NZ620339B2 - N-hetero-ring-substituted amide derivative - Google Patents

Abstract

Provided are N-hetero-ring-substituted amide oxadiazole derivative compounds of the general formula (I), wherein the variables are as defined in the specification. Examples of the compounds include 4-(5-{(1R)-1-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1,2,4-oxadiazol-3-yl)-2-fluoro-N-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]benzamide and 4-(S-{(1R)-1-[4-(cyclopropylcarbonyl)phenoxy]ethyl}-1,2,4-oxadiazol-3-yl)-2-fluoro-N-[(3S)-2-oxopyrrolidin-3-yl]benzamide. The compounds may be useful in the treatment of diabetes and obesity. xytetrahydrofuran-3-yl]benzamide and 4-(S-{(1R)-1-[4-(cyclopropylcarbonyl)phenoxy]ethyl}-1,2,4-oxadiazol-3-yl)-2-fluoro-N-[(3S)-2-oxopyrrolidin-3-yl]benzamide. The compounds may be useful in the treatment of diabetes and obesity.

Description

PTION N—HETERO-RING-SUBSTITUTED AMIDE DERIVATIVE Technical Field The present invention relates to novel ro~ring— substituted amide derivatives which have a hypoglycemic effect and/or B cell— or pancreas~protecting effects, or pharmacologically acceptable salts thereof, and pharmaceutical compositions containing those active ients.

Background Art Diabetes mellitus is a metabolic disease primarily characterized by a chronic hyperglycemic state due to impaired insulin action. The treatment of diabetes is generally performed by drug therapy together with diet and exercise therapy. Examples of oral anti—diabetic agents include ides and thiazolidinediones that improve insulin resistance; sulfonylureas and es that promote n secretion from pancreatic B cells; and @— glucosidase inhibitors that inhibit sugar absorption.

However, it is reported that they have side effects: ides produce gastrointestinal symptoms and lactic acidosis; thiazolidinediones produce weight gain and edema; sulfonylureas and glinides produce hypoglycemia or FP12255 SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905SWALLACE secondary failure due to long—term use; and g—glucosidase tors e diarrhea etc. Therefore, pment of an oral hypoglycemic agent which can address such problems is desired.

In recent years, piperidine compounds have been developed as oral anti~diabetic agents having new structures. (see, for example, Patent Literature 1 to 4).

Citation List Patent Literature Patent Literature 1: Patent Literature 2: Patent Literature 3: Patent Literature 4: Patent Literature 5: Patent Literature 6: Summary of the Invention Problems to be Solved by the Invention However, the compounds described in the above patent ture 1 to 4, have an insufficient hypoglycemic effect and insufficient B cell— or pancreas—protecting effects.

Furthermore, the present invention is neither described nor suggested in the above patent literature 1 to 6. Thus, an object of the present invention is to provide a compound FP1225$ SJW/PN811150/ h ation of PCTJP2012/069098 specification 4624905SWALLACE which has a new structure that is neither described nor ted in the above patent literature and has an excellent hypoglycemic effect and a B cell~ or pancreas— protecting effect, or a pharmaceutically acceptable salt thereof; a pharmaceutical composition having an excellent therapeutic effect and/or prophylactic effect on type 1 diabetes, type 2 diabetes and the like, which cause an increase in blood sugar levels due to abnormal glucose metabolism; and a pharmaceutical composition having a B cell~ or pancreas—protecting .

Means for Solving the Problems The present invention provides: (1) a nd ented by general formula (I): [Chemical Formula 1] 1 >~©~<i R——N\ \ H F wherein R1 represents cal Formula 2], FP12255 SJW/PN811150/ English translation of PCTJP2012/089098 specification 4624905SWALLACE Q: 02% if OH , O I I * HN OH o * represents a binding site with a nitrogen atom, and R2 represents a methyl group or an ethyl group; or a pharmaceutically acceptable salt thereof; (2) a nd as set forth in item (1) selected from the group consisting of the following compounds: 4-(5-{(lR)—l—[4—(cyclopropylcarbonyl)phenoxy]propyll— oxadiazol-3—yl)—2-fluoro-N-[(38,4R)-4— hydroxytetrahydrofuran—B—yl]benzamide; 4-(5—{(1R)—l—[4—(cyclopropylcarbonyl)phenoxy]propyl}— 1,2,4—oxadiazol—3—yl)—2—fluoro—N-[(3R,4S)-4— hydroxytetrahydrofuran-3~yl]benzamide; 4—(5—{(lR)—l—[4—(cyclopropylcarbonyl)phenoxy]ethyl)- 1,2,4—oxadiazol—3—yl)—2—fluoro-N—[(3R,4S)-4— hydroxytetrahydrofuran—3—yl]benzamide; 4—(5—{(lR)-l—[4-(cyclopropylcarbonyl)phenoxy]ethyl}— 1,2,4—oxadiazol—3—yl)—2—fluoro—N—[(3S,4R)—4— hydroxytetrahydrofuran-B—yl]benzamide; 4-(5—{(lR)—l-[4—(cyclopropylcarbonyl)phenoxy1propyl}— 1,2,4—oxadiazol—3—yl)—2—fluoro—N—[(3R)-2— oxotetrahydrofuran—3-yl]benzamide; 4—(5—{(1R)—l—[4—(cyclopropylcarbonyl)phenoxy]propyl}— 1,2,4—oxadiazol—3—yl)-2—fluoro—N*[(38)—2— oxotetrahydrofuran*3—yl]benzamide; (1R)—l—[4—(cyclopropylcarbonyl)phenoxy]propyl}— l,2,4~oxadiazol—3—yl)—2—fluoro—N—[(3S)~5— oxotetrahydrofuran~3—yl]benzamide; 4—(5—{(1R)~1-[4—(cyclopropylcarbonyl)phenoxy]propyl}~ l,2,4—oxadiazol—3~yl)~2—fluoro—N—[(3R)—2—oxopyrrolidin—3— zamide; 4—(5—{(lR)—1—[4*(cyclopropylcarbonyl)phenoxy]propyl}— 1,2,4—oxadiazol—3—yl)~2—fluoro—N—[(3S)—2—oxopyrrolidin—3— yl]benzamide; 4—(5—{(1R)—l—[4—(cyclopropylcarbonyl)phenoxy]propyl}— 1,2,4—oxadiazol—3—yl)—2—fluoro—N—[(3S,4S)—4—hydroxy—2— oxotetrahydrofuran—3—yl]benzamide; 4—(5—{(1R)—1—[4-(cyclopropylcarbonyl)phenoxy]ethyl}— l,2,4—oxadiazol~3~yl)—2—fluoro—N—[(3R)—2—oxopyrrolidin—3- yl]benzamide; 4—(5—{(1R)—1—[4—(cyclopropylcarbonyl)phenoxy]ethyl}— 1,2,4—oxadiazol—3—yl)—2—fluoro~N—[(3S)—2—oxopyrrolidin—3— yl]benzamide; 4—(5—{(1R)—1—[4—(cyclopropylcarbonyl)phenoxy]propyl}— 1,2,4—oxadiazol—3—yl)—2—fluoro—N—[(3S,4R)~4~hydroxy—2— oxotetrahydrofuran—B—yl]benzamide; (1R)—1—[4—(cyclopropylcarbonyl)phenoxy]ethyl}— 1,2,4—oxadiazol—3—yl)—2~fluoro—N-[(3R,4R)—4— hydroxytetrahydrofuran—B—yl]benzamide; and FP1225s SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905~1—SWALLACE 4-(5—{(lR)—l—[4—(cyclopropylcarbonyl)phenoxy]ethyl}— oxadiazol—3—yl)—2—fluoro—N—[(3S,4S)—4— hydroxytetrahydrofuran—3—yl]benzamide; or a pharmaceutically able salt thereof; (3) a pharmaceutical composition containing, as an active ingredient, a compound as set forth in item (1) or (2), or a pharmaceutically acceptable salt thereof; (4) a pharmaceutical composition as set forth in item (3), for treating type 1 diabetes, type 2 diabetes, or obesity; (5) a pharmaceutical composition as set forth in item (3), for protecting B cells or the pancreas; (6) use of a compound as set forth in item (1) or (2) or a pharmaceutically acceptable salt thereof, for preparing a pharmaceutical composition; (7) use of a compound, as set forth in item (1) or (2) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating type 1 diabetes, type 2 es, or obesity; (8) use of a compound, as set forth in item (1) or (2) or a ceutically acceptable salt thereof for the manufacture of a medicament for protecting B cells or the pancreas. s of the Invention The present invention provides an N—hetero—ring— substituted amide derivative having an ent hypoglycemic effect, and a B cell~ or pancreas—protecting effect, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition having an excellent therapeutic effect and/or lactic effect on type 1 diabetes, type 2 diabetes and the like due to hyperglycemia, and a pharmaceutical composition having a B cell— or pancreas- ting effect.

Best Modes for Carrying out the Invention A "pharmaceutically acceptable salt" as used in the present specification means a salt formed by allowing the compound of the present invention to react With an acid or a base.

Examples of the salt include hydrohalogenic acid salts such as hydrofluorides, hydrochlorides, hydrobromides, - and hydroiodides; inorganic acid salts such as [FOLLOWED BY PAGE 8] hydrochlorides, nitrates, perchlorates, sulfates and phosphates; lower sulfonic acid salts such as methanesulfonates, oromethanesulfonates, and ethanesulfonates; lfonic acid salts such as benzenesulfonates, and p—toluenesulfonates; organic acid salts such as acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, and maleates; alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; metal salts such as aluminum salts and iron salts; inorganic salts such as ammonium salts; amine salts including organic salts such as t—octylamine salts, dibenzylamine salts, morpholine salts, amine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N~methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N‘—dibenzylethylenediamine salts, procaine salts, procaine salts, diethanolamine salts, N—benzylphenethylamine salts, piperazine salts, tetramethylammonium salts, and tris(hydroxymethyl)aminomethane salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ine salts, glutamates, and aspartates.

The compound of the present invention absorbs water when, for example, left to stand in the atmosphere, so that the absorbed water can adhere to the compound and a hydrate FP1225$ SJW/PN811150/ English translation of 012/069098 specification 4624905SWALLACE may be formed. Therefore, such a hydrate is also included in the concept of the salt of the present invention.

Since the nd of the present invention may have asymmetric carbon atoms in the molecule, the compound has optical isomers. These isomers and mixtures of these isomers are all represented by a single formula, that is, the general a (I). Therefore, the present invention encompasses all of the l isomers of the compound represented by the general formula (I), and mixtures of these optical isomers at any ratios. Such an optical isomer can be produced by, for example, using raw als having optical activity instead of the raw materials used in the production s, Reference Examples and Examples that will be described below, or can be obtained by subjecting a compound that has been produced by making reference to the production methods, Reference Examples, Examples and the like that will be described below, to an l resolution method that is known in the pertinent art, for example, a diastereomer method, an enzymatic reaction method, or an optical resolution method based on chromatography.

The present invention may also ass compounds in which one or more of the atoms constituting the compound represented by the general formula (I) have been substituted with isotopes of the atoms. Isotopes e FP1225s SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905—1-SWALLACE the two classes of radioactive isotopes and stable isotopes, and examples of the isotopes include, for e, isotopes of hydrogen (2H and 3H), isotopes of carbon (lRL 13C and 14C), isotopes of nitrogen (”N and 15N), isotopes of oxygen U50, 170 and 18O), and isotopes of fluorine (HEW. A composition containing a compound labeled with an isotope is useful as, for example, a therapeutic agent, a prophylactic agent, a research reagent, an assay reagent, a diagnostic agent, or an in vivo diagnostic imaging agent.

Compounds labeled with isotopes and mixtures of compounds labeled with es at any ratios are all included in the present invention. A compound labeled with an isotope can be produced by a method that is known in the pertinent art, for example, using raw materials labeled with isotopes instead of the raw materials used in the production methods that will be described below.

The present invention may also ass prodrugs of the compound represented by the general formula (I). A prodrug is a tive of the compound represented by the general formula (I), and means a compound which is enzymatically or chemically converted to the nd of the present invention in the living body. es of a g include compounds in which an amino group in the molecule has been acylated, ted or phosphorylated; compounds in which a carboxyl group in the FP1225s SJW/PN811150/ English ation of PCTJP2012/069098 specification 4624905v1-SWALLACE molecule has been esterified or amidated; and compounds in which a yl group in the le has been acylated, alkylated or phosphorylated (see, for example, Povl Krogsgaard—Larsen, et al., "A Textbook of Drug Design and Development", Second Edition, Harwood Academic Publishers, 1996, pp. 351—385). Such a prodrug can be produced from the compound represented by the general formula (I) by a method known in the pertinent art.

The compound of the t invention can be easily produced from known compounds according to the Reference Examples and Examples that will be bed below.

The compound of the present invention or a pharmaceutically able salt thereof obtained by the methods described above has an excellent hypoglycemic effect, and can therefore be used as an active ingredient of a ceutical composition that can be used in the treatment and/or prevention of type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, impaired e nce (IGT), obesity, diabetes~associated diseases (for example, hyperlipidemia, hypercholesterolemia, abnormal lipid metabolism, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina pectoris, myocardial infarction, arteriosclerosis, hyperuricemia, and gout), or diabetic complications (for example, sis, kidney failure, FP1225s SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905SWALLACE neuropathy, cataract, gangrenous leg, infections, and ketosis).

Furthermore, the compound of the present invention or a pharmaceutically acceptable salt thereof has an excellent B cell— or as—protecting effect, and can therefore be used as an active ient of a pharmaceutical composition that can be used to protecting B cells or the pancreas.

The compound of the present ion can also be used in combination with a therapeutic drug for diabetes other than the compound of the t invention, a therapeutic drug for diabetic complications, hyperlipidemia, hypertension, and the like.

When a pharmaceutical composition containing the nd of the present invention or a pharmaceutically acceptable salt thereof is administered to a mammal (for example, human, horse, cow or pig; preferably a human being), the pharmaceutical composition can be administered systemically or topically, and orally or parenterally.

Appropriate dosage forms of the pharmaceutical composition of the present ion can be selected in accordance with the administration mode. The pharmaceutical ition of the present invention can be FP1225$ SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905SWALLACE prepared ing to the ation methods for various conventionally used formulations.

Examples of the dosage form of the ceutical composition for oral use include tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, syrups, and elixirs. ceutical compositions of such dosage forms can be prepared according to conventional methods, by appropriately selecting as ary, excipients, binders, disintegrants, lubricating agents, ng agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, antioxidants, colorants, dissolution aids, suspending agents, emulsifiers, sweeteners, preservatives, s, diluents, wetting agents and the like, which are conventionally used as additives.

Examples of the dosage forms of a pharmaceutical ition for parenteral use include injections, ointments, gels, creams, poultices, s, aerosols, inhalants, sprays, eye drops, nose drops, and suppositories.

Pharmaceutical compositions of such dosage forms can be prepared according to conventional methods, by appropriately selecting as necessary, stabilizers, antiseptics, dissolution aids, rizers, preservatives, antioxidants, fragrances, gelling agents, neutralizing agents, buffers, isotonic agents, surfactants, colorants, buffering agents, thickeners, wetting agents, fillers, FP12255 SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905—1—SWALLACE absorption promoting agents, suspending agents, binders, and the like, which are conventionally used as additives.

The administration amount of the compound of the present invention or a pharmaceutically acceptable salt thereof may vary with the symptoms, age, body weight or the like. However, in the case of oral administration, the compound or the salt is administered once or several times a day, in an amount of 1 to 2000 mg, and ably 1 to 400 mg, in terms of the compound, per dose for an adult; and in the case of parenteral administration, the compound or the salt is administered once or several times a day, in an amount of 0.01 to 500 mg, and preferably 0.1 to 300 mg, in terms of the compound, per dose for an adult.

Examples Hereinafter, the present invention will be described in more detail by way of Reference es, Examples, a Formulation e and Test Examples, but the scope of the present invention is not intended to be limited to these. ence Example 1) tert—Butyl 4—cyano—2— fluorobenzoate [Chemical Formula 3] FP1225$ SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905SWALLACE Hac+o H3C \\ o N Di—tert—butyl dicarbonate (145.4 g, 666 mmol), and 4— ylaminopyridine (7.40 g, 60.6 mmol) were added to a tert—butyl alcohol (1000 mL)—tetrahydrofuran (500 mL) solution of 4—cyano—2—fluorobenzoate (100.0 g, 606 mmol), and the mixture was d at 60°C for 3 hours. The reaction mixture was cooled to room temperature, and the insoluble al was removed by filtration through .

The solvent was distilled off under reduced pressure. Thus, a crude product of the title compound was obtained.

(Reference Example 2) tert—Butyl 4— amino(hydroxyimino)methyl—Z—fluorobenzoate [Chemical Formula 4] o NH2 H3C \ O N—OH A 50% aqueous solution of hydroxylamine (60 mL, 100 mmol) was added to an ethanol (100 mL)-tetrahydrofuran (50 mL) solution of the compound obtained in Reference Example 1 (11.0 g, 66.6 mmol), and the mixture was stirred at 80°C FF’12258 SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905SWALLACE for 2 hours. The reaction e was cooled to room temperature, and then the solvent was distilled off under d pressure. The resulting residue was washed with water, and was dried at 40°C for 2 days under reduced pressure. Thus, the title compound (150.0 g, yield: 98%) was obtained. 1H—NMR (400 MHZ, CDC13) 5 ppm: 7.89 (1H, t, J = 8 HZ), 7.44 (2H, dd, J = 8, 2 Hz), 7.39 (2H, dd, J H 11, 2 HZ), 4.90 (2H, s), 1.60 (9H, s).

(Reference e 3) Cyclopropyl(4— hydroxypheny1)methanone [Chemical Formula 5] 4—Chloropropyl(4—hydroxyphenyl)methanone (25.1 g, 127 mmol) was added to a 2 N aqueous solution of sodium hydroxide (283 mL, 566 mmol) in several portions under ice cooling. The reaction mixture was allowed to warm up to room temperature, and was stirred for 6 hours, and then dilute sulfuric acid (1.8 N) was added to the reaction mixture under ice cooling until a pH value of 2 was obtained. The on mixture was subjected to extraction twice with ethyl acetate. The organic layer thus obtained FP1225$ SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905—1-SWALLACE was washed with water and brine, and then was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was ed by silica gel column chromatography (hexanezethyl acetate = 4:1 —9 2:1, v/v) to give the title compound (17.7 g, yield: 86%). lH—NMR (400 MHZ, CDClg) 5 ppm: 7.99—7.96 (2H, m), 6.93~6.89 (2H, m), 6.16 (1H, s), 2.67— 2.61 (1H, m), 1.28—1.18 (2H, m), 1.09—0.97 (2H, m).

(Reference Example 4) (28)—2—Acetoxy butyric acid [Chemical Formula 6] H3C\\ 0 HO023%" JL 0 CH3 Sodium e (11.9 g, 146 mmol) and tert—butyl nitrite (15.0 g, 146 mmol) were added to an acetic acid (300 mL) solution of (2S)—2—aminobutyric acid (10.0 g, 97.0 mmol) under ice cooling, and was stirred at 60°C for 2 hours. The reaction e was cooled to room temperature, and then the t was distilled off under reduced pressure. Water was added to the residue, and the mixture was subjected to extraction twice with ethyl acetate. The organic layer thus obtained was washed with water and brine, and then was dried over anhydrous sodium sulfate. The FP1225$ 811150/ English translation of PCTJP2012/069098 specification 4624905SWALLACE solvent was distilled off under reduced pressure.

Furthermore, the residue was azeotropically boiled with l,4—dioxane (50 mL) twice. Thus, the title compound (8.4 gr yield: 609)0 was obtained. 1H—NMR (400 MHZ, CDCl3) 5 ppm: .00 (1H, m), 2.15 (3H, s), 1.94—1.90 (2H, m), 1.03 (3H, t, J = 7 Hz); MS (FAB) m/z: 147 [M+H]+.

(Reference Example 5) tert—Butyl 4—{5—[(lS)—l— acetoxypropyl]—l,2,4—oxadiazol—3—yl}~2—fluorobenzoate [Chemical Formula 7] H3C \E O H3C+O [vi/\O CH3 H3C \ o N’ l—Hydroxybenzotriazole drate (7.2 g, 53.0 mmol) and N—(3—dimethylaminopropyl)—N‘—ethylcarbodiimide (20.3 g, 159 mmol) were added to an N,N—dimethylformamide (200 mL) solution of the compound obtained in Reference Example 4 (7.8 g, 53.0 mmol) at room temperature, and the mixture was stirred at the same ature for 30 minutes. The compound ed in Reference Example 2 (13.5 g, 53.0 mmol) was added, and the mixture was stirred for 30 minutes, and r stirred at 100°C for 3 hours. After the FP1225$ SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905-1—SWALLACE reaction mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was subjected to extraction twice with ethyl acetate. The organic layer thus obtained was washed with water and a 10% aqueous solution of sodium chloride, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was ed by silica gel column chromatography ezethyl acetate = 95:5 —> 85:15, V/v) to give the title compound (14.7 g, yield: 76%). 1H—NMR (400 MHZ, CDC13) 5 ppm: 7.96 (1H, t, J = 8 HZ), 7.90 (1H, dd, J = 8, 2 HZ), 7.84 (1H, dd, J 11, 2 Hz), 5.92 (1H, t, J = 7 Hz), 2.21 (3H, s), 2.16—2.08 (2H, m), 1.62 (9H, s), 1.05 (3H, t, J = 7 HZ); MS (FAB) m/z: 365 [M+H]*. ence Example 6) tert—Butyl 2~fluoro—4—{5—[(1S)— 1—hydroxypropyl]—l,2,4—oxadiazol-3—yl}benzoate [Chemical Formula 8] H3013H3 \E H éy—{J \th//\TDH 3 o N’0 Potassium ate (8.4 g, 61 mmol) was added to a FP1225$ SJMHPN8H150/EnmbhtmnsmfionofPCTUPZO12M69098specficafion 46249054-SVVALLACE methanol (100 mL) on of the compound obtained in Reference Example 5 (14.7 g, 40.3 mmol) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. 2 N Hydrochloric acid was added to the reaction mixture at the same temperature until a pH value of 6.0 was ed. The reaction mixture was subjected to extraction twice with ethyl acetate, and the organic layer thus obtained was washed with water and brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexanezethyl acetate = 95:5 —9 80:20, v/v) to give the title compound (12.9 g, yield: 84%). lH-NMR (400 MHZ, CDCl3) 5 ppm: 7.97 (1H, t, J = 8 Hz), 7.91 (1H, d, J = 8 Hz), 7.85 (1H, d, J = 11 Hz), 4.98 (1H, q, J = 6 Hz), 2.54 (1H, brs), 2.14~ 1.96 (2H, m), 1.62 (9H, s), 1.08 (3H, t, J 7 Hz); MS (FAB) m/z: 323 [M+H]+. ence e 7) tert—Butyl 4—(5—{(lR)—1—[4— (cyclopropylcarbonyl)phenoxy]propyl}—1,2,4—oxadiazol~3~yl)— 2~fluorobenzoate [Chemical Formula 9] FP1225$ SJW/PN811150/ English ation of PCTJP2012/069098 specification 4624905SWALLACE H3C CH3 3 >L02 Q Pic \:N\ O N’0 di~Tert~butyl azodicarboxylate (260 mg, 1.11 mmol) and triphenylphosphine (300 mg, 1.11 mmol) were added to a tetrahydrofuran solution (10 mL) of the compound obtained in Reference Example 6 (300 mg, 0.931 mmol) and the nd obtained in Reference Example 3 (150 mg, 0.925 mmol) at room ature, and the mixture was stirred at the same temperature for one hour. The solvent was distilled off under reduced pressure, and the ing residue was purified by silica gel column chromatography (hexanezethyl acetate = 95:5 —% 80:20, v/v) to give the title compound (236 mg, yield: 55%). 1H—NMR (400 MHZ, CDC13) 5 ppm: 8.00~7.94 (3H, m), 7.90—7.87 (1H, m), 7.84—7.81 (1H, m), 7.06—7.04 (2H, m), 5.52 (1H, dd, J = 7, 6 Hz), .57 (1H, m), 2.3412.25 (2H, m), 1.61 (9H, s), 1.21-1.18 (2H, m), 1.14 (3H, t, J = 7 Hz), 1.01—0.98 (2H, m); MS (FABU m/z: 466 [M+H]+.

(Reference Example 8) 4—(5—{(1R)—1—[4— (Cyclopropylcarbonyl)phenoxy]propyl}—1,2,4—oxadiazol—3—yl)— 2—fluorobenzoic acid FP12253 SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905—1-SWALLACE [Chemical Formula 10] I40 N\~ o o \N’0 Trifluoroacetic acid (10 mL) was added to a dichloromethane (1 mL) on of the compound obtained in nce Example 7 (236 mg, 0.506 mmol) at room temperature, and the mixture was stirred for 40 s.

The solvent was distilled off under reduced pressure, and the resulting residue was washed with isopropyl ether.

Thus, the title compound (195 mg, yield: 94%) was obtained. 1H—NMR (400 MHZ, CDC13) 5 ppm: 8.14 (1H, t, J = 8 Hz), 8.01—7.89 (4H, m), 7.04 (2H, dd, J = 7, 2 Hz), 5.54 (1H, dd, J = 7, 6 Hz), 2.63—2.57 (1H, m), 2.35—2.21 (2H, m), 1.22—1.18 (2H, m), 1.15 (3H, q, J = 5 Hz), 1.02—0.99 (2H, m); MS (FAB) m/z: 411 [M+H]t (Reference Example 9) tert—Butyl ro~4—{5~[(1S)— l—hydroxyethyl]—1,2,4—oxadiazol~3~yl}benzoate [Chemical Formula 11] FP12255 SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905~1-SWALLACE Hsc CH3 gHs 0 N\ CH 3 \ o N’0 1—Hydroxybenzotriazole monohydrate (16.7 g, 109 mmol) and N—(3—dimethylaminopropy1)—N'—ethylcarbodiimide (41.8 g, 218 mmol) were added to a dimethylformamide (540 mL) solution of (28)—2—acetoxy propionic acid (14.4 g, 109 mmol) at room temperature, and the mixture was stirred at the same temperature for 30 s. The compound ed in Reference Example 2 (27.7 g, 109 mmol) was added, and the mixture was stirred for 10 minutes, and further stirred at 90°C for 3 hours. After the reaction mixture was cooled to room temperature, water and a 10% aqueous solution of sodium chloride were added to the reaction mixture, and the e was ted to extraction twice with ethyl e. The organic layer thus obtained was washed with a % aqueous solution of sodium chloride and a saturated aqueous solution of sodium hydrogen carbonate, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexanezethyl acetate = 95:5 —9 85:15, v/v).

Potassium carbonate (12.7 g, 91.6 mmol) was added to a methanol (360 mL) solution of the obtained tert—butyl 4~ FP12255 SJW/PN811150/ English ation of PCTJP2012/O69098 specification 4624905—1-SWALLACE {5—[(lS)—1—acetoxyethyl]—1,2,4—oxadiazol-3—yl}—2— fluorobenzoate (32.1 g, 91.6 mmol) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. 2 N Hydrochloric acid was added to the reaction e at the same temperature until a pH value of 6.0 was obtained, and the solvent was distil'ed off under reduced re. Water was added to the resultirg residue, and the mixture was subjected to extraction twice with ethyl acetate. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the ing residue was solidified by using hexane. Thus, the title compound (26.4 g, yield: 93%) was obtained. 1H-NMR (400 MHZ, CDCl3) 5 ppm: 7.97 (1H, t, J = 8 Hz), 7.90 (1H, d, J = 8 Hz), 7.84 (1H, d, J = 5 Hz), 5.18 (1H, q, J = 7 Hz), 1.73 (4H, d, J = 7 Hz), 1.60 (9H, 8); MS (FAB) m/z: 309 [M+H]+.

(Reference e 10) utyl 4—(5—{(lR)—1—[4— (cyclopropylcarbonyl)phenoxy]ethyl}—l,2,4—oxadiazol—3—yl)— 2~fluorobenzoate [Chemical Formula 12] FP1225$ SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905—1-SWALLACE Triphenylphosphine (5.62 g, 21.4 mmol) and di~tert— butyl azodicarboxylate (4.93 g, 21.4 mmol) were added to a ydrofuran solution (190 mL) of the compound ed in Reference Example 9 (6.00 g, 19.5 mmol) and the compound obtained in Reference Example 3 (3.47 g, 21.4 mmol) at room temperature, and the mixture was d at the same temperature for 40 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 —% 75:25, V/v) to give the title compound (7.65 g, yield: 87%). lH—NMR (400 MHZ, CDCl3) 5 ppm: 8.02—7.94 (3H, m), 7.89 (1H, d, J = 8 Hz), 7.83 (1H, d, J = 8 Hz), 7.05 (2H, d, J = 8 Hz), 5.75 (1H, g, J = 7 Hz), 2.63—2.59 (1H, m), 1.92 (3H, d, J = 4 Hz), 1.48 (9H, s), 1.20 (2H, m), 1.01—0.99 (2H, m).

(Reference Example 11) 4—(5—{(1R)—1—[4— (Cyclopropylcarbonyl)phenoxy]ethyl}—1,2,4-oxadiazol—3—yl)— 2—fluorobenzoic acid [Chemical Formula 13] s SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905-1—SWALLACE o :3 N’0 A dichloromethane (20 mL) solution of trifluoroacetic acid (20 mL) was added to a dichloromethane (40 mL) solution of the compound obtained in Reference Example 10 (7.65 g, 16.9 mmol) at room temperature, and the mixture was d for one hour. The solvent was distilled off under reduced pressure, and the ing residue was solidified by using hexanezethyl acetate(4:1, V/v). Thus, the title compound (4.90 g, yield: 73%) was obtained. 1H~NMR (400 MHz, CDC13) 5 ppm: 8.14 (1H, t, J z 8 Hz), 8.01 (2H, d, J = 9 Hz), 7.98—7.96 (1H, m), 7.93—7.90 (1H, m), 7.06 (2H, d, J = 9 Hz), 5.76 (1H, q, J = 7 Hz), 2.64—2.57 (1H, m), 1.92 (3H, d, J = 7 Hz), 1.23-1.18 (2H, m), 1.03—0.98 (2H, m); MS (FAB) m/z: 397 [M+H]+.

(Reference Example 12) (4S)—4—aminodihydrofuran~ 2(3H)—one [Chemical a 14] FP1225s SJMflPN8111SO/EngfishflandafionofPCTJP2012KB9098specmcafion 4624905~1~SWALLACE w% palladium on carbon (60 mg) was added to a tetrahydrofuran (6 mL) solution of benzyl[(3S)—5* oxotetrahydrofuran—3—yl]carbamate (600 mg, 2.55 mmol) at room temperature, and the mixture was stirred for 2 hours under hydrogen flow. Methanol (60 uL) was added at room ature, and the mixture was stirred for 2 hours under hydrogen flow. The insoluble material was removed by filtration through Celite. Thus, a tetrahydrofuran solution of the title compound was obtained.

(Reference Example 13) (3S,4S)—3—amino—4— ydihydrofuran—Z—(3H)—one [Chemical Formula 15] % palladium ide on carbon (9.5 mg) was added to an ethanol (5.0 mL) solution of benzyl [(3S,4S)—4— hydroxy—Z-oxotetrahydrofuran—3—ylicarbamate (Bioorg. Med.

Chem. Lett. 2002, 12, 325—328.)(94.8 mg, 0.377 mmol) at room temperature, and the mixture was stirred at the same temperature for 3.5 hours under hydrogen flow. The insoluble material was removed by filtration through Celite.

The solvent was led off under reduced pressure. Thus, $ SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905-1—SWALLACE the crude title compound (44.2 mg) was obtained.

(Reference Example 14) (38,4R)—3—amino~4— hydroxydihydrofuran—2~(3H)~one [Chemical a 16] % palladium hydroxide on carbon (12.2 mg) was added to an ethanol (5.0 mL) solution of benzyl [(38,4R)—4~ hydroxy—2-oxotetrahydrofuran—3—yl]carbamate (Bioorg. Med.

Chem. Lett. 2002, 12, 325—328.)(122 mg, 0.486 mmol) at room temperature, and the mixture was stirred at the same ature for 3.5 hours under hydrogen flow. The insoluble material was removed by filtration through Celite.

The t was distilled off under reduced pressure. Thus, the crude title compound (85.4 mg) was obtained.

(Example 1) (1R)—1—[4— (cyclopropylcarbonyl)phenoxy]propyl}—l,2,4~oxadiazol—3—yl)— 2~fluoro—N—[(38,4R)—4—hydroxytetrahydrofuran—3—yl]benzamide, and 4—(5—{(1R)—1—[4—(cyclopropylcarbonyl)phenoxy]propyl}— 1,2,4—oxadiazol—3—yl)—2—fluoro—N—[(3R,4S)-4— hydroxytetrahydrofuran—3—yl]benzamide FP1225$ SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905—1-SWALLACE [Chemical Formula 17] 0Q N\ o H \N’O o‘fiw ° N H N’0 1—Hydroxybenzotriazole monohydrate (153 mg, 1.00 mmol) and N—(3—dimethy1aminopropyl)~N‘—ethylcarbodiimide hloride (383 mg, 2.00 mmol) were added to an N,N— dimethylformamide (4 mL) solution of the compound obtained in Reference Example 8 (410 mg, 1.00 mmol) at room temperature. The mixture was stirred at the same temperature for 30 minutes. Subsequently, (3RS,4SR)~4~ aminotetrahydrofuran—3—01 (J. Org. Chem. 1997, 62, 4197.) (155 mg, 1.50 mmol) was added, and the mixture was further stirred at the same temperature for 30 minutes. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction mixture, and the e was subjected to extraction three times with ethyl acetate.

The c layer thus obtained was washed with a 10% aqueous solution of sodium chloride, and then was dried over anhydrous sodium sulfate. The t was distilled off under reduced pressure, and the resulting e was FP1225$ SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905—1—SWALLACE purified by silica gel column chromatography ezethyl acetate = 50:50 —9 0:100, v/v) to give the title compounds (241 mg, yield: 49%). 1H—NMR (400 MHZ, CDCl3) 5 ppm: 8.20 (1H, t, J = 8 Hz), 8.04—7.95 (3H, m), 7.87 (1H, d, J = 12 Hz), 7.04 (2H, d, J = 9 Hz), 6.97—6.87 (1H, m), 5.53 (1H, t, J = 6 Hz), 4.44—4.37 (2H, m), 4.22 (1H, dd, J = 8, 6 Hz), 4.15 (1H, dd, J = 9, 6 Hz), 3.84—3.72 (2H, m), 3.19—3.16 (1H, m), 2.63-2.55 (1H, m), 2.35—2.18 (2H, m), 1.23-1.10 (5H, m), 1.03~0.96 (2H, m); MS (FAB) m/z: 496 [M+H]+.

(Example 2) 4—(5—{(1R)[4— (cyclopropylcarbonyl)phenoxy]ethyl}~l,2,4—oxadiazol—3—yl)— 2~fluoro—N—[(3R,4S)—4—hydroxytetrahydrofuran—3—yl]benzamide [Chemical Formula 18] 0 “SO/UV CO.>‘Q~<§\7/L°NH NvO 1—Hydroxybenzotriazole monohydrate (153 mg, 1.00 mmol) and N—(3~dimethylaminopropyl)—N'—ethylcarbodiimide hydrochloride (383 mg, 2.00 mmol) were added to an N,N— dimethylformamide (5 mL) solution of the compound obtained in Reference Example 11 (396 mg, 1.00 mmol) at room FP1225$ SJW/PN811150/ English translation of 012/069098 specification 4624905—1-SWALLACE temperature. The mixture was stirred at the same temperature for 30 minutes. Subsequently, (38,4R)—4— aminotetrahydrofuran~3—ol (J. Org. Chem. 1997, 62, 4197.) (155 mg, 1.50 mmol) was added, and the mixture was further stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was subjected to extraction three times with ethyl acetate.

The organic layer thus obtained was washed with a saturated aqueous solution of sodium hydrogen carbonate and a 10% aqueous solution of sodium chloride, and then was dried over anhydrous sodium sulfate. The t was led off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexanezethyl acetate = 50:50 —9 0:100, v/v) to give the title compound (393 mg, yield: 82%). lH~NMR (400 MHZ, CDC13) 5 ppm: 8.19 (1H, t, J = 8 Hz), 8.02—7.97 (3H, m), 7.87 (1H, dd, J = 12, 1 Hz), 7.05 (2H, d, J = 9 Hz), 6.95—6.87 (1H, m), .76 (1H, q, J = 7 Hz), 4.44—4.37 (2H, m), 4.21 (1H, dd, J = 10, 5 Hz), 4.15 (1H, dd, J 10, 5 Hz), 3.82 (1H, dd, J = , 3 Hz), 3.75 (1H, dd, J 10, 3 Hz), 3.32 (1H, d, J = 2 Hz), 2.63~2.57 (1H, m), 1.92 (3H, d, J = 7 Hz), 1.22—1.19 (2H, m), .98 (2H, m); MS (FAB) m/z: 482 [M+H]+.

(Example 3) 4—(5—{(1R)—1-[4- (cyclopropylcarbonyl)phenoxy]ethy1}—1,2,4—oxadiazol—3—yl)— FP1225S SJW/PN811150/ English translation of 012/069098 specification 4624905—1-SWALLACE 2—fluoro—N-[(3S,4R)—4—hydroxytetrahydrofuran—3—yl]benzamide [Chemical Formula 19] o GHQ/{V \N\ o H NrO 1—Hydroxybenzotriazole monohydrate (153 mg, 1.00 mmol) and N—(3—dimethylaminopropyl)~N'—ethylcarbodiimide hloride (383 mg, 2.00 mmol) were added to an N,N— ylformamide (5 mL) solution of the compound obtained in Reference Example 11 (396 mg, 1.00 mmol) at room ature. The mixture was stirred at the same temperature for 30 minutes. Subsequently, (3R,4S)—4— etrahydrofuran-3—ol (J. Org. Chem. 1997, 62, 4197.) (155 mg, 1.50 mmol) was added, and the mixture was further d at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was subjected to extraction three times with ethyl acetate.

The organic layer thus obtained was washed with a saturated aqueous solution of sodium hydrogen carbonate and a 10% aqueous solution of sodium chloride, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexanezethyl FP12255 SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905SWALLACE acetate = 50:50 —+ 0:100, v/v) to give the title compound (410 mg, yield: 85%). lH—NMR (400 MHz, CDC13) 5 ppm: 8.20 (1H, t, J = 8 Hz), 8.04—7.97 (3H, m), 7.87 (1H, dd, J = 12, 1 Hz), 7.06 (2H, d, J = 9 Hz), 6.97—6.87 (1H, m), .76 (1H, q, J = 7 Hz), 4.46—4.38 (2H, m), 4.22 (1H, dd, J = 10, 5 Hz), 4.l5 (1H, dd, J = 10, 5 HZ), 3.82 (1H, dd, J = , 3 Hz), 3.75 (1H, dd, J 10, 4 Hz), 3.21~3.l8 (1H, m), 2.65—2.56 (1H, m), 1.92 (3H, d, J = 7 Hz), 1.24—1.18 (2H, m), 1.04—0.98 (2H, m); MS (FAB) m/z: 482 [M+H]+ (Example 4) 4—(5—{(1R)—l—[4— (cyclopropylcarbonyl)phenoxy]propyl}-l,2,4-oxadiazol—3—yl)— 2—fluoro—N—[(3R)—2—oxotetrahydrofuran—3—yl]benzamide cal Formula 20] $1: ~30I) 3 ll" \N’O 1—Hydroxybenzotriazole monohydrate (153 mg, 1.00 mmol) and N-(3—dimethylaminopropyl)—N'—ethylcarbodiimide hydrochloride (383 mg, 2.00 mmol) were added to an N,N— dimethylformamide (5 mL) solution of the compound obtained in Reference Example 8 (410 mg, 1.00 mmol) at room FP1225$ SJW/PN811150/ h translation of PCTJP2012/069098 ication 4624905SWALLACE temperature. The mixture was stirred at the same temperature for 30 minutes. Subsequently, — aminodihydrofuran—Z(3H)—one hydrochloride (206 mg, 1.50 mmol) and triethylamine (140 uL, 1.00 mmol) were added, and the mixture was further stirred at the same temperature for minutes. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction mixture, and the e was subjected to extraction three times with ethyl acetate. The organic layer thus obtained was washed with a 10% aqueous solution of sodium chloride, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexanezethyl acetate = 95:5 —a 50:50, V/v) to give the title nd (382 mg, yield: 77%). 1H—NMR (400 MHZ, CDClg) 8 ppm: 8.21 (1H, t, J = 8 Hz), 8.03—7.96 (3H, m), 7.89 (1H, dd, J 13, 1 Hz), 7.42—7.24 (1H, m), 7.04 (2H, d, J = 9 Hz), .53 (1H, t, J = 7 Hz), .71 (1H, m), 4.56 (1H, t, J = 9 Hz), .34 (1H, m), 3.01—2.94 (1H, m), 2.63—2.57 (1H, m), 2.40—2.20 (3H, m), 1.22—1.18 (2H, m), 1.15 (3H, t, J = 7 Hz), 1.02—0.97 (2H, m); MS (FAB) m/z: 494 [M+H]t (Example 5) (1R)—1—[4— (cyclopropylcarbonyl)phenoxy]propyl}—1,2,4—oxadiazol—3—yl)— 2—fluoro—N—[(38)—2—oxotetrahydrofuran—3—yl]benzamide FP1225s SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905—1-SWALLACE [Chemical Formula 21] 1—Hydroxybenzotriazole monohydrate (153 mg, 1.00 mmol) and N—(3—dimethylaminopropyl)—N'—ethy1carbodiimide hydrochloride (383 mg, 2.00 mmol) were added to an N,N— ylformamide (5 mL) solution of the compound obtained in Reference Example 8 (410 mg, 1.00 mmol) at room temperature. The mixture was stirred at the same temperature for 30 minutes. Subsequently, (3S)—3— aminodihydrofuran—Z(3H)—one hydrobromide (270 mg, 1.50 mmol) and triethylamine (140 uL, 1.00 mmol) were added, and the e was further stirred at the same temperature for minutes. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to the on mixture, and the mixture was subjected to extraction three times with ethyl acetate. The organic layer thus obtained was washed with a 10% aqueous solution of sodium chloride, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under d pressure, and the ing residue was purified by silica gel column chromatography (hexanezethyl acetate 95:5 —9 50:50, V/V) to give the title compound (390 mg, yield: 79%).

FP1225$ SJW/PN811150/ English transiation of PCTJP2012/069098 specification 4624905—1-SWALLACE lH-NMR (400 MHZ, CDCl3) 5 ppm: 8.22 (1H, t, J = 8 Hz), 8.03—7.96 (3H, m), 7.89 (1H, dd, J = 13, 1 Hz), 7.42—7.37 (1H, m), 7.04 (2H, d, J = 9 Hz), .53 (1H, t, J = 7 Hz), 4.74—4.71 (1H, m), 4.56 (1H, t, J = 9 Hz), 4.41—4.34 (1H, m), 3.01—2.94 (1H, m), 2.63—2.57 (1H, m), 2.40—2.20 (3H, m), 1.22—1.18 (2H, m), 1.15 (3H, t, J = 7 Hz), 1.02—0.97 (2H, m); MS (FAB) m/z: 494 [M+H]+ (Example 6) (lR)—l—[4— propylcarbonyl)phenoxy]propyl}—1,2,4-oxadiazol—3—yl)~ 2—fluoro—N—[(3S)—5~oxotetrahydrofuran~3-yl]benzamide [Chemical Formula 22] l—Hydroxybenzotriazole monohydrate (81.3 mg, 0.531 mmol) and N—(3—dimethylaminopropyl)—N'—ethylcarbodiimide hydrochloride (204 mg, 1.06 mmol) were added to an N,N— dimethylformamide (3 mL) solution of the compound obtained in Reference Example 8 (218 mg, 0.531 mmol) at room temperature. The mixture was stirred at the same temperature for 30 minutes. Subsequently, a tetrahydrofuran on of the —aminodihydrofuran—2(3H)—one obtained FP1225$ SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905-1—SWALLACE in Reference Example 12 (76 mg, 0.797 mmol) was added, and the mixture was further stirred at the same temperature for minutes. Water and a saturated s solution of sodium hydrogen carbonate were added to the reaction mixture, and the mixture was subjected to extraction three times with ethyl acetate. The organic layer thus obtained was washed with a 10% aqueous solution of sodium chloride, and then was dried over ous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting e was purified by silica gel column chromatography (hexanezethyl e = 95:5 —% 50:50, V/V) to give the title compound (88.7 mg, yield: 34%). 1H-NMR (400 MHZ, CDClfl 5 ppm: 8.20 (1H, t, J = 8 Hz), 8.03—7.97 (3H, m), 7.89 (1H, dd, J = 13, 2 Hz), 7.05—6.96 (3H, m), 5.53 (1H, t, J = 7 Hz), 4.98—4.88 (1H, m), 4.66 (1H, dd, J = 10, 6 Hz), 4.37 (1H, dd, J 10, 4 Hz), 3.01 (1H, dd, J 18, 8 Hz), 2.67—2.55 (2H, m), 2.35—2.19 (2H, m), 1.23~1.10 (5H, m), 1.02—0.97 (2H, m); MS (FAB) m/z: 494 [M+H]+.

(Example 7) 4—(5—{(1R)—1—[4~ (cyclopropylcarbonyl)phenoxy]propyl}—1,2,4—oxadiazol~3~yl)— ro—N—[(3R)—2—oxopyrrolidin—3—yl]benzamide [Chemical Formula 23] FP1225S SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905SWALLACE 0 0 HM N\ o H \N’O 1—Hydroxybenzotriazole drate (129 mg, 0.840 mmol) and N—(3—dimethylaminopropyl)—N'~ethylcarbodiimide hydrochloride (242 mg, 1.26 mmol) were added to an N,N— dimethylformamide (4 mL) solution of the nd obtained in Reference Example 8 (345 mg, 0.840 mmol) at room ature. The mixture was stirred at the same temperature for 30 minutes. Subsequently, (3R)—3— aminopyrrolidin—Z—one (101 mg, 1.01 mmol) was added, and the mixture was further stirred at the same temperature for minutes. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction mixture, and the mixture was subjected to extraction five times with ethyl e. The organic layer thus obtained was washed with a 10% s solution of sodium de, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetatezmethanol = 100:0 —9 90:10, v/v) to give the title compound (285 mg, yield: 69%). lH—NMR (400 MHZ, CDC13) 5 ppm: 8.21 (1H, t, J = 8 Hz), 8.03—7.96 (3H, m), 7.87 (1H, dd, J ll 12, 1 Hz), 7.34—7.27 (1H, m), 7.04 (2H, d, J = 9 Hz), FP1225S SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905-1—SWALLACE .98-5.90 (1H, m), 5.53 (1H, t, J = 6 Hz), 4.62—4.55 (1H, m), 3.50—3.45 (2H, m), 2.97—2.89 (1H, m), 2.63—2.57 (1H, m), 2.35—2.19 (2H, m), .05 (1H, m), 1.23—1.17 (2H, m), 1.14 (3H, t, J = 7 Hz), 1.04—0.97 (2H, m); M8 (E81) m/Z: 493 [M+H]+.

(Example 8) (1R)—1—[4— (cyclopropylcarbonyl)phenoxy]propyl}—1,2,4—oxadiazol—3—yl)— 2~fluoro~N~[(3S)—2—oxopyrrolidin~3—yl]benzamide [Chemical Formula 24] “d‘flfit ° N H NvO 1—Hydroxybenzotriazole monohydrate (129 mg, 0.840 mmol) and N—(3—dimethylaminopropyl)—N'—ethylcarbodiimide hydrochloride (242 mg, 1.26 mmol) were added to an N,N— dimethylformamide (4 mL) solution of the nd obtained in Reference Example 8 (345 mg, 0.840 mmol) at room temperature. The mixture was stirred at the same temperature for 30 minutes. Subsequently, (3S)—3— aminopyrrolidin—Z—one (101 mg, 1.01 mmol) was added, and the mixture was further stirred at the same ature for minutes. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction FP1225s SJW/PN811150/ h translation of PCTJP2012/069098 specification 4624905SWALLACE mixture, and the e was subjected to extraction five times with ethyl acetate. The organic layer thus obtained was washed with a 10% aqueous solution of sodium chloride, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetatezmethanol = 100:0 —+ 90210, v/v) to give the title compound (225 mg, yield: 54%). 1H—NMR (400 MHZ, CDC13) 8 ppm: 8.21 (1H, t, J = 8 Hz), 8.03—7.97 (3H, m), 7.88 (1H, dd, J = 12, 1 Hz), .27 (1H, m), 7.03 (2H, d, J = 9 Hz), .81—5.75 (1H, m), 5.53 (1H, t, J = 6 Hz), 4.63—4.55 (1H, m), 3.51—3.42 (2H, m), 2.96—2.88 (1H, m), 2.64—2.56 (1H, m), 2.35—2.19 (2H, m), 2.18—2.05 (1H, m), 1.23—1.17 (2H, m), 1.14 (3H, t, J = 7 Hz), 1.03—0.97 (2H, m); MS (ESI) m/z: 493 [M+H]+ (Example 9) 4—(5-{(1R)—1—[4— (cyclopropylcarbonyl)phenoxy]propyl}—1,2,4-oxadiazol—3—yl)— 2—f1uoro—N*[(38,48)—4—hydroxy—2—oxotetrahydrofuran—3~ y1]benzamide [Chemical Formula 25] 0 o 0&F%%KN.. H $ SJW/PN811150/ h translation of PCTJP2012/069098 specification 4624905-1—SWALLACE 1—Hydroxybenzotriazole monohydrate (46.1 mg, 0.301 mmol) and N—(3—dimethylaminopropyl)—N'—ethylcarbodiimide hloride (57.7 mg, 0.301 mmol) were added to an N,N— dimethylformamide (0.5 mL) solution of the 4—(5—{(1R)—1—[4— (cyclopropylcarbonyl)phenoxy]propyl}—1,2,4—oxadiazol—3—yl)~ 2—fluorobenzoic acid synthesized in Reference Example 8 (103 mg, 0.252 mmol) at room temperature, and the mixture was stirred at the same temperature for 30 minutes.

Subsequently, an methylformamide (1.0 mL) on of the (3S,4S)—3—amino—4—hydroxydihydrofuran—2~(3H)—one sized in Reference Example 13 (44.2 mg) was added, and the mixture was further stirred at the same ature for 30 minutes. Water was added to the reaction mixture, and the mixture was subjected to extraction twice with ethyl acetate. The organic layer thus obtained was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and then was dried over ous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexanezethyl acetate = 70:30 —§ 30:70, v/v) to give the title compound (48.5 mg, yield: 38%). 1H—NMR (500 MHz, CDCl3) 5 ppm: 8.21 (1H, t, J = 8 Hz), 8.06—7.97 (3H, m), 7.92 (1H, dd, J = 13, 1 Hz), 7.64—7.57 (1H, m), 7.04 (2H, d, J = 9 Hz), .54 (1H, dd, J = 7, 6 Hz), 5.40—5.38 (lH, m), 4.69—4.60 FP12255 SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905—1-SWALLACE (2H, m), .51 (1H, m), 4.21—4.14 (1H, m), 2.63—2.57 (1H, m), 2.36—2.20 (2H, m), 1.22—1.18 (2H, m), 1.15 (3H, t, J = 7 Hz), 1.03—0.97 (2H, m); MS (ES) m/z: 510 .

(Example 10) 4—(5—{(1R)—1—[4— (cyclopropylcarbonyl)phenoxy]ethy1}—1,2,4—oxadiazol—3—y1)~ 2—fluoro—N—[(3R)~2~oxopyrrolidin—3—y1]benzamide [Chemical Formula 26] 0 0 ”km Hi5 \N\ 0 H N’O 1—Hydroxybenzotriazole drate (137 mg, 0.896 mmol) and N—(3—dimethylaminopropyl)—N'—ethylcarbodiimide hydrochloride (258 mg, 1.34 mmol) were added to an N,N— dimethylformamide (4 mL) solution of the compound obtained in Reference Example 11 (355 mg, 0.896 mmol) at room temperature. The mixture was stirred at the same temperature for 30 minutes. Subsequently, (3R)—3— aminopyrrolidin—Z—one (108 mg, 1.07 mmol) was added, and the mixture was further stirred at the same temperature for minutes. Water was added to the reaction mixture, and the mixture was subjected to extraction five times with ethyl acetate. The organic layer thus obtained was washed FP1225s SJW/PN811150/ English translation of 012/069098 specification 4624905—1-SWALLACE with a saturated aqueous solution of sodium hydrogen carbonate and a 10% aqueous solution of sodium chloride, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the ing residue was purified by silica gel column chromatography (ethyl acetate:methanol = 100:0 —9 90:10, v/v) to give the title compound (14.3 mg, yield: 3%). 1H—NMR (400 MHZ, CDC13) 8 ppm: 8.21 (1H, t, J = 8 Hz), 8.02—7.97 (3H, m), 7.87 (1H, dd, J H 12, 1 Hz), 7.34—7.30 (1H, m), 7.05 (2H, d, J = 9 Hz), .78~5.74 (2H, m), 4.62—4.54 (1H, m), 3.49~3.45 (2H, m), 2.98—2.89 (1H, m), 2.64—2.57 (1H, m), 2.17—2.07 (1H, m), 1.92 (3H, d, J = 7 Hz), 1.22—1.18 (2H, m), 1.03—0.97 (2H, MS (ESI) m/z: 479 [M+H]+.

(Example 11) 4—(5—{(1R)—1—[4— (cyclopropylcarbonyl)phenoxy]ethyl}~l,2,4—oxadiazol~3—yl)— 2-fluoro—N—[(38)—2—oxopyrrolidin-3—yl]benzamide cal Formula 27] ° 0 “gm ””5; *QWNYLOE N’0 1—Hydroxybenzotriazole monohydrate (137 mg, 0.896 FP1225s SJW/PN811150/ English ation of PCTJP2012/069098 specification 4624905SWALLACE mmol) and N—(3—dimethylaminopropyl)—N‘—ethylcarbodiimide hydrochloride (258 mg, 1.34 mmol) were added to an N,N— dimethylformamide (4 mL) solution of the compound obtained in Reference Example 11 (355 mg, 0.896 mmol) at room temperature. The mixture was stirred at the same temperature for 30 minutes. Subsequently, (BS)—3— aminopyrrolidin—2~one (108 mg, 1.07 mmol) was added, and the mixture was further stirred at the same temperature for minutes. Water was added to the reaction mixture, and the mixture was subjected to extraction five times with ethyl acetate. The organic layer thus obtained was washed with a saturated aqueous solution of sodium hydrogen carbonate and a 10% aqueous solution of sodium chloride, and then was dried over anhydrous sodium e. The solvent was led off under reduced pressure, and the ing e was purified by silica gel column chromatography (ethyl ezmethanol = 100:0 ~9 90:10, v/v) to give the title compound (257 mg, yield: 60%). lH—NMR (400 MHZ, CDCl3) 5 ppm: 8.21 (1H, t, J = 8 HZ), 8.08~7.96 (3H, m), 7.87 (1H, dd, J 12, 1 Hz), 7.38—7 30 (1H, m), 7.06 (2H, d, J = 9 Hz), .75 (2H, m), 4.64—4.55 (1H, m), 3 53—3 43 (2H, m), 2.98—2.89 (1H, m), 2.68—2.57 (1H, m), 2.19—2.07 (1H, m), 1.92 (3H, d, J = 7 Hz), 1 25—1.17 (2H, m), 1.09—0.96 (2H, MS(ESI) m/z: 479 [M+H]+.

FP12255 SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905SWALLACE (Example 12) 4—5-{ (1R) —1- [4~ (cyclopropylcarbonyl)phenoxy]propyl}—1,2,4—oxadiazol—3~yl)—2— fluoro-N—[(38,4R)—4—hydroxy—2-oxotetrahydrofuran~3-yl]benzamide [Chemical Formula 28] N\ O H ‘3, o l—Hydroxybenzotriazole monohydrate (44.6 mg, 0.291 mmol) and N-(3—dimethylaminopropyl)—N’-ethylcarbodiimide hloride (55.8 mg, 0.291 mmol) were added to an N,N—dimethylformamide (0.5 mL) solution of the 4—(5—{(1R)—1—[4— propylcarbonyl)phenoxy]propyl}—1,2,4—oxadiazol—3—yl)~2— fluorobenzoic acid synthesized in Reference Example 8 (99.6 mg, 0.243 mmol) at room temperature, and the mixture was stirred at the same temperature for 30 s. Subsequently, an N,N— dimethylformamide (1.0 mL) solution of the crude (3S,4R)—3—amino— 4—hydroxydihydrofuran—2~(3H)—one synthesized in Reference Example 14 (85.4 mg) was added, and the e was further stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was subjected to extraction twice with ethyl acetate. The organic layer thus obtained was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and then was dried over anhydrous sodium sulfate. The solvent was led off under reduced pressure, and the resulting residue was purified by silica gel column tography (hexanezethyl acetate = 70:30 —9 30:70, v/V) to give the title compound (22.5 mg, yield: 18%). 1H—NMR (500 MHZ, CDC13) 8 ppm: 8.20 (1H, t, J = 8 Hz), 8.02—7.97 (3H, m), 7.89 (1H, d, J = 12 Hz), 7.35—7.28 (1H, m), 7.04 (2H, d, J = 9 Hz), 5.53 (1H, dd J = 7, 6 Hz), 4.09~4.86 (2H, m), 4.54 (1H, dd, J 11, 1 Hz), 4.49 (1H, d, J = 11 Hz), 2.64~2.56 (2H, m), 2.36—2.20 (2H, m), 1.22—1.17 (2H, m), 1.15 (3H, t, J = 7 Hz), 1.02— 0.98 (2H, m); MS (ES) m/z: 510 [M+H]+.

(Example 13) 4—(5—{(1R)—1-[4— (cyclopropylcarbonyl)phenoxy]ethy1}—1,2,4—oxadiazol—3—yl)~ 2*f1uoro—N~[(3R,4R)—4~hydroxytetrahydrofuran—3—yl]benzamide [Chemical Formula 29] O CH3/[:::r/u\\;7 0K} )‘Q‘W/LONH N’0 1—Hydroxybenzotriazole monohydrate (132 mg, 0.864 FP1225$ SJW/PN811150/ English translation of PCTJP2012/069098 ication 4624905—1-SWALLACE mmol) and N—(3—dimethylaminopropyl)—N'—ethylcarbodiimide hydrochloride (249 mg, 1.30 mmol) were added to an N,N— dimethylformamide (4 mL) solution of the nd obtained in Reference e 11 (343 mg, 0.864 mmol) at room temperature. The mixture was stirred at the same temperature for 30 minutes. Subsequently, (3R,4R)—4— aminotetrahydrofuran—3—ol (J. Org. Chem. 1997, 62, 4197.) (181 mg, 1.30 mmol) and triethylamine (181 uL, 1.30 mmol) were added, and the mixture was further stirred at the same ature for 30 minutes. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction mixture, and the mixture was subjected to extraction three times with ethyl e. The organic layer thus obtained was washed with a 10% aqueous solution of sodium de, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexanezethyl acetate = 50:50 —% 0:100, v/v) to give the title compound (240 mg, yield: 58%). 1H~NMR (400 MHz, CDClg) 5 ppm: 8.20 (1H, t, J = 8 Hz), 8.02—7.96 (3H, m), 7.86 (1H, dd, J = 12, 1 Hz), 7.47~7.42 (1H, m), 7.05 (2H, d, J = 9 Hz), .76 (1H, q, J = 7 Hz), 4.70—4.63 (1H, m), 4.54—4.49 (1H, m), 4.22 (1H, dd, J = 9, 8 Hz), 4.07 (1H, dd, J = 10, 4 Hz), 3.87 (1H, dd, J = 10, 2 Hz), 3.72 (1H, dd, J = 9, 7 Hz), 2.63e2.57 (1H, m), 2.29—2.23 (1H, m), 1.92 (3H, d, J = 7 FP1225$ SJW/PN811150/ h translation of PCTJP2012/069098 specification 4624905—1-SWALLACE Hz), .18 (2H, m), 1.03—0.98 (2H, m); MS (FAB) m/z: 482 [M+H]+.

(Example 14) 4—(5—{(1R)—1—[4— (cyclopropylcarbonyl)phenoxy]ethyl}—1,2,4—oxadiazol—3~yl)— 2—fluoro—N—[(38,48)—4—hydroxytetrahydrofuran—3—yl]benzamide [Chemical Formula 30] OH 0 CH3m 0'jQ‘Q‘fiN‘V/L" H N’0 oxybenzotriazole monohydrate (132 mg, 0.864 mmol) and N—(3—dimethylaminopropyl)—N'—ethylcarbodiimide hydrochloride (249 mg, 1.30 mmol) were added to an N,N— dimethylformamide (4 mL) on of the compound obtained in Reference Example 11 (343 mg, 0.864 mmol) at room temperature. The mixture was stirred at the same temperature for 30 minutes. Subsequently, (3S,4S)—4— aminotetrahydrofuran—3—ol (J. Org. Chem. 1997, 62, 4197.) (181 mg, 1.30 mmol) and triethylamine (181 ML, 1.30 mmol) were added, and the mixture was further stirred at the same temperature for 30 minutes. Water and a ted aqueous solution of sodium hydrogen carbonate were added to the reaction mixture, and the mixture was subjected to extraction three times with ethyl acetate. The organic $ SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905~1~SWALLACE layer thus obtained was washed with a 10% aqueous solution of sodium chloride, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexanezethyl acetate = 50:50 —+ 0:100, v/V) to give the title compound (275 mg, yield: 66%). 1H—NMR (400 MHZ, CDCl3) 8 ppm: 8.21 (1H, t, J = 8 Hz), 8.02—7.96 (3H, m), 7.87 (1H, dd, J 12, 1 Hz), .42 (1H, m), 7.05 (2H, d, J = 9 Hz), .76 (1H, q, J = 7 Hz), 4.70—4.63 (1H, m), 4.54—4.49 (1H, m), 4.23 (1H, dd, J = 9, 8 Hz), 4.07 (1H, dd, J 10, 4 Hz), 3.88 (1H, dd, J = 10, 2 Hz), 3.72 (1H, dd, J = 9, 7 Hz), 2.63—2.57 (1H, m), 2.15 (1H, d, J = 5 Hz), 1.92 (3H, d, J = 7 Hz), 1.22—1.18 (2H, m), 1.03—0.98 (2H, m); Ms (FAB) m/z: 482 [M+H]+.

(Formulation Example) g of each of the compounds obtained in the Examples, 90 g of lactose, 34 g of corn starch, 20 g of crystalline ose, and 1 g of magnesium stearate are mixed with a blender, and then the mixture is tableted with a ing machine. Thereby, tablets are obtained.

(Test Example 1) Mouse oGTT (oral e tolerance test) A dosing preparation (lmg/mL of each compound) was $ SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905—1-SWALLACE produced by suspending in a 0.5 w/v% methyl cellulose solution and then grinding in an agate mortar. Male C57/BL6J mice (Charles River Laboratories Japan, Inc.) were purchased at 6 to 8 weeks of age, and then used at 9 to 13 weeks of age. The mice were fasted between 17:00 and 18:00 one day before the test day, and the test was started after 16 to 17 hours of fasting. Five mice were used for each group. After collecting blood from the tail vein, a suspension of the compound was administered orally at a dosage of 10 mg/kg. The 0.5 w/v% methyl cellulose solution was administered to a negative control group. Blood was collected from the tail vein 25 minutes after stration of the compound, and then 30 w/v% glucose solution was administered orally at a volume of 10 mL/kg 30 minutes after the compound administration. Blood was collected from the tail vein 15, 30, 60 and 120 minutes after the glucose administration. Each of the blood samples was centrifuged to obtain the plasma, and the plasma e level ) was measured with a glucose analyzer (Glucoloader—GXT, A&T . The plasma glucose AUC (mg/dLfldn) in each mouse was calculated using the plasma glucose levels at 5 minutes before and 15, 30, 60 and 120 minutes after the glucose administration. The etic mean of the AUC was calculated for each group and the percentage se in plasma glucose AUC (%) compared with the negative control group was calculated as an index of the cy.

FP12255 SJW/PN811150/ English translation of PCTJP2012/O69098 specification 4624905—1—SWALLACE As a result, the compounds of Examples 3, 8, 10, and 13 showed a 5% or more to less than 15% percentage decrease in plasma glucose AUC (%) and the compounds of Examples 1, 2, 4 to 7, 9, 11, 12, and 14 showed a 15% or more percentage decrease in plasma glucose AUG.

(Test e 2) Rat oGTT and measurement of plasma compound concentration Each compound is suspended in vehicle (0.5 w/V% methyl ose or 20 w/v% cyclodextrin on) at a concentration of 1 to 10 mg/mL. When ing the dose dependency, the prepared suspension is diluted with the above—described vehicle in a stepwise fashion. Male Zucker fatty rats (Charles River tories Japan, Inc.) or Zucker diabetic fatty (ZDF) rats (Charles River Laboratories Japan, Inc.) are used at 10 to 18 weeks of age.

Two days before the oGTT, plasma glucose and insulin concentrations and body weight are measured, and rats are equally allocated to each group (n = 5 to 8) based on these parameters. The rats are fasted from around 15:00 one day before the oGTT day. On the oGTT day, the suspension prepared by the method described above is administered orally to the rats at a volume of 1 to 5 mL/kg, and 30 minutes after the dosing, 25 to 50 w/v% e solution is administered orally at a volume of 4 mL/kg. Blood is collected from the tail vein before the administration of FF’12255 SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905-1—SWALLACE the compound, 5 minutes before the stration of glucose, and 30, 60, 120, and 180 minutes after the administration of glucose. The obtained blood samples are centrifuged to separate the plasma, and the plasma glucose level is ed with a glucose analyzer (Glucoloader—GXT, A&T Corp.). The plasma glucose AUC in each rat is calculated using the plasma e levels before and after the glucose stration. The etic mean of the AUC is calculated in each group and the percentage se in the AUC (%) compared with the vehicleeadministered group is calculated as an index of the efficacy.

The plasma samples obtained by the method described above are used for measurement of the plasma concentration of the test compound. In order to fy the plasma concentration of the test compound, blood is additionally collected 4 to 8 hours and 24 hours after the administration of the compound. The plasma is subjected to protein removal, and applied to a liquid chromatography/mass analyzer to quantify the plasma concentration of the test compound.

(Test Example 3) Assessment for the protective effect on pancreatic B cells The protective effect of the test compound on pancreatic B cells can be confirmed with reference to the method described in Junko Ogawa, et al., Life Sciences, Vol.

FP1225$ SJW/PN811150/ English translation of PCTJF’2012/069098 specification 4624905SWALLACE 65, No. 12, pp. 1287-1296 (1999).

Industrial Applicability The compounds of the present invention or pharmaceutically acceptable salts thereof are capable of treating and/or preventing type 1 es, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, impaired glucose tolerance, diabetes—associated diseases, diabetic complications and the like, and are ore useful as an active ingredient of a pharmaceutical composition for protecting E cells or the as.

FP12255 SJW/PN811150/ English translation of PCTJP2012/069098 specification 4624905SWALLACE

Claims (2)

WHAT IS CLAIMED IS:

1. A compound represented by general a (I): [Chemical Formula 1] wherein R} represents [Chemical Formula 2], Q* oq; 33* OH I 0 I I OH 0 * represents a binding site with a nitrogen atom, and R? represents a methyl group or an ethyl group; or a ceutically acceptable salt thereof.

2. A compound according to claim 1 selected from the group consisting of the following compounds: 4—(5—{(lR)—1—[4-(cyclopropylcarbonyl)phenoxy]propyl}- 1,2,4—oxadiazol—3—yl)—2—fluoro—N—[(38,4R)—4— hydroxytetrahydrofuran—3—yl]benzamide; 4—(5-{(lR)—l—[4—(cyclopropylcarbonyl)phenoxy]propyl}— 1,2,4—oxadiazol—3—yl)—2-fluoro—N—[(3R,4S)—4— hydroxytetrahydrofuran—3—yl]benzamide; 4—(5—{(1R)—l—[4—(cyclopropylcarbonyl)phenoxy]ethyl}— 1,2,4—oxadiazol~3—yl)—2—fluoro—N—[(3R,4S)—4— ytetrahydrofuran—B—yl]benzamide; 4—(5—{(1R)—l—[4—(cyclopropylcarbonyl)phenoxy]ethyl}— 1,2,4—oxadiazol—3—yl)—2—fluoro—N—[(3S,4R)—4— hydroxytetrahydrofuran—B—yl]benzamide; 4—(5—{(1R)~l—[4—(cyclopropylcarbonyl)phenoxy]propyl}— l,2,4—oxadiazol~3~yl)—2—fluoro—N—[(3R)—2— oxotetrahydrofuran—B—yl]benzamide; 4—(5—{(1R)~1—[4—(cyclopropylcarbonyl)phenoxy]propyl}— 1,2,4—oxadiazol—3—yl)—2—fluoro—N—[(38)-2— rahydrofuran—3—yl]benzamide; 4—(5—{(1R)—l-[4—(cyclopropylcarbonyl)phenoxy]propyl}— l,2,4—oxadiazol—3~yl)—2—fluoro-N—[(38)—5— oxotetrahydrofuran—B—yl]benzamide; 4—(5~{(1R)—l—[4—(cyclopropylcarbonyl)phenoxy]propyl}— 1,2,4—oxadiazol—3—yl)~2~fluoro—N—[(3R)—2—oxopyrrolidin—3— yl]benzamide; 4—(5~{(1R)—l—[4—(cyclopropylcarbonyl)phenoxy]propyl}— 1,2,4—oxadiazol—3—yl)—2~fluoro—N—[(3S)~2~oxopyrrolidin—3— yl]benzamide; 4—(5—{(1R)~1—[4—(cyclopropylcarbonyl)phenoxy]propyl}— l,2,4~oxadiazol—3—yl)—2—fluoro—N—[(35,4S)~4~hydroxy—2— oxotetrahydrofuran—3—yl]benzamide; 4—(5—{(1R)—l-[4-(cyclopropylcarbonyl)phenoxy]ethyl}— oxadiazol—3—yl)—2—fluoro—N-[(3R)—2—oxopyrrolidin—3— FP1225S SJW/PN811150/ English translation of PCTJP