WO2004048341A1

WO2004048341A1 - Novel heteroaryl derivative

Info

Publication number: WO2004048341A1
Application number: PCT/JP2003/015197
Authority: WO
Inventors: Kantaro Ushiroda; Katsunori Maruta; Ryu Nagata
Original assignee: Sumitomo Pharmaceuticals Co., Ltd.
Priority date: 2002-11-28
Filing date: 2003-11-27
Publication date: 2004-06-10
Also published as: AU2003284479A1; JPWO2004048341A1

Abstract

A novel therapeutic agent for diabetes which is represented by the formula (1): (1) wherein ring Z represents one of the formulae (2): (2) wherein Ar1 represents optionally substituted arylene, etc.; Ar2 represents optionally substituted aryl, etc.; W1 represents optionally substituted C1-5 alkylene, etc.; X1 represents a single bond, oxygen, etc.; Y1 represents optionally substituted C1-5 alkylene, etc.; and R1 represents carboxy, etc.

Description

Specification

New heteroaryl derivatives

Technical field

The present invention relates to a novel heteroaryl derivative having an antidiabetic action or a salt thereof.

More specifically, the present invention relates to a novel heteroaryl derivative having an antiglycaemic effect that improves insulin resistance and controls blood glucose more safely. More specifically, a novel agent that has a peroxisome proliferator-activated receptor (PPAR) α-activating action, a PPARa-activating action, a PPARα / a-activating action, or a PPAR herring activation-regulating action. It relates to a heteroaryl derivative. Background art

The number of diabetics has been increasing steadily due to recent changes in lifestyle.In a survey conducted in Japan in 1997, 6.9 million people were strongly suspected of having diabetes and denied the possibility of diabetes It is estimated that 6.8 million people cannot. Most of the diabetic patients in Japan are classified as type 2 diabetes, whose basic condition is reduced insulin secretion and insulin resistance, and drugs have been developed for each condition.

For the decrease in insulin secretion ability, the long-known sulfonylprea (SU) agent is widely used, but there is a risk of severe hypoglycemia as a serious side effect and that obesity is likely to occur It has been known.

On the other hand, there are thiazolidinedione drugs as insulin sensitizers. Troglitazone was first launched as a thiazolidinedione drug, but was discontinued due to severe liver damage. In Japan, pioglizozone is currently used in clinical settings.However, as a serious side effect was reported as heart failure due to an increase in circulating plasma volume, emergency safety information was issued in October 2000. It has been shown that attention should be paid to heart failure and edema (Japanese clinical study, Vol. 59, 2228, 2 0 0 1). Oral siglisun, which is used in Europe and the United States, is also reported to have side effects such as upper respiratory tract infection, anemia, edema, and weight gain. Has not yet been released.

It is thought that thiazolidinedione drugs exert an antidiabetic effect by activating PPAR. It is known that P PAR has subtypes such as τ δ (/ 3). However, fibrates used as therapeutic agents for hyperlipidemia (such as clofibrate and fenofibrate) ) Is thought to exert pharmacological effects by activating PPARa. It has recently been reported that administration of a PPARa activator to animal models improves insulin resistance (Jornal of Biological Chemistry, Vol. 27, 166, 38, 2000). ), It is being shown that the PPARα activator may have a good effect not only on hyperlipidemia but also on diabetes mellitus.

Many compounds that activate PP AR or both a and γ have been reported in addition to thiazolidinedione drugs, such as isoxazolidinedione (Jornal of Medicinal Chemistry, Vol. 43, 527). , 2 000), however, its efficacy and safety in clinical settings are still unknown. Therefore, there is a strong need for a PPARα agonist, a PPARαagonist, a PPARα / argonist or a PPARα / α activation modulator which exhibits a good antidiabetic effect and is highly safe. Also, an antidiabetic agent having a pyrrole group in which the type of heterocycle is different from that of the present application is known (for example, see Japanese Patent Application Laid-Open No. 2002-121816, WO 02/085851). However, there is no report on its efficacy and safety in clinical settings. Disclosure of the invention

The problem to be solved by the present invention is to have an action of activating PPARa, an action of activating PPARa, an action of activating PPAR / a, or an action of regulating PPARhear activation to improve insulin resistance. Supply safe and safe diabetes prevention or treatment agents It is in.

The present inventors have conducted intensive studies and have found that a novel heteroaryl derivative activates PPARα, ΡPARr, or PPARa / a, or modulates PPARα / a activation to improve insulin resistance. As a result, the present inventors have found that while improving the hyperglycemic state, they are excellent in safety, and are useful for the prevention and treatment of diabetes, and completed the present invention.

The present invention relates to the following novel heteroaryl derivatives and salts thereof.

That is, the present invention

(1) Equation (1)

(Where the ring 式 is the formula (2)

(R ² and R ³ are each independently a hydrogen atom, a C, 1 group which may be substituted by a halogen atom; an alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or a halogen atom Or R ² and R ³ may combine with each other to form an optionally substituted ring)

Ar ¹ represents an optionally substituted arylene or an optionally substituted heteroarylene,

Ar ² represents an optionally substituted aryl or an optionally substituted heteroaryl, W ¹ shows an optionally substituted C ₅ alkylene, optionally substituted C ₂ _ _<5 Aruke two Ren, optionally substituted C ₂ - C ₅ alkynylene or, - Y- W ² one (wherein, Y represents an oxygen atom, a sulfur atom or NR,, W ² is optionally substituted C, one C ₅ alkylene, optionally substituted C ₂ - Ji ₅ Aruke two Ren, Represents an optionally substituted C ₂ -C ₅ alkynylene, and R represents a hydrogen atom, C, 1 C ₄ alkyl, or optionally substituted aryl, 1 C ₄ alkyl. And

X ¹ is a single bond, an oxygen atom, a sulfur atom, or

0

II

— S—

Represents

丫丄 represents ① ^ -alkylalkylene, ②may be substituted with a halogen atom, C, _C ₄ 7 alkyl or may be substituted with a halogen atom (:, —. 4 alkoxy, may be substituted.) Aryl, optionally substituted aryloxy, optionally substituted aryl C, —C ₄ alkyloxy, formylamino, C ₂ —C ₆ alkanoylamino, C, 1-C ₄ alkyl optionally substituted power Ruponiruokishi, C, - C ₄ it may also be substituted with Al kill I O carboxymethyl Cal Poni Rua amino, C, _ C ₄ alkyl optionally substituted force Rubamoiruokishi, hydroxyl, C, one c ₄ alkyl Cal Poni Le Okishi, C substituted by any group selected from a halogen atom or Shiano, - C ₅ § alkylene, ®C ₂ - (: ₅ Aruke two alkylene, C be substituted by ④ halogen atom, C ₄ alkyl, optionally substituted with a halogen atom 〇, - ₍₄ alkoxy, hydroxyl, C, one C ₄ alkyl force Ruponiruokishi, c ₂ which is substituted with a group of have Zureka selected from halogen atoms or Shiano - 〇 ₅ Aruke two Ren, ⑤ c ₂ - c ₅ alkynylene, ⑥ optionally substituted with halo gen atom C, one c ₄ alkyl, optionally substituted with a halogen atom C, one C ₄ alkoxy, hydroxyl, C ₂ — C ₅ alkynyl substituted by CC ^ alkylcarbonyloxy, halogen atom or cyano Emissions or ⑦ may be substituted by a halogen atom C,, - C ₄ alkyl, optionally substituted with Izu Re one of groups selected from a halogen atom in the optionally substituted _alkoxy, or Okiso Represents a C ₃ _C ₈ alkylene having a cyclic structure, and R ¹ is carboxyl, which may be substituted

Represents a substituent selected from alkylsulfonylcarbamoyl, optionally substituted arylsulfonylcarbamoyl, and tetrazolyl. Or a salt thereof.

)

A compound represented by the above (1) or a salt thereof.

(3) Ring Z is the formula (4)

A compound represented by the above (1) or a salt thereof.

(4) Ring Z is the formula (5)

A compound represented by the above (1) or a salt thereof.

(5) The compound represented by the above formula (1), wherein ring Z is phenylimidazole or benzimidazole, or a salt thereof.

(6) The compound represented by the above (1) to (5), wherein X ¹ is an oxygen atom, or a salt thereof. (7) The compound represented by the above (1) to (6), wherein R ¹ is carboxyl, or a salt thereof. (8) Y ¹ is a C, —C ₅ alkylene or (2) a C, —C ₄ alkyl optionally substituted with a halogen atom, optionally substituted with a halogen atom ((: ₄ alkoxy, substituted which may be Ariru, optionally substituted Ariruokishi, it may also be substituted I Ariru C, _C ₄ Arukiruokishi, Horumiruamino, C ₂ _C ₆ Arukanoiru Amino, optionally substituted with _〇 ₄ alkyl O alkoxycarbonyl Oxy,-oxycarbonylamino optionally substituted with C ₄ alkyl, carbamoyloxy optionally substituted with C, _C ₄ alkyl, hydroxyl, alkylcarbonyloxy, any one selected from halogen atom or cyano Or a salt thereof represented by any one of the above (1) to (7), which is 1 C ₅ alkylene substituted with a group represented by the formula:

(9) The compound represented by any one of the above (1) to (7), wherein Y ¹ is C—Cs alkylene, or C, mono (: ₅ alkylene substituted with (:, —. 4alkyl) or a salt thereof.

(10) The compound or a salt thereof represented by any one of the above (1) to (9), wherein W ¹ is an optionally substituted C ^ —Cs alkylene.

(1 1) W ¹ is an optionally substituted C ₂ - C ₅ 7 Luque two alkylene in the above (1) to (9

Or a salt thereof.

(12) A r ¹ is phenylene which may be substituted, and the bonding position of A r ¹ of X ¹ is

The compound or salt thereof according to any one of the above (1) to (11), wherein the compound is in the meta or para position with respect to the bonding position of W ¹ .

(13) A r ¹ is phenylene which may be substituted, and the bonding position of A r ¹ of X ¹ is

The compound or salt thereof according to any one of the binding position of W ¹ to a meta position (1) Single (1 1).

(14) A r ¹ is a good phenylene which may be substituted, the bonding position of A r ¹ X ¹ 'is a para-position to the bonding position of W ¹ (1) i (1 1) Or the salt thereof.

(15) W ¹ is trans C ₃ - (: ₄ Aruke a two lens, the bonding position of Ar ¹ of X ¹ The meta-position to the bonding position of W ¹ (1) i (9), (1 1), (1 3) noise or a salt thereof according to any misalignment.

(16) W ¹ is trans C ₃ - (: ₄ Aruke a two lens, the bonding position of A r ¹ of X ¹

The para-position to the bonding position of W ¹ (1) i (9), (1 1), (14) Neu compound or salt thereof according to any misalignment.

(17) W ¹ is a good Ci-Cs alkylene optionally substituted, eight 1 ^"1 binding position of ^1, the meta-position to the bonding position of W ^{1 (1)} - (10 ) Or the compound according to any one of (13) or a salt thereof.

(18) W ¹ is a good Ci_C ₅ alkylene optionally substituted, binding position of A r ¹ X ¹ ', the (1) in the para-position to the bonding position of W ¹ - (10) Or the compound according to any one of (14) or a salt thereof.

(19) 2-methyl-2- [4- (3- {2- [4- (trifluoromethyl) benzoyl] -1Η-benzimidazole-tolyl} propyl) phenoxy] propanoic acid, (2S)- 2- [3- (3- {4-methyl-2- [4- (trifluoromethyl) benzoyl] -1H-imidazole-triyl} propyl) phenoxy] propanoic acid, 2-methyl-2- [ 3- (4- {4-phenyl-2- [4- (trifluoromethyl) benzoyl] -1H-imidazole-1-yl} butyl) phenoxy] propanoic acid, 2- (3- {4- [ 2- (3-methoxybenzoyl) -4-phenyl-1H-imidazole-1-yl] butyl} phenoxy)-2-methylpropanoic acid, 2-methyl-2- (3-{(1E) -4- [2- (4-Methylbenzoyl) -1H-benzimidazol-1-yl] but-1-ene-1-yl} phenoxy) propanoic acid or 2-methyl-2- (3 -{3- [2- (4-Methylbenzoyl) -1H-benzimidazole-tolyl] propyle} phenoki ) Compound or its salt of the above (1), wherein the propanoic acid.

(20) A prodrug of the compound according to any one of (1) to (19).

(21) A medicament comprising the compound according to (1) to (19) and a prodrug thereof.

(22) PPARαagonist, PPARagonist or PPARα / argonist comprising as an active ingredient the compound according to (1) to (19) and a prodrug thereof. (23) A PPARr partial agonist, an engonist, or a PPARα activation modifier (Module-Ichiichi) comprising, as an active ingredient, the compound according to any of (1) to (19) and a prodrug thereof.

(24) A hepatic gluconeogenesis inhibitor comprising the compound according to (1) to (19) and a prodrug thereof as an active ingredient.

(25) An antidiabetic agent comprising the compound according to (1) to (19) and a prodrug thereof as an active ingredient.

(26) A method for treating diabetes comprising the compound according to (1) to (19) and a prodrug thereof as an active ingredient.

(27) Use of the compound according to any one of (1) to (19) and a prodrug thereof as an active ingredient for preparing a therapeutic agent for diabetes.

The definition of the heteroaryl derivative represented by the formula (1) according to the present invention in the formula will be specifically described below.

Examples of the “C _t —C ₄ alkyl” of “C, 1 C ₄ alkyl” or “C—C alkyl optionally substituted with a halogen atom” in YR include, for example, linear or branched Ci—C ₄ alkyl, specifically, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, etc., and more preferably, methyl, ethyl, 1-propyl, 2-propyl Is mentioned.

The “C, 1. Alkyl” in R ² and R ³ is, for example, a linear or branched C 1. Alkyl, specifically, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, t-butyl, 1-pentyl, 2-hexyl, 1-heptyl, Examples include 1-octyl, 1-nonyl, 1-decyl, and more preferably, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, t-butyl, and 1-pentyl. . More preferably, methyl and ethyl are mentioned. Of the "optionally substituted C, one C ₄ alkylsulfonylcarbamoyl"

Examples of the “alkyl” include linear or branched Ci— ^ alkyl, and specific examples include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl and the like. And more preferably, methyl, ethyl, 1-propyl and 2-propyl.

"Ariru C, _C ₄ alkyl", or "Ariru C, one C ₄ Arukiruokishi" as "C, one C ₄ alkyl" is for example a straight or branched chain Flip E - Ji alkyl are mentioned, specifically Examples include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, and the like, and more preferably, methyl and ethyl.

The “C, 1C ₄ alkoxy” for Y ¹ includes, for example, a linear or branched Ci—C ₄ alkoxy, specifically, methoxy, ethoxy, propoxy, butoxy and the like, and more preferably. Includes methoxy and ethoxy.

RA r YR, “optionally substituted aryl”, “optionally substituted aryloxy”, “optionally substituted aryl” —C ₄ alkyloxy ”in R ² and R ³ ,“ is set to "Ariru" of the optionally substituted § Li one also be Rusuru Honi carbamoyl "or" substituted Ariru CI- C ₄ alkyl ", include for example phenyl, 1-naphthyl, 2-naphthyl and And preferably phenyl.

The “heteroaryl” in A r R ² and R ³ includes, for example, a monocyclic or bicyclic monocyclic or bicyclic heterocycle containing 1 to 3 heteroatoms arbitrarily selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. And heteroaryl. Specifically, monocyclic 5-membered heteroaryl such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, and isooxazole, monocyclic 6-membered such as pyridine, pyrimidine, pyrazine, pyridazine, triazine, etc. Membered heteroaryl, indole, isoindole, indolizine, indazole, purine, 4-H-quinolidine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline And bicyclic heteroaryls such as benzthiazole, benzoxazole, benzofuran, benzothiophene and benzimidazole, and more preferably pyridin, thiophene, indole, benzthiazole, benzoxazole, benzofuran, Benzothiophene.

Examples of “arylene” in Ar ¹ include C ₆ —C ₁₀ arylene, specifically, 1,3-phenylene, 1,4-phenylene, and naphthene. Len-1,3-zil, Naphne 1,1,4-zil and the like. Preferred are 1,3-phenylene and 1,4-phenylene.

As "Heteroari one Ren" in A r ^1, for example, nitrogen atom, oxygen atom, from 1 selected arbitrarily from the group consisting of sulfur atoms 3 of the monocyclic containing hetero atoms or bicyclic into the Terrorism; Specifically, monocyclic 5-membered heteroarylenes such as thiophen-zyl, furan-zyl, and pyrroyl-zilyl, pyridine-diyl, pyrimidine-zil, pyrazine-diyl, pyridazine-diyl, and triazine-diyl-like Cyclic 6-membered heteroarylene, indole-zil, isoindyl-zyl, indolizine-zil, indazoyl-zyl, pudding-zyl, 4-H-quinolidine-dzyl, quinoline-dzyl, isoquinoline-dzyl, phthalazine And bicyclic heteroaryls such as benzyl, naphthyridine-diyl, quinoxaline-diyl, quinazoline-diyl, benzothiazole-diyl, benzoxazol-diyl, benzofuran-diyl and benzothiophen-diyl, and more preferred. Or Chioffen Jiiru, pyridine over Jiiru, Ru pyrimidine one Jiiru can be mentioned.

Examples of the “c, _c ₅ alkylene” for W ² include straight-chain or branched-chain mono-c ₅ alkylene, and specific examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and propane. Examples thereof include 1,2-diyl and butane-1,1,3-diyl, and more preferred examples include methylene, ethylene, trimethylene, and tetramethylene. The “C, —C ₅ alkylene” for Y ¹ includes, for example, straight-chain or branched-chain Ci—c ₅ alkylene, and specifically, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, propane 1 1 , 2-diyl, butane-1,1,3-diyl, etc., more preferably, methylene, ethylene, trimethylene, and tetramethylene, and further preferably, methylene.

, "C ₂ - (3 ₅ Aruke two Len" in W ^2, Y ¹ as the, C ₂ straight-chain or branched - C ₅ alkenylene and the like, in particular cis- or trans - vinylene, cis or Trans-1-probenylene, cis or trans-2-propenylene, cis or trans-1-butenylene, cis or trans-1-butenylene, cis or trans-3-butenylene, cis or trans-13-methyl 12-propenylene, cis or trans-12-methyl-2-probenylene, cis or trans-11-methyl-12-probenylene and the like, and more preferably, trans-1- Probenylene, trans-11-butenylene.

Examples of “c ₂ _c ₅ alkynylene” in, W ² and Y ¹ include straight-chain or branched C ₂ _C ₅ alkynylene, and specifically include ethinylene, 1-propynylene, and 3-methyl-1-alkyl. —Propynylene, 2-propynylene, and the like, more preferably, 1-propynylene.

As the “C ₂ —C ₆ alkanoylamino” for Y ¹ , for example, a linear or branched C ₂ —C ₆ alkanoylamino can be mentioned, and more preferably acetylamino, propanoylamino, and bushinoylamino. And pentanoylamino.

"R ² and R ^3, taken together, ring which may be substituted" as the "ring" of, heptyl cyclobutyl, cyclopentyl, hexyl, cyclohexane cyclopentane, sik clever speech corruptible, phenyl, pyridyl, naphthyl And the like, but preferably include phenyl, pyridyl, and cyclohexyl.

The “halogen atom” includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. "Optionally substituted by a halogen atom C, one C ₄ alkyl" in Y ¹ "C substituted with halo gen atom, one C ₄ alkyl" is replacement in the "halogen atom in R ^2, R ³ which may be C, one C ₁₀ alkyl C substituted with "halogen atoms", - it includes C ₁₀ alkyl ", fluorine atom, chlorine atom, alkyl of straight or branched Edakusari substituted by a bromine atom Specific examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and the like, more preferably trifluoromethyl and 2,2,2-trifluoroethyl. Can be

"C substituted with C androgenic atoms, one C ₄ alkoxy" of the "halogen good Ci-C alkoxy optionally substituted with atoms" in Y ¹ as a fluorine atom, a chlorine atom, a straight substituted with bromine Specific examples include a chain or branched chain C ₄ alkoxy, and specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy. Methoxy, 2,2,2-trifluoroethoxy.

The "Ariru one C ₄ Arukiruokishi" in Y ^1, for example, base Njiruoki shea, Fuenechiruokishi, 2 _ phenylalanine propoxy, 3-phenylpropyl propoxy, 4_ Fuenirubutokishi, 1 one naphthylmethoxy, 2-naphthylmethoxy and the like.

In Y ¹ as "C, one C ₄ which may O alkoxycarbonyl O carboxymethyl also be substituted with alkyl" include straight or branched chain Flip the E one C ₄ alkoxy force Lupo two Ruokishi is ani Gerare, specifically Specific examples include methoxycarbonyloxy, ethoxycarbonyloxy, 1-propoxycarbonyloxy, 2-propoxycarbonyloxy, 1-butoxycarbonyloxy, 2-butoxycarponyloxy, and the like. More preferably, Examples include methoxycarbonyloxy, ethoxycarbonyloxy, and 11-propoxycarbonyl.

As the “oxycarbonylamino optionally substituted with d—C ₄ alkyl” for Y ¹ , for example, a linear or branched Ci—C ₄ alkyloxycarbonylamino can be mentioned. Is methoxycarbonylamino, ethoxycarbonylamino 1-propoxycarbonylamino, 2-propoxycarbonylamino, 1-butoxycarbonylamino, 2-butoxycarbonylamino and the like, more preferably methoxycarbonylamino, ethoxycarbonylamino, _Propoxy force Luponylamino.

In Y ^1: as a "(one C ₄ alkyl optionally substituted force Rubamoiruokishi", for example linear or branched 〇 E one C ₄ alkyl force Rubamoiruokishi is exemplified et al are specifically Are methylcarbamoyloxy, dimethylcarbamoyloxy, ethylcarbamoyloxy, getylcarbamoyloxy, 1-propyl rubamoyloxy, 2-propyl rubamoyloxy, 1-butyl carbamoyloxy, 2-butyl carbamoyloxy And more preferably, methyl carbamoyloxy, ethyl carbamoyloxy, 1-propyl rubamoyloxy.

The “., — 04 alkylcarbonyloxy” for Y ¹ includes, for example, straight-chain or branched-chain alkylcarbonyloxy, and specific examples thereof include methylcarbonyloxy, ethoxylcarbonyl, 1-propylcarbonyloxy, 2-propylpyrucarbonyloxy, 1-butylcarbonyloxy, 2-butylcarbonyloxy, and the like, more preferably, methylcarbonyloxy, ethylcarboxy, 1-propylcarbonyl Oxy.

Examples of the “C ₃ —C ₈ alkylene having a cyclic structure” in Y ¹ include those having a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl group, for example, those shown below.

« As the “C, 1C ₄ alkylsulfonylcarbamoyl” for R ¹ , for example, a linear or branched Ci—

Examples of the alkyl include, specifically, methylsulfonylcarbamoyl, ethylsulfonylcarbamoyl, 1-propylsulfonylcarbamoyl, 2-propylsulfonylcarbamoyl, 1-butylsulfonylcarbamoyl, and 2-butylsulfonylcarbamoyl. More preferred are methylsulfonylcarbamoyl, ethylsulfonylcarbamoyl, 1-propylsulfonylcarbamoyl, and 2-propylsulfonylcarbamoyl.

The “arylsulfonylcarbamoyl” for R ¹ includes, for example, phenylsulfonylcarbamoyl, 1-naphthylsulfonylcarbamoyl, 2-naphthylsulfonylcarbamoyl and the like, preferably phenylsulfonylcarbamoyl.

Examples of “aryl C, —C ₄ alkyl” for R include benzyl, phenyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl, and the like. Preferable examples include benzyl and phenyl.

Ganmaupushiron Ariruokishi may be substituted in the ¹ ", Ariru may be substituted in Ganmaupushiron ¹ C, one C ₄ Arukiruokishi", "R ² and R ^3, taken together, ring which may be substituted""Ar ^2, YR ² and Ariru substituted at R ^3", "A r ^2, Te Roariru R ² and the optionally substituted in R ³ ', substituted in the" A r ¹ which may be Ariren "," Teroari one Ren also to the good have been your Keru replaced by Ar '", which may have been not good § Li one Rusuru Honi carbamoyl substitutions in the FR ^1", be substituted in the ^"1 . good C, _ C ₄ alkylsulfonylcarbamoyl "," which may § Li one also be-substituted in R ₁ _ Ji _alkyl "may be substituted in the" WW ² C, - C ₅ Aruki Len "," WW C ₂ _C may be substituted in the ² ₅ 7 Luque two Ren "," W The “substituent” of the optionally substituted C ₂ -C ₅ alkynylene in W ² includes a halogen atom, a hydroxyl group, an optionally substituted alkyl, an optionally substituted alkenyl, and a substituted Aryl, optionally substituted heteroaryl, formyloxy, alkanoyloxy, cyano, formyl, alkanol, optionally substituted alkoxy, alkoxycarbonyl group, carboxyl group, and optionally substituted alkyl Good amino, cyclic amino, alkoxyalkyl-substituted amino, alkyl-substituted rubamoyl, cyclic aminocarbonyl, alkyl-substituted sulfamoyl group, cyclic aminosulfonyl group, alkylsulfonyl group, Arylsulfonyl group, a And alkylthio groups, more preferably a halogen atom, a hydroxyl group, an optionally substituted alkyl, an optionally substituted alkoxy, a cyclic amino, and an alkoxyalkyl-substituted amino. Can be More preferably, a halogen atom, an optionally substituted alkoxy, an optionally substituted alkyl, and a cyclic amino are exemplified. The number of substituents may be one or more, and is preferably from 1 to 2. When there are a plurality of substituents, they may be the same or different.

Examples of the halogen atom of the “substituent” include fluorine, chlorine, bromine and iodine, and more preferably fluorine and chlorine.

Examples of the alkyl which may be substituted in the above-mentioned "substituent" include a linear or branched C i-C e alkyl which may be substituted, and specifically, methyl, ethyl, and propyl , Butyl, pentyl, 2-propyl, 2-methyl-1-propyl, 2-butyl, t-butyl, 3-methyl-2-butyl, 2-methyl-2-butyl, hexyl, trifluoromethyl, methoxy Methyl, 1-methoxy-2-ethyl, morpholinometyl and the like are more preferable, and methyl, methyl, 1-propyl, 2-propyl, 2-methyl-1-propyl, 1-pentyl and trifluoromethyl are more preferable. Be Examples of the alkenyl which may be substituted as the “substituent” include linear or branched C ₂ -C ₆ alkenyl, and specific examples thereof include vinyl, 2-probenyl and 1-probenyl. N-yl, 2-butenyl, 1-butenyl, and 2-methyl-1-propenyl, and more preferably 2-proenyl, 2-butenyl, and 2-methyl-1-proenyl.

Examples of the aryl which may be substituted for the "substituent" include, for example, phenyl, p-chlorophenyl, m-chlorophenyl, o_chlorophenyl, p-fluorophenyl, m-fluorophenyl, o-fluoro Phenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, ρ_methylphenyl, m-methylphenyl, o_methylphenyl, p-trifluoromethylphenyl, m-trifluoromethylphenyl, 0-trifluoro And more preferably phenyl, p-chlorophenyl, p-methoxyphenyl, p-methylphenyl, p-trifluoromethylphenyl.

Examples of the optionally substituted heteroaryl of the `` substituent '' include 1 to 3 arbitrarily selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, which may have a substituent. Monocyclic or bicyclic heteroaryl containing a heteroatom is mentioned. Specifically, thiophene, furan, pyrrol, imidazole, pyrazole, thiazol, oxazole, isothiazol, isoxoxazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine, indole, isoindole, indine Unsubstituted heteroaryl such as drizine, indazole, purine, 4-H-quinolidine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, benzothiazole, benzoxazole, benzofuran, benzothiophene, or 2-methylthiophene, 2 — Substituted heteroaryls such as furan, 2-methylpyrrol, 4-methylimidazole, 2-chloropyridine, 2-chloroindole, and 3-bromoquinoline; and more preferably Benzene, pyridine, pyrimidine, indole, benzothiazole, benzoxazole, benzofura And benzothiophene.

Examples of the alkanoyloxy of the “substituent” include straight-chain or branched-chain C ₂ -C ₆ alkanoyloxy, more preferably acetyloxy, propanoyloxy, butanoyloxy, isobutanoyloxy. Pentanoyloxy and hexanoyloxy.

Examples of the alkanoyl of the above “substituent” include straight-chain or branched-chain C ₂ — (: ₆ alkanol, and more preferably acetyl, propanoyl, butanoyl, isobutynoyl, pentanoyl, hexanoyl. Is mentioned.

Examples of the optionally substituted alkoxy of the “substituent” include, for example, an optionally substituted linear or branched mono-C ₈ alkoxy. Specifically, methoxy, ethoxy, propoxy, 2- Proboxy, 2-methyl-propoxy, butoxy, pentyloxy, hexyloxy, cyclopentyloxy, cyclohexyloxy, cyclohexylmethoxy, 1-methoxy-12-ethoxy, 1-morpholino1-2-ethoxy, 1-thiomorpholino-2-ethoxy , 1-piberidino 2-ethoxy, trifluoromethoxy, etc., and more preferably, methoxy, ethoxy, 2-propoxy, cyclopentyloxy, 1-morpholino-2-ethoxy, trifluoromethoxy. In addition, when there is an adjacent alkyl or alkoxy, a ring having a substituent and the adjacent group may be formed. Specifically, methylenedioxy, ethylenedioxy, 2-methyl-methylenedioxy, 2 —Methyl-ethylenedioxy, 1-hydroxy-12-ethylene, 1-oxy-2-propylene and the like, and more preferably, methylenedioxy and ethylenedioxy.

Examples of the alkoxycarbonyl of the “substituent” include, for example, a linear or branched C ₂ _C ₆ alkoxycarbonyl group, more preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, 2 —Methyl-1-propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl. Examples of the above-mentioned “substituent” which may be alkyl-substituted include, for example, a linear or branched C i -C ₆ alkylamino or a linear or branched C ₂ -C ₂ dialkylamino. Is mentioned. The linear or branched C ^ -C e alkylamino preferably includes methylamino, ethylamino, propylamino, 2-propylamino, and butylamino. Examples of the linear or branched C ₂ -C ₁₂ dialkylamino include amino substituted with the same or different alkyl, and more preferably dimethylamino, getylamino, dipropylamino, diisopropyl. Amino, dibutylamino, ethylmethylamino, methylpropylamino, butylmethylamino, ethylbutylamino, dicyclohexylamino.

Examples of the cyclic amino of the `` substituent '' include a 5- to 7-membered cyclic amino which may contain an oxygen atom, a sulfur atom, or a nitrogen atom as a ring-constituting atom. It may be substituted with an alkyl, a hydroxyl group or the like. Specific examples include pyrrolidino, piperidino, piperazinyl, 4-methylbiperazinyl, morpholino, thiomorpholino, and 4-hydroxypiperidino, and more preferably, morpholino and 4-hydroxypiperidino. Can be

As the alkoxyalkyl optionally substituted Amino the "substituent", eg if straight or C ₂ _ C ₈ alkoxyalkyl optionally substituted amino branched may be mentioned, specifically 2 —Methoxyethylamino, 2-Ethoxyethylamino, 2-Proboxyethylamino, 2-Isopropoxyethylamino, 2-Butoxyethylamino, 2-Cyclohexyloxyamino, 2-methoxy-1-methylethylamino, 2-methoxy-1-methylethylamino, and more preferably, 2-methoxyethylamino, 2-propoxyshetylamino, and 2-isopropanol. Quichetilamino.

Examples of the optionally substituted alkyl rubamoyl of the above “substituent” include linear or branched C ₂ —C ₆ alkylaminocarbonyl or linear or branched C ₃ _C i ₂ dialkyl And aminocarbonyl. Straight or branched chain C _2- More preferably, C ₆ alkylaminocarbonyl includes methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, 2-propylaminocarbonyl, and butylaminocarbonyl. Examples of the straight-chain or branched-chain C ₃ -C ₁₂ dialkylaminocarbonyl include rubamoyl substituted with the same or different alkyl, and more preferably dimethylamino propylonyl, dimethylaminocarbonyl, Dipropylaminocarbonyl, diisopropylaminocarbonyl, dibutylaminocarbonyl, ethylmethylaminocarbonyl, methylpropylaminocarbonyl, butylmethylaminocarbonyl, ethylbutylaminocarbonyl, dicyclohexylaminocarbonyl. .

Examples of the cyclic aminocarbonyl group of the “substituent” include a 5- to 7-membered cyclic aminocarbonyl which may contain an oxygen atom, a sulfur atom, or a nitrogen atom as a ring-constituting atom. May be further substituted with an alkyl, a hydroxyl group or the like. Specific examples include pyrrolidinocarbonyl, piperidinocarbonyl, piperazinylcarbonyl, 4-methylbiperazinylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, 4-hydroxypiperidinocarbonyl, and more preferably. Include morpholinocarbonyl and 4-hydroxypiperidinocarbonyl.

The alkyl optionally substituted sulfamoyl group "substituent", eg if linear or branched C i-C ₆ alkylamino sulfonyl or straight-chain or branched Flip ₂ _〇 _{1 2} dialkyl Aminosulfonyl; More preferred are methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, 2-propylaminosulfonyl, and butylaminosulfonyl. Examples of the linear or branched C ₂ -C ₁₂ dialkylaminosulfonyl include sulfamoyl substituted with the same or different alkyl, and more preferably dimethylaminosulfonyl, getylaminosulfonyl, dipropylaminosulfonyl , Diisopropylaminosulfonyl, dibutylaminosulfonyl And methylethylaminosulfonyl, methylpropylaminosulfonyl, butylmethylaminosulfonyl, ethylbutylaminosulfonyl and dicyclohexylaminosulfonyl.

Examples of the cyclic aminosulfonyl group of the “substituent” include a 5- to 7-membered cyclic aminosulfonyl which may contain an oxygen atom, a sulfur atom, or a nitrogen atom as a ring-constituting atom. Sulfonyl may be further substituted with alkyl, hydroxyl group and the like. Specific examples include pyrrolidinosulfonyl, piperidinosulfonyl, piperazinylsulfonyl, 4-methylpiperazinylsulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, and 4-hydroxypiperidinosulfonyl. More preferred are morpholinosulfonyl and 4-hydroxypiberidinosulfonyl.

Examples of the alkylsulfonyl group of the “substituent” include a linear or branched C i-Ce alkylsulfonyl group, and specifically, methylsulfonyl, ethylsulfonyl, 1-propylsulfonyl, 2 —Propylsulfonyl, 1-butylsulfonyl, 2-butylsulfonyl and the like, more preferably methylsulfonyl and 2-propylsulfonyl.

Examples of the arylsulfonyl group of the above “substituent” include benzenesulfonyl, p-toluenesulfonyl, p-chlorobenzenesulfonyl, p-fluorobenzenesulfonyl, p-methoxybenzenesulfonyl, p-methoxybenzenesulfonyl, and p-trifluoromethylbenzene Examples include sulfonyl, m-chlorobenzene benzenesulfonyl, and 0-chlorobenzenebenzenesulfonyl, and more preferably benzenesulfonyl, p-chlorobenzenebenzenesulfonyl, p-methoxybenzenesulfonyl, and p-trifluoromethylbenzenesulfonyl. Can be

Examples of the alkylsulfonyloxy of the “substituent” include linear or branched C i-Ce alkylsulfonyloxy, and specific examples include methylsulfonyloxy, ethylsulfonyloxy, and Propylsulfonyloxy, 2 —Propylsulfonyloxy, 1-butylsulfonyloxy, 2-butylsulfonyloxy and the like, more preferably methylsulfonyloxy and 2-propylsulfonyloxy.

Examples of the alkylthio group as the “substituent” include a straight-chain or branched-chain C ₆ alkylthio group. Specific examples include methylthio, ethylthio, propylthio, butylthio, pentylthio, 2-propylthio, and 2-propylthio. —Methyl_1-propylthio, 2-butylthio, t-butylthio, 3-methyl-2-butylthio, 2-methyl-2-butylthio, hexylthio, etc., more preferably, methylthio, ethylthio, and 2-propylthio. No.

As the pharmaceutically acceptable salts, when the heteroaryl derivative of the present invention has an acidic group, examples thereof include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, zinc, and the like. And inorganic bases such as salts, organic bases such as triethylamine, triethanolamine, tris (hydroxymethyl) aminomethane, and amino acids. When the heteroaryl derivative of the present invention has a basic group, examples thereof include inorganic salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate, and acetate, propionate, and succinic acid. Organic salts such as salt, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, and ascorbate The present invention also includes a prodrug of a heteroaryl derivative represented by the formula (1). Further, the present invention also includes a heteroaryl derivative or a prodrug of the formula (1), or a hydrate of such a pharmaceutically acceptable salt thereof, or a solvate thereof such as an ethanol solvate. Refers to those which are chemically or biochemically hydrolyzed in vivo to regenerate the compound of the present invention. For example, when the heteroaryl derivative of the present invention has a carboxyl, a compound in which the lipoxyl is converted to an appropriate ester is obtained. No. Specific examples of this ester include methyl ester, ethyl ester, 1-propyl ester, 2-propyl ester, pivaloyloxymethyl ester, acetyloxymethyl ester, cyclohexyl acetyloxymethyl ester, 1-methylcycloalkyl ester Examples include hexyl carbonyloxy methyl ester, ethoxy carboxy oxy-1-ethyl ester, cyclohexyl carbonyl carbonyloxy 1-ethyl ester, and the like.

The heteroaryl derivative of the present invention can be produced, for example, by the production method (1) described in detail below or a method analogous thereto.

The compounds used as the starting compounds may each be used as a salt. Such salts include pharmaceutically acceptable salts.

The heteroaryl moiety of the heteroaryl derivative of the present invention can be prepared by a method known per se, for example, The Chemistry of Heterocyclic Compounds (eg, a pyrazole derivative: Vo 1.22; an imidazole derivative: vo 1.6 parti; Triazole derivatives: vo 1.6 arti; indazole derivatives: V o 1.22; benzimidazole derivatives: V 01. 40 part 1, part 2 etc.), Methodender Organischen Chem ie (Ho ube n-We y 1) (eg, pyrazole derivative: Hetarene III, TEIL 2, E8 b, p 399-710; imidazole derivative: Hetarene III, TE IL 3, E8 c , pl -215; Triazole derivative: He tarene II, TE IL 2, E7 b, p 286-686; Indazole derivative: He tarene III, TE IL 2, E 8 b, P 764-856; Benzimidazole derivative: He tarene III, TE IL 3, E8 c, p 216—391, etc.), Comprehensive Heteroc yclic Ch emi stry (for example, 5 derivatives; indazole derivatives: vol. 5; imidazole derivatives, benzimidazole derivatives: Vo 1.5; triazole derivatives: Vo 5; Comprehensive Heterocyclic Chemistry II (for example, pyrazole derivative, indazole derivative: vol.3; imidazole derivative, benzimidazole derivative: Vo1.3; triazole derivative: Vo1. 4), heterocyclic compound chemistry (Kodansha, 1988), New Experimental Chemistry Lecture Vol. 14 [IV] (Maruzen, 1977), or a method similar thereto. be able to.

Manufacturing method (1)

)

The heteroaryl derivative of the formula (1) can be produced by bonding at the ad portions. The method for forming the bond of the a-d portion can be exemplified as in the production method (1-1-1) -1 (1-4). Note that these reactions are merely examples, and can be produced by other methods as appropriate based on the knowledge of those skilled in organic synthesis. The order of bond formation of the a-d portion can be appropriately changed.

In each of the subsequent reactions, a functional group can be protected as necessary. Protecting groups and their protection and deprotection techniques are described in detail in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2nd Ed., John Wiley and Sons, inc., New York (1991).

Manufacturing method (1-1) Bonding Method for manufacturing part a

0

^ HO 儿丫¹ -X ¹ -Ar ¹ -Q ¹

(104)

(In the formula, Ar ¹ , X ¹ , and Y ¹ have the same meanings as described above, R ^1G represents an alkoxy group such as methoxy and ethoxy, an alkylamino such as morpholine, and a hydroxyl group, and L ¹ represents a chlorine atom or bromine. An atom, a halogen atom such as an iodine atom, a leaving group such as trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy, and Q ¹ represents an organic group.)

Compound (100) and compound (101) are described in, for example, Experimental Chemistry Course 19-26 (Maruzen, published in 1992), precision organic synthesis (Nankodo, published in 1983), Co Immediate endium of Organic Synthetic Methods, Vol. 1-9 (John Wiley & Sons), Co-immediate rehensive Organic Synthesis, Vol. 1-9 (1991, Pergamon Press), Comprehensive Organic Transformations (1989, VCH Publishers), etc. It can be manufactured by a method.

When X ¹ represents an oxygen atom or a sulfur atom, compound (102) can be obtained by reacting compound (100) with compound (101) in an inert solvent in the presence of a base. Examples of the inert solvent include ether solvents such as ether, tetrahydrofuran (THF), and dioxane; hydrocarbon solvents such as toluene, benzene, and xylene; and halogens such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride. Aprotic solvents such as fluorinated hydrocarbon solvents, dimethyl sulfoxide, N, N-dimethylformamide, and acetonitrile. These solvents may be used by mixing two or more kinds in an appropriate ratio. As the base, for example, sodium hydride, potassium hydride Examples include metal hydrides such as platinum, metal carbonates such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, and cesium carbonate; alkylamines such as triethylamine and ethyldiisopropylamine; and metal alkoxides such as sodium methoxide. The reaction temperature is selected from the range of about 120 to about the boiling point of the solvent, preferably the range of about 0 to about the boiling point of the solvent.

When X ¹ is a sulfur atom, compound (1 0 3) is obtained in Rukoto by reacting the compound (1 0 2) and an oxidizing agent.

Examples of the oxidizing agent include organic peracids such as perbenzoic acid and perbenzoic acid, organic peroxides such as t-butyl peroxide, oxone, sodium periodate, and hydrogen peroxide.

When R ^{1 Q} is other than a hydroxyl group, the compound (104) can be obtained by using a usual deprotection technique for the compound (102). For example, it can be obtained by a hydrolysis reaction in the presence of an acid or a base.

Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, trifluoroacetic acid, methanesulfonic acid and the like.

Examples of the solvent include ether solvents such as ether, THF, and dioxane; aprotic solvents such as acetone, dimethyl sulfoxide, N, N-dimethylformamide, and acetonitrile; and alcohol solvents such as methanol and ethanol. For example, one or more solvents and water may be mixed in an appropriate ratio and used, or may be used without a solvent.

The reaction temperature is selected from the range of about −20 ° C. to around the boiling point of the solvent, and preferably from about 10 to about the boiling point of the solvent.

Examples of the base include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; and metal carbonates such as potassium carbonate, sodium carbonate, potassium hydrogencarbonate, and sodium hydrogencarbonate. Done in

Examples of the aqueous solvent include ether solvents such as ether, THF, and dioxane; A mixed solvent of one or more solvents selected from aprotic solvents such as acetone, dimethyl sulfoxide, N, N-dimethylformamide, and acetonitrile, and alcohol solvents such as methanol and ethanol, and an appropriate ratio of water. Used.

The reaction temperature is selected from the range of about 120 to about the boiling point of the solvent, and preferably ranges from about -1 O: to about the boiling point of the solvent.

Manufacturing method (1-1-2) Bonding Method for manufacturing part b

^{^{^{Q 2 - X 1 - Ar 1}}} - tooth ² HW ¹ - Q ³

Q ²

(108) (109)

^{(Wherein, Ar L, X 1 · Y} , WW 2 has the same meaning as above, L ² represents a chlorine atom, a bromine atom, a halogen atom such as iodine atom, a triflate Ruo b methanesulfonyl Ruo key sheet, Q ² and Q ³ represent an organic group.)

Compound (105), Compound (106), Compound (108), Compound (109) are, for example, Experimental Chemistry Course 19-26 (Maruzen, published in 1992), Precision Organic Synthesis (Nankodo, published in 1983) ), Compendium of Organic Synthetic Methods, Vol. 1-9 (John Wiley & Sons), Comprehensive Organic Synthesis, Vol. 1-9 (1991, Pergamon Press), Comprehensive Organic Transformations (1989, VCH Publ ishers)), etc. It can be manufactured by the method described above or a method according to it.

Compound (107) can be produced by reacting compound (105) with compound (106) or by reacting compound (108) with compound (109).

Compound (105) is reacted with compound (106) in an inert solvent in the presence of a transition metal catalyst and a base to give compound (107).

Examples of inert solvents include ether solvents such as THF, dioxane, and dimethoxyethane. Solvents, hydrocarbon solvents such as toluene, benzene, and xylene; aprotic solvents such as N, N-dimethylformamide, acetonitrile, and 1-methyl-2-pyrrolidinone. These solvents may be used as a mixture of two or more kinds in an appropriate ratio. Examples of the base include metal carbonates such as potassium carbonate, sodium hydrogen carbonate and silver carbonate, triethylamine, ethyldiisopropylamine, N, And alkylamines such as N-dicyclohexylmethylamine.

Examples of the transition metal catalyst include zero-valent palladium catalysts such as tetrakis (triphenylphosphine) palladium, bis (tri-t-butylphosphine) palladium, and palladium dibenzylidene complex; Valent palladium catalyst and the like.

A reaction assistant can be added to this reaction as needed. Examples of the reaction assistant include monodentate ligands such as triphenylphosphine and tris (o_tolyl) phosphine, diphenylphosphinopropane, and the like. Bidentate ligands such as diphenylphosphinobutane and diphenylphosphinophenol and quaternary ammonium salts such as benzyltriethylammonium chloride and benzyltriethylammonium bromide may be added. The reaction temperature under the transition metal catalyst is selected from the range of about 0 to about 100, and preferably the range of about 5 Ot: to about 100.

The compound (107) is obtained by reacting the compound (108) with the compound (109) in an inert solvent in the presence of a base.

Examples of the inert solvent include aprotic solvents such as N, N-dimethylformamide, ethyl acetate, acetonitrile, and dimethyl sulfoxide; ether solvents such as THF and dioxane; halogens such as chloroform and dichloromethane. And hydrocarbon solvents such as toluene and benzene. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. Examples of the base include metal alkoxides such as t-butoxy potassium and sodium methoxide, potassium carbonate, and sodium carbonate. And metal carbonates such as cesium carbonate, alkylamines such as triethylamine and ethyldiisopropylamine, and metal hydrides such as sodium hydride.

The reaction temperature is selected from the range of about 120 to about the boiling point of the solvent, and preferably the range of about 0 ° C to about the boiling point of the solvent.

Compound (1 0 7) may be subjected to catalytic hydrogenation reaction if necessary, rw ¹ by the contact Hydrogen addition reaction can experience a producing or one C ₅ alkylene "which may be substituted it can.

The reaction can be performed in a hydrogen atmosphere, in an inert solvent, in the presence of a metal catalyst. Examples of the inert solvent include alcohol solvents such as methanol and ethanol, aprotic solvents such as ethyl acetate, acetonitrile and dimethyl sulfoxide, and ether solvents such as THF and dioxane. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. Metal catalysts include platinum oxide, activated carbon with platinum, activated carbon with palladium, palladium hydroxide, palladium black, barium sulfate with palladium, calcium carbonate with palladium, Lind 1 ar catalyst, nickel nickel, rhodium carbon, and rhodium. Alumina, tris (triphenylphosphine) chloride rhodium, ruthenium carbon, bis (triphenylphosphine) dicarbonyldilute dimethyldichloride and the like can be mentioned.

The hydrogen pressure in a hydrogen atmosphere is selected from the range of 1 to 150 atm, preferably the range of 1 to 10 atm.

In this reaction, a reaction aid can be added as necessary.

As the reaction aid, for example, acids such as sulfuric acid, hydrochloric acid, perchloric acid, phosphoric acid, acetic acid, oxalic acid, and trifluoroacetic acid, and bases such as phenylethylamine and triethylamine may be added.

The reaction temperature is selected from the range of about 0 to about 150, preferably the range of about 20 to about 100.

In the catalytic hydrogenation reaction, when the ketone is reduced to an alcohol, the acid It can be converted to a ketone body by an agent.

Examples of the oxidizing agent include chromic acids such as manganese dioxide and pyridinum chromate, oxidation with dimethyl sulfoxide in combination with oxalyl chloride, and complex oxidation of 4-methylmorpholine / tetra-n-propylammonium pearl tenate. Agents and the like. The reaction temperature is selected from the range of about −20 to about the boiling point of the solvent, preferably the range of about 0 to about the boiling point of the solvent.

Manufacturing method (1-1-3) Manufacturing method of the c-part

(Wherein, ΙW ¹ ′ ring Z has the same meaning as described above, and Q ⁴ and Q ⁵ represent organic groups.) Compound (110) and compound (111) are, for example, Lectures 19-26 (Maruzen, published in 1992), precision organic synthesis (Nankodo, published in 1983), Co immediately endium of Organic Synthetic Methods, Vol. 1-9 (John Wiley & Sons), Comprehensive Organic Synthesis, Vol. 1-9 (1991, Pergamon Press), Comprehensive Organic Transformations (1989, VCH Publishers) and the like, or a method analogous thereto.

Compound (112) can be obtained by reacting compound (110) with compound (111) in an inert solvent in the presence of a base.

Examples of the inert solvent include aprotic solvents such as N, N-dimethylformamide, ethyl acetate, acetonitrile, and dimethyl sulfoxide; ether solvents such as THF and dioxane; halogens such as chloroform and dichloromethane. And hydrocarbon solvents such as toluene and benzene. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. Examples of the base include metal alkoxides such as t-butoxy potassium and sodium methoxide; metal carbonates such as potassium carbonate and sodium carbonate; and alkyl cations such as triethylamine and ethyldiisopropylamine. And hydrides such as amines and sodium hydride.

The reaction temperature is selected from the range of about −20 to about the boiling point of the solvent, preferably the range of about ot: to about the boiling point of the solvent.

Manufacturing method (1-4) Manufacturing method of d part

(116) (118)

(Wherein, Ar ² has the same meaning as described above, and L ³ is an alkoxy such as methoxy and ethoxy, an alkylamino such as N-methyl-N-methoxyamino, N, N-dimethylamino and the like, and a deprotection of chloro group and the like. Represents a leaving group, M represents an alkali metal such as lithium, magnesium halide, zinc halide or the like, and Q ⁶ represents an organic group.)

Compound (113), compound (116) and compound (118) are, for example, Experimental Chemistry Lectures 19-26 (Maruzen, published in 1992), precision organic synthesis (Nankodo, published in 1983), Compend 1 um (Organic Synthetic Met hod s, Vo l. 1-9 (John Wiley & S on s), Compreh ensive Org anic Syn thesis, Vo l. 1-9 (1991 , Pe rg amon n Press), Comprehensive Organic Tran sfo rma ti ons (1989, VCH Pub1 ishers), etc., or a method analogous thereto. .

Compound (114) is prepared by treating compound (113) in an inert solvent with a base. Obtained by reacting aldehyde.

Examples of the inert solvent include ether solvents such as ether, THF, and dioxane; hydrocarbon solvents such as toluene, benzene, and xylene; and halogen solvents such as chloroform and dichloromethane. These solvents may be used by mixing two or more kinds in an appropriate ratio.

Examples of the base include alkylamines such as triethylamine and ethyldiisopropylamine, n-butyllithium, lithium diisopropylamide and the like.

The reaction temperature is selected from the range of from about 1 to about 78 when the base is treated, preferably from about −78 to about 0, and the reaction with the aldehyde is about −7. The temperature ranges from 8 ° C to around the boiling point of the solvent, and preferably ranges from about 178 to about 50.

Compound (114) can also be obtained by reacting compound (116) with compound (117) in an inert solvent.

Examples of the inert solvent include ether solvents such as ether, THF, and dioxane; hydrocarbon solvents such as toluene, benzene, and hexane; and halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride. . Compound (117) represents an organic metal compound such as aryl lithium salt and aryl magnesium halide.

Compound (115) can be obtained by reacting compound (114) with an oxidizing agent in an inert solvent.

Examples of the inert solvent include halogen-based solvents such as chloroform and dichloromethane. Examples of the oxidizing agent include chromic acids such as manganese dioxide, pyridinum bromide chromate, and dimethyl sulfoxide in combination with oxalyl chloride. Oxidation with sides, and complex oxidizing agents such as 4-methylmorpholine-no-tetra-n-propylammonium palmitate. The reaction temperature is selected from the range of about −78 to about the boiling point of the solvent, and preferably the range of about −2 to about 60. In addition, compound (115) is obtained by dissolving compound (118) in an inert solvent. Can also be obtained by reacting with the compound (117).

Examples of the inert solvent include ether solvents such as ether, THF, and dioxane; hydrocarbon solvents such as toluene, benzene, and hexane; and halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride. . Compound (117) represents an organic metal compound such as aryl aryl salt and aryl magnesium octalide. Examples of the inert solvent include ether solvents such as ether, THF, and dioxane; hydrocarbon solvents such as toluene, benzene, and xylene; and halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride. And the like.

The reaction temperature is selected from the range of about 120 to about the boiling point of the solvent, and preferably the range of about 0 to about the boiling point of the solvent.

Compound (115) can also be obtained by reacting compound (113) with aryl aryl halide in the presence of triethylamine in pyridine, followed by alkali hydrolysis (the method described in Synthesis, 1978, 675, Alternatively, it can be produced by a method according to it.) This reaction can be carried out in a closed reaction vessel such as an autoclave if necessary.

The reaction temperature in the reaction between compound (115) and aryl acid halide is about 0 From 150 to 150, preferably in the range of about 0 to 110.

Examples of the base for the alkali hydrolysis reaction include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide, and the reaction is performed in a water-containing solvent. As the aqueous solvent, for example, a mixed solvent of one or more solvents selected from ether solvents such as ether, THF, and dioxane, and alcohol solvents such as methanol and ethanol, and an appropriate ratio of water is used. Can be

The reaction temperature is selected from the range of about −2 Ot: to about the boiling point of the solvent, and preferably about 0 to the range of about the boiling point of the solvent.

Manufacturing method (1-5)

In the formula (1), when R ¹ is “optionally substituted C ₄ alkylsulfonylcarbamoyl, optionally substituted arylsulfonylcarbamoyl”, the compound (104) and the compound ( Compound (120) can be produced by reacting 119) in an inert solvent in the presence of a base and a dehydrating condensing agent. .

0 R "z ^b , NH ₂ O _N 09

HO Children Y ¹ -X ¹ _Ar ¹ -Q ⁷ (* R ", _N people Y ¹ — X ¹ — Ar ¹ ~ Q ⁷

(104) ^H (120)

(Wherein, YX ¹ and Ar ¹ have the same meaning as described above, R ¹¹ represents Ci—C ₄ alkyl or aryl, and Q 7 represents an organic group.)

Examples of the inert solvent include: aprotic solvents such as N, N-dimethylformamide, ethyl acetate, acetonitrile, and dimethyl sulfoxide; ether solvents such as THF and dioxane; and chloroform, dichloromethane and the like. Halogen solvents and the like. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. Examples of the base include metal alkoxides such as potassium t-butoxide and sodium methoxide; metal carbonates such as potassium carbonate and sodium carbonate; triethylamine; Alkylamines such as rudiisopropylamine and 1,8-diazabicyclo [5,4,0] indene-1-ene. Examples of the dehydrating condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3′-dimethylaminopropyl) -capillium imide, N, N-bis (2-oxo-13-oxazolidinyl) phosphinic acid chloride, N, N'-carbonyldiimidazole and the like.

A reaction aid can be added to the reaction as required.

Examples of the reaction assistant include N-hydroxybenztriazole, N, N-dimethyl-4-aminopyridine and the like.

Manufacturing method (1-1-6)

In the formula (1), when aryl or heteroaryl is present in one or both of R ² and R ³ , for example, Comprehensive Heterocyclic Chemistry (for example, pyrazole or indazole derivatives: voll) .5; imidazole derivatives, benzimidazole derivatives: V0.1.5; triazole derivatives: Vo1.5; and the like, Comprehensive Heterocyclic Chemistry II (for example, pyrazole derivatives, indazole derivatives: vo1). 3; imidazole derivatives, benzimidazole derivatives: V o 1.3; triazo derivatives: V 0. 1.4, etc.), Org. Lett., 1, 1521 (1999), Tetrahedron Lett. , 29, 5013 (1999), etc., or a method analogous thereto. When ring Z is imidapool, it can be produced, for example, by heating compound (150) or compound (151) with formamide at 150-200.

(150) (151) (152)

(Wherein, one or both of R ² and R ³ are aryl or heteroaryl) And the other represents a C ₄ alkyl which may be substituted with a hydrogen atom or a halogen atom, and L ⁴ represents a hydroxyl group, an amino group, bromine, chlorine, etc.) ^When bromine or iodine is present in ² or R ³ , Suzuki coupling reaction with arylboronic acid or heteroarylporonic acid (J. rganomet. Chem., 576, 147 (1999), J. Am. Chem. Soc. , 122,4020 (2000),

J. Am. Chem. Soc, 124, 6343 (2002) or the like, or a method analogous thereto), an Sti 11 e coupling reaction with an aryl tin compound or a heteroaryl tin compound ( Angew. Chem. Int. Ed. Engl, 25, 508 (1986) or a method analogous thereto) can be used to introduce aryl or heteroaryl into R ² or R ^3. Can be.

The following compound (129) can be produced as follows, for example, by combining the production methods (111) and (114).

(In the formula, Ar Ar ² and LR ^{1 Q} have the same meaning as described above, and Pg represents a protecting group.)

In this case, compound (121) can be protected by a dimethylsulfamoyl group as a protecting group, and the subsequent reaction can be performed. To protect one of the nitrogen atoms on ring Z with a dimethylsulfamoyl group, for example, in an inert solvent such as toluene, The reaction can be carried out by reacting dimethylsulfamoyl chloride or the like in the presence of a base such as luamine.

Compound (122) can be produced by treating compound (121) with a base in an inert solvent and then reacting with arylaldehyde. This reaction is produced, for example, according to the method described in J. Chem. Soc. Perkin Trans. I, 481 (1984), Chem. Pharm. Bull., 41, 1226 (1993), or a method analogous thereto. be able to.

Examples of the inert solvent include ether solvents such as THF, halogen solvents such as dichloromethane, hydrocarbon solvents such as toluene, and the like. Preferred bases include n-butyllithium and lithium diisopropylamide. The reaction temperature is selected from the range of about 178 to about the boiling point of the solvent, preferably in the range of about _78: to about 0, and the reaction with the aldehyde is preferably in the range of about Ot: to about 50. Can be

Compound (123) can be produced by reacting compound (122) with an oxidizing agent in an inert solvent.

Examples of the inert solvent include halogen solvents such as chloroform and dichloromethane, and examples of the oxidizing agent include manganese dioxide.The reaction temperature ranges from about −78 ° C. to about the boiling point of the solvent. And preferably ranges from about 20 to about 60.

Compound (124) can be obtained by deprotecting compound (123).

For example, when a dimethylsulfamoyl group is used as a protecting group, deprotection can be performed, for example, using a mixed solvent system of an acidic aqueous solution such as aqueous hydrochloric acid and an alcoholic solvent such as ethanol, or an ethereal solvent such as THF. It can be carried out by heating to reflux. This reaction can be produced, for example, according to the method described in J. Org. Chem., 61, 4405 (1996) or a method analogous thereto.

Compound (124) is reacted with an aryl halide in an inert solvent in the presence of a base. Thus, the compound (125) can be produced.

Examples of the inert solvent include aprotic solvents such as N, N-dimethylformamide, ether solvents such as THF, and halogen solvents such as dichloromethane. Examples of the base include, for example, potassium t-butoxy. Metal alkoxides, metal carbonates such as potassium carbonate, alkylamines such as ethyldiisopropylamine, and metal hydrides such as sodium hydride.The reaction temperature ranges from about 12 to about the boiling point of the solvent. Selected from a range, preferably a range from about 0 to about 60. The compound (127) can be produced by reacting the compound (127) with α-haloisobutyric acid in an inert solvent in the presence of a base.

Examples of the inert solvent include aprotic solvents such as Ν and Ν-dimethylformamide, ether solvents such as THF, and halogen solvents such as dichloromethane. Examples of the base include t-butoxy potassium and the like. Metal alkoxides, metal carbonates such as potassium carbonate, alkylamines such as ethyldiisopropylamine, and metal hydrides such as sodium hydride. The reaction temperature ranges from about 120 to about the boiling point of the solvent. And preferably ranges from about 0 to about 60.

When R ^{1 Q} is other than a hydroxyl group, compound (1 28) can be produced by using conventional deprotection techniques for compound (1 27). For example, it can be obtained by a hydrolysis reaction in the presence of an acid or a base.

In the case of acid hydrolysis, examples of the acid include hydrochloric acid, sulfuric acid, and methanesulfonic acid. Examples of the solvent include ether solvents such as THF and dioxane, acetone, dimethyl sulfoxide, N, N-dimethyl, and the like. Examples include aprotic solvents such as formamide and acetonitrile, and alcoholic solvents such as methanol and ethanol.One or more solvents and water may be mixed in an appropriate ratio and used, or may be used without a solvent. .

The reaction temperature is selected from the range of about 120 to about the boiling point of the solvent, and preferably the range of about 110 to about the boiling point of the solvent. In the case of alkali hydrolysis, examples of the base include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; and metal carbonates such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. The reaction is performed in a hydrated solvent.

The aqueous solvent is selected from, for example, ether solvents such as THF and dioxane, aprotic solvents such as acetone, dimethyl sulfoxide, N, N-dimethylformamide, and acetonitrile, and alcohol solvents such as methanol and ethanol. A mixed solvent of more than one kind of solvent and an appropriate ratio of water is used.

The reaction temperature is selected from the range of about 120 to about the boiling point of the solvent, and preferably the range of about 110 to the vicinity of the boiling point of the solvent.

The compound (125) can be produced by reacting the compound (125) with the compound (128) in an inert solvent in the presence of a palladium catalyst and a base.

Examples of the inert solvent include ether solvents such as THF and dioxane, hydrocarbon solvents such as toluene, and aprotic solvents such as N, N-dimethylformamide, 1-methyl-2-pyrrolidinone, and acetonitrile. Examples of the base include metal carbonates such as potassium carbonate, sodium hydrogen carbonate, and silver carbonate; alkylamines such as triethylamine, ethyldiisopropylamine, and N, N-dicyclohexylmethylamine; and palladium. Examples of the catalyst include a zero-valent palladium catalyst such as tetrakis (triphenylphosphine) palladium complex, bis (tri-t-butylphosphine) palladium, and a divalent palladium catalyst such as palladium acetate.

A reaction aid can be added to this reaction as needed. Examples of the reaction aid include phosphine ligands such as triphenylphosphine and tris (o-tolyl) phosphine, and benzyltriethylammonium chloride. A quaternary ammonium salt such as benzyltriethylammonium bromide may be added.

The reaction temperature is selected from the range of about 0 ° C. to about 100, preferably the range of about 50 to about 100. The heteroaryl derivative or prodrug of the present invention may have asymmetry or may have a substituent having an asymmetric carbon, and such a compound has an optical isomer. The compounds of the present invention include mixtures of these isomers and isolated ones. A method for obtaining such an optical isomer purely includes, for example, optical resolution.

As the optical resolution method, when the compound of the present invention or an intermediate thereof has a basic substituent, the compound is dissolved in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, or 2-propanol, or an ether such as getyl ether). Solvents, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, acetonitrile, etc. and mixed solvents thereof, optically active acids (eg, mandelic acid, N-benzyloxyalanine) And monocarboxylic acids such as lactic acid, tartaric acid, dicarboxylic acids such as o-diisopropylidene tartaric acid and malic acid, and sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid).

When the heteroaryl derivative or prodrug of the present invention or an intermediate thereof has an acidic substituent such as dexamethasyl, optically active amines (for example, α-phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, 2-amino) It can also form salts with organic amines such as 1,2-diphenylethanol and 2-amino-1,1,1-diphenylpropanol.

The temperature at which the salt is formed may be in the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. Before the precipitated salt is collected by filtration, the salt can be cooled if necessary to improve the yield. The amount of the optically active acid or amine used is in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, relative to the substrate. If necessary, crystallize in an inert solvent (for example, alcohol solvents such as methanol, ethanol, and 2-propanol, ether solvents such as ethyl ether, ester solvents such as ethyl acetate, and aromatic hydrocarbon solvents such as toluene. , Acetonitrile, etc. and their mixed solvents) An optically active salt of a purity can also be obtained. If necessary, the obtained salt can be treated with an acid or a base by a usual method to obtain a free form.

The heteroaryl derivative of the present invention or a salt thereof can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of topical administration, injection, transdermal, nasal, and the like. Examples of the oral or rectal preparation include capsules, tablets, pills, powders, cachets, suppositories, and liquid preparations. Examples of the injection include a sterile solution or suspension. Examples of the topical administration agent include creams, ointments, lotions, transdermal agents (ordinary patches, matrixes) and the like.

The above dosage forms are formulated in a conventional manner, together with pharmaceutically acceptable excipients and additives. Pharmaceutically acceptable excipients and additives include carriers, binders, flavors, buffers, thickeners, coloring agents, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, etc. Can be Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, cacao Butter and the like. Capsules can be formulated by incorporating a compound of the present invention together with a pharmaceutically acceptable carrier. The compounds of the present invention can be mixed with pharmaceutically acceptable excipients or placed in a capsule without excipients. Cassiers can be produced in a similar manner.

Solutions for injection include solutions, suspensions, emulsions and the like. For example, an aqueous solution, water-propylene glycol solution and the like can be mentioned. Solutions can also be prepared in the form of a solution of polyethylene glycol or Z and propylene glycol, which may contain water. A liquid preparation suitable for oral administration can be produced by adding the compound of the present invention to water and adding a coloring agent, a flavor, a stabilizing agent, a sweetening agent, a solubilizing agent, a thickening agent and the like as needed. Also, a liquid preparation suitable for oral administration can be produced by adding the compound of the present invention to water together with a dispersant to make it viscous. As thickeners, for example, pharmaceutically acceptable natural Or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose or a known suspending agent.

Examples of the topical preparation include the above-mentioned liquid preparations, creams, aerosols, sprays, powders, lotions, ointments and the like. The above-mentioned preparation for topical administration can be produced by mixing the compound of the present invention with a pharmaceutically acceptable diluent and carrier usually used. Ointments and creams are obtained, for example, by formulating an aqueous or oily base with a thickener and / or a gelling agent. Examples of the base include water, liquid paraffin, vegetable oil (peanut oil, castor oil, and the like). Examples of the thickener include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, lanolin, hydrogenated lanolin, honey bean, and the like.

Lotions may be added to an aqueous or oily base with one or more pharmaceutically acceptable stabilizers, suspending agents, emulsifiers, diffusing agents, thickeners, coloring agents, fragrances, etc. .

The powder is formulated with a pharmaceutically acceptable powder base. Examples of the base include sugar, lactose, starch and the like. Drops may be formulated with an aqueous or non-aqueous base and one or more pharmaceutically acceptable diffusing agents, suspending agents, solubilizing agents, and the like.

The topical preparation may contain, if necessary, a preservative such as methyl hydroxybenzoate, propyl hydroxybenzoate, black cresol, benzalkonidum bride, and a bacterial growth inhibitor.

The heteroaryl derivative of the present invention or a salt thereof can be administered to a diabetic patient, particularly a type 2 diabetic or non-insulin-dependent diabetic patient. Further, or the heteroaryl derivative or a salt thereof of the present invention can control the blood glucose level of a diabetic patient. The dosage and frequency of administration at this time vary depending on the symptoms, age, body weight, dosage form, etc., but in the case of oral administration, usually about 1 to about 50 per day for adults. The Omg range, preferably from about 5 to about 10 Omg, can be administered once or in several divided doses. When administered as an injection, it can be administered in the range of about 0.1 to about 30 mg, preferably in the range of about 1 to about 100 mg, in one or several divided doses

Specific examples of the compound having the general formula (1) obtained by the present invention include, for example, the compounds shown in Tables 1 to 6 below.

Table 2

Table 3

Table 5

Table 6

Example

Hereinafter, the present invention will be described specifically with reference to Reference Examples and Examples, but the present invention is not limited thereto.

LC-MS analysis conditions

(method A)

Body: ZQ2000 (waters), ionization method: ESI

_{Column: XTerra MS C 18 2 · 5} ΠΙ (2.1x20mm) (waters Corporation)

Solution A: H ₂ 〇, Solution B: acetonitrile, Flow rate: lml / min

Analysis conditions;

O.Omin → 0.5min: A solution 95% —constant (B solution 5%)

0.5min → 2.5min: Solution A 95% → 1% (solution B 5% → 99%) 2.5min → 3.5min A solution 1% —constant (B solution 99%)

From Omin to 3.5min, analysis is performed in the presence of 0.06% formic acid with respect to solution A + solution B (= total amount)

(method B)

Main unit: AP I 150 EX (PESC IEX), Ionization method: ESI Column: Combi Screen Hydrosphere C18 S-5 m (4.6x50 marauder) (YMC)

Solution A: 0.05% aqueous trifluoroacetic acid

Solution B: acetonitrile containing 0.035% trifluoroacetic acid

Flow rate: 3.5ml / min

Analysis conditions;

O.Omin → 0.5min: A solution 90% —constant (B solution 10%)

0.5min → 4.2min: Solution A 90% → 1% (solution B 10% → 99%)

4.2min → 4.4min A solution 1% —constant (B solution 99%)

R.T. = Retention Time Reference Example 1

Synthesis of (1-aryl-1H-imidazole-2-yl) [4- (trifluoromethyl) phenyl] methanone

Reference Example 1 1 1

Synthesis of N, N-dimethyl-1H-imidazole-1-sulfonamide

Dissolve Me ₂ N0 ₂ S and imidazole (5.00 g, 73.6 in 01) in 80 ml of toluene, add triethylamine (9.52 ml, 68.4 mmol) and dimethylsulfamoyl chloride (6.77 ml, 63.3 mmol). The mixture was stirred at room temperature for 8 hours. The resulting precipitate was removed by filtration, and the filtrate was distilled off under reduced pressure. The obtained residue was azeotroped with hexane to give the title compound (10.9 g, 98¾).

_{Ή NMR (CDC1 3, 400 MHz} ) 6 7.87 (s, 1 H), 7.23 (d, 1 H, J = 1.4 Hz), 7.11 (d, 1 H, J = 1.4 Hz), 2.82 (s, 6 H ).

Reference Example 11-2

Synthesis of 1H-imidazole-2-yl [4- (trifluoromethyl) phenyl] methanone

N, N-Dimethyl-1H-imidazole-1-sulfonamide (1.00 g, 5.71 r. Ol) was dissolved in 30 ml of THF and stirred at -78. To this solution was added n-butyllithium (1.57M hexane solution, 3.9 ml, 6.3 mmol), and the mixture was stirred at -78 for 30 minutes. Then, a solution of 4- (trifluoromethyl) benzaldehyde (1.49 g, 8.57 mmol) in THF (5 ml) was added, and the mixture was heated to room temperature and stirred overnight. To the reaction solution was added 2.5 N diluted hydrochloric acid and a solution of ethyl hexane monoacetate (3: 1), and the aqueous layer was extracted. The aqueous layer was made basic by adding a 4N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in 150 ml of chloroform, and manganese dioxide (20.0 g, 23.0 mmol) was added, followed by stirring at 70 for 2 hours. The reaction solution was filtered through Celite, and the solvent in the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in 20 ml of THF, 50 ml of 4N diluted hydrochloric acid was added, and the mixture was heated under reflux for 4 hours. While stirring under ice-cooling, a 4 N aqueous sodium hydroxide solution was added dropwise to neutralize the mixture, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the title compound (320 mg, 23%).

_{Ή NMR (CDC1 3, 400 MHz} ) 6 10.61 (brs, 1 H), 8.69 (d, 2 H, J = 8.2 Hz), 7.78 (d, 2 H, J - 8.2 Hz), 7.42 (d, 1 H , J = 0.9 Hz), 7.34 (d, 1 H, J = 0.9 Hz). Reference Example 11

Synthesis of (1-aryl-1H-imidazole-2-yl) [4- (trifluoromethyl) phenyl] methanone

Dissolve 1H-imidazole-2-yl [4- (trifluoromethyl) phenyl] methanone (320 mg, 1.33 mmol) in 5 ml of THF, and add potassium t-butoxide (164 mg, 1.46 bandol) Was added. After stirring at room temperature for 30 minutes, acrylyl bromide (213 mg, 2.00 thigh 01) was added, and the mixture was stirred at 40 for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and azeotroped with hexane to obtain the title compound (368 mg, 99%).

Ή thigh _{(CDC1 3, 400 MHz) 6} 8.34 (d, 2 H, J = 8.2 Hz), 7.74 (d, 2 H, J = 8.2 Hz), 7.28 (d, 1 H, J = 0.8 Hz), 7.22 (d, 1 H, J = 0.8 Hz), 6.08 (ddt, 1 H, J = 10.3, 17.0, 5.8 Hz), 5.28 (d, 1 H, J = 10.3 Hz), 5.16 (d, 1 H, J = 17.0 Hz), 5.13 (d, 2 H, J = 5.8 Hz).

Reference example 2

Synthesis of (Triaryl-1H-1,2,4-triazol-5-yl) [4- (trifluoromethyl) phenyl] methanone

Reference Example 2-1

Synthesis of N, N-dimethyl-1H-1,2,4-triazole-1-sulfonamide

Triazole (5.08 g, 73.6 recited 01) was dissolved in 80 ml of toluene, and triethylamine (9.52 ml, 68.4 mmol) and dimethylsulfamoyl chloride (10.6 ml, 73.6 mmol) were added, followed by stirring for 2 hours. The resulting precipitate is removed by filtration, and the filtrate is depressurized. Distilled off. The obtained residue was purified by silica gel column chromatography to give the title compound (4.52 g, 38%).

Ή thigh _{(CDC1 3, 400 MHz) δ} 8.58 (s, 1 H), 8.06 (s, 1 H), 2.99 (s, 6 H). Reference Example 2-2

Synthesis of 1H-1,, 4-triazol-5-yl [4- (trifluoromethyl) phenyl] methanone

N, N-Dimethyl-1H-1,2,4-triazole-1-sulfonamide (2.00 g, 11.4 mmol) was dissolved in 60 ml of THF and stirred at -78. To this solution was added n-butyllithium (1.57 M hexane solution, 8.0 ml, 13 mmol), and the mixture was stirred at -78 for 1 hour. Then, a solution of 4_ (trifluoromethyl) benzaldehyde (2.98 g, 17.1 mmol) in THF (20 ml) was added, the temperature was raised to room temperature, and the mixture was stirred overnight. An aqueous solution of ammonium chloride was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in 150 ml of chloroform, and manganese dioxide (12.0 g, 13.8 mmol) was added, followed by stirring at 70 ° C for 2 hours. The reaction solution was filtered through celite, and the solvent in the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in 40 ml of THF, 100 ml of 4N diluted hydrochloric acid was added, and the mixture was heated under reflux for 4 hours. While stirring under ice-cooling, a 4 N aqueous sodium hydroxide solution was added dropwise to neutralize the mixture, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was recrystallized from ethyl acetate to give the title compound (1.54 g, 56%).

Ή NMR (DMS0-d ₆₎ 400 MHz) 6 14.96 (brs, 1 H), 8.80 (s, 1 H), 8.43 (d, 2 H, J-8.3 Hz), 7.96 (d, 2 H, J = (8.3 Hz).

Reference Example 2-3

(1-7Ril -1H-1,2,4-triazol-5-yl) [4- (trifluoromethyl) phenyl] meta Non-synthesis

1H-1,2,4-triazol-5-yl [4- (trifluoromethyl) phenyl] methanone (241 mg, 1.00 mmol) was dissolved in 3 ml of DMF and stirred under ice-cooling. After adding sodium hydride (60%, 44.0 mg, 1.10 mmol), the mixture was stirred at 5CT for 1 hour. Further, a solution of 5 (aryl bromide (107 mg, 1.00 mmol) in DMF (1 ml) was added to the reaction solution as it was. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue, which was purified by silica gel column chromatography. The title compound was obtained (41.8 mg, 15%).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.47 (d, 2 H, J = 8.2 Hz), 8.07 (s, 1 H), 7.78 (d, 2 H, J = 8.2 Hz), 6.07 (ddt, 1 H , J = 10.3, 17.0, 5.8 Hz), 5.28 (d, 1 H, J = 10.3 Hz), 5.26 (d, 2 H, J = 5.8 Hz), 5.24 (d, 1 H, J = 17.0 Hz).

Reference example 3

Synthesis of (1-aryl-1H-pyrazole-5-yl) (4-propylphenyl) methanone Reference Example 3-1

Synthesis of triaryl-1H-pyrazole-5-hydroxylaldehyde

Dissolve pyrazole-3-carbaldehyde (3.00 g, 31.2 band01) in 20 ml of DMF and stir while stirring with potassium carbonate (6.47 g, 46.8 mmol) and aryl bromide (3.50 g, 32.8 office 01). Was added. After stirring at room temperature for 6 hours, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography. Thus, the title compound was obtained (429 mg, 10).

_{Ή NMR (CDC1 3, 400 MHz} ) <5 9.86 (s, 1 H), 7.59 (d, 1 H, J = 2.0 Hz), 6.93 (d, 1 H, J = 2.0 Hz), 5.99 (ddt, 1 H, J = 10.3, 17.1, 5.7 Hz), 5.19 (dd, 1 H, J = 1.2, 10.3 Hz), 5.16 (d, 2 H, J = 5.7 Hz), 5.09 (dd, 1 H, J = 1.2 , 17.1 Hz).

Reference Example 3-2

Synthesis of (1-aryl-1H-birazol-5-yl) (4-propylphenyl) methanone

1_n-Propyl-4-bromobenzene (220 mg, 1.10 bandol) was added dropwise to powdered magnesium (26.7 mg, 1.10 mmol) at room temperature. The reaction solution was further stirred at 50 at 1 hour, and then cooled at -78. A solution of triaryl-1H-pyrazole-5-carbaldehyde (75,0 mg, 0.551 mmol) in THF (1 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in 50 ml of chloroform, and manganese dioxide (5.00 g, 5.75 described in 01) was added, followed by stirring at 60 ° C for 3 hours. The reaction was cooled to room temperature and filtered through celite. The solvent of the filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (64.0 mg, 46Ή NMR (CDCI3, 400 MHz) δ 7.81 (d, 2 Η, J = 8.2 Hz), 7.56 (d, 1 H, J = 2.0 Hz), 7.29 (d, 2 H, J = 8.2 Hz), 6.67 (d, 1 H, J = 2.0 Hz), 6.06 (ddt , 1 H, J = 10.3, 17.1, 5.7 Hz), 5.19 (d, 1 H, J = 10.3 Hz), 5.17 (d, 2 H, J = 5.7 Hz), 5.13 (d, 1 H, J = 17.1 Hz), 2.67 (t, 2 H, J = 7.4 Hz), 1.69 (tq, 2 H, J = 7.4, 7.3 Hz), 0.96 (t, 3 H, J-7.3 Hz). Reference example 4

Synthesis of (2S) -2- (3-odophenoxy) butanoic acid

Reference Example 41

Synthesis of (1 R) — 1-Methyl-2 _ morpholine-1-yl-2-oxethyl 4-methylbenzenesulfonate

Under a nitrogen atmosphere, D-(+)-methyl lactate (20.8 g, 200 mmo 1) and morpholine (19.1 ml, 220 mmol) were stirred under ice cooling with sodium hydride (60% in parafin liquid) (800 mg, 20.0 g). After stirring at room temperature for 3 hours, the mixture was cooled and stirred at room temperature to remove excess morpholine by azeotropic distillation with toluene, and dried under reduced pressure to give (2R) -1-morpholine-1-yl. 1-oxopropane-1-ol (32.1 g) was obtained.

Then, under a nitrogen atmosphere, a suspension of sodium hydride (60¾ in parafin liquid) (8.41 g, 210 t ol) in tetrahydrofuran (120 ml) was added under ice-cooling and stirring, and the (2R) -1—morpholine— A solution of yl-11-oxopropan-2-ol (32.1 g) in furan (150 ml) with tetrahydrid was added dropwise, and the mixture was heated and stirred at 50 ° C for 30 minutes. After cooling with ice, a solution of p-toluenesulfonyl chloride (45.8 g, 234 mmol) in tetrahydrofuran (180 ml) was added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 1N aqueous hydrochloric acid, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Getyl ether was added to the oily residue, and the precipitated crystals were collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound as a white solid (36.1 g, 58 °).

_{Ή NMR (CDC1 3, 400 MHz} ) (57.81 (d, 2 H, J = 8.0 Hz), 7.35 (d, 2 H, J - 8.0 Hz), 5.27 (q, 1 H, J = 6.8 Hz), 3.64 -3.46 (m, 8 H), 2.46 (s, 3 H), 1.47 (d, 3 H, J = 6.8 Hz).

Reference Example 4 1 2

4-Synthesis of [(2 S) — 2-— (3-D-phenoxy) propanoyl] morpholine

Potassium carbonate (10.0 g, 72.4 mmol) was added to a solution of m-phenol phenol (11.0 g, 50.0 mmol) in dimethylformamide (100 ml), and then (1R) —1-methyl—21-morpholine—4-yl 2-oxoethyl 4-methylbenzenesulfonate (16.45 g, 52.5 mmol) was added, and the mixture was heated with stirring at 50 for 3 hours. After cooling at room temperature, a 5% aqueous solution of potassium hydrogen sulfate was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (15.40 g, 85%) as a white solid.

_{Ή NMR (CDC1 3, 400 MHz} ) (57.32 (dd, 1 H, J = 1.7 and 7.8 Hz), 7.25 (dd, 1 H, J = 1.7 and 2.4 Hz), 7.00 (dd, 1 H, J = 7.8 and 8.1 Hz), 6.87 (dd, 1 H, J = 2.4 and 8.1 Hz), 4.92 (q, 1 H, J = 6.8 Hz), 3.67-3.46 (m, 8 H), 1.60 (d, 3 H, J = 6.8 Hz).

Reference Example 4 1 3

Synthesis of (2S) -2-(3-odophenoxy) propanoic acid

4-[(2S) -2- (3-Fedophenoxy) propanoyl] Dissolve morpholine (3.00 g, 8.31 mmol) in THF (50 ml) / methanol (50 ml) and add a 2N aqueous solution of lithium hydroxide (50 ml). ml) and stirred at 60 for 3 hours. After the temperature was lowered to room temperature, a 1N aqueous solution of sodium hydroxide was added, and the aqueous layer was washed with a mixed solvent of hexane and ethyl acetate (3: 1). The aqueous layer was made acidic by dropwise addition of concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 1N diluted hydrochloric acid and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.51 g, quant.). Ή NMR (CDCI3, 400 MHz) δ 7.33 (d, 1 H, J = 7.8 Hz), 7.26 (s, 1 H), 7.00 (dd, 1 H, J = 7.8, 8.3 Hz), 6.85 (d, 1 H, J = 8.3 Hz), 4.77 (q, 1 H, J = 6.9 Hz), 1.65 (d, 3 H, J = 6.9 Hz).

Reference example 5

Synthesis of 2- (4-iodophenoxy) -2-methylpropanoic acid

Dissolve p-phenol (5.00 g, 22.7 mmol) in 150 ml of DMF, add potassium carbonate (4.72 g, 34.1 mmol) and ethyl-α-bromoisobutyrate (4.21 g, 21.6 recited ol). For 6 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The residue was dissolved in 100 ml of ethanol, and 100 ml of 4N aqueous sodium hydroxide solution was added. After stirring overnight at room temperature, the mixture was neutralized with 4N diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 1N diluted hydrochloric acid and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (4.50 g, 68%).

Ή NMR (CDCI3, 400 MHz) δ 7.56 (d, 2 Η, J = 8.9 Hz), 6.70 (d, 2 H, J = 8.9 Hz), 1.60 (s, 6 H).

Example 1

(2S) -2- [3-((IE) -3- {2- [4- (trifluoromethyl) benzoyl] -1H-imidazole-1-yl} prop-1-enyl) phenoxy] propanoic acid Synthesis of

(2S) -2- (3-iodophenoxy) propanoic acid (62.4 mg, 0.214 mol), (triaryl-1H- Imidazole-2-yl) [4- (trifluoromethyl) phenyl] methanone (57.0 mg, 0.203 mmol) was dissolved in 2 ml of DMF, and palladium acetate (4.6 mg, 0.02 mmol) and sodium hydrogen carbonate ( 34.1 mg, 0.406 mmol) and triethylbenzylammonium chloride (92.5 mg, 0.406 mmol) were added, respectively, and the mixture was stirred at 60 ° C for 4 hours. After the temperature was lowered to room temperature, a saturated aqueous solution of sodium dihydrogen phosphate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (58.3 mg, 65 mg).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.32 (d, 2 H, J = 8.2 Hz), 7.73 (d, 2 H, J = 8.2 Hz), 7.30 (s, 1 H), 7.26 (s, 1 H ), 7.23 (dd, 1 H, J = 7.6, 8.2 Hz), 7.01 (d, 1 H, J = 7.6 Hz), 6.92 (s, 1 H); 6.78 (d, 1 H, J = 8.2 Hz), 6.54 (d, 1 H, J = 15.8 Hz), 6.38 (dt, 1 H, J = 15.8, 6.2 Hz), 5.24 (d, 2 H, J = 6.2 Hz), 4.77 (q, 1 H , J = 6.8 Hz), 1.62 (d, 3 H, J = 6.8 Hz).

In the same manner as in Example 1, the compounds of Examples 2 to 19 were synthesized.

Example 2

(2S) -2- (3-{(1E) -3- [2- (4-Isobutylbenzoyl) -1H-imidazole-1-yl] prop-thenyl} phenoxy) propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.14 (d, 2 H, J = 8.3 Hz), 7.28 (d, 1 H, J = 0.9 Hz), 7.23 (d, 2 H, J = 8.3 Hz), 7.22 (dd, 1 H, J = 7.7, 8.1 Hz), 7.21 (d, 1 H, J = 0.9 Hz), 6.99 (d, 1 H, J = 7.7 Hz), 6.91 (d, 1 H, J = 2.2 Hz), 6.79 (dd, 1 H, J = 2.2, 8.1 Hz), 6.52 (d, 1 H, J = 15.8 Hz), 6.38 (dt, 1 H, J = 15.8, 6.3 Hz), 5.20 (d, 2 H, J = 6.3 Hz), 4.76 (q, 1 H, J = 6.8 Hz), 2.53 (d, 2H, J = 7.2 Hz), 1.90 (tsept, 1H, J = 7.2, 6.6 Hz), 1.62 (d, 3H, J = 6.8 Hz), 0.91 (d, 6H, J = 6.6 Hz).

Example 3

(2S) -2- (3-{(IE) -3- [2- (4-Chen _3-ylpenzyl) -1H-imidazole-1-yl] prob-thenyl} phenoxy) propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.27 (d, 2 H, J = 8.4 Hz), 7.70 (d, 2 H, J = 8.4 Hz), 7.58 - 7.57 (m, 1 H), 7.46 - 7.41 ( m, 2 H), 7.30 (s, 1 H), 7.23 (s, 1 H), 7.21 (dd, 1 H, J = 7.7, 8.1 Hz), 7.00 (d, 1 H, J = 7.7 Hz), 6.91 (d, 1 H, J = 2.3 Hz), 6.78 (dd, 1 H, J = 2.3, 8.1 Hz), 6.53 (d, 1 H, J = 15.8 Hz), 6.39 (dt, 1 H, J = 15.8, 6.2 Hz), 5.22 (d, 2 H, J = 6.2 Hz), 4.76 (q, 1 H, J = 6.8 Hz), 1.61 (d, 3 H, J = 6.8 Hz).

Example 4

(2S) -2- (3-{(IE) -3- [2- (4-Chen_2-ylbenzyl) -1H-imidazole-1-yl]

Ή thigh _{(CDC1 3, 400 MHz) δ} 8.23 (d, 2 H, J = 8.3 Hz), 7.66 (d, 2 H, J = 8.3 Hz), 7.39 - 7.37 (m, 1 H), 7.31 - 7.30 ( m, 1 H), 7.24 (s, 1 H), 7.18 (s, 1 H), 7.17 (dd, 1 H, J = 7.5, 8.3 Hz), 7.07-7.05 (m, 1 H), 6.96 (d , 1 H, J = 7.5 Hz), 6.86 (d, 1 H, J = 2.1 Hz), 6.74 (dd, 1 H, J = 2.1, 8.3 Hz), 6.47 (d, 1 H, J = 15.9 Hz), 6.34 (dt, 1 H, J = 15.9, 6.3 Hz), 5.17 (d, 2 H, J = 6.3 Hz), 4.73 (q, 1 H, J = 6.9 Hz), 1.57 (d, 3 H, J = 6.9 Hz).

Example 5

(2S) -2- (3-{(IE) -3- [2- (4-pentylbenzoyl) -1H-imidazole-tolyl] prop-1-enyl} phenoxy) propanoic acid

H0 ₂ C

Ή NMR (CDC13 _> 400 MHz) δ 8.15 (d, 2 H, J = 8.2 Hz), 7.31 (s, 1 H), 7.30 (d, 2 H, J = 8.2 Hz), 7.26 (s, 1H), 7.23 (dd, 1 H, J = 7.7, 8.0 Hz), 7.01 (d, 1 H, J-7.7 Hz), 6.92 (d, 1 H, J-2.3 Hz), 6.81 (dd, 1 H, J = 2.3, 8.0 Hz), 6.53 (d, 1 H, J = 15.9 Hz), 6.39 (dt, 1 H, J = 15.9, 6. Hz), 5.21 (d, 2 H, J = 6.2 Hz) ), 4.79 (q, 1 H, J = 6.8 Hz), 2.67 (t, 2 H, J = 7.8 Hz), 1.64 (d, 3 H, J = 6.8 Hz), 1.42-1.28 (m, 6 H) , 0.89 (t, 3 H, J = 7.0 Hz).

(2S) -2- (3-{(IE) -3- [2- (4-bromobenzoyl) -1H-imidazole-1-yl] propenyl} phenoxy) propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.03 (d, 2 H, J = 8.6 Hz), 7.53 (d, 2 H, J = 8.6 Hz), 7.21 (d, 1 H, J = 0.8 Hz), 7.16 (d, 1 H, J = 0.8 Hz), 7.15 (dd, 1 H, J = 7.7, 8.2 Hz), 6.92 (d, 1 H, J = 7.7 Hz), 6.84 (d, 1 H, J = 2.1 Hz), 6.71 (dd, 1 H, J = 2.1, 8.2 Hz), 6.45 (d, 1 H, J = 15.8 Hz), 6.29 (dt, 1 H, J = 15.8, 6.3 Hz), 5.13 (d, 2 H, J = 6.3 Hz), 4.68 (q, 1 H, J = 6.8 Hz), 1.54 (d, 3 H, J = 6.8 Hz).

Example 7

(2S) -2- (3-{(IE) -3- [2- (4-propylbenzoyl) -1H-imidazole-toyl] probutenyl} phenoxy) propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.15 (d, 2 H, J = 8.2 Hz), 7.28 (d, 2 H, J = 8.2 Hz), 7.27 (s, 1 H), 7.22 (dd, 1 H , J = 7.7, 8.1 Hz), 7.21 (s, 1 H), 7.00 (d, 1 H, J = 7.7 Hz), 6.91 (d, 1 H, J = 2.1 Hz), 6.79 (dd, 1 H, J = 2.1, 8.1 Hz), 6.52 (d, 1 H, J = 15.9 Hz), 6.38 (dt, 1 H, J = 15.9, 6.2 Hz), 5.20 (d, 2 H, J = 6.2 Hz), 4.77 (q, 1 H,] = 6.8 Hz), 2.65 (t, 2 H, J = 7.3 Hz), 1.64 (tq, 2 H, J = 7.3, 7.3 Hz), 1.62 (d, 3 H, J = 6.8 Hz) Hz), 0.95 (t, 3 H, J = 7.3 Hz).

(2S) -2- [3-((1E) —3- {5-methyl-2- [4- (trifluoromethyl) benzoyl] 1H-imidazole-triyl} prop-thenyl) phenoxy ] Propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.27 (d, 2 H, J = 8.2 Hz), 7.72 (d, 2 H, J = 8.2 Hz), 7.22 (dd, 1 H, J = 7.7, 8.1 Hz) , 7.10 (s, 1 H), 6.99 (d, 1 H, J = 7.7 Hz), 6.89 (d, 1 H, J = 1.9 Hz), 6.78 (dd, 1 H, J = 1.9, 8.1 Hz), 6.37 (d, 1 H, J = 16.1 Hz), 6.32 (dt, 1 H, J = 16.1, 3.8 Hz), 5.21 (d, 2 H, J = 3.8 Hz), 4.78 (q, 1 H, J = 6.8 Hz), 2.35 (s, 3 H), 1.62 (d, 3 H, J = 6.8 Hz).

Example 9

(2S) -2- (3-{(IE) -3- [4-methyl-2- (4-methylbenzoyl) -1H-imidazole-1-yl] proprothenyl} phenoxy) propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) <5 8.10 (d, 2 H, J = 8.2 Hz), 7.25 (d, 2 H, J = 8.2 Hz), 7.20 (dd, 1 H, J = 7.7, 8.2 Hz ), 6.98 (d, 1 H, J = 7.7 Hz), 6.93 (s, 1 H), 6.89 (s, 1 H), 6.77 (d, 1 H, J = 8.2 Hz), 6.49 (d, 1 H , J = 15.9 Hz), 6.35 (dt, 1 H, J = 15.9, 6.2 Hz), 5.12 (d, 2 H, J = 6.2 Hz), 4.71 (q, 1 H, J = 6.8 Hz), 2.40 ( s, 3 H), 2.24 (s, 3 H), 1.57 (d, 3 H, J = 6.8 Hz).

Example 10

(2S) -2- [3-((IE) -3- {4-methyl-2- [4- (trifluoromethyl) benzoyl] -1H-imidazol-1-yl} probate Phenyl) phenoxy] propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.30 (d, 2 H, J = 8.1 Hz), 7.72 (d, 2 H, J = 8.1 Hz), 7.22 (dd, 1 H, J = 7.5, 8.1 Hz) , 7.00 (s, 1 H), 6.99 (d, 1 H, J = 7.5 Hz), 6.90 (d, 1 H, J = 2.1 Hz), 6.77 (dd, 1 H, J = 2.1, 8.1 Hz), 6.52 (d, 1 H, J = 15.8 Hz), 6.35 (dt, 1 H, J = 15.8, 6.3 Hz), 5.17 (d, 2 H, J = 6.3 Hz), 4.73 (q, 1 H, J = 6.8 Hz), 2.26 (s, 3 H), 1.59 (d, 3 H, J = 6.8 Hz).

Example 11 (2S) -2- (3-{(IE) -3- [2- (4-methylbenzoyl) -1H-benzimidazol-1-yl] prop-1-enyl} phenoxy) propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) <5 8.21 (d, 2 H, J = 8.2 Hz), 7.93 (d, 1 H, J = 8.1 Hz), 7.53 (d, 1 H, J = 8.1 Hz), 7.42 (dd, 1 H, J = 7.1, 8.1 Hz), 7.37 (dd, 1 H, J = 7.1, 8.1 Hz), 7.31 (d, 2 H, J = 8.2 Hz), 7.18 (dd, 1 H, J = 7.8, 8.1 Hz), 6.95 (d, 1 H, J = 7.8 Hz), 6.86 (d, 1 H, J = 2.2 Hz), 6.74 (dd, 1 H, J = 2.2, 8.1 Hz), 6.51 (d, 1 H, J = 15.9 Hz), 6.42 (dt, 1 H, J = 15.9, 5.3 Hz), 5.34 (d, 2 H, J = 5.3 Hz), 4.74 (q, 1 H, J = 6.8 Hz), 2.43 (s, 3 H), 1.60 (d, 3 H, J = 6.8 Hz).

Example 12

(2S) -2- (3-{(IE) -3- [2- (4- (trifluoromethyl) benzoyl) -1H-benzimidazole-triyl] prop-thenyl} phenoxy) propanoic acid

Ή Anonymous _{(CDC1 3, 400 MHz) δ} 8.41 (d, 2 H, J = 8.1 Hz), 7.93 (d, 1 H, J = 8.2 Hz), 7.78 (d, 2 H, J = 8.1 Hz), 7.55 (d, 1 H, J = 8.2 Hz), 7.47 (dd, 1 H, J = 7.1, 8.1 Hz), 7.39 (dd, 1 H, J = 7.1, 8.1 Hz), 7.18 (dd, 1 H, J = 7.8, 8.1 Hz), 6.96 (d, 1 H, J = 7.8 Hz), 6.87 (d, 1 H, J = 2.3 Hz), 6.74 (dd, 1 H, J = 2.3, 8.1 Hz), 6.53 ( d, 1 H, J = 15.9 Hz), 6.41 (dt, 1 H, J = 15.9, 5.8 Hz), 5.40 (d, 2 H, J-5.8 Hz), 4.73 (q, 1 H, J = 6.8 Hz ), 1.58 (d, 3 H, J = 6.8 Hz).

Example 13

2- (3-{(IE) -3- [2- (4-isobutylbenzoyl) -1H-imidazolyl-tolyl] prop-toluene} phenoxy) -2-methylpropane Acid

_{Ή NMR (CDC1 3, 400 MHz} ) <5 8.14 (d, 2 H, J = 8.3 Hz), 7.27 (d, 1 H, J = 0.9 Hz), 7.23 (d, 2 H, J = 8.3 Hz), 7.21 (dd, 1 H, J = 7.8, 8.1 Hz), 7.20 (d, 1 H, J = 0.9 Hz), 7.04 (d, 1 H, J = 7.8 Hz), 6.95 (d, 1 H, J- 2.3 Hz), 6.81 (dd, 1 H, J = 2.3, 8.1 Hz), 6.51 (d, 1 H, J = 15.8 Hz), 6.37 (dt, 1 H, J = 15.8, 6.3 Hz), 5.19 (d , 2 H, J = 6.3 Hz), 2.52 (d, 2 H, J = 7.2 Hz), 1.90 (tsept, 1 H, J = 7.2, 6.6 Hz), 1.55 (s, 6 H), 0.91 (d, 6 H, J = 6.6 Hz).

Example 14

(2S) -2- [3-((IE) -4- {2- [4- (trifluoromethyl) benzoyl] -1H-imidazole-1-yl} but-thenyl) phenoxy] propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.15 (d, 2 H, J = 8.2 Hz), 7.65 (d, 2 H, J = 8.2 Hz), 7.26 (s, 1 H), 7.18 (s, 1 H ), 7.12 (dd, 1 H, J = 7.7, 8.2 Hz), 6.84 (d, 1 H, J = 7.7 Hz), 6.73 (s, 1 H), 6.71 (d, 1 H, J = 8.2 Hz) , 6.22 (d, 1 H, J = 15.8 Hz), 6.07 (dt, 1 H, J = 15.8, 7.2 Hz), 4.69 (q, 1 H, J = 6.8 Hz), 4.62 (dq, 2 H, J = 7.2, 6.9 Hz), 2.71 (q, 2 H, J = 6.9 Hz), 1.59 (d, 3 H, J = 6.8 Hz).

Example 15

2-methyl-2- (4-{(IE) -3- [2- (4-methylbenzoyl) -1H-benzimidazol-1-yl] proprothenyl} phenoxy) propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.22 (d, 2 H, J = 8. Hz), 7.94 (d, 1 H, J = 7.9 Hz), 7.54 (d, 1 H, J = 8.1 Hz), 7.44 (dd, 1 H, J = 7.1, 7.9 Hz), 7.37 (dd, 1 H, J = 7.1, 8.1 Hz), 7.32 (d, 2 H, J = 8.2 Hz), 7.24 (d, 2 H, J = 8.7 Hz), 6.83 (d, 2 H, J = 8.7 Hz), 6.53 (d, 1 H, J = 15.9 Hz), 6.34 (dt, 1 H, J = 15.9, 6.0 Hz), 5.34 (d , 2 H, J = 6.0 Hz), 2.44 (s, 3 H), 1.55 (s, 6 H).

Example 16

2- (4-{(IE) -3- [2- (4-isobutylbenzoyl) -1H-imidazole-1-yl] probutanol} phenoxy) -2-methyl Propanoic acid

Ή thigh _{(CDC1 3, 400 MHz) δ} 8.18 (d, 2 H, J = 8.3 Hz), 7.29 (d, 2 H, J = 8.3 Hz), 7.28 (s, 1 H), 7.27 (s, 1 H ), 7.23 (d, 2 H, J = 8.6 Hz), 6.88 (d, 2 H, J = 8.6 Hz), 6.48 (d, 1 H, J = 15.7 Hz), 6.32 (dt, 1 H, J = 15.7, 6.3 Hz), 5.21 (d, 2 H, J = 6.3 Hz), 2.54 (d, 2 H, J = 7.2 Hz), 1.91 (tsept, 1 H, J = 7.2, 6.6 Hz), 1.57 (s , 6 H), 0.91 (d, 6 H, J = 6.6 Hz).

Example 17

2-Methyl-2- [4-((IE) -3- {2- [4- (trifluoromethyl) benzoyl] -1H-imidazole-1-yl} prop-1-enyl) phenoxy] propanoic acid

NMR (CDClj, 400 MHz) δ 8.31 (d, 2 H, J = 8.1 Hz), 7.71 (d, 2 H, J = 8.1 Hz), 7.31 (d, 1 H, J = 0.9 Hz), 7.28 (d , 2 H, J = 8.7 Hz), 7.27 (d, 1 H, J = 0.9 Hz), 6.85 (d, 2 H, J-8.7 Hz), 6.55 (d, 1 H, J = 15.8 Hz), 6.29 (dt, 1 H, J = 15.8, 6.5 Hz), 5.23 (d, 2 H, J = 6.5 Hz), 1.58 (s, 6 H).

Example 18

2-Methyl-2- [4-((IE) -3--3- {2- [4- (trifluoromethyl) benzoyl] -1H-benzimidazol-1-yl} prop-1-enyl) phenoxy ] Propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.45 (d, 2 H, J = 8.1 Hz), 7.95 (d, 1 H, J = 8.2 Hz), 7.79 (d, 2 H, J = 8.1 Hz), 7.57 (d, 1 H, J = 8.2 Hz), 7.48 (dd, 1 H, J = 7.1, 8.2 Hz), 7.41 (dd, 1 H, J = 7.1, 8.2 Hz), 7.26 (d, 2 H, J = 8.6 Hz), 6.85 (d, 2 H, J = 8.6 Hz), 6.55 (d, 1 H, J = 15.9 Hz), 6.35 (dt, 1 H, J = 15.9, 6.0 Hz), 5.41 (d, 2 H, J = 6.0 Hz), 1.55 (s, 6 H).

Example 19

2-Methyl-2- (4-{(IE) -4- [2- (4-methylbenzoyl) -1H-benzimidazole-1-yl] butrothenyl} phenoxy) propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.09 (d, 2 H, J = 8.2 Hz), 7.92 (d, 1 H, J = 8.1 Hz), 7.52 (d, 1 H, J = 8.1 Hz), 7.45 (dd, 1 H, J = 7.1, 8.1 Hz), 7.37 (dd, 1 H, J = 7.1, 8.1 Hz), 7.21 (d, 2 H, J = 8.2 Hz), 7.04 (d, 2 H, J = 8.7 Hz), 6.74 (d, 2 H, J = 8.7 Hz), 6.23 (d, 1 H, J = 15.8 Hz), 6.03 ( dt, 1 H, J = 15.8, 7.2 Hz), 4.73 (t, 2 H, J = 7.0 Hz), 2.78 (dt, 2 H, J = 7.2, 7.0 Hz), 2.40 (s, 3 H), 1.55 (s, 6H).

Example 20

(2S) -2- [3-((IE) -3- {5- [4- (trifluoromethyl) benzoyl] -1H-1,2,4-triazole-triyl} prop-thenyl ) Phenoxy] propanoic acid synthesis

(1-7 ril-1H-1,2,4-triazol-5-yl) [4- (trifluoromethyl) phenyl] methanone (41.8 mg, 0.149 mmol), (2S) -2- ( Dissolve 3- (iodophenoxy) propanoic acid (43.5 mg, 0.149 orchid ol) in 1 ml of DMF, palladium acetate (3.3 mg, 0.015 dragon ol), sodium bicarbonate (25.0 mg, 0.298 t ol), triethyl Benzyl ammonium chloride (67.9 mg, 0.298 mmol) was added, respectively, and the mixture was stirred at 70 for 8 hours. After the temperature was lowered to room temperature, a saturated aqueous solution of sodium dihydrogen phosphate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (41.0 mg, 62%).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.48 (d, 2 H, J = 8.2 Hz), 8.08 (s, 1 H), 7.79 (d, 2 H, J = 8.2 Hz), 7.23 (dd, 1 H , J = 7.8, 8.1 Hz), 7.03 (d, 1 H, J = 7.8 Hz), 6.93 (d, 1 H, J = 2.4 Hz), 6.79 (dd, 1 H, J = 2.4, 8.1 Hz), 6.65 (d, 1 H, J = 15.8 Hz), 6.40 (dt, 1 H, J = 15.8, 6.6 Hz), 5.40 (d, 2 H, J = 6.6 Hz), 4.80 (q, 1 H, J- 6.8 Hz), 1.64 (d, 3 H, J = 6.8 Hz). In the same manner as in Example 20, the compounds of Example 21 and Example 22 were synthesized.

Example 2 1

(2S) -2- (3-KlE) -3- 3- [5- (4-Isobutylpentyl) -1H-1,2,4-triazol-1-yl] probutenyl} phenoxy ) Propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) <5 8.25 (d, 2 H, J = 8.3 Hz), 8.06 (s, 1 H), 7.29 (d, 2 H, J = 8.3 Hz), 7.21 (dd, 1 H, J = 7.7, 7.7 Hz), 7.01 (d, 1 H, J = 7.7 Hz), 6.91 (d, 1 H, J = 2.2 Hz), 6.77 (dd, 1 H, J = 2.2, 7.7 Hz) , 6.62 (d, 1

H, J = 15.9 Hz), 6.41 (dt, 1 H, J = 15.9, 6.5 Hz), 5.35 (d, 2 H, J = 6.5 Hz), 4.79 (q, 1 H, J = 6.8 Hz), 2.56 (d, 2 H, J = 7. Hz), 1.92 (tsept, 1 H, J = 7.2, 6.6 Hz), 1.61 (d, 3 H, J = 6.8 Hz), 0.92 (d, 6 H, J = 6.6 Hz).

Example 22

2- (4-{(IE) -3- [5- (4-Isobutylbenzoyl) -1H-1,2,4-triazole-1-yl] probutenyl} phenoxy)- 2-methylpropanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.26 (d, 2 H, J = 8.4 Hz), 8.05 (s, 1 H), 7.30 (d, 2 H, J = 8.4 Hz), 7.29 (d, 2 H , J = 8.5 Hz), 6.87 (d, 2 H, J = 8.5 Hz), 6.64 (d, 1 H, J = 16.0 Hz), 6.35 (dt, 1 H, J = 16.0, 6.6 Hz), 5.34 ( d, 2 H, J = 6.6 Hz), 2.56 (d, 2 H, J = 7.2 Hz), 1.92 (tsept, 1 H, J = 7.2, 6.6 Hz),

I.56 (s, 6 H), 0.92 (d, 6 H, J = 6.6 Hz).

Example 23 Synthesis of (2S) -2- (3-{(IE) -3- [5- (4-propylbenzoyl) -1H-pyrazole-1-yl] prop-phenyl} phenoxy) propanoic acid

(Toryl-1H-pyrazol-5-yl) (4-propylphenyl) methanone (30.2 mg, 0.119 dragon ol), (2S) -2- (3-odophenol) propanoic acid (43.5 mg, 0.149 The thigh was dissolved in 1 ml of DMF, and palladium acetate (2.7 mg, 0.012 mmol), sodium hydrogen carbonate (20 · Omg, 0.238 mmol), and triethylbenzylammonium chloride (54.2 mg, 0.238 ol) And the mixture was stirred at 6 (TC for 5 hours. After the temperature was lowered to room temperature, a saturated aqueous solution of sodium dihydrogen phosphate was added to the reaction solution, and the mixture was extracted with ethyl acetate. After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (16.4 mg, 33).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 7.81 (d, 2 H, J = 8.2 Hz), 7.58 (d, 1 H, J = 2.0 Hz), 7.29 (d, 2 H, J = 8.2 Hz), 7.17 (dd, 1 H, J = 7.7, 8.2 Hz), 6.97 (d, 1 H, J = 7.7 Hz), 6.89 (d, 1 H, J = 2.3 Hz), 6.75 (dd, 1 H, J = 2.3 , 8.2 Hz), 6.68 (d, 1 H, J-2.0 Hz), 6.53 (d, 1 H, J = 15.9 Hz), 6.41 (dt, 1 H, J = 15.9, 6.1 Hz), 5.31 (d, 2 H, J = 6.1 Hz), 4.77 (q, 1 H, J-6.8 Hz), 2.67 (t, 2 H, J = 7.9 Hz), 1.67 (tt, 2 H, J = 7.4, 7.9 Hz), 1.62 (d, 3 H, J = 6.8 Hz), 0.96 (d, 3 H, J = 7.4 Hz).

As in Example 23, the compounds of Example 24 and Example 25 were synthesized.

Example 24

(2S) _2-[3-((1Ε)-3- {5- [4- (trifluoromethyl) benzoyl] -1H-pyrazole-1-yl} prop-thenyl) phenoxy] propanoic acid

_{ΉΉ NNMMRR ((CCDDCCI13 3 ,, 440000} MMHHzz)) δδ 77..9966 ((dd ,, 22 HH ,, JJ == 88..11 HHzz)) ,, 77..7766 ((dd ,, 22 HH, , JJ-88..11 HHzz)) ,, 77..6600 ((dd ,, 11 HH ,, JJ == 22..11 HHzz)) ,, 77..1199 ((dddd ,, 11 HH, , JJ == 77 ... 77, 88..11 HHzz)) ,, 66..9999 ((dd ,, 11 HH ,, JJ == 77..77 HHzz)) ,, 66..9911 (( dd ,, 11 HH ,, JJ == 22..22 HHzz)) ,, 66..7766 ((dddd ,, 11 HH ,, JJ == 22..22 ,, 88..11 HHzz)) ,, 66..6677 ((dd ,, 11 HH ,, JJ == 22..11 HHzz)) ,, 66..5555 ((dd ,, 11 HH ,, JJ == 1155..99 HHzz)) ,, 66..4400 ((ddtt ,, 11 HH ,, JJ == 1155..99 ,, 66..44 HHzz)) ,, 55..3355 ((dd ,, 22 HH ,, JJ == 66 .. 44.H778)), 44..7788 ((qq ,, 11HH ,, JJ == 66..88HHzz)) ,, 11..6633 ((dd ,, 33HH ,, JJ == 66 .. 88 HHzz)) ..

Example of actual implementation 2255

22 --Memethicylul-- 22-- ((44-- ({((IIEE)) --33-- [(55-- ((44--Pupropropirpirbenbenzozoyl))-11HH--Vivilarazolul --Utiril]]]

_{Ή NMR (CDC1 3, 400 MHz} ) δ 7.81 (d, 2 H, J = 8.3 Hz), 7.59 (d, 1 H, J = 2.0 Hz), 7.30 (d, 2 H, J = 8.3 Hz), 7.22 (d, 2 H, J = 8.7 Hz), 6.84 (d, 2 H, J = 8.7 Hz), 6.68 (d, 1 H, J = 2.0 Hz), 6.55 (d, 1 H, J = 15.8 Hz) , 6.32 (dt, 1 H, J = 15.8, 6.5 Hz), 5.32 (d, 2 H, J = 6.5 Hz), 2.67 (t, 2 H, J = 7.4 Hz), 1.68 (tq, 2 H, J = 7.4, 7.3 Hz), 1.58 (s, 6 H), 0.96 (t, 3 H, J = 7.3 Hz).

Synthesis of (2S) -2- (3- {3- [2- (4-methylbenzoyl) -1H-benzimidazolyl-tolyl] propyl) phenoxy) propanoic acid

(2S) -2- (3-{(IE) -3- [2- (4-methylbenzoyl) -1H-benzimidazol-1-yl] prob-thenyl} phenoxy) propanoic acid (21.2 mg , 48.1 mmol) was dissolved in 4 ml of methanol, 2.1 mg of 10 palladium-carbon (50% wet) was added, and the mixture was stirred at room temperature under normal pressure hydrogen for 3 hours. After filtration, the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (16.8 mg, 79%).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.16 (d, 2 H, J = 8.2 Hz), 7.87 (d, 1 H, J = 7.6 Hz), 7.38 (dd, 1 H, J = 7.1, 7.6 Hz) , 7.33-7.29 (m, 4 H), 7.18 (dd, 1 H, J = 7.7, 8.2 Hz), 6.81 (d, 1 H, J = 7.7 Hz), 6.74 (d, 1 H, J = 2.3 Hz) ), 6.71 (dd, 1 H, J = 2.3, 8.2 Hz), 4.75 (q, 1 H, J = 6.8 Hz), 4.53 (t, 2 H, J = 7.5 Hz), 2.71 (t, 2 H, J = 7.5 Hz), 2.44 (s, 3 H), 2.23 (tt, 2 H, J = 7.5, 7.5 Hz), 1.60 (d, 3 H, J = 6.8 Hz).

In the same manner as in Example 26, the compounds of Examples 27 to 35 were synthesized.

Example 27

(2S) -2- (3- {3- [2- (4-Isobutylbenzoyl) -1H-imidazole-1-yl] propyl} phenoxy) propanoic acid

Ή corrupt (CDC1 ₃ , 400 MHz) δ 8.07 (d, 2 H, J = 8.3 Hz), 7.24 (d, 2 H, J = 8.3 Hz), 7.20 (d, 1 H, J = 1.0 Hz), 7.18 (dd, 1 H, J = 7.6, 8.1 Hz), 7.05 (d, 1 H, J = 1.0 Hz), 6.80 (d, 1 H, J = 7.6 Hz), 6.73 (dd, 1 H, J = 2.0, 8.1 Hz), 6.71 (d, 1 H, J-2.0 Hz), 4.71 (q, 1 H, J = 6.8 Hz), 4.36 (m, 2 H), 2.66 (t, 2 H, J = 7.5 Hz), 2.54 (d, 2 H, J = 7.2 Hz), 2.16 (tt, 2 H, J = 7.5, 7.5 Hz), 1.91 (tsept, 1 H, J = 7.2, 6.6 Hz), 1.58 (d, 3 H, J = 6.8 Hz), 0.92 (d, 6 H, J = 6.6 Hz) ).

Example 28

2- (3- {3- [2- (4-isobutylbenzoyl) -1H-imidazole-1-yl] propyl} phenoxy) -2-methylpropanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.13 (d, 2 Η, J = 8.1 Hz), 7.25 (d, 2 H, J = 8.1 Hz), 7.22 (s, 1 H), 7.18 (dd, 1 H , J = 7.1, 7.6 Hz), 7.11 (s, 1 H), 6.88 (d, 1 H, J-7.6 Hz), 6.78 (s, 1 H), 6.77 (d, 1 H, J = 7.1 Hz) , 4.39 (t, 2 H, J = 7.4 Hz), 2.69 (t, 2 H, J = 7.4 Hz), 2.54 (d, 2 H, J = 7.2 Hz), 2.18 (tt, 2 H, J = 7.4 Hz) , 7.4 Hz), 1.91 (tsept, 1 H, J = 7.2, 6.6 Hz), 1.58 (s, 6 H), 0.91 (d, 6 H, J = 6.6 Hz).

Example 29

(2S) -2- [3 -— (4- {2- [4- (trifluoromethyl) benzoyl] -1H-imidazole-tolyl} butyl) phenoxy] propanoic acid

H0 ₂ C

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.25 (d, 2 H, J = 8.1 Hz), 7.72 (d, 2 H, J = 8.1 Hz), 7.25 (d, 1 H, J = 0.9 Hz), 7.16 (dd, 1 H, J = 7.6, 7.9 Hz), 7.15 (d, 1

H, J = 0.9 Hz), 6.77 (d, 1 H, J = 7.6 Hz), 6.70 (s, 1 H), 6.69 (d, 1 H, J = 7.9 Hz), 4.72 (q, 1 H, J = 6.9 Hz), 4.44 (t, 2 H, J = 7.5 Hz), 2.62 (t, 2 H, J = 7.4 Hz), 1.88 (tt, 2 H, J = 7.4, 7.5 Hz), 1.85 (tt, 2 H, J = 7.4, 7.4 Hz),

I.59 (d, 3 H, J = 6.9 Hz).

Example 30

(2S) -2- [3- (3-U-methyl-2- [4- (trifluoromethyl) benzoyl] -1H-imidazole-triyl} propyl) phenoxy] propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.31 (d, 2 H, J = 8.1 Hz), 7.73 (d, 2 H, J = 8.1 Hz), 7.20 (dd, 1 H, J = 7.8, 7.9 Hz) , 6.90 (s, 1 H), 6.83 (d, 1 H, J = 7.8 Hz), 6.75 (s, 1 H), 6.74 (d, 1 H, J = 7.9 Hz), 4.79 (q, 1 H, J = 6.8 Hz), 4.0 (t, 2 H, J = 7.4 Hz), 2.69 (t, 2 H, J = 7.5 Hz), 2.27 (s, 3 H), 2.18 (tt, 2 H, J = 7.4, 7.5 Hz), 1.63 (d, 3 H, J = 6.8 Hz).

Example 31

2-methyl-2- [4- (3- {2- [4- (trifluoromethyl) benzoyl] -1H-imidazol-1-yl} propyl) phenoxy] propanoic acid

Ή thigh _{(CDC1 3, 400 MHz) δ} 8.30 (d, 2 H, J = 8.1 Hz), 7.73 (d, 2 H, J = 8.1 Hz), 7.25 (d, 1 H, J = 0.8 Hz),. 7.16 (d, 1 H, J-0.8 Hz), 7.09 (d, 2 H, J = 8.5 Hz), 6.86 (d, 2 H, J = 8.5 Hz), 4.48 (t, 2 H, J = 7.3 Hz) ), 2.68 (t, 2 Example 32: H, J = 7.5 Hz), 2.19 (tt, 2 H, J = 7.3, 7.5 Hz), 1.56 (s, 6 H).

2-Methyl-2- [4--1H-benzimidazole-toluyl} pro

_{NMR (CDC1 3, 400 MHz)} δ 8.39 (d, 2 H, J = 8.1 Hz), 7.91 (d, 1 H, J = 8.2 Hz), 7.79 (d, 2 H, J = 8.1 Hz), 7.44 ( dd, 1 H, J = 7.1, 8.2 Hz), 7.38 (dd, 1 H, J = 7.1, 8.2 Hz), 7.34 (d, 1 H, J = 8.2 Hz), 7.08 (d, 2 H, J = 8.5 Hz), 6.86 (d, 2 H, J = 8.5 Hz), 4.63 (t, 2 H, J = 7.5 Hz), 2.73 (t, 2 H, J = 7.6 Hz), 2.25 (tt, 2 H, J = 7.5, 7.6 Hz), 1.56 (s, 6 H).

Example 33

2-methyl-2- (4_ {3- [2- (4-methylbenzoyl) -1H-benzimidazolyl-tolyl] propyl} phenoxy) propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.17 (d, 2 H, J = 8.2 Hz), 7.90 (d, 1 H, J - 8.0 Hz), 7.42 (dd, 1 H, J = 7.1, 8.0 Hz) , 7.37 (dd, 1 H, J = 7.1, 8.0 Hz), 7.34 (d, 1 H, J = 8.0 Hz), 7.31 (d, 2 H, J = 8.2 Hz), 7.01 (d, 2 H, J = 8.3 Hz), 6.80 (d, 2 H, J-8.3 Hz), 4.55 (t, 2 H, J = 7.5 Hz), 2.67 (t, 2 H, J = 7.6 Hz), 2.43 (s, 3 H ), 2.21 (tt, 2 H, J = 7.5, 7.6 Hz), 1.50 (s, 6 H).

Example 34

2-Methyl-2- (4-U- [2- (4-methylbenzoyl) -1H-benzimidazol-1-yl] buty {Phenoxy) propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.17 (d, 2 H, J = 8.2 Hz), 7.91 (d, 1 H, J = 8.0 Hz), 7.46 - 7.34 (m, 2 H), 7.41 (d, 1H, J = 8.0 Hz), 7.30 (d, 2 H, J = 8.2 Hz), 6.99 (d, 2 H, J = 8.1 Hz), 6.78 (d, 2 H, J = 8.1 Hz), 4.56 ( t, 2 H, J = 7.1 Hz), 2.58 (t, 2 H, J = 7.5 Hz), 2.43 (s, 3 H), 1.93 (tt, 2 H, J = 7.1, 7.2 Hz), 1.67 (tt , 2 H, J = 7.2, 7.5 Hz), 1.48 (s, 6 H).

Reference example 6

Synthesis of (3-Methoxyphenyl) [4- (4-methoxyphenyl) -1H-imidazole-2-yl] methanone

Reference Example 6-1

Synthesis of 4- (4-methoxyphenyl) -1H-imidazole

4′-Methoxyphenacyl bromide (2.29 g, 10.0 mmol) was dissolved in formamide (45.0 g, 1.00 mol) and stirred at 170 for 6 hours. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 200 ml of hexane monoacetate (5: 1) was added. The suspension was stirred at 50 at 2 hours for 2 hours, and further stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration and washed with hexane to give the title compound (1.52 g, 87%). _{NMR (CDC1 3, 400 MHz)} δ 8.05 (brs, 1 H), 7.68 (d, 1 H, J = 1.1 Hz), 7.63 (d, 2 H, J = 8.9 Hz), 7.23 (d, 1 H, J = 1.1 Hz), 6.91 (d, 2 H, J = 8.9 Hz), 3.81 (s, 3 H).

Reference Example 6-2

Synthesis of 4- (4-methoxyphenyl) -N, N-dimethyl-1H-imidazole-1-sulfonamide

Dissolve 4- (4-methoxyphenyl) -1H-imidazole (1.02 g, 5.86 band01) in 100 ml of acetonitrile, and add potassium carbonate (1.21 g, 8.78 reference01) and dimethylsulfamoyl chloride ( 1.01, 7.03 mmol), and the mixture was stirred at 70 ° C. for 7 hours. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was azeotroped with toluene three times to obtain the title compound (1.60 g, 97%).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 7.95 (d, 1 Η, J = 1.2 Hz), 7.72 (d, 2 H, J = 8.9 Hz), 7.40 (d, 1 H, J = 1.2 Hz), 6.95 (d, 2 H, J = 8.9 Hz), 3.84 (s, 3 H), 2.90 (s, 6 H).

Reference Example 6-3

Synthesis of 2- (3-methoxybenzoyl) -4- (4-methoxyphenyl) -Ν, Ν-dimethyl-1H-imidazole-1-sulfonamide

4- (4-Methoxyphenyl) -N, N-dimethyl-1H-imidazole-1-sulfonamide (1.60 g, 5.69 miol) was dissolved in 50 ml of THF and stirred at —78. To this solution was added n-butyllithium (1.58 M hexane solution, 4.7 ml, 7.4 mmol), and the mixture was stirred at -78 for 30 minutes. Then, a solution of N, 3-dimethoxy-N-methylbenzamide in THF (5 ml) was added, the temperature was raised to room temperature, and the mixture was stirred overnight. To the reaction solution was added a 2N aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (1.12 g, 48¾).

Ή thigh _{(CDC1 3, 400 MHz) δ} 7.75 (d, 2 H, J = 8.8 Hz), 7.73 (s, 1 H), 7.72 (d, 1 H, J = 8.0 Hz), 7.69 (s, 1 H ), 7.40 (dd, 1 H, J = 8.0, 8.2 Hz), 7.18 (d, 1 H, J = 8.2 Hz), 6.94 (d, 2 H, J = 8.8 Hz), 3.87 (s, 3 H) , 3.84 (s, 3 H), 3.13 (s, 6 H).

Reference Example 6-4

2- (3-Methoxybenzoyl) -4- (4-methoxyphenyl) -Ν, Ν-dimethyl-1H-imidazole-tolsulfonamide (1.12 g, 2.70 mmol) is suspended in 100 ml of ethanol. The mixture was made turbid, 100 ml of 4N diluted hydrochloric acid was added, and the mixture was stirred at 70 for 3 hours. After the solvent was roughly distilled off under reduced pressure, a 2N aqueous sodium hydroxide solution was added to adjust the pH of the solution to about 4, and crystals were precipitated. The crystals were collected by filtration and washed with water to give the title compound (832 mg, quant.).

Ή NMR (DMS0-d ₆ , 400 MHz) δ 8.11 (d, 1 H, J = 7.5 Hz), 8.10 (s, 1 H), 7.92 (s, 1 H), 7.86 (d, 2 H, J- 8.8 Hz), 7.51 (dd, 1 H, J = 7.5, 8.2 Hz), 7.26 (d, 1 H, J = 8.2 Hz), 7.01 (d, 2 H, J = 8.8 Hz), 3.86 (s, 3 H), 3.79 (s, 3 H).

In the same manner as in Reference Example 6, the compounds of Reference Examples 7 to 10 were synthesized.

Reference Example 7

(3-methoxyphenyl) (4-phenyl-1H-imidazole-2-yl) methanone

LC-MS R.T. 2.37 min., M / z 279 (M + l)

Reference Example 8

(4-phenyl-1H-imidazo-2-yl) [4- (trifluoromethyl) phenyl] methanone

LC-MS R.T.2.59 min., M / z 317 (M + l)

Reference Example 9 (3-methoxyphenyl) [4- (2-methoxyphenyl) -1H-imidazol-2-yl] methanone

LC-MS R.T.2.42 min., M / z 309 (Mil)

Reference example 10

(4-phenyl-1H-imidazole-2-yl) [6- (trifluoromethyl) pyridine-3-yl] methanone

LC-MS R.T.2.45 min., M / z 318 (M + l)

Reference Example 11

Synthesis of (3-butene-3-yl-4-phenyl-1H-imidazole-2-yl) (3-methoxyphen) methanone

(3-Methoxyphenyl) (4-phenyl-1H-imidazo-2-yl) methanone (278 mg, 1.00 mmol) was dissolved in 3 ml of DMF, and potassium carbonate (207 mg, 1.50 mmol), 18-Cran-6 (26.4 mg, 0.100 mmol) and 4-bromo-1-butene (162 mg, 1.20 mmol) were added, respectively, and the mixture was stirred at 80 for 5 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. After evaporating the solvent under reduced pressure, the obtained residue was azeotroped with toluene to obtain the title compound (309 mg, 93%). Ή NMR (CDC13 _> 400 MHz) δ 8.07 (d, 1 H, J = 7.7 Hz), 8.00 (s, 1 H), 7.83 (d,

2 H, J = 8.0 Hz), 7.44 (s, 1 H), 7.42 (dd, 1 H, J = 7.7, 8.2 Hz), 7.40 (dd,

2 H, J = 7.4, 8.0 Hz), 7.29 (t, 1 H, J = 7.4 Hz), 7.16 (d, 1 H, J = 8.2 Hz),

5.88-5.78 (m, 1 H), 5.12-5.07 On, 2 H), 4.55 (t, 2 H, J = 7.1 Hz), 3.90

(s, 3 H), 2.66 (dt, 2 H, J = 7.0, 7.1 Hz).

In the same manner as in Reference Example 11, the compounds of Reference Examples 12 and 13 were synthesized.

Reference Example 12

(Tobut-3-en-toyl-4-phenyl-1H-imidazole-2-yl) [4- (trifluoromethyl) / phenylene] methanone

LC-MS R.T. 2.82 min., M / z 371 (M + l)

Reference Example 13

(Butbut _3 -en-tolyl-4-phenyl -1H -imidazole-2-yl) [6- (Trifluorme tyrele) pyridine-3-yl] methanone

LC-MS R.T. 2.67 min., M / z 372 (M + l)

Reference Example 14

Synthesis of tert-butyl 2- [3- (4-bromobutyl) phenoxy] -2-methylpropanoate Reference Example 141-1

Synthesis of tert-butyl 2- (3-odophenoxy) -2-methylpropanoate

m-Ed phenol (22.0 g, 100 nimol) was dissolved in 200 ml of DMF, and potassium carbonate (20.7 g, 150 tmol), tert-butyl 2-bromoisobutyrate (26.8 g, 120 mmol), 18 -Crown-6 (2.64 g, 10.0 dragon ol) was added sequentially. The reaction solution was stirred at 80 for 27 hours, cooled to room temperature, added with water, and extracted with ethyl acetate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel chromatography, and the title compound was obtained (13.4 g, 37%).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 7.29 (d, 1 H, J = 7.8 Hz), 7.20 (s, 1 H), 6.95 (dd, 1 H, J = 7.8, 8.3 Hz), 6.81 (d, 1 H, J = 8.3 Hz), 1.56 (s, 6 H), 1.45 (s, 9 H).

Reference Example 14-2 was synthesized in the same manner as Reference Example 14_1.

Reference Example 14 1 2

2-Ethyl 2- (3-phenylphenoxy) -2-methylpropanoate

_{Ή NMR (CDC1 3, 400 MHz} ) δ 7.31 (d, 1 H, J = 7.8 Hz), 7.22 (s, 1 H), 6.95 (dd, 1 H, J = 7.8, 8.3 Hz), 6.79 (d, 1 H, J = 8.3 Hz), 4.24 (q, 2 H, J = 7.1 Hz), 1.59 (s, 6 H), 1.26 (t, 3 H, J = 7.1 Hz).

Reference Example 14 1 3

2- [3- (4-Hydroxybutyl) phenoxy] tert-butyl 2-methylpropanoate

i-BuC ^ C

Dissolve tert-butyl 2- (3-odophenoxy) -2-methylpropanoate (9.00 g, 24.8 mmol) in 180 ml of DMF and add 3-buten-1-ol (3.57 g, 49.6 mmol), palladium acetate ( 558 mg, 2.48 mmol), sodium bicarbonate (4.17 g, 49.5 bandol), and triethylbenzylammonium chloride (11.3 g, 49.5 mmol) were sequentially added. After stirring at room temperature for 13 hours, water was added and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium thiosulfate, dehydrated with a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The obtained concentrated residue was dissolved in 50 ml of methanol, added with 240 mg of 10 palladium-hydrocarbon (50% water-containing product), and stirred at room temperature under a normal pressure hydrogen atmosphere for 1 hour. The reaction solution was filtered through celite, and the solvent of the filtrate was distilled off under reduced pressure to obtain the title compound (2.30 g, 32%).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 7.12 (dd, 1 H, J = 7.6, 8.1 Hz), 6.79 (d, 1 H, J = 7.6 Hz), 6.70 (d, 1 H, J = 1.8 Hz) , 6.66 (dd, 1 H, J = 1.8, 8.1 Hz), 3.64 (t, 2 H, J = 6.5 Hz), 2.58 (t, 2 H, J = 7.2 Hz), 1.66 (tt, 2 H, J = 6.4, 6.5 Hz), 1.59 (tt, 2 H, J = 6.4, 7.2 Hz), 1.56 (s, 6 H), 1.44 (s, 9 H).

Reference Example 1 4 1 4

Tert-butyl 2- [3- (4-bromobutyl) phenoxy] -2-methylpropanoate

Dissolve tert-butyl 2- [3- (4-hydroxybutyl) phenoxy] -2-methylpropanoate (2.26 g, 7.33 referred to in 01) in 100 ml of dichloromethane and stir at 0 with N-promosuccinimide ( 1.57 g, 8.80 mmol) and triphenylphosphine (1.96 g, 7.48 mmol) were added. The reaction solution was stirred at room temperature for 2 hours, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.03 g, 74.6%). ' Ή NMR (CDC1 _3! 400 MHz) 6 7.13 (dd, 1 H, J = 7.7, 8.0 Hz), 6.78 (d, 1 H, J = 7.7 Hz), 6.69 (s, 1 H), 6.67 (d, 1 H, J = 8.0 Hz), 3.43 (t, 2 H, J = 6.7 Hz), 2.56 (t, 2 H, J = 7.5 Hz), 1.89 (tt, 2 H, J = 6.4, 6.7 Hz), 1.74 (tt, 2 H, J = 6.4, 7.5 Hz), 1.55 (s, 6 H), 1.40 (s, 9 H).

Reference Example 15

Synthesis of tert-butyl 2- [3- (3-bromopropyl) phenoxy] -2-methylpropanoate Reference Example 15-1

Synthesis of tert-butyl 2-methyl-2- {3-[(1Ε) -3-oxopropan-toluene] phenoxy} propanoate

Dissolve tert-butyl 2- (3-rhodophenoxy) -2-methylpropanoate (4.69 g, 12.9 thigh 01) in 30 ml of DMF, add acrolein (purity 90%, 884 mg, 14.2 mmol), palladium acetate ( 290 mg, 1.29 mmol), sodium hydrogen carbonate (2.17 g, 25.8 mmol) and triethylbenzylammonium chloride (5.88 mg, 25.8 mmol) were added, respectively, and the mixture was stirred at 70 for 5 hours. After the reaction solution was cooled to room temperature, the reaction was terminated by adding water and extracted with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium thiosulfate, and saturated saline. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (3.53 g, 94%).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 9.69 (d, 1 Η, J = 7.7 Hz), 7.40 (d, 1 H, J = 15.9 Hz), 7.30 (dd, 1 H, J = 7.7, 8.2 Hz) , 7.18 (d, 1 H, J = 7.7 Hz), 7.06 (s, 1 H), 6.93 (d, 1 H, J = 8.2 Hz), 6.66 (dd, 1 H, J = 7.7, 15.9 Hz), 1.59 (s, 6 H), 1.43 (s, 9 H).

Reference Example 15-2

Synthesis of tert-butyl 2- [3- (3-hydroxypropyl) phenoxy] -2-methylpropanoate

Dissolve tert-butyl 2-methyl-2- {3-[(IE) _3-oxoprop-phen-toyl] phenoxy} propanoate (3.21 g, 11.1 删 ol) in 200 ml of methanol. Stirred. After sodium borohydride (836 mg, 22.1 mmol) was added to the solution little by little, the mixture was stirred at room temperature for 1 hour. To the reaction solution, a 2N aqueous ammonium chloride solution was added little by little, and extracted with ethyl acetate. It was washed with water and dehydrated with saturated saline. The residue obtained by distilling off the solvent under reduced pressure is dissolved in 150 ml of ethanol, and 300 mg of 10% palladium-carbon (50% water-containing product) is added. Stirred. The reaction solution is filtered through celite, and the solvent in the filtrate is distilled off under reduced pressure.

The title compound was obtained (3.08 g, 99%).

Ή Tsuyoshi _{R (CDC1 3, 400 MHz)} δ 7.13 (dd, 1 H, J = 7.5, 7.7 Hz), 6.81 (d, 1 H, J two 7.5 Hz), 6.72 (s, 1 H), 6.67 (d , 1 H, J = 7.7 Hz), 3.66 (t, 2 H, J = 6.4 Hz), 2.65 (t, 2 H, J = 7.4 Hz), 1.87 (tt, 2 H, J = 6.4, 7.4 Hz) , 1.56 (s, 6 H), 1.44 (s, 9 H).

Reference Example 15-3

Synthesis of tert-butyl 2- [3- (3-bromopropyl) phenoxy] -2-methylpropanoate

Tert-butyl 2- [3- (3-hydroxypropyl) phenoxy] -2-methylpropanoate (1.00 g, 3.40 mmol) was dissolved in 50 ml of dichloromethane and stirred at 0. To the solution, N-bromosuccinimide (726 mg, 4.08 mol) and triphenylphosphine (918 mg, 3.50 mmol) were added. The reaction solution was stirred at room temperature for 2 hours, and the solvent was distilled off under reduced pressure. By purifying the residue by silica gel column chromatography, The title compound was obtained (903 mg, 74.3%).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 7.36 (d, 1 Η, J = 8.7 Hz), 7.26 (s, 1 H), 6.78 (d, 1 H, I = 3.0 Hz), 6.58 (dd, 1 H , J = 3.0, 8.7 Hz), 3.42 (t, 2 H, J-6.6 Hz), 2.81 (t, 2 H, J = 7.3 Hz), 2.15 (tt, 2 H, J = 6.6, 7.3 Hz), 1.55 (s, 6 H), 1.45 (s, 9 H).

Reference Example 16

Synthesis of tert-butyl 2- (4-phenylphenoxy) -2-methylpropanoate

Dissolve 4-phenol (5.00 g, 22.8 mmol) in 100 ml of DMF and add potassium carbonate (4.72 g, 34.2 mmol) and t-butyl 2-bromoisobutyrate (6.10 g, 27.3 mmol). And stirred at 80 for 5 hours. The reaction solution was cooled to room temperature, added with water, and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, by resulting residue was purified by silica gel column chromatography to give the title compound (6.48 g, 79 ¾) Ή NMR (CDC1 3, 400 MHz) <5 7.51 (d, 2H, J = 6.8 Hz), 6.62 (d, 2H, J = 6.8 Hz), 1.55 (s, 6H), 1.43 (s, 9H).

Reference Example 17

Synthesis of tert-butyl 2- [3- (3-propopropoxy) phenoxy] -2-methylpropanoate Reference Example 17-1

Synthesis of tert-butyl 2- (3-hydroxyphenoxy) -2-methylpropanoate

Dissolve resorcinol (11.0 g, 100 mmol) in 200 ml of DMF and add potassium carbonate (20.7 g, 150 mmol) and t-butyl 2-bromoisobutyrate (22.3 g, 100 mmol). Then, the mixture was stirred at 80 ° C for 7 hours. The reaction solution was cooled to room temperature, added with water, and extracted with ethyl acetate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain the title compound (3.60 g, 14%).

_{Ή NMR (CDC1 3, 400 MHz} ) <5 7.06 (dd, 1 H, J = 8.1, 8.3 Hz), 6.44 (d, 1 H, J = 8.1 Hz), 6.42 (d, 1 H, J = 8.3 Hz ), 6.38 (s, 1 H), 4.91 (brs, 1 H), 1.56 (s, 6 H), 1.44 (s, 9 H).

Reference example 17-2

Synthesis of tert-butyl 2- [3- (3-propopropoxy) phenoxy] -2-methylpropanoate

Dissolve tert-butyl 2- (3-hydroxyphenoxy) -2-methylpropanoate (270 mg, 1.07 mmol) in 10 ml of DMF, add potassium carbonate (222 mg, 1.60 t), One dopropane (3.17 g, 10.7 t ol) was added and stirred at 40 for 3 hours. The reaction solution was cooled to room temperature, added with water, and extracted with ethyl acetate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain the title compound (253 mg, 56%).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 7.10 (dd, 1 Η, J = 7.6, 8.1 Hz), 6.51 (d, 1 H, J = 7.6 Hz), 6.44 (s, 1 H), 6.42 (d, 1 H, J = 8.1 Hz), 3.98 (t, 2 H, J = 5.8 Hz), 3.35 (t, 2 H, J = 6.7 Hz), 2.25 (tt, 2 H, J = 5.8, 6.7 Hz), 1.57 (s, 6 H), 1.44 (s, 9 H).

Reference Example 18

Synthesis of N-methoxy-N-methyl-4_ (trifluoromethyl) benzamide

4— (Trifluoromethyl) benzoic acid (20.0 g, 105 ol) to 200 ml DMF Dissolve and stir at 0 to give Ν, Ο-dimethylhydroxylamine hydrochloride (12.3 g, 126 mmol), WSC I hydrochloride (24.2 g, 126 ol), HOBt (17.1 g, 126 mmol), Triethylamine (11.9 g, 117 mmol) was added sequentially. The mixture was stirred at room temperature for 2 hours, added with water, and extracted with ethyl acetate. The solvent was distilled off under reduced pressure and azeotroped with toluene to obtain the title compound (25.3 g, quant.).

Ή NMR (CDC ", 400 MHz) <5 7.79 (d, 2 H, J = 8.1 Hz), 7.67 (d, 2 H, J = 8.1 Hz), 3.53 (s, 3 H), 3.38 (s, 3 H).

In the same manner as in Reference Example 18, the compounds of Reference Examples 19 and 20 were synthesized.

Reference Example 19

N, 3-dimethoxy-N-methylbenzamide

LC-MS R.T.1.83 min., M / z 196 (M + l)

Reference Example 20

N-methoxy-N-methyl-6- (trifluoromethyl) nicotinamide

LC-MS R.T.1.91 min., M / z 235 (Mil)

Example 35

2-Methyl-2- [3- (3- {4-enyl-2- [4- (trifluoromethyl) benzoyl] -1H-imidazol-1-yl} propoxy) phenoxy] propanoic acid Synthesis

Dissolve tert-butyl 2- [3- (3-iodopropoxy) phenoxy] -2-methylpropanoate (42.0 mg, 0.100 mmol) in 2 ml of DMF and add potassium carbonate (20.7 mg, 0.150 mmol), (4- Phenyl-1Η-imidazole-2-yl) [4- (trifluoromethyl) phenyl] methanone (31.6 mg, 0.100 mmol) was added, and the mixture was stirred at 40 for 3 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography. The obtained concentrated residue was dissolved in 5 ml of chloroform, and 2.5 ml of trifluoroacetic acid was added. The mixture was stirred at 50 for 2 hours. The solvent was distilled off under reduced pressure and azeotroped with toluene to obtain the title compound (46.3 mg, 84 mg).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.49 (d, 2 H, J = 8.1 Hz), 7.76 (d, 2 H, J = 8.1 Hz), 7.74 (d, 2 H, J = 7.0 Hz), 7.46 (s, 1 H), 7.39 (dd, 2 H, J = 7,0, 7.3 Hz), 7.30 (t, 1 H, J = 7.3 Hz), 7.16 (dd, 1 H, J = 8.2, 8.3 Hz ), 6.60 (d, 1 H, J = 8.3 Hz), 6.53 (d, 1 H, J = 8.2 Hz), 6.49 (s, 1 H), 4.71 (t, 2 H, J = 6.7 Hz), 3.99 (t, 2 H, J = 5.6 Hz), 2.39 (tt, 2 H, J = 5.6, 6.7 Hz), 1.57 (s, 6 H).

The compounds of Examples 36 to 42 were synthesized in the same manner as in Example 35. Example 36

2- (3- {3- [2- (3-methoxybenzoyl) -4-phenyl-1H-imidazole-tolyl] propoxy} phenoxy) -2-methylpropanoic acid

LC-MS R.T. 2.64 min., M / z 515 (M + l)

Example 37

2- (3- {3- [2- (3-methoxybenzoyl) -4- (4-methoxyphenyl) -1H-imidazole-1-yl] propoxy} phenoxy) phenoxy) -2-methylpropane Acid

LC-MS R.T.2.61 min., M / z 545 (M + l)

Example 38

2- (3- {3- [2- (3-methoxybenzoyl) -4- (2-methoxyphenyl) -1H-imidazole-1-yl] propoxy} phenoxy) -2-methylpropanoic acid

LC-MS R.T. 2.64 min., M / z 545 (M + l)

Example 39

2- (3- {3- [2- (3-methoxybenzoyl) -4-phenyl-1H-imidazole-tolyl] propyl} phenoxy) -2-methylpropanoic acid

LC-MS R.T.2.63 min., M / z 499 (Mil)

Example 40

2-Methyl-2- [3- (3- {4-7 xnyl-2- [4- (trifluoromethyl) benzoyl] -1H-imidazol-triyl} propyl) phenoxy] propanoic acid

LC-MS R.T. 2.78 min., M / z 537 (Mil)

Example 41

2-Methyl-2- {3- [3- (4-7nyl-2-{[6- (trifluoromethyl) pyridine_3-yl] carbonyl} -1Η-imidazole-1-yl) Propyl] phenoxy} propanoic acid

LC-MS R.T.2.68 min., M / z 538 (M + l)

Example 42

2- (3- {4- [2- (3-methoxybenzoyl) -4- (4-methoxy

Yl] butyl} phenoxy) -2-methylpropanoic acid

LC-S RT 2.55 min., M / z 543 (M + l)

Example 43

2-Methyl-2- [3-((IE) -4- {4-phenyl-2- [4- (trifluoromethylyl) benzoyl] -1H-imidazole-1-yl} but-1 Synthesis of -en-triyl) phenoxy] propanoic acid

Dissolve (4-but-3-ene-4-phenyl-1H-imidazole-2-yl) [4- (trifluoromethyl) phenyl] methanone (111 mg, 0.300 mmol) in 3 ml of DMF. 2- (3-chlorophenoxy) -2-methylpropanoate, palladium acetate (6.7 mg, 0.030 t ol), sodium hydrogen carbonate (50.4 mg, 0.600 mmol), triethylbenzylammonium chloride (137 mg) , 0.600 t) and stirred for 7 hours with TC. The reaction solution was cooled to room temperature, water was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and the obtained concentrated residue was dissolved in 3 ml of ethanol and 3 ml of 2N Add sodium hydroxide aqueous solution, and The reaction solution was neutralized with 1 N diluted hydrochloric acid, extracted with ethyl acetate, dehydrated with a saturated saline solution, and the obtained solution was concentrated to obtain the title compound (84.8 mg, 51%).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.44 (d, 2 H, J = 8.1 Hz), 7.80 (d, 2 H, J = 7.1 Hz), 7.72 (d, 2 H, J = 8.1 Hz), 7.48 (s, 1 H), 7.40 (dd, 2 H, J = 7.1, 7.3 Hz), 7.31 (t, 1 H, J = 7.3 Hz), 7.13 (dd, 1 H, J = 7.7, 8.0 Hz), 6.95 (d, 1 H, J = 7.7 Hz), 6.84 (s, 1 H), 6.75 (d, 1 H, J = 8.0 Hz), 6.33 (d, 1 H, J = 15.8 Hz), 6.15 (dt , 1 H, J = 15.8, 7.2 Hz), 4.64 (t, 2 H, J = 7.0 Hz), 2.78 (dt, 2 H, J = 7.2, 7.0 Hz), 1.54 (s, 6 H). In the same manner as in Example 43, the compounds of Examples 44 to 46 were synthesized. Example 44

2-methyl-2- {3-[(1E) -4- (4-phenyl-2-{[6- (trifluoromethyl) pyridin-3-yl] capillonyl 1H-imidazole-toluyl ) Butenoyl-phenoxy} propanoic acid

LC-MS R.T. 2.67 min., M / z 550 (M + l)

Example 45

2- (3-{(IE) -4- [2- (3-methoxybenzoyl) -4-phenyl-1H-imidazole-toyl] but-2-ene-1-yl} phenoxy) -2 _Methylpropanoic acid

LC-MS R.T.2.65 min., M / z 511 (M + l)

Example 46

(2S) -2- (3-{(IE) -4- [2- (3-methoxybenzoyl) -4-phenyl-1H-imidazole-1-yl] but-toluene-tolyl} Phenoxy) propanoic acid

LC-MS RT 2.65 min., M / z 497 (M + l) Example 47

Synthesis of 2-methyl-2- [3- (4- {4-phenyl-2- [4- (trifluoromethyl) benzoyl] -1H-imidazole-1-yl} butyl) phenoxy] propanoic acid

2-methyl-2- [3-((1E) -4- {4-7enyl-2- [4- (trifluoromethyl) benzoyl] -1H-imidazoyl-tolyl} but-1- [Entyl) phenoxy] propanoic acid (367 rag, 0.669 t) was dissolved in 60 ml of methanol and 360 mg of 5% rhodium-carbon was added. The reaction solution was stirred for 3 hours at room temperature under a hydrogen atmosphere at normal pressure. After filtration through celite, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (229 mg, 62%).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.50 (d, 2 H, J = 8.2 Hz), 7.81 (d, 2 H, J = 8.4 Hz), 7.77 (d, 2 H, J = 8.2 Hz), 7.45 (s, 1 H), 7.40 (dd, 2 H, J = 7.4, 8.4 Hz), 7.30 (t, 1 H, J = 7.4 Hz), 7.16 (dd, 1 H, J-7.7, 8.0 Hz), 6.86 (d, 1 H, J = 7.7 Hz), 6.76 (s, 1 H), 6.74 (d, 1 H, J-8.0 Hz), 4.48 (t, 2 H, J = 7.3 Hz), 2.65 (t , 2 H, J = 7.4 Hz), 1.91 (tt, 2 H, J = 7.3, 7.3 Hz), 1.70 (tt, 2 H, J = 7.3, 7.4 Hz), 1.57 (s, 6 H).

The compounds of Examples 48 to 53 were synthesized in the same manner as in Example 47. Example 48

2- (3- {4- [2- (3-methoxybenzoyl) -4-phenyl- 1H-imidazo-1-l-yl] butyl} phenoxy) -2-methylpropanoic acid

LC-MS R.T.2.68 min., M / z 513 (M + l)

Example 49

2-methyl-2- {3- [4- (4-phenyl-2--2-[[6- (trifluoromethyl) pyridine-3-yl] carbonyl} -1H-imidazole-

LC-MS R.T.2.73 min., M / z 552 (M + l)

Example 50

2-Methyl-2- [4-((IE) -4- {4-7enyl-2- [4- (trifluoromethyl) benzoyl] -1H-imidazolyl-butyr-but- 1-en-yl) phenoxy] butanoic acid

LC-MS R.T. 2.79 min., M / z 549 (M + l)

Example 51

2-methyl-2- [4- (4-phenyl-2- [4- (trifluoromethyl) benzoyl] -1H-imidazole-1-yl} butyl) phenoxy] propanoic acid > _ ^CF 3

LC-MS R.T. 2.83 min., M / z 551 (M + l)

Example 52

(2S) -2- (3- {4- [2- (3-methoxybenzoyl) -4- 4-phenyl-1H-imidazole-butyl] butyl} phenoxy) propanoic acid

LC-MS R.T.2.63 min., M / z 499 (Mil)

Example 53

2- (4- {4- [2- (3-methoxybenzoyl) -4-phenyl-1H-imidazole-1-yl] butyl} phenoxy) -2-methylpropanoic acid

LC-MS R.T.2.57 min., M / z 513 (M + l)

Reference Example 21

Synthesis of (3-butene-3-yl-1H-benzimidazole-2-yl) (3-methoxyphenyl) methanone

Reference Example 21-1

Synthesis of 1H-benzimidazole-2-yl (3-methoxyphenyl) methanone

Benzimidazole (3.54 g, 30.0 mol) was dissolved in 10 ml of pyridine, and triethylamine (13.3 g, 132 mol) was added, followed by stirring at room temperature. To the solution, m-anis chloride (15.3 g, 90.0 mmol) was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 1 hour. Further, the reaction temperature was raised to 50 and the mixture was stirred for 2 hours. Next, 150 ml of 4N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was stirred at 60 for 3 hours. After allowing the reaction solution to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water, 1N diluted hydrochloric acid, and saturated saline, and dried over magnesium sulfate. After filtering off magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The title compound was obtained by recrystallization from ethyl acetate (4.60 g, 61%).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.39 (d, 1 Η, J = 8.1 Hz), 8.14 (s, 1 H), 7.79 (brd, 2 H), 7.48 (dd, 1 H, J = 8.1, 8.2 Hz), 7.43-7.41 (m, 2 H), 7.21 (d, 1 H, J = 8.2 Hz), 3.91 (s, 3 H).

Reference Example 21-2

Synthesis of (3-butene-3-yl-1H-benzimidazol-2-yl) (3-methoxyphenyl) methanone

1H-benzimidazole-2-yl (3-methoxyphenyl) methanone (2.52 g, 10.0 ol) was dissolved in 20 ml of DMF, and potassium carbonate (2.07 g, 15.0 mmol) and 18-crown-6- Ether (396 mg, 1.50 mmol) and 4-bromo-1-butene (2.03 g, 15.0 mmol) were sequentially added, followed by stirring at 80 for 4 hours. After allowing the reaction solution to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed successively with water and saturated saline, Dried with Nesium. After filtering off the magnesium sulfate, the solvent was distilled off under reduced pressure. Furthermore, the title compound was obtained by purification by silica gel column chromatography (3.01 g, 98 mg).

Ή thigh _{(CDC1 3, 400 MHz) δ} 7.93 (d, 1 H, J = 8.1 Hz), 7.92 - 7.90 (m, 1 H), 7.79 (s, 1 H), 7.48 (dd, 1 H, J = 8.1, 8.2 Hz), 7.46-7.38 (m, 3 H), 7.18 (d, 1 H, J = 8.2 Hz), 5.82 (ddt, 1 H, J = 5.1, 15.2, 7.1 Hz), 5.02 ( d, 1 H, J = 15.2 Hz), 5.01 (d, 1 H, J = 5.1 Hz), 4.67 (t, 2 H, J = 7.4 Hz), 3.89 (s, 3 H), 2.66 (dt, 2 H, J = 7.1, 7.4 Hz).

Reference Example 22

Synthesis of (tobut-3-one-tolyl-4-tert-butyl-1H-imidazole-2-yl) (4-methylphenyl) methanone

Reference Example 22-1

Synthesis of 4-tert-butyl-1H-imidazole

Tribromo-3,3-dimethyl-2-butanone (5.00 g, 27.9 ol) was dissolved in formamide (37.7 g, 83.7 bc01) and stirred at 160 for 5 hours. After the reaction solution was allowed to cool to room temperature, 100 ml of water was added, and the aqueous layer was washed with 50 ml of hexane. A 2N aqueous sodium hydroxide solution was added to the obtained aqueous layer to adjust the pH of the solution to about 10, and the solution was extracted with a black hole form. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the title compound (1.67 g, 48%).

_{Ή NMR (CDC1 3, 400 MHz} ) 6 7.56 (d, 1 H, J = 1.1 Hz), 6.77 (d, 1 H, J = 1.1 Hz), 1.31 (s, 9 H).

Reference Example 22-2

Synthesis of tribut-3-en-1-yl-4-ter tributyl-1H-imidazole

4-tert-Butyl-1H-imidazole (992 mg, 8.00 mmol) was dissolved in 10 ml of DMF, potassium t-butoxide (990 mg, 8.80 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. 4-Bromo_1-butene (1.62 g, 12.0 mmol) was added to the reaction solution, and the mixture was stirred at 80 for 2 hours. The reaction solution was allowed to cool to room temperature and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. Next, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (623 mg, 44%).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 7.38 (s, 1 H), 6.60 (s, 1 H), 5.74 (ddt, 1 H, J = 5.1, 15.2, 7.4 Hz), 5.09 (d, 1 H, J = 15.2 Hz), 5.08 (d, 1 H, J = 5.1 Hz), 3.92 (t, 2 H, J = 7.2 Hz), 2.51 (dt, 2 H, J = 7.4, 7.2 Hz), 1.28 (s , 9H).

Reference Example 22-3

Synthesis of (1-but-3-ene-toluyl-4-tert-butyl-1H-imidazole-2-yl) (4-methylphenyl) methanone

Tobut-3-ene-4-tol-4-tert-butyl-1H-imidazole (53.5 mg, 0.300 mmol) was dissolved in 1 ml of pyridine, and triethylamine (91.1 mg, 0.900% ol), 4-Toluoyl chloride (139 mg, 0.900 mmol) was sequentially added, and the mixture was stirred at 60 ° C for 5 hours. After allowing the reaction solution to cool to room temperature, 5 ml of a 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added with 10 ml of water, and extracted with ethyl acetate. The organic layer was washed with water, 1N diluted hydrochloric acid and saturated saline, and dried over magnesium sulfate. Next, the solvent was distilled off under reduced pressure, and then purified by silica gel column chromatography. The title compound was obtained (29.4 mg, 33 mg).

_{Ή NR (CDC1 3, 400 MHz} ) δ 8.30 (d, 2 Η, J = 8.3 Hz), 7.27 (d, 2 H, J = 8.3 Hz), 6.86 (s, 1 H), 5.77 (ddt, 1 H , J = 6.2, 17.1, 7.0 Hz), 5.07 (d, 1 H, J = 17.1 Hz), 5.06 (d, 1 H, J = 6.2 Hz), 4.42 (t, 2 H, J = 7.2 Hz), 2.59

(dt, 2 H, J = 7.0, 7.2 Hz), 2.42 (s, 3 H), 1.32 (s, 9 H).

In the same manner as in Example 1, the compounds of Examples 54 to 63 were synthesized.

Example 54

[3-((1Ε) -3- (2- [4- (Trifluoromethyl) benzoyl] -1H-imidazole-1-yl] prop-throen-1-yl) phenoxy] cyclobutanoic acid

LC-MS (Method B) R.T.4.36 min., M / z 471 (M + l)

Example 55

2-Methyl-2- [3-((IE) -4- {4-methyl-2- [4- (trifluoromethyl) benzoyl] -1H-dimidazole-butyl} butane -Tolyl) phenoxy] propanoic acid

LC-MS (Method B) R.T.4.11 min., M / z 487 (M + l)

Example 56

2-methyl-2- [3-((IE) -4- {4-pentyl-2- [4- (trifluoromethyl) benzoyl] -1H-imidazole-triyl} but-triene Yl) phenoxy] propanoic acid

LC-MS (Method B) R.T.4.76 min., M / z 543 (M + l)

Example 57

2- (3-{(IE) -4- [2- (4-trifluoromethylbenzoyl) -5-pentyl-1H-imidazo-tril] but-triene-triyl} phenoxy ) -2-Methylpropanoic acid

LC-MS (Method B) R.T. 4.86 min., M / z 543 (M + l)

Example 58

2- (3-{(1Ε) -4- [4-ter-tert-butyl-2- (4-methylbenzoyl) -1H-imidazolyl-tolyl] but-toluene-tolyl} phenoxy) 2-methylpropanoic acid

LC-MS (Method B) R.T.4.11 min., M / z 475 (M + l)

Example 59

2-methyl-2- (3- {(IE) -4- [2- (4-methylbenzoyl) -4- (trifluoromethyl) -1H-imidazole-butyl-butene -Tolyl) phenoxy) propanoic acid

LC-MS (Method B) R.T.4.57 min., M / z 487 (M + l)

Example 60

2-Methyl-2- (3-{(IE) -4- [2- (4-methylbenzoyl) -1H-benzimidazol-1-yl] but-toluene-tolyl} phenoxy) propane Acid

LC-MS (Method B) R.T.4.43 min., M / z 469 (M + l)

Example 6 1

(2R) -2- (3-{(IE) -4- [2- (4-methylbenzoyl) -1H-benzimidazol-1-yl] but-triene-triyl} phenoxy) Propanoic acid

LC-MS (Method B) R.T.4.32 min., M / z 455 (M + l)

Example 62

(2S) -2- (3-{(IE) -4- [2- (4-methylbenzoyl) -1H-benzimidazolyl-butyl] but-1-butene-phenyl} phenoxy ) Propanoic acid

LC-MS (Method B) R.T.4.30 min., M / z 455 (M + l)

Example 6 3

2,2-dimethyl-3- (3-{(IE) -4- [2- (4-methylbenzoyl) -1H-benzimidazolyl] but-trien-tolyl} phenoxy) butanoic acid

LC-MS (Method B) R.T.4.86 min., M / z 483 (M + l)

In the same manner as in Example 26, the compounds of Examples 64 to 69 were synthesized.

Example 6 4

2-Methyl-2- [3- (4- {2- [4- (trifluoromethyl) benzoyl] -1H-imidazole-l] butyl) phenoxy] propanoic acid

LC-MS (Method B) R.T.4.38 min., M / z 475 (M + l)

Example 6 5

2-methyl-2- [3- (4- {5-methyl-2- [4- (trifluoromethyl) benzoyl] -1H-imidazole-triyl} butyl) phenoxy] propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.20 (d, 2 H, J = 8.1 Hz), 7.71 (d, 2 H, J = 8.1 Hz), 7.16 (dd, 1 H, J = 7.7, 8.1 Hz) , 7.05 (s, 1 H), 6.85 (d, 1 H, J = 7.7 Hz), 6.76 (s, 1 H), 6.75 (d, 1 H, J = 8.1 Hz), 4.37 (t, 2 H, J = 7.1 Hz), 2.66 (t, 2 H, J = 7.2 Hz), 2.29 (s, 3 H), 1.76 (m, 4 H), 1.57 (s, 6 H).

2-Methyl-2- (3- {3- [2- (4-methylbenzoyl) -1H-benzimidazol-1-yl] propyl} phenoxy) propanoic acid

LC-MS (Method B) R.T. 4.40 min., M / z 457 (M + l)

Example 67

2-methyl-2- [3- (3- {2- [3- (trifluoromethyl) benzoyl] -1H-benzimidazole-tolyl} propyl) phenoxy] propanoic acid

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.52 (s, 1 H), 8.49 (d, 1 H, J = 7.8 Hz), 7.90 - 7.86 (m, 2 H), 7.65 (dd, 1 H, J = 7.8, 7.8 Hz), 7.46-7.37 (m, 4 H), 7.34 (d, 1 H, J = 8.7 Hz), 6.81 (s, 1 H), 6.60 (d, 1 H, J = 8.7 Hz), 4.60 (t, 2 H, J = 7.4 Hz), 2.78 (t, 2 H, J = 7.5 Hz), 2.20 (tt, 2 H, J = 7.4, 7.5 Hz), 1.53 (s, 6 H) .

Example 68 2-Methyl-2- (3- {4- [2- (4-methylbenzoyl) -4-phenyl-1H-imidazole-toluyl] butyl} phenoxy) propanoic acid

LC-S (Method A) R.T.4.82 min., M / z 497 (M + l)

Example 6 9

2-Methyl-2- (4- {3- [2- (4-methylbenzoyl) -4-phenyl-1H-imidazole-toluyl] propyl} phenoxy) propanoic acid

LC-MS (Method A) R.T.4.74 min., M / z 483 (M + l)

In the same manner as in Example 35, the compound of Example 70 was synthesized.

Example 7 0

2- (3- {3- [2- (3-Methoxybenzoyl) -1H-benzimidazole-1-yl] propoxy} phenoxy) -2-methylpropanoic acid

LC-MS (Me thod B) R.T.4.26 min., M / z 489 (M + l)

In the same manner as in Example 43, the compounds of Examples 71 to 73 were synthesized. 2-Methyl-2- (4-{(IE) -4- [2- (4-methylbenzoyl) -4-phenyl-1H-imidazolyl-tolyl] but-toluene-tolylene} phenoxy) Propanoic acid

LC-MS (Method B) R.T.4.74 min., M / z 495 (Mil)

Example 72

3- (3-{(IE) -4- [2- (3-methoxybenzoyl) -4-phenyl-1H-imidazole-1-yl] but-1-ene-tolyl} phenoxy ) -2,2-Dimethylpropanoic acid

LC-MS (Method B) R.T.5.03 min., M / z 525 (M + l)

Example 73

2-methyl-2- (3-{(IE) -3- [2- (4-methylbenzoyl) -4,5,6,7-tetrahydrido-1H-benzimidazole-tril] propene -Tolyl) phenoxy) propanoic acid

LC-MS (Method B) R.T.3.72 min., M / z 459 (M + l)

Example 74

Evaluation of PPARα or agonist activity

Creation of plasmid for repo overnight>

Coding the ligand binding region of human PPARa (including amino acid residues 167-468) Gene fragment to be loaded or the ligand binding region of human PPARr (amino acid residue 2

04-505) is inserted into the multiclonindin site of the expression vector pM (Clontech) containing the yeast GAL4 protein DNA binding region, and the GAL4 protein DNA binding region and the human PPARα or ligand binding region are inserted. A vector plasmid expressing the fusion protein of the region was obtained.

As a reporter plasmid, a plasmid in which a GAL4 protein response element UAS and a heron) 3 globin motor were inserted into a pGL3-basic vector (Promega) containing a firefly luciferase gene was used. To correct the transformation efficiency, a plasmid p) 3g a1 contro1 (Clontech) containing the 1 ac Z gene was used.

Luciferase Atsushi>

COS-1 cells are cultured in Dulbecco's modified Eagle's medium (DMEM) without phenol red containing 5% activated carbon and dextran-treated fetal serum (Gibco) in the presence of 5% carbon dioxide at 37. did. COS-1 cells were seeded at a density of 5 × 10 ⁴ cells in a 24-well plate and cultured overnight. Replace the medium with 5% charcoal * dextran-treated medium without fetal serum, and use 5 ng of GAL4-PPARα or α expression plasmid, 50 ng of reporter plasmid, pj3 ga 1 con trol per 1 μl 350 ng of DNA was transfected using Lipofectamine Plus reagent (Gibco). After culturing for 4 hours, the medium was replaced with a medium containing 5% activated carbon / dextran-treated fetal bovine serum, and the compound of the present invention was added to a final concentration of 1 or 10 M. After culturing for 24 hours, the cells were lysed using the cell lysis solution attached to Luciferase Assay System (Promega), and the luciferase activity was measured with a luminometer using the attached luciferase measurement reagent. / 3—Galactosidase activity was measured using a galactosidase enzyme assay system (Promega) to correct for transformation efficiency.

PPARα or argonist activity was determined by adding solvent (DMSO) as a control. The luciferase activity of Dwell was shown as a relative activity with respect to 1. In 10 ^^? ? VIII α-agonist activity and PPAR-agonist activity (Table 7) are shown.

Table 7 Test substance PPAR agonist activity PPAR agonist activity

(Example number) (10 / ιΜ) (ΙΟ Μ)

Example 1 8.0 2.1

Example 2 10.2 3.1

Example 10 12.5 2.7

Example 1 2 3.1 4.3

Example 13 16.7 6.7

Example 14 24.2 7.7

Example 15 '19 .9 13.9

Example 16 27.0 7.1

Example 2 1 10.7 5.3

Example 22 20.7 3.6

Example 23 9.8 4.6

Example 25 17.3 5.8

Example 26 8.1 5.1

Example 28 35.7 9.7

Example 32 11.2 3.9

Example 36 13.3 4.9

Example 38 10.1 4.9

Example 40 9.9 2.5

Example 42 8.7 3.0

Example 44 11.0 3.2

Example 47 18.4 5.1

Example 48 8.8 4.4

Example 50 7.0 2.6

Example 52 16.0 4.4

Example 53 11.4 3.6

Example 58 6.7 3.0

Example 59 10.2 3.6

Example 60 8.5 4.0 Example 75

Evaluation of gluconeogenesis inhibitory activity using primary cultured hepatocytes

Material)

Rats: Wistar rats (male, 7 weeks old, SPF standard) were purchased from Charles River Japan and used after one week of quarantine. After an overnight fast from the day before hepatocyte preparation, it was used in the experiments.

Before reflux: NaCl 8g / L, KCl 0.4g / L, NaH 2 P0 4 - H 2 00.078g / L, Na 2 HP0 4 - 12H 2 00.151g / L, HEPES 2.38g / L, Phenol red 0.006g / _{L, EGTAO.19g / L, NaHC0 3} 0.35g / L, was used Glucose 0.9g / L (pH7.2) 0.22 filter filtered.

Collagenase solution: aCl 8g / L, KCl 0.4g / L, NaH 2 P0 4 · 2H 2 00.078g / L, Na 2 HP0 4 · 12H 2 0 0.151g / L, CaC "0.56g / L, HEPES 2.38g / L, Phenol red 0.006g / L, Collagenase 0.5g / L, Trypsin inhibitor 0.05g / L, NaHC0 3 0.35g / L of (pH 7.5) 0. fill evening was used as one filtered.

William's E medium (WE medium): A liquid medium (500 ml bottle) was purchased from Gibco and used after adding 10% FBS and 2 mM glutamine.

Krebs- Henseleit Solut ion (KHS): NaCl 6.92 g / L, KCl 0.354g / L, CaCl 2 0.258g / L, KH 2 P0 4 0.162g / L, MgS0 4 - 7H 2 0 0.292g / L, NaHC0 3 2. lg / L (ρΗ7.5) was used after filtering through a 0.22 filter.

Preparation of primary cultured hepatocytes>

The rats fasted overnight are anesthetized with Nembutal and laparotomized. After placing the force neura in the portal vein, the abdominal vein was incised and perfusion was started. After perfusion with the pre-perfusate for 3-5 minutes, collagenase perfusion was performed for 6-10 minutes. The liver was excised, minced with a scalpel, and suspended in WE medium. The suspension was filtered with a cell strainer, and the filtrate was centrifuged at 600 rpm for 1 minute. The supernatant was removed, suspended by adding KHS, and centrifuged again. The same operation was repeated again, and the obtained hepatocytes were diluted with KHS to 6 × 10 ⁵ cells / ml, and seeded at 0.5 ml / well on a 24-well plate containing gelatin. Measurement of hepatic gluconeogenesis inhibitory effect>

The total amount was added to the drug and substrate liver cells prepared above and lml / wel 1, the supernatant was collected after 3 hours incubation at 37 / 5¾ C0 ₂ conditions. Lactic acid / pyruvic acid UOmM / lmM) was used as a substrate. The glucose concentration in the collected supernatant was measured by the mutarotase-GOD method to calculate the amount of hepatic gluconeogenesis. Metformin (10 mM) was used as a positive control, and the action of each drug was calculated as a relative value with the gluconeogenesis inhibition rate as 100%. Table 8 shows the results.

Table 8

Example 76

Dissolve or suspend the test substance described in the Examples in 0.5% strength lupomethylcellulose solution and give a final dose of 30 mg / kg once a day to 7- to 8-week-old male db / db mice. Gavage was administered for 2 weeks. On the last day, the blood collected from the tail vein was immediately added with perchloric acid to remove the protein, and the blood glucose level was measured using Glucose CII Test II Co. (Wako Pure Chemical Industries). The results are shown in Table 9.

The hypoglycemic effect was derived from the following formula.

Blood glucose lowering ffl (%, Vehicle blood glucose level (last day)-Blood glucose level of test substance administration group (last day) _{iι ()}

Vehicle blood glucose (last day) Table 9

Industrial applicability

According to the present invention, it has become possible to provide a heteroaryl derivative or a salt thereof, which is useful as a preventive or therapeutic drug for diabetes, improving insulin resistance and controlling blood sugar level more safely.

Claims

1. Equation (1)

(Wherein, ring Z is the formula (2)

(R ² and R ³ are each independently a hydrogen atom, a C, — which may be substituted with a halogen atom; an alkyl, an aryl which may be substituted, a heteroaryl which may be substituted, or a halogen atom Or R ² and R ³ may be bonded to each other to form an optionally substituted ring)

Ar ¹ represents an optionally substituted arylene or an optionally substituted heteroarylene;

Ar ² represents an optionally substituted aryl or an optionally substituted heteroaryl,

W ¹ is an optionally substituted one c ₅ alkylene, an optionally substituted c ₂ _C ₅ alkenylene, an optionally substituted C ₂ _C ₅ alkynylene, or one Y-W ^2- (wherein Y represents an oxygen atom, a sulfur atom, or NR; W ² represents an optionally substituted c, — c ₅ alkylene, an optionally substituted c ₂ _c ₅ alkenylene, or an optionally substituted Represents a good C ₂ _C ₅ alkynylene, and R represents a hydrogen atom, C, mono C ₄ alkyl, or an optionally substituted aryl_C ₄ alkyl.

X ¹ is a single bond, an oxygen atom, a sulfur atom, or

0 II

— S—

Represents gamma ¹ is (Dc, - c ₅ alkylene, ② optionally substituted with a halogen atom c, one c ₄ alkyl, optionally substituted with a halogen atom C, one c ₄ alkoxy, optionally substituted Ariru, optionally substituted Ariruokishi, it may also be substituted I Ariru d-c ₄ Arukiruokishi, Horumiruamino, c ₂ - c ₆ Arukanoirua amino, C, may be substituted by _C ₄ alkyl O alkoxycarbonyl O alkoxy, c ₄ alkyl optionally substituted O alkoxycarbonyl § amino, c, - c ₄ alkyl optionally substituted force Rubamoiruokishi, hydroxyl, C, one c ₄ alkyl carbonylation Ruokishi, halogen atom or Shiano C substituted by any group selected from alkylene, ®c ₂ - c ₅ alkenylene, optionally substituted by ④ halogen atom - C ₄ alkyl, Optionally substituted with androgenic atom C, one c ₄ alkoxy, hydroxyl,, -. (4 alkyl force Ruponiruokishi, c ₂ which is substituted with any group selected from a halogen atom or Shiano - c ₅ alkenylene, ®c ₂ — c ₅ alkynylene, ても optionally substituted by halogen atom — c ₄ alkyl, optionally substituted by halogen atom C, _C ₄ alkoxy, hydroxyl group, _ (: ₄ alkylcarponyloxy, C ₂ —C ₅ alkynylene substituted with any group selected from a halogen atom or cyano, or C, —C ₄ alkyl optionally substituted with a halogen atom, C optionally substituted with a halogen atom C-containing a cyclic structure, which may be substituted with any group selected from the group consisting of: c ₄ alkoxy and oxo

Represents 3 -C ₈ alkylene;

R ¹ represents a substituent selected from carboxyl, optionally substituted C, —C ₄ alkylsulfonylcarbamoyl, optionally substituted arylsulfonylcarbamoyl, and tetrazolyl. Or a salt thereof.

2. Ring Z is the formula (3)

A compound represented by claim 1 or a salt thereof.

3. Ring Z is the formula (4)

(Four)

A compound represented by claim 1 or a salt thereof.

4. Ring Z is the formula (5)

A compound represented by claim 1 or a salt thereof.

5. The compound according to claim 1, wherein Ring Z is phenylimidazole or benzimidazole, or a salt thereof.

6. The compound according to any one of claims 1 to 5, wherein X ¹ is an oxygen atom, or a salt thereof.

7. The compound according to claims 1 to 6, wherein R ¹ is carboxyl, or a compound thereof.

¾.

8. Y ¹ is (DCi-Cs alkylene or, ② optionally substituted by a halogen atom C, one c ₄ alkyl, optionally substituted with a halogen atom c, -c ₄ alkoxy, optionally substituted Good aryl, optionally substituted aryloxy, optionally substituted aryl c, _c ₄ alkyloxy, formylamino, c ₂ _

C ₆ alkanoyloxy Noi Rua amino, C, substituted one c ₄ may be substituted by alkyl Okishikarubo Niruokishi, C, one c ₄ alkyl optionally substituted O alkoxycarbonyl § amino, c, -c ₄ alkyl May be powered by rubamoyloxy, hydroxyl, C, one C

₄ alkyl force Ruponiruokishi, C substituted by any group selected from a halogen atom or Shiano, - C ₅ compounds or salts of its represented by claims 1-7 alkylene.

9. Y ¹ is Ci-Cg alkylene or C,, - C ₄ C substituted with alkyl, or a salt thereof according to claim 1-7 is -C ₅ alkylene.

10. W ¹ is an optionally substituted C, or a salt thereof according to claim 1-9 which is an C ₅ alkylene.

1 1. W ¹ is an optionally substituted C ₂ - C _5, or a salt thereof according to claim 1-9 is alkenylene.

12. A r ¹ is by-phenylene optionally alkylene substituted, the bonding position of Ar ¹ X ¹ ', according to claim 1 1 1 Neu bonding position of W ¹ to a meta or para position A compound or salt thereof according to any one of the above.

13. A r ¹ is a good phenylene which may be substituted, the bonding position of A r ¹ X ¹ ', according to any of claims 1 1 1 is meta to the bonding position of W ¹ Or a salt thereof.

14. A r ¹ is a good phenylene which may be substituted, the bonding position of Ar ¹ X ¹ ', the bonding position of W ¹ to a para claim 1 one 1 1 according any Compound or salt thereof.

15. The method according to claim 11, wherein W ¹ is trans C ₃ —C ₄ alkenylene, and the bonding position of Ar ¹ of X ¹ is a meta position with respect to the bonding position of Or a salt thereof.

16. W ¹ is trans C ₃ - is a C ₄ alkenylene, binding position of A r ¹ X ¹ ', according to claim 1 one 9 binding position of W ¹ to a para position, 1 1, 14 The compound or salt thereof according to any one of the above.

17. W ¹ is an optionally substituted C, 1 C ₅ alkylene, and the bonding position of Ar ¹ of X ¹ is a meta position with respect to the bonding position of W ¹ . The compound or salt thereof according to any one of the above.

18. The method according to claim 11, wherein W ¹ is an optionally substituted C, —C ₅ alkylene, and the bonding position of Ar ¹ of X ¹ is para to the bonding position of The compound or salt thereof according to any one of the above.

1 9. 2-Methyl-2- [4- (3- {2- [4- (trifluoromethyl) benzoyl] -1H-benzimidazol-1-yl} propyl) phenoxy] propanoic acid, 2S) -2- [3- (3- {4-methyl-2- [4- (trifluoromethyl) benzoyl] -1H-imidazole-1-yl} propyl) phenoxy] propanoic acid, 2 -Methyl-2- [3- (4- {4-phenyl-2- [4- (trifluoromethyl) benzoyl] -1H-imidazole-1-yl} butyl) phenoxy] propanoic acid,

2- (3- {4- [2- (3-methoxybenzoyl) -4-phenyl-1H-imidazole-toyl] butyl} phenoxy) -2-methylpropanoic acid, 2-methyl-2- (3- {(1E) -4- [2- (4-methylbenzoyl) -1H-benzimidazole-triyl] but-toluene-tolyl} phenoxy) propanoic acid or 2-methyl-2- ( The compound according to claim 1, which is 3- {3- [2- (4-methylbenzoyl) -1H-benzimidazole-tolyl] propyl} phenoxy) propanoic acid or a salt thereof.

20. A prodrug of the compound of claims 1 to 19.

21. A medicament comprising the compound according to claims 1 to 19 and a prodrug thereof.

22. PPARαagonist, PPARragonist or PPARα / argonist comprising the compound according to claim 1 to 19 and a prodrug thereof as an active ingredient

23. A PPARr partial agonist, an engonist, or a PPARa / r activation regulator (modulator) comprising the compound according to claim 1 or 19 and a prodrug thereof as an active ingredient.

24. A hepatic gluconeogenesis inhibitor comprising the compound according to claims 1 to 19 and a prodrug thereof as an active ingredient.

25. An antidiabetic agent comprising the compound according to any one of claims 1 to 19 and a prodrug thereof as an active ingredient.

26. A method for treating diabetes comprising the compound according to claims 1 to 19 and a prodrug thereof as an active ingredient.

27. Use of the compound according to any one of claims 1 to 19 and a prodrug thereof as an active ingredient for preparing a therapeutic agent for diabetes.