KR20140117301A - A medicine comprising phenyl derivatives - Google Patents

Abstract

The purpose of the present invention is to provide a medicine composition containing a compound represented by chemical formula (I-1) so as to develop a medicine product which is useful in treating S1P_2-interposed diseases, for example diseases caused by the shrinkage of blood vessels, fibrosis, and respiratory system diseases. The compound represented by chemical formula (I-1) has strong human S1P_2-antagonistic activities and has remarkable portal blood pressure reducing functions so as to be used as an agent for preventing and/or treating S1P_2-interposed diseases - for example, diseases caused by the shrinkage of blood vessels and fibrosis. (In the formula, all marks are the same as written in the specification.).

Description

A MEDICINE COMPRISING PHENYL DERIVATIVES < RTI ID = 0.0 >

The present invention relates to a pharmaceutical composition comprising a compound represented by the following formula (I-1), a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof (hereinafter sometimes referred to as a compound of the present invention) A prophylactic and / or therapeutic agent for S1P ₂ reperfusion disease, and a pharmaceutical composition containing the compound of the present invention.

(Wherein all symbols have the same meaning as in the latter case)

Sphingosine-1-phosphate [(2S, 3R, 4E) -2-amino-3-hydroxyoctadec-4-enyl-1-phosphoric acid; Hereinafter, it is abbreviated as S1P) is a lipid synthesized by the action of sphingolipid metabolism in the cell or secreted sphingosin kinase of extracellular secretion, It is proposed to act as a transferring material.

As for the S1P receptor _{during, S1P 2 (EDG-5 /} AGR16 / H218) receptors, the expression of the mRNA heart, lungs, stomach, it is strongly confirmed in tissue of the intestine, and the rat carotid atherosclerosis model of coronary artery In the balloon injury model of the present invention, it has been reported that the expression amount of the mRNA in the endothelial cells is significantly reduced compared to normal endothelial cells (see Patent Document 1).

In addition, it has been reported that S1P receptors (especially S1P ₂ receptors) are involved in portal hypertension and asthma (see Non-Patent Document 1). In addition, it is known that it participates in the expression of CTGF (Connective Tissue Growth Factor) associated with the development of pheochromocytoma or cancer.

However, as the prior art of the present invention, the following compounds are known.

As a compound having S1P ₂ antagonistic activity, it has been disclosed that a pyrazopyridine compound represented by the following formula (a) or a pharmaceutically acceptable salt thereof specifically acts on the S1P ₂ receptor and is useful as an antineoplastic agent (See Patent Document 2).

In the above formulas, R ^1a , R ^2a and R ^3a represent a C1-8 alkyl group and the like; R ^4a represents a hydrogen atom or the like; R ^5a and R ^6a are the same or different and each represents a hydrogen atom, a C1-8 alkyl group, a C1-6 alkoxy group, a halogen atom or the like; X ^a represents -NH-, -O-, -CH ₂ - and the like; Y ^a represents -NH- or the like; Z ^a represents -CO- or the like; W ^a represents -NH- or the like; The ring A ^a represents an aryl group, a heteroaryl group or the like (with the exception of the definition of each group).

Also, as a compound having S1P ₂ antagonistic activity, a compound having a piperidine skeleton represented by the following formula (b) (see Patent Document 3) and a compound having an azetidine skeleton (see Patent Document 4) are also known.

In the above formula, A ^b represents a cyclic group which may have a substituent, X ^b represents a single bond or a spacer having 1 to 3 atoms of the main chain, Y ^b represents a single bond or a spacer having 1 to 3 atoms of the main chain , Z ^b represents a single bond or a spacer having 1 to 3 atoms of the main chain, and B ^b represents a cyclic group which may have a substituent.

On the other hand, as a compound having a benzene skeleton in which two cyclic groups are substituted, for example, a compound represented by the following formula (c) is known as a matriptase inhibitor (see Patent Document 5).

Wherein P ₁ ^c and P ₂ ^c independently represent a bond (bond) or C _1-3 alkyl; A ^c represents CH or N; B ^c represents CH or N; R ₁ ^c represents hydrogen, amino, -NR ₄ ^c -CO-Z ^c R ₉ ^c R ₁₃ ^c and the like; R ₃ ^c is -C (NR ₁₇ ^c ) NH ₂ , or, when A ^c is CH, R ₃ ^c is also amino C _1-7 alkyl; R ₁₀ ^c , R ₁₄ ^c and R ₁₅ ^c independently represent hydrogen, halogen, C _1-7 alkyl and the like; Q ^c represents hydrogen or halogen; R ₄ ^c represents hydrogen or C _1-7 alkyl; Z ^c is a saturated, partially saturated or aromatic ring of 5-12 atoms, which may be monocyclic or bicyclic; R ₉ ^c and R ₁₃ ^c independently represent hydrogen, halogen, C _1-7 alkyl and the like; R ₂ ^c represents C _1-7 alkyl, optionally substituted phenyl, etc.; R ₁₇ ^c represents hydrogen, -OH, C _1-7 alkoxy, etc. (with the exception of definitions of each group).

It has been found that the compound of the present invention in which two cyclic groups, particularly a phenoxy group, is introduced into a specific substitution site has remarkably improved human S1P ₂ antagonistic activity and has a remarkable effect of decreasing portal pressure, There is no.

Patent Document 1: JP-A-6-234797 Patent Document 2: International Publication No. 01/98301 pamphlet Patent Document 3: International Publication No. 2004/002531 pamphlet Patent Document 4: International Publication No. 2005/063704 pamphlet Patent Document 5: International Publication No. 2010/133748 pamphlet

Non-Patent Document 1: Biochemical and Biophysical Research Communications, Vol. 320, No. 3, 754-759, 2004] Non-Patent Document 2: Molecular Cancer Research, Vol. 6, No. 10, pp. 1649-1656, 2008]

An object of the present invention, in the compound described in Patent Document 3 had insufficient improve human S1P ₂ antagonistic activity and, also, to provide a pharmaceutical composition containing a compound having a remarkable lowering action portal.

In order to solve the above problems, the present inventors have intensively studied in order to find a compound having improved human S1P ₂ antagonistic activity. As a result, surprisingly, the present inventors have found that two cyclic groups, 1) of the present invention has remarkable potency decreasing effect in addition to the remarkably improved human S1P ₂ antagonistic activity as compared with the compound described in Patent Document 3. Accordingly, it has been found that a compound represented by the formula (I-1) is very useful for practical use as a medicine, and the present invention has been completed.

That is, the present invention relates to the following [1] to [20] and the like.

[1] A pharmaceutical composition comprising a compound represented by the following formula (I-1), a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof:

Wherein R ¹ is (1) a C 1-8 alkyl group which may be substituted with 1 to 5 R ²¹ , (2) a C 2-8 alkenyl group which may be substituted with 1 to 5 R ²¹ , (3) (4) a C1-4 alkyl group, a C1-4 haloalkyl group, a C1-4 alkoxy group, and a halogen atom, which is optionally substituted with one to five R < ²¹ > Or (5) -CONR ³¹ R ³² ,

R ²¹ represents a halogen atom, (2) -OR ²² (in which R ²² represents (1) a hydrogen atom, (2) a C 1-4 alkyl group, or (3) a C 1-4 haloalkyl group) (3) -NR ²³ R ²⁴ (wherein R ²³ and R ²⁴ each independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group), or (4)

R ³¹ and R ³² each independently represent (1) a hydrogen atom or (2) a C 1-4 alkyl group,

R ² represents (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group,

R ³ and R ⁴ each independently represent a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) -L-CONR ⁶ R ⁷ , (7) -L-SO ₂ R ⁸ or (8) -L-COOR ⁹ ,

R ⁵ represents (1) a halogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group,

L represents a group represented by the following formula (1), (2) a group represented by the following formula, (3) a C2-4 alkenylene group, (4) -O-C2-4 alkenylene group, A nitrogen atom which may be substituted with a C1-4 alkyl group,

(Wherein, A is (1) can be coupled, or (2) represents an oxygen atom, R ¹² and R ¹³ are each independently (1) hydrogen atom, (2) C1~4 alkyl, (3) a hydroxyl group, or (4) NH ₂ , or (5) R ¹² and R ¹³ may form a C3-7 carbon ring together with the bonding carbon atom, and the right arrow represents -CONR ⁶ R ⁷ , -SO ₂ R ⁸ , or -COOR ⁹ )

R ⁶ and R ⁷ are each independently (1) hydrogen atom, (2) C1~4 alkyl, (3) C1~4 haloalkyl group, (4) a hydroxyl ^{group, (5) -CONR 15 R 16} , (6) -SO ₂ NR ¹⁵ R ¹⁶ , (7) -COR ¹⁷ , or (8) -SO ₂ R ¹⁷ , or R ⁶ and R ⁷ , together with the nitrogen atom to which they are bonded, A nitrogen-containing saturated heterocyclic ring may be formed,

R ⁸ is (1) C1~4 alkyl, (2) C1~4 haloalkyl refers to an alkyl group, or (3) NR ¹⁰ R ^11,

R ⁹ represents (1) a hydrogen atom, or (2) a C 1-8 alkyl group,

R ¹⁰ and R ¹¹ are each independently (1) hydrogen atom, (2) C1~4 ^{alkyl, (3) -CONR 15 R 16} , (4) -SO 2 NR 15 R 16, (5) -COR 17 , Or (6) -SO ₂ R ¹⁷ ,

ring1 and ring2 each independently represent a cyclic group of 5 to 7 members,

R ¹⁴ represents (1) a hydrogen atom, or (2) a hydroxyl group,

R ¹⁵ and R ¹⁶ each independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a 5-7 membered cyclic group,

R ¹⁷ represents (1) a C1-4 alkyl group, or (2) a 5-7 membered cyclic group,

M ¹ and M ² are each independently selected from the group consisting of (1) a bond, (2) -C (O) -, (3) -O-, (4) , (6) -CH ₂ O-, or (7) -C (O) NH-,

n represents an integer of 1 to 2,

m represents an integer of 1 to 2,

p represents an integer of 0 to 5,

q represents an integer of 0 to 5,

r represents an integer of 0 to 4,

t represents an integer of 1 to 4,

When p is 2 or more, a plurality of R < ³ > s may be the same or different,

When q is 2 or more, a plurality of R ^{4 s} may be the same or different,

When r is 2 or more, plural R ^{5 s} may be the same or different,

When t is 2 or more, a plurality of R ¹² and R ¹³ may be the same or different.

[2] The composition of [1] a compound represented by formula (I-1) described in, its salts, its solvates, its N- oxide thereof, or prevention of comprising the prodrug thereof S1P ₂ gae intrinsic diseases and / Or therapeutic agent.

[3] The use of a compound according to any one of [1] to [3], wherein the S1P ₂ reperfusion disease is selected from the group consisting of diseases caused by contraction of blood vessels, neurodegeneration, respiratory diseases, arteriosclerosis, peripheral arterial occlusion, retinopathy, glaucoma, (2), wherein the agent is selected from the group consisting of hepatitis, hepatitis, liver cirrhosis, hepatic insufficiency, neuropathy, rheumatism, wound, pain, hemorrhage, systemic erythematosus (SLE) or cancer.

[4] The use of a compound according to any one of [1] to [4], wherein the disease caused by vasoconstriction is selected from the group consisting of cerebral vasoconstrictive disease, cardiovascular inflammatory disease, coronary angiopathic disease, hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, ), Portal hypertension, varicose veins, ascites, splenomegaly, hepatic encephalopathy or ischemic reperfusion injury.

[5] The agent according to the above [4], wherein the disease caused by contraction of blood vessels is portal hypertension or varicose vein.

[6] The agent according to [4] or [5], which has a continuous portal pressure lowering action.

[7] The agent according to [6] above, which is capable of administration once a day.

[8] The agent according to any one of [4] to [7] above, which is a preventive agent for primary bleeding or secondary bleeding from esophageal varices according to portal hypertension.

[9] The preparation according to [2], wherein R ¹⁴ is a hydroxyl group.

[10] A compound of the formula (I) wherein M ¹ and M ² are each independently selected from the group consisting of (1) -C (O) -, (2) -O-, 5) agents described in the -CH ₂ O- the above [2].

[11] The preparation according to [10], wherein M ¹ and M ² are -O-.

[12] The preparation according to [2], which is a compound represented by the following formula (I).

[Wherein all symbols have the same meanings as defined above]

[13] The compound according to [1], wherein R ¹ is (1) a C1-8 alkyl group which may be substituted with 1 to 5 R ²¹ or (2) a group consisting of C1-4 alkyl group, C1-4 alkoxy group, a halogen atom and a trifluoromethyl group , Or a C 3 to C 7 carbon atom which may be substituted with 1 to 5 substituents selected from Substituent group?

[14] The preparation according to [12] or [13], wherein R ² is a hydrogen atom.

[15] The agent according to any one of the above-mentioned [12] to [14], wherein ring1 and ring2 are each independently selected from the group consisting of (1) benzene, (2) cyclohexane or (3) pyridine ring.

[16] The compound represented by the general formula (I-1) is (1) 4- (2- Fluorophenoxy) phenyl} -4-hydroxy-1-piperidinecarboxamide, (2) 4- [3- (4-fluorophenoxy) -5 - ({[4- Phenoxy] benzoic acid, (3) 4- (2-ethylbutyl) -N- [3- (4-fluorophenoxy) (4) Synthesis of 2- {4 - [(4-hydroxy-1-piperidinyl) carbonyl] phenoxy} Carbonyl] amino} phenoxy] phenyl} -2-methylpropanoic acid, < RTI ID = 0.0 & (5) Synthesis of 1- {4- [3- (4-fluorophenoxy) -5 - ({[4-hydroxy- Phenyl} cyclopropanecarboxylic acid, (6) 2- {4- [3- (4-fluorophenoxy) -5 - {[(3-hydroxy-3-isobutyl-1-azetidinyl ) Carbonyl] amino} phenoxy] phenyl} -2-methylpropanoic acid, (7) 4- (4-fluorophenoxy) phenoxy] benzoic acid, (8) < RTI ID = 0.0 & Amino} -5- (4-fluorophenoxy) phenoxy] - < / RTI > Phenyl} -2-methylpropanoic acid or (9) 2- (4 - {[3- (4-fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- Yl) carbonyl] amino} benzoyl] oxy} phenyl) -2-methylpropanoic acid.

[17] A pharmaceutical composition comprising a compound represented by the formula (I-1), a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof, a calcium antagonist, a thrombolytic agent, Antioxidants, radical scavengers, PARP inhibitors, astrocyte remedies, Rho kinase inhibitors, angiotensin II antagonists, angiotensin converting enzyme inhibitors, diuretics, phosphodiesterase inhibitors 4 inhibitors, prostaglandins, aldosterone antagonists, endothelin antagonists, prostacyclin agents, nitrate drugs,? Brokers, and vasodilators.

[18] 2- {4- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1 -piperidinyl) carbonyl] amino} phenoxy] phenyl } -2-methylpropanoic acid.

Amino] -5- (4-fluorophenoxy) -1-piperidinyl] carbonyl} Phenoxy] phenyl} -2-methylpropanoic acid.

[20] 1- {4- [3- (4-Fluorophenoxy) -5 - ({[4-hydroxy-4- Yl] phenyl} cyclopropanecarboxylic acid.

The compound of the present invention has potent human S1P ₂ antagonistic activity and has a remarkable effect of lowering portal pressure. Therefore, the compound of the present invention is useful as a preventive and / or therapeutic agent for S1P ₂ reperfusion diseases such as diseases caused by contraction of blood vessels, useful.

Figure 1 shows a powder X-ray diffraction spectrum chart of the compound of the present invention (Example A).
Fig. 2 shows a differential scanning calorimetry (DSC) chart of the compound of the present invention (Example A).
Figure 3 shows a powder X-ray diffraction spectrum chart of the compound of the present invention (Example B).
Fig. 4 shows a differential scanning calorimetry (DSC) chart of the compound of the present invention (Example B).
Figure 5 shows a powder X-ray diffraction spectrum chart of the compound of the present invention (Example C).
Fig. 6 shows a differential scanning calorimetry (DSC) chart of the compound of the present invention (Example C).

Hereinafter, the present invention will be described in detail.

In the present invention, the halogen atom means fluorine, chlorine, bromine and iodine.

In the present invention, the C1-8 alkyl group includes straight or branched C1-8 alkyl groups, and examples thereof include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, Butyl, tert-butyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2- dimethylpropyl, 2- methylbutyl, 3- methylbutyl, 2,2- Ethyl-2-methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethyl Methylbutyl, 1-methylbutyl, 1-methylpentyl, 2-ethylpentyl, 1-propylbutyl, 2-methyl-3- Ethyl-1-methylbutyl, 1-methyl-2-ethylbutyl, 1-ethyl-2-methylbutyl, 2-methylbutyl, Methylbutyl, 1,1-dimethylbutyl, 1,1-diethylpropyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- methyl Methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 3- ethyl Ethyl-4-methylpentyl, 1-propyl-3-methylbutyl, 1,1-dimethylhexyl, 1-ethyl-1- Methylpentyl, or 1,1-diethylbutyl group.

In the present invention, the C1-4 alkyl group includes straight or branched C1-4 alkyl groups, and examples thereof include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, .

In the present invention, the C1-4 haloalkyl group is preferably a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, A chloropropyl group, a 2-chloropropyl group, a 3-fluoropropyl group, a 3-chloropropyl group, a 4,4,4-trifluorobutyl group, a 4-bromo Butyl group.

In the present invention, the C2-8 alkenyl group includes straight or branched C2-8 alkenyl groups such as vinyl, propenyl, butenyl, pentenyl, hexenyl, hexadienyl, heptenyl, 2-methylbutene-2-yl, or 2-methylpentene-2-yl, A diary can be heard.

In the present invention, the C2-4 alkenylene group includes ethenylene, propenylene, and butenylene group.

In the present invention, the C2-8 alkynyl group includes a linear or branched C2-8 alkynyl group such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, hexadienyl, heptynyl , Heptadienyl, octynyl, octadienyl, or 3,3-dimethyl-1-butyn-1-yl group.

In the present invention, the C1-4 alkoxy group includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy group.

In the present invention, the carbon ring of C3 to C7 means a monocyclic carbon ring of C3 to C7, a carbon ring which may be partially or completely saturated, and examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane , Cycloheptane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclobutadiene, cyclopentadiene, cyclohexadiene, cycloheptadiene, or benzene rings.

In the present invention, the carbon ring of C5-7 means a monocyclic carbon ring of C5-7, a carbon ring which may be partially or completely saturated, and examples thereof include cyclopentane, cyclohexane, cycloheptane, cyclopentene , Cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene, and benzene rings.

In the present invention, the 4- to 7-membered nitrogen-containing saturated heterocycle is a partially or fully saturated 4- to 7-membered monocyclic hetero ring containing 1 to 5 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom Refers to a ring containing at least one nitrogen atom. For example, there may be mentioned azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, And examples thereof include piperidine, dihydroxypyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, (Oxazolidine), dihydroisooxazole, tetrahydroisooxazole (tetrahydrofuran), tetrahydrofuran, tetrahydrofuran, dioxane, tetrahydrofuran, dioxane, tetrahydrofuran, (Isothiazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetra (Oxadiazoline), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetra (tetrahydroisoquinoline), tetra (Thiadiazolidine), dihydrothiazine, dihydrothiazines, thiothiazines, thiadiothiazines, thiadiothiazines, thiadiothiazines, thiadiothiazines, thiadiothiazines, thiadiothiazines, There may be mentioned tetrahydrothiazines, dihydrothiadiazines, tetrahydrothiadiazines, dihydrothiazepines, tetrahydrothiazepines, perhydrothiazepines, dihydrothiadiazepines, tetrahydrothiadiazepines, perhydrothiadiazepines, Morpholine, or thiomorpholine ring.

In the present invention, the 5-7 membered cyclic group means a C 5-7 carbon ring and a 5-7 membered heterocycle. Here, the carbon ring of C5 to C7 has the same meaning as described above, and the 5- to 7-membered heterocycle includes 5- to 7-membered unsaturated heterocycle and 5- to 7-membered saturated heterocycle. Examples of the 5- to 7-membered heterocycle include pyrrole, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydro And examples thereof include pyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine , Dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxyne But are not limited to, triphenylphosphine, triphenylphosphine, triphenylphosphine, triphenylphosphine, triphenylphosphine, triphenylphosphine, triphenylphosphine, triphenylphosphine, triphenylphosphine, triphenylphosphine, triphenylphosphine, (Tetrahydrothiophene), tetrahydrothiazole (thiazolidine), tetrahydrothiophene, dihydrothiazole, tetrahydrothiazole, thiazolidine, dihydrothiazole, ), Dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazane, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydro But are not limited to, oxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxazine Diazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazine There is provided a dithiocarbamate derivative which is selected from the group consisting of ziprin, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathian, dioxolane, dioxane, A pyrimidine, a pyrazine, an azepine, a diazepine, a furan, a pyran, an oxepine, a thiophene, a thiopyran, a thiepine, an oxazole, , Thiazepine, thiadiazine, thiadiazine, thiadiazine, thiadiazine, thiadiazine, thiadiazine, thiadiazine, thiadiene, thiadiene, thiadiene, thiadiene, Zepin ring can be heard.

In the present invention, R ¹ as selected from 1 to 5 may be substituted with one R ²¹ good C1~8 alkyl, or C1~4 alkyl, C1~4 haloalkyl group, C1~4 alkoxy group, a halogen atom and the group consisting of A C5-7 carbon ring which may be substituted with 1 to 5 substituents selected from the group consisting of a halogen atom and a trifluoromethyl group, and is substituted with 1 to 5 substituents selected from the group consisting of a branched C1-8 alkyl group, More preferably benzene or cycloheptane ring. Here, the branched C1-8 alkyl group is preferably isopropyl, isobutyl, 2-ethylbutyl, 2-methylpentyl or 3-methylpentyl.

In the present invention, R ² is preferably a hydrogen atom.

In the present invention, ring 1 is preferably benzene, pyridine, or cyclohexane ring, more preferably a benzene ring.

In the present invention, as the ring 2, benzene, pyridine, or cyclohexane ring is preferable, and a benzene ring is more preferable.

In the present invention, preferred compounds are the compounds described in the examples. (1) 4- (2-ethylbutyl) -N- {3- [4- (ethylcarbamoyl) phenoxy] (4-fluorophenoxy) phenyl} -4-hydroxy-1-piperidinecarboxamide, (2) 4- [3- (2-ethylbutyl) -N- [3- (4-fluoro-phenyl) Phenoxy) phenyl] -4-hydroxy-1-piperidinecarboxamide, (4) 2- (4-fluoro- Carbonyl] amino} phenoxy] phenyl} -2-methyl < / RTI > ({[4-hydroxy-4- (3-fentanyl) -1-piperidinyl] carbonyl} propanoic acid, Amino] phenoxy] phenyl} cyclopropanecarboxylic acid, (6) 2- {4- [3- (4- fluorophenoxy) -5 - {[ Azetidinyl) carbo (2-ethylbutyl) -4-hydroxy-1-piperidinyl] carbonyl} Phenoxy] benzoic acid, (8) 2- {4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy-1-piperidylamino] Yl] carbonyl} amino) -5- (4-fluorophenoxy) phenoxy] phenyl} -2-methylpropanoic acid is more preferable.

[Isomer]

In the present invention, unless specified otherwise, the isomer includes all such isomers. For example, the alkyl group includes straight chain and branched chain. In addition, optical isomers (R, S, α, β configuration, enantiomer) by the presence of double bonds, rings, geometric isomers (E, Z, cis, trans) (High polarity, low polarity) due to chromatographic separation, an equilibrium compound, a rotamer, and an arbitrary ratio therebetween of the optically active substance (D, L, d, , Racemic mixtures are all included in the present invention. In the present invention, all of the isomers formed by tautomers are also included.

In addition, the optical isomer in the present invention may contain not only 100% pure but also other optical isomers of less than 50%.

는 지면의 반대쪽(즉 α 배치)에 결합되어 있는 것을 나타내고,

는 지면의 앞쪽(즉 β 배치)에 결합되어 있는 것을 나타내며,

는 α 배치, β 배치 또는 이들의 임의의 비율의 혼합물인 것을 나타낸다.In the present invention, as apparent to those skilled in the art, unless specifically denied,

(I.e.,? Arrangement) on the opposite side of the paper surface,

(That is, &thetas; arrangement) of the paper surface,

Quot; refers to an alpha arrangement, a beta arrangement, or a mixture of any of these ratios.

The compound represented by the formula (I-1) is converted into the corresponding salt by a known method. The salt is preferably water-soluble. Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium etc.), ammonium salts, pharmaceutically acceptable organic amines (such as tetramethylammonium, triethylamine, methylamine, dimethyl Salts of amines, cyclopentylamines, benzylamines, phenethylamines, piperidines, monoethanolamines, diethanolamines, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D- (Acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate), organic acid salts (acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate Benzenesulfonic acid salts, toluenesulfonic acid salts, isethionic acid salts, glucuronic acid salts, gluconic acid salts and the like), and the like.

The compound represented by the formula (I-1) and a salt thereof may be converted into a solvate. Solvates are preferably low toxicity and water soluble. Suitable solvates include, for example, solvates with water and alcohol solvents (such as ethanol).

The N-oxide compound of the compound represented by the formula (I-1) means that the nitrogen atom of the compound represented by the formula (I-1) is oxidized. The N-oxide compound of the compound represented by the formula (I-1) may also be an alkali (earth) metal salt, an ammonium salt, an organic amine salt or an acid moiety.

The prodrug of the compound represented by the formula (I-1) refers to a compound which is converted in vivo into a compound represented by the formula (I-1) by reaction with an enzyme or gastric acid. As the prodrug of the compound represented by the formula (I-1), when the compound represented by the formula (I-1) has a hydroxyl group, the hydroxyl group is acylated, alkylated, phosphorylated, Compounds in which the hydroxyl groups of the compounds are acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); The carboxyl group of the compound represented by the formula (I-1) is esterified or amidated (e.g., the carboxyl group of the compound represented by the formula (I-1) is ethyl esterified, isopropyl esterified, phenyl esterified, (5-methyl-2-oxo-1,3-dioxolen-1-yl) -pyrrolidone, 4-yl) methyl esterification, cyclohexyloxycarbonyl ethyl esterification, methyl amidated compounds, etc.); And the like. These compounds can be prepared by a known method. The prodrug of the compound represented by the formula (I-1) may be either a hydrate or a non-hydrate. The prodrug of the compound represented by the formula (I-1) can be prepared according to physiological conditions as described in Hirokawa Shoten, 1990, Development of Drugs, Vol. 7, Molecular Design, pages 163-198 May be changed to a compound represented by the formula (I-1). Further, the compound represented by the formula (I-1) is isotope ^{(e.g., 2 H, 3 H, 11} C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 35 S , ¹⁸ F, ³⁶ Cl, ¹²³ I, ¹²⁵ I, etc.).

[Production method of the compound of the present invention]

The compound of the present invention may be prepared by a known method, for example, a method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999) And the like can be appropriately improved and used in combination.

In the formula (I), a compound wherein R ² is a hydrogen atom, that is, a compound represented by the formula (IA) can be produced according to the reaction scheme 1 shown below.

(Wherein all symbols have the same meanings as defined above)

Wherein, T is, represents a protective group for amino group having a carbonyl group (for example, 2,2,2-trichloroethoxycarbonyl (Troc) group, a phenoxycarbonyl group, p- nitrophenoxy group, etc.), X ^1, X ² and X ³ each independently represent a halogen atom, and X ¹ , X ² and X ³ may be the same or different, and other symbols have the same meanings as defined above.

In the reaction scheme 1, Reaction 1 can be carried out by treating with a compound represented by the formula (A) and a compound represented by the formula (II) by an etherification reaction. This etherification reaction is well known and can be carried out, for example, in an organic solvent (N, N-dimethylacetamide, N, N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t- (Such as sodium hydroxide, potassium hydroxide and lithium hydroxide), alkali metal hydrides (such as sodium hydride), alkaline earth metal hydroxides (such as barium hydroxide and calcium hydroxide), phosphates (such as potassium phosphate) , Or in the presence of a carbonate (cesium carbonate, sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof at 0 ° C to 100 ° C.

In the reaction scheme 1, Reaction 2 can be carried out by treating with a compound represented by the formula (B) and a compound represented by the formula (III) by an etherification reaction in the same manner as in the reaction 1.

In the reaction scheme 1, Reaction 3 can be carried out by treating the compound represented by the formula (C) with a nitro group reduction reaction. The reduction reaction of the nitro group is known, and is carried out, for example, by the following method.

(Such as methanol, ethanol, etc.), benzene (benzene, toluene, etc.), ketones (such as acetone, methyl (meth) acrylate, (Palladium-carbon, palladium black, palladium (II), palladium (II), palladium (II) and the like) in a solvent such as acetonitrile or the like), nitrile (Such as hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, acetic acid, p-toluenesulfonic acid, oxalic acid, p-toluenesulfonic acid, and the like) in the presence of a base (e.g., sodium hydroxide, potassium hydroxide, Trifluoroacetic acid, formic acid and the like) in the presence of ammonium formate or in the presence of hydrazine at a temperature of 0 ° C to 200 ° C under a hydrogen atmosphere under normal pressure or under pressure.

(2) a metal reagent (such as zinc, copper, or the like) in the presence or in the absence of an acid (hydrochloric acid, hydrobromic acid, acetic acid, ammonium formate, etc.) in a solvent (ethanol, methanol, tetrahydrofuran, At a temperature of 0 占 폚 to 150 占 폚 using a metal such as iron, tin, tin chloride, iron chloride, samarium, indium, sodium borohydride, nickel chloride or the like.

Reaction Scheme 1 is known in Reaction Scheme 1 wherein the compound represented by the formula (IV) is reacted with a compound represented by the formula (D) and a compound represented by the formula (IV) (Chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) in the presence of a solvent such as tetrahydrofuran, tetrahydrofuran, tetrahydrofuran, dimethylformamide, Lt; RTI ID = 0.0 > 40 C < / RTI > Alternatively, the compound represented by the formula (IV) can be obtained by reacting the compound represented by the formula (D) and the compound represented by the formula (IV) in an organic solvent (such as ethyl acetate, dioxane or tetrahydrofuran) with an aqueous alkali solution (sodium hydrogen carbonate solution, sodium hydroxide solution or the like) Deg.] C to 40 [deg.] C.

In reaction scheme 1, Reaction 5 is known. For example, a compound represented by the formula (E) is reacted with a compound represented by the formula (E) and a compound represented by the formula (V) (N, N-dimethylacetamide, chloroform, dichloromethane, diethyl ether, tetra (dimethylamino) pyridine, etc.) in the presence of a base such as triethylamine, Hydrofuran, etc.) at a temperature of 0 ° C to reflux temperature.

When a protecting group is present in the compound represented by each chemical formula in the reaction scheme 1, for example, when R ³ or R ⁴ is protected, the deprotection reaction can be carried out if necessary. The deprotection reaction of this protecting group is well known and can be carried out by the following method. For example, (1) deprotection reaction by alkaline hydrolysis, (2) deprotection reaction under acidic conditions, (3) deprotection reaction by hydrolysis, (4) deprotection reaction of silyl group, ) Deprotection reaction using a metal, (6) deprotection reaction using a metal complex, and the like.

Describing these methods in detail,

(1) The deprotection reaction by alkaline hydrolysis can be carried out, for example, by reacting a hydroxide of an alkali metal (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkali (For example, barium hydroxide, calcium hydroxide, etc.) or a carbonate (for example, sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof at 0 ° C to 40 ° C.

(2) The deprotection reaction under acidic conditions can be carried out in the presence of an organic acid (for example, acetic acid, trifluoroacetic acid, and the like) in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, tetrahydrofuran, Trifluoroacetic acid, methanesulfonic acid, p-tosyl acid and the like) or inorganic acid (e.g. hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (for example, hydrogen bromide / In the presence or in the absence of a solvent, at 0 ° C to 100 ° C.

(3) The deprotection reaction by hydrolysis is carried out, for example, in a solvent (for example, ethers such as tetrahydrofuran, dioxane, dimethoxyethane and diethyl ether), alcohols (for example, methanol, (E.g., acetone, methyl ethyl ketone, etc.), nitrile (e.g., acetonitrile), amide (e.g., N, N-dimethylformamide) Under atmospheric pressure or under pressure, in the presence of a catalyst (for example, palladium-carbon, palladium black, palladium hydroxide, carbon hydroxide, platinum oxide, Raney nickel, etc.) in a solvent such as water, ethyl acetate, acetic acid, Or in the presence of ammonium formate at a temperature of 0 ° C to 200 ° C.

(4) The deprotection reaction of the silyl group is carried out at 0 ° C to 40 ° C, for example, in tetrabutylammonium fluoride in an organic solvent capable of being miscible with water (for example, tetrahydrofuran, acetonitrile, etc.) . Among the organic acids (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosyl acid, etc.) or inorganic acids (e.g., hydrochloric acid, sulfuric acid, etc.) -10 캜 to 100 캜.

(5) The deprotection reaction using a metal can be carried out in the presence of powdered zinc in an acidic solvent (for example, a buffer solution of acetic acid, a pH of 4.2 to 7.2, or a solution thereof and an organic solvent such as tetrahydrofuran) If necessary, ultrasonic waves are applied at 0 ° C to 40 ° C.

(6) The deprotection reaction using a metal complex is carried out, for example, in an organic solvent (for example, dichloromethane, N, N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, (For example, hydrogenated tributyltin, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine and the like), organic acids (for example, acetic acid, formic acid and 2-ethylhexanoic acid) In the presence or absence of a phosphine-based reagent (for example, triphenylphosphine) in the presence of an organic acid salt (for example, sodium carbonate, potassium carbonate and the like) and / or an organic acid salt (for example, sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, For example, by using tetrakistriphenylphosphine palladium (0), dichloride bis (triphenylphosphine) palladium (II), palladium (II) acetate, tris (triphenylphosphine) rhodium , At 0 캜 to 40 캜.

Further, in addition to the above, for example, T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999).

Examples of the protecting group of the hydroxyl group include a methyl group, a trityl group, a methoxymethyl (MOM) group, a 1-ethoxyethyl (EE) group, a methoxyethoxymethyl (MEM) group, a 2- tetrahydropyranyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), acetyl Benzyl (Bn) group, p-methoxybenzyl group, allyloxycarbonyl (Alloc) group, 2,2,2-trichloroethoxycarbonyl (Troc) group and the like.

Examples of the protecting group of the amino group include a benzyloxycarbonyl group, a t-butoxycarbonyl group, an allyloxycarbonyl (Alloc) group, a 1-methyl-1- (4biphenyl) ethoxycarbonyl (Bpoc) group, (Bn) group, a p-methoxybenzyl group, a benzyloxymethyl (BOM) group, and a 2- (trimethylsilyl) ethoxymethyl (SEM) group.

The protecting group for the hydroxyl group and the amino group is not particularly limited as long as it is a group which can be easily and selectively removed in addition to the above. See, for example, T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999).

The compound represented by the formula (A), (II), (III), (IV) or (V) is used in the respective reactions in the present specification, Can be easily produced.

In each reaction in this specification, the reaction involving the heating can be carried out using a water bath, an oil bath, a sand bath or a microwave, as will be apparent to those skilled in the art.

A solid phase supporting reagent carried on a polymer polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol or the like) suitably may be used in each reaction in the present specification.

In each reaction described herein, the reaction product may be purified by conventional purification means such as distillation under atmospheric pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, scavenger resin Alternatively, purification can be carried out by a method such as column chromatography or washing or recrystallization. The purification may be performed for each reaction or may be performed after completion of several reactions.

[toxicity]

The toxicity of the compound of the present invention is sufficiently low and can be used safely as a medicine.

[Application to medicine]

Since the compound of the present invention has S1P ₂ antagonistic activity, it is useful as a prophylactic and / or therapeutic agent for S1P ₂ reperfusion disease. Examples of the S1P ₂ reperfusion disease include diseases caused by contraction of blood vessels, asthenopia, respiratory diseases, arteriosclerosis, peripheral arterial occlusion, retinopathy, glaucoma, macular degeneration, nephritis (including kidney failure), diabetes, diabetic complications (Including diabetic retinopathy, diabetic nephropathy, etc.), lipid disorders, hepatitis (including nonalcoholic fatty liver disease, alcoholic fat hepatitis, viral hepatitis, etc.), cirrhosis, liver failure, neurological disorders, joint rheumatism, , Dementia, systemic erythrometeses (SLE), and cancer.

In the present invention, diseases caused by contraction of blood vessels include cerebrovascular inflammatory diseases, cardiovascular inflammatory diseases, coronary artery inflammation diseases, hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, atrial fibrillation, portal hypertension, Ascites, ascites, hepatic encephalopathy, ischemic reperfusion injury, and the like.

In the present invention, examples of spongiform encephalopathy include, but are not limited to, rheumatoid arthritis, hepatic encephalopathy, scleroderma, myocardial sclerosis, and skin sclerosis.

In the present invention, examples of respiratory diseases include bronchial asthma, acute lung disorder, sepsis, chronic obstructive pulmonary disease and the like.

In the present invention, examples of the varicose veins include esophageal varices, gastric varices, duodenal varices, small intestine varices, colonic varices, or rectal varices.

Since the compound of the present invention has a portal pressure lowering effect, it can be used as a preventive agent for primary bleeding or secondary bleeding from esophageal varices according to portal hypertension, in addition to being able to be used as a preventive and / or therapeutic agent for portal hypertension.

Since the compound of the present invention has a constant portal pressure lowering effect, it can exert the preventive and / or therapeutic effect of portal hypertension by administration once a day.

The compound of the present invention,

1) complementing and / or enhancing the preventive and / or therapeutic effect of the compound,

2) improvement of dynamics / absorption of the compound, reduction of dose, and / or

3) Reduction of side effects of the compound

May be administered as a concomitant drug in combination with another drug.

The combination of the compound of the present invention and another drug may be administered in the form of a compounding agent in which both components are combined in one preparation, or may be administered in the form of a separate preparation. When administered by the respective formulations, simultaneous administration and administration by time lag are included. In addition, the administration by the time difference may be carried out by administering the compound of the present invention first and the other drug later, or by administering the other drug first and then administering the compound of the present invention. Each of the administration methods may be the same or different.

The disease causing the preventive and / or therapeutic effect by the above-mentioned concomitant drug is not particularly limited, and it may be a disease complementing and / or enhancing the preventive and / or therapeutic effect of the compound of the present invention.

Other drugs for complementing and / or enhancing the preventive and / or therapeutic effect of diseases caused by contraction of blood vessels of the present invention include calcium antagonists, thrombolytics, thromboxane synthetase inhibitors, endothelin Antagonists, antioxidants, radical scavengers, PARP inhibitors, astrocyte remedies, Rho kinase inhibitors, angiotensin II antagonists, angiotensin converting enzyme inhibitors, diuretics, phosphodiesterase (PDE) 4 inhibitors, Prostaglandins (hereinafter sometimes abbreviated as PG or PG), aldosterone antagonists, endothelin antagonists, prostacyclin agents, nitrate drugs,? Brokers, and vasodilators.

Other drugs for complementing and / or enhancing the prophylactic and / or therapeutic effect of the compounds of the present invention include steroid drugs, immunosuppressive drugs, TGF-beta inhibitors, PDE5 inhibitors and the like.

Other drugs for complementing and / or enhancing the preventive and / or therapeutic effect of the compounds of the present invention on respiratory diseases include, for example, PDE4 inhibitors, steroid drugs, beta agonists, leukotriene receptor antagonists, thromboxane synthetase inhibitors Antagonist drugs, cytokine inhibitors, PGs, phoscholines, elastase inhibitors, metalloproteinase inhibitors, antihistamines, antihistamines, anticholinergics, , A giant drug or an antibiotic substance.

Examples of the calcium antagonist include nifedipine, benzindipine hydrochloride, diltiazem hydrochloride, verapamil hydrochloride, nisol dipine, nitrendipine, bepridil hydrochloride, amlodipine hydrochloride, romeridine hydrochloride, .

Examples of thrombotic abortions include alteplase, urokinase, thyso kinase, nasar flas, natuplasia, tissue plus minogen activator, pamitheplasma, and monteflazine.

Examples of the thromboxane synthetase inhibitor include ozagrel hydrochloride, and mitrostast sodium.

Examples of the radical scavenger include radicals and the like.

Examples of the PARP inhibitor include 3-aminobenzamide, 1,3,7-trimethylxanthin, PD-141076, PD-141703 and the like.

Examples of astrocyte function improving drugs include ONO-2506 and the like.

Examples of the Rho kinase inhibitor include fasdill hydrochloride and the like.

Examples of the angiotensin II antagonist include losartan, candesartan, valsartan, irbesartan, olmesartan, and telmisartan.

Examples of the angiotensin converting enzyme inhibitor include aracepril, imidapril hydrochloride, quinapril hydrochloride, temocapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, captopropril, trandolapril, perindopril erbumine, maleic acid Enalapril, lisinopril, and the like.

Examples of the diuretic agents include mannitol, furosemide, acetazolamide, dichlorphenamide, metazolamide, trichloromethyazide, mefenacid, spironolactone, aminopyrine and the like.

PDE4 inhibitors include, for example, ROLLIPRAM, CILO MILEST, Bay19-8004, NIK-616, roflumilast, sipampilin, artilouram, SCH-351591, YM-976, V- 11294A, PD-168787, ONO -6126, D-4396, IC-485, and the like.

Examples of prostaglandins (PG) include PG receptor agonists or PG receptor antagonists.

Examples of the PG receptor include PGE receptor (EP1, EP2, EP3, EP4), PGD receptor (DP, CRTH2), PGF receptor (FP), PGI receptor (IP) or thromboxane receptor (TP).

Examples of the aldosterone antagonist include drospirenone, methylafon, potassium cannonate, karenone, eplerenone, ZK-91587, and the like.

Examples of prostacyclin preparations include treprostinil sodium, epoprostanol sodium, and veraprost sodium.

Examples of the nitric acid drug include amyl nitrite, nitroglycerin, and isosorbide nitrate.

As the? broker, there may be mentioned, for example, alfrenolol hydrochloride, buprenol hydrochloride, bupitol hydrochloride, oxprenolol hydrochloride, atenolol, nonaspoolol fumarate, betetholol hydrochloride, bevantolol hydrochloride, methoprolol hydrochloride, The present invention relates to a medicament for the treatment and prophylaxis of diabetes mellitus such as celluloprolol, nifadilol hydrochloride, tilysolol hydrochloride, nadolol hydrochloride, propranolol hydrochloride, indenol hydrochloride, hydrochloric acid carteolol, pinolol, Diol, thymolol maleate, and the like.

Examples of the vasodilator include diltiazem hydrochloride, trimetadine hydrochloride, dipyridamole, etanophene hydrochloride, dilazepine hydrochloride, tripyridyl, nicorandil and the like.

Examples of the steroid medicines include, but are not limited to, corticosteroids such as cortisone, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, cortisone acetic acid, prednisolone, acetic acid prednisolone, sodium borosilicate prednisolone, butyl acetic acid prednisolone, sodium prednisolone phosphate, There may be mentioned haloperidone, methylprednisolone, methylprednisolone acetate, sodium methylprednisolone succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone acetate, dexamethasone phosphate, dexamethasone palmitate, paramethasone acetate and betamethasone . Examples of the steroid drugs of the inhaler include steroids such as beclomethasone propionate, fluticasone propionate, budesonide, fluney solid, triamcinolone, ST-126P, cyclosonide, dexamethasone pyromitonate, Prasetron sulphonate, Deplaar coat, methylprednisolone sulphate, methylprednisolone sodium succinate, and the like.

Examples of immunosuppressive drugs include azathiopurine, mizoribine, methotrexate, mycophenolate, cyclophosphamide, cyclosporin A, tacholimus, sirolimus, everolimus, prednisolone, methylprednisolone, orthoclone OKT3, Anti-human lymphocyte globulin, deoxyspergualin, and the like.

Examples of PDE5 inhibitors include sildenafil, tadalafil, valenaphil, and udenafil.

Examples of the [beta] -activating agent include, for example, phenol hydrobromide, salbutamol sulfate, terbutaline sulfate, formoterol fumarate, salmeterol xinafosan sulfate, isoproteren sulfate, orcipherin sulfate, chlorprenaline sulfate, Epinephrine, trimethoquinol hydrochloride, hexoprenaline mesyl sulfate, procaterol hydrochloride, tulobuterol hydrochloride, tulobuterol, pyruvate hydrochloride, clenbuterol hydrochloride, mabuterol hydrochloride, ritodrine hydrochloride, bambu terol, hydrochloric acid R-formoterol, KUR-1246, KUL-7211, AR-C89855, S-1319 and the like can be mentioned.

Examples of the leukotriene receptor antagonist include pranlukast hydrate, montelukast, zafirlukast, ceratostast, and the like.

Examples of the thromboxane A2 receptor antagonist include ceratologist, lamatroban, and ditprovan calcium hydrate.

Examples of the mediator freezing suppressing agent include tranilast, sodium cromoglycoxate, amelaxanth, repirinast, ibudilast, tazanorast, femalostar potassium and the like.

Examples of the antihistamine drug include fentanyl fentanate, fentanyl fentanyl, fentanyl fentanyl, fentanyl fentanyl, fentanyl fentanyl, fentanyl fentanyl, , Lauratadine, desloratadine hydrochloride, olopatadine hydrochloride, TAK-427, ZCR-2060, NIP-530, Mometasone proate, Mizorastine, BP-294, Andorast, auranopin, .

Examples of xanthine derivatives include aminophylline, theophylline, toxin filine, sipampiline, dipropylin and the like.

Examples of the anticholinergic drugs include ipratropium bromide, oxitropium bromide, flutropium bromide, metropium bromide, timiberine, thiotropium bromide, levatropheate and the like.

Examples of cytokine inhibiting drugs include tosyl acid supplytastes and the like.

Examples of the antilastase inhibitor include ONO-5046, ONO-6818, MR-889, PBI-1101, EPI-HNE-4 and R-665.

Examples of the sweet potato preparations include, but are not limited to, ammoniacal felids, sodium bicarbonate, bromhexine hydrochloride, carbosystane, ambroxol hydrochloride, Ambrosol hydrochloride hydrochloride, methylcysteine hydrochloride, acetylcysteine, L-ethylcysteine hydrochloride, .

Examples of the antibiotic substance include antibiotics such as Sephrox sodium, Meropenem trihydrate, Nethylmyrc sulfate, Sethomycin sulfate, Ceftibuten, PA-1806, IB-367, Tobramycin, PA-1420, doxorubicin, And a ceftazam hydrochloride coated cloth. Examples of the inhalation antibiotics include PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromethosulfuric acid, cephetam hydrochloride hydrochloride and the like.

In addition, the concomitant drug to be used in combination with the compound of the present invention includes not only those found up to now, but also those to be discovered in the future.

The compound of the present invention is usually administered systemically or locally, orally or parenterally. Examples of the oral preparation include oral liquid preparations (for example, tablets (including tablets, intraoral disintegrating tablets), tabletting agents (for example, tablets, , Pills, capsules (including hard capsules, soft capsules, gelatine capsules, microcapsules), powders, granules, troches). Examples of the parenteral preparation include liquid preparations such as liquid preparations such as injections (subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip agent and the like), eye drops (such as aqueous eye drops (aqueous eye drops, aqueous suspension, viscous drops, (Non-aqueous eye drops, non-aqueous suspensions, etc.)), external preparations (for example, ointments and the like), dots and the like. These preparations may be release-controlling agents such as accelerating agents and sustained-release agents. These preparations can be prepared by a known method, for example, a method described in Japanese Pharmacopoeia.

The oral solution for oral administration is prepared, for example, by dissolving, suspending or emulsifying the active ingredient in a commonly used diluent (for example, purified water, ethanol or a mixture thereof). The liquid agent may further contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.

As the oral solid preparations for internal use, for example, the active ingredient may be mixed with an excipient such as an excipient (e.g., lactose, mannitol, glucose, microcrystalline cellulose, starch and the like), a binder (such as hydroxypropylcellulose, polyvinylpyrrolidone, Magnesium stearate, etc.), a stabilizer, a solubilizing aid (glutamic acid, aspartic acid, etc.), and the like, by a conventional method. Further, it may be coated with a coating agent (for example, white sugar, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like) if necessary, or may be coated with two or more layers.

The external preparation for parenteral preparation is prepared by a known method or a commonly used formulation. For example, ointments are prepared by softening or melting an active ingredient to a base. The ointment base is selected from those known or commonly used. For example, there may be mentioned higher fatty acids or higher fatty acid esters such as adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc. (E.g., beeswax, wax, ceresin and the like), a surfactant (e.g., a polyoxyethylene alkyl ether phosphate ester and the like), a higher alcohol (such as a cetanol, a stearyl alcohol and a cetostearyl alcohol) (E.g., dimethylpolysiloxane, etc.), hydrocarbons (e.g., hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (e.g., ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, Vegetable oils (e.g., castor oil, olive oil, sesame oil, paraffin oil and the like), animal oils (such as mink oil, egg yolk oil, squalane, squalene, etc.) Or a mixture of two or more of them. Moisturizers, preservatives, stabilizers, antioxidants, flavors, and the like.

Injections as parenteral preparations include solid injections used in solutions, suspensions, emulsions, and solutions dissolved or suspended in solvents. The injection agent is used, for example, by dissolving, suspending or emulsifying the active ingredient in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, alcohols such as propylene glycol, polyethylene glycol, ethanol and the like, and a combination thereof are used. The injectable preparation may further contain a stabilizer, a solubilizing aid (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifying agent, a wetting agent, a buffering agent and a preservative. They are either sterilized in the final process or prepared by aseptic manipulation. It is also possible to prepare sterile solid preparations, such as freeze-dried preparations, before use, by dissolving them in sterilized or sterile distilled water for injection or other solvents.

In order to use the compound of the present invention or a combination of the compound of the present invention and another drug, the compound is usually administered systemically or locally, orally or parenterally. The dosage varies depending on the age, body weight, symptom, therapeutic effect, administration method, treatment time and the like, but is normally administered orally once a day to several times per day in the range of 1 ng to 1000 mg per one adult , Or parenterally once a day to several times per day in the range of 0.1 ng to 10 mg per adult, or continuously administered intravenously in the range of 1 hour to 24 hours per day. Of course, as described above, since the dosage varies depending on various conditions, an amount smaller than the above dose may be sufficient, and a case where administration is required beyond the above range may be required.

Example

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.

The solvent in the parentheses indicated by the chromatographic separation and the TLC indicates the elution solvent or developing solvent used, and the ratio represents the volume ratio.

The parentheses enclosed in the NMR section indicate the solvent used for the measurement.

The name of the compound used in this specification is a computer program naming in accordance with the rules of IUPAC, ACD / Name (registered trademark) of Advanced Chemistry Development Co., Ltd. or the name according to IUPAC nomenclature.

Example 1 : Methyl [4- (benzyloxy) phenyl] acetic acid

Methyl (4-hydroxyphenyl) acetic acid (202 g) and potassium carbonate (233 g) were added to a 3 liter eggplant-shaped flask at room temperature and dissolved in N, N-dimethylacetamide (DMA) (1 liter). Benzyl chloride (117 ml) was added at room temperature and stirred. Thereafter, the mixture was heated to 60 DEG C and stirred for 16 hours. The mixture was allowed to cool to room temperature, the reaction solution was diluted with methyl tert-butyl ether (MTBE) (1.3 L), water (3 L) was added, and the organic layer was extracted. The obtained organic layer was washed three times with 1N aqueous sodium hydroxide solution, and then washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (245 g) having the following physical data.

TLC: Rf 0.68 (hexane: AcOEt = 3: 1);

¹ H-NMR (CDCl ₃ ):? 3.56 (3H), 3.68 (3H), 5.05 (2H), 6.93 (3H), 7.19 (2H), 7.26-7.50 (5H).

Example 2 : Methyl 2- [4- (benzyloxy) phenyl] -2-methylpropanoate

Under argon atmosphere, the compound (66.5 g) prepared in Example 1 was added to a 1 liter four-necked flask and dissolved in tetrahydrofuran (THF) (260 ml). The solution was cooled to -10 DEG C, and a THF solution of methyl iodide (8.1 mL) and 1.53 M potassium tert-butoxide (85 mL) was added successively while keeping the internal temperature of the reaction solution at -10 DEG C to -7.5 DEG C . This operation was repeated eight times. Thereafter, the mixture was stirred at -10 DEG C for 10 minutes, and acetic acid (50.5 mL) was slowly added dropwise. This was neutralized with aqueous 2N sodium hydroxide solution and saturated aqueous sodium bicarbonate, and extracted with ethyl acetate and hexane. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure. Activated charcoal (4 g) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Activated charcoal was filtered and the solvent was distilled off under reduced pressure to obtain the title compound (73.0 g) having the following physical data.

TLC: Rf 0.54 (hexane: AcOEt = 5: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 1.55 (6H), 3.64 (3H), 5.05 (2H), 6.93 (2H), 7.26 (2H), 7.30-7.48 (5H).

Example 3 : Synthesis of methyl 2- (4-hydroxyphenyl) -2-methylpropanoate

Under argon atmosphere, a mixed solution of methanol (420 ml) and ethyl acetate (150 ml) of the compound (72.0 g) prepared in Example 2 was added to a 2 liter eggplant-shaped flask. After argon displacement, 20% palladium on carbon (7.60 g) was added. Degassed, and filled with hydrogen gas. And vigorously stirred at room temperature for 4 hours. The reaction system was purged with argon, filtered through celite, and washed with ethyl acetate. The filtrate was distilled off under reduced pressure, and then diluted with ethyl acetate (150 ml) and hexane (50 ml). Dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a grayish white solid (50 g). Ethyl acetate (70 ml) was added, the solid was heated and dissolved, hexane (700 ml) was added, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration, washed with hexane / ethyl acetate (10: 1) and dried to give the title compound (41.1 g) having the following physical data.

TLC: Rf 0.27 (hexane: AcOEt = 5: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 1.55 (6H), 3.65 (3H), 6.77 (2H), 7.19 (2H).

Example 4 : Methyl 2- [4- (3-fluoro-5-nitrophenoxy) phenyl] -2-methylpropanoate

The compound (41.1 g) prepared in Example 3 and potassium phosphate (81.5 g) were added to a 500 ml eggplant-shaped flask under an argon atmosphere at room temperature. 1,3-difluoro-5-nitrobenzene (30.6 g) dissolved in DMA (128 mL) was added to the reaction system and stirred. Thereafter, the mixture was heated to 70 占 폚 and stirred for 6 hours and 30 minutes. The mixture was allowed to cool to room temperature, the reaction solution was diluted with MTBE (150 ml), and ice water (150 ml) was added and stirred. MTBE and water were further added to extract the organic layer. MTBE and water were added to the aqueous layer to extract an organic layer. The organic layer was collected, washed twice with 1N aqueous sodium hydroxide solution, and then washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To obtain the title compound (66.0 g) having the following physical data.

TLC: Rf 0.68 (hexane: AcOEt = 3: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 1.62 (6H), 3.69 (3H), 6.91 (2H), 6.96-7.08 (4H), 7.40 (2H), 7.65 (1H).

Example 5 : Methyl 2- {4- [3- (4-fluorophenoxy) -5-nitrophenoxy] phenyl} -2-methylpropanoate

(64 g), 4-fluorophenol (40 g) and potassium phosphate (102 g) were added to a 500 ml eggplant type flask under an argon atmosphere at room temperature, DMA (130 ml) And stirred. It was then heated to 100 占 폚 and stirred for 10 hours. The mixture was allowed to cool to room temperature, the reaction solution was diluted with MTBE (200 ml), and ice water (400 ml) was added and stirred. Further washed with MTBE, 1N aqueous sodium hydroxide solution, and water. The aqueous layer was extracted twice with MTBE. The organic layer was collected, washed twice with 1N aqueous sodium hydroxide solution, and then washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (104 ml) was added to the obtained residue, and the mixture was heated and dissolved. Hexane (520 mL) was slowly added and stirred at room temperature to precipitate a solid. Filtered through a Kiriyama funnel (# 5B-φ95), washed with hexane / ethanol (10: 1), and the obtained residue was dried under reduced pressure at 50 ° C. The title compound (54.8 g) having the following physical data was obtained.

TLC: Rf 0.57 (hexane: AcOEt = 5: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 1.60 (6H), 3.68 (3H), 6.91 (1H), 6.91 (1H), 6.98-7.14 (4H), 7.36 (1H), 7.39 (1H), 7.40 (1H ), 7.46 (1H).

Example 6 : Synthesis of methyl 2- {4- [3-amino-5- (4-fluorophenoxy) phenoxy] phenyl} -2-methylpropanoate

Under an argon atmosphere, the compound (53.6 g) prepared in Example 5 was added to a 500 ml eggplant type flask, and a mixed solution of methanol (50 ml) and ethyl acetate (175 ml) was added. After heating to dissolution and argon replacement, 5% palladium on carbon (10.8 g) was added. Degassed, and filled with hydrogen gas. And vigorously stirred at room temperature for 3 hours. The inside of the reaction system was replaced with argon, and the resulting mixture was filtered through celite and washed with ethyl acetate. The obtained filtrate was distilled off under reduced pressure to obtain the title compound (43.9 g) having the following physical data.

TLC: Rf 0.13 (hexane: AcOEt = 5: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 1.57 (6H), 3.66 (3H), 3.69 (NH, 2H), 5.97 (1H), 6.02 (2H), 6.96 (2H), 6.99 (2H), 7.01 (2H ), 7.28 (2H).

Example 7 : Preparation of methyl 2- {4- [3- (4-fluorophenoxy) -5 - {[(2,2,2-trichloroethoxy) carbonyl] amino} phenoxy] phenyl} - methyl propanoate

Sodium hydrogen carbonate (18.6 g) was added to the compound (43.9 g) prepared in Example 6 in a 500 ml eggplant-shaped flask at room temperature under argon atmosphere and dissolved in ethyl acetate (111 ml). The mixture was cooled to 0 占 폚 and 2,2,2-trichloroethyl chloroformate (15.7 ml) was slowly added dropwise over 15 minutes so that the internal temperature did not exceed 10 占 폚. Thereafter, the mixture was stirred at room temperature for 60 minutes. After confirming that 2,2,2-trichloroethyl chloroformate disappeared by thin-layer chromatography, water was added to the reaction solution and stirred. More hexane was added to precipitate a solid. Filtered through a Kiriyama funnel (# 5B-φ95), washed with water and hexane / ethyl acetate (3: 1), and the obtained residue was dried under reduced pressure at 50 ° C. The title compound (58.5 g) having the following physical data was obtained.

TLC: Rf 0.45 (hexane: AcOEt = 5: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 1.58 (6H), 3.66 (3H), 4.77 (2H), 6.36 (1H), 6.73 (1H), 6.78 (br, 1H), 6.82 (br, 1H), 6.93 -7.10 (6H), 7.31 (2H).

Example 8 : Preparation of methyl 2- {4- [3- (4-fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1 -piperidinyl) carbonyl] amino} phenoxy ] Phenyl} -2-methylpropanoate

Compound (26.6 g) prepared in Example 7 was dissolved in DMA (31 ml), and 4-isobutyl-4-piperidinol (9.53 g) was added to a 500 ml eggplant type flask under an argon atmosphere at room temperature And the mixture was stirred. It was then heated to 90 DEG C and stirred for 2 hours. 4-isobutyl-4-piperidinol (1.45 g) and diisopropylethylamine (818 쨉 l) were further added, followed by stirring for 2 hours. The mixture was allowed to cool to room temperature, the reaction solution was diluted with MTBE, and ice water was added to extract an organic layer. The obtained aqueous layer was extracted with MTBE. The organic layer was collected, washed twice with 1N aqueous hydrochloric acid solution, three times with 1N sodium hydroxide aqueous solution, and with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The title compound (24.8 g) having the following physical data was obtained.

TLC: Rf 0.46 (hexane: AcOEt = 1: 1);

¹ H-NMR (CDCl ₃ ):? 0.97 (6H), 1.05 (1H), 1.41 (2H), 1.50-1.70 (10H), 1.75-1.90 (1H), 3.20-3.35 , 3.70-3.80 (2H), 6.25-6.35 (2H), 6.71 (1H), 6.81 (1H), 6.90-7.05 (6H), 7.29 (2H).

Example 9 : 2- {4- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4- isobutyl- 1 -piperidinyl) carbonyl] amino} phenoxy] Phenyl} -2-methylpropanoic acid

At room temperature, the compound (24.8 g) prepared in Example 8 was dissolved in a mixed solution of methanol (150 ml) and THF (150 ml) and stirred. Thereafter, the reaction mixture was heated to 45 ° C, 1N sodium hydroxide aqueous solution (107 ml) was added slowly, and the mixture was stirred overnight at 45 ° C. A 2N aqueous sodium hydroxide solution (20 mL) was added. After stirring for 1 hour, the solvent was distilled off under reduced pressure, and the mixture was further stirred at 45 캜 for 1 hour and 30 minutes. 2N aqueous sodium hydroxide solution (12 ml) was added, and the mixture was stirred at 55 캜 for 45 minutes. The mixture was cooled to 0 占 폚, and ice and a 5N hydrochloric acid aqueous solution were added thereto, and the reaction system was added until acidic (pH = 2). Diluted with ethyl acetate, and extracted. The organic layer was further washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 65: 35 → 44: 56 → 30:70) to obtain the title compound (20 g) having the following physical data.

TLC: Rf 0.53 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.28-7.33 (m, 2H), 6.94-7.01 (m, 4H), 6.89-6.93 (m, 2H), 6.80 (t, 1H), 6.61 (t, 1H) 2H), 1.71-1.85 (m, 1H), 1.46-1.59 (m, 10H), 1.34 (d, 2H) , 0.92 (d, 6H).

Example 9 (1) to 9 (64)

1,3-difluoro-5-nitrobenzene, the compound prepared in Example 3 or an equivalent phenol derivative, 4-fluorophenol or its equivalent phenol derivative, 2,2,2-trichloro Example 4? Example 5? Example 6? Example 7? Example 8? Using ethyl chloroformate and 4-isobutyl-4-piperidinol or the equivalent piperidine derivative instead, By the same procedure as in Example 9, the following compounds were obtained.

Example 9 (1) : Synthesis of 4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy-1- piperidinyl] carbonyl} amino) -5- (4-fluorophenoxy ) Phenoxy] benzoic acid

TLC: Rf 0.28 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 8.01 (d, 2H), 7.18-6.99 (m, 6H), 6.94-6.87 (m, 2H), 6.29 (t, 1H), 3.90-3.75 (m, 2H ), 3.28-3.15 (m, 2H), 1.63-1.47 (m, 4H), 1.45-1.26 (m, 7H), 0.87 (t, 6H).

Example 9 (2) : 4- [3 - ({[4- (4-Bromophenyl) -4-hydroxy-1-piperidinyl] carbonyl} amino) -5- Yl) phenoxy] benzoic acid

TLC: Rf 0.38 (dichloromethane: methanol = 10: 1);

^{1 H-NMR (DMSO-d} 6): δ 8.63 (s, 1H), 7.95 (d, 2H), 7.48 (d, 2H), 7.41 (d, 2H), 7.24 (t, 2H), 7.15-7.07 (m, 2H), 3.17-3.10 (m, 2H), 1.83-1.76 (m, 1H), 7.02 (dd, , ≪ / RTI > 2H), 1.57-1.53 (m, 2H).

Example 9 (3) : 4- [3- (4-Fluorophenoxy) -5 - ({[4- (4- fluorophenyl) -4- hydroxy- 1- piperidinyl] carbonyl} Amino) phenoxy] benzoic acid

TLC: Rf 0.38 (dichloromethane: methanol = 10: 1);

^{1 H-NMR (DMSO-d} 6): δ 8.63 (s, 1H), 7.95 (d, 2H), 7.48 (dd, 2H), 7.24 (t, 2H), 7.15-7.07 (m, 7H), 7.02 2H), 1.84-1.77 (m, 2H), 1.59-1.54 (m, 2H), 6.31 (d, (m, 2H).

Example 9 (4) : Synthesis of 4- [3- (4-chlorophenoxy) -5 - ({[4- (2-ethylbutyl) -4- hydroxy- 1- piperidinyl] carbonyl} amino) Phenoxy] benzoic acid

TLC: Rf 0.33 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 8.48 (s, 1H), 8.02 (d, 2H), 7.36 (d, 2H), 7.00-7.12 (m, 4H), 6.95 (t, 2H), 6.34 ( t, 1H), 3.83 (d, 2H), 3.14-3.29 (m, 2H), 1.28-1.68 (m, 11H), 0.87 (t, 6H).

Example 9 (5) : Synthesis of 4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy-1-piperidinyl] carbonyl} amino) -5- (4-methoxyphenoxy ) Phenoxy] benzoic acid

TLC: Rf 0.33 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 8.43 (s, 1H), 7.97-8.04 (m, 2H), 7.04 (d, 2H), 6.90-7.02 (m, 4H), 6.86-6.89 (m, 1H ), 6.85 (t, 1H), 6.15-6.29 (m, 1H), 3.78-3.85 (m, 5H), 3.13-3.28 (m, 2H), 1.49-1.71 (m, 4H), 1.23-1.44 , 7H), 0.87 (t, 6H).

Example 9 (6) : Synthesis of 4- [3- (3,4-difluorophenoxy) -5 - ({[4- (2-ethylbutyl) -4-hydroxy- 1- piperidinyl] Carbonyl] amino} phenoxy] benzoic acid

TLC: Rf 0.37 (dichloromethane: methanol = 9: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 8.03 (d, 2H), 7.06-7.18 (m, 1H), 7.03 (d, 2H), 6.84-6.93 (m, 3H), 6.73-6.81 (m, 1H) , 6.53 (br s, 1H), 6.37-6.41 (m, 1H), 3.73-3.83 (m, 2H), 3.22-3.34 (m, 2H), 1.55-1.65 (m, 7H), 0.79-0.90 (m, 6H).

Example 9 (7) : Synthesis of 4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy- 1- piperidinyl] carbonyl} amino) Phenoxy] benzoic acid

TLC: Rf 0.24 (dichloromethane: methanol = 1: 2);

_{^{1 H-NMR (CDCl 3)}} : δ 8.02 (d, 2H), 7.14 (d, 2H), 7.02 (d, 2H), 6.97-6.91 (m, 3H), 6.72 (t, 1H), 6.42-6.31 (m, 2H), 3.84-3.73 (m, 2H), 3.37-3.14 (m, 2H), 2.33 (t, 6 H).

Example 9 (8) : 4- {3 - ({[4- (2-ethylbutyl) -4-hydroxy-1- piperidinyl] carbonyl} amino) -5- [4- (trifluoro Methyl) phenoxy] phenoxy} benzoic acid

TLC: Rf 0.26 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 8.09-7.97 (m, 2H), 7.58 (d, 2H), 7.09 (d, 2H), 7.07-7.01 (m, 2H), 6.97 (t, 1H), 6.92 (m, 2H), 1.65-1.51 (m, 4H), 1.45-1.26 (m, 2H) (m, 9H), 0.84 (t, 6H).

Example 9 (9) : Synthesis of 2-chloro-4- [3 - ({[4- (2-ethylbutyl) -4- hydroxy- 1- piperidinyl] carbonyl} amino) Fluorophenoxy) phenoxy] benzoic acid

TLC: Rf 0.33 (CHCl 3: MeOH = 5: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.60 (d, 1H), 7.08-6.80 (m, 8H), 6.25 (t, 1H), 3.83 (m, 2H), 3.22 (m, 2H), 1.66- 1.30 (m, 11 H), 0.86 (t, 6 H).

Example 9 (10) : Synthesis of 4- [3- (cyclohexyloxy) -5 - ({[4- (2-ethylbutyl) -4- hydroxy- 1 -piperidinyl] carbonyl} amino) City] Benzoic acid

TLC: Rf 0.38 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.97-8.05 (m, 2H), 6.97-7.05 (m, 2H), 6.87 (t, 1H), 6.66 (t, 1H), 6.38 (s, 1H), 6.31 (m, 2H), 1.69-1.84 (m, 2H), 1.46 (m, 2H) -1.65 (m, 6H), 1.22-1.45 (m, 11H), 0.85 (t, 6H).

Example 9 (11) : Synthesis of 4- [3- (2-chlorophenoxy) -5 - ({[4- (2-ethylbutyl) -4- hydroxy- 1- piperidinyl] carbonyl} amino) Phenoxy] benzoic acid

TLC: Rf 0.25 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 8.07-7.95 (m, 2H), 7.44 (dd, 1H), 7.30-7.20 (m, 1H), 7.15-7.05 (m, 2H), 7.05-6.99 (m, 2H), 6.96 (t, IH), 6.75 (t, IH), 6.45 (s, IH), 6.34 -1.57 (m, 4H), 1.45-1.24 (m, 8H), 0.84 (t, 6H).

Example 9 (12) : 4- [3- (3-Chlorophenoxy) -5 - ({[4- (2-ethylbutyl) -4- hydroxy- 1- piperidinyl] carbonyl} amino) Phenoxy] benzoic acid

TLC: Rf 0.24 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CDCl ₃ ):? 8.11-7.96 (m, 2H), 7.31-7.20 (m, 1H), 7.11-7.02 1H), 6.83 (t, IH), 6.43 (s, IH), 6.41 (t, IH), 3.86-3.74 (m, 2H), 3.39-3.14 , 1.44-1.25 (m, 7H), 0.85 (t, 6H).

Example 9 (13) : Preparation of {4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy- 1 -piperidinyl] carbonyl} amino) -5- (4-fluorophenoxy Yl) phenoxy] phenyl} acetic acid

TLC: Rf 0.36 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.24 (d, 2H), 7.03-6.96 (m, 6H), 6.81 (dd, 1H), 6.65 (dd, 1H), 6.40 (brs, 1H), 6.31 (dd (M, 2H), 3.76-3.72 (m, 2H), 3.62 (s, 2H), 3.28-3.20 (m, 2H), 1.60-1.58 , 6H).

Example 9 (14) : Synthesis of 4- [3- (2,4-difluorophenoxy) -5 - ({[4- (2-ethylbutyl) -4-hydroxy- 1- piperidinyl] Carbonyl] amino} phenoxy] benzoic acid

TLC: Rf 0.29 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CDCl ₃ ): δ 8.01 (d, 2H), 7.19-7.06 (m, 1H), 7.06-6.69 (m, 6H), 6.51 ), 3.85-3.65 (m, 2H), 3.35-3.11 (m, 2H), 1.67-1.50 (m, 4H), 1.43-1.18 (m, 8H), 0.84 (t, 6H).

Example 9 (15) : Synthesis of 4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy-1-piperidinyl] carbonyl} amino) -5- (4-fluorophenoxy ) Phenoxy] -2-hydroxybenzoic acid

TLC: Rf 0.16 (dichloromethane: methanol: ethanol = 100: 10: 1);

¹ H-NMR ₍₃ CDCl): δ 7.48-7.62 (m, 1H), 6.91-7.10 (m, 5H), 6.77-6.87 (m, 1H), 6.67 (t, 1H), 6.57 (s br.. 1H), 6.25 (br.s, 1H), 3.55-3.83 (m, 2H), 3.03-3.30 (m, 2H), 1.41-1.57 (m, 4H), 1.21-1.40 0.81 (t, 6 H).

Example 9 (16) : Synthesis of 4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy-1- piperidinyl] carbonyl} amino) -5- (4-fluorophenoxy ) Phenoxy] -3-fluorobenzoic acid

TLC: Rf 0.48 (dichloromethane: methanol = 8: 2);

_{^{1 H-NMR (CD 3 OD}} ): δ 8.46 (s, 1H), 7.77-7.86 (m, 2H), 7.00-7.20 (m, 5H), 6.83-6.91 (m, 2H), 6.25-6.30 (m 2H), 1.20-1.67 (m, 11H), 0.86 (t, 6H).

Example 9 (17) : Preparation of {4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy- 1 -piperidinyl] carbonyl} amino) -5- (4-fluorophenoxy Yl) phenoxy] -2-fluorophenyl} acetic acid

TLC: Rf 0.19 (CHCl 3: MeOH = 19: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 6.54-7.20 (m, 10H), 6.30 (s, 1H), 3.71 (.. Br s, 2H), 3.56 (.. Br s, 2H), 3.19 (br. s., 2H), 1.13-1.47 (m, 13H), 0.64-0.93 (m, 6H).

Example 9 18 : 4- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1 -piperidinyl) carbonyl] amino} phenoxy] Benzoic acid

TLC: Rf 0.22 (dichloromethane: methanol = 9: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.95-8.05 (m, 2H), 6.99-7.16 (m, 6H), 6.89-6.90 (m, 2H), 6.27 (dd, 1H), 3.77-3.82 (m , 2H), 3.18-3.28 (m, 2H), 1.76-1.93 (m, 1H), 1.46-1.65 (m, 4H), 1.38 (d, 2H), 0.96 (d, 6H).

Example 9 (19) : Preparation of 4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy- 1 -piperidinyl] carbonyl} amino) -5- (4-fluorobenzoyl) Phenoxy] benzoic acid

TLC: Rf 0.25 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.88-7.96 (m, 2H), 7.71-7.80 (m, 2H), 7.40-7.47 (m, 2H), 7.02-7.11 (m, 2H), 6.90-6.97 ( m, 3H), 3.69-3.73 (m, 2H), 3.11-3.20 (m, 2H), 1.45-1.54 (m, 4H), 1.19-1.33 (m, 7H), 0.75 (t, 6H).

Example 9 (20) : Synthesis of 2- {4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy- 1 -piperidinyl] carbonyl} amino) -5- Phenoxy) phenoxy] phenyl} -2-methylpropanoic acid

TLC: Rf 0.39 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CDCl ₃ ):? 7.33 (d, 2H), 6.92-7.05 (m, 6H), 6.77-6.78 2H), 3.14-3.31 (m, 2H), 1.52-1.65 (m, 10H), 1.29-1.42 (m, 7H), 0.84 (t, 6H).

Example 9 (21) : 2-Chloro-4- [3- (4-fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl) carbonyl] amino } Phenoxy] benzoic acid

TLC: Rf 0.30 (chloroform: methanol = 5: 1);

_{^{1 H-NMR (CDCl 3 +}} CD 3 OD): δ 7.69 (d, 1H), 7.20-6.84 (m, 9H), 6.26 (t, 1H), 3.80 (m, 2H), 3.23 (m, 2H) , 1.87 (m, 1H), 1.66-1.48 (m, 4H), 1.37 (d, 2H), 0.95 (d, 6H).

Example 9 (22) : Synthesis of 4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy-1-piperidinyl] carbonyl} amino) -5- (4-fluorophenoxy ) Phenoxy] -2-methylbenzoic acid

TLC: Rf 0.33 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.81 (d, 1H), 6.96-7.05 (m, 4H), 6.67-6.82 (m, 4H), 6.29 (t, 1H), 3.66-3.76 (m, 2H) , 3.14-3.25 (m, 2H), 2.46 (s, 3H), 1.49-1.62 (m, 4H), 1.23-1.39 (m, 7H), 0.82 (t, 6H).

Example 9 (23) : 4- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4- isobutyl- 1 -piperidinyl) carbonyl] amino} phenoxy] -2-methylbenzoic acid

TLC: Rf 0.70 (CHCl 3: MeOH = 5: 1);

_{^{1 H-NMR (CDCl 3 +}} CD 3 OD): δ 7.81 (d, 1H), 7.18-6.78 (m, 8H), 6.24 (t, 1H), 3.80 (m, 2H), 3.23 (m, 2H) , 2.52 (s, 3H), 1.84 (m, 1H), 1.68-1.48 (m, 4H), 1.40 (d, 2H), 0.95 (d, 6H).

Example 9 (24) : Synthesis of 3-fluoro-4- [3- (4-fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1- piperidinyl) carbonyl] Amino} phenoxy] benzoic acid

TLC: Rf 0.20 (dichloromethane: methanol = 9: 1);

¹ H-NMR (CD ₃ OD):? 7.68-7.77 (m, 2H), 6.98-7.12 (m, 5H), 6.90 (dd, (D, 2H), 1.96 (d, 2H), 1.96 (d, 2H), 3.76-3.80 (m, 2H), 3.15-3.28 (m, 2H), 1.83-1.93

Example 9 (25) : Synthesis of 4- [3- (4-fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1 -piperidinyl) carbonyl] amino} phenoxy] -2-methoxybenzoic acid

TLC: Rf 0.47 (dichloromethane: methanol = 9: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.87 (d, 1H), 7.03-7.13 (m, 4H), 6.88-6.94 (m, 2H), 6.76 (d, 1H), 6.58 (dd, 1H), 2H), 3.11-3.28 (m, 2H), 1.81-1.90 (m, 1H), 1.48-1.64 (m, 4H) 1.38 (d, 2H), 0.96 (d, 6H).

Example 9 26 : 2- {4- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4- isobutyl- 1- piperidinyl) carbonyl] amino} Phenoxy] phenyl} propanoic acid

TLC: Rf 0.31 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.24 (d, 2H), 6.96-7.05 (m, 4H), 6.92 (d, 2H), 6.82 (t, 1H), 6.60-6.66 (m, 1H), 6.27 (m, 3H), 1.44 (d, 3H), 1.36 (m, (d, 2 H), 0.94 (d, 6 H).

Example 9 (27) : {2-fluoro-4- [3- (4-fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl) carbonyl ] Amino} phenoxy] phenyl} acetic acid

TLC: Rf 0.17 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CDCl ₃ ):? 7.10 (t, 1H), 6.93-7.02 (m, 4H), 6.87 (s, 2H), 3.75 (m, 2H), 3.47 (br s, 2H), 3.08-3.26 (m, 2H), 1.77 (dquin, 0.91 (d, 6H).

Example 9 (28) : {4- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1 -piperidinyl) carbonyl] amino} phenoxy ] Phenyl} acetic acid

TLC: Rf 0.17 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 8.38 (s, 1H), 7.27 (d, 2H), 7.01-7.12 (m, 4H), 6.94-7.00 (m, 2H), 6.81 (dq, 2H), 2H), 3.16-3.29 (m, 2H), 1.77-1.93 (m, 1H), 1.45-1.64 (m, 4H) 1.38 (d, 2H), 0.97 (d, 6H).

Example 9 (29) : 2-Fluoro-4- [3- (4-fluorophenoxy) -5 - ({[4- (4- fluorophenyl) -4- Yl] carbonyl} amino) phenoxy] benzoic acid

TLC: Rf 0.34 (CHCl 3: MeOH = 4: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.91 (t, 1H), 7.53-7.47 (m, 2H), 7.16-6.95 (m, 8H), 6.88-6.76 (m, 2H), 6.33 (t, 1H ), 4.08-3.97 (m, 2H), 3.40-3.30 (m, 2H), 2.07-1.94 (m, 2H), 1.77-1.67 (m, 2H).

Example 9 (30) : Synthesis of {2-fluoro-4- [3- (4-fluorophenoxy) -5 - ({[4- (4-fluorophenyl) -4- Pyridinyl] carbonyl} amino) phenoxy] phenyl} acetic acid

TLC: Rf 0.41 (CHCl 3: MeOH = 4: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.53-7.46 (m, 2H), 7.28 (t, 1H), 7.15-7.00 (m, 6H), 6.91-6.87 (m, 2H), 6.83-6.76 (m (M, 2H), 6.28 (t, 1H), 4.06-3.97 (m, 2H), 3.63 (s, 2H), 3.38-3.30 , 2H).

Example 9 (31) : 2- {4- [3- (4-Fluorophenoxy) -5 - ({[4- (4- fluorophenyl) -4- hydroxy- 1- piperidinyl] Carbonyl} amino) phenoxy] phenyl} propanoic acid

TLC: Rf 0.32 (CHCl 3: MeOH = 9: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.41-7.56 (m, 2H), 7.24-7.36 (m, 2H), 6.91-7.15 (m, 8H), 6.85 (t, 1H), 6.80 (t, 1H ), 6.21 (t, IH), 4.00 (d, 2H), 3.69 (q, IH), 3.19-3.41 (m, 2H), 1.98 (td, 2H) 3H).

Example 9 (32) : Synthesis of 4- [3- (2,4-difluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1- piperidinyl) Phenoxy] benzoic acid

TLC: Rf 0.63 (chloroform: methanol: ethanol = 9: 1: 0.1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.97 (d, 2H), 7.18-7.06 (m, 1H), 7.02-6.75 (m, 6H), 6.28 (m, 1H), 3.73 (m, 2H), 3.30 2H), 1.89-1.75 (m, 1H), 1.65-1.43 (m, 4H), 1.38 (d, 2H), 1.29-1.23 (m, 1H), 0.95 (d, 6H).

Example 9 (33) : Synthesis of {4- [3- (2,4-difluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl) carbonyl] amino } Phenoxy] phenyl} acetic acid

TLC: Rf 0.63 (chloroform: methanol: ethanol = 9: 1: 0.1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.22 (d, 2H), 7.10 (td, 1H), 7.00-6.79 (m, 5H), 6.60 (t, 1H), 6.27 (t, 1H), 3.70 (m (M, 2H), 3.52 (s, 2H), 3.28-3.13 (m, 2H), 1.90-1.73 ).

Example 9 (34) : 2-Chloro-4- [3- (2,4-difluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl) Carbonyl] amino} phenoxy] benzoic acid

TLC: Rf 0.68 (chloroform: methanol: ethanol = 9: 1: 0.1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.70 (d, 2H), 7.13 (m, 1H), 7.03-6.81 (m, 5H), 6.72 (t, 1H), 6.27 (t, 1H), 3.74 (m 2H), 1.31-1.30 (m, 2H), 1.92-1.72 (m, 1H), 1.48-1.65 (m, 4H), 1.33-1.42 -1.01 (d, 6H).

Example 9 (35) : Synthesis of {4- [3- (2,4-difluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1 -piperidinyl) carbonyl] amino } Phenoxy] -2-fluorophenyl} acetic acid

TLC: Rf 0.56 (dichloromethane: methanol = 8: 2);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.16-7.33 (m, 2H), 7.11 (ddd, 1H), 6.92-7.03 (m, 1H), 6.85 (s, 2H), 6.72-6.82 (m, 2H 2H), 3.16-3.29 (m, 2H), 1.77-1.95 (m, 1H), 1.43-1.67 (m, 4H) 1.38 (d, 2H), 0.97 (d, 6H).

Example 9 (36) : 2- {4- [3- (2,4-Difluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl) carbonyl ] Amino} phenoxy] phenyl} propanoic acid

TLC: Rf 0.72 (dichloromethane: methanol = 8: 2);

¹ H-NMR (CD ₃ OD):? 7.31 (d, 2H), 7.19 (td, IH), 7.06-7.15 (m, IH), 6.91-7.02 2H), 1.78-1.94 (m, 1H), 1.48-7.68 (m, 2H) 1.64 (m, 4H), 1.45 (d, 3H), 1.38 (d, 2H), 0.97 (d, 6H).

Example 9 (37) : 4- [3- (4-Fluorophenoxy) -5 - ({[4-hydroxy- 4- (3- fentanyl) -1- piperidinyl] carbonyl} amino) Phenoxy] benzoic acid

TLC: Rf 0.58 (CHCl 3: MeOH = 5: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.98 (d, 1H), 7.18-6.98 (m, 6H), 6.88 (d, 2H), 6.25 (m, 1H), 3.90 (m, 2H), 3.11 ( m, 2H), 1.66-1.40 (m, 7H), 1.22-1.10 (m, 2H), 0.86 (t, 6H).

Example 9 (38) : (2E) -3- {4- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl) Carbonyl] amino} phenoxy] phenyl} acrylic acid

TLC: Rf 0.31 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.49 (dd, 1H), 7.37-7.45 (m, 2H), 6.89-7.01 (m, 6H), 6.75-6.81 (m, 2H), 6.21-6.33 (m, 2H), 0.88 (dd, 2H), 3.61-3.73 (m, 2H), 3.09-3.23 (m, 2H), 1.68-1.82 6H).

Example 9 (39) : Synthesis of 4- [3- (2,4-difluorophenoxy) -5 - ({[4- (4-fluorophenyl) -4- hydroxy- 1- piperidinyl] Carbonyl} amino) phenoxy] benzoic acid

TLC: Rf 0.68 (chloroform: methanol: ethanol = 9: 1: 0.1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.99 (d, 2H), 7.50-7.35 (m, 2H), 7.19-6.80 (m, 9H), 6.30 (t, 1H), 3.94 (m, 2H), 3.39 -3.24 (m, 2H), 1.98 (m, 2H), 1.75 (d, 2H).

Example 9 (40) : 3- {4- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1- piperidinyl) carbonyl] amino} Phenoxy] phenyl} propanoic acid

TLC: Rf 0.40 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.13 (d, 2H), 6.95-7.05 (m, 4H), 6.90 (d, 2H), 6.72-6.77 (m, 1H), 6.62-6.67 (m, 1H) 2H), 2.80-2.93 (m, 2H), 2.48-2.59 (m, 2H), 1.80 (dquin, 1H), 1.43-1.62 (m, 4H), 1.35 (d, 2H), 0.93 (d, 6H).

Example 9 (41) : {4- [3- (4-Fluorophenoxy) -5 - ({[4-hydroxy-4- ) Phenoxy] phenyl} acetic acid

TLC: Rf 0.58 (chloroform: methanol: ethanol = 9: 1: 0.1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.22 (d, 2H), 7.06-6.90 (m, 6H), 6.83 (t, 1H), 6.63 (t, 1H), 6.30 (t, 1H), 3.79 (m 2H), 3.56 (s, 2H), 3.26-3.01 (m, 2H), 1.67-1.41 (m, 6H), 1.34-1.08 (m, 3H), 1.06-0.84 (m, 7H).

Example 9 (42) : 2-Chloro-4- [3- (4-fluorophenoxy) -5 - ({[4-hydroxy- Carbonyl] amino} phenoxy] benzoic acid

TLC: Rf 0.51 (chloroform: methanol: ethanol = 9: 1: 0.1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.80 (m, 1H), 7.07-6.95 (m, 5H), 6.93-6.72 (m, 3H), 6.30 (t, 1H), 3.82 (m, 2H), 3.28 -3.03 (m, 2H), 1.73-1.45 (m, 6H), 1.34-1.11 (m, 3H), 1.06-0.83 (m, 7H).

Example 9 (43) : 2- {4- [3- (4-Fluorophenoxy) -5 - ({[4-hydroxy-4- } Amino) phenoxy] phenyl} -2-ethylpropanoic acid

TLC: Rf 0.56 (chloroform: methanol: ethanol = 9: 1: 0.1);

¹ H-NMR (CDCl ₃ ):? 7.39-7.29 (m, 2H), 7.07-6.92 (m, 6H), 6.81 (t, (m, 2H), 3.27-3.08 (m, 2H), 1.66-1.42 (m, 12H), 1.33-1.10 (m, 3H), 1.05-0.87 (m, 7H).

Example 9 44 : 4- [3- (3,4-Difluorophenoxy) -5 - ({[4-hydroxy-4- (3-fentanyl) -1-piperidinyl] carbonyl } Amino) phenoxy] benzoic acid

TLC: Rf 0.76 (dichloromethane: methanol = 3: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 8.49 (s, 1H), 8.07-7.97 (m, 2H), 7.32-7.23 (m, 1H), 7.11-6.92 (m, 5H), 6.90-6.80 (m (M, 2H), 1.06-0.91 (m, 2H), 6.35 (m, 2H) (m, 7H).

Example 9 (45) : 2-Chloro-4- [3- (3,4-difluorophenoxy) -5 - ({[4-hydroxy- Yl] carbonyl} amino) phenoxy] benzoic acid

TLC: Rf 0.51 (dichloromethane: methanol = 3: 1);

¹ H-NMR (CD ₃ OD):? 8.52 (s, IH), 7.92 (d, IH), 7.31-7.19 2H), 1.73-1.46 (m, 6H), 1.29-1. 06 (m, 2H), 6.92-6.81 (m, ), 1.05-0.90 (m, 7H).

Example 9 (46) : 2- {4- [3- (3,4-Difluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl) carbonyl ] Amino} phenoxy] phenyl} -2-methylpropanoic acid

TLC: Rf 0.32 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CD ₃ OD): 隆 7.43-7.35 (m, 2H), 7.31-7.16 (m, 1H), 7.04-6.91 (m, 3H), 6.90-6.86 (m, 2H), 6.25 (t, 1H), 3.90-3.70 (m, 2H), 3.28-3.14 (m, 2H), 1.95-1.75 (d, 2H), 0.97 (d, 6H).

Example 9 (47) : Synthesis of 4- [3- (3,4-difluorophenoxy) -5 - {[(4-hydroxy-4- isobutyl- 1- piperidinyl) carbonyl] amino} Phenoxy] -3-fluorobenzoic acid

TLC: Rf 0.52 (dichloromethane: methanol = 3: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 8.47 (s, 1H), 7.88-7.78 (m, 2H), 7.34-7.09 (m, 2H), 7.05-6.94 (m, 1H), 6.94-6.89 (m (M, 2H), 6.89-6.79 (m, IH), 6.33 (t, IH), 3.86-3.69 (m, 2H), 3.28-3.16 (m, 4H), 1.38 (d, 2H), 0.96 (d, 6H).

Example 9 (48) : {4- [3- (3,4-Difluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1 -piperidinyl) carbonyl] amino } Phenoxy] -2-fluorophenyl} acetic acid

TLC: Rf 0.72 (dichloromethane: methanol = 3: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 8.45 (s, 1H), 7.34-7.15 (m, 2H), 7.05-6.94 (m, 1H), 6.93-6.87 (m, 2H), 6.86-6.73 (m (M, 2H), 1.92-1.75 (m, 1H), 1.67-1.44 (m, , 4H), 1.38 (d, 2H), 0.96 (d, 6H).

Example 9 (49) : 2- {4- [3- (3,4-Difluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl) carbonyl ] Amino} phenoxy] phenyl} propanoic acid

TLC: Rf 0.29 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CD ₃ OD):? 8.42 (s, 1H), 7.36-7.29 (m, 2H), 7.29-7.17 (M, 2H), 1.96-1.76 (m, 1H), 1.66-1.50 (m, , 4H), 1.45 (d, 3H), 1.39 (d, 2H), 0.97 (d, 6H).

Example 9 (50) : Preparation of {4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy-1-piperidinyl] carbonyl} amino) -5- Yl) phenoxy] phenoxy} acetic acid

TLC: Rf 0.29 (chloroform: methanol: ethanol = 9: 1: 0.1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.01-6.89 (m, 4H), 6.85-6.66 (m, 5H), 6.58 (m, 1H), 6.18 (m, 1H), 4.37-4.20 (m, 2H) , 3.69 (m, 2H), 3.14 (m, 2H), 1.59-1.21 (m, 11H), 0.72-0.87 (m, 6H).

Example 9 51 : 2- {4- [3- (4-Fluorophenoxy) -5 - ({[4-hydroxy-4- (3- methylbutyl) -1-piperidinyl] Amino} phenoxy] phenyl} -2-methylpropanoic acid

TLC: Rf 0.28 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.33-7.39 (m, 2H), 6.96-7.06 (m, 6H), 6.78-6.81 (m, 1H), 6.69 (t, 1H), 6.38 (s, 1H) , 6.30-6.32 (m, 1H), 3.71-3.77 (m, 2H), 3.20-3.31 (m, 2H), 1.53-1.64 (m, 8H), 1.43-1.53 m, 4H), 0.90 (d, 6H).

Example 9 (52) : Preparation of 2- (4- {3 - [(4,4-difluorocyclohexyl) oxy] -5 - ({[4- (2-ethylbutyl) -4- - piperidinyl] carbonyl} amino) phenoxy} phenyl) -2-methylpropanoic acid

TLC: Rf 0.45 (CHCl 3: MeOH = 9: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.29 (d, 2H), 6.97-6.84 (m, 3H), 6.63 (m, 1H), 6.41 (m, 1H), 6.27 (m, 1H), 4.43 (m 1H), 3.80-3.63 (m, 2H), 3.32-3.13 (m, 2H), 2.10-1.71 (m, 7H), 1.21-1.53 (m, 18H), 0.90-0.75 (t, 6H).

Example 9 (53) : Preparation of 2- {4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy- 1 -piperidinyl] carbonyl} amino) -5- Phenoxy) phenoxy] phenyl} -2-methylpropanoic acid

TLC: Rf 0.40 (CHCl 3: MeOH = 9: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.33 (d, 2H), 7.16-7.03 (m, 3H), 6.96 (d, 2H), 6.79-6.64 (m, 2H), 6.42 (m, 1H), 6.35 2H), 1.62-1.52 (m, 8H), 1.46-1.20 (m, 4H), 0.93-0.69 (t, 6H) .

Example 9 (54) : 2- {4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy-1- piperidinyl] carbonyl} amino) Phenoxy) phenoxy] phenyl} -2-ethylpropanoic acid

TLC: Rf 0.45 (CHCl 3: MeOH = 9: 1);

¹ H-NMR (CDCl ₃ ):? 7.31-7.17 (m, 2H), 7.15-6.98 (m, 2H), 6.95-6.81 (m, 4H), 6.62 2H), 2.14 (s, 3H), 1.47 (m, 4H), 1.36-1.18 (m, 8H), 0.88-0.73 , 6H).

Example 9 (55) : 2- {4- [3 - {[(4-cyclopentyl-4-hydroxy- 1 -piperidinyl) carbonyl] amino} -5- (4-fluorophenoxy) Phenoxy] phenyl} -2-methylpropanoic acid

TLC: Rf 0.49 (CHCl 3: MeOH = 9: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.32 (m, 2H), 7.08-6.90 (m, 6H), 6.76 (m, 1H), 6.66 (m, 1H), 6.48 (m, 1H), 6.29 (m (M, 2H), 1.74 (m, 2H), 1.74 (m, 2H) m, 2H).

Example 9 (56) : 2- {4- [3 - {[(4-cyclohexyl-4-hydroxy- 1 -piperidinyl) carbonyl] amino} -5- (4- fluorophenoxy) Phenoxy] phenyl} -2-methylpropanoic acid

TLC: Rf 0.33 (CHCl 3: MeOH = 19: 1);

¹ H-NMR (CD ₃ OD):? 1.00-1.30 (m, 6H), 1.49-1.71 (m, 11H), 1.76-1.86 (m, 4H), 3.10-3.22 (m, 2H), 6.19 (t, 1H), 6.78-6.84 (m, 2H), 6.95-7.12 (m, 6H), 7.35-7.41 (m, 2H), 8.36 (brs, 1H).

Example 9 (57) : 2- {3- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1 -piperidinyl) carbonyl] amino} Phenoxy] phenoxy} -2-methylpropanoic acid

TLC: Rf 0.35 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.21 (t, 1H), 7.04 (d, 4H), 6.82 (t, 1H), 6.71 (d, 1H), 6.69 (d, 1H), 6.50 (t, 1H ), 6.46 (t, 1H), 6.33-6.29 (m, 2H), 3.74 (s, 2H), 3.36-3.21 1.55 (m, 10H), 1.40 (d, 2H), 0.96 (d, 6H).

Example 9 58 : 2- {3- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4- isobutyl- 1- piperidinyl) carbonyl] amino} Phenoxy] phenyl} -2-methylpropanoic acid

TLC: Rf 0.41 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CDCl ₃ ):? 7.34-7.28 (m, 1 H), 7.18-7.10 (m, 2H), 7.05-6.99 (m, 4H), 6.92 2H), 3.30-3.17 (m, 2H), 1.83 (dt, 1H), 1.62 (t, -1.55 (m, 10H), 1.40 (d, 2H), 0.97 (d, 6H).

Example 9 (59) : Synthesis of 2- [4- (3 - [(4,4-difluorocyclohexyl) oxy] -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl ) Carbonyl] amino} phenoxy) phenyl] -2-methylpropanoic acid

TLC: Rf 0.38 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CD ₃ OD):? 7.41-7.33 (m, 2H), 7.01-6.91 (m, 2H), 6.91-6.84 ), 4.54-4.40 (m, 1H), 3.90-3.73 (m, 2H), 3.28-3.16 (m, 2H), 2.19-1.75 (m, 9H), 1.55 (s, 6H), 1.68-1.45 , 4H), 1.40 (d, 2H), 0.98 (d, 6H).

Example 9 (60) : 2- {3-Fluoro-4- [3- (4-fluorophenoxy) -5 - {[(4-hydroxy- Carbonyl] amino} phenoxy] phenyl} -2-methylpropanoic acid

TLC: Rf 0.40 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.29-7.22 (m, 1H), 7.22-7.16 (m, 1H), 7.14-6.98 (m, 5H), 6.85-6.81 (m, 1H), 6.75 (t 1H), 6.17 (t, 1H), 3.86-3.71 (m, 2H), 3.29-3.15 (m, 2H), 1.95-1.73 , 4H), 1.39 (d, 2H), 0.97 (d, 6H).

Example 9 (61) : 1- {4- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4- isobutyl- 1 -piperidinyl) carbonyl] amino} Phenoxy] phenoxy} cyclopropanecarboxylic acid

TLC: Rf 0.31 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.06-6.86 (m, 8H), 6.69 (t, 1H), 6.58 (s, 1H), 6.53 (t, 1H), 6.28 (t, 1H), 3.70 (dt (M, 2H), 1.96-1.33 (m, 4H), 1.97-1.63 (d, 6 H).

Example 9 62 : N- {3- (4-Fluorophenoxy) -5- [(6-isopropyl-3-pyridinyl) oxy] phenyl} -4-hydroxy- 1-piperidinecarboxamide

TLC: Rf 0.53 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 8.32 (d, 1H), 7.31-7.27 (m, 1H), 7.15 (d, 1H), 7.07-6.98 (m, 4H), 6.80-6.75 (m, 2H) , 6.34 (s, IH), 6.29 (t, IH), 3.81-3.70 (m, 2H), 3.34-3.23 2H), 1.30 (d, 6H), 1.07 (s, 1H), 0.98 (d, 6H).

Example 9 (63) : Synthesis of 2- {4- [3 - {[(4-cyclopentyl-4-hydroxy-1- piperidinyl) carbonyl] amino} -5- (4-fluorophenoxy) Phenoxy] phenoxy} -2-methylpropanoic acid

TLC: Rf 0.13 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CDCl ₃ ):? 7.37 (s, 1H), 6.99-6.89 (m, 4H), 6.83 2H), 3.18-3.02 (m, 2H), 1.83-1.68 (m, 1H), 1.62-1.38 (m, 16H), 1.35-1.23 m, 2H).

Example 9 (64) : 2- {4- [3 - {[(4-cyclopentyl-4-hydroxy-1- piperidinyl) carbonyl] amino} -5- (4- fluorophenoxy) Phenoxy] -2-fluorophenyl} -2-methylpropanoic acid

TLC: Rf 0.47 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.30-7.21 (m, 1H), 7.08-6.97 (m, 4H), 6.84 (t, 1H), 6.81-6.65 (m, 3H), 6.50 (s, 1H) 2H), 1.93-1.79 (m, 1H), 1.73-1.49 (m, 16H), 1.42-1.31 (m, m, 2H).

Example 10 : 1-Fluoro-3- (4-fluorophenoxy) -5-nitrobenzene

4-Fluorophenol (18.5 g) and 1,3-difluoro-5-nitrobenzene (25.0 g) were dissolved in DMA (300 ml) in a 500 ml eggplant type flask under an argon atmosphere at room temperature. Cesium carbonate (15.3 g) was added to the reaction system and stirred. Thereafter, the mixture was heated to 50 캜, stirred for 3 hours, heated to 65 캜, stirred for 1 hour, heated to 85 캜 and further stirred for 1 hour. The mixture was allowed to cool to room temperature, the reaction solution was diluted with ethyl acetate, water was added, and the organic layer was extracted. Ethyl acetate was added to the water layer to extract the organic layer. The organic layer was collected and washed with water and saturated brine, and then the solvent was distilled off under reduced pressure to obtain the title compound (35.0 g) having the following physical data.

TLC: Rf 0.83 (hexane: AcOEt = 5: 1);

¹ H-NMR (CDCl ₃ ):? 6.98 (dt, J = 9.3, 2.3 Hz, 1H), 7.03-7.18 (m, 4H), 7.56 (td, J = 2.1, 1.1 Hz, 1H), 7.62 , J = 8.1, 2.2 Hz, 1H).

Example 11 : 1- (4-Fluorophenoxy) -3- (4-iodophenoxy) -5-nitrobenzene

At room temperature, 4-iodophenol (44.4 g) was added to a 300-ml three-necked flask, and the compound (34.9 g) prepared in Example 10 dissolved in DMA (140 ml) and potassium phosphate (59.2 g) , And the atmosphere was replaced with argon. It was then heated to 105 DEG C and stirred for 7 hours. The mixture was allowed to cool to room temperature, the reaction solution was diluted with ethyl acetate, water was added, and the organic layer was extracted. The organic layer was washed with water twice, with 1N sodium hydroxide twice, with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue was added seed crystals (5 mg) and the pressure was reduced to precipitate a solid. Hexane (300 ml) was added, and the mixture was stirred and allowed to stand at room temperature to precipitate a solid. The solution was filtered through a Kiriyama funnel, washed with hexane, and the obtained residue was dried under reduced pressure at 60 ° C to obtain the title compound (53.1 g). The filtrate was purified by silica gel column chromatography (hexane: MTBE = 99: 1 - > 95: 5) to obtain a pale yellow oil. Hexane and MTBE mixed solvent system, followed by filtration with a Kiriyama funnel and washing with hexane to obtain the title compound (14.4 g). A total of 67.5 g of the title compound having the following physical data was obtained.

TLC: Rf 0.31 (hexane: AcOEt = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 6.81-6.87 (m, 2H), 6.91 (dd, J = 2.1Hz, 1H), 7.02-7.14 (m, 4H), 7.42-7.45 (m, 2H), 7.68 -7.73 < / RTI > (m, 2H).

Example 12 : Methyl 1- {4- [3- (4-bromophenoxy) -5-nitrophenoxy] phenyl} cyclopropanecarboxylate

Lithium chloride (37.6 mg) and chlorotrimethylsilane (TMSCl) (11.3 [mu] l) were added to a 100 ml three-necked flask under argon atmosphere at room temperature, to a solution of zinc (87 mg) in dimethoxyethane (DME) . The mixture was heated to 75 DEG C, and methyl 1-bromocyclopropanecarboxylate was added dropwise, and the mixture was further stirred at 75 DEG C for 2 hours (this solution was taken as one solution). N-methyl-2-pyrrolidone (NMP) (1.0 mL) was added at room temperature under an argon atmosphere, further degassed and argon was filled. To this solution was added bis (tri-tert-butylphosphine) palladium (0) (Pd (t-Bu ₃ P) ₂ ) (23 mg) and the mixture was stirred for 10 minutes. mg) was added. The mixture was heated to 95 占 폚, and one solution adjusted in the above was added dropwise over 30 minutes. Followed by further stirring at 95 ° C for 1 hour and 30 minutes. The reaction solution was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The solid was further filtered and the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 90:10 → 80:20 → 50:50 → 0: 100) to obtain the title compound (143 mg) having the following physical data .

TLC: Rf 0.42 (hexane: ethyl acetate = 4: 1).

Example 13 : 1- {4- [3- (4-Fluorophenoxy) -5 - ({[4-hydroxy- Phenoxy] phenyl} cyclopropanecarboxylic acid

(22.4 g), the compound prepared in Example 12, 2,2,2-trichloroethyl chloroformate and 4- (2-ethylbutyl) -4-piperidino instead of 4-isobutyl- Using the knot, the title compound (12.0 g) having the following physical data was obtained by carrying out the same procedures as those of Example 6? Example 7? Example 8?

TLC: Rf 0.32 (chloroform: ethanol = 20: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.30-7.25 (m, 2H), 7.05-6.97 (m, 3H), 6.96-6.90 (m, 2H), 6.88 (t, 1H), 6.65 (t, 1H) , 6.30 (t, 1H), 3.81 (m, 2H), 3.25-3.09 (m, 2H), 1.69-1.43 (m, 8H), 1.23-1.10 .

Example 13 (1) to Example 13 (8)

1,3-difluoro-5-nitrobenzene, 4-iodophenol or an equivalent phenol derivative, 4-fluorophenol or its equivalent phenol derivative, 2,2,2-trichloroethyl chloro Using the corresponding bromide and 4-isobutyl-4-piperidino or a corresponding piperidine derivative instead of the formate, methyl 1-bromocyclopropanecarboxylate or the equivalent, Example 11? Example 12? The same procedure as in Example 13 was followed to obtain the following example compounds.

Example 13 (1) : Synthesis of 1- {4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy- 1 -piperidinyl] carbonyl} amino) -5- Phenoxy) phenoxy] phenyl} cyclopropanecarboxylic acid

TLC: Rf 0.30 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CDCl ₃ ):? 7.29-7.32 (m, 2H), 7.01 (d, 4H), 6.88-6.97 (m, 3H), 6.55-6.61 1H), 3.74 (d, 2H), 3.13-3.20 (m, 2H), 1.51-1.58 (m, 4H), 1.40-1.45 2H), 0.84 (t, 6H).

Example 13 (2) : 1- {4- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4- isobutyl- 1- piperidinyl) carbonyl] amino} Phenoxy] phenyl} cyclopropanecarboxylic acid

TLC: Rf 0.16 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.24-7.29 (m, 2H), 6.95-7.02 (m, 4H), 6.91 (d, 2H), 6.85 (t, 1H), 6.60 (t, 1H), 6.27 (m, 2H), 1.63 (d, 2H), 1.63 (d, 2H) (m, 2 H), 0.92 (d, 6 H).

Example 13 (3) : 1- {4- [3- (3,4-Difluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl) carbonyl ] Amino} phenoxy] phenyl} cyclopropanecarboxylic acid

TLC: Rf 0.47 (ethyl acetate: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.39-7.30 (m, 2H), 7.31-7.16 (m, 1H), 7.04-6.92 (m, 3H), 6.88 (t, 1H), 6.86-6.81 (m, 2H), 6.26 (t, 1H), 3.90-3.75 (m, 2H), 3.28-3.16 (m, 2H), 1.95-1.75 2H), 1.22-1.13 (m, 2H), 0.97 (d, 6H).

Example 13 (4) : 1- {4- [3- (4-Fluorophenoxy) -5- ({[4- (4- fluorophenyl) -4- hydroxy- 1- piperidinyl] Carbonyl} amino) phenoxy] phenyl} cyclopropanecarboxylic acid

TLC: Rf 0.38 (CHCl 3: MeOH = 9: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.43-7.57 (m, 2H), 7.28-7.39 (m, 2H), 6.91-7.16 (m, 8H), 6.86 (t, 1H), 6.77-6.84 (m 2H), 1.71 (d, 2H), 1.48-1.63 (m, 2H), 2.32 (t, ), 1.07-1.24 (m, 2H).

Example 13 (5) : 1- {4- [3- (2,4-Difluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl) carbonyl ] Amino} phenoxy] phenyl} cyclopropanecarboxylic acid

TLC: Rf 0.62 (chloroform: methanol: ethanol = 9: 1: 0.1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.35-7.22 (m, 2H), 7.10 (td, 1H), 6.99-6.81 (m, 5H), 6.62 (t, 1H), 6.28 (t, 1H), 3.72 (m, 2H), 3.30-3.16 (m, 2H), 1.90-1.70 (m, 1H), 1.67-1.44 (d, 6 H).

Example 13 (6) : 1- {2-Fluoro-4- [3- (4-fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl) Carbonyl] amino} phenoxy] phenyl} cyclopropanecarboxylic acid

TLC: Rf 0.32 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CDCl ₃ ):? 7.11-7.20 (m, 1H), 6.95-7.07 (m, 4H), 6.88 2H), 1.63-1.86 (m, 1H), 1.49-1.65 (m, 6H), 1.36 (d, 2H), 1.06-1.14 (m, 2H), 0.93 (d, 6H).

Example 13 (7) : 1- {4- [3 - {[(4-cyclopentyl-4-hydroxy-1- piperidinyl) carbonyl] amino} -5- (4- fluorophenoxy) Phenoxy] phenoxy} cyclopropanecarboxylic acid

TLC: Rf 0.15 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.07-6.84 (m, 8H), 6.73 (s, 1H), 6.60-6.50 (m, 2H), 6.28 (t, 1H), 3.80-3.69 (m, 2H) , 3.24-3.10 (m, 2H), 1.91-1.76 (m, 1H), 1.70-1.47 (m, 12H), 1.41-1.31 (m, 4H).

Example 13 (8) : 1- {3- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4- isobutyl- 1- piperidinyl) carbonyl] amino} Phenoxy] phenoxy} cyclopropanecarboxylic acid

TLC: Rf 0.16 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CDCl ₃ ):? 7.26-7.21 (m, 1 H), 7.07-7.01 (m, 4H), 6.77-6.64 (m, 4H), 6.48-6.43 (m, 1H), 1.63 (m, 2H), 1.63 (m, d, 2H), 1.33-1.25 (m, 2H), 0.96 (d, 6H).

Example 14 : Preparation of N- [3- (4-carbamoylphenoxy) -5- (4-fluorophenoxy) phenyl] -4- (2-ethylbutyl) -4-hydroxy- Din carboxamide

Phenol derivatives corresponding to 1,3-difluoro-5-nitrobenzene and 4-iodophenol, 4-fluorophenol, 2,2,2-trichloroethyl chloroformate and 4-isobutyl- By using 4- (2-ethylbutyl) -4-piperidinol instead of piperidino in the same manner as in Example 10? Example 11? Example 6? Example 7? Example 8, The title compound having the following physical data was obtained.

TLC: Rf 0.59 (ethyl acetate);

_{^{1 H-NMR (CDCl 3)}} : δ 7.74 (d, 2H), 6.99-7.08 (m, 6H), 6.79 (s, 1H), 6.83 (s, 1H), 6.62 (s, 1H), 6.33 (t 1H), 3.76 (d, 2H), 3.11-3.36 (m, 2H), 1.25-1.62 (m, 11H), 1.15 (s, 1H), 0.78-0.94 (m, 6H).

Example 14 (1) to 14 (30)

1,3-difluoro-5-nitrobenzene, phenol derivatives corresponding to 4-iodophenol, 4-fluorophenol or equivalent phenol derivatives, 2,2,2-trichloroethyl chloroformate And the piperidine derivative corresponding to 4-isobutyl-4-piperidino was used in the same manner as in Example 10? Example 11? Example 6? Example 7? Example 8 , The following example compounds were obtained.

Example 14 (1) : Synthesis of 4- (2-ethylbutyl) -N- {3- (4-fluorophenoxy) -5- [4- (methylsulfonyl) phenoxy] phenyl} -4- -1-piperidinecarboxamide

TLC: Rf 0.34 (dichloromethane: methanol = 30: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.79-7.94 (m, 2H), 6.90-7.17 (m, 7H), 6.77 (t, 1H), 6.42 (s, 1H), 6.29-6.39 (m, 1H) , 3.77 (d, 2H), 3.18-3.38 (m, 2H), 3.04 (s, 3H), 1.19-1.66 (m, 11H), 1.06 (s, 1H), 0.75-0.92 (m, 6H).

Example 14 (2) : Synthesis of 5- [3 - ({[4- (2-ethylbutyl) -4-hydroxy-1- piperidinyl] carbonyl} amino) -5- (4-fluorophenoxy ) Phenoxy] -2-pyridinecarboxamide

TLC: Rf 0.31 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 8.30 (d, 1H), 8.14 (d, 1H), 7.68 (d, 1H), 7.38 (dd, 1H), 7.11-6.91 (m, 5H), 6.77 (t 2H), 3.40-3.18 (m, 2H), 1.69-1.52 (m, 2H), 6.45 (s, m, 4H), 1.47-1.20 (m, 7H), 1.06 (s, 1H), 0.85 (t, 6H).

Example 14 (3) : Synthesis of N- [3- (4-carbamoylphenoxy) -5- (4-fluorophenoxy) phenyl] -4- (4-chlorophenyl) -4- - piperidinecarboxamide

TLC: Rf 0.41 (dichloromethane: methanol = 9: 1);

¹ H-NMR (CDCl ₃ + CD ₃ OD):? 7.78 (m, 2H), 7.41-7.29 (m, 6H), 7.06-7.01 (m, 4H), 6.88-6.82 t, 1 H), 3.94 (m, 2H), 3.33 (m, 2H), 1.95 (m, 2H), 1.72 (m, 2H).

Example 14 (4) : Synthesis of N- [3- (4-carbamoylphenoxy) -5- (4-fluorophenoxy) phenyl] -4- (4-fluorophenyl) -4- 1-piperidinecarboxamide

TLC: Rf 0.39 (CHCl 3: MeOH = 9: 1);

_{^{1 H-NMR (CDCl 3 +}} CD 3 OD): δ 7.78 (m, 2H), 7.45-7.40 (m, 4H), 7.06-6.85 (m, 7H), 6.89-6.84 (m, 2H), 6.33 ( t, 1 H), 3.94 (m, 2H), 3.33 (m, 2H), 1.95 (m, 2H), 1.72 (m, 2H).

Example 14 (5) : 4- (2-Ethylbutyl) -N- {3- (4-fluorophenoxy) -5- [ Hydroxy-1-piperidinecarboxamide

TLC: Rf 0.45 (ethyl acetate: methanol = 20: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 8.36 (.. Br s, 1H), 8.28 (d, 1H), 7.09-6.95 (m, 4H), 6.91 (t, 1H), 6.80 (t, 1H), 2H), 3.67-3.16 (m, 2H), 2.26 (s, 3H), 1.79-1.46 (m, 2H) m, 4H), 1.46-1.21 (m, 7H), 1.11 (br s, 1H), 0.85 (t, 6H).

Example 14 (6) : Synthesis of N- {3 - [(2,6-dimethyl-3-pyridinyl) oxy] -5- (4-fluorophenoxy) 4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.17 (hexane: AcOEt = 3: 7);

_{^{1 H-NMR (CDCl 3)}} : δ 7.16 (d, 1H), 7.09-6.92 (m, 5H), 6.72 (t, 1H), 6.63 (t, 1H), 6.35 (s, 1H), 6.20 (t (M, 2H), 3.35-3.17 (m, 2H), 2.51 (s, 3H), 2.42 , 7H), 1.04 (s, IH), 0.85 (t, 6H).

Example 14 (7) : 4- (2-Ethylbutyl) -N- [3- (4-fluorophenoxy) -5- (4-sulfamoylphenoxy) phenyl] -4- Piperidine carboxamide

TLC: Rf 0.36 (hexane: AcOEt = 2: 1);

^{1 H-NMR (DMSO-d} 6): δ 8.57 (s, 1H), 7.81 (d, 2H), 7.31 (s, 2H), 7.27-7.09 (m, 6H), 7.05 (dd, 1H), 6.99 (m, 2H), 1.46-1.24 (m, 11H), 0.78 (t, 1H) , 6H).

Example 14 (8) : 4- (4-Bromophenyl) -N- [3- (4-fluorophenoxy) -5- (4-sulfamoylphenoxy) phenyl] -4- - piperidinecarboxamide

TLC: Rf 0.27 (hexane: AcOEt = 1: 2);

^{1 H-NMR (DMSO-d} 6): δ 8.64 (s, 1H), 7.82 (d, 2H), 7.48 (d, 2H), 7.41 (d, 2H), 7.32 (s, 2H), 7.27-7.10 (m, 6H), 7.08 (dd, IH), 7.02 (dd, IH), 6.32 (dd, IH), 5.18 (s, IH), 3.98-3. ), 1.83-1.76 (m, 2H), 1.58-1.53 (m, 2H).

Example 14 (9) : 4- (4-Bromophenyl) -N- {3- (4-fluorophenoxy) -5- [4- (methylsulfonyl) phenoxy] phenyl} Roxy-1-piperidinecarboxamide

TLC: Rf 0.35 (hexane: AcOEt = 1: 2);

_{^{1 H-NMR (CDCl 3)}} : δ 7.87 (d, 2H), 7.48 (d, 2H), 7.33 (d, 2H), 7.11 (d, 2H), 7.05-7.01 (m, 4H), 6.97 (dd (M, 2H), 3.42-3.44 (m, 2H), 3.04 (s, 3H) 2.06-1.95 (m, 2H), 1.79-1.75 (m, 2H), 1.66 (brs, 1H).

Example 14 (10) : Synthesis of N- {3- (4-fluorophenoxy) -5- [4- (methylsulfonyl) phenoxy] phenyl} -4-hydroxy-4- [4- Phenyl) -1-piperidinecarboxamide

TLC: Rf 0.35 (hexane: AcOEt = 1: 2);

_{^{1 H-NMR (CDCl 3)}} : δ 7.87 (d, 2H), 7.63 (d, 2H), 7.58 (d, 2H), 7.11 (d, 2H), 7.07-7.01 (m, 4H), 6.97 (dd 2H), 3.45-3. 37 (m, 2H), 3.05 (s, 3H) 2.11-2.01 (m, 2H), 1.82-1.77 (m, 2H), 1.71 (brs, 1H).

Example 14 (11) : Synthesis of N- [3- (4-carbamoyl-3-methylphenoxy) -5- (4- fluorophenoxy) Hydroxy-1-piperidinecarboxamide

TLC: Rf 0.15 (hexane: AcOEt = 3: 7);

_{^{1 H-NMR (CDCl 3)}} : δ 7.40 (d, 1H), 7.09-6.95 (m, 4H), 6.86 (d, 1H), 6.83-6.77 (m, 2H), 6.73 (t, 1H), 6.54 (s, IH), 6.32 (t, IH), 5.95 (br. s., IH), 5.60 , 2.46 (s, 3H), 1.64-1.45 (m, 4H), 1.43-1.26 (m, 7H), 1.12 (s, 1H), 0.84 (t, 6H).

Example 14 (12) : Synthesis of N- [3- (2-carbamoylphenoxy) -5- (4-fluorophenoxy) phenyl] -4- (2-ethylbutyl) -4- - piperidinecarboxamide

TLC: Rf 0.20 (hexane: AcOEt = 3: 7);

_{^{1 H-NMR (CDCl 3)}} : δ 8.20 (dd, 1H), 7.48-7.37 (m, 2H), 7.21 (t, 1H), 7.08-6.96 (m, 4H), 6.93 (d, 1H), 6.87 (t, IH), 6.79 (t, IH), 6.41 (s, IH), 6.33 (t, IH), 5.73 (br. s., IH), 3.83-3.72 (m, 2H), 3.34-3.15 m, 2H), 1.66-1.50 (m, 4H), 1.44-1.29 (m, 7H), 1.06 (s,

Example 14 (13) : Synthesis of N- [3- (4-carbamoylphenoxy) -5- (4-fluorophenoxy) phenyl] -4- Piperidine carboxamide

TLC: Rf 0.37 (CHCl 3: MeOH = 9: 1);

¹ H-NMR (CDCl ₃ + CD ₃ OD):? 7.74 (m, 2H), 7.10-6.84 (m, 6H), 6.84 , 6.33 (t, IH), 3.81 (m, 2H), 3.19 (m, 2H), 1.80-1.40 (m, 5H), 1.20-1.08 (m, 4H), 0.94 (t, 6H).

Example 14 (14) : N- [3- (4-Carbamoylphenoxy) -5- (4-fluorophenoxy) phenyl] -4-hydroxy-4-phenyl-1-piperidinecarboxylic acid Copy Mid

TLC: Rf 0.35 (dichloromethane: methanol = 10: 1);

¹ H-NMR (DMSO-d ₆ ):? 8.61 (s, IH), 7.90 (d, 3H), 7.45 (d, 2H), 7.32-7.05 (d, 1H), 5.05 (s, 1H), 3.97-3.93 (m, 2H), 3.19-3.11 (m, 2H), 1.85-1.78 (m, 2H), 1.60-1.55 (m, 2H).

Example 14 (15) : N- [3- (4-Fluorophenoxy) -5- (4-sulfamoylphenoxy) phenyl] -4- (4- fluorophenyl) -4- - piperidinecarboxamide

TLC: Rf 0.38 (hexane: AcOEt = 1: 2);

_{^{1 H-NMR (CDCl 3)}} : δ 7.87 (d, 2H), 7.44 (d, 2H), 7.41 (d, 2H), 7.09-7.01 (m, 6H), 6.94 (dd, 1H), 6.77 (dd (M, 2H), 3.44-3.35 (m, 2H), 2.07-1.97 (m, 2H) ), 1.82-1.78 (m, 2H).

Example 14 (16) : N- {3- (4-Fluorophenoxy) -5- [4- (methylsulfonyl) phenoxy] phenyl} -4- Roxy-1-piperidinecarboxamide

TLC: Rf 0.38 (hexane: AcOEt = 1: 2);

_{^{1 H-NMR (CDCl 3)}} : δ 7.87 (d, 2H), 7.43 (dd, 2H), 7.12 (d, 2H), 7.09-7.01 (m, 6H), 6.98 (dd, 1H), 6.79 (dd 2H), 3.45-3.66 (m, 2H), 3.05 (s, 3H), 2.08-1.98 (m, 2H) ), 1.83-1.79 (m, 2H).

Example 14 (17) : N- [3- (4-Carbamoylphenoxy) -5- (4-fluorophenoxy) phenyl] -4- (3- fluorophenyl) -4- 1-piperidinecarboxamide

TLC: Rf 0.53 (ethyl acetate);

_{^{1 H-NMR (CDCl 3)}} : δ 7.87-7.71 (m, 2H), 7.40-7.30 (m, 1H), 7.23-7.13 (m, 2H), 7.09-6.91 (m, 7H), 6.86 (t, 2H), 3.47-3.33 (m, 2H), 6.81 (m, 2H), 6.81 (t, , 2.12-1.92 (m, 2H), 1.85-1.75 (m, 2H), 1.60 (s, 1H).

Example 14 (18) : N- [3- (4-Carbamoyl-2-chlorophenoxy) -5- (4- fluorophenoxy) Hydroxy-1-piperidinecarboxamide

TLC: Rf 0.67 (CHCl 3: MeOH = 9: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 8.02 (d, 1H), 7.79 (m, 1H), 7.18-7.00 (m, 5H), 6.85 (m, 2H), 6.23 (t, 1H), 3.82 ( m, 2H), 3.20 (m, 2H), 1.64 - 1.42 (m, 11H), 0.86 (t, 6H).

Example 14 (19) : Synthesis of N- [3- (4-carbamoylphenoxy) -5- (4-fluorophenoxy) phenyl] -4- (3,3- Yl) -4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.49 (CHCl 3: MeOH = 9: 1);

¹ H-NMR (CDCl ₃ ):? 7.76 (d, 2H), 6.93-7.12 (m, 6H), 6.81-6.85 ), 6.35 (t, IH), 5.77 (brs, 2H), 3.63-3.84 (m, 2H), 3.27 1.21 (s, 9 H).

Example 14 (20) : Synthesis of N- [3- (4-carbamoylphenoxy) -5- (4-fluorophenoxy) phenyl] -4-hydroxy-4-isopropyl-1-piperidine Carboxamide

TLC: Rf 0.39 (dichloromethane: methanol = 10: 1);

^{1 H-NMR (DMSO-d} 6): δ 8.54 (s, 1H), 7.92 (brs, 1H), 7.89 (d, 2H), 7.30 (brs, 1H), 7.23 (t, 2H), 7.13-7.04 (m, 4H), 7.02 (dd, IH), 6.98 (dd, IH), 6.26 (dd, IH), 4.00 (s, IH), 3.84-3.80 ), 1.49-1.27 (m, 5H), 0.81 (d, 6H).

Example 14 (21) : Synthesis of N- [3- (4-carbamoyl-3-chlorophenoxy) -5- (4- fluorophenoxy) Hydroxy-1-piperidinecarboxamide

TLC: Rf 0.54 (CHCl 3: MeOH = 9: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.74 (m, 2H), 7.10-6.80 (m, 8H), 6.58-6.30 (m, 3H), 5.78 (m, 1H), 3.76 (m, 2H), 3.28 (m, 2H), 1.70-1.20 (m, 11H), 1.04 (s, 1H), 0.85 (t, 6H).

Example 14 (22) : N- [3- (4-Carbamoylphenoxy) -5- (4-fluorophenoxy) phenyl] -4-cycloheptyl-4-hydroxy-1-piperidine Carboxamide

TLC: Rf 0.27 (ethyl acetate);

_{^{1 H-NMR (CDCl 3)}} : δ 7.77 (d, 2H), 6.96-7.09 (m, 6H), 6.85 (t, 1H), 6.79 (t, 1H), 6.44 (s, 1H), 6.34 (t 2H), 1.16-1.88 (m, 17H), 1.07 (m, 1H), 6.04 (br s, (s, 1 H).

Example 14 (23) : Synthesis of N- [3- (4-carbamoylphenoxy) -5- (4-fluorophenoxy) phenyl] -4- -4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.48 (CHCl 3: MeOH = 9: 1);

¹ H-NMR (CDCl ₃ ):? 7.75 (d, 2H), 6.93-7.18 (m, 6H), 6.70-6.93 (d, 2H), 5.17 (s, IH), 3.62 (d, 2H), 3.18-3.52 (m, 2H), 2.36 , 4H), 1.31-1. 46 (m, 1H), 0.99 (q, 6H).

Example 14 (24) : 4- (2-Ethylbutyl) -N- {3- (4-fluorophenoxy) -5- [4- (methylsulfamoyl) phenoxy] phenyl} -4- -1-piperidinecarboxamide

TLC: Rf 0.38 (hexane: AcOEt = 3: 7);

_{^{1 H-NMR (CDCl 3)}} : δ 7.83-7.71 (m, 2H), 7.12-6.96 (m, 6H), 6.93 (t, 1H), 6.78 (t, 1H), 6.47 (s, 1H), 6.34 (m, 4H), 1.42-1.29 (m, 2H), 2.36 (d, 3H) (m, 7 H), 1.08 (s, 1 H), 0.85 (t, 6 H).

Example 14 (25) : Synthesis of N- {3- [4- (dimethylsulfamoyl) phenoxy] -5- (4-fluorophenoxy) phenyl} -4- -1-piperidinecarboxamide

TLC: Rf 0.46 (hexane: AcOEt = 3: 7);

_{^{1 H-NMR (CDCl 3)}} : δ 7.77-7.66 (m, 2H), 7.12-6.98 (m, 6H), 6.95 (t, 1H), 6.79 (t, 1H), 6.41 (s, 1H), 6.34 (m, 4H), 1.44-1.28 (m, 7H), 1.04 (m, 2H) (s, 1 H), 0.85 (t, 6 H).

Example 14 (26) : 4- (2-Ethylbutyl) -N- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] -4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.60 (CHCl 3: MeOH = 9: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.74 (m, 1H), 7.66 (m, 1H), 7.14 (t, 1H), 7.10-6.98 (m, 5H), 6.76 (t, 1H), 6.47 (m 1H), 6.37 (t, 1H), 3.78 (m, 2H), 3.28 (m, 2H), 3.07 t, 6H).

Example 14 (27) : 4- (2-Ethylbutyl) -N- {3- (4-fluorophenoxy) -5- [ -4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.39 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CDCl ₃ ):? 7.58 (d, 1H), 6.89-7.07 (m, 5H), 6.82 (br. S., 1H), 6.39-6.63 3H), 1.55-1.63 (m, 4H), 1.30-1.42 (m, 6H), 0.85 (m, 2H) (t, 6 H).

Example 14 (28) : N- [3- (4-Carbamoyl-3-hydroxyphenoxy) -5- (4- fluorophenoxy) - hydroxy-1-piperidinecarboxamide

TLC: Rf 0.16 (hexane: AcOEt = 2: 3);

_{^{1 H-NMR (CDCl 3)}} : δ 7.30 (d, 1H), 7.15 (dd, 1H), 6.93-7.08 (m, 5H), 6.80-6.83 (m, 1H), 6.49 (t, 1H), 6.42 (m, 2H), 3.18-3.33 (m, 2H), 1.54-1.61 (m, 4H), 1.29-1.43 (m, 7H) , 0.85 (t, 6H).

Example 14 (29) : Synthesis of 4- (2-ethylbutyl) -N- {3- [4- (ethylsulfonyl) phenoxy] -5- (4-fluorophenoxy) phenyl} -4- -1-piperidinecarboxamide

TLC: Rf 0.29 (hexane: AcOEt = 2: 3);

_{^{1 H-NMR (CDCl 3)}} : δ 7.83 (dd, 2H), 7.10 (dd, 2H), 7.01-7.05 (m, 4H), 6.95-6.97 (m, 1H), 6.76-6.79 (m, 1H) , 6.37 (s, 1H), 6.33-6.36 (m, IH), 3.77 (dt, 2H), 3.21-3.34 (m, 2H), 3.10 (q, 2H), 1.57-1.65 -1.44 (m, 7H), 1.24-1.32 (m, 3H), 1.02 (s, 1H), 0.85 (t, 6H).

Example 14 (30) : Synthesis of 4- (2-ethylbutyl) -N- {3- (4-fluorophenoxy) -5- [4- (methylcarbamoyl) phenoxy] phenyl} Roxy-1-piperidinecarboxamide

TLC: Rf 0.20 (hexane: AcOEt = 3: 7);

_{^{1 H-NMR (CDCl 3)}} : δ 7.83-7.58 (m, 2H), 7.10-6.93 (m, 6H), 6.80 (d, 2H), 6.37 (s, 1H), 6.33 (t, 1H), 6.07 (m, 2H), 3.39-3.14 (m, 2H), 3.00 (d, 3H), 1.62-1.55 (m, 4H), 1.44-1.28 ), 1.03 (s, 1 H), 0.86 (t, 6 H).

Example 15 : 4- (2-Ethylbutyl) -N- [3- (4-fluorophenoxy) -5- {4 - [(tetrahydro- Phenoxy} phenyl] -4-hydroxy-1-piperidinecarboxamide

The compound (20 mg) prepared in Example 9 (1) was dissolved in DMF (200 μl) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (4.2 mg) Carbodiimide hydrochloride (EDC) (19 mg) and 1-hydroxybenzotriazolyl hydrate (HOBt) (15 mg) were added to the solution, and the mixture was stirred at room temperature for 24 hours. After the reaction solution was diluted with ethyl acetate, water was added, and the aqueous layer was extracted with MTBE. The organic layers were combined, washed with water, a saturated aqueous sodium hydrogen carbonate solution and saturated aqueous ammonium chloride, and then concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain the title compound (19.6 mg) having the following physical data.

TLC: Rf 0.42 (dichloromethane: methanol = 10: 1).

Example 15 (1) to 15 (7)

By treating the compound prepared in Example 9 (1) and an amine derivative corresponding to O- (tetrahydro-2H-pyran-2-yl) hydroxylamine in the same manner as in Example 15, The following example compounds were obtained.

Example 15 (1) : Synthesis of 4- (2-ethylbutyl) -N- {3- [4- (ethylcarbamoyl) phenoxy] -5- (4- fluorophenoxy) Roxy-1-piperidinecarboxamide

TLC: Rf 0.39 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.77-7.64 (m, 2H), 7.08-6.94 (m, 6H), 6.83-6.75 (m, 2H), 6.42 (s, 1H), 6.33 (t, 1H) 2H), 3.34-3.16 (m, 2H), 1.64-1.50 (m, 4H), 1.43-1.29 (m, m, 7H), 1.25 (t, 3H), 1.04 (s, 1H), 0.85 (t, 6H).

Example 15 (2) : 4- (2-Ethylbutyl) -N- {3- (4-fluorophenoxy) -5- [4- (isopropylcarbamoyl) phenoxy] Hydroxy-1-piperidinecarboxamide

TLC: Rf 0.42 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.71 (d, 2H), 7.07-6.97 (m, 6H), 6.83-6.78 (m, 2H), 6.37 (d, 1H), 6.32 (t, 1H), 5.92 2H), 1.66-1. 49 (m, 4H), 1.45-1.30 (m, 2H), 3.38-3.13 7H), 1.26 (d, 6H), 1.03 (s, 1H), 0.85 (t, 6H).

Example 15 (3) : Synthesis of 4- (2-ethylbutyl) -N- {3- (4-fluorophenoxy) -5- [4- (4-morpholinylcarbonyl) phenoxy] phenyl} 4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.42 (dichloromethane: methanol = 1: 2);

_{^{1 H-NMR (CDCl 3)}} : δ 7.45-7.34 (m, 2H), 7.08-6.97 (m, 6H), 6.83 (t, 1H), 6.74 (t, 1H), 6.39 (s, 1H), 6.33 (m, 1H), 1.05 (s, 1H), 0.85 (m, 1H), 3.89-3.49 (t, 6 H).

Example 15 (4) : 4- (2-Ethylbutyl) -N- [3- (4-fluorophenoxy) -5- {4 - [(3-hydroxy-1-azetidinyl) ] Phenoxy} phenyl] -4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.25 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.58-7.49 (m, 2H), 7.08-6.95 (m, 6H), 6.89 (t, 1H), 6.83 (d, 1H), 6.74 (t, 1H), 6.32 (m, 2H), 3.34-3.01 (m, 2H), 3.94-3.52 (m, 2H) ), 1.61 (s, 1H), 1.60-1.52 (m, 4H), 1.45-1.27 (m, 7H), 1.24 (d, 1H), 0.83 (t, 6H).

Example 15 (5) : 4- (2-Ethylbutyl) -N- [3- (4-fluorophenoxy) -5- {4 - [(3-hydroxy-1-pyrrolidinyl) carbonyl ] Phenoxy} phenyl] -4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.23 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CDCl ₃ ):? 7.55-7.40 (m, 2H), 7.10-7.00 (m, 6H), 6.99-6.92 1H), 6.32 (t, IH), 4.65-4.35 (m, IH), 3.90-3.68 (m, 4H), 3.67-3.34 (m, 2H), 3.30-3.05 m, 1H), 2.15-1.92 (m, 2H), 1.64-1.51 (m, 4H), 1.42-1.25 (m, 7H), 1.16 (br.

Example 15 (6) : 4- (2-Ethylbutyl) -N- [3- (4-fluorophenoxy) -5- {4 - [(4-hydroxy- 1 -piperidinyl) carbonyl ] Phenoxy} phenyl] -4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.30 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.39-7.31 (m, 2H), 7.06-6.96 (m, 6H), 6.93 (t, 1H), 6.79-6.70 (m, 1H), 6.65 (t, 1H) 2H), 1.80-1.70 (m, 2H), 6.32 (t, 1H), 4.40-3.90 (m, 3H), 3.85-3.70 1H), 1.66-1.45 (m, 6H), 1.43-1.24 (m, 7H), 1.17 (br s, 1H), 0.84 (t, 6H).

Example 15 (7) : 4- (2-Ethylbutyl) -N- [3- (4-fluorophenoxy) -5- {4 - [(3-hydroxy- 1- piperidinyl) carbonyl ] Phenoxy} phenyl] -4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.35 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.36 (d, 2H), 7.06-6.94 (m, 6H), 6.93-6.72 (m, 3H), 6.64 (s, 1H), 6.32 (t, 1H), 4.05 (M, 2H), 1.70-1.40 (m, 6H), 1.40-1.20 (m, 2H) 7H), 1.20 (d, 1 H), 0.84 (t, 6H).

Example 16 : Preparation of 4- (2-ethylbutyl) -N- {3- (4-fluorophenoxy) -5- [4- (hydroxycarbamoyl) phenoxy] phenyl} -4- 1-piperidinecarboxamide

The compound (19 mg) prepared in Example 15 was dissolved in ethyl acetate (0.5 ml), and a hydrochloric acid / ethyl acetate solution (4 mol / l, 0.1 ml) was added and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated and purified by preparative TLC (dichloromethane: methanol = 10: 1) to obtain the title compound (5.1 mg) having the following physical data.

TLC: Rf 0.23 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.75 (d, 2H), 7.15-6.99 (m, 6H), 6.91 (t, 1H), 6.87 (t, 1H), 6.27 (t, 1H), 3.88- 2H), 3.70 (m, 2H), 3.28-3.14 (m, 2H), 1.68-1.48 (m, 4H), 1.44-1.26 (m, 7H), 0.87 (t, 6H).

Example 17 : Preparation of 2-methyl-2-propanyl-3-hydroxy-3-isobutyl-1-azetidinecarboxylate

A THF solution (31.0 ml) of 0.6M lithium chloride lanthanum chloride (LaCl ₃ .2LiCl) was added to a 100 ml three-necked flask under argon atmosphere, and a THF solution of 2.0 M isobutylmagnesium chloride 6.9 mL) was added. After stirring at 0 占 폚 for 3 hours, 2-methyl-2-propanyl-3-oxo-1-azetidinecarboxylate (1.6 g) dissolved in THF (4.0 ml) was added at 0 占 폚. After stirring for 15 hours at 0 ° C to room temperature, a 5% aqueous acetic acid solution (30 ml) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a brown oily product (3.2 g). The residue was purified by column chromatography (medium pressure preparative liquid chromatograph W-prep 2XY (column: main column 2L, inject column L: hexane: ethyl acetate 9: 1 -> 7: 3) (2.0 g).

TLC: Rf 0.53 (hexane: ethyl acetate = 2: 1).

Example 18 : Synthesis of 3-isobutyl-3-azetidinol

To a 200 ml eggplant type flask was added the compound (2.0 g) prepared in Example 17 and methanol (9 ml), and 4N hydrochloric acid / ethyl acetate solution (11 ml) was added at 0 ° C. After stirring at room temperature for 7 hours, the reaction mixture was cooled to 0 ° C, and a 5N aqueous sodium hydroxide solution (43.5 ml) was added thereto. The mixture was extracted twice with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound (973.5 mg) having the following physical data. The title compound thus obtained was used in the next reaction without purification.

TLC: Rf 0.69 (ethyl acetate: methanol = 3: 1).

Example 19 : 2- {4- [3- (4-Fluorophenoxy) -5 - {[(3-hydroxy-3-isobutyl- 1- azetidinyl) carbonyl] amino} phenoxy] Phenyl} -2-methylpropanoic acid

The compound (64.6 mg) prepared in Example 18 and the compound (342.5 mg) prepared in Example 7 were treated in the same manner as in Example 8? Example 9 to give the title compound ( 41 mg).

TLC: Rf 0.15 (dichloromethane: ethanol = 20: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.31 (d, 2H), 6.87-7.11 (m, 6H), 6.76 (s, 1H), 6.66 (s, 1H), 6.21-6.37 (m, 2H), 3.70 2H), 1.61 (d, 2H), 1.56 (s, 6H), 0.91 (d, 6H).

Example 19 (1) to 19 (9)

The following example compounds were obtained by treating the compound of Example 7 with the corresponding cyclic amine derivative and the corresponding compound in place of the compound prepared in Example 18, by the same procedure as in Example 19.

Example 19 (1) : Synthesis of 2- {4- [3- (4-fluorophenoxy) -5 - {[(3-hydroxy-3- isobutyl- 1 -pyrrolidinyl) carbonyl] amino} Phenoxy] phenyl} -2-methylpropanoic acid

TLC: Rf 0.13 (dichloromethane: ethanol = 20: 1):

_{^{1 H-NMR (CDCl 3)}} : δ 7.29-7.39 (m, 2H), 6.89-7.07 (m, 6H), 6.84 (t, 1H), 6.71 (t, 1H), 6.30 (t, 1H), 6.20 (s, 2H), 1.73-2.06 (m, 3H), 1.44-1.68 (m, 8H) 0.97 (dd, 6H).

Example 19 (2) : Synthesis of 2- {4- [3 - ({[(3R, 4S) -3-fluoro-4-hydroxy-4-isobutyl- 1- piperidinyl] carbonyl} amino) -5- (4-fluorophenoxy) phenoxy] phenyl} -2-methylpropanoic acid

TLC: Rf 0.31 (dichloromethane: ethanol = 20: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.29-7.43 (m, 2H), 6.90-7.10 (m, 6H), 6.77 (t, 1H), 6.65 (t, 1H), 6.43 (s, 1H), 6.31 (m, 2H), 1.93-2. 25 (m, 2H), 1.73-1.97 (m, (m, 2H), 1.34-1.69 (m, 9H), 0.98 (dd, 6H).

Example 19 (3) : 2- {4- [3- (4-Fluorophenoxy) -5 - {[(3-hydroxy- 3- isopropyl- 1 -pyrrolidinyl) carbonyl] amino} Phenoxy] phenyl} -2-methylpropanoic acid

TLC: Rf 0.45 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.42-7.34 (m, 2H), 7.14-6.94 (m, 6H), 6.93-6.90 (m, 1H), 6.87 (t, 1H), 6.21 (t, 1H ), 3.57 (dd, 2H), 3.48-3.32 (m, 2H), 2.04-1.68 (m, 3H), 1.55 (s, 6H), 0.98 (d, 6H).

Example 19 (4) : 2- {4- [3 - {[(3-cyclopentyl-3-hydroxy-1-pyrrolidinyl) carbonyl] amino} -5- (4-fluorophenoxy) Phenoxy] phenyl} -2-methylpropanoic acid

TLC: Rf 0.47 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.41-7.34 (m, 2H), 7.15-6.95 (m, 6H), 6.94-6.91 (m, 1H), 6.87 (t, 1H), 6.21 (t, 1H 2H), 1.55 (s, 6H), 1.78-1.40 (m, 8H), 3.45-3.50 (m, ).

Example 19 (5) : 2- {4- [3 - {[(3-cyclohexyl-3-hydroxy- 1 -pyrrolidinyl) carbonyl] amino} -5- (4- fluorophenoxy) Phenoxy] phenyl} -2-methylpropanoic acid

TLC: Rf 0.48 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.41-7.35 (m, 2H), 7.13-6.94 (m, 6H), 6.93-6.90 (m, 1H), 6.87 (t, 1H), 6.21 (t, 1H ), 3.60-3.50 (m, 2H), 3.47-3.32 (m, 2H), 1.98-1.61 (m, 7H), 1.55 (s, 6H), 1.49-1.09 (m, 6H).

Example 19 (6) : 1- {4- [3 - {[(3-cyclopentyl-3-hydroxy- 1 -pyrrolidinyl) carbonyl] amino} -5- (4- fluorophenoxy) Phenoxy] phenyl} cyclopropanecarboxylic acid

TLC: Rf 0.49 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.32-7.26 (m, 2H), 7.07-6.97 (m, 4H), 6.96-6.91 (m, 2H), 6.90 (t, 1H), 6.70 (t, 1H) , 6.32 (t, IH), 6.20 (s, IH), 3.64-3.47 (m, 2H), 3.43 (d, IH), 3.30 (m, 2H), 1.77-1.49 (m, 8H), 1.46-1.33 (m, 2H), 1.27-1.19 (m, 2H).

Example 19 (7) : 1- {4- [3 - {[(3-cyclohexyl-3-hydroxy- 1 -pyrrolidinyl) carbonyl] amino} -5- (4-fluorophenoxy) Phenoxy] phenyl} cyclopropanecarboxylic acid

TLC: Rf 0.49 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.31-7.26 (m, 2H), 7.06-6.97 (m, 4H), 6.96-6.91 (m, 2H), 6.90 (t, 1H), 6.70 (t, 1H) , 6.32 (t, IH), 6.21 (s, IH), 3.64-3. 50 (m, 2H), 3.46 (d, (m, 2 H), 1.30 - 1.07 (m, 6 H).

Example 19 (8) : 2- {4- [3 - {[(3-cyclohexyl-3-hydroxy- 1 -pyrrolidinyl) carbonyl] amino} -5- (4- fluorophenoxy) Phenoxy] phenoxy} -2-methylpropanoic acid

TLC: Rf 0.28 (dichloromethane: methanol = 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.05-6.94 (m, 4H), 6.92-6.86 (m, 4H), 6.75 (t, 1H), 6.60 (t, 1H), 6.30-6.25 (m, 2H) (M, 6H), 1.58 (s, 6H), 1.45 (d, IH), 3.55-3.47 -1.33 (m, 1 H), 1.24-1.11 (m, 5 H).

Example 19 (9) : 1- {4- [3 - {[(3-cyclohexyl-3-hydroxy- 1 -pyrrolidinyl) carbonyl] amino} -5- (4- fluorophenoxy) Phenoxy] phenoxy} cyclopropanecarboxylic acid

TLC: Rf 0.28 (dichloromethane: methanol = 10: 1);

¹ H-NMR (CDCl ₃ ):? 7.06-6.92 (m, 4H), 6.89-6.78 (m, 4H), 6.63-6.51 3H), 3.15 (d, 1H), 1.89-1.59 (m, 6H), 1.58-1.48 (m, 3H), 1.35-1.03 (m, 8H).

Example 20 : Methyl 4 - {[3- (4-fluorophenoxy) -5-nitrophenyl] thio} benzoate

The compound (6.01 g) prepared in Example 10 was dissolved in DMA (60 ml) under an argon atmosphere, potassium carbonate (7.62 g) and 4-carbomethoxybenzenethiol (2.80 g) Lt; 0 > C for 3 hours. After cooling to room temperature, the reaction mixture was poured into water, extracted with MTBE, washed successively with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 -> 4: 1) to obtain the title compound (2.28 g) having the following physical data.

TLC: Rf 0.59 (hexane: ethyl acetate = 4: 1).

Example 21 : methyl 4 - {[3-amino-5- (4-fluorophenoxy) phenyl] thio} benzoate

The compound (1.12 g) prepared in Example 20 was dissolved in acetic acid (11.2 ml) and water (0.86 ml), and iron (777 mg) was added in several portions and reacted at 90 ° C for 1 hour and 30 minutes. The mixture was cooled to room temperature, ethyl acetate (30 ml) was added, and the mixture was stirred for 20 minutes. The mixture was filtered using Celite (trade name), toluene was added, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water, saturated sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 -> 1: 1) to obtain the title compound (830 mg) having the following physical data.

TLC: Rf 0.17 (hexane: ethyl acetate = 4: 1).

Example 22 : Preparation of 4 - {[3- (4-fluorophenoxy) -5 - ({[4- (4-fluorophenyl) -4- hydroxy- 1- piperidinyl] carbonyl} amino) Phenyl] thio} benzoic acid

(4-fluorophenyl) -4-piperidinol was used instead of the compound prepared in Example 21, 2,2,2-trichloroethyl chloroformate and 4-isobutyl-4-piperidinol , And then treated in the same manner as in Example 7? Example 8? Example 9 to obtain the title compound (12.0 g) having the following physical data.

TLC: Rf 0.52 (chloroform: methanol: ethanol = 9: 1: 0.1);

¹ H-NMR (CD ₃ OD):? 1.73, 2.00, 3.32-3.44, 4.03, 6.62, 6.95-7.18, 7.24-7.36, 7.46-7.55, 7.86-7.99.

Example 23 : tert-Butyl 4-hydroxy-4-isobutyl-2-methylpiperidine-1-carboxylate

Under an argon atmosphere, a THF solution (15.6 ml) of a lithium lanthanum chloride chloride complex was weighed into a 50 ml eggplant type flask and cooled to 0 占 폚. To this solution, a THF solution (3.5 ml) of isobutyl magnesium chloride was added dropwise, and the mixture was stirred at 0 ° C for 3 hours, and tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate g) in THF (2.0 ml) was further added dropwise. The reaction solution was stirred at 0 ° C for 1 hour, then heated to 25 ° C, poured into hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was concentrated, and the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1 -> 3: 1) to obtain the title compound (450 mg) having the following physical data.

TLC: Rf 0.51 (hexane: AcOEt = 3: 1).

Example 24 : 2-Methyl-4-isobutyl-4-hydroxypiperidine hydrochloride

In a 100 ml eggplant type flask, the compound (440 mg) prepared in Example 23 was weighed and a 1,4-dioxane solution (5.0 ml) of hydrogen chloride (4 mol / l) was added. The reaction solution was stirred at 25 占 폚 for 30 minutes and then concentrated to obtain the title compound (336 mg) having the following physical data.

¹ H-NMR (CD ₃ OD):? 1.01 (d, 6H), 1.34 (d, 3H), 1.50-1.58 (m, 3H), 1.67-1.88 (m, 2H), 1.92-2.02 ), 3.03 (dt, 1H), 3.27-3.38 (m, 2H).

Example 25 : 2- {4- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-2-methyl- 1 -piperidinyl) carbonyl] amino } Phenoxy] phenyl} -2-methylpropanoic acid

The compound (48 mg) prepared in Example 24 and the compound (100 mg) prepared in Example 7 were treated in the same manner as in Example 8? Example 9 to give the title compound ( 60 mg).

TLC: Rf 0.33 (CHCl 3: MeOH = 19: 1);

¹ H-NMR (CDCl ₃ ):? 0.97 (dd, 6H), 1.36 (t, 2H), 1.38 (d, 3H), 1.47-1.75 (d, IH), 3.71-3.79 (m, IH), 4.26-4.35 (m, IH), 6.29 (t, IH), 6.38 ), 6.96-7.02 (m, 6H), 7.35 (d, 2H).

Example 26 : Ethyl 2- (benzhydridenamino) -2- [4- {3- (4-fluorophenoxy) -5-nitro-phenoxy} phenyl] acetate

To the compound (1.0 g) prepared in Example 11, ethyl [(diphenylmethylene) amino] acetat (652 mg) and potassium phosphate (1.41 g) were added and suspended in toluene (7.4 ml). Pd (t-Bu ₃ P) ₂ (23 mg) was added to the reaction system by degassing and argon substitution, followed by deaeration and argon replacement. The reaction solution was stirred at 100 ° C for 17 hours, then cooled to 0 ° C, adjusted to pH 7 with water and 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate Lt; / RTI > The residue obtained by concentration was purified by silica gel chromatography (hexane: ethyl acetate = 100: 0 - > 9: 1) to obtain the title compound (456 mg) having the following physical data.

TLC: Rf 0.36 (hexane: AcOEt = 3: 1).

Example 27 : Ethylamino {4- [3- (4-fluorophenoxy) -5-nitrophenoxy] phenyl} acetate

The compound (356 mg) prepared in Example 26 was dissolved in ethanol (4 ml) and DME (3 ml), 1N hydrochloric acid (1.8 ml) was added, and the mixture was stirred at room temperature for 15 hours. The concentrated reaction solution was cooled at 0 占 폚, neutralized with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentration was purified by silica gel chromatography (hexane: ethyl acetate = 80:20 to 60:40) to obtain the title compound (253 mg) having the following physical data.

TLC: Rf 0.28 (hexane: ethyl acetate = 1: 1).

Example 28 : Ethyl 2- (benzyloxycarbonylamino) -2- {4- [3- (4-fluorophenoxy) -5-nitrophenoxy] phenyl} acetate

The compound (253 mg) prepared in Example 27 was dissolved in ethyl acetate (2.5 ml) and sodium hydrogencarbonate (100 mg) and benzyl chloroformate (112 mg) were added at 0 ° C. The reaction solution was stirred at room temperature for 13 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 100: 0 to 85: 15) to obtain the title compound (234 mg) having the following physical data.

TLC: Rf 0.32 (hexane: AcOEt = 5: 1).

Example 29 : Ethyl 2- {4- [3-amino-5- (4-fluorophenoxy) phenoxy] phenyl} -2- (benzyloxycarbonylamino) acetate

Iron (166 mg), zinc (194 mg), ammonium chloride (32 mg), water (0.2 ml) and ethanol (1.5 ml) were added to the compound prepared in Example 28 (253 mg) Lt; / RTI > The reaction solution was cooled to room temperature, diluted with water, ethyl acetate, and filtered through celite. Saturated aqueous sodium hydroxide was added to the obtained filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous magnesium sulfate to obtain the title compound (278 mg) having the following physical data.

TLC: Rf 0.17 (hexane: AcOEt = 3: 1).

Example 30 : Synthesis of amino {4- [3- (4-fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1 -piperidinyl) carbonyl] amino} phenoxy] phenyl } Acetic acid

By using the compound prepared in Example 29 and 4-isobutyl-4-piperidino in the same manner as in Example 7? Example 8? Example 9? Example 6, The title compound (28.4 mg) was obtained.

TLC: Rf 0.15 (dichloromethane: methanol: aqueous ammonia = 160: 30: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.45 (d, 2H), 7.13-6.97 (m, 6H), 6.83 (dt, 2H), 6.20 (t, 1H), 4.50 (s, 1H), 3.80 ( d, 2H), 3.29-3.16 (m, 2H), 1.92-1.80 (m, 1H), 1.67-1.45 (m, 4H), 1.39 (d, 2H), 0.97 (d,

Example 31 : Benzyl 3- (diethylcarbamoyl) -1-pyrrolidinecarboxylate

(500 mg) was dissolved in DMF (5 ml), and N, N-diethylamine (0.293 g) was added to the solution under argon atmosphere. , EDC (769 mg) and HOBt (542 mg) were further added, and the mixture was stirred at room temperature for 72 hours. The reaction solution was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 95: 5 -> 0: 1) to obtain the title compound (556 mg) having the following physical data.

_{^{1 H-NMR (CDCl 3)}} : δ 7.38-7.25 (m, 5H), 5.13 (s, 2H), 3.75-3.04 (m, 8H), 2.20 (m, 2H), 1.20 (t, 3H), 1.11 (t, 3 H).

Example 32 : N, N-diethyl-3-pyridinecarboxamide

The compound (556 mg) prepared in Example 31 was dissolved in ethanol (10 ml) and ethyl acetate (20 ml), and 5% palladium carbon (100 mg) was added thereto under hydrogen atmosphere. After stirring for a period of time, the mixture was filtered using celite, and the solvent was distilled off to obtain the title compound having the following physical data. The title compound thus obtained was used for the next reaction without further purification.

_{^{1 H-NMR (CDCl 3)}} : δ 3.50-2.74 (m, 8H), 1.97 (m, 2H), 1.20 (t, 3H), 1.11 (t, 3H).

Example 33 : 2- {4- [3 - ({[3- (diethylcarbamoyl) -1-pyrrolidinyl] carbonyl} amino) -5- (4- fluorophenoxy) phenoxy] Phenyl} -2-methylpropanoic acid

The compound (29.8 mg) prepared in Example 32 and the compound (100 mg) prepared in Example 7 were treated in the same manner as in Example 8? Example 9 to give the title compound ( 59.4 g).

TLC: Rf 0.60 (CHCl 3: MeOH = 9: 1);

¹ H-NMR (CDCl ₃ ):? 7.31 (m, 2H), 7.98-6.88 (m, 7H), 6.68 (m, 8H), 2.25-2.00 (m, 2H), 1.55 (s, 6H), 1.19 (t, 3H), 1.09 (t, 3H).

Example 33 (1) : 2- {4- [3- (4-Fluorophenoxy) -5 - ({[3- (isopropylcarbamoyl) -1- pyrrolidinyl] carbonyl} amino) Phenoxy] phenyl} -2-methylpropanoic acid

Using the compound (100 mg) prepared in Example 7 and the corresponding pyrrolidine derivative (27.4 mg) instead of the compound prepared in Example 32, the title compound having the following physical data (63.6 mg).

TLC: Rf 0.54 (CHCl 3: MeOH = 9: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.31 (m, 2H), 7.04-6.80 (m, 7H), 6.68 (m, 1H), 6.48 (m, 1H), 6.30 (m, 1H), 5.64 (d 2H), 1.56 (s, 6H), 1.11 (m, IH), 4.03 (m, IH), 3.62-3.50 m, 6H).

Example 34 : Methyl 3,5-dinitrobenzoate

3,5-dinitrobenzoyl chloride was dissolved in methanol (100 ml), and diisopropylethylamine (4.53 ml) was added under ice-cooling. The reaction solution was stirred for 1 hour, and then the solvent was distilled off. Diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain the title compound (4.73 g) having the following physical data.

TLC: Rf 0.31 (hexane: AcOEt = 5: 1).

Example 35 : Methyl 3- (4-fluorophenoxy) -5-nitrobenzoate

The compound (4.73 g) prepared in Example 34 was dissolved in DMF (40 ml), 4-fluorophenol (2.34 g) and potassium phosphate (5.32 g) were added and stirred overnight at 80 ° C. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1 -> 1: 1) to obtain the title compound (4.81 g) having the following physical data.

TLC: Rf 0.47 (hexane: AcOEt = 5: 1).

Example 36 : Methyl 3- (4-fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl) carbonyl] amino} benzoate

Using the compound prepared in Example 35 and 4-isobutyl-4-piperidino in the same manner as in Example 6? Example 7? Example 8, the title compound having the following physical data (495 mg ).

_{^{1 H-NMR (CDCl 3)}} : δ 7.40-7.20 (m, 7H), 5.13 (s, 2H), 3.94 (m, 2H), 3.22 (m, 2H), 2.46 (m, 1H), 1.83 (m , ≪ / RTI > 2H), 1.57 (m, 6H).

Example 37 : 3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl) carbonyl] amino}

The compound (495 mg) prepared in Example 36 was dissolved in methanol (5 ml), and a 2N aqueous sodium hydroxide solution (1.11 ml) was added, followed by stirring at 45 ° C for 2 hours. The reaction solution was neutralized with an equal amount of hydrochloric acid, and then the solvent was distilled off, diluted with ethanol, filtered and desalted to obtain the title compound (490 mg). The title compound thus obtained was used for the next reaction without further purification.

Example 38 : 2- (4 - {[3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4- isobutyl- 1 -piperidinyl) carbonyl] amino} benzoyl] Oxy} phenyl) -2-methylpropanoic acid

The compound (75 mg) prepared in Example 37 was dissolved in DMF (1 ml) under an argon atmosphere and EDC (55.5 mg), HOBt (39.1 mg), diisopropylethylamine (0.05 ml) (4-hydroxyphenyl) -2-methylpropanoate (56.5 mg) was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. Subsequently, the obtained residue was dissolved in methanol (1 ml) and ethyl acetate (1 ml), and 5% palladium carbon (50 mg) was added thereto, followed by stirring at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered using celite, and the solvent was distilled off. The resulting residue was purified by thin layer chromatography (chloroform: methanol = 5: 1) to obtain the title compound (59.1 mg) having the following physical data.

TLC: Rf 0.62 (CHCl 3: MeOH = 5: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.58 (m, 2H), 7.32 (m, 3H), 7.18-6.90 (m, 6H), 3.79 (m, 2H), 3.24 (m, 2H), 1.80 (m , 1 H), 1.70-1. 45 (m, 4H), 1.52 (s, 6H), 1.37 (d, 2H), 0.95 (d, 6H).

Example 39 : Synthesis of 4-cyclopropyl-N- [3- (4-fluorophenoxy) -5- (hydroxymethyl) phenyl] -4-hydroxy- 1- piperidinecarboxamide

Obtained in the same manner as in Example 36, using 4-cyclopropyl-4-piperidinol in place of the compound prepared in Example 35 and 4-isobutyl-4-piperidinol in an argon atmosphere. - (4-fluorophenoxy) benzoate (201 mg) was dissolved in THF (10 ml) And diisobutylaluminum hydride (1.407 ml, 1.0 M, toluene solution) was added thereto, followed by stirring at 0 ° C for 1 hour and 30 minutes. An aqueous solution of sodium sulfate was added to the reaction solution, which was then filtered using Celite, and the solvent was distilled off. The mixture was further diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 95: 5 to 0: 1) to obtain the title compound (161 mg) having the following physical data.

_{^{1 H-NMR (CDCl 3)}} : δ 7.06 (m, 1H), 7.00-6.88 (m, 5H), 6.79 (m, 1H), 6.58 (m, 1H), 4.52 (s, 2H), 3.78 (m , 2H), 3.18 (m, 2H), 1.68-1.44 (m, 4H), 0.89 (m, 1H), 0.39-0.32 (m, 4H).

Example 40 : 2- (4 - {[3 - {[(4-cyclopropyl-4-hydroxy-1- piperidinyl) carbonyl] amino} -5- (4- fluorophenoxy) benzyl] Oxy} phenyl) -2-methylpropanoic acid

The compound (153 mg) prepared in Example 39 was dissolved in THF (12 ml) under an argon atmosphere, and the compound (89.2 mg) prepared in Example 3, diisopropyl azodicarboxylate (0.114 ml) Phenylphosphine (110 mg) was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1 -> 0: 1). Further, the obtained product was dissolved in methanol (2 ml), 2N aqueous sodium hydroxide solution (0.575 ml) was added, and the mixture was stirred at 45 캜 for 2 hours. The reaction mixture was neutralized with an equal volume of hydrochloric acid and then concentrated. The resulting residue was purified by thin layer chromatography (chloroform: methanol = 5: 1) to obtain the title compound (99.0 mg) having the following physical data.

TLC: Rf 0.58 (CHCl 3: MeOH = 5: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.30-6.70 (m, 10H), 6.67 (m, 1H), 6.51 (s, 1H), 4.96 (s, 2H), 3.80 (m, 2H), 3.24 (m , 2H), 1.70-1.48 (m, 4H), 1.56 (s, 6H), 0.93 (m, 1H), 0.44-0.32 (m, 4H).

Example 41 : Synthesis of N- [3- (4-fluorophenoxy) -5-hydroxyphenyl] -4-hydroxy-4-isobutyl-1-piperidinecarboxamide

Example 4? Example 5? Example 6? Example 7? Using 3-difluoro-5-nitrobenzene, phenylmethanol, 4-fluorophenol and 4-isobutyl- → The title compound having the following physical data was obtained by the same procedure as in Example 8.

TLC: Rf 0.52 (hexane: ethyl acetate = 1: 2).

Example 42 : Ethyl {4- [3- (4-fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1 -piperidinyl) carbonyl] amino} phenoxy] phenyl } (Oxo) acetate

The compound (100 mg) prepared in Example 41 and ethyl 2- (4-fluorophenyl) -2-oxoacetate (73 mg) were dissolved in DMF (0.7 ml) and cesium carbonate (79 mg) Stir at 60 < 0 > C. After 2 hours from the initiation of the reaction, ethyl 2- (4-fluorophenyl) -2-oxoacetate (73 mg) Cesium carbonate (132 mg) was further added and the mixture was stirred for 18 hours in total. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distillation under reduced pressure was purified by silica gel chromatography (hexane: ethyl acetate = 90: 10 - > 50: 50) to obtain the title compound (43 mg) having the following physical data.

TLC: Rf 0.28 (hexane: ethyl acetate = 1: 1).

Example 43: ethyl {4- [3- (4-fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl-1-piperidinyl) carbonyl] amino} phenoxy] phenyl } (Hydroxy) acetate

The compound (43 mg) prepared in Example 42 was dissolved in methanol (1 ml) and stirred at 0 占 폚. Sodium borohydride (3 mg) was added to the reaction solution, and the mixture was stirred for 15 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 75:25 - > 50:50) to obtain the title compound (24 mg) having the following physical data.

TLC: Rf 0.12 (hexane: AcOEt = 1: 1).

Example 44 : {4- [3- (4-Fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1 -piperidinyl) carbonyl] amino} phenoxy] phenyl} (Hydroxy) acetic acid

The compound (24 mg) prepared in Example 43 was dissolved in methanol (0.4 ml), and a 2N aqueous sodium hydroxide solution (52 쨉 l) was added thereto, followed by stirring at 35 째 C for 13 hours. The reaction mixture was neutralized by addition of 1N hydrochloric acid at 0 ° C, and extracted with water and ethyl acetate. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (21.6 mg) having the following physical data.

TLC: Rf 0.16 (dichloromethane: methanol: acetic acid = 100: 10: 1);

_{^{1 H-NMR (CDCl 3)}} : δ 7.38 (d, 2H), 7.03-6.90 (m, 6H), 6.78 (s, 1H), 6.64 (s, 1H), 6.27 (t, 1H), 5.08 (s 1H), 3.67 (d, 2H), 3.30-3.18 (m, 2H), 1.77 (dd, 1H), 1.63-1.46 (m, 4H), 1.34 (d, 2H), 0.92

Example 45 : Synthesis of N- [3- (4-fluorophenoxy) -5- (4- {2-methyl- 1 - [(methylsulfonyl) amino] -1-oxo-2-propanyl} phenoxy ) Phenyl] -4-hydroxy-4-isobutyl-1-piperidinecarboxamide

The compound (320 mg), methanesulfonamide (80 mg), EDC (160 mg) and 4-dimethylaminopyridine (104 mg) prepared in Example 9 were suspended in dichloromethane (12 ml) 0.0 > 70 C < / RTI > for 2 hours. The reaction solution was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed twice with 1N hydrochloric acid and once with saturated brine. The organic layer was subjected to solvent distillation, and the obtained residue was purified by silica gel chromatography (dichloromethane: methanol = 16: 1). The resulting residue was further washed with hexane and t-butyl methyl ether to obtain the title compound (215 mg) having the following physical data.

TLC: Rf 0.45 (dichloromethane: methanol = 8: 1);

_{^{1 H-NMR (CD 3 OD}} ): δ 7.32 (d, 2H), 7.16-6.97 (m, 6H), 6.85 (t, 1H), 6.79 (t, 1H), 6.21 (t, 1H), 3.88- 2H), 3.72 (m, 2H), 3.27-3.15 (m, 5H), 1.98-1.76 (m, 1H), 1.54 (s, 6H), 1.66-1.47 d, 6H).

[Process for producing crystal of the present invention compound]

In the present invention, each of the crystal forms of the compound of the present invention can be produced by the method described in the examples, or a method similar thereto.

The physical property data of each crystal described in the examples was performed according to the following measurement conditions.

[1] Powder X-ray diffraction spectrum

<Measurement Conditions>

Device: BRUKER axs Manufacturing BRUKER D8 DISCOVER with GADDS,

Target: Cu,

Filter: None,

Voltage: 40 kV,

Current: 40 mA,

Exposure time: 3 min.

[2] Differential Scanning Calorimetry (DSC)

<Measurement Conditions>

Device: manufactured by METTLER TOLEDO DSC 822e,

Sample volume: 1 to 2 mg,

Sample cell: 40 ㎕ of aluminum pan,

Nitrogen gas flow rate: 40 ml / min,

Temperature raising rate: 10 占 폚 / min (25 占 폚 to 220 占 폚, 25 占 폚 to 240 占 폚, 25 占 폚 to 250 占 폚).

Example A: Synthesis of 2- {4- [3- (4-fluorophenoxy) -5 - {[(4-hydroxy-4-isobutyl- 1 -piperidinyl) carbonyl] amino} phenoxy] Phenyl} -2-methylpropanoic acid (Form A crystal)

In Example 9, ethyl acetate (7 v / w) was added to the obtained purified product, and the mixture was stirred at 0 캜 to 30 캜. After the solution was filtered once, toluene (3 v / w) was added and the seeds were seeded and stirred at 25 ° C for 3 hours. Toluene (10 v / w) was added, cooled to 0 占 폚 and stirred for 1 hour and 30 minutes. The obtained crystals were filtered and washed with toluene (2 v / w) to obtain the titled crystals. A powder X-ray diffraction spectrum of the obtained crystal is shown in Fig. 1, and a differential scanning calorimetry (DSC) chart is shown in Fig. 2, respectively. The diffraction angles 2? And the relative intensities in the powder X-ray diffraction spectrum are shown in the following table.

Powder X-ray diffraction spectrum:

This crystal showed the onset of the endothermic peak at about 143 ° C.

Example B: Preparation of 2- {4- [3 - ({[4- (2-ethylbutyl) -4-hydroxy- 1 -piperidinyl] carbonyl} amino) -5- (4-fluorophenoxy ) Phenoxy] phenyl} -2-methylpropanoic acid (Form A crystal)

To the compound prepared in Example 9 (20), ethanol (35 v / w) and water (10 v / w) were added. The solution was heated to dissolve in an oil bath at 70 占 폚. The solution was allowed to stand from 70 DEG C to 25 DEG C, and the resulting crystals were collected by filtration and dried under reduced pressure to obtain the titled crystals. The obtained crystals were analyzed, the powder X-ray diffraction spectrum thereof was shown in Fig. 3, and the differential scanning calorimetry chart was shown in Fig. 4, respectively. The diffraction angles 2? And the relative intensities in the powder X-ray diffraction spectrum are shown in the following table.

Powder X-ray diffraction spectrum:

This crystal showed the onset of the endothermic peak at about 170 캜.

Example C: Preparation of 1- {4- [3- (4-fluorophenoxy) -5- ({[4-hydroxy- 4- (3- fentanyl) -1- piperidinyl] carbonyl} amino) Phenoxy] phenyl} cyclopropanecarboxylic acid (Form A crystal)

To the compound prepared in Example 13, 15 占 퐇 (15 v / w) of ethanol was added. The solution was heated and dissolved in an oil bath at 70 占 폚. After cooling from 70 DEG C to 25 DEG C, the obtained crystals were collected by filtration and dried under reduced pressure at room temperature to obtain the titled crystals. The obtained crystals were analyzed, the powder X-ray diffraction spectrum thereof was shown in Fig. 5, and the differential scanning calorimetry (DSC) chart thereof was shown in Fig. 6, respectively. The diffraction angles 2? And the relative intensities in the powder X-ray diffraction spectrum are shown in the following table.

Powder X-ray diffraction spectrum:

This crystal showed the onset of the endothermic peak at about 182 &lt; 0 &gt; C.

[Experimental Example]

Examples of biological experiments and physical experiments are shown below, and the effects of the compounds of the present invention were confirmed based on the experimental methods.

Biological Test Example _{1: S1P 2 (EDG-5} ) Evaluation of the antagonist activity resulting from the cell to monitor the concentration of intracellular calcium ions

Human S1P ₂ (EDG-5) varnish difference hamster O Bari (CHO) cells that over-express the gene, 10% fetal bovine serum (FBS), antibiotics were cultured in Ham's F12 medium containing an antifungal agent and G418. Rat S1P ₂ (EDG-5) CHO cells which over-express the gene, 10% FBS, penicillin-streptomycin and were cultured in Ham's F12 medium Blind stitch between Dean S contained. The cultured cells were cultured in a Fura2-AM solution (5 μM) (Ham's F12 medium containing FBS (10%), HEPES buffer (20 mM, pH 7.2 to 7.5) and proveness , And incubated for 60 minutes. Washed twice with Hanks equilibrium saline containing HEPES buffer (20 mM, pH 7.2-7.5) and probenecid (2.5 mM), and immersed in the same solution. Plates were set in the fluorescence drug screening system, and intracellular calcium ion concentration was measured by stimulation for 30 seconds. After 3 minutes, S1P (species concentration: 0.25 nM to 25 μM, species concentration of human S1P ₂ : species concentration of rat S1P ₂ : 0.25 nM to 2.5 μM) or dimethylsulfoxide (DMSO) 300 nM) was added, and the increase in intracellular calcium ion concentration before and after S1P addition was measured at intervals of 3 seconds (excitation wavelength: 340 nm and 380 nm, fluorescence wavelength: 540 nm).

The S1P ₂ (EDG-5) antagonistic activity was determined by using a control value (A) as the peak value due to S1P (final concentration: 300 nM) in the well to which DMSO was added instead of the test substance, Was compared with the rising value (B) after addition of S1P to calculate the inhibition rate (%) using the following equation.

[Equation 1]

Inhibition rate (%) = [(A-B) / A] 100

The IC ₅₀ value was calculated as the concentration of the compound of the present invention showing an inhibition rate of 50%.

(Hereinafter referred to as Comparative Compound A) and Example 1 (85) (hereinafter, referred to as Comparative Compound B), which are described in Patent Document 3 (International Patent Publication No. 2004/002531 pamphlet) ) Were used. The structural formulas of the respective comparative compounds are as follows.

The compound of the present invention and compared to human and rat S1P ₂ (EDG-5) antagonist activity of the compounds were as shown in Table 4 below.

As a result, the compound of the present invention relative to the comparison compound, it was found that the human S1P ₂ antagonistic activity is remarkably improved. In addition, the compounds of the present invention, compounds enhancing the extrapolated sex (外揷性) for improving FIG jongcha (種差) of S1P ₂ antagonistic activity in human and rat, and the validity of the conditions in the model of the rat to humans.

Physical experiment 2 : Determination of solubility

For the calibration curve solution, the test substance (10 mmol / L, DMSO solution) was diluted with acetonitrile, and acetonitrile containing an internal standard substance (warfarin) was added to prepare 0.1, 0.4 and 2 μmol / l. As a sample solution, 495 占 퐇 of a solution of two national solutions (250 ml of 0.2 mol / l potassium dihydrogen phosphate solution, 118 ml of 0.2 mol / l sodium hydroxide solution and 1000 ml of water was used) 5 μl of the test substance (10 mmol / l, DMSO solution) was added to the solution (pH 6.8) and stirred at room temperature for 5 hours. Then, the solution was transferred to a plate having a filter attached thereto and subjected to suction filtration. 20 μl of the filtrate was dissolved in acetonitrile , And acetonitrile containing an internal standard was added. 5 ㎕ each of the calibration curve solution and the sample solution was injected into LC-MS / MS (Discovery Max, manufactured by Thermo Scientific) (quantitative range 0.1 to 2 탆 ol / ℓ). The solubility was calculated by multiplying the quantitative value by 50. When a value outside the quantitative range was obtained, the solubility was <5 μmol / l or 100 μmol / l.

The solubility of the compound of the present invention and the comparative compound was as shown in Table 5 below.

As a result, it was found that the compound of the present invention had better solubility than the comparative compound.

BIOLOGICAL EXAMPLE 3 : Review of the action of SlP ₂ (EDG-5) antagonist on portal hypertension in bile duct ligation interstitial rat model

Pentobarbital sodium (50 mg / kg, intraperitoneal injection) Two portions of the total bile ducts of rats (Crl: CD (SD), male, Nippon Charles River, 7 weeks old) under anesthesia were ligated with a suture chamber, Of the choledochal cysts of the liver, resulting in portal hypertension due to liver failure three weeks after treatment. The rats were orally administered with a compound or medium (distilled water) at a dose of 5 ml / kg, anesthetized with urethane (1.3 g / kg, subcutaneously) about 2 hours before the portal pressure measurement, A catheter (20G: Terumo) was inserted into the portal. In order to prevent the body temperature from dropping, the portal pressure was measured at a warming-up mat (37 ° C). To prevent clogging of the catheter due to thrombus, physiological saline solution containing heparin (10 heparin units / (0.8 ml / h). The portal pressure was recorded on a recorder (WR3320 or WR3701: Graftech) recording paper through a modified pressure amplifier (AP-601G: Nihon Kohden Kogyo).

1 mg / kg of the comparative compound, the compound of the present invention or the medium was orally administered, the portal pressure was measured 4 hours after the administration, and 0.3 mg / kg of the compound or the medium of the present invention was orally administered. Are shown in Tables 6 and 7, respectively. The hypotensive action of each compound was expressed as a percentage reduction (%) to the portal pressure of the control group (vehicle-administered group). Also, in this model, it has been reported that losartan, an angiotensin II receptor antagonist, decreases portal pressure by up to 14% (Journal of Hepatology, 37, 773-780, 2002).

As a result, at 4 hours after administration, the effect of lowering the portal pressure of Comparative Compound A was insufficient at 6%. In contrast, the compound of the present invention exhibited a strong portal pressure lowering action. It was also found that the compound of the present invention was continuously maintained at a low dose even after 24 hours from the administration of the effect of decreasing the portal pressure after 4 hours of administration. In addition, since the compound of the present invention exhibited an equivalent or lower portal pressure lowering effect at a dose lower than that of the comparative compound, it is presumed that the effective dose is lowered. Therefore, it was found that the compound of the present invention is useful when it is used as a medicine as compared with the comparative compound.

[Formulation Example]

Formulation Example 1

Each of the following ingredients was mixed by a conventional method and then tableted to obtain a tablets containing 10 mg of the active ingredient per tablet.

- ({[4-hydroxy-4- (3-fentanyl) -1-piperidinyl] carbonyl} amino) phenoxy] Phenyl} cyclopropanecarboxylic acid &lt; RTI ID = 0.0 &gt; 100 g

· Carboxymethylcellulose calcium (disintegrating) ... 20 g

· Magnesium stearate ... 10 g

· Microcrystalline cellulose ... 870 g

Formulation Example 2

Each of the following components was mixed by a conventional method and then filtered with a dust-removing filter to fill the ampoule in an amount of 5 ml. The mixture was then sterilized by heating with an autoclave to obtain an ampoule containing 20 mg of the active ingredient in 1 ampoule I got 10,000.

- [(4-hydroxy-4-isobutyl-1-piperidinyl) carbonyl] amino} phenoxy] phenyl} - 2-methylpropanoic acid ... 200 g

· Mannitol ... 20 g

·Distilled water … 50 ℓ

The compound of the present invention has potent human S1P ₂ antagonistic activity and has a remarkable effect of lowering portal pressure. Therefore, the compound of the present invention is useful as a preventive and / or therapeutic agent for S1P ₂ reperfusion diseases such as diseases caused by contraction of blood vessels, useful.

Claims (16)

A pharmaceutical composition comprising a compound represented by the following formula (I-1), a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof:

Wherein R ¹ is (1) a C 1-8 alkyl group which may be substituted with 1 to 5 R ²¹ , (2) a C 2-8 alkenyl group which may be substituted with 1 to 5 R ²¹ , (3) (4) a C1-4 alkyl group, a C1-4 haloalkyl group, a C1-4 alkoxy group, and a halogen atom, which is optionally substituted with one to five R &lt; ²¹ &gt; Or (5) -CONR ³¹ R ³² ,
R ²¹ represents a halogen atom, (2) -OR ²² (in which R ²² represents (1) a hydrogen atom, (2) a C 1-4 alkyl group, or (3) a C 1-4 haloalkyl group) (3) -NR ²³ R ²⁴ (wherein R ²³ and R ²⁴ each independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group), or (4)
R ³¹ and R ³² each independently represent (1) a hydrogen atom or (2) a C 1-4 alkyl group,
R ² represents (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group,
R ³ and R ⁴ each independently represent a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) -L-CONR ⁶ R ⁷ , (7) -L-SO ₂ R ⁸ or (8) -L-COOR ⁹ ,
R ⁵ represents (1) a halogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group,
L represents a group represented by the following formula (1), (2) a group represented by the following formula, (3) a C2-4 alkenylene group, (4) -O-C2-4 alkenylene group, A nitrogen atom which may be substituted with a C1-4 alkyl group,

(Wherein, A is (1) can be coupled, or (2) represents an oxygen atom, R ¹² and R ¹³ are each independently (1) hydrogen atom, (2) C1~4 alkyl, (3) a hydroxyl group, or (4) NH ₂ , or (5) R ¹² and R ¹³ may form a C3-7 carbon ring together with the bonding carbon atom, and the right arrow represents -CONR ⁶ R ⁷ , -SO ₂ R ⁸ , or -COOR ⁹ )
R ⁶ and R ⁷ are each independently (1) hydrogen atom, (2) C1~4 alkyl, (3) C1~4 haloalkyl group, (4) a hydroxyl ^{group, (5) -CONR 15 R 16} , (6) -SO ₂ NR ¹⁵ R ¹⁶ , (7) -COR ¹⁷ , or (8) -SO ₂ R ¹⁷ , or R ⁶ and R ⁷ , together with the nitrogen atom to which they are bonded, A nitrogen-containing saturated heterocyclic ring may be formed,
R ⁸ is (1) C1~4 alkyl, (2) C1~4 haloalkyl refers to an alkyl group, or (3) NR ¹⁰ R ^11,
R ⁹ represents (1) a hydrogen atom, or (2) a C 1-8 alkyl group,
R ¹⁰ and R ¹¹ are each independently (1) hydrogen atom, (2) C1~4 ^{alkyl, (3) -CONR 15 R 16} , (4) -SO 2 NR 15 R 16, (5) -COR 17 , Or (6) -SO ₂ R ¹⁷ ,
ring1 and ring2 each independently represent a cyclic group of 5 to 7 members,
R ¹⁴ represents (1) a hydrogen atom, or (2) a hydroxyl group,
R ¹⁵ and R ¹⁶ each independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a 5-7 membered cyclic group,
R ¹⁷ represents (1) a C1-4 alkyl group, or (2) a 5-7 membered cyclic group,
M ¹ and M ² are each independently selected from the group consisting of (1) a bond, (2) -C (O) -, (3) -O-, (4) , (6) -CH ₂ O-, or (7) -C (O) NH-,
n represents an integer of 1 to 2,
m represents an integer of 1 to 2,
p represents an integer of 0 to 5,
q represents an integer of 0 to 5,
r represents an integer of 0 to 4,
t represents an integer of 1 to 4,
When p is 2 or more, a plurality of R &lt; ³ &gt; s may be the same or different,
When q is 2 or more, a plurality of R ^{4 s} may be the same or different,
When r is 2 or more, plural R ^{5 s} may be the same or different,
When t is 2 or more, plural R &lt; ¹² &gt; and R &lt; ¹³ &gt; may be the same or different. Formula (I-1) compound, a salt thereof represented by the following set forth in claim 5, solvate, N- oxide thereof thereof, or S1P ₂ gae agent for preventing and / or treating diseases of the regeneration comprising the prodrug thereof. 3. The method of claim 2, S1P ₂ gae endogenous diseases, disorders due to the contraction of blood vessels, lines fibrosis, respiratory diseases, arteriosclerosis, peripheral arterial occlusion, retinopathy, glaucoma, for example (加齡) macular degeneration, nephritis, diabetes , Lipid disorders, hepatitis, cirrhosis, liver failure, neurological disorders, joint rheumatism, wounds, pain, dullness, systemic erythematous (SLE), or cancer. The method according to claim 3, wherein the disease caused by contraction of blood vessels is selected from the group consisting of cerebrovascular inflammatory diseases, cardiovascular inflammatory diseases, coronary artery spasmodic diseases, hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, atrial fibrillation, , Ascites, spleen, hepatic encephalopathy or ischemia reperfusion. The pharmaceutical preparation according to claim 4, which has a continuous portal pressure lowering action. The preparation according to claim 5, which is capable of administration once a day. The formulation according to any one of claims 4 to 6, which is a preventive agent for primary bleeding or secondary bleeding from esophageal varices according to portal hypertension. The preparation according to claim 2, wherein R ¹⁴ is a hydroxyl group. A compound according to claim 2, wherein M ¹ and M ² are each independently selected from the group consisting of (1) -C (O) -, (2) -O-, (3) , Or (5) -CH ₂ O-. The preparation according to claim 9, wherein M ¹ and M ² are -O-. The preparation according to claim 2, which is a compound represented by the following formula (I).

[Wherein all symbols have the same meanings as defined above] 12. The compound according to claim 11, wherein R ¹ is (1) a C1-8 alkyl group which may be substituted with 1 to 5 R ²¹ or (2) a C1-4 alkyl group, a C1-4 alkoxy group, a halogen atom and a trifluoromethyl group And a C3-7 carbon ring which may be substituted with 1 to 5 substituents selected from the group consisting of The preparation according to claim 11 or 12, wherein R ² is a hydrogen atom. 14. The formulation according to any one of claims 11 to 13, wherein ring1 and ring2 are each independently, (1) benzene, (2) cyclohexane, or (3) pyridine ring. The compound according to claim 2, wherein the compound represented by the formula (I-1) is (1) 4- (2- ethylbutyl) -N- {3- [4- (ethylcarbamoyl) phenoxy] (4-fluorophenoxy) phenyl} -4-hydroxy-1-piperidinecarboxamide, (2) 4- [3- (2-ethylbutyl) -N- [3- (4-fluoro-phenyl) Phenoxy) phenyl] -4-hydroxy-1-piperidinecarboxamide, (4) 2- (4-fluoro- Carbonyl] amino} phenoxy] phenyl} -2-methyl &lt; / RTI &gt; ({[4-hydroxy-4- (3-fentanyl) -1-piperidinyl] carbonyl} propanoic acid, Amino] phenoxy] phenyl} cyclopropanecarboxylic acid, (6) 2- {4- [3- (4- fluorophenoxy) -5 - {[ Azetidinyl) carbonyl] amino} phenoxy] phenyl} -2-methylpyridine (7) Synthesis of 4- [3 - ({[4- (2-ethylbutyl) -4- hydroxy- 1 -piperidinyl] carbonyl} amino) -5- (4-fluorophenoxy) (4-hydroxy-1-piperidinyl) carbonyl} amino) -5- (4- (4-fluoro-phenoxy) -phenoxy] phenyl} -2-methylpropanoic acid or (9) 2- (4- { - isobutyl-1-piperidinyl) carbonyl] amino} benzoyl] oxy} phenyl) -2-methylpropanoic acid. A compound represented by the formula (I-1), a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof, a calcium antagonist, a thrombolytic agent, a thromboxane synthetase inhibitor , Endothelin antagonists, antioxidants, radical scavengers, PARP inhibitors, astrocyte function improving agents, Rho kinase inhibitors, angiotensin II antagonists, angiotensin converting enzyme inhibitors, diuretics, phosphodiesterase 4 inhibitors, A medicament comprising a combination of at least one agent selected from prostaglandins, aldosterone antagonists, endothelin antagonists, prostacyclin agents, nitrate drugs, beta brothers, and vasodilators.

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