JP2008120794A - Pharmaceutical composition containing heterocyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition containing a new compound having excellent immunosuppressive action with low toxicity or a pharmacologically permissible salt thereof. <P>SOLUTION: The pharmaceutical composition contains the compound expressed by general formula (I) [wherein A expresses a carboxyl group or the like; B expresses H or the like; V expresses a single bond, a methylene group or the like; n expresses an integer of 0-2; W expresses a 5-7 membered heterocyclic group or the like; Z expresses a group or the like selected from a group A consisting of substituent groups, wherein the group A expresses a group consisting of halogen atoms, 1-6C alkyl groups, 3-7C cycloalkyl groups and the like] or the pharmacologically permissible salt thereof. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition containing a heterocyclic derivative having an excellent immunosuppressive action or a pharmacologically acceptable salt thereof.

  Conventionally, in the treatment of autoimmune diseases and the like, anti-inflammatory drugs such as steroids have been used as symptomatic therapy, and the development of a fundamental treatment method is desired. In addition, it has been reported that abnormalities of the immune system are involved in the onset of diabetes and nephritis (see, for example, Non-Patent Documents 1 and 2), but no drug has been developed to improve the abnormalities.

  On the other hand, the development of a method for suppressing an immune response is extremely important for preventing rejection in organs and cell transplants and for treating and preventing various autoimmune diseases. However, conventionally known immunosuppressive agents such as cyclosporin A (CsA) and tacrolimus (TRL) are known to be toxic to the kidney and liver, and in order to reduce such side effects, Although treatments such as using steroids have been widely used, the current situation is that they do not necessarily exhibit sufficient immunosuppressive effects without showing side effects.

  Against this background, attempts have been made to find compounds having low toxicity and excellent immunosuppressive action. So far, the following documents are known as background art of the present invention.

  For example, Patent Document 1 discloses the following compounds.

  For example, Patent Document 2 discloses the following compounds.

  For example, Patent Document 3 discloses the following compounds.

  For example, Patent Document 4 discloses the following compounds.

  For example, Patent Document 5 discloses the following compounds.

  For example, Patent Document 6 discloses the following compounds.

International Publication No. 03/062252 Pamphlet International Publication No. 03/107771 Pamphlet International Publication No. 2004/058149 Pamphlet International Publication No. 2004/103306 Pamphlet International Publication No. 2004/103309 Pamphlet International Publication No. 2005/000833 Pamphlet Kidney International, vol.51, 94 (1997) Journal of Immunology, vol.157, 4691 (1996)

  As a result of intensive studies over many years on novel compounds with low toxicity and excellent immunosuppressive activity, the present inventors have found that rejection in various organ transplants or skin transplants, systemic lupus erythematosus, rheumatoid arthritis, Myositis, connective tissue inflammation, skeletal myositis, osteoarthritis, osteoarthritis, dermatomyositis, scleroderma, Behcet's disease, Chron's disease, ulcerative colitis, autoimmune hepatitis, aplastic anemia, idiopathic thrombocytopenia Purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullosis, psoriasis vulgaris, vascular inflammation group, Wegener granulomas, uveitis, Sjogren's syndrome, idiopathic interstitial pneumonia, Goodpasture syndrome , Sarcoidosis, allergic granulomatous vasculitis, bronchial asthma, myocarditis, cardiomyopathy, aortitis syndrome, post-myocardial infarction syndrome, primary pulmonary hypertension, minimal change nephrosis, membranous nephropathy Membranoproliferative nephritis, focal glomerulosclerosis, crescent nephritis, myasthenia gravis, inflammatory neuropathy, atopic dermatitis, chronic actinic dermatitis, photosensitivity, pressure ulcer, Sydenham chorea, Sclerosis, adult-onset diabetes, insulin-dependent diabetes, juvenile diabetes, atherosclerosis, glomerulonephritis, IgA nephropathy, tubulointerstitial nephritis, primary biliary cirrhosis, primary sclerosing cholangitis, Fulminant hepatitis, viral hepatitis, GVHD, contact dermatitis, autoimmune diseases such as sepsis or other immune related diseases, infections such as fungi, mycoplasma, virus, protozoa, heart failure, cardiac hypertrophy, arrhythmia, angina Cardiovascular ischemia, arterial embolism, aneurysm, varicose vein, circulatory disease such as blood circulation disorder, Alzheimer's disease, dementia, Parkinson's disease, stroke, cerebral infarction, cerebral ischemia, depression, manic depression, schizophrenia, Huntington's choreography disease, Various diseases such as sputum, convulsions, hyperactivity, encephalitis, meningitis, anorexia and bulimia, lymphoma, leukemia, polyuria, frequent urination, diabetic retinopathy (especially in various organ transplants or skin transplants) The present invention was completed by finding novel compounds useful for autoimmune diseases such as rejection, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and atopic dermatitis.

  Accordingly, an object of the present invention is to provide a pharmaceutical composition containing a novel compound having a low toxicity and an excellent immunosuppressive action or a pharmacologically acceptable salt thereof.

  As a result of intensive studies on compounds having an immunosuppressive action, the present inventors have found that the compounds having the general formula (I) of the present invention, pharmacologically acceptable salts thereof or pharmacologically acceptable prodrugs (hereinafter referred to as “drugs”) Have been found to be useful for the prevention or treatment of the above-mentioned diseases.

  The present invention is described below.

  The present invention relates to (1) general formula (I)

[Where:
A represents a carboxyl group, a phospho group, a sulfo group or a 1H-tetrazol-5-yl group,
B represents a hydrogen atom or a group selected from the substituent group A;
n represents an integer of 0 to 2,
V represents a methylene group or a single bond that may be substituted with a group selected from the substituent group A;
When V is a methylene group which may be substituted with a group selected from Substituent Group A, W is a 5-membered ring to 7-membered which may be substituted with 1 to 3 groups selected from Substituent Group A A ring heterocyclic group,
When V is a single bond, W represents a condensed heterocyclic group which may be substituted with 1 to 3 groups selected from the substituent group A;
X is a C ₁ -C ₈ alkylene group which may be substituted with 1 to 5 groups selected from the substituent group A, and a chain which may be substituted with 1 to 5 groups selected from the substituent group A A C ₁ -C ₈ alkylene group having an oxygen atom or a sulfur atom therein, a C ₆ -C ₁₀ arylene group optionally substituted with a group selected from the substituent group A, and a substituent group A A 5- to 7-membered heterocyclic group which may be substituted with 1 to 3 groups or a condensed heterocyclic group which may be substituted with 1 to 3 groups selected from substituent group A Show
Y is a C ₆ -C ₁₀ arylene group which may be substituted by 1 to 3 groups selected from the substituent group A, and 1 to 3 groups which may be substituted by a group selected from the substituent group A 5 A condensed ring type heterocyclic group which may be substituted with 1 to 3 members selected from a member ring to a 7 member ring heterocyclic group or a group selected from the substituent group A;
Z is a group selected from Substituent Group A, a C ₁ -C ₈ alkyl group that may be substituted with 1 to 5 groups selected from Substituent Group A, or a group selected from Substituent Group A. C ₁ -C ₈ alkyl group having an oxygen atom or a sulfur atom in the chain which may be substituted by 1 to 5 groups, or C ₃ -C which may be substituted by a group selected from substituent group A 1 to 5 C ₇ -C ₁₀ aryl groups which may be substituted with 1 to 5 groups selected from ₇ cycloalkyl groups and substituent group A, and 1 to 5 groups which may be substituted with groups selected from substituent group A good _C 6 _{-C 10} aryloxy group, which may be one to five substituents groups selected from substituent group A _C 6 _{-C 10} arylthio group, 1 to a radical selected from the substituent group A 5 is selected from optionally C ₆ -C ₁₂ aralkyl group or a substituted group A be pieces substituted In 1 to indicate the five optionally substituted _C 6 _{-C 10} arylcarbonyl group,
Substituent group A includes a halogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₇ cycloalkyl group, a C ₆ -C ₁₀ aryl group, a C ₆ -C ₁₀ aryloxy group, and a C ₆ -C ₁₂ aralkyl group. Halogeno C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, halogeno C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, carboxy group, C ₁ -C ₆ alkyl carboxy group, hydroxy group, C ₁ -C ₆ aliphatic acyl group, an amino _group, C 1 -C ₆ monoalkylamino _group, C 1 -C ₆ dialkylamino _group, C 1 -C ₆ aliphatic acylamino group, the group consisting of cyano group and a nitro group And a pharmacologically acceptable salt thereof or a pharmacologically acceptable prodrug thereof, preferably a pharmaceutical composition,
(2) A pharmaceutical composition comprising the composition described in (1), wherein B is a hydrogen atom,
(3) The pharmaceutical composition according to (1) or (2), wherein A is a carboxyl group,
(4) The pharmaceutical composition according to any one of (1) to (3), wherein n is 0,
(5) V is a methylene group, and W is a 5-membered to 7-membered heterocyclic group optionally substituted by 1 to 3 groups selected from the substituent group A. (1) to (4 Any one of the pharmaceutical compositions selected from:
(6) The pharmaceutical composition according to (5), wherein the 5-membered to 7-membered heterocyclic group is a thienylene, furylene, pyrrolene, or pyridylene group,
(7) The pharmaceutical composition according to (5), wherein W is a thienylene or pyridylene group which may be substituted by 1 to 2 groups selected from substituent group A,
(8) Thienylene or pyridylene group

The pharmaceutical composition according to (6),
(9) selected from (1) to (4), wherein V is a single bond, and W is a condensed heterocyclic group which may be substituted by 1 to 3 groups selected from Substituent Group A The pharmaceutical composition described in any one of the above,
(10) The pharmaceutical composition according to (9), wherein W is a condensed heterocyclic group,
(11) The pharmaceutical composition according to (10), wherein the condensed heterocyclic group is a tetrahydrobenzofuranylene, tetrahydrobenzothienylene or N-methyltetrahydroindolinylene group,
(12) The pharmaceutical composition according to (11), wherein the substituted positions of the condensed heterocyclic group are the 2-position and the 4-position,
(13) The pharmaceutical composition according to (12), wherein the substituent at the 2-position is ZYX-
(14) X is _C 1 -C ₈ alkylene group, _C 1 -C ₈ alkylene group having an oxygen atom or a sulfur atom in the _chain, C 6 _{-C 10} arylene group, 5-membered ring or 7-membered ring heterocyclic group, or The pharmaceutical composition according to any one of (1) to (13), which is a condensed heterocyclic group,
(15) The pharmaceutical composition according to any one of (1) to (13), wherein X is a 5-membered to 7-membered heterocyclic group,
(16) Y is a group selected from a 5-membered to 7-membered heterocyclic group which may be substituted with 1 to 3 groups selected from a phenylene group and a substituent group A, and a group selected from substituent group A; The pharmaceutical composition according to any one of (1) to (15), which is any one group selected from the group consisting of three optionally substituted condensed heterocyclic groups ,
(17) Any one selected from (1) to (15), wherein Y is a thienylene, pyridylene, or indylene group optionally substituted by 1 to 3 groups selected from a phenylene group and a substituent group A The pharmaceutical composition described in the paragraph,
(18) The pharmaceutical composition according to any one of (1) to (15), wherein Y is a phenylene or pyridylene group,
(19) Any one selected from (1) to (18), wherein Z is a C ₆ -C ₁₀ aryloxy group optionally substituted by 1 to 5 groups selected from the substituent group A (20) The pharmaceutical composition according to any one of (1) to (18), wherein Z is a phenoxy group, and more preferably,
(21) General formula (I) is represented by general formula (I ′)

[Where:
R ¹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ² represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ represents a hydrogen atom, a halogen atom or a C ₁ -C ₆ alkyl group,
R ⁴ represents a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group,
R ⁵ represents a hydrogen atom or a halogen atom. Or a pharmacologically acceptable salt thereof according to (1),
(22) The pharmaceutical composition according to (21), wherein R ¹ is a hydrogen atom.
(23) The pharmaceutical composition according to (21) or (22), wherein R ² is a hydrogen atom, a methyl group or an ethyl group.
(24) The pharmaceutical composition according to any one of (21) and (23), wherein R ³ is a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group,
(25) The pharmaceutical composition according to any one of (21) and (24), wherein R ⁴ is a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a methyl group, or a methoxy group,
(26) The pharmaceutical composition according to any one of (21) and (25), wherein R ⁵ is a hydrogen atom or a fluorine atom,
(27) The general formula (I) is converted to the general formula (I ″)

[Where:
R ⁶ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ⁷ represents a hydrogen atom, a halogen atom or a C ₁ -C ₆ alkyl group,
R ⁸ represents a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group], and the pharmaceutical composition according to (1),
(28) The pharmaceutical composition according to (27), wherein R ⁶ is a hydrogen atom, a methyl group or an ethyl group,
(29) The pharmaceutical composition according to any one of (27) and (28), wherein R ⁷ is a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group,
(30) The pharmaceutical composition according to any one of (27) and (29), wherein R ⁸ is an n-propyl group, an n-butyl group, or an iso-butyl group,
(31) The pharmaceutical composition according to (1), wherein the compound having the general formula (I) is any one selected from the following:
1-[(4- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -2-furyl) methyl] azetidine-3- carboxylic acid,
1-({5- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} methyl) azetidine-3-carboxylic acid,
1-({5- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} methyl) azetidine-3-carboxylic acid,
1- (2- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -4,5,6,7-tetrahydro-1 -Benzofuran-4-yl) azetidine-3-carboxylic acid,
1-({5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-({4- [5- (4-benzoylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-({4- [5- (4-benzylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-({4- [5- (1-isobutyl-1H-indol-5-yl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-({6- [5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-3-yl} methyl) azetidine-3-carboxylic acid and 1-({5- [ 5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid,
(32) The pharmaceutical composition according to (1), wherein the compound having the general formula (I) is any one selected from the following:
1-({5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-({4-methyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-({5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-methyl-2-thienyl} methyl) azetidine-3-carboxylic acid,
1-({4-ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-[(4-Ethyl-5- {5- [4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3-carboxylic acid ,
1-({4-ethyl-5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-[(4-Ethyl-5- {5- [3-fluoro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine- 3-carboxylic acid,
1-[(4-Ethyl-5- {5- [4- (2-methoxyphenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3-carboxylic acid ,
1-[(5- {5- [3-Chloro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] azetidine- 3-carboxylic acid,
1-[(4-Ethyl-5- {5- [4- (2-methoxyphenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3-carboxylic acid ,
1-[(4-Ethyl-5- {5- [4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3-carboxylic acid ,
1-[(5- {5- [4- (2,3-Difluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] azetidine-3- carboxylic acid,
1-[(4-Ethyl-5- {5- [3-fluoro-4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine- 3-carboxylic acid,
1-[(5- {5- [4- (2,3-Difluorophenoxy) -3-fluorophenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] Azetidine-3-carboxylic acid,
1-[(5- {5- [3-Chloro-4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] azetidine- 3-carboxylic acid,
1-[(5- {5- [3-Chloro-4- (2,3-difluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] Azetidine-3-carboxylic acid,
1-[(5- {5- [4- (2-Chlorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] azetidine-3-carboxylic acid ,
1-[(5- {5- [4- (2-Chlorophenoxy) -3-fluorophenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] azetidine- 3-carboxylic acid,
1-({3-methyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid and 1-({ 3-ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
And (33) The pharmaceutical composition according to (1), wherein the compound having the general formula (I) is any one selected from the following:
1-({5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid,
1-({5- [5- (3-Fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid (,
1-({5- [5- (3-chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid,
1-({5- [5- (4-Isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({5- [5- (3-Fluoro-4-propylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({5- [5- (4-Butyl-3-fluorophenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({5- [5- (3-Fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({6-Ethyl-5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({6-Ethyl-5- [5- (3-fluoro-4-propylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({5- [5- (4-Butyl-3-fluorophenyl) -1,2,4-oxadiazol-3-yl] -6-ethylpyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({6-Ethyl-5- [5- (3-fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid And 1-({5- [5- (3-chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-ethylpyridin-2-yl} methyl) azetidine-3-carvone It is an acid. Furthermore, the present invention provides
(34) The pharmaceutical composition according to (1) for suppressing rejection in skin transplantation or organ transplantation,
(35) The pharmaceutical composition described in (1) for preventing or treating an autoimmune disease,
(36) The autoimmune disease is one or more selected from the group consisting of rheumatoid arthritis, psoriasis, atopic dermatitis, multiple sclerosis, ulcerative colitis, and Crohn's disease. Pharmaceutical composition,
(37) A method for suppressing rejection in skin transplantation or organ transplantation, which comprises administering an effective amount of the pharmaceutical composition described in (1) to a mammal,
(38) A method for preventing or treating an autoimmune disease, comprising administering an effective amount of the pharmaceutical composition described in (1) to a mammal, and (39) the autoimmune disease is rheumatoid arthritis, psoriasis, atopy The prophylactic or therapeutic method according to (38), which is one or more selected from the group consisting of dermatitis, multiple sclerosis, ulcerative colitis and Crohn's disease.

As the substituent group A, preferably, halogen _atom, C 1 -C _{6 alkyl,} C 3 -C ₇ cycloalkyl _group, C 6 _{-C 10} aryl _group, C 6 _{-C 10} aryloxy group, _{C 6} -C ₁₂ aralkyl group, a halogeno _C 1 -C ₆ alkyl _group, C 1 -C ₆ alkoxy group, a halogeno _C 1 -C ₆ alkoxy _group, the group consisting of C 1 -C ₆ alkylthio group.

In the above formula, “5-membered to 7-membered heterocyclic group” in the definition of W, X and Y is, for example, one or more heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms A 5- or 7-membered aromatic heterocyclic group including (for example, 1 to 3) and the like, and having two bonds, specifically, thienylene, furylene, pyrrolylene, imidazolylene, pyrazolylene, thiazolylene, It can be an isothiazolylene, oxazolylene, isoxazolylene, pyridylene, pyrazinylene, pyrimidinylene, pyridazinylene, oxadiazolylene, thiadiazolylene, flazanylene group, etc.
W is preferably a furylene, thienylene, pyrrolylene or pyridylene group,
X is preferably an isoxazoylene or oxadiazolylene group,
Y is preferably a phenylene, pyridylene or thienylene group.

In the above formula, the “condensed heterocyclic group” in the definition of W, X and Y is a substituent obtained by condensing another cyclic group to the above “5-membered to 7-membered heterocyclic group”. 9- to 14-membered, preferably 9- or 10-membered condensed polycyclic aromatic heterocycle containing one or more hetero atoms (for example, 1 to 3) selected from a nitrogen atom, sulfur atom and oxygen atom in addition to the carbon atom A group having two bonds, preferably a bicyclic to tetracyclic group, more preferably a bicyclic group, such as benzothienylene, benzofuranylene, benzimidazolylene, benzoxazolylene, Benzothiazolylene, benzisothiazolylene, naphtho [2,3-b] thiophenylene, isoquinolylene, quinolylene, indolylene, quinoxalinylene, phenanthridinylene, phenothiazinylene, phenoxadi Len, phthalazinylene, naphthyridinylene, quinazolinylene, cinnolinylene, carbazolylene, β-carbolinylene, acridinylene, phenazinylene, phthalimidylene, thioxanthenyltetrahydroquinolylene, tetrahydroisoquinolylene, tetrahydroindolinylene, tetrahydrobenzofurylene, tetrahydrobenzothienylene , 6-dihydro-4H-cyclopenta [b] furylene, 5,6-dihydro-4H-cyclopenta [b] thienylene or 1,4,5,6-tetrahydrocyclopenta [b] pyrrolylene group, etc.
For W, preferably tetrahydrobenzofuranylene, tetrahydrobenzothienylene, tetrahydroindolinylene, 5,6-dihydro-4H-cyclopenta [b] furylene, 5,6-dihydro-4H-cyclopenta [b] thienylene or 1,4,5,6-tetrahydrocyclopenta [b] pyrrolylene group,
Y is preferably an indoleylene group.

In the above formula, the “C ₁ -C ₈ alkylene group” in the definition of X represents a linear or branched C ₁ -C ₈ alkylene group, such as methylene, ethylene, propylene, butylene, Pentylene, hexylene, heptylene, octylene, isopropylene, s-butylene, t-butylene, 3,3-dimethylpropylene, 4,4-dimethylbutylene group, etc., preferably methylene, ethylene, propylene group.

In the above formula, the “C ₁ -C ₈ alkylene group having an oxygen atom or sulfur atom in the chain” in the definition of X is, for example, — (CH ₂ ) _m1 O (CH ₂ ) _m2 —, — (CH ₂ ) _m1 S (CH ₂ ) _{m 2} −, — (CH ₂ ) _{m 1} CO (CH ₂ ) _{m 2} —, — (CH ₂ ) _{m 1} SO (CH ₂ ) _{m 2} —, — (CH ₂ ) _{m 1} SO ₂ (CH _{2 M2} −; (m1 and m2 represent an integer of 0 to 7, provided that the sum of m1 and m2 represents 0 to 7), preferably —CH ₂ OCH ₂ —, —CH ₂ SCH _{2 -, - OCH 2 -,} - SCH 2 -, - CH 2 O- or _-CH 2 is S-.

In the above formula, the “C ₁ -C ₈ alkyl group” in the definition of Z represents a linear or branched C ₁ -C ₈ alkyl group, for example, methyl, ethyl, propyl, butyl, Examples include pentyl, hexyl, heptyl, octyl, isopropyl, s-butyl, t-butyl, 3,3-dimethylpropyl, 4,4-dimethylbutyl groups, and preferably methylene, ethylene, and propylene groups.

In the above formula, the “C ₁ -C ₈ alkyl group having an oxygen atom or sulfur atom in the chain” in the definition of Z is, for example, H (CH ₂ ) _m1 O (CH ₂ ) _m2 —, H (CH ₂ ) _m1 S (CH ₂ ) _{m 2-} , H (CH ₂ ) _{m 1} CO (CH ₂ ) _{m 2-} , H (CH ₂ ) _{m 1} SO (CH ₂ ) _{m 2-} , H (CH ₂ ) _{m 1} SO ₂ (CH _{2 M2-} (m1 and m2 represent an integer of 0 to 7, provided that the sum of m1 and m2 represents 0 to 7), and is preferably a methoxymethyl, methylthiomethyl, methoxy or methylthio group .

In the above formula, “C ₃ -C ₇ cycloalkyl group” in the definition of Z and substituent group A is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a cycloheptyl group.

In the above formula, the “C ₆ -C ₁₀ arylene group” in the definition of X and Y can be, for example, a phenylene group, an indenylene group, or a naphthylene group, and is preferably a phenylene group.

In the above formula, the “C ₆ -C ₁₀ aryl group” in the definition of Z and substituent group A can be, for example, a phenyl group, an indenyl group, or a naphthyl group, and is preferably a phenyl group.

In the above formula, the “C ₆ -C ₁₀ aryloxy group” in the definition of Z and substituent group A can be, for example, a phenyloxy group, an indenyloxy group, a naphthyloxy group, It is an oxy group.

In the above formula, the “C ₆ -C ₁₀ arylthio group” in the definition of Z can be, for example, a phenylthio group, an indenylthio group, or a naphthylthio group, and is preferably a phenylthio group.

In the above formula, the “C ₆ -C ₁₀ aralkyl group” in the definition of Z can be, for example, a benzyl group, an indenylmethyl group, or a naphthylmethyl group, and is preferably a benzyl group.

In the above formula, the “C ₆ -C ₁₀ arylcarbonyl group” in the definition of Z can be, for example, a benzoyl group, an indenylcarbonyl group, or a naphthylcarbonyl group, and preferably a benzoyl group.

In the above formula, the “halogen atom” in the definition of the substituent group A is a fluorine atom, a chlorine atom, a bromine or an iodine atom.
In the above formula, the “C ₁ -C ₆ alkyl group” in the definition of the substituent group A is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t -It may be a butyl group, a pentyl group, an isopentyl group, or a hexyl group, and preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, or an isobutyl group.

In the above formula, the “halogeno C ₁ -C ₆ alkyl group” in the definition of the substituent group A is a group in which a halogen atom is substituted on the C ₁ -C ₆ alkyl group as much as possible. For example, fluoromethyl Group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, difluoroethyl group, trifluoroethyl group, fluoropropyl group, difluoropropyl group, trifluoropropyl group, fluorobutyl group, difluorobutyl group, trifluorobutyl group, Fluoropentyl group, difluoropentyl group, trifluoropentyl group, fluorohexyl group, difluorohexyl group, trifluorohexyl group, pentafluoroethyl group, hexafluoropropyl group, nonafluorobutyl group, chloromethyl group, dichloromethyl group, trichloro Methyl group, chloroe Group, dichloroethyl group, trichloroethyl group, chloropropyl group, dichloropropyl group, trichloropropyl group, chlorobutyl group, dichlorobutyl group, trichlorobutyl group, chloropentyl group, dichloropentyl group, trichloropentyl group, chlorohexyl group, It can be a dichlorohexyl group, a trichlorohexyl group, a pentachloroethyl group, a hexachloropropyl group, a nonachlorobutyl group, preferably a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a difluoroethyl group, A trifluoroethyl group, a fluoropropyl group, a difluoropropyl group or a trifluoropropyl group, and more preferably a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a difluoroethyl group. Or trifluoroethyl group.
In the above formula, the “C ₁ -C ₆ alkoxy group” in the definition of the substituent group A is a group in which an oxygen atom is bonded to the C ₁ -C ₆ alkyl group, preferably a methoxy group, ethoxy Group, propoxy group, isopropoxy group and butoxy group, more preferably methoxy group and ethoxy group.

In the above formula, the “C ₁ -C ₆ alkylthio group” in the definition of the substituent group A is a group in which a sulfur atom is bonded to the C ₁ -C ₆ alkyl group, and preferably a methylthio group, ethylthio Group, propylthio group, isopropylthio group and butylthio group, more preferably methylthio group and ethylthio group.

In the above formula, the “C ₁ -C ₆ alkylcarboxy group” in the definition of the substituent group A is a group in which a carboxyl group is bonded to the C ₁ -C ₆ alkyl group, preferably a methyl carboxyl group. Ethyl carboxyl group, propyl carboxyl group, isopropyl carboxyl group and butyl carboxyl group, more preferably methyl carboxyl group and ethyl carboxyl group.

In the above formula, the “C ₁ -C ₆ aliphatic acyl group” in the definition of the substituent group A is a group in which a carbonyl group is bonded to the C ₁ -C ₆ alkyl group. A carbonyl group, a propylcarbonyl group, a butylcarbonyl group, a pentylcarbonyl group, and a hexylcarbonyl group can be used, and an acetyl group, an ethylcarbonyl group, and a propylcarbonyl group are preferable.

In the above formula, the “C ₁ -C ₆ monoalkylamino group” in the definition of the substituent group A is a group in which an amino group is bonded to the C ₁ -C ₆ alkyl group. A methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, and a butylamino group are preferable, and a methylamino group and an ethylamino group are more preferable.

In the above formula, the “C ₁ -C ₆ dialkylamino group” in the definition of the substituent group A is a group in which one amino group is bonded to the two C ₁ -C ₆ alkyl groups. Are a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, and a dibutylamino group, and more preferably a dimethylamino group and a diethylamino group.

In the above formula, the “C ₁ -C ₆ aliphatic acylamino group” in the definition of the substituent group A means that a carbonyl group is bonded to the C ₁ -C ₆ alkyl group, and further, an amino group is bonded to the carbonyl group. A bonded group, for example, an acetylamino group, an ethylcarbonylamino group, a propylcarbonylamino group, a butylcarbonylamino group, a pentylcarbonylamino group, a hexylcarbonylamino group, preferably an acetylamino group, an ethylcarbonyl group An amino group and a propylcarbonylamino group.

The compound having the general formula (I) is preferably a compound having the general formula (I ′) or a compound having the general formula (I ″).

  In the compound having the general formula (I), A is preferably a carboxyl group.

  B is preferably a hydrogen atom.

  n is preferably 0.

  V is preferably a methylene group.

  W is preferably a 5- to 7-membered heterocyclic group which may be substituted with 1 to 3 groups selected from Substituent Group A, and more preferably selected from Substituent Group A. Thienylene, furylene, pyrrolene or pyridylene group which may be substituted by 1 to 3 groups, and more preferably, thienylene which may be substituted by 1 or 2 groups selected from substituent group A Or it is a pyridylene group.

As X, _preferably, C 1 -C ₈ alkylene group, _C 1 -C ₈ alkylene group having an oxygen atom or a sulfur atom in the _chain, C 6 _{-C 10} arylene group, 5-membered ring or 7-membered heterocyclic ring A group or a condensed heterocyclic group, and more preferably a 5-membered to 7-membered heterocyclic group.

  Y is preferably a group selected from a phenylene group, a 5-membered to 7-membered heterocyclic group which may be substituted by 1 to 3 groups selected from substituent group A, and substituent group A. Any one group selected from the group consisting of 1 to 3 optionally substituted condensed heterocyclic groups, and more preferably 1 to 3 groups selected from a phenylene group and a substituent group A; A thienylene, pyridylene or indylene group which may be substituted three is more preferable, and a phenylene or pyridylene group is more preferable.

Z is preferably a C ₆ -C ₁₀ aryloxy group which may be substituted with 1 to 5 groups selected from the substituent group A, and more preferably a phenoxy group.

In the compound having the general formula (I ′) of the present invention, R ¹ is preferably a hydrogen atom.

R ² is preferably a hydrogen atom, a methyl group or an ethyl group.

R ³ is preferably a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group.
R ⁴ is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a methyl group or a methoxy group.

R ⁵ is preferably a hydrogen atom or a fluorine atom.

In the compound having the general formula (I ″) of the present invention, R ⁶ is preferably a hydrogen atom, a methyl group or an ethyl group.

R ⁷ is preferably a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group.

R ⁸ is preferably an n-propyl group, an n-butyl group or an iso-butyl group.

In the above, “the pharmacologically acceptable salt” means that when the compound having the general formula (I) has an acidic group or a basic group, it is reacted with a base or an acid to react with a basic salt or an acidic salt. The salt is shown.

  The pharmacologically acceptable “basic salt” of the compound having the general formula (I) is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkali such as magnesium salt or calcium salt. Earth metal salts; organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt Alternatively, it is an amino acid salt such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartate, and preferably an alkali metal salt.

  The pharmacologically acceptable “acid salt” of the compound having the general formula (I) is preferably a halogenated salt such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide. Inorganic acid salts such as hydrogenates, nitrates, perchlorates, sulfates, phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonic acid Salts, aryl sulfonates such as p-toluenesulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleic acid Organic acid salts such as salts; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartate, and most preferably hydrohalide salt.

  The “pharmacologically acceptable prodrug” in the above is a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, hydrolyzed. Or the like, or a compound that is changed to compound (I) by hydrolysis with gastric acid or the like.

  As the prodrug, when a carboxyl group is present in the compound (I), a compound in which the carboxyl group is esterified or amidated (for example, the carboxyl group of the compound (I) is ethyl esterified or phenyl esterified). Carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl ) Methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compounds, etc.).

  These compounds can be produced from compound (I) by a known method.

  In addition, the prodrug of the compound of the present invention is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. Is also included.

  When the compound having the general formula (I) is left in the air or recrystallized, it may absorb water, and adsorbed water or hydrate may be formed. Japanese products are also included.

The compound having the general formula (I) includes those labeled with an isotope element (eg, ³ H, ¹⁴ C, ³⁵ S, etc.).

  When the compound having the general formula (I) has an asymmetric carbon atom in the molecule, optical isomers exist. In this compound, all optical isomers and mixtures of optical isomers are represented by a single formula. Therefore, the present compound includes all optical isomers and mixtures containing optical isomers in an arbitrary ratio.

Preferable specific examples of the compound having the general formula (I) include, for example, the general formulas (I-1), (I-2), and (I′−) described in the following Table 1, Table 2, Table 3, and Table 4. Although it is a compound which has 1) or (I ''-1), it is not limited to these compounds.

The abbreviations in the table are as follows, and the dotted line (---) indicates a single bond or a double bond, and is uniquely determined by the type of substituent atom.
n Linear i Isoc CycloMe Methyl group MeO Methoxy group Et Ethyl group Bn Benzyl group Bu Butyl group Hex Hexyl group Ph Phenyl group (Table 1)

Compound No. R J K L U V
---------------------------------
1-1 n-Bu N N O S CH
1-2 i-Bu N N O S CH
1-3 c-Hex N N O S CH
1-4 PhO N N O S CH
1-5 Bn N N O S CH
1-6 n-Bu N N O O CH
1-7 i-Bu N N O O CH
1-8 c-Hex N N O O CH
1-9 PhO N N O O CH
1-10 Bn N N O O CH
1-11 n-Bu N N O NMe CH
1-12 i-Bu N N O NMe CH
1-13 c-Hex N N O NMe CH
1-14 PhO N N O NMe CH
1-15 Bn N N O NMe CH
1-16 n-Bu N N O N —CH═CH—
1-17 i-Bu N N O N —CH═CH—
1-18 c-Hex N N O N —CH═CH—
1-19 PhO N N O N —CH═CH—
1-20 BnNNON-CH = CH-
1-21 n-BuNNOCH-N = CH-
1-22 i-BuNNOCH-N = CH-
1-23 c-Hex N N O CH —N═CH—
1-24 PhO N N O CH —N═CH—
1-25 BnNNOCH-N = CH-
1-26 n-Bu N N O CH S
1-27 i-Bu N N O CH S
1-28 c-Hex N N O CH S
1-29 PhO N N O CH S
1-30 Bn N N O CH S
1-31 n-Bu N N O CH O
1-32 i-Bu N N O CH O
1-33 c-Hex N N O CH O
1-34 PhO N N O CH O
1-35 Bn N N O CH O
1-36 n-Bu N N O CH NMe
1-37 i-Bu N N O CH NMe
1-38 c-Hex N N O CH NMe
1-39 PhO N N O CH NMe
1-40 Bn N N O CH NMe
1-41 n-Bu CH N O S CH
1-42 i-Bu CH N O S CH
1-43 c-Hex CH N O S CH
1-44 PhO CH N O S CH
1-45 Bn CH N O S CH
1-46 n-Bu CH N O O CH
1-47 i-Bu CH N O O CH
1-48 c-Hex CH N O O CH
1-49 PhO CH N O O CH
1-50 Bn CH N O O CH
1-51 n-Bu CH N O NMe CH
1-52 i-Bu CH N O NMe CH
1-53 c-Hex CH N O NMe CH
1-54 PhO CH N O NMe CH
1-55 Bn CH N O NMe CH
1-56 n-Bu CHNON-CH = CH-
1-57 i-Bu CHNON-CH = CH-
1-58 c-Hex CHNON-CH = CH-
1-59 PhO CH N O N —CH═CH—
1-60 Bn CHNON-CH = CH-
1-61 n-Bu CH N O CH —N═CH—
1-62 i-Bu CH N O CH —N═CH—
1-63 c-Hex CH N O CH —N═CH—
1-64 PhO CH N O CH —N═CH—
1-65 Bn CH N O CH —N═CH—
1-66 n-Bu CH N O CH S
1-67 i-Bu CH N O CH S
1-68 c-Hex CH N O CH S
1-69 PhO CH N O CH S
1-70 Bn CH N O CH S
1-71 n-Bu CH N O CH O
1-72 i-Bu CH N O CH O
1-73 c-Hex CH N O CH O
1-74 PhO CH N O CH O
1-75 Bn CH N O CH O
1-76 n-Bu CH N O CH NMe
1-77 i-Bu CH N O CH NMe
1-78 c-Hex CH N O CH NMe
1-79 PhO CH N O CH NMe
1-80 Bn CH N O CH NMe
1-81 n-Bu N ON S CH
1-82 i-Bu N ON S CH
1-83 c-Hex N ON S CH
1-84 PhO N O N S CH
1-85 Bn N ON S CH
1-86 n-Bu N O N O CH
1-87 i-Bu N O N O CH
1-88 c-Hex N O N O CH
1-89 PhO N O N O CH
1-90 Bn N O N O CH
1-91 n-Bu N ON NMe CH
1-92 i-Bu N ON NMe CH
1-93 c-Hex N ON NMe CH
1-94 PhO N O N NMe CH
1-95 Bn N O N NMe CH
1-96 n-BuNONN-CH = CH-
1-97 i-BuNONN-CH = CH-
1-98 c-Hex N O N N —CH═CH—
1-99 PhO N O N N —CH═CH—
1-100 BnNONN-CH = CH-
1-101 n-BuNONCH-N = CH-
1-102 i-BuNONCH-N = CH-
1-103 c-Hex N ON CH-N = CH-
1-104 PhO N O N CH —N═CH—
1-105 BnNONCH-N = CH-
1-106 n-Bu N ON CH S
1-107 i-Bu N ON CH S
1-108 c-Hex N ON CH S
1-109 PhO N ON CH S
1-110 Bn N ON CH S
1-111 n-Bu N O N CH O
1-112 i-Bu N O N CH O
1-113 c-Hex N O N CH O
1-114 PhO N O N CH O
1-115 Bn N O N CH O
1-116 n-Bu N ON CH NMe
1-117 i-Bu N ON CH NMe
1-118 c-Hex N ON CH NMe
1-119 PhO N ON CH NMe
1-120 Bn N ON CH NMe
1-121 n-Bu CH ON S CH
1-122 i-Bu CH ON S CH
1-123 c-Hex CH ON S CH
1-124 PhO CH ONSCH
1-125 Bn CH O N S CH
1-126 n-Bu CH O N O CH
1-127 i-Bu CH O N O CH
1-128 c-Hex CH O N O CH
1-129 PhO CH O N O CH
1-130 Bn CH O N O CH
1-131 n-Bu CH ON NMe CH
1-132 i-Bu CH ON NMe CH
1-133 c-Hex CH ON NMe CH
1-134 PhO CH ON NMe CH
1-135 Bn CH ON NMe CH
1-136 n-Bu CH 2 O N N —CH═CH—
1-137 i-Bu CHONN-CH = CH-
1-138 c-Hex CHONN-CH = CH-
1-139 PhO CH ON N —CH═CH—
1-140 Bn CH 2 O N N —CH═CH—
1-141 n-Bu CH ON CH-N = CH-
1-142 i-Bu CH ON CH-N = CH-
1-143 c-Hex CH ON CH-N = CH-
1-144 PhO CH ON CH-N = CH-
1-145 Bn CH ON CH-N = CH-
1-146 n-Bu CH ON CH S
1-147 i-Bu CH ON CH S
1-148 c-Hex CH ON CH S
1-149 PhO CH ON CH S
1-150 Bn CH ON CH S
1-151 n-Bu CH 2 O 2 CH 2 O
1-152 i-Bu CH 2 O 2 CH 2 O
1-153 c-Hex CH 2 O 2 CH 2 O
1-154 PhO CH O N CH O
1-155 Bn CH O N CH O
1-156 n-Bu CH ON CH NMe
1-157 i-Bu CH ON CH NMe
1-158 c-Hex CH ON CH NMe
1-159 PhO CH ON CH NMe
1-160 Bn CH O N CH NMe
---------------------------------
In the table, as preferred compounds, Exemplified Compound No. 1-3: 1-({4- [3- (4-cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -2-thienyl} methyl) azetidine -3-carboxylic acid,
Exemplified compound number 1-8: 1-({4- [3- (4-cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -2-furyl} methyl) azetidine-3-carboxylic acid,
Exemplified compound number 1-17: 1-({5- [3- (4-isobutylphenyl) -1,2,4-oxadiazol-5-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid,
Illustrative compound number 1-22: 1-({6- [3- (4-isobutylphenyl) -1,2,4-oxadiazol-5-yl] pyridin-3-yl} methyl) azetidine-3-carboxylic acid,
Illustrative compound number 1-28: 1-({5- [3- (4-cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
Exemplified compound number 1-33: 1-({5- [3- (4-cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -2-furyl} methyl) azetidine-3-carboxylic acid,
Exemplified Compound No. 1-43: 1-({4- [3- (4-cyclohexylphenyl) isoxazol-5-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
Exemplified compound number 1-48: 1-({4- [3- (4-cyclohexylphenyl) isoxazol-5-yl] -2-furyl} methyl) azetidine-3-carboxylic acid,
Exemplified compound number 1-57: 1-({5- [3- (4-isobutylphenyl) isoxazol-5-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid,
Exemplified compound number 1-62: 1-({6- [3- (4-isobutylphenyl) isoxazol-5-yl] pyridin-3-yl} methyl) azetidine-3-carboxylic acid,
Exemplified Compound No. 1-68: 1-({5- [3- (4-cyclohexylphenyl) isoxazol-5-yl] 2-thienyl} methyl) azetidine-3-carboxylic acid,
Exemplified compound number 1-73: 1-({5- [3- (4-cyclohexylphenyl) isoxazol-5-yl] 2-furyl} methyl) azetidine-3-carboxylic acid,
Illustrative compound number 1-82: 1-({4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] 2-thienyl} methyl) azetidine-3-carboxylic acid,
Illustrative compound number 1-83: 1-({4- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] 2-thienyl} methyl) azetidine-3-carboxylic acid,
Exemplary Compound No. 1-84: 1-({4- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] 2-thienyl} methyl) azetidine-3-carboxylic acid,
Exemplified Compound No. 1-88: 1-({4- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] 2-furyl} methyl) azetidine-3-carboxylic acid,
Illustrative compound number 1-97: 1-({5- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid,
Exemplified compound number 1-102: 1-({6- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-3-yl} methyl) azetidine-3-carboxylic acid,
Exemplified compound number 1-107: 1-({5- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
Illustrative compound number 1-108: 1-({5- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
Exemplified Compound No. 1-109: 1-({5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
Exemplified Compound No. 1-113: 1-({5- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} methyl) azetidine-3-carboxylic acid,
Exemplified compound number 1-122: 1-({4- [5- (4-isobutylphenyl) isoxazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
Illustrative compound number 1-123: 1-({4- [5- (4-cyclohexylphenyl) isoxazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
Exemplified compound number 1-124: 1-({4- [5- (4-phenoxyphenyl) isoxazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
Exemplified compound number 1-128: 1-({4- [5- (4-cyclohexylphenyl) isoxazol-3-yl] -2-furyl} methyl) azetidine-3-carboxylic acid,
Exemplified compound number 1-137: 1-({5- [5- (4-isobutylphenyl) isoxazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid,
Illustrative compound number 1-142: 1-({6- [5- (4-isobutylphenyl) isoxazol-3-yl] pyridin-3-yl} methyl) azetidine-3-carboxylic acid,
Exemplified compound number 1-147: 1-({5- [5- (4-isobutylphenyl) isoxazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
Illustrative compound number 1-148: 1-({5- [5- (4-cyclohexylphenyl) isoxazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
Exemplary Compound No. 1-149: 1-({5- [5- (4-phenoxyphenyl) isoxazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid and Exemplary Compound No. 1-153: 1 -({5- [5- (4-cyclohexylphenyl) isoxazol-3-yl] -2-furyl} methyl) azetidine-3-carboxylic acid can be mentioned, and particularly preferably, Exemplified Compound No. 1-83 1-84, 1-88, 1-97, 1-102, 1-108, 1-109, 1-113, 1-123, 1-124, 1-137, 1-142 and 1-148. I can do things.

(Table 2)

Compound No. R J K L U V m
--------------------------------
2-1 n-Bu N N O S CH 2
2-2 i-Bu N N O S CH 2
2-3 c-Hex N N O S CH 2
2-4 PhO N N O S CH 2
2-5 BnNNOSCH2
2-6 n-Bu N N O S CH 3
2-7 i-Bu N N O S CH 3
2-8 c-Hex N N O S CH 3
2-9 PhO N N O S CH 3
2-10 Bn N N O S CH 3
2-11 n-Bu N N O O CH 2
2-12 i-Bu N N O O CH 2
2-13 c-Hex N N O O CH 2
2-14 PhO N N O O CH 2
2-15 Bn N N O O CH 2
2-16 n-Bu N N O O CH 3
2-17 i-Bu N N O O CH 3
2-18 c-Hex N N O O CH 3
2-19 PhO N N O O CH 3
2-20 Bn N N O O CH 3
2-21 n-Bu N N O NMe CH 2
2-22 i-Bu N N O NMe CH 2
2-23 c-Hex N N O NMe CH 2
2-24 PhO N N O NMe CH 2
2-25 Bn N N O NMe CH 2
2-26 n-Bu N N O NMe CH 3
2-27 i-Bu N N O NMe CH 3
2-28 c-Hex N N O NMe CH 3
2-29 PhO N N O NMe CH 3
2-30 Bn N N O NMe CH 3
2-31 n-Bu N N O CH S 2
2-32 i-Bu N N O CH S 2
2-33 c-Hex N N O CH S 2
2-34 PhO N N O CH S 2
2-35 Bn N N O CH S 2
2-36 n-Bu N N O CH S 3
2-37 i-Bu N N O CH S 3
2-38 c-Hex N N O CH S 3
2-39 PhO N N O CH S 3
2-40 Bn N N O CH S 3
2-41 n-Bu N N O CH O 2
2-42 i-Bu N N O CH O 2
2-43 c-Hex N N O CH O 2
2-44 PhO N N O CH O 2
2-45 Bn N N O CH O 2
2-46 n-Bu N N O CH O 3
2-47 i-Bu N N O CH O 3
2-48 c-Hex N N O CH O 3
2-49 PhO N N O CH O 3
2-50 Bn N N O CH O 3
2-51 n-Bu N N O CH NMe 2
2-52 i-Bu N N O CH NMe 2
2-53 c-Hex N N O CH NMe 2
2-54 PhO N N O CH NMe 2
2-55 Bn N N O CH NMe 2
2-56 n-Bu N N O CH NMe 3
2-57 i-Bu N N O CH NMe 3
2-58 c-Hex N N O CH NMe 3
2-59 PhO N N O CH NMe 3
2-60 Bn N N O CH NMe 3
2-61 n-Bu CH N O S CH 2
2-62 i-Bu CH N O S CH 2
2-63 c-Hex CH N O S CH 2
2-64 PhO CH N O S CH 2
2-65 Bn CH N O S CH 2
2-66 n-Bu CH N O S CH 3
2-67 i-Bu CH N O S CH 3
2-68 c-Hex CH N O S CH 3
2-69 PhO CH N O S CH 3
2-70 Bn CH N O S CH 3
2-71 n-Bu CH N O O CH 2
2-72 i-Bu CH N O O CH 2
2-73 c-Hex CH N O O CH 2
2-74 PhO CH N O O CH 2
2-75 Bn CH N O O CH 2
2-76 n-Bu CH N O O CH 3
2-77 i-Bu CH N O O CH 3
2-78 c-Hex CH N O O CH 3
2-79 PhO CH N O O CH 3
2-80 Bn CH N O O CH 3
2-81 n-Bu CH N O NMe CH 2
2-82 i-Bu CH N O NMe CH 2
2-83 c-Hex CH N O NMe CH 2
2-84 PhO CH N O NMe CH 2
2-85 Bn CH N O NMe CH 2
2-86 n-Bu CH N O NMe CH 3
2-87 i-Bu CH N O NMe CH 3
2-88 c-Hex CH N O NMe CH 3
2-89 PhO CH N O NMe CH 3
2-90 Bn CH N O NMe CH 3
2-91 n-Bu CH N O CH S 2
2-92 i-Bu CH N O CH S 2
2-93 c-Hex CH N O CH S 2
2-94 PhO CH N O CH S 2
2-95 Bn CH N O CH S 2
2-96 n-Bu CH N O CH S 3
2-97 i-Bu CH N O CH S 3
2-98 c-Hex CH N O CH S 3
2-99 PhO CH N O CH S 3
2-100 Bn CH N O CH S 3
2-101 n-Bu CH N O CH O 2
2-102 i-Bu CH N O CH O 2
2-103 c-Hex CH N O CH O 2
2-104 PhO CH N O CH O 2
2-105 Bn CH N O CH O 2
2-106 n-Bu CH N O CH O 3
2-107 i-Bu CH N O CH O 3
2-108 c-Hex CH N O CH O 3
2-109 PhO CH N O CH O 3
2-110 Bn CH N O CH O 3
2-111 n-Bu CH N O CH NMe 2
2-112 i-Bu CH N O CH NMe 2
2-113 c-Hex CH N O CH NMe 2
2-114 PhO CH N O CH NMe 2
2-115 Bn CH N O CH NMe 2
2-116 n-Bu CH N O CH NMe 3
2-117 i-Bu CH N O CH NMe 3
2-118 c-Hex CH N O CH NMe 3
2-119 PhO CH N O CH NMe 3
2-120 Bn CH N O CH NMe 3
2-121 n-Bu N ON S CH 2
2-122 i-Bu N ON S CH 2
2-123 c-Hex N ON S CH 2
2-124 PhO N ON S CH 2
2-125 Bn N ON S CH 2
2-126 n-Bu N ON S CH 3
2-127 i-Bu N ON S CH 3
2-128 c-Hex N ON S CH 3
2-129 PhO N O N S CH 3
2-130 Bn N ON S CH 3
2-131 n-Bu N O N O CH 2
2-132 i-Bu N O N O CH 2
2-133 c-Hex N O N O CH 2
2-134 PhO N O N O CH 2
2-135 Bn N O N O CH 2
2-136 n-Bu N O N O CH 3
2-137 i-Bu N O N O CH 3
2-138 c-Hex N O N O CH 3
2-139 PhO N O N O CH 3
2-140 Bn N O N O CH 3
2-141 n-Bu N ON NMe CH 2
2-142 i-Bu N ON NMe CH 2
2-143 c-Hex N ON NMe CH 2
2-144 PhO N O N NMe CH 2
2-145 Bn N O N NMe CH 2
2-146 n-Bu N ON NMe CH 3
2-147 i-Bu N ON NMe CH 3
2-148 c-Hex N ON NMe CH 3
2-149 PhO N O N NMe CH 3
2-150 Bn N O N NMe CH 3
2-151 n-Bu N ON CH S 2
2-152 i-BuNONCHS2
2-153 c-Hex N ON CH S 2
2-154 PhO N ON CH S 2
2-155 Bn N ON CH S 2
2-156 n-Bu N ON CH S 3
2-157 i-Bu N ON CH S 3
2-158 c-Hex N ON CH S 3
2-159 PhO N ON CH S 3
2-160 Bn N ON CH S 3
2-161 n-Bu N O N CH O 2
2-162 i-Bu N O N CH O 2
2-163 c-Hex N O N CH O 2
2-164 PhO N O N CH O 2
2-165 Bn N O N CH O 2
2-166 n-Bu N O N CH O 3
2-167 i-Bu N O N CH O 3
2-168 c-Hex N O N CH O 3
2-169 PhO N O N CH O 3
2-170 Bn N O N CH O 3
2-171 n-Bu N ON CH NMe 2
2-172 i-Bu N ON CH NMe 2
2-173 c-Hex N ON CH NMe 2
2-174 PhO N ON CH NMe 2
2-175 Bn N ON CH NMe 2
2-176 n-Bu N ON CH NMe 3
2-177 i-Bu N ON CH NMe 3
2-178 c-Hex N ON CH NMe 3
2-179 PhO N ON CH NMe 3
2-180 Bn N ON CH NMe 3
2-181 n-Bu CH 2 ON S CH 2
2-182 i-Bu CH 2 ON S CH 2
2-183 c-Hex CH 2 ON S CH 2
2-184 PhO CH ON S CH 2
2-185 Bn CH ON S CH 2
2-186 n-Bu CH ON S CH 3
2-187 i-Bu CH ON S CH 3
2-188 c-Hex CH ON S CH 3
2-189 PhO CH ON NS CH 3
2-190 Bn CH ON NS CH 3
2-191 n-Bu CH 2 O 2 O 2 CH 2
2-192 i-Bu CH 2 O 2 N 2 CH 2
2-193 c-Hex CH 2 O 2 O 2 CH 2
2-194 PhO CH O N O CH 2
2-195 Bn CH 2 O 2 O 2 CH 2
2-196 n-Bu CH 2 O 2 O 3 CH 3
2-197 i-Bu CH 2 N 2 O 3 CH 3
2-198 c-Hex CH O N O CH 3
2-199 PhO CH O N O CH 3
2-200 Bn CH O N O CH 3
2-201 n-Bu CH ON NMe CH 2
2-202 i-Bu CH ON NMe CH 2
2-203 c-Hex CH ON NMe CH 2
2-204 PhO CH ON NMe CH 2
2-205 Bn CH ON NMe CH 2
2-206 n-Bu CH ON NMe CH 3
2-207 i-Bu CH ON NMe CH 3
2-208 c-Hex CH ON NMe CH 3
2-209 PhO CH ON NMe CH 3
2-210 Bn CH ON NMe CH 3
2-211 n-Bu CH ON CH S 2
2-212 i-Bu CH ON CH S 2
2-213 c-Hex CH ON CH S 2
2-214 PhO CH ON CH S 2
2-215 Bn CH ON CH S 2
2-216 n-Bu CH ON CH S 3
2-217 i-Bu CH ON CH S 3
2-218 c-Hex CH ON CH S 3
2-219 PhO CH ON CH S 3
2-220 Bn CH ON CH S 3
2-221 n-Bu CH 2 O 2 CH 2
2-222 i-Bu CH 2 O 2 CH 2
2-223 c-Hex CH 2 O 2 CH 2
2-224 PhO CH 2 O 2 CH 2
2-225 Bn CH 2 O 2 CH 2
2-226 n-Bu CH 2 O 2 CH 2 O 3
2-227 i-Bu CH 2 O 2 CH 2 O 3
2-228 c-Hex CH 2 O 2 CH 2 O 3
2-229 PhO CH O N CH O 3
2-230 Bn CH O N CH O 3
2-231 n-Bu CH 2 ON CH NMe 2
2-232 i-Bu CH ON CH NMe 2
2-233 c-Hex CH ON CH NMe 2
2-234 PhO CH ON CH NMe 2
2-235 Bn CH O N CH NMe 2
2-236 n-Bu CH ON CH NMe 3
2-237 i-Bu CH ON CH NMe 3
2-238 c-Hex CH ON CH NMe 3
2-239 PhO CH ON CH NMe 3
2-240 Bn CH ON CH NMe 3
--------------------------------
In the table, as a suitable compound,
Illustrative compound number 2-33: 1- {2- [3- (4-cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -5,6-dihydro-4H-cyclopenta [b] thien-4 -Yl} azetidine-3-carboxylic acid,
Illustrative compound number 2-38: 1- {2- [3- (4-cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -4,5,6,7-tetrahydro-1-benzothien-4 -Yl} azetidine-3-carboxylic acid,
Illustrative compound number 2-43: 1- {2- [3- (4-cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -5,6-dihydro-4H-cyclopenta [b] furan-4 -Yl} azetidine-3-carboxylic acid,
Illustrative compound number 2-48: 1- {2- [3- (4-cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -4,5,6,7-tetrahydro-1-benzofuran-4 -Yl} azetidine-3-carboxylic acid,
Illustrative compound number 2-93: 1- {2- [3- (4-cyclohexylphenyl) isoxazol-5-yl] -5,6-dihydro-4H-cyclopenta [b] thien-4-yl} azetidine-3- carboxylic acid,
Illustrative compound number 2-98: 1- {2- [3- (4-cyclohexylphenyl) isoxazol-5-yl] -4,5,6,7-tetrahydro-1-benzothien-4-yl} azetidine-3- carboxylic acid,
Illustrative compound number 2-103: 1- {2- [3- (4-cyclohexylphenyl) isoxazol-5-yl] -5,6-dihydro-4H-cyclopenta [b] furan-4-yl} azetidine-3- carboxylic acid,
Illustrative compound number 2-108: 1- {2- [3- (4-cyclohexylphenyl) isoxazol-5-yl] -4,5,6,7-tetrahydro-1-benzofuran-4-yl} azetidine-3- carboxylic acid,
Illustrative compound number 2-153: 1- {2- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -5,6-dihydro-4H-cyclopenta [b] thien-4 -Yl} azetidine-3-carboxylic acid,
Illustrative compound number 2-158: 1- {2- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -4,5,6,7-tetrahydro-1-benzothien-4 -Yl} azetidine-3-carboxylic acid,
Illustrative compound number 2-163: 1- {2- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -5,6-dihydro-4H-cyclopenta [b] furan-4 -Yl} azetidine-3-carboxylic acid,
Illustrative compound number 2-168: 1- {2- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -4,5,6,7-tetrahydro-1-benzofuran-4 -Yl} azetidine-3-carboxylic acid,
Illustrative compound number 2-213: 1- {2- [5- (4-cyclohexylphenyl) isoxazol-3-yl] -5,6-dihydro-4H-cyclopenta [b] thien-4-yl} azetidine-3- carboxylic acid,
Illustrative compound number 2-218: 1- {2- [5- (4-cyclohexylphenyl) isoxazol-3-yl] -4,5,6,7-tetrahydro-1-benzothien-4-yl} azetidine-3- carboxylic acid,
Illustrative compound number 2-223: 1- {2- [5- (4-cyclohexylphenyl) isoxazol-3-yl] -5,6-dihydro-4H-cyclopenta [b] furan-4-yl} azetidine-3- Carboxylic acid and exemplified compound number 2-228: 1- {2- [5- (4-cyclohexylphenyl) isoxazol-3-yl] -4,5,6,7-tetrahydro-1-benzofuran-4-yl} azetidine Examples of compound numbers 2-43, 2-48, 2-103, 2-108, 2-163, 2-168, 2-223, and 2- 228.
(Table 3)

Compound No. R ¹ R ² R ³ R ⁴ R ⁵
----------------------------
3-1 H H H H H
3-2 H H H H F
3-3 H H F H H
3-4 H H F H F
3-5 H H Cl H H
3-6 H H Cl H F
3-7 H H H MeO H
3-8 H H H MeO F
3-9 H H F MeO H
3-10 H H F MeO F
3-11 H H Cl MeO H
3-12 H H Cl MeO F
3-13 H H H F H
3-14 H H H F F
3-15 H H F F H
3-16 H H F F F
3-17 H H Cl F H
3-18 H H Cl F F
3-19 H H H Cl H
3-20 H H H Cl F
3-21 H H F Cl H
3-22 H H F Cl F
3-23 H H Cl Cl H
3-24 H H Cl Cl F
3-25 H Me H H H
3-26 H Me H H F
3-27 H Me F H H
3-28 H Me F H F
3-29 H Me Cl H H
3-30 H Me Cl H F
3-31 H Me H MeO H
3-32 H Me H MeOF
3-33 H Me F MeO H
3-34 H Me F MeO F
3-35 H Me Cl MeO H
3-36 H Me Cl MeO F
3-37 H Me H F H
3-38 H Me H F F
3-39 H Me F F H
3-40 H Me FF F
3-41 H Me Cl F H
3-42 H Me Cl FF
3-43 H Me H Cl H
3-44 H Me H Cl F
3-45 H Me F Cl H
3-46 H Me F Cl F
3-47 H Me Cl Cl H
3-48 H Me Cl Cl F
3-49 H Et H H H
3-50 H Et H H F
3-51 H Et F H H
3-52 H Et F H F
3-53 H Et Cl H H
3-54 H Et Cl H F
3-55 H Et H MeO H
3-56 H Et H MeO F
3-57 H Et F MeO H
3-58 H Et F MeO F
3-59 H Et Cl MeO H
3-60 H Et Cl MeO F
3-61 H Et H F H
3-62 H Et H F F
3-63 H Et F F H
3-64 H Et F F F
3-65 H Et Cl F H
3-66 H Et Cl FF
3-67 H Et H Cl H
3-68 H Et H Cl F
3-69 H Et F Cl H
3-70 H Et F Cl F
3-71 H Et Cl Cl H
3-72 H Et Cl Cl F
3-73 Me H H H H
3-74 Me H H H F
3-75 Me H F H H
3-76 Me H F H F
3-77 Me H Cl H H
3-78 Me H Cl H F
3-79 Me H H MeO H
3-80 Me H H MeO F
3-81 Me H F MeO H
3-82 Me H F MeO F
3-83 Me H Cl MeO H
3-84 Me H Cl MeO F
3-85 Me H H F H
3-86 Me H H F F
3-87 Me H F F H
3-88 Me H F F F
3-89 Me H Cl F H
3-90 Me H Cl F F
3-91 Me H H Cl H
3-92 Me H H Cl F
3-93 Me H F Cl H
3-94 Me H F Cl F
3-95 Me H Cl Cl H
3-96 Me H Cl Cl F
3-97 Et H H H H
3-98 Et H H H F
3-99 Et H F H H
3-100 Et H F H F
3-101 Et H Cl H H
3-102 Et H Cl H F
3-103 Et H H MeO H
3-104 Et H H MeO F
3-105 Et H F MeO H
3-106 Et H F MeO F
3-107 Et H Cl MeO H
3-108 Et H Cl MeO F
3-109 Et H H F H
3-110 Et H H F F
3-111 Et H F F H
3-112 Et H F F F
3-113 Et H Cl F H
3-114 Et H Cl F F
3-115 Et H H Cl H
3-116 Et H H Cl F
3-117 Et H F Cl H
3-118 Et H F Cl F
3-119 Et H Cl Cl H
3-120 Et H Cl Cl F
----------------------------
In the table, as a suitable compound,
Exemplified compound number 3-1: 1-({5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid Example 5),
Exemplified Compound No. 3-25: 1-({4-Methyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3- Carboxylic acid (Example 12),
Exemplified compound number 3-27: 1-({5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-methyl-2-thienyl} methyl) Azetidine-3-carboxylic acid (Example 11),
Exemplified compound number 3-49: 1-({4-ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3- Carboxylic acid (Example 13),
Exemplified compound number 3-50: 1-[(4-ethyl-5- {5- [4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl Azetidine-3-carboxylic acid (Example 17),
Illustrative compound number 3-51: 1-({4-ethyl-5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) Azetidine-3-carboxylic acid (Example 14),
Exemplary compound number 3-52: 1-[(4-ethyl-5- {5- [3-fluoro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2 -Thienyl) methyl] azetidine-3-carboxylic acid (Example 20),
Exemplified compound number 3-53: 1-[(4-ethyl-5- {5- [4- (2-methoxyphenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl Azetidine-3-carboxylic acid (Example 15),
Exemplified compound number 3-54: 1-[(5- {5- [3-chloro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2 -Thienyl) methyl] azetidine-3-carboxylic acid (Example 16),
Exemplified compound number 3-55: 1-[(4-ethyl-5- {5- [4- (2-methoxyphenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl Azetidine-3-carboxylic acid (Example 21),
Exemplary compound number 3-61: 1-[(4-ethyl-5- {5- [4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl Azetidine-3-carboxylic acid (Example 10),
Illustrative compound number 3-62: 1-[(5- {5- [4- (2,3-difluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl ) Methyl] azetidine-3-carboxylic acid (Example 18),
Illustrative compound number 3-63: 1-[(4-ethyl-5- {5- [3-fluoro-4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2 -Thienyl) methyl] azetidine-3-carboxylic acid,
Illustrative compound number 3-64: 1-[(5- {5- [4- (2,3-difluorophenoxy) -3-fluorophenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl -2-thienyl) methyl] azetidine-3-carboxylic acid,
Exemplified compound number 3-65: 1-[(5- {5- [3-chloro-4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2 -Thienyl) methyl] azetidine-3-carboxylic acid,
Illustrative compound number 3-66: 1-[(5- {5- [3-chloro-4- (2,3-difluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl -2-thienyl) methyl] azetidine-3-carboxylic acid,
Exemplified compound number 3-67: 1-[(5- {5- [4- (2-chlorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl Azetidine-3-carboxylic acid (Example 19),
Illustrative compound number 3-69: 1-[(5- {5- [4- (2-chlorophenoxy) -3-fluorophenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2 -Thienyl) methyl] azetidine-3-carboxylic acid,
Illustrative compound number 3-73: 1-({3-methyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3- Carboxylic acid and exemplified compound number 3-97: 1-({3-ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine -3-carboxylic acid (Example 22)
Particularly preferred are Exemplified Compound Nos. 3-25, 3-27, 3-49, 3-50, 3-51, 3-52, 3-53, 3-54, 3-55, 3-61, 3-67.

(Table 4)

Compound No. R ⁶ R ⁷ R ⁸
------------------------
4-1 H H Pr
4-2 H H Bu
4-3 H H iBu
4-4 H Me Pr
4-5 H Me Bu
4-6 H Me iBu
4-7 H F Pr
4-8 H F Bu
4-9 H F iBu
4-10 H Cl Pr
4-11 H Cl Bu
4-12 H Cl iBu
4-13 H CF ₃ Pr
4-14 H CF ₃ Bu
4-15 H CF ₃ iBu
4-16 Me H Pr
4-17 Me H Bu
4-18 Me H iBu
4-19 Me Me Pr
4-20 Me Me Bu
4-21 Me Me iBu
4-22 Me F Pr
4-23 Me F Bu
4-24 Me FiBu
4-25 Me Cl Pr
4-26 Me Cl Bu
4-27 Me Cl iBu
4-28 Me CF ₃ Pr
4-29 Me CF ₃ Bu
4-30 Me CF ₃ iBu
4-31 Et H Pr
4-32 Et H Bu
4-33 Et H iBu
4-34 Et Me Pr
4-35 Et Me Bu
4-36 Et Me iBu
4-37 Et F Pr
4-38 Et F Bu
4-39 Et FiBu
4-40 Et Cl Pr
4-41 Et Cl Bu
4-42 Et Cl iBu
4-43 Et CF ₃ Pr
4-44 Et CF ₃ Bu
4-45 Et CF ₃ iBu
------------------------
In the table, as a suitable compound,
Exemplified compound number 4-6: 1-({5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3 A carboxylic acid (Example 28),
Illustrative compound number 4-9: 1-({5- [5- (3-fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3 A carboxylic acid (Example 23),
Exemplary Compound No. 4-12: 1-({5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3 A carboxylic acid (Example 26),
Exemplary compound number 4-21: 1-({5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl ) Azetidine-3-carboxylic acid (Example 27),
Exemplified Compound No. 4-22: 1-({5- [5- (3-Fluoro-4-propylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl ) Azetidine-3-carboxylic acid Exemplified Compound No. 4-23: 1-({5- [5- (4-Butyl-3-fluorophenyl) -1,2,4-oxadiazol-3-yl] -6-methyl Pyridin-2-yl} methyl) azetidine-3-carboxylic acid Exemplified Compound No. 4-24: 1-({5- [5- (3-Fluoro-4-isobutylphenyl) -1,2,4-oxadiazole-3 -Yl] -6-methylpyridin-2-yl} methyl) azetidine-3-carboxylic acid Exemplified Compound No. 4-27: 1-({5- [5- (3-chloro-4-isobutylphenyl) -1, 2,4-oxadiazole -3-yl] -6-methylpyridin-2-yl} methyl) azetidine-3-carboxylic acid (Example 24),
Exemplified compound number 4-36: 1-({6-ethyl-5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl ) Azetidine-3-carboxylic acid (Example 29),
Exemplified compound number 4-37: 1-({6-ethyl-5- [5- (3-fluoro-4-propylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl ) Azetidine-3-carboxylic acid Exemplified Compound No. 4-38: 1-({5- [5- (4-Butyl-3-fluorophenyl) -1,2,4-oxadiazol-3-yl] -6-ethyl Pyridin-2-yl} methyl) azetidine-3-carboxylic acid Illustrative compound number 4-39: 1-({6-ethyl-5- [5- (3-fluoro-4-isobutylphenyl) -1,2,4 -Oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid (Example 30) and Exemplified Compound No. 4-42: 1-({5- [5- (3-Chloro-4- Isobutylphenyl) -1,2, 4-oxadiazol-3-yl] -6-ethylpyridin-2-yl} methyl) azetidine-3-carboxylic acid (Example 25)
In particular, exemplary compound numbers 4-6, 4-9, 4-12, 4-21, 4-27, 4-36 and 4-42 can be mentioned.

  Since the pharmaceutical composition of the present invention has an excellent immunosuppressive effect and weak toxicity, it is useful as a prophylactic or therapeutic agent (especially therapeutic agent) for diseases related to the immunosuppressive effect on mammals (especially humans). It is.

  The compound having the general formula (I) can be produced according to the method described below.

  The following production methods were usually performed according to known methods. Known methods include, for example, Organic Functional Group PREPARATIONS, 2nd edition, Academic Press, Inc., 1989, Comprehensive Organic Transformation (Comprehensive Organic Transformation). Inc. , 1989, etc.

  Method A is a method for producing a compound having the general formula (I).

  Method A

In the above formula, A, B, V, W, X, Y, Z and n are as defined above,
LG represents a group known as a leaving group in the field of synthetic organic chemistry, and is, for example, a halogen atom or a group represented by the general formula —O—S (O) ₂ ^RC , preferably a chlorine atom Bromine atom, iodine atom, methanesulfonyloxy group, p-toluenesulfonyloxy group.

Here, R ^C is a methoxy group, a C ₁ -C ₆ alkyl group optionally substituted with 1 to 3 halogen atoms, or 1 to 3 groups selected from the group consisting of a halogen atom and a methyl group. The phenyl group which may be substituted by is shown.

AP represents a group in which the functional group represented by the definition of A is protected in a form considered appropriate in organic synthetic chemistry. Examples of the protecting group P include “Protective Groups in Organic Synthesis third edition” (edited Green). , TW; Wuts, PGM, John Wiley & Sons, 1999) and the like,
When A is a carboxyl group, P, which is a protecting group thereof, is preferably a lower alkyl group such as a methyl group, an ethyl group, or a propyl group, and particularly preferably an ethyl group.

  When A is a phospho group, the protecting group P is preferably a lower alkyl group such as a methyl group or an ethyl group; an allyl group or a 2,2,2-trichloroethyl group, An allyl group is preferred.

  When A is a sulfo group, its protecting group P is preferably a phenyl group, a p-methoxyphenyl group, or a p-nitrophenyl group, and particularly preferably a phenyl group.

  When A is a 1H-tetrazol-5-yl group, the protecting group P is preferably a triphenylmethyl group, p-methoxyphenyldiphenylmethyl group, di (p-methoxyphenyl) phenylmethyl. And particularly preferably a triphenylmethyl group.

Step A1 Step A1 is a step for producing a compound having the general formula (III) by converting the hydroxyl group of the compound having the general formula (II) into a leaving group.

  This step is carried out by allowing a halogenating agent to act on the compound having the general formula (II) in a solvent or by allowing a sulfonylating agent to act. Preferably, the halogenating agent is allowed to act. It is.

  Examples of the halogenating agent include phosphorus trihalides such as phosphorus trichloride and phosphorus tribromide; phosphines such as triarylphosphine including triphenylphosphine and tri-lower alkylphosphine such as tributylphosphine; In addition, halogens such as bromine and iodine, or combinations of halogen equivalents such as carbon tetrachloride, carbon tetrabromide, and hexachloroacetone can be used. Triarylphosphines and halogen equivalents are preferred. Particularly preferred is a combination of triphenylphosphine and carbon tetrabromide.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; tetrahydrofuran, 1,2-dimethoxyethane, etc. Of ethers. Preferred are halogenated hydrocarbons, and particularly preferred is dichloromethane.

  The reaction temperature is usually -23 ° C to 60 ° C, preferably 0 ° C to 30 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 3 hours, preferably 30 minutes to 1 hour.

  After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, and then the reaction solution is extracted with an organic solvent immiscible with water such as toluene, washed with water, etc. The target compound is obtained by concentrating the organic layer containing the compound under reduced pressure and distilling off the solvent.

  If necessary, the obtained target compound can be obtained by a conventional method such as recrystallization, reprecipitation or a method commonly used for separation and purification of ordinary organic compounds (for example, silica gel, alumina, magnesium-silica gel-based Florisil, etc. Adsorption column chromatography using a carrier, a carrier such as Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical) Column chromatography, ion exchange chromatography, or normal / reverse phase column chromatography using silica gel or alkylated silica gel, preferably silica gel column chromatography).

Step A2 Step A2 is a step for producing a compound having the general formula (V) by substituting the leaving group LG of the compound having the general formula (III) with a compound having the general formula (IV).

  This step is performed in a solvent in the presence of a base.

  Examples of the base include trialkylamines such as triethylamine, N, N-diisopropylethylamine, and tributylamine; pyridines such as pyridine, lutidine, and collidine; carbonates such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate. Alkali metal salts are exemplified, and trialkylamines are preferable, and N, N-diisopropylethylamine is particularly preferable.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; diethyl ether, tetrahydrofuran, 1,2- Mention may be made of ethers such as dimethoxyethane and dioxane. Preferred are halogenated hydrocarbons, and particularly preferred is dichloromethane.

  The reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 3 hours, preferably 30 minutes to 2 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step A3 Step A3 is a process for producing a compound having the general formula (I) by performing a deprotection reaction on the substituent AP of the compound having the general formula (V).

  In this step, in the substituent AP in which the substituent A is protected, the deprotection conditions differ depending on the protecting group used. For example, the substituent A is a carboxyl group, and the substituent AP is a lower alkyl ester. The general manufacturing method when it is a base is described below.

  This step is performed in a water-containing solvent in the presence of a base.

  Examples of the base used include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; lithium methoxide, sodium methoxide In addition, metal alkoxides such as sodium ethoxide can be mentioned, and alkali metal hydroxides are preferable, and lithium hydroxide is particularly preferable.

  The solvent to be used is not particularly limited as long as it is inert to the reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane; methanol, ethanol, isopropanol, t- Examples include alcohols such as butanol; water; a mixed solvent of water and the above solvent. Preferable is a mixed solvent of ethers, alcohols and water, and particularly preferable is a mixed solvent of tetrahydrofuran, methanol and water.

  The reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 3 hours, preferably 30 minutes to 2 hours.

  Further, even when the substituent is not specifically described in this step, for example, “Protective Groups in Organic Synthesis Third Edition” (edited Green, TW; Wuts, PGM, John). This step can be performed according to the method described in Wiley & Sons, 1999).

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

The method for producing the compound having the general formula (II) used in the method A differs depending on the type of the substituent X. For example, the general method for the case where the substituent X is an oxadiazole ring and an isoxazole ring is used. A typical method will be described below.

Method B is a method for producing a compound having the general formula (II-1), which is a compound having the general formula (II) when the substituent X is an oxadiazole ring.

  Method B

In the above formula, V, W, Y and Z are as defined above,
LG is as defined above or represents a hydroxyl group,
P represents a hydroxyl-protecting group. Here, the protecting group for a hydroxyl group is described in, for example, “Protective Groups in Organic Synthesis Third Edition” (edited Green, TW; Wuts, PGM, John Wiley & Sons, 1999). Preferably a trialkylsilyl group such as triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group; methoxymethyl group, tetrahydropyranyl group, 2- ( Substituted methyl ether groups such as trimethylsilyl) ethoxymethyl group; acyl groups such as acetyl group, benzoyl group and pivaloyl group can be mentioned, and trialkylsilyl groups are preferred, and particularly preferred t-Butyldimethylsilyl group.

Step B1 Step B1 is a step for producing a compound having the general formula (VII) by carrying out addition reaction of hydroxyamine to the compound having the general formula (VI).

  This step is carried out by allowing hydroxyamine or a hydroxyamine equivalent to act on the compound having the general formula (VI) in a solvent.

  Hydroxylamine equivalents include hydroxyamine solutions such as hydroxyamine aqueous solution, hydroxyamine-methanol mixed solution, hydroxyamine-ethanol mixed solution; hydroxyamines such as hydroxyamine hydrochloride, hydroxyamine phosphate, hydroxyamine sulfate, etc. A combination of a salt and a tri-lower alkylamine such as triethylamine, N, N-diisopropylethylamine, or tributylamine, or an alkali metal carbonate such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate can be given. Are preferably hydroxyamine solutions, and particularly preferably an aqueous hydroxyamine solution.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; tetrahydrofuran, 1,2-dimethoxyethane, etc. And ethers such as methanol, ethanol, isopropanol, and t-butanol. Among them, alcohols are preferable, and ethanol is particularly preferable.

  The reaction temperature is 0 ° C. to 80 ° C., preferably 30 ° C. to 60 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 min to 5 hr, preferably 30 min to 2 hr.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step B2 Step B2 is a process for producing a compound having the general formula (IX) by reacting a compound having the general formula (VII) with a compound having the general formula (VIII).

  (1) In the compound having the general formula (VIII), the production method will be described below for the case where the substituent LG is a hydroxyl group, and (2) in the compound having the general formula (VIII), where the substituent LG is other than a hydroxyl group.

(1) In the compound having the general formula (VIII), when the substituent LG is a hydroxyl group This step has the general formula (VIII) in the presence of a condensing agent for the compound having the general formula (VII) in the solvent. This is done by reacting the compound.

  Examples of the condensing agent used include carbodiimides such as N, N′-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide, 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide (WSCI); BOP [Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate], HBTU [O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluro O-benzotriazoles such as, but not limited to, nitrohexafluorophosphate], HATU [O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium hexafluorophosphate]. Are carbodiimides, particularly preferably N, N′-dicyclo A hexyl carbodiimide.

The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; tetrahydrofuran, 1,2-dimethoxyethane And ethers such as benzene, toluene, xylene and the like. Preferred are halogenated hydrocarbons, and particularly preferred is dichloromethane.
The reaction temperature is −20 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C.
While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 min to 5 hr, preferably 30 min to 2 hr.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

(2) When the substituent LG is other than a hydroxyl group in the compound having the general formula (VIII) In this step, the general formula (XIII) is added to the compound having the general formula (VII) in an inert solvent in the presence of a base. It is carried out by reacting a compound having

  The substituent LG is preferably a chlorine atom.

  Examples of the base to be used include trialkylamines such as triethylamine, N, N-diisopropylethylamine, and tributylamine; pyridines such as pyridine, lutidine, collidine, and the like, preferably trialkylamines, Particularly preferred is N, N-diisopropylethylamine.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; diethyl ether, tetrahydrofuran, 1,2- Examples include ethers such as dimethoxyethane; benzenes such as benzene, toluene, and xylene. Preferred are halogenated hydrocarbons, and particularly preferred is dichloromethane.

  The reaction temperature is −20 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 min to 5 hr, preferably 30 min to 2 hr.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step B3 Step B3 is a process for producing a compound having the general formula (X) from a compound having the general formula (IX).

  This step is performed by allowing a base to act on the compound having the general formula (IX) in a solvent.

  Examples of the base used include tetra-lower alkylammonium fluorides such as tetrabutylammonium fluoride, benzyltrimethylammonium fluoride, and benzyltriethylammonium fluoride; tri-lower amines such as triethylamine, N, N-diisopropylethylamine, and tributylamine. Alkylamines; pyridines such as pyridine, lutidine, collidine; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, and the like. Preferred are tetra-lower alkyl ammonium fluorides. Particularly preferred is tetrabutylammonium fluoride.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane; dichloromethane, chloroform, 1,2-dichloroethane and the like Halogenated hydrocarbons: Amides such as dimethylformamide and dimethylacetamide can be mentioned, and ethers are preferred, and tetrahydrofuran is particularly preferred.

  The reaction temperature is usually 0 ° C. to 80 ° C., preferably 30 ° C. to 60 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 min to 5 hr, preferably 30 min to 2 hr.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step B4 Step B4 is a process for producing a compound having the general formula (II-1) by deprotecting the hydroxyl-protecting group P of the compound having the general formula (X).

  The method for deprotecting the protecting group P varies depending on the type of the protecting group, but is usually “Protective Groups in Organic Synthesis Third Edition” (edited Green, TW; Wuts, PGM, John Wiley & Sons). , 1999) and the like.

  Here, a general production method in the case where the protecting group is a trialkylsilyl group will be described below. This step is performed by allowing a fluorine anion equivalent to act on the compound having the general formula (X) in a solvent.

  Fluorine anion equivalents used include, for example, tetraalkylammonium fluorides such as tetrabutylammonium fluoride and benzyltrimethyl fluoride; hydrogen fluoride-triethylamine complex, hydrogen fluoride such as hydrogen fluoride-pyridine complex Examples of the amine complex include tetraalkylammonium fluorides, and tetrabutylammonium fluoride is particularly preferable.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane; dichloromethane, chloroform, 1,2-dichloroethane and the like Halogenated hydrocarbons: Amides such as dimethylformamide and dimethylacetamide can be mentioned, and ethers are preferred, and tetrahydrofuran is particularly preferred.

  The reaction temperature is usually 0 ° C. to 80 ° C., preferably 30 ° C. to 60 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 min to 5 hr, preferably 30 min to 2 hr.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Method C is a method for producing a compound having the general formula (II-2), which is a compound having the general formula (II) when the substituent X is an isoxazole ring.

  Method C

In the above formula, V, P, W, Y and Z are as defined above,
Hal represents a halogen atom.

Step C1 Step C1 is a process for producing a compound having the general formula (XII) by converting a formyl group of a compound having the general formula (XI) into a dihalovinyl group.

  This step is performed by allowing a gem-dihalomethylene agent to act on the compound having the general formula (XI) in a solvent.

  Examples of gem-dihalomethylene agents used include phosphines such as triarylphosphine including triphenylphosphine and tri-lower alkylphosphine such as tributylphosphine, carbon tetrachloride, carbon tetrabromide, carbon tetraiodide. A combination of tetrahalogenated carbons such as: diethyl (trichloromethyl) phosphonate, diethyl (tribromomethyl) phosphonate, dimethyl (trichloromethyl) phosphonate, di-lower alkyl (trihalogenated) such as dimethyl (tribromomethyl) phosphonate Examples include combinations of methyl) phosphonates and alkyllithiums such as methyllithium, n-butyllithium, s-butyllithium, and t-butyllithium. Preferred are triarylphosphines and tetrahalogenated compounds. A combination of Motorui, particularly preferably a combination of triphenylphosphine and carbon tetrabromide.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; diethyl ether, tetrahydrofuran, 1,2- Mention may be made of ethers such as dimethoxyethane and dioxane. Preferred are ethers, and particularly preferred is tetrahydrofuran.

  The reaction temperature is -23 ° C to 60 ° C, preferably 0 ° C to 30 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 min to 5 hr, preferably 30 min to 3 hr.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step C2 Step C2 is a process for producing a compound having the general formula (XIII) by converting a dihalovinyl group in a compound having the general formula (XII) with an ethynyl group.

  This step is performed by allowing an alkyl metal to act on compound (XII) in a solvent.

  Examples of the alkyl metal used include alkyl lithiums such as methyl lithium, n-butyl lithium, s-butyl lithium and t-butyl lithium; alkyl sodiums such as methyl sodium, butyl sodium and s-butyl sodium. However, alkyl lithiums are preferable, and n-butyl lithium is particularly preferable.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and dioxane; benzene such as benzene, toluene and xylene Preferred are ethers, and particularly preferred is tetrahydrofuran.

  The reaction temperature is −100 ° C. to 0 ° C., preferably −78 ° C. to −45 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 2 hours, preferably 30 minutes to 1 hour.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step C3 Step C3 is a process for producing a compound having the general formula (XV) by reacting a compound having the general formula (XIII) with a compound having the general formula (XIV).

This step is performed by allowing a base to act on both compounds in a solvent.
In addition, about the compound which has general formula (XIV), literature J.M. Org. Chem 1980, 45, 3916 to the literature Acta. Chemica. Scandinavica, 1987, item 426 describes the general production method, and can be easily synthesized from known compounds.

  Examples of the base to be used include trialkylamines such as triethylamine, N, N-diisopropylethylamine and tributylamine; pyridines such as pyridine, lutidine and collidine; Particularly preferred is triethylamine.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane; ethyl acetate, propyl acetate, butyl acetate Esters such as: halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane and the like, and esters are preferred, and ethyl acetate is particularly preferred.

  The reaction temperature is -20 ° C to 80 ° C, preferably 0 ° C to 40 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 5 to 72 hours, preferably 24 to 48 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step C4 Step C4 is a process for producing a compound having the general formula (II-2) by deprotecting the hydroxyl-protecting group P of the compound having the general formula (XV).

  This step can be performed by the same method as the above-mentioned Method B, Step B4.

The method for producing the compound having the general formula (VI) used in Method B varies depending on the type of the substituent W. For example, the production method when the substituent W is a thiophene ring or a furan ring is Method D, A method for producing a condensed structure such as a 1,7-tetrahydrobenzothiophene ring or a 4,5,6,7-tetrahydrobenzofuran ring is described below as E method.

Method D Method D is a method for producing a compound having the general formula (VI-1), which is a compound having the general formula (VI) when the substituent W is a thiophene ring or a furan ring.

  In the above formula, Hal represents a halogen atom as described above, preferably a bromine atom or an iodine atom, Q represents an oxygen atom or a sulfur atom, and P represents a hydroxyl protecting group as described above. .

Step D1 Step D1 is a process for producing a compound having the general formula (XVII) by converting a formyl group of a compound having the general formula (XVI) into a hydroxymethyl group.
This step is performed by allowing a reducing agent to act on the compound having the general formula (XVI) in a solvent. In addition, many of the compounds having the general formula (XVI) which are starting materials are commercially available, can be easily obtained, and can be easily synthesized by known methods.

  Examples of the reducing agent used include aluminum hydrides such as lithium aluminum hydride, sodium aluminum hydride and diisobutylaluminum hydride; borohydrides such as lithium borohydride, sodium borohydride and borane. However, borohydrides are preferred, and sodium borohydride is particularly preferred.

  The solvent to be used is not particularly limited as long as it is inert to the reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and dioxane; alcohols such as methanol, ethanol and isopropanol Preferred are alcohols, and particularly preferred is methanol.

  The reaction temperature is −23 ° C. to 50 ° C., preferably 0 ° C. to 30 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 2 hours, preferably 30 minutes to 1 hour.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step D2 Step D2 is a process for producing a compound having the general formula (XVIII) by protecting the hydroxy group of the compound having the general formula (XVII) with an appropriate protecting group for a hydroxyl group. The protecting group to be used is not particularly limited as long as it does not affect the reaction in a later step and can be easily deprotected, but is preferably a trialkylsilane. A general production method when trialkylsilanes are used as protecting groups is described below.

  This step is performed by allowing a silylating agent to act on the compound having the general formula (XVII) in a solvent in the presence of a suitable base.

  The silylating agents used are, for example, trialkylsilyl chlorides such as triethylsilyl chloride, t-butyldimethylsilyl chloride, triisopropylsilyl chloride, t-butyldiphenylsilyl chloride; triethylsilyl trifluoromethanesulfonate, t-butyl Examples thereof include trialkylsilyl trifluoromethanesulfonates such as dimethylsilyltrifluoromethanesulfonate, triisopropylsilyltrifluoromethanesulfonate, and t-butyldiphenylsilyltrifluoromethanesulfonate. Trialkylsilyl chlorides are preferred. Particularly preferred is t-butyldimethylsilyl chloride.

  Examples of the base used include trialkylamines such as triethylamine and N, N-diisopropylethylamine; imidazoles such as imidazole and 2-methylimidazole; and pyridines such as pyridine, lutidine and collidine. Is an imidazole, particularly preferably imidazole.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane; dichloromethane, 1,2-dichloroethane, Halogenated hydrocarbons such as chloroform; amides such as N, N-dimethylformamide and N, N-dimethylacetamide can be mentioned, and amides are preferable, and N, N- Dimethylformamide.

  The reaction temperature is −23 ° C. to 50 ° C., preferably 0 ° C. to 30 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 30 minutes to 4 hours, preferably 1 to 3 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step D3 Step D3 is a process for producing a compound having the general formula (VI-1) by converting a halogen atom of a compound having the general formula (XVIII) into a nitrile group.

  In this step, a method of directly converting a halogen atom of a compound having the general formula (XVIII) into a nitrile group (Step D3a), a compound having a formyl group (XI-1), an oximation reaction and It can be carried out by two methods, ie, a method of converting to a nitrile group via a dehydration reaction (Step D3b). Each process is described below.

Step D3a Step D3a is a process for producing a compound having the general formula (VI-1) by converting a halogen atom of a compound having the general formula (XVIII) into a nitrile group.
This step is achieved by allowing a suitable nitrating agent to act on the compound having the general formula (XVIII) in a solvent.

  Nitrilating agents used include, for example, copper compounds such as copper cyanide; palladium catalysts such as tetrakistriphenylphosphine palladium and dichlorobistriphenylphosphine palladium and cyanide such as zinc cyanide, trimethylsilyl cyanide and tributyltin cyanide. Although combinations with metals can be mentioned, copper cyanide or a combination of tetrakistriphenylphosphine palladium and zinc cyanide is preferable, and copper cyanide is particularly preferable.

  The solvent to be used is not particularly limited as long as it is inert to the reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane; N, N-dimethylformamide, N , N-dimethylacetamide and the like, and amides are preferable, and N, N-dimethylformamide is particularly preferable.

  The reaction temperature is 20 ° C. to 180 ° C., preferably 100 ° C. to 140 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 2 hours to 12 hours, preferably 3 hours to 10 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step D3b Step D3b-1 Step D3b-1 is a step for producing a compound having the general formula (XI-1) by converting a halogen atom of a compound having the general formula (XVIII) into a formyl group.

  This step is also used as a general production method of the compound having the general formula (XI) used as a raw material for the above-mentioned Method C.

  This step can be achieved by subjecting the compound having the general formula (XVIII) to a halogen-metal exchange in a solvent and then applying an appropriate formylating agent.

  Examples of the metallizing agent to be used include metal simple substances such as metal lithium, metal magnesium and metal zinc; alkyllithiums such as n-butyllithium, s-butyllithium and t-butyllithium. Alkyl lithiums are preferable, and n-butyl lithium is particularly preferable.

  Examples of the formylating agent used include formic acid amides such as N, N-dimethylformamide, N-methylformanilide, and N-formylpiperidine; formic acid esters such as methyl formate, ethyl formate, and propyl formate. Are formic amides, particularly preferably N, N-dimethylformamide.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and dioxane; aromatic carbonization such as toluene and xylene Hydrogen can be mentioned, and ethers are preferred, and tetrahydrofuran is particularly preferred.

  The reaction temperature is −100 ° C. to 0 ° C., preferably −78 ° C. to −45 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 2 hours, preferably 30 minutes to 1 hour.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step D3b-2 Step D3b-2 is a process for producing a compound having the general formula (XIX) by converting a formyl group of a compound having the general formula (XI-1) into an oxime group.

  This step is performed by allowing hydroxyamine or a hydroxyamine equivalent to act on the compound having the general formula (XI-1) in a solvent.

  Hydroxylamine equivalents are hydroxyamine solutions such as hydroxyamine aqueous solution, hydroxyamine-methanol mixed solution, hydroxyamine-ethanol mixed solution; hydroxyamines such as hydroxyamine hydrochloride, hydroxyamine phosphate, hydroxyamine sulfate, etc. A combination of a salt and a tri-lower alkylamine such as triethylamine, N, N-diisopropylethylamine, or tributylamine, or an alkali metal carbonate such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate can be given. Is preferably a combination of hydroxyamine salts and tri-lower alkylamines, and particularly preferably a combination of hydroxyamine hydrochloride and triethylamine.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; tetrahydrofuran, 1,2-dimethoxyethane, etc. Among these, halogenated hydrocarbons are preferable, and dichloromethane is particularly preferable.

  The reaction temperature is 0 ° C. to 80 ° C., preferably 20 ° C. to 60 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 30 min to 5 hr, preferably 1 hr to 3 hr.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step D3b-3 Step D3b-3 is a process for producing a compound having the general formula (VI-1) by converting an oxime group of a compound having the general formula (XIX) into a nitrile group.

  This step is achieved by allowing a suitable dehydrating agent to act on the compound having the general formula (XIX) in a solvent.

  Examples of dehydrating agents used include carbodiimides such as N, N′-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide, 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide (WSCI); diphosphorus pentoxide , Phosphorus compounds such as phosphorus oxychloride; thionyl chloride and the like, and carbodiimides are preferable, and N, N′-dicyclohexylcarbodiimide is particularly preferable.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; tetrahydrofuran, 1,2-dimethoxyethane, Examples include ethers such as dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene. Among them, aromatic hydrocarbons are preferable, and toluene is particularly preferable.

  The reaction temperature is 20 ° C to 150 ° C, preferably 60 ° C to 110 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 2 to 24 hours, preferably 6 to 12 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Method E Method E represents the general formula (VI) when the substituent W has a condensed structure such as a 4,5,6,7-tetrahydrobenzothiophene ring to a 4,5,6,7-tetrahydrobenzofuran ring. This is a method for producing a compound having the general formula (VI-2).

  In the above formula, P and Q are as defined above, and m is an integer of 1 to 2.

Step E1 Step E1 is a process for the preparation of a compound having the general formula (XXI) by converting a carbonyl group of a compound having the general formula (XX) into a hydroxy group.

  This step is performed by allowing an appropriate reducing agent to act on the compound having the general formula (XX) in a solvent. Further, among the compounds having the general formula (XX) as a starting material, a compound having m = 2 is commercially available and can be easily obtained. Also, compounds in which m is 1 are described in the literature J. Am. Chem. Soc. It is possible to synthesize in accordance with the production method described in 2005, 127, No. 10, pages 3248-3249.

  Examples of the reducing agent used include aluminum hydrides such as lithium aluminum hydride, sodium aluminum hydride and diisobutylaluminum hydride; borohydrides such as lithium borohydride, sodium borohydride and borane. However, borohydrides are preferred, and sodium borohydride is particularly preferred.

  The solvent to be used is not particularly limited as long as it is inert to the reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and dioxane; alcohols such as methanol, ethanol and isopropanol Preferred are alcohols, and particularly preferred is methanol.

  The reaction temperature is −23 ° C. to 50 ° C., preferably 0 ° C. to 30 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 2 hours, preferably 30 minutes to 1 hour.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step E2 Step E2 is a process for the preparation of a compound having the general formula (XXII) by protecting the hydroxy group of a compound having the general formula (XXI) with an appropriate hydroxyl-protecting group. The hydroxyl-protecting group used is not particularly limited as long as it does not affect the reaction in the subsequent step and can be easily deprotected, but is preferably a trialkylsilane. A general production method when trialkylsilanes are used as protecting groups is described below.

  This step is performed by allowing a silylating agent to act on the compound having the general formula (XXI) in a solvent in the presence of a suitable base.

  The silylating agents used are, for example, trialkylsilyl chlorides such as triethylsilyl chloride, t-butyldimethylsilyl chloride, triisopropylsilyl chloride, t-butyldiphenylsilyl chloride; triethylsilyl trifluoromethanesulfonate, t-butyl Examples thereof include trialkylsilyl trifluoromethanesulfonates such as dimethylsilyltrifluoromethanesulfonate, triisopropylsilyltrifluoromethanesulfonate, and t-butyldiphenylsilyltrifluoromethanesulfonate. Trialkylsilyl chlorides are preferred. Especially preferred is t-butyldiphenylsilyl chloride.

  Examples of the base used include trialkylamines such as triethylamine and N, N-diisopropylethylamine; imidazoles such as imidazole and 2-methylimidazole; and pyridines such as pyridine, lutidine and collidine. Is an imidazole, particularly preferably imidazole.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane; dichloromethane, 1,2-dichloroethane, Halogenated hydrocarbons such as chloroform; amides such as N, N-dimethylformamide and N, N-dimethylacetamide can be mentioned, and amides are preferable, and N, N- Dimethylformamide.

  The reaction temperature is −23 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 30 minutes to 4 hours, preferably 1 to 3 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step E3 Step E3 is a process for the preparation of a compound having the general formula (XXIII) by introducing a formyl group into a compound having the general formula (XXII).

  This step is achieved by allowing a strong base to act on the compound having the general formula (XXII) in a solvent and then allowing an appropriate formylating agent to act.

  Examples of the strong base used include alkyllithiums such as n-butyllithium, s-butyllithium, t-butyllithium; lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyl Alkali metal amides such as disilazide can be mentioned, and alkyllithiums are preferable, and n-butyllithium is particularly preferable.

  Examples of the formylating agent used include formic acid amides such as N, N-dimethylformamide, N-methylformanilide, and N-formylpiperidine; formic acid esters such as methyl formate, ethyl formate, and propyl formate. Are formic amides, particularly preferably N, N-dimethylformamide.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and dioxane; aromatic carbonization such as toluene and xylene Hydrogen can be mentioned, and ethers are preferred, and tetrahydrofuran is particularly preferred.

  The reaction temperature is −100 ° C. to 0 ° C., preferably −78 ° C. to 0 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 4 hours, preferably 1 hour to 3 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step E4 Step E4 is a process for the preparation of a compound having the general formula (XXIV) by converting a formyl group of a compound having the general formula (XXIII) into an oxime group.

  This step is carried out by allowing hydroxyamine or a hydroxyamine equivalent to act on the compound having the general formula (XXIII) in a solvent, and can be carried out in the same manner as in the above-mentioned Method D, Step D3b-2.

Step E5 Step E5 is a process for the preparation of a compound having the general formula (VI-2) by converting an oxime group of a compound having the general formula (XXIV) into a nitrile group.
This step is carried out by allowing a suitable dehydrating agent to act on the compound having the general formula (XXIV) in a solvent, and can be carried out in the same manner as in the above Method D, Step D3b-2.

Method F Method F is a method for producing a compound having the general formula (VI-3), which is the general formula (VI) when the substituent W is a thiophene ring or a furan ring and has an alkyl group as the substituent R. is there.

In the above formula, Hal represents a halogen atom as described above, preferably a bromine atom or an iodine atom, Q represents an oxygen atom or a sulfur atom, and P represents a hydroxyl protecting group as described above. , R ^d represents a C ₁ -C ₆ alkyl group.

Step F1 Step F1 is a process for producing a compound having the general formula (XXVI) by converting a halogen atom of a compound having the general formula (XXV) into an alkyl group.
This step is performed by allowing an alkylating agent to act on the compound having the general formula (XXV) in a solvent. Many of the compounds having the general formula (XXV) as a starting material can be synthesized by the above-described method D.

  The alkylating agents used are, for example, 1,3-bis (diphenylphosphino) propanedichloronickel, bis (triphenylphosphine) dichloronickel, [1,1′-bis (diphenylphosphino) ferrocene] dichloronickel. Nickel catalysts in combination with Grignard reagents such as alkylmagnesium chloride, alkylmagnesium bromide, alkylmagnesium iodide; palladium catalysts such as tetrakistriphenylphosphine palladium, dichlorobis (triphenylphosphine) palladium and monoalkylborates Examples thereof include combinations with alkylboric acids such as acids, monoalkylborates, dialkylborates, and dialkylborates. A combination of a Yaru reagents, particularly preferably a combination of 1,3-bis (diphenylphosphino) propane dichloronickel and an alkylmagnesium bromide.

  The solvent to be used is not particularly limited as long as it is inert to the reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane; benzene, toluene, xylene, etc. Aromatic hydrocarbons can be mentioned, and ethers are preferred, and tetrahydrofuran is particularly preferred.

  The reaction temperature is -23 ° C to 60 ° C, preferably -10 ° C to 40 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 4 hours, preferably 1 hour to 2 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step F2 Step F2 is a process for producing a compound having the general formula (XXVII) by converting a hydrogen atom of a compound having the general formula (XXVI) into a formyl group.

  This step is performed by allowing a suitable base to act on the compound having the general formula (XXVI) in a solvent and then allowing a formylating agent to act.

  Examples of the base used include alkyllithiums such as n-butyllithium, sec-butyllithium and t-butyllithium; metals such as lithium diisopropylamide, lithium hexamethyldisilazide and potassium hexamethyldisilazide Amides can be mentioned, and alkyllithiums are preferred, and n-butyllithium is particularly preferred.

  Examples of the formylating agent used include formic amides such as N, N-dimethylformamide, 1-formylpyrrolidine and 1-formylpiperidine; t-butylisocyanide, 1,1,3,3-tetramethylbutylisocyanide, and the like The formic acid amides are preferable, and formic acid amides are preferable, and N, N-dimethylformamide is particularly preferable.

  The solvent to be used is not particularly limited as long as it is inert to the reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane; benzene, toluene, xylene, etc. Aromatic hydrocarbons can be mentioned, and ethers are preferred, and tetrahydrofuran is particularly preferred.

  The reaction temperature is -78 ° C to room temperature, preferably -78 ° C to 0 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 30 minutes to 4 hours, preferably 1 to 3 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step F3 Step F3 is a process for the preparation of a compound having the general formula (XXVIII) by converting a formyl group of a compound having the general formula (XXVII) into an oxime group.

  This step is performed by allowing hydroxyamine or a hydroxyamine equivalent to act on the compound having the general formula (XXVII) in a solvent.

  Hydroxylamine equivalents include hydroxyamine solutions such as hydroxyamine aqueous solution, hydroxyamine-methanol mixed solution, hydroxyamine-ethanol mixed solution; hydroxyamines such as hydroxyamine hydrochloride, hydroxyamine phosphate, hydroxyamine sulfate, etc. A combination of a salt and a tri-lower alkylamine such as triethylamine, N, N-diisopropylethylamine, or tributylamine, or an alkali metal carbonate such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate can be given. Is preferably a combination of hydroxyamine salts and tri-lower alkylamines, and particularly preferably a combination of hydroxyamine hydrochloride and triethylamine.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; tetrahydrofuran, 1,2-dimethoxyethane, etc. Examples of ethers include alcohols such as methanol, ethanol, and isopropanol. Halogenated hydrocarbons are preferable, and dichloromethane is particularly preferable.

  The reaction temperature is 0 ° C. to 80 ° C., preferably 20 ° C. to 60 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 30 min to 5 hr, preferably 1 hr to 3 hr.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step F4 Step F4 is a process for the preparation of a compound having the general formula (VI-3) by converting an oxime group of a compound having the general formula (XXVIII) into a nitrile group.

  This step is achieved by allowing a suitable dehydrating agent to act on the compound having the general formula (XXVIII) in a solvent.

  Examples of dehydrating agents used include carbodiimides such as N, N′-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide, 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide (WSCI); diphosphorus pentoxide , Phosphorus compounds such as phosphorus oxychloride; thionyl chloride and the like, and carbodiimides are preferable, and N, N′-dicyclohexylcarbodiimide is particularly preferable.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; tetrahydrofuran, 1,2-dimethoxyethane, Examples include ethers such as dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene. Among them, aromatic hydrocarbons are preferable, and toluene is particularly preferable.

  The reaction temperature is 20 ° C to 150 ° C, preferably 60 ° C to 110 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 2 to 24 hours, preferably 6 to 12 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Method G Method G is a method for producing a compound having the general formula (VI-4), which is a compound having the general formula (VI) when the substituent W is a pyridine ring.

In the above formula, Hal represents a halogen atom as described above, preferably a bromine atom or an iodine atom, and P represents a hydroxyl-protecting group as described above.

Step G1 Step G1 is a process for the preparation of a compound having the general formula (XXX) by converting the 2-position halogen atom of a compound having the general formula (XXIX) into a formyl group.
This step is achieved by subjecting the compound having the general formula (XXIX) to a compound in a solvent, and then subjecting the compound to a halogen-metal exchange, and then an appropriate formylating agent.

  Examples of the metallizing agent to be used include metal simple substances such as metal lithium, metal magnesium and metal zinc; alkyllithiums such as n-butyllithium, s-butyllithium and t-butyllithium. Alkyl lithiums are preferable, and n-butyl lithium is particularly preferable.

  Examples of the formylating agent used include formic acid amides such as N, N-dimethylformamide, N-methylformanilide, and N-formylpiperidine; formic acid esters such as methyl formate, ethyl formate, and propyl formate. Are formic amides, particularly preferably N, N-dimethylformamide.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and dioxane; aromatic carbonization such as toluene and xylene Examples of hydrogen include aromatic hydrocarbons, and particularly preferable is toluene.

  The reaction temperature is −100 ° C. to 0 ° C., preferably −78 ° C. to −45 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 min to 5 hr, preferably 30 min to 3 hr.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step G2 Step G2 is a process for the preparation of a compound having the general formula (XXXI) by converting a formyl group of a compound having the general formula (XXX) into a hydroxymethyl group.
This step is performed by allowing a reducing agent to act on the compound having the general formula (XXX) in a solvent.

  Examples of the reducing agent used include aluminum hydrides such as lithium aluminum hydride, sodium aluminum hydride and diisobutylaluminum hydride; borohydrides such as lithium borohydride, sodium borohydride and borane. However, borohydrides are preferred, and sodium borohydride is particularly preferred.

  The solvent to be used is not particularly limited as long as it is inert to the reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and dioxane; alcohols such as methanol, ethanol and isopropanol Preferred are alcohols, and particularly preferred is methanol.

  The reaction temperature is −23 ° C. to 50 ° C., preferably 0 ° C. to 30 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 2 hours, preferably 30 minutes to 1 hour.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step G3 Step G3 is a process for the preparation of a compound having the general formula (XXXII) by protecting the hydroxy group of a compound having the general formula (XXXI) with an appropriate hydroxyl-protecting group. The protecting group to be used is not particularly limited as long as it does not affect the reaction in a later step and can be easily deprotected, but is preferably a trialkylsilane. A general production method when trialkylsilanes are used as protecting groups is described below.

  This step is carried out by reacting a compound having the general formula (XXXI) with a silylating agent in the presence of a suitable base in a solvent.

  The silylating agents used are, for example, trialkylsilyl chlorides such as triethylsilyl chloride, t-butyldimethylsilyl chloride, triisopropylsilyl chloride, t-butyldiphenylsilyl chloride; triethylsilyl trifluoromethanesulfonate, t-butyl Examples thereof include trialkylsilyl trifluoromethanesulfonates such as dimethylsilyltrifluoromethanesulfonate, triisopropylsilyltrifluoromethanesulfonate, and t-butyldiphenylsilyltrifluoromethanesulfonate. Trialkylsilyl chlorides are preferred. Particularly preferred is t-butyldimethylsilyl chloride.

  Examples of the base used include trialkylamines such as triethylamine and N, N-diisopropylethylamine; imidazoles such as imidazole and 2-methylimidazole; and pyridines such as pyridine, lutidine and collidine. Is an imidazole, particularly preferably imidazole.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane; dichloromethane, 1,2-dichloroethane, Halogenated hydrocarbons such as chloroform; amides such as N, N-dimethylformamide and N, N-dimethylacetamide can be mentioned, and amides are preferable, and N, N- Dimethylformamide.

  The reaction temperature is −23 ° C. to 50 ° C., preferably 0 ° C. to 30 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 30 minutes to 4 hours, preferably 1 to 3 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step G4 Step G4 is a process for the preparation of a compound having the general formula (VI-4) by converting a halogen atom of a compound having the general formula (XXXII) into a nitrile group.

This step is achieved by allowing a suitable nitrating agent to act on the compound having the general formula (XXXII) in a solvent.

  Nitrilating agents used are, for example, copper compounds such as copper cyanide; tetrakistriphenylphosphine palladium, bis (triphenylphosphine) dichloropalladium, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium, etc. The combination of a palladium catalyst and a metal cyanide such as zinc cyanide, trimethylsilylcyanide, and tributyltin cyanide is preferable. Is a combination of [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium and zinc cyanide.

  The solvent to be used is not particularly limited as long as it is inert to the reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane; N, N-dimethylformamide, N , N-dimethylacetamide, N-methyl-2-pyrrolidinone and the like, and preferred are amides, and particularly preferred is N-methyl-2-pyrrolidinone.

  The reaction temperature is 20 ° C. to 180 ° C., and preferably 80 ° C. to 120 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 30 minutes to 4 hours, preferably 1 to 3 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Method H Method H is a method for producing a compound having the general formula (VI-5), which is a compound having the general formula (VI) when the substituent W is a pyridine ring and has an alkyl group as a substituent.

In the above formula, R ^e and R ^f are the same or different and each represents a C ₁ -C ₆ alkyl group, preferably a methyl group or an ethyl group, and P represents a hydroxyl-protecting group as described above. Show.

Step H1 Step H1 is a process for the preparation of a compound having the general formula (XXXIV) by converting a formyl group of a compound having the general formula (XXXIII) into a hydroxymethyl group. Moreover, about the compound which has general formula (XXXIII) which is a starting material, the 6-formyl-2- (methylsulfanyl) nicotinonitrile etc. which are marketed from the Maybridge company etc. can be used, for example.
This step is performed by allowing a reducing agent to act on the compound having the general formula (XXXIII) in a solvent.

  Examples of the reducing agent used include aluminum hydrides such as lithium aluminum hydride, sodium aluminum hydride and diisobutylaluminum hydride; borohydrides such as lithium borohydride, sodium borohydride and borane. However, borohydrides are preferred, and sodium borohydride is particularly preferred.

  The solvent to be used is not particularly limited as long as it is inert to the reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and dioxane; alcohols such as methanol, ethanol and isopropanol Preferred are alcohols, and particularly preferred is methanol.

  The reaction temperature is −23 ° C. to 50 ° C., preferably 0 ° C. to 30 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 2 hours, preferably 30 minutes to 1 hour.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step H2 Step H2 is a step for producing a compound having the general formula (XXXV) by protecting the hydroxy group of the compound having the general formula (XXXIV) with an appropriate hydroxyl-protecting group. The protecting group to be used is not particularly limited as long as it does not affect the reaction in a later step and can be easily deprotected, but is preferably a trialkylsilane. A general production method when trialkylsilanes are used as protecting groups is described below.

  This step is performed by allowing a silylating agent to act on the compound having the general formula (XXXIV) in a solvent in the presence of a suitable base.

  The silylating agents used are, for example, trialkylsilyl chlorides such as triethylsilyl chloride, t-butyldimethylsilyl chloride, triisopropylsilyl chloride, t-butyldiphenylsilyl chloride; triethylsilyl trifluoromethanesulfonate, t-butyl Examples thereof include trialkylsilyl trifluoromethanesulfonates such as dimethylsilyltrifluoromethanesulfonate, triisopropylsilyltrifluoromethanesulfonate, and t-butyldiphenylsilyltrifluoromethanesulfonate. Trialkylsilyl chlorides are preferred. Particularly preferred is triisopropylsilyl chloride.

  Examples of the base used include trialkylamines such as triethylamine and N, N-diisopropylethylamine; imidazoles such as imidazole and 2-methylimidazole; and pyridines such as pyridine, lutidine and collidine. Is an imidazole, particularly preferably imidazole.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane; dichloromethane, 1,2-dichloroethane, Halogenated hydrocarbons such as chloroform; amides such as N, N-dimethylformamide and N, N-dimethylacetamide can be mentioned, and amides are preferable, and N, N- Dimethylformamide.

  The reaction temperature is −23 ° C. to 50 ° C., preferably 0 ° C. to 30 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 30 minutes to 4 hours, preferably 1 to 3 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step H3 Step H3 is a process for producing a compound having the general formula (XXXVI) by oxidizing the alkylthio group of the compound having the general formula (XXXV).

  This step is performed by allowing a suitable oxidizing agent to act on the compound having the general formula (XXXV) in a solvent.

  Examples of the oxidizing agent used include peracids such as peracetic acid, perbenzoic acid, and m-chloroperbenzoic acid; and permanganates such as sodium permanganate and potassium permanganate, Preferred are peracids, and particularly preferred is m-chloroperbenzoic acid.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, alcohols such as methanol, ethanol and isopropanol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform Preferred are alcohols, and particularly preferred is ethanol.

  The reaction temperature is −23 ° C. to 50 ° C., preferably 0 ° C. to 30 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 30 minutes to 4 hours, preferably 1 to 3 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step H4 Step H4 is a process for the preparation of a compound having the general formula (VI-5) by converting an alkylsulfone group of a compound having the general formula (XXXVI) into an alkyl group.
This step is performed by allowing an alkylating agent to act on the compound having the general formula (XXXVI) in a solvent.

  Examples of the alkylating agent to be used include Grignard reagents such as alkylmagnesium chloride, alkylmagnesium bromide and alkylmagnesium iodide; alkyllithiums such as methyllithium, ethyllithium and isopropyllithium are preferable. There are Grignard reagents.

  The solvent to be used is not particularly limited as long as it is inert to the reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane; benzene, toluene, xylene, etc. Aromatic hydrocarbons can be mentioned, and ethers are preferable, and diethyl ether is particularly preferable.

  The reaction temperature is −100 ° C. to 0 ° C., preferably −78 ° C. to −23 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 4 hours, preferably 1 hour to 2 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Method I Method I is a general formula in which substituent Z is a phenoxy group which may have a substituent, substituent Y is a benzene ring which may have a substituent, and LG is a hydroxyl group. This is a method for producing a compound having the general formula (VIII-1), which is a compound having VIII).

In the above formula, R ^g and R ^h each independently represent a group selected from the above substituent group A.

Step I1 Step I1 is a step of producing a compound having the general formula (XXXVIII) by substituting the fluorine atom of the compound having the general formula (XXXVII) with a phenoxy group which may have a substituent.
This step is performed by allowing various phenols to act on the compound having the general formula (XXXVII) in a solvent in the presence of an appropriate base.

  Examples of the base used include alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride. Is an alkali metal carbonate, particularly preferably potassium carbonate.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone; Although ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like can be mentioned, amides are preferable, and N, N-dimethylformamide is particularly preferable.

  The reaction temperature is 0 ° C. to 140 ° C., preferably 60 ° C. to 100 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 1 to 24 hours, preferably 3 to 12 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step I2 Step I2 is a step for producing a compound having the general formula (VIII-1) by oxidizing the formyl group of the compound having the general formula (XXXVIII).
This step is performed by allowing a suitable oxidizing agent to act on the compound having the general formula (XXXVIII) in a solvent.

  The oxidizing agents used are hypochlorites such as sodium hypochlorite and potassium hypochlorite; chlorites such as sodium chlorite and potassium chlorite; sodium permanganate, Permanganates such as potassium manganate can be raised, but chlorites are preferred, and sodium chlorite is particularly preferred.

  The solvent used is not particularly limited as long as it is inert to this reaction. For example, a combination of water and a tertiary alcohol such as t-butanol or t-amyl alcohol; water and dichloromethane, , 2-dichloroethane, and a combination with halogenated hydrocarbons such as chloroform can be mentioned, and a combination of water and a tertiary alcohol is preferable, and a combination of water and t-butanol is particularly preferable. It is.

  The reaction temperature is 0 ° C. to 60 ° C., preferably 0 ° C. to 40 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 30 minutes to 24 hours, preferably 1 hour to 4 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Method J Method J represents a general formula (VIII) in which substituent Z is an alkyl group which may be branched, substituent Y is a benzene ring which may have a substituent, and LG is a hydroxyl group. This is a method for producing a compound having the general formula (VIII-2).

In the above formula, the substituent R ⁱ represents a group selected from the substituent group A, Hal represents a halogen atom as described above, and is preferably a bromine atom or an iodine atom, and R ^j and R ^k each independently represents a C ₁ -C ₆ alkyl group which may be substituted with a group selected from the above substituent group A.

Step J1 Step J1 is a process for the preparation of a compound having the general formula (XL) by converting a formyl group of a compound having the general formula (XXXIX) into an alkenyl group.
This step is carried out by reacting various alkyltriphenylphosphonium salts in a solvent in the presence of a suitable base with respect to the compound having the general formula (XXXIX).

  Bases used are for example alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; n-butyllithium, Alkyllithiums such as s-butyllithium and t-butyllithium can be exemplified, but alkoxides are preferred, and potassium t-butoxide is particularly preferred.

  The solvent to be used is not particularly limited as long as it is inert to this reaction. For example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone; Although ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like can be mentioned, amides are preferable, and N, N-dimethylformamide is particularly preferable.

  The reaction temperature is -45 ° C to 100 ° C, preferably 0 ° C to 40 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 4 hours, preferably 30 minutes to 2 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step J2 Step J2 is a process for producing a compound having the general formula (XLI) by converting a halogen atom of a compound having the general formula (XL) into a carboxyl group.
This step is performed by allowing carbon dioxide to act after halogen-metal exchange is performed on the compound having the general formula (XL) in a solvent.

  Examples of the metallizing agent to be used include metal simple substances such as metal lithium, metal magnesium and metal zinc; alkyllithiums such as n-butyllithium, s-butyllithium and t-butyllithium. Alkyl lithiums are preferable, and n-butyl lithium is particularly preferable.

  The solvent to be used is not particularly limited as long as it is inert to the reaction. For example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane; benzene, toluene, xylene, etc. Aromatic hydrocarbons can be mentioned, and ethers are preferred, and tetrahydrofuran is particularly preferred.

  The reaction temperature is −100 ° C. to 0 ° C., preferably −78 ° C. to −23 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 4 hours, preferably 30 minutes to 2 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

Step J3 Step J3 is a process for producing a compound having the general formula (VIII-2) by reducing the double bond site of the compound having the general formula (XLI).
This step is performed by allowing hydrogen to act on the compound having the general formula (XLI) in a solvent in the presence of a suitable transition metal catalyst.

  Examples of the transition metal catalyst used include heterogeneous catalysts such as palladium-carbon, platinum oxide and Raney nickel; and homogeneous catalysts such as chlorotris (triphenylphosphine) rhodium and tetrakistriphenylphosphine palladium. However, heterogeneous catalysts are preferable, and palladium-carbon is particularly preferable.

  The solvent to be used is not particularly limited as long as it is inert to the reaction. For example, alcohols such as methanol, ethanol and isopropanol; diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like Ethers; aromatic hydrocarbons such as benzene, toluene and xylene can be mentioned, but alcohols are preferred, and ethanol is particularly preferred.

  The reaction temperature is 0 ° C. to 80 ° C., preferably 20 ° C. to 40 ° C.

  While the reaction time varies depending on the reaction temperature, raw materials, reagents and solvent used, it is generally 15 minutes to 4 hours, preferably 30 minutes to 2 hours.

  After completion of the reaction, the target compound can be purified in the same manner as described in Step A1 if necessary.

  When the compound having the general formula (I), which is the active ingredient of the present invention, or a pharmacologically acceptable salt thereof is used as the above-mentioned pharmaceutical composition, itself or an appropriate pharmacologically acceptable, It can be mixed with excipients, diluents, etc. and can be administered orally, for example, orally by tablets, capsules, granules, powders or syrups, or parenterally by injections or suppositories, etc. Orally as tablets or capsules.

  These formulations include excipients (eg sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; Gum arabic; dextran; organic excipients such as pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium magnesium aluminosilicate; phosphates such as calcium hydrogen phosphate Carbonates such as calcium carbonate; inorganic excipients such as sulfates such as calcium sulfate), lubricants (eg stearic acid, calcium stearate, metal stearate such as magnesium stearate) Talc; colloidal silica; bee gum, gay wax Borax; adipic acid; sulfate such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic anhydride, silicic acid Silicates such as hydrates and the above starch derivatives), binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients. ), Disintegrants (eg, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethylcellulose; carboxymethyl starch, carboxy Sodium starch, chemically modified starch and cellulose such as cross-linked polyvinyl pyrrolidone), stabilizers (paraoxybenzoates such as methylparaben and propylparaben; chlorobutanol, benzyl alcohol, phenylethyl alcohol, etc.) Alcohols; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid), and additives such as diluents.

  The dose of the compound having the general formula (I) as an active ingredient or a pharmacologically acceptable salt thereof varies depending on symptoms, age, etc., but for example, for oral administration, adults (weight approximately 60 kg) As) 0.01 to 200 mg (preferably 0.1 to 50 mg) per dose, and for intravenous administration, adult (with a body weight of about 60 kg) per dose 0.005 to 100 mg (preferably 0.01-10 mg). The frequency of administration is 1 to 6 times (preferably 1 or 2 times) per day for an adult (with a body weight of about 60 kg).

  Example 1 1-[(4- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -2-furyl) methyl Azetidine-3-carboxylic acid

(1a) [(4-Bromo-2-furyl) methoxy] (t-butyl) dimethylsilane 4-bromo-2-furaldehyde (5.0 g, 29 mmol) was dissolved in methanol (40 mL) and cooled to 0 ° C. After that, sodium borohydride (1.1 g, 29 mmol) was added and stirred for 1 hour. The solvent was distilled off under reduced pressure, and the residue was diluted with ether, poured into water (40 mL), and extracted with ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (30 mL), imidazole (3.9 g, 57 mmol) and t-butyldimethylchlorosilane (4.7 g, 31 mmol) were added, and the mixture was stirred for 4 hours. The reaction solution was poured into water (50 mL) to stop the reaction, and then a liquid separation operation was performed using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 3: 97) to obtain the title compound (7.4 g, 89%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.09 (s, 6H), 0.90 (s, 9H), 4.60 (s, 2H), 6.29 (s, 1H), 7.36 (s) , 1H).
IR spectrum (Liquid film) 1230, 1257, 1464, 1473 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 290 (M ^<+> ).

(1b) 5-({[t-Butyl (dimethyl) silyl] oxy} methyl) -3-furaldehyde [(4-Bromo-2-furyl) methoxy] (t-) obtained in Example 1 (1a) (Butyl) dimethylsilane (7.3 g, 25 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to -78 ° C. n-Butyllithium (1.6M hexane solution, 17 mL, 28 mmol) was slowly added dropwise and stirred for 5 minutes, then N, N-dimethylformamide (3.8 mL, 50 mmol) was added and stirred for 45 minutes. Saturated aqueous ammonium chloride solution (10 mL) was added to stop the reaction, and the reaction solution was poured into water (100 mL), followed by liquid separation using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 49 to 1:19) to obtain the title compound (3.3 g, 55%) as a colorless oily substance.
¹ HNMR spectrum (500 MHz, CDCl ₃ ) δ0.10 (s, 6H), 0.91 (s, 9H), 4.65 (s, 2H), 6.62 (s, 1H), 8.00 (s , 1H), 9.90 (s, 1H).
IR spectrum (Liquid film) 1083, 1139, 1258, 1473, 1544, 1693 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 241 ((M + H) ^<+> ).

(1c) 5-({[t-butyl (dimethyl) silyl] oxy} methyl) -3-furonitrile 5-({[t-butyl (dimethyl) silyl] oxy} methyl obtained in Example 1 (1b) ) -3-furaldehyde (3.2 g, 13 mmol) was dissolved in methylene chloride (40 mL), hydroxyamine hydrochloride (1.0 g, 15 mmol) and triethylamine (3.7 mL, 27 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Stir. After evaporating the solvent under reduced pressure, the residue was dissolved in toluene (40 mL), N, N′-dicyclohexylcarbodiimide (3.1 g, 15 mmol) was added, and the mixture was stirred at 90 ° C. for 16 hr. After cooling to room temperature, hexane (40 mL) was added, the insoluble material was filtered through celite, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 3: 97) to obtain the title compound (1.8 g, 57%) as a colorless oily substance.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 0.10 (s, 6H), 0.91 (s, 9H), 4.64 (s, 2H), 6.45 (s, 1H), 7.88 (s) 1H).
IR spectrum (Liquid film) 1087, 1142, 1258, 1464, 1473, 1540, 2238 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 238 ((M + H) ^<+> ).

(1d) 5-({[t-Butyl (dimethyl) silyl] oxy} methyl) -N′-hydroxyfuran-3-carboxyimidamide 5-({[t-Butyl] obtained in Example 1 (1c) (Dimethyl) silyl] oxy} methyl) -3-furonitrile (1.8 g, 7.6 mmol) was dissolved in ethanol (10 mL), 40% aqueous hydroxyamine solution (1.0 mL) was added, and the mixture was added at 60 ° C. for 1 hour. Stir. The solvent was distilled off under reduced pressure, and the residue was diluted with ether, poured into water (40 mL), and extracted with ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (2.0 g, 97%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.09 (s, 6H), 0.90 (s, 9H), 4.62 (s, 2H), 4.69 (brs, 2H), 6.44 (s , 1H), 7.30 (br, 1H), 7.64 (s, 1H).
IR spectrum (KBr) 1059, 1594, 1613, 1671, 3203, 3376, 3498 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 271 ((M + H) ⁺ ), 309 ((M + K) ⁺ ).

(1e) (4- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -2-furyl) methanol Example 1 (1d )-({[T-butyl (dimethyl) silyl] oxy} methyl) -N′-hydroxyfuran-3-carboxyimidamide (0.14 g, 0.50 mmol), 4-phenyl-5- ( Trifluoromethyl) thiophene-2-carbonyl chloride (0.17 g, 0.60 mmol) was dissolved in methylene chloride (1.0 mL), cooled to 0 ° C., and then cooled to N, N-diisopropylethylamine (0.17 mL, 1. 0 mmol) was added and stirred for 1 hour. Saturated aqueous sodium bicarbonate (1.0 mL) was added to stop the reaction, the solution was poured into water (20 mL), and extraction operation was performed using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (1.0 mL), tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.75 mL, 0.75 mmol) was added, and the mixture was stirred at 60 ° C. for 3 hr. The reaction solution was poured into water (20 mL) to stop the reaction, and then a liquid separation operation was performed using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (0.20 g, 100%) as a crystalline white solid.
¹ HNMR spectrum (500 MHz, CDCl ₃ ) δ 4.69 (s, 2H), 6.83 (s, 1H), 7.47 (s, 5H), 7.88 (s, 1H), 8.12 (s , 1H).
IR spectrum (KBr) 1143, 1179, 1416, 1581, 1605, 1629, 3326 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 393 ((M + H) ⁺ ).

(1f) Ethyl 1-[(4- {5- [4-phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -2-furyl) methyl] Azetidine-3-carboxylate (4- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3- obtained in Example 1 (1e) Yl} -2-furyl) methanol (0.20 g, 0.50 mmol), carbon tetrabromide (0.20 g, 0.60 mmol), triphenylphosphine (0.16 g, 0.60 mmol) in methylene chloride (1. 0 mL) and stirred at 0 ° C. for 1 hour, then ethyl 3-azetidinecarboxylate hydrochloride (0.12 g, 0.75 mmol), N, N-diisopropylethylamine (0.26). L, 1.5 mmol) and the mixture was stirred for 2 hours at room temperature. Saturated aqueous sodium bicarbonate (1.0 mL) was added to stop the reaction, the solution was poured into water (20 mL), and extraction operation was performed using ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to 2: 1) to obtain the title compound (0.21 g, 84%) as a crystalline white solid.
¹ HNMR spectrum (500 MHz, CDCl ₃ ) δ 1.27 (t, 3H, J = 7.3 Hz), 3.35 (quintet, 1H, J = 7.3 Hz), 3.41 (t, 2H, J = 7 .3 Hz), 3.62 (t, 2H, J = 7.3 Hz), 3.66 (s, 2H) 4.16 (q, 2H, J = 7.3 Hz), 6.72 (s, 1H) , 7.46 (s, 5H), 7.87 (s, 1H), 8.09 (s, 1H).
IR spectrum (KBr) 1125, 1178, 1203, 1216, 1581, 1606, 1624, 1727 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 504 ((M + H) ⁺ ).

(1g) 1-[(4- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -2-furyl) methyl] azetidine -3-Carboxylic acid Ethyl 1-[(4- {5- [4-phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazole obtained in Example 1 (1f) -3-yl} -2-furyl) methyl] azetidine-3-carboxylate (0.20 g, 0.40 mmol) dissolved in tetrahydrofuran (0.50 mL), methanol (0.50 mL), water (0.50 mL). Then, lithium hydroxide monohydrate (37 mg, 0.88 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Acetic acid (48 μL, 0.88 mmol) was added to stop the reaction, a methanol solution (0.5 mL) of oxalic acid (18 mg, 0.20 mmol) was added, and the mixture was stirred for 30 minutes. The precipitated white solid was collected by filtration with a Kiriyama funnel, washed with a water-methanol solution (3: 7), and dried under reduced pressure to obtain the title compound (82 mg, 39%) as a crystalline white solid.
¹ HNMR spectrum (500 MHz, CD ₃ OD) δ 3.35 (quintet, 1H, J = 7.8 Hz), 3.93 (t, 2H, J = 8.3 Hz), 4.01 (t, 2H, J = 9.3 Hz), 4.19 (s, 2H), 7.04 (s, 1H), 7.47-7.52 (m, 5H), 8.03 (s, 1H), 8.34 (s) , 1H).
IR spectrum (KBr) 1135, 1177, 1379, 1410, 1594, 1626, 3421 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 476 ((M + H) ^<+> ).

  Example 2 1-({5- [5- (4-Cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} methyl) azetidine-3-carboxylic acid

(2a) 5-({[t-butyl (dimethyl) silyl] oxy} methyl) -2-furonitrile 5-({[t-butyl (dimethyl) silyl] oxy} methyl) -2-furaldehyde (9.1 g , 38 mmol) [Reference: Tetrahedron 1994, Vol. 50, No. 23, 6767], hydroxyamine hydrochloride (2.9 g, 42 mmol), triethylamine (11 mL, 76 mmol), N, N′-dicyclohexylcarbodiimide (8. 6g, 42 mmol), and the same operation as in Example 1 (1c) was performed to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to obtain the title compound (7.5 g, 84%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.11 (s, 6H), 0.82 (s, 9H), 4.67 (s, 2H), 6.36 (d, 1H, J = 3.4 Hz) 7.04 (d, 1H, J = 3.4 Hz).
IR spectrum (Liquid film) 1093, 1122, 1258, 1464, 1473, 1524, 2120, 2233 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 238 (M ^<+> ).

(2b) 5-({[t-Butyl (dimethyl) silyl] oxy} methyl) -N′-hydroxyfuran-2-carboxyimidamide 5-({[t-Butyl] obtained in Example 2 (2a) (Dimethyl) silyl] oxy} methyl) -2-furonitrile (7.5 g, 32 mmol) and 40% aqueous hydroxyamine solution (4.0 mL) were used, and the same procedure as in Example 1 (1d) was carried out to give the title crude product Got. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (8.1 g, 95%) as a crystalline white solid.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 0.09 (s, 6H), 0.91 (s, 9H), 4.66 (s, 2H), 4.99 (brs, 2H), 6.28 (d , 1H, J = 3.4 Hz), 6.70 (d, 1H, J = 3.4 Hz), 8.76 (br, 1H).
IR spectrum (KBr) 1255, 1613, 1669, 3243, 3367, 3474 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 270 (M ^<+> ).

(2c) {5- [5- (4-Cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} methanol 5-({[t -Butyl (dimethyl) silyl] oxy} methyl) -N'-hydroxyfuran-2-carboxyimidamide (0.19 g, 0.70 mmol), 4-cyclohexylbenzoic acid (0.16 g, 0.77 mmol), N, N′-dicyclohexylcarbodiimide (0.17 g, 0.84 mmol) was dissolved in methylene chloride (1.5 mL) and stirred for 1 hour. The reaction solution was diluted with ether, the insoluble material was filtered through celite, and the obtained filtrate was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (1.0 mL), tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 1.1 mL, 1.1 mmol) was added, and the mixture was stirred at 60 ° C. for 1 hr. The reaction solution was poured into water (20 mL) to stop the reaction, and then a liquid separation operation was performed using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (0.18 g, 81%) as a crystalline white solid.
¹ HNMR spectrum (500 MHz, CDCl ₃ ) δ 1.24-1.51 (m, 5H), 1.75-1.81 (m, 1H), 1.84-1.96 (m, 4H), 2. 56-2.64 (m, 1H), 4.74 (d, 2H, J = 8.3 Hz), 6.50 (d, 1H, J = 3.4 Hz), 7.16 (d, 1H, J = 3.4 Hz), 7.38 (d, 2H, J = 7.8 Hz), 8.11 (d, 2H, J = 7.8 Hz).
IR spectrum (KBr) 1157, 1216, 1344, 1406, 1561, 1584, 1613, 3369 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 325 ((M + H) ⁺ ).

(2d) Ethyl 1-({5- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} methyl) azetidine-3-carboxylate Example 2 (2c ) Obtained from {5- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} methanol (0.18 g, 0.55 mmol), carbon tetrabromide (0.22 g, 0.67 mmol), triphenylphosphine (0.18 g, 0.67 mmol), ethyl 3-azetidinecarboxylate hydrochloride (0.14 g, 0.83 mmol), N, N-diisopropylethylamine (0 .30 mL, 1.7 mmol) was used in the same manner as in Example 1 (1f) to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to 2: 1) to obtain the title compound (0.23 g, 96%) as a crystalline white solid.
¹ HNMR spectrum (500 MHz, CDCl ₃ ) δ 1.24-1.32 (m, 4H), 1.37-1.51 (m, 4H), 1.78 (d, 1H, J = 12.7 Hz), 1.84-1.94 (m, 4H), 2.56-2.63 (m, 1H), 3.34 (quintet, 1H, J = 7.8 Hz), 3.44 (t, 2H, J = 7.8 Hz), 3.64 (t, 2H, J = 7.8 Hz), 3.73 (s, 2H), 4.16 (q, 2H, J = 7.3 Hz), 6.37 (d) , 1H, J = 3.4 Hz), 7.13 (d, 1H, J = 3.4 Hz), 7.37 (d, 2H, J = 8.3 Hz), 8.10 (d, 2H, J = 8.3 Hz).
IR spectrum (KBr) 1374, 1561, 1614, 1736 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 436 ((M + H) ^<+> ).

(2e) 1-({5- [5- (4-Cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} methyl) azetidine-3-carboxylic acid Example 2 (2d) 1-({5- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} methyl) azetidine-3-carboxylate (0.23 g) , 0.53 mmol) in tetrahydrofuran (0.50 mL), methanol (0.50 mL), water (0.50 mL), lithium hydroxide monohydrate (50 mg, 1.2 mmol) was added, and Stir for 1 hour. Acetic acid (65 μL, 1.2 mmol) was added to stop the reaction. The precipitated white solid was collected by filtration with a Kiriyama funnel, washed with a water-methanol solution (3: 7), and dried under reduced pressure to obtain the title compound (122 mg, 56%) as a crystalline white solid.
¹ HNMR spectrum (500 MHz, CD ₃ OD) δ 1.30-1.40 (m, 1H), 1.43-1.57 (m, 4H), 1.79 (d, 1H, J = 11.7 Hz) , 1.87-1.94 (m, 4H), 2.63-2.69 (m, 1H), 3.36 (quintet, 1H, J = 8.3 Hz), 3.97 (t, 2H, J = 8.3 Hz), 4.05 (t, 2H, J = 8.3 Hz), 4.27 (s, 2H), 6.77 (d, 1H, J = 3.4 Hz), 7.26 ( d, 1H, J = 3.4 Hz), 7.48 (d, 2H, J = 8.3 Hz), 8.11 (d, 2H, J = 8.3 Hz).
IR spectrum (KBr) 1346, 1410, 1442, 1503, 1561, 1588, 1618, 3105, 3430 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 408 ((M + H) ^<+> ).

  Example 3 1-[(4- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl Azetidine-3-carboxylic acid

(3a) 5-({[t-Butyl (dimethyl) silyl] oxy} methyl) thiophene-3-carbonitrile [(4-bromo-2-thienyl) methoxy] t-butyldimethylsilane (9.0 g, 29 mmol) [Reference: J.M. Med. Chem. 2002, 45, 5005] was dissolved in N, N-dimethylformamide (20 mL), copper cyanide (4.7 g, 53 mmol) was added, and the mixture was heated to reflux for 2 hours. After cooling to room temperature, the mixture was diluted with ether (80 mL), 28% aqueous ammonium solution (50 mL) was added, and the mixture was stirred at room temperature for 1 hr. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 50 to 1: 4) to obtain the title compound (4.3 g, 58%) as a colorless oily substance.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 0.11 (s, 6H), 0.93 (s, 9H), 4.85 (s, 2H), 7.06 (s, 1H), 7.82 (s , 1H).
IR spectrum (Thin film) 1086, 1128, 1258, 2229 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 253 (M ^<+> ).

(3b) 5-({[t-Butyl (dimethyl) silyl] oxy} methyl) -N′-hydroxythiophene-3-carboxyimidamide 5-({[t-Butyl] obtained in Example 3 (3a) (Dimethyl) silyl] oxy} methyl) thiophene-3-carbonitrile (4.3 g, 17 mmol) and 40% aqueous hydroxyamine solution (2.2 mL) were used for the reaction in the same manner as in Example 1 (1d). The title crude product was obtained. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 10 to 2: 5) to obtain the title compound (4.7 g, 97%) as a crystalline white solid.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ0.10 (s, 6H), 0.93 (s, 9H), 1.69 (brs, 1H), 4.79 (brs, 2H), 4.84 (s , 2H), 7.02 (d, 1H, J = 1.4 Hz), 7.31 (d, 1H, J = 1.4 Hz).
IR spectrum (KBr) 1101, 1256, 1371, 1655, 3208, 3389, 3495 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 287 ((M + H) ^<+> ).

(3c) (4- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methanol Example 3 (3b )-({[T-butyl (dimethyl) silyl] oxy} methyl) -N′-hydroxythiophene-3-carboxyimidamide (0.43 g, 1.5 mmol), 4-phenyl-5- (Trifluoromethyl) thiophene-2-carbonyl chloride (0.52 g, 1.8 mmol), N, N-diisopropylethylamine (0.52 mL, 3.0 mmol), 1.0 M tetrabutylammonium fluoride (3.0 mL, 3.0 mmol) was used in the same manner as in Example 1 (1e) to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 2 to 1: 1) to obtain the title compound (0.60 g, 99%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.95 (brs, 1H), 4.89 (s, 2H), 7.45 (s, 5H), 7.56 (s, 1H), 7.87 (d , 1H, J = 1.2 Hz), 8.07 (d, 1H, J = 1.2 Hz).
IR spectrum (KBr) 1126, 1183, 1268, 1313, 1417, 1578, 1606, 3324 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 409 ((M + H) ^<+> ).

(3d) ethyl 1-[(4- {5- [4-phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] Azetidine-3-carboxylate (4- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3- obtained in Example 3 (3c) Yl} -2-thienyl) methanol (0.10 g, 0.25 mmol), carbon tetrabromide (0.17 g, 0.50 mmol), triphenylphosphine (0.13 g, 0.50 mmol), ethyl 3-azetidine Carboxylate hydrochloride (62 mg, 0.38 mmol) and N, N-diisopropylethylamine (0.11 mL, 0.63 mmol) were used in the same manner as in Example 1 (1f). It was carried out, to give the title crude product. Purification by thin layer silica gel chromatography (ethyl acetate: hexane = 2: 3) gave the title compound (73 mg, 56%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.27 (t, 3H, J = 7.0 Hz), 3.31-3.41 (m, 3H), 3.55-3.68 (m, 2H), 3.83 (s, 2H), 4.17 (q, 2H, J = 7.0 Hz), 7.47 (s, 6H), 7.89 (d, 1H, J = 1.2 Hz), 8. 04 (d, 1H, J = 1.2 Hz).
IR spectrum (KBr) 1132, 1180, 1197, 1272, 1316, 1577, 1608, 1720 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 520 ((M + H) ^<+> ).

(3e) 1-[(4- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine -3-Carboxylic acid Ethyl 1-[(4- {5- [4-phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazole obtained in Example 3 (3d) -3-yl} -2-thienyl) methyl] azetidine-3-carboxylate (70 mg, 0.13 mmol) was dissolved in dioxane (2 mL) and 1N aqueous sodium hydroxide solution (0.39 mL, 0.39 mmol) was added. The mixture was stirred at room temperature for 2 hours. Acetic acid (22 μL, 0.39 mmol) was added to stop the reaction, the solvent was distilled off under reduced pressure, and methanol (1 mL) and water (1 mL) were added. The precipitated white solid was collected by filtration with a Kiriyama funnel, washed with a water-methanol solution (3: 7), and dried under reduced pressure to obtain the title compound (34 mg, 53%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 3.75-3.88 (m, 1H), 4.35-4.46 (m, 2H), 4.46-4.58 (m, 2H) , 4.76 (s, 2H), 7.45-7.60 (m, 5H), 7.93 (s, 1H), 8.03 (s, 1H), 8.37 (s, 1H).
IR spectrum (KBr) 1133, 1178, 1270, 1579, 1605, 3429 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 492 ((M + H) ^<+> ).

  Example 4 1-[(5- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl Azetidine-3-carboxylic acid

(4a) 5-({[t-Butyl (dimethyl) silyl] oxy} methyl) thiophene-2-carbonitrile [(5-Bromo-2-thienyl) methoxy] t-butyldimethylsilane (2.4 g, 7. 8 mmol) [Reference: Tetrahedron, 1983, 39, 2531], using copper cyanide (1.3 g, 14 mmol) in the same manner as in Example 3 (3a). I got a thing. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 50 to 1: 7) to obtain the title compound (1.1 g, 56%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.12 (s, 6H), 0.93 (s, 9H), 4.88 (d, 2H, J = 1.2 Hz), 6.70 (dt, 1H, J = 3.9 Hz, 1.2 Hz), 7.46 (d, 1H, J = 3.9 Hz).
IR spectrum (Thin film) 1096, 1258, 1377, 1464, 1472, 2219 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 253 (M ^<+> ).

(4b) 5-({[t-Butyl (dimethyl) silyl] oxy} methyl) -N′-hydroxythiophene-2-carboxyimidamide 5-({[t-Butyl] obtained in Example 4 (4a) (Dimethyl) silyl] oxy} methyl) thiophene-2-carbonitrile (1.3 g, 5.0 mmol), 40% hydroxyamine aqueous solution (0.7 mL) was used in the same manner as in Example 1 (1d). To obtain the title crude product. Purification was performed by recrystallization (ethyl acetate-hexane) to obtain the title compound (1.2 g, 81%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ0.10 (s, 6H), 0.93 (s, 9H), 4.82 (brs, 2H), 4.84 (s, 2H), 6.81 (brs) , 1H), 6.84 (d, 1H, J = 3.7 Hz), 7.11 (d, 1H, J = 3.7 Hz).
IR spectrum (KBr) 1067, 1250, 1256, 1368, 1387, 1588, 1658, 3306, 3384, 3498 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 286 (M ^<+> ).

(4c) (5- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methanol Example 4 (4b )-({[T-butyl (dimethyl) silyl] oxy} methyl) -N′-hydroxythiophene-2-carboxyimidamide (0.43 g, 1.5 mmol), 4-phenyl-5- (Trifluoromethyl) thiophene-2-carbonyl chloride (0.52 g, 1.8 mmol), N, N-diisopropylethylamine (0.52 mL, 3.0 mmol), 1.0 M tetrabutylammonium fluoride (3.0 mL, 3.0 mmol) was used in the same manner as in Example 1 (1e) to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the title compound (0.60 g, 99%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.97 (brs, 1H), 4.89 (s, 2H), 7.06 (d, 1H, J = 3.7 Hz), 7.45 (s, 5H) , 7.72 (d, 1H, J = 3.7 Hz), 7.88 (q, 1H, J = 1.6 Hz).
IR spectrum (KBr) 1108, 1126, 1176, 1269, 1373, 1572, 3322 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 409 ((M + H) ^<+> ).

(4d) Ethyl 1-[(5- {5- [4-phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] Azetidine-3-carboxylate (5- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3- obtained in Example 4 (4c) Yl} -2-thienyl) methanol (0.12 g, 0.29 mmol), carbon tetrabromide (0.19 g, 0.58 mmol), triphenylphosphine (0.15 g, 0.58 mmol), ethyl 3-azetidine Carboxylate hydrochloride (62 mg, 0.38 mmol) and N, N-diisopropylethylamine (0.13 mL, 0.73 mmol) were used in the same manner as in Example 1 (1f). It was carried out, to give the title crude product. Purification by thin layer silica gel chromatography (ethyl acetate: hexane = 4: 5) gave the title compound (0.12 g, 80%) as a colorless oil.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.28 (t, 3H, J = 7.0 Hz), 3.30-3.42 (m, 3H), 3.59-3.69 (m, 2H), 3.84 (s, 2H), 4.17 (q, 2H, J = 7.0 Hz), 6.96 (d, 1H, J = 3.7 Hz), 7.45 (s, 5H), 7. 69 (d, 1H, J = 3.7 Hz), 7.87 (s, 1H).
IR spectrum (Liquid film) 1133, 1182, 1214, 1269, 1284, 1373, 1571, 1734 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 520 ((M + H) ^<+> ).

(4e) 1-[(5- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine -3-Carboxylic acid Ethyl 1-[(5- {5- [4-phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazole obtained in Example 4 (4d) -3-yl} -2-thienyl) methyl] azetidine-3-carboxylate (0.12 g, 0.23 mmol), 1N aqueous sodium hydroxide solution (0.69 mL, 0.69 mmol) was used for Example 3 (3e). ) To give the title compound (60 mg, 53%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 3.80-3.92 (m, 1H), 4.33-4.48 (m, 2H), 4.52-4.65 (m, 2H) 4.80 (s, 2H), 7.45-7.57 (m, 6H), 7.87 (s, 1H), 8.02 (s, 1H).
IR spectrum (KBr) 1134, 1179, 1214, 1267, 1366, 1379, 1570, 1605, 3429 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 492 ((M + H) ^<+> ).

  Example 5 1-({5- [5- (4-Phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid

(5a) {5- [5- (4-Phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methanol 4-phenoxybenzoic acid (0.12 g, 0.55 mmol) in acetonitrile (5 mL), 1-hydroxybenzotriazole (88 mg, 0.65 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.12 g, 0.60 mmol), Example 4 ( 4-({[t-Butyl (dimethyl) silyl] oxy} methyl) -N′-hydroxythiophene-2-carboxyimidamide (0.14 g, 0.5 mmol) obtained in 4b) was added, and 30 at room temperature was added. Stir for minutes. Water (5 mL) was added to stop the reaction, and extraction operation was performed using ethyl acetate. The organic layer was washed with 0.1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (4.0 mL), tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 1.0 mL, 1.0 mmol) was added, and the mixture was stirred at 60 ° C. for 3 hr. The reaction solution was poured into water (20 mL) to stop the reaction, and then a liquid separation operation was performed using ether. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (97 mg, 55%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.89 (t, 1H, J = 5.9 Hz), 4.89 (d, 2H, J = 5.9 Hz), 7.03-7.10 (m, 4H) ), 7.19-7.28 (m, 2H), 7.35-7.44 (m, 2H), 7.71 (d, 1H, J = 3.5 Hz), 8.61 (d, 2H) , J = 8.6 Hz).
IR spectrum (KBr) 1241, 1366, 1487, 1575, 1590, 1613, 3331 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 351 ((M + H) ^<+> ).

(5b) Ethyl 1-({5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylate Example 5 (5a 5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methanol (97 mg, 0.28 mmol), carbon tetrabromide (0. 19 g, 0.56 mmol), triphenylphosphine (0.15 g, 0.56 mmol), ethyl 3-azetidinecarboxylate hydrochloride (70 mg, 0.42 mmol), N, N-diisopropylethylamine (0.18 mL, 1. 1 mmol) was used in the same manner as in Example 1 (1f) to obtain the title crude product. Purification by thin layer silica gel chromatography (ethyl acetate: hexane = 4: 3) gave the title compound (93 mg, 72%) as a colorless oil.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.27 (t, 3H, J = 7.0 Hz), 3.29-3.41 (m, 3H), 3.59-3.68 (m, 2H), 3.84 (s, 2H), 4.17 (q, 2H, J = 7.0 Hz), 6.96 (d, 1H, J = 3.3 Hz), 7.06-7.15 (m, 4H) ), 7.23 (t, 1H, J = 7.4 Hz), 7.42 (t, 2H, J = 7.8 Hz), 7.70 (d, 1H, J = 3.3 Hz), 8.14 (D, 2H, J = 9.0 Hz).
IR spectrum (Liquid film) 1168, 1196, 1246, 1367, 1489, 1732 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 462 ((M + H) ^<+> ).

(5c) 1-({5- [5- (4-Phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid Example 5 (5b) 1-({5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylate (90 mg, 0 .20 mmol) using a 1N aqueous sodium hydroxide solution (0.60 mL, 0.60 mmol) in the same manner as in Example 3 (3e) to give the title compound (69 mg, 80%) as a crystalline white solid Obtained.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 3.76-3.87 (m, 1H), 4.35-4.44 (m, 2H), 4.49-4.57 (m, 2H) , 4.74 (s, 2H), 7.15 (d, 4H, J = 8.6 Hz), 7.25 (t, 1H, J = 7.8 Hz), 7.40-7.48 (m, 3H), 7.84 (d, 1H, J = 3.9 Hz), 8.18 (d, 2H, J = 8.6 Hz).
IR spectrum (KBr) 1243, 1366, 1488, 1569, 1591, 1613, 3469 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 434 ((M + H) ^<+> ).

  Example 6 1-({4- [5- (4-Benzylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid

(6a) {4- [5- (4-Benzylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methanol 4-benzylbenzoic acid (0.12 g, 0.55 mmol), 1 -Hydroxybenzotriazole (88 mg, 0.65 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.12 g, 0.60 mmol), 5-obtained in Example 3 (3b) ({[T-Butyl (dimethyl) silyl] oxy} methyl) -N′-hydroxythiophene-3-carboxyimidamide (0.14 g, 0.5 mmol), tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 1 0.0 mL, 1.0 mmol) was used in the same manner as in Example 5 (5a) to obtain the title crude product. Purification was performed by recrystallization (ethyl acetate-hexane) to obtain the title compound (99 mg, 57%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.68 (brs, 1H), 4.08 (s, 2H), 4.90 (s, 2H), 7.18-7.43 (m, 7H), 7 .59 (s, 1H), 8.07-8.15 (m, 3H).
IR spectrum (KBr) 1019, 1418, 1495, 1563, 1585, 16161, 3334 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 349 ((M + H) ^<+> ).

(6b) Ethyl 1-({4- [5- (4-benzylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylate Example 6 (6a {4- [5- (4-benzylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methanol (95 mg, 0.27 mmol), carbon tetrabromide (0 .18 g, 0.54 mmol), triphenylphosphine (0.14 g, 0.54 mmol), ethyl 3-azetidinecarboxylate hydrochloride (67 mg, 0.41 mmol), N, N-diisopropylethylamine (0.12 mL, 0 .68 mmol) was used in the same manner as in Example 1 (1f) to obtain the title crude product. Purification by thin layer silica gel chromatography (ethyl acetate: hexane = 6: 4) gave the title compound (84 mg, 68%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.27 (t, 3H, J = 7.0 Hz), 3.30-3.39 (m, 3H), 3.56-3.66 (m, 2H), 3.82 (s, 2H), 4.06 (s, 2H), 4.15 (q, 2H, J = 7.0 Hz), 7.16-7.38 (m, 7H), 7.47 ( s, 1H), 8.01 (s, 1H), 8.08 (d, 2H, J = 8.2 Hz).
IR spectrum (KBr) 1184, 1296, 1356, 1423, 1585, 1735 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 460 ((M + H) ^<+> ).

(6c) 1-({4- [5- (4-Benzylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid Example 6 (6b) 1-({4- [5- (4-Benzylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylate (82 mg, 0 .18 mmol) 1N aqueous sodium hydroxide solution (0.54 mL, 0.54 mmol) was used in the same manner as in Example 3 (3e) to obtain the title compound (67 mg, 86%) as a crystalline white solid. .
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 3.74-3.86 (m, 1H), 4.07 (s, 2H), 4.34-4.43 (m, 2H), 4.45 -4.55 (m, 2H), 4.72 (s, 2H), 7.16-7.31 (m, 5H), 7.42 (d, 2H, J = 8.2 Hz), 7.89 (S, 1H), 8.11 (d, 2H, J = 7.8 Hz), 8.31 (s, 1H).
IR spectrum (KBr) 1323, 1387, 1428, 1562, 1587, 1604, 1616, 3427 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 432 ((M + H) ^<+> ).

  Example 7 1- {2- [5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -4,5,6,7-tetrahydro-1-benzofuran-4-yl } Azetidine-3-carboxylic acid 1/2 oxalate

(7a) t-Butyl (dimethyl) (4,5,6,7-tetrahydro-1-benzofuran-4-yloxy) silane 6,7-dihydro-4 (5H) -benzofuranone (5.0 g, 37 mmol) in methanol After dissolving in (50 mL) and cooling to 0 ° C., sodium borohydride (1.4 g, 37 mmol) was added and stirred for 1 hour. The solvent was distilled off under reduced pressure, and the residue was diluted with ether, poured into water (40 mL), and extracted with ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in dimethylformamide (30 mL), imidazole (4.0 g, 59 mmol) and t-butyldimethylchlorosilane (4.9 g, 32 mmol) were added, and the mixture was stirred for 2 hours. The reaction solution was poured into water (50 mL) to stop the reaction, and then a liquid separation operation was performed using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 49 to 3:97) to obtain the title compound (7.2 g, 77%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.12 (s, 3H), 0.13 (s, 3H), 0.92 (s, 9H), 1.63-1.79 (m, 2H), 1 .89-1.94 (m, 1H), 1.98-2.08 (m, 1H), 2.51 (dt, 1H, J = 16.4 Hz, 6.3 Hz), 2.62 (dt, 1H, J = 16.4 Hz, 6.3 Hz), 4.74 (t, 1 H, J = 6.3 Hz), 6.30 (d, 1 H, J = 1.6 Hz), 7.24 (d, 1 H) , J = 1.6 Hz).
IR spectrum (liquid film) 1074, 1255, 2858, 2932 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 252 (M ^<+> ).

(7b) 4-{[t-Butyl (dimethyl) silyl] oxy} -4,5,6,7-tetrahydro-1-benzofuran-2-carbaldehyde t-Butyl obtained in Example 7 (7a) ( Dimethyl) (4,5,6,7-tetrahydro-1-benzofuran-4-yloxy) silane (4.1 g, 16 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to -78 ° C. n-Butyllithium (1.6M hexane solution, 31 mL, 49 mmol) was slowly added dropwise, and the mixture was heated to 0 ° C. and stirred for 30 minutes. The reaction solution was cooled again to −78 ° C., N, N-dimethylformamide (13 mL, 162 mmol) was added, and the mixture was stirred for 30 minutes. Saturated aqueous ammonium chloride solution (10 mL) was added to stop the reaction, and the reaction solution was poured into water (50 mL), followed by liquid separation using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to obtain the title compound (4.3 g, 94%) as a crystalline white solid.
¹ HNMR spectrum (500 MHz, CDCl ₃ ) δ 0.14 (s, 3H), 0.16 (s, 3H), 0.92 (s, 9H), 1.66 to 1.86 (m, 2H), 1 .90-1.99 (m, 1H), 2.04-2.14 (m, 1H), 2.61 (dt, 1H, J = 17.6 Hz, 6.3 Hz), 2.73 (dt, 1H, J = 17.6 Hz, 6.3 Hz), 4.75 (t, 1H, J = 5.9 Hz), 7.15 (s, 1H), 9.53 (s, 1H).
IR spectrum (KBr) 1074, 1085, 1525, 1678 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 280 ((M + H) ^<+> ).

(7c) 4-{[t-Butyl (dimethyl) silyl] oxy} -4,5,6,7-tetrahydro-1-benzofuran-2-carbonitrile 4-{[obtained in Example 7 (7b) t-butyl (dimethyl) silyl] oxy} -4,5,6,7-tetrahydro-1-benzofuran-2-carbaldehyde (4.3 g, 15.3 mmol), hydroxyamine hydrochloride (1.2 g, 17 mmol) , Triethylamine (4.3 mL, 31 mmol) and N, N′-dicyclohexylcarbodiimide (3.5 g, 17 mmol) were used, and the same operation as in Example 1 (1c) was performed. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to obtain the title compound (3.0 g, 71%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.12 (s, 3H), 0.14 (s, 3H), 0.91 (s, 9H), 1.16-1.38 (m, 1H), 1 .65-1.82 (m, 1H), 1.86-1.96 (m, 1H), 2.02-2.12 (m, 1H), 2.55 (dt, 1H, J = 17. 2 Hz, 5.9 Hz), 2.66 (dt, 1 H, J = 17.2 Hz, 5.9 Hz), 4.70 (t, 1 H, J = 5.9 Hz), 6.99 (s, 1 H).
IR spectrum (liquid film) 1087, 1255, 1526, 1616, 2120, 2227 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 278 ((M + H) ^<+> ), 300 ((M + Na) ^<+> ).

(7d) 4-{[t-Butyl (dimethyl) silyl] oxy} -N′-hydroxy-4,5,6,7-tetrahydro-1-benzofuran-2-carboximidamide obtained in Example 7 (7c) 4-{[t-butyl (dimethyl) silyl] oxy} -4,5,6,7-tetrahydro-1-benzofuran-2-carbonitrile (3.0 g, 11 mmol), 40% aqueous hydroxyamine solution (3 0.0 mL), and the same operation as in Example 1 (1d) was performed to obtain the title crude purified product. Purification by silica gel column chromatography (ethyl acetate: hexane = 3: 7) gave the title compound (2.7 g, 82%) as a crystalline white solid.
¹ HNMR spectrum (500 MHz, CDCl ₃ ) δ 0.12 (s, 3H), 0.13 (s, 3H), 0.91 (s, 9H), 1.64-1.81 (m, 2H), 1 .85-1.93 (m, 1H), 2.00-2.10 (m, 1H), 2.54 (dt, 1H, J = 17.4 Hz, 5.1 Hz), 2.65 (dt, 1H, J = 17.2 Hz, 5.1 Hz), 4.72 (t, 1H, J = 5.1 Hz), 4.85 (brs, 2H), 6.57 (brs, 1H), 6.62 ( s, 1H).
IR spectrum (KBr) 1252, 1362, 1377, 1569, 1544, 1645, 1670, 3171, 3371, 3484 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 311 ((M + H) ⁺ ).

(7e) 2- [5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -4,5,6,7-tetrahydro-1-benzofuran-4-ol 4-isobutylbenzoic acid (0.12 g, 0.66 mmol), 1-hydroxybenzotriazole (0.11 g, 0.78 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.14 g, 0.72 mmol) 4-{[t-butyl (dimethyl) silyl] oxy} -N′-hydroxy-4,5,6,7-tetrahydro-1-benzofuran-2-carboxyimidamide obtained in Example 7 (7d) (0.19 g, 0.6 mmol), tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 1.2 mL, 1.2 mmol) was used. The same procedure as in Example 5 (5a), to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 2 to 1: 1) to obtain the title compound (0.15 g, 75%) as a pale yellow oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.93 (d, 6H, J = 6.7 Hz), 1.80-2.12 (m, 5H), 2.56 (d, 2H, J = 7.4 Hz) ), 2.64-2.72 (m, 1H), 2.76-2.86 (m, 1H), 4.80 (brs, 1H), 7.21 (s, 1H), 7.29 ( d, 2H, J = 8.2 Hz), 8.08 (d, 2H, J = 8.2 Hz).
IR spectrum (Thin film) 1204, 1343, 1386, 1420, 1505, 1560, 1590, 1616, 3389 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 339 ((M + H) ^<+> ).

(7f) Ethyl 1- {2- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -4,5,6,7-tetrahydro-1-benzofuran-4-yl} Azetidine-3-carboxylate 2- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -4,5,6,7-tetrahydro obtained in Example 7 (7e) -1-benzofuran-4-ol (0.15 g, 0.45 mmol), carbon tetrabromide (0.30 g, 0.90 mmol), triphenylphosphine (0.24 g, 0.90 mmol), ethyl 3-azetidine The same operation as in Example 1 (1f) was performed using carboxylate hydrochloride (0.11 g, 0.68 mmol) and N, N-diisopropylethylamine (0.20 mL, 1.1 mmol). There, to give the title crude product. Purification by thin layer silica gel chromatography (ethyl acetate: hexane = 4: 3) gave the title compound (27 mg, 13%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.93 (d, 6H, J = 6.6 Hz), 1.29 (t, 3H, J = 7.4 Hz), 1.60-1.87 (m, 3H) ), 1.87-2.00 (m, 1H), 2.00-2.14 (m, 1H), 2.56 (d, 2H, J = 7.4 Hz), 2.60-2.83. (M, 2H), 3.27-3.44 (m, 3H), 3.51 (t, 1H, J = 6.8 Hz), 3.58-3.70 (m, 2H), 4.18 (Q, 2H, J = 7.4 Hz), 7.12 (s, 1H), 7.31 (d, 2H, J = 8.0 Hz), 8.10 (d, 2H, J = 8.0 Hz) .
IR spectrum (Liquid film) 1186, 1208, 1342, 1387, 1560, 1590, 1616, 1733 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 450 ((M + H) ^<+> ).

(7g) 1- {2- [5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -4,5,6,7-tetrahydro-1-benzofuran-4-yl} azetidine -3-Carboxylic acid 1/2 oxalate Ethyl 1- {2- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl]-obtained in Example 7 (7f) 4,5,6,7-tetrahydro-1-benzofuran-4-yl} azetidine-3-carboxylate (25 mg, 0.056 mmol), 1N aqueous sodium hydroxide solution (0.17 mL, 0.17 mmol), oxalic acid ( 3 mg, 0.028 mmol) was used in the same manner as in Example 3 (3e) to give the title compound (13 mg, 50%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 0.94 (d, 6H, J = 6.3 Hz), 1.90-2.23 (m, 5H), 2.60 (d, 2H, J = 7.0 Hz), 2.69-2.79 (m, 1H), 2.79-2.90 (m, 1H), 3.79-3.92 (m, 1H), 4.38-4. 73 (m, 5H), 7.40 (d, 2H, J = 7.4 Hz), 7.43 (s, 1H), 8.13 (d, 2H, J = 7.4 Hz).
IR spectrum (KBr) 1387, 1409, 1559, 1592, 1613, 3431 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 422 ((M + H) ^<+> ).

  Example 8 1- {2- [5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -4,5,6,7-tetrahydro-1-benzothien-4-yl } -Azetidine-3-carboxylic acid

(8a) 2-Bromo-4,5,6,7-tetrahydro-1-benzothiophen-4-ol 4,5,6,7-tetrahydro-1-benzothien-4-yl acetate (5.1 g, 26 mmol) Was dissolved in chloroform (30 mL), cooled to 0 ° C., N-bromosuccinimide (5 g, 28 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water (40 mL), and an extraction operation was performed using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (20 mL) and water (20 mL), sodium hydroxide (2.3 g, 57 mmol) was added, and the mixture was stirred for 2 hr. The reaction solution was poured into water (50 mL) to stop the reaction, and then a liquid separation operation was performed using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 3: 7) to obtain the title compound (5.0 g, 82%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.67 (d, 1H, J = 6.6 Hz), 1.75-1.89 (m, 2H), 1.90-2.04 (m, 2H), 2.57-2.67 (m, 1H), 2.69-2.77 (m, 1H), 4.66-4.72 (m, 1H), 6.97 (s, 1H).
IR spectrum (liquid film) 1182, 1435, 1453, 3330 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 232 (M ^<+> ).

(8b) [(2-Bromo-4,5,6,7-tetrahydro-1-benzothiophen-4-yl) oxy] (t-butyl) dimethylsilane 2-bromo obtained in Example 8 (8a) -4,5,6,7-tetrahydro-1-benzothiophen-4-ol (5.0 g, 21 mmol) was dissolved in N, N-dimethylformamide (30 mL) and imidazole (2.9 g, 43 mmol), t -Butyldimethylchlorosilane (3.5 g, 24 mmol) was added and stirred for 2 hours. The reaction solution was poured into water (50 mL) to stop the reaction, and then a liquid separation operation was performed using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to obtain the title compound (6.8 g, 91%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.12 (s, 3H), 0.14 (s, 3H), 0.92 (s, 9H), 1.66 to 1.81 (m, 2H), 1 .88-2.06 (m, 2H), 2.59 (dt, 1H, J = 5.5 Hz, 16.4 Hz), 2.68 (dt, 1H, J = 5.5 Hz, 16.4 Hz), 4.68 (t, 1H, J = 5.5 Hz), 6.84 (s, 1H).
IR spectrum (liquid film) 1101, 1255, 2858, 2930 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 346 (M ^<+> ).

(8c) 4-{[t-Butyl (dimethyl) silyl] oxy} -4,5,6,7-tetrahydro-1-benzothiophene-2-carbaldehyde obtained in Example 8 (8b) [(2 -Bromo-4,5,6,7-tetrahydro-1-benzothiophen-4-yl) oxy] (t-butyl) dimethylsilane (5.6 g, 16 mmol) was dissolved in tetrahydrofuran (30 mL) and -78 ° C. Cooled to. n-Butyllithium (1.6M hexane solution, 11 mL, 18 mmol) was slowly added dropwise and stirred for 5 minutes, then N, N-dimethylformamide (2.5 mL, 32 mmol) was added and stirred for 30 minutes. Saturated aqueous ammonium chloride solution (10 mL) was added to stop the reaction, and the reaction solution was poured into water (50 mL), followed by liquid separation using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to obtain the title compound (4.4 g, 92%) as a colorless oily substance.
¹ H NMR spectrum (500 MHz, CDCl ₃ ) δ 0.16 (s, 3H), 0.18 (s, 3H), 0.94 (s, 9H), 1.72-1.86 (m, 2H), 1 97-2.11 (m, 2H), 2.78 (dt, 1H, J = 5.4 Hz, 16.5 Hz), 2.87 (dt, 1H, J = 5.4 Hz, 16.5 Hz), 4.77 (t, 1H, J = 5.4 Hz), 7.58 (s, 1H), 9.82 (s, 1H).
IR spectrum (liquid film) 1240, 1255, 1462, 1673 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 296 (M ^<+> ).

(8d) 4-{[t-Butyl (dimethyl) silyl] oxy} -4,5,6,7-tetrahydro-1-benzothiophene-2-carbonitrile 4- {obtained in Example 8 (8c) [T-Butyl (dimethyl) silyl] oxy} -4,5,6,7-tetrahydro-1-benzothiophene-2-carbaldehyde (4.4 g, 15.3 mmol), hydroxyamine hydrochloride (1.1 g, 16 mmol), triethylamine (4.1 mL, 30 mmol), N, N′-dicyclohexylcarbodiimide (3.4 g, 16 mmol), and the same operation as in Example 1 (1c) was performed. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to obtain the title compound (4.1 g, 94%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.14 (s, 3H), 0.16 (s, 3H), 0.92 (s, 9H), 1.70-1.85 (m, 2H), 1 96-2.10 (m, 2H), 2.70-2.85 (m, 2H), 4.72 (t, 1H, J = 5.5 Hz), 7.43 (s, 1H).
IR spectrum (liquid film) 1103, 1256, 1460, 2215 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 294 ((M + H) ^<+> ), 332 ((M + K) ^<+> ).

(8e) 4-{[t-Butyl (dimethyl) silyl] oxy} -N′-hydroxy-4,5,6,7-tetrahydro-1-benzothiophene-2-carboximidamide In Example 8 (8d) Obtained 4-{[t-butyl (dimethyl) silyl] oxy} -4,5,6,7-tetrahydro-1-benzothiophene-2-carbonitrile (4.1 g, 13.9 mmol), 40% hydroxy The same operation as in Example 1 (1d) was performed using an aqueous amine solution (2.0 mL). The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7) to obtain the title compound (3.9 g, 96%) as a crystalline white solid.
¹ HNMR spectrum (500 MHz, CDCl ₃ ) δ 0.14 (s, 3H), 0.16 (s, 3H), 0.93 (s, 9H), 1.70-1.82 (m, 2H), 1 .94-2.07 (m, 2H), 2.69 (dt, 1H, J = 16.5 Hz, 5.5 Hz), 2.76 (dt, 1H, J = 16.5 Hz, 5.5 Hz), 4.73 (t, 1H, J = 5.5 Hz), 4.78 (brs, 2H), 7.06 (s, 1H), 7.31 (brs, 1H).
IR spectrum (KBr) 1255, 1361, 1584, 1648, 3295, 3370, 3462 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 327 ((M + H) ^<+> ).

(8f) 2- [5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -4,5,6,7-tetrahydro-1-benzothiophen-4-ol Example 8 ( 4-{[t-butyl (dimethyl) silyl] oxy} -N′-hydroxy-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxyimidamide (0.15 g) obtained in 8e). , 0.50 mmol), 4-isobutylbenzoic acid (89 mg, 0.50 mmol), N, N′-dicyclohexylcarbodiimide (0.11 g, 0.55 mmol), 1.0 M tetrabutylammonium fluoride (0.75 mL, 0 .75 mmol) was used in the same manner as in Example 2 (2c) to obtain the title crude purified product. Purification by silica gel column chromatography (ethyl acetate: hexane = 1: 1) gave the title compound (92 mg, 52%) as a colorless oil.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 0.93 (d, 6H, J = 6.6 Hz), 1.84-1.97 (m, 2H), 1.97-2.11 (m, 2H), 2.56 (d, 2H, J = 7.4 Hz), 2.78 (dt, 1H, J = 16.0 Hz, 4.7 Hz), 2.90 (dt, 1H, J = 16.0 Hz, 4. 7 Hz), 4.80-4.85 (d, 2H, J = 7.8 Hz), 7.31 (d, 2H, J = 7.8 Hz), 7.81 (s, 1H), 8.08 ( d, 2H, J = 7.8 Hz).
IR spectrum (Liquid film) 1363, 1519, 1559, 1584, 1614, 3385 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 355 ((M + H) ^<+> ).

(8 g) Ethyl 1- {2- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -4,5,6,7-tetrahydro-1-benzothien-4-yl} -Azetidine-3-carboxylate 2- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -4, 5, 6, 7- obtained in Example 8 (8f) Tetrahydro-1-benzothiophen-4-ol (92 mg, 0.26 mmol), carbon tetrabromide (0.10 g, 0.31 mmol), triphenylphosphine (81 mg, 0.31 mmol), ethyl 3-azetidinecarboxylate The same operation as in Example 1 (1f) using hydrochloride (65 mg, 0.39 mmol) and N, N-diisopropylethylamine (0.14 mL, 0.78 mmol). Conducted to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to 2: 1) to obtain the title compound (44 mg, 36%) as a colorless oily substance.
¹ HNMR spectrum (500 MHz, CDCl ₃ ) δ 0.93 (d, 6H, J = 6.8 Hz), 1.29 (t, 3H, J = 7.3 Hz), 1.70 (dt, 1H, J = 11 .2 Hz, 4.4 Hz), 1.75-1.83 (m, 3H), 1.93 (septet, 1H, J = 6.8 Hz), 2.04-2.13 (m, 1H), 2 .56 (d, 2H, J = 7.3 Hz), 2.75-2.82 (m, 1H), 2.91 (dt, 1H, J = 12.7 Hz, 4.5 Hz), 3.30 ( quintet, 1H, J = 7.8 Hz), 3.37 (t, 1H, J = 6.8 Hz), 3.41 (t, 1H, J = 3.9 Hz), 3.56 (t, 1H, J = 7.3 Hz), 3.59-3.65 (m, 2H), 4.18 (q, 2H, J = 6.8 Hz), 7.31 (d, H, J = 8.3Hz), 7.65 (s, 1H), 8.09 (d, 2H, J = 8.3Hz).
IR spectrum (Thin film) 1186, 1332, 1363, 1450, 1517, 1560 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 466 ((M + H) ⁺ ).

(8h) 1- {2- [5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] -4,5,6,7-tetrahydro-1-benzothien-4-yl}- Azetidine-3-carboxylic acid Ethyl 1- {2- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -4, 5, 6 obtained in Example 8 (8 g) , 7-Tetrahydro-1-benzothien-4-yl} -azetidine-3-carboxylate (44 mg, 0.094 mmol), lithium hydroxide monohydrate (8.7 mg, 0.20 mmol), acetic acid (11 μL, 0.20 mmol) was used for the same operation as in Example 2 (2e) to give the title compound (26 mg, 64%) as a crystalline white solid.
¹ H NMR spectrum (500 MHz, CD ₃ OD) δ 0.94 (d, 6H, J = 6.8 Hz), 1.90-2.01 (m, 3H), 2.02-2.08 (m, 2H) , 2.60 (d, 2H, J = 7.3 Hz), 2.91 (dt, 1H, J = 17.5 Hz, 7.3 Hz), 3.01 (dt, 1H, J = 17.5 Hz, 5 .4 Hz), 3.37 (quintet, 1H, J = 7.8 Hz), 4.16-4.24 (m, 2H), 4.31 (t, 1H, J = 9.3 Hz), 4.35. -4.45 (m, 2H), 7.41 (d, 2H, J = 8.3 Hz), 7.86 (s, 1H), 8.09 (d, 2H, J = 8.3 Hz).
IR spectrum (Thin film) 1517, 1559, 1613, 1714, 3428 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 438 ((M + H) ^<+> ).

  Example 9 1-({4- [3- (4-Isobutylphenyl) isoxazol-5-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid

(9a) 4-[(Trimethylsilyl) ethynyl] thiophene-2-carbaldehyde 4-Bromo-2-thiophenecarboxaldehyde (3.0 g, 16 mmol) was dissolved in N, N-dimethylformamide (30 mL) and under nitrogen atmosphere. , Trimethylsilylacetylene (11 mL, 79 mmol), triethylamine (13 mL, 94 mmol), dichlorobis (triphenylphosphine) palladium (1.1 g, 1.6 mmol) were added, and the mixture was stirred at 80 ° C. for 2 hours. The reaction solution was diluted with ethyl acetate, poured into a saturated aqueous ammonium chloride solution (250 mL), and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 1 to 1:19) to obtain the title compound (3.3 g, 100%) as a brown oily substance.
¹ H NMR spectrum (500 MHz, CDCl ₃ ) δ 0.25 (s, 9H), 7.77 (s, 1H), 7.81 (s, 1H), 9.88 (s, 1H).
IR spectrum (liquid film) 665, 761, 847, 966, 1182, 1230, 1250, 1434, 1684, 2163, 2823, 2899, 2960, 3097 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 208 (M ^<+> ).

(9b) 4-Ethynylthiophene-2-carbaldehyde 4-[(Trimethylsilyl) ethynyl] thiophene-2-carbaldehyde (3.3 g, 16 mmol) obtained in Example 9 (9a) was dissolved in methanol (160 mL). Potassium carbonate (4.3 g, 31 mmol) was added and stirred at room temperature for 1 hour. Insoluble matter was filtered off, the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate, poured into water (100 mL), and liquid separation was performed using ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 1 to 1:19) to obtain the title compound (1.5 g, 69%) as a brown solid.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 3.10 (s, 1H), 7.79 (s, 1H), 7.86 (s, 1H), 9.90 (s, 1H).
IR spectrum (KBr) 616,661,726,800,858,1124,1190,1231,1364,1432,1673,3098,3426cm < ^-1 >
Mass spectrum (EI ^<+> ) m / z: 136 (M ^<+> ).

(9c) (4-Ethynyl-2-thienyl) methanol 4-Ethynylthiophene-2-carbaldehyde (1.5 g, 11 mmol) obtained in Example 9 (9b) was dissolved in methanol (30 mL). After cooling to 0, sodium borohydride (0.49 g, 13 mmol) was added and stirred at room temperature for 15 minutes. The reaction solution was cooled to 0 ° C., water (100 mL) was added, and liquid separation operation was performed using ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 3: 7) to obtain the title compound (0.88 g, 60%) as a brown oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ1.82 (t, 1H, J = 6.1 Hz), 3.01 (s, 1H), 4.75 (d, 1H, J = 6.1 Hz), 4. 79 (d, 1H, J = 6.1 Hz), 7.04 (d, 1H, J = 1.0 Hz), 7.46 (d, 1H, J = 1.0 Hz).
IR spectrum (liquid film) 609, 660, 761, 846, 1012, 1116, 1165, 1185, 1356, 1370, 2111, 2875, 2932, 3107, 3289 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 138 (M ^<+> ).

(9d) t-Butyl [(4-ethynyl-2-thienyl) methoxy] dimethylsilane (4-Ethynyl-2-thienyl) methanol (0.88 g, 6.4 mmol) obtained in Example 9 (9c) Dissolve in methylene chloride (20 mL), add triethylamine (1.3 mL, 9.6 mmol), t-butyldimethylchlorosilane (1.2 g, 7.6 mmol), 4-dimethylaminopyridine (78 mg, 0.64 mmol), Stir at room temperature for 1 hour. Water (50 mL) was added to the reaction solution, and a liquid separation operation was performed using methylene chloride. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 1 to 1: 9) to obtain the title compound (1.5 g, 94%) as a brown oily substance.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 0.10 (s, 6H), 0.92 (s, 9H), 2.98 (s, 1H), 4.80 (s, 2H), 6.91 (d , 1H, J = 1.2 Hz), 7.38 (d, 1H, J = 1.2 Hz).
IR spectrum (liquid film) 778, 838, 1080, 1122, 1171, 1257, 1374, 1464, 1472, 2858, 2930, 2956, 3313 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 252 (M ^<+> ).

(9e) 4-Isobutylbenzaldehyde oxime 4-Isobutylbenzaldehyde (5.0 g, 31 mmol) was dissolved in ethanol (25 mL) and pyridine (25 mL), hydroxylamine hydrochloride (2.4 g, 34 mmol) was added, and 18 at room temperature. Stir for hours. The solvent was distilled off under reduced pressure, and the residue was diluted with ether and poured into water (150 mL), followed by liquid separation using ether. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 19 to 1: 9) to obtain the title compound (4.6 g, 84%) as a colorless oily substance.
¹ HNMR spectrum (500 MHz, CDCl ₃ ) δ 0.90 (d, 6H, J = 6.8 Hz), 1.87 (m, 1H), 2.49 (d, 2H, J = 7.3 Hz), 7. 16 (d, 2H, J = 8.3 Hz), 7.48 (d, 2H, J = 8.3 Hz), 7.63 (brs, 1H), 8.12 (s, 1H).
IR spectrum (liquid film) 534, 790, 845, 962, 1296, 1466, 1517, 1611, 2869, 2925, 2957, 3308 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 177 (M ^<+> ).

(9f) N-hydroxy-4-isobutylbenzenecarboximidoyl chloride 4-isobutylbenzaldehyde oxime (1.0 g, 5.6 mmol) obtained in Example 9 (9e) was added to N, N-dimethylformamide (10 mL). After dissolution, N-chlorosuccinimide (0.15 g, 1.1 mmol) and a small amount of hydrochloric acid gas were added, and the mixture was stirred at room temperature for 10 minutes. After repeating the same operation 5 times in total, the reaction solution was poured into ice water (100 mL), and liquid separation operation was performed using ether. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (1.2 g, 100%) as a yellow oil. .
¹ H NMR spectrum (500 MHz, CDCl ₃ ) δ 0.91 (d, 6H, J = 6.8 Hz), 1.88 (m, 1H), 2.51 (d, 2H, J = 7.3 Hz), 7. 18 (d, 2H, J = 8.3 Hz), 7.75 (d, 2H, J = 8.3 Hz), 7.82 (s, 1H).
IR spectrum (liquid film) 795,850,937,994,1185,1249,1413,1466,1609,2957,3380 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 211 (M ^<+> ).

(9 g) {4- [3- (4-Isobutylphenyl) isoxazol-5-yl] -2-thienyl} methanol N-hydroxy-4-isobutylbenzenecarboximidoyl chloride obtained in Example 9 (9f) ( 0.50 g, 2.4 mmol), t-butyl [(4-ethynyl-2-thienyl) methoxy] dimethylsilane (0.72 g, 2.8 mmol) obtained in Example 9 (9d) was added to ethyl acetate (10 mL). ) And cooled to 0 ° C., triethylamine (0.40 mL, 2.8 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into water (50 mL), and a liquid separation operation was performed using ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (15 mL), cooled to 0 ° C., tetrabutylammonium fluoride (1.0 M tetrahydrofuran, 2.8 mL, 2.8 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was poured into water (50 mL), and a liquid separation operation was performed using ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. Ethyl acetate-hexane (1: 3) solution was added to the resulting residue, and the precipitated solid was collected by filtration with a Kiriyama funnel and washed to obtain the title compound (0.44 g, 59%) as a crystalline white solid.
¹ HNMR spectrum (500 MHz, CDCl ₃ ) δ 0.93 (d, 6H, J = 6.3 Hz), 1.91 (m, 1H), 1.98 (brs, 1H), 2.53 (d, 2H, J = 6.8 Hz), 4.89 (s, 2H), 6.64 (s, 1H), 7.25 (d, 2H, J = 8.3 Hz), 7.35 (s, 1H), 7 .73-7.77 (m, 3H).
IR spectrum (KBr) 774, 794, 847, 1018, 1380, 1440, 1467, 1615, 2869, 2926, 2953, 3344 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 313 (M ^<+> ).

(9h) Ethyl 1-({4- [3- (4-isobutylphenyl) isoxazol-5-yl] -2-thienyl} methyl) azetidine-3-carboxylate {4 obtained in Example 9 (9 g) -[3- (4-Isobutylphenyl) isoxazol-5-yl] -2-thienyl} methanol (0.43 g, 1.4 mmol), carbon tetrabromide (0.68 g, 2.1 mmol), triphenylphosphine ( 0.54 g, 2.1 mmol) was dissolved in methylene chloride (15 mL) and stirred at 0 ° C. for 5 minutes, then ethyl 3-azetidinecarboxylate hydrochloride (0.34 g, 2.1 mmol), N, N— Diisopropylethylamine (0.60 mL, 3.4 mmol) was added and stirred at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate (5 mL) was added to stop the reaction, the solution was poured into water (50 mL), and extraction operation was performed using methylene chloride. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 3: 2) to obtain the title compound (0.48 g, 82%) as a crystalline white solid.
¹ HNMR spectrum (500 MHz, CDCl ₃ ) δ 0.93 (d, 6H, J = 6.7 Hz), 1.27 (t, 3H, J = 7.0 Hz), 1.90 (m, 1H), 2. 52 (d, 2H, J = 7.0 Hz), 3.32-3.38 (m, 3H), 3.56-3.64 (m, 2H), 3.81 (s, 2H), 4. 16 (q, 2H, J = 7.0 Hz), 6.60 (s, 1H), 7.21-7.26 (m, 3H), 7.68 (s, 1H), 7.72 (d, 2H, J = 8.2 Hz).
IR spectrum (KBr) 797, 1193, 1369, 1436, 1607, 1731, 2955, 3115 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 425 ((M + H) ^<+> ).

(9i) 1-({4- [3- (4-Isobutylphenyl) isoxazol-5-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid Ethyl 1- obtained in Example 9 (9h) ({4- [3- (4-Isobutylphenyl) isoxazol-5-yl] -2-thienyl} methyl) azetidine-3-carboxylate (0.47 g, 1.1 mmol) in 1,4-dioxane (15 mL) After cooling to 0 ° C., 1N aqueous sodium hydroxide solution (3.3 mL, 3.3 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Methanol (15 mL) and water (5 mL) were added to the reaction solution, and after heating until the precipitated white solid was dissolved, acetic acid (0.19 mL, 3.3 mmol) was added. The precipitated white solid was collected by filtration with a Kiriyama funnel, washed with methanol, and dried under reduced pressure to obtain the title compound (0.35 g, 78%) as a crystalline white solid.
¹ HNMR spectrum (500 MHz, CD ₃ CO ₂ D) δ 0.93 (d, 6H, J = 6.6 Hz), 1.92 (m, 1H), 2.54 (d, 2H, J = 7.3 Hz) , 3.77-3.87 (m, 1H), 4.35-4.60 (m, 4H), 4.73 (s, 2H), 6.98 (s, 1H), 7.30 (d , 2H, J = 8.2 Hz), 7.77 (d, 1H, J = 1.4 Hz), 7.82 (d, 2H, J = 8.2 Hz), 8.06 (d, 1H, J = 1.4 Hz).
IR spectrum (KBr) 792, 826, 951, 1386, 1440, 1614, 2924, 2954, 3103, 3423 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 397 ((M + H) ^<+> ).

  Example 10 1-[(4-Ethyl-5- {5- [4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine -3-carboxylic acid 0.5 oxalate

(10a) t-butyl [(4-ethyl-2-thienyl) methoxy] dimethylsilane [(4-bromo-2-thienyl) methoxy] (t-butyl) dimethylsilane (0.61 g, 2.0 mmol), [ 1,3-bis (diphenylphosphino) propane] dichloronickel (54 mg, 0.1 mmol) was dissolved in ether (5 mL) and cooled to 0 ° C., then 1.0 M ethylmagnesium bromide / tetrahydrofuran solution (3.0 mL) 3.0 mmol) was slowly added, and the mixture was warmed to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride solution (5 mL) was added to stop the reaction, and the reaction solution was poured into water (20 mL) and extracted with ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 10-5: 95) to obtain the title compound (0.44 g, 95%) as a pale yellow oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ0.10 (s, 6H), 0.93 (s, 9H), 1.21 (t, 3H, J = 7.4 Hz), 2.58 (q, 2H, J = 7.4 Hz), 4.82 (s, 2H), 6.77 (s, 1H), 6.81 (s, 1H).
IR spectrum (liquid film) 1077, 1131, 1174, 1255, 1463, 1471 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 255 ((M-H) ^<+> ).

(10b) 5-({[t-Butyl (dimethyl) silyl] oxy} methyl) -3-ethylthiophene-2-carbaldehyde (t-Butyl [(4-ethyl- 2-Thienyl) methoxy] dimethylsilane (1.3 g, 5.6 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to −78 ° C. 1.6 M n-butyllithium / hexane solution (4.2 mL, 6. mL). 7 mmol), the temperature was raised to 0 ° C. and the mixture was stirred for 30 minutes, and then cooled again to −78 ° C., N, N-dimethylformamide (0.86 mL, 11 mmol) was added, and the mixture was stirred for 30 minutes. The reaction was stopped by adding an aqueous ammonium solution (5 mL), and the reaction solution was poured into water (20 mL) and extracted with ether, and the organic layer was washed with saturated brine. After drying with magnesium sulfate, after filtration, the solvent was distilled off under reduced pressure to obtain the title crude product, which was purified by silica gel column chromatography (ethyl acetate: hexane = 0: 10-5: 95). The title compound (1.3 g, 86%) was obtained as a pale yellow oil.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.12 (s, 6H), 0.94 (s, 9H), 1.29 (t, 3H, J = 7.4 Hz), 2.94 (q, 2H, J = 7.4 Hz), 4.86 (s, 2H), 6.84 (s, 1H), 9.99 (s, 1H).
IR spectrum (liquid film) 1092, 1156, 1225, 1256, 1461, 1659 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 285 (M ^<+> ).

(10c) 5-({[t-Butyl (dimethyl) silyl] oxy} methyl) -3-ethylthiophene-2-carbonitrile 5-({[t-Butyl (dimethyl)] obtained in Example 10 (10b) ) Silyl] oxy} methyl) -3-ethylthiophene-2-carbaldehyde (1.3 g, 4.8 mmol), hydroxyamine hydrochloride (0.37 g, 5.3 mmol) in methylene chloride (20 mL). Thereafter, methanol (2 mL) and triethylamine (1.3 mL, 9.6 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, toluene (10 mL) was added and azeotropic operation was performed under reduced pressure. Dicyclohexylcarbodiimide (1.1 g, 5.3 mmol) was added to the resulting residue, suspended in toluene (20 mL), heated to 90 ° C. and stirred for 15 hours. After cooling to room temperature, hexane (20 mL) was added and filtered through celite. The filtrate was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 10-5: 95) to obtain the title compound (0.94 g, 69%) as a pale yellow oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.11 (s, 6H), 0.93 (s, 9H), 1.25 (t, 3H, J = 7.8 Hz), 2.75 (q, 2H, J = 7.8 Hz), 4.83 (s, 2H), 6.74 (s, 1H).
IR spectrum (liquid film) 1093, 1149, 1256, 2212 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 282 (M ^<+> ).

(10d) 5-({[t-Butyl (dimethyl) silyl] oxy} methyl) -3-ethyl-N′-hydroxythiophene-2-carboxyimidamide 5-({ Example 1 using [t-butyl (dimethyl) silyl] oxy} methyl) -3-ethylthiophene-2-carbonitrile (0.93 g, 3.3 mmol), 40% aqueous hydroxyamine (0.5 mL). The reaction was carried out in the same manner as in 1d) to obtain the title crude product. Purification was performed by recrystallization (hexane) to obtain the title compound (0.60 g, 60%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.11 (s, 6H), 0.93 (s, 9H), 1.20 (t, 3H, J = 7.8 Hz), 2.76 (q, 2H, J = 7.8 Hz), 4.80 (s, 4H), 6.76 (s, 1H), 7.10 (br, 1H).
IR spectrum (KBr) 1059, 1590, 1643, 3284, 3357, 3491 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 315 (M ^<+> ).

(10e) 4- (2-Fluorophenoxy) benzoic acid 4-Fluorobenzaldehyde (1.2 g, 10 mmol), 2-fluorophenol (1.3 g, 12 mmol) are dissolved in N, N-dimethylformamide (10 mL), After adding potassium carbonate (2.8 g, 20 mmol), the mixture was heated to 100 ° C. and stirred for 16 hours. After cooling to room temperature, the reaction solution was poured into water (20 mL), and an extraction operation was performed using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (5 mL), t-butanol (10 mL), water (5 mL), 2-methyl-2-butene (5.3 mL, 50 mmol), monopotassium phosphate (3.4 g, 25 mmol). ), Sodium hypochlorite (2.7 g, 30 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (20 mL), extracted with ether, 1 M aqueous sodium hydroxide solution (20 mL) was added, and the resulting aqueous layer was acidified with 10 M aqueous hydrochloric acid solution (2 mL). The extraction operation was performed again using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (2.0 g, 87%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 6.98 (d, 2H, J = 8.6 Hz), 7.15-7.24 (m, 4H), 8.07 (d, 2H, J = 8.6 Hz) ).
IR spectrum (KBr) 1266, 1290, 1428, 1498, 1594, 1682, 2544, 2672, 2884, 2990 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 232 (M ^<+> ).

(10f) (4-Ethyl-5- {5- [4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methanol In Example 10 (10d) The resulting 5-({[t-butyl (dimethyl) silyl] oxy} methyl) -3-ethyl-N′-hydroxythiophene-2-carboxyimidamide (0.16 g, 0.50 mmol), and Example 10 4- (2-Fluorophenoxy) benzoic acid (0.13 g, 0.55 mmol) obtained in (10e) was dissolved in methylene chloride (1.5 mL), and dicyclohexylcarbodiimide (0.11 g, 0.55 mmol) was dissolved. The mixture was stirred at room temperature for 30 minutes. Hexane (2 mL) was added to the reaction solution, insolubles were filtered off, and the filtrate was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (1 mL), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (0.75 mL, 0.75 mmol) was added, and the mixture was heated to 60 ° C. and stirred for 1 hr. After cooling to room temperature, the reaction solution was poured into water (10 mL) and extracted with ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 3: 7-5: 5) to obtain the title compound (0.18 g, 89%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.29 (t, 3H, J = 7.8 Hz), 3.05 (q, 2H, J = 7.8 Hz), 4.83 (s, 2H), 6. 98 (s, 1H), 7.07 (d, 2H, J = 8.6 Hz), 7.17-7.25 (m, 4H), 8.15 (d, 2H, J = 8.6 Hz).
IR spectrum (KBr) 1270, 1353, 1497, 1602, 3340 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 397 ((M + H) ^<+> ).

(10 g) methyl 1-[(4-ethyl-5- {5- [4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine- 3-Carboxylate (4-Ethyl-5- {5- [4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2 obtained in Example 10 (10f) -Thienyl) methanol (0.17 g, 0.43 mmol), carbon tetrabromide (0.17 g, 0.51 mmol), triphenylphosphine (0.13 g, 0.51 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.10 g, 0.65 mmol), N, N-diisopropylethylamine (0.23 mL, 1.3 mmol) was used in the same manner as in Example 1 (1f). Carried out, to give the title crude product. Purification was performed by silica gel chromatography (ethyl acetate: hexane = 5: 5) to obtain the title compound (0.19 g, 90%) as a colorless oily substance.
¹ H NMR spectrum (500 MHz, CDCl ₃ ) δ 1.28 (t, 3H, J = 7.8 Hz), 3.03 (q, 2H, J = 7.8 Hz), 3.32-3.40 (m, 4H) ), 3.60-3.66 (m, 1H), 3.72 (s, 3H), 3.79 (s, 2H), 6.86 (s, 1H), 7.07 (d, 2H, J = 8.8 Hz), 7.17-7.25 (m, 4H), 8.13 (d, 2H, J = 8.8 Hz).
IR spectrum (Liquid film) 1497, 1514, 1557, 1604, 1737 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 494 ((M + H) ^<+> ).

(10h) 1-[(4-Ethyl-5- {5- [4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3 -Carboxylic acid 0.5 oxalate Methyl 1-[(4-ethyl-5- {5- [4- (2-fluorophenoxy) phenyl] -1,2,4 obtained in Example 10 (10 g) -Oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3-carboxylate (0.19 g, 0.38 mmol), lithium hydroxide monohydrate (36 mg, 0.85 mmol), acetic acid (46 μL, 0 .85 mmol) and oxalic acid (17 mg, 0.19 mmol) in the same manner as in Example 1 (1 g) to give the title compound (77 mg, 39%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ OD) δ 1.26 (t, 3H, J = 7.4 Hz), 3.03 (q, 2H, J = 7.4 Hz), 3.22 (quintet, 1H, J = 8.6 Hz), 3.37 (t, 2H, J = 8.2 Hz), 3.62 (t, 2H, J = 7.0 Hz), 3.82 (s, 2H), 6.98 (s, 1H), 7.12 (d, 2H, J = 9.0 Hz), 7.25-7.33 (m, 4H), 8.16 (d, 2H, J = 9.0 Hz).
IR spectrum (KBr) 1420, 1497, 1601, 1659, 3413 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 480 ((M + H) ^<+> ).

Example 11 1-({5- [5- (3-Fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-methyl-2-thienyl} methyl) azetidine- 3-carboxylic acid

(11a) t-Butyl (dimethyl) [(4-methyl-2-thienyl) methoxy] silane 2-hydroxymethyl-4-methylthiophene (1.8 g, 14 mmol) (reference: J. Heterocycl. Chem. 1982) 19), 1125), imidazole (1.9 g, 28 mmol) was dissolved in N, N-dimethylformamide (20 mL), t-butyldimethylsilyl chloride (2.3 g, 15 mmol) was added, and 2 at room temperature was added. Stir for hours. The reaction solution was poured into water (20 mL), and an extraction operation was performed using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 10 to 1:19) to obtain the title compound (2.5 g, 74%) as a colorless oily substance.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 0.10 (s, 6H), 0.93 (s, 9H), 2.22 (s, 3H), 4.81 (s, 2H), 6.72 (s , 1H), 6.78 (s, 1H).
IR spectrum (liquid film) 1077, 1130, 1256, 1464 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 242 ((M + H) ^<+> ).

(11b) 5-({[t-Butyl (dimethyl) silyl] oxy} methyl) -3-methylthiophene-2-carbaldehyde t-butyl (dimethyl) obtained in Example 11 (11a) [(4- Methyl-2-thienyl) methoxy] silane (2.5 g, 10 mmol), 1.6 M n-butyllithium / hexane solution (7.8 mL, 12 mmol), N, N-dimethylformamide (1.6 mL, 21 mmol) The reaction was conducted in the same manner as in Example 10 (10b) to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 10-5: 95) to obtain the title compound (2.5 g, 89%) as a pale yellow oily substance.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 0.12 (s, 6H), 0.94 (s, 9H), 2.52 (s, 3H), 4.85 (s, 2H), 6.78 (s , 1H), 9.98 (s, 1H).
IR spectrum (liquid film) 1092, 13631393, 1472, 1661 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 271 ((M + H) ^<+> ).

(11c) 5-({[t-Butyl (dimethyl) silyl] oxy} methyl) -3-methylthiophene-2-carbonitrile 5-({[t-Butyl (dimethyl)] obtained in Example 11 (11b) ) Silyl] oxy} methyl) -3-methylthiophene-2-carbaldehyde (2.5 g, 9.2 mmol), hydroxyamine hydrochloride (0.71 g, 10 mmol), triethylamine (2.6 mL, 18 mmol) dicyclohexylcarbodiimide ( 2.1 g, 10 mmol) was used in the same manner as in Example 10 (10c) to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 10-5: 95) to obtain the title compound (2.5 g, 100%) as a pale yellow oily substance.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 0.11 (s, 6H), 0.93 (s, 9H), 2.39 (s, 3H), 4.83 (s, 2H), 6.71 (s , 1H).
IR spectrum (liquid film) 1093, 1150, 1258, 2120, 2214 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 268 ((M + H) ^<+> ).

(11d) 5-({[t-Butyl (dimethyl) silyl] oxy} methyl) -N′-hydroxy-3-methylthiophene-2-carboxyimidamide 5-({obtained in Example 11 (11c) Example 1 using [t-butyl (dimethyl) silyl] oxy} methyl) -3-methylthiophene-2-carbonitrile (2.5 g, 9.2 mmol), 40% aqueous hydroxyamine (2.0 mL). The reaction was carried out in the same manner as in 1d) to obtain the title crude product. Purification was performed by recrystallization (ethyl acetate-hexane) to obtain the title compound (1.4 g, 52%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ0.10 (s, 6H), 0.93 (s, 9H), 2.35 (s, 3H), 4.79 (s, 4H), 6.68 (s) , 1H), 7.16 (br, 1H).
IR spectrum (KBr) 1255, 1651, 327735353, 3455 cm ⁻¹
Mass spectrum (FAB) m / z: 301 ((M + H) ⁺ ).

(11e) 3-Fluoro-4-phenoxybenzoic acid 3,4-difluorobenzaldehyde (0.71 g, 5.0 mmol), phenol (0.56 g, 6.0 mmol), potassium carbonate (1.4 g, 10 mmol), 2 Similar to Example 10 (10e) using methyl-2-butene (2.5 mL, 23 mmol), monopotassium phosphate (1.6 g, 12 mmol), sodium hypochlorite (1.3 g, 14 mmol). The title compound (1.1 g, 93%) was obtained as a crystalline white solid.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 6.96 (t, 1H, J = 8.2 Hz)), 7.04-7.07 (m, 2H), 7.19 (t, 1H, J = 7. 4 Hz), 7.37 (d, 1 H, J = 7.4 Hz), 7.39 (d, 1 H, J = 7.4 Hz), 7.80-7.83 (m, 1 H), 7.89 ( dd, 1H, J = 11.0 Hz, 2.0 Hz).
IR spectrum (KBr) 1025, 1275, 1444, 1492, 1692, 2596, 2673, 2983, 3065 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 232 (M ^<+> ).

(11f) {5- [5- (3-Fluoro-4-phenoxyphenyl] -1,2,4-oxadiazol-3-yl) -4-methyl-2-thienyl} methanol Obtained in Example 11 (11d) 5-({[t-butyl (dimethyl) silyl] oxy} methyl) -N′-hydroxy-3-methylthiophene-2-carboxyimidamide (0.18 g, 0.60 mmol), Example 11 (11e) 3-fluoro-4-phenoxybenzoic acid (0.15 g, 0.66 mmol), dicyclohexylcarbodiimide (0.14 g, 0.66 mmol), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (0. 90 mL, 0.90 mmol) was used in the same manner as in Example 10 (10f) to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (0.21 g, 93%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 2.60 (s, 3H), 4.84 (d, 2H, J = 5.9 Hz), 6.92 (s, 1H), 7.06-7.11 ( m, 3H), 7.22 (t, 1H, J = 7.4 Hz), 7.42 (t, 2H, J = 6.6 Hz), 7.91 (dd, 1H, J = 1.2 Hz, 8 .6 Hz), 8.01 (dd, 1H, J = 2.3 Hz, 10.9 Hz).
IR spectrum (KBr) 1444, 1488, 1577, 1590, 1626, 3264, 3327 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 383 ((M + H) ^<+> ).

(11 g) Methyl 1-({5- [5- (3-Fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-methyl-2-thienyl} methyl) azetidine-3 -Carboxylate {5- [5- (3-Fluoro-4-phenoxyphenyl] -1,2,4-oxadiazol-3-yl) -4-methyl-2-thienyl obtained in Example 11 (11f) } Methanol (0.21 g, 0.55 mmol), carbon tetrabromide (0.22 g, 0.66 mmol), triphenylphosphine (0.17 g, 0.66 mmol), methyl 3-azetidinecarboxylate hydrochloride (0 .13 g, 0.83 mmol) and N, N-diisopropylethylamine (0.30 mL, 1.7 mmol) were used in the same manner as in Example 1 (1f). , To give the title crude product. Purification was performed by silica gel chromatography (ethyl acetate: hexane = 5: 5) to obtain the title compound (0.23 g, 86%) as a colorless oily substance.
¹ H NMR spectrum (500 MHz, CDCl ₃ ) δ 2.56 (s, 3H), 3.30-3.39 (m, 4H), 3.58-3.64 (m, 1H), 3.71 (s, 3H), 3.76 (s, 2H), 7.02-7.08 (m, 3H), 7.19 (t, 1H, J = 7.4 Hz), 7.38 (t, 2H, J = 7.4 Hz), 7.85-7.89 (m, 1H), 7.97 (dd, 1H, J = 2.0 Hz, 10.5 Hz).
IR spectrum (Liquid film) 1489, 1514, 1562, 1590, 1621, 1737 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 480 ((M + H) ^<+> ).

(11h) 1-({5- [5- (3-Fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-methyl-2-thienyl} methyl) azetidine-3- Carboxylic acid Methyl 1-({5- [5- (3-Fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-methyl- obtained in Example 11 (11 g) Example using 2-thienyl} methyl) azetidine-3-carboxylate (0.23 g, 0.48 mmol), lithium hydroxide monohydrate (46 mg, 1.1 mmol), acetic acid (60 μL, 1.1 mmol) The reaction was performed in a similar manner to 2 (2e) to give the title compound (0.17 g, 74%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ OD) δ 2.61 (s, 3H), 3.50-3.62 (m, 1H), 4.22-4.33 (m, 4H), 4.58 (s , 2H), 7.09 (d, 2H, J = 7.8 Hz), 7.15 (t, 1H, J = 8.6 Hz), 7.19-7.24 (m, 2H), 7.42. (T, 2H, J = 7.8 Hz), 7.94 (d, 1H, J = 8.2 Hz), 8.02 (d, 1H, J = 11.0 Hz).
IR spectrum (KBr) 1272, 1340, 1507, 1515, 1561, 1591, 1619, 3404 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 466 ((M + H) ⁺ ).

Example (12) 1-({4-Methyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid

(12a) {4-Methyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methanol 4-phenoxybenzoic acid (0.14 g,. 63 mmol) in acetonitrile (4 mL) and tetrahydrofuran (2 mL), 1-hydroxybenzotriazole (89 mg, 0.66 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.13 g, 0.66 mmol), 5-({[t-Butyl (dimethyl) silyl] oxy} methyl) -N′-hydroxy-3-methylthiophene-2-carboxyimidamide obtained in Example 11 (11d) (0 .18 g, 0.60 mmol) was added, and the mixture was stirred at 50 ° C. for 30 minutes. Water (5 mL) was added to stop the reaction, and extraction operation was performed using ethyl acetate. The organic layer was washed with 0.1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (5 mL), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (1.2 mL, 1.2 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hr. The reaction solution was poured into water (20 mL) to stop the reaction, and then a liquid separation operation was performed using ether. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 2) to obtain (0.19 g, 86%) as a crystalline light yellow solid.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.87 (bs, 1H), 2.59 (s, 3H), 4.83 (s, 2H), 6.91 (s, 1H), 7.09 (d , 2H, J = 8.8 Hz), 7.10 (d, 2H, J = 8.3 Hz), 7.22 (t, 1H, J = 7.1 Hz), 7.42 (t, 2H, J = 7.8 Hz), 8.14 (d, 2H, J = 8.3 Hz).
IR spectrum (KBr) 1249, 1341, 1489, 1514, 1588, 1612, 3279, 3393 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 365 ((M + H) ^<+> ).

(12b) methyl 1-({4-methyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylate {4-Methyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methanol (0.19 g, 0) obtained in Example 12 (12a) .51 mmol), carbon tetrabromide (0.22 g, 0.66 mmol), triphenylphosphine (0.17 g, 0.66 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.12 g, 0.77 mmol), The reaction was carried out in the same manner as in Example 1 (1f) using N, N-diisopropylethylamine (0.27 mL, 1.5 mmol) to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 2: 3) to obtain the title compound (0.20 g, 85%) as a pale yellow oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 2.57 (s, 3H), 3.31-3.40 (m, 3H), 3.59-3.61 (m, 2H), 3.72 (s, 3H), 3.77 (s, 2H), 6.80 (s, 1H), 7.07-7.13 (m, 4H), 7.22 (t, 1H, J = 7.1 Hz), 7 .42 (t, 2H, J = 7.8 Hz), 8.14 (d, 2H, J = 8.3 Hz).
IR spectrum (KBr) 1166, 1201, 1242, 1341, 1488, 1516, 1592, 1613, 1732 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 462 ((M + H) ^<+> ).

(12c) 1-({4-Methyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid Methyl 1-({4-methyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine- obtained in 12 (12b) The reaction was carried out in the same manner as in Example 3 (3e) using 3-carboxylate (0.20 g, 0.42 mmol), 1N aqueous sodium hydroxide solution (1.3 mL, 1.3 mmol), and the title compound (0 .16 g, 85%) was obtained as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 2.61 (s, 3H), 3.77-3.86 (m, 1H), 4.34-4.44 (m, 2H), 4.50 -4.58 (m, 2H), 4.67 (s, 2H), 7.15 (d, 4H, J = 8.6 Hz), 7.21-7.26 (m, 1H), 7.26 (S, 1H), 7.45 (t, 2H, J = 7.8 Hz), 8.18 (d, 2H, J = 9.0 Hz).
IR spectrum (KBr) 1244, 1336, 1488, 1593, 1612, 3429 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 448 ((M + H) ^<+> ).

Example 13 1-({4-Ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid

(13a) {4-Ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methanol 4-phenoxybenzoic acid (0.12 g,. 53 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.11 g, 0.55 mmol), obtained in Example 10 (10d). 5-({[t-butyl (dimethyl) silyl] oxy} methyl) -3-ethyl-N′-hydroxythiophene-2-carboxyimidamide (0.16 g, 0.50 mmol), 1.0 M tetrabutyl Similar to Example 12 (12a) using ammonium fluoride / tetrahydrofuran solution (1.0 mL, 1.0 mmol). The reaction was carried out in the law, to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain the title compound (0.17 g, 89%) as a crystalline light yellow solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.29 (t, 3H, J = 7.4 Hz), 1.88 (t, 1H, J = 5.9 Hz), 3.05 (q, 2H, J = 7) .4 Hz), 4.83 (d, 2H, J = 5.9 Hz), 6.96 (s, 1H), 7.04-7.10 (m, 4H), 7.20 (t, 1H, J = 7.4 Hz), 7.39 (t, 2H, J = 7.4 Hz), 8.12 (d, 2H, J = 9.0 Hz).
IR spectrum (KBr) 1248, 1353, 1490, 1496, 1515, 1588, 1612, 3356 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 379 ((M + H) ^<+> ).

(13b) methyl 1-({4-ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylate {4-Ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methanol (0.17 g, 0) obtained in Example 13 (13a). .44 mmol), carbon tetrabromide (0.19 g, 0.57 mmol), triphenylphosphine (0.15 g, 0.57 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.10 g, 0.66 mmol), Reaction was carried out in the same manner as in Example 1 (1f) using N, N-diisopropylethylamine (0.23 mL, 1.3 mmol) to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 2) to obtain the title compound (0.19 g, 89%) as a pale yellow oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.27 (t, 3H, J = 7.4 Hz), 3.03 (q, 2H, J = 7.4 Hz), 3.30-3.40 (m, 3H ), 3.59-3.67 (m, 2H), 3.71 (s, 3H), 3.78 (s, 2H), 6.84 (s, 1H), 7.04-7.10 ( m, 4H), 7.20 (t, 1H, J = 7.4 Hz), 7.39 (t, 2H, J = 7.4 Hz), 8.11 (d, 2H, J = 9.0 Hz).
IR spectrum (Liquid film) 1168, 1200, 1245, 1346, 1489, 1514, 1589, 1613, 1737 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 476 ((M + H) ^<+> ).

(13c) 1-({4-Ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid 13 (13b) methyl 1-({4-ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine- The reaction was carried out in the same manner as in Example 3 (3e) using 3-carboxylate (0.18 g, 0.39 mmol), 1N aqueous sodium hydroxide solution (1.2 mL, 1.2 mmol), and the title compound (0 .15 g, 86%) was obtained as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 1.30 (t, 3H, J = 7.4 Hz), 3.09 (q, 2H, J = 7.4 Hz), 3.76-3.87 ( m, 1H), 4.33-4.45 (m, 2H), 4.45-4.57 (m, 2H), 4.68 (s, 2H), 7.15 (d, 4H, J = 9.0 Hz), 7.24 (t, 1H, J = 7.4 Hz), 7.32 (s, 1H), 7.45 (t, 2H, J = 7.4 Hz), 8.17 (d, 2H, J = 9.0 Hz).
IR spectrum (KBr) 1167, 1249, 1347, 1489, 1517, 1557, 1592, 1613, 3422 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 462 ((M + H) ^<+> ).

Example 14 1-({4-Ethyl-5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine- 3-carboxylic acid

(14a) {4-Ethyl-5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methanol Obtained in Example 11 (11e) 3-fluoro-4-phenoxybenzoic acid (0.12 g, 0.50 mmol), 1-hydroxybenzotriazole (72 mg, 0.53 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.10 g, 0.53 mmol), 5-({[t-butyl (dimethyl) silyl] oxy} methyl) -3-ethyl-N′-hydroxythiophen-2-yl obtained in Example 10 (10d) Carboxymidamide (0.15 g, 0.48 mmol), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (0.9 mL, the reaction was carried out in the same manner as in Example 12 (12a) using 0.96 mmol), to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain the title compound (0.16 g, 85%) as a crystalline light yellow solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.29 (t, 3H, J = 7.4 Hz), 1.91 (t, 1H, J = 5.9 Hz), 3.05 (q, 2H, J = 7) .4 Hz), 4.84 (d, 2H, J = 5.9 Hz), 6.96 (s, 1H), 7.02-7.09 (m, 3H), 7.19 (t, 1H, J = 7.4 Hz), 7.39 (t, 2H, J = 7.4 Hz), 7.88 (dd, 1H, J = 8.4 Hz, 1.4 Hz), 7.99 (dd, 1H, J = 10.6 Hz, 2.0 Hz).
IR spectrum (KBr) 1207, 1270, 1283, 1342, 1436, 1456, 1492, 1513, 1576, 1595, 3433 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 397 ((M + H) ^<+> ).

(14b) Methyl 1-({4-Ethyl-5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3 -Carboxylate {4-Ethyl-5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl obtained in Example 14 (14a) } Methanol (0.16 g, 0.40 mmol), carbon tetrabromide (0.17 g, 0.52 mmol), triphenylphosphine (0.14 g, 0.52 mmol), methyl 3-azetidinecarboxylate hydrochloride (91 mg , 0.60 mmol), N, N-diisopropylethylamine (0.21 mL, 1.2 mmol) was used for the reaction in the same manner as in Example 1 (1f). To give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 2) to obtain the title compound (0.15 g, 77%) as a pale yellow oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.28 (t, 3H, J = 7.4 Hz), 3.02 (q, 2H, J = 7.4 Hz), 3.31-3.40 (m, 3H) ), 3.58-3.67 (m, 2H), 3.71 (s, 3H), 3.78 (s, 2H), 6.85 (s, 1H), 7.02-7.09 ( m, 3H), 7.19 (t, 1H, J = 7.4 Hz), 7.38 (t, 2H, J = 7.4 Hz), 7.87 (dt, 1H, J = 9.0 Hz, 1 .7 Hz), 7.98 (dd, 1 H, J = 10.8 Hz, 2.2 Hz).
IR spectrum (liquid film) 1204, 1272, 1348, 1454, 1489, 1523, 1559, 1590, 1737 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 494 ((M + H) ^<+> ).

(14c) 1-({4-Ethyl-5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3- Carboxylic acid Methyl 1-({4-ethyl-5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl]-obtained in Example 14 (14b) 2-thienyl} methyl) azetidine-3-carboxylate (0.15 g, 0.30 mmol) and 1N aqueous sodium hydroxide solution (0.9 mL, 0.9 mmol) in a similar manner to Example 3 (3e). Reaction was performed to obtain the title compound (0.11 g, 77%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 1.31 (t, 3H, J = 7.4 Hz), 3.09 (q, 2H, J = 7.4 Hz), 3.75-3.87 ( m, 1H), 4.33-4.44 (m, 2H), 4.44-4.58 (m, 2H), 4.68 (s, 2H), 7.09-7.20 (m, 3H), 7.23 (t, 1H, J = 7.6 Hz), 7.33 (s, 1H), 7.44 (t, 2H, J = 7.6 Hz), 7.97 (d, 1H, J = 9.0 Hz), 8.04 (d, 1H, J = 10.6 Hz).
IR spectrum (KBr) 1201, 1275, 1349, 1491, 1515, 1556, 1591, 3427 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 480 ((M + H) ^<+> ).

Example 15 1-({5- [5- (3-Chloro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-ethyl-2-thienyl} methyl) azetidine- 3-carboxylic acid

(15a) 3-chloro-4-phenoxybenzoic acid 3-chloro-4-fluorobenzaldehyde (0.80 g, 5.0 mmol), phenol (0.66 g, 7.0 mmol), potassium carbonate (1.7 g, 13 mmol) Example 10 (10e) with 2-methyl-2-butene (2.7 mL, 25 mmol), monopotassium phosphate (1.7 g, 13 mmol), sodium hypochlorite (1.4 g, 15 mmol) The reaction was performed in the same manner to obtain the title compound (0.95 g, 77%) as a crystalline yellowish white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 6.87 (d, 1H, J = 8.6 Hz), 7.05 (dd, 2H, J = 7.4 Hz, 1.2 Hz), 7.21 (t, 1H , J = 7.4 Hz), 7.39 (t, 2H, J = 7.4 Hz), 7.88 (dd, 1H, J = 8.6 Hz, 2.0 Hz), 8.19 (d, 1H, J = 2.0 Hz).

(15b) {5- [5- (3-Chloro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-ethyl-2-thienyl} methanol Obtained in Example 15 (15a) 3-chloro-4-phenoxybenzoic acid (0.12 g, 0.50 mmol), 1-hydroxybenzotriazole (72 mg, 0.53 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.10 g, 0.53 mmol), 5-({[t-butyl (dimethyl) silyl] oxy} methyl) -3-ethyl-N′-hydroxythiophen-2-yl obtained in Example 10 (10d) Carboxymidamide (0.15 g, 0.48 mmol), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran (0.96 mL, The reaction was carried out in the same manner as in Example 12 (12a) using .96mmol), to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain the title compound (0.17 g, 87%) as a crystalline light yellow solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.30 (t, 3H, J = 7.4 Hz), 1.90 (t, 1H, J = 5.8 Hz), 3.06 (q, 2H, J = 7) .4 Hz), 4.85 (d, 2H, J = 5.8 Hz), 6.98 (d, 1H, J = 8.6 Hz), 6.99 (s, 1H), 7.09 (d, 2H) , J = 8.6 Hz), 7.23 (t, 1H, J = 7.4 Hz), 7.43 (t, 2H, J = 7.4 Hz), 7.99 (dd, 1H, J = 8. 6 Hz, 2.1 Hz), 8.31 (d, 1 H, J = 2.1 Hz).
IR spectrum (KBr) 1242, 1265, 1393, 1480, 1591, 3250, 3335 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 413 ((M + H) ^<+> ).

(15c) Methyl 1-({5- [5- (3-chloro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-ethyl-2-thienyl} methyl) azetidine-3 -Carboxylate {5- [5- (3-Chloro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-ethyl-2-thienyl obtained in Example 15 (15b) } Methanol (0.17 g, 0.41 mmol), carbon tetrabromide (0.18 g, 0.53 mmol), triphenylphosphine (0.14 g, 0.53 mmol), methyl 3-azetidinecarboxylate hydrochloride (93 mg , 0.62 mmol) and N, N-diisopropylethylamine (0.21 mL, 1.2 mmol) in the same manner as in Example 1 (1f). A crude product was obtained. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain the title compound (0.15 g, 73%) as a pale yellow oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.28 (t, 3H, J = 7.8 Hz), 3.03 (q, 2H, J = 7.8 Hz), 3.32-3.43 (m, 3H ), 3.59-3.69 (m, 2H), 3.79 (s, 3H), 3.84 (s, 2H), 6.87 (s, 1H), 6.98 (d, 1H, J = 8.6 Hz), 7.09 (d, 2H, J = 7.4 Hz), 7.24 (t, 1H, J = 7.4 Hz), 7.43 (t, 2H, J = 7.4 Hz) ), 7.98 (dd, 1H, J = 8.6 Hz, 2.2 Hz), 8.30 (d, 1H, J = 2.2 Hz).
IR spectrum (Thin film) 1198, 1245, 1266, 1343, 1483, 1513, 1737 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 510 ((M + H) ^<+> ).

(15d) 1-({5- [5- (3-Chloro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-ethyl-2-thienyl} methyl) azetidine-3- Carboxylic acid Methyl 1-({5- [5- (3-Chloro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-ethyl- obtained in Example 15 (15c) 2-thienyl} methyl) azetidine-3-carboxylate (0.15 g, 0.29 mmol) and 1N aqueous sodium hydroxide solution (0.87 mL, 0.87 mmol) in a manner similar to Example 3 (3e). Reaction was performed to obtain the title compound (0.13 g, 88%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 1.31 (t, 3H, J = 7.6 Hz), 3.09 (q, 2H, J = 7.6 Hz), 3.75-3.87 ( m, 1H), 4.33-4.44 (m, 2H), 4.48-4.59 (m, 2H), 4.68 (s, 2H), 7.07 (d, 1H, J = 8.6 Hz), 7.13 (d, 2H, J = 7.8 Hz), 7.25 (t, 1H, J = 7.8 Hz), 7.33 (s, 1H), 7.45 (t, 2H, J = 7.8 Hz), 8.06 (dd, 1H, J = 8.6 Hz, 2.2 Hz), 8.31 (s, 1H).
IR spectrum (KBr) 1265, 1344, 1392, 1484, 1514, 1591, 1609, 3414 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 496 ((M + H) ^<+> ).

Example 16 1-[(5- {5- [3-Chloro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl ) Methyl] azetidine-3-carboxylic acid

(16a) 3-chloro-4- (3-fluorophenoxy) benzoic acid 3-chloro-4-fluorobenzaldehyde (1.0 g, 6.3 mmol), 3-fluorophenol (1.1 g, 9.5 mmol), carbonic acid Using potassium (2.2 g, 16 mmol), 2-methyl-2-butene (3.0 mL, 28 mmol), monopotassium phosphate (1.9 g, 14 mmol), sodium hypochlorite (1.5 g, 17 mmol) In the same manner as in Example 10 (10e), the title compound (1.3 g, 79%) was obtained as a crystalline light yellow solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 6.75-6.95 (m, 3H), 7.04 (d, 1H, J = 8.6 Hz), 7.33-7.38 (m, 1H), 7.96 (dd, 1H, J = 8.6 Hz, 2.2 Hz), 8.23 (d, 1H, J = 2.2 Hz).
IR spectrum (KBr) 1123, 1269, 1423, 1486, 1592, 1705, 2663, 2982, 3078 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 266 (M ^<+> ).

(16b) (5- {5- [3-Chloro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methanol Example 16 3-chloro-4- (3-fluorophenoxy) benzoic acid (0.14 g, 0.53 mmol) obtained in (16a), 1-hydroxybenzotriazole (0.086 g, 0.56 mmol), 1-ethyl- 3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (0.11 g, 0.56 mmol), 5-({[t-butyl (dimethyl) silyl] oxy} methyl)-obtained in Example 10 (10d)- 3-ethyl-N′-hydroxythiophene-2-carboxyimidamide (0.16 g, 0.51 mmol), 1.0 M tetrabutylammonium fluoride The same procedure as in Example 5 (5a) with tetrahydrofuran (1.0mL, 1.0mmol), to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 2: 8 to 5: 5) to obtain the title compound (0.15 g, 70%) as a crystalline light yellow solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.30 (t, 3H, J = 7.6 Hz), 1.89 (t, 1H, J = 5.9 Hz), 3.06 (q, 2H, J = 7) .6 Hz), 4.86 (d, 2H, J = 5.9 Hz), 6.75-6.97 (m, 3H), 6.99 (s, 1H), 7.09 (d, 1H, J = 8.6 Hz), 7.33-7.40 (m, 1 H), 8.04 (dd, 1 H, J = 8.6 Hz, 2.0 Hz), 8.32 (d, 1 H, J = 2. 0 Hz).
IR spectrum (KBr) 759, 958, 1120, 1269, 1393, 1480, 1603, 2928, 2973, 3334 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 431 ((M + H) ⁺ ).

(16c) methyl 1-[(5- {5- [3-chloro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) [Methyl] azetidine-3-carboxylate (5- {5- [3-Chloro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3- obtained in Example 16 (16b) Yl} -4-ethyl-2-thienyl) methanol (0.15 g, 0.34 mmol), carbon tetrabromide (0.16 g, 0.51 mmol), triphenylphosphine (0.13 g, 0.51 mmol), methyl Example using 3-azetidinecarboxylate hydrochloride (0.073 g, 0.51 mmol), N, N-diisopropylethylamine (0.14 mL, 0.84 mmol) (1f) The reaction was conducted in the same manner as to give the title crude product. Purification was performed by silica gel chromatography (ethyl acetate: hexane = 2: 8 to 5: 5) to obtain the title compound (0.16 g, 88%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.28 (t, 3H, J = 7.4 Hz), 3.02 (q, 2H, J = 7.4 Hz), 3.32-3.42 (m, 3H ), 3.60-3.67 (m, 2H), 3.71 (s, 3H), 3.78 (s, 2H), 6.75-6.93 (m, 4H), 7.06 ( d, 1H, J = 8.2 Hz), 7.30-7.37 (m, 1H), 7.99-8.03 (m, 1H), 8.29 (d, 1H, J = 2.0 Hz) ).
IR spectrum (Liquid film) 959, 1120, 1270, 1343, 1483, 1513, 1604, 1738, 2846, 2966 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 528 ((M + H) ⁺ ).

(16d) 1-[(5- {5- [3-Chloro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl Azetidine-3-carboxylic acid
Methyl 1-[(5- {5- [3-chloro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4 obtained in Example 16 (16c) -Ethyl-2-thienyl) methyl] azetidine-3-carboxylate (0.16 g, 0.30 mmol), 1N aqueous sodium hydroxide solution (0.89 mL, 0.89 mmol), acetic acid (51 μL, 0.89 mmol) were used. In the same manner as in Example 3 (3e), the title compound (0.14 g, 92%) was obtained as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 1.31 (t, 3H, J = 7.5 Hz), 3.10 (q, 2H, J = 7.5 Hz), 3.78-3.89 ( m, 1H), 4.30-4.65 (m, 4H), 4.71 (s, 2H), 6.87-7.01 (m, 3H), 7.20 (d, 1H, J = 8.6 Hz), 7.38 (s, 1 H), 7.39-7.46 (m, 1 H), 8.12 (dd, 1 H, J = 8.6 Hz, 2.1 Hz), 8.33 ( d, 1H, J = 2.1 Hz).
IR spectrum (KBr) 769, 847, 959, 1118, 1231, 1272, 1344, 1393, 1447, 1486, 1514, 1552, 1603, 2969, 3429 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 514 ((M + H) ^<+> ).

Example 17 1-[(4-Ethyl-5- {5- [4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine -3-carboxylic acid

(17a) 4- (3-Fluorophenoxy) benzoic acid 4-fluorobenzaldehyde (1.5 g, 12 mmol), 3-fluorophenol (1.2 mL, 13 mmol), potassium carbonate (3.3 g, 24 mmol), 2-methyl In the same manner as in Example 10 (10e), using 2-butene (4.8 mL, 45 mmol), monopotassium phosphate (3.1 g, 23 mmol), and sodium hypochlorite (2.5 g, 27 mmol). Reaction was performed to obtain the title compound (2.0 g, 96%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 6.75-6.92 (m, 3H), 7.03 (d, 2H, J = 8.6 Hz), 7.27-7.37 (m, 1H), 8.08 (d, 2H, J = 8.6 Hz).
IR spectrum (KBr) 1117, 1226, 1271, 1293, 1314, 1484, 1597, 1689, 2553, 2671, 2842, 2984 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 232 (M ^<+> ).

(17b) (4-Ethyl-5- {5- [4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methanol In Example 10 (10d) The resulting 5-({[t-butyl (dimethyl) silyl] oxy} methyl) -3-ethyl-N′-hydroxythiophene-2-carboxyimidamide (0.16 g, 0.50 mmol), and Example 17 4- (3-Fluorophenoxy) benzoic acid (0.13 g, 0.55 mmol), dicyclohexylcarbodiimide (0.11 g, 0.55 mmol), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution obtained in (17a) (0.75 mL, 0.75 mmol) was used for the reaction in the same manner as in Example 10 (10f) to give the title crude product. It was. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 3: 7 to 5: 5) to obtain the title compound (0.15 g, 73%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.30 (t, 3H, J = 7.4 Hz), 1.87 (br, 1H), 3.07 (q, 2H, J = 7.8 Hz), 4. 85 (d, 2H, J = 4.7 Hz), 6.82 (dt, 1H, J = 7.4 Hz, 2.3 Hz), 6.85-6.95 (m, 3H), 6.99 (s) , 1H), 7.14 (d, 2H, J = 9.0 Hz), 7.35-7.40 (m, 1H), 8.18 (d, 2H, J = 9.0 Hz).
IR spectrum (KBr) 1341, 1486, 1515, 1557, 1603, 3373 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 397 ((M + H) ^<+> ).

(17c) Methyl 1-[(4-Ethyl-5- {5- [4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine- 3-Carboxylate (4-Ethyl-5- {5- [4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2 obtained in Example 17 (17b) -Thienyl) methanol (0.15 g, 0.38 mmol), carbon tetrabromide (0.15 g, 0.45 mmol), triphenylphosphine (0.12 g, 0.45 mmol), methyl 3-azetidinecarboxylate hydrochloride (86 mg, 0.57 mmol), N, N-diisopropylethylamine (0.19 mL, 1.1 mmol) was used in the same manner as in Example 1 (1f). There, to give the title crude product. Purification was performed by silica gel chromatography (ethyl acetate: hexane = 5: 5) to obtain the title compound (0.16 g, 85%) as a pale yellow oily substance.
¹ HNMR spectrum (500 MHz, CDCl ₃ ) δ 1.28 (t, 3H, J = 7.8 Hz), 3.03 (q, 2H, J = 7.8 Hz), 3.33-3.40 (m, 4H) ), 3.60-3.66 (m, 1H), 3.72 (s, 3H), 3.79 (s, 2H), 6.80 (dt, 1H, J = 7.4 Hz, 2.4 Hz) ), 6.86-6.94 (m, 3H), 7.13 (d, 2H, J = 8.8 Hz), 7.35 (q, 1H, J = 8.3 Hz), 8.17 (d , 2H, J = 8.8 Hz).
IR spectrum (Liquid film) 1346, 1485, 1498, 1514, 1603, 1737 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 494 ((M + H) ^<+> ).

(17d) 1-[(4-Ethyl-5- {5- [4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3 -Carboxylic acid Methyl 1-[(4-ethyl-5- {5- [4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl obtained in Example 17 (17c) } -2-thienyl) methyl] azetidine-3-carboxylate (0.16 g, 0.32 mmol), lithium hydroxide monohydrate (30 mg, 0.71 mmol), acetic acid (39 μL, 0.71 mmol). The reaction was carried out in the same manner as in Example 2 (2e) to obtain the title compound (83 mg, 54%) as a crystalline white solid.
¹ HNMR spectrum (500 MHz, CD ₃ OD) δ 1.29 (t, 3H, J = 7.3 Hz), 3.07 (q, 2H, J = 7.3 Hz), 3.34 (quintet, 1H, J = 8.8 Hz), 3.84-3.90 (m, 2H), 3.94-4.01 (m, 2H), 4.27 (s, 2H), 6.88-7.01 (m, 3H), 7.17 (s, 1H), 7.20 (d, 2H, J = 8.8 Hz), 7.44 (q, 1H, J = 7.8 Hz), 8.20 (d, 2H, J = 8.8 Hz).
IR spectrum (KBr) 1224, 1273, 1342, 1498, 1514, 3428 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 480 ((M + H) ^<+> ).

Example 18 1-[(5- {5- [4- (2,3-difluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl Azetidine-3-carboxylic acid

(18a) 4- (2,3-difluorophenoxy) benzoic acid 4-fluorobenzaldehyde (1.3 g, 10 mmol), 2,3-difluorophenol (2.0 g, 15 mmol), potassium carbonate (2.8 g, 20 mmol) Example 10 (10e) with 2-methyl-2-butene (4.9 mL, 46 mmol), monopotassium phosphate (3.1 g, 23 mmol), sodium hypochlorite (2.5 g, 27 mmol) Reaction was performed in the same manner to obtain the title compound (2.2 g, 94%) as a crystalline white solid.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 6.88-6.95 (m, 1H), 6.98-7.12 (m, 4H), 8.08 (d, 2H, J = 9.0 Hz).
IR spectrum (KBr) 1170, 1249, 1297, 1498, 1603, 1678, 1703, 2565, 2683, 2839, 2991 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 250 (M ^<+> ).

(18b) (5- {5- [4- (2,3-difluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methanol Example 10 (10d )-({[T-butyl (dimethyl) silyl] oxy} methyl) -3-ethyl-N′-hydroxythiophene-2-carboxyimidamide (0.16 g, 0.50 mmol) obtained from 4- (2,3-difluorophenoxy) benzoic acid (0.14 g, 0.55 mmol), dicyclohexylcarbodiimide (0.11 g, 0.55 mmol), 1.0 M tetrabutylammonium fluoride obtained in Example 18 (18a) Reaction was carried out in the same manner as in Example 10 (10f) using a ride / tetrahydrofuran solution (0.75 mL, 0.75 mmol). To obtain the serial crude. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 2: 8 to 3: 7) to obtain the title compound (0.18 g, 88%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.29 (t, 3H, J = 7.4 Hz), 3.04 (q, 2H, J = 7.4 Hz), 4.84 (s, 2H), 6. 90-7.13 (m, 5H), 8.14 (d, 2H, J = 9.0 Hz).
IR spectrum (KBr) 1248, 1352, 1474, 1512, 1607, 1628, 3305 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 415 ((M + H) ⁺ ).

(18c) Methyl 1-[(5- {5- [4- (2,3-difluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] Azetidine-3-carboxylate (5- {5- [4- (2,3-difluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4 obtained in Example 18 (18b) -Ethyl-2-thienyl) methanol (0.18 g, 0.43 mmol), carbon tetrabromide (0.17 g, 0.52 mmol), triphenylphosphine (0.14 g, 0.52 mmol), methyl 3-azetidine Similar to Example 1 (1f) using carboxylate hydrochloride (0.10 g, 0.86 mmol), N, N-diisopropylethylamine (0.15 mL, 1.1 mmol). The reaction was carried out in the way, to give the title crude product. Purification was performed by silica gel chromatography (ethyl acetate: hexane = 5: 5) to obtain the title compound (0.20 g, 91%) as a pale yellow oily substance.
¹ HNMR spectrum (500 MHz, CDCl ₃ ) δ 1.28 (t, 3H, J = 7.4 Hz), 3.03 (q, 2H, J = 7.4 Hz), 3.32-3.40 (m, 4H) ), 3.58-3.68 (m, 1H), 3.72 (s, 3H), 3.79 (s, 2H), 6.92-6.97 (m, 1H), 7.03- 7.16 (m, 4H), 8.16 (d, 2H, J = 9.0 Hz).
IR spectrum (Liquid film) 1250, 1346, 1476, 1498, 1512, 1557, 1608, 1737 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 512 ((M + H) ⁺ ).

(18d) 1-[(5- {5- [4- (2,3-difluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] azetidine -3-Carboxylic acid Methyl 1-[(5- {5- [4- (2,3-difluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl obtained in Example 18 (18c) } -4-ethyl-2-thienyl) methyl] azetidine-3-carboxylate (0.20 g, 0.39 mmol), lithium hydroxide monohydrate (36 mg, 0.86 mmol), acetic acid (47 μL, 0.86 mmol) The title compound (77 mg, 38%) was obtained as a crystalline white solid using the same method as in Example 2 (2e).
¹ HNMR spectrum (500 MHz, CD ₃ OD) δ 1.29 (t, 3H, J = 7.4 Hz), 3.07 (q, 2H, J = 7.4 Hz), 3.40 (quintet, 1H, J = 6.1 Hz), 4.07 (t, 2H, J = 10.2 Hz), 4.13 (t, 2H, J = 9.8 Hz), 4.44 (s, 2H), 7.04-7. 10 (m, 1H), 7.16-7.28 (m, 4H), 8.19 (d, 2H, J = 8.6 Hz).
IR spectrum (KBr) 1498, 1511, 1607, 3320, 3444 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 498 ((M + H) ^<+> ).

Example 19 1-[(5- {5- [4- (2-Chlorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] azetidine -3-carboxylic acid 0.5 oxalate

(19a) 4- (2-Chlorophenoxy) benzoic acid 4-fluorobenzaldehyde (0.60 g, 5.0 mmol), 2-chlorophenol (0.90 g, 7.0 mmol), potassium carbonate (1.7 g, 13 mmol) Example 10 (10e) with 2-methyl-2-butene (2.7 mL, 25 mmol), monopotassium phosphate (1.7 g, 13 mmol), sodium hypochlorite (1.4 g, 15 mmol) Reaction was performed in the same manner to obtain the title compound (1.0 g, 84%) as a crystalline yellowish white solid. ¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 6.95 (d, 2H, J = 8.9 Hz), 7.13 (dd, 1H, J = 7.8 Hz, 1.5 Hz), 7.20 (td, 1H , J = 7.8 Hz, 1.5 Hz), 7.31 (td, 1 H, J = 7.8 Hz, 1.5 Hz), 7.50 (dd, 1 H, J = 7.8 Hz, 1.5 Hz), 8.08 (d, 2H, J = 8.9 Hz).

(19b) (5- {5- [4- (2-Chlorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methanol In Example 10 (10d) The resulting 5-({[t-butyl (dimethyl) silyl] oxy} methyl) -3-ethyl-N′-hydroxythiophene-2-carboxyimidamide (0.16 g, 0.50 mmol), and Example 19 4- (2-Chlorophenoxy) benzoic acid (0.14 g, 0.55 mmol), dicyclohexylcarbodiimide (0.11 g, 0.55 mmol), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution obtained in (19a) (0.75 mL, 0.75 mmol) was used for the reaction in the same manner as in Example 10 (10f) to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 3: 7 to 5: 5) to obtain the title compound (0.19 g, 92%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.29 (t, 3H, J = 7.4 Hz), 3.04 (q, 2H, J = 7.4 Hz), 4.83 (s, 2H), 6. 96 (s, 1H), 7.01 (d, 2H, J = 8.6 Hz), 7.13 (dd, 1H, J = 1.2 Hz, 7.8 Hz), 7.19 (dt, 1H, J = 1.2 Hz, 7.4 Hz), 7.30 (dt, 1 H, J = 1.2 Hz, 7.4 Hz), 7.49 (dd, 1 H, J = 1.2 Hz, 7.8 Hz), 8. 12 (d, 2H, J = 9.0 Hz).
IR spectrum (KBr) 1245, 1259, 1353, 1473, 1498, 1517, 1556, 1612, 3329 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 413 ((M + H) ^<+> ).

(19c) Methyl 1-[(5- {5- [4- (2-chlorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] azetidine- 3-Carboxylate 5- {5- [4- (2-Chlorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2- obtained in Example 19 (19b) Thienyl) methanol (0.19 g, 0.46 mmol), carbon tetrabromide (0.18 g, 0.55 mmol), triphenylphosphine (0.14 g, 0.55 mmol), methyl 3-azetidinecarboxylate hydrochloride ( 0.10 g, 0.69 mmol) and N, N-diisopropylethylamine (0.16 mL, 0.92 mmol) were used for the reaction in the same manner as in Example 1 (1f). , To give the title crude product. Purification was performed by silica gel chromatography (ethyl acetate: hexane = 5: 5) to obtain the title compound (0.21 g, 91%) as a pale yellow oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.28 (t, 3H, J = 7.4 Hz), 3.03 (q, 2H, J = 7.4 Hz), 3.32-3.40 (m, 4H) ), 3.58-3.66 (m, 1H), 3.72 (s, 3H), 3.78 (s, 2H), 6.86 (s, 1H), 7.03 (d, 2H, J = 7.9 Hz), 7.15 (dd, 1 H, J = 1.6 Hz, 7.8 Hz), 7.21 (dt, 1 H, J = 1.6 Hz, 7.4 Hz), 7.32 (dt , 1H, J = 1.6 Hz, 7.4 Hz), 7.51 (dd, 1H, J = 1.6 Hz, 7.8 Hz), 8.14 (d, 2H, J = 9.0 Hz).
IR spectrum (Liquid film) 1475, 1514, 1557, 1581, 1613, 1737 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 510 ((M + H) ^<+> ).

(19d) 1-[(5- {5- [4- (2-Chlorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] azetidine-3 -Carboxylic acid 0.5 oxalate Methyl 1-[(5- {5- [4- (2-chlorophenoxy) phenyl] -1,2,4-oxadiazole-3 obtained in Example 19 (19c) -Yl} -4-ethyl-2-thienyl) methyl] azetidine-3-carboxylate (0.21 g, 0.41 mmol), lithium hydroxide monohydrate (38 mg, 0.90 mmol), acetic acid (49 μL, 0 .90 mmol) and oxalic acid (18 mg, 0.20 mmol) in the same manner as in Example 1 (1 g) to give the title compound (140 mg, 67%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ OD + CD ₃ CO ₂ D (5: 1)) δ 1.29 (t, 3H, J = 7.4 Hz), 3.08 (q, 2H, J = 7.4 Hz), 3 .56 (quintet, 1H, J = 7.4 Hz), 4.25 (t, 2H, J = 10.2 Hz), 4.29 (t, 2H, J = 10.2 Hz), 4.58 (s, 2H), 7.08 (d, 2H, J = 9.0 Hz), 7.24 (dd, 1H, J = 1.6 Hz, 7.8 Hz), 7.30 (dt, 1H, J = 1.6 Hz) , 8.2 Hz), 7.42 (dt, 1H, J = 1.6 Hz, 8.2 Hz), 7.57 (dd, 1H, J = 1.6 Hz, 7.8 Hz), 8.17 (d, 2H, J = 9.0 Hz).
IR spectrum (KBr) 1475, 1497, 1515, 1613, 1665, 3418 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 496 ((M + H) ^<+> ).

Example 20 1-[(4-Ethyl-5- {5- [3-fluoro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl ) Methyl] azetidine-3-carboxylic acid

(20a) 3-fluoro-4- (3-fluorophenoxy) benzoic acid 3,4-difluorobenzaldehyde (1.4 g, 10 mmol), 3-fluorophenol (1.6 g, 14 mmol), potassium carbonate (3.5 g, 25 mmol), 2-methyl-2-butene (5.1 mL, 48 mmol), monopotassium phosphate (3.3 g, 24 mmol), sodium hypochlorite (2.6 g, 29 mmol). ) To give the title compound (2.0 g, 84%) as a crystalline yellowish white solid.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 6.76 (dt, 1 H, J = 9.8 Hz, 2.3 Hz), 6.82 (dd, 1 H, J = 8.2 Hz, 2.3 Hz), 6.88 (Tdd, 1H, J = 8.2 Hz, 2.3 Hz, 0.8 Hz), 7.06 (t, 1H, J = 8.2 Hz), 7.31 (td, 1H, J = 8.2 Hz, 6 .7 Hz), 7.86 (ddd, 1H, J = 8.6 Hz, 2.0 Hz, 1.2 Hz), 7.91 (dd, 1H, J = 11.0 Hz, 2.0 Hz).

(20b) (4-Ethyl-5- {5- [3-fluoro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methanol Example 20 3-Fluoro-4- (3-fluorophenoxy) benzoic acid obtained in (20a) (0.13 g, 0.53 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 1-ethyl-3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (0.11 g, 0.55 mmol), 5-({[t-butyl (dimethyl) silyl] oxy} methyl) -3- obtained in Example 10 (10d) Ethyl-N′-hydroxythiophene-2-carboxyimidamide (0.16 g, 0.50 mmol), 1.0 M tetrabutylammonium fluoride The reaction was carried out in the same manner as in Example 12 (12a) using tetrahydrofuran solution (1.0mL, 1.0mmol), to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain the title compound (0.18 g, 87%) as a crystalline light yellow solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.30 (t, 3H, J = 7.4 Hz), 1.89 (t, 1H, J = 6.3 Hz), 3.06 (q, 2H, J = 7) .4 Hz), 4.86 (d, 2H, J = 6.3 Hz), 6.79 (dt, 1H, J = 9.8 Hz, 2.3 Hz), 6.84 (dd, 1H, J = 8. 2 Hz, 2.3 Hz), 6.90 (td, 1 H, J = 8.2 Hz, 2.3 Hz), 6.99 (s, 1 H), 7.17 (t, 1 H, J = 8.2 Hz), 7.34 (td, 1H, J = 8.2 Hz, 6.6 Hz), 7.96 (dt, 1H, J = 9.0 Hz, 2.0 Hz), 8.03 (dd, 1H, J = 10. 6 Hz, 2.0 Hz).
IR spectrum (KBr) 1127, 1277, 1354, 1488, 1516, 1558, 1607, 3318 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 415 ((M + H) ⁺ ).

(20c) methyl 1-[(4-ethyl-5- {5- [3-fluoro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) [Methyl] azetidine-3-carboxylate (4-Ethyl-5- {5- [3-fluoro-4- (3-fluorophenoxy) phenyl] -1,2,4- obtained in Example 20 (20b) Oxadiazol-3-yl} -2-thienyl) methanol (0.18 g, 0.43 mmol), carbon tetrabromide (0.22 g, 0.65 mmol), triphenylphosphine (0.17 g, 0.65 mmol), methyl Example 1 using 3-azetidinecarboxylate hydrochloride (99 mg, 0.65 mmol), N, N-diisopropylethylamine (0.22 mL, 1.3 mmol). 1f) was reacted in the same manner as to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 2) to obtain the title compound (0.14 g, 64%) as a pale yellow oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.28 (t, 3H, J = 7.4 Hz), 3.03 (q, 2H, J = 7.4 Hz), 3.32-3.43 (m, 3H ), 3.60-3.68 (m, 2H), 3.72 (s, 3H), 3.79 (s, 2H), 6.79 (dt, 1H, J = 9.8 Hz, 2.3 Hz) ), 6.85 (dd, 1H, J = 8.2 Hz, 2.3 Hz), 6.87 (s, 1H), 6.90 (td, 1H, J = 8.6 Hz, 0.8 Hz), 7 .17 (t, 1H, J = 8.2 Hz), 7.34 (td, 1H, J = 8.2 Hz, 6.6 Hz), 7.95 (dt, 1H, J = 8.6 Hz, 2.0 Hz) ), 8.02 (dd, 1H, J = 10.6 Hz, 2.0 Hz).
IR spectrum (Liquid film) 1128, 1200, 1275, 1348, 1451, 1486, 1513, 1605, 1737 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 512 ((M + H) ⁺ ).

(20d) 1-[(4-Ethyl-5- {5- [3-fluoro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl Azetidine-3-carboxylic acid Methyl 1-[(4-ethyl-5- {5- [3-fluoro-4- (3-fluorophenoxy) phenyl] -1,2 obtained in Example 20 (20c) , 4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3-carboxylate (0.14 g, 0.27 mmol), performed with 1N aqueous sodium hydroxide solution (0.81 mL, 0.81 mmol). The reaction was carried out in the same manner as in Example 3 (3e) to obtain the title compound (0.11 g, 83%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 1.31 (t, 3H, J = 7.4 Hz), 3.10 (q, 2H, J = 7.4 Hz), 3.75-3.87 ( m, 1H), 4.34-4.45 (m, 2H), 4.50-4.59 (m, 2H), 4.69 (s, 2H), 6.88-7.00 (m, 3H), 7.28 (t, 1H, J = 8.6 Hz), 7.34 (s, 1H), 7.37-7.47 (m, 1H), 8.02 (d, 1H, J = 8.6 Hz), 8.06 (d, 1H, J = 11.0 Hz).
IR spectrum (KBr) 1130, 1278, 1488, 1515, 1607, 3434 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 498 ((M + H) ^<+> ).

Example 21 1-[(4-Ethyl-5- {5- [4- (2-methoxyphenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine -3-carboxylic acid 0.5 oxalate

(21a) 4- (2-Methoxyphenoxy) benzoic acid 4-fluorobenzaldehyde (1.2 g, 10 mmol), 2-methoxyphenol (1.7 g, 14 mmol), potassium carbonate (3.5 g, 25 mmol), 2-methyl In the same manner as in Example 10 (10e) using 2-butene (3.9 mL, 37 mmol), monopotassium phosphate (2.5 g, 19 mmol), and sodium hypochlorite (2.0 g, 22 mmol). Reaction was performed to obtain the title compound (1.6 g, 89%) as a crystalline yellowish white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 3.80 (s, 3H), 6.93 (dd, 2H, J = 8.6 Hz, 2.0 Hz), 6.99 (td, 1H, J = 7.4 Hz) , 1.6 Hz), 7.04 (dd, 1 H, J = 8.2 Hz, 1.6 Hz), 7.09 (dd, 1 H, J = 8.2 Hz, 1.6 Hz), 7.23 (td, 1H, J = 7.4 Hz, 1.6 Hz), 8.04 (dd, 1H, J = 8.6 Hz, 2.0 Hz).

(21b) (4-Ethyl-5- {5- [4- (2-methoxyphenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methanol In Example 21 (21a) 4- (2-methoxyphenoxy) benzoic acid obtained (0.13 g, 0.53 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Hydrochloride (0.11 g, 0.55 mmol), 5-({[t-butyl (dimethyl) silyl] oxy} methyl) -3-ethyl-N′-hydroxythiophene- obtained in Example 10 (10d) 2-Carboximimidamide (0.16 g, 0.50 mmol), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (1 0 mL, the reaction was carried out in the same manner as in Example 12 (12a) using 1.0 mmol), to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 2: 5) to obtain the title compound (0.15 g, 72%) as a crystalline yellowish white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.29 (t, 3H, J = 7.4 Hz), 1.85 (t, 1H, J = 6.3 Hz), 3.06 (q, 2H, J = 7) .4 Hz), 3.81 (s, 3H), 4.85 (d, 2H, J = 6.3 Hz), 6.98 (s, 1H), 6.99-7.07 (m, 4H), 7.11 (dd, 1H, J = 7.8 Hz, 1.6 Hz), 7.24 (dt, 1H, J = 7.8 Hz, 1, 6 Hz), 8.11 (dd, 2H, J = 9. 0 Hz, 2.0 Hz).
IR spectrum (KBr) 1228, 1262, 1354, 1497, 1513, 1612, 3316, 3379 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 409 ((M + H) ^<+> ).

(21c) Methyl 1-[(4-ethyl-5- {5- [4- (2-methoxyphenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine- 3-Carboxylate (4-Ethyl-5- {5- [4- (2-methoxyphenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2 obtained in Example 21 (21b) -Thienyl) methanol (0.14 g, 0.35 mmol), carbon tetrabromide (0.17 g, 0.53 mmol), triphenylphosphine (0.14 g, 0.53 mmol), methyl 3-azetidinecarboxylate hydrochloride (80 mg, 0.53 mmol) and N, N-diisopropylethylamine (0.18 mL, 1.1 mmol) in the same manner as in Example 1 (1f). There, to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 2: 5 to 1: 2) to obtain the title compound (89 mg, 50%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.27 (t, 3H, J = 7.4 Hz), 3.03 (q, 2H, J = 7.4 Hz), 3.31-3.41 (m, 3H ), 3.59-3.68 (m, 2H), 3.72 (s, 3H), 3.78 (s, 2H), 3.81 (s, 3H), 6.86 (s, 1H) 6.97-7.07 (m, 4H), 7.11 (dd, 1H, J = 8.2 Hz, 1.6 Hz), 7.24 (td, 1H, J = 7.4 Hz, 1.6 Hz) ), 8.10 (dd, 2H, J = 9.0 Hz, 2.2 Hz).
IR spectrum (Thin film) 1168, 1176, 1201, 1265, 1346, 1455, 1496, 1513, 1613, 1737 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 506 ((M + H) ^<+> ).

(21d) 1-[(4-Ethyl-5- {5- [4- (2-methoxyphenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3 -Carboxylic acid 0.5 oxalate Methyl 1-[(4-ethyl-5- {5- [4- (2-methoxyphenoxy) phenyl] -1,2,4 obtained in Example 21 (21c) -Oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3-carboxylate (86 mg, 0.17 mmol) was dissolved in dioxane (3 mL) and 1N aqueous sodium hydroxide solution (0.51 mL, 0.51 mmol). And stirred at room temperature for 2 hours. Acetic acid (29 μL, 0.51 mmol) was added to stop the reaction, the solvent was distilled off under reduced pressure, and methanol (2 mL) and water (1 mL) were added. Further, a methanol solution (0.5 mL) of oxalic acid (8 mg, 0.09 mmol) was added and stirred for 30 minutes. The precipitated white solid was collected by filtration with a Kiriyama funnel, washed with a water-methanol solution (3: 7), and dried under reduced pressure to obtain the title compound (63 mg, 69%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 1.30 (t, 3H, J = 6.8 Hz), 3.09 (q, 2H, J = 6.8 Hz), 3.78 (s, 3H) , 3.76-3.89 (m, 1H), 4.33-4.43 (m, 2H), 4.50-4.61 (m, 2H), 4.68 (s, 2H), 6 .98-7.07 (m, 3H), 7.10-7.18 (m, 2H), 7.27 (t, 1H, J = 6.6 Hz), 7.34 (s, 1H), 8 .12 (d, 2H, J = 8.6 Hz).
IR spectrum (KBr) 1233, 1265, 1346, 1497, 1515, 1614, 3422 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 492 ((M + H) ^<+> ).

Example 22 1-({3-Ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid

(22a) [5-({[t-Butyl (dimethyl) silyl] oxy} methyl) -3-ethyl-2-thienyl] methanol 5-({[t-Butyl (a) obtained in Example 10 (10b) Dimethyl) silyl] oxy} methyl) -3-ethylthiophene-2-carbaldehyde (1.5 g, 5.8 mmol) was dissolved in methanol (10 mL) and cooled to 0 ° C., and then sodium borohydride (0. 22 g, 5.8 mmol) was slowly added and stirred for 30 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in ether, poured into water (20 mL), and extracted with ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 3: 7) to obtain the title compound (1.4 g, 94%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.11 (s, 6H), 0.93 (s, 9H), 1.18 (t, 3H, J = 7.4 Hz), 2.57 (q, 2H, J = 7.4 Hz), 4.71 (d, 2H, J = 5.9 Hz), 4.80 (s, 2H), 6.72 (s, 1H).
IR spectrum (liquid film) 1075, 1149, 1255, 1362, 1390, 1463, 3352 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 285 ((M-H) ^<+> ).

(22b) 4-Ethyl-5-[(tetrahydro-2H-pyran-2-yloxy) methyl] thiophene-2-carbaldehyde [5-({[t-butyl (dimethyl ether)] obtained in Example 22 (22a) ) Silyl] oxy} methyl) -3-ethyl-2-thienyl] methanol (1.4 g, 5.3 mmol) dissolved in methylene chloride (10 mL), cooled to 0 ° C., and then 3,4-dihydro-2H -Pyran (0.58 mL, 6.4 mmol) and p-toluenesulfonic acid (10 mg, 0.04 mmol) were added and stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate (5 mL) was added to stop the reaction, and then the reaction solution was poured into water (20 mL) and extracted with ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (5 mL), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (6.4 mL, 6.4 mmol) was added, and the mixture was stirred at room temperature for 30 min. The reaction solution was poured into water (20 mL), and an extraction operation was performed using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methylene chloride (30 mL), molecular sieves 4A (10 g) was added, and after cooling to 0 ° C., pyridinium dichromate (3.3 g, 8.7 mmol) was added, and at room temperature for 2 hours. Stir. Ether (150 mL) was added to the reaction solution, the insoluble material was filtered through silica gel, and then the solvent was distilled off under reduced pressure to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 10-2: 8) to obtain the title compound (0.97 g, 78%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.23 (t, 3H, J = 7.6 Hz), 1.50-1.92 (m, 6H), 2.61 (q, 2H, J = 7.6 Hz) ), 3.53-3.59 (m, 1H), 3, 84-3.92 (m, 1H), 4.65 (d, 1H, J = 13.5 Hz), 4.74 (t, 1H) , J = 3.5 Hz), 4.87 (d, 1H, J = 13.5 Hz), 7.55 (s, 1H), 9.80 (s, 1H).
IR spectrum (liquid film) 1023, 1036, 1121, 1158, 1454, 1670, 2873, 2942, 3440 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 254 (M ^<+> ).

(22c) 4-ethyl-5-[(tetrahydro-2H-pyran-2-yloxy) methyl] thiophene-2-carbonitrile 4-ethyl-5-[(tetrahydro-2H) obtained in Example 22 (22b) -Pyran-2-yloxy) methyl] thiophene-2-carbaldehyde (0.97 g, 3.6 mmol), hydroxyamine hydrochloride (0.29 g, 3.9 mmol), triethylamine (1.1 mL, 7.2 mmol), Reaction was carried out in the same manner as in Example 1 (1c) using dicyclohexylcarbodiimide (0.87 g, 3.9 mmol) to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 10-10: 90) to obtain the title compound (0.86 g, 95%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.19 (t, 3H, J = 7.6 Hz), 1.52-1.90 (m, 6H), 2.58 (q, 2H, J = 7.6 Hz) ), 3.52-3.59 (m, 1H), 3,82-3.90 (m, 1H), 4.62 (d, 1H, J = 13.3 Hz), 4.71 (t, 1H) , J = 3.3 Hz), 4.84 (d, 1H, J = 13.3 Hz), 7.38 (s, 1H).
IR spectrum (liquid film) 903, 1024, 1036, 1066, 1077, 1123, 1174, 1201, 1342, 1454, 2216, 2873, 2942 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 251 (M ^<+> ).

(22d) 4-Ethyl-N′-hydroxy-5-[(tetrahydro-2H-pyran-2-yloxy) methyl] thiophene-2-carboxyimidamide 4-ethyl-5 obtained in Example 22 (22c) Example 1 (1d) using-[(tetrahydro-2H-pyran-2-yloxy) methyl] thiophene-2-carbonitrile (0.86 g, 3.4 mmol), 50% aqueous hydroxyamine (0.5 mL) The reaction was carried out in the same manner as above to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 5: 5) to obtain the title compound (0.96 g, 98%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.20 (t, 3H, J = 7.6 Hz), 1.47-1.89 (m, 6H), 2.59 (q, 2H, J = 7.6 Hz) ), 3.52-3.59 (m, 1H), 3,87-3.94 (m, 1H), 4.61 (d, 1H, J = 12.9 Hz), 4.71 (t, 1H) , J = 3.3 Hz), 4.80 (d, 1H, J = 12.9 Hz), 4.82 (br, 2H), 7.07 (s, 1H), 7.23 (br, 1H).
IR spectrum (liquid film) 1022, 1117, 1344, 1390, 1588, 1635, 2872, 2942, 3353 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 285 ((M + H) ^<+> ).

(22e) 3- {4-Ethyl-5-[(tetrahydro-2H-pyran-2-yloxy) methyl] -2-thienyl} -5- (4-phenoxyphenyl) -1,2,4-oxadiazole 4-phenoxybenzoic acid (0.16 g, 0.73 mmol), 1-hydroxybenzotriazole (0.12 g, 0.76 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.15 g , 0.76 mmol), 4-ethyl-N′-hydroxy-5-[(tetrahydro-2H-pyran-2-yloxy) methyl] thiophene-2-carboxyimidamide (0) obtained in Example 22 (22d) .17 g, 0.69 mmol), tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 1.4 mL, 1.4 The reaction was carried out in the same manner as in Example 5 (5a) using mol), to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 10-2: 8) to obtain the title compound (0.25 g, 78%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.26 (t, 3H, J = 7.6 Hz), 1.50-1.93 (m, 6H), 2.65 (q, 2H, J = 7.6 Hz) ), 3.55-3.61 (m, 1H), 3,89-3.96 (m, 1H), 4.69 (d, 1H, J = 12.9 Hz), 4.77 (t, 1H) , J = 3.5 Hz), 4.88 (d, 1H, J = 12.9 Hz), 7.07-7.12 (m, 4H), 7.20-7.25 (m, 1H), 7 .41 (d, 1H, J = 7.4 Hz), 7.43 (d, 1H, J = 7.4 Hz), 7.66 (s, 1H), 8.15 (d, 2H, J = 9. 0 Hz).
IR spectrum (liquid film) 761, 1022, 1167, 1245, 1488, 1589, 1613, 2872, 2940 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 463 ((M + H) ^<+> ).

(22f) {3-Ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methanol 3-obtained in Example 22 (22e) {4-Ethyl-5-[(tetrahydro-2H-pyran-2-yloxy) methyl] -2-thienyl} -5- (4-phenoxyphenyl) -1,2,4-oxadiazole (0.25 g, 0.54 mmol) was dissolved in ethanol (5 mL), pyridinium p-toluenesulfonate (0.014 g, 0.054 mmol) was added, and the mixture was stirred at 60 ° C. for 4 hours. The reaction solution was poured into water (20 mL) to stop the reaction, and then a liquid separation operation was performed using ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (0.19 g, 92%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.27 (t, 3H, J = 7.6 Hz), 1.79 (t, 1H, J = 5.9 Hz), 2.67 (q, 2H, J = 7) .6 Hz), 4.83 (d, 2H, J = 5.9 Hz), 7.07-7.12 (m, 4H), 7.20-7.25 (m, 1H), 7.41 (d , 1H, J = 7.4 Hz), 7.43 (d, 1H, J = 7.4 Hz), 7.67 (s, 1H), 8.15 (d, 2H, J = 8.6 Hz).
IR spectrum (KBr) 760,998,1232,1422,1487,1579,1591,1615,2964,3452cm < ^-1 >
Mass spectrum (FAB ^<+> ) m / z: 379 ((M + H) ^<+> ).

(22g) methyl 1-({3-ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylate {3-Ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methanol (0.19 g, 0) obtained in Example 22 (22f). .50 mmol), carbon tetrabromide (0.33 g, 0.99 mmol), triphenylphosphine (0.26 g, 0.99 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.11 g, 0.75 mmol), Reaction was performed in the same manner as in Example 1 (1f) using N, N-diisopropylethylamine (0.22 mL, 1.2 mmol) to obtain the title crude product. Purification was performed by silica gel chromatography (ethyl acetate: hexane = 2: 8 to 4: 6) to obtain the title compound (0.17 g, 72%) as a crystalline light yellow solid.
¹ H NMR spectrum (500 MHz, CDCl ₃ ) δ 1.23 (t, 3H, J = 7.6 Hz), 2.61 (q, 2H, J = 7.6 Hz), 3.33-3.41 (m, 3H ), 3.62-3.70 (m, 2H), 3.72 (s, 3H), 3.77 (s, 2H), 7.06-7.12 (m, 4H), 7.20- 7.24 (m, 1H), 7.38-7.43 (m, 2H), 7.62 (s, 1H), 8.14 (d, 2H, J = 8.8 Hz).
IR spectrum (KBr) 1167, 1249, 1367, 1490, 1589, 1736, 2963 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 476 ((M + H) ^<+> ).

(22h) 1-({3-Ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid
Methyl 1-({3-ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) obtained in Example 22 (22 g) Example 3 (3e) with azetidine-3-carboxylate (0.17 g, 0.36 mmol), 1N aqueous sodium hydroxide solution (1.1 mL, 1.1 mmol), acetic acid (62 μL, 1.1 mmol) and Reaction was performed in the same manner to obtain the title compound (0.16 g, 95%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 1.29 (t, 3H, J = 7.5 Hz), 2.78 (q, 2H, J = 7.5 Hz), 3.75-3.86 ( m, 1H), 4.30-4.60 (m, 2H), 4.71 (s, 2H), 7.11-7.17 (m, 4H), 7.22-7.27 (m, 1H), 7.41-7.48 (m, 2H), 7.80 (s, 1H), 8.15-8.21 (m, 2H).
IR spectrum (KBr) 761, 1170, 1241, 1368, 1487, 1591, 1614, 2969, 3536 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 462 ((M + H) ^<+> ).

  Example 23 1-({5- [5- (3-Fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carvone acid

(23a) 5-Bromo-2-({[t-butyl (dimethyl) silyl] oxy} methyl) pyridine 5-Bromo-2-formylpyridine (4.6 g, 25 mmol) was dissolved in methanol (30 mL) and 0 After cooling to ° C., sodium borohydride (0.93 g, 25 mmol) was added and stirred for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with ethyl acetate, poured into water (20 mL), and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. Imidazole (3.4 g, 49 mmol) was added to the obtained residue, and the residue was dissolved with N, N-dimethylformamide (30 mL). t-Butyldimethylsilyl chloride (4.1 g, 27 mmol) was added and stirred at room temperature for 1 hour, and then the reaction solution was poured into water (50 mL) and extracted with ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 49 to 1: 9) to obtain the title compound (6.8 g, 90%) as a crystalline white solid.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 0.12 (s, 6H), 0.95 (s, 9H), 4.78 (s, 2H), 7.42 (d, 1H, J = 8.6 Hz) 7.82 (dd, 1H, J = 2.3 Hz, 8.6 Hz), 8.56 (d, 1H, J = 2.3 Hz).
IR spectrum (KBr) 1008, 1104, 1258, 1377, 1471, 1578 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 302 ((M + H) ⁺ ).

(23b) 6-({[t-butyl (dimethyl) silyl] oxy} methyl) nicotinonitrile 5-bromo-2-({[t-butyl (dimethyl) silyl] obtained in Example 23 (23a) Oxy} methyl) pyridine (0.30 g, 1.0 mmol), zinc cyanide (0.18 g, 1.5 mmol), bis (dibenzylideneacetone) palladium (18 mg, 0.02 mmol), 1,1′-bis ( Diphenylphosphino) ferrocene (44 mg, 0.08 mmol) was dissolved in N-methyl-2-pyrrolidinone (4 mL), heated to 100 ° C. and stirred for 1 hour. After cooling to room temperature, the reaction solution was poured into water and extracted with ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to obtain the title compound (0.23 g, 93%) as a crystalline white solid.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 0.14 (s, 6H), 0.96 (s, 9H), 4.87 (s, 2H), 7.67 (d, 1H, J = 8.2 Hz) 7.98 (dd, 1H, J = 2.0 Hz, 8.2 Hz), 8.78 (d, 1H, J = 2.0 Hz).
IR spectrum (KBr) 1110, 1254, 1470, 1594, 2230 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 249 ((M + H) ^<+> ).

(23c) 6-({[t-Butyl (dimethyl) silyl] oxy} methyl) -N'-hydroxypyridine-3-carboxyimidamide 6-({[t-Butyl] obtained in Example 23 (23b) (Dimethyl) silyl] oxy} methyl) nicotinonitrile (2.0 g, 8.1 mmol), 40% aqueous hydroxyamine solution (1 mL) was used for the reaction in the same manner as in Example 1 (1d), and the title crude product I got a thing. Purification was performed by recrystallization (ethyl acetate: hexane = 1: 9) to obtain the title compound (2.1 g, 94%) as a crystalline white solid.
¹ H NMR spectrum (500 MHz, CDCl ₃ ) δ 0.13 (s, 6H), 0.96 (s, 9H), 4.86 (s, 2H), 4.89 (br, 2H), 7.56 (d , 1H, J = 8.3 Hz), 7.95 (dd, 1H, J = 2.4 Hz, 8.3 Hz), 8.77 (d, 1H, J = 2.4 Hz).
IR spectrum (KBr) 1258, 1380, 1397, 1645, 3166, 3299, 3467 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 282 ((M + H) ^<+> ).

(23d) 4-Bromo-2-fluoro-1- (2-methylprop-1-en-1-yl) benzene Isopropyltriphenylphosphonium iodide (0.65 g, 1.5 mmol) was added to N, N-dimethylformamide. (6 mL) and cooled to 0 ° C. A solution of potassium t-butoxide (0.18 g, 1.6 mmol) in N, N-dimethylformamide (2 mL) was slowly added dropwise and stirred for 30 minutes, and then 4-bromo-2-fluorobenzaldehyde (0.20 g, 1.0 mmol). ) In N, N-dimethylformamide (2 mL) was added, and the mixture was warmed to room temperature and stirred for 1 hour. After adding saturated ammonium chloride aqueous solution (5 mL) to stop the reaction, the reaction solution was poured into water (20 mL), and extraction operation was performed using ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 10-5: 95) to obtain the title compound (0.19 g, 82%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.76 (s, 3H), 1.92 (s, 3H), 6.13 (s, 1H), 7.09 (t, 1H, J = 8.2 Hz) , 7.19-7.24 (m, 2H).
IR spectrum (Liquid film) 1403, 1483, 1562, 1599 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 228 (M ^<+> ).

(23e) 3-Fluoro-4-isobutylbenzoic acid 4-Bromo-2-fluoro-1- (2-methylprop-1-en-1-yl) benzene (0.19 g) obtained in Example 23 (23d) , 0.81 mmol) was dissolved in tetrahydrofuran (4 mL) and cooled to -78 ° C. A 1.6 M n-butyllithium / hexane solution (0.62 mL, 0.97 mmol) was added dropwise, and then carbon dioxide was blown into the solution and stirred for 1 hour. 1N Aqueous sodium hydroxide solution (2 mL) was added to stop the reaction, and the aqueous layer was washed with ether, acidified with a 10M aqueous hydrochloric acid solution, and extracted again with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (3 mL), 10% palladium carbon (30 mg) was added, and the mixture was stirred at room temperature for 1 hr in a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was evaporated under reduced pressure to give the title compound (0.12 g, 77%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.93 (t, 6H, J = 6.6 Hz), 1.88-2.00 (m, 1H), 2.58 (d, 2H, J = 7.4 Hz) ), 7.25 (t, 1 H, J = 7.8 Hz), 7.73 (dd, 1 H, J = 7.8 Hz, 1.6 Hz), 7.81 (dd, 1 H, J = 10.2 Hz, 1.6 Hz).

(23f) {5- [5- (3-Fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methanol 3 obtained in Example 23 (23e) -Fluoro-4-isobutylbenzoic acid (0.12 g, 0.63 mmol), 1-hydroxybenzotriazole (89 mg, 0.66 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0. 13 g, 0.66 mmol), 6-({[t-butyl (dimethyl) silyl] oxy} methyl) -N′-hydroxypyridine-3-carboxyimidamide (0.17 g) obtained in Example 23 (23c). 0.60 mmol), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (1.2 mL, 1.2 mmol) The reaction was carried out in the same manner as in Example 12 (12a) using, to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 2: 3 to 1: 1) to obtain the title compound (0.16 g, 80%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.96 (d, 6H, J = 6.6 Hz), 1.62 (bs, 1H), 1.91-2.04 (m, 1H), 2.62 ( d, 2H, J = 8.2 Hz), 4.87 (s, 2H), 7.36 (t, 1H, J = 7.8 Hz), 7.43 (d, 1H, J = 8.2 Hz), 7.87 (dd, 1H, J = 10.2 Hz, 1.6 Hz), 7.93 (dd, 1H, J = 7.8 Hz, 1.6 Hz), 8.44 (dd, 1H, J = 8. 2 Hz, 2.0 Hz), 9.34 (d, 1 H, J = 1.6 Hz).
IR spectrum (KBr) 1030, 1128, 1394, 1500, 1560, 1594, 1612, 3170 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 328 ((M + H) ^<+> ).

(23 g) Methyl 1-({5- [5- (3-Fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylate {5- [5- (3-Fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methanol (0.16 g) obtained in Example 23 (23f) , 0.47 mmol), carbon tetrabromide (0.23 g, 0.71 mmol), triphenylphosphine (0.19 g, 0.71 mmol) dissolved in methylene chloride (6 mL) and stirred at 0 ° C. for 10 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6). The resulting intermediate was dissolved in methylene chloride (7 mL) and methyl 3-azetidinecarboxylate hydrochloride (0.11 g, 0.71 mmol), N, N-diisopropylethylamine (0.25 mL, 1.4 mmol) was added. The mixture was further stirred at room temperature for 13 hours. Saturated aqueous sodium hydrogen carbonate (2 mL) was added to stop the reaction, the solution was poured into water (20 mL), and extraction operation was performed using ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 12) to obtain the title compound (0.12 g, 59%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.96 (d, 6H, J = 6.6 Hz), 1.90-2.04 (m, 1H), 2.62 (d, 2H, J = 7.0 Hz) ), 3.35-3.46 (m, 1H), 3.48 (t, 2H, J = 7.2 Hz), 3.66 (t, 2H, J = 7.4 Hz), 3.73 (s , 3H), 3.87 (s, 2H), 7.35 (t, 1H, J = 8.2 Hz), 7.48 (d, 1H, J = 7.4 Hz), 7.86 (dd, 1H) , J = 10.0 Hz, 1.6 Hz), 7.93 (dd, 1 H, J = 7.8 Hz, 1.6 Hz), 8.39 (dd, 1 H, J = 8.2 Hz, 2.1 Hz), 9.30 (d, 1H, J = 1.2 Hz).
IR spectrum (KBr) 1218, 1340, 1373, 1398, 1500, 1559, 1729 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 425 ((M + H) ^<+> ).

(23h) 1-({5- [5- (3-Fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid Methyl 1-({5- [5- (3-fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) obtained in Example 23 (23 g) The reaction was conducted in the same manner as in Example 3 (3e) using azetidine-3-carboxylate (0.12 g, 0.27 mmol), 1N aqueous sodium hydroxide solution (0.81 mL, 0.81 mmol), and the title compound (90 mg, 81%) was obtained as a crystalline white solid.
¹ H NMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 0.97 (d, 6H, J = 6.6 Hz), 1.93-2.05 (m, 1H), 2.65 (d, 2H, J = 7.0 Hz), 3.83-3.94 (m, 1H), 4.48-4.57 (m, 2H), 4.60-4.71 (m, 2H), 4.82 (s, 2H), 7.47 (t, 1H, J = 7.8 Hz), 7.77 (d, 1H, J = 8.2 Hz), 7.92 (d, 1H, J = 9.8 Hz), 7. 99 (d, 1H, J = 7.8 Hz), 8.60 (d, 1H, J = 8.2 Hz), 9.34 (s, 1H).
IR spectrum (KBr) 1129, 1344, 1367, 1399, 1500, 1602, 1627, 2128, 2958 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 411 ((M + H) ^<+> ).

Example 24 1-({5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine -3-carboxylic acid

(24a) 2- (Methylthio) -6-{[(triisopropylsilyl) oxy] methyl} nicotinonitrile 6-formyl-2- (methylthio) nicotinonitrile (1.0 g, 5.6 mmol) in methanol (10 mL) ) And cooled to 0 ° C., sodium borohydride was slowly added and stirred for 10 minutes. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, poured into water (20 mL), and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. Imidazole (0.76 g, 11 mmol) was added to the resulting residue and dissolved in N, N-dimethylformamide (6 mL), then triisopropylsilyl chloride (1.3 mL, 6.2 mmol) was added and stirred at room temperature for 2 hours. did. The reaction solution was poured into water (20 mL), and an extraction operation was performed using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 10-3: 97) to obtain the title compound (1.7 g, 91%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.10 (d, 18H, J = 6.6 Hz), 1.18-1.25 (m, 3H), 2.60 (s, 3H), 4.89 ( s, 2H), 7.34 (d, 1H, J = 7.8 Hz), 7.80 (d, 1H, J = 7.8 Hz).
IR spectrum (KBr) 1372, 1423, 1552, 1573, 2220 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 337 ((M + H) ^<+> ).

(24b) 2- (Methylsulfonyl) -6-{[(triisopropylsilyl) oxy] methyl} nicotinonitrile 2- (methylthio) -6-{[(triisopropylsilyl) obtained in Example 24 (24a) ) Oxy] methyl} nicotinonitrile (1.5 g, 4.5 mmol) was dissolved in ethanol (10 mL) and cooled to 0 ° C. After adding m-chloroperbenzoic acid (2.3 g, 14 mmol), the mixture was warmed to room temperature and stirred for 3 hours. The residue obtained by evaporating the solvent under reduced pressure was diluted with ether (20 mL), saturated aqueous potassium carbonate solution (10 mL) was added, and the mixture was stirred for 1 hr. The reaction solution was poured into water (20 mL), and an extraction operation was performed using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 2: 8 to 3: 7) to obtain the title compound (1.7 g, 100%) as a white crystalline solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.12 (d, 18H, J = 6.8 Hz), 1.19-1.28 (m, 3H), 3.36 (s, 3H), 5.02 ( s, 2H), 7.99 (d, 1H, J = 7.8 Hz), 8.26 (d, 1H, J = 7.8 Hz).
IR spectrum (KBr) 1317, 1384, 1463, 1585, 2237 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 369 ((M + H) ^<+> ).

(24c) 2-Methyl-6-{[(triisopropylsilyl) oxy] methyl} nicotinonitrile 2- (methylsulfonyl) -6-{[(triisopropylsilyl) oxy obtained in Example 24 (24b) ] Methyl} nicotinonitrile (0.80 g, 2.2 mmol) was dissolved in ether (10 mL) and cooled to -78 ° C. A 3.0M methylmagnesium bromide / ether solution (1.5 mL, 4.4 mmol) was added and stirred for 1 hour. After adding saturated ammonium chloride aqueous solution (1 mL) to stop the reaction, the reaction solution was poured into water (20 mL), and extraction operation was performed using ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 10 to 1: 9) to obtain the title compound (0.64 g, 95%) as a white crystalline solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.09 (d, 18H, J = 6.6 Hz), 1.18-1.26 (m, 3H), 2.74 (s, 3H), 4.92 ( s, 2H), 7.55 (d, 1H, J = 7.8 Hz), 7.92 (d, 1H, J = 7.8 Hz).
IR spectrum (KBr) 1128, 1410, 1463, 1567, 1590, 2227 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 305 ((M + H) ⁺ ).

(24d) N′-hydroxy-2-methyl-6-{[(triisopropylsilyl) oxy] methyl} pyridine-3-carboxyimidamide 2-methyl-6-{[obtained in Example 24 (24c) (Triisopropylsilyl) oxy] methyl} nicotinonitrile (0.63 g, 2.1 mmol), 40% hydroxyamine aqueous solution (0.5 mL) was used for the reaction in the same manner as in Example 1 (1d), The title crude was obtained. Purification was performed by recrystallization (ethyl acetate: hexane = 1: 9) to obtain the title compound (0.61 g, 86%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.09 (d, 18H, J = 6.8 Hz), 1.15 to 1.26 (m, 3H), 2.63 (s, 3H), 4.79 ( brs, 2H), 4.92 (s, 2H), 7.18 (br, 1H), 7.46 (d, 1H, J = 7.8 Hz), 7.72 (d, 1H, J = 7. 8 Hz).
IR spectrum (KBr) 1124, 1462, 1579, 1597, 1644, 3050, 3337, 3449 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 338 ((M + H) ⁺ ).

(24e) (4-Bromo-2-chlorophenyl) methanol 4-Bromo-2-chlorobenzoic acid (3.1 g, 13.2 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to 0 ° C. A 1.0 M borane-tetrahydrofuran complex / tetrahydrofuran solution (13.8 mL, 13.8 mmol) was added and stirred for 20 minutes, and then the mixture was warmed to room temperature and stirred for 4 hours. Water (10 mL) was added to stop the reaction, and the reaction solution was poured into saturated aqueous sodium hydrogen carbonate (50 mL), followed by extraction using ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 9-7: 3) to obtain the title compound (2.8 g, 97%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 7.51 (d, 1H, J = 2.0 Hz), 7.40 (dd, 1H, J = 8.2 Hz, 2.0 Hz), 7.36 (d, 1H , J = 8.2 Hz), 4.73 (d, 2H, J = 6.3 Hz), 1.90 (t, 1H, J = 6.3 Hz).
IR spectrum (KBr) 1036, 1063, 1385, 1469, 1561, 1586, 3239 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 220 (M ^<+> ).

(24f) 4-Bromo-2-chlorobenzaldehyde (4-Bromo-2-chlorophenyl) methanol (2.8 g, 12.8 mmol) obtained in Example 24 (24e) was dissolved in methylene chloride (50 mL). Pyridinium dichromate (7.2 g, 19.2 mmol) was added and stirred at room temperature for 1 hour. After completion of the reaction, ether (250 mL) was poured into the reaction solution. After filtration through Celite, the solvent was distilled off under reduced pressure to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 20) to obtain the title compound (2.0 g, 70%) as a crystalline white solid.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 7.55 (dd, 1 H, J = 8.2 Hz, 1.6 Hz), 7.66 (d, 1 H, J = 1.6 Hz), 7.79 (d, 1 H , J = 8.2 Hz), 10.42 (s, 1H).
IR spectrum (KBr) 1201, 1374, 1577, 1693 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 218 (M ^<+> ).

(24 g) 4-Bromo-2-chloro-1- (2-methylprop-1-en-1-yl) benzene isopropyl triphenylphosphonium iodide (5.4 g, 12.6 mmol), potassium t-butoxide (1 0.5 g, 13.5 mmol), and 4-bromo-2-chlorobenzaldehyde (2.0 g, 9.0 mmol) obtained in Example 24 (24f) was used in the same manner as in Example 23 (23d). To obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 10-6: 94) to obtain the title compound (2.1 g, 94%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.74 (s, 3H), 1.93 (s, 3H), 6.20 (s, 1H), 7.10 (d, 2H, J = 8.2 Hz) , 7.33 (dd, 1H, J = 8.2 Hz, 2.0 Hz), 7.53 (d, 1H, J = 2.0 Hz).
IR spectrum (Thin film) 1045, 1083, 1373, 1468, 1579 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 244 (M ^<+> ).

(24h) 3-Chloro-4-isobutylbenzoic acid 4-Bromo-2-chloro-1- (2-methylprop-1-en-1-yl) benzene (2.1 g) obtained in Example 24 (24 g) 8.5 mmol), 1.6 M n-butyllithium / hexane solution (5.6 mL, 8.9 mmol), 5% platinum / carbon (200 mg), and the reaction was conducted in the same manner as in Example 23 (23e). The title compound (1.5 g, 99%) was obtained as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.95 (d, 6H, J = 6.6 Hz), 1.96-2.08 (m, 1H), 2.68 (d, 2H, J = 7.4 Hz) ), 7.28 (d, 1H, J = 7.8 Hz), 7.90 (d, 1H, J = 7.0 Hz), 8.08 (s, 1H).
Mass spectrum (FAB ^<+> ) m / z: 212 (M ^<+> ).

(24i) {5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methanol In Example 24 (24h) Obtained 3-chloro-4-isobutylbenzoic acid (0.11 g, 0.50 mmol), 1-hydroxybenzotriazole (72 mg, 0.53 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salt (0.10 g, 0.53 mmol), N′-hydroxy-2-methyl-6-{[(triisopropylsilyl) oxy] methyl} pyridine-3-carboxyimidamide obtained in Example 24 (24d) (0.16 g, 0.48 mmol), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (0.96 mL, 0 The reaction was carried out in the same manner as in Example 12 (12a) using 96 mmol), to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (0.15 g, 89%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.97 (d, 6H, J = 6.8 Hz), 2.00-2.09 (m, 1H), 2.71 (d, 2H, J = 7.3 Hz) ), 2.95 (s, 3H), 3.87 (t, 1H, J = 4.9 Hz), 4.81 (d, 2H, J = 4.9 Hz), 7.24 (d, 1H, J = 7.8 Hz), 7.38 (d, 1 H, J = 7.8 Hz), 8.01 (dd, 1 H, J = 7.8 Hz, 1.5 Hz), 8.21 (d, 1 H, J = 1.5 Hz), 8.39 (d, 1 H, J = 7.8 Hz).
IR spectrum (KBr) 1332, 1407, 1454, 1591, 3238 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 358 ((M + H) ^<+> ).

(24j) Methyl 1-({5- [5- (3-chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine- 3-Carboxylate {5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridine-2 obtained in Example 24 (24i) -Yl} methanol (0.15 g, 0.42 mmol), carbon tetrabromide (0.22 g, 0.67 mmol), triphenylphosphine (0.18 g, 0.67 mmol), methyl 3-azetidinecarboxylate hydrochloride (96 mg, 0.63 mmol), N, N-diisopropylethylamine (0.22 mL, 1.3 mmol) was used in the same manner as in Example 23 (23 g). It was carried out, to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to 2: 1 to 3: 1) to obtain the title compound (0.11 g, 58%) as a crystalline light yellow solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.97 (d, 6H, J = 6.6 Hz), 1.98-2.10 (m, 1H), 2.70 (d, 2H, J = 7.4 Hz) ), 2.91 (s, 3H), 3.34-3.45 (m, 1H), 3.47 (t, 2H, J = 7.2 Hz), 3.66 (t, 2H, J = 7) .6 Hz), 3.73 (s, 3H), 3.83 (s, 2H), 7.32 (d, 1H, J = 7.8 Hz), 7.37 (d, 1H, J = 7.8 Hz) ), 8.01 (dd, 1H, J = 7.8 Hz, 1.9 Hz), 8.21 (d, 1H, J = 1.6 Hz), 8.34 (d, 1H, J = 7.8 Hz) .
IR spectrum (KBr) 1203, 1332, 1405, 1438, 1450, 1589, 1735, 2957 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 455 ((M + H) ^<+> ).

(24k) 1-({5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine-3 -Carboxylic acid Methyl 1-({5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-methyl obtained in Example 24 (24j) Similar to Example 3 (3e) using pyridin-2-yl} methyl) azetidine-3-carboxylate (0.11 g, 0.24 mmol), 1N aqueous sodium hydroxide (0.72 mL, 0.72 mmol). Reaction was performed by the method to obtain the title compound (76 mg, 72%) as a crystalline white solid.
¹ H NMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 0.98 (d, 6H, J = 6.6 Hz), 2.00-2.09 (m, 1H), 2.75 (d, 2H, J = 7.0 Hz), 2.93 (s, 3H), 3.83-3.94 (m, 1H), 4.46-4.58 (m, 2H), 4.61-4.71 (m, 2H), 4.77 (s, 2H), 7.49 (d, 1H, J = 7.8 Hz), 7.55 (d, 1H, J = 7.8 Hz), 8.08 (d, 1H, J = 6.6 Hz), 8.23 (s, 1H), 8.53 (d, 1H, J = 7.8 Hz).
IR spectrum (KBr) 1335, 1385, 1568, 1589, 1611, 3412, 3480 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 441 ((M + H) ^<+> ).

Example 25 1-({5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-ethylpyridin-2-yl} methyl) azetidine -3-carboxylic acid

(25a) 2-Ethyl-6-{[(triisopropylsilyl) oxy] methyl} nicotinonitrile 2- (methylsulfonyl) -6-{[(triisopropylsilyl) oxy obtained in Example 24 (24b) ] The reaction was carried out in the same manner as in Example 24 (24c) using methyl} nicotinonitrile (0.78 g, 2.1 mmol) and 3.0 M ethylmagnesium bromide / ether solution (1.4 mL, 4.2 mmol). The title crude product was obtained. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 10 to 1: 9) to obtain the title compound (0.65 g, 97%) as a white crystalline solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.09 (d, 18H, J = 6.8 Hz), 1.16-1.25 (m, 3H), 1.34 (t, 3H, J = 7.4 Hz) ), 3.02 (q, 2H, J = 7.4 Hz), 4.94 (s, 2H), 7.55 (d, 1H, J = 7.8 Hz), 7.92 (d, 1H, J = 7.8 Hz).
IR spectrum (KBr) 1125, 1409, 1464, 1564, 1587, 2227 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 319 ((M + H) ^<+> ).

(25b) 2-Ethyl-N′-hydroxy-6-{[(triisopropylsilyl) oxy] methyl} pyridine-3-carboxyimidamide 2-ethyl-6-{[obtained in Example 25 (25a) (Triisopropylsilyl) oxy] methyl} nicotinonitrile (0.75 g, 2.4 mmol), 40% hydroxyamine aqueous solution (0.5 mL) was used for the reaction in the same manner as in Example 1 (1d), The title crude was obtained. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 3: 7 to 1: 1) to obtain the title compound (0.80 g, 95%) as a white crystalline solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.10 (d, 18 H, J = 6.8 Hz), 1.16-1.24 (m, 3 H), 1.28 (t, 3 H, J = 7.4 Hz) ), 2.93 (q, 2H, J = 7.4 Hz), 4.80 (brs, 2H), 4.93 (s, 2H), 7.45 (d, 1H, J = 7.8 Hz), 7.69 (d, 1H, J = 7.8 Hz), 8.08 (br, 1H).
IR spectrum (KBr) 1120, 1385, 1404, 1462, 1573, 1596, 1637, 3161, 3282, 3362 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 352 ((M + H) ^<+> ).

(25c) {5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-ethylpyridin-2-yl} methanol In Example 24 (24h) Obtained 3-chloro-4-isobutylbenzoic acid (0.10 g, 0.48 mmol), 1-hydroxybenzotriazole (69 mg, 0.51 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salt (97 mg, 0.51 mmol), 2-ethyl-N′-hydroxy-6-{[(triisopropylsilyl) oxy] methyl} pyridine-3-carboxyimidamide (0) obtained in Example 25 (25b) .16 g, 0.46 mmol), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (0.92 mL,. The reaction was carried out in the same manner as in Example 12 (12a) using 2 mmol), to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the title compound (0.15 g, 89%) as a crystalline white solid.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 0.97 (d, 6H, J = 6.8 Hz), 1.38 (t, 3H, J = 7.3 Hz), 2.00-2.10 (m, 1H) ), 2.71 (d, 2H, J = 7.3 Hz), 3.29 (q, 2H, J = 7.3 Hz), 4.09 (t, 1H, J = 4.7 Hz), 4.82 (D, 2H, J = 4.7 Hz), 7.21 (d, 1H, J = 8.3 Hz), 7.38 (d, 1H, J = 7.8 Hz), 8.01 (dd, 1H, J = 7.8 Hz, 1.5 Hz), 8.21 (d, 1 H, J = 1.5 Hz), 8.34 (d, 1 H, J = 8.3 Hz).
IR spectrum (KBr) 1324, 1442, 1451, 1567, 1587, 3286, 3366 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 372 ((M + H) ^<+> ).

(25d) Methyl 1-({5- [5- (3-chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-ethylpyridin-2-yl} methyl) azetidine- 3-Carboxylate {5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-ethylpyridine-2 obtained in Example 25 (25c) -Yl} methanol (0.15 g, 0.40 mmol), carbon tetrabromide (0.27 g, 0.80 mmol), triphenylphosphine (0.21 g, 0.80 mmol), methyl 3-azetidinecarboxylate hydrochloride (91 mg, 0.60 mmol) and N, N-diisopropylethylamine (0.21 mL, 1.2 mmol) in the same manner as in Example 23 (23 g). It was carried out, to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to 2: 1 to 3: 1) to obtain the title compound (0.16 g, 83%) as a pale yellow oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.97 (d, 6H, J = 6.6 Hz), 1.26 (t, 3H, J = 7.4 Hz), 1.99-2.10 (m, 1H) ), 2.71 (d, 2H, J = 7.0 Hz), 3.24 (q, 2H, J = 7.4 Hz), 3.35-3.46 (m, 1H), 3.49 (t , 2H, J = 7.2 Hz), 3.67 (t, 2H, J = 7.8 Hz), 3.73 (s, 3H), 3.84 (s, 2H), 7.30 (d, 1H) , J = 7.8 Hz), 7.37 (d, 1H, J = 8.2 Hz), 8.00 (dd, 1H, J = 8.2 Hz, 1.6 Hz), 8.20 (d, 1H, J = 1.6 Hz), 8.28 (d, 1H, J = 7.8 Hz).
IR spectrum (KBr) 1179, 1203, 1405, 1449, 1589, 1740 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 469 ((M + H) ^<+> ).

(25e) 1-({5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-ethylpyridin-2-yl} methyl) azetidine-3 -Carboxylic acid Methyl 1-({5- [5- (3-chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-ethyl obtained in Example 25 (25d) Similar to Example 3 (3e) using pyridin-2-yl} methyl) azetidine-3-carboxylate (0.15 g, 0.32 mmol), 1N aqueous sodium hydroxide (0.96 mL, 0.96 mmol). Reaction was performed by the method to obtain the title compound (0.10 g, 71%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 0.98 (d, 6H, J = 6.3 Hz), 1.37 (t, 3H, J = 7.2 Hz), 1.95-2.09 ( m, 1H), 2.74 (d, 2H, J = 7.0 Hz), 3.29 (q, 2H, J = 7.2 Hz), 3.87-3.97 (m, 1H), 4. 47-4.60 (m, 2H), 4.67-4.78 (m, 2H), 4.79 (s, 2H), 7.49 (d, 1H, J = 7.8 Hz), 7. 51 (d, 1H, J = 7.4), 8.08 (d, 1H, J = 7.4 Hz), 8.23 (s, 1H), 8.47 (d, 1H, J = 7.8 Hz) ).
IR spectrum (KBr) 1337, 1389, 1397, 1589, 1611, 3432 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 455 ((M + H) ^<+> ).

Example 26 1-({5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carvone acid

(26a) {5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methanol 3 obtained in Example 24 (24h) -Chloro-4-isobutylbenzoic acid (0.13 g, 0.61 mmol), 1-hydroxybenzotriazole (86 mg, 0.64 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0. 12 g, 0.64 mmol), 6-({[t-butyl (dimethyl) silyl] oxy} methyl) -N'-hydroxypyridine-3-carboxyimidamide (0.16 g) obtained in Example 23 (23c). 0.58 mmol), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (1.2 mL, 1.2 mmol) The reaction was carried out in the same manner as in Example 12 (12a) Te, to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 2: 3 to 1: 1) to obtain the title compound (0.19 g, 94%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.98 (d, 6H, J = 6.6 Hz), 1.99-2.10 (m, 1H), 2.71 (d, 2H, J = 7.4 Hz) ), 3.62 (bs, 1H), 4.87 (s, 2H), 7.39 (d, 1H, J = 7.8 Hz), 7.44 (d, 1H, J = 8.2 Hz), 8.03 (dd, 1H, J = 7.8 Hz, 1.6 Hz), 8.23 (d, 1H, J = 1.6 Hz), 8.44 (dd, 1H, J = 8.2 Hz, 2. 2 Hz), 9.34 (d, 1 H, J = 1.2 Hz).
IR spectrum (KBr) 1336, 1393, 1411, 1488, 1607, 3213, 3353, 3436 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 344 ((M + H) ⁺ ).

(26b) Methyl 1-({5- [5- (3-chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylate {5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methanol (0.18 g) obtained in Example 26 (26a) , 0.54 mmol), carbon tetrabromide (0.36 g, 1.1 mmol), triphenylphosphine (0.28 g, 1.1 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.12 g, 0.81 mmol) ) And N, N-diisopropylethylamine (0.28 mL, 1.6 mmol) in the same manner as in Example 23 (23 g) to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 2: 1 to 3: 1) to obtain the title compound (0.15 g, 61%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.97 (d, 6H, J = 6.7 Hz), 1.98-2.08 (m, 1H), 2.70 (d, 2H, J = 7.0 Hz) ), 3.33-3.46 (m, 1H), 3.47 (t, 2H, J = 7.0 Hz), 3.65 (t, 2H, J = 7.6), 3.72 (s) , 3H), 3.86 (s, 2H), 7.35 (d, 1H, J = 7.8 Hz), 7.46 (d, 1H, J = 8.2 Hz), 7.99 (dd, 1H) , J = 7.8 Hz, 1.6 Hz), 8.19 (d, 1H, J = 1.6 Hz), 8.36 (dd, 1H, J = 8.2 Hz, 2.0 Hz), 9.28 ( d, 1H, J = 2.0 Hz).
IR spectrum (KBr) 1207, 1339, 1352, 1389, 1486, 1605, 1738 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 441 ((M + H) ^<+> ).

(26c) 1-({5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid Methyl 1-({5- [5- (3-chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) obtained in Example 26 (26b) The reaction was conducted in the same manner as in Example 3 (3e) using azetidine-3-carboxylate (0.14 g, 0.32 mmol), 1N aqueous sodium hydroxide solution (0.96 mL, 0.96 mmol), and the title compound (0.12 g, 90%) was obtained as a crystalline white solid.
¹ H NMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 0.98 (d, 6H, J = 6.6 Hz), 1.94-2.07 (m, 1H), 2.75 (d, 2H, J = 7.0 Hz), 3.83-3.94 (m, 1H), 4.49-4.60 (m, 2H), 4.60-4.70 (m, 2H), 4.83 (s, 2H), 7.50 (d, 1H, J = 7.8 Hz), 7.78 (d, 1H, J = 7.4 Hz), 8.09 (d, 1H, J = 7.8 Hz), 8. 25 (s, 1H), 8.60 (d, 1H, J = 7.4 Hz), 9.35 (s, 1H).
IR spectrum (KBr) 1368, 1403, 1569, 1587, 1605, 3431 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 427 ((M + H) ^<+> ).

Example 27 1-({5- [5- (4-Isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine -3-carboxylic acid 0.5 oxalate

(27a) (4-Bromo-2-methylphenyl) methanol Performed using 4-bromo-2-methylbenzoic acid (4.0 g, 19 mmol), 1.0 M borane-tetrahydrofuran complex / tetrahydrofuran solution (20 mL, 20 mmol). Reaction was carried out in the same manner as in Example 24 (24e) to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 19-3: 2) to obtain the title compound (3.7 g, 99%) as a colorless oily substance.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.60 (t, 1H, J = 5.5 Hz), 2.32 (s, 3H), 4.65 (d, 2H, J = 5.5 Hz), 7. 23 (d, 1H, J = 8.6 Hz), 7.32-7.36 (m, 2H).
IR spectrum (Thin film) 1006, 1040, 1396, 1454, 1483, 1594, 3328 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 200 (M ^<+> ).

(27b) 4-Bromo-2-methylbenzaldehyde (4-Bromo-2-methylphenyl) methanol (3.7 g, 19 mmol) and pyridinium dichromate (11 g, 28 mmol) obtained in Example 27 (27a) were used. And the reaction was conducted in the same manner as in Example 24 (24f) to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 19 to 1: 4) to obtain the title compound (2.4 g, 64%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 2.65 (s, 3H), 7.45 (s, 1H), 7.51 (dd, 1H, J = 8.2 Hz, 1.6 Hz), 7.66 ( d, 1H, J = 8.2 Hz), 10.25 (s, 1H).
IR spectrum (KBr) 1288, 1301, 1588, 1686 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 198 (M ^<+> ).

(27c) 4-Bromo-2-methyl-1- (2-methylprop-1-en-1-yl) benzene Isopropyltriphenylphosphonium iodide (7.2 g, 17 mmol), potassium t-butoxide (2.0 g) 18 mmol), 4-bromo-2-methylbenzaldehyde (2.4 g, 12 mmol) obtained in Example 27 (27b) was used in the same manner as in Example 23 (23d) to give the title crude product. Got. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 0: 10-6: 94) to obtain the title compound (2.2 g, 84%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 1.67 (d, 3H, J = 1.2 Hz), 1.89 (d, 3H, J = 1.6 Hz), 2.19 (s, 3H), 6. 09 (s, 1H), 6.95 (d, 1H, J = 8.2 Hz), 7.23 (dd, 1H, J = 8.2 Hz, 2.0 Hz), 7.28 (d, 1H, J = 2.0 Hz).
IR spectrum (Thin film) 1444, 1478, 1587 cm ⁻¹
Mass spectrum (EI ^<+> ) m / z: 224 (M ^<+> ).

(27d) 4-Isobutyl-3-methylbenzoic acid 4-Bromo-2-methyl-1- (2-methylprop-1-en-1-yl) benzene (2.2 g) obtained in Example 27 (27c) 9.8 mmol), 1.6 M n-butyllithium / hexane solution (6.5 mL, 10 mmol), 10% palladium on carbon (200 mg), and the reaction was carried out in the same manner as in Example 23 (23e). The compound (1.4 g, 95%) was obtained as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.94 (d, 6H, J = 6.3 Hz), 1.84 to 1.96 (m, 1H), 2.36 (s, 3H), 2.54 ( d, 2H, J = 7.0 Hz), 7.19 (d, 1H, J = 7.8 Hz), 7.84 (d, 1H, J = 7.8 Hz), 7.88 (s, 1H).

(27e) {5- [5- (4-Isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methanol In Example 27 (27d) The resulting 4-isobutyl-3-methylbenzoic acid (96 mg, 0.50 mmol), 1-hydroxybenzotriazole (72 mg, 0.53 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 0.10 g, 0.53 mmol), N′-hydroxy-2-methyl-6-{[(triisopropylsilyl) oxy] methyl} pyridine-3-carboxyimidamide (0) obtained in Example 24 (24d) .16 g, 0.48 mmol), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (0.96 mL,. The reaction was carried out in the same manner as in Example 12 (12a) using 6 mmol), to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the title compound (0.15 g, 91%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.96 (d, 6H, J = 6.6 Hz), 1.87-1.98 (m, 1H), 2.42 (s, 3H), 2.57 ( d, 2H, J = 7.0 Hz), 2.95 (s, 3H), 3.92 (bs, 1H), 4.81 (s, 2H), 7.24 (d, 1H, J = 8. 2 Hz), 7.28 (d, 1 H, J = 8.2 Hz), 7.95 (dd, 1 H, J = 7.8 Hz, 1.6 Hz), 7.99 (s, 1 H), 8.39 ( d, 1H, J = 8.2 Hz).
IR spectrum (KBr) 1334, 1445, 1460, 1557, 3204, 3445 cm ⁻¹
Mass spectrum (FAB ⁺ ) m / z: 338 ((M + H) ⁺ ).

(27f) Methyl 1-({5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine- 3-carboxylate {5- [5- (4-Isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridine-2 obtained in Example 27 (27e) -Yl} methanol (0.14 g, 0.43 mmol), carbon tetrabromide (0.29 g, 0.86 mmol), triphenylphosphine (0.23 g, 0.86 mmol), methyl 3-azetidinecarboxylate hydrochloride (98 mg, 0.65 mmol) and N, N-diisopropylethylamine (0.22 mL, 1.3 mmol) in the same manner as in Example 23 (23 g). It was carried out, to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 2: 1 to 3: 1) to obtain the title compound (0.12 g, 66%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.96 (d, 6H, J = 6.6 Hz), 1.88-1.97 (m, 1H), 2.41 (s, 3H), 2.57 ( d, 2H, J = 7.4 Hz), 2.91 (s, 3H), 3.36-3.44 (m, 1H), 3.47 (t, 2H, J = 7.4 Hz), 3. 65 (t, 2H, J = 7.2 Hz), 3.73 (s, 3H), 3.83 (s, 2H), 7.27 (d, 1H, J = 7.8 Hz), 7.31 ( d, 1H, J = 7.8 Hz), 7.95 (dd, 1H, J = 7.8 Hz, 1.8 Hz), 7.99 (s, 1H), 8.33 (d, 1H, J = 8) .2 Hz).
IR spectrum (Liquid film) 1176, 1202, 1336, 1561, 1592, 1739 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 435 ((M + H) ^<+> ).

(27 g) 1-({5- [5- (4-Isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine-3 -Carboxylic acid 0.5 oxalate Methyl 1-({5- [5- (4-Isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-] obtained in Example 27 (27f) Yl] -6-methylpyridin-2-yl} methyl) azetidine-3-carboxylate (0.12 g, 0.28 mmol), 1N aqueous sodium hydroxide solution (0.84 mL, 0.84 mmol), acetic acid (48 μL, 0 .84 mmol) and oxalic acid (13 mg, 0.14 mmol) in the same manner as in Example 21 (21d) to give the title compound (0.10 g, 78%) as a crystalline white solid It was obtained.
¹ H NMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 0.97 (d, 6H, J = 6.6 Hz), 1.88-1.99 (m, 1H), 2.43 (s, 3H), 2 .61 (d, 2H, J = 7.4 Hz), 2.93 (s, 3H), 3.84-3.96 (m, 1H), 4.46-4.56 (m, 2H), 4 .62-4.74 (m, 2H), 4.77 (s, 2H), 7.35 (d, 1H, J = 8.2 Hz), 7.55 (d, 1H, J = 8.2 Hz) , 7.9 (d, 1H, J = 7.4 Hz), 8.03 (s, 1H), 8.53 (d, 1H, J = 8.2 Hz).
IR spectrum (KBr) 1337, 1382, 1565, 1588, 1618, 3410 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 421 ((M + H) ^<+> ).

Example 28 1-({5- [5- (4-Isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carvone Acid 0.5 oxalate

(28a) {5- [5- (4-Isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methanol 4 obtained in Example 27 (27d) -Isobutyl-3-methylbenzoic acid (0.12 g, 0.61 mmol), 1-hydroxybenzotriazole (86 mg, 0.64 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0. 12 g, 0.64 mmol), 6-({[t-butyl (dimethyl) silyl] oxy} methyl) -N'-hydroxypyridine-3-carboxyimidamide (0.16 g) obtained in Example 23 (23c). , 0.58 mmol), tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 1.2 mL, 1.2 mmol) The reaction was carried out in the same manner as in Example 12 (12a) Te, to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 2: 3 to 1: 1) to obtain the title compound (0.19 g, 99%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.97 (d, 6H, J = 6.6 Hz), 1.65 (bs, 1H), 1.84-1.97 (m, 1H), 2.42 ( s, 3H), 2.58 (d, 2H, J = 7.0 Hz), 4.87 (s, 2H), 7.28 (d, 1H, J = 8.2 Hz), 7.42 (d, 1H, J = 8.2 Hz), 7.96 (dd, 1H, J = 7.8 Hz, 1.6 Hz), 8.00 (s, 1H), 8.44 (dd, 1H, J = 8.2 Hz) , 2.4 Hz), 9.35 (d, 1H, J = 2.4 Hz).
IR spectrum (KBr) 1066, 1394, 1559, 1612, 3203 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 324 ((M + H) ^<+> ).

(28b) Methyl 1-({5- [5- (4-Isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylate {5- [5- (4-Isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methanol (0.19 g) obtained in Example 28 (28a) , 0.58 mmol), carbon tetrabromide (0.39 g, 1.2 mmol), triphenylphosphine (0.30 g, 1.2 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.13 g, 0.87 mmol) ) And N, N-diisopropylethylamine (0.30 mL, 1.7 mmol) in the same manner as in Example 23 (23 g) to obtain the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to 2: 1 to 3: 1) to obtain the title compound (0.15 g, 60%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.96 (d, 6H, J = 6.7 Hz), 1.86-1.97 (m, 1H), 2.41 (s, 3H), 2.57 ( d, 2H, J = 7.4 Hz), 3.34-3.44 (m, 1H), 3.47 (t, 2H, J = 7.2 Hz), 3.64 (t, 2H, J = 7) .6), 3.72 (s, 3H), 3.85 (s, 2H), 7.25 (d, 1H, J = 7.8 Hz), 7.45 (d, 1H, J = 8.2 Hz) ), 7.93 (d, 1H, J = 7.8 Hz), 7.97 (s, 1H), 8.37 (dd, 1H, J = 8.2 Hz, 2.0 Hz), 9.28 (d , 1H, J = 2.0 Hz).
IR spectrum (KBr) 1191, 1208, 1224, 1388, 1732 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 421 ((M + H) ^<+> ).

(28c) 1-({5- [5- (4-Isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid 0 .5 oxalate methyl 1-({5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridine- obtained in Example 28 (28b) 2-yl} methyl) azetidine-3-carboxylate (0.14 g, 0.34 mmol), 1N aqueous sodium hydroxide solution (1.0 mL, 1.0 mmol), acetic acid (58 μL, 1.0 mmol), oxalic acid (15 mg , 0.17 mmol) was used in the same manner as in Example 21 (21d) to give the title compound (0.13 g, 83%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 0.98 (d, 6H, J = 6.6 Hz), 1.88-2.01 (m, 1H), 2.44 (s, 3H), 2 .61 (d, 2H, J = 7.4 Hz), 3.84-3.95 (m, 1H), 4.28-4.60 (m, 2H), 4.60-4.72 (m, 2H), 4.82 (s, 2H), 7.35 (d, 1H, J = 7.8 Hz), 7.78 (d, 1H, J = 7.8 Hz), 8.00 (d, 1H, J = 7.8 Hz), 8.04 (s, 1 H), 8.60 (d, 1 H, J = 7.8 Hz), 9.34 (s, 1 H).
IR spectrum (KBr) 1343, 1366, 1398, 1591, 1606, 3431 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 407 ((M + H) ^<+> ).

Example 29 1-({6-Ethyl-5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine -3-carboxylic acid

(29a) {6-Ethyl-5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methanol In Example 27 (27d) The resulting 4-isobutyl-3-methylbenzoic acid (92 mg, 0.48 mmol), 1-hydroxybenzotriazole (69 mg, 0.51 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 97 mg, 0.51 mmol), 2-ethyl-N′-hydroxy-6-{[(triisopropylsilyl) oxy] methyl} pyridine-3-carboxyimidamide (0.16 g) obtained in Example 25 (25b). 0.46 mmol), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (0.92 mL, 0.9 The reaction was carried out in the same manner as in Example 12 (12a) using mmol), to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain the title compound (0.15 g, 93%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.96 (d, 6H, J = 6.3 Hz), 1.37 (t, 3H, J = 7.4 Hz), 1.85-1.98 (m, 1H) ), 2.41 (s, 3H), 2.57 (d, 2H, J = 7.0 Hz), 3.29 (q, 2H, J = 7.4 Hz), 4.14 (bs, 1H), 4.82 (s, 2H), 7.21 (d, 1H, J = 8.2 Hz), 7.28 (d, 1H, J = 7.8 Hz), 7.95 (dd, 1H, J = 7) .8 Hz, 1.6 Hz), 7.99 (s, 1 H), 8.34 (d, 1 H, J = 8.2 Hz).
IR spectrum (KBr) 1071, 1322, 1342, 1454, 1556, 1591, 3266, 3342 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 352 ((M + H) ^<+> ).

(29b) Methyl 1-({6-ethyl-5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine- 3-Carboxylate {6-Ethyl-5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridine-2 obtained in Example 29 (29a) -Yl} methanol (0.15 g, 0.42 mmol), carbon tetrabromide (0.28 g, 0.84 mmol), triphenylphosphine (0.22 g, 0.84 mmol), methyl 3-azetidinecarboxylate hydrochloride (96 mg, 0.63 mmol), N, N-diisopropylethylamine (0.22 mL, 1.3 mmol) was used in the same manner as in Example 23 (23 g). It was carried out, to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to 2: 1) to obtain the title compound (0.13 g, 71%) as a colorless oily substance.
¹ HNMR spectrum (400 MHz, CDCl ₃ ) δ 0.96 (d, 6H, J = 6.3 Hz), 1.33 (t, 3H, J = 7.4 Hz), 1.87-1.97 (m, 1H) ), 2.41 (s, 3H), 2.57 (d, 2H, J = 7.0 Hz), 3.24 (q, 2H, J = 7.4 Hz), 3.33-3.44 (m , 1H), 3.49 (t, 2H, J = 7.2 Hz), 3.67 (t, 2H, J = 7.6), 3.73 (s, 3H), 3.84 (s, 2H) ), 7.27 (d, 1H, J = 8.2 Hz), 7.29 (d, 1H, J = 7.8 Hz), 7.95 (d, 1H, J = 7.8 Hz), 7.9 (S, 1H), 8.27 (d, 1H, J = 8.2 Hz).
IR spectrum (Liquid film) 1176, 1202, 1340, 1560, 1591, 1739 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 449 ((M + H) ^<+> ).

(29c) 1-({6-Ethyl-5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3 -Carboxylic acid Methyl 1-({6-ethyl-5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] obtained in Example 29 (29b) Similar to Example 3 (3e) using pyridin-2-yl} methyl) azetidine-3-carboxylate (0.13 g, 0.29 mmol), 1 N aqueous sodium hydroxide (0.87 mL, 0.87 mmol). Reaction was performed by the method to obtain the title compound (0.10 g, 82%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 0.97 (d, 6H, J = 6.6 Hz), 1.36 (t, 3H, J = 7.4 Hz), 1.89-2.00 ( m, 1H), 2.43 (s, 3H), 2.61 (d, 2H, J = 7.4 Hz), 3.29 (q, 2H, J = 7.4 Hz), 3.84-3. 95 (m, 1H), 4.47-4.61 (m, 2H), 4.61-4.73 (m, 2H), 4.78 (s, 2H), 7.35 (d, 1H, J = 7.8 Hz), 7.49 (d, 1H, J = 7.8 Hz), 7.98 (d, 1H, J = 7.8 Hz), 8.02 (s, 1H), 8.47 ( d, 1H, J = 8.2 Hz).
IR spectrum (KBr) 1327, 1338, 1400, 1563, 1590, 1617, 3451 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 435 ((M + H) ^<+> ).

Example 30 1-({6-Ethyl-5- [5- (3-fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine -3-carboxylic acid

(30a) {6-Ethyl-5- [5- (3-fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methanol In Example 23 (23e) Obtained 3-fluoro-4-isobutylbenzoic acid (0.11 g, 0.54 mmol), 1-hydroxybenzotriazole (86 mg, 0.56 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salt (0.11 g, 0.56 mmol), 2-ethyl-N′-hydroxy-6-{[(triisopropylsilyl) oxy] methyl} pyridine-3-carboxyimidamide obtained in Example 25 (25b) (0.18 g, 0.51 mmol), 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (1.0 mL The reaction was carried out in the same manner as in Example 12 (12a) using 1.0 mmol), to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 2: 8-4: 6) to obtain the title compound (0.13 g, 74%) as a crystalline white solid.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 0.96 (d, 6H, J = 6.7 Hz), 1.37 (t, 3H, J = 7.4 Hz), 1.91-2.03 (m, 1H ), 2.61 (d, 2H, J = 7.0 Hz), 3.28 (q, 2H, J = 7.4 Hz), 4.09 (br, 1H), 4.80 (s, 2H), 7.19 (d, 1H, J = 7.8 Hz), 7.31-7.36 (m, 1H), 7.81-7.91 (m, 2H), 8.32 (d, 1H, J = 7.8 Hz).
IR spectrum (KBr) 762, 899, 1078, 1427, 1453, 1509, 1568, 1593, 2957, 3294 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 356 ((M + H) ^<+> ).

(30b) Methyl 1-({6-Ethyl-5- [5- (3-fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine- 3-Carboxylate {6-Ethyl-5- [5- (3-fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridine-2 obtained in Example 30 (30a) -Yl} methanol (0.13 g, 0.38 mmol), carbon tetrabromide (0.25 g, 0.75 mmol), triphenylphosphine (0.20 g, 0.75 mmol), methyl 3-azetidinecarboxylate hydrochloride (78 mg, 0.51 mmol), N, N-diisopropylethylamine (0.15 mL, 0.86 mmol) and the same method as in Example 23 (23 g) In carrying out the reaction, to give the title crude product. Purification was performed by silica gel column chromatography (ethyl acetate: hexane = 3: 7-7: 3) to obtain the title compound (0.11 g, 69%) as a pale yellow oily substance.
¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 0.96 (d, 6H, J = 6.6 Hz), 1.33 (t, 3H, J = 7.4 Hz), 1.92-2.03 (m, 1H ), 2.61 (d, 2H, J = 7.0 Hz), 3.24 (q, 2H, J = 7.4 Hz), 3.35-3.45 (m, 1H), 3.49 (t , 2H, J = 7.8 Hz), 3.67 (t, 2H, J = 7.8 Hz), 3.73 (s, 3H), 3.84 (s, 2H), 7.28-7.37. (M, 2H), 7.83-7.93 (m, 2H), 8.27 (d, 1H, J = 8.2 Hz).
IR spectrum (liquid film) 1203, 1342, 1562, 1590, 1739, 2958cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 453 ((M + H) ^<+> ).

(30c) 1-({6-Ethyl-5- [5- (3-fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3 -Carboxylic acid Methyl 1-({6-ethyl-5- [5- (3-fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] obtained in Example 30 (30b) Similar to Example 3 (3e) using pyridin-2-yl} methyl) azetidine-3-carboxylate (0.11 g, 0.24 mmol), 1N aqueous sodium hydroxide (0.71 mL, 0.71 mmol). Reaction was performed by the method to give the title compound (90 mg, 87%) as a crystalline white solid.
¹ HNMR spectrum (400 MHz, CD ₃ CO ₂ D) δ 0.97 (d, 6H, J = 6.6 Hz), 1.37 (t, 3H, J = 7.5 Hz), 1.92 to 2.04 ( m, 1H), 2.65 (d, 2H, J = 7.3 Hz), 3.29 (q, 2H, J = 7.5 Hz), 3.86-3.97 (m, 1H), 4. 45-4.77 (m, 4H), 4.79 (s, 2H), 7.43-7.53 (m, 2H), 7.87-8.00 (m, 2H), 8.47 ( d, 1H, J = 8.1 Hz).
IR spectrum (KBr) 760, 900, 1103, 1342, 1402, 1508, 1561, 1592, 2873, 2963, 3438 cm ⁻¹
Mass spectrum (FAB ^<+> ) m / z: 439 ((M + H) ^<+> ).

Hereinafter, the present invention will be described in more detail with reference to test examples and formulation examples, but the scope of the present invention is not limited thereto.

(Test Example 1) Evaluation of anti-arthritic effect Using a rat adjuvant arthritis model that develops arthritis similar to human rheumatoid arthritis, the effect of the compound of the present invention on arthritis is evaluated using the inhibition rate of footpad volume increase as an index. .

The test uses 8 week old female Lewis rats.
(1) Preparation of Adjuvant Mycobacterium butyrricum heat-killed cells are refined in an agate mortar, suspended in dry paraffin sterilized liquid paraffin to 2 mg / mL, and sonicated to prepare an adjuvant.
(2) Preparation of test compound A test compound is used by suspending or dissolving it in a 0.5% tragacanth solution.
(3) Induction of adjuvant arthritis 0.05 ml of the adjuvant prepared in (1) is injected into the right hind paw skin of the rats of the control group and the test compound administration group. A normal control group is provided as a group not injected with adjuvant.
(4) Administration of test compound The test compound prepared in (2) is orally administered once a day for 5 days from the day of adjuvant injection at 5 ml / kg. For the control group, only 0.5% tragacanth solution is administered in the same manner.
(5) Calculation method of inhibition rate of footpad volume increase of test compound After the start of administration, the volume of the right hind limb was measured on the 11th and 18th days with a foot volume measuring device, and the average value of the swelling volume of each group was calculated. To do.
The toe volume increase inhibition rate (%) is calculated by the following formula.

Footpad volume increase inhibition rate (%) = (1 − ([footpad volume of test compound administration group] − [footpad volume of normal control group]) / [footpad volume of control group] − [normal control group] Footpad volume])) × 100

(Test Example 2) Measurement of inhibitory activity against rat HvGR (Host Vers Graft Reaction) (1) Two strains of rats [Lewis (male, 6 weeks old, Charles River Japan, Japan) and WKAH / Hkm (male, 7 weeks) Age, Nippon SLC Co., Ltd.)]. One group of 5 rats (host) was used.
(2) Induction of HvGR Spleen cells were isolated from the spleens of WKAH / Hkm rats and Lewis rats and suspended at a concentration of 1 × 10 ⁸ cells / ml in RPMI 1640 medium (Life Technology). Lewis rats were injected with 0.1 ml (1 × 10 ⁷ spleen cells) of the spleen cell suspension of WKAH / Hkm rats or Lewis rats in both hind footpads.
(3) Administration of compound The compound was suspended in 0.5% tragacanth solution. A suspension of the compound (5 ml per kg body weight of the rat) was administered once a day to the compound administration group (Lewis rats injected with the WKAH / Hkm rat spleen cells and administered with the specimen) 4 times from the day of spleen cell injection. It was orally administered every day. In the syngeneic group (Lewis rats injected with Lewis rat spleen cells) and the control group (Lewis rats injected with WKAH / Hkm rat spleen cells and not administered with specimen), 0.5% tragacanth solution was used instead of the specimen. Was administered orally.
(4) Method for measuring inhibitory activity against HvGR Subtract the mean popliteal lymph node weight of the syngeneic group from the popliteal lymph node weight of each individual in each treatment group ("popliteal lymph node weight by HvGR"), control The inhibition rate was calculated from “popliteal lymph node weight by HvGR” of each individual in the compound administration group with respect to the average “popliteal lymph node weight by HvGR” of the group. The results are shown in Table 5 below.
(Table 5)
―――――――――――――――――――――――――――
Compound inhibition rate (%, at the time of 1 mg / kg administration)
―――――――――――――――――――――――――――
Example 10 61.8
Example 11 51.6
Example 12 55.4
Example 13 61.3
Example 14 65.6
Example 17 65.0
Example 26 80.0
Example 27 80.6
Example 28 77.5
Example 29 83.5
Comparative compound 1-15.5
Comparative compound 2-19.0
―――――――――――――――――――――――――――.

As a result of this test, the compound of the present invention showed excellent inhibitory activity.
Comparative compound 1 and comparative compound 2 are the compounds described in Example 19 and Example 21 of the above-mentioned Patent Document 1 (International Publication No. 03/105771 pamphlet), and the structural formulas thereof are as shown below.

Test Example 3 Evaluation of Rat Peripheral Blood Lymphocyte Decrease Action A LEW rat (male, 5 weeks old, Charles River Japan Co., Ltd.) is used. One group of 5 rats is used.

(1) Administration of test compound The test compound is suspended in 1% tragacanth solution (solvent). The test compound suspension is orally administered by gavage at a rate of 5 mL per kg body weight of the rat.
In the normal group, a solvent is administered instead of the test compound suspension.

(2) Measurement of peripheral blood lymphocyte count Three hours after administration of the solvent or test compound suspension, blood is collected from the inferior vena cava under ether anesthesia and transferred to a tube containing EDTA. The absolute number of lymphocytes is measured with a hematology test device on the collected blood. When the lymphocyte count of the normal group is taken as 100%, the lymphocyte count reducing action by the test compound is calculated as a relative value (%).

(Formulation example 1)
Tablet 10 mg of the compound of the present invention
Lactose 163mg
Corn starch 25mg
Magnesium stearate 2mg
―――――――――――――――――――――――――――
200mg
The powder of the said prescription is mixed and tableted by a tableting machine to make one tablet of 200 mg.

Since the pharmaceutical composition of the present invention has an excellent immunosuppressive action and weak toxicity, it is useful as a prophylactic or therapeutic agent for diseases related to the immunosuppressive action on mammals (particularly humans).

Claims (12)

Formula (I)

[Where:
A represents a carboxyl group, a phospho group, a sulfo group or a 1H-tetrazol-5-yl group,
B represents a hydrogen atom or a group selected from the substituent group A;
n represents an integer of 0 to 2,
V represents a methylene group or a single bond that may be substituted with a group selected from the substituent group A;
When V is a methylene group which may be substituted with a group selected from Substituent Group A, W is a 5-membered ring to 7-membered which may be substituted with 1 to 3 groups selected from Substituent Group A A ring heterocyclic group,
When V is a single bond, W represents a condensed heterocyclic group which may be substituted with 1 to 3 groups selected from the substituent group A;
X is a C ₁ -C ₈ alkylene group which may be substituted with 1 to 5 groups selected from the substituent group A, and a chain which may be substituted with 1 to 5 groups selected from the substituent group A A C ₁ -C ₈ alkylene group having an oxygen atom or a sulfur atom therein, a C ₆ -C ₁₀ arylene group optionally substituted with a group selected from the substituent group A, and a substituent group A A 5- to 7-membered heterocyclic group which may be substituted with 1 to 3 groups or a condensed heterocyclic group which may be substituted with 1 to 3 groups selected from substituent group A Show
Y is a C ₆ -C ₁₀ arylene group which may be substituted by 1 to 3 groups selected from the substituent group A, and 1 to 3 groups which may be substituted by a group selected from the substituent group A 5 A condensed ring type heterocyclic group which may be substituted with 1 to 3 members selected from a member ring to a 7 member ring heterocyclic group or a group selected from the substituent group A;
Z is a group selected from Substituent Group A, a C ₁ -C ₈ alkyl group that may be substituted with 1 to 5 groups selected from Substituent Group A, or a group selected from Substituent Group A. C ₁ -C ₈ alkyl group having an oxygen atom or a sulfur atom in the chain which may be substituted by 1 to 5 groups, or C ₃ -C which may be substituted by a group selected from substituent group A 1 to 5 C ₇ -C ₁₀ aryl groups which may be substituted with 1 to 5 groups selected from ₇ cycloalkyl groups and substituent group A, and 1 to 5 groups which may be substituted with groups selected from substituent group A good _C 6 _{-C 10} aryloxy group, which may be one to five substituents groups selected from substituent group A _C 6 _{-C 10} arylthio group, 1 to a radical selected from the substituent group A 5 is selected from optionally C ₆ -C ₁₂ aralkyl group or a substituted group A be pieces substituted In 1 to indicate the five optionally substituted _C 6 _{-C 10} arylcarbonyl group,
Substituent group A includes a halogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₇ cycloalkyl group, a C ₆ -C ₁₀ aryl group, a C ₆ -C ₁₀ aryloxy group, and a C ₆ -C ₁₂ aralkyl group. Halogeno C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, halogeno C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, carboxy group, C ₁ -C ₆ alkyl carboxy group, hydroxy group, C ₁ -C ₆ aliphatic acyl group, an amino _group, C 1 -C ₆ monoalkylamino _group, C 1 -C ₆ dialkylamino _group, C 1 -C ₆ aliphatic acylamino group, the group consisting of cyano group and a nitro group Or a pharmacologically acceptable salt thereof. The general formula (I) is represented by the general formula (I ′)

[Where:
R ¹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ² represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ represents a hydrogen atom, a halogen atom or a C ₁ -C ₆ alkyl group,
R ⁴ represents a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group,
R ⁵ represents a hydrogen atom or a halogen atom. The pharmaceutical composition according to claim 1. The general formula (I) is the general formula (I ″)

[Where:
R ⁶ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ⁷ represents a hydrogen atom, a halogen atom or a C ₁ -C ₆ alkyl group,
The pharmaceutical composition according to claim 1, wherein R ⁸ represents a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group. The pharmaceutical composition according to claim 1, wherein the compound having the general formula (I) is a compound selected from the following:
1-[(4- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -2-furyl) methyl] azetidine-3- carboxylic acid,
1-({5- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} methyl) azetidine-3-carboxylic acid,
1-({5- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} methyl) azetidine-3-carboxylic acid,
1- (2- {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl} -4,5,6,7-tetrahydro-1 -Benzofuran-4-yl) azetidine-3-carboxylic acid,
1-({5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-({4- [5- (4-benzoylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-({4- [5- (4-benzylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-({4- [5- (1-isobutyl-1H-indol-5-yl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-({6- [5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-3-yl} methyl) azetidine-3-carboxylic acid and 1-({5- [ 5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid. The pharmaceutical composition according to claim 1, wherein the compound having the general formula (I) is a compound selected from the following:
1-({5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-({4-methyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-({5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-methyl-2-thienyl} methyl) azetidine-3-carboxylic acid,
1-({4-ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-[(4-Ethyl-5- {5- [4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3-carboxylic acid ,
1-({4-ethyl-5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid,
1-[(4-Ethyl-5- {5- [3-fluoro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine- 3-carboxylic acid,
1-[(4-Ethyl-5- {5- [4- (2-methoxyphenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3-carboxylic acid ,
1-[(5- {5- [3-Chloro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] azetidine- 3-carboxylic acid,
1-[(4-Ethyl-5- {5- [4- (2-methoxyphenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3-carboxylic acid ,
1-[(4-Ethyl-5- {5- [4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3-carboxylic acid ,
1-[(5- {5- [4- (2,3-Difluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] azetidine-3- carboxylic acid,
1-[(4-Ethyl-5- {5- [3-fluoro-4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine- 3-carboxylic acid,
1-[(5- {5- [4- (2,3-Difluorophenoxy) -3-fluorophenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] Azetidine-3-carboxylic acid,
1-[(5- {5- [3-Chloro-4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] azetidine- 3-carboxylic acid,
1-[(5- {5- [3-Chloro-4- (2,3-difluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] Azetidine-3-carboxylic acid,
1-[(5- {5- [4- (2-Chlorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] azetidine-3-carboxylic acid ,
1-[(5- {5- [4- (2-Chlorophenoxy) -3-fluorophenyl] -1,2,4-oxadiazol-3-yl} -4-ethyl-2-thienyl) methyl] azetidine- 3-carboxylic acid,
1-({3-methyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid and 1-({ 3-ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid. The pharmaceutical composition according to claim 1, wherein the compound having the general formula (I) is a compound selected from the following:
1-({5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid,
1-({5- [5- (3-Fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid (,
1-({5- [5- (3-chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid,
1-({5- [5- (4-Isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({5- [5- (3-Fluoro-4-propylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({5- [5- (4-Butyl-3-fluorophenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({5- [5- (3-Fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({6-Ethyl-5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({6-Ethyl-5- [5- (3-fluoro-4-propylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({5- [5- (4-Butyl-3-fluorophenyl) -1,2,4-oxadiazol-3-yl] -6-ethylpyridin-2-yl} methyl) azetidine-3-carboxylic acid ,
1-({6-Ethyl-5- [5- (3-fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid And 1-({5- [5- (3-chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-ethylpyridin-2-yl} methyl) azetidine-3-carvone acid. The pharmaceutical composition according to any one of claims 1 to 6, which suppresses rejection in skin transplantation or organ transplantation. The pharmaceutical composition according to any one of claims 1 to 6, for preventing or treating an autoimmune disease. The medicament according to claim 8, wherein the autoimmune disease is one or more selected from the group consisting of rheumatoid arthritis, psoriasis, atopic dermatitis, multiple sclerosis, ulcerative colitis and Crohn's disease. Composition. A method for suppressing rejection in skin transplantation or organ transplantation, which comprises administering an effective amount of the pharmaceutical composition according to any one of claims 1 to 6 selected to mammals. A method for preventing or treating an autoimmune disease, comprising administering an effective amount of the pharmaceutical composition according to any one of claims 1 to 6 selected from mammals to a mammal. The prevention according to claim 11, wherein the autoimmune disease is one or more selected from the group consisting of rheumatoid arthritis, psoriasis, atopic dermatitis, multiple sclerosis, ulcerative colitis and Crohn's disease. Or a treatment method.