Nitrogen-containing saturated heterocyclic compound

Abstract

The present invention provides a nitrogen-containing saturated heterocyclic compound of the formula [I]: ##STR00001##
wherein R.sup.1 is a cycloalkyl group and the like, R.sup.22 is an optionally substituted aryl and the like, R is a lower alkyl and the like, T is a carbonyl group, Z is O and the like, and R.sup.3 to R.sup.6 are the same or different and a hydrogen atom and the like; or a pharmaceutically acceptable salt, that is useful as a renin inhibitor.

Claims

1. An isolated stereoisomer of a compound of the formula I.sup.c2: ##STR00462## wherein R.sup.b is lower alkyl, R.sup.b1 is cycloalkyl or alkyl, the ring B is selected from 1) a tetrahydronaphthyl group, or 2) a pyridyl group, and R.sup.b21 to R.sup.b23 are the same of different, and a group selected from 1) hydrogen, 2) halogen, 3) alkyl optionally substituted with a group selected from halogen, alkoxy and alkoxycarbonylamino, 4) alkoxy optionally substituted with a group selected from alkoxy and alkoxycarbonylamino, 5) cyano, 6) carbamoyl optionally substituted with alkyl, or 7) oxo, or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the isolated stereoisomer according to claim 1.

3. A pharmaceutical composition for use in the treatment of hypertension, cardiac failure, or diabetic nephropathy, comprising the isolated stereoisomer according to claim 1, or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

Example 1

(1) (2R)N-Cyclopropyl-N-{1-[4-(3-methoxypropoxy)-1-benzofuran-6-yl]ethyl}morpholine-2-carboxamide [Ex(1-1), Ex(1-2)]

(2) ##STR00029##

(3) To a solution of tert-butyl (2R)-2-[(cyclopropyl {1-[4-(3-methoxypropoxy)-1-benzofuran-6-yl]ethyl}amino)carbonyl]morpholine-4-carboxylate (200 mg) and 2,6-lutidine (0.142 mL) in chloroform (4 mL) was added trimethylsilyltriflate (0.180 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then, thereto was added aqueous saturated sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol/ammonia water=200/2/1) to give (2R)N-cyclopropyl-N-{(1R)-1-[4-(3-methoxypropoxy)-1-benzofuran-6-yl]ethyl}morpholine-2-carboxamide [Ex(1-1)] (12.5 mg) and (2R)N-cyclopropyl-N-{(1S)-1-[4-(3-methoxypropoxy)-1-benzofuran-6-yl]ethyl}morpholine-2-carboxamide [Ex(1-2)] (20.2 mg) as a colorless oil.

(4) APCI-MS m/z: 403 [M+H].sup.+.

Example 2

(5) (2R)N-{(1R)-1-[3-Chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethyl}-N-cyclopropylpiperazine-2-carboxamide [Ex(2-1)]

(6) ##STR00030##

(7) To a solution of di-tert-butyl (2R)-2-{[{(1R)-1-[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethyl}(cyclopropyl)amino]carbonyl}piperazine-1,4-dicarboxylate (44.0 mg) and 2,6-lutidine (0.050 mL) in dichloromethane (1.0 mL) was added trimethylsilyltriflate (0.051 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Then, thereto were added aqueous saturated sodium hydrogen carbonate solution and methanol (2.0 mL) under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: ethyl acetate.fwdarw.ethyl acetate/methanol=5/1) to give (2R)N-{(1R)-1-[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethyl}-N-cyclopropylpiperazine-2-carboxamide [Ex(2-1)] (25.4 mg) as a colorless oil.

(8) APCI-MS m/z: 419/421 [M+H].sup.+.

Example 3

(9) (2R)NCyclopropyl-N-{(1R)-1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}-morpholine-2-carboxamide hydrochloride [Ex(3-1)]

(10) ##STR00031##

(11) To a solution of tert-butyl (2R)-2-[(cyclopropyl{(1R)-1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}amino)carbonyl]morpholine-4-carboxylate (44.4 mg) in chloroform (2.0 mL) was added 4-normal hydrogen chloride-dioxane solution (0.75 mL) under ice-cooling, and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in water (1 mL), and then washed with diethyl ether. The aqueous layer was freeze-dried to give (2R)N-cyclopropyl-N-{(1R)-1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}morpholine-2-carboxamide hydrochloride [Ex(3-1)] (25 mg) as a colorless powder.

(12) APCI-MS m/z: 401 [M+H].sup.+.

Example 4

(13) (2R)N-{1-[4-Chloro-1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}-N-cyclopropyl morpholine-2-carboxamide [Ex(4-1), Ex(4-2)]

(14) ##STR00032##

(15) To a solution of tert-butyl (2R)-2-{[{1-[4-chloro-1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}(cyclopropyl)amino]carbonyl}morpholine-4-carboxylate (146 mg) in chloroform (2.0 mL) was added 4-normal hydrogen chloride-dioxane solution (2.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and then thereto was added aqueous saturated sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol/ammonia water=500/10/1) to give (2R)N-{(1R)-1-[4-chloro-1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}-N-cyclopropylmorpholine-2-carboxamide [Ex(4-1)] (50.2 mg) and (2R)N{(1S)-1-[4-chloro-1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}-N-cyclopropylmorpholine-2-carboxamide [Ex(4-2)] (18.4 mg) as a colorless oil.

(16) APCI-MS m/z: 435/437 [M+H].sup.+.

Example 5A

(17) (2R)N-{1-[3-Bromo-4-methoxy-5-(3-methoxypropoxy)phenyl]ethyl}-N-cyclopropylmorpholine-2-carboxamide [Ex(5-1), Ex(5-2)]

(18) ##STR00033##

(19) To a solution of tert-butyl (2R)-2-{[{1-[3-bromo-4-methoxy-5-(3-methoxypropoxy)-phenyl]ethyl}(cyclopropyl)amino]carbonyl}morpholine-4-carboxylate (135 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and to the resulting residue was added chloroform, and the mixture was filtered through (Bond-Elute: registered trademark) (NH.sub.2). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (eluent: ethyl acetate/methanol/ammonia water=200/10/1) to give (2R)N-{(1R)-1-[3-bromo-4-methoxy-5-(3-methoxypropoxy)phenyl]ethyl}-N-cyclopropylmorpholine-2-carboxamide [Ex(5-1)] (53.7 mg) and (2R)N-{(1S)-1-[3-bromo-4-methoxy-5-(3-methoxypropoxy)phenyl]ethyl}-N-cyclopropylmorpholine-2-carboxamide [Ex(5-2)] (30.5 mg) as a colorless oil.

(20) APCI-MS m/z: 471/473[M+H].sup.+.

Example 5B

(21) Methyl

{3-[3-((1-{cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino}ethyl)-1H-pyrrolo[2,3-b]-pyridin-1-yl]propyl}carbamate

(22) ##STR00034##

(23) To a solution of t-butyl (2R)-2-({cyclopropyl[1-(1-{3-[(methoxycarbonyl)amino]propyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]amino}carbonyl)morpholin-4-carboxylate (116 mg) and 2,6-lutidine (0.077 mL) in dichloromethane (2 mL) was added trimethylsilyltriflate (0.099 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Then, thereto were added aqueous sodium hydrogen carbonate solution and methanol (2.0 mL) under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: ethyl acetate.fwdarw.ethyl acetate/methanol=9/1) to give methyl {3-[3-(1-cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino ethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl}carbamate (50 mg) as a colorless oil. Methyl {3-[3-(1-cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino ethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl}carbamate (40 mg) was separated by CHIRALPAK IC (eluent: n-hexane/ethanol/diethylamine=50/50/0.1; instrument: Waters 302 (600E system)) into diastereomers to give methyl {3-[3-((1R)-1-cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino-ethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl}carbamate (18 mg) as a colorless oil and methyl {3-[3-((1S)-1-{cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino}ethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl}carbamate (18 mg) as a colorless oil.

(24) APCI-MS m/z: 430 [M+H].sup.+.

Examples 6 to 160

(25) The following nitrogen-containing saturated heterocyclic compounds, etc. were prepared in the similar manner to the above Examples 1 to 5. Each symbol of Methods A to C refers to each method according to the following method of Examples.

(26) Method A: Examples 1, 2

(27) Method B: Examples 3, 4

(28) Method C: Example 5A

(29) TABLE-US-00001 TABLE 1 EX. No. Chemical formula a MW b c d e 6 392.4928 B 393 [M + H]+ O 7 HCl 360.8826 B 325 [M + H]+ P 8 HCl 360.8826 B 325 [M + H]+ P 9 HCl 428.9538 B 393 [M + H]+ O

(30) TABLE-US-00002 TABLE 2 10 HCl 436.9808 B 401 [M + H]+ P 11 0 HCl 398.928 B 363 [M + H]+ P 12 HCl 370.8744 B 335 [M + H]+ O 13 334.4134 A 335 [M + H]+ O

(31) TABLE-US-00003 TABLE 3 14 334.4134 A 335 [M + H]+ O 15 348.4402 A 349 [M + H]+ O 16 348.4402 A 349 [M + H]+ O 17 HCl 436.9808 B 401 [M + H]+ P

(32) TABLE-US-00004 TABLE 4 18 374.478 A 375 [M + H]+ O 19 376.4938 A 377 [M + H]+ O 20 380.4571 A 381 [M + H]+ O 21 0 392.4928 A 393 [M + H]+ O

(33) TABLE-US-00005 TABLE 5 22 376.4938 A 377 [M + H]+ O 23 380.4571 A 381 [M + H]+ O 24 392.4928 A 393 [M + H]+ O 25 376.4938 A 377 [M + H]+ O

(34) TABLE-US-00006 TABLE 6 26 376.4938 A 377 [M + H]+ O 27 374.478 A 375 [M + H]+ O 28 419.95 A 420/422 [M + H]+ O 29 419.95 A 420/422 [M + H]+ O

(35) TABLE-US-00007 TABLE 7 30 418.9659 A 419/421 [M + H]+ O 31 0 418.9659 A 419/421 [M + H]+ O 32 380.4571 A 381 [M + H]+ O 33 380.4571 A 381 [M + H]+ O

(36) TABLE-US-00008 TABLE 8 34 HCl 446.817 B 411 [M + H]+ P 35 453.38 A 453/455 [M + H]+ O 36 414.5466 A 415 O 37 418.5099 A 419 [M + H]+ O

(37) TABLE-US-00009 TABLE 9 38 418.5099 A 419 [M + H]+ O 39 434.9649 B 435/437 [M + H]+ O 40 434.9649 B 435/437 [M + H]+ O 41 0 414.5466 B 415 [M + H]+ O

(38) TABLE-US-00010 TABLE 10 42 429.5179 A 430 [M + H]+ O 43 402.488 A 403 [M + H]+ O 44 402.488 A 403 [M + H]+ O 45 450.5722 A 451 [M + H]+ O

(39) TABLE-US-00011 TABLE 11 46 450.5722 A 451 [M + H]+ O 47 368.8585 A 369/371 [M + H]+ O 48 368.8585 A 369/371 [M + H]+ O 49 368.8585 A 369/371 [M + H]+ O

(40) TABLE-US-00012 TABLE 12 50 387.4771 A 388 [M + H]+ P 51 0 387.4771 A 388 [M + H]+ P 52 355.4355 B 356 [M + H]+ P 53 355.4355 B 356 [M + H]+ O

(41) TABLE-US-00013 TABLE 13 54 HCl 390.9084 B 355 [M + H]+ P 55 404.5038 A 405 [M + H]+ O 56 404.5038 A 405 [M + H]+ O 57 468.5169 A 469 [M + H]+ O

(42) TABLE-US-00014 TABLE 14 58 468.5169 A 469 [M + H]+ O 59 385.5049 A 386 O 60 387.5207 A 388 [M + H]+ O 61 0 385.5049 A 386 O

(43) TABLE-US-00015 TABLE 15 62 418.9659 A 419/421 [M + H]+ O 63 418.9659 A 419/421 [M + H]+ O 64 400.5198 A 401 [M + H]+ O 65 400.5198 A 401 [M + H]+ O

(44) TABLE-US-00016 TABLE 16 66 HCl 477.9859 B 442 [M + H]+ P 67 HCl 477.9859 B 442 [M + H]+ P 68 HCl 420.9818 C 385 [M + H]+ O 69 414.5466 B 415 [M + H]+ O

(45) TABLE-US-00017 TABLE 17 70 418.5099 A 419 [M + H]+ O 71 00 418.5099 A 419 [M + H]+ O 72 01 434.9649 A 435/437 [M + H]+ O 73 02 434.9649 A 435/437 [M + H]+ O

(46) TABLE-US-00018 TABLE 18 74 03 388.5048 A 389 [M + H]+ O 75 04 399.5357 A 400 [M + H]+ O 76 05 401.5039 A 402 [M + H]+ O 77 06 388.5048 A 389 [M + H]+ O

(47) TABLE-US-00019 TABLE 19 78 07 399.5317 A 400 [M + H]+ O 79 08 418.5099 A 419 [M + H]+ O 80 09 418.5099 A 419 [M + H]+ O 81 0 401.5039 A 402 [M + H]+ O

(48) TABLE-US-00020 TABLE 20 82 398.5476 A 399 [M + H]+ O 83 398.5476 A 399 [M + H]+ O 84 387.4771 A 388 [M + H]+ O 85 410.4829 A 411 [M + H]+ O

(49) TABLE-US-00021 TABLE 21 86 430.4641 A 431 [M + H]+ O 87 414.5466 A 415 [M + H]+ O 88 467.4009 A 467/469 [M + H]+ O 89 471.3889 C 471/473 [M + H]+ O

(50) TABLE-US-00022 TABLE 22 90 471.3889 C 471/473 [M + H]+ O 91 0 433.9808 A 434/436 [M + H]+ O 92 433.9808 A 434/436 [M + H]+ O 93 413.5625 A 414 [M + H]+ O

(51) TABLE-US-00023 TABLE 23 94 413.5625 A 414 [M + H]+ O 95 403.5197 A 404 [M + H]+ O 96 403.51971 A 404 [M + H]+ O 97 400.5198 C 401 [M + H]+ O

(52) TABLE-US-00024 TABLE 24 98 400.5198 C 401 [M + H]+ O 99 386.493 C 387 [M + H]+ O 100 386.493 C 387 [M + H]+ O 101 0 417.5029 A 418 [M + H]+ O

(53) TABLE-US-00025 TABLE 25 102 417.5029 A 418 [M + H]+ O 103 402.488 A 403 [M + H]+ O 104 402.488 A 403 [M + H]+ O 105 404.5038 A 405 [M + H]+ O

(54) TABLE-US-00026 TABLE 26 106 404.5038 A 405 [M + H]+ O 107 416.5188 A 417 [M + H]+ O 108 416.5188 A 417 [M + H]+ O 109 416.5188 A 417 [M + H]+ O

(55) TABLE-US-00027 TABLE 27 110 416.5188 A 417 [M + H]+ O 111 0 HCl 378.8578 B 343 [M + H]+ P 112 HCl 378.8578 B 343 [M + H]+ P 113 330.4254 A 331 [M + H]+ P

(56) TABLE-US-00028 TABLE 28 114 400.5198 A 401 [M + H]+ O 115 402.5109 A 403 [M + H]+ O 116 398.5476 A 399 [M + H]+ O 117 405.4919 C 406 [M + H]+ O

(57) TABLE-US-00029 TABLE 29 118 419.5187 C 420 [M + H]+ O 119 433.5455 C 434 [M + H]+ O 120 2*HCl 432.7768 B 360/362 [M + H]+ P 121 0 2*HCl 432.7768 B 360/362 [M + H]+ P

(58) TABLE-US-00030 TABLE 30 122 386.489 A 387 [M + H]+ O 123 386.489 C 387 [M + H]+ O 124 386.493 A 387 [M + H]+ O 125 386.493 A 387 [M + H]+ O

(59) TABLE-US-00031 TABLE 31 126 426.9379 C 427/429 [M + H]+ O 127 426.9379 C 427/429 [M + H]+ O 128 401.5079 C 402 [M + H]+ O 129 401.5079 C 402 [M + H]+ O

(60) TABLE-US-00032 TABLE 32 130 384.5208 C 385 [M + H]+ O 131 0 384.5208 C 385 [M + H]+ O 132 468.5904 A 469 [M + H]+ O 133 495.6203 A 496 [M + H]+ O

(61) TABLE-US-00033 TABLE 33 134 495.6203 A 496 [M + H]+ O 135 428.473 C 429 [M + H]+ O 136 386.493 A 387 [M + H]+ O 137 420.9381 A 421/423 [M + H]+ O

(62) TABLE-US-00034 TABLE 34 138 420.9381 A 421/423 [M + H]+ O 139 390.5206 A 391 [M + H]+ O 140 400.5198 A 401 [M + H]+ O 141 0 404.4831 A 405 [M + H]+ O

(63) TABLE-US-00035 TABLE 35 142 404.4831 A 405 [M + H]+ O 143 399.5357 A 400 [M + H]+ O 144 414.503 C 415 [M + H]+ O 145 414.503 C 415 [M + H]+ O

(64) TABLE-US-00036 TABLE 36 146 386.493 A 387 [M + H]+ O 147 416.5188 C 417 [M + H]+ O 148 416.5188 C 417 [M + H]+ O 149 406.5196 A 407 [M + H]+ O

(65) TABLE-US-00037 TABLE 37 150 420.5464 A 421 [M + H]+ O 151 0 450.5722 A 451 [M + H]+ O 152 414.5466 A 415 [M + H]+ O 153 414.5466 A 415 [M + H]+ O

(66) TABLE-US-00038 TABLE 38 154 400.5145 A 401 [M + H]+ O 155 400.5145 A 401 [M + H]+ O 156 429.5126 C 430 [M + H]+ O 157 447.5031 C 448 [M + H]+ O

(67) TABLE-US-00039 TABLE 39 158 447.5031 C 448 [M + H]+ O 159 400.5198 A 401 [M + H]+ O 160 400.5198 A 401 [M + H]+ O

(68) Ex. No.: Example Number

(69) a: Salt

(70) b: Method

(71) C: MS Results APCI

(72) d: Ion species

(73) e: Form

(74) O: Oil

(75) P: Powder

Example 161

tert-Butyl (2R)-2-[(cyclopropyl{1-[4-(3-methoxypropoxy)-1-benzofuran-6-yl]ethyl}amino)-carbonyl]morpholine-4-carboxylate [Ex(161-1)]

(76) ##STR00190##

(77) To a solution of N-{1-[4-(3-methoxypropoxy)-1-benzofuran-6-yl]ethyl}-cyclopropanamine (200 mg) and (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (240 mg) in N,N-dimethylformamide (7 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (212 mg) and 1-hydroxybenzotriazole (140 mg) under ice-cooling, and then stirred at room temperature for 18 hours. To the reaction mixture was added aqueous saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water, 10% aqueous citric acid solution and saturated saline, and then concentrated under reduced pressure to give tert-butyl (2R)-2-[(cyclopropyl {1-[4-(3-methoxypropoxy)-1-benzofuran-6-yl]ethyl}amino)carbonyl]morpholine-4-carboxylate [Ex(161-1)] (306 mg) as a yellow oil.

(78) APCI-MS m/z: 503 [M+H].sup.+.

Example 162

tert-Butyl (2R)-2-[(cyclopropyl{1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}amino)-carbonyl]morpholine-4-carboxylate [Ex(162-1), Ex(162-2)]

(79) ##STR00191##

(80) To a solution of N-{1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}-cyclopropanamine (2.63 g) and (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (2.32 g) in N,N-dimethylformamide (25 mL) were added 1-hydroxybenzotriazole (1.36 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.11 g) under ice-cooling, and then the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added ethyl acetate, and the mixture was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol=30/3/1.fwdarw.9/3/1) to give tert-butyl (2R)-2-[(cyclopropyl {(1R)-1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}amino)carbonyl]morpholine-4-carboxylate [Ex(162-1)] (1.71 g) and tert-butyl (2R)-2-[(cyclopropyl {(1S)-1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}amino)carbonyl]morpholine-4-carboxylate [Ex(162-2)] (468 mg) as a colorless oil.

(81) APCI-MS m/z: 435 [M+H].sup.+.

Example 163

tert-Butyl (2R)-2-({cyclopropyl[1-(2-naphthyl)ethyl]amino}carbonyl)morpholine-4-carboxylate [Ex(163-1)]

(82) ##STR00192##

(83) To a solution of N-[1-(2-naphthyl)ethyl]cyclopropylamine hydrochloride (149 mg), (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (208 mg) and 1-hydroxybenzotriazole (122 mg) in N,N-dimethylformamide (6 mL) was added diisopropylethylamine (0.125 L), and the thereto was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (207 mg) under ice-cooling. The mixture was stirred at room temperature for 19 hours, and then to the reaction solution was added 1-normal aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water twice, saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was triturated with n-hexane-diethyl ether (5:1) to give tert-butyl (2R)-2-(cyclopropyl[1-(2-naphthyl)ethyl]amino carbonyl)morpholine-4-carboxylate [Ex(163-1)] (153 mg) as a colorless powder.

(84) APCI-MS m/z: 425 [M+H].sup.+.

Example 164

Di-tert-butyl (2R)-2-{[{1-[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethyl}(cyclopropyl)-amino]carbonyl}piperazine-1,4-dicarboxylate [Ex(164-1), Ex(164-2)]

(85) ##STR00193##

(86) To a solution of N-{1-[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethyl}-cyclopropanamine (60 mg) and piperazinecarboxylic acid (77.5 mg) in dichloromethane (2 mL) were added diisopropylethylamine (0.085 mL) and diphenyl phosphorochloridate (0.037 mL) under ice-cooling, and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added 0.5% aqueous hydrochloric acid solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=99/1.fwdarw.2/1) to give di-tert-butyl (2R)-2-{[{(1R)-1-[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethyl}(cyclopropyl)amino]carbonyl}piperazine-1,4-dicarboxylate [Ex(164-1)] (47.5 mg) and di-tert-butyl (2R)-2-{[{(1S)-1-[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethyl}-(cyclopropyl)amino]carbonyl}piperazine-1,4-dicarboxylate [Ex(164-2)] (26.8 mg) as a colorless oil.

(87) APCI-MS m/z: 636/638 [M+H].sup.+.

Example 165

Di-tert-butyl (2R)-2-[(cyclopropyl{1-[1-(3-methoxypropyl)-3,4-dimethyl-1H-indazol-6-yl]-ethyl}amino]carbonyl}piperazine-1,4-dicarboxylate [Ex(165-1), EX(165-2)]

(88) ##STR00194##

(89) To a solution of N-{1-[1-(3-methoxypropyl)-3,4-dimethyl-1H-indazol-6-yl]ethyl}cyclopropanamine (137 mg) and piperazinecarboxylic acid (180 mg) in dichloromethane (2.5 mL) were added diisopropylethylamine (0.20 mL) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (150 mg) under ice-cooling, and the mixture was stirred at room temperature for 15 hours. To the reaction solution was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1.fwdarw.4/1) to give di-tert-butyl (2R)-2-[(cyclopropyl{(1R)-1-[1-(3-methoxypropyl)-3,4-dimethyl-1H-indazol-6-yl]ethyl}amino]carbonyl}piperazine-1,4-dicarboxylate [Ex(165-1)] (45.6 mg) and di-tert-butyl (2R)-2-[(cyclopropyl{(1S)-1-[1-(3-methoxypropyl)-3,4-dimethyl-1H-indazol-6-yl]ethyl}-amino]carbonyl}piperazine-1,4-dicarboxylate [Ex(165-2)] (53.8 mg) as a colorless oil.

(90) APCI-MS m/z: 614 [M+H].sup.+.

Example 166

tert-Butyl tert-butyl 2-[(cyclopropyl {1-[7-(3-methoxypropoxy)-2,3-dihydro-1-benzofuran-5-yl]-ethyl}amino)carbonyl]morpholine-4-carboxylate [Ex(166-1)]

(91) ##STR00195##

(92) To a solution of tert-butyl (2R)-2-[(cyclopropyl {1-[7-(3-methoxypropoxy)-1-benzofuran-5-yl]ethyl}amino)carbonyl]morpholine-4-carboxylate (200 mg) in ethanol (5.0 mL) was added 20% palladium hydroxide on carbon (100 mg), and the mixture was stirred under hydrogen for 5 hours. An insoluble was filtered, and then concentration under reduced pressure gave tert-butyl tert-butyl 2-[(cyclopropyl {1-[7-(3-methoxypropoxy)-2,3-dihydro-1-benzofuran-5-yl]ethyl}amino)carbonyl]morpholine-4-carboxylate [Ex(166-1)] (193 mg) as a colorless oil.

(93) APCI-MS m/z: 505 [M+H].sup.+.

Example 167

tert-Butyl (2R)-2-[[(1R)-5-bromo-6-(3-methoxypropoxy)-2,3-dihydro-1H-inden-1-yl]-(cyclopropyl)amino)carbonyl]morpholine-4-carboxylate [Ex(167-1)]

(94) ##STR00196##

(95) To a suspension of N-bromosuccinimide (23.4 mg) in dichloromethane (0.5 mL) was added dropwise a solution of tert-butyl (2R)-2-({cyclopropyl[(1R)-6-(3-methoxypropoxy)-2,3-dihydro-1H-inden-1-yl]amino)carbon yl]morpholine-4-carboxylate (62.4 mg) in dichloromethane (1.5 mL) under ice-cooling, and the mixture was stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate, and then sequentially washed with 1-normal aqueous sodium hydrogen carbonate solution, saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure to give a crude product of tert-butyl (2R)-2-{[[(1R)-5-bromo-6-(3-methoxypropoxy)-2,3-dihydro-1H-inden-1-yl](cyclopropyl)amino)carbonyl]morpholine-4-carboxylate [Ex(167-1)] (74 mg) as a yellow oil.

(96) APCI-MS m/z: 553/555 [M+H].sup.+.

Example 168

tert-Butyl (2R)-2-[(cyclopropyl{(1R)-1-[4-(3-methoxypropyl)quinazolin-2-yl]ethyl}amino)-carbonyl]morpholin-4-carboxylate [Ex(168-1)]

(97) ##STR00197##

(98) To a solution of tert-butyl (2R)-2-({cyclopropyl[(1R)-1-(4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]amino}carbonyl)morpholin-4-carboxylate (88 mg), 3-methoxy-1-propanol (36 mg) and triphenylphosphine (105 mg) in tetrahydrofuran (4 mL) was added dropwise diisopropyl azodicarboxylate (84 L) under ice-cooling, and the mixture was stirred at room temperature for 19 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1.fwdarw.1/2) to give tert-butyl (2R)-2-[(cyclopropyl{(1R)-1-[4-(3-methoxypropyl)quinazolin-2-yl]ethyl}amino)carbonyl]morpholin-4-carboxylate [Ex(168-1)] (38 mg) as a colorless oil.

(99) APCI-MS m/z: 515 [M+H].sup.+.

Example 169

tert-Butyl (2R)-2-[(cyclopropyl{(1R)-1-[4-ethoxy-3-(3-methoxypropoxy)phenyl]ethyl}amino)-carbonyl]morpholin-4-carboxylate [Ex(169-2)]

(100) (1)

(101) ##STR00198##

(102) To a solution of tert-butyl (2R)-2-{[{1-[4-(benzyloxy)-3-(3-methoxypropoxy)phenyl]-ethyl}(cyclopropyl)amino]carbonyl}morpholin-4-carboxylate (1.45 g) in methanol (12 mL) was added 10% palladium on carbon (200 mg), and the mixture was stirred under hydrogen for 2 hours. An insoluble was filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1.fwdarw.1/2) to give tert-butyl (2R)-2-[(cyclopropyl{(1R)-1-[4-hydroxy-3-(3-methoxypropoxy)phenyl]ethyl}amino)carbonyl]morpholin-4-carboxylate [Ex(169-1)] (913 mg) as a colorless oil.

(103) (2) Titled Compound [Ex(169-2)]

(104) ##STR00199##

(105) To a solution of the compound obtained in the above (1) (100 mg) in acetonitrile (1.0 mL) were added potassium carbonate (34.7 mg) and iodoethane (35.8 mg), and the mixture was heated to reflux for 20 hours. The reaction solution was cooled to room temperature, and then diluted with ethyl acetate. An insoluble was filtered, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1.fwdarw.2/1) to give tert-butyl (2R)-2-[(cyclopropyl{(1R)-1-[4-ethoxy-3-(3-methoxypropoxy)phenyl]ethyl}amino)carbonyl]morpholin-4-carboxylate [Ex(169-2)] (60 mg) as a colorless oil.

(106) APCI-MS m/z: 507 [M+H].sup.+.

Example 170

Methyl {3-[3-(1-{cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino}ethyl)-1H-indazol-1-yl]-propyl}carbamate [Ex(170-2)]

(107) ##STR00200##
(1) To a solution of methyl 3-{1-[{[(2R)-4-(tert-butoxycarbonyl)morpholin-2-yl]carbonyl}-(cyclopropyl)amino]ethyl}-1H-indazole-1-carboxylate (695 mg) in methanol (10 mL) was added potassium carbonate (407 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and then thereto was added ethyl acetate, and the mixture was washed with aqueous saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure to give tert-butyl (2R)-2-({cyclopropyl[1-(1-{3-[(methoxycarbonyl)amino]propyl}-1H-indazol-3-yl)-ethyl]amino}carbonyl)morpholine-4-carboxylate [Ex(170-1)] (577 mg) as a colorless powder.

(108) APCI-MS m/z: 415 [M+H].sup.+.

(109) (2) To a solution of the compound obtained in (1) (90 mg) and methyl (3-bromopropyl)carbamate (64 mg) in N,N-dimethylformamide (2 mL) was added potassium carbonate (60 mg), and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added ethyl acetate, and the mixture was washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/20.fwdarw.1/1) to give methyl {3-[3-(1-{cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino}ethyl)-1H-indazol-1-yl]propyl}carbamate [Ex(170-2)] (74 mg) as a yellow oil.

Examples 171 to 267

(110) The following N-protected nitrogen-containing saturated heterocyclic compounds were prepared in the similar manner to the above Examples 161 to 169. Each symbol of Methods A to C refers to each method according to the following method of Examples.

(111) Method A: Examples 161 to 163

(112) Method B: Example 164

(113) Method C: Example 165

(114) Method D: Example 166

(115) Method E: Example 167

(116) Method F: Example 168

(117) Method G: Example 169

(118) TABLE-US-00040 TABLE 40 EX. No. Structure a b c d e 171 01 492.609 O 493 [M + H]+ A 172 02 424.5378 P 425 [M + H]+ A 173 03 500.636 O 501 [M + H]+ A 174 04 434.5296 O 435 [M + H]+ A

(119) TABLE-US-00041 TABLE 41 175 05 448.5564 O 449 [M + H]+ A 176 06 434.5296 O 435 [M + H]+ A 177 07 500.636 O 501 [M + H]+ A 178 08 599.7681 O 600 [M + H]+ B

(120) TABLE-US-00042 TABLE 42 179 09 474.5942 O 492 [M + NH4]+ 180 0 476.61 O 477 [M + H]+ 181 476.61 O 494 [M + NH4]+ 182 480.5733 O 498 [M + NH4]+

(121) TABLE-US-00043 TABLE 43 183 492.609 O 510 [M + NH4]+ A 184 480.5733 O 481 [M + H]+ A 185 535.0811 O 535/537 [M + H]+ A 186 514.6628 O 515 [M + H]+ A

(122) TABLE-US-00044 TABLE 44 187 518.6261 O 519 [M + H]+ A 188 514.6628 O 515 [M + H]+ A 189 502.6042 O 503 [M + H]+ A 190 0 504.62 O 505 [M + H]+ D

(123) TABLE-US-00045 TABLE 45 191 550.6884 O 568 [M + NH4]+ A 192 468.9747 O 469/471 [M + H]+ A 193 468.9747 P 469/471 [M + H]+ A 194 487.5933 O 488 [M + H]+ A

(124) TABLE-US-00046 TABLE 46 195 510.4722 O 511 [M + H]+ A 196 553.4903 O 553/555 [M + H]+ E 197 529.6341 O 530 [M + H]+ A 198 454.5636 O 455 [M + H]+ A

(125) TABLE-US-00047 TABLE 47 199 541.6411 P 542 [M + H]+ A 200 0 455.5517 P 456 [M + H]+ A 201 462.5832 O 463 [M + H]+ A 202 487.5933 O 505 [M + NH4]+ A

(126) TABLE-US-00048 TABLE 48 203 530.5803 O 531 [M + H]+ A 204 484.637 O 485 [M + H]+ A 205 535.0811 O 535/537 [M + H]+ A 206 500.636 O 501 [M + H]+ A

(127) TABLE-US-00049 TABLE 49 207 518.6261 O 519 [M + H]+ A 208 488.621 O 489 [M + H]+ A 209 567.5171 O 567/569 [M + H]+ E 210 0 510.5991 O 511 [M + H]+ A

(128) TABLE-US-00050 TABLE 50 211 571.5051 O 571/573 [M + H]+ A 212 499.6479 O 500 [M + H]+ A 213 598.78 O 616 [M + NH4]+ B 214 634.2132 O 634/636 [M + H]+ C

(129) TABLE-US-00051 TABLE 51 215 613.7949 O 614 [M + H]+ C 216 601.7363 O 602 [M + H]+ B 217 603.7521 O 604 [M + H]+ D 218 517.6191 O 518 [M + H]+ A

(130) TABLE-US-00052 TABLE 52 219 486.6092 O 487 [M + H]+ A 220 0 500.636 O 501 [M + H]+ A 221 527.0541 O 527/529 [M + H]+ A 222 514.6628 O 515 [M + H]+ A

(131) TABLE-US-00053 TABLE 53 223 430.5416 O 431 [M + H]+ A 224 502.6271 O 503 [M + H]+ A 225 498.6638 O 499 [M + H]+ A 226 533.6617 O 534 [M + H]+ A

(132) TABLE-US-00054 TABLE 54 227 505.6081 O 506 [M + H]+ A 228 519.6349 O 520 [M + H]+ A 229 502.6042 O 503 [M + H]+ A 230 0 504.62 O 505 [M + H]+ D

(133) TABLE-US-00055 TABLE 55 231 484.637 O 485 [M + H]+ A 232 516.635 O 517 [M + H]+ A 233 442.513 P 443 [M + H]+ A 234 442.513 P 443 [M + H]+ A

(134) TABLE-US-00056 TABLE 56 235 459.971 P 460/462 [M + H]+ A 236 459.971 P 460/462 [M + H]+ A 237 514.6192 O 515 [M + H]+ F 238 514.6192 P 515 [M + H]+ F

(135) TABLE-US-00057 TABLE 57 239 490.6368 O 491 [M + H]+ A 240 0 520.0662 O 520/522 [M + H]+ A 241 619.1983 O 636/638 [M + H]+ B 242 568.6331 O 569 [M + H]+ A

(136) TABLE-US-00058 TABLE 58 243 487.6369 O 488 [M + H]+ A 244 487.6369 O 488 [M + H]+ A 245 485.6211 O 486 [M + H]+ A 246 486.6052 O 504 [M + NH4]+ A

(137) TABLE-US-00059 TABLE 59 247 486.6092 O 487 [M + H]+ A 248 516.635 O 517 [M + H]+ A 249 516.635 O 517 [M + H]+ A 250 0 488.625 O 489 [M + H]+ A

(138) TABLE-US-00060 TABLE 60 251 595.7365 O 596 [M + H]+ A 252 504.5993 O 505 [M + H]+ A 253 550.6884 O 568 [M + NH4]+ G 254 520.6626 O 521 [M + H]+ G

(139) TABLE-US-00061 TABLE 61 255 506.6358 O 507 [M + H]+ G 256 568.7066 O 569 [M + H]+ A 257 528.5892 O 529 [M + H]+ A 258 500.636 O 501 [M + H]+ A

(140) TABLE-US-00062 TABLE 62 259 486.6092 O 487 [M + H]+ A 260 0 521.0543 O 521/523 [M + H]+ A 261 518.6261 O 519 [M + H]+ A 262 486.6092 O 487 [M + H]+ A

(141) TABLE-US-00063 TABLE 63 263 514.6628 O 515 [M + H]+ A 264 500.636 O 501 [M + H]+ A 265 529.6285 O 530 [M + H]+ H 266 547.6189 O [M + H]+ A

(142) TABLE-US-00064 TABLE 64 267 472 5341 P 490 [M + NH4]+ A

(143) Ex. No.: Example Number

(144) a: Molecular weight

(145) b: Properties

(146) c: MS Results APCI

(147) d: Ion species

(148) e: Method

(149) O: Oil

(150) P: Powder

Examples 268 to 287

(151) The following nitrogen-containing saturated heterocyclic compounds, etc. were prepared in the similar manner to the above Examples 1 to 5. Each symbol of Methods A to C refers to each method according to the following method of Examples.

(152) Method A: Examples 1, 2

(153) Method B: Examples 3, 4

(154) Method C: Example 5A

(155) TABLE-US-00065 TABLE 65 EX. No. Structure a MW b c d e 268 430.5007 C 431 [M + H].sup.+ O 269 430.5007 C 431 [M + H].sup.+ O 270 00 444.5273 C 445 [M + H].sup.+ O 271 01 444.5273 C 445 [M + H].sup.+ O 272 02 414.5411 C 415 [M + H].sup.+ O 273 03 414.5411 C 415 [M + H].sup.+ O

Ex. No.: Example Number

(156) a: Salt

(157) b: Method

(158) c: MS Results APCI

(159) d: Ion species

(160) e: Form

(161) O: Oil

(162) TABLE-US-00066 TABLE 66 EX. No. Structure a MW b c d e 274 04 414.5411 A 415 [M + H].sup.+ O 275 05 414.5411 A 415 [M + H].sup.+ O 276 06 390.5164 A 391 [M + H].sup.+ O 277 07 390.5164 A 391 [M + H].sup.+ O 278 08 419.5145 A 420 [M + H].sup.+ O 279 09 419.5145 A 420 [M + H].sup.+ O

Ex. No.: Example Number

(163) a: Salt

(164) b: Method

(165) c: MS Results APCI

(166) d: Ion species

(167) e: Form

(168) O: Oil

(169) TABLE-US-00067 TABLE 67 EX. No. Structure a MW b c d e 280 0 420.5026 C 421 [M + H].sup.+ O 281 420.5026 C 421 [M + H].sup.+ O 282 418.5298 C 419 [M + H].sup.+ O 283 418.5298 C 419 [M + H].sup.+ O 284 420.5026 C 421 [M + H].sup.+ O 285 420.5026 C 421 [M + H].sup.+ O

Ex. No.: Example Number

(170) a: Salt

(171) b: Method

(172) c: MS Results APCI

(173) d: Ion species

(174) e: Form

(175) O: Oil

(176) TABLE-US-00068 TABLE 68 EX. No. Structure a MW b c d e 286 418.5298 C 419 [M + H].sup.+ O 287 418.5298 C 419 [M + H].sup.+ O

(177) Ex. No.: Example Number

(178) a: Salt

(179) b: Method

(180) c: MS Results APCI

(181) d: Ion species

(182) e: Form

(183) O: Oil

Examples 288 to 294

(184) The following N-protected nitrogen-containing saturated heterocyclic compounds were prepared in the similar manner to the above Examples 161 to 163 (Method A).

(185) TABLE-US-00069 TABLE 69 EX. No. Structure a b c d e 288 530.6165 O 531 [M + H].sup.+ A 289 544.6431 O 545 [M + H].sup.+ A 290 0 514.6569 O 515 [M + H].sup.+ A 291 514.6569 O 515 [M + H].sup.+ A 292 514.6569 O 515 [M + H].sup.+ A 293 490.6322 O 491 [M + H].sup.+ A

(186) Ex. No.: Example Number

(187) a: Molecular weight

(188) b: Properties

(189) C: MS Results APCI

(190) d: Ion species

(191) e: Method

(192) O: Oil

(193) TABLE-US-00070 TABLE 70 EX. No. Structure a b c d e 294 518.6456 O 519 [M + H].sup.+ A

(194) Ex. No.: Example Number

(195) a: Molecular weight

(196) b: Properties

(197) C: MS Results APCI

(198) d: Ion species

(199) e: Method

(200) O: Oil

Example 295

(201) ##STR00325## ##STR00326##
1) To a solution of 1-(3-iodo-4-methoxyphenyl)ethanone (10 g) in diethylamine (181 mL) were added benzyl prop-2-yn-1-ylcarbamate (8.2 g), dichlorobis(triphenylphosphine)palladium (II) (2.54 g) and copper (I) iodide (689 mg), and the mixture was stirred at 50 C. for 2 hours. The reaction solution was cooled, and then thereto was added water, and the mixture was extracted with chloroform. The organic layer was sequentially washed with 2-normal hydrochloric acid, water, and then dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform.fwdarw.chloroform/ethyl acetate=1/1) to give benzyl[3-(5-acetyl-2-methoxyphenyl)prop-2-yn-1-yl]carbamate [Ex(295-1)] (5.3 g) as a red solid.

(202) APCI-MS m/z: 355[M+NH.sub.4].sup.+.

(203) 2) Benzyl[3-(5-acetyl-2-methoxyphenyl)prop-2-yn-1-yl]carbamate and cyclopropylamine were treated in the similar manner to Reference Example 6(6) to give benzyl (3-{5-[1-(cyclopropylamino)ethyl]-2-methoxyphenyl}prop-2-yn-1-yl)carbamate [Ex(295-2)] as a yellow oil.

(204) APCI-MS m/z: 379 [M+H].sup.+.

(205) 3) Benzyl (3-{5-[1-(cyclopropylamino)ethyl]-2-methoxyphenyl}prop-2-yn-1-yl)carbamate and (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid were treated in the similar manner to Example 162 to give tert-butyl (2R)-2-{[{1-[3-(3-[(benzyloxy)carbonyl]amino prop-1-yn-1-yl)-4-methoxyphenyl]ethyl}(cyclopropyl)amino]carbonyl}morpholine-4-carboxylate [Ex(295-3)] as a colorless solid.

(206) APCI-MS m/z: 609[M+NH.sub.4].sup.+.

(207) 4) To a solution of tert-butyl (2R)-2-{[{1-[3-(3-{[(benzyloxy)carbonyl]amino}prop-1-yn-1-yl)-4-methoxyphenyl]ethyl}(cyclopropyl)amino]carbonyl}morpholin-4-carboxylate (2.82 g) in methanol (25 mL) was added 10% palladium on carbon (282 mg), and the mixture was stirred under hydrogen for 7 hours. An insoluble was filtered off, and then the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (eluent: chloroform.fwdarw.chloroform/methanol=33/1) to give tert-butyl (2R)-2-[1-[3-(3-aminopropyl)-4-methoxyphenyl]ethyl (cyclopropyl)amino]carbonyl morpholin-4-carboxylate [Ex(295-4)] (1.49 g) as a colorless oil.

(208) APCI-MS m/z: 462 [M+H].sup.+.

(209) 5) tert-Butyl (2R)-2-{[{1-[3-(3-aminopropyl)-4-methoxyphenyl]ethyl}(cyclopropyl)amino]-carbonyl}morpholin-4-carboxylater and methyl chloroformate were treated in the similar manner to Reference Example 28(5) to give tert-butyl (2R)-2-({cyclopropyl[1-(4-methoxy-3-{3-[(methoxycarbonyl)amino]propyl}phenyl)ethyl]amino}carbonyl)morpholin-4-carboxylate [Ex(295-5)] as a colorless oil.

(210) APCI-MS m/z: 504 [M+H].sup.+.

Example 296

(211) ##STR00327##
1) 5-Bromo-6-methoxynicotinic acid and N,O-dimethylhydroxylamine hydrochloride were treated in the similar manner to Reference Example 7(5), and then the resulting compound and methylmagnesium bromide were treated in the similar manner to Reference Example 7(6) to give 1-(5-bromo-6-methoxypyridin-3-yl)ethanone [Ex(296-1)] as a colorless powder.

(212) APCI-MS m/z: 230/232 [M+H].sup.+.

(213) 2) Bis(benzonitrile)dichloropalladium (II) (12 mg) and copper (I) iodide (3.8 mg) were added to 1,4-dioxane (1 mL) under argon, and then thereto were added a solution of 10% tri-t-butylphosphine in hexane (179 L), diisopropylamine (168 L), 1-(5-bromo-6-methoxypyridin-3-yl)ethanone (230 mg) and a solution of methyl prop-2-yn-1-ylcarbamate (149 mg) in 1,4-dioxane (1 mL). The mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1.fwdarw.1/3) to give methyl [3-(5-acetyl-2-methoxypyridin-3-yl)prop-2-yn-1-yl]carbamate [Ex(296-2)] (188 mg) as a pale yellow powder.

(214) APCI-MS m/z: 263 [M+H].sup.+.

(215) 3) Methyl[3-(5-acetyl-2-methoxypyridin-3-yl)prop-2-yn-1-yl]carbamate and cyclopropylamine were treated in the similar manner to Reference Example 6(6) to give methyl (3-{5-[1-(cyclopropylamino)ethyl]-2-methoxypyridin-3-yl}prop-2-yn-1-yl)carbamate [Ex(296-3)] as a colorless oil.

(216) APCI-MS m/z: 304 [M+H].sup.+.

(217) 4) Methyl (3-{5-[1-(cyclopropylamino)ethyl]-2-methoxypyridin-3-yl}prop-2-yn-1-yl)carbamate and (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid were treated in the similar manner to Example 162 to give tert-butyl (2R)-2-({cyclopropyl[1-(6-methoxy-5-{3-[(methoxycarbonyl)amino]prop-1-yn-1-yl}pyridin-3-yl)ethyl]amino}carbonyl)morpholine-4-carboxylate [Ex(296-4)] as a colorless oil.

(218) APCI-MS m/z: 517 [M+H].sup.+.

(219) 5) To a solution of tert-butyl (2R)-2-({cyclopropyl[1-(6-methoxy-5-{3-[(methoxycarbonyl)-amino]prop-1-yn-1-yl}pyridin-3-yl)ethyl]amino}carbonyl)morpholin-4-carboxylate (150 mg) in ethyl acetate (2.5 mL)-tetrahydrofuran (2.5 mL) was added 10% palladium on carbon (30 mg), and the mixture was stirred under hydrogen for 45 minutes. An insoluble was filtered off, and then the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (eluent: ethyl acetate) to give tert-butyl (2R)-2-({cyclopropyl[1-(6-methoxy-5-{3-[(methoxycarbonyl)amino]propyl}pyridin-3-yl)ethyl]amino}carbonyl)morpholine-4-carboxylate [Ex(296-5)] (159 mg) as a colorless oil.

(220) APCI-MS m/z: 521 [M+H].sup.+.

Example 297

(221) ##STR00328## ##STR00329##
1) 1-(2,6-Dichloropyridin-4-yl)ethanone and cyclopropylamine were treated in the similar manner to Reference Example 6(6) to give N-[1-(2,6-dichloropyridin-4-yl)ethyl]-cyclopropylamine [Ex(297-1)] as a pale yellow oil.

(222) APCI-MS m/z: 231/233 [M+H].sup.+.

(223) 2) To a solution of N-[1-(2,6-dichloropyridin-4-yl)ethyl]cyclopropylamine (430 mg) in tetrahydrofuran (5 mL) were added di-tert-butyl dicarbonate (487 mg) and triethylamine (518 L), and the mixture was heated to reflux for 24 hours. The reaction solution was cooled, and then thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1.fwdarw.4/1) to give tert-butyl cyclopropyl[1-(2,6-dichloropyridin-4-yl)ethyl]carbamate [Ex(297-2)] (420 mg) as a pale yellow oil.

(224) APCI-MS m/z: 331/333 [M+H].sup.+.

(225) 3) To a solution of tert-butyl cyclopropyl[1-(2,6-dichloropyridin-4-yl)ethyl]carbamate (155 mg) in dimethoxyethane (4 mL) were added methyl [(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)prop-2-en-1-yl]carbamate (113 mg), 2M potassium carbonate (257 L) and tetrakis(triphenylphosphine)palladium (0) (27 mg), and the mixture was heated to reflux for 3 hours. The reaction solution was cooled, and then thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1.fwdarw.ethyl acetate) to give methyl [(2E)-3-(4-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-6-chloropyridin-2-yl)prop-2-en-1-yl]carbamate [Ex(297-3)] (98 mg) as a pale yellow oil.

(226) APCI-MS m/z: 410/412 [M+H].sup.+.

(227) 4) Methyl [(2E)-3-(4-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-6-chloropyridin-2-yl)-prop-2-en-1-yl]carbamate and vinyl boronic acid pinacol ester were treated in the similar manner to Reference Example 113(6) to give methyl [(E)-2-(4-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-6-vinylpyridin-2-yl)vinyl]carbamate [Ex(297-4)] as a yellow oil.

(228) APCI-MS m/z: 402 [M+H].sup.+.

(229) 5) Methyl [(E)-2-(4-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-6-vinylpyridin-2-yl)vinyl]carbamate and trifluoroacetic acid were treated in the similar manner to Reference Example 113(8) to give methyl ((E)-2-{4-[1-(cyclopropylamino)ethyl]-6-vinylpyridin-2-yl}vinyl)carbamate [Ex(297-5)] as a pale yellow oil.

(230) APCI-MS m/z: 302 [M+H].sup.+.

(231) 6) Methyl ((E)-2-{4-[1-(cyclopropylamino)ethyl]-6-vinylpyridin-2-yl}vinyl)carbamate and (2R)-4-(tert-butoxycarbonyl)morpholin-2-carboxylic acid were treated in the similar manner to Example 162 to give tert-butyl (2R)-2-({cyclopropyl[1-(2-{(1E)-3-[(methoxycarbonyl)amino]prop-1-en-1-yl}-6-vinylpyridin-4-yl)ethyl]amino}carbonyl)morpholin-4-carboxylate [Ex(297-6)] as a yellow oil. APCI-MS m/z: 515 [M+H].sup.+.
7) tert-Butyl (2R)-2-({cyclopropyl[1-(2-{(1E)-3-[(methoxycarbonyl)amino]prop-1-en-1-yl}-6-vinylpyridin-4-yl)ethyl]amino}carbonyl)morpholine-4-carboxylate was reduced in the similar manner to Example 296(5) to give tert-butyl (2R)-2-({cyclopropyl[1-(2-ethyl-6-{3-[(methoxycarbonyl)amino]propyl}pyridin-4-yl)ethyl]amino}carbonyl)morpholin-4-carboxylate [Ex(297-7)] as a colorless oil.

(232) APCI-MS m/z: 519 [M+H].sup.+.

Example 298

(233) ##STR00330##
1) 1-(2-Chloro-6-methoxypyridin-4-yl)ethanone and methyl [(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)prop-2-en-1-yl]carbamate were treated in the similar manner to Example 297(3) to give methyl [(2E)-3-(4-acetyl-6-methoxypyridin-2-yl)prop-2-en-1-yl]carbamate [Ex(298-1)] as a colorless powder.

(234) APCI-MS m/z: 265 [M+H].sup.+.

(235) 2) Methyl [(2E)-3-(4-acetyl-6-methoxypyridin-2-yl)prop-2-en-1-yl]carbamate and cyclopropylamine were treated in the similar manner to Reference Example 6(6) to give methyl ((2E)-3-{4-[1-(cyclopropylamino)ethyl]-6-methoxypyridin-2-yl}prop-2-en-1-yl)carbamate [Ex(298-2)] as a colorless oil.

(236) APCI-MS m/z: 306 [M+H].sup.+.

(237) 3) Methyl ((2E)-3-{4-[1-(cyclopropylamino)ethyl]-6-methoxypyridin-2-yl}prop-2-en-1-yl)carbamate and (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid were treated in the similar manner to Example 162 to give tert-butyl (2R)-2-({cyclopropyl[1-(2-methoxy-6-{(1E)-3-[(methoxycarbonyl)amino]prop-1-en-1-yl}pyridin-4-yl)ethyl]amino}carbonyl)morpholine-4-carboxylate [Ex(298-3)] as a colorless oil.

(238) APCI-MS m/z: 519 [M+H].sup.+.

(239) 4) tert-Butyl (2R)-2-({cyclopropyl[1-(2-methoxy-6-{(1E)-3-[(methoxycarbonyl)amino]-prop-1-en-1-yl}pyridin-4-yl)ethyl]amino}carbonyl)morpholin-4-carboxylate was reduced in the similar manner to Example 296(5) to give tert-butyl (2R)-2-({cyclopropyl[1-(2-methoxy-6-{3-[(methoxycarbonyl)amino]propyl}pyridin-4-yl)ethyl]amino}carbonyl)morpholin-4-carboxylate [Ex(298-4)] as a colorless oil.

(240) APCI-MS m/z: 521 [M+H].sup.+.

(241) Examples 299 to 308 were synthesized according to a combination of the methods described herein and conventional methods.

(242) TABLE-US-00071 TABLE 71 EX. No. Structural formula a b c 299 2HCl 465 [M + H].sup.+ 300 2HCl 465 [M + H].sup.+ 301 2HCl 463 [M + H].sup.+ 302 2HCl 463 [M + H].sup.+ 303 2HCl 449 [M + H].sup.+

(243) Ex. No.: Example Number

(244) a: Salt

(245) b: Mass spectrometric value

(246) c: Ion species

(247) TABLE-US-00072 TABLE 72 EX. No. Structural formula a b c 304 2HCl 449 [M + H].sup.+ 305 2HCl 483 [M + H].sup.+ 306 2HCl 483 [M + H].sup.+ 307 2HCl 483 [M + H].sup.+ 308 0 2HCl 483 [M + H].sup.+

(248) Ex. No.: Example Number

(249) a: Salt

(250) b: Mass spectrometric value

(251) c: Ion species

Reference Example 1

N-[1-(2-Naphthyl)ethyl]cyclopropylamine hydrochloride [REx(1-2)]

(252) ##STR00341##
(1) N-Cyclopropyl-N-[1-(2-naphthyl)ethyl]-2-nitrobenzenesulfonamide [REx(1-1)]:

(253) To a solution of 1-(2-naphthyl)ethanol (344 mg), N-cyclopropyl-2-nitrobenzenesulfonamide (581 mg) and triphenylphosphine (787 mg) in tetrahydrofuran (10 mL) was added dropwise diisopropyl azodicarboxylate (590 L) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1.fwdarw.41/1), and then triturated with diethyl ether-n-hexane (1:1) to give N-cyclopropyl-N-[1-(2-naphthyl)ethyl]-2-nitrobenzenesulfonamide [REx(1-1)] (499 mg) as a colorless powder.

(254) APCI-MS m/z: 397 [M+H].sup.+.

(255) (2) N-[1-(2-Naphthyl)ethyl]cyclopropylamine hydrochloride [REx(1-2)]:

(256) To a solution of the compound obtained in (1) (480 mg) and 4-bromothiophenol (250 mg) in N,N-dimethylformamide (12 mL) was added potassium carbonate (304 mg), and the mixture was stirred at room temperature for 17 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water twice and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (5 mL), and then thereto was added 4-normal hydrogen chloride-ethyl acetate (1 mL). The precipitated solid was filtered to give N-[1-(2-naphthyl)ethyl]cyclopropylamine hydrochloride [REx(1-2)] (211 mg) as a colorless powder.

(257) APCI-MS m/z: 212 [M+H].sup.+.

Reference Example 2

(258) ##STR00342## ##STR00343##
(1) 3-Methoxypropyl 4-fluoro-3-(3-methoxypropoxy)benzoate [REx(2-1)]:

(259) To a solution of 4-fluoro-3-hydroxybenzoic acid (2.0 g) in acetonitrile (100 mL)-N,N-dimethylformamide (50 mL)-water (2.0 mL) were added potassium carbonate (5.31 g) and 1-bromo-3-methoxypropane (4.32 g), and the mixture was heated to reflux at 90 C. for 18 hours. To the reaction mixture was added water under ice-cooling, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1.fwdarw.1/2 to give 3-methoxypropyl 4-fluoro-3-(3-methoxypropoxy)benzoate [REx(2-1)] (2.72 g) as a colorless oil.

(260) APCI-MS m/z: 301 [M+H].sup.+.

(261) (2) [Fluoro-3-(3-methoxypropoxy)phenyl]methanol [REx(2-2)]:

(262) To a suspension of lithium aluminum hydride (344 mg) in tetrahydrofuran (20 mL) was added dropwise a solution of the compound obtained in the above (1) (2.72 g) in tetrahydrofuran (8 mL) under ice-cooling, and then the mixture was stirred under the cooling for 1 hour. Under the cooling, to the reaction mixture were sequentially and slowly added water and 2-normal aqueous sodium hydroxide solution (1 mL), and then the mixture was stirred at room temperature for 1 hour. An insoluble was filtered off through Celite, and the filtrate was washed with aqueous saturated sodium hydrogen carbonate solution, and then dried over magnesium sulfate. The resultant was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1.fwdarw.1/2) to give [fluoro-3-(3-methoxypropoxy)phenyl]methanol [REx(2-2)] (1.78 g) as a colorless oil.

(263) APCI-MS m/z: 232[M+NH.sub.4].sup.+.

(264) (3) 4-Fluoro-3-(3-methoxypropoxy)benzaldehyde [REx(2-3)]:

(265) To a solution of the compound obtained in the above (2) (1.65 g) in dichloromethane (43 mL) was added 85% activated manganese dioxide (7.88 g), and the mixture was stirred at room temperature for 1 hour, and then the mixture was heated to reflux for 2 hours. An insoluble was filtered off through Celite, and then the filtrate was concentrated under reduced pressure to give 4-fluoro-3-(3-methoxypropoxy)benzaldehyde [REx(2-3)] (1.59 g) as a colorless oil.

(266) APCI-MS m/z: 213 [M+H].sup.+.

(267) (4) 1-[4-Fluoro-3-(3-methoxypropoxy)phenyl]ethanol [REx(2-4)]:

(268) To a solution of the compound obtained in the above (3) (1.55 g) in tetrahydrofuran (30 mL) was added dropwise a solution of methylmagnesium bromide in 3M diethyl ether (2.68 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. Under ice-cooling, thereto was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, and then dried over magnesium sulfate and concentrated under reduced pressure to give 1-[4-fluoro-3-(3-methoxypropoxy)phenyl]ethanol [REx(2-4)] (1.43 g) as a yellow oil.

(269) APCI-MS m/z: 246 [M+NH.sub.4].sup.+.

(270) (5) Then, an amine compound [REx(2-6)] may be obtained in the similar manner to Reference Example 1.

Reference Example 3

(271) ##STR00344## ##STR00345##
(1) tert-Butyl {[4-(benzyloxy)-2-naphthyl]methyl}cyclopropylcarbamate [REx(3-1)]:

(272) To a solution of N-{[4-(benzyloxy)-2-naphthyl]methyl}cyclopropylamine (12.3 g) in dichloromethane (150 mL) were added triethylamine (5.93 mL) and di-t-butyl dicarbonate (9.29 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added saturated aqueous ammonium chloride solution under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=19/1.fwdarw.9/1) to give tert-butyl {[4-(benzyloxy)-2-naphthyl]methyl}cyclopropylcarbamate [REx(3-1)] (15.8 g) as a colorless powder.

(273) APCI-MS m/z: 404 [M+H].sup.+.

(274) (2) tert-Butyl {1-[4-(benzyloxy)-2-naphthyl]ethyl}cyclopropylcarbamate [REx(3-2)]:

(275) To a solution of the compound obtained in the above (1) (807 mg) and tetramethylethylenediamine (0.39 L) in tetrahydrofuran (10 mL) were added dropwise a solution of 1.55M n-butyllithium in hexane (1.55 mL) at 78 C. under argon over 5 minutes. The mixture was stirred at the same temperature for 1 hour, and then thereto was added iodomethane (0.187 L) at 78 C. The mixture was stirred at the same temperature for 30 minutes, and then stirred under ice-cooling for 2 hours. To the reaction solution was added saturated aqueous ammonium chloride solution under ice-cooling, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water twice and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1.fwdarw.6/1) to give tert-butyl {1-[4-(benzyloxy)-2-naphthyl]ethyl}cyclopropylcarbamate [REx(3-2)] (611 mg) as a colorless oil.

(276) APCI-MS m/z: 418 [M+H].sup.+.

(277) (3) tert-Butyl[1-(4-hydroxy2-naphthyl)ethyl]carbamate [REx(3-3)]:

(278) To a solution of the compound obtained in the above (2) (126 mg) in methanol (3 mL) was added 10% palladium on carbon (13 mg), and the mixture was stirred under hydrogen for 3 hours. The reaction solution was diluted with ethyl acetate, and a catalyst was filtered, and then the resultant was concentrated under reduced pressure. The resulting residue was triturated with isopropyl ether/n-hexane (1:1) to give tert-butyl cyclopropyl[1-(4-hydroxy2-naphthyl)ethyl]carbamate [REx(3-3)] (50 mg) as a colorless powder.

(279) ESI-MS m/z: 326[MH].sup..

(280) (4) Methyl {2-[(3-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-1-naphthyl)oxy]ethyl}carbamate [REx(3-4)]:

(281) To a solution of the compound obtained in the above (3) (243 mg) and methyl (2-bromoethyl)carbamate (203 mg) in acetonitrile (10 mL) was added potassium carbonate (205 mg), and the mixture was stirred at 80 C. for 7 hours. After cooling, to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1.fwdarw.1/1) to give methyl {2-[(3-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-1-naphthyl)oxy]ethyl}carbamate [REx(3-4)] (161 mg) as a pale yellow oil.

(282) APCI-MS m/z: 429 [M+H].sup.+.

(283) (5) Methyl[2-({3-[1-(cyclopropylamino)ethyl]-1-naphthyl}oxy)ethyl]carbamate [REx(3-5)]:

(284) To a solution of the compound obtained in the above (4) (156 mg) in chloroform (2 mL) was added 4-normal hydrogen chloride-dioxane solution (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and to the resulting residue was added aqueous saturated sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate.fwdarw.ethyl acetate/methanol=10/1) to give methyl [2-({3-[1-(cyclopropylamino)ethyl]-1-naphthyl}oxy)ethyl]carbamate [REx(3-5)] (76 mg) as a pale yellow oil.

(285) APCI-MS m/z: 329 [M+H].sup.+.

Reference Example 4

[1-(4-Methoxy-2-naphthyl)ethyl]cyclopropylamine [REx(4-1)]

(286) ##STR00346##

(287) To a mixture of tert-butyl cyclopropyl[1-(4-hydroxy2-naphthyl)ethyl]carbamate (43 mg) and potassium carbonate (27 mg) was added N,N-dimethylformamide (2.0 mL), and then thereto added methyl iodide (0.016 mL), and the mixture was stirred at room temperature for 4 hours. After cooling, to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water twice and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1.fwdarw.4/1) to give tert-butyl cyclopropyl[1-(4-methoxy-2-naphthyl)ethyl]carbamate [REx(4-1)] (33 mg) as a colorless oil.

(288) APCI-MS m/z: 342 [M+H].sup.+.

(289) Then, deprotection of Boc group according to any one of methods of Examples 1 to 5 may give the desired amine compound.

Reference Example 5

(290) ##STR00347## ##STR00348##
(1) tert-Butyl[3-(benzyloxy)-5-(3-methoxypropoxy)benzyl]cyclopropylcarbamate [REx(5-1)]:

(291) To a solution of N-[3-(benzyloxy)-5-(3-methoxypropoxy)benzyl]cyclopropylamine (15.4 g) in dichloromethane (190 mL) were added triethylamine (6.60 mL) and di-t-butyl dicarbonate (10.3 g) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. To the reaction solution was added saturated aqueous ammonium chloride solution under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=14/1) to give tert-butyl [3-(benzyloxy)-5-(3-methoxypropoxy)benzyl]cyclopropylcarbamate [REx(5-1)] (20.0 g) as a colorless oil.

(292) APCI-MS m/z: 459[M+NH4].sup.+.

(293) (2) tert-Butyl cyclopropyl[3-hydroxy5-(3-methoxypropoxy)benzyl]carbamate [REx(5-2)]:

(294) To a solution of the compound obtained in the above (1) (14.0 g) in ethanol (210 mL) was added 20% palladium hydroxide on carbon (2.80 g), and the mixture was stirred under hydrogen for 30 minutes. An insoluble was filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1.fwdarw.2/1) to give tert-butyl cyclopropyl[3-hydroxy5-(3-methoxypropoxy)benzyl]carbamate [REx(5-2)] (11.0 g) as a colorless oil.

(295) APCI-MS m/z: 352 [M+H].sup.+.

(296) (3) tert-Butyl cyclopropyl[3-methoxy-5-(3-methoxypropoxy)benzyl]carbamate [REx(5-3)]:

(297) To a solution of the compound obtained in the above (2) (3.51 g) in N,N-dimethylformamide (50 mL) was added potassium carbonate (2.07 g), and then thereto was added iodomethane (0.75 mL) under ice-cooling, and the mixture was stirred at room temperature for 23 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water twice and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure.

(298) The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to give tert-butyl cyclopropyl[3-methoxy-5-(3-methoxypropoxy)benzyl]carbamate [REx(5-3)] (3.65 g) as a colorless oil.

(299) APCI-MS m/z: 366 [M+H].sup.+.

(300) (4) Methylation according to the method of Reference Example 3(2), then deprotecting Boc group according to any one of methods of Examples 1 to 5 give the desired amine compound [REx(5-5)].

Reference Example 6

(301) ##STR00349## ##STR00350##
(1) Methyl 1-(3-methoxypropyl)-1H-indole-6-carboxylate [REx(6-1)]:

(302) To a solution of methyl 1H-indole-6-carboxylate (5.0 g) in N,N-dimethylformamide (40 mL) was added drop by drop 60% oil-based sodium hydride (1.37 g) under ice-cooling, and then the mixture was stirred at room temperature for 15 minutes. Then, thereto was added dropwise a solution of 1-bromo-3-methoxypropane (5.24 g) in N,N-dimethylformamide (10 mL) under ice-cooling, and then thereto was added potassium iodide (948 mg), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was sequentially added ethyl acetate and water under ice-cooling, and the organic layer was separated. The organic layer was washed with water twice and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1.fwdarw.4/1) to give methyl 1-(3-methoxypropyl)-1H-indole-6-carboxylate [REx(6-1)] (5.8 g) as a colorless oil.

(303) APCI-MS m/z: 248 [M+H].sup.+.

(304) (2) Methyl 3-chloro-1-(3-methoxypropyl)-1H-indole-6-carboxylate [REx(6-2)]:

(305) To a solution of the compound obtained in the above (1) (2.78 g) in dichloromethane (35 mL) was added N-chlorosuccinimide (1.65 g) under ice-cooling, and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added water, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane.fwdarw.n-hexane/ethyl acetate=2/1) to give methyl 3-chloro-1-(3-methoxypropyl)-1H-indole-6-carboxylate [REx(6-2)] (3.10 g) as a yellow oil.

(306) APCI-MS m/z: 282/284 [M+H].sup.+.

(307) (3) 3-Chloro-1-(3-methoxypropyl)-1H-indole-6-carboxylic acid [REx(6-3)]:

(308) To a solution of the compound obtained in the above (2) (1.20 g) in ethanol (10 mL) was added 2-normal aqueous sodium hydroxide solution (4.26 mL) under ice-cooling, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated, and then the mixture was acidified by adding 2-normal hydrochloric acid under ice-cooling, and then thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, and then concentrated under reduced pressure to give 3-chloro-1-(3-methoxypropyl)-1H-indole-6-carboxylic acid [REx(6-3)] (1.14 g) as a colorless powder.

(309) ESI-MS m/z: 266/268[MH].sup..

(310) (4) 3-Chloro-N-methoxy-1-(3-methoxypropyl)-N-methyl-1H-indole-6-carboxamide [REx(6-4)]:

(311) To a solution of the compound obtained in the above (3) (1.14 g), N,O-dimethylhydroxyamine hydrochloride (831 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.25 g) and 1-hydroxybenzotriazole (863 mg) in chloroform (12 mL) was added diisopropylethylamine (1.85 mL) under ice-cooling, and then the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added aqueous saturated sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with chloroform. The organic layer was sequentially washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1.fwdarw.1/3) to give 3-chloro-N-methoxy-1-(3-methoxypropyl)-N-methyl-1H-indole-6-carboxamide [REx(6-4)] (1.20 g) as a pale yellow oil.

(312) APCI-MS m/z: 311/313 [M+H].sup.+.

(313) (5) 1-[3-Chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethanone [REx(6-5)]:

(314) To a solution of the compound obtained in the above (4) (1.20 g) in tetrahydrofuran (15 mL) was added dropwise a 3M solution of methylmagnesium bromide in diethyl ether (2.56 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction solution was added 1-normal hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, and then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1.fwdarw.1/1) to give 1-[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethanone [REx(6-5)] (945 mg) as a pale yellow oil.

(315) APCI-MS m/z: 266/268 [M+H].sup.+.

(316) (6) N-{1-[3-Chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethyl}cyclopropanamine [REx(6-6)]:

(317) To a solution of the compound obtained in the above (5) (155 mg) and cyclopropylamine (99.9 mg) in dichloroethane (3.0 mL) were added magnesium sulfate (351 mg), sodium triacetoxyborohydride (371 mg) and acetic acid (105 mg), and then the mixture was stirred at room temperature for 17 hours. To the reaction mixture was added aqueous saturated sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate.fwdarw.ethyl acetate/methanol=20/1) to give N-{1-[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethyl}cyclopropanamine [REx(6-6)] (111 mg) as a pale yellow oil.

(318) APCI-MS m/z: 307/309 [M+H].sup.+.

Reference Example 7

(319) ##STR00351## ##STR00352##
(1) Ethyl 4-(acetyloxy)benzofuran-6-carboxylate:

(320) To a suspension of 60% oil-based sodium hydride (6.50 g) in tetrahydrofuran (400 mL) was added dropwise a solution of 4-tert-butyl 1-ethyl 2-(diethoxyphosphoryl)succinate (55.0 g) in tetrahydrofuran (100 mL) under ice-cooling over 30 minutes, and then the mixture was stirred under the cooling for 1 hour. Then, thereto was added a solution of 2-furaldehyde (12.8 mL) in tetrahydrofuran (40 mL) under ice-cooling over 15 minutes, and the mixture was stirred at room temperature for 1 hour. Ice water was poured into the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure to give 4-tert-butyl 1-ethyl (2E)-2-(2-furylmethylene)succinate (47.0 g) as a brown oil crude. Then, the oil (47.0 g) was stirred in trifluoroacetic acid (100 mL) at room temperature for 1 hour, and then concentrated under reduced pressure. The resulting residue was treated azeotropically with toluene several times to give (3E)-3-(ethoxycarbonyl)-4-(2-furyl)-but-3-enoic acid (39.2 g) as a brown oil crude. Then, the oil (39.2 g) was dissolved in acetic anhydride (100 mL), and thereto was added potassium acetate (19.8 g), and then the mixture was heated to reflux for 45 minutes. The reaction mixture was let stand to be cooled, and then thereto was added water (100 mL), and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to give ethyl 4-(acetyloxy)benzofuran-6-carboxylate (24.7 g) as a pale orange solid. APCI-MS m/z: 266[M+NH.sub.4].sup.+.

(321) (2) Ethyl 4-hydroxy-1-benzofuran-6-carboxylate [REx(7-1)]:

(322) To a solution of the compound obtained in the above (1) (24.7 g) in ethanol (150 mL) was added potassium carbonate (42.0 g), and the mixture was heated to reflux for 30 minutes. The reaction mixture was ice-cooled, and then acidified by 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with n-hexane-dichloromethane (5:1) to give ethyl 4-hydroxy-1-benzofuran-6-carboxylate [REx(7-1)] (19.6 g) as a pale yellow powder.

(323) APCI-MS m/z: 207 [M+H].sup.+.

(324) (3) Ethyl 4-(3-methoxypropoxy)-1-benzofuran-6-carboxylate [REx(7-2)]:

(325) To a solution of the compound obtained in the above (2) (5.0 g) in acetonitrile (50 mL) were added potassium carbonate (5.0 g) and 1-bromo-3-methoxypropane (4.54 g), and the mixture was heated to reflux for 1.5 hours. To the reaction mixture was added water under ice-cooling, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1.fwdarw.2/1) to give ethyl 4-(3-methoxypropoxy)-1-benzofuran-6-carboxylate [REx(7-2)] (6.61 g) as a colorless oil.

(326) APCI-MS m/z: 279 [M+H].sup.+.

(327) (4) 4-(3-Methoxypropoxy)-1-benzofuran-6-carboxylic acid [REx(7-3)]:

(328) To a solution of the compound obtained in the above (3) (2.64 g) in ethanol (20 mL) was added 2-normal aqueous sodium hydroxide solution (9.5 mL), and the mixture was stirred at room temperature for 3 hours. Then, thereto was added 2-normal hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure to give 4-(3-methoxypropoxy)-1-benzofuran-6-carboxylic acid [REx(7-3)] (2.40 g) as a colorless powder.

(329) APCI-MS m/z: 265 [M+H+MeOHH.sub.2O].sup.+.

(330) (5) N-Methoxy-4-(3-methoxypropoxy)-N-methyl-1-benzofuran-6-carboxamide [REx(7-4)]:

(331) To a solution of the compound obtained in the above (4) (2.39 g), N,O-dimethylhydroxyamine.hydrochloride (1.86 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.74 g) and 1-hydroxybenzotriazole (1.93 g) in chloroform (30 mL) was added diisopropylethylamine (4.2 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. Under ice-cooling, to the reaction mixture was added aqueous saturated sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was sequentially washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1.fwdarw.1/3) to give N-methoxy-4-(3-methoxypropoxy)-N-methyl-1-benzofuran-6-carboxamide [REx(7-4)] (2.67 g) as a pale yellow oil.

(332) APCI-MS m/z: 294 [M+H].sup.+.

(333) (6) 1-[4-((3-Methoxypropoxy)-1-benzofuran-6-yl]ethanone [REx(7-5)]:

(334) To a solution of the compound obtained in the above (5) (2.67 g) in tetrahydrofuran (30 mL) was added dropwise a 3M solution of methylmagnesium bromide in diethyl ether (6.1 mL) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. Under ice-cooling, 10% hydrochloric acid was poured into the mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, and then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1.fwdarw.1/1) to give 1-[4-((3-methoxypropoxy)-1-benzofuran-6-yl]ethanone [REx(7-5)] (2.15 g) as a colorless powder.

(335) APCI-MS m/z: 249 [M+1-1].sup.+.

(336) (7) N-{1-[4-(3-Methoxypropoxy)-1-benzofuran-6-yl]ethyl}cyclopropanamine [REx(7-6)]:

(337) To a solution of the compound obtained in the above (6) (2.15 g) and cyclopropylamine (2.10 mL) in dichloroethane (150 mL) were added sodium triacetoxyborohydride (5.50 g), acetic acid (1.48 mL) and magnesium sulfate (5.20 g), and then the mixture was stirred at room temperature for 23 hours. Thereto was added aqueous saturated sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1.fwdarw.13/1) to give N-{1-[4-(3-methoxypropoxy)-1-benzofuran-6-yl]ethyl}cyclopropanamine [REx(7-6)] (2.47 g) as a pale yellow oil.

(338) APCI-MS m/z: 290 [M+H].sup.+.

Reference Example 8

(339) ##STR00353##
(1) 1-(6-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone [REx(8-1)]:

(340) To a solution of 6-methyl-1H-pyrrolo[2,3-b]pyridine (500 mg) in dichloroethane (6 mL) were added aluminum chloride (1.09 g) and acetyl chloride (0.40 mL), and then the mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into aqueous saturated sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with isopropyl ether to give 1-(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone [REx(8-1)] (481 mg) as a yellow powder.

(341) APCI-MS m/z: 175 [M+H].sup.+.

(342) (2) 1-[1-(4-Methoxybutyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]ethanone [REx(8-2)]:

(343) To a solution of the compound obtained in the above (1) (280 mg) in N,N-dimethylformamide (6 mL) was added 60% oil-based sodium hydride (83.6 mg), and then the mixture was stirred at room temperature for 30 minutes. Thereto was added dropwise a solution of 4-methoxybutyl 4-methylbenzenesulfonate in N,N-dimethylformamide (1 mL), and then thereto was added potassium iodide (267 mg), and the mixture was stirred at 50 C. for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with water twice and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1.fwdarw.1/9) to give 1-[1-(4-methoxybutyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]ethanone [REx(8-2)] (366 mg) as a yellow oil.

(344) APCI-MS m/z: 261 [M+H].sup.+.

(345) (3) An amine compound [REx(8-3)] is obtained in the similar manner to Reference Example 7(7).

Reference Example 9

1-[1-(3-Methoxypropyl)-3-methyl-1H-indol-6-yl]ethanone [REx(9-1)]

(346) ##STR00354##

(347) To a solution of 1-[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethanone (843 mg) in 1,4-dioxane (15 mL) were added potassium phosphate (1.35 g), trimethylboroxine (883 mg), tris(dibenzylideneacetone)dipalladium (290 mg) and 2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl (X-Phos) (605 mg) under argon, and the mixture was heated to stir at 110 C. for 4 hours. Thereto was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1.fwdarw.3/2) to give 1-[1-(3-methoxypropyl)-3-methyl-1H-indol-6-yl]ethanone [REx(9-1)] (663 mg) as a yellow oil.

(348) APCI-MS m/z: 246 [M+H].sup.+.

Reference Example 10

Methyl 1-(3-methoxypropyl)indoline-6-carboxylate [REx(10-1)]

(349) ##STR00355##

(350) To a mixture of methyl 1-(3-methoxypropyl)-1H-indole-6-carboxylate (1.5 g) and sodium cyanohydroborate (1.61 g) was added acetic acid (15 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added aqueous saturated sodium hydrogen carbonate solution under ice-cooling, and the mixture was neutralized by adding sodium hydrogen carbonate, and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane.fwdarw.n-hexane/ethyl acetate=2/1) to give methyl 1-(3-methoxypropyl)indoline-6-carboxylate [REx(10-1)] (1.20) as a pale yellow oil.

(351) APCI-MS m/z: 250 [M+H].sup.+.

Reference Example 11

6-(3-Methoxypropoxy)indan-1-one [REx(11-1)]

(352) ##STR00356##

(353) To a solution of 6-hydroxyindan-1-one (1.48 g) in acetonitrile (30 mL) were added 4-methoxybutyl 4-methylbenzenesulfonate (2.93 g), potassium iodide (166 mg) and potassium carbonate (2.07 g), and the mixture was heated to stir at 80 C. for 5 hours. To the reaction mixture was added water under ice-cooling, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=7/3), and then triturated with n-hexane/isopropyl ether (2:1) to give 6-(3-methoxypropoxy)indan-1-one [REx(11-1)] (1.1 g) as a colorless powder.

(354) APCI-MS m/z: 221 [M+H].sup.+.

Reference Example 12

7-(3-Methoxypropoxy)-3,4-dihydronaphthalen-1(2H)-one [REx(12-1)]

(355) ##STR00357##

(356) To a solution of 7-hydroxy-1-tetralone (4.05 g) in acetonitrile (75 mL) were added 1-bromo-3-methoxypropane (4.59 g), potassium iodide (415 mg) and potassium carbonate (5.18 g), and the mixture was heated to stir at 80 C. for 23 hours. To the reaction mixture was added water under ice-cooling, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with n-hexane to give 7-(3-methoxypropoxy)-3,4-dihydronaphthalen-1(2H)-one [REx(12-1)] (4.80 g) as a colorless powder.

(357) APCI-MS m/z: 235 [M+H].sup.+.

Reference Example 13

N-(2-Methoxyethyl)-3-oxoindan-5-carboxamide [REx(13-1)]

(358) ##STR00358##

(359) To a suspension of 1-indanone-6-carboxylic acid (1.76 g) in N,N-dimethylformamide (50 mL) was added carbonyldiimidazole (3.24 g), and the mixture was stirred at room temperature for 1 hour. Thereto was added a solution of 2-methoxyethylamine (3.76 g) in dichloromethane (50 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and then dissolved in chloroform. The organic layer was washed with aqueous saturated sodium hydrogen carbonate solution, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (20 mL), and then thereto was added 1-normal hydrochloric acid (20 mL), and the mixture was stirred at room temperature for 12 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with isopropyl ether-ethyl acetate (2:1) to give N-(2-methoxyethyl)-3-oxoindan-5-carboxamide [REx(13-1)] (1.87 g) as a brown powder.

(360) APCI-MS m/z: 234 [M+H].sup.+.

Reference Example 14

(361) ##STR00359##
(1) Methyl 3-iodo-4-methyl-5-nitrobenzoate [REx(14-1)]:

(362) To a suspension of methyl 3-amino-4-methyl-5-nitrobenzoate (36.0 g) in 6-normal hydrochloric acid (276 mL) was added dropwise a solution of sodium nitrite (13.0 g) in water (35 mL) under ice-salt-cooling over 20 minutes, and the mixture was stirred under ice-cooling for 1 hour. Then, thereto was added dropwise a solution of potassium iodide (34.1 g) in water (280 mL) under ice-cooling over 20 minutes, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added water under ice-cooling, and the mixture was extracted with chloroform. The organic layer was sequentially washed with aqueous saturated sodium thiosulfate solution and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=50/1) to give methyl 3-iodo-4-methyl-5-nitrobenzoate [REx(14-1)] (40.5 g) as a yellow powder.

(363) (2) Methyl 3-amino-5-iodo-4-methylbenzoate [REx(14-2)]:

(364) To a solution of the compound obtained in the above (1) (40.5 g) in ethyl acetate (500 mL) was added tin (II) chloride dihydrate (142 g), and the mixture was heated to stir at 60 C. for 1 hour. Aqueous sodium hydrogen carbonate solution was poured into the reaction mixture under ice-cooling, and then an insoluble was filtered through Celite. The organic layer was separated, and then washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure to give methyl 3-amino-5-iodo-4-methylbenzoate [REx(14-2)] (35.3 g) as a pale yellow powder.

(365) APCI-MS m/z: 292 [M+H].sup.+.

(366) (3) Methyl 4-iodo-1H-indazole-6-carboxylate [REx(14-3)]:

(367) To a suspension of the compound obtained in the above (2) (35.3 g) in water (615 mL) were added concentrated hydrochloric acid (102 mL) and ammonium tetrafluoroborate (16.5 g), and the mixture was cooled to 3 C. Under the cooling, thereto was added dropwise a solution of sodium nitrite (9.20 g) in water (34 mL) over 20 minutes. The mixture was stirred at 3 C. for 1 hour, and then the precipitated crystal was filtered, sequentially washed with water (100 mL) and diethyl ether (100 mL), and then dried under reduced pressure. The resulting solid was suspended in chloroform (420 mL), and then thereto were added potassium acetate (13.1 g) and 18-crown-6 (801 mg), and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added water under ice-cooling, and then the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with chloroform to give methyl 4-iodo-1H-indazole-6-carboxylate [REx(14-3)] (18.9 g) as a pale orange powder.

(368) APCI-MS m/z: 303 [M+H].sup.+.

(369) (4) Methyl 3-bromo-4-iodo-1H-indazole-6-carboxylate [REx(14-4)]:

(370) The compound obtained in the above (3) (24.5 g) was dissolved in acetic acid (720 mL), and after blocking out light, bromine (8.30 mL) was added dropwise to the mixture at room temperature. After stirring at room temperature for 40 hours, bromine (4.15 mL) was added thereto, and the mixture was stirred for additional 24 hours at room temperature. Then, thereto were added acetic acid (100 mL) and bromine (4.15 mL), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into ice water, and then thereto was added sodium thiosulfate, and the mixture was stirred at room temperature for 20 minutes, and then the precipitated solid was filtered. The solid was washed with water, and then dissolved in ethyl acetate and washed with saturated saline. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with isopropyl ether to give methyl 3-bromo-4-iodo-1H-indazole-6-carboxylate [REx(14-4)] (27.3 g) as a pale yellow powder.

(371) APCI-MS m/z: 381/383 [M+H].sup.+.

(372) (5) Methyl 3-bromo-4-iodo-1-(3-methoxypropyl)-1H-indazole-6-carboxylate [REx(14-5)]:

(373) To a solution of the compound obtained in the above (4) (22.3 g) in N,N-dimethylformamide (200 mL) was added 60% oil-based sodium hydride (2.81 g) under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. To the mixture was added a solution of 1-bromo-3-methoxypropane (10.8 g) in N,N-dimethylformamide (40 mL) under ice-cooling, and the mixture was stirred at room temperature for 18 hours. 10% Hydrochloric acid was poured into the reaction solution under ice-cooling, and then the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1) to give methyl 3-bromo-4-iodo-1-(3-methoxypropyl)-1H-indazole-6-carboxylate [REx(14-5)] (23.5 g) as a pale orange powder.

(374) APCI-MS m/z: 453/455 [M+H].sup.+.

Reference Example 15

1-[4-Chloro-1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethanone [REx(15-1)]

(375) ##STR00360##

(376) To a solution of 1-[3-bromo-4-chloro-1-(3-methoxypropyl)-1H-indazol-6-yl]ethanone (1.0 g) in 1,4-dioxane (20 mL) were added potassium carbonate (1.2 g), trimethylboroxine (0.41 mL) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (II) (212 mg) under argon, and the mixture was heated to stir at 80 C. for 24 hours. Then, thereto was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1.fwdarw.3/2) to give 1-[4-chloro-1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethanone [REx(15-1)] (392 mg) as a pale yellow oil.

(377) APCI-MS m/z: 281/283 [M+H].sup.+.

Reference Example 16

1-[1-(3-Methoxypropyl)-3,4-dimethyl-1H-indazol-6-yl]ethanone [REx(16-1)]

(378) ##STR00361##

(379) To a solution of 1-[3-bromo-4-chloro-1-(3-methoxypropyl)-1H-indazol-6-yl]ethanone (1.0 g) in 1,4-dioxane (7.5 mL) were added potassium carbonate (1.2 g), trimethylboroxine (1.0 mL) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (II) (212 mg) under argon, and the mixture was heated to stir at 110 C. for 24 hours. Then, thereto was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1.fwdarw.1/1) to give 1-[1-(3-methoxypropyl)-3,4-dimethyl-1H-indazol-6-yl]ethanone [REx(16-1)] (689 mg) as an orange oil.

(380) APCI-MS m/z: 261 [M+H].sup.+.

Reference Example 17

1-[3-Bromo-1-(3-methoxypropyl)-4-(trifluoromethyl)-1H-indazol-6-yl]ethanone [REx(17-1)]

(381) ##STR00362##

(382) A mixture of 1-[3-bromo-4-iodo-1-(3-methoxypropyl)-1H-indazol-6-yl]ethanone (500 mg), methyl fluorosulfonyldifluoroacetate (1.36 g), hexamethylphosphorylamide (1.27 g) and copper (I) iodide (337 mg) was heated to stir in N,N-dimethylformamide (7.0 mL) under argon at 75 C. for 15 hours. Water and ethyl acetate were poured into the reaction mixture under ice-cooling, and then an insoluble was filtered through Celite. The organic layer was separated, and then sequentially washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane.fwdarw.n-hexane/ethyl acetate=1/1) to give 1-[3-bromo-1-(3-methoxypropyl)-4-(trifluoromethyl)-1H-indazol-6-yl]ethanone [REx(17-1)] (87 mg) as a yellow oil.

(383) APCI-MS m/z: 379/381 [M+H].sup.+.

Reference Example 18

(384) ##STR00363##
(1) Methyl 1-(3-methoxypropyl)-1H-indazole-6-carboxylate [REx(18-1)]:

(385) To a solution of methyl 3-bromo-1-(3-methoxypropyl)-1H-indazole-6-carboxylate (3.0 g) and diisopropylethylamine (2.4 mL) in methanol (60 mL) was added 10% palladium on carbon catalyst (600 mg), and the mixture was stirred under hydrogen for 1 hour. An insoluble was filtered, and then the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, sequentially washed with 10% hydrochloric acid water and saturated saline, and then concentrated under reduced pressure to give methyl 1-(3-methoxypropyl)-1H-indazole-6-carboxylate [REx(18-1)] (2.40 g) as a pale yellow oil.

(386) (2) Methyl 3-fluoro-1-(3-methoxypropyl)-1H-indazole-6-carboxylate [REx(18-2)]:

(387) To a solution of the compound obtained in the above (1) (2.20 g) in acetonitrile (30 mL) was added Selectfluor (Registered trademark) (3.45 g), and the mixture was stirred at 80 C. for 15 hours. Then, thereto was added aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane.fwdarw.n-hexane/ethyl acetate=5/1) to give methyl 3-fluoro-1-(3-methoxypropyl)-1H-indazole-6-carboxylate [REx(18-2)] (1.01 g) as a colorless oil.

(388) APCI-MS m/z: 267 [M+H].sup.+.

Reference Example 19

1-[3-Fluoro-5-(3-methoxypropoxy)phenyl]ethanone [REx(19-2)]

(389) ##STR00364##

(390) 1-Bromo-3-fluoro-5-(3-methoxypropoxy)benzene (4.0 g) was added to water (30.4 mL), and then thereto were added ethylene glycol monovinyl ether (6.8 mL), potassium carbonate (2.52 g), 1,3-bis(diphenylphosphino)propane (125 mg) and palladium acetate (34 mg), and the mixture was heated to stir at 90 C. for 22 hours. After cooling, thereto was added concentrated hydrochloric acid (7.2 mL), and the mixture was stirred at room temperature for 20 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and then dried over magnesium sulfate. After concentrating under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1.fwdarw.2/1) to give 1-[3-fluoro-5-(3-methoxypropoxy)phenyl]ethanone [REx(19-2)] (1.03 g) as a yellow oil.

(391) APCI-MS m/z: 227 [M+H].sup.+.

(392) A starting material is prepared from 1-bromo-3-fluoro-phenol, for example, in the similar manner to Reference Example 11 or 12.

Reference Example 20

1-[3-Hydroxy-5-(3-methoxypropoxy)phenyl]ethanone [REx(20-1)]

(393) ##STR00365##

(394) To a solution of 1-(3,5-dihydroxyphenyl)ethanone (10 g) in N,N-dimethylformamide (164 mL)-water (5 mL) were added potassium carbonate (13.6 g) and 3-methoxypropyl 4-methylbenzene sulfonate (16.1 g), and the mixture was heated to stir at 80 C. for 2 hours. The reaction solution was concentrated under reduced pressure, and then thereto was added water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1.fwdarw.1/1) to give 1-[3-hydroxy-5-(3-methoxypropoxy)phenyl]ethanone [REx(20-1)] (4.65 g) as a colorless powder and 1-[3,5-bis(3-methoxypropoxy)phenyl]ethanone [REx(20-2)] (4.98 g) as a colorless oil.

(395) 2: APCI-MS m/z: 225 [M+H].sup.+.

(396) 3: APCI-MS m/z: 297 [M+H].sup.+.

Reference Example 21

(397) ##STR00366##
(1) 3-Acetyl-5-(3-methoxypropoxy)phenyltrifluoromethanesulfonate [REx(21-1)]:

(398) To a solution of 1-[3-hydroxy-5-(3-methoxypropoxy)phenyl]ethanone (4.65 g) in chloroform (100 mL) was added pyridine (5.02 mL) under ice-cooling, and then thereto was added dropwise trifluoromethanesulfonic anhydride (3.67 mL) under the ice-cooling, and then the mixture was stirred at the same temperature for 20 minutes. Then, thereto was added 1-normal hydrochloric acid, and the mixture was extracted with chloroform, and then the organic layer was sequentially washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure to give a crude product of 3-acetyl-5-(3-methoxypropoxy)phenyltrifluoromethanesulfonate [REx(21-1)] (8.22 g) as a yellow oil.

(399) APCI-MS m/z: 374[M+NH.sub.4].sup.+.

(400) (2) 1-[3-(3-Methoxypropoxy)-5-methylphenyl]ethanone [REx(21-2)]:

(401) To a solution of the compound obtained in the (1) (8.22 g) in 1,4-dioxane (100 mL) were added potassium carbonate (8.6 g), trimethylboroxine (3.5 mL) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (II) (1.51 g), and the mixture was heated to stir at 110 C. for 2 hours. After cooling to room temperature, thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane.fwdarw.n-hexane/ethyl acetate=5/1) to give 1-[3-(3-methoxypropoxy)-5-methylphenyl]ethanone [REx(21-2)] (4.15 g) as a brown oil.

(402) APCI-MS m/z: 223 [M+H].sup.+.

Reference Example 22

(403) ##STR00367##
(1) 1-(4-Chloro-3,5-dimethoxyphenyl)ethanol [REx(22-1)]:

(404) To a solution of 4-chloro-3,5-dimethoxybenzaldehyde (1.0 g) in tetrahydrofuran (20 mL) was added dropowise a 3M solution of methylmagnesium bromide in diethyl ether (1.83 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Then, thereto was added aqueous ammonium chloride solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, and then dried over magnesium sulfate and concentrated under reduced pressure to give a crude product of 1-(4-chloro-3,5-dimethoxyphenyl)ethanol [REx(22-1)] (1.23 g) as a colorless powder.

(405) APCI-MS m/z: 200 [M+HH.sub.2O].sup.+.

(406) (2) 1-(4-Chloro-3,5-dimethoxyphenyl)ethanone [REx(22-2)]:

(407) To a solution of the compound obtained in the above (1) (1.23 g) in dichloromethane (28 mL) was added 85% activated manganese dioxide (5.81 g), and the mixture was stirred at 40 C. for 4 hours. The reaction solution was cooled to room temperature, and then thereto was added water-chloroform, and an insoluble was filtered off through Celite, and then the organic layer was separated. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1.fwdarw.1/1) to give 1-(4-chloro-3,5-dimethoxyphenyl)ethanone [REx(22-2)] (723 mg) as a colorless powder.

(408) APCI-MS m/z: 215 [M+H].sup.+.

Reference Example 23

(409) ##STR00368##
(1) 6-(1-Ethoxyvinyl)-1-(3-methoxypropyl)-1H-pyrrolo[3,2-b]pyridine [REx(23-2)]:

(410) To a solution of 6-bromo-1-(3-methoxypropyl)-1H-pyrrolo[3,2-b]pyridine (1.5 g) in toluene (30 mL) were added tri-n-butyltin-1-ethoxyvinyl (5.65 mL) and dichlorobis-(triphenylphosphine)palladium (II) (782 mg), and the mixture was heated to stir at 110 C. for 30 minutes. The reaction solution was cooled to room temperature, and then thereto was added water-ethyl acetate, and an insoluble was filtered through Celite. The organic layer was separated, and then washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1.fwdarw.1/1) to give 6-(1-ethoxyvinyl)-1-(3-methoxypropyl)-1H-pyrrolo[3,2-b]pyridine [REx(23-2)] (1.69 g) as a yellow oil.

(411) A starting compound [REx(23-1)] is obtained by 3-methoxypropylation at N of 6-bromo-1-1H-pyrrolo[3,2-b]pyridine.

(412) APCI-MS m/z: 261 [M+H].sup.+.

(413) (2) 1-[1-(3-Methoxypropyl)-1H-pyrrolo[3,2-b]pyridin-6-yl]ethanone [REx(23-3)]:

(414) The compound obtained in the above (1) (1.69 g) was dissolved in chloroform (20 mL), and then thereto was added 4-normal hydrogen chloride/1,4-dioxane under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. Then, thereto was added aqueous saturated sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1.fwdarw.1/1) to give 1-[1-(3-methoxypropyl)-1H-pyrrolo[3,2-b]pyridin-6-yl]ethanone [REx(23-3)] (766 mg) as a yellow oil.

(415) APCI-MS m/z: 233 [M+H].sup.+.

Reference Example 24

1-[4-Methoxy-3-(4-methoxybutyl)phenyl]ethanone [REx(24-1)]

(416) ##STR00369##

(417) To a solution of 4-bromo-1-methoxy-2-(4-methoxybutyl)benzene (523 mg) in tetrahydrofuran (10 mL) were added lithium chloride (326 mg), tetrakis(triphenylphosphine)palladium (0) (381 mg) and tri-n-butyltin-1-ethoxyvinyl (1.11 mL), and the mixture was heated to stir at 80 C. for 20 hours. The reaction solution was cooled to room temperature, and then thereto was added aqueous potassium fluoride solution, and the mixture was stirred for 30 minutes. The mixture was extracted with diethyl ether, and then thereto was added 10% hydrochloric acid, and the mixture was stirred for 1 hour. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1.fwdarw.1/1) to give 1-[4-methoxy-3-(4-methoxybutyl)phenyl]ethanone [REx(24-1)] (195 mg) as a yellow oil.

(418) APCI-MS m/z: 237 [M+H].sup.+.

Reference Example 25

(419) ##STR00370##
(1) tert-Butyl 1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(25-1)]:

(420) To a solution of tert-butyl 1H-pyrrolo[3,2-c]pyridine-6-carboxylate (2.0 g) in N,N-dimethylformamide (15 mL) was added drop by drop 60% oil-based sodium hydride (385 mg) under ice-cooling, and then the mixture was stirred at room temperature for 15 minutes. Then, thereto was added dropwise a solution of 1-bromo-3-methoxypropane (1.47 g) in N,N-dimethylformamide (5 mL) under ice-cooling, and then the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to give tert-butyl 1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(25-1)] (2.52 g) as a yellow oil.

(421) APCI-MS m/z: 291 [M+H].sup.+.

(422) (2) tert-Butyl 3-chloro-1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(25-2)]:

(423) To a solution of the compound obtained in the above (1) (2.52 g) in dichloromethane (50 mL) was added N-chlorosuccinimide (1.50 g) under ice-cooling, and the mixture was stirred at room temperature for 72 hours. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1) to give tert-butyl 3-chloro-1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(25-2)] (2.45 g) as a colorless powder.

(424) APCI-MS m/z: 325/327 [M+H].sup.+.

(425) (3) 3-Chloro-1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid. hydrochloride [REx(25-3)]:

(426) The compound obtained in the above (2) (2.42 g) was added to trifluoroacetic acid (24 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 1-normal hydrochloric acid water (15 mL) under ice-cooling, and then the mixture was concentrated under reduced pressure. The resulting residue was triturated with isopropyl ether to give 3-chloro-1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid hydrochloride [REx(25-3)] (2.20 g) as a brown powder.

(427) ESI-MS m/z: 267/269[MH].sup..

Reference Example 26

(428) ##STR00371##
(1) 1-[4-(Benzyloxy)-3-hydroxyphenyl]ethanone [REx(26-1)]:

(429) To a solution of 3,4-dihydroxyacetophenone (25.4 g) in N,N-dimethylacetamide (420 mL) were added potassium carbonate (23.1 g) and benzyl bromide (19.9 mL) under ice-cooling, and the mixture was stirred at room temperature for 90 minutes. An insoluble was filtered, and then diluted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane.fwdarw.n-hexane/ethyl acetate=20/1), and then triturated with ethyl acetate to give 1-[4-(benzyloxy)-3-hydroxyphenyl]ethanone [REx(26-1)] (11.0 g) as a colorless powder.

(430) APCI-MS m/z: 243 [M+H].sup.+.

(431) (2) 1-[4-(Benzyloxy)-3-(3-methoxypropyl)phenyl]ethanone [REx(26-2)]:

(432) To a solution of the compound obtained in the above (1) (11.0 g) in acetonitrile (113 mL) were added potassium carbonate (9.37 g) and 3-methoxypropyl 4-methylbenzene sulfonate (13.2 g), and the mixture was heated to reflux for 20 hours. The reaction solution was cooled to room temperature, and then thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with diisopropyl ether to give 1-[4-(benzyloxy)-3-(3-methoxypropyl)phenyl]ethanone [REx(26-2)] (8.75 g) as a colorless powder.

(433) APCI-MS m/z: 315 [M+H].sup.+.

Reference Example 27

(434) ##STR00372##
(1) 4-Bromo-2-(3-methoxypropoxy)benzoic acid [REx(27-1)]:

(435) To a solution of 3-methoxy-1-propanol (5.02 g) in N,N-dimethylformamide (37 mL) was added 60% oil-based sodium hydride (2.05 g), and the mixture was stirred at room temperature for 30 minutes. Then, thereto was added dropwise a solution of 4-bromo-2-fluorobenzoic acid (300 mg) in N,N-dimethylformamide (60 mL), and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added water and n-hexane, and then the mixed solution was acidified by concentrated hydrochloric acid. The resulting colorless powder was filtered to give 4-bromo-2-(3-methoxypropoxy)benzoic acid [REx(27-1)] (4.43 g).

(436) ESI-MS m/z: 289[MH].

(437) (2) Methyl 4-bromo-2-(3-methoxypropoxy)benzoate [REx(27-2)]:

(438) To a mixture of the compound obtained in the above (1) (4.42 g) and potassium carbonate (4.22 g) was added N,N-dimethylformamide (20 mL), and then thereto was added methyl iodide (1.43 mL), and the mixture was stirred at room temperature for 30 minutes. After cooling, to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water twice and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1.fwdarw.3/1) to give methyl 4-bromo-2-(3-methoxypropoxy)benzoate [REx(27-2)] (4.01 g) as a colorless oil.

(439) APCI-MS m/z: 343/305 [M+H].sup.+.

(440) (3) Methyl 4-acetyl-2-(3-methoxypropoxy)benzoate [REx(27-3)]:

(441) To a solution of the compound obtained in the above (2) (4.0 g) in toluene (44 mL) were added tri-n-butyltin-1-ethoxyvinyl (8.90 mL) and dichlorobis(triphenylphosphine)palladium (II) (1.85 g), and the mixture was heated to stir at 100 C. for 17 hours. The reaction solution was cooled to room temperature, and then thereto was added 4-normal hydrogen chloride-1,4-dioxane (24 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, and then thereto were added magnesium sulfate and NH-silica gel, and an insoluble was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1) to give methyl 4-acetyl-2-(3-methoxypropoxy)benzoate [REx(27-3)] (1.02 g) as a yellow oil.

(442) APCI-MS m/z: 267 [M+H].sup.+.

Reference Example 28

(443) ##STR00373##
(1) N-[(1E)-1H-Pyrrolo[2,3-b]pyridin-3-ylmethylene]cyclopropylamine [REx(28-1)]:

(444) To a suspension of 1H-pyrrolo[2,3-b]pyridin-3-carbaldehyde (1.46 g) in ethanol (30 mL) was added cyclopropylamine (1.41 mL), and the mixture was stirred at 50 C. for 19 hours. The reaction solution was concentrated under reduced pressure, and then treated azeotropically with toluene. The resulting residue was triturated with isopropyl ether/n-hexane (3:1) to give N-[(1E)-1H-pyrrolo[2,3-b]pyridin-3-ylmethylene]cyclopropylamine [REx(28-1)] (1.75 g) as a colorless powder.

(445) APCI-MS m/z: 186 [M+H].sup.+.

(446) (2) N-[1-(1H-Pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropylamine [REx(28-2)]:

(447) To a suspension of the compound obtained in the above (1) (1.11 g) and 1-(trimethylsilyl)-1H-benzotriazole (2.20 mL) in toluene (50 mL) was added dropwise a 3M solution of methylmagnesium bromide in diethyl ether (10 mL) under ice-cooling over 10 minutes, and the mixture was stirred at 110 C. for 6 hours. The reaction solution was poured into ice-cooled ammonium chloride solution, and extracted with ethyl acetate. An insoluble was filtered, and then the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layers were collected, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and extracted with 10% aqueous citric acid solution. The aqueous layer was alkalified by aqueous potassium carbonate solution, and then extracted with chloroform. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure to give a crude product of N-[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropylamine [REx(28-2)] (800 mg) as a yellow oil.

(448) (3) tert-Butyl cyclopropyl[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]carbamate [REx(28-3)]:

(449) To a solution of the compound obtained in the above (2) (800 mg) and potassium carbonate (1.10 g) in tetrahydrofuran (10 mL)-water (10 mL) was added a solution of di-t-butyl dicarbonate (786 mg) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 6 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (20 mL), and then thereto were added sodium hydroxide (320 mg) and tetrabutylammonium hydrogen sulfate (68 mg), and the mixture was stirred at 50 C. for 30 minutes. The reaction solution was cooled, and then an insoluble was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1.fwdarw.1/3) to give tert-butyl cyclopropyl[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]carbamate [REx(28-3)] (338 mg) as a pale yellow oil.

(450) APCI-MS m/z: 302 [M+H].sup.+.

(451) (4) tert-Butyl {1-[1-(3-aminopropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]ethyl}-cyclopropylcarbamate [REx(28-4)]:

(452) To a solution of the compound obtained in the above (3) (301 mg) in acetonitrile (10 mL) were added sodium hydroxide (300 mg) and tetrabutylammonium hydrogen sulfate (17 mg), and the mixture was stirred at room temperature for 15 minutes. Then, thereto was added 3-chloropropylamine hydrochloride (650 mg), and the mixture was stirred at 70 C. for 4 hours. The reaction solution was cooled, and then an insoluble was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and sequentially washed with water and saturated saline. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure to give a crude product of tert-butyl {1-[1-(3-aminopropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]ethyl}cyclopropylcarbamate [REx(28-4)] (378 mg) as a yellow oil.

(453) APCI-MS m/z: 359 [M+H].sup.+.

(454) (5) Methyl [3-(3-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-1H-pyrrolo[2,3-b]pyridin-1-yl)propyl]carbamate [REx(28-5)]:

(455) To a solution of the compound obtained in the above (4) (370 mg) in chloroform (10 mL) were added pyridine (0.25 mL) and methyl chloroformate (0.16 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and then treated azeotropically with toluene. The resulting residue was dissolved in chloroform, and washed with 1-normal aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1.fwdarw.ethyl acetate) to give methyl [3-(3-{1-[(tert-butoxycarbonyl)-(cyclopropyl)amino]ethyl}-1H-pyrrolo[2,3-b]pyridin-1-yl)propyl]carbamate [REx(28-5)] (203 mg) as a colorless oil.

(456) APCI-MS m/z: 417 [M+H].sup.+.

(457) (6) Methyl (3-{3-[1-(cyclopropylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-1-yl}propyl)carbamate [REx(28-6)]:

(458) To a solution of the compound obtained in the above (5) (187 mg) and 2,6-lutidine (0.157 mL) in dichloromethane (4 mL) was added trimethylsilyltriflate (0.180 L) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Then, thereto were added aqueous saturated sodium hydrogen carbonate solution and methanol (2 mL) under ice-cooling, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform.fwdarw.chloroform/methanol=5/1.fwdarw.chloroform/methanol/ammonia water=50/10/1) to give methyl (3-{3-[1-(cyclopropylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-1-yl}propyl)carbamate [REx(28-6)] (89 mg) as a colorless oil.

Reference Example 29

(459) ##STR00374##
(1) tert-Butyl N-{1-[3-bromo-4-iodo-1-(3-methoxypropyl)-1H-indazol-6-yl]ethyl}-cyclopropylcarbamate [REx(29-1)]:

(460) To a solution of N-{1-[3-bromo-4-iodo-1-(3-methoxypropyl)-1H-indazol-6-yl]ethyl}cyclopropanamine (10.2 g) in dichloromethane (200 mL) was added di-t-butyl dicarbonate (5.12 g) under ice-cooling, and the mixture was stirred at room temperature for 21 hours. Then, thereto was added dimethylaminopyridine (261 mg), and the mixture was stirred for additional 6 hours at room temperature. To the reaction solution was added water under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1.fwdarw.4/1) to give tert-butyl N-{1-[3-bromo-4-iodo-1-(3-methoxypropyl)-1H-indazol-6-yl]ethyl}cyclopropylcarbamate [REx(29-1)] (7.62 g) as a yellow oil.

(461) (2) tert-Butyl {1-[3-bromo-4-(3,5-dimethylisoxazol-4-yl)-1-(3-methoxypropyl)-1H-indazol-6-yl]ethyl}-cyclopropylcarbamate [REx(29-2)]:

(462) To a solution of the compound obtained in the above (1) (300 mg) and 3,5-dimethylisoxazol-4-boronic acid (146 mg) in dimethoxyethane (5.0 mL) was added 2M aqueous sodium carbonate solution (2.6 mL) under argon, and then thereto was added tetrakis(triphenylphosphine)palladium (0) (30 mg), and the mixture was stirred at 105 C. for 22 hours. Then, thereto was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane.fwdarw.n-hexane/ethyl acetate=3/2) to give tert-butyl {1-[3-bromo-4-(3,5-dimethylisoxazol-4-yl)-1-(3-methoxypropyl)-1H-indazol-6-yl]ethyl}-cyclopropylcarbamate [REx(29-2)] (154 mg) as a colorless oil.

(463) APCI-MS m/z: 547/549 [M+H].sup.+.

(464) Deprotection of Boc group is done according to the above method.

Reference Example 30

tert-Butyl cyclopropyl {1-[1-(3-methoxypropyl)-1H-indazol-6-yl]ethyl}carbamate [REx(30-1)]

(465) ##STR00375##

(466) To a solution of tert-butyl N-{1-[3-bromo-4-iodo-1-(3-methoxypropyl)-1H-indazol-6-yl]ethyl}cyclopropylcarbamate (1.0 g) in 1,4-dioxane (20 mL) were added diisopropylethylamine (0.90 mL) and 10% palladium on carbon catalyst (200 mg), and the mixture was stirred under hydrogen for 42 hours. An insoluble was filtered, and then the filtrate was sequentially washed with aqueous saturated sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=911-411) to give tert-butyl cyclopropyl {1-[1-(3-methoxypropyl)-1H-indazol-6-yl]ethyl}carbamate [REx(30-1)] (167 mg) as a colorless oil.

(467) APCI-MS m/z: 374 [M+H].sup.+.

Reference Example 31

N-{1-[3-(3-Methoxypropyl)-5-(trifluoromethyl)phenyl]ethyl}cyclopropanamine [REx(31-1)]

(468) ##STR00376##

(469) To a solution of 3-methoxy-1-propanol (0.14 mL) in N,N-dimethylformamide (3.0 mL) was added 60% oil-based sodium hydride (97 mg), and the mixture was stirred at room temperature for 10 minutes. Then, thereto was added dropwise a solution of N-{1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}cyclopropylamine (300 mg) in N,N-dimethylformamide (1.0 mL), and the mixture was heated to stir at 40 C. for 4 hours. After cooling to room temperature, thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1.fwdarw.2/3) to give N-{1-[3-(3-methoxypropyl)-5-(trifluoromethyl)phenyl]ethyl}cyclopropanamine [REx(31-1)] (227 mg) as a colorless oil.

(470) APCI-MS m/z: 318 [M+H].sup.+.

Reference Example 32

(471) ##STR00377##
(1) Methyl 4-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-(3-methoxypropoxy)benzoate [REx(32-1)]:

(472) To a solution of methyl 4-[1-(cyclopropylamino)ethyl]-2-(3-methoxypropoxy)benzoate (1.20 g) in chloroform (9.6 mL) were added di-t-butyl dicarbonate (2.00 g) and triethylamine (2.34 mL) under ice-cooling, and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added water under ice-cooling, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1.fwdarw.2/1) to give methyl 4-{1-[(tert-butoxycarbonyl)-(cyclopropyl)amino]ethyl}-2-(3-methoxypropoxy)benzoate (7.62 g) as a colorless oil.

(473) APCI-MS m/z: 408 [M+H].sup.+.

(474) (2) 4-{1-[(tert-Butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-(3-methoxypropoxy)benzoic acid [REx(32-2)]:

(475) To a solution of the compound obtained in the above (1) (1.10 g) in methanol (13.5 mL) was added 2-normal aqueous sodium hydroxide solution (13.5 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added chloroform, and then thereto was added 2-normal hydrochloric acid (13.5 mL) under ice-cooling. The organic layer was separated, and then washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform.fwdarw.chloroform/methanol=20/1) to give 4-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-(3-methoxypropoxy)benzoic acid (1.14 g) as a colorless oil.

(476) ESI-MS m/z: 392[MH].sup.

(477) (3) tert-butyl 1-[4-(aminocarbonyl)-3-(3-methoxypropoxy)phenyl]ethyl-cyclopropylcarbamate [REx(32-3)]:

(478) To a solution of the compound obtained in the above (2) (250 mg) in N,N-dimethylformamide (3.2 mL) were added ammonium chloride (40.8 mg), diisopropylethylamine (0.133 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (146 mg) and 1-hydroxybenzotriazole (103 mg), and then the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/2.fwdarw.1/6) to give tert-butyl {1-[4-(aminocarbonyl)-3-(3-methoxypropoxy)phenyl]ethyl}cyclopropylcarbamate (164 mg) as a colorless oil.

(479) APCI-MS m/z: 393 [M+H].sup.+.

(480) Similarly, deprotection of Boc group is done according to the above method.

Reference Example 33

2-[1-(Cyclopropylamino)ethyl]quinazolin-4(3H)-one [REx(33-1)]

(481) ##STR00378##

(482) To a suspension of 2-(1-bromoethyl)quinazolin-4(3H)-one (2.53 g) in N,N-dimethylformamide (30 mL) was added cyclopropylamine (3.46 mL), and the mixture was diluted with N,N-dimethylformamide (20 mL) and water (1 mL), and then stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added aqueous sodium hydrogen carbonate solution, and then the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with diisopropyl ether/ethyl acetate (20:1) to give 2-[1-(cyclopropylamino)ethyl]quinazolin-4(3H)-one [REx(33-1)] (1.71 g) as a colorless powder.

(483) APCI-MS m/z: 230 [M+H].sup.+.

Reference Examples 34 to 100

(484) The following compounds of Reference Examples 34 to 100 were prepared according to the methods of the above Reference Examples. Each symbol of Methods A-1 to F refers to each method according to the following methods of Reference Examples.

(485) Method A-1 Reference Example 1

(486) Method A-2 Reference Example 2

(487) Method B Reference Example 3

(488) Method C-1 Reference Example 6

(489) Method C-2 Reference Example 7

(490) Method C-3 Reference Example 8

(491) Method D Reference Example 28

(492) Method E-1 Reference Example 29

(493) Method E-2 Reference Example 30

(494) Method E-3 Reference Example 31

(495) Method E-4 Reference Example 32

(496) Method F Reference Example 33

(497) TABLE-US-00073 TABLE 73 Ref. EX. No. Structural formula a b c d e f 34 HCl 279.3746 P 280 [M + H]+ B 35 0 HCl 221.2955 P 222 [M + H]+ C-2 36 287.3999 O 288 [M + H]+ C-3 37 221.29551 O 222 [M + H]+ C-2

(498) TABLE-US-00074 TABLE 74 38 235.322 O 236 [M + H]+ C-2 39 HCl 211.3022 P 212 [M + H]+ A 40 HCl 261.3593 P 262 [M + H]+ C-2 41 267.3391 O 268 [M + H]+ C-2

(499) TABLE-US-00075 TABLE 75 42 263.3752 O 264 [M + H]+ A-2 43 267.3391 O 268 [M + H]+ A-2 44 263.3752 O 264 [M + H]+ C-2 45 0 279.3746 O 280 [M + H]+ C-2

(500) TABLE-US-00076 TABLE 76 46 301.4265 O 302 [M + H]+ C-3 47 305.3904 O 306 [M + H]+ C-3 48 321.845 O 322/324 [M + H]+ C-1 49 301.4265 O 302 [M + H]+ C-1

(501) TABLE-US-00077 TABLE 77 50 242.3162 P 243 [M + H]+ C--2 51 274.3581 O 275 [M + H]+ C-2 52 HCl 297.2394 P 298 [M + H]+ C-2 53 316.3981 O 317 [M + H]+ D

(502) TABLE-US-00078 TABLE 78 54 241.3282 O 242 [M + H]+ B 55 00 328.4055 O 329 [M + H]+ B 56 01 317.3466 O 318 [M + H]+ E-3 57 02 255.7405 O 256/258 [M + H]+ C-2

(503) TABLE-US-00079 TABLE 79 58 03 255.7405 O 256/258 [M + H]+ C-2 59 04 337.4537 O 338 [M + H]+ C-2 60 05 274.3581 O 275 [M + H]+ C-2 61 06 274.4011 O 275 [M + H]+ C-1

(504) TABLE-US-00080 TABLE 80 62 07 275.3859 O 276 [M + H]+ C-2 63 08 289.3694 O 290 [M + H]+ C-2 64 09 306.8303 O 307/309 [M + H]+ C-1 65 0 249.3486 O 250 [M + H]+ C-2

(505) TABLE-US-00081 TABLE 81 66 297.3651 O 298 [M + H]+ B 67 355.3979 O 356 [M + H]+ C-1 68 321.845 O 322/ 324 [M + H]+ C-3 69 287.3999 O 288 [M + H]+ C-3

(506) TABLE-US-00082 TABLE 82 70 305.3904 O 306 [M + H]+ C-3 71 358.2707 O 358/360 [M + H]+ C-2 72 273.3733 O 274 [M + H]+ C-3 73 287.3999 O 288 [M + H]+ C-3

(507) TABLE-US-00083 TABLE 83 74 286.4118 O 287 [M + H]+ C-1 75 0 304.3841 O 305 [M + H]+ C-2 76 289.3694 O 290 [M + H]+ C-2 77 287.3999 O 288 [M + H]+ C-1

(508) TABLE-US-00084 TABLE 84 78 313.8197 O 314/316 [M + H]+ C-2 79 288.388 O 289 [M + H]+ C-3 80 301.4265 O 302 [M + H]+ C-3 81 217.3068 O 218 [M + H]+ C-2

(509) TABLE-US-00085 TABLE 85 82 355.4706 O 356 [M + H]+ C-2 83 320.4265 O 321 [M + H]+ E-4 84 306.3999 O 307 [M + H]+ E-4 85 0 292.3734 P 293 [M + H]+ E-4

(510) TABLE-US-00086 TABLE 86 86 229.2777 P 230 [M + H]+ F 87 246.7353 O 247/249 [M + H]+ C-2 88 277.4018 O 278 [M + H]+ C-2 89 273.3733 O 274 [M + H]+ C-1

(511) TABLE-US-00087 TABLE 87 90 303.3993 O 304 [M + H]+ C-2 91 303.3993 O 304 [M + H]+ C-2 92 382.4992 O 383 [M + H]+ E-1 93 291.3638 O 292 [M + H]+ C-1

(512) TABLE-US-00088 TABLE 88 94 315.3555 O 316 [M + H]+ C-2 95 0 287.3999 O 288 [M + H]+ C-1 96 307.8184 O 308/310 [M + H]+ C-1 97 273.3733 O 274 [M + H]+ E-2

(513) TABLE-US-00089 TABLE 89 98 305.3904 O 306 [M + H]+ C-1 99 259.3037 O 260 [M + H]+ C-1 100 334.3885 O 335 [M + H]+ C-1

(514) Ref Ex. No.: Reference Example Number

(515) a: Salt

(516) b: Molecular weight

(517) c: Properties

(518) d: MS Results APCI

(519) e: Ion species

(520) f: Method

(521) O: Oil

(522) P: Powder

Reference Example 101

Methyl 3-acetyl-1H-indazole-1-carboxylate

(523) ##STR00446##

(524) To a solution of 1-(1H-indazol-3-yl)ethanone (5.0 g) and triethylamine (6.53 mL) in chloroform (80 mL) was added dropwise a solution of methyl chlorocarbonate (3.24 g) in chloroform (20 mL) under ice-cooling over 1 hour, and the mixture was stirred at room temperature for 14 hours. The reaction solution was washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with n-hexane to give methyl 3-acetyl-1H-indazole-1-carboxylate) [REx(101-1)] (6.67 g) as a colorless powder.

(525) APCI-MS m/z: 219 [M+H].sup.+.

Reference Example 102

Methyl[3-(3-acetyl-6-fluoro-1H-indazol-1-yl)propyl]carbamate [REx(102-2)]

(526) ##STR00447##
(1) To a solution of 6-fluoro-3-iodo-1H-indazole (1.5 g) and methyl (3-bromopropyl)carbamate (1.68 g) in N,N-dimethylformamide (5 mL) was added potassium carbonate (1.58 g), and the mixture was stirred at room temperature for 3 days. To the reaction solution was added ethyl acetate, and the mixture was washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/20.fwdarw.3/2) to give methyl [3-(6-fluoro-3-iodo-1H-indazol-1-yl)propyl]carbamate [REx(102-1)] (836 mg) as a red oil.

(527) APCI-MS m/z: 378 [M+H].sup.+.

(528) (2) To a solution of the compound obtained in (1) (830 mg) in 1,4-dioxane (10 mL) were added tri-n-butyltin-1-ethoxyvinyl (1.03 and dichlorobis(triphenylphosphine)palladium (II) (155 mg), and the mixture was heated to reflux for 17 hours. The reaction solution was cooled to room temperature, and then thereto was added a solution of potassium fluoride (250 mg) in water (3 mL), and the mixture was stirred at room temperature for 15 minutes. Then, thereto was added 1-normal hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 1 hour, and then an insoluble was filtered. To the filtrate was added ethyl acetate, and the mixture was washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1.fwdarw.4/1) to give methyl [3-(3-acetyl-6-fluoro-1H-indazol-1-yl)propyl]carbamate [REx(102-2)] (437 mg) as a red oil.

(529) APCI-MS m/z: 294 [M+H].sup.+.

Reference Example 103

(530) ##STR00448##
1) To 1-[1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]ethanone (3.14 g) was added trifluoroacetic acid (20 mL), and the mixture was heated to reflux for 2 days. The reaction solution was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, and then sequentially washed with aqueous saturated sodium hydrogen carbonate solution and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5-7/3) to give 1-(1H-pyrazolo[3,4-b]pyridin-3-yl)ethanone) [REx(103-1)] (1.73 g) as a pale yellow powder.

(531) APCI-MS m/z: 162 [M+H].sup.+.

(532) 2) To a solution of 1-(1H-pyrazolo[3,4-b]pyridin-3-yl)ethanone (500 mg) and methyl (3-bromopropyl)carbamate (912 mg) in N,N-dimethylformamide (5 mL) was added potassium carbonate (864 mg), and the mixture was stirred at room temperature for 3 days. To the reaction solution was added ethyl acetate, and the mixture was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5.fwdarw.1/1) to give methyl [3-(3-acetyl-1H-pyrazolo[3,4-b]pyridin-1-yl)propyl]carbamate) [REx(103-2)] (308 mg) as a red oil.

(533) APCI-MS m/z: 277 [M+H].sup.+.

Reference Example 104

(534) ##STR00449##
1) To a mixture of 2-chloro-6-methylnicotinaldehyde (5.0 g) and hydrazine monohydrate (6.24 mL) was added para-toluenesulfonic acid monohydrate (3.67 g), and the mixture was stirred at 130 C. for 18 hours. The reaction solution was cooled, and then thereto was added 10% aqueous citric acid solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate, and washed with saturated saline. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure to give 6-methyl-1H-pyrazolo[3,4-b]pyridine [REx(104-1)] (3.61 g) as a brown powder.

(535) APCI-MS m/z: 134 [M+H].sup.+.

(536) 2) To a solution of 6-methyl-1H-pyrazolo[3,4-b]pyridine (4.44 g) and iodine (16.9 g) in N,N-dimethylformamide (100 mL) was added potassium hydroxide (7.48 g) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into ice water, and the precipitate was filtered. The filtrate was extracted with ethyl acetate, washed with saturated saline, and then dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was combined with the above-mentioned precipitate and purified by silica gel column chromatography (eluent: chloroform.fwdarw.chloroform/methanol=19/1) to give 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine [REx(104-2)] (6.48 g) as a brown powder.

(537) APCI-MS m/z: 260 [M+H].sup.+.

(538) 3) 3-Iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine and methyl (3-bromopropyl)carbamate were treated in the similar manner to Reference Example 102(1) to give methyl[3-(3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)propyl]carbamate [REx(104-3)] as a colorless powder.

(539) APCI-MS m/z: 375 [M+H].sup.+.

(540) 4) Methyl[3-(3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)propyl]carbamate and tri-n-butyltin-ethoxyvinyl were treated in the similar manner to Reference Example 102(2) to give methyl [3-(3-acetyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)propyl]carbamate [REx(104-4)] as a colorless powder.

(541) APCI-MS m/z: 291 [M+H].sup.+.

Reference Example 105

(542) ##STR00450## ##STR00451##
1) To a solution of 1H-pyrrole (5.0 g) in N,N-dimethylformamide (40 mL) was added drop by drop sodium hydride (3.58 g) under ice-cooling, and then the mixture was stirred at room temperature for 20 minutes. Then, thereto was added dropwise a solution of 1-bromo-3-methoxypropane (2.74 g) in N,N-dimethylformamide (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water under ice-cooling, and then the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=100/1.fwdarw.20/1) to give 1-(3-methoxypropyl)-1H-pyrrole [REx(105-1)] (9.07 g) as a colorless oil. 2) A solution of 1-(3-methoxypropyl)-1H-pyrrole (3.92 g), ethyl 3-dimethylamino-2-(dimethylaminomethyleneamino)acrylate (7.20 g) (ref. Liebigs Ann. Chem. 1980, 344-357) and trifluoroacetic acid (8.33 mL) in acetic acid (32 mL) was stirred at room temperature for 18 hours, and then heated to reflux for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure. To the resulting residue was added aqueous saturated sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1.fwdarw.AcOEt) to give ethyl 1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(105-2)] (4.79 g) as a brown oil.

(543) APCI-MS m/z: 263 [M+H].sup.+.

(544) 3) To a solution of ethyl 1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (2.00 g) in dichloromethane (40 mL) was added N-bromosuccinimide (1.49 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1.fwdarw.4/1) to give ethyl 3-bromo-1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(105-3)] (2.12 g) as a yellow oil.

(545) APCI-MS m/z: 341/343 [M+H].sup.+.

(546) 4) To a solution of ethyl 3-bromo-1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1.70 g) in 1,4-dioxane (25 mL) were added trimethylboroxine (2.09 mL), cesium carbonate (4.87 g), 2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl (X-Phos) (297 mg) and tris(dibenzylideneacetone)dipalladium (228 mg) under argon, and the mixture was stirred at 110 C. for 15 hours. The reaction solution was cooled, and then thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane.fwdarw.ethyl acetate) to give ethyl 1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(105-4)] (831 mg) as a yellow oil.

(547) APCI-MS m/z: 277 [M+H].sup.+.

(548) 5) To a solution of ethyl 1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (100 mg) in chloroform (2 mL) was added meta-chloroperoxybenzoic acid (250 mg) under ice-cooling, and then the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and then the resulting residue was purified by NH-silica gel column chromatography (eluent: ethyl acetate.fwdarw.ethyl acetate/methanol=10/1) to give ethyl 1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate 5-oxide [REx(105-5)] (41 mg) as a pale yellow oil.

(549) APCI-MS m/z: 293 [M+H].sup.+.

(550) 6) A solution of ethyl 1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate 5-oxide (40 mg) in phosphorus oxychloride (2 mL) was stirred at 100 C. for 1 hour. The reaction solution was concentrated, and the resulting residue was dissolved in ethyl acetate. It was sequentially washed with aqueous saturated sodium hydrogen carbonate solution and saturated saline, and dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: 4-chloro-1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(105-6)] (23 mg) as a colorless powder.

(551) APCI-MS m/z: 311/313[M+H].sup.+.

(552) 7) To a solution of ethyl 4-chloro-1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (290 mg) in ethanol (6 mL) was added 2-normal aqueous sodium hydroxide solution (0.95 mL) under ice-cooling, and the mixture was stirred at room temperature for 90 minutes. Then, thereto was added 2-normal hydrochloric acid (0.95 mL) under ice-cooling, and then the reaction solution was concentrated. To a solution of the residue in chloroform (6 mL) were added N,O-dimethylhydroxyamine hydrochloride (137 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (268 mg), 1-hydroxybenzotriazole (189 mg) and diisopropylethylamine (325 L) under ice-cooling, and then the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added aqueous saturated sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with chloroform. The organic layer was sequentially washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane.fwdarw.ethyl acetate) to give 4-chloro-N-methoxy-1-(3-methoxypropyl)-N,3-dimethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxamide [REx(105-7)] (277 mg) as a colorless oil.

(553) APCI-MS m/z: 326/328 [M+H].sup.+.

(554) 8) 4-Chloro-N-methoxy-1-(3-methoxypropyl)-N,3-dimethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxamide and methylmagnesium bromide were treated in the similar manner to Reference Example 6(5) to give 1-[4-chloro-1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl]ethanone [REx(105-8)] as a colorless powder.

(555) APCI-MS m/z: 281/283 [M+H].sup.+.

(556) 9) To a solution of 1-[4-chloro-1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl]ethanone (50 mg) in 1,4-dioxane (2 mL) were added trimethylboroxine (50 L), cesium carbonate (174 mg), 2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl (X-Phos) (17 mg) and tris(dibenzylideneacetone)dipalladium (8 mg) under argon, and the mixture was stirred at 80 C. for 2 hours. The reaction solution was cooled, and then thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane.fwdarw.n-hexane/ethyl acetate=1/1) to give 1-[1-(3-methoxypropyl)-3,4-dimethyl-1H-pyrrolo[3,2-c]pyridin-6-yl]ethanone [REx(105-9)] (105 mg) as a colorless oil.

(557) APCI-MS m/z: 261 [M+H].sup.+.

Reference Example 106

(558) ##STR00452##
1) To a solution of ethyl 3-bromo-1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (200 mg) in 1,4-dioxane (2 mL) were added trivinylboroxine pyridine complex (141 mg), cesium 3-Ethyl-N-methoxy-1-(3-methoxypropyl)-N-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxamide and methylmagnesium bromide were treated in the similar manner to Reference Example 6(5) to give 1-[3-ethyl-1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]ethanone [REx(106-4)] as a pale yellow oil.

(559) APCI-MS m/z: 261 [M+H].sup.+.

Reference Example 107

(560) ##STR00453##

(561) 4-Bromo-1-methoxy-2-(4-methoxybutyl)benzene and tri-n-butyltin-1-ethoxyvinyl were treated in the similar manner to Reference Example 27(3) to give 1-[4-methoxy-3-(4-methoxybutyl)phenyl]ethanone as a yellow oil.

(562) APCI-MS m/z: 237 [M+H].sup.+.

Reference Examples 108 to 112

(563) Compounds of Reference Examples 103 to 107 were treated in the similar manner to Reference Example 6-(6) to give the following compounds.

(564) TABLE-US-00090 TABLE 90 Ref. EX. No. Structural formula a b c d e 108 317.3861 O 318 [M + H].sup.+ 109 331.4127 O 332 [M + H].sup.+ 110 301.4265 O 302 [M + H].sup.+ 111 301.4265 O 302 [M + H].sup.+ 112 277.4018 O 278 [M + H].sup.+

Ref Ex. No.: Reference Example Number

(565) a: Salt

(566) b: Molecular weight

(567) d: MS Results APCI

(568) e: Ion species

(569) O: Oil

(570) c: Properties

Reference Example 113

(571) ##STR00459## ##STR00460##
1) 5-Bromo-6-chloronicotinic acid and N,O-dimethylhydroxyamine hydrochloride were treated in the similar manner to Reference Example 7(5), and then the resulting compound and methylmagnesium bromide were treated in the similar manner to Reference Example 7(6) to give 1-(5-bromo-6-chloropyridin-3-yl)ethanone [REx(113-1)] as a colorless powder.

(572) APCI-MS m/z: 234/236 [M+H].sup.+.

(573) 2) 1-(5-Bromo-6-chloropyridin-3-yl)ethanone and cyclopropylamine were treated in the similar manner to Reference Example 6(6) to give N-[1-(5-bromo-6-chloropyridin-3-yl)ethyl]cyclopropylamine [REx(113-2)] as a pale yellow oil.

(574) APCI-MS m/z: 275/277 [M+H].sup.+.

(575) 3) To a solution of N-[1-(5-bromo-6-chloropyridin-3-yl)ethyl]cyclopropylamine (2.47 g) in ethyl acetate (15 mL)-tetrahydrofuran (15 mL)-water (15 mL) were added sodium hydrogen carbonate (3.78 g) and di-tert-butyl dicarbonate (3.94 g), and the mixture was stirred at room temperature for 41 hours. To the reaction solution was added water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1.fwdarw.4/1) to give tert-butyl [1-(5-bromo-6-chloropyridin-3-yl)ethyl]cyclopropylcarbamate [REx(113-3)] (2.6 g) as a pale yellow oil.
4) To a solution of t-butyl [1-(5-bromo-6-chloropyridin-3-yl)ethyl]cyclopropylcarbamate (530 mg) in N,N-dimethylformamide (8 mL) were added methyl prop-2-yn-1-ylcarbamate (384 mg), triethylamine (1.96 mL), dichlorobis(triphenylphosphine)palladium (II) (69 mg) and copper (I) iodide (40 mg), and the mixture was stirred at 60 C. for 2 hours. The reaction solution was cooled, and then diluted with ethyl acetate, and an insoluble was filtered off. The filtrate was sequentially washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1.fwdarw.1/1) to give methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-chloropyridin-3-yl)prop-2-yn-1-yl]carbamate [REx(113-4)] (362 mg) as a pale yellow oil.

(576) APCI-MS m/z: 408/410 [M+H].sup.+.

(577) 5) Methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-chloropyridin-3-yl)prop-2-yn-1-yl]carbamate was reduced in the similar manner to Example 296(5) to give methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-chloropyridin-3-yl)propyl]carba mate [REx(113-5)] as a pale yellow oil.

(578) APCI-MS m/z: 412/414 [M+H].sup.+.

(579) 6) To a solution of methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-chloropyridin-3-yl)propyl]carbamate (380 mg) in dimethoxyethane (8 mL) were added vinyl boronic acid pinacol ester (235 L), 2M sodium carbonate (1.38 mL) and dichlorobis(triphenylphosphine)palladium (II) (65 mg), and the mixture was stirred at 85 C. for 17 hours. The reaction solution was cooled, and then an insoluble was filtered off through Celite, and to the filtrate was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1.fwdarw.4/4) to give methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-vinylpyridin-3-yl)propyl]carba mate [REx(113-6)] (282 mg) as a pale yellow oil.

(580) APCI-MS m/z: 404[M+H].sup.+.

(581) 7) To a solution of methyl [3(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-vinylpyridin-3-yl)propyl]carbamate (280 mg) in methanol (10 mL) was added 10% palladium on carbon (140 mg), and the mixture was stirred under hydrogen for 2 hours. An insoluble was filtered off, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform.fwdarw.chloroform/methanol=4/1) to give methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]-ethyl}-2-ethylpyridin-3-yl)propyl]carbamate [REx(113-7)] (210 mg) as a pale yellow oil.

(582) APCI-MS m/z: 406 [M+H].sup.+.

(583) 8) To a solution of methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-ethylpyridin-3-yl)propyl]carbamate (204 mg) in dichloromethane (1.5 mL) was added trifluoroacetic acid (1.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice-cooled aqueous saturated sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: chloroform.fwdarw.chloroform/methanol=20/1) to give methyl (3-{5-[1-(cyclopropylamino)ethyl]-2-ethylpyridin-3-yl}propyl)carbamate [REx(113-8)] (142 mg) as a pale yellow oil.

(584) APCI-MS m/z: 306 [M+H].sup.+.

Reference Example 114

(585) ##STR00461##

(586) To a solution of ()--pinene (3.64 mL) in tetrahydrofuran (5 mL) was added dropwise borane-dimethyl sulfide complex (1.09 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 hours. To the reaction solution was added dropwise a solution of methyl prop-2-yn-1-ylcarbamate (1.0 g) in tetrahydrofuran (3 mL) under ice-cooling, and then the mixture was stirred at room temperature for 17 hours. To the reaction solution was added dropwise acetaldehyde (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in diethyl ether (15 mL). To the solution was added pinacol (1.56 g), and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with water, and then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1.fwdarw.3/2) to give methyl [(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)prop-2-en-1-yl]carbamate (1.18 g) as a pale yellow oil.

(587) APCI-MS m/z: 242 [M+H].sup.+.

Test Example

Inhibitory Activity Against Human Renin

(588) A substrate of synthetic peptide (Nma-KHPFH LVIHK(Dnp)-NH.sub.2) and test compound were mixed, and fluorescence intensity was assayed using a fluorophotometer before starting an enzymatic reaction (exciting wavelength: 340 nm, measuring wavelength: 460 nm). Recombinant human renin was added and the mixture was incubated at 37 C. for 1 hour, and the fluorescence intensity was measured after the reaction using a fluorophotometer (exciting wavelength: 340 nm, measuring wavelength: 460 nm). Renin activity was evaluated on the ground of fluorescence intensity which was obtained by deduction of the intensity before the reaction from the intensity after the reaction, and 50% inhibitory concentration (IC50) was calculated from renin activities under the existence of various concentration of the test compound. Example compounds herein showed the following values.

(589) Test Result 1

(590) TABLE-US-00091 TABLE 91 Example IC50 (nM) 6 13 7 13 8 490 9 7.3 10 1.2 12 73 17 210 18 44 19 10 21 8.4 22 270 24 240 25 19 26 320 27 300 28 1.4 29 5.9 30 30 31 580 35 6.8 36 0.5 37 6.6 38 3.7 39 1.4 40 14 41 2.3 42 1.5 43 1.6 44 30 45 8.5 46 17 49 89 52 4.2 53 72 54 31 55 1.9 56 35 57 0.4 58 16 59 2.1 60 7 61 14 62 12 63 800 64 0.9 65 6.4 66 2.4 67 1.5 68 140 69 21 70 0.6 71 21 75 78 76 37 78 1 79 1.1 80 8.4 81 25 82 16 83 330 85 11 86 16 87 7 88 52 89 3.9 90 71 91 15 92 62 93 41 94 120 97 0.7 98 4.4 99 7.3 100 41 101 29 102 290 103 2.4 104 89
Test Result 2

(591) TABLE-US-00092 TABLE 92 Example IC50 (nM) 105 8.1 106 530 109 500 110 67 113 540 114 4.1 115 87 116 16 122 19 123 42 124 3.2 125 12 126 6.6 127 15 128 3.3 129 42 132 16 133 20 134 250 135 11 136 33 137 6.3 138 12 139 2.5 140 10 141 4 142 17 143 58 144 4.8 145 63 146 28 147 16 149 13 150 8.7 151 34 152 1.2 153 46 268 3.6 269 6.6 270 0.4 271 3.7 276 2.5 280 0.9 281 6.7 284 0.5 285 6.1 286 3 287 35
Test Result 3

(592) TABLE-US-00093 TABLE 93 Example IC50 (nM) 299 1.6 301 3.3 304 1.3 305 12 306 230

INDUSTRIAL APPLICABILITY

(593) The compound [I] of the present invention or a pharmaceutically acceptable salt thereof has renin inhibitory activity and may be useful for treatment and/or prophylaxis of hypertension, cardiac failure, diabetic nephropathy and the like. Furthermore, the compound [II] is useful as a synthetic intermediate for preparing the compound [I].