MX2007013170A - Heterocyclic compound. - Google Patents

Abstract

Disclosed is a novel low toxic compound having an excellent immunosuppressive action or a pharmacologically acceptable salt thereof. Specifically disclosed is a compound represented by the general formula (I) below, a pharmacologically acceptable salt thereof or a pharmacologically acceptable prodrug thereof. (I) (In the formula, A represents a carboxyl group or the like; B represents a hydrogen atom or the like; V represents a single bond, a methylene group or the like; n represents an integer of 0-2; W represents a 5- to 7-membered heterocyclic group or the like; and Z represents a group or the like selected from a substituent group A consisting of halogen atoms, C1-C6 alkyl groups, C3-C7 cycloalkyl groups and the like.).

Description

COMPOSITE HETEROC1CLICO TECHNICAL FIELD The present invention relates to a heterocyclic compound which exhibits an excellent immunosuppressive activity, a phcologically acceptable salt thereof, or a prodrug I phcologically acceptable thereof.

BACKGROUND OF THE INVENTION Anti-inflammatory drugs such as steroids have conventionally been used as symptomatic therapy in the treatment of autoimmune diseases and the like, but better radical therapy for these diseases is required. Additionally, abnormal changes in the immune system have been reported in relation to the incidence of diabetes mellitus and nephritis (for example, refer to Literature 1 not Patent and Literature 2 not Patent). However, to date, no drugs have been developed to alleviate abnormal changes in the immune system. On the other hand, it is important to develop a method to suppress immune responses not only to avoid rejection symptoms in organ transplants and cellular transplants, but also to avoid treating various autoimmune diseases. However, because it is known that previously known immunosuppressants such as cyclosporin A (CsA for its acronym in English), tacolimus (TRL), and the like exhibit toxicity to the liver and kidney, the concomitant use of a steroid or the like has been widely used to suppress such side effects. On the other hand, a significant immunosuppressive effect without secondary effects has not yet been obtained. Based on this background, many attempts have been made to discover an agent that exerts excellent immunosurveillance activity with low toxicity. The following reports describing the background of the present invention are described. For example, the following compounds shown below are discussed in Patent Literature 1.

For example, the following compounds below are described in Patent Literature 2 For example, the following compounds shown below are describe OOH For example, the following compounds shown below are described in Patent Literature 4.

For example, the following compounds shown below are described in Patent Literature 5.

For example, the following compounds shown below are described in Patent Literature 6.

However, the chemical structures of the compounds described in the literatures of Patent Literature 1 to Patent Literature 6 described above differ from those compounds of the present invention.

Patent Literature 1 International Publication number WO 03/062252 pamfleto Patent Literature 2 International Publication number WO 03/105771 pamfleto Patent Literature 3 International Publication Number WO 2004/058149 pamfleto Patent Literature 4 International Publication number WO 2004/103306 pamfleto Patent Literature 5 International Publication Number WO 2004/103309 pamfleto Patent Literature 6 International Publication Number WO 2005/000833 Pamphlet Non-Patent Literature 1 Kidney International, Vol. 51, 94 (1997) Non-Patent Literature 2 'Journal of Immunology, Vol. 157, 4691 (1996) DETAILED DESCRIPTION OF THE BNVENC-QN OBJECTIVE OF THE INVENTION The inventors of the present invention have for a long time diligently investigated various novel compounds that can exert excellent immunosuppressive activity with low toxicity. As a result, the present inventors discovered novel compounds that are useful against rejection symptoms in transplantation of various organs or in skin tissue grafting and against autoimmune diseases such as systemic lupus erythematosus, chronic rheumatic arthritis, polymystosis, fibrositis, skeletal muscle myositis, arthritis, osteoarthritis, dermatomibsitis, scleroderma, Behcets syndrome, Crohn's disease, ulcerative colitis, autoimmune hepatitis, aplastic anemia, idiopathic purple thrombocytopenia, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullous dermatitis, psoriasis, vasculitis syndrome , Wegener's granulomatosis, uveitis, Sjögren's syndrome, idiopathic interstitial pneumonia, good shepherd syndrome, sarcoidosis, allergic granulomftous anginitis, bronchial asthma, myocarditis, cardiomyopathy, I syndrome of aortitis, post-myocardial infarction syndrome, hypertension pulmonary disease, nephrotic syndrome of minimal change, nephropathy membranous, membranoproliferative glomerulonephritis, glomerular sclerosis focal, growing glomerulonephritis, myasthenia gravis, inflammatory neuropathy, dermatisis! atopic, chronic actinic dermatitis, photosensitivity, ulcer pressure, Syndenham forea, sclerosis, type diabetes mellitus activation in adult, insulin-dependent diabetes mellitus, diabetes juvenile mellitus, atherosclerosis, glomerular nephritis, IgA nephropathy (by its initials in English), tubulointerstitial nephritis, primary biliary cirrhosis, primary sclerosis cholangitis, fulminant hepatitis, viral hepatitis, GVHD (for short) in English), contact dermatitis, sepsis, and the like, or other diseases immune systems, and additionally, for infectious disease caused by fungi, mycoplasma, viruses, and protozoa, for diseases cardiovascular events such as heart failure, cardiac hypertrophy, arrhythmia, angina, cardiac ischemia, arterial embolus, aneurysm, varicose vein and disturbance of blood circulation, diseases of the central nervous system such such as Alzheimer's disease, dementia, Parkinson's disease, cerebro-vascular disorder, cerebral infarction, cerebral ischemia, depression, depression and mania, schizophrenia, Huntington's chorea, epilepsy, convulsion, Attention deficit hyperactivity disorder (ADHD) English), encephalitis, meningitis, anorexia, and hyperphagia, and for other diverse diseases such as lymphomatosis, leukemia, polyuria, frequent urination, diabetic retinopathy, and the like (particularly useful against rejection symptoms in transplantation of various organs or in skin tissue graft and against autoimmune diseases such as systemic lupus erythomatous , chronic rheumatoid artitis, multiple sclerosis, atopic dermatitis, and the like) and consequently, the inventors completed the present invention. Therefore, the object of the present invention is to provide novel compounds having excellent immunosuppressive activity with low toxicity, pharmacologically acceptable salts thereof, and pharmacologically acceptable prodrugs thereof.

Means to achieve the objective The present inventors have diligently explored compounds having immunosuppressive activity and discovered that the compounds having the general formula (I) of the present invention, pharmacologically acceptable salts thereof, or pharmacologically acceptable prodrugs thereof (in the following, expressed as "a compound of the present intention" in some cases) have excellent immunosuppressive activity with low toxicity and are useful for the prophylaxis or treatment of the diseases described above, and then the present inventors completed the present invention. The present invention is then described in detail in the following.

! The present invention relates to (1) a compound having the general formula (I) shown below, wherein A represents a carboxyl group, a phospho group, a sulfo group, or a 1-H-tetrazol-5-yl group. B represents a hydrogen atom or a group selected from the group U-constituent A, n represents an integer from 0 to 2, V represents a methylene group which may optionally be substituted with substituent (s) selected from the Substituent group A or a sym linkage. ple, W represents a 5- to 7-membered heterocyclic group which may optionally be substituted with 1 to 3 substituents selected from the group Substituent A, in the case where V represents a methylene group which may optionally be substituted with substituent (s) selected from the Substituent group A, while in the case that V represents a single bond, W represents a fused ring heterocyclic group which may optionally be substituted with 1 3 substituents selected from the Substituent group AX represents a C 8 alkylene group which can optionally be substituted with from 1 to 5 substituents selected from the group Substituted A, an alkylene group CrC 8 containing an oxygen atom? a sulfur atom in the carbon chain which may optionally be substituted with from 1 to 5 substituents selected from the group Substituent A, a C 6 -C arylene group which may optionally be substituted with from 1 to 3 substituents selected from the group Substituent A, a 5- to 7-membered heterocyclic group which may optionally be substituted with 1 to 3 substituents selected from the Substituent group A, or a fused ring heterocyclic group which may optionally be substituted with from 1 to 3 substituents selected from Substituent group A, Y represents an arylene group Cß-C-io which may optionally be substituted with from 1 to 3 substituents selected from the group Substituent A, a 5- to 7-membered heterocyclic group which may optionally be substituted with from 1 to 3 substituents selected from the group Substituent A, or a fused ring heterocyclic group which may optionally be substituted with 1 to 3 substituents selected from the Subjituant A group, Z represents a group selected from Substituent group A, CrC8 alkyl group which may be optionally substituted with from 1 to 5 substituents selected from the Substituent group A, a C -Cß alkyl group containing an oxygen atom or a sulfur atom in the carbon chain which may be optionally substituted with from 1 to 5 substitutes that selected from the Substituent group A, a C3 cycloalkyl group -C7 which may optionally be substituted with from 1 to 5 substituents selected from the Substituent group A, a C6-C10 aryl group which may optionally be substituted with from 1 to 5 substituents selected from the Substituyeme A group, a Cß-C-aryloxy group which may optionally be substituted with from 1 to 5 substituents selected from the Substituent group A, an aryl group io C-C-io which may be optionally substituted with from 1 to 5 substituents selected from the Substituent group A, a C6-Ci2 aralkyl group which may be optionally substituted with 1 to 5 substituents selected from the Substituent A group, or a C6 arylcarbonyl group -C-? 0 which may be optionally substituted with from 1 to 5 substituents selected from Substituent group A, Substituent group A represents the group consisting of a halogen atom, a CrC6 alkyl group, a C3-C7 cycloalkyl group, a aryl group Ce-Cio, a C6-C10 aryloxy group, a C6-C12 aralkyl group, a C-C6-haloalkyl group, a C6-C6 alkoxy group, a C-C6-alkoxy halo group, a C1-Cd alkylthio group, a carboxyl group, a C-alkyl group Cecarboxylo, a hydroxyl group, an aliphatic acyl Ci-Cß group, an amino group, a Ci-Cβ amino monoalkyl group, a Ci-Cβ amino dialkyl group, an aliphatic Ci-Cβ acylamino group, a cyano group, and a nitro group], a salt pharmacologically acceptable thereof, or a pharmacologically acceptable prodrug thereof, and preferably, (2) a compound as described in (1) wherein B is a hydrogen atom, or a pharmacologically acceptable salt thereof, (3) a compound as described in (1) or (2) wherein A is a carboxyl group, or a pharmacologically acceptable salt thereof,. (4) a compound as described in any one selected from (1) ai (3) wherein n represents an integer of 0, or a pharmacologically acceptable salt thereof, (5) a compound as described in any selected from ( 1) to (4) wherein V represents a methylene group and W represents a 5- to 7-membered heterocyclic group which may optionally be substituted with 1 to 3 substituents selected from the Substituent group A, or a pharmacologically acceptable salt thereof. same, (6) a compound as described in (5) wherein the 5- to 7-membered heterocyclic group represents a thienyl, furylene, pyrrolene or pyridylene group, a pharmacologically acceptable salt thereof, (7) a compound such as is described in (5) wherein W represents a thienylene group or a pyridylene which may optionally be substituted with 1 to 2 substituents selected from the Substituent group A, or a pharmacologically acceptable salt thereof, (8) a compound as described e in (6) wherein the thienylene or pyridylene group represents a group shown below, respectively, or a pharmacologically acceptable salt thereof, (9) a compound as described in any one selected from (1) to (4) wherein V represents a single bond and W represents a heterocyclic ring fused group which may optionally be substituted with from 1 to 3 substituents selected from Substituyeme A group, or a pharmacologically acceptable salt thereof, i (10) a compound as described in (9) wherein W represents a fused ring heterocyclic group or a pharmacologically acceptable salt thereof, (11) a group as described in (10) wherein the heterocyclic group of fused ring is a tetrahydrobenzofuranylene, tetrahydrobenzothienylene or N-methyltetrahydroinolylene group, or a pharmacologically acceptable salt thereof, (12) a compound as described in (11) wherein the fused ring heterocyclic group has two positions available for attachment in the posicin 2- and 4-, or a pharmacologically acceptable salt thereof, (13) a compound as described in (12) wherein the substitution in position 2- represents the group of formula ZYX, or a pharmacologically salt acceptable thereof, (14) a compound as described in any selected from (1) to (13) wherein X represents an alkyl group C? -C8, an alkyl group C Cs containing an oxygen atom or an atom e sulfur in the carbon chain, a C6-C10 arylene group, a 5- to 7-member heterocyclic group 1 or a fused ring heterocyclic group, or a pharmacologically acceptable salt thereof, (15) a compound as described in any selected from (1) to (13) wherein X represents a 5- to 7-membered heterocyclic group, or a pharmacologically acceptable salt thereof, (16) a compound as described in any selected from (1) a (15) wherein Y represents any of a group selected from the group consisting of a phenylene group, a 5- to 7-membered heterocyclic group which may optionally be substituted with from 1 to 3 substituents selected from the Substituent group A, and a fused ring heterocyclic group which may optionally be substituted with 1 to 3 substituents selected from Substituent group A, or a pharmacologically acceptable salt thereof, (17) a compound as described in any selection of (1) to (15) wherein Y represents a phenylene group, or a thienylene, pyridylene, or indolylene group which may be optionally substituted with from 1 to 3 substitutes selected from the Substituent group A, or a salt pharmacologically acceptable thereof, (18) a compound as described in any selected from (1) to (15) wherein Y represents a phenylene or a pyridylene group, or a salt pharmacologically acceptable thereof, (19) a compound as described in any selected from (1) to (18) where Z represents a C6-C10 aryloxy group that can optionally being substituted with from 1 to 5 substituents selected from group Substitute A, or a pharmacologically acceptable salt thereof, and i (20) a compound as described in any one selected from (1) to (18) wherein Z represents a phenoxy group, or a salt pharmacologically acceptable thereof, (21) a compound as described in (1) wherein the formula general (I) is the general formula (I ') shown below: where R represents a hydrogen atom or a Ci-Ce alkyl group, R2 represents a hydrogen atom or a C? -C6 alkyl group, R3 represents a hydrogen atom, a halogen atom, or a CrC6 alkyl group, R4 represents a hydrogen atom, a halogen atom, a cyan group, a Ci-Cβ alkyl group, or a Ci-Cβ alkoxy group, and R5 represents a hydrogen atom or a halogen atom], or a pharmacologically acceptable salt thereof, | (22) a compound as described in (21) wherein R1 represents a hydrogen atom, or a pharmacologically acceptable salt thereof; I '(23) a compound as described in (21) or (22) wherein R2 represents! a hydrogen atom, a methyl group, or an ethyl group, or a pharmacologically acceptable salt thereof, (24) a compound as described in any one selected from (21) to (23) wherein R3 represents a hydrogen atom, a fluoro atom, a chlorine atom, or a methyl group, or a pharmacologically aceotable salt thereof, (25) a compound as described in any one selected from (21) to (24) wherein R4 represents a hydrogen, a fluoro atom, a chlorine atom, a cyano group, or a methyl group, or a methoxy group, or a pharmacologically acceptable salt thereof, (26) a compound as described in any selected from (21) a (25) wherein R5 represents a hydrogen atom or a fluoro atom, or a pharmacologically acceptable salt thereof, (27) a compound as described in (1) wherein the general formula is the general formula (I ") shown below: wherein R .6 represents a hydrogen atom or a CvCß alkyl group, R7 represents a hydrogen atom, a halogen atom, or a C? -C6 alkyl group, and R8 represents a C? -C alkyl group or an alkoxy group C? -Cβ], or a pharmacologically acceptable salt thereof, (28) a compound as described in (27) wherein R6 represents a hydrogen atom, a methyl group, or an ethyl group, or a pharmacologically acceptable salt thereof, (29) a compound as described in any one selected from (27) or (28) wherein R7 represents a hydrogen atom, a fluoro atom, a chlorine atom, or a methyl group, or a pharmacologically acceptable salt! thereof, (30) a compound as described in any one selected from (27) to (29) wherein R8 represents an n-propyl group, an n-butyl group or an isobutyl group, or a pharmacologically acceptable salt thereof . (31) a compound as described in (1) wherein said compound is any of one selected from the following compounds, or a pharmacologically acceptable salt thereof: Acid 1 - [(4- {5- [4-Phenyl] -5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl.} -2-furyl) methyl] azetidine-3-carboxylic acid, acid 1- (. {5- [ 5- (4-lsobutylphenyl) -1,4,4-oxadiazol-3-yl] -2-furyl} methyl) azetidine-3-carboxylic acid, 1- (. {5- [5- (4- Cyclohexylphenyl) -1,4, 2,4-oxadiazol-3-yl] -2-furyl} methyl) a] -zetidine-3-carboxylic acid, 1- (2. {5- [4-Phenyl-5- (trifluoromethyl) -2-thienyl] -1,4-oxadiazol-3-yl.} -4,5,6,7-tetrahydro-1-benzofuran-4-yl) azetidine-3-carboxylic acid, Acid 1 - ( { 5- [5- (4-Phenoxyphenyl) -1, 2,4-oxadiazol-3-yl] -2-thienyl} methyla) azetidine-3-carboxylic acid, 1- (. {4- [5- (4-Benzoylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl] zetidine-3-carboxylic acid, 1- (. {4- [5- (4-Benzylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid Acid 1- ( { 4- [5- (1-lsobutyl-1 H-indol-5-yl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azet Α-3-carboxylic acid, 1- (. {6- [5- (4-lsobuyylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-3-yl} methyl) azet Idine-3-carboxylic acid and 1- (. {5- [5- (4-lsobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine- 3-carboxylic, (32) a compound as described in (1) wherein said compound is one of any of the following selected compounds, or a pharmacologically acceptable salt thereof: 1- (. {5- [5- (4-Phenoxyphenyl) -1,4, 2,4-oxadiazol-3-yl] -2-thienyl} -methyl) azeididine-3-carboxylic acid, 1- (. {4-Methyl-5- [5- ( 4-phenoxyphenyl) -1,4,4-oxadiazol-3-yl] -2-thienyl.} Methyl) azeidyne-3-carboxylic acid 1 - (. {5- [5- (3-Fluoro-4-phenoxyphenyl) -1,2,4-oxadiazo! -3-yl] -4-methy1-2-t'ef? Il} methyl) azetidine-3-carboxylic acid, 1- (. {4-Ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-lienyl acid} methyl] azetidine-3-carboxylic acid, i 1 - [(4-Ethyl-5-. {5- [4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl acid .} -2-thienyl) methyl] azetidine-3-carboxylic acid, 1 - ( {4-Ethyl-5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazole- 3-yl] -2-lienyl.} 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] azelidine-3-carboxylic acid, 1 - [(4-Ethyl-5-. {5- [4- (2 -methoxyphenoxy) phenyl] -1,4, 2,4-oxadiazol-3-yl.} -2-thienyl) meityl] azetidine-3-carboxylic acid, 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, 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] azide idine-3-carboxyl, Acid 1 - [(5-. { 5- [4- (2,3-Difluorophenoxy) phenyl] -1,4, 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] -1,4,4-oxadiazol-J 3 -yl.} -4-ethyl-2-thienyl) methyl] azetidine-3-carboxylic acid, 1 - [(5- {5- [3-chloro]] -4- (2-fluorophenoxy) phenyl] -1,4, 2,4-oxadiazol-3-yl.} -4-eyl-2-thienyl) methyl] azetidine-3-carboxylic acid, 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 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-lienyl) methyl ] azetidine-3-carboxylic acid, 1- (. {3-Methyl-5- [5- (4-phenoxyphenyl) -1, 2) 4-oxadiazol-3-yl] -2-ynyl acid} methyl) azetidine-3-carboxylic acid and 1 - (. {3-Ellyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-ynyl} methyl ester |) azetidine-3-carboxylic acid, and (33) a compound as described in (1) wherein said compound is any one of the following compounds, or a pharmacologically acceptable salt thereof: 1 Acid 1- ( (5- (5- (4-lsobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) zetidine-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, Acid 1 - ( { 5- [5- (4-lsobutyl-3-methylphenyl) -1, 2,4-oxadiazol-3-yl] -6-methyl-pyridyl-2 -yl.} methyl) azetidine-3-carboxylic acid, 1 - (. {5- [5- (3-Fluoro-4-propylphenyl) -1,2,4-oxadiazol-3-yl) ] -6-meilypyridyl-2-yl.) Methyl) azelidine-3-carboxylic acid, 1- (. {5- [5- (4-Butyl-3-fluorophenyl) -1,2} 4-Oxadiazol-3-yl] -6-meilypyridin-2-yl.} Meityl) azeididine-3-carboxylic acid, 1 - (. {5- [5- (3-Fluoro-4-isobuylphenyl) -1) , 2,4-oxadiazol-3-yl] -6-methylpyridi? -2-yl.} .methyl) azetidine-3-carboxylic acid,, 1- ( { 5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -6-meilypyridyr-2-yl} .methyl) azetidine -3-carboxylic acid, 1- (. {6-Eylyl-5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl}. me yl) 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; -il} methyl) azetidine-3-carboxylic acid, 1- (. {6-Ethyl-5- [5- (3-fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridine- 2-! L.] Methyl) azetidine-3-carboxylic acid, and 1- (. {5- [5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl) acid. ] -6-ethylpyridin-2-yl} .methyl) azetidine-3-carboxylic acid. Moreover, the present invention provides. (34) a medicinal composition comprising one or two or more compounds as described in any of (1) to (33) as an active ingredient, or a pharmacologically acceptable salt thereof, (35) a medicinal composition as set forth in (34) which can be used to suppress immune rejection symptoms that occur after skin tissue grafting or transplantation of various organs, (36) a medicinal composition as set forth in (34) that can be used for prophylaxis or therapy of autoimmune diseases , (37) a medicinal composition as set forth in (36) wherein said autoimmune disease is one or two or more conditions selected from the group consisting of rheumatoid arthritis, psoriasis, atopic dermatitis, multiple sclerosis, ulcerative colitis, and Crohn. (38) a method for suppressing immune rejection symptoms that occur after skin tissue implantation or transplantation of various organs which is characterized by administering an effective dose of a pharmaceutical composition as set forth in (34) to a mammal, (39) a method for prophylaxis or therapy of autoimmune diseases that is characterized by administering an effective dose of a pharmaceutical composition as set forth in (34) to a mammal, and (40) a method for prophylaxis or therapy as set forth in (39) wherein said autoimmune disease is one, or 2, or more conditions selected from the group consisting of rheumatoid arthritis, psoriasis, atopic dermatitis, multiple sclerosis, ulcerative colitis, and Crohn's disease. Substituent group A described above is preferably a group consisting of a halogen atom, a Ci-Cß alkyl group, a C3-C7 cycloalkyl group, a C6-C10 aryl group, a C6-C6 aryloxy group, a group C6-C2 aralkyl, a halogen group, a C6-C6 alkoxy group, a C1-C6 alkoxy halogen group, and an Ci-C3 alkylthio group- The "5- to 7- member heterocyclic group" in the definitions of W, X, and Y in the above formula is, for example, a 5- or 7-membered aromatic heterocyclic group containing one or more (eg, 1 to 3) heteroatoms selected from a nitrogen atom, an atom of sulfur, and an oxygen atom additionally to the carbon atoms, which has two positions! available for linking, and can be specifically a group of thienylene, furylene, pyrrolylene, imidazolylene, pyrazolylene, thiazolylene, isothiazolylene, oxazolylene, isoxazolylene, pyridylene, pyrazinylene, pyrimidinylene, pyridazinyle, oxadiazolylene, thiadiazolylene, or furazanylene, W is preferably a furylene group, Thienylene, pyrrolylene, or pyridylene, X is preferably an isoxazolylene or oxadiazolylene group, and Y is preferably a phenylene, pyridylene, or thienylene group. The "heterocyclic ring-fused group" in the definitions of W, X, and Y in the above formula represents a substituent in which "the 5- to 7-membered heterocyclic group" described above is fused with another cyclic graph (s), and specifically a fused, multi-ring aromatic heterocyclic group of 9- to 14-membered (preferably 9- or 10-membered) containing one more heteroatoms (eg, 1 to 3 heteroatoms) selected from a nitrogen atom, an atom of sulfur and an oxygen atom additionally to the carbon atoms, which has two positions! available for bonding, and is preferably a bicyclic, tricyclic, or tetracyclic group and more preferably a bicyclic group, and may be, for example, a benzothienylene, benzofuranylene, benzimidazolylene, benzoxazylidene, benzothiazolylene, benzisothiazolylene, naphtho [2,3-b] group. ] thiophenylene, isoquinolylene, quinolylene, indolylene, quinoxalinileno, fenantridinileno, fenotiaziniléno, fenoxazinileno, ftalazinileno, naftíridinileno, quinazolinylene, cinolinileno, carbazolileno, ß-carbolinileno, acridínileno, fenaziníleno, ftalimidoileno, (tioxantenil) tetrahidroquinolileno, tetrahidroisoquinolileno, tetrahidroindolileno, tetrahidrobenzofuranileno, tetrahidrobenzotienileno, 5,6-dihydro-4H-cyclopenta [b] furanylene, 5,6-dihydro-4H-cyclopenta [b] thienylene, or 1, 4,5,6-tetrahydrocyclopenta [b] pyrrolylene, W is preferably a tetrahydrobenzofuranylene group , tetrahydrobenzothienylene, tetrahydroindolylene, 5,6-dihydro-4H-cyclopenta (b) furanylene, 5,6-dihydro-4H-cyclop enta [b] thienylene, or 1, 4,5,6-tetrahydrocyclopenta [b] pyrrolylene, or the like, and Y is preferably an indolylene group. The "alkylene group CrC8" in the definition of X in the above formula represents a straight or branched CrC8 alkylene group and can be, for example, a methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, isopropylene, s-butylene, t-butylene, 3,3-I dimethylprolene, or 4,4-dimethylbutylene, or the like, and is preferably a methylene, ethylene, or propylene group. The "C 8 C alkylene group containing an oxygen atom or a sulfur atom in the carbon chain" in the definition of X in the above formula represents, for example, a - (CH 2) m 1 O (CH 2) m2- , - (CH2) m1S (fH2) m2-, - (CH2) m1CO (CH2) m2-, - (CH2) m1SO (CH2) m2-, (CH2) miS02 (CH2) 2- or similar (where m1 and m2 are the same or different and each represents an integer from 0 to 7, but the sum of m1 and m2 represents an integer from 0 to 7), and is preferably a group -CH2OCH2-, -CH2SCH2-, -OCH2-, -S H2-, -CH2O-, or -CH2S-. The "C8 alkyl group" in the definition of Z in the above formula is a straight or branched chain C8 alkyl group, and may be, for example, a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl group , octyl, isopropyl, s-butyl, t-butyl, 3,3-d? methylpropyl, or 4,4-dimethylbutyl, or the like, and is preferably a methylene, ethylene, or propylene group.

The "C8 alkyl group containing an oxygen atom or a Sulfur atom in the carbon chain "in the definition of Z in the formula above represents, for example, an H (CH2)? O (CH2) m2-, H (CH2) m? S (CH2) m2-, H (CH2) m? C; 0 (CH2) m2-, H (CH2) m1SO (CH2) m2-, or H (CH2) m? S02 (CH2) m2- (in Where m1 and m2 are the same or different and each represents an integer of 0 to 7, and additionally the sum of m1 and m2 represents an integer from 0 to 7), and is preferably a methoxymethyl, methylthiomethyl, methoxy, or methylthio group. The "C3-C7 cycloalkyl group" in the definitions of Z and group Substituent A in the above formula represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a group cycloheptyl.

The "C6-C10 arylene group" in the definitions of X and Y in the above formula may be, for example, a phenlene group, a group indenylene ,! or a naphthylene group, and is preferably a phenylene group.

The "aryl group C6-C? 0" in the definitions of Z and group Substituent A in the above formula can be, for example, a phenyl group, a denyl group, or a naphthyl group, and is preferably a phenyl group.

The "C6-C10 aryloxy group" in the definitions of Z and group Substituent A in the above formula can be, for example, a phenyloxy group, an iridinyloxy group, or a naphthyloxy group, and is preferably a phenyloxy group.

The "arylthio group Ce-Cio" in the definition of Z in the above formula can be, for example, a phenylthio group, an indenylthio group, or a naphthylthio group, and is preferably a phenylthio group. The "C6-C- aralkyl group" in the definition of Z in the above formula can be, for example, a benzyl group, an indenylmethyl group, or a naphthi) methyl group, and is preferably a benzyl group. The "arylcarbonyl group C6-C-? 0" in the definition of Z in the above formula can be, for example, a benzoyl group, an indenylcarbonyl group, or a group; naphthylcarbonyl, and is preferably a benzoyl group. The "halogen atom" in the definition of the Substituent group A in the above formula is a fluoro atom, a chlorine atom, a bromine atom, or an iodine atom. The "CrC6 alkyl group" in the definition of Substituent group A in the above formula can be, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a group s -butyl, a t-butyl group, a pentyl group, an isopentyl group, or a heteroxy group, and is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, or an isobutyl group. The "haloalkyl group CrC 6" in the definition of the group Substitute A in the above formula represents a group wherein a C 1 -C 6 alkyl group described above is substituted as much as possible with a halogen atom, and may be, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a difluoroethyl group, a trifluoroethyl group, a fluoropropyl group, a group Difluoropropyl, a trifluoropropyl group, a fluorobutyl group, a group difluorobuityl, a trifluorobutyl group, a fluoropentyl group, a group difluoropentyl, a trifluoropentyl group, a fluorohexyl group, a group difluorohexyl, a trifluorohexyl group, a pentafluoroethyl group, a group hexafluoropropyl, a nonafluorobutyl group, a chloromethyl group, a group dichloromejyl, a trichloromethyl group, a chloroethyl group, a dichloroethyl group, a trichloroethyl group, a chloropropyl group, a dichloropropyl group, a group trichloropropyl, a chlorobutyl group, a dichlorobutyl group, a group I trichlorobutyl, a chloropentyl group, a dichloropentyl group, a group trichloroperityl, a chlorhexyl group, a dichlorohexyl group, a group trichlorohexyl, a pentachloroethyl group, a hexachloropropyl group, or a group nonachlorobutyl, and is preferably a fluoromethyl group, a group difluoromethyl, a trifluoromethyl group, a fluoroethyl group, a group difluoroethyl, a trifluoroethyl group, a fluoropropyl group, a group difluoropropyl or a trifluoropropyl group, and more preferably a group fluorometilp, a difluoromethyl group, a trifluoromethyl group, a group fluoroethyl, a difluoroethyl group, or a trifluoroethyl group.

The "C-C alkoxy group" in the definition of Substituent group A in the previous formula represents a group where an oxygen atom is bonded to the C -Cß alkyl group described above, and is preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, or a group but i, and more preferably a methoxy group or an ethoxy group.

The "Ccy6 alkylthio group" in the definition of Substituent group A in the above formula represents a group wherein the sulfur atom is attached to the C -Cß alkyl group described above, and is preferably a methylthio group, an ethylthio group, a group propylthio, an isopropylthio group, or a butyl group, and more preferably a methylthio group or an ethylthio group. The "C6-C6 alkylcarboxy group" in the definition of the group Substitute A in the above formula represents a group wherein a carboxyl group is attached to the C-Cß alkyl group described above, and a methylcarboxyl group, an ethylcarboxyl group, a propylcarbyl group, an isopropolcarboxyl group, or a butolcarboxyl group, and more preferably a methocarboxyl group or an etolcarboxyl group is preferable. The "aliphatic acyl group Ci-Ce" in the definition of the substituent group A in the above formula represents a group in which a carbonyl group is attached to the C6 alkyl group described above, and can be, for example, a group acetyl, an ethylcarbonyl group, a propylcarbonyl group, a butylcarbonyl group, a pentylcarbonyl group, or a hexylcarbonyl group, and is preferably an acetyl group, an ethylcarbonyl group, or a p-propylcarbonyl group. The "C6 amino monoalkyl group" in the definition of Substituent group A in the above formula represents a group wherein an amino group is attached to the C6-C6 alkyl group described above, and is preferably a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, or a butylamino group and more preferably a methylamino group or an ethylamino group. The "dialkyl Ci-Cβ amino group" in the definition of the group Substitute A in the above formula represents a group in which two C-pCß alkyl groups described above are attached to an amino group, and is, for example, preferably a dimethylamino group , a diethylamino group, an ipropylamino group, a diisoproprilamino group, or a dibutylamino group, and more preferably a dimethylamino group or a diethylamino group. The "aliphatic C6-acylamino group" in the definition of the Substituyer A group in the above formula represents a group in which a carbonyl group is attached to the Ci-Cß alkyl group and, optionally, an amino group is attached to said carbonyl group, and it may be, for example, an acetylamino group, an ethylcarbonylamino group, a propylcarbonylamino group, a butylcarbonylamino group, a pentylcarbonylamino group, or a hexylcarbohilamino group, and is preferably an acetylamino group, a group Ethylcarbonylamino, or a propylcarbonylamino group. A compound having the general formula (I) of the present invention 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) I) of the present invention, 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 optionally be substituted with 1 to 3 substituents selected from the Substituent group A, more preferably a thienylene, furylene, pyrrolene or pyridylene group which may be optionally substituted with 1 to 3 substituents selected from the Substituent group A, and even more preferably a thienylene or pyridylene group which may be optionally substituted with one or two substituents selected from the Substituent group A. X is preferably a C---C8 alkylene group, an alkylene group C C 8 containing an oxygen atom or a sulfur atom in the carbon chain, a Cd-Cio arylene group, a 5- to 7-membered heterocyclic group or a fused ring heterocyclic group, and more preferably a heterocyclic group from 5- to 7- members. And it is preferably any of a group selected from the group consisting of a phenylene group, a 5- to 7-membered heterocyclic group which may be optionally substituted with 1 to 3 substituents selected from the Substituent group A, and a heterocyclic group of fused ring which may be optionally substituted with from 1 to 3 substituents selected from the group of Substituent A, more preferably a phenylene group, or a thienylene, pyridylene or indolylene group which may optionally be substituted with from 1 to 3 substituents selected from the group Substituyenlte A, and even more preferably a phenylene or a pyrridylene group.

Z is preferably a C 1 -C 12 aryloxy group which may be optionally substituted with from 1 to 5 substituents selected from the group Substituyer A, and more preferably a phenoxy group. ! In a compound having the general formula (I ') of the invention; R1 is preferably a hydrogen atom. R2 is preferably a hydrogen atom, a methyl group, or a lime group. R3 is preferably a hydrogen atom, a fluoro atom, a chlorine atom, or a methyl group. R4 is preferably a hydrogen atom, a fluoro atom, a chlorine atom, a cyano group, a methyl group, or a methoxy group. R5 is preferably a hydrogen atom or a fluoro atom. In a compound having the general formula (I ") of the present invention, R6 is preferably a hydrogen atom, a methyl group or an ethyl group, R7 is preferably a hydrogen atom, a fluoro atom, an chlorine or a methyl group R8 is preferably an n-propyl group, an n-butyl group or an isobutyl group The "pharmacologically acceptable salt thereof" described above means a salt that can be prepared by reacting a compound having the formula (I) of the present invention having an acidic group a basic group, and can be prepared as a basic salt or an acid salt by reaction with a base or an acid, respectively.

Said salt is described in the following. The pharmacologically acceptable "basic salt" of a compound having the general formula (I) of the present invention is preferably an alkali metal salt such as sodium salt, potassium salt, or lithium salt; an alkali metal salt such as a magnesium salt or calcium salt; an organic-based salt such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperijdine salt, pyridine salt, 4-pyrrolidinopyridine salt, or picoline salt, or a salt of! amino acid such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt, or aspartic acid salt. The salt is preferably an alkali metal salt. The pharmacologically acceptable "acid salt" of a compound having the general formula (I) of the present invention is preferably an inorganic acid salt eg a halohydrate such as a fluorohydrate, hydrochloride, hydrobromide, or hydroiodide, a nitrate, a perchlorate , a sulfate, a phosphate, or the like; an organic acid salt, for example, a lower alkanesulfonate such as a methanesulfonate, trifluoromethanesulfonate, or ethanesulfonate, an arisulfonate such as a benzenesulfonate or p-toluensulfo-Inato, an acetate, a malate, a fumarate, a succinate, a citrate, an ascorbate , a tartrate, an oxalate, a maleate, or the like; or an amino acid salt such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt, or aspartic acid salt, and more preferably a halohydrate. The "pharmacologically acceptable prodrug thereof" described below is a compound that is converted to the compound (I) through the reaction of enzymes, gastric acid, or the like under physiological conditions, that is, a compound that is converted to the compound (I) by oxidation, reduction, enzymatic hydrolysis or the like, or a compound that is converted to the compound (I) by hydrolysis induced by gastric acid. The prodrug described above is a compound which, when the compounds (I) have a carboxyl group, can be derivatized by esterification or amidation of said carboxyl group (for example, compounds derived by ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, esterification of (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, cyclohexyloxycarbonylethyl esterification, or methylamidation of the carboxyl group of a compound (I)) or similar. These compounds can be prepared from the compound (I) by known methods. Moreover, as the prodrug of the compounds (I) of the present invention, various derivatives are also included which are described in the literature ("Development of medicine" Vol. 7, Molecular design, pp. 163-198, published in 1990 by Hirokawa Shoten) and unfold in the compunds (I) under physiological conditions. When the compounds of the present invention are allowed to come into contact with the atmosphere or recrystallize, they can absorb water or the water can bind to them to form a hydrate. The present invention encompasses said hydrates. The compounds of the present invention also include the corresponding compounds that are labeled as isotopes (for example JH, 14C, 35S, etc.). When the compounds of the present invention have asymmetric carbon atoms in their structures, these compounds can exist as optical isomers due to said asymmetric carbon atoms. In the present invention, a simple optical isomer and mixtures of optical isomers are represented by a single chemical formula. The present invention encompasses both individual optical isomers and mixtures thereof in any proportion. Preferred examples of the compounds having the general formula (I) of the present invention are, for example, the compounds having the general formula (1-1), (I-2), (l'-1), or ( l "-1" shown in Tables 1, 2, 3 and 4 below, but within the scope of the present invention should not be limited to these compounds.The meaning of the abbreviations in the following Tables is shown below. -) represents a single bond or a double bond, and which link will be adopted is determined logically depending on the nature of the substituted atoms.

TABLE 1 Compound R J K L U No. 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 - . 1 - . 1 - . 1 - . 1 - . 1 - . 1 - . 1 -9 PhO N N O O CH 1 -10 Bn N N O O CH 1 -1 1 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 NNON -CH = CH- 1-17 i-Bu NNON -CH = CH- 1-18 c-Hex NNO -CH = CH- 1-19 PhO NNON -CH = CH- 1-20 Bn NNON -CH = CH- 1-21 n-Bu NNO CH -N = CH- 1-22 i-Bu NNO CH -N = CH- 1-23 c-Hex NNO CH -N = CH- 1-24 PhO NNO CH -N = CH- 1-25 Bn NNO CH -N = CH- 1-26 n-Bu NNO 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 1-30 Bn N N O CH 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 CH NON -CH = CH- 1-57 i-Bu CH NON -CH = CH- 1-58 c-Hex CH NO -CH = CH- 1-59 PhO CH NON -CH = CH- 1-60 Bn CH NON -CH = CH- 1-61 n-Bu CH NO CH -N = CH- 1-62 -Bu CH NO CH -N = CH- 1-63 c-Hex CH NO CH -N = CH- 1-64 PhO CH NO CH -N = CH- 1-65 Bn CH NO CH -N = CH- 1-66 n-Bu CH NO CH 1-67 i-Bu CH NO CH 1-68 c-Hex CH NO CH 1-69 PhO CH NO CH 1-70 Bn CH NO 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 O N S CH 1-82 i-Bu N O N S CH 1-83 c-Hex N O N S CH 1-84 PhO N O N S CH 1-85 Bn N O N 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 O N NMe CH 1-92 i-Bu N O N NMe CH 1-93 c-Hex N O N NMe CH 1-94 PhO N O N NMe CH 1-95 Bn N O N NMe CH 1-96 n-Bu NONN -CH = CH- 1-97 i-Bu NONN -CH = CH-1-98 c-Hex NONN -CH = CH- 1 -99 PhO NONN -CH = CH- 1-100 Bn NONN -CH = CH- 1 -101 n-Bu NON CH -N = CH- 1-102 i-Bu NO CH -N = CH- 1 -103 c-Hex NON CH -N = CH- 1-104 PhO NON CH -N = CH- 1-105 Bn NON CH -N = CH- 1-106 n-Bu NON CH S 1-107 i-Bu N O N CH S 1-108 c-Hex N O N CH S 1-109 PhO N O N CH S 1-110 Bn N O N 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 O N CH O 1-115 Bn N O N CH O 1-116 n-Bu N O N CH NMe 1-117 i-Bu N O N CH NMe 1-118 c-Hex N O N CH NMe 1-119 PhO N O N CH NMe 1-120 Bn N O N CH NMe 1-121 n-Bu CH O N S CH 1-122 i-Bu CH O N S CH 1-123 c-Hex CH O N S CH 1-124 PhO CH O N S CH 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 O N NMe CH 1-132 i-Bu CH O N NMe CH 1-133 c-Hex CH O N NMe CH 1-134 PhO CH O N NMe CH 1-135 Bn CH O N NMe CH 1-136 n-Bu CH ONN -CH = CH- 1-137 i-Bu CH ONN -CH = CH- 1-138 c-Hex CH ONN -CH = CH- 1-139 PhO CH ONN -CH = CH- 1-140 Bn CH ONN -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 ON CH O 1-152 i-Bu CH ON CH O 1-153 c-Hex CH ON CH O 1-154 PHO CH ON CH O 1-155 Bn CH ON 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 ON CH NMe In Table 1 described above, the preferred compounds (ll) of the present invention include Example Compound No. 1-3: 1- (. {4- [3- (4-Cyclohexylphenyl) -1, 2,4- oxadiazol-5-yl] -2-thienyl.} methyl) azetidine-3-carboxylic acid Example compound number 1-8: 1- ( { 4- [3- (4-Cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -2-furyl} methyl) azetidine-3-carboxylic acid Example compound number 1- 17: 1- (. {5- [3- (4-lsobutylphenyl) -1,2,4-oxadiazol-5-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid Example Compound No. 1-22: 1- (. {6- [3- (4-lsobutylphenyl) -1,2,4-oxadiazol-5-yl] pyridin-3-yl} methyl) azetidine-3 acid carboxyl Compound example number 1-28: 1- (. {5- [3- (4-Cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -2-thienyl} methyl) azetidine acid -3-carboxylic Example compound number 1-33: 1- (. {5- [3- (4-Cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -2-furyl} methyl} acid ) azetidine-3-carboxylic acid Example compound number 1-43: 1- (. {4- [3- (4-Cyclohexylphenyl) isooxazol-5-yl] -2-thienyl} methyl) azetidine-3-acid carboxyl Compound of example number 1-48: 1- ( { 4- [3- (4-Cyclohexylphenyl) isooxazol-5-yl] -2-furyl} methyl) azetidine-3-carboxylic acid, Compound of example number 1-57: 1- ( { 5- [3 - (4-lsobutylphenyl) isooxazol-5-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid, Example compound number 1-62: 1- (. {6- [3- (4-lsobutylphenyl) isooxazol-5-yl] pyridin-2-yl} methyl) azetidine -3-carboxylic acid, Example compound number 1-68: 1- (. {5- [3- (4-Cyclohexylphenyl) isooxazol-5-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid Compound example number 1-73: '1- (. {5- [3- (4-Cyclohexylphenyl) isooxazol-5-yl] -2-furyl} methyl] azetidine-3-carboxylic acid, Compound of example number 1-82: 1- (. {4- [5- (4-lsobutylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl] azetidine-3-acid. carboxylic, Example compound number 1-83: 1- (. {4- [5- (4-Cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} -methyl) azetidine acid -3-carboxylic acid, Example compound number 1-84: Acid 1 - (. {4- [5- (4-Cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl}. methyl) azetidine-3-carboxylic acid, Example compound number 1-88: 1- (. {4- [5- (4-Cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-furyl acid .}. methyl) azeti dina-3-carboxylic acid, Example compound number 1-97: Acid 1 - (. {5- [5- (4-lsobutylphenyl) -1,4, 2,4-oxadiazol-3-yl] pyridin-2-yl}. Methyl) azetidine-3-carboxylic acid, Example Compound number 1-102: 1- (. {6- [5- (4-lsobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azetidine-3-carboxylic acid, Example compound number 1-107: 1- (. {5- [5- (4-lsobutylphenyl) -1,2,4-oxadiazo! -3-yl] -2-thienyl} methyl] azetidine acid 3-carboxylic acid, Example Compound No. 1-108: 1- (. {5- [5- (4-Cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} acid. methyll) azetidine-3-carboxylic acid, Example compound number 1-109: 1- (. {5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] acid] -2-tienyl.} Methyl) azetidine-3-carboxylic acid, Compound example number 1-113: 1- (. {5- [5- (4-Cclohexylphenyl) -1,2,4-oxadiazole- 3-yl] -2-furyl.} Methyl) azetidine-3-carboxylic acid, Example compound number 1-122: 1 - (. {4- [5- (4-lsobutylphenyl) isoxazole-3-yl! l] -2-thienyl] methyl) azetidine-3-carboxylic acid, Example compound or number 1-123: Acid 1 - (. { 4- [5- (4-Cyclohexylphenyl) isoxazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid, Example Compound No. 1-124: 1- (. {4- [5- (4-Phenoxyphenyl) -isoxazol-3-yl] -2-thienyl} -methyl) azetidine -3-carboxylic acid, I Example compound number 1-128: 1- (. {4- [5- (4-Cyclohexylphenyl) isoxazol-3-yl] -2-furyl} methyl) azetidine- acid 3-carboxylic acid, Example compound number 1-137: 1 - (. {5- [5- (4-lsobutylphenyl) isoxazol-3-yl] pyridin-2-yl} methyl) azetidine-3-acid carboxylic, Example compound number 1-142: 1- (. {6- [5- (4-lsobutylphenyl) isoxazol-3-yl] pyridin-3-yl} methyl) azetidine-3-carboxylic acid, Compound Example number 1-147: 1- (. {5- [5- (4-lsobutylphenyl) isoxazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid, Example Compound No. 1 -148: 1- ( { 5- [5- (4-Cyclohexylphenyl) isoxazol-3-yl] -2-thienyl} -methyl) azetidine-3-carboxylic acid, Example Compound No. 1-149: Acid 1 - (. {5- [5- (4-Phenoxyphenyl) isoxazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid, and Comp Example example number 1-153: Acid 1 - ( { 5- [5- (4-Cyclohexylphenyl) isoxazol-3-yl] -2-furyl} methyl) azetidine-3-carboxylic acid, The most preferred compounds are the compounds of the Example Compounds Nos. 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.

TABLE 2 Compound R J K L V m No. 2-1 n-Bu NNOS CH 2 2-2 i-Bu NNOS CH 2 2-3 c-Hex NNOS CH 2 2-4 PhO NNOS CH 2 2-5 Bn NNOS CH 2 2-6 n-Bu NNOS CH 3 2-7 i-Bu NNOS CH 3 2-8 c-Hex NNOS CH 3 2-9 PhO NNOS 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 -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 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 O N S CH 2 2-122 i-Bu N O N S CH 2 2-123 c-Hex N O N S CH 2 2-124 PhO N O N S CH 2 2-125 Bn N O N S CH 2 2-126 n-Bu N O N S CH 3 2-127 i-Bu N O N S CH 3 2-128 c-Hex N O N S CH 3 2-129 PhO N O N S CH 3 2-130 Bn N O N 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 -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 O N NMe CH 2 2-142 i-Bu N O N NMe CH 2 2-143 c-Hex N O N 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 O N NMe CH 3 2-147 i-Bu N O N NMe CH 3 2-148 c-Hex N O N 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 O N CH S 2 2-152 i-Bu N O N CH S 2 2-153 c-Hex N O N CH S 2 2-154 PhO N O N CH S 2 2-155 Bn N O N CH S 2 2-156 n-Bu N O N CH S 3 2-157 i-Bu N O N CH S 3 2-158 c-Hex N O N CH S 3 2-159 PhO N O N CH S 3 2-160 Bn N O N 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 O N CH NMe 2 2-172 i-Bu N O N CH NMe 2 2-173 c-Hex N O N CH NMe 2 2-174 PhO N O N CH NMe 2 2-175 Bn N O N CH NMe 2 2-176 n-Bu N O N CH NMe 3 2-177 i-Bu N O N CH NMe 3 2-178 c-Hex O N CH NMe 3 2-179 PhO N O N CH NMe 3 2-180 Bn N O N CH NMe 3 2-181 n-Bu CH O N S CH 2 2-182 i-Bu CH O N S CH 2 2-183 c-Hex CH O N S CH 2 2-184 PhO CH O N S CH 2 2-185 Bn CH O N S CH 2 2-186 n-Bu CH O N S CH 3 2-187 i-Bu CH O N S CH 3 2-188 c-Hex CH O N S CH 3 2-189 PhO CH O N S CH 3 2-190 Bn CH O N S CH 3 2-191 n-Bu CH O N O CH 2 2-192 i-Bu CH O N O CH 2 2-193 c-Hex CH O N O CH 2 2-194 PhO CH O N O CH 2 2-195 Bn CH O N O CH 2 2-196 n-Bu CH O N O CH 3 2-197 i-Bu CH O N O 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 O N NMe CH 2 2-202 i-Bu CH O N NMe CH 2 2-203 c-Hex CH O N NMe CH 2 2-204 PhO CH O N NMe CH 2 2-205 Bn CH O N NMe CH 2 2-206 n-Bu CH O N NMe CH 3 2-207 i-Bu CH O N NMe CH 3 2-208 c-Hex CH O N NMe CH 3 2-209 PhO CH O N NMe CH 3 2-210 Bn CH O N NMe CH 3 2-211 n-Bu CH O N CH S 2 2-212 i-Bu CH O N CH S 2 2-213 c-Hex CH O N CH S 2 2-214 PhO CH O N CH S 2 2-215 Bn CH O N CH S 2 2-216 n-Bu CH O N CH S 3 2-217 i-Bu CH O N CH S 3 2-218 c-Hex CH O N CH S 3 2-219 PhO CH O N CH S 3 2-220 Bn CH O N CH S 3 2-221 n-Bu CH O N CH O 2 2-222 i-Bu CH O N CH O 2 2-223 c-Hex CH O N CH O 2 2-224 PhO CH O N CH O 2 2-225 Bn CH O N CH O 2 2-226 n-Bu CH O N CH O 3 2-227 i-Bu CH O N CH O 3 2-228 c-Hex CH O N CH 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 O N CH NMe 2 2-232 i-Bu CH O N CH NMe 2 2-233 c-Hex CH O N CH NMe 2 2-234 PhO CH O N CH NMe 2 2-235 Bn CH O N CH NMe 2 2-236 n-Bu CH O N CH NMe 3 2-237 -Bu CH O N CH NMe 3 2-238 c-Hex CH O N CH NMe 3 2-239 PhO CH O N CH NMe 3 2-240 Bn CH O N CH NMe 3 In Table 2 described above, the preferred compounds (I-2) of the present invention include Example Compound No. 2-33: Acid 1-. { 2- [3- (4-Cyclohexyl. {Enyl) -1,4,4-oxadiazol-5-yl] -5,6-dihydro-4H-cyclopenta [b] thien-4-yl} azetidine-3-carboxylic acid, Example compound number 2-38: Acid 1-. { 2- [3- (4-Cyclohexyl) -1, 2,4-oxadiazol-5-yl] -4,5,6,7-tetrahydro-1-benzothien-4-yl} azetidine-3-carboxylic acid, Example compound number 2-43: Acid 1-. { 2- [3- (4-Cyclohexyl) -1, 2,4-oxadiazol-5-yl] -5,6-dihydro-4H-cyclopenta [b] furan-4-yl} azetidine-3-carboxylic acid, Example compound number 2-48: Acid 1-. { 2- [3- (4- i Cyclohexylthhenyl) -1,4,4-oxadiazol-5-yl] -4,5,6,7-tetrahydro-1-benzofuran-4-yl} azetidine-3-carboxylic, Example compound number 2-93: Acid 1-. { 2- [3- (4-Cyclohexylphenyl) isoxazol-5-yl] -5,6-dihydro-4H-cyclopenta [b] thien-4-yl} azetidine-3-carboxylic acid, Example compound number 2-98: Acid 1-. { 2- [3- (4-Cyclohexylphenyl) isoxazol-5-yl] -4,5,6,7-tetrahydro-1-benzothien-4-yl} azetidine-3-carboxylic acid, Example compound number 2-103: Acid 1-. { 2- [3- (4-Cyclohexylphenyl) isoxazol-5-yl] -5,6-dihydro-4H-cyclopenta [b] thien-4-yl} azetidine-3-carboxylic, Example compound number 2-108: Acid 1-. { 2- [3- (4-Cyclohexyl-enyl) isoxazol-5-yl] -4,5,6,7-tetrahydro-1-benzofuran-4-yl} azetidine-3-carboxylic, Example compound number 2-153: Acid 1-. { 2- [5- (4-Cyclohexylphenyl) -1,4, 2,4-oxadiazol-3-yl] -5,6-dihydro-4H-cyclopenta [b] thien-4-yl} azetidine-3-carboxylic acid, Example compound number 2-158: Acid 1-. { 2- [5- (4- Cyclohexylphenyl) -1,4, 2,4-oxadiazol-3-yl] -4,5,6,7-tetrahydro-1-benzothien-4-yl} azetidine-3-carboxylic acid, Example compound number 2-163: Acid 1-. { 2- [5- (4-Cyclohexylphenyl) 1Al. , 2,4-oxadiazol-3-yl] -5,6-dihydro-4H-cyclopenta [b] furan-4-yl} azetidine-3-carboxylic acid, Example compound number 2-168: Acid 1-. { 2- [5- (4-Cyclohexylphenyl) -1,4, 2,4-oxadiazol-3-yl] -4,5,6,7-tetrahydro-1-benzofuran-4-yl} azetidine-3-carboxylic acid, Example compound number 2-213: Acid 1-. { 2- [5- (4-Cyclohexyl-1-enyl) -soxazol-3-yl] -5,6-dihydro-4H-cyclopenta [b] thien-4-yl} azetidine-3-carboxylic acid, Example compound number 2-218: Acid 1-. { 2- [5- (4-Cyclohexylphenyl) isoxazol-3-yl] -4,5,6,7-tetrahydro-1-benzothien-4-yl} azetidine-3-carboxylic acid, Example Compound No. 2-223: Acid 1-. { 2- [5- (4-Cyclohexyl-fienyl) -isoxazol-3-yl] -5,6-dihydro-4H-cyclopenta [b] furan-4-yl} azetidine-3-carboxylic ?, and Example Compound No. 2-228: Acid 1-. { 2- [5- (4-Cyclohexylphenyl) isoxazol-3-yl] -4,5,6,7-tetrahydro-1-benzofuran-4-yl} azetidine-3-carboxylic acid, The most preferred compounds are the compounds of the Example Compounds Nos. 2-43, 2-48, 2-103, 2-108, 2-163, 2-168, 2-223, and 2-228.

TABLE 3 Compound R1 R¿ RJ Q * 4? 5 ' Do not. 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 3-5 H H Cl H H 3-6 H H Cl H 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 3-1 1 H H Cl MeO H 3-12 H H Cl MeO F 3-13 H H H H 3-14 H H H 3-15 H H F H 3-16 H H F 3-17 H H Cl F H 3-18 H H Cl 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 3-27 H Me F H H 3-28 H Me F H 3-29 H Me Cl H H 3-30 H Me Cl H 3-31 H Me H MeO H 3-32 H Me H MeO F 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 H 3-38 H Me H 3-39 H Me F H 3-40 H Me F 3-41 H Me Cl F H 3-42 H Me Cl F 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 Cl Cl Cl H 3-48 H Cl Cl Cl 3-49 H Et H H H 3-50 H Et H H 3-51 H Et F H H 3-52 H Et F H 3-53 H Et Cl H H 3-54 H Et Cl H 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 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 F F 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 3-75 Me H F H H 3-76 Me H F H 3-77 Me H Cl H H 3-78 Me H Cl H 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 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 3-99 Et H F H H 3-100 Et H F H 3-101 Et H Cl H H 3-102 Et H Cl H 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 H 3-110 Et H H 3-1 1 1 Et H F H 3-112 Et H 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 Table 3 described above, the preferred compounds (l'-1) of the | present invention include Example Compound No. 3-1: 1- (. {5- (5- (4-Phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl} acid) azetidine-3-carboxylic (Example 5). ! Compound example number 3-25: 1- (4-Methyl-5- [5- (4-phenoxyphenyl) -1,4,4-oxadiazol-3-yl] -2-thienyl acid}. methyl) azetidine-3-carboxylic acid (Example 12), Example compound number 3-27: 1- (. {5- [5- (3-Fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-methyl- acid 2-thienyl.} Methyl) azetidine-3-carboxylic acid (Example 11), Example compound number 3-49: 1- (. {4-Ethyl-5- [5- (4-phenoxyphenyl) -1 acid, 2,4-oxadiazol-3-yl] -2-thienyl.} Methyl) azetidine-3-carboxylic acid (Example 13), Example compound number 3-50: Acid 1 - [(4-Ethyl-5- { 5- [4- (3-fluorophen i) phenyl] -1,2,4-oxadiazol-3-yl .} -2-thienyl) methyl] azetidine-3-carboxylic acid (Example 1.7), Example compound number 3-51: 1- (. {4-Ethyl-5- [5- (3-fluoro) acid -4-phenylnoxy) -1, 2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid (Example 14), Example Compound No. 3-52: Acid 1 - [(4-Ethyl-5-. {5- [3-fluoro-4 - (^ -fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3-carboxylic acid (Example 20), Example compound number 3-53: Acid 1 - [(4-Ethyl-5-. {5- [4- (2-methoxyphenoxy) phenyl] -1 , 2,4-oxadiazol-3-yl.} -2-thienyl) methyl] azetidine-3-carboxylic acid (Example 15), Example compound number 3-54: 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 (Example 16), Example compound number 3-55: 1 - [(4-Ethyl-5-. {5- [4- (2-methoxyphenoxy) phenyl] -1,2,4-oxadiazol-3-yl} acid. 2-tien il) methyl] azetidine-3-carboxylic acid (Example 21), Example compound number 3-61: 1 - [(4-Ethyl-5-. {5- [4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} acid. -2-thienyl) methyl] azetidine-3-carboxylic acid (Example 1 | 0), Example Compound No. 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), Example Compound No. 3-63: Acid 1 - [( 4-Ethyl-5- { 5- [3-fluoro-4- (2-difluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) methyl] azetidine-3 -carboxylic compound, Example compound number 3-64: 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, Example compound number 3-65: 1 - [(5-. {5- [3-Chloro-4- (2- fluorophenoxy) phenyl] -1,4,4-oxadiazol-3-yl.} -4-ethyl-2-thienyl) methyl] azetidine-3-carboxylic acid, Example Compound No. 3-66: Acid 1 - [( - { 5- [3-Chloro-4- (2,3-dlfl? Orophenoxy) phenyl] -1,4, 2,4-oxadiazol-3-yl.} -4-ethyl-2-thienyl) methyl] azetíd ina-3-carboxylic acid, Example compound number 3-67: Acid 1 - [(5-. { 5- [4- (2-Chlorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} 4-ethyl-2-thienyl) methyl] azetidine-3-carboxylic acid (Example 19), Example compound number 3-69: Acid 1 - [(5-. {5- [4- (2-Chlorophene)] ) -3-fluorophenyl] -1,4, 2,4-oxadiazol-3-yl.} -4-ethyl-2-thienyl) methyl] azetidine-3-carboxylic acid, Example compound number 3-73: Acid 1- ( (3-Methyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methyl) azetidine-3-carboxylic acid, and Example Compound number 3-97: 1- (. {3-Etyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} -methyl) azetidine-3-acid carboxylic (Example 22), The most preferred compounds are the compounds of Example Compounds Nos. 3-25, 3-27, 3-49, 3-50, 3-51, 3-52, 3-53, 3 -54, 3-55, 3-61, and 3-67.

TABLE 4 Compound R6 R7 R8 No. 4-1 HH Pr 4-2 HH Bu 4-3 HH iBu 4-4 H Me Pr 4-5 H Me Bu 4-6 H Me Bu, 4-7 HF Pr 4-8 HF Bu 4-9 HF iBu 4-10 H Cl Pr 4-11 H Cl Bu 4-12 H Cl Bu 4-13 H CF3 Pr 4-14 H CF3 Bu 4-15 H CF3 Bu 4-16 Me H Pr 4-17 Me H Bu 4-18 Me H Bu 4-19 Me Me Pr 4-20 Me Me Bu 4-21 Me Me Bu 4-22 Me F Pr 4-23 Me F Bu 4-24 Me F Bu 4-25 Me Cl Pr 4-26 Me Cl Bu 4-27 Me Cl iBu 4-28 Me CF3; Pr 4-29 Me CF3; Bu 4-30 Me CF3, Bu 4-31 Et H Pr 4-32 Et H Bu 4-33 Et H Bu 4-34 Et Me Pr 4-35 Et Me Bu 4-36 Et Me Bu 4-37 Et F Pr 4-38 Et F Bu 4-39 Et F iBu 4-40 Et Cl Pr 4-41 Et Cl Bu 4 -42 Et Cl iBu 4-43 Et CF3 Pr 4-44 Et CF3 Bu 4-45 Et CF3 iBu In Table 4 described above, the preferred compounds l (1"-1) of the present invention include Example Compound No. 4-6: 1- (. {5- [5- (4-lsobutyl-3-methylphen 1) -1,4, 2,4-oxadiazol-3-yl] pyridin-2-yl) methyl) azetidine-3-carboxylic acid (Example i 28), example number 4-9: 1- (. {5- [5- (3-Fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl acid .) methyl) azetidine-3-carboxylic acid (Example 2 ~ 3), Example compound number 4-12: 1- (. {5- [5- (3-Chloro-4-isobutylphenol ) -1,4, 2,4-oxadiazol-3-yl] pyridin-2-yl.] Methy1) azetidine-3-carboxylic acid (Example 2-6), Example Compound No. 4-21: Acid 1- ( { 5- [5- (4-lsobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl}. L) azetidine-3-carboxylic acid (Example 27), 'Example Compound No. 4-22: Acid 1- (. {5- [5- (3-Fluoro-4-propylpholine) r1 , 2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl.] Methyl) azetidine-3-carboxylic acid, Example Compound number 4-23: 1- (. {5- [5- (4-Butyl-3-fluorophenyl) j-1, 2,4-oxadiazol-3-yl] -6-methy1pyridine acid 2-il} methyl) azetidione-3-carboxylic acid, Example compound number 4-24: 1- (. {5- [5- (3-Fluoro-4-isobutylphenyl) -1,4- Oxadiazol-3-yl] -6-methy1-pyrid-2-yl} methyl) azetidine-3-carboxylic acid, Example Compound No. 4-27: Acid 1- (. { 5- [5- (3-Chloro-4-isobutylphenyl) -1,4,4-oxadiazol-3-yl] -6-methylpyridin-2-yl.] Metl) azetidine-3 carboxylic (Example 24), Example compound number 4-36: 1- (. {6-Ethyl-5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazole-3-acid 1) pyridin-2-yl) methyl) azetidine-3-carboxylic acid (Example 2d), Example Compound No. 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, Compound of example number 4-38: 1- (. {5- [5- (4-Butyl-3-fluorophenyl) -1,4-oxadiazol-3-yl] -6-ethylpyridin-2-yl acid} methyl) azetidine-3-carboxylic acid, Example compound number 4-39: 1- (. {6-Ethyl-5- [5- (3-fluoro-4-isobutylphenyl) -1, 2 , 4-oxadiazol-3-yl] pyridin-2-yl 1) methyl) azetidine-3-carboxylic acid (Example 30), and Example Compound number 4-42: 1- (. { 5- [5- (3-Chloro-4-isobutyl-phenyl) -1, 2,4-oxadiazol-3-yl] -6-ethylpyridin-2-yl} methyl) azetidine-3-carboxylic acid (Example 5), The most preferred compounds are the compounds of Example Compounds Nos. 4-6, 4-9, 4-12, 4-21, 4 -27, 4-36, and 4-42.

Advantages of the Invention Because the compounds of the present invention exert excellent immunosuppressive activity with low toxicity, the compounds of the present invention are useful as a prophylactic agent or as a therapeutic agent (particularly a therapeutic agent) for diseases related to the suppression of immune system in mammals (particularly humans)., BEST MODE FOR CARRYING OUT THE INVENTION The compound having the general formula (I) of the present invention can be prepared according to the methods described in the following. The preparation methods described in the following were generally established in accordance with known procedures. As known procedures, the described procedures are found, for example, in "Organic Functional Group Preparation", Second Edition, Academic Press, Inc., 1989, and "Comprehensive Organic Transformations", VCH Publi hers Inc., 1989, and the like.

Method A is a method for the preparation of a compound which has the general formula (I).

Method A L Y XW'V ^ N ^ \ .B Eta a A3 nni.XMXfi A (l) In the previous reaction scheme, A, B, V, W, X, Y, Z and n They have the same meanings as those indicated above.

LG represents a group that is known as an outgoing group in the chemistry of organic synthesis chemistry, and can be, for example, a halogen atom or a group of formula-O-S (O) 2Rc (wherein, Rc is a methoxy group, a C6 alkyl group which can optionally be substituted with 1 to 3 halogen atoms, or a phenyl group that may be optionally substituted with 1 to 3 Substituents selected from the group which consists of a halogen atom and a methyl group), and preferably a chlorine atom, a bromine atom, an iodine atom, an Methanesulfonyloxy group or a p-toluenesulfonyloxy group. AP represents a group in which a functional group indicated in the definition of A is protected by a protecting group as a form considered suitable in organic synthesis chemistry, and said protecting group P can be, for example, a protective group found in "Protective Groups in Organic Synthesis third edition" (ed by Green, TW and Wuts, PGM, John Wiley and Sons, Inc., 1999).; In case A is a carboxyl group, said protecting group is preferably a lower alkyl group such as a methyl group, u? ethyl group, a propyl group, or the like, and particularly preferably an ethyl group. In case A is a phospho group, said 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, and particularly preferably an allyl group. In the case where A is a sulfo group, said protecting group P is preferably a phenyl group, a p-methoxyphenyl group or a p-nitrophenyl group, and particularly more preferably a phenyl group. In the case where A is a 1 H-tetrazol-5-yl group, said protecting group P is preferably a triphenylmethyl group, a p-methoxyphenyl-lifenylmethyl group or a di (p-methoxyphenyl) phenylmethyl group, and particularly preferably a triphenylmethyl group.

Step A1, Step A1 is a process for the preparation of a compound having the general formula (III) by converting a hydroxyl group of a compound having the general formula (II) to a leaving group. This process is carried out by reacting the compound having the general formula (II) with a halogenating agent or a sulfonylating agent, and is preferably carried out by reacting with a halogenating agent in a solvent. ! The halogenating agent described above can be, for example, a phosphorus trihalide such as phosphorus trichloride or phosphorus tribromide; or a combination of a phosphine, which consists of a triarylphosphine which includes triphenylphosphine and a lower trialkylphosphine such as tributylphosphine, and any | of a simple molecular halogen such as bromine or iodine, or a quivalent halogen such as carbon tetrachloride, carbon tetrabromide or hexachloroacetone, and is preferably a combination of a triarylphosphine and a halogen equivalent, and particularly preferably a combination of triphenylphosphine and carbon trabromide. The solvent used in the above reaction is not particularly restricted provided it has no adverse effect on the reaction, and may be, for example, a halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloroethane, or the like.; or an ether such as tetrahydrofyirane, 1,2-dimethoxyethane, or the like, and is preferably a halogenated hydrocarbon and particularly preferably dichloromethane.

The reaction temperature employed in the above reaction is generally between -23X and 60 ° C, and preferably between 0 ° C and 30 ° C. The reaction time used in the previous reaction is different depending on the reaction temperature, the starting material, the reagent used or the type of solvent used, but is generally between 15 minutes to three hours, and preferably 30 minutes to one hour. After completion of the reaction, the desired compound of this reaction can be isolated from the reaction mixture by conventional treatments. The desired compound can be obtained, for example, by neutralization of the reaction mixture, if necessary, or filtration of the reaction mixture when insoluble material is present in the reaction mixture, extraction of the neutralized solution or filtrate with an organic solvent immiscible with water such as toluene, washing the resulting organic layer with water, separated from the organic layer containing the desired compound, and then evaporating the organic solvent under reduced pressure. The desired product thus obtained can, if necessary, be further isolated and purified by conventional treatments, for example, by recrystallization, reprecipitation, or by conventional procedures generally used in the isolation and purification of organic compounds (for example, column chromatography). absorption using a carrier such as silica gel, alumina or Florisil consisting of magnesium and silica gel; column chromatography by partition using Sephadex¡LH-20 (product of Pharmacia Co., Ltd.), Amberlite XAD-11 (product of Rohm &Hass Co., Ltd.) or Diaion HP-20 (product of Mitsubishi Chemicals Co., Ltd.); ion exchange chromatography; or normal phase or reverse phase column chromatography using silica gel or alkylated silica gel, and preferably by column chromatography using silica gel).

Step A2 Step A2 is a process for the preparation of a compound having the general formula (V) by substituting a leaving group LG of a compound having the general formula (III) with a compound having the general formula (IV) . This procedure is carried out in the presence of a base in a solvent. The base employed in the above reaction may be, for example, a trialkylamine such as N, N-diisopropylethylamine, tributylamine, or the like; or a pyridine such as pyridine, lutidine, collidine, or the like; an alkali metal carbonate such as sodium acid carbonate, potassium acid carbonate, sodium carbonate or potassium carbonate, or the like, and preferably a trialkylamine and particularly preferably N, N-diisopropylethylamine. The solvent employed in the above reaction is not particularly restricted on the condition that it has no adverse effect on the reaction and may be, for example, a halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloroethane, or the like; or an ether such as diethyl ether, tetirahydrofuran, 1,2-dimethoxyethane, dioxane, or the like, and is preferably a halogenated hydrocarbon and particularly preferably dichloromethane. The reaction temperature employed in the above reaction is generally between 0 ° C and 100 ° C, and preferably between 0 ° C and 30 ° C. The reaction time used in the previous reaction is different depending on the reaction temperature, the starting material, the I used reagent or solvent used, but is generally between 15 minutes to 3 hours, and preferably between 30 minutes to 2 hours. After the reaction has been completed, the desired reaction compound can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in step A1.

Step A3 The step A3 is a process for the preparation of a compound having the general formula (I) by carrying out the deprotection reaction in the AP substituent of a compound having the general formula (V). the deprotection reaction in this process are different depending on the protecting group used for the preparation of the AP substituent, wherein the substituent A is kept under the protected condition In the following, general preparation methods are described, for example, for the case the substituent A is a carboxyl group and the substituent AP is a lower alkyl ester group. This process is carried out in the presence of a base in a solvent containing water.The base used in the above reaction can be, for example , an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like; an alkali metal carbonate such as carbon onatoj of lithium, carbonate of sodium, carbonate of potassium, or similar; or a metal alkoxide such as lithium methoxide, sodium methoxide or sodium ethoxide, and is preferably an alkali metal hydroxide and particularly preferably lithium hydroxide. The solvent used in the above reaction is not particularly restricted on the condition that it has no adverse effect on the reaction, and may be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or dioxane; an alcohol such as methanol, ethanol, is-propanol, t-butanol, or the like; Water; or a mixture of water and solvent (s) described above, and is preferably a mixture of an ether, an alcohol and water, and particularly preferably a mixture of tetrahydro uran, methanol and water. The reaction temperature used in the above reaction is generally between OX and 100X, preferably between OX and 40 ° C.

The reaction time used in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but is generally from 15 minutes to 3 hours; and preferably 30 minutes to 2 hours. Furthermore, even if a substituent is other than that specifically indicated in this procedure, this procedure can be performed according to the procedures, for example, found in "Protectivé Groups in Organic Synthesis third edition" (ed. , TW and Wuts, PGM, John Wiley and Sons, Inc., 1999), and the like. : After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1. The method of preparing a compound having the general formula (II) used in Method A is different depending on the nature of the substituent X, in the following, a general preparation method is described, for example, for the case where the substituent X is an oxadiazole ring or an isoxazole ring. Method B is a method for the preparation of a compound having the general formula (11-1), which is included in a compound having the general formula (II), wherein the substituent X is an oxadiazole ring.

Method B (X) (11-1) In the previous reaction scheme, V, W, Y and Z have the same meanings as those indicated above.

LG has the same meaning as that indicated above or represents a hydroxyl group, I P represents a protecting group for a hydroxyl group. Saying protective group for a hydroxyl group is, for example, a protective group for a hydroxyl group found in "Protective Groups in Organic Synthesis t, hird edition "(ed by Green, T. W. and Wuts, P. G. M., John Wiley and Sons, Inc., 1999), and the like, and may preferably be a tri-alkylsilyl group, a t-butyldimethylsilyl group or t-butyldiphenylsilyl group; a methyl ether group replaced! such as a methoxymethyl group, tetrahydropyranyl group or a group 2- (trimethylsilyl) ethoxymethyl; or an acyl group such as an acetyl group, a group benzoyl or a pivaloyl group. Said protective group is preferably a tri-alkylsilyl group and particularly preferably a t-butyldimethylsilyl group.

: Step B1 'Stage B1 is a procedure for the preparation of a compound having the general formula (VII) when carrying out a reaction of the addition of hydroxylamine in a compound having the general formula (VI).

! This procedure can be carried out by reacting compound having the general formula (VI) with hydroxylamine or a equivalent of hydroxylamine in a solvent. '< The hydroxylamine equivalent can be a solution of one hydroxylamine such as an aqueous solution of hydroxylamine, a solution I mixed a hydroxylamine and methanol, a mixed solution of hydroxylamine and ethanol, or the like; or a combination of a salt of I hydroxylamine, such as hydroxylamine hydrochloride, hydroxylamine phosphate, Hydroxylamine sulfate, or the like, and a lower trialkylamine, such as triethylamine !, N, N-diisopropylethylamine or tributylamine, or a metal carbonate alkaline, t ^ l as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, or the like, and is preferably a solution of hydroxylamine and particularly preferably a solution Aqueous hydroxylamine.

: The solvent used in the previous reaction is not restricted particularly on the condition that it does not have an adverse effect on the reaction y, may be, for example, a halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloroethane, or the like; or an ether such as tetrahydrofuran, 1,2-dimethoxyethane, or the like, or an alcohol such as methanol, ethanol, iso-propanol, t-butanol, or the like, and is preferably an alcohol and particularly preferably ethanol. The reaction temperature used in the above reaction is generally between OX and 80X, preferably between 30X and 60X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but it is generally between 15 minutes to 5 hours, and preferably 30 minutes to 2 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Step B2 Step B2 is a process for the preparation of a compound having the general formula (IX) by reacting a compound having the general formula (VII) with a compound having the general formula (VIII). In the following, methods of preparation for cases are described which (1) the LG substituent in a compound having the general formula (VIII) is a hydroxyl group, and (2) the LG substituent in a compound having the General formula (VIII) is a different group than a hydroxyl group. (1) The case in which LG substituent is a compound that has the general formula (VIII) is a hydroxyl group.

This procedure is carried out by reacting a compound that has the general formula (VII) with a compound that has the general formula (VIII) in the | presence of a condensing agent in a solvent.

The condensation agent used in the reaction and above it can be, for example, a carbodiimide such as N, N'-dicyclohexylcarbodiimide, N, N'-diisopropylcarbodiimide, 1-ethyl-3- (3'- i dimethylamihopropyl) carbodiimide (WSCI), or the like; or such an O-benzotriazole I as BO¡P [benzotriazol-1-yloxytris (dimethylamino) phosphono hexafluorophosphate], HATU [O-J7-azabenzotriazole-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate], HBTU [O benzotriazol-1-yl- N, N, N ', N'-tetramethyluronium hexafluorophosphate], and similar, and is preferably a carbodiimide and particularly preferably N, N'-dicyclohexylcarbodiimida.

The solvent used in the previous reaction is not restricted particularly on the condition that it does not have an adverse effect on the reaction and can be, for example, a halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloroethane, or the like; an ether such as tetrahydrofuran, 1,2-dimethoxyethane, or the like; or a benzene such as benzene, toluene or xylene, and is preferably a halogenated hydrocarbon and particularly preferably dichloromethane.

! The reaction temperature used in the previous reaction it is generally between -20X and 40X, preferably between OX and 30X.

The reaction time used in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but it is generally between 15 and 20 minutes. ! minutes to 5 hours, and preferably from 30 minutes to 2 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the I reaction and purified in the same manner as described in Step A1. (2) The case in which the LG substituent in a compound having the general formula (HIV) is a different group than a hydroxyl group. i, This process is carried out by reacting a compound having the general formula (VII) with a compound having the general formula (VIII) in the presence of a base or an inert solvent. The LG substitute is preferably a chlorine atom. The base employed in the above reaction may be, for example, a trialkylamine such as triethylamine, N, N-diisopropylethylamine, tributylamine, or the like; or a pyridine such as pyridine, lutidine, collidine, or the like, and is preferably a trialkylamine and particularly preferably N, N-d soopropylethylamine. The solvent employed in the above reaction is not particularly restricted on the condition that it has no adverse effect on the reaction can be, for example, a halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloroethane, or the like; an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, or the like; a benzene such as benzene, toluene or xylene, or the like, and is preferably a halogenated hydrocarbon and particularly preferably dichloromethane. The reaction temperature used in the above reaction is generally between -20X and 40X, preferably between OX and 30X. The reaction time used in the previous reaction is different depending on the reaction temperature, the starting material, the The reagent used or the solvent used, but is generally between 15 minutes to 5 hours, and preferably 30 minutes to 2 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Step B3 Step B3 is a process for the preparation of a compound having the general formula (X) of a compound having the general formula (IX). This process can be carried out by reacting a compound having the general formula (IX) with a base in a solvent. The base employed in the above reaction can be a tetra-tetra-ammonium-lower fluoride such as tetrabutylammonium fluoride, benzyltrimethylammonium fluoride, benzyltriethylammonium fluoride, or the like; a lower trialkylamine such as triethylamine, N, N-diisopropylethylamine or tributylamine; a pyridine such as pyridine, lutidine, collidine, or the like, or an alkali metal hydride such as lithium hydride, sodium hydride, potassium hydride, oxysimilar, and is preferably a lower tetraalkylammonium fluoride and particularly preferably tetrabutylammonium fluoride. The solvent employed in the above reaction is not particularly restricted on the condition that it has no adverse effect on the reaction and may be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, or the like; a halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloroethane, or the like; or an amide such as N | N-dimethylformamide, N, N-dimethylacetamide, or the like, and is preferably an ether and particularly preferably tetrahydrofuran. The reaction temperature used in the above reaction is generally between OX and 80X, preferably between 30X and 60X. The reaction time used in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but it is generally between 15 minutes to 5 hours, and preferably 30 minutes to 2 hours . After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Step B4 1 Step B4 is a process for the preparation of a compound having the general formula (11-1) by removing the protecting group from the hydroxyl group of a compound having the general formula (X). The method for removing the protecting group is different depending on the nature of the protective group used, but is generally done according to the deprotection method for a hydrioxyl group described in "Protective Groups in Organizational Synthesis third edition" (ed. , TW and Wuts, PGM, John Wiley and Sons, Inc., 1999), and the like. In the following, a general preparation method is described for the case where the protecting group is a trialkylsilyl group. This process is carried out by reacting a compound having the general formula (X) with one equivalent of fluoro anion in a solvent. The fluorine anion equivalent employed in the above reaction may be, for example, tetralkylammonium fluoride such as tetrabutylammonium fluoride or benzyltrimethylammonium fluoride; an acid fluoride-amine complex such as fluoride-triethylamine acid complex or fl oruro-pyridine acid complex, and is preferably a tetralkylammonium fluoride and particularly preferably tetrabutylammonium fluoride. The solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction and can be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, or the like; a halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloroethane, or the like; or an amide such as N-N-dimethylformamide, N, N-dimethylacetamide, or the like, and is preferably an ether and particularly preferably tetrahydrofuran. The reaction temperature used in the above reaction is generally between OX and 80X, preferably between 30X and 60X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but it is generally between 15 minutes to 5 hours, and preferably 30 minutes to 2 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1. Method C is a method for the preparation of a compound having the general formula (II-2), which is included in a compound having I the general formula (II), wherein the substituent X is an isoxazole ring.

Method C 7 2- "YM T-MVB and ~ op - - ^" v I ^ Vw ^ V_ 0H N ~ 0 Stage C4 N "0 (XV) (H -2) In the above reaction scheme, V, P, W, Y and Z have the same meanings as those indicated above. , Hal represents a halogen atom.

Step C1: Step C1 is a process for the preparation of a compound having the general formula (Xll) by converting a formyl group of a compound having the general formula (XI) to a dihalovinyl group. This process is carried out by reacting the compound having the general formula (XI) with a gem-dihalomethylating agent in a solvent. The gem-dihalomethylating agent employed in this process can be a combination of a phosphine, which consists of a triarylphosphine which includes triphenylphosphine and a lower trialkylphosphine such as tributylphosphine, and a carbon tetrahajide, such as carbon tetrachloride, carbon tetrabromide or tetraiodide. of carbon; or a combination of a dialkyl (trichloride) -alphagenadomethyl) phosphonate, such as a diethyl (trichloromethyl) phosphonate, diethyl (tribromomethyl) phosphonate, dimethyl (trichloromethyl) phosphonate or dimethyl (tribromomethyl) phosphonate, and an alkyl lithium, such as a methylthio, n-butylithio, s-butylithio or t-butylitio, and is preferably a combinacilon of a triarylphosphine and a carbon tetrahalide and particularly preferably a combination of triphenylphosphine and carbon tetrabromide. The solvent used in the above reaction is not particularly restricted provided it has no adverse effect on the reaction and may be, for example, a halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloroethane, or the like.; or an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, or the like, and is preferably an ether and particularly preferably tetrahydrofuran. The reaction temperature used in the above reaction is generally between -23X and 60X, preferably between OX and 30 ° C. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but is generally between 15 minutes to 5 hours, and preferably 30 minutes to 3 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Step C2 Step C2 is a process for the preparation of a compound having the general formula (XIII) by converting a dihalovinyl group of a compound having the general formula (II) to an ethynyl group. This process is carried out by reacting the compound (Xll) with an alkyl metal in a solvent. The alkyl metal used in the above reaction can be, for example, an alkyl lithium such as methyl lithium, n-butyl lithium, s-butyl lithium or t-butyl lithium; or an alkylsodium such as a methylsodium, butylsodium, s-butylsodium, or the like, and is preferably an alkyl lithium and particularly preferably n-butyllithium. The solvent employed in the above reaction is not particularly restricted provided it has no adverse effect on the reaction and can be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, or the like , or a benzene such as benzene, toluene, xylene, or the like, and is preferably an ether and particularly preferably tetrahydrofuran. The reaction temperature employed in the above reaction is generally between -100X and OX, preferably between -78X and -45X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but it is generally between 15 minutes to 2 hours, and preferably 30 minutes to 1 hour.

After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Step C3 Step C3 is a process for the preparation of 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 procedure can be carried out when both compounds react with a base in a solvent. The general method of preparation of the compounds having the general formula (XIV) is described in the literatures J. Org. Chem., 45, 3916 (1980) and Acta. Chemica, Scandinavica, 426 (1987), and these compounds can be easily synthesized from well-known compounds. The base used in the above reaction may be, for example, trialkylamine such as a triethylamine, N, N-diisopropylethylamine, tributylamine, or the like; or a pyridine such as pyridine, lutidine, collidine, or the like, and is preferably a trialkylamine and particularly preferably triethylamine. The solvent used in the above reaction is not restricted in particular provided that it has no adverse effect on the reaction; and may be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, or the like, an ester such as ethyl acetate, propyl acetate, butyl acetate, or the like; or a halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloroethane, or the like; and is preferably an ester and particularly preferably ethyl acetate.; The reaction temperature used in the above reaction is generally between -20X and 80X, preferably between OX and -40 ° C. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but it is generally between 5 hours to 72 hours, and preferably 24 hours to 48 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Step C4 Step C4 is a process for the preparation of a compound having the general formula (II-2) by removing the protecting group P from the hydroxyl group of a compound having the general formula (XV). This process can be carried out in the same manner as described in Step B4 or Method B. The method of preparing the compound having the general formula (VI) used in Method B is different depending on the nature of the substituent W. following, general preparation methods are described, for example, as Method D for the case where the substituent W is a thiophene ring or a furan ring and as Method E for the case where the substituent W is a group having a structure will work such as a 4,5,6,7-tetrahydrobenzothiophene ring or a 4,5,6,7-tetrahydrobenzofuran ring, respectively.

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

I a a D3b- 1 f EQ a? r > 3b-3 Q (X I- 1) (XIX) In the above reaction scheme, Hal represents a halogen atom as described above, and is preferably a bromine atom or iodine atom, Q represents an oxygen atom or a sulfur atom, and P represents a protecting group for a hydroxyl group as described above.

Step D1 Step D1 is a process for the preparation of a compound having the general formula (XVII) by converting a formyl group of a compound having the general formula (XVI) to a hydroxymethyl group. This process is carried out by reacting the compound (XVI) with a reducing agent in a solvent. Additionally, many of the compounds having the general formula (XVI) employed as the starting compounds are commercially available, and can also be easily synthesized according to publicly known preparation methods. The reducing agent employed in the above reaction may be, for example, an aluminum hydroxide such as lithium aluminum hydroxide, aluminum sodium hydroxide or diisobutylaluminum hydride; a borohydride such as lithium borohydride, sodium borohydride or borane, and is preferably a borohydride and particularly preferably sodium borohydride. The solvent used in the above reaction is not particularly restricted provided it has no adverse effect on the reaction and may be, for example, an ether such as diethyl ether, tetrahydronyl ether, 1,2 dimethoxyethane, dioxane, or the like, or an alcohol such as methanol, ethanol, isopropanol, or the like; and is preferably an alcohol and particularly preferably methanol. The reaction temperature used in the above reaction is generally between -23X and 50X, preferably between OX and 30X.

The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but it is generally between 15 minutes to 2 hours, and preferably 30 minutes to 1 hour. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

, Step D2 Step D2 is a process for the preparation of a compound having the general formula (XVIII) by protecting a hydroxyl group of a compound having the general formula (XVII) with an appropriate protecting group for a hydroxyl group. The protective group employed in this reaction is not particularly restricted provided that it does not adversely affect the reaction in successive processes and additionally that it can be easily removed, and is preferably a tricalkylsilane. The general preparation method for the case in which trialkylsilane is used as the protecting group is described in the following. This process can be carried out by reacting a compound having general formula (XVII) with a silating agent in the presence of a base in a solvent. The silating agent employed in the above reaction can be, for example, a chloride. trialkylsilyl such as triethylsilyl chloride, t-butyldimethylsilyl, triisopropylsilyl chloride or t-butyldiphenylsilyl; or trifluoromdtanosulfonato trialquillsililo triethylsilyl trifluoromethanesulfonate as, t-butyldimethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate or t-butyldiphenylsilyl trifluoromethanesulfonate, and is preferiblenpente a trialkylsilyl chloride , and particularly preferably t-butyldimethylsilyl chloride The base used in the above reaction can be, for example, a trialkylamine such as a triethylamine, N, N-diisopropylethalamine, or the like; an imidazole such as imidazole, 2-methylimidazole, or the like; or a pyridine such as pyridine, lutidine, collidine, or the like, and an imidazole and particularly preferably imidazole is preferably preferable. The solvent employed in the above reaction is not particularly restricted provided it has no adverse effect on the reaction and can be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, or the like , a halogenated hydrocarbon such as dichloromethane, 1,2-dichloromethane, chloroform, or the like; or an amide such as N, N-dimethylformamide, N, N-dimethylacetamide, or the like, and is preferably an amide and particularly preferably N, N-dimethylformamide. The reaction temperature used in the above reaction is generally between -23X and 50X, preferably between OX and 30X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but is generally between 30 and 30 minutes. minutes to 4 hours, and preferably from 1 hour to 3 hours.

After the reaction has been completed, the compound desired from this reaction can, if necessary, be isolated from the reaction and purified in the same manner as described in Step A1.

Stage D3 Step D3 is a procedure for the preparation of a compound! which has the general formula (VI-1) when converting an atom of halogen of a compound having the general formula (XVIII) in a nitrile group.

This procedure can be performed according to two methods, one of which is a method by a direct conversion of a halogen atom of a compound having the general formula (XVIII) in one nitrile group (Step D3a) and the other is a method by derivatization of a compound (XVIII) to a compound having a formyl group (XI-1), followed by conversion of the formyl group to a nitrile group through a reaction Of oximation and a dehydration reaction (Step D3b). In the following, these procedures are described individually.

Stage D3a ; Step D3a is a process for the preparation of 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. 1 This process can be carried out by reacting a compound having the general formula (XVIII) with an appropriate cyanidation agent in a solvent. The cyanidation agent employed in this reaction may be, for example, a copper compound such as copper cyanide, or a combination of a palladium catalyst, such as tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, or the like. , and a cyanide of | metal, such as zinc cyanide, trimemethylsilyl cyanide, or tributyltin cyanide, and is preferably copper cyanide or a combination of tetrakis (triphenylphosphine) palladium and zinc cyanide and particularly preferably copper cyanide. The solvent used in the above reaction is not particularly restricted provided it has no adverse effect on the reaction and can be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, or the like. , or an amide such as N.N-dimethyltarmamide, N, N-dimethylacetamide, or the like, and is preferably an amide and particularly preferably N, N-dimethylformamide. : The reaction temperature used in the above reaction is generally between 20X and 180X, preferably between 100X and 140X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but is generally between 2 hours to 12 hours, and preferably 3 hours to 10 hours. . After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Stage D3b Step D3b-1 Step D3b-1 is a process for the preparation of 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 process can also be used as the process of general preparation of a compound having the general formula (X1) which is used as the starting material in Method C described in the above.; This process is carried out by carrying out an exchange of halogen-npetal with a compound having the general formula (XVIII) followed by the reaction of the resulting product with a suitable formylating agent in a solvent. The metallating agent employed in the above reaction can be, for example, a metal such as metallic lithium, metallic magnesium, metallic zinc, or the like; or an alkyl lithium such as n-butylithium, s-butylithium, t-butylithium, or I similar; and fs preferably an alkyl lithium and particularly preferably n-butyl lithium. 1 The formylating agent employed in this reaction can be a formamide) such as N, N-dimethylformamide, N-methylformanilide, N-formylpiperidine, or the like; a format such as methyl formate, ethyl formate, propyl formate, or the like, and is preferably a formamide and particularly preferably N, N-dimethylformamide. The solvent used in the above reaction is not particularly restricted provided it has no adverse effect on the reaction and can be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, or the like. , an aromatic hydrocarbon such as toluene, xylene, or the like; and is preferably an ether and particularly preferably tetrahydrofuran. The reaction temperature employed in the above reaction is generally between -100X and OX, preferably between -78X and -45X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but it is generally between 15 minutes to 2 hours, and preferably 30 minutes to 1 hour. After the reaction has been completed, the desired compound giving this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Step D3b-2 Step D3b-2 is a process for the preparation of 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 process can be carried out by reacting a compound having the general formula (XI-1) with a hydroxylamine or an equivalent of hydroxylamine in a solvent. The hydroxylamine equivalent can be a hydroxylamine solution such as an aqueous solution of hydroxylamine, a mixed solution and hydroxylamine and methanol, a mixed solution of hydroxylamine and ethanol, q similar; or a combination of a hydroxylamine salt such as hydroxylamine hydrochloride, hydroxylamine phosphate, hydroxylamine sulfate, or the like, lower triyalkylamine, such as triethylamine, N, N-diisopropylethylamine or tributylamine, or an alkali metal carbonate, such as sodium acid carbonate, potassium acid carbonate, sodium carbonate, potassium carbonate, or the like, and is preferably a combination of a hydroxylamine salt and a lower trialqullamine and particularly preferably a combination of hydroxylamine hydrochloride and triethylamine. The solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction and; it can be, for example, a halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloromethane, or the like; or an ether such as tetrahydrofuran, 1,2-dimethoxyethane, or the like, and is preferably a halogenated hydrocarbon and particularly preferably dichloromethane. The reaction temperature used in the above reaction is generally between OX and 80X, preferably between 20X and 60X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but is generally between 30 minutes to 5 hours, and preferably 1 hour to 3 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Step D3b-3 Step D3b-3 is a process for the preparation of a compound i having the general formula (VI-1) by converting an oxime group of a compound having the general formula (XIX) to a nitrile group. This process can be carried out by reacting a compuestol having the general formula (XIX) with an appropriate dehydrating agent in a solvent. The dehydrating agent used in the above reaction can be a carbodiimide such as N, N'-dicyclohexylcarbodiimide, N, N'-diisopropylcarbodiimide, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide (WSCI), or similar; a phosphorus compound such as phosphorus pentaoxide or phosphorus oxychloride or thionyl chloride or the like, and is preferably a carbodiimide and particularly preferably N, N'-dicyclohexylcarbodiimide. The solvent employed in the above reaction is not particularly restricted on the condition that it has no adverse effect on the reaction and can be, for example, a halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloroethane, or the like; or an ether such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane or the like, or an aromatic hydrocarbon such as benzene, toluene, xylene, or the like, and is preferably an aromatic hydrocarbon and particularly preferably toluene. The reaction temperature employed in the above reaction is generally between 20X and 150X, preferably between 60X and 110X. i, The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but is generally between 2 hours to 24 hours and preferably from 6 hours to 12 hours . After the reaction has been completed, the desired compound giving this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Method E The method E is a method for the preparation of a compound having the general formula (VI-2), which is included in a compound having the general formula (VI), wherein the substituent W is a group that has a fused structure such as a 4,5,6,7-tetrahydrobenzothiophene ring or a 4,5,6,7-tetrahydrobenzofuran ring.

I I) In the above reaction scheme, P and Q have the same meanings as those indicated above, and m represents an integer from 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) to a hydroxyl group. This process can be carried out by reacting a compound having the general formula (XX) with an appropriate reducing agent, in a solvent. Additionally, of the compounds having the general formula (XX) employed as starting compounds, the compounds wherein m is 2 are commercially available and can be easily obtained. Moreover, the compounds wherein m is 1 can also be synthesized according to the preparation methods described in the literature, Jl. Am. Chem. Soc, 127 (10), 3248-3249 (2005). The reducing agent employed in the above reaction may be, for example, an aluminum hydride such as a lithium aluminum hydride, a sodium aluminum hydride or a diisobutylaluminum hydride; a borohydride such as lithium borohydride, sodium borohydride, or borane, and is preferably a borohydride and particularly preferably sodium borohydride.; The solvent used in the above reaction is not particularly restricted on the condition that it has no adverse effect on the The reaction can be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, or the like; or an alcohol such as methanol, ethanol, isopropanol, or the like, and is preferably an alcohol and particularly preferably methanol. The reaction temperature used in the above reaction is generally between -23X and 50X, preferably between OX and 30X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but is generally between 15 minutes to 2 hours, and preferably 30 minutes to 1 hour. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Step E2 Step E2 is a process for the preparation of a compound having the general formula (XXII) by protecting a hydroxyl group of a conhpound having the general formula (XXI) with an appropriate protecting group! for a hydroxyl group. Said protecting group used in this reaction is particularly restricted on the condition that it has no adverse effect on the reaction in successive processes and that it can be easily removed further, and is preferably a trialkylsilaho. The general preparation method for the case in which a | trialkylsilane as the protecting group is described in the following. This process can be carried out by reacting a compound having the general formula (XXI) with a silating agent in the presence of a suitable base in a solvent. The syllable employed in the above reaction may be, for example, trialkylsilyl chloride, such as triethylsilyl chloride, t-butoldimethylsilyl chloride, triisopropylsilyl chloride or t-butyldiphenylsilyl chloride; or a trialkylsilyl trifluoromethanesulfonate such as triethylsilyl trifluoromethanesulfonate, t-butyldimethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate or t-butyldiphenylsilyl trifluoromethanesulfonate, and is preferably a trialkylsilyl chloride and particularly preferably t-butyldiphenylsilyl chloride. The base employed in the above reaction may be, for example, trialkylamine urges such as a triethylamine, N, -diisopropylethylamine, or the like; An imidazole such as imidazole, 2-methylimidazole, or the like; or a pyridine such as pyridine, lutidine, collidine, or the like and is preferably an imidazole and particularly preferably imidazole. The solvent used in the above reaction is not particularly restricted on the condition that it has no adverse effect on the reaction and may be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxy- lene, dioxane, or similar; a hydrocarbon halogenadb such as dichloromethane, 1,2-dichloroethane or chloroform; or an amide such as N, N-dimethylformamide, N, N-dimethylaceamide, or the like; and an amide and particularly preferably N, N-dimethylformamide is preferably preferable. The reaction temperature employed in the above reaction is generally between -23X and 100X, preferably between OX and 60X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reactant used or the solvent used, but is generally between 30 minutes to 4 hours, and preferably 1 hour to 3 hours.; After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

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 process can be carried out by reacting a compound having the general formula (XXII) with a strong base, followed by the reaction of the resulting product with an appropriate formylating agent in a solvent. ! The strong base employed in the above reaction may be, for example, up to alkyl lithium such as n-butyllithium, s-butyllium or t-butyl lithium or an alkali metal amide such as lysium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldsilazide, hexamethyldisilazide. of potassium, or the like, and is preferably an alkyl lithium and particularly preferably n-butyllithium. The formylating agent employed in this reaction can be a formamide such as N, N-dimethylformamide, N-methylformanilide, N-formylpiperildine, or the like; a format such as methyl formate, ethyl formate, propyl formate, or the like, and is preferably a formamide and particularly preferably N, N-dimethyloformamide. The solvent used in the above reaction is not particularly restricted on the condition that it has no adverse effect on the reaction, it may be, for example, an ether such as diethyl ether, telra hydrofuran, Uranus, 1,2-dimethyloxyan. , dioxane, or similar; or an aromatic hydrocarbon such as toluene, xylene, or the like, and is preferably an ether and particularly preferably a hydrofuran. The reaction time employed in the above reaction is generally between -100X and OX, preferably between -78X and OX. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but is generally between 15 minutes to 4 hours, and preferably 1 hour to 3 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Epapa E4 Epapa 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) to an oxime group. This process can be effected by reacting a compound having the general formula (XXIII) with a hydroxylamine or an equivalent of hydroxylamine in a solvent, and it can be carried out in the same manner as described in 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) to a nihryl group. . This process can be carried out by reacting a compound having the general formula (XXIV) with an appropriate dehydration group in a solution, and it can be carried out in the same manner as described in Step D3b-2.

Method F Method F is a method for the preparation of a compound that has the general formula (VI-3) that is included in a compound that has the general formula (VI), in which the substituent W is a thiophene ring or a furano ring and additionally, these rings are substituted with an alkyl group as a susíiuuyeníe R.

(XXV) (XXVI) (XXVI I) Stage F 3 Stage F 4 I) A ° > (VI-3) In the above reaction scheme, Hal represented a halogen atom as described above, and is preferably a bromine atom or an iodine atom, Q represents an oxygen atom or a sulfur atom, P! represents a protecting group for a hydroxyl group as described above, and Rd represented a C1-C6 alkyl group.

Epaque F1 1 The elapa F1 is a process for the preparation of a compound having the general formula (XXVI) by converting a halogen atom of a compound to form the general formula (XXV) into an alkyl group. This procedure can be effected by reacting a compound that has the general formula (XXV) with a rental agent in a solution., many of the compounds that have the general formula (XXV) used as starting compounds can be synthesized according to the D-period described above. The alkylating agent employed in the initial reaction may, for example, be a combination of a nickel catalyst, such as [1,3-bis (diphenylphosphino) propane] dichloroniquel, bis (disiphenylphosphine) dichloroniquel or [1, 1 ' -bis (diphenylphosphino) ferrocene] dichloroniquel, and a Grignard reaction, as an alkylmagnesium chloride, an alkylmagnesium bromide or an alkylmagnesium iodide; or a combination of a palladium catalyst, such as tetrakis (glyphylphosphine) palladium or dichlorobis (triphenylphosphine) palladium, and an alkyl-bromide acid, such as a mono-alkyl-boronic acid, an ether of a mono-alkyl-chloric acid, an dialkylboric acid or an ester of a dialkylboric acid, and is preferably a combination of a nickel catalyst and a reactant of Grignard and particularly preferably a combination of [1, 3-bis (diphenyl-phenyfine) propane] dichloroniquel and an alkylmagnesium bromide.

The solvent used in the previous reaction is not restricted particularly on the condition that it does not have an adverse effect on the reaction and can be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, or the like; or a hydrocarbon Ital aromatic such as benzene, toluene, or xylene, and is preferably an ether and particularly preferably tetrahydrofuran.

The reaction temperature used in the previous reaction it is generally between -23X and 60X, and preferably between -10X and 40X.

The reaction time used in the previous reaction is differentiate depending on the reaction temperature, the starting machining, the used or the solvent used, but is generally 15 minutes to 4 hours, and preferably from 1 hour to 2 hours.

After the reaction has been completed, the desired compound i of this reaction can, if necessary, be isolated from the mixture of reaction and purified in the same manner as described in Step A1.

Step F2 Step F2 is a process for the preparation of a compound having the general formula (XXVII) by converting a hydrogen atom to a compound having the general formula (XXVI) in a formyl group. This process can be carried out by reacting a compound having the general formula (XXVI) with a suitable base, followed by the reaction of the resulting product with a formylating agent i in a solvent. The base employed in the above reaction may be, for example, alkyl lithium such as n-butylithium, sec-butylthio or t-butylthio; or a metal amide such as a lithium diisopropylamide, lithium hexamethyldisilazide or hexamethyl (potassium isylazide, and is preferably an alkali metal and particularly preferably n-butyllithium. The formylating agent employed in this reaction can be a formamide such as N , N-dimethylformamide, 1-formylpyrrolidine or 1-formylpiperidine, or an isocyanide such as t-butyl isocyanide, 1,1, 3,3-telmethylbryl isocyanide, or the like, and is preferably a formamide and particularly preferably N, N- dimethylformamide The solvent used in the above reaction is not particularly restricted on the condition that it does not have an adverse effect on the reaction and can be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxy? EIA, dioxane, or the like, or an aromatic hydrocarbon such as benzene, toluene, or xylene, and is preferably an ether and particularly preferably terahydrofuran. The reaction employed in the above reaction is generally between -78X and ambient temperature, and preferably between -78X and OX. The reaction time used in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but is generally between 30 minutes to 4 hours, and preferably 1 hour to 3 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

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) to an oxime group. This process can be carried out by reacting a compound having the general formula (XXVII) with a hydroxylamine or an equivalent of hydroxylamine in a solvent. The hydroxylamine equivalent may be a solution of hydroxylamine such as an aqueous solution of hydroxylamine, a mixed solution of hydroxylamine and methanol, a mixed solution of hydroxylamine and eneol, or the like; or a combination of a hydroxylamine salt, such as hydroxylamine hydrochloride, hydroxylamine phosphate, hydroxylamine sulfate, or the like, and a lower trialkylamine, such as triethylamine, N, N-diisopropylamylamine or trilamylamine, or alkali metal carbonate, such like carbonaio! Sodium acid, Carbonaceous acid carbonate, Sodium carbonate, Carbonaceous potassium, or the like, and is preferably a combination of a hydroxylamine salt and a lower trialkeramine and particularly preferably a combination of hydroxylamine hydrochloride and triethylamine. The solvent employed in the above reaction is not particularly restricted provided it has no adverse effect on the reaction and can be, for example, a halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloromelan, or the like; or an ether such as tetrahydrofuran, 1,2-dimethyloxy anhydrous, or the like; or an alcohol such as meianol, eneol, or isopropanol, and is preferably a halogenated hydrocarbon and particularly preferably dichloromethane. The reaction temperature used in the above reaction is generally between OX and 80X, and preferably between 20X and 60X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but is generally from 30 minutes to 5 hours, and preferably from 1 hour to 3 hours.

After the reaction has been completed, the compound desired of this reaction can, if necessary, be isolated from the mixture of reaction and purify in the same manner as described in Step A1.

, Stage F4 Step F4 is a process for the preparation of a compound that has the general formula (VI-3) when converting an oxime group from a compuejsto that has the general formula (XXVIII) in a nitrile group.

This procedure can be carried out by reacting compound! that you ne the general formula (XXVIII) with an appropriate dehydrated agent in a solvent.

The dehydrating agent used in the above reaction can Carbodiimide such as N, N'-dicyclohexylcarbodiimide, N, N'-düsopropylcarbodiimide, 1-eyl-3- (3'-dimethylaminopropyl) carbodimide (WSCI), or the like; a 'phosphorus compound such as di-phosphorus pentoxide or phosphorus oxychloride'; or thionyl chloride, or the like, and is preferably a carbodiimide and particularly preferably N.N'-dicyclohexylcarbodiimide.

The solvent used in the previous reaction is not restricted particularly on the condition that it does not have an adverse effect on the reaction and may be, for example, a halogenated hydrocarbon such as dichloromethane, chloroform, 1,2-dichloroethane, or the like; or an ether such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane, or the like; or an aromatic hydrocarbon such as benzene, toluene or xylene, or the like, and is preferably an aromatic hydrocarbon and particularly preferably toluene. The reaction temperature employed in the above reaction is generally between 20X and 150X, and preferably between 60X and 110X. The reaction time used in the initial reaction is different depending on the reaction temperature, the starting material, the reactive used or the solvent used, but is generally between 2 hours to 24 hours] and preferably 6 hours to 12 hours . After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in EIApa A1.

Period G The Period G is a period for the preparation of a compound that has the general formula (VI-4), which is included in a compound that has the general formula (VI), where the W subside is a pyridine ring.

Stage G3 (XXIX) (XX) (XXXI) (XXXII) (VI-4) In the above reaction scheme, Hal represents a halogen atom as previously described, and is preferably a bromine atom or an iodine atom, and P represents a protecting group for a hydroxyl group as described above.

• Step G1 Stage G1 is a process for the preparation of a compound having the general formula (XXX) by converting an amino acid I halogen in the 2- position of a compound that has the general formula (XXIX) in a formyl group. This process is carried out by carrying out the halogen-metal exchange in a compound having the general formula (XXIX), followed by the reaction of the resulting product with a suitable formylation agent in a solution. The metallating agent employed in the above reaction may be, for example, a metal such as lithium metal, metallic magnesium, metallic zinc, or the like; or an alkyl lithium such as n-butyllithium, s-butyllium, t-butylithium, or the like, and is preferably an alkyl lithium and particularly preferably n-buyliumium. The formylation agent employed in this reaction can be a formamide such as N, N-dimethylformamide, N-methylformanilide, N-formylpyperidine, or the like; or a formal formate, such as methyl formate, ethyl formate, propyl formate, or the like, and is preferably a formamide and particularly preferably N, N-dimethylaminformamide. The solvent used in the above reaction is not particularly restricted as long as it does not have an adverse effect on the reaction and may be, for example, an ether such as diethyl ether, teirahydrofuran, 1,2-dimethyloxylan, dioxane, or the like.; or an aromatic hydrocarbon such as toluene, xylene, or the like, and is preferably an aromatic hydrocarbon and particularly preferably isoluene. The reaction time employed in the above reaction is generally between -100X and OX, and preferably between -78X and -45X. The reaction time used in the above reaction is different depending on the reaction time, the starting material, the reacted reactant or the solvent used, but it is generally between 15 minutes to 5 hours, and preferably 30 minutes to 3 hours. hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Step G2 The 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) to a hydroxymethyl group.

This procedure can be effected by reacting a compound having the general formula (XXX) with a reducing agent in a solvent. The reducing agent employed in the above reaction may be, for example, an aluminum hydride lal such as lithium aluminum hydride, aluminum sodium hydride or diisobutylaluminum hydride; a borohydride such as lithium borohydride, sodium borohydride or borane, and is preferably a borohydride? and particularly preferably sodium borohydride. The solvent used in the above reaction is not particularly restricted on the condition that it has no adverse effect on the ! reaction and may be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethyloxy anhydrous, dioxane, or the like; or an alcohol such as melanol, ejlanol, isopropanol, or the like, and is preferably an alcohol and particularly preferably methanol. The reaction temperature employed in the above reaction is generally between -23X and 50X, and preferably between OX and 30X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but it is generally between 15 minutes to 2 hours, and preferably 30 minutes to 1 hour. : After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Step G3 Step G3 is a process for the preparation of a compound having the general formula (XXXII) by protecting a hydroxyl group from a compound having the general formula (XXXI) with an appropriate protecting group; for a hydroxyl group. The protecting group employed in this reaction is particularly resisted with the proviso that it does not adversely affect the reaction in successive processes and can additionally be easily removed, and is preferably a trialkylsilane. The method of general preparation for the case in which a trialkylsilane is used as the leaving group is described as follows. This process can be carried out by reacting a compound having the general formula (XXXI) with a silating agent in the presence of a suitable base in a solvent. The silating agent employed in the above reaction may be, for example, a trialkulsilyl chloride such as an arylsilyl chloride, t-butyldimethylsilyl chloride, yisopropylsilyl chloride or α-buyldiphenylsilyl chloride; or an ialkyl silyl trifluoromethylene sulfonate, such as triethylsilyl trifluoromethylene sulfonate, l-? butyldimethylsilyltrifluoromethanesulphonates, irisopropylsilyl, Irifluoromethanesulfonaryl, or -buyldiphenylsilyltrifluoromethanesulfonates, and is preferably an alkylhydrosilyl chloride. and particularly preferably t-butyldimethylsilyl chloride. The base employed in the above reaction may be, for example, a trialkylamine such as triethylamine, N, N-diisopropylethylamine, or the like; an imidazole such as imidazole or 2-methylimidazole; or a pyridine such as pyridine, liiitidine, collidine, or the like, and is preferably an imidazole and particularly preferably imidazole. The solvent used in the above reaction is not particularly restricted on the condition that it has no adverse effect on the reaction and may be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, or similar; a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane or chloroform; or an amide such as N, N-dimethylformamide, N, N-dimethylacetamide, or the like; and is preferably an amide and particularly preferably N, N-dimethylformamide. The reaction temperature used in the above reaction is generally between -23X and 50X, and preferably between OX and 30X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but is generally between 30 minutes to hours, and preferably 1 hour to 3 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in EIAA A1.

Epaque G4 i Stage G4 is a procedure for the preparation of a compound! having the general formula (VI-4) by converting an allogene of an allogen of a compound having the general formula (XXXII) to a nitrile group. This process is carried out by reacting a compound having the general formula (XXXII) with a cyanidation agent in a solvent. The cyanidation agent employed in this reaction can be, for example, a copper compound such as copper cyanide, or a combination of a palladium catalyst, such as tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, [1 1'-bis (diphenylphosphino) ferrocene] dichloropalladium, or the like, and a metal cyanide, such as zinc cyanide, trimethylsilyl cyanide, or butyltin cyanide, and a combination of palladium catalyst and zinc cyanide is preferable. and particularly preferably a combination of [1, 1 '-bis (diphenylphosphino) ferrocene] dichloropalladium and zinc cyanide. The solvent used in the above reaction is not restricted particularly with the proviso that it has no adverse effect on the reaction and may be, for example, an ether such as diethyl ether, terahydrofuran, 1,2-dimethyloxy-a, dioxane, or similar; or an amide such as N, N-dimethylylformamide, N, N-dimethylacetamide, N-methyl-pyrrolidone, or the like; and it is preferably an amide and particularly preferably N, N-methyl-2-pyrrolidone. The reaction temperature employed in the above reaction is generally 20X and 180X, and preferably 80X and 120X.

The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but it is generally between 30 minutes to 4 hours, and preferably 1 hour to 3 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1. i ! Medo H: Medo H is a method for preparing a compound that has the general formula (VI-5), which is included in a compound having the general formula (VI), where the substituent W is a ring pyridine and additionally, the ring is substituted with an alkyl group as a substituent. p (XXXII I) (XXXIV) (XXXV) (XXXVI) (VI-5) In the above reaction scheme, Re and Rf are the same or different each represents a C? -C6 alkyl group, and is preferably a methyl group or an ethyl group, and P represents a group for a hydroxyl group it was described earlier.

Eiapa H1 Step H1 is a process for the preparation of a compound that has the general formula (XXXIV) when converting a formyl group of a compound having the general formula (XXXIII) in a group hydroxymethyl. Additionally, as the compound having the general formula (XXXIII) and in the form of the starting compounds, commercially available 6-formyl-2- (methylsulfanyl) -aryloninitrile, or the like can be used (Maybridge Chemicals Ltd.).

This procedure can be effected by reacting compound having the general formula (XXXIII) with a reducing agent in a solvent.

The reducing agent employed in the above reaction may be, for example, aluminum hydride such as a lithium aluminum hydride, hydride sodium aluminum, or diisobutylaluminum hydride; a borohydride lal like Lilio borohydride, sodium borohydride or borane, and is preferably a borohydrurf and particularly preferably sodium borohydride.

The solvent used in the previous reaction is not restricted particularly with the proviso that it does not have an adverse effect on the reaction and may be, for example, an ether such as diethyl ether, hydrohydrofuran, 1,2-dimelloxylene, dioxane, or the like; or an alcohol such as methanol, ethanol, isopropanol, or the like, and is preferably an alcohol and particularly preferably methanol. The reaction temperature employed in the above reaction is generally between -23X and 50X, and preferably between OX and 30X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but is generally from 15 minutes to 2 hours, and preferably from 30 minutes to 1 hour. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Step H2: Step H2 is a process for the preparation of a compound having the general formula (XXXV) by protecting a hydroxyl group of a compound having the general formula (XXXIV) with an appropriate protein group for a hydroxy group. The proleary group employed in this reaction is not particularly resistant on the condition that it does not adversely affect the reaction in successive procedures and that it may additionally be easily removed, and is preferably a trialkylsilane. The general preparation method for the case in which an ialiailsilarho is used as the propellant group is described as follows.

This procedure can be done by reacting a compound they have! the general formula (XXXIV) with a silating agent in the presence of a suitable base in a solvent. The silant agent employed in the above reaction may be, for example, triacylsilyl chloride such as triethylsilyl chloride, t-butyldimethylylenyl chloride, yisopropylsilyl chloride, or butyldiphenylsilyl chloride; or a trialkylsilyltrifluoromethanesulphonates such as Irieylsilyl, trifluoromethanesulfonate, t-butyldimethylsilyl trifluoromethylsulfonate, trifluoromethylsulfonates, iisopropylsulphonyl or i-buyldiphenylsilyl trifluoromethanesulfonates, and is preferably an ialkylsilyl chloride and particularly preferably iisopropylsilyl chloride. The base used in the above reaction may be, for example, a trialkylamine such as triethylamine, N, N-diisopropylethylamine, or the like; an imidazole such as an imidazole, 2-methylimidazole, or the like, or a pyridine such as a pyridine, luidine, collidine, or the like; and is preferably an imidazole and particularly preferably midazole. The solvent used in the above reaction is not particularly resisted, provided that it has no adverse effect on the reaction and can be, for example, an ether such as diethyl ether, tetrahydrofiran, 1,2-dimethoxy-a, dioxane, or similar; a halogenated hydrocarbon such as a dichloromean, 1,2-dichloroean or chloroform; or an i amide such as N, N-dimethylylformamide, N, N-dimethylacetamide, or the like; and it is preferable to include an amide and particularly preferably N, N-dimethyldformhamide. The reaction time employed in the above reaction is generally between -23X and 50X, and preferably between OX and 30X. The reaction time employed in the initial reaction is different depending on the reaction time, the starting material, the reactive used or the solvent used, but is generally between 30 minutes to 4 hours, and preferably 1 hour to 3 hours . : After the reaction has been completed, the desired compound giving this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1. i . Step H3 Step H3 is a process for the preparation of a compound having the general formula (XXXVI) by oxidizing an alkylthio group of a compound having the general formula (XXXV). This process is carried out by reacting a compound having the general formula (XXXV) with an appropriate oxidizing agent in a solvent.; The oxidizing agent used in the above reaction may be, for example, peracid such as peracetic acid, perbenzoic acid, or m-chloroperozoic acid; a permanganate such as sodium permanganate or permanganum of potassium, and is preferably a peracid and particularly preferable m-chloroperbenzoic acid. • The solvent used in the above reaction is not particularly resistant provided it does not have an adverse effect on the reaction and may be, for example, an alcohol such as melanol, ethanol, isopropanol, or the like; or a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, chloroform, or the like, and is preferably an alcohol and particularly preferably ethanol. The reaction temperature used in the above reaction is generally between -23X and 50X, and preferably send OX and 30X. The reaction time used in the above reaction is different depending on the reaction temperature, the starting material, the reactant used or the solvent used, but is generally 30 minutes at 4 hours, and preferably 1 hour at 3 hours. hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Epapa H4 Epapa H4 is a process for the preparation of a compound having the general formula (VI-5) by converting an alkylsulforia group of a compound having the general formula (XXXVI) into a group alkylo.

This process is carried out by reacting a compound which has the general formula (XXXVI) with an alkylating agent in a solvent. The alkylating agent employed in the above reaction may be, for example, a Grignard al reagent such as an alkylmagnesium chloride, an alkylmagnesium bromide or an alkylmagnesium iodide; or an alkyl lithium such as rhethylium, ethylthio or isopropylium, and is preferably a reagent of Grignard The solvent employed in the above reaction is not particularly restricted on the condition that it has no adverse effect on the reaction and may be, for example, an ether such as diethyl ether, telrahydrofiuran, 1,2-dimethoxyethane, dioxane or the like; or an aromatic hydrocarbon such as benzene, toluene or xylene, and is preferably an ether and particularly preferably diethyl ether. The reaction temperature used in the above reaction is generally between -100X and OX, and preferably between -78X and -23X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but is generally between 15 minutes to hours, and preferably 1 hour to 2 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Method I Method I is a method for the preparation of a compound having the general formula (VIII-1), which is included in a compound having the general formula (VIII), wherein the substituent Z is a phenoxy group which it may be optionally substituted with sustiluyenle (s) and additionally, the substitute Y is a benzene ring which may optionally be susliuid with substituent (s), and the LG is a hydroxyl group.

(X XXVI I) (XXXVIII) (VI II-1) In the above reaction scheme, R9 and Rh are the same or different and each represents a group selected from the Substituent group A described above.

Step 11 Step 11 is a process for the preparation of a compound, having the general formula (XXXVIII) by substituting a chlorine atom of a compound having the general formula (XXXVII) with a phenoxy group, which may optionally be susiíuido with susíiuuyenle (s). This process is carried out by reacting a compound having the general formula (XXXVII) with various phenols in the presence of a suitable base in a solvent.

The base employed in the above reaction may be, for example, an alkali metal carbonate such as lithium carbonate, carbonate ! of sodium ? poasium carbonate; or an alkali metal hydride such as sodium hydride or potassium hydride, and is preferably an alkaline metal carbonate and particularly preferably a carbonate carbonate. The solvent used in the above reaction is not particularly resolved provided it has no adverse effect on the reaction and may be, for example, an amide such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylated 2-pyrrolidinone, or the like; or an ether such as diethyl ether, hydrohydrofuran, 1,2-dimethyloxy, dioxane, or the like, and is preferably an amide and particularly preferably N, N-dimethylformamide. The reaction temperature used in the above reaction is generally OX and MOX, and preferably between 60X and 100X.; The reaction time used in the previous reaction is different depending on the reaction temperature, the starting material, the Used reagent or the solvent employed, but is generally between 1 hour to 24 hours, and preferably from 3 hours to 12 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Eiapa 12 The step 12 is a process for the preparation of a compound having the general formula (VIII-1) by oxidizing a formyl group of a compound having the general formula (XXXVIII). This process is carried out by reacting a compound having the general formula (XXXVIII) with an appropriate oxidant group in a solvent. The oxidizing agent used in the above reaction can be, for example, a hypochloride such as sodium hypochloride or potassium hypochlorite; a chlorite such as sodium chlorite or potassium chlorite; or a permanganate such as sodium permanganate or potassium permanganate, and is preferably a chlorite and particularly preferably sodium clopto. The solvent used in the above reaction is not particularly restricted on the condition that it does not have an adverse effect on the reaction and | it may be, for example, a combination of water and a tertiary alcohol such as alcohol-buanol or amyl; or a combination of water and I is a halogenated hydrocarbon such as dichloromelan, 1,2-dichloroethane, chloroform or the like, and is preferably a combination of water and a tertiary alcohol and particularly preferably a combination of water and t-butanol. The reaction temperature used in the above reaction is generally between OX and 60X, and preferably between OX and 40X.

The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent used, but is generally between 30 minutes to 24 hours, and preferably 1 hour to 4 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Method J The J-period is a method for the preparation of a compound having the general formula (VIII-2), it is included in a compound having the general formula (VIII), wherein the Z-substituent is an alkyl group which can be optionally branched and additionally, the suspending agent is a benzene ring which may optionally be suspended with suslidium (s) and the LG is a hydroxyl group.

(XXXIX) (XL) (XLl) In the above reaction scheme, R 'represents a group selected from the group Substituted A described above, Hal represents a halogen atom as described above, and it is preferable that a bromine atom or an iodine atom, and RJ and Rk are equal or different and each represented a C-i-Ce alkyl group which may optionally be subsumed with group (s) selected from the group A below.

Step J1 Step J1 is a process for the preparation of a compound which has the general formula (XL) by converting a formyl group of a compound having the general formula (XXXIX) into an alkenyl group. This process is carried out by reacting a compound having the general formula (XXXIX) with various alkyltriphenylphosphonium salts in the presence of a suitable base in a solvent. The base used in the anterior reaction can be, for example, u? alkoxide such as sodium methoxide, sodium oxide or potassium l-buidoxide or an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; or an alkyl lithium such as n-buililithium, s-butylithium or t-buylium, and is preferably an alkoxide and particularly preferably t-buidoxide of poasium. The solvent used in the above reaction is not particularly restricted provided it does not have an effect adverse in the reaction and may be, for example, an amide such as N, N-dimethylformamide, N, N-dimethylacetamide, N-meityl-2-pyrrolidinone, or the like; or an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxy-olean, dioxane, or the like, and is preferably an amide and particularly preferably N, N-dimethylformamide. The reaction time used in the previous reaction is generally between -45X and 100X, and preferably send OX and 40X. The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but is generally from 15 minutes to 4 hours, and preferably from 30 minutes to 2 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

Step J2 Step J2 is a procedure for the preparation of a compound; having the general formula (XLl) by converting a halogen atom d and a compound having the general formula (XL) into a carboxyl compound. This procedure is carried out by carrying out a halogen-eial exchange in a compound having the general formula (XL), followed by the reaction of the resulting product with carbon dioxide in a solvent. The metallating agent employed in the above reaction may be, for example, a metal such as metallic lithium, metallic magnesium, melicic zinc, or the like; or an alkali metal such as n-butylitol, s-butylium, t-butylithium, or the like; and is preferably an alkyltium and particularly preferably n-buylium. The solvent used in the above reaction is not restricted to the condition that it has no adverse effect on the reaction and may be, for example, an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethyloxylan, dioxane, or the like.; or an aromatic hydrocarbon such as benzene, toluene, xylene, or the like, and is preferably an ether and particularly preferably tetra hydrotreated no. The reaction temperature employed in the above reaction is generally between -100X and OX, and preferably between -78X and -23X. The reaction time used in the above reaction is different depending on the reaction temperature, the starting material, the reagent used or the solvent employed, but it is generally in the case of minutuses at 4 hours, and preferably at least 30 minutes at 2 hours. After the reaction has been completed, the desired compound of this reaction can, if necessary, be isolated from the reaction mixture and purified in the same manner as described in Step A1.

. Step J3 Step J3 is a procedure for the preparation of a compound with the general formula (VIII-2) by reducing a double-bond portion of a compound that is the general formula (XLl).

This procedure is carried out by reacting a compound that they have the ! general formula (XLl) with hydrogen in the presence of a Appropriate transition metal catalyst in a solvent.

The transition metal catalyst used in the reaction For example, a heterogeneous signaling device such as palladium can be on carbon, platinum oxide or Raney nickel; a homogeneous signaller as clqroíris (triphenylphosphine) rhodium or telrakis (iodiphenphosphine) palladium, and is preferably a heterogeneous calyser and particularly preferably palladium on carbon. The solvent used in the above reaction is not particularly restricted on the condition that it has no adverse effect on the reaction and! it can be, for example, an alcohol such as methanol, ethanol or isopropanol; an ether such as diethyl ether, teirahydrofuran, 1,2-dimethoxyethane, dioxane, or the like; or an aromatic hydrocarbon such as benzene, uenole, or xylene, and is preferably an alcohol and particularly preferably ethanol.

The reaction temperature used in the previous reaction it is generally between OX and 80X, and preferably enire 20X and 40X. The reaction time used in the previous reaction is different depending on the reaction temperature, the starting material, the used or the solvent used, but is generally between I minutes to hours, and preferably 30 minutes to 2 hours.

After the reaction has been completed, the compound desired from this reaction can, if necessary, be isolated from the reaction and purified in the same manner as described in Elapa A1.

EXAMPLES EXAMPLE 1 Acid 1 (4 5-r4-Pheni-5- (trifluoromethyl-2-thieniyl-1, 2,4-c>; adiazoleMMD2-I furyl) methyl] az? Tidine-3-carboxylic acid (1a) [(4-Bromo-2-furyl) -methioxy-1 (-buyl) -dimethylsilane To a solution of 4-bromo-2-furaldehyde (5.0 g, 29 mmol) in methanol (40 ml) was added sodium borohydride (1.1 g, 29 mmol) at 0 ° C with stirring, and the resulting mixture was stirred for 1 hour. After evaporating the reaction mixture in vacuo, the residue obtained was diluted with ether, poured in water and extracted with ether. The extract was washed with aqueous solution saturated sodium chloride and dried over magnesium sulfate. After After filtration, the filtrate was evaporated in vacuo. Subsequently, at a The solution obtained from the residue obtained in N, N-dimethylformamide (30 ml) was successively added with imidazole (3.9 g, 57 mmol) and t-butyldimethylchlorosilane (4.7 g, 31 mmol) with stirring, and the resulting mixture was stirred for 4 hours. hours. After the stirring, the reaction mixture was poured into water (50 ml) to heat the reaction and extracted with ether. The extract was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixture of ethyl acetate and hexane (! 3: 97 solvents). ) as the eluent to obtain the title compound (7.4 g) with a yield of 89% as a colorless oily product. i, 1 HNRM (400 MHz, CDCl 3) d ppm: 0.09 (s, 6H), 0.90 (s, 9H), 4.60 (s, 2H), 6.29 (s, 1 H), 7.36 (s, 1 H). IR spectrum (liquid film): 1230, 1257, 1464, 1473crt? 1. Mass spectrum (+) m / z: 290 (M +). (1b) 5 - ((rt-Butyl (dimethyl) silyl-oxo) methylene-3-furaldehyde To a solution of [(4-bromo-2-furyl) methoxy] (t-butyl) dimethylsilane (7.3 g, mmoles) which was obtained in Example 1 (1a) in tetrahydrofuran (50 ml) was slowly added dropwise n-butyllium (a 1.6 M solution in hexane, 1 ml, 28 mmol) at -78 ° C with stirring, The mixture was subsequently stirred by 5 min.Subsequently, N, N-dimethylformamide (3.8 ml, 50 mmol) was subsequently added to the reaction mixture at the same time with stirring, and the mixture was stirred for 45 min. After stirring, a saline aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture to heat the reaction, and the resulting mixture was poured into water (100 ml) and extracted with ether. a saturated aqueous solution of sodium chloride was added and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. or, and the production without purification of the compound thus obtained was purified by chromatography on a silica gel column using a mixture of acetone solvents of hexane and hexane (1:49 to 1:19) as the eluent to obtain the eluant. Composed of the title (3.3 g) with a yield of 55% as a colorless, oily product. i 1HRMN spectrum (500MHz, CDCI3) d ppm: 0.10 (s, 6H), 0.91 (s, 9H), 4.65 (p, 2H), 6.62 (s, 1 H), 8.00 (s, 1 H), 9.90 (s, 1 H). IR spectrum (liquid film): 1083, 1139, 1258, 1473, 1544, 1693cm Mass spectrum (FAB +) m / z: 241 ((M + H) +). (1c) 5- (ffl-Butyl (dimeiyl) silinoxy) meiyl) -3-furoniiril 1 To a solution of 5- ( { [T-butyl (dimethyl) silyl] oxy} -methyl) -3 -furaldehyde (3.2 g, 13 Immoles) which was worked up in Example 1 (1 b) in dichloromene (40 ml) was successively added hydroxylamine hydrochloride (1.0 g, 15 mmol) and triethylamine (3.7 ml, 27 mmol) with The mixture was stirred at ambient temperature for 2 hours. After agitation, the reaction mixture was evaporated in vacuo. Subsequently, to a solution of the residue obtained in toluene (40 ml) was added N, N'-dicyclohexylcarbodiimide (3.1 g, 15 mmol) with stirring, and the mixture was stirred at 90 ° C for 16 hours. After cooling to room temperature, hexane (40 ml) was added to the reaction mixture, and the insoluble materials were removed by filtration with Celile. The filtrate was evaporated off vacuo, and the unpurified production of the title compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (3:97) as the eluyenine for obtain the compound of the extract (1.8 g) with a yield of 57 % as a colorless oily product 'Spectrum HRMN (400 MHz, CDCI3) d ppm: 0.10 (s, 6H), 0.91 (s, 9H), 4.64 (^, 2H), 6.45 (s, 1 H), 7.88 (s, 1 H). IR spectrum (liquid film): 1087, 1142, 1258, 1464, 1473, 1540, 2238 cm \ Mass spectrum (FAB +) m / z: 238 ((M + H) +).

(Id) 5 - ((fi-Builyl (dylmethyl) sililloxy) meilyl) -N'-hydroxyfuran-3. carboxymidiamide To a solution of 5- ( { [t-buyl (dimethylsilyl) oxy) oxymethyl) -3-furoniyryl (1.8 g, 7.6 mmol) which was obtained in Example 1 (1c) in ethanol (10 ml) was added an aqueous solution of hydroxylamine (1.0 ml) with stirring, and the resulting mixture was stirred at 60 ° C for 1 hour. After evaporation in vacuo of the reaction mixture, the obtained residue was diluted with ether, poured into water (40 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the purification product of the title compound thus obtained was purified by column chromatography. of silica gel using a mixture of acetate solvents! of ethyl and hexane (1: 1) as the eluent to obtain the title compound (2.0 g) with a yield of 97% as a white crystalline solid. Spectrum 1HRMN (400MHz, CDCI3) d ppm: 0.09 (s, 6H), 0.90 (s, 9H), 4.62 (js, 2H), 4.69 (brs, 2H), 6.44 (s, 1 H), 7.30 (br, 1 H), 7.64 (s, 1 H). IR spectrum (KBr): 1059, 1594, 1613, 1671, 3203, 3376, 3498 cm "1. Mass spectrum (FAB +) m / z: 271 ((M + H) +), 309 ((M + K) +). de) (4- (5-f4-phenyl-5- (irifluoromethyl) -2-lienyl-1,2,4-oxadiazol-3-yl) -2-furiDmetanbl i To a solution of 5- ( { [ ε-buylyl (dimethylsilyl) oxy} oxymethyl) -N'-hydroxy-3-carboxy-tri-amide (0.14 g, 0.50 mmol) which was obtained in Example 1 (1d) and 4-phenyl-5- ( trifluoromethyl) -iophene-2-carbonyl (0.17 g, 0.60 mmol) in dichlororinean (10 ml) was added NN-diisopropylethylamine (0.17 ml, 1.0 i mmol) at 0 ° C with stirring, and the resulting mixture was stirred for 1 hour. After stirring, a saturated aqueous solution of sodium hydrogencarbonate (1.0 ml) was added to the reaction mixture to heat the reaction, and the mixture was poured into water (20 ml) and extracted with ether. The solution was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate, after filtration the filtrate was evaporated in vacuo, subsequently a solution of the residue obtained in tetrahydrofuran (1.0 ml) was added. He added urea-builaminemonium fluoride (1.0M solution in tetrahydrofiliran, 0.75ml, 0.75mmol) with stirring, and the resulting reaction mixture was stirred at 60 ° C for 3 hours. After the stirring, the reaction mixture was poured into water (20 ml) to heat the reaction and extracted with ether. The extract was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After filtration, the filtrate was evaporated i? vacuo, and the unpurified product of the title compound thus obtained was purified by silica gel column chromatography using a solvent mixture of ethyl acetate and hexane (1: 1) as the eluent to obtain the title compound (0.20 g) with a yield of 10% as a white crystalline solid. Specimen 1 H NMR (500 MHz, CDCl 3) d ppm: 4.69 (s, 2 H), 6.83 (s, 1 H), 7.47 (s, 5 H), 7.88 (s, 1 H), 8.12 (s, 1 H). IR spec (KBr): 1143, 1179, 1416, 1581, 1605, 1629, 3326 cm "1., Mass specimen (FAB +) m / z: 393 ((M + H) +). (1f) 1 - [(4- (5-R4-phenyl-5- (trifluoromethyl) -2-thienyl-1,2,4-oxadiazol-3-yl) -2-furyl) methyl-eilaidyne-3-carboxylic acid eylyl ester solution of (4-. {5- [4-phenyl-5- (l-trifluoromethyl) -2-ynyl] -1,2,4-oxadiazol-3-yl} -2-furyl) methanol (0.20 g, 0.50 mmole) which was obtained in Example 1 (1e), carbon bromide letter (0.20 g, 0.60 mmoles), and Iriphenylphosphyria (0.16 g, 0.60 mmol) in dichloromethane (1.0 ml) was stirred at 0 ° C for 1 hour. Subsequently, the reaction mixture was added successively ethyl 3-azetidinecarboxylate hydrochloride (0.12 g, 0.75 mmoles) and N, N-diisopropylethylamine (0.26 ml, 1.5 mmol) at the same temper with agitation, and the mixture turned out to be stirring at the same time environment for 2 hours. After stirring, an aqueous solution was added saturated sodium carbonate acid (1.0 ml) to the reaction mixture for heat the reaction, and the resulting mixture was poured into water (20 ml) and exirajo cori aceíaío de eíílo. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After of the filtration, the filtrate was evaporated in vacuo, and the product was purified without purifying the The title compound thus obtained was purified by column chromatography of silica gel using a solvent mixture of ethyl acetate and hexane (1: 1 to 2: 1) as the eluent to obtain the title compound (0.21 g) with an 84% yield as a white crystalline solid. Specimen 1HRMN (500MHz, CDCI3) d ppm: 1.27 (l, 3H, J = 7.3 Hz), 3. 35 (quintet, 1 H, 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, 1 H), 7.46 (s, 5H), 7.87 (s, 1 H), 8. 09 (s, 1 H).; IR Spectrum (KBr): 1125, 1178, 1203, 1216, 1581, 1606, 1624, 1727 cm "1.

Mass specimen (FAB +) m / z: 504 ((M + H) +). (1q) 1-((4- (5-4 4-phenyl-5- (frifluoromethyl) -2-fienyl-1,2,4-oxadiazol-3-yl) -2-furyl) -mefipazephdine-3-carboxylic acid, To a solution of 1 - [(4- {5- [4-phenyl] -5- (l-trifluoromethyl) -2-yl] -1, 2,4-oxadiazol-3-yl}. 2-furyl) meyyl] azyldine-3-carboxylic acid (0.20 g, 0.40 I mmoles) which was worked up in Example 1 (1f) in a mixture of disolveníes of lelrahidrofúrano (0.50 ml), meianol (0.50 ml) and water (0.50 ml) was added lihíio hydroxide monohydrate (37 mg, 0.88 mmoles) with The mixture was then stirred at ambient temperature for 1 hour. After stirring, acetic acid (48 [mu] L, 0.88 mmol) was added to the reaction mixture I heat the! reaction. Subsequently, a solution of oxalic acid (18 mg, 0.20 mmol) in methanol (0.5 ml) was added to the mixture, with stirring, and the resulting mixture was stirred for 30 minutes. The precipitated white solid was collected by filtration using a Kiriyama funnel, washed with a mixed solvent of water and methanol (3: 7), and dried in vacuo to obtain the compound of the extract (82 mg) with a yield of 39% as a white crystalline solid. Specimen HRMN (500 MHz, CD3OD) d ppm: 3.35 (quintet, 1 H, J = 7.8 Hz), 3.93 (t, 2H, J = 8.3 Hz), 4.01 (í, 2H, J = 9.3 Hz), 4.19 ( s, 2H), 7.04 (s, 1 H), 7.47-7.52 (m, 5H), 8.03 (s, 1 H), 8.34 (s, 1 H). IR specimen (KBr): 1135, 1177, 1379, 1410, 1594, 1626, 3421 cm "1. Mass specimen (FAB +) m / z: 476 ((M + H) +).

EXAMPLE 2 1 - ((5-R5- (4-C-Clohexylphenyl) -1, 2,4-oxadiazoP ill-2-furyl) methyl) azetidine-3-carboxylic acid (2a) 5- phybuyl (dimethyl) silyloxy) methyl) -2-furonitrile The unpurified production of the compound of the compound was synthesized by conducting a reaction similar to that mentioned in Example 1 (1c) using 5- ( { [t -buyl (dimethyl) silyl] oxy} methyl) -2-furaldehyde (9.1 g, 38 mmol) [Reference literature: Teírahedron, vol. 50 (23), 6767 (1994)], hydroxylamine hydrochloride (2.9 g, 42 mmol), triethylamine (11 ml, 76 mmol) and N, N'-dichyclohexylcarbodiimide (8.6 g, 42 mmol). Subsequently the product without purifying the title compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 9) as the eluent to obtain the title compound (7.5 g) with a yield of 84% as a colorless oily prodigal. Specimen 1HRMN (400 MHz, CDCI3) d ppm: 0.11 (s, 6H), 0.82 (s, 9H), 4.67 (s;, 2H), 6.36 (d, 1 H, J = 3.4 Hz), 7.04 (d, 1 H, J = 3.4 Hz). IR spectrum (liquid film): 1093, 1122, 1258, 1464, 1473, 1524, 2120, 2233 cm "1.! Mass spectrum (+) m / z: 238 (M +). (2b) 5- "ít-bufil (dimefil) silillox) mephyl) -N'-hydroxyfuran-2-l carboximidamide I 1 The unpurified product of the title compound was synleized to conduct the reaction similar to that mentioned in Example 1 (1d) using 5- ( { [I-buyyl (climethyl) silyl] oxy} methyl) -2-furonyl-ryl (7.5 g, 32 mmol) which was obtained in Example 2 (2a) and an aqueous solution of 40% hydroxylamine (4.0 ml). Subsequently, the unpurified product of the compound thus obtained was purified by silica gel column chromatography using a solvent mixture of ethyl acetate and hexane (1: 1) as the eluent to obtain the title compound ( 8.1 g) with a yield of 95% as a white qristamine solid. Spectrum 1HRMN (400 MHz, CDCI3) d 0.09 (s, 6H), 0.91 (s, 9H), 4.66. { s, 2H), 4.99 (brs, 2H), 6.28 (d, 1 H, J = 3.4 Hz), 6.70 (d, 1 H, J = 3.4 Hz), 8.76 (br, 1 H). 'IR spectrum (KBr): 1255, 1613, 1669, 3243, 3367, 3474 cm "1 Mass spectrum (+) m / z: 270 (M +). (2 C) . { 5- [5- (4-c.clohexylphenyl) -1,4, 2,4-oxadiazol-3-ill-2-furyl) mephanol; A solution of 5- ( { [T-buyl (dimethylsilyl) oxy] oxymethyl) -N'-hydroxyfuran-2-carboximidamide (0.19 g, 0.70 mmol) which was obtained in Example 2 (2b) , 4-cyclohexylbenzoic acid (0.16 g, 0.77 mmole), and N, N'-dicyclohexylparbodiimide (0.17 g, 0.84 mmole) in dichloromethane (1.5 ml) and stirred for 1 hour. After stirring, the reaction mixture was diluted with ether, and the insolubles were removed by filtration with Celite, and so! the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained in tetrahydrofuran (1.0 ml) was added fluoride terabrabilaphonium (a 1.0 M solution in leirahydrofuran, 1.1 ml, 1.1 mmol) with stirring, and the resulting mixture was stirred at 60 ° C for 1 hour. After stirring, the reaction mixture was poured into water (20 ml) to heat the reaction and exfoliated with ether. The extract was washed with an aqueous solution saturated sodium chloride and dried over magnesium sulfate. After of the filtration, the filtrate was evaporated in vacuo, and the production without purification of the compound; of the product thus obtained was purified by chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (1: 1) as the eluent to obtain the title compound (0.18 g) with an 81% yield as a white crystalline crystalline solid.

Specimen 1 HNRM (500 MHz, CDCl 3) d ppm: 1.24-1.51 (m, 5H), 1. 75-1.81 | m, 1 H), 1.84-1.96 (m, 4H), 2.56-2.64 (m, 1 H), 4.74 (d, 2H, J = 8.3 Hz), 6.50 (; d, 1 H, J = 3.4 Hz), 7.16 (d, 1 H, 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) 1 - «5- [5- (4-cyclohexylphenyl) -1,2,4-oxadiazol-3-yl-1-2-furyl) -methyl) -acetylidine-3-carboxylic acidyl ester The unpurified production of the compound of the thioule The reaction similar to that mentioned in Example 1 (1f) was used to conduct the reaction. { 5- [5- (4-Cyclohexylphenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} meianol (0.18 g, 0.55 mmol) which was worked up in Example 2 (2c), carbon dioxide (0.22 g, 0.67 mmq), triphenylphosphine (0.18 g, 0.67 mmol), ethyl 3-azetidinecarboxylate hydrochloride (0 14 g) , 0.83 mmole) and N, N-diisopropylethylamine (0.30 ml, 1.7 mmole). Subsequently, the unpurified product of the compound; of the thus obtained thiule was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 1 to 2: 1) as the eluent to obtain the title compound (0.23 g) with a 96% yield as a white cristalaline solid. Spectrum 1HRMN (500 MHz, CDCI3) d ppm: 1.24-1.32 (m, 4H), 1.37-1.51 (m, 4H), 1.78 (d, 1 H, J = 12.7 Hz), 1.84-1.94 (m, 4H ), 2.56-2.63 (m, 1 H), 3.34 (quintet, 1 H, 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, 1 H, J = 3.4 Hz), 7.13 (d, 1 H, J = 3.4 Hz), .37 (d, 2H, J = 8.3 Hz), 8.10 (d, 2H, J = 8.3 Hz). IR specimen (KBr) - 1374, 1561, 1614, 1736 cm "1. Mass specimen (FAB +) m / z: 436 ((M + H) +). (2e) 1- '5- [5- (4-Cyclohexylphenyl) -1,2,4-oxadiazol-3-yn-2-furyl) methyl) azetidine-3-carboxylic acid To a solution of 1- (. {5 - [5- (4-cyclohexyphenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} -methyl) azyidine-3-carboxylic acid ester (0.23 g, 0.53 mmol) which was obtained in Example 2 (2d) in a mixture of terahydrofuran (0.50 ml) solvents, meianol (0.50 ml) and water (0.50 ml) was added with lithium hydroxide monohydrate (50 mg, 1.2 mmol) with stirring, and the mixture resulted in it was stirred at room temperature for 1 hour. After stirring, acetic acid (65 μL, 1.2 mmol) was added to the reaction mixture to heat the reaction. The precipitated white solid was collected by filtration using a Kiriyama funnel, washed with a mixture of water solvents and meianol. (3: 7) and dried vacuo to leave the title compound (122 mg) in a 56% yield as a white crystalline solid. Spectrum 1HRMN (500 MHz, CD3OD) d ppm: 1.30-1.40 (m, 1 H), 1.43-1.57 (? M, 4H), 1.79 (d, 1 H, J = 11.7 Hz), 1.87-1.94 (m, 4H), 2 63-2.69 (m, 1 H), 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, 1 H, J = 3.4 Hz), 7.26 (d, 1 H, 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 Acid 1 [(4-5-r4-Phenyl-5 (trifluoromethyl-2-tier? In 1,2,4 or>: adiazoi: Mi.D2-thienyl) methyl] azetidine-3-carboxylic acid (3a) 5- ( { [T-butyl (dimethy) silinoxy) methyl) thiophene-3-carbonyiyl To a solution of [(4-bromo-2-thienyl) -methio] l-buildyldimethylsilane (9.0 g, mmoles) [reference line: J. Med Chem., vol. 45, 5005 (2002)] in N, N-dimethylformamide (20 ml) was added copper cyanide (4.7 g, 53 mmol) with stirring, and the resulting mixture was heated to reflux for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ether (80 ml), and after adding an aqueous solution of 28% ammonia (5Q ml), the resulting mixture was stirred at room temperature for 1 hour. After stirring, the reaction mixture was extracted with ether, and the extract was washed successively with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1:50 a). 1: 4) as the eluent to obtain the title compound (4.3 g) with a yield of 58% as a colorless oily product.

Specimen 1 HNRM (400 MHz, CDCl 3) d ppm: 0.11 (s, 6H), 0.93 (s, 9H), 4.85 (s, 2H), 7.06 (s, 1 H), 7.82 (s, 1 H). IR specimen (thin film): 1086, 1128, 1258, 2229 cm "1. Mass specimen (The +) m / z: 253 (M +). , (3b) 5- rí-Buíil (dímeíil) silyloxy) meíil) -n'-hidroxiíiofeno-3-carboximidamida! The unpurified product of the title compound was synthesized by driving the! reaction similar to that mentioned in Example 1 (1d) using 5- ( { [t-Butyl (dimethylsilyl) oxy] oxymethyl) -iophene-3-carbonyl ether (4.3 g, 17 mmol) obtained in Example 3 (3a) and an aqueous solution of 40% hydroxylamine (2.2 ml). Subsequently, the unpurified product of the thioule compound thus obtained was purified by chromatography on a silica gel column using a mixture of acetone solvent and hexane (1: 10 to 2: 5) as the luyenie to obtain the compound of the tííulo (4.7 g) with a yield? of 97% as a white crystalline solid. Species 1HRMN (400 MHz, CDCI3) d ppm: 0.10 (s, 6H), 0.93 (s, 9H), 1.69 (brs, 1 H), 4.79 (brs, 2H), 4.84 (s, 2H), 7.02 ( d, 1 H, J = 1.4 Hz), 7.31 (d, 1 H, J = 1 ',., 4 Hz). IR spec (KBr): 1101, 1256, 1371, 1655, 3208, 3389, 3495 cm Mass spectrum (FAB +) m / z: 287 ((M + H) +). (3c) (4- (5-r4-phenyl-5- (trifluoromethyl) -2-lienyl] -1,4, 2,4-oxadiazol-3-yl) -2-dieneh The crude product of the title compound was synthesized. by conducting the reaction similar to that mentioned in Example 1 (1e) using 5- ( { [i-buyyl (dimethyl) s1l] oxy] oxymethyl) -N'-hydroxyl-pheno- 3-carboximidamide (0.43 g, 1.5 mmol) which was worked up in Example 3 (3b), 4-phenyl-5- (trifluoromethyl) -iophene-2-carbonyl chloride (0.52 g, 1.8 mmol), N, N-diisopropyl-erylamine (0.52 ml, 3.0 mmol), and a solution of 1.0 M ethylene glyphonium fluoride (3.0 ml, 3.0 mmol) Subsequently, the unpurified production of the title compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 2 to 1: 1) as the eluent to obtain the title compound (0.60 μg) as a white crystalline solid Spectrum 1HRMN (400MHz, CDCl 3) d ppm : 1.95 (brs, 1 H), 4.89 (s, 2H), 7 5 (s, 5H), 7.56 (s, 1 H), 7.87 (d, 1 H, J = 1.2 Hz), 8.07 (d, 1 H, J = 1.2 Hz). • Spectrum (KBr): 1126, 1183, 1268, 1313, 1417, 1578, 1606, 3324 cm Mass specimen (FAB +) m / z: 409 ((M + H) +). (3d) 1-((4- (5-4 4-phenyl-5- (trifluorome! Il) -2-! Ienip-1, 2,4-oxadiazol-3-yl) -2-ienyl) useful! Eryl azeididine-3-carboxylate The unpurified production of the compound of the compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (4-. {5- [4-feryl-5- (l-trifluoromethyl) ) -2-thienyl] -1,4, 2,4-oxadiazol-3-yl.} -2-yl) methynol (0.10 g, 0.25 mmol) which was worked up in Example 3 (3c), carbon dioxide (0.17 g, 0.50 mmol), triphenylphosphine (0.13 g, 0.50 mmol), ethyl 3-azelidinecarboxylamino hydrochloride (62 mg, 0.38 mmol), and N, N-diisopropyl-ylamine (0.11 ml, 0.63 mmol). Subsequently, the product without purification of the compound of the thus obtained was purified by thin layer chromatography on a silica gel plate using a mixture of acetylene solvents. of ethylene and hexane (2: 3) as the developing solvent to obtain the title compound (73 mg) with a yield of 56% as a white crystalline crystalline solid. Specimen 1HRMN (400 MHz, CDCI3) d ppm: 1.27 (l, 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 , 1 H, J = 1.2 Hz), 8.04 (d, 1 H, J = 1.2 Hz). IR specimen (KBr): 1132, 1180, 1197, 1272, 1316, 1577, 1608, 1720 cm "1; Mass specimen (FAB +) m / z: 520 ((M + H) +). (3e) Acid 1 - [(4- {5- [4-phenyl] -5- (trifluoromethyl) -2-lienin-1,2,4-oxadiazol-3! -yl) -2-thienyl) methyl] azeidin-3-carboxylic acid To a solution of 1 - [(4- {5- [4-phenyl-5- (trifluoromethyl) -2-ynyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) ethyl] azeidin-3-carboxylic acid (70 mg, 0.13 mmol) which was worked up in Example 3 (3d) in dioxane (2 ml) was added to an aqueous solution of sodium hydroxide 1 N (0.39 ml, 0.39 mmol) with agitation, and the mixture was stirred at ambient temperature for 2 hours.

After agitation, acetic acid (22 μL, 0.39 mmol) was added to the reaction mixture to heat the reaction, and the resulting mixture was evaporated in vacuo. To the residue thus obtained was added successively meianol (1 ml) and water (1 ml) with stirring, and the precipitated white solid was collected by filtration using a Kiriyama funnel, washed with a mixture of solvents of water and methanol (3: 7). ) and dried vacuo to obtain the title compound (34 rrig) with a yield of 53% as a white crystalline solid. Specimen HRMN (400 MHz, CD3CO2D) d ppm: 3.75-3.88 (m, 1 H), 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, 1 H), 8.03 (s, 1 H), 8.37 (s, 1 H). : IR spec (KBr): 1133, 1178, 1270, 1579, 1605, 3429 cm "1 Mass specimen (FAB +) m / z: 492 ((M + H) +).

EXAMPLE 4 Acid 1 (5- (5-r4-phenyl-5- (trifluoromethyl) -2-thienin-1,2,4-oxadiazol-1-thienyl) methyl] azetidine-3-carboxylic acid : (4a) 5 - (([f-bufil (dimefil) silyl] oxy) methyl) phofen-2-carbonifril 1 The unpurified product of the title compound was synthesized at conduct the similar reaction as mentioned in Example 3 (3a) using [(5-bromo-2-ynyl) -methioxy] t-butyldimethylsilane (2.4 g, 7.8 mmol) reference: Tetrahedron, vol. 39, 2531 (1983)] and copper cyanide (1.3 g, 14 mmoles). Subsequently, the unpurified product of the title compound This was purified by column chromatography on silica gel using a solvent mixture of ethyl acetate and hexane (1:50 to 1: 7) as the eluent to obtain the compound of the extract (1.1 g) with a yield of 56% as a white crystalline solid.

Specimen 1 HNRM (400 MHz, CDCl 3) d ppm: 0.12 (s, 6H), 0.93 (s, 9H), 4.88 (d, 2H, J = 1.2 Hz), 6.70 (di, 1 H, J = 3.9 Hz, 1.2 Hz), 7.46 (d, 1 H, J = 3.9 Hz).

IR spectrum (thin film)]: 1096, 1258, 1377, 1464, 1472, 2219 cm "1., Mass spectrum (+) m / z: 253 (M +). (4b) 5- ry-buyl (dimethylsilyl) oxy) meityl) -N'-hydroxy-iiophene-2-carboximidamide The crude product of the compound of the amino acid was synthesized by conducting the reaction similar to that mentioned in Example 1 (1d) ) using i 5- ( { [t-buyyl (dimethyl) silyl] oxy} -methyl) iiophen-2-carbonyl (1.3 g, 5.0 mmol) which was worked up in Example 4 (4a) and an aqueous solution of 40% hydroxylamine (0.7 ml). Subsequently, the unpurified production of the title compound thus obtained was purified by recrystallization from a solvent mixture? of acetyl of hexane and hexane to obtain the compound of the extract (1.2 g) yielded an 81% yield as a white crystalline solid. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.10 (s, 6H), 0.93 (s, 9H), 4.82 (brs, 2H), 4.84 (s, 2H), 6.81 (brs, 1 H), 6.84 (d, 1 H, J = 3.7 Hz), 7.11 (d, 1 H, J = 3.7 Hz) . , IR spectrum (KBr): 1067, 1250, 1256, 1368, 1387, 1588, 1658, 3206, 3384, 3498 cm "1. Mass spectrum (+) m / z: 286 (M +). (4c) (5- (5-r4-phenyl-5- (trifluoromethyl) -2-lienin-1, 2,4-oxadiazol-3-yl) -2-thieniDmetaijiol The crude product of the title compound was synthesized at The reaction similar to that mentioned in Example 1 (1e) was carried out using 5- ( { [t-buyyl ((. {1-methyl) silyl] oxy} -methyl) -N'-hydroxy-iiophene -2-carboxyamidamide (0.43 g, 1.5 mmol) which was worked up in Example 4 (4b), 4-phenyl-5- (trifluoromethyl) -iophene-2-carbonyl chloride (0.52 g, 1.8 mmol), N , N-diisopropylethylamine (0.52 ml, 3.0 mmoles), and a 1.0 M (3.0 ml, 3.0 mmoles) solution of fluoride-butadiene, Subsequently, the product without purification of the title compound thus obtained was purified by gel column chromatography. silica using a mixture of acetone solvents of ethyl and hexane (1: 2) as the eluent to obtain the title compound (0.60 g) with a yield of 99% as a white crystalline solid; 1H NMR spectrum (400 MHz) , CDCI3) dp pm: 1.97 (brs, 1 H), 4.89 (s, 2H), 7.06 (d, 1 H, J = 3.7 Hz), 7.45 (s, 5H), 7.72 (d, 1H, J = 3.7 Hz), 7.88 (q, 1 H, J = 1.6 hz). IR spectrum (KBr): 1108, 1126, 1176, 1269, 1373, 1572, 3322 cm "1. Mass spectrum (FAB +) m / z: 409 ((M + H) +).

I (4d) 1 -f (5- (5-f4-phenyl-5- (trifluoromethyl) -2-thienin-1, 2,4-oxadiazol-3-yl-2-thienyl) methyl-1-azeidin-3-carboxylic acid The crude product of the title was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (5- {5- [4-phenyl-5- (l-trifluoromethyl) -2-yenyl] -1, 2,4-Oxadiazol-3-yl.} -2-ynyl) -meanol (0.12 g, 0.29 mmol) which was obtained in Example 4 (4c), carbon tetrabromide (0.19 g, 0.58 mmqies), triphenylphosphine (0.15 g) g, 0.58 mmol), ethyl 3-azetidinecarboxylate hydrochloride (62 mg, 0.38 mmol), and N, N-diisopropylethylamine (0.13 ml, Q.73 mmol) Subsequently, the unpurified product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a solvent mixture of ethyl acetate and hexane (4: 5) as the developing solvent to obtain the title compound (0.12 g) with a yield of 80. % as an oily product i ncoloro Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 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, 1 H, J = 3.7 Hz), 7.45 (s, 5H), 7.69 (d, 1 H, J = 3.7 Hz), 7.87 (s, 1 H). IR specimen (liquid film): 1133, 1182, 1214, 1269, 1284, 1373, 1571, 1734 cm "1. Mass spec (FAB +) m / z: 520 ((M + H) +). (4e) Acid 1 - [(5- (5-4 4-phenyl-5- (frifluoromethyl) -2-thienin-1,4-oxadiazol-3-yl) -2-thienyl) methyNazetidine-3 carboxylic acid The title compound (60 mg) was synthesized with a yield of 53% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using 1 - [(5-. { 5- [4-phenyl-5- (trifluoromethyl) -2-eneyl] -1,2,4-oxadiazol-3-yl} -2-thienyl) -methyl] azeididine-3-carboxylic acid ester ( 0:12 g, 0.23 mmoles) which was obtained in example 4 (4d) and a 1 N aqueous solution of sodium hydroxide (0.69 ml, 0.69 mmoles). , Spectrum 1HRMN (400 MHz, CD3CO2D) d ppm: 3.80-3.92 (m, 1 H), 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, 1 H), 8.02 (s, 1 H).

IR Spectrum (KBr): 1134, 1179, 1214, 1267, 1366, 1379, 1570, 1605, 3429 cm "Mass Spec (FAB +) m / z: 492 ((M + H) +).

EXAMPLE 5 Acid 1 - ((5-r5- (4-Phenoxyphenyl) -1,2,4-oxadiazole-3H 2 -thieni? Methy) azeD; Hna-3-carboxylic acid (5a) { 5- [5- (4-Phenoxyphenyl) -1,4, 2,4-oxadiazol-3-yl-1-yl-2-ynyl) melanol To a solution of 4-phenoxybenzoic acid (0.12 g, 0.55 mmole) in acetylphril (5 ml) was they added successively 1-hydroxybenzoyriazole (88 mg, 0.65 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.12 g, 0.60 mmol), 5- ( { [i-butyl ( dimethyl) silyl] oxy} .methyl) -N'-hydroxy-phenyl-2-carboximidamide (0.14 g, 0.5 mmol) which was obtained in Example 4 (4b) with stirring, and the resulting mixture was stirred at room temperature. for 30 minutes. After stirring, water (5 ml) was added to the reaction mixture to stop the reaction, and the resulting mixture was extracted with ethyl acetate. The extra was washed successively with 0.1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained in teirahydrofuran (4.0 ml) was added ferrous ammonium fluoride (1.0 M solution in hydrofuran, 1.0 ml, 1.0 mmol) with agitation, and the resulting mixture was stirred at 60X for 3 hours. After stirring, the reaction mixture was poured into water (20 ml) to stop the reaction and extracted with ether. The extract was washed with a saline aqueous solution of sodium chloride and dried over sodium sulfate. After the filing, the filirado evaporated i? Vacuum, and the unpurified production of the compound thus obtained was purified by chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (1: 1) as the eluent to obtain the title compound ( 97 mg) with a yield of 55% as a white crystalline crystalline solid. Specimen 1 HNRM (400 MHz, CDCl 3) d ppm: 1.89 (1, 1 H, J = 5.9 Hz), 4.89 (d, 2 H, J = 5.9 Hz), 7.03-7.10 (m, 4 H), 7.19-7.28 (m , 2H), 7.35-7.44 (m, 2H), 7.71 (d, 1 H, J = 3.5 Hz), 8.61 (d, 2H, J = 8.6 Hz). i IR Spec (KBr): 1241, 1366, 1487, 1575, 1590, 1613, 3331 cm "1. Mass Spec (FAB +) m / z: 351 ((M + H) +). (5b) 1 - ((5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl-2-fienyl) mephyl) azetidin-3-carboxylic acid ester without purifying the title compound was synthesized by conducting the reaction similar to that mentioned in example 1 (1f) using. { 5- [5- (4-phenoxyphenyl) -1,4,4-oxadiazol-3-yl] -2-thienyl} meianol (97 μg, 0.28 mmol) which was obtained in Example 5 (5a), carbon tetrahydromide (0.19 g, 0.56 mmole), pyridylphosphine (0.15 g, 0.56 mmole), 3-azelidincarboxylase hydrochloride of eryl (70 mg, 0.42 mmole), and N, N-diisopropylethylamine (0.18 ml, 1.1 mmol). Subsequently, the unpurified product of The title compound thus obtained was purified by layer chromatography fine on a plate in silica gel using a mixture of solvents from I ethyl acetate and hexane (4: 3) as the developing solvent to obtain I the compound of the tíulo (93 mg) with a yield of 72% like a produelo oily folero Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.27 (l, 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, 1 H, J = 3.3Hz), 7.06-7.15 (m, 4H), 7.23 (l, 1 H, J = 7.4 Hz), 7.42 (t, 2H, i J = 7.8 Hz), 7.70 (d, 1 H, 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) +). (5cL Acid 1 - ((5-5 5 - (4-phenoxyphenyl) -1,4-oxadiazol-3-ip-2-thienyl) methyl) gzetidin-3-carboxylic acid The title compound (69 mg) was synthesized with a yield of 80% as a white crystalline solid when driving the reaction similar to that mentioned in example 3 (3e) using 1- (. {5- [5- (4-phenoxyphenyl) | 1, 2,4-oxadiazol-3-yl] -2-thienyl}. methyl) azetidine-3-carboxyl ether (90 mg, 0J20 mmol) which was worked up in example 5 (5b) and a 1 N aqueous solution of sodium hydroxide (0.60 ml, 0.60 mmol).

I Specimen 1HRMN (400 MHz, CD3CO2D) d ppm: 3.76-3.87 (m, 1 H), 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 (i, 1 H¡ J = 7.8 Hz), 7.40-7.48 (m, 3H), 7.84 (d, 1 H, J = 3.9 Hz), 8.18 (d, 2H, I J = 8.6Hz). i ', Specter IR (KBr): 1243, 1366, 1488, 1569, 1591, 1613, 3469 cm " 1 Mass Spec (FAB +) m / z: 434 ((M + H) +).

EXAMPLE 6 3 - . 3 -carboxylic : (6a) (4-r5- (4-Benzylphenyl) -1, 2,4-oxadiazol-3-yl-2-ynyl) meianol The unpurified product of the title compound was synthesized at conduct the reaction similar to that mentioned in example 5 (5a) using 4-benzylbenzoic acid (0.12 g, 0.55 mmol), 1-hydroxybenzotriazole (88 mg, 0.6 ^ 5 mmole), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.12 g, 0.60 mmoles), 5- ( { [t-Butyl (dimethyl) silyl] oxy} methyl) -N'-hydroxythiophen-3-carboxylamide (0.14 g, 0. 5 mmol) which was obtained in Example 3 (3b), and urea-tallowammonium fluoride (1.0 M solution in hydrofuran, 1.0 mL, 1.0 mmol).

Subsequently, the unpurified production of the title compound thus obtained was purified by recrystallization from a mixture of ethyl acetate and hexane dissolvents to obtain the title compound (99 mg) with a yield of 57% as a white crisíalino solid. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.68 (brs, 1 H), 4.08 (s, 2H), 4.90 (s, 2H), 7.18-7.43 (m, 7H), 7.59 (s, 1 H), 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) 1 - ( { 4- [5- (4-benzylphenyl) -1,2,4-oxadiazol-3-yl1-2-ynyl) mephyl)! Azyphidine-3-carboxylic acid ethyl ester The unpurified product of the thioule compound was synthesized by conducting the reaction similar to that mentioned in example 1 (1f) using,. { 4- [5- (4-benzylphenyl) -1,4, 2,4-oxadiazol-3-yl] -2-thienyl} melanol (95 mg, 0.27 mmol) which was worked up in Example 6 (6a), carbon dioxide (0.18 g, 0.54 mmol), triphenylphosphine (0.14 g, 0.54 mmol), 3-azelidinecarboxylase hydrochloride of eryl (67 mg, 0.41 mmole), and N, N-diisopropylethylamine (0.12 ml, 0.68 mmole). Subsequently, the unpurified product of the compound! of the title thus obtained was purified by thin-layer chromatography on a silica gel plate using a solvent mixture of ethyl acetate and hexane (6: 4) as the developing solvent to obtain the compound of the extract (84 mg). with a yield of 68% as a solid white criales. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 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, 1 H), 8.01 (s, 1 H), 8.08 (d, 2H, J = 8.2 Hz). IR spec (KBr): 1184, 1296, 1356, 1423, 1585, 1735 cm "1. Mass spec (FAB +) m / z: 460 ((M + H) +). (6c) 1 - ((4- [5- (4-Benzylphenyl) -1,2,4-oxadiazol-3-ill-2-thienyl) methyl) 'azetidine-3-carboxylic acid The title compound (67 mg) was synthesized with a yield of 86% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using 1- (. {4- [5- (4-benzylphenyl) -1, 2,4-oxadiazol-3-yl] -2-thienyl} -methyl) azelidine-3-carboxylic acid eilate (82 mg, 0.118 mmol) which was obtained in Example 6 (6b), and an aqueous solution 1 Nl of sodium hydroxide (0.54 ml, 0.54 mmole). Specimen 1 HNRM (400 MHz, CD3CO2D) d ppm: 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 spectra (FAB +) m / z: 432 ((M + H) +).

EXAMPLE 7 1/2 oxalate of 1- (2-r5- (4-sobutilfeniB 2.4-oxa l, gazo-3-in-4,5,6,7-tetrahydro-1-benzofuran-4-yl) acid > azetidine-3-earboxyliet3) (7a) β-Builyl (dimethyl) (4,5,6,7-e -hydro-1-benzofuran-4-yloxy) silane To a solution of 6,7-dihydro-4- (5H) -benzofuranone (5.0 g, 37 mmol) in meianol (50 ml) was added sodium borohydride (1.4 g, 37 mmol) to OX with stirring, and the resulting mixture was stirred for 1 hour.

After evaporating the reaction mixture in vacuo, the residue obtained was diluted with ether, poured into water (40 ml), and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate After filtration, the filtrate was evaporated in vacuo, Subsequently, to a solution of the residue thus obtained in dimethylformamide. ml) were added successively to imidazole (4.0 g, 59 mmole) and 1-buyldimethylchlorosilane (4.9 g, 32 mmole) with stirring, and the resulting mixture was stirred for 2 hours.After stirring, the reaction mixture was poured into the mixture. water (50 ml) to stop the reaction and extracted with ! ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After the filtration, the filtering will evaporated in vacuo, and the unpurified product of the title compound obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1:49). at 3:97) as the eluent to obtain the title compound (7.2 g) with a 77% yield as a colorless oily product. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.12 (s, 3H), 0.13 (s, 3H), 0.92! (S, 9H), 1.63-1.79 (m, 2H), 1.89-1.94 (m, 1 H), 1.98-2.08 (m, 1 H), 2. 51 (dt, 1 H, J = 16.4 Hz, 6.3 Hz), 2.62 (dt, 1 H, 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 spec (liquid film): 1074, 1255, 2858, 2932cm "1. Mass spec (+) m / z: 252 (M +). (7b) 4 - ([t-Butyl (dimethyl) silyl-oxy) -4,5,6,7-tetrahydro-1-benzofuran-2-carboxaldehyde To a solution of t-buil (dimethyl) (4,5,6 , 7-leihydro-1-benzofuran- 4-yloxy) sila or (4.1 g, 16 mmol) which was obtained in Example 7 (7a) in tetrahydrofiliran (30 ml) was added dropwise n-butyllithium (one 1.J6M solution in hexane, 31 ml, 49 mmol) at -78X with stirring, and then to raise the reaction temperature to 0X, the mixture was agitated by 30 minutes ^. After cooling the reaction mixture again to -78X While stirring, N, N-dimethylformamide (13 ml, 162 mmol) was added to the mixture of < reaction with agitation, and the resulting mixture was stirred for 30 minutes. After stirring, a saturated aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture to stop the reaction, and the resulting mixture was poured into water (50 ml) and extracted with ether. The extract was washed co [? a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the unpurified product of the thus-obtained title compound was purified by chromatography on a column of silica gel using a mixture of acetyl elution solvents and hexane (1: 9) as the eluent to obtain the title compound (4.3 g) with a yield of 94% as a white crystalline solid. : Spectrum 1HRMN (500 MHz, CDCI3) d ppm: 0.14 (s, 3H), 0.16 (s, 3H), 0.92 ¡(s, 9H), 1.66-1.86 (m, 2H), 1.90-1.99 (m, 1 H), 2.04-2.14 (m, 1 H), 2.61 (di, 1 H, J = 17.6 Hz, 6.3 Hz), 2.73 (dt, 1 H, J = 17.6 Hz, 6.3 Hz), 4.75 (t, 1 H, J = 5.9 Hz), '7.15 (s, 1 H), 9.53 (s, 1 H). IR specimen (KBr): 1074, 1085, 1525, 1678 cm "1. 'Mass spectrum (FAB +) m / z: 280 ((M + H) +). (7c) 4- (ry-Buyyl (dimethyl) silinoxy) -4.5.6.7-eyrahydro-1-benzofuran-2-carboniiryl The unpurified production of the compound was synthesized by conducting the reaction similar to that mentioned in the example 1 (1c) using 4-. { [t -buyyl (dimethyl) silyl] oxy} 4,5,5,7,7-Hydro-1-benzofuran-2-carboxaldehyde (4.3 g, 15.3 mmol) which was obtained in Example 7 (7b), hydrochloride! of hydroxylamine (1.2 g, 17 mmol), eryrylamine (4.3 ml, 31 mmol), and N.N'-dicyclohexylcarbodiimide (3.5 g, 17 mmol). Subsequently, the unpurified production of the thus obtained thiol compound was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 9) as the developer to obtain the title compound. (3.0 g) with a yield of 71% as a colorless oily product. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.12 (s, 3H), 0.14 (s, 3H), 0.91 js, 9H), 1.16-1.38 (m, 1H), 1.65-1.82 (m, 1 H), 1.86-1.96 (m, 1H), and 2.02-2.12 (m, 1 H), 2.55 ( dt, 1 H, J = 17.2 Hz, 5.9 Hz), 2.66 (di, 1 H, J = 17.2 Hz, i 5.9 Hz), 4.70 (l, 1 H, J = 5.9 Hz), 6.99 (s, 1 H ). IR specimen (liquid film): 1087, 1255, 1526, 1616, 2120, 2227 cm "1. Mass spectrum (FAB +) m / z: 278 ((M + H) +), 300 ((M + Na) + ). (7d) 4-. { rt-Butyl (dimethyl) silyloxy) -N'-hydroxy-4,5,6,7-teirahydro-1-benzofurarj-2-carboximidamide The unpurified product of the title compound was syntheized by conducting the reaction similar to that mentioned in example 1 (1d) using 4. { [α-builyl (dimethyl) silyl] oxy} -4,5,6,7-teirahydro-1-benzofuran-2-carbonitrile (3.0 g, 11 mmol) which was obtained in example 7 (7c) and a 40% aqueous solution of hydroxylamine (3.0 ml) ). Subsequently, the unpurified product of the thioule compound thus obtained was purified by chromatography on a column of silica gel using a mixture of ethylene glycol and hexane (3: 7) solvents as the eluyenle to obtain the compound of the column ( 2.7 g) with a yield of 82% as a white crystalline solid. '1HRMN spectral (500 MHz, CDCI3) d ppm: 0.12 (s, 3H), 0.13 (s, 3H), 0.91 (s, 9H), 1.64-1.81 (m, 2H), 1.85-1.93 (m, 1 H), 2.00-2.10 (m, 1 H), 2.54 (di, 1 H, J = ¡17.4 Hz, 5.1 Hz), 2.65 (dt, 1 H, J = 17.2 Hz, 5.1 Hz), 4.72 (t, 1 H, J = 5.1 Hz), 4.85 (brs, 2H), 6.57 (brs, 1 H), 6.62 (s, 1 H).; 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-l5- (4-lsobutylphenol) -1.2.4-oxadiazol-3-n-4,5,6,7-tetrahydro-1-benzofuran-4-ol The crude product of the title compound synthesized by conducting the reaction similar to that mentioned in Example 5 (5a) using 4-isobutylbenzoic acid (0.12 g, 0.66 mmol), 1-hydroxybenzoyriazole (0.11 g, 0.78 mmol), 1-ethyl-3- (3 hydrochloride -dimetilami? opropyl) carbodiimide (0.14 g, 0.72 mmol), 4-. { [t-butyl (dimethyl) silyl] oxy} -N'-hydroxy-4,5,6,7-tetrahydro-1-benzofuran-2-carboximidimide (0.19 g, 0.6 mmol) which was obluvored in example 7 (7d), and terarabutylammonium fluoride (a solution 1.0 M in tetrahydrofuran, 1.2 ml, 1.2 mmolefe). Subsequently, the unpurified product of the thus obtained thioule compound was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 2 - 1: 1) as the eluent to obtain the compound of the title (0.15 g) with a yield of 75% as an oily production of pale yellowish color. Specimen 1HRMN (400 MHz, CDCI3) d ppm: 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, 1 H), 2.76-2.86 (m, 1 H), 4J.80 (brs, 1 H), 7.21 (s, 1 H), 7.29 (d, 2H, J = 8.2 Hz), 8.08 (d, 2H, J = 8.2Hz).; , IR spectrum (thin film): 1204, 1343, 1386, 1420, 1505, 1560, 1590, 1616, 3389 cm "1. Mass spectrum (FAB +) m / z: 339 ((M + H) +). (7f) 1- (2- [5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl-1, 4,6,6,7-eeryhydro-1-benzofuran-4-yl) azeidyne-3 Eryl carboxylate The unpurified product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) by using 2- [5- (4-isobuylphenyl) -1,2,4-oxadiazole-3- il] -4,5,6,7-и-tetrahydro-1-benzofurari-4-ol (0.15 g, 0.45 mmol) which was obtained in Example 7 (7e), carbon telbromide (0.30 g, 0.90 mmol), triphenylphosphine (0.24 g, 0.90 mmol), ethyl 3-azetidinecarboxylamino hydrochloride (0.11 g, 0.68 mmol), and N, N-diisopr | opylethylamine (0.20 ml, 1.1 mmol). Subsequently, the purified product of the compound thus obtained was purified by thin-layer chromatography on a silica gel plate using a mixture of acetone and hexane (4: 3) acetone solvents as the solvent. development to obtain the compound of the tíulo (27 mg) with a yield of 13% as a crystalline white solid. Specimen 1HRMN (400 MHz, CDCI3) d ppm: 0.93 (d, 6H, J = 6.6 Hz), 1.29 (\, 3H, J = 7.4 Hz), 1.60-1.87 (m, 3H), 1.87-2.00 (m, 1 H), 2.00-2.14 (m, 1 H), 2.56 (d, 2H, J = 7.4 Hz), 2.60-2.83 (m, 2H), 3.27-3.44 (m, 3H), 3.51 (1, 1 H, J = 6.8 Hz), 3.58-3.70 (m, 2H), 4.18 (q, 2H, J = 7.4 Hz), 7.12 (s, 1 H), 7.31 (d, 2H, i J = 8.0 Hz),. 10 (d, 2H, J = 8.0 Hz). IR Spec (liquid film): 1186, 1208, 1342, 1387, 1560, 1590, 1616 ^ 1733 cm "1. Mass Spec (FAB +) m / z: 450 ((M + H) +). (7q) 1/2 1- (2- [5- (4-lsobutylphenyl) -1,2,4-oxadiazol-3-p-4,5,6,7-tetrahydro-1-benzofuran-4-oxalate -il) azetidine-3-carboxylic acid The title compound (13 mg) was synthesized with a yield of 50% as a white crislallic solid when conducting the reaction I similar to that mentioned in example 3 (3e) using 1-. { 2- [5- (4-isobuylphenyl) -1-, 2,4-oxadiazol-3-yl] -4,5,6,7-letrahydro-1-benzofuran-4-yl} azetidine-3-carboxylic acid ether (25 mg, 0.056 mmol) which was obtained in example 7 (7f), a 1 N aqueous solution of sodium hydroxide (0.17 ml, 0.17 mmol), and oxalic acid (3 mg, 0.028) mmoles). Spectrum 1HRMN (400 MHz, CD3CO2D) d ppm: 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, 1 H), 2.79- 2.90 (m, 1IH), 3.79-3.92 (m, 1 H), 4.38-4.73 (m, 5H), 7.40 (d, 2H, J = 7.4 Hz), 7.43 (s, 1 H), 8.13 (d, 2H, J = 7.4 Hz). IR Spec (KBr): 1387, 1409, 1559, 1592, 1613, 3431 cm "1. Mass Spec (FAB +) m / z: 422 ((M + H) +).

EXAMPLE 8 Acid 1j- (2-5- (4-isobutylpheni0-1,2,4-oxadiazo ^ 3-yl1-4,5,6J-tetrahyl-a-benzothien-4 ° ii) azetidine-3-carboxy-8C? (8a) 2-Bromo-4,5,6,7-lelhydro-1-benzothiophen-4-ol To a solution of 4,5,6,7-telrahydro-1-benzoin-4-yl acetate (5.1 g, 26 mmoles) in chloroform (30 ml) was added N-bromosuccinimide (5 g, 28 mmol) to OX with stirring, and the resulting mixture was stirred at room temperature fj. or 3 hours. After stirring, the reaction mixture was poured into water (40 njil) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue thus obtained in a mixed solvent of teirahydrofuran (20 ml) and water (20 ml) was added sodium hydroxide (2.3 g, 57 mmol) with agitation, and the resulting mixture was stirred for 2 hours. hours. After stirring, the reaction mixture was poured into water (50 ml) to stop the reaction and exfoliated with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulphonium. After filtration, the filtrate was evaporated in vacuo, and the unpurified product of the thus-obtained title compound was purified by chromatography on a column of silica gel using a solvent mixture of ethalic acid and hexane (3: 7). as the eluent to obtain the title compound (5.0 g) with! A yield of 82% as a colorless oily prodigal. ! Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 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, 1 H) , 2.69-2.77 (m, 1H), 4.66-4.72 (m, 1 H), 6.97 (s, 1H). IR spectrum (liquid film): 1182, 1435, 1453, 3330 cm "1. Mass spectrum (+) m / z: 232 (M +). (8b) [(2-Bromo-4,5,6,7-tetrahydro-1-benzothiophen-4-yl) oxy] (t-butyl) dimethylsilane I; To a solution of 2-bromo-4,5,6,7-tetrahydro-1-benzothiophen-4-ol (5.0 g, 21 mmol) which was obtained in Example 8 (8a) in N, N-dimethylformamide (30). ml) were added successively imidazole (2.9 g, 43 mmol) and t-butyldimethylchlorosilane (3.5 g, 24 mmol) with stirring, and the resulting mixture was stirred for 2 hours. After stirring, the reaction mixture was poured into water (50 ml) to stop the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated iri vacuo, and the unpurified product of the title compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 9). as the extender to obtain the title compound (6.8 g) with a yield of 91% as a colorless oily product. '1HRMN spectrum (400 MHz), CDCl 3) d ppm: 0.12 (s, 3H), 0.14 (s, 3H), 0.92 (, s, 9H), 1.66-1.81 (m, 2H), 1.88-2.06 (m, 2H), 2.59 (dt, 1 H, J = 5.5 Hz, 16.4 Hz), 2.68 (dt, 1 H, J = 5.5 Hz, 16.4 Hz), 4.68 (t, 1 H, J = 5.5 Hz), 6.84 (s, 1 H). IR spectrum (liquid film): 1101, 1255, 2858, 2930 cm "1. Mass spectrum (+) m / z: 346 (M +). (8c) 4- (ft-Butyl (dimethyl) sililloxy) -4.5.6.7-tetrahydro-1-benzothiophen-2-carboxaldehyde To a solution of [(2-bromo-4,5,6,7-leihydro-1- benzoyiophen-4-yl) oxy] (γ-bulyl) dimethyl silane (5.6 g, 16 mmol) which was obtained in Example 8 (8b) in lelyxahydrofuran (30 ml) was added leniamenie gola to gola n-butyllithium (a solution 1.6 M in hexane, 11 ml, 18 mmol) at -78X with stirring, and the resulting mixture was stirred for 5 minutes. Subsequently, to the resulting mixture was added N, N-dimethylformamide (2.5 ml, 32 mmol) at the same temperature with stirring, and the resulting mixture was stirred for 30 minutes. After shaking, a saturated aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture to stop the reaction, and the resulting mixture was poured into water (50 ml) and extracted with ether. The extra was washed with a saline aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the unpurified prod- uct of the title compound thus obtained was purified by chromatography on a silica gel column using a mixture of eluate and hexane aceolvent (1: 9). ) as the eluent to obtain the title compound (4.4 g) with a yield of 92% as a colorless oily product. : 1H NMR spectrum (500 MHz, CDCI3) d ppm: 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, 1 H, J = 5.4 Hz, 16.5 Hz), 2.87 (dt, 1 H, J = 5.4 Hz, 16.5 Hz), 4.77 (t, 1 H, J = 5.4 Hz), 7.58 (s) , 1 H), 9.82 (s, 1 hi). IR specimen (liquid film): 1240, 1255, 1462, 1673 cm "1. Mass spec (+) m / z: 296 (M +). (8d) 4-. { rí-Buíil (dimeíil) silinoxi) -4,5,6,7-íéírahidro-1-benzoiiofen-2-carboniírilo The unpurified production of the compound of the tííulo sinieíizó to conduct the reaction similar to that mentioned in example 1 (1 c) using 4. { [α-buíyl (dimethyl) silyl] oxy} 4,5,5,7,7-Hydro-1-benzophenone-2-carboxaldehyde (4.4 g, 15.3 mmol) which was obtained in Example 8 (8c), Hydroxylamine hydrochloride (1.1 g, 16 mmol), triethylamine ( 4.1 ml, 30 mmol), and N, N'-dicyclohexylcarbodiimide (3.4 g, 16 mmol). Subsequently, the unpurified product of the title compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 9) as the fluent to obtain the title compound (4.1 g) with a yield of 94% as a colorless oily product. 1 Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 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, 1 H). 'IR spectrum (liquid film): 1103, 1256, 1460, 2215 cm "1.' Mass spectrum (FAB +) m / z: 294 ((M + H) +), 332 ((M + K) +). (8e) 4-. { [I-Builyl (dimeiyl) -silyloxy-n'-hydroxy-4,5,6,7-eryhydro-1-benzothioferi-2-carboximidamide The unpurified production of the compound of the compound was reduced by conducting the reaction similar to that mentioned in example 1 (1d) using 4. { [i-bulyl (dimethyl) silyl] oxy} 4,5,6,7-iorahydro-1-benzoyiophen-2-carbonylriloj (4.1 g, 13.9 mmol) which was obtained in Example 8 (8d) and a 40% hydroxylamine solution (2.0 mL). Subsequently, the production by purification of the thus obtained compound was purified by chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (3: 7) as the eluent to obtain the compound of the title compound. tíulo (3.9 g) with a yield of 96% as a crjislalino solid of white color.

Specimen 1HRMN (500 MHz, CDCl 3) d ppm: 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 (di, 1 H, J = 16.5 Hz, 5.5 Hz), 2.76 (di, 1 H, J = 16.5 Hz, 5.5 Hz), 4.73 (t, 1 H, J = 5.5 Hz), 4.78 (brs, 2H ), 7.06 (s, 1 H), 7.31 (brs, 1 H). IR spectrum (KBr): 1255, 1361, 1584, 1648, 3295, 3370, 3462 cm "1. Mass spectrum (FAB +) m / z: 327 ((M + H) +). , (8f) 2- [5- (4-lsobutylphenyl) -1,4,4-oxadiazol-3-n-4,5,6,7-tetrahydro-1-benzothiophene-4-ol: The unpurified product of the compound of The title was synthesized by conducting the reaction similar to that mentioned in example 2 (2c) using ¡4-. { [t-buyl (dimethyl] silyl] oxy} -N'-hydroxy-4,5,6,7-telrahydro-1-benzoliofen-2-carboxyrridamide (0.15 g, 0.50 mmol) which was obtained in example 8 (8e), 4-isqbuylbenzoic acid (89 mg, 0.50) mmoles), N, N'-dicyclohexylcarbodiimide (0.11 g, 0.55 mmoles), and a 1.0 M solution of iso-arabylammonium fluoride (0.75 ml, 0.75 mmol). Subsequently, the unpurified production of the compound! The thus obtained thiuli was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 1) as the eluent to obtain the title compound (92 mg) with a yield of 52%. as a colorless oily product. Specimen 1 HNRM (400 MHz, CDCl 3) d ppm: 0.93 (d, 6H, J = 6.6 Hz), 1.84-11.97 (m, 2H), 1.97-2.11 (m, 2H), 2.56 (d, 2H, J = 7.4 Hz), 2.78 (di, 1 H, J = 16.0 Hz, 4.7 Hz), 2.90 (dt, 1 H, 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, 1 H), 8.08 (d, 2H, J = 7.8 Hz). IR spectrum (liquid film): 1363, 1519, 1559, 1584, 1614, 3385 cm "1.1 Mass spectrum (FAB +) m / z: 355 ((M + H) +). (8q) 1-. { 2- [5- (4-Isobutylphenyl) -1,4, 2,4-oxadiazol-3-ill-4,5,6,7-teirahydro-1-benzothien-4-yl) -zezeidin-3-carboxylic acid eyryl The unpurified product of The compound of the title was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) by using 2- [5- (4-isobutylphenyl) -1,4, 2,4-oxadiazol-3-yl] -4.5, 6,7-iorahydro-1-benzoliofem-4-ol (92 mg, 0.26 mmol) which was obluvored in example 8 (8f), carbon iodide (0.10 g, 0.31 mmol), ureapiphenylphosphine (81 mg, 0.31 mmol) 3-azetidinecarboxylamine hydrochloride of eryl (65 mg, 0.39 mmol), and N, N-di-propylpilelallamine (0.14 ml, 0.78 mmol). Subsequently, the unpurified product of the title compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 1 to 2: 1) as the eluent to obtain the compound of the tíulo (44 mg) with a yield of 36% like a colorless oily product.; Spectrum 1HRMN (500 MHz, CDCI3) d ppm: 0.93 (d, 6H, J = 6.8 Hz), 1.29?, 3H, J = 7.3 Hz), 1.70 (dt, 1 H, J = 11.2 Hz, 4.4 Hz), 1.75-1.83 (m, 3H), 1.93 (sepie, 1 H, J = 6.8 Hz), 2.04-2.13 (m, 1 H), 2.56 (d, 2H, J = 7.3 Hz), 2.75-2.82 (m , 1 H), 2.91 (dt, 1 H, J = 12.7 Hz, 4.5 Hz), 3.30 (quintet, 1 H, J = 7.8 Hz), 3.37 (f, 1 H, 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, 2H, J = 8.3 Hz), 7.65 (s, 1 H), 8.09 (d, 2H, J = 8.3 Hz). IR specifier (thin film): 1186, 1332, 1363, 1450, 1517, 1560 cm "Mass Spec (FAB +) m / z: 466 ((M + H) +). (8h) 1 - (2- [5- (4-Isobuylphenyl) -1,2,4-oxadiazol-3-N-4,5,6,7-tetrahydro-1-benzothien-4-yl) azetidine-3-carboxylic acid The title compound (26 mg) was synthesized with a yield of 64% as a white crystalline solid when conducting the reaction similar to that mentioned in example 2 (2e) using 1-. { 2- [5- (4-isobuylphenyl) -1, 2,4-oxadiazol-3-yl] -4,5,6,7-iorahydro-1-benzothien-4-yl} acetyl-3-carboxylaryl ether (44 mg, 0.094 mmol) which was obtained in Example 8 (8g), hydroxide of monohydric acid (8.7 mg, 0.20 mmol), and acetic acid (11 μl, 0.20 mmol). i Specimen 1HRMN (500 MHz, CD3OD) d ppm: 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, 1 H, J = 17.5 Hz, 7.3 Hz), 3.01 (dt, 1 H, J = 17.5 Hz, 5.4 Hz), 3.37 (quintet, 1 H, J = 7.8 Hz), 4.16-4.24 (m, 2H), 4.31 (t, 1 H, J = 9.3 Hz), 4.35-4.45 (m, 2H), 7.41 (d, 2H, J = 8.3 Hz), 7.86 (s, 1 H), 8.09 (d, 2H, J = 8.3 Hz).

IR spec (thin film): 1517, 1559, 1613, 1714, 3428 cm Mass spectra (FAB +) m / z: 438 ((M + H) +).

EXAMPLE 9 Acid 1 - ( { 4- [3- (4-lsobutylphenyl) isoxazo! -5- n-2-thienyl} metii) azetidfi [p) ii-3 »I carboxylic acid (9a) 4-f (Trimethylsilyl) ethynyl] thiophen-2-carboxaldehyde To a solution of 4-bromo-2-thiophenecarboxaldehyde (3.0 g, 16 mmoles) in N, N-dimethylformamide (30 ml) were added successively (trimethylsilyl) acetylene (11 ml, 79 mmol), triethylamine (13 ml, 94 mmol), and dichlorobis (t'-phenylphenylphosphine) palladium (1.1 g, 1.6 mmole) under a nihinogen aosphere with stirring, and the resulting mixture was stirred at 80X for 2 hours under a nitrogen atmosphere. After stirring, the reaction mixture was diluted with ethyl acetate, poured into a saline aqueous solution of Ammonium chloride (250 ml) and extracted with ethyl acetate. The extract is washed with upa saturated aqueous solution of sodium chloride and dried over magnesium sulphate. After filtration, the filtrate was evaporated in vacuo, and the unpurified product of the compound of the title thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (0: 1 to 1: 19) as the eluent to obtain the title compound (3.3 g) with a yield of 100% compose an oily brown product.

Spectrum 1HRMN (500 MHz, CDCI3) d ppm: 0.25 (s, 9H), 7.77 (s, 1 H), 7 81 (s, 1 H), 9.88 (s, 1 H).

IR spectrum (liquid film): 665, 761, 847, 966, 1182, 1230, 1250, 1434¡, 1684, 2163, 2823, 2899, 2960, 3097 cm "1. 1 Mass spectrum (+) m / z: 208 (M +). i (9b) 4-Ethyl-phenyl-2-carboxaldehyde To a solution of 4 - [(l-rimethylsilyl) ein-l] lyofen-2-carboxaldehyde (3.3 g, 16 rnols) which was obtained in Example 9 (9a) in melanol (160 ml) was I added potassium carbonate (4.3 g, 31 mmol) with stirring, and the mixture It turned out to be stirred at ambient temperature for 1 hour. After agilar, the materials ! insolubles were removed by filtration, and the filtrate was evaporated inj vacuo. The residue thus obtained was diluted with ethyl acephele, poured into water (100 ml) and extracted with ethyl acetate. The extra was washed with a saturated aqueous solution of sodium chloride and dried over sulphate of magnesium. After filtering, the filtrate was evaporated in vacuo, and the Unpurified product of the compound thus obtained was purified by chromatography on a column of silica gel using a mixture of ethyl acetate and hexane solvents (0: 1 to 1 19) as the eluent to obtain the title compound (1.5 g) with a yield of 69% combined a brown solid. 1 H NMR spectrum (400 MHz, CDCl 3) d ppm: 3.10 (s, 1 H), 7.79 (s, 1 H), 7.86 (s, 1 H), 9.90 (s, 1 H). 'IR Spectrum (KBr): 616, 661, 726, 800, 858, 1124, 1190, 1231, 1364, 1432, 1673, 3098, 3426 cm "1. Mass spec (+) m / z: 136 (M +). '(9c) (4-Elinyl-2-thienyl) methanol To a solution of 4-ethynylthiophen-2-carboxaldehyde (1.5 g, 11 mmol) which was obtained in Example 9 (9b) in methanol (30 ml) was add sodium borohydride (0.49 g, 13 mmol) at 0X with stirring, and then the resulting mixture was stirred at room temperature for 15 min. After cooling the reaction mixture to 0X, water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the unpurified product of the thus obtained title compound was purified by (chromatography on a column of silica gel using a mixture of ethyl acetate and hexane solvents (1: 9 to 3: 7) as the eluent to obtain the title compound (0.88 g) with a yield of 60% as an oily brown oily prodrug.

Spectrum 1HRMN (400 MHz, CDCl 3) d ppm: 1.82 (1, 1 H, J = 6.1 Hz), 3.01 (s, 1 H), 4.75 (d, 1 H, J = 6.1 Hz), 4.79 (d, 1 H, J = 6.1 Hz), 7.04 (d, 1H, J = 1.0 Hz), 7.46 (d, 1 H, J = 1.0 Hz) IR specimen (liquid film): 609, 660, 761, 846, 1012, 1116 , 1165, 1185, 1356, 1370, 2111, 2875, 2932, 3107, 3289 cm "1. Mass spectrum (+) m / z: 138 (M +). (9d) t-Butyl [(4-ethynyl-2-thienyl) methoxy-1-dimethylsilane To a solution of (4-ethynyl-2-ynyl) -melanol (0.88 g, 6.4 mmol) obtained in the example 9 (9c) in dichloromelane (20 ml) was successively added triethylamine (1.3 ml, 9.6 mmol), t-buildyl-methylchlorosilane (1.2 g, 7.6 mmol), and 4-dimethylaminopyridine (78 mg, 0.64 mmol) with stirring, and the ijesuliense mixture was stirred at ambient temperature for 1 hour. After souring, water (50 ml) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixture of ethyl acetate and hexane (0 1) at 1: 9) as the eluent to obtain the title compound (1.5 g) with a yield of 94% as an oily brown product.

Specimen 1HRMN (400 MHz, CDCI3) d ppm: 0.10 (s, 6H), 0.92 (s, 9H), 2.98 (s, 1 H), 4.80 (s, 2H), 6.91 (d, 1 H, J = 1.2 Hz), 7.38 (d, 1 H, J = 1.2 Hz).

IR specimen (liquid film): 778, 838, 1080, 1122, 1171, 1257, 1374, 1464, 1472, 2858, 2930, 2956, 3313 cm "1.

Mass Spec (+) m / z: 252 (M +). (9e) 4-lsobuylbenzaldehyde oxime To a solution of 4-isobuylbenzaldehyde (5.0 g, 31 mmol) in a mixture of etholol disolvenids (25 ml) and pyridine (25 ml) was added hydrochloride! of hydroxylamine (2.4 g, 34 mmol) with stirring, and the mixture was stirred at ambient temperature for 18 hours. After The reaction mixture was evaporated in vacuo. The residue thus obtained was diluted with ether, poured into water (150 ml) and extracted with ether. The extract was washed successively with 1 N hydrochloric acid and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After the filtration, The filtrate was evaporated in vacuo, and the crude product of the The thus obtained tíulo was purified by chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (1: 19 to 1: 9) as the eluent to obtain the title compound (4.6 g) with a yield of 84% as a colorless oily product.

; Spectrum 1HRMN (500 MHz, CDCI3) d ppm: 0.90 (d, 6H, J = 6.8 Hz), 1.87 (m, 1 H), 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 , 1 H), 8.12 (s, 1 H).

IR specimen (liquid film): 534, 790, 845, 962, 1296, 1466, 1517, 1611, 2869, 2925, 2957, 3308 cm "1. Mass spec (+) m / z: 177 (M +). (9f) n-Hydroxy-4-isobuylbenzenecarboximidoyl chloride To a solution of 4-isobuylbenzaldehyde oxime (1.0 g, 5.6 mmol) which was cross-reacted in Example 9 (9e) in N, N-dimethylylformamide (10 ml) was added N-chlorosuccinimide (0.15 g, 1.1 mmol) with stirring, and further, a small amount of gaseous hydrochloric acid was bubbled into the resulting mixture under stirring, and then the resulting mixture was stirred at room temperature for 10 minutes. After repeating the series of the same procedures previously described five times in total, the reaction mixture was poured into ice water (100 ml) and extracted with ether. The extract was washed successively with water and a saturated aqueous solution of chloride, sodium and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo to obtain the title compound (1.2 g) with a yield of 100% as a yellow oily product. \ Spectrum 1HRMN (500 MHz, CDCI3) d ppm: 0.91 (d, 6H, J = 6.8 Hz), 1.88 (m, 1 H), 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, 1 H). IR spectrum (liquid film): 795, 850, 937, 994, 1185, 1249, 1413, 1466, 1609, 2957, 3380 cm "1.

Mass Spec (Ef) m / z: 211 (M +). (9q) (4- [3- (4-lsobuyl-phenyl) -isoxazol-5-yl-1-2-ynyl) melanol To a solution of N-hydroxy-4-isobuylbenzenecarboximidoyl chloride (0.50 g), 2.4 mmoles) which was obluvo in example 9¡ (9f) and t-buíil [(4-eíin¡l-2-íienil) meióxi] dimetllsilano (0.72 g, 2.8 mmoles) that was worked out in the example 9 (9d) in elilocephalus (10 ml) triethylamine (0.40 ml, 2.8 mmol) was added at 0X with stirring, and the resultant mixture was stirred at ambient lemperairy for 18 hours. After agilling, the reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue thus obtained in hydrohydrofuran (15 ml) was added urea-builaylmonium fluoride (a 1.0 M solution in ureahydrofuran, 2.8 ml, 2.8 mmol) at 0X with stirring, and the resulting mixture was stirred at ambient temperature for 1 hour. After agilling, the reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated) in vacuo. Subsequently, a solvent mixture of ethyl acetate and hexane (1: 3) was added to the residue with stirring, and the precipitated solid was collected by filtration using a Kiriyama funnel and washed with the same solvent to obtain the compound of the title (0.44jg) with a yield of 59% as a white crystalline solid. ¡: Spectrum 1HRMN (500 MHz, CDCI3) d ppm: 0.93 (d, 6H, J = 6.3 Hz), 1.91 (, 1 H), 1.98 (brs, 1 H), 2.53 (d, 2H, J = 6.8 Hz ), 4.89 (s, 2H), 6.64 (s, 1 H), 7.25 (d, 2H, J = 8.3 Hz), 7.35 (s, 1 H), 7.73-7.77 (m, 3H). IR spectrum (KBr): 774, 794, 847, 1018, 1380, 1440, 1467, 1615, 2869, 2926J, 2953, 3344 cm "1. Mass spectrum (Ef) m / z: 313 (M +). (9h) 1 - ((4-f3- (4-isobutylphenyl) isoxazol-5-yn-2-ynyl) methyl) azeididine-3-carboxylic acid ethyl ester A solution of. { 4- [3- (4-isobutylphenyl) isoxazol-5-yl] -2-aminoethyl-eneol (0.43 g, 1.4 mmol) which was prepared in Example 9 (9 g), carbon felbromide (0.68 g, 2.1 mmol) and triphenylphosphine (0.54 g, 2.1 mmol) in dichloromethane (15 mL) was stirred at 0X for 5 minutes.

Subsequently, 3-azetidinecarboxylamide hydrochloride (0.34 mg, 2.1 mmol) and N, N-diisopropylethylamine (0.60 ml, 3.4 mmol) were successively added to the reaction mixture in succession with agitation, and the resulting mixture was added to the reaction mixture. stirred at room temperature for 18 hours. After stirring, a saturated aqueous solution of sodium acid carbonate (5 ml) was added to the reaction mixture to stop the reaction, and the resulting mixture was poured into water (50 ml) and exfoliated with dichloromelan. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate.

I After filtration, the filtrate was evaporated in vacuo, and the product without purifying the title compound thus purified was purified in vacuo. chromatography on a column of silica gel using a mixture of solvent solvents of hexane and ethyl (1: 4 to 3: 2) as the eluent for obtain the compound of the íílulo (0.48 g) with a yield of 82% as a Solid crystal I linen white.

I Spectrum 1HRMN (500 MHz, CDCI3) d ppm: 0.93 (d, 6H, J = 6.7 Hz), 1.27 (t, 3H, J = 7.0 Hz), 1.90 (m, 1 H), 2.52 (d, 2H, J = 7.0 Hz), 3.32-3.38 (m, I 3H), 3.56-3.64 (m, 2H), 3.81 (s, 2H), 4.16 (q, 2H, J = 7.0 Hz), 6.60 (s, 1 H), 7.21- I 7.26 (m, 3), 7.68 (s, 1 H), 7.72 (d, 2H, J = 8.2 Hz). IR Spectrum (KBr): 797, 1193, 1369, 1436, 1607, 1731, 2955, 3115 cm "1., , Mass Spec (FAB +) m / z: 425 ((M + H) +). ; (9i) Acid 1 - ((4-y3- (4-lsobuiylphenyl) isoxazo.-5-yl-2-thienyl) mephyl) zephidine-3-carboxylic acid | To a solution of ethyl 1- (. {4- [3- (4-isobuyl-phenyl) -isoxazol-5-yl] -2-lienyl} -methyl) -zelide-3-carboxylamino (0.47 g, 1.1 mmol) what was obtained in Example 9 (9h) in 1,4-dioxane (15 ml) was added a 1 N aqueous solution of sodium hydroxide (3.3 ml, 3.3 mmol) at 0X with stirring, and then the The highlight mix was stirred at ambient temperature for 30 minutes. After of adding rnetanoleol (15 ml) and water (5 ml) to the reaction mixture, the mixture The mixture was heated under stirring until the precipitated white solid dissolved, and then acetic acid (0.19 ml, 3.3 mmol) was added. The precipitated white solid was collected by filtration using a funnel! Kiriyama was washed with methanol and dried in vacuo to obtain the title compound (0.35 g) with a yield of 78% as a white crystalline solid. i 1H NMR spectrum (500 MHz, CD3CO2D) d ppm: 0.93 (d, 6H, J = 6.6 Hz), 1.92 (m, 1 H), 2.54 (d, 2H, J = 7.3 Hz), 3.77-3.87 (m , 1 H), 4.35-4.60 (m, 4H), 4.73 (s, 2H), 6.98 (s, 1 H), 7.30 (d, 2H, J = 8.2 Hz), 7.77 (d, 1 H, J = 1.4 Hz), 7.82 (d, 2H, J = 8.2 Hz), 8.06 (d, 1 H, 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 1/2 1H-oxalate (4-ethyl-5-f4- (2-fluorophenoxy-) phenin-1,2, -oxadiazol-3-yl> -2-thienyl) methylazetidine-3-carboxylic acid (10a) t-Bufyl (4-ethyl-2-ynyl) -meioxy-1-dimethylsilane 1 To a solution of [(4-bromo-2-thienyl) -methioxy] (1-bujyl) dimethylsilane (0.61 g, 2.Q mmoles) and [1, 3-bis (diphenylphosphino) propane] dichloronickel (54 mg, 0.1 mmol) in ether (5 ml) was added slowly with a 1.0 M solution of ethylmagnesium bromide in tetrahydrofuran (3.0 ml, 3.0 mmol) at OX with stirring, and after raising the reaction time to room temperature, the resulting mixture was stirred for 1 hour. After stirring, a saturated aqueous solution of ammonium chloride (5 ml) was added to the mixture.

I reacted to stop the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the unpurified prod- uct of the title compound thus obtained was purified by chromatography on a column of silica gel using a mixture of ethylene glycol and IJiexane (0:10 at 5:95) as the eluent to obtain the title compound (0.44 g) with a yield of 95% as a pale yellow oily product. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.10 (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, 1 H), 6.81 (s, 1H). IR specimen (liquid film): 1077, 1131, 1174, 1255, 1463, 1471 cm "1. Mass spec (FAB +) m / z: 255 ((M-H) +). (10b) 5 - ((ít-Buiyl (dimethyl) silyloxi) meiyl) -3-eylylofen-2-carboxaldehyde To a solution of ε-buíyl [(4-eyl-2-lienyl) meioxy] dimethylsilane (1.3 g, 5. 6 mmole) which was obtained in Example 10 (10a) in leihydrofuran (10 ml) a 1.6 M solution of n-butyllithium in hexane (4.2 ml, 6. 7 mmole) at -78X with stirring, and after raising the reaction temperature to OX, the resulting mixture was stirred for 30 minutes.

Subsequently, the reaction temperature was lowered to -78X again under I stirring, and N, N-dimethylformamide (0.86) was added to the reaction mixture. ml, 11 mmol) with stirring, and the resulting mixture was stirred for 30 min.

After stirring, a saline aqueous solution of sodium chloride was added.

Ammonium (5 ml) to the reaction mixture to stop the reaction, and the mixture The mixture was poured into water (20 ml) and extracted with ether. The extract was washed i with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the unpurified product of the title compound thus obtained was purified mediating < j.romafog raffia on a column of silica gel using a mixture of acetone solvents of ethyl and hexane (0:10 to 5:95) as the eluent to obtain the title compound (1.3 g) with a yield of 86% as an oily pale yellow product. j 1HRMN spectrum (400 MHz, CDCI3) d ppm: 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, 1 H), and 9.99 (s, 1 H) .

IR specimen (liquid film): 1092, 1156, 1225, 1256, 1461, 1659 cm "Mass spectrum (Ef) m / z: 285 (M +). (10c) 5 - (([t-Buyyl (d -methyl) silyloxid) meilyl) -3-eylylofen-2-carbonitrile To a suspension of 5- ( { [T-buiyl (dimethyl)) silyl] oxymethyl) -3-yl-phenyl-2-carboxaldehyde (1.3 g, 4.8 mmol) which was obtained in example 10 (10b) and hydroxylamine hydrochloride (0.37 g, 5.3 mmol) in dichloromethane (20 g). ml) was added successively methanol (2 ml) and trieylamine (1.3 ml, 9.6 mmol) with agitation, and the resulting mixture was stirred at room temperature for 2 hours. After removing the solvent in vacuo, toluene (10 ml) was added to residue 1 and the resulting mixture was azeotropically evaporated in vacuo.

Subsequently, the residue obtained and N, N'-dicyclohexylcarbodimid (1.1 g, 5. 3 mmol) were suspended in toluene (20 ml) and stirred at 90X for 15 hours. After cooling to room temperature, hexane (20 ml) was added to the reaction mixture, and the resulting mixture was filtered with Celiie. The filtrate was evaporated in vacuo, and the unpurified production of the thus obtained compound was purified by means of chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (0:10 to 5:95). as the eluent to obtain the title compound (0.94 g) with a yield of 69% as an oily pale yellow product. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 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, 1 H).

IR specimen (liquid film): 1093, 1149, 1256, 2212 cm "1. Mass spec (Ef) m / z: 282 (M +). (10d) 5- ( { [T-Butyl (dimethyl) silyl-oxy) -methyl) -3-eyl-n'-hydroxiiiofen-2-carboximid-1-amide The unpurified product of the title compound was synchronized when the reaction was conducted similar to that mentioned in Example 1 (1d) using 5- ( { [t-bulyl (dimethyl) silyl] oxy} -methyl) -3-ethylthiophen-2-carbonylyl (0.93 g, 3.3 mmol) obtained in Example 10 (10c) and a 40% aqueous solution of hydroxyamine (0.5 mL)). Subsequently, the unpurified product of the thioule compound thus obtained was purified by recrystallization from hexane (6: 4) to obtain the title compound (0.60 g) in 60% yield as a white crislallic solid. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.11 (s, 6H), 0.93 (s, 9H), 1.20 (l, 3H, J = 7.8 Hz), 2.76 (q, 2H, J = 7.8 Hz), 4.80 (s, 4H), 6.76 (s, 1 H), 7.10 (br, 1 H). IR spectrum (KBr): 1059, 1590, 1643, 3284, 3357, 3491 cm "1. Mass spectrum (Ef) m / z: 315 (M +). (10e) 4- (2-Fluorophenoxy) benzoic acid To a solution of 4-fluorobenzaldehyde (1.2 g, 10 mmol) and 2-fluorophenol (1.3 g, 12 mmol) in N, N-dimethylformamide (10 mL) was added carbonate of potassium (2.8 g, 20 mmol) with stirring, and the resulting mixture was stirred at 100 C for 16 hours. After cooling to ambient temperature, the reaction mixture was poured into water (20 ml) and exlushed with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over niagnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained in a mixture of 1-hydrofuran (5 ml), 1-butanol (10 ml), and water (5 ml) were successively added 2-methyl-2-buiene (5.3 ml, 50 mmol). ), diazodium phosphate of poasium (3.4 g, 25 mmol), and sodium hypochloride (2.7 g, 30 mmol) with stirring, and the mixture was stirred at ambient temperature for 2 hours. After stirring, the reaction mixture was poured in water (20 I ml) and exírajo with éler. Subsequently, a 1 M aqueous solution of sodium hydroxide (20 ml) was added to the aqueous l, and the resulting aqueous l was acidified with a 10 M aqueous solution of hydrochloric acid (2 ml) and extracted again with ether. . The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulphonium.

After filtration, the filtrate was evaporated in vacuo to obtain the title compound (2.0 g) in 87% yield as a white crystalline solid. ! Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 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 (Ef) m / z: 232 (M +). (1 Of) (4-Eiyl-5- (5- [4- (2-fluorophenoxy) phenyl-1, 2,4-oxadiazol-3-yl) -2-fieni -mephanol To a solution of 5- ( { [ ε-buylyl (dimethylsilyl) oxy) oxymethyl) -3-eyl-N'-hydroxyiiophen-2-carboximidamide (0.16 g, 0.50 mmol) which was obtained in example 10 (10d) and acid 4- (2 -fluorophenoxy) benzoic acid (0.13 g, 0.55 mmol) which was obtained in example 10 (10e) in dichloromean (1.5 ml) was added N, N'- i dicyclohexylcarbodiimide (0.11 g, 0.55 mmole) with agitation, and the resulting mixture was stirred at room temperature for 30 min. After agilling, hexane (2 ml) was added to the reaction mixture, and the insoluble materials were removed by filtration, and the obtained filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained in terahydrofuran (1 ml) was added a 1.0 M solution of ioarabuylomonium fluoride in ureahydrofuran (0.75 ml, 0.75 mmole) with stirring, and the mixture was stirred at 60X for 1 hour. After cooling to room temperature, the reaction mixture was poured into water (10 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the thus-obtained compound was purified by chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (3: 7 a). 5: 5) as the eluyenle to obíener the compound of the title (0.18 g) with a yield of 89% as a white crystalline solid.

Specimen 1HRMN (400 MHz, CDCI3) d ppm: 1.29 (l, 3H, J = 7.8 Hz), 3.05 jq, 2H, J = 7.8 Hz), 4 83 (s, 2H), 6.98 (s, 1 H), 7.07 (d, 2H, J = 8.6 Hz), 7.17-7.25 jm, 4H), 8.15 (d, 2H, J = 8.6 Hz). IR specimen (KBr): 1270, 1353, 1497, 1602, 3340 cm "1. Mass spectrum (FAB +) m / z: 397 ((M + H) +). (10g) 1-r (4-etl-5- (5-f4- (2-fluorophenoxy) phenin-1,2,4-oxadiazol-3-yl) -2-ynyl) -methyl] azeidin-3-carboxylane The unpurified production of the compound of the compound was synthesized by conducting the reaction similar to that mentioned in example 1 (1f) using (4-ethyl-5-. {5- [4- (2-fluorophenoxy) phenyl] -1, 2,4-oxadiazol-3-yl.} -2-yenyl) metal (0.17 g, 0.43 mmol) which was obtained in Example 10 (10f), carbon leirabromium (0.17 g, 0.51 mmol) ), triphenylphosphine (0.13 g, 0.51 mmol), 3-azetidinecarboxylamine hydrochloride (0.10 g, 0.65 mmol), i N, N-diisopropylethylamine (0.23 mL, 1.3 mmol). Subsequently, the product to be purified from the title compound thus obtained was purified by chromatography using a solvent mixture of ethyl acetate and hexane (5: 5) to obtain the title compound (0.19 g) with a I 90% yield as a white crystalline solid. , Spectrum 1HRMN (500 MHz, CDCI3) d ppm: 1.28 (t, 3H, J = 7.8 Hz), 3.03 (< j ?, 2H, J = 7.8 Hz), 3.32-3.40 (m, 4H), 3.60-3.66 (m, 1 H), 3.72 (s, 3H), 3.79 (s, 2H) , 6.86 (s, 1 H), 7.07 (d, 2H, J = 8.8 Hz), 7.17-7.25 (m, 4H), 8.13 (d, 2H, J = 8.8 Hiz).

IR specimen (liquid film): 1497, 1514, 1557, 1604, 1737 cm Mass spectrum (FAB +) m / z: 494 ((M + H) +). (10h) 1/2 1 - [(4-eyl-5- (5- [4- (2-fluorophenoxy) phenyl-1, 2,4-oxadtazol-3-yl) -2-thienyl) -methyl-1-azidine acid oxalate -3-carboxylic acid The compound of the tíulo (77 mg) was siníelizó with a yield of 39% like a crystalline white solid when conducting the reaction similar to that mentioned in example 1 (1g) using 1 - [(4 -ethyl-5- { 5- [4- (2-fluoroferroxy) phenyl] -1,2,4-oxadiazol-3-yl.} -2-thienyl) methyl] azeidin-3-carboxylane meilyl (0.19 g, 0.38 mmol) which was obtained in example 10 (10 g), lithium hydroxide monohydrate (36 mg, 0.85 mmol), acetic acid (46 μL, 0. 85 mmol), and oxalic acid (17 mg, 0.19 mmol). Spectrum 1HRMN (400 MHz, CD3OD) d ppm: 1.26 (t, 3H, J = 7.4 Hz), 3.03 (q, 2H, J = 7.4 Hz), 3.22 (quinone, 1 H, J = 8.6 Hz), 3.37 ( i, 2H, J = 8.2 Hz), 3.62 (i, 2H, J = 7.0 Hz), 3.82 (s, 2H), 6.98 (s, 1 H), 7.12 (d, 2H, J = 9.0 Hz), and 7.25-7.33 (m, 4H ), 8.16 (d, 2H, J = 9.0 Hz). IR spec (KBr): 1420, 1497, 1601, 1659, 3413 cm'1. Mass Spec (FAB +) m / z: 480 ((M + H) +).

EXAMPLE 11 Acid 1 - ((5-r5- (3-Fluoro-4-phenoxyphenyl) -1, 2,4-oxadiazoi-3-n-4-m®W-2- thienyl) methyl) azetidine-3-carboxylic acid (11 a) t-Butyl (dimethyl) [(4-methyl-2-thienyl) methoxy] silane To a solution of 2-hydroxymethyl-4-methylthiophene (1.8 g, 14 mmoles) (reference literature: J. Heterocycl, Chem., vol 19, 1125 (1982)) and imidazole (1.9 g, 28 mmol) in N, N-dimethylformamide (20 ml) was added t-butyldimethylsilyl chloride (2.3 g, 15 mmol) with stirring, and the mixture The resulting mixture was stirred at room temperature for 2 hours. After agiir, the The reaction mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulphate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixture of ethyl acetate and hexane solvents (0:10 to 1: 19) as the eluent to obtain the title compound (2.5 g) with a yield of 74% as a colorless oily product.

Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.10 (s, 6H), 0.93 (s, 9H), 2.22 (s, 3H), 4.81 (s, 2H), 6.72 (s, 1 H), 6.78 (s, 1 H). IR spectrum (liquid film): 1077, 1130, 1256, 1464 cm'1.

Mass Spec (Ef) m / z: 242 ((M + H) +). (11 b) 5 - ((--Butyl (dimethyl) silyl] oxy) mephyl) -3-mephyliophene-2-carboxaldehyde The unpurified production of the title compound was synthesized by conducting the reaction similar to that mentioned in the example 10 (10b) Using 1-buylyl (dimethy) (4-meityl-2-yl) -methioxy] silane (2.5 g, 10 mmol) which was obtained in example 11 (11a), 1.6 M solution of n-butyllithium in hexane (7.8 mL, 12 mmol), and N, N-dimethylformamide (1.6 mL, 21 mmol). Subsequently, the unpurified product of the title compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (0:10 to 5:95) as the eluent to obtain the compound of the title (2.5 g) with a yield of 89% as an oily production of pale yellowish color. : Specimen 1HRMN (400 MHz, CDCI3) d ppm: 0.12 (s, 6H), 0.94 (s, 9H), 2.52 (s, 3H), 4.85 (s, 2H), 6.78 (s, 1 H), 9.98 (s, 1 H). IR spec (liquid film): 1092, 1363, 1393, 1472, 1661 cm1. Mass Spec (FAB +) m / z: 271 ((M + H) +). (11c) 5- ( { [L-Butyl (dimethyl) silyloxy) methyl) -3-methylthiophen-2-carbonitrile The crude product of the thioule compound was synthesized by conducting the reaction similar to that mentioned in Example 10 (10c) using 5- ( { [T-buyyl (dimethylsilyl) oxy] oxy} -methyl) -3-methyl-phenylene-2-carboxaldehyde (2.5) g, 9.2 mrjnoles) that was obtained in example 11 (11 b), hydrochloride hydroxylamine (0.71 g, 10 mmol), triethylamine (2.6 mL, 18 mmol), and N, N'- dicyclohexylcarbodiimide (2.1 g, 10 mmol). Subsequently, the product Without purification of the title compound thus obtained it was purified by means of chromatography on a column of silica gel using a mixture of ethyl acetate and hexane solvents (0:10 to 5:95) as the eluent for obtain the title compound (2.5 g) with a yield of 100% as a I oily product of pale yellowish color.

! Specimen 1HRMN (400 MHz, CDCI3) d ppm: 0.11 (s, 6H), 0.93 (s, 9H), 2.39 (s, 3H), 4.83 (s, 2H), 6.71 (s, 1 H).

IR spectrum (liquid film): 1093, 1150, 1258, 2120, 2214 cm "1.

Mass spectrum (FAB +) m / z: 268 ((M + H) +). : (11d) 5 - ((rt-Buyyl (dimethy) silinoxy> methyl) -n'-hydroxy-3-meilyliophen-2-carboximidjamide The unpurified product of the title compound was synthesized at lead reaction similar to that mentioned in example 1 (1d) using 5- ( { [t-butyl (dimethyl] silyl] oxy} methyl) -3-methyl-iiophen-2-carboniiryl (2.5 g, 9.2 mmol) which was obtained in example 11 (11c) and a 40% aqueous solution of hydroxylamine (20 mL). Subsequently, the unpurified product of the compound! of the title thus obtained was purified by chromatography on a column of silica gel using a mixture of acetone solvent and hexane (0:10 to 5:95) as the eluent to obtain the compound of the extract (1.4 g) with a yield of 52% as a white crystalline solid. '1H NMR Spectrum (400 MHz, CDCl 3) d ppm: 0.10 (s, 6H), 0.93 (s, 9H), 2.35 f, 3H), 4.79 (s, 4H), 6.68 (s, 1 H), 7.16 (br, 1 H). j IR Spec (KBr): 1255, 1651, 3277, 3353, 3455 cm "1.: Mass Spec (FAB) m / z: 301 ((M + H) +). (11e) 3-Fluoro-4-phenoxybenzoic acid The compound of the extract (1.1 g) was synthesized with a yield of 93% as a white crystalline solid when conducting a reaction similar to that mentioned in example 10 (10e). using 3,4-difluorobenzaldehyde (0.71 g, 5.0 mmol), phenol (0.56 g, 6.0 mmol), potassium carbonate (1.4 g, 10 mmol), 2-methyl-2-bulene (2.5 mL, 23 mmol), phosphate diacid of polasium (1.6 g, 12 mmol), and sodium hypochlorite (1.3 g, 14 rhmoles). Specimen 1 HNRM (400 MHz, CDCl 3) d ppm: 6.96 (1, 1 H, J = 8.2 Hz)), 7.04-7.07 (m, 2H), 7.19 (1, 1 H, 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, 1 H, J = 11.0 Hz, 2.0 Hz). IR specimen (KBr): 1025, 1275, 1444, 1492, 1692, 2596, 2673, 2983, 3065 cm "1. Mass spec (Ef) m / z: 232 (M +). (11f) { 5- [5- (3-Fluoro-4-phenoxyphenyl-1, 2,4-oxadiazol-3-yl) -4-methyl-2-tieniDmetariiol The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 10 (10f) using -5- ( { [t-bulyl (dimethylsilyl) silyl] oxy} -methyl) -N'-hydroxy-3-meilyliophen-2-carboximidamide (0.18 g), 0.60 mmole) which was obtained in example 11 (11d), 3-fluoro-4-phenoxybenzoic acid (0.15 g, 0.66 mmole) which was obtained in example 11 (11e), N, N'-dicyclohexylcarbodiimide (0.14 g) , 0.66 mmole), and 1.p M solution of phycoalkyl ammonium fluoride in hydrofuran (0.90 mL, 0.90 mmol s). Subsequently, the unpurified product of the title compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 1) as eluyeny to elute the title compound ( 0.21 g) with a yield of 93% as a white crystalline solid. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 2.60 (s, 3H), 4.84 (d, 2H, J = 5.9 Hz), 6.92 (s, 1 H), 7.06-7.11 (m, 3H), 7.22 (t, 1 H, J = 7.4 Hz), 7.42 (t, 2H, J = 6.6 tz), 7.91 (dd, 1 H, J = 1.2 Hz, 8.6 Hz), 8.01 (dd, 1 H, 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 q) 1 - ((5-f5- (3-fluoro-4-phenoxyphenyl) -1, 2,4-oxadiazol-3-1,1-methyl-2-fienyl) methyl) azephidine- 3-carboxylamino methyl I The unpurified production of the compound of the amino acid was synthesized at conduct the reaction similar to that mentioned in example 1 (1f) using it. { 5- [5- (3-fluoro-4-phenoxyphenyl] -1,4,4-oxadiazol-3-yl) -4-meityl-2-thienyljmetayiol (0.21 g, 0.55 mmol) which was worked up in example 11 ( 11f), I carbon dioxide (0.22 g, 0.66 mmole), triphenylphosphine (0.17 g, 0.66 g) I mmoles), 3-azetidinecarboxylazole hydrochloride of meilyl (0.13 g, 0.83 mmoles), i and N, N-diis-propylethylamine (0.30 mL, 1.7 mmoles). Subsequently, the Production without purification of the compound of the thus-purified product was purified by chromatography using a mixture of sodium acetate solvents.

I ethyl and hexane (5: 5) to obtain the title compound (0.23 g) with a 86% yield as a colorless oily product.

Spectrum 1HRMN (500 MHz, CDCI3) d ppm: 2.56 (s, 3H), 3.30- 3.39 (m, 3.58-3.64 (m, 1 H), 3.71 (s, 3H), 3.76 (s, 2H), 7.02- 7.08 (m, 3H), 7. 19 (t, 1 Hj J = 7.4 Hz), 7.38 (1, 2H, J = 7.4 Hz), 7.85-7.89 (m, 1 H), 7.97 (dd, 1 H, J = 2.0 Hz, 10.5 Hz).

IR specimen (liquid film): 1489, 1514, 1562, 1590, 1621, 1737 cm "1. ' , Mass Spec (FAB +) m / z: 480 ((M + H) +). (11h) 1- (. {5- [5- (3-Fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yn-4-methyl-2-tienyl) methyl) azetidine- acid 3-carboxylic acid The compound of the tíulo (0.17 g) sinieíizó with a yield of 74% as a white crystalline solid when driving the reaction similar to the one mentioned in Example 2 (2e) using 1- (. {5- [5- (3-fluoro-I 4-phenoxiferiyl) -1, 2,4-oxadiazol-3-yl] -4- Melyl-2-ynyl} -methyl) azeididine-3-carboxylic acid methyloyl (0.23 g, 0.48 mmol) which was obluvored in example 11 (11 g), I hydroxide dje lithium monohydrate (46 mg, 1.1 mmol), and acetic acid (60 μL, 1. 1 mmol). i 1H NMR spectrum (400 MHz, CD3OD) d ppm: 2.61 (s, 3H), 3.50- 3.62 (m, l lk), 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 (l, 2H, J = 7.8 Hz), 7.94 (d, 1H, J = 8.2 Hz), 8.02 (di, 1 H, J = 11.0 Hz).

IR Spec (KBr): 1272, 1340, 1507, 1515, 1561, 1591, 1619, 3404 cm "1; 1 Mass Spec (FAB +) m / z: 466 ((M + H) +).

EXAMPLE 12 1 - ((4-Methyl-5-r5- (4-phenoxyphenyl) -1,2,4-oxadiazl-3-in-2-thienyl) methyl) azetidine-3-carboxylic acid (12a) (4-Methyl-5-5 5 - (4-phenoxyphenyl) -1,4, 2,4-oxadiazol-3-ill-2-ieniDmearpol To a solution of 4-phenoxybenzoic acid (0.14 g, 0.63 mmole) in a mixture of acetyloiryl (4 ml) and tetrahydrofuran (2 ml) was successively added 1-hydroxybenzoyriazole (89 mg, 0.66 mmole), 1-elyll-3- (3-dinhelylaminopropyl) carbodiimide hydrochloride (0.13 g, 0.66 mmole) and 5- ( { [i-bulyl (dimethyl) silyl] oxy] -methyl) -N'-hydroxy-3-mellylliophen-2-carboxylamide (0.18 g, 0.60 mmol) which is worked in Example 11 (11d) with agitation, and the resulting mixture was stirred at 50X for 30 minutes.After stirring, water (5 mL) was added to the reaction mixture to stop the reaction, and the resulting mixture was exfoliated. The acetone was washed successively with 0.1N hydrochloric acid, a saline aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. he The filtrate was evaporated in vacuo Subsequently, to a solution of the residue obtained in telrahydrofuran (5 ml) was added a 1.0 M solution of ilarabulomammonium fluoride in the hydrofuran (1.2 ml, 1.2 mmol) with stirring, and the mixture resulted Stir at 50X for 2 hours. After stirring, the reaction mixture was poured in water (20 ml) to stop the reaction and evaporate with ether. The exile was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo, and the I unpurified product of the thioule compound thus obtained was purified I by chromatography on a column of silica gel using a Mixing the solvents of ethyl acetate and hexane (1: 3 to 1: 2) as the eluent to obtain the title compound (0.19 g) with a yield of 86% as a white crislallic solid.

Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.87 (bs, 1 H), 2.59 (s, 3H), 4.83 (s, 2H), 6.91 (s, 1 H), 7.09 (d, 2H, J = 8.8 Hz), 7.10 (d, 2H, J = 8.3 Hz), 7.22 (t, 1 H, J = 7.1 Hz), 7.42 (t, 2H, J = 7.8 Hz), 8.14 (d, 2H, J = 8.3 Hz). , Specter IR (KBr): 1249, 1341, 1489, 1514, 1588, 1612, 3279, 3393 cm "1! I Mass spectra (FAB +) m / z: 365 ((M + H) +). : (12b) 1 - ((4-meityl-5-f5- (4-phenoxyphenyl) -1,4,4-oxadiazol-3-yn-2-thieniDmethylVazefidina-S-carboxilaío of methyl The unpurified product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using j. { 4-meityl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-ynyl} meianol (0.19 g, 0.51 mmole) which was obtained in example 12 (12a), carbon tetrahydromide (j? 22 g, 0.66 mmole), pyridylphosphine (0.17 g, 0.66 mmole), [3-azeidincarboxylamine hydrochloride of meityl (0.12 g, 0.77 mmol), and N, N-diisopropylethylamine (0.27 mL, 1.5 mmol). Subsequently, the production Without purifying the compound of the element thus obtained, it was purified by means of chromatography on a column of silica gel using a mixture of solvents of ethyl acetate and hexane (2: 3) as the eluent to obtain the compound of the ileum (0.20 g) with a yield of 85% as an oily production of a pale yellowish odor.

Specimen 1 HNRM (400 MHz, CDCl 3) d ppm: 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, 1 H), 7.07-7.13 (m, 4lft), 7.22 (t, 1 H, 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) +). i (12c) 1-q4-Methyl-5-y5- (4-phenoxyphenyl) -1, 2,4-oxadiazol-3-yH-2-ynyl) meilyyl) lazeidin-3-carboxylic acid i The thioule compound ( 0.16 g) was synthesized with a yield of 85% as a white crystalline solid when driving the reaction similar to that mentioned in example 3 (3e) using 1- ( { 4-methyl-5- [5- (4-phenoxyphenyl) -1, 2,4-oxadiazol-3-yl] -2-thienyl} meilyl azetidine-3-carboxylic acid methylate (0.20 g, 0.42 mmol) which was obtained in Example 12 (12b) and a 1 N aqueous solution of sodium hydroxide (1.3 mL, 1.3 mmol). Spectrum 1HRMN (400 MHz, CD3CO2D) d ppm: 2.61 (s, 3H), 3.77-3.86 jm, 1 H), 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, 1 H), 7.26 (s, 1 H), 7.45 (t, 2H, J = 7.8 Hz), 8.18 (d, 2H, J = 9.0 Hz). IR spec (KBr): 1244, 1336, 1488, 1593, 1612, 3429 cm "1. Mass spec (FAB +) m / z: 448 ((M + H) +).

EXAMPLE 13 Acid 1 - ((4-ethyl-5-yl- (4-phenoxyphenyl) -1, 2,4-oxadiazo.-3-ill-2 thienyl) methyl) azetidine-3-carboxylic acid (13a) (4-Ethyl-5-f5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yn-2-thieniDmetariol The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 12 (12a) using 4-phenoxybenzoic acid (0.12 g, 0.53 mmole), 1-hydroxybenzotriazole I (74 mg, 0.55 mmol), 1-ethyl-3- (3-dimethylamino-opropyl) carbodiimide hydrochloride (0.11 g, 0.55 mmol), 5- ( { [T-buyl (dimethyl! Silyl)] oxymethyl) -3-ethyl-N'-hydroxy-phenyl-2-carboximidamide (0.16 g, 0. 50 mmoi) which was obtained in Example 10 (10d), and 1.0 M solution of terabubylammonium fluoride in hydrofuran (1.0 mL, 1.0 mmol). Subsequently, the unpurified production of the title compound thus obtained was purified by chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (1: 3) as the eluent to obtain the title compound. (0.17 g) with a yield of 89% as a pale yellowish crystalline solid. 1HRMN spectrum (400 MHz, CDCI3) d ppm: 1.29 (t, 3H, J = 7.4 Hz), 1.88 (t, 1 H, J = 5.9 Hz), 3.05 (q, 2H, J = 7.4 Hz), 4.83 (d, 2H, J = 5.9 Hz), 6.96 (s, 1 H), 7.04-7.10 (m, 4H), 7.20 (t, 1 H, J = 7.4 Hz), 7.39 (t, 2H, J = 7.4 Hz), 8.12 ( d, 2H, J = 9.0.0 Hz). IR spectrum (KBr): 1248, 1353, 1490, 1496, 1515, 1588, 1612, 3356 cm'1. , Mass spectrum (FAB +) m / z: 379 ((M + H) +). . (13b) 1 - ( { 4-Ethyl-5-yl- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-ill-2-ynyl) mephyl) Ezephidine-3-carboxylic acid of meylyl Unpurified production of the compound of the isolate was synthesized by conducting the reaction similar to that mentioned in example 1 (1f) using. { 4-ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-lienyl} meianol (0.17 g, 0.44 mrtiol) which was obtained in example 13 (13a), carbon terarabide ((j) .19 g, 0.57 mmole), triphenylphosphine (0.15 g, 0.57 mmole), hydrochloride; of meityl 3-azelidinecarboxylate (0.10 g, 0.66 mmol), and N, N-I dipropyl propiolamine (0.23 mL, 1.3 mmol). Subsequently, the unpurified product of the thus-obtained title compound was purified by chromatography on a column of silica gel using a mixture of acetone solvents of ethyl and hexane (1: 3 to 1: 2) as the eluent to obtain the compound of the title (0.19 g) with a yield of 89% as a pale yellow oily product. : 1H NMR spectrum (400 MHz, CDCI3) d ppm: 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, 2ljl), 6.84 (s, 1 H), 7.04-7.10 (m, 4H), 7.20 (í, 1 H, J = 7.4 Hz), 7.39 ( 1, 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-f5- (4-phenoxyphenyl) -1,4-oxadiazol-3-yn-2-ynyl) mephile acid-3-carboxylic acid The title compound (0.15 g) ) was synthesized with an 86% yield as a white crystalline solid using the reaction similar to that mentioned in Example 3 (3e) using 1- (. {4-eyl-5- [5- (4 phenoxyphenyl) -1,4,4-oxadiazol-3-yl] -2-yenyl} -methyl) azetidine-3-carboxylic acid methyl ester (0.180 g, 0.39 mmol) which was obluvored in example 13 (13b) and a 1 N aqueous solution of sodium hydroxide (1.2 ml, 1.2 mmol).

Specimen 1HRMN (400 MHz, CD3CO2D) d ppm: 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), 468 (s, 2H), 7.15 (d, 4H, J = 9.0 Hz), 7.24 (i, 1H, J = 7.4 Hz), 7.32 (s, 1H), 7.45 (,, 2H, J = 7.4 Hz), 8.17 (d, 2H, J = 9.0 Hz). Specter IR (KBr): 1167, 1249, 1347, 1489, 1517, 1557, 1592, 1613, 342¿cm'1. ! Mass spectrum (FAB +) m / z: 462 ((M + H) +).

EXAMPLE I Acid 1 - ((4-ethyl-5-r5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-thienyl) methyl) azetidine-3-carboxylic acid (14 to) . { 4-Ethyl-5-f5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-ill-2-dihydroben The unpurified product of the thioule compound was syni- conduct the reaction similar to that mentioned in example 12 (12a) using 3-fluoro-4-phenoxybenzoic acid (0.12 g, 0.50 mmole) which was obluvored in example 11 (11e), 1-hydroxybenzoyriazole (72 mg, 0.53 mmole), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.10 g, 0.53 mmol), 5- ( { [t-buyl (dimethyl) silyl] oxy} methyl) -3-eyl- N'-hydroxyiiophen-2-carboximidamide (0.15 g, 0.48 mmol) which was obtained in Example 10 (10d), and a 1.0 M solution of leirabutylammonium fluoride in hydrofuran (0.96 mL, 0.96 mmol). Subsequently, the unpurified product of the title compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 3) as the eluent to obtain the title compound. (0.16 g) with a yield of 85% as a pale yellowish crystalline solid.; Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.29 (t, 3H, J = 7.4 Hz), 1.91 (t, 1 H, J = 5.9 Hz), 3.05 (q, 2H, J = 7.4 Hz), 4.84 ( d, 2H, J = 5.9 Hz), 6.96 (s, 1 H), 7. 2-7.09 (m, 3H), 7.19 (t, 1 H, J = 7.4 Hz), 7.39 (t, 2H, J = 7.4 Hz), 7.88 (dd, 1 H, J = 8.4 Hz, 1.4 Hz), 7.99 (dd, 1 H, 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) 1 - ((4-ethyl-5-f5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yn-2-thienyl) methyl) azetidine-3-carboxylic acid methyl ester The unpurified product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1) by using it. { 4-eyl-5- [5- (3-fluoro-4-phenoxyphenyl) -1, 2,4-oxadiazol-3-yl] -2-lienyljmeanol (0.16 g, 0.40 mmole) which was obtained in example 14 (14a), carbon dioxide (0.17 g, 0.52 mmole), pyridylphosphine (0.14 g, 0.52 mmoles), melon 3-azeididcarboxylate hydrochloride (91 mg, 0.60 mmole), and N, N-diisopropylethylamine (0.21 mL, 1.2 mmole). Subsequently, the unpurified product of the thioule compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl hexane and hexane (1: 3 to 1: 2) as the eluent to obtain the compound of the title (0.15 g) with a yield of 77% like! an oily pale yellow product. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.28 (1, 3H, J = 7.4 Hz), 3.02 (ci, 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, 1 H), 7.02-7.09 (m, 3H), 7.19 (1, 1 H, J = 7.4 Hz), 7.38 ( t, 2H, J = 7.4 Hz), 7.87 (di, 1 H, J = 9.0 Hz, 1.7 Hz), 7.98 (dd, 1 H, J = 10.8 Hz, 2.2 Hz). IR specimen (liquid film): 1204, 1272, 1348, 1454, 1489, 1523, 1559, 1590, 1737 cm "1. Mass spec (FAB +) m / z: 494 ((M + H) +). (14c) 1 - ((4-Ethyl-5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-ip-2-ynyl} .methyl) azide acid Na-3-carboxylic The thiful compound (0.11 g) was synthesized with a yield of 77% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using 1- (. {4-eyl-5- [5- (3-fluoro-4-ferioxyphenyl) -1,2,4-oxadiazol-3-yl] -2-yenyl} -methyl) azidene-3 -carboxylane of melil (0.15 g, 0.30 mmol) which was obtained in example 14 (14b) and a I 1N aqueous solution of sodium hydroxide (0.9 mL, 0.9 mmol).; Spectrum 1HRMN (400 MHz, CD3CO2D) d ppm: 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 , 2HY 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 "Mass spectrum (FAB +) m / z: 480 ((M + H) +).

EXAMPLE 15 Acid 1 - ((5-r5- (3-chloro-4-tenoxyphenylH, 2,4-oxadiazoB-3-in-4-eti. Thienyl) methyl) azetidine-3-carboxyllic (Cl) 15a) 3-chloro-4-phenoxybenzoic acid The title compound (0.95 g) was synthesized with a yield of 77% as a white crystalline solid by conducting the reaction similar to that mentioned in example 10 (10e) using 3-chloro-4-phenoxybenzoic acid. -chloro-4-fluorobenzaldehyde (0.80 g, 5.0 mmol), phenol (0.66 g, 7.0 mmol), potassium carbonate (1.7 g, 13 mmol), 2-meityl-2-butene (2.7 ml, 25 mmol), diacidium phosphate (1.7 g, 13 mmol) and sodium hypochlorite (1.4 g, 15 mmol) Species 1 HNRM (400 MHz, CDCl 3) d ppm: 6.87 (d, 1 H, J = 8.6 Hz), 7.05 (dd) , 2H, J = 7.4 Hz, 1.2 Hz), 7.21 (,, 1 H, J = 7.4 Hz), 7.39 (,, 2H, J = 7.4 Hz), 7.88 (dd, 1 H, J = 8.6 Hz, 2.0 Hz), 8.19 (d, 1 H, J = 2.0 Hz). (15b) { 5- [5- (3-Chloro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-ill-4-eyl-2-tieniDmearpol The unpurified production of the title compound was synthesized by conducting the reaction similar to that mentioned in example 12 (12a) using 3-chloro-4-phenoxybenzoic acid (0.12 g, 0.50 mmol) which was obtained in example 15 (15a), 1-hydroxybenzotriazole (72 mg, 0.53 mmol), 1-ethyl hydrochloride -3- (3-dimethylaminopropyl) carbodiimide (0.10 g, 0.53 mmole), 5- (. {[[I-buyyl (dimethyl) silyl] oxy} -methyl) -3-elyl-N'-hydroxy-phenyl 2-carboximidamide (0.15 g, 0.48 mmol) which was obtained in example 10 (10d), and solution, 1.0 M of ilarabulyl ammonium fluoride in leiram id no break (0.96 mL, 0.96 mmol). Subsequently, the unpurified product of the title compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 3) as the eluent to obtain the title compound (0.17). g) with a yield of 87% as a pale yellow crystalline solid. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.30 (t, 3H, J = 7.4 Hz), 1.90 (1, 1 H, 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 (l, 1H, J = 7.4 Hz), 7. 43 (1, 2H, J = 7.4 Hz), 7.99 (dd, 1H, J = 8.6 Hz, 2.1 Hz), 8.31 (d, 1H, J = 2.1 Hz).

; IR specimen (KBr): 1242, 1265, 1393, 1480, 1591, 3250, 3335 cm "1.

; Mass Spec (FAB +) m / z: 413 ((M + H) +). • (15c) 1- ( {5-r5- (3-Chloro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-n-4-eyl-2-ynyl) -methyl) 'azideidin-3- carboxylium of meyilo The unpurified production of the compound of the seed was synthesized at conduct the reaction similar to that mentioned in example 1 (1f) using. { 5- [5- (3-Chloro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -4-eyl-2-eneyljmeyarjiol (0.17 g, 0.41 mmol) which was obtained in Example 15 ( 15b), Carbon dioxide (0.18 g, 0.53 mmole), triphenylphosphine (0.14 g, 0.53 mmoles), 3-azetidinecarboxylamine hydrochloride of meylyl (93 mg, 0.62 mmol), and N, N-diispropyl-amine (0.21 mL, 1.2 mmol). Subsequently, the unpurified production of the compound of the particle thus purified was purified Measure chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (1: 3) as the eluent. to obtain the title compound (0.15 g) with a yield of 73% as an oily product with a pale yellowish color.

Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.28 (t, 3H, J = 7.8 Hz), 3.03 (ci, 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, 1 H), 6.98 (d, 1 H, J = 8.6 Hz), 7.09 (d, 2H, J = 7.4 Hz), 7.24 (t, 1 H, J = 7¡ 4 Hz), 7.43 (t, 2H, J = 7.4 Hz), 7.98 (dd, 1 H, J = 8.6 Hz, 2.2 Hz), 8.30 (d, 1 H, J = 2.2 Hz). IR spectrum (thin film): 1198, 1245, 1266, 1343, 1483, 1513, 1731 cm'1. Mass spectrum (FAB +) m / z: 510 ((M + H) +). • (15d) Acid 1 - «5-f5- (3-chloro-4-phenoxyphenyl) -1,4, 2,4-oxadiazol-3-yl] -4-ethyl-2-thienyl) meilyl) azepidine-3-carboxylic acid The compound of the extract (0.13 g) was synthesized with a yield of 88% as a white crystalline solid by conducting the reaction similar to the one mentioned in Example 3 (3e) by using 1- (. {5- [5] - (3-chloro-4-phenoxyphenyl) -1,4,4-oxadiazol-3-yl] -4-etl-2-thienyl} methyl) azetidine-3-carboxylate methyl ( 0.1 5 g, 0.29 mmol) which was obtained in Example 15 (15c) and a 1 N aqueous solution of sodium hydroxide (0.87 mL, 0.87 mmol). . Spectrum 1HRMN (400 MHz, CD3CO2D) d ppm: 1.31 (l, 3H, J = 7.6 Hz), 3.09 (? Q, 2H, J = 7.6 Hz), 3.75-3.87 (m, 1 H), 4.33-4.44 (m, 2H), 4.48-4.59 (m, 2H), 4.J68 (s, 2H), 7.07 (d, 1 H, J = 8.6 Hz), 7.13 (d, 2H, J = 7.8 Hz), 7.25 (t, 1 H, J = 7.8 Hz), 7.33 (s, 1 H), 7.45 (,, 2H, J = 7.8 Hz), 8.06 (dd, 1 H, J = 8.6 Hz, 2.2 Hz), 8.31 (,, 1 H). IR Spectrum (KBr): 1265, 1344, 1392, 1484, 1514, 1591, 1609, 3414 cm "Mass spectrum (FAB +) m / z: 496 ((M + H) +).

EXAMPLE 16 Acid 1-f (5-l5-r3-chloro-4- (3-fluorophenoxy) phenin-1,2,4-oxadiazo-3-yl-eS »a-2-thienyl) methylazepidine-3 -carboxylic H (16a) 3-Chloro-4- (3-fluorophenoxy) benzoic acid 1 The compound of the extract (1.3 g) was synthesized with a yield of 79% as a pale yellow crystalline solid when conducting the reaction similar to that mentioned. in Example 10 (10e) using 3-chloro-4-fluorobenzaldehyde (1.0 g, 6.3 mmol), 2-fluorophenol (1.1 g, 9.5 mmol), potassium carbonate (2.2 g, 16 mmol), 2-methyl-2 -butene (3.0 ml, 28 mmol), diacyl pheasium phosphate (1.9 g, 14 mmol), and sodium hypochloride (1.5 g, 17 mmol). , Specimen 1HRMN (400 MHz, CDCI3) d ppm: 6.75-6.95 (m, 3H), 7. 04 (d, 1 H, J = 8.6 Hz), 7.33-7.38 (m, 1 H), 7.96 (dd, 1 H, J = 8.6 Hz, 2.2 Hz), 8. 23 (d, 1 H, J = 2.2 Hz). 'Specter IR (KBr): 1123, 1269, 1423, 1486, 1592, 1705, 2663, 2982, 3078 'cm "1. Mass Spec (Ef) m / z: 266 (M +). (16b) (5- (5-3 3-Chloro-4- (3-fluorophenoxy) phenyl-1, 2,4-oxadiazol-3-yl) -4-ethyl-2-tertiary) mephanol The unpurified product of the title compound was synthesized at conduct the reaction similar to that mentioned in example 5 (5a) using 3-chloro-4- (3-fluorophenoxy) benzoic acid (0.14 g, 0.53 mmol) it was obtained in example 16 (16a), 1-hydroxybenzoyriazole (0.086 g, 0.56 mmoles), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.11 g, 0.56 rt) moles), 5- ( { [t-butyl (dimethyl) silyl] oxy} methyl) -3 -ethyl-N, -hydroxythiophen-2-carboximid-amide (0.16 g, 0.51 mmol) which was obtained in example 10 (10d), and 11.0 M solution of urea-builammonium fluoride in hydrofuran (1.0 mL, 1.0 mmol). Subsequently, the unpurified prodrug of the title compound thus obtained was purified by chromatography on a silica gel using a solvent mixture of ethyl acetate and hexane (2: 8 to 5: 5) as the eluent to obtain the title compound (0.17 g) with an 89% yield as a pale yellowish crystalline solid.

Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.30 (t, 3H, J = 7.6 Hz), 1.89 (t, 1 H, J = 5.9 Hz), 3.06 (q, 2H, J = 7.6 Hz), 4.86 (d, 2H, J = 5.9 Hz), 6. 75-6.97 (rii, 3H), 6.99 (s, 1 H), 7.09 (d, 1 H, 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 Spec (FAB +) m / z: 431 ((M + H) +). ; (16c) 1-r (5- (5- [3-chloro-4- (3-fluorophenoxy) phenyl-1, 2,4-oxadiazol-3-yl) -4-eyl-2-t-eneyl) methenazei 3-carboxymethyl melamine The unpurified production of the compound of the compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (5-. {5- [3-chloro-4- ( 3-fluorophenoxy) phenyl] -1,4, 2,4-oxadiazol-3-yl.} -4-ethyl-2-ynyl) meiahol (0.15 g, 0.34 mmol) which was obtained in Example 16 (16b), Irabolide carbon (0.16 g, 0.51 mmol), triphenylphosphine (0.13 g, 0.51 mmol), 3-azetidinecarboxylamine hydrochloride of melile (0.073 g, 0.51 mmol), and N, N-diiso-propylethylamine (0.14 mL, 0.84 mmol) . Subsequently, the unpurified product of the thioule compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (2: 8 to 5:15) as the eluent to obtain the compound of the íílulo (0.16 g) with a yield of 88% as a colorless oily product. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.28 (l, 3H, J = 7.4 Hz), 3.02 (¿i, 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, 1 H, J = 8.2 Hz), 7.30-7.37 (m, 1 H), 7.99-8.03 (m, 1 H), 8.29 (d, 1 H, 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-f (5- (5- [3-chloro-4- (3-fluorophenoxy)) phen-1, 2,4-I-oxadiazol-3-yl-4-ethyl-2- acid fienil) mefipazefidine-3-carboxylic acid The compound of the title (0.14 g) was synthesized with a yield of 92% cpmo a white crystalline solid when driving the reaction similar to that mentioned in Example 3 (3e) using 1 - [(5-. {5- [3-chloro-i 4- (3-fluoroflenoxy) phenyl] -1,2,4-oxadiazole-3- I.) -4.-ethyl-2-thienyl) methyl] azeididine-3-carboxylamino of meilyl (0.16 g, 0.30 mmol) which was obtained in Example 16 (16c), a 1 N aqueous solution of sodium hydroxide (0.89 mL, 0.89 mmol), and acetic acid (51 μL, 0.89 mmol). I Spectrum 1HRMN (400 MHz, CD3CO2D) d ppm: 1.31 (l, 3H, J = 7.5 Hz), 3.10 (ci, 2H, J = 7.5 Hz), 3.78-3.89 (m, 1 H), 4.30-4.65 (m, 4H), 4.71 (s, 2H), 6. 87-7.01 (m, 3H), 7.20 (d, 1 H, 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, 1 H, J = 2.1 Hz).

IR spectrum (KBr): 769, 847, 959, 1118, 1231, 1272, 1344, 1393, 1447, 148q, 1514, 1552, 1603, 2969, 3429 cm "1.

Mass spectrum (FAB +) m / z: 514 ((M + H) +).

EXAMPLE 17 Acid | 1-rf4-ethyl-5- (5-r4-f3-fluorophenoxy) phenin-1,2,4-oxadiazol-3-thienyl) methyl] azetidine-3-carboxylic acid (17a) 4- (3-Fluorophenoxy) benzoic acid The title compound (2.0 g) was synthesized in a 96% yield as a white crystalline solid by conducting the reaction similar to that mentioned in Example 10 (10e) using 4-fluorobenzaldehyde (1.5 g, 12 mmol), 3-fluorophenol (1.2 ml, 13 mmol), potassium carbonate (3.3 g, 24 mmol), 2-methyl-2-bulene (4.8 ml, 45 mmol), phosphate diacid of polasium (3.1 g, 23 mmol), and sodium hypochloride (2.5 g, 27 mmol). Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 6.75-6.92 (m, 3H), 7.03 (d, 2H, J = 8.6 Hz), 7.27-7.37 (m, 1 H), 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 (Ef) m / z: 232 (M +). (17b) (4-Ethyl-5- (5- [4- (3-fluorophenoxy) phenyl-1,2,4-oxadiazol-3-yl) -2-fieni -mefarjiol The unpurified production of the compound of the amino acid was synthesized by conducting the reaction similar to that mentioned in Example 10 (10f) using '5- ( { [t-Butyl (dimethyl) silyl] oxy} methyl) -3-ethyl-N'-hydroxythiophen-2-yl carboxyamide ( 0.16 g, 0.50 mmol) which was obtained in Example 10 (10d), 4- (3-Fluorophenoxy) benzoic acid (0.13 g, 0.55 mmol) obtained in the Example 1.7 (17a), N.N'-dicyclohexylcarbodiimide (0.11 g, 0.55 mmole), and solution 1 J0 M of teirabuyilamonium fluoride in hydrofuran (0.75 mL, 0. 75 mmoles). Subsequently, the unpurified product of the The title thus obtained was purified by chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane i (3: 7 to 5: 5) as the eluent to obtain the compound of the extract (0.15 g) with a yield of 73% as a crislallic solid of White color. Specimen 1HRMN (400 MHz, CDCI3) d ppm: 1.30 (l, 3H, J = 7.4 Hz), 1.87 (br, 1 H), 3.07 (q, 2H, J = 7.8 Hz), 4.85 (d, 2H, J = 4.7 Hz), 6.82 (di, 1H, J = 7.4 Hz, 2.3 Hz), 6.85-6.95 (m, 3H), 6.99 (s, 1 H), 7.14 (d, 2H, J = 9.0 Hz), 7. 35-7.40 (m, 1H), 8.18 (d, 2H, J = 9.0 Hz). i IR Spec (KBr): 1341, 1486, 1515, 1557, 1603, 3373 cm "1. Mass Spec (FAB +) m / z: 397 ((M + H) +). (17c) 1-((4-ethyl-5-. {5-44- (3-fluorophenoxy) -phenin-1,2,4-oxadiazol-3-yD-2-thienyl) methyl-methyazidine-3-carboxylic acid The unpurified production of the title compound was synthesized at conduct the reaction similar to that mentioned in example 1 (1f) using I (4-ethyl-5- { 5- [4- (3-fluorophenoxy) phenyl] -1,4, 2,4-oxadiazol-3-yl.} -2-thienyl) methanediol (0.15 g , 0.38 mmol) which was obtained in example 17 (17b), carbon tetrabromide (0.15 g, 0.45 mmol), triphenylphosphine (0.12 g, 0.45 mmol), methyl 3-azetidinecarboxylate hydrochloride (86 mg, 0.57 mmol) , and N, N-diis-Jopropylethylamine (0.19 mL, 1.1 mmol). Subsequently, the unpurified product of the thioule compound thus obtained was purified by chromatography using a mixture of ethyl acetate and hexane (5: 5) solvents to obtain the iole compound (0.16 g) with a yield of 85%. as an oily pale yellow product. I Spectrum 1HRMN (500 MHz, CDCI3) d ppm: 1.28 (t, 3H, J = 7.8 Hz), 3.03, 2H, J = 7.8 Hz), 3.33-3.40 (m, 4H), 3.60-3.66 (m, 1 H), 3.72 (s, 3H), 3.79 (s, 2?), 6.80 (dt, 1 H, J = 7.4 Hz, 2.4 Hz), 6.86-6.94 (m, 3H), 7.13 (d, 2H, J = 8.8 Hz), 7.35 (q, 1 H, 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-f (4-ethyl-5-. {5-f4- (3-fluorophenoxy) phenyl-1,2,4-oxadiazol-3-yl) -2-thienyl) -mef-1-azeidin-3-carboxylic acid The title compound (83 mg) was synthesized with a yield of 54% as a white crystalline solid when conducting the reaction similar to that mentioned in example 2 (2e) using 1 - [(4-eyl-5- {5- [4- (3-fluorophe- loxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-eneyl) -methyl] azeididine-3-carboxylalkyl (0.16) mg, 0.32 mmol) which was obtained in example 17 (17c), lithium hydroxide monohydrate (30 mg, 0.71 mmol), and acetic acid (39 μL, 0. 71 mmoles).

Spectrum 1HRMN (500 MHz, CD3OD) d ppm: 1.29 (t, 3H, J = 7.3 Hz), 3.07 (jq, 2H, J = 7.3 Hz), 3.34 (quiníaio, 1 H, 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, 1 H), 7.20 (d, 2H, J = 8.8 Hz), 7.44 (q, 1 H, J = 7.8 Hz), 8.20 (d, 2H, J = 8.8 Hz).

IR spec (KBr): 1224, 1273, 1342, 1498, 1514, 3428 cm "1. 1 Mass Spec (FAB +) m / z: 480 ((M + H) +).

EXAMPLE 18 Acid 1 -r (5 5 -r 4 - (2,3-difluorophenoxy) phenyl-1,2,4-oxadiazol-3-ylM-aftyl-2] thienyl) metM1azetidine-3-carboxylic acid > (18a) 4- (2,3-difluorophenoxy) benzoic acid 1 The compound of the tíulo (2.2 g) was synthesized with a yield of 94% as: a white crislallic solid when driving the reaction similar to that mentioned in example 10 (10e) using 4-fluorobenzaldehyde (1.3 g, 10 mmol), 2,3-difluorophenol (2.0 g, 15 mmol), potassium carbonate (2.8 g, 20 mmol), 2-methyl-2-bulene (4.9 ml, 46 mmol), diacid phosphate polasium (3.1 g, 23 mmol) and sodium hypochlorite (2.5 g, 27 mmol).

Specimen 1 H NMR (400 MHz, CDCl 3) d ppm: 6.88-6.95 (m, 1 H), 6.98-7.12 (m, 4 H), 8.08 (d, 2 H, J = 9.0 Hz). 'IR Spec (KBr): 1170, 1249, 1297, 1498, 1603, 1678, 1703, 2565, 2683, 2839, 2991 cm. "1 Mass Species (Ef) m / z: 250 (M +). , (18b) (5- { 5-í4- (2,3-Difluorophenoxy) fenin-1, 2,4-oxadiazol-3-yl) -4-eyl-2-fienyl) meianol The unpurified product of the The compound of the illole was synthesized by conducting the reaction similar to that mentioned in example 10 (1 Of) using 'S-1-t-butyl dimethyl silyloxymethyl S-ethyl-N'-hydroxythiophene ^ -carboximidam.da (0.16 g, 0.50 mmole) which was obtained in Example 10 (10d), 4- (2,3-difluorophenoxy) benzoic acid (0.14 g, 0.55 mmole) which was obtained in example 1JB (18a), N, N'-dicyclohexylcarbodi Mida (0.11 g, 0.55 mmoles), and solution 110 of tetrabuylammonium fluoride in the hydrofuran (0.75 mL, 0.75 mmoles). Subsequently, the unpurified production of the title compound thus obtained was purified by chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane.

I (2: 8 to 3: 7)? As the eluent to obtain the title compound (0.18 g) with a yield of 88% as a white crystalline crystalline solid.; Specimen HRMN (400 MHz, CDCI3) d ppm: 1.29 (i, 3H, J = 7.4 Hz), 3.04 (i, 2H, J = 7.4 Hz), 4.84 (s, 2H), 6.90-7.13 (m, 5H ), 8.14 (d, 2H, J = 9.0 Hz). 1 IR Spec (KBr): 1248, 1352, 1474, 1512, 1607, 1628, 3305 cm "1., Mass Spec (FAB +) m / z: 415 ((M + H) +). (18c) 1-r (5- {5-y4- (2,3-d? -fluorophenoxy) phenin-1, 2,4-oxadiazol-3-yl) -4-eyl-2-ynyl) meilyl-azide-3-yl meyyl carboxylate! The unpurified product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (5-. {5- [4- (2,3-difluorophenoxy) phenyl] -1,2 , 4-oxadiazol-3-yl.} -4-ethyl-2-thienyl) metapol (0.18 g, 0.43 mmol) which was obtained in example 18 (18b), carbon dioxide (0.17 g, 0.52 mmol), triphenylphosphine (0.14 g, 0.52 mmol), 3-azetidinecarboxylamine hydrochloride (0.10 g, 0.86 mmol), and N, N-diisopropylethylamine (0.15 mL, 1.1 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography using a solvent mixture of ethyl acetate and hexane (5: 5) to obtain the title compound (0.20 g) in a yield of 91% as a oily pale yellow product. 1H NMR spectrum (500 MHz, CDCI3) d ppm: 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 , 1 H), 3.72 (s, 3H), 3.79 (s, 2H), 6.92-6.97 (m, 1 H), 7.03-7.16 (m, 4H), 8.16 (d, 2H, J = 9.0 Hz). IR spec (liquid film): 1250, 1346, 1476, 1498, 1512, 1557, 160, 1737 cm "1. Mass spectrum (FAB +) m / z: 512 ((M + H) +). (18d) 1-f (5- (5- [4- (2,3-difluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl) -4-eyl-2-ynyl) -methyl-1-azeidin-3-carboxylic acid The compound composed of the íílulo (77 mg) was synthesized with a yield of 38% cpmo a white crystalline solid when conducting the reaction similar to that mentioned in example 2 (2e) using 1 - [(5-. {5- [4- (2,3-difluorophenpxi) phenyl] -1,4-oxadiazol-3-yl] -4-eyl-2-ynyl) me'yl] azeididine-3-carboxylamino-methyl (0.20 g , 0.39 mmol) which was obtained in Example 18 (18c), lithium hydroxide monohydrate (36 mg, 0.86 mmol), and acetic acid (47 μL, O.d'ß mmol). ! Spectrum 1HRMN (500 MHz, CD3OD) d ppm: 1.29 (t, 3H, J = 7.4 Hz), 3.07 (q, 2H, J = 7.4 Hz), 3.40 (quintet, 1 H, 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 Spec (KBr): 1498, 1511, 1607, 3320, 3444 cm "1. Mass Spec (FAB +) m / z: 498 ((M + H) +).

EXAMPLE 19 1/2 1-l (5-r4- (2-chlorophenoxy) phenylD, 2, oxadiaz JD 4-ethyl-2-thienyl) methylazetidine-3-carboxylic acid oxalate (19a) 4- (2-chlorophenoxy) benzoic acid The compound of the extract (1.0 g) was synthesized with a yield of 84% eat! a yellowish-white crystalline solid by conducting the reaction similar to that mentioned in Example 10 (10e) using 4-fluorobenzaldehyde (0.60 g, 5.0 mmol), 2-chlorophenol (0.90 g, 7.0 mmol), carbonate potassium (1.7 g, 13 mmol), 2-methyl-2-bulene (2.7 ml, 25 mmol), potassium diacid phosphate (1.7 g, 13 mmol) and sodium hypochlorite (1.4 g, 15 mmol). ! Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 6.95 (d, 2H, J = 8.9 Hz), 7.13 (Id, 1 H, J = 7.8 Hz, 1.5 Hz), 7.20 (td, 1 H, 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) fenin-1, 2,4-oxadiazol-3-yl) -4-ethyl-2-fieni -mefariol The unpurified product of the compound The reaction was similar to the one mentioned in Example 10 (10f), which was used to conduct the reaction, using 5- (. {[[i-butyl (dimethyl) silyl] oxy] -methyl) -3-eyl-N , -hydroxy-iiophen-2-carboximidamide (0.16 g, 0.50 mmol) which was obtained in Example 10 (10d), 4- (2-chlorophenoxy) benzoic acid (0.14 g, 0.55 mmol) which was obtained in Example 19 (19a) ), dicyclohexylcarbodiimide (0.11 g, 0.55 mmole), and 1.0 M solution of fluoride ammonium fluoride in urea hydrofuran (0.75 mL, 0.75 mmol). Subsequently, the crude product of the thus-obtained compound was purified by chromatography on a column of silica gel using a mixture of ethyl acetate hexane (3: 7 to 5: 5) as eluyeny to obtain the compound of the ileum (0.19 g) with a yield of 92% as a white crystalline chrysaline. Specimen 1HRMN (400 MHz, CDCI3) d ppm: 1.29 (l, 3H, J = 7.4 Hz), 3.04 (jq, 2H, J = 7.4 Hz), 4.83 (s, 2H), 6.96 (s, 1 H), 7.01 (d, 2H, J = 8.6 Hz), 7.13 (dd, 1 H, J = 1.2 Hz, 7.8 Hz), 7.19 (di, 1 H, J = 1.2 Hz, 7.4 Hz), 7.30 (di, 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 Spec (KBr): 1245, 1259, 1353, 1473, 1498, 1517, 1556, 1612, 3329 cm "1. Mass Spec (FAB +) m / z: 413 ((M + H) +). (19c) 1-r (5- (5-f4- (2-chlorophenoxy) phenin-1, 2,4-oxadiazol-3-yl) -4-eyl-2-thienyl) -methyl-1-azeididine-3-carboxylane The unpurified production of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using, (5-. {5- [4- (2-chlorophenoxy) phenyl] -1, 2,4-oxadiazol-3-yl.} -4-eyl-2-ynyl) mei-arnol (0.19 g, 0.46 mmol) which was obtained in Example 19 (19b), carbon dioxide (0.18 g, 0.55 mmol) , rhiphenylphosphine (0.14 g, 0.55 mmoles), 3-azeidincarboxylamino hydrochloride of meityl (0.10 g, 0.69 mmol), and N, N-diis propylethylamine (0.16 mL, 0.92 mmol). Subsequently, the produced without purifying the compound of the egg thus purified was purified I by chromatography using a mixture of acetone solvents of ethyl and hexane (5: 5) to obtain the title compound (0.21 g) with a yield of 91% as a pale yellow oily product. í 1H NMR spectrum (400 MHz, CDCI3) d ppm: 1.28 (t, 3H, J = 7.4 Hz), 3.03 (jq, 2H, J = 7.4 Hz), 3.32-3.40 (m, 4H), 3.58-3.66 (m, 1 H), 3.72 (s, 3H), 3. 78 (s, 2). 6.86 (s, 1 H), 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, 1 H, J = 1.6 Hz, 7.4 Hz), 7.51 (dd, ! 1 H, 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 " Mass spectrum (FAB +) m / z: 510 ((M + H) +). (19d) 1/2 acid oxalate 1 - [(5- (5-f4- (2-chlorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl-4-eyl-2-ynyl) meily] azeidin-3-carboxylic acid The title compound (140 mg) was synthesized with a yield of 67% how a white crystalline solid when driving the reaction I similar to that mentioned in Example 1 (1g) using 1 - [(5-. {5- [4- (2-chlorophenoxy] phenyl] -1,2,4-oxadiazol-3-yl}. Methyl 4-ethyl-2-ynyl) methyl] azetidine-3-carboxylate (0.21 g, 0.41 mmol) which was cross-linked in Example 19 (19c), lithium hydroxide monohydrate (38 mg, 0.90 mmol), acid acetic (49 μL, 0.9J0 mmoles), and oxalic acid (18 mg, 0.20 mmol). Spectrum 1HRMN (400 MHz, CD3OD + CD3CO2D (5: 1)) d ppm: 1.29 (t, 3H, J = 7.4 Hz), 3.08 (q, 2H, J = 7.4 Hz), 3.56 (quintet, 1 H, J = 7.4 Hz), 4.25 (í, 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, 1 H, J = 1.6 Hz, 7.8 Hz), 7.30 (dt, 1 H, J = 1.6 Hz, 8.2 Hz), 7.42 (dt, 1 (H, J = 1.6 Hz, 8.2 Hz), 7.57 ( dd, 1 H, 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. (FAB +) m / z: 496 ((M + H) +).

EXAMPLE 20 Acid 1 -r (: 4-ethyl-5-r3-fluoro-4- (3-fluorophenoxy) phen-1-l, 2,4-oxadiazo-3 -3l.] - 2-thienyl) methylazetid Na-3-carboxylic (20a) 3-Fluoro-4- (3-fluorophenoxy) benzoic acid The compound of the icle (2.0 g) was synthesized with a yield of 84% with a yellowish-white crystalline solid when conducting the reaction to the one mentioned in Example 10 (10e) using 3,4-difluorobenzaldehyde (1.4 g, 10 mmol), 3-fluorophenol (1.6 g, 14 mmol), carbonate potassium (3.5 g, 25 mmol), 2-methyl-2-buiene (5.1 ml, 48 mmol), potassium diacid phosphate (3.3 g, 24 mmol), and sodium hypochlorite (2.6 g, 29 mmol). Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 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, 1 H , J = 8.2 Hz, 2.3 Hz, 0.8 Hz), 7.06 (l, 1 H, J = 8.2 Hz), 7.31 (id, 1 H, J = 8.2 Hz, 6.7 Hz), 7.86 (ddd, 1 H, J = 8.6 Hz, 2.0 Hz, 1.2 Hz), 7.91 (dd, 1 H, J = 11.0 Hz, 2.0 Hz). (20b) (4-Ethyl-5- (5-r3-fluoro-4- (3-fluorophenoxy) phenyl1-1,2,4-oxadiazol-3-yl) -2-iienyl) meianol • The unpurified product of the compound of the The title was synthesized by conducting the reaction similar to that mentioned in Example 12 (12a) using 3-fluoro-4- (3-fluorophenoxy) benzoic acid (0.13 g, 0.53 mmol) which was obtained in Example 20 (20a), 1-hydroxybenzoyriazole (74 mg, 0.55 mmol), 1-eyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.11 g, 0.55 mmol), 5- (4-dimethyl) sulfyl ] oxymethyl) -3-elyl-N'-hydroxylophen-2-carboximidimide (0.16 g, 0.50 mmol) which was obtained in Example 10 (10d), and 1.0 M solution of terarabulyl ammonium fluoride in tetrahydrofuran (1.0. mL, 1.0 mmol). Subsequently, the unpurified production of the compund of the thus obtained lilium was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 3) as the eluent to obtain the title compound (0.18). g) with a yield of 87% as a pale yellow crystalline solid.

Specimen 1HRMN (400 MHz, CDCI3) d ppm: 1.30 (l, 3H, J = 7.4 Hz), 1.89 (¡, 1 H, J = 6.3 Hz), 3.06 (q, 2H, J = 7.4 Hz), 4.86 (d, 2H, J = 6.3 Hz), 6 79 (di, 1 H, J = ¡9.8 Hz, 2.3 Hz), 6.84 (dd, 1 H, J = 8.2 Hz, 2 3 Hz), 6.90 (Id, 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 (id, 1 H, J = 8.2 Hz, 6.6 Hz), 7.96 (dt, 1 H, J = 9.0 Hz, 2.0 Hz), 8.03 (dd, 1 H, J = 10.6 Hz, 2.0 Hz). IR specimen (KBr). 1127, 1277, 1354, 1488, 1516, 1558, 1607, 3318 cm'1. Mass Spec (FAB +) m / z: 415 ((M + H) +). (20c) 1-r (4-eyl-5-. {5-r3-fluoro-4- (3-fluorophenoxy) -phenin-1, 2,4-y-oxadiazol-3-yl) -2-fienyl) mef Methyl azephidine-3-carboxylate The unpurified production of the title compound was synthesized by conducting the reaction similar to that mentioned in example 1 (1f) using (4-ethyl-5-. {5- [3] -fluoro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl.} -2-yenyl) metal (0.18 g, 0.43 mmol) which was obtained in Example 20 (20b) , carbon dioxide (0.22 g, 0.65 mmol), triphenylphosphine (0.17 g, 0.65 mmol), 3-azeidincarboxylamine hydrochloride of meityl (99 mg, 0.65 mmol), NN-diphosophopylethylamine (0.22 mL, 1.3 mmol). Subsequently, the unpurified product of the compound thus obtained was purified by chromatography on a column of silica gel using a mixture of. Dissolveníes of ethyl acetate and hexane (1: 3 to 1: 2) as the eluent to obtain the title compound (0.14 g) with a yield of 64% as | an oily pale yellow product.

Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.28 (l, 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 (di, 1 H, J = 9.8 Hz, 2.3 Hz), 6.85 (dd, 1 H, J = 8.2 Hz, 2.3 Hz), 6.87 (s, 1 H), 6.90 (Id, 1 H, J = 8.6 Hz, 0.8 Hz), 7.17 (t, 1 H, J = 8.2 Hz), 7.34 (td, 1 H, J = 8.2 Hz, 6.6 Hz), 7.95 (dt, 1 H, J = 8.6 Hz, 2.0 Hz), 8.02 (dd, 1 H, 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) Acid 1 - [(4-eti.-5- { 5 -3-fluoro-4- (3-fluorophenoxy) -phenin-1,2,4-oxadiazol-3-yl-2-thienyl) methyl-1-azetidine -3-carboxylic acid The title compound (0.11 g) was synthesized with a yield of 83% as a white crystalline solid by conducting the reaction similar to that mentioned in example 3 (3e) using 1 - [(4-eyl) -5- { 5- [3-fluoro-4- (3! Fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl.} -2-yl) methyl] azeidyne-3 carboxyl melon (0.14 g, 0.27 mmol) which was obtained in Example 20 (20c) and a 1 N aqueous solution of sodium hydroxide (0.81 mL, 0.81 mmol). Spectrum 1HRMN (400 MHz, CD3CO2D) d ppm: 1.31 (t, 3H, J = 7.4 Hz), 3.10 (q, 2H, J = 7.4 Hz), 3.75-3.87 (m, 1 H), 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, 1 H, J = 8.6 Hz), 7.34 (s, 1 H), 7.37-7.47 (m, Hj.), 8.02 (d, 1 H, J = 8.6 Hz), 8.06 (d, 1 H, J = 11.0 Hz).

IR spec (KBr): 1130, 1278, 1488, 1515, 1607, 3434 cm "1. Mass spec (FAB +) m / z: 498 ((M + H) +).

EXAMPLE 21 1/2 oxalate of -r (4-etii-5- [5-y4- (2-methoxyphenoxy] JJenin-1, I4, oxadiazol-3-yl> -2-thienyl) metipazetidine-3-carboxylic acid 0 5 (C02H) 2 (21a) 4- (2-Methoxyphenoxy) benzoic acid The title compound (1.6 g) was synthesized with a yield of 89% as a yellowish white crystalline solid by conducting the silmilar reaction to that mentioned in Example 10 (10e) using 4-fluorobenzaldehyde (1.2 g, 10 mmol), 2-methoxyphenol (1.7 g, 14 mmol), I potassium carbonate (3.5 g, 25 mmol), 2-methyl-2-bulene (3.9 ml, 37 mmol), dialysis phosphate (2.5 g, 19 mmol) and sodium hypochloride (2.0 g, 22 mmol). , Specimen 1HRMN (400 MHz, CDCI3) d ppm: 3.80 (s, 3H), 6.93 (dd, 2H, J = 8.6 Hz, 2 0 Hz), 6 99 (íd, 1 H, 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 (íd, 1 H, J = 7.4 Hz, 1.6 Hz), 8.04 (dd, 1 l., J = 8.6 Hz, 2.0 Hz). (21 b) (4-Ethyl-5- (5-f4- (2-meioxyphenoxy) phenyl-1 ^^ -oxadiazol-S-yl) -2-Di-methanol The unpurified production of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 12 (12a) using 4- (2-methoxyphenoxy) benzoic acid (0.13 g, 0.53 mmol) which was obtained in example 21 (21a), 1-hydroxybenzoyriazole (74 mg, 0.55 mmol) ), hydrochloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodimide (0.11 g, 0.55 mmol), 5- (. {[[i-buyyl (dimethyl) silyl] oxy} -methyl) -3-eyl -N'-hydroxylfiofen-2-carboxymethide (0.16 g, 0.50 mmol) which was obtained in Example 10 (10d), and 1.0 M solution of telrabutylammonium fluoride in idyr id not (1.0 mL, 1. 0 mmol). Subsequently, the unpurified product of the compound of The title thus obtained was purified by chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (2: 5) as the eluent to obtain the title compound (0.15 g) with a yield of 72%. as a crystalline solid of yellowish white color. • Specimen 1HRMN (400 MHz, CDCI3) d ppm: 1.29 (l, 3H, J = 7.4 Hz), 1.85 (t, 1 H, 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, 1 H), 6.99-7.07 (m, 4H), 7.11 (dd, 1 H, J = 7.8 Hz, 1.6 Hz ), 7.24 (di, 1 H, 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) 1 - [(4-ethyl-5- (5- [4- (2-methoxyphenoxy) phenyl-1, 2,4-oxadiazol-3-yl) -2-ynyl) methyl-1-azeidin-3-carboxylic acid The unpurified production of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using '(4-ethyl-5-. {5- [4- (2-meioxyphenoxy) phenyl] - 1, 2,4-oxadiazol-3-yl.} -2-lienyl) melanol (0.14 g, 0.35 mmol) which was obtained in Example 21 (21 b), carbon lobranhydride (0.17 g, 0.53 mmol), pyriphenylphosphine (0.14 g, 0.53 I mmoles), methylated 3-azeididcarboxylate hydrochloride (80 mg, 0.53 mmoles), and N, N-diisopropylethyllamino (0.18 mL, 1.1 mmoles). Subsequently, the production of the title compound thus obtained was purified by chromatography on a silica gel column using a mixture of ethyl acetate and hexane (2: 5 to 1: 2) solvents as the eluent for Obtain the title compound (89 mg) with a yield of 50% as a colorless oily product. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 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, 1 H), 6.97-7.07 (m, 4H), 7.11 (dd, 1 H, J = 8.2 Hz, 1.6 Hz), 7.24 (id, 1 H, J = 7.4 Hz, 1.6 Hz), 8.10 (dd, 2H, J = 9.0 Hz, 2.2 Hz). IR specimen (thin film): 1168, 1176, 1201, 1265, 1346, 1455, 1496? 1513, 1613, 1737 cm "1. Mass Spec (FAB +) m / z: 506 ((M + H) +). , (21d) 1/2 oxalate of acid 1 - [(4-eyl-5- (5-f4- (2-meioxyphenoxy) -phenip-1, 2,4-oxadiazol-3-yl) -2-thienyl) -methyl-1-azetidine -3-carboxylic acid A solution of 1 - [(4-eyl-5-. {5- [4- (2-meioxyphenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2 Tethylene] azetidine-3-carboxylic acid (86 mg, 0.17 mmol), which was worked up in Example 21 (21c) in dioxane (3 ml), was added a 1 N aqueous solution of Sodium hydroxide (0.51 ml, 0.51 mmol) with stirring, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, acyl acid (29 μl, 0.51 mmol) was added to the reaction mixture to quench the reaction, and the resulting mixture was evaporated in vacuo. Subsequently, meianol (2 ml) and water (1 ml) were added successively to the obtained residue with agitation, and in addition a solution of oxalic acid (8 mg, 0.09 mmol) in melanol (0.5 ml) was added, and then The resulting mixture was stirred for 30 minutes. The precipitated white solid was collected by filtration using a Kiriyama funnel, washed with a mixture of solvents of water and methanol (3: 7) and dried in vacuo to obtain the title compound (63 mg) in a yield 69% as a solid white linen. Spectrum 1HRMN (400 MHz, CD3C02D) d ppm: 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 Spec (FAB +) m / z: 492 ((M + H) +).

EXAMPLE 22 Acid 1 - ((3-ethyl-5-rS- (4-phenoxyphenyl) -1,2,4-oxadiaz®, -3-ill-2-thienyl) methyl) azetidine-3-carboxylic acid (22a) [5- rt-Builyl (dimethylsilyl-oxy) -methyl) -3-eyl-2-lienyl-1-methanol To a solution of 5- ( { [T-butyl (dimethyl) silyl] oxy} methyl) - 3-ethylthiophene-2-carboxaldehyde which was obtained in example 10 (10b) (1.5 g, 5.8 mmol) in meianol (10 mL) was added leniamenie sodium borohydride (0.22 g, 5.8 mmol) at 0 ° C with stirring , and the resulting mixture was stirred for 30 minutes. After stirring, the solvent was evaporated in vacuo. Subsequently, a solution of the residue obtained in ether was poured into water (20 mL) and extracted with ether. The extract was washed with a saline aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 4). at 3: 7) as the eluent to obtain the pure title compound (1.4 g) with a yield of 94% as a colorless oily product.

, Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 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), 6.7.2 (s, 1 H). • IR spectrum (liquid film): 1075, 1149, 1255, 1362, 1390, 1463, 3352 cm "1. 'Mass spectrum (FAB +) m / z: 285 ((M-H) +). 1 (22b) 4-Ethyl-5-((ieirahydro-2H-pyran-2-yloxy) meiilliiofen-2-carboxaldehyde To a solution of [5- ( { [T-builyl (dylmethyl) syl) oxy] (methylene) -3-ethyl-2-ethylbenzene (1.4 g, 5.3 mmol) which was worked up in example 22 (22a) in dichloromelan (10 ml) was successively added 3,4-dihydro-2H- Piranone (0.58 ml, 6.4 mmol) and p -oluenesulfonic acid (10 mg, 0.04 mmol) at 0 ° C with stirring, and the mixture was stirred at ambient temperature for 30 minutes. After stirring, a saturated aqueous solution of sodium acid carbonate (5 ml) was added to the reaction mixture to stop the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtaiin tetrahydrofufhane (5 ml) was added a 1.0 M solution of tetrahydrofuran ferrous fluoride (6.4 ml, 6.4 mmol) with stirring, and the resulting mixture was stirred at ambient temperature for 30 min. After stirring, the reaction mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated iri vacuo. Subsequently, to a solution of the residue obtaiin dichloromethane (30 ml) were added 4A molecular sieves (10 g), and after cooling to 0 ° C, pyridinium dichromate (3.3 g, 8.7 mmol) was further added to the mixture. they were agitated, and the mixture was stirred at ambient temperature for 2 hours. After stirring, ether (150 ml) was added to the reaction mixture with stirring, and the insoluble materials were removed by filtration with silica gel. The filtrate was evaporated in vacuo, and the unpurified product of the title compound thus obtaiwas purified by chromatography on a column of silica gel using a mixture of ethyl acetate and hexane (0:10 to 2: 8) as solvent. eluyenle to obiener the compound of íííulo (0.97 g) with a yield of i 78% like! a colorless oily production. I Specimen 1HRMN (400 MHz, CDCI3) d ppm: 1.23 (l, 3H, J = 7.6 Hz), 1.50-1.92 (m, 6H), 2.61 (q, 2H, J = 7.6 Hz), 3.53-3.59 (m, 1 H), 3.84-3.92 (m, 1 H), 4.65 (d, 1 H, J = 13.5 Hz), 4.74 (1, 1 H, J = 3.5 Hz), 4.87 (d, 1 H, J = 13.5 Hz), 7.55 (s, 1 H), 9.80 (s, 1 H). IR specimen (liquid film): 1023, 1036, 1121, 1158, 1454, 1670.2873.2942, 3440 cm "1. Mass Spec (+) m / z: 254 (M +). (22c) 4-Ethyl-5 - [(tetrahydro-2h-pyran-2-yloxy) methyl] thiophene-2-carbonitrile The unpurified product of the thioule compound was synthesized by conducting the reaction similar to that mentioned in example 1 (1c) using 4-ethyl-5 - [(1-hydrohydro-2H-pyran-2-yloxy) -methyl] -iophen-2-carbonyliryl (0.97 g, 3.6 mmol) which was obluded in Example 22 (22b), Hydroxylamine hydrochloride (0.29 g, 3.9 mmol), triethylamine (1.1 mL, 7.2 mmol), and N, N'-dicyclohexylcarbodiimide (0.87 g, 3.9 mmol). Subsequently, the unpurified production of the thus obtained thioule compound was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (0:10 to 10:90) as the eluent to obtain the Composed of the tíulo (0.86 g) with a yield of 95% as a colorless oily production. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.19 (1, 3H, J = 7.6 Hz), 1.52-1.90 (m, 6H), 2.58 (q, 2H, J = 7.6 Hz), 3.52-3.59 (m, 1 H), 3.82-3.90 (m, 1 H), 4 | 62 (d, 1 H, J = 13.3 Hz), 4.71 (t, 1 H, J = 3.3 Hz), 4.84 (d, 1 H) , J = 13.3 Hz), 7.38 (s, 1 H). IR spectrum (liquid film): 903, 1024, 1036, 1066, 1077, 1123, 1174, 1201, 1342, 1454, 2216. 2873, 2942 cm "1. Mass spectrum (Ef) m / z: 251 (M +) . (22d) 4-Ethyl-N'-hydroxy-5-f (tetrahydro-2H-pyran-2-yloxy) methyl-1-pheno-2-carboximidamide The unpurified production of the compound of the compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1d) using 4-eyl-5 - [(1-hydrohydro-2H-pyran-2-yloxy) -methyl] -iophen-2-carbonyl-trile (0.86 g, 3.4 mmol) which was obtained in the example 22 (22c) and a 50% aqueous solution of hjdroxylamine (0.5 mL). Subsequently, the unpurified production of the thus-obtained compound was purified by chromatography on a silica gel column using a mixture of ethyl acetate and Ifiexane (1: 3 to 5: 5) as the eluent to obtain the compound of the tíulo (0.96¡g) with a yield of 98% as a colorless oily production. '1H NMR Spectrum (400 MHz, CDCl 3) d ppm: 1.20 (1, 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, 1 H), 4.61 (d, 1 H, J = 12.9 Hz), 4.71 (i, 1 H, J = 3.3 Hz), 4.80 (d, 1 H, J = 12.9 Hz), 4.82 (br, 2H), 7.07 (s, 1 H), 7.23 (br, 1 H). IR specimen (liquid film): 1022, 1117, 1344, 1390, 1588, 1635, 2872, 2942, 3353 cm "1. Mass spec (FAB +) m / z: 285 ((M + H) +). (22e) 3- (4-Ethyl-5 - [(1-hydra-2H-pyran-2-yloxy) -meiill-2-ynyl) -5- (4-phenoxyphenyl) -1,4-oxadiazole The product purification of the title compound was synthesized by conducting the reaction similar to that mentioned in example 5 (5a) using 4-phenoxybenzoic acid (0.16 g, 0.73 mmol), 1-hydroxybenzotriazole (0.12 g, 0.76 mmol), hydrochloride 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.15 g, 0.76 mmol), 4-eyl-N'-hydroxy-5 - [(telrahydrd-2H-pyrn-2-yloxy) methyl] lofen -2-carboximidamide (0.17 g, 0.69 mmole) which was obtained in example 22 (22d) and urea-builabylmonium fluoride (a 1.0 M solution in tetrahydrofuran, 14 ml, 1.4 mmoles). Subsequently, the crude product of the thus-obtained compound was purified by chromatography on a column of silica gel using a solvent mixture of ethyl hexane and hexane (0:10 to 2: 8) the eluent was run to obtain the compound of the title (0.25 g) with a yield of 78% as a colorless oily product. Specimen HRMN (400M Hz, CDCI3) d ppm: 1.26 (l, 3H, J = 7.6 Hz), 1.50-1.93 (m, 6H), 2.65 (q, 2H, J = 7.6 Hz), 3.55-3.61 (m, 1 H), 3.89-3.96 (m, 1 H), 4 ¡69 ( d, 1 H, J = 12.9 Hz), 4.77 (t, 1 H, J = 3.5 Hz), 4.88 (d, 1 H, J = 12.9 Hz), 7.07-7.12 (m, 4H), 7.20-7.25 ( m, 1 H), 7.41 (d, 1 H, J = 7.4 Hz), 7.43 (d, 1 H, J = 7.4 Hz), 7.66 (s, 1 H), 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) meta? Ol I 1 To a solution of 3-. { 4-ethyl-5 - [(ε -hydro-2H-pyran-2-yloxy) methyl] -2-ienyl} -5- (4-phenoxyphenyl) -1,2,4-oxadiazole (0.25 g, 0.54 mmol) which was obtained in example 22 (22e) in ethanol (5 ml) was added p-toluenesulfonated pyridinium (0.014 g, 0.54 mmole) with agitation, and the resulting mixture was stirred at 60 ° C for 4 hours. After stirring, the reaction mixture was poured into water (20 ml) to quench the reaction and excyroed with ethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo to obtain the title compound (0.19 g) in 92% yield as a white crystalline solid. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.27 (t, 3H, J = 7.6 Hz), 1.79 (t, 1 H, 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, 1 H), 7.41 (d, 1 H, J = 7.4 Hz), 7.43 (d, 1 H, J = 7.4 Hz), 7.67 (s, 1 H), 8.15 (d, 2H, J = 8.6 Hz). IR specimen (KBr): 760, 998, 1232, 1422, 1487, 1579, 1591, 1615, 2964, 3452 cm "1. Mass spectrum (FAB +) m / z: 379 ((M + H) +). (22q) 1 - «3-ethyl-5-5 5 - (4-phenoxyphenyl) -1, 2,4-oxadiazol-3---2-ynyl) mephyl) azetidine-3-carboxylic acid of meylyl The unpurified prod of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using. { 3-ethyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} methanol (0.19 g, 0.50 mmol) which was obtained in Example 22 (22f), carbon tetrabromide (0.33 g, 0.99 mmol), triphenylphosphine (0.26 g, 0.99 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.11 g) g, 0.75 mmole), N, N-diisopropyljgthylamine (0.22 mL, 1.2 mmole). Subsequently, the non-purified product of the title compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (2: 8 to 4: 6) as the eluent to obtain the < compound of the tíulo (0.17 g) with a yield of 72% as a crystalline solid of pale yellow color. Spectrum 1HRMN (500 MHz, CDCI3) d ppm: 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, 1 H), 7.38-7.43 (m, 2H), 7.62 (s, 1 H), 8.14 (| d, 2H, J = 8.8 Hz). i 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-yl) methyl) azeididine-3-carboxylic acid Compound of the tíulo (0.16 g) sinieíizó with a yield of 95% like a crystalline white solid when conducting the reaction similar to that mentioned in the example 3 (3e) uilizing 1- (. {3-eil-5- [5- (4-Phenoxyphenyl) -1, 2,4-oxadiazol-3-yl] -2-ynyl} -methyl) azeididine-3-carboxylalkyl (0.17 g, 0.36 mmoles) which In Example 22 (22g), a 1 N aqueous solution of sodium hydroxide (1.1 mL, 1.1 mmol), and acetic acid (62 μL, 1.1 mmol) were obtained.

Spectrum 1HRMN (400 MHz, CD3CO2D) d ppm: 1.29 (1, 3H, J = 7.5 Hz), 2.78 fa, 2H, J = 7.5 Hz), 3.75-3.86 (m, 1 H), 4.30-4 60 (m , 2H), 4.71 (s, 2H), 7.11-7.17 (m, 4H), 7.22-7.27 (m, 1 H), 7.41-7.48 (m, 2H), 7.80 (s, 1 H), 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 Acid i - ( {5-f5- (3-Fluoro-4-isobutylphenyl) -1,2,4-oxadsazot 3-illpyrir i: -2-yl) methyl) azetidine-3-carboxylic acid F (23a ) 5-Bromo-2- ( { [T-butyl (dimethyl) silyloxy) methyl) pyridine To a solution of 5-bromo-2-formylpyridine (4.6 g, 25 mmol) in methanol (30 ml) was added sodium borohydride (0.93 g, 25 mmol) at 0 ° C with stirring, and the resulting mixture was stirred for 1 hour. After evaporating the solvent in vacuoThe residue obtained was diluted with ether, poured into water (20 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulphonium. After filtering, the filtrate was evaporated in vacuo. Subsequently, to a solution of the obtained residue and imidazole (3.4 g, 49 mmol) in N, N-dimethylfromiamide (30 ml) was added t-butyldimethylsilyl chloride (4.1 g, 27 mmol) with agitation, and the resulting mixture was stirred at room temperature for 1 h. After stirring, the reaction mixture was poured into water (50 ml) and extracted with ether. The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the unpurified product of the thus obtained lyrium compound was purified by chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (1:49 a). 1: 9) as the eluent to obtain the title compound (6.8 g) with a yield of 90% as a white crystalline crystalline solid. Spectrum 1HRMN (400 MHz, CDCl 3) d ppm: 0.12 (s, 6H), 0.95 (s, 9H), 4.78 (s, 2H), 7.42 (d, 1 H, J = 8.6 Hz), 7.82 (dd, 1 H, J = 2.3 Hz, 8.6 Hz), 8.56 (d, 1 H, J = 2.3 Hz). , IR spec (KBr): 1008, 1104, 1258, 1377, 1471, 1578 cm "1. Mass spectrum (FAB +) m / z: 302 ((M + H) +). (23b) 6 - (([t-Butyl (d -methyl) silyl-oxy) methyl) nicotinonitrile A solution of 5-bromo-2- ( { [T-bulyl (dimethyl) s1l] oxy]. methyl) pyridine (0.30 g, 1.0 mmol) which was obtained in example 23 (23a), zinc cyanide (0.18 g, 1.5 mmol), bis (dibenzylideneacetone) palladium (18 mg, 0.02 mmol) and 1, 1'-bis (diphenophosphino) ferrocene (44 mg, 0.08 mmol) in N-methyl-2-pyrrolidinone (4 ml) was stirred at 100 ° C for 1 hour. After cooling to room temperature, the reaction mixture was poured into water and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the unpurified production of the thus obtained compound was purified by chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (1: 9). as the eluent to obtain the title compound (0.23 g) with a yield of 93% as a white crystalline crystalline solid. Specimen 1HRMN (400 MHz, CDCI3) d ppm: 0.14 (s, 6H), 0.96 (s, 9H), 4.87 (s, 2H), 7.67 (d, 1 H, J = 8.2 Hz), 7.98 (dd, 1 H, J = 2.0 Hz, 8.2 Hz), 8.78 (d, 1 H, J = 2.0 Hz). IR spec (KBr): 1110, 1254, 1470, 1594, 2230 cm "1. Mass spec (FAB +) m / z: 249 ((M + H) +). ; (23c) 6 - ((--Butyl (dimeiyl) sililloxy) methyl) -N'-hydroxypyridine-3-carboximidimide i • The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in example 1 (1d) ! Using 6- ( { [t-buyl (dimethyl) silyl] oxy} -methyl) nicoininyl-trichloride (2.0 g, 8.1 mmol) which was obtained in Example 23 (23b) and a 40% aqueous solution of hydroxylamir ( 1 ml). Subsequently, the unpurified product of the thus-obtained compound was purified by recrystallisation from a solvent mixture of ethyl acetate and hexane (1: 9) to obtain the title compound (2.1 g) in 94% yield as a solid I crystalline dje white color. Spectrum 1HRMN (500 MHz, CDCI3) d ppm: 0.13 (s, 6H), 0.96 (s, 9H), 4.86 (s, 2H), 4.89 (br, 2H), 7.56 (d, 1 H, J = 8.3 Hz ), 7.95 (dd, 1 H, J = 2.4 Hz, 8.3 Hz), 8.77 (d, 1 H, 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 To a solution of isopropylriphenylphosphonium iodide (0.65 g, 1.5 mmol) and N, N-dimethylylformamide (6 ml ) a solution of potassium iobuoxide (0.18 g, 1.6 mmol) in N, N-dimethylformamide (2 ml) was added at 0 ° C with agitation, and the mixture was stirred for 30 min. In addition, to the reaction mixture was added a solution of 4-bromo-2-fluorobenzaldehyde (0.20 g, 1.0 mmol) in N, N-dimethylylformamide (2 ml) at the same temperature with agitation, and after raising the Reaction temperature at room temperature, the resulting mixture was further stirred for 1 hour: After stirring, a saturated aqueous solution of ammonium chloride (5 ml) was added to the reaction mixture to stop the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo, and the unpurified production of the thus-obtained compound was purified by chromatography on a column of silica gel using a mixture of acetone and hexane solvent disolvenies (0:10 a). 5:95) as eluyenie to make the title compound (0.19 g) with a yield of 82% as a colorless oily product. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.76 (s, 3H), 1.92 (s, 3H), 6.13 (s, 1 H), 7.09 (t, 1 H, J = 8.2 Hz), 7.19-7.24 (m, 2H). 'IR specimen (liquid film): 1403, 1483, 1562, 1599 cm. "1 Mass spec (+) m / z: 228 (M +). (23e) 3-Fluoro-4-isobuylbenzoic acid To a solution of 4-bromo-2-fluoro-1- (2-meityprop-1-en-1-yl) benzene (0.19 g)0.81 mmole) which was obtained in example 23 (23d) in hydrohydrofuran (4 ml) was added with a 1.6 M solution of n-butyllithium in hexane (0.62 ml, 0.97 mmole) at -78 ° C with stirring, and the resulting mixture was stirred at the same time for 1 hour while carbon dioxide was bubbled into the solution. After stirring, a 1 N aqueous solution of sodium hydroxide (2 ml) was added to the reaction mixture to stop the reaction, and the resulting aqueous layer was washed with ether, acidified with a 10 M aqueous solution of hydrochloric acid and extracted with ethyl acetate again. The extract was washed with a saline aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained in hydrogen (3 ml) was added 10% palladium on carbon (30 mg), and the resulting mixture was stirred at room temperature for 1 hour under a Amosphere of hydrogen. After stirring, the reaction mixture was filtered with Celite, and the filtrate was evaporated in vacuo to obtain the compound of element I (0.12 g) with a yield of 77% as a white crystalline solid.

Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.93 (t, 6H, J = 6.6 Hz), 1.88-2.00 (m, 1 H), 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-r5- (3-Fluoro-4-isobutylphenyl) -1, 2,4-oxadiazol-3-yl-1-pyridin-2-yl) methanol The unpurified production of the title compound was synthesized at conduct the reaction similar to that mentioned in Example 12 (12a) using 3-fluoro-4-isobutylbenzoic acid (0.12 g, 0.63 mmol) which is I isolate in Example 23 (23e), 1-hydroxybenzoyriazole (89 mg, 0.66 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.13 g, 0.66 mmoles), 6- ( { [t-Butyl (dimethyl) silyl] oxy} methyl) -N'-hydroxypyridine-3-carboximidamide (0.17 g, 0.60 mmol) which was obtained in example 23 (23c), and 1.0 M solution of terarabulomammonium fluoride in teirahydrofuran (1.2 mL, 1.2 mmol).

Subsequently, the production without purifying the compound of the obtained was purified by chromatography on a gel column of silica using a mixed solvent of ethyl acetate and hexane (2: 3 to 1: 1) as the eluent to obtain the title compound (0.16 g) with a 80% yield as a white crystalline solid.

Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.96 (d, 6H, J = 6.6 Hz), 1.62 (bs, 1 H), 1.91-2.04 (m, 1 H), 2.62 (d, 2H, J = 8.2 Hz), 4.87 (s, 2H), 7.36 (t, 1 H, J = 7.8 Hz), 7.43 (d, 1 H, J = 8.2 Hz), 7.87 (dd, 1 H, J = 10.2 Hz, 1.6 Hz), 7. 93 (dd, 1 H, J = 7.8 Hz, 1.6 Hz), 8.44 (dd, 1 H, J = 8.2 Hz, 2.0 Hz), 9.34 (d, 1 H, J = 1.6 Hz) .. 1 IR spectrum (KBr): 1030, 1128, 1394, 1500, 1560, 1594, 1612, 3170 cm "1.1 Mass spectrum (FAB +) m / z: 328 ((M + H) +). (23q) 1 - (. {5- [5- (3-fluoro-4-isobutyl) -1-, 2,4-oxadiazol-3-yl-1-pyridin-2-yl) methyl) azetidine- 3-carboxylated meyyl . { 5- [5- (3-Fluoro-4-isobulinyl) -1,4, 2,4-oxadiazol-3-yl] pyridin-2-ymelanol (0.16 g, 0.47 mmol) which was obtained in the example 23 (23f), Carbon dioxide (0.23 g, 0.71 mmol), and phenylphenylphosphine (0.19 g, 0.71 μmol) were dissolved in dichloromethane (6 ml) at 0 ° C and agitated thereto.

Imperator for 10 minutes. After stirring, the reaction mixture was evaporated in vacuo, and the residue obtained was purified by means of chromatography on a column of silica gel using a mixture of solvents of acetyl of ethyl and hexane (1: 6) to obtain the intermediate of the reaction.

Subsequently, to a solution of the reaction intermediate obtained in dichloro-thieriene (7 ml), there was added successively meilyyl 3- azeididcarboxylate hydrochloride (0.11 g, 0.71 mmole) and N, N-diisopropylethylamine (0.25 ml, 1.4 mmole) with agitation, and the resulting mixture was stirred at room temperature for 13 hours. After stirring, a saturated aqueous solution of sodium acid carbonate (2 ml) was added to the reaction mixture to stop the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ethyl acetate. The extra was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfalous.

After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a column of silica gel using a solvent mixture of ethyl hexane and hexane (1: 12). as the eluent to obtain the title compound (0.12 g) with a yield of 59% as a white crystalline solid. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.96 (d, 6H, J = 6.6 Hz), 1.90-2.04 (m, 1 H), 2.62 (d, 2H, J = 7.0 Hz), 3.35-3.46 (m , 1 H), 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, 1 H, J = 8.2 Hz), 7.48 (d, 1 H, J = 7.4 Hz), 7.86 (dd, 1 H, 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, 1 H, J = 1.2 Hz). : IR spec (KBr): 1218, 1340, 1373, 1398, 1500, 1559, 1729 cm "1. Mass spec (FAB +) m / z: 425 ((M + H) +). (23h) 1 - ((5- [5- (3-Fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl-1-pyridin-2-yl) methyl) azetidine-3-carboxylic acid The compound of the tíulo (90 mg) was synthesized with a yield 81% as a white crystalline solid using 1- (. {5- [5- (3-fluoro-4-isobutylphenyl) -1,4-oxadiazol-3-yl] pyridin-2-yl azimidine-3-carboxylane of meyilo (0.12 g, 0.27 mmol) that was obtained in example 23 (23g) and a 1 N aqueous solution of sodium hydroxide (0.81 mL, 0.81 mmol) when conducting the reaction similar to that mentioned in Example 3 (3e).

Specimen 1HRMN (400 MHz, CD3CO2D) d ppm: 0.97 (d, 6H, J = 6.6 Hz); 1.93-2.05 (m, 1 H), 2.65 (d, 2H, J = 7.0 Hz), 3.83-3.94 (m, 1 H), 4.48- 4.57 (m, 2¡H), 4.60-4.71 (m, 2H) ), 4.82 (s, 2H), 7.47 (l, 1 H, J = 7.8 Hz), 7.77 (d, 1 H, J = 8.2 | Hz), 7.92 (d, 1 H, J = 9.8 Hz), 7.99 (d, 1 H, J = 7.8 Hz), 8.60 (d, 1 H, J = 8.2 Hz), 9.34 (s, 1 H).

IR Spectrum (KBr): 1129, 1344, 1367, 1399, 1500, 1602, 1627, 2128, 295 $ cm "1.

Mass Spec (FAB +) m / z: 411 ((M + H) +).

EXAMPLE 24 Acid 1 f5-r5- (3-Chloro-4-isobutylphenyl) -1, 2,4-oxadiazole-3-yn-6-methyndiin-2-yl) methyl) azetidine-3-carboxylic acid , (24a) 2- (Methyllium) -6-. { [(tri-isopropylsilyl) oxy] -methyl) -nonichinoniiryl To a solution of 6-formyl-2- (methyllum) -omycinoniyryl (1.0 g, 5.6 mmol) in meianol (10 ml) was added leniamenle sodium borohydride a 0 ° C with agitation, and the resulting mixture was agitated at the same lemperairy by 10 minutes. After evaporating the solvent in vacuo, the obtained residue was diluted with ethyl acetate, poured into water (20 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the obtained residue and imidazole (0.76 g, 11 mmol) in N, N-dimethylformamide (6 ml) was added triisopropylsilyl chloride (1.3 ml, 6.2 mmol) with agitation, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, the reaction mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the unpurified production of the title compound thus obtained was purified by chromatography on a column of silica gel using a mixture of ethyl acetate and hexane (0:10 a). 3:97) as the eluent to obtain the title compound (1.7 g) with a yield of 91% as a colorless oily product. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 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, 1 H, J = 7.8 Hz), 7.80 (d, 1 H, J = 7.8 Hz). IR spectrum (KBr): 1372, 1423, 1552, 1573, 2220 cm "1. Mass spec (FAB +) m / z: 337 ((M + H) +). (24b) 2- (Meilylsulfonyl) -6-. { [(yisopropylsilyl) oxpmelyyl) nicoylinomeri To a solution of 2- (methylio) -6-. { [(xypropyl) oxy] methyl} pyrimonobenzoic acid (1.5 g, 4.5 mmol) which was obtained in the example 24 (24a) in ethanol (10 ml) was added with m-chlorobenzoic acid (2.3 g, 14 m.sup.10) at 0 ° C with stirring, and after raising the reaction temperature at ambient temperature, the resulting mixture was stirred for 3 hours and then it was vaporized in vacuo. Subsequently, to a solution of the residue obtained in ether (20 ml) was added a saturated aqueous solution of potassium carbonate (10 ml) with stirring, and the resulting mixture was stirred for 1 hour. After stirring, the reaction mixture was poured into water (20 ml) and I went to bed with him. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After the filing, the filtrate was evaporated in vacuo, and the unpurified production of the thus obtained compound was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2: 8 to 3: 7). ) as the eluent to obtain the title compound (1.7 g) with a yield of 100% as a white crystalline solid. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 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, 1 H, J = 7.8 Hz), 8.26 (d, 1 H, 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-. { f (ioisopropylsilyl) oxymethyl) nicoylinoniiryl To a solution of 2- (methylsulfonyl) -6-. { [(triisoprofi) ilsilyl) oxy] meityl} nicoinone (0.80 g, 2.2 mmoles) that was obluded in the example! 24 (24b) in ether (10 ml) was added a 3.0 M solution of methylmagnesium bromide in ether (1.5 ml, 4.4 mmol) at -78 ° C with stirring, and the resulting mixture was stirred at the same temperature for 1 hour. hour. After stirring, a saturated aqueous solution of ammonium chloride (1 ml) was added to the reaction mixture to stop the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the unpurified product of the thioule compound thus obtained was purified by chromatography on a silica gel column using a mixture of ethyl acetate and hexane (0:10 a). 1: 9) as the eluent to obtain the title compound (0.64 g) with a yield of 95% as a white crystalline solid. , Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 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 , 1 H, J = 7.8 Hz), 7.92 (d, 1 H, 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-. { [(yisopropylsilyl) oxpmeryl) pyridine-3-carboximidimide The unpurified production of the compound of the amino acid was synthesized by conducting the reaction similar to that mentioned in Example 1 (1d) by using 2-meityl-6. { [(triisopropyl) oxy] methyl} ionichloride (0.63 g, 2.1 mmol) which was obtained in Example 24 (24c) and a 40% aqueous solution of hydroxylamine (0.5 mL). Subsequently, the unpurified production of the thus obtained thioule compound was purified by recrystallization from a mixture of ethyl acetate and hexane (1: 9) solvents to obtain the title compound (0.61 g) in 86% yield as a white crystalline solid. 1 Specimen 1HRMN (400 MHz, CDCI3) d ppm: 1.09 (d, 18H, J = 6.8 Hz), 1.15-126 (m, 3H), 2.63 (s, 3H), 4.79 (brs, 2H), 4.92 (s, 2H), 7.18 (br, 1 H), 7.46 (d, 1 H, J = 7.8 Hz), 7.72 (d, 1 H, J = 7.8 Hz). IR specimen (KBr): 1124, 1462, 1579, 1597, 1644, 3050, 3337, 3449 cm 1, Mass Spec (FAB +) m / z: 338 ((M + H) +). (24e) (4-Bromo-2-chlorophenyl) mefanol To a solution of 4-bromo-2-chlorobenzoic acid (3.1 g, 13.2 mmole) in tetrahydrofuran (30 ml) was added a 1.0 M solution of the borane complex. -lehydrohydrofuran in urea hydrate no (13.8 ml, 13.8 mmol) at 3 ° C with agitation, and the resulting mixture was stirred at the same temperature for 20 minutes, and after raising the reaction temperature to ambient temperature , the reaction mixture was further stirred for 4 hours. After stirring, water (10 ml) was added to the reaction mixture to stop the reaction, and the resulting mixture was poured into a saturated aqueous sodium hydrogen carbonate solution (50 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated iri vacuo, and the unpurified production of the title compound thus obtained was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1: 9 a). 7: 3) with eluyenie to obtain the compound of the tíulo (2.8 g) with a yield of 97% as a crystalline white solid. Specimen 1HRMN (400 MHz, CDCI3) d ppm: 7.51 (d, 1 H, J = 2.0 Hz), 7.40 (d, 1 H, J = 8.2 Hz, 2.0 Hz), 7.36 (d, 1 H, J = 8.2 Hz), 4.73 (d, 2H, J = 6.3 Hz), 1.90 (t, 1 H, J = 6.3 Hz). IR spectrum (KBr): 1036, 1063, 1385, 1469, 1561, 1586, 3239 cm -1 Mass spectrum (El +) m / z: 220 (M +). (24f) 4-Bromo-2-chlorobenzaldehyde To a solution of (4-bromo-2-chlorophenyl) melanol (2.8 g, 12.8 mmol) which was obtained in Example 24 (24e) in dichloromethane (50 ml) was added pyridinium dichromate (7.2 g, 19.2 mmol) with stirring, and the mixture was stirred at ambient temperature for 1 hour. After stirring, ether (250 ml) was added to the reaction mixture under stirring, and the mixture was filtered with Celite. The filtrate was evaporated in vacuo, and the product without purification of the title compound thus obtained was purified by chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (1: 20) as the eluent. to obtain the title compound (2.0 g, yield: 70%) as a white crystalline solid.; Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 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, 1 H).

IR specimen (KBr): 1201, 1374, 1577, 1693 cm'1. Mass Spec (+) m / z: 218 (M +). (24q) 4-Bromo-2-chloro-1- (2-methylprop-1-en-1-yl) benzene The unpurified production of the compound of the illole was synthesized by conducting the reaction similar to that mentioned in example 23 ( 23d) using isopropyltriphenylphosphonium iodide (5.4 g, 12.6 mmol), potassium t-butoxide (1.5 g, 13.5 mmol) and 4-bromo-2-chlorobenzaldehyde (2.0 g, 9.0 mmol) which was obtained in Example 24 (24 f). ). Subsequently, the unpurified product of the thus-obtained title compound was purified by means of chromatography on a column of silica gel using a mixture of ethyl acetate and hexane (0:10 to 6:94) as the eluent to obtain the compound of the title (2.1 g) with a yield of 94% as a colorless oily product. HRMN spectrum (400 MHz, CDCI3) d ppm: 1.74 (s, 3H), 1.93 (s, 3H), 6.20 (s, 1 H), 7.10 (d, 2H, J = 8.2 Hz), 7.33 (d, 1 H, J = 8.2 Hz, 2.0 Hz), 7.53 (d, 1 H, J = 2.0 Hz ). IR spectrum (thin film): 1045, 1083, 1373, 1468, 1579 Mass spectrum (El +) m / z: 244 (M +). (24h) 3-Chloro-4-isobutylbenzoic acid The compound of the tíulo (1.5 g) was synthesized with a yield of 99% comb a crislalino solid of white color when conducting the reaction similar to that mentioned in the example 23 (23e) using 4-bromo-2-chloro-1- (2-methylprop-? | -en-1-yl) benzene (2.1 g, 8.5 mmol) which was obtained in example 24 (24 g), 1.6 M solution of n- butyllithium in hexane (5.6 mL), and 5% platinum on carbonate (200 mg). 1 H NMR spectrum (400 MHz, CDCI3) d ppm: 0.95 (d, 6H, J = 6.6 Hz), 1.96-108 (m, 1 H), 2.68 (d, 2H, J = 7.4 Hz), 7.28 (d, 1 H, J = 7.8 Hz), 7.90 (d, 1 H, J = 7.0 Hz), 8.08 (s, 1 H). Mass spectrum (FAB +) m / z: 212 (M +). (24i) (5- [5- (3-Chloro-4-isobuhylphenyl) -1,4, 2,4-oxadiazol-3-ill-6-mephylpyridin-2-yl) mephanol The unpurified production of the title compound was synthesized at conduct the reaction similar to that mentioned in example 12 (12a) using 3-chloro-4-isobutylbenzoic acid (0.11 g, 0.50 mmol) which was obtained in example 24 (24h), 1-hydroxybenzolyrolzole (72 mg, 0.53 mmole), hydrochloride of 1-eyl-3- (3-dimethylaminopropyl) carbodimide (0.10 g, 0.53 mmole), N'-hydroxy-2-meityl-6. { [(ioisopropylsilyl) oxy] meityl} pyridine-3-carboximid'amide (0.16 g, 0.48 mmole) which was obtained in example 24 (24d), and a 1.0 M solution of tetrabuylammonium fluoride in iara hid break (0.96 ml, 0.96 min). Subsequently, the unpurified product of the compound thus obtained was purified by chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (1: 1) as the eluent to obtain the title compound (0.15). g) with a yield of 89% as a white crislallic solid. Specimen 1HRMN (400 MHz, CDCI3) d ppm: 0.97 (d, 6H, J = 6.8 Hz), 2.00-¿.09 (m, 1 H), 2.71 (d, 2H, J = 7.3 Hz), 2.95 (s, 3H), 3.87 (t, 1 H, J = 4.9 Hz), 4.81 ¡(d, 2H, J = 4.9 Hz), 7.24 (d, 1 H, J = 7.8 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), 8.39 (d, 1 H, J = 7.8 Hz).

! IR spectrum (KBr): 1332, 1407, 1454, 1591, 3238 cm'1. ! Mass Spec (FAB +) m / z: 358 ((M + H) +). (24j) 1 - ((5-f5- (3-chloro-4-isobuylphenyl) -1,4,4-oxadiazol-3-ill-6-methylpyridi? -2-yl) meityl) azetidine- 3-Carboxylamide of meylyl The unpurified production of the thioule compound was synthesized by conducting the reaction similar to that mentioned in Example 23 (23g) using. { 5- [5- (3-chloro-4-isobutylphenyl) -1,4,4-oxadiazol-3-yl] -6-methylpyridin-2-yl-melanolol (0.15 g, 0.42 mmol) which was obluded in Example 24 ( 24i), carbon bromide (0.22 g, 0.67 mmol), triphenylphosphine (0.18 g, 0.67 mmol), methyl 3-azetidinecarboxylate hydrochloride (96 mg, 0.63 mmol), and N, N-diisopropylethylamine (0.22 mL, 1.3 mmol) ). Subsequently, the unpurified product of the title compound thus obtained was purified by chromatography on a column of silica gel using a mixture of. solvents of ethyl acetate and hexane (1: 1 to 2: 1 or 3: 1) as the eluent to obtain the title compound (0.11 g) with a yield of 58% as an oily product with a pale yellowish color. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.97 (d, 6H, J = 6.6 Hz), 1.98-2.10 (m, 1 H), 2.70 (d, 2H, J = 7.4 Hz), 2.91 (s, 3H), 3.34-3.45 (m, 1 H), 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, 1 H, J = 7.8 Hz), 7.37 (d, 1 H, J = 7.8 Hz), 8.01 (dd, 1 H, J = 7.8 Hz, 1.9 Hz), 8.21 (d, I 1 H, J = 1.6 Hz), 8.34 (d, 1 H, J = 7.8 Hz). IR spectrum (KBr): 1203, 1332, 1405, 1438, 1450, 1589, 1735, 2957cm "1. Mass spectrum (FAB +) m / z: 455 ((M + H) +). , (24k) 1 - ((5-l5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-ill-6-meilypyridin-2-yl) methyl) azetidine-3-carboxylic acid The title compound (76 mg) was synthesized with a yield of 72% of a white crystalline solid by conducting the ajquella-like reaction mentioned in Example 3 (3e) using 1- (. {5- [5- ( 3-Chloro-4-isobuyl-phenyl) -1, 2,4-oxadiazol-3-yl] -6-methyl-pyridin-2-yl.) Methyl) azide-3-carboxylic acid (0.11 g , 0.24 mmole) which was obtained in Example 24 (24j) and a 1 N aqueous solution of sodium hydroxide (0.72 mL, 0.72 mmole). Spectrum 1HRMN (400 MHz, CD3CO2D) d ppm: 0.98 (d, 6H, J = 6.6 Hz), 2.00-2.09 (m, 1 H), 2.75 (d, 2H, J = 7.0 Hz), 2.93 (s, 3H), 3.83-3.94 (m, 1 H), 4.46-4.58 ( m, 2H), 4.61-4.71 (m, 2H), 4.77 (s, 2H), 7.49 (d, 1 H, J = 7.8 Hz), 7.55 Jd, 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 Mass spectrum (FAB +) m / z: 441 ((M + H) +).

EXAMPLE 25 Acid 1 - (5-r5- (3-oro-4-isobutylphenylH, 2,4-oxadiazc IMM) -6-ethylpiPMu-2-yl) methyl) azetidine-3-carboxylic Cl (25a) 2-Ethyl-6 - ([(iisopropylsilyl) oxymethyl) nicoiinoniyryl The unpurified production of the title compound was synthesized at conduct the reaction similar to that mentioned in example 24 (24c) using 2- (methylsulfonyl) -6-. { [(lysopropylsilyl) oxy] meilyl} nicoíinoníírilo (0.78 g, 2.1 mmoles) which was obtained in Example 24 (24b) and a 3.0 M solution of Ethylmagnesium bromide in ether (1.4 ml, 4.2 mmol). Subsequently, the produced purify the compound of the title thus purified purified they measured bromine on a column of silica gel using a Solvent mixture of ethyl acetate and hexane (0:10 to 1: 9) as eluyenfe to obtain the compound of the eluate (0.65 g) with a yield of 97% as a white crystalline crystalline solid. Specimen 1HRMN (400 MHz, CDCI3) d ppm: 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, 1 H, J = 7.8 Hz), 7.92 (d, 1 H, J = 7.8 Hz). IR spec (KBr): 1125, 1409, 1464, 1564, 1587, 2227 cm "1. Mass spec (FAB +) m / z: 319 ((M + H) +). (25b) 2-Elyl-N'-hydroxy-6-. { [(1-pyridinyl) oxypropyl) pyridin-3-carboxyamide The unpurified product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1d) using 12-ethylene. 6- { [(lysopropylsilyl) oxy] methyl} Nicoinitrile (0.75 g, 2.4 mmol) which was obtained in Example 25 (25a) and a 40% aqueous solution of hydroxylamine (0.5 mL) Subsequently, the unpurified production of the compound of the extract thus obtained was purified by chromatography over a column of silica gel using a solvent mixture of ethyl acetate and hexane (3: 7 to 1: 1) as the eluent to obtain the title compound (0.80 g) in 95% yield as a crystalline solid of White color. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.10 (d, 18H, J = 6.8 Hz), 1 16-1.24 (m, 3H), 1.28 (t, 3H, J = 7.4 Hz), 2.93 (q, 2H) , J = 7.4 Hz), 4.80 (brs, 2H), 4.93 (s, 2H), 7.45 (d, 1 H, J = 7.8 Hz), 7.69 (d, 1 H, J = 7.8 Hz), 8.08 (br , 1 HOUR). IR Spec (KBr): 1120, 1385, 1404, 1462, 1573, 1596, 1637, 3161, 3282, 3362 cm "1. Mass Spec (FAB +) m / z: 352 ((M + H) +). (25c) (5-r5- (3-Chloro-4-isobuylphenyl) -1,2,4-oxadiazol-3-yl-1-6-eylpyridin-2-yl) melanol The unpurified product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 12 (12a) using 3-chloro-4-isobutylbenzoic acid (0.10 g), 0.48 mmole) which was obtained in Example 24 (24h), 1-hydroxybenzolyriazole (69 mg, 0.51 mmol), 1-eyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (97 mg, 0.51 mmol), 2- eíl-N'-hydroxy-6-. { [(ioisopropylsilyl) oxy] meityl} pyridine-3-carboximidamide (0.16 g, 0.46 mmol) which was obtained in example 25 (25b), and a 1.0 M solution of telrabutylammonium fluoride in leirahydrofuran (0.92 ml, 0.92 njimoles). Subsequently, the unpurified production of the thus-obtained compound was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (1 → 2) as the eluent to obtain the title compound. (0.15 g) with a yield of 89% as a white crystalline solid. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.97 (d, 6H, J = 6.8 Hz), 1.38 (t, 3H, J = 7.3 Hz), 2.00-2.10 (m, 1 H), 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, 1H, I J = 1.5 Hz), 8.34 (d, 1H, 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) 1 - ((5-f5- (3-chloro-4-isobutylphenyl) -1, 2,4-oxadiazol-3-ill-6-ethylpyridin-2-yl) methyl) azetidine-3-carboxylic acid methyl The unpurified product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 23 (23g) | using ¡. { 5- [5- (3-chloro-4-isobutylphenyl) -1,4,4-oxadiazol-3-yl] -6-eylpyridin-2- Imemelanol (0.15 g, 0.40 mmole) which was obtained in example 25 (25c), carbon terarabide (0.27 g, 0.80 mmole), triphenylphosphine (0.21 g, 0.80 g) mmoles), 3-azetidinecarboxylane hydrochloride of melile (91 mg, 0.60 mmol) and N, N-diis'opropylethylamine (0.21 ml, 1.2 mmol). Subsequently, the Unpurified product of the title compound thus obtained was purified by chromatography on a column of silica gel using a mixture of ethyl acetate and hexane (1: 1 to 2: 1 or 3: 1) as the eluent to obtain the title compound (0.16 g) with a yield of 83% like! an oily production of pale yellowish color.

Specimen 1 HNRM (400 MHz, CDCl 3) d ppm 0.97 (d, 6H, J = 6.6 Hz), 1.26 (1, 3H, J = 7.4 Hz), 1.99-2.10 (m, 1 H), 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 Spec (KBr): 1179, 1203, 1405, 1449, 1589, 1740 cm "1., Mass Spec (FAB +) m / z: 469 ((M + H) +). i (25e) 1 - ((5-f5- (3-Chloro-4-isobutylphenyl) -1,2,4-oxadiazol-3-yl-1-6-ethylpyridin (2-yl) methyl) azepide na-3-carboxylic acid 1 The compound of the particle (0.10 g) was sini fi elized with a yield of 71% as a white crislallic solid when conducting the reaction similar to that mentioned in example 3 (3e) using 1- (. { 5- [5- (3-chloro-4-isobutylphenyl) -1,4,4-oxadiazol-3-yl] -6-ethylpyridin-2-yl} methyl) azetidine-3-carboxylate i of methyl (0.15 g, 0.32 mmol) which was obtained in Example 25 (25d) and a 1 N aqueous solution of sodium hydroxide (0.96 mL, 0.96 mmol). Specimen 1 HNRM (400 MHz, CD3CO2D) d ppm 0.98 ( d, 6H, J = 6.3 Hz), 1.37 (i 3H, J = 7.2 Hz), 1.95-2.09 (m, 1 H), 2.74 (d, 2H, J = 7.0 Hz), 3.29 (q, 2H, J = 7.2 Mz), 3.87-3.97 (m, 1 H), 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 Acid 1 - ((5-r5- (3-chloro-4-isobutylphenylH .2.4-oxadiazcM Dil ipiridij Jg) methyl) azetidine-3-carboxylic Cl (26a) (5-l5- (3-Chloro-4-isobutylphenyl) -1.2.4-oxadiazol-3-illpyridin-2-iflmephanol The unpurified production of the title compound was sini fi ed by conducting the reaction similar to that mentioned in Example 12 (12a) using 3-chloro-4-isobutylbenzoic acid (0.13 g, 0.61 mmol) which was obtained in Example 24 (24h), 1-hydroxybenzoyriazole (86 mg, 0.64 mmol), hydrochloride: 1-eyl-3- (3-dimethylaminopropyl) carbodiimide (0.12 g, 0.64 mmol), 6- ( { [1-buyl (dimethyl) silyl] oxy} methyl) -N ' -hydroxypyridine-3-carboxylamide (0.16 g, 0.58 mmole) which was obtained in example 23 (23c), and a 1.0 M solution of letterbumylammonium fluoride in hydrofuran (1.2 ml, 1.2 mmoles). Production without purification of the compund of the thus obtained liqueur was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (2: 3 to 1: 1) as the eluent to obtain the solvent. The product was 0.19 g) with a yield of 94% as a white crystalline solid.

Specimen 1HRMN (400 MHz, CDCI3) d ppm: 0.98 (d, 6H, J = 6.6 Hz), 1.99-2.10 (m, 1 H), 2.71 (d, 2H, J = 7.4 Hz), 3.62 (bs, 1 H), 4.87 (s, 2H), 7.39 (d, 1 H, J = 7.8 Hz), 7.44 (d, 1 H, J = 8.2 Hz), 8.03 (dd, 1 H, J = 7.8 Hz, 1.6 Hz ), 8.23 (d, 1 H, J = 1.6 Hz), 8.44 (dd, 1 H, 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 Spec (FAB +) m / z: 344 ((M + H) +). (26b) 1 - ((5- [5- (3-Chloro-4-isobuylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl) mephyl) a'zephidine-3-carboxylamino-mephile Unpurified product of the title compound was synthesized by conducting the reaction similar to that mentioned in example 23 (23g) using '. { 5- [5- (3-chloro-4-isobuyl-phenyl) -1,4,4-oxadiazol-3-yl] pyridin-2-yl} meianol (0.18 g, 0.54 mmole) which was obluded in Example 26 (26a), carbon tetrabromide (0.36 g, 1.1 mmol), triphenylphosphine (0.28 g, 1.1 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.12 g, 0.81 mmole), and N, N-düsopropylphthylamine (0.28 mL, 1.6 mmole). Subsequently, the unpurified product of the title compound thus obtained was purified by chromatography on a column of silica gel using a solvent mixture of ethyl hexane (2: 1 to 3: 1) as the eluent to obtain the solvent. composed of the tíulo (0.15 g) with a yield of 61% as a white crystalline solid.

Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.97 (d, 6H, J = 6.7 Hz), 1.98-2.08 (m, 1 H), 2.70 (d, 2H, J = 7.0 Hz), 3.33-3.46 (m , 1 H), 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, 1 H, J = 7.8 Hz), 7.46 (d, 1 H, J = 8.2 Hz) , 7.99 (dd, 1 H, J = 7.8 Hz, 1.6 Hz), 8.19 (d, 1 H, J = 1.6 Hz), 8.36 (dd, 1 H, J = 8.2 Hz, 2.0 Hz), 9.28 (d, 1 H, J = 2.0 Hz). IR Spec (KBr): 1207, 1339, 1352, 1389, 1486, 1605, 1738 cm 1 Mass Spec (FAB +) m / z: 441 ((M + H) +). (26c) Acid 1 - ( {5-r5- (3-Chloro-4-isobuylphenyl) -1, 2,4-oxadiazol-3-yl] pyridin-2-yl) mephyl) azephydine-3-carboxylic acid The title compound (0.12 g) was synthesized with a 90% yield of a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using 1- ( { 5- [5- (3-Chloro-4-isobutylphenyl) -1,4-oxadiazol-3-yl] pyridin-2-yl.} Methyl) azeidine-3-carboxylamino-meityl (0.14 g, 0.32 mmol) obtained in Example 26 (26b) and a 1 N aqueous solution of sodium hydroxide (0.96 mL, 0.96 mmol). Specimen 1HRMN (400 MHz, CD3CO2D) d ppm: 0.98 (d, 6H, J = 6.6 Hz); 1.94-2.07 (m, 1 H), 2.75 (d, 2H, J = 7.0 Hz), 3.83-3.94 (m, 1 H), 4.49-4.60 (m, 2H), 4.60-4.70 (m, 2H), 4.83 (s, 2H), 7.50 (d, 1 H, J = 7.8 Hz), 7.78 (d, 1 H, J = 7.4 Hz), 8.09 (d, 1 H, J = 7.8 Hz), 8.25 (s, 1 H), 8.60 (d, 1 H, J = 7.4 Hz), 9. 35 (s, 1 H). IR Spectrum (KBr): 1368, 1403, 1569, 1587, 1605, 3431 cm "1. 1 Mass Spec (FAB +) m / z: 427 ((M + H) +).

EXAMPLE 27 1/2 acid oxalate - ((S-f5- (4-lsobutyl-3-methylphenyl? D-M4-oxadia 6-methylpyridin-2-yl) methyl) azetidine-3-carboxylic acid 0 5 (CO-H). (27a) (4-Bromo-2-methylphenyl) methanol The unpurified production of the iole compound was synthesized by conducting the reaction similar to that mentioned in Example 24 (24e) using 4-bromo-2-methylbenzoic acid (4.0 g, 19 mmoles) and a 1.0 M solution of the borane-tetrahydrofuran complex in teirahydrofuran (20 ml, 20 mmoles). Subsequently, the unpurified production of the title compound thus obtained was purified by chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (1: 19 to 3: 2) as the eluent to obtain the compound of the tíulo (3.7 g) with a yield of 99% as a colorless oily product.

Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.60 (1, 1 H, J = 5.5 Hz), 2.32 js, 3H), 4.65 (d, 2H, J = 5.5 Hz), 7.23 (d, 1 H, J = 8.6 Hz), 7.32-7.36 (m, 2H). IR spectrum (thin film): 1006, 1040, 1396, 1454, 1483, Mass spectrum (+) m / z: 200 (M +). (27b) 4-Bromo-2-methylbenzaldehyde The unpurified production of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 24 (24f) ! using (4-bromo-2-methylphenyl) melanol (3.7 g, 19 mmol) which was obtained in Example 27 (27a) and pyridinium dichromate (11 g, 28 mmol).

Subsequently, the unpurified production of the thus-obtained compound was purified by means of chromatography on a column of silica gel using a solvent mixture of ethyl hexane and hexane (1: 19 to 1: 4) as the eluent to obtain the compound of the title (2.4 g) with a yield of 64% as a colorless oily product. ! 1HRMN spectrum (400 MHz, CDCI3) d ppm: 2.65 (s, 3H), 7.45 (s, 1 H), 7.51 (dd, 1 H. J = 8.2 Hz, 1.6 Hz), 7.66 (d, 1 H, J = 8.2 Hz), 10.25 (s, 1 H). IR spectrum (KBr): 1288, 1301, 1588, 1686 cm'1. Mass spectrum (El +) m / z: 198 (M +). (27c) 4-Bromo-2-methyl-1- (2-methylprop-1-en-1-yl) benzene The crude product of the thioule compound was synthesized by conducting the reaction similar to that mentioned in example 23 (23d) using isopropyltriphenylphosphonium iodide (7.2 g, 17 mmol), potassium t-butoxide (2.0 g, 18 mmol), and 4-bromo-2-methyl benzaldehyde (2.4 g, 12 mmol) which was obtained in Example 27 (27b). Subsequently, the unpurified product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixture of acetone solvent and hexane solvent (0:10 to 6:94) as eluyenie for I obtained the compound of the product (2.2 g) with a yield of 84% as a colorless oily product. I 1 Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 1.67 (d, 3H, J = 1.2 Hz), 1.89 (d, 3H, J = 1.6 Hz), 2.19 (s, 3H), 6.09 (s, 1 H ), 6.95 (d, 1 H, J = 8.2 Hz), 7.23 (dd, 1 H, J = 8.2 Hz, 2.0 Hz), 7.28 (d, 1 H, J = 2.0 Hz). ! IR spectrum (thin film): 1444, 1478, 1587 cm "1. Mass spectrum (+) m / z: 224 (M +). (27d) 4-Isobutyl-3-meiylbenzoic acid The compound of the ileum (1.4 g) was synthesized with a yield of 95% as a white crystalline solid by conducting the reaction similar to that mentioned in example 23 (23e) using 4-bromo-2-meityl-1- (2-methylprop-1-en-1-yl) benzene (2.2 g, 9.8 mmol) which was worked up in the example; 27 (27c), 1.6 M solution of n-butyllithium in hexane (6.5 mL, 10 mmol), and 10% palladium on carbon (200 mg). ! Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.94 (d, 6H, J = 6.3 Hz), 1.84-1.96 (m, 1 H), 2.36 (s, 3H), 2.54 (d, 2H, J = 7.0 Hz ), 7.19 (d, 1 H, J = 7.8 Hz), 7.84 jd, 1 H, J = 7.8 Hz), 7.88 (s, 1 H). , (27e). { 5-í5- (4-lsobufil-3-methylphenyl) -1, 2,4-oxadiazol-3-ill-6-methylpyridi? I? -2-yl) melanol The unpurified production of the compound of the compound was synthesized when driving The reaction similar to that mentioned in example 12 (12a) using 4-isobuyl-3-methylbenzoic acid (96 mg, 0.50 mmol) which was obtained in example 27 (27d), 1-hydroxybenzoyriazole (72 mg, 0.53 mmol) ), 1-eyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.10 g, 0.53 mmol), N'-hydroxy-2-methyl-6-. { [(iisopropylsilyl) oxy] methyl} pyridine-3-carboximidamide (0.16 g, 0.48 mmol) which was obtained in Example 24 (24d) and a 1.0 M solution of tetrabuylammonium fluoride in tetrahydrofuran (0.96 mL, 0.96 mmol). Subsequently, the unpurified product of the title compound itself was purified by chromatography on a column of silica gel using a mixture of ethyl hexane disulfide (1: 2) as the eluent to obtain the title compound (0.15 g) with a yield of 91% as a white crystalline solid. ! Specimen 1 HNRM (400 MHz, CDCl 3) d ppm: 0.96 (d, 6H, J = 6.6 Hz), 1.87-H .98 (m, 1 H), 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, 1H, J = 8.2 Hz), 7.95 (dd, 1H, J = 7.8 Hz, 1.6 Hz), 7.99 (s, 1H), 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) 1- ( {5-f5- (4-budoyl-3-mephylphenyl) -1,2,4-oxadiazol-3-ill-6-meilypyridyl-2-yl) meityl) azide-3 -carboxilaio de meíilo l The unpurified production of the title compound was synthesized at drive the reaction similar to that mentioned in example 23 (23g) I using! . { 5- [5- (4-isobutyl-3-methylphenyl) -1,4,4-oxadiazol-3-yl] -6-meilypyridin-2-ylmelanol (0.14 g, 0.43 mmol) which was obtained in the example 27 (27e), carbon tetrahydromide (0.29 g, 0.86 mmol), triphenylphosphine (0.23 g, 0.86 mmol), 3-azetidinecarboxylate hydrochloride of meityl (98 mg, 0.65 mmol), and N.N-dι-opropylethylamine (0.22 mL, 1.3 mmol). Subsequently, the Unpurified product of the thioule compound thus obtained was purified mediate chromatography on a column of silica gel using a solvent mixture of ethyl acetate and hexane (2: 1 to 3: 1) as the eluent to obtain the title compound (0.12 g) with a yield of 66% as! a colorless oily production.

Specimen 1HRMN (400 MHz, CDCI3) d ppm: 0.96 (d, 6H, J = 6.6 Hz), 1.88-1.97 (m, 1 H), 2.41 (s, 3H), 2.57 (d, 2H, J = 7.4 Hz), 2.91 (s, 3H), 3.36- 3.44 (m, 1 H), 3.47 (,, 2H, J = 7.4 Hz), 3.65 (,, 2H, J = 7.2 Hz), 3.73 (s, 3H), 3.83 (s, 2H), 7.27 (d, 1 H, J = 7.8 Hz), 7.31 (d, 1 H, J = 7.8 Hz), 7.95 (dd, 1 H, J = 7.8 Hz, 1.8 Hz), 7.Í99 (s, 1 H), 8.33 (d, 1 H, J = 8.2 Hz ). IR specimen (liquid film): 1176, 1202, 1336, 1561, 1592, 1739 cm "1. Mass spec (FAB +) m / z: 435 ((M + H) +). (27q) 1/2 oxalate of 1 - ((5-5 5 - (4-isobutyl-3-mephylphenyl) -1, 2,4-oxadiazol-; 3-yl-1-6-methylpyridin-2-yl ) meiyl) azeididine-3-carboxylic acid; The compound of the tíulo (0.10 g) sinieíizó with a yield of 78% as a crystalline white solid to conduct the reaction similar to that mentioned in example 21 (21d) ulilizando 1- (. {5- 5- (4-isobutyl-3-methylphenyl) -1,4,4-oxadiazol-3-yl] -6-methylpyridin-2-yl.] Methyl) azetidine-3-carboxylic acid methyl ester (0.12 g, 0.28 mmoles) obtained in example 27 (27f), a 1 N aqueous solution of sodium hydroxide (0.84 ml, 0.84 mmole), acetic acid (48 μl, 0.84 mmole), and oxalic acid (13 mg, 0.14 mmole) ). Spectrum 1HRMN (400 MHz, CD3CO2D) d ppm: 0.97 (d, 6H, J = 6.6 Hz), 1.88-1.99 (m, 1 H), 2.43 (s, 3H), 2.61 (s, 2H, J = 7.4 Hz), 2.93 (s, 3H), 3. 84-3.96 (m, 1 H), 4.46-4.56 (m, 2H), 4.62-4.74 (m, 2H), 4.77 (s, 2H), 7.35 (d, 1 H, J = 8.2! Hz), 7.55 (d, 1 H, J = 8.2 Hz), 7.99 (d, 1 H, J = 7.4 Hz), 8.03 (s, 1 H), 8.53 (d, 1 H, J = 8.2 Hz). IR Spec (KBr): 1337, 1382, 1565, 1588, 1618, 3410 cm "1. Mass spectrum (FAB +) m / z: 421 ((M + H) +).

EXEMPLQ 28 1/2 oxalate of 1 - ((5-r5- (4-lsobutii-3-methylphenyl) -D; 4-oxadia: J; -3- i illpyridin-2-yl) methyl) azetidine-3-carboxy acid. ie @ 0 5 (C02H) 2 (28a) (5-í5- (4-lsobutyl-3-methylphenyl) -1, 2,4-oxadiazol-3-yl-1-pyridin-2-ylmethanol The unpurified production of the title compound was synthesized at conduct the reaction similar to that mentioned in example 12 (12a) using 4-isobutyl-3-meiylbenzoic acid (0.12 g, 0.61 mmol) which is Obtained in Example 27 (27d), 1-Hydroxybenzotriazole (86 mg, 0.64 mmol), 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.12 g, 0.64 mmol), 6- (. {[[i-Butyl (dimethyl) silyl] oxy} -methyl) -N'-hydroxypyr dina-3-carboximidamide (0.16 g, 0 | 58 mmol) which was obtained in example 23 (23c), and fluoride of Tetrabuild ionium (a 1.0 M solution in hydrohydrofuran, 1.2 ml, 1.2 mmol).

Subsequently, the unpurified product of the title compound thus obtained was purified by chromatography on a gel column of ! silica using a solvent mixture of ethyl acetate and hexane (2: 3 to 1: 1) with the eluent to obtain the thioule compound (0.19 g) with a I 99% yield as a white crystalline solid. Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.97 (d, 6H, J = 6.6 Hz), 1.65. { bs, 1 H), 1.84-1.97 (m, 1 H), 2.42 (s, 3H), 2.58 (d, 2H, J = 7.0 Hz), 4.87 (s, 2H), 7.28 (d, 1 H, J = 8.2 Hz), 7.42 (d, 1 H, J = 8.2 Hz), 7.96 (dd, 1 H, J = 7.8 Hz, 1.6 Hz), 8. 0 (s, 1 H), 8.44 (dd, 1 H , J = 8.2 Hz, 2.4 Hz), 9.35 (d, 1 H, J = 2.4 Hz). IR spectrum (KBr): 1066, 1394, 1559, 1612, 3203 cm "1. 'Mass spectrum (FAB +) m / z: 324 ((M + H) +). (28b) 1 - ((5-R5- (4-isobuyyl-3-meitylphenyl) -1,2,4-oxadiazol-3-illpyridin-2-yl) methyl) azepidine-3-carboxylamino-mephyl The unpurified production of the compound of the title was synthesized by conducting the reaction similar to that mentioned in example 23 (23g) using. { 5- [5- (4-isobutyl-3-methylphenyl) -1,4,4-oxadiazol-3-yl] pyridin-2-yl} methanol (0.19 g, 0.! 8 mmol) which was obtained in example 28 (28a), carbon tetrabromide (0.39 g, 1.2 mmol), triphenylphosphine (0.30 g, 1.2 mmol), 3- hydrochloride azeíjdincarboxilalo de melilo (0.13 mg, 0.87 mmoles), and N, N-diisopropyletilamina (0.30 ml, 1.7 mmoles). Subsequently, the unpurified product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixture of solvents! of ethyl acetate and hexane (1: 1 to 2: 1 or 3: 1) as the eluent to obtain the title compound (0.15 g) in 60% yield as a white crystalline solid.

Specimen 1HRMN (400 MHz, CDCI3) d ppm: 0.96 (d, 6H, J = 6.7 Hz), 1.86-1.97 (m, 1 H), 2.41 (s, 3H), 2.57 (d, 2H, J = 7.4 Hz), 3.34-3.44 (m, 1H), 3. 47 (i, 2, J = 7.2 Hz), 3.64 (l, 2H, J = 7.6), 3.72 (s, 3H), 3.85 (s, 2H), 7.25 (d, 1 H, J = 7.8i Hz), 7.45 (d, 1 H, J = 8.2 Hz), 7.93 (d, 1 H, J = 7.8 Hz), 7.97 (s, 1 H), 8.37 (dd, 1 H , J = 8.2 Hz, 2.0 Hz), 9.28 (d, 1 H, J = 2.0 Hz). IR specimen (KBr): 1191, 1208, 1224, 1388, 1732 cm'1. Mass Spec (FAB +) m / z: 421 ((M + H) +). (28c) 1/2 oxalation of 1 - ((5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-j3-yl] pyridin-2-yl) methyl) azetidine-3-carboxylic acid The title compound (0.13 g) was synthesized with a yield of 83% as a white crystalline solid by conducting the reaction similar to that mentioned in example 21 (21d) using 1- ( { 5- [5- (4-isobuyyl-3-methyl-phenyl) -1,4-oxadiazol-3-yl] pyridin-2-yl} -methyl) azyididine-3-carboxylic acid (0.14 g, 0.34 mmole) which was obtained in example 28 (28b), a 1 N aqueous solution of sodium hydroxide (1.0 mL, 1.0 mmol), acetic acid (58 μL, 1.0 mmol), and oxalic acid ( 15 mg, 0.17 mmol). Specimen HRMN (400 MHz, CD3CO2D) d ppm: 0.98 (d, 6H, J = 6.6 Hz), 1.88-2.01 (m, 1 H), 2.44 (s, 3H), 2.61 (d, 2H, J = 7.4 Hz), 3.84-3.95 (m, 1 H), 4.28-4.60 (m , 2H), 4.60-4.72 (m, 2H), 4.82 (s, 2H), 7.35 (d, 1 H, J = 7.8 Hz), 7.78 ¡(d, 1 H, J = 7.8 Hz), 8.00 (d, 1 H, 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 Spec (FAB +) m / z: 407 ((M + H) +).

EXAMPLE 29 Acid 1 -j (6-ethyl-5-r5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-Bl) methyl) azetidine-3-carboxylic acid (29a) (6-Ethyl-5-f5- (4-isobuyl-3-methyl-phenyl) -1,2,4-oxadiazol-3-yl-1-pyridin-2-yl}. Melanol The unpurified production of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 12 (12a) using 4-isobuyl-3-meiylbenzoic acid (92 mg, 0.48 mmole) which was obtained in Example 27 (27d), 1-hydroxybenzoyriazole (69 mg, 0.51 mmol), 1-eyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (97 mg, 0.51 mmol), '2-ellyl-N'-hydroxy-6-. {[[(isopropyl) silyl ) oxy] methyl.} pyridine-3-carboximicjamide (0.16 g, 0.46 mmol) which was obtained in example 25 (25b), and a 1.0 M solution of tetrabutylammonium fluoride in teirahydrofuran (0.92 ml, 0.92 njimoles). , the crude product of the title compound thus obtained was purified by chromatography on a silica gel column i using a mixed solvent of ethyl acetate and hexane (1: 3) as the eluyeny obtain the compound of the tíulo (0.15 g) with a yield of 93% as a crystalline white solid. 'Specimen 1 HNRM (400 MHz, CDCI3) d ppm: 0.96 (d, 6H, J = 6.3 Hz), 1.37 (l, 3H, J = 7.4 Hz), 1.85-1.98 (m, 1 H), 2.41 (s, 3H), 2.57 (d, 2H, J = 7.0 Hz), 3.29 (q, 2H, J = 7.4 Hz), 4.14 (bs, 1 H), 4.82 (s, 2H), 7.21 (d, 1 H, J = 8.2 Hz), 7. 28 (d, 1 H, J = 7.8 Hz), 7.95 (dd, 1 H, J = 7.8 Hz, 1.6 Hz), 7.99 (s, 1 H), 8.34 (d, 1 H, J = 8.2 Hz). 1 IR spec (KBr): 1071, 1322, 1342, 1454, 1556, 1591, 3266, 3342 cm "1. Mass spectrum (FAB +) m / z: 352 ((M + H) +). (29b) 1 - ((6-ethyl-5- [5- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl) methyl) azetidine-3- Methyl carboxylate The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 23 (23g) by using it. { 6-eyl-5- [5- (4-isobuyl-3-meitylphenyl) -1,4,4-oxadiazol-3-yl] pyridin-2-ymelanol (0.15 g, 0.42 mmol) which was obtained in the example 29 (29a), carbon leirabromium (0.28 g, 0.84 mmol), triphenylphosphine (0.22 g, 0.84 mmol), 3-azeidincarboxylamine hydrochloride of meityl (96 mg, 0.63 mmol), and NN-d-propylene-diamine (0.22 ml, 1.3 mmoles). Subsequently, the unpurified production of the title compound thus obtained was purified by chromatography on a column of silica gel using a mixture of ethyl hexane disulfide and hexane (1: 1 to 2: 1) as the eluent to obtain the compound of the title (0.13 g) with a yield of 71% as a colorless oily product. , Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.96 (d, 6H, J = 6.3 Hz), 1.33 (t, 3H, J = 7.4 Hz), 1.87-1.97 (m, 1 H), 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, 1 H), 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, 1 H, J = 8.2 Hz), 7.29 (d, 1 H, J = 7.8 Hz), > 7.95 (d, 1 H, J = 7.8 Hz), 7.99 (s, 1 H), 8.27 (d, 1 H, J = 8.2 Hz). IR spec (liquid film): 1176, 1202, 1340, 1560, 1591, 1739 cm "1. Mass spec (FAB +) m / z: 449 ((M + H) +). (29c) 1 - ((6-etl-5-yl- (4-isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-inpyridin-2-yl) methyl) azetidine-3- acid carboxyl I The thioule compound (0.10 g) was synthesized with a yield of 82% as a white crystalline solid by conducting the reaction similar to that mentioned in example 3 (3e) using 1- (. {6-eyl) -5- [5- (4-isobuyl-3-meilyl-phenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} .methyl) azeidin-3-carboxylamino-methylaly (Ó.13 g) , 0.29 mmole) which was obtained in Example 29 (29b) and a 1 N aqueous solution of sodium hydroxide (0.87 mL, 0.87 mmol). Specimen 1HRMN (400 MHz, CD3CO2D) d ppm: 0.97 (d, 6H, J = 6.6 Hz), jl .36 (l, 3H, J = 7.4 Hz), 1.89-2.00 (m, 1 H), 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, 1 H), 4.47-4.61 (m, 2H), 4.61-4.73 (m, 2¡H), 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 specimen (KBr): 1327, 1338, 1400, 1563, 1590, 1617, 3451 cm Mass specimen (FAB +) m / z: 435 ((M + H) +).

EXAMPLE 30 Acid 1- (. {6-ethyl-5-r5- (3-fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-ylpñrñ? D? N-2-yl) methyl) azetidine-3-carboxtílico , (30a) (6-Ethyl-5- [5- (3-fluoro-4-isobuhylphenyl) -1, 2,4-oxadiazol-3-illpyridin-2-yl) methanol, The crude product of the title compound the reaction similar to that mentioned in Example 12 (12a) was synthesized by using 3-fluoro-4-isobutylbenzoic acid (0.11 g, 0.54 mmole) which was obtained in Example 23 (23e), 1-hydroxybenzotriazole (86 mg) , 0.56 mmole), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.11 g, 0.56 mmol), '2-elyl-N'-hydroxy-6-. { [(lysopropylsilyl) oxy] meily} pyridine-3-carboximidimide (0.18 g, 0.51 mmol) which was obtained in Example 25 (25b), and a 1.0 M solution of leirabuylylammonium fluoride in non-ruptured water (1.0 mL, 1.0 mmol). Subsequently, the unpurified product of the obtained allyl title compound was purified by chromatography on a silica gel column using a solvent mixture of ethyl acetate and hexane (2: β to 4: 6) as the eluent to obtain the compound of the title (0.13 g) with a yield of 74% as a white crystalline crystalline solid. Specimen 1 HNRM (400 MHz, CDCI3) d ppm: 0.96 (d, 6H, J = 6.7 Hz), 1.37 (l, 3H, J = 7.4 Hz), 1.91-2.03 (m, 1 H), 2.61 (d, 2H , J = 7.0 Hz), 3.28 (q, 2H, J = 7.4 Hz), 4.09 (br, 1 H), 4.80 (s, 2H), 7.19 (d, 1 H, J = 7.8 Hz), 7.31-7.36 (m, 1 H), 7.81-7.91 (m, 2H), 8.32 (d, 1 H, 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) 1 - ((6-ethyl-5- [5- (3-fluoro-4-isobuylphenyl) -1, 2,4-oxadiazol-3-ippyridin-2-yl) methyl) azetidine-3-carboxylaph The unpurified product of the compound of the product was synthesized by conducting the reaction similar to that mentioned in Example 23 (23g) using it. { 6-ethyl-5- [5- (3-fluoro-4-isobuylphenyl) -1,4, 2,4-oxadiazol-3-yl] pyridin-2-yl-methanol (0.13 g, 0.38 mmol) which was obtained in Example 30 (30a), carbon tetrabromurb (0.25 g, 0.75 mmol), triphenylphosphine (0.20 g, 0.75 mmol), 3-azetidinecarboxylamine hydrochloride of meityl (78 mg, 0.51 mmol), and N, N-diisopropylethylamine (0.15) ml, 0.86 mmol). Subsequently, the production without purification of the compound of the product thus obtained was purified by chromatography on a column of silica gel using a Solvent mixture of ethyl acetate and hexane (3: 7 to 7: 3) as the eluent pjara obíener the compound of the tíulo (0.11 g) with a yield of 69% as an oily pale yellow product.

Spectrum 1HRMN (400 MHz, CDCI3) d ppm: 0.96 (d, 6H, J = 6.6 Hz), 1.33 (jt, 3H, J = 7.4 Hz), 1.92-2.03 (m, 1 H), 2.61 (d, 2H, J = 7.0 Hz), 3.24 (q, 2H, J = 7.4 | Hz), 3.35-3.45 (m, 1 H), 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, 1 H, J = 8.2 Hz). IR specimen (liquid film): 1203, 1342, 1562, 1590, 1739, 2958 cm "1.

Mass Spec (FAB +) m / z: 453 ((M + H) +). (30c) 1- (. {6-Ethyl-5-y5- (3-fluoro-4-isobutylphenyl) -1,2,4-oxadiazol-3-ippyridin-2-yl) methyl) azeididine- 3-carboxylic acid I The compound of the tíulo (90 mg) was synthesized with a yield of 87% how a solid white crislaine when driving the reaction similar to that mentioned in example 3 (3e) using 1- (. {6-ethyl-5- [5- (3-fluoro-4-isopropyl) -1, 2,4-oxadiazol-3-yl ] pyridin-2-yl.} methyl) azetidine-3-methyl carboxylate (0.11 g, 0.24 mmol) which was obtained in Example 30 (30b) and a 1 N aqueous solution of sodium hydroxide (0.71 mL, 0.71 mmoles).

Specimen 1HRMN (400 MHz, CD3CO2D) d ppm: 0.97 (d, 6H, J = 6.6 Hz) | 1.37 (t, 3H, J = 7.5 Hz), 1.92-2.04 (m, 1 H), 2.65 (d, 2H, J = 7.3 Hz), 3.29 (q, 2H, J = 7.5 Hz), 3.86-3.97 ( m, 1 H), 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). Specter IR (KBr): 760, 900, 1103, 1342, 1402, 1508, 1561, 1592, 2873, 2963, 3438 cm "1. Mass Spec (FAB +) m / z: 439 ((M + H) +). The present invention will be described in greater detail by means of the test examples and the examples of formulation below, but the scope of the present invention should not be limited to these examples.

EXAMPLE OF TEST 1 Evaluation of the antiartritic activity of the compounds The inhibitory activity of a medicinal composition comprising a compound of the present invention was investigated using arthritic rats induced by adjuvant, which exhibit symptoms similar to those of human arthritis, using the swelling inhibition ratio! from the right side of the blood (siiio injected with the adjuvant) as an indicator. Lewis rats aged 8 weeks are used for this study. (1) Preparation of the dry heat-killed Mycobacterium butyricum adjuvant was ground in a pestle mortar and then suspended in dry sterilized liquid paraffin to make a 2 mg / ml suspension. The suspended solution resulted then sonic and was used as an adjuvant. (2) Preparation of the test compounds The test compounds were dissolved or suspended in a 0.5% chilli solution of tragacanth. i (3) Induction of adjuvant-induced arthritis Arthritis was induced by intradermal injection of adjuvanle prepared in (1) above described (0.05 ml) into the foot pad of the hind limb of the rats in the group brought with the drug and | in the control group. Rats that are not brought with the adjuvant were used separately, the normal group conírol. (4) Compound administration Test compounds prepared in (2) above described were orally administered to rats from the group brought with the compound at a volume of 5 ml / kg once a day from the day of injection of the compound. adjuvant (day 0) for 18 successive days. The raias in the conírol sel group similarly administered a single 0.5% tragacanth solution. (5) Calculation of the swollen paw volume inhibition ratio by the test compound. On the 11th and 18th day after starting the administration of the drug, the volume of the right paw of each rat was measured by a manufactured apparatus. for the determination of the volume. The volume of average swelling of each group was then calculated. The swelling inhibition percentage of the injected population of the traced animals was calculated in comparison with that of the animals conirol according to the following equation: Inhibition ratio of the volume of the swollen blade (%) =. { 1- [(volume of the swollen blade of the animals treated with a compound) - (volume of the paw of the normal control animals)] / [(volume of the swollen leg of the control animals) - (volume of the pa of normal animals conírol)]} x 100 EXAMPLE OF TRIAL 2 Determination of the inhibitory activities of the compound against I of the host-versus-graft reaction (HvGR1 was the rat (1) Two strains of the rats were used [Lewis rats (males, 6 weeks of age, Charles River Japan Inc.) and WKAH / Hkm rats (males, 7 weeks of age, Japan SLC Inc.)]. Five rats (hosts) were used per group. (2) Induction of HvGR Spleen cells were isolated from the spleens of rats WKAH / Hki or Lewis rats and were floated in RPMl 1640 medium (Life Technologies Inc.) at a concentration of 1 x 108 cells / ml. then a aliquot of 0.1 ml aliquot of the medium that conies the spleen cells blooming free way (1 x 107 cells) of the WKAH / Hkm or Lewis rations Inírjadermalmenie inírio of the bilateral pads of the paía of the exíremidades Iraseras of both sides of the Lewis rails. (3) Administering the compound test The test compound was suspended in 0.5% solution of tragacanth The suspended solution of a compound of the present invention (5 ml / kg of rat body weight) was administered orally to the rats of the group brought with the drug (the Lewis rats in which spleen cells from the WKAH / Hkm rats were injected and the compound test was administered) once a day for 4 successive days starting the day of the spleen cell injection. In addition, the tragacanth solution was administered orally} (0.5%) instead of the substance, test the rats in the "same strain group" (Lewis rats injected with Lewis rabies spleen cells) and the ponlrol group (Lewis rats injected with rats spleen cells i WKAH / Hk? Ny not unraveled with the test compound). (4) Determination of the inhibitory activity against HvGR The average weight of the popliteal lymph nodes of rats of the same strain was subtracted from the individual weights of the popliteal lymph nodes of individual rats ("weight of the popliteal lymph nodes. after induction by HvGR "). The inhibitory activity of a compound was calculated from the "weight of the popliteal lymph nodes after induction by HvGR" of the individual rats in the group irradiated by the drug conira the "weight of the popliteal lymph nodes after the Induction by HvGR "average in the control group. The results are summarized in Table 5 shown below.

TABLE 5 Compound Inhibition ratio (%, mg / kg of 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 Reference compound 1 -15.5 Compound of reference 2 -19.0 From the present results, the compounds of the present invention exhibited excellent inhibitory activity against HvGR.

Reference Compound 1 and Reference Compound 2 are compounds described as Example 19 and Example 21 in the literature patent '2 (International Publication number WO 03/105771 pamphlet), and its chemical laboratories are the following: WO03.1 05771 Example 1 WOO 3/1 05771 EXAMPLE 21 TEST EXAMPLE 3 Evaluation of the inhibitory activity of the compounds in rat count of peripheral lymphocytes The Lewis rats were used (males, 5 weeks of age, Charles Riyer Japan Inc.). Five rats / group were used. i (1) Administration of the compound • The test compound was suspended in a 1% tragacanth solution (vehicle). The solution suspended from the test compound was orally administered to the rats in a volume of 5 ml / kg. In conirol rats, the vehicle was orally administered instead of the suspended solution of the test compound. (2) Conversion of peripheral lymphocytes Three hours after administration of either the vehicle or the suspended solution of the test compound, blood was collected from; the poscacava vein of the rats under anesthesia with ether. Subsequently, the collected blood was placed inside a tube containing EDTA. The absolute number of lymphocytes in the blood collected was counted using an analyzer for loyal blood count. The inhibitory activity (%) of the test compound was determined by calculating the relative number of peripheral lymphocytes with the number of lymphocytes in the blood collected from the normal rats being defined as 100%.

EXAMPLE OF FORMULATION Tablet The tablets (200 mg in a tablet) were prepared by mixing the powders of the above-described prescription in a mixer, and tabletting the mixture using a tablet-forming machine.

Advantages of the Invention Since the compounds of the present invention exert an excellent immunosuppressive activity with low toxicity, the compounds of the present invention are useful as a prophylactic agent or a therapeutic agent for diseases related to the suppression of the immune system in mammals (particularly in humans).

Claims (6)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound that has the general formula (I) shown below, wherein A represents a carboxyl group, a phospho group, a sulfo group, or a jl H-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 which can be substituted with a susíituyenfe (s) selected from the group susíiuuyenie A or a single bond, W represented a heierocyclic group of 5 to 7 members which can be optionally subsituted with 1 to 3 susíituyeníes selected from group A susíiluyeníe, in the case that V represents a methylene group which can be susíiuuido with a susíiíuent (s) selected from the group susíííuent A, while in the case that V represents a single bond, W represents a fused ring heterocyclic group which may optionally be substituted with from 1 to 3 substituents selected from the group A, X represented a g C8 alkylene radical which may optionally be substituted with 1 to 5 subsitutes selected from the group A, an alkylene group of C8 which contains an oxygen atom or a sulfur atom in the carbon chain which may optionally be replaced with 1 to 5 susíjituyentes selected from the group sustiluyeníe A, an arylene group of | C6-C-? 0 which may optionally be substituted with from 1 to 3 substituents selected from the group substituted for A, a 5- to 7-membered heterocyclic group which may optionally be substituted with from 1 to 3 substituents selected from substitute group A, or a fused ring heyerocyclic group which may optionally be subsituted with 1 to 3 members selected from substituent group A, and represented an aryl group of C 6 -C 0 which may optionally be substituted with from 1 to 3 substitutes selected from the group A substitute, a heterocyclic group of 5 to 7 members which may be optionally substituted with 1 to 3 selected sustiluyeníes from the group A substitute, or a heierocyclic group of fused ring which it can optionally be subsumed with 1 to 3 susíiluyeníes selected from the substituent group A, Z represents a group selected from the substituent group A, an alkyl group of Ci-Cß which may optionally be substituted with from 1 to 5 substituents selected from the group A, a Ci-Cß alkyl group containing an oxygen atom or a A sulfur atom in the carbon chain which optionally may be substituted with 1 to 5 substituents selected from the group A substitution, a C3-C7 cycloalkyl group which may optionally be susiiuuided with from 1 to 5 susíiuyenyes selected from of the substituent group A, an aryl group of C6-C ?O which may optionally be subsided with from 1 to 5 subsi- dients selected from the group A, a C6-C? aryloxy group which may optionally be subsi- didated with from 1 to 5 substituents selected from the group A, a C6-C10 arylthio group which may be optionally substituted with from 1 to 5 substituents entities selected from the group substitute A, an aralkyl group of C6-C? 2 which may optionally be subsumed with from 1 to 5 susligens selected from the group A, or a C6-Cyl arylcarbonyl group which may be optionally substituted with 1 to 5 substitutes selected from the group substitute A, the group subscribed to A represented! the group consisting of a halogen atom, an alkyl group of C? -C6, a cycloalkyl group of C3-C7, an aryl group of Ce-Cio, an aryloxy group of Ce-Cio, an aralkyl group of C6-C ?2, a haloalkyl group of C? -C6, a C? -C6 alkoxy group, a C? -C6 halogenoalkoxy group, an C-C? alkylthio group, a carboxyl group, a C-C? alkylcarboxy group, a hydr? xyl, an aliphatic acyl group of Ci-Ce, an amino group, a monoalkylamino group of CrC6, a dialkylamino group of C Cß, an aliphatic acylamino group of CrC6, a cyano group, and a nitro group], a pharmaceutically salt acceptable thereof, or a pharmacologically acceptable prodrug thereof. 2 - . 2 - The compound according to claim 1, further characterized in that B represents a hydrogen atom, or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1 or claim 2, further characterized in that A represents a carboxyl group, or a pharmaceutically acceptable salt thereof. 4. The compound according to any claim selected from claim 1 to claim 3, further characterized in that n represents an integer of 0, or a pharmaceutically acceptable salt thereof. 5. The composite according to any claim selected from claim 1 to claim 4, further characterized in that V represents a methylene group, and W represents a heterocyclic group of 5-7 members which may be optionally substituted with from 1 to 3 susyiluyeníes selected from the substituent group A, or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 5, further characterized because the 5 to 7 member heyerocyclic group represented! a thienylene, furylene, pyrrolylene, or pyridylene group, or a pharmaceutically acceptable salt thereof.; 7. The compound according to claim 5, further characterized in that W represents a thienylene or pyridylene group which may be optionally substituted with 1 to 2 substituents selected from the group A, or a pharmaceutically acceptable salt thereof. . 8. The compound according to claim 6, further characterized in that the thienylene or pyridylene group represents a moside group below, respectively, or a pharmaceutically acceptable salt thereof. 9. - The compound according to any selected claim of claim 1 to claim 4, further characterized pprque V represent a single bond and W represent a fused ring heterocyclic group which may be optionally substituted with 1 to 3 substituents selected from the substituent group A, or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 9, further characterized in that W represents a fused ring heterocyclic group, or a pharmaceutically acceptable salt thereof. 11. The compound according to claim 10, further characterized in that the fused ring heterocyclic group i represents a terahydrobenzofuranylene, eeryhydrobenzothienylene, or N -methylhydroindolylene group, or a pharmaceutically acceptable salt thereof. 12 - The compound according to claim 11, further characterized in that the fused ring heyerocyclic group has its two available positions to form bonds in positions 2 and 4, or a faimaceutically acceptable salt thereof. 13. The compound according to claim 12, further characterized in that the substitution in position 2 represents the group of formula Z-Y-X-, or a pharmaceutically acceptable salt thereof. 14. The compound according to any claim selected from claim 1 to claim 13, further characterized in that X represents an alkylene group of C? -C8, an alkylene group of C C8 containing an oxygen atom or a sulfur atom in the carbon chain, an arylene group of Ce-Cio, a 5 to 7 membered helerocyclic group, or a fused ring helerocyclic group, or a pharmaceutically acceptable salt thereof. The compound according to any claim selected from claim 1 to claim 13, further characterized in that X represents a 5- to 7-membered heterocyclic group, to a pharmaceutically acceptable salt thereof. 16 - The compound according to any claim selected from claim 1 to claim 15, further characterized because Y represented any group selected from the group consisting of a phenylene group, a 5- to 7-membered heterocyclic group which may optionally be substituted with 1 to 3 substituents selected from the group A, and a fused ring heterocyclic group which may optionally be susiuuid with 1 to 3 substituents selected from the substituent group A, or a pharmaceutically acceptable salt thereof. 17. The compound according to any claim selected from claim 1 to claim 15, further characterized in that Y represents a phenylene group, or a thienylene, pyridylene, or indolylene group which may be optionally substituted with from 1 to 3 Subsidiaries selected from the group A, or a pharmaceutically acceptable salt thereof. 18. The compound according to any claim selected from claim 1 to claim 15, further characterized in that Y represents a phenylene group or a pyridylene group, or a pharmaceutically acceptable salt thereof. 19. The compound according to any claim selected from claim 1 to claim 18, further characterized in that Z represents a C6-C10 aryloxy group which may be optionally substituted with from 1 to 5 substituents. selected from the substituent group A, or a pharmaceutically acceptable salt thereof. 20. The compound according to any claim selected from claim 1 to claim 18, further characterized in that Z represents a phenoxy group, or a pharmaceutically acceptable salt thereof. twenty-one - . 21 - The compound according to claim 1, further characterized in that the general formula (I) is the general formula (I1) shown below, wherein R 1 represents a hydrogen atom or a C Cß 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, an alkyl group of C Ce, or an alkoxy group of Ci-Ce, and R5 i representing a hydrogen atom or a halogen atom], or a pharmaceutically acceptable salt thereof. 22. The compound according to claim 21, further characterized in that R1 represents a hydrogen atom, or a pharmaceutically acceptable salt thereof. 23 - The compound according to claim 21 or claim 22, further characterized in that R 2 represents a hydrogen atom, a meiyl group, or an ethyl group, or a pharmaceutically acceptable salt thereof. 24. The compound according to any claim selected from claim 21 to claim 23, further characterized in that R3 represents a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group, or a salt pharmaceutically acceptable 25. The compound according to any selected claim as set forth in claim 21 to claim 24, further characterized in that R4 represents a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a methyl group , or a methoxy group, or a pharmaceutically acceptable salt thereof. 26. The compound according to any claim selected from claim 21 to claim 25, further characterized in that R represents a hydrogen atom or a fluorine atom, or a pharmaceutically acceptable salt thereof. 27. The compound according to claim 1, further characterized in that the general formula (I) is the general formula (I ") shown below, wherein R6 represents a hydrogen atom or a C6 alkyl group, R7 represents a hydrogen atom, a halogen atom, or an alkyl group of CrC6, and R8 represented an alkyl group of C6-C6 or a group CrC6 alkoxy], or a pharmaceutically acceptable salt thereof. 28. - The compound according to claim 27, also characterized because R6 represented a hydrogen atom, a group meilyl, or an ethyl group, or a pharmaceutically acceptable salt thereof. 29. - The compound in accordance with any claim selected from claim 27 or claim 28, further characterized in that R7 represents a hydrogen atom, a fluorine atom i, a chlorine atom, or a methyl group, or a pharmaceutically salt acceptable of it. 30. - The compound in accordance with any claim selected from claim 27 to claim 29, further characterized in that R8 represented an n-propyl group, a n-buylloyl group, or u? isobuyl group, or a pharmaceutically acceptable salt thereof. 31 -. 31 - The compound according to claim 1, also characterized because said compound is any selected to from the following compounds, or a pharmaceutically acceptable salt of the same: Acid 1 - [(4- {5- [4-phenyl-5- (trifluoromethyl) -2-thienyl] -1,2,4-oxadiazol-3-yl}. -furyl) methyl] azetidine-3-carboxylic acid, 1- (. {5- [5- (4-isobutyl-phenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} -methyl) azeidin-3-carboxylic acid, 1 - (. {5- [5- (4-cyclohexyl-phenyl) -1,2,4-oxadiazol-3-yl] -2-furyl} -methyl) azide Na-3-carboxylic acid 1- (2- { 5- [4-phenyl-5- (trifluoromethyl) -2-lienyl] -1,4, 2,4-oxadiazol-3-yl.} -4,5,6,7-ehydrohydrate -1-benzofuran-4-yl) azetidine-3-carboxylic acid, 1- (. {5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-lienyl acid} .methyl) azeididine-3-carboxylic acid, 1 - (. {4- [5- (4-benzoylphenyl) -1), 2,4-oxadiazol-3-yl] -2-lienyl} meylyl) azeididine-3-carboxylic acid, 1- (. {4- [5- (4-b! encylphenyl) -1, 2,4-oxadiazol-3-yl] -2-thienyl} -methyl acid. ) azeidin-3-carboxylic acid. 1- ( { 4- [5- (1-isobutyl-1 H -indol-5-yl) -1,2,4-oxadiazol-3-yl] -2-tylphenyl} methyl) azeidin-3-carboxylic acid, 1 - (. {6- [5- (4-isobuylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-3-yl} methyl) azeididine -3-carboxylic acid, and 1- (. {5- [5- (4-isobutyl-phenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl}. meily) azelidine-3-carboxylic acid. 32. The compound according to claim 1, further characterized in that said compound is any selected from the following compounds, or a pharmaceutically acceptable salt thereof: 1- (. {5- [5- (4- Phenoxyphenyl) -1,4,4-oxadiazol-3-yl] -2-thienyl] methyl) azetidine-3-carboxylic acid, 1- (4-methyl-5- [5- (4 -phenoxyphenyl) -1, 2,4- and oxadiazol-8-yl] -2-thienyl} -methyl) azelidine-3-carboxylic acid, 1 - (. {5- [5- (3-fluoro-4 phenoxyphenyl) -1, 2.4"? xadiazol-3-yl] -4-methyl-2-thienyl} methyl) azetidine-3-carboxylic acid, 1- (. {4-ethyl} 5- [5- (4-phenoxyphenyl) -1,4,4-oxadiazol-3-yl] -2-ynyl} -methyl) azeididine-3-carboxylic acid, 1 - [(4-ethyl-) 5- {5- [4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-ynyl) -methyl] azeidin-3-carboxylic acid 1- (. {4-eyl-5- [5- (3-fluoro-4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-ylene} -methyl) azeididine-3 carboxylic acid, 1 - [(4-eyl-5-. {5- [3-fluoro-4- (3-fluorophenoxy?) phenyl] ] -1, 2,4-oxadiazol-3-yl.} -2-yl) -methyl] -zezeidin-3-carboxylic acid, 1 - [(4-ellyl-5. { 5- [4- (2-meioxyphenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2-ethylene) -methyl] azeididine-3-carboxylic acid, 1 - [(5-. {5- [3-chloro-4- (3-fluorophenoxy) phenyl] -1,2,4-oxadiazole- 3-yl.} -4-eyl-2-yl) -methyl] azeididine-3-carboxylic acid, 1-l (4-eyl-5-. {5- [4- (2-meioxyphenoxy)) phenyl] -1,4,4-oxadiazol-3-yl.} -2-ynyl) methyl] azetidine-3-carboxylic acid, 1 - [(4-eyl-5-. {5- [4- ( 2-fluorofen >;? i) tenyl] -1,4, 2,4-oxadiazole-3-yl} -2-ethylene) -methyl] azeididine-3-carboxylic acid, 1 '- [(5- {5- [4- (2,3-difluorophenoxy) phenyl] -1,2,4-oxadiazole-3} -yl.} -4-eyl-2-ynyl) -methyl;] azeidine-3-carboxylic acid, 1 - [(4-ethyl-5-. {5- [3-fluoro-4- (2-fluorophenoxy)] ) phenyl] -1,4, 2,4-oxadiazol-3-yl.} -2-thienyl) methyl] azelidine-3-carboxylic acid, 1 - [(5-. {5- [4- (2,3-difluorophenoxy) -3-fluorophenyl] -1,4, 2,4-oxadiazol-3-yl.} -4-eyl-2-yl] -methyl] azelidine-3-carboxyl co, 1 - [(5-. {5- [3-chloro-4- (2-fluorophenoxy) phenyl] -1,2,4-oxadiazol-3-yl} -4-eyl- 2-ynyl) -methyl] azeididine-3-carboxylic acid, 1 - [(5- {5- [3-chloro-4- (2,3-difluorophenoxy) phenyl] -1,2,4-oxadiazole-3} -yl.} -4-eyl-2-thienyl) -methyl] azeidin-3-carboxylic acid, 1 - [(5- {5- [4- (2-chlorophenoxy) phenyl] -1,2} 4-Oxadiazol-3-yl.} -4-eyl-2-ynyl) methyl] azide-3-carboxylic acid, 1 - [(5-. {5- [4- (2- chlorophenoxy) -3-fluorophenyl] -1,4,4-oxadiazol-3-yl} -4-ethyl-2-yl) methyl) azetidine-3-carboxylic acid - ( { 3-Methyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-lienyl} me yl) azetidine-3-carboxylic acid and 1- (. {3-elyl-5- [5- (4-phenoxyphenyl) -1,2,4-oxadiazol-3-yl] -2-thienyl} -methyl acid. ) azeididine-3-carboxylic acid. 33. The compound according to claim 1, further characterized in that said compound is any one selected from the following compounds, or a pharmaceutically acceptable salt thereof; 1- (. {5- [5- (4-Isobutyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azide Na-3-carboxylic acid, 1- (. {5- [5- (3-fluoro-4-isobuylphenyl) -1,2,4-oxadiazol-3-yl] pyridine-2-yl]. (methylene) azeididine-3-carboxylic acid, 1 - (. {5- [5- (3-chloro-4-isobuylphenyl) -1,2,4-oxad? azol-3-yl] pyridin-2 acid methyl) azelidine-3-carboxylic acid, 1- (. {5- [5- (4-l-isobuyl-3-meitylphenyl) -1,2,4-oxadiazole-3-yl] -6-methylpyridin-2-yl.) Methyl) azeotidine-3-carboxylic acid, 1 - (. {5- [5- (3-fluoro-4-propylphenyl) -1, 2,4-Oxadiazol-α-yl] -6-meilypyridin-2-yl} methyl) azelidine-3-carboxylic acid, 1- (. {5- [5- (4-butyl-3-fluo-phenyl)) -1, 2,4-oxadiazol-3-yl] -6-meityl-pyridin-2-yl.} -methyl) azeidin-3-carboxylic acid, 1- (. {5- [5- (3-fluoro 4-isobuylphenyl) -1, 2,4-oxadiazol-3-yl] -6-methyl-pyridyl-2-yl.} Methyl) azeidin-3-carboxylic acid, 1 - (. {5- [ 5- (3-chloro-4-isobuylphenyl) -1,4, 2,4-oxadiazol-3-yl] -6-methylpyridin-2-yl} .methyl) azeididine -3-carboxylic acid, 1- (. {6-eyl-5- [5- (4-isobuyl-3-methylphenyl) -1,2,4-oxadiazol-3-yl] pyridin-2-yl} methyl) azeidin-3-carboxylic acid, 1 - (. {6-eyl-5- [5- (3-fluoro-4-propylphenyl) -1, 2,4-oxadiazol-3-yl] pyridin-2 acid methyl) azeididine-3-carboxylic acid, 1- (. {5- [5- (4-buyyl-3-fluorophenyl) -1,2,4-oxadiazol-3-yl] -6- eylpyridin-2-yl.} meityl) azeididine-3-carboxylic acid, 1- (. {6-ethyl-5- [5- (3-fluoro-4-isobuylphenyl) -1,2,4-oxadiazole- 3-yl] pyridin-2-jl.] Metl) azeididine-3-carboxylic acid and 1- (. {5- [5- (3-chloro-4-isobuylphenol) -1, 2 , 4-Oxadiazol-3-yl] -6-eylpyridin-2-yl} .methyl) azeidin-3-carboxylic acid. 34 - A medicinal composition comprising one or more compounds or a pharmaceutically acceptable salt thereof according to any of claims 1 to 33, as an active ingredient. 35.- The medicinal composition according to claim 34 for suppressing the immunological rejection symptoms that occur after the grafting of skin tissue or transplantation of various organs. 36 - The medicinal composition according to claim 34 for prophylaxis or therapy of autoimmune diseases. 37.- The medicinal composition according to claim 36, further characterized in that said auinoinmurje disease is one or more conditions selected from the group that consists of rheumatic arthritis, psoriasis, atopic dermatitis, multiple sclerosis, ulcerative coliitis, and Crohn's disease. 38. - The use of one or more compounds or a salt pharmaceutically acceptable thereof of any one of the claims 1 to 33, for the preparation of a medicinal composition useful for suppressing symptoms of immune rejection that occur after grafting skin tissue or transplanle of various organs. 39. - The use of one or more compounds or a salt pharmaceutically acceptable thereof of any one of claims 1 to 33, for the manufacture of a medicinal composition useful for prophylaxis or therapy of autoimmune diseases. 40. - The use as claimed in claim 39, in where said immune-immune disease is one or more conditions selected from the group consisting of rheumatic arthritis, psoriasis, and atopic dermatitis, multiple sclerosis, ulcerative colitis, and Crohn.