidazolide, mixed acid anhydride (for example, methyl carbonate, ethyl carbonate, isobutyl carbonate, Pivalic acid, anhydrides with substituted benzoic acid, etc.), aryl esters (eg pentafluorophenyl ester, p-nitrophenyl ester, N-methylpyridinium-2-yl ester, 4,6-dimethoxytriazin-2-yl ester) Etc.

The method of directly condensing compound (I-3) and compound (VIII) is performed in the presence of a condensing agent in a solvent that does not adversely influence the reaction.
Examples of the condensing agent include carbodiimide condensing reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropyl carbodiimide and hydrochloride thereof; phosphoric acid condensing reagents such as diethyl cyanophosphate and diphenylphosphoric acid azide; N , N′-carbonyldiimidazole, 2-methyl-6-nitrobenzoic anhydride, 2-chloro-1,3-dimethylimidazolium tetrafluoroborate, 2-chloro-1-methylpyridinium, N, N-dimethylsulfate Famoyl chloride, 2-chloro-4,6-dimethoxytriazine, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methyl-morpholinium chloride, etc. are generally known. A condensing agent.
Examples of the solvent that does not adversely influence the reaction include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene Ethers such as tetrahydrofuran, dioxane and diethyl ether; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and isopropyl acetate; alcohols such as methanol and ethanol; water and the like. These solvents may be mixed and used at an appropriate ratio.
The amount of compound (VIII) to be used is generally 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of compound (I-3).
The amount of the condensing agent to be used is generally 0.1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (I-3).
When a carbodiimide-based condensation reagent, 2-methyl-6-nitrobenzoic anhydride, or the like is used as the condensing agent, an appropriate condensation accelerator (for example, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzo The reaction efficiency can be improved by using triazole, N-hydroxysuccinimide, N-hydroxyphthalimide, 4-dimethylaminopyridine and the like. In addition, when using a phosphoric acid-based condensing reagent, 2-methyl-6-nitrobenzoic anhydride, etc. as the condensing agent, reaction efficiency is usually improved by adding an organic amine base such as triethylamine or diisopropylethylamine. Can be made.
The amount of the condensation accelerator and organic amine base used is usually 0.1 to 10 mol, preferably 0.3 to 3 mol, per 1 mol of compound (I-3).
The reaction temperature is usually −30 ° C. to 100 ° C.
The reaction time is usually 0.5 to 60 hours.

When the reactive derivative of compound (I-3) is reacted with compound (VIII), when an acid halide is used as the reactive derivative of compound (I-3), compound (I) is used in a solvent that does not adversely influence the reaction. -3) is reacted with a halogenating agent, and is reacted with compound (VIII) in the presence of a base.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; ketones such as acetone and 2-butanone; chloroform, dichloromethane and the like Halogenated hydrocarbons; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and isopropyl acetate; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Examples thereof include imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
Examples of the halogenating agent include thionyl chloride, oxalyl chloride, phosphoryl chloride and the like.
The reaction efficiency can be improved by adding a catalytic amount of N, N-dimethylformamide as necessary.
The amount of N, N-dimethylformamide to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 0.3 molar equivalents, relative to compound (I-3).
Examples of the base include amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene; Examples thereof include alkali metal salts such as sodium hydrogen, sodium carbonate, and potassium carbonate.
The amount of compound (VIII) to be used is generally 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of compound (I-3).
The amount of the halogenating agent to be used is generally 1-50 mol, preferably 1-10 mol, per 1 mol of compound (I-3).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (I-3).
The reaction temperature is usually −30 ° C. to 100 ° C.
The reaction time is usually 0.5 to 30 hours.

When a mixed acid anhydride is used as the reactive derivative of compound (I-3), compound (I-3) and chlorocarbonate or acid halide are added in the presence of a base in a solvent that does not adversely influence the reaction. The reaction is carried out by further reacting compound (VIII).
Examples of the solvent that does not adversely influence the reaction include those similar to the case of the acid halide described above.
Examples of the chlorocarbonate include methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate and the like.
Examples of the acid halide include pivaloyl chloride, 2,6-dichlorobenzoyl chloride, N, N-dimethylsulfamoyl chloride, methanesulfonyl chloride, and the like.
Examples of the base include amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine and N, N-dimethylaniline; alkali metal salts such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate.
The amount of compound (VIII) to be used is generally 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of compound (I-3).
The amount of the chlorocarbonate or acid halide to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (I-3).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (I-3).
The reaction temperature is usually −30 ° C. to 100 ° C.
The reaction time is usually 0.5 to 30 hours.

In addition, when imidazolide is used as a reactive derivative of compound (I-3), compound (I-3) is reacted with N, N′-carbonyldiimidazole in a solvent that does not adversely influence the reaction, and the presence of a base The reaction is then carried out by reacting with compound (VIII).
Examples of the solvent and base that do not adversely influence the reaction include those similar to the case of the acid halide described above.
The amount of compound (VIII) to be used is generally 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of compound (I-3).
The amount of N, N′-carbonyldiimidazole to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (I-3).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (I-3).
The reaction temperature is usually −30 ° C. to 100 ° C.
The reaction time is usually 0.5 to 30 hours.

When an aryl ester is used as the reactive derivative of compound (I-3), compound (I-3) is reacted with a halogenated arene or substituted phenol in a solvent that does not adversely influence the reaction, and the presence of a base The reaction is then carried out by reacting with compound (VIII).
Examples of the solvent that does not adversely influence the reaction include those similar to the case of the acid halide described above.
Examples of the halogenated arene include 2-chloro-1-methylpyridinium, 2-fluoro-1-methylpyridinium, 2-chloro-4,6-dimethoxytriazine and the like.
When reacting compound (I-3) with a substituted phenol, a condensing agent is used, and the reaction is carried out in the same manner as when reacting compound (I-3) and compound (VIII).
Examples of the substituted phenol include pentafluorophenol and p-nitrophenol.
Examples of the base include amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine and N, N-dimethylaniline; alkali metal salts such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate.
The amount of compound (VIII) to be used is generally 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of compound (I-3).
The amount of the substituted phenol to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (I-3).
The amount of the halogenated arene to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (I-3).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (I-3).
The reaction temperature is usually −30 ° C. to 100 ° C.
The reaction time is usually 0.5 to 30 hours.

  In addition, the compound (I-2) used as a raw material compound in this method is, for example, the above-mentioned A1 method, B method, N method, S method, T1 method, T2 method, U method, AE method described later or these It can be produced according to a similar method. Compound (VIII) can be produced according to a method known per se.

In formula (I), compound (I-5) in which R ^6a or R ^6b is —SO ₂ R ^A1 , and compound (I-6) in which —SOR ^A1 can be produced, for example, by the following Method D.
[Method D]

[Wherein each symbol is as defined above. ]
In this method, compound (I-5) or compound (I-6) can be produced by subjecting compound (IX) to an oxidation reaction.
This reaction is carried out according to a method known per se in the presence of an oxidizing agent in a solvent that does not adversely influence the reaction.
Examples of the solvent that does not adversely influence the reaction include ketones such as acetone, 2-butanone, 1,1,1-trifluoroacetone; methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, and tert-butanol. Alcohols such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and dimethoxyethane A halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane; water and the like. These solvents may be mixed and used at an appropriate ratio.
Examples of the oxidizing agent include hydrogen peroxide, m-chloroperbenzoic acid, potassium persulfate, and peracids such as sodium periodate.
When manufacturing compound (I-5), the usage-amount of an oxidizing agent is 1-50 mol normally with respect to 1 mol of compound (IX), Preferably it is 2-10 mol.
When manufacturing a compound (I-6), the usage-amount of an oxidizing agent is 0.5-10 mol normally with respect to 1 mol of compound (IX), Preferably it is 1-1.5 mol.
This reaction may be carried out in the presence of a base (for example, an alkali metal salt such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.). The amount is usually 1 to 50 mol, preferably 1 to 10 mol.
In addition, compound (IX) used as a raw material compound by this method can be manufactured according to the method W mentioned later or the method according to this, for example.

In formula (I), compound (I-7) in which R ^6a or R ^6b is —SO ₂ NR ^A2 R ^B2 can be produced, for example, by the following method E1.
[E1 method]

[Wherein, Y ⁴ and Y ⁵ each independently represent a leaving group, and other symbols are as defined above. ]
Examples of the “leaving group” represented by Y ⁴ include the same “leaving group” represented by Y ¹ or Y ² . Y ⁴ is preferably a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, or the like.
Y ⁵ is preferably a halogen atom, particularly preferably a chlorine atom.
In this method, compound (XI) can be produced from compound (X), and compound (XI) can be reacted with compound (VIII) to produce compound (I-7).

[Step 1]
In this step, compound (XI) can be produced by a method known per se, for example, by subjecting compound (X) to sulfuration and subjecting the obtained compound to an oxidative halogenation reaction.
The sulfurization reaction of compound (X) is carried out in the presence of a sulfurizing agent, and optionally in the presence of a base or an organometallic catalyst and a phosphorus ligand, in a solvent that does not adversely influence the reaction.
Examples of the sulfurizing agent include thiourea, potassium thiocyanate, potassium thioacetate, benzyl mercaptan, triisopropylsilyl mercaptan, and potassium xanthate.
Examples of the base include amines such as N-methylmorpholine, triethylamine and diisopropylethylamine; alkali metal carbonates such as potassium carbonate and sodium carbonate; alkali metal C _1-6 alkoxide such as sodium methoxide; potassium hydroxide and water Examples thereof include alkali metal hydroxides such as sodium oxide and lithium hydroxide.
Examples of the organometallic catalyst include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), and the like. It is done.
Examples of the phosphorus ligand include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), tris (2-methylphenyl) phosphine, and 1,1′-bis (diphenylphosphino). ) Ferrocene, (2-biphenyl) dicyclohexylphosphine (XPhos), 1,2,3,4,5-pentaphenyl-1 ′-(ditert-butylphosphino) ferrocene (Q-Phos), (R) -1 -[(1S) -2- (diphenylphosphino) ferrocenyl] ethylditert-butylphosphine, (S) -1-[(1R) -2- (diphenylphosphino) ferrocenyl] ethylditert-butylphosphine, 5- ( Di-tert-butyl-phosphino) -1 ′, 3 ′, 5′-triphenyl-1′H- [1,4 ′] bipyrazole, (4- (N, N-di Chiruamino) phenyl) di -tert- butylphosphine.
The usage-amount of a sulfurizing agent is 1-20 mol normally with respect to 1 mol of compounds (X).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (X).
The usage-amount of an organometallic catalyst is 0.001-1 mol normally with respect to 1 mol of compound (X), Preferably it is 0.01-0.5 mol.
The usage-amount of a phosphorus ligand is 0.001-1 mol normally with respect to 1 mol of compounds (X), Preferably it is 0.01-0.5 mol.
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol, ethanol, propanol, 2-propanol, 2-methoxyethanol, butanol, isobutanol and tert-butanol; aromatic carbonization such as benzene, toluene and xylene Hydrogens; Aliphatic hydrocarbons such as hexane and heptane; Ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane; Dichloromethane, chloroform, 1,2-dichloroethane Halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; ethyl acetate, acetic acid and the like These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is generally −30 to 180 ° C., preferably −10 to 150 ° C.
The reaction time is usually 0.5 to 100 hours.

The oxidative halogenation reaction of the compound obtained by the sulfuration reaction of compound (X) is carried out in the presence of an oxidative halogenating agent, using an acid, if necessary, in a solvent that does not adversely influence the reaction. .
Examples of the oxidative halogenating agent include chlorine, sulfuryl chloride, N-chlorosuccinimide and the like.
Examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; organic acids such as formic acid and acetic acid.
The amount of the oxidative halogenating agent to be used is usually an excess amount in the case of chlorine and 1 to 20 mol in the case of sulfuryl chloride, N-chlorosuccinimide or the like with respect to 1 mol of compound (X).
The amount of the acid used is usually an excess amount relative to 1 mol of compound (X).
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol, ethanol, propanol, 2-propanol, 2-methoxyethanol, butanol, isobutanol and tert-butanol; aliphatic hydrocarbons such as hexane and heptane Ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane; dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc. Halogenated hydrocarbons; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone; ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is generally −70 to 150 ° C., preferably −20 to 80 ° C.
The reaction time is usually 0.1 to 50 hours.

[Step 2]
In this step, compound (I-7) can be produced by reacting compound (XI) with compound (VIII). This reaction is carried out in the same manner as the condensation reaction in Method C step 2.

  In addition, the compound (X) used as a raw material compound by this method can be manufactured, for example according to the W method mentioned later, X1 method, or the method according to these.

In formula (I), R ^6a or R ^6b is —SO ₃ R ¹⁰ (I-8) can be produced, for example, by the following E2 method.
[E2 method]

[Wherein R ¹⁰ represents a hydrogen atom or an alkali metal, and other symbols are as defined above. ]
Examples of the “alkali metal” represented by R ¹⁰ include sodium and potassium.
In this method, compound (I-8) can be produced by reacting compound (X) with sulfite. This reaction is performed according to a method known per se in the presence of sulfite in a solvent that does not adversely influence the reaction.
Examples of the sulfite include sodium sulfite.
The amount of sulfite to be used is generally 1 to 50 mol, preferably 1 to 10 mol, per 1 mol of compound (X).
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, dioxane and diethyl ether; dimethyl sulfoxide, acetone and the like. These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 80 ° C.
The reaction time is usually 0.1 to 20 hours.

  In formula (I), A is

The compound (I-9a) in which R ^6a is —PO ₃ R ^9a R ^9b and the compound (I-9b) in which —PO ₃ H ₂ can be produced by the following Method F, for example.
[F method]

[Wherein, R ^9a and R ^9b each independently represent a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and other symbols are as defined above. ]
As the “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group” represented by R ^9a or R ^9b , “optionally substituted” represented by R ^A1 or R ^B1 above. Examples thereof include the same as the “hydrocarbon group” and “optionally substituted heterocyclic group” (excluding a hydrogen atom). R ^9a and R ^9b are each preferably a C _1-6 alkyl group, more preferably methyl, ethyl, tert-butyl, or the like.
In this method, compound (I-9a) can be obtained by reacting compound (VI) with compound (VII-2), and then compound (I-9b) can be produced from compound (I-9a).

[Step 1]
In this step, compound (I-9a) can be produced by reacting compound (VI) with compound (VII-2). This reaction is carried out in the same manner as in the above Method B.

[Step 2]
In this step, compound (I-9b) can be produced from compound (I-9a). This reaction is performed in the same manner as the dealkylation reaction in Step 1 of the above-mentioned Method C.
Compound (VII-2) can be produced according to a method known per se.

  In formula (I), A is

And R ^6a is

Compound (I-10) and Compound (I-10a) in which R ¹¹ is a hydrogen atom among Compound (I-10) can be produced, for example, by the following Method G.
[G method]

[Wherein R ¹¹ represents an optionally substituted hydrocarbon group or amino-protecting group, and other symbols are as defined above. ]
Examples of the “optionally substituted hydrocarbon group” for R ¹¹ include the same as the “optionally substituted hydrocarbon group” for R ^A1 or R ^B1 .
Examples of the “protecting group for amino group” represented by R ¹¹ include trityl, methoxymethyl, p-methoxybenzyl, tert-butoxycarbonyl, allyloxycarbonyl, C _7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl) and the like. Among them, trityl is preferable.

[Step 1]
In this step, compound (I-10) can be produced by reacting compound (VI) with compound (VII-3). This reaction is carried out in the same manner as in the above Method B.

[Step 2]
In this step, compound (I-10a) can be produced by subjecting compound (I-10) to a deprotection reaction.
This reaction is carried out in a solvent that does not adversely influence the reaction in the presence of an acid when R ¹¹ is, for example, trityl, methoxymethyl, p-methoxybenzyl or tert-butoxycarbonyl.
Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as acetic acid, trifluoroacetic acid and p-toluenesulfonic acid; hydrogen chloride-methanol and chloride in which hydrogen chloride is dissolved in a solution such as methanol and ethyl acetate. Examples thereof include hydrogen-ethyl acetate.
Examples of solvents that do not adversely affect the reaction include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, isopropanol, and tert-butanol Ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio.
The amount of the acid to be used is generally 0.01 to 1000 mol, preferably 0.1 to 100 mol, per 1 mol of compound (I-10).
The reaction temperature is generally −80 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.1 to 30 hours.
Compound (VII-3) can be produced according to a method known per se.

In the formula (I), R ^6a or R ^6b is

The compound (I-11),

Compound (I-12),

The compound (I-13), and

Compound (I-14) can be produced, for example, by the following Method H.
This reaction is carried out by a method known per se, for example, the method described in Journal of Medicinal Chemistry (J. Med. Chem.), 39, 5228 (1996), or a method analogous thereto. That is, in this reaction, compound (XII) is reacted with a hydroxylamine source to obtain compound (XIII), and then the corresponding cyclizing agent is allowed to act, whereby compounds (I-11) and (I-12) are obtained, respectively. ), (I-13) and (I-14) can be produced.
[Method H]

[Wherein Y ⁵ and Y ⁶ are independently a leaving group, and other symbols are as defined above. ]
Here, examples of the “leaving group” represented by Y ⁵ or Y ⁶ include a hydroxy group, a C _1-4 alkoxy group, a halogen atom, an imidazolyl group, a succinimideoxy group, —OSO ₂ R ^{8 ′} (in the formula, , R ^{8 'is} _{C 1-4} alkyl _group, a _{C 1-4} alkyl optionally _{C 6-10} aryl group optionally substituted with a group) and the like.
Y ⁵ is preferably a halogen atom or an imidazolyl group.
Y ⁶ is preferably a halogen atom or an imidazolyl group.

[Step 1]
In this step, compound (XIII) can be produced by reacting compound (XII) with a hydroxylamine source. This reaction is usually performed in the presence of a hydroxylamine source, using a base as necessary, in a solvent that does not adversely influence the reaction.
Examples of the hydroxylamine source include hydroxylamine salts such as hydroxylamine, hydroxylamine hydrochloride, hydroxylamine sulfate, and the like.
Examples of the base include amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene; Examples thereof include alkali metal salts such as sodium hydrogen, sodium carbonate, and potassium carbonate.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; 1,3-dimethyl- Examples thereof include imides such as 2-imidazolidinone; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The amount of the hydroxylamine source to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (XII).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (XII).
The reaction temperature is generally −30 ° C. to 150 ° C., preferably 30 ° C. to 100 ° C.
The reaction time is usually 0.5 to 30 hours.

[Step 2]
In this step, compound (I-11) can be produced by reacting compound (XIII) with compound (XIV) as a cyclizing agent. This reaction is usually performed in the presence of a base in a solvent that does not adversely influence the reaction.
Examples of the base include amines such as pyridine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene. An alkali metal salt such as pyridine, sodium hydrogen carbonate, sodium carbonate or potassium carbonate; an alkali metal C _1-6 alkoxide such as sodium methoxide, sodium ethoxide or potassium tert-butoxide;
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone And sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The amount of compound (XIV) to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (XIII).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (XIII).
The reaction temperature is usually −30 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
The reaction time is usually 0.5 to 30 hours.

[Step 3]
In this step, compound (I-12) can be produced by reacting compound (XIII) with compound (XV) as a cyclizing agent. This reaction is usually performed in the presence of a base in a solvent that does not adversely influence the reaction.
Examples of the base include amines such as pyridine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene. An alkali metal salt such as pyridine, sodium hydrogen carbonate, sodium carbonate or potassium carbonate; an alkali metal C _1-6 alkoxide such as sodium methoxide, sodium ethoxide or potassium tert-butoxide;
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone And sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The amount of compound (XV) to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (XIII).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (XIII).
The reaction temperature is usually −30 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
The reaction time is usually 0.5 to 30 hours.

[Step 4]
In this step, compound (I-13) can be produced by reacting compound (XIII) with compound (XV) as a cyclizing agent, followed by treatment with an acid. This reaction is carried out in a solvent that does not adversely influence the reaction.
Examples of the acid include Lewis acids such as boron trifluoride diethyl ether complex.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone And sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The amount of compound (XV) to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (XIII).
The amount of the acid to be used is generally 1 to 20 mol per 1 mol of compound (XIII).
The reaction temperature is usually −30 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
The reaction time is usually 0.5 to 30 hours.

[Step 5]
In this step, compound (I-14) can be produced by reacting compound (XIII) with thionyl chloride as a cyclizing agent. This reaction is usually performed in the presence of a base in a solvent that does not adversely influence the reaction.
Examples of the base include amines such as pyridine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene. Alkali metal salts such as pyridine, sodium hydrogen carbonate, sodium carbonate and potassium carbonate; alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; metals such as potassium hydride and sodium hydride A hydride etc. are mentioned.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone And sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The amount of thionyl chloride to be used is generally 1 to 0 mol, preferably 1 to 5 mol, per 1 mol of compound (XIII).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (XIII).
The reaction temperature is usually −30 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
The reaction time is usually 0.5 to 30 hours.

  In addition, the compound (XII) used as a raw material compound by this method can be manufactured, for example according to the X1 method, X2 method mentioned later, or a method according to these. Compound (XIV) and compound (XV) can be produced according to a method known per se.

In the formula (I), R ^6a or R ^6b is

And L ^1a is —L ^2a —CH ₂ — or L ^1b is —L ^2b —CH ₂ — can be produced, for example, by the following Method I.
In this method, compound (XVIII) is obtained by reacting compound (XVI) with compound (XVII), and then compound (I-15) can be produced from compound (XVIII).
[Method I]

[Wherein B ² is

L ^2a and L ^2b are each a spacer having a main chain of 1 to 4 carbon atoms, and ring C is optionally substituted, and includes —CH ₂ —CO—NH— as a ring member. Heterocycles and other symbols are as defined above. ]
Here, examples of the “heterocycle containing —CH ₂ —CO—NH— as a ring constituent member” represented by C include, for example, 2-oxopyrroline, 2-oxopyrrolidine, 4-oxoimidazolidine, 2-oxopiperidine. 4-oxothiazolidine, 1,1-dioxide-3-oxoisothiazolidine, 6-oxohexahydropyrimidine, 1,1-dioxide-3-oxo-1,2-thiazinane, 1,1-dioxide-3-oxo -Thiadiazolidine and the like.

[Step 1]
In this step, compound (XVIII) can be produced by subjecting compound (XVI) and compound (XVII) to a condensation reaction. This reaction is usually performed in the presence of a base in a solvent that does not affect the reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate; piperidine, pyrrolidine, pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1, Amines such as 8-diazabicyclo [5.4.0] undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal C such as sodium methoxide, sodium ethoxide and potassium tert-butoxide _1-6 alkoxide is mentioned.
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol, ethanol, propanol, 2-propanol, 2-methoxyethanol, butanol, isobutanol and tert-butanol; aromatic carbonization such as benzene, toluene and xylene Hydrogen; Aliphatic hydrocarbons such as hexane and heptane; Ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane; Halogenated hydrocarbons such as chloroform and dichloromethane Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide and the like. These solvents may be mixed and used at an appropriate ratio.
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (XVI).
The amount of compound (XVII) to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (XVI).
The reaction temperature is generally −30 to 150 ° C., preferably 0 to 100 ° C.
The reaction time is usually 0.1 to 30 hours.

[Step 2]
In this step, compound (I-15) can be produced by subjecting compound (XVIII) to a hydrogenation reaction. This reaction can be carried out in the presence of a metal catalyst and a hydrogen source in a solvent that does not adversely influence the reaction.
Examples of the metal catalyst include palladium-carbon, palladium black, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney nickel, Raney cobalt, and the like.
Examples of the hydrogen source include hydrogen gas, formic acid, formic acid amine salt, phosphinate, hydrazine and the like.
The amount of the metal catalyst to be used is generally 0.001 to 1000 mol, preferably 0.01 to 100 mol, per 1 mol of compound (XVIII).
The amount of the hydrogen source to be used is usually an excess amount in the case of hydrogen gas with respect to 1 mol of compound (XVIII). In the case of formic acid, formic acid amine salt, phosphinate, hydrazine, etc., usually 1 to 200 mol, Preferably it is 1-50 mol.
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol, ethanol, propanol, 2-propanol, 2-methoxyethanol, butanol, isobutanol and tert-butanol; aromatic carbonization such as benzene, toluene and xylene Hydrogens; Aliphatic hydrocarbons such as hexane and heptane; Ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane; Dichloromethane, chloroform, 1,2-dichloroethane Halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; ethyl acetate, acetic acid and the like These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is usually 0 to 120 ° C, preferably 10 to 80 ° C.
The reaction time is usually 0.5 to 100 hours.

  In addition, the compound (XVI) used as a raw material compound by this method can be manufactured according to the V1 method, V2 method mentioned later, or the method according to these, for example. Compound (XVII) can be produced according to a method known per se.

In the formula (I), R ^6a or R ^6b is

Compound (I-16) can be produced, for example, by the following method J.
In this method, compound (XX) can be obtained by reacting compound (X) with compound (XIX), and then compound (I-16) can be produced from compound (XX).
[J method]

[Wherein, R ¹² represents a protecting group for an amino group, ring D may be substituted and a heterocyclic ring containing two or more nitrogen atoms, and other symbols are as defined above]. ]
Here, examples of the “heterocycle containing two or more nitrogen atoms” represented by D include imidazolidine, tetrahydropyrimidine, piperazine, hexahydropyrimidine, 1,1-dioxide-thiadiazolidine, piperazine, oxadiazoline. , Tetrazole, pyrazole, oxadiazolidine and the like.
Examples of the protecting group for the amino group represented by R ¹² include tert-butoxycarbonyl, allyloxycarbonyl, C _7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl), tert-butyl, benzyl, substituted benzyl (eg, 4 -Methoxybenzyl, 2,4-dimethoxybenzyl) and the like.

[Step 1]
In this step, compound (XX) can be produced by reacting compound (X) with compound (XIX). This reaction is usually performed in the presence of a base, and optionally in the presence of an organometallic catalyst and a phosphorus ligand, in a solvent that does not adversely influence the reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, potassium phosphate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline. Amines such as 1,8-diazabicyclo [5.4.0] undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium Alkali metal C _1-6 alkoxides such as tert-butoxide can be mentioned.
Examples of the organometallic catalyst include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), and the like.
Examples of the phosphorus ligand include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), tris (2-methylphenyl) phosphine, and 1,1′-bis (diphenylphosphino). ) Ferrocene, (2-biphenyl) dicyclohexylphosphine (XPhos), 1,2,3,4,5-pentaphenyl-1 ′-(ditert-butylphosphino) ferrocene (Q-Phos), (R) -1 -[(1S) -2- (diphenylphosphino) ferrocenyl] ethylditert-butylphosphine, (S) -1-[(1R) -2- (diphenylphosphino) ferrocenyl] ethylditert-butylphosphine, 5- ( Di-tert-butyl-phosphino) -1 ′, 3 ′, 5′-triphenyl-1′H- [1,4 ′] bipyrazole, (4- (N, N-dimethyl) Arylamino) phenyl) di -tert- butylphosphine.
The amount of compound (XIX) to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (X).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (X).
The usage-amount of an organometallic catalyst is 0.001-1 mol normally with respect to 1 mol of compound (X), Preferably it is 0.01-0.5 mol.
The usage-amount of a phosphorus ligand is 0.001-1 mol normally with respect to 1 mol of compounds (X), Preferably it is 0.01-0.5 mol.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Examples include ethers such as dioxane and 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide, and the like. These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is usually −10 to 250 ° C., preferably 20 to 150 ° C.
The reaction time is usually 0.5 to 100 hours.

[Step 2]
In this step, compound (I-16) can be produced by subjecting compound (XX) to a deprotection reaction.
When R ¹² is tert-butoxycarbonyl, tert-butyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, the reaction is performed in the presence of an acid in a solvent that does not adversely influence the reaction.
Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as trifluoroacetic acid and p-toluenesulfonic acid; and hydrogen chloride-methanol and hydrogen chloride in which hydrogen chloride is dissolved in a solution such as methanol and ethyl acetate. Examples include ethyl acetate.
Examples of solvents that do not adversely affect the reaction include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, isopropanol, and tert-butanol Ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio.
The amount of the acid to be used is generally 0.01 to 1000 mol, preferably 0.1 to 100 mol, per 1 mol of compound (XX).
The reaction temperature is generally −80 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.1 to 30 hours.
When R ¹² is benzyloxycarbonyl or benzyl, for example, reaction in the presence of a metal catalyst such as palladium-carbon, palladium black, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney nickel, Raney cobalt, and a hydrogen source. In a solvent that does not adversely affect the reaction.
The amount of the metal catalyst to be used is generally 0.001 to 1000 mol, preferably 0.01 to 100 mol, per 1 mol of compound (XX).
Examples of the hydrogen source include hydrogen gas, formic acid, formic acid amine salt, phosphinate, hydrazine and the like.
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol, ethanol, propanol, 2-propanol, 2-methoxyethanol, butanol, isobutanol and tert-butanol; aromatic carbonization such as benzene, toluene and xylene Hydrogens; Aliphatic hydrocarbons such as hexane and heptane; Ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane; Dichloromethane, chloroform, 1,2-dichloroethane Halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; ethyl acetate, acetic acid and the like These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is usually 0 to 120 ° C, preferably 10 to 80 ° C.
The reaction time is usually 0.5 to 100 hours.

  Compound (XIX) can be produced according to a method known per se.

In the formula (I), R ^6a or R ^6b is

Compound (I-17) can be produced, for example, by the following K method.
In this method, compound (XXII) can be obtained by reacting compound (X) with compound (XXI), and then compound (XXII) can be produced from compound (XXII) via compound (XXIII). .
[K method]

Wherein the protecting group of R ¹³ is an amino group, a protecting group of R ^{13 'is} hydroxy group, and other symbols are as defined above. ]
Examples of the “amino-protecting group” for R ¹³ include those similar to the “amino-protecting group” for R ¹² . Of these, tert-butoxycarbonyl is preferred.
Examples of the “protecting group for hydroxy group” represented by R ^{13 ′} include tert-butoxycarbonyl, allyloxycarbonyl, C _7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl), tert-butyl, benzyl, substituted And benzyl (eg, 4-methoxybenzyl, 2,4-dimethoxybenzyl). Of these, tert-butoxycarbonyl is preferred.

[Step 1]
In this step, compound (XXII) can be produced by reacting compound (X) with compound (XXI). This reaction is usually performed in the presence of a base, and optionally in the presence of an organometallic catalyst and a phosphorus ligand, in a solvent that does not adversely influence the reaction. This reaction is carried out in the same manner as the reaction described in [Step 1] of Method J above.

[Step 2]
In this step, compound (XXIII) can be produced by subjecting compound (XXII) to a deprotection reaction. This reaction is carried out in the same manner as the reaction described in [Step 2] of Method J above.

[Step 3]
In this step, compound (I-17) can be produced by reacting compound (XXIII) with isocyanatocarbonyl chloride. This reaction is carried out by a method known per se, for example, the method described in Journal of Medicinal Chemistry (J. Med. Chem.), Volume 43, page 995 (2000), or a method analogous thereto.

  Compound (XXI) can be produced according to a method known per se.

In the formula (I), R ^6a or R ^6b is

Compound (I-18) can be produced, for example, by the following method L.
[L method]

[Wherein, ring E represents an optionally substituted nitrogen-containing heterocyclic ring, and other symbols are as defined above. ]
Here, as the “nitrogen-containing heterocycle” represented by E, for example, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-triazole, tetrazole, Examples include pyrrolidine, piperidine, morpholine, oxadiazoline, oxadiazolidine, thiazolidine, 1,1-dioxide-thiadiazolidine, imidazolidine and the like.

In this method, compound (I-18) can be produced by reacting compound (X) with compound (XXIV). This reaction is usually performed in the presence of a base, and optionally in the presence of an organometallic catalyst and a phosphorus ligand, in a solvent that does not adversely influence the reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, potassium phosphate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline. Amines such as 1,8-diazabicyclo [5.4.0] undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium Alkali metal C _1-6 alkoxides such as tert-butoxide can be mentioned.
Examples of the organometallic catalyst include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), and the like.
Examples of the phosphorus ligand include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), tris (2-methylphenyl) phosphine, and 1,1′-bis (diphenylphosphino). ) Ferrocene, (2-biphenyl) dicyclohexylphosphine (XPhos), 1,2,3,4,5-pentaphenyl-1 ′-(ditert-butylphosphino) ferrocene (Q-Phos), (R) -1 -[(1S) -2- (diphenylphosphino) ferrocenyl] ethylditert-butylphosphine, (S) -1-[(1R) -2- (diphenylphosphino) ferrocenyl] ethylditert-butylphosphine, 5- ( Di-tert-butyl-phosphino) -1 ′, 3 ′, 5′-triphenyl-1′H- [1,4 ′] bipyrazole, (4- (N, N-di Chiruamino) phenyl) di -tert- butylphosphine.
The amount of compound (XXIV) to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (X).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (X).
The usage-amount of an organometallic catalyst is 0.001-1 mol normally with respect to 1 mol of compound (X), Preferably it is 0.01-0.5 mol.
The usage-amount of a phosphorus ligand is 0.001-1 mol normally with respect to 1 mol of compounds (X), Preferably it is 0.01-0.5 mol.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Examples include ethers such as dioxane and 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide, and the like. These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is usually −10 to 250 ° C., preferably 20 to 150 ° C.
The reaction time is usually 0.5 to 100 hours.
Compound (XXIV) can be produced according to a method known per se.

Compound (I-3) used as a starting compound of compound (I-4) in Method C can also be produced, for example, by the following Method M.
[M method]

[Wherein each symbol is as defined above. ]
In this method, compound (I-3) can be produced by subjecting compound (XVI-2) to an oxidation reaction. This reaction is performed according to a method known per se, for example, using sodium dihydrogen phosphate, sodium chlorite and 2-methyl-2-butene in a solvent that does not adversely influence the reaction.
Examples of the solvent that does not adversely influence the reaction include tert-butanol, tetrahydrofuran, dimethyl sulfoxide, water and the like. These solvents may be mixed and used at an appropriate ratio.
The amount of sodium dihydrogen phosphate, sodium chlorite and 2-methyl-2-butene to be used is usually 1 to 50 mol, preferably 1 to 20 mol, per 1 mol of compound (XVI-2), respectively. is there.
The reaction temperature is generally −30 to 150 ° C., preferably −10 to 50 ° C.
The reaction time is usually 0.5 to 30 hours.
In addition, the compound (XVI-2) used as a raw material compound by this method can be manufactured in accordance with the V1 method, V2 method mentioned later, or the method according to these, for example.

Regarding compound (I-1), compound (I- ^1a ) in which L ^1a is —CH═CH— and R ^6a is —CO—OR ⁹ can be produced, for example, by the following Method N.
[N method]

[Wherein each symbol is as defined above. ]
In this method, compound (I-1a) can be produced by reacting compound (VI) with compound (XXV). This reaction is carried out according to a method known per se, for example, usually in the presence of a base, in a solvent that does not adversely influence the reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide Etc.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; ketones such as acetone and 2-butanone; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and isopropyl acetate; N, N-dimethylformamide; Examples thereof include amides such as N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The amount of compound (XXV) to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (VI).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (VI).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.
Compound (XXV) can be produced according to a method known per se.

  For compound (II), A is

Compound (II-1) can be produced, for example, by the following method O.
[O method]

[Wherein Y ⁷ is a leaving group, ring F is a benzene ring or pyridine ring, R ¹⁴ is a substituent of ring F, and other symbols are as defined above. ]
Here, the “substituent” represented by R ¹⁴ may have a “benzene ring or pyridine ring” which R ^4a and R ^5a may form together with adjacent carbon atoms. The same thing as "substituent" is mentioned.
Examples of the “leaving group” represented by Y ⁷ include the same “leaving group” represented by Y ¹ or Y ² . Of these, a fluorine atom, a chlorine atom, trifluoromethanesulfonyloxy and the like are preferable.

[Step 1]
In this step, compound (XXVIII) can be produced by reacting compound (XXVI) with compound (XXVII). This reaction is carried out according to a method known per se, for example, usually in the presence of a base, in a solvent that does not adversely influence the reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide Etc.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; ketones such as acetone and 2-butanone; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and isopropyl acetate; N, N-dimethylformamide; Examples thereof include amides such as N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The amount of compound (XXVII) to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXVI).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXVI).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.

[Step 2]
In this step, compound (XXIX) can be produced by subjecting compound (XXVIII) to a hydrogenation reaction. This reaction can be carried out according to a method known per se, usually in the presence of a metal catalyst and a hydrogen source, in a solvent that does not adversely influence the reaction.
Examples of the metal catalyst include palladium-carbon, palladium black, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney nickel, Raney cobalt, and the like.
Examples of the hydrogen source include hydrogen gas, formic acid, formic acid amine salt, phosphinate, hydrazine and the like.
The amount of the metal catalyst to be used is generally 0.001 to 1000 mol, preferably 0.01 to 100 mol, per 1 mol of compound (XXVIII).
The amount of the hydrogen source to be used is usually an excess amount in the case of hydrogen gas with respect to 1 mol of the compound (XXVIII). Preferably it is 1-50 mol.
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol, ethanol, propanol, 2-propanol, 2-methoxyethanol, butanol, isobutanol and tert-butanol; aromatic carbonization such as benzene, toluene and xylene Hydrogens; Aliphatic hydrocarbons such as hexane and heptane; Ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane; Dichloromethane, chloroform, 1,2-dichloroethane Halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; ethyl acetate, acetic acid and the like These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is usually 0 to 120 ° C, preferably 10 to 80 ° C.
The reaction time is usually 0.5 to 100 hours.

[Step 3]
In this step, compound (II-1) can be produced by reacting compound (XXIX) with compound (XV). This reaction is carried out according to a method known per se, for example, usually in the presence of a base as necessary in a solvent that does not adversely influence the reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene; alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; ketones such as acetone and 2-butanone; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and isopropyl acetate; N, N-dimethylformamide; Examples thereof include amides such as N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The amount of compound (XV) to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXIX).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXIX).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.

  Compound (XXVI) and compound (XXVII) can be produced according to a method known per se.

Compound (XXVIII) used as the starting compound of compound (XXIX) in Method O can also be produced, for example, by the following Method P1 or Method P2.
[P1 method]

[Wherein, R ¹⁵ represents an amino-protecting group, and other symbols are as defined above. ]
Here, examples of the protecting group for the amino group represented by R ¹⁵ include tert-butoxycarbonyl, allyloxycarbonyl, C _7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl), trifluoroacetyl and the like. . Of these, trifluoroacetyl is preferred.

[Step 1]
In this step, compound (XXXI) can be produced by protecting the amino group of compound (XXX). This reaction is performed according to a method known per se, for example, usually in the presence of a protecting agent for an amino group, and optionally in the presence of a base, in a solvent that does not adversely influence the reaction.
Examples of the amino group protecting agent include acid anhydrides and acid halides corresponding to R ¹⁵ .
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] amines such as undec-7-ene.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; Nitriles such as acetonitrile and propionitrile; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Examples include imides such as dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The amount of the amino group-protecting agent to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXX).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXX).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.

[Step 2]
In this step, compound (XXXII) can be produced by reacting compound (XXXI) with compound (VII). This reaction is usually performed in the presence of a base in a solvent that does not adversely influence the reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide Etc.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; ketones such as acetone and 2-butanone; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and isopropyl acetate; N, N-dimethylformamide; Examples thereof include amides such as N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The amount of compound (VII) to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXXI).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXXI).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.

[Step 3]
In this step, compound (XXXVIII) can be produced by subjecting compound (XXXII) to a deprotection reaction. This reaction is usually performed in the presence of a base in a solvent that does not adversely influence the reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide Etc.
Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane; methanol, ethanol, propanol, 2-propanol, butanol , Alcohols such as isobutanol and tert-butanol; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone Sulfoxides such as dimethyl sulfoxide, water and the like. These solvents may be mixed and used at an appropriate ratio.
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXXII).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.

[Step 4]
In this step, compound (XXVIII) can be produced by reacting compound (XXX) with compound (VII). This reaction is carried out in the same manner as the reaction described in Step 2 of Method P1.

Compound (XXX) can be produced according to the AA method described later or a method analogous thereto, or a method known per se.
[P2 method]

[Wherein, R ^15a represents an amino-protecting group, and other symbols are as defined above. ]
Here, examples of the protecting group for the amino group represented by R ^15a include tert-butoxycarbonyl, allyloxycarbonyl, C _7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl) and the like. Of these, tert-butoxycarbonyl and benzyloxycarbonyl are preferred.

[Step 1]
In this step, compound (XXXI-2) can be produced from compound (XXXIII). This reaction was carried out by reacting compound (XXXIII) and diphenylphosphoric acid azide in the presence of a base in a solvent that does not adversely influence the reaction at a reaction temperature of −10 ° C. to 40 ° C. for 0.5 to 10 hours. The isocyanate formed by thermal decomposition of the acyl azide and the alcohol corresponding to R ^15a are carried out in the presence of a base in a solvent that does not adversely influence the reaction.
Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, 4-dimethyl. Examples include amines such as aminopyridine; alkali metal salts such as sodium hydrogen carbonate, sodium carbonate, and potassium carbonate.
Examples of the alcohol corresponding to R ^15a include C _1-6 alkanol (eg, tert-butanol, allyl alcohol), C _7-13 aralkyl alcohol (eg, benzyl alcohol) and the like.
Examples of the solvent that does not adversely influence the reaction include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene Ethers such as tetrahydrofuran, dioxane, diethyl ether; acetonitrile, ethyl acetate, pyridine, water, alcohols such as the above-mentioned tert-butanol, benzyl alcohol, and allyl alcohol. These solvents may be mixed and used at an appropriate ratio.
The amount of diphenyl phosphate azide to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (XXXIII).
The amount of the base to be used is generally 1 to 10 mol per 1 mol of compound (XXXIII).
The amount of the alcohol corresponding to R ^15a to be used is generally 1 to excess moles with respect to 1 mole of compound (XXXIII).
The reaction temperature is usually 60 ° C to 150 ° C.
The reaction time is usually 0.5 to 30 hours.

[Step 2]
In this method, compound (XXXII-2) can be produced by reacting compound (XXXI-2) with compound (VII). This reaction is carried out in the same manner as the reaction described in Step 2 of Method P1.

[Step 3]
In this step, compound (XXXVIII) can be produced by subjecting compound (XXXII-2) to a deprotection reaction.
For example, when R ^15a is tert-butoxycarbonyl, this reaction is performed in the presence of an acid in a solvent that does not adversely influence the reaction.
Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as trifluoroacetic acid and p-toluenesulfonic acid; and hydrogen chloride-methanol and hydrogen chloride in which hydrogen chloride is dissolved in a solution such as methanol and ethyl acetate. Examples include ethyl acetate.
Examples of solvents that do not adversely affect the reaction include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, isopropanol, and tert-butanol Ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio.
The amount of the acid to be used is generally 0.01 to 1000 mol, preferably 0.1 to 100 mol, per 1 mol of compound (XXXII-2).
The reaction temperature is generally −80 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.1 to 30 hours.
In addition, when R ^15a is, for example, benzyloxycarbonyl, this reaction may be performed by, for example, palladium-carbon, palladium black, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney nickel, Raney cobalt, and other metal catalysts and hydrogen The reaction can be carried out in the presence of a source in a solvent that does not adversely influence the reaction.
The amount of the metal catalyst to be used is generally 0.001 to 1000 mol, preferably 0.01 to 100 mol, per 1 mol of compound (XXXII-2).
Examples of the hydrogen source include hydrogen gas, formic acid, formic acid amine salt, phosphinate, hydrazine and the like.
The amount of the hydrogen source to be used is usually an excess amount in the case of hydrogen gas with respect to 1 mol of the compound (XXXII-2), and is usually 1 to 200 in the case of formic acid, amine formate, phosphinate, hydrazine and the like. Mol, preferably 1 to 50 mol.
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol, ethanol, propanol, 2-propanol, 2-methoxyethanol, butanol, isobutanol and tert-butanol; aromatic carbonization such as benzene, toluene and xylene Hydrogens; Aliphatic hydrocarbons such as hexane and heptane; Ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane; Dichloromethane, chloroform, 1,2-dichloroethane Halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; ethyl acetate, acetic acid and the like These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is usually 0 to 120 ° C, preferably 10 to 80 ° C.
The reaction time is usually 0.5 to 100 hours.

  Compound (XXXIII) can be produced according to a method known per se.

  For compound (IV), A is

Compound (IV-1) can be produced, for example, by the following Q1 method or Q2 method.
[Q1 method]

[Wherein each symbol is as defined above. ]
In this method, compound (XXXIV) can be obtained from compound (XXIX), and then compound (IV-1) can be produced from compound (XXXIV).

[Step 1]
In this step, compound (XXXIV) can be produced by reacting compound (XXIX) with compound (XIV) as a cyclizing agent. This reaction is carried out in the same manner as the reaction described in Step 2 of Method H above.

[Step 2]
In this step, compound (IV-1) can be produced by subjecting compound (XXXIV) to a sulfonylation reaction or halogenation reaction.
The sulfonylation reaction of compound (XXXIV) is carried out in the presence of a base using a sulfonyl halide in a solvent that does not adversely influence the reaction.
Examples of the sulfonyl halide include R ⁸ SO ₂ Cl (wherein R ⁸ is as defined above), and preferably methanesulfonyl chloride, p-toluenesulfonyl chloride, and the like.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide Is mentioned.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; dimethyl sulfoxide and the like Sulfoxides; acetonitrile and the like. These solvents may be mixed and used at an appropriate ratio.
The amount of the sulfonyl halide to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (XXXIV).
The amount of the base to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (XXXIV).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.1 to 20 hours.
The halogenation reaction of compound (XXXIV) is performed in the presence of a halogenating agent in a solvent that does not adversely influence the reaction.
Examples of the halogenating agent include thionyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus tribromide and the like.
The amount of the halogenating agent to be used is generally 1 to 20 mol per 1 mol of compound (XXXIV).
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Examples include ethers such as dioxane and 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane. These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.1 to 50 hours.

[Q2 method]

[Wherein each symbol is as defined above. ]
In this method, compound (IV-1) can be produced by reacting compound (XXXV) with compound (VII). This reaction is carried out in the same manner as the reaction described in Step 2 of Method P1.
Compound (XXXV) can be produced according to a method analogous to the aforementioned Q1 method or a method known per se.

The compound (VI) used as a raw material compound in the above-mentioned Method B, Method F, Method G, Method N, Method S and Method X1 described later can be produced, for example, by the following Method R1 or Method R2.
[R1 method]

[Wherein each symbol is as defined above. ]
In this method, compound (VI) can be produced by reacting compound (XXXVI) with compound (III). This reaction is carried out in the same manner as the reaction described in the aforementioned method A1.
In addition, the compound (XXXVI) used as a raw material compound by this method can be manufactured, for example according to AC method, AD method mentioned later, or a method according to these.

[R2 method]

[Wherein each symbol is as defined above. ]
In this method, compound (VI) can be produced by reacting compound (XXXVII) with compound (V). This reaction is carried out in the same manner as the reaction described in the aforementioned method A1.
Compound (XXXVII) can be produced according to a method analogous to the aforementioned Q1 method or a method known per se.

For compound (I-1), L ^1a is

Compound (I-1b) can be produced, for example, by the following Method S.
[S method]

[Wherein L ^3a is a spacer having 1 to 3 atoms in the main chain consisting of carbon atoms, and other symbols are as defined above. ]

[Step 1]
In this step, compound (XXXVIII) can be produced by reacting compound (VI) with (VII-4). This reaction is carried out in the same manner as the reaction described in Method B above.

[Step 2]
In this step, compound (I-1b) can be produced by reacting compound (XXXVIII) with compound (VII-5) using an organometallic catalyst. This reaction is usually performed in a solvent that does not adversely influence the reaction, if necessary, in the presence of a ligand.
Examples of the organometallic catalyst include palladium (II) acetate, copper triflate (I), rhodium acetate (II) dimer, and the like.
Examples of the ligand include 2,2′-diisopropylidenebis [(4S) -4-tert-butyl-2-oxazoline], 2,6-bis (4,5-dihydro-4-isopropyl-2-oxazolyl). ) Pyridine (Pybox) and the like.
Examples of the solvent that does not adversely influence the reaction include aliphatic hydrocarbons such as hexane and heptane; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; dichloromethane, chloroform, And halogenated hydrocarbons such as 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. These solvents may be mixed and used at an appropriate ratio.
The amount of compound (VII-5) to be used is generally 0.1 to 50 mol, preferably 1 to 5 mol, per 1 mol of compound (XXXVIII).
The amount of the organometallic catalyst to be used is generally 0.01 to 2 mol, preferably 0.01 to 0.5 mol, per 1 mol of compound (XXXVIII).
The amount of the ligand to be used is generally 0.01 to 2 mol, preferably 0.01 to 0.5 mol, per 1 mol of compound (XXXVIII).
The reaction temperature is generally −70 to 150 ° C., preferably −20 to 30 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 40 hours.
Compound (VII-4) and compound (VII-5) can be produced according to a method known per se.

For compound (I-1), R ^4a and R ^5a together form an optionally substituted ring F, R ^6a is —CO—OR ⁹ and L ^1a is L ^2a —CH ( Compound (I-1c) which is OH) — and compound (I-1d) wherein L ^1a is L ^2a —CH (F) — can be produced, for example, by the following T1 method.
[T1 method]

[Wherein R ¹⁶ represents a protecting group for a hydroxy group, and other symbols have the same meaning as described above. ]
Here, examples of the “hydroxy-protecting group” represented by R ¹⁶ include 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- Butyldimethylsilyl, tert-butyldimethylsilyl) and the like. Of these, a substituted silyl group is preferred.

[Step 1]
In this step, compound (XXVIII-2) can be produced by reacting compound (XXVI) with compound (XXVII-2). This reaction is performed in the same manner as the reaction described in Step 1 of Method O above.

[Step 2]
In this step, compound (XXVIII-3) can be produced by subjecting compound (XXVIII-2) to an alkylation reaction. This reaction is carried out according to a method known per se, usually in the presence of an alkylating agent and a base, in a solvent that does not adversely influence the reaction.
Examples of the alkylating agent include halogenated C _1-6 alkyl (eg, methyl iodide, ethyl iodide, isopropyl iodide), halogenated C _7-13 aralkyl (eg, benzyl bromide, p-methoxybenzyl chloride) and the like. Is mentioned.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide Etc.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; Ketones such as acetone and 2-butanone; Nitriles such as acetonitrile and propionitrile; N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl Amides such as pyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide, and the like. These solvents may be mixed and used at an appropriate ratio.
The amount of the alkylating agent to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXVIII-2).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXVIII-2).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.
For compound (XXVIII-3), when R ⁹ is methyl, this reaction may use a diazomethane derivative as the alkylating agent. In this case, this reaction does not adversely affect the reaction in the presence of the diazomethane derivative. It is carried out in a solvent.
Examples of the diazomethane derivative include diazomethane and trimethylsilyldiazomethane.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, And ethers such as dioxane and 1,2-dimethoxyethane. These solvents may be mixed and used at an appropriate ratio.
The amount of the diazomethane derivative to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXVIII-2).
The reaction temperature is generally −30 to 100 ° C., preferably −10 to 30 ° C.
The reaction time is usually 0.5 to 100 hours.

[Step 3]
In this step, compound (XXVIII-4) can be produced by subjecting compound (XXVIII-3) to a protection reaction. This reaction is performed according to a method known per se. For example, when R ¹⁶ is a substituted silyl group, the reaction is usually performed in the presence of a silylating agent and a base in a solvent that does not adversely influence the reaction.
Examples of the silylating agent include substituted silyl chlorides (eg, trimethylsilyl chloride, triethylsilyl chloride, tert-butyldimethylsilyl chloride, tert-butyldimethylsilyl chloride), substituted silyl trifluoromethanesulfonates (eg, trimethylsilyltrifluoromethanesulfonate). , Triethylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate) and the like.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide And imidazole.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; Ketones such as acetone and 2-butanone; Nitriles such as acetonitrile and propionitrile; N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl Amides such as pyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide, and the like. These solvents may be mixed and used at an appropriate ratio.
The amount of the silylating agent to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXVIII-3).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXVIII-3).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.

[Step 4]
In this step, compound (XXIX-2) can be produced by subjecting compound (XXVIII-4) to a hydrogenation reaction. This reaction is performed in the same manner as in the method described in Step 2 of Method O above.

[Step 5]
In this step, compound (II-1b) can be produced by reacting compound (XXIX-2) with compound (XV). This reaction is performed in the same manner as in the method described in Step 3 of Method O above.

[Step 6]
In this step, compound (XXXIX) can be produced by reacting compound (II-1b) with compound (III). This reaction is carried out in the same manner as described in the above method A1.

[Step 7]
In this step, compound (I-1c) can be produced by subjecting compound (XXXIX) to a deprotection reaction. This reaction is performed according to a method known per se. For example, when R ¹⁶ is a substituted silyl group, the reaction is usually performed in the presence of fluoride in a solvent that does not adversely influence the reaction.
Examples of the fluoride include alkali metal fluorides such as potassium fluoride and cesium fluoride; quaternary ammonium salts such as tetrabutylammonium fluoride and benzyltrimethylammonium fluoride.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; Ketones such as acetone and 2-butanone; Nitriles such as acetonitrile and propionitrile; N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl Examples include amides such as pyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide, and acetic acid. These solvents may be mixed and used at an appropriate ratio.
The amount of the fluoride to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXXIX).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.

[Step 8]
In this step, compound (I-1d) can be produced by subjecting compound (I-1c) to a fluorination reaction. This reaction is usually performed in the presence of a fluorinating agent in a solvent that does not adversely influence the reaction.
Examples of the fluorinating agent include (diethylamino) sulfur trifluoride (DAST), bis (2-methoxyethyl) aminosulfur trifluoride (Deoxo-Fluor (registered trademark)), 1,1,2,2-tetrafluoroethyl. -N, N-dimethylamine (TFEDMA) and the like.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran, dioxane and diethyl ether. These solvents may be mixed and used at an appropriate ratio.
The amount of the fluorinating agent to be used is generally 1-50 mol, preferably 1-10 mol, per 1 mol of compound (I-1c).
The reaction temperature is usually −30 ° C. to 100 ° C.
The reaction time is usually 0.5 to 30 hours.

  Compound (XXVII-2) can be produced according to a method known per se.

The optical isomer (I-1cb) and the carboxylic acid (I-1ca) corresponding to the compound (I-1cb) at the hydroxy site of the compound (I-1c) obtained by the method T1 are, for example, the following method T2. Can be manufactured.
[T2 method]

[Wherein R ¹⁷ represents an acyl group, and other symbols are as defined above. ]
Here, examples of the acyl group represented by R ¹⁷ include acetyl, benzoyl, p-nitrobenzoyl, and the like.
In this method, compound (I-1c) is subjected to Mitsunobu reaction to obtain compound (XXXIX-2), followed by deprotection reaction to obtain compound (I-1ca), and then compound (I-1ca) ) To produce compound (I-1cb).

[Step 1]
In this step, compound (XXXIX-2) can be produced by subjecting compound (I-1c) to Mitsunobu reaction. This reaction is carried out by a method known per se, for example, the method described in Synthesis, page 1 (1981), or a method analogous thereto. That is, this reaction is usually performed in the presence of an organic phosphorus compound and an electrophilic agent in a solvent that does not adversely influence the reaction.
Examples of the organic phosphorus compound include triphenylphosphine and tributylphosphine.
Examples of the electrophilic agent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1′-azodicarbonyldipiperidine, and the like.
The amount of the organophosphorus compound and electrophilic agent used is preferably 1 to 5 moles per 1 mole of compound (I-1c).
The amount of compound (XXXX) to be used is preferably 1 to 10 mol per 1 mol of compound (I-1c).
Examples of the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is generally −50 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 50 hours.

[Step 2]
In this step, compound (I-1ca) can be produced by subjecting compound (XXXIX-2) to a deprotection reaction. This reaction is carried out in the same manner as in the method described in Step 1 of Method C above.

[Step 3]
In this step, compound (I-1cb) can be produced by subjecting compound (I-1ca) to an alkylation reaction. This reaction is carried out in the same manner as in the method described in Step 2 of the above T1 method.

For compound (I-1), R ^4a and R ^5a together form an optionally substituted ring F, R ^6a is —CO—OR ⁹ and L ^1a is L ^2a —CH ( Compound (I-1eb) which is NH ₂ ), and Compound (I-1ec) where L ^1a is L ^2a —CH (NHR ^18a ), and R ^4a and R ^5a may be substituted together Good ring F, R ^6a is

Compound (I-1f) in which L ^1a is L ^2a can be produced, for example, by the following U method.
[U method]

[Wherein, R ^18a and R ^18b independently represent a substituent, and other symbols are as defined above. ]
Here, examples of the substituent represented by R ^18a include C _1-6 alkyl, C _1-6 alkyl-carbonyl, and C _1-6 alkoxy-carbonyl.
Examples of the substituent represented by R ^18b include C _1-6 alkyl.
In this method, compound (I-1eb) is obtained by subjecting compound (I-1ea) to a deprotection reaction, and then producing compound (I-1ec) or compound (I-1f) from compound (I-1eb) can do.

[Step 1]
In this step, compound (I-1eb) can be produced by subjecting compound (I-1ea) to a deprotection reaction. This reaction is carried out in the same manner as in the method described in Step 2 of Method J above.

[Step 2]
In this step, compound (I-1ec) can be produced by subjecting compound (I-1eb) to a reductive amination or acylation reaction. This reaction is performed according to a method known per se. For example, when R ^18a is a C _1-6 alkyl-carbonyl group or a C _1-6 alkoxy-carbonyl group, usually in the presence of an acylating agent and a base corresponding to R ^18a in a solvent that does not adversely influence the reaction. Done.
The acylating agent, e.g., acetyl chloride, propionyl chloride, halogenated C _1-6 alkyl such as acetyl bromide; methyl chloroformate, such as ethyl chloroformate halogen formate C _1-6 alkyl; acetic anhydride, dicarbonate And acid anhydrides such as di-tert-butyl.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] amines such as undec-7-ene.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; ketones such as acetone and 2-butanone; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and isopropyl acetate; N, N-dimethylformamide; Examples thereof include amides such as N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The amount of the acylating agent to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (I-1eb).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (I-1eb).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.

[Step 3]
In this step, compound (I-1f) can be produced by reacting compound (I-1eb) with an alkyl isocyanate corresponding to R ^18b and then treating the resulting compound with a base. This reaction is generally carried out according to a method known per se in a solvent that does not adversely influence the reaction.
Examples of the alkyl isocyanate corresponding to R ^18b include methyl isocyanate and ethyl isocyanate.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; ketones such as acetone and 2-butanone; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and isopropyl acetate; N, N-dimethylformamide; Examples thereof include amides such as N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The amount of alkyl isocyanate to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (I-1eb).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.
Examples of the base to be reacted with the compound obtained above include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N- And amines such as dimethylaniline and 1,8-diazabicyclo [5.4.0] undec-7-ene.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; ketones such as acetone and 2-butanone; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and isopropyl acetate; N, N-dimethylformamide; Examples thereof include amides such as N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (I-1eb).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.

  In addition, the compound (I-1ea) used as a raw material compound in this method can be produced, for example, according to the aforementioned method A1, method O, method T1 or a method analogous thereto.

  Compound (XVI-2) used as a raw material compound in Method M can be produced, for example, by the following Method V1 or Method V2.

[V1 method]

[Wherein each symbol is as defined above. ]
In this method, compound (XVI-2) can be produced by subjecting compound (XVI-3) to an oxidation reaction. This reaction is generally carried out according to a method known per se in the presence of an oxidizing agent in a solvent that does not adversely influence the reaction.
Examples of the oxidizing agent include metal oxidizing agents such as manganese dioxide, pyridinium chlorochromate, pyridinium dichromate, ruthenium oxide, and tetrapropylammonium perruthenate (TPAP); 1,1,1-triacetoxy-1,1 -Dihydro-1,2-benziodoxol-3 (1H) -one (Dess-Martin periodinane), 2-iodoxybenzoic acid (IBX), sulfur trioxide pyridine complex, 2,2,6,6-tetra Examples include methylpiperidine 1-oxyl (TEMPO). These oxidizing agents can be used together with a reoxidizing agent as required. For example, when tetrapropylammonium perruthenate (TPAP) is used as an oxidizing agent, N-methylmorpholine-N-oxide or the like is used as a reoxidizing agent such as 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO). ), Sodium chlorite etc. are mentioned as a reoxidant.
The amount of the oxidizing agent to be used is generally 1-50 mol, preferably 1-10 mol, relative to compound (XVI-3). When using a reoxidant together, it is 0.01-1 mol normally with respect to compound (XVI-3), Preferably it is 0.05-0.2 mol.
The amount of the reoxidant to be used is generally 1-50 mol, preferably 1-10 mol, relative to compound (XVI-3).
Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; nitriles such as acetonitrile and propionitrile; halogenated hydrocarbons such as chloroform and dichloromethane; benzene, toluene, xylene and the like Aromatic hydrocarbons, water and the like. These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is generally −50 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 50 hours.
In addition, the compound (XVI-3) used as a raw material compound by this method can be manufactured, for example according to the X1 method, X2 method mentioned later, or the method according to these.

[V2 method]

[Wherein, R ¹⁹ independently represents a C _1-6 alkyl group, or two R ¹⁹ may be combined to form a C _1-6 alkylene group, and other symbols are as defined above. Shows the same significance. ]
Examples of the C _1-6 alkylene group which may be formed by combining two R ¹⁹ include ethylene, trimethylene and the like.

In this method, compound (XVI-2) can be produced by subjecting compound (XVI-4) to hydrolysis. This reaction is generally carried out according to a method known per se in the presence of an acid in a solvent that does not adversely influence the reaction.
Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and pyridinium p-toluenesulfonate; and hydrogen chloride dissolved in a solution such as methanol and ethyl acetate. And hydrogen chloride-methanol, hydrogen chloride-ethyl acetate and the like.
Examples of solvents that do not adversely affect the reaction include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, isopropanol, and tert-butanol Ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio.
The amount of the acid to be used is generally 0.01 to 1000 mol, preferably 0.1 to 100 mol, per 1 mol of compound (XVI-4).
The reaction temperature is generally −80 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.1 to 30 hours.
In addition, the compound (XVI-4) used as a raw material compound by this method can be manufactured in accordance with the X1 method, X2 method mentioned later, or the method according to these, for example.
Further, the compound (XVI) used as the starting compound in the above method I can also be produced from the corresponding starting compound in the same manner as in the above method V1 or V2.

  The compound (IX) used as a raw material compound in the method D and the compound (X) used as a raw material compound in the method E can be produced, for example, by the following method W.

[W method]

[Wherein each symbol is as defined above. ]
In this method, compound (X) can be obtained from compound (XVI-3a), and then compound (IX) can be produced from compound (X).

[Step 1]
In this step, compound (X) can be produced by subjecting compound (XVI-3a) to a sulfonylation reaction or halogenation reaction.
The sulfonylation reaction of compound (XVI-3a) is carried out in the presence of a base using a sulfonyl halide in a solvent that does not adversely influence the reaction.
Examples of the sulfonyl halide include R ⁸ SO ₂ Cl (wherein R ⁸ is as defined above), preferably methanesulfonyl chloride, p-toluenesulfonyl chloride, and the like.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide Is mentioned.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; dimethyl sulfoxide and the like Sulfoxides; acetonitrile and the like. These solvents may be mixed and used at an appropriate ratio.
The amount of the sulfonyl halide to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (XVI-3a).
The amount of the base to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (XVI-3a).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.1 to 20 hours.
The halogenation reaction of compound (XVI-3a) is performed in the presence of a halogenating agent in a solvent that does not adversely influence the reaction.
Examples of the halogenating agent include thionyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus tribromide and the like.
The amount of the halogenating agent to be used is generally 1 to 20 mol per 1 mol of compound (XVI-3a).
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Examples include ethers such as dioxane and 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane. These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.1 to 50 hours.

[Step 2]
In this step, compound (IX) can be produced by reacting compound (X) with compound (VII-6). This reaction is generally carried out according to a method known per se in the presence of a base in a solvent that does not adversely influence the reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide Etc.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; Ketones such as acetone and 2-butanone; Alcohols such as methanol and ethanol; Nitriles such as acetonitrile and propionitrile; Esters such as ethyl acetate and isopropyl acetate Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide; . These solvents may be mixed and used at an appropriate ratio.
The amount of compound (VII-6) to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (X).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (X).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.

  Compound (XVI-3a) used as a raw material compound in Method W, Compound (XVI-3) used as a raw material compound in Method V1, Compound (XVI-4) used as a raw material compound in Method V2, Raw material in Method H For compound (XII) used as a compound and compound (X) used as a raw material compound in methods E1, E2, J, K, and L, B is

Compound (XVI-3aa), Compound (XVI-3b), Compound (XVI-4a), Compound (XII-1) and Compound (X-1), which can be produced by, for example, the following method X1 .

[Method X1]

[Wherein, R ²⁰ represents —OH, —CH ₂ OH, —CH (OR ¹⁹ ) ₂ , CN or Y ⁴ , and other symbols are as defined above. ]
In this method, compound (VI) and compound (VII-7) are reacted to give compound (XVI-3aa), compound (XVI-3b), compound (XVI) corresponding to R ²⁰ of compound (VII-7). -4a), compound (XII-1) or compound (X-1) can be produced. This reaction is carried out in the same manner as described in the above-mentioned Method B.

In the above compound (XVI-3aa), compound (XVI-3b), compound (XVI-4a) and compound (XII-1), R ^4a and R ^5a are substituted together with adjacent carbon atoms, respectively. Compound (XVI-3ab), Compound (XVI-3c), Compound (XVI-4b) and Compound (XII-1a), which form ring F (a benzene ring or a pyridine ring), may be represented by, for example, the following method X2. Can be manufactured.

[Method X2]

[Wherein, R ^20a represents —OH, —CH ₂ OH, —CH (OR ¹⁹ ) ₂ or CN, and other symbols are as defined above. ]
In this method, compound (XXVI) and compound (VII-7a) are reacted to obtain compound (XXIX-3) via compound (XXVIII-5), and then compound (XXIX-3) and compound (XV) To obtain compound (II-2), and react compound (II-2) with compound (III) to give compound (XVI-3ab) corresponding to R ²⁰ of compound (VII-7a), compound (XVI-3c), compound (XVI-4b) or compound (XII-1a) can be produced. This method is carried out in the same manner as described in Steps 1 to 3 of the O method and Step 6 of the T1 method.
Compound (VII-7a) can be produced according to a method known per se.

Regarding compound (XVI-4b), compound (XVI-4e) in which substituent R ¹⁴ on ring F is —CO—NR ^21a R ^21b and compound (XVI-4f) in which —CN is represented by the following method Y, for example: Can be manufactured.

[Y method]

[Wherein, R ^21a and R ^21b independently represent a hydrogen atom or an optionally substituted alkyl group, and other symbols are as defined above. ]

[Step 1]
In this step, compound (XVI-4d) can be produced by subjecting compound (XVI-4c) to a hydrolysis reaction. This reaction is performed in the same manner as in the case of using a base among the methods described in Step 1 of Method C above.

[Step 2]
In this step, compound (XVI-4e) can be produced by subjecting compound (XVI-4d) and compound (VIII-2) to a condensation reaction. This reaction is performed in the same manner as in the method described in Step 2 of Method C above.

[Step 3]
In this step, compound (XVI-4f) can be produced by subjecting compound (XVI-4e) to a dehydration reaction of compounds in which R ^21a and R ^21b are both hydrogen atoms. This reaction is carried out according to a method known per se, usually in the presence of a dehydrating agent and optionally a base, in a solvent that does not adversely influence the reaction.
Examples of the dehydrating agent include phosphoryl chloride, thionyl chloride, p-toluenesulfonyl chloride, dicyclohexylcarbodiimide and the like.
Examples of the base include amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine and N, N-dimethylaniline; alkali metal salts such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Examples include ethers such as dioxane and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane. These solvents may be mixed and used at an appropriate ratio.
The amount of the dehydrating agent to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XVI-4e).
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XVI-4e).
The reaction temperature is generally −30 to 180 ° C., preferably −10 to 120 ° C.
The reaction time is usually 0.5 to 30 hours.
In addition, the compound (XVI-4c) used as a raw material compound by this method can be manufactured according to the said X2 method or the method according to these, for example.

Regarding compound (VI), compound (VI-1) in which R ^4a or R ^5a is a halogen atom can be produced, for example, by the following Z method.

[Z method]

[Wherein Y ⁸ represents a halogen atom, and other symbols are as defined above. ]
In this method, compound (VI-1) can be produced by subjecting compound (VI-1a) to a halogenation reaction. This reaction is carried out according to a method known per se, usually in the presence of a halogenating agent and optionally in the presence of an activating agent in a solvent that does not adversely influence the reaction.
Examples of halogenating agents include succinimides such as N-chlorosuccinimide, N-bromosuccinimide, and N-iodosuccinimide; halogens such as bromine and iodine; N-fluorobis (benzenesulfonyl) imide, fluoride Fluorinating agents such as xenon, (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate) (Selectfluor®); And pyridinium.
Examples of the activator include organic acids such as acetic acid and trifluoroacetic acid; silver salts such as silver acetate, silver sulfate and silver oxide.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Examples include ethers such as dioxane and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane. These solvents may be mixed and used at an appropriate ratio.
The amount of the halogenating agent to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (VI-1a).
The amount of the activator to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (VI-1a).
The reaction temperature is generally −30 to 180 ° C., preferably −10 to 80 ° C.
The reaction time is usually 0.5 to 100 hours.

Regarding the compound (XXX) used in the P1 method and the like, the compound (XXX-1) in which R ¹⁴ is an optionally substituted C _1-6 alkoxy group can be produced, for example, by the following method AA. .

[AA method]

[Wherein, Y ⁹ represents a leaving group, R ²² represents an optionally substituted C _1-6 alkyl group, and other symbols have the same meaning as described above. ]
Here, examples of the “leaving group” represented by Y ⁹ include the same “leaving group” represented by Y ¹ or Y ² . Of these, a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy and the like are preferable.
In this method, compound (XXX-1) can be produced by subjecting compound (XXX-1a) to an alkylation reaction. This reaction is generally carried out according to a method known per se in the presence of compound (XXXXI) and a base in a solvent that does not adversely influence the reaction. This reaction is carried out in the same manner as in the method described in Step 2 of the above T1 method.
Compound (XXX-1a) and compound (XXXXI) can be produced according to a method known per se.

  Compound (VII) used as a raw material compound in the above-mentioned Method B can be produced, for example, by the following AB method.

[AB method]

[Wherein each symbol is as defined above. ]
In this method, compound (VII) can be produced by subjecting compound (VII-8) to a sulfonylation reaction or halogenation reaction. This reaction is carried out in the same manner as in the method described in Step 1 of Method W above.
Compound (VII-8) can be produced according to a method known per se.

Regarding compound (XXXVI), compound (XXXVI-1) in which R ^4a and R ^5a together with the adjacent carbon atom form an optionally substituted ring F is produced by, for example, the following AC method can do.

[AC method]

[Each symbol in the formula is as defined above. ]
In this method, compound (XXXVI-1) can be produced by reacting compound (XXIX-4) with compound (XV). This reaction is performed in the same manner as in the method described in Step 3 of Method O above.
Compound (XXIX-4) can be produced according to a method known per se.

Regarding compound (XXXVI), compound (XXXVI-2) in which R ^4a and R ^5a do not form ring F which may be substituted together with the adjacent carbon atom is produced, for example, by the following AD method Can do.

[AD method]

[ ^Wherein , R ^4aa and R ^5aa are substituents, and other symbols are as defined above. ]
Here, as the substituent ^represented by R ^4aa or R ^5aa , the substituents exemplified as the aforementioned R ^4a and R ^5a (provided that R ^4a and R ^5a are bonded together with adjacent carbon atoms to form a benzene ring or Does not form a pyridine ring).
In this method, compound (XXXVI-2) can be produced by reacting compound (XXXXII) with a cyclizing agent. This reaction can be produced by a method known per se, for example, the method described in Journal of Medicinal Chemistry (J. Med. Chem.), Volume 38, page 1067 (1995), or a method analogous thereto. it can. That is, this reaction is usually performed in the presence of a cyclizing agent in a solvent that does not adversely influence the reaction.
Examples of the cyclizing agent include thiourea and ammonium thiocyanate.
Solvents that do not adversely affect the reaction include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane; methanol, ethanol, isopropanol, tert-butanol, pentanol, Alcohols such as hexanol; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Imides such as 1,3-dimethyl-2-imidazolidinone; Sulfoxides such as dimethyl sulfoxide And the like. These solvents may be mixed and used at an appropriate ratio.
The amount of the cyclizing agent to be used is generally 1-50 mol, preferably 1-20 mol, per 1 mol of compound (XXXXII).
The reaction temperature is usually 20 to 180 ° C, preferably 50 to 180 ° C.
The reaction time is usually 1 to 60 hours.
Compound (XXXXII) can be produced according to a method known per se.

  For compound (I-2), B is

Compound (I-2a) in which L ^1b is —CH═CH— can be produced, for example, by the following AE method.

[AE method]

[Wherein each symbol is as defined above. ]
In this method, compound (I-2a) can be produced by subjecting compound (XXXXIII) to a carbon increase reaction. This reaction is usually carried out using an organic phosphorus reagent in the presence of a base in a solvent that does not adversely influence the reaction.
Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal C _1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide Is mentioned.
Examples of the organic phosphorus reagent include ethyl (diethoxyphosphoryl) acetate, ethyl 2- (diethoxyphosphoryl) propanoate, tert-butyl (diethoxyphosphoryl) acetate and the like.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; dimethyl sulfoxide and the like And the like. These solvents may be mixed and used at an appropriate ratio.
The amount of the base to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (XXXXIII).
The amount of the organic phosphorus reagent to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (XXXXIII).
The reaction temperature is generally −80 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.1 to 30 hours.

  For compound (I-7), B is

L ^1b is —CH═CH—, and R ^A2 and R ^B2 are hydrogen atoms (I-7a), R ^A2 is a hydrogen atom, and R ^B2 is —CH ₂ CO—OR ^The compound (I-7b) which is ²³ and the compound (I-7c) in which R ^A2 is a hydrogen atom and R ^B2 is —CH ₂ COOH can be produced, for example, by the following AF method.

[AF method]

[Wherein, R ²³ represents an optionally substituted alkyl group, and other symbols are as defined above. ]

[Step 1]
In this step, compound (XXXXV) can be produced by reacting compound (XXXXIII) with compound (XXXXIV). This reaction is carried out by a method known per se (eg, the method described in Synthesis, page 2321 (2003)), the method described in the above AE method, or a method analogous thereto.
Compound (XXXXIV) can be produced according to a method known per se.

[Step 2]
In this step, compound (I-7a) can be produced by subjecting compound (XXXXV) to a deprotection reaction. This reaction is performed according to a method known per se in the presence of an acid in a solvent that does not adversely influence the reaction.
Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as trifluoroacetic acid and p-toluenesulfonic acid; and hydrogen chloride-methanol and hydrogen chloride in which hydrogen chloride is dissolved in a solution such as methanol and ethyl acetate. Examples include ethyl acetate.
Examples of solvents that do not adversely affect the reaction include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, isopropanol, and tert-butanol Ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio.
The usage-amount of an acid is 0.01-1000 mol normally with respect to 1 mol of compounds (XXXXV).
The reaction temperature is generally −80 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.1 to 30 hours.

[Step 3]
In this step, compound (XXXXVI) can be produced by reacting compound (XXXXV) with compound (VII-9). This reaction is carried out in the same manner as the method described in the above Method B.

[Step 4]
In this step, compound (I-7b) can be produced by subjecting compound (XXXXVI) to a deprotection reaction. This reaction is carried out in the same manner as in the method described in Step 2 of the AF method. Note that the compound (XXXXVI) when ^{R 23} is a tert- butyl group, can be prepared Compound (I-7c) in this step.

  Compound (XXXXIII) used as a raw material compound in the above AE method and AF method can be produced, for example, according to the AG method described later or a method analogous thereto.

[AG method]

Wherein, Y ⁹ is a halogen atom, and other symbols are as defined above. ]

[Step 1]
In this step, compound (XXXXVIII) can be produced by subjecting compound (XXXXVII) to a chloroformylation reaction. This reaction is carried out according to a method known per se, usually in the presence of a chloroformylating agent, in the absence of a solvent or in a solvent that does not adversely influence the reaction.
Examples of the chloroformylating agent include a combination of phosphoryl chloride and N, N-dimethylformamide.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; N, N-dimethylformamide and the like. These solvents may be mixed and used at an appropriate ratio.
The amount of the chloroformylylating agent to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXXXVII).
The reaction temperature is generally −30 to 150 ° C., preferably −10 to 120 ° C.
The reaction time is usually 0.5 to 100 hours.

[Step 2]
In this step, compound (XXXXIX) can be produced by subjecting compound (XXXXVIII) to a sulfurization reaction. This reaction is carried out according to a method known per se, usually in the presence of a sulfurizing agent, in a solvent that does not adversely influence the reaction.
Examples of the sulfurizing agent include potassium thioacetate, thiourea, hydrogen sulfide and the like.
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; Ketones such as acetone and 2-butanone; Nitriles such as acetonitrile and propionitrile; Esters such as ethyl acetate and isopropyl acetate; Alcohols such as methanol and ethanol Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; imides such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide, water and the like Can be mentioned. These solvents may be mixed and used at an appropriate ratio.
The amount of the sulfurizing agent to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXXXVIII).
The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C.
The reaction time is usually 0.5 to 100 hours.

[Step 3]
In this step, compound (XXXXIII) can be produced by reacting compound (XXXIX) with compound (III). This reaction is carried out in the same manner as the reaction described in the aforementioned method A1.
The compound (XXXXVII) used as a raw material compound in this method is produced according to a method known per se.

  In each of the above reactions, when the raw material compound has an amino group, carboxy group, hydroxy group, carbonyl group or mercapto group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction.

Examples of the amino-protecting group include those described above as R ¹¹ , R ¹² , R ¹⁵ and R ^15a .

Examples of the protecting group for the carboxy group include a C _1-6 alkyl group, a C _7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C _2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkoxy group and a nitro group.

Examples of the protective group for the hydroxy group include a C _1-6 alkyl group, a phenyl group, a trityl group, a C _7-10 aralkyl group (eg, benzyl), a formyl group, a C _1-6 alkyl-carbonyl group, a benzoyl group, C _7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert -Butyldiethylsilyl), a _C2-6 alkenyl group (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group and a nitro group.

Examples of the protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C _1-6 alkylacetal) and the like.

Examples of the protecting group for mercapto group include trityl group, benzyl group, p-methoxybenzyl group, formyl group, C _1-6 alkyl-carbonyl group, benzoyl group, C _7-10 aralkyl-carbonyl group (eg, benzylcarbonyl). ), N, N-dimethylcarbamoyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl) Etc.

  The protecting group removal method described above can be carried out according to a method known per se, for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980), and the like. . Specifically, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide), etc. are used. And a reduction method.

  The compound of the present invention obtained by each of the above production methods can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography and the like. Moreover, each raw material compound used in each of the above production methods can be isolated and purified by the same known means as described above. On the other hand, you may use these raw material compounds as a reaction mixture as it is as a raw material for the next step without isolation.

  When compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and they are synthesized by known synthesis methods and separation methods, respectively. Can be obtained as a single product. For example, when compound (I) has an optical isomer, the optical isomer resolved from the compound is also encompassed in compound (I).

  Hereinafter, the present invention will be described in more detail with reference to Test Examples, Reference Examples, Examples and Formulation Examples, but the present invention is not limited thereto.

  In the following Reference Examples and Examples,% indicates weight percent unless otherwise specified. Moreover, unless otherwise indicated, room temperature shows the temperature of 1-30 degreeC.

Reference Example 1 1-Methyl-2-sulfanyl-1H-indole-3-carbaldehyde

To a solution of 2-chloro-1-methyl-1H-indole-3-carbaldehyde (1.78 g) in ethanol (20 mL) was added 65% sodium hydrogen sulfide n hydrate (1.58 g), and the mixture was heated under reflux. Stir for hours. The reaction mixture was concentrated, water was added to the residue, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (0.70 g, yield 96%) as yellow crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.67 (s, 3 H), 7.12 (d, J = 8.0 Hz, 1 H), 7.19 (t, J = 7.0 Hz, 1 H), 7.30 (t , J = 7.2 Hz, 1 H), 7.48 (d, J = 7.6 Hz, 1 H), 8.34 (s, 1 H), 14.45 (s, 1 H).

Reference Example 2 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indole-3-carbaldehyde

To a solution of 1-methyl-2-sulfanyl-1H-indole-3-carbaldehyde (0.87 g) obtained in Reference Example 1 in N, N-dimethylformamide (10 mL), potassium carbonate (945 mg) and 2, 3-Dichloro-5- (trifluoromethyl) pyridine (1.23 g) was added and stirred at 80 ° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 87:13, v / v) to obtain the title compound (1.49 g, yield 88%) as a colorless solid. Crystallization from hexane-ethyl acetate gave white crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.80 (s, 3 H), 7.34-7.48 (m, 3 H), 7.88 (d, J = 1.5 Hz, 1 H), 8.36-8.40 (m, 1 H), 8.42-8.48 (m, 1 H), 10.24 (s, 1 H).

Reference Example 3 {[(E) -2- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indol-3-yl) ethenyl] Sulfonyl} tert-butyl carbamate

{[(Diphenylphosphoryl) methyl] sulfonyl} carbamic acid tert-butyl (720 mg) in N, N-dimethylformamide (10 mL) with stirring at 0 ° C, 60% sodium hydride (oil, 203 mg) And stirred at 0 ° C. for 1 hour. 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indole-3-carbaldehyde obtained in Reference Example 2 (605 mg) Of N, N-dimethylformamide (10 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 72:28, v / v) and crystallized from hexane-ethyl acetate to give the title compound (660 mg, yield 73%) as colorless crystals. It was.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41 (s, 9 H), 3.78 (s, 3 H), 7.00 (s, 1 H), 7.13 (d, J = 15.4 Hz, 1 H), 7.32-7.39 (m, 1 H), 7.41-7.51 (m, 2 H), 7.86 (d, J = 1.5 Hz, 1 H), 7.92 (d, J = 7.9 Hz, 1 H), 8.04 (d, J = 15.4 Hz, 1 H), 8.33-8.37 (m, 1 H).

Reference Example 4 2-{[3-Fluoro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indole-3-carbaldehyde

From 1-methyl-2-sulfanyl-1H-indole-3-carbaldehyde obtained in Reference Example 1 and 2,3-difluoro-5- (trifluoromethyl) pyridine, the title was prepared in the same manner as in Reference Example 2. A compound was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.83 (s, 3 H), 7.34-7.47 (m, 3 H), 7.60 (dd, J = 8.7, 1.5 Hz, 1 H), 8.30-8.38 ( m, 1 H), 8.41-8.49 (m, 1 H), 10.25 (s, 1 H).

Reference Example 5 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole

1H-benzimidazol-2-thiol (3.00 g), 2,3-dichloro-5- (trifluoromethyl) pyridine (4.58 g) and potassium carbonate (4.15 g) mixed with N, N-dimethylformamide (40 mL) The solution was stirred at 80 ° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was crystallized from hexane-ethyl acetate to give the title compound (4.90 g) as colorless crystals. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 70:30, v / v) to obtain the title compound (0.96 g) as a colorless solid (total 5.86 g, yield 89%) ).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.27-7.34 (m, 2 H), 7.51-7.58 (m, 1 H), 7.73-7.80 (m, 1 H), 7.94 (d, J = 1.9 Hz, 1 H), 8.74 (s, 1 H), 11.84 (br s, 1 H).

Reference Example 6 4-Methyl-1H-benzimidazol-2-thiol

N, N′-thiocarbonyldiimidazole (7.70 g) was added to a tetrahydrofuran (40 mL) solution of 2,3-diaminotoluene (5.00 g), and the mixture was stirred at 80 ° C. for 14 hours. The reaction solution was cooled to room temperature, 1N hydrochloric acid was added to the reaction solution, water was further added, and the resulting solid was filtered and dried. The obtained solid was crystallized from diisopropyl ether-ethyl acetate to give the title compound (5.38 g, yield 80%) as brown crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.37 (s, 3 H), 6.53-7.23 (m, 3 H), 12.47 (br s, 1 H), 12.60 (br s, 1 H).

Reference Example 7 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-methyl-1H-benzimidazole

The title compound was obtained in the same manner as in Reference Example 5 from 4-methyl-1H-benzimidazole-2-thiol and 2,3-dichloro-5- (trifluoromethyl) pyridine obtained in Reference Example 6. .
¹ H-NMR (300 MHz, CDCl ₃ , tautomeric equilibrium, integral ratio about 1: 1) δ: 2.59 (s, 3/2 H), 2.68 (s, 3/2 H), 7.03-7.14 ( m, 1 H), 7.21 (t, J = 7.8 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1/2 H), 7.61 (d, J = 8.0 Hz, 1/2 H), 7.94 (s, 1 H), 8.72 (br s, 1 H), 11.67 (br s, 1 H).

Reference Example 8 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methoxy-1H-benzimidazole

6-Methoxy-1H-benzimidazole-2-thiol (4.95 g), 2,3-dichloro-5- (trifluoromethyl) pyridine (3.90 mL) and potassium carbonate (4.55 g) in N, N-dimethylformamide ( (25 mL) The mixture was stirred at room temperature for 12 hours. 2,3-Dichloro-5- (trifluoromethyl) pyridine (1.00 mL) was added, and the mixture was further stirred for 3 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction solution, and the resulting solid was filtered and dried. The obtained solid was crystallized from hexane-ethyl acetate to give the title compound (8.30 g, yield 84%) as white crystals.
¹ H-NMR (300 MHz, CDCl ₃ , tautomeric equilibrium, integral ratio about 1: 1) δ: 3.87 (s, 3/2 H), 3.88 (s, 3/2 H), 6.90-7.00 ( m, 1 H), 7.02 (d, J = 2.3 Hz, 1/2 H), 7.24 (d, J = 2.3 Hz, 1/2 H), 7.41 (d, J = 8.7 Hz, 1/2 H) , 7.65 (d, J = 8.9 Hz, 1/2 H), 7.88-7.96 (m, 1 H), 8.70 (s, 1/2 H), 8.74 (s, 1/2 H).

Reference Example 9 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5,6-difluoro-1H-benzimidazole

The title compound is obtained from 5,6-difluoro-1,3-dihydro-2H-benzimidazol-2-thione and 2,3-dichloro-5- (trifluoromethyl) pyridine in the same manner as in Reference Example 5. It was.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34-7.56 (m, 2 H), 7.98 (d, J = 1.9 Hz, 1 H), 8.77 (d, J = 0.8 Hz, 1 H). NH proton is not detected.

Reference Example 10 2,2-Dimethyl-3-[(2-nitrophenyl) amino] propan-1-ol

A mixture of 2-fluoronitrobenzene (2.30 mL), 3-amino-2,2-dimethylpropan-1-ol (4.51 g) and triethylamine (6.2 mL) in acetonitrile (100 mL) was stirred with heating under reflux for 10 hours. did. 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5 to 1: 1, v / v) to give the title compound (5.42 g, quantitative) as a yellow oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.06 (s, 6 H), 1.58 (br s, 1 H), 3.23 (d, J = 5.5 Hz, 2 H), 3.52 (d, J = 5.3 Hz, 2 H), 6.62 (ddd, J = 8.5, 7.1, 1.2 Hz, 1 H), 6.93 (dd, J = 8.7, 0.8 Hz, 1 H), 7.42 (ddd, J = 8.5, 7.1, 1.5 Hz , 1 H), 8.17 (dd, J = 8.7, 1.7 Hz, 1 H), 8.42 (br s, 1 H).

Reference Example 11 2,2-Dimethyl-3- (2-sulfanyl-1H-benzoimidazol-1-yl) propan-1-ol

To a solution of 2,2-dimethyl-3-[(2-nitrophenyl) amino] propan-1-ol (5.41 g) obtained in Reference Example 10 in methanol (100 mL), 10% palladium on carbon (5.40 g) And stirred at room temperature for 4 hours under a hydrogen atmosphere of 1 atm. After removing the catalyst by filtration, the filtrate was concentrated. N, N′-thiocarbonyldiimidazole (5.16 g) was added to a solution of this residue in tetrahydrofuran (100 mL), and the mixture was stirred at room temperature for 78 hours. Further, N, N′-thiocarbonyldiimidazole (5.16 g) was added, and the mixture was stirred at room temperature for 6 hours. 6N Hydrochloric acid was added to the reaction mixture, and water was further added. The resulting solid was filtered, washed with water and dried to give the title compound (3.69 g, yield 65%) as a white powder. . Crystallization with hexane-ethyl acetate gave white crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.92 (s, 6 H), 3.17 (d, J = 5.7 Hz, 2 H), 4.14 (s, 2 H), 4.91 (t, J = 5.7 Hz , 1 H), 7.14-7.22 (m, 3 H), 7.48-7.59 (m, 1 H), 12.82 (s, 1 H).

Reference Example 12 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) -2,2-dimethylpropan-1-ol

2,2-Dimethyl-3- (2-sulfanyl-1H-benzoimidazol-1-yl) propan-1-ol (4.66 g), 2,3-dichloro-5- (trifluoro) obtained in Reference Example 11 A mixture of methyl) pyridine (4.10 mL) and potassium carbonate (4.10 g) in N, N-dimethylformamide (40 mL) was stirred at 50 ° C. for 12 hours. Further, 2,3-dichloro-5- (trifluoromethyl) pyridine (4.10 mL) and potassium carbonate (4.10 g) were added and stirred for 4 hours. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-60: 40, v / v) to give the title compound (2.95 g, yield 36%) as a colorless solid. Crystallization with hexane-ethyl acetate gave white crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.87 (s, 6 H), 3.22 (d, J = 5.3 Hz, 2 H), 4.15 (s, 2 H), 4.91 (t, J = 5.2 Hz , 1 H), 7.21-7.31 (m, 1 H), 7.32-7.42 (m, 1 H), 7.68 (d, J = 7.6 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H) , 8.51 (d, J = 1.5 Hz, 1 H), 8.58-8.68 (m, 1 H).

Reference Example 13 Methyl 2,2-difluoro-3- (2-sulfanyl-1H-benzimidazol-1-yl) propionate

A mixture of 2-fluoronitrobenzene (2.00 g), 3-amino-2,2-difluoropropionate hydrochloride (9.46 g) and triethylamine (36.0 mL) in acetonitrile (600 mL) was stirred with heating under reflux for 24 hours. . The reaction mixture was cooled to room temperature, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-60: 40, v / v) to give a yellow oil. A mixture of a portion of the obtained yellow oil, concentrated sulfuric acid (0.50 mL) and trimethyl orthoformate (4.70 mL) in methanol (20 mL) was stirred at 60 ° C. for 2 hours. A mixture of the remaining yellow oil, concentrated sulfuric acid (0.50 mL) and trimethyl orthoformate (4.70 mL) in methanol (20 mL) was stirred at 60 ° C. for 4 hours. These methanol reaction solutions were cooled to room temperature, combined, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-65: 35, v / v) to give a yellow oil. To a solution of the obtained yellow oil in methanol (30 mL), 10% palladium carbon (1.90 g) was added, and the mixture was stirred at room temperature for 2.5 hours under a hydrogen atmosphere of 1 atm. After removing the catalyst by filtration, the filtrate was concentrated. N, N′-thiocarbonyldiimidazole (2.70 g) was added to a solution of this residue in tetrahydrofuran (40 mL), and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was washed with diisopropyl ether-ethyl acetate, and the filtrate was concentrated to give the title compound (0.97 g, yield 25%) as a pale yellow oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.83 (s, 3 H), 5.10 (t, J = 14.2 Hz, 2 H), 7.00-7.47 (m, 4 H), 13.04 (br s, 1 H).

Reference Example 14 1- (3-Bromopropyl) -2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (3.11 g), 1,3-dibromopropane (15.6 g) obtained in Reference Example 5 And a mixture of cesium carbonate (4.61 g) in N, N-dimethylformamide (50 mL) was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-65: 35, v / v) to give the title compound (3.60 g, yield 85%) as a colorless oil. Crystallization from hexane-ethyl acetate gave white crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.40 (tt, J = 6.9, 6.2 Hz, 2 H), 3.38 (t, J = 6.2 Hz, 2 H), 4.44 (t, J = 7.0 Hz, 2 H), 7.29-7.46 (m, 2 H), 7.55 (d, J = 7.5 Hz, 1 H), 7.79-7.87 (m, 2 H), 8.35 (d, J = 1.1 Hz, 1 H).

Reference Example 15 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (prop-2-en-1-yl) -1H-benzimidazole

Similar to Reference Example 14 from 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole, cesium carbonate and allyl bromide obtained in Reference Example 5. The title compound was obtained by the method.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.83-4.93 (m, 2 H), 5.06-5.25 (m, 2 H), 5.82-5.98 (m, 1 H), 7.31-7.47 (m, 3 H), 7.79-7.90 (m, 2 H), 8.35 (dd, J = 1.9, 0.9 Hz, 1 H).

Reference Example 16 2-[(2,5-dichlorophenyl) sulfanyl] -1H-benzimidazole

Mix N-methyl-2-pyrrolidinone (50 mL) of 2-chloro-1H-benzimidazole (4.26 g), 2,5-dichlorobenzenethiol (5.0 g) and potassium carbonate (5.53 g) at 130 ° C. Stir for 6 hours. After cooling to room temperature, water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 50: 50-0: 100, v / v) to give the title compound (6.21 g, yield 75%) as a colorless solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.00-7.03 (m, 1 H), 7.16-7.28 (m, 3 H), 7.33 (s, 1 H), 7.53 (br s, 2 H), 11.16 (br s, 1 H).

Reference Example 17 1- (2-Bromoethyl) -2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole

From 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole, cesium carbonate and 1,2-dibromoethane obtained in Reference Example 5, Reference Example 14 In the same manner as described above, the title compound was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.67 (t, J = 7.3 Hz, 2 H), 4.65 (t, J = 7.3 Hz, 2 H), 7.32-7.57 (m, 3 H), 7.80 -7.89 (m, 2 H), 8.35 (d, J = 1.1 Hz, 1 H).

Reference Example 18 4-[(4-Methoxy-2-nitrophenyl) amino] butanoic acid methyl ester

2,2,2-trifluoro-N- (4-methoxy-2-nitrophenyl) acetamide (12.6 g), sodium iodide (10.8 g), cesium carbonate (23.4 g) and tert-butyl 4-bromobutanoate ( A mixed solution of 16.0 g) of N, N-dimethylformamide (100 mL) was stirred at 80 ° C. for 18 hours and at 100 ° C. for 6 hours. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. To a solution of the obtained residue in methanol (100 mL) was added potassium carbonate (10.5 g), and the mixture was stirred at room temperature for 16 hours. Further, potassium carbonate (39.5 g) was added and stirred for 6 hours. The insoluble material was removed by filtration and washed with tetrahydrofuran, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-0: 100, v / v) to give an orange solid. The mixture was washed with hexane-ethyl acetate, filtered, and the filtrate was concentrated to give the title compound (4.66 g, yield 36%) as an orange oil.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.73-1.95 (m, 2 H), 2.41 (t, J = 7.3 Hz, 2 H), 3.34-3.43 (m, 2 H), 3.58 ( s, 3 H), 3.75 (s, 3 H), 7.03-7.13 (m, 1 H), 7.27 (d, J = 3.0 Hz, 1 H), 7.50 (d, J = 3.0 Hz, 1 H), 8.09 (t, J = 5.8 Hz, 1 H).

Reference Example 19 Methyl 4- (5-methoxy-2-sulfanyl-1H-benzoimidazol-1-yl) butanoate

To a solution of methyl 4-[(4-methoxy-2-nitrophenyl) amino] butanoate (4.66 g) obtained in Reference Example 18 in tetrahydrofuran (50 mL) was added 10% palladium carbon (4.70 g), and 1 The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere at atmospheric pressure. The catalyst was removed by filtration, and then washed with tetrahydrofuran (10 mL). N, N′-thiocarbonyldiimidazole (3.90 g) was added to the filtrate, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 85: 15-50: 50, v / v) to give the title compound (2.97 g, yield 61%) as a white solid. Crystallization with hexane-ethyl acetate gave white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ , tautomeric equilibrium, integral ratio about 85:15) δ: 1.68-2.08 (m, 2 H), 2.38 (t, J = 7.3 Hz, 2 H) , 3.56 (s, 3 H), 3.74 (s, 3/2 H), 3.76 (s, 3/2 H), 4.20 (t, J = 7.2 Hz, 2 H), 6.67 (d, J = 2.3 Hz , 1/2 H), 6.69-6.76 (m, 1 H), 6.81 (dd, J = 8.7, 2.3 Hz, 1/2 H), 7.02 (d, J = 8.7 Hz, 1/2 H), 7.30 (d, J = 8.7 Hz, 1/2 H), 12.56 (br s, 1 H).

Reference Example 20 (2S) -2-hydroxy-4-[(2-nitrophenyl) amino] butanoic acid

A mixture of 2-fluoronitrobenzene (10.0 g), (2S) -4-amino-2-hydroxybutanoic acid (24.5 g) and triethylamine (50 mL) in N, N-dimethylformamide (100 mL) at 100 ° C was mixed with 48 Stir for 5 hours at 120 ° C. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 85:15 to 65:35, v / v) to give the title compound (14.4 g, yield 85%) as a red-orange solid. Crystallization with hexane-ethyl acetate gave red crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.55-1.96 (m, 1 H), 1.94-2.12 (m, 1 H), 3.41-3.63 (m, 2 H), 4.09 (dd, J = 8.7, 3.8 Hz, 1 H), 6.68 (t, J = 7.2 Hz, 1 H), 7.05 (d, J = 7.9 Hz, 1 H), 7.33-7.85 (m, 1 H), 8.06 (dd, J = 8.7, 1.5 Hz, 1 H), 8.29 (t, J = 5.7 Hz, 1 H). OH proton is not detected.

Reference Example 21 (2S) -2-Hydroxy-4-[(2-nitrophenyl) amino] butanoic acid methyl ester

To a solution of (2S) -2-hydroxy-4-[(2-nitrophenyl) amino] butanoic acid (18.0 g) obtained in Reference Example 20 in tetrahydrofuran (100 mL) was added trimethylsilyldiazomethane (2M diethyl ether) with stirring. Solution, 80 mL) was added, and the mixture was stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction solution until it no longer foamed, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5 to 60:40, v / v), and the obtained oily substance was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5 to 60:40, v / v) to give the title compound (15.2 g, 80% yield) as an orange oil.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.79-2.11 (m, 2 H), 3.36-3.52 (m, 2 H), 3.61 (s, 3 H), 4.08-4.35 (m, 1 H), 5.71 (d, J = 5.3 Hz, 1 H), 6.68 (t, J = 7.6 Hz, 1 H), 7.05 (d, J = 8.7 Hz, 1 H), 7.54 (t, J = 7.8 Hz , 1 H), 8.06 (dd, J = 8.5, 1.3 Hz, 1 H), 8.23 (t, J = 5.3 Hz, 1 H).

Reference Example 22 (2S) -2-{[tert-butyl (diphenyl) silyl] oxy} -4-[(2-nitrophenyl) amino] butanoic acid methyl

N, N-dimethylformamide (50 mL) of methyl (2S) -2-hydroxy-4-[(2-nitrophenyl) amino] butanoate (6.96 g) and imidazole (9.32 g) obtained in Reference Example 21 To the mixture was added tert-butylchlorodiphenylsilane (7.80 mL) with stirring, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-70: 30, v / v) to give the title compound (13.3 g, yield 98%) as a yellow oil.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.04 (s, 9 H), 2.03 (q, J = 6.5 Hz, 2 H), 3.39 (s, 3 H), 3.44 (q, J = 6.8 Hz, 2 H), 4.36 (t, J = 5.7 Hz, 1 H), 6.70 (t, J = 7.3 Hz, 1 H), 6.92 (d, J = 8.3 Hz, 1 H), 7.27-7.54 ( m, 6 H), 7.54-7.62 (m, 4 H), 7.61-7.78 (m, 1 H), 8.01 (t, J = 5.7 Hz, 1 H), 8.06 (dd, J = 8.7, 1.5 Hz, 1 H).

Reference Example 23 (2S) -2-{[tert-butyl (diphenyl) silyl] oxy} -4- (2-sulfanyl-1H-benzoimidazol-1-yl) butanoic acid methyl ester

In the same manner as in Reference Example 19, from (2S) -2-{[tert-butyl (diphenyl) silyl] oxy} -4-[(2-nitrophenyl) amino] butanoic acid methyl obtained in Reference Example 22. The title compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.06 (s, 9 H), 1.93-2.19 (m, 2 H), 3.46 (s, 3 H), 4.05-4.37 (m, 2 H) , 4.42 (t, J = 5.3 Hz, 1 H), 6.92-7.29 (m, 4 H), 7.29-7.53 (m, 6 H), 7.53-7.80 (m, 4 H), 12.73 (br s, 1 H).

Reference Example 24 (2S) -2-{[tert-butyl (diphenyl) silyl] oxy} -4- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H -Benzimidazol-1-yl) butanoic acid methyl ester

From methyl (2S) -2-{[tert-butyl (diphenyl) silyl] oxy} -4- (2-sulfanyl-1H-benzimidazol-1-yl) butanoate obtained in Reference Example 23, Reference Example 12 In the same manner as described above, the title compound was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.07 (s, 9 H), 2.09-2.37 (m, 2 H), 3.45 (s, 3 H), 4.27-4.42 (m, 3 H), 7.29 -7.48 (m, 9 H), 7.50-7.66 (m, 4 H), 7.69-7.89 (m, 2 H), 8.32 (s, 1 H).

Reference Example 25 N- (4,4-diethoxybutyl) -4-methyl-2-nitroaniline

4-Aminobutyraldehyde diethyl acetal (1.18 g) was added to a mixed solution of 4-fluoro-3-nitrotoluene (509 mg) and triethylamine (996 mg) in acetonitrile (15 mL), and the mixture was heated to reflux for 18 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-50: 50, v / v) to give the title compound (923 mg, yield 95%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.21 (t, J = 7.1 Hz, 6 H), 1.70-1.86 (m, 4 H), 2.26 (s, 3 H), 3.29-3.36 (m, 2 H), 3.44-3.57 (m, 2 H), 3.60-3.72 (m, 2 H), 4.51-4.56 (m, 1 H), 6.77 (d, J = 8.9 Hz, 1 H), 7.23-7.28 (m, 1 H), 7.93-8.00 (m, 2 H).

Reference Example 26 N- (4,4-diethoxybutyl) -4-methylbenzene-1,2-diamine

To a solution of N- (4,4-diethoxybutyl) -4-methyl-2-nitroaniline (442 mg) obtained in Reference Example 25 in ethanol (15 mL) was added 10% palladium carbon (44 mg), The mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere of 1 atm. The catalyst was removed by filtration, and the filtrate was concentrated to give the title compound (414 mg, yield 99%) as a black oil.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.11 (t, J = 7.1 Hz, 6 H), 1.51-1.67 (m, 4 H), 2.07 (s, 3 H), 2.96 (br s , 2 H), 3.36-3.48 (m, 2 H), 3.50-3.62 (m, 2 H), 4.14 (br s, 1 H), 4.40 (br s, 2 H), 4.45-4.51 (m, 1 H), 6.25-6.32 (m, 2 H), 6.36 (s, 1 H).

Reference Example 27 1- (4,4-diethoxybutyl) -5-methyl-1H-benzimidazol-2-thiol

To a solution of N- (4,4-diethoxybutyl) -4-methylbenzene-1,2-diamine (372 mg) obtained in Reference Example 26 in tetrahydrofuran (15 mL), 1,1-thiocarbonyldiimidazole ( 261 mg) was added and the mixture was heated to reflux for 6 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 80: 20-25: 75, v / v) to give the title compound (372 mg, yield 86%) as a colorless oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.16-1.23 (m, 6 H), 1.71-1.80 (m, 2 H), 1.88-2.00 (m, 2 H), 2.41 (s, 3 H) , 3.44-3.56 (m, 2 H), 3.59-3.71 (m, 2 H), 4.30 (t, J = 7.4 Hz, 2 H), 4.56 (t, J = 5.7 Hz, 1 H), 6.99-7.11 (m, 3 H), 11.45 (br s, 1 H).

Reference Example 28 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-diethoxybutyl) -5-methyl-1H-benzimidazole

1- (4,4-Diethoxybutyl) -5-methyl-1H-benzimidazol-2-thiol (315 mg) and potassium carbonate (183 mg) obtained in Reference Example 27 (N, N-dimethylformamide) 10 mL) 2,3-Dichloro-5- (trifluoromethyl) pyridine (287 mg) was added to the mixture and stirred at 60 ° C. for 2 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 80: 20-25: 75, v / v) to give the title compound (455 mg, yield 91%) as a colorless oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.15 (t, J = 7.1 Hz, 6 H), 1.59-1.68 (m, 2 H), 1.85-1.97 (m, 2 H), 2.50 (s, 3 H), 3.35-3.49 (m, 2 H), 3.51-3.63 (m, 2 H), 4.25 (t, J = 7.4 Hz, 2 H), 4.42 (t, J = 5.5 Hz, 1 H), 7.18-7.23 (m, 1 H), 7.35 (d, J = 8.5 Hz, 1 H), 7.61 (s, 1 H), 7.81-7.83 (m, 1 H), 8.33-8.35 (m, 1 H) .

Reference Example 29 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-benzimidazol-1-yl) butanal

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-diethoxybutyl) -5-methyl-1H-benzox obtained in Reference Example 28 1N Hydrochloric acid (60 mL) was added to a solution of imidazole (14.36 g) in tetrahydrofuran (60 mL), and the mixture was stirred at 50 ° C. for 2 hr. 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 80: 20-20: 80, v / v) to give the title compound (10.31 g, yield 85%) as a colorless oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.09-2.20 (m, 2 H), 2.47-2.54 (m, 5 H), 4.26 (t, J = 7.2 Hz, 2 H), 7.20-7.25 ( m, 1 H), 7.38 (d, J = 8.3 Hz, 1 H), 7.62 (s, 1 H), 7.83 (d, J = 1.5 Hz, 1 H), 8.33 (s, 1 H), 9.73 ( s, 1 H).

Reference Example 30 5,6-Dimethyl-1H-benzimidazol-2-thiol

The title compound was obtained from 4,5-dimethyl-1,2-phenylenediamine in the same manner as in Reference Example 6.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.23 (s, 6 H), 6.93 (s, 2 H), 12.32 (br s, 2 H).

Reference Example 31 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5,6-dimethyl-1H-benzimidazole

From the 5,6-dimethyl-1H-benzimidazole-2-thiol and 2,3-dichloro-5- (trifluoromethyl) pyridine obtained in Reference Example 30, the title compound was prepared in the same manner as in Reference Example 5. Obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.33 (s, 6 H), 7.37 (s, 2 H), 8.52 (d, J = 1.5 Hz, 1 H), 8.71 (d, J = 0.8 Hz, 1 H), 12.90 (br s, 1 H).

Reference Example 32 5,6-dichloro-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole

The title compound was obtained from 5,6-dichloro-1H-benzimidazole-2-thiol and 2,3-dichloro-5- (trifluoromethyl) pyridine in the same manner as in Reference Example 5.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.65 (s, 1 H), 7.80 (s, 1 H), 7.96 (d, J = 1.5 Hz, 1 H), 8.72-8.75 (m, 1 H ), 12.19 (br s, 1 H).

Reference Example 33 N- (3,3-diethoxypropyl) -4-methyl-2-nitroaniline

The title compound was obtained from 4-fluoro-3-nitrotoluene and 3-aminopropionaldehyde diethyl acetal in the same manner as in Reference Example 25.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.21-1.27 (m, 6 H), 1.99-2.08 (m, 2 H), 2.26 (s, 3 H), 3.36-3.44 (m, 2 H) , 3.49-3.60 (m, 2 H), 3.65-3.76 (m, 2 H), 4.65 (t, J = 5.2 Hz, 1 H), 6.79 (d, J = 8.9 Hz, 1 H), 7.23-7.29 (m, 1 H), 7.96 (d, J = 1.1 Hz, 1 H), 8.14 (br s, 1 H).

Reference Example 34 N- (3,3-diethoxypropyl) -4-methylbenzene-1,2-diamine

The title compound was obtained from N- (3,3-diethoxypropyl) -4-methyl-2-nitroaniline obtained in Reference Example 33 by a method similar to that in Reference Example 26.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.22 (t, J = 7.0 Hz, 6 H), 1.94-2.02 (m, 2 H), 2.21 (s, 3 H), 3.17 (t, J = 6.4 Hz, 2 H), 3.30-3.58 (m, 5 H), 3.62-3.73 (m, 2 H), 4.65 (t, J = 5.5 Hz, 1 H), 6.51-6.63 (m, 3 H).

Reference Example 35 1- (3,3-diethoxypropyl) -5-methyl-1H-benzimidazol-2-thiol

The title compound was obtained from N- (3,3-diethoxypropyl) -4-methylbenzene-1,2-diamine obtained in Reference Example 34 by a method similar to that in Reference Example 27.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.22 (t, J = 7.1 Hz, 6 H), 2.14-2.23 (m, 2 H), 2.41 (s, 3 H), 3.46-3.58 (m, 2 H), 3.62-3.74 (m, 2 H), 4.32-4.38 (m, 2 H), 4.59 (t, J = 5.6 Hz, 1 H), 6.99-7.13 (m, 3 H), 11.36 (br s, 1 H).

Reference Example 36 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (3,3-diethoxypropyl) -5-methyl-1H-benzimidazole

From 1- (3,3-diethoxypropyl) -5-methyl-1H-benzimidazole-2-thiol and 2,3-dichloro-5- (trifluoromethyl) pyridine obtained in Reference Example 35, Reference Example In the same manner as in No. 12, the title compound was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.17 (t, J = 7.1 Hz, 6 H), 2.06-2.15 (m, 2 H), 2.50 (s, 3 H), 3.34-3.49 (m, 2 H), 3.51-3.64 (m, 2 H), 4.28-4.35 (m, 2 H), 4.44 (t, J = 5.4 Hz, 1 H), 7.21 (dd, J = 8.3, 1.1 Hz, 1 H ), 7.37 (d, J = 8.3 Hz, 1 H), 7.61 (s, 1 H), 7.82 (d, J = 1.7 Hz, 1 H), 8.32-8.35 (m, 1 H).

Reference Example 37 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-benzimidazol-1-yl) propanal

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (3,3-diethoxypropyl) -5-methyl-1H-benzox obtained in Reference Example 36 The title compound was obtained from imidazole in the same manner as in Reference Example 29.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.50 (s, 3 H), 3.04 (t, J = 7.3 Hz, 2 H), 4.56 (t, J = 7.2 Hz, 2 H), 7.23 (dd , J = 8.4, 1.2 Hz, 1 H), 7.32-7.37 (m, 1 H), 7.61 (s, 1 H), 7.84 (d, J = 1.5 Hz, 1 H), 8.32-8.35 (m, 1 H), 9.77 (s, 1 H).

Reference Example 38 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) butan-1-ol

N, N of 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (516 mg) and cesium carbonate (1.02 g) obtained in Reference Example 5 4-Bromo-1-butanol (932 mg) was added to a mixed solution of dimethylformamide (16 mL), and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 75: 25-30: 70, v / v) and crystallized from hexane-ethyl acetate to give the title compound (316 mg, yield 50%). Obtained as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.36 (t, J = 4.9 Hz, 1 H), 1.54-1.65 (m, 2 H), 1.89-2.01 (m, 2 H), 3.59-3.67 ( m, 2 H), 4.29 (t, J = 7.4 Hz, 2 H), 7.29-7.42 (m, 2 H), 7.44-7.49 (m, 1 H), 7.81-7.86 (m, 2 H), 8.35 (s, 1 H).

Reference Example 39 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) butanenitrile

N, N of 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (1.63 g) and cesium carbonate (3.22 g) obtained in Reference Example 5 4-Bromobutyronitrile (1.10 g) was added to a mixed solution of dimethylformamide (50 mL), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 80: 20-40: 60, v / v) to give the title compound (1.69 g, yield 86%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.18-2.29 (m, 2 H), 2.35-2.41 (m, 2 H), 4.43 (t, J = 6.9 Hz, 2 H), 7.33-7.53 ( m, 3 H), 7.83-7.88 (m, 2 H), 8.34-8.37 (m, 1 H).

Reference Example 40 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propanenitrile

Similar to Reference Example 39 from 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole and 3-bromopropionitrile obtained in Reference Example 5. The title compound was obtained by the method.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.87-2.94 (m, 2 H), 4.61 (t, J = 7.3 Hz, 2 H), 7.35-7.52 (m, 3 H), 7.84-7.89 ( m, 2 H), 8.35-8.37 (m, 1 H).

Reference Example 41 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) butanal

4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) butan-1-ol (1.16) obtained in Reference Example 38 To a solution of g) in dimethyl sulfoxide (30 mL) were added sulfur trioxide pyridine complex (1.38 g) and triethylamine (2.92 g), and the mixture was stirred at room temperature for 18 hours. Further, sulfur trioxide pyridine complex (1.38 g) and triethylamine (2.92 g) were added to the reaction solution, and the mixture was stirred at 60 ° C. for 6 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 85: 15-35: 65, v / v) to give the title compound (973 mg, yield 84%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.11-2.22 (m, 2 H), 2.53 (t, J = 6.8 Hz, 2 H), 4.26-4.33 (m, 2 H), 7.30-7.44 ( m, 2 H), 7.49-7.54 (m, 1 H), 7.82-7.87 (m, 2 H), 8.33-8.36 (m, 1 H), 9.75 (s, 1 H).

Reference Example 42 N- (tert-butoxycarbonyl) -N-{[(E) -2- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl -1H-Indol-3-yl) ethenyl] sulfonyl} glycine tert-butyl ester

{[(E) -2- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indole-3- obtained in Reference Example 3 Yl) ethenyl] sulfonyl} carbamate tert-butyl (455 mg) and potassium carbonate (137 mg) in N, N-dimethylformamide (8.3 mL) mixed with tert-butyl bromoacetate (178 mg) at room temperature For 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-50: 50, v / v) to give the title compound (468 mg, yield 85%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.37 (s, 9 H), 1.45 (s, 9 H), 3.77 (s, 3 H), 4.39 (s, 2 H), 7.28-7.38 (m , 2 H), 7.40-7.50 (m, 2 H), 7.85 (d, J = 1.9 Hz, 1 H), 7.94-8.01 (m, 2 H), 8.33 (s, 1 H).

Reference Example 43 N- (tert-butoxycarbonyl) -N-{[(E) -2- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl -1H-Indol-3-yl) ethenyl] sulfonyl} glycine ethyl ester

{[(E) -2- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indole-3- obtained in Reference Example 3 Yl) ethenyl] sulfonyl} The title compound was obtained from tert-butyl carbamate and ethyl bromoacetate in the same manner as in Reference Example 42.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.24-1.30 (m, 3 H), 1.35 (s, 9 H), 3.78 (s, 3 H), 4.22 (q, J = 7.2 Hz, 2 H ), 4.51 (s, 2 H), 7.30 (d, J = 15.4 Hz, 1 H), 7.33-7.50 (m, 3 H), 7.85 (d, J = 1.5 Hz, 1 H), 7.96-8.02 ( m, 2 H), 8.34 (d, J = 1.1 Hz, 1 H).

Reference Example 44 N- (4,4-dimethoxybutyl) -4-fluoro-2-nitroaniline

To a mixed solution of 1,4-difluoro-2-nitrobenzene (8.0 g) and triethylamine (13.23 g) in acetonitrile (200 mL), add 4,4-dimethoxybutan-1-amine (13.39 g) at 0 ° C and heat to reflux. The mixture was stirred for 13 hours. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0-80: 20, v / v) to give the title compound (13.63 g, quantitative) as a brown solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.71-1.86 (m, 4 H), 3.27-3.38 (m, 8 H), 4.42 (t, J = 5.1 Hz, 1 H), 6.83 (dd, J = 9.5, 4.5 Hz, 1 H), 7.21-7.31 (m, 1 H), 7.89 (dd, J = 9.3, 3.2 Hz, 1 H), 7.96 (br s, 1 H).

Reference Example 45 N '-(4,4-dimethoxybutyl) -4-fluorobenzene-1,2-diamine

To a solution of N- (4,4-dimethoxybutyl) -4-fluoro-2-nitroaniline (16.4 g) obtained in Reference Example 44 in ethanol (600 mL) was added 10% palladium carbon (1.60 g), The mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere of 1 atm. The catalyst was removed by filtration, and the filtrate was concentrated to give the title compound (12.49 g, yield 86%) as a brown oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.65-1.81 (m, 4 H), 3.07 (t, J = 6.6 Hz, 2 H), 3.34 (s, 6 H), 4.38-4.47 (m, 1 H), 6.40-6.50 (m, 2 H), 6.54-6.60 (m, 1 H).

Reference Example 46 1- (4,4-Dimethoxybutyl) -5-fluoro-1H-benzimidazole-2-thiol

To a solution of N ′-(4,4-dimethoxybutyl) -4-fluorobenzene-1,2-diamine (12.28 g) obtained in Reference Example 45 in tetrahydrofuran (400 mL), N, N′-thiocarbonyldi Imidazole (9.48 g) was added, and the mixture was stirred at 90 ° C. for 3.5 hours. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 70:30, v / v), and the fraction containing impurities was again silica gel column chromatography (hexane-ethyl acetate 100: 0 to 80:20, v / v) to give the title compound (12.09 g, 84% yield) as a colorless oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-1.79 (m, 2 H), 1.86-1.97 (m, 2 H), 3.34 (s, 6 H), 4.23-4.36 (m, 2 H) , 4.44 (t, J = 5.5 Hz, 1 H), 6.86-7.03 (m, 2 H), 7.08-7.16 (m, 1 H), 11.35 (br s, 1 H).

Reference Example 47 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -5-fluoro-1H-benzimidazole

1- (4,4-Dimethoxybutyl) -5-fluoro-1H-benzimidazole-2-thiol (1.57 g), 2,3-dichloro-5- (trifluoromethyl) pyridine obtained in Reference Example 46 ( 1.43 g) and potassium carbonate (9.15 g) in N, N-dimethylformamide (40 mL) were stirred at 50 ° C. for 1 hour and at room temperature for 13 hours. 2,3-Dichloro-5- (trifluoromethyl) pyridine (350 mg) was added to the reaction mixture, and the mixture was further stirred at 70 ° C. for 1 hour. The reaction solution was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0-80: 20, v / v) to give the title compound (1.33 g, yield 52%) as a colorless oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.54-1.66 (m, 2 H), 1.81-1.95 (m, 2 H), 3.28 (s, 6 H), 4.22-4.35 (m, 3 H) , 7.07-7.20 (m, 1 H), 7.33-7.43 (m, 1 H), 7.46-7.54 (m, 1 H), 7.81-7.86 (m, 1 H), 8.37 (s, 1 H).

Reference Example 48 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-fluoro-1H-benzimidazol-1-yl) butanal

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -5-fluoro-1H-benzimidazole obtained in Reference Example 47 (1.19 g) and 1N hydrochloric acid (20 mL) in tetrahydrofuran (20 mL) were stirred at 50 ° C. for 3.5 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0-80: 20, v / v) to obtain the title compound (946 mg, yield 88%) as a colorless amorphous.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.10-2.26 (m, 2 H), 2.43-2.57 (m, 2 H), 4.19-4.32 (m, 2 H), 7.10-7.23 (m, 1 H), 7.41-7.54 (m, 2 H), 7.82-7.89 (m, 1 H), 8.33-8.38 (m, 1 H), 9.76 (s, 1 H).

Reference Example 49 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- [2- (1H-1,2,4-triazol-3-ylsulfanyl) ethyl] -1H-benzimidazole

1- (2-Bromoethyl) -2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (800 mg), 1H- A mixture of 1,2,4-triazole-3-thiol (204 mg) and potassium carbonate (380 mg) in N, N-dimethylformamide (8 mL) was stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0-50: 50, v / v) to give the title compound (150 mg, yield 18%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.48-3.66 (m, 2 H), 4.63-4.71 (m, 2 H), 7.26-7.44 (m, 2 H), 7.63-7.69 (m, 1 H), 7.78-7.88 (m, 2 H), 8.00-8.13 (m, 1 H), 8.26-8.36 (m, 1 H), 12.33 (br s, 1 H).

Reference Example 50 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- [3- (1H-1,2,4-triazol-3-ylsulfanyl) propyl] -1H-benzimidazole

1- (3-Bromopropyl) -2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole and 1H-1,2 obtained in Reference Example 14 The title compound was obtained from 1,4-triazole-3-thiol in the same manner as in Reference Example 49.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.25-2.40 (m, 2 H), 3.13 (t, J = 6.8 Hz, 2 H), 4.42 (t, J = 7.1 Hz, 2 H), 7.29 -7.41 (m, 2 H), 7.45-7.52 (m, 1 H), 7.78-7.91 (m, 2 H), 8.08 (s, 1 H), 8.30-8.34 (m, 1 H), 11.63 (br s, 1 H).

Reference Example 51 3-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] benzonitrile

Similar to Reference Example 14 from 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole and 3- (bromomethyl) benzonitrile obtained in Reference Example 5. The title compound was obtained by this method.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.51 (s, 2 H), 7.22-7.26 (m, 1 H), 7.32-7.41 (m, 4 H), 7.46-7.48 (m, 1 H) , 7.50-7.56 (m, 1 H), 7.75-7.84 (m, 1 H), 7.84-7.93 (m, 1 H), 8.19-8.27 (m, 1 H).

Reference Example 52 3-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) methyl] -N′-hydroxybenzenecarboximide Amide

3-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] benzonitrile (600) obtained in Reference Example 51 mg), hydroxylamine hydrochloride (469 mg) and triethylamine (682 mg) in dimethyl sulfoxide (13 mL) were stirred at 75 ° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0-50: 50, v / v) to give the title compound (568 mg, yield 88%) as a colorless amorphous.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.76 (br s, 2 H), 5.48 (s, 2 H), 7.14-7.20 (m, 1 H), 7.25-7.37 (m, 5 H), 7.41-7.53 (m, 2 H), 7.72-7.82 (m, 1 H), 7.84-7.94 (m, 1 H), 8.21-8.33 (m, 1 H).

Reference Example 53 2-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] benzonitrile

Similar to Reference Example 14 from 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole and 2- (bromomethyl) benzonitrile obtained in Reference Example 5. The title compound was obtained by this method.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.69 (s, 2 H), 6.81-7.00 (m, 1 H), 7.25-7.29 (m, 1 H), 7.32-7.49 (m, 4 H) , 7.60-7.70 (m, 1 H), 7.77-7.83 (m, 1 H), 7.87-7.96 (m, 1 H), 8.19-8.27 (m, 1 H).

Reference Example 54 4-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] benzonitrile

Similar to Reference Example 14 from 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole and 4- (bromomethyl) benzonitrile obtained in Reference Example 5. The title compound was obtained by this method.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.52 (s, 2 H), 7.15-7.26 (m, 3 H), 7.32-7.41 (m, 2 H), 7.50-7.64 (m, 2 H) , 7.77-7.83 (m, 1 H), 7.85-7.92 (m, 1 H), 8.15-8.33 (m, 1 H).

Reference Example 55 4-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) methyl] -N′-hydroxybenzenecarboximide Amide

From 4-[(2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] benzonitrile obtained in Reference Example 54, The title compound was obtained in the same manner as in Reference Example 52.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.78 (br s, 2 H), 5.49 (s, 2 H), 7.18 (d, J = 8.7 Hz, 2 H), 7.23-7.35 (m, 3 H), 7.47-7.56 (m, 2 H), 7.75-7.81 (m, 1 H), 7.85-7.91 (m, 1 H), 8.19-8.32 (m, 1 H).

Reference Example 56 N- (4,4-dimethoxybutyl) -5-fluoro-2-nitroaniline

Add triethylamine (13.4 mL) to a solution of 2,4-difluoro-1-nitrobenzene (5.00 g) in acetonitrile (120 mL) in an ice-water bath, and add 4,4-dimethoxybutan-1-amine (4.40 mL). The solution was slowly added dropwise and stirred at room temperature for 6 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 70:30, v / v) to give the title compound (7.40 g, yield 87%) as a brown oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-1.90 (m, 4 H), 3.24-3.39 (m, 8 H), 4.42 (t, J = 5.2 Hz, 1 H), 6.31-6.41 ( m, 1 H), 6.49 (dd, J = 11.5, 2.6 Hz, 1 H), 8.02-8.31 (m, 2 H).

Reference Example 57 1- (4,4-Dimethoxybutyl) -6-fluoro-1H-benzimidazol-2-thiol

To a solution of N- (4,4-dimethoxybutyl) -5-fluoro-2-nitroaniline (7.40 g) obtained in Reference Example 56 in methanol (270 mL), 10% palladium carbon (0.74 g) was added, The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere of 1 atm. After removing the catalyst by filtration, the filtrate was concentrated. N, N′-thiocarbonyldiimidazole (5.17 g) was added to a solution of this residue in tetrahydrofuran (270 mL), and the mixture was stirred at room temperature for 4 hours. Further, N, N′-thiocarbonyldiimidazole (0.99 g) was added, and the mixture was stirred at room temperature for 16 hours. Water was poured into the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 50:50, v / v) to give the title compound (7.20 g, yield 92%) as a brown oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.69-1.80 (m, 2 H), 1.85-1.99 (m, 2 H), 3.35 (s, 6 H), 4.24-4.33 (m, 2 H) , 4.45 (t, J = 5.6 Hz, 1 H), 6.88-7.01 (m, 2 H), 7.15-7.24 (m, 1 H), 11.64 (br s, 1 H).

Reference Example 58 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -6-fluoro-1H-benzimidazole

1- (4,4-Dimethoxybutyl) -6-fluoro-1H-benzimidazol-2-thiol (7.20 g) obtained in Reference Example 57, 2,3-dichloro-5- (trifluoromethyl) pyridine ( 5.13 mL) and potassium carbonate (5.12 g) in N, N-dimethylformamide (100 mL) were stirred at room temperature for 7 hours and at 50 ° C. for 24 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 50:50, v / v) to give the title compound (10.84 g, yield 82%) as a colorless oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.55-1.69 (m, 2 H), 1.81-1.98 (m, 2 H), 3.27 (s, 6 H), 4.22 (t, J = 7.4 Hz, 2 H), 4.31 (t, J = 5.5 Hz, 1 H), 7.02-7.19 (m, 2 H), 7.76 (dd, J = 8.9, 4.7 Hz, 1 H), 7.84 (d, J = 1.5 Hz , 1 H), 8.31-8.40 (m, 1 H).

Reference Example 59 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -6-fluoro-1H-benzimidazol-1-yl) butanal

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -6-fluoro-1H-benzimidazole obtained in Reference Example 58 1N Hydrochloric acid (100 mL) was added to a solution of (10.75 g) in tetrahydrofuran (100 mL), and the mixture was stirred at room temperature for 19 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 50:50, v / v) to give the title compound (10.15 g, quantitative) as a colorless oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.09-2.18 (m, 2 H), 2.54 (t, J = 6.8 Hz, 2 H), 4.22 (m, 2 H), 7.04-7.14 (m, 1 H), 7.22 (dd, J = 8.6, 2.4 Hz, 1 H), 7.77 (dd, J = 8.9, 4.8 Hz, 1 H), 7.85 (d, J = 1.5 Hz, 1 H), 8.33-8.38 (m, 1 H), 9.76 (s, 1 H).

Reference Example 60 N- (4,4-dimethoxybutyl) -5-methyl-2-nitroaniline

The title compound was obtained from 2-fluoro-4-methyl-1-nitrobenzene and 4,4-dimethoxybutan-1-amine in the same manner as in Reference Example 25.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.69-1.89 (m, 4 H), 2.34 (s, 3 H), 3.26-3.40 (m, 8 H), 4.43 (t, J = 5.2 Hz, 1 H), 6.45 (dd, J = 8.9, 1.5 Hz, 1 H), 6.62 (s, 1 H), 7.96-8.18 (m, 2 H).

Reference Example 61 1- (4,4-Dimethoxybutyl) -6-methyl-1H-benzimidazol-2-thiol

From N- (4,4-dimethoxybutyl) -5-methyl-2-nitroaniline obtained in Reference Example 60, a method similar to Reference Example 26 was followed by a method similar to Reference Example 27. The title compound was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.69-1.80 (m, 2 H), 1.86-2.00 (m, 2 H), 2.44 (s, 3 H), 3.34 (s, 6 H), 4.22 -4.34 (m, 2 H), 4.44 (t, J = 5.7 Hz, 1 H), 6.96-7.05 (m, 2 H), 7.10-7.16 (m, 1 H), 10.70 (br s, 1 H) .

Reference Example 62 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -6-methyl-1H-benzimidazole

The title compound was obtained from 1- (4,4-dimethoxybutyl) -6-methyl-1H-benzimidazole-2-thiol obtained in Reference Example 61 in the same manner as in Reference Example 12.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58-1.67 (m, 2 H), 1.83-1.96 (m, 2 H), 2.54 (s, 3 H), 3.26 (s, 6 H), 4.23 (t, J = 7.4 Hz, 2 H), 4.31 (t, J = 5.6 Hz, 1 H), 7.15 (dd, J = 8.4, 1.2 Hz, 1 H), 7.24 (s, 1 H), 7.71 ( d, J = 8.5 Hz, 1 H), 7.81-7.83 (m, 1 H), 8.33-8.36 (m, 1 H).

Reference Example 63 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -6-methyl-1H-benzimidazol-1-yl) butanal

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -6-methyl-1H-benzimidazole obtained in Reference Example 62 From the above, the title compound was obtained in the same manner as in Reference Example 29.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.09-2.22 (m, 2 H), 2.49-2.53 (m, 2 H), 2.55 (s, 3 H), 4.25 (t, J = 7.3 Hz, 2 H), 7.16 (dd, J = 8.3, 1.1 Hz, 1 H), 7.27 (s, 1 H), 7.71 (d, J = 8.3 Hz, 1 H), 7.83 (d, J = 1.3 Hz, 1 H), 8.30-8.36 (m, 1 H), 9.75 (s, 1 H).

Reference Example 64 N- (4,4-dimethoxybutyl) -2-fluoro-6-nitroaniline

The title compound was obtained from 1,2-difluoro-3-nitrobenzene and 4,4-dimethoxybutan-1-amine in the same manner as in Reference Example 25.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.66-1.79 (m, 4 H), 3.33 (s, 6 H), 3.51-3.68 (m, 2 H), 4.40 (t, J = 5.4 Hz, 1 H), 6.52-6.63 (m, 1 H), 7.11-7.23 (m, 1 H), 7.84 (br s, 1 H), 7.92-7.99 (m, 1 H).

Reference Example 65 1- (4,4-Dimethoxybutyl) -7-fluoro-1H-benzimidazol-2-thiol

By performing the same method as in Reference Example 27 from N- (4,4-dimethoxybutyl) -2-fluoro-6-nitroaniline obtained in Reference Example 64, following the same method as in Reference Example 26, The title compound was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-1.83 (m, 2 H), 1.85-2.01 (m, 2 H), 3.33 (s, 6 H), 4.37-4.52 (m, 3 H) , 6.87-6.98 (m, 1 H), 7.01-7.18 (m, 2 H), 11.53 (br s, 1 H).

Reference Example 66 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -7-fluoro-1H-benzimidazole

The title compound was obtained from 1- (4,4-dimethoxybutyl) -7-fluoro-1H-benzimidazole-2-thiol obtained in Reference Example 65 in the same manner as in Reference Example 12.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.55-1.70 (m, 2 H), 1.84-1.97 (m, 2 H), 3.25 (s, 6 H), 4.31 (t, J = 5.5 Hz, 1 H), 4.39 (t, J = 7.6 Hz, 2 H), 7.06 (dd, J = 11.5, 7.4 Hz, 1 H), 7.17-7.27 (m, 1 H), 7.60 (d, J = 8.7 Hz , 1 H), 7.85 (d, J = 1.9 Hz, 1 H), 8.39 (s, 1 H).

Reference Example 67 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -7-fluoro-1H-benzimidazol-1-yl) butanal

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -7-fluoro-1H-benzimidazole obtained in Reference Example 66 From the above, the title compound was obtained in the same manner as in Reference Example 29.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.11-2.25 (m, 2 H), 2.53 (t, J = 7.2 Hz, 2 H), 4.41 (t, J = 7.0 Hz, 2 H), 7.07 (dd, J = 11.5, 7.4 Hz, 1 H), 7.19-7.29 (m, 1 H), 7.62 (d, J = 7.6 Hz, 1 H), 7.86 (d, J = 1.5 Hz, 1 H), 8.37 (s, 1 H), 9.73 (s, 1 H).

Reference Example 68 Benzyl (3-methoxy-2-nitrophenyl) carbamate

Diphenyl azidophosphate (7.80 mL) was added to a toluene (120 mL) mixture of 3-methoxy-2-nitrobenzoic acid (6.00 g) and triethylamine (5.40 mL), and the mixture was stirred at 90 ° C. for 1.5 hours. Benzyl alcohol (3.78 mL) and triethylamine (17.4 mL) were added, and the mixture was further stirred at 90 ° C. for 6 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5 to 1: 1, v / v) to give the title compound (7.12 g, yield 77%) as a yellow solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.90 (s, 3 H), 5.20 (s, 2 H), 6.75 (d, J = 8.3 Hz, 1 H), 7.31-7.46 (m, 6 H ), 7.76 (s, 1 H), 7.79 (s, 1 H).

Reference Example 69 4-{[(Benzyloxy) carbonyl] (3-methoxy-2-nitrophenyl) amino} butanoic acid tert-butyl ester

N, N-dimethylformamide of benzyl (3-methoxy-2-nitrophenyl) carbamate (4.00 g), tert-butyl 4-bromobutyrate (5.94 g) and cesium carbonate (8.67 g) obtained in Reference Example 68 (100 mL) The mixture was stirred at 50 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-50: 50, v / v) to give the title compound (6.12 g, quantitative) as a yellow oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41 (s, 9 H), 1.77-1.94 (m, 2 H), 2.22 (t, J = 7.2 Hz, 2 H), 3.28-3.79 (m, 2 H), 3.91 (s, 3 H), 5.14 (br s, 2 H), 6.87 (d, J = 8.0 Hz, 1 H), 7.01 (d, J = 7.6 Hz, 1 H), 7.14-7.35 (m, 5 H), 7.37-7.46 (m, 1 H).

Reference Example 70 tert-butyl 4- (4-methoxy-2-sulfanyl-1H-benzimidazol-1-yl) butanoate

From tert-butyl 4-{[(benzyloxy) carbonyl] (3-methoxy-2-nitrophenyl) amino} butanoate obtained in Reference Example 69, following the same method as Reference Example 26, Reference Example 27 and The title compound was obtained by carrying out the same method.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (s, 9 H), 2.06-2.19 (m, 2 H), 2.28-2.48 (m, 2 H), 3.94 (s, 3 H), 4.16 -4.57 (m, 2 H), 6.70 (d, J = 8.1 Hz, 1 H), 6.88 (d, J = 8.1 Hz, 1 H), 7.08-7.21 (m, 1 H), 10.40 (br s, 1 H).

Reference Example 71 tert-butyl 4-[(3-nitropyridin-4-yl) amino] butanoate

A mixture of 3-nitropyridin-4-amine (2.09 g), tert-butyl 4-bromobutanoate (3.68 g) and cesium carbonate (5.38 g) in N, N-dimethylformamide (150 mL) Stir for hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-40: 60, v / v) to give the title compound (1.50 g, yield 36%) as a yellow oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (s, 9 H), 1.90-2.12 (m, 2 H), 2.38 (t, J = 6.9 Hz, 2 H), 3.30-3.51 (m, 2 H), 6.79 (d, J = 6.0 Hz, 1 H), 8.23 (br s, 1 H), 8.31 (d, J = 6.2 Hz, 1 H), 9.22 (s, 1 H).

Reference Example 72 4- (2-sulfanyl-1H-imidazo [4,5-c] pyridin-1-yl) butanoic acid tert-butyl ester

From tert-butyl 4-[(3-nitropyridin-4-yl) amino] butanoate obtained in Reference Example 71, the same method as in Reference Example 27 is carried out following the same method as in Reference Example 26. Gave the title compound.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (s, 9 H), 2.04-2.22 (m, 2 H), 2.38 (t, J = 6.8 Hz, 2 H), 4.30-4.40 (m, 2 H), 7.24-7.33 (m, 1 H), 8.48 (d, J = 5.7 Hz, 1 H), 8.61 (s, 1 H), 11.28 (br s, 1 H).

Reference Example 73 4-[(3-Nitropyridin-2-yl) amino] butanoic acid tert-butyl

The title compound was obtained in the same manner as in Reference Example 71 from 3-nitropyridin-2-amine and tert-butyl 4-bromobutanoate.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (s, 9 H), 1.92-2.03 (m, 2 H), 2.28-2.38 (m, 2 H), 3.66-3.72 (m, 2 H) , 6.59-6.68 (m, 1 H), 8.28 (br s, 1 H), 8.37-8.44 (m, 2 H).

Reference Example 74 tert-butyl 4- (2-sulfanyl-3H-imidazo [4,5-b] pyridin-3-yl) butanoate

From tert-butyl 4-[(3-nitropyridin-2-yl) amino] butanoate obtained in Reference Example 73, the same method as in Reference Example 27 is carried out following the same method as in Reference Example 26. Gave the title compound.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (s, 9 H), 2.13-2.28 (m, 2 H), 2.30-2.42 (m, 2 H), 4.45 (t, J = 7.1 Hz, 2 H), 7.14 (dd, J = 7.9, 5.1 Hz, 1 H), 7.47 (dd, J = 7.8, 1.4 Hz, 1 H), 8.24 (dd, J = 5.1, 1.5 Hz, 1 H), 10.56 (br s, 1 H).

Reference Example 75 4-[(2-nitropyridin-3-yl) amino] butanoic acid tert-butyl ester

The title compound was obtained in the same manner as in Reference Example 71 from 2-nitropyridin-3-amine and tert-butyl 4-bromobutanoate.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.34-1.55 (m, 9 H), 2.20-2.44 (m, 2 H), 3.62-3.73 (m, 2 H), 4.29-4.42 (m, 2 H), 7.55-7.71 (m, 1 H), 7.80-7.97 (m, 2 H), 8.47 (dd, J = 4.5, 1.5 Hz, 1 H).

Reference Example 76 tert-butyl 4- (2-sulfanyl-1H-imidazo [4,5-b] pyridin-1-yl) butanoate

From tert-butyl 4-[(2-nitropyridin-3-yl) amino] butanoate obtained in Reference Example 75, the same method as in Reference Example 27 is carried out following the same method as in Reference Example 26. Gave the title compound.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (s, 9 H), 2.03-2.19 (m, 2 H), 2.37 (t, J = 6.9 Hz, 2 H), 4.20-4.69 (m, 2 H), 7.19 (dd, J = 8.0, 5.2 Hz, 1 H), 7.56 (dd, J = 8.1, 1.3 Hz, 1 H), 8.31 (dd, J = 5.1, 1.3 Hz, 1 H), 11.54 (br s, 1 H).

Reference Example 77 N- (4,4-dimethoxybutyl) -2-nitro-4- (trifluoromethyl) aniline

The title compound was obtained from 1-fluoro-2-nitro-4- (trifluoromethyl) benzene in the same manner as in Reference Example 25.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.66-1.94 (m, 4 H), 3.25-3.52 (m, 8 H), 4.42 (t, J = 5.1 Hz, 1 H), 6.95 (d, J = 9.0 Hz, 1 H), 7.61 (dd, J = 9.0, 2.3 Hz, 1 H), 8.30 (br s, 1 H), 8.47 (s, 1 H).

Reference Example 78 1- (4,4-Dimethoxybutyl) -5- (trifluoromethyl) -1H-benzimidazol-2-thiol

From N- (4,4-dimethoxybutyl) -2-nitro-4- (trifluoromethyl) aniline obtained in Reference Example 77, a method similar to Reference Example 27 was followed by a method similar to Reference Example 27. The title compound was obtained by carrying out.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-1.79 (m, 2 H), 1.85-1.99 (m, 2 H), 3.34 (s, 6 H), 4.31-4.36 (m, 2 H) , 4.44 (t, J = 5.5 Hz, 1 H), 7.17-7.33 (m, 1 H), 7.41-7.59 (m, 2 H), 10.58 (br s, 1 H).

Reference Example 79 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -5- (trifluoromethyl) -1H-benzimidazole

The title compound was obtained from 1- (4,4-dimethoxybutyl) -5- (trifluoromethyl) -1H-benzimidazole-2-thiol obtained in Reference Example 78 in the same manner as in Reference Example 12. .
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.56-1.70 (m, 2 H), 1.81-1.98 (m, 2 H), 3.27 (s, 6 H), 4.23-4.39 (m, 2 H) , 7.55-7.57 (m, 2 H), 7.61-7.69 (m, 1 H), 7.86 (d, J = 1.5 Hz, 1 H), 8.12 (s, 1 H), 8.30-8.42 (m, 1 H ).

Reference Example 80 4- [2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (trifluoromethyl) -1H-benzimidazol-1-yl] butanal

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -5- (trifluoromethyl)-obtained in Reference Example 79 The title compound was obtained from 1H-benzimidazole in the same manner as in Reference Example 29.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.08-2.26 (m, 2 H), 2.55 (t, J = 6.6 Hz, 2 H), 4.29-4.34 (m, 2 H), 7.56-7.69 ( m, 2 H), 7.87 (d, J = 1.5 Hz, 1 H), 8.12 (s, 1 H), 8.34 (s, 1 H), 9.77 (s, 1 H).

Reference Example 81 N- (4,4-dimethoxybutyl) -6-methyl-2-nitropyridin-3-amine

The title compound was obtained from 6-methyl-2-nitropyridin-3-yl trifluoromethanesulfonate in the same manner as in Reference Example 25.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.69-1.86 (m, 4 H), 2.46-2.55 (m, 3 H), 3.28-3.40 (m, 8 H), 4.42 (t, J = 5.1 Hz, 1 H), 7.25-7.36 (m, 2 H), 7.71 (br s, 1 H).

Reference Example 82 1- (4,4-Dimethoxybutyl) -5-methyl-1H-imidazo [4,5-b] pyridine-2-thiol

From N- (4,4-dimethoxybutyl) -6-methyl-2-nitropyridin-3-amine obtained in Reference Example 81, the same method as Reference Example 27 was followed by the same method as Reference Example 27. The title compound was obtained by carrying out.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.67-1.78 (m, 2 H), 1.83-2.00 (m, 2 H), 2.82 (s, 3 H), 3.34 (s, 6 H), 4.30 (t, J = 7.4 Hz, 2 H), 4.42 (t, J = 5.5 Hz, 1 H), 7.03 (d, J = 8.3 Hz, 1 H), 7.34 (d, J = 7.9 Hz, 1 H) , 12.37 (br s, 1 H).

Reference Example 83 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -5-methyl-1H-imidazo [4,5- b] pyridine

From the 1- (4,4-dimethoxybutyl) -5-methyl-1H-imidazo [4,5-b] pyridine-2-thiol obtained in Reference Example 82, the title compound was prepared in the same manner as in Reference Example 12. Got.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.53-1.67 (m, 2 H), 1.81-1.97 (m, 2 H), 2.66-2.75 (m, 3 H), 3.22-3.31 (m, 6 H), 4.19-4.37 (m, 3 H), 7.17 (d, J = 8.3 Hz, 1 H), 7.67 (d, J = 8.3 Hz, 1 H), 7.82-7.89 (m, 1 H), 8.36 (s, 1 H).

Reference Example 84 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-imidazo [4,5-b] pyridin-1-yl) Butanal

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -5-methyl-1H-imidazo obtained in Reference Example 83 The title compound was obtained from 4,5-b] pyridine in the same manner as in Reference Example 29.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.08-2.22 (m, 2 H), 2.53 (t, J = 6.6 Hz, 2 H), 2.71 (s, 3 H), 4.20-4.36 (m, 2 H), 7.20 (d, J = 8.3 Hz, 1 H), 7.75 (d, J = 8.3 Hz, 1 H), 7.85 (d, J = 1.9 Hz, 1 H), 8.35 (s, 1 H) , 9.76 (s, 1 H).

Reference Example 85 Ethyl 4- (chloromethyl) pyridine-2-carboxylate

A mixture of ethyl 4- (hydroxymethyl) pyridine-2-carboxylate (1.00 g) and thionyl chloride (0.73 g) in acetonitrile (50 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with diethyl ether, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 1: 1, v / v) to give the title compound (1.08 g, yield 98%) as a colorless oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (t, J = 7.2 Hz, 3 H), 4.50 (q, J = 7.2 Hz, 2 H), 4.62 (s, 2 H), 7.52 (dd , J = 4.9, 1.9 Hz, 1 H), 8.15 (s, 1 H), 8.76 (d, J = 4.9 Hz, 1 H).

Reference Example 86 tert-butyl 4- (2-chloro-1H-benzimidazol-1-yl) butanoate

The title compound was obtained from 2-chloro-1H-benzimidazole and tert-butyl 4-bromobutanoate in the same manner as in Reference Example 14.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (s, 9 H), 2.05-2.17 (m, 2 H), 2.25-2.32 (m, 2 H), 4.27 (t, J = 7.0 Hz, 2 H), 7.23-7.39 (m, 3 H), 7.66-7.73 (m, 1 H).

Reference Example 87 [(tert-butoxycarbonyl) oxy] [2- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) ethyl ] Tert-butyl carbamate

Add tert-butyl [(tert-butoxycarbonyl) oxy] carbamate (233 mg) to a mixture of ice-cooled 60% sodium hydride (oil, 44.0 mg) in N, N-dimethylformamide (10 mL) and add 30 Stir for minutes. 1- (2-Bromoethyl) -2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (437 mg) obtained in Reference Example 17 was added, Stir at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 80:20, v / v) to give the title compound (337 mg, yield 57%) as a colorless oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.35 (s, 9 H), 1.49 (s, 9 H), 3.99 (t, J = 6.6 Hz, 2 H), 4.50 (t, J = 6.8 Hz , 2 H), 7.29-7.46 (m, 2 H), 7.55 (d, J = 7.6 Hz, 1 H), 7.79-7.89 (m, 2 H), 8.35 (s, 1 H).

Reference Example 88 [(tert-butoxycarbonyl) oxy] [3- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propyl ] Tert-butyl carbamate

From 1- (3-bromopropyl) -2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole obtained in Reference Example 14, Reference Example 87 and In the same manner, the title compound was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (s, 9 H), 1.53 (s, 9 H), 2.05-2.21 (m, 2 H), 3.64 (t, J = 6.2 Hz, 2 H ), 4.32-4.43 (m, 2 H), 7.28-7.42 (m, 2 H), 7.55 (d, J = 7.2 Hz, 1 H), 7.77-7.88 (m, 2 H), 8.35 (s, 1 H).

Reference Example 89 Ethyl 4-[(4,4-dimethoxybutyl) amino] -3-nitrobenzoate

The title compound was obtained in the same manner as in Reference Example 25 from commercially available ethyl 4-fluoro-3-nitrobenzoate and 4,4-dimethoxybutan-1-amine.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.39 (t, J = 7.2 Hz, 3 H), 1.68-1.89 (m, 4 H), 3.28-3.49 (m, 8 H), 4.29-4.48 ( m, 3 H), 6.87 (d, J = 9.1 Hz, 1 H), 8.06 (dd, J = 8.7, 2.3 Hz, 1 H), 8.37 (br s, 1 H), 8.88 (d, J = 2.3 Hz, 1 H).

Reference Example 90 Ethyl 1- (4,4-dimethoxybutyl) -2-sulfanyl-1H-benzimidazole-5-carboxylate

From ethyl 4-[(4,4-dimethoxybutyl) amino] -3-nitrobenzoate obtained in Reference Example 89, the same method as in Reference Example 27 is carried out following the same method as in Reference Example 26. Gave the title compound.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.42 (t, J = 7.2 Hz, 3 H), 1.69-1.80 (m, 2 H), 1.86-2.01 (m, 2 H), 3.34 (s, 6 H), 4.30-4.51 (m, 5 H), 7.21 (d, J = 8.5 Hz, 1 H), 7.90-8.06 (m, 2 H), 11.15 (s, 1 H).

Reference Example 91 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -1H-benzimidazole-5-carboxylate

The title compound was obtained in the same manner as in Reference Example 12 from ethyl 1- (4,4-dimethoxybutyl) -2-sulfanyl-1H-benzimidazole-5-carboxylate obtained in Reference Example 90.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.42 (t, J = 7.0 Hz, 3 H), 1.53-1.70 (m, 5 H), 1.79-2.02 (m, 2 H), 3.20-3.38 ( m, 6 H), 4.36-4.51 (m, 2 H), 7.48 (d, J = 8.7 Hz, 1 H), 7.85 (d, J = 1.9 Hz, 1 H), 8.11 (dd, J = 8.7, 1.5 Hz, 1 H), 8.36 (s, 1 H), 8.55 (s, 1 H).

Reference Example 92 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -1H-benzimidazole-5-carboxylic acid

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -1H-benzimidazole-5-carvone obtained in Reference Example 91 A mixture of ethyl acid (5.00 g) and lithium hydroxide monohydrate (980 mg) in tetrahydrofuran (100 mL) and water (100 mL) was stirred at 50 ° C. for 20 hours. The reaction mixture was neutralized with 1N hydrochloric acid under ice cooling, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was crystallized from diisopropyl ether-ethyl acetate to give the title compound (3.41 g, yield 72%) as a colorless solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.44-1.57 (m, 2 H), 1.65-1.82 (m, 2 H), 3.06-3.18 (m, 6 H), 4.19-4.38 (m , 3 H), 7.82 (d, J = 8.3 Hz, 1 H), 7.99 (dd, J = 8.7, 1.5 Hz, 1 H), 8.29 (s, 1 H), 8.55 (d, J = 1.9 Hz, 1 H), 8.66 (s, 1 H), 12.81 (s, 1 H).

Reference Example 93 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -N-ethyl-1H-benzimidazole-5-carboxamide

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -1H-benzimidazole-5-carvone obtained in Reference Example 92 Acid (490 mg), ethylamine (2M in tetrahydrofuran, 0.70 mL), N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride (250 mg), and 1H-benzotriazol-1-ol ( 176 mg) of N, N-dimethylformamide (10 mL) was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was crystallized from hexane-ethyl acetate to give the title compound (406 mg, yield 79%) as a colorless solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.51-1.79 (m, 5 H), 1.82-1.99 (m, 2 H), 3.17-3.30 (m, 6 H), 3.46-3.61 (m, 2 H), 4.19-4.38 (m, 3 H), 6.08-6.29 (m, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.84 (d, J = 1.9 Hz, 1 H), 7.93 (dd, J = 8.7, 1.5 Hz, 1 H), 8.13 (s, 1 H), 8.33 (s, 1 H).

Reference Example 94 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -N-ethyl-1- (4-oxobutyl) -1H-benzimidazole-5-carboxamide

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -N-ethyl-1H-benzimidazole obtained in Reference Example 93 The title compound was obtained from -5-carboxamide in the same manner as in Reference Example 29.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.25-1.33 (m, 3 H), 2.09-2.22 (m, 2 H), 2.54 (t, J = 6.7 Hz, 2 H), 3.45-3.62 ( m, 2 H), 4.27-4.32 (m, 2 H), 6.17 (br s, 1 H), 7.56 (d, J = 8.5 Hz, 1 H), 7.86 (d, J = 1.5 Hz, 1 H) , 7.93 (dd, J = 8.6, 1.6 Hz, 1 H), 8.15 (d, J = 1.1 Hz, 1 H), 8.31-8.39 (m, 1 H), 9.75 (s, 1 H).

Reference Example 95 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -N, N-diethyl-1H-benzimidazole-5 -Carboxamide

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -1H-benzimidazole-5-carvone obtained in Reference Example 92 The title compound was obtained from an acid and diethylamine in the same manner as in Reference Example 93.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.12-1.34 (m, 4 H), 1.56-1.70 (m, 8 H), 1.83-1.98 (m, 2 H), 3.23-3.30 (m, 6 H), 4.21-4.38 (m, 3 H), 7.39-7.55 (m, 2 H), 7.79-7.88 (m, 2 H), 8.37 (s, 1 H).

Reference Example 96 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -N, N-diethyl-1- (4-oxobutyl) -1H-benzimidazole-5-carboxamide

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -N, N-diethyl-1H- obtained in Reference Example 95 The title compound was obtained from benzimidazole-5-carboxamide in the same manner as in Reference Example 29.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.07-1.31 (m, 6 H), 2.10-2.27 (m, 2 H), 2.53 (t, J = 6.6 Hz, 2 H), 3.29-3.66 ( m, 4 H), 4.30 (t, J = 7.4 Hz, 2 H), 7.41-7.50 (m, 1 H), 7.52-7.59 (m, 1 H), 7.76-7.92 (m, 2 H), 8.35 (s, 1 H), 9.76 (s, 1 H).

Reference Example 97 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -1H-benzimidazole-5-carboxamide

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -1H-benzimidazole-5-carvone obtained in Reference Example 92 The title compound was obtained from an acid and ammonium chloride in the same manner as in Reference Example 93.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.56-1.69 (m, 2 H), 1.83-1.98 (m, 2 H), 3.26 (s, 6 H), 4.21-4.36 (m, 3 H) , 5.83 (br s, 1 H), 6.52 (br s, 1 H), 7.53 (d, J = 8.7 Hz, 1 H), 7.86 (d, J = 1.5 Hz, 1 H), 7.99 (dd, J = 8.6, 1.6 Hz, 1 H), 8.29 (d, J = 1.1 Hz, 1 H), 8.35 (d, J = 1.1 Hz, 1 H).

Reference Example 98 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4-oxobutyl) -1H-benzimidazole-5-carboxamide

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -1H-benzimidazole-5-carboxamide obtained in Reference Example 97 From the above, the title compound was obtained in the same manner as in Reference Example 29.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.09-2.24 (m, 2 H), 2.53-2.56 (m, 2 H), 4.28-4.33 (m, 2 H), 5.79 (br s, 1 H ), 6.31 (br s, 1 H), 7.51-7.66 (m, 1 H), 7.87 (s, 1 H), 7.99 (d, J = 8.5 Hz, 1 H), 8.26 (s, 1 H), 8.34 (s, 1 H), 9.76 (d, J = 1.7 Hz, 1 H).

Reference Example 99 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -5- (morpholin-4-ylcarbonyl) -1H -Benzimidazole

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -1H-benzimidazole-5-carvone obtained in Reference Example 92 The title compound was obtained from an acid and morpholine in the same manner as in Reference Example 93.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.54-1.73 (m, 5 H), 1.82-1.99 (m, 2 H), 2.05 (s, 3 H), 3.27 (s, 6 H), 4.06 -4.19 (m, 2 H), 4.23-4.36 (m, 3 H), 7.45-7.56 (m, 2 H), 7.81-7.91 (m, 2 H), 8.36 (d, J = 0.8 Hz, 1 H ).

Reference Example 100 4- [2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (morpholin-4-ylcarbonyl) -1H-benzimidazol-1-yl] Butanal

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -5- (morpholin-4-yl) obtained in Reference Example 99 The title compound was obtained from carbonyl) -1H-benzimidazole in the same manner as in Reference Example 29.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.09-2.23 (m, 2 H), 2.54 (t, J = 6.6 Hz, 2 H), 3.72 (br s, 8 H), 4.30 (t, J = 7.4 Hz, 2 H), 7.45-7.67 (m, 2 H), 7.87 (s, 2 H), 8.35 (s, 1 H), 9.76 (s, 1 H).

Reference Example 101 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -1H-benzimidazole-5-carbonitrile

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -1H-benzimidazole-5-carboxamide obtained in Reference Example 97 (630 mg) and 4-methylbenzenesulfonyl chloride (745 mg) in pyridine (7.5 mL) were stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 50:50, v / v) to give the title compound (425 mg, yield 70%) as a colorless oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.53-1.69 (m, 2 H), 1.85-1.98 (m, 2 H), 3.22-3.32 (m, 6 H), 4.22-4.40 (m, 3 H), 7.50-7.59 (m, 1 H), 7.60-7.70 (m, 1 H), 7.88 (d, J = 1.9 Hz, 1 H), 8.17 (s, 1 H), 8.36 (s, 1 H ).

Reference Example 102 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4-oxobutyl) -1H-benzimidazole-5-carbonitrile

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4,4-dimethoxybutyl) -1H-benzimidazole-5-carbohydrate obtained in Reference Example 101 The title compound was obtained from nitrile in the same manner as in Reference Example 29.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.08-2.24 (m, 2 H), 2.57 (t, J = 6.6 Hz, 2 H), 4.23-4.38 (m, 2 H), 7.66 (s, 2 H), 7.88 (d, J = 1.9 Hz, 1 H), 8.17 (s, 1 H), 8.35 (s, 1 H), 9.78 (s, 1 H).

Reference Example 103 (2S) -2-[(tert-butoxycarbonyl) amino] -4-{[2-nitro-4- (trifluoromethyl) phenyl] amino} butanoic acid

1-fluoro-2-nitro-4- (trifluoromethyl) benzene (2.09 g), (2S) -4-amino-2-[(tert-butoxycarbonyl) amino] butanoic acid (3.30 g), and triethylamine ( 3 mL) of acetonitrile (100 mL) was stirred at 70 ° C. for 20 hours. Water was poured into the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give the title compound (1.51 g, yield 37%) as a yellow oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.35-1.54 (m, 9 H), 2.07-2.20 (m, 1 H), 2.22-2.47 (m, 1 H), 3.54-3.56 (m, 2 H), 3.86-4.23 (m, 1 H), 4.47-4.49 (m, 1 H), 5.27 (br s, 1 H), 6.97 (d, J = 8.9 Hz, 1 H), 7.63 (dd, J = 8.9, 2.0 Hz, 1 H), 8.45 (d, J = 1.3 Hz, 2 H).

Reference Example 104 (2S) -2-[(tert-butoxycarbonyl) amino] -4-{[2-nitro-4- (trifluoromethyl) phenyl] amino} butanoic acid methyl

Tetrahydrofuran of (2S) -2-[(tert-butoxycarbonyl) amino] -4-{[2-nitro-4- (trifluoromethyl) phenyl] amino} butanoic acid (3.05 g) obtained in Reference Example 103 (75 mL) To the solution was added trimethylsilyldiazomethane (2M diethyl ether solution, 7.5 mL) in an ice-water bath, and the mixture was stirred at room temperature for 3 days. Acetic acid (2 mL) was added in an ice-water bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 80:20, v / v) to give the title compound (2.55 g, yield 81%) as a yellow oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.40-1.52 (m, 9 H), 1.92-2.03 (m, 1 H), 2.20-2.41 (m, 1 H), 3.42-3.60 (m, 2 H), 3.76 (s, 3 H), 4.45 (br s, 1 H), 5.28 (d, J = 7.6 Hz, 1 H), 6.95 (d, J = 9.1 Hz, 1 H), 7.63 (dd, J = 9.1, 1.9 Hz, 1 H), 8.40 (br s, 1 H), 8.48 (s, 1 H).

Reference Example 105 (2S) -2-[(tert-butoxycarbonyl) amino] -4- [2-sulfanyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] methyl butanoate

From the methyl (2S) -2-[(tert-butoxycarbonyl) amino] -4-{[2-nitro-4- (trifluoromethyl) phenyl] amino} butanoate obtained in Reference Example 104, Reference Example 26 Subsequent to the same method as in Example 27, the title compound was obtained in the same manner as in Reference Example 27.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.23-1.33 (m, 1 H), 1.40 (s, 9 H), 1.92-2.10 (m, 1 H), 2.11-2.31 (m, 1 H) , 2.43-2.63 (m, 1 H), 3.34 (br s, 1 H), 3.96-4.09 (m, 1 H), 4.16-4.47 (m, 2 H), 7.43 (s, 1 H), 7.48- 7.71 (m, 3 H), 13.17 (br s, 1 H).

Reference Example 106 2-[(3,5,6-Trichloropyridin-2-yl) sulfanyl] -1H-benzimidazole

The title compound was obtained from 1H-benzimidazole-2-thiol and 2,3,5,6-tetrachloropyridine in the same manner as in Reference Example 5.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.28-7.35 (m, 2 H), 7.50-7.58 (m, 1 H), 7.70-7.78 (m, 1 H), 7.78-7.82 (m, 1 H), 11.52 (br s, 1 H).

Reference Example 107 2-{[6-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole

The title compound was obtained from 1H-benzimidazol-2-thiol and 2,6-dichloro-3- (trifluoromethyl) pyridine in the same manner as in Reference Example 5.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.27-7.39 (m, 3 H), 7.50-7.61 (m, 1 H), 7.76 (d, J = 7.9 Hz, 1 H), 7.87 (d, J = 8.3 Hz, 1 H), 11.64 (br s, 1 H).

Reference Example 108 4- (2-methoxyethoxy) -2-nitroaniline

A mixture of 4-amino-3-nitrophenol (924 mg) and potassium tert-butoxide (1.00 g) in N, N-dimethylformamide (30 mL) was stirred for 1.5 hours while cooling with ice. 1-Bromo-2-methoxyethane (739 mg) was slowly added dropwise. After stirring at room temperature for 4 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 1: 1, v / v) to give the title compound (550 mg, yield 43%) as a red oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.45 (s, 3 H), 3.66-3.81 (m, 2 H), 4.02-4.16 (m, 2 H), 5.90 (br s, 2 H), 6.76 (d, J = 9.0 Hz, 1 H), 7.13 (dd, J = 9.2, 2.8 Hz, 1 H), 7.57 (d, J = 3.0 Hz, 1 H).

Reference Example 109 2,2,2-trifluoro-N- [4- (2-methoxyethoxy) -2-nitrophenyl] acetamide

A mixture of 4- (2-methoxyethoxy) -2-nitroaniline (440 mg) and trifluoroacetic anhydride (0.43 mL) obtained in Reference Example 108 with N, N-dimethylformamide (15 mL) was added to an ice-water bath. The mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 1: 1, v / v) to obtain the title compound (640 mg, quantitative) as a yellow solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.48 (s, 3 H), 3.75-3.89 (m, 2 H), 4.16-4.29 (m, 2 H), 7.34 (dd, J = 9.1, 3.0 Hz, 1 H), 7.81 (d, J = 3.0 Hz, 1 H), 8.63 (d, J = 9.5 Hz, 1 H), 11.12 (br s, 1 H).

Reference Example 110 4-{[4- (2-methoxyethoxy) -2-nitrophenyl] (trifluoroacetyl) amino} butanoic acid ethyl

In the same manner as in Reference Example 69, 2,2,2-trifluoro-N- [4- (2-methoxyethoxy) -2-nitrophenyl] acetamide and ethyl 4-bromobutanoate obtained in Reference Example 109 were used. The title compound was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.20-1.36 (m, 3 H), 2.08-2.25 (m, 2 H), 2.45-2.55 (m, 2 H), 3.46 (s, 3 H) , 3.74-3.85 (m, 2 H), 4.06-4.24 (m, 4 H), 4.39 (t, J = 6.4 Hz, 2 H), 6.80 (d, J = 9.0 Hz, 1 H), 7.17 (dd , J = 8.7, 3.0 Hz, 1 H), 7.60 (d, J = 2.6 Hz, 1 H).

Reference Example 111 4-{[4- (2-methoxyethoxy) -2-nitrophenyl] amino} butanoic acid methyl

Ethyl 4-{[4- (2-methoxyethoxy) -2-nitrophenyl] (trifluoroacetyl) amino} butanoate (670 mg) and potassium carbonate (440 mg) obtained in Reference Example 110 (15 mL) The mixture was stirred at room 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-1: 1, v / v) to give the title compound (350 mg, yield 70%) as a red oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.92-2.13 (m, 2 H), 2.42-2.54 (m, 2 H), 3.29-3.51 (m, 5 H), 3.63-3.81 (m, 5 H), 4.05-4.17 (m, 2 H), 6.87 (d, J = 9.5 Hz, 1 H), 7.18-7.26 (m, 1 H), 7.64 (d, J = 3.0 Hz, 1 H), 8.01 (br s, 1 H).

Reference Example 112 4- [5- (2-Methoxyethoxy) -2-sulfanyl-1H-benzimidazol-1-yl] butanoic acid methyl ester

From the methyl 4-{[4- (2-methoxyethoxy) -2-nitrophenyl] amino} butanoate obtained in Reference Example 111, the same method as in Reference Example 27 was followed by the same method as in Reference Example 27. The title compound was obtained by carrying out.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.99-2.30 (m, 2 H), 2.38-2.56 (m, 2 H), 3.46 (s, 3 H), 3.64-3.83 (m, 5 H) , 4.01-4.20 (m, 2 H), 4.22-4.41 (m, 2 H), 6.73-6.97 (m, 2 H), 7.14 (d, J = 8.7 Hz, 1 H), 10.40 (s, 1 H ).

Reference Example 113 3-Chloro-2-[(4,5-dimethyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine

While stirring a solution of 4-methyl-1H-imidazole-2-thiol (4.89 g) and potassium carbonate (6.85 g) in N, N-dimethylformamide (100 mL), 2,3-dichloro-5- (trifluoro Methyl) pyridine (10.7 g) was added. The reaction mixture was stirred at room temperature for 4 hours and then concentrated. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was crystallized from ethyl acetate to give the title compound (7.02 g, yield 60%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.22 (d, J = 15.3 Hz, 6 H), 7.78 (d, J = 1.5 Hz, 1 H), 8.53 (s, 1 H), 10.33 (br s, 1 H).

Reference Example 114 3-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) methyl] benzonitrile

From 3-chloro-2-[(4,5-dimethyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine and 3- (bromomethyl) benzonitrile obtained in Reference Example 113, The title compound was obtained in the same manner as in Reference Example 14.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.10 (s, 3 H), 2.28 (s, 3 H), 5.19 (s, 2 H), 7.19-7.42 (m, 3 H), 7.49-7.59 (m, 1 H), 7.70-7.76 (m, 1 H), 8.34-8.45 (m, 1 H).

Reference Example 115 3-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) methyl] -N ′ -Hydroxybenzenecarboximidamide

3-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) methyl obtained in Reference Example 114 The title compound was obtained from benzonitrile and hydroxylamine hydrochloride in the same manner as in Reference Example 52.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.09 (s, 3 H), 2.26 (s, 3 H), 4.82 (br s, 2 H), 5.17 (s, 2 H), 7.02-7.11 ( m, 1 H), 7.28-7.33 (m, 1 H), 7.37 (s, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.68-7.73 (m, 1 H), 8.40 (s , 1 H).

Reference Example 116 3-Chloro-2-[(4-phenyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine

The title compound was obtained from 4-phenyl-1H-imidazole-2-thiol and 2,3-dichloro-5- (trifluoromethyl) pyridine in the same manner as in Reference Example 113.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.01-7.95 (m, 7 H), 8.56 (br s, 1 H), 10.98-11.67 (m, 1 H).

Reference Example 117 3-chloro-2-[(4-methyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine

The title compound was obtained from 4-methyl-1H-imidazole-2-thiol and 2,3-dichloro-5- (trifluoromethyl) pyridine in the same manner as in Reference Example 113.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.31 (d, J = 14.5 Hz, 3 H), 6.87-7.00 (m, 1 H), 7.80 (s, 1 H), 8.54 (d, J = 0.9 Hz, 1 H), 10.54-11.08 (m, 1 H).

Reference Example 118 3,5-dichloro-2-[(4,5-dimethyl-1H-imidazol-2-yl) sulfanyl] pyridine

The title compound was obtained from 4-methyl-1H-imidazole-2-thiol and 2-bromo-3,5-dichloropyridine in the same manner as in Reference Example 113.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.19 (s, 3 H), 2.25 (s, 3 H), 7.63 (d, J = 2.3 Hz, 1 H), 8.27 (d, J = 2.3 Hz , 1 H), 9.98 (br s, 1 H).

Reference Example 119 3-chloro-2-[(5-chloro-4-phenyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine

3-chloro-2-[(4-phenyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine (3.87 g) obtained in Reference Example 116, N-iodosuccinimide (1.60) g) and a mixture of acetonitrile (30 mL) was stirred at room temperature for 72 hours and then concentrated. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was crystallized from ethyl acetate to give the title compound (3.16 g, yield 74%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.32-7.42 (m, 1 H), 7.43-7.53 (m, 2 H), 7.71 (d, J = 7.5 Hz, 2 H), 7.89 (d, J = 1.5 Hz, 1 H), 8.61-8.66 (m, 1 H), 11.49 (br s, 1 H).

Reference Example 120 3-chloro-2-[(5-chloro-4-methyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine

The title was obtained from 3-chloro-2-[(4-methyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine obtained in Reference Example 117 in the same manner as in Reference Example 119. A compound was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.30 (s, 3 H), 2.77 (s, 1 H), 7.81 (d, J = 1.5 Hz, 1 H), 8.52-8.61 (m, 1 H ).

Reference Example 121 2-[(5-Bromo-4-methyl-1H-imidazol-2-yl) sulfanyl] -3-chloro-5- (trifluoromethyl) pyridine

From 3-chloro-2-[(4-methyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine and N-bromosuccinimide obtained in Reference Example 117, Reference Example 119 and In the same manner, the title compound was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.33 (s, 3 H), 7.84 (s, 1 H), 8.59 (s, 1 H), 10.65 (br s, 1 H).

Example 1 (2E) -3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indol-3-yl) ethyl acrylate

While stirring a solution of ethyl (diethoxyphosphoryl) acetate (604 mg) in tetrahydrofuran (15 mL) cooled to 0 ° C in an ice bath, 60% sodium hydride (oil, 115 mg) was added, and the mixture was stirred at 0 ° C for 20 minutes. Stir. To this reaction solution, 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indole-3-carbaldehyde obtained in Reference Example 2 (829 mg) was added at 0 ° C., then the reaction mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 6 hours. The reaction mixture was concentrated, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was crystallized from hexane-ethanol to give the title compound (929 mg, yield 94%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.33 (t, J = 7.2 Hz, 3 H), 3.76 (s, 3 H), 4.25 (q, J = 7.1 Hz, 2 H), 6.63 (d , J = 16.0 Hz, 1 H), 7.27-7.35 (m, 1 H), 7.37-7.49 (m, 2 H), 7.84 (d, J = 1.5 Hz, 1 H), 8.03 (d, J = 8.1 Hz, 1 H), 8.10 (d, J = 16.0 Hz, 1 H), 8.33-8.36 (m, 1 H).

Example 2 (2E) -3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indol-3-yl) acrylic acid

(2E) -3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indol-3-yl) obtained in Example 1 To a solution of ethyl acrylate (600 mg) in tetrahydrofuran (5 mL) was added 2N aqueous lithium hydroxide solution (4.0 mL), and the mixture was stirred at 50 ° C. for 24 hours and heated under reflux for 24 hours. After cooling to room temperature, the reaction solution was neutralized with an aqueous potassium hydrogen sulfate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 70:30, v / v), and the obtained residue was crystallized from hexane-ethyl acetate to give the title compound (433 mg, yield 77%) Was obtained as a colorless solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.75 (s, 3 H), 6.53 (d, J = 16.3 Hz, 1 H), 7.31 (t, J = 7.2 Hz, 1 H), 7.42 (t, J = 7.4 Hz, 1 H), 7.70 (d, J = 8.3 Hz, 1 H), 7.87 (d, J = 16.3 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H) , 8.54 (d, J = 1.9 Hz, 1 H), 8.67 (s, 1 H), 12.19 (s, 1 H).

Example 3 (E) -2- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indol-3-yl) ethenesulfonamide

{[(E) -2- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indole-3- obtained in Reference Example 3 (Il) ethenyl] sulfonyl} tert-butyl carbamate (601 mg) was added with trifluoroacetic acid (10 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and then dissolved in ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 60:40, v / v) and crystallized from hexane-ethyl acetate to give the title compound (266 mg, yield 54%) as colorless crystals. It was.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.76 (s, 3 H), 4.63 (s, 2 H), 7.10 (d, J = 15.4 Hz, 1 H), 7.30-7.51 (m, 3 H ), 7.83-7.99 (m, 3 H), 8.35 (s, 1 H).

Example 4 (2E) -3- (2-{[3-Fluoro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indol-3-yl) ethyl acrylate

2-{[3-Fluoro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indole-3-carbaldehyde and ethyl (diethoxyphosphoryl) obtained in Reference Example 4 The title compound was obtained from the acetate in the same manner as in Example 1.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.33 (t, J = 7.1 Hz, 3 H), 3.78 (s, 3 H), 4.25 (q, J = 7.2 Hz, 2 H), 6.63 (d , J = 16.2 Hz, 1 H), 7.27-7.36 (m, 1 H), 7.37-7.49 (m, 2 H), 7.56 (dd, J = 8.7, 1.5 Hz, 1 H), 8.03 (d, J = 8.1 Hz, 1 H), 8.10 (d, J = 16.0 Hz, 1 H), 8.27-8.37 (m, 1 H).

Example 5 (2E) -3- (2-{[3-Fluoro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indol-3-yl) acrylic acid

(2E) -3- (2-{[3-Fluoro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indol-3-yl) obtained in Example 4 The title compound was obtained from ethyl acrylate in the same manner as in Example 2.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.77 (s, 3 H), 6.54 (d, J = 15.9 Hz, 1 H), 7.31 (t, J = 7.2 Hz, 1 H), 7.43 (t, J = 7.2 Hz, 1 H), 7.70 (d, J = 8.3 Hz, 1 H), 7.89 (d, J = 15.9 Hz, 1 H), 8.02 (d, J = 8.3 Hz, 1 H) , 8.38 (dd, J = 9.7, 1.7 Hz, 1 H), 8.61 (s, 1 H), 12.20 (s, 1 H).

Example 6 Ethyl 4- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) butanoate

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (620 mg), ethyl 4-bromobutanoate (570 mg) obtained in Reference Example 5 and A mixture of potassium carbonate (537 mg) and N, N-dimethylformamide (8 mL) was stirred at 80 ° C. for 4 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 85:15, v / v) and crystallized from hexane-ethyl acetate to give the title compound (608 mg, yield 72%) as colorless crystals. It was.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.23 (t, J = 7.2 Hz, 3 H), 2.09-2.23 (m, 2 H), 2.33 (t, J = 7.0 Hz, 2 H), 4.11 (q, J = 6.9 Hz, 2 H), 4.27-4.39 (m, 2 H), 7.29-7.43 (m, 2 H), 7.48-7.56 (m, 1 H), 7.81-7.87 (m, 2 H ), 8.34 (s, 1 H).

Example 7 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) butanoic acid tert-butyl

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (550 mg), tert-butyl 4-bromobutanoate (593 mg) obtained in Reference Example 5 ) And potassium carbonate (459 mg) in N, N-dimethylformamide (8 mL) was stirred at 80 ° C. for 4 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 80:20, v / v) to give the title compound (753 mg, yield 96%) as a colorless solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41 (s, 9 H), 2.04-2.16 (m, 2 H), 2.24 (t, J = 6.4 Hz, 2 H), 4.31 (t, J = 7.2 Hz, 2 H), 7.29-7.44 (m, 2 H), 7.50-7.55 (m, 1 H), 7.81-7.86 (m, 2 H), 8.34 (s, 1 H).

Example 8 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) butanoic acid

4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) butanoic acid tert-butyl (593) obtained in Example 7 mg) was added with trifluoroacetic acid (6 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 40:60, v / v) and crystallized from hexane-ethyl acetate to give the title compound (346 mg, yield 66%) as colorless crystals. It was. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 60:40, v / v) to give the title compound (89 mg) as a colorless solid (total 435 mg, yield 83% ). The obtained colorless solid was crystallized from hexane-acetone, and the obtained colorless crystals were suspended in water and stirred at 75 ° C. for 24 hours. After cooling to 0 ° C., the mixture was filtered and dried to obtain colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.87-2.01 (m, 2 H), 2.26 (t, J = 7.1 Hz, 2 H), 4.27 (t, J = 7.3 Hz, 2 H) , 7.26-7.44 (m, 2 H), 7.73 (dd, J = 8.1, 4.1 Hz, 2 H), 8.52 (d, J = 1.9 Hz, 1 H), 8.65 (s, 1 H), 12.14 (br s, 1 H).

Example 9 Methyl 3- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propionate

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (610 mg), methyl 3-bromopropionate (658 mg) obtained in Reference Example 5 A mixture of potassium carbonate (390 mg) with N, N-dimethylformamide (8 mL) was stirred at 80 ° C. for 5 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 50:50, v / v) and crystallized from hexane-ethyl acetate to give the title compound (680 mg, yield 88%) as colorless crystals. It was.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.82-2.93 (m, 2 H), 3.65 (s, 3 H), 4.53-4.63 (m, 2 H), 7.30-7.44 (m, 2 H) , 7.47-7.53 (m, 1 H), 7.81-7.86 (m, 2 H), 8.33-8.36 (m, 1 H).

Example 10 tert-Butyl 3- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) propionate

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (1.00 g), tert-butyl 3-bromopropionate (1.15) obtained in Reference Example 5 A mixture of g) and potassium carbonate (628 mg) in N, N-dimethylformamide (15 mL) was stirred at 80 ° C. for 4 hours. To the reaction mixture was added tert-butyl 4-bromopropionate (0.43 g), and the mixture was further stirred for 4 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 75:25, v / v) to give the title compound (1.18 g, yield 85%) as a colorless solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.38 (s, 9 H), 2.72-2.83 (m, 2 H), 4.48-4.56 (m, 2 H), 7.30-7.44 (m, 2 H) , 7.49-7.55 (m, 1 H), 7.81-7.86 (m, 2 H), 8.35 (s, 1 H).

Example 11 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) propionic acid

Tert-Butyl 3- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propionate obtained in Example 10 (927 mg) was added trifluoroacetic acid (20 mL) and stirred at room temperature. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate-methanol 100: 0 to 95: 5, v / v) and crystallized from hexane-ethyl acetate-ethanol to give the title compound (710 mg, yield 87% ) Was obtained as colorless crystals. The colorless crystals obtained were crystallized from water-ethanol to obtain colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.76 (t, J = 7.3 Hz, 2 H), 4.48 (t, J = 7.2 Hz, 2 H), 7.26-7.42 (m, 2 H) , 7.68-7.80 (m, 2 H), 8.53 (d, J = 1.5 Hz, 1 H), 8.65 (d, J = 0.9 Hz, 1 H), 12.45 (br s, 1 H).

Example 12 tert-butyl (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) acetate

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (403 mg), tert-butyl 2-bromoacetate (358 mg) obtained in Reference Example 5 ) And potassium carbonate (354 mg) in N, N-dimethylformamide (6 mL) was stirred at 45 ° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 88:12, v / v) and crystallized from hexane-ethyl acetate to give the title compound (463 mg, yield 85%) as colorless crystals. It was.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.42 (s, 9 H), 4.85 (s, 2 H), 7.31-7.46 (m, 3 H), 7.82-7.89 (m, 2 H), 8.25 -8.42 (m, 1 H).

Example 13 (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) acetic acid

To (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) acetic acid tert-butyl (308 mg) obtained in Example 12 Trifluoroacetic acid (4 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was crystallized from diisopropyl ether-methanol to give the title compound (237 mg, yield 88%) as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 5.07 (s, 2 H), 7.27-7.44 (m, 2 H), 7.72 (t, J = 8.7 Hz, 2 H), 8.53 (d, J = 1.9 Hz, 1 H), 8.62 (s, 1 H), 13.27 (s, 1 H).

Example 14 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propanamide

The same method as in Example 6 from 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole and 3-bromopropionamide obtained in Reference Example 5 Gave the title compound.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.73 (t, J = 7.2 Hz, 2 H), 4.63 (t, J = 7.2 Hz, 2 H), 5.22 (s, 1 H), 5.51 (d , J = 2.4 Hz, 1 H), 7.30-7.44 (m, 2 H), 7.54 (d, J = 7.5 Hz, 1 H), 7.82 (d, J = 7.3 Hz, 1 H), 7.86 (d, J = 1.9 Hz, 1 H), 8.34 (d, J = 0.9 Hz, 1 H).

Example 15 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-methyl-1H-benzimidazol-1-yl) propionic acid

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-methyl-1H-benzimidazole, cesium carbonate and tert-bromobromopropionate obtained in Reference Example 7 The title compound was obtained from butyl by conducting the same method as in Example 13 following the same method as in Example 12.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.53 (s, 3 H), 2.75 (t, J = 7.2 Hz, 2 H), 4.46 (t, J = 7.2 Hz, 2 H), 7.11 (d, J = 7.2 Hz, 1 H), 7.27 (t, J = 7.7 Hz, 1 H), 7.56 (d, J = 8.1 Hz, 1 H), 8.53 (d, J = 1.9 Hz, 1 H) , 8.66 (d, J = 1.1 Hz, 1 H), 12.40 (br s, 1 H).

Example 16 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-methyl-1H-benzimidazol-1-yl) butanoic acid

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-methyl-1H-benzimidazole, cesium carbonate and tert-butyl 4-bromobutanoate obtained in Reference Example 7 Thus, the title compound was obtained by conducting the same method as in Example 13, following the same method as in Example 12.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.93 (tt, J = 7.2, 7.2 Hz, 2 H), 2.26 (t, J = 7.1 Hz, 2 H), 2.55 (s, 3 H) , 4.26 (t, J = 7.4 Hz, 2 H), 7.13 (d, J = 7.2 Hz, 1 H), 7.30 (t, J = 7.7 Hz, 1 H), 7.56 (d, J = 8.1 Hz, 1 H), 8.53 (d, J = 1.5 Hz, 1 H), 8.65 (d, J = 0.9 Hz, 1 H). OH proton is not detected.

Example 17 tert-Butyl 3- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -6-methoxy-1H-benzimidazol-1-yl) propionate

Example 18 tert-Butyl 3- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methoxy-1H-benzimidazol-1-yl) propionate

  2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methoxy-1H-benzimidazole (1.50 g), tert-bromopropionic acid obtained in Reference Example 8 A mixture of -butyl (1.75 mL) and cesium carbonate (3.40 g) in N, N-dimethylformamide (15 mL) was stirred at 50 ° C. for 8 hours. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5 to 1: 1, v / v), and the title compound (Example 17) was obtained as a white solid from the fraction having a short retention time. Subsequently, the title compound (Example 18) was obtained as a white solid from the fraction having a long retention time. The residue obtained from the fraction containing both compounds was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-75: 25, v / v), and the title compound (Example 17) was obtained from the fraction with a short retention time. Was obtained as a white solid. Combined with the previously obtained white solid (Example 17), crystallization from hexane-ethyl acetate gave white crystals (392 mg, 19% yield). Subsequently, the title compound (Example 18) was obtained as a white solid from the fraction having a long retention time. Together with the previously obtained white solid (Example 18), crystallization from hexane-ethyl acetate gave white crystals (227 mg, yield 11%).

Example 17 (Retention time short)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.39 (s, 9 H), 2.75 (t, J = 7.4 Hz, 2 H), 3.92 (s, 3 H), 4.47 (t, J = 7.4 Hz , 2 H), 6.92-6.94 (m, 1 H), 6.95-7.00 (m, 1 H), 7.70 (d, J = 8.7 Hz, 1 H), 7.83 (d, J = 1.9 Hz, 1 H) , 8.36 (s, 1 H).

Example 18 (large retention time)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.38 (s, 9 H), 2.75 (t, J = 7.4 Hz, 2 H), 3.87 (s, 3 H), 4.49 (t, J = 7.4 Hz , 2 H), 7.04 (dd, J = 8.9, 2.4 Hz, 1 H), 7.27 (s, 1 H), 7.40 (d, J = 9.0 Hz, 1 H), 7.83 (d, J = 1.9 Hz, 1 H), 8.36 (d, J = 1.1 Hz, 1 H).

Example 19 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -6-methoxy-1H-benzimidazol-1-yl) butanoic acid tert-butyl

Example 20 tert-Butyl 4- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methoxy-1H-benzimidazol-1-yl) butanoate

  2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methoxy-1H-benzimidazole (1.50 g) obtained in Reference Example 8, 4-bromobutanoic acid tert- A mixture of butyl (1.40 g) and cesium carbonate (2.90 g) in N, N-dimethylformamide (15 mL) was stirred at room temperature for 12 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-75: 25, v / v), and the title compound (Example 19) was obtained as a white solid from the fraction having a short retention time. Subsequently, the title compound (Example 20) was obtained as a white solid from the fraction having a long retention time. The residue obtained from the fraction containing both compounds was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5 to 80:20, v / v). From the fraction with a short retention time, the title compound (Example 19) Was obtained as a white solid. Combined with the previously obtained white solid (Example 19) and crystallized from hexane-ethyl acetate, white crystals (387 mg, yield 19%) were obtained. Subsequently, the title compound (Example 20) was obtained as a white solid from the fraction having a long retention time. Together with the previously obtained white solid (Example 20), crystallization from hexane-ethyl acetate gave white crystals (219 mg, yield 10%).

Example 19 (holding time short)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.42 (s, 9 H), 2.03-2.16 (m, 2 H), 2.25 (t, J = 7.2 Hz, 2 H), 3.92 (s, 3 H ), 4.24 (t, J = 7.2 Hz, 2 H), 6.93-7.07 (m, 2 H), 7.71 (d, J = 9.4 Hz, 1 H), 7.82 (d, J = 1.5 Hz, 1 H) , 8.35 (d, J = 1.1 Hz, 1 H).

Example 20 (large retention time)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.42 (s, 9 H), 2.03-2.14 (m, 2 H), 2.23 (t, J = 7.1 Hz, 2 H), 3.87 (s, 3 H ), 4.27 (t, J = 7.1 Hz, 2 H), 7.05 (dd, J = 8.9, 2.4 Hz, 1 H), 7.27 (d, J = 2.3 Hz, 1 H), 7.39 (d, J = 8.9 Hz, 1 H), 7.82 (d, J = 1.5 Hz, 1 H), 8.35 (dd, J = 2.0, 0.8 Hz, 1 H).

Example 21 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -6-methoxy-1H-benzimidazol-1-yl) propionic acid

3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -6-methoxy-1H-benzimidazol-1-yl) propionic acid tert obtained in Example 17 -Trifluoroacetic acid (5 mL) was added to -butyl (380 mg), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from heptane-ethyl acetate to give the title compound (349 mg, 90% yield) as white crystals of 1 water and 0.40 trifluoroacetic acid solvate. Obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.75 (t, J = 7.3 Hz, 2 H), 3.86 (s, 3 H), 4.44 (t, J = 7.3 Hz, 2 H), 6.92 (dd, J = 8.9, 2.4 Hz, 1 H), 7.32 (d, J = 2.4 Hz, 1 H), 7.58 (d, J = 8.9 Hz, 1 H), 8.52 (d, J = 1.9 Hz, 1 H), 8.66 (d, J = 0.9 Hz, 1 H), 12.34 (s, 1 H).

Example 22 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methoxy-1H-benzimidazol-1-yl) propionic acid

3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methoxy-1H-benzimidazol-1-yl) propionic acid tert obtained in Example 18 -Trifluoroacetic acid (5 mL) was added to -butyl (215 mg), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from heptane-ethyl acetate to give the title compound (206 mg, 84% yield) as white crystals of 0.50 water and 0.1 trifluoroacetic acid solvate. Obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.74 (t, J = 7.0 Hz, 2 H), 3.81 (s, 3 H), 4.45 (t, J = 7.3 Hz, 2 H), 7.02 (dd, J = 8.9, 2.4 Hz, 1 H), 7.21 (d, J = 2.3 Hz, 1 H), 7.66 (d, J = 8.9 Hz, 1 H), 8.53 (d, J = 1.5 Hz, 1 H), 8.66 (dd, J = 2.0, 0.8 Hz, 1 H). OH proton is not detected.

Example 23 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -6-methoxy-1H-benzimidazol-1-yl) butanoic acid

4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -6-methoxy-1H-benzimidazol-1-yl) butanoic acid tert-obtained in Example 19 -Trifluoroacetic acid (5 mL) was added to -butyl (350 mg), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-0: 100, v / v) and crystallized from heptane-ethyl acetate. The title compound (270 mg, yield 85%) was obtained as white crystals of 0.50 hydrate.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.92 (tt, J = 7.2, 7.0 Hz, 2 H), 2.26 (t, J = 7.1 Hz, 2 H), 3.86 (s, 3 H) , 4.22 (t, J = 7.3 Hz, 2 H), 6.92 (dd, J = 8.9, 2.4 Hz, 1 H), 7.28 (d, J = 2.3 Hz, 1 H), 7.59 (d, J = 9.0 Hz , 1 H), 8.51 (d, J = 1.9 Hz, 1 H), 8.64 (dd, J = 1.9, 0.8 Hz, 1 H), 12.14 (br s, 1 H).

Example 24 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methoxy-1H-benzimidazol-1-yl) butanoic acid

4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methoxy-1H-benzimidazol-1-yl) butanoic acid tert obtained in Example 20 -Trifluoroacetic acid (5 mL) was added to -butyl (205 mg), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-0: 100, v / v) and crystallized from heptane-ethyl acetate. The title compound (122 mg, 62% yield) was obtained as white crystals of 0.50 water and 0.25 trifluoroacetic acid solvate. Recrystallization from water-acetone gave the title compound as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.80-1.97 (m, 2 H), 2.12-2.30 (m, 2 H), 3.81 (s, 3 H), 4.23 (t, J = 7.3 Hz, 2 H), 7.02 (dd, J = 8.9, 2.4 Hz, 1 H), 7.22 (d, J = 2.3 Hz, 1 H), 7.62 (d, J = 8.9 Hz, 1 H), 8.52 (d , J = 1.3 Hz, 1 H), 8.65 (d, J = 0.9 Hz, 1 H), 12.10 (br s, 1 H).

Example 25 tert-Butyl 3- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5,6-difluoro-1H-benzimidazol-1-yl) propionate

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5,6-difluoro-1H-benzimidazole, cesium carbonate and 3-bromopropionic acid obtained in Reference Example 9 The title compound was obtained from tert-butyl in the same manner as in Example 12.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.38 (s, 9 H), 2.73 (t, J = 7.2 Hz, 2 H), 4.47 (t, J = 7.3 Hz, 2 H), 7.36 (dd , J = 9.8, 7.0 Hz, 1 H), 7.59 (dd, J = 10.2, 7.3 Hz, 1 H), 7.85 (d, J = 1.5 Hz, 1 H), 8.36 (dd, J = 1.9, 0.9 Hz , 1 H).

Example 26 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5,6-difluoro-1H-benzimidazol-1-yl) propionic acid

3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5,6-difluoro-1H-benzimidazol-1-yl) propion obtained in Example 25 The title compound was obtained from tert-butyl acid in the same manner as in Example 13.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.75 (t, J = 7.2 Hz, 2 H), 4.45 (t, J = 7.2 Hz, 2 H), 7.82 (dd, J = 10.7, 7.5 Hz, 1 H), 8.01 (dd, J = 10.8, 7.3 Hz, 1 H), 8.54 (d, J = 1.5 Hz, 1 H), 8.66 (dd, J = 1.9, 0.9 Hz, 1 H), 12.43 (br s, 1 H).

Example 27 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5,6-difluoro-1H-benzimidazol-1-yl) butanoic acid

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5,6-difluoro-1H-benzimidazole, cesium carbonate and tert-bromobutyrate obtained in Reference Example 9 The title compound was obtained from -butyl by carrying out the same method as in Example 13 following the same method as in Example 12.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.91 (tt, J = 7.3, 7.3 Hz, 2 H), 2.25 (t, J = 7.1 Hz, 2 H), 4.24 (t, J = 7.4 Hz, 2 H), 7.83 (dd, J = 10.9, 7.5 Hz, 1 H), 7.98 (dd, J = 10.6, 7.3 Hz, 1 H), 8.53 (d, J = 1.9 Hz, 1 H), 8.65 (d, J = 1.1 Hz, 1 H), 12.12 (br s, 1 H).

Example 28 (2E) -3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) acrylic acid

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (1.53 g), tert-butyl propiolate (950 μL) and carbonic acid obtained in Reference Example 5 A mixture of cesium (1.53 g) in N, N-dimethylformamide (15 mL) was stirred at room temperature for 12 hours. Tert-butyl propiolate (100 μL) was added, and the mixture was further stirred for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-55: 45, v / v) to give a brown oil. Trifluoroacetic acid (10 mL) was added to the resulting brown oil and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-60: 40, v / v) and crystallized from heptane-ethyl acetate. The title compound (240 mg, yield 13%) was obtained as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 6.53 (d, J = 14.5 Hz, 1 H), 7.38-7.63 (m, 2 H), 7.79-7.89 (m, 1 H), 8.09 ( d, J = 8.1 Hz, 1 H), 8.14 (d, J = 14.5 Hz, 1 H), 8.58 (d, J = 1.5 Hz, 1 H), 8.68 (d, J = 0.9 Hz, 1 H), 12.65 (br s, 1 H).

Example 29 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) -2,2-dimethylpropionic acid

3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) -2,2-dimethylpropane obtained in Reference Example 12 In a mixture of -1-ol (2.80 g), molecular sieves 4A (granule, 25.0 g) and N-methylmorpholine N-oxide (1.58 g) in acetonitrile (50 mL), tetrapropylammonium perruthenate (115 mg) And stirred at room temperature for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated. The obtained residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-60: 40, v / v) to give a yellow oil. The resulting yellow oil, 2-methyl-2-butene (1.60 mL), and sodium dihydrogen phosphate (1.75 g) in tert-butanol (15 mL) and water (10 mL) were mixed with chlorous acid. Sodium (528 mg) was added and stirred at room temperature for 20 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-60: 40, v / v) to give a yellow solid. The obtained yellow solid was dissolved in ethyl acetate, activated carbon was suspended, and the mixture was stirred at room temperature for 2 hours. Then, insoluble matters were removed by filtration, and the filtrate was concentrated. The obtained residue was crystallized from hexane-diisopropyl ether-ethyl acetate to give the title compound (2440 mg, yield 19%) as pale-yellow crystals of 0.20 diisopropyl ether solvate.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.15 (s, 6 H), 4.42 (s, 2 H), 7.19-7.44 (m, 2 H), 7.69 (d, J = 8.1 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 8.51 (d, J = 1.3 Hz, 1 H), 8.64 (d, J = 1.1 Hz, 1 H), 12.71 (br s, 1 H ).

Example 30 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-fluoro-1H-benzimidazol-1-yl) butanoic acid

A mixture of 2,6-difluoronitrobenzene (4.82 g), 4-aminobutyraldehyde diethyl acetal (6.50 mL) and triethylamine (6.30 mL) in acetonitrile (60 mL) was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5 to 1: 1, v / v) to give a pale yellow oil. To a solution of the obtained pale yellow oil in methanol (100 mL), 10% palladium carbon (4.81 g) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere of 1 atm. After removing the catalyst by filtration, the filtrate was concentrated. N, N′-thiocarbonyldiimidazole (3.43 g) was added to a solution of this residue in tetrahydrofuran (100 mL), and the mixture was stirred at room temperature for 78 hours. Further, N, N′-thiocarbonyldiimidazole (3.43 g) was added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. A mixture of the obtained residue, 2,3-dichloro-5- (trifluoromethyl) pyridine (6.50 mL) and potassium carbonate (6.64 g) in N, N-dimethylformamide (30 mL) at 50 ° C. for 18 hours. Stir. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-65: 35, v / v) to give a brown oil. 1N Hydrochloric acid (50 mL) was added to a solution of the obtained brown oil in tetrahydrofuran (50 mL), and the mixture was stirred at 50 ° C. for 1 hr. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate) to give a brown oil. To a mixture of the resulting brown oil, 2-methyl-2-butene (4.00 mL) and sodium dihydrogen phosphate (4.70 g) in tert-butanol (30 mL) and water (15 mL), add sodium chlorite. (1.78 g) was added and stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 85: 15-50: 50, v / v) to give a yellow oil. Preparative HPLC [Equipment: Gilson high-throughput purification system, column: SepaxHP C18 (30 × 100 mm S-10 μm), solvent: solution A; 0.1% trifluoroacetic acid-containing water, solution B; 0.1 % Acetonitrile with trifluoroacetic acid, gradient cycle: 0.00 min (A / B solution = 60/40), 1.20 min (A / B solution = 60/40), 5.25 min (A / B solution = 0/100 ), 7.75 minutes (A solution / B solution = 0/100), 7.85 minutes (A solution / B solution = 60/40), flow rate: 60 mL / min, detection method: UV 220 nm] Crystallization from water-tetrahydrofuran gave the title compound (1.15 g, yield 9%) as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.93 (tt, J = 7.0, 6.8 Hz, 2 H), 2.26 (t, J = 7.1 Hz, 2 H), 4.29 (t, J = 7.3 Hz, 2 H), 7.13 (dd, J = 11.0, 8.0 Hz, 1 H), 7.38 (ddd, J = 8.1, 8.1, 4.8 Hz, 1 H), 7.60 (d, J = 8.3 Hz, 1 H) , 8.54 (d, J = 1.9 Hz, 1 H), 8.66 (d, J = 1.1 Hz, 1 H), 12.14 (br s, 1 H).

Example 31 tert-Butyl 4- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-diphenyl-1H-imidazol-1-yl) butanoate

4,5-Diphenyl-1H-imidazole-2-thiol (2.52 g), 2,3-dichloro-5- (trifluoromethyl) pyridine (1.45 mL) and potassium carbonate (1.45 g) in N, N-dimethylformamide (30 mL) The mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. A mixture of the obtained residue, tert-butyl 4-bromobutanoate (790 mg) and cesium carbonate (1.56 g) in N, N-dimethylformamide (20 mL) was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-65: 35, v / v) to give the title compound (490 mg, yield 9%) as a white solid. Crystallization from hexane-ethyl acetate gave white crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.33 (s, 9 H), 1.78 (tt, J = 7.3, 7.3 Hz, 2 H), 2.03 (t, J = 7.3 Hz, 2 H), 3.93 (t, J = 7.3 Hz, 2 H), 7.11-7.22 (m, 3 H), 7.39-7.54 (m, 7 H), 7.80 (d, J = 1.5 Hz, 1 H), 8.49 (dd, J = 2.0, 0.8 Hz, 1 H).

Example 32 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-diphenyl-1H-imidazol-1-yl) butanoic acid

4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-diphenyl-1H-imidazol-1-yl) butanoic acid obtained in Example 31 The title compound was obtained from tert-butyl in the same manner as in Example 13.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.61 (tt, J = 7.3, 7.1 Hz, 2 H), 2.00 (t, J = 7.2 Hz, 2 H), 3.88 (t, J = 7.5 Hz, 2 H), 7.09-7.27 (m, 3 H), 7.30-7.40 (m, 2 H), 7.40-7.52 (m, 2 H), 7.51-7.62 (m, 3 H), 8.50 (d, J = 1.5 Hz, 1 H), 8.77 (dd, J = 1.9, 0.9 Hz, 1 H), 12.01 (br s, 1 H).

Example 33 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) -2,2-difluoropropionic acid

Methyl 2,2-difluoro-3- (2-sulfanyl-1H-benzoimidazol-1-yl) propionate (0.90 g), 2,3-dichloro-5- (trifluoromethyl) obtained in Reference Example 13 A mixture of pyridine (920 μL) and potassium carbonate (920 mg) in N, N-dimethylformamide (15 mL) was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-60: 40, v / v), and the residue was crystallized from water-acetone to give the title compound (171 mg, yield 12%) Was obtained as white crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.95-5.16 (m, 2 H), 7.26-7.54 (m, 2 H), 7.63-7.84 (m, 2 H), 8.53 (d, J = 2.1 Hz, 1 H), 8.64 (dd, J = 1.9, 0.9 Hz, 1 H). OH proton is not detected.

Example 34 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) -2-methylbutanoic acid

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (3.00 g), methyl 4-chloro-2-methylbutanoate (3.00 g) obtained in Reference Example 5 1.53 mL), sodium iodide (1.64 g) and cesium carbonate (3.56 g) in N, N-dimethylformamide (20 mL) were stirred at 120 ° C. for 4 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 60:40, v / v) to give a colorless oil. Lithium hydroxide monohydrate (877 mg) was added to a mixture of the obtained colorless oily tetrahydrofuran (40 mL) and water (20 mL), and the mixture was stirred at 50 ° C. for 4 hr. After cooling to room temperature, the reaction mixture was neutralized with 1N hydrochloric acid (21 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90:10 to 65:35, v / v), and the obtained residue was crystallized from heptane-diisopropyl ether-ethyl acetate to give the title compound (2.90 g, yield 75%) was obtained as white crystals of 0.10 diisopropyl ether solvate.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.05 (d, J = 7.2 Hz, 3 H), 1.60-1.84 (m, 1 H), 1.91-2.16 (m, 1 H), 2.26- 2.46 (m, 1 H), 4.26 (t, J = 7.6 Hz, 2 H), 7.21-7.51 (m, 2 H), 7.71 (t, J = 8.7 Hz, 2 H), 8.52 (d, J = 1.9 Hz, 1 H), 8.66 (s, 1 H), 12.19 (br s, 1 H).

Example 35 Methyl 3-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] benzoate

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (1.69 g), methyl 3-bromomethylbenzoate (1.37 g) obtained in Reference Example 5 And a mixture of cesium carbonate (2.01 g) in N, N-dimethylformamide (30 mL) was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-55: 45, v / v) to give the title compound (1.98 g, yield 81%) as a white solid. Crystallization from hexane-ethyl acetate gave white crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.88 (s, 3 H), 5.51 (s, 2 H), 7.27-7.38 (m, 5 H), 7.76 (d, J = 1.5 Hz, 1 H ), 7.84-7.91 (m, 3 H), 8.24 (dd, J = 1.9, 0.9 Hz, 1 H).

Example 36 3-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) methyl] benzoic acid

Methyl 3-[(2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] benzoate obtained in Example 35 ( Lithium hydroxide monohydrate (399 mg) was added to a mixture of 1.80 g) of tetrahydrofuran (20 mL) and water (10 mL), and the mixture was stirred at 50 ° C. for 30 minutes. Lithium hydroxide monohydrate (399 mg) was added, and the mixture was further stirred for 30 min. After cooling to room temperature, the reaction mixture was neutralized with 1N hydrochloric acid (20 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was crystallized from heptane-ethyl acetate to give the title compound (1.49 g, yield 85%) as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 5.60 (s, 2 H), 7.18-7.44 (m, 4 H), 7.54-7.78 (m, 4 H), 8.40 (s, 2 H) . OH proton is not detected.

Example 37 4-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] methyl benzoate

Similar to Example 35 from 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole and methyl 4-bromomethylbenzoate obtained in Reference Example 5. The title compound was obtained by the method.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.89 (s, 3 H), 5.51 (s, 2 H), 7.20 (d, J = 8.7 Hz, 2 H), 7.23-7.41 (m, 3 H ), 7.76 (d, J = 1.5 Hz, 1 H), 7.84-7.94 (m, 3 H), 8.19 (dd, J = 2.0, 0.8 Hz, 1 H).

Example 38 4-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] benzoic acid

From methyl 4-[(2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] benzoate obtained in Example 37 The title compound was obtained in the same manner as in Example 36.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 5.60 (s, 2 H), 7.21 (d, J = 8.1 Hz, 2 H), 7.29-7.40 (m, 2 H), 7.63 (d, J = 8.1 Hz, 1 H), 7.71-7.80 (m, 3 H), 8.43 (s, 2 H), 12.90 (br s, 1 H).

Example 39 2-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] methyl benzoate

Performed from 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole, methyl 2-chloromethylbenzoate and sodium iodide obtained in Reference Example 5 The title compound was obtained in the same manner as in Example 35.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.93 (s, 3 H), 5.95 (s, 2 H), 6.65-6.70 (m, 1 H), 7.19-7.25 (m, 1 H), 7.27 -7.39 (m, 4 H), 7.74 (dd, J = 2.1, 0.4 Hz, 1 H), 7.85-7.94 (m, 1 H), 7.97-8.05 (m, 1 H), 8.25 (dd, J = 1.9, 0.9 Hz, 1 H).

Example 40 2-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] benzoic acid

From methyl 2-[(2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] benzoate obtained in Example 39 The title compound was obtained in the same manner as in Example 36.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 5.91 (s, 2 H), 6.63 (d, J = 7.0 Hz, 1 H), 7.23-7.42 (m, 4 H), 7.48-7.61 ( m, 1 H), 7.74-7.88 (m, 2 H), 8.43 (d, 1 H), 8.53 (dd, J = 1.9, 0.9 Hz, 1 H), 13.21 (br s, 1 H).

Example 41 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propane-1-sulfonic acid sodium salt

1- (3-Bromopropyl) -2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (1.50 g) obtained in Reference Example 14 in ethanol A mixed solution of (30 mL) solution and saturated aqueous sodium sulfite solution (30 mL) was heated to reflux for 18 hours with stirring. The reaction solution was concentrated and suspended in ethanol. The insoluble material was removed by filtration, and the filtrate was concentrated to give the title compound (1.06 g, yield 70%) as a pale yellow oil.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.02 (tt, J = 7.2, 7.2 Hz, 2 H), 2.41 (t, J = 7.4 Hz, 2 H), 4.37 (t, J = 7.4 Hz, 2 H), 7.20-7.45 (m, 2 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 8.51 (d, J = 1.9 Hz , 1 H), 8.64 (d, J = 1.1 Hz, 1 H).

Example 42 2-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] cyclopropanecarboxylic acid

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (prop-2-en-1-yl) -1H-benzimidazole obtained in Reference Example 15 ( 1.57 g) and rhodium (II) acetate dimer (94 mg) in toluene (15 mL) mixed with toluene (200 mL) solution of ethyl diazoacetate (490 μL) over 12 hours with stirring at 50 ° C The mixture was added dropwise and stirred for another 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-60: 40, v / v) to give a yellow oil. Lithium hydroxide monohydrate (198 mg) was added to a mixture of this yellow oily tetrahydrofuran (3 mL) and water (3 mL), and the mixture was stirred at 50 ° C. for 2 hr. After cooling to room temperature, the reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-65: 35, v / v) to give a pale yellow oil. The obtained yellow oil was again subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5 to 80:20, v / v), and preparative HPLC “Equipment: Gilson High Throughput Purification System, Column: SepaxHP C18 (30 × 100mm S-10μm), solvent: solution A; 0.1% trifluoroacetic acid-containing water, solution B; 0.1% trifluoroacetic acid-containing acetonitrile, gradient cycle: 0.00 minutes (solution A / solution B = 60/40) , 1.20 minutes (A liquid / B liquid = 60/40), 5.25 minutes (A liquid / B liquid = 0/100), 7.75 minutes (A liquid / B liquid = 0/100), 7.85 minutes (A liquid / B Liquid = 60/40), flow rate: 60 mL / min, detection method: UV 220 nm "and crystallized from water to give the title compound (2 mg, yield 0.1%) as a white powder. Obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.44-1.95 (m, 3 H), 3.53-3.81 (m, 2 H), 4.07-4.82 (m, 1 H), 7.06-7.47 (m , 2 H), 7.71 (t, 2 H), 8.52 (s, 1 H), 8.66 (s, 1 H), 12.38 (s, 1 H).

Example 43 2-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] pyridine-4-carboxylate methyl

2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole, methyl 2- (chloromethyl) pyridine-4-carboxylate obtained in Reference Example 5 and The title compound was obtained from sodium iodide in the same manner as in Example 35.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.87 (s, 3 H), 5.66 (s, 2 H), 7.28-7.47 (m, 3 H), 7.59 (s, 1 H), 7.71 (dd , J = 5.0, 1.4 Hz, 1 H), 7.79 (d, J = 1.9 Hz, 1 H), 7.83-8.03 (m, 1 H), 8.32 (dd, J = 2.0, 0.8 Hz, 1 H), 8.69 (dd, J = 5.0, 0.7 Hz, 1 H).

Example 44 2-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] pyridine-4-carboxylic acid

2-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] pyridine-4- obtained in Example 43 The title compound was obtained from methyl carboxylate in the same manner as in Example 36.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 5.68 (s, 2 H), 7.33 (qd, J = 7.5, 6.0 Hz, 2 H), 7.50-7.69 (m, 3 H), 7.75 ( dd, J = 6.7, 1.2 Hz, 1 H), 8.42 (s, 2 H), 8.48 (d, 1 H). OH proton is not detected.

Example 45 Ethyl 5-[(2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] furan-2-carboxylate

2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole obtained in Reference Example 5, ethyl 5- (chloromethyl) furan-2-carboxylate and The title compound was obtained from sodium iodide in the same manner as in Example 35.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.35 (s, 3 H), 3.99-4.52 (m, 2 H), 5.49 (d, 2 H), 5.96-6.30 (m, 1 H), 6.72 -7.18 (m, 1 H), 7.31-7.56 (m, 3 H), 7.57-8.00 (m, 2 H), 8.24 (s, 1 H).

Example 46 5-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] furan-2-carboxylic acid

5-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] furan-2- obtained in Example 45 The title compound was obtained from ethyl carboxylate in the same manner as in Example 36.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 5.62 (s, 2 H), 6.47 (d, J = 3.4 Hz, 1 H), 6.95 (d, J = 3.4 Hz, 1 H), 7.22 -7.53 (m, 2 H), 7.70-7.84 (m, 2 H), 8.44 (d, J = 9.1 Hz, 2 H), 13.00 (br s, 1 H).

Example 47 2-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] -1,3-thiazole-4 -Ethyl carboxylate

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole, 2- (chloromethyl) -1,3-thiazole-4 obtained in Reference Example 5 -The title compound was obtained in the same manner as in Example 35 from ethyl carboxylate and sodium iodide.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.40 (t, J = 7.2 Hz, 3 H), 4.42 (q, J = 7.2 Hz, 2 H), 5.81 (s, 2 H), 7.28-7.50 (m, 3 H), 7.83 (d, J = 2.1 Hz, 1 H), 7.89 (dd, J = 6.9, 2.7 Hz, 1 H), 8.09 (s, 1 H), 8.23 (s, 1 H) .

Example 48 4- (2-{[2-Chloro-4- (trifluoromethyl) phenyl] sulfanyl} -1H-benzoimidazol-1-yl) butanoic acid

Following the same method as in Reference Example 5 from 1H-benzimidazol-2-thiol, 2-chloro-1-fluoro-4- (trifluoromethyl) benzene and ethyl 4-bromobutanoate, the same method as in Example 6 Then, the title compound was obtained in the same manner as in Example 36.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.81-2.00 (m, 2 H), 2.11-2.39 (m, 2 H), 4.34 (t, J = 7.2 Hz, 2 H), 7.17 ( d, J = 8.0 Hz, 1 H), 7.23-7.34 (m, 1 H), 7.32-7.47 (m, 1 H), 7.65 (dd, J = 8.5, 1.3 Hz, 1 H), 7.67-7.80 ( m, 2 H), 8.01 (s, 1 H), 12.18 (br s, 1 H).

Example 49 4- {2-[(2,5-dichlorophenyl) sulfanyl] -1H-benzimidazol-1-yl} butanoic acid

To a solution of 2-[(2,5-dichlorophenyl) sulfanyl] -1H-benzimidazole obtained in Reference Example 16 in N, N-dimethylformamide (100 mL), add 60% sodium hydride (oil, 880 mg). In addition, the mixture was stirred at room temperature for 30 minutes. Ethyl 4-bromobutanoate (4.29 g) was added, and the mixture was stirred 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 and saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 85: 15-80: 20, v / v) to give an oil. 8N aqueous sodium hydroxide solution (15 mL) was added to a mixture of the obtained oily tetrahydrofuran (75 mL) and methanol (75 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (5.9 g, 74%) as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.94 (quin, J = 7.2 Hz, 2 H), 2.29 (t, J = 7.2 Hz, 2 H), 4.35 (t, J = 7.2 Hz, 2 H), 7.22-7.39 (m, 3 H), 7.44-7.48 (m, 1 H), 7.58-7.69 (m, 3 H), 12.19 (br s, 1 H).

Example 50 2- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) ethanesulfonamide

1- (2-Bromoethyl) -2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (3.35 g) obtained in Reference Example 17 in ethanol ( (20 mL) To the solution was added potassium thioacetate (1.32 g), and the mixture was stirred at 50 ° C. for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5 to 60:40, v / v) to obtain a light brown solid. To a solution of the obtained light brown solid in acetonitrile (25 mL), 2N hydrochloric acid (5 mL) and N-chlorosuccinimide (2.40 g) were added at 0 ° C., and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with diisopropyl ether, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. To a solution of the obtained residue in tetrahydrofuran (20 mL) was added 35% aqueous ammonia (10 mL) at 0 ° C., and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-50: 50, v / v) and crystallized from hexane-ethyl acetate to give the title compound (359 mg, yield 11%). Obtained as light brown crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.49 (t, J = 7.5 Hz, 2 H), 4.63 (t, J = 7.5 Hz, 2 H), 7.08 (s, 2 H), 7.19 -7.39 (m, 1 H), 7.38-7.55 (m, 1 H), 7.72 (t, J = 8.3 Hz, 2 H), 8.54 (d, J = 1.9 Hz, 1 H), 8.62-8.85 (m , 1 H).

Example 51 4- {2-[(3,5-dichloropyridin-2-yl) sulfanyl] -5-methoxy-1H-benzimidazol-1-yl} butanoic acid

Methyl 4- (5-methoxy-2-sulfanyl-1H-benzoimidazol-1-yl) butanoate (800 mg), 3,5-dichloro-2-fluoropyridine (560 mg) obtained in Reference Example 19 and A mixture of potassium carbonate (480 mg) in N, N-dimethylformamide (10 mL) was stirred at 60 ° C. for 24 hours. 3,5-Dichloro-2-fluoropyridine (250 mg) and potassium carbonate (400 mg) were added, and the mixture was further stirred at 100 ° C. for 3 hours. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-65: 35, v / v) to give a white solid. Lithium hydroxide monohydrate (490 mg) was added to a mixture of the obtained white solid tetrahydrofuran (20 mL) and water (10 mL), and the mixture was stirred at 50 ° C. for 30 min. After cooling to room temperature, the reaction mixture was neutralized with 1N hydrochloric acid (12 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-60: 40, v / v) and crystallized from water-ethanol to give the title compound (430 mg, yield 37%) as white Obtained as crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.89-2.11 (m, 2 H), 2.34 (t, J = 7.4 Hz, 2 H), 3.70 (s, 3 H), 4.33 (t, J = 7.2 Hz, 2 H), 6.66 (d, J = 2.3 Hz, 1 H), 6.94 (dd, J = 8.7, 2.3 Hz, 1 H), 7.50 (d, J = 8.7 Hz, 1 H), 8.66 (d, J = 2.3 Hz, 1 H), 8.79 (d, J = 2.3 Hz, 1 H), 12.18 (br s, 1 H).

Example 52 (2S) -4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) -2-hydroxybutanoic acid methyl ester

(2S) -2-{[tert-butyl (diphenyl) silyl] oxy} -4- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] obtained in Reference Example 24 Sulfanyl} -1H-benzoimidazol-1-yl) butanoate (8.01 g) and acetic acid (2.50 mL) in tetrahydrofuran (30 mL) were mixed with tetrabutylammonium fluoride (1M tetrahydrofuran solution, 15 mL) was added and stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-60: 40, v / v) to give the title compound (4.92 g, yield 94%) as a white solid. Crystallization with hexane-ethyl acetate gave white crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.84-2.23 (m, 1 H), 2.24-2.45 (m, 1 H), 2.94 (d, J = 4.5 Hz, 1 H), 3.64 (s, 3 H), 4.14 (dt, J = 8.8, 4.1 Hz, 1 H), 4.33-4.61 (m, 2 H), 7.28-7.48 (m, 2 H), 7.49-7.64 (m, 1 H), 7.68 -8.00 (m, 2 H), 8.16-8.39 (m, 1 H).

Example 53 (2S) -4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) -2-hydroxybutanoic acid

(2S) -4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) -2- obtained in Example 52 The title compound was obtained from methyl hydroxybutanoate in the same manner as in Example 36.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.62-2.03 (m, 1 H), 1.99-2.33 (m, 1 H), 3.62-4.06 (m, 1 H), 4.06-4.60 (m , 2 H), 7.05-7.50 (m, 2 H), 7.70 (dd, J = 11.1, 8.1 Hz, 2 H), 8.53 (s, 1 H), 8.64 (s, 1 H). Two OH protons are not detected.

Example 54 (2R) -4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) -2-fluorobutanoic acid

(2S) -4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) -2- obtained in Example 52 To a solution of methyl hydroxybutanoate (743 mg) in tetrahydrofuran (5 mL) was added N, N-diethylaminosulfur trifluoride (450 μL) under ice cooling, and the mixture was stirred for 30 minutes. Further, N, N-diethylaminosulfur trifluoride (450 μL) was added under ice cooling, and the mixture was stirred 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 and saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-55: 45, v / v) to give a pale yellow oil. Lithium hydroxide monohydrate (220 mg) was added to a mixture of the resulting oily tetrahydrofuran (10 mL) and water (5 mL), and the mixture was stirred at 0 ° C. for 1 hr. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was crystallized from heptane-ethyl acetate to give the title compound (360 mg, yield 81%) as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.96-2.34 (m, 2 H), 4.05-4.64 (m, 2 H), 4.70-5.18 (m, 1 H), 6.92-7.36 (m , 1 H), 7.36-7.51 (m, 1 H), 7.52-7.86 (m, 2 H), 8.54 (s, 1 H), 8.65 (s, 1 H), 13.42 (br s, 1 H).

Example 55 (2R) -4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) -2-hydroxybutanoic acid

(2S) -4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) -2- obtained in Example 52 Methyl hydroxybutanoate (2.67 g), acetic acid (514 μL) and triphenylphosphine (3.14 g) in tetrahydrofuran (30 mL) were mixed with diethyl azodicarboxylate (40% toluene solution, 5.5 mL) under ice-cooling. The solution was added dropwise and stirred at 0 ° C. for 5 minutes and at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-1: 1, v / v) to give a colorless oil. Lithium hydroxide monohydrate (750 mg) was added to a mixture of the obtained oily tetrahydrofuran (20 mL) and water (10 mL), and the mixture was stirred at 0 ° C. for 30 min. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was crystallized from heptane-ethyl acetate to give the title compound (360 mg, yield 81%) as pale-brown crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.72-2.01 (m, 1 H), 1.99-2.20 (m, 1 H), 3.68-3.97 (m, 1 H), 4.15-4.58 (m , 2 H), 7.19-7.35 (m, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.70 (t, J = 8.7 Hz, 2 H), 8.53 (s, 1 H), 8.65 (s, 1 H). Two OH protons are not detected.

Example 56 (2S) -4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) -2-fluorobutanoic acid

(2R) -4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) -2- obtained in Example 55 The title compound was obtained from hydroxybutanoic acid by the same method as in Example 54, followed by the same method as in Example 54.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.01-2.46 (m, 2 H), 4.15-4.65 (m, 2 H), 4.66-5.24 (m, 1 H), 7.13-7.36 (m , 1 H), 7.36-7.54 (m, 1 H), 7.71 (dd, J = 14.7, 7.9 Hz, 2 H), 8.53 (d, J = 1.9 Hz, 1 H), 8.65 (s, 1 H) , 13.28 (s, 1 H).

Example 57 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- [2- (2,2-dimethyl-1,3-dioxolan-4-yl) ethyl ] -1H-Benzimidazole

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole and 4- (2-iodoethyl) -2,2-dimethyl- obtained in Reference Example 5 The title compound was obtained from 1,3-dioxolane in the same manner as in Example 35.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.31 (s, 3 H), 1.40 (s, 3 H), 1.86-2.16 (m, 2 H), 3.48 (dd, J = 7.9, 6.6 Hz, 1 H), 3.91-4.01 (m, 1 H), 4.01-4.11 (m, 1 H), 4.33-4.48 (m, 2 H), 7.29-7.44 (m, 2 H), 7.50-7.57 (m, 1 H), 7.77-7.87 (m, 2 H), 8.35 (dd, J = 2.0, 0.8 Hz, 1 H).

Example 58 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-benzimidazol-1-yl) butanoic acid

4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-benzimidazol-1-yl) butanal (259) obtained in Reference Example 29 mg), 2-methyl-2-butene (220 mg) and sodium dihydrogen phosphate (225 mg) in tert-butanol (6 mL) and water (1.2 mL) in a mixture of sodium chlorite (85 mg) And stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate-methanol 100: 0 to 95: 5, v / v), and the obtained residue was crystallized from hexane-ethyl acetate to give the title compound (215 mg, yield). 80%) was obtained as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.86-1.99 (m, 2 H), 2.20-2.27 (m, 2 H), 2.44 (s, 3 H), 4.24 (t, J = 7.3 Hz, 2 H), 7.22 (dd, J = 8.4, 1.2 Hz, 1 H), 7.51 (s, 1 H), 7.61 (d, J = 8.5 Hz, 1 H), 8.51 (d, J = 1.5 Hz , 1 H), 8.63 (d, J = 0.9 Hz, 1 H), 12.10 (br s, 1 H).

Example 59 tert-Butyl 4- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5,6-dimethyl-1H-benzimidazol-1-yl) butanoate

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5,6-dimethyl-1H-benzimidazole (1.32 g) and cesium carbonate (2.40) obtained in Reference Example 31 To a mixed solution of g) in N, N-dimethylformamide (40 mL) was added tert-butyl 4-bromobutanoate (1.23 g), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-50: 50, v / v) to give the title compound (1.70 g, yield 93%) as a colorless solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.42 (s, 9 H), 2.04-2.15 (m, 2 H), 2.20-2.26 (m, 2 H), 2.39 (s, 3 H), 2.43 (s, 3 H), 4.26 (t, J = 7.1 Hz, 2 H), 7.25 (s, 1 H), 7.58 (s, 1 H), 7.81 (d, J = 1.5 Hz, 1 H), 8.30 -8.33 (m, 1 H).

Example 60 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5,6-dimethyl-1H-benzimidazol-1-yl) butanoic acid

4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5,6-dimethyl-1H-benzimidazol-1-yl) butane obtained in Example 59 Trifluoroacetic acid (30 mL) was added to tert-butyl acid (1.62 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate-methanol 100: 0 to 95: 5, v / v) and crystallized from hexane-ethyl acetate to give the title compound (1.43 g, yield 99%). Obtained as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.88-2.01 (m, 2 H), 2.26 (t, J = 7.1 Hz, 2 H), 2.36 (s, 3 H), 2.40 (s, 3 H), 4.27 (t, J = 7.3 Hz, 2 H), 7.53 (s, 1 H), 7.60 (s, 1 H), 8.54 (d, J = 1.7 Hz, 1 H), 8.63 (d, J = 0.9 Hz, 1 H), 11.41 (br s, 1 H).

Example 61 tert-Butyl 4- (5,6-dichloro-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) butanoate

From 5,6-dichloro-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole obtained in Reference Example 32 and tert-butyl 4-bromobutanoate In the same manner as in Example 35, the title compound was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (s, 9 H), 2.05-2.13 (m, 2 H), 2.21-2.27 (m, 2 H), 4.27 (t, J = 7.2 Hz, 2 H), 7.64 (s, 1 H), 7.85 (d, J = 1.5 Hz, 1 H), 7.92 (s, 1 H), 8.33-8.36 (m, 1 H).

Example 62 4- (5,6-Dichloro-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) butanoic acid

4- (5,6-Dichloro-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) butane obtained in Example 61 The title compound was obtained from tert-butyl acid in the same manner as in Example 13.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.85-1.97 (m, 2 H), 2.23-2.31 (m, 2 H), 4.27 (t, J = 7.4 Hz, 2 H), 8.04 ( s, 1 H), 8.21 (s, 1 H), 8.54 (d, J = 1.9 Hz, 1 H), 8.63 (s, 1 H), 12.13 (s, 1 H).

Example 63 4- {2-[(5-bromo-3-methylpyridin-2-yl) sulfanyl] -1H-benzimidazol-1-yl} butanoic acid tert-butyl ester

2,5-Dibromo-3-methylpyridine (15.28 g) was added to a mixture of 1H-benzimidazol-2-thiol (7.04 g) and potassium carbonate (8.42 g) in N, N-dimethylformamide (400 mL). Stir at 60 ° C. for 18 hours. Furthermore, potassium carbonate (19 g) and 2,5-dibromo-3-methylpyridine (5.80 g) were added to the reaction solution, and the mixture was stirred at 60 ° C. for 18 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 80: 20-25: 75, v / v) and crystallized with hexane-ethyl acetate to give colorless crystals. To a mixed solution of the obtained colorless crystals (2.06 g) and cesium carbonate (6.29 g) in N, N-dimethylformamide (60 mL) was added tert-butyl 4-bromobutanoate (3.59 g), and the mixture was heated at 60 ° C. for 3 hours. Stir. 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was crystallized from hexane-ethyl acetate to give the title compound (2.30 g, yield 77%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.42 (s, 9 H), 2.05-2.16 (m, 2 H), 2.22-2.29 (m, 2 H), 2.41 (s, 3 H), 4.31 (t, J = 7.2 Hz, 2 H), 7.28-7.38 (m, 2 H), 7.47 (d, J = 7.3 Hz, 1 H), 7.56-7.58 (m, 1 H), 7.77-7.82 (m , 1 H), 8.14 (d, J = 2.3 Hz, 1 H).

Example 64 4- {2-[(5-Bromo-3-methylpyridin-2-yl) sulfanyl] -1H-benzimidazol-1-yl} butanoic acid

From tert-butyl 4- {2-[(5-bromo-3-methylpyridin-2-yl) sulfanyl] -1H-benzoimidazol-1-yl} butanoate obtained in Example 63, In the same manner, the title compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.86-1.99 (m, 2 H), 2.25 (t, J = 7.0 Hz, 2 H), 2.38 (s, 3 H), 4.24 (t, J = 7.2 Hz, 2 H), 7.23-7.41 (m, 2 H), 7.63-7.74 (m, 2 H), 7.99 (s, 1 H), 8.26 (s, 1 H), 12.15 (br s, 1 H).

Example 65 tert-butyl 3- {2-[(5-bromo-3-methylpyridin-2-yl) sulfanyl] -1H-benzimidazol-1-yl} propionate

2,5-Dibromo-3-methylpyridine (15.28 g) was added to a mixture of 1H-benzimidazol-2-thiol (7.04 g) and potassium carbonate (8.42 g) in N, N-dimethylformamide (400 mL). Stir at 60 ° C. for 18 hours. Furthermore, potassium carbonate (19 g) and 2,5-dibromo-3-methylpyridine (5.80 g) were added to the reaction solution, and the mixture was stirred at 60 ° C. for 18 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 80: 20-25: 75, v / v) and crystallized with hexane-ethyl acetate to give colorless crystals. To a mixed solution of the obtained colorless crystals (2.01 g) and cesium carbonate (6.14 g) in N, N-dimethylformamide (60 mL) was added tert-butyl 3-propionate (3.28 g), and the mixture was stirred at 50 ° C. for 7 hours. Stir. Further, tert-butyl 3-propionate (1.97 g) and cesium carbonate (4.09 g) were added to the reaction mixture, and the mixture was stirred at 50 ° C. for 18 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-50: 50, v / v) to give the title compound (2.23 g, yield 79%) as a colorless oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.39 (s, 9 H), 2.42 (s, 3 H), 2.73-2.80 (m, 2 H), 4.50-4.57 (m, 2 H), 7.28 -7.38 (m, 2 H), 7.45-7.50 (m, 1 H), 7.57 (d, J = 1.5 Hz, 1 H), 7.77-7.81 (m, 1 H), 8.14 (d, J = 1.7 Hz , 1 H).

Example 66 3- {2-[(5-Bromo-3-methylpyridin-2-yl) sulfanyl] -1H-benzimidazol-1-yl} propionic acid

From tert-butyl 3- {2-[(5-bromo-3-methylpyridin-2-yl) sulfanyl] -1H-benzimidazol-1-yl} propionate obtained in Example 65, Example 13 and In the same manner, the title compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.38 (s, 3 H), 2.74 (t, J = 7.3 Hz, 2 H), 4.46 (t, J = 7.3 Hz, 2 H), 7.22 -7.37 (m, 2 H), 7.63-7.74 (m, 2 H), 7.99 (d, J = 1.7 Hz, 1 H), 8.27 (d, J = 2.1 Hz, 1 H), 12.43 (br s, 1 H).

Example 67 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-benzimidazol-1-yl) propionic acid

From 3- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-benzimidazol-1-yl) propanal obtained in Reference Example 37 In the same manner as in Example 58, the title compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.44 (s, 3 H), 2.74 (t, J = 7.1 Hz, 2 H), 4.45 (t, J = 7.2 Hz, 2 H), 7.21 (dd, J = 8.4, 1.2 Hz, 1 H), 7.49 (s, 1 H), 7.63 (d, J = 8.5 Hz, 1 H), 8.52 (d, J = 1.9 Hz, 1 H), 8.64 ( d, J = 0.9 Hz, 1 H), 12.43 (br s, 1 H).

Example 68 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- [2- (1,3-dioxolan-2-yl) ethyl] -1H-benzimidazole

N, N of 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (1.04 g) and cesium carbonate (2.06 g) obtained in Reference Example 5 2- (2-Bromoethyl) -1,3-dioxolane (856 mg) was added to a mixed solution of dimethylformamide (30 mL), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 85: 15-40: 60, v / v) to give the title compound (1.09 g, yield 81%) as a colorless solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.16-2.24 (m, 2 H), 3.78-3.90 (m, 2 H), 3.91-4.02 (m, 2 H), 4.37-4.45 (m, 2 H), 4.88 (t, J = 4.2 Hz, 1 H), 7.29-7.42 (m, 2 H), 7.50-7.55 (m, 1 H), 7.81-7.86 (m, 2 H), 8.33-8.36 ( m, 1 H).

Example 69 3- [3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propyl] -1,2,4 -Oxadiazole-5 (4H) -one

4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) butanenitrile (355 mg) obtained in Reference Example 39 and To a mixed solution of triethylamine (272 mg) in dimethyl sulfoxide (10 mL) was added hydroxylammonium chloride (186 mg), and the mixture was stirred at 75 ° C. for 18 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. N, N'-Carbonyldiimidazole (217 mg) and 1,8-diazabicyclo [5.4.0] undec-7-ene (544 mg) were added to a solution of the residue in tetrahydrofuran (10 mL) and stirred at 50 ° C for 5 hours. Stir. The reaction mixture was cooled to room temperature, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 50:50 to 0: 100, v / v), and the obtained crystals were subjected to preparative HPLC “instrument: Gilson high-throughput purification system, column: SepaxHP C18 ( 30 × 100mm S-10μm), solvent: solution A; 0.1% trifluoroacetic acid-containing water, solution B; 0.1% trifluoroacetic acid-containing acetonitrile, gradient cycle: 0.00 minutes (solution A / solution B = 60/40), 1.20 Minutes (A liquid / B liquid = 60/40), 5.25 minutes (A liquid / B liquid = 0/100), 7.75 minutes (A liquid / B liquid = 0/100), 7.85 minutes (A liquid / B liquid = 60/40), flow rate: 60 mL / min, detection method: UV 220 nm ”and crystallized from hexane-ethyl acetate to give the title compound (57 mg, yield 14%) as colorless crystals Got as.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.02-2.15 (m, 2 H), 2.49-2.59 (m, 2 H), 4.34 (t, J = 7.2 Hz, 2 H), 7.27- 7.45 (m, 2 H), 7.70-7.81 (m, 2 H), 8.53 (d, J = 1.5 Hz, 1 H), 8.64 (d, J = 0.8 Hz, 1 H), 12.08 (br s, 1 H).

Example 70 3- [2- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) ethyl] -1,2,4 -Oxadiazole-5 (4H) -one

3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propanenitrile (355 mg) obtained in Reference Example 40 The title compound was obtained in the same manner as in Example 39 from hydroxylammonium chloride and N, N′-carbonyldiimidazole.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.02 (t, J = 7.0 Hz, 2 H), 4.56 (t, J = 7.0 Hz, 2 H), 7.30-7.45 (m, 2 H) , 7.71-7.77 (m, 2 H), 8.55 (d, J = 1.7 Hz, 1 H), 8.64 (d, J = 0.9 Hz, 1 H), 12.33 (br s, 1 H).

Example 71 N- [3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propanoyl] serine methyl ester

3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propionic acid (753 mg) obtained in Example 11 To the acetonitrile (18 mL) solution, DL-serine methyl ester hydrochloride (321 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (395 mg), 1-hydroxybenzotriazole (316 mg) ) And triethylamine (228 mg) were added, and the mixture was stirred at room temperature for 15 hours. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was crystallized from hexane-ethyl acetate to give the title compound (783 mg, yield 83%) as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.73 (t, J = 7.0 Hz, 2 H), 3.41-3.50 (m, 1 H), 3.52-3.64 (m, 4 H), 4.21- 4.31 (m, 1 H), 4.46 (t, J = 7.0 Hz, 2 H), 5.03 (t, J = 5.4 Hz, 1 H), 7.26-7.41 (m, 2 H), 7.67-7.74 (m, 2 H), 8.33 (d, J = 7.5 Hz, 1 H), 8.53 (d, J = 1.5 Hz, 1 H), 8.65 (s, 1 H).

Example 72 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- [3- (1H-tetrazol-5-yl) benzyl] -1H-benzimidazole

N-bromosuccinimide (489 mg) and 2,2'-azobisisobutyronitrile in a solution of 5- (3-methylphenyl) -2-trityl-2H-tetrazole (1.10 g) in benzene trifluoride (30 mL) (45 mg) was added and heated to reflux for 7 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-70: 30, v / v) to obtain colorless crystals. The obtained colorless crystals (1.69 g) were obtained from 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (925 mg) obtained in Reference Example 5 and To a mixed solution of cesium carbonate (1.83 g) in N, N-dimethylformamide (30 mL), the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 85: 15-50: 50, v / v) to give a colorless solid. 1N Hydrochloric acid (20 mL) was added to a solution of the obtained colorless solid in tetrahydrofuran (20 mL), and the mixture was stirred at 65 ° C. for 1 hr. 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate-methanol 100: 0 to 95: 5, v / v) and crystallized from hexane-ethanol to give the title compound (687 mg, yield 67%) as colorless Obtained as crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 5.65 (s, 2 H), 7.28-7.52 (m, 4 H), 7.69 (d, J = 7.3 Hz, 1 H), 7.76-7.89 ( m, 3 H), 8.36 (d, J = 1.5 Hz, 1 H), 8.42 (s, 1 H). NH proton is not detected.

Example 73 N-{[(E) -2- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indol-3-yl) Ethenyl] sulfonyl} glycine

N- (tert-butoxycarbonyl) -N-{[(E) -2- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} obtained in Reference Example 42 Trifluoroacetic acid (10 mL) was added to -1-methyl-1H-indol-3-yl) ethenyl] sulfonyl} glycine tert-butyl ester (468 mg), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate-methanol 100: 0 to 95: 5, v / v) to obtain crystals. The obtained crystals were subjected to preparative HPLC “Equipment: Gilson High Throughput Purification System, Column: SepaxHP C18 (30 × 100 mm S-10 μm), Solvent: Solution A; 0.1% trifluoroacetic acid-containing water, Solution B; 0.1% Tri Fluoracetic acid-containing acetonitrile, gradient cycle: 0.00 minutes (A liquid / B liquid = 60/40), 1.20 minutes (A liquid / B liquid = 60/40), 5.25 minutes (A liquid / B liquid = 0/100), 7.75 min (A solution / B solution = 0/100), 7.85 min (A solution / B solution = 60/40), flow rate: 60 mL / min, detection method: UV 220 nm " Crystallization from ethyl acetate gave the title compound (57 mg, yield 15%) as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.66 (d, J = 4.3 Hz, 2 H), 3.75 (s, 3 H), 7.14 (d, J = 15.6 Hz, 1 H), 7.27 -7.35 (m, 1 H), 7.40-7.61 (m, 3 H), 7.71 (d, J = 8.3 Hz, 1 H), 8.03 (d, J = 8.1 Hz, 1 H), 8.53 (d, J = 1.5 Hz, 1 H), 8.66 (s, 1 H), 12.74 (br s, 1 H).

Example 74 N-{[(E) -2- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1-methyl-1H-indol-3-yl) Ethenyl] sulfonyl} glycine ethyl ester

N- (tert-butoxycarbonyl) -N-{[(E) -2- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} obtained in Reference Example 43 The title compound was obtained in the same manner as in Example 73 from 1-methyl-1H-indol-3-yl) ethenyl] sulfonyl} glycine ethyl ester.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.17 (t, J = 7.2 Hz, 3 H), 3.77 (s, 3 H), 3.82 (d, J = 5.3 Hz, 2 H), 4.12 (q , J = 7.2 Hz, 2 H), 4.88 (t, J = 5.5 Hz, 1 H), 6.89 (d, J = 15.5 Hz, 1 H), 7.30-7.37 (m, 1 H), 7.39-7.49 ( m, 2 H), 7.84-7.92 (m, 3 H), 8.35 (s, 1 H).

Example 75 4- {2-[(3,5-dichloropyridin-2-yl) sulfanyl] -1H-benzimidazol-1-yl} butanoic acid ethyl ester

A mixture of 1H-benzimidazol-2-thiol (1.00 g), 2-bromo-3,5-dichloropyridine (1.66 g), and potassium carbonate (1.11 g) in N, N-dimethylformamide (16 mL) Stir at 100 ° C. for 18 hours. Water was added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours, and then a light brown solid (1.93 g) was obtained by filtration. A mixture of the obtained solid (1.93 g), commercially available ethyl 4-bromobutanoate (2.54 g), and cesium carbonate (4.25 g) in N, N-dimethylformamide (20 mL) was stirred at 60 ° C. for 3 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 60:40, v / v) to obtain the title compound (1.79 g, yield 65%) as a colorless solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.24 (t, J = 7.2 Hz, 3 H), 2.08-2.23 (m, 2 H), 2.28-2.38 (m, 2 H), 4.12 (q, J = 7.2 Hz, 2 H), 4.32 (t, J = 7.2 Hz, 2 H), 7.28-7.41 (m, 2 H), 7.49 (d, J = 7.6 Hz, 1 H), 7.65 (d, J = 2.3 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1 H), 8.08 (d, J = 2.3 Hz, 1 H).

Example 76 4- {2-[(3,5-dichloropyridin-2-yl) sulfanyl] -1H-benzimidazol-1-yl} butanoic acid

4- {2-[(3,5-dichloropyridin-2-yl) sulfanyl] -1H-benzoimidazol-1-yl} butanoic acid ethyl (1.79 g) obtained in Example 75 and 2N lithium hydroxide A mixture of an aqueous solution (6.50 mL) in tetrahydrofuran (30 mL) was stirred at 60 ° C. for 5 hours. The reaction mixture was cooled in an ice bath, the reaction mixture was acidified with 1N hydrochloric acid, and water was added. After stirring for 2 hours in an ice-water bath, a solid was obtained by filtration. The obtained solid was crystallized from water-ethanol to give the title compound (1.43 g, yield 86%) as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.80-2.04 (m, 2 H), 2.25 (t, J = 7.0 Hz, 2 H), 4.25 (t, J = 7.4 Hz, 2 H) , 7.18-7.47 (m, 2 H), 7.70 (dd, J = 7.8, 3.7 Hz, 2 H), 8.18-8.43 (m, 2 H), 12.12 (br s, 1 H).

Example 77 3- {2-[(3,5-dichloropyridin-2-yl) sulfanyl] -1H-benzimidazol-1-yl} tert-butyl propionate

The title compound was obtained in the same manner as in Example 75 from 1H-benzimidazole-2-thiol, 2,3,5-trichloropyridine, and tert-butyl 3-bromopropionate.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.39 (s, 9 H), 2.67-2.82 (m, 2 H), 4.46-4.56 (m, 2 H), 7.28-7.43 (m, 2 H) , 7.46-7.57 (m, 1 H), 7.66 (d, J = 1.9 Hz, 1 H), 7.82 (d, J = 7.6 Hz, 1 H), 8.08 (d, J = 2.3 Hz, 1 H).

Example 78 3- {2-[(3,5-dichloropyridin-2-yl) sulfanyl] -1H-benzimidazol-1-yl} propionic acid

Similar to Example 13 from tert-butyl 3- {2-[(3,5-dichloropyridin-2-yl) sulfanyl] -1H-benzimidazol-1-yl} propionate obtained in Example 77 The title compound was obtained by the method.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.75 (t, J = 7.3 Hz, 2 H), 4.47 (t, J = 7.3 Hz, 2 H), 7.08-7.44 (m, 2 H) , 7.63-7.85 (m, 2 H), 8.26-8.39 (m, 2 H), 12.43 (br s, 1 H).

Example 79 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-fluoro-1H-benzimidazol-1-yl) butanoic acid

4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-fluoro-1H-benzimidazol-1-yl) butanal (2.0) obtained in Reference Example 48 g), sodium dihydrogen phosphate (1.72 mg) and 2-methyl-2-butene (1.68 g) in tert-butyl alcohol (48 mL) -water (9.6 mL) solution with sodium chlorite (649 mg) After adding at 0 ° C., the mixture was stirred at 0 ° C. for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0-80: 20, v / v) and recrystallized from ethyl acetate-hexane to give the title compound (1.49 g, yield 72%). Obtained as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.81-1.95 (m, 2 H), 2.18-2.29 (m, 2 H), 4.23-4.33 (m, 2 H), 7.19-7.35 (m , 1 H), 7.55 (dd, J = 9.5, 2.3 Hz, 1 H), 7.74-7.88 (m, 1 H), 8.53 (s, 1 H), 8.65 (s, 1 H), 12.13 (br s , 1 H).

Example 80 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- [2- (1H-1,2,4-triazol-3-ylsulfonyl) ethyl] -1H-benzimidazole

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- [2- (1H-1,2,4-triazol-3-yl) obtained in Reference Example 49 Sulfanyl) ethyl] -1H-benzimidazole (120 mg) and metachloroperbenzoic acid (45 mg) in ethyl acetate (3 mL) at 0 ° C. for 1 hour, at room temperature for 1 hour, at 40 ° C. for 40 minutes and at 60 ° C. For 1.5 hours. Metachloroperbenzoic acid (90 mg) was added, and the mixture was stirred at 50 ° C. for 2 hr. A sodium thiosulfate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 67:33, v / v) and crystallized from ethyl acetate-hexane to give the title compound (16 mg, yield 13%). Obtained as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 4.02 (t, J = 7.0 Hz, 2 H), 4.69 (t, J = 7.0 Hz, 2 H), 7.26-7.44 (m, 2 H) , 7.66-7.76 (m, 2 H), 8.50 (s, 1 H), 8.62 (s, 1 H), 8.73 (s, 1 H), 15.05 (br s, 1 H).

Example 81 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- [3- (1H-1,2,4-triazol-3-ylsulfinyl) propyl] -1H-benzimidazole

Example 82 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- [3- (1H-1,2,4-triazol-3-ylsulfonyl) propyl] -1H-benzimidazole

  2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- [3- (1H-1,2,4-triazol-3-yl) obtained in Reference Example 50 A solution of (sulfanyl) propyl] -1H-benzimidazole (1.0 g) and metachloroperbenzoic acid (548 mg) in ethyl acetate (10 mL) was stirred at room temperature for 30 minutes. A sodium thiosulfate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 75:25, v / v), and the residue obtained from the fraction having a long retention time was crystallized from ethyl acetate-hexane. The compound of Example 82 (676 mg, 66% yield) was converted to colorless amorphous, and the residue obtained from the fraction having a short retention time was crystallized from ethyl acetate-hexane to give the compound of Example 82 (113 mg, yield). 11%) was obtained as a colorless amorphous.

Example 81 (large retention time)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.17-2.54 (m, 2 H), 3.09-3.35 (m, 2 H), 4.42 (t, J = 7.1 Hz, 2 H), 7.30-7.40 ( m, 2 H), 7.41-7.54 (m, 1 H), 7.74-7.88 (m, 2 H), 8.29-8.33 (m, 1 H), 8.40 (s, 1 H).

Example 82 (small holding time)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.40-2.52 (m, 2 H), 3.39 (t, J = 7.4 Hz, 2 H), 4.47 (t, J = 7.0 Hz, 2 H), 7.30 -7.45 (m, 2 H), 7.47-7.56 (m, 1 H), 7.77-7.84 (m, 2 H), 8.31-8.35 (m, 1 H), 8.40 (s, 1 H).

Example 83 3- {3-[(2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] phenyl} -1, 2,4-oxadiazol-5 (4H) -one

3-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] -N′- obtained in Reference Example 52 N, N'-Carbonyldiimidazole (250 mg) and 1,8-diazabicyclo- [5.4.0] unde-7-cene (627) were added to a mixture of hydroxybenzenecarboximidamide (492 mg) in tetrahydrofuran (10 mL). mg) was added and stirred at room temperature for 2 hours. 1N Hydrochloric acid was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 0: 100, v / v) and recrystallized from ethyl acetate-hexane to give the title compound (322 mg, yield 62%). Obtained as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.50 (s, 2 H), 7.11-7.23 (m, 2 H), 7.28-7.40 (m, 2 H), 7.43-7.60 (m, 2 H) , 7.74-7.81 (m, 2 H), 7.86-7.92 (m, 1 H), 8.27-8.33 (m, 1 H).

Example 84 3- {4-[(2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] phenyl} -1, 2,4-oxadiazol-5 (4H) -one

4-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] -N′- obtained in Reference Example 55 The title compound was obtained from hydroxybenzenecarboximide amide in the same manner as in Example 83.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 5.62 (s, 2 H), 7.17-7.44 (m, 4 H), 7.58-7.68 (m, 3 H), 7.75-7.81 (m, 1 H), 8.35-8.44 (m, 2 H), 12.91 (br s, 1 H).

Example 85 1- [2- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) ethyl] -1H-pyrazole-4 -Ethyl carboxylate

Sodium hydride (50 mg, 60% oily) was added to a solution of ethyl 1H-pyrazole-4-carboxylate (160 mg) in N, N-dimethylformamide (8 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 30 min. . 1- (2-Bromoethyl) -2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (500 mg) obtained in Reference Example 17 was added to the reaction mixture. And stirred at room temperature for 3.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 75:25, v / v) to obtain the title compound (370 mg, yield 65%) as a colorless amorphous.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.22-1.30 (m, 3 H), 4.15-4.25 (m, 2 H), 4.45-4.56 (m, 2 H), 4.67-4.80 (m, 2 H), 7.05-7.11 (m, 1 H), 7.26-7.32 (m, 2 H), 7.49 (s, 1 H), 7.72-8.04 (m, 3 H), 8.32-8.41 (m, 1 H) .

Example 86 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -6-fluoro-1H-benzimidazol-1-yl) butanoic acid

From 4- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -6-fluoro-1H-benzimidazol-1-yl) butanal obtained in Reference Example 59, In the same manner as in Example 58, the title compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.83-1.99 (m, 2 H), 2.26 (t, J = 7.1 Hz, 2 H), 4.24 (t, J = 7.4 Hz, 2 H) , 7.02-7.26 (m, 1 H), 7.63-7.79 (m, 2 H), 8.53 (d, J = 1.5 Hz, 1 H), 8.65 (d, J = 0.9 Hz, 1 H), 12.13 (s , 1 H).

Example 87 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -6-methyl-1H-benzimidazol-1-yl) butanoic acid

From 4- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -6-methyl-1H-benzimidazol-1-yl) butanal obtained in Reference Example 63, In the same manner as in Example 58, the title compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.83-2.00 (m, 2 H), 2.25 (t, J = 7.2 Hz, 2 H), 2.50 (s, 3 H), 4.22 (t, J = 7.4 Hz, 2 H), 7.13 (dd, J = 8.5, 1.1 Hz, 1 H), 7.53 (s, 1 H), 7.59 (d, J = 8.3 Hz, 1 H), 8.51 (d, J = 1.5 Hz, 1 H), 8.63 (dd, J = 2.1, 0.9 Hz, 1 H), 12.15 (br s, 1 H).

Example 88 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -7-fluoro-1H-benzimidazol-1-yl) butanoic acid

From 4- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -7-fluoro-1H-benzimidazol-1-yl) butanal obtained in Reference Example 67, In the same manner as in Example 58, the title compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.85-2.07 (m, 2 H), 2.25 (t, J = 7.1 Hz, 2 H), 4.34 (t, J = 7.3 Hz, 2 H) , 7.14-7.36 (m, 2 H), 7.57 (d, J = 7.5 Hz, 1 H), 8.54 (d, J = 1.9 Hz, 1 H), 8.68 (d, J = 1.1 Hz, 1 H), 12.10 (br s, 1 H).

Example 89 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-methoxy-1H-benzimidazol-1-yl) butanoic acid

From tert-butyl 4- (4-methoxy-2-sulfanyl-1H-benzoimidazol-1-yl) butanoate obtained in Reference Example 70, the same method as in Reference Example 12 was followed by the same as in Example 13. The title compound was obtained by carrying out the method.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.07-2.23 (m, 2 H), 2.40 (t, J = 7.2 Hz, 2 H), 4.01 (s, 3 H), 4.30 (t, J = 7.2 Hz, 2 H), 6.72 (d, J = 7.6 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 7.22-7.35 (m, 1 H), 7.80 (s, 1 H) , 8.32 (s, 1 H). OH proton is not detected.

Example 90 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-imidazo [4,5-c] pyridin-1-yl) butanoic acid

Following the same procedure as in Reference Example 12 from tert-butyl 4- (2-sulfanyl-1H-imidazo [4,5-c] pyridin-1-yl) butanoate obtained in Reference Example 72, Example 13 The title compound was obtained by carrying out the same method as.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.80-2.05 (m, 2 H), 2.26 (t, J = 7.0 Hz, 2 H), 4.30 (t, J = 7.2 Hz, 2 H) , 7.84 (d, J = 5.7 Hz, 1 H), 8.37-8.71 (m, 3 H), 9.07 (s, 1 H), 12.12 (br s, 1 H).

Example 91 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -3H-imidazo [4,5-b] pyridin-3-yl) butanoic acid

From tert-butyl 4- (2-sulfanyl-3H-imidazo [4,5-b] pyridin-3-yl) butanoate obtained in Reference Example 74, a method similar to that in Reference Example 12 was followed by Example 13 The title compound was obtained by carrying out the same method as.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.92-2.10 (m, 2 H), 2.13-2.32 (m, 2 H), 4.30 (t, J = 7.2 Hz, 2 H), 7.39 ( dd, J = 8.0, 4.5 Hz, 1 H), 8.09-8.24 (m, 1 H), 8.46-8.52 (m, 1 H), 8.55 (d, J = 1.9 Hz, 1 H), 8.66 (s, 1 H), 12.04 (s, 1 H).

Example 92 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-imidazo [4,5-b] pyridin-1-yl) butanoic acid

From tert-butyl 4- (2-sulfanyl-1H-imidazo [4,5-b] pyridin-1-yl) butanoate obtained in Reference Example 76, following the same method as in Reference Example 12, Example 13 The title compound was obtained by carrying out the same method as.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.83-2.07 (m, 2 H), 2.27 (t, J = 7.2 Hz, 2 H), 4.33 (t, J = 7.3 Hz, 2 H) , 7.43 (dd, J = 8.3, 4.7 Hz, 1 H), 8.24 (dd, J = 8.2, 1.4 Hz, 1 H), 8.46-8.61 (m, 2 H), 8.66 (d, J = 1.1 Hz, 1 H), 12.14 (br s, 1 H).

Example 93 4- [2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (trifluoromethyl) -1H-benzimidazol-1-yl] butanoic acid

4- [2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (trifluoromethyl) -1H-benzoimidazol-1-yl obtained in Reference Example 80 The title compound was obtained from butanal in the same manner as in Example 58.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.87-2.04 (m, 2 H), 2.21-2.41 (m, 2 H), 4.34 (t, J = 7.3 Hz, 2 H), 7.73 ( dd, J = 8.8, 1.4 Hz, 1 H), 7.99 (d, J = 8.7 Hz, 1 H), 8.13 (s, 1 H), 8.55 (d, J = 1.5 Hz, 1 H), 8.63 (d , J = 0.9 Hz, 1 H), 12.14 (br s, 1 H).

Example 94 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-imidazo [4,5-b] pyridin-1-yl) Butanoic acid

4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-imidazo [4,5-b] pyridine- obtained in Reference Example 84 The title compound was obtained from 1-yl) butanal in the same manner as in Example 58.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.86-2.01 (m, 2 H), 2.12-2.37 (m, 2 H), 2.59 (s, 3 H), 4.28 (t, J = 7.2 Hz, 2 H), 7.29 (d, J = 8.3 Hz, 1 H), 8.09 (d, J = 8.3 Hz, 1 H), 8.54 (d, J = 1.9 Hz, 1 H), 8.64 (s, 1 H), 12.10 (s, 1 H).

Example 95 2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- [3- (methylsulfonyl) propyl] -1H-benzimidazole

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (330 mg), 3- (methylsulfonyl) propyl 4-methyl obtained in Reference Example 5 A mixture of benzenesulfonate (321 mg), cesium carbonate (489 mg), and sodium iodide (150 mg) in N, N-dimethylformamide (10 mL) was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 80: 20-30: 70, v / v), and the obtained residue was crystallized from hexane-ethyl acetate to give the title compound (450 mg, quantitative) Was obtained as a colorless solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.33-2.52 (m, 2 H), 2.87 (s, 3 H), 3.02 (t, J = 7.4 Hz, 2 H), 4.49 (t, J = 7.0 Hz, 2 H), 7.31-7.59 (m, 3 H), 7.82-7.91 (m, 2 H), 8.36 (s, 1 H).

Example 96 4-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] pyridine-2-carboxylate

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (1.50 g) obtained in Reference Example 5 and 4- ( A mixture of ethyl chloromethyl) pyridine-2-carboxylate (1.00 g), cesium carbonate (2.22 g), and sodium iodide (689 mg) in N, N-dimethylformamide (25 mL) was stirred at room temperature for 17 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was crystallized from hexane-ethyl acetate to give the title compound (1.01 g, yield 45%) as a colorless solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.28 (t, J = 7.2 Hz, 3 H), 4.29 (q, J = 6.9 Hz, 2 H), 5.70 (s, 2 H), 7.26 -7.44 (m, 3 H), 7.61 (d, J = 6.8 Hz, 1 H), 7.74-7.85 (m, 2 H), 8.44 (s, 2 H), 8.55 (d, J = 4.9 Hz, 1 H).

Example 97 ethyl 6-[(2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] pyridine-2-carboxylate

From the 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole obtained in Reference Example 5 and ethyl 6- (chloromethyl) pyridine-2-carboxylate In the same manner as in Example 35, the title compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.31 (t, J = 7.2 Hz, 3 H), 4.29 (q, J = 7.2 Hz, 2 H), 5.71 (s, 2 H), 7.27 -7.43 (m, 3 H), 7.74-7.79 (m, 2 H), 7.81-7.89 (m, 2 H), 8.32 (d, J = 1.1 Hz, 1 H), 8.41 (d, J = 1.9 Hz , 1 H).

Example 98 6-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] pyridine-2-carboxylic acid

6-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) methyl] pyridin-2- obtained in Example 97 The title compound was obtained from ethyl carboxylate in the same manner as in Example 36.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 5.69 (s, 2 H), 7.26-7.41 (m, 3 H), 7.66-7.72 (m, 1 H), 7.74-7.79 (m, 1 H), 7.81-7.86 (m, 2 H), 8.41 (s, 2 H), 13.15 (br s, 1 H).

Example 99 4- {2-[(2,4-dichlorophenyl) sulfanyl] -1H-benzoimidazol-1-yl} butanoic acid tert-butyl ester

The title compound was prepared from tert-butyl 4- (2-chloro-1H-benzoimidazol-1-yl) butanoate and 2,4-dichlorobenzenethiol obtained in Reference Example 86 in the same manner as in Reference Example 16. Obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (s, 9 H), 2.05 (quin, J = 7.2 Hz, 2 H), 2.25 (t, J = 7.2 Hz, 2 H), 4.32 (t , J = 7.2 Hz, 2 H), 7.14-7.16 (m, 2 H), 7.28-7.37 (m, 2 H), 7.42-7.46 (m, 2 H), 7.74-7.81 (m, 1 H).

Example 100 4- {2-[(2,4-Dichlorophenyl) sulfanyl] -1H-benzoimidazol-1-yl} butanoic acid

The title compound was obtained from tert-butyl 4- {2-[(2,4-dichlorophenyl) sulfanyl] -1H-benzoimidazol-1-yl} butanoate obtained in Example 99 in the same manner as in Example 13. Got.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.93 (quin, J = 7.3 Hz, 2 H), 2.28 (t, J = 7.3 Hz, 2 H), 4.32 (t, J = 7.3 Hz, 2 H), 7.20-7.36 (m, 3 H), 7.40-7.45 (m, 1 H), 7.65 (t, J = 7.7 Hz, 2 H), 7.80 (d, J = 2.3 Hz, 1 H), 12.17 (br s, 1 H).

Example 101 5- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) pentanoic acid

Examples were obtained from 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole, ethyl 5-bromopentanoate and potassium iodide obtained in Reference Example 5. The title compound was obtained by carrying out the same method as Example 36 following the same method as 35.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.34-1.57 (m, 2 H), 1.64-1.83 (m, 2 H), 2.17 (t, J = 7.3 Hz, 2 H), 4.25 ( t, J = 7.2 Hz, 2 H), 7.22-7.45 (m, 2 H), 7.72 (d, J = 8.3 Hz, 2 H), 8.53 (d, J = 1.9 Hz, 1 H), 8.65 (d , J = 0.9 Hz, 1 H), 11.99 (br s, 1 H).

Example 102 6- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) hexanoic acid

Examples were obtained from 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole, ethyl 6-bromohexanoate and potassium iodide obtained in Reference Example 5. The title compound was obtained by carrying out the same method as Example 36 following the same method as 35.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.16-1.32 (m, 2 H), 1.35-1.50 (m, 2 H), 1.62-1.80 (m, 2 H), 2.10 (t, J = 7.3 Hz, 2 H), 4.23 (t, J = 7.3 Hz, 2 H), 7.23-7.45 (m, 2 H), 7.71 (d, J = 9.2 Hz, 2 H), 8.52 (d, J = 1.9 Hz, 1 H), 8.67 (d, J = 0.9 Hz, 1 H), 11.94 (br s, 1 H).

Example 103 5- [2- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) ethyl] -1,2,5 -Thiadiazolidin-3-one 1,1-dioxide

2- (4-Methoxybenzyl) -1,2,5-thiadiazolidine-3- (II) was added to a suspension of ice-cold 60% sodium hydride (oil, 40.0 mg) in N, N-dimethylformamide (10 mL). On 1,1-dioxide was added and stirred for 30 minutes. 1- (2-Bromoethyl) -2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole (400 mg) obtained in Reference Example 17 was added, Stir at 50 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 50:50, v / v) to give a colorless oil. Trifluoroacetic acid (10 mL) was added to the obtained colorless oil, and the mixture was stirred at 60 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (methanol-ethyl acetate 0: 100 to 10:90, v / v), and the obtained residue was crystallized from hexane-ethyl acetate to give the title compound (203 mg, yield). 40%) was obtained as a colorless solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.45 (t, J = 6.2 Hz, 2 H), 3.95 (s, 2 H), 4.46 (t, J = 6.4 Hz, 2 H), 7.30 -7.35 (m, 1 H), 7.39-7.44 (m, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 8.53 (d, J = 1.5 Hz, 1 H), 8.63 (s, 1 H). NH proton is not detected.

Example 104 5- [3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propyl] -1,2,5 -Thiadiazolidin-3-one 1,1-dioxide

1- (3-Bromopropyl) -2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole obtained in Reference Example 14 and 2- (4- The title compound was obtained from methoxybenzyl) -1,2,5-thiadiazolidin-3-one 1,1-dioxide in the same manner as in Example 103.
^{1 H-NMR (300 MHz,} DMSO-d 6) δ: 1.95 - 2.09 (m, 2 H), 3.06 (t, J = 6.8 Hz, 2 H), 3.89 (s, 2 H), 4.35 (t, J = 7.4 Hz, 2 H), 7.26-7.46 (m, 2 H), 7.68-7.84 (m, 2 H), 8.51 (d, J = 1.9 Hz, 1 H), 8.64 (s, 1 H). NH proton is not detected.

Example 105 2- [2- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) ethyl] -1,2,4 -Oxadiazolidine-3,5-dione

[(Tert-Butoxycarbonyl) oxy] [2- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole-1 obtained in Reference Example 87 To the tert-butyl carbamate (330 mg) was added trifluoroacetic acid (4 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (10 mL). Isocyanatocarbonyl chloride (90 μL) was added with ice cooling, and the mixture was stirred for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 0 to 50:50, v / v), and the obtained residue was crystallized from hexane-ethyl acetate to give the title compound (141 mg, yield). Yield 55%) as a colorless solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 4.01 (t, J = 5.3 Hz, 2 H), 4.56 (t, J = 5.5 Hz, 2 H), 7.22-7.49 (m, 2 H) , 7.73 (d, J = 8.7 Hz, 2 H), 8.52 (d, J = 1.9 Hz, 1 H), 8.62 (s, 1 H), 11.98-12.39 (m, 1 H).

Example 106 2- [3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propyl] -1,2,4 -Oxadiazolidine-3,5-dione

[(Tert-Butoxycarbonyl) oxy] [3- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole-1 obtained in Reference Example 88 The title compound was obtained from tert-butyl carbamate in the same manner as in Example 105.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.02-2.16 (m, 2 H), 3.55-3.66 (m, 2 H), 4.37 (t, J = 7.3 Hz, 2 H), 7.25- 7.47 (m, 2 H), 7.72-7.77 (m, 2 H), 8.50 (d, J = 1.5 Hz, 1 H), 8.61-8.68 (m, 1 H), 12.06 (br s, 1 H).

Example 107 4- [2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (ethylcarbamoyl) -1H-benzimidazol-1-yl] butanoic acid

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -N-ethyl-1- (4-oxobutyl) -1H-benzimidazole-5- obtained in Reference Example 94 The title compound was obtained from carboxamide in the same manner as in Example 58.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.08-1.23 (m, 3 H), 1.85-2.04 (m, 2 H), 2.26 (t, J = 7.0 Hz, 2 H), 3.24- 3.43 (m, 2 H), 4.29 (t, J = 7.4 Hz, 2 H), 7.73-7.84 (m, 1 H), 7.87-7.97 (m, 1 H), 8.25 (s, 1 H), 8.47 -8.59 (m, 2 H), 8.64 (s, 1 H), 12.13 (br s, 1 H).

Example 108 4- [2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (diethylcarbamoyl) -1H-benzimidazol-1-yl] butanoic acid

2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -N, N-diethyl-1- (4-oxobutyl) -1H-benzimidazole- obtained in Reference Example 96 The title compound was obtained from 5-carboxamide in the same manner as in Example 58.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.85-2.06 (m, 2 H), 2.25-2.30 (m, 2 H), 3.26-3.36 (m, 10 H), 4.29 (t, J = 7.4 Hz, 2 H), 7.37 (dd, J = 8.3, 1.5 Hz, 1 H), 7.68 (s, 1 H), 7.79 (d, J = 8.3 Hz, 1 H), 8.53 (d, J = 1.9 Hz, 1 H), 8.65 (s, 1 H), 12.12 (br s, 1 H).

Example 109 4- [2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (morpholin-4-ylcarbonyl) -1H-benzimidazol-1-yl] Butanoic acid

4- [2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (morpholin-4-ylcarbonyl) -1H-benzimidazole- obtained in Reference Example 100 The title compound was obtained from 1-yl] butanal in the same manner as in Example 58.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.85-2.05 (m, 2 H), 2.20-2.35 (m, 2 H), 3.62 (br s, 8 H), 4.29 (t, J = 7.4 Hz, 2 H), 7.39-7.51 (m, 1 H), 7.72-7.88 (m, 2 H), 8.53 (d, J = 1.9 Hz, 1 H), 8.63 (s, 1 H), 12.10 ( br s, 1 H).

Example 110 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-cyano-1H-benzimidazol-1-yl) butanoic acid

From 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1- (4-oxobutyl) -1H-benzimidazole-5-carbonitrile obtained in Reference Example 102, In the same manner as in Example 58, the title compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.86-2.03 (m, 2 H), 2.17-2.34 (m, 2 H), 4.32 (t, J = 7.4 Hz, 2 H), 7.80 ( dd, J = 8.3, 1.5 Hz, 1 H), 7.97 (d, J = 8.3 Hz, 1 H), 8.32 (d, J = 1.5 Hz, 1 H), 8.55 (d, J = 1.9 Hz, 1 H ), 8.65 (s, 1 H), 12.12 (br s, 1 H).

Example 111 (2S) -2-[(tert-butoxycarbonyl) amino] -4- [2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (tri Fluoromethyl) -1H-benzoimidazol-1-yl] butanoic acid methyl ester

Methyl (2S) -2-[(tert-butoxycarbonyl) amino] -4- [2-sulfanyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] butanoic acid obtained in Reference Example 105 Thus, the title compound was obtained in the same manner as in Reference Example 12.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.35-1.47 (m, 9 H), 2.07-2.29 (m, 1 H), 2.36-2.57 (m, 1 H), 3.64 (s, 3 H) , 4.25-4.55 (m, 3 H), 5.21 (br s, 1 H), 7.49-7.60 (m, 1 H), 7.60-7.69 (m, 1 H), 7.87 (d, J = 1.5 Hz, 1 H), 8.11 (s, 1 H), 8.35 (s, 1 H).

Example 112 (2S) -2-[(tert-butoxycarbonyl) amino] -4- [2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (tri Fluoromethyl) -1H-benzimidazol-1-yl] butanoic acid

(2S) -2-[(tert-Butoxycarbonyl) amino] -4- [2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl}-obtained in Example 111 The title compound was obtained from methyl 5- (trifluoromethyl) -1H-benzoimidazol-1-yl] butanoate in the same manner as in Example 36.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.36 (s, 9 H), 2.00-2.30 (m, 2 H), 3.76-3.88 (m, 1 H), 4.28-4.51 (m, 2 H), 7.31 (d, J = 7.9 Hz, 1 H), 7.71 (d, J = 8.7 Hz, 1 H), 7.99 (d, J = 8.7 Hz, 1 H), 8.12 (s, 1 H), 8.55 (s, 1 H), 8.61 (s, 1 H), 12.56 (br s, 1 H).

Example 113 (2S) -2- (acetylamino) -4- [2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (trifluoromethyl) -1H -Benzoimidazol-1-yl] butanoic acid methyl ester

(2S) -2-[(tert-Butoxycarbonyl) amino] -4- [2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl}-obtained in Example 111 Trifluoroacetic acid (7 mL) was added to methyl 5- (trifluoromethyl) -1H-benzoimidazol-1-yl] butanoate (1.04 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (methanol-ethyl acetate 0: 100 to 10:90, v / v) to give a yellow oil (1.08 g). A mixture of the obtained yellow oil (182 mg) and acetyl chloride (73 μL) in pyridine (1 mL) was stirred at room temperature for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-0: 100, v / v) to give the title compound (150 mg, yield 76%) as a colorless solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.95 (s, 3 H), 2.14-2.35 (m, 1 H), 2.43-2.54 (m, 1 H), 3.59 (s, 3 H), 4.24 -4.50 (m, 2 H), 4.55-4.73 (m, 1 H), 6.21 (d, J = 7.2 Hz, 1 H), 7.49-7.61 (m, 1 H), 7.62-7.71 (m, 1 H ), 7.89 (d, J = 2.3 Hz, 1 H), 8.11 (s, 1 H), 8.35 (s, 1 H).

Example 114 (2S) -2- (acetylamino) -4- [2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (trifluoromethyl) -1H -Benzimidazol-1-yl] butanoic acid

(2S) -2- (acetylamino) -4- [2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (trifluoro) obtained in Example 113 The title compound was obtained in the same manner as in Example 36 from methyl) -1H-benzoimidazol-1-yl] butanoate.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.81 (s, 3 H), 2.00-2.13 (m, 1 H), 2.16-2.35 (m, 1 H), 4.05-4.17 (m, 1 H), 4.28-4.51 (m, 2 H), 7.74 (dd, J = 8.7, 1.5 Hz, 1 H), 7.94 (d, J = 8.7 Hz, 1 H), 8.13 (s, 1 H), 8.27 (d, J = 7.9 Hz, 1 H), 8.56 (d, J = 1.5 Hz, 1 H), 8.62 (s, 1 H), 12.67 (br s, 1 H).

Example 115 (2S) -4- [2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (trifluoromethyl) -1H-benzimidazol-1-yl ] -2-[(Methoxycarbonyl) amino] butanoic acid

(2S) -2-[(tert-Butoxycarbonyl) amino] -4- [2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl}-obtained in Example 111 5- (Trifluoromethyl) -1H-benzoimidazol-1-yl] butanoate and methyl chloroformate were carried out in the same manner as in Example 113, followed by the same method as in Example 36. A compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.00-2.15 (m, 1 H), 2.17-2.31 (m, 1 H), 3.52 (s, 3 H), 3.83-3.97 (m, 1 H), 4.31-4.52 (m, 2 H), 7.64 (d, J = 8.3 Hz, 1 H), 7.73 (dd, J = 8.7, 1.5 Hz, 1 H), 7.98 (d, J = 8.7 Hz, 1 H), 8.13 (s, 1 H), 8.55 (d, J = 1.5 Hz, 1 H), 8.61 (s, 1 H), 12.67 (br s, 1 H).

Example 116 (5S) -5- {2- [2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (trifluoromethyl) -1H-benzimidazole- 1-yl] ethyl} -3-ethylimidazolidine-2,4-dione

(2S) -2-[(tert-Butoxycarbonyl) amino] -4- [2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl}-obtained in Example 111 Trifluoroacetic acid (7 mL) was added to methyl 5- (trifluoromethyl) -1H-benzoimidazol-1-yl] butanoate (1.04 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (methanol-ethyl acetate 0: 100 to 10:90, v / v) to give a yellow oil (1.08 g). A mixture of the obtained yellow oil (200 mg) and commercially available ethyl isocyanate (93 μL) in N, N-dimethylformamide (5 mL) was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The obtained residue was subjected to silica gel column chromatography (hexane-ethyl acetate 90: 10-20: 80, v / v) to give a colorless solid (150 mg). A mixture of the obtained colorless solid (140 mg) and 2N aqueous lithium hydroxide solution (0.5 mL) in tetrahydrofuran (10 mL) was stirred at 50 ° C. for 2 hr. The reaction mixture was acidified with 1N hydrochloric acid in an ice-water bath and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 0 to 40:60, v / v) and crystallized from hexane-ethyl acetate to give the title compound (37 mg, yield 18%). Obtained as a colorless solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.11-1.23 (m, 3 H), 2.23-2.55 (m, 2 H), 3.51 (q, J = 7.2 Hz, 2 H), 3.93- 4.08 (m, 1 H), 4.34-4.62 (m, 2 H), 6.32 (s, 1 H), 7.60-7.75 (m, 2 H), 7.89 (d, J = 1.5 Hz, 1 H), 8.11 (s, 1 H), 8.37 (s, 1 H).

Example 117 4- {2-[(3,5,6-Trichloropyridin-2-yl) sulfanyl] -1H-benzimidazol-1-yl} ethyl butanoate

In the same manner as in Example 35, the title compound was obtained from 2-[(3,5,6-trichloropyridin-2-yl) sulfanyl] -1H-benzimidazole and ethyl 4-bromobutanoate obtained in Reference Example 106. Got.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.24 (t, J = 7.2 Hz, 3 H), 2.10-2.26 (m, 2 H), 2.29-2.40 (m, 2 H), 4.11 (q, J = 7.2 Hz, 2 H), 4.35 (t, J = 7.2 Hz, 2 H), 7.29-7.45 (m, 2 H), 7.51 (d, J = 7.5 Hz, 1 H), 7.73 (s, 1 H), 7.82 (d, J = 7.2 Hz, 1 H).

Example 118 4- {2-[(3,5,6-trichloropyridin-2-yl) sulfanyl] -1H-benzimidazol-1-yl} butanoic acid

Similar to Example 36 from ethyl 4- {2-[(3,5,6-trichloropyridin-2-yl) sulfanyl] -1H-benzimidazol-1-yl} butanoate obtained in Example 117 The title compound was obtained by the method.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.88-1.98 (m, 2 H), 2.18-2.34 (m, 2 H), 4.29 (t, J = 7.5 Hz, 2 H), 7.23- 7.52 (m, 2 H), 7.73 (t, J = 7.0 Hz, 2 H), 8.51 (s, 1 H), 12.12 (s, 1 H).

Example 119 4- (2-{[6-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzoimidazol-1-yl) butanoic acid

The same method as in Example 35, from 2-{[6-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole and ethyl 4-bromobutanoate obtained in Reference Example 107 Subsequent to the same method as in Example 36, the title compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.86-2.02 (m, 2 H), 2.19-2.32 (m, 2 H), 4.36 (t, J = 7.4 Hz, 2 H), 7.28- 7.47 (m, 3 H), 7.71-7.83 (m, 2 H), 8.19 (d, J = 8.3 Hz, 1 H), 12.76 (s, 1 H).

Example 120 4- [2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5- (2-methoxyethoxy) -1H-benzimidazol-1-yl] butanoic acid

From methyl 4- [5- (2-methoxyethoxy) -2-sulfanyl-1H-benzoimidazol-1-yl] butanoate obtained in Reference Example 112, following the same method as in Reference Example 12, Example 36 The title compound was obtained by carrying out the same method as.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.80-1.98 (m, 2 H), 2.24 (t, J = 7.2 Hz, 2 H), 3.26-3.36 (m, 3 H), 3.58- 3.79 (m, 2 H), 4.08-4.33 (m, 4 H), 7.04 (dd, J = 8.9, 2.4 Hz, 1 H), 7.23 (d, J = 2.3 Hz, 1 H), 7.62 (d, J = 9.0 Hz, 1 H), 8.52 (d, J = 1.5 Hz, 1 H), 8.65 (s, 1 H), 12.11 (br s, 1 H).

Example 121 3- {3-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) methyl] Phenyl} -1,2,4-oxadiazol-5 (4H) -one

3-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) methyl obtained in Reference Example 115 The title compound was obtained from] -N′-hydroxybenzenecarboxmidamide in the same manner as in Example 83.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.11 (s, 3 H), 2.14 (s, 3 H), 5.24 (s, 2 H), 7.24-7.39 (m, 1 H), 7.39 -7.53 (m, 2 H), 7.62 (d, J = 8.0 Hz, 1 H), 8.28-8.39 (m, 1 H), 8.54 (s, 1 H), 13.00 (br s, 1 H).

Example 122 tert-Butyl 3- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) propionate

3-Chloro-2-[(4,5-dimethyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine, cesium carbonate and tert-bromopropionic acid obtained in Reference Example 113 The title compound was obtained from -butyl in the same manner as in Example 12.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.35-1.45 (m, 9H), 2.24 (d, J = 13.2 Hz, 6H), 2.55-2.66 (m, 2H), 4.08-4.20 (m, 2H ), 7.77 (d, J = 1.5 Hz, 1H), 8.40-8.46 (m, 1H).

Example 123 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) propionic acid

3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) propionic acid obtained in Example 122 The title compound was obtained from tert-butyl in the same manner as in Example 13.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.07 (s, 3 H), 2.22 (s, 3 H), 2.58 (t, J = 7.5 Hz, 2 H), 4.09 (t, J = 7.6 Hz, 2 H), 8.45 (d, J = 1.5 Hz, 1 H), 8.70 (d, J = 0.9 Hz, 1 H), 12.41 (br s, 1 H).

Example 124 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-phenyl-1H-imidazol-1-yl) propionic acid

From 3-chloro-2-[(4-phenyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine obtained in Reference Example 116, following the same method as in Example 12, The title compound was obtained by carrying out the same method as in Example 13.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.82 (d, J = 14.1 Hz, 2 H), 4.20 (d, J = 14.1 Hz, 2 H), 7.25 (t, J = 7.3 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.76 (d, J = 7.2 Hz, 2 H), 8.15 (s, 1 H), 8.50 (d, J = 2.1 Hz, 1 H) , 8.70 (d, J = 1.1 Hz, 1 H), 12.54 (br s, 1 H).

Example 125 tert-Butyl 4- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-phenyl-1H-imidazol-1-yl) butanoate

From the 3-chloro-2-[(4-phenyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine obtained in Reference Example 116, the title was prepared in the same manner as in Example 12. A compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.32 (s, 9 H), 1.96 (quin, J = 6.8 Hz, 2 H), 2.22 (t, J = 7.3 Hz, 2 H), 4.00 (t, J = 7.2 Hz, 2 H), 7.19-7.29 (m, 1 H), 7.38 (t, J = 7.6 Hz, 2 H), 7.72-7.83 (m, 2 H), 8.13 (s, 1 H), 8.47-8.52 (m, 1 H), 8.68 (dd, J = 2.0, 0.8 Hz, 1 H).

Example 126 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-phenyl-1H-imidazol-1-yl) butanoic acid

4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-phenyl-1H-imidazol-1-yl) butanoic acid tert- The title compound was obtained from butyl in the same manner as in Example 13.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.98 (quin, J = 7.1 Hz, 2 H), 2.24 (d, J = 14.5 Hz, 2 H), 4.02 (t, J = 7.2 Hz, 2 H), 7.20-7.28 (m, 1 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.78 (d, J = 7.2 Hz, 2 H), 8.16 (s, 1 H), 8.49 ( d, J = 1.3 Hz, 1 H), 8.68 (d, J = 0.9 Hz, 1 H), 12.10 (br s, 1 H).

Example 127 tert-Butyl 4- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) butanoate

3-Chloro-2-[(4,5-dimethyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine obtained in Reference Example 113 was used in the same manner as in Example 12. The title compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.31 (s, 9 H), 1.69-1.83 (m, 2 H), 2.08 (s, 3 H), 2.14-2.24 (m, 5 H) 3.86 (t, J = 7.3 Hz, 2 H), 8.45 (d, J = 1.5 Hz, 1 H), 8.70 (d, J = 0.9 Hz, 1 H).

Example 128 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) butanoic acid

4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) butanoic acid obtained in Example 127 The title compound was obtained from tert-butyl in the same manner as in Example 13.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.76 (quin, J = 7.5 Hz, 2 H), 2.08 (s, 3 H), 2.14-2.25 (m, 5 H), 3.87 (t, J = 7.5 Hz, 2 H), 8.43 (d, J = 1.5 Hz, 1 H), 8.69 (d, J = 0.9 Hz, 1 H), 12.10 (br s, 1 H).

Example 129 3-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) methyl] methyl benzoate

3-chloro-2-[(4,5-dimethyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine (1.45 g), 3- (bromomethyl) obtained in Reference Example 113 A mixture consisting of methyl benzoate (1.62 g), cesium carbonate (3.08 g) and acetonitrile (20 mL) was stirred at 40 ° C. for 1 hour. 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 19: 1-7: 3, v / v) and crystallized from ethyl acetate-hexane to give the title compound (1.86 g, yield 86%). Obtained as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.09 (s, 3 H), 2.26 (s, 3 H), 3.90 (s, 3 H), 5.20 (s, 2 H), 7.18-7.25 (m , 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.71 (d, J = 1.5 Hz, 1 H), 7.79 (s, 1 H), 7.89 (d, J = 7.9 Hz, 1 H ), 8.38 (dd, J = 2.0, 0.8 Hz, 1 H).

Example 130 3-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) methyl] benzoic acid

3-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) methyl obtained in Example 129 The title compound was obtained from methyl benzoate in the same manner as in Example 36.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.08 (s, 3 H), 2.13 (s, 3 H), 5.24 (s, 2 H), 7.31 (d, J = 7.7 Hz, 1 H ), 7.40 (t, J = 7.7 Hz, 1 H), 7.64 (s, 1 H), 7.75 (d, J = 7.7 Hz, 1 H), 8.34 (d, J = 1.7 Hz, 1 H), 8.54 (dd, J = 1.9, 0.9 Hz, 1 H), 13.01 (br s, 1 H).

Example 131 6-[(2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) methyl] pyridine-2 -carboxylic acid

N, N-dimethyl of 3-chloro-2-[(4,5-dimethyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine (1.25 g) obtained in Reference Example 113 While stirring the formamide solution, 60% sodium hydride (oily, 170 mg) was added. The reaction mixture was stirred at room temperature for 30 min, ethyl 6- (chloromethyl) pyridine-2-carboxylate (974 mg) was added, and the mixture was further stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 9: 1 to 2: 3, v / v), and the solvent was distilled off to obtain a colorless oil. This oil was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (5 mL), lithium hydroxide monohydrate (201 mg) was added, and the mixture was stirred at 50 ° C. for 4 hr. The reaction mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was crystallized from hexane-ethyl acetate to give the title compound (175 mg, yield 25%) as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.13 (s, 3 H), 2.20 (s, 3 H), 5.29 (s, 2 H), 7.15 (t, J = 4.3 Hz, 1 H ), 7.78-7.88 (m, 2 H), 8.35 (d, J = 1.5 Hz, 1 H), 8.45 (s, 1 H), 13.15 (br s, 1 H).

Example 132 (2E) -3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4,5-dimethyl-1H-imidazol-1-yl) acrylic acid

In the same manner as in Example 28, 3-chloro-2-[(4,5-dimethyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine obtained in Reference Example 113 was used. The title compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.14 (s, 3 H), 2.36 (s, 3 H), 6.15 (d, J = 14.5 Hz, 1 H), 7.79 (d, J = 14.5 Hz, 1 H), 8.51 (d, J = 1.9 Hz, 1 H), 8.73 (dd, J = 1.8, 0.8 Hz, 1 H), 12.65 (br s, 1 H).

Example 133 tert-Butyl 3- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-methyl-1H-imidazol-1-yl) propionate

Example 134 tert-Butyl 3- (2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-imidazol-1-yl) propionate

  3-chloro-2-[(4-methyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine, cesium carbonate and tert-butyl 3-bromopropionate obtained in Reference Example 117 To silica gel chromatography (hexane-ethyl acetate), and the title compound (Example 133) was obtained as a white solid from the fraction having a short retention time. It was. Subsequently, the title compound (Example 134) was obtained as a white solid from the fraction having a long retention time.

Example 133 (small holding time)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.43 (s, 9 H), 2.26 (s, 3 H), 2.66 (t, J = 6.9 Hz, 2 H), 4.20 (t, J = 6.9 Hz , 2 H), 7.00 (s, 1 H), 7.78 (d, J = 1.5 Hz, 1 H), 8.44 (s, 1 H).

Example 134 (long holding time)
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.31 (s, 9 H), 2.29 (d, J = 0.6 Hz, 3 H), 2.60 (t, J = 7.4 Hz, 2 H), 4.13 (t, J = 7.4 Hz, 2 H), 6.93 (d, J = 0.8 Hz, 1 H), 8.48 (d, J = 1.9 Hz, 1 H), 8.70 (d, J = 0.9 Hz, 1 H) .

Example 135 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-methyl-1H-imidazol-1-yl) propionic acid

3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-methyl-1H-imidazol-1-yl) propionic acid tert--obtained in Example 133 The title compound was obtained as a trifluoroacetate salt from butyl in the same manner as in Example 13.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.24 (s, 3 H), 2.77 (t, J = 6.9 Hz, 2 H), 4.22 (t, J = 6.9 Hz, 2 H), 7.61 (s, 1 H), 8.56 (d, J = 1.9 Hz, 1 H), 8.69-8.77 (m, 1 H), 12.53 (br s, 1 H).

Example 136 3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-imidazol-1-yl) propionic acid

3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-imidazol-1-yl) propionic acid tert- The title compound was obtained from butyl in the same manner as in Example 13.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.29 (d, J = 0.8 Hz, 3 H), 2.61 (t, J = 7.6 Hz, 2 H), 4.13 (t, J = 7.6 Hz, 2 H), 6.94 (d, J = 0.9 Hz, 1 H), 8.46 (d, J = 1.5 Hz, 1 H), 8.68 (dd, J = 1.9, 0.9 Hz, 1 H), 12.41 (s, 1 H).

Example 137 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-methyl-1H-imidazol-1-yl) butanoic acid tert-butyl

Example 138 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-imidazol-1-yl) butanoic acid tert-butyl

  From 3-chloro-2-[(4-methyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine, cesium carbonate and tert-butyl 4-bromobutanoate obtained in Reference Example 117 The reaction was carried out in the same manner as in Example 17 and Example 18, and the product was subjected to silica gel chromatography (hexane / ethyl acetate) to give the title compound (Example 137) from the fraction having a short retention time. Subsequently, the title compound (Example 138) was obtained from the fraction having a long retention time.

Example 137 (holding time is short)
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.31 (s, 9 H), 1.85 (quin, J = 7.2 Hz, 2 H), 2.07-2.20 (m, 5 H), 3.88 (t, J = 7.2 Hz, 2 H), 7.30 (s, 1 H), 8.46 (d, J = 1.5 Hz, 1 H), 8.68 (dd, J = 1.9, 0.8 Hz, 1 H).

Example 138 (long holding time)
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.32 (s, 9 H), 1.78 (quin, J = 7.3, 7.3, 7.1 Hz, 2 H), 2.20 (t, J = 7.0 Hz, 2 H), 2.27 (d, J = 0.8 Hz, 3 H), 3.90 (t, J = 7.6 Hz, 2 H), 6.94 (d, J = 0.9 Hz, 1 H), 8.46 (dd, J = 2.1, 0.6 Hz, 1 H), 8.68 (dd, J = 2.0, 0.8 Hz, 1 H).

Example 139 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-methyl-1H-imidazol-1-yl) butanoic acid

4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-methyl-1H-imidazol-1-yl) butanoic acid tert-obtained in Example 137 The title compound was obtained as a trifluoroacetate salt from butyl in the same manner as in Example 13.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.92 (quin, J = 7.2 Hz, 2 H), 2.21 (t, J = 7.2 Hz, 2 H), 2.25 (s, 3 H), 4.05 (t, J = 7.2 Hz, 2 H), 7.64 (s, 1 H), 8.56 (d, J = 1.9 Hz, 1 H), 8.66-8.75 (m, 1 H), 12.12 (br s, 1 H ).

Example 140 4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-imidazol-1-yl) butanoic acid

4- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-imidazol-1-yl) butanoic acid tert- obtained in Example 138 The title compound was obtained as a 0.5 trifluoroacetate salt from butyl in the same manner as in Example 13.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.81 (quin, J = 7.2 Hz, 2 H), 2.25 (t, J = 7.2 Hz, 2 H), 2.35 (s, 3 H), 4.04 (t, J = 7.2 Hz, 2 H), 7.35 (s, 1 H), 8.54 (d, J = 1.7 Hz, 1 H), 8.70 (d, J = 0.9 Hz, 1 H), 12.14 (br s , 1 H).

Example 141 4- {2-[(3,5-dichloropyridin-2-yl) sulfanyl] -4,5-dimethyl-1H-imidazol-1-yl} butanoic acid tert-butyl ester

From the 3,5-dichloro-2-[(4,5-dimethyl-1H-imidazol-2-yl) sulfanyl] pyridine, tert-butyl 4-bromobutanoate and cesium carbonate obtained in Reference Example 118, Example 12 In the same manner as described above, the title compound was obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.33 (s, 9 H), 1.75 (quin, J = 7.4 Hz, 2 H), 2.07 (s, 3 H), 2.13-2.22 (m, 5 H), 3.85 (t, J = 7.4 Hz, 2 H), 8.24 (d, J = 1.9 Hz, 1 H), 8.38 (d, J = 2.3 Hz, 1 H).

Example 142 4- {2-[(3,5-dichloropyridin-2-yl) sulfanyl] -4,5-dimethyl-1H-imidazol-1-yl} butanoic acid

Performed from tert-butyl 4- {2-[(3,5-dichloropyridin-2-yl) sulfanyl] -4,5-dimethyl-1H-imidazol-1-yl} butanoate obtained in Example 141 In the same manner as in Example 13, the title compound was obtained as a trifluoroacetate salt.
^{1 H-NMR (300 MHz,} DMSO-d 6) δ: 1.81 (quin, J = 7.5 Hz, 2 H), 2.22 - 2.30 (m, 5 H), 2.32 (s, 3 H), 4.08 (t, J = 7.5 Hz, 2 H), 8.38 (d, J = 1.9 Hz, 1 H), 8.42 (d, J = 1.9 Hz, 1 H), 12.18 (br s, 1 H).

Example 143 4- (5-chloro-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-phenyl-1H-imidazol-1-yl) butanoic acid tert- Butyl

Example 144 4- (4-Chloro-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-phenyl-1H-imidazol-1-yl) butanoic acid tert- Butyl

  3-chloro-2-[(5-chloro-4-phenyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine, cesium carbonate and 4-bromobutanoic acid obtained in Reference Example 119 The reaction is carried out from tert-butyl in the same manner as in Example 17 and Example 18, and subjected to silica gel chromatography (hexane-ethyl acetate) to give the title compound (Example 143) from the fraction having a short retention time. It was. Subsequently, the title compound (Example 144) was obtained from the fraction having a long retention time.

Example 143 (small holding time)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.42 (s, 9 H), 2.06 (quin, J = 7.2 Hz, 2 H), 2.28 (t, J = 7.2 Hz, 2 H), 4.12 (t , J = 7.2 Hz, 2 H), 7.27-7.34 (m, 1 H), 7.38-7.45 (m, 2 H), 7.81 (d, J = 1.5 Hz, 1 H), 7.95-8.03 (m, 2 H), 8.44 (dd, J = 1.9, 1.1 Hz, 1 H).

Example 144 (long holding time)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.33 (s, 9 H), 1.77 (quin, J = 7.3 Hz, 2 H), 2.02 (t, J = 7.3 Hz, 2 H), 4.03 (t , J = 7.3 Hz, 2 H), 7.42-7.58 (m, 5 H), 7.81 (d, J = 1.5 Hz, 1 H), 8.50 (dd, J = 1.9, 1.1 Hz, 1 H).

Example 145 4- (5-chloro-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-phenyl-1H-imidazol-1-yl) butanoic acid

4- (5-Chloro-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-phenyl-1H-imidazol-1-yl) obtained in Example 143 The title compound was obtained from tert-butyl butanoate in the same manner as in Example 13.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.91 (quin, J = 7.3 Hz, 2 H), 2.28 (t, J = 7.3 Hz, 2 H), 4.09 (t, J = 7.3 Hz, 2 H), 7.29-7.39 (m, 1 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.83-7.97 (m, 2 H), 8.51 (d, J = 1.5 Hz, 1 H), 8.75 (dd, J = 1.9, 0.8 Hz, 1 H), 12.16 (br s, 1 H).

Example 146 4- (4-Chloro-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-phenyl-1H-imidazol-1-yl) butanoic acid

4- (4-Chloro-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-phenyl-1H-imidazol-1-yl) obtained in Example 144 The title compound was obtained from tert-butyl butanoate in the same manner as in Example 13.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.58 (quin, J = 7.3 Hz, 2 H), 1.99 (t, J = 7.2 Hz, 2 H), 4.03 (t, J = 7.2 Hz, 2 H), 7.47-7.62 (m, 5 H), 8.51 (d, J = 1.5 Hz, 1 H), 8.78 (dd, J = 1.9, 1.1 Hz, 1 H), 12.03 (br s, 1 H) .

Example 147 4- (5-chloro-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-methyl-1H-imidazol-1-yl) butanoic acid

Example 148 4- (4-Chloro-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-imidazol-1-yl) butanoic acid

  3-chloro-2-[(5-chloro-4-methyl-1H-imidazol-2-yl) sulfanyl] -5- (trifluoromethyl) pyridine, tert-butyl 4-bromobutanoate obtained in Reference Example 120 The mixture of the title compounds (Example 147 and Example 148) was obtained from cesium carbonate by following the same method as in Example 12 and then the same method as in Example 13. The obtained mixture was purified using preparative HPLC (same preparative conditions as in Example 30), and the title compound (Example 147) was obtained from the fraction having a short retention time. Subsequently, the title compound (Example 148) was obtained from the fraction having a long retention time.

Example 147 (short holding time)
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.71-1.86 (m, 2 H), 2.17-2.30 (m, 5 H), 3.96 (t, J = 7.6 Hz, 2 H), 8.45- 8.50 (m, 1 H), 8.72 (dd, J = 1.9, 0.8 Hz, 1 H), 12.14 (br s, 1 H).

Example 148 (long holding time)
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.73-1.85 (m, 2 H), 2.22 (t, J = 7.0 Hz, 2 H), 2.27 (s, 3 H), 3.96 (t, J = 7.5 Hz, 2 H), 8.48 (d, J = 1.5 Hz, 1 H), 8.72 (dd, J = 1.9, 0.8 Hz, 1 H), 12.14 (br s, 1 H).

Example 149 4- (5-Bromo-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -4-methyl-1H-imidazol-1-yl) butanoic acid

Example 150 4- (4-Bromo-2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -5-methyl-1H-imidazol-1-yl) butanoic acid

  2-[(5-Bromo-4-methyl-1H-imidazol-2-yl) sulfanyl] -3-chloro-5- (trifluoromethyl) pyridine, tert-butyl 4-bromobutanoate obtained in Reference Example 121 Then, the mixture of title compounds (Example 149 and Example 150) was obtained from cesium carbonate by following the procedure of Example 12 and the same method as in Example 13. The obtained mixture was purified using preparative HPLC (preparation conditions similar to those of Example 30), and the title compound (Example 149) was obtained from the fraction having a short retention time. Subsequently, the title compound (Example 150) was obtained from the fraction having a long retention time.

Example 149 (short holding time)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.98-2.11 (m, 2 H), 2.26 (s, 3 H), 2.38 (t, J = 7.3 Hz, 2 H), 4.04-4.10 (m, 2 H), 7.79 (d, J = 1.5 Hz, 1 H), 8.44 (d, J = 0.9 Hz, 1 H).

Example 150 (long holding time)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.94-2.07 (m, 2 H), 2.33 (s, 3 H), 2.40 (t, J = 7.0 Hz, 2 H), 3.98-4.05 (m, 2 H), 7.79 (d, J = 1.5 Hz, 1 H), 8.42-8.44 (m, 1 H).

Example 151 [3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propyl] diethyl phosphonate

Similar to Example 12 from 2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazole and diethyl 3-bromopropylphosphonate obtained in Reference Example 5. The title compound was obtained by this method.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.27 (t, J = 7.1 Hz, 6 H), 1.67-1.80 (m, 2 H), 2.10-2.22 (m, 2 H), 3.98-4.11 ( m, 4 H), 4.36 (t, J = 7.3 Hz, 2 H), 7.30-7.43 (m, 2 H), 7.50-7.54 (m, 1 H), 7.81-7.88 (m, 2 H), 8.35 (d, J = 0.9 Hz, 1 H).

Example 152 [3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propyl] phosphonic acid

[3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propyl] phosphonic acid diethyl ester obtained in Example 151 ( 200 mg), sodium iodide (413 mg), and acetonitrile (5 mL) were added to a mixture of trimethylsilyl chloride (299 mg), and the mixture was stirred at room temperature for 12 hours under a nitrogen atmosphere. Water (10 mL) was added to the reaction solution, and the mixture was heated to reflux for 10 minutes and then cooled to room temperature. The reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified using preparative HPLC (preparation conditions similar to those of Example 30) to obtain the trifluoroacetate salt of the title compound (74 mg, yield 33%) as a colorless amorphous solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.44-1.58 (m, 2 H), 1.85-2.02 (m, 2 H), 4.34 (t, J = 7.2 Hz, 2 H), 7.28- 7.45 (m, 2 H), 7.71-7.82 (m, J = 18.3, 7.9 Hz, 2 H), 8.53 (d, J = 1.5 Hz, 1 H), 8.62-8.65 (m, 1 H), 10.34 ( br s, 2 H).

Example 153 3- [3- (2-{[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl} -1H-benzimidazol-1-yl) propyl] -1,3-thiazolidine -2,4-dione

To a tetrahydrofuran solution (5 mL) of 1,3-thiazolidine-2,4-dione (195 mg) was added n-butyllithium hexane solution (2.1 mL) at -78 ° C, and the mixture was stirred for 15 minutes. Stir for 30 minutes. After the reaction solution was cooled again to -78 ° C, 1- (3-bromopropyl) -2-{[3-chloro-5- (trifluoromethyl) pyridin-2-yl] sulfanyl obtained in Reference Example 14 was obtained. } -1H-benzimidazole (500 mg) was added, and the mixture was stirred for 30 minutes, and further stirred at room temperature for 15 hours. Tetrabutylammonium iodide (328 mg) was added to the reaction mixture, and the mixture was stirred at 60 ° C. for 15 hr. 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 saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 19: 1-7: 3, v / v) to give the title compound (4.0 mg, yield 1%) as a colorless powder.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.92-2.04 (m, 2 H), 3.46-3.59 (m, 2 H), 4.08 (s, 2 H), 4.21-4.32 (m, 2 H), 7.25-7.44 (m, 2 H), 7.67-7.78 (m, 2 H), 8.54 (d, J = 1.9 Hz, 1 H), 8.63 (d, J = 0.9 Hz, 1 H).

Test Example 1 PPARγ-RXRα Heterodimer Ligand Activity PPARγ: RXRα: 4ERPP / CHO-K1 cells described in WO03 / 099973 were treated with 10% fetal calf serum (Life Technologies, Inc., USA). After culturing with Ham's F12 medium (Life Technologies, Inc., USA) containing 1 × 10 ⁴ cells / 96 well white half area plate (Corning Coster Corporation, USA) It seed | inoculated so that it might become well, and it culture | cultivated overnight in a 37 degreeC carbon dioxide incubator.

  Next, after removing the medium from the 96-well white half area plate, 45 μl of Ham's F12 medium containing 0.1% fatty acid-free bovine serum albumin (BSA) and 5 μl of the test compound are added, and in a 37 ° C. carbon dioxide incubator. For 1 day. After removing the medium, 20 μl of Biccagene 7.5 (manufactured by Wako Pure Chemical Industries, Ltd.) diluted 2-fold with HBSS (HANKS 'BALANCED SALT SOLUTION) [manufactured by BIO WHITTAKER, USA] was added, and after stirring, 1420 ARVO Luciferase activity was measured using a Multilabel Counter (PerkinElmer, USA).

The induction ratio was calculated from the luciferase activity of each test compound when the luciferase activity of the test compound non-administered group was 1. By analyzing the concentration of the test compound and the value of induction ratio using Prism (manufactured by GraphPad Software, Inc., USA), the EC ₅₀ value of the test compound (maximum induction ratio) Compound concentration showing 50% of the value) was calculated. The results are shown in Table 1.

  Thus, the compound of the present invention was shown to have excellent PPARγ-RXRα heterodimer ligand activity.

Formulation Example 1 (Manufacture of capsules)
1) 30 mg of the compound of Example 1
2) Fine powder cellulose 10mg
3) Lactose 19mg
4) Magnesium stearate 1mg
60mg total
1), 2), 3) and 4) are mixed and filled into gelatin capsules.

Formulation Example 2 (Manufacture of tablets)
1) 30 g of the compound of Example 1
2) Lactose 50g
3) Corn starch 15g
4) Carboxymethylcellulose calcium 44g
5) Magnesium stearate 1g
1000 tablets total 140g
The total amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, and after vacuum drying, the particles are sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

  The compound of the present invention is useful as a preventive or therapeutic agent for diabetes having an excellent blood glucose lowering effect and few side effects such as weight gain.

Claims (13)

Formula (I)

[Where:
A is the formula

(Where
R ^6a and R ^6b are independently of the formula —CO—OR ^A1 ,
-CO-NR ^A2 R ^B2 ,
-SOR ^A1 ,
—SO ₂ R ^A1 ,
-SO ₃ R ^A1 ,
—SO ₂ NR ^A2 R ^B2 , or —PO ₃ R ^A1 R ^B1
(Wherein, R ^A1 and R ^B1 are independently a hydrogen atom, a an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,; R ^A2 and R ^B2 are, independently A hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or R ^A2 and R ^B2 are substituted together with the adjacent nitrogen atom; Or a nitrogen-containing heterocycle may be formed.)
Or a 5- to 7-membered heterocyclic group which may be substituted;
R ^4a , R ^5a , R ^4b and R ^5b are
(1) Independently, (a) a hydrogen atom, (b) a halogen atom, (c) an optionally substituted C _1-6 alkyl group, (d) an optionally substituted C _1-6 alkoxy group (E) represents an optionally substituted 5- or 6-membered ring group, (f) a cyano group, or (g) an optionally amidated carboxy group, or
(2) R ^4a and R ^5a are combined with adjacent carbon atoms to form a benzene ring or a pyridine ring (the benzene ring and the pyridine ring are (a) a halogen atom, (b) an optionally substituted C ₁ 1 to 3 substituents selected from a _-6 alkyl group, (c) an optionally substituted C _1-6 alkoxy group, (d) a cyano group, and (e) an optionally amidated carboxy group Or (3) R ^4b and R ^5b together with adjacent carbon atoms can be combined with a benzene ring or a pyridine ring (the benzene ring and the pyridine ring are (A) a halogen atom, (b) an optionally substituted C _1-6 alkyl group, (c) an optionally substituted C _1-6 alkoxy group, (d) a cyano group, and (e) an amide May be . It 1 selected from carboxy group in 3 substituents may be substituted, respectively) may be formed;
R ⁷ represents a hydrogen atom, an optionally halogenated C _1-6 alkyl group, or an optionally halogenated C _3-10 cycloalkyl group; and L ^1a and L ^1b are independently (A) a halogen atom, (b) a hydroxy group, and (c) a substituent selected from a C _1-6 alkyl group, a C _1-6 alkyl-carbonyl group, and a C _1-6 alkoxy-carbonyl group. A spacer having 1 to 5 atoms in the main chain consisting of carbon atoms, which may be substituted with 1 to 3 substituents selected from an optionally substituted amino group. )
A group represented by:
X represents N or CH;
R ¹ and ^{R 2} are independently (1) hydrogen atom, (2) a halogen atom, (3) optionally substituted _{C 1-6} alkyl group, (4) optionally substituted _{C 1 -6} alkoxy group, (5) optionally halogenated _{C 3-10} cycloalkyl group, (6) halogenated which may be _{C 3-10} cycloalkyloxy group, it has been (7) halogenated And may represent a C _6-14 aryl group, or (8) a cyano group; and R ³ represents a hydrogen atom, a halogen atom, or an optionally halogenated C _1-6 alkyl group.
However,
(I) when any one of R ¹ , R ² and R ³ is a hydrogen atom, the other two are not hydrogen atoms; and (ii) R ¹ is of the formula —COO—R ^C1 (wherein R ^C1 is _{C 1-6} alkyl radical, and the formula ^{-COO-R C2} (formula substituted in.) of a hydrogen atom or an optionally substituted _{C 1-6} alkyl ^{group, R C2} is hydrogen It is not a C _1-6 alkoxy group substituted by an atom or an optionally substituted C _1-6 alkyl group. ]
Or a salt thereof. R ¹ is a hydrogen atom, a halogen atom, an optionally halogenated C _1-6 alkyl group, or an optionally halogenated C _1-6 alkoxy group;
R ² is a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group; and R ³ is a halogen atom, or C _1-6 alkyl The group,
The compound of claim 1. A is the formula

(In the formula, each symbol has the same meaning as in claim 1.)
The compound of Claim 1 which is group represented by these. The compound according to claim 1, wherein R ^6a and R ^6b are independently of the formula —CO—OR ^A1 (wherein R ^A1 is as defined in claim 1). R ^4a and R ^5a , or R ^4b and R ^5b , together with the adjacent carbon atom, is a benzene ring (the benzene ring is (a) a halogen atom, (b) an optionally substituted C _1-6 alkyl group, to form a (c) optionally substituted C _1-6 alkoxy group, and (d) to 1 selected from cyano group 3 substituents may be substituted.), claims 1. The compound according to 1. L ^1a and L ^1b are independently selected from (a) a halogen atom, (b) a hydroxy group, and (c) an amino group optionally mono- or disubstituted with a C _1-6 alkoxy-carbonyl group. The compound according to claim 1, which is a C _2-4 alkylene group or a C _2-4 alkenylene group, each of which may be substituted with 1 to 3 substituents. A is the formula

(Where
R ^6a is of the formula —CO—OR ^A1 (wherein R ^A1 is as defined in claim 1);
R ^4a and R ^5a are combined with adjacent carbon atoms to form a benzene ring (the benzene ring is (a) a halogen atom, (b) an optionally substituted C _1-6 alkyl group, (c) substituted) A C _1-6 alkoxy group which may be substituted, and (d) optionally substituted by 1 to 3 substituents selected from a cyano group; and L ^1a is (a) a halogen Optionally substituted with 1 to 3 substituents selected from an atom, (b) a hydroxy group, and (c) an amino group optionally mono- or di-substituted with a C _1-6 alkoxy-carbonyl group. , A C _2-4 alkylene group or a C _2-4 alkenylene group. )
A group represented by:
X is N or CH;
R ¹ is a hydrogen atom, a halogen atom, an optionally halogenated C _1-6 alkyl group, or an optionally halogenated C _1-6 alkoxy group;
R ² is a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group; and R ³ is a halogen atom, or C _1-6 alkyl The group,
The compound of claim 1.   A prodrug of the compound of claim 1.   A medicament comprising the compound according to claim 1 or a prodrug thereof.   The medicament according to claim 9, which is an insulin resistance improving agent.   The medicament according to claim 9, which is an agent for preventing or treating diabetes.   A method for preventing or treating diabetes in a mammal, comprising administering an effective amount of the compound according to claim 1 or a prodrug thereof to the mammal.   Use of the compound according to claim 1 or a prodrug thereof for the manufacture of a prophylactic or therapeutic agent for diabetes.