HK1116180A

HK1116180A - Aryloxy-substituted benzimidazole derivatives

Info

Publication number: HK1116180A
Application number: HK08106494.0A
Authority: HK
Inventors: 桥本宪明; 高桥啓治; 中间千智; 荻野悦夫; 坂井富美子; 西村辉之; 永木淳一
Original assignee: 万有制药株式会社
Priority date: 2004-11-02
Filing date: 2005-11-01
Publication date: 2008-12-19

Description

Aryloxy-substituted benzimidazole derivatives

Technical Field

The present invention relates to a glucokinase activator containing an aryloxy-substituted benzimidazole derivative useful in the field of medicine as an active ingredient. Further relates to novel aryloxy substituted benzimidazole derivatives.

Background

Glucokinase (GK) (ATP: D-hexose 6-phosphotransferase, EC2.7.1.1) is one of four kinds of hexokinases (hexokinase IV) of mammals. Hexokinase is the first enzyme in the glycolytic system, catalyzing the conversion of glucose to glucose 6 phosphate. Glucokinase is mainly limited to expression in liver and pancreatic beta cells, and plays an important role in sugar metabolism throughout the body by controlling the rate-determining step of glucose metabolism of these cells. The beta-cell glucokinase of liver and pancreas has different sequences of 15 amino acids at the N-terminal depending on cleavage, but has the same enzymatic properties. Three hexokinases (I, II, III) other than glucokinase are saturated in enzyme activity at a glucose concentration of 1mM or less, and the kM of glucokinase for glucose is 8mM, which is close to physiological blood glucose level. Therefore, when the blood glucose level changes from normal blood glucose (5mM) to postprandial blood glucose elevation (10-15mM), intracellular glucose metabolism is accelerated by glucokinase.

About 10 years ago, a hypothesis that glucokinase functions as a glucose sensor for pancreatic β -cells or liver was proposed [ see, for example, Garfinkel D et al, computer modeling additives glucose sensor of pancreatic beta-cells, American Journal Physiology, Vol.247 (3Pt2), 1984, pp.527-536 ].

From the results of recent mouse manipulation with glucokinase gene, glucokinase actually plays an important role in the systemic glucose homeostasis. Mice in which the glucokinase gene has been disrupted die shortly after birth [ see, for example, Grupe A et al, transgenic knockouts, genetic a genetic requirement for transgenic beta Cell glucokinase in main diabetes mellitus, Cell, Vol.83, p.1995, pp.69-78 ], while normal and diabetic mice in which glucokinase is overexpressed have a reduced blood glucose level [ see, for example, Ferre T, Correction of metabolic alterations by glucokinase, Proceedings of the National Academy of science of the U.S.A., Vol.93, 1996, p.7225).

As the glucose concentration increases, the pancreatic β -cell and the hepatocyte respond differently, but each corresponds to a direction in which blood glucose is decreased. The pancreatic beta cells secrete more insulin, while the liver takes up the sugars, stores them as glycogen, and decreases the release of sugars.

The above-mentioned change in the glucokinase activity plays an important role in the glucose homeostasis of mammals via liver and pancreatic β cells. Mutations in the glucokinase gene have been found in cases of onset of diabetes in young years called MODY2 (adult-onset diabetes of young years), and decreased glucokinase activity is responsible for the increase in blood glucose [ see, for example, Vinonet N, Nonsensomentation in the glucose genes utilization early-onset non-insulin-dependent diabetes media, Nature Genetics, volume 356, 1992, page 721) -722 ].

In addition, a family of mutations which increase glucokinase activity has been found, and these persons show hypoglycemic symptoms [ see, for example, Glaser B, family hyperinsulinism captured byan activating glucokinase mutation, New England Journal Medicine, Vol. 338, 1998, p. 226-230 ].

From the above, glucokinase plays a role as a glucose sensor in the human body, and plays an important role in glucose homeostasis. Glucokinase sensor systems are used for blood glucose regulation in many type II diabetic patients. The glucokinase activating substance is expected to exert an insulin secretion promoting action of pancreatic beta cells and a sugar uptake resistance and sugar release inhibiting action of the liver, and thus can be used as a therapeutic agent for type II diabetic patients.

In recent years it has become apparent that: pancreatic β -type glucokinase is expressed in the brain of rats, particularly in the feeding center (hypothalamic ventral medial nucleus, VMH). Approximately two-fold nerve cells in VMH are called glucose-responsive neurons (glucose-responsive neurons), and have been considered to play an important role in controlling body weight. The food intake is reduced by administering glucose into the brain of the rat, whereas polyphagia occurs if the glucose analog, glucosamine, inhibits glucose metabolism by administering intracerebrally. Electrophysiology experiments show that: glucose-responsive neurons are activated in response to physiological glucose concentration changes (5 to 20mM), but their activity is inhibited by inhibition of glucose metabolism by glucosamine or the like. It is presumed that the glucose concentration sensing system of VHM is a mechanism via glucokinase, similar to insulin secretion by pancreatic β cells. Therefore, substances that activate the glucokinase activity of VHM, in addition to liver and pancreatic β cells, have not only the effect of regulating blood glucose, but also the potential to regulate obesity that is distressed by many type II diabetics.

As is clear from the above description, a compound having glucokinase activating activity is useful as a therapeutic and/or prophylactic agent for diabetes, or a therapeutic and/or prophylactic agent for chronic complications of diabetes such as retinopathy, nephropathy, neurosis, ischemic heart disease, and arteriosclerosis, and further useful as a therapeutic and/or prophylactic agent for obesity.

The benzimidazole derivative is a compound represented by the following formula (for example, Japanese patent application laid-open No. O2002/032872).

The compounds described in the above formula having a 2-pyridyl group at the 6-position and a phenoxy group at the 4-position of the 7H-pyrrolo [2, 3-d ] -pyrimidinyl skeleton are common to the compounds of the present invention from this point of view, but the compound has one substituent on the 7H-pyrrolo [2, 3-d ] pyrimidinyl group and the substituent on the phenoxy group is an amino group, which is structurally different from the compound of the present invention.

The compound is an intermediate of an angiogenesis inhibiting compound, and is not described to be effective for the treatment and/or prevention of specific diabetes and obesity, nor is it described to exhibit the above-mentioned effects.

Disclosure of Invention

The present invention addresses the problem of providing novel aryloxy-substituted benzimidazole derivatives or glucokinase activators using the same, particularly therapeutic and/or prophylactic agents for diabetes and obesity.

The present inventors have conducted intensive studies to develop a novel diabetes drug having a higher drug efficacy and a novel drug efficacy than the conventional diabetes drug due to a different action from the conventional drug, and as a result, have found that: the present inventors have completed the present invention by finding that a novel aryloxy-substituted benzimidazole derivative has glucokinase activating activity.

That is, the present invention relates to

(1) A compound of formula (I) or a pharmaceutically acceptable salt thereof:

(in the formula, R¹And R²Each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, a cyano group or a lower alkoxy group,

R³independently of each other, represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyalkyl group, a trifluoromethyl group, a lower alkenyl group or a cyano group,

R⁴each independently represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a hydroxyalkyl group (a hydroxyl group in the hydroxyalkyl group)The hydrogen atom of the group may be substituted by a lower alkyl group), an aminoalkyl group (the amino group may be substituted by a lower alkyl group), an alkanoyl group, a carboxyl group, a lower alkoxycarbonyl group or a cyano group,

q represents a carbon atom, a nitrogen atom or a sulfur atom (the sulfur atom may be substituted with one or two oxo groups),

R⁵and R⁶Each independently represents a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkyl group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, an alkanoyl group, a formyl group, an aryl group, a mono-or di-lower alkylcarbamoyl group or a mono-or di-lower alkylsulfamoyl group, or Q, R ⁵And R⁶Formed together

(A) A 5-to 6-membered aliphatic nitrogen-containing heterocyclic group which may have one or two double bonds therein and which may have 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in the ring, at least one nitrogen atom, a nitrogen,

(B) A 5-to 6-membered aromatic nitrogen-containing heterocyclic group which may have, in the ring, 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and which has at least one nitrogen atom other than the hetero atoms, or

(C) A phenyl group,

the aliphatic nitrogen-containing heterocyclic group, the aromatic nitrogen-containing heterocyclic group or the phenyl group represents the following group: may have 1 to 3 groups selected from substituent group α, and/or may have, as a substituent, a 3 to 6-membered ring formed by bonding mutually bondable groups among the groups selected from substituent group α, and/or a group which may be fused with the group represented by formula (A),

(in the formula, wherein,represents a single bond or a double bond),

X¹、X²、X³and X⁴Each independently represents a carbon atom or a nitrogen atom,

z represents an oxygen atom, a sulfur atom or a nitrogen atom,

ar represents aryl and heteroaryl which may be substituted by 1 to 3 groups selected from substituent group beta,

ring A represents a 5-6 membered nitrogen-containing heteroaromatic ring group represented by the formula (III):

(wherein X represents a carbon atom),

m represents an integer of 1 to 6,

n represents an integer of 0 to 3

p represents an integer of 0 to 2 (X)¹-X⁴At least two of which represent carbon atoms),

q represents 0 or 1.

Substituent group alpha

Oxo, thioxo, lower alkyl, lower alkoxy, alkanoyl, formyl, hydroxy, carboxy, trifluoromethyl, hydroxyalkyl (the hydrogen atom in the hydroxy may be substituted by lower alkyl), cyano, mono-or di-lower alkylcarbamoyl, lower alkylsulfinyl, lower alkylsulfonyl and a halogen atom

Substituent group beta

Lower alkyl, lower alkoxy, halogen atom, trifluoromethyl, hydroxyalkyl (the hydrogen atom of the hydroxyl group in the hydroxyalkyl may be substituted by lower alkyl), lower alkylsulfonyl, lower alkylsulfanyl, lower alkylsulfinyl, aminoalkyl (the amino group may be substituted by lower alkyl), alkanoyl, carboxyl, mono-or di-lower alkylcarbamoyl, mono-or di-lower alkylsulfamoyl, lower alkoxycarbonyl, cyano, and heteroaryl having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom in the aryl or ring (the aryl and heteroaryl may have one or two groups selected from substituent group γ)

Substituent group gamma

Lower alkyl group, lower alkoxy group, halogen atom, hydroxy group, lower alkylsulfonyl group, lower alkylsulfinyl group, alkanoyl group, cyano group, and mono-or di-lower alkylcarbamoyl group

(2) The compound according to the above (1) wherein the ring A is thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl or pyrimidinyl, or a pharmaceutically acceptable salt thereof.

(3) The compound of claim, wherein ring A is thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl or pyrimidinyl, and formula (I) is represented by the following formula (I-1):

(in the formula, the symbols are the same as those described above).

(4) A compound of the above (1) wherein the a ring is thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl or pyrimidinyl, or a pharmaceutically acceptable salt thereof, and the formula (I) is represented by the formula (I-2):

(in the formula, the symbols are the same as those described above).

(5) A compound of the above (1) wherein the a ring is thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl or pyrimidinyl, or a pharmaceutically acceptable salt thereof, and the formula (I) is represented by the formula (I-3):

(in the formula, the symbols are the same as those described above).

(6) The compound according to the above (3) or a pharmaceutically acceptable salt thereof, wherein m is 1 to 4.

(7) The compound according to the above (3) wherein Z is an oxygen atom or a sulfur atom, or a pharmaceutically acceptable salt thereof.

(8) The compound according to the above (3) wherein Ar is phenyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl which may be substituted by a group selected from the substituent group β, or a pharmaceutically acceptable salt thereof.

(9) The compound of the above (3) or a pharmaceutically acceptable salt thereof, wherein R⁵And R⁶Each independently, a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkyl group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, an alkanoyl group or a formyl group.

(10) The compound according to the above (3) wherein Q is a nitrogen atom, or a pharmaceutically acceptable salt thereof.

(11) The compound according to the above (3) wherein Q is a carbon atom, or a pharmaceutically acceptable salt thereof.

(12) The compound of the above (3) wherein the group represented by the formula (I-A) in the formula (I-1) is a pharmaceutically acceptable salt thereof

Is a group of the formula:

(in the formula, R¹¹Represents a hydrogen atom or a lower alkyl group, and the other symbols are the same as those described above).

(13) The compound according to the above (3) wherein Q is a nitrogen atom and R is a pharmaceutically acceptable salt thereof⁵And R⁶Is a 5-6-membered aliphatic nitrogen-containing heterocyclic group which may have one or two double bonds therein and which may be substituted by the same or different one or two groups selected from substituent group α 1), the 5-6-membered aliphatic nitrogen-containing heterocyclic group being the above-mentioned nitrogen atom, R⁵And R⁶Together, may have 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in the ring, and at least one nitrogen atom in addition to the heteroatoms (, m is 1, Z is an oxygen atom, Ar is phenyl or pyridyl (which may be substituted by one or two identical or different groups selected from substituent group β 1), R is¹And R²Each independently is a hydrogen atom or a lower alkyl group.

Substituent group alpha 1

Oxo, thioxo, lower alkyl, lower alkoxy, alkanoyl, halogen atom, cyano and mono-or di-lower alkylcarbamoyl

Substituent group beta 1

Lower alkyl, lower alkoxy, halogen atom, trifluoromethyl, hydroxyalkyl (the hydrogen atom of the hydroxyl group in the hydroxyalkyl may be substituted by lower alkyl), lower alkylsulfonyl, alkanoyl, carboxyl, mono-or di-lower alkylcarbamoyl, mono-or di-lower alkylsulfamoyl, lower alkoxycarbonyl or cyano, or heteroaryl having 2 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom in the ring (the aryl and heteroaryl may have one or two groups selected from substituent group γ)

(14) The compound of the above (3) or a pharmaceutically acceptable salt thereof, wherein, Q, R⁵And R⁶Is a 5-6 membered aromatic nitrogen-containing heterocyclic group consisting of Q, R⁵And R⁶Taken together, at least one nitrogen atom (which may have 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in the ring other than the nitrogen atom), (the aromatic heterocyclic group or the phenyl group may have 1 to 3 groups selected from substituent group α 2), Z is an oxygen atom, Ar is a phenyl group or a pyridyl group (which may be substituted by one or two same or different groups selected from substituent group β 1), R¹And R²Each independently is a hydrogen atom or a lower alkyl group.

Substituent group alpha 2

Hydroxy, lower alkyl, lower alkoxy, alkanoyl, halogen atom, cyano and mono-or di-lower alkylcarbamoyl

Substituent group beta 1

(15) The compound of the above (1) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is the following compound:

1)1- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -5-thioxo-2-pyrrolidinone,

2)4- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } morpholine-3, 5-dione,

3)3- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -1, 3- チアゾラン -2, 4-dione,

4)3- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -1, 3- チアゾラン -2-one,

5)1- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } pyrrolidine-2, 5-dione,

6)1- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -3-methyl-imidazolidine-2, 5-dione,

7)2- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } isothiazolidine-1, 1-dioxide,

8)3- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyrazinyl) -1H-benzimidazol-6-yl ] methyl } -2-oxazolidinone,

9)1- { [5- { [6- (ethylsulfonyl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1H-benzimidazol-6-yl ] methyl } pyrrolidine-2, 5-dione,

10)1- [ (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1H-benzimidazol-6-yl) methyl ] -2-pyrrolidinone,

11) N- ({5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl } methyl) -N-methylacetamide,

12)3- { [5- [4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenoxy ] -2- (2-pyridinyl) -1H-benzimidazol-6-yl ] methyl } -1, 3-oxazolidin-2, 4-dione,

13)5- [4- (ethylsulfonyl) phenoxy ] -6- ((2-methyl-2H-tetrazol-5-yl) methyl) -2- (2-pyridinyl) -1H-benzimidazole,

14)5- [4- (ethylsulfonyl) phenoxy ] -6- (1- (1-methyl-1H-tetrazol-5-yl) ethyl) -2- (2-pyridyl) -1H-benzimidazole,

15)1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1H-benzimidazol-4-yl) methyl ] pyrrolidin-2-one, or

16)4- (2, 6-difluorobenzyl) -6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyrazin-2-yl-1H-benzimidazole.

(16) A compound of the above (1) wherein the formula (I) is 1- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -5-thioxo-2-pyrrolidinone, or a pharmaceutically acceptable salt thereof.

(17) A compound of the above (1) wherein the formula (I) is 4- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } morpholine-3, 5-dione, or a pharmaceutically acceptable salt thereof.

(18) The compound of the above (1) wherein the formula (I) is 3- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -1, 3- チアゾラン -2, 4-dione, or a pharmaceutically acceptable salt thereof.

(19) The compound of the above (1) wherein the formula (I) is 3- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -1, 3- チアゾラン -2-one, or a pharmaceutically acceptable salt thereof.

(20) A compound of the above (1) wherein the formula (I) is 1- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } pyrrolidine-2, 5-dione, or a pharmaceutically acceptable salt thereof.

(21) The compound of the above (1) wherein the formula (I) is 1- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -3-methyl-imidazolidine-2, 5-dione, or a pharmaceutically acceptable salt thereof.

(22) A compound of the above (1) wherein the formula (I) is 2- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } isothiazolidine-1, 1-dioxide, or a pharmaceutically acceptable salt thereof.

(23) A compound of the above (1) wherein the formula (I) is 3- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyrazinyl) -1H-benzimidazol-6-yl ] methyl } -2-oxazolidinone, or a pharmaceutically acceptable salt thereof.

(24) A compound of the above (1) wherein the formula (I) is 1- { [5- { [6- (ethylsulfonyl) -3-pyridyl ] oxy } -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } pyrrolidine-2, 5-dione, or a pharmaceutically acceptable salt thereof.

(25) The compound of the above (1) wherein the formula (I) is 1- [ (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1H-benzimidazol-6-yl) methyl ] -2-pyrrolidone, or a pharmaceutically acceptable salt thereof.

(26) The compound according to the above (1) wherein the formula (I) is N- ({5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl } methyl) -N-methylacetamide, or a pharmaceutically acceptable salt thereof.

(27) A compound of the above (1) wherein the formula (I) is 3- { [5- [4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -1, 3-oxazolidin-2, 4-dione, or a pharmaceutically acceptable salt thereof.

(28) The compound according to the above (1) wherein the formula (I) is 5- [4- (ethylsulfonyl) phenoxy ] -6- ((2-methyl-2H-tetrazol-5-yl) methyl) -2- (2-pyridyl) -1H-benzimidazole, or a pharmaceutically acceptable salt thereof.

(29) The compound according to the above (1) wherein the formula (I) is 5- [4- (ethylsulfonyl) phenoxy ] -6- (1- (1-methyl-1H-tetrazol-5-yl) ethyl) -2- (2-pyridyl) -1H-benzimidazole, or a pharmaceutically acceptable salt thereof.

(30) The compound of the above (1) wherein the formula (I) is 1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1H-benzimidazol-4-yl) methyl ] pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

(31) The compound according to the above (1) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is 4- (2, 6-difluorobenzyl) -6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyrazin-2-yl-1H-benzimidazole.

(32) A pharmaceutical composition comprising the following (1) to (3) for the treatment, prevention and/or delay of onset of type II diabetes:

(1) a compound of claim 1 or a pharmaceutically acceptable salt thereof,

(2) 1 or 2 or more compounds selected from the following (a) to (h):

(a) other glucokinase activators,

(b) Biguanide, biguanide,

(c) PPAR agonists,

(d) Insulin, insulin,

(e) Somatostatin

(f) Alpha-glucosidase inhibitors,

(g) An insulin secretion promoter, and

(h) DP-IV inhibitors (dipeptidyl peptidase IV inhibitors),

(3) a pharmaceutically acceptable carrier.

(33) A glucokinase activator comprising the compound according to any one of the above (1) to (31) or a pharmaceutically acceptable salt thereof as an active ingredient.

(34) A therapeutic and/or remedy for diabetes, which comprises the compound according to any one of the above (1) to (31) or a pharmaceutically acceptable salt thereof as an active ingredient.

(35) A therapeutic and/or prophylactic agent for obesity, which comprises a compound according to any one of the above (1) to (31) or a pharmaceutically acceptable salt thereof as an active ingredient.

Detailed Description

The meaning of the terms used in the present specification will be described below, and the compounds of the present invention will be described in detail.

In the present specification, the following groups are specifically as follows, unless otherwise specified.

Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

"lower alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, isopentyl, 1-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and the like.

"lower alkoxy" refers to a group obtained by substituting a hydrogen atom of a hydroxyl group with the above-mentioned lower alkyl, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy and the like.

"hydroxyalkyl" refers to a group obtained by substituting the lower alkyl group with a hydroxyl group, and examples thereof include hydroxymethyl, 2-hydroxyethyl and 1-hydroxy-ethyl.

The "lower alkenyl group" means a lower alkenyl group having a straight chain or branched chain of 2 to 6 carbon atoms, and examples thereof include a vinyl group, an allyl group, a 1-butenyl group, a 2-butenyl group, and a 1-pentenyl group.

"aminoalkyl" refers to a group in which one of the hydrogen atoms constituting the alkyl group is replaced with an amino group, and examples thereof include aminomethyl, aminoethyl, aminopropyl, and the like.

"alkanoyl" refers to a group obtained by bonding the above-mentioned alkyl group and carbonyl group, and examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl and isopropylcarbonyl.

The "lower alkoxycarbonyl group" refers to a group obtained by substituting a hydrogen atom of a carboxyl group with the above lower alkyl group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propylcarbonyl group and an isopropylcarbonyl group.

"lower alkylsulfonyl" means a group obtained by combining the above-mentioned lower alkyl group and sulfonyl group, and examples thereof include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-propylsulfonyl and the like.

The "lower alkylsulfinyl" refers to a group obtained by bonding the above-mentioned lower alkyl group and sulfinyl group, and examples thereof include methylsulfinyl, ethylsulfinyl, isopropylsulfinyl and the like.

The "lower alkylsulfanyl group" refers to a group in which the above alkyl group is bonded to a sulfanyl group, and examples thereof include methylsulfanyl group, ethylsulfanyl group, and isopropylsulfanyl group.

"Mono-lower alkylcarbamoyl" refers to a carbamoyl group mono-substituted with the above-mentioned lower alkyl, and examples thereof include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl and the like.

"Di-lower alkylcarbamoyl" means a carbamoyl group which is disubstituted by the same or different lower alkyl as mentioned above, and there are exemplified dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, dipropylcarbamoyl, methylpropylcarbamoyl, diisopropylcarbamoyl and the like.

"Mono-lower alkylsulfamoyl" refers to a sulfamoyl group mono-substituted with the above-mentioned lower alkyl group, and examples thereof include methylsulfamoyl, ethylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl and the like.

"Di-lower alkylsulfamoyl" refers to a sulfamoyl group which is disubstituted with the same or different lower alkyl groups as described above, and examples thereof include dimethylsulfamoyl, diethylsulfamoyl, ethylmethylsulfamoyl and isopropylmethylsulfamoyl.

In order to further specifically disclose the compound represented by the formula (I) of the present invention, specific examples of the various symbols used in the formula (I) will be described.

[ in the formula, the symbols are as defined above ].

R¹And R²Each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, a cyano group or a lower alkoxy group.

R¹And R²The "halogen atom", "lower alkyl group" or "lower alkoxy group" as represented means the same groups as defined above.

R¹And R²One is preferably a hydrogen atom and the other is a lower alkyl group, or both are hydrogen atoms, more preferably both are hydrogen atoms.

R³Each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyalkyl group, a trifluoromethyl group, a lower alkenyl group or a cyano group.

R³The "halogen atom", "lower alkyl", "lower alkoxy", "hydroxyalkyl" or "lower alkenyl" as represented means the same groups as defined above.

R³Preferably a hydrogen atom.

R⁴Each independently represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a hydroxyalkyl group (the hydroxy group in the hydroxyalkyl group may have a hydrogen atom substituted by a lower alkyl group), an aminoalkyl group (the amino group may have a lower alkyl group), an alkanoyl group, a carboxyl group, a lower alkoxycarbonyl group or a cyano group.

R⁴The "lower alkyl group", "lower alkoxy group", "halogen atom", "alkanoyl group" or "lower alkoxycarbonyl group" means the same groups as defined above, respectively.

R⁴The "hydroxyalkyl group" as referred to includes, in addition to the "hydroxyalkyl group" as defined above, a group in which a hydrogen atom of a hydroxyl group in the group is substituted with a lower alkyl group.

R⁴Examples of the "hydroxyalkyl group" include a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxy-ethyl group, a methoxymethyl group, a methoxyethyl group, and an ethoxyethyl group.

R⁴Preferably a hydrogen atom, a lower alkyl group, a halogen atom, a trifluoromethyl group or a hydroxyalkyl group (the hydrogen atom of the hydroxyl group in the hydroxyalkyl group may be substituted by a lower alkyl group), more preferably a hydrogen atom, a lower alkyl group, a halogen atom or a trifluoromethyl group.

Q represents a carbon atom, a nitrogen atom or a sulfur atom (the sulfur atom may be substituted with one or two oxo groups). Q is preferably a carbon atom or a nitrogen atom.

R⁵And R⁶Independently of each other, represents a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkyl group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, an alkanoyl group, a formyl group, an aryl group, a mono-or di-lower alkylcarbamoyl group or a mono-or di-lower alkylsulfamoyl group, or represents in the formula (II),

Q、R⁵and R⁶A 5-6 membered aliphatic nitrogen-containing heterocyclic group which may have 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in the ring (which group may have one or two double bonds therein), or an aromatic nitrogen-containing heterocyclic group or a phenyl group formed together.

The aliphatic nitrogen-containing heterocyclic group, the aromatic nitrogen-containing heterocyclic group or the phenyl group may have 1 to 3 groups selected from substituent group α, and/or have a 3 to 6-membered ring formed by combining mutually combinable groups among the groups selected from substituent group α as a substituent, and/or be fused with the group represented by formula (a).

(in the formula, wherein,represents a single bond or a double bond).

R⁵And R⁶The "lower alkyl group", "halogen atom", "lower alkyl group", "lower alkylsulfonyl group", "lower alkylsulfinyl group" or "alkanoyl group" each represents the same group as defined above.

Q is a carbon atom, a nitrogen atom or a sulfur atom, and R⁵And R⁶When each independently represents a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkyl group or a lower alkylsulfonyl group, a lower alkylsulfinyl group, an alkanoyl group, a formyl group, an aryl group, a mono-or di-lower alkylcarbamoyl group or a mono-or di-lower alkylsulfamoyl group, the group represented by the formula (II) is, for example, acetylamino group, methanesulfonylamino group, benzenesulfonylamino group, phenylsulfinyl group, methanesulfonyl group or the like, and among them, acetylamino group, acetylaminomethyl group, methanesulfonylamino group or the like is preferable.

Q、R⁵And R⁶The 5-to 6-membered aliphatic nitrogen-containing heterocyclic group which may have 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in a ring formed together (1 to 2 double bonds may be present in the group) or aromatic nitrogen-containing heterocyclic group or phenyl group is preferably Q, R⁵And R⁶Together forming a ring having an orA 5-6-membered aliphatic nitrogen-containing heterocyclic group which may have one or two double bonds therein and two hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, or a 5-6-membered aromatic nitrogen-containing heterocyclic group which may have 1-4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in the ring, or a phenyl group.

The substituent group of the 5-to 6-membered aliphatic nitrogen-containing heterocyclic group which may have one or two double bonds is preferably an oxo group, a thioxo group, a lower alkyl group, a lower alkoxy group, an alkanoyl group, a halogen atom, a cyano group, a mono-or di-lower alkylcarbamoyl group in the substituent group α.

The substituent group possessed by the 5-to 6-membered aromatic nitrogen-containing heterocyclic group or phenyl group is preferably a hydroxyl group, a lower alkyl group, a lower alkoxy group, an alkanoyl group, a halogen atom, a cyano group, a mono-or di-lower alkylcarbamoyl group in the substituent group α.

Specific examples of the 5-to 6-membered aliphatic nitrogen-containing heterocyclic group represented by the formula (II) include those represented by the formula (II-1).

Or

Among them, the group represented by the formula (II-2) is preferable.

Specific examples of the 5-to 6-membered aromatic nitrogen-containing heterocyclic group or phenyl group represented by the formula (II) include those represented by the formula (II-2).

X¹、X²、X³And X⁴Each independently represents a carbon atom or a nitrogen atom, preferably X¹-X⁴All being carbon atoms.

Z represents an oxygen atom, a sulfur atom or a nitrogen atom, with an oxygen atom or a sulfur atom being preferred, and an oxygen atom being more preferred.

Ar represents an aryl or heteroaryl group which may be substituted with 1 to 3 groups selected from substituent group beta.

The "aryl group" represented by Ar is a phenyl group or a naphthyl group, and among them, a phenyl group is preferable.

The "heteroaryl group" represented by Ar means a 5-or 6-membered monocyclic ring having 1 to 3 heteroatoms selected from nitrogen atoms, sulfur atoms and oxygen atoms in the ring.

Specific examples of the heteroaryl group include: furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrazinyl and the like, and among them, pyridyl and the like are preferable.

The substituent that Ar may have is a group selected from the above substituent group β, among which a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a hydroxyalkyl group (the hydrogen atom of the hydroxyl group in the hydroxyalkyl group may be substituted by a lower alkyl group), a lower alkylsulfonyl group, an alkanoyl group, a carboxyl group, a mono-or di-lower alkylcarbamoyl group, a mono-or di-lower alkylsulfamoyl group, a lower alkoxycarbonyl group or a cyano group, or an aryl group or a heteroaryl group having 2 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring (the aryl group and the heteroaryl group may have one or two groups selected from the substituent group γ) is preferable.

The substituent group γ means a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, an alkanoyl group, a cyano group and a mono-or di-lower alkylcarbamoyl group, of which a lower alkylsulfonyl group, a cyano group or a halogen atom is preferable.

The A ring represents a nitrogen-containing heteroaryl group represented by the formula (III).

(in the formula, the symbols are the same as those described above). The a ring may have one or two hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom in the ring in addition to at least one nitrogen atom.

Specific examples of the group represented by the formula (III) include thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl and pyrimidinyl, and among them, pyridyl, thiazolyl, pyrazolyl, pyrazinyl and thiadiazolyl are preferable.

n represents an integer of 0 to 3, with 0 to 2 being preferred.

R⁴The lower alkyl group is preferably a methyl group, an ethyl group, a propyl group, or the like.

R⁴The lower alkoxy group is preferably methoxy, ethoxy, propoxy, isopropoxy, or the like.

R⁴The halogen atom represented by (a) is preferably a fluorine atom, a chlorine atom, a bromine atom or the like.

R⁴The hydroxyalkyl group is preferably a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxyethyl group, a 2-hydroxy-1-methylethyl group or the like. The hydrogen atom of the hydroxyl group in the hydroxyalkyl group may be substituted by a lower alkyl group, and examples of the hydroxyalkyl group which may be substituted by a lower alkyl group include methoxymethyl group, ethoxymethyl group and the like.

R⁴Examples of the aminoalkyl group include a methylamino group, an ethylamino group, and an isopropylamino group.

The amino group of the aminoalkyl group may be substituted by a lower alkyl group.

R⁴Examples of the aminoalkanoyl group include an acetylamino group, an ethylcarbonylamino group, a propylcarbonylamino group, and an isopropylcarbonylamino group.

R⁴Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, and an isopropylcarbonyl group.

Above, formula (III-1)

Specific examples of the group represented by the formula [ wherein each symbol is the same as the above ] include: thiazol-2-yl, 5-chloro-thiazol-2-yl, 4-methyl-thiazol-2-yl, 5-methyl-thiazol-2-yl, 4-hydroxymethylthiazol-2-yl, 4-methoxycarbonyl-thiazol-2-yl, 4-methoxymethyl-thiazol-2-yl, 4-cyano-thiazol-2-yl, 4-fluoro-thiazol-2-yl, imidazol-2-yl, 4-methyl-imidazol-2-yl, 4-methoxycarbonyl-imidazol-2-yl, 4-acetyl-imidazol-2-yl, 5-hydroxymethyl-imidazol-2-yl, Isothiazol-3-yl, 4-hydroxymethyl-isothiazol-3-yl, 5-acetyl- [1, 3, 4] thiadiazol-2-yl, 5-methyl- [1, 3, 4] thiadiazol-2-yl, 5-fluoro- [1, 3, 4] thiadiazol-2-yl, [1, 2, 4] thiadiazol-5-yl, 3-methyl- [1, 2, 4] thiadiazol-5-yl, [1, 2, 4] triazol-3-yl, 5-hydroxymethyl- [1, 2, 4] triazol-3-yl, 5-acetyl- [1, 2, 4] triazol-3-yl, Oxazol-2-yl, isoxazol-3-yl, pyrazin-2-yl, 5-methyl-pyrazin-2-yl, pyridin-2-yl, 4-methyl-pyridin-2-yl, pyridazin-3-yl, 6-methyl-pyridazin-3-yl, 1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-3-yl, pyrimidin-2-yl, pyrimidin-4-yl and the like.

m represents an integer of 1 to 6, preferably 1 to 4, more preferably 1 or 2, and further preferably 1.

p represents an integer of 0 to 2, with 0 or 1 being preferred.

q represents 0 or 1, wherein q is preferably 1.

Among the compounds represented by the formula (I) of the present invention, preferred are compounds represented by the formula (I-11) or the formula (I-1) or pharmaceutically acceptable salts thereof:

[ in the formula, each symbol is as defined above ], and a compound represented by the formula (I-2) or a compound represented by the formula (I-3) contained in the formula (I-1) is more preferable.

[ in the formula, the symbols are the same as those described above ]

The formula (I-A) in the formula (I-1) is preferably a group represented by the following formula.

[ in the formula, R¹¹Represents a hydrogen atom or a lower alkyl group, and the other symbols are the same as those described above]。

Examples of the compound represented by the formula (I) include the following compounds and pharmaceutically acceptable salts thereof.

The following is a description of the process for preparing the compounds of the present invention.

The compound represented by the formula (I-11) or the formula (I-21) contained in the formula (I) of the present invention can be produced, for example, by the following method.

[ wherein Ar is¹The same meanings as those of Ar and other symbols are as defined above]。

(' R represents lower alkyl, R^proRepresents a protecting group of an aromatic amino group, L₁And L₂Represents a leaving group, Met represents a metal atom, and other symbols are the same as those described above).

(step 1)

This step is a method for producing a compound (3) by reacting a compound (1) with a compound (2) in the presence of an acid catalyst.

L₁Any substance may be used as long as it produces the compound (8) by the reaction with the compound (7) Ar-ZH in step 4, and examples thereof include a fluorine atom, a chlorine atom, a bromine atom, and the like, and among them, a fluorine atom is preferable.

Examples of the acid catalyst used in this step include sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, and thionyl chloride.

The amount of the acid catalyst to be used is usually 0.01 to 10 equivalents, preferably 0.1 to 1 equivalent, relative to 1 equivalent of the compound (1).

Examples of the compound (1) to be used include 2-fluoro-4-nitrobenzoic acid, 2-fluoro-5-nitrobenzoic acid, 5-fluoro-2-nitrobenzoic acid, and 3-fluoro-5-nitrobenzoic acid.

The lower alkyl group represented by R represents the same group as the lower alkyl group defined above.

The compound (2) is used as a reaction solvent, for example, methanol, ethanol, etc.

The amount of the compound (2) used is a usual solvent amount relative to 1 equivalent of the compound (1).

The reaction temperature is usually room temperature-the reflux temperature of the reaction solvent, preferably 60-the reflux temperature of the reaction solvent.

The reaction time is usually 1 to 120 hours, preferably 24 to 72 hours.

Examples of the reaction solvent used in this step include methanol, ethanol, toluene, tetrahydrofuran, and dimethylformamide.

The compound (3) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 2)

This step is a method for producing the compound (4) by reducing the nitro group of the compound (3) obtained in the above step 1.

The reduction reaction employed in this step is a method well known to those skilled in the art.

The reduction reaction adopted in the step specifically comprises the following steps: for example, a contact reduction method using hydrogen, formic acid, ammonium formate, hydrazine hydrate, or the like, and a palladium, platinum, nickel catalyst, or the like; reduction using hydrochloric acid or ammonium chloride and iron; reduction methods using methanol and tin chloride, and the like.

The amount of the reducing agent used in the present step varies depending on the kind of the compound and the solvent used, and is usually 1 to 50 equivalents, preferably 2 to 20 equivalents, relative to 1 equivalent of the compound (3).

The reaction temperature is usually from-10 to 100 ℃ and preferably from 0 to 50 ℃.

The reaction time is usually 1 to 20 hours, preferably 1 to 5 hours.

The reaction solvent to be used is not particularly limited as long as it does not hinder the reaction, and examples thereof include methanol, N-dimethylformamide, ethyl acetate, tetrahydrofuran, and the like, and mixed solvents thereof.

The compound (4) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 3)

This step is a method for producing a compound (6) by reacting the compound (4) obtained in the above step 2 with a compound (5).

The amide bond formation reaction in this step is carried out using a carboxylic acid represented by the compound (5) or a reactive derivative thereof.

Examples of the compound (5) to be used include pyridine-2-carboxylic acid, pyrazine-2-carboxylic acid, pyrimidine-4-carboxylic acid, pyrimidine-2-carboxylic acid, thiazole-2-carboxylic acid, isoxazole-3-carboxylic acid, 5-methyl-isoxazole-3-carboxylic acid, 1-methyl-1H-imidazole-4-carboxylic acid, imidazole-2-carboxylic acid, 1-methyl-1H-imidazole-2-carboxylic acid, imidazole-1-carboxylic acid, [1, 2, 4] triazole-3-carboxylic acid, [1, 2, 3] triazole-4-carboxylic acid, 3-methyl- [1, 2, 4] thiadiazole-5-carboxylic acid, and the like, [1, 2, 5] thiadiazole-3-carboxylic acid, [1, 2, 3] oxadiazole-3-carboxylic acid, pyrazole-3-carboxylic acid, and the like.

The amount of the compound (5) or a reactive derivative thereof used is usually 0.1 to 100 equivalents, preferably 0.1 to 20 equivalents, more preferably 0.1 to 3 equivalents, relative to 1 equivalent of the compound (4).

The reactive derivative of the compound (5) may be, for example, a mixed acid anhydride, an activated ester, an activated amide, etc., and they can be obtained by, for example, the method described in WO 98/05641.

In the above reaction, when the carboxylic acid represented by the compound (5) is used, the reaction is preferably carried out in the presence of a condensing agent such as carbonyldiimidazole, N' -dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyl disulfide-triphenylphosphine, and the like, preferably carbonyldiimidazole.

The amount of the condensing agent to be used is not particularly limited, but is usually 0.1 to 100 equivalents, preferably 0.1 to 10 equivalents, relative to the compound (5).

The reaction is usually carried out in an inert solvent such as tetrahydrofuran, N-dimethylformamide, 1, 4-dioxane, benzene, toluene, methylene chloride, chloroform, carbon tetrachloride, 1, 2-dichloroethane, pyridine, etc., or a mixture of these solvents.

The reaction temperature is usually 0 ℃ to the reflux temperature of the reaction solvent, preferably room temperature to the reflux temperature of the reaction solvent.

The reaction time is usually 0.1 to 72 hours, preferably 0.5 to 24 hours.

In order to smoothly proceed the reaction, the reaction may be carried out in the presence of a base and a condensation assistant.

The base includes 4-dimethylaminopyridine, triethylamine and the like.

The amount of the base to be used is usually 0.1 to 100 equivalents, preferably 0.1 to 1 equivalent, based on 1mol of the carboxylic acid represented by the compound (5) or a reactive derivative thereof.

The condensation assistant includes N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, etc.

The amount of the condensation assistant to be used is usually 1 to 100 equivalents, preferably 1 to 5 equivalents, relative to 1mol of the carboxylic acid represented by the compound (5) or its reactive derivative.

In the above reaction, if an amino group or an imino group which is not involved in the reaction is present in the reaction substance, it is preferable that the amino group or the imino group is protected with a suitable protecting group for the amino group or the imino group and then the reaction is carried out, and the protecting group can be removed after the reaction.

The above-obtained compound (6) can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 3-1)

This step is a method for producing the compound (6-1) by reacting the compound (6) obtained in the above step 3 with fuming nitric acid.

The amount of fuming nitric acid used in this step is usually 1 to 100 equivalents, preferably 2 to 20 equivalents, relative to 1 equivalent of the compound (6).

The reaction temperature is usually 0 to 100 ℃ and preferably 10 to 50 ℃.

The reaction time is usually 0.1 to 48 hours, preferably 0.5 to 12 hours.

Compound (6-1) can be produced by reacting the above-mentioned compound (6) with potassium nitrate in the presence of an acid.

The amount of potassium nitrate used is usually 1 to 100 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of the compound (6).

Examples of the acid used include trifluoroacetic acid, hydrochloric acid, sulfuric acid, and nitric acid.

The amount of the acid used is usually 1 equivalent to the amount of the solvent, preferably 1 to 100 equivalents, relative to 1 equivalent of the compound (6), and the reaction temperature is usually 0 ℃ to the reflux temperature of the solvent, preferably room temperature to 100 ℃.

The reaction time is usually 0.1 to 72 hours, preferably 0.5 to 12 hours.

The reaction solvent may be any solvent as long as it does not inhibit the reaction, and examples thereof include chloroform and dichloromethane.

The compound (7) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 4)

This step is a method for producing a compound (8) by reacting the compound (6-1) obtained in the above step 3-1 with a compound (7) in the presence of a base.

The amount of the compound (7) used is usually 0.1 to 20 equivalents, preferably 0.5 to 5 equivalents, relative to 1 equivalent of the compound (6-1).

Examples of the compound (7) to be used include 4-methanesulfonylphenol, 4-ethanesulfonylphenol, 3-chloro-4-methanesulfonylphenol, 6-methanesulfonyl-pyridin-3-ol, 6-ethanesulfonyl-pyridin-3-ol, 4-cyanophenol, 6- (5-methyl- [1, 2, 4] thiadiazol-3-yl) -pyridin-3-ol, 6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinol, and 4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenol. These compounds can be synthesized using commercially available compounds or starting materials from commercially available compounds according to methods known to those skilled in the art, methods similar thereto, or combinations thereof with conventional methods.

The amount of the base used is usually 0.1 to 20 equivalents, preferably 0.5 to 5 equivalents, relative to 1 equivalent of the compound (6-1).

The base to be used may be any base as long as it can produce the compound (8) in the reaction of the compound (6-1) and the compound (7) in the present step, and examples thereof include sodium hydride, cesium carbonate, sodium carbonate, potassium phosphate, potassium acetate, potassium tert-butoxide, triethylamine and the like, and among them, potassium carbonate, cesium carbonate and the like are preferable. When the compound (7) is a primary or secondary amine, the reaction in this step can be carried out without using a base.

The reaction temperature is usually 0-the reflux temperature of the reaction solvent, preferably room temperature-the reflux temperature of the reaction solvent.

The reaction time is usually 0.1 to 72 hours, preferably 0.5 to 5 hours.

The reaction solvent is not particularly limited as long as it is an inert solvent and does not hinder the reaction, and specifically, examples thereof include pyridine, toluene, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, and 1-methyl-2-pyrrolidone.

The compound (8) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 5)

This step is a method for producing the compound (9) by subjecting the compound (8) obtained in the above step 4 to cyclodehydration in the presence of an acid catalyst while reducing the nitro group.

The reaction conditions in this step may be carried out in the same manner as in step 2 described above, in a similar manner thereto, or in combination with conventional methods.

The compound (9) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 6)

This step is a method for producing a compound (11) by reacting a compound (9) obtained in the above step 8 with a compound (10) in the presence of a base.

The reaction of this step is a method of introducing a protecting group into an aromatic amino group, and can be carried out according to a method described in the literature (for example, protective Groups in Organic Synthesis, T.W. Green, 2 nd edition, published by John Wiley & Sons, 1991, etc.), a method similar thereto, or a combination thereof with a conventional method.

L2 in compound (10) is, for example, a halogen atom or the like, and among them, a chlorine atom or a bromine atom is preferable.

As the compound (10), 2- (trimethylsilyl) ethoxymethyl chloride (SEMCl), methoxymethyl chloride (MOMCl) and the like can be used.

The amount of the compound (10) used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (9).

Examples of the base used include sodium hydride.

The amount of base used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents.

The reaction temperature is usually-20 to 50 ℃ and preferably 0 ℃ to room temperature.

The reaction time is usually 0.1 to 12 hours, preferably 0.1 to 3 hours.

The reaction solvent may be any solvent as long as it does not hinder the reaction, and examples thereof include N, N-dimethylformamide, tetrahydrofuran, and dichloromethane.

The compound (11) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 7)

This step is a method for producing the compound (12) by reducing the ester group of the compound (11) obtained in the above-mentioned step 6.

The reducing agent used in this step is lithium aluminum hydride (LiAlH)₄) Lithium borohydride, sodium borohydride, and the like. Can also be prepared by subjecting the compound (11) toSome esters are hydrolyzed to carboxylic acids, and then the compound (12) is prepared according to a method described in the literature (e.g., SYNLETT, 1995, volume 8, page 839-840, etc.), a method similar thereto, or a combination thereof with a conventional method.

The amount of the reducing agent used is usually 1 to 20 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (11).

The reaction temperature is usually 0 to 80 ℃ and preferably 0 ℃ to room temperature.

The reaction time is usually 0.1 to 24 hours, preferably 0.1 to 3 hours.

The reaction solvent to be used is not particularly limited as long as it does not hinder the reaction, and for example, methanol, N-dimethylformamide, ethyl acetate, tetrahydrofuran, and the like, and a mixed solvent thereof can be used.

The compound (12) thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 8)

This step is a method for producing compound 13 by reacting compound (13) with compound (12) obtained in step 7.

The reaction in this step may be carried out, for example, by a so-called mitsunobu reaction (step 8-1), or a nucleophilic reaction in the presence of a base (step 8-2).

(step 8-1)

The reaction in this step is a so-called mitsunobu reaction, and is carried out according to a method described in The literature (for example, Mitsunobu. O, The use of ethylene diamine and triphenylphosphine in Synthesis and transformation of natural products, Synthesis, volume 1, 1981, pages 1 to 28), a method similar thereto, or a combination thereof with a conventional method, in The presence of a phosphine compound and an azo compound.

Examples of the compound (13) to be used include succinimide, morpholine-3, 5-dione, phthalimide, 1-methylhydantoin, and 1-methyluracil.

The amount of the compound (13) used is usually 0.5 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (12).

The phosphine compound to be used is usually, for example, triphenylphosphine, triethylphosphine or the like.

The amount of the phosphine compound to be used is usually 0.5 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (12).

Examples of the azo compound to be used include diethyl azodicarboxylate and diisopropyl azodicarboxylate.

The amount of the azo compound used is usually 0.5 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (12).

The reaction time in this step is usually 1 to 48 hours, preferably 4 to 12 hours.

The reaction temperature in this step is usually 0 ℃ to the reflux temperature of the reaction solvent, preferably 15 to 30 ℃.

The reaction solvent used in the present step is not particularly limited as long as it does not inhibit the reaction, and specific examples thereof include tetrahydrofuran and toluene.

The compound (14) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 8-2)

This step is a method for producing compound (14) by reacting compound (12) with compound (13) in the presence of a base.

Examples of the base used include sodium hydride, butyllithium, and lithium diisopropylamide.

The amount of the base used is usually 0.5 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (12).

Specific examples of the compound (13) to be used include: the same compounds as exemplified in the above step 8-1, pyrrolidone, oxazolone, 3-methyluracil, 1-methylimidazolidone and the like.

The reaction temperature is usually-78 to 50 ℃ and preferably 0 ℃ to room temperature.

The reaction time is usually 0.1 to 24 hours, preferably 0.1 to 6 hours.

The reaction solvent may be any reaction solvent as long as it does not hinder the reaction, and examples thereof include N, N-dimethylformamide, tetrahydrofuran, and dichloromethane.

(step 8-3)

This step is a method for producing the compound (15) by oxidizing the hydroxyl group of the compound (12) obtained in the above step 7.

The reaction in this step can be carried out according to a method described in the literature (for example, Journal of the American Chemical Society, 1967, vol. 89, pp. 5505-5507), a method similar thereto, or a combination thereof with a conventional method.

The compound (15) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 9)

In this step, the protecting group R for an amino group of the compound (14) obtained in the above step 8-1 or 8-2 is^proA process for producing the compound (I-1) of the present invention by removing it.

The removal of the protecting group can be carried out according to a method described in the literature (e.g., Protective group in Organic Synthesis, T.W.Green, 2 nd edition, published by John Wiley & Sons, 1991), a method similar thereto, or a combination thereof with a conventional method, and for example, when the protecting group is an SEM group, the SEM group can be removed by reacting the compound (14) with trifluoroacetic acid.

The compound (I-1) thus obtained can be isolated and purified by a known separation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, and the like.

(step 10)

This step is a method for producing compound (17) by reacting compound (16) with compound (15) obtained in step 8-3.

Ar in Compound (16) and Compound (17)¹The same meanings as those of Ar are shown.

Examples of the compound (16) to be used include 4-fluorophenylmagnesium bromide, 2-fluorophenylmagnesium bromide, 3-lithium-2-fluoropyridine and the like.

The amount of the compound (16) used is usually 1 to 5 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of the compound (15).

The reaction temperature is usually from-78 to 50 ℃ and preferably from-78 ℃ to room temperature.

The reaction time is usually 0.1 to 24 hours, preferably 0.1 to 12 hours.

The reaction solvent may be any reaction solvent as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran and diethyl ether.

The compound (17) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 11)

This step is a method for producing the compound (I-2) of the present invention by removing the protecting group of the compound (17) obtained in the above step 10.

The reaction of this step can be carried out in the same manner as in the above-mentioned step 9, in a similar manner thereto, or in combination with a conventional method.

The compound (I-2) of the present invention obtained as described above can be isolated and purified by a known separation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, and the like.

The above compound (12) can also be produced by the following method.

[ in the formula, R⁷Represents a lower alkyl group, M represents a metal atom, and the other symbols are the same as those described above]。

(step 12)

This step is a method for producing compound (19) by reacting compound (18) with compound (5) described above.

The reaction of this step can be carried out in the same manner as in the above step 3, in a similar manner thereto, or in combination with a conventional method.

Examples of the compound (18) to be used include 4-bromo-3-fluoroaniline and 3-bromo-5-fluoroaniline.

The compound (19) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 13)

This step is a method for producing compound (20) by reacting compound (19) obtained in step 12 with potassium nitrate in the presence of an acid.

The amount of potassium nitrate used is usually 1 to 100 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of the compound (19).

The amount of the acid used is usually 1 equivalent to the solvent amount, preferably 1 to 100 equivalents, relative to 1 equivalent of the compound (19).

The reaction temperature is usually from 0 ℃ to the reflux temperature of the reaction solvent, preferably from room temperature to 100 ℃.

The reaction time is usually 0.1 to 72 hours, preferably 0.5 to 12 hours.

Any reaction solvent may be used as long as it does not hinder the reaction, and examples thereof include chloroform and dichloromethane.

The compound (20) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 14)

This step is a method for producing a compound (21) by reacting the compound (20) obtained in the above step 13 with a compound (7).

The reaction of this step can be carried out in the same manner as in the above step 4, in a similar manner thereto, or in combination with a conventional method.

The compound (21) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 15)

This step is a method for producing the compound (22) by reducing the nitro group of the compound (21) obtained in the above step 14.

The reaction in this step can be carried out in the same manner as in the above-mentioned step 2 or 5, in a similar manner thereto, or in combination with a conventional method.

The compound (22) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 16)

This step is a method for producing compound (23) by reacting compound (22) obtained in step 15 with compound (10).

The reaction in this step can be carried out in the same manner as in step 6 described above, in a similar manner thereto, or in combination with a conventional method.

The compound (23) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 17)

This step is a method for producing a compound (25) by reacting the compound (23) obtained in the above step 16 with a compound (24) in the presence of a metal catalyst.

Examples of the compound (24) to be used include tributyl (vinyl) tin, and potassium vinyltrifluoroborate described in the literature (Organic Letters, 2002, vol. 4, No. 1, p. 107-109, etc.).

The amount of the compound (24) used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (23).

Examples of the metal catalyst to be used include tetrakis (triphenylphosphino) palladium, dichlorobis (triphenylphosphino) palladium, and dichloro (1, 1' -bis (diphenylphosphino) ferrocene) palladium.

The amount of the metal catalyst used is usually 0.01 to 10 equivalents, preferably 0.05 to 5 equivalents.

The reaction solvent used in the present step is not particularly limited as long as it does not hinder the reaction, and examples thereof include ethylene glycol dimethyl ether, water, toluene, tetrahydrofuran, N-dimethylformamide, 1, 4-dioxane, benzene, acetone, and isopropyl alcohol.

The reaction temperature in this step is usually 0 ℃ to the reflux temperature of the reaction solvent, preferably room temperature to 150 ℃. The reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 12 hours.

The compound (25) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 18)

This step is a method for producing the diol compound (26) by oxidizing the compound (25) obtained in the above step 17.

The reaction in this step is carried out by reacting compound (25) with osmium oxide.

4-methylmorpholine-N-oxide may coexist in the reaction system.

The amount of osmium oxide to be used is usually 0.001 to 3 equivalents, preferably 0.01 to 0.5 equivalent, relative to 1 equivalent of the compound (25).

The amount of 4-methylmorpholine-N-oxide used is generally 1 to 50 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (25).

The reaction temperature is usually 0 to 70 ℃ and preferably 0 ℃ to room temperature.

The reaction time is usually 0.5 to 72 hours, preferably 6 to 48 hours.

Any reaction solvent may be used as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran, water, acetone, ethylene glycol dimethyl ether, N-dimethylformamide, 1, 4-dioxane, and isopropanol.

The compound (26) thus obtained can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 19)

This step is a method for producing the compound (27) by oxidizing the compound (26) obtained in the above-mentioned step 18.

The reaction in this step can be carried out by reacting compound (26) with sodium periodate.

The amount of sodium periodate used is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (26).

The reaction temperature is usually 0 to 80 ℃ and preferably room temperature to 50 ℃.

The reaction time is usually 0.5 to 72 hours, preferably 12 to 48 hours.

The reaction solvent may be any reaction solvent as long as it does not hinder the reaction, and examples thereof include water, tetrahydrofuran, acetone, ethylene glycol dimethyl ether, N-dimethylformamide, 1, 4-dioxane, and isopropyl alcohol.

The compound (27) thus obtained can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 20)

This step is a method for producing the compound (12) by reducing the compound (27) obtained in the above-mentioned step 19.

The reaction in this step can be carried out by reacting compound (27) with a reducing agent.

Examples of the reducing agent to be used include sodium borohydride, sodium triacetoxyborohydride and the like.

The amount of the reducing agent used is usually 1 to 50 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of the compound (27).

The reaction temperature is usually 0 to 100 ℃ and preferably 0 to 50 ℃.

The reaction time is usually 0.1 to 72 hours, preferably 0.5 to 24 hours.

The reaction solvent may be any reaction solvent as long as it does not hinder the reaction, and examples thereof include methanol, tetrahydrofuran, 1, 4-dioxane, and isopropyl alcohol.

The compound (12) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the step 8 above without isolation and purification.

The compound (12-1) contained in the compound (12) can be prepared by the following method.

[ in the formula, L₃Represents a leaving group, R^PROA protective group for an aromatic amino group, the other symbols being as defined above]。

(step 22)

This step is a method for producing compound (30) by reacting compound (29) with compound (2) in the presence of an acid catalyst.

Examples of the compound (29) to be used include 5-fluoro-2-nitrobenzoic acid.

The reaction in this step can be carried out in the same manner as in step 1 above, in a similar manner thereto, or in combination with a conventional method.

The compound (30) thus obtained can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 23)

This step is a method for producing compound (31) by reacting compound (7) with compound (30) obtained in step 22.

The reaction in this step can be carried out in the same manner as in the above step 4, in a similar manner thereto, or in combination with a conventional method.

The compound (31) thus obtained can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 24)

This step is a method for producing the compound (32) by reducing the nitro group of the compound (31) obtained in the above step 23.

The reaction in this step can be carried out in the same manner as in step 2 described above, in a similar manner thereto, or in combination with a conventional method.

The compound (32) thus obtained can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 25)

This step is a method for producing a compound (33) by reacting the compound (32) obtained in the above step 24 with a compound (5).

The reaction in this step can be carried out in the same manner as in step 3 described above, in a similar manner thereto, or in combination with a conventional method.

The compound (33) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 26)

This step is a method for producing the compound (34) by reacting the compound (33) obtained in the above step 25 with potassium nitrite in the presence of an acid.

The reaction in this step can be carried out in the same manner as in step 13 described above, in a similar manner thereto, or in combination with a conventional method.

The compound (34) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 27)

This step is a method for producing the compound (35) by reacting the nitro group of the compound (34) obtained in the above step 26.

The reaction in this step can be carried out in the same manner as in the above step 5, in a similar manner thereto, or in combination with a conventional method.

The compound (35) thus obtained can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 28)

This step is a method for producing compound (36) by reacting compound (35) obtained in step 27 above with compound (10).

The compound (36) thus obtained can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 29)

This step is a method for producing a compound (37) by reducing the compound (36) obtained in the above-mentioned step 28.

The reaction in this step can be carried out in the same manner as in the above step 7, in a similar manner thereto, or in combination with a conventional method.

The compound (37) thus obtained can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 30)

This step is carried out by removing the protecting group R of the aromatic amino group of the compound (37) obtained in the above-mentioned step 29^ProA process for producing the compound (12-1).

The reaction in this step can be carried out in the same manner as in step 9 described above, in a similar manner thereto, or in combination with a conventional method.

The compound (12-1) thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

The compound represented by the compound (I-1-1) of the present invention or a pharmaceutically acceptable salt thereof can be produced, for example, by the following method.

[ in the formula, the symbols are as defined above ].

(step 31)

This step is a method for producing compound (39) by reacting compound (38) with compound (7) in the presence of a base.

The compound (38) used in the present step may be a commercially available compound or a compound synthesized by a method known to those skilled in the art using a commercially available compound as a starting material, a method similar thereto, or a combination thereof with a conventional method, and specifically, for example, 2-chloro-5-nitrobenzaldehyde or the like may be used.

The amount of the compound (7) used in the present step is usually 0.1 to 20 equivalents, preferably 0.5 to 5 equivalents, relative to 1 equivalent of the compound (38).

The compound (7) used may be the same as the compound listed in the above step 4.

The amount of the base used is usually 0.1 to 20 equivalents, preferably 0.5 to 5 equivalents, relative to 1 equivalent of the compound (38).

The base used may be any base as long as it can produce the compound (39) in the reaction of the compound (38) with the compound (7) in the present step, and examples thereof include sodium hydride, cesium carbonate, sodium carbonate, potassium phosphate, potassium acetate, potassium tert-butoxide, triethylamine and the like, and among them, potassium carbonate, cesium carbonate and the like are preferable.

The reaction time is usually 0.1 to 72 hours, preferably 0.5 to 5 hours.

The compound (39) thus obtained can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 32)

This step is a method for producing a compound (41) by reacting a compound (39) with a compound (40).

Examples of the compound (40) used in the present step include compounds wherein R is methylethyl.

As the compound (40), an acid addition salt such as hydrochloride can be used, and when an acid addition salt of the compound (40) is used, a base such as triethylamine can be added to the reaction system.

The amount of the compound (40) used is usually 0.5 to 20 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of the compound (39).

The amount of the base used is an approximately equimolar amount with respect to 1 equivalent of the compound (40).

Examples of the reducing agent used in this step include triacetoxyborohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.

The amount of the hydrogenation agent used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (39).

The reaction solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include methanol, ethanol, acetic acid, tetrahydrofuran, dichloromethane, and a mixed solvent thereof, and among them, methanol, ethanol, tetrahydrofuran, and a mixed solvent thereof are preferable.

The reaction time is usually 1 hour to 8 hours, preferably 1 hour to 24 hours.

The reaction temperature is usually from 0 ℃ to 100 ℃, preferably from 0 ℃ to 40 ℃.

The compound (41) thus obtained can be isolated and purified by a known separation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, and the like.

(step 33)

This step is a method for producing the compound (42) by reducing the nitro group of the compound (41).

The reduction reaction in this step may be carried out, for example, by a contact reduction reaction using a catalyst such as Raney nickel under a hydrogen atmosphere.

The amount of Raney nickel or the like in this step is 0.001 to 5 equivalents, preferably 0.01 to 1 equivalent, relative to 1 equivalent of the compound (41).

The reaction temperature is usually 0 to 80 ℃ and preferably 20 to 50 ℃.

The reaction time is usually 1 to 24 hours, preferably 1 to 10 hours.

The compound (42) obtained above can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 34)

This step is a method for producing the compound (3) by reacting the carboxylic acid derivative (5) or a reactive derivative thereof with the compound (42).

The reaction can be carried out by a conventional amide-forming reaction according to a method described in the literature (e.g., a method for the basic and experimental peptide Synthesis, kukukungfu et al, bolus, 1983, Comprehensive Organic Synthesis, vol. 6, Pergamon Press, 1991, etc.), a method similar thereto or a combination thereof with a conventional method, that is, by using a condensing agent well known to those skilled in the art, or by an ester activation method, a mixed acid anhydride method, an acid chloride method, a carbodiimide method, etc., which can be used by those skilled in the art. Examples of the amide-forming reagent include thionyl chloride, oxalyl chloride, N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridine iodide, N ' -carbonyldiimidazole, diphenylphosphoryl chloride, diphenylphosphoryl azide, N ' -disuccinyl dicarbonate, N ' -disuccinyl oxalate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, ethyl chloroformate, isobutyl chloroformate, or benzotriazol-1-yl-oxy-tris (dimethylamino) hexafluorophosphate, and the like, and among these, thionyl chloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N-dicyclohexylcarbodiimide, or benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate is preferable, and the like ) Hexafluorophosphoric acid _, and the like. In the amide forming reaction, a base or a condensation assistant may be used together with the amide forming reagent.

Examples of the base to be used include tertiary aliphatic amines such as trimethylamine, triethylamine, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N-dimethylaniline, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), and 1, 5-azabicyclo [4.3.0] non-5-ene (DBN); examples of the amine include aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline, among which aliphatic tertiary amines are preferable, and triethylamine and N, N-diisopropylethylamine are particularly preferable.

Examples of the condensation assistant to be used include N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, N-hydroxy-5-norbornene-2, 3-dicarboximide, and 3-hydroxy-3, 4-dihydro-4-oxo-1, 2, 3-benzotriazole, and among these, N-hydroxybenzotriazole is preferable.

The amount of the compound (42) to be used varies depending on the kind of the compound and the solvent to be used and other reaction conditions, and is usually 0.1 to 10 equivalents, preferably 0.5 to 3 equivalents, relative to 1 equivalent of the carboxylic acid derivative (5) or its reactive derivative.

The amount of the amide-forming reagent to be used varies depending on the kind of the compound and the solvent to be used, and other reaction conditions, and is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the carboxylic acid derivative (5) or its reactive derivative.

The amount of the condensation assistant used varies depending on the kind of the compound and the solvent used, and other reaction conditions, and is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the carboxylic acid compound (5) or its reactive derivative.

The amount of the base used varies depending on other reaction conditions such as the kind of the compound and the solvent used, and is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of the compound (42).

The reaction solvent used in the present step is not particularly limited as long as it is an inert solvent and does not hinder the reaction, and specific examples thereof include dichloromethane, chloroform, 1, 2-dichloroethane, N-dimethylformamide, ethyl acetate, methyl acetate, acetonitrile, benzene, xylene, toluene, 1, 4-dioxane, tetrahydrofuran, dimethoxyethane, and a mixed solvent thereof, and in view of ensuring an appropriate reaction temperature, for example, dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, and the like are preferable.

The reaction temperature in this step is usually from-78 ℃ to the boiling temperature of the solvent, preferably from 0 to 30 ℃.

The reaction time in this step is usually 0.5 to 96 hours, preferably 3 to 24 hours.

The base, the amide forming agent, and the condensation assistant used in this step may be used singly or in combination of two or more.

The compound (43) thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 35)

This step is a method for producing the compound (44) by reacting the compound (43) with fuming nitric acid.

The amount of fuming nitric acid used in this step is usually 1 to 100 equivalents, preferably 2 to 20 equivalents, relative to 1 equivalent of the compound (43).

The reaction temperature is usually 0 to 100 ℃ and preferably 10 to 50 ℃.

The reaction time is usually 0.1 to 48 hours, preferably 0.5 to 12 hours.

Compound (44) can be produced by reacting compound (43) described above with potassium nitrate in the presence of an acid.

The amount of the acid used is usually 1 equivalent to the solvent amount, preferably 1 to 100 equivalents, relative to 1 equivalent of the compound (6). The reaction temperature is usually from 0 ℃ to the reflux temperature of the solvent, preferably from room temperature to 100 ℃.

The reaction time is usually 0.1 to 72 hours, preferably 0.5 to 12 hours.

The reaction solvent may be any reaction solvent as long as it does not hinder the reaction, and examples thereof include chloroform and dichloromethane.

The compound (44) thus obtained can be isolated and purified by a known isolation and purification method, for example, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be used in the subsequent step without isolation and purification.

(step 45)

This step is a method for producing the compound (I-1-1) of the present invention by reducing the nitro group possessed by the compound (44) and then carrying out a cyclization reaction.

Examples of the reducing agent used in this step include tin chloride(SnCl₂) And the like. As the reducing agent, a hydrate thereof or the like can be used.

The amount of the reducing agent used in this step is usually 1 to 20 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of the compound (44).

Examples of the base used in this step include triethylamine.

The amount of the base used is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of the compound (44).

The reaction temperature is usually from 0 ℃ to 100 ℃, preferably from 20 ℃ to 80 ℃.

The reaction time is usually 0.5 to 20 hours, preferably 1 to 5 hours.

The reaction solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include methanol, chloroform, N-dimethylformamide, ethyl acetate, tetrahydrofuran, and the like, and a mixed solvent thereof.

The compound (I-1-1) thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

The aryloxy-substituted benzimidazole derivative provided by the present invention may be present in the form of a pharmaceutically acceptable salt, which can be prepared according to a conventional method using the compound represented by the above formula (I-1) or (I-2) contained in the compound (I) of the present invention.

Specifically, when the compound of the above formula (I-1) or (I-2) has a basic group derived from, for example, an amino group, a pyridyl group or the like in the molecule, the compound can be converted into a corresponding pharmaceutically acceptable salt by treating the compound with an acid.

Examples of the acid addition salts include hydrohalic acid salts such as hydrochloride, hydrofluoride, hydrobromide and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate, and carbonate; lower alkylsulfonic acid salts such as methanesulfonic acid salt, trifluoromethanesulfonic acid salt, ethanesulfonic acid salt and the like; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate and maleate; and acid addition salts of organic acids such as amino acids including glutamate and aspartic acid ammonia. When the compound of the present invention has an acidic group in its group, for example, a carboxyl group, the compound can be converted into a corresponding pharmaceutically acceptable salt by treating the compound with a base. Examples of the base addition salt include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and salts with organic bases such as ammonium salts, guanidine, triethylamine, and dicyclohexylamine. The compounds of the invention may also be present in the form of any hydrate or solvate of the free compound or salt thereof.

The compound of formula (I) of the present invention may be used in combination with a carrier substance in the preparation of a prophylactic or therapeutic agent for type II diabetes or a disease or condition associated therewith.

The amount of the compound of formula (I) of the present invention to be administered in the prophylaxis or treatment will, of course, vary depending on the nature of the condition to be treated, the particular compound selected and the route of administration.

But also on age, weight and the variability of the individual patient's sensitivity. Generally, the amount administered is from about 0.001mg to about 100mg per day in a single or multiple dose of 1kg body weight, preferably from about 0.01mg to about 50mg per day of 1kg body weight, more preferably from about 0.1mg to about 10mg per day. It is also necessary to use an amount exceeding the above-defined range.

Examples of suitable orally administered amounts are at least about 0.01mg and at most 2.0g in a single dose or in 2-4 divided doses per day. Preferred amounts for administration range from about 1.0mg to about 200mg administered once or twice daily. More preferably, the amount is in the range of 10mg to 100mg once daily.

When administered intravenously or orally, a typical administration range is from about 0.001mg to about 100mg (preferably from 0.01mg to about 10mg) of the compound of formula (I) per day, 1kg body weight, more preferably from about 0.1mg to 10mg per day, 1kg body weight.

As described above, the pharmaceutical composition comprises a compound of formula (I) and a pharmaceutically acceptable carrier. "composition" means a composition, which is obtained by combining, complexing, or coagulating two or more of any of the components, either directly or indirectly; separating one or more components; or as a result of other types of interactions or interactions between the ingredients, and in addition to that, active and inert ingredients (pharmaceutically acceptable excipients) which constitute the carrier.

Preferably a pharmaceutically acceptable carrier, in combination with an amount of a compound of formula (I) effective for the treatment, prevention or delay of onset of type II diabetes.

For administering an effective amount of a compound of the present invention to a mammal, particularly a human, any suitable route of administration may be employed. For example, oral, rectal, topical, intravenous, ocular, pulmonary, nasal, etc. administration may be used. Examples of administration forms are tablets, troches, powders, suspensions, solutions, capsules, ointments, aerosols, etc., preferably tablets for oral administration.

When preparing a composition for oral administration, any usual pharmaceutical media can be used, and examples thereof include water, glycols, oils, alcohols, flavor additives, preservatives, coloring agents, and the like; for preparing liquid compositions for oral use, there are, for example, suspensions, elixirs and solutions, and carriers such as starches, sucrose, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like; examples of the solid composition for oral administration include powder, capsule, and tablet, and among them, the solid composition for oral administration is preferable.

Tablets or capsules are the most advantageous form of oral administration in view of ease of administration, and tablets may be coated, if desired, by standard aqueous or non-aqueous techniques.

In addition to the usual forms of administration described above, the compounds of formula (I) may be administered by controlled release methods and/or delivery devices as described, for example, in U.S. patent nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 3,630,200 and 4,008,719.

The pharmaceutical compositions of the present invention suitable for oral administration may be in the form of powder or granules, or in the form of water-soluble liquid, water-insoluble liquid, oil-in-water emulsion or water-in-oil emulsion, formulated into capsules, カシユ tablets containing a predetermined amount of active ingredient. The above compositions may be prepared by any of the methods in pharmacy, all of which methods comprise bringing into association the active ingredient and the carrier which comprises one or more of the necessary ingredients.

In general, the compositions can be prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or an intimately dispersed solid carrier or both, and then bringing the product into an appropriate form, if necessary. For example, a tablet can be prepared by compression and molding, and if necessary, together with one or two or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredient freely, in powder or granule form, by suitable machinery, and optionally mixing with a binder, lubricant, inert excipient, surfactant or dispersant.

Shaped tablets may be prepared by suitably mechanically shaping a mixture of the wet compound in powder form and an inert liquid diluent.

Preferably, each tablet contains about 1mg to 1g of active ingredient, each カシユ a vehicle or capsule containing about 1mg to 500mg of active ingredient.

Examples of pharmaceutical administration forms of the compounds of formula (I) are as follows.

(Table 1)

Injectable suspension (I.M.)

mg/mL

Compound 10 of formula (I)

Methyl cellulose 5.0

Tween 800.5

Benzyl alcohol 9.0

Benzalkonium chloride 1.0

Adding water for injection to make into 1.0mL

(Table 2)

Tablet formulation

mg/tablet

Compound 25 of formula (I)

Methylcellulose 415

Tween 8014.0

Benzyl alcohol 43.5

Magnesium stearate 2.5

Total 500mg

(Table 3)

Capsule preparation

mg/capsule

Compound 25 of formula (I)

Lactose powder 573.5

Magnesium stearate 1.5

Total 600mg

(Table 4)

Aerosol and method of making

Each container

24mg of a Compound of formula (I)

Lecithin, NF Liq. Con. 1.2mg

Trichlorofluoromethane, NF 4.025g

Dichlorodifluoromethane, NF 12.15g

The compounds of formula (I) may be used not only for diseases or conditions associated with type II diabetes, but also in combination with other drugs for the treatment/prevention/delay of onset of type II diabetes. The other drug may be administered simultaneously or separately with the compound of formula (I) according to a commonly used administration route or administration amount.

When the compound of formula (I) is used simultaneously with one or more drugs, a pharmaceutical composition containing the compound of formula (I) and the above-mentioned other drugs is preferred. Accordingly, the pharmaceutical compositions of the present invention comprise, in addition to the compound of formula (I), one or more further active ingredients. Examples of the active ingredient used in combination with the compound of formula (I) are as follows, and they may be administered separately or in the same pharmaceutical composition, but are not limited to the drugs described below.

(a) Other glucokinase activators,

(b) Biguanides (e.g. buformin, metformin, phenformin),

(c) PPAR agonists (troglitazone, pioglitazone, nosiglitazon),

(d) Insulin, insulin,

(e) Somatostatin

(f) Alpha-glucosidase inhibitors (e.g. voglibose, miglitol, acarbose),

(g) Insulin secretion enhancers (acetohexamide, chlorbutamide, chlorpropamide, glybomide, gliclazide, glyerpide, glipizide, glyquindine, glimeperide, glyburide, glibenclamide, chlordiazuron, phenbutamide, tolazamide, tolbutamide, tolcyclamide, nateglinide, repaglinide), and

(h) DPP-IV inhibitors (dipeptidyl peptidase IV inhibitors),

the weight ratio of the compound of formula (I) to the second active ingredient may vary within wide limits and is related to the effective amount of each active ingredient. Thus, for example, when a compound of formula (I) is used in combination with a PPAR agonist, the weight ratio of the compound of formula (I) to the PPAR agonist is generally from about 1000: 1 to 1: 1000, preferably from about 200: 1 to 1: 200. Although it is stated that the combination of the compound of formula (I) with the other active ingredients should be within the above-mentioned ranges, an effective amount of each active ingredient should be used in any case.

Next, the glucokinase activating ability exhibited by the compound represented by the compound (I) of the present invention and the test method thereof will be described.

The excellent glucokinase activation of the compound represented by the above formula (I) can be measured by a method described in the literature (for example, Diabetes, Vol. 45, pp. 1671-1677, 1996, etc.) or a method similar thereto.

The degree of glucokinase activation was investigated by measuring the amount of Thio-NADH produced when phosphogluconolactone is produced from glucose-6-phosphate by glucose-6-phosphate-dehydrogenase, which is a reporter enzyme, instead of directly measuring glucose-6-phosphate.

Recombinant human liver GK used in this assay was expressed in e.coli as FLAG fusion protein and purified by ANTIFLAG M2 AFFINITY GEL (Sigma).

The assay was performed at 30 ℃ using flat bottom 96-well plates. 69. mu.l of a test buffer (25mM Hepes buffer: pH 7.2, 2mM MgCl)₂1mM ATP, 0.5mM TNAD, and 1mM dithiothreitol), 1. mu.l of a DMSO solution of the compound or DMSO as a control was added, 20. mu.l of an enzyme mixture (FLAG-GK, 20U/ml G6PDH) cooled in ice water was dispensed, and 10. mu.l of 25mM glucose as a substrate was added to initiate a reaction (final glucose concentration: 2.5 mM).

After the reaction was started, the increase in absorbance at 405nm was measured every 30 seconds for 12 minutes, and the compound was evaluated using the increase of the first 5 minutes. The increase in FLG-GK is: in the presence of 1% DMSO, the absorbance increased between 0.04 and 0.06 after 5 minutes.

The OD value of each compound was measured at each concentration with the OD value of the DMSO control as 100%. From the OD values at each concentration, Emax (%) and EC50(μ M) were calculated as indices of GK activity of the compound.

The GK activity of the compounds of the invention was determined by this method. The results are shown in Table 5 below.

(Table 5)

(GK activation energy of Compound of the present invention)

Compound number Emax (%) EC50(μ M)

Example 110900.12

Example 319820.49

Example 658050.36

Therefore, the compound of the present invention has excellent GK activation energy with Emax and EC50 as indicators.

Examples

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Formulation example 1

10 parts of the compound of production example 1, 15 parts of heavy magnesium oxide and 75 parts of lactose were uniformly mixed to prepare powder of 350 μm or less in powder form and fine particles. The powder is filled into a capsule container to be made into capsules.

Preparation example 2

45 parts of the compound of formulation example 1, 15 parts of starch, 16 parts of lactose, 21 parts of crystalline cellulose, 3 parts of polyvinyl alcohol and 30 parts of distilled water were uniformly mixed, and then crushed, granulated, dried and sieved to prepare granules having a particle size of 1410-.

Preparation example 3

Granules were prepared in the same manner as in preparation example 2, and then 96 parts of the granules were added with 3 parts of calcium stearate and compression-molded to prepare tablets having a diameter of 10 mm.

Preparation example 4

To 90 parts of the granules obtained by the method of preparation example 2, 10 parts of crystalline cellulose and 3 parts of calcium stearate were added, compression-molded to prepare tablets having a diameter of 8mm, and then a mixed suspension of gelatin syrup (syrup gel) and precipitated calcium carbonate was added to prepare sugar-coated tablets.

The present invention will be further specifically described below by way of formulation examples, preparation examples and reference examples, but the present invention is not limited thereto at all.

The thin layer chromatography of the examples was performed using silica gel 60F₂₄₅(Merck) as thin layer plate, UV detector was used as detection means. Using a Wakogel^TMC-300 (Wako pure chemical industries, Ltd.) as silica gel for column, and LC-SORB was used^TMSP-B-ODS (Chemco) or YMC-GEL^TMODS-AQ120-S50 was used as a gel for reverse-phase column (Yamamura chemical research institute).

The abbreviations in the following examples have the following meanings.

i-Bu: isobutyl radical

n-Bu: n-butyl

t-Bu: tert-butyl radical

Me: methyl radical

Et: ethyl radical

Ph: phenyl radical

i-Pr: isopropyl group

n-Pr: n-propyl radical

CDCl₃: deuterated chloroform

CD₃OD: deuterated methanol

DMSO-d₆: deuterated dimethyl sulfoxide

The following is a shorthand notation of NMR spectra

s: single peak

d: double peak

dd: double peak

t: triplet peak

m: multiple peaks

br: broad peak

q: quartet peak

J: coupling constant

Hz: hertz's scale

Example 1

1- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all Radical } pyrrolidine-2, 5-dione

(step 1) Synthesis of N- (4-bromo-3-fluorophenyl) -2-pyridinecarboxamide

To a solution of 1g of 4-bromo-3-fluoroaniline in 30ml of chloroform were added 2.9ml of triethylamine and 1.87g of picolinoyl chloride hydrochloride, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with chloroform, washed with saturated sodium bicarbonate water and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, it was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 4/1), to give 1.44g of the title compound as pale yellow crystals.

(step 2) Synthesis of N- (4-bromo-5-fluoro-2-nitrophenyl) -2-pyridinecarboxamide

1.71g of potassium nitrite was dissolved in 10ml of N- (4-bromo-3-fluorophenyl) -2-pyridinecarboxamide and stirred at 70 ℃ overnight. After the solvent was distilled off, the mixture was diluted with chloroform and washed with saturated sodium bicarbonate water and saturated brine. Drying over anhydrous magnesium sulfate and then distilling off the solvent gave 1.17g of the title compound as yellow crystals.

(step 3) Synthesis of N- { 4-bromo-5- (4- (methylsulfonyl) phenoxy) -2-nitrophenyl } -2-pyridinecarboxamide

100mg of N- (4-bromo-5-fluoro-2-nitrophenyl) -2-pyridinecarboxamide and 55mg of 4- (methylsulfonyl) phenol obtained in reference example 1, 88mg of potassium carbonate were suspended in 2ml of dimethylformamide, and stirred at 70 ℃ for 30 minutes. The reaction solution was returned to room temperature, water was then added thereto, and the resulting crystals were collected by filtration to obtain 145mg of the title compound as pale yellow crystals.

(step 4) Synthesis of 6-bromo-5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazole

145mg of N- { 4-bromo-5- (4- (methylsulfonyl) phenoxy) -2-nitrophenyl } -2-pyridinecarboxamide were suspended in 1ml of dimethylformamide, 1ml of methanol and 0.5ml of concentrated hydrochloric acid, 327mg of tin (II) chloride dihydrate were added, and the mixture was stirred at 70 ℃ for 30 minutes. The reaction solution was neutralized with sodium hydrogencarbonate and diluted with chloroform. Insoluble matter was filtered off, and then the filtrate was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off to leave 121mg of the title compound as pale yellow crystals.

(step 5) Synthesis of 6-bromo-5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole and 5-bromo-6- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole

6.50g of 6-bromo-5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazole was dissolved in 65ml of dimethylformamide, and 0.71g of sodium hydride (to which 30% liquid paraffin was added) was added under ice-cooling. After stirring for 15 minutes, 3.9ml of 2-trimethylsilyl-ethoxymethyl chloride were added and stirred for a further 30 minutes. Saturated ammonium chloride water was added, the mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off and purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 9/1 → 6/4) to give 7.39g of the title compound as pale yellow crystals.

(step 6) Synthesis of 5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -6-vinyl-1H-benzimidazole and 6- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -5-vinyl-1H-benzimidazole

1g of the crystal obtained in step 5 was dissolved in 10ml of toluene, 0.83g of tributyl (vinyl) tin and 0.1g of tetrakis (triphenylphosphine) palladium were added thereto, nitrogen substitution was performed, and then stirring was performed at 110 ℃ for 3 hours. Purification by silica gel column chromatography (developing solvent: hexane/ethyl acetate 9/1 → 3/1) gave 0.69g of the title compound as a white amorphous state.

(step 7) Synthesis of 1- (5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) -1, 2-ethanediol and 1- (6- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) -1, 2-ethanediol

0.69g of the vinyl compound obtained in step 6 was dissolved in 7ml of tetrahydrofuran and 1ml of water, and 0.23g of 4-methylmorpholine N-oxide and 17mg of osmium (VIII) oxide were added thereto, followed by stirring at room temperature overnight. Aqueous sodium thiosulfate solution was added, diluted with ethyl acetate, and the organic layer was washed with saturated brine. Dried over anhydrous magnesium sulfate, the solvent was distilled off, and then purified by silica gel column chromatography (developing solvent: chloroform → chloroform/methanol: 98/2), to give 0.57g of the title compound as a white amorphous state.

(step 8) Synthesis of 5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-6-carbaldehyde and 6- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-5-carbaldehyde

1.7g of the diol compound obtained in step 7 was dissolved in 16ml of chloroform, and 11ml of water and 0.84g of sodium periodate were added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was diluted with chloroform and washed with saturated brine. Dried over anhydrous magnesium sulfate, the solvent was distilled off, and then purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 9/1 → 3/1 → 1/1) to obtain 1.2g of the title compound as a white amorphous state.

(step 9) Synthesis of (5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) methanol or (6- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) methanol

100mg of the aldehyde compound obtained in step 8 was dissolved in 1ml of methanol, and 15mg of sodium borohydride was added thereto and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. Dried over anhydrous magnesium sulfate, the solvent was distilled off, and then purified by silica gel column chromatography (developing solvent: chloroform → chloroform/methanol-98/2), to give 94mg of the title compound as a white amorphous state.

(step 10) Synthesis of 1- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } pyrrolidine-2, 5-dione

50mg of the alcohol compound obtained in step 9, 47.5mg of succinimide and 127mg of triphenylphosphine were dissolved in 1ml of tetrahydrofuran, and 0.21ml of diethyl diethylazodicarboxylate (40% toluene solution) was added under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction solvent was distilled off, followed by purification by silica gel column chromatography (developing solvent: hexane/ethyl acetate: 9/1 → 5/5 → 8/2) to give 52.3mg of a yellow oil.

52.3mg of the resulting oil was dissolved in 1ml of trifluoroacetic acid and stirred at room temperature for 2 hours. The solvent was distilled off, neutralized with triethylamine,by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Ar 5744(Merck), chloroform/methanol 10/1) to yield 11.2mg of the title compound as a white solid.

¹H NMR(CDCl₃)δ：2.56(2H，m)，2.66(2H，m)，3.06(3H，s)，4.79(2H，s)，7.02-7.20(2H+1/2H，m)，7.40(1H，m)，7.44(1/2H，m)，7.65(1/2H，m)，7.76(1/2H，m)，7.85-7.90(3H，m)，8.35(m，1H)，8.64(m，1H)，10.5(br，1H)

ESI-MASS(m/e)：477[M+H]

Example 2

1- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 2-pyrrolidone radical

To a solution of 75mg of the alcohol compound obtained in example 1 (step 9) and 40. mu.l of triethylamine in 0.75ml of tetrahydrofuran was added 22. mu.l of methanesulfonyl chloride under ice-cooling, and the mixture was stirred for 30 minutes. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure to obtain 62mg of pale yellow amorphous substance.

To a solution of 62mg of the obtained amorphous and 46mg of 2-pyrrolidone in 0.5ml of dimethylformamide under ice-cooling, 22mg of sodium hydride (30% liquid paraffin was added) was added, and the mixture was stirred at room temperature for 40 minutes. Saturated aqueous ammonium chloride was added thereto under ice cooling, extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying, the solvent was distilled off under reduced pressure and purified by preparative thin layer chromatography (Kieselgel)^TM 60F₂₅₄Purified by wet purification with art5744(Merck) and chloroform/methanol 10/1 to yield 22.1mg of a colorless oil.

22.1mg of the resulting oil was dissolved in 1ml of trifluoroacetic acid and stirred at room temperature for 1 hour. The solvent was distilled off, neutralized with triethylamine and then purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄And Art5744(Merck) and chloroform/methanol 10/1 to yield 9.3mg of the title compound as a pale yellow amorphous substance.

¹H NMR(CDCl₃)δ：1.85-2.00(2H，m)，2.30-2.38(2H，m)，3.06(3H，s)，3.25-3.35(2H，m)，4.54(2H，m)，7.04-7.10(2H，m)，7.19(1/2H，s)，7.40(1H，m)，7.49(1/2H，s)，7.57(1/2H，s)，7.77(1/2H，s)，7.85-7.92(3H，m)，8.40(1H，m)，8.65(1H，m)，10.7(1/2H.brs)，10.8(1/2H，brs)

ESI-MS(m/e)：463[M+H]

Example 3

3- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 2-oxazolidinone radical

The title compound was obtained in the same manner as in example 2, in a similar manner thereto or in combination with a conventional method using 2-oxazolidinone.

¹HNMR(CDCl₃)δ：3.06(3H，s)，3.42-3.60(2H，m)，4.22-4.28(2H，m)，4.52(2H，m)，7.09(2H，m)，7.21(1/2H，s)，7.41(1H，m)，7.51(1/2H，s)，7.65(1/2H，s)，7.82-7.95(3H+1/2H，m)，8.40(1H，m)，6.67(1H，m)，10.7(br，1H)

ESI-MS(m/e)：465[M+H]

Example 4

1- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl ]First of all Yl-piperidine-2, 6-dione

The title compound was obtained using glutarimide by the same method as in example 1 (step 10), a method similar thereto, or a combination thereof with a conventional method.

¹HNMR(CD₃OD)δ：0.93(1H，m)，1.29(1H，s)，1.85-1.92(2H，m)，2.66(2H，m)，.3.11(3H，s)，5.02(2H，s)，7.14(m，2H)，7.29(s，1H)，7.49(m，2H)，7.87-7.98(3H，m)，8.26(1H，m)，8.71(1H，m)

ESI-MASS(m/e)：491(M+H)

Example 5

1- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 2(1H) -pyridones

The title compound was obtained by using 2-hydroxypyridine in the same manner as in example 2, in a similar manner thereto, or in combination with a conventional method.

¹HNMR(CDCl₃)δ：3.05(3H，s)，5.21(2H，s)，6.08(1H，m)，6.56(1H，m)，7.07(2H，m)，7.26(1H，m)，7.37(2H，m)，7.42(1H，s)，7.74(1H，s)，7.87(3H，m)，8.35(1H，m)，8.62(1H，m)

ESI-MASS(m/e)：473(M+H)

Example 6

1- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all Phenyl } -piperidones

The title compound was obtained by the same method as in example 2, a method similar thereto, or a combination thereof with a conventional method using δ -valerolactone.

¹HNMR(CDCl₃)δ：0.91(2H，m)，1.75(2H，m)，2.37(2H，m)，3.04(3H，s)，3.24(2H，m)，4.66(2H，s)，7.06(2H，m)，7.37-7.40(1H，m)，7.53(1H，m)，7.68(1H，m)，7.86(3H，m)，8.38(1H，m)，8.64(1H，m)

ESI-MASS(m/e)：477

Example 7

2- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 1H-isoindole-1, 3(2H) -dione

The title compound was obtained by using phthalimide in the same manner as in example 1 (step 10), in a similar manner thereto, or in combination with a conventional method.

¹H NMR(CDCl₃)δ：3.03(3H，s)，4.99(2H，s)，7.05(3H，m)，7.40(1H，m)，7.80(8H，m)，8.38(1H，d，J＝7.8Hz)，8.64(1H，d，J＝3.9Hz)，10.79(1H，brs)

ESI-MASS(m/e)：525(M+H)

Example 8

2- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl ]First of all -cis-3 a, 4, 7, 7 a-tetrahydro-1H-isoindole-1, 3(2H) -dione

The title compound was obtained in the same manner as in example 1 (step 10), in a similar manner to the above process, or in combination with a conventional process, using cis-1, 2, 3, 6-tetrahydrophthalimide.

¹HNMR(CDCl₃)δ：2.21(2H，m)，2.59(2H，m)，2.99(2H，m)，3.05(3H，m)，4.73(2H，s)，5.91(2H，m)，7.09(2H，m)，7.29(1H，m)，7.39(1H，m)，7.51(1H，m)，7.86(3H，m)，8.37(1H，m)，8.62(1H，m)

ESI-MASS(m/e)：529(M+H)

Example 9

5-methyl-1- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridyl) -1H-benzimidazole- 6-yl]Methyl } -2-pyrrolidone

The title compound was obtained in the same manner as in example 2, in a similar manner to example 2, or in combination with a conventional method using 5-methyl-2-pyrrolidone.

¹H NMR(CDCl₃)δ：0.89(1H，m)，1.16(3H，m)，2.11(1H，m)，2.25-2.33(1H，m)，2.46(1H，m)，3.07(3H，d，J＝3.5Hz)，3.62(1H、m)，4.17(1H，d，J＝15.2Hz)，4.95(2H，d，J＝15.2Hz)，7.08(2H，m)，7.35(1H，s)，7.42(1H，m)，7.69(1H，s)，7.89(3H，m)，8.41(1H，m)，8.66(1H，m)

ESI-MASS(m/e)：477(M+H)

Example 10

3-methyl-1- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridyl) -1H-benzimidazole- 6-yl]Methyl } -2-pyrrolidone

The title compound was obtained in the same manner as in example 2, in a similar manner to example 2, or in combination with a conventional method using 3-methyl-2-pyrrolidone.

¹H NMR(CDCl₃)δ：0.87(1H，s)，1.10-1.15(3H，m)，1.51(1H，m)，2.41(1H，m)，3.04(3H，m)，3.21(2H，m)，4.44-4.61(2H，m)，7.01-7.06(2H，m)，7.38-7.40(1H，m)，7.50(1H，d，J＝19.2Hz)，7.74(1H，s)，7.85-7.90(3H，m)，8.36-8.41(1H，m)，8.63-8.64(1H，m)，10.91(1H，brs)

ESI-MASS(m/e)：477(M+H)

Example 11

1- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 5-oxo-2-pyrrolidinecarboxylic acid methyl ester

(step 1) Synthesis of methyl Pyroglutamate

1g of dl-pyroglutamic acid was dissolved in a mixed solvent of 25ml of methanol and 15ml of chloroform, and 7.7ml of trimethylsilyldiazomethane (2M hexane solution) was added thereto at room temperature, followed by direct stirring for 20 minutes. The solvent was distilled off under reduced pressure, and then the residue was dissolved in chloroform and washed with saturated brine. After drying, the solvent was removed to give 1.03g of the title compound as a pale yellow oil.

(step 2) Synthesis of methyl 1- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -5-oxo-2-pyrrolidinecarboxylate

The title compound was obtained by the same method as in example 2, a method similar thereto, or a combination thereof with a conventional method using pyroglutamic acid methyl ester.

¹HNMR(CDCl₃)δ：2.01(1H，m)，2.13(1H，m)，2.24(1H，m)，2.44-2.50(1H，m)，3.04(3H，m)，3.67(3H，m)，4.03-4.16(2H，m)，5.01(1/2H，m)，5.12(1/2H，m)，7.01-7.09(2H，m)，7.16(1/2H，d，J＝2.0Hz)，7.40(1H，dd，J＝5.5，6.7Hz)，7.48(1/2H，d，J＝21.5Hz)，7.60(1/2H，s)，7.77(1/2H，d，J＝2.3Hz)，7.87(3H，m)，8.36-8.39(1H，m)，8.64-8.65(1H，m)，10.65(1H，d，J＝13.7Hz)

ESI-MASS(m/e)：521(M+H)

Example 12

1- (1- { [5- [4- (methylsulfonyl) phenoxy)]-2- (2-pyridinyl) -1H-benzimidazol-6-yl] Methyl } -1H-pyrrol-2-yl) -1-ethanone

The title compound was obtained by using 2-acetylpyrrole in the same manner as in example 2, in a similar manner thereto or in combination with a conventional method.

¹HNMR(CDCl₃)δ：2.29-2.39(3H，m)，3.05(3H，m)，5.64(2H，s)，6.17(1H，m)，6.91(1H，m)，6.9 8(1H，m)，7.04-7.20(3H，m)，7.34-7.37(2H，m)，7.85(3H，m)，8.53(1H，d，J＝7.8Hz)，8.59(1H，d，J＝4.7Hz)

ESI-MASS(m/e)：487(M+H)

Example 13

1- { [5- [4- (methylsulfonyl) amideRadical) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all Radical } -5-thio-2-pyrrolidinone

(step 1) Synthesis of 5-thio-2-pyrrolidone

300mg of succinimide was dissolved in 3ml of tetrahydrofuran at 60 ℃ and 606mg of Lawson's reagent (Aldrich) was added. After stirring at 60 ℃ for 1.5 hours, the solvent was distilled off. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. Dried over anhydrous magnesium sulfate, the solvent was distilled off, and purification was performed by silica gel column chromatography (developing solvent: hexane/ethyl acetate 20/1 → 7/3 → 1/1) to obtain 255mg of the title compound as a pale yellow solid.

(step 2) Synthesis of 1- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -5-thioxo-2-pyrrolidinone

The title compound was obtained in the same manner as in example 1 (step 10), in a similar manner thereto, or in combination with a conventional method using 5-thioxo-2-pyrrolidone.

¹HNMR(CDCl₃)δ：2.62(1H，m)，2.72(1H，m)，3.05(1H，m)，3.07(3H，s)，3.12(1H，m)，5.18(2H，s)7.00-7.20(2H+1/2H，m)，7.39-7.43(1H，m)，7.44(1/2H，brs)，7.49(1/2H，brs)，7.60(1/2H，brs)，7.82-7.90(3H，m)，8.36(1H，d，J＝8.0Hz)，8.63(1H，brs)，10.6(1H，br)

ESI-MS(m/e)：493[M+H]

Example 14

5- [4- (methylsulfonyl) phenoxy group]-2- (2-pyridinyl) -6- (1H-1, 2, 4-thiazol-1-ylmethyl 1H-benzimidazoles

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method using 1, 2, 4-triazole.

¹H NMR(CDCl₃)δ：3.05-3.10(3H，m)，5.46(2H，s)，7.06(2H，m)，7.36-7.44(2H，m)，7.83-7.93(5H，m)，8.05(1H，s)，8.41(1H，d，J＝7.8Hz)，8.66(1H，d，J＝4.3Hz)

ESI-MASS(m/e)：447(M+H)

Example 15

Cis-3, 4-dimethyl-1- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzene And-imidazole-6-yl]Methyl pyrrolidine-2, 5-dione

(step 1) Synthesis of cis-3, 4-dimethylpyrrolidine-2, 5-dione

To 500mg of meso-2, 3-dimethylsuccinic acid were added 2.3ml of acetyl chloride and 0.24ml of thionyl chloride, and the mixture was refluxed for 2 hours. The reaction mixture was returned to room temperature, and the solvent was then distilled off under reduced pressure. The residue was recrystallized from toluene and hexane to give 398mg of meso-2, 3-dimethylsuccinic anhydride as a white solid.

Ammonia gas was bubbled through a solution of 390mg of cis-2, 3-dimethylsuccinic anhydride in 5ml of toluene for 30 minutes while cooling on ice. The solvent was distilled off under reduced pressure to obtain a white solid. This was dissolved in 10ml of DMF and 0.5ml of thionyl chloride was added at-78 ℃ and stirred at 0 ℃ for 2 hours. The reaction mixture was returned to room temperature, and then the solvent was distilled off under reduced pressure, ethyl acetate was added, the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, the solvent was removed after drying, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 7/3-0/1) to give 269mg of the title compound as a white solid.

(step 2) Synthesis of cis-3, 4-dimethyl-1- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } pyrrolidine-2, 5-dione

The title compound was obtained in the same manner as in example 1 (step 10), in a similar manner to this, or in combination with a conventional method using the cis-3, 4-dimethylpyrrolidine-2, 5-dione thus obtained.

¹HNMR(CDCl₃)δ：1.19(6H，m)，2.84(2H，m)，3.04(3H，m)，4.74(2H，s)，7.08(3H，m)，7.38-7.42(2H，m)，7.84-7.86(3H，m)，8.37(1H，d，J＝7.4Hz)，8.61(1H，s)，10.88(1H，s)

ESI-MASS(m/e)：505(M+H)

Example 16

4- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all Group } morpholine-3, 5-dione

The title compound was obtained in the same manner as in example 1 (step 10), in a similar manner thereto, or in combination with a conventional method using morpholine-3, 5-dione.

¹HNMR(CDCl₃)δ：3.05(3/2H，s)，3.06(3/2H，s)，4.27(2H，s)，4.34(2H，s)，5.07(2H，s)，7.05-7.10(2H+1/2H，m)，7.35-7.42(1H，m)，7.44(1/2H，m)，7.53(1/2H，m)，7.74(1/2H，m)，7.85-7.92(3H，m)，8.38(1H，m)，8.61(1H，m)，10.9(1H，br)

ESI-MS(m/e)：493[M+H]

Example 17

3- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all Radical }1, 3- チアゾラン -2, 4-dione

The title compound was obtained by the same method as in example 1 (step 10), a method similar thereto, or a combination thereof with a conventional method using 2, 4-thiazolidinedione.

¹HNMR(CDCl₃)δ：3.06(3/2H，s)，3.07(3/2H，s)，3.77(1H，s)，3.87(1H，s)，4.89(1H，s)，4.91(1H，s)，7.02-7.12(2H+1/2H，m)，7.35-7.44(1H，m)，7.45(1/2H，s)，7.62(1/2H，s)，7.81(1/2H，s)，7.85-7.92(3H，m)，8.37(1H，m)，8.63(1H，m)，10.7(1/2H，br)，10.8(.1/2H，br)

ESI-MS(m/e)：495[M+H]

Example 18

3- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all Yl }1, 3- チアゾラン -2-one

The title compound was obtained by the same method as in example 2, a method similar thereto, or a combination thereof with a conventional method, using 2-thiazolidine synthesized according to Synthetic communications, 1987, Vol.17, No. 13, p.1577-1785.

¹HNMR(CDCl₃)δ：3.06(3H，s)，3.16(2H，m)，3.55(2H，m)，4.55(1H，s)，4.57(1H，s)，7.03-7.09(2H，m)，7.17(1/2H，s)，7.41(1H，m)，7.49(1/2H，s)，7.58(1/2H，s)，7.83-7.92(3H+1/2H，m)，8.41(1H，m)，8.65(1H，m)，10.95(1/2H，br)，10.91(1/2H，br)

ESI-MS(m/e)：481[M+H]

Example 19

1- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all Radical } pyrrolidine-2, 5-dione

(step 1) Synthesis of methyl 2-fluoro-4-nitrobenzoate

To 1300ml of a methanol solution of 140g of 2-fluoro-4-nitrobenzoic acid was added 5ml of concentrated sulfuric acid, and the mixture was refluxed for 48 hours. The solvent was distilled off under reduced pressure, then water was added, and the resulting solid was collected by filtration. Drying under reduced pressure gave 141g of the title compound as a yellow solid.

(step 2) Synthesis of methyl 4-amino-2-fluorobenzoate

141g of methyl 2-fluoro-4-nitrobenzoate are dissolved in 1000ml of methanol and 400ml of tetrahydrofuran, 20g of Raney nickel are added and stirring is carried out overnight under a hydrogen atmosphere. The catalyst was filtered off, and the solvent was distilled off under reduced pressure to give 119g of methyl 4-amino-2-fluorobenzoate.

(step 3) Synthesis of methyl 2-fluoro-4- [ (2-pyridylcarbonyl) amino ] benzoate

To a solution of 18.9g of methyl 4-amino-2-fluorobenzoate and 16.5g of picolinic acid in 500ml of pyridine was added 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, then 600ml of ethyl acetate was added, and the organic layer was washed with a 0.25N aqueous hydrochloric acid solution, a 0.25N aqueous sodium hydroxide solution and a saturated saline solution, dried, concentrated under reduced pressure, solidified from a mixed solvent of hexane/ethyl acetate, and the solid matter was filtered off. Drying under reduced pressure gave 28.3g of the title compound as a white solid.

(step 4) Synthesis of methyl 2-fluoro-5-nitro-4- [ (2-pyridylcarbonyl) amino ] benzoate

To 27.7g of methyl 2-fluoro-4- [ (2-pyridylcarbonyl) amino ] benzoate was slowly added 110ml of fuming nitric acid under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was slowly added to 2000ml of an aqueous solution of 138g of sodium carbonate under ice-cooling, and the resultant solid was collected by filtration. Drying under reduced pressure gave 27.5g of the title compound as a yellow solid.

(step 5) Synthesis of methyl 2- [4- (ethylsulfonyl) phenoxy ] -5-nitro-4- [ (2-pyridylcarbonyl) amino ] benzoate

To a solution of 6g of methyl 2-fluoro-5-nitro-4- [ (2-pyridylcarbonyl) amino ] benzoate and 3.48g of 4- (ethylsulfonyl) phenol obtained in reference example 2 in 110ml of dimethylformamide was added 3.5g of potassium carbonate, and the mixture was stirred at 80 ℃ for 30 minutes. The reaction solution was returned to room temperature, and then poured into 300ml of water, and the resulting solid was collected by filtration. Drying under reduced pressure gave 7.46g of the title compound as a yellow solid.

(step 6) Synthesis of methyl 5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-6-carboxylate and methyl 6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-5-carboxylate

7.46g of methyl 2- [4- (ethylsulfonyl) phenoxy ] -5-nitro-4- [ (2-pyridylcarbonyl) amino ] benzoate was suspended in 37ml of dimethylformamide and 37ml of methanol, and 17.3g of tin (II) chloride dihydrate and 15ml of concentrated hydrochloric acid were added to stir the mixture at 80 ℃ for 40 minutes. The reaction solution was returned to room temperature, and then slowly added to an aqueous sodium hydrogencarbonate solution to neutralize the reaction solution. Ethyl acetate was added thereto, and the mixture was stirred at room temperature for 30 minutes, then the formed salt was filtered off, and the filtrate was washed with water and saturated brine. After drying, the solvent was distilled off to leave 6.9g of a crude methyl 5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazole-6-carboxylate as a yellow solid.

To a solution of 6.9g of the crude product in 70ml of dimethylformamide was added 4ml of 2- (trimethylsilyl) ethoxymethyl chloride and 0.92g of sodium hydride (30% liquid paraffin was added) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added under ice cooling, extraction was performed with ethyl acetate, and then the organic layer was washed with water and saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: hexane/ethyl acetate 9/1-3/2) to give 6.43g of the title compound as a yellow oil.

(step 7) Synthesis of (5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) methanol and (6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) methanol

To 60ml of tetrahydrofuran, 0.99g of lithium aluminum hydride and 5.9g of the above ester compound in 50ml of tetrahydrofuran solution were slowly added under ice-cooling. Stirring at room temperature for 15 minutes, then slowly adding sodium sulfate decahydrate under ice cooling until no foaming, adding ethyl acetate, stirring at room temperature for 1 hour, filtering off the generated salt, and distilling off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 9/1-3/2) to give 4.5g of the title compound as a yellow oil.

(step 8) Synthesis of 1- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } pyrrolidine-2, 5-dione

To a 24ml tetrahydrofuran solution of 2.4g of the obtained alcohol compound were added 1.3g of succinimide and 3.5g of triphenylphosphine, and 5.8ml of diethyl azodicarboxylate (40% toluene solution) was added under ice cooling, and stirred at room temperature for 1 hour. The reaction solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (developing solvent: hexane/ethyl acetate: 8/2-1/1-1/9) to give 2.3g of a yellow oil.

To the resulting oil, 15ml of trifluoroacetic acid was added and stirred for 2 hours. The solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (developing solvent: chloroform-chloroform/methanol-99/1) and by recrystallization (ethyl acetate), 1.02g of the title compound was obtained as white crystals.

¹HNMR(CDCl₃)δ：1.30(3H，m)，2.54(2H，s)，2.65(2H，s)，3.12(2H，m)，4.79(1H，m)，4.80(1H，s)，7.05-7.12(2H+1/2H，m)，7.39(1H，m)，7.44(1/2H，s)，7.64(1/2H，s)，7.76(1/2H，s)，7.81-7.90(3H，m)，8.38(1H，m)，8.65(1H，m)，10.5(1/2H，br)，10.6(1/2H，br)

ESI-MASS(m/e)：491(M+H)

Example 20

1- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 2-pyrrolidone radical

The title compound was obtained by using the alcohol compound obtained in example 19 (step 7) and following the same method as in example 2, a method similar thereto, or a combination thereof with a conventional method.

¹HNMR(CDCl₃)δ：1.24-1.30(3H，m)，1.91(2H，dt，J＝23.7，7.8Hz)，2.32(2H，m)，3.06-3.13(2H，m)，3.26(2H，q，J＝10.4Hz)，4.53(2H，s)，7.05(2H，m)，7.39(2H，m)，7.79-7.89(4H，m)，8.38(1H，d，J＝8.2Hz)，8.63(1H，d，J＝4.7Hz)

ESI-MASS(m/e)：477(M+H)

Example 21

3- { [5- [4- (ethylsulfonyl) phenoxy ]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 2-oxazolidinone radical

The title compound was obtained in the same manner as in example 2, a method similar thereto or a combination thereof with a conventional method using the alcohol compound obtained in example 19 (step 7) and 2-oxazolone.

¹HNMR(CDCl₃)δ：1.28(3H，t，J＝7.4Hz)，3.11(2H，q，J＝7.4Hz)，3.46(2H，m)，4.23(2H，t，J＝8.2Hz)，4.51(2H，s)，7.08(2H，q，J＝9.0Hz)，7.40(1H，t，J＝6.3Hz)，7.50(1H，m)，7.65-7.68(1H，m)，7.83-7.86(3H，m)，8.36-8.38(1H，m)，8.64(1H，s)，10.63(1H，s)

ESI-MASS(m/e)：479(M+H)

Example 22

1- ({2- (5-bromo-2-pyridinyl) - [5- [4- (ethylsulfonyl) phenoxy]-1H-benzimidazole-6- Base of]Methyl pyrrolidine-2, 5-dione

The title compound was obtained in the same manner as in example 19, a method similar thereto, or a combination thereof with a conventional method, using 5-bromopicolinic acid in example 19 (step 3).

¹HNMR(CDCl₃)δ：1.29(3H，m)，2.55(2H，s)，2.65(2H，s)，3.12(2H，s)，4.79(1H，s)，4.80(1H，s)，7.05-7.15(2H+1/2H，m)，7.44(1/2H，s)，7.65(1/2H，s)，7.76(1/2H，s)，7.82-7.90(2H，m)，8.00(1H，m)，8.26(1H，m)，8.70(1H，m)，10.3(1/2H，br)，10.4(1/2H，br)

ESI-MS(m/e)：569，571[M+H]

Example 23

1- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all Radical } -2-imidazolidinone

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound and ethylene urea obtained in example 19 (step 7).

¹HNMR(CDCl₃1 drop of CD3OD) δ: 1.28(3H, t, J ═ 7.2Hz), 3.11(2H, q, J ═ 7.2Hz), 3.25-3.28(4H, m), 4.41(2Hx1/2, s), 4.44(2Hx1/2, s), 4.63(1Hx1/2, s), 4.65(1Hx1/2, s), 7.05(2H, d, J ═ 8.2Hz), 7.20(1Hx1/2, s), 7.37-7.41(1H, m), 7.45(1Hx1/2, s), 7.59(1Hx1/2, s), 7.77(1Hx1/2, s), 7.82(2H, d, J ═ 8.2Hz), 7.85-7.90(1H, 8.65, 8H, 1H, 8.61 Hz), 7.61H (1H, 8.61, s).

ESI-MASS(m/e)：ND

Example 24

1- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all Radical [ imidazolidine-2, 5-dione ]

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound and hydantoin obtained in example 19 (step 7).

¹HNMR(CDCl₃)δ：1.31(3H，t，J＝7.4Hz)，3.13(2H，q，J＝7.4Hz)，3.70-4.00(2H，m)，4.77-4.89(3H，m)，7.05-7.90(8H，m)，8.37-8.42(1H，m)，8.62-8.67(1H，m)，10.64-10.95(1H，m).

ESI-MASS(m/e)：492(M+H)

Example 25

1- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 1H-pyrimidine-2, 4-diones

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound and uracil obtained in example 19 (step 7).

¹HNMR(CDCl₃)δ：1.12(3H，t，J＝7.4Hz)，3.24(2H，q，J＝7.4Hz)，4.94(2H，s)，5.47(1H，d，J＝8.2Hz)，7.10(2H，d，J＝8.2Hz)，7.55(1H，dd，J＝7.8，5.5Hz)，7.57(1H，s)，7.59(1H，s)，7.83(2H，d，J＝8.2Hz)，8.02(1H，dd，J＝7.8，7.8Hz)，8.31(1H，d，J＝7.8Hz)，8.75(1H，d，J＝5.5Hz)，11.18(1H，brs)

ESI-MASS(m/e)：504(M+H)

Example 26

1- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 3-methyl-imidazolidine-2, 5-dione

The title compound was obtained in the same manner as in example 19 (step 8), in a similar manner thereto, or in combination with a conventional method using 1-methylhydantoin.

¹H NMR(CDCl₃)δ：1.29(3H，t，J＝7.0Hz)，2.85(3Hx1/2，s)，2.92(3Hx1/2，s)，3.11(2H，q，J＝7.0Hz)，3.59(2Hx1/2，s)，3.74(2Hx1/2，s)，4.77(2Hx1/2，s)，4.78(2Hx1/2，s)，7.06(2H，d，J＝9.0Hz)，7.10(1Hx1/2，s)，7.36-7.40(1H，m)，7.45(1Hx1/2，s)，7.66(1Hx1/2，s)，7.79-7.89(3H，m)，7.79-7.89(1Hx1/2，m)，8.37(1Hx1/2，d，J＝8.2Hz)，8.40(1Hx1/2，d，J＝8.2Hz)，8.60-8.65(1H，m)，10.63(1Hx1/2，brs)，10.67(1Hx1/2，brs).

ESI-MASS(m/e)：506(M+H)

Example 27

3- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 1-methyl-1H-pyrimidine-2, 4-dione

The title compound was obtained in the same manner as in example 19 (step 8), in a similar manner thereto or in combination with a conventional method using 1-methyluracil.

¹HNMR(CDCl₃)δ：1.28(3Hx1/2，t，J＝7.4Hz)，1.28(3Hx1/2，t，J＝7.4Hz)，3.10(2Hx1/2，q，J＝7.4Hz)，3.10(2Hx1/2，q，J＝7.4Hz)，3.25(3Hx1/2s)，3.33(3Hx1/2，s)，5.23(2Hx1/2，s)，5.24(2Hx1/2，s)，5.63(1Hx1/2，d，J＝7.8Hz)，5.72(1Hx1/2，d，J＝7.8Hz)，6.99(1Hx1/2，d，J＝7.8Hz)，7.04(2Hx1/2，d，J＝9.0Hz)，7.09(1Hx1/2，s)，7.10(2Hx1/2，d，J＝9.0Hz)，7.10(1Hx1/2，d，J＝7.8Hz)，7.34-7.38(1H，m)，7.43(1Hx1/2，s)，7.52(1Hx1/2，s)，7.63(1Hx1/2，s)，7.78(2Hx1/2，d，J＝9.0Hz)，7.81-7.87(1H，m)，7.82(2Hx1/2，d，J＝9.0Hz)，8.35(1H，d，J＝7.8Hz)，8.60(1Hx1/2，d，J＝5.1Hz)，8.61(1Hx1/2，d，J＝5.1Hz)，10.65(1H，brs).

ESI-MASS(m/e)：518(M+H)

Example 28

1- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 3-methyl-1H-pyrimidine-2, 4-dione

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound obtained in example 19 (step 7) and 3-methyluracil.

¹HNMR(CDCl₃)δ：1.31(3H，t，J＝7.4Hz)，3.12(2H，q，J＝7.4Hz)，3.26(3Hx1/2，s)，3.29(3Hx1/2，s)，5.00(2Hx1/2，s)，5.03(2Hx1/2，s)，5.65(1Hx1/2，d，J＝7.8Hz)，5.65(1Hx1/2，d，J＝7.8Hz)，7.05(2Hx1/2，d，J＝8.6Hz)，7.09(2Hx1/2，d，J＝8.6Hz)，7.13(1Hx1/2，s)，7.19(1Hx1/2，d，＝7.8Hz)，7.27(1Hx1/2，s)，7.38-7.42(1H，m)，7.43(1Hx1/2，s)，7.70(1Hx1/2，s)，7.83-7.90(3H，m)，7.83-7.90(1Hx1/2，m)，8.36(1H，d，J＝7.8Hz)，8.39(1H，d，J＝7.8Hz)，8.61-8.65(1H，m)，10.80(1H，brs).

ESI-MASS(m/e)：518(M+H)

Example 29

1- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 3-methyl-2-imidazolidinone radical

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound obtained in example 19 (step 7) and 1-methylimidazolidinone.

¹HNMR(CDCl₃)δ：1.28(3H，t，J＝7.4Hz)，2.73(3Hx1/2，s)，2.75(3Hx1/2，s)，3.10(2H，q，J＝7.4Hz)，3.16-3.20(4H，m)，4.43(2Hx1/2，s)，4.43(2Hx1/2，s)，7.03(2H，d，J＝9.0Hz)，7.06(1Hx1/2，s)，7.16(1Hx1/2，s)，7.37-7.40(1H，m)，7.47(1Hx1/2，s)，7.61.(1Hx1/2s)，7.80(2H，d，J＝9.0Hz)，7.84-7.89(1H，m)，8.37(1Hx1/2，d，J＝7.8Hz)，8.40(1Hx1/2，d，J＝7.8Hz)，8.62(1Hx1/2，d，J＝4.7Hz)，8.64(1Hx1/2，d，J＝4.7Hz)，10.81(1Hx1/2，brs)，10.84(1Hx1/2，brs).

ESI-MASS(m/e)：492(M+H)

Example 30

3- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 3-chloro-3-azabicyclo [3.1.0] radicals]Hexane-2, 4-dione

The title compound was obtained in the same manner as in example 19[ step 7), a method similar thereto or a combination thereof with a conventional method using 3-azabicyclo [3.1.0] hexane-2, 4-dione.

¹H NMR(CDCl₃)δ：1.17-1.75(5H，m)，2.40-2.50(2H，m)，3.05-3.18(2H，m)，4.61(1H，s)，4.63(1H，s)，7.05-7.13(2H+1/2H，m)，7，39-7.44(1H，m)，7.44(1/2H，s)，7.54(1/2H，s)，7.73(1/2H，s)，7.82-7.90(3H，m)，8.39(1H，m)，8.63(1H，m)，10.8(1/2H，br)，10.9(1/2H，br)

ESI-MASS(m/e)：503(M+H)

Example 31

N- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl ]First of all Methyl sulfonamide

(step 1) Synthesis of (5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) methylamine or (6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) methylamine

To a solution of 260mg of the alcohol compound obtained in example 19 (step 7) and 134. mu.l of triethylamine in 2.6ml of tetrahydrofuran was added 74. mu.l of methanesulfonyl chloride under ice-cooling, and stirred for 30 minutes. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure to obtain a pale yellow oil.

To a solution of the obtained oily substance in 3ml of dimethylformamide was added 156mg of sodium azide, and the mixture was stirred at room temperature for 1 hour. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 9/1-3/2) to give 177mg of a yellow oil.

To a solution of the resulting oil in 3.2ml of methanol were added 5mg of copper (II) sulfate pentahydrate and 53mg of sodium borohydride, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride was added, the mixture was neutralized with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform → chloroform/methanol: 20/1), whereby 141mg of the title compound was obtained as a yellow oil.

(step 2) Synthesis of N- (5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) methanesulfonamide or N- (6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) methanesulfonamide

To a solution of 63mg of the obtained amine compound in 1ml of chloroform was added 25. mu.l of triethylamine and 11. mu.l of methanesulfonyl chloride under ice-cooling. After stirring for 30 minutes, a saturated aqueous sodium bicarbonate solution was added, extraction was performed with ethyl acetate, and the organic layer was washed with a saturated saline solution. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform → chloroform/methanol: 20/1), whereby 77mg of the title compound was obtained as a yellow oil.

(step 3) Synthesis of N- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } methanesulfonamide

To 77mg of the resulting yellow oil, 0.5ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, neutralized with triethylamine and then purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄And Art 5744(Merck) and chloroform/methanol 10/1 to yield 9.4mg of the title compound as a white amorphous substance.

¹HNMR(CDCl₃) δ: 1.30(3H, t, J ═ 7.3Hz), 2.84 and 2.86 (total 3H,s), 3.14(2H, q, J ═ 7.3Hz), 4.41(2H, m), 4.93(1H, m), 7.07-7.13(2H +1/2H, m), 7.41(1H, m), 7.45(1/2H, s), 7.67(1/2H, s), 7.87(3H, m), 7.93(1/2H.s), 8.40(1H, m), 8.65(1H, m), 10.7 and 10.8 (1H, br in total)

ESI-MASS(m/e)：487(M+H)

Example 32

N- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all methyl-N-methylsulfonyl amides

To a solution of 60mg of the sulfonamide compound obtained in example 31 (step 2) in 0.6ml of dimethylformamide was added 14. mu.l of methyl iodide and 5.3mg of sodium hydride (30% liquid paraffin was added) under ice-cooling. After stirring at room temperature for 30 minutes, a saturated aqueous ammonium chloride solution was added, extraction was performed with ethyl acetate, and the organic layer was washed with water and a saturated saline solution. After drying, the solvent was distilled off under reduced pressure to obtain a yellow oil.

To the resulting yellow oil, 0.5ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, neutralized with triethylamine and then purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄And Art 5744(Merck) and chloroform/methanol 10/1 to yield 38.4mg of the title compound as a white amorphous substance.

¹H NMR(CDCl₃) δ: 1.30(3H, t, J ═ 7.4Hz), 2.83(6H, m), 3.12(2H, q, J ═ 7.4Hz), 4.40 and 4.42 (total of 2H, s), 7.00-7.10(2H, m), 7.14(1/2H, s), 7.41(1H, m), 7.48(1/2H, s), 7.72(1/2H, s), 7.83-7.95(3H, m), 7.97(1/2H, s), 8.41(1H, m), 8.65(1H, m), 11.0(1H, br)

ESI-MASS(m/e)：501(M+H)

Example 33

2- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all A group } isothiazolidine-1, a pharmaceutically acceptable salt thereof,1-dioxides

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound obtained in example 19 (step 7) and isothiazolidine-1, 1-dioxide synthesized by the methods described in Organic letters, 2003, volume five, No. 22, page 4175-4277.

¹HNMR(CDCl₃)δ：1.30(3H，t，J＝7.5Hz)，2.20-2.30(2H，m)，3.05-3.20(6H，m)，4.28(2H，brs)，7.08(2H，d，J＝8.9Hz)，7.19(1/2H，brs)，7.41(1H，m)，7.50(1/2H，brs)，7.71(1/2H，brs)，7.84(2H，d，J＝8.9Hz)，7.89(1H，m)，7.96(1/2H，brs)，8.41(1H，m)，8.65(1H，m)，10.7(1H，br)

ESI-MASS(m/e)：513(M+H)

Example 34

1- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyrazinyl) -1H-benzimidazol-6-yl]First of all Radical } pyrrolidine-2, 5-dione

(step 1) Synthesis of methyl 2-fluoro-5-nitro-4- [ (2-pyrazinylcarbonyl) amino ] benzoate

Using methyl 4-amino-2-fluorobenzoate and pyrazine-2-carboxylic acid obtained in example 19 (step 2), the title compound was obtained in the same manner as in example 19 (step 3 to step 4), a method similar thereto, or a combination thereof with a conventional method.

(step 2) Synthesis of methyl 5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyrazinyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-6-carboxylate and methyl 6- [4- (methylsulfonyl) phenoxy ] -2- (2-pyrazinyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-5-carboxylate

The title compound was obtained in the same manner as in example 19 (step 5 to step 6), in a similar manner to the above-mentioned example, or in combination with a conventional method, using methyl 2-fluoro-5-nitro-4- [ (2-pyrazinylcarbonyl) amino ] benzoate obtained above and 4- (methylsulfonyl) phenol obtained in reference example 1.

(step 3) Synthesis of 5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyrazinyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) methanol and (6- [4- (methylsulfonyl) phenoxy ] -2- (2-pyrazinyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) methanol

570mg of the resulting methyl ester compound was dissolved in 4ml of methanol and 1ml of tetrahydrofuran, and 1ml of a 5N aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 2 hours. The pH was adjusted to 3 with 10% aqueous citric acid, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure to obtain 447mg of a pale yellow solid.

To 5ml of a tetrahydrofuran solution of the obtained yellow solid, 201mg of 1, 1' -carbodiimide was added, and the mixture was stirred for 12 hours.

The reaction solution was added to 5ml of an aqueous solution of 1.57mg of sodium borohydride under ice cooling, and stirred at room temperature for 30 minutes. 10% aqueous citric acid solution was added thereto, and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: hexane/ethyl acetate 9/1-1/9) to give 234mg of the title compound as a yellow oil.

(step 4) Synthesis of 1- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyrazinyl) -1H-benzimidazol-6-yl ] methyl } pyrrolidine-2, 5-dione

The title compound was obtained by using the obtained alcohol compound in the same manner as in example 19 (step 8), a method similar thereto, or a combination thereof with a conventional method.

¹HNMR(CDCl₃)δ：1.71(3H，s)，2.57(2H，s)，2.69(2H，s)，3.06(3/2H，s)，3.07(3/2H，s)，4.79(1H，s)，4.80(1H，s)，7.05-7.15(2H+1/2H，m)，7.47(1/2H，s)，7，68(1/2H，s)，7.77(1/2H，s)，7.85-7.95(2H，m)，8.60(1H，m)，8.68(1H，m)，9.6 1(1 H，d d，J＝1.6， 7.0Hz)，10.59(1H，br)

ESI-MS(m/e)：478[M+H]

Example 35

1- { [5- [4- (methylsulfonyl) phenoxy]-2- (2-pyrazinyl) -1H-benzimidazol-6-yl]First of all 2-pyrrolidone radical

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 34 (step 3).

¹HNMR(CDCl₃)δ：1.90-2.02(2H，m)，2.30-2.4 (2H，m)，3.07(3H，s)，3.30-3.40(2H，m)，4.55(2H，s)，7.00-7.10(2H，m)，7.18(3/7H，s)，7.50(4/7H，s)，7.68(4/7H，s)，7.78(3/7H，s)，7.83-7.92(2H，m)，8.55-8.66(1H，m)，8.67(1H，m)，9.62(1H，m)，11.0(3/7H，br)，11，5(4/7H，br)

ESI-MS(m/e)：464[M+H]

Example 36

1- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyrazinyl) -1H-benzimidazol-6-yl]First of all Radical } pyrrolidine-2, 5-dione

(step 1) Synthesis of (5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyrazinyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) methanol and (6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyrazinyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) methanol

The title compound was obtained in the same manner as in example 34 (step 2 to step 3), in a similar manner thereto, or in combination with a conventional method using 4- (ethylsulfonyl) phenol obtained in reference example 2.

(step 2) Synthesis of 1- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyrazinyl) -1H-benzimidazol-6-yl ] methyl } pyrrolidine-2, 5-dione

The title compound was obtained by using the obtained alcohol in the same manner as in example 19 (step 8), a method similar thereto, or a combination thereof with a conventional method.

¹HNMR(CDCl₃)δ：1.23-1.31(3.H，m)，2.54(2H，s)，2.67(2H，s)，3.11(2H，q，J＝14.8Hz)，4.79(2H，s)，7.06(1/2H，s)，7.08-7.11(2H，m)，7.46(1/2H，s)，7.67(1/2H，s)，7.7 6(1/2 H，s)，7.81-7.87(2H，m)，8.57-8.60(1H，m)，8.66(1H，m)，9.60(1H，m)，10.48(1H，d，J＝11.7Hz)

ESI-MASS(m/e)：492(M+H)

Example 37

1- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyrazinyl) -1H-benzimidazol-6-yl]First of all 2-pyrrolidone radical

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 36 (step 1).

¹HNMR(CDCl₃)δ：1.32(3H，t，J＝7.4Hz)，1.94-2.01(2H，m)，2.35-2.41(2H，m)，3.14(2H，q，J＝7.4Hz)，3.33-3.36(2H，m)，4.58(2H，d，J＝3.5Hz)，7.09(2H，m)，7.22(1/2H，m)，7.53(1/2H，s)，7.66(1/2H，s)，7.82(1/2H，s)，7.87(2H，d，J＝8.2Hz)，8.62(1H，m)，8.70(1H，d，J＝2.3Hz)，9.63-9.66(1H，m)，10.48(1/2H，s，)，10.73(1/2H，s)

ESI-MASS(m/e)：478(M+H)

Example 38

3- { [5- [4- (ethylsulfonyl) benzeneOxy radical]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 2-oxazolidinone radical

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound obtained in example 36 (step 1) and 2-oxazolidinone.

¹HNMR(CDCl₃)δ：1.29(3H，t，7.4Hz)，3.11(2H，q，J＝7.4Hz)，3.50(2H，m)，4.25(2H，m)，4.53(2 H，s)，7.06-7.09(3H，m)，7.84-7.86(3H，m)，8.61(1H，m)，8.68(1H，d，J＝2.3Hz)，9.62(1H，d，J＝1.6Hz)，

ESI-MASS(m/e)：480(M+H)

Example 39

1- { [5- [6- (ethylsulfonyl) -3-pyridinyl]Oxy radical]-2- (2-pyridyl) -1H-benzimidazole- 6-yl]Methyl pyrrolidine-2, 5-dione

(step 1) Synthesis of (5- { [6- (ethylsulfonyl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) methanol and (6- { [6- (ethylsulfonyl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) methanol

The title compound was obtained in the same manner as in example 19 (step 5 to step 7), in a similar manner to or in combination with the conventional method using 6- (ethylsulfonyl) -3-pyridinol obtained in reference example 4.

(step 2) Synthesis of 1- { [5- [6- (ethylsulfonyl) -3-pyridyl ] oxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl } methyl } pyrrolidine-2, 5-dione

¹H NMR(CDCl₃)δ：1.27-1.37(3H，m)，2.63(2H，s)，2.70(2H，s)，3.30-3.45(2H，m)，4.77(1H，2)，4.79(1H，s)，7.10(1/2H，s)，7.35-7.45(2H，m)，7.45(1/2H，m)，7.67(1/2H，s)，7.80(1/2H，s)，7.88(1H，m)，8.03(1H，m)，8.39(1H，m)，8.49(1H，m)，8.64(1H，m)，10.8(1H，br)

ESI-M S(m/e)：492[M+H]

Example 40

1- { [5- [6- (ethylsulfonyl) -3-pyridinyl]Oxy radical]-2- (2-pyridyl) -1H-benzimidazole- 6-yl]Methyl } -2-pyrrolidone

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 39 (step 1).

¹HNMR(CDCl₃)δ：1.31(3H，t，J＝7.6Hz)，1.95(2H，m)，2.34(2H，dt，J＝8.0，16Hz)，3.30(2H，q，J＝7.0Hz)，3.39(2H，q，J＝7.6Hz)，4.54(1H，s)，4.55(1H，s)，7.17(1/2H，s)7.33(1H，dd，J＝2.7，8.8Hz)，7.41(1H，m)，7.48(1/2H，s)，7.58(1/2H，s)，7.79(1/2H，s)，7.91(1H，m)，8.01(1H，m)，8.38-8.45(1H+1/2H，m)，8.47(1/2H，m)，8.65(1H，m)，11.0(1/2H，br)，11.1(1/2H，br)

ESI-MS(m/e)：478[M+H]

EXAMPLE 41

3- { [5- { [6- (ethylsulfonyl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1H-benzimidazol-6-yl ] methyl } -2- _ oxazolidinone

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound obtained in example 39 (step 1) and 2-oxazolidinone.

¹HNMR(CDCl₃)δ：1.31(3H，t J＝7.6Hz)，3.34-3.42(2H，q，J＝7.6Hz)，3.43-3.53(2H，m)，4.25(2H，q，J＝8.0Hz)，4.52(1H，s)，4.54(1H，s)，7.20(1/2H，m)，7.32-7.37(1H，m)，7.38-7.45(1H，m)，7.50(1/2H，s)，7.63(1/2H，s)，7.85-7.92(1H+1/2H，m)，8.01(1H，d，J＝8.6Hz)，8.37-8.45(1H+1/2H，m)，8.48(1/2H，m)，8.65(1H，m)，11.1(1H，br)

ESI-MS(m/e)：480[M+H]

Example 42

1- { [5- { [ 6-methylsulfonyl ] -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1H-benzimidazol-6-yl ] methyl } pyrrolidine-2, 5-dione

(step 1) Synthesis of (5- { [6- (methylsulfonyl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) methanol and (6- { [6- (methylsulfonyl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) methanol

The title compound was obtained in the same manner as in example 19 (step 5 to step 7), in a similar manner to or in combination with the conventional method using 6- (methylsulfonyl) -3-pyridinol obtained in reference example 3.

(step 2) Synthesis of 1- { [5- { [ 6-methylsulfonyl ] -3-pyridyl } oxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl } methyl } pyrrolidine-2, 5-dione

¹HNMR(CDCl₃)δ：2.61(2H，m)，2.69(2H，m)，3.24(3H，m)，4.77(2H，d，J＝9.0Hz)，7.12(1/2H，s)，7.35-7.41(2H，m)，7.44(1/2H，s)，7.69(1/2H，s)，7.80(1/2H，s)，7.87(1H，m)，8.02(1H，d，J＝13.7，8.6Hz)，8.37(1H，m)，8.48(1H，m)，8.64(1H，m)，10.57(1H，s)

ESI-MASS(m/e)：478(M+H)

Example 43

1- { [5- { [ 6-methylsulfonyl group]-3-pyridyl]Oxy } -2- (2-pyridyl) -1H-benzimidazole- 6-yl]Methyl } -2-pyrrolidone

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 42 (step 1).

¹HNMR(CDCl₃)δ：1.90-1.98(2H，m)，2.30-2.35(2H，m)，3.21(3H，s)，3.30(2H，m)，4.53(2H，d，J＝3.9Hz)，7.19(1/2H，s)，7.33(1H，s)，7.40(1H，m)，7.49(1/2H，m)，7.57(1/2H，m)，7.78(1/2 H，m)，7.88(1H，s)，8.00-8.01(1H，m)，8.36-8.46(2H，m)，8.64(1H，s)，10.65(1H，s)

ESI-MASS(m/e)：464(M+H)

Example 44

1- { [5- [ 3-chloro-4- (methylsulfonyl) phenoxy]-2- (2-pyridyl) -1H-benzimidazole-6- Methyl radical]Pyrrolidine-2, 5-diones

(step 1) Synthesis of (5- [ 3-chloro-4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) methanol and (6- [ 3-chloro-4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) methanol

The title compound was obtained in the same manner as in example 19 (step 5 to step 7), in a similar manner to this, or in combination with a conventional method using 3-chloro-4- (methylsulfonyl) phenol obtained in reference example 5.

(step 2) Synthesis of 1- { [5- [ 3-chloro-4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl } methyl ] pyrrolidine-2, 5-dione

¹HNMR(CDCl₃)δ：2.63(4Hx1/2，s)，2.71(4Hx1/2，s)，3.28(3Hx1/2，s)，3.28(3Hx1/2，s)，4.77(2Hx1/2，s)，4.78(2Hx1/2，s)，6.99-7.04(2Hx1/2，m)，7.11(1Hx1/2，d，J＝2.3Hz)，7.15(1Hx1/2，d，J＝2.3Hz)，7.15(1Hx1/2，s)，7.40-7.44(1H，m)，7.47(1Hx1/2，s)，7.69(1Hx1/2，s)，7.81(1Hx1/2，s)，7.86-7.94(1H，m)，8.08-8.15(1H，m)，8.38-8.45(1H，m)，8.64-8.69(1H，m)，10.62(1Hx1/2，brs)，10.65(1Hx1/2，brs).

ESI-MASS(m/e)：511(M+H)

Example 45

1- { [5- [ 3-chloro-4- (methylsulfonyl) phenoxy]-2- (2-pyridyl) -1H-benzimidazole-6- Methyl radical]-2-pyrrolidone

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 44 (step 1).

¹HNMR(CDCl₃)δ：1.93-2.02(2H，m)，2.33-2.41(2H，m)，3.27(3H，s)，3.31-3.34(2H，m)，4.53(2Hx1/2，s)，4.54(2Hx1/2，s)，6.93-7.03(1H，m)7.08-7.10(1H，m)，7.21(1Hx1/2，s)，7.41-7.44(1H，m)，7.51(1Hx1/2，s)，7.59(1Hx1/2，s)，7.80(1Hx1/2，s)，7.88-7.93(1H，m)，8.08(1H，d，J＝9.0Hz)，8.42(1H，t，J＝8.4Hz)，8.65-8.69(1H，m)，10.79(1Hx1/2，brs)，10.85(1Hx1/2，brs).

ESI-MASS(m/e)：497(M+H)

Example 46

3- { [5- [ 3-chloro-4- (methylsulfonyl) phenoxy]-2- (2-pyridyl) -1H-benzimidazole-6- Methyl radical]-2-oxazolidinone

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound obtained in example 44 (step 1) and 2-oxazolidinone.

¹HNMR(CDCl₃)δ：3.25(3H，s)，3.42-3.51(2H，m)，4.22-4.29(2H，m)，4.48(2Hx1/2，s)，4.50(2Hx1/2，s)，6.93-6.99(1H，m)，7.05-7.10(1H，m)，7.20(1Hx1/2，s)，7.39-7.44(1H，m)，7.50(1Hx1/2，s)，7.64(1Hx1/2，s)，7.85-7.90(1H，m)，7.90(1Hx1/2，s)，8.06(1H，d，J＝8.6Hz)，8.39(1Hx1/2，d，J＝8.6Hz)，8.41(1Hx1/2，d，J＝8.，6Hz)8.63-8.68(1H，m)，10.84(1H，brs).

ESI-MASS(m/e)：499(M+H)

Example 47

4- { [6- [ (2, 5-dioxo-1-pyrrolidinyl) methyl group]-2- (2-pyridyl) -1H-benzimidazole-5- Base of]Oxy benzonitrile

The title compound was obtained in the same manner as in example 19 (step 5 to step 8), in a similar manner thereto or in combination with a conventional method using 4-cyanophenol.

¹H NMR(CDCl₃)δ：2.53(4Hx1/2，s)，2.63(4Hx1/2，s)，4.76(2Hx1/2，s)，4.77(2Hx1/2，s)，6.99(1H，d，J＝9.0Hz)，7.02(1H，d，J＝9.0Hz)，7.11(1Hx1/2，s)，7.36-7.40(1H，m)，7.43(1Hx1/2，s)，7.58(1H，d，J＝9.0Hz)，7.61(1H，d，J＝9.0Hz)，7.63(1Hx1/2，s)，7.75(1Hx1/2，s)，7.84-7.89(1H，m)，8.34-8.39(1H，m)，8.60-8.66(1H，m)，10.46(1Hx1/2，brs)，10.52(1Hx1/2，brs).

ESI-MASS(m/e)：424(M+H)

Example 48

1- { [5- [ (6-methyl-3-pyridinyl) oxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all Radical } pyrrolidine-2, 5-dione

The title compound was obtained in the same manner as in example 19 (step 5 to step 8), in a similar manner to this, or in combination with a conventional method using 4-hydroxy-6-methylpyridine.

¹H NMR(CDCl₃)δ：2.53(3H，d，J＝8.2Hz)，2.60(2H，s)，2.69(2H，s)，4.87(2H，d，J＝9.4Hz)，7.08-7.13(1H，m)，7.32(2H，m)，7.52(1H，m)，7.65(1/2H，m)，7.83-7.85(1H，m)，8.26(1/2 H，s)，8.32-8.34(2H，m)，8.60(1H，m)

ESI-MASS(m/e)：414(M+H)

Example 49

1- { [5- [ 6-methyl-3-pyridinyl]Sulfanyl radical]-2- (2-pyridinyl) -1H-benzimidazol-6-yl] Methyl pyrrolidine-2, 5-dione

The title compound was obtained by the same method as in example 19 (steps 5 to 8), a method similar thereto, or a combination thereof with a conventional method using 6-methylpyridine-3-thiol synthesized according to the method described in WO 2004081001.

¹H NMR(CDCl₃)δ：10.59(brs，1H)，8.62(d，1H，J＝4.7Hz)，8.40-8.37(m，2H)，7.85(m，1H)，7.56(d，1H，J＝15.7Hz)，7.42-7.43(m，3H)，7.03(s，1H)，4.99(s，2H)，2.76(s，2H)，2.68(s，2H)，2.47(s，3H)

ESI-MASS(m/e)：414(M+H)

Example 50

1- { [5- [4- (methoxymethyl) methyl) Phenoxy radical]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all Radical } pyrrolidine-2, 5-dione

(step 1) Synthesis of methyl 5- (4-formylphenoxy) -2- (2-pyridyl) - { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-6-carboxylate and methyl 6- (4-formylphenoxy) -2- (2-pyridyl) - { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-5-carboxylate

The title compound was obtained in the same manner as in example 19 (step 5 to step 6), in a similar manner thereto or in combination with a conventional method using 4-hydroxybenzaldehyde.

(step 2) Synthesis of methyl 5- [4- (hydroxymethyl) phenoxy ] -2- (2-pyridyl) - { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-6-carboxylate and methyl 6- [4- (hydroxymethyl) phenoxy ] -2- (2-pyridyl) - { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-5-carboxylate

To a solution of 362mg of the resultant in 5ml of methanol, 54mg of sodium borohydride was added under ice bath, followed by stirring at room temperature for 20 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate and washing of the organic layer with a saturated saline solution. After drying, the solvent was removed to give 337mg of the crude product of the title compound as a yellow solid.

(step 3) Synthesis of methyl 5- [4- (methoxymethyl) phenoxy ] -2- (2-pyridyl) - { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-6-carboxylate and methyl 6- [4- (methoxymethyl) phenoxy ] -2- (2-pyridyl) - { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-5-carboxylate

To a 5ml DMF solution of 337mg of the obtained product was added 89. mu.l of methyl iodide and 57mg of sodium hydride (30% liquid paraffin was added) while cooling on ice, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate and washing of the organic layer with a saturated saline solution. After drying, the solvent was removed to give 346mg of the crude title compound as a light brown oil.

(step 4) Synthesis of 1- { [5- [4- (methoxymethyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } pyrrolidine-2, 5-dione

Using the obtained product, the title compound was obtained in the same manner as in example 19 (step 7 to step 8), in a similar manner thereto, or in combination with a conventional method.

¹H NMR(CDCl₃)δ：2.57(4H，d，J＝24.3Hz)，3.37(3H，s)，4.40(2H，s)，4.85(2H，s)，6.93(2H，d，J＝8.2Hz)，7.27(3H，d，J＝8.2Hz)，7.33-7.37(1H，m)，7.60(1H，brs)，7.84(1H，td，J＝7.8，8.1Hz)，8.35(1H，d，J＝7.8Hz)，8.60(1H，d，J＝4.3Hz)

ESI-MASS(m/e)：443(M+H)

Example 51

1- {5- [4- (2-oxo-1, 3-oxazolidin-3-yl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazole Azol-6-yl } methyl } pyrrolidine-2, 5-dione

(step 1) Synthesis of methyl 5- (4-iodophenoxy) -2- (2-pyridinyl) - { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-6-carboxylate and methyl 6- (4-iodophenoxy) -2- (2-pyridinyl) - { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-5-carboxylate

The title compound was obtained in the same manner as in example 19 (step 5 to step 6), in a similar manner thereto or in combination with a conventional method using 4-iodophenol.

(step 2) Synthesis of methyl 5- [4- (2-oxo-1, 3-oxazolidin-3-yl) ] -2- (2-pyridyl) -1H-benzimidazole-6-carboxylate and methyl 6- [4- (2-oxo-1, 3-oxazolidin-3-yl) ] -2- (2-pyridyl) -1H-benzimidazole-5-carboxylate

To 642mg of the resultant product in 7ml of DMF were added 186mg of 2-oxazolidinone, 20mg of copper (I) iodide, 148mg of potassium carbonate, and the mixture was stirred with heating at 150 ℃ for 28 hours. The reaction solution was allowed to return to room temperature, and then a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate and washing of the organic layer with a saturated saline solution. After drying, the residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol 100/0-100/1) to give 427mg of the title compound as a pale brown oil.

(step 3) Synthesis of 1- {5- [4- (2-oxo-1, 3-oxazolidin-3-yl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl } methyl } pyrrolidine-2, 5-dione

Using the obtained product, the title compound was obtained in the same manner as in example 34 (step 3 to step 4), in a similar manner thereto, or in combination with conventional methods.

¹HNMR(CDCl₃)δ：2.51-2.53(2H，m)，2.65-2.71(2H，m)，4.05-4.10(2H，m)，4.56-4.49(2H，m)，4.86(2H，d，J＝12.5Hz)，6.98(2H，d，J＝12.5Hz)，7.32(2H，m)，7.49(2H，m)，7.63(1H，d，J＝9.8Hz)，7.84(1H，dd，J＝7.8，5.9H2)，8.34-8.36(1H，m)，8.59-8.61(1H，m)

ESI-MASS(m/e)：484(M+H)

Example 52

1- [ (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl]Oxy } -2- (2-pyridyl) - 1H-benzimidazol-6-yl) methyl]Pyrrolidine-2, 5-diones

(step 1) Synthesis of methyl 5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-6-carboxylate and methyl 6- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-5-carboxylate

The title compound was obtained in the same manner as in example 19 (step 5 to step 6), in a similar manner to this, or in combination with a conventional method using 6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinol obtained in referential example 6.

(step 2) (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1- [ {2- (trimethylsilyl) ethoxy } methyl } -1H-benzimidazol-6-yl) methanol and (6- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1- [ {2- (trimethylsilyl) ethoxy } methyl ] -1H-benzimidazol-5-yl) methanol

The title compound was obtained in the same manner as in example 34 (step 3), in a similar manner thereto or in combination with a conventional method.

(step 3)1- [ (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1H-benzimidazol-6-yl) methyl ] pyrrolidine-2, 5-dione

¹HNMR(CDCl₃)δ：2.58(2H，s)，2.67(2H，s)，2.67(3H，s)，4.82(2Hx1/2，s)，4.84(2Hx1/2，s)，7.08(1Hx1/2，s)，7.30-7.40(2H，m)，7.44(1Hx1/2，s)，7.61(1Hx1/2，s)，7..74(1Hx1/2，s)，7.86(1Hx1/2，t，J＝8.2Hz)，7.86(1Hx1/2，t，J＝8.2Hz)，8.02(1Hx1/2，d，J＝8.6Hz)，8.06(1Hx1/2，d，J＝9.4Hz)，8.35(1Hx1/2，d，J＝8.2Hz)，8.37(1Hx1/2，d，J＝8.2Hz)，8.53(1Hx1/2，d，J＝2.3Hz)，8.57(1Hx1/2，d，J＝2.3Hz)，8.61(1Hx1/2，d，J＝4.3Hz)，8.63(1H，dx1/2，J＝4.3Hz)，10.60(1Hx1/2，brs)，10.64(1Hx1/2，brs).

ESI-MASS(m/e)：482(M+H)

Example 53

1- [ (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl]Oxy } -2- (2-pyridyl) - 1H-benzimidazol-6-yl) methyl]-2-pyrrolidone

The title compound was obtained by using the alcohol compound obtained in example 52 (step 2) and following the same method as in example 2, a method similar thereto, or a combination thereof with a conventional method.

¹HNMR(CDCl₃)δ：1.90-1.98(2H，m)，2.30-2.38(2H，m)，2.67(3H，s)，3.29-3.35(2H，m)，4.57(2Hx1/2，s)，4.59(2Hx1/2，s)，7.14(1Hx1/2，s)，7.30(1Hx1/2，dd，J＝9.0，2.7Hz)，7.33(1Hx1/2，dd，J＝9.0，2.3Hz)，7.38(1Hx1/2，dd，J＝8.2，5.5Hz)，7.38(1Hx1/2，dd，J＝8.2，5.1Hz)，7.47(1Hx1/2，s)，7.57(1Hx1/2，s)，7.77(1Hx1/2，s)，7.86(1Hx1/2，t，J＝8.2Hz)，7.87(1Hx1/2，t，J＝8.2Hz)，8.02(1Hx1/2，d，J＝9.0Hz)，8.04(1Hx1/2，d，J＝9.0Hz)，8.37(1Hx1/2，d，J＝8.2Hz)，8.40(1Hx1/2，d，J＝8.2Hz)，8.47(1Hx1/2，d，J＝2.3Hz)，8.54(1Hx1/2，d，J＝2.7Hz)，8.62(1Hx1/2，d，J＝5.5Hz)，8.64(1Hx1/2，d，J＝5.1Hz)，10.84(1Hx1/2，brs)，10.94(1Hx1/2，brs).

ESI-MASS(m/e)：468(M+H)

Example 54

1- [ (5- { {6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridyl]Oxy } -2- (2-pyridyl) - 1H-benzimidazol-6-yl) methyl]-2-oxazolidinone

The title compound was obtained in the same manner as in example 2, a method similar thereto or a combination thereof with a conventional method using the alcohol compound obtained in example 52 (step 2) and 2-oxazolidinone.

¹HNMR(CDCl₃)δ：2.67(3H，s)，3.46-3.53(2H，m)，4.21-4.27(2H，m)，4.55(2Hx1/2，s)，4.58(2Hx1/2，s)，7.17(1Hx1/2，s)，7.32(1Hx1/2，dd，J＝8.6，2.7Hz)，7.35(1Hx1/2，dd，J＝8.6，2.3Hz)，7.39(1Hx1/2，dd，J＝8.2，5.5Hz)，7.39(1Hx1/2，dd，J＝8.2，5.0Hz)，7.49(1Hx1/2，s)，7.64(1Hx1/2，s)，7.84-7.90(1H，m)，7.87(1Hx1/2，s)，8.04(1Hx1/2，d，J＝8.6Hz)，8.06(1Hx1/2，d，J＝8.6Hz)，8.38(1Hx1/2，d，J＝8.2Hz)，8.40(1Hx1/2，d，J＝8.2Hz)，8.47(1Hx1/2，d，J＝2.3Hz)，8.54(1Hx1/2，d，J＝2.7Hz)，8.62(1Hx1/2，d，J＝5.5Hz)，8.65(1Hx1/2，d，J＝5.0Hz)，10.79(1Hx1/2，brs)，10.85(1Hx1/2，brs).

ESI-MASS(m/e)：470(M+H)

Example 55

1- { [5- [4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenoxy]-2- (2-pyridinyl) -1H-benzo Imidazol-6-yl]Methyl pyrrolidine-2, 5-dione

(step 1) Synthesis of (5- [4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) methanol and (6- [4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) methanol

The title compound was obtained in the same manner as in example 52 (step 1-step 2), a similar manner to this, or a combination thereof with a conventional method using 4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenol obtained in referential example 7.

(step 2) Synthesis of 1- { [5- [4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } pyrrolidine-2, 5-dione

H₁-NMR(CDCl₉)δ：2.44(4Hx1/2，s)，2.57(4Hx1/2，s)，2.63(3Hx1/2，s)，2.64(3Hx1/2，s)，4.82(2Hx1/2，s)，4.85(2Hx1/2，s)，6.99(2Hx1/2，d，J＝8.6Hz)，7.04(2Hx1/2，d，J＝8.6Hz)，7.10(1Hx1/2，s)，7.34-7.39(1H，m)，7.45(1Hx1/2，s)，7.61(1Hx1/2，s)，7.73(1Hx1/2，s)，7.83-7.87(1H，m)，7.99(2Hx1/2，d，J＝8.6Hz)，8.02(2Hx1/2，d，J＝8.6Hz)，8.35(1Hx1/2，d，J＝7.0Hz)，8.37(1Hx1/2，d，J＝6.7Hz)，8.60(1Hx1/2，d，J＝5.3Hz)，8.64(1Hx1/2，d，J＝5.1Hz)，10.46(1Hx1/2，s)，10.55(1Hx1/2，s).

ESI-MASS(m/e)：481(M+H)

Example 56

1- { [5- [4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenoxy]-2- (2-pyridinyl) -1H-benzo Imidazol-6-yl]Methyl } -2-pyrrolidone

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 55 (step 1).

¹HNMR(CDCl₃)δ：1.87-1.95(2H，m)，2.30-2.36(2H，m)，3.27-3.33(2H，m)，4.7(2Hx1/2，s)，4.59(2Hx1/2，s)，7.01(2Hx1/2，d，J＝8.6Hz)，7.03(2Hx1/2，d，J＝8.6Hz)，7.15(1Hx1/2，s)，7.35-7.39(1H，m)，7.49(1Hx1/2，s)，7.56(1Hx1/2，s)，7.75(1Hx1/2，s)，7.83-7.88(1H，m)，8.00(2Hx1/2，d，J＝8.6Hz)，8.00(2Hx1/2，d，J＝8.6Hz)，8.37(1Hx1/2，d，J＝8.6Hz)，8.39(1Hx1/2，d，J＝8.6Hz)，8.61(1Hx1/2，d，J＝5.5Hz)，8.64(1Hx1/2，d，J＝5.3Hz)，10.57(1Hx1/2，brs)，10.66(1Hx1/2，brs).

ESI-MASS(m/e)：467(M+H)

Example 57

1- [5- [4- (methylsulfonyl) phenoxy group]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]-1-ethyl Alcohol(s)

(step 1) Synthesis of methyl 5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-6-carboxylate and methyl 6- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-5-carboxylate

The title compound was obtained from the aldehyde compound of example 1(8) according to the procedure described in j. org. chem, 64(4), 1191 (1999). The title compound can be similarly obtained by the same method as in example 19 (steps 5 to 6), a method similar thereto, or a combination thereof with a conventional method using 4- (methylsulfonyl) phenol obtained in reference example 1.

(step 2) Synthesis of 1- (5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) -1-ethanol or 1- (6- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) -1-ethanol

400mg of the obtained methyl ester compound was dissolved in 4ml of tetrahydrofuran and 4ml of methanol, and 1.5ml of a 5N aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 3 hours. The mixture was neutralized with a 10% citric acid aqueous solution, extracted with ethyl acetate, and washed with saturated brine. The mixture was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 376mg of a yellow solid.

376mg of the resulting solid was dissolved in 5ml of dimethylformamide, and 0.29ml of triethylamine, 205mg of N, O-dimethylhydroxylamine hydrochloride, 284mg of 1-hydroxybenzotriazole monohydrate, and 205mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added thereto, followed by stirring at room temperature overnight. Water was added to the reaction solution, which was diluted with ethyl acetate, and the organic layer was washed with saturated brine. Dried over anhydrous magnesium sulfate, the solvent was distilled off, and then purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 9/1 → 3/1 → 1/1) to give 347mg of white amorphous substance.

110mg of the resulting white amorphous was dissolved in 2ml of tetrahydrofuran, and 0.76ml of methyllithium (1.02M diethyl ether solution) was added at-78 ℃ and stirred at-78 ℃ for 30 minutes. Saturated aqueous ammonium chloride was added, diluted with ethyl acetate, and the organic layer was washed with saturated brine. With anhydrous sulfur Magnesium was dried, the solvent was distilled off, and the residue was purified by preparative thin layer chromatography (Kieselgel)^TM 60F₂₅₄Ar t 5744(Merck), hexane/ethyl acetate 1/2) to yield 66.3mg of the title compound as a light yellow oil.

(step 3) Synthesis of 1- (5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) -1-ethanol or 1- (6- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) -1-ethanol

20mg of the obtained acetyl compound was dissolved in 0.5ml of methanol, and 20mg of sodium borohydride was added thereto and stirred at room temperature for 15 minutes. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. Drying over anhydrous magnesium sulfate, distilling off the solvent, and purifying by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 20/1) to yield 18.3mg of the title compound as a colorless oil.

(step 4) Synthesis of 1- [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] -1-ethanol

18.3mg of the resulting product were dissolved in 1ml of trifluoroacetic acid and stirred at room temperature for 2 hours. The solvent was distilled off, neutralized with triethylamine and then purified by preparative thin layer chromatography (Kieselgel) ^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 10/1) to yield 11.2mg of the title compound as a white solid.

¹HNMR(CDCl₃)δ：1.53(3H，m)，3.06(3H，s)，5.18(1H，m)，7.05-7.10(2H+1/2H，m)，7.40(1H+1/2H，m)，7.80(1/2H，s)，7.82-7.90(2H，m)，8.10(1/2H，s)，8.37-8.43(1H，m)，8.64(1H，m)，10.6(1/2H，br)，10.8(1/2H，br)

ESI-MASS(m/e)：410[M+H]

Example 58

1- [5- [4- (methylsulfonyl)) Phenoxy radical]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]-1，2- Ethanediol trifluoroacetate salt

The diol compound obtained in example 1 (step 7) was subjected to the same method as in example 57 (step 4), a method similar thereto, or a combination thereof with a conventional method to obtain the title compound.

¹HNMR(CD₃OD)δ：2.69(1H，brs)，3.17(3H，s)，3.62-3.67(1H，m)，3.82-3.83(1H，m)，5.12-5.13(1H，m)，7.27-7.29(2H，m)，7.42(1H，s)，7.67-7.71(1H，m)，8.00-8.02(2H，m)，8.14-8.17(2H，m)，8.32-8.34(1H，m)，8.89(1H，m)

ESI-MASS(m/e)：410[M+H]

Example 59

[5- [4- (methylsulfonyl) phenoxy group]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]Methanol

¹HNMR(CDCl₃)δ：3.18-3.19(3H，m)，4.48-4.51(2H，m)，5.18-5.19(1/2H，m)，5.21-5.28(1/2H，m)，7.05-7.13(2H，m)，7.40(1H，s)，7.51-7.55(1H，m)，7.75(1H，s)，7.86-7.90(2H，m)，7.98-8.02(1H，m)，8.29-8.34(1H，m)，8.72-8.75(1H，m)，13.12(1/2H，brs)，13.25(1/2H，brs)

ESI-MASS(m/e)：396(M+H)

Example 60

N-methyl-N- {1- [5- [4- (methylsulfonyl) phenoxy ] benzene]-2- (2-pyridinyl) -1H-benzimidazole Azol-6-yl]Ethyl amine

(step 1) Synthesis of N-1- [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl ] ethyl-N-methylamine or N-1- [6- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl ] ethyl-N-methylamine

33mg of the acetyl compound obtained in example 57 (step 2) was dissolved in 0.2ml of methanol, 0.2ml of methylamine (40% methanol solution) was added, and a methanol solution of 41mg of zinc chloride and 38mg of sodium cyanoborohydride was further added, followed by stirring at room temperature for 6 hours. 10% aqueous citric acid solution was added, neutralized with sodium hydrogencarbonate, and then extracted with ethyl acetate. The mixture was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 30mg of the title compound as a yellow oil.

(step 2) Synthesis of N-methyl-N- {1- [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] ethyl } amine

The obtained oil was subjected to the same method as in example 57 (step 4), a method similar thereto or a combination thereof with a conventional method to obtain the title compound.

¹HNMR(CDCl₃)δ：1.36(3H，m)，2.30(3H，s)，3.07(3H，s)，3.98(1H，m)，7.08(2H+2/5H，m)，7.39(1H，m)，7.45(3/5H，m)，77.75(3/5H.m)，7.88(3H，m)，7.98(2/5H，m)，8.40(1H，m)，8.65(1H，m)

ESI-MASS(m/e)：423(M+H)

Example 61

N-methyl-N- {1- [5- [4- (methylsulfonyl) phenoxy ] benzene]-2- (2-pyridinyl) -1H-benzimidazole Azol-6-yl]Ethyl acetamide

(step 1) Synthesis of N-methyl-N- (1- [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl ] ethyl) acetamide or N-methyl-N- (1- [6- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl ] ethyl) acetamide

30mg of the N-methylamine compound obtained in example 60 (step 1) was dissolved in 0.3ml of chloroform, and 15. mu.l of triethylamine and 8. mu.l of acetyl chloride were added thereto and stirred at room temperature for 30 minutes. After water was added, the mixture was diluted with ethyl acetate and washed with brine. Drying over anhydrous magnesium sulfate, distilling off the solvent, and purifying by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 20/1) gave 19.1mg of a colorless oil.

(step 2) Synthesis of N-methyl-N- {1- [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] ethyl } acetamide

The title compound was obtained in the same manner as in example 57 (step 4), in a similar manner thereto or in combination with a conventional method.

¹H NMR(CDCl₃)δ：1.55(3H，d，J＝7.0Hz)，1.86(3H，s)，2.68(3H，s)，3.06(3H，s)，6.03(1H，m)，6.98(2H，d，J＝8.9Hz)，7.33(1H，s)，7.56(1H，m)，7.85(2H，d，J＝8.9Hz)，7.90-8.06(2H，m)，8.53(1H，m)，8.71(1H，m)

ESI-MASS(m/e)：465[M+H]

Example 62

N, N-dimethyl-N- {1- [5- [4- (methylsulfonyl) phenoxy ] benzene]-2- (2-pyridinyl) -1H-benzene And-imidazole-6-yl]Ethyl amine

The title compound was obtained in the same manner as in example 60 (step 1), in a similar manner thereto, or in combination with a conventional method using N, N-dimethylamine.

¹HNMR(CDCl₃)δ：1.33(3H，m)，2.20(6H，m)，3.07(3H，s)，3.57(3/5H，m)，3.71(2/5H，m)，7.07(2H，m)，7.14(2/5H，s)，7.39(1H，m)，7.45(3/5H，s)，7.75(3/5H，s)，7.84-7.90(3H，m)，8.02(2/5H，s)，8.40(1H，m)，8.65(1H，m)，10.5(1H，br)

ESI-MASS(m/e)：437[M+H]

Example 63

1- {1- [5- [4- (methylsulfonyl) phenoxy ] benzene]-2- (2-pyridinyl) -1H-benzimidazol-6-yl] Ethyl } pyrrolidine-2, 5-dione

The title compound was obtained in the same manner as in example 1 (step 10), a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 57 (step 3).

¹HNMR(CDCl₃)δ：1.79(3H，m)，2.10-2.28(2H，m)，2.28-2.40(2H，m)，3.06(3H，s)，5.69(1H，m)，7.00(2H，m)，7.42(1H+1/2H，m)，7.80-8.00(3H+1/2H，m)，8.20-8.50(2H，br)，8.67(1H，m)，10.8(1H，br)

ESI-MASS(m/e)：491[M+H]

Example 64

{5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridyl) -1H-benzimidazol-6-yl } (4-fluoro Phenyl) methanol

(step 1) Synthesis of 5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-6-carbaldehyde and 6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-5-carbaldehyde

To 1.0g of a 10ml dimethylsulfoxide solution of the alcohol compound obtained in example 19 (step 7) were added 5ml of triethylamine and 750mg of pyridine sulfur trioxide, and the reaction solution was stirred at room temperature for 15 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.0g of the title compound as an orange solid.

(step 2) Synthesis of {5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl } (4-fluorophenyl) methanol or {6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl } (4-fluorophenyl) methanol

To a solution of 45mg of the resulting aldehyde in 1ml of tetrahydrofuran was added 0.5ml of 4-fluorophenylmagnesium bromide (1M tetrahydrofuran solution) at 0 ℃ and the reaction mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with a saturated aqueous ammonium chloride solution and a saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: hexane/ethyl acetate 1/2) to give 35mg of the title compound as a colorless solid.

(step 3) Synthesis of {5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl } (4-fluorophenyl) methanol

20mg of the resulting product was dissolved in 1ml of a trifluoroacetic acid solution, and the reaction solution was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase medium-pressure liquid chromatography [ ODS-AS-360-CC (manufactured by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid ]. The solvent of the resultant fraction was diluted with ethyl acetate, washed with saturated sodium hydrogencarbonate water, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 5.4 mg of the title compound as a colorless solid.

¹H NMR(CD3OD)δ：1.24(3H，t，J＝7.4Hz)，3.18(2H，q，J＝7.4Hz)，6.05(1H，s)，6.88-6.95(4H，m)，7.20-7.42(1H，m)，7.30(2H，dd，J＝8.2，5.5Hz)，7.48-7.53(1H，m)，7.76(2H，d，J＝8.6Hz)，7.99(1H，t，J＝8.0Hz)，8.02-8.20(1H，m)，8.28-8.34(1H，m)，8.73-8.78(1H，m).

ESI-MASS(m/e)：504

Example 65

5- [4- (B)Radical sulfonyl) phenoxy]-6- (4-fluorobenzyl) -2- (2-pyridyl) -1H-benzimidazole

To a solution of 4.9mg of the alcohol compound obtained in example 64 (step 2) in 0.2ml of trifluoroacetic acid was added 0.5ml of triethylsilane, and the reaction mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then the residue was purified by reverse-phase medium-pressure liquid chromatography [ ODS-AS-360-CC (manufactured by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid ]. The solvent of the resultant fraction was diluted with ethyl acetate, washed with saturated sodium bicarbonate water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 5.5mg of the title compound as a pale yellow solid.

¹H NMR(CD3OD)δ：1.17(3H，t，J＝7.4Hz)，3.12(2H，q，J＝7.4Hz)，3.96(2H，s)，6.83(2H，t，J＝8.8Hz)，6.92(2H，d，J＝9.0Hz)，7.09(2H，dd，J＝8.8，5.0Hz)，7.27(1H，s)，7.43(1H，dd，J＝7.0，5.0Hz)，7.58(1H，s)，7.72(2H，d，J＝9.0Hz)，7.92(1H，t，J＝7.4Hz)，8.22(1H，d，J＝7.4Hz)，8.68(1H，d，J＝5.0Hz).

ESI-MASS(m/e)：488

Example 66

{5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridyl) -1H-benzimidazol-6-yl } (4-fluoro Phenyl) methanones

To 15mg of a solution of the alcohol compound obtained in example 64 (step 3) in 0.2ml of dimethyl sulfoxide were added 0.1ml of triethylamine and 15mg of pyridine sulfur trioxide, and the reaction solution was stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was dissolved in 1ml of a trifluoroacetic acid solution, and the reaction solution was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase medium-pressure liquid chromatography [ ODS-AS-360-CC (manufactured by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid ]. The solvent of the resultant fraction was diluted with ethyl acetate, washed with saturated sodium bicarbonate water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 7.9 mg of the title compound as a colorless solid.

¹HNMR(CD3OD)δ：1.18(3H，t，J＝7.4Hz)，3.16(2H，q，J＝7.4Hz)，6.93-6.99(2H，m)，7.18(2H，t，J＝8.6Hz)，7.40-7.60(2H，m)，7.77(2H，d，J＝8.6Hz)，7.82(2H，dd，J＝8.4，5.3Hz)，7.84-8.00(1H，m)，8.02(1H，t，J＝7.6Hz)，8.35(1H，d，J＝7.6Hz)，8.77-8.80(1H，m)

ESI-MASS(m/e)：502

Example 67

(2-fluorophenyl) [5- [4- (methylsulfonyl) phenoxy group]-2- (2-pyridyl) -1H-benzimidazole- 6-yl]Methanol

(step 1) Synthesis of {5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl } (2-fluorophenyl) methanol or {6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl } (2-fluorophenyl) methanol

The title compound was obtained in the same manner as in example 64 (step 2), a method similar thereto, or a combination thereof with a conventional method, using the aldehyde compound obtained in example 1 (step 8) and 2-fluorophenylmagnesium bromide.

(step 2) Synthesis of (2-fluorophenyl) [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methanol

Using the obtained product, the title compound was obtained in the same manner as in example 64 (step 3), in a similar manner thereto, or in combination with a conventional method.

¹H NMR(CDCl₃)δ：3.05(3H，s)，6.39(1H，s)，6.84(1H，s)，6.85(2H，d，J＝8.7Hz)，6.98-7.02(1H，m)，7.10-7.15(1H，m)，7.25-7.31(3H，m)，7.49-7.53(1H，m)，7.75(2H，d，J＝8.7Hz)，7.97-8.01(1H，m)，8.15(1H，s)，8.50(1H，d，J＝8.0Hz)，8.73(1H，d，J＝5.1Hz)

ESI-MASS(m/e)：490(M+H)

Example 68

(2-bromophenyl) [5- [4- (methylsulfonyl) phenoxy ] benzene]-2- (2-pyridyl) -1H-benzimidazole- 6-yl]Methanol

The title compound was obtained in the same manner as in example 64 (step 2 to step 3), in a similar manner thereto, or in combination with a conventional method, using the aldehyde compound obtained in example 1 (step 8) and 2-bromophenyl magnesium bromide.

¹HNMR(CDCl₃)δ：3.15(3H，s)，6.20(1H，s)，6.95-7.60(2H，m)，6.96(2H，d，J＝8.5Hz)，7.08-7.13(1H，m)，7.29-7.33(1H，m)，7.62(1H，d，J＝8.2Hz)，7.49-7.53(1H，m)，7.67(1H，s)，7.77(2H，d，J＝8.5Hz)，7.96-8.00(1H，m)，8.27-8.31(1H，m)，8.70-8.72(1H，m)

ESI-MASS(m/e)：550，552(M+H)

Example 69

6- (2-Fluorobenzyl) -5- [4- (methylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazole

The title compound was obtained in the same manner as in example 65, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 67 (step 1).

¹HNMR(CDCl₃)δ：3.06(3H，s)，4.00-4.05(2H，m)，6.96-7.02(3H，m)，7.08-7.17(2H，m)，7.25-7.28(1H，m)，7.37-7.43(1H，m)，7.53-7.58(1H，m)，7.68-7.80(1H，m)，7.80-7.94(3H，m)，8.38-8.55(1H，m)，8.60-8.75(1H，m)

ESI-MASS(m/e)：474(M+H)

Example 70

1- ({5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-7-yl } methyl Yl) pyrrolidine-2, 5-diones

(step 1) Synthesis of methyl 5-fluoro-2-nitrobenzoate

To a solution of 10g of 5-fluoro-2-nitrobenzoic acid in 200ml of methanol was added 2ml of concentrated sulfuric acid, and the mixture was refluxed for 22 hours. 200ml of an aqueous sodium hydrogencarbonate solution was added, and the resulting solid was collected by filtration. Drying under reduced pressure gave 10.7g of the title compound as a yellow solid.

(step 2) Synthesis of methyl 5- [4- (ethylsulfonyl) phenoxy ] -2-nitrobenzoate

To a solution of 10.7g of methyl 5-fluoro-2-nitrobenzoate and 11.1g of 4- (ethylsulfonyl) phenol obtained in referential example 2 in 150ml of dimethylformamide was added 11g of potassium carbonate, and the mixture was stirred at 80 ℃ for 90 minutes. The reaction mixture was returned to room temperature, 300ml of water was added thereto, and the resulting solid was collected by filtration. Drying under reduced pressure gave 19.7g of the title compound as a milky white solid.

(step 3) Synthesis of methyl 2-amino-5- [4- (ethylsulfonyl) phenoxy ] benzoate

To a solution of 6.98g of methyl 5- [4 (ethylsulfonyl) phenoxy ] -2-nitrobenzoate in 150ml of methanol was added 0.7g of Raney nickel and the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was filtered off, the solvent was then distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: hexane/ethyl acetate 2/1-1/1) to give 2.65g of the title compound as a colorless oil.

(step 4) Synthesis of methyl 5- [4- (ethylsulfonyl) phenoxy ] -2- [ (2-pyridylcarbonyl) amino ] benzoate

To a solution of 2.65g of methyl 2-amino-5- [ 4-ethylsulfonyl ] phenoxy ] benzoate in 30ml of chloroform under ice-cooling were added 4.4ml of triethylamine and 2.8g of picolinoyl chloride hydrochloride, followed by stirring at room temperature for 90 minutes. After a saturated aqueous sodium bicarbonate solution was added to the reaction solution, extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 2/1-1/1) to give 1.9g of the title compound as an off-white solid.

(step 5) Synthesis of methyl 5- [4- (ethylsulfonyl) phenoxy ] -3-nitro-2- [ (2-pyridylcarbonyl) amino ] benzoate

1.9g of methyl 5- [4- (ethylsulfonyl) phenoxy ] -2- [ (2-pyridylcarbonyl) amino ] benzoate was dissolved in 20ml of trifluoroacetic acid, and 2.2g of potassium nitrate was added thereto, followed by stirring at 80 ℃ for 2 hours. The reaction mixture was returned to room temperature, and then trifluoroacetic acid was distilled off under reduced pressure, and the residue was dissolved in chloroform and then saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 2/1-1/1) to give 1.86g of the title compound as a yellow solid.

(step 6) Synthesis of methyl 6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-4-carboxylate and methyl 5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-7-carboxylate

1.86g of methyl 5- [4- (ethylsulfonyl) phenoxy ] -3-nitro-2- [ (2-pyridylcarbonyl) amino ] benzoate was suspended in 15ml of dimethylformamide and 15ml of methanol, and 4.3g of tin (II) chloride dihydrate and 11ml of concentrated hydrochloric acid were added thereto, followed by heating and stirring at 80 ℃ for 81 hours. The reaction mixture was returned to room temperature, and was slowly added to an aqueous sodium bicarbonate solution to neutralize the reaction mixture. Ethyl acetate was added, and the mixture was stirred at room temperature for 30 minutes, then the formed salt was filtered off, the filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off to leave 1.44g of a crude methyl 5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazole-7-carboxylate as a yellow oil.

To a solution of 1.44g of methyl 5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazole-7-carboxylate in 15ml of dimethylformamide was added 0.87ml of 2- (trimethylsilyl) ethoxymethyl chloride and 197mg of sodium hydride (30% liquid paraffin was added) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Under ice-cooling, a saturated aqueous ammonium chloride solution was added, extraction was performed with ethyl acetate, and then the organic layer was washed with a saturated saline solution. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: hexane/ethyl acetate 1/1) to give 1.34g of the title compound as a pale brown oil.

(step 7) Synthesis of (6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-4-yl) methanol and (5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-7-yl) methanol

To 5ml of tetrahydrofuran, 113mg of lithium aluminum hydride and 681mg of a 5ml tetrahydrofuran solution of the above ester compound were slowly added under ice-cooling. After stirring at room temperature for 15 minutes, sodium sulfate decahydrate was slowly added until no foaming occurred, ethyl acetate was added, and stirring was carried out at room temperature for 1 hour. The resulting salt was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol 100/0-100/5) to give 519mg of the title compound as a yellow oil.

(step 8) Synthesis of 1- ({5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-7-yl } methyl) pyrrolidine-2, 5-dione

Using the purified product obtained, the title compound was obtained in the same manner as in example 1 (step 10), in a similar manner thereto, or in combination with a conventional method.

¹HNMR(CDCl₃)δ：1.32(3H，t，J＝7.4Hz)，2.80(4H，s)，3.13(2H，q，J＝7.4Hz)，4.94(2H，s)，7.10(2H，d，J＝9.4Hz)，7.23(1H，d，J＝9.4Hz)，7.40-7.42(1H，m)，7.53-7.54(1H，m)，7.85-7.88(3H，m)，8.38(1H，t，J＝4,5Hz)，8.80(1H，dd，J＝3.9，0.8Hz)，11.55(1H，brs)

ESI-MASS(m/e)：491(M+H)

Example 71

5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazole-7-carboxylic acid methyl ester

The title compound was obtained in the same manner as in example 57 (step 4), in a similar manner to this, or in combination with a conventional method using the product obtained in example 70 (step 6).

¹HNMR(CDCl₃)δ：1.27(3H，t，J＝7.4Hz)，3.11(2H，q，J＝7.4Hz)，4.04(3H，s)，7.09(2H，dd，J＝7.0，2.0Hz)，7.40-7.43(1H，m)，7.71(1H，d，J＝2.3Hz)，7.76(1H，d，J＝2.3Hz)，7.82-7.90(3H，m)，8.39(1H，d，J＝7.8Hz)，8.70(1H，d，J＝5.1Hz)，11.36(1H，brs)

ESI-MASS(m/e)：438(M+H)

Example 72

[5- [4- (ethylsulfonyl) phenoxy ] ethyl ester]-2- (2-pyridinyl) -1H-benzimidazol-7-yl]Methanol

The title compound was obtained in the same manner as in example 57 (step 4), a similar manner to this, or a combination of these with a conventional method using the product obtained in example 70 (step 7).

¹HNMR(CDCl₃)δ：1.28(3H，t，J＝11.1Hz)，3.14(2H，q，J＝11.1Hz)，5.12-5.16(2H，m)，6.94(1H，d，J＝20.7Hz)，7.07-7.12(2H，m)，7.17(1/2H，d，J＝2.0Hz)，7.39(1H，dd，J＝18.2，10.7Hz)，7.48(1/2H，s)，7.84-7.89(3H，m)，8.41(1H，d，J＝7.8Hz)，8.66-8.67(1H，m)，10.62(1/2H，brs)，11.02(1/2H，brs)

ESI-MASS(m/e)：410(M+H)

Example 73

5- [4- (ethylsulfonyl) phenoxy]-7- (methoxymethyl) -2- (2-pyridyl) -1H-benzimidazole Azole

To 53mg of the product obtained in example 70 (step 7) in 1ml of DMF was added 12. mu.l of methyl iodide and 7.8mg of sodium hydride (to which 30% liquid paraffin was added) while cooling on ice, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate and washing of the organic layer with water and a saturated saline solution. After drying, the solvent was distilled off under reduced pressure to obtain a crude product as a light brown oil. The title compound was obtained by following the same procedures as in example 57 (step 4), procedures similar thereto or in combination with conventional procedures.

¹HNMR(CDCl₃)δ：1.27(3H，t，J＝7.4Hz)，3.10(2H，q，J＝7.4Hz)，3.51(9/4H，s)，3.53(3/4H，s)，4.81(3/2H，s)，5.02(1/2H，s)，6.90(1H，s)，7.09-7.12(2H，m)，7.38-7.39(1H，m)，7.47(1H，s)，7.82-7.86(3H，m)，8.39(3/4H，d，J＝7.8Hz)，8.43(1/4H，d，J＝7.8Hz)，8.61(1/4H，s，J＝4.7Hz)，8.67(3/4H，d，J＝7.8Hz)，10.67(1/4H，brs)，10.81(3/4H，brs)

ESI-MASS(m/e)：424(M+H)

Example 74

5- [4- (ethylsulfonyl) phenoxy]-7- (2-phenoxymethyl) -2- (2-pyridyl) -1H-benzo Imidazole

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the product obtained in example 70 (step 7) and phenol.

¹H NMR(CDCl₃)δ：1.32-1.33(3H，m)，3.12(2H，q，J＝7.5Hz)，5.41(1H，s)，5.69(1H，s)，6.82-6.76(1/2H，m)，7.02-7.06(5H，m)，7.30-7.42(4H，m)，7.54-7.56(1/2H，m)，7.83-7.89(3H，m)，8.41-8.44(1H，m)，8.69-8.72(1H，m)，10.75(1/2H，brs)，10.90(1/2H，brs)

ESI-MASS(m/e)：486(M+H)

Example 75

N- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-7-yl]First of all Radical } -N, N-dimethylamine

The title compound was obtained in the same manner as in example 2, a similar manner to that described in example 4 (step 7), or a combination thereof with a conventional method, using the product obtained in example 70 and dimethylamine.

¹HNMR(CDCl₃)δ：1.29-1.31(3H，m)，2.33(6H，s)，3.07-3.15(2H，m)，3.76(2H，s)，6.90(1H，s)，7.11(2H，d，J＝9.4Hz)，7.39-7.41(1H，m)，7.46(1H，s)，7.82-7.90(3H，m)，8.42(1H，d，J＝8.2Hz)，8.71(1H，d，J＝4.3Hz)，

ESI-MASS(m/e)：437(M+H)

Example 76

7- (2, 6-difluorobenzyl) -5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzo Imidazole

(step 1) Synthesis of 6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-4-carbaldehyde and 5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-7-carbaldehyde

The title compound was obtained in the same manner as in example 64 (step 1), in a similar manner to this, or in combination with a conventional method using the product obtained in example 70 (step 7).

(step 2) Synthesis of {6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [ 2-trimethylsilyl ] ethoxy } methyl } -1H-benzimidazol-4-yl } (2, 6-difluorophenyl) methanol or {5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [ 2-trimethylsilyl ] ethoxy } methyl } -1H-benzimidazol-7-yl } (2, 6-difluorophenyl) methanol

The title compound was obtained in The same manner as in example 64 (step 2), a method similar thereto, or a combination thereof with a conventional method, using The obtained aldehyde compound and 2, 6-difluorophenylphenyllithium prepared by The method described in Journal of The American chemical society, 1966, volume 31, page 746.

(step 3) Synthesis of 7- (2, 6-difluorobenzyl) -5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazole

The title compound was obtained by using the obtained alcohol compound in the same manner as in example 65, a method similar thereto, or a combination thereof with a conventional method.

¹H NMR(CDCl₃)δ：1.24-1.33(3H，m)，3.12(2H，q，J＝25Hz)，4.17(1H，s)，4.59(1H，s)，6.93(1H，s)，7.03-7.06(3H，m)，7.19(1H，m)，7.39-7.48(2H，m)，7.81-7.84(4H，m)，8.34-8.44(1H，m)，8.59-8.67(1H，m)

ESI-MASS(m/e)：506(M+H)

Example 77

7- (4-Fluorobenzyl) -5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazole

The title compound was obtained in the same manner as in example 76 (step 2 to step 3), in a similar manner to this or in combination with a conventional method using the aldehyde compound obtained in example 76 (step 1) and 4-fluorophenylmagnesium bromide.

¹H NMR(CDCl₃)δ：1.27(3H，t，J＝13.8Hz)，3.10(2H，q，J＝13.8Hz)，4.23(1H，s)，4.44(1H，s)，6.72(1H，s)，6.85(1H，s)，6.97-7.01(4H，m)，7.21(1/2H，m)，7.34-7.38(2H，m)，7.43(1/2H，m)，7.81-7.85(3H，m)，8.39-8.44(1H，m)，8.61(1H，s)，10.60(1H，brs)

ESI-MASS(m/e)：488(M+H)

Example 78

1- ({5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-7-yl } methyl 2-pyrrolidone radical

The title compound was obtained in the same manner as in example 2, in a similar manner to example 2, or in combination with a conventional method using the product obtained in example 70 (step 7).

¹HNMR(CDCl₃)δ：1.27-1.42(3H，m)，2.00-2.13(2H，m)，2.51(2H，m)，3.13(2H，q，J＝8.3Hz)，3.43-3.50(2H，m)，4.67(2H，s)，6.93(1H，d，J＝2.0Hz)，7.10(2H，d，J＝18.0Hz)，7.38(1H，dd，J＝7.0，4.3Hz)，7.53(1H，s)，7.86-7.88(3H，m)，8.39(1H，d，J＝9.2Hz)，8.79-8.82(1H，m)，12.04(1H，s)

ESI-MASS(m/e)：477(M+H)

The structures of the compounds of examples 1-78 are shown in tables 6-8.

(Table 6)

(Table 7)

(Table 8)

Example 79

6- [ (ethylsulfonyl) methyl group]-5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridyl) -1H- Benzimidazole compounds

(step 1)5- [4- (ethylsulfonyl) phenoxy ] -6- [ (ethylthio) methyl ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole and 6- [4- (ethylsulfonyl) phenoxy ] -5- [ (ethylthio) methyl ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole

To a solution of 50mg of the alcohol compound obtained in example 19 (step 7) and 26. mu.l of triethylamine in 0.5ml of tetrahydrofuran was added 15. mu.l of methanesulfonyl chloride under ice-cooling, and the mixture was stirred for 30 minutes. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure to obtain pale yellow amorphous.

To 15. mu.l of the resulting amorphous and ethanethiol solution in 0.5ml dimethylformamide was added 11mg sodium hydride (30% liquid paraffin was added) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Adding saturated ammonium chloride aqueous solution under ice cooling, extracting with ethyl acetate, adding water and saturated salt The organic layer was washed with water. After drying, the solvent was distilled off under reduced pressure and purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 10/1) to yield 15.5mg of the title compound.

(step 2)6- [ (ethylsulfonyl) methyl ] -5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazole

To 15.5mg of the oil obtained in step 1 in 0.6ml of methanol was added 0.67ml of a 0.4M solution of oxone in methanol and the mixture was stirred at room temperature for 2 hours. Insoluble matter was filtered off, and then the filtrate was diluted with chloroform and washed with water and saturated brine. After drying, the solvent was distilled off under reduced pressure. A yellow amorphous is obtained.

The resulting yellow amorphous was dissolved in 1ml of trifluoroacetic acid and stirred at room temperature for 1 hour. The solvent was distilled off, neutralized with triethylamine and then purified by preparative thin layer chromatography (Kieselgel)^TM 60F₂₅₄Art 5744(Merck), chloroform/methanol-10/1) to yield 9.8mg of the title compound as a pale yellow solid.

¹H NMR(CDCl₃)δ：1.31(3H，t，J＝7.5Hz)，1.39(3H，t，J＝7.0Hz)，2,98(2H，q，J＝7.5Hz)，3.13(2H，q，J＝7.0Hz)，4.39(2HX1/2，s)，4.41(2HX1/2，s)，7.10-7.20(3H+1/2H，m)，7.42(1H，m)，7.47(1/2H，s)，7.81(1/2H，s)，7.88(3H，m)，8.02(1/2H，s)，8.38(1H，m)，8.67(1H，m)，10.7(1/2H，br)，10.8(1/2H，br)

ESI-MASS(m/e)：486(M+H)

Example 80

1- { [5- [4- (isopropylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl] Methyl } -2-pyrrolidone

(step 1)6- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole and 5- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole

To a solution of 100mg of the alcohol compound obtained in example 19 (step 7) in 2ml of N, N-dimethylformamide were added 34mg of imidazole and 30mg of tert-butyl (dimethyl) silyl chloride, followed by stirring at room temperature overnight. Saturated aqueous ammonium chloride was added under ice cooling, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: hexane/ethyl acetate) to give 69mg of the title compound as a yellow oil.

(step 2)6- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -5- [4- (isopropylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole and 5- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -6- [4- (isopropylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole

To a solution of 69mg of the silyl ether compound obtained in step 1 in 1ml of tetrahydrofuran, 1ml of a 0.126M tetrahydrofuran solution of lithium diisopropylamide prepared in advance was added dropwise under a nitrogen atmosphere at-78 ℃ and stirred at that temperature for 30 minutes. A solution of 45mg of methyl iodide in 1ml of tetrahydrofuran was added dropwise at-78 ℃ and stirred for a further 1 hour, after which the temperature was slowly raised to 0 ℃. Saturated aqueous ammonium chloride was added, extraction was performed with ethyl acetate, and then the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (Kieselgel) ^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 1/1) to yield 30mg of the title compound as a yellow oil.

(step 3) (5- [4- (isopropylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) methanol and (6- [4- (isopropylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) methanol

To a solution of 30mg of the silyl ether compound obtained in step 2 in 1ml of tetrahydrofuran was added dropwise a solution of tetrabutylammonium fluoride in 1.0M tetrahydrofuran under ice-cooling, and the mixture was stirred for 10 minutes. Saturated aqueous ammonium chloride was added, extraction was performed with ethyl acetate, and then the organic layer was washed with phosphate buffer solution of pH 7.0. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 1/2) to yield 24mg of the title compound as a yellow oil.

(step 4) Synthesis of 1- { [5- [4- (isopropylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -2-pyrrolidinone

The title compound was obtained by using the alcohol compound obtained in step 3 and following the same method as in example 2, a method similar thereto, or a combination thereof with a conventional method.

¹HNMR(CDCl₃) δ: 1.30(6H, d, J ═ 7.0Hz), 1.88-1.96(2H, m), 2.29-2.36(2H, m), 3.17(1H, heptad, J ═ 7.0Hz), 3.26-3.31(2H, m), 4.53(2Hx1/2, s), 4.54(2Hx1/2, s), 7.04(2Hx1/2, d, J ═ 9.0Hz), 7.06(2Hx1/2, d, J ═ 9.0Hz), 7.17(1Hx1/2, s), 7.37-7.41(1H, m), 7.48(1Hx1/2, s), 7.56(1Hx1/2, s), 7.76(1Hx1/2, 7.80 (7 Hx 3528/2, 7.80 (1H, m), 7.48(1Hx1/2, s), 7.56(1Hx 368, 8H, 3.8H, 8H, 3.8, 8H, 3H, 3.8H, 3H, s), brs), 10.73(1Hx1/2, brs)

ESI-MASS(m/e)：491(M+H)

Example 81

4- ({5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl } methyl Yl) morpholin-3-one

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound obtained in example 19 (step 7) and morpholin-3-one (synthesized using the method described in US 5349045).

¹HNMR(CDCl₃)δ：1.30(3H，t，J＝7.4Hz)，3.11(2H，q，J＝7.4Hz)，3.34(2H，m)，3.81(2H，m)，4.15(2H，m)，4.72(2H，m)，7.07(2H，m)，7.18(1/2H，s)，7.40(1H，m)，7.49(1/2H，s)，7.68(1/2H，s)，7.80-7.90(1H+1/2H，m)，7.84(2H，d，J＝8.8Hz)，8.39(1H，m)，8.66(1H，m)，10.7(1/2H，br)，10.8(1/2H，br)

ESI-MASS(m/e)：493(M+H)

Example 82

1- ({5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl } methyl 1H-imidazole-2-carbonitrile

(step 1) Synthesis of 2-Cyanoimidazole

Synthesized according to the method described in WO 20031011836.

(step 2) Synthesis of 1- ({5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl } methyl) -1H-imidazole-2-carbonitrile

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound obtained in example 19 (step 7) and 2-cyanoimidazole.

¹HNMR(CDCl₃)δ：1.31(3H，m)，3.13(2H，m)，5.41(2H，s)，7.00-7.15(4H+1/2H，m)，7.42(1H，m)，7.47(1/2H，m)，7.55(1/2H，s)，7.80-7.95(3H+1/2H，m)，8.39(1H，m)，8.65(1H，m)，10.75(1/2H，br)，10.83(1/2H，br)

ESI-MASS(m/e)：485(M+H)

Example 83

N-({5- [4- (ethylsulfonyl) phenoxy)]-2- (2-pyridinyl) -1H-benzimidazol-6-yl } methyl Yl) acetamide

(step 1) Synthesis of N- ({5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl } methyl) acetamide or N- ({6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl } methyl) acetamide

To a solution of 81.5mg of the amine compound obtained in example 31 (step 1) and 42. mu.l of triethylamine in 0.8ml of chloroform was added 21. mu.l of acetyl chloride. After stirring for 30 minutes, a saturated aqueous sodium bicarbonate solution was added, extraction was performed with ethyl acetate, and the organic layer was washed with a saturated saline solution. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform → chloroform/methanol: 20/1), whereby 82mg of the title compound was obtained as a yellow oil.

(step 2) Synthesis of N- ({5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl } methyl) acetamide

12mg of the resulting yellow oil were dissolved in 0.5ml of trifluoroacetic acid and stirred at room temperature for 2 hours. The solvent was distilled off, neutralized with triethylamine and then purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol-10/1) to yield 9.8mg of the title compound as a pale yellow solid.

¹H NMR(CDCl₃)δ：1.30(3H，t，J＝7.4Hz)，1.95(3H，s)，3.11(2H，q，J＝7.4Hz)，4.49(2H，m)，5.83(1/2H，br)，5.97(1/2H，br)，7.15(1/2H，s)，7.40(1H，m)，7.46(1/2H，s)，7.65(1/2H，s)，7.85(3H+1/2H，m)，8.39(1H，m)，8.65(1H，m)，10.7(1/2H，br)，10，8(1/2H，br)

ESI-MASS(m/e)：451(M+H)

Example 84

N-({5-[4-(ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl } methyl Yl) -N-methylacetamide

To a solution of 38mg of the acetamide compound obtained in example 83 (step 1) in 0.3ml of dimethylformamide was added 18. mu.l of methyl iodide and 5.2mg of sodium hydride (30% liquid paraffin was added) under ice-cooling. After stirring at room temperature for 2 hours, a saturated aqueous ammonium chloride solution was added, extraction was performed with ethyl acetate, and the organic layer was washed with water and a saturated saline solution. After drying, the solvent was distilled off under reduced pressure to obtain 18.1mg of a yellow oil.

To 18.1mg of the resulting yellow oil, 0.5ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, neutralized with triethylamine and then purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 10/1) to yield 13.2mg of the title compound as a white amorphous substance.

¹HNMR(CDCl₃) δ: 1.28(3H, m), 2.05 and 2.08 (total of 3H, s), 2.96 and 2.99 (total of 3H, s), 3.12(2H, m), 4.58 and 4.66 (total of 2H, m), 7.08(2H, m), 7.17-7.73 (total of 3H, m), 7.82-7.90(3H, m), 8.40(1H, m), 8.65(1H, m), 10.8(1H, br)

ESI-MASS(m/e)：465(M+H)

Example 85

3- { [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]First of all 1, 3-oxazolidine-2, 4-dione

The title compound was obtained in the same manner as in example 19 (step 8), a method similar thereto, or a combination thereof with a conventional method, using 1, 3-oxazolidine-2, 4-dione synthesized according to the method described in juournal OF MEDICINAL CHEMISTRY, 1991, volume 34, No. 5, pages 1538 to 1544.

¹HNMR(CDCl₃)δ：1.30(3H，t，J＝7.4Hz)，3.12(2H，q，J＝7.4Hz)，4.52(2Hx1/2，s)，4.59(2Hx1/2，s)，4.81(2Hx1/2，s)，4.83(2Hx1/2，s)，7.10(2H，d，J＝8.2Hz)，7.11(1Hx1/2，s)，7.38-7.44(1H，m)，7.47(1Hx1/2，s)，7.70(1Hx1/2，s)，7.83-7.92(3H，m)，7.83-7.92(1Hx1/2，m)，8.37-8.42(1H，m)，8.62-8.67(1H，m)，10.85(1Hx1/2，brs)，10.90(1Hx1/2，brs)

ESI-MASS(m/e)：493(M+H)

Example 86

N-acetyl-N- ({5- [4- (ethylsulfonyl) phenoxy)]-2- (2-pyridinyl) -1H-benzimidazole Azol-6-yl } methyl) acetamide

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound and the diethylamide obtained in example 19 (step 7).

¹H NMR(CDCl₃)δ：1.30(3H，t，J＝7.4Hz)，3.11(2H，q，J＝7.4Hz)，2.42(6HX1/2，s)，2.43(6HX1/2，s)，5.00(2H，s)，7.11(2H，d，J＝8.6Hz)，7.15(1/2H，s)，7.25(1/2H，s)，7.41(1H，m)，7.48(1/2H，s)，7.57(1/2H，s)，7.88(3H，m)，8.38(1H，m)，8.64(1H，m)，10.75(1H，br)

ESI-MASS(m/e)：493(M+H)

Example 87

5- [4- (ethylsulfonyl) phenoxy]-6- (1H-pyrazol-1-ylmethyl) -2- (2-pyridinyl) -1H- Benzimidazole compounds

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound and pyrazole obtained in example 19 (step 7).

¹HNMR(CDCl₃)δ：1.29(3H，t，J＝7.4Hz)，3.11(2H，q，J＝7.4Hz)，5.41(2H，s)，6.19(1H，s)，7.01(2H，m)，7.11(1/2H，s)，7.35-7.50(4H，m)，7.65(1/2H，s)，7.80(2H，m)，7.86(1H，m)，8.38(1H，m)，8.62(1H，m)，10.8(1/2H，br)，10.9(1/2H，br)

ESI-MASS(m/e)：460(M+H)

Example 88

5- [4- (ethylsulfonyl) phenoxy ]-6- (1H-imidazol-1-ylmethyl) -2- (2-pyridyl) -1H- Benzimidazole compounds

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound obtained in example 19 (step 7) and imidazole.

¹H NMR(CDCl₃)δ：1.34(3H，m)，3.13(2H，m)，5.20(2H，s)，6.88-7.20(4H，m)，7.40(1H，m)，7.45-7.60(2H，m)，7.70-7.80(1H，m)，7.80-7.94(3H，m)，8.39(1H，m)，8.64(1H，m)，10.7(1/2H，br)，10.8(1/2H，br)

ESI-MASS(m/e)：460(M+H)

Example 89

4- [ ({5- [4- (ethylsulfonyl) phenoxy)]-2- (2-pyridinyl) -1H-benzimidazol-6-yl } methyl Radical) amino]-4-oxobutanoic acid (trifluoroacetate)

50mg of the final compound obtained in example 19 was dissolved in 1ml of tetrahydrofuran and 0.2ml of water, and 60. mu.l of 5N sodium hydroxide was added thereto and stirred at room temperature for 1 hour. Neutralized with 2N hydrochloric acid, then diluted with chloroform, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase medium-pressure liquid chromatography [ ODS-AS-360-CC (manufactured by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid ]. The solvent of the resultant fraction was distilled off under reduced pressure to obtain 21.1mg of the title compound as a colorless solid.

¹H NMR(DMSO-d₆)δ：1.12(3H，t，J＝7.5Hz)，2.34(2H，m)，2.41(2H，m)，3.28(2H，q，J＝7.5Hz)，4.29(2H，d，J＝5.5Hz)，7.14(2H，J＝8.8Hz)，7.37(1H，s)，7.60(1H，m)，7.69(1H，s)，7.87(2H，d，J＝8.8Hz)，8.07(1H，m)，8.34(2H，m)，8.79(1H，d，J＝4.5Hz)

ESI-MASS(m/e)：508(M+H)

Example 90

N- (cyanomethyl) -N- ({5- [4- (ethylsulfonyl) phenoxy)]-2- (2-pyridinyl) -1H-benzo Imidazol-6-yl } methyl) acetamide

(step 1) Synthesis of [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methanol

The title compound was obtained in the same manner as in example 57 (step 4), a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 19 (step 7).

(step 2) Synthesis of 6- (chloromethyl) -5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazole

To a solution of 30mg of the obtained alcohol compound in 3ml of chloroform was added 11. mu.l of thionyl chloride, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with saturated sodium bicarbonate solution, extracted with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure to obtain 30mg of the title compound as a pale yellow amorphous substance.

(step 3) Synthesis of N- (cyanomethyl) -N- ({5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl } methyl) acetamide

2.1g of aminoacetonitrile was suspended in 50ml of chloroform, and 5.6ml of triethylamine and 2ml of acetyl chloride were added under ice cooling, followed by stirring at room temperature for 3 hours. Saturated sodium bicarbonate was added, extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure and purified by silica gel column chromatography (developing solvent (hexane/ethyl acetate ═ 4/1 → 1/1 → 1/9 → chloroform/methanol) to give 0.85g of N- (cyanomethyl) acetamide as white crystals.

To a solution of 21.6mg of the obtained N- (cyanomethyl) acetamide in 0.25ml of dimethylformamide was added 5.2mg of sodium hydride (30% liquid paraffin was added) under ice-cooling. After stirring at room temperature for 30 minutes, 30mg of the chlorine compound obtained in step 2 in 0.75ml of dimethylformamide was added, and the mixture was stirred for another 1 hour. Saturated aqueous ammonium chloride was added, extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure and purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 10/1) to yield 3.3mg of the title compound as a white amorphous substance.

¹HNMR(CDCl₃)δ：1.31(3H，m)，2.22(3H，m)，3.15(2H，m)，4.10-4.30(2H，m)，4.75(2H，m)，7.12-7.20(2H+1/2H，m)，7.42(1H，m)，7.50(1H，s)，7.77(1/2H，s)，7.90(3H，m)，8.39(1H，m)，8.65(1H，m)，10.6(1/2H，br)，10.7(1/2H，br)

ESI-MASS(m/e)：490(M+H)

Example 91

1- ({5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridyl) -1H-benzimidazol-6-yl } } formazan 1H-pyrrole-2, 5-dione

To a solution of 50mg of triphenylphosphine in 0.5ml of tetrahydrofuran was added 0.21ml of diethyl diethylazodicarboxylate (40% in toluene) at-78 deg.C, and the mixture was stirred for 5 minutes. To the reaction mixture was slowly added a solution of 100mg of the alcohol compound obtained in example 19 (step 7) in 0.5ml of tetrahydrofuran at-78 ℃ and 18mg of maleimide. After dissolving the maleimide, the reaction mixture was returned to room temperature and stirred for 2 hours. The reaction solution was distilled off under reduced pressure, and then the residue was subjected to reverse-phase medium-pressure liquid chromatography [ ODS-AS-360-CC (manufactured by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid ]. The solvent of the resultant fraction was distilled off under reduced pressure to obtain 11mg of a yellow oil.

11mg of the resulting yellow oil were dissolved in 0.3ml of trifluoroacetic acid and stirred at room temperature for 2 hours. The solvent was distilled off, neutralized with triethylamine and then purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 10/1) to yield 4.1mg of the title compound as a pale yellow amorphous substance.

¹HNMR(CDCl₃)δ：1.30(3H，m)，3.12(2H，m)，4.80(2H，s)，6.62(2HX1/2，s)，6.67(2HX1/2，s)，7.08(2H，m)，7.13(1/2H，s)，7.40(1H，m)，7.46(1/2H，s)，7.59(1/2H，s)，7.78(1/2H，s)，7.80(3H，m)，8.37(1H，m)，8.67(1H，m)，10.6(1H，m)

ESI-MASS(m/e)：489(M+H)

Example 92

1- [1- ({5- [4- (ethylsulfonyl) phenoxy)]-2- (2-pyridyl) -1H-benzimidazol-6-yl } Methyl) -1H-imidazol-2-yl]Ethanones

(step 1) Synthesis of 2-acetylimidazole

To a solution of 151mg of 1H-imidazole-2-carbonitrile obtained in example 82 (step 1) in 3ml of tetrahydrofuran at-78 ℃ was added 1.6ml of methylmagnesium bromide (3M, diethyl ether solution), and the mixture was stirred at that temperature for 1 hour. Saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate and chloroform, and the organic layer was dried and the solvent was distilled off under reduced pressure to give 187mg of the title compound as a yellow solid.

(step 2) Synthesis of 1- [1- ({5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl }) methyl ] -1H-imidazol-2-yl ] ethanone

Using the obtained 2-acetylimidazole and the alcohol compound obtained in example 19 (step 7), the title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method.

¹HNMR(CDCl₃)δ：1.31(3H，t，J＝7.2Hz)，2.61(3HX1/2，s)，2.64(3HX1/2，s)，3.13(2H，d，J＝7.2Hz)，5.71(2HX1/2，s)，5.74(2HX1/2，s)，7.05-7.15(4H+1/2H，m)，7.32(1/2 H，s)，7.38(1H，m)，7.41(1/2 H，s)，7.53(1/2H，s)，7.85(3H，m)，8.37(1H，m)，8.67(1H，m)，10.80(1/2H，br)，10.82(1/2H，br)

ESI-MASS(m/e)：502(M+H)

Example 93

N- ({5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridyl) -1H-benzimidazol-6-yl } } formazan 2, 2, 2-trifluoro-N-methylacetamide

To a 50mg solution of the amine compound obtained in example 31 (step 1) in 0.5ml of pyridine was added 40. mu.l of trifluoroacetic anhydride under ice-cooling, and the mixture was stirred for 30 minutes. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform → chloroform/methanol: 20/1), whereby 37.8mg of the title compound was obtained as a white solid.

The title compound was obtained in the same manner as in example 84, in a similar manner to example 84, or in a combination of the above with a conventional method, using 25mg of the obtained white solid.

¹HNMR(CDCl₃)δ：1.28(3H，m)，3.00-3.20(5H，m)，4.73(2HX1/2，s)，4.76(2HX1/2，s)，7.00-7.10(2H，m)，7.19(1/2H，s)，7.41(1H，m)，7.50(1/2H，s)，7.55(1/2H，s)，7.70-7.90(3H+1/2H，m)，8.41(1H，m)，8.64(1H，m)，10.8(1H，br)

ESI-MASS(m/e)：519(M+H)

Example 94

N-Ethyl-N- ({5- [4- (ethylsulfonyl) phenoxy)]-2- (2-pyridyl) -1H-benzimidazole- 6-yl } methyl) acetamide

The title compound was obtained in the same manner as in example 84, in a similar manner thereto or in combination with a conventional method using ethyl iodide.

¹HNMR(CDCl₃)δ：1.13(3H，m)，1.29(3H，m)，2.07(3HX1/2，s)，2.11(3HX1/2，s)，3.11(2H，m)，3.29(2HX2，m)，3.45(2HX1/2，m)，4.56(2HX1/2，s)，4.66(2HX1/2，m)，7.00-7.11(2H+1/2H，m)，7.41(1H+1/2H，m)，7.64(1/2H，m)，7.86(3H+1/2H，m)，8.39(1H，m)，8.64(1H，m)，10.8(1H，br)

ESI-MASS(m/e)：479(M+H)

Example 94

1- ({5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridyl) -1H-benzimidazol-6-yl } } formazan 3-hydroxypyrrolidine-2, 5-diones

(step 1) Synthesis of 1- [ (5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl) -1H-benzimidazol-6-yl) methyl ] -3-hydroxypyrrolidine-2, 5-dione or 1- [ (6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) methyl ] -3-hydroxypyrrolidine-2, 5-dione

31mg of [ 5-oxo-2- (trichloromethyl) -1, 3-dioxolan-4-yl ] acetyl chloride synthesized by the method described in Synthesis, 2002, 15 vol.2165 to 2166 pp.l and 40. mu.l of pyridine were added to a solution of 54mg of the amine compound obtained in example 31 (step 1) in 0.5ml of chloroform, and stirred at 80 ℃ for 3 hours. The reaction mixture was returned to room temperature, diluted with ethyl acetate and washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase medium-pressure liquid chromatography [ ODS-AS-360-CC (manufactured by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid ]. The solvent of the resultant fraction was distilled off under reduced pressure, diluted with ethyl acetate, washed with saturated sodium hydrogencarbonate water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 20.8mg of the title compound as colorless crystals.

(step 2) Synthesis of 1- ({5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl }) methyl) -3-hydroxypyrrolidine-2, 5-dione

20.8mg of the resulting crystals were dissolved in 0.5ml of trifluoroacetic acid and stirred at room temperature for 2 hours. The solvent was distilled off, saturated sodium bicarbonate was added, extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure and purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 10/1) to yield 9.1mg of the title compound as colorless crystals.

¹HNMR(CDCl₃)δ：1.27(3H，t，J＝7.2Hz)，2.47(1H，m)，2.97(1H，m)，3.23(2H，q，J＝7.2Hz)，4.79(1H，m)，4.88(2H，m)，7.16(2H，d，J＝8.8Hz)，7.35(1H，m)，7.52(1H，m)，7.78(1H，m)，7.91(2H，d，J＝8.8Hz)，8.00(1H，t，J＝8.2Hz)，8.30(1H，d，J＝8.2Hz)，8.76(1H，m)

ESI-MASS(m/e)：507(M+H)

Example 96

4- [ ({5- [4- (ethylsulfonyl) phenoxy)]-2- (2-pyridinyl) -1H-benzimidazol-6-yl } methyl Radical) amino]-2-hydroxy-4-oxobutanoic acid (trifluoroacetate salt)

To a solution of 50mg of the compound obtained in example 95 (step 1) in 0.5ml of tetrahydrofuran was added a 1N aqueous solution of sodium hydroxide, and the mixture was stirred at room temperature for 15 minutes. Neutralized with 2N hydrochloric acid, then diluted with chloroform, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase medium-pressure liquid chromatography [ ODS-AS-360-CC (manufactured by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid ]. The solvent of the resultant fraction was distilled off under reduced pressure to obtain 43.5mg of yellow amorphous substance.

The resulting crystals were dissolved in 1ml of trifluoroacetic acid and stirred at room temperature for 2 hours. The solvent was distilled off, and the residue was purified by reverse-phase medium-pressure liquid chromatography [ ODS-AS-360-CC (manufactured by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid ]. The solvent of the resultant fractions was distilled off under reduced pressure to obtain 19.9mg of the title compound as a pale yellow amorphous state.

¹H NMR(CD₃OD)δ：1.27(3H，t，J＝7.4Hz)，2.59(1H，dd，J＝8.2Hz，14.5Hz)，2.71(1H，d，J＝4.1，14.5Hz)，3.25(2H，q，J＝7.4Hz)，4.55(1H，m)，4.56(2H，m)，7.27(2H，d，J＝8.8Hz)，7.45(1H，s)，7.70(1H，m)，7.94(1H，s)，7.97(2H，d，J＝8.8Hz)，8.15(1H，t，J＝7.6Hz)，8.32(1H，d，J＝7.6Hz)，8.90(1H，d，J＝4.7Hz)

ESI-MASS(m/e)：507(M+H)

Example 97

(2Z) -4- [ ({5- [4- (ethylsulfonyl) phenoxy)]-2- (2-pyridyl) -1H-benzimidazole-6- Methyl) amino]-4-oxo-2-butenoic acid (trifluoroacetate)

To 100mg of the amine compound obtained in example 31 (step 1) in 1ml of chloroform was added 27mg of maleic anhydride, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was purified by reverse-phase medium-pressure liquid chromatography [ ODS-AS-360-CC (manufactured by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid ]. The solvent of the resultant fraction was distilled off under reduced pressure to give 121.8 yellow oil.

40mg of the resulting yellow oil were dissolved in 0.5ml of trifluoroacetic acid and stirred at room temperature for 2 hours. The solvent was distilled off, and the residue was purified by reverse-phase medium-pressure liquid chromatography [ ODS-AS-360-CC (manufactured by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid ]. The solvent of the resultant fractions was distilled off under reduced pressure to give 19.3mg of the title compound as colorless crystals.

¹HNMR(DMSO-d₈)δ：1.12(3H，t，J＝7.2Hz)，3.27(2H，q，J＝7.2Hz)，4.45(2H，d，J＝5.3Hz)，6.23(1H，d，J＝12.3Hz)，6.35(1H，d，J＝12.3Hz)，7.15(2H，d，J＝8.8Hz)，7.39(1H，s)，7.60(1H，m)，7.79(1H，s)，7.86(2H，d，J＝8.8Hz)，8.06(1H，t，J＝7.6Hz)，8.35(1H，d，J＝7.6Hz)，8.79(1H，d，J＝7.6Hz)，9.39(1H，m)

ESI-MASS(m/e)：507(M+H)

Example 98

(4S) -1- ({5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridyl) -1H-benzimidazole-6- Yl }) methyl) -4-hydroxypyrrolidin-2-one

(step 1) Synthesis of (S) -4- { [ tert-butyl (dimethyl) silyl ] oxy } pyrrolidin-2-one

To a solution of 1.01g of (S) -4-hydroxy-2-pyrrolidone in 5ml of dimethylformamide were added 1.02g of imidazole and 1.58g of t-butyldimethylsilyl chloride, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was stirred under ice-cooling.

The precipitated crystals were collected by filtration and dried to obtain 2.07g of the title compound as colorless crystals.

(step 2) Synthesis of (4S) -4- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({5- [ 4-ethylsulfonyl ] phenoxy } -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl)) methyl) pyrrolidin-2-one or (4S) -4- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({6- [ 4-ethylsulfonyl ] phenoxy } -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl)) methyl) pyrrolidin-2-one.

To a solution of 50mg of the alcohol compound obtained in example 19 (step 7) and 26. mu.l of triethylamine in 0.5ml of tetrahydrofuran was added 15. mu.l of methanesulfonyl chloride under ice-cooling, and the mixture was stirred for 30 minutes. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure to obtain yellow amorphous.

To a solution of 120mg of the colorless crystals obtained in step 1 in 1ml of dimethylformamide was added 22mg of sodium hydride (30% liquid paraffin was added) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, 1.5ml of the pale yellow amorphous tetrahydrofuran solution obtained in the above procedure was added, followed by stirring at room temperature for 1 hour. Saturated aqueous ammonium chloride was added thereto under ice cooling, extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase medium-pressure liquid chromatography [ ODS-AS-360-CC (manufactured by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid ]. The solvent of the resultant fraction was distilled off under reduced pressure, diluted with ethyl acetate, washed with saturated sodium hydrogencarbonate water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 55.5mg of the title compound as a yellow oil.

(step 3) Synthesis of (4S) -1- ({5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl }) methyl) -4-hydroxypyrrolidin-2-one

55.5mg of the resulting yellow oil were dissolved in 1ml of trifluoroacetic acid and 0.2ml of water and stirred at room temperature for 2 hours. The solvent was distilled off, saturated sodium bicarbonate was added, extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure and purified by preparative thin layer chromatography (Kieselgel) ^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 10/1) to yield 24.2mg of the title compound as a white amorphous substance.

¹HNMR(CDCl₃)δ：1.28(3H，t，J＝7.4Hz)，2.43(1H，m)，2.65(1H，m)，3.10(2H，q，J＝7.4Hz)，3.30(1H，m)，3.55(1H，m)，4.30-4.70(3H，m)，7.00(2H，d，J＝8.4Hz)，7.09(1/3H，s)，7.30-7.45(1H+2/3H)，5.51(2/3H，m)，7.62-7.90(3H+1/3H，m)，8.36(1H，d，J＝7.6Hz)，8.62(1H，d，J＝4.5Hz)，11.0(1/3H，br)，11.4(2/3H，br)

ESI-MASS(m/e)：493(M+H)

Example 99

(4R) -1- ({5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridyl) -1H-benzimidazole-6- Methyl } } 4-hydroxypyrrolidin-2-one

The title compound was obtained in the same manner as in example 98, a similar manner to that described in example 98, or a combination of the above with a conventional method using (R) -4-hydroxy-2-pyrrolidone.

¹H NMR(CDCl₃)δ：1.28(3H，t，J＝7.4Hz)，2.43(1H，m)，2.65(1H，m)，3.10(2H，q，J＝7.4Hz)，3.30(1H，m)，3.55(1H，m)，4.30-4.70(3H，m)，7.00(2H，d，J＝8.4Hz)，7.09(1/3H，s)，7.30-7.45(1H+2/3H)，5.51(2/3H，m)，7.62-7.90(3H+1/3H，m)，8.36(1H，d，J＝7.6Hz)，8.62(1H，d，J＝4.5Hz)，11.0(1/3H，br)，11.4(2/3H，br)

ESI-MASS(m/e)：493(M+H)

Example 100

(4R) -1- ({5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridyl) -1H-benzimidazole-6- Methyl } methyl) -4-fluoropyridin-2-one

(step 1) (4S) -1- ({5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl }) methyl) -4-hydroxypyridin-2-one or (4S) -1- ({6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { (2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl }) methyl) -4-hydroxypyridin-2-one

To 267mg of the compound obtained in example 98 (step 2) in 2.5ml of tetrahydrofuran was added a solution of tetrabutylammonium fluoride in 0.72ml of tetrahydrofuran (1M), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 0.1M phosphino-phenol buffer (pH6), and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform → chloroform/methanol: 20/1), whereby 77.5mg of the title compound was obtained as a colorless oil.

(step 2) (4R) -1- ({5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl }) methyl) -4-fluoropyridin-2-one

To 0.8ml of chloroform (77.5 mg) of the obtained oily substance was added 46. mu.l of bis (2-methoxymethyl) aminosulfur trifluoride, and the mixture was stirred at room temperature for 15 minutes. Purification by silica gel column chromatography (developing solvent: chloroform → chloroform/methanol ═ 20/1) gave 42.1mg of the title compound as a colorless oil.

42.1mg of the resulting yellow oil were dissolved in 1ml of trifluoroacetic acid and stirred at room temperature for 2 hours. The solvent was distilled off, saturated sodium bicarbonate was added, extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure and purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 10/1) to yield 11.1mg of the title compound as a white amorphous substance.

¹HNMR(CDCl₃)δ：1.30(3H，t，J＝7.4Hz)，2.55-2.75(2H，m)，3.11(2H，q，J＝7.4Hz)，3.45-3.70(2H，m)，4.47-4.75(2H，m)，5.10-5.30(1H，m)，7.03-7.10(2H，m)，7.16(1/2H，s)，7.40(1H，m)，7.49(1/2H，s)，7.56(1/2H，s)，7.75-7.92(3H+1/2H，m)，8.40(1H，m)，8.64(1H，m)，10.9(1/2H，br)，11.0(1/2H，br)

ESI-MASS(m/e)：495(M+H)

Example 101

6- [ (1, 1-isothiazolidin-2-yl) dioxide) methyl group]-5- [ (6-methylpyridin-3-yl) oxy]-2- (2-pyridinyl) -1H-benzimidazoles

(step 1) Synthesis of (5- [ (6-methylpyridin-3-yl) oxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) methanol and (6- [ (6-methylpyridin-3-yl) oxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) methanol

The title compound was obtained in the same manner as in example 19 (step 5 to step 7), in a similar manner to this, or in combination with a conventional method using 4-hydroxy-6-methylpyridine.

(step 2)6- [ (1, 1-isothiazolidin-2-yl) methyl ] -5- [ (6-methylpyridin-3-yl) oxy ] -2- (2-pyridyl) -1H-benzimidazole

The title compound was obtained by using the obtained alcohol compound in the same manner as in example 33, a method similar thereto, or a combination thereof with a conventional method.

¹HNMR(CDCl₃)δ：2.29(2H，m)，2.54(3H，s)，3.14(2H，m)，3.24(2H，m)，4.37(2HX1/2，s)，4.38(2HX1/2，s)，7.00(1/2H，s)，7.05-7.24(2H，m)，7.35(1/2H，s)，7.38(1H，m)，7.67(1/2H，s)，7.86(1H，m)，7.92(1/2H，s)，8.27(1H，m)，8.38(1H，m)，8.64(1H，m)，10.6(1/2H，br)，10.7(1/2H，br)

ESI-MASS(m/e)：495(M+H)

Example 102

1- [4- [ (6- ((2-oxopyrrolidin-1-yl) methyl) -2- (2-pyridyl) -1H-benzimidazole-5- Radical) oxy]Phenyl radical]-2-pyrrolidone

(step 1) Synthesis of 2-fluoro-4-nitrobenzaldehyde

43.3g of 2-fluoro-4-nitrobenzoic acid was dissolved in 600ml of dimethylformamide, 43.7g of 1, 1' -carbodiimide was added thereto, and the mixture was stirred at room temperature for 2 hours. 11.1g of sodium borohydride was added and stirred for another 30 minutes. Saturated aqueous ammonium chloride solution was added, 800ml of water was added, extraction was performed with 1.2L of ethyl acetate, and the organic layer was washed with saturated brine. The solvent was distilled off under reduced pressure, and then diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 32.7g of a light brown oil.

The resulting oil was dissolved in 200ml of dimethyl sulfoxide and 60ml of triethylamine, 88.7g of sulfur trioxide pyridine complex was slowly added, and stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, and the organic layer was washed with water, 0.1N aqueous hydrochloric acid solution and saturated brine. The solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (developing solvent: hexane/ethyl acetate) and crystallization (methanol/diethyl ether) to give 14.0g of the title compound as an orange solid.

(step 2) Synthesis of 1- (2-fluoro-4-nitrobenzyl) pyrrolidin-2-one

To 1g of the obtained 2-fluoro-4-nitrobenzaldehyde and 3.0g of methyl 4-aminobutyrate hydrochloride were added 100ml of methanol, 87ml of a 0.3M methanolic solution of zinc cyanoborohydride (a 1: 2 solution of zinc chloride and sodium cyanoborohydride in methanol) and the mixture was stirred for 1 hour. Saturated aqueous sodium bicarbonate was added, diluted with ethyl acetate, and washed with water and saturated brine. After drying, the solvent was distilled off under reduced pressure to obtain 5.2g of red amorphous substance.

The resulting amorphous was dissolved in methanol, and 1.5ml of a 4.7M sodium methoxide methanol solution was added thereto, followed by stirring at room temperature for 1.5 hours and further at 45 ℃ for 30 minutes. The solvent was distilled off, and purification was performed by silica gel column chromatography (developing solvent: hexane/ethyl acetate ═ 5/1 → 1: 1 → 0: 1) to give 1.9g of the title compound as an orange oil.

(step 3) Synthesis of 1- (4-amino-2-fluorobenzyl) pyrrolidin-2-one

Raney nickel was added to a solution of 1.5g of the compound obtained in step 2 in 20ml of methanol, and the mixture was stirred at room temperature overnight. After filtration, the filtrate was distilled off under reduced pressure to obtain 1.4g of the title compound as an orange oil.

(step 4) Synthesis of N- { 5-fluoro-2-nitro-4- [ (2-oxopyrrolidin-1-yl) methyl ] phenyl } pyridine-2-carboxamide

To a solution of 1.13g of the compound obtained in step 3 and 801mg of 2-picolinic acid in 25ml of pyridine was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then the residue was dissolved in 200ml of chloroform and washed with 80ml of 0.2N hydrochloric acid (. times.4), 50ml of 0.5N sodium hydroxide solution (. times.3), and saturated brine. After drying, the solvent was distilled off under reduced pressure to obtain 1.51g of a pale yellow solid.

A solution of 1.51g of a pale yellow solid in 7ml of fuming nitric acid was stirred at room temperature for 1 hour, and then poured into an ice-cooled saturated aqueous sodium hydrogencarbonate solution and stirred at room temperature for 1 hour. The insoluble matter was collected by filtration, washed with water, and then dried overnight under reduced pressure to give 1.56g of the title compound as a pale yellow solid.

(step 5) Synthesis of 1- [4- [ (6- ((2-oxopyrrolidin-1-yl) methyl) -2- (2-pyridyl) -1H-benzimidazol-5-yl) oxy ] phenyl ] -2-pyrrolidone

To a solution of 20mg of the compound obtained in step 4 and 12mg of 1- (4-hydroxyphenyl) pyrrolidin-2-one obtained in reference example 8 in 0.5ml of dimethylformamide was added 20mg of calcium carbonate, and the mixture was stirred at 80 ℃ for 30 minutes. 126mg of tin chloride dihydrate was added thereto, and the mixture was stirred at 80 ℃ for 30 minutes. Water and chloroform were added to the reaction solution, and insoluble matter was filtered. The filtrate was extracted with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase medium-pressure liquid chromatography [ ODS-AS-360-CC (manufactured by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid ]. The solvent of the resultant fraction was distilled off under reduced pressure, diluted with chloroform, washed with saturated sodium bicarbonate water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure.

Then subjecting to preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 10/1) to yield 13.7mg of the title compound as a white amorphous substance.

¹HNMR(CDCl₃)δ：1.91-2.02(2H，m)，2.14-2.22(2H，m)，2.36-2.41(2H，m)，2.60-2.65(2H，m)，3.33-3.39(2H，m)，3.84-3.88(2H，m)，4.60(2Hx1/2，s)，4.63(2Hx1/2，s)，6.96(1Hx1/2，s)，6.98(2Hx1/2，d，J＝9.0Hz)，6.99(2Hx1/2，d，J＝9.0Hz)，7.34-7.39(1H，m)，7.38(1Hx1/2，s)，7.53(1Hx1/2，s)，7.54(2Hx1/2，d，J＝9.0Hz)，7.55(2Hx1/2d，J＝9.0Hz)，7.71(1Hx1/2，s)，7.82-7.88(1H，m)，8.34-8.40(1H，m)，8.60-8.65(1H，m)，10.55(1Hx1/2，brs)，10.63(1Hx1/2，brs)

ESI-MASS(m/e)：468(M+H)

Example 103

1- [4- [ (6- ((2-oxopyrrolidin-1-yl) methyl) -2- (2-pyridyl) -1H-benzimidazole-5- Radical) oxy]Phenyl radical]Pyridin-2 (1H) -ones

The title compound was obtained in the same manner as in example 102 (step 5), a method similar thereto, or a combination thereof with a conventional method using 1- (4-hydroxyphenyl) pyridin-2 (1H) -one obtained in referential example 12.

¹HNMR(CDCl₃)δ：1.93-2.00(2H，m)，2.35-2.41(2H，m)，3.31-3.38(2H，m)，4.60(2Hx1/2，s)，4.61(2Hx1/2，s)，6.22-6.28(1H，m)，6.64-6.69(1H，m)，7.01(2Hx1/2，d，J＝8.6Hz)，7.05(2Hx1/2，d，J＝8.6Hz)，7.10(1Hx1/2，s)，7.31-7.43(3H，m)，7.32(2H，d，J＝8.6Hz)，7.48(1Hx1/2，s)，7.56(1Hx1/2，s)，7.74(1Hx1/2，s)，7.84-7.89(1H，m)，8.36-8.40(1H，m)，8.63-8.66(1H，m)，10.73(1Hx1/2，brs)，10.82(1Hx1/2，brs)

ESI-MASS(m/e)：478(M+H)

Example 104

5- ((6- ((2-oxopyrrolidin-1-yl) methyl) -2- (2-pyridinyl) -1H-benzimidazol-5-yl) Oxy) pyridine-2-carbonitriles

The title compound was obtained in the same manner as in example 102 (step 5), a similar manner to this, or a combination thereof with a conventional method using 5-hydroxypyridine-2-carbonitrile obtained in referential example 10.

¹HNMR(CDCl₃)δ：1.91-1.99(2H，m)，2.27-2.37(2H，m)，3.27-3.33(2H，m)，4.53(2H，s)，7.20(1Hx1/2，s)，7.23-7.28(1H，m)，7.40-7.43(1H，m)，7.49(1Hx1/2，s)，7.57(1Hx1/2，s)，7.62(1Hx1/2，d，J＝8.6Hz)，7.64(1Hx1/2，d，J＝8.2Hz)，7.79(1Hx1/2，s)，7.87-7.92(1H，m)，8.37-8.45(2H，m)，8.64-8.67(1H，m)，10.75(1Hx1/2，brs)，10.84(1Hx1/2，brs).

ESI-MASS(m/e)：411(M+H)

Example 105

1- { [5- [ (6- (methoxymethyl) pyridin-3-yl) oxy]-2- (2-pyridyl) -1H-benzimidazole- 6-yl]Methyl } -2-pyrrolidone

The title compound was obtained in the same manner as in example 102 (step 5), a method similar thereto, or a combination thereof with a conventional method using 6- (methoxymethyl) pyridin-3-ol obtained in referential example 11.

¹H NMR(CDCl₃)δ：1.93-2.00(2H，m)，2.35-2.41(2H，m)，3.32-3.39(2H，m)，3.48(3Hx1/2，s)，3.48(3Hx1/2，s)，4.57(2H，s)，4.61(2Hx1/2，s)，4.63(2Hx1/2，s)，7.03(1Hx1/2，s)，7.25-7.29(1H，m)，7.35(1Hx1/2，s)，7.36-7.40(2H，m)，7.55(1Hx1/2，s)，7.74(1Hx1/2，s)，7.84-7.90(1H，m)，8.30-8.41(2H，m)，8.61-8.65(1H，m)，10.73(1Hx1/2，brs)，10.84(1Hx1/2，brs)

ESI-MASS(m/e)：430(M+H)

Example 106

1- ({5- [4- (5-methyl-13, 4-oxadiazol-2-yl) phenoxy]-2- (2-pyridinyl) -1H-benzo Imidazol-6-yl } methyl) pyrrolidin-2-one

The title compound was obtained in the same manner as in example 102 (step 5), a method similar thereto or a combination thereof with a conventional method using 6- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyridin-3-ol obtained in referential example 12.

¹HNMR(CDCl₃)δ：1.95(2H，m)，2.33(2H，m)，2.61(3H，s)，3.31(2H，m)，4.58(2H，s)，7.04(2H，d，J＝8.8Hz)，7.10-7.80(2H，br)，7.39(1H，m)，7.88(1H，dt，J＝1.7，8.0Hz)，7.97(2H，d，J＝8.8Hz)，8.39(1H，d，J＝8.0Hz)，8.65(1H，d，J＝5.0Hz)，10.0-11.0(1H，br)

ESI-MASS(m/e)：467(M+H)

Example 107

1- ({5- [4- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenoxy]-2- (2-pyridinyl) -1H-benzo Imidazol-6-yl } methyl) pyrrolidin-2-one

The title compound was obtained in the same manner as in example 102 (step 5), a method similar thereto, or a combination thereof with a conventional method using 6- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyridin-3-ol obtained in referential example 13.

¹HNMR(CDCl₃)δ：1.93(2H，m)，2.33(2H，m)，2.46(3H，m)，3.30(2H，m)，4.57(2H，m)，7.05(2H，m)，7.19(1/2H，s)，7.40(1H，m)，7.52(1/2H，s)，7.57(1/2H，s)，7.78(1/2H，s)，7.86(1H，m)，8.06(2H，d，J＝8.8Hz)，8.40(1H，m)，8.66(1H，m)，10.7(1H，br)，10.8(1/2H，br)

ESI-MASS(m/e)：467(M+H)

Example 108

1- ({5- [4- (1-methyl-1H-tetrazol-5-yl) phenoxy]-2- (2-pyridyl) -1H-benzimidazole- 6-yl } methyl) pyrrolidin-2-one

The title compound was obtained in the same manner as in example 102 (step 5), in a similar manner to the above described method, or in combination with a conventional method using 6- (1-methyl-1H-tetrazol-5-yl) pyridin-3-ol obtained in reference example 14.

¹H NMR(CDCl₃)δ：1.94(2H，m)，2.35(2H，m)，3.33(2H，m)，4.18(3H，s)，4.59(2H，s)，7.13(2H，s)，7.20(1/2H，s)，7.40(1H，m)，7.51(1/2H，s)，7.56(1/2H，s)，7.70(2H，d，J＝8.8Hz)，7.77(1/2H，s)，7.88(1H，m)，8.39(1H，m)，8.64(1H，m)，10.9(1/2H，br)，11.0(1/2H，br)

ESI-MASS(m/e)：467(M+H)

Example 109

1- ({5- [4- (1, 3-oxazol-4-yl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl } methyl Yl) pyrrolidin-2-one

The title compound was obtained in the same manner as in example 102 (step 5), in a similar manner to this or in combination with a conventional method using 6- (1, 3-oxazol-4-yl) pyridin-3-ol obtained in referential example 15.

¹H NMR(CDCl₃)δ：1.94(2H，m)，2.36(2H，m)，3.34(2H，m)，4.62(2H，m)，7.00(2H，m)，7.07(1/2H，m)，7.37(1H，m)，7.46(1/2H，s)，7.54(1/2H，s)，7.69(2H，d.J＝8.8Hz)，7.74(1/2H，s)，7.86(1H，m)，7.90(1H，s)，7.94(1H，s)，8.39(1H，m)，8.63(1H，m)，10.8(1/2H，br)，10.9(1/2H，br)

ESI-MASS(m/e)：452(M+H)

Example 110

1- [ (5- ((2' -Fluorobiphenyl-4-yl) oxy) -2- (2-pyridinyl) -1H-benzimidazol-6-yl) methyl 2-pyrrolidone radical

(step 1) Synthesis of N- { 5-fluoro-2-nitro-4- ([ (2-oxopyrrolidin-1-yl) methyl ] phenyl) pyrazine-2-carboxamide

The title compound was obtained in the same manner as in example 102 (step 4), in a similar manner thereto, or in combination with a conventional method using pyrazine-2-carboxylic acid.

(step 2) Synthesis of 1- [ (5- ((2' -Fluorobiphenyl-4-yl) oxy) -2- (2-pyridyl) -1H-benzimidazol-6-yl) methyl ] -2-pyrrolidone

The title compound was obtained in the same manner as in example 102 (step 5), in a similar manner to this, or in combination with a conventional method, using the compound obtained in step 1 and 6- (2-fluorophenyl) pyridin-3-ol obtained in reference example 16.

¹HNMR(CDCl₃)δ：1.94-2.02(2H，m)，2.37-2.44(2H，m)，3.36-3.46(2H，m)，4.67(2H，s)，7.05(2H，d，J＝8.6Hz)，7.13-7.34(3H，1Hx1/2，m)，7.40-7.45(1H，m)，7.48(1Hx1/2，s)，7.51(2H，d，J＝8.6Hz)，7.66(1Hx1/2，s)，7.77(1Hx1/2，s)，8.59(1H，s)，8.64(2H，d，J＝2.7Hz)，9.62(1H，s)，10.47(1Hx1/2，brs)，10.95(1Hx1/2，brs)

ESI-MASS(m/e)：480(M+H)

Example 111

1- { [2- (5-bromo-2-pyridinyl) -5- [ (6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl) Oxy radical]-1H-benzimidazol-6-yl]Methyl } -2-pyrrolidone

(step 1) Synthesis of methyl 4- { [ (5-bromopyrazin-2-yl) carbonylamino ] -2-fluorobenzoate

Using methyl 4-amino-2-fluorobenzoate and 5-bromopyrazine-2-carboxylic acid obtained in example 19 (step 2), the title compound was obtained in the same manner as in example 19 (step 3), a method similar thereto, or a combination thereof with a conventional method.

(step 2) (2- (5-bromopyrazin-2-yl) -5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) methanol and (2- (5-bromopyrazin-2-yl) -6- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) methanol.

The title compound was obtained by using the compound obtained in step 1 and following the same method as in example 52 (step 1-2), a method similar thereto, or a combination thereof with a conventional method.

(step 3)1- { [2- (5-bromo-2-pyridinyl) -5- [ (6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl) oxy ] -1H-benzimidazol-6-yl ] methyl } -2-pyrrolidinone

The title compound was obtained by the same method as in example 2, a method similar thereto, or a combination thereof with a conventional method using the alcohol obtained in step 2.

¹HNMR(CDCl₃)δ：1.92-1.99(2H，m)，2.31-2.39(2H，m)，3.30-3.36(2H，m)，4.59(2Hx1/2，s)，4.61(2Hx1/2，s)，7.17(1Hx1/2，s)，7.30-7.37(1H，m)，7.47(1Hx1/2，s)，7.60(1Hx1/2，s)，7.78(1Hx1/2，s)，7.98-8.02(1H，m)，8.04(1Hx1/2，d，J＝8.6Hz)，8.07(1Hx1/2，d，J＝9.0Hz)，8.26(1Hx1/2，d，J＝8.6Hz)，8.29(1Hx1/2，d，J＝8.6Hz)，8.49(1Hx1/2，d，J＝2.3Hz)，8.55(1Hx1/2，d，J＝2.3Hz)，8.69(1Hx1/2，d，J＝1.6Hz)，8.71(1Hx1/2，d，J＝2.0Hz)，10.40(1Hx1/2，brs)，10.52(1Hx1/2，brs).

ESI-MASS(m/e)：546，548(M+H)

Example 112

1-methyl-3- { [5- [ (6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl) oxy]-2-(2- Pyridyl) -1H-benzimidazol-6-yl]Methyl imidazolidine-2, 4-dione

The title compound was obtained in the same manner as in example 19 (step 8), in a similar manner to the above, or in combination with a conventional method, using the alcohol compound obtained in example 52 (step 2) and 1-methylhydantoin.

¹HNMR(CDCl₃)δ：2.68(3H，s)，2.89(3Hx1/2，s)，2.95(3Hx1/2，s)，3.70(2Hx1/2，s)，3.82(2Hx1/2，s)，4.83(2Hx1/2，s)，4.85(2Hx1/2，s)，7.07(1Hx1/2，s)，7.30-7.41(2H，m)，7.45(1Hx1/2，s)，7.66(1Hx1/2，s)，7.81(1Hx1/2，s)，7.84-7.89(1H，m)，8.02(1Hx1/2，d，J＝8.6 Hz)，8.05(1Hx1/2，d，J＝9.0Hz)，8.36(1Hx1/2，d，J＝7.8Hz)，8.38(1Hx1/2，d，J＝7.8Hz)，8.55-8.59(1H，m)，8.61-8.65(1H，m)，10.63(1H，brs).

ESI-MASS(m/e)：497(M+H)

Example 113

6- ((1, 1-isothiazolin-2-yl) dioxide methyl) -5- ((6- (5-methyl-1, 2, 4-oxadiazole-3-) 3-pyridyl) oxy) -2- (2-pyridyl) -1H-benzimidazole

The title compound was obtained in the same manner as in example 33, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 52 (step 2).

¹H NMR(CDCl₃)δ：2.19-2.27(2H，m)，2.69(3H，s)，3.04-3.12(2H，m)，3.16-3.23(2H，m)，4.33(2Hx1/2，s)，4.35(2Hx1/2，s)，7.18(1Hx1/2，s)，7.31-7.43(2H，m)，7.50(1Hx1/2，s)，7.72(1Hx1/2，s)，7.85-7.92(1H，m)，7.96(1Hx1/2，s)，8.04(1Hx1/2，d，J＝8.6Hz)，8.07(1Hx1/2，d，J＝8.6Hz)，8.38(1Hx1/2，d，I＝7.8Hz)，8.41(1Hx1/2，d，J＝8.2Hz)，8.48(1Hx1/2，d，J＝2.7Hz)，8.55(1Hx1/2，d，J＝2.3Hz)，8.64(1Hx1/2，d，J＝4.3Hz)，8.66(1Hx1/2，d，J＝4.7Hz)，10.57(1Hx1/2，brs)，10.60(1Hx1/2，brs).

ESI-MASS(m/e)：504(M+H)

Example 114

4- { [5- [ (6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl) oxy]-2- (2-pyridyl) - 1H-benzimidazol-6-yl]Methyl morpholin-3-ones

The title compound was obtained in the same manner as in example 81, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 52 (step 2).

¹HNMR(CDCl₃)δ：2.69(3H，s)，3.35(2Hx1/2，t，J＝5.1Hz)，3.39(2Hx1/2，t，J＝5.1Hz)，3.83(2Hx1/2，t，J＝5.1Hz)，3.84(2Hx1/2，t，J＝5.1Hz)，4.15(2Hx1/2，s)，4.19(2Hx1/2，s)，4.7 6(2 H x 1/2，s)，4.7 8(2 H x 1/2，s)，7.1 7(1 Hx1/2，s)，7.29-7.35(1H，m)，7.38-7.42(1H，m)，7.49(1Hx1/2，s)，7.65(1Hx1/2，s)，7.83(1Hx1/2，s)，7.85-7.91(1H，m)，8.04(1Hx1/2，d，J＝8.6H2)，8.07(1Hx1/2，d，J＝8.6Hz)，8.37(1Hx1/2，d，J＝7.8Hz)，8.40(1Hx1/2，d，J＝8.2Hz)，8.52(1Hx1/2，d，J＝2.7Hz)，8.57(1Hx1/2，d，J＝2.7Hz)，8.64(1Hx1/2，d，J＝5.1Hz)，8.66(1Hx1/2，d，J＝5.5Hz)，10.59(1Hx1/2，brs)，10.68(1Hx1/2，brs).

ESI-MASS(m/e)：484(M+H)

Example 115

3- { [5- [ (6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl) oxy]-2- (2-pyridyl) - 1H-benzimidazol-6-yl]Methyl }1, 3-oxazolidine-2, 4-dione

The title compound was obtained in the same manner as in example 85, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 52 (step 2).

¹HNMR(CDCl₃)δ：2.68(3H，s)，4.58(2Hx1/2，s)，4.64(2Hx1/2，s)，4.86(2Hx1/2，s)，4.89(2Hx1/2，s)，7.06(1Hx1/2，s)，7.32-7.42(2H，m)，7.46(1Hx1/2，s)，7.68(1Hx1/2，s)，7.86(1Hx1/2，s)，7.89(1H，d，J＝6.3Hz)，8.02-8.08(1H，m)，8.37-8.42(1H，m)，8.53-8.58(1H，m)，8.61-8.66(1H，m)，10.97(1H，brs).

ESI-MASS(m/e)：484(M+H)

Example 116

1- { [5- [ (6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl) oxy]-2- (2-pyridyl) - 1H-benzimidazol-6-yl]Methyl } -1H-imidazole-2-carbonitrile

The title compound was obtained in the same manner as in example 82, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 52 (step 2).

¹HNMR(DMSO-d₆)δ：2.66(3H，s)，5.52(2H，s)，7.09(1H，d，J＝6.7Hz)，7.15(1Hx1/2，s)，7.26-7.35(1H，m)，7.50-7.62(2H，m)，7.50-7.62(1Hx1/2，s，overlap)，7.71(1Hx1/2，s)，7.93-8.04(2H，m)，7.93-8.04(1Hx1/2，s，invisible)，8.29-8.34(1H，m)，8.42-8.45(1H，m)，8.72-8.77(1H，m)，13.26(1Hx1/2，brs)，13.45(1Hx1/2，brs).

ESI-MASS(m/e)：476(M+H)

Example 117

4- { [5- [ (6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl) oxy]-2- (2-pyridyl) - 1H-benzimidazol-6-yl]Methyl morpholine-3, 5-dione

The title compound was obtained in the same manner as in example 16, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 52 (step 2).

¹HNMR(CDCl₃)δ：2.69(3H，s)，4.29(4Hx1/2，s)，4.36(4Hx1/2，s)，5.13(2Hx1/2，s)，5.13(2Hx1/2，s)，7.08(1Hx1/2，s)，7.30-7.39(2H，m)，7.45(1Hx1/2，s)，7.53(1Hx1/2，s)，7.73(1Hx1/2，s)，7.85-7.89(1H，m)，8.03(1Hx1/2，d，J＝9.0Hz)，8.07(1Hx1/2，d，J＝9.4Hz)，8.37(1Hx1/2，d，J＝7.0Hz)，8.39(1Hx1/2，d，J＝7.0Hz)，8.58-8.65(2H，m)，10.74(1H，brs).

ESI-MASS(m/e)：498(M+H)

Example 118

3- { [5- [ (6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl) oxy]-2- (2-pyridyl) - 1H-benzimidazol-6-yl]Methyl } -1, 3-thiazolidine-2, 4-dione

The title compound was obtained in the same manner as in example 17, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 52 (step 2).

¹HNMR(CDCl₃)δ：2.69(3H，s)，3.82(2Hx1/2，s)，3.90(2Hx1/2，s)，4.94(2Hx1/2，s)，4.97(2Hx1/2，s)，7.08(1Hx1/2，s)，7.30-7.41(2H，m)，7.45(1Hx1/2，s)，7.60(1Hx1/2，s)，7.80(1Hx1/2，s)，7.86-7.90(1H，m)，8.03-8.08(1H，m)，8.36-8.40(1H，m)，8.55-8.65(2H，m)，10.74(1Hx1/2，brs)，10.79(1Hx1/2，brs).

ESI-MASS(m/e)：500(M+H)

Example 119

1- { [5- [4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenoxy]-2- (2-pyrazinyl) -1H-benzo Imidazol-6-yl]Methyl } -2-pyrrolidone

The title compound was obtained in the same manner as in example 102 (step 5), a method similar thereto, or a combination thereof with a conventional method using N- { 5-fluoro-2-nitro-4- [ (2-oxopyrrolidin-1-yl) methyl ] phenyl } pyrazine-2-carboxamide obtained in example 110 (step 1) and 4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenol obtained in reference example 7.

¹HNMR(CDCl₃)δ：1.92-2.00(2H，m)，2.34-2.41(2H，m)，3.32-3.39(2H，m)，4.61(2Hx1/2，s)，4.62(2Hx1/2，s)，7.04(2Hx1/2，d，J＝8.6Hz)，7.05(2Hx1/2，d，J＝8.6Hz)，7.17(1Hx1/2，s)，7.51(1Hx1/2，s)，7.65(1Hx1/2，s)，7.79(1Hx1/2，s)，8.02(2H，d，J＝8.6Hz)，8.57-8.61(1H，m)，8.66(1H，d，J＝2.0Hz)，9.61-9.64(1H，m)，10.45(1Hx1/2，brs)，10.83(1Hx1/2，brs).

ESI-MASS(m/e)：468(M+H)

Example 120

3- { [5- [4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenoxy ]-2- (2-pyridinyl) -1H-benzo Imidazol-6-yl]Methyl } -1, 3-oxazolidine-2, 4-dione

The title compound was obtained in the same manner as in example 85, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 55 (step 1).

¹HNMR(CDCl₃2 drops of CD3OD) δ: 2.66(3H, s), 4.44(2Hx1/2, s), 4.52(2Hx1/2, s), 4.87(2Hx1/2, s), 4.90(2Hx1/2, s), 7.03(2Hx1/2, d, J ═ 8.6Hz), 7.06(2Hx1/2, d, J ═ 8.6Hz), 7.17(1Hx1/2, s), 7.38-7.43(1H, m), 7.47(1Hx1/2, s), 7.71(1Hx 5/2, s), 7.88-7.91(1H, m), 7.92(1Hx1/2, s), 8.01(2Hx1/2, d, J ═ 8.6, 8.03(2Hx 5639, 8.42H, 8.38H, 8H, 8.61 Hz), 8.61H, 8.8.38H, 8.61H, 8.38H, 8.6, 8.3H, 8.3, 8.6, 8H, 8.3H.

ESI-MASS(m/e)：483(M+H)

Example 121

3- { [5- [ (6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl) oxy]-2- (2-pyridyl) - 1H-benzimidazol-6-yl]Methyl } -2-pyrrolidone

The title compound was obtained in the same manner as in example 102 (step 5), a method similar thereto, or a combination thereof with a conventional method using N- { 5-fluoro-2-nitro-4- [ (2-oxopyrrolidin-1-yl) methyl ] phenyl } pyrazine-2-carboxamide obtained in example 110 (step 1) and 6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinol obtained in reference example 6.

¹HNMR(CDCl₃)δ：1.95-2.02(2H，m)，2.36-2.42(2H，m)，2.69(3H，s)，3.34-3.41(2H，m)，4.62(2H，s)，7.18(1Hx1/2，s)，7.34(1H，d，J＝7.8Hz)，7.50(1Hx1/2，s)，7.69(1Hx1/2，s)，7.79(1Hx1/2，s)，8.06(1H，d，J＝8.6Hz)，8.49-8.57(1H，m)，8.60(1H，s)，8.67(1H，d，J＝2.7Hz)，9.63(1H，s)，10.58(1Hx1/2，brs)，10.98(1Hx1/2，brs).

ESI-MASS(m/e)：469(M+H)

Example 122

5-hydroxy-1- [ (6- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl)]Oxy } -2-pyridines -2-yl-1H-benzimidazol-5-yl) methyl]Pyrrolidin-2-ones

To a solution of 30mg of the compound obtained in example 51 in 2ml of tetrahydrofuran and 0.2ml of methanol were added 7mg of sodium borohydride and 8mg of lithium chloride, and the mixture was stirred at room temperature for 1 hour. A10% citric acid aqueous solution was added, followed by extraction with chloroform, and the organic layer was dried and the solvent was distilled off under reduced pressure. The residue was purified by thin layer chromatography (developing solvent: chloroform/methanol-9/2) to give 7mg of the title compound as a white solid.

¹HNMR(CDCl₃)δ：1.91-1.88(1H，m)，2.22-2.20(2H，m)，2.57-2.55(1H，m)，2.64(3H，s)4.37(2H，d，J＝15.5Hz)，5.24(1H，m)，7.36-7.35(2H，m)，7.83(2H，d，J＝7.8Hz)，7.96(1H，d，J＝8.8Hz)，8.34-8.33(3H，m)，8.63-8.60(1H，m)

ESI-MASS(m/e)：484(M+H)

Example 123

1- { [5- [ (6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl) oxy]-2- (1-pyridine oxide) -2-yl) -1H-benzimidazol-6-yl]Methyl } -2-pyrrolidone

To 20mg of the compound obtained in example 53 in 2ml of chloroform was added 2mg of methyltrioxorhenium (VII), and 100. mu.l of 30% hydrogen peroxide water was added, followed by stirring at room temperature for 4 hours. An aqueous sodium thiosulfate solution was added thereto, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (Kieselgel)^TM 60F₂₅₄Art 5744(Merck), chloroform/methanol 5/1) to yield 1.0mg of the title compound as white crystals.

¹HNMR(CDCl₃)δ：1.99(2H，m)，2.40(2H，m)，2.71(3H，s)，3.36(2H，m)，4.46(2Hx1/2，m)，4.65(2Hx1/2，s)，7.27(1/2H，s)，7.40(2H，m)，7.45-7.60(1H+1/2H，m)，7.66(1/2H，m)，7.82(1/2 H.s)，8.09(1H，m)，8.41(1H，m)，8.57(1H，m)，8.72(1H，m)，13.2(1/2H，s)，13.3(1/2H，s)

ESI-MASS(m/e)：484(M+H)

Example 124

4-hydroxy-1- { [5- [ (6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl) oxy]-2-(2- Pyridyl) -1H-benzimidazol-6-yl]Methyl } pyrrolidin-2-one

The title compound was obtained in the same manner as in example L-001471821, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 52 (step 2).

¹HNMR(CDCl₃)δ：2.30-2.50(1H，m)，2.60-2.75(1H，m)，2.68(3H，s)，3.30-3.55(1H，m)，3.55-3.70(1H，m)，4.40-4.80(3H，m)，7.10-7.80(4H，m)，7.86(1H，m)，8.02(1H，d，J＝8.8Hz)，8.38(1H，d，J＝7.8Hz)，8.46(1H，d，J＝2.7Hz)8.65(1H，d，J＝4.9Hz)

ESI-MASS(m/e)：484(M+H)

Example 125

1- [ hydroxy- (5- { [6- [ 5-methyl-1, 2, 4- ] oxadiazol-3-yl)]-3-pyridyl]Oxy } -2- (2-pyrine) Pyridyl) -1H-benzimidazol-6-yl) methyl]-2-pyrrolidone

(step 1) Synthesis of (5- [ {6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl } oxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl) methanol

The alcoholate obtained in example 52 (step 2) is subjected to the same method as in example 59, a method similar thereto, or a combination thereof with a conventional method to obtain the title compound.

(step 2) Synthesis of 5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2- (2-pyridyl) -1H-benzimidazole-6-carbaldehyde

To a solution of 400mg of the obtained alcohol compound in 5ml of dimethyl sulfoxide were added 1.5ml of triethylamine and 796mg of sulfur trioxide pyridine complex, and the mixture was stirred at room temperature for 30 minutes. Water was added, followed by extraction with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was crystallized from diethyl ether-methanol to obtain 183mg of the title compound as a pale yellow amorphous substance.

(step 3) Synthesis of 1- [ hydroxy- (5- { [6- [ 5-methyl-1, 2, 4-oxadiazol-3-yl ] -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1H-benzimidazol-6-yl) methyl ] -2-pyrrolidone

To a solution of 8.7. mu.l 2-pyrrolidone in 500. mu. l N, N-dimethylformamide was added 7mg sodium carbonate. 10mg of the aldehyde compound previously synthesized was added at 80 ℃ with stirring, and stirred at 80 ℃ overnight. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol-5/1) to yield 1.0mg of the title compound as a pale yellow amorphous substance.

¹HNMR(CDCl₃)δ：0.79-0.94(1H，m)，1.77-1.91(1H，m)，1.97-2.09(1H，m)，2.14-2.34(1H，m)，2.68(3H，s)，2.83-2.94(1H，m)，3.37-3.52(1H，m)，6.87-6.95(1H，m)，7.18(1Hx1/2，s)，7.33-7.46(2H，m)，7.50(1Hx1/2，s)，7.86-7.94(1H，m)，7.99-8.08(1H，m，1Hx1/2，s)，8.31(1Hx1/2，s)，8.36-8.46(2H，m)，8.60-8.72(1H，m)，10.58(1Hx1/2，brs)，10.86(1Hx1/2，brs).

ESI-MASS(m/e)：484(M+H)

Example 126

5- [4- (ethylsulfonyl) phenoxy]-6- [ (2-fluoropyridin-3-yl) methyl group]-2- (2-pyridyl) - 1H-benzimidazoles

(step 1) Synthesis of (5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) (2-fluorophenyl) methanol or (6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) (2-fluorophenyl) methanol

6.2ml of a 1.5 molar solution of butyllithium in hexane were added to 1.31ml of a solution of diisopropylethylamine in 10ml of tetrahydrofuran at-78 ℃ and stirred for 30 minutes at 0 ℃. To the reaction mixture was added 0.8ml of 2-fluoropyridine at-78 ℃ and stirred at-78 ℃ for 2 hours, and then 1g of a solution of the aldehyde compound obtained in example 64 (step 1) in 5ml of tetrahydrofuran was added and stirred at-78 ℃ for 1 hour. Saturated aqueous ammonium chloride was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. After drying, purification by silica gel column chromatography (developing solvent: chloroform → chloroform/methanol 50/1) gave 0.72g of the title compound as a light brown oil.

(step 2) Synthesis of 5- [4- (ethylsulfonyl) phenoxy ] -6- [ (2-fluoropyridin-3-yl) methyl ] -2- (2-pyridyl) -1H-benzimidazole

To a solution of 75mg of the obtained oil in 0.75ml of chloroform was added 26. mu.l of thionyl chloride, and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure, and then 0.7ml of trifluoroacetic acid and 39mg of zinc were added thereto, followed by heating and refluxing for 30 minutes. The solvent was distilled off under reduced pressure, and then diluted with chloroform, saturated sodium bicarbonate water and aqueous ammonia were added, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure and purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol-10/1) to yield 15.2mg of the title compound as colorless crystals.

¹HNMR(CDCl₃)δ：1.30(3H，m)，3.11(2H，m)，4.03(2H，s)，7.00(3H，m)，7.15(1/2H，s)，7.37-7.57(3H，m)，7.75(1/2H，s)，7.79(2H，m)，7.87(1H，m)，8.02(1H，m)，8.39(1H，m)，8.64(1H，m)，10.6(1/2H，br)，10.7(1/2H，br)

ESI-MASS(m/e)：489(M+H)

Example 127

(5- (4-ethylsulfonyl) phenoxy) -2- (2-pyridyl) -1H-benzimidazol-6-yl) acetonitrile

(step 1) Synthesis of (5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- [ {2- (trimethylsilyl) ethoxy } methyl ] -1H-benzimidazol-6-yl) acetonitrile or (6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- [ {2- (trimethylsilyl) ethoxy } methyl ] -1H-benzimidazol-5-yl) acetonitrile

To a solution of 930mg of the alcohol compound obtained in example 19 (step 7) and 494. mu.l of triethylamine in 20ml of tetrahydrofuran under ice-cooling was added 268. mu.l of methanesulfonyl chloride, and the mixture was stirred for 20 minutes. Diluted with 60ml of ethyl acetate and then water was added. The organic layer was separated and washed with brine. After drying, the solvent was distilled off under reduced pressure to obtain colorless amorphous.

To a 20ml solution of the obtained amorphous N, N-dimethylformamide was added 269mg of sodium cyanide under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate was added under ice cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: hexane/ethyl acetate) to give 623mg of a yellow oil.

(step 2) Synthesis of (5- (4-ethylsulfonyl) phenoxy) -2- (2-pyridyl) -1H-benzimidazol-6-yl) acetonitrile

28mg of the resulting oil was dissolved in 1ml of trifluoroacetic acid and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, diluted with chloroform, and then neutralized with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine. Drying, distilling off solvent under reduced pressure, and introducing the residuePreparative thin layer chromatography (Kieselgel)^TM 60F₂₅₄Art 5744(Merck), chloroform/methanol 10/1) to yield 14mg of the title compound as a colorless amorphous substance.

¹HNMR(CDCl₃)δ：1.30(3H，t，J＝7.4Hz)，3.13(2H，q，J＝7.4Hz)，3.82(2H，s)，7.10-7.16(1Hx1/2，s，overlap)，7.13(2H，d，J＝8.2Hz)，7.39-7.44(1H，m)，7.48(1Hx1/2，s)，7.71(1Hx1/2，s)，7.85-7.91(1H，m)，7.88(2H，d，J＝8.2Hz)，7.91(1Hx1/2，s)，8.37-8.42(1H，m)，8.63-8.69(1H，m)，10.72(1Hx1/2，brs)，10.79(1Hx1/2，brs).

ESI-MASS(m/e)：419(M+H)

Example 128

2- (5- (4- (ethylsulfonyl) phenoxy) -2- (2-pyridyl) -1H-benzimidazol-6-yl) acetyl Amines as pesticides

30mg of the cyano compound obtained in example 127 in 1ml of 80% sulfuric acid were stirred overnight at 70 ℃. The reaction solution was added dropwise to an ice-cooled saturated aqueous sodium bicarbonate solution, neutralized, and then extracted with chloroform. The organic layer was dried and the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (Kieselgel) ^TM60F₂₅₄Art 5744(Merck), chloroform/methanol-10/1) to yield 5.7mg of the title compound as a colorless amorphous substance.

¹HNMR(CDCl₃2 drops of CD3OD) δ: 1.30(3H, t, J ═ 7.4Hz), 3.13(2H, q, J ═ 7.4Hz), 3.61(2Hx1/2, s), 3.63(2Hx1/2, s), 7.10(2H, d, J ═ 9.0Hz), 7.18(1Hx1/2, s), 7.40-7.43(1H, m), 7.47(1Hx1/2, s), 7.62(1Hx1/2, s), 7.83(1Hx1/2, s), 7.84(2H, d, J ═ 9.0Hz), 7.88-7.93(1H, m), 8.37-8.42(1H, m), 8.62-8.66(1H, m), and peaks of NH and NH2 cannot be seen

ESI-MASS(m/e)：437(M+H)

Example 129

2- [5- (4- (ethylsulfonyl) phenoxy) -2- (2-pyridyl) -1H-benzimidazol-6-yl]- N, N-dimethyl acetamide

(step 1) Synthesis of (5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) acetic acid or (6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) acetic acid

To 1.04g of a cyano compound obtained in example 127 (step 1) in 15ml of an ethanol solution was added 10ml of a 5N aqueous sodium hydroxide solution, followed by stirring at 70 ℃ overnight. Ethanol was distilled off under reduced pressure, diluted with chloroform, and then 10% citric acid aqueous solution was added under ice cooling to make the reaction solution slightly acidic. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain 631mg of a yellow amorphous substance.

(step 2) Synthesis of the title Compound

To a solution of 17.7mg of the resulting carboxylic acid in 1ml of chloroform, 8.7mg of 1-hydroxybenzotriazole and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added, followed by addition of 48. mu.l of a 2.0M solution of dimethylamine in tetrahydrofuran, and stirring was carried out at room temperature for 1.5 hours. Water was added under ice cooling, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 20/1) gave 10.8mg of yellow amorphous material.

The same procedures as in example 127 (step 2), methods similar thereto, or combinations thereof with conventional ones were carried out using 10.8mg of the obtained amorphous product to give 8.6mg of the title compound as a colorless amorphous state.

¹HNMR(CDCl₃)δ：1.29(3H，t，J＝7.4Hz)，2.90(3Hx1/2，s)，2.91(3Hx1/2，s)，2.98(3H，s)，3.11(2H，q，J＝7.4Hz)，3.73(2Hx1/2，s)，3.74(2Hx1/2，s)，7.08(2H，d，J＝9.0Hz)，7.12(1Hx1/2，s)，7.37-7.40(1H，m)，7.44(1Hx1/2，s)，7.55(1Hx1/2，s)，7.77(1Hx1/2，s)，7.80-7.89(1H，m)，7.82(2H，d，J＝9.0Hz)，8.36-8.42(1H，m)，8.61-8.65(1H，m)，10.88(1Hx1/2，brs)，10.94(1Hx1/2，brs).

ESI-MASS(m/e)：465(M+H)

Example 130

[5- [4- (ethylsulfonyl) phenoxy ] ethyl ester]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]Acetic acid A Esters

To a mixed solution of 27.8mg of the carboxylic acid obtained in example 129 (step 1) in 500. mu.l of tetrahydrofuran and 500. mu.l of methanol was added 80. mu.l of (trimethylsilyl) diazomethane, and the mixture was stirred for 1 hour. Then, 80. mu.l of (trimethylsilyl) diazomethane was added thereto, and the mixture was stirred for 30 minutes. The solvent was distilled off under reduced pressure, diluted with ethyl acetate, and then saturated aqueous sodium hydrogencarbonate solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (Kieselgel) ^TM 60F₂₅₄Art 5744(Merck), chloroform/methanol 20/1) to yield 11.9mg of SEM compound.

The same procedures as in example 127 (step 2), methods similar thereto, or combinations thereof with conventional methods were carried out using 10.8mg of the obtained SEM compound to give 7.4mg of the title compound.

¹HNMR(CDCl₃)δ：1.29(3H，t，J＝7.4Hz)，3.12(2H，q，J＝7.4Hz)，3.57(3Hx1/2，s)，3.58(3Hx1/2，s)，3.72(2H，s)，7.09(2H，d，J＝9.0Hz)，7.10(1Hx1/2，s)，7.38-7.42(1H，m)，7.47(1Hx1/2，s)，7.50(1Hx1/2，s)，7.83(1Hx1/2，s)，7.83(2H，d，J＝9.0Hz)，7.86-7.91(1H，m)，8.38-8.43(1H，m)，8.62-8.67(1H，m)，10.82(1H，brs).

ESI-MASS(m/e)：452(M+H)

Example 131

5- [4- (ethylsulfonyl) phenoxy]-6- (2-oxo-2- (1-pyrrolidinyl) ethyl) -2- (2-pyri-dinePyridine (I)1H-benzimidazoles

The title compound was obtained in the same manner as in example 129 (step 2), in a similar manner thereto or in combination with a conventional method using pyrrolidine.

¹HNMR(CDCl₃)δ：1.29(3H，t，J＝7.4Hz)，1.72-1.89(4H，m)，3.11(2H，q，J＝7.4Hz)，3.38(4H，t，J＝6.7Hz)，3.68(2Hx1/2，s)，3.69(2Hx1/2，s)，7.06(2Hx1/2，d，J＝9.0Hz)，7.06(2Hx1/2，d，J＝9.0Hz)，7.09(1Hx1/2，s)，7.36-7.40(1H，m)，7.43(1Hx1/2，s)，7.60(1Hx1/2，s)，7.79-7.89(3H，m)，7.81(1Hx1/2，s)，8.36(1Hx1/2，d，J＝8.2Hz)，8.40(1Hx1/2，d，J＝8.2Hz)，8.61-8.65(1H，m)，10.78(1Hx1/2，brs)，10.90(1Hx1/2，brs).

ESI-MASS(m/e)：491(M+H)

Example 132

N, N-diethyl-2- [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazole Azol-6-yl]Acetamide

The title compound was obtained in the same manner as in example 129 (step 2), in a similar manner to the above-mentioned method, or in combination with a conventional method using N, N-diethylamine.

¹HNMR(CDCl₃)δ：0.98(3Hx1/2，t，J＝5.9Hz)，1.00(3Hx1/2，t，J＝5.9Hz)，1.05(3H，t，J＝7.0Hz)，1.24(3H，t，J＝7.4Hz)，3.07(2H，q，J＝7.4Hz)，3：22-3.32(4H，m)，3.67(2Hx1/2，s)，3.69(2Hx1/2，s)，7.04(2H，d，J＝9.0Hz)，7.05(1Hx1/2，s)，7.32-7.37(1H，m)，7.40(1Hx1/2，s)，7.51(1Hx1/2，s)，7.77(2H，d，J＝9.0Hz)，7.79(1Hx1/2，s)，7.83(1H，t，J＝8.0Hz)，8.33(1Hx1/2，d，J＝8.0Hz)，8.36(1Hx1/2，d，J＝8.0Hz)，8.57-8.61(1H，m)，10.76(1Hx1/2，brs)，10.86(1Hx1/2，brs).

ESI-MASS(m/e)：493(M+H)

Example 133

6- (2- (1-azetidinyl) -2-oxoethyl) -5- [4- (ethylsulfonyl) phenoxy]-2-(2- Pyridyl) -1H-benzimidazoles

The title compound was obtained in the same manner as in example 129 (step 2), in a similar manner thereto or in combination with a conventional method using azetidine hydrochloride and diisopropylethylamine.

¹HNMR(CDCl₃)δ：1.29(3H，t，J＝7.4Hz)，2.11-2.21(2H，m)，3.12(2H，q，J＝7.4Hz)，3.47(2Hx1/2，s)，3.49(2Hx1/2，s)，3.88-3.94(2H，m)，4.03-4.08(2H，m)，7.07-7.11(2H，1Hx1/2，m)，7.37-7.41(1H，m)，7.43(1Hx1/2，s)，7.63(1Hx1/2，s)，7.82-7.90(2H，1H，1Hx1/2，m)，8.36(1Hx1/2，d，J＝7.8Hz)，8.40(1Hx1/2，d，J＝7.8Hz)，8.62-8.66(1H，m)，10.78(1H，brs)，10.90(1H，brs).

ESI-MASS(m/e)：477(M+H)

Example 134

2- [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]-N- Methyl acetamide

The title compound was obtained in the same manner as in example 129 (step 2), in a similar manner thereto or in combination with a conventional method using methylamine hydrochloride and diisopropylethylamine.

¹HNMR(CDCl₃)δ：1.29(3H，t，J＝7.4Hz)，2.70(3Hx1/2，s)，2.72(3Hx1/2，s)，3.11(2H，q，J＝7.4Hz)，3.59(2Hx1/2，s)，3.62(2Hx1/2，s)，5.52(1Hx1/2，brs)，5.59(1Hx1/2，brs)，7.05(2Hx1/2，d，J＝8.6Hz)，7.07(2Hx1/2，d，J＝8.6Hz)，7.15(1Hx1/2，s)，7.39-7.43(1H，m)，7.48(1Hx1/2，s)，7.56(1Hx1/2，s)，7.83(2H，d，J＝8.6Hz)，7.87-7.91(1H，m)，7.88(1Hx1/2，s)，8.37-8.42(1H，m)，8.63-8.67(1H，m)，10.81(1Hx1/2，brs)，10.85(1Hx1/2，brs).

ESI-MASS(m/e)：451(M+H)

Example 135

2- [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]Ethanol

(step 1) Synthesis of 2- (5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) ethanol or 2- (6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) ethanol

To 100mg of the formic acid obtained in example 129 (step 1) in 2ml of tetrahydrofuran was added 43mg of 1, 1' -dicarbonyl-1H-imidazole under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. The resulting reaction mixture was added dropwise to 1.5ml of an aqueous solution of 34mg of sodium borohydride under ice-cooling, and stirred for 5 minutes. A 10% citric acid solution was added for neutralization, extraction was performed with ethyl acetate, and then the organic layer was washed with a saturated saline solution. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: chloroform/methanol) to give 95.3mg of an alcohol compound.

(step 2) Synthesis of 2- [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] ethanol

9.0mg of the obtained alcohol compound was dissolved in 1ml of trifluoroacetic acid, and stirred at room temperature for 1.5 hours. The solvent was distilled off, diluted with chloroform, and then neutralized with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure to obtain 9.0mg of trifluoroacetate. To 9.0mg of trifluoroacetate in 1ml of methanolPotassium carbonate was added to the solution, and the mixture was stirred at room temperature for 30 minutes. Diluted with chloroform, a saturated aqueous ammonium chloride solution was added, extraction was performed with chloroform, and then the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck) and chloroform/methanol (10/1) to yield 6.6mg of the title compound as a colorless amorphous substance.

¹H NMR(CDCl₃2 drops of CD3OD) δ: 1.30(3H, t, J ═ 7.4Hz), 2.89-2.93(2H, m), 3.12(2H, q, J ═ 7.4Hz), 3.85-3.89(2H, m), 7.05(2H, d, J ═ 8.6Hz), 7.16(1Hx1/2, s), 7.39-7.44(1H, m), 7.41(1Hx1/2, s), 7.53(1Hx1/2, s), 7.79(1Hx1/2, s), 7.82(2H, d, J ═ 8.6Hz), 7.88-7.93(1H, m), 8.37-8.41(1H, m), 8.62-8.67(1H, m), and no peaks of NH and OH were visible.

ESI-MASS(m/e)：424(M+H)

Example 136

1- (2- [5- [4- (ethylsulfonyl) phenoxy)]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]Second step Yl) pyrrolidine-2, 5-diones

To 1ml of a tetrahydrofuran solution of 20mg of the alcohol compound obtained in example 135 (step 1), 10.7mg of succinimide and 28.3mg of triphenylphosphine were added, and then 42. mu.l of diethyl diethylazodicarboxylate (40% toluene solution) was added under ice-cooling, and stirred at room temperature for 30 minutes. Water was added, extraction was performed with ethyl acetate, and then the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol) and reverse phase preparative LC to give 14.8mg of a yellow oil.

14.8mg of the resulting oil was dissolved in 1ml of trifluoroacetic acid and stirred at room temperature for 1 hour. The solvent was distilled off, diluted with chloroform, and then neutralized with a saturated aqueous sodium bicarbonate solution, extracted with chloroform, and the organic layer was washed with a saturated brine. Drying, distilling off solvent under reduced pressure, and introducing the residuePreparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol-10/1) to yield 11mg of the title compound as a colorless amorphous substance.

¹HNMR(CDCl₃)δ：1.29(3Hx1/2，t，J＝7.2Hz)，1.30(3Hx1/2，t，J＝7.2Hz)，2.63(4Hx1/2，s)，2.65(4Hx1/2，s)，2.90-2.96(2H，m)，3.11(2Hx1/2，q，J＝7.2Hz)，3.12(2Hx1/2，q，J＝7.2Hz)，3.79-3.83(2H，m)，7.12(2Hx1/2，d，J＝8.6Hz)，7.17(2Hx1/2，d，J＝9.0Hz)，7.37-7.42(1H，m)，7.46(1Hx1/2，s)，7.48(1Hx1/2，s)，7.65(1Hx1/2，s)，7.82-7.89(1H，m)，7.83(2Hx1/2，d，J＝8.6Hz)，7.86(2Hx1/2，d，J＝9.0Hz)，7.89(1Hx1/2，s)，8.36-8.40(1H，m)，8.62-8.67(1H，m)，10.54(1H，brs).

ESI-MASS(m/e)：505(M+H)

Example 137

1- (2- [5- [4- (ethylsulfonyl) phenoxy) ]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]Second step 2-pyrrolidone radical

(step 1) Synthesis of (5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-6-yl) acetaldehyde or (6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-5-yl) acetaldehyde

To 28.9mg of a solution of the alcohol compound synthesized in example 135 (step 1) in 1ml of dimethyl sulfoxide were added 300. mu.l of triethylamine and 120mg of sulfur trioxide pyridine complex, and stirred at room temperature for 5 minutes. Water was added, followed by extraction with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by reverse phase preparative liquid chromatography to give 11.7mg of the title compound as a colorless amorphous state.

(step 2) Synthesis of 1- (2- [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] ethyl) -2-pyrrolidone

To a solution of 11.7mg of the obtained aldehyde compound in 1ml of tetrahydrofuran was added 6.6mg of methyl 4-aminobutyrate hydrochloride, followed by stirring at room temperature for 10 minutes, and then 106. mu.l of a 0.25M solution of sodium cyanoboroborate 1/2 zinc chloride complex in methanol was added, followed by stirring at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added under ice cooling, followed by extraction with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (Kieselgel) ^TM60F₂₅₄Art 5744(Merck) and chloroform/methanol (10/1) gave 4.4mg of colorless amorphous substance.

To a mixed solution of 4.4mg of amorphous 250. mu.l tetrahydrofuran and 250. mu.l methanol was added 100. mu.l of a 5N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 45 minutes. The organic layer was neutralized with 10% citric acid under ice cooling, extracted with chloroform, and washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and then the residue was dissolved in 500. mu.l of trifluoroacetic acid and stirred at room temperature for 2.5 hours. The solvent was distilled off, diluted with chloroform, and then neutralized with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck) and chloroform/methanol (10/1) to yield 3.3mg of the title compound as a colorless amorphous substance.

¹HNMR(CDCl₃)δ：1.30(3H，t，J＝7.6Hz)，1.90-1.98(2H，m)，2.30-2.38(2H，m)，2.87(2H，t，J＝7.0Hz)，3.12(2H，q，J＝7.6Hz)，3.20-3.29(2H，m)，3.57(2H，t，J＝7.0Hz)，7.09(2H，d，J＝8.6Hz)，7.11(1Hx1/2，s)，7.12(2H，d，J＝8.6Hz)，7.37-7.42(1H，m)，7.48(1Hx1/2，s)，7.52(1Hx1/2，s)，7.73(1Hx1/2，s)，7.82-7.90(3H，m)，8.37-8.41(1H，m)，8.62-8.68(1H，m)，10.64(1Hx1/2，brs)，10.71(1Hx1/2，brs).

ESI-MASS(m/e)：491(M+H)

Example 138

2- [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]-N- methoxy-N-methylacetamide

The title compound was obtained in the same manner as in example 129 (step 2), in a similar manner thereto or in combination with a conventional method using N, O-dimethylhydroxylamine hydrochloride and diisopropylethylamine.

¹HNMR(CDCl₃)δ：1.29(3H，t，J＝7.4Hz)，3.11(2H，q，J＝7.6Hz)，3.12(3Hx1/2，s)，3.13(3Hx1/2，s)，3.58(3Hx1/2，s)，3.60(3Hx1/2，s)，3.84(2H，s)，7.09(1Hx1/2，s)，7.10(2H，d，J＝8.6Hz)，7.36-7.40(1H，m)，7.45(1Hx1/2，s)，7.53(1Hx1/2，s)，7.80-7.85(1Hx1/2，m(s))，7.82(2Hx1/2，d，J＝8.6Hz)，7.83(2Hx1/2，d，J＝8.6Hz)，7.85-7.90(1H，m)，8.36-8.42(1H，m)，8.62-8.66(1H，m)，10.76(1H，brs).

ESI-MASS(m/e)：481(M+H)

Example 139

1- [5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridinyl) -1H-benzimidazol-6-yl]Acetone (II)

To a 500. mu.l tetrahydrofuran solution of 8.7mg of the compound obtained in example 138 was added 14. mu.l of a 3.0M tetrahydrofuran solution of methylmagnesium bromide under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, 14. mu.l of a 3.0M tetrahydrofuran solution of methyl magnesium bromide was added thereto, and the mixture was stirred at room temperature for 5 minutes. Saturated aqueous ammonium chloride was added under ice cooling, extraction was performed with chloroform, and then the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 20/1) to yield 4.0mg of the title compound.

¹HNMR(CDCl₃)δ：1.30(3H，t，J＝7.4Hz)，2.16(3H，s)，3.12(2H，q，J＝7.4Hz)，3.78(2H，s)，7.09(2H，d，J＝8.6Hz)，7.12(1Hx1/2，s)，7.37-7.44(1H，m)，7.43(1Hx1/2，s)，7.47(1Hx1/2，s)，7.74(1Hx1/2，s)，7.84(2Hx1/2，d，J＝8.6Hz)，7.85(2Hx1/2，d，J＝8.6Hz)，7.85-7.91(1H，m)，8.36-8.42(1H，m)，8.63-8.67(1H，m)，10.68(1H，brs).ESI-MASS(m/e)：436(M+H)

Example 140

5- [4- (ethylsulfonyl) phenoxy]-6- ((5-methyl-1, 2, 4-oxadiazol-3-yl) methyl) -2- (2-pyridinyl) -1H-benzimidazoles

To a solution of 33mg of the cyano compound obtained in example 127 (step 1) in 1ml of ethanol was added 8. mu.l of a 50% aqueous hydroxylamine solution, and the mixture was stirred overnight. After concentration, 6. mu.l of acetic anhydride was added to a 500. mu.l acetic acid solution of the resulting residue, and stirred at room temperature for 1 hour and then at 70 ℃ for 5 hours. After concentration, the mixture was dissolved in 1ml of trifluoroacetic acid and stirred at room temperature for 1 hour. The solvent was distilled off, diluted with chloroform, and then neutralized with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was subjected to preparative reverse phase liquid chromatography and preparative thin layer chromatography (Kieselgel) ^TM60F₂₅₄Art 5744(Merck) and chloroform/methanol (15/1) to give 9.1mg of the title compound as a colorless amorphous substance.

¹H NMR(CDCl₃)δ：1.29(3H，t，J＝7.2Hz)，2.48(3Hx1/2，s)，2.49(3Hx1/2，s)，3.11(2H，q，J＝7.2Hz)，4.12(2H，s)，7.06(2H，d，J＝8.2Hz)，7.14(1Hx1/2，s)，7.37-7.43(1H，m)，7.49(1Hx1/2，s)，7.55(1Hx1/2，s)，7.7 8(1Hx1/2，s)，7.82(2H，d，J＝8.2Hz)，7.86-7.90(1H，m)，8.37-8.41(1H，m)，8.62-8.66(1H，m)，10.70(1H，brs).

ESI-MASS(m/e)：476(M+H)

Example 141

5- [4- (ethylsulfonyl) phenoxy]-2- (2-pyridyl) -6-(2H-tetrazol-5-ylmethyl) -1H- Benzimidazole (trifluoroacetate)

(step 1) Synthesis of 5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -6- (2H-tetrazol-5-ylmethyl) -1- [ {2- (trimethylsilyl) ethoxy } methyl ] -1H-benzimidazole or 6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -6- (2H-tetrazol-5-ylmethyl) -1- [ {2- (trimethylsilyl) ethoxy } methyl ] -1H-benzimidazole

To a solution of 35mg of the cyano compound obtained in example 127 (step 1) in 3ml of toluene were added 162. mu.l of triethylsilylazide and 30.4mg of dibutyltin oxide, and the mixture was refluxed overnight. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: chloroform/methanol) to give 160mg of yellow amorphous K.

(step 2) Synthesis of 5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -6- (2H-tetrazol-5-ylmethyl) -1H-benzimidazole (trifluoroacetate salt)

13.3mg of the resulting yellow amorphous substance was dissolved in 1ml of trifluoroacetic acid, and stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by preparative reverse phase liquid chromatography to give 11.1mg of the title compound as a colorless amorphous state.

¹HNMR(CD₃OD)δ：1.23(3H，t，J＝7.4Hz)，3.19(2H，q，J＝7.4Hz)，4.48(2H，s)，7.07(2H，d，J＝9.0Hz)，7.41(1H，s)，7.63(1H，dd，J＝8.2，4.7Hz)，7.84(2H，d，J＝9.0Hz)，7.95(1H，s)，8.09(1H，td，J＝8.2，1.6Hz)，8.30(1H，d，J＝8.2Hz)，8.84(1H，d，J＝4.7Hz).

ESI-MASS(m/e)：462(M+H)

Example 142

5- [4- (ethylsulfonyl) phenoxy]-6- ((2-methyl-2H-tetrazol-5-yl) methyl) -2- (2-pyrazin-5-yl) methyl Pyridyl) -1H-benzimidazoles

(step 1) Synthesis of 5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -6- (2-methyl-2H-tetrazol-5-ylmethyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole or (6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -6- (2-methyl-2H-tetrazol-5-ylmethyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole

To a solution of 50mg of the tetrazolium compound obtained in example 141 (step 1) in 1ml of N, N-dimethylformamide were added 12.5mg of potassium tert-butoxide and 13.3mg of methyl iodide, and the mixture was stirred at room temperature for 1 hour. Then, 12.5mg of potassium tert-butoxide was added thereto, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added under ice cooling, extraction was performed with ethyl acetate, and then the organic layer was washed with water and saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol ═ 15/1) to give 15.0mg of the low-polar compound (the title compound) and 17.5mg of the high-polar compound as colorless amorphous states.

(step 2) Synthesis of 5- [4- (ethylsulfonyl) phenoxy ] -6- ((2-methyl-2H-tetrazol-5-yl) methyl) -2- (2-pyridyl) -1H-benzimidazole

The title compound was obtained by following the same procedure as in example 127 (step 2), a similar procedure to that described for 15.0mg of the obtained low-polar compound, or a combination thereof with a conventional procedure.

¹HNMR(CDCl₃)δ：1.29(3Hx1/2，t，J＝7.4Hz)，1.30(3Hx1/2，t，J＝7.4Hz)，3.11(2Hx1/2，q，J＝7.4Hz)，3.11(2Hx1/2，q，J＝7.4Hz)，4.18(3Hx1/2，s)，4.21(3Hx1/2，s)，4.31(2H，s)，7.00(2Hx1/2，d，J＝8.6Hz)，7.02(2Hx1/2，dJ＝8.6Hz)，7.17(1Hx1/2，s)，7.37-7.42(1H，m)，7.49(1Hx1/2，s)，7.59(1Hx1/2，s)，7.77(2Hx1/2，d，J＝8.6Hz)，7.80(2Hx1/2，d，J＝8.6Hz)，7.81(1Hx1/2，s)，7.85-7.91(1H，m)，8.36-8.41(1H，m)，8.62-8.67(1H，m)，10.58(1H，brs).

ESI-MASS(m/e)：476(M+H)

Example 143

5- [4- (ethylsulfonyl) phenoxy]-6- ((1-methyl-1H-tetrazol-5-yl) methyl) -2- (2-pyrazin-5-yl) methyl Pyridyl) -1H-benzimidazoles

The title compound was obtained by following the same procedures as in example 127 (step 2), a similar procedure to those used for the preparation of the highly polar compound obtained in example 142 (step 1) and/or a combination of these procedures and conventional procedures, in an amount of 17.5 mg.

¹HNMR(CDCl₃)δ：1.31(3H，t，J＝7.4Hz)，3.13(2H，q，J＝7.4Hz)，3.90(3Hx1/2，s)，3.91(3Hx1/2，s)，4.34(2H，s)，7.02(2Hx1/2，d，J＝8.6Hz)，7.05(2Hx1/2，d，J＝8.6Hz)，7.17(1Hx1/2，s)，7.39-7.43(1H，m)，7.46(1Hx1/2，s)，7.48(1Hx1/2，s)，7.70(1Hx1/2，s)，7.84(2H，d，J＝8.6Hz)，7.85-7.91(1H，m)，8.35-8.40(1H，m)，8.63-8.67(1H，m)，10.65(1H，brs).

ESI-MASS(m/e)：476(M+H)

Example 144

5- [4- (ethylsulfonyl) phenoxy]-6- (1- (1-methyl-1H-tetrazol-5-yl) methyl) -2- (2- Pyridyl) -1H-benzimidazoles

To a solution of 64mg of the tetrazole compound obtained in example 141 (step 1) in 2ml of N, N-dimethylformamide were added 7.1mg of sodium hydride and 20mg of methyl iodide under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added under ice cooling, extraction was performed with ethyl acetate, and then the organic layer was washed with water and saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol 15/1) gave 10.0mg of pale yellow amorphous substance. 10.0mg of pale yellow amorphous substance was dissolved in 1ml of trifluoroacetic acid, and stirred at room temperature for 1 hour. The solvent was distilled off, diluted with chloroform, and then neutralized with a saturated aqueous sodium bicarbonate solution. Extracting with chloroform, washing with saturated saline An organic layer. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck) and chloroform/methanol (10/1) to yield 7.1mg of the title compound as a colorless amorphous substance.

¹HNMR(CDCl₃)δ：1.31(3H，t，J＝7.4Hz)，1.81(3Hx1/2，d，J＝7.2Hz)，1.84(3Hx1/2，d，J＝6.8Hz)，3.14(2H，q，J＝7.4Hz)，3.74(3Hx1/2，s)，3.79(3Hx1/2，s)，4.60-4.75(1H，m)，7.03-7.13(2H，m)，7.16(1Hx1/2，s)，7.37-7.44(1H，m)，7.39(1Hx1/2，s)，7.48(1Hx1/2，s)，7.71(1Hx1/2，s)，7.75-7.91(3H，m)，8.32-8.42(1H，m)，8.58-8.70(1H，m)，10.63(1Hx1/2，brs)，10.66(1Hx1/2，brs).

ESI-MASS(m/e)：490(M+H)

Example 145

N- [ {6- [ (4-ethylsulfonyl) phenoxy]-2-pyridin-2-yl-1H-benzimidazol-4-yl } methyl Base of]Methanesulphonamides

The title compound was obtained in the same manner as in example 31, a method similar thereto, or a combination thereof with a conventional method using the product obtained in example 70 (step 7).

¹HNMR(CDCl₃)δ：1.28(3H，q，J＝10.6Hz)，2.83(3H，s)，3.10(2H，t，J＝10.6Hz)，4.74(2H，d，J＝6.3Hz)，6.34(1H，s)，6.98(1H，s)，7.08(2H，d，J＝6.3Hz)，7.18(1H，s)，7.48-7.42(1H，m)，7.90-7.85(3H，m)，8.37(1H，d，J＝7.4Hz)，8.64(1H，d，J＝5.1Hz)，10.64(1H，brs)

ESI-MASS(m/e)：487(M+H)

Example 146

3- [ {6- [ 4-ethylsulfonyl ] -amide derivatives]Phenoxy radical]-2-pyridin-2-yl-1H-benzimidazol-4-yl } methyl Base of]-1, 3-oxazolidin-2-one

The title compound was obtained in the same manner as in example 3, a similar manner to that of example 3, or a combination of the same and a conventional method using the product obtained in example 70 (step 7).

¹HNMR(CDCl₃)δ：1.29(3H，t，J＝7.4Hz)，3.11(2H，q，J＝7.4Hz)，3.62-3.57(2H，m)，4.35-4.33(2H，m)，4.67(2H，s)，6.91(1H，s)，7.09(2H，d，J＝8.6Hz)，7.37-7.35(1H，m)，7.52(1H，s)，7.84-7.82(3H，m)，8.34(1H，d，J＝8.2Hz)，8.74(1H，d，J＝3.9Hz)，11.72(1H，brs)

ESI-MASS(m/e)：479(M+H)

Example 147

1- [ {6- [ 4-ethylsulfonyl ] -amide derivatives]Phenoxy radical]-2-pyridin-2-yl-1H-benzimidazol-4-yl } methyl] Piperidin-2-ones

The title compound was obtained in the same manner as in example 6, a similar manner to that of example 6, or a combination of the same and a conventional method using the product obtained in example 70 (step 7).

¹HNMR(CDCl₃)δ：1.29(3H，t，J＝7.4Hz)，1.77-1.70(4H，m)，2.51(2H，m)，3.11(2H，q，J＝7.4Hz)，3.34-3.32(2H，m)，4.76(2H，s)，6.90-6.98(1H，m)，7.08(2H，d，J＝8.8Hz)，7.36-7.34(1H，m)，7.51-7.50(1H，m)，7.83-7.82(3H，m)，8.34(1H，d，J＝7.8Hz)，8.78(1H，d，J＝5.1Hz)，12.13(1H，brs)

ESI-MASS(m/e)：491(M+H)

Example 148

6- [4- (ethylsulfonyl) phenoxy]-4- (3-fluorobenzyl) -2-pyridin-2-yl-1H-benzimidazole

The title compound was obtained in the same manner as in example 76 (steps 2 to 3), a similar manner to this or a combination of these with a conventional method using the aldehyde compound obtained in example 76 (step 1) and 3-fluorophenylmagnesium bromide.

¹HNMR(CDCl₃)δ：1.26-1.23(3H，m)，3.11-2.92(2H，m)，4.23(1H，s)，4.44(1H，s)，6.72(1/2H，s)，6.89-6.86(2H，m)，7.12-7.02(5H，m)，7.35-7.33(1H，m)，7.84-7.75(4H，m)，8.43(1/2H，d，J＝8.6Hz)，8.58-8.54(1H，m)，10.66(1H，brs)

ESI-MASS(m/e)：488(M+H)

Example 149

4- (3, 4-difluorobenzyl) -6- [4- (ethylsulfonyl) phenoxy]-2-pyridin-2-yl-1H-benzo Imidazole

The title compound was obtained in the same manner as in example 76 (steps 2 to 3), in a similar manner thereto or in combination with a conventional method using the aldehyde compound obtained in example 76 (step 1) and 3, 4-difluorophenylmagnesium bromide.

¹HNMR(CDCl₃)δ：1.28-1.22(3H，m)，3.11-3.05(2H，m)，4.11(1H，s)，4.39(1H，s)，6.72(1H，s)，7.06-7.03(5H，m)，7.40-7.35(2H，m)，7.85-7.78(3H，m)，8.41(1H，s)，8.60-8.54(1H，m)，10.59(1H，brs)

ESI-MASS(m/e)：506(M+H)

Example 150

1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl)]Oxy } -2-pyridin-2-yl-1H-benzimidazol-one 4-yl) methyl]Pyrrolidin-2-ones

(step 1 Synthesis of (6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-4-yl) methanol and (5- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-7-yl) methanol

The title compound was obtained in the same manner as in example 70 (steps 2 to 7), in a similar manner to the above described example 70 using 6- (ethylsulfonyl) -3-pyridinol obtained in referential example 4, or in combination with a conventional method.

(step 2) Synthesis of 1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1H-benzimidazol-4-yl) methyl ] pyrrolidin-2-one

The title compound was obtained by using the obtained alcohol compound in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method.

¹HNMR(CDCl₃)δ：1.28(3H，t，J＝7.6Hz)，2.05-1.97(2H，m)，2.48-2.46(2H，m)，3.39-3.36(4H，m)，4.64(2H，s)，6.89(1H，d，J＝1.6Hz)，7.36-7.34(2H，m)，7.49(1H，s)，7.82(1H，t，J＝7.0Hz)，7.98(1H，d，J＝8.6Hz)，8.33(1H，d，J＝7.8Hz)，8.46(1H，d，J＝2.7Hz)，8.75-8.73(1H，m)

ESI-MASS(m/e)：478(M+H)

Example 151

4- ({6- [4- (ethylsulfonyl) phenoxy]-2-pyridin-2-yl-1H-benzimidazol-4-yl } methyl) Morpholin-3-ones

The title compound was obtained in the same manner as in example 81, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 150 (step 1).

¹HNMR(CDCl₃)δ：1.26(3H，t，J＝7.4Hz)，3.08(2H，q，J＝7.4Hz)，3.40(2H，s)，3.82-3.80(2H，m)，4.26(2H，s)，4.77(2H，s)，6.89(1H，s)，7.07-7.05(2H，m)，7.35-7.33(1H，m)，7.51(1H，s)，7.81(3H，d，J＝9.0Hz)，8.33(1H，d，J＝7.4Hz)，8.76-8.73(1H，m)，11.93(1H，brs)

ESI-MASS(m/e)：493(M+H)

Example 152

1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl)]Oxy } -2-pyridin-2-yl-1H-benzimidazol-one 4-yl) methyl]Pyridin-2 (1H) -ones

The title compound was obtained in the same manner as in example 5, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 150 (step 1).

¹HNMR(CDCl₃)δ：1.26(3H，t，J＝8.6Hz)，3.39-3.32(2H，m)，5.36(2H，s)，6.26(1H，t，J＝6.8Hz)，6.75(1H，d，J＝9.0Hz)，7.03(1H，d，J＝2.0Hz)，7.36-7.34(3H，m)，7.43(1H，d，J＝6.7Hz)，7.51(1H，d，J＝2.0Hz)，7.86-7.78(1H，m)，7.99-7.95(1H，m)，8.31(1H，d，J＝7.8Hz)，8.47(1H，d，J＝2.7Hz)，8.77(1H，d，J＝4.7Hz)，12.49(1H，s)

ESI-MASS(m/e)：488(M+H)

Example 153

6- { [6- (ethylsulfonyl) pyridin-3-yl]Oxy } -2-pyridin-2-yl-4- [ (pyridin-2-yloxy) Methyl radical]-1H-benzimidazole

¹HNMR(CDCl₃)δ：1.30-1.22(3H，m)，3.36(2H，q，J＝7.6Hz)，5.68(2H，s)，6.82(1H，d，J＝8.2Hz)，6.97-6.95(1H，m)，7.12(1H，s)，7.37-7.34(2H，m)，7.51(1H，s)，7.62-7.60(1H，m)，7.85-7.83(1H，m)，7.97(1H，d，J＝8.6Hz)，8.35(1H，d，J＝7.8Hz)，8.43-8.42(1H，m)，8.49-8.48(1H，m)，8.70(1H，d，J＝5.1Hz)，12.27(1H，s)

ESI-MASS(m/e)：488(M+H)

Example 154

1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl)]Oxy } -2-pyridin-2-yl-1H-benzimidazol-one 4-yl) methyl]-3-methylpyrrolidin-2-one

The title compound was obtained in the same manner as in example 10, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 150 (step 1).

¹HNMR(CDCl₃)δ：1.28-1.23(6H，m)，1.64-1.55(1H，m)，2.18-2.14(1H，m)，2.43-2.34(1H，m)，2.58-2.50(1H，m)，3.36(2H，q，J＝7.4Hz)，3.61(1H，m)，4.40(1H，d，J＝14,9Hz)，4.89(1H，d，J＝14.9Hz)，6.88(1H，s)，7.34-7.32(2H，m)，7.48(1H，s)，7.82-7.80(1H，m)，7.98(1H，d，J＝8.6Hz)，8.34(1H，d，J＝10.4Hz)，8.45-8.44(1H，m)，8.77-8.74(1H，m)，12.12(1H，brs)

ESI-MASS(m/e)：492(M+H)

Example 155

1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl)]Oxy } -2-pyridin-2-yl-1H-benzimidazol-one 4-yl) methyl]-1H-imidazole-4, 5-dicarbonitrile

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound obtained in example 150 (step 1) and 4, 5-dicyanoimidazole.

¹HNMR(CDCl₃)δ：1.29(3H，t，J＝7.4Hz)，3.37(2H，q，J＝7.4Hz)，5.66(2H，s)，7.12(1H，d，J＝2.0Hz)，7.32(1H，d，J＝2.0Hz)，7.40(1H，dd，J＝8.6，2.7Hz)，7.49-7.47(1H，m)，7.99-7.97(1H，m)，8.03(1H，d，J＝8.6Hz)，8.22(1H，s)，8.42(1H，s，J＝8.2Hz)，8.47(1H，m)，8.64-8.63(1H，m)

ESI-MASS(m/e)：511(M+H)

Example 156

1- {1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl)]Oxy } -2-pyridin-2-yl-1H-benzimidazoles Oxazol-4-yl) methyl]-1H-pyrrol-3-yl } ethanone

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound obtained in example 150 (step 1) and 3-acetylpyrrole.

¹HNMR(CDCl₃)δ：1.27(3H，t，J＝7.4Hz)，2.36(3H，s)，3.35(2H，q，J＝7.4Hz)，5.55(2H，s)，6.57(1H，s)，6.67(1H，s)，6.80(1H，s)，7.12(1H，s)，7.36-7.32(2H，m)，7.48(1H，s)，7.88-7.86(1H，m)，7.97(1H，d，J＝8.6Hz)，8.42-8.39(2H，m)，8.60(1H，s)，10.95(1H，s)

ESI-MASS(m/e)：502(M+H)

Example 157

1- {1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl)]Oxy } -2-pyridin-2-yl-1H-benzimidazoles Oxazol-4-yl) methyl]-1H-pyrrol-2-yl } ethanone

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol compound obtained in example 150 (step 1) and 2-acetylpyrrole.

¹HNMR(CDCl₃)δ：1.30-1.22(3H，m)，2.39(1H，s)，2.54(2H，s)，3.39-3.32(2H，m)，5.81(1H，s)，6.08(1H，s)，6.15-6.14(1/2H，s)，6.21-6.20(1/2H，s)，6.61(1/2H，s)，6.97-6.95(1H，m)，7.07-7.02(2H，m)，7.38-7.30(2H，m)，7.47(1/2H，s)，7.88-7.80(1H，m)，7.96-7.94(1H，m)，8.31(1H，d，J＝7.4Hz)，8.38-8.37(1/2H，s)，8.46-8.43(1H，m)，8.60-8.59(1/2H，m)，8.70-8.69(1/2H，s)，10.62(1/2H，brs)，11.61(1/2H，brs)

ESI-MASS(m/e)：502(M+H)

Example 158

1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl)]Oxy } -2-pyridin-2-yl-1H-benzimidazol-one 4-yl) methyl]-5-methylpyrrolidin-2-one

The title compound was obtained in the same manner as in example 9, in a similar manner to the above alcohol compound obtained in example 150 (step 1), or in combination with a conventional method.

¹HNMR(CDCl₃)δ：1.21-1.20(3H，m)，1.28(3H，t，J＝7.4Hz)，1.63-1.56(1H，m)，2.24-2.23(1H，m)，2.56-2.54(1H，m)，3.36-3.31(4H，m)，4.36(2H，s)，6.89(1H，m)，7.36-7.34(2H，m)，7.49(1H，s)，7.83-7.80(1H，m)，7.99(1H，d，J＝8.6Hz)，8.33(1H，d，J＝7.8Hz)，8.46-8.45(1H，m)，8.84-8.75(1H，m)

ESI-MASS(m/e)：492(M+H)

Example 159

1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl)]Oxy } -2-pyridin-2-yl-1H-benzimidazol-one 4-yl) methyl]-1H-imidazole-2-carbonitrile

The title compound was obtained in the same manner as in example 82, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 150 (step 1).

¹HNMR(CDC1₃)δ：1.28(3H，t，J＝7.4Hz)，3.36(2H，q，J＝7.4Hz)，5.72(2H，s)，6.95(1H，s)，7.14(1H，s)，7.18(1H，s)，7.34(1H，dd，J＝8.6，2.7Hz)，7.40-7.38(1H，m)，7.46(1H，s)，7.89(1H，t，J＝7.8Hz)，8.00(1H，d，J＝8.6Hz)，8.44-8.43(2H，m)，8.61-8.60(1H，m)，11.09(1H，brs)

ESI-MASS(m/e)：486(M+H)

Example 160

6- { [6- (ethylsulfonyl) pyridin-3-yl]Oxy } -4- [ (2-fluoropyridin-3-yl) methyl group]-2-pyridine Pyridin-2-yl-1H-benzimidazoles

(step 1)6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-4-carbaldehyde and 5- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-7-carbaldehyde

The title compound was obtained in the same manner as in example 64 (step 1), in a similar manner to the above alcohol compound obtained in example 150 (step 1), or in combination with a conventional method.

(step 2) Synthesis of (6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-4-yl) (2-fluoropyridin-3-yl) methanol or (5- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-7-yl) (2-fluoropyridin-3-yl) methanol

To 169. mu.l of a solution of diisopropylamine in 1ml of tetrahydrofuran at-78 ℃ were added 0.80ml of n-butyllithium (1.5M hexane solution), and the mixture was stirred for 30 minutes under ice-cooling to give lithium diisopropylamide. To this was added 103. mu.l of 2-fluoropyridine at-78 ℃ and stirred at this temperature for 3 hours. 130mg of the aldehyde compound obtained in step 1 in 2ml of tetrahydrofuran solution was added to the above reaction solution at-78 ℃ and stirred at that temperature for about 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was dried, and then the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (developing solvent: hexane/ethyl acetate ═ 2/1), to give 106mg of (6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-4-yl) (2-fluoropyridin-3-yl) methanol as an orange oil.

(step 3) Synthesis of 6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -4- [ (2-fluoropyridin-3-yl) methyl ] -2-pyridin-2-yl-1H-benzimidazole

To a solution of 24mg of the alcohol compound obtained in step 2 in 0.5ml of chloroform was added 8.2. mu.l of thionyl chloride at room temperature, and the mixture was stirred for 30 minutes, and then the solvent was distilled off under reduced pressure to obtain a crude product. To 0.7ml of a trifluoroacetic acid solution of the crude product was added 12mg of zinc, and the mixture was stirred at 100 ℃ for 30 minutes, brought to room temperature, filtered through Celite (eluting solvent: chloroform, methanol), evaporated under reduced pressure, washed with a saturated aqueous solution of sodium hydrogencarbonate, dried, evaporated under reduced pressure, and purified by thin layer column chromatography (developing solvent: chloroform/methanol: 9/1) to give 3.5mg of the title compound as a white solid.

¹HNMR(CDCl₃)δ：1.28(3H，t，J＝7.6Hz)，3.35(2H，q，J＝7.6Hz)，4.25(1H，s)，4.46(1H，s)，6.86-6.82(1H，m)，7.10-7.08(2H，m)，7.35-7.32(2H，m)，7.87-7.85(2H，m)，7.98(1H，d，J＝8.6Hz)，8.10-8.04(1H，m)，8.43-8.40(2H，m)，8.62-8.60(1H，m)，10.53(1H，brs)

ESI-MASS(m/e)：490(M+H)

Example 161

1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl)]Oxy } -2-pyrazin-2-yl-1H-benzimidazol- 4-yl) methyl]Pyrrolidin-2-ones

(step 1) Synthesis of methyl 2-amino-5- [ { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } benzoate

The title compound was obtained in the same manner as in example 70 (steps 2 to 3), in a similar manner to or in combination with the conventional method using 6- (ethylsulfonyl) -3-pyridinol obtained in example 4.

(step 2) Synthesis of methyl 5- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -3-nitro-2- [ (pyrazin-2-ylcarbonyl) amino ] benzoate

To a solution of 5.5g of methyl 2-amino-5- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } benzoate and 2.4g of pyrazine-2-carboxylic acid in 150ml of pyridine was added 4.71- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, chloroform was added thereto, and the organic layer was washed with a 0.25N aqueous hydrochloric acid solution, a 0.25N aqueous sodium hydroxide solution and a saturated saline solution. After drying, the mixture was concentrated under reduced pressure, crystallized from toluene, and the crystals were collected by filtration. Drying under reduced pressure gave 5.6g of the title compound as pale brown crystals.

Using 5.6g of the obtained solid, according to the same method as in example 70 (step 5), a method similar thereto or a combination thereof with a conventional method, 5.44g of the title compound was obtained as pale brown amorphous state.

(step 3) Synthesis of methyl 6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyrazin-2-yl-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-4-carboxylate and methyl 5- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyrazin-2-yl-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-7-carboxylate

To a solution of 5.44g of the obtained amorphous in 60ml of acetic acid was added 3.1g of iron, and the mixture was stirred at 80 ℃ for 40 minutes. After filtration, the solvent was evaporated under reduced pressure, water was added thereto, extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying, the residue was evaporated under reduced pressure, crystallized from toluene, and the crystals were collected by filtration and dried under reduced pressure to obtain 4.0g of the title compound as gray crystals.

80ml of dimethylformamide and 80ml of tetrahydrofuran were added to 4.0g of the obtained crystals, and the mixture was dissolved by heating. 2.4ml of 2- (trimethylsilyl) ethoxymethyl chloride and 476mg of sodium hydride (to which 30% liquid paraffin was added) were added under water cooling, and stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added under ice cooling, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 9/1 → 1/9) to give 5.22g of the title compound as a yellow amorphous.

(step 4) Synthesis of (6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyrazin-2-yl-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-4-yl) methanol and (5- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyrazin-2-yl-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-7-yl) methanol

The same procedures as in example 34 (step 3), methods similar thereto, or combinations thereof with conventional ones, were repeated using 5.22g of the obtained methyl ester compound to give 1.57g of the title compound as a yellow amorphous substance.

(step 5) Synthesis of 1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyrazin-2-yl-1H-benzimidazol-4-yl) methyl ] pyrrolidin-2-one

¹HNMR(CDCl₃)δ：1.29(3H，t，J＝7.4Hz)，2.07-1.99(2H，m)，2.48(2H，t，J＝8.2Hz)，3.44-3.34(4H，m)，4.62(2H，s)，6.92(1H，m)，8.36(1H，m)，7.53(1H，m)，8.00(1H，d，J＝8.6Hz)，8.47-8.46(1H，m)，8.63-8.62(1H，m)，8.72-8.70(1H，m)，9.57(1H，d，J＝1.2Hz)，12.18(1H，s)

ESI-MASS(m/e)：479(M+H)

Example 162

4- [ (2-Chloropyridin-3-yl) methyl group]-6- { [6- (ethylsulfonyl) pyridin-3-yl]Oxy } -2-pyridine Pyridin-2-yl-1H-benzimidazoles

The title compound was obtained in the same manner as in example 160 (step 2-3), in a similar manner thereto or in combination with a conventional method using 2-chloropyridine.

¹HNMR(CDCl₃)δ：1.30-1.21(3H，m)，3.35(2H，q，J＝7.4Hz)，4.34(1H，s)，4.57(1H，s)，6.80-6.78(1H，m)，7.15-7.13(1H，m)，7.46-7.31(3H，m)，7.75(1H，d，J＝7.8Hz)，7.86-7.85(1H，m)，7.97(1H，d，J＝8.6Hz)，8.40-8.29(3H，m)，8.61(1H，s)，10.63(1H，s)

ESI-MASS(m/e)：506(M+H)

Example 163

6- { [6- (ethylsulfonyl) pyridin-3-yl]Oxy } -4- [ (3-fluoropyridin-4-yl) methyl group]-2-pyridine Pyridin-2-yl-1H-benzimidazoles

(step 1) Synthesis of (6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1- [ {2- (trimethylsilyl) ethoxy } methyl ] -1H-benzimidazol-4-yl) (3-fluoropyridin-4-yl) methanol or (5- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1- [ {2- (trimethylsilyl) ethoxy } methyl ] -1H-benzimidazol-7-yl) (3-fluoropyridin-4-yl) methanol

To a solution of 154mg of 4-diazabicyclo [2, 2, 2] octane in 1.5ml of diethyl ether at-20 ℃ was added 0.92ml of n-butyllithium (1.5M, hexane solution), and the mixture was stirred at that temperature for 1 hour. 119. mu.l of 3-fluoropyridine were further added at-78 ℃ and stirred at that temperature for 2 hours. 149mg of 6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1- [ {2- (trimethylsilyl) ethoxy } methyl ] -1H-benzimidazole-4-carbaldehyde in 2ml of tetrahydrofuran were added at-60 ℃ and stirred at that temperature for 1 hour, followed by addition of a saturated aqueous ammonium chloride solution and extraction with ethyl acetate. The organic layer was dried, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 2/1-0/1) to give 32mg of the title compound as a yellow oil.

(step 2) Synthesis of 6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -4- [ (3-fluoropyridin-4-yl) methyl ] -2-pyridin-2-yl-1H-benzimidazole

The title compound was obtained in the same manner as in example 160 (step 3), in a similar manner thereto or in combination with a conventional method.

¹HNMR(CDCl₃)δ：1.30-1.21(3H，m)，3.35(2H，q，J＝7.4Hz)，4.49(2H，s)，6.80(1H，s)，7.10(1H，s)，7.38-7.32(3H，m)，7.86(1H，t，J＝7.2Hz)，7.98(1H，t，J＝8.6Hz)，8.28-8.26(1H，m)，8.45-8.41(3H，m)，8.61-8.60(1H，m)，10.56(1H，s)

ESI-MASS(m/e)：490(M+H)

Example 164

1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl)]Oxy } -2-pyridin-2-yl-1H-benzimidazol-one 4-yl) methyl]-1H-pyrrole-2-carbonitrile

The title compound was obtained in the same manner as in example 150, in a similar manner thereto, or in combination with a conventional method using 2-cyanopyrrole.

¹HNMR(CDC1₃)δ：1.28(3H，t，J＝7.4Hz)，3.36(2H，q，J＝7.4Hz)，5.68(2H，s)，6.16(1H，s)，6.79-6.75(2H，m)，7.17-7.12(2H，m)，7.32(1H，dd，J＝8.8，2.5Hz)，7.39-7.37(1H，m)，7.89-7.87(1H，m)，7.97(1H，d，J＝8.6Hz)，8.44-8.41(2H，m)，8.61-8.60(1H，m)，10.92(1H，brs)

ESI-MASS(m/e)：485(M+H)

Example 165

(6- { [6- (ethylsulfonyl) pyridin-3-yl]Oxy } -2-pyridin-2-yl-1H-benzimidazol-4- Yl) (3-fluoropyridin-2-yl) methanol

The title compound was obtained in the same manner as in example 160 (step 2-3), in a similar manner to that described above, or in combination with a conventional method using 3-fluoropyridine.

¹HNMR(CDCl₃)δ：1.28(3H，t，J＝7.6Hz)，3.36(2H，q，J＝7.6Hz)，6.67(1H，s)，6.80(1H，s)，7.33-7,29(3H，m)，7.53-7.51(1H，m)，7.77-7.74(1H，m)，7.99(2H，d，J＝9.0Hz)，8.41-8.39(2H，m)，8.48-8.45(1H，m)，8.68-8.66(1H，m)

ESI-MASS(m/e)：506(M+H)

Example 166

1- {1- { (6- { [6- (ethylsulfonyl) pyridin-3-yl]Oxy } -2-pyridin-2-yl-1H-benzimidazoles Oxazol-4-yl) methyl]-1H-imidazol-2-yl } ethanone

The title compound was obtained in the same manner as in example 150, a method similar thereto, or a combination thereof with a conventional method, using 2-acetylimidazole synthesized in example 92 (step 1).

¹HNMR(CDCl₃)δ：1.42(3H，t，J＝7.4Hz)，2.78(2H，s)，2.91(1H，s)，3.50(2H，q，J＝7.4Hz)，5.99(2/3H，s)，6.24(4/3H，s)，7.03(2/3H，s)，7.12(1/3H，s)，7.25(1H，d，J＝7.8Hz)，7.53-7.40(3H，m)，7.64(2/3H，s)，7.70(1/3H，s)，8.03-8.01(1H，m)，8.12-8.10(1H，m)，8.57-8.48(2H，m)，8.75-8.74(2/3H，m)，8.85-8.82(1/3H，m)，11.08(2/3H，s)，11.70(1/3H，s)

ESI-MASS(m/e)：503(M+H)

Example 167

4- [ (3, 5-Difluoropyridin-4-yl) methyl group]-6- { [6- (ethylsulfonyl) pyridin-3-yl]Oxy } -2- pyridin-2-yl-1H-benzimidazoles

The title compound was obtained in the same manner as in example 160 (step 2-3), in a similar manner to that described in example 2, 5-difluoropyridine, or in combination with conventional methods.

¹HNMR(CDC1₃)δ：1.26(3H，t，J＝7.6Hz)，3.36(2H，q，J＝7.6Hz)，4.46(2H，s)，6.81(1H，s)，7.30(2H，m)，7.40-7.39(1H，m)，7.88(1H，t，J＝7.0Hz)，7.97(1H，d，J＝8.6Hz)，8.33(2H，s)，8.42-8.39(2H，m)，8.64-8.63(1H，m)

ESI-MASS(m/e)：508(M+H)

Example 168

1- {1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl)]Oxy } -2-pyridin-2-yl-1H-benzimidazoles Oxazol-4-yl) methyl]-1H-pyrrol-2-yl } -2, 2, 2-trifluoroacetone

The title compound was obtained in the same manner as in example 150, a method similar thereto, or a combination thereof with a conventional method using 2, 2, 2-trifluoro-1- (1H-pyrrol-2-yl) -1-ethanone.

¹HNMR(CDCl₃)δ：1.27(3H，t，J＝7.4Hz)，3.35(2H，q，J＝7.4Hz)，6.05(2H，s)，6.29(1H，s)，6.73(1H，s)，7.09(1H，s)，7.39-7.37(1H，m)，7.58(1H，s)，7.89-7.86(1H，m)，7.94(1H，d，J＝8.2Hz)，8.41-8.38(3H，m)，8.62-8,60(2H，m)，10.90(1H，s)

ESI-MASS(m/e)：556(M+H)

Example 169

4- (2, 6-difluorobenzyl) -6- { [6- (ethylsulfonyl) pyridin-3-yl]Oxy } -2-yl-1H-benzene Benzimidazole (I) derivatives

¹HNMR(CDCl₃)δ：1.27(3H，t，J＝7.4Hz)，3.35(2H，q，J＝7.4Hz)，4.24(1H，s)，4.57(1H，s)，6.89-6.91(3H，m)，7.19-7.17(1H，m)，7.29-7.27(1H，m)，7.39-7.37(2H，m)，7.85-7.84(1H，m)，7.95(1H，d，J＝8.6Hz)，8.45-8.35(2H，m)，8.69-8.66(1H，m)，10.74(1H，s)

The title compound was obtained in the same manner as in example 160 (steps 2 to 3), in a similar manner thereto or in combination with a conventional method using 1, 3-difluorobenzene.

ESI-MASS(m/e)：507(M+H)

Example 170

1- {1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl)]Oxy } -2-pyridin-2-yl-1H-benzimidazoles Oxazol-4-yl) methyl]-1H-pyrazol-3-yl } ethanone

The title compound was obtained in the same manner as in example 150, in a similar manner to that described in example 150, or in combination with a conventional method using 5-acetylpyrazole hydrochloride.

¹H NMR(CDCl₃)δ：1.30-1.24(3H，m)，2.54(1H，s)，2.88(2H，s)，3.39-3.33(2H，m)，5.59(1H，s)，5.85(1H，s)，6.84-6.75(1H，m)，7.02(1H，s)，7.38-7.33(2H，m)，7.51-7.50(1H，m)，7.90-7.82(1H，m)，7.99-7.97(1H，m)，8.33(1H，d，J＝7.8Hz)，8.43-8.41(1H，m)，8.47-8.46(1H，m)，8.62-8.61(1H，m)，10.81(1/3H，s)，11.79(2/3H，s)

ESI-MASS(m/e)：503(M+H)

Example 171

1- [ (6- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl]Oxy } -2-pyridin-2-yl- 1H-benzimidazol-4-yl) methyl]Pyrrolidin-2-ones

To a solution of 955mg of methyl 5-fluoro-2-nitrobenzoate in 10ml of dimethylformamide were added 1.54g of 6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-ol and 1.86g of potassium carbonate, and the mixture was stirred at 80 ℃ for 1 hour. After the mixture was brought to room temperature, saturated aqueous ammonium chloride was added, the mixture was extracted with ethyl acetate, and the organic layer was dried and the solvent was distilled off under reduced pressure to give 1.38g of methyl 5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2-nitrobenzoate as a yellow solid.

To a solution of 700mg of methyl 5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2-nitrobenzoate in 5ml of methanol and 5ml of tetrahydrofuran was added 1.96ml of a 5N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 2.5 hours. 10% aqueous citric acid solution was added for neutralization, followed by extraction with ethyl acetate, and the organic layer was dried and the solvent was distilled off under reduced pressure to give 399mg of 5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2-nitrobenzoic acid as a pale yellow solid.

To a solution of 399mg of the above carboxylic acid in 5ml of tetrahydrofuran was added 282mg of N, N' -carboxydiimidazole, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to 5ml of an aqueous solution of 219mg of sodium borohydride under ice cooling, and stirred for 20 minutes. 10% aqueous citric acid solution was added for neutralization, followed by extraction with ethyl acetate, and the organic layer was dried and the solvent was distilled off under reduced pressure to give 367mg of (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2-nitrophenyl) methanol as a pale yellow solid.

To a solution of 367mg (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2-nitrophenyl) methanol in 5ml of dimethyl sulfoxide were added 0.92ml of triethylamine and 530mg of sulfur trioxide pyridine complex, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate, and the organic layer was dried, then the solvent was distilled off under reduced pressure, and purification was performed by silica gel column chromatography (developing solvent: hexane/ethyl acetate 9/1-3/7) to give 174mg of 5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2-nitrobenzaldehyde as a yellow solid.

To a solution of 174mg of the above compound in 4ml of chloroform were added 123mg of 4-aminobutyric acid hydrochloride and 0.11ml of triethylamine, and the mixture was stirred at room temperature for 30 minutes, then 339mg of sodium triacetoxyborohydride was added and the mixture was stirred overnight. Saturated saline was added thereto, the mixture was extracted with chloroform, the organic layer was dried, and the solvent was distilled off under reduced pressure to give 210mg of 1- (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2-nitrobenzyl) pyrrolidin-2-one as a pale yellow solid.

To a solution of 210mg of the above compound in 2ml of dimethyl sulfoxide and 2ml of methanol was added 599mg of tin chloride dihydrate. Heated and stirred at 80 ℃ for 90 minutes. After the temperature was returned to room temperature, a saturated aqueous sodium bicarbonate solution was added thereto to neutralize the reaction solution, the formed salt was filtered off, and the organic layer of the filtrate was washed with water and a saturated brine. After drying, the solvent was distilled off to leave 144mg of crude 1- (2-amino-5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } benzyl) pyrrolidin-2-one as a yellow oil.

To a solution of 144mg of 1- (2-amino-5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } benzyl) pyrrolidin-2-one in 2ml of chloroform were added 0.33ml of triethylamine and 210mg of picolinoyl chloride under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water was added, extraction was performed with chloroform, the organic layer was dried and the solvent was removed, and purification was performed by silica gel column chromatography (developing solvent: hexane/ethyl acetate ═ 9/1-2/8) to give 117mg of N- {4- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2- [ (2-oxopyrrolidin-1-yl) methyl ] phenyl } pyridine-2-carboxamide as a pale yellow solid.

To a solution of 117mg of N- {4- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2- [ (2-oxopyrrolidin-1-yl) methyl ] phenyl } pyridine-2-carboxamide in 3ml of trifluoroacetic acid was added 126mg of potassium nitrate, and the mixture was stirred at 80 ℃ for 7 hours. Trifluoroacetic acid was distilled off under reduced pressure, followed by addition of chloroform and washing with a saturated aqueous sodium bicarbonate solution. The organic layer was dried and the solvent was distilled off under reduced pressure to give 122mg of N- {4- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2-nitro-6- [ (2-oxopyrrolidin-1-yl) methyl ] phenyl } pyridine-2-carboxamide as a pale brown oil.

To a solution of 122mg of the above compound in 1ml of dimethylformamide and 1ml of methanol was added 266mg of tin chloride dihydrate, and the mixture was stirred overnight at 80 ℃. After the temperature was returned to room temperature, a saturated aqueous sodium bicarbonate solution was added thereto, the formed salt was filtered off, and the organic layer of the filtrate was washed with water and a saturated brine. After drying, the solvent was distilled off, and purified by thin layer chromatography (developing solvent: chloroform/methanol 9/1) to give 20mg of 1- [ (6- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1H-benzimidazol-4-yl) methyl ] pyrrolidin-2-one as a pale brown solid.

¹HNMR(CDCl₃)δ：2.03-1.98(2H，m)，2.48-2.46(2H，m)，2.66(3H，s)，3.39(2H，t，J＝7.2Hz)，4.62(2H，s)，6.90(1H，d，J＝2.3Hz)，7.34-7.31(2H，m)，7.50(1H，s)，7.82-7.80(1H，m)，8.01-7.99(1H，m)，8.33(1H，d，J＝7.4Hz)，8.53(1H，d，J＝2.7Hz)，8.76-8.75(1H，m)，11.99(1H，s)

ESI-MASS(m/e)：468(M+H)

Example 172

4- [ (2, 4-dichloropyridin-3-yl) methyl group]-6- { [6- (ethylsulfonyl) pyridin-3-yl]Oxy } -2- pyridin-2-yl-1H-benzimidazoles

The title compound was obtained in the same manner as in example 160 (step 2-3), in a similar manner to that described in example 2, or in combination with conventional methods using 3, 5-dichloropyridine.

¹HNMR(CDCl₃)δ：1.28-1.20(3H，m)，3.34(2H，q，J＝7.4Hz)，4.54(1H，s)，4.84(1H，s)，6.37(1H，s)，7.03(1H，d，J＝2.0Hz)，7.27-7.23(1H，m)，7.41-7.31(2H，m)，7.87-7.85(1H，m)，7.94(1H，q，J＝9.0Hz)，8.23-8.22(1H，m)，8.44-8.36(2H，m)，8.65-8.60(1H，m)，11.00(1H，s)

ESI-MASS(m/e)：540(M+H)

Example 173

4- (2, 6-difluorobenzyl) -6- { [6- (ethylsulfonyl) pyridin-3-yl]Oxy } -2-pyrazin-2-yl- 1H-benzimidazoles

To a solution of 57mg of the alcohol compound obtained in example 161 (step 4) in 1.0ml of tetrahydrofuran was added 44. mu.l of triethylamine and 16. mu.l of methanesulfonyl chloride under ice-cooling, and the mixture was stirred at that temperature for 30 minutes. The reaction mixture was added with saturated brine, extracted with ethyl acetate, and the organic layer was dried and the solvent was distilled off under reduced pressure to obtain 67mg of a crude product as a yellow oil.

To a solution of 67mg of the above crude product in 1ml of dimethylformamide was added 27mg of lithium bromide, and the mixture was stirred at room temperature for 40 minutes. To the reaction solution was added water, followed by extraction with ethyl acetate, and then the organic layer was dried, the solvent was distilled off under reduced pressure, and purification was performed by silica gel column chromatography (developing solvent: hexane/ethyl acetate 9/1-2/8) to obtain 32mg of 4- (bromomethyl) -6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyrazin-2-yl-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole as a yellow oil.

To a solution of 31mg of the obtained bromine compound in 1.0ml of dimethoxyethane was added 5.9mg of tetrakis (triphenylphosphine) palladium, and the mixture was stirred at 50 ℃ for 10 minutes. 12mg of (2, 6-difluorophenyl) boric acid, 0.5ml of ethanol and 0.1ml of an aqueous solution (2M) of sodium carbonate were added thereto, and the mixture was refluxed for 1.5 hours. The reaction mixture was returned to room temperature, followed by extraction with chloroform, drying of the organic layer and removal of the solvent by evaporation under reduced pressure to obtain 39mg of a crude product as a yellow oil.

To 39mg of the above crude product, 0.7ml of trifluoroacetic acid was added, and the mixture was stirred for 1 hour. Excess trifluoroacetic acid was distilled off under reduced pressure, dissolved in chloroform, and then washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried, then the solvent was removed, and purification was performed by thin layer chromatography (developing solvent: chloroform/methanol-9/1) to obtain 13mg of the title compound as a yellow solid.

¹HNMR(CDCl₃)δ：1.26(3H，t，J＝7.4Hz)，3.36(2H，q，J＝7.4Hz)，4.25(4/3H，s)，4.56(2/3H，s)，6.93-6.91(2H，m)，7.06-7.04(1H，m)，7.20-7.18(1H，m)，7.32-7.30(1H，m)，7.43(1H，s)，7.97(1H，d，J＝9.0Hz)，8.44(1H，d，J＝16.0Hz)，8.66-8.64(2H，m)，9.66-9.58(1H，m)，10.39(1/3H，s)，10.61(2/3H，s)

ESI-MASS(m/e)：508(M+H)

Example 174

6- (4- (ethylsulfonyl) phenoxy) -2-pyridin-2-yl-1H-benzimidazole-5-carboxylic acid methyl ester

Methyl 6- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazole-5-carboxylate, obtained in example 19 (step 6), was reacted with trifluoroacetic acid to give the title compound.

Example 175

6- (4- (ethylsulfonyl) phenoxy) -2-pyridin-2-yl-1H-benzimidazole-5-carboxylic acid

To 2.3g of the methyl ester compound obtained in example 174 was added 10ml of a 1-eq aqueous sodium hydroxide solution, and the reaction mixture was stirred overnight at 50 ℃. 4ml of 3 equivalents hydrochloric acid was added to the reaction solution, and the precipitate was filtered off, whereby the title compound was obtained.

Example 176

(6- (4-ethylsulfonyl) phenoxy) -2-pyridin-2-yl-1H-benzimidazol-5-yl) methanol

To a solution of 1.5g of formic acid obtained in example 175 in 5ml of dimethylformamide was added 700mg of 1, 1' -carbonyldiimidazole, and the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was added to 5ml of an aqueous solution of 1.5g of sodium borohydride, and the reaction mixture was stirred at room temperature for 5 minutes, then diluted with ethyl acetate, washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound as an orange solid.

Example 177

6- (4- (ethylsulfonyl) phenoxy) -2-pyridin-2-yl-1H-benzimidazole-5-carbaldehyde

To 1.0g of a 10ml dimethylsulfoxide solution of the alcohol compound obtained in example 176, 5ml of triethylamine and 750mg of pyridine sulfur trioxide were added, and the reaction solution was stirred at room temperature for 15 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound as an orange solid.

Using the phenol compound obtained in the reference example, the compounds of examples 178 to 209 were obtained in the same manner as in example 174-177 and in combination with the conventional methods.

Example 178

6- (4- (methylsulfonyl) phenoxy) -2-pyridin-2-yl-1H-benzimidazole-5-carboxylic acid methyl ester

Example 179

6- (4- (methylsulfonyl) phenoxy) -2-pyridin-2-yl-1H-benzimidazole-5-carboxylic acid

Example 180

(6- (4-methylsulfonyl) phenoxy) -2-pyridin-2-yl-1H-benzimidazol-5-yl) methanol

Example 181

6- (4- (methylsulfonyl) phenoxy) -2-pyridin-2-yl-1H-benzimidazole-5-carbaldehyde

Example 182

6- ((6- (ethylsulfonyl) pyridin-3-yl) oxy) -2-pyridin-2-yl-1H-benzimidazole-5-carba Acid methyl ester

Example 183

6- ((6- (ethylsulfonyl) pyridin-3-yl) oxy) -2-pyridin-2-yl-1H-benzimidazole-5-carba Acid(s)

Example 184

(6- ((6- (ethylsulfonyl) pyridin-3-yl) oxy) -2-pyridin-2-yl-1H-benzimidazol-5-) Based) methanol

Example 185

6- ((6- (ethylsulfonyl) pyridin-3-yl) oxy) -2-pyridin-2-yl-1H-benzimidazole-5-carba Aldehydes

Example 186

6 - ((6- (methylsulfonyl) pyridin-3-yl) oxy) -2-pyridin-2-yl-1H-benzimidazole-5-carbaldehyde Acid methyl ester

Example 187

6- ((6- (methylsulfonyl) pyridin-3-yl) oxy) -2-pyridin-2-yl-1H-benzimidazole-5-carbaldehyde Acid(s)

Example 188

(6- ((6-methylsulfonyl) pyridin-3-yl) oxy) -2-pyridin-2-yl-1H-benzimidazol-5-yl) Methanol

Example 189

6- ((6-methylsulfonyl) pyridin-3-yl) oxy) -2-pyridin-2-yl-1H-benzimidazole-5-carbaldehyde Aldehydes

Example 190

6- (6- (5-methyl- (1, 2, 4) oxadiazol-3-yl) -pyridin-3-yloxy) -2-pyridin-2-yl-1H- Benzimidazole-5-carboxylic acid methyl ester

Example 191

6- (6- (5-methyl- (1, 2, 4) oxadiazol-3-yl) -pyridin-3-yloxy) -2-pyridin-2-yl-1H- Benzimidazole-5-carboxylic acid

Example 192

(6- (6- (5-methyl- (1, 2, 4) oxadiazol-3-yl) -pyridin-3-yloxy) -2-pyridin-2-yl-1H-) Benzimidazol-5-yl) methanol

Example 193

6- (6- (5-methyl- (1, 2, 4) oxadiazol-3-yl) -pyridin-3-yloxy) -2-pyridin-2-yl-1H- Benzimidazole-5-carbaldehyde

Example 194

6- ((6- (methoxymethyl) pyridin-3-yl) oxy) -2-pyridin-2-yl-1H-benzimidazol-5-carboxylic acid methyl ester Acid methyl ester

Example 195

6- ((6- (methoxymethyl) pyridin-3-yl) oxy) -2-pyridin-2-yl-1H-benzimidazol-5-carboxylic acid methyl ester Acid(s)

Example 196

(6- ((6- (methoxymethyl) pyridin-3-yl) oxy) -2-pyridin-2-yl-1H-benzimidazol-5-) Based) methanol

Example 197

6- ((6- (methoxymethyl) pyridin-3-yl) oxy) -2-pyridin-2-yl-1H-benzimidazol-5-carboxylic acid methyl ester Aldehydes

Example 198

6- (4-ethylsulfonyl) phenoxy) -2-pyrazin-2-yl-1H-benzimidazole-5-carboxylic acid methyl ester Example 199

6- (4-ethylsulfonyl) phenoxy) -2-pyrazin-2-yl-1H-benzimidazole-5-carboxylic acid

Example 200

(6- (4-ethylsulfonyl) phenoxy) -2-pyrazin-2-yl-1H-benzimidazol-5-yl) methanol

Example 201

6- (4-ethylsulfonyl) phenoxy) -2-pyrazin-2-yl-1H-benzimidazole-5-carbaldehyde

Example 202

6- ((6-ethylsulfonyl) pyridin-3-yl) oxy) -2-pyrazin-2-yl-1H-benzimidazole-5-carbaldehyde Acid methyl ester

Example 203

6- ((6-ethylsulfonyl) pyridin-3-yl) oxy) -2-pyrazin-2-yl-1H-benzimidazole-5-carbaldehyde Acid(s)

Example 204

(6- ((6-ethylsulfonyl) pyridin-3-yl) oxy) -2-pyrazin-2-yl-1H-benzimidazol-5-yl) Methanol

Example 205

6- ((6-ethylsulfonyl) pyridin-3-yl) oxy) -2-pyrazin-2-yl-1H-benzimidazole-5-carbaldehyde Aldehydes

Example 206

6- ((6-Cyanopyridin-3-Yl) oxy) -2-pyridin-2-Yl-1H-benzimidazole-5-Carboxylic acid methyl ester

Example 207

6- ((6-cyanopyridin-3-yl) oxy) -2-pyrazin-2-yl-1H-benzimidazole-5-carboxylic acid

Example 208

(6- ((6-cyanopyridin-3-yl) oxy) -2-pyrazin-2-yl-1H-benzimidazol-5-yl) methanol

Example 209

6- ((6-cyanopyridin-3-yl) oxy) -2-pyrazin-2-yl-1H-benzimidazole-5-carbaldehyde

Example 210

1- ({5- [4- (2-methyl)radical-2H-tetrazol-5-yl) phenoxy]-2-pyridin-2-yl-1H-benzimidazol- 6-yl } methyl) pyrrolidin-2-one

The title compound was obtained in the same manner as in example 102 (step 5), a method similar thereto, or a combination thereof with a conventional method using 4- (2-methyl-2H-tetrazol-5-yl) phenol obtained in reference example 17.

¹HNMR(CDCl₃)δ：1.95(2H，m)，2.37(2H，m)，3.33(2H，m)，4.39(3H，s)，4.61(2H，s)，7.05(2H，d，J＝8.8Hz)，7,20-7.60(1H，br)，7.38(1H，m)，7.65(1H，br)，7.87(1H，m)，8.08(2H，d，J＝8.8Hz)，8.39(1H，d，J＝8.0Hz)，8.64(1H，d，J＝4.5Hz)

ESI-MASS(m/e)：467(M+H)

Example 211

1- [ (2- (5-Fluoropyridin-2-yl) -5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl] Oxy } -1H-benzimidazol-6-yl) methyl]Pyrrolidin-2-ones

The title compound was obtained in the same manner as in example 53, a method similar thereto, or a combination thereof with a conventional method using 5-fluoropyridine-2-carboxylic acid obtained in referential example 18.

¹H NMR(CDCl₃)δ：1.97(2H，m)，2.35(2H，m)，2.69(3H，s)，3.33(2H，m)，4.60(2H，s)，7.17(1/2H，s)，7.33(1H，m)，7.46(1/2H，s)，7.58(2H+1/2H，m)，7.76(1/2H，s)，8.03(1H，m)，8.40-8.60(3H，m)，10.5(1/2H，br)，10.8(1/2H，br)

ESI-MASS(m/e)：486(M+H)

Example 212

(3S) -1- ({6- [4- (ethylsulfonyl) phenoxy]-2-pyridin-2-yl-1H-benzimidazol-5-yl } Methyl) -3-hydroxypyrrolidin-2-one

(step 1 Synthesis of (3S) -3- { [ tert-butyldimethylsilyl ] oxy } pyrrolidin-2-one

To a solution of 500mg of (2S) -4-amino-2-hydroxybutyric acid in 5ml of methanol and 4ml of chloroform was added 3.1ml of trimethylsilyldiazomethane (2.0M, hexane solution) while stirring overnight. The solvent was distilled off under reduced pressure to give 503mg of (3S) -3-hydroxypyrrolidin-2-one as a white solid.

To a solution of 503mg of (3S) -3-hydroxypyrrolidin-2-one in 5ml of dimethylformamide was added 570mg of imidazole and 947mg of tert-butyldimethylsilyl chloride under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, which was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried. The solvent was distilled off under reduced pressure to give 452mg of the title compound as a pale yellow oil.

(step 2) (3S) -1- ({6- [4- (ethylsulfonyl) phenoxy ] -2-pyridin-2-yl-1H-benzimidazol-5-yl } methyl) -3-hydroxypyrrolidin-2-one

The title compound was obtained in the same manner as in example 2, a method similar thereto, or a combination thereof with a conventional method, using the alcohol obtained in example 19 (step 7) and (3S) -3- { [ tert-butyldimethylsilyl ] oxy } pyrrolidin-2-one obtained in step 1.

1HNMR(CDCl₃)δ：1.25(3H，t，J＝7.4Hz)，1.95(1H，s)，2.43(1H，s)，3.09(2H，q，J＝7.4Hz)，3.37-3.47(2H，m)，4.45-4.49(2H，m)，4.68(1H，m)，7.07(2H，d，J＝8.0Hz)，7.37-7.39(1H，m)，7.43(1H，s)，7.81-7.89(3H，m)，7.99(1H，s)，8.44(1H，d，J＝8.0Hz)，8.60(1H，d，J＝4.1Hz)

ESI-MASS(m/e)：493(M+H)

Example 213

1- [ (2- (5-methoxypyridin-2-yl) -5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl- Base of]Oxy } -1H-benzimidazol-6-yl) methyl]Pyrrolidin-2-ones

The title compound was obtained in the same manner as in example 53, a method similar thereto, or a combination thereof with a conventional method using 5-methoxypyridine-2-carboxylic acid obtained in referential example 19.

1HNMR(CDCl₃)δ：1.94(2H，m)，2.35(2H，m)，2.68(3H，s)，3.30(2H，m)，3.94(3H，s)，4.58(2H，m)，7.14(1/2H，s)，7.25-7.38(2H，m)，7.45(1/2H，s)，7.55(1/2H，s)，7.74(1/2H，s)，8.03(1H，m)，8.28-8.38(2H，m)，8.47(1/2H，m)，8.54(1/2H，m)，10.7(1/2H，m)，10.8(1/2H，br)

ESI-MASS(m/e)：498(M+H)

Example 214

(6- { [6- (ethylsulfonyl) pyridin-3-yl]Oxy } -2-pyridin-2-yl-1H-benzimidazol-4- Yl) acetonitrile

The title compound was obtained in the same manner as in example 127, in a similar manner to example 127, or in combination with a conventional method using the alcohol compound obtained in example 150 (step 1).

1HNMR(CDCl₃)δ：1.29(3H，m)，3.37(2H，q，J＝7.4Hz)，4.27(2H，s)，7.16(2H，d，J＝13.3Hz)，7.35-7.39(2H，m)，7.87(1H，t，J＝7.8Hz)，8.01(1H，s)，8.39(1H，d，J＝7.8Hz)，8.46(1H，d，J＝2.7Hz)，8.62(1H，s)，10.83(1H，brs)

ESI-MASS(m/e)：420(M+H)

Example 215

6- { [6- (ethylsulfonyl) pyridin-3-yl]Oxy } -4- [ (5-methyl-1, 2, 4-oxadiazol-3-yl) Methyl radical]-2-pyridin-2-yl-1H-benzimidazoles

The title compound was obtained in the same manner as in example 140, a method similar thereto, or a combination thereof with a conventional method using the alcohol compound obtained in example 150 (step 1).

1HNMR(CDCl₃)δ：1.26(3H，m)，2.56(3H，s)，3.33-3.38(2H，m)，4.28(1H，s)，4.59(1H，s)，6.91-7.00(1H，m)，7.31-7.37(2H，m)，7.45(1H，s)，7.85(1H，t，J＝8.6Hz)，7.97-8.01(1H，m)，8.37-8.44(2H，m)，8.59-8.61(1/2H，m)，8.68(1/2H，d，J＝4.7Hz)

ESI-MASS(m/e)：477(M+H)

Example 216

1- {2- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl)]Oxy } -2-pyridin-2-yl-1H-benzimidazoles Oxazol-4-yl) methyl]Phenyl ethyl ketone

The title compound was obtained in the same manner as in example 173, by using the alcohol compound obtained in example 150 (step 1) and a method similar thereto, or by combining these with a conventional method.

1HNMR(CDCl₃)δ：1.28(3H，q，J＝7.4Hz)，2.53(1H，s)，2.71(2H，s)，3.36(2H，q，J＝7.4Hz)，4.36(4/3H，s)，4.76(2/3H，s)，6.96(1H，d，J＝2.2Hz)，7.51(2H，dd，J＝10.3，4.6Hz)，7.61-7.68(5H，m)，7.79(1H，t，J＝8.6Hz)，7.98(1H，d，J＝8.6Hz)，8.30(1H，d，J＝8.6Hz)，8.48(1H，d，J＝2.9Hz)，8.66(1H，d，J＝4.9Hz)，12.11(1H，brs)

ESI-MASS(m/e)：513(M+H)

Example 217

2- [ (6- {6- (ethylsulfonyl) pyridin-3-yl } oxy } -2-pyridin-2-yl-1H-benzimidazol-one- 4-yl) methyl]Benzonitrile

1HNMR(CDCl₃)δ：1.22-1.29(3H，m)，3.30-3.37(2H，m)，4.45(2/3H，s)，4.68(4/3H，s)，6.79-6.81(1H，m)，7.03(1H，d，J＝2.0Hz)，7.28-7.34(2H，m)，7.57(1H，d，J＝7.8Hz)，7.61-7.66(3H，m)，7.85(1H，t，J＝7.6Hz)，7.95(1H，d，J＝8.6Hz)，8.37-8.44(2H，m)，8.56(1H，d，J＝4.7Hz)，11.08(1/3H，brs)，11.26(2/3H，brs)

ESI-MASS(m/e)：496(M+H)

Example 218

6- { [6- (ethylsulfonyl) pyridin-3-yl]Oxy } -2-pyridin-2-yl-4- (2H-tetrazol-5-yl) Methyl) -1H-benzimidazoles

To a solution of 116mg of (6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-benzimidazol-4-yl) acetonitrile obtained in example 214 in 2ml of toluene were added 41mg of sodium azide and 87mg of triethylamine hydrochloride, and the mixture was stirred at 100 ℃ overnight. The reaction solution was returned to room temperature, hydrochloric acid (1N) was then added thereto, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. The solvent was distilled off under reduced pressure to obtain 121mg of a crude product as a yellow oil.

To 121mg of the above crude product was added 0.7ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 1 hour. Excess trifluoroacetic acid was distilled off under reduced pressure, followed by purification by reverse-phase high performance liquid chromatography (water/acetonitrile: 90/10-10/90) to give 14mg of the title compound as a white solid.

1HNMR(CDCl₃)δ：1.29(3H，m)，3.37(2H，q，J＝7.4Hz)，4.68(2H，s)，7.07(1H，s)，7.33-7.36(2H，m)，7.48-7.50(1H，m)，7.98-8.00(2H，m)，8.44(2H，m)，8.69(1H，m)

ESI-MASS(m/e)：463(M+H)

Example 219

2- [ (6- { 6-ethylsulfonyl } pyridin-3-yl } oxy } -2-pyridin-2-yl-1H-benzimidazol-4- Base)Methyl radical]Benzamide derivatives

1HNMR(CDCl₃)δ：1.32-1.56(3H，m)，3.33-3.40(2H，m)，4.40(2H，s)，7.06(1H，d，J＝8.6Hz)，7.27-7.42(5H，m)，7.48-7.50(2H，m)，7.76-7.80(2H，m)，7.97-8.01(1H，m)，8.47-8.48(1H，m)，8.63(1H，m)

ESI-MASS(m/e)：514(M+H)

Example 220

1- [ hydroxy (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl)]Oxy } -2-pyridine-2- 1H-benzimidazol-6-yl) methyl]Pyrrolidin-2-ones

(step 1) Synthesis of (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1H-benzimidazol-6-yl) methanol

The title compound was obtained in the same manner as in example 19 (step 5) and example 34 (step 3), in a similar manner to the above or in combination with a conventional method using 6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinol obtained in referential example 6.

(step 2) Synthesis of 5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1H-benzimidazole-6-carbaldehyde

To 400mg of a solution of the alcohol compound obtained in step 1 in 5ml of dimethyl sulfoxide were added 1.5ml of triethylamine and 796mg of sulfur trioxide pyridine complex, and the mixture was stirred at room temperature for 30 minutes. Water was added, followed by extraction with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was crystallized from diethyl ether-methanol to obtain 183mg of the title compound as a pale yellow amorphous substance.

(step 3) Synthesis of 1- [ hydroxy (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1H-benzimidazol-6-yl) methyl ] pyrrolidin-2-one

To a solution of 8.7. mu.l 2-pyrrolidone in 500. mu. l N, N-dimethylformamide was added 7mg sodium carbonate. 10mg of the aldehyde compound obtained in step 2 was added thereto at 80 ℃ with stirring, and stirred at 80 ℃ overnight. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (Kieselgel)^TM60F₂₅₄Art 5744(Merck), chloroform/methanol-5/1) to yield 1.0mg of the title compound as a pale yellow amorphous substance.

¹HNMR(CDCl₃)δ：0.79-0.94(1H，m)，1.77-1.91(1H，m)，1.97-2.09(1H，m)，2.14-2.34(1H，m)，2.68(3H，s)，2.83-2.94(1H，m)，3.37-3.52(1H，m)，6.87-6.95(1H，m)，7.18(1Hx1/2，s)，7.33-7.46(2H，m)，7.50(1Hx1/2，s)，7.86-7.94(1H，m)，7.99-8.08(1H，m，1Hx1/2，s)，8.31(1Hx1/2，s)，8.36-8.46(2H，m)，8.60-8.72(1H，m)，10.58(1Hx1/2，brs)，10.86(1Hx1/2，brs)

ESI-MASS(m/e)：484(M+H)

Example 221

The title compound was obtained in the same manner as in example 53 (step 2 to step 3), in a similar manner to this, or in combination with a conventional method using 5-fluoropyridine-2-carboxylic acid obtained in referential example 18.

¹HNMR(CDCl₃)δ：1.97(2H，m)，2.35(2H，m)，2.69(3H，s)，3.33(2H，m)，4.60(2H，s)，7.17(1/2H，s)，7.33(1H，m)，7.46(1/2H，s)，7.58(2H+1/2H，m)，7.76(1/2H，s)，8.03(1H，m)，8.40-8.60(3H，m)，10.5(1/2H，br)，10.8(1/2H，br)

ESI-MASS(m/e)：486(M+H)

Example 222

The title compound was obtained in the same manner as in example 53 (step 2 to step 3), a method similar thereto, or a combination thereof with a conventional method using 5-methoxypyridine-2-carboxylic acid obtained in referential example 19.

¹HNMR(CDCl₃)δ：1.94(2H，m)，2.35(2H，m)，2.68(3H，s)，3.30(2H，m)，3.94(3H，s)，4.58(2H，m)，7.14(1/2H，s)，7.25-7.38(2H，m)，7.45(1/2H，s)，7.55(1/2H，s)，7.74(1/2H，s)，8.03(1H，m)，8.28-8.38(2H，m)，8.47(1/2H，m)，8.54(1/2H，m)，10.7(1/2H，m)，10.8(1/2H，br)

ESI-MASS(m/e)：498(M+H)

Example 223

1- [ (2- (5-methylpyridin-2-yl) -5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl] Oxy } -1H-benzimidazol-6-yl) methyl]Pyrrolidin-2-ones

The title compound was obtained in the same manner as in example 53 (step 2 to step 3), in a similar manner to this, or in combination with a conventional method using 6-methylpyridine-2-carboxylic acid.

¹HNMR(CDCl₃)δ：1.95(2H，m)，2.33(2H，m)，2.60(3H，s)，2.68(3H，s)，3.32(2H，m)，4.58(2H，s)，7.10-7.35(2H+1/2H，m)，7.47(1/2H，s)，7.56(1/2H，s)，7.75(1H+1/2H，m)，8.03(1H，m)，8.19(1H，m)，8.47(1/2H，s)，8.54(1/2H，s)，10.9(1H，br)

ESI-MASS(m/e)：482(M+H)

Example 224

1- [ (2- (6-methoxypyridin-2-yl) -5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl- Base of]Oxy } -1H-benzimidazol-6-yl) methyl]Pyrrolidin-2-ones

¹HNMR(CDCl₃)δ：1.96(2H，m)，2.34(2H，m)，2.69(3H，s)，3.34(2H，m)，4.03(3/2H，s)，4.07(3/2H，s)，4.58(2/2H，s)，4.59(2/2H，s)，6.86(1H，d，J＝8.2Hz)，7.16(1/2H，s)，7.32(1H，m)，7.46(1/2H，s)，7.61(1/2H，s)，7.78(1H+1/2H，m)，7.96-8.06(2H，m)，8.46(1/2H，d，J＝2.9Hz)，8.54(1/2H，d，J＝2.5Hz)，10.5(1/2H，br)，10.6(1/2H，br)

ESI-MASS(m/e)：498(M+H)

Example 225

6- {5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl]Oxy } -6- [ (2-oxopyrazine) Pyrrolidin-1-yl) methyl]-1H-benzimidazol-2-yl } nicotinic acid methyl ester

The title compound was obtained in the same manner as in example 53 (step 2 to step 3), in a similar manner to this, or in combination with a conventional method using 5- (methoxycarbonyl) pyridine-2-carboxylic acid.

¹HNMR(CDCl₃)δ：1.99(2H，m)，2.40(2H，m)，2.69(3H，s)，3.35(2H，m)，4.00(3H，s)，4.61(2H，s)，7.19(1/2H，s)，7.35(1H，m)，7.53(1/2H，s)，7.65(1/2H，s)，7.80(1/2H，s)，8.05(1H，m)，8.45(2H，m)，8.48(1/2H，d，J＝3.0Hz)，8.55(1/2H，d，J＝2.6Hz)，9.22(1H，m)，10.8(1/2H，br)，11.1(1/2H，br)

ESI-MASS(m/e)：526(M+H)

Example 226

1- [ (2- (4-methylpyridin-2-yl) -5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] Oxy } -1H-benzimidazol-6-yl) methyl]Pyrrolidin-2-ones

The title compound was obtained in the same manner as in example 53 (step 2 to step 3), in a similar manner to this, or in combination with a conventional method using 4-methylpyridine-2-carboxylic acid.

¹HNMR(CDCl₃)δ：1.94(2H，m)，2.34(2H，m)，2.46(3/2H，s)，2.47(3/2H，s)，2.68(3H，s)，3.32(2H，m)，4.58(2/2H，s)，4.61(2/2H，s)，7.16(1/2H，s)，7.72(1H，d，J＝4.7Hz)，7.33(1H，m)，7.48(1/2H，s)，7.57(1/2H，s)，7.77(1/2H，s)，8.05(1H，m)，8.23(1/2H，s)，8.26(1/2H，s)，8.49(1H+1/2H，m)，8.55(1/2H，d，J＝2.7Hz)，10.8(1H，br)

ESI-MASS(m/e)：482(M+H)

Example 227

3-hydroxy-1- [ (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl)]Oxy } -2-pyridines -2-yl-1H-benzimidazol-6-yl) methyl]Pyrrolidin-2-one trifluoroacetate salt

(step 1) Synthesis of 3- { [ tert-butyl (dimethyl) silyl ] oxy } pyrrolidin-2-one

5g dl-maleic acid was dissolved in 20ml acetyl chloride and stirred at 45 ℃ for 3 hours. Acetyl chloride was distilled off under reduced pressure, and then the crude product was dissolved in 30ml of methanol and stirred overnight. The solvent was distilled off under reduced pressure to give 5.3g of 3- (acetoxy) -4-methoxy-4-oxobutanoic acid as a pale yellow oil. To a solution of 5.3g of 3- (acetoxy) -4-methoxy-4-oxobutanoic acid in 25ml of tetrahydrofuran was added 10ml of 10M borane-dimethylsulfide complex under ice bath, and stirred at room temperature for 24 hours. A10% citric acid aqueous solution was added to the reaction mixture, followed by extraction with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure to obtain 5.1g of methyl 2- (acetyloxy) -4-hydroxybutyrate as a colorless transparent oil.

6.1ml of triethylamine and 2.3ml of methanesulfonyl chloride were added to a solution of 2.59g of methyl 2- (acetyloxy) -4-hydroxybutyrate in 15ml of chloroform under ice bath, and stirred for 30 minutes. Saturated brine was added to the reaction mixture, followed by extraction with chloroform and drying of the organic layer. The solvent was distilled off under reduced pressure to give 2.54g of methyl 2- (acetyloxy) -4- [ (methylsulfonyl) oxy ] butanoate as a pale brown liquid.

To a solution of 2.54g of methyl 2- (acetyloxy) -4- [ (methylsulfonyl) oxy ] butanoate in 10ml of dimethylformamide was added 1.91g of sodium azide, and the mixture was stirred at 70 ℃ for 8 hours. The reaction solution was returned to room temperature, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and the solvent was distilled off under reduced pressure to give 2.70g of methyl 2- (acetyloxy) -4-azidobutyrate as a pale brown oil.

To a solution of 2.47g of methyl 2- (acetyloxy) -4-azidobutyrate in 15ml of methanol were added 2.53g of potassium carbonate and 1ml of water, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried. The solvent was distilled off under reduced pressure to give 591mg of methyl 4-azido-2-hydroxybutyrate as an orange oil.

To a solution of 351mg of methyl 4-azido-2-hydroxybutyrate in 3ml of tetrahydrofuran were added 692mg of triphenylphosphine and 8. mu.l of water, followed by stirring at room temperature for 24 hours and then heating at 50 ℃ and stirring overnight. The tetrahydrofuran was distilled off under reduced pressure, followed by extraction with ethyl acetate to give 255mg of 3-hydroxypyrrolidin-2-one as a pale brown oil.

300mg of imidazole and 497mg of t-butyldimethylsilyl chloride were added to a solution of 255mg of 3-hydroxypyrrolidin-2-one in 2ml of dimethylformamide while cooling on ice, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, which was extracted with ethyl acetate and washed with 1N hydrochloric acid and saturated brine. The organic layer was dried to yield 370mg of crude product. Of these, 208mg was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 9/1-2/8) to give 62mg of the title compound as a white solid.

(step 2) Synthesis of 3-hydroxy-1- [ (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1H-benzimidazol-6-yl) methyl ] pyrrolidin-2-one trifluoroacetate

To a solution of 47mg of the alcohol obtained in example 52 (step 2) in 1ml of tetrahydrofuran was added 36. mu.l of triethylamine and 14. mu.l of methanesulfonyl chloride while cooling on ice, and the mixture was stirred for 30 minutes. To the reaction mixture was added saturated brine, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and then dried. The solvent was distilled off under reduced pressure to give 48mg of a crude product as a pale yellow oil.

To a solution of the above crude product in 2ml of dimethylformamide were added 62mg of 3- { [ tert-butyl (dimethyl) silyl ] oxy } pyrrolidin-2-one obtained in step 1 and 11mg of sodium hydride (60%) under ice bath, and the mixture was stirred at room temperature for 90 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, and the organic layer was washed with water, saturated brine and dried. The solvent was distilled off under reduced pressure, followed by purification by thin layer silica gel column chromatography (developing solvent: chloroform/methanol: 9/1), to give 38mg of the crude product as a yellow oil.

To a solution of 20mg of the above crude product in 0.2ml of tetrahydrofuran was added 83. mu.l of tetrabutylammonium fluoride (1.0M, tetrahydrofuran solution), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then 0.7ml of trifluoroacetic acid was added thereto and stirred for 1 hour. Excess trifluoroacetic acid was distilled off under reduced pressure, followed by purification by reverse-phase high performance liquid chromatography (eluting solvent: water/acetonitrile 9/1-1/9) to give 6mg of the title compound as a colorless transparent oil.

¹HNMR(CD₃OD)δ：1.79-1.85(1H，m)，2.36(1H，m)，2.69(3H，s)，3.26-3.31(1H，m)，3.39(1H，d，J＝6.5Hz)，4.19(1H，t，J＝8.2Hz)，4.72-4.66(2H，m)，7.49(1H，s)，7.60-7.62(1H，m)，7.66-7.68(1H，m)，7.85(1H，s)，8.11-8.16(2H，m)，8.29(1H，d，J＝8.0Hz)，8.48(1H，d，J＝2.3Hz)，8.86(1H，d，J＝4.7Hz)

ESI-MASS(m/e)：484(M+H)

Reference example 14 Synthesis of- (methylsulfonyl) phenol

In a water bath, 18.5ml of methyl iodide and 28.7g of potassium carbonate were added to a solution of 25g of 4-hydroxythiophenol in 250ml of acetone, and stirred at room temperature for 5 hours. After the salts were filtered off, the solvent was distilled off under reduced pressure, diethyl ether was added thereto, and the mixture was extracted with a 2N aqueous solution of sodium hydroxide. The aqueous layer was acidified with 6N aqueous hydrochloric acid, extracted with diethyl ether, and the organic layer was washed with saturated aqueous sodium chloride. After drying, the solvent was distilled off under reduced pressure to obtain 27.3g of 4- (methylsulfanyl) phenol as a pale yellow solid. In a water bath, 67ml of 30% hydrogen peroxide water was slowly added dropwise to a solution of 27.3g of 4- (methylsulfanyl) phenol in 130ml of acetic acid. After the dropwise addition, the temperature was slowly raised to 100 ℃ and stirred for 1 hour. The reaction solution was returned to room temperature, and neutralized with saturated sodium bicarbonate. The extract was extracted with ethyl acetate, and washed with saturated sodium bicarbonate water and saturated brine. After drying, the solvent was distilled off to obtain 31.6g of the title compound as a pale yellow solid.

Reference example 24 Synthesis of- (ethylsulfonyl) phenol

The title compound was obtained in the same manner as in reference example 1, in a similar manner thereto or in combination with a conventional method using ethyl iodide.

Reference example Synthesis of 36- (methylsulfonyl) -3-pyridinol

To a solution of 4.72g of 3-bromo-6- (methylsulfonyl) pyridine in 80ml of dimethyl sulfoxide were added 6.6g of bis (valeryl) diboron (ビス (ピナコレ - ト) ジボロン), 5.9g of potassium acetate and 980mg of (1, 1' -bis (diphenylphosphino) ferrocene) dichloropalladium (II) dichloromethane complex, and the reaction mixture was stirred at 80 ℃ for 2 hours. Ethyl acetate and water were added to the reaction solution, insoluble matters were filtered off through Celite, and then the organic layer was separated. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

To 200ml of a tetrahydrofuran solution of the obtained residue were added 60ml of a 5-equivalent aqueous sodium hydroxide solution and 30ml of a 30% hydrogen peroxide water at 0 ℃, and the reaction solution was stirred at room temperature overnight. The reaction solution was diluted with diethyl ether and washed with water. The aqueous layer was made acidic with 5 equivalents hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with a mixed solvent of chloroform and hexane to obtain 1.17g of the title compound as a brown solid.

Reference example 46 Synthesis of- (ethylsulfonyl) -3-pyridinol

The title compound was obtained in the same manner as in reference example 3, in a similar manner to reference example 3, or in combination with a conventional method using 3-chloro-6- (ethylsulfonyl) pyridine.

Reference example 53 Synthesis of chloro-4- (methylsulfonyl) phenol

To 108ml of methanesulfonic acid, 48.3ml of thionyl chloride was added, and the mixture was refluxed for 1 hour. After the reaction mixture was returned to room temperature, 1, 3-dichlorobenzene and 2.9ml of trifluorosulfonic acid were added thereto, and the mixture was stirred at 120 ℃ for 4 hours. The reaction mixture was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate water and saturated brine, dried and the solvent was distilled off under reduced pressure. Recrystallization from a mixed solvent of hexane/ethyl acetate gave 48.3g of 2, 4-dichlorophenyl methylsulfone.

To a solution of 1g of 2, 4-dichlorophenyl methyl sulfone in 3ml of dimethyl sulfoxide was added 1ml of an aqueous solution of 360mg of potassium hydroxide, and the mixture was stirred at 100 ℃ for 4 hours. The mixture was acidified with 1N aqueous hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate-9/1-2/1) to give 300mg of 3-chloro-4- (methylsulfonyl) phenol.

Reference example 66- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinol trifluoroacetate

(step 1) Synthesis of 6-bromo-3-pyridinol

435ml of isopropyl magnesium bromide (2M tetrahydrofuran solution) was added to 200g of 2, 5-dibromopyridine in 800ml of tetrahydrofuran under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. A solution of 214ml of triisopropyl borate in 200ml of tetrahydrofuran was added under ice cooling, and the mixture was stirred at room temperature overnight. The reaction solution was slowly added to a 2.5L aqueous solution of 160g of sodium hydroxide under ice-cooling. 1L of water and 1L of hexane were added to extract the aqueous layer. To this aqueous layer, 150ml of hydrogen peroxide water (30%) was slowly added under ice cooling for 1 hour, and stirred at room temperature overnight. The reaction mixture was neutralized with concentrated hydrochloric acid under ice-cooling, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure to obtain 130g of the title compound.

(step 2) Synthesis of 2-bromo-5- (methoxymethoxy) pyridine

To 129g of the resulting 6-bromo-3-pyridinol solution in 1.3L of tetrahydrofuran were added 73ml of methoxymethyl chloride, and 32g of sodium hydride (to which 30% liquid paraffin was added) was added under such a condition that the internal temperature did not exceed-10 ℃. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure and purified by means of a silica gel column chromatography (developing solvent: hexane/ethyl acetate 9/1-8/1) to give 105g of the title compound as a colorless oil.

(step 3) Synthesis of 5- (methoxymethoxy) -2-pyridinecarbonitrile

88.9g of zinc cyanide and 29.1g of tetrakis (triphenylphosphine) palladium (0) were added to a solution of 105g of the obtained oil in 1100ml of dimethylformamide, and the mixture was stirred at 105 ℃ for 1 hour. The mixture was cooled to room temperature, and 1.5L of ethyl acetate and 1.2L of water were added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was removed by distillation under the reduced pressure, followed by purification by silica gel column chromatography (developing solvent: hexane/ethyl acetate 8/1-7/1-2/1) to obtain 53.4g of the title compound.

(step 4) Synthesis of 6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinol

To a 400ml ethanol solution of 41g of the obtained product was added 35.4ml of hydroxylamine (50% aqueous solution) under ice-cooling, and stirred at room temperature for 30 minutes. 1L of water was added thereto under ice cooling, and stirred for 1 hour. The resulting crystals were collected by filtration to obtain 39.5g of a product.

To 39.5g of the obtained crystals were added 200ml of acetic acid, and 20.8ml of acetic anhydride was added under ice-cooling, followed by stirring at room temperature for 1 hour. Directly heated to 70 ℃ and stirred overnight. The reaction solvent was distilled off under reduced pressure, and 100ml of trifluoroacetic acid was added to the resulting pale brown solid, followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and a mixed solvent of hexane/ethyl acetate 20/1 was added thereto and stirred. The resulting solid was collected by filtration and dried to obtain 57.1g of the title compound as a trifluoroacetate salt.

Reference example 74- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenol

(step 1) Synthesis of 4- (methoxymethoxy) benzonitrile

The title compound was obtained by the same method as in reference example 6 (step 2), a method similar thereto, or a combination thereof with a conventional method using 4-cyano-phenol.

(step 2)4- (5-methyl-1, 2, 4-oxadiazole-3-yl) phenol

The title compound was obtained by the same method as in reference example 6 (step 4), a method similar thereto or a combination thereof with a conventional method using 4- (methoxymethoxy) benzonitrile.

Reference example 81- (4-hydroxyphenyl) pyrrolidin-2-one

(step 1) Synthesis of 1-iodo-4- (methoxymethoxy) benzene

To a solution of 2g of 4-iodophenol in 20ml of chloroform were added 2.33ml of N, N-diisopropylethylamine and 900. mu.l of methoxymethyl chloride, and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride was added under ice cooling, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: hexane/ethyl acetate) to give 1.08g of the title compound as a colorless oil.

(step 2) Synthesis of 1- (4-hydroxyphenyl) pyrrolidin-2-one

To a solution of 200mg of the compound obtained in step 1 and 70. mu.l of 2-pyrrolidone in 2ml of 1, 4-dioxane were added 5. mu.l of ethylenediamine, 14.5mg of copper (I) iodide and 321mg of potassium phosphate, and the mixture was stirred under nitrogen at 110 ℃ overnight. Saturated aqueous ammonium chloride solution was added under ice cooling, followed by dilution with ethyl acetate and filtration through Celite to remove insoluble matter. Extraction was performed with ethyl acetate, and then the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: chloroform/methanol) to give 174mg of an intermediate product.

To 1.0ml of a 1, 4-dioxane solution of 80mg of the resulting intermediate product were added 250. mu.l of a 4N hydrochloric acid/dioxane solution and 10. mu.l of water, and the mixture was stirred at room temperature for 2.5 hours. After concentration, the residue was azeotroped with chloroform and solidified with diethyl ether to obtain 60.1mg of the title compound as a white solid.

Reference example Synthesis of 91- (4-hydroxyphenyl) pyridin-2 (1H) -one

200mg of the compound obtained in referential example 11 (step 11), 72mg of 2-hydroxypyridine, 29mg of copper (I) iodide, 210mg of potassium carbonate, 22mg of (1R, 2R) - (-) -N, N' -dimethylcyclohexane-1, 2-diamine in 1ml of toluene were stirred overnight at 115 ℃ under a nitrogen atmosphere. Diluted with chloroform, followed by Celite to remove insoluble matter, and the organic layer was washed with water and saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: chloroform/methanol) to give 163mg of an intermediate product.

80mg of the resulting intermediate was dissolved in 1.5ml of 1, 4-dioxane and 500. mu.l of chloroform, and 500. mu.l of 4N hydrochloric acid-dioxane solution and 10. mu.l of water were added thereto, followed by stirring at room temperature for 40 minutes. After concentration, the residue was azeotroped with chloroform and solidified with diethyl ether to give 65.6mg of the title compound as a white solid.

Reference example 105-hydroxypyridine-2-carbonitrile

Synthesis was carried out by combining reference example 6 (step 3) and (step 4).

Reference example 116- (methoxymethyl) pyridin-3-ol

(step 1) Synthesis of 5-benzyloxy-2-methylpyridine

140g of 3-hydroxy-6-methylpyridine was dissolved in 1.4L of dimethylformamide, and 178ml of benzyl chloride was added thereto under ice cooling, followed by stirring at room temperature overnight. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 40/1 → 2/1) to give 246.7g of the title compound as an orange oil.

(step 2) Synthesis of [5- (benzyloxy) pyridin-2-yl ] methanol

To a 2.8L chloroform solution of 246.7g of the obtained oily substance was added 335.8g of m-chloroperbenzoic acid under ice-cooling, and the mixture was stirred for 1 hour. The reaction mixture was washed with a 10% aqueous sodium carbonate solution and a saturated brine. After drying, the solvent was distilled off under reduced pressure, and 256.2g of pale yellow crystals were obtained by recrystallization (hexane/ethyl acetate).

To 266g of the crystals obtained, 600ml of acetic anhydride was added, the temperature was slowly raised, and the mixture was stirred at 120 ℃ for 20 minutes. The solvent was distilled off under reduced pressure, and then saturated sodium bicarbonate was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: hexane/ethyl acetate: 50/1 → 2/1) to give 259g of a light brown oil.

259g of the obtained oil was dissolved in 2L of ethanol and 500ml of water, and 80g of sodium hydroxide was added thereto, followed by heating and refluxing for 30 minutes. The solvent was distilled off under reduced pressure, and then 300ml of water was added to conduct extraction with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure, and 142.2g of the title compound was obtained as pale brown crystals by recrystallization (diethyl ether).

(step 3) Synthesis of 6- (methoxymethyl) pyridin-3-ol

169g of the resulting pale brown crystals were dissolved in 1.6L of tetrahydrofuran, and 37.7g of sodium hydride (30% liquid paraffin was added) was added thereto under ice cooling, followed by stirring at room temperature for 1 hour. 53.7ml of methyl iodide was slowly added dropwise under ice cooling, and stirred at room temperature overnight. Water was added thereto under ice cooling, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 60/1 → 2/1) to give 162.7g of an orange oil. 91.4g of the resulting oil was dissolved in 900ml of ethanol, and 13g of 10% palladium on carbon was added thereto, followed by stirring under a hydrogen atmosphere for 2 hours. After filtration, the solvent was distilled off under reduced pressure, and 53.0g of the title compound was obtained as pale yellow crystals by recrystallization (ethyl acetate/hexane).

Reference example 126- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyridin-3-ol

Synthesized according to the method described in European Journal of Pharmaceutical Science, Vol.15, No. 4, pages 367 to 378.

Reference example 136- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyridin-3-ol

Reference example 146- (1-methyl-1H-tetrazol-5-yl) pyridin-3-ol

(step 1) Synthesis of 4- (benzyloxy) -N-methylbenzamide

To a solution of 3g of 4-benzyloxybenzoic acid in 60ml of pyridine was added 1.77g of methylamine hydrochloride and 5.04g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and the mixture was stirred at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure, and the mixture was diluted with ethyl acetate and washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the product was crystallized from chloroform/hexane to obtain 2.272g of the title compound by filtration.

(step 2) Synthesis of 6- (1-methyl-1H-tetrazol-5-yl) pyridin-3-ol

1g of the resulting crystals were dissolved in 20ml of toluene, 0.36ml of thionyl chloride was added, and the mixture was stirred at 90 ℃ overnight. The solvent was distilled off under reduced pressure, and 10ml of acetonitrile, 0.54g of sodium azide and 1.1ml of chlorotrimethylsilane were added thereto and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate water and saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane → hexane/ethyl acetate 1/1) to give 0.75g of an intermediate product.

0.75g of the obtained intermediate was dissolved in 10ml of ethanol, and 30mg of palladium on carbon was added thereto, followed by stirring at room temperature under a hydrogen atmosphere. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform → chloroform/methanol 5/1) to give 0.24g of the title compound as crystals.

Reference example 156- (1, 3-oxazol-4-yl) pyridin-3-ol

(step 1) Synthesis of 4- (4-methoxyphenyl) -1, 3-oxazole

To 2g of 2-bromo-4' -methoxyacetophenone was added 10ml of formamide, and the mixture was stirred at 180 ℃ for 20 minutes. The reaction mixture was allowed to return to room temperature, and then diluted with ethyl acetate and washed with water and saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane → hexane/ethyl acetate 7/3) to give 0.76g of the title compound.

(step 2) Synthesis of 6- (1, 3-oxazol-4-yl) pyridin-3-ol

To 8ml of a chloroform solution of 0.76g of the obtained compound was added 12ml of a 1M boron tribromide dichloromethane solution under ice-cooling, and the mixture was stirred for 4 hours. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate 9/1 → 1/1) to give 0.36g of the title compound.

Reference example Synthesis of 166- (2-fluorophenyl) pyridin-3-ol

To a solution of 200mg of 1-iodo-4- (methoxymethoxy) benzene in 4ml of tetrahydrofuran obtained in reference example 11 (step 1), 127mg of 2-fluorophenylboronic acid, 1ml of an aqueous solution of 240mg of sodium carbonate, and 53.4mg of bis (triphenylphosphino) palladium dichloride were added, and the mixture was refluxed overnight under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution was added under ice cooling, followed by dilution with ethyl acetate and filtration through Celite to remove insoluble matter. Extraction was performed with ethyl acetate, and then the organic layer was washed with a saturated ammonium chloride aqueous solution and a saturated saline solution. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: hexane/ethyl acetate) to give 135mg of a colorless oil.

To 3ml of a 1, 4-dioxane solution of 67mg of the resulting colorless oil were added 750. mu.l of a 4N hydrochloric acid-dioxane solution and 10. mu.l of water, and the mixture was stirred at room temperature for 3 hours. After concentration, the mixture was azeotroped with chloroform to obtain 53.7mg of the title compound as a white solid.

Reference example 174 Synthesis of (2-methyl-2H-tetrazol-5-yl) phenol

Reference example 185 Synthesis of fluoropyridine-2-carboxylic acid

(step 1) Synthesis of 2-chloro-5-fluoropyridine

16.3ml of 42% tetrafluoroboric acid was added to a 50ml ethanol solution of 5g of 5-amino-2-chloropyridine under ice-cooling, and then a 10ml aqueous solution of 2.95g of sodium nitrite was slowly dropped thereinto and stirred for 10 minutes. The resulting solid was collected by filtration to obtain 9.9g of a yellow solid. 100ml of heptane was added thereto, and heated under reflux. After completion of the reaction, sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with diethyl ether, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: hexane/chloroform) to give 1.32g of the title compound as a pale yellow oil.

(step 2) Synthesis of Ethyl 5-fluoropyridine-2-carboxylate

To a solution of 1g of 2-chloro-5-fluoropyridine in 8ml of dimethylformamide and 8ml of ethanol were added 1.57g of potassium carbonate and 0.34g of 1, 3-bis (diphenylphosphino) propane, and 0.17g of palladium acetate, followed by stirring under carbon monoxide atmosphere at 90 ℃ for 2 hours. The reaction solution was filtered, the filtrate was extracted with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: hexane/ethyl acetate) to give 0.97g of the title compound as white crystals.

(step 3) Synthesis of 5-fluoropyridine-2-carboxylic acid

To a solution of 0.44g of ethyl 5-fluoropyridine-2-carboxylate in 5ml of tetrahydrofuran and 2ml of methanol was added 2.4ml of a 2.5N aqueous solution of sodium hydroxide, and the mixture was stirred at room temperature for 15 minutes. The mixture was neutralized with 10% aqueous citric acid solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure to obtain 0.41g of the title compound as white crystals.

Reference example 195 Synthesis of methoxypyridine-2-carboxylic acid

100mg of ethyl 5-fluoropyridine-2-carboxylate obtained in referential example 18 (step 2) was dissolved in 1ml of dimethylformamide and 1ml of methanol, and 163mg of potassium carbonate was added, followed by heating and stirring at 90 ℃ for 40 minutes. The mixture was neutralized with a 10% aqueous citric acid solution, extracted with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (developing solvent: hexane/ethyl acetate) to give 46.5mg of methyl 5-methoxypyridine-2-carboxylate as white crystals.

The resulting ester compound was dissolved in 0.5ml of methanol and 0.5ml of tetrahydrofuran, and 0.52ml of a 1N aqueous solution of sodium hydroxide was added thereto, followed by stirring at room temperature for 2 hours. The mixture was neutralized with a 10% aqueous citric acid solution, extracted with chloroform, and the organic layer was washed with saturated brine. After drying, the solvent was distilled off under reduced pressure to obtain 17.2mg of the title compound as white crystals.

Industrial applicability

The aryloxy-substituted benzimidazole derivative of the present invention represented by formula (I) or a pharmaceutically acceptable salt thereof exhibits excellent glucokinase activation, and thus is useful for the treatment and/or prevention of diabetes, diabetic complications, or obesity in the field of medicine.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

R³each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyalkyl group, a trisFluoromethyl, lower alkenyl or cyano,

R⁴independently represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a hydroxyalkyl group in which the hydrogen atom of the hydroxyl group may be substituted by a lower alkyl group, an aminoalkyl group in which the amino group may be substituted by a lower alkyl group, an alkanoyl group, a carboxyl group, a lower alkoxycarbonyl group or a cyano group,

R⁵and R⁶Each independently represents a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkyl group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, an alkanoyl group, a formyl group, an aryl group, a mono-or di-lower alkylcarbamoyl group or a mono-or di-lower alkylsulfamoyl group, or Q, R⁵And R⁶Formed together

(A) A 5-6-membered aliphatic nitrogen-containing heterocyclic group which may have one or two double bonds therein and which may have 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom within the ring, and which has at least one nitrogen atom in addition to the hetero atom;

(B) A 5-6-membered aromatic nitrogen-containing heterocyclic group which may have 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in the ring, and which has at least one nitrogen atom other than the hetero atoms; or

(C) A phenyl group,

the aliphatic nitrogen-containing heterocyclic group, the aromatic nitrogen-containing heterocyclic group or the phenyl group represents the following group: may have 1 to 3 groups selected from substituent group α, and/or may have, as a substituent, a 3 to 6-membered ring formed by bonding mutually bondable groups among the groups selected from substituent group α, and/or a group which is fusible with the group represented by formula (A),

(in the formula, wherein,represents a single bond or a double bondA key),

z represents an oxygen atom, a sulfur atom or a nitrogen atom,

(wherein X represents a carbon atom),

m represents an integer of 1 to 6,

n represents an integer of 0 to 3

q represents 0 or 1),

substituent group α:

oxo, thio, lower alkyl, lower alkoxy, alkanoyl, formyl, hydroxy, carboxy, trifluoromethyl, hydroxyalkyl (the hydrogen atom in the hydroxy may be substituted by lower alkyl), cyano, mono-or di-lower alkylcarbamoyl, lower alkylsulfinyl, lower alkylsulfonyl and a halogen atom;

Substituent group β:

lower alkyl, lower alkoxy, halogen atom, trifluoromethyl, hydroxyalkyl (the hydrogen atom of the hydroxyl group in the hydroxyalkyl may be substituted by lower alkyl), lower alkylsulfonyl, lower alkylsulfanyl, lower alkylsulfinyl, aminoalkyl (the amino group may be substituted by lower alkyl), alkanoyl, carboxyl, mono-or di-lower alkylcarbamoyl, mono-or di-lower alkylsulfamoyl, lower alkoxycarbonyl, cyano, and heteroaryl having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the aryl or the ring (the aryl and the heteroaryl may have one or two groups selected from the substituent group γ);

substituent group γ:

lower alkyl, lower alkoxy, halogen atom, hydroxy, lower alkylsulfonyl, lower alkylsulfinyl, alkanoyl, cyano, and mono-or di-lower alkylcarbamoyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a is thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl, or pyrimidinyl.

3. The compound of claim 1, wherein ring a is thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl or pyrimidinyl, and formula (I) is represented by the following formula (I-1):

(in the formula, the symbols are the same as those described above).

4. The compound of claim 1, wherein ring a is thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl or pyrimidinyl, and formula (I) is represented by formula (I-2):

(in the formula, the symbols are the same as those described above).

5. The compound of claim 1, wherein ring a is thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl or pyrimidinyl, and formula (I) is represented by formula (I-3):

(in the formula, the symbols are the same as those described above).

6. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein m is 1-4.

7. The compound according to claim 3, wherein Z is an oxygen atom or a sulfur atom, or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, which may be substituted by a group selected from the substituent group β.

9. A compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R⁵And R⁶Each independently, a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkyl group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, an alkanoyl group or a formyl group.

10. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein Q is a nitrogen atom.

11. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein Q is a carbon atom.

12. The compound according to claim 3, wherein the group represented by the formula (I-A) in the formula (I-1), or a pharmaceutically acceptable salt thereof

Is a group of the formula:

13. A compound of claim 3, wherein Q is a nitrogen atom and R is a pharmaceutically acceptable salt thereof⁵And R⁶Is a 5-6-membered aliphatic nitrogen-containing heterocyclic group (which may have one or two double bonds therein, the aliphatic nitrogen-containing heterocyclic group may be substituted by the same or different one or two groups selected from substituent group α 1), the 5-6-membered aliphatic nitrogen-containing heterocyclic group being the above-mentioned nitrogen atom, R⁵And R⁶Together, may have 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in the ring, at least one nitrogen atom in addition to the heteroatoms, m is 1, Z is an oxygen atom, Ar is phenyl or pyridyl (which may be substituted by one or two identical or different groups selected from substituent group β 1), R is ¹And R²Each independently is a hydrogen atom or a lower alkyl group,

substituent group α 1:

oxo, thioxo, lower alkyl, lower alkoxy, alkanoyl, a halogen atom, cyano and mono-or di-lower alkylcarbamoyl;

substituent group β 1:

lower alkyl, lower alkoxy, a halogen atom, trifluoromethyl, hydroxyalkyl (a hydrogen atom of a hydroxyl group in the hydroxyalkyl may be substituted by lower alkyl), lower alkylsulfonyl, alkanoyl, carboxyl, mono-or di-lower alkylcarbamoyl, mono-or di-lower alkylsulfamoyl, lower alkoxycarbonyl or cyano, or heteroaryl having 2 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in an aryl group or a ring (the aryl group and the heteroaryl group may have one or two groups selected from the substituent group γ).

14. The compound of claim 3Or a pharmaceutically acceptable salt thereof, wherein, Q, R⁵And R⁶Is a 5-6 membered aromatic nitrogen-containing heterocyclic group consisting of Q, R⁵And R⁶Taken together, at least one nitrogen atom (which may have 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in the ring other than the nitrogen atom), (the aromatic heterocyclic group or the phenyl group may have 1 to 3 groups selected from substituent group α 2), Z is an oxygen atom, Ar is a phenyl group or a pyridyl group (which may be substituted by one or two same or different groups selected from substituent group β 1), R ¹And R²Each independently is a hydrogen atom or a lower alkyl group,

substituent group α 2:

hydroxy, lower alkyl, lower alkoxy, alkanoyl, a halogen atom, cyano and mono-or di-lower alkylcarbamoyl;

substituent group β 1:

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein formula (I) is the following:

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein formula (I) is 1- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -5-thioxo-2-pyrrolidinone.

17. The compound of claim 1, wherein formula (I) is 4- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } morpholine-3, 5-dione, or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein formula (I) is 3- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -1, 3- チアゾラン -2, 4-dione, or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein formula (I) is 3- { [5- [4- (methylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -1, 3- チアゾラン -2-one, or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein formula (I) is 1- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } pyrrolidine-2, 5-dione, or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, wherein formula (I) is 1- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } -3-methyl-imidazolidine-2, 5-dione, or a pharmaceutically acceptable salt thereof.

22. A compound according to claim 1, wherein formula (I) is 2- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl ] methyl } isothiazolidine-1, 1-dioxide, or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1, wherein formula (I) is 3- { [5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyrazinyl) -1H-benzimidazol-6-yl ] methyl } -2-oxazolidinone, or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein formula (I) is 1- { [5- { [6- (ethylsulfonyl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1H-benzimidazol-6-yl ] methyl } pyrrolidine-2, 5-dione.

25. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein formula (I) is 1- [ (5- { [6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyridinyl ] oxy } -2- (2-pyridinyl) -1H-benzimidazol-6-yl) methyl ] -2-pyrrolidone.

26. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein formula (I) is N- ({5- [4- (ethylsulfonyl) phenoxy ] -2- (2-pyridyl) -1H-benzimidazol-6-yl } methyl) -N-methylacetamide.

27. The compound of claim 1, wherein formula (I) is 3- { [5- [4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenoxy ] -2- (2-pyridinyl) -1H-benzimidazol-6-yl ] methyl } -1, 3-oxazolidin-2, 4-dione, or a pharmaceutically acceptable salt thereof.

28. The compound of claim 1, wherein formula (I) is 5- [4- (ethylsulfonyl) phenoxy ] -6- ((2-methyl-2H-tetrazol-5-yl) methyl) -2- (2-pyridinyl) -1H-benzimidazole, or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1 wherein formula (I) is 5- [4- (ethylsulfonyl) phenoxy ] -6- (1- (1-methyl-1H-tetrazol-5-yl) ethyl) -2- (2-pyridyl) -1H-benzimidazole, or a pharmaceutically acceptable salt thereof.

30. The compound of claim 1, wherein formula (I) is 1- [ (6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyridin-2-yl-1H-benzimidazol-4-yl) methyl ] pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein formula (I) is 4- (2, 6-difluorobenzyl) -6- { [6- (ethylsulfonyl) pyridin-3-yl ] oxy } -2-pyrazin-2-yl-1H-benzimidazole.

32. A pharmaceutical composition comprising the following (1) to (3) for the treatment, prevention and/or delay of onset of type II diabetes:

(1) the compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof,

(2) 1 or 2 or more compounds selected from the following (a) to (h):

(a) other glucokinase activators,

(b) Biguanide, biguanide,

(c) PPAR agonists,

(d) Insulin, insulin,

(e) Somatostatin

(f) Alpha-glucosidase inhibitors,

(g) An insulin secretion promoter, and

(h) DP-IV inhibitors (dipeptidyl peptidase IV inhibitors),

(3) a pharmaceutically acceptable carrier.

33. A glucokinase activator comprising the compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof as an active ingredient.

34. A therapeutic and/or remedy for diabetes, which comprises the compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof as an active ingredient.

35. A therapeutic and/or prophylactic agent for obesity, which comprises the compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof as an active ingredient.