Guanidinobenzoic acid ester compound

Abstract

[Problem] To provide a compound which is useful as an agent for preventing and/or treating kidney diseases. [Means for Solution] The present inventors have studied compounds having a trypsin inhibitory activity, and have confirmed that a guanidinobenzoic acid ester compound has a trypsin inhibitory activity, thereby completing the present invention. The guanidinobenzoic acid ester compound of the present invention can be used as an agent for preventing and/or treating kidney diseases (for example, chronic kidney disease, acute glomerulonephritis, acute kidney injury, and the like) as an agent which will substitute low-protein diet therapy, and/or as an agent for preventing and/or treating trypsin-related diseases (for example, chronic pancreatitis, gastroesophageal reflux disease, hepatic encephalopathy, influenza, and the like).

Claims

1. A compound of Formula (I) or a salt thereof: ##STR00217## wherein L.sup.1 is a bond or -lower alkylene-, L.sup.2 is an optionally substituted lower alkylene, R.sup.1 is H or lower alkyl optionally substituted with at least one substituent selected from the group consisting of an optionally substituted aryl, an optionally substituted aromatic heterocyclic group, and CO.sub.2H, or R.sup.1 with the nitrogen atom bonded thereto and the HO.sub.2C-L.sup.2 group on the nitrogen atom form a cyclic amino optionally substituted with CO.sub.2H, and Ring B is naphthalenediyl, 1,2,3,4-tetrahydronaphthalenediyl, 2,3-dihydroindenediyl, benzothiophenediyl, benzofurandiyl, or 2,3-dihydrobenzofurandiyl.

2. The compound or a salt thereof according to claim 1, wherein L.sup.1 is a bond or C.sub.1-3 alkylene, L.sup.2 is lower alkylene optionally substituted with a substituent D1, and R.sup.1 is H or lower alkyl optionally substituted with at least one substituent selected from the group consisting of (i) aryl optionally substituted with a substituent D2, (ii) an aromatic heterocyclic group optionally substituted with a substituent D2, and (iii) CO.sub.2H, or R.sup.1 with the nitrogen atom bonded thereto and the HO.sub.2C-L.sup.2 group on the nitrogen atom form, 1,2,3,4-tetrahydroisoquinolin-2-yl substituted with at least one CO.sub.2H group, the substituent D1 is halogen, OH, O-lower alkyl, SH, S-lower alkyl, S(O)-lower alkyl, S(O).sub.2-lower alkyl, CN, NO.sub.2, NH.sub.2, NH-(lower alkyl), N(lower alkyl).sub.2, C(O)-lower alkyl, aryl substituted with at least one substituent selected from the group consisting of O-(lower alkyl optionally substituted with at least one CO.sub.2H group), halogen, CO.sub.2H, and lower alkyl which is optionally substituted with at least one substituent selected from the group consisting of halogen and CO.sub.2H, C(O)O-lower alkyl, CO.sub.2H, C(O)NHOH, C(O)NHO-lower alkyl, C(O)NHCN, C(O)NHS(O).sub.2-lower alkyl, C(O)NHS(O).sub.2N(lower alkyl).sub.2, tetrazolyl, oxadiazolonyl, oxadiazolethionyl, oxathiadiazolyl, thiadiazolonyl, triazolethionyl, or hydroxvisoxazolyl, and each substituent D2 is independently halogen, OH, O-lower alkyl, SH, S-lower alkyl, S(O)-lower alkyl, S(O).sub.2-lower alkyl, CN, NO.sub.2, NH.sub.2, NH-(lower alkyl), N(lower alkyl).sub.2, C(O)-lower alkyl, C(O)NH.sub.2, C(O)NH-(lower alkyl), C(O)N(lower alkyl).sub.2, C(O)O-lower alkyl, CO.sub.2H, C(O)NHOH, C(O)NHO-lower alkyl, C(O)NHCN, C(O)NHS(O).sub.2-lower alkyl, C(O)NHS(O).sub.2N(lower alkyl).sub.2, tetrazolyl, oxadiazolonyl, oxadiazolethionyl, oxathiadiazolyl, thiadiazolonyl, triazolethionyl, or hydroxyisoxazolyl, lower alkyl optionally substituted with halogen, OH, O-lower alkyl, SH, S-lower alkyl, S(O)-lower alkyl, S(O).sub.2-lower alkyl, CN, NO.sub.2, NH.sub.2, NH-(lower alkyl), N(lower alkyl).sub.2, C(O)-lower alkyl, C(O)NH.sub.2, C(O)NH-(lower alkyl), C(O)N(lower alkyl).sub.2, C(O)O-lower alkyl, CO.sub.2H, C(O)NHOH, C(O)NHO-lower alkyl, C(O)NHCN, C(O)NHS(O).sub.2-lower alkyl, C(O)NHS(O).sub.2N(lower alkyl).sub.2, tetrazolyl, oxadiazolonyl, oxadiazolethionyl, oxathiadiazolyl, thiadiazolonyl, triazolethionyl, or hydroxyisoxazolyl, or O-lower alkyl optionally substituted with halogen, OH, O-lower alkyl, SH, S-lower alkyl, S(O)-lower alkyl, S(O).sub.2-lower alkyl, CN, NO.sub.2, NH.sub.2, NH-(lower alkyl), N(lower alkyl).sub.2, C(O)-lower alkyl, C(O)NH.sub.2, C(O)NH-(lower alkyl), C(O)N(lower alkyl).sub.2, C(O)O-lower alkyl, CO.sub.2H, C(O)NHOH, C(O)NHO-lower alkyl, C(O)NHCN, C(O)NHS(O).sub.2-lower alkyl, C(O)NHS(O).sub.2N(lower alkyl).sub.2, tetrazolyl, oxadiazolonyl, oxadiazolethionyl, oxathiadiazolyl, thiadiazolonyl, triazolethionyl, or hydroxyisoxazolyl.

3. The compound or a salt thereof according to claim 2, wherein L.sup.1 is a bond or methylene, L.sup.2 is lower alkylene optionally substituted with a substituent R.sup.1 is H or lower alkyl optionally substituted with at least one substituent selected from the group consisting of (i) aryl optionally substituted with a substituent D2, (ii) an aromatic heterocyclic group optionally substituted with a substituent D2, and (iii) CO.sub.2H, Ring B is naphthalenediyl, 1,2,3,4-tetrahydronaphthalenediyl, 2,3-dihydroindenediyl, or benzothiophenediyl.

4. The compound or a salt thereof according to claim 3, wherein L.sup.2 is methylene, ethylene, or ethylene substituted with (phenyl substituted with CO.sub.2H).

5. The compound or a salt thereof according to claim 3, wherein L.sup.2 is methylene, methylmethylene, ethylene, or methylmethylene substituted with (phenyl substituted with CO.sub.2H).

6. The compound or a salt thereof according to claim 4, wherein R.sup.1 is H or lower alkyl optionally substituted with at least one substituent selected from the group consisting of (i) phenyl substituted with at least one substituent selected from the group consisting of CO.sub.2H and lower alkyl substituted with CO.sub.2H, (ii) thienyl substituted with at least one substituent selected from the group consisting of CO.sub.2H and lower alkyl substituted with CO.sub.2H, and (iii) CO.sub.2H.

7. The compound or a salt thereof according to claim 6, wherein Ring B is naphthalene-1,6-diyl, naphthalene-2,6-diyl, 1,2,3,4-tetrahydronaphthalene-1,6-diyl, 1,2,3,4-tetrahydronaphthalene-2,6-diyl, 2,3-dihydroindene-1,5-diyl, or benzothiophene-3,6-diyl.

8. The compound or a salt thereof according to claim 7, wherein either L.sup.2 is methylene or methylmethylene, and R.sup.1 is lower alkyl substituted with at least one substituent selected from the group consisting of (i) phenyl substituted with at least one substituent selected from the group consisting of CO.sub.2H and lower alkyl substituted with CO.sub.2H, and (ii) thienyl substituted with at least one substituent selected from the group consisting of CO.sub.2H and lower alkyl substituted with CO.sub.2H, or L.sup.2 is methylmethylene substituted with (phenyl substituted with CO.sub.2H), and R.sup.1 is H.

9. The compound or a salt thereof according to claim 8, wherein L.sup.2 is methylene or methylmethylene, and R.sup.1 is (phenyl substituted with CO.sub.2H)CH.sub.2, (phenyl substituted with CH.sub.2CO.sub.2H)CH.sub.2, or (thienyl substituted with CO.sub.2H)CH.sub.2.

10. The compound or a salt thereof according to claim 2, wherein L.sup.1 is a bond or methylene, Ring B is naphthalene-1,6-diyl, naphthalene-2,6-diyl, 1,2,3,4-tetrahydronaphthalene-1,6-diyl, 1,2,3,4-tetrahydronaphthalene-2,6-diyl, 2,3-dihydroindene-1,5-diyl, benzothiophene-3,6-diyl, benzofuran-3,6-diyl, or 2,3-dihydrobenzofuran-3,6-diyl, and (a) L.sup.2 is C.sub.1-3 alkylene, and R.sup.1 is lower alkyl which is substituted with at least one substituent selected from the group consisting of (i) phenyl optionally substituted with at least one substituent selected from the group consisting of CO.sub.2H and lower alkyl substituted with CO.sub.2H, and (ii) thienyl or benzothienyl, either of which is substituted with at least one substituent selected from the group consisting of CO.sub.2H and lower alkyl substituted with CO.sub.2H, the lower alkyl of R.sup.1 optionally substituted with at least one CO.sub.2H group, (b) L.sup.2 is C.sub.1-3 alkylene substituted with (phenyl substituted with CO.sub.2H), and R.sup.1 is H, or (c) R.sup.1 with the nitrogen atom bonded thereto and the HO.sub.2C-L.sup.2 group on the nitrogen atom form 1,2,3,4-tetrahydroisoquinolin-2-yl substituted with two CO.sub.2H groups.

11. The compound or a salt thereof according to claim 1, which is 4-{[{6-[(4-carbamimidamidobenzoyl)oxy]-2-naphthoyl}(carboxymethyl)amino]methyl}thiophene-2-carboxylic acid, 3-{[({6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid, 3-{[({(1R)-6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid, 3-{[({(1 S)-6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid, N-{6-[(4-carbamimidamidobenzoyl)oxy]-1-naphthoyl-4-carboxy-L-phenylalanine, 4-{[({6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)(carboxymethyl)amino]methyl}thiophene-2-carboxylic acid, 3-{[({5-[(4-carbamimidamidobenzoyl)oxy]-2,3-dihydro-1H-inden-1-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid, 4-{[({6-[(4-carbamimidamidobenzoyl)oxy]-1-benzothiophen-3-yl}carbonyl)(carboxymethyl)amino]methyl}thiophene-2-carboxylic acid, 3-{[{6-[(4-carbamimidamidobenzoyl)oxy]-1-naphthoyl}(carboxymethyl)amino]methyl}benzoic acid, N-{6-[(4-carbamimidamidobenzoyl)oxy]-1-naphthoyl}-N-[4-(carboxymethyl)benzyl]glycine, 4-({({6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acetyl)[(1R)-1-carboxyethyl]amino}methyl)thiophene-2-carboxylic acid, 4-({({6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)[(1R)-1-carboxyethyl]amino}methyl)thiophene-2-carboxylic acid, or N-({6-[(4-carbamimidamidobenzoyl)oxy]-1-benzothiophen-3-yl}carbonyl)-N-[4-(carboxymethyl)benzyl]glycine.

12. A pharmaceutical composition comprising a compound or a salt thereof according to claim 11, and a pharmaceutically acceptable excipient.

13. A method for treating a kidney disease, the method comprising: administering an effective amount of a compound or a salt thereof according to claim 11 to a subject in need thereof.

14. The compound or a salt thereof according to claim 11 wherein the compound is 3-{[({(1R)-6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid.

15. The compound or a salt thereof according to claim 11 wherein the compound is 4-[({6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)(carboxymethyl)amino]methyllthiophene-2-carboxylic acid.

16. The compound or a salt thereof according to claim 11 wherein the compound is 3-{[({5-[(4-carbamimidamidobenzoyl)oxy]-2,3-dihydro-1H-inden-1-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid.

17. The compound or a salt thereof according to claim 1, which is 3-{[({6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid.

18. The compound or a salt thereof according to claim 1, which is 3-{[({6-[(4-carbamimidamidobenzoyl)oxy]-2,3-dihydro-1-benzofuran-3-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid.

19. The compound or a salt thereof according to claim 1, which is 3-{[({5-[(4-carbamimidamidobenzoyl)oxy]-2,3-dihydro-1H-inden-1-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid.

20. The compound or a salt thereof according to claim 1, which is 3-{[({6-[(4-carbamimidamidobenzoyl)oxy]-1-benzofuran-3-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid.

21. The compound or a salt thereof according to claim 1, which is 3-{[({6-[(4-carbamimidamidobenzoyl)oxy]-2-naphthoyl)(carboxymethyl)amino]methyl}benzoic acid.

22. The compound or a salt thereof according to claim 1, which is 4-{[({6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acetyl)(carboxymethyl)amino]methyl}thiophene-2-carboxylic acid.

23. The compound or a salt thereof according to claim 1, which is 3-{[({6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)(carboxymethyl)amino]methyl}benzoic acid.

Description

EXAMPLES

(1) Hereinbelow, the preparation methods for the compound of the formula (I) or a salt thereof will be described in more detail with reference to Examples, but the present invention is not limited to the compounds described in the Examples as described below. Furthermore, the production processes for the starting compounds will be described in Preparation Examples. Further, the preparation methods for the compound of the formula (I) are not limited to the preparation methods of the specific Examples as below, but the compound of the formula (I) can be prepared by any combination of the preparation methods or the methods that are apparent to a person skilled in the art.

(2) Furthermore, the following abbreviations may be used in some cases in the Examples, Preparation Examples, and Tables below.

(3) PEx: Preparation Example No. (the compounds in which * is marked in the chemical and structural formulae denote that the compounds are single isomers having steric configurations of the denoted structures; the compounds in which ** is marked in the chemical and structural formulae denote that the compounds are single isomers, but have no steric configuration determined; and the compounds in which # is marked in the chemical and structural formulae denote a diastereomeric mixture), Ex: Example No. (the compounds in which * is marked in the chemical and structural formulae denote that the compounds are single isomers having steric configurations of the denoted structures; the compounds in which ** is marked in the chemical and structural formulae denote that the compounds are single isomers, but have no steric configuration determined; and the compounds in which # is marked in the chemical and structural formulae denote a diastereomeric mixture), PSyn: Preparation Example No. prepared by the same method, Syn: Example No. prepared by the same method, Str: Chemical Structural formula (Me: methyl, .sup.tBu: tert-butyl, Ph: phenyl, Boc: tert-butoxycarbonyl, Bn: benzyl, OMe: O methyl, OBn: O-benzyl, O.sup.tBu: O-tert-butyl, and NBoc: N-tert-butoxycarbonyl), Data: Physicochemical Data, ESI+: m/z values in mass spectroscopy (Ionization ESI, representing (M+H).sup.+ unless otherwise specified), ESI?: m/z values (Ionization ESI, representing (M?H).sup.? unless otherwise specified), APCI+: m/z values (atmospheric pressure chemical ionization APCI, representing (M+H).sup.+ unless otherwise specified), APCI/ESI+: APCI/ESI?MS[M+H].sup.+ (APCI/ESI means the simultaneous measurement of APCI and ESI), NMR1: characteristic ? (ppm) in .sup.1H NMR in dimethylsulfoxide-d.sub.6, NMR2: characteristic ? (ppm) in .sup.1H NMR in CDCl.sub.3, M in Preparation Examples and Examples: mol/L, and RT: a retention time in supercritical chromatography or liquid chromatography, in a unit of minutes (min).

(4) In addition, in the structural formulae, HCl represents hydrochloride, and TFA represents trifluoroacetate.

Preparation Example 1

(5) A mixture of tert-butyl 4-methylthiophene-2-carboxylate (12.0 g), N-bromosuccinimide (10.8 g), 2,2-azobis(isobutyronitrile) (496 mg), and carbon tetrachloride (119 mL) was stirred at 90? C. for 1 hour. Further, N-bromosuccinimide (1.08 g) was added thereto, and the mixture was stirred at 90? C. for 1 hour. The reaction suspension was cooled to room temperature, then the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-(bromomethyl)thiophene-2-carboxylate (16.3 g).

(6) To a solution of tert-butyl 4-(bromomethyl)thiophene-2-carboxylate (9.90 g) in N,N-dimethylformamide (100 mL) were added tert-butyl glycinate hydrochloride (18.0 g) and triethylamine (19.9 mL), followed by stirring at 60? C. for 15 hours. The reaction suspension was cooled to room temperature, and then sodium triacetoxyborohydride (22.7 g) was added thereto, followed by stirring at room temperature for 5 hours. To the reaction suspension were added water and an aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with a 5% aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}thiophene-2-carboxylate (5.67 g).

Preparation Example 2

(7) To a solution of 6-hydroxy-2-naphthoic acid (220 mg) in N,N-dimethylformamide (3.30 mL) were added tert-butyl 4-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}thiophene-2-carboxylate (383 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (489 mg), and N,N-diisopropylethylamine (500 ?L), followed by stirring at room temperature for 20 hours. Further, O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (222 mg) and N,N-diisopropylethylamine (200 ?L) were added thereto, followed by stirring at room temperature for 6 hours. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-{[(2-tert-butoxy-2-oxoethyl)(6-hydroxy-2-naphthoyl)amino]methyl}thiophene-2-carboxylate (277 mg).

Preparation Example 3

(8) To a solution of 4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoic acid (194 mg) in dichloromethane (7.29 mL) were added N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (118 mg), tert-butyl 4-{[(2-tert-butoxy-2-oxoethyl)(6-hydroxy-2-naphthoyl)amino]methyl}thiophene-2-carboxylate (255 mg), and 4-dimethylaminopyridine (18.8 mg), followed by stirring at room temperature for 24 hours. To the reaction liquid was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-({[6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-2-naphthoyl](2-tert-butoxy-2-oxoethyl)amino}methyl)thiophene-2-carboxylate (137 mg).

Preparation Example 4

(9) To a solution of 6-methoxy-1-benzothiophene-2-carboxylic acid (960 mg) in dichloromethane (5.76 mL) was added dropwise a 1 M solution (37.5 mL) of boron tribromide in dichloromethane over 10 minutes under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction liquid was added dropwise to ice, followed by stirring. The precipitate was collected by filtration, and dried under reduced pressure to obtain 6-hydroxy-1-benzothiophene-2-carboxylic acid (920 mg).

Preparation Example 5

(10) To a solution of 2-tert-butyl 3,7-dimethyl (3R)-3,4-dihydroisoquinoline-2,3,7(1H)-tricarboxylate (345 mg) in methanol (7.00 mL) was added a 1 M aqueous sodium hydroxide solution (3.50 mL), followed by stirring at room temperature for 3 hours. The mixture was neutralized by the addition of 1 M hydrochloric acid (3.50 mL), and then water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain (3R)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3,7-dicarboxylic acid (328 mg).

Preparation Example 6

(11) To a solution of (6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetic acid (1.03 g) in N,N-dimethylformamide (20.5 mL) were added tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate hydrochloride (1.96 g), triethylamine (762 ?L), N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (1.00 g), and 1H-benzotriazol-1-ol (705 mg), followed by stirring at room temperature for 13 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-({(2-tert-butoxy-2-oxoethyl) [(6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetyl]amino}methyl)benzoate (2.41 g).

Preparation Example 7

(12) Under a nitrogen atmosphere, to a solution of tert-butyl 3-(chloromethyl)benzoate (29.1 g) in N,N-dimethylformamide (300 mL) were added tert-butyl glycinate hydrochloride (43.0 g) and triethylamine (71.6 mL), followed by stirring at 60? C. to 63? C. for 3 hours. The reaction mixture was ice-cooled, and then water was added thereto, followed by extraction with ethyl acetate. The organic layer was sequentially washed with a 10% aqueous ammonium chloride solution and a 20% aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (400 mL), and then a 4 M solution (32.1 mL) of hydrogen chloride in ethyl acetate was added dropwise thereto under ice-cooling in a nitrogen atmosphere, followed by stirring for 1 hour. The precipitate was collected by filtration, washed with ethyl acetate, and then dried at 50? C. under reduced pressure to obtain tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate hydrochloride (28.5 g).

Preparation Example 8

(13) A mixture of ethyl (6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetate (2.08 g) and 48% hydrobromic acid (40.0 mL) was stirred at 120? C. for 17 hours. The reaction mixture was left to be cooled and then concentrated under reduced pressure. To the residue was added tetrahydrofuran (100 mL), followed by stirring at room temperature for 1 hour, and then the precipitate was collected by filtration. The filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane-ethyl acetate). To the purified product was added diisopropylether (15.0 mL), followed by stirring at room temperature for 1 hour. The precipitate was collected by filtration, washed with diisopropylether, and then dried at room temperature under reduced pressure to obtain (6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetic acid (1.06 g).

Preparation Example 9

(14) To a solution of 4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoic acid (1.97 g) in dichloromethane (48.0 mL) were added tert-butyl 3-({(2-tert-butoxy-2-oxoethyl)[(6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetyl]amino}methyl)benzoate (2.40 g), N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (1.17 g), and 4-dimethylaminopyridine (173 mg), followed by stirring at room temperature for 2 hours. Further, 4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoic acid (179 mg) and N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (100 mg) were added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-{[{[6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamnide]benzoyl}oxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate (3.71 g).

Preparation Example 10

(15) To a solution of tert-butyl N-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)-L-phenylalaninate (570 mg) in tetrahydrofuran (3.00 mL) and ethanol (3.00 mL) was added 10% palladium-carbon (138 mg, a 50% wet product) in an argon atmosphere, followed by stirring at room temperature overnight at normal pressure in a hydrogen atmosphere. The reaction suspension was filtered by passing it through a Celite (registered trademark) layer, and then the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(tert-butoxycarbonyl)-L-phenylalaninate (431 mg).

Preparation Example 11

(16) A mixture of 3-[(benzyl {[6-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}amino)methyl]pentanedioic acid (886 mg), N,N-dimethylformamide di-tert-butyl acetal (1.60 mL), and toluene (4.43 mL) was stirred at 80? C. for 4 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain di-tert-butyl 3-[(benzyl {[6-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}amino)methyl]pentanedioate (232 mg).

Preparation Example 12

(17) To 3,7-dibenzyl 2-tert-butyl (3R)-3,4-dihydroisoquinoline-2,3,7(1H)-tricarboxylate (413 mg) was added a 4 M solution (4.00 mL) of hydrogen chloride in 1,4-dioxane, followed by stirring at room temperature overnight. The reaction suspension was concentrated under reduced pressure, and the residue was dried under reduced pressure to obtain dibenzyl (3R)-1,2,3,4-tetrahydroisoquinoline-3,7-dicarboxylate hydrochloride (358 mg).

Preparation Example 13

(18) To a solution of 6-hydroxy-1-benzothiophene-3-carboxylic acid (100 mg), tert-butyl 4-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}thiophene-2-carboxylate (186 mg), and N,N-diisopropylethylamine (88.2 ?L) in N,N-dimethylformamide (3.00 mL) was added (1-cyano-2-ethoxy-2-oxoethylidenaminoxy)dimethylaminomorpholinocarbenium hexafluorophosphate (243 mg), followed by stirring at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was sequentially washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-({(2-tert-butoxy-2-oxoethyl)[(6-hydroxy-1-benzothiophen-3-yl)carbonyl]amino}methyl)thiophene-2-carboxylate (230 mg).

Preparation Example 14

(19) To a solution of tert-butyl [4-(aminomethyl)phenyl]acetate (1.00 g) in acetonitrile (15.0 mL) were added triethylamine (693 ?L) and tert-butyl bromoacetate (668 ?L), followed by stirring at room temperature for 4 hours. The reaction liquid was concentrated under reduced pressure, and then ethyl acetate was added thereto. The organic layer was sequentially washed with 0.1 M hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-[4-(2-tert-butoxy-2-oxoethyl)benzyl]glycinate (747 mg).

Preparation Example 15

(20) To a solution of 6-hydroxy-1-naphthoic acid (190 mg) in N,N-dimethylformamide (2.85 mL) were added tert-butyl 4-({[(2R)-1-tert-butoxy-1-oxopropan-2-yl]amino}methyl)thiophene-2-carboxylate (345 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (422 mg), and N,N-diisopropylethylamine (190 ?L), followed by stirring at 50? C. for 19 hours. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-({[(2R)-1-tert-butoxy-1-oxopropan-2-yl](6-hydroxy-1-naphthoyl)amino}methyl)thiophene-2-carboxylate (101 mg).

Preparation Example 16

(21) To a solution of N-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)-L-phenylalanine (500 mg) in tetrahydrofuran (4.00 mL) and tert-butyl alcohol (4.00 mL) were added di-tert-butyl dicarbonate ester (656 mg) and 4-dimethylaminopyridine (30.6 mg), followed by stirring at room temperature overnight. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water, an aqueous saturated sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain tert-butyl N-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)-L-phenylalaninate (641 mg).

Preparation Example 17

(22) To a solution of (6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetic acid (150 mg), tert-butyl N-(2-tert-butoxy-2-oxoethyl)-L-phenylalaninate (293 mg), and N,N-diisopropylethylamine (147 ?L) in N,N-dimethylformamide (4.50 mL) was added (1-cyano-2-ethoxy-2-oxoethylidenaminoxy)dimethylaminomorpholinocarbenium hexafluorophosphate (368 mg), followed by stirring at 60? C. for 8 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was sequentially washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-(2-tert-butoxy-2-oxoethyl)-N-[(6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetyl]-L-phenylalaninate (347 mg).

Preparation Example 18

(23) To a solution of 5-methyl-1-benzothiophene-2-carboxylic acid (1.50 g) in N,N-dimethylformamide (10.5 mL) was added 1,1-carbonylbis-1H-imidazole (1.27 g), followed by stirring at room temperature for 2 hours and 30 minutes. To the reaction mixture were added tert-butyl alcohol (1.44 mL) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (1.17 mL), followed by stirring at 50? C. for 24 hours. The reaction mixture was diluted with ethyl acetate, and then the organic layer was sequentially washed with 0.1 M hydrochloric acid and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 5-methyl-1-benzothiophene-2-carboxylate (1.78 g).

Preparation Example 19

(24) To a mixture of tert-butyl 5-methyl-1-benzothiophene-2-carboxylate (1.77 g), carbon tetrachloride (17.7 mL), and N-bromosuccinimide (2.16 g) was added 2,2-azobis(isobutyronitrile) (58.5 mg), followed by stirring at 90? C. overnight. The reaction suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 5-(bromomethyl)-1-benzothiophene-2-carboxylate (1.51 g).

Preparation Example 20

(25) To a solution of tert-butyl 5-(bromomethyl)-1-benzothiophene-2-carboxylate (1.00 g) in N,N-dimethylformamide (10.0 mL) were added tert-butyl glycinate hydrochloride (1.02 g) and triethylamine (1.70 mL), followed by stirring at 85? C. to 95? C. overnight. The reaction mixture was cooled to room temperature, followed by extraction with ethyl acetate. The organic layer was washed with a 25% aqueous ammonium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 5-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}-1-benzothiophene-2-carboxylate (359 mg).

Preparation Example 21

(26) To a solution of 2-tert-butyl 3-methyl (3R)-7-hydroxy-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (1.00 g) in dichloromethane (20.0 mL) were added trifluoromethane sulfonic acid anhydride (770 ?L) and 2,6-dimethyl pyridine (800 ?L) under ice-cooling, followed by stirring for 2 hours under ice-cooling. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue were added N,N-dimethylformamide (15.0 mL), methanol (3.00 mL), palladium (II) acetate (37.0 mg), 1,1-bis(diphenylphosphino)ferrocene (90.0 mg), and triethylamine (1.10 mL), followed by stirring at 80? C. overnight in a carbon monoxide atmosphere. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To the residue was added water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2-tert-butyl 3,7-dimethyl (3R)-3,4-dihydroisoquinoline-2,3,7(1H)-tricarboxylate (350 mg).

Preparation Example 22

(27) To a solution of (3R)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3,7-dicarboxylic acid (320 mg) in N,N-dimethylformamide (6.00 mL) were added potassium carbonate (315 mg) and benzyl bromide (275 ?L), followed by stirring at room temperature overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3,7-dibenzyl 2-tert-butyl (3R)-3,4-dihydroisoquinoline-2,3,7(1H)-tricarboxylate (415 mg).

Preparation Example 23

(28) To a solution of 2-bromo-1,3,5-trimethylbenzene (925 ?L) in tetrahydrofuran (20.0 mL) was added dropwise a 1.59 M solution (3.86 mL) of n-butyllithium in hexane at ?78? C., followed by stirring at ?78? C. for 30 minutes. To the reaction mixture was added dropwise a solution of tert-butyl (4-bromo-2-thienyl)acetate (1.55 g) in tetrahydrofuran (15.0 mL), followed by stirring at ?78? C. for 30 minutes. Subsequently, to the reaction mixture was added dropwise a 1.59 M solution (3.51 mL) of n-butyllithium in hexane, followed by stirring at ?78? C. for 30 minutes. To the reaction mixture was added dropwise N,N-dimethylformamide (451 ?L), followed by stirring at 78? C. for 1 hour. To the reaction liquid were added an aqueous ammonium chloride solution and ethyl acetate, thereby extracting the organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl (4-formyl-2-thienyl)acetate (355 mg).

Preparation Example 24

(29) To a solution of tert-butyl (4-formyl-2-thienyl)acetate (350 mg), tert-butyl glycinate (243 mg), and acetic acid (265 ?L) in dichloromethane (4.05 mL) was added sodium triacetoxyborohydride (656 mg) under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was neutralized by the addition of an aqueous saturated sodium hydrogen carbonate solution, and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-{[5-(2-tert-butoxy-2-oxoethyl)-3-thienyl]methyl}glycinate (237 mg).

Preparation Example 25

(30) A mixture of tert-butyl [3-(aminomethyl)phenyl]acetate (1.00 g), tert-butyl bromoacetate (700 ?L), potassium carbonate (650 mg), and acetonitrile (20.0 mL) was stirred at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-[3-(2-tert-butoxy-2-oxoethyl)benzyl]glycinate (1.14 g).

Preparation Example 26

(31) To a mixture of N-benzyl-N-(cyclopenta-3-en-1-ylmethyl)-2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (430 mg), potassium carbonate (174 mg), and N,N-dimethylformamide (4.30 mL) was added benzyl bromide (177 ?L), followed by stirring at 50? C. for 6 hours. The reaction mixture was cooled, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain N-benzyl-2-[6-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl]-N-(cyclopenta-3-en-1-ylmethyl)acetamide (416 mg).

Preparation Example 27

(32) To a mixture of N-benzyl-2-[6-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl]-N-(cyclopenta-3-en-1-ylmethyl)acetamide (100 mg), tert-butyl alcohol (2.40 mL), and water (600 ?L) were added a 2.5% solution (269 ?L) of osmium tetraoxide in tert-butyl alcohol, and 4-methylmorpholine 4-oxide (75.5 mg), followed by stirring at room temperature for 2 hours. To the reaction mixture was added an aqueous sodium thiosulfate solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain N-benzyl-2-[6-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl]-N-[(3,4-dihydroxycyclopentyl)methyl]acetamide (107 mg).

Preparation Example 28

(33) To a mixture of N-benzyl-2-[6-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl]-N-[(3,4-dihydroxycyclopentyl)methyl]acetamide (106 mg), iodobenzene diacetate (322 mg), dichloromethane (3.00 mL), and water (1.00 mL) was added 1-methyl-2-azaadamantan-N-oxyl (3.33 mg), followed by stirring at room temperature for 3 hours. To the reaction mixture was added a 20% aqueous sodium thiosulfate solution, followed by stirring at room temperature for 5 minutes. Subsequently, 1 M hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3-[(benzyl {[6-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}amino)methyl]pentanedioic acid (110 mg).

Preparation Example 29

(34) To a mixture of a (1S)-1-phenylethanamine salt (370 mg) of [(1R)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetic acid or an enantiomer thereof, and ethyl acetate (4.50 mL) was added 3 M hydrochloric acid (4.50 mL), followed by stirring at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain [(1R)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetic acid or an enantiomer thereof (243 mg).

Preparation Example 30

(35) To a mixture of a (1R)-1-phenylethanamine salt (450 mg) of [(1R)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetic acid or an enantiomer thereof, and ethyl acetate (5.51 mL) was added a 4 M solution (4.13 mL) of hydrogen chloride in ethyl acetate, followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain [(1R)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetic acid or an enantiomer thereof (290 mg).

Preparation Example 31

(36) To a solution of [(1R)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetic acid or an enantiomer thereof (238 mg) obtained in Preparation Example 29 in dichloromethane (8.00 mL) was added a 1 M solution (2.20 mL) of boron tribromide in dichloromethane under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture was added ice-water, followed by extraction with ethyl acetate. The organic layer was washed with water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain [(1R)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetic acid or an enantiomer thereof (147 mg).

Preparation Example 32

(37) To a solution of [(1R)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetic acid or an enantiomer thereof (288 mg) obtained in Preparation Example 30 in dichloromethane (9.77 mL) was added dropwise a 1 M solution (2.66 mL) of boron tribromide in dichloromethane under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture was added ice-water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain [(1R)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetic acid or an enantiomer thereof (230 mg).

Preparation Example 33

(38) To a solution of [(1R)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetic acid or an enantiomer thereof (145 mg) obtained in Preparation Example 31 in N,N-dimethylformamide (2.90 mL) were added tert-butyl 4-({[(2R)-1-tert-butoxy-1-oxopropan-2-yl]amino}methyl)thiophene-2-carboxylate (255 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (295 mg), and N,N-diisopropylethylamine (135 ?L), followed by stirring at room temperature overnight. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-[([(2R)-1-tert-butoxy-1-oxopropan-2-yl]{[(1R)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}amino)methyl]thiophene-2-carboxylate or an epimer at position 1 of the 1,2,3,4-tetrahydronaphthalene (237 mg).

Preparation Example 34

(39) To a solution of tert-butyl 4-[([(2R)-1-tert-butoxy-1-oxopropan-2-yl]{[(1R)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}amino)methyl]thiophene-2-carboxylate or an epimer at position 1 of the 1,2,3,4-tetrahydronaphthalene (235 mg) obtained in Preparation Example 33 in dichloromethane (3.00 mL) were added N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (115 mg), 4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoic acid (220 mg), and 4-dimethylaminopyridine (18.0 mg), followed by stirring at room temperature for 3 hours. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-[({[(1R)-6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamnide]benzoyl}oxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}[(2R)-1-tert-butoxy-1-oxopropan-2-yl]amino)methyl]thiophene-2-carboxylate or an epimer at position 1 of the 1,2,3,4-tetrahydronaphthalene (325 mg).

Preparation Example 35

(40) To a solution of [(1R)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetic acid or an enantiomer thereof (228 mg) obtained in Preparation Example 32 in N,N-dimethylformamide (4.56 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (504 mg), N,N-diisopropylethylamine (227 ?L), and tert-butyl 4-({[(2R)-1-tert-butoxy-1-oxopropan-2-yl]amino}methyl)thiophene-2-carboxylate (453 mg), followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate. The organic layer was sequentially washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-[([(2R)-1-tert-butoxy-1-oxopropan-2-yl]{[(1R)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}amino)methyl]thiophene-2-carboxylate or an epimer at position 1 of the 1,2,3,4-tetrahydronaphthalene (330 mg).

Preparation Example 36

(41) To a mixture of tert-butyl 4-[([(2R)-1-tert-butoxy-1-oxopropan-2-yl]{[(1R)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}amino)methyl]thiophene-2-carboxylate or an epimer at position 1 of the 1,2,3,4-tetrahydronaphthalene (328 mg) obtained in Preparation Example 35, 4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoic acid (282 mg), 4-dimethylaminopyridine (22.7 mg), and dichloromethane (4.92 mL) was added N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (154 mg), followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-[({[(1R)-6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}[(2R)-1-tert-butoxy-1-oxopropan-2-yl]amino)methyl]thiophene-2-carboxylate or an epimer at position 1 of the 1,2,3,4-tetrahydronaphthalene (460 mg).

Preparation Example 37

(42) tert-Butyl 3-{[{[6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate (395 mg) was preparatively purified by a supercritical chromatography method (carbon dioxide-methanol) by means of a UV trigger, and then concentrated under reduced pressure to obtain PEx. 37-1 (188 mg, RT: 4.02 min) and PEx. 37-2 (187 mg, RT: 4.87 min) as the tert-butyl 3-{[{[(1R)-6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate and an enantiomer thereof. Further, the analysis conditions for the supercritical chromatography method carried out to determine RT are shown below.

(43) Column: CHIRALCEL OZ-H/SFC 4.6 mm I.D.?250 mm (particle diameter: 5 ?m), manufactured by Daicel Chemical Industries, Ltd.

(44) Mobile phase: carbon dioxide 65%, methanol 35%

(45) Flow rate: 3 mL/min (6 min)

(46) Detection wavelength: 220 nm to 300 nm

(47) Column temperature: 40? C.

(48) Discharge pressure: 100 bar

Preparation Example 38

(49) A mixture of 6-hydroxy-1-naphthoic acid (150 mg), tert-butyl 4-(tert-butoxycarbonyl)-L-phenylalaninate (200 mg), N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (160 mg), 1H-benzotriazol-1-ol (110 mg), and N,N-dimethylformamide (4.00 mL) was stirred at room temperature overnight. To the reaction mixture was added water, followed by stirring for 1 hour. The precipitate was collected by filtration, washed with water, and then dried under reduced pressure to obtain tert-butyl 4-(tert-butoxycarbonyl)-N-(6-hydroxy-1-naphthoyl)-L-phenylalaninate (183 mg).

Preparation Example 39

(50) A mixture of tert-butyl 4-(tert-butoxycarbonyl)-N-(6-hydroxy-1-naphthoyl)-L-phenylalaninate (180 mg), 4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoic acid (180 mg), N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (90.0 mg), 4-dimethylaminopyridine (15.0 mg), and dichloromethane (2.00 mL) was stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-[6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-1-naphthoyl]-4-(tert-butoxycarbonyl)-L-phenylalaninate (303 mg).

Preparation Example 40

(51) To a solution of 6-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (200 mg) in N,N-dimethylformamide (3.00 mL) were added tert-butyl 4-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}thiophene-2-carboxylate (341 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (435 mg), and N,N-diisopropylethylamine (196 ?L), followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-({(2-tert-butoxy-2-oxoethyl) [(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)carbonyl]amino}methyl)thiophene-2-carboxylate (522 mg).

Preparation Example 41

(52) To a solution of tert-butyl 4-({(2-tert-butoxy-2-oxoethyl)[(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)carbonyl]amino}methyl)thiophene-2-carboxylate (520 mg) in dichloromethane (10.4 mL) were added 4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoic acid (433 mg), N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (298 mg), and 4-dimethylaminopyridine (38.0 mg) under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction solution were added water and 1 M hydrochloric acid, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-{[{[6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbonyl}(2-tert-butoxy-2-oxoethyl)amino]methyl}thiophene-2-carboxylate (723 mg).

Preparation Example 42

(53) To a solution of (3R)-2-(tert-butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1.50 g) in toluene (60.0 mL), and methanol (9.00 mL) was added dropwise a 0.60 M solution (10.0 mL) of trimethylsilyldiazomethane in hexane, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added acetic acid (300 ?L), and then an aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2-tert-butyl 3-methyl (3R)-7-hydroxy-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (1.47 g).

Preparation Example 43

(54) To a solution of dibenzyl (3R)-2-{[6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}-1,2,3,4-tetrahydroisoquinoline-3,7-dicarboxylate (257 mg) in ethanol (5.00 mL) was added 10% palladium-carbon (52.0 mg, 50% wet product), followed by stirring at room temperature for 2 hours at normal pressure in a hydrogen atmosphere. The reaction mixture was filtered by passing it through a Celite (registered trademark) layer, and then the filtrate was concentrated under reduced pressure to obtain (3R)-2-{[6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}-1,2,3,4-tetrahydroisoquinoline-3,7-dicarboxylic acid (213 mg).

Preparation Example 44

(55) A mixture of di-tert-butyl 3-[(benzyl {[6-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}amino)methyl]pentanedioate (230 mg), 10% palladium-carbon (38.1 mg, 50% wet product), and methanol (4.60 mL) was stirred at room temperature for 16 hours at normal pressure in a hydrogen atmosphere. The reaction mixture was filtered by passing it through a Celite (registered trademark) layer, and then the filtrate was concentrated under reduced pressure to obtain di-tert-butyl 3-({benzyl[(6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetyl]amino}methyl)pentanedioate (186 mg).

Example 1

(56) To tert-butyl 4-({[6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-2-naphthoyl](2-tert-butoxy-2-oxoethyl)amino}methyl)thiophene-2-carboxylate (132 mg) was added a 4 M solution (2.02 mL) of hydrogen chloride in 1,4-dioxane, followed by stirring at room temperature for 24 hours. The reaction suspension was concentrated under reduced pressure, and then the residue was purified by octadecylsilyl (hereinafter referred to as ODS) column chromatography (0.01 M hydrochloric acid-acetonitrile) to obtain 4-{[{6-[(4-carbamimidamidobenzoyl)oxy]-2-naphthoyl}(carboxymethyl)amino]methyl}thiophene-2-carboxylic acid monohydrochloride (62.7 mg).

Example 2

(57) To a solution of tert-butyl 3-{[{[6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate (528 mg) in dichloromethane (5.00 mL) was added trifluoroacetic acid (2.00 mL), followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then to the residue were added 1 M hydrochloric acid (606 ?L) and acetonitrile (10.0 mL), followed by concentrating under reduced pressure. The residue was purified by ODS column chromatography (0.01 M hydrochloric acid-acetonitrile) and dried under reduced pressure to obtain 3-{[({6-[(4-carbamimidamnidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid monohydrochloride (227 mg).

Example 3

(58) To a solution of tert-butyl N-[6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-1-naphthoyl]-4-(tert-butoxycarbonyl)-L-phenylalaninate (300 mg) in dichloromethane (1.50 mL) was added trifluoroacetic acid (1.50 mL), followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then to the residue were added 1 M hydrochloric acid (1.00 mL) and acetonitrile (1.00 mL), followed by concentrating under reduced pressure. The residue was purified by ODS column chromatography (0.01 M hydrochloric acid-acetonitrile) to obtain N-{6-[(4-carbamimidamidobenzoyl)oxy]-1-naphthoyl}-4-carboxy-L-phenylalanine monohydrochloride (158 mg).

Example 4

(59) To a solution of tert-butyl 4-{[{[6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbonyl}(2-tert-butoxy-2-oxoethyl)amino]methyl}thiophene-2-carboxylate (720 mg) in dichloromethane (5.33 mL) was added trifluoroacetic acid (5.36 mL), followed by stirring at room temperature for 5 hours. To the reaction mixture was added acetonitrile, followed by concentrating under reduced pressure. The residue was purified by ODS column chromatography (0.01 M hydrochloric acid-acetonitrile) to obtain 4-{[({6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)(carboxymethyl)amino]methyl}thiophene-2-carboxylic acid monohydrochloride (440 mg).

Example 5

(60) To a solution of tert-butyl 3-{[{[(1R)-6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate or an enantiomer thereof (PEx. 37-1, 181 mg) obtained in Preparation Example 37 in dichloromethane (3.00 mL) was added trifluoroacetic acid (686 ?L), followed by stirring at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and then to the residue were added 1 M hydrochloric acid (208 ?L) and acetonitrile (10.0 mL), followed by concentrating under reduced pressure. The residue was purified by ODS column chromatography (0.01 M hydrochloric acid-acetonitrile) and dried under reduced pressure to obtain a monohydrochloride (91 mg, RT 10.6 min) of 3-{[({(1R)-6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid or an enantiomer thereof. Further, the analysis conditions for the chiral column chromatography method carried out to determine RT are shown below.

(61) Column: CHIRALPAK IE-3 4.6 mm I.D.?250 mm (particle diameter: 3 ?m), manufactured by Daicel Chemical Industries, Ltd.

(62) Mobile phase: hexane (containing 0.1% trifluoroacetic acid) 60%, ethanol (containing 0.1% trifluoroacetic acid) 40%

(63) Flow rate: 1 mL/min

(64) Detection wavelength: 254 nm

(65) Column temperature: 40? C.

Example 6

(66) To a solution of tert-butyl 3-{[{[(1R)-6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate or an enantiomer thereof (PEx. 37-2, 183 mg) obtained in Preparation Example 37 in dichloromethane (3.03 mL) was added trifluoroacetic acid (693 ?L), followed by stirring at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and then to the residue were added 1 M hydrochloric acid (210 ?L) and acetonitrile (10.0 mL), followed by concentrating under reduced pressure. The residue was purified by ODS column chromatography (0.01 M hydrochloric acid-acetonitrile) and dried under reduced pressure to obtain a monohydrochloride (98 mg, RT 14.1 min) of 3-{[({(1R)-6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid or an enantiomer thereof. Further, the analysis conditions for the chiral column chromatography method carried out to determine RT are shown below.

(67) Column: CHIRALPAK IE-3 4.6 mm I.D.?250 mm (particle diameter: 3 ?m), manufactured by Daicel Chemical Industries, Ltd.

(68) Mobile phase: hexane (containing 0.1% trifluoroacetic acid) 60%, ethanol (containing 0.1% trifluoroacetic acid) 40%

(69) Flow rate: 1 mL/min

(70) Detection wavelength: 254 nm

(71) Column temperature: 40? C.

Example 7

(72) To a solution of tert-butyl 4-[({[(1R)-6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}[(2R)-1-tert-butoxy-1-oxopropan-2-yl]amino)methyl]thiophene-2-carboxylate or an epimer at position 1 of the 1,2,3,4-tetrahydronaphthalene (324 mg) obtained in Preparation Example 34 in dichloromethane (3.00 mL) was added trifluoroacetic acid (1.50 mL), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then to the residue were added 1 M hydrochloric acid (2.00 mL) and acetonitrile (1.50 mL), followed by concentrating under reduced pressure. The residue was purified by ODS column chromatography (0.01 M hydrochloric acid-acetonitrile) to obtain hydrochloride (46 mg) of 4-({({(1R)-6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acetyl) [(1R)-1-carboxyethyl]amino}methyl)thiophene-2-carboxylic acid or an epimer at position 1 of the 1,2,3,4-tetrahydronaphthalene.

Example 8

(73) To a solution of tert-butyl 4-[({[(1R)-6-({4-[N,N-bis(tert-butoxycarbonyl)carbamimidamide]benzoyl}oxy)-1,2,3,4-tetrahydronaphthalen-1-yl]acetyl}[(2R)-1-tert-butoxy-1-oxopropan-2-yl]amino)methyl]thiophene-2-carboxylate or an epimer at position 1 of the 1,2,3,4-tetrahydronaphthalene (460 mg) obtained in Preparation Example 36 in dichloromethane (3.07 mL) was added trifluoroacetic acid (2.06 mL), followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then to the residue were added 1 M hydrochloric acid (588 ?L) and acetonitrile (3.07 mL), followed by concentrating under reduced pressure. To the residue was added ethyl acetate, followed by concentrating under reduced pressure. The obtained solid was washed with acetonitrile to obtain 4-({({(1R)-6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acetyl) [(1R)-1-carboxyethyl]amino}methyl)thiophene-2-carboxylic acid or an epimer at position 1 of the 1,2,3,4-tetrahydronaphthalene (44 mg).

Example 9

(74) To a 50% aqueous acetonitrile solution (80.0 mL) of a monohydrochloride (3.83 g) of 3-{[({(1R)-6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid or an enantiomer thereof obtained in Example 6 was added dropwise a 1 M aqueous sodium hydroxide solution (6.44 mL) under ice-cooling, followed by stirring at room temperature for 3 hours. The precipitate was collected by filtration, then washed with a 50% aqueous acetonitrile solution, and dried in air for 1 hour. The dried product was suspended in a 50% aqueous acetonitrile solution (400 mL), followed by stirring at 120? C. for 30 minutes. The reaction mixture was stirred at room temperature for 12 hours. The precipitate was collected by filtration, then washed with a 50% aqueous acetonitrile solution, and dried at room temperature under reduced pressure to obtain 3-{[({(1R)-6-[(4-carbamimidamidobenzoyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acetyl)(carboxymethyl)amino]methyl}benzoic acid or an enantiomer thereof (2.89 g).

(75) The compounds of Preparation Examples and Examples shown in Tables below were prepared in the same manner as in Preparation Examples and Examples as described above.

(76) TABLE-US-00003 TABLE 3 PEx PSyn Str Data 1 P1 ESI+: 328 2 P2 0 ESI+: 520 [M + Na]+ 3 P3 ESI+: 859 4 P4 ESI+: 195 5 P5 ESI+: 344 [M + Na]+

(77) TABLE-US-00004 TABLE 4 PEx PSyn Str Data 6 P6 ESI+: 532 [M + Na]+ 7 P7 ESI+: 322 8 P8 ESI+: 229 [M + Na]+ 9 P9 ESI+: 871 10 P10 ESI+: 322

(78) TABLE-US-00005 TABLE 5 PEx PSyn Str Data 11 P11 ESI+: 664 [M + Na]+ 12 P12 0 ESI+: 402 13 P13 ESI+: 526 [M + Na]+ 14 P14 ESI+: 336 15 P15 ESI+: 534 [M + Na]+

(79) TABLE-US-00006 TABLE 6 PEx PSyn Str Data 16 P16 ESI+: 478 [M + Na]+ 17 P17 ESI+: 546 [M + Na]+ 18 P18 ESI+: 271 [M + Na]+ 19 P19 ESI+: 349 [M + Na]+ 20 P20 ESI+: 378 21 P21 ESI+: 372 [M + Na]+ 22 P22 0 ESI+: 524 [M + Na]+ 23 P23 ESI+: 249 [M + Na]+

(80) TABLE-US-00007 TABLE 7 PEx PSyn Str Data 24 P24 ESI+: 342 25 P25 ESI+: 336 26 P26 ESI+: 466 27 P27 ESI+: 522 [M + Na]+ 28 P28 ESI+: 530 29 P29 ESI?: 219

(81) TABLE-US-00008 TABLE 8 PEx PSyn Str Data 30 P30 ESI?: 219 31 P31 ESI?: 205 32 P32 0 ESI?: 205 33 P33 ESI+: 552 [M + Na]+ 34 P34 ESI+: 891 35 P35 ESI+: 552 [M + Na]+

(82) TABLE-US-00009 TABLE 9 PEx PSyn Str Data 36 P36 ESI+: 891 37-1 P37 ESI+: 893 [M + Na]+ 37-2 P37 ESI+: 871 38 P38 ESI+: 514 [M + Na]+

(83) TABLE-US-00010 TABLE 10 PEx PSyn Str Data 39 P39 ESI+: 853 40 P40 ESI+: 524 [M + Na]+ 41 P41 0 ESI+: 863 42 P42 ESI+: 330 [M + Na]+ 43 P43 ESI+: 771

(84) TABLE-US-00011 TABLE 11 PEx PSyn Str Data 44 P44 ESI+: 574 [M + Na]+ 45 P2 ESI+: 526 [M + Na]+ 46 P3 ESI+: 865 47 P6 ESI+: 520 [M + Na]+

(85) TABLE-US-00012 TABLE 12 PEx PSyn Str Data 48 P3 ESI+: 859 49 P2 ESI+: 520 [M + Na]+ 50 P3 ESI+: 859 51 P2 0 ESI+: 518 [M + Na]+

(86) TABLE-US-00013 TABLE 13 PEx PSyn Str Data 52 P3 ESI+: 879 [M + Na]+ 53 P2 ESI+: 520 [M + Na]+ 54 P3 ESI+: 881 [M + Na]+ 55 P2 ESI+: 518 [M + Na]+

(87) TABLE-US-00014 TABLE 14 PEx PSyn Str Data 56 P3 ESI+: 857 57 P2 ESI+: 518 [M + Na]+ 58 P3 ESI+: 879 [M + Na]+ 59 P3 ESI+: 887 [M + Na]+

(88) TABLE-US-00015 TABLE 15 PEx PSyn Str Data 60 P2 ESI+: 514 [M + Na]+ 61 P3 0 ESI+: 875 [M + Na]+ 62 P2 ESI+: 514 [M + Na]+ 63 P3 ESI+: 875 [M + Na]+ 64 P2 ESI+: 528 [M + Na]+

(89) TABLE-US-00016 TABLE 16 PEx PSyn Str Data 65 P3 ESI+: 867 66 P2 ESI+: 528 [M + Na]+ 67 P3 ESI+: 867 68 P1 ESI+: 342

(90) TABLE-US-00017 TABLE 17 PEx PSyn Str Data 69 P3 ESI+: 873 70 P2 ESI+: 552 [M + Na]+ 71 P3 0 ESI+: 891 72 P6 ESI+: 532 [M + Na]+ 73 P3 ESI+: 871

(91) TABLE-US-00018 TABLE 18 PEx PSyn Str Data 74 P2 ESI+: 538 [M + Na]+ 75 P3 ESI+: 877 76 P3 ESI+: 885 77 P6 ESI+: 552

(92) TABLE-US-00019 TABLE 19 PEx PSyn Str Data 78 P3 ESI+: 913 79 P6 ESI+: 588 [M + Na]+ 80 P3 ESI+: 927 81 P6 0 ESI+: 546 [M + Na]+ 82 P3 ESI+: 885 83 P6 ESI+: 538 [M + Na]+

(93) TABLE-US-00020 TABLE 20 PEx PSyn Str Data 84 P3 ESI+: 877 85 P20 ESI+: 336 86 P6 ESI+: 546 [M + Na]+ 87 P3 ESI+: 885 88 P17 ESI+: 540 [M + Na]+

(94) TABLE-US-00021 TABLE 21 PEx PSyn Str Data 89 P3 ESI+: 879 90 P6 ESI+: 612 [M + Na]+ 91 P3 00 ESI+: 951 92 P17 01 ESI+: 532 [M + Na]+ 93 P3 02 ESI+: 871

(95) TABLE-US-00022 TABLE 22 PEx PSyn Str Data 94 P17 03 ESI+: 576 [M + Na]+ 95 P3 04 ESI+: 915 96 P6 05 ESI+: 570 [M + Na]+ 97 P3 06 ESI+: 909 98 P6 07 ESI+: 570 [M + Na]+

(96) TABLE-US-00023 TABLE 23 PEx PSyn Str Data 99 P3 08 ESI+: 909 100 P6 09 ESI+: 518 [M + Na]+ 101 P3 0 ESI+: 857 102 P6 ESI+: 532 [M + Na]+ 103 P3 ESI+: 871

(97) TABLE-US-00024 TABLE 24 PEx PSyn Str Data 104 P6 ESI+: 492 105 P3 ESI+: 853 106 P16 ESI+: 299 [M + Na]+ 107 P2 ESI+: 552 [M + Na]+ 108 P3 ESI+: 891 109 P17 ESI+: 528 [M + Na]+

(98) TABLE-US-00025 TABLE 25 PEx PSyn Str Data 110 P3 ESI+: 867 111 P17 0 ESI+: 528 [M + Na]+ 112 P3 ESI+: 867 113 P6 ESI+: 546 [M + Na]+ 114 P3 ESI+: 885

(99) TABLE-US-00026 TABLE 26 PEx PSyn Str Data 115 P6 ESI+: 528 [M + Na]+ 116 P3 ESI+: 867 117 P1 APCI/ESI+: 342 118 P17 APCI/ESI+: 512 119 P3 NMR2: 1.33- 1.65(36H, m), 2.25- 5.09(6H, m), 7.11- 7.98(10H, m), 8.16- 8.26(2H, m), 10.66(1 H, brs), 11.63(1H, brs)

(100) TABLE-US-00027 TABLE 27 PEx PSyn Str Data 120 P6 ESI+: 376 121 P3 0 ESI+: 913 122 P6 ESI+: 538 [M + Na]+ 123 P3 ESI+: 877 124 P17 ESI+: 532 [M + Na]+ 125 P3 ESI+: 871

(101) TABLE-US-00028 TABLE 28 PEx PSyn Str Data 126 P17 ESI+: 520 [M + Na]+ 127 P3 ESI+: 859 128 P6 ESI+: 538 [M + Na]+ 129 P3 ESI+: 877 130 P6 ESI+: 524 [M + Na]+

(102) TABLE-US-00029 TABLE 29 PEx PSyn Str Data 131 P3 0 ESI+: 863 132 P6 ESI+: 538 [M + Na]+ 133 P3 ESI+: 877 134 P6 ESI+: 574 [M + Na]+ 135 P3 ESI+: 913 136 P6 ESI+: 532 [M + Na]+

(103) TABLE-US-00030 TABLE 30 PEx PSyn Str Data 137 P3 ESI+: 871 138 P6 ESI+: 518 [M + Na]+ 139 P3 ESI+: 857 140 P17 ESI+: 540 [M + Na]+ 141 P3 0 ESI+: 879

(104) TABLE-US-00031 TABLE 31 PEx PSyn Str Data 142 P2 ESI+: 530 143 P3 ESI+: 891 144 P2 ESI+: 534 [M + Na]+ 145 P3 ESI+: 873

(105) TABLE-US-00032 TABLE 32 PEx PSyn Str Data 146 P13 ESI+: 534 [M + Na]+ 147 P3 ESI+: 895 [M + Na]+

(106) TABLE-US-00033 TABLE 33 Ex Str 1 2 3 4 0

(107) TABLE-US-00034 TABLE 34 Ex Str 5 6 7 8

(108) TABLE-US-00035 TABLE 35 Ex Str 9 10 11 12

(109) TABLE-US-00036 TABLE 36 Ex Str 13 14 0 15 16

(110) TABLE-US-00037 TABLE 37 Ex Str 17 18 19 20

(111) TABLE-US-00038 TABLE 38 Ex Str 21 22 23

(112) TABLE-US-00039 TABLE 39 Ex Str 24 0 25 26 27

(113) TABLE-US-00040 TABLE 40 Ex Str 28 29 30 31

(114) TABLE-US-00041 TABLE 41 Ex Str 32 33 34 0 35

(115) TABLE-US-00042 TABLE 42 Ex Str 36 37 38 39

(116) TABLE-US-00043 TABLE 43 Ex Str 40 41 42 43

(117) TABLE-US-00044 TABLE 44 Ex Str 44 00 45 01 46 02 47 03

(118) TABLE-US-00045 TABLE 45 Ex Str 48 04 49 05 50 06

(119) TABLE-US-00046 TABLE 46 Ex Str 51 07 52 08 53 09 54 0

(120) TABLE-US-00047 TABLE 47 Ex Str 55 56 57 58

(121) TABLE-US-00048 TABLE 48 Ex Str 59 60

(122) TABLE-US-00049 TABLE 49 Ex Syn Data 1 1 ESI+: 547 NMR1: 4.00 (2H ? 0.5, brs), 4.13 (2H ? 0.5, brs), 4.55 (2H ? 0.5, brs), 4.69 (2H ? 0.5, brs), 7.43-7.60 (4H, m), 7.70-7.96 (3H, m), 7.82 (4H, brs), 7.98-8.12 (3H, m), 8.19-8.27 (2H, m), 10.20-10.56 (1H, br), 12.50-13.53 (2H, br) 2 2 ESI+: 559 NMR1: 1.50-1.92 (4H, m), 2.57-2.84 (4H, m), 3.28-3.44 (1H, m), 3.93-4.19 (2H, m), 4.57 (1H ? 0.5, d, J = 15.1 Hz), 4.65 (1H ? 0.5, d, J = 15.1 Hz), 4.69-4.82 (1H, m), 6.87-7.00 (2H, m), 7.23 (1H, dd, J = 8.5, 12.4 Hz), 7.39-7.57 (4H, m), 7.78-7.94 (6H, m), 8.10-8.17 (2H, m), 10.47 (1H, d, J = 3.8 Hz), 12.00-13.72 (2H, br) 3 3 ESI+: 541 NMR1: 3.09 (1H, dd, J = 11.0, 13.8 Hz), 3.27-3.38 (1H, m), 4.75-4.86 (1H, m), 7.37 (1H, dd, J = 2.4, 9.2 Hz), 7.42-7.51 (5H, m), 7.59 (1H, dd, J = 7.1, 8.2 Hz), 7.83 (4H, brs), 7.86-7.93 (3H, m), 7.95-8.05 (2H, m), 8.19-8.26 (2H, m), 8.93 (1H, d, J = 8.3 Hz), 10.20-10.81 (1H, br), 12.62-13.16 (2H, br) 4 4 ESI+: 551 NMR1: 1.58-1.99 (2H, m), 2.71-3.15 (5H, m), 3.93-4.09 (2H ? 0.5, m), 4.15-4.30 (2H ? 0.5, m), 4.50 (2H ? 0.5, brs), 4.71 (2H ? 0.5, brs), 6.93-7.01 (2H, m), 7.11-7.21 (1H, m), 7.39-7.46 (2H, m), 7.59-7.85 (2H, m), 7.78 (4H, brs), 8.10-8.17 (2H, m), 10.32 (1H, brs), 11.77-14.23 (2H, br) 5 5 ESI+: 559 NMR1: 1.48-1.90 (4H, m), 2.55-2.84 (4H, m), 3.30-3.41 (1H, m), 3.95-4.21 (2H, m), 4.57 (1H ? 0.5, d, J = 15.1 Hz), 4.65 (1H ? 0.5, d, J = 15.1 Hz), 4.69-4.82 (1H, m), 6.88-7.00 (2H, m), 7.23 (1H, dd, J = 8.5, 12.4 Hz), 7.38-7.58 (4H, m), 7.74-7.92 (6H, m), 8.08-8.18 (2H, m), 10.41 (1H, d, J = 3.8 Hz), 12.10-13.81 (2H, br) 6 6 ESI+: 559 NMR1: 1.50-1.92 (4H, m), 2.55-2.84 (4H, m), 3.34-3.44 (1H, m), 3.93-4.18 (2H, m), 4.57 (1H ? 0.5, d, J = 15.1 Hz), 4.65 (1H ? 0.5, d, J = 15.1 Hz), 4.69-4.82 (1H, m), 6.87-7.00 (2H, m), 7.23 (1H, dd, J = 8.5, 12.2 Hz), 7.36-7.56 (4H, m), 7.74-7.91 (6H, m), 8.08-8.17 (2H, m), 10.43 (1H, brs), 12.86 (2H, brs) 7 7 ESI+: 579 8 8 ESI+: 579

(123) TABLE-US-00050 TABLE 50 Ex Syn Data 9 9 ESI+: 559 NMR1: 1.50-1.88 (4H, m), 2.53-2.73 (4H, m), 2.90-3.54 (1H, m), 3.55-3.70 (2H ? 0.4, m), 3.76-4.07 (2H ? 0.6, m), 4.43 (2H ? 0.4, d, J = 15.2 Hz), 4.60-4.90 (2H ? 0.6, m), 6.60-6.70 (2H ? 0.4, m), 6.80-6.91 (2H ? 0.6, m), 7.10-7.28 (1H, m), 7.30-7.52 (4H, m), 7.77-7.88 (2H, m), 8.07 (2H, d, J = 8.6 Hz), 8.17-8.80 (4H, br), 12.20-13.60 (2H, br) 10 2 ESI+: 547 11 2 ESI+: 545 NMR1: 1.59-1.78 (1H, m), 2.24-2.40 (1H, m), 2.44-2.59 (1H, m), 2.65-2.90 (3H, m), 3.49-3.62 (1H, m), 3.70-4.10 (2H, m), 4.50-4.85 (2H, m), 6.77-6.85 (1H ? 0.7, m), 6.86-6.93 (1H ? 0.3, m), 6.98-7.05 (1H, m), 7.13- 7.54 (5H, m), 7.79-7.89 (2H, m), 7.96-8.40 (6H, m), 11.02-13.60 (2H, br) 12 2 ESI+: 545 13 2 ESI+: 553 NMR1: 4.08-4.20 (2H, m), 4.53 (2H ? 0.5, brs), 4.72 (2H ? 0.5, brs), 7.33-7.43 (1H, m), 7.43-7.49 (2H, m), 7.50-8.09 (5H, m), 7.80 (4H, brs), 8.17-8.23 (2H, m), 10.31 (1H, s), 12.62-13.35 (2H, m) 14 2 ESI+: 541 15 2 ESI+: 541 NMR1: 3.53-5.19 (4H, m), 7.37-8.31 (14H, m), 7.83 (4H, brs), 10.33 (1H, s), 12.37-13.46 (2H, br) 16 2 ESI+: 555 17 2 ESI+: 555 NMR1: 3.20-5.04 (6H, m), 7.04-8.30 (14H, m), 7.83 (4H, brs), 10.39 (1H, s), 11.72-13.46 (2H, br) 18 2 ESI+: 561 19 2 ESI+: 579 NMR1: 1.19-1.36 (3H, m), 1.38-1.88 (4H, m), 2.31-2.81 (4H, m), 3.20-3.40 (1H, m), 4.08-4.86 (3H, m), 6.82-6.98 (2H, m), 7.12-7.30 (1H, m), 7.34-7.59 (4H, m), 7.97-8.40 (2H, m), 8.18 (4H, brs), 11.30-13.63 (2H, br) 20 2 ESI+: 559 21 2 ESI+: 565 NMR1: 1.22-1.41 (3H, m), 1.58-2.02 (2H, m), 2.56-3.12 (5H, m), 4.10-4.97 (3H, m), 6.90-7.04 (2H, m), 7.08-7.24 (1H, m), 7.38-7.48 (2H, m), 7.55-7.94 (2H, m), 7.79 (4H, brs), 8.08-8.19 (2H, m), 10.33 (1H, s), 12.15-13.48 (2H, br) 22 2 ESI+: 573

(124) TABLE-US-00051 TABLE 51 Ex Syn Data 23 2 ESI+: 561 NMR1: 3.49-3.90(4H, m), 4.36(2H ? 0.67, brs), 4.76(2H ? 0.33, brs), 6.66-7.58(7H, m), 7.70-8.73(9H, m), 11.93-14.29(2H, m) 24 2 ESI+: 601 25 2 ESI+: 615 26 2 ESI+: 573 27 2 ESI+: 565 28 2 ESI+: 573 29 2 ESI+: 567 30 2 ESI+: 571 31 2 ESI+: 559 32 2 ESI+: 603 33 2 ESI+: 597 34 2 ESI+: 597 35 2 ESI+: 545 36 2 ESI+: 559 37 2 ESI+: 541 38 2 ESI+: 579 39 2 ESI+: 555 40 2 ESI+: 555 41 2 ESI+: 573 42 2 ESI+: 555 43 2 ESI+: 561 44 2 ESI+: 601 45 2 ESI+: 565 46 2 ESI+: 559 47 2 ESI+: 547 48 2 ESI+: 565 49 2 ESI+: 551 50 2 ESI+: 565 51 2 ESI+: 601 52 2 ESI+: 559 53 2 ESI+: 545 54 2 ESI+: 567 55 2 ESI+: 579 56 2 ESI+: 561 57 2 ESI+: 547 58 2 ESI+: 545 59 1 ESI+: 553 60 2 ESI+: 547

INDUSTRIAL APPLICABILITY

(125) The compound of Formula (I) or a salt thereof has a trypsin inhibitory action, and therefore, can be used as an agent for preventing and/or treating kidney diseases as an agent which will substitute low-protein diet therapy, and/or an agent for preventing and/or treating trypsin-related diseases such as chronic pancreatitis, gastroesophageal reflux disease, hepatic encephalopathy, and influenza.