JP2003277379A - Nitrogen-containing heterocyclic compound, method for producing the same and use thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an HER2 inhibitor represented by general formula (I) and useful as an anticancer agent. <P>SOLUTION: The present invention provides the compound represented by general formula [wherein a ring A is a nitrogen-containing heterocyclic ring; a ring B is an aromatic isocyclic ring which may be substituted; a ring C is a 5- or 6-membered nitrogen-containing heterocyclic ring which may be substituted; R is an aromatic isocyclic ring or the like which may be substituted; m is an integer of 0-2, n is an integer of 1-5; X is an oxygen atom or the like; Y and Z are the same or different and they are each a single bond, an oxygen atom or carbon atom or the like which may be substituted] or its salts. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a heterocyclic compound useful as a growth factor receptor tyrosine kinase (particularly, HER2) inhibitor, a method for producing the same, and a pharmaceutical composition containing the same.

[0002]

2. Description of the Related Art The gene for cell growth factor and growth factor receptor is called protooncodin and plays an important role in the pathological condition of human tumors such as breast cancer (Non-patent Document 1). H having homology with the receptor for epidermal growth factor EGF
The ER2 (Human EGF Receptor-2) gene is a transmembrane receptor glycoprotein gene, and this receptor has tyrosine kinase activity (Non-Patent Document 2). HER2 is found in human breast cancer and ovarian cancer (Non-Patent Document 3), and also in prostate cancer (Non-Patent Document 4) and gastric cancer (Non-Patent Document 5). In addition, HER2 tyrosine kinase substrates have been found in 90% of pancreatic cancers. A transgenic mouse into which the HER2 gene is introduced develops breast cancer when grown (Non-patent document 6). It has been shown that an antibody against HER2 suppresses in vitro cell proliferation of cancer cells (Non-Patent Document 7), and further, a humanized monoclonal antibody against HER2 showed promising results in clinical trials for breast cancer patients (Non-Patent Document 8). ). These antibodies prevent growth factors from binding to the HER2 receptor and inhibit tyrosine kinase activation. As a result, it was shown that the cancer progression of breast cancer patients was suppressed, and thus it was shown that a drug that directly inhibits HER2 tyrosine kinase is effective as a therapeutic drug for breast cancer (Non-Patent Document 9). HE
As a compound that inhibits a receptor tyrosine kinase containing R2, a compound represented by the general formula in Patent Document 1

[Chemical 16] [In the formula, R _x represents an optionally substituted aromatic heterocyclic group, and X _x is an oxygen atom, an optionally oxidized sulfur atom, —C (═O) — or —CH (OH) — , Y _x
Represents CH or N, mx represents an integer of 0 to 10,
nx represents an integer of 1 to 5 and is a cyclic group.

[Chemical 17] Represents an optionally substituted aromatic azole group, and ring A
_x may be further substituted] or a salt thereof. In addition, Patent Document 2
To the general formula

[Chemical 18] [In the formula, m _y is 1 or 2, R ^y1 is a halogen atom or an optionally halogenated C _1-2 alkyl group, one of R ^y2 and R ^y3 is a hydrogen atom, and the other is a formula.

[Chemical 19] (In the formula, ny is 3 or 4, R^y4Is one or two hides
C substituted with a roxy group _1-4Represents an alkyl group)
Or a salt thereof is described.
Has been.

[0003]

[Non-Patent Document 1] Aaronson et al., Science 254.
Volume 1146-1153, 1991

[Non-Patent Document 2] Akiyama et al., Science 232, 164
Pp 4-1646, 1986

[Non-Patent Document 3] Slammon et al., Science 244 Vol. 7
07-712, 1989

[Non-Patent Document 4] Lean et al., Proceeding of
American Association for Cancer Research Vol. 37, page 243, 1996

[Non-Patent Document 5] Yonemura et al., Cancer Research
Volume 51, page 1034, 1991

[Non-Patent Document 6] Guy et al., Proceeding of National Academy of Science USA 89
Volume 10578-10582, 1992

[Non-Patent Document 7] Mackenzie et al., Onkojin, Vol. 4, 5
Pages 43-548, 1989

[Non-Patent Document 8] Baselga et al., Journal of Clinical Oncology, Vol. 14, pp. 737-744,
1996

[Non-Patent Document 9] Haze, Journal of Clinical Oncology 14: 697-699, 19
96 years

[Patent Document 1] Japanese Patent Laid-Open No. 11-60571

[Patent Document 2] Japanese Patent Laid-Open No. 2001-348385

[0004]

It is desired to develop a compound having an excellent tyrosine kinase inhibitory action, low toxicity, and satisfactory as a pharmaceutical.

[0005]

[Means for Solving the Problems] As a result of various investigations on heterocyclic compounds having a tyrosine kinase inhibitory action, the present inventors have found that

[Chemical 20] [Wherein, ring A is a nitrogen-containing heterocycle, ring B is an optionally substituted aromatic homocycle or an optionally substituted aromatic heterocycle, and ring C is optionally substituted 5 Or a 6-membered nitrogen-containing heterocycle, R is an optionally substituted aromatic homocyclic group, an optionally substituted aromatic heterocyclic group or an optionally substituted styryl group, and m is 0 To 2; n is an integer from 1 to 5; X is an oxygen atom, methylene group, ethylene group or ethenyl group; Y and Z are the same or different and may be a single bond, an oxygen atom or a substituent A carbon atom, an optionally substituted nitrogen atom, and an optionally oxidized sulfur atom are respectively shown. However, m
When = 0, X is an ethylene group or an ethenyl group. Also, the general formula

[Chemical 21] The group represented by

[Chemical formula 22] Except for the optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group represented by, when X is an oxygen atom, Y and Z are methylene groups. ] Was first synthesized, and it was found that this compound or its salt unexpectedly has an excellent tyrosine kinase inhibitory action based on its unique chemical structure. Based on this, the present invention has been completed.

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

[Chemical formula 23] [Wherein, ring A is a nitrogen-containing heterocycle, ring B is an optionally substituted aromatic homocycle or an optionally substituted aromatic heterocycle, and ring C is optionally substituted 5 Or a 6-membered nitrogen-containing heterocycle, R is an optionally substituted aromatic homocyclic group, an optionally substituted aromatic heterocyclic group or an optionally substituted styryl group, and m is 0 To 2; n is an integer from 1 to 5; X is an oxygen atom, methylene group, ethylene group or ethenyl group; Y and Z are the same or different and may be a single bond, an oxygen atom or a substituent A carbon atom, an optionally substituted nitrogen atom, and an optionally oxidized sulfur atom are respectively shown. However, m
When = 0, X is an ethylene group or an ethenyl group. Also, the general formula

[Chemical formula 24] The group represented by

[Chemical 25] It is an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group represented by and when X is an oxygen atom, Y and Z are the same or different and each is a single bond or a methylene group. ] Or a salt thereof; (2) the compound according to (1) above, wherein ring A is a monocyclic or bicyclic nitrogen-containing heterocycle; (3) the above, wherein ring A is oxazole or thiazole (1) The compound as described above; (4) benzene in which each ring B may be substituted,
The compound according to (1) above, which is pyridine, naphthalene, benzofuran or quinoline; (5) General formula

[Chemical formula 26] The group represented by

[Chemical 27] The compound according to (1) above, which is an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group;

[Chemical 28] The group represented by

[Chemical 29] The compound according to (1) above, which is an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group; (7) Pyrrole in which each ring C may be substituted,
Imidazole, pyrazole, triazole, pyridine,
The compound according to (1) above, which is oxazole, thiazole or benzimidazole; (8) the compound according to (1), wherein R is an optionally substituted styryl group; (9) the above, wherein X is an oxygen atom. (1) The compound described in (1), wherein m is 1, (10) The compound described in (1), wherein Y is an oxygen atom or a sulfonyl group, (12) The general formula

[Chemical 30] [Wherein R ¹ is a halogen atom or an optionally halogenated C _1-4 alkyl group, and R ² and R ³ are the same or different and may be a halogen atom, a C _1-3 alkyl group or a substituted group] A good hydroxyl group, W is an oxygen atom or a sulfur atom, p is an integer of 1 to 3, ring C is an optionally substituted 5- or 6-membered nitrogen-containing heterocycle, and m ′ is 1 or 2. n is an integer of 1 to 5, Y and Z are the same or different and each is a single bond, an oxygen atom, an optionally substituted carbon atom, an optionally substituted nitrogen atom or an optionally oxidized sulfur atom. Shown respectively. p is 2 or 3
R ¹ may be the same or different. However, the general formula

[Chemical 31] The group represented by

[Chemical 32] In the case of the optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group, the case where Y and Z are the same or different and each is a single bond or a methylene group is excluded. ] Or a salt thereof; (13) The above (12), wherein R ¹ is a trifluoromethyl group, a fluorine atom, a chlorine atom or a bromine atom, and R ² is a fluorine atom, a chlorine atom or a methyl group. (14) General formula

[Chemical 33] [Wherein R ¹ is a halogen atom or an optionally halogenated C _1-4 alkyl group, and R ² and R ³ are the same or different and may be a halogen atom, a C _1-3 alkyl group or a substituted group]. A good hydroxyl group, W is an oxygen atom or a sulfur atom, p is an integer of 1 to 3, and ring B ′ is an optionally substituted benzene ring or an optionally substituted 5- or 6-membered aromatic heterocycle. , Ring C is an optionally substituted 5- or 6-membered nitrogen-containing heterocycle, and m ′ is 1 or 2
Where n is an integer of 1 to 5 and Y and Z are the same or different and each is a single bond, an oxygen atom, an optionally substituted carbon atom, an optionally substituted nitrogen atom or an optionally oxidized sulfur. Each atom is shown. When p is 2 or 3, R ¹ may be the same or different. ] Or a salt thereof; (15) The above (12) or (1) in which W is an oxygen atom.
(4) The compound according to (4); (16) The compound according to (12) or (14), wherein m ′ is 1;

[Chemical 34] The group represented by

[Chemical 35] [In the formula, R ⁴ is a hydrogen atom or a substituent, 1) a hydroxyl group, 2) an optionally substituted alkoxycarbonyl group, 3) a optionally substituted carbamoyl group, 4) Cyclic aminocarbonyl group which may have a substituent, 5) carbamoyloxy group which may have a substituent, 6) cyclic aminocarbonyloxy group which may have a substituent, 7) substituent An optionally substituted alkylsulfonyl group, 8) an optionally substituted alkylsulfinyl group, 9) an optionally substituted sulfamoyl group, and 10) an optionally substituted group. Good cyclic aminosulfonyl group, 11) Carbamoylamino group which may have a substituent, 12) Cyclic aminocarbonylamino group which may have a substituent, 13) Alkyl which may have a substituent Honiruamino group, 14) an optionally substituted alkylsulfonylamino group and 1
5) C _1-4 alkyl group having 1 to 3 groups selected from acylamino groups. ] The compound of the above (1) which is a group represented by:

[Chemical 36] The group represented by

[Chemical 37] [In the formula, R ^4'is a hydrogen atom or a substituent, 1) a hydroxyl group, 2) an alkoxycarbonyl group which may have a substituent, 3) a carbamoyl group which may have a substituent, 4 ) Cyclic aminocarbonyl group which may have a substituent, 5) carbamoyloxy group which may have a substituent, 6) cyclic aminocarbonyloxy group which may have a substituent, 7) substitution An alkylsulfonyl group optionally having a group, 8) an alkylsulfinyl group optionally having a substituent, 9) a sulfamoyl group optionally having a substituent, 10) having a substituent A cyclic aminosulfonyl group, 11) a carbamoylamino group which may have a substituent, 12) a cyclic aminocarbonylamino group which may have a substituent, and 13) a substituent which may have a substituent. Alkyls Honiruamino group, 14) an optionally substituted alkylsulfonylamino group and 1
5) C _1-4 alkyl group having 1 to 3 groups selected from acylamino groups. [19] 1- (3- {4-[(2-{(E) -2- [4- (trifluoromethyl)) which is a ring group represented by:
Phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenoxy} propyl) -1H-1,2,3-triazole; 1-
[3-({4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl]]
Ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} thio) propyl] -1H-1,2,3-triazole; 1- [3-({4-
[(2-{(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} sulfonyl) propyl] -1H-1,2,3 -Triazole; {1- [3-({4-
[(2-{(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} sulfanyl) propyl] -1H-imidazol-2-yl } Methanol, {1- [3-({4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy]
Phenyl} sulfonyl) propyl] -1H-imidazol-2-yl} methanol, 1- [4-[[2-[(E) -2- (4-trifluoromethylphenyl) ethenyl] -1,3-oxazole- 4-yl] methoxy] phenyl] -4- (1H-1,2,3-triazol-1-yl) -1-
Butanol, 1- [3- [4- [2- [2-[(E)-
2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] ethyl] phenoxy] propyl] -1H-1,2,3-triazole, 2-[(E) -2 -[2-Fluoro-4- (trifluoromethyl) phenyl] ethenyl] -4-[[4- [4- (1H-pyrazol-3-yl) butyl] phenoxy] methyl] -1,3-oxazole, 2 -[5- [4-
[4-[[2-[(E) -2- [2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy]
Phenyl] butyl] -1H-pyrazol-1-yl] ethanol,
2-[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl] ethenyl] -4-[[4- [4- [1- [2- (tetrahydro-2H-pyran-2- Iloxy) ethyl] -1H-pyrazol-5-yl] butyl] phenoxy] methyl] -1,3-oxazole, 2- [5- [4- [4
-[[2-[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy]-
2-Methylphenyl] butyl] -1H-pyrazol-1-yl] ethanol and 2- [5- [4- [4-[[2-[(E) -2- [4-bromo-2-fluoro-4] -Phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] -2-methylphenyl] butyl] -1H-pyrazol-1-yl] ethanol, or a compound thereof; 20) A prodrug of the compound according to the above (1); (21) A drug containing the compound according to (1) or a salt thereof or a prodrug thereof; (22) The above (21), which is a tyrosine kinase inhibitor. (23) The medicine according to (21) above, which is a preventive / therapeutic agent for cancer; (24) The medicine according to (23) above, wherein the cancer is breast cancer, prostate cancer, lung cancer, pancreatic cancer or kidney cancer; Administration of an effective amount of the compound described in (1) above, a salt thereof or a prodrug thereof to a mammal (26) A method for preventing / treating cancer, which comprises administering an effective amount of the compound according to (1) or a salt thereof or a prodrug thereof to a mammal. (27) Use of the compound according to (1) or a salt thereof or a prodrug thereof for producing a tyrosine kinase inhibitor; and (28) (1) for producing a prophylactic / therapeutic agent for cancer.
It relates to the use of the described compound or a salt thereof or a prodrug thereof.

Further, the present invention is (29) General formula

[Chemical 38] [Wherein T ¹ is a leaving group, Ring A is a nitrogen-containing heterocycle, R is an optionally substituted aromatic homocyclic group, an optionally substituted aromatic heterocyclic group or a substituted And m represents an integer of 0 to 2, respectively. ] Or a salt thereof represented by the general formula

[Chemical Formula 39] [In the formula, Ring B is an optionally substituted aromatic homocycle or an optionally substituted aromatic heterocycle, and Ring C is an optionally substituted 5- or 6-membered nitrogen-containing heterocycle. , N is 1
To an integer of 5, X is an oxygen atom, a methylene group, an ethylene group or an ethenyl group, and Y and Z are the same or different and each is a single bond, an oxygen atom, an optionally substituted carbon atom, or an optionally substituted one. Represents a nitrogen atom or an optionally oxidized sulfur atom, respectively. ] The compound or its salt represented by these is made to react, The manufacturing method of the compound or its salt of said (1) characterized by the above-mentioned;

(30) A drug comprising a combination of the compound or salt thereof described in (1) above or a prodrug thereof and an anticancer agent; (31) A compound or salt thereof described above in (1) or a prodrug thereof and a hormone therapeutic agent. (32) The pharmaceutical according to (31) above, wherein the hormone therapeutic agent is an LH-RH modulator; (33) The pharmaceutical according to (32) above, wherein the LH-RH modulator is an LH-RH agonist. (34) The medicament according to (33) above, wherein the LH-RH agonist is leuprorelin or a salt thereof.

(35) Prevention of cancer, which comprises administering to a mammal an effective amount of the compound according to (1) or a salt thereof or a prodrug thereof in combination with an effective amount of another anticancer agent. -Treatment method: (36) A cancer characterized by administering to a mammal a combination of an effective amount of the compound according to (1) or a salt thereof or a prodrug thereof, and an effective amount of a hormone therapeutic agent. Preventive / therapeutic method: (37) The method according to (36) above, wherein the hormone therapeutic agent is an LH-RH modulator; (38) The method according to (37) above, wherein the LH-RH modulator is an LH-RH agonist; (39) The method according to (38) above, wherein the LH-RH agonist is leuprorelin or a salt thereof; (40) the compound according to (1) or a salt thereof after administration of another anticancer agent, or (41) A method for preventing and / or treating cancer, which comprises administering an effective amount of a prodrug thereof; (41) prior to applying surgery, radiation therapy, gene therapy, hyperthermia therapy, cryotherapy and / or laser ablation therapy, A method for preventing or treating cancer, which comprises administering an effective amount of the compound according to (1) or a salt thereof or a prodrug thereof to an animal; and (42) surgery, radiation therapy, gene therapy, hyperthermia Therapy, cryotherapy and / or laser ablation therapy, followed by administration to a mammal of an effective amount of the compound according to (1) or a salt thereof or a prodrug thereof. Regarding treatment methods, etc.

The "nitrogen-containing heterocycle" represented by ring A means a ring containing at least one nitrogen atom as an atom (ring atom) constituting the ring system. In addition to carbon atom, hetero atom 1 arbitrarily selected from oxygen atom, sulfur atom, nitrogen atom, etc.
Or 3 may be included. Specific examples of the "nitrogen-containing heterocycle" include, for example, pyrrole, pyrroline, pyrrolidine, imidazolidine, imidazoline, thiazolidine, oxazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, oxazole, isoxazole, thiazole, isothiazole, imidazole. , Pyrazole, 1,2,3-oxadiazole, 1,
2,4-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,4-
Thiadiazole, 1,3,4-thiadiazole, 1,2,3
-5- to 6-membered monocyclic nitrogen-containing heterocycles such as triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine, and for example indoline, isoindoline, 1H-indazole, benzindazole , Benzoxazole, 1,
2-benzisoxazole, benzothiazole, 1,
2-benzisothiazole, 1H-benzotriazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine, pteridine, carbazole, α-carboline, β-
Carboline, γ-carboline, acridine, phenoxazine, phenothiazine, phenazine, phenatridine,
Phenanthroline, indolizine, pyrrolo [1,2-
b ] pyridazine, pyrazolo [1,5- a ] pyridine, imidazo [1,2- a ] pyridine, imidazo [1,5- a ]
Pyridine, imidazo [1,2- b ] pyridazine, imidazo [1,2- a ] pyrimidine, 1,2,4-triazolo [4,3- a ] pyridine, 1,2,4-triazolo [4,3]
- b] can be used a condensed polycyclic 8-12 membered like pyridazine nitrogen-containing heterocyclic ring.

Examples of the "monocyclic or bicyclic nitrogen-containing heterocycle" include, for example, oxazole, isoxazole, thiazole, imidazole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2. 5- to 6-membered monocyclic nitrogen-containing heterocycles such as 1,4-triazole, pyridine, pyridazine and pyrimidine, and, for example, indoline,
8 such as isoindoline, benzindazole, benzoxazole, benzothiazole, quinoline, isoquinoline, quinazoline, pyrrolo [1,2- b ] pyridazine, imidazo [1,2- a ] pyridine, imidazo [1,5- a ] pyridine A 12-membered bicyclic nitrogen-containing heterocycle or the like can be used.

The "aromatic homocyclic ring" in the "optionally substituted aromatic homocyclic ring" represented by ring B is a monocyclic or condensed polycyclic aromatic homocyclic ring, etc., preferably C
_{6-14 An} aromatic homocycle is used. Specifically, for example, C _6-14 aromatic homocyclic ring such as benzene, naphthalene, anthracene, azulene, phenanthrene, phenalene, fluorene, indacene, biphenylene, heptalen, acenaphthylene, etc. are preferable, and more preferably benzene, naphthalene, anthracene, etc. Is more preferably benzene,
1-naphthalene, 2-naphthalene, etc. are used.

The "aromatic heterocycle" in the "optionally substituted aromatic heterocycle" represented by ring B means carbon atoms as well as oxygen atoms as atoms (ring atoms) constituting the ring system,
It may contain 1 to 3 heteroatoms arbitrarily selected from a sulfur atom, a nitrogen atom and the like. Specific examples of the "aromatic heterocycle" include, for example, pyrrole, oxazole, isoxazole, thiazole, isothiazole,
Imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2,3-thiadiazole, 1,
2,4-thiadiazole, 1,3,4-thiadiazole,
5- to 6-membered monocyclic aromatic heterocycles such as 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, and benzothiophene, benzofuran, indole 1H-indazole, benzindazole,
Benzoxazole, 1,2-benzisoxazole, benzothiazole, 1,2-benzisothiazole, quinoline, isoquinoline, cinnoline, quinazoline, carbazole, phenoxazine, indolizine, pyrrolo [1,2- b ] pyridazine, pyrazolo [ 1,5- a ]
Pyridine, imidazo [1,2- a ] pyridine, imidazo [1,5- a ] pyridine, imidazo [1,2- b ] pyridazine, imidazo [1,2- a ] pyrimidine, 1,2,4-
An 8- to 12-membered condensed polycyclic aromatic heterocycle such as triazolo [4,3- a ] pyridine and 1,2,4-triazolo [4,3- b ] pyridazine can be used.

As the "optionally substituted 5- or 6-membered aromatic heterocycle" represented by ring B ', thiophene, furan, pyrrole, pyridine, pyridazine, pyrimidine, pyrazine and the like can be used.

"Optionally substituted 5" represented by ring C
The "5- or 6-membered nitrogen-containing heterocycle" in the "or 6-membered nitrogen-containing heterocycle" refers to a ring containing at least one nitrogen atom as an atom (ring atom) constituting the ring system. In addition to carbon atoms, it may contain 1 to 3 heteroatoms arbitrarily selected from oxygen atom, sulfur atom, nitrogen atom and the like.
Specific examples of the "5- or 6-membered nitrogen-containing heterocycle" include, for example, pyrrole, pyrroline, pyrrolidine, imidazolidine, imidazoline, thiazolidine, oxazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, oxazole, isoxazole, thiazole. , Isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazan,
1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyridazine,
Pyrimidine, pyrazine, triazine and the like can be used.

The "aromatic homocyclic group" in the "optionally substituted aromatic homocyclic group" represented by R is a monocyclic or condensed polycyclic aromatic homocyclic group, preferably Is C
_{6-14 An} aromatic homocyclic group is used. Specifically, for example, phenyl, naphthyl, anthryl, azulenyl, phenanthryl, phenalenyl, fluorenyl, indacenyl,
C _6-14 aromatic homocyclic groups such as biphenylenyl, heptanenyl, acenaphthylenyl and the like are preferable, phenyl, naphthyl, anthryl and the like are more preferable, and phenyl, 1-naphthyl, 2-naphthyl and the like are more preferable.

The "aromatic heterocyclic group" in the "optionally substituted aromatic heterocyclic group" represented by R means an atom (ring atom) constituting the ring system, as well as a carbon atom, an oxygen atom and a sulfur atom. It may contain 1 to 3 heteroatoms arbitrarily selected from atoms, nitrogen atoms and the like. Specific examples of the "aromatic heterocyclic group" include thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,
2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,3-triazolyl,
5- to 6-membered monocyclic aromatic heterocycles such as 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, and 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α- Carborinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenatridinyl, phenanthrolinyl, indolizinyl, pyrrolo [1,2- b ]
Pyridazinyl, pyrazolo [1,5- a ] pyridyl, imidazo [1,2- a ] pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,2- b ] pyridazinyl, imidazo [1,2- a ] Pyrimidinyl, 1,2,4-triazolo [4,3- a ] pyridyl, 1,2,4-triazolo [4,3
An 8- to 12-membered condensed polycyclic aromatic heterocyclic group such as -b ] pyridazinyl can be used. Preferably, a 5- to 6-membered monocyclic aromatic heterocyclic group can be used.

Here, a substituent of the "optionally substituted aromatic homocycle" represented by ring B, a substituent of the "optionally substituted aromatic heterocycle"; a ring B '. Substituent of "optionally substituted benzene ring", Substituent of "optionally substituted 5- or 6-membered aromatic heterocycle"; ring C
A substituent of the "optionally substituted 5- or 6-membered nitrogen-containing heterocycle", "optionally substituted pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, oxazole, thiazole or benzimidazole" A substituent of the "optionally substituted aromatic homocyclic group" represented by R, a substituent of the "optionally substituted aromatic heterocyclic group", and a "optionally substituted" The substituent of the "styryl group" and the substituent of the "optionally substituted carbon atom" represented by Y and Z may be the same or different, and may be protected by a conventional method of organic chemical synthesis, if necessary. Although not particularly limited, for example (i) an optionally substituted alkyl group, (ii)
Optionally substituted alkenyl group, (iii) optionally substituted alkynyl group, (iv) optionally substituted aryl group, (v) optionally substituted aralkyl group, (v
i) optionally substituted cycloalkyl group, (vii) optionally substituted cycloalkenyl group, (viii) optionally substituted heterocyclic group, (ix) optionally substituted amino group, (x) optionally substituted imidoyl group (for example, formula -C (U ') = N-U [in the formula, U and U'represent a hydrogen atom or a substituent (U is preferably a hydrogen atom) Group represented by the formula), (xi) optionally substituted amidino group (for example, formula -C (NE'E '') = N
-E [in the formula, E, E'and E "each represent a hydrogen atom or a substituent (E preferably represents a hydrogen atom)]
Represented by), (xii) optionally substituted hydroxyl group, (xiii) optionally substituted thiol group, (xiv) optionally substituted alkylsulfinyl group, (xv) esterified or An optionally amidated carboxyl group, (xvi) optionally substituted thiocarbamoyl group,
(xvii) optionally substituted sulfamoyl group, (xvii
i) Halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.,
Preferably chlorine, bromine, etc.), (xix) cyano group, (xx) isocyano group, (xxi) cyanate group, (xxii) isocyanate group, (xxiii) thiocyanate group, (xxiv) isothiocyanate group, (xxv) nitro group , (Xxvi) nitroso group, (xxvii) sulfonic acid-derived acyl group, (xxviii) carboxylic acid-derived acyl group, (xxix) oxo group, (xxx) C _1-4 alkylenedioxy group, etc. are used. 1 to 5 (preferably 1 to 3) of the optional substituents may be substituted at substitutable positions.

As the substituent, “may be substituted”
Examples of the alkyl group in the “alkyl group” include
Chill, ethyl, n-propyl, isopropyl, n-butyl
, Isobutyl, sec-butyl, tert-butyl, n-pe
Methyl, isopentyl, neopentyl, 1-methylpro
Pill, n-hexyl, isohexyl, 1,1-dimethyl
Butyl, 2,2-dimethylbutyl, 3,3-dimethylbuty
C such as 3,3 dimethylpropyl_1-6For alkyl etc.
Can be Here, as a substituent of the alkyl group
Is a lower alkoxy group (eg, methoxy, ethoxy, pro
C such as poxy _1-6Alkoxy, etc.), halogen atom (eg,
Fluorine, chlorine, bromine, iodine, etc.), lower alkyl group
(Eg C such as methyl, ethyl, propyl, etc._1-6Alkyl
Etc.), lower alkenyl groups (eg, C such as vinyl and allyl)
_2-6Alkenyl, etc., lower alkynyl group (eg, ethini)
C such as Le and Propargil_2-6Alkynyl, etc.), substituted
Optionally an amino group, an optionally substituted hydroxyl group,
Cyano group, optionally substituted amidino group, carboxy
Si group, lower alkoxycarbonyl group (eg, methoxycarl
C such as bonyl and ethoxycarbonyl_1-6Alkoxycar
Carbonyl, etc.), an optionally substituted carbamoyl group
(Eg, a 5- to 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
C which may be substituted with_1-6Alkyl group
Is an acyl group (eg formyl, C_2-6Alkanoyl, ben
Zoyl, optionally halogenated C_1-6Alkoxy
Carbonyl, optionally halogenated C_1-6Archi
Sulfonyl, benzenesulfonyl, etc.)
Optionally carbamoyl group, 1-azetidinylcarbonyl
L, 1-pyrrolidinylcarbonyl, piperidinocarboni
L, morpholino carbonyl, 1-piperazinyl carbonyl
Etc.) and the like, and these optional substituents are
1 to 3 may be substituted at the substitutable position.

The "optionally substituted amino group", the "optionally substituted hydroxyl group" and the "optionally substituted amidino" as the substituents of the above-mentioned "optionally substituted alkyl group". As the "group", "optionally substituted amino group", "optionally substituted hydroxyl group", and "substituted" as substituents such as "optionally substituted aromatic homocyclic ring" described later The same as the "optional amidino group" can be used.

Examples of the alkenyl group in the above-mentioned "optionally substituted alkenyl group" include vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1
-Butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,
C _2-6 alkenyl such as 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like can be used. Here, as the substituent of the alkenyl, the same number of the same substituents as those in the above-mentioned “optionally substituted alkyl group” as the substituent can be used.

Examples of the alkynyl group in the above-mentioned "optionally substituted alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl. C _2-6 alkynyl such as 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl can be used. Here, as the substituent of the alkynyl group, the same number of substituents as those in the above-mentioned "optionally substituted alkyl group" as the substituent can be used.

As the aryl group in the “optionally substituted aryl group” as the substituent, for example, C _6-14 aryl such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like can be used. Here, as the substituent of the aryl group, the same number of substituents as those in the above-mentioned “optionally substituted alkyl group” as the substituent can be used.

The aralkyl group in the "optionally substituted aralkyl group" as the substituent is, for example, C _7-11 such as benzyl, phenethyl, naphthylmethyl and the like.
Aralkyl and the like can be used. Here, as the substituent of the aralkyl group, the same number of substituents as those in the above-mentioned "optionally substituted alkyl group" as the substituent can be used.

As the cycloalkyl group in the "optionally substituted cycloalkyl group" as the above-mentioned substituent, for example, C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like can be used. You can Here, as the substituent of the cycloalkyl group, the same number of substituents as those in the above-mentioned "optionally substituted alkyl group" as the substituent can be used.

As the cycloalkenyl group in the "optionally substituted cycloalkenyl group" as the above-mentioned substituent, for example, C _3-7 cycloalkenyl such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like are used. You can Here, as the substituent of the optionally substituted cycloalkenyl group, the same number of the same substituents as those in the above-mentioned "optionally substituted alkyl group" can be used. .

The heterocyclic group in the "optionally substituted heterocyclic group" as the substituent is, for example, an atom (ring atom) constituting the ring system selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like. Aromatic heterocyclic group containing at least one (preferably 1 to 4, more preferably 1 to 2) heteroatoms 1 to 3 (preferably 1 to 2), saturated or unsaturated non-aromatic Group heterocyclic groups (aliphatic heterocyclic groups) and the like can be used. Here, examples of the “aromatic heterocyclic group” include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,
2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,3-triazolyl,
5- to 6-membered monocyclic aromatic heterocyclic groups such as 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, and for example benzofuranyl, isobenzofuranyl, benzo [ b ].
Thienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl,
1,2-benzisoxazolyl, benzothiazolyl,
Benzopyranyl, 1,2-benzisothiazolyl, 1H
-Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxadinyl. Nyl, thianthrenyl, phenatoridinyl, phenatorolinyl, indoridinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo [1,5- a ] pyridyl, imidazo [1,2- a ].
Pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,2,4-triazolo [4,3- a ] pyridyl, 1, 8 to 12-membered condensed polycyclic aromatic heterocyclic group such as 2,4-triazolo [4,3- b ] pyridazinyl (preferably, the aforementioned 5- to 6-membered monocyclic aromatic heterocyclic group is benzene). A heterocyclic group condensed with a ring or a heterocyclic group in which two identical or different heterocycles of the above-mentioned 5 to 6-membered monocyclic aromatic heterocyclic group are condensed), more preferably the above-mentioned 5 to 6-membered A heterocyclic group in which a monocyclic aromatic heterocyclic group is condensed with a benzene ring, particularly preferably benzofuranyl,
Benzopyranyl, benzo [ b ] thienyl and the like can be used.

The "non-aromatic heterocyclic group" used herein is, for example, 3 to 8-membered (such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl ( Preferably 5 to 6 membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group), or 1,2,3,4-tetrahydroquinolyl, 1,2, Three and four
Using a non-aromatic heterocyclic group in which some or all of the double bonds are saturated in the above-mentioned monocyclic aromatic heterocyclic group or condensed polycyclic aromatic heterocyclic group such as tetrahydroisoquinolyl be able to. The substituent which the “optionally substituted heterocyclic group” as a substituent may have is a lower alkyl group (eg, C _1-6 such as methyl, ethyl, propyl and the like).
Alkyl, etc.), lower alkenyl groups (eg, C _2-6 alkenyl such as vinyl and allyl), lower alkynyl groups (eg, C _2-6 alkynyl such as ethynyl, propargyl, etc.), acyl groups (eg formyl, acetyl) , C _1-6 alkanoyl such as propionyl and pivaloyl, benzoyl etc.), an optionally substituted amino group, an optionally substituted hydroxyl group, a halogen atom (eg fluorine, chlorine, bromine, iodine etc., preferably chlorine, Bromine, etc.), an optionally substituted imidoyl group, an optionally substituted amidino group, etc. can be used. These optional substituents may be substituted at 1 to 5 (preferably 1 to 3) at substitutable positions. The “optionally substituted heterocyclic group” as the substituent may have “optionally substituted amino group”, “optionally substituted hydroxyl group”, “optionally substituted” As the "imidoyl group", and "optionally substituted amidino group", "optionally substituted amino group" as a substituent such as "optionally substituted aromatic homocycle" described later, The same groups as the “optionally substituted hydroxyl group”, the “optionally substituted imidoyl group”, and the “optionally substituted amidino group” can be used.

As the above-mentioned substituent, "optionally substituted amino group", "optionally substituted imidoyl group", "optionally substituted amidino group", "optionally substituted hydroxyl group". Examples of the substituent in the “optionally substituted thiol group” include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an optionally halogenated C _1-6 alkoxy (eg, methoxy, Ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trichloromethoxy, 2,2,2
-Trichloroethoxy etc.) and a C _7-11 alkylaryl group (eg o-toluyl, m-toluyl, p-toluyl, xylyl, mesityl etc., preferably C _1-5 alkyl-phenyl etc.) An optionally substituted lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,
C _1-6 alkyl such as hexyl), acyl group (C _1-6 alkanoyl (eg, formyl, acetyl, propionyl, pivaloyl etc.), benzoyl, C _1-6 alkylsulfonyl (eg, methanesulfonyl), benzenesulfonyl) Etc.), an optionally halogenated C _1-6 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, trifluoromethoxycarbonyl, 2,2,2-
Trifluoroethoxycarbonyl, trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), a C _1-6 alkoxycarbonyl group optionally substituted by a phenyl group (eg, benzyloxycarbonyl etc.), aryl (eg, C _6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl, etc.), aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl, etc., preferably phenyl-C _1-4 alkyl, etc.), arylalkenyl (eg, , C _8-10 arylalkenyl such as cinnamyl, preferably phenyl-C _2-4 alkenyl, etc., and a heterocyclic group (“heterocyclic group” in the “optionally substituted heterocyclic group” as the substituent). The same thing, preferably pyridyl, more preferably 4-pyridyl etc.) can be used. These optional substituents have 1 at the substitutable position.
Or 3 may be substituted.

The "amino group" in the "optionally substituted amino group" as the substituent is an optionally substituted imidoyl group (for example, C _1-6 alkylimidoyl (eg, formylimido). yl, acetyl imidoyl etc.), C _1-6 alkoxy imidoyl, C _1-6 alkyl thio imidoyl, amidino, etc.), with one to two C _1-6 alkyl amino group which may be substituted with a group such as It may be substituted. These optional substituents have 1 at the substitutable position.
Or two may be substituted. In addition, two substituents may combine with a nitrogen atom to form a cyclic amino group. In such a case, the cyclic amino group may be, for example, 1
-Azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1-piperazinyl and lower alkyl at the 4-position (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl) Etc.), aralkyl (eg C _7-10 aralkyl such as benzyl and phenethyl), aryl (eg C _6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl etc.) and the like. 1-piperazinyl, 1-pyrrolyl, 1-imidazolyl and the like 3-8 member (preferably 5
~ 6-membered) cyclic amino and the like can be used.

Examples of the alkylsulfinyl group in the “optionally substituted alkylsulfinyl group” as the substituent include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, se
C _1-6 such as c-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl and hexylsulfinyl
Alkylsulfinyl can be used. Here, as the substituent of alkylsulfinyl, the same number of substituents as the above-mentioned substituent in the “optionally substituted alkyl” can be used.

As the above-mentioned "carboxyl group which may be esterified or amidated" as the substituent,
Carboxyl groups, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, carbamoyl, N-monosubstituted carbamoyl and N, N-disubstituted carbamoyl can be used. Here, as the “alkoxycarbonyl”, for example, methoxycarbonyl,
C _1-6 alkoxycarbonyl such as ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl (lower Alkoxycarbonyl) and the like, among which C such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl can be used.
_1-3 alkoxycarbonyl and the like are preferable. The “lower alkoxycarbonyl” may have a substituent, and examples of the substituent include a hydroxyl group and an optionally substituted amino group [the amino group is, for example, 1 to 5 halogen atoms (eg, fluorine). , A lower alkyl group optionally substituted with chlorine, bromine, iodine, etc. (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc., preferably methyl, ethyl, etc.), an acyl group (eg formyl, acetyl, propionyl, C _1-6 alkanoyl pivaloyl, benzoyl, etc.), a carboxyl group, a one or two substituents such as C _{1 -6} alkoxycarbonyl You may have. ], A halogen atom (eg fluorine, chlorine, bromine, iodine etc.), a nitro group, a cyano group, 1 to 5 halogen atoms (eg fluorine, chlorine, bromine, iodine etc.)
A lower alkoxy group optionally substituted with (for example, methoxy, ethoxy, n-propoxy, isopropoxy, n
- butoxy, isobutoxy, sec- butoxy, C _1-6 alkoxy such as tert- butoxy, preferably methoxy,
Ethoxy etc.) and the like can be used. Further, these substituents are preferably the same or different and substituted by 1 or 2 to 3 (preferably 1 or 2).

Here, "aryloxycarbonyl"
For example, phenoxycarbonyl, 1-naphthoxyca
Lubonyl, 2-naphthoxycarbonyl, 1-phenanth
C such as oxycarbonyl_6-14Aryloxycarbonyl, etc.
Is preferred. The "aryloxycarbonyl" is a substituent
May have a substituent represented by the above-mentioned substituents.
With a substituent in "alkoxycarbonyl" as a group
A similar number of similar things can be used. here
Examples of the “aralkyloxycarbonyl” include benzene
Diloxycarbonyl, phenethyloxycarbonyl, etc.
C_7-14Aralkyloxycarbonyl and the like (preferably,
C_6-10Aryl-C_1-4Alkoxy-carbonyl etc.)
preferable. The "aralkyloxycarbonyl" is a substituent
May have a substituent represented by the above-mentioned substituents.
With a substituent in "alkoxycarbonyl" as a group
A similar number of similar things can be used. here
Examples of the "N-monosubstituted carbamoyl" include, for example, lower alkenyl.
Rutile (eg methyl, ethyl, propyl, isopropyl)
Ru, butyl, isobutyl, tert-butyl, pentyl,
C such as Kicil_1-6Alkyl, etc.), lower alkenyl (eg,
Vinyl, allyl, isopropenyl, propenyl, buteni
C such as le, pentenyl and hexenyl _2-6Alkenyl
Etc.), cycloalkyl (eg, cyclopropyl, cyclobu
C such as chill, cyclopentyl, cyclohexyl_3-6Shiku
Low alkyl etc.), aryl (eg phenyl, 1-naphthyl)
C such as le and 2-naphthyl_6-10Aryl etc.), aralkyl
(Eg C such as benzyl, phenethyl, etc._7-10Aralkyl, good
More preferably Phenyl-C_1-4Alkyl, etc.), arylal
Kenyl (eg C such as cinnamyl)_8-10Aryl alkeni
Preferably phenyl-C_2-4Alkenyl etc.), complex
A cyclic group (for example, "may be substituted" as the aforementioned substituent)
Same as "heterocyclic group" in "heterocyclic group", etc.
Can be used. The lower alkyl, lower alkene
Ru, cycloalkyl, aryl, aralkyl, aryl
The alkenyl and heterocyclic groups may have a substituent,
Examples of the substituent of are:
A similar number of substituents in "carbonyl"
Can be used.

Here, "N, N-disubstituted carbamoyl"
Means a carbamoyl group having two substituents on the nitrogen atom, and as one example of the substituent, the same substituent as the above-mentioned "N-monosubstituted carbamoyl" is used. And the other example is
For example, lower alkyl (eg, methyl, ethyl, propyl,
C _1-6 alkyl such as isopropyl, butyl, tert-butyl, pentyl, hexyl, etc., C _3-7 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _7-10 aralkyl (eg, benzyl) , Phenethyl and the like, preferably phenyl-C _1-4 alkyl and the like) and the like can be used. Further, two substituents may combine with a nitrogen atom to form a cyclic amino, and examples of the cyclic aminocarbamoyl in such a case include 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl and 4-position a lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, pentyl, C _{1 6} alkyl hexyl, etc.), 1-pipe that may have aralkyl (eg, C _7-10 aralkyl such as benzyl and phenethyl), aryl (eg, C _6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl, etc.) and the like A 3- to 8-membered (preferably 5- to 6-membered) cyclic aminocarbonyl such as radinylcarbonyl can be used.

The substituents of the “optionally substituted thiocarbamoyl group” and the “optionally substituted sulfamoyl group” as the above-mentioned substituents are “esterified or amidated as the above-mentioned substituents. The same substituents as "N-monosubstituted carbamoyl" and "N, N-disubstituted carbamoyl" in the "good carboxyl group" can be used.

As the "acyl derived from sulfonic acid" as the substituent, for example, the above-mentioned "N-monosubstituted carbamoyl" having one substituent on the nitrogen atom and sulfonyl is bonded can be used. However, preferably, acyl such as C _1-6 alkylsulfonyl such as methanesulfonyl and ethanesulfonyl can be used.

As the "acyl derived from carboxylic acid" as a substituent, use is made of a hydrogen atom or the above-mentioned "N-monosubstituted carbamoyl" having one substituent on the nitrogen atom and a carbonyl bond. However, preferably, C _1-6 alkanoyl such as formyl, acetyl, propionyl and pivaloyl, and acyl such as benzoyl can be used.

As the substituent of the "optionally substituted nitrogen atom" represented by Y and Z, the same number of substituents as those in the above-mentioned "optionally substituted amino group" is the same. Any thing can be used.

As the "optionally oxidized sulfur atom" represented by Y and Z, for example, a thio group, a sulfinyl group, a sulfonyl group and the like can be used.

The "halogen atom" represented by R ¹ , R ² and R ³ is, for example, fluorine atom, chlorine atom, bromine atom,
An iodine atom or the like can be used.

The "optionally halogenated C _1-4 alkyl group" represented by R ¹ is, for example, methyl, ethyl, propyl, butyl, trifluoromethyl, 2,2,2.
2-trifluoroethyl, trichloromethyl, 2,2
2-Trichloroethyl or the like can be used.

Examples of the "C _1-3 alkyl group" represented by R ² and R ³ include methyl, ethyl, n-propyl, i-
Propyl and the like can be used.

The substituent of the "optionally substituted hydroxyl group" represented by R ² and R ³ is the same number as the substituent in the "optionally substituted hydroxyl group" as the substituent. Any thing can be used.

Examples of the leaving group represented by T ¹ include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), 1
To C _1-6 alkylsulfonyloxy groups optionally substituted with 3 halogen atoms (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), optionally substituted arylsulfonyloxy groups ( (Eg, benzenesulfonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy, etc.) or a hydroxyl group, and a free carboxylic acid, its salt (inorganic salt, organic salt, etc.) or its reactive derivative (eg,
A group forming an acid halide, an ester, an acid azide, an acid anhydride, a mixed acid anhydride, an active amide, an active ester, an active thioester and the like can be used.

"As a substituent, 1) a hydroxyl group, 2) an alkoxycarbonyl group which may have a substituent, 3) a carbamoyl group which may have a substituent, represented by R ⁴ .
4) Cyclic aminocarbonyl group which may have a substituent, 5) Carbamoyloxy group which may have a substituent, 6) Cyclic aminocarbonyloxy group which may have a substituent, 7) An alkylsulfonyl group which may have a substituent, 8) an alkylsulfinyl group which may have a substituent, 9) a sulfamoyl group which may have a substituent, 10) which has a substituent A cyclic aminosulfonyl group, 11) a carbamoylamino group which may have a substituent, 12) a cyclic aminocarbonylamino group which may have a substituent, and 13) a substituent which may have a substituent. Good alkylsulfonylamino group, 14) optionally substituted alkylsulfonylamino group or 1
5) "C _1-4 alkyl group having an acylamino group", "C
_{As the} “ _1-4 alkyl group”, for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec
-Butyl, tert-butyl, etc. are used. Of these, methyl, ethyl and the like are preferable.

Specific examples of the "C _1-4 alkyl group having a hydroxyl group" include hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group and 1-hydroxy-1.
-Methylethyl group or the like is used. Examples of the "alkoxycarbonyl" in the "alkoxycarbonyl group which may have a substituent" as the substituent of the "C _1-4 alkyl group" include, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n. C _1-4 alkoxy such as -butoxy, i-butoxy and t-butoxy is used, and as the substituent, for example, halogen, hydroxy and the like are used. As the “cyclic aminocarbonyl” in the “cyclic aminocarbonyl group which may have a substituent”, for example, piperidinocarbonyl, morpholinocarbonyl, piperazinocarbonyl and the like are used, and the substituent is For example, C _1-4 alkyl (eg, methyl, ethyl, etc.), C _1-4 alkoxy (eg, methoxy, ethoxy, etc.), halogen (eg, fluorine, chlorine, bromine, etc.), hydroxy, amino, nitro, cyano, oxo. Etc. are used. Examples of the “cyclic aminocarbonyloxy” in the “cyclic aminocarbonyloxy group which may have a substituent (s)” include piperidinocarbonyloxy,
Morpholinocarbonyloxy, piperazinocarbonyloxy and the like are used, and examples of the substituent include C _1-4
Alkyl (eg, methyl, ethyl, etc.), C _1-4 alkoxy (eg, methoxy, ethoxy, etc.), halogen (eg, fluorine, chlorine, bromine, etc.), hydroxy, amino, nitro, cyano, oxo, etc. are used. As the “cyclic aminosulfonyl” in the “cyclic aminosulfonyl group optionally having substituent (s)”, for example, piperidinosulfonyl, morpholinosulfonyl, piperazinosulfonyl and the like are used, and the substituent is For example, C _1-4 alkyl (eg, methyl, ethyl, etc.), C _1-4 alkoxy (eg, methoxy, ethoxy, etc.), halogen (eg, fluorine, chlorine,
Bromine etc.), hydroxy, amino, nitro, cyano, oxo, etc. are used. As the “cyclic aminocarbonylamino” in the “cyclic aminocarbonylamino group optionally having substituent (s)”, for example, piperidinocarbonylamino, morpholinocarbonylamino, piperazinocarbonylamino and the like are used, Examples of the substituent include C _1-4 alkyl (eg, methyl, ethyl, etc.), C _1-4
Alkoxy (eg, methoxy, ethoxy, etc.), halogen (eg, fluorine, chlorine, bromine, etc.), hydroxy, amino,
Nitro, cyano, oxo and the like are used. Examples of the substituent of the "alkylsulfonyl group optionally having substituent (s)", "alkylsulfinyl group optionally having substituent (s)" and "sulfamoyl group optionally having substituent (s)" such as methyl, C _1-4 alkyl ethyl, etc., hydroxymethyl, hydroxy -C _1-4 alkyl such as hydroxyethyl are used. As the substituents of the "carbamoyl group optionally having substituents", "carbamoyloxy group optionally having substituents" and "carbamoylamino group optionally having substituents", For example, C _1-4 alkyl such as methyl and ethyl is used, and these may be mono-substituted or di-substituted. The “alkyl” of the “alkylsulfonylamino group optionally having substituent (s)” is, for example, methyl,
C _1-4 alkyl such as ethyl is used, and examples of the “substituent” include halogen such as fluorine and chlorine. Examples of the "acylamino group" include acetylamino, propionylamino, etc., C _2-4 alkanoylamino, etc. Specific examples of R ⁴ include, for example, methylcarbamoylethyl, acetamidoethyl, methanesulfonamidoethyl, methylsulfonylethyl, methylsulfonylmethyl, methylsulfinylethyl, hydroxymethyl, 1-hydroxyethyl, and the like.
Among them, methylsulfonylethyl, hydroxymethyl, 1
-Hydroxyethyl is preferred.

In the general formula (I) of the present invention, the general formula

[Chemical 40] The group represented by

[Chemical 41] An optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group, or

[Chemical 42] In the case of the optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group, the "5- or 6-membered nitrogen-containing heterocyclic group which may be substituted" The "nitrogen-containing heterocyclic group" refers to a 5- or 6-membered ring containing at least one nitrogen atom as an atom (ring atom) constituting the ring system, and can be any of carbon atom, oxygen atom, sulfur atom and nitrogen atom. The heteroatom selected from 1 to 3 may be included and is not particularly limited.
For example, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, thiazolidinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, 3-pyrazolyl, 1,2,2,1,2,2,2,2
2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl, 1,2,4
-Thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,
3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like can be used. The substituent of the “optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group” is the above-mentioned “optionally substituted 5”.
Alternatively, the same number of similar substituents as the “6-membered aromatic heterocycle” can be used.

Further, the general formula

[Chemical 43] The group represented by

[Chemical 44] In the case of the optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group represented by, the ring C ′ means to be bonded to the side chain on the nitrogen atom. For example

[Chemical formula 45] [The symbols in the formulas have the same meanings as described above. ] The group represented by these is illustrated. Furthermore, the general formula

[Chemical formula 46] The group represented by

[Chemical 47] In the case of the optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group represented by, the ring C ″ means to be bonded to the side chain on the carbon atom. For example,

[Chemical 48] [The symbols in the formulas have the same meanings as described above. ] The group represented by these is illustrated.

Specific preferred compounds in the present application are as follows. General formula

[Chemical 49] [In the formula, each symbol has the same meaning as described above. ] The compound of the present invention represented by or a salt thereof or a prodrug thereof is preferable, more preferably a compound represented by the general formula:

[Chemical 50] [In the formula, each symbol has the same meaning as described above. ] The compound of the present invention represented by or a salt thereof or a prodrug thereof, and a general formula

[Chemical 51] [In the formula, each symbol has the same meaning as described above. ] The compound of the present invention represented by: or a salt thereof or a prodrug thereof.

In the above formula, the nitrogen-containing heterocycle represented by ring A is preferably a 5- to 10-membered monocyclic or bicyclic nitrogen-containing heterocycle. As specific examples of the monocyclic or bicyclic nitrogen-containing heterocyclic ring, oxazole, thiazole, benzoxazole, benzothiazole and benzimidazole, which may be each substituted, are preferable, and oxazole is more preferable. The optionally substituted aromatic homocyclic ring represented by ring B is preferably an optionally substituted C _6-10 aromatic homocyclic ring, particularly preferably a benzene ring or a naphthalene ring. The optionally substituted aromatic heterocycle represented by ring B is preferably an optionally substituted 5- to 10-membered aromatic heterocycle, particularly preferably a pyridine ring, a benzofuran ring, a benzothiophene ring or a quinoline ring. And so on. When Ring B represents an optionally substituted benzene ring, the bonding position is preferably the para position or the meta position, and in the case of an optionally substituted pyridine ring, the 2,5-position or the 2,4-position is preferable. The ring B ′ is preferably a benzene ring, a pyridine ring, a thiophene ring, a furan ring, a pyridine ring or the like. The 5- or 6-membered nitrogen-containing heterocycle represented by ring C may be each substituted with imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, pyrazole, pyridine. , Pyrimidine and the like are preferable, and imidazole and 1,2,3-triazole which may be substituted are more preferable. As the optionally substituted aromatic homocyclic group represented by R, phenyl, thienyl, 1-naphthyl, 2-naphthyl and the like are preferable. A styryl group which may be substituted is more preferable, and a styryl group substituted with a trifluoromethyl group or a halogen atom is more preferable. m or m ′ represents an integer of 0 to 2, and 1 is preferable. n represents an integer of 1 to 5,
2 or 3 is preferred. X is preferably an oxygen atom or methylene. Y and Z are the same or different and each is a single bond,
A carbon atom which may be substituted, an oxygen atom, a nitrogen atom which may be substituted, and a sulfur atom which may be oxidized are shown, and Y and Z are combined and methyleneoxy (-CH ₂ O
-, - OCH ₂ -) group, a methylene sulfonyl group (-SO ₂
CH ₂ —, —CH ₂ SO ₂ —), N-substituted methyleneamino group, amide group, ethylene group and the like are preferable. The "halogen" for R ¹ is preferably fluoro, chloro and bromo. As the “halogen” of the “optionally halogenated C _1-4 alkyl” represented by R ¹ , fluoro is preferable. Methyl is preferable as the "C _1-4 alkyl" of the " _optionally halogenated C _1-4 alkyl" represented by R ¹ . The “C _1-4 alkyl” may have 1 to 3, preferably 2 to 3 halogens at the substitutable position, and the number of halogens is 2
In the case of one or more, each halogen may be the same or different. As R ¹ , fluoro and trifluoromethyl are more preferable. When p is 2 or 3, each R ¹ may be the same or different.

Preferred as R ² and R ³ are halogen atoms such as fluoro and chloro; and C _1-6 alkoxy groups such as methoxy and ethoxy groups. General formula

[Chemical 52] The group represented by

[Chemical 53] [Wherein R ⁴ has the same meaning as defined above]

[Chemical 54] The ring group represented by the formula [wherein R ⁴ has the same meaning as defined above] is preferably a ring group represented by the formula:

[Chemical 55] [Wherein R ⁴ has the same meaning as described above].

Specific examples of the compound (I) include, for example,
1- (3- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenoxy} propyl) -1H -1,2,3-triazole; 1- [3-({4-
[(2-{(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} thio) propyl] -1H-1,2,3 -Triazole; 1- [3-({4-[(2-
{(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl}-
1,3-Oxazol-4-yl) methoxy] phenyl} sulfonyl) propyl] -1H-1,2,3-triazole; {1- [3-({4-[(2-
{(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl}-
1,3-oxazol-4-yl) methoxy] phenyl} sulfanyl) propyl] -1H-imidazol-2-yl} methanol;
{1- [3-({4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} sulfonyl) Propyl] -1H-imidazol-2-yl}
Methanol; 1- [4-[[2-[(E) -2- (4-trifluoromethylphenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] -4- (1H-1 , 2,3-Triazol-1-yl) -1-butanol; 1- [3- [4- [2- [2-[(E) -2
-[4- (trifluoromethyl) phenyl] ethenyl]
-1,3-Oxazol-4-yl] ethyl] phenoxy] propyl] -1H-1,2,3-triazole; 2-
[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl]]
Ethenyl] -4-[[4- [4- (1H-pyrazol-3-yl) butyl] phenoxy] methyl] -1,3-oxazole; 2- [5- [4- [4-[[2-
[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl]]
Ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] butyl] -1H-pyrazol-1-yl] ethanol; 2-[(E)
-2- [2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -4-[[4- [4- [1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H -Pyrazol-5-yl] butyl] phenoxy] methyl] -1,3-oxazole; 2- [5- [4- [4-[[2-
[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl]]
Ethenyl] -1,3-oxazol-4-yl] methoxy] -2-methylphenyl] butyl] -1H-pyrazol-1-yl] ethanol; or 2- [5- [4- [4-[[2- [(E) -2- [4-Bromo-2-fluoro-4-phenyl] ethenyl] -1,3-oxazol-4-yl]
Methoxy] -2-methylphenyl] butyl] -1H-pyrazole
1-yl] ethanol or a salt thereof or the like is preferable.

The general formula of the compound of the present invention

[Chemical 56] [In the formula, each symbol has the same meaning as described above. ] In the compound or its salt represented by these, when Y shows a single bond, the said general formula (I) is the following general formula.

[Chemical 57] [In the formula, each symbol has the same meaning as described above. ] It represents the compound represented by this, or its salt.

Similarly, a compound of the general formula

[Chemical 58] [In the formula, each symbol has the same meaning as described above. ] In the compound represented by these or its salt, when Z shows a single bond, the said general formula (I) is the following general formula.

[Chemical 59] [In the formula, each symbol has the same meaning as described above. ] It represents the compound represented by this, or its salt.

Further, a compound represented by the general formula

[Chemical 60] [In the formula, each symbol has the same meaning as described above. ] In the compound or its salt represented by these, when Y and Z show a single bond, the said general formula (I) has the following general formula.

[Chemical formula 61] [In the formula, each symbol has the same meaning as described above. ] It represents the compound represented by this, or its salt.

The general formula of the compound of the present invention

[Chemical formula 62] [In the formula, each symbol has the same meaning as described above. ] In the compound or its salt represented by these, when m shows 0, the said general formula (I) is the following general formula.

[Chemical formula 63] [In the formula, each symbol has the same meaning as described above. ] It represents the compound represented by this, or its salt.

The general formula of the compound of the present invention

[Chemical 64] [In the formula, each symbol has the same meaning as described above. ] In the compound or its salt represented by these, when m shows 0, X shows an ethylene group or an ethenyl group. In addition, the general formula
General formula in (I)

[Chemical 65] The group represented by

[Chemical formula 66] When an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group represented by and X is an oxygen atom, compounds in which Y and Z are the same or different and each is a single bond or a methylene group are included in the present invention. Excluded.

The salt of the compound of the present invention is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a basic or A salt with an acidic amino acid or the like is used. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt. Preferable examples of the salt with an organic base include:
For example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
A salt with N, N'-dibenzylethylenediamine or the like is used. Suitable examples of salts with inorganic acids include hydrochloric acid,
Salts with hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. are used. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid,
Salts with maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. are used. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. To be The compound (II) has two types, a (Z) -ethenyl form and a (E) -ethenyl form, and these isomers are included in the present invention either individually or as a mixture thereof. Further, when the compound (I) has an asymmetric carbon, optical isomers are produced, and the present invention includes both these isomers alone and a mixture thereof.

[General Production Method] The compound (I) of the present invention or a salt thereof

[Chemical formula 67] [In the formula, each symbol has the same meaning as described above. Are obtained by a method known per se, for example, a method similar to the method described in JP-A Nos. 11-60571 and 2001-348385, and the following reaction formulas A to E, for example.
It can be manufactured by the method shown in. Each symbol in the following reaction formulas has the same meaning as described above. The compound in the reaction formula includes a case where it forms a salt, and as the salt, for example, the same as the salt of compound (I) and the like can be used.

Production Method A

[Chemical 68] [In the formula, T ¹ represents a leaving group. Other symbols have the same meanings as described above. Examples of the “leaving group” represented by T ¹ include a halogen atom (eg, chlorine, bromine, etc.) or a formula: —OSO ₂ R
¹⁰ A group represented by the formula [wherein R ¹⁰ represents an alkyl group or an aryl group which may be substituted] is used.
As the “alkyl group” represented by R ¹⁰ , for example, a C _1-6 alkyl group such as methyl, ethyl, propyl and the like can be used. As the "aryl group" of the "optionally substituted aryl group" represented by R ¹⁰ , for example, a C _6-14 aryl group such as phenyl is used. As the "substituent" of the "optionally substituted aryl group" represented by R ¹⁰ , a C _1-6 alkyl group such as methyl, ethyl, propyl and the like can be used. Specific examples of the "aryl group which may be substituted" include phenyl optionally having a C _1-6 alkyl group (eg, p-tolyl, etc.) and the like.

[Step A] In this step, compound (IV) is reacted with compound (V) to give compound (I). In this reaction, compound (IV) and compound (V) are usually condensed in the presence of a base. Examples of the "base" include hydroxides of alkali metals or alkaline earth metals (eg, sodium hydroxide, potassium hydroxide, etc.), carbonates of alkali metals or alkaline earth metals (eg, sodium hydrogen carbonate, carbonic acid). Sodium, potassium carbonate, etc.), amines (eg, pyridine, triethylamine, N, N-dimethylaniline, etc.), alkali metal or alkaline earth metal hydrides (eg, sodium hydride, potassium hydride, etc.)
Calcium hydride), lower alkoxide of alkali metal or alkaline earth metal (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.) and the like are used. The preferable amount of the "base" to be used is about 1-5 molar equivalents relative to compound (V). The preferred amount of "compound (IV)" used is about 0.5 to 5 molar equivalents relative to compound (V). This reaction is advantageously performed in the presence of a solvent that does not influence the reaction. The solvent is not particularly limited as long as the reaction proceeds, but, for example, aromatic hydrocarbons, ethers, ketones, halogenated hydrocarbons, amides, sulfoxides, or a mixture of two or more thereof or the like is used. The reaction temperature is generally -50 to + 150 ° C, preferably about -10.
It is + 100 ° C. The reaction time is usually 0.5 to 48 hours.

Process B The compound (Va) in which Z of the compound (V) is methylene is
According to the description of reaction formula B, compound (VI), compound (VII)
It can be obtained by deprotecting the compound (VIII) synthesized from if necessary.

[Chemical 69] [In the formula, P¹Is a hydrogen atom or a protecting group, T²Is a leaving group
Other symbols have the same meanings as described above. ] P¹Examples of the "protecting group" represented by are alkyl
(Eg C such as methyl, ethyl, etc._1-6Alkyl, etc.)
Phenyl-C_1-6Alkyl (eg, benzyl, etc.), C _1-6A
Alkyl-carbonyl, alkyl-substituted silyl (eg, trimester
Tylsilyl, tert-butyldimethylsilyl, etc.)
Which is used. T²The "leaving group" represented by
For example, the T¹The same as the "leaving group" shown in
Can be Step B is performed under the same reaction conditions as Step A.
It The "deprotection reaction" of step C is appropriately selected from conventional methods.
can do. For example P¹Is a compound,
(VIII) with an acid (eg, mineral acid such as hydrobromic acid, tetrachloromethane
Lewis acid such as tongue). For example P¹Is
Phenyl-C_1-6In the case of alkyl, hydrogen compound (VIII)
Subject to addition reaction. For example P¹Is an alkyl-substituted silyl
Compound (VIII) and fluoride (eg, tetrabutylammonium)
To obtain compound (Va)
be able to.

Process C The compound (Vb) in which Y of the compound (V) is methylene is
According to the description of reaction formula C, compound (IX), compound (X)
It can be obtained by deprotecting the compound (VIIIa) synthesized from if necessary.

[Chemical 70] [In the formula, P ² represents a hydrogen atom or a protecting group, T ³ represents a leaving group, and other symbols have the same meanings as described above. As the "protecting group" represented by P ² , for example, the same "protecting group" represented by P ¹ can be used. As the “leaving group” represented by T ³ , for example, the same as the above-mentioned “leaving group” represented by T ¹ can be used. Step D can be carried out under the same reaction conditions as in the above step A and step E.

Production Method D Compound (V) wherein Y and Z are methylene (V
c) is obtained by subjecting compound (VIIIb) synthesized from compound (XI) and compound (XII) to deprotection and hydrogenation reaction as necessary according to the description of reaction formula D.

[Chemical 71] [In the formula, P ³ represents a hydrogen atom or a protecting group, T ⁴ represents a leaving group, and other symbols have the same meanings as described above. As the "protecting group" represented by P ³ , for example, the same "protecting group" represented by P ¹ can be used. As the “leaving group” represented by T ⁴ , for example, halogen (eg, bromine, iodo, etc.) or a group represented by the formula: —OSO ₂ CF ₃ is used.

[Step F] In this step, compound (XI) is reacted with compound (XII) to give compound (VIIIb). In this reaction, compound (XI) and compound (XII) are usually condensed in the presence of a palladium catalyst. As the "palladium catalyst", for example, dichlorobis (triphenylphosphine) palladium, dichlorobis (benzonitrile) palladium, palladium acetate, tetrakis (triphenylphosphine) palladium, palladium carbon and the like are used. Further, if necessary, copper iodide and amines are used together with a palladium catalyst. Examples of the “amine” include triethylamine, diethylamine, pyrrolidine, butylamine and the like. The preferable amount of the "compound (XII)" used is about 1 to 5 molar equivalents relative to the compound (XI). The preferred amount of "palladium catalyst" is
It is about 0.05 to 0.5 molar equivalents relative to compound (XI). The preferred amount of “copper iodide” is compound (XI)
To about 0.05 to 0.5 molar equivalent. Amines may be used as a solvent. This reaction is advantageously performed in the presence of a solvent that does not influence the reaction. The solvent is not particularly limited as long as the reaction proceeds, but for example, the amines, ethers, amides, water, or a mixture of two or more kinds of these are used. The reaction temperature is usually -5.
The temperature is 0 to + 150 ° C, preferably about -10 to + 100 ° C. The reaction time is usually 1 to 72 hours.

[Step G] In this step, compound (VIIIb) is deprotected and hydrogenated to obtain compound (Vc). Deprotection can be carried out under the same reaction conditions as in step C. The hydrogenation reaction is usually performed in the presence of a metal catalyst.
As the "metal catalyst", for example, palladium carbon, platinum carbon, platinum oxide, Raney nickel, reduced iron and the like are used. In addition, this reaction is usually performed in a hydrogen stream,
Cyclohexene, cyclohexadiene, formic acid, ammonium formate and the like can be used instead of hydrogen.
The preferable amount of the “metal catalyst” used is about 5 to 50% by weight based on the compound (VIIIb). This reaction is advantageously performed in the presence of a solvent that does not influence the reaction. The solvent is not particularly limited as long as the reaction proceeds, but for example, alcohols, esters, ethers, or a mixture of two or more kinds of these are used. The reaction temperature is usually room temperature to + 50 ° C., preferably room temperature. The reaction time is usually 1 to 72 hours. The protecting group P ³ is phenyl-
In the case of C _1-6 alkyl, deprotection and hydrogenation reaction can be carried out simultaneously.

Production Method E Compound (Vc) wherein Y and Z are methylene was obtained by reacting compound (XIV) obtained from compound (XIII) with compound (XV) according to the following reaction formula E. Compound (V
It can be obtained by subjecting IIIc) to a deprotection and a hydrogenation reaction if necessary.

[Chemical 72] [In the formula, P ⁴ represents a hydrogen atom or a protecting group, T ⁵ represents a leaving group, and other symbols have the same meanings as described above. As the "protecting group" represented by P ⁴ , for example, the same "protecting group" represented by P ¹ can be used. As the “leaving group” represented by T ⁵ , for example, a group represented by halogen (eg, chloro, bromo, iodo, etc.) and the like can be used.

[Step H] In this step, compound (XIII) is reacted with triphenylphosphine to obtain compound (XIV). The preferred amount of "triphenylphosphine" used is
It is 1 equivalent to the compound (XIII). This reaction is advantageously performed in the presence of a solvent that does not influence the reaction. The solvent is not particularly limited as long as the reaction proceeds, but for example, aromatic hydrocarbons are used. The reaction temperature is usually room temperature to + 200 ° C, preferably room temperature to +15.
It is 0 ° C. The reaction time is usually 1 to 72 hours.

[Step I] In this step, compound (XIV) is reacted with compound (XV) to give compound (VIIIc). This reaction is generally carried out in the presence of a base, compound (XIV) and compound (XIV).
V) and condense with. Examples of the "base" include hydroxides of alkali metals or alkaline earth metals (eg, sodium hydroxide, potassium hydroxide, etc.), carbonates of alkali metals or alkaline earth metals (eg, sodium hydrogen carbonate, carbonic acid). Sodium, potassium carbonate, etc.), alkali metal or alkaline earth metal hydrides (eg, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal or alkaline earth metal lower alkoxides (eg, sodium methoxide) , Sodium ethoxide,
Potassium tert-butoxide), amine salts of alkali metals or alkaline earth metals (eg, lithium diisopropylamide, hexamethyldisilazide, etc.) and the like are used. The preferred amount of the "base" to be used is about 1-5 molar equivalents relative to compound (XIV). "Compound (X
V) ”is preferably used in an amount of about 0.5 to 5 molar equivalents relative to compound (XIV). This reaction is advantageously performed in the presence of a solvent that does not influence the reaction. The solvent is not particularly limited as long as the reaction proceeds, but for example, aromatic hydrocarbons, ethers, amides, sulfoxides, or a mixture of two or more kinds thereof or the like is used. The reaction temperature is generally -50 to + 150 ° C, preferably about -10.
~ + 100 ° C. The reaction time is usually 0.5 to 48 hours. Step J is performed under the same reaction conditions as in step G.

Process F The compound (Ia) in which Z is methylene has the following reaction formula F
Compound (XV), compound (VII) according to the description of.

[Chemical formula 73] [In the formula, each symbol has the same meaning as described above. The step K can be carried out under the same reaction conditions as the step A.

Production Method G Compound (XIX) is a compound (XVI) synthesized from compound (XVI) and compound (XVII) according to the following reaction formula G.
Obtained by deprotecting II) as required.

[Chemical 74] [In the formula, P ⁵ represents a hydrogen atom or a protecting group, T ⁶ represents a leaving group, and other symbols have the same meanings as described above. As the "protecting group" represented by P ⁵ , for example, the same "protecting group" represented by P ¹ can be used. As the "leaving group" for T ⁶ , for example, the same "leaving group" for T ¹ is used. Step L can be performed under the same reaction conditions as those in Step A and Step M described above.

Compound (Ib) wherein Production Method HY is methylene can be obtained from Compound (XX) and Compound (X) according to the following Reaction Scheme H.

[Chemical 75] [In the formula, symbols have the same meanings as described above. Step N can be carried out under the same reaction conditions as in step A above.

Production Method I Compound (XXIV) is a compound (XXI) synthesized from compound (XXI) and compound (XXII) according to the following reaction scheme I.
Obtained by deprotecting II) as required.

[Chemical 76] [In the formula, P ⁶ represents a hydrogen atom or a protective group, and other symbols have the same meanings as described above. As the "protecting group" represented by P ⁶ , for example, the same "protecting group" represented by P ¹ can be used. Step O can be carried out under the same reaction conditions as those of step A and step P described above.

Production Method J Compound (Ic) in which ring C is a nitrogen-containing heterocycle can be prepared according to the following reaction formula J: compound (XXV), compound (XXVI)
Obtained from

[Chemical 77] [In the formula, T ⁷ represents a leaving group, and other symbols have the same meanings as described above. As the “leaving group” for T ⁷ , for example, those similar to the above-mentioned “leaving group” for T ¹ can be used. Step Q can be carried out under the same reaction conditions as in step A above.

Production Method K Compound (XXX) is a compound (XXV) synthesized from compound (IV) and compound (XXVII) according to the following reaction scheme K.
Compound (XXIX) obtained by deprotecting III)
On the other hand, it can be synthesized by introducing a leaving group.

[Chemical 78] [In the formula, P ⁷ represents a hydrogen atom or a protective group, and other symbols have the same meanings as described above. As the "protecting group" represented by P ⁷ , for example, the same "protecting group" represented by P ¹ can be used. Step R can be carried out under the same reaction conditions as those in Step A and Step S described above in Step C. The "Leaving group introduction reaction" in step T is described in "Protective Groups in Organic Synthesis (edited by TWGreene, PGWuts, John Wiley & Sons, 199).
9) ”can be selected as appropriate.

Production Method L Compound (Ie) is a compound (I) synthesized from compound (XXXI) and compound (XXXII) according to the following reaction scheme L.
Obtained by hydrogenating d).

[Chemical 79] [In the formula, each symbol has the same meaning as described above. Step U can be carried out under the same reaction conditions as those in Step I and Step X described above in Step G.

In each of the above reactions, when the product is obtained as a free form, it can be converted into a salt thereof, and when it is obtained as a salt, it can be converted into a free form according to a conventional method. In the above reaction, when amino (NH ₂ ), hydroxy (OH), carboxyl (COOH) and the like are contained in the substituents, those protected with these groups are used as the starting materials, and they are known per se after the reaction. The target compound may be produced by removing the protecting group by a method. Examples of the amino-protecting group include acyl (eg, C _1-6 alkyl-carbonyl such as acetyl; benzyloxycarbonyl; C _1-6 alkoxy-carbonyl such as tert-butoxycarbonyl; phthaloyl; formyl). . Examples of the hydroxy protecting group include C _1-6 alkyl (eg, methyl, ethyl etc.), phenyl-C _1-6 alkyl (eg, benzyl etc.), C _1-6 alkyl-carbonyl (eg, acetyl etc.), Benzoyl, alkyl-substituted silyl (eg, trimethylsilyl, tert-butyldimethylsilyl, etc.) and the like are used. Examples of the carboxyl protecting group include C
_1-6 alkyl (eg, methyl, ethyl, etc.), phenyl-C _1
-6 alkyl (eg, benzyl, etc.) and the like are used.

The compound (I) thus obtained is isolated by a separation means known per se, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
It can be purified. When compound (I) is obtained as a free form, it can be converted into a desired salt by a method known per se or a method analogous thereto, and conversely, when it is obtained as a salt, a method known per se. Alternatively, it can be converted into the free form or other desired salt by a method similar thereto. The compound (I) may be a hydrate or a non-hydrate. When compound (I) is obtained as a mixture of optically active compounds, it can be separated into the desired (R) form or (S) form by an optical resolution means known per se. Compound (I) is an isotope (eg, ³
H, ¹⁴ C, etc.) and the like.

A prodrug of compound (I) or a salt thereof (hereinafter abbreviated as compound (I)) is a compound which is converted into compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, It refers to a compound which is enzymatically oxidized, reduced, hydrolyzed or the like to be converted into the compound (I), or a compound which is hydrolyzed or the like to be converted to the compound (I) by gastric acid or the like. As a prodrug of compound (I), the amino group of compound (I) is acylated, alkylated,
A phosphorylated compound (eg, amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, Tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated compounds, etc.); Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, borated (eg, A compound wherein the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); the carboxyl group of compound (I) is esterified, Amidated compounds (eg, carboxyl group of compound (I) is ethyl esterified, phenyl ester , Carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolene-4 -Yl) methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compound etc.) and the like are used. These compounds can be produced from compound (I) by a method known per se. Further, the prodrug of compound (I) is a compound which is changed to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Development of Pharmaceuticals”, Volume 7, Molecular Design, pages 163 to 198. It may be.

The compound (I) of the present invention or a salt thereof or a prodrug thereof (hereinafter, may be abbreviated as the compound of the present invention) has a tyrosine kinase inhibitory action and is effective for treating tyrosine kinase-dependent diseases in mammals. It can be used for prevention or treatment. Tyrosine kinase-dependent diseases include diseases in which cell growth is promoted due to abnormal tyrosine kinase enzyme activity. Furthermore, since the compound of the present invention specifically inhibits HER2 tyrosine kinase, it serves as a therapeutic agent that suppresses the growth of HER2-expressing cancer, and also shifts hormone-dependent cancer to hormone-independent cancer. It is also useful as a preventive agent for preventing That is, the compounds of the present invention are various cancers (among others, breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, schwannoma, non-cancer). Small cell lung cancer,
Small cell lung cancer, Liver cancer, Kidney cancer, Bile duct cancer, Endometrial cancer, Cervical cancer, Ovarian cancer, Bladder cancer, Skin cancer, Hemangioma, Malignant lymphoma, Melanoma, Thyroid cancer, Bone tumor, Angiofibroma , Retinal sarcoma, penile cancer, pediatric solid tumor, Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, leukemia, etc.), atherosclerosis, Abnormal cell proliferation such as angiogenesis (eg, angiogenesis associated with growth of solid tumors and sarcomas, angiogenesis associated with tumor metastasis, and angiogenesis associated with diabetic retinopathy), viral disease (HIV infection, etc.) It can be used as a safe preventive or therapeutic agent for diseases caused by
Tyrosine kinase dependent diseases further include cardiovascular diseases associated with abnormal tyrosine kinase enzyme activity. Therefore, the compound of the present invention can also be used as a prophylactic or therapeutic agent for cardiovascular diseases such as restenosis. The compound of the present invention is useful as an anticancer agent for the prevention / treatment of cancer, particularly breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, colon cancer and the like. The compound of the present invention has low toxicity and can be used as a medicine as it is, or as a mixture with a pharmaceutically acceptable carrier known per se or the like (eg, human, horse, cow, dog, cat, rat, mouse, rabbit). , Pigs, monkeys, etc.) as a pharmaceutical composition.
Other active ingredients together with the compound of the present invention in a pharmaceutical composition, such as the following hormone therapeutic agents, anticancer agents (eg, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factor and its receptor, etc.) ) Etc. may be contained.

When the compound of the present invention is administered as a medicine to mammals such as humans, the administration method is usually orally as tablets, capsules (including soft capsules and microcapsules), powders, granules and the like, or by injection. It can be parenterally administered as a drug, suppository, pellet or the like.
“Parenteral” means intravenous, intramuscular, subcutaneous, internal organ, intranasal, intradermal, eye drop, intracerebral, rectal, vaginal and intraperitoneal, intratumoral, proximal to tumor, or the like. Includes direct lesion administration. The dose of the compound of the present invention varies depending on the administration route, symptoms, etc., but when it is orally administered as an anti-cancer agent to a patient (body weight 40 to 80 kg) having breast cancer or prostate cancer, for example, 0.5 to 100 mg / kg per day body weight,
The daily dose is preferably 1 to 50 mg / kg body weight, more preferably 1 to 25 mg / kg body weight per day. This amount can be administered once a day or divided into two to three times a day.

The compound of the present invention is blended with a pharmaceutically acceptable carrier and is orally or parenterally administered as a solid preparation such as tablets, capsules, granules and powders; or as a liquid preparation such as syrups and injections. Can be administered to. As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances that are commonly used as a formulation material are used. Excipients, lubricants, binders, disintegrants in solid formulations; solvents and dissolutions in liquid formulations Auxiliary agents, suspending agents, isotonic agents, buffering agents,
It is used as a soothing agent. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used. Preferable examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Suitable examples of disintegrants include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium,
Croscarmellose sodium, sodium carboxymethyl starch and the like are used. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Suitable examples of the suspending agent include, for example, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate and other surfactants; for example, polyvinyl alcohol, Hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose are used. Preferable examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffering agent include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Preferable examples of soothing agents include benzyl alcohol and the like. Preferable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite, ascorbic acid and the like.

The pharmaceutical composition varies depending on the dosage form, administration method, carrier, etc., but the compound of the present invention is usually added in an amount of 0.1 to 95% (w / w) with respect to the total amount of the preparation, and according to a conventional method. It can be manufactured. Also, a group consisting of (1) administering an effective amount of a compound of the present invention, (2) administering an effective amount of another anticancer agent, administering an effective amount of a hormone therapeutic agent, and non-drug therapy. By combining 1 to 3 selected from the above, it is possible to more effectively prevent and treat cancer. Examples of the non-pharmaceutical therapy include surgery, radiation therapy, gene therapy, hyperthermia therapy, cryotherapy, laser ablation therapy, and the like, and two or more of these may be combined. For example, the compound of the present invention includes other hormone therapeutic agents, anticancer agents (for example, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factors and their receptors), etc. (hereinafter abbreviated as concomitant drugs). And can be used in combination. The compound of the present invention shows an excellent anticancer activity even when used as a single agent, but by further combining with one or several of the above-mentioned concomitant drugs (multi-drug combination), the effect can be further enhanced. it can. Examples of the “hormone therapeutic agent” include, for example, phosfestrol, diethylstilbestrol, chlorotrianiserine, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, Mepartricin, raloxifene, olmeroxifene, levormeloxifene, antiestrogens (eg, tamoxifen citrate, toremifene citrate, etc.), pills, mepithiostane, testrolactone,
Aminoglutethimide, LH-RH agonist (eg, goserelin acetate, buserelin, leuprorelin, etc.), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitor (eg, fadrozole hydrochloride, anastrozole, retro) Sol, exemestane, borozole, formestane, etc.), antiandrogens (eg, flutamide, bicalutamide, nilutamide, etc.), 5α-reductase inhibitors (eg, finasteride, epristeride, etc.), corticosteroids (eg, dexamethasone, prednisolone, etc.) Betamethasone, triamcinolone, etc.), androgen synthesis inhibitors (eg, abiraterone, etc.), retinoids and drugs that delay the metabolism of retinoids (eg, rearozole, etc.), etc. are used, among which LH-RH Marianist (eg, goserelin acetate, buserelin, leuprorelin etc.) are preferable.

As the “chemotherapeutic agent”, for example, an alkylating agent, an antimetabolite, an anticancer antibiotic, a plant-derived anticancer agent and the like are used. Examples of the “alkylating agent” include, for example,
Nitrogen Mustard, Nitrogen Mustard-N-Oxide, Chlorambutyl, Cyclophosphamide, Ifosfamide, Thiotepa, Carbocon, Improsulfan Tosylate, Busulfan, Nimustine Hydrochloride, Mitobronitol, Melphalan, Dacarbazine,
Ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etogluside, carboplatin, cisplatin, miboplatin, nedaplatin,
Oxaliplatin, altretamine, ambamustine,
Dibrospidium hydrochloride, fotemustine, predonimustine, pumitepa, ribomustine, temozolomide, threosulfan, trofosfamide, dinostatin stimalamer, carbocon, adzelecin, systemustin,
Viseresin or the like is used. As an "antimetabolite",
For example, mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine ocfosphate, ancitabine hydrochloride, 5-FU drug (eg, fluorouracil, tegafur, UFT, doxyfluridine, carmofur, gallocitabine, emitefur, emitefur). ), Aminopterin, leucovorin calcium, tabloid, butosine,
Folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexime, idoxyuridine, mitoguazone, thiazofurin, ambamustine and the like are used. Examples of the "anticancer antibiotic" include actinomycin D, actinomycin C, mitomycin C, chromomycin A.
3, Bleomycin hydrochloride, Bleomycin sulfate, Pepuromycin sulfate, Daunorubicin hydrochloride, Doxorubicin hydrochloride, Aclarubicin hydrochloride, Pirarubicin hydrochloride, Epirubicin hydrochloride, Neocarzinostatin, Mithramycin, Zarcomycin, Carcinophylline, Mitotan, Zorubicin hydrochloride, Mitoxantrone hydrochloride, Idarubicin hydrochloride or the like is used. As the “plant-derived anticancer agent”, for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine and the like are used.

Examples of the "immunotherapeutic agent (BRM)" include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin,
BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazole and the like are used. The “cell growth factor” in the “drug that inhibits the action of cell growth factor and its receptor” is
Any substance may be used as long as it is a substance that promotes cell growth, and is usually a peptide having a molecular weight of 20,000 or less,
Factors that exert an action at low concentrations by binding to receptors are used. Specifically, (1) EGF (epidermal growth
factor) or a substance having substantially the same activity as that (eg, EGF, hallegulin (HER2 ligand))
Etc.), (2) Insulin or a substance having substantially the same activity as insulin [eg, insulin, IGF (insulin
-like growth factor) -1, IGF-2, etc.], (3) F
GF (fibroblast growth factor) or a substance having substantially the same activity as that [eg, acidic FGF, basic F
GF, KGF (keratinocyte growth factor), FG
F-10, etc.], (4) Other cell growth factors [eg, CSF
(Colony stimulating factor), EPO (erythropoie
tin), IL-2 (interleukin-2), NGF (nerve grow
th factor), PDGF (platelet-derived growth fact
or), TGFβ (transforming growth factor β), H
GF (hepatocyte growth factor), VEGF (vascul
ar endothelial growth factor), etc.] and the like.
The "cell growth factor receptor" may be any one as long as it is a receptor capable of binding to the above-mentioned cell growth factor, and specifically, EGF receptor, hallegulin receptor (HER2). , Insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2. Examples of the “drug that inhibits the action of cell growth factor” include trastuzumab (Herceptin ™; HER
2 antibody), imatinib mesylate, ZD1839 or cetuximab. In addition to the above-mentioned agents, L-asparaginase, asegraton, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercury hematoporphyrin sodium, topoisomerase 1I inhibitor (eg, irinotecan, topotecan, etc.), topoisomerase II inhibitor (eg, sobuzoxane, etc.) ), Differentiation inducers (eg, retinoids, vitamin Ds, etc.), angiogenesis inhibitors, α-blockers (eg, tamsulosin hydrochloride, etc.) and the like can also be used. Among the above, as the concomitant drug, LH-RH agonist (eg, goserelin acetate, buserelin, leuprorelin, etc.), trastuzumab (HER2 antibody) and the like are preferable.

When the compound of the present invention is used in combination with a concomitant drug, the timing of administration of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug are administered to an administration subject.
It may be administered at the same time or at different times. The dose of the concomitant drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like. The administration form of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such a dosage form include (1)
Administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, (2) by the same administration route of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug Simultaneous administration of (3) the compound of the present invention and the concomitant drug, which are obtained by separately formulating two types of preparations, with different time lags in the same administration route, (4) the compound of the present invention and the concomitant drug Simultaneous administration of two kinds of preparations obtained by separately formulating and, (5) Different administration routes of two kinds of preparations obtained by separately formulating the compound of the present invention and a concomitant drug (For example, administration of the compound of the present invention → concomitant drug in this order, or administration in the reverse order) is used. Hereinafter, these administration forms will be collectively referred to as the concomitant drug of the present invention.

The concomitant drug of the present invention has low toxicity.
According to a method known per se, the compound of the present invention or (and) the concomitant drug is mixed with a pharmacologically acceptable carrier to give a pharmaceutical composition such as a tablet (including a sugar-coated tablet and a film-coated tablet), a powder, and a granule. It can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration, etc.), as a capsule, (including soft capsule), solution, injection, suppository, sustained-release agent and the like. Injectables are administered intravenously, intramuscularly, subcutaneously, in organs, intranasally, intradermally, eye drops, intracerebrally, rectally, intravaginally and intraperitoneally, inside tumors, in the vicinity of tumors, or directly into the lesion. It can be administered.
As the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention, the same carriers as those used in the above-mentioned pharmaceutical composition of the present invention can be used.

The compounding ratio of the compound of the present invention to the concomitant drug in the combination agent of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like. For example, the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight based on the whole preparation. And more preferably about 0.5 to 20% by weight. The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably It is about 0.5 to 20% by weight. The content of additives such as a carrier in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. . Also, when the compound of the present invention and the concomitant drug are separately formulated, the same content may be used.

These formulations can be produced by a method known per se which is generally used in the formulation process. For example, the compound of the present invention or a concomitant drug is a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethyl cellulose, sodium alginate, hydroxypropyl methyl cellulose). ,
Dextrin, etc.), stabilizer (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactant (eg, polysorbate 80, macrogol, etc.), solubilizer (eg, glycerin, ethanol, etc.), buffer (eg, phosphorus) Acid and its alkali metal salt, citric acid and its alkali metal salt, etc., isotonicity agent (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), pH adjuster (eg,
Hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, ethyl paraoxybenzoate, benzoic acid, methylparaben, propylparaben, benzyl alcohol, etc.), solubilizers (eg, concentrated glycerin, meglumine, etc.), solubilizing agents (eg, propylene) Glycol, sucrose, etc.), soothing agent (eg, glucose, benzyl alcohol, etc.), etc. in an aqueous injection, or in vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, etc., and in solubilizing agents such as propylene glycol, etc. Alternatively, it can be emulsified and molded into an oil-based injection to prepare an injection.

In order to prepare a preparation for oral administration, the compound of the present invention or the concomitant drug is used according to a method known per se, for example, an excipient (eg lactose, sucrose, starch etc.), a disintegrant (eg starch, carbonic acid). Calcium, etc., binders (eg starch,
Gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, etc.) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) is added and compression-molded, and if necessary, taste masking, An oral administration preparation can be prepared by coating by a method known per se for the purpose of enteric property or sustainability. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (loam). Company, Germany, methacrylic acid / acrylic acid copolymerization) and pigments (eg red iron oxide, titanium dioxide, etc.) are used. The preparation for oral administration may be either an immediate release preparation or a sustained release preparation.

For example, in the case of a suppository, the compound of the present invention or the concomitant drug can be made into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se. The oily base used in the composition includes, for example, glycerides of higher fatty acids [eg, cacao butter, Witepsols (manufactured by Dynamite Nobel, Germany), etc.], intermediate fatty acids [eg, Miglyols (manufactured by Dynamite Nobel,
Germany) etc.] or vegetable oil (eg sesame oil, soybean oil,
Cottonseed oil, etc.) is used. Also, as an aqueous base,
Examples of polyethylene glycols, propylene glycol, and aqueous gel bases that can be used include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers. As the sustained-release preparation, sustained-release microcapsules and the like are used. The sustained-release microcapsules can be prepared by a method known per se, but for example, it is preferable that the sustained-release microcapsules are molded into a sustained-release preparation and administered. The compound of the present invention is a solid preparation (eg, powder, granule,
Tablets, capsules, etc.) for oral administration
It is preferably molded into a preparation for rectal administration such as a suppository. Particularly preferred is a preparation for oral administration. The concomitant drug can be in the above-mentioned dosage form depending on the type of drug.

In the following, [1] an injection of the compound of the present invention or a concomitant drug and its preparation, [2] a sustained release preparation or an immediate release preparation of the compound of the present invention or a concomitant drug, and its preparation, [3] The sublingual tablet, buccal or buccal disintegrant of the compound of the present invention or the concomitant drug and its preparation will be specifically described. [1] Injection and preparation thereof An injection prepared by dissolving the compound of the present invention or the concomitant drug in water is preferable. The injection may contain benzoate and / or salicylate. The injection can be obtained by dissolving both the compound of the present invention or the concomitant drug and optionally a benzoate and / or a salicylate in water. Examples of the salts of benzoic acid and salicylic acid include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and other organic acid salts such as trometamol. The concentration of the compound of the present invention or the concomitant drug in the injection is 0.5 to 50 w / v%, preferably 3 to
It is about 20 w / v%. The concentration of benzoate and / or salicylate is preferably 0.5 to 50 w / v%, more preferably 3 to 20 w / v%.

In addition, additives generally used for injection such as stabilizers (ascorbic acid, sodium pyrosulfite, etc.), surfactants (polysorbate 80, macrogol, etc.), soluble agents (glycerin, Ethanol, etc.), buffers (phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), isotonic agents (sodium chloride, potassium chloride, etc.), dispersants (hydroxypropyl methylcellulose, dextrin), pH adjustment Agents (hydrochloric acid, sodium hydroxide, etc.), preservatives (ethyl paraoxybenzoate, benzoic acid, etc.), solubilizers (concentrated glycerin, meglumine, etc.), solubilizers (propylene glycol, sucrose, etc.), soothing agents (glucose, Benzyl alcohol, etc.) and the like can be appropriately mixed. These additives are generally added in the proportions usually used for injections. Injection p
2-12, preferably 2.5-8.0 by addition of H-regulator.
It is better to adjust to. The injectable preparation is obtained by dissolving both the compound of the present invention or the concomitant drug, and optionally benzoate and / or salicylate, and, if necessary, the additive in water. These may be dissolved in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injectable solution. The aqueous solution for injection is preferably heated, and can be provided as an injectable solution by performing, for example, filter sterilization, high-pressure heat sterilization and the like in the same manner as a normal injectable solution. The aqueous solution for injection is preferably subjected to high-pressure heat sterilization at 100 ° C. to 121 ° C. for 5 minutes to 30 minutes. Furthermore, it may be a preparation in which the solution has antibacterial properties so that it can be used as a multiple-dose preparation.

[2] Sustained release preparation or immediate release preparation and preparation thereof Release formulations are preferred. For example, a once-daily type sustained release preparation for oral administration is preferable. Examples of the water-insoluble substance used in the coating agent include cellulose ethers such as ethyl cellulose and butyl cellulose, cellulose esters such as cellulose acetate and cellulose propionate, polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate, and acrylic acid / Methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate) , Polymethacrylate, polymethacrylamide, aminoalkylmethacrylate copolymer, poly (methacrylic acid anhydride), glycidylmethacrylate copolymer, especially oi Ragitto RS-100, RL-100, RS-30
D, RL-30D, RL-PO, RS-PO (Ethyl acrylate / methyl methacrylate / methacrylic acid trimethyl / ammonium ethyl copolymer), Eudragit NE-30D (Methyl methacrylate / ethyl acrylate) Acrylic polymers such as Eudragits (ROHM PHARMA CO., LTD.) Such as polymers, hardened oils such as hydrogenated castor oil (eg, Lovely wax (Freund Industries) etc.), carnauba wax, fatty acid glycerin ester,
Waxes such as paraffin and polyglycerin fatty acid ester are used.

As the swelling polymer, a polymer having an acidic dissociative group and exhibiting pH-dependent swelling is preferable. Swelling is small in an acidic region such as the stomach and swelling in a neutral region such as small intestine or large intestine. Polymers having acidic dissociative groups that increase Examples of the polymer having such an acidic dissociative group and exhibiting pH-dependent swelling include, for example, Carbomer 934P, 940, 941, 974P, 9
80, 1342, etc., polycarbophi
l), calcium polycarbo fill (carcium polycarbo
phil) (all of which are manufactured by BF Goodrich Co., Ltd.), Hibiswako 103, 104, 105, 304 (all manufactured by Wako Pure Chemical Industries, Ltd.) and the like are used.

The coating agent used in the sustained release preparation may further contain a hydrophilic substance. As the hydrophilic substance,
For example, pullulan, dextrin, polysaccharides which may have a sulfate group such as alkali metal alginate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polysaccharides having a hydroxyalkyl group or a carboxyalkyl group such as sodium carboxymethyl cellulose, methyl cellulose, Polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and the like are used. The content of the water-insoluble substance in the film preparation of the sustained-release preparation is about 30 to about 90% (w / w), preferably about 35.
To about 80% (w / w), more preferably about 40 to 75% (w / w), the content of swellable polymer is about 3 to about 30% (w / w), preferably about 3 to about 15 % (W /
w). The coating agent may further contain a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 5
It is 0% (w / w) or less, preferably about 5 to about 40% (w / w), more preferably about 5 to about 35% (w / w). Here, the above-mentioned% (w / w) indicates the weight% with respect to the coating agent composition obtained by removing the solvent (eg, water, lower alcohols such as methanol, ethanol, etc.) from the coating agent liquid.

The sustained-release preparation is a film prepared by preparing a core containing a drug as illustrated below, and then dissolving the obtained core by heating or dissolving or dispersing a water-insoluble substance or a swelling polymer in a solvent. It is manufactured by coating with a chemical solution. I. Preparation of drug-containing nuclei. The form of the core containing the drug to be coated with the coating agent (hereinafter sometimes simply referred to as the core) is not particularly limited, but is preferably formed into particles such as granules or fine particles. When the core is a granule or a fine granule, its average particle size is preferably about 15
It is 0 to 2,000 μm, more preferably about 500 to about 1,400 μm. The core can be prepared by an ordinary manufacturing method. For example, a drug is mixed with an appropriate excipient, a binder, a disintegrating agent, a lubricant, a stabilizer and the like and prepared by a wet extrusion granulation method, a fluidized bed granulation method or the like. The drug content of the nucleus is about 0.5 to about 95% (w / w), preferably about 5.0 to about 80% (w / w), more preferably about 30 to about 70% (w / w). Is.

As the excipient contained in the core, for example, saccharose, lactose, mannitol, saccharides such as glucose, starch,
Crystalline cellulose, calcium phosphate, corn starch and the like are used. Among them, crystalline cellulose and corn starch are preferable. Examples of the binder include polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone, Pluronic F6.
8. Gum arabic, gelatin, starch and the like are used. As the disintegrant, for example, carboxymethyl cellulose calcium (ECG505), croscarmellose sodium (Ac-Di
-Sol), cross-linked polyvinylpyrrolidone (crospovidone), low-substituted hydroxypropyl cellulose (L-HP
C) etc. are used. Of these, hydroxypropyl cellulose, polyvinylpyrrolidone, and low-substituted hydroxypropyl cellulose are preferable. Examples of lubricants and anti-agglomeration agents include talc, magnesium stearate and its inorganic salts, and lubricants such as polyethylene glycol. Acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used as the stabilizer.

In addition to the above-mentioned production method, the core is sprayed with a binder dissolved in a suitable solvent such as water or lower alcohol (eg, methanol, ethanol, etc.) on the inert carrier particles which are the core of the core. , Drug or this and excipient,
It can also be prepared by a tumbling granulation method, a pan coating method, a fluidized bed coating method or a melt granulation method in which a mixture with a lubricant or the like is added little by little. As the inert carrier particles, for example, those produced from sucrose, lactose, starch, crystalline cellulose, waxes can be used, and the average particle diameter thereof is preferably about 100 μm to about 1,500 μm. The surface of the core may be coated with a protective agent in order to separate the drug contained in the core from the coating agent. As the protective agent, for example, the hydrophilic substance, the water-insoluble substance or the like is used. The protective agent is preferably polyethylene glycol or a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group, more preferably hydroxypropylmethyl cellulose or hydroxypropyl cellulose. The protective agent includes tartaric acid, citric acid, as a stabilizer,
An acid such as succinic acid, fumaric acid or maleic acid, or a lubricant such as talc may be contained. When a protective agent is used, its coverage is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% (w / w) based on the core. w / w). The protective agent can be coated by a conventional coating method, and specifically, the core can be spray-coated with the protective agent by, for example, a fluidized bed coating method, a pan coating method or the like.

II. Coating of the core with a coating agent The core obtained in the above I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swelling polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent. To produce a sustained release formulation. As a method of coating the core with the coating agent liquid, for example, a spray coating method or the like is used. The composition ratio of the water-insoluble substance, the swelling polymer or the hydrophilic substance in the coating agent liquid is appropriately selected so that the content of each component in the coating is the above content. The coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w), and more preferably, the core (excluding the coating amount of the protective agent). About 5 to 35
% (W / w).

As the solvent for the coating agent liquid, water or an organic solvent may be used alone or a mixture of both may be used. Mixing ratio of water and organic solvent (water / organic solvent:
The weight ratio can vary from 1 to 100%, preferably 1 to about 30%. The organic solvent is not particularly limited as long as it dissolves a water-insoluble substance, for example, lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, lower alkanones such as acetone, acetonitrile, chloroform, Methylene chloride or the like is used. Of these, lower alcohols are preferable, and ethyl alcohol and isopropyl alcohol are particularly preferable. Water and a mixed liquid of water and an organic solvent are preferably used as the solvent of the film forming agent. At this time, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, and maleic acid may be added to the coating agent solution for stabilizing the coating agent solution. The operation in the case of coating by spray coating can be carried out by a usual coating method, and specifically, it is carried out by spray coating the core with a coating agent solution by, for example, a fluidized bed coating method, a pan coating method or the like. You can If necessary at this time, talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid, etc. are used as lubricants, and glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc. are plasticized. You may add as an agent. After coating with the coating agent, an antistatic agent such as talc may be mixed if necessary.

The immediate release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particle, pill, tablet, etc.). Oral administration agents, parenteral administration agents such as injection agents are used, and oral administration agents are preferred. The immediate-release preparation may usually contain, in addition to the active ingredient drug, a carrier, an additive or an excipient (hereinafter sometimes abbreviated as an excipient) commonly used in the field of formulation. . The formulation excipient used is not particularly limited as long as it is an excipient that is commonly used as a formulation excipient. For example, as an excipient for an oral solid preparation,
Lactose, starch, corn starch, crystalline cellulose (Asahi Kasei Co., Ltd., Avicel PH101 etc.), powdered sugar, granulated sugar, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, L-cysteine, etc. are used,
Preferably, corn starch, mannitol and the like are used. These excipients can be used alone or in combination of two or more. The content of the excipient is, for example, about 4.5 to about 99.4 w / w%, preferably about 20 to about 98.5 w / w%, more preferably about 3 to the total amount of the immediate release preparation.
0 to about 97 w / w%. The content of the drug in the immediate release preparation is about 0.5 to about 95 with respect to the total amount of the immediate release preparation.
%, Preferably from about 1 to about 60%.

When the immediate-release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components. As such a disintegrant, for example, carboxymethyl cellulose calcium (manufactured by Gotoku Yakuhin, ECG-505), croscarmellose sodium (for example, Asdi Kasei Co., Ltd., Aczisol), crospovidone (for example, BASF, Kollidon CL). , Low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (Matsuya Chemical Co., Ltd.), sodium carboxymethyl starch (Kimura Sangyo, Explotab), partially pregelatinized starch (Asahi Kasei Co., Ltd.) , PCS) and the like, and those which disintegrate the granules by, for example, contacting with water to absorb water, swell, or form a channel between the active ingredient forming the nucleus and the excipient can be used. . These disintegrants may be used alone or in combination of two or more. The amount of the disintegrant to be added is appropriately selected depending on the type and amount of the drug to be used, the release formulation design, etc., but is, for example, about 0.05 to about 30 w / w%, preferably the total amount of the immediate release formulation. Is about 0.5 ~
It is about 15 w / w%.

When the immediate-release preparation is an oral solid preparation, in the case of an oral solid preparation, it may further contain, if desired, additives conventionally used in solid preparations in addition to the above composition. Examples of such additives include binders (for example, sucrose, gelatin, gum arabic powder, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose,
Polyvinylpyrrolidone, pullulan, dextrin, etc.),
Lubricants (for example, polyethylene glycol, magnesium stearate, talc, light anhydrous silicic acid (for example, Aerosil (Japan Aerosil)), surfactants (for example,
Anionic surfactants such as sodium alkylsulfate, polyoxyethylene fatty acid esters and polyoxyethylene sorbitan fatty acid esters, nonionic surfactants such as polyoxyethylene castor oil derivatives), colorants (for example, tar dyes, Caramel, red iron oxide, titanium oxide, riboflavins), and if necessary, cross-linking agents (eg, sweeteners, flavors, etc.), adsorbents, preservatives, wetting agents, antistatic agents, etc. are used. Also, tartaric acid as a stabilizer,
Organic acids such as citric acid, succinic acid and fumaric acid may be added. As the binder, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone and the like are preferably used. The quick-release preparation can be prepared by mixing the above-mentioned components, and if necessary, further kneading and molding, based on the usual manufacturing technology for preparations. The mixing is a commonly used method, for example,
It is performed by mixing, kneading and the like. Specifically, for example, when forming an immediate release preparation in the form of particles, by the same method as the method for preparing the core of the sustained release preparation, a vertical granulator, a universal kneader (manufactured by Hata Tekko Co., Ltd.), a flower Layer Granulator FD-5
It can be prepared by mixing using S (manufactured by Paulec Co.) or the like, and then granulating by a wet extrusion granulation method, a fluidized bed granulation method, or the like. The immediate-release preparation and the sustained-release preparation thus obtained are formulated as they are or separately separately with a formulation excipient by a conventional method, and then administered simultaneously or in combination with an arbitrary administration interval interposed. Alternatively, both may be directly or appropriately formulated into one orally-administered preparation (eg, granules, fine granules, tablets, capsules, etc.) together with a preparation excipient and the like. Both preparations may be made into granules or fine granules and filled in the same capsule or the like to give a preparation for oral administration.

[3] Sublingual tablet, buccal or intraoral quick disintegrating agent and preparation thereof The sublingual tablet, buccal preparation and intraoral quick disintegrating agent may be solid preparations such as tablets, or tablets for oral mucosa sticking ( Film). As the sublingual tablet, buccal or buccal disintegrant, a formulation containing the compound of the present invention or the concomitant drug and an excipient is preferable. Further, an auxiliary agent such as a lubricant, a tonicity agent, a hydrophilic carrier, a water-dispersible polymer and a stabilizer may be contained. In addition, β-cyclodextrin or a β-cyclodextrin derivative (eg, hydroxypropyl-β-cyclodextrin, etc.) may be contained in order to facilitate absorption and increase bioavailability. As the excipient, lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like are used.
As the lubricant, magnesium stearate, calcium stearate, talc, colloidal silica, etc. are used,
Particularly, magnesium stearate and colloidal silica are preferable. As the isotonicity agent, sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like are used, and mannitol is particularly preferable. As the hydrophilic carrier, swelling hydrophilic carriers such as crystalline cellulose, ethyl cellulose, crosslinkable polyvinylpyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate are used,
Particularly, crystalline cellulose (eg, microcrystalline cellulose etc.) is preferable. Examples of the water-dispersible polymer include gum (eg, tragacanth gum, acacia gum, guar gum), alginate (eg, sodium alginate), cellulose derivative (eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose),
Gelatin, water-soluble starch, polyacrylic acid (eg carbomer), polymethacrylic acid, polyvinyl alcohol,
Polyethylene glycol, polyvinylpyrrolidone, polycarbophil, ascorbyl palmitate, etc. are used, and hydroxypropylmethylcellulose, polyacrylic acid, alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol and the like are preferable. Hydroxypropyl methylcellulose is particularly preferred. As a stabilizer, cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate,
Ascorbic acid, glycine, sodium sulfite and the like are used, and citric acid and ascorbic acid are particularly preferable.

Sublingual tablets, buccal or buccal disintegrants are
It can be produced by mixing the compound of the present invention or the concomitant drug and an excipient by a method known per se.
Further, if desired, the above-mentioned lubricant, tonicity agent, hydrophilic carrier, water-dispersible polymer, stabilizer, colorant, sweetener,
You may mix auxiliary agents, such as a preservative. Sublingual tablets, buccal tablets or rapidly disintegrating buccal tablets can be obtained by mixing the above components at the same time or with a time lag and press-molding the mixture. In order to obtain an appropriate hardness, it may be manufactured by moistening / wetting with a solvent such as water or alcohol as needed before and after the tableting process, followed by molding and drying.

In the case of molding into a mucoadhesive tablet (film), the compound of the present invention or the concomitant drug and the above-mentioned water-dispersible polymer (preferably hydroxypropylcellulose, hydroxypropylmethylcellulose), excipients, etc. Dissolve in solvent and cast the resulting solution
(cast) Film. Further, additives such as a plasticizer, a stabilizer, an antioxidant, a preservative, a colorant, a buffer and a sweetener may be added. Contains glycols such as polyethylene glycol and propylene glycol to give the film an appropriate elasticity, and bioadhesive polymers (eg, polycarbophil, carbopol) to enhance the adhesion of the film to the mucous membrane lining of the oral cavity You may let me. Casting is performed by pouring the solution onto a non-adhesive surface, spreading it to a uniform thickness (preferably about 10 to 1000 microns) with a coating tool such as a doctor blade, and then drying the solution to form a film. To be achieved. The film thus formed may be dried at room temperature or under heating and cut into a desired surface area.

A preferred oral rapid disintegrating agent is a solid form consisting of a reticulate body of the compound of the present invention or the concomitant drug and a water-soluble or water-diffusible carrier inert to the compound of the present invention or the concomitant drug. Rapid diffusion dosage forms are used. The reticulate body is obtained by sublimating a solvent from the solid composition composed of a solution of the compound of the present invention or a concomitant drug in a suitable solvent. It is preferable that, in addition to the compound of the present invention or the concomitant drug, the composition of the quick disintegrating agent in the oral cavity contains a matrix forming agent and a secondary component. Examples of the matrix-forming agent include gelatins, dextrins, soybeans, wheat and psyllium seed proteins, and other animal or plant proteins; gum arabic, guar gum, agar and xanthan, and other gum substances; polysaccharides. ;
Alginic acids; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; substances derived from gelatin-gum arabic complex and the like. Further, sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartic acid, L- Glutamic acid, L-hydrocyclyproline, L-isoleucine, L
-Amino acids having 2 to 12 carbon atoms such as leucine and L-phenylalanine are included. One or more matrix forming agents may be introduced into the solution or suspension prior to solidification. Such a matrix forming agent may be present in addition to the surfactant, or the surfactant may be excluded. In addition to forming the matrix, the matrix-forming agent can help maintain the diffusional state of the compound of the present invention or the concomitant drug in its solution or suspension.

The composition may contain secondary components such as preservatives, antioxidants, surfactants, thickeners, colorants, pH adjusters, flavors, sweeteners or taste masking agents. Suitable colorants include red, black and yellow iron oxides and FD & Eberd & Eberard FD &
FD & such as C Blue No. 2 and FD & C Red No. 40
C dye is used. Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit,
Includes caramel, vanilla, terry and grape flavors and combinations thereof. Suitable pH adjusters include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. As a suitable sweetener, aspartame,
Acesulfame K and thaumatin are included.
Suitable taste masking agents include sodium bicarbonate,
Included are ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials and microencapsulated apomorphine. The formulation usually contains about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of the compound of the present invention or the concomitant drug, and the period of about 1 minute to about 60 minutes, preferably about 1 minute.
A formulation capable of dissolving 90% or more of the compound of the present invention or the concomitant drug (in water) between minutes and about 15 minutes, more preferably between about 2 minutes and about 5 minutes (the above-mentioned sublingual tablet , Buccal, etc.) or within 1 to 60 seconds after being placed in the oral cavity,
Preferably within 1 to 30 seconds, more preferably 1
Oral fast disintegrating agents that disintegrate within 10 seconds are preferred.

The content of the above-mentioned excipient in the whole preparation is
It is about 10 to about 99% by weight, preferably about 30 to about 90% by weight. The content of β-cyclodextrin or β-cyclodextrin derivative in the whole preparation is 0 to about 30.
% By weight. The content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight.
Is. The content of the isotonicity agent in the whole preparation is about 0.
1 to about 90% by weight, preferably about 10 to about 70% by weight
Is. The content of the hydrophilic carrier in the whole preparation is about 0.
1 to about 50% by weight, preferably about 10 to about 30% by weight. The content of the water-dispersible polymer in the whole preparation is
It is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight. The content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight. The above-mentioned preparation may further contain additives such as a coloring agent, a sweetening agent and a preservative, if necessary.

The dose of the concomitant drug of the present invention varies depending on the kind, age, body weight, symptom, dosage form, administration method, administration period and the like of the compound of the present invention. For example, a patient with breast cancer (adult, body weight about 60 kg) ) Per person, as a compound of the present invention and a concomitant drug, usually about 0.01 to about 1000 m / day
g / kg, preferably about 0.01 to about 100 mg / kg, more preferably about 0.1 to about 100 mg / kg, especially about 0.1 to about 50 mg / kg, especially about 1.5 to about 3
0 mg / kg is intravenously administered once to several times a day.
Of course, as described above, the dose varies depending on various conditions, so a dose smaller than the above dose may be sufficient in some cases,
In some cases, it may be necessary to administer more than the range. It is possible to set any amount of the concomitant drug as long as side effects do not pose a problem. The daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, weight, sensitivity difference, administration timing, interval, properties of pharmaceutical preparation, preparation, type, type of active ingredient, etc. Although not limited, the amount of the drug is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, and more preferably about 0.1 to 100 mg per kg body weight of the mammal by oral administration. Usually 1 to 4 a day
Administer in divided doses.

When the concomitant drug of the present invention is administered, it may be administered at the same time, but after the concomitant drug is administered first,
The compound of the invention may be administered, or the compound of the invention may be administered first, followed by the concomitant drug. When administered with a time lag, the time lag is the active ingredient to be administered,
Depending on the dosage form and administration method, for example, when the concomitant drug is administered first, 1 minute to 3 days, preferably 10 minutes to 1 day, more preferably 15 minutes after the concomitant drug is administered.
A method of administering the compound of the present invention within minutes to 1 hour is used. When the compound of the present invention is administered first, it is preferably within 1 minute to 1 day, preferably 10 after the administration of the compound of the present invention.
A method of administering the concomitant drug within minutes to 6 hours, more preferably within 15 minutes to 1 hour is used. As a preferable administration method, for example, about 0.001 to 200 mg / kg of a concomitant drug formed into an oral administration preparation is orally administered, and about 15 minutes later, the compound of the present invention formed into the oral administration preparation.
The daily dose of about 0.005 to 100 mg / kg is orally administered.

The pharmaceutical composition of the present invention or the concomitant drug of the present invention may be administered, for example, in (1) surgery or (2) angiotensin.
Pressor chemotherapy using II, etc., (3) gene therapy, (4)
Hyperthermia, (5) cryotherapy, (6) laser ablation,
(7) It can also be combined with non-drug therapy such as radiation therapy. For example, by using the pharmaceutical composition of the present invention or the concomitant drug of the present invention before or after surgery, etc., or before or after treatment in which two or three of these are combined, inhibition of resistance development, disease-free (Disease- Free Surviva
The effects of prolonging l), suppressing cancer metastasis or recurrence, and prolonging life can be obtained. Further, treatment with the pharmaceutical composition of the present invention or the concomitant drug of the present invention, supportive therapy [(i) antibiotics against various complications of infectious diseases (for example, β-lactams such as pansporin, macrolides such as clarithromycin) System, etc.), (ii) high-calorie infusion for improving nutritional disorders, amino acid preparations, multivitamin preparations, (iii) morphine administration for pain relief, (iv) nausea, vomiting, anorexia, diarrhea ,
Administration of agents that improve side effects such as leukopenia, thrombocytopenia, hemoglobin concentration reduction, hair loss, liver damage, renal damage, DIC, fever, and (v) administration of drugs to suppress multidrug resistance of cancer, etc. ] Can also be combined. Before or after the above treatment, the pharmaceutical composition of the present invention or the combination drug of the present invention is orally administered (including sustained release),
It is preferably administered by intravenous administration (including bolus, infusion, clathrate), subcutaneous and intramuscular injection (including bolus, infusion, sustained release), transdermal, intratumoral and proximal administration. When the pharmaceutical composition of the present invention or the concomitant drug of the present invention is administered before surgery or the like, for example, it may be administered once about 30 minutes to 24 hours before surgery or the like.
Alternatively, it may be administered in 1 to 3 cycles divided about 3 to 6 months before surgery and the like. Thus, by administering the pharmaceutical composition of the present invention or the concomitant drug of the present invention before surgery or the like, for example, cancer tissue can be reduced, and thus surgery or the like is facilitated. When the pharmaceutical composition of the present invention or the combination drug of the present invention is administered after surgery or the like, it can be repeatedly administered about 30 minutes to 24 hours after surgery or the like, for example, for several weeks to 3 months. . Thus, by administering the pharmaceutical composition of the present invention or the combination agent of the present invention after surgery or the like, the effect of surgery or the like can be enhanced.

[0114]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in detail below with reference to Reference Examples, Examples, Formulation Examples and Test Examples, but the present invention is not limited thereto. Elution by column chromatography of Reference Example and Example was carried out by TL
It was performed under observation by C (Thin Layer Chromatography). In the observation of TLC, Kieselgel 6 manufactured by Merck Ltd. was used as a TLC plate.
The 0F ₂₅₄ plate was used, and the solvent used as the elution solvent in column chromatography was used as the developing solvent.
A UV detector was adopted as the detection method. The silica gel for the column is Kieselgel 60F ₂₅₄ (7
0-230 mesh) was used. The NMR spectrum is
Proton NMR is shown, using VARIAN Gemini-200 (2
00MHz type spectrometer) and δ value is p
Expressed in pm. The abbreviations used in Reference Examples and Examples have the following meanings. s: singlet br: broad (wide) d: doublet t: triplet q: quartet dd: double doublet ddd: double double doublet dt: double triplet m: multiplet J: coupling constant Hz: Hertz DMF: N, N-dimethyl Formamide THF: Tetrahydrofuran

[0115]

[Example] Reference example 1. 4-chloromethyl-2-[(E)-
2- (4-trifluoromethylphenyl) ethenyl] -1,
3-Oxazole (i) (E) -3- (4-trifluoromethylphenyl) -2-propenamide 4-trifluoromethylcinnamic acid (19.4 g), DMF
Oxalyl chloride (11.7 ml) was added dropwise to a suspension of (6 drops) in THF (100 ml) at 0 ° C, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the residue was washed with ethyl acetate (60 m
l) and dissolved in 25% aqueous ammonia-ethyl acetate (5:
1, 120 ml). The aqueous layer was salted out, extracted with a mixed solution of ethyl acetate-THF (12: 1) (650 ml) and ethyl acetate (100 ml × 2), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethyl acetate-hexane to give the title compound (18.0 g) as colorless plate crystals. ¹ H-NMR (CDCl ₃ ) δ: 5.58 (2H, br s), 6.53 (1H, d, J =
15.8 Hz), 7.63-7.72 (5H, m). IR (KBr): 3326, 3167, 1686, 1636, 1617, 1404, 119
0 cm ^-1 .

(Ii) 4-chloromethyl-2-[(E)-
2- (4-trifluoromethylphenyl) ethenyl]-
1,3-oxazole (E) -3- (4-trifluoromethylphenyl) -2
A solution of propenamide (17.9 g) and 1,3-dichloroacetone (14.8 g) in toluene (83 ml) was heated under reflux for 9 hours using a Dean-Stark apparatus. After cooling, water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane: methyl acetate = 6: 1 → 5: 1) to give the title compound (1
5.1 g) was obtained as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 4.55 (2H, d, J = 0.8 Hz), 7.00 (1
H, d, J = 16.2 Hz), 7.56 (1H, d, J = 16.2 Hz), 7.6
4-7.68 (5H, m). IR (KBr): 1350, 1325, 1170, 1136, 1113, 1071, 95
9, 826, 727, 708 cm ^-1 .

Reference Example 2. 4-chloromethyl-2-
[(E) -2- (2,4-difluorophenyl) etheni
Reference Example using the Le] -1,3-oxazole (E) -3- (2,4- difluorophenyl) -2-propenamide (9.16 g), 1,3-dichloroacetone (7.62 g) 1- The same reaction as in (ii) was performed to give the title compound (6.31 g) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 4.55 (2H, s), 6.8-7.0 (2H, m),
6.96 (1H, d, J = 16.8), 7.45-7.7 (3H, m).

Reference Example 3. 4-chloromethyl-2-
[(E) -2- (2,6-difluorophenyl) etheni
] -1,3-Oxazole (E)-(2,6-difluorophenyl) -2-propenamide (9.0 g) and 1,3-dichloroacetone (7.49 g) in Reference Example 1- (ii). The same reaction as the above) was performed to give the title compound (7.18 g) as a pale-yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 4.55 (2H, s), 6.85-7.0 (2H,
m), 7.2-7.35 (2H, m), 7.55-7.7 (1H, m), 7.66 (1H,
s).

Reference Example 4. 1- [2- (4-benzyloxyfuran
Preparation of enoxy) ethyl] -1H-imidazole 1H-imidazole (0.93g) in DMF (30 ml) at 0 ℃
Sodium hydride (0.59g) was added at 60 ° C, and the mixture was stirred at room temperature for 1 hour, 1-benzyloxy-4- (2-chloroethoxy) benzene (3.00g) was added at the same temperature, and the mixture was stirred at 60 ° C for 2 hours. did. The reaction solution was poured into water, and the precipitated crystals were collected by filtration and washed with water-diethyl ether to give the title compound (3.04 g) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 138-139 ° C. ¹ H-NMR (CDCl ₃ ) δ: 4.16 (2H, t, J = 5.4 Hz), 4.30 (2
H, t, J = 5.4 Hz), 5.01 (2H, s), 6.76-6.92 (4H, m),
7.03-7.07 (2H, m), 7.33-7.44 (5H, m), 7.59 (1H,
s) .IR (KBr): 3101, 2943, 2878, 1593,1512, 1462, 1383,
1282, 1234, 1205, 1107, 1076, 1060, 1045, 1030, 9
14, 831, 754, 738, 675 cm ^-1 .

Reference Example 5. 4- [2- (1H-imidazole
Preparation of 1 -yl) ethoxy] phenol 1- [2- (4-benzyloxyphenoxy) ethyl] -1H-
Imidazole (2.80g), 5% palladium on carbon (wet, 2.0
A mixture of g) and tetrahydrofuran (150 ml) was catalytically reduced at 1 atm. After removing the catalyst by filtration, the solvent was evaporated under reduced pressure to give the title compound (1.66 g) as colorless crystals. Recrystallization from ethanol gave colorless prism crystals. Melting point 144-145 [deg.] C. ¹ H-NMR (DMSO-d ₆ ) δ: 4.12 (2H, t, J = 5.0 Hz), 4.30
(2H, t, J = 5.0 Hz), 6.62-6.75 (4H, m), 6.88 (1H,
s), 7.21 (1H, s), 7.65 (1H, s), 8.93 (1H, br s) .IR (KBr): 3113, 2939, 2795, 2669, 2590, 1510, 144
8, 1375, 1240, 1072, 829, 754, 663, 526 cm ^-1 .

Reference Example 6. 1- (4-benzyloxyphenyl
( 2) Bromo (2.73 ml) in ethanol (25 ml) was added dropwise to an ethanol solution (150 ml) of 4-benzyloxyacetophenone (9.56 g) at room temperature and stirred for 1 hour. The reaction solution was cooled to -20 ° C, and the precipitated crystals were collected by filtration and washed with ethanol to give the title compound (8.28 g) as crystals. ¹ H-NMR (CDCl ₃ ) δ: 4.39 (2H, s), 5.15 (2H, s), 7.01
-7.07 (2H, m), 7.30-7.46 (5H, m), 7.94-8.00 (2H,
m). IR (KBr): 1672, 1599, 1260, 1173 cm ^-1 .

Reference Example 7. 1- (4-benzyloxyphenyl
) -2- (1H-imidazol-1-yl) ethanone
Preparation A mixture of 1- (4-benzyloxyphenyl) -2-bromoethanone (6.71 g), 1H-imidazole (2.25 g), potassium carbonate (4.56 g) and DMF (40 ml) was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with ethyl acetate to give colorless crystals. The crystals were recrystallized from ethyl acetate to give the title compound (4.18 g) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 5.16 (2H, s), 5.34 (2H, s), 6.95
(1H, t, J = 1.2 Hz), 7.03-7.11 (2H, m), 7.14 (1H,
d, J = 1.2 Hz), 7.32-7.46 (5H, m), 7.51 (1H, s), 7.9
1-7.99 (2H, m). IR (KBr): 1688, 1601, 1238, 912, 743 cm ^-1 .

Reference Example 8. 1-[(4-hydroxyphenyl)
Preparation of 2- (1H-imidazol-1-yl) ethanone 1- (4-benzyloxyphenyl) -2- (1H-imidazol-1-yl) ethanone (1.86 g), 10% palladium on carbon (wet, 0.51 A mixture of g), tetrahydrofuran (20 ml) and methanol (30 ml) was catalytically reduced at 1 atm. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain crystals. Recrystallization from methanol gave the title compound (0.83 g) as colorless crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 5.61 (2H, s), 6.86-6.92 (3H,
m), 7.09 (1H, s), 7.57 (1H, s), 7.87-7.95 (2H, m).

Reference Example 9. 4-[(4-nitrophenoxy) me
Cyl] -2- (2-thienyl) -1,3-oxazole preparation 4-nitrophenol (1.16 g) in DMF (20 ml) solution 0
60% Sodium hydride (0.36 g) was added at 0 ° C., the mixture was stirred at room temperature for 1 hr, and then 4-chloromethyl-2- (2-thienyl) was added at the same temperature.
-1,3-Oxazole (2.00 g) was added, and the mixture was stirred at 80 ° C for 2 hr. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to give the title compound (2.21 g) as colorless crystals. Ethyl acetate-
Recrystallization from hexane gave colorless prism crystals. Melting point 161-162 ° C. ¹ H-NMR (CDCl ₃ ) δ: 5.15 (2H, s), 7.04-7.11 (2H, m),
7.14 (1H, dd, J = 5.0, 3.8 Hz), 7.47 (1H, dd, J = 5.0,
1.2 Hz), 7.70-7.73 (2H, m), 8.19-8.26 (2H, m). IR (KBr): 3165, 3103, 2920, 2872, 1593, 1504, 141
9, 1334, 1269, 1168, 1111, 1041, 1006, 866, 841, 7
52, 729, 686, 638, 617 cm ^-1 .

Reference Example 10. 4-[[2- (2-thienyl) -1,
Preparation of 3-oxazol-4-yl] methoxy] aniline 4-[(4-nitrophenoxy) methyl] -2- (2-thienyl)
-1,3-Oxazole (1.00 g), 5% palladium on carbon (we
t, 1.00 g) and tetrahydrofuran (30 ml) were catalytically reduced at 1 atm. After removing the catalyst by filtration, the solvent was evaporated under reduced pressure to give the title compound (0.82 g) as brown crystals. Recrystallization from ethyl acetate-hexane gave brown prism crystals. Melting point 112-113 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.10 (2H, br s), 4.98 (2H, d, J =
0.8 Hz), 6.62-6.69 (2H, m), 6.79-6.86 (2H, m), 7.1
1 (1H, dd, J = 5.2, 3.6 Hz), 7.43 (1H, dd, J = 5.2, 1.
2 Hz), 7.63 (1H, br s), 7.68 (1H, dd, J = 3.6, 1.2 H
z). IR (KBr): 3412, 3321, 3211, 3134, 2937, 2874, 163
0, 1583, 1510, 1462, 1425, 1383, 1369, 1271, 1224,
1182, 1101, 1051, 1020, 858, 825, 698 cm ^-1 .

Reference Example 11. 2-chloro-N- [4-[[2- (2
-Thienyl) -1,3-oxazol-4-yl] methoxy]
Preparation of phenyl] acetamide 4-[[2- (2-thienyl) -1,3-oxazol-4-yl] methoxy] aniline (500 mg) in N, N-dimethylacetamide (5 ml) was mixed with chloroacetyl chloride ( 210
(mg) was added dropwise at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with water to give the title compound (600 mg) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 156-157 ° C. ¹ H-NMR (CDCl ₃ ) δ: 4.19 (2H, s), 5.05 (2H, d, J = 0.8
Hz), 6.97-7.02 (2H, m), 7.13 (1H, dd, J = 5.0, 3.8
Hz), 7.45 (1H, dd, J = 5.0, 1.2 Hz), 7.45-7.50 (2H,
m), 7.67 (1H, m), 7.70 (1H, dd, J = 3.8, 1.2 Hz), 8.
16 (1H, br s) .IR (KBr): 3310, 3103, 2939, 2866, 1668, 1533, 141
9, 1257, 1176, 1101, 1051, 1005, 856, 827, 771, 72
5, 713 cm ^-1 .

Reference Example 12. 4- (chloromethyl) -2- (2-
Preparation of thienyl) -1,3-oxazole A mixture of thiophene-2-carboxamide (5.09g) and 1,3-dichloro-2-propanone (4.57g) was stirred at 120 ° C for 2 hours. Water and ethyl acetate were added to the reaction mixture, and potassium carbonate was further added to make the mixture basic, and the mixture was extracted with ethyl acetate. The extract was washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane-diethyl ether (9: 1)) to give the title compound (4.09 g) as colorless crystals. Recrystallization from diisopropyl ether gave colorless needle crystals. Melting point 58-59 ° C. ¹ H-NMR (CDCl ₃ ) δ: 4.55 (2H, s), 7.09-7.14 (1H,
m), 7.45 (1H, d, J = 5.0Hz), 7.64 (1H, s), 7.69
(1H, d, J = 3.6 Hz). IR (KBr): 3177, 3144, 3094, 3007, 2959, 1589, 156
0, 1494, 1421, 1346, 1271, 1232, 1151, 1109, 1084,
1005, 923, 908, 854, 781, 744, 694 cm ^-1 .

Reference Example 13. [2- (2-thienyl) chloride-1,
3-Oxazol-4-yl] methyltriphenylphospho
Manufacture of 4- (chloromethyl) -2- (2-thienyl) -1,3-oxazole (2.0 g), triphenylphosphine (2.62 g) and acetonitrile (20 ml) under heating and stirring for 16 hours did. The reaction mixture was concentrated under reduced pressure, and the obtained crystals were washed with acetonitrile to give the title compound (4.00g) as colorless crystals. Recrystallization from acetonitrile gave colorless prism crystals. Melting point 245-246 ° C. ¹ H-NMR (CDCl ₃ ) δ: 5.62 (2H, d, J = 14.4 Hz), 7.06 (1
H, dd, J = 5.0, 3.6 Hz), 7.38 (1H, dd, J = 5.0, 0.8 H
z), 7.49 (1H, dd, J = 3.6, 0.8 Hz), 7.61-7.97 (15H,
m), 8.32 (1H, d, J = 4.4 Hz) .IR (KBr): 3075, 3050, 2846, 2765, 1592, 1495, 143
8, 1345, 1291, 1160, 1114, 1075, 1000, 982, 880, 8
42, 789, 745, 730, 691, 521 cm ^-1 .

Reference Example 14 4- [2- (1H-imidazole
Preparation of 1-yl) ethoxy] benzaldehyde 4- (2-bromoethoxy) benzaldehyde (5.04 g),
A mixture of potassium carbonate (4.56g), 1H-imidazole (2.25g) and DMF (40ml) was stirred at 80 ° C for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate-methanol (9
5: 5)) to give the title compound (2.81 g) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 4.10-4.33 (2H, m), 4.36-4.43 (2
H, m), 6.96-7.10 (4H, m), 7.61 (1H, s), 7.80-7.85
(2H, m), 9.89 (1H, s). IR (KBr): 1686, 1601, 1578, 1508, 1254, 1163, 833
cm ^-1 .

Reference Example 15. 4- [3- (1H-imidazole-
Preparation of 1-yl) propoxy] benzaldehyde 4- (3-chloropropoxy) benzaldehyde (4.70
To a mixture of g), 1H-imidazole (1.77 g) and DMF (40 ml), 60% sodium hydride (1.04 g) was added at room temperature, and the mixture was stirred at 80 ° C for 1 hr. The reaction solution was poured into saturated saline and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate-methanol (9: 1)) to give the title compound (4.65 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 2.20-2.40 (2H, m), 4.00 (2H, t,
J = 5.6 Hz), 4.22 (2H, t, J = 6.6 Hz), 6.92-7.08 (4H,
m), 7.49 (1H, s), 7.83-7.88 (2H, m), 9.91 (1H,
s).

Reference Example 16. 4- [(2-hydroxyethyl)
Preparation of (methyl) amino] benzonitrile 4-fluorobenzonitrile (12.4 g), 2-methylaminoethanol (8.41 g), potassium carbonate (15.5 g) and DMF
The mixture (50 ml) was stirred at 70 ° C. for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate-hexane (1: 1)) to give the title compound (10.58 g) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 2.12 (1H, br s), 3.07 (3H, s),
3.56 (2H, t, J = 5.6 Hz), 3.80-3.90 (2H, m), 6.70 (2
H, d, J = 8.0 Hz), 7.37-7.44 (2H, m) .IR (KBr): 3391, 2885, 2212, 1606, 1523, 1386, 135
6, 1178, 1049, 815, 545cm ^-1 .

Reference Example 17 : 4- [N- [2- (1-1H-imidazo
Production of 4-((2-hydroxyethyl) (methyl) amino] benzonitrile (4.50 g), triethylamine (3.88 g) and ethyl acetate (300 ml), Methanesulfonyl chloride (4.
39 g) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The reaction solution
It was washed successively with water, saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give an oil. 1H-imidazole (3.47g) DMF (100 m
l) Add 60% sodium hydride (2.24g) to the solution at 0 ° C,
After stirring at room temperature for 1 hour, a solution of the oily substance in DMF (10 ml) was added dropwise at the same temperature, and the mixture was further stirred at the same temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was washed with hexane to give the title compound (5.31 g) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 122-123 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.78 (3H, s), 2.74 (2H, t, J = 6.0
Hz), 4.18 (2H, t, J = 6.0 Hz), 6.55-6.63 (2H, m),
6.89 (1H, t, J = 1.2 Hz), 7.09 (1H, m), 7.38 (1H,
m), 7.46-7.54 (2H, m). IR (KBr): 3140, 2912, 2210, 1604, 1521, 1506, 137
7, 1331, 1282, 1230, 1180, 1120, 1080, 956, 817, 7
56, 661, 542 cm ^-1 .

Reference Example 18. 4-[[2- (1H-imidazole
1-yl) ethyl] (methyl) amino] benzaldehyde
Production 4- [N- [2- (1-1H-imidazolyl) ethyl] -N-methylamino] benzonitrile (5.0 g), Raney nickel (7.5
A mixture of g) and 80% formic acid (200 ml) was stirred with heating under reflux for 1 hour. The solid was filtered off and the filtrate was concentrated under reduced pressure. Water was added to the residue, the mixture was made basic with 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate-methanol (20: 1, v / v)) to give the title compound (3.33 g)
Got Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 98-99 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.81 (3H, s), 3.79 (2H, t, = 6.0
Hz), 4.20 (2H, t, J = 6.0 Hz), 6.67 (2H, d, J = 9.2 H
z), 6.89-6.90 (1H, m), 7.08-7.09 (1H, m), 7.39 (1
H, brs), 7.74-7.79 (2H, m), 9.78 (1H, s) .IR (KBr): 3117, 2914, 2827, 2756, 1658, 1593, 155
6, 1527, 1377, 1315, 1230, 1174, 1120, 1080, 817,
769, 717, 661, 516 cm ^-1 .

Reference Example 19. 4-[(2-hydroxyethyl)
Production of [thio] benzaldehyde 4-fluorobenzaldehyde (20.0 g), potassium carbonate
(20.2g), 2-mercaptoethanol (11.41g) and DMF
The mixture (100 ml) was stirred at 70 ° C. for 15 hours. Water was poured into the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography.
(Eluent, ethyl acetate-hexane (2: 1, v / v)) to give the title compound (22.26 g) as pale yellow crystals. Recrystallization from ethyl acetate-hexane gave yellow prism crystals. Melting point 59-60 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.05 (1H, br s), 3.24 (2H, t, J
= 6.2 Hz), 3.83-3.89 (2H, m), 7.40-7.45 (2H, m), 7.
75-7.80 (2H, m), 9.94 (1H, s). IR (KBr): 3420, 2883, 2827, 1653, 1589, 1556, 143
3, 1392, 1315, 1286, 1226, 1178, 1074, 1016, 842,
812, 561 cm ^-1 .

Reference Example 20. 4-[[2- (1H-imidazole
Preparation of 1-yl) ethyl] thio] benzaldehyde 4-[(2-hydroxyethyl) thio] benzaldehyde (11.
6g), triethylamine (8.38g) and ethyl acetate (300m
l) to the mixture, methanesulfonyl chloride (9.48g) at 0 ℃
Was added dropwise and stirred at room temperature for 2 hours. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give an oil. A mixture of the obtained oily substance, 1H-imidazole (13.00 g) and DMF (100 ml) was stirred at 50 ° C for 15 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate-methanol (20: 1)) to give the title compound (7.92 g) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 3.37 (2H, t, J = 6.8 Hz), 4.23 (2
H, t, J = 6.8 Hz), 6.95 (1H, s), 7.07 (1H, s), 7.35-
7.40 (2H, m), 7.50 (1H, s), 7.73-7.84 (2H, m), 9.9
5 (1H, s) .IR (KBr): 3111, 2833, 2743, 1693, 1591, 1560, 150
8, 1388, 1288, 1217, 1170, 1087, 839, 814, 742, 66
3 cm ^-1 .

Reference Example 21. 6-[[2-[(E) -2-Phenylethene
Nyl] -1,3-oxazol-4-yl] methoxy] -2-naphthale
Preparation of ethyl 6-hydroxy-2-naphthalenecarboxylate (700 m
g), 4-chloromethyl-2-[(E) -2-phenylethenyl] -1,3-oxazole (835 mg), potassium carbonate (88
A mixture of 5 mg) and DMF (30 ml) was stirred at 90 ° C for 13 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was washed with hexane to give the title compound (1.18 g) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 164-165 [deg.] C. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.0 Hz), 4.43 (2
H, q, J = 7.0 Hz), 5.17 (2H, s), 6.96 (1H, d, J = 16.6
Hz), 7.25-7.50 (5H, m), 7.52-7.61 (3H, m), 7.71-
7.90 (3H, m), 8.04 (1H, d, J = 8.8 Hz), 8.53 (1H,
s) .IR (KBr): 2920, 1705, 1630, 1286, 1203, 1095, 754
cm ^-1 .

Reference Example 22. [6-[[2-[(E) -2-Phenyl ether
]]-1,3-Oxazol-4-yl] methoxy] -2-naphthyl]
Preparation of methanol 6-[[2-[(E) -2-phenylethenyl] -1,3-oxazole-4-
Il] methoxy] -2-naphthalenecarboxylate ethyl ester (1.00 g)
Lithium aluminum hydride (146 mg) was added to a tetrahydrofuran solution (30 ml) at 0 ° C. The mixture at room temperature
After stirring for 2 hours, water and 1N hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (78
0 mg) was obtained as colorless crystals. Recrystallization with acetone-methanol gave colorless prism crystals. Melting point 196-197
° C. ¹ H-NMR (CDCl ₃ ) δ: 4.83 (2H, br s), 5.16 (2H, s),
6.96 (1H, d, J = 15.8 Hz), 7.20-7.80 (13H, m). IR (KBr): 3300, 2920, 1635, 1604, 1277, 1180, 104
7, 752 cm ^-1 .

Reference Example 23. 4- (6-chloromethyl-2-naphth
Tyloxymethyl) -2-[(E) -2-phenylethenyl] -1,3-
Production of oxazole [6-[[2-[(E) -2-phenylether] -1,3-oxazole-4-
Il] methoxy] -2-naphthyl] methanol (640 mg), triethylamine (545 mg) and tetrahydrofuran (30 ml)
Methanesulfonyl chloride (620 mg) was added dropwise to the above mixture at 0 ° C., the mixture was stirred at room temperature for 2 hours, heated under reflux for 2 hours, and further stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and then saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 4: 1) to give the title compound (380 m
g) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 171-172 ° C. ¹ H-NMR (CDCl ₃ ) δ: 4.75 (2H, s), 5.16 (2H, s), 6.96
(1H, d, J = 16.4 Hz), 7.26-7.61 (9H, m), 7.70-7.78
(4H, m). IR (KBr): 3142, 3055, 2872, 1630, 1604, 1234, 118
0, 858 cm ^-1 .

Reference Example 24. 3- [6-[[2-[(E) -2-Phenyle
Tenyl] -1,3-oxazol-4-yl] methoxy] -2-naphthyl
Preparation of ethyl] -propionate Ethyl 3- (6-hydroxynaphthalen-2-yl) propionate (1.40 g), 4-chloromethyl-2-[(E) -2-phenylethenyl] -1,3- Add a mixture of oxazole (1.49g), potassium carbonate (1.58g) and DMF (50ml) at 90 ° C for 14
Stir for hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.06 g) as pale brown crystals. Recrystallization from ethyl acetate-hexane gave pale brown prism crystals. Melting point 130-131 [deg.] C. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.0 Hz), 2.69 (2
H, t, J = 7.2 Hz), 3.09 (2H, t, J = 7.2 Hz), 4.13 (2H,
q, J = 7.0 Hz), 5.15 (2H, s), 6.96 (1H, d, J = 16.2 H
z), 7.19-7.27 (13H, m). IR (KBr): 3059, 2976, 2928, 1724, 1606, 1182, 856,
756 cm ^-1 .

Reference Example 25. 3- [6-[[2-[(E) -2-Phenyle
Tenyl] -1,3-oxazol-4-yl] methoxy] -2-naphthyl
Le] -1-propanol prepared 3- [6 - [[2 - [(E) -2- phenylethenyl] -1,3-oxazole
-4-yl] methoxy] -2-naphthyl] ethyl propionate (1.
Lithium aluminum hydride (165 mg) was added to a tetrahydrofuran solution (50 ml) of 85 g at 0 ° C. The mixture was stirred at room temperature for 1 hour, water and 1N hydrochloric acid were added, and the mixture was extracted with ethyl acetate. After washing the extract with water and then saturated saline,
It was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure,
The residue was subjected to silica gel column chromatography (eluent,
Purified with hexane: ethyl acetate = 1: 1) to give the title compound (1.
46 g) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 148-150 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (1H, br s), 1.90-2.05 (2H,
m), 2.86 (2H, t, J = 7.5Hz), 3.67-3.75 (2H, m), 5.15
(2H, s), 6.96 (1H, d, J = 16.4 Hz), 7.18-7.73 (13H,
m). IR (KBr): 3335, 2934, 2868, 1604, 1444, 1275, 104
7, 752 cm ^-1 .

Reference Example 26. Methanesulfonic acid 3- [6-({2-
[(E) -2-Phenylethenyl] -1,3-oxazol-4-yl}
Preparation of ( methoxy) -2-naphthyl] propyl 3- [6-[[2-[(E) -2-phenylethenyl] -1,3-oxazole
-4-yl] methoxy] -2-naphthyl] -1-propanol (1.00
g), triethylamine (525 mg) and tetrahydrofuran (30 ml) in a mixture of methanesulfonyl chloride (595 m
g) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and then saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.13 g) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 139-140 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.00-2.20 (2H, m), 2.89 (2H, t,
J = 7.5 Hz), 2.99 (3H, s), 4.26 (2H, t, J = 6.2 Hz),
5.14 (2H, s), 6.96 (1H, d, J = 16.2 Hz), 7.20-7.72
(13H, m). IR (KBr): 3111, 3024, 2943, 1604, 1338, 1165, 96
2,854 cm ^-1 .

Reference Example 27. (5-benzyloxy-2-ho
Preparation of methyl rumilphenoxy) acetate A mixture of 4-benzyloxy-2-hydroxybenzaldehyde (5.82g), methyl bromoacetate (4.10g), potassium carbonate (4.23g) and DMF (50ml) at 90-100 ° C for 1 hour. It was stirred. The reaction solution was poured into water, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-hexane to give the title compound (7.10 g) as colorless needle crystals. Melting point 131-132 [deg.] C. ¹ H-NMR (CDCl ₃ ) δ: 3.81 (3H, s), 4.72 (2H, s), 5.11
(2H, s), 6.40 (1H, d, J = 2.0 Hz), 6.69 (1H, ddd, J =
8.5, 2.0, 0.5 Hz), 7.30-7.50 (5H, m), 7.86 (1H, d,
J = 8.5 Hz), 10.39 (1H, d, J = 0.5 Hz).

Reference Example 28. 6- (benzyloxy) -1-be
Preparation of methyl nzofuran-2-carboxylate Methyl (5-benzyloxy-2-formylphenoxy) acetate (6.90 g), 1,8-diazabicyclo [5.4.0] -7-undecene (5.25 g), and toluene (150 mL The mixture was heated to reflux for 3 hours while azeotropically dehydrating. Ethyl acetate (150 ml) was added to the reaction solution, and the mixture was washed successively with 2N hydrochloric acid and water.
The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 2: 1) to obtain the title compound (3.86 g). Recrystallization from acetone-diisopropyl ester gave colorless prism crystals. Melting point 112-113 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.96 (3H, s), 5.13 (2H, s), 7.03
(1H, dd, J = 8.5, 2.0 Hz), 7.12 (1H, d, J = 2.0 Hz),
7.30-7.50 (6H, m), 7.55 (1H, d, J = 8.5 Hz).

Reference Example 29. [6- (benzyloxy) -1-be
Preparation of Nzofuran-2-yl] methanol Methyl 6- (benzyloxy) -1-benzofuran-2-carboxylate (3.76g) in tetrahydrofuran (40ml)
To this, lithium aluminum hydride (505 mg) was added at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes, water and 2N hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was washed with hexane, and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (3.00 g) as colorless prism crystals. Melting point 92-93 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.84 (1H, br s), 4.72 (2H, br s),
5.11 (2H, s), 6.59 (1H, s), 6.94 (1H, dd, J = 8.5,
2.0 Hz), 7.07 (1H, d, J = 2.0 Hz), 7.25-7.50 (6H,
m).

Reference Example 30. 1- (6-benzyloxy-1-
Preparation of benzofuran-2-yl) methyl-1H-imidazole [6- (benzyloxy) -1-benzofuran-2-yl] methanol (1.20g), 1H-imidazole (480mg), tributylphosphine (1.43g) in acetonitrile Diethyl azodicarboxylate (1.23 g) was added dropwise to the solution (20 ml) at room temperature, and the mixture was stirred for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, chloroform: methanol = 9
After purification with 7: 3), the product was further purified with ethyl acetate-acetone (4: 1) to obtain the title compound (0.23 g). Recrystallization from acetone-diisopropyl ether gave colorless prism crystals. Melting point 99-100 ° C. ¹ H-NMR (CDCl ₃ ) δ: 5.10 (2H, s), 5.19 (2H, s), 6.6
0 (1H, s), 6.95 (1H, dd, J = 8.5, 2.0 Hz), 7.00-7.10
(3H, m), 7.30-7.50 (6H, m), 7.61 (1H, s).

Reference Example 31. 2- (1H-imidazol-1-yl
Preparation of methyl) -1-benzofuran-6-ol 1- [6- (benzyloxy) -1-benzofuran-2-yl] methyl-1H-imidazole (200 mg), 5% palladium on carbon (w
et, 50 mg) and ethanol (10 ml) was catalytically reduced at 1 atm. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain crystals. Recrystallization from acetone-diisopropyl ether gave the title compound (120 mg) as colorless prism crystals. Melting point 191-192 [deg.] C. ¹ H-NMR (DMSO-d ₆ ) δ: 5.33 (2H, s), 6.72 (1H, dd, J =
8.5, 2.0 Hz), 6.74 (1H, s), 6.86 (1H, d, J = 2.0 H
z), 6.91 (1H, t, J = 1.0 Hz), 7.20 (1H, t, J = 1.0 Hz),
7.37 (1H, d, J = 8.5 Hz), 7.74 (1H, br s), 9.54 (1
H, s).

Reference Example 32. (7-methoxyquinoline-3-i
Preparation of methanol ) A tetrahydrofuran solution (50 ml) of ethyl 7-methoxyquinoline-3-carboxylate (3.00 g) was added dropwise at 0 ° C to a mixture of lithium aluminum hydride (495 mg) and tetrahydrofuran (50 ml). The mixture was stirred at 0 ° C for 30 minutes then washed with water.
(1 ml) was added, and the insoluble material was filtered. The filtrate was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 4: 1) to give the title compound
(1.52 g) was obtained as colorless crystals. Recrystallization from hexane-ethyl acetate gave colorless scale crystals. Melting point 113-114 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.94 (3H, s), 4.87 (2H, s), 7.22
(1H, dd, J = 8.8, 2.2 Hz), 7.41 (1H, d, J = 2.2 Hz),
7.69 (1H, d, J = 8.8 Hz), 8.07 (1H, m), 8.81 (1H, d,
J = 1.8 Hz). IR (KBr): 3214, 2842, 1621, 1423, 1330, 1216, 103
5, 906 cm ^-1 .

Reference Example 33. 3-chloromethyl-7-methoki
Production of shiquinoline (7- methoxyquinolin -3-yl) methanol (1.47 g), a mixture of triethylamine (2.37 g) and ethyl acetate (50 ml), methanesulfonyl chloride (2.68 g) was added dropwise at 0 ° C.,
After stirring at room temperature for 3 hours, the mixture was heated under reflux for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and then saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane: ethyl acetate = 1: 1).
The title compound (940 mg) was obtained. Recrystallization from ethyl acetate-hexane gave colorless needle crystals. Melting point 79-80 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.96 (3H, s), 4.76 (2H, s), 7.23
(1H, dd, J = 8.8, 2.2 Hz), 7.43 (1H, d, J = 2.2 Hz),
7.71 (1H, d, J = 8.8 Hz), 8.09 (1H, d, J = 2.2 Hz), 8.
85 (1H, d, J = 2.2 Hz). IR (KBr): 2950, 1618, 1492, 1427, 1226, 1162, 102
5, 844 cm ^-1 .

Reference Example 34. 3- (1H-imidazol-1-y
Lumethyl) -7-methoxyquinoline 1H-Imidazole (355 mg) in DMF (15 ml) at room temperature
60% Sodium hydride (225 mg) was added, and the mixture was stirred at room temperature for 1.5 hr, and then at the same temperature, 3-chloromethyl-7-methoxyquinoline.
(900 mg) was added, and the mixture was stirred at 80 ° C for 2 hr. Water was poured into the reaction solution, which was extracted with ethyl acetate. The extract was washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate-methanol (10: 1) to give the title compound (680 mg) as brown crystals. Recrystallization from ethyl acetate-hexane. The melting point was 108-109 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.96 (3H, s), 5.30 (2H, s), 6.95.
(1H, s), 7.14 (1H, s), 7.23 (1H, dd, J = 8.8, 2.6 H
z), 7.43 (1H, d, J = 2.6 Hz), 7.63-7.68 (2H, m), 7.7
8 (1H, m), 8.74 (1H, d, J = 2.2 Hz). IR (KBr): 3092, 3022, 1622, 1498, 1211, 1078, 103
0, 841 cm ^-1 .

Reference Example 35. 3- (1H-imidazol-1-y
Preparation of Lumethyl) quinolin-7-ol A mixture of 3- (1H-imidazol-1-ylmethyl) -7- methoxyquinoline (480 mg) and 47% hydrobromic acid (30 ml) was heated under reflux for 8 hours. The reaction mixture was basified by adding saturated aqueous sodium hydrogen carbonate, and the precipitated crystals were collected by filtration to give the title compound (310 mg) as dark brown crystals. Recrystallization from methanol gave colorless prism crystals. Melting point 260-262 (dec) ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 5.34 (2H, s), 6.91 (1H, s),
7.16 (1H, dd, J = -8.8, 2.3 Hz), 7.22-7.25 (2H, m),
7.78 (1H, d, J = 8.8 Hz), 7.82 (1H, s), 8.06 (1H,
s), 8.73 (1H, d, J = 2.3 Hz), 10.19 (1H, s) .IR (KBr): 3115, 1622, 1473, 1269, 1222, 1093, 839,
663 cm ^-1 .

Reference Example 36. [1- (2-aminoethyl) -1H-I
Preparation of imidazol-2-yl] methanol (i) Preparation of benzyl 2-[(2-hydroxymethyl) -1H-imidazol-1-yl] ethylcarbamate Benzyl N- (2-hydroxyethyl) carbamate (12.0
g), triethylamine (13.0 ml) and methanesulfonyl chloride (5.7 ml) were used to carry out the same reaction as in Example 51- (vii) to obtain a crude mesylate. The crude mesylate,
Example 46- (ii) using 2-formylimidazole (6.4 g), sodium iodide (10.9 g) and potassium carbonate (10.1 g) and sodium borohydride (1.1 g).
The same reaction as in i) was performed to give the title compound (6.3 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.56 (2H, q, J = 6.0 Hz), 4.15
(2H, t, J = 5.8 Hz), 4.60 (2H, s), 5.08 (2H, s),
5.65 (1H, br s), 6.82 (1H, br s), 6.86 (1H, br s),
7.32 (5H, s). IR (KBr): 3300, 1694, 1549, 1262, 1
030 cm ^-1 .

(Ii) Preparation of [1- (2-aminoethyl) -1H-imidazol-2-yl] methanol Benzyl 2-[(2-hydroxymethyl) -1H-imidazole-1
-Yl] ethyl carbamate (3.5 g) in methanol (80
(10 ml) palladium carbon (0.5 g) was added to the solution, and the mixture was stirred under a hydrogen atmosphere at room temperature for 15 hours. After the reaction was completed, the reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure.
(1.4 g) was obtained as a pale yellow oil. ¹ H-NMR (CD ₃ OD) δ: 2.99 (2H, t, J = 6.2 Hz), 4.11
(2H, t, J = 6.2 Hz), 4.63 (2H, s), 6.91 (1H, d, J
= 1.0 Hz), 7.13 (1H, d, J = 1.0 Hz). IR (KBr): 309
0, 1590, 1495, 1289, 1026 cm ^-1 .

Reference Example 37. 1-bromo-4- (4-methoxy-3-
Methylphenyl) -2-butanone and 3-bromo-4- (4-meth)
Production of xy-3-methylphenyl) -2-butanone (i) Production of 4- (4-methoxy-3-methylphenyl) -2-butanone 4-methoxy-3-methylbenzaldehyde (133 g), ethyl acetoacetate A solution of (133 ml), piperidine (9.1 ml) and p-tolylacetic acid (3.0 g) in cyclohexane (1 L) was heated under reflux for 16 hours using a Dean-Stark apparatus. After cooling to room temperature, the reaction solution was washed with saturated sodium hydrogen carbonate and water, respectively. After extraction with ether, the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The obtained compound was dissolved in ethanol (1 L), 10% palladium carbon (10 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hr. The reaction solution was filtered, 5N-HCl (400 ml) was added to the obtained filtrate, and the mixture was heated under reflux. After cooling, ethanol was distilled off under reduced pressure. The residue was extracted with ether, and the organic layer was washed with saturated sodium hydrogen carbonate and water, respectively, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 3) to obtain the title compound (170 g) as a pale yellow oily liquid. ¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.19 (3H, s), 2.6
8-2.83 (4H, m), 3.79 (3H, s), 6.72 (1H, d, J = 8.7
Hz), 6.94 (1H, s), 6.95 (1H, d, J = 8.7 Hz) .IR (KBr): 2949, 1716, 1506, 1253, 1134, 1033 c
m ^-1 .

(Ii) Production of 1-bromo-4- (4-methoxy-3-methylphenyl) -2-butanone and 3-bromo-4- (4-methoxy-3-methylphenyl) -2-butanone 4 -(4-Methoxy-3-methylphenyl) -2-butanone (161 g)
A solution of bromine (147 g) in methanol (500 ml) was added dropwise at 0 ° C. to the solution of methanol in (500 ml) over 1.5 hours. After the dropping was completed, the mixture was stirred at 0 ° C. for 1 hour, water was added, and the mixture was further stirred at room temperature for 16 hours. After extraction with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 6 to 1: 3), and a mixture of two isomers of the title compound (mixing ratio, 1-bromo form: 3-bromo form) = 3: 1, 174 g) was obtained as a pale yellow oily liquid. 1-Bromo-4- (4-methoxy-3-methylphenyl) -2-butanone: ¹
H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 2.83-2.97 (4H, m),
3.80 (3H, s), 3.84 (2H, s), 6.74 (1H, d, J = 8.4 H
z), 6.94-6.99 (2H, m). 3-Bromo-4- (4-methoxy-3-methylphenyl) -2-butanone: ¹
H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 2.30 (3H, s), 3.03-
3.38 (2H, m), 3.80 (3H, s), 4.42 (1H, t, J = 7.8 H
z), 6.74 (1H, d, J = 8.4 Hz), 6.94-6.99 (2H, m) .IR (KBr): 2947, 1716, 1610, 1506, 1253, 1134 c
m ^-1 .

Reference Example 38. 4- (2- (4- (3-chloropropoxy
Si) -3-methylphenyl) ethyl) -2-((E) -2- (2-fluoro-
4- (trifluoromethyl) phenyl) ethenyl) -1,3-oxy
Production of sazole (i) 2-methyl-4- (2- (2-((E) -2- (4- (trifluoromethyl) phenyl) ethenyl) -1,3-oxazol-4-yl) ethyl) Production of phenol 1-bromo-4- (4-methoxy-3-methylphenyl) -2-butanone and 3-bromo-4- (4-methoxy-3-methylphenyl) -2-butanone mixture (24.1 g, Mixing ratio, 1-bromo form: 3-bromo form = 3: 1), (2E) -3- (2-fluoro-4- (trifluoromethyl))
Toluene (100 ml) of phenyl) acrylamide (13.8 g)
The solution was heated to reflux for 16 hours using the Dean-Stark apparatus. After cooling to room temperature, saturated sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 4). Dissolve the obtained compound in dichloromethane (100 ml), and under a nitrogen atmosphere.
Boron tribromide 4.2M dichloromethane solution (9.6 ml) was added at 0 ° C. After stirring at room temperature for 4 hours, water was added and the mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography.
The product was purified with (eluate, ethyl acetate: hexane = 1: 3) to obtain the title compound (5.45 g) as a pale yellow solid powder. ¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 2.79-2.93 (4H,
m), 4.75 (1H, s), 6.67-7.15 (4H, m), 7.59-7.70 (5
H, m). IR (KBr): 3130, 1508, 1429, 1332, 1265, 1132 c
m ^-1 .

(Ii) 4- (2- (4- (3-chloropropoxy) -3-methylphenyl) ethyl) -2-((E) -2- (2-fluoro-4- (trifluoromethyl)) Preparation of (phenyl) ethenyl) -1,3-oxazole 2-methyl-4- (2- (2- (2-((E) -2- (4- (trifluoromethyl) phenyl) ethenyl) -1,3-oxazole- 4-yl) ethyl) phenol (2.5 g), 1-bromo-3-chloropropane (1.26 m
Potassium carbonate (1.76 g) was added to a solution of l) in acetone (50 ml), and the mixture was heated under reflux for 24 hours. After cooling to room temperature, water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 3) to give the title compound (1.86 g) as a colorless white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s), 2.20-2.31 (2H,
m), 2.80-2.93 (4H, m), 3.77 (2H, t, J = 6.2 Hz),
4.09 (2H, t, J = 6.0 Hz), 6.73-7.16 (4H, m), 7.32-
7.71 (5H, m). IR (KBr): 2928, 2253, 1793, 1504, 1331, 1132, 912
cm ^-1 .

Reference Example 39. 2-((E) -2- (4-bromo-2-full
Orophenyl) ethenyl) -4- (2- (4- (3-chloropropoxy)
Si) -3-methylphenyl) ethyl) -1,3-oxazole
Concrete (i) 2 - ((E) -2- (4-bromo-2-fluorophenyl) ethenyl) -4- (2- (4-methoxy-3-methylphenyl) ethyl) -1,3
Preparation of Oxazole 1-Bromo-4- (4-methoxy-3-methylphenyl) butane-2-
A mixture of one and 3-bromo-4- (4-methoxy-3-methylphenyl) butan-2-one (20 g, mixing ratio, 1-bromo form: 3-bromo form = 3: 1), (2E) -3- (4-Bromo-2-fluorophenyl) acrylamide (21.6 g), using toluene (200 ml), the same cyclization reaction as in Reference Example 38- (i) was performed to give the title compound (11.3 g).
Got ¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s), 2.78-2.95 (4H,
m), 3.81 (3H, s), 6.74 (1H, d, J = 9.0 Hz), 6.95-
7.04 (3H, m), 7.24-7.53 (5H, m). IR (KBr): 2951, 2253, 1705, 1504, 1253, 912 cm ^-1 .

(Ii) 4- (2- (2-((E) -2- (4-bromo-2-fluorophenyl) ethenyl) -1,3-oxazol-4-yl) ethyl) -2-methyl Production of phenol 2-((E) -2- (4-bromo-2-fluorophenyl) ethenyl) -4-
Example using (2- (4-methoxy-3-methylphenyl) ethyl) -1,3-oxazole (11.3 g), dichloromethane (30 ml), boron tribromide 4.2M dichloromethane solution (78 ml) 38-
The same demethylation reaction as in (i) was performed to give the title compound (5.0 g) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 2.77-2.92 (4H,
m), 5.00 (1H, s), 6.69 (1H, d, J = 8.0 Hz), 6.85-
7.05 (3H, m), 7.25-7.55 (5H, m). IR (KBr): 3152, 1599, 1508, 1265, 1217, 1118 c
m ^-1 .

(Iii) 2-((E) -2- (4-bromo-2-fluorophenyl) ethenyl) -4- (2- (4- (3-chloropropoxy) -3-methylphenyl) ethyl) Preparation of -1,3-oxazole 4- (2- (2-((E) -2- (4-bromo-2-fluorophenyl) ethenyl) -1,3-oxazol-4-yl) ethyl) -2 -Methylphenol (2.0 g), acetone (50 ml), potassium carbonate (1.38
g) and 1-bromo-3-chloropropane (1.0 ml) were used to carry out the same reaction as in Reference Example 38- (ii) to obtain the title compound (2.33 g) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 2.19-2.31 (2H,
m), 2.77-2.93 (4H, m), 3.77 (2H, t, J = 6.6 Hz),
4.09 (2H, t, J = 5.8 Hz), 6.75 (1H, d, J = 8.2Hz),
6.94-7.06 (3H, m), 7.25-7.55 (5H, m). IR (KBr): 2928, 2253, 1817, 1599, 1504, 1251 c
m ^-1 .

Example 1. 1- (3- {4-[(2-{(E) -2- [4- (
Fluoromethyl) phenyl] ethenyl} -1,3-oxazole
-4-yl) methoxy] phenoxy} propyl) -1H-1,2,3-to
Manufacture of riazole

[Chemical 80] (i) 4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl]
Ethenyl} -1,3-oxazol-4-yl) methoxy] phenol production p-hydroquinone (0.77 g) dimethylformamide
(15 ml) 60% oily sodium hydride under ice cooling
(0.34 g) was added. After stirring for 30 minutes at room temperature, under ice cooling, 4
-Chloromethyl-2-[(E) -2- (4-trifluoromethylphenyl) ethenyl] -1,3-oxazole (2.0 g) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, add water to the reaction solution,
It was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 2) to give the title compound (1.4
g) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 4.97 (2H, s), 6.77-6.88 (4H,
m), 7.02 (1H, d, J = 16.5Hz), 7.56 (1H, d, J = 16.5
Hz), 7.64 (4H, s), 7.68 (1H, s). IR (KBr): 3137, 1516, 1327, 1240, 1109 cm ^-1 .

(Ii) 1- (3- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] Preparation of phenoxy} propyl) -1H-1,2,3-triazole 4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazole-4- Ile) methoxy] phenol
To a solution of (0.55 g) in dimethylformamide (2 ml), 60% oily sodium hydride (72 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, 1- (chloropropyl) -1H- under ice cooling.
1,2,3-Triazole (0.22 g) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added to the reaction solution, the precipitate was dissolved in ethyl acetate, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethyl acetate-hexane to give the title compound (0.38 g)
Was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.35-2.42 (2H, m), 3.91 (2H, t,
J = 5.7 Hz), 4.63 (2H, t, J = 6.9 Hz), 4.99 (2H, s),
6.83 (2H, d, J = 9.0 Hz), 6.94 (2H, d, J = 9.0 Hz),
7.02 (1H, d, J = 16.5 Hz), 7.55 (1H, d, J = 16.5 H
z), 7.55 (1H, s), 7.64 (4H, s), 7.68 (1H, s), 7.70
(1H, s). IR (KBr): 1507, 1329, 1236, 1221, 1163 cm ^-1 .

Example 2. 1- [2-({4-[(2-{(E) -2- [4- (
Lifluoromethyl) phenyl] ethenyl} -1,3-oxazol
Lu-4-yl) methoxy] benzyl} oxy) ethyl] -1H-1,2,
Production of 3-triazole

[Chemical 81] (i) 4-{[4- (dimethoxymethyl) phenoxy] methyl} -2-
Preparation of ((2- (E) -2- [4- (trifluoromethyl) phenyl] ethenyl) -1,3-oxazole 4- (dimethoxymethyl) phenol (5.9 g), 4-chloromethyl-2- [ Same as Example 1- (i) using (E) -2- (4-trifluoromethylphenyl) ethenyl] -1,3-oxazole (10.0 g) and 60% oily sodium hydride (1.8 g) The title compound (6.1 g) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.32 (6H, s), 5.06 (2H, s), 5.3
6 (1H, s), 6.97-7.06 (3H, m), 7.39 (2H, d, J = 8.8
Hz), 7.56 (1H, d, J = 16.4 Hz), 7.64 (4H, s), 7.69
(1H, s). IR (KBr): 1512, 1327, 1252, 1127, 1069 cm ^-1 .

(Ii) Preparation of 4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] benzylaldehyde 4- {[4- (dimethoxymethyl) phenoxy] methyl} -2-{(2-
(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl) -1,
3-Oxazole (2.0 g) in tetrahydrofuran (20 m
l) To the solution, add 90% formic acid aqueous solution (10 ml) at 60 ° C.
Stir for 2 hours. After completion of the reaction, 10% aqueous sodium hydroxide solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 2) to obtain the title compound (1.4 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 5.13 (2H, s), 7.02 (1H, d, J = 1
6.5 Hz), 7.12 (2H, d, J = 8.7 Hz), 7.57 (1H, d, J = 1
6.5 Hz), 7.65 (4H, s), 7.73 (1H, s), 7.87 (2H, d,
J = 8.7 Hz), 9.91 (1H, s). IR (KBr): 1692, 1601, 1321, 1179, 1067 cm ^-1 .

(Iii) Preparation of 4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} methanol 4 -[(2-{(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] benzyl aldehyde (2.0 g) in methanol (20 ml) Sodium borohydride (100 mg) was added to the mixture under ice cooling, and the mixture was stirred for 30 minutes. After completion of the reaction, water was added to the reaction solution, the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, washed with saturated brine,
It was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure,
The residue was subjected to silica gel column chromatography (eluent,
Purified with ethyl acetate: hexane = 1: 1) to give the title compound
(1.8 g) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 4.64 (1H, d, J = 5.7 Hz), 5.05
(2H, s), 6.98-7.04 (3H, m), 7.32 (2H, d, J = 9.0 H
z), 7.55 (1H, d, J = 16.5 Hz), 7.64 (4H, s) 7.69 (1
H, s). IR (KBr): 3218, 1609, 1586, 1514, 1323 cm ^-1 .

(Iv) 4-[(4-{[2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] methyl} phenoxy) methyl]
-2-{(E) -2- [4- (trifluoromethyl) phenyl] vinyl}-
Preparation of 1,3-oxazole 4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl] methanol (1.0 g), 2- (2-bromoethoxy) tetrahydro-2H-pyran (0.77 g) and 60% oily sodium hydride (160 mg) were used to carry out the same reaction as in Example 1- (i) to give the title compound. (0.7 g) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.52-1.84 (6H, m), 3.47-3.56 (2
H, m), 3.64-3.73 (2H, m), 3.83-3.94 (2H, m), 4.53
(2H, s), 4.65 (1H, t, J = 3.0 Hz), 5.04 (2H, s) 6.95
-7.05 (3H, m), 7.30 (2H, d, J = 10.0 Hz), 7.55 (1H,
d, J = 16.5 Hz), 7.63 (4H, s) 7.69 (1H, s).

(V) 2-({4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl)
Preparation of [methoxy] benzyl} oxy) ethanol 4-[(4-{[2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] methyl} phenoxy) methyl] -2-{(E) -2- [4 1-N- (trifluoromethyl) phenyl] vinyl} -1,3-oxazole (1.0 g) in tetrahydrofuran (20 ml)
Hydrochloric acid (10 ml) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 10% aqueous sodium hydroxide solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate:
Purification with hexane = 1: 2) gave the title compound (0.7 g) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 3.57-3.61 (2H, m), 3.72-3.80 (2
H, m), 4.51 (2H, s), 5.05 (2H, s), 6.97-7.06 (3H,
m), 7.29 (2H, d, J = 8.8 Hz), 7.55 (1H, d, J = 16.6 H
z), 7.64 (4H, s) 7.69 (1H, s). IR (KBr): 1613, 1331, 1256, 1128, 1071 cm ^-1 .

(Vi) 4-({4-[(2-iodoethoxy) methyl]]
Preparation of phenoxy} methyl) -2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazole 2-({4-[(2-{(E) -2 -[4- (trifluoromethyl) phenyl]
Ethenyl} -1,3-oxazol-4-yl) methoxy] benzyl} oxy) ethanol (0.4 g) in methylene chloride (10 ml)
Triethylamine (0.24 ml) and methanesulfonyl chloride (0.1 ml) were added to the solution at 0 ° C., and the mixture was stirred for 10 minutes. After completion of the reaction, water was added to the reaction solution to separate the organic layer,
The extract was washed with 5% aqueous sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of mesylate. Sodium iodide (0.8 g) was added to a tetrahydrofuran (10 ml) solution of this product, and the mixture was heated under reflux for 3 hours. After completion of the reaction, water and ethyl acetate were added to the reaction solution, the organic layer was separated, washed with water and 10% hypo-water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the title compound (0.
42 g) was obtained as pale yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.27 (2H, t, J = 6.9 Hz), 3.72
(2H, t, J = 6.6 Hz), 4.52 (2H, s), 5.05 (2H, s), 6.
97-7.04 (3H, m), 7.26-7.32 (2H, m), 7.56 (1H, d, J =
16.8 Hz), 7.64 (4H, s) 7.69 (1H, s).

(Vii) 1- [2-({4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazole-4-
Il) methoxy] benzyl} oxy) ethyl] -1H-1,2,3-triazole production 1H-1,2,3-triazole (73 mg) in 2-methyl-2-butanol (3 ml), Sodium hydroxide (51 mg) was added, and the mixture was heated under reflux for 1 hr. Then 4-({4-[(2-iodoethoxy) methyl] phenoxy} methyl) -2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazole
Add a solution of (0.4 g) in 2-methyl-2-butanol (1 ml),
The mixture was heated under reflux for another 3 hours. After completion of the reaction, water was added to the reaction solution, extracted with toluene, washed with saturated saline, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 1) to give the title compound (0.3
g) was obtained as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.83 (2H, t, J = 5.4 Hz), 4.44
(2H, s), 4.59 (2H, t, J = 4.8 Hz), 5.04 (2H, s), 6.
94-7.21 (5H, m), 7.56 (1H, d, J = 16.4 Hz), 7.64 (4
H, s) 7.69 (3H, s). IR (KBr): 1611, 1584, 1514, 1329, 1111 cm ^-1 .

Example 3. N- [3- (1H-1,2,3-triazole
-1-yl) propyl] -4-[(2-{(E) -2- [4- (trifluorometh
(Cyl) phenyl] ethenyl} methoxy) -1,3-oxazole-
Production of 4-yl] methoxy] aniline

[Chemical formula 82] (i) Preparation of benzyl 4-hydroxyphenylcarbamate Ether of 4-hydroxyaniline (7.6 g) (500 ml)
Benzyl chloroformate (5 ml) was added to the solution, and the mixture was stirred at room temperature for 10
Stir for hours. After completion of the reaction, water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline solution, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate:
Purification with hexane = 1: 1) gave the title compound (6.0 g) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 5.08 (1H, s), 5.19 (2H, s), 6.5
4 (1H, br s), 6.72-6.80 (2H, m), 7.19-7.26 (2H,
m), 7.33-7.38 (5H, m) .IR (KBr): 3304, 1699, 1541, 1522, 1241 cm ^-1 .

(Ii) Preparation of benzyl 4- (methoxymethoxy) phenylcarbamate Benzyl 4-hydroxyphenylcarbamate (5.2 g)
Potassium carbonate (4.6 g) and chloromethyl methyl ether (2 ml) to an acetone (100 ml) solution of
Stir for 1 hour. After completion of the reaction, water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline solution, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate:
Purification with hexane = 1: 5) gave the title compound (4.4 g) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 3.47 (3H, s), 5.13 (2H, s), 5.1
9 (2H, s), 6.60 (1H, br s), 6.96-7.02 (2H, m), 7.2
6-7.41 (7H, m). IR (KBr): 1722, 1699, 1541, 1508, 1235 cm ^-1 .

(Iii) Preparation of benzyl 3-chloropropyl [4- (methoxymethoxy) phenyl] carbamate Benzyl 4- (methoxymethoxy) phenylcarbamate
To a solution of (2.0 g) in dimethylformamide (20 ml) was added 60% oily sodium hydride (0.36 g) under ice cooling. After stirring at room temperature for 30 minutes, 1-bromo-3-chloropropane (0.9 ml) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added to the reaction solution, the precipitate was dissolved in ethyl acetate, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate:
Purification with hexane = 1: 3) gave the title compound (2.4 g) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.98-2.05 (2H, m), 3.48 (3H,
s), 3.52 (2H, t, J = 6.3Hz), 3.79 (2H, t, J = 6.9 H
z), 5.13 (2H, br s), 5.17 (2H, s), 7.00-7.09 (4H,
m), 7.29 (5H, m).

(Iv) Preparation of benzyl 4- (methoxymethoxy) phenyl [3- (1H-1,2,3-triazol-1-yl) propyl] carbamate 1H-1,2,3-triazole (0.29 g) Sodium hydroxide (0.17 mg) and sodium iodide (0.4 g) were added to a 2-methyl-2-butanol (2 ml) solution of and the mixture was heated under reflux for 1 hour.
Then, a solution of benzyl 3-chloropropyl [4- (methoxymethoxy) phenyl] carbamate (1.0 g) in 2-methyl-2-butanol (2 ml) was added to the reaction solution, and the mixture was heated under reflux for 3 hours. After completion of the reaction, water was added to the reaction solution, extracted with toluene, washed with saturated saline, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 1) to obtain the title compound (0.9 g) as pale yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.13-2.19 (2H, m), 3.49 (3H,
s), 3.71 (2H, t, J = 6.9Hz), 4.40 (2H, t, J = 6.9 H
z), 5.13 (2H, s), 5.17 (2H, s), 7.01-7.06 (5H, m),
7.23-7.33 (5H, m), 7.63 (1H, s). IR (KBr): 1703, 1694, 1607, 11514, 1071 cm ^-1 .

(V) Benzyl 4-hydroxyphenyl [3- (1H
Preparation of -1,2,3-triazol-1-yl) propyl] carbamate Benzyl 4- (methoxymethoxy) phenyl [3- (1H-1,2,3-
Triazol-1-yl) propyl] carbamate (0.2 g)
In tetrahydrofuran (4 ml), 1N hydrochloric acid (1 ml)
An aqueous solution was added, and the mixture was stirred at room temperature for 24 hours. After the reaction,
The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution under ice cooling, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.17 g) as pale-yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.10-2.18 (2H, m), 3.68 (2H, t,
J = 6.6 Hz), 4.37-4.39 (2H, m), 5.11 (2H, br s), 6.
82-6.85 (2H, m), 6.94 (2H, br s), 7.11-7.42 (6H,
m), 7.62 (1H, s). IR (KBr): 3123, 1725, 1626, 1514, 1223 cm ^-1 .

(Vi) Benzyl 3- (1H-1,2,3-triazole-
Preparation of 1-yl) propyl {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} carbamate Benzyl 4-Hydroxyphenyl [3- (1H-1,2,3-triazol-1-yl) propyl] carbamate (0.17 g), 4-chloromethyl-2-[(E) -2- (4-trifluoromethyl) (Phenyl)
Ethenyl] -1,3-oxazole (0.14 g) and 60% oily sodium hydride (21 mg) were used to carry out the same reaction as in Example 1- (i) to give the title compound (0.16 g) as pale yellow crystals. Obtained as a powder. ¹ H-NMR (CDCl ₃ ) δ: 2.12-2.21 (2H, m), 3.71 (2H, t,
J = 7.0 Hz), 4.41 (2H, t, J = 6.0 Hz), 5.04 (2H, s),
5.13 (2H, s), 6.96-7.11 (6H, m), 7.26-7.35 (6H,
m), 7.57 (1H, t, J = 16.6 Hz), 7.64 (4H, s), 7.71
(1H, s). IR (KBr): 1698, 1514, 1325, 1167, 1132 cm ^-1 .

(Vii) N- [3- (1H-1,2,3-triazol-1-yl) propyl] -4-[(2-{(E) -2- [4- (trifluoromethyl))
Phenyl] ethenyl} methoxy) -1,3-oxazol-4-yl] methoxy] aniline preparation Benzyl 3- (1H-1,2,3-triazol-1-yl) propyl
{4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} carbamate (0.1 g) on 6N hydrochloric acid (2 ml) aqueous solution was added, and the mixture was heated under reflux for 40 minutes. After completion of the reaction, sodium hydroxide was added to the reaction solution under ice cooling to neutralize it, and the precipitate was collected by filtration. The filtered material was washed with water and diisopropyl ether and recrystallized from ethyl acetate-hexane to obtain the title compound (76 mg) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.16-2.25 (2H, m), 3.13 (2H, t,
J = 6.2 Hz), 4.54 (2H, t, J = 6.6 Hz), 4.97 (2H, s),
6.57 (2H, d, J = 8.8 Hz), 6.88 (2H, d, J = 8.8 Hz),
7.01 (1H, d, J = 16.4 Hz), 7.54 (1H, d, J = 16.4 H
z), 7.56 (1H, s), 7.64 (4H, s), 7.67 (1H, s), 7.73
(1H, s). IR (KBr): 3310, 3142, 1514, 1327, 1125 cm ^-1 .

Example 4. N- [3- (1H-1,2,3-triazole
-1-yl) propyl] -N- {4-[(2-{(E) -2- [4- (trifluoro
(Methyl) phenyl] ethenyl} -1,3-oxazol-4-yl)
Methoxy] phenyl} acetamide production

[Chemical 83] N- [3- (1H-1,2,3-triazol-1-yl) propyl] -4-[(2
-{(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl}
To a solution of (methoxy) -1,3-oxazol-4-yl] methoxy] aniline (0.2 g) in methylene chloride (3 ml) was added pyridine (0.07 ml) and acetic anhydride (0.06 ml) at 0 ° C, and the mixture was stirred for 1 hour. did. After completion of the reaction, 10% hydrochloric acid aqueous solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline solution, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 10: 1) to give the title compound (0.22
g) was obtained as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.84 (3H, s), 2.09-2.21 (2H,
m), 3.76 (2H, t, J = 6.6Hz), 4.45 (2H, t, J = 6.8 H
z), 5.06 (2H, s), 6.99-7.12 (5H, m), 7.57 (1H, d, J
= 16.4 Hz), 7.65 (4H, s), 7.69 (1H, s), 7.71 (1H,
s), 7.73 (1H, s). IR (KBr): 3086, 1651, 1508, 1321, 1215 cm ^-1 .

Example 5. 2,2,2-trifluoro-N- [3- (1H
-1,2,3-triazol-1-yl) propyl] -N- {4-[(2-{(E)
-2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-
Of oxazol-4-yl) methoxy] phenyl} acetamide
Manufacturing

[Chemical 84] N- [3- (1H-1,2,3-triazol-1-yl) propyl] -4-[(2
-{(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl}
Methoxy) -1,3-oxazol-4-yl] methoxy] aniline (0.15 g) in methylene chloride (3 ml) at 0 ° C pyridine (0.05 ml), trifluoroacetic anhydride (0.07 ml)
Was added and stirred for 1 hour. After completion of the reaction, 10% hydrochloric acid aqueous solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline solution, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 10: 1) to obtain the title compound (0.12 g) as a pale yellow crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 2.19-2.33 (2H, m), 3.78 (2H, t,
J = 7.4 Hz), 4.46 (2H, t, J = 6.6 Hz), 5.06 (2H, s),
6.98-7.15 (6H, m), 7.57 (1H, d, J = 16.4 Hz), 7.65
(4H, s), 7.71 (1H, s), 7.72 (1H, s). IR (KBr): 1694, 1510, 1325, 1208, 1157 cm ^-1 .

Example 6. 1- [3-({4-[(2-{(E) -2- [4- (
Lifluoromethyl) phenyl] ethenyl} -1,3-oxazol
Lu-4-yl) methoxy] phenyl} thio) propyl] -1H-1,2,
Production of 3-triazole

[Chemical 85] (i) Preparation of 4-[(3-chloropropyl) thio] phenol 1-Brom-3 was added to a solution of 4-hydroxythiophenol (5.0 g) and triethylamine (7.2 ml) in ethanol (60 ml) under ice cooling. -Add chloropropane (3.9 ml) and add 2
Stir for hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 10) to give the title compound (4.6
g) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.97-2.05 (2H, m), 2.95 (2H, t,
J = 6.6 Hz), 3.65 (2H, t, J = 6.3 Hz), 6.79 (2H, d,
J = 9.0 Hz), 7.32 (2H, d, J = 9.0 Hz). IR (KBr): 3216, 1599, 1584, 1495, 1219 cm ^-1 .

(Ii) Preparation of 1-[(3-chloropropyl) thio] -4- (methoxymethoxy) benzene 4-[(3-chloropropyl) thio] phenol (1.0 g), chloromethyl methyl ether (0.56 ml), potassium carbonate
The same reaction as in Example 3- (ii) was performed using (1.4 g) to give the title compound (0.99 g) as a pale-yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.97-2.06 (2H, m), 2.98 (2H, t,
J = 6.6 Hz), 3.48 (3H, s), 3.65 (2H, t, J = 6.2 Hz),
5.16 (2H, s), 6.98 (2H, d, J = 9.2 Hz), 7.34 (2H,
d, J = 9.2 Hz). IR (KBr): 1593, 1493, 1235, 1154, 9
99 cm ^-1 .

(Iii) Preparation of 1- (3-{[4- (methoxymethoxy) phenyl] thio} propyl) -1H-1,2,3-triazole 1H-1,2,3-triazole (0.21 g) , Sodium hydroxide (0.12 g), sodium iodide (0.3 g) and 1-[(3-
Chloropropyl) thio] -4- (methoxymethoxy) benzene (0.5 g) was used to perform the same reaction as in Example 3- (iii) to obtain the title compound (0.5 g) as pale yellow crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 2.13-2.23 (2H, m), 2.80 (2H, t,
J = 6.9 Hz), 3.48 (3H, s), 4.53 (2H, t, J = 6.9 Hz),
5.17 (2H, s), 6.98 (2H, d, J = 9.2 Hz), 7.34 (2H,
d, J = 9.2 Hz), 7.52 (1H, s), 7.70 (1H, s) .IR (KBr): 1493, 1235, 1154, 1078, 997 cm ^-1 .

(Iv) Preparation of 4-{[3- (1H-1,2,3-triazol-1-yl) propyl] thio} phenol 1- (3-{[4- (methoxymethoxy) phenyl] thio } Propyl)
-1H-1,2,3-triazole (0.35 g), 1N hydrochloric acid (2 ml)
The same reaction as in Example 3- (iv) was performed using an aqueous solution to obtain the title compound (0.29 g) as a pale yellow crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 2.12-2.21 (2H, m), 2.77 (2H, t,
J = 6.9 Hz), 4.53 (2H, t, J = 6.9 Hz), 6.84 (2H, d,
J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.53 (1H, s),
7.71 (1H, s). IR (KBr): 3129, 1582, 1497, 1269, 1
221 cm ^-1 .

(V) 1- [3-({4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy ] Phenyl} thio) propyl] -1H-1,2,3-triazole Preparation 4-{[3- (1H-1,2,3-triazol-1-yl) propyl] thio}
Phenol (0.16 g), 4-chloromethyl-2-[(E) -2- (4-
Trifluoromethylphenyl) ethenyl] -1,3-oxazole (0.2 g) and 60% oily sodium hydride (30 mg) were used to carry out the same reaction as in Example 1- (i) to give the title compound.
(0.24 g) was obtained as a white crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 2.11-2.25 (2H, m), 2.80 (2H, t,
J = 7.0 Hz), 4.53 (2H, t, J = 6.6 Hz), 5.03 (2H, s),
6.95 (2H, d, J = 8.8 Hz), 7.02 (1H, d, J = 16.4 H
z), 7.35 (2H, d, J = 8.8 Hz), 7.51 (1H, d, J = 0.8 H
z), 7.56 (1H, d, J = 16.4 Hz), 7.64 (4H, s), 7.70 (2
H, s) .IR (KBr): 1495, 1323, 1177, 1138, 1069 cm ^-1 .

Example 7. 1- (3-{[4-({2-[(E) -2- (2,4-di
(Fluorophenyl) ethenyl] -1,3-oxazol-4-i
Ru} methoxy) phenyl] thio} propyl) -1H-1,2,3-tri
Manufacture of azoles

[Chemical 86] 4-{[3- (1H-1,2,3-triazol-1-yl) propyl] thio}
Phenol (0.16 g), 4-chloromethyl-2-[(E) -2- (2,4-
Difluorophenyl) ethenyl] -1,3-oxazole (0.1
7 g) and 60% oily sodium hydride (30 mg) were used to carry out the same reaction as in Example 1- (i) to give the title compound (0.
25 g) was obtained as a pale yellow crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 2.11-2.24 (2H, m), 2.80 (2H, t,
J = 7.0 Hz), 4.53 (2H, t, J = 7.0 Hz), 5.02 (2H, s),
6.81-7.02 (6H, m), 7.31-7.39 (2H, m), 7.48-7.56
(2H, m), 7.64-7.69 (2H, m). IR (KBr): 1495, 1281, 1246, 1140, 1088 cm ^-1 .

Example 8. 1- [3-({4-[(2-{(E) -2- [4- (
Lifluoromethyl) phenyl] ethenyl} -1,3-oxazol
Lu-4-yl) methoxy] phenyl} sulfonyl) propyl] -1
Production of H-1,2,3-triazole

[Chemical 87] (i) 1- (3-{[4- (methoxymethoxy) phenyl] sulfonyl}
Propyl) -1H-1,2,3-triazole preparation 1- (3-{[4- (methoxymethoxy) phenyl] thio} propyl)
-1H-1,2,3-triazole (0.48 g) in methylene chloride (20
ml) solution at 0 ° C with metachloroperbenzoic acid (70%, 1.1%).
g) was added and stirred for 1 hour. After the reaction is complete, add 10%
Aqueous sodium hydroxide solution was added, extracted with ethyl acetate,
The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 2).
The title compound (0.52 g) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 2.37-2.47 (2H, m), 3.04 (2H, t,
J = 7.4 Hz), 3.49 (3H, s), 4.60 (2H, t, J = 6.6 Hz),
5.25 (2H, s), 7.18 (2H, d, J = 9.2 Hz), 7.63 (1H,
s), 7.72 (1H, s), 7.80 (2H, d, J = 9.2 Hz). IR (KBr): 1593, 1291, 1144, 1082, 980 cm ^-1 .

(Ii) Preparation of 4-{[3- (1H-1,2,3-triazol-1-yl) propyl] sulfonyl} phenol 1- (3-{[4- (methoxymethoxy) phenyl] sulfonyl } Propyl) -1H-1,2,3-triazole (0.52 g), 1N hydrochloric acid
The same reaction as in Example 3- (iv) was performed using an aqueous solution (2 ml) to give the title compound (0.39 g) as pale yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.18-2.32 (2H, m), 3.16 (2H, t,
J = 7.2 Hz), 4.55 (2H, t, J = 7.0 Hz), 6.91-6.97 (2
H, m), 7.68-7.74 (3H, m), 7.96 (1H, s) .IR (KBr): 3123, 1585, 1449, 1298, 1145 cm ^-1 .

(Iii) 1- [3-({4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazole-4-
Il) methoxy] phenyl} sulfonyl) propyl] -1H-1,
Preparation of 2,3-triazole 4-{[3- (1H-1,2,3-triazol-1-yl) propyl] sulfonyl} phenol (0.16 g), 4-chloromethyl-2-[(E)-
2- (4-Trifluoromethylphenyl) ethenyl] -1,3-oxazole (0.17 g), 60% oily sodium hydride (26 m
g) was used and the same reaction as in Example 1- (i) was performed to obtain the title compound (0.27 g) as white crystal powder. ¹ H-NMR (CDCl ₃ ) δ: 2.38-2.50 (2H, m), 3.05 (2H, t,
J = 7.4 Hz), 4.60 (2H, t, J = 6.6 Hz), 5.12 (2H, s),
7.02 (1H, d, J = 16.4 Hz), 7.14 (2H, d, J = 8.8 Hz),
7.54-7.63 (2H, m), 7.65 (4H, s), 7.72-7.73 (2H,
m), 7.80-7.85 (2H, m). IR (KBr): 1325, 1294, 127, 1140, 1069 cm ^-1 .

Example 9. 1- (3-{[4-({2-[(E) -2- (2,4 di
(Fluorophenyl) ethenyl] -1,3-oxazol-4-i
Ru} methoxy) phenyl] sulfonyl} propyl) -1H-1,2,3
-Production of triazole

[Chemical 88] 4-{[3- (1H-1,2,3-triazol-1-yl) propyl] sulfonyl} phenol (0.16 g), 4-chloromethyl-2-[(E)-
2- (2,4-Difluorophenyl) ethenyl] -1,3-oxazole (0.15 g) and 60% oily sodium hydride (26
was used in the same reaction as in Example 1- (i) to give the title compound (0.26 g) as pale-yellow crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 2.36-2.50 (2H, m), 3.05 (2H, t,
J = 7.0 Hz), 4.60 (2H, t, J = 6.6 Hz), 5.11 (2H, s),
6.82-7.16 (6H, m), 7.48-7.85 (6H, m). IR (KBr): 1593, 1497, 1275, 1144, 743 cm ^-1 .

Example 10. 4-[[4- [4- (1-methyl-1H-imi
Dazol-5-yl) butyl] phenoxy] methyl] -2-[(E) -2
-[4- (Trifluoromethyl) phenyl] ethenyl] -1,3-o
Manufacture of xazole

[Chemical 89] (i) 4- [4- (1-Methyl-1H-imidazol-5-yl) butyl]
Production of phenol 1-benzyloxy-4- (3-iodopropyl) benzene (20.
A toluene solution of 0 g) and triphenylphosphine (14.9 g) was heated under reflux for 60 hours. The precipitated crystals were filtered, washed with diethyl ether, and then iodinated [3- [4- (benzyloxy)
Phenyl] propyl] (triphenyl) phosphonium (31.9
g) was obtained as colorless powder crystals. This product (768 mg), 1-methyl-1H-imidazole-5-carbaldehyde (110 mg), potassium carbonate (207 mg), water (18.0 μl) in 1,4-dioxane
The (1 ml) suspension was stirred at 95 ° C. for 108 hours. After the reaction solution was concentrated, the residue was diluted with ethyl acetate-diethyl ether (1: 1) and the insoluble material was filtered off. The filtrate was washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, dichloromethane → dichloromethane: methanol = 4
0: 1), 4-[(E) -4- (1-methyl-1H-imidazole-5
-Yl) -3-butenyl] phenol and 4-[(Z) -4- (1-methyl)
A crude product (460 mg) of a mixture of -1H-imidazol-5-yl) -3-butenyl] phenol was obtained as a pale yellow amorphous substance. 10% of this product (448 mg) in methanol (10 ml)
Palladium on carbon (60 mg) was added, and the mixture was stirred at room temperature in a hydrogen atmosphere at room temperature.
Stir for hours. The reaction solution is filtered, the filtrate is concentrated, the residue is purified by silica gel column chromatography (eluent, dichloromethane → dichloromethane: methanol = 30: 1 → 10: 1), and recrystallized from ethyl acetate-methanol-hexane. The title compound (121 mg) was obtained as colorless flaky crystals. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.61-1.66 (4H, m), 2.50-2.
59 (4H, m), 3.51 (3H, s), 6.73 (1H, d, J = 0.6 Hz),
6.75-6.80 (2H, m), 6.97-7.01 (2H, m), 7.38 (1H, d,
J = 0.6 Hz) .IR (KBr): 1518, 1254, 1109, 822, 662 cm ^-1 .

(Ii) 4-[[4- [4- (1-methyl-1H-imidazol-5-yl) butyl] phenoxy] methyl] -2-[(E) -2- [4-
Preparation of (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole To a solution of 4- [4- (1-methyl-1H-imidazol-5-yl) butyl] phenol (100 mg) in DMF (3 ml). 65% Sodium hydride (17.5 mg) was added at 0 ° C, and the mixture was stirred at room temperature for 30 min. 0
4-Chloromethyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (137 mg) was added at ° C, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, and the precipitated crystals were filtered and washed with diisopropyl ether. Silica gel column chromatography (Chromatore
x, 100-200 mesh, Fuji Silysia Chemical Ltd.) (eluent, hexane: ethyl acetate = 1: 3 → ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (112 mg) as colorless Obtained as needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.65-1.69 (4H, m), 2.51-2.61 (4
H, m), 3.52 (3H, s), 5.02 (2H, d, J = 0.8 Hz), 6.7
6 (1H, s), 6.90-7.13 (5H, m), 7.36 (1H, s), 7.52-7.
69 (6H, m). IR (KBr): 1514, 1505, 1333, 1111, 1071, 828 cm ^-1 .

Example 11. 3- [4- [4-[[2-[(E) -2- [4- (
Lifluoromethyl) phenyl] ethenyl] -1,3-oxazol
Production of lu-4-yl] methoxy] phenyl] butyl] pyridine

[Chemical 90] (i) Production of 4- [4- (3-pyridinyl) butyl] phenol [3- [4- (benzyloxy) phenyl] propyl] (triphenyl) phosphonium iodide (400 mg), 3-pyridinecarbaldehyde ( 49.2 μl), potassium carbonate (108 mg), water
(9.4 μl), 10% palladium carbon (50 mg), and methanol (3 ml) were used to carry out the same reaction as in Example 10- (i) to obtain the title compound (109 mg) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.62-1.64 (4H, m), 2.56 (2H, t,
J = 6.9 Hz), 2.63 (2H, t, J = 7.5 Hz), 6.75-6.78
(2H, m), 6.99-7.01 (2H, m), 7.21-7.25 (1H, m), 7.4
9-7.52 (1H, m), 8.42-8.44 (2H, m). IR (KBr): 1508, 1458, 1275, 1240, 824 cm ^-1 .

(Ii) 3- [4- [4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] Production of phenyl] butyl] pyridine 4- [4- (3-pyridinyl) butyl] phenol (131 mg), 65
% Sodium hydride (16.8 mg), 4-chloromethyl-2-[(E)
-2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-
The same reaction as in Example 10- (ii) was carried out using oxazole (131 mg) to give the title compound (101 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.61-1.69 (4H, m), 2.59-2.66 (4
H, m), 5.02 (2H, s), 6.89-7.23 (6H, m), 7.45-7.69
(7H, m), 8.44 (2H, s) .IR (KBr): 1514, 1333, 1115, 1071, 828 cm ^-1 .

Example 12. 4-[[4- [4- (1H-imidazole-
4-yl) butyl] phenoxy] methyl] -2-[(E) -2- [4- (tri
Fluoromethyl) phenyl] ethenyl] -1,3-oxazole
Manufacturing of

[Chemical Formula 91] (i) Production of 4- [4- (1-Trityl-1H-imidazol-4-yl) butyl] phenol [3- [4- (Benzyloxy) phenyl] propyl] (triphenyl) phosphonium (2.30 g ), 1-Trityl-1H-imidazole-4-carbaldehyde (1.02 g), potassium carbonate
(622 mg), water (54.1 μl) and 10% palladium on carbon (1
41 mg) and ethyl acetate (26 ml) were used to carry out the same reaction as in Example 10- (i) to obtain the title compound (733 mg) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.52-1.68 (4H, m), 2.49 (2H, t,
J = 7.5 Hz), 2.56 (2H, t, J = 6.0 Hz), 6.51 (1H,
s), 6.73 (2H, d, J = 8.7 Hz), 6.93 (2H, d, J = 8.7
Hz), 7.11-7.14 (6H, m), 7.31-7.38 (10H, m), 7.82
(1H, br s). IR (KBr): 1514, 1493, 1447, 748, 702 cm ^-1 .

(Ii) 2-[(E) -2- [4- (trifluoromethyl)
Preparation of phenyl] ethenyl] -4-[[4- [4- (1-trityl-1H-imidazol-4-yl) butyl] phenoxy] methyl] -1,3-oxazole 4- [4- (1-trityl -1H-imidazol-4-yl) butyl] phenol (700 mg), 65% sodium hydride (62.0 mg),
4-chloromethyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (484 mg) was used in the same manner as in Example 10- (ii). The reaction was performed to give the title compound (929
mg) was obtained as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.62-1.66 (4H, m), 2.53-2.59 (4
H, m), 5.02 (2H, s), 6.50 (1H, d, J = 1.4 Hz), 7.1
8-7.91 (11H, m), 7.28-7.34 (10H, m), 7.52-7.68 (6
IR (KBr): 1512, 1327, 1127, 1069, 702 cm ^-1 .

(Iii) 4-[[4- [4- (1H-imidazol-4-yl) butyl] phenoxy] methyl] -2-[(E) -2- [4- (trifluoromethyl) phenyl] Preparation of ethenyl] -1,3-oxazole 2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl]
4-[[4- [4- (1-Trityl-1H-imidazol-4-yl) butyl] phenoxy] methyl] -1,3-oxazole (400 mg) 9
A 0% formic acid (2 ml) -THF (2 ml) solution was heated under reflux at 60 ° C. for 1.5 hours. The reaction mixture was concentrated, 4N aqueous sodium hydroxide solution was added to the residue, and the precipitated crystals were filtered, washed with diisopropyl ether, and recrystallized from ethyl acetate-hexane to give the title compound (203 mg) as colorless flaky crystals. Got as. ¹ H-NMR (CDCl ₃ ) δ: 1.65-1.68 (4H, m), 2.59-2.63 (4
H, m), 5.02 (2H, s), 6.76 (1H, s), 6.88-7.12 (5H,
m), 7.51-7.68 (7H, m). IR (KBr): 1512, 1327, 1130, 1069, 828 cm ^-1 .

Example 13. 3- [4- (2- {4-[(2-{(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl} -1,3-oxa
Zol-4-yl) methoxy] phenyl} ethyl) -1,3-oxa
Zol-5-yl] pyridine production

[Chemical Formula 92] (I) Production of 2- [4- (benzyloxy) phenyl] ethanol Parahydroxyphenylethanol (15.0 g) in dimethylformamide (150 ml) was added to potassium carbonate (19.5 g)
And benzyl bromide (14.0 ml) were added, and the mixture was stirred at 40 ° C for 10
Stir for hours. After completion of the reaction, water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline solution, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was washed with ethyl acetate.
-Recrystallization from hexane gave the title compound (20.0 g) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (1H, t, J = 5.7 Hz), 2.81
(2H, t, J = 6.3 Hz), 3.82 (2H, dd, J = 12.6, 6.3 H
z), 5.05 (2H, s), 6.93 (2H, d, J = 8.4 Hz), 7.14 (2
H, d, J = 8.4 Hz), 7.32-7.45 (5H, m). IR (KBr): 3250, 1610, 1250, 1020, 820 cm ^-1 .

(Ii) Preparation of 1- (benzyloxy) -4- (2-iodoethyl) benzene 2- [4- (benzyloxy) phenyl] ethanol (25.0
g), triethylamine (23.0 ml), methanesulfonyl chloride (10.0 ml) and sodium iodide (82.0 g) were used to carry out the same reaction as in Example 2- (vi) to give the title compound.
(30.8 g) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 3.10 (2H, t, J = 7.8 Hz), 3.32
(2H, t, J = 7.8 Hz), 5.05 (2H, s), 6.92 (2H, d, J =
8.0 Hz), 7.14 (2H, d, J = 8.0 Hz), 7.31-7.44 (5H,
m).

(Iii) Preparation of N- {2- [4- (benzyloxy) phenyl] -1-[(4-methylphenyl) sulfonyl] ethyl} -N-methyleneamine 1- (benzyloxy) -4- (2-iodoethyl) benzene (5.9
paratoluenesulfonylmethyl isocyanide (2.4 g) and tetrabutylammonium iodide (480 mg) were added to a mixed solution of g) in methylene chloride (50 ml) and 30% sodium hydroxide (50 ml), and the mixture was stirred at room temperature for 24 hours. did. After completion of the reaction, the reaction solution was extracted with ethyl acetate, washed with saturated saline and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethyl acetate-hexane to obtain the title compound (3.9 g) as pale brown powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.11 (1H, m), 2.42 (1H, m),
2.45 (3H, s), 2.68 (1H, m), 2.95 (1H, m), 4.35 (1H,
dd, J = 11.1, 3.3 Hz), 5.02 (2H, s), 6.92 (2H, d,
J = 8.0 Hz), 7.08 (2H, t, J = 8.0 Hz), 7.25-7.45 (7
H, m), 7.78-7.92 (2H, m) .IR (KBr): 2134, 1608, 1597, 1514, 1244 cm ^-1 .

(Iv) Preparation of 3- (4- {2- [4- (benzyloxy) phenyl] ethyl} -1,3-oxazol-5-yl) pyridine N- {2- [4- (benzyloxy ) Phenyl] -1-[(4-methylphenyl) sulfonyl] ethyl} -N-methyleneamine (0.38 g)
Solution of nicotinaldehyde (0.
1 g) and potassium carbonate (0.19 g) were added and the mixture was heated under reflux for 3 hours. After completion of the reaction, water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline solution, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (0.28 g) as a pale-yellow powder crystal. Got as. ¹ H-NMR (CDCl ₃ ) δ: 3.02 (4H, s), 5.02 (2H, s), 6.8
7 (2H, d, J = 8.4 Hz), 7.09 (2H, d, J = 8.4 Hz), 7.26
-7.44 (6H, m), 7.68 (1H, dt, J = 8.4, 2.4 Hz), 7.93
(1H, s), 8.54 (1H, dd, J = 4.5, 1.2 Hz), 8.73 (1H,
dd, J = 2.1, 0.9 Hz) .IR (KBr): 3110, 1609, 1514, 1238, 1010 cm ^-1 .

(V) Preparation of 4- [2- (5- (pyridin-3-yl) -1,3-oxazol-4-yl) ethyl] phenol 3- (4- {2- [4- (benzyl (Oxy) phenyl] ethyl} -1,3-oxazol-5-yl) pyridine (0.2 g) in methanol (4
ml) solution, 10% palladium-carbon (20 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hours. After the reaction was completed, the reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent, ethyl acetate).
: Hexane = 1: 1). The crystals were recrystallized from ethyl acetate-hexane to give the title compound (0.11 g) as pale-yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.00-3.01 (4H, m), 6.75 (2H, d,
J = 8.4 Hz), 6.97 (2H, d, J = 8.4 Hz), 7.37 (1H, dd
d, J = 8.2, 5.2, 1.2 Hz), 7.79 (1H, ddd, J = 8.0, 2.
2, 1.4 Hz), 7.97 (1H, s), 8.52 (1H, dd, J = 5.2, 2.
0 Hz), 8.59 (1H, dd, J = 2.2, 0.6 Hz). IR (KBr): 3119, 1608, 1591, 1516, 1256 cm ^-1 .

(Vi) 3- [4- (2- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazole-4
-Yl) methoxy] phenyl} ethyl) -1,3-oxazole-5
Preparation of 4-yl] pyridine 4-chloromethyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (0.12 g), 4- [2-
(5- (Pyridin-3-yl) -1,3-oxazol-4-yl) ethyl] phenol (0.1 g), 60% oily sodium hydride (1
7 mg) and dimethylformamide (2 ml),
The title compound (0.18 g) was reacted in the same manner as in Example 1- (i).
Was obtained as pale yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.03 (4H, s), 5.00 (2H, s), 6.8
9 (2H, d, J = 8.8 Hz), 7.02 (1H, d, J = 16.4 Hz), 7.1
1 (2H, d, J = 8.8 Hz), 7.31 (1H, ddd, J = 8.0, 4.8,
1.4 Hz), 7.55 (1H, d, J = 16.4 Hz), 7.64 (4H, br
s), 7.65-7.73 (2H, m), 7.93 (1H, s), 8.55 (1H, dd,
J = 4.8, 1.4 Hz), 8.72 (1H, dd, J = 2.2, 0.8 Hz). IR (KBr): 1614, 1512, 1327, 1125 cm ^-1 .

Example 14 3- [4- (4- {4-[(2-{(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl} -1,3-oxa
Zol-4-yl) methoxy] phenyl} butyl) -1,3-oxa
Zol-5-yl] pyridine production

[Chemical formula 93] (i) N-methylene-1- [4-toluenesulfonyl] -5- {4-[(2-
{(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl}-
1,3-oxazol-4-yl) methoxy] phenyl} pentane
Preparation of -1-amine 4-[[4- (4-iodobutyl) phenoxy] methyl] -2-[(E) -2-
Using [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (2.0 g), paratoluenesulfonylmethyl isocyanide (0.57 g) and tetrabutylammonium iodide (0.1 g), Example 13- The same reaction as in (iii) was performed to give the title compound (1.6 g) as pale-yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.63-1.80 (4H, m), 2.02-2.21 (2
H, m), 2.48 (3H, s), 2.58 (2H, m), 4.31 (1H, dd, J
= 10.8, 3.4 Hz), 5.01 (2H, s), 6.88 (2H, d, J = 8.4
Hz), 7.01 (1H, d, J = 16.2 Hz), 7.08 (2H, d, J = 8.4
Hz), 7.54 (1H, d, J = 16.2 Hz), 7.62 (4H, br s), 7.
68 (1H, s).

(Ii) 3- [4- (4- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazole-4
-Yl) methoxy] phenyl} butyl) -1,3-oxazole-5
Preparation of -yl] pyridine N-methylene-1-[(4-methylphenyl) sulfonyl] -5- {4-
[(2-{(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} pentan-1-amine (0.25 g), nicotinaldehyde (45 m
g), potassium carbonate (87 mg) and methanol (5 ml)
Was used to perform the same reaction as in Example 13- (iv) to obtain the title compound (0.2 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.63-1.83 (4H, m), 2.61 (2H, t,
J = 7.8 Hz), 2.80 (2H, t, J = 7.2 Hz), 5.02 (2H, s),
6.90 (2H, d, J = 8.7 Hz), 7.02 (1H, d, J = 16.2 H
z), 7.09 (2H, d, J = 8.7 Hz), 7.38 (1H, m), 7.56 (1
H, d, J = 16.2 Hz), 7.64 (4H, br s), 7.68 (1H, s),
7.84-7.90 (2H, m), 8.58 (1H, dt, J = 5.1, 1.5 Hz),
8.87 (1H, m). IR (KBr): 2920, 1514, 1327, 1111, 821 cm ^-1 .

Example 15. 4-[(4- {4- [5- (1H-Imidazo
Lu-4-yl) -1,3-oxazol-4-yl] butyl} phenoxy
Si) methyl] -2-{(E) -2- [4- (trifluoromethyl) phenyl
[L] ethenyl} -1,3-oxazole

[Chemical 94] (i) 2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -4-[(4- {4- [5- (1-trityl-1H-imidazol-4-yl)) Preparation of -1,3-oxazol-4-yl] butyl} phenoxy) methyl] -1,3-oxazole N-methylene-1-[(4-methylphenyl) sulfonyl] -5- {4-
[(2-{(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} pentan-1-amine (0.4 g), 1- Trityl-1H-imidazole-
4-aldehyde (0.23 g), potassium carbonate (0.14 g) and methanol (8 ml) were used to carry out the same reaction as in Example 13- (iv) to obtain the title compound (0.47 g) as white powder crystals. . ¹ H-NMR (CDCl ₃ ) δ: 1.58-1.66 (2H, m), 1.67-1.80 (2
H, m), 2.56 (2H, t, J = 7.5 Hz), 2.87 (2H, t, J = 6.6
Hz), 5.01 (2H, s), 6.88 (2H, d, J = 8.4 Hz), 7.02
(1H, d, J = 16.2 Hz), 7.04 (2H, d, J = 1.5 Hz), 7.07
(2H, d, J = 8.4Hz), 7.14-7.20 (7H, m), 7.32-7.38
(8H, m), 7.52 (1H, d, J = 1.5 Hz), 7.55 (1H, d, J =
16.2 Hz), 7.64 (4H, br s), 7.67 (1H, s), 7.70 (1H,
s) .IR (KBr): 2930, 1508, 1325, 1238, 826 cm ^-1 .

(Ii) 4-[(4- {4- [5- (1H-imidazol-4-yl) -1,3-oxazol-4-yl] butyl} phenoxy) methyl] -2-{(E ) -2- [4- (Trifluoromethyl) phenyl] ethenyl} -1,3-oxazole production 2-{(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl} -4-[( 4- {4- [5- (1-Trityl-1H-imidazol-4-yl) -1,3-oxazol-4-yl] butyl} phenoxy) methyl] -1,3-oxazole (0.4 g) in tetrahydrofuran
To the (2 ml) solution, add 90% formic acid (2 ml) in water, and then at 60 ° C.
It was stirred for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure,
A 4N aqueous sodium hydroxide solution was added under ice cooling. The precipitated crystals were filtered, washed with water and isopropanol, and recrystallized from ethyl acetate-hexane to give the title compound (0.18
g) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.66-1.82 (4H, m), 2.61 (2H, t,
J = 6.6 Hz), 2.86 (2H, t, J = 6.9 Hz), 5.01 (2H, s),
6.88 (2H, d, J = 8.4 Hz), 7.01 (1H, d, J = 16.5 H
z), 7.09 (2H, d, J = 8.4 Hz), 7.13 (1H, m), 7.55 (1
H, d, J = 16.5 Hz), 7.63 (4H, d, J = 1.2 Hz), 7.69
(1H, s), 7.72 (1H, s), 7.77 (1H, s), 9.62 (1H, s). IR (KBr): 3098, 1514, 1336, 1327, 1134 cm ^-1 .

Example 16. 4-[(4- {2- [5- (1H-Imidazo
Lu-4-yl) -1,3-oxazol-4-yl] ethyl} phenoxy
Si) Methyl] -2-{(E) -2- [4- (trifluoromethyl) phenyl
[L] ethenyl} -1,3-oxazole

[Chemical 95] (i) 4- {2- [4- (benzyloxy) phenyl] ethyl} -5- (1-
Preparation of trityl-1H-imidazol-4-yl) -1,3-oxazole N- {2- [4- (benzyloxy) phenyl] -1-[(4-methylphenyl) sulfonyl] ethyl} -N-methylene Amine (0.48
g), 1-trityl-1H-imidazol-4-aldehyde (0.4
g), potassium carbonate (0.25 g) and methanol (12 ml)
Was used to perform the same reaction as in Example 13- (iv) to obtain the title compound (0.49 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.90-2.95 (2H, m), 3.01-3.06 (2
H, m), 4.98 (2H, s), 6.80 (2H, d, J = 8.7 Hz), 6.91
(1H, d, J = 1.5 Hz), 7.02 (2H, d, J = 8.7 Hz), 7.13
-7.19 (5H, m), 7.31-7.44 (15H, m), 7.51 (1H, d, J =
1.5 Hz), 7.74 (1H, s).

(Ii) Preparation of 4- {2- [5- (1-trityl-1H-imidazol-4-yl) -1,3-oxazol-4-yl] ethyl} phenol 4- {2- [4 -(Benzyloxy) phenyl] ethyl} -5- (1-trityl-1H-imidazol-4-yl) -1,3-oxazole (0.4
9 g), 10% palladium on carbon (50 mg), ethyl acetate (10 m
l) Using the solution, the same reaction as in Example 13- (v) was performed to give the title compound (0.28 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.90-2.94 (2H, m), 3.01-3.05 (2
H, m), 6.81 (2H, d, J = 8.4 Hz), 6.91 (1H, d, J = 1.2
Hz), 7.02 (2H, d, J = 8.4 Hz), 7.30-7.41 (15H, m),
7.50 (1H, d, J = 1.2 Hz), 7.69 (1H, s) .IR (KBr): 3135, 1663, 1514, 1445, 1233 cm ^-1 .

(Iii) 2-{(E) -2- [4- (trifluoromethyl)
Phenyl] ethenyl} -4-[(4- {2- [5- (1-trityl-1H-imidazol-4-yl) -1,3-oxazol-4-yl] ethyl} phenoxy) methyl] -1, Preparation of 3-oxazole 4-chloromethyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (0.13 g), 4- {2-
[5- (1-Trityl-1H-imidazol-4-yl) -1,3-oxazol-4-yl] ethyl} phenol (0.23 g), 60% oily sodium hydride (20 mg) and dimethylformamide (4 ml) was used to carry out the same reaction as in Example 1- (i) to obtain the title compound (0.28 g) as pale yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.91-2.96 (2H, m), 3.03-3.09 (2
H, m), 4.97 (2H, s), 6.83 (2H, d, J = 8.4 Hz), 6.92
(1H, d, J = 1.2 Hz), 7.02 (1H, d, J = 16.2 Hz), 7.0
7 (2H, d, J = 8.4 Hz), 7.15-7.18 (7H, m), 7.35-7.37
(8H, m), 7.51 (1H, d, J = 1.2 Hz), 7.55 (1H, d, J =
16.2 Hz), 7.64 (4H, br s), 7.66 (1H, s), 7.74 (1
H, s) .IR (KBr): 3061, 1614, 1510, 1323, 1167 cm ^-1 .

(Iv) 4-[(4- {2- [5- (1H-imidazol-4-yl) -1,3-oxazol-4-yl] ethyl} phenoxy) methyl] -2-{(E ) -2- [4- (Trifluoromethyl) phenyl] ethenyl} -1,3-oxazole production 2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl}
-4-[(4- {2- [5- (1-trityl-1H-imidazol-4-yl)-
1,3-Oxazol-4-yl] ethyl} phenoxy) methyl]
1,3-oxazole (0.2 g), 90% formic acid (2 ml) aqueous solution and tetrahydrofuran (2 ml) solution were used to carry out the same reaction as in Example 15- (ii) to give the title compound (0.11 g)
Was obtained as pale yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.97-3.02 (2H, m), 3.11-3.18 (2
H, m), 5.00 (2H, s), 6.88 (2H, d, J = 8.4 Hz), 7.01
(1H, s), 7.01 (1H, d, J = 16.5 Hz), 7.15 (2H, d, J
= 8.4 Hz), 7.55 (1H, d, J = 16.5 Hz), 7.64 (4H, br
s), 7.67 (1H, s), 7.70 (1H, s), 7.81 (1H, s), 9.60
(1H, s). IR (KBr): 3117, 1508, 1325, 1132, 828 cm ^-1 .

Example 17 3- (3- {4-[(2-{(E) -2- [4- (
Lifluoromethyl) phenyl] ethenyl} -1,3-oxazol
Preparation of lu-4-yl) methoxy] phenyl} propyl) pyridine
Construction

[Chemical 96] (i) Preparation of 4- (3-pyridin-3-ylpropyl) phenol Iodide prepared from 1- (benzyloxy) -4- (2-iodoethyl) benzene and triphenylphosphine {2- [4- (benzyl To a solution of (oxy) phenyl] ethyl} triphenylphosphonium (1.0 g) in 1,4-dioxane (1.3 ml), nicotinaldehyde (0.14 g), potassium carbonate (0.27 g) and water (23 mg) were added, and the temperature was 95 ° C. And stirred for 15 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate, washed with saturated saline and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography.
(Eluate, ethyl acetate: hexane = 1: 5) to give an olefin (0.38 g) as pale yellow powder crystals. This product (0.34 g) in methanol (5 ml) and tetrahydrofuran (2 ml) was mixed with 10% palladium carbon (35 m
g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hours.
After the reaction was completed, the reaction solution was filtered through Celite, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 2) to give the title compound (0.2 g) as a pale yellow color. Obtained as a powder crystal. ¹ H-NMR (CDCl ₃ ) δ: 1.84-1.99 (2H, m), 2.53-2.67 (4
H, m), 6.82 (2H, d, J = 8.4 Hz), 7.01 (2H, d, J = 8.4
Hz), 7.26 (1H, m), 7.56 (1H, dt, J = 7.6, 2.2 Hz),
8.40-8.46 (2H, m).

(Ii) 3- (3- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] Production of (phenyl} propyl) pyridine 4-chloromethyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (0.12 g), 4- (3-
Pyridin-3-ylpropyl) phenol (0.09 g), 60%
Using oily sodium hydride (19 mg) and dimethylformamide (1 ml), the same reaction as in Example 1- (i) was performed to obtain the title compound (0.17 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.88-1.98 (2H, m), 2.62 (4H, d
d, J = 15.0, 6.9 Hz), 5.03 (2H, s), 6.93 (2H, d, J =
8.4 Hz), 7.02 (1H, d, J = 16.5 Hz), 7.11 (2H, d, J =
8.4 Hz), 7.21 (1H, dd, J = 8.1, 5.1 Hz), 7.49 (1H,
dt, J = 7.5, 1.2Hz), 7.55 (1H, d, J = 16.5 Hz), 7.6
3 (4H, br s), 7.69 (1H, s), 8.45 (2H, br s). IR (KBr): 3120, 1614, 1512, 1337, 1109 cm ^-1 .

Example 18. 4-({4-[(3- (1H-imidazole
-4-yl) propyl) phenoxy] methyl} -2-{(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl} -1,3-oxa
Manufacture of sol

[Chemical 97] (i) Production of 4- [3- (1-trityl-1H-imidazol-4-yl) propyl] phenol {2- [4- (benzyloxy) phenyl] ethyl} triphenylphosphonium iodide (5.0 g), 1-Trityl-1H-imidazol-4-aldehyde (2.25 g), potassium carbonate (1.4
g), water (0.12 g) and 10% palladium carbon (0.28 g)
Using g), the same reaction as in Example 17- (i) was performed to give the title compound (1.3 g) as pale-yellow powder crystals.

(Ii) 2-{(E) -2- [4- (trifluoromethyl)
Preparation of phenyl] ethenyl} -4-({4- {3- (1-trityl-1H-imidazol-4-yl) propyl} phenoxy} methyl) -1,3-oxazole 4-chloromethyl-2-[( E) -2- [4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (0.13 g), 4- [3-
Using (1-trityl-1H-imidazol-4-yl) propyl] phenol (0.2 g), 60% oily sodium hydride (20 mg) and dimethylformamide (1.5 ml).
The same reaction as in 1- (i) was performed to give the title compound (0.17 g) as white powder crystals.

(Iii) 4-({4-[(3- (1H-imidazol-4-yl) propyl) phenoxy] methyl} -2-{(E) -2- [4- (trifluoromethyl) phenyl ] Ethenyl} -1,3-oxazole production 2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -4-({4- {3- (1-trityl-1H-imidazole -4-yl) propyl} phenoxy} methyl) -1,3-oxazole (0.12
g), 90% formic acid (1 ml) aqueous solution and tetrahydrofuran (1 ml) solution were used to carry out the same reaction as in Example 15- (ii) to obtain the title compound (53 mg) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.05 (2H, m), 2.63 (4H, t,
J = 7.4 Hz), 5.02 (2H, s), 6.78 (1H, s), 6.91 (2
H, d, J = 8.8 Hz), 7.01 (1H, d, J = 16.4 Hz), 7.11 (2
H, d, J = 8.8 Hz), 7.54 (1H, s), 7.55 (1H, d, J = 1
6.4 Hz), 7.63 (4H, br s), 7.68 (1H, s). IR (KBr): 3472, 3112, 1512, 1329, 1125 cm ^-1 .

Example 19. 4- [4- [4-[[2-[(E) -2- [4- (
Lifluoromethyl) phenyl] ethenyl] -1,3-oxazol
Production of lu-4-yl] methoxy] phenyl] butyl] pyridine

[Chemical 98] (i) Production of 4- [4- (4-pyridinyl) butyl] phenol [3- [4- (Benzyloxy) phenyl] propyl] (triphenyl) phosphonium iodide (300 mg), 4-pyridinecarbaldehyde ( 41.8 μl), potassium carbonate (81.1 mg), water
(7.1 μl), 10% palladium carbon (35 mg), and methanol (3 ml) were used to perform the same reaction as in Example 10- (i) to obtain the title compound (68.3 mg) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.61-1.65 (4H, m), 2.49-2.63 (4
H, m), 6.73-6.70 (2H, m), 6.98-7.12 (4H, m), 8.45-
8.49 (2H, m). IR (KBr): 2932, 1611, 1514, 1454, 1250 cm ^-1 .

(Ii) 4- [4- [4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] Production of phenyl] butyl] pyridine 4- [4- (4-pyridinyl) butyl] phenol (60.8 mg), 65
% Sodium hydride (10.8 mg), 4-chloromethyl-2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl]-
Example 10- (ii) using 1,3-oxazole (80.8 mg)
The title compound (61.5 mg) was obtained as colorless needle crystals by performing the same reaction as in. ¹ H-NMR (CDCl ₃ ) δ: 1.63-1.66 (4H, m), 2.59-2.62 (4
H, m), 5.02 (2H, d, J = 0.8 Hz), 6.89-7.11 (7H, m),
7.51-7.68 (6H, m), 8.47-8.49 (2H, m) .IR (KBr): 1512, 1327, 1167, 1128, 1069 cm ^-1 .

Example 20. 2- [4- [4-[[2-[(E) -2- [4- (
Lifluoromethyl) phenyl] ethenyl] -1,3-oxazol
Production of lu-4-yl] methoxy] phenyl] butyl] pyridine

[Chemical 99] (i) Production of 4- [4- (2-pyridinyl) butyl] phenol [3- [4- (Benzyloxy) phenyl] propyl] (triphenyl) phosphonium iodide (300 mg), 2-pyridinecarbaldehyde ( 41.8 μl), potassium carbonate (81.1 mg), water
(7.1 μl), 10% palladium carbon (35 mg), and methanol (3 ml) were used to carry out the same reaction as in Example 10- (i) to obtain the title compound (63.8 mg) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.58-1.81 (4H, m), 2.55 (2H, t,
J = 7.8 Hz), 2.82 (2H, t, J = 7.4 Hz), 6.70-6.76
(2H, m), 7.01-7.01 (2H, m), 7.09-7.15 (2H, m), 7.6
1 (1H, dt, J = 1.8, 7.2 Hz), 8.50-8.52 (1H, m). IR (KBr): 2930, 1595, 1514, 1480, 1246 cm ^-1 .

(Ii) 2- [4- [4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] Production of phenyl] butyl] pyridine 4- [4- (2-pyridinyl) butyl] phenol (55.7 mg), 65
% Sodium hydride (9.95 mg), 4-chloromethyl-2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl]-
Example 10- (ii) using 1,3-oxazole (74.0 mg)
The same reaction as in (1) was performed to give the title compound (65.2 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.68-1.84 (4H, m), 2.62 (2H, t,
J = 7.6 Hz), 2.83 (2H, t, J = 7.4 Hz), 5.04 (2H,
d, J = 0.6 Hz), 6.90-7.16 (7H, m), 7.53-7.70 (7H,
m), 8.54 (1H, d, J = 5.0 Hz). IR (KBr): 1333, 1169, 1109, 1071, 826 cm ^-1 .

Example 21. {1- [3-({4-[(2-{(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl} -1,3-oxa
Zol-4-yl) methoxy] phenyl} sulfanyl) pro
Pill] -1H-imidazol-2-yl} methanol production

[Chemical 100] (i) Preparation of 1- (3-{[4- (methoxymethoxy) phenyl] thio} propyl) -1H-imidazole-2-carbaldehyde 1-[(3-chloropropyl) thio] -4- (methoxymethoxy ) Benzene (3.3 g) in dimethyl sulfoxide (50 ml), 2-formylimidazole (1.5 g), potassium carbonate
(2.0 g) and sodium iodide (2.6 g) and add 70
The mixture was stirred at ℃ for 17 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 2) to obtain an olefin compound (3.1 g) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 2.01-2.08 (2H, m), 2.78 (2H, t,
J = 6.6 Hz), 3.48 (3H, s), 4.52 (2H, d, J = 6.9 Hz),
5.17 (2H, s), 6.99 (2H, d, J = 8.8 Hz), 7.16 (1H,
br s), 7.28 (1H, br s), 7.33 (2H, d, J = 8.8 Hz),
9.80 (1H, s).

(Ii) Preparation of [1- (3-{[4- (methoxymethoxy) phenyl] thio} propyl) -1H-imidazol-2-yl] methanol 1- (3-{[4- (methoxymethoxy ) Phenyl] thio} propyl)
Example 1 using -1H-imidazole-2-carbaldehyde (3.1 g) and sodium borohydride (0.25 g)
The same reaction as- (iii) was performed to obtain the title compound (3.0 g) as pale yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.01-2.08 (2H, m), 2.80 (2H, t,
J = 6.9 Hz), 3.48 (3H, s), 4.14 (2H, d, J = 6.9 Hz),
5.16 (2H, s), 6.83 (1H, br s), 6.87 (1H, br s),
6.98 (2H, d, J = 8.7 Hz), 7.32 (2H, d, J = 8.7 Hz). IR (KBr): 3112, 1670, 1593, 1493, 912 cm ^-1 .

(Iii) 4-({3- [2- (hydroxymethyl) -1H-
Preparation of imidazol-1-yl] propyl} thio) phenol [1- (3-{[4- (methoxymethoxy) phenyl] thio} propyl) -1H-imidazol-2-yl] methanol (3.0 g) in tetrahydrofuran ( 4N hydrochloric acid (30 ml) aqueous solution was added to 30 ml), and the mixture was stirred at room temperature for 10 hours. After completion of the reaction, sodium hydroxide was added to the reaction solution under ice cooling to adjust the pH to 6, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, methanol: chloroform = 1: 9) to give the title compound.
(2.7 g) was obtained as a yellow oil. ¹ H-NMR (CD ₃ OD) δ: 1.84-1.92 (2H, m), 2.63 (2H, t,
J = 6.6 Hz), 4.06 (2H, t, J = 7.2 Hz), 4.50 (2H, s),
6.61 (2H, d, J = 8.7 Hz), 6.78 (1H, s), 6.95 (1H,
s), 7.14 (2H, d, J = 8.7 Hz). IR (KBr): 3117, 1599, 1582, 1495, 1269 cm ^-1 .

(Iv) {1- [3-({4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazole-4-
Preparation of (yl) methoxy] phenyl} thio) propyl] -1H-imidazol-2-yl} methanol 4-({3- [2- (hydroxymethyl) -1H-imidazol-1-yl] propyl} thio) phenol ( 1.5 g), 4-chloromethyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (1.6 g), 60% oily sodium hydride (0.27 g ) And dimethylformamide (20 ml)
Was used to perform the same reaction as in Example 1- (i) to give the title compound (0.95 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.98-2.11 (2H, m), 2.81 (2H, t,
J = 7.0 Hz), 4.13 (2H, t, J = 6.8 Hz), 4.66 (2H, br
s), 5.03 (2H, s), 6.86-6.99 (3H, m), 6.95 (2H, d,
J = 8.8 Hz), 7.02 (1H, d, J = 16.4 Hz), 7.35 (2H, d,
J = 8.8 Hz), 7.55 (1H, d, J = 16.4 Hz), 7.64 (4H,
s), 7.70 (1H, s). IR (KBr): 3153, 1495, 1327, 1246, 1167 cm ^-1 .

Example 22. {1- [3-({4-[(2-{(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl} -1,3-oxa
Zol-4-yl) methoxy] phenyl} sulfonyl) propyi
]]-1H-imidazol-2-yl} methanol production

[Chemical 101] {1- [3-({4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} thio) Propyl] -1H-imidazol-2-yl} methanol (0.74 g), metachloroperbenzoic acid (70%, 0.88 g)
Was used to perform the same reaction as in Example 8- (i) to obtain the title compound (0.61 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.21-2.32 (2H, m), 3.06 (2H, t,
J = 7.0 Hz), 4.18 (2H, t, J = 7.0 Hz), 4.63 (2H, s),
5.11 (2H, s), 6.87 (2H, br s), 7.02 (1H, d, J = 1
6.6 Hz), 7.14 (2H, d, J = 9.2 Hz), 7.56 (1H, d, J =
16.6 Hz), 7.64 (4H, s), 7.73 (1H, s), 7.84 (2H, d,
J = 9.2 Hz). IR (KBr): 3063, 1593, 1580, 1327, 1136 cm ^-1 .

Example 23. 2- [5- [4- [4-[[2-[(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl] -1,3-oxa
Zol-4-yl] methoxy] phenyl] butyl] -1H-imidazole
Zol-1-yl] ethanol production

[Chemical 102] 2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl]
-4-[[4- [4- (1-Trityl-1H-imidazol-4-yl) butyl] phenoxy] methyl] -1,3-oxazole (160 mg), 2
-Iodoethanol (0.20 ml) in DMF (1 ml) at 50 ° C
It was stirred for 22 hours. After concentrating the reaction solution, acetic acid-water (1: 1) (1
ml) was added, and the mixture was stirred at 100 ° C for 1 hr. The reaction mixture was concentrated, 4N aqueous sodium hydroxide solution was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (Chromatorex, eluent, ethyl acetate → ethyl acetate: methanol = 30: 1) and purified with ethyl acetate-
Recrystallization from methanol-hexane gave the title compound (30.
9 mg) was obtained as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.65-1.68 (4H, m), 2.52 (2H, t,
J = 6.9 Hz), 2.60 (2H, t, J = 6.9 Hz), 3.82 (2H,
t, J = 5.1 Hz), 3.93 (2H, t, J = 5.1 Hz), 5.02 (2
H, d, J = 1.2 Hz), 6.67 (1H, s), 6.90-7.12 (5H,
m), 7.37 (1H, s), 7.52-7.69 (6H, m). IR (KBr): 1508, 1323, 1231, 1181, 1069 cm ^-1 .

Example 24. Ethyl [5- [4- [4-[[2-[(E)-
2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-o
Xazol-4-yl] methoxy] phenyl] butyl] -1H-I
[Midazol-1-yl] acetic acid production

[Chemical 103] 2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl]
-4-[[4- [4- (1-trityl-1H-imidazol-4-yl) butyl] phenoxy] methyl] -1,3-oxazole (390 mg),
The same reaction as in Example 23 was performed using ethyl bromoacetate (67.0 μl) to give the title compound (79.3 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.2 Hz), 1.65-
1.68 (4H, m), 2.48 (2H, t, J = 6.9 Hz), 2.59 (2H,
t, J = 6.9 Hz), 4.22 (2H, q, J = 7.2 Hz), 4.56 (2
H, s), 5.02 (2H, d, J = 0.9 Hz), 6.79 (1H, s), 6.9
0-7.11 (5H, m), 7.42 (1H, s), 7.53-7.69 (6H, m). IR (KBr): 1742, 1507, 1208, 1175, 1128 cm ^-1 .

Example 25. N, N-Dimethyl-2- [5- [4- [4-
[[2-[(E) -2- [4- (trifluoromethyl) phenyl] etheni
L] -1,3-Oxazol-4-yl] methoxy] phenyl] buty
Of [L] -1H-imidazol-1-yl] acetamide

[Chemical 104] (i) [5- [4- [4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy]
Phenyl] butyl] -1H-imidazol-1-yl] acetic acid production [5- [4- [4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1 , 3-Oxazol-4-yl] methoxy] phenyl] butyl] -1H-imidazol-1-yl] ethyl acetate (7
To a solution of 9.3 mg) in methanol (3 ml) was added a 1N aqueous sodium hydroxide solution (0.43 ml), and the mixture was heated under reflux for 4 hours. Water was added to the reaction solution, and the precipitated crystals were filtered to give the title compound (73.2
mg) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.69-1.70 (4H, m), 2.59-
2.61 (4H, m), 4.56 (2H, s), 5.01 (2H, d, J = 0.9 H
z), 6.85 (1H, s), 6.91-7.12 (5H, m), 7.54-7.73 (6
H, m), 8.34 (1H, s). IR (KBr): 1327, 1236, 1175, 1128, 1067 cm ^-1 .

(Ii) N, N-dimethyl-2- [5- [4- [4-[[2-[(E)-
Production of 2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] butyl] -1H-imidazol-1-yl] acetamide [5- [4- [ 4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] butyl] -1H-imidazol-1-yl ] Acetic acid (64.0 mg)
Solution of N, N-dimethylamine in THF (2M; 0.608 ml) and diethyl cyanophosphate (55.6 μl) in DMF (2 ml)
After stirring for 15 minutes, add triethylamine (51.1
μl) was added and the mixture was stirred at room temperature for 46 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, dichloromethane → dichloromethane: methanol = 20:
The product was purified in 1) and recrystallized from ethyl acetate-methanol-hexane to give the title compound (24.2 mg) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.65-1.69 (4H, m), 2.46 (2H, t,
J = 7.8 Hz), 2.60 (2H, t, J = 7.4 Hz), 2.99 (3H,
s), 3.05 (3H, s), 4.61 (2H, s), 5.02 (2H, d, J = 0.
8 Hz), 6.79 (1H, br s), 6.89-7.12 (5H, m), 7.38 (1
H, br s), 7.52-7.68 (6H, m). IR (KBr): 1667, 1510, 1327, 1127, 1069 cm ^-1 .

Example 26. 4- [4- [4-[[2-[(E) -2- [4- (
Lifluoromethyl) phenyl] ethenyl] -1,3-oxazol
Lu-4-yl] methoxy] phenyl] butyl] -1H-1,2,3-tri
Manufacture of azoles

[Chemical 105] (i) Production of 4- [4- (1H-1,2,3-triazol-4-yl) butyl] phenol [3- [4- (benzyloxy) phenyl] propyl] (triphenyl) phosphonium ( 1.50 g), (1-trityl-1H-
1,2,3-Triazol-4-yl) carbaldehyde (663 m
g), potassium carbonate (404 mg), water (35.1 μl) and 10%
Palladium on carbon (793 mg), methanol-THF (1: 1) (50 m
Using l), the same reaction as in Example 10- (i) was performed to give the title compound (310 mg) as colorless powder crystals. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.57-1.74 (4H, m), 2.55
(2H, t, J = 6.9 Hz), 2.73 (2H, t, J = 7.5 Hz), 6.7
2-6.77 (2H, m), 6.96-7.01 (2H, m), 7.42 (1H, s). IR (KBr): 1514, 1451, 1240, 990, 822 cm ^-1 .

(Ii) Preparation of 4- [4- (1-trityl-1H-1,2,3-triazol-4-yl) butyl] phenol 4- [4- (1H-1,2,3-triazole Add 4-ethyl) butyl] phenol (304 mg) in DMF (7 ml) at 0 ° C to triethylamine.
(0.429 ml) and trityl chloride (429 mg) were added, and the mixture was stirred at room temperature for 10
Stir for hours. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 10: 1 → 2: 1) to obtain the title compound (415 mg) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.60-1.73
(4H, m), 2.53 (2H, t, J = 6.9 Hz), 2.72 (2H, t, J
= 7.5 Hz), 5.09 (1H, s), 6.70-6.75 (2H, m), 6.97-
7.00 (2H, m), 7.10-7.23 (7H, m), 7.28-7.35 (9H,
m). IR (KBr): 1514, 1493, 1447, 748, 700 cm ^-1 .

(Iii) 4- [4- [4 [[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl ] Butyl] -1-trityl-1H-1,2,3-
Preparation of triazole 4- [4- (1-Trityl-1H-1,2,3-triazol-4-yl) butyl] phenol (406 mg), 65% sodium hydride (35.9
mg), 4-chloromethyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (280 mg) was used in Example 10- (ii). The title compound
(575 mg) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.64-1.68 (4H, m), 2.57 (2H, t,
J = 7.0 Hz), 2.72 (2H, t, J = 7.0 Hz), 5.01 (2H,
s), 6.87-7.16 (12H, m), 7.29-7.36 (9H, m), 7.36-7.
51 (6H, m). IR (KBr): 1510, 1325, 1125, 1069, 700 cm ^-1 .

(Iv) 4- [4- [4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] Production of phenyl] butyl] -1H-1,2,3-triazole 4- [4- [4 [[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3 -Oxazol-4-yl] methoxy]
Phenyl] butyl] -1-trityl-1H-1,2,3-triazole
The same reaction as in Example 12- (iii) was performed using (555 mg) to give the title compound (227 mg) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.67-1.71 (4H, m), 2.60 (2H, t,
J = 7.2 Hz), 2.76 (2H, t, J = 7.0 Hz), 5.03 (2H,
s), 6.89-7.12 (5H, m), 7.47-7.68 (7H, m) .IR (KBr): 1508, 1321, 1171, 1132, 1069 cm ^-1 .

Example 27. 4- [4- [2- (1H-imidazo
1-yl) ethoxy] phenoxymethyl] -2- (2-
Production of thienyl) -1,3-oxazole

[Chemical formula 106] To a solution of 4- [2- (1H-imidazol-1-yl) ethoxy] phenol (500 mg) in DMF (10 ml) was added 60% sodium hydride (105 mg) at 0 ° C, and the mixture was stirred at room temperature for 1 hour. Then, 4-chloromethyl-2- (2-thienyl) -1,3-oxazole (580 mg) was added at the same temperature, and the mixture was stirred at 70 ° C for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with 2N aqueous sodium hydroxide solution, water, and then saturated saline,
It was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure,
The residue was subjected to silica gel column chromatography (eluent,
Purification with ethyl acetate: methanol = 100: 1) gave colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (600 mg) as colorless prism crystals. Melting point 148-149 ° C. ¹ H-NMR (CDCl ₃ ) δ: 4.17 (2H, t, J = 5.0 Hz), 4.31 (2H,
t, J = 5.0 Hz), 4.99 (2H, s), 6.78-6.84 (2H, m), 6.
88-6.94 (2H, m), 7.04 (1H, s), 7.07 (1H, s), 7.12
(1H, dd, J = 5.0, 3.8 Hz), 7.44 (1H, dd, J = 5.0, 1.2
Hz), 7.59 (1H, s), 7.64 (1H, s), 7.69 (1H, dd, J =
3.8, 1.2 Hz) .IR (KBr): 3132, 3082, 2935, 2868, 1577, 1508, 145
8, 1383, 1284, 1219, 1057, 1010, 928, 858, 823, 73
1, 671 cm ^-1 .

Example 28. 2- (1H-imidazole-1
-Yl) -1- [4-[[2- (2-thienyl) -1,3-oxazol
Preparation of ol-4-yl] methoxy] phenyl] ethanone

[Chemical formula 107] To a solution of 1-[(4-hydroxyphenyl) -2- (1H-imidazol-1-yl) ethanone (606 mg) in DMF (15 ml) was added 0.
60% sodium hydride (132 mg) was added at 0 ° C, the mixture was stirred at room temperature for 1 hr, and then 4-chloromethyl-2- (2-thienyl) -at 0 ° C.
1,3-Oxazole (659 mg) was added, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with 2N aqueous sodium hydroxide solution, water, and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 95: 5) to obtain crystals. Recrystallization from ethyl acetate gave the title compound (349 mg) as pale-yellow prism crystals. Melting point 177-178 ° C. ¹ H-NMR (CDCl ₃ ) δ: 5.14 (2H, s), 5.35 (2H, s), 6.95
(1H, s), 7.08-7.16 (4H, m), 7.48 (1H, dd, J = 5.0,
1.0 Hz), 7.52 (1H, s), 7.02-7.72 (2H, m), 7.94-8.0
0 (2H, m). IR (KBr): 1694, 1601, 1507, 1233, 741, 731 cm ^-1 .

Example 29. 2- (1H-imidazole-1
-Yl) -N- [4-[[2- (2-thienyl) -1,3-oxa
Preparation of zol-4-yl] methoxy] phenyl] acetamide
Construction

[Chemical 108] 1H-imidazole (95 mg) in DMF (10 ml) at 0 ° C
After adding 0% sodium hydride (55 mg) and stirring at room temperature for 1 hour, 2-chloro-N- [4-[[2- (2-thienyl)-] was added at the same temperature.
1,3-Oxazol-4-yl] methoxy] phenyl] acetamide (410 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was poured into water, and the precipitated crystals were collected by filtration to give colorless crystals.
The title compound was recrystallized from methanol-acetone.
(295 mg) was obtained as colorless prism crystals. Melting point 204-205 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 4.86 (2H, s), 4.99 (2H, s), 6.
89 (1H, s), 7.01 (2H, d, J = 8.8 Hz), 7.15 (1H, m),
7.19-7.24 (1H, m), 7.52 (2H, d, J = 8.8 Hz), 7.62 (1
H, s), 7.70-7.73 (1H, m), 7.79 (1H, d, J = 4.8 Hz),
8.22 (1H, s), 10.18 (1H, s). IR (KBr): 3261, 3053, 2903, 1697, 1603, 1562, 150
8, 1458, 1415, 1367, 1304, 1240, 1172, 1105, 1080,
1057, 1003, 916, 850, 833, 723, 661 cm ^-1 .

Example 30. 4- [2- [4- [2- (1H-immi
Dazol-1-yl) ethoxy] phenyl] ethyl] -2-
Preparation of (2-thienyl) -1,3-oxazole

[Chemical 109] 4-[(E) -2- [4- [2- (1H-imidazol-1-yl)
Ethoxy] phenyl] ethenyl] -2- (2-thienyl) -1,
3-oxazole (190 mg), 10% palladium on carbon (wet, 9
0 mg) and methanol (50 ml) at 4.6 kgf / cm ² , 5
Catalytic reduction was performed at 0 ° C. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain crystals. Recrystallized from ethyl acetate-hexane,
The title compound (130 mg) was obtained as colorless prism crystals. Melting point 111-112 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.78-2.99 (4H, m), 4.19 (2H, t,
J = 5.2 Hz), 4.32 (2H, t, J = 5.2 Hz), 6.76-6.81 (2H,
m), 7.03-7.14 (5H, m), 7.24 (1H, s), 7.41 (1H, dd,
J = 5.2, 1.2 Hz), 7.59 (1H, s), 7.64 (1H, dd, J = 3.
8, 1.2 Hz). IR (KBr): 3108, 2930, 1593, 1512, 1240, 912, 743 c
m ^-1 .

Example 31. 4-[(E) -2- [4- [2- (1H
-Imidazol-1-yl) ethoxy] phenyl] etheni
Preparation of [L] -2- (2-thienyl) -1,3-oxazole

[Chemical 110] [2- (2-thienyl) -1.3-oxazol-4-yl] chloride
Methyltriphenylphosphonium (2.54g) and DMF
(20 ml) to a mixture of 60% sodium hydride (0.
24 g) was added and the mixture was stirred at room temperature for 1 hour, and then 4- [2- (1H-imidazol-1-yl) ethoxy] benzaldehyde (1.08
A solution of g) in tetrahydrofuran (5 ml) was added at 0 ° C.
The reaction solution was further stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with 2N aqueous sodium hydroxide solution, water, and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 95: 5) to give the title compound (730 m
g) was obtained as pale yellow crystals. Recrystallization from ethyl acetate gave pale yellow prism crystals. Melting point 143-144 ° C. ¹ H-NMR (CDCl ₃ ) δ: 4.23 (2H, t, J = 4.6 Hz), 4.34 (2
H, t, J = 4.6 Hz), 6.76-6.88 (3H, m), 7.04-7.08 (2H,
m), 7.13 (1H, dd, J = 4.8, 3.8 Hz), 7.34 (1H, d, J = 1
6.0 Hz), 7.42-7.47 (3H, m), 7.61 (2H, s), 7.71 (1
H, dd, J = 3.8, 1.2Hz). IR (KBr): 1605, 1508, 1250, 909, 748, 733 cm ^-1 .

Example 32. 4-[(E) -2- [4- [3- (1H
-Imidazol-1-yl) propoxy] phenyl] etheni
Preparation of [L] -2- (2-thienyl) -1,3-oxazole

[Chemical 111] [2- (2-thienyl) -1.3-oxazol-4-yl] chloride
Methyltriphenylphosphonium (3.33g), 4- [3- (1
H-imidazol-1-yl) propoxy] benzaldehyde (1.50g), potassium carbonate (1.00g) and DMF (50m
The mixture of l) was stirred at room temperature for 15 hours. Chloride [2]
-(2-Thienyl) -1.3-oxazol-4-yl] methyltriphenylphosphonium (600 mg) and potassium carbonate (180 mg) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate: methanol = 10).
The crystals thus obtained were recrystallized from ethyl acetate to obtain the title compound (0.99 g) as pale yellow prism crystals. Melting point 125-126 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.17-2.30 (2H, m), 3.93 (2H, t,
J = 5.8 Hz), 4.20 (2H, t, J = 6.8 Hz), 6.81 (1H, d, J =
16.0 Hz), 6.85-6.93 (3H, m), 7.07 (1H, m), 7.13 (1
H, dd, J = 5.2, 3.6 Hz), 7.35 (1H, d, J = 16.0 Hz), 7.
43-7.49 (4H, m), 7.61 (1H, s), 7.72 (1H, dd, J = 3.6,
1.2 Hz). IR (KBr): 3157, 3103, 2934, 2872, 1603, 1589, 155
0, 1508, 1417, 1386, 1300, 1248, 1174, 1105, 1051,
1032, 1006, 966, 854, 819, 736, 661, 648 cm ^{- 1} .

Example 33. N- [2- (1H-imidazole
1-yl) ethyl] -N-methyl-4-[(E) -2-[(2-
Thienyl) -1,3-oxazol-4-yl] ethenyl] a
Nirin production

[Chemical 112] [2- (2-thienyl) -1.3-oxazol-4-yl] chloride
Methyltriphenylphosphonium (4.52g), 4- [N- [2
-(1H-imidazol-1-yl) ethyl] -N-methylamino] benzaldehyde (1.50 g), potassium carbonate (1.35
A mixture of g) and DMF (50 ml) was stirred at room temperature for 24 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate:
The crystals obtained were purified by recrystallization from ethyl acetate-hexane to give the title compound (0.71 g) as brown prism crystals. Melting point 118-119 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.77 (3H, s), 3.70 (2H, t, J = 6.0
Hz), 4.16 (2H, t, J = 6.0 Hz), 6.63 (2H, d, J = 8.8 H
z), 6.76 (1H, d, J = 16.2 Hz), 6.91 (1H, t, J = 1.2 H
z), 7.09 (1H, s), 7.13 (1H, dd, J = 5.2, 3.6 Hz), 7.
32 (1H, d, J = 16.2Hz), 7.40-7.46 (4H, m), 7.60 (1H,
s), 7.72 (1H, dd, J = 3.6, 1.2 Hz). IR (KBr): 3138, 2910, 1604, 1518, 1419, 1379, 134
2, 1230, 1213, 1184, 1089, 1003, 966, 906, 806, 73
3, 665, 648 cm ^-1 .

Example 34. 4-[(E) -2- [4- [2- (1
H-imidazol-1-yl) ethylthio] phenyl] e
[Tenyl] -2- (2-thienyl) -1,3-oxazole
Construction

[Chemical 113] [2- (2-thienyl) -1.3-oxazol-4-yl] chloride
Methyltriphenylphosphonium (7.16g), 4-[[2-
(1H-imidazol-1-yl) ethyl] thio] benzaldehyde (3.0 g), potassium carbonate (2.14 g) and DMF (5
(0 ml) was stirred at room temperature for 15 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: methanol = 50: 1), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (2.43 g) Was obtained as light brown prism crystals. Melting point 116-117 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.25 (2H, t, J = 6.8 Hz), 4.14 (2
H, t, J = 6.8 Hz), 6.92-6.93 (2H, m), 6.94 (1H, d, J
= 15.8 Hz), 7.06-7.07 (1H, m), 7.14 (1H, ddt, J = 4.8,
3.6, 1.0 Hz), 7.31-7.49 (6H, m), 7.66 (1H, s), 7.
73 (1H, dt, J = 3.6, 1.0 Hz). IR (KBr): 3146, 3105, 3034, 1593, 1508, 1491, 142
1, 1288, 1228, 1107, 1087, 1005, 964, 906, 848, 81
0, 734, 723, 663 cm ^-1 .

Example 35. 4-[(E) -2- [4-[[2- (1H
-Imidazol-1-yl) ethyl] sulfinyl] phenyl
L] ethenyl] -2- (2-thienyl) -1,3-oxazole
Manufacturing of

[Chemical 114] 4-[(E) -2- [4- [2- (1H-imidazol-1-yl) ethylthio] phenyl] ethenyl] -2- (2-thienyl) -1,3-oxazole (500 mg) in tetrahydrofuran (10 ml), m-chloroperbenzoic acid (280 mg) 0
The mixture was added at ℃, and stirred at the same temperature for 2 hours. Aqueous sodium sulfite solution was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate-methanol = 10: 1) to obtain the title compound (260 mg). Recrystallization from acetone-methanol gave colorless prism crystals. Melting point 182-183 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.04-3.28 (2H, m), 4.18-4.32 (1
H, m), 4.47-4.63 (1H, m), 6.95-7.09 (3H, m), 7.15
(1H, dd, J = 5.0, 3.6 Hz), 7.43 (1H, d, J = 15.4Hz),
7.48 (1H, dd, J = 5.0, 1.0 Hz), 7.53-7.69 (6H, m),
7.74 (1H, dd, J = 3.6, 1.0 Hz). IR (KBr): 3146, 3094, 2959, 1581, 1549, 1508, 149
3, 1423, 1369, 1290, 1240, 1087, 1047, 1030, 968,
906, 850, 817, 706, 648 cm ^-1 .

Example 36. 4-[(E) -2- [4-[[2- (1H
-Imidazol-1-yl) ethyl] sulfonyl] phenyl
L] ethenyl] -2- (2-thienyl) -1,3-oxazole
Manufacturing of

[Chemical 115] 4-[(E) -2- [4- [2- (1H-imidazol-1-yl) ethylthio] phenyl] ethenyl] -2- (2-thienyl) -1,3-oxazole (500 mg) in tetrahydrofuran (10 ml), m-chloroperbenzoic acid (535 mg) 0
The mixture was added at ℃, and stirred at the same temperature for 2 hours. Aqueous sodium sulfite solution was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: methanol = 20: 1) to obtain the title compound (440 mg). Recrystallization from acetone-methanol gave colorless prism crystals. Melting point 197-198 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.54 (2H, t, J = 7.2 Hz), 4.34 (2
H, t, J = 7.2 Hz), 6.85 (1H, s), 7.01 (1H, s), 7.09
(1H, d, J = 16.2 Hz), 7.15 (1H, dd, J = 5.2, 3.8Hz),
7.40-7.51 (2H, m), 7.64-7.86 (7H, m). IR (KBr): 3153, 3123, 3065, 1581, 1516, 1406, 130
5, 1253, 1238, 1149, 1136, 1105, 1078, 960, 904, 7
92, 736, 665, 576 cm ^-1 .

Example 37. N- [2- (2-pyridinyl) ethyl]
-N- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl]
Ethenyl} -1,3-oxazol-4-yl) methoxy] benz
Production of amine

[Chemical formula 116] 4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] benzyl aldehyde (0.4 g) in methylene chloride (6 ml) ) To the solution, molecular sieves 4A (0.4 g), 2- (pyridin-2-yl) ethylamine (0.17 g) and acetic acid (66 mg) were added, and the mixture was stirred at room temperature for 1 hour. Subsequently, sodium triacetoxyborohydride (0.34 g) was added, and the mixture was further stirred at room temperature for 3 hours. After the reaction, add water to the reaction solution,
The generated precipitate was collected by filtration. The filtered material was washed with water and diisopropanol, and the residue was recrystallized from ethyl acetate-hexane to give the title compound (0.35 g) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.98-3.06 (4H, m), 3.77 (2H,
s), 5.03 (2H, s), 6.94 (2H, d, J = 8.7 Hz), 7.02
(1H, d, J = 16.2 Hz), 7.10-7.18 (2H, m), 7.23 (2H,
d, J = 8.7 Hz), 7.55 (1H, d, J = 16.2 Hz), 7.56-7.62
(2H, m), 7.64 (4H, s), 7.68 (1H, s), 8.53 (1H, m). IR (KBr): 3302, 3156, 1613, 1591, 1514 cm ^-1 .

Example 38. 4-[[6- (1H-imidazole
1-ylmethyl) -2-naphthyloxy] methyl] -2-
Preparation of [(E) -2-phenylethenyl] -1,3-oxazole
Construction

[Chemical 117] 1H-imidazole (60 mg) in DMF (5 ml) at room temperature
After adding 60% sodium hydride (40 mg) and stirring for 1 hour, 4- (6-chloromethyl-2-naphthyloxymethyl) -2- was added at the same temperature.
[(E) -2-Phenylethenyl] -1,3-oxazole (280mg)
Was added and stirred at 90 ° C. for 1.5 hours. Pour the reaction solution into water,
It was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The extract was washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethanol to give the title compound (180 mg)
Was obtained as colorless prism crystals. Melting point 172-173 ° C. ¹ H-NMR (CDCl ₃ ) δ: 5.16 (2H, s), 5.24 (2H, s), 6.91
-7.00 (2H, m), 7.11 (1H, s), 7.21-7.28 (3H, m), 7.
36-7.40 (3H, m), 7.52-7.61 (5H, m), 7.70-7.77 (3H,
m). IR (KBr): 3119, 2920, 1608, 1506, 1394, 1267, 122
2,758 cm ^-1 .

Example 39. 4-[[6--3- (1H-imidazo
1-yl) propyl] -2-naphthyloxy] methyl]
-2-[(E) -2-Phenylethenyl] -1,3-oxazole
Manufacturing of

[Chemical 118] To a solution of 1H-imidazole (110 mg) in DMF (10 ml) was added 60% sodium hydride (70 mg) at room temperature, and after stirring for 1 hour,
3- [6-({2-[(E) -2-Phenylethenyl] -1,3-oxazol-4-yl} methoxy) -2-naphthyl] propyl (600mg) was added at the same temperature. The mixture was stirred at 90 ° C for 2 hours. The reaction solution was poured into water, and the precipitated crystals were collected by filtration and washed with diisopropyl ether to give the title compound (455 mg) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 169-170 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.10-2.30 (2H, m), 2.75 (2H, t,
J = 7.5 Hz), 3.96 (2H, t, J = 7.0 Hz), 5.15 (2H, s),
6.91-7.00 (3H, m), 7.20-7.61 (11H, m), 7.68-7.73
(3H, m). IR (KBr): 3123, 2945, 1606, 1506, 1444, 1213, 107
6, 819 cm ^-1 .

Example 40. 4-[[[2- (1H-imidazole
1-ylmethyl) -1-benzofuran-6-yl] oxy]
Methyl] -2-((E) -2-phenylethenyl) -1,3-oxy
Sazol production

[Chemical formula 119] 2- (1H-imidazol-1-ylmethyl) -1-benzofuran-6-
To a solution of all (115 mg) in DMF (5 ml) was added 60% sodium hydride (26 mg) at room temperature, and 4-chloromethyl-2-
[(E) -2-Phenylethenyl] -1,3-oxazole (140
mg) was added and the mixture was stirred at 70-80 ° C for 10 minutes. The reaction solution was poured into ice water, neutralized with acetic acid, and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 97: 3), and the obtained crystals were washed with diisopropyl ether to give the title compound (180 mg) as crystals. . Recrystallization from acetone-diisopropyl ether gave colorless prism crystals. Melting point 156-157 ° C. ¹ H-NMR (CDCl ₃ ) δ: 5.06 (2H, d, J = 1.0 Hz), 5.20 (2
H, s), 6.60 (1H, br s), 6.95 (1H, d, J = 16.5 Hz),
6.97 (1H, dd, J = 8.5, 2.0 Hz), 7.03 (1H, t, J = 1.0 H
z), 7.05-7.10 (2H, m), 7.65-7.30 (8H, m), 7.68 (1
H, br s).

Example 41. 3- (1H-imidazol-1-yl
Methyl) -7-[[2-[(E) -2-phenylethenyl] -1,3-
Preparation of oxazol-4-yl] methoxy] quinoline

[Chemical 120] 3- (1H-imidazol-1-ylmethyl) quinolin-7-ol (300 mg), 4-chloromethyl-2-[(E) -2-phenylethenyl] -1,3-oxazole (350 mg), potassium carbonate (180 mg) and DMF (10 ml) at 80-90 ° C
It was stirred for 2 hours. Water was poured into the reaction solution, which was extracted with ethyl acetate. The extract was washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent, ethyl acetate: methanol = 10: 1) to give the title compound (270 m
g) was obtained as colorless crystals. Recrystallization from ethanol gave colorless prism crystals. Melting point 182-183 ° C. ¹ H-NMR (CDCl ₃ ) δ: 5.19 (2H, s), 5.31 (2H, s), 6.9
2-7.00 (2H, m), 7.14 (1H, s), 7.29-7.80 (12H, m),
8.76 (1H, s) .IR (KBr): 3047, 1618, 1500, 1334, 1211, 970, 760 c
m ^-1 .

Example 42. 1- [4-[[2-[(E) -2- (4-trif
Luoromethylphenyl) ethenyl] -1,3-oxazole-4-
Ill] methoxy] phenyl] -4- (1H-1,2,3-triazole-1
-Yl) -1-butanone production

[Chemical 121] i) Preparation of 1- (4-hydroxyphenyl) -4- (1H-1,2,3-triazol-1-yl) -1-butanone 4-iodo- (4-methoxyphenyl) butanone (10.5 g),
1H-1,2,3-triazole (7.15g), potassium carbonate (7.15g
g) was stirred in DMF at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water and brine, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel chromatography (eluent: hexane: ethyl acetate = 1: 1 → ethyl acetate) to give 1- (4-
Methoxyphenyl) -4- (1H-1,2,3-triazol-1-yl)
-1-Butanone (2.05g) was obtained. This product (2.0 g) was stirred in 48% hydrobromic acid (7 mL) at 100 ° C. for 20 hours. After cooling, 3
The reaction solution was adjusted to pH 6 with 0% aqueous sodium hydroxide solution. The precipitated crystals were collected by filtration, washed with water and dried to give the title compound (1.8 g) as light brown needle crystals.

Ii) 1- [4-[[2-[(E) -2- (4-trifluoromethylphenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] -4- ( 1H-1,2,3-triazol-1-yl)-
Preparation of 1-butanone 1- (4-hydroxyphenyl) -4- (1H-1,2,3-triazole-
1-yl) -1-butanone (1.4 g), 2-[(E) -2- (4-trifluoromethylphenyl) ethenyl] -4- (chloromethyl) -1,3-oxazole (1.74 g), Add potassium carbonate (1.67 g) to DMF (10 m
L) and stirred overnight at room temperature. Water was added to the reaction solution, and the precipitated solid was collected by filtration. Purification by silica gel chromatography (eluent: dichloromethane: methanol = 20: 1) gave the title compound (931 mg) as pale yellow needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.25-2.50 (2H, m), 2.97 (2H, t,
J = 6.6 Hz), 4.53 (2H, t, J = 7.0 Hz), 5.10 (2H,
s), 6.97-7.08 (3H, m), 7.53-7.95 (8H, m), 7.89-7.9
5 (2H, m). IR (KBr): 1682, 1599, 1510, 1325, 1259 cm ^-1 .

Example 43. 1- [4-[[2-[(E) -2- (4-trif
Luoromethylphenyl) ethenyl] -1,3-oxazole-4-
Ill] methoxy] phenyl] -4- (1H-1,2,3-triazole-1
-Yl) -1-butanol production

[Chemical formula 122] 1- [4-[[2-[(E) -2- (4-trifluoromethylphenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] -4
-(1H-1,2,3-triazol-1-yl) -1-butanone (250 mg)
Sodium borohydride (59 mg) was added to a methanol-THF mixed solution (1: 2, 30 ml) solution of the above at 0 ° C, and the mixture was stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was stirred, neutralized with a 1N aqueous sodium hydroxide solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane: methanol = 20: 1),
The crystals were recrystallized from ethyl acetate to give the title compound (62 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.60-2.18 (4H, m), 4.39 (2H, t,
J = 7.6 Hz), 4.58-4.70 (1H, m), 4.99 (2H, s), 6.9
1-7.00 (3H, m), 7.18-7.35 (2H, m), 7.48-7.70 (8H,
m) .IR (KBr): 1612, 1510, 1327, 1248, 1172 cm ^-1 .

Example 44. 1- [4-[[2-[(E) -2- (4-bromo-
2-Fluorophenyl) ethenyl] -1,3-oxazole-4-i
]] Methoxy] phenyl] -4- (1H-1,2,3-triazole-1-
Ill) -1-butanol production

[Chemical 123] (I) 1- [4-[[2-[(E) -2- (4-bromo-2-fluorophenyl)
Preparation of ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] -4- (1H-1,2,3-triazol-1-yl) -1-butanone 1- (4-hydroxyphenyl)- 4- (1H-1,2,3-triazole-
1-yl) -1-butanone (300 mg), 65% sodium hydride (5
2.8 mg), 2-[(E) -2- (4-bromo-2-fluorophenyl) ethenyl] -4- (chloromethyl) -1,3-oxazole (452 mg) was used in Example 10- ( Perform the same reaction as for ii) to give the title compound (1
99 mg) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.30-2.43 (2H, m), 2.97 (2H, t,
J = 6.6 Hz), 4.53 (2H, t, J = 7.0 Hz), 5.10 (2H,
s), 6.99-7.08 (3H, m), 7.28-7.71 (7H, m), 7.89-7.9
4 (2H, m). IR (KBr): 1674, 1601, 1481, 1267, 1173 cm ^-1 .

(Ii) 1- [4-[[2-[(E) -2- (4-bromo-2-fluorophenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl]- 4- (1H-1,2,3-triazol-1-yl)-
Preparation of 1-butanol 1- [4-[[2-[(E) -2- (4-bromo-2-fluorophenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] -4
-(1H-1,2,3-triazol-1-yl) -1-butanone (150 m
Sodium borohydride (24.4 mg) was added to a methanol-THF mixed solution (2: 3; 25 ml) solution of g) at 0 ° C, and the mixture was stirred at room temperature for 3 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was stirred, 1N aqueous sodium hydroxide solution was added, and the solvent was evaporated under reduced pressure. The residue is water,
Then, after washing with diisopropyl ether, ethyl acetate-
Recrystallization from hexane gave the title compound (102 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.63-2.08 (4H, m), 4.43 (2H, t,
J = 7.0 Hz), 4.64-4.72 (1H, m), 5.03 (2H, s), 6.9
5-7.07 (3H, m), 7.21-7.69 (9H, m). IR (KBr): 1599, 1512, 1483, 1248, 1217 cm ^-1 .

Example 45. 4- [2- (hydroxymethyl) -1H
-Imidazol-1-yl] -1- [2-methyl-4-[[2-[(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl] -1,3-oxa
Zol-4-yl] methoxy] phenyl] -1-butanol
Construction

[Chemical formula 124] (i) Production of 1-bromo-4- (methoxymethoxy) -2-methylbenzene 4-bromo-3-methylphenol (10.0 g) in acetone (2
Potassium carbonate (11.1 g) and chloromethyl methyl ether (5.68 ml) were added to the (00 ml) solution, and the mixture was stirred at room temperature for 17 hr. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 50: 1) to give the title compound (12.4 g) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 2.36 (3H, s), 3.47 (3H, s), 5.1
4 (2H, s), 6.75 (1H, dd, J = 3.0, 8.8 Hz), 6.93 (1
H, d, J = 3.0 Hz), 7.40 (1H, d, J = 8.8 Hz) .IR (KB
r): 1478, 1238, 1155, 1082, 1022 cm ^-1 .

(Ii) Preparation of 4-hydroxy-1- [4- (methoxymethoxy) -2-methylphenyl] -1-butanone 1-Bromo-4- (methoxymethoxy) -2-methylbenzene (50
(0 mg) in THF (15 ml) at -78 ° C, hexane solution of n-butyllithium (1.6M; 1.49 ml) was added dropwise, and after stirring at the same temperature for 30 minutes, γ-butyrolactone (0.830 ml) was added dropwise. Then, the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane: ethyl acetate =
Purification by 3: 1 → 2: 1) gave the title compound (237 mg) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.84 (1H, br s), 1.94-2.04 (2H,
m), 2.53 (3H, s), 3.04 (2H, t, J = 7.5 Hz), 3.47
(3H, d, J = 0.9 Hz), 3.72-3.73 (2H, m), 5.03 (2H,
d, J = 0.9 Hz), 6.88-6.90 (2H, m), 7.73 (1H, d, J
= 9.3Hz) .IR (KBr): 1674, 1603, 1242, 1155, 992 cm ^-1 .

(Iii) 4-hydroxy-1- (4-hydroxy-2-
Preparation of methylphenyl) -1-butanone 4-hydroxy-1- [4- (methoxymethoxy) -2-methylphenyl] -1-butanone (510 mg) in THF (5 ml) was added 4N hydrochloric acid.
(5 ml) was added, and the mixture was stirred at 40 ° C for 3 hr. The reaction solution was extracted with ethyl acetate, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 1: 1) to obtain the title compound (291 mg) as a colorless amorphous substance. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.90-1.99 (2H, m), 2.49
(3H, s), 3.01 (2H, t, J = 6.6 Hz), 3.68 (2H, d, J =
5.7 Hz), 6.64-6.67 (2H, m), 7.69 (1H, d, J = 9.3H
z) .IR (KBr): 1653, 1603, 1260, 1204, 1055 cm ^-1 .

(Iv) 4-hydroxy-1- [2-methyl-4-[[2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl]-
Preparation of 1,3-oxazol-4-yl] methoxy] phenyl] -1-butanone 4-hydroxy-1- (4-hydroxy-2-methylphenyl) -1-butanone (250 mg), sodium hydride (52.4
mg), 4- (chloromethyl) -2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (370 mg)
Was performed in the same manner as in Example 10- (ii) to give the title compound
(257 mg) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.84 (1H, t, J = 5.4 Hz), 1.94-
2.03 (2H, m), 2.55 (3H, s), 3.05 (2H, t, J = 6.9 H
z), 3.70-3.76 (2H, m), 5.08 (2H, d, J = 0.6Hz), 6.
85-6.86 (2H, m), 7.01 (1H, d, J = 16.5 Hz), 7.53-
7.79 (7H, m). IR (KBr): 1325, 1248, 1169, 1127, 1069 cm ^-1 .

(V) 4-[[tert-butyl (dimethyl) silyl] oxy] -4- [2-methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) acetate] Preparation of phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] butyl 4-hydroxy-1- [2-methyl-4-[[2-[(E) -2- [4- ( Trifluoromethyl) phenyl] ethenyl] -1,3-oxazole-4-
Acetic anhydride (158 μl) was added to a solution of yl] methoxy] phenyl] -1-butanone (249 mg) in pyridine (3 ml), and the mixture was allowed to stand at room temperature for 1
It was stirred for 6 hours. After concentrating the reaction mixture, the residue is methanol-TH.
Dissolve in F mixture (5: 2; 14 ml) and add sodium borohydride.
(78.0 mg) was used to perform the same reaction as in Example 44- (ii), and 4-hydroxy-4- [2-methyl-4-[[2-[(E) -2- [4-
Crude product of (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] butyl
(251 mg) was obtained as a colorless amorphous. This product (251 m
To a solution of g) in DMF (3 ml) was added imidazole (135 mg) and tert-butyldimethylchlorosilane (273 mg), and the mixture was stirred at room temperature for 16
Stir for hours. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 8: 1) to obtain the title compound (266 mg) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: -0.01 (6H, s), 0.87 (9H, s), 1.5
7-1.65 (4H, m), 2.03 (3H, s), 2.28 (3H, s), 4.06
(2H, t, J = 5.8 Hz), 4.82 (1H, t, J = 6.9 Hz), 5.0
1 (2H, s), 6.73-6.84 (2H, m), 7.02 (1H, d, J = 16.
6 Hz), 7.35 (1H, d, J = 8.4 Hz), 7.51-7.68 (6H, m). IR (KBr): 1738, 1325, 1252, 1128, 1069 cm ^-1 .

(Vi) 1- [4-hydroxy-4- [2-methyl-4-[[2
-[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl]-
1,3-Oxazol-4-yl] methoxy] phenyl] butyl]-
Production of 1H-imidazole-2-carbaldehyde 4-[[tert-butyl (dimethyl) silyl] oxy] -4- [2-
Methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] butyl (256 mg) in methanol ( Potassium carbonate (175 mg) was added to the 4 ml) solution, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction solution, and the mixture was extracted with a mixed solution of ethyl acetate-isopropyl ether, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was depressurized to 4-[[tert-butyl (dimethyl) silyl] oxy] -4- [2-methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl]]. A crude product of ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] butan-1-ol (224 mg) was obtained as a colorless oil. This product (221 mg)
Solution of triethylamine (8 ml) in ethyl acetate (5 ml) at 0 ° C.
2.3 μl) and methanesulfonyl chloride (45.7 μl) were added, and the mixture was stirred at 0 ° C. for 1 hr. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to remove 4-[[tert-butyl (dimethyl) silyl] oxy] -4- [2-methyl-4-[[2-[(E) -2- [4- (tri A crude product of fluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] butyl was obtained. This product, 2-formylimidazole (39.7 mg), potassium carbonate
(54.3 mg), sodium iodide (58.9 mg) in DMF (4 ml)
The solution was heated at 70 ° C. for 18 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate. Reduce the solvent pressure to 1- [4-
[[tert-Butyl (dimethyl) silyl] oxy] -4- [2-methyl
-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] butyl] -1H-imidazol-2- Crude product of carbaldehyde
(251 mg) was obtained as a colorless oil. This product (244 mg) THF
(3 ml) solution with tetrabutylammonium fluoride T
HF solution (1.0 M; 1.18 ml) was added, and the mixture was stirred at room temperature for 20 hr. Saturated aqueous ammonium chloride was added to the reaction solution, which was extracted with ethyl acetate, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 1: 3) to obtain the title compound (151 mg) as a colorless amorphous substance. ¹ H-NMR (CDCl ₃ ) δ: 1.69-2.00 (4H, m), 2.29 (3H,
s), 4.44 (2H, t, J = 7.2Hz), 4.88-4.92 (1H, m), 5.
00 (2H, d, J = 0.6 Hz), 6.76 (1H, d, J = 2.4Hz),
6.84 (1H, dd, J = 2.4, 8.4 Hz), 7.00 (1H, d, J = 1
6.5 Hz), 7.15 (1H, s), 7.35 (1H, d, J = 8.4 Hz),
7.51-7.67 (7H, m), 9.77 (1H, d, J = 0.9Hz). IR (KBr): 1688, 1325, 1165, 1125, 1067 cm ^-1 .

(Vii) 4- [2- (hydroxymethyl) -1H-imidazol-1-yl] -1- [2-methyl-4-[[2-[(E) -2- [4- (tri Fluoromethyl) phenyl] ethenyl] -1,3-oxazole
Preparation of 4-yl] methoxy] phenyl] -1-butanol 1- [4-hydroxy-4- [2-methyl-4-[[2-[(E) -2- [4- (trifluoromethyl)) Phenyl] ethenyl] -1,3-oxazole
-4-yl] methoxy] phenyl] butyl] -1H-imidazole-
2-carbaldehyde (141 mg), sodium borohydride
(25.4 mg) was used to carry out the same reaction as in Example 44- (ii),
The title compound (91.1 mg) was obtained as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.69-2.02 (4H, m), 2.28 (3H,
s), 4.06 (2H, t, J = 6.8Hz), 4.64 (2H, s), 4.88 (1
H, t, J = 7.0 Hz), 5.00 (2H, s), 6.76-6.85 (4H,
m), 6.99 (1H, d, J = 16.4 Hz), 7.36 (1H, d, J = 8.
4 Hz), 7.50-7.68 (6H, m). IR (KBr): 1325, 1167, 1125, 1069, 758 cm ^-1 .

Example 46. [1- [3- [2-Methyl-4-[[2-[(E)
-2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-
Oxazol-4-yl] methoxy] phenoxy] propyl]-
Production of 1H-imidazol-2-yl] methanol

[Chemical 125] (i) 4-[[tert-butyl (diphenyl) silyl] oxy] -2-me
Preparation of tylphenol Methylhydroquinone (8.4 g)
Add imidazole to dimethylformamide (80 ml) solution.
(4.9 g) and tert-butylchlorodiphenylsilane (1
7.4 ml) was added, and the mixture was stirred under ice cooling for 3 hours. End of reaction
After that, water was added to the reaction solution, extracted with ethyl acetate, and saturated sodium chloride was added.
After washing with water, it was dried over anhydrous magnesium sulfate. Solvent
After evaporation under reduced pressure, the residue is subjected to silica gel column chromatography.
-(Eluent, ethyl acetate: hexane = 1:10)
The title compound (12.0 g) was obtained as a pale yellow oil.¹ H-NMR (CDCl₃) δ: 1.08 (9H, s), 2.11 (3H, s), 6.3
2 (1H, br s), 7.26-7.43 (10H, m), 7.62-7.68 (3H,
m). IR (KBr): 3140, 1522, 1488, 1256, 1160 cm ^-1.

(Ii) Preparation of tert-butyl [4- (3-chloropropoxy) -3-methylphenoxy] diphenylsilane 4-[[tert-butyl (diphenyl) silyl] oxy] -2-methylphenol (10.6 g To an acetone (250 ml) solution of) was added potassium carbonate (8.9 g) and 1-bromo-3-chloropropane (6.4 ml), and the mixture was heated under reflux for 20 hours. After completion of the reaction, water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline solution, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 15) to give the title compound (10.0 g) as a pale-yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (9H, s), 2.11 (3H, s), 2.1
8-2.20 (2H, m), 3.74 (2H, t, J = 6.2 Hz), 4.09 (2
H, t, J = 6.0 Hz), 7.26-7.43 (10H, m), 7.62-7.68
(3H, m). IR (KBr): 2976, 1675, 1488, 1435, 1264 cm
^-1 .

(Iii) [1- [3- [4-[[tert-butyl (diphenyl) silyl] oxy] -2-methylphenoxy] propyl] -1H-
Preparation of imidazol-2-yl] methanol tert-Butyl [4- (3-chloropropoxy) -3-methylphenoxy] diphenylsilane (10.0 g) in dimethylformamide (15 ml) in 2-formylimidazole (2.6
g), sodium iodide (4.1 g) and potassium carbonate (3.8 g) were added, and the mixture was heated at 70 ° C for 15 hours. After completion of the reaction, water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained crude aldehyde was used for the next reaction without purification. Methanol of the above crude aldehyde
(80 ml) solution, under ice-cooling, sodium borohydride
(0.43 g) was added and the mixture was stirred for 15 minutes. After completion of the reaction, water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline solution, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 1) to obtain the title compound (9.5 g) as pale yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (9H, s), 2.11 (3H, s), 2.1
5-2.23 (2H, m), 3.80 (2H, t, J = 5.4 Hz), 4.20 (2
H, t, J = 7.0 Hz), 4.63 (2H, br s), 6.42 (2H, d, J
= 1.4 Hz), 6.65 (1H, br s), 6.82 (1H, d, J = 1.4 H
z), 6.89 (1H, d, J = 1.4 Hz), 7.26-7.42 (6H, m), 7.
68-7.73 (4H, m). IR (KBr): 3136, 1499, 1474, 1427,
1219 cm ^-1 .

(Iv) Preparation of 4- [3- [2-[(hydroxymethyl) -1H-imidazol-1-yl] propoxy] -3-methylphenol [1- [3- [4-[[tert- Butyl (diphenyl) silyl] oxy] -2
-Methylphenoxy] propyl] -1H-imidazol-2-yl] methanol (5.0 g) in tetrahydrofuran (80 m
l) In solution, add tetra-n-butylammonium chloride
(13.0 ml) was added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent, ethyl acetate: methanol =
Purification with 10: 1) gave the title compound (2.1 g) as white powder crystals. ¹ H-NMR (d ₆ -DMSO) δ: 2.11 (3H, s), 2.10-2.16 (2H,
m), 3.80 (2H, t, J = 6.0 Hz), 4.17 (2H, t, J = 6.9
Hz), 4.44 (2H, d, J = 5.7 Hz), 5.26 (1H, t, J = 5.
7 Hz), 6.48 (1H, dd, J = 2.4, 9.3 Hz), 6.55 (1H,
d, J = 2.4 Hz), 6.66 (1H, d, J = 9.3 Hz), 6.78 (1H,
s), 7.10 (1H, s), 8.79 (1H, s). IR (KBr): 3142, 1
491, 1473, 1223, 1022 cm ^-1 .

(V) [1- [3- [2-methyl-4-[[2-[(E) -2- [4-
Preparation of (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] phenoxy] propyl] -1H-imidazol-2-yl] methanol 4- [3- [2-[(hydroxymethyl ) -1H-Imidazol-1-yl] propoxy] -3-methylphenol (0.50 g) in dimethylformamide (7 ml) was added 60% oily sodium hydride (74 mg) under ice-cooling at room temperature. Stir for minutes. 4- (chloromethyl) -2-[(E)-was added to the reaction solution under ice cooling.
2- [4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (0.55 g) was added, and the mixture was stirred at room temperature for 5 hours.
After the reaction was completed, water was added to the reaction solution and extracted with ethyl acetate,
The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate: methanol = 10:
Purification in 1) gave the title compound (0.52 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.25 (3H, s), 2.25-2.30 (2H,
m), 3.90 (2H, t, J = 5.4Hz), 4.25 (2H, t, J = 6.6
Hz), 4.68 (2H, s), 4.98 (2H, s), 6.65-6.86 (3H,
m), 6.88 (1H, d, J = 1.0 Hz), 6.93 (1H, d, J = 1.0
Hz), 7.01 (1H, d, J = 16.4 Hz), 7.55 (1H, d, J = 1
6.4 Hz), 7.64 (4H, s), 7.67 (1H, s). IR (KBr): 334
3, 1501, 1325, 1219, 1069 cm ^-1 .

Example 47. [1- [3- [4-[[2-[(E) -2- (4-block
Lomo-2-fluorophenyl) ethenyl] -1,3-oxazole
-4-yl] methoxy] -2-methylphenoxy] propyl] -1H-
Production of imidazol-2-yl] methanol

[Chemical formula 126] 4- [3- [2-[(Hydroxymethyl) -1H-imidazol-1-yl] propoxy] -3-methylphenol (0.40 g), 60%
Oily sodium hydride (59 mg) and 2-[(E) -2- [4-
Bromo-2-fluoromethyl] ethenyl] -4- (chloromethyl)
Example 46- (v) using -1,3-oxazole (0.48 g)
The title compound (0.43 g) was obtained as a white powder crystal by performing the same reaction as described above. ¹ H-NMR (CDCl ₃ ) δ: 2.25 (3H, s), 2.25-2.30 (2H,
m), 3.89 (2H, t, J = 5.4Hz), 4.25 (2H, t, J = 6.8
Hz), 4.68 (2H, s), 4.98 (2H, s), 6.65-6.86 (3H,
m), 6.89 (1H, d, J = 1.0 Hz), 6.94 (1H, d, J = 1.0
Hz), 7.04 (1H, d, J = 16.4 Hz), 7.26-7.47 (3H, m),
7.57 (1H, d, J = 16.4 Hz), 7.66 (1H, s). IR (KB
r): 3136, 1505, 1480, 1223, 1034 cm ^-1 .

Example 48. [1- [3-[[2-methyl-4-[[2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl]-
1,3-Oxazol-4-yl] methoxy] phenoxy] ami
[] Propyl] -1H-imidazol-2-yl] methanol
Construction

[Chemical 127] (i) Preparation of benzyl 4-hydroxy-2-methylphenylcarbamate Benzyl chloroformate was added to a solution of 4-amino-3-methylphenol (25.0 g) in diethyl ether (900 ml) under ice cooling.
Add a solution of (14.5 ml) in diethyl ether (100 ml),
The mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was filtered through Celite and the solvent was evaporated under reduced pressure to give the title compound (26.0 g)
Was obtained as brown powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.14 (3H, s), 5.20 (2H, s), 6.3
4 (1H, br s), 6.50-6.60 (3H, m), 7.21 (1H, br s),
7.39 (5H, br s). IR (KBr): 3268, 1692, 1510,1453,
1217 cm ^-1 .

(Ii) Benzyl 4- (methoxymethoxy) -2-
Preparation of methylphenyl carbamate Benzyl 4-hydroxy-2-methylphenyl carbamate
(15.0 g) in acetone (200 ml) in potassium carbonate
(15.0 g) and chloromethyl methyl ether (5.3 m
l) was added and the mixture was heated under reflux for 18 hours. After completion of the reaction, water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline solution, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 5) to obtain the title compound (9.3 g) as brown powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 3.21 (3H, s), 3.4
6 (3H, s), 5.13 (2H, s), 5.18 (2H, s), 6.85-6.89
(3H, m), 7.33-7.39 (5H, m), 7.58 (1H, br s) .IR (KB
r): 3312, 1707, 1526, 1217, 1026 cm ^-1 .

(Iii) Benzyl 3- [2- (hydroxymethyl)
Preparation of -1H-imidazol-1-yl] propyl [4- (methoxymethoxy) -2-methylphenyl] carbamate Benzyl 4- (methoxymethoxy) -2-methylphenylcarbamate (8.8 g) in dimethylformamide (150 ml) To the solution was added 60% oily sodium hydride (1.4 g) under ice cooling, and the mixture was stirred at room temperature for 20 minutes. Add 1- to the reaction solution under ice cooling.
Bromo-3-chloropropane (3.8 ml) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline solution, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 5), and benzyl 3-chloropropyl [4-
(Methoxymethoxy) -2-methylphenyl] carbamate
(1.0 g) was obtained as pale yellow powder crystals. Benzyl 3-chloropropyl [4- (methoxymethoxy) -2-methylphenyl] carbamate (1.0 g), 2-formylimidazole (0.31 g), sodium iodide (0.48 g) and potassium carbonate (0.44 g) and hydrogenation Sodium boron (49
was carried out in the same manner as in Example 46- (iii) to give the title compound (0.8 g) as pale yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.03 (3H, s), 2.02-2.15 (2H,
m), 3.33 (1H, m), 3.46 (3H, s), 3.84 (1H, m), 3.95
-4.09 (2H, m), 4.54 (2H, br s), 5.01-5.13 (2H, m),
5.14 (2H, s), 6.76-7.00 (6H, m), 7.13-7.34 (4H,
m). IR (KBr): 3112, 1696, 1505, 1454, 1013 cm ^-1 .

(Iv) Benzyl 3- [2- (hydroxymethyl)-
Preparation of 1H-imidazol-1-yl] propyl [4-hydroxy-2-methylphenyl] carbamate Benzyl 3- [2- (hydroxymethyl) -1H-imidazol-1
-Yl] propyl [4- (methoxymethoxy) -2-methylphenyl] carbamate (8.0 g) in tetrahydrofuran (100 m
l) A 2N hydrochloric acid (80 ml) aqueous solution was added to the solution, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, 2N aqueous sodium hydroxide solution was added to neutralize under ice cooling. Toluene was added to the reaction solution and evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography.
(Eluate, ethyl acetate: methanol = 9: 1) to give the title compound (6.7 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.98 (3H, s), 1.98-2.05 (2H,
m), 3.26 (1H, m), 3.80 (1H, m), 3.84-4.01 (2H, m),
4.53 (2H, br s), 4.97-5.15 (2H, m), 6.54-6.65 (2H,
m), 6.79 (3H, br s), 7.15-7.34 (6H, m). IR (KBr):
3031, 1682, 1505, 1456, 1300 cm ^-1 .

(V) Benzyl 3- [2- (hydroxymethyl) -1
H-imidazol-1-yl] propyl [2-methyl-4-[[2-[(E)
-2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-
Preparation of oxazol-4-yl] methoxy] phenyl] carbamate Benzyl 3- [2- (hydroxymethyl) -1H-imidazol-1
-Yl] propyl [4-hydroxy-2-methylphenyl] carbamate (0.78 g), 60% oily sodium hydride (76
mg) and 4- (chloromethyl) -2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (0.
The same reaction as in Example 46- (v) was performed using 57 g) to give the title compound (0.57 g) as pale-yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.05 (3H, s), 2.03-2.10 (2H,
m), 3.35 (1H, m), 3.86 (1H, m), 3.91-4.10 (2H, m),
4.56-4.59 (2H, m), 5.02 (2H, br s), 5.07-5.17 (2H,
m), 6.66-6.86 (6H, m), 7.03 (1H, d, J = 16.6 Hz),
7.17-7.37 (4H, m), 7.55 (1H, d, J = 16.6 Hz),
7.64 (4H, s), 7.69 (1H, s). IR (KBr): 3028, 1684,
1536, 1420, 1223 cm ^-1 .

(Vi) [1- [3-[[2-Methyl-4-[[2-[(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] phenoxy] amino] propyl]
Production of -1H-imidazol-2-yl] methanol Benzyl 3- [2- (hydroxymethyl) -1H-imidazol-1
-Yl] propyl [2-methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole-4-
Il] methoxy] phenyl] carbamate (0.2 g), 6N
An aqueous solution of hydrochloric acid (3 ml) was added and the mixture was heated under reflux for 1 hour. After completion of the reaction, sodium hydroxide was added thereto for neutralization under ice cooling, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound.
(80 mg) was obtained as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.14 (3H, s), 2.11-2.17 (2H,
m), 3.13 (2H, t, J = 6.0Hz), 4.16 (2H, t, J = 6.3
Hz), 4.69 (2H, s), 4.96 (2H, s), 6.48 (1H, d, J =
8.4 Hz), 6.75-6.80 (2H, m), 6.89 (1H, d, J = 1.2 H
z), 6.93 (1H, d, J = 1.2 Hz), 7.01 (1H, d, J = 16.5
Hz), 7.53 (1H, d, J = 16.5 Hz), 7.62 (4H, s),
7.65 (1H, s). IR (KBr): 3362, 3100, 1514, 1325, 11
67 cm ^-1 .

Example 49. N- [3- [2- (hydroxymethyl)
-1H-imidazol-1-yl] propyl] -N- [2-methyl-4-
[[2-[(E) -2- [4- (trifluoromethyl) phenyl] etheni
L] -1,3-Oxazol-4-yl] methoxy] phenyl] ace
Toamide production

[Chemical 128] [1- [3-[[2-Methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] Phenoxy] amino] propyl] -1H-imidazole-2
-Yl] methanol (60 mg) in methylene chloride (2 ml), pyridine (50 μl) and acetic anhydride (34 μl)
Was added, and the mixture was stirred at room temperature for 10 hours. After completion of the reaction, toluene was added to the reaction solution and the solvent was distilled off under reduced pressure to obtain crude bisacetate. Potassium carbonate (48 mg) was added to a solution of the crude bisacetate in methanol (2 ml), and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 95: 5) to give the title compound (35 mg) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.76 (3H, s), 1.97-2.13 (2H,
m), 2.19 (3H, s), 3.10 (1H, m), 4.06-4.24 (3H, m),
4.63 (2H, br s), 5.03 (3H, s), 7.01 (1H, d, J = 1
6.2 Hz), 6.83-7.02 (5H, m), 7.55 (1H, d, J = 16.2
Hz), 7.63 (4H, s), 7.70 (1H, s). IR (KBr): 3123, 1
651, 1502, 1325, 1167 cm ^-1 .

Example 50. [1- [3- [4-[[2-[(E) -2- [2-
Luoro-4- (trifluoromethyl) phenyl] ethenyl] -1,
3-Oxazol-4-yl] methoxy] -2-methylphenoxy
[] Propyl] -1H-imidazol-2-yl] methanol
Construction

[Chemical formula 129] 4- [3- [2-[(Hydroxymethyl) -1H-imidazol-1-yl] propoxy] -3-methylphenol (0.30 g), 60%
Oily sodium hydride (44 mg) and 4- (chloromethyl) -2-[(E) -2- [2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (0.35 g ) Was used to perform the same reaction as in Example 46- (v), and the title compound (0.
29 g) was obtained as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.25 (3H, s), 2.21-2.30 (2H,
m), 3.90 (2H, t, J = 5.8Hz), 4.25 (2H, t, J = 7.0
Hz), 4.67 (2H, s), 4.98 (2H, s), 6.65-6.79 (2H,
m), 6.84-6.93 (3H, m), 7.13 (1H, d, J = 16.8 Hz),
7.35-7.46 (2H, m), 7.60-7.71 (3H, m). IR (KBr): 332
6, 1501, 1429, 1333, 1219 cm ^-1 .

Example 51. [1- [2-[[2-Methyl-4-[[2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl]-
1,3-Oxazol-4-yl] methoxy] benzyl] oxy]
Production of ethyl] -1H-imidazol-2-yl] methanol

[Chemical 130] (i) Preparation of 4-methoxy-2-methylbenzaldehyde 2-Bromo-5-methoxytoluene (5.0 g) in tetrahydrofuran (80 ml) was added to butyllithium (1.6 g) at -78 ° C.
M hexane solution: 19.1 ml) was added and the mixture was stirred for 30 minutes.
Subsequently, a dimethylformamide (3.9 ml) solution was added and the mixture was stirred at the same temperature for 1 hour. After the reaction, add water to the reaction solution,
It was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate
: Hexane = 1: 7) to give the title compound (3.2 g) as pale yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.65 (3H, s), 3.87 (3H, s), 6.7
4 (1H, d, J = 2.6 Hz), 6.84 (1H, dd, J = 2.6, 8.6 H
z), 7.75 (1H, d, J = 8.6 Hz), 10.11 (1H, s). IR (K
Br): 1688, 1599, 1566, 1499, 1250 cm ^-1 .

(Ii) Preparation of 4-hydroxy-2-methylbenzaldehyde A solution of 4-methoxy-2-methylbenzaldehyde (3.0 g) in methylene chloride (40 ml) was added to boron tribromide (0.
7 M methylene chloride solution: 36 ml) was added and the mixture was stirred for 3 days. After completion of the reaction, water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline solution, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate: hexane = 1:
Purification in 4) gave the title compound (1.9 g) as pale-yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.64 (3H, s), 6.29 (1H, br s),
6.72 (1H, d, J = 2.6 Hz), 6.81 (1H, dd, J = 2.6,
8.2 Hz), 7.73 (1H, d, J = 8.2 Hz), 10.09 (1H, s). I
R (KBr): 3130, 1680, 1561, 1305, 1205 cm ^-1 .

(Iii) 2-Methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole-4
Preparation of 4-yl] methoxy] benzaldehyde To a solution of 4-hydroxy-2-methylbenzaldehyde (1.1 g) in dimethylformamide (20 ml) was added 4- (chloromethyl) -2-[(E) -2- [4- (tri Fluoromethyl) phenyl] ethenyl] -1,3-oxazole (2.3 g), sodium iodide (1.5 g) and potassium carbonate (1.7 g) were added, and the temperature was 40 ° C.
Heated for 12 hours. After the reaction, add water to the reaction solution,
It was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate
: Hexane = 1: 4) to give the title compound (1.4 g) as pale yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.66 (3H, s), 5.10 (2H, s), 6.8
5 (1H, d, J = 2.7 Hz), 6.94 (1H, dd, J = 2.7, 8.7 H
z), 7.01 (1H, d, J = 16.5 Hz), 7.55 (1H, d, J = 16.
5 Hz), 7.63 (4H, s), 7.70 (1H, s), 7.76 (1H, d, J
= 8.7 Hz), 10.12 (1H, s). IR (KBr): 1674, 1599, 13
27, 1252, 1175 cm ^-1 .

(Iv) [2-Methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole-4
Preparation of 2-yl] methoxy] phenyl] methanol 2-methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] To a solution of [methoxy] benzaldehyde (1.0 g) in methanol (20 ml) was added sodium borohydride (40 mg) under ice cooling.
Stir for 15 minutes. After completion of the reaction, water was added to the reaction solution and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, water,
The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 1).
The title compound (0.95 g) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.37 (3H, s), 4.65 (2H, s), 5.0
3 (2H, s), 6.78-6.84 (2H, m), 7.02 (1H, d, J = 16.
4 Hz), 7.25 (1H, d, J = 8.2 Hz), 7.55 (1H, d, J =
16.4 Hz), 7.63 (4H, s), 7.68 (1H, s). IR (KBr): 34
25, 1605, 1510, 1327, 1127 cm ^-1 .

(V) tert-butyl [[2-methyl-4-[[2-[(E) -2
Preparation of-[4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] benzyl] oxy] acetate [2-methyl-4-[[2-[(E) -2 -[4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] methanol (0.27 g) in toluene (4 ml) and 50% sodium hydroxide (1 ml) mixed To the solution were added tert-butyl bromoacetate (205 μl) and tetrabutylammonium hydrogen sulfate (24 mg), and the mixture was stirred for 15 hours. After completion of the reaction, the mixture was neutralized with 3N hydrogen chloride aqueous solution under ice cooling, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 3) to give the title compound (0.28 g) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.38 (3H, s), 3.9
7 (2H, s), 4.57 (2H, s), 5.03 (2H, s), 6.77-6.84
(2H, m), 7.01 (1H, d, J = 16.4 Hz), 7.24 (1H, d, J
= 8.4 Hz), 7.55 (1H, d, J = 16.4 Hz), 7.64 (4H,
s), 7.68 (1H, s). IR (KBr): 1748, 1615, 1505, 1325, 1167 cm ^-1 .

(Vi) 2-[[2-Methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] Production of methoxy] benzyl] oxy] ethanol tert-butyl [[2-methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole- Lithium aluminum hydride (21 mg) was added to a solution of 4-yl] methoxy] benzyl] oxy] acetate (0.4 g) in tetrahydrofuran (10 ml) under ice cooling, and the mixture was stirred for 30 minutes. After completion of the reaction, an appropriate amount of water was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was filtered through Celite, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 1) to give the title compound (0.32 g) as colorless powder crystals. It was ¹ H-NMR (CDCl ₃ ) δ: 2.35 (3H, s), 3.57-3.64 (2H,
m), 3.76 (2H, t, J = 4.0Hz), 4.50 (2H, s), 5.03 (2
H, s), 6.77-6.85 (2H, m), 7.01 (1H, d, J = 16.4 H
z), 7.22 (1H, d, J = 8.0 Hz), 7.55 (1H, d, J = 16.
4 Hz), 7.63 (4H, s), 7.68 (1H, s). IR (KBr): 336
6, 1615, 1505, 1325, 1123 cm ^-1 .

(Vii) [1- [2-[[2-methyl-4-[[2-[(E) -2- [4
-(Trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] benzyl] oxy] ethyl] -1H-
Preparation of imidazol-2-yl] methanol 2-[[2-methyl-4-[[2-[(E) -2- [4- (trifluoromethyl))
Phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] benzyl] oxy] ethanol (0.2 g) in methylene chloride (4 ml) was added to triethylamine (0.1 m
l) and methanesulfonyl chloride (45 μl) were added 15
Stir for minutes. After completion of the reaction, water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained crude mesylate was used for the next reaction without purification. Using the above crude mesylate, 2-formylimidazole (54 mg), sodium iodide (84 mg) and potassium carbonate (80 mg), and sodium borohydride (10 mg), the same reaction as in Example 46- (iii) The title compound (0.1 g)
Was obtained as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s), 3.71 (2H, t, J =
5.0 Hz), 4.18 (2H, t, J = 5.0 Hz), 4.43 (2H, s), 4.
66 (2H, s), 5.02 (2H, s), 6.73-6.81 (2H, m), 6.92-
6.97 (2H, m), 7.01 (1H, d, J = 16.4 Hz), 7.09 (1H,
d, J = 8.0 Hz), 7.55 (1H, d, J = 16.4 Hz), 7.64
(4H, s), 7.68 (1H, s). IR (KBr): 3431, 1611, 1505,
1325, 1125 cm ^-1 .

Example 52. [1- [2-[[2-methyl-4- [2- [2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl]-
1,3-oxazol-4-yl] ethyl] benzyl] amino] d
[Chill] -1H-imidazol-2-yl] methanol production

[Chemical 131] To a solution of [1- (2-aminoethyl) -1H-imidazol-2-yl] methanol (0.14 g) in methylene chloride (6 ml) was added 2-methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] benzaldehyde (0.3 g), 4A molecular sieves (0.3 g),
Acetic acid (47 mg) was added, and the mixture was stirred at room temperature for 1 hr. Subsequently, sodium triacetoxyborohydride (0.5 g) was stirred at the same temperature for 2 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added for neutralization under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crystals are ethyl acetate
Recrystallization from -hexane gave the title compound (0.4 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.26 (3H, s), 2.98 (2H, t, J =
5.1 Hz), 3.16 (2H, s), 4.10 (2H, t, J = 5.1 Hz), 4.
66 (2H, s), 5.00 (2H, s), 6.75-6.98 (2H, m), 6.89
(1H, d, J = 0.9 Hz), 6.99 (1H, d, J = 0.9 Hz), 7.0
1 (1H, d, J = 16.5 Hz), 7.07 (1H, d, J = 8.1 Hz),
7.54 (1H, d, J = 16.5 Hz), 7.63 (4H, s), 7.66 (1H,
s) .IR (KBr): 3308, 3187, 1671, 1578, 1327 cm ^-1 .

Example 53. N- [2- [2- (hydroxymethyl)
-1H-imidazol-1-yl] ethyl] -N- [2-methyl-4- [2-
[2-[(E) -2- [4- (trifluoromethyl) phenyl] etheni
]]-1,3-Oxazol-4-yl] ethyl] benzyl] aceto
Amide production

[Chemical 132] [1- [2-[[2-Methyl-4- [2- [2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl]] Ethyl] benzyl] amino] ethyl] -1H-imidazol-2-yl] methanol (0.2 g), pyridine (0.16 ml) and acetic anhydride (0.15 ml) and potassium carbonate (0.1 g) were used to give Example 49 and The title compound (0.
12 g) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 2.10 (3H, s), 2.14 (3H, s), 3.6
3 (2H, t, J = 6.6 Hz), 4.15 (2H, s), 4.17 (2H, t, J
= 6.6 Hz), 4.58 (2H, s), 5.00 (2H, s), 6.81-6.89
(5H, m), 7.00 (1H, d, J = 16.2 Hz), 7.53 (1H, d, J
= 16.2 Hz), 7.62 (4H, s), 7.67 (1H, s). IR (KBr):
3136, 1645, 1501, 1325, 1127 cm ^-1 .

Example 54. [1- [2-[[2-Methyl-4-[[2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl]-
1,3-oxazol-4-yl] methoxy] benzyl] thio] d
[Chill] -1H-imidazol-2-yl] methanol production

[Chemical 133] (I) 2-[[2-Methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] benzyl ] Thio] ethanol production [2-methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl ] Methanol (0.6 g) in methylene chloride (5 ml)
Add pyridine (1.2 ml), tri-n-butylphosphine to the solution.
(1.2 ml) and 2- [2-[[2- (tetrahydro-2H-pyran-2
-Nyloxy) ethyl] dithio] ethoxy] tetrahydro-2H
-Pyran (1.5 g) was added and stirred at room temperature for 13 hours. After the reaction was completed, 2N sodium hydroxide aqueous solution was added to the reaction solution,
The mixture was extracted with ethyl acetate, washed with 2N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane: methylene chloride = 1: 10: 1) to obtain a crude sulfide. To a solution of the above crude sulfide in tetrahydrofuran (10 ml), add 1
An aqueous solution of N hydrogen chloride (5 ml) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 1N aqueous sodium hydroxide solution was added to the reaction solution under ice cooling to neutralize it, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 2: 3) to give the title compound (0.45 g)
Was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.39 (3H, s), 2.82 (2H, t, J =
6.6 Hz), 3.61 (2H, s), 4.01-4.04 (2H, m), 5.02 (2H,
s), 6.77 (1H, dd, J = 2.6, 8.4 Hz), 6.84 (1H, d,
J = 2.6 Hz), 7.01 (1H, d, J = 16.6 Hz), 7.11 (1H,
d, J = 8.4 Hz), 7.55 (1H, d, J = 16.6 Hz), 7.64 (4
H, s), 7.68 (1H, s). IR (KBr): 3340, 1613, 1568, 1
233, 1058 cm ^-1 .

(Ii) [1- [2-[[2-Methyl-4-[[2-[(E) -2- [4-
Preparation of (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] benzyl] thio] ethyl] -1H-imidazol-2-yl] methanol 2-[[2-methyl-4- [[2-[(E) -2- [4- (trifluoromethyl)
Phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] benzyl] thio] ethanol (0.7 g), triethylamine (0.33 ml) and methanesulfonyl chloride (0.15 m
l) was used to carry out the same reaction as in Example 51- (vii) to obtain a crude mesylate. Using the above crude mesylate, 2-formylimidazole (0.18 mg), sodium iodide (0.29 g) and potassium carbonate (0.27 g) and sodium borohydride (14 mg), the same as in Example 46- (iii) The reaction was performed to give the title compound (0.35 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.36 (3H, s), 2.82 (2H, t, J =
6.6 Hz), 3.61 (2H, s), 4.05 (2H, t, J = 6.6 Hz), 4.
66 (2H, br s), 5.02 (2H, s), 6.75-6.96 (4H, m), 7.0
1 (1H, d, J = 16.4 Hz), 7.07 (1H, d, J = 10.0 Hz),
7.55 (1H, d, J = 16.4 Hz), 7.64 (4H, s), 7.68 (1H,
s) .IR (KBr): 3354, 1614, 1578, 1499, 1167 cm ^-1 .

Example 55. 1- [2-[[2-methyl-4-[[2-[(E)
-2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-
Oxazol-4-yl] methoxy] benzyl] sulfini
Of [L] ethyl] -1H-imidazol-2-yl] methanol

[Chemical 134] [1- [2-[[2-Methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] Benzyl] thio] ethyl] -1H-imidazol-2-yl]
Methanol (50 mg) in methylene chloride (2 ml) at -78 ° C
At 70%, metachloroperbenzoic acid (24 mg) was added and the mixture was stirred for 1 hour. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by amine silica gel column chromatography (eluent, ethyl acetate: methanol = 4: 1) to obtain the title compound (31 mg) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.34 (3H, s), 3.01-3.18 (2H,
m), 3.94 (1H, d, J = 13.6 Hz), 4.07 (1H, d, J = 1
3.6 Hz), 4.50 (2H, t, J = 5.6 Hz), 4.67 (2H, brs),
5.01 (2H, s), 6.78-6.85 (2H, m), 6.91-6.95 (2H,
m), 7.03 (1H, d, J = 16.4 Hz), 7.09 (1H, d, J = 8.0
Hz), 7.54 (1H, d, J = 16.4 Hz), 7.64 (4H, s), 7.6
8 (1H, s). IR (KBr): 3287, 1615, 1578, 1501, 1327
cm ^-1 .

Example 56. 1- [2-[[2-methyl-4-[[2-[(E)
-2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-
Oxazol-4-yl] methoxy] benzyl] sulfonyl
Of [L] ethyl] -1H-imidazol-2-yl] methanol

[Chemical 135] [1- [2-[[2-Methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] Benzyl] thio] ethyl] -1H-imidazol-2-yl]
To methylene chloride (2 ml) in methanol (0.15 g), add 70% metachloroperbenzoic acid (0.18 g) under ice cooling.
Stir for minutes. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated brine,
It was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure,
Amine silica gel column chromatography of the residue
(Eluate, ethyl acetate: methanol = 10: 1) to give the title compound (0.12 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.39 (3H, s), 3.50 (2H, t, J =
7.0 Hz), 4.11 (2H, s), 4.44 (2H, t, J = 7.0 Hz), 4.
71 (2H, s), 5.02 (2H, s), 6.86 (1H, m), 6.88 (1H,
d, J = 1.0 Hz), 6.97 (1H, s), 6.99 (1H, d, J = 1.0
Hz), 7.01 (1H, d, J = 16.4 Hz), 7.16 (1H, d, J =
8.0 Hz), 7.55 (1H, d, J = 16.4 Hz), 7.64 (4H, s),
7.68 (1H, s). IR (KBr): 3371, 1617, 1577, 1458, 12
98 cm ^-1 .

Example 57. [1- [3- [4- [2- [2-[(E) -2- (4-
Bromo-2-fluorophenyl) ethenyl] -1,3-oxazol
Lu-4-yl] ethyl] phenoxy] propyl] -1H-imidazo
-2- yl] Methanol production

[Chemical 136] (i) Preparation of 2-[(E) -2- (4-bromo-2-fluorophenyl) ethenyl] -4- [2- (4-methoxyphenyl) ethyl] -1,3-oxazole 4- (4 -Methoxyphenyl) butan-2-one (40.0 g) in methanol (90 ml) was added dropwise with bromine (37.7 g) in methanol (90 ml) at 7-10 ° C over 30 minutes, and the mixture was stirred for 1 hour. After the reaction was completed, water (224 ml) was added to the reaction solution and the mixture was stirred at room temperature for 1
Stir for 5 hours. The aqueous layer was extracted with ethyl acetate, washed with water and saturated saline, and then dried over anhydrous magnesium sulfate together with the organic layer. After distilling off the solvent under reduced pressure, hexane (500 m
l) was added and the mixture was cooled at -10 ° C for 24 hours. The obtained crystals were collected by filtration, and 1-bromo-4- (4-methoxyphenyl) butane-
2-one and 3-bromo-4- (4-methoxyphenyl) butane
The 2-one was obtained as a 4: 1 inseparable mixture. To a solution of the above mixture (6.3 g) in toluene (100 ml), add (2E)-
3- (4-bromo-2-fluorophenyl) pro-2-pentamide
(5 g) was added and the mixture was heated under reflux for 10 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, water,
The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane: methylene chloride = 1: 10: 1) to give the title compound (1.3 g)
Was obtained as brown powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.81-3.00 (4H, m), 3.79 (3H,
s), 6.83 (2H, d, J = 8.4Hz), 7.02 (1H, d, J = 16.4
Hz), 7.11 (2H, d, J = 8.4 Hz), 7.28-7.46 (4H, m),
7.51 (1H, d, J = 16.4 Hz). IR (KBr): 1636, 1590,
1514, 1480, 1252cm ^-1 .

(Ii) Preparation of 4- [2- [2-[(E) -2- (4-bromo-2-fluorophenyl) ethenyl] -1,3-oxazol-4-yl] ethyl] phenol 2 -[(E) -2- (4-Bromo-2-fluorophenyl) ethenyl] -4-
[2- (4-methoxyphenyl) ethyl] -1,3-oxazole
(4.4 g), boron tribromide (1.0 M methylene chloride solution: 13
The reaction (reaction time: 3.5 hours) was performed in the same manner as in Example 51- (ii) to give the title compound (3.2 g) as pale yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.79-2.94 (4H, m), 5.24 (1H,
s), 6.76 (2H, d, J = 7.5Hz), 7.01 (1H, d, J = 16.5
Hz), 7.05 (2H, d, J = 7.5 Hz), 7.27-7.43 (4H, m),
7.51 (1H, d, J = 16.5 Hz). IR (KBr): 3322, 1595,
1536, 1422, 1200cm ^-1 .

(Iii) 2-[(E) -2- (4-bromo-2-fluorophenyl) ethenyl] -4- [2- [4- (3-chloropropoxy) phenyl] ethyl] 1,3- Preparation of oxazole 4- [2- [2-[(E) -2- (4-bromo-2-fluorophenyl) ethenyl] -1,3-oxazol-4-yl] ethyl] phenol (1.0
5 g), potassium carbonate (0.56 g) and 1-bromo-3-chloropropane (0.4 ml) were used to carry out the same reaction as in Example 46- (ii) to give the title compound (0.71 g) as pale yellow powder crystals. Got as. ¹ H-NMR (CDCl ₃ ) δ: 2.18-2.22 (2H, m), 2.79-2.99 (4
H, m), 3.75 (2H, t, J = 6.4 Hz), 4.09 (2H, t, J =
6.0 Hz), 6.82 (2H, d, J = 8.6 Hz), 7.02 (1H, d, J =
16.4 Hz), 7.11 (2H, d, J = 8.6 Hz), 7.27-7.46 (4
H, m), 7.51 (1H, d, J = 16.4 Hz). IR (KBr): 1694, 1
597, 1584, 1514, 1477 cm ^-1 .

(Iv) [1- [3- [4- [2- [2-[(E) -2- (4-bromo-2
-Fluorophenyl) ethenyl] -1,3-oxazol-4-yl] ethyl] phenoxy] propyl] -1H-imidazol-2-
2-[(E) -2- (4-Bromo-2-fluorophenyl) ethenyl] -4-
[2- [4- (3-chloropropoxy) phenyl] ethyl] 1,3-oxazole (0.3 g), 2-formylimidazole (74 m
g), sodium iodide (116 mg) and potassium carbonate (107 mg) and sodium borohydride (12 mg)
Was used to perform the same reaction as in Example 46- (iii) to obtain the title compound (0.2 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.19-2.31 (2H, m), 2.78-2.98 (4
H, m), 3.91 (2H, t, J = 5.8 Hz), 4.24 (2H, t, J =
6.6 Hz), 4.66 (2H, s), 6.80 (2H, d, J = 8.8Hz), 6.
87 (1H, br s), 6.90 (1H, br s), 7.02 (1H, d, J = 1
6.6 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.26-7.46 (4H,
m), 7.51 (1H, d, J = 16.6 Hz). IR (KBr): 3108, 160
1, 1582, 1512, 1240 cm ^-1 .

Example 58. [1- [3- [4- [2- [2-[(E) -2- (4-
Bromo-2-fluorophenyl) ethenyl] -1,3-oxazol
Lu-4-yl] ethyl] phenoxy] propyl] -1H-1,2,3-to
Manufacture of riazole

[Chemical 137] Sodium hydroxide (39 mg) and sodium iodide (0.12 g) were added to a solution of 1H-1,2,3-triazole (67 mg) in 2-methyl-2-butanol (7 ml), and the mixture was heated under reflux for 1 hour. did. Subsequently) 2-[(E) -2- (4-bromo-2-fluorophenyl) ethenyl] -4- [2- [4- (3-chloropropoxy) phenyl]
A solution of ethyl] 1,3-oxazole (0.3 g) in 2-methyl-2-butanol (1 ml) was added, and the mixture was heated under reflux for 3 hr. After completion of the reaction, water was added to the reaction solution, extracted with toluene, washed with saturated saline, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate: hexane = 1:
Purification in 1) gave the title compound (0.22 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.37-2.46 (2H, m), 2.81-2.97 (4
H, m), 3.93 (2H, t, J = 5.6 Hz), 4.63 (2H, t, J =
6.4 Hz), 6.80 (2H, d, J = 8.8 Hz), 7.02 (1H, d, J =
16.6 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.26-7.46 (4
H, m), 7.51 (1H, d, J = 16.6 Hz), 7.54 (1H, d, J =
1.2 Hz), 7.69 (1H, d, J = 1.2 Hz). IR (KBr): 1603,
1581, 1514, 1248, 1231 cm ^-1 .

Example 59. 1- [3- [4- [2- [2-[(E) -2- (4-block
Lomo-2-fluorophenyl) ethenyl] -1,3-oxazole
-4-yl] ethyl] phenoxy] propyl] -1H-imidazo
Production of le-2-carboxamide

[Chemical 138] (i) Methyl 1- [3- [4- [2- [2-[(E) -2- (4-bromo-2-fluorophenyl) ethenyl] -1,3-oxazol-4-yl] ethyl] Preparation of phenoxy] propyl] -1H-imidazole-2-carboxylate 2-[(E) -2- (4-bromo-2-fluorophenyl) ethenyl] -4-
To a solution of [2- [4- (3-chloropropoxy) phenyl] ethyl] 1,3-oxazole (0.4 g) in dimethylformamide (6 ml), methyl 1H-imidazole-2-carboxylate (0.12
g), sodium iodide (0.16 g) and potassium carbonate (0.15 g) were added, and the mixture was heated at 70 ° C for 12 hours. After completion of the reaction, water was added to the reaction solution and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 3) to give the title compound (0.4
5 g) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.22-2.38 (2H, m), 2.80-2.99 (4
H, m), 3.90 (2H, t, J = 6.0 Hz), 3.92 (3H, s), 4.63
(2H, t, J = 7.0 Hz), 6.80 (2H, d, J = 8.8Hz), 7.0
2 (1H, d, J = 16.6 Hz), 7.07 (1H, d, J = 1.0 Hz),
7.11 (2H, d, J = 8.8 Hz), 7.13 (1H, d, J = 1.0 Hz),
7.26-7.46 (4H, m), 7.51 (1H, d, J = 16.6 Hz). IR
(KBr): 1717, 1512, 1478, 1441, 1260 cm ^-1 .

(Ii) 1- [3- [4- [2- [2-[(E) -2- (4-bromo-2-
Fluorophenyl) ethenyl] -1,3-oxazol-4-yl] ethyl] phenoxy] propyl] -1H-imidazol-2-
Preparation of Carboxamide Methyl 1- [3- [4- [2- [2-[(E) -2- (4-bromo-2-fluorophenyl) ethenyl] -1,3-oxazol-4-yl] ethyl ] Phenoxy] propyl] -1H-imidazole-2-carboxylate (0.3 g) in 12N ammonia methanol (15 ml)
The solution was added, and the mixture was heated under reflux at 100 ° C. for 15 hours in a sealed tube.
After completion of the reaction, the crystals were collected by filtration and washed with ethyl acetate to obtain the title compound (0.24 g) as pale yellow plate crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.24-2.36 (2H, m), 2.78-2.98 (4
H, m), 3.91 (2H, t, J = 5.8 Hz), 4.66 (2H, t, J =
7.0 Hz), 5.37 (1H, br s), 6.80 (2H, d, J = 8.8 H
z), 7.00 (1H, s), 7.01 (1H, s), 7.02 (1H, d, J = 1
6.6 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.20 (1H, br s),
7.26-7.46 (4H, m), 7.51 (1H, d, J = 16.6 Hz). IR
(KBr): 3303, 3164, 1686, 1514, 1235 cm ^-1 .

Example 60. (1- (3- (2,3,6-trimethyl-4
-((2-((E) -2- (4- (trifluoromethyl) phenyl) ethenyl)
Ru) -1,3-oxazol-4-yl) methoxy) phenoxy) p
Production of ropyr) -1H-imidazol-2-yl) methanol

[Chemical 139] (I) Production of tert-butyl (4- (3-chloropropoxy) -2,3,5-trimethylphenoxy) diphenylsilane 4-((tert-butyl (diphenyl) silyl) oxy) -2,3,6- A solution of trimethylphenol (3.0 g) and 1-bromo-3-chloropropane (1.14 ml) in acetone (50 ml) was added to potassium carbonate (1.5 g).
9 g) was added and the mixture was heated under reflux for 48 hours. After cooling to room temperature, water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 30) to obtain the title compound (2.94 g) as a colorless oily liquid. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (9H, s), 1.87 (3H, s), 2.1
9 (3H, s), 2.27 (3H, s), 2.14-2.30 (2H, m), 3.75
(2H, t, J = 5.8 Hz), 3.78 (2H, t, J = 5.8 Hz), 6.1
0 (1H, s), 7.31-7.42 (6H, m), 7.68-7.73 (4H, m) .IR (KBr): 2930, 1587, 1473, 1224, 1114, 1030 c
m ^-1 .

(Ii) 1- (3- (4-((tert-butyl (diphenyl)
(Silyl) oxy) -2,3,6-trimethylphenoxy) propyl) -1H-imidazole-2-carbaldehyde production tert-butyl (4- (3-chloropropoxy) -2,3,5-trimethylphenoxy) diphenyl Silane (2.64 g) in DMF (20 ml)
2-Formylimidazole (651 mg), sodium iodide (1.22 g) and potassium carbonate (1.12 g) were added to the solution, and the mixture was added at 70 ° C for 16
Stir for hours. After cooling, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, ethyl acetate: hexane = 1:
Purification in 1) gave the title compound (1.84 g) as a colorless oily liquid. ¹ H-NMR (CDCl ₃ ) δ: 1.09 (9H, s), 1.85 (3H, s), 2.1
4-2.26 (2H, m), 2.17 (3H, s), 2.26 (3H, s), 3.66
(2H, t, J = 5.8 Hz), 4.62 (2H, t, J = 7.4 Hz), 6.0
9 (1H, s), 7.22-7.73 (12H, m), 9.81 (1H, s) .IR (KBr): 2932, 1689, 1587, 1473, 1224, 1113 c
m ^-1 .

(Iii) 4- (3- (2- (hydroxymethyl) -1H-
Preparation of imidazol-1-yl) propoxy) -2,3,5-trimethylphenol 1- (3- (4-((tert-butyl (diphenyl) silyl) oxy) -2,
3,6-Trimethylphenoxy) propyl) -1H-imidazole
To a solution of -2-carbaldehyde (1.71 g) in methanol (10 ml) was added sodium borohydride (122 mg) at 0 ° C, and the mixture was stirred for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate-THF (3: 1) and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (5 ml), tetrabutylammonium fluoride 1M solution (4.86 ml) was added, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction solution, the mixture was extracted with a mixed solution of ethyl acetate-THF (3: 1), and dried over anhydrous sodium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 1) to give the title compound (517 mg)
Was obtained as a white solid powder. ¹ H-NMR (CDCl ₃ + DMSO-d ₆ ) δ: 2.11 (3H, s), 2.14 (3H,
s), 2.16 (3H, s), 2.20-2.33 (2H, m), 3.71 (2H, t,
J = 5.8 Hz), 4.29 (2H, t, J = 6.8 Hz), 4.72 (2H,
s), 6.52 (1H, s), 6.96 (1H, s), 6.98 (1H, s) .IR (KBr): 3115, 1739, 1591, 1456, 1377, 1222, 108
2 cm ^-1 .

(Iv) (1- (3- (2,3,6-trimethyl-4-((2-
((E) -2- (4- (trifluoromethyl) phenyl) ethenyl)-
Preparation of 1,3-oxazol-4-yl) methoxy) phenoxy) propyl) -1H-imidazol-2-yl) methanol 4- (3- (2- (hydroxymethyl) -1H-imidazol-1-yl)
Propoxy) -2,3,5-trimethylphenol (200 mg) DM
To the F (3 ml) solution, 65% sodium hydride (25.8 mg) was added at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. 4-chloromethyl-2- at 0 ° C
((E) -2- (4- (trifluoromethyl) phenyl) ethenyl)-
1,3-Oxazole (198 mg) was added, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction solution, which was extracted with ethyl acetate and then dried over anhydrous sodium sulfate. After concentration, the residue was subjected to silica gel column chromatography (eluent, methanol: ethyl acetate
= 1: 9) and recrystallized from methanol-ethyl acetate-hexane to give the title compound (186 mg) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.15 (3H, s), 2.17 (3H, s), 2.2
4 (3H, s), 2.20-2.32 (2H, m), 3.74 (2H, t, J = 5.8
Hz), 4.29 (2H, t, J = 7.4 Hz), 4.74 (2H, s), 4.99
(2H, s), 6.64 (1H, s), 6.98-7.06 (3H, m), 7.55 (1
H, d, J = 16.6 Hz), 7.64 (4H, s), 7.67 (1H, s) .IR (KBr): 3144, 2926, 1616, 1464, 1327, 1122 c
m ^-1 .

Example 61. (1- (3- (2,3,5-trimethyl-4
-((2-((E) -2- (4- (trifluoromethyl) phenyl) ethenyl)
Ru) -1,3-oxazol-4-yl) methoxy) phenoxy) p
Production of ropyr) -1H-imidazol-2-yl) methanol

[Chemical 140] (i) 4-((4-((tert-butyl (diphenyl) silyl) oxy)
-2,3,6-Trimethylphenoxy) methyl) -2-((E) -2- (4-
Preparation of (trifluoromethyl) phenyl) ethenyl) -1,3-oxazole 4-((tert-butyl (diphenyl) silyl) oxy) -2,3,6-trimethylphenol (3.0 g) DMF (15 ml) 65% at 0 ° C in solution
Sodium hydride (316 mg) was added, and the mixture was stirred at room temperature for 30 minutes. 4-chloromethyl-2-((E) -2- (4- (trifluoromethyl) phenyl) ethenyl) -1,3-oxazole (2.43
g) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, extracted with ethyl acetate, and then dried over anhydrous sodium sulfate.
After concentration, the residue is subjected to silica gel column chromatography.
The product was purified with (eluate, ethyl acetate: hexane = 1: 4) to obtain the title compound (3.18 g) as a colorless oily liquid. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (9H, s), 1.92 (3H, s), 2.2
4 (3H, s), 2.28 (3H, s), 4.67 (2H, s), 6.12 (1H,
s) 7.01 (1H, d, J = 16.4 Hz), 7.31-7.43 (8H, m), 7.
53 (1H, d, J = 16.4 Hz), 7.62-7.73 (7H, m). IR (KBr): 2932, 1473, 1325, 1113, 1068, 883 cm ^-1 .

(Ii) 2,3,5-trimethyl-4-((2-((E) -2- (4-
Preparation of (trifluoromethyl) phenyl) ethenyl) -1,3-oxazol-4-yl) methoxy) phenol 4-((4-((tert-butyl (diphenyl) silyl) oxy) -2,3,
6-Trimethylphenoxy) methyl) -2-((E) -2- (4- (trifluoromethyl) phenyl) ethenyl) -1,3-oxazole
To a solution of (4.18 g) in THF (25 ml) was added tetrabutylammonium fluoride 1M solution (9.78 ml), and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate and then dried over anhydrous sodium sulfate. After concentration, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate: hexane =
It was purified by 1: 4-1: 2) and washed with diisopropyl ether to give the title compound (1.23 g) as a white solid powder. ¹ H-NMR (CDCl ₃ ) δ: 2.14 (3H, s), 2.24 (3H, s), 2.2
5 (3H, s), 4.64 (1H, s), 4.71 (2H, s), 6.50 (1H,
s), 7.04 (1H, d, J = 16.2 Hz), 7.56 (1H, d, J = 16.
2 Hz), 7.64 (4H, s), 7.73 (1H, s) .IR (KBr): 3202, 1614, 1462, 1331, 1221, 1122, 107
0 cm ^-1 .

(Iii) 4-((4- (3-chloropropoxy) -2,3,6
-Trimethylphenoxy) methyl) -2-((E) -2- (4- (trifluoromethyl) phenyl) ethenyl) -1,3-oxazole production 2,3,5-trimethyl-4-((2- ((E) -2- (4- (Trifluoromethyl) phenyl) ethenyl) -1,3-oxazol-4-yl) methoxy) phenol (1.2 g), 1-bromo-3-chloropropane
(441 μl) in acetone (30 ml) in potassium carbonate (616 m
g) was added and the mixture was heated under reflux for 48 hours. After cooling to room temperature, water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 4),
The title compound (1.37 g) was obtained as a white powder solid. ¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.25 (3H, s), 2.3
1 (3H, s), 2.19-2.31 (2H, m), 3.78 (2H, t, J = 6.4
Hz), 4.07 (2H, t, J = 6.0 Hz), 4.72 (2H, s), 6.57
(1H, s), 7.04 (1H, d, J = 16.4 Hz), 7.56 (1H, d,
J = 16.4 Hz), 7.64 (4H, s), 7.73 (1H, s) .IR (KBr): 2926, 1614, 1469, 1325, 1228, 1124 c
m ^-1 .

(Iv) (1- (3- (2,3,5-trimethyl-4-((2-
((E) -2- (4- (trifluoromethyl) phenyl) ethenyl)-
Preparation of 1,3-oxazol-4-yl) methoxy) phenoxy) propyl) -1H-imidazol-2-yl) methanol 4-((4- (3-chloropropoxy) -2,3,6-trimethylphenoxy) Methyl) -2-((E) -2- (4- (trifluoromethyl) phenyl) ethenyl) -1,3-oxazole (750 mg) in DMF (10 m
l) 2-formyl imidazole (179 mg), sodium iodide (350 mg) and potassium carbonate (323 mg) were added to the solution at 70 ° C for 16
Stir for hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Methanol (10 ml) of the residue
, Sodium borohydride (141 mg) was added at 0 ° C., and the mixture was stirred for 1 hr. Water was added to the reaction solution, which was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: methanol = 9: 1) and recrystallized from methanol-ethyl acetate-hexane to give the title compound (652 mg).
Was obtained as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, s), 2.26 (3H, s), 2.2
9 (3H, s), 2.20-2.32 (2H, m), 3.90 (2H, t, J = 5.4
Hz), 4.25 (2H, t, J = 6.6 Hz), 4.69 (2H, s), 4.72
(2H, s), 6.48 (1H, s), 6.91 (1H, s), 6.95 (1H,
s), 7.04 (1H, d, J = 16.4 Hz), 7.56 (1H, d, J = 16.
6 Hz), 7.64 (4H, s), 7.73 (1H, s) .IR (KBr): 2930, 1471, 1325, 1230, 1124, 1068 c
m ^-1 .

Example 62. 1- [2-[[2-methyl-4-[[2-[(E)
-2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-
Oxazol-4-yl] methoxy] benzyl] oxy] ethyl
]]-1H-Imidazole-2-carboxamide

[Chemical 141] (i) Methyl 1- [2-[[2-methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole-4
Preparation of 2-yl] methoxy] benzyl] oxy] ethyl] -1H-imidazole-2-carboxylate 2-[[2-methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) )
Phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] benzyl] oxy] ethanol (0.23 g), triethylamine (0.1 ml) and methanesulfonyl chloride (49 μ)
l) was used to carry out the same reaction as in Example 51- (vii) to obtain crude mesylate. Using the above crude mesylate, methyl 1H-imidazole-2-carboxylate (80 mg), sodium iodide (0.1 g) and potassium carbonate (0.1 g), the same reaction as in Example 59- (i) was performed. The compound (0.17 g) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s), 3.77 (2H, t, J =
4.6 Hz), 3.91 (3H, s), 4.40 (2H, s), 4.63 (2H, t, J
= 4.6 Hz), 5.02 (2H, s), 6.74-6.82 (2H, m), 7.01
(1H, d, J = 16.6 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.
15 (1H, d, J = 0.6 Hz), 7.18 (1H, d, J = 0.6 Hz),
7.55 (1H, d, J = 16.6 Hz), 7.63 (4H, s), 7.68 (1H,
s) .IR (KBr): 1714, 1615, 1505, 1441, 1325 cm ^-1 .

(Ii) 1- [2-[[2-methyl-4-[[2-[(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] benzyl] oxy] ethyl] -1H-
Preparation of imidazole-2-carboxamide Methyl 1- [2-[[2-methyl-4-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3- Oxazol-4-yl] methoxy] benzyl] oxy] ethyl] -1H-imidazole-2-carboxylate (0.17 g), 12N ammonia in methanol (15 ml) was used as in Example 59- (ii). The reaction was carried out to obtain the title compound (0.1 g) as pale yellow plate crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 3.79 (2H, t, J =
4.6 Hz), 3.41 (2H, s), 4.68 (2H, t, J = 4.6 Hz), 5.
02 (2H, s), 5.28 (1H, br s), 6.73-6.82 (2H, m), 7.0
1 (1H, d, J = 0.8 Hz), 7.02 (1H, d, J = 16.4 Hz),
7.11 (1H, d, J = 8.4 Hz), 7.13 (1H, d, J = 0.8 Hz),
7.20 (1H, br s), 7.55 (1H, d, J = 16.4 Hz), 7.64
(4H, s), 7.68 (1H, s). IR (KBr): 3333, 3177, 1682,
1615,1466 cm ^-1 .

Example 63. 1- [2-[[2-methyl-4-[[2-[(E)
-2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-
Oxazol-4-yl] methoxy] benzyl] oxy] ethyl
]]-1H-1,2,3-triazole

[Chemical 142] 2-[[2-methyl-4-[[2-[(E) -2- [4- (trifluoromethyl)
Phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] benzyl] oxy] ethanol (0.11 g), triethylamine (53 μl) and methanesulfonyl chloride (24 μ
l) was used to carry out the same reaction as in Example 51- (vii) to obtain crude mesylate. Using the above crude mesylate, 1H-1,2,3-triazole (26 mg), sodium hydroxide (15 mg) and sodium iodide (46 mg), the same reaction as in Example 58 was carried out to give the title compound (84 mg) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.22 (3H, s), 3.84 (2H, t, J =
5.2 Hz), 4.44 (2H, s), 4.59 (2H, t, J = 5.2 Hz), 5.
02 (2H, s), 6.75-6.83 (2H, m), 7.01 (1H, d, J = 16.
6 Hz), 7.13 (1H, d, J = 8.0 Hz), 7.55 (1H, d, J =
16.6 Hz), 7.66 (1H, d, J = 0.6 Hz), 7.68 (1H, d, J
= 0.6 Hz), 7.68 (1H, s). IR (KBr): 1615, 1505, 132
7, 1125, 1069 cm ^-1 .

Example 64. [1- [2-[[4-[[2-[(E) -2-Full
Oro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-
Oxazol-4-yl] methoxy] -2-methylbenzyl] o
[Xy] ethyl] -1H-imidazol-2-yl] methanol
Construction

[Chemical 143] (i) 4-[[2-[(E) -2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy]
Preparation of 2-methylbenzaldehyde 4-hydroxy-2-methylbenzaldehyde (1.3 g), 4-
(Chloromethyl) -2-[(E) -2- [2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (3.0
g), sodium iodide (1.8 g) and potassium carbonate (1.6 g) were used to perform the same reaction as in Example 51- (iii) to obtain the title compound (3.7 g) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.66 (3H, s), 5.10 (2H, s), 6.8
5 (1H, d, J = 2.4 Hz), 6.94 (1H, dd, J = 2.4, 8.4 H
z), 7.12 (1H, d, J = 16.5 Hz), 7.36-7.45 (2H, m),
7.65 (1H, d, J = 16.5 Hz), 7.67 (1H, t, J = 7.5 H
z), 7.72 (1H, s), 7.77 (1H, d, J = 8.4 Hz), 10.12
(1H, s). IR (KBr): 1682, 1607, 1429, 1333, 1252 cm
^-1 .

(Ii) 4-[[2-[(E) -2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole-4-
Production of [yl] methoxy] -2-methylphenyl] methanol 4-[[2-[(E) -2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] Methoxy] -2-
The same reaction as in Example 51- (iv) was performed using methylbenzaldehyde (3.5 g) and sodium borohydride (0.17 g) to obtain the title compound (3.4 g) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.50 (1H, br s), 2.37 (3H, s),
4.65 (2H, s), 5.03 (2H, s), 6.78-6.84 (2H, m), 7.1
3 (1H, d, J = 16.6 Hz), 7.26 (1H, d, J = 8.0Hz),
7.36-7.46 (2H, m), 7.65 (1H, d, J = 16.6 Hz), 7.68
(1H, t, J = 7.6Hz), 7.70 (1H, s). IR (KBr): 339
3, 1605, 1429, 1333, 1130 cm ^-1 .

(Iii) tert-butyl 4-[[2-[(E) -2-fluoro
-4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxy
Sazol-4-yl] methoxy] -2-methylbenzyl] oxy]
Manufacture of acetate 4-[[2-[(E) -2-fluoro-4- (trifluoromethyl) phenyl
L] ethenyl] -1,3-oxazol-4-yl] methoxy] -2-
Methylphenyl] methanol (3.3 g), 50% sodium hydroxide
Lithium (10 ml) in water, tert-butyl bromoacetate (1.8
 ml) and tetrabutylammonium hydrogen sulfate (0.27
g) was used to perform the same reaction as in Example 51- (v).
The compound (4.1 g) was obtained as colorless powder crystals.¹ H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.38 (3H, s), 3.9
7 (2H, s), 4.57 (2H, s), 5.03 (2H, s), 6.76-6.84
(2H, m), 7.13 (1H, d, J = 16.4 Hz), 7.24 (1H, d, J
= 8.0 Hz), 7.36-7.46 (2H, m), 7.64 (1H, d, J = 16.
4 Hz), 7.68 (1H, t, J = 7.7 Hz), 7.69 (1H, s). IR
(KBr): 1748, 1609, 1505, 1429, 1331 cm ^-1.

(Iv) 2-[[4-[[2-[(E) -2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole
Preparation of 4-yl] methoxy] -2-methylbenzyl] oxy] ethanol tert-butyl 4-[[2-[(E) -2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1, 3-Oxazol-4-yl] methoxy] -2-methylbenzyl] oxy] acetate (4.0
g), using lithium aluminum hydride (0.4 g),
The reaction was performed in the same manner as in Example 51- (vi), and the title compound (2.3
g) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.97 (1H, t, J = 6.2 Hz), 2.35
(3H, s), 3.59 (2H, t, J = 4.0 Hz), 3.72-3.80 (2H,
m), 4.51 (2H, s), 5.03 (2H, s), 6.77-6.85 (2H, m),
7.13 (1H, d, J = 16.6 Hz), 7.22 (1H, d, J = 8.0 H
z), 7.36-7.46 (2H, m), 7.64 (1H, d, J = 16.6 Hz),
7.67 (1H, t, J = 7.6 Hz), 7.69 (1H, s). IR (KBr):
3350, 1609, 1580, 1217, 1169 cm ^-1 .

(V) [1- [2-[[4-[[2-[(E) -2-fluoro-4-
Preparation of (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] -2-methylbenzyl] oxy] ethyl] -1H-imidazol-2-yl] methanol 2-[[4- [[2-[(E) -2-Fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy]
-2-Methylbenzyl] oxy] ethanol (0.7 g), triethylamine (0.3 ml) and methanesulfonyl chloride
(0.15 ml) was used to carry out the same reaction as in Example 51- (vii) to obtain a crude mesylate. The above crude mesylate, 2-formylimidazole (0.18 g), sodium iodide (0.28 g)
g) and potassium carbonate (0.26 g) and sodium borohydride (30 mg) were used to carry out the same reaction as in Example 46- (iii) to obtain the title compound (0.6 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.66 (1H, br s), 2.20 (3H, s),
3.71 (2H, t, J = 5.0 Hz), 4.18 (2H, t, J = 5.0 H
z), 4.43 (2H, s), 4.65 (2H, s), 5.02 (2H, s), 6.74-
6.82 (2H, m), 6.92 (1H, s), 6.95 (1H, s), 7.12 (1
H, d, J = 16.6 Hz), 7.14 (1H, d, J = 9.6 Hz), 7.35
-7.46 (2H, m), 7.64 (1H, d, J = 16.6 Hz), 7.68 (1
H, t, J = 7.9 Hz), 7.69 (1H, s). IR (KBr): 3108, 1
615, 1580, 1254, 1219 cm ^-1 .

Example 65. 1- [2-[[4-[[2-[(E) -2-fluor
B-4- (trifluoromethyl) phenyl] ethenyl] -1,3-o
Xazol-4-yl] methoxy] -2-methylbenzyl] oxy
Production of [] ethyl] -1H-1,2,3-triazole

[Chemical 144] 2-[[4-[[2-[(E) -2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy]
-2-Methylbenzyl] oxy] ethanol (0.3 g), triethylamine (0.14 ml) and methanesulfonyl chloride
(62 μl) was used to carry out the same reaction as in Example 51- (vii) to obtain crude mesylate. The above crude mesylate, 1H-1,2,3-
Example 58 using triazole (69 mg), sodium hydroxide (40 mg) and sodium iodide (0.12 g)
The title compound (0.23 g) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.22 (3H, s), 3.84 (2H, t, J =
5.2 Hz), 4.44 (2H, s), 4.59 (2H, t, J = 5.2 Hz), 5.
03 (2H, s), 7.13 (1H, d, J = 16.4 Hz), 7.13 (1H, d,
J = 8.0 Hz), 7.36-7.47 (2H, m), 7.61-7.72 (5H,
m). IR (KBr): 1615, 1580, 1427, 1337, 1123 cm ^-1 .

Example 66. 1- [2-[[4-[[2-[(E) -2-fluor
B-4- (trifluoromethyl) phenyl] ethenyl] -1,3-o
Xazol-4-yl] methoxy] -2-methylbenzyl] oxy
[] Ethyl] -1H-imidazole-2-carboxamide
Construction

[Chemical 145] (I) Methyl 1- [2-[[4-[[2-[(E) -2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole-4
-Yl] methoxy] -2-methylbenzyl] oxy] ethyl] -1H
Preparation of 2-imidazole-2-carboxylate 2-[[4-[[2-[(E) -2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] Methoxy]
-2-Methylbenzyl] oxy] ethanol (0.5 g), triethylamine (0.2 ml) and methanesulfonyl chloride
(0.1 ml) was used to carry out the same reaction as in Example 51- (vii) to obtain crude mesylate. Crude mesylate above, methyl 1H
-Imidazole-2-carboxylate (0.17 g), sodium iodide (0.2 g) and potassium carbonate (0.19 g) were used to carry out the same reaction as in Example 59- (i) to give the title compound.
(0.5 g) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s), 3.77 (2H, t, J =
4.6 Hz), 3.92 (3H, s), 4.40 (2H, s), 4.63 (2H, t, J
= 4.6 Hz), 5.02 (2H, s), 6.74-6.82 (2H, m), 7.13
(1H, d, J = 16.4 Hz), 7.14 (1H, d, J = 1.0 Hz), 7.
15 (1H, d, J = 8.0 Hz), 7.17 (1H, d, J = 1.0 Hz),
7.35-7.46 (2H, m), 7.65 (1H, d, J = 16.4 Hz), 7.70
(1H, s). IR (KBr): 1715, 1609, 1580, 1441, 1331 c
m ^-1 .

(Ii) 1- [2-[[4-[[2-[(E) -2-fluoro-4-
Preparation of (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] -2-methylbenzyl] oxy] ethyl] -1H-imidazole-2-carboxamide Methyl 1- [2- [ [4-[[2-[(E) -2-Fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] -2-methylbenzyl] oxy] ethyl] -1H-Imidazole-2-carboxylate (0.5 g), 12N ammonia in methanol (20 ml) was used in Example 59- (i
The same reaction as in i) was performed to obtain the title compound (0.4 g) as pale yellow plate crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 3.79 (2H, t, J =
5.2 Hz), 4.41 (2H, s), 4.67 (2H, t, J = 5.2 Hz), 5.
02 (2H, s), 5.37 (1H, br s), 6.74-6.81 (2H, m), 7.0
1 (1H, d, J = 1.2 Hz), 7.12 (1H, d, J = 8.0 Hz),
7.13 (1H, d, J = 1.2 Hz), 7.14 (1H, d, J = 16.6 H
z), 7.68 (1H, t, J = 7.7 Hz), 7.69 (1H, s). IR (KB
r): 3316, 3169, 1698, 1464, 1335 cm ^-1 .

Example 67. 2- (4- {4-[(2-{(E) -2- [4- (
Lifluoromethyl) phenyl] ethenyl} -1,3-oxazol
Lu-4-yl) methoxy] phenyl} butyl) -1,3-thiazole
-4-Production of ethyl carboxylate

[Chemical 146] (i) Production of 5- (4-tert-butoxyphenyl) pentanenitrile 4- (4-tert-butoxyphenyl) -1-butanol (15.00 g) and triethylamine (8.87 g) in tetrahydrofuran (80 mL)
And dissolved in water, and methanesulfonyl chloride (9.27 g) was added dropwise under ice cooling. After stirring at room temperature for 1 hour, water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The extract was washed twice with saturated aqueous sodium hydrogen carbonate solution and once with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an oil. This oil was dissolved in acetonitrile (260 mL) and potassium iodide was added.
(13.44 g) was added and the mixture was heated under reflux for 7 hours. After adding water to the reaction solution and extracting with ethyl acetate twice, the extract was extracted with saline four times,
It was washed once with a 10% aqueous sodium thiosulfate solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 21.5 g of an oily substance. This oil (21.5 g) was added to dimethyl sulfoxide (50 m
L), add potassium cyanide (5.06g) and add 5
Stir for hours. After adding water to the reaction solution and extracting twice with ethyl acetate, the extract was washed twice with water and once with a saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate,
After concentration under reduced pressure, the residue was subjected to column chromatography (silica gel, ethyl acetate / n-hexane = 1/10 → 1/5). The target fraction was concentrated under reduced pressure to give the title compound (7.16 g) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (9H, s), 1.63-1.82 (4H,
m), 2.35 (2H, t, J = 6.9Hz), 2.61 (2H, t, J = 7.4Hz),
6.90 (2H, d, J = 8.3Hz), 7.04 (2H, d, J = 8.3Hz).

(Ii) Preparation of 5- (4-hydroxyphenyl) pentanenitrile 5- (4-tert-butoxyphenyl) pentanenitrile (1.71 g)
Was dissolved in a mixed solution of tetrahydrofuran (25 mL) and water (5 mL), concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 60 ° C for 5 hr. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, ethyl acetate / n-hexane).
= 1/2). The desired fraction was concentrated under reduced pressure and the title compound (1.
30 g) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.58-1.84 (4H, m), 2.34 (2H, t,
J = 6.7Hz), 2.59 (2H, t, J = 7.2Hz), 4.77 (1H, s), 6.
76 (2H, d, J = 8.4Hz), 7.03 (2H, d, J = 8.4Hz).

(Iii) 5- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl)
Methoxy] phenyl} pentanenitrile production 5- (4-hydroxyphenyl) pentanenitrile (1.30 g)
It was dissolved in N, N-dimethylformamide (8 mL), 60% sodium hydride (0.36 g) was added, and the mixture was stirred at room temperature for 30 min. 4- (Chloromethyl) -2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazole (2.13g) was added at room temperature to 1
Stir for hours. Water was added to the reaction solution and extracted three times with ethyl acetate, and then the extract was washed twice with water. After drying over anhydrous magnesium sulfate, concentration under reduced pressure and purification of the residue by column chromatography (silica gel, ethyl acetate), ethyl acetate
-Recrystallization from hexane gave the title compound (2.83 g). ¹ H-NMR (CDCl ₃ ) δ: 1.60-1.85 (4H, m), 2.35 (2H, t,
J = 6.6Hz), 2.61 (2H, t, J = 7.0Hz), 5.03 (2H, s), 6.
93 (2H, d, J = 8.6Hz), 7.02 (1H, d, J = 16.6Hz), 7.11
(2H, d, J = 8.6Hz), 7.56 (1H, d, J = 16.6Hz), 7.64 (4
H, s), 7.69 (1H, s). IR (KBr): 2245, 1615, 1514, 1323, 1165, 1128, 106
9, 828cm ^-1 .

(Iv) 5- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl)
Preparation of [methoxy] phenyl} pentanethioamide 5- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl }
Pentanenitrile (900 mg) in 4N hydrochloric acid / ethyl acetate solution (12 m
It was dissolved in L), diethyl dithiophosphate (1.40 g) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted twice with ethyl acetate, and the extract was extracted with saturated aqueous sodium hydrogen carbonate solution.
Washed twice. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, the residue was purified by column chromatography (silica gel, ethyl acetate / n-hexane = 1/1), and recrystallized from ethyl acetate / diethyl ether / hexane to give the title compound (417m
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.62-1.75 (2H, m), 1.75-1.87 (2
H, m), 2.60 (2H, t, J = 7.5Hz), 2.67 (2H, t, J = 7.5H
z), 5.01 (2H, s), 6.70 (1H, br), 6.91 (2H, d, J = 8.7
Hz), 7.01 (1H, d, J = 16.5Hz), 7.10 (2H, d, J = 8.7H
z), 7.30 (1H, br), 7.54 (1H, d, J = 16.5Hz), 7.63 (4
H, s), 7.67 (1H, s). IR (KBr): 3347, 3130, 1644, 1514, 1325, 1177, 112
8, 1069, 949, 826, 783cm ^-1 .

(V) 2- (4- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] Preparation of ethyl (phenyl} butyl) -1,3-thiazole-4-carboxylate 5- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3 -Oxazol-4-yl) methoxy] phenyl}
Pentanethioamide (417 mg) was dissolved in N, N-dimethylformamide 6 ml, and ethyl 3-bromopyruvate 212 mg (1.09 m
mol) was added and the mixture was stirred at 60 ° C. for 1 hour. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with water. The crystals were dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Column chromatography of the residue (silica gel,
It was purified with ethyl acetate / n-hexane = 1/2) and recrystallized from ethyl acetate / diethyl ether to obtain the title compound (411 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.2Hz), 1.62-1.9
5 (4H, m), 2.61 (2H, t, J = 7.0Hz), 3.08 (2H, t, J =
7.5Hz), 4.42 (2H, q, J = 7.2Hz), 5.02 (2H, s), 6.91
(2H, d, J = 8.6Hz), 7.01 (1H, d, J = 16.4Hz), 7.10 (2
H, d, J = 8.6Hz), 7.55 (1H, d, J = 16.4Hz), 7.64 (4H,
s), 7.68 (1H, s), 8.05 (1H, s) .IR (KBr): 3100, 1723, 1512, 1340, 1230, 1169, 112
5, 823cm ^-1 .

Example 68. [1- [2-[[4-[[2-[(E) -2- [4-
Lomo-2- (fluorophenyl) ethenyl] -1,3-oxazo
Lu-4-yl] methoxy] -2-methylbenzyl] oxy] eth
[1H] -1H-imidazol-2-yl] methanol

[Chemical 147] (i) Preparation of 4-[[2-[(E) -2- [4-bromo-2- (fluorophenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] -2-methylbenzaldehyde 4 -Hydroxy-2-methylbenzaldehyde (1.3 g), 2-
[(E) -2- (4-Bromo-2-fluorophenyl) ethenyl] -4-
The title compound was obtained by the same reaction as in Example 51- (iii) using (chloromethyl) -1,3-oxazole (3.0 g), sodium iodide (1.7 g) and potassium carbonate (2.0 g).
(3.9 g) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.66 (3H, s), 5.10 (2H, s), 6.8
5 (1H, d, J = 2.4 Hz), 6.95 (1H, dd, J = 2.4, 8.8 H
z), 7.04 (1H, d, J = 16.4 Hz), 7.28-7.47 (3H, m),
7.59 (1H, d, J = 16.4 Hz), 7.70 (1H, s), 7.77 (1H,
d, J = 8.8 Hz), 10.13 (1H, s). IR (KBr): 1680, 16
07, 11568, 1477, 1254 cm ^-1 .

(Ii) 4-[[2-[(E) -2- [4-bromo-2- (fluorophenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] -2-methylphenyl ] Preparation of Methanol 4-[[2-[(E) -2- [4-Bromo-2- (fluorophenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] -2-methylbenzaldehyde (3.9 g), sodium borohydride (0.18
Using g), the same reaction as in Example 51- (iv) was performed to give the title compound (3.7 g) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.57 (1H, t, J = 5.4 Hz), 2.36
(3H, s), 4.64 (2H, d, J = 5.4 Hz), 5.01 (2H, s), 6.
77-6.83 (2H, m), 7.03 (1H, d, J = 16.4 Hz), 7.23-7.
46 (4H, m), 7.57 (1H, d, J = 16.4 Hz), 7.67 (1H,
s). IR (KBr): 3399, 1603, 1478, 1410, 1273 cm ^-1 .

(Iii) tert-Butyl 4-[[2-[(E) -2- [4-bromo-2- (fluorophenyl) ethenyl] -1,3-oxazole-
Preparation of 4-yl] methoxy] -2-methylbenzyl] oxy] acetate 4-[[2-[(E) -2- [4-bromo-2- (fluorophenyl) ethenyl] -1,3-oxazole- 4-yl] methoxy] -2-
Methylphenyl] methanol (3.5 g), 50% aqueous sodium hydroxide (15 ml) solution, tert-butyl bromoacetate (1.9
ml) and tetrabutylammonium hydrogen sulfate (0.28
Using g), the same reaction as in Example 51- (v) was performed to give the title compound (4.4 g) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.37 (3H, s), 3.9
6 (2H, s), 4.57 (2H, s), 5.02 (2H, s), 6.76-6.84
(2H, m), 7.03 (1H, d, J = 16.6 Hz), 7.21-7.47 (4H,
m), 7.57 (1H, d, J = 16.6 Hz), 7.66 (1H, s). IR (K
Br): 2978, 1748, 1599, 1480, 1256 cm ^-1 .

(Iv) 2-[[4-[[2-[(E) -2- [4-bromo-2- (fluorophenyl) ethenyl] -1,3-oxazol-4-yl]]
Preparation of methoxy] -2-methylbenzyl] oxy] ethanol tert-butyl 4-[[2-[(E) -2- [4-bromo-2- (fluorophenyl) ethenyl] -1,3-oxazole-4 -Yl] methoxy] -2
-Methylbenzyl] oxy] acetate (4.4 g) and lithium aluminum hydride (0.5 g) were used in Example 51-
The same reaction as in (vi) was performed to obtain the title compound (4.0 g) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.34 (3H, s), 3.56-3.64 (2H,
m), 3.73-3.76 (2H, m), 4.50 (2H, s), 5.02 (2H, s),
6.76-6.84 (2H, m), 7.03 (1H, d, J = 16.6 Hz), 7.20
-7.46 (4H, m), 7.57 (1H, d, J = 16.6 Hz), 7.67 (1
H, s). IR (KBr): 3393, 1599, 1481, 1288, 1256 c
m ^-1 .

(V) [1- [2-[[4-[[2-[(E) -2- [4-bromo-2-
Preparation of (fluorophenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] -2-methylbenzyl] oxy] ethyl] -1H-imidazol-2-yl] methanol 2-[[4-[[2 -[(E) -2- [4-Bromo-2- (fluorophenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] -2-methylbenzyl] oxy] ethanol (0.8 g), triethylamine ( 0.36 ml) and methanesulfonyl chloride (0.16 ml)
Was used to perform the same reaction as in Example 51- (vii) to obtain a crude mesylate. The above crude mesylate, 2-formylimidazole (0.2 g), sodium iodide (0.31 g) and potassium carbonate (0.29 g), and sodium borohydride
(32 mg) was used to carry out the same reaction as in Example 46- (iii) to obtain the title compound (0.7 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s), 3.71 (2H, t, J =
5.0 Hz), 4.18 (2H, t, J = 5.0 Hz), 4.43 (2H, s), 4.
65 (2H, s), 5.02 (2H, s), 6.73-6.81 (2H, m), 6.92
(1H, s), 6.95 (1H, s), 7.03 (1H, d, J = 16.6 Hz),
7.09 (1H, d, J = 8.4 Hz), 7.26-7.47 (3H, m), 7.57
(1H, d, J = 16.6 Hz), 7.67 (1H, s). IR (KBr): 325
0, 1501, 1481, 1289, 1254 cm ^-1 .

Example 69. 1- [2-[[4-[[2-[(E) -2- [4-
Lomo-2- (fluorophenyl) ethenyl] -1,3-oxazo
Lu-4-yl] methoxy] -2-methylbenzyl] oxy] eth
]]-1H-Imidazole-2-carboxamide

[Chemical 148] (I) Methyl 1- [2-[[4-[[2-[(E) -2- [4-bromo-2- (fluorophenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] 2-Methylbenzyl] oxy] ethyl] -1H-imidazole-2-carboxylate preparation 2-[[4-[[2-[(E) -2- [4-bromo-2- (fluorophenyl) ethenyl] ] -1,3-Oxazol-4-yl] methoxy] -2-methylbenzyl] oxy] ethanol (0.5 g), triethylamine (0.2 ml) and methanesulfonyl chloride (0.1 ml) were used in Example 51- ( The same reaction as in vii) was performed to obtain crude mesylate. Using the above crude mesylate, methyl 1H-imidazole-2-carboxylate (0.16 g), sodium iodide (0.2 g) and potassium carbonate (0.18 g), a reaction similar to that in Example 59- (i) was performed. Compound (0.44 g)
Was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s), 3.76 (2H, t, J =
8.4 Hz), 3.92 (3H, s), 4.40 (2H, s), 4.62 (2H, t, J
= 8.4 Hz), 5.01 (2H, s), 6.74-6.81 (2H, m), 7.04
(1H, d, J = 16.6 Hz), 7.10 (1H, d, J = 8.2 Hz), 7.
13 (1H, d, J = 0.8 Hz), 7.17 (1H, d, J = 0.8 Hz),
7.27-7.46 (3H, m), 7.56 (1H, d, J = 16.6 Hz), 7.67
(1H, s). IR (KBr): 1713, 1601, 1441, 1264, 1123 c
m ^-1 .

(Ii) 1- [2-[[4-[[2-[(E) -2- [4-bromo-2-
Preparation of (fluorophenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] -2-methylbenzyl] oxy] ethyl] -1H-imidazole-2-carboxamide Methyl 1- [2-[[4- [[2-[(E) -2- [4-Bromo-2- (fluorophenyl) ethenyl] -1,3-oxazol-4-yl] methoxy]
-2-Methylbenzyl] oxy] ethyl] -1H-imidazole-2
-Carboxylate (0.44 g) and 12N ammonia methanol (20 ml) were used to carry out the same reaction as in Example 59- (ii) to obtain the title compound (0.36 g) as pale yellow plate crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 3.79 (2H, t, J =
4.8 Hz), 4.41 (2H, s), 4.67 (2H, t, J = 4.8 Hz), 5.
01 (2H, s), 5.38 (1H, br s), 6.73-6.81 (2H, m), 7.0
1 (1H, d, J = 1.0 Hz), 7.03 (1H, d, J = 16.6 Hz),
7.11 (1H, d, J = 7.2 Hz), 7.12 (1H, d, J = 1.0 Hz),
7.23 (1H, br s), 7.26-7.47 (3H, m), 7.57 (1H, d,
J = 16.6 Hz), 7.67 (1H, s). IR (KBr): 3299, 3167,
1698, 1601, 1464 cm ^-1 .

Example 70. 1- [2-[[4-[[2-[(E) -2- [4-
Lomo-2- (fluorophenyl) ethenyl] -1,3-oxazo
Lu-4-yl] methoxy] -2-methylbenzyl] oxy] eth
]]-1H-1,2,3-triazole

[Chemical 149] 2-[[4-[[2-[(E) -2- [4-bromo-2- (fluorophenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] -2-methylbenzyl] oxy ] Ethanol (0.5 g), triethylamine (0.23 ml) and methanesulfonyl chloride (0.1 ml)
Was used to carry out the same reaction as in Example 51- (vii) to obtain crude mesylate. Using the above crude mesylate, 1H-1,2,3-triazole (0.11 g), sodium hydroxide (65 mg) and sodium iodide (0.2 g), the same reaction as in Example 58 was carried out to give the title compound (0.32 g ) Was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.22 (3H, s), 3.84 (2H, t, J =
4.8 Hz), 4.44 (2H, s), 4.59 (2H, t, J = 4.8 Hz), 5.
02 (2H, s), 6.75-6.82 (2H, m), 7.04 (1H, d, J = 16.
6 Hz), 7.13 (1H, d, J = 8.0 Hz), 7.26-7.47 (3H,
m), 7.57 (1H, d, J = 16.6 Hz), 7.66 (1H, s), 7.67
(1H, s), 7.68 (1H, s). IR (KBr): 1610, 1599, 1480,
1250, 1121 cm ^-1 .

Example 71. 1- [2-[[4-[[2-[(E) -2-fluor
B-4- (trifluoromethyl) phenyl] ethenyl] -1,3-o
Xazol-4-yl] methoxy] -2-methylbenzyl] oxy
[Ethyl] -1H-imidazole-2-carboxamide
Mansensulfonate production

[Chemical 150] 1- [2-[[4-[[2-[(E) -2-Fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] -2-methyl Benzyl] oxy] ethyl] -1H-imidazole-2-carboxamide (0.2 g) in tetramethylfuran: methanol: toluene (1: 1: 1, 6 ml) mixed solvent, benzenesulfonic acid monohydrate (65 mg) was added and the mixture was stirred at room temperature for 15 hours. After the reaction was completed, the solvent was distilled off from the reaction solution under reduced pressure. The residue was collected by filtration and washed with diisopropyl ether to give the title compound (0.23 g) as colorless powder crystals. ¹ H-NMR (d ₆ -DMSO) δ: 2.13 (3H, s), 3.71 (2H, t, J
= 5.1 Hz), 4.36 (2H, s), 4.61 (2H, t, J = 5.1 Hz),
4.98 (2H, s), 6.76-6.82 (2H, m), 7.10 (1H, d, J =
8.4 Hz), 7.20 (1H, m), 7.26-7.40 (5H, m), 7.48 (1
H, m), 7.55-7.64 (5H, m), 7.76 (1H, m), 7.92 (1H, b
rs), 8.14 (1H, t, J = 8.4 Hz), 8.24 (1H, m). IR (K
Br): 3187, 3137, 1701, 1503, 1329 cm ^-1 .

Example 72. [1- [3- [4- [2- [2-[(E) -2- [2-
Fluoro-4- (trifluoromethyl) phenyl] ethenyl]-
1,3-oxazol-4-yl] ethyl] phenoxy] propyi
[1H] -1H-imidazol-2-yl] methanol

[Chemical 151] (i) Production of 4- [2- [2-[(E) -2- [2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] ethyl] phenol 1-bromo-4- (4-methoxyphenyl) butan-2-one and
4- of 4-bromo-4- (4-methoxyphenyl) butan-2-one
: 1 mixture (5.0 g), using (2E) -3- [2-fluoro-4- (trifluoromethyl) phenyl] pro-2-pentamide (8.3 g) as in Example 57- (i) Was carried out to obtain crude anisole. The above crude anisole and boron tribromide (1.0 M
Example 51- (ii) using a methylene chloride solution: 26 ml)
Perform the same reaction (reaction time: 3.5 hours) as for the title compound.
(3.4 g) was obtained as pale yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.79-2.97 (4H, m), 4.88 (1H,
s), 6.75 (2H, d, J = 8.4Hz), 7.06 (2H, d, J = 8.4)
Hz), 7.10 (2H, d, J = 16.4 Hz), 7.30 (1H, s), 7.32-
7.45 (2H, m), 7.59 (1H, d, J = 16.4 Hz), 7.66 (2H,
d, J = 7.0 Hz) .IR (KBr): 3179, 1516, 1429, 1333,
1132 cm ^-1 .

(Ii) 4- [2- [4- (3-chloropropoxy) phenyl] ethyl] -2-[(E) -2- [2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] Preparation of -1,3-oxazole 4- [2- [2-[(E) -2- [2-fluoro-4- (trifluoromethyl))
Phenyl] ethenyl] -1,3-oxazol-4-yl] ethyl]
Phenol (3.0 g), potassium carbonate (1.65 g) and 1
-Bromo-3-chloropropane (1.2 ml)
The same reaction as in 46- (ii) was performed to give the title compound (2.7 g) as pale-yellow powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.17-2.34 (2H, m), 2.81-2.96 (4
H, m), 3.74 (2H, t, J = 6.6 Hz), 4.08 (2H, t, J =
7.4 Hz), 6.83 (2H, d, J = 8.8 Hz), 7.11 (1H, d, J =
16.4 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.30 (1H, s),
7.34-7.45 (2H, m), 7.58 (1H, d, J = 16.4 Hz), 7.67
(1H, d, J = 7.2 Hz). IR (KBr): 1688, 1534, 1443, 1345, 1253 cm ^-1 .

(Iii) [1- [3- [4- [2- [2-[(E) -2- [2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole -4-yl] ethyl] phenoxy] propyl] -1H-
Preparation of imidazol-2-yl] methanol 4- [2- [4- (3-chloropropoxy) phenyl] ethyl] -2-
[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl]]
Ethenyl] -1,3-oxazole (0.6 g), 2-formylimidazole (0.15 g), sodium iodide (0.24 g) and potassium carbonate (0.22 g) and sodium borohydride (18 mg) The same reaction as in Example 46- (iii) was performed to give the title compound (0.33 g) as white powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.05-2.31 (2H, m), 2.82-2.99 (4
H, m), 3.91 (2H, t, J = 5.6 Hz), 4.24 (2H, t, J =
7.0 Hz), 4.66 (2H, s), 6.81 (2H, d, J = 12.2Hz),
6.87 (1H, d, J = 1.0 Hz), 6.91 (1H, d, J = 1.0 H
z), 7.11 (2H, d, J = 12.2 Hz), 7.12 (1H, d, J = 16.
2 Hz), 7.31 (1H, s), 7.35-7.45 (2H, m), 7.59 (1H,
d, J = 16.2 Hz), 7.67 (1H, t, J = 7.8 Hz). IR (KBr): 3113, 1611, 1512, 1427, 1335 cm ^-1 .

Example 73. [1- [3- [4- [2- [2-[(E) -2- [2-
Fluoro-4- (trifluoromethyl) phenyl] ethenyl]-
1,3-oxazol-4-yl] ethyl] phenoxy] propyi
]]-1H-1,2,3-triazole

[Chemical 152] 4- [2- [4- (3-chloropropoxy) phenyl] ethyl] -2-
[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl]]
Example 58 and ethenyl] -1,3-oxazole (0.25 g), 1H-1,2,3-triazole (57 mg), sodium hydroxide (33 mg) and sodium iodide (0.1 g) were used. The same reaction was performed to give the title compound (0.15 g) as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.34-2.46 (2H, m), 2.81-3.00 (4
H, m), 3.93 (2H, t, J = 5.8 Hz), 4.63 (2H, t, J =
7.0 Hz), 6.81 (2H, d, J = 8.4 Hz), 7.11 (1H, d, J =
16.4 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.31 (1H, s),
7.35-7.45 (2H, m), 7.55 (1H, s), 7.58 (1H, d, J =
16.4 Hz), 7.67 (1H, m), 7.69 (1H, s). IR (KBr): 15
14, 1427, 1337, 1152, 1132 cm ^-1 .

Example 74. 1- [3- [4- [2- [2-[(E) -2- [2-
Luoro-4- (trifluoromethyl) phenyl] ethenyl] -1,
3-Oxazol-4-yl] ethyl] phenoxy] propyl]-
Production of 1H-imidazole-2-carboxamide

[Chemical 153] 4- [2- [4- (3-chloropropoxy) phenyl] ethyl] -2-
[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl]]
Example 59- (Ethenyl] -1,3-oxazole (0.37 g), methyl 1H-imidazole-2-carboxylate (0.12 g), sodium iodide (0.15 g) and potassium carbonate (0.14 g) were used. The same reaction as in i) was performed to obtain a crude ester. The above crude ester, 12N ammonia methanol (2
The same reaction as in Example 59- (ii) was performed using the solution (0 ml) to give the title compound (0.2 g) as pale yellow plate crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.26-2.34 (2H, m), 2.82-2.96 (4
H, m), 3.90 (2H, t, J = 5.7 Hz), 4.66 (2H, t, J =
6.6 Hz), 5.36 (1H, br s), 6.80 (2H, d, J = 8.7 H
z), 7.00 (1H, d, J = 0.9 Hz), 7.01 (1H, d, J = 0.9
Hz), 7.10 (1H, d, J = 8.7 Hz), 7.11 (1H, d, J = 1
6.2 Hz), 7.22 (1H, br s), 7.30 (1H, s), 7.35-7.44
(2H, m), 7.58 (1H, d, J = 16.2 Hz), 7.66 (1H, t, J
= 7.5 Hz) .IR (KBr): 3300, 3162, 1684, 1514, 1327
cm ^-1 .

Example 75. [2- (4- {4-[(2-{(E) -2- [4- (
Lifluoromethyl) phenyl] ethenyl} -1,3-oxazol
Lu-4-yl) methoxy] phenyl} butyl) -1,3-thiazole
-4-yl] methanol production

[Chemical 154] 2- (4- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} butyl) -1 Ethyl 3,3-thiazole-4-carboxylate (306
mg) was dissolved in tetrahydrofuran (6 mL), lithium aluminum hydride (24 mg) was added, and the mixture was stirred at room temperature for 1 hr. Water (24 μL) and 15% aqueous sodium hydroxide solution (24 μL)
L) and water (72 μL) were sequentially added, and the mixture was stirred and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / n-hexane = 1/1 → 1/0),
Recrystallization from ethyl acetate / diethyl ether / n-hexane gave the title compound (167 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.63-1.75 (2H, m), 1.75-1.88 (2
H, m), 2.23 (1H, br), 2.61 (2H, t, J = 7.5Hz), 3.00
(2H, t, J = 7.5Hz), 4.73 (2H, d, J = 6.0Hz), 5.01 (2H,
s), 6.90 (2H, d, J = 8.4Hz), 7.00 (1H, d, J = 16.2H)
z), 7.01 (1H, s), 7.09 (2H, d, J = 8.4Hz), 7.54 (1H,
d, J = 16.2Hz), 7.63 (4H, s), 7.67 (1H, s) .IR (KBr): 3225, 3134, 3077, 1615, 1508, 1325, 123
1, 1179, 1132, 1067, 821cm ^-1 .

Example 76. 1- [3- [4- [2- [2
-[(E) -2- [4- (trifluoromethyl) phenyl]
]] Ethenyl] -1,3-oxazol-4-yl] e
Cyl] phenoxy] propyl] -1H-1,2,3-to
Manufacture of riazole

[Chemical 155] (I) 4- [2- (4-methoxyphenyl) ethyl]-
2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole and 5- (4
-Methoxybenzyl) -4-methyl-2-[(E) -2
-[4- (trifluoromethyl) phenyl] ethenyl]
Preparation of -1,3-oxazole 4- (4-methoxyphenyl) butan-2-one (10
0 g) is dissolved in methanol (400 ml) and the temperature is 0 to 5 ° C.
A solution of bromine (98.6 g) in methanol (300 ml) was added dropwise. After the reaction solution became transparent, stir for 15 minutes,
Water (300 ml) was added and the mixture was stirred at room temperature for 12 hours. After removing methanol under reduced pressure and separating the oil layer, the aqueous layer was extracted with dichloromethane. The organic layer was mixed with the oil layer and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 3), -2
Cooled to 0 ° C. The precipitate was washed with hexane to give 1-bromo-4- (4-methoxyphenyl) butan-2-one and 3-bromo-4- (4-methoxyphenyl) butan-2.
Obtained as a mixture of -ones (105 g, mixing ratio 3: 1). Toluene (560 m) was added to (2E) -3- [4- (trifluoromethyl) phenyl] acrylamide (28 g).
l), a mixture of 1-bromo-4- (4-methoxyphenyl) butan-2-one and 3-bromo-4- (4-methoxyphenyl) butan-2-one (50.1 g) was added,
The mixture was heated under reflux for 24 hours while dehydrating with a Dean-Stark apparatus. After cooling to room temperature, saturated multistory water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 4- [2- (4-methoxyphenyl) ethyl].
-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (14.5
g) and 5- (4-methoxybenzyl) -4-methyl-
2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (5.2 g)
Got 4- [2- (4-methoxyphenyl) ethyl]
-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole ¹ H-NMR (CDCl ₃ ) δ: 2.79-3.01 (4H, m), 3.78 (3H ,
s), 6.78-6.87 (2H, m), 6.99 (1H, d, J = 16.4 Hz),
7.09-7.15 (2H, m), 7.28 (1H, s), 7.49 (1H, d, J = 1
6.2 Hz), 7.57-7.65 (4H, m). 5- (4-methoxybenzyl) -4-methyl-2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxazole ¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, s), 3.79 (3H, s), 3.9
3 (2H, s), 6.83-6.89 (2H, m), 6.90 (1H, d, J = 16.6
Hz), 7.14 (2H, d, J = 8.8 Hz), 7.39 (1H, d, J = 16.4
Hz), 7.54-7.65 (4H, m).

(Ii) 4- [2- [2-[(E) -2-
[4- (trifluoromethyl) phenyl] ethenyl]-
Preparation of 1,3-oxazol-4-yl] ethyl] phenol 4- [2- (4-methoxyphenyl) ethyl] -2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (22.6 g)
Was dissolved in dichloromethane (452 ml), and a 4.2N boron tribromide / dichloromethane solution (17.3) was dissolved at 0 ° C.
ml) was added and the mixture was stirred at room temperature for 5 hours. 8N at 0 ℃
After adjusting the pH to 5 to 6 by adding sodium hydroxide, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 2) to give the title compound (14.3 g) as white crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 2.67-2.89 (4H, m), 6.67 (2H,
d, J = 8.4 Hz), 7.01 (2H, d, J = 11.6 Hz), 7.30 (1H,
d, J = 16.4 Hz), 7.56 (1H, d, J = 16.4Hz), 7.75 (2
H, d, J = 8.4 Hz), 7.83 (1H, s), 7.94 (2H, d, J = 8.
2 Hz), 9.15 (1H, s).

(Iii) 4- [2- [4- (3-chloropropoxy) phenyl] ethyl] -2-[(E) -2-
[4- (trifluoromethyl) phenyl] ethenyl]-
Preparation of 1,3-oxazole 4- [2- [2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] ethyl] phenol (5 0.0 g) was dissolved in acetone (150 ml) and potassium carbonate (4.8 g) was added.
g), 1-bromo-3-chloropropane (2.1 ml)
Was added and the mixture was heated under reflux for 24 hours. After cooling to room temperature, the solvent was removed under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (5.3 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.16-2.28 (2H, m), 2.76-3.02 (4
H, m), 3.74 (2H, t, J = 6.2 Hz), 4.09 (2H, t, J = 6.0
Hz), 6.81-6.86 (2H, m), 7.00 (1H, d, J = 16.6 Hz),
7.12 (2H, d, J = 8.8 Hz), 7.29 (1H, s), 7.49 (1H,
d, J = 16.4 Hz), 7.57-7.66 (4H, m).

(Iv) 1- [3- [4- [2- [2-
Preparation of [(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] ethyl] phenoxy] propyl] -1H-1,2,3-triazole 1, Tert- to 2,3-triazole (130 μl)
Amyl alcohol (7.0 ml), sodium hydroxide (90 mg) and sodium iodide (241 mg) were added, and the mixture was heated under reflux for 1 hr. 4- [2- [4- (3-chloropropoxy) phenyl] ethyl] -2-[(E) -2-
[4- (trifluoromethyl) phenyl] ethenyl]-
A solution of 1,3-oxazole (700 mg) in tert-amyl alcohol (7.0 ml) was added dropwise, and the mixture was heated under reflux for 24 hours. After cooling to room temperature, saturated aqueous citric acid solution was added,
It was extracted with a mixed solution of toluene-ethyl acetate. The extract was washed with saturated multistory water and saturated saline and then dried over magnesium sulfate.
The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate: hexane =
It was purified by 3: 1) and recrystallized from hexane-ethyl acetate to give the title compound (272 mg) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.36-2.44 (2H, m), 2.81-2.87 (2
H, m), 2.91-2.97 (2H, m), 3.93 (2H, t, J = 6.0 Hz),
4.63 (2H, t, J = 6.9 Hz), 6.79-6.83 (2H, m), 7.00 (1
H, d, J = 16.5 Hz), 7.10-7.14 (2H, m), 7.30 (1H,
s), 7.49 (1H, d, J = 16.2 Hz), 7.55 (1H, s), 7.59-7.
65 (4H, m), 7.69 (1H, s) .IR (KBr): 3096, 1582, 1514, 1323, 1167, 1069, 826
cm ^-1 .

Example 77. [1- [3- [4- [2-
[2-[(E) -2- [4- (trifluoromethyl) phenyl]
[Ethenyl] ethenyl] -1,3-oxazol-4-i
L] ethyl] phenoxy] propyl] -1H-imidazo
Lu-2-yl] Methanol production

[Chemical 156] (I) 1- [3- [4- [2- [2-[(E) -2-
[4- (trifluoromethyl) phenyl] ethenyl]-
Preparation of 1,3-oxazol-4-yl] ethyl] phenoxy] propyl] -1H-imidazole-2-carbaldehyde 4- [2- [4- (3-chloropropoxy) phenyl]
Ethyl] -2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (3.5 g) was dissolved in DMF (70 ml) and potassium carbonate (1.8 g) was added. ), 2-formyl imidazole (0.9
3 g) and sodium iodide (1.3 g) were added. 70
After stirring at ℃ for 5 hours, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 2: 1) to give the title compound (3.1 g) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.20-2.31 (2H, m), 2.81-3.02 (4
H, m), 3.89 (2H, t, J = 5.8 Hz), 4.61 (2H, t, J = 6.6
Hz), 6.77-6.82 (2H, m), 7.00 (1H, d, J = 16.6 Hz),
7.10-7.15 (3H, m), 7.29 (1H, s), 7.49 (1H, d, J =
16.6 Hz), 7.60-7.66 (4H, m), 9.82 (1H, s).

(Ii) [1- [3- [4- [2- [2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] ethyl] phenoxy] propyl] -1H-imidazole-
Preparation of 2-yl] methanol 1- [3- [4- [2- [2-[(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl] -1,3
-Oxazol-4-yl] ethyl] phenoxy] propyl] -1H-imidazole-2-carbaldehyde (3.1 g) was dissolved in methanol (62 ml) and the mixture was cooled to 0 ° C.
Sodium borohydride (0.12 g) was added at
The mixture was stirred at 0 ° C for 30 minutes. After concentrating the solvent to half,
The precipitated powder was collected by filtration. Recrystallization from ethyl acetate-methanol gave the title compound (2.2 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.21-2.29 (2H, m), 2.80-2.87 (2
H, m), 2.90-2.96 (2H, m), 3.90 (2H, t, J = 6.0 Hz),
4.23 (2H, t, J = 6.6 Hz), 4.65 (2H, s), 6.78-6.82
(3H, m), 6.85-6.89 (1H, m), 6.99 (1H, d, J = 16.5 H
z), 7.08-7.12 (2H, m), 7.28 (1H, s), 7.48 (1H, d,
J = 16.2 Hz), 7.48 (1H, d, J = 16.2 Hz), 7.58-7.65 (4
H, m) .IR (KBr): 3123, 1512, 1325, 1167, 1069, 828 cm ^-1 .

Example 78. [1- [3- [4-[[4-
Methyl-2-[(E) -2- [4- (trifluoromethyi
Lu) phenyl] ethenyl] -1,3-oxazole-5
-Yl] methyl] phenoxy] propyl] -1H-imi
Dazol-2-yl] methanol production

[Chemical 157] (I) 4-[[4-methyl-2-[(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl] -1,3
Preparation of -oxazol-5-yl] methyl] phenol 5- (4-methoxybenzyl) -4-methyl-2-
[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (6.2 g),
The same reaction as in Example 76- (ii) was performed using dichloromethane (124 ml) and a 4.2N boron tribromide / dichloromethane solution (4.7 ml) to give the title compound (2.8).
g) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.16 (3H, s), 3.92 (2H, s), 5.9
6 (1H, br), 6.78-6.85 (2H, m), 6.90 (1H, d, J = 16.4
Hz), 7.08 (2H, d, J = 8.4 Hz), 7.39 (1H, d, J = 16.4
Hz), 7.47-7.63 (4H, m).

(Ii) 5- [4- (3-chloropropoxy) benzyl] -4-methyl-2-[(E) -2- [4
-(Trifluoromethyl) phenyl] ethenyl] -1,
Preparation of 3-oxazole 4-[[4-methyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-5-yl] methyl] phenol (5 .0
g), (150 ml), potassium carbonate (4.8 g) and 1-bromo-3-chloropropane (2.1 ml) were used to carry out the same reaction as in Example 76- (iii) to give the title compound (5.3 g). ) Was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.16-2.26 (2H, s), 2.17 (3H,
s), 3.73 (2H, t, J = 6.6Hz), 3.93 (2H, s), 4.09 (2
H, t, J = 6.0 Hz), 6.84-6.87 (2H, m), 6.90 (1H, d, J
= 15.6 Hz), 7.11-7.15 (2H, m), 7.38 (1H, d, J = 16.
5 Hz), 7.53-7.62 (4H, m).

(Iii) 1- [3- [4-[[4-methyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole-5-] Preparation of [yl] methyl] phenoxy] propyl] -1H-imidazole-2-carbaldehyde 5- [4- (3-chloropropoxy) benzyl] -4-methyl-2-[(E)
2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (0.80 g) was added to DMF.
Dissolved in (16 ml) and potassium carbonate (0.46 g),
Sodium iodide (0.33 g) and 2-formylimidazole (0.25 g) were added. After stirring at 70 ° C. for 24 hours, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (0.69 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.05 (3H, s), 2.21-2.30 (2H,
m), 3.90 (2H, t, J = 5.7Hz), 3.94 (2H, s), 4.61 (2
H, t, J = 6.6 Hz), 6.83 (2H, d, J = 8.7 Hz), 6.91 (1
H, d, J = 16.5 Hz), 7.12-7.17 (3H, m), 7.25 (1H,
s), 7.40 (1H, d, J = 16.5 Hz), 7.55-7.63 (4H, m), 9.
81 (1H, s).

(Iv) [1- [3- [4-[[4-methyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole-5] -Yl] methyl] phenoxy] propyl] -1H-imidazol-2-yl] methanol preparation 1- [3- [4-[[4-methyl-2-[(E) -2-]
[4- (trifluoromethyl) phenyl] ethenyl]-
1,3-Oxazol-5-yl] methyl] phenoxy] propyl] -1H-imidazole-2-carbaldehyde (0.67 g) was dissolved in methanol (20.1 ml), and sodium borohydride ( 26 mg) was added and the mixture was stirred at 0 ° C. for 30 minutes. The solvent was concentrated to half, water was added, and the mixture was extracted with a mixed solution of ethyl acetate-THF. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and recrystallized from hexane-ethyl acetate to give the title compound (0.49 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, s), 2.20-2.31 (2H,
m), 3.91 (2H, t, J = 5.8Hz), 3.93 (2H, s), 4.23 (2
H, t, J = 6.6 Hz), 4.64 (2H, s), 6.81-6.95 (5H, m),
7.13 (2H, d, J = 8.6 Hz), 7.40 (1H, d, J = 16.2 Hz),
7.53-7.64 (4H, m). IR (KBr): 3123, 1613, 1512, 1323, 1113, 822 cm ^-1 .

Example 79. [1- [3- [2-methyl-
4- [2- [2-[(E) -2- [4- (trifluoro
Methyl) phenyl] ethenyl] -1,3-oxazole
-4-yl] ethyl] phenoxy] propyl] -1H-
Imidazol-2-yl] methanol production

[Chemical 158] (I) 4- [2- (4-methoxy-3-methylphenyl) ethyl] -2- [2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3- Preparation of oxazole and 5- (4-methoxy-3-methylbenzyl) -4-methyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (2E ) -3- [4- (Trifluoromethyl) phenyl] acrylamide (66 g) in toluene (990 m
l), a mixture of 1-bromo-4- (4-methoxy-3-methylphenyl) butan-2-one and 3-bromo-4- (4-methoxy-3-methylphenyl) butan-2-one (124 g ) Was added and the mixture was heated under reflux for 24 hours while dehydrating. After cooling to room temperature, saturated multistory water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 4) to give 4- [2- (4-
Methoxy-3-methylphenyl) ethyl] -2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (38.1 g)
And 5- (4-methoxy-3-methylbenzyl) -4-
Methyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (1
5.7 g) was obtained. 4- [2- (4-Methoxy-3-methylphenyl) ethyl] -2- [2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole ¹ H -NMR (CDCl ₃ ) δ: 2.20 (3H, s), 2.82-2.92 (4H,
m), 3.81 (3H, s), 6.75 (1H, d, J = 8.8 Hz), 6.95-7.
05 (2H, m), 7.00 (1H, d, J = 16.6 Hz), 7.30 (1H,
s), 7.49 (1H, d, J = 16.4 Hz), 7.59-7.65 (4H, m). 5- (4-methoxy-3-methylbenzyl) -4-methyl-2-[(E) -2- [4- (trifluoromethyl)
Phenyl] ethenyl] -1,3-oxazole ¹ H-NMR (CDCl ₃ ) δ: 2.18 (3H, s), 2.21 (3H, s), 3.8
1 (3H, s), 3.90 (2H, s), 6.77 (1H, d, J = 7.8 Hz),
6.91 (1H, d, J = 16.5 Hz), 6.98-7.03 (2H, m), 7.40
(1H, d, J = 16.2 Hz), 7.54-7.64 (4H, m).

(Ii) 2-methyl-4- [2- [2-
Preparation of [(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] ethyl] phenol 4- [2- (4-methoxy-3-methylphenyl) Ethyl] -2- [2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (15 g), dichloromethane (300 ml) and 4.2.
Using a solution of N boron tribromide in dichloromethane (13.8 ml), the same reaction as in Example 76- (ii) was performed to give the title compound (4.1 g) as white crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 2.08 (3H, s), 2.71-2.78 (4H,
m), 6.66 (1H, d, J = 8.1 Hz), 6.80-6.85 (2H, m), 6.
92 (1H, s), 7.30 (1H, d, J = 16.2 Hz), 7.55 (1H, d,
J = 16.5 Hz), 7.75 (2H, d, J = 8.1 Hz), 7.83 (1H,
s), 7.94 (2H, d, J = 8.1 Hz), 9.02 (1H, s).

(Iii) 4- [2- [4- (3-chloropropoxy) -3-methylphenyl] ethyl] -2-
Preparation of [(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole 2-Methyl-4- [2- [2-[(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl] -1,3
-Oxazol-4-yl] ethyl] phenol (3.
0 g), acetone (90 ml), potassium carbonate (2.8
g) and 1-bromo-3-chloropropane (1.2 m
The same reaction as in Example 76- (iii) was performed using l) to obtain the title compound (2.0 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.18-2.32 (2H, m), 2.20 (3H,
s), 2.83-2.92 (2H, m), 3.77 (2H, t, J = 6.2 Hz), 4.
09 (2H, t, J = 5.8 Hz), 6.75 (1H, d, J = 8.4 Hz), 6.
95-7.01 (2H, m), 7.00 (1H, d, J = 16.2 Hz), 7.31 (1
H, s), 7.49 (1H, d, J = 16.2 Hz), 7.58-7.66 (4H,
m).

(Iv) 1- [3- [2-methyl-4- [2]
-[2-[(E) -2- [4- (trifluoromethyl)
Preparation of phenyl] ethenyl] -1,3-oxazol-4-yl] ethyl] phenoxy] propyl] -1H-imidazole-2-carbaldehyde 4- [2- [4- (3-chloropropoxy) -3-methyl Phenyl] ethyl] -2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (0.60 g), DMF (12 ml), potassium carbonate (0.33 g). , Sodium iodide (0.24
g) and 2-formylimidazole (0.18 g) were used to carry out the same reaction as in Example 78- (iii) to obtain the title compound (0.51 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.23-2.33 (2H, m), 2.24 (3H,
s), 2.80-2.93 (4H, m), 3.90 (2H, t, J = 5.7 Hz), 4.
63 (2H, t, J = 6.6 Hz), 6.94-7.02 (2H, m), 6.99 (1H,
d, J = 16.2 Hz), 7.12 (1H, s), 7.25 (1H, s), 7.30
(1H, s), 7.49 (1H, d, J = 16.2 Hz), 7.59-7.63 (4H,
m), 9.81 (1H, s).

(V) [1- [3- [2-methyl-4-]
[2- [2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole-4
Preparation of -yl] ethyl] phenoxy] propyl] -1H-imidazol-2-yl] methanol 1- [3- [2-methyl-4- [2- [2-[(E)-
2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] ethyl] phenoxy] propyl] -1H-imidazole-2-carbaldehyde (0.50 g), methanol (20 ml) And sodium borohydride (19 mg) were used to carry out the same reaction as in Example 78- (iv) to give the title compound (0.29
g) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.23-2.32 (2H, m), 2.25 (3H,
s), 2.81-2.94 (4H, m), 3.93 (2H, t, J = 5.4 Hz), 4.
25 (2H, t, J = 6.9 Hz), 4.32 (1H, br), 4.67 (2H,
s), 6.68 (1H, d, J = 8.1 Hz), 6.87-7.03 (5H, m), 7.
31 (1H, s), 7.50 (1H, d, J = 16.5 Hz), 7.61-7.67 (4
H, m). IR (KBr): 3146, 1582, 1501, 1323, 1146, 1067, 829
cm ^-1 .

Example 80. 1- (3- (4- (2- (2-((E) -2- (2-
Fluoro-4- (trifluoromethyl) phenyl) ethenyl)-
1,3-oxazol-4-yl) ethyl) -2-methylphenoxy
(Ci) propyl) -1H-1,2,3-triazole production

[Chemical 159] 1H-1,2,3-triazole (154 μl), sodium hydroxide (9
A solution of 0 mg) and sodium iodide (336 mg) in 2-methyl-2-butanol (5 ml) was heated under reflux for 1 hour. After cooling to room temperature, 4
-(2- (4- (3-chloropropoxy) -3-methylphenyl) ethyl) -2-((E) -2- (2-fluoro- (trifluoromethyl) phenyl) ethenyl) -1,3- Oxazole (700 mg) 2-methyl-
2-Butanol (5 ml) solution was added, and the mixture was heated under reflux for 16 hr. After water was added and the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 2) and recrystallized from ethyl acetate-hexane to give the title compound (407 mg) as white needle crystals. Got as. ¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 2.38-2.49 (2H,
m), 2.80-2.95 (4H, m), 3.94 (2H, t, J = 5.8 Hz),
4.65 (2H, t, J = 6.6 Hz), 6.68 (1H, d, J = 8.0Hz),
6.94-7.70 (10H, m) .IR (KBr): 2926, 1583, 1504, 1427, 1327, 1140 c
m ^-1 .

Example 81. (1- (3- (4- (2- (2-((E) -2- (2-
Fluoro-4- (trifluoromethyl) phenyl) ethenyl)-
1,3-oxazol-4-yl) ethyl) -2-methylphenoxy
Di) propyl) -1H-imidazol-2-yl) methanol
Construction

[Chemical 160] (i) 1- (3- (4- (2- (2-((E) -2- (2-fluoro-4- (trifluoromethyl) phenyl) ethenyl) -1,3-oxazol-4-yl ) Ethyl) -2-methylphenoxy) propyl) -1H-imidazole-2-carbaldehyde production 4- (2- (4- (3-chloropropoxy) -3-methylphenyl) ethyl) -2-((E ) -2- (2-Fluoro- (trifluoromethyl) phenyl) ethenyl) -1,3-oxazole (700 mg) in DMF (10 m
l) 2-formylimidazole (172 mg), sodium iodide (336 mg) and potassium carbonate (310 mg) were added to the solution at 70 ° C for 16
Stir for hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Silica gel column chromatography of the residue (eluent, ethyl acetate: hexane = 1: 2)
The title compound (588 mg) was obtained as a white powder solid. ¹ H-NMR (CDCl ₃ ) δ: 2.20-2.36 (2H, m), 2.24 (3H,
s), 2.80-2.94 (4H, m), 3.91 (2H, t, J = 5.4 Hz),
4.63 (2H, t, J = 7.0 Hz), 6.67 (1H, d, J = 8.0Hz),
6.95-7.71 (10H, m), 9.82 (1H, s). IR (KBr): 2924, 1689, 1504, 1331, 1130, 912, 742
cm ^-1 .

(Ii) (1- (3- (4- (2- (2-((E) -2- (2-fluoro
Preparation of 4- (trifluoromethyl) phenyl) ethenyl) -1,3-oxazol-4-yl) ethyl) -2-methylphenoxy) propyl) -1H-imidazol-2-yl) methanol 1- (3- (4- (2- (2-((E) -2- (2-fluoro-4- (trifluoromethyl) phenyl) ethenyl) -1,3-oxazol-4-yl) ethyl) -2-methylphenoxy ) Propyl) -1H-imidazole
To a solution of -2-carbaldehyde (588 mg) in methanol (10 ml) was added sodium borohydride (141 mg) at 0 ° C, and the mixture was stirred for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: methanol = 20: 1) and recrystallized from ethyl acetate-hexane to give the title compound (496 mg) as white needle crystals. Got as. ¹ H-NMR (CDCl ₃ ) δ: 2.20-2.36 (2H, m), 2.24 (3H,
s), 2.80-2.94 (4H, m), 3.93 (2H, t, J = 5.8 Hz),
4.25 (2H, t, J = 6.8 Hz), 4.68 (2H, s), 6.67 (1H,
d, J = 8.6 Hz), 6.88-7.71 (10H, m). IR (KBr): 2924, 1504, 1429, 1332, 1130 cm ^-1 .

Example 82. [1- [3- [2-methyl-
4-[[4-methyl-2-[(E) -2- [4- (tri
Fluoromethyl) phenyl] ethenyl] -1,3-oxy
Sazol-5-yl] methyl] phenoxy] propyl]
Production of -1H-imidazol-2-yl] methanol

[Chemical 161] (I) 2-methyl-4-[[4-methyl-2-[(E)
Preparation of 2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-5-yl] methyl] phenol 5- (4-methoxy-3-methylbenzyl) -4-methyl-2- [(E) -2- [4- (trifluoromethyl)
Phenyl] ethenyl] -1,3-oxazole (26.
5 g), dichloromethane (400 ml) and 4.2N boron tribromide dichloromethane solution (24.4 ml) were used to carry out the same reaction as in Example 76- (ii) to give the title compound (4.9 g) as white crystals. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.08 (3H, s), 2.11 (3H, s), 3.8
8 (2H, s), 6.70 (1H, d, J = 8.4 Hz), 6.82-6.86 (2H,
m), 6.91 (1H, s), 7.18 (1H, d, J = 16.2 Hz), 7.41
(1H, d, J = 16.5 Hz), 7.71 (2H, d, J = 8.4 Hz), 7.88
(2H, d, J = 8.1Hz), 9.14 (1H, s).

(Ii) 5- [4- (3-chloropropoxy) -3-methylbenzyl] -4-methyl-2-
Preparation of [(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole 2-Methyl-4-[[4-methyl-2-[(E) -2-]
[4- (trifluoromethyl) phenyl] ethenyl]-
Example using 1,3-oxazol-5-yl] methyl] phenol (2.4 g), acetone (72 ml), potassium carbonate (2.2 g) and 1-bromo-3-chloropropane (0.95 ml). The same reaction as in 76- (iii) was performed to give the title compound (1.6 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, s), 2.20 (3H, s), 2.2
0-2.29 (2H, m), 3.75 (2H, t, J = 6.3 Hz), 3.90 (2H, m
s), 4.09 (2H, t, J = 5.7 Hz), 6.77 (1H, d, J = 9.0
Hz), 6.90 (1H, d, J = 16.2 Hz), 6.97-7.01 (2H, m),
7.39 (1H, d, J = 16.5 Hz), 7.53-7.62 (4H, m).

(Iii) 1- [3- [2-methyl-4-]
[[4-Methyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-5-yl] methyl] phenoxy] propyl] -1
Preparation of H-imidazole-2-carbaldehyde 5- [4- (3-chloropropoxy) -3-methylbenzyl] -4-methyl-2-[(E) -2- [4- (trifluoromethyl) phenyl ] Ethenyl] -1,3-oxazole (0.60 g), DMF (12 ml), potassium carbonate (0.33 g), sodium iodide (0.24)
g) and 2-formylimidazole (0.18 g) were used to carry out the same reaction as in Example 78- (iii) to obtain the title compound (0.42 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.18 (3H, s), 2.23-2.32 (2H,
m), 2.24 (3H, s), 3.90 (2H, s), 3.90 (2H, t, J = 5.
4 Hz), 4.62 (2H, t, J = 6.6 Hz), 6.69 (1H, d, J = 8.
1 Hz), 6.91 (1H, d, J = 16.5 Hz), 6.95-7.00 (2H,
m), 7.11 (1H, s), 7.25 (1H, s), 7.39 (1H, d, J = 1
6.2 Hz), 7.54-7.61 (5H, m), 9.81 (1H, s).

(Iv) [1- [3- [2-methyl-4-]
[[4-Methyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-5-yl] methyl] phenoxy] propyl] -1
Preparation of H-imidazol-2-yl] methanol 1- [3- [2-methyl-4-[[4-methyl-2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-5-yl] methyl] phenoxy] propyl] -1H-imidazole-
2-carbaldehyde (0.41 g), methanol (1
2.3 ml) and sodium borohydride (15 mg) were used to carry out the same reaction as in Example 78- (iv) to obtain the title compound (0.28 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, s), 2.22-2.31 (2H,
m), 2.24 (3H, s), 3.90 (2H, s), 3.92 (2H, t, J = 5.
4 Hz), 4.25 (2H, t, J = 6.6 Hz), 4.63 (2H, s), 6.68
(1H, d, J = 8.1 Hz), 6.82-7.00 (5H, m), 7.11 (1H,
s), 7.39 (1H, d, J = 16.5 Hz), 7.53-7.62 (4H, m) .IR (KBr): 3137, 2928, 1615, 1507, 1325, 1254, 111
1, 820 cm ^-1 .

Example 83. [1- [4- [2-methyl-
4-[[4-methyl-2-[(E) -2- [4- (tri
Fluoromethyl) phenyl] ethenyl] -1,3-oxy
Sazol-5-yl] methyl] phenoxy] butyl]-
Production of 1H-imidazol-2-yl] methanol

[Chemical 162] (I) 5- [4- (3-chlorobutoxy) -3-methylbenzyl] -4-methyl-2-[(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl] -1,3
-Preparation of oxazole 2-methyl-4-[[4-methyl-2-[(E) -2-
[4- (trifluoromethyl) phenyl] ethenyl]-
1,3-Oxazol-5-yl] methyl] phenol (1.2 g), acetone (48 ml), potassium carbonate (1.1 g) and 1-bromo-4-chlorobutane (0.
The same reaction as in Example 76- (iii) was carried out using 56 ml) to obtain the title compound (1.6 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.94 (2H, m), 2.17 (3H, s), 2.2
1 (3H, s), 3.60-3.65 (2H, m), 3.90 (2H, s), 3.98
(2H, t, J = 5.4 Hz), 6.75 (1H, d, J = 9.0 Hz), 6.91
(1H, d, J = 16.5 Hz), 6.97-7.00 (2H, m), 7.40 (1H,
d, J = 16.5 Hz), 7.54-7.63 (4H, m).

(Ii) 1- [3- [2-methyl-4-]
[[4-Methyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-5-yl] methyl] phenoxy] butyl] -1H
-Preparation of imidazole-2-carbaldehyde 5- [4- (3-chlorobutoxy) -3-methylbenzyl] -4-methyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] Ethenyl] -1,3-oxazole (0.92 g), DMF (18.4 ml), potassium carbonate (0.51 g), sodium iodide (0.37).
g) and 2-formylimidazole (0.28 g) were used to carry out the same reaction as in Example 78- (iii) to obtain the title compound (0.61 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.76-1.86 (2H, m), 1.95-2.05 (2
H, m), 2.17 (3H, s), 2.19 (3H, s), 3.89 (2H, s),
3.96 (2H, t, J = 6.0 Hz), 4.48 (2H, t, J = 7.2Hz),
6.72 (1H, d, J = 9.0 Hz), 6.90 (1H, d, J = 16.5 Hz),
6.97-6.99 (2H, m), 7.17 (1H, s), 7.28 (1H, s), 7.
38 (1H, d, J = 16.2 Hz), 7.53-7.62 (4H, m), 9.81 (1
H, s).

(Iii) [1- [4- [2-methyl-4-]
[[4-Methyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-5-yl] methyl] phenoxy] butyl] -1H
-Preparation of imidazol-2-yl] methanol 1- [3- [2-methyl-4-[[4-methyl-2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-5-yl] methyl] phenoxy] butyl] -1H-imidazole-2
-Carbaldehyde (0.61 g), methanol (18.
3 ml) and sodium borohydride (22 mg) were used to carry out the same reaction as in Example 78- (iv) to obtain the title compound (0.38 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.77-1.89 (2H, m), 1.94-2.06 (2
H, m), 2.17 (3H, s), 2.20 (3H, s), 3.89 (2H, s),
3.96 (2H, t, J = 6.0Hz), 4.08 (2H, t, J = 7.2Hz),
4.66 (2H, s), 6.72 (1H, d, J = 9.0 Hz), 6.86-6.98
(2H, m), 7.38 (1H, d, J = 16.5 Hz), 7.53-7.62 (4H,
m). IR (KBr): 3104, 2948, 1746, 1613, 1507, 1323, 110
0, 820 cm ^-1 .

Example 84. 1- [3- [4-[[4-me
Chill-2-[(E) -2- [4- (trifluoromethyi
Lu) phenyl] ethenyl] -1,3-oxazole-5
-Yl] methyl] phenoxy] propyl] -1,2,3
-Production of triazole

[Chemical formula 163] 1,2,3-triazole (90 μl), tert-amyl alcohol (4.5 ml), sodium hydroxide (6
2 mg), sodium iodide (170 mg) and 5-
[4- (3-Chloropropoxy) benzyl] -4-methyl-2-[(E) -2- [4- (trifluoromethyl)]
Phenyl] ethenyl] -1,3-oxazole (450
mg) in tert-amyl alcohol (4.5 ml) to carry out the same reaction as in Example 78- (iv) to obtain the title compound (174 mg) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, s), 2.36-2.45 (2H,
m), 3.93 (2H, s), 3.93 (2H, t, J = 5.4 Hz), 4.62 (2
H, t, J = 6.6 Hz), 6.80-6.85 (2H, m), 6.90 (1H, d, J
= 16.5 Hz), 7.11-7.15 (2H, m), 7.39 (1H, d, J = 16.
5 Hz), 7.52-7.62 (5H, m), 7.68 (1H, s). IR (KBr): 3125, 1613, 1512, 1325, 1123, 1067, 826
cm ^-1 .

Example 85. 3- [4- [2-methyl-4-[[2-[(E)-
2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-o
Xazol-4-yl] methoxy] phenyl] butyl] -1H-1,
Production of 2,4-triazole

[Chemical 164] (i) (2E) -3- (4-methoxy-2-methylphenyl) prop-2-
Production of ethyl enoate Bromo-5-methoxytoluene (50.0 g), ethyl acrylate (32.3 ml), tris (2-methylphenyl) phosphine
(11.4 g), triethylamine (69.4 ml) and palladium (II) acetate (4.20 g) in 1,4-dioxane (300 ml) suspension 43
Heated to reflux for hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 10: 1) to give the title compound (25.9
g) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.2 Hz), 2.43
(3H, s), 3.82 (3H, s), 4.26 (2H, q, J = 7.2 Hz), 6.
26 (1H, d, J = 15.8 Hz), 6.73-6.78 (2H, m), 7.53 (1
H, d, J = 8.8 Hz), 7.92 (1H, d, J = 15.8 Hz). IR (KBr): 1709, 1603, 1501, 1258, 1159 cm ^-1 .

(Ii) Production of ethyl 3- (4-methoxy-2-methylphenyl) propanoate Under a hydrogen atmosphere, (2E) -3- (4-methoxy-2-methylphenyl)
Ethyl prop-2-enoate (25.5 g) in ethanol (300 ml)
10% Palladium on carbon (5.1 g) was added to the solution, and the mixture was stirred at room temperature for 16 hours. The reaction solution was filtered and the filtrate was concentrated to give the title compound (25.1 g) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0 Hz), 2.30
(3H, s), 2.53 (2H, d, J = 7.0 Hz), 2.87 (2H, d, J =
7.0 Hz), 3.77 (3H, s), 4.13 (2H, q, J = 7.0 Hz),
6.65-6.70 (2H, m), 7.05 (1H, d, J = 8.2 Hz). IR (KBr): 1732, 1505, 1292, 1254, 1161 cm ^-1 .

(Iii) 3- (4-methoxy-2-methylphenyl)
Production of propan-1-ol lithium aluminum hydride (4.29 g) in THF (250 ml)
A solution of ethyl 3- (4-methoxy-2-methylphenyl) propanoate (25.1 g) in THF (100 ml) was added dropwise to the solution at 0 ° C., and the mixture was stirred at the same temperature for 1.5 hr. Sodium sulfate decahydrate (43.7
g) was added, and the mixture was stirred at room temperature overnight. After filtering the reaction solution, the filtrate was concentrated and the residue was subjected to silica gel column chromatography.
(Eluent, hexane: ethyl acetate = 2: 1) to give the title compound (19.8 g) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (1H, t, J = 6.3 Hz), 1.77-
1.87 (2H, m), 2.04 (3H, s), 2.63 (2H, d, J = 7.8
Hz), 3.64 (2H, dt, J = 6.3, 6.3 Hz), 3.77 (3H, s),
6.65-6.71 (2H, m), 7.04 (1H, d, J = 8.1 Hz). IR (KBr): 1609, 1503, 1287, 1254, 1049 cm ^-1 .

(Iv) 4- (3-iodopropyl) -3-methylphenyl methyl ether 3- (4-methoxy-2-methylphenyl) propan-1-ol
(19.5 g) in ethyl acetate (250 ml) at 0 ° C with triethylamine (22.6 ml) and methanesulfonyl chloride (12.5 g).
ml) was added, and the mixture was stirred at 0 ° C for 1 hr. Water was added to the reaction solution, the organic layer was separated, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 3- (4-methoxy-2-methylphenyl) propyl methanesulfonate. Add 2.5 parts of this product and a suspension of sodium iodide (48.6 g) in acetone (300 ml).
Heated to reflux for hours. Water and diisopropyl ether were added to the reaction solution, the organic layer was separated, and the organic layer was washed with water, 10% hypo-water, and then with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (30.0 g) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 2.00-2.10 (2H, m), 2.29 (3H,
s), 2.66 (2H, d, J = 7.2 Hz), 3.20 (2H, t, J = 6.9
Hz), 3.77 (3H, s), 6.65-6.71 (2H, m), 7.04 (1H,
d, J = 8.1 Hz) .IR (KBr): 1609, 1503, 1254, 1204, 1051 cm ^-1 .

(V) 3- [4- (4-methoxy-2-methylphenyl)
Preparation of butyl] -1H-1,2,4-triazole 4- (3-iodopropyl) -3-methylphenyl methyl ether (30.0 g), triphenylphosphine (27.1 g) Example 10- (i ) Was performed to obtain [3- (4-methoxy-2-methylphenyl) propyl] (triphenyl) phosphonium iodide (52.6 g). This product (5.00 g), 1-Trityl-1H-1,2,4-triazole-3-carbaldehyde (2.46
g), potassium carbonate (1.50 g), water (0.261 ml) and 10% palladium carbon (3.36 g), ethanol-THF mixed solution (4: 1; 6
The same reaction as in Example 10- (i) was performed using 0 ml) to give the title compound (1.45 g) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.59-1.66 (2H, m), 1.79-1.89
(2H, m), 2.24 (3H, d, J = 3.9 Hz), 2.53-2.60 (2H,
m), 2.84 (2H, d, J = 7.8 Hz), 3.76 (3H, d, J = 2.4
Hz), 6.62-6.68 (2H, m), 6.99 (1H, dd, J = 4.8, 8.1
Hz), 7.97 (1H, s) .IR (KBr): 2936, 1503, 1466, 1256, 1047 cm ^-1 .

(Vi) Preparation of 3-methyl-4- [4- (1H-1,2,4-triazol-3-yl) butyl] phenol 3- [4- (4-methoxy-2-methylphenyl) Butyl] -1H-1,2,4-triazole
A solution of (1.43 g) in 48% hydrobromic acid (6 ml) was stirred at 110 ° C for 16 hours. Water and then a 4N aqueous sodium hydroxide solution were added, and after salting out, the mixture was extracted with a THF-ethyl acetate mixed solution (2: 1) and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (Chromatore
x, eluent, ethyl acetate → ethyl acetate: methanol = 10: 1)
The title compound (1.26 g) was obtained as a colorless amorphous. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.52-1.64 (2H, m), 1.72-
1.87 (2H, m), 2.20 (3H, s), 2.54 (2H, t, J = 7.6 H
z), 2.79 (2H, d, J = 7.2 Hz), 6.55-6.62 (2H, m), 6.
91 (1H, d, J = 8.2 Hz), 7.43 (1H, s). IR (KBr): 1497, 1464, 1283, 1233, 853 cm ^-1 .

(Vii) 3-methyl-4- [4- (1-trityl-1H-1,
Production of 2,4-triazol-3-yl) butyl] phenol 3-methyl-4- [4- (1H-1,2,4-triazol-3-yl) butyl] phenol (1.24 g), triethylamine (1.64 m
The same reaction as in Example 26- (ii) was performed using l) and trityl chloride (1.52 g) to give the title compound (1.25 g) as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.51-1.58 (2H, m), 1.75-1.85
(2H, m), 2.17 (3H, s), 2.49 (2H, t, J = 7.8 Hz), 2.
80 (2H, d, J = 7.8 Hz), 5.92 (1H, s), 6.54-6.60 (2
H, m), 6.89 (1H, d, J = 8.4 Hz), 7.11-7.16 (6H,
m), 7.27-7.33 (8H, m), 7.87 (1H, s). IR (KBr): 1501, 1447, 747, 733, 700 cm ^-1 .

(Viii) 3- [4- [2-methyl-4-[[2-[(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] butyl] -1H-1,2,4-
Preparation of triazole 3-methyl-4- [4- (1-trityl-1H-1,2,4-triazole-3-
0) in DMF (5 ml) solution of (yl) butyl] phenol (350 mg)
Add 65% sodium hydride (30.0 mg) at 30
Stir for minutes. 4- (chloromethyl) -2-[(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (213 mg) was added, and the mixture was stirred at room temperature for 14 hours. 90% Formic acid (3 ml) was added to the reaction mixture, and the mixture was heated under reflux at 60 ° C. for 1.5 hr. The reaction mixture was concentrated, 4N aqueous sodium hydroxide solution was added to the residue, the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography.
(Eluent, dichloromethane → dichloromethane: methanol
= 20: 1) and recrystallized from ethyl acetate-methanol-hexane to give the title compound (282 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.58-1.66 (2H, m), 1.78-
1.88 (2H, m), 2.26 (3H, s), 2.58 (2H, t, J = 7.5 H
z), 2.81 (2H, d, J = 7.2 Hz), 5.00 (2H, d, J = 0.9
Hz), 6.78-6.79 (2H, m), 6.99-7.05 (2H, m), 7.55 (1
H, d, J = 16.7Hz), 7.65-7.69 (5H, m), 7.45 (1H,
s) .IR (KBr): 1329, 1165, 1109, 1069, 1042 cm ^-1 .

Example 86. 3- [4- [4-[[2-[(E) -2- [2-Full
Oro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-
Oxazol-4-yl] methoxy] -2-methylphenyl] bu
Chill] -1H-1,2,4-triazole

[Chemical 165] 3-methyl-4- [4- (1-trityl-1H-1,2,4-triazole-3-
(Butyl) butyl] phenol (350 mg), 65% sodium hydride (30.0 mg), 4- (chloromethyl) -2-[(E) -2- [2-fluoro-4- (trifluoromethyl) phenyl] Example 85 using ethenyl] -1,3-oxazole (226 mg) and 90% formic acid (3 ml)
The same reaction as in-(viii) was performed to give the title compound (272 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.57-1.67 (2H, m), 1.79-1.89
(2H, m), 2.25 (3H, s), 2.58 (2H, t, J = 7.8 Hz), 2.
83 (2H, d, J = 7.5 Hz), 5.01 (2H, d, J = 0.6Hz),
6.72-6.79 (2H, m), 7.02 (1H, d, J = 8.4 Hz), 7.13
(1H, d, J = 16.8Hz), 7.36-7.46 (2H, m), 7.62-7.70
(3H, m), 7.97 (1H, s). IR (KBr): 1501, 1333, 1167, 1115, 1042 cm ^-1 .

Example 87. 2- [1- [3- [4- [2
-[2-[(E) -2- [4- (trifluoromethyl)
Phenyl] ethenyl] -1,3-oxazol-4-i
L] ethyl] phenoxy] propyl] -1H-imidazo
2-l] Ethanol production

[Chemical 166] 2- (1H-imidazol-2-yl) ethanol (1
24 mg) was dissolved in DMF (3.7 ml), 60% sodium hydride (49 mg) was added at 0 ° C, and the mixture was stirred at 0 ° C for 20 min. 4- [2- [4- (3-chloropropoxy) phenyl] ethyl] -2-[(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl] -1,3
-Oxazole (0.58g) and sodium iodide (0.20g) were added, and it stirred at 70 degreeC for 6 hours.
After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate.
The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate: ethanol = 15: 1) and recrystallized from hexane-ethyl acetate to give the title compound (0.23 g). Obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.13-2.21 (2H, m), 2.78-2.87 (2
H, m), 2.81 (2H, t, J = 5.7 Hz), 2.90-2.97 (2H, m),
3.88 (2H, t, J = 5.7 Hz), 3.97 (2H, t, J = 5.4 Hz),
4.09 (2H, t, J = 6.9 Hz), 6.78-6.85 (3H, m), 6.94
(2H, d, J = 1.5 Hz), 7.00 (1H, d, J = 16.5 Hz), 7.12
(2H, d, J = 8.7 Hz), 7.28 (1H, d, J = 9.6 Hz), 7.50
(1H, d, J = 16.2 Hz), 7.60-7.66 (4H, m). IR (KBr): 3162, 2919, 1582, 1512, 1323, 1148, 106
9,828 cm ^-1 .

Example 88. 5- (3- {4- [2- (2-{(E) -2- [4-
(Trifluoromethyl) phenyl] vinyl} -1,3-oxazo
4-yl) ethyl] phenoxy} propyl) pyrimidine
Manufacturing of

[Chemical 167] (i) Production of 3- (pyrimidin-5-yl) prop-2-yn-1-ol propargyl alcohol (2.52 g), 5-bromopyrimidine
A mixture of (4.77 g), trans-dichlorobis (triphenylphosphine) palladium (II) (632 mg), copper iodide (86 mg) and triethylamine (30 ml) was stirred at 50 ° C. for 5 hours.
The reaction solution was diluted with THF (60 ml) and filtered. The filtrate was concentrated under reduced pressure, ethyl acetate (80 ml) was added to the residue, and the mixture was washed with water (20 ml) and saturated brine (20 ml × 3). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent, hexane-ethyl acetate = 6/4 → ethyl acetate) to give the title compound (1.18 g)
Was obtained as a light brown solid. ¹ H-NMR (CDCl ₃ ) δ: 2.34 (1H, br t, OH), 4.55 (2H,
d, J = 6.0Hz), 8.79 (2H, s), 9.15 (1H, s).

(Ii) 3- (pyrimidin-5-yl) propane-1-
Preparation of oar 3- (pyrimidin-5-yl) prop-2-yn-1-ol (805mg)
In methanol (15 mL) solution of 10% palladium carbon (50% water content,
200 mg) was added and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent, ethyl acetate: methanol = 1/0 → 4/1) to give the title compound (757 mg) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.87-1.96 (2H, m), 2.75 (2H,
t, J = 7.7Hz), 3.68-3.74 (2H, m), 8.60 (2H, s), 9.06
(1H, s).

(Iii) 5- (3- {4- [2- (2-{(E) -2- [4- (trifluoromethyl) phenyl] vinyl} -1,3-oxazole-4-
Preparation of (yl) ethyl] phenoxy} propyl) pyrimidine 3- (pyrimidin-5-yl) propan-1-ol (166 mg) and triethylamine (0.335 ml) in THF (10 ml) under ice-cooled stirring under methanesulfonyl chloride ( 0.167 ml) was added, and the mixture was stirred under ice cooling for 1 hour. Water (10 ml) and saturated brine (10 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (20 × 4). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DMF (10 ml) and 4- [2- (2-{(E) -2- [4
-(Trifluoromethyl) phenyl] vinyl} -1,3-oxazol-4-yl) ethyl] phenol (359 mg) and potassium carbonate
(415 mg, 3.0 mmol) was added, and the mixture was stirred at 80 ° C for 5 hr.
The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (40 ml) and washed with water (10 ml) and saturated brine (10 ml). The organic layer was concentrated under reduced pressure, the residue was subjected to silica gel chromatography (eluent, hexane: ethyl acetate = 1/1 → ethyl acetate), and the target fraction was concentrated under reduced pressure. Methanol was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to give the title compound (340 mg, 0.
71 mmol, yield 71%) was obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.08-2.17 (2H, m), 2.84 (4H,
t, J = 7.5Hz), 2.92-2.97 (2H, m), 3.97 (2H, t, J = 5.9H
z), 6.81 (2H, d, J = 8.7Hz), 7.00 (1H, d, J = 16.4Hz),
7.12 (2H, d, J = 8.7Hz), 7.30 (1H, s), 7.50 (1H, d,
J = 16.4Hz), 7.60-7.66 (4H, m), 8.62 (2H, s), 9.09
(1H, s) .IR (KBr): 1512, 1414, 1327, 1240, 1167, 1142, 1069
cm ^-1 .

Example 89. [1- (3- {5-[(2-{(E) -2- [4- (
Lifluoromethyl) phenyl] ethenyl} -1,3-oxazol
Ru-4-yl) methoxy] -1H-indol-1-yl} propyl)
Of -1H-imidazol-2-yl] methanol

[Chemical 168] (i) Preparation of 5- (benzyloxy) -1- (3-chloropropyl) -1H-indole 5- (benzyloxy) -1H-indole (6.70 g) in DMF (30 mL)
Sodium hydride (60% oily, 1.
56g) was added and stirred for 15 minutes. 1-Bromo-3 under ice cooling
After adding -chloropropane (4.45 mL), the mixture was stirred at room temperature for 1 hour. Under ice cooling, add water (150 mL) and add ethyl acetate (100 m
L, twice). The organic layer was washed successively with water (20 mL, twice) and saturated brine (20 mL), and concentrated under reduced pressure. Column chromatography of the residue (silica gel, hexane / ethyl acetate
1/0 → 9/1) and concentrate the target fraction under reduced pressure to give the title compound.
(8.14 g) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 2.25 (2H, quint, J = 6.1Hz), 3.44
(2H, t, J = 6.1Hz), 4.30 (2H, t, J = 6.4Hz), 5.10 (2
H, s), 6.41 (1H, dd, J = 0.7, 3.2Hz), 6.96 (1H, dd, J
= 2.2, 8.8Hz), 7.10 (1H, d, J = 3.2Hz), 7.17 (1H, d,
J = 2.2Hz), 7.2-7.55 (5H, m), 7.27 (1H, d, J = 8.8Hz).

(Ii) Preparation of 1- {3- [5- (benzyloxy) -1H-indol-1-yl] propyl} -1H-imidazole-2-carbaldehyde 5- (benzyloxy) -1- ( 3-chloropropyl) -1H-indole (3.00 g, 10 mmol), 2-formylimidazole (1.25
g), potassium iodide (1.66g), potassium carbonate (1.80g), DM
The mixture of F (20 mL) was stirred at 70 ° C. for 15 hours. Water (100m
L) was added and the mixture was extracted with ethyl acetate (50 mL, 3 times). The organic layer was washed successively with water (20 mL, twice) and saturated brine (20 mL), and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, hexane / ethyl acetate 1/1 → 1/3), and the target fraction was concentrated under reduced pressure to give the title compound (3.31 g) as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.35 (2H, quint, J = 7.2Hz), 4.1
5 (2H, t, J = 6.7Hz), 4.34 (2H, t, J = 7.3Hz), 5.11 (2
H, s), 6.44 (1H, dd, J = 0.7, 3.2Hz), 6.97 (1H, dd,
J = 2.2, 8.8Hz), 6.99 (1H, s), 7.06 (1H, d, J = 3.2H
z), 7.17 (1H, d, J = 8.8Hz), 7.18 (1H, d, J = 2.2Hz),
7.25-7.55 (5H, m), 7.27 (1H, d, J = 0.6Hz), 9.81 (1
H, d, J = 1.2Hz).

(Iii) (1- {3- [5- (benzyloxy) -1H-indol-1-yl] propyl} -1H-imidazol-2-yl)
Preparation of methanol 1- {3- [5- (benzyloxy) -1H-indol-1-yl] propyl} -1H-imidazole-2-carbaldehyde (3.26g) in THF
Sodium borohydride (515 mg) was added to a (50 mL) -methanol (50 mL) solution under ice-cooling stirring, and the mixture was stirred at room temperature for 30 minutes. 1N Hydrochloric acid (14 mL) was added under ice-cooling, the mixture was stirred for 15 min, 1N aqueous sodium hydroxide solution (14 mL) was added, and the mixture was concentrated under reduced pressure. Ethyl acetate (150 mL), THF (150 mL) in the residue
Was added and the mixture was washed with water (30 mL) and saturated brine (30 mL, twice) in that order. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate was added to the residue, the precipitate was collected by filtration,
The solid was dried under reduced pressure to give the title compound (3.11 g) as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.36 (2H, quint, J = 7.1Hz), 3.97
(2H, t, J = 7.2Hz), 4.12 (2H, t, J = 7.0Hz), 4.57 (2
H, s), 5.10 (2H, s), 6.43 (1H, dd, J = 0.8, 2.9Hz),
6.79 (1H, d, J = 1.1Hz), 6.89 (1H, d, J = 1.1Hz), 6.95
(1H, dd, J = 2.3,8.9Hz), 7.04 (1H, d, J = 2.9Hz), 7.1
3 (1H, d, J = 8.9Hz), 7.17 (1H, d, J = 2.3Hz), 7.2-7.5
5 (5H, m).

(Iv) Preparation of 1- {3- [2- (hydroxymethyl) -1H-imidazol-1-yl] propyl} -1H-indole-5-ol (1- {3- [5- (benzyl Oxy) -1H-indol-1-yl] propyl} -1H-imidazol-2-yl) methanol (904mg)
10% Palladium on carbon in THF (20 mL) -methanol (50 mL) solution
(50% water content, 270 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 17 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to give the title compound (690 mg). ¹ H-NMR (CD ₃ OD) δ: 2.34 (2H, quint, J = 7.1Hz), 4.0
1 (2H, t, J = 7.3Hz), 4.13 (2H, t, J = 6.9Hz), 4.46 (2
H, s), 6.29 (1H, dd, J = 0.7, 3.3Hz), 6.69 (1H, dd,
J = 2.6, 8.8Hz), 6.89 (1H, d, J = 1.3Hz), 6.92 (1H, d,
J = 2.6Hz), 7.07 (1H, d, J = 1.3Hz), 7.09 (1H, d, J = 8.
8Hz), 7.12 (1H, d, J = 3.3Hz).

(V) [1- (3- {5-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy ] -1H-Indol-1-yl} propyl) -1H-imidazol-2-yl] methanol production (1- {3- [5- (benzyloxy) -1H-indol-1-yl] propyl} -1H -Imidazol-2-yl) methanol (326 mg,
Sodium hydride (60% oil, 58 mg, 1.5 mmol) was added to a DMF (5 mL) solution of 1.2 mmol) under ice-cooling stirring, and the mixture was stirred for 30 minutes. Under ice cooling, 4- (chloromethyl) -2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazole
After adding (345 mg, 1.2 mmol), the mixture was stirred at room temperature for 4 hours. Water (25 mL) and 1N aqueous sodium hydroxide solution (20 mL) were added, and the mixture was extracted with ethyl acetate (40 mL, 20 mL, twice). The organic layer was 1N aqueous sodium hydroxide solution (10 mL, twice), saturated saline solution.
After washing sequentially with (10 mL), the mixture was concentrated under reduced pressure. The residue was subjected to column chromatography (NH silica gel, ethyl acetate / methanol 1/0 → 9/1), and the target fraction was concentrated under reduced pressure. Diethyl ether-ethyl acetate was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to give the title compound (393 mg) as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 2.37 (2H, quint, J = 7.1Hz), 3.9
7 (2H, t, J = 7.1Hz), 4.13 (2H, t, J = 6.8Hz), 4.57 (2
H, s), 5.08 (2H, d, J = 1.0Hz), 6.45 (1H, d, J = 3.4H
z), 6.80 (1H, d, J = 1.5Hz), 6.91 (1H, d, J = 1.5Hz),
6.95 (1H, dd, J = 2.2, 9.0Hz), 7.02 (1H, d, J = 16.4H
z), 7.06 (1H, d, J = 3.4Hz), 7.14 (1H, d, J = 9.0Hz),
7.20 (1H, d, J = 2.2Hz), 7.55 (1H, d, J = 16.4Hz), 7.6
3 (4H, s), 7.70 (1H, s). IR (KBr) 3121, 2936, 2870, 1615, 1487, 1325, 1238,
1159, 1125, 1067 cm ^-1 .

Example 90. [1- [3- [5-[[2-
[(E) -2- [4- (trifluoromethyl) phenyl]
]] Ethenyl] -1,3-oxazol-4-yl] me
Toxy] -2H-indazol-2-yl] propyl]
Production of -1H-imidazol-2-yl] methanol

[Chemical 169] (I) Preparation of 1-acetyl-5-benzyloxy-1H-indazole N- (4-benzyloxy-2-methylphenyl) acetamide (14.5 g) was added to chloroform (218 ml).
Dissolved in potassium acetate (11.1 g), acetic anhydride (1
6.1 ml) was added and the mixture was stirred at 60 ° C. for 1 hour. Isoamyl nitrite (14.6 g) and 18-crown-6-ether (1.5 g) were added, and the mixture was heated under reflux for 16 hr. After cooling to room temperature, saturated multistory water was added for neutralization, followed by extraction with chloroform. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 4) to give the title compound (9.
0 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.76 (3H, s), 5.13 (2H, s), 7.1
5-7.17 (1H, m), 7.24-7.46 (6H, m), 8.03 (1H, s),
8.34 (1H, d, J = 9.2 Hz).

(Ii) Preparation of 1-acetyl-1H-indazol-5-ol 1-Acetyl-5-benzyloxy-1H-indazole (5.0 g) was dissolved in ethyl acetate (150 ml),
10% Palladium on carbon (0.5 g) was added under a nitrogen atmosphere, the atmosphere was replaced with hydrogen, and the mixture was stirred at room temperature for 3 days. The reaction solution was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 2).
The title compound (3.2 g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 2.68 (3H, s), 7.06-7.15 (2H,
m), 8.13 (2H, d, J = 8.8 Hz), 8.30 (1H, s), 9.70 (1
H, s).

(Iii) 1-acetyl-5-[[2-
Preparation of [(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] -1H-indazole 1-acetyl-1H-indazol-5-ol ( 3.
2 g) was dissolved in acetone (64 ml), potassium carbonate (5.8 g), sodium iodide (3.3 g), 4-
(Chloromethyl) -2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (5.8 g) was added, and the mixture was heated under reflux for 18 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the resulting residue was washed with water,
Wash with hexane / ethyl acetate to give the title compound (5.3
g) was obtained as white crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 2.70 (3H, s), 5.12 (2H, s),
7.28-7.39 (2H, m), 7.53 (1H, d, J = 2.2 Hz), 7.64 (1
H, d, J = 16.6 Hz), 7.74-7.79 (2H, m), 7.96 (2H, d,
J = 8.2 Hz), 8.22 (1H, d, J = 8.8 Hz), 8.30 (1H,
s), 8.39 (1H, s).

(Iv) 2- (3-chloropropyl) -5-
[[2-[(E) -2- [4- (trifluoromethyl)
Phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] -2H-indazole and 1- (3-chloropropyl) -5-[[2-[(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl] -1,3
Preparation of -oxazol-4-yl] methoxy] -1H-indazole 1-acetyl-5-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole -4-yl] methoxy] -1H-indazole (5.2 g) was dissolved in acetic acid (52 ml), 48% hydrobromic acid was added, and the mixture was stirred at 80 ° C for 4 hr. After cooling to room temperature, the solvent was removed under reduced pressure, and the precipitated crystals were washed with 48% hydrobromic acid and dried to give 5-[[2-[(E) -2
-[4- (trifluoromethyl) phenyl] ethenyl]
-1,3-Oxazol-4-yl] methoxy] -1H
-Indazole hydrobromide (5.5 g) was obtained. 5
-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole-4
-Yl] methoxy] -1H-indazole hydrobromide (5.5 g) was dissolved in DMF (110 ml) and the mixture was cooled to 0 ° C.
60% sodium hydride (1.5 g) was added at 0 ° C.
It was stirred for 30 minutes. 1-Bromo-3-chloropropane (1.8 ml) was added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane = 2: 1) and 2- (3-chloropropyl) -5-[[2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] -2H-indazole (2.3 g) and 1-
(3-chloropropyl) -5-[[2-[(E) -2-
[4- (trifluoromethyl) phenyl] ethenyl]-
1,3-Oxazol-4-yl] methoxy] -1H-
Indazole (1.0 g) was obtained as white crystals. 2- (3-chloropropyl) -5-[[2-[(E)-
2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy]-
² H-indazole ¹ H-NMR (CDCl ₃ ) δ: 2.35-2.44 (2H, m), 3.49 (2H, t,
J = 6.0 Hz), 4.53 (2H, t, J = 6.3 Hz), 5.08 (2H, s),
7.03 (1H, d, J = 16.5 Hz), 7.14-7.20 (2H, m), 7.39
-7.43 (1H, m), 7.56 (1H, d, J = 16.5 Hz), 7.61-7.66
(4H, m), 7.72 (1H, s), 7.93 (1H, s). 1- (3-chloropropyl) -5-[[2-[(E)-
2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy]-
¹ H-indazole ¹ H-NMR (CDCl ₃ ) δ: 2.41-2.50 (2H, m), 3.47 (2H, t,
J = 6.0 Hz), 4.57 (2H, t, J = 6.0 Hz), 4.57 (2H, t,
J = 6.3 Hz), 5.05 (2H, s), 6.99-7.09 (3H, m), 7.53-
7.72 (7H, m), 7.85 (1H, s).

(V) 1- [3- [5-[[2-[(E)
-2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy]-
Preparation of 2H-indazol-2-yl] propyl] -1H-imidazole-2-carbaldehyde 2- (3-chloropropyl) -5-[[2-[(E)-
2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy]-
2H-indazole (0.70 g) was added to DMF (14 m
l), and potassium carbonate (0.38 g), sodium iodide (0.25 g), and 2-formylimidazole (0.20 g) were added. After stirring for 16 hours at 70 ° C,
The mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate.
The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate: ethanol = 10: 1) to give the title compound (0.40 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.38-2.47 (2H, m), 4.32-4.41 (4
H, m), 5.08 (2H, s), 7.02 (1H, d, J = 16.5 Hz), 7.1
4-7.30 (5H, m), 7.56 (1H, d, J = 16.2 Hz), 7.58-7.6
4 (5H, m), 7.72 (1H, s), 7.94 (1H, s), 9.78 (1H,
s).

(Vi) [1- [3- [5-[[2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] -2H-indazol-2-yl] propyl]
Preparation of -1H-imidazol-2-yl] methanol 1- [3- [5-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole- 4-yl] methoxy] -2H-indazol-2-yl] propyl] -1H-imidazol-2-carbaldehyde (0.37 g) was added to methanol (14.8 m).
l) and dissolved in sodium borohydride (13
mg) was added and the mixture was stirred at 0 ° C. for 30 minutes. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography, and recrystallized from hexane-ethyl acetate-methanol to give the title compound (0.27 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.39-2.51 (2H, m), 4.04 (2H, t,
J = 6.2 Hz), 4.36 (2H, t, J = 6.2 Hz), 4.61 (2H, s),
5.08 (2H, s), 6.89-6.93 (2H, m), 7.02 (1H, d, J = 1
6.4 Hz), 7.12-7.22 (3H, m), 7.57 (1H, d, J = 16.4 H
z), 7.59-7.65 (4H, m), 7.72 (1H, s), 7.93 (1H, s) .IR (KBr): 3146, 1742, 1508, 1319, 1117, 756 cm ^-1 .

Example 91. [1- [3- [5-[[2-
[(E) -2- [4- (trifluoromethyl) phenyl]
]] Ethenyl] -1,3-oxazol-4-yl] me
Toxy] -1H-indazol-1-yl] propyl]
Production of -1H-imidazol-2-yl] methanol

[Chemical 170] (I) 1- [3- [5-[[2-[(E) -2- [4-
(Trifluoromethyl) phenyl] ethenyl] -1,3
-Oxazol-4-yl] methoxy] -1H-indazol-1-yl] propyl] -1H-imidazole-
Preparation of 2-carbaldehyde 1- (3-chloropropyl) -5-[[2-[(E)-
2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy]-
1H-indazole (0.50 g), DMF (10 m
1), potassium carbonate (0.27 g), sodium iodide (0.18 g) and 2-formyl imidazole (0.1
The same reaction as in Example 90- (v) was performed using 5 g) to give the title compound (0.10 g) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.45-2.55 (2H, m), 4.40 (2H, t,
J = 6.3 Hz), 4.42 (2H, t, J = 6.9 Hz), 5.06 (2H, s),
7.00-7.12 (3H, m), 7.30 (2H, s), 7.57 (1H, d, J = 1
6.5 Hz), 7.62-7.65 (5H, m), 7.73 (1H, s), 7.82 (1
H, s), 9.82 (1H, s).

(Ii) [1- [3- [5-[[2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] -1H-indazol-1-yl] propyl]
Preparation of -1H-imidazol-2-yl] methanol 1- [3- [5-[[2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole- 4-yl] methoxy] -1H-indazol-1-yl] propyl] -1H-imidazol-2-carbaldehyde (95 mg), methanol (3.8 ml)
And sodium borohydride (3.5 mg),
The reaction was performed in the same manner as in Example 90- (vi), and the title compound (5
7 mg) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.41-2.56 (2H, m), 4.07 (2H, t,
J = 6.6 Hz), 4.40 (2H, t, J = 6.6 Hz), 4.67 (2H, s),
5.05 (2H, s), 6.91-6.96 (3H, m), 7.02 (1H, d, J = 1
6.2 Hz), 7.09 (1H, dd, J = 9.3, 2.4 Hz), 7.56 (1H,
d, J = 16.2 Hz), 7.60-7.65 (5H, m), 7.71 (1H, s), 7.
81 (1H, s). IR (KBr): 3142, 1522, 1329, 1196, 1069, 824 cm ^-1 .

Example 92. 1- [3- (1H-1,2,3-triazo
L-1-yl) propyl] -5-[(2-{(E) -2- [4- (trifluoro
Methyl) phenyl] vinyl} -1,3-oxazol-4-yl) me
Toxi] -1H-Indole production

[Chemical 171] (i) 5- (benzyloxy) -1- [3- (1H-1,2,3-triazole
Preparation of 1-yl) propyl] -1H-indole 1H-1,2,3-Triazole (691mg) in tert-amyl alcohol (30mL) was added sodium hydroxide (powder, 400mg) under heating and reflux. , Stirred for 1 hour. 5- (Benzyloxy) -1- (3-chloropropyl) -1H-indole (1499 mg) and sodium iodide (749 mg) were added, and the mixture was stirred with heating under reflux for 18 hr. The reaction solution was cooled to room temperature, and toluene (100 m
L) was added and the mixture was washed with water (30 mL × 2) and saturated brine (30 mL) in that order, and the organic layer was concentrated under reduced pressure. Column chromatography of the residue (silica gel, hexane / ethyl acetate 1/1 → 0/1)
The target fraction was concentrated under reduced pressure to give the title compound (1233 mg) as a white solid. ¹ H-NMR (200MHz, CDCl ₃ ) δ: 2.48 (2H, quint, J = 6.6
Hz), 4.16 (2H, t, J = 6.4Hz), 4.29 (2H, t, J = 6.8Hz),
5.10 (2H, s), 6.43 (1H, dd, J = 0.7, 3.2Hz), 6.95 (1
H, dd, J = 2.2, 8.8Hz), 7.09 (1H, d, J = 3.2Hz), 7.15
(1H, d, J = 8.8Hz), 7.18 (1H, d, J = 2.2Hz), 7.2-7.55
(6H, m), 7.72 (1H, d, J = 1.0Hz).

(Ii) Preparation of 1- [3- (1H-1,2,3-triazol-1-yl) propyl] -1H-indole-5-ol 5- (benzyloxy) -1- [3- (1H-1,2,3-triazole-1-
Isopropyl) -1H-indole (665 mg) in THF (20 mL) -methanol (20 mL) solution with 10% palladium on carbon (50% water content, 133
mg) was added and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 days.
After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. Column chromatography of the residue (silica gel, hexane / ethyl acetate 1
1/1 → 0/1) and the target fraction was concentrated under reduced pressure to give the title compound (3
72 mg) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ 2.48 (2H, quint, J = 6.5Hz), 4.15
(2H, t, J = 6.4Hz), 4.29 (2H, t, J = 6.7Hz), 4.91 (1H,
s), 6.39 (1H, dd, J = 0.8, 3.4Hz), 6.80 (1H, dd, J = 2.
6, 8.8Hz), 7.0-7.15 (3H, m), 7.45 (1H, d, J = 0.9H
z), 7.73 (1H, d, J = 0.9Hz).

(Iii) 1- [3- (1H-1,2,3-triazol-1-yl) propyl] -5-[(2-{(E) -2- [4- (trifluoromethyl))
Preparation of [phenyl] ethenyl} -1,3-oxazol-4-yl) methoxy] -1H-indole 1- [3- (1H-1,2,3-triazol-1-yl) propyl] -1H-indole- To a solution of 5-ol (361 mg) in DMF (5 mL) was added sodium hydride (60% oily, 72 mg) under ice-cooled stirring, and the mixture was stirred for 30 minutes. Under ice cooling, 4- (chloromethyl) -2-{(E) -2-
After adding [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazole (429 mg, 1.5 mmol), the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (20 mL),
THF (20 mL) was added, and the mixture was washed successively with water (10 mL), 1N aqueous sodium hydroxide solution (5 mL, 2 times) and saturated saline (5 mL, 3 times). The organic layer was concentrated under reduced pressure, the residue was subjected to column chromatography (silica gel, hexane / ethyl acetate 1/1 → 0/1), and the target fraction was concentrated under reduced pressure. Ethyl acetate was added to the residue and the precipitate was collected by filtration and dried under reduced pressure to give the title compound (585 mg)
Was obtained as a white solid. ¹ H-NMR (300MHz, CDCl ₃ ) δ: 2.49 (2H, quint, J = 6.6
Hz), 4.17 (2H, t, J = 6.5Hz), 4.30 (2H, t, J = 6.6Hz),
5.08 (2H, s), 6.45 (1H, d, J = 3.0Hz), 6.96 (1H, d
d, J = 2.5, 8.9Hz), 7.02 (1H, d, J = 16.4Hz), 7.10 (1
H, d, J = 3.0Hz), 7.16 (1H, d, J = 8.9Hz), 7.20 (1H,
d, J = 2.5Hz), 7.45 (1H, s), 7.55 (1H, d, J = 16.4Hz),
7.63 (4H, s), 7.69 (1H, s), 7.72 (1H, s). IR (KBr) 1487, 1325, 1240, 1159, 1119, 1069 cm ^-1 .

Example 93. 2-[(E) -2- [2-fluoro-4- (
Lifluoromethyl) phenyl] ethenyl] -4-[[4- [4- (1H-
Pyrazol-3-yl) butyl] phenoxy] methyl] -1,3-o
Manufacture of xazole

[Chemical 172] (i) 4- [4- (1-Trityl-1H-pyrazol-3-yl) butyl]
Production of phenol [3- [4- (benzyloxy) phenyl] propyl] (triphenyl) phosphonium (10.0 g), 1-trityl-1H-pyrazole-3-carbaldehyde (4.41 g), potassium carbonate
(2.70 g), water (0.234 ml) and 10% palladium on carbon (2.13 g).
The reaction was performed in the same manner as in Example 10- (i) using g) and ethyl acetate (130 ml) to give the title compound (3.61 g) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.59-1.61 (4H, m), 2.52 (2H,
t, J = 7.2 Hz), 2.66 (2H, d, J = 6.6 Hz), 4.65 (1
H, s), 5.98 (1H, d, J = 2.2 Hz), 6.68-6.73 (2H,
m), 6.96-7.01 (2H, m), 7.12-7.19 (8H, m), 7.26-7.2
9 (8H, m). IR (KBr): 1514, 1493, 1445, 748, 700 cm ^-1 .

(Ii) 2-[(E) -2- [2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -4-[[4- [4- (1H-pyrazol-3-yl) Butyl] phenoxy] methyl] -1,3-oxazole production 4- [4- (1-trityl-1H-pyrazol-3-yl) butyl] phenol (346 mg), 65% sodium hydride (26.4 mg), Four-
(Chloromethyl) -2-[(E) -2- [2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (200
mg) and 90% formic acid (3 ml) and the same reaction as in Example 85- (viii) was carried out to obtain the title compound (202 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.66-1.70 (4H, m), 2.60 (2H,
t, J = 7.4 Hz), 2.69 (2H, d, J = 7.0 Hz), 5.02 (2
H, d, J = 0.8 Hz), 6.08 (1H, d, J = 1.8 Hz), 6.89-
6.95 (2H, m), 7.08-7.17 (3H, m), 7.35-7.48 (3H,
m), 7.60-7.70 (3H, m). IR (KBr): 1512, 1431, 1333, 1175, 1130 cm ^-1 .

Example 94. 2- [5- [4- [4-[[2-[(E) -2- [2-
Fluoro-4- (trifluoromethyl) phenyl] ethenyl]-
1,3-Oxazol-4-yl] methoxy] phenyl] butyl]-
Production of 1H-pyrazol-1-yl] ethanol

[Chemical 173] 2-[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl] ethenyl] -4-[[4- [4- [1- [2- (tetrahydro-2H-pyran-2- (Iloxy) ethyl] -1H-pyrazol-5-yl] butyl] phenoxy] methyl] -1,3-oxazole (165 mg) in methanol (3 ml) in p-toluenesulfonic acid monohydrate (102 mg) Was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give the title compound (115 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.66-1.68 (4H, m), 2.58-2.63
(4H, m), 3.67 (1H, d, J = 6.0 Hz), 3.95-4.01 (2H,
m), 4.08 (2H, d, J = 4.5 Hz), 5.02 (2H, d, J = 0.6
Hz), 6.01 (1H, d, J = 2.1 Hz), 6.88-6.94 (2H, m),
7.07-7.15 (3H, m), 7.35-7.45 (3H, m), 7.61-7.69 (3
H (m,). IR (KBr): 1510,1335, 1235, 1179, 1132 cm ^-1 .

Example 95. 2-[(E) -2- [2-fluoro-4- (
Lifluoromethyl) phenyl] ethenyl] -4-[[4- [4- [1- [2
-(Tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-
Pyrazol-3-yl] butyl] phenoxy] methyl] -1,3-o
Manufacture of xazole

[Chemical 174] 2-[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl] ethenyl] -4-[[4- [4- (1H-pyrazol-3-yl) butyl] phenoxy] methyl] -1,3-Oxazole (400 mg) in D
65% sodium hydride (36.5 m in MF (6 ml) solution at 0 ° C
g) was added, and the mixture was stirred at room temperature for 20 minutes. 2- (2-Bromoethoxy) tetrahydro-2H-pyran (149 μl) was added at 0 ° C.,
The mixture was stirred at 0 ° C for 1.5 hours and at room temperature for 14 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 2: 1 → 3: 2). The title compound (240 mg) as a low-polarity compound was obtained as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.46-1.77 (10H, m), 2.58 (2H,
t, J = 6.9 Hz), 2.64 (2H, d, J = 7.2 Hz), 3.39-3.5
8 (1H, m), 3.59-3.66 (1H, m), 3.69-3.76 (1H, m), 3.
98-4.05 (1H, m), 4.23-4.49 (2H, m), 4.50 (1H, t, J
= 2.7 Hz), 5.01 (2H, d, J = 0.9 Hz), 5.98 (1H, d,
J = 2.4 Hz), 6.88-6.93 (2H, m), 7.08-7.15 (3H,
m), 7.35-7.45 (3H, m), 7.61-7.68 (3H, m). IR (KBr): 1510, 1429, 1331, 1173, 1132 cm ^-1 .

Example 96. 2-[(E) -2- [2-fluoro-4- (
Lifluoromethyl) phenyl] ethenyl] -4-[[4- [4- [1- [2
-(Tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-
Pyrazol-5-yl] butyl] phenoxy] methyl] -1,3-o
Manufacture of xazole

[Chemical 175] The silica gel chromatography of Example 95 gave the title compound (185 mg) as a highly polar compound as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.47-1.73 (10H, m), 2.60 (2H,
t, J = 6.0 Hz), 2.68 (2H, d, J = 6.6 Hz), 3.40-3.4
4 (1H, m), 3.58-3.65 (1H, m), 3.73-3.80 (1H, m), 4.
01-4.06 (1H, m), 4.22 (2H, d, J = 5.7 Hz), 4.27 (1
H, t, J = 3.9 Hz), 5.02 (2H, s), 5.96 (1H, d, J =
1.5 Hz), 6.88-6.94 (2H, m), 7.08-7.15 (3H, m), 7.35
-7.45 (3H, m), 7.61-7.69 (3H, m). IR (KBr): 1510, 1429, 1331, 1171, 1132 cm ^-1 .

Example 97. [3- [4- [4-[[2-[(E) -2- [2-
Luoro-4- (trifluoromethyl) phenyl] ethenyl] -1,
3-Oxazol-4-yl] methoxy] phenyl] butyl] -1H
-Pyrazol-1-yl] ethyl acetate production

[Chemical 176] 2-[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl] ethenyl] -4-[[4- [4- (1H-pyrazol-3-yl) butyl] phenoxy] methyl] -1,3-oxazole (1.00 g), 6
5% sodium hydride (99.0 mg), ethyl bromoacetate
(0.457 ml) was used to carry out the same reaction as in Example 95. Silica gel chromatography (eluent, hexane: ethyl acetate = 3: 1 → 1: 1) gave the title compound (520 mg) as a low polar compound. Colorless needle crystals ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.2 Hz), 1.66-
1.68 (4H, m), 2.59 (2H, t, J = 6.9 Hz), 2.66 (2H,
t, J = 6.9 Hz), 4.22 (2H, q, J = 7.2 Hz), 4.83 (2
H, s), 5.02 (2H, s), 6.09 (1H, d, J = 2.1 Hz), 6.9
0 (2H, d, J = 8.4 Hz), 7.09-7.16 (3H, m), 7.35-7.4
6 (3H, m), 7.62-7.69 (3H, m). IR (KBr): 1744, 1385, 1225, 1175, 1127 cm ^-1 .

Example 98. [5- [4- [4-[[2-[(E) -2- [2-
Luoro-4- (trifluoromethyl) phenyl] ethenyl] -1,
3-Oxazol-4-yl] methoxy] phenyl] butyl] -1H
-Pyrazol-1-yl] ethyl acetate production

[Chemical 177] The title compound (256 mg) was obtained as a highly polar compound by silica gel chromatography of Example 97. Colorless needles. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.2 Hz), 1.66-
1.69 (4H, m), 2.56-2.60 (4H, m), 4.21 (2H, q, J =
7.2 Hz), 4.83 (2H, s), 5.03 (2H, d, J = 0.6Hz), 6.
05 (1H, d, J = 1.5 Hz), 6.92 (2H, d, J = 9.0 Hz),
7.09-7.16 (3H, m), 7.36-7.45 (3H, m), 7.62-7.70 (3
H (m, m). IR (KBr): 1752, 1510, 1331, 1213 1130 cm ^-1 .

Example 99. 2- [5- [4- [4-[[2-[(E) -2- [2-
Fluoro-4- (trifluoromethyl) phenyl] ethenyl]-
1,3-Oxazol-4-yl] methoxy] phenyl] butyl]-
1H-pyrazol-1-yl] -N, N-dimethylacetamide
Construction

[Chemical 178] Diisopropylethylamine (0.165 ml), dimethylamine in THF (2M; 0.315 ml) in dichloromethane (2 ml)
Dimethyl aluminum chloride in hexane solution at 0 ° C
(1.03M; 0.612 ml) was added, and the mixture was stirred at room temperature for 1 hr, then [5- [4-
[4-[[2-[(E) -2- [2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy]
Phenyl] butyl] -1H-pyrazol-1-yl] ethyl acetate
(120 mg) in dichloromethane (2 ml) was added at room temperature.
It was stirred for 16 hours. After adding saturated aqueous sodium hydrogen carbonate to the reaction mixture and filtering,
The filtrate was extracted with dichloromethane and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate → ethyl acetate: methanol = 10: 1), and recrystallized from ethyl acetate-hexane to give the title compound (87.4 mg) as colorless Obtained as needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.66-1.71 (4H, m), 2.58-2.62
(4H, m), 2.96 (3H, s), 3.07 (3H, s), 4.89 (2H, s),
5.02 (2H, d, J = 0.9 Hz), 6.03 (1H, d, J = 2.1 H
z), 6.89-6.93 (2H, m), 7.07-7.15 (3H, m), 7.35-7.4
5 (3H, m), 7.61-7.69 (3H, m). IR (KBr): 1667, 1512, 1429, 1333, 1128 cm ^-1 .

Example 100. 2- [5- [4- [4-[[2-[(E) -2- [2-
Fluoro-4- (trifluoromethyl) phenyl] ethenyl]-
1,3-Oxazol-4-yl] methoxy] phenyl] butyl]-
Production of 1H-pyrazol-1-yl] -N-methylacetamide

[Chemical 179] [5- [4- [4-[[2-[(E) -2- [2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl ] Butyl] -1H-pyrazol-1-yl] ethyl acetate (120 mg), diisopropylethylamine (0.165
ml), methylamine in THF (2M; 0.315 ml), dimethylaluminum chloride in hexane (1.03M; 0.612 ml)
Was carried out in the same manner as in Example 99 to give the title compound (8
9.0 mg) was obtained as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.63-1.66 (4H, m), 2.56-2.61
(4H, m), 2.75 (3H, d, J = 5.1 Hz), 4.71 (2H, s),
5.02 (2H, d, J = 0.9 Hz), 6.03 (1H, br s), 6.07 (1
H, d, J = 2.1 Hz), 6.89-6.93 (2H, m), 7.05-7.15 (3
H, m), 7.35-7.50 (3H, m), 7.61-7.69 (3H, m) .IR (KBr): 1663, 1512, 1337, 1144, 1128 cm ^-1 .

Example 101. 4-[[3-methyl-4- [4- (1H-pi
Razol-3-yl) butyl] phenoxy] methyl] -2-[(E) -2
-[4- (Trifluoromethyl) phenyl] ethenyl] -1,3-o
Manufacture of xazole

[Chemical 180] (i) 3- [4- (4-methoxy-2-methylphenyl) butyl] -1H-
Production of pyrazole [3- (4-methoxy-2-methylphenyl) propyl] (triphenyl) phosphonium iodide (20.0 g), potassium carbonate (6.
01 g), water (1.05 ml) and 10% palladium on carbon (7.0 g),
Ethanol THF mixture (4: 1; 250 ml), 4N hydrochloric acid (14.5 ml)
Was performed in the same manner as in Example 10- (i) to give the title compound
(6.42 g) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.55-1.65 (2H, m), 1.68-1.78
(2H, m), 2.04 (3H, s), 2.56 (2H, s, J = 7.8 Hz), 2.
71 (2H, d, J = 6.9 Hz), 3.76 (3H, s), 6.07 (1H, d,
J = 2.1 Hz), 6.63-6.69 (2H, m), 7.00 (1H, d, J =
8.4 Hz), 7.47 (1H, J = 2.1 Hz). IR (KBr): 2934, 1503, 1466, 1254, 1049 cm ^-1 .

(Ii) Preparation of 3-methyl-4- [4- (1H-pyrazol-3-yl) butyl] phenol 3- [4- (4-methoxy-2-methylphenyl) butyl] -1H-pyrazole (6.40 g) and 48% hydrobromic acid (18 ml) were used to carry out the same reaction as in Example 85- (vi) to obtain the title compound (5.69 g) as a colorless oil. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.50-1.75 (4H, m), 2.21
(3H, s), 2.53 (2H, s, J = 7.0 Hz), 2.68 (2H, d, J =
7.2 Hz), 6.06 (1H, d, J = 1.8 Hz), 6.56-6.62 (2H,
m), 6.93 (1H, d, J = 7.6 Hz), 7.44 (1H, J = 1.8 H
z) .IR (KBr): 1460, 1254, 1194, 937, 808 cm ^-1 .

(Iii) 3- [4- [2-methyl-4-[[tert-butyl
Preparation of (diphenyl) silyl] oxy] phenyl] butyl] -1H-pyrazole 3-methyl-4- [4- (1H-pyrazol-3-yl) butyl] phenol (2.85 g) in DMF (30 ml) solution Imidazole at 0 ° C
(2.28 g), tert-butyldiphenylchlorosilane (6.76
ml) was added, and the mixture was stirred at room temperature for 18.5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 3: 1 → 1: 2) to give the title compound (5.64 g) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (9H, s), 1.49-1.59 (2H,
m), 1.63-1.72 (2H, m), 2.10 (3H, s), 2.48 (2H, s,
J = 7.8 Hz), 2.66 (2H, d, J = 7.2 Hz), 6.04 (1H,
d, J = 1.5 Hz), 6.43 (1H, dd, J = 2.7, 8.1 Hz), 6.
60 (1H, d, J = 2.7Hz), 6.76 (1H, d, J = 8.1Hz),
7.31-7.45 (7H, m), 7.68-7.71 (4H, m). IR (KBr): 2934, 1499, 1287, 1113, 700 cm ^-1 .

(Iv) Preparation of 3-methyl-4- [4- (1-trityl-1H-pyrazol-3-yl) butyl] phenol 3- [4- [2-methyl-4-[[tert-butyl] (Diphenyl) silyl]
Oxy] phenyl] butyl] -1H-pyrazole (5.62 g) DM
Triethylamine (2.51 ml) and trityl chloride (3.51 g) were added to the F (25 ml) solution at 0 ° C, and the mixture was stirred at room temperature for 19 hours and then at 0 ° C.
Tetrabutylammonium Fluoride THF solution (1.0
M; 13.2 ml) was added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography.
(Eluent, hexane: ethyl acetate = 6: 1 → 4: 1) to give the title compound (5.19 g) as a colorless amorphous substance. ¹ H-NMR (CDCl ₃ ) δ: 1.48-1.72 (4H, m), 2.20 (3H,
s), 2.50 (2H, s, J = 7.6 Hz), 2.67 (2H, d, J = 7.0
Hz), 4.59 (1H, s), 5.99 (1H, d, J = 2.2 Hz), 6.53-
6.58 (2H, m), 6.92 (1H, d, J = 7.8 Hz), 7.14-7.29
(16H, m) .IR (KBr): 1501, 1447, 748, 733, 700 cm ^-1 .

(V) 4-[[3-methyl-4- [4- (1H-pyrazole-3
Preparation of 2-yl) butyl] phenoxy] methyl] -2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole 3-methyl-4- [4- (1 -Trityl-1H-pyrazol-3-yl) butyl] phenol (400 mg), 65% sodium hydride
(34.4 mg), 4- (chloromethyl) -2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (24
The same reaction as in Example 85- (viii) was performed using 3 mg) and 90% formic acid (3 ml) to obtain the title compound (293 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.57-1.81 (4H, m), 2.27 (3H,
s), 2.57 (2H, t, J = 7.8 Hz), 2.71 (2H, d, J = 6.8
Hz), 5.01 (2H, d, J = 1.0 Hz), 6.09 (1H, d, J = 2.
2 Hz), 6.73-6.79 (2H, m), 6.97-7.05 (2H, m), 7.48-
7.67 (7H, m) .IR (KBr): 2934, 1601, 1501, 1480, 1252 cm ^-1 .

Example 102. 2-[(E) -2- (4-bromo-2-full
Orophenyl) ethenyl] -4-[[3-methyl-4- [4- (1H-pyra
Zol-3-yl) butyl] phenoxy] methyl] -1,3-oxa
Manufacture of sol

[Chemical 181] 3-Methyl-4- [4- (1-trityl-1H-pyrazol-3-yl) butyl] phenol (400 mg), 65% sodium hydride (3
4.4 mg), 2-[(E) -2- (4-bromo-2-fluorophenyl) ethenyl] -4- (chloromethyl) -1,3-oxazole (268 mg)
And 90% formic acid (3 ml) were used to perform the same reaction as in Example 85- (viii) to obtain the title compound (299 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.56-1.81 (4H, m), 2.26 (3H,
s), 2.57 (2H, t, J = 7.4 Hz), 2.71 (2H, d, J = 7.0
Hz), 5.00 (2H, d, J = 1.2 Hz), 6.09 (1H, d, J = 2.
2 Hz), 6.72-6.78 (2H, m), 6.99-7.07 (2H, m), 7.27-
7.66 (6H, m) .IR (KBr): 2934, 1599, 1501, 1480, 1252 cm ^-1 .

Example 103. 2-[(E) -2- [2-fluoro-4-
(Trifluoromethyl) phenyl] ethenyl] -4-[[3-methyl
Lu-4- [4- (1H-pyrazol-3-yl) butyl] phenoxy] me
Chill] -1,3-oxazole production

[Chemical 182] 3-Methyl-4- [4- (1-trityl-1H-pyrazol-3-yl) butyl] phenol (4.46 g), 65% sodium hydride (38
0 mg), 4- (chloromethyl) -2-[(E) -2- [2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (2.86 g) and 90% formic acid (15 ml) was used in Example 85- (vi
The same reaction as in ii) was performed to give the title compound (4.01 g) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.61-1.74 (4H, m), 2.27 (3H,
s), 2.58 (2H, t, J = 7.4 Hz), 2.71 (2H, d, J = 7.4
Hz), 5.01 (2H, d, J = 0.8 Hz), 6.09 (1H, d, J = 2.
2 Hz), 6.74-6.78 (2H, m), 7.03 (1H, d, J = 7.6 H
z), 7.13 (1H, d, J = 17.0 Hz), 7.35-7.49 (3H, m),
7.60-7.71 (3H, m). IR (KBr): 1501, 1429, 1331, 1171, 1130 cm ^-1 .

Example 104. [3- [4- [4-[[2-[(E) -2- [2-
Luoro-4- (trifluoromethyl) phenyl] ethenyl] -1,
3-Oxazol-4-yl] methoxy] -2-methylphenyl]
Production of butyl] -1H-pyrazol-1-yl] ethyl acetate

[Chemical 183] 2-[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl] ethenyl] -4-[[3-methyl-4- [4- (1H-pyrazol-3-yl) butyl] Phenoxy] methyl] -1,3-oxazole (2.45
g), 65% sodium hydride (217 mg), and ethyl bromoacetate (1.09 ml) were used to carry out the same reaction as in Example 95.
By silica gel chromatography (eluent: hexane: ethyl acetate = 3: 1 → 1: 1), the title compound (1.16 g) as a low-polar compound was obtained as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 6.9 Hz), 1.56-
1.77 (4H, m), 2.26 (3H, s), 2.56 (2H, t, J = 7.5 H
z), 2.67 (2H, t, J = 7.8 Hz), 4.21 (2H, q, J = 6.9
Hz), 4.83 (2H, s), 5.00 (2H, s), 6.10 (1H, d, J =
2.4 Hz), 6.72-6.78 (2H, m), 7.03 (1H, d, J = 8.4 H
z), 7.12 (1H, d, J = 16.5 Hz), 7.35-7.44 (3H, m),
7.60-7.69 (3H, m) .IR (KBr): 1740, 1333, 1235, 1175, 1111 cm ^-1 .

Example 105. [5- [4- [4-[[2-[(E) -2- [2-
Luoro-4- (trifluoromethyl) phenyl] ethenyl] -1,
3-Oxazol-4-yl] methoxy] -2-methylphenyl]
Production of butyl] -1H-pyrazol-1-yl] ethyl acetate

[Chemical 184] The title compound (708 mg) as a highly polar compound was obtained as colorless needle crystals by silica gel chromatography in Example 104. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.2 Hz), 1.58-
1.77 (4H, m), 2.27 (3H, s), 2.54-2.60 (4H, m), 4.2
1 (2H, q, J = 7.2 Hz), 4.83 (2H, s), 5.01 (2H, s),
6.06 (1H, d, J = 1.8 Hz), 6.74-6.80 (2H, m), 7.02
(1H, d, J = 8.1Hz), 7.12 (1H, d, J = 16.8 Hz), 7.
35-7.45 (3H, m), 7.60-7.68 (3H, m). IR (KBr): 1753, 1331, 1204, 1171, 1130 cm ^-1 .

Example 106. 2- [5- [4- [4-[[2-[(E) -2- [2-
Fluoro-4- (trifluoromethyl) phenyl] ethenyl]-
1,3-oxazol-4-yl] methoxy] -2-methylpheny
Of [l-butyl] -1H-pyrazol-1-yl] ethanol

[Chemical 185] [5- [4- [4-[[2-[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy]- 2-Methylphenyl] butyl] -1H-pyrazole-1-
Ilyl] ethyl acetate (350 mg) and lithium aluminum hydride (24.8 mg) were subjected to the same reaction as in Example 85- (iii) to obtain the title compound (117 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.63-1.70 (4H, m), 2.27 (3H,
s), 2.56-2.65 (4H, m), 3.68 (1H, t, J = 5.7 Hz),
3.97-4.02 (2H, m), 4.09 (2H, t, J = 6.3 Hz), 5.01
(2H, s), 6.02 (1H, d, J = 1.8 Hz), 6.74-6.80 (2H,
m), 7.02 (1H, d, J = 8.7 Hz), 7.12 (1H, d, J = 16.8
Hz), 7.35-7.45 (3H, m), 7.61-7.68 (3H, m). IR (KBr): 1501, 1429, 1333, 1171, 1130 cm ^-1 .

Example 107. 1- (3- (4- (2- (2-((E) -2- (4-
Bromo-2-fluorophenyl) ethenyl) -1,3-oxazol
Ru-4-yl) ethyl) -2-methylphenoxy) propyl) -1H-
Production of 1,2,3-triazole

[Chemical 186] (iv) 1- (3- (4- (2- (2-((E) -2- (4-bromo-2-fluorophenyl) ethenyl) -1,3-oxazol-4-yl) ethyl)- 2-
Preparation of methylphenoxy) propyl) -1H-1,2,3-triazole 2-((E) -2- (4-bromo-2-fluorophenyl) ethenyl) -4-
(2- (4- (3-chloropropoxy) -3-methylphenyl) ethyl) -1,3-oxazole (700 mg), 1H-1,2,3-triazole (127 μl), sodium hydroxide (88 mg), sodium iodide (329 mg) and 2-methyl-2-butanol (10 ml) were used to carry out the same reaction as in Example 76- (iv) to give the title compound (580
(mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 2.36-2.49 (2H,
m), 2.77-2.93 (4H, m), 3.94 (2H, t, J = 5.8 Hz),
4.64 (2H, t, J = 7.0 Hz), 6.67 (1H, d, J = 8.4Hz),
6.93-7.05 (3H, m), 7.25-7.69 (7H, m). IR (KBr): 3155, 2253, 1817, 1599, 1477, 1386 c
m ^-1 .

Example 108. (1- (3- (4- (2- (2-((E) -2- (4-
Bromo-2-fluorophenyl) ethenyl) -1,3-oxazol
Ru-4-yl) ethyl) -2-methylphenoxy) propyl) -1H-
Production of imidazol-2-yl) methanol

[Chemical 187] 2-((E) -2- (4-bromo-2-fluorophenyl) ethenyl) -4-
(2- (4- (3-chloropropoxy) -3-methylphenyl) ethyl) -1,3-oxazole (700 mg), DMF (10 ml), 2-formylimidazole (168 mg), sodium iodide ( 328 m
g), potassium carbonate (302 mg), and sodium borohydride (200 mg), methanol (10 ml), THF (10 ml), using the same reaction as in Example 78- (iii), (iv). The title compound (552 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.24 (3H, s), 2.20-2.34 (2H,
m), 2.78-2.92 (4H, m), 3.92 (2H, t, J = 5.8 Hz),
4.26 (2H, t, J = 7.0 Hz), 6.66 (1H, d, J = 8.0Hz),
6.86-7.06 (5H, m), 7.26-7.55 (5H, m). IR (KBr): 3153, 2932, 2253, 1817, 1599, 1504 c
m ^-1 .

Example 109. 4- [2- [3-methyl-4- [3- (1H-
Pyrazol-3-yl) propoxy] phenyl] ethyl] -2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl]-
Production of 1,3-oxazole

[Chemical 188] (i) Preparation of (2E) -3- (1-trityl-1H-pyrazol-3-yl) ethyl acrylate 1-Trityl-1H-pyrazole-3-carbaldehyde (20.0
g), diethyl phosphonoethyl acetate (12.9 ml) in DMF (150
65% sodium hydride (2.40 g) was added to the solution at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. Add water to the reaction mixture and
The mixture was extracted with a mixed solution of ethyl acetate (1: 1), washed with brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, recrystallization from ethyl acetate-hexane was performed to give the title compound (18.7
g) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.2 Hz), 4.21
(2H, q, J = 7.2 Hz), 6.35 (1H, d, J = 16.2 Hz), 6.
47 (1H, d, J = 2.1 Hz), 7.10-7.17 (6H, m), 7.27-7.
33 (10H, m), 7.72 (1H, d, J = 16.2 Hz). IR (KBr): 1713, 1265, 1163, 747, 700 cm ^-1 .

(Ii) Production of ethyl 3- (1H-pyrazol-3-yl) propanoate Ethyl (2E) -3- (1-trityl-1H-pyrazol-3-yl) acrylate (18.6 g), 10 % Palladium carbon (3.72 g), ethanol-THF mixed solution (2: 1; 450 ml), 4N hydrochloric acid (22.8 ml) using the same reaction as in Example 85- (ii), the title compound
(6.04 g) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.2 Hz), 2.67
(2H, t, J = 7.2 Hz), 3.00 (2H, t, J = 7.2 Hz), 4.1
5 (2H, q, J = 7.2 Hz), 6.10 (1H, d, J = 2.1Hz), 7.
47 (1H, d, J = 2.1 Hz). IR (KBr): 2980, 1732, 1375, 1186, 1157 cm ^-1 .

(Iii) Preparation of 3- (1-trityl-1H-pyrazol-3-yl) -1-propanol Ethyl 3- (1H-pyrazol-3-yl) propanoate (6.00
g), triethylamine (7.46 ml), trityl chloride (10.4
g) was used to carry out the same reaction as in Example 26- (ii), and 3- (1-
A crude product of ethyl trityl-1H-pyrazol-3-yl) propanoate was obtained as a yellow oil. Using this product and lithium aluminum hydride (1.49 g), the same reaction as in Example 85- (iii) was performed to give the title compound (12.1 g) as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.80-1.88 (2H, m), 2.34 (1H, t,
J = 6.0 Hz), 2.76 (2H, t, J = 6.6 Hz), 3.51-3.58
(2H, m), 6.02 (1H, d, J = 2.1 Hz), 7.10-7.17 (6H,
m), 7.25-7.31 (10H, m). IR (KBr): 1493, 1445, 1059, 748, 700 cm ^-1 .

(Iv) Methanesulfonic acid 3- (1-trityl-1H-)
Preparation of pyrazol-3-yl) propyl 3- (1-trityl-1H-pyrazol-3-yl) -1-propanol
(4.00 g) in ethyl acetate (60 ml) in triethylamine
(2.27 ml) and methanesulfonyl chloride (1.26 ml) were added, and the mixture was stirred at 0 ° C for 45 min. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 3: 1 → 2: 1) to obtain the title compound (4.65 g) as a colorless amorphous substance. ¹ H-NMR (CDCl ₃ ) δ: 1.98-2.11 (2H, m), 2.73-2.80 (5
H, m), 4.17 (2H, t, J = 6.2 Hz), 6.03 (1H, d, J =
2.6 Hz), 7.08-7.18 (6H, m), 7.23-7.33 (10H, m). IR (KBr): 1341, 1177, 934, 750, 700 cm ^-1 .

(V) 4- [2- [3-methyl-4- [3- (1H-pyrazole
-3-yl) propoxy] phenyl] ethyl] -2-[(E) -2- [4-
Preparation of (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole 2-methyl-4- [2- [2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1 , 3-Oxazol-4-yl] ethyl] phenol (668 mg), 65% sodium hydride (72.2 mg),
Example using 3- (1-trityl-1H-pyrazol-3-yl) propyl methanesulfonate (726 mg) and 90% formic acid (3 ml)
The same reaction as in 85- (viii) was performed to give the title compound (597 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.12-2.21 (2H, m) 2.22 (3H, s),
2.80-2.93 (6H, m), 3.39 (2H, t, J = 6.3 Hz), 6.13
(1H, d, J = 2.1 Hz), 6.71 (1H, d, J = 8.1 Hz), 6.
93-7.02 (3H, m), 7.29 (1H, s), 7.45-7.51 (2H, m),
7.58-7.65 (4H, m) .IR (KBr): 1325, 1254, 1167, 1144, 1067 cm ^-1 .

Example 110. 2-[(E) -2- [2-fluoro-4-
(Trifluoromethyl) phenyl] ethenyl] -4- [2- [3-me
Tyl-4- [3- (1H-pyrazol-3-yl) propoxy] pheny
Production of ru] ethyl] -1,3-oxazole

[Chemical 189] 4- [2- [2-[(E) -2- [2-fluoro-4- (trifluoromethyl)
Phenyl] ethenyl] -1,3-oxazol-4-yl] ethyl]
-2-Methylphenol (700 mg), 65% sodium hydride
(72.2 mg), 3- (1-Trityl-1H-pyrazol-3-yl) propyl methanesulfonate (726 mg) and 90% formic acid (3 ml)
The same reaction as in Example 85- (viii) was performed using the above, and the title compound (341 mg) was obtained as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.12-2.21 (2H, m) 2.23 (3H, s),
2.80-2.93 (6H, m), 3.99 (2H, t, J = 6.0 Hz), 6.13
(1H, d, J = 2.1 Hz), 6.71 (1H, d, J = 8.1 Hz), 6.
93-6.99 (2H, m), 7.11 (1H, d, J = 16.2 Hz), 7.31-
7.44 (3H, m), 7.49 (1H, d, J = 2.1 Hz), 7.55-7.68
(2H, m). IR (KBr): 1505, 1429, 1331, 1254, 1130 cm ^-1 .

Example 111. 4-[[3-methyl-4- [4- (1H-pi
Razol-4-yl) butyl] phenoxy] methyl] -2-[(E) -2
-[4- (Trifluoromethyl) phenyl] ethenyl] -1,3-o
Manufacture of xazole

[Chemical 190] (i) Production of 3-methyl-4- [4- (1H-pyrazol-4-yl) butyl] phenol [3- (4-methoxy-2-methylphenyl) propyl] (triphenyl) phosphonium (5.00 g), 1-Trityl-1H-pyrazole-4-carbaldehyde (2.45 g), potassium carbonate
(1.50 g), water (0.261 ml) and 10% palladium on carbon (458
mg), ethanol-THF mixed solution (4: 1; 50 ml), 4N hydrochloric acid (4.73
ml) was used to carry out the same reaction as in Example 10- (i) to give 4- [4-
A crude product of (4-methoxy-2-methylphenyl) butyl] -1H-pyrazole was obtained as a colorless oil. Using this product and 48% hydrobromic acid (5 ml), the same reaction as in Example 85- (vi) was performed to give the title compound (564 mg) as a colorless amorphous. ¹ H-NMR (DMSO-d ₆ ) δ: 1.43-1.59 (4H, m), 2.14 (3H,
s), 2.41-2.47 (4H, m), 6.47 (1H, dd, J = 2.4, 7.8 H
z), 6.51 (1H, d, J = 2.4 Hz), 6.85 (1H, d, J = 7.8
Hz), 7.28 (1H, br s), 7.45 (1H, br s), 8.96 (1H,
s) .IR (KBr): 1586, 1499, 1339, 856, 808 cm ^-1 .

(Ii) 4- [4- [4-[[tert-butyl (diphenyl)
Production of silyl] oxy] -2-methylphenyl] butyl] -1H-pyrazole 3-Methyl-4- [4- (1H-pyrazol-4-yl) butyl] phenol (558 mg), imidazole (445 mg), Example 101-using tert-butyldiphenylchlorosilane (1.32 ml)
The same reaction as in (iii) was performed to give the title compound (1.13 g) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (9H, s), 1.49-1.62 (4H,
m), 2.11 (3H, s), 2.44-2.51 (4H, m), 6.44 (1H, dd,
J = 2.7, 8.1 Hz), 6.60 (1H, d, J = 2.7 Hz), 6.76
(1H, d, J = 8.4 Hz), 7.25-7.43 (8H, m), 7.69-7.72
(4H, m) .IR (KBr): 1499, 1287, 1262, 1113, 700 cm ^-1 .

(Iii) Preparation of 3-methyl-4- [4- (1-trityl-1H-pyrazol-4-yl) butyl] phenol 4- [4- [4-[[tert-butyl (diphenyl) silyl] ] Oxy] -2-
Methylphenyl] butyl] -1H-pyrazole (1.13 g), triethylamine (0.506 ml), trityl chloride (675 mg),
Tetrabutylammonium Fluoride THF solution (1.0 M;
2.66 ml) to carry out the same reaction as in Example 101- (iv),
The title compound (1.07 g) was obtained as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.51-1.59 (4H, m), 2.20 (3H,
s), 2.42-2.52 (4H, m), 4.53 (1H, br s), 6.56 (1H,
dd, J = 2.7, 8.1 Hz), 6.60 (1H, d, J = 2.7 Hz), 6.
92 (1H, d, J = 8.1 Hz), 7.10-7.31 (16H, m), 7.47
(1H, s). IR (KBr): 1501, 1445, 752, 733, 700 cm ^-1 .

(Iv) 4-[[3-methyl-4- [4- (1H-pyrazole-
Preparation of 4-yl) butyl] phenoxy] methyl] -2-[(E) -2- [4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole 3-methyl-4- [4- ( 1-Trityl-1H-pyrazol-4-yl) butyl] phenol (703 mg), 65% sodium hydride (60.5 mg), 4- (chloromethyl) -2-[(E) -2- [4- ( Trifluoromethyl) phenyl] ethenyl] -1,3-oxazole
(428 mg) and 90% formic acid (3 ml) were used to perform the same reaction as in Example 85- (viii) to obtain the title compound (523 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.56-1.65 (4H, m), 2.27 (3H,
s), 2.51-2.58 (4H, m), 5.00 (2H, d, J = 0.9 Hz),
6.73-6.79 (2H, m), 6.98-7.04 (2H, m), 7.38 (2H, s),
7.51-7.66 (6H, m) .IR (KBr): 1501, 1325, 1163, 1127, 1069 cm ^-1 .

Example 112. 2-[(E) -2- [2-fluoro-4-
(Trifluoromethyl) phenyl] ethenyl] -4-[[3-methyl
Lu-4- [4- (1H-pyrazol-4-yl) butyl] phenoxy] me
Chill] -1,3-oxazole production

[Chemical 191] 3-Methyl-4- [4- (1-trityl-1H-pyrazol-4-yl) butyl] phenol (350 mg), 65% sodium hydride (3
0.1 mg), 4- (chloromethyl) -2-[(E) -2- [2-fluoro-4-
Example 85-using (trifluoromethyl) phenyl] ethenyl] -1,3-oxazole (226 mg) and 90% formic acid (3 ml)
The same reaction as in (viii) was performed to give the title compound (226 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.57-1.65 (4H, m), 2.27 (3H,
s), 2.51-2.58 (4H, m), 5.01 (2H, d, J = 0.9 Hz),
6.73-6.79 (2H, m), 7.02 (1H, d, J = 8.1 Hz), 7.12
(1H, d, J = 16.5 Hz), 7.35-7.44 (4H, m), 7.60-7.69
(3H, m). IR (KBr): 1333, 1323, 1163, 1132, 1123 cm ^-1 .

Example 113. 4-[[3-methyl-4- [4- [1- [2-
(Tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pi
Razol-4-yl] butyl] phenoxy] methyl] -2-[(E) -2
-[4- (Trifluoromethyl) phenyl] ethenyl] -1,3-o
Manufacture of xazole

[Chemical 192] 4-[[3-Methyl-4- [4- (1H-pyrazol-4-yl) butyl] phenoxy] methyl] -2-[(E) -2- [4- (trifluoromethyl)
Phenyl] ethenyl] -1,3-oxazole (300 mg), 65%
The reaction was performed in the same manner as in Example 95 using sodium hydride (27.6 mg) and 2- (2-bromoethoxy) tetrahydro-2H-pyran (113 μl) to give the title compound (360 mg) as colorless needles. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.47-1.77 (10H, m), 2.27 (3H,
s), 2.48 (2H, t, J = 6.6 Hz), 2.55 (2H, t, J = 7.5
Hz), 3.40-3.42 (1H, m), 3.59-3.67 (1H, m), 3.70-
3.77 (1H, m), 3.99-4.06 (1H, m), 4.26 (2H, d, J =
6.0 Hz), 4.50 (1H, t, J = 2.7 Hz), 5.00 (2H, d, J =
0.6 Hz), 6.73-6.79 (2H, m), 6.98-7.03 (2H, m), 7.2
5 (1H, s) 7.31 (1H, s), 7.51-7.66 (6H, m). IR (KBr): 1325, 1165, 1123, 1067, 1036 cm ^-1 .

Example 114. 2- [4- [4- [2-methyl-4-[[2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl]-
1,3-Oxazol-4-yl] methoxy] phenyl] butyl]-
Production of 1H-pyrazol-1-yl] ethanol

[Chemical formula 193] 4-[[3-methyl-4- [4- [1- [2- (tetrahydro-2H-pyran-2-
Iloxy) ethyl] -1H-pyrazol-4-yl] butyl] phenoxy] methyl] -2-[(E) -2- [4- (trifluoromethyl)
Example 94 using phenyl] ethenyl] -1,3-oxazole (240 mg), p-toluenesulfonic acid monohydrate (150 mg)
The same reaction as in (1) was performed to give the title compound (180 mg) as colorless needle crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.59-1.62 (4H, m), 2.27 (3H,
s), 2.48 (2H, t, J = 6.9Hz), 2.56 (2H, t, J = 7.2
Hz), 3.18 (1H, br t, J = 6.0 Hz), 3.96-3.99 (2H,
m), 4.17 (2H, d, J = 4.5 Hz), 5.00 (2H, d, J = 0.6
Hz), 6.73-6.79 (2H, m), 6.98-7.04 (2H, m), 7.17
(1H, s), 7.33 (1H, s), 7.51-7.66 (6H, m). IR (KBr): 1325, 1161, 1125, 1109, 1069 cm ^-1 .

Example 115. (+)-1- [4-[[2-[(E) -2- (4-
Lifluoromethylphenyl) ethenyl] -1,3-oxazol
Lu-4-yl] methoxy] phenyl] -4- (1H-1,2,3-triazo
1-yl) -1-butanol

[Chemical 194] 1- [4-[[2-[(E) -2- (4-trifluoromethylphenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] -4
-(1H-1,2,3-triazol-1-yl) -1-butanol (400
(mg) was subjected to column chromatography (eluent: hexane: 2-propanol = 3: 7) using a chiral column (CHIRALCEL OJ, manufactured by Daicel Chemical Industries) for optical resolution. The title compound (174 mg) was obtained as an optical antipode with a short retention time. Specific rotation [α] _D + 11.1 ° (C = 0.24, ethanol)

Example 116. (-)-1- [4-[[2-[(E) -2- (4-
Lifluoromethylphenyl ) ethenyl] -1,3-oxazol
Lu-4-yl] methoxy] phenyl] -4- (1H-1,2,3-triazo
1-yl) -1-butanol

[Chemical 195] 1- [4-[[2-[(E) -2- (4-trifluoromethylphenyl) ethenyl] -1,3-oxazol-4-yl] methoxy] phenyl] -4
-(1H-1,2,3-triazol-1-yl) -1-butanol (400
column chromatography (eluent: hexane: 2-propanol = 3: 7) using a chiral column (CHIRALCEL OJ, manufactured by Daicel Chemical Industries, Ltd.) to give the title compound (180 mg) as an optical antipode with a long retention time. It was Specific rotation [α] _D −10.5 ° (C = 0.22, ethanol)

Formulation Example 1 (Dose per tablet) (1) Compound obtained in Example 4 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5 ) Magnesium stearate 2.0 mg 10.0 mg of the compound obtained in Example 4 and 60.0 lactose
mg and corn starch 35.0 mg to a mixture of 10
Using 0.03 ml of a weight% gelatin aqueous solution (3.0 mg as gelatin), the mixture is granulated through a 1 mm mesh sieve, dried at 40 ° C. and filtered again. The obtained granules are mixed with 2.0 mg of magnesium stearate and compressed. The obtained central tablets are coated with a sugar coating of a suspension of sucrose, titanium dioxide, talc and gum arabic, and frosted with beeswax to give sugar-coated tablets. Formulation Example 2 (Dose per tablet) (1) Compound obtained in Example 4 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Solubilized starch 7.0 mg (5) Magnesium stearate 3.0 mg 10.0 mg of the compound obtained in Example 4 and 3.0 mg of magnesium stearate were added to an aqueous solution of solubilized starch.
Granulated with 07 ml (7.0 mg as solubilized starch), dried, lactose 70.0 mg and corn starch 5
Mix 0.0 mg. The mixture is compressed to give tablets.

In the following test examples, the compound number indicates the example number (for example, the compound of Example 2 is indicated as compound 2). Test Example 1. Phosphorylation of receptor tyrosine on human breast cancer cells
Inhibition of human breast cancer cells BT-474 cell suspension 500 μl (3
(10,000 cells) were seeded on a 24-well plate and cultured at 37 ° C. in a 5% carbon dioxide gas incubator. The next day, 250 μl of a 4-fold serially diluted test compound solution was added, and after 2 hours, an extract was added to stop the reaction and the protein was extracted. After fractionating this protein by the protein electrophoresis method, the protein in the electrophoresis gel was transferred to a nylon filter. This filter was reacted with a phosphorylated tyrosine-specific antibody, and the reaction product was fluorescently labeled and quantified by an image analyzer. HER2 tyrosine phosphorylation of cells in the untreated group was set to 100%, and HER of cells in the group to which each concentration of the test compound solution was added
The ratio of the phosphorylation amount of 2 tyrosine was calculated and the test compound was H
The compound concentration (IC ₅₀ value) required to suppress the phosphorylation amount of ER2 tyrosine to 50% of the control was calculated. The results are shown in [Table 1]. From this, it was shown that the compound of the present invention strongly inhibits the phosphorylation reaction of the tyrosine residue of the receptor protein, which is caused by the activation of the receptor tyrosine kinase in human breast cancer cells.

[Table 1] Example number (Compound number) Inhibition of intracellular HER2 phosphorylation BT-474 (IC ₅₀ : nM) 1 6.0 6 16 9 8.5 10 6.8 12 <4.0

Test Example 2. Breast cancer cells BT in vitro
-474 Growth inhibitory action 100 μl of cell suspension of human breast cancer cells BT-474
(6,000 cells) on a 96-well microplate,
The cells were cultured at 37 ° C in a 5% carbon dioxide gas incubator. On the next day, 100 μl of each 2-fold serially diluted test compound solution was added, and the cells were cultured for 5 days. After removing the culture medium containing the test compound and washing the cells, the cells were fixed with 50% trichloroacetic acid solution, and then the dye SRB 0.4% (W / V) solution (dissolved in 1% acetic acid) was added to fix the cell proteins. Stained with (Sukehan et al., Journal of National Cancer Institute, Vol. 82, 1107-111.
2 pages, 1990). After removing the dye solution and washing with 1% acetic acid solution, 100 μl of extract solution (10 mM Tris buffer) was added to extract the dye, and the absorption wavelength was 550 nm.
The absorbance was measured and the amount of cells was measured as the amount of protein. The ratio of the residual protein amount of each treatment group was calculated when the protein amount of the control group to which the test compound solution was not added was 100%, and the compound concentration necessary to suppress the residual cell amount to 50% of the control ( IC ₅₀ ) values were calculated. The results are shown in [Table 2]. From this, it was shown that the compound of the present invention strongly suppressed the growth of the human breast cancer cell line BT-474.

[Table 2] Example No. (Compound No.) Cell growth inhibition BT-474 (IC ₅₀ : μM) 4 <0.05 6 <0.05 7 <0.05 8 0.11 16 0.20

Test Example 3. In vivo suppression of breast cancer growth
The use 5 million human breast cancer cell BT-474, were suspended in Matrigel solution Balb / C strain female nude mice (6 weeks old) implanted into the chest subcutaneously (Friedman et al. Proceedings Day ring of the National Academy of Sciences USA 87 Volume 6698 -6702 page, 19
90 years). At the time of transplantation and 7 days after transplantation, 50 μL of estradiol dipropionate (5 mg / mL solution) is intramuscularly administered to the hind legs for the purpose of increasing the tumor engraftment rate. On the 14th day after transplantation, the tumor diameter was measured and the tumor size was adjusted to 5 mice per group and used in the experiment. 30% of a 5% gum arabic suspension (physiological saline solution) of the test compound was added.
Oral administration is performed twice a day at a concentration of mg / kg for a total of 10 days. The tumor diameter is measured on the day of administration, and the tumor volume is calculated by the formula: tumor volume = major axis x minor axis x minor axis x (1/2). The value obtained by subtracting the tumor volume from the tumor start date in the control group of the gum arabic solution administration day on the administration start date and the tumor volume on the drug administration group from the administration end date to the administration start day The ratio of and is obtained as the growth rate.

[0428]

INDUSTRIAL APPLICABILITY Since the compound (I) of the present invention or a salt thereof or a prodrug thereof has a tyrosine kinase inhibitory action and low toxicity, it can be used for the prevention or treatment of tyrosine kinase-dependent diseases in mammals. You can Tyrosine kinase-dependent diseases include diseases in which cell growth is promoted due to abnormal tyrosine kinase enzyme activity. Furthermore, since the compound (I) of the present invention or a salt thereof or a prodrug thereof specifically inhibits tyrosine kinase, it can be used as a therapeutic agent for suppressing the growth of HER2-expressing cancer, or a hormone-dependent cancer. It is also useful as a prophylactic agent for preventing the transition to a hormone-independent cancer.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/506 A61K 31/506 A61P 9/00 A61P 9/00 9/10 9/10 101 101 31/18 31/18 35/00 35/00 35/04 35/04 43/00 111 43/00 111 123 123 123 C07D 413/14 C07D 413/14 417/12 417/12 (72) Inventor Yu Momose Takarazuka City, Hyogo Prefecture Sumiregaoka 2-8-7 (72) Inventor Kenichiro Naito 2-11-17 Segawa, Minoh City, Osaka Prefecture (72) Inventor Saori Tsujimoto 1-26-10-303 F-term, Mukonosou Higashi, Amagasaki City, Hyogo Prefecture (Reference) 4C063 AA01 AA03 BB01 BB03 BB07 BB08 CC52 CC62 CC76 CC92 DD06 DD12 DD14 DD22 DD25 DD29 DD41 DD42 DD52 EE01 4C086 AA01 AA02 AA03 BC69 BC82 GA02 GA04 GA07 GA08 GA09 GA10 MA01 MA04 MA17 MA22 MA37 MA37 MA31 MA31 MA31 MA31 MA35 6 MA58 MA59 MA60 MA65 MA66 NA14 NA15 ZA33 ZA36 ZA45 ZB26 ZB33 ZC20

Claims (28)

[Claims] 1. A general formula: [Wherein, ring A is a nitrogen-containing heterocycle, ring B is an optionally substituted aromatic homocycle or an optionally substituted aromatic heterocycle, and ring C is optionally substituted 5 Or a 6-membered nitrogen-containing heterocycle, R is an optionally substituted aromatic homocyclic group, an optionally substituted aromatic heterocyclic group or an optionally substituted styryl group, and m is 0 To 2; n is an integer from 1 to 5; X is an oxygen atom, methylene group, ethylene group or ethenyl group; Y and Z are the same or different and may be a single bond, an oxygen atom or a substituent A carbon atom, an optionally substituted nitrogen atom, and an optionally oxidized sulfur atom are respectively shown. However, m
When = 0, X is an ethylene group or an ethenyl group. In addition, the general formula: The group represented by is It is an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group represented by and when X is an oxygen atom, Y and Z are the same or different and each is a single bond or a methylene group. ] The compound or its salt represented by these. 2. The compound according to claim 1, wherein ring A is a monocyclic or bicyclic nitrogen-containing heterocycle. 3. The compound according to claim 1, wherein ring A is oxazole or thiazole. 4. The compound according to claim 1, wherein ring B is benzene, pyridine, naphthalene, benzofuran or quinoline, each of which may be substituted. 5. A general formula: The group represented by is The compound according to claim 1, which is an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group. 6. A general formula: The group represented by is The compound according to claim 1, which is an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group. 7. The compound according to claim 1, wherein each ring C is an optionally substituted pyrrole, imidazole, pyrazole, triazole, pyridine, oxazole, thiazole or benzimidazole. 8. The compound according to claim 1, wherein R is an optionally substituted styryl group. 9. The compound according to claim 1, wherein X is an oxygen atom. 10. The compound according to claim 1, wherein m is 1. 11. The compound according to claim 1, wherein Y is an oxygen atom or a sulfonyl group. 12. A general formula: [Wherein R ¹ is a halogen atom or an optionally halogenated C _1-4 alkyl group, and R ² and R ³ are the same or different and may be a halogen atom, a C _1-3 alkyl group or a substituted group] A good hydroxyl group, W is an oxygen atom or a sulfur atom, p is an integer of 1 to 3, ring C is an optionally substituted 5- or 6-membered nitrogen-containing heterocycle, and m ′ is 1 or 2. n is an integer of 1 to 5, Y and Z are the same or different and each is a single bond, an oxygen atom, an optionally substituted carbon atom, an optionally substituted nitrogen atom or an optionally oxidized sulfur atom. Shown respectively. p is 2 or 3
R ¹ may be the same or different. However, the general formula: The group represented by is In the case of the optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group, the case where Y and Z are the same or different and each is a single bond or a methylene group is excluded. ] The compound or its salt represented by these. 13. The compound according to claim 12, wherein R ¹ is a trifluoromethyl group, a fluorine atom, a chlorine atom or a bromine atom, and R ² is a fluorine atom, a chlorine atom or a methyl group. 14. A general formula: [Wherein R ¹ is a halogen atom or an optionally halogenated C _1-4 alkyl group, and R ² and R ³ are the same or different and may be a halogen atom, a C _1-3 alkyl group or a substituted group]. A good hydroxyl group, W is an oxygen atom or a sulfur atom, p is an integer of 1 to 3, and ring B ′ is an optionally substituted benzene ring or an optionally substituted 5- or 6-membered aromatic heterocycle. , Ring C is an optionally substituted 5- or 6-membered nitrogen-containing heterocycle, and m ′ is 1 or 2
Where n is an integer of 1 to 5 and Y and Z are the same or different and each is a single bond, an oxygen atom, an optionally substituted carbon atom, an optionally substituted nitrogen atom or an optionally oxidized sulfur. Each atom is shown. When p is 2 or 3, R ¹ may be the same or different. ] The compound or its salt represented by these. 15. The method according to claim 12, wherein W is an oxygen atom.
4. The compound according to 4. 16. The compound according to claim 12 or 14, wherein m ′ is 1. 17. A general formula: The group represented by is [In the formula, R ⁴ is a hydrogen atom or a substituent, 1) a hydroxyl group, 2) an optionally substituted alkoxycarbonyl group, 3) a optionally substituted carbamoyl group, 4) Cyclic aminocarbonyl group which may have a substituent, 5) carbamoyloxy group which may have a substituent, 6) cyclic aminocarbonyloxy group which may have a substituent, 7) substituent An optionally substituted alkylsulfonyl group, 8) an optionally substituted alkylsulfinyl group, 9) an optionally substituted sulfamoyl group, and 10) an optionally substituted group. Good cyclic aminosulfonyl group, 11) Carbamoylamino group which may have a substituent, 12) Cyclic aminocarbonylamino group which may have a substituent, 13) Alkyl which may have a substituent Honiruamino group, 14) an optionally substituted alkylsulfonylamino group and 1
5) C _1-4 alkyl group having 1 to 3 groups selected from acylamino groups. ] The compound of Claim 1 which is a group represented by these. 18. A general formula: The group represented by is [In the formula, R ^4'is a hydrogen atom or a substituent, 1) a hydroxyl group, 2) an alkoxycarbonyl group which may have a substituent, 3) a carbamoyl group which may have a substituent, 4 ) Cyclic aminocarbonyl group which may have a substituent, 5) carbamoyloxy group which may have a substituent, 6) cyclic aminocarbonyloxy group which may have a substituent, 7) substitution An alkylsulfonyl group optionally having a group, 8) an alkylsulfinyl group optionally having a substituent, 9) a sulfamoyl group optionally having a substituent, 10) having a substituent A cyclic aminosulfonyl group, 11) a carbamoylamino group which may have a substituent, 12) a cyclic aminocarbonylamino group which may have a substituent, and 13) a substituent which may have a substituent. Alkyls Honiruamino group, 14) an optionally substituted alkylsulfonylamino group and 1
5) C _1-4 alkyl group having 1 to 3 groups selected from acylamino groups. ] The compound of Claim 1 which is a ring group represented by these. 19. 1- (3- {4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl)
Methoxy] phenoxy} propyl) -1H-1,2,3-triazole; 1- [3-({4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl}- 1,3-oxazol-4-yl) methoxy]
Phenyl} thio) propyl] -1H-1,2,3-triazole; 1-
[3-({4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl]]
Ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} sulfonyl) propyl] -1H-1,2,3-triazole; {1-
[3-({4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl]]
Ethenyl} -1,3-oxazol-4-yl) methoxy] phenyl} sulfanyl) propyl] -1H-imidazol-2-yl}
Methanol, {1- [3-({4-[(2-{(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,3-oxazol-4-yl)
Methoxy] phenyl} sulfonyl) propyl] -1H-imidazol-2-yl} methanol, 1- [4-[[2-[(E) -2- (4-trifluoromethylphenyl) ethenyl] -1,3- Oxazole-4-
Ill] methoxy] phenyl] -4- (1H-1,2,3-triazole-1
-Yl) -1-butanol, 1- [3- [4- [2- [2-
[(E) -2- [4- (Trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] ethyl] phenoxy] propyl] -1H-1,2,3-triazole, 2- [ (E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl] ethenyl] -4-[[4- [4- (1H-pyrazole-3-
Il) butyl] phenoxy] methyl] -1,3-oxazole, 2
-[5- [4- [4-[[2-[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy] Phenyl] butyl] -1H-pyrazol-1-yl] ethanol, 2-[(E) -2- [2-fluoro-4- (trifluoromethyl) phenyl] ethenyl] -4-[[4- [4- [1- [2- (tetrahydro
-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-5-yl] butyl] phenoxy] methyl] -1,3-oxazole, 2-
[5- [4- [4-[[2-[(E) -2- [2-Fluoro-4- (trifluoromethyl) phenyl] ethenyl] -1,3-oxazol-4-yl] methoxy]- 2-Methylphenyl] butyl] -1H-pyrazole-1
-Yl] ethanol and 2- [5- [4- [4-[[2-[(E) -2- [4-bromo-2-fluoro-4-phenyl] ethenyl] -1,3-oxazole-4 -Yl] methoxy] -2-methylphenyl] butyl] -1
[1] A compound selected from the group consisting of [H-pyrazol-1-yl] ethanol or a salt thereof. 20. A prodrug of the compound according to claim 1. 21. A medicine containing the compound according to claim 1, a salt thereof or a prodrug thereof. 22. A tyrosine kinase inhibitor.
The medicine according to 1. 23. The medicine according to claim 21, which is a preventive / therapeutic agent for cancer. 24. The medicine according to claim 23, wherein the cancer is breast cancer, prostate cancer, lung cancer, pancreatic cancer or kidney cancer. (25) A method for inhibiting tyrosine kinase, which comprises administering an effective amount of the compound according to (1) or a salt thereof or a prodrug thereof to a mammal. [26] A method for preventing / treating cancer, which comprises administering an effective amount of the compound according to [1] or a salt thereof or a prodrug thereof to a mammal. 27. Use of the compound according to claim 1 or a salt thereof or a prodrug thereof for producing a tyrosine kinase inhibitor. 28. Use of the compound according to claim 1 or a salt thereof or a prodrug thereof for producing a preventive / therapeutic agent for cancer.